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This is to certify that the
dissertation entitled

DEVELOPMENT OF TITANIUM PYRROLYL
HYDROAMINATION CATALYSTS
AND
URANIUM PYRROLYL COMPLEXES

presented by

Douglas L. Swartz II

has been accepted towards fulfillment
of the requirements for the

 

 

 

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DEVELOPMENT OF TITANIUM PYRROLYL HYDROAMINATION CATALYSTS
AND
URANIUM PYRROLYL COMPLEXES
By

Douglas L. Swartz II

A DISSERTATION
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree
DOCTOR OF PHILOSOPHY
Chemistry

2009

ABSTRACT
DEVELOPMENT OF TITANIUM PYRROLYL HYDROAMINATION CATALYSTS
URANIUM PYRfiOqfYL COMPLEXES
By
Douglas L. Swartz II

The primary focus of this thesis is the design and development of pyrrolyl based
titanium hydroamination catalysts with applications towards multi-component coupling
reactions involving a primary amine, alkyne, and isonitrile. Hydroamination is an atom
efficient process for the production amines and imines from the formal addition of an N-
H bond across a C—C unsaturated bond. Titanium-catalyzed hydroamination has seen an
explosion of activity and has led to new methodologies in a variety of C—N containing
molecules. The first chapter briefly discusses the types of ancillary ligands employed for
titanium hydroarnination catalysts with the main focus being on the development of
titanium pyrrolyl complexes for the development of C—N bond forming reactions.

Since the first successful hydroamination of a primary amine and alkyne by a
titanimn pyrrolyl complex our goal has been to optimize the most promising catalysts that
carry out these reactions to expand the scope of this methodology. Chapters 2 — 4 discuss
the types of electronic features and steric profiles in catalyst design that encourage these
useful C-N bond forming reactions.

Ligand isomerization in titanium dipyrrolylmethane complexes is common due to
the different bonding hapticities the ligand can adopt. Methods for altering this barrier
may provide clues to the active species in catalysis and allow control of complex

structures. Chapter 5 discusses the effects 5,5-substitution has on dipyrrolylmethane

ligand isomerization and the parameters for pyrrolyl exchange.

Since the discovery of uranium bis(imido) analogues of the uranyl ion, U022”:
actinide chemists have been intrigued with the bonding and reactivity of this functional
group. Pyrrolyl ligands have proven to be a useful class of ancillary ligands for transition
metals, however their employment in actinide chemistry is relatively scarce. The
synthesis, structure, and reactivity of uranium bis(imido) dipyrrolylmethane complexes

are discussed in Chapter 6.

To my wife, I hope it was all worth it

ACKNOWLEDGEMENTS

First and foremost I have to thank wife, Melesa, for all the love and support she
has given to me over the past 11 years we have been together, especially the past 5 years
during my time as a graduate student at Michigan State. I also want to thank my son,
Lucelus, for being the best part of my day everyday when I get home, greeting me with
the best hug and smile a dad can ever get.

I would like to thank my advisor, Aaron Odom, for all his patience, guidance and
support during my time at Michigan State. Working under his direction provided me with
wonderful opportunities that have lead to a satisfying graduate career. Among the many
opportunities I was able to take part in, working with Dr. Jim Boncella at Los Alamos
National Lab was an absolute pleasure and privilege. I would like to thank Jim for all his
advice, patience, support he gave to my family and I while we were in Los Alamos.

I would also like to acknowledge all my past and present group members: Jim,
Bala, Kapil, Sanjukta, Sam, Supriyo, Steve, and Eyal. I would like to give Supriyo a
special “thank you” for being such a wonderful friend and colleague. I will miss working
alongside him, “Absolutely.”

I would like to acknowledge Professor Mitch Smith, Professor Jim McCusker,
and Professor Bill Wulff for serving on my committee, for their guidance, and teaching
me a degree of professionalism in presenting my research.

A special thanks goes to Dan Holmes for assisting me with all the NMR

experiments I had to conduct throughout my graduate career.

Lastly, I would like to thank my parents for all the love, support and faith they put

in me that helped me succeed in so aspects of life. I hope that I have made them proud.

Douglas L. Swartz II

vi

TABLE OF CONTENTS

List of Tables .................................................................................................................... ix
List of Figures ..................................................................................................................... x
List of Abbreviations ....................................................................................................... xiii
List of Schemes ................................................................................................................. xv
1. Titanium pyrrolyl catalysts in C—N bond formation ................................................. l
1.1 Introduction .............................................................................................................. 1
1.2 Hydroamination with titanium Cp complexes .......................................................... 3
1.3 Hydroamination with titanium amido complexes .................................................... 5
1.4 Hydroamination with titanium amidate complexes .................................................. 7
1.5 Hydroamination with titanium pyrrolyl complexes ................................................. 8
1.6 Iminoamination ...................................................................................................... 16
1.7 Conclusions ............................................................................................................ 18
1.8 References .............................................................................................................. 19
2. Synthesis, structure, and hydroamination kinetics of 2,2’-
diaryldipyrrolylmethane and bis(2-arylpyrrolyl)titanium complexes .................. 21
2.1 Introduction ............................................................................................................ 21
2.2 Titanium pyrrolyl hydroamination ......................................................................... 22
2.3 Hyrdoamination kinetics with titanium dipyrrolylmethane derivatives ................. 26
2.4 Conclusion .............................................................................................................. 41
2.5 Experimental .......................................................................................................... 43
2.6 References .............................................................................................................. 57
3. Synthesis, structure, and hydroamination reactivity of electron deficient titanium
complexes hearing bis- and mono(pyrrolyl) ligands ............................................... 59
3.1 Introduction ............................................................................................................ 59
3.2 Results and discussions .......................................................................................... 60
3.3 Conclusion .............................................................................................................. 70
3.4 Experimental .......................................................................................................... 71
3.5 References .............................................................................................................. 81
4. Synthesis, structure, and hydroamination kinetics of 3,3’-
diaryldipyrrolylmethane titanium complexes .......................................................... 82
4.1 Introduction ............................................................................................................ 82
4.2 Results and discussions .......................................................................................... 83
4.3 Conclusion .............................................................................................................. 90
4.4 Experimental .......................................................................................................... 91

vii

4.4 Experimental .......................................................................................................... 91

4.5 References ............................................................................................................. 104
5. Effects of 5,5-substitution on dipyrrolylmethane ligand isomerization ................ 105
5.1 . Introduction .......................................................................................................... 105
5.2 Ligand isomerization study ................................................................................... 109
5.3 Conclusion ............................................................................................................. 115
5.4 Experimental ......................................................................................................... 116
5.5 References ............................................................................................................. 122
6. Uranium (VI) bis(imido) pyrrolyl complexes: synthesis, structure,
and reactivity ............................................................................................................. 123
6.1 Introduction ........................................................................................................... 123
6.2 Uranium bis(imido) dipyrrolylmethane complexes .............................................. 126
6.3 Conclusion ............................................................................................................. 135
6.4 Experimental ......................................................................................................... 136
6.5 References ............................................................................................................. 141
7. Appendix
A Kinetic plots for selected catalysts from Chapter 2 ............................................... 143
B Kinetic plots for selected catalysts from Chapter 3 ............................................... 149
C Kinetics plots for selected catalysts from Chapter 4 ............................................. 152
D NMR spectra for selected compounds ................................................................... 155

viii

Table 1.1

Table 1.2

Table 1.3

Table 1.4

Table 1.5

Table 2.1

Table 2.2

Table 3.1

Table 4.1

Table 4.2

Table 5.1

LIST OF TABLES

Representative hydroamination results with 10 mol%
Ti(NMe2)2(dpma) (8) ............................................................................... 10

Representative hydroamination results with Ti(NMe2)2(dpm) (9) as
the catalyst ................................................................................................ 12

Rate constants for Ti(NMe2)2(dpma) (8), Ti(NMe2)2(dpm) (9),

TiCNMe2)2(pyrr-Cp) (10) for the hydroamination of aniline and 1-
phenylpropyne ........................................................................................... 1 3

Respresentative hydroamination results with Ti(NMe2)2(dap)2 (11) at
10 mol% catalyst loading .......................................................................... 15

Results of 3-component coupling with Ti(NMe2)2(dpma) (8) at 10
mol% catalyst loading at 100 °C in toluene .............................................. 17

Observed rate constants for catalysts TiCNMe2)2(dpm) (9),

Ti(NM62)2(dpm;n:l%2). Ti<NMez>2<dpm3’5'CF3) (13>.

. , . mes

T1(NMe2)2(pyrr )2 (14), T1(NMe2)2(pyrr )2 (15) ...................... 35
Comparison of rate constants for hydroamination of the bis(pyrroly1)
catalysts ..................................................................................................... 37
Comparison of Ti(NMe2)2(pyr2_CF3—4C6F5) (20), Ti(NMe2)2(pyrrmes)2

(l3), and Ti(indenyl)2Me2 (21) ................................................................. 69

Comparison of hydroamination catalysis rate constants

. 3,5—CF3 . 4—CF3
T10‘1M62)2(Pyrr )2 (14) and T1(N1\/It‘=2)2(pyrr )2 (16) from
Chapter 2 ................................................................................................... 84

Representative catalysis rates for Ti(NMe2)2(dpm) (9),

Ti(NMe2)2(NHMe2)(3-dpm3’5—CF3) (22) and Ti(NMe2)2(NHMe2)(3-
dme6F3) (23) ........................................................................................... 89
Parameters for pyrrolyl exchange for 9, 24, and 25 at 25 °C .................. 113

ix

Figure 1.1

Figure 2.1

Figure 2.2

Figure 2.3

Figure 2.4

Figure 2.5

Figure 3.1

Figure 3.2

Figure 4.1

Figure 4.2

Figure 5.1

Figure 5.2

Figure 5.3

Figure 5.4

LIST OF FIGURES
Titanium amidate complex ......................................................................... 7

ORTEP structure from single-crystal X-ray diffraction of

Ti(NMe2)2(dpm3’5—CF3) (13) ................................................................... 29
ORTEP structure from single-crystal X-ray diffraction on
Ti(NMe2)2(pyrrmes)2(15) ......................................................................... 31
ORTEP structure from single-crystal X-ray diffraction on
Ti(NMe2)2(pyrr3’5‘CF3)2 (14) .................................................................. 32

Plot of catalyst concentration of 9 versus pseudo first-order rate
constant for kinetic reaction conditions .................................................... 33

Representative plot of ln[l-phenylpropyne] vs time with complex 9
as the hydroamination catalyst .................................................................. 34

ORTEP structure from singgle5 03;? X-ray diffraction on

Ti(NMe2)2(NHMe2)(3-pyr ’ )2 (19) with thermal ellipsoids at 50%
probability level ........................................................................................ 62

ORTEP structure from single crystal X-ray diffraction on

Ti(NMe2)2(NHMe2)(3-pyr3’S'CF3)2 (20) with thermal ellipsoids at 50%
probability level ........................................................................................ 65

Solid-state structure of Ti(NMe2)2(dpm) (9) ............................................ 82

Solid-state structure of Ti(NMe2)2(NHMe2)(3-dpm3’5'CF3) (22) from

single crystal X-ray diffraction ................................................................. 87

Use of 1,3-diaxial interactions to affect dipyrrolylmethane
isomerizations barriers ............................................................................. 106

ORTEP diagram of the X-ray diffraction model for Ti(NMe2)2(tmcpm)

(25) ........................................................................................................... 110
1H spectra of 24 at room temperature and —40 °C in CDC13 ................... 1 11
Eyring plot of pyrrolyl exchange in TiCNMe2)2(tmcpm) (25) ................. 112

Figure 6.1

Figure 6.2

Figure 6.3

Figure 6.4

Figure Al.l

Figure A1.2

Figure Al.3

Figure A1.4

Figure Al.5

Figure A1.6

CS)

ORTEP structure of U(NBut)2(dpmm (26) from single crystal X-ray
diffraction ................................................................................................. 127

ORTEP structure of UCNBut)2(dpmmcs)(dmpe) (27) from single crystal
X-ray diffraction ...................................................................................... 128

ORTEP structure of U(NBu‘)2(dpm)(THF)2 (28) from single crystal
X-ray diffraction ...................................................................................... 131

ORTEP structure of U(NBut)2(pyrrmes)(THF)2(I) (29) from single
crystal X-ray diffraction ........................................................................... 133

Representative plot of [l-phenylpropyne] versus time with 10 mol%
Ti(NMe2)2(dpmmeS) (12) at 75 °C .......................................................... 142

Representative plot of [l-phenylpropyne] versus time with 10 mol%
Ti(NMe2)2(dprn3’5‘CF3) (13) at 75 °c .................................................... 143

Representative plot of [l-phenylpropyne] versus time with 10 mol%
Ti(NMe2)2(pyrr3’5’CF3)2 (14) at 75 °c ................................................... 144

Representative plot of [l-phenylpropyne] versus time with 10 mol%
Ti(NMe2)2(pyrrmeS)2 (15) at 75 °c ......................................................... 145

Representative plot of [l-phenylpropyne] versus time with 10 mol%
Ti(NMe2)2(pyrr4’CF3)2 (16) at 75 °c ..................................................... 146

Representative plot of [1-phenylpropyne] versus time with 10 mol%
Ti(NMe2)2(pyrr‘°‘)2 (17) at 75 °c ........................................................... 147

Figure Bl.l Representative plot of [l-phenylpropyne] versus time with 10 mol%

Figure Bl.2

Figure Bl.3

Figure C1.l

Ti(NMe2)2(_pyrrmes)2 (15) at 100 °c ....................................................... 143

Representative plot of [l-phenylpropyne] versus time with 10 mol%
Ti(indenyl)2(Me)2 (21) at 100 °C ............................................................ 149

Representative plot of [1- henylpropyne] versus time with 10 mol%
I’

Ti(NMe)3(pyr2'CF3'4C6F ) (20) at 100 °C .............................................. 150

Representative plot of L1 -phenylpropyne] versus time with 10 mol%
Ti(NMe)2(3-dpm3’5_c 3) (22) at 75 °c .................................................. 151

xi

Figure Cl.2

Figure Cl.3

Figure D1.l

Figure Dl.2

Figure D1.3

Figure Dl.4

Figure Dl.5

Figure D1.6
Figure Dl.7

Figure Dl.8

Representative plot of [l-phenylpropyne] versus time with 10 mol%
Ti(NMe)2(3-dme6F3) (23) at 75 °c ....................................................... 152

Representative plot of % conversion versus time with 10 mol%

Ti(NMe)2(3-dpm3’5-CF3) (22) at 75 °C using reaction calorimetry ....... 153
1 . mes

H spectrum for T1(NMe2)2(dpm )(12) .............................................. 154
13C spectrum for Ti(NMe2)2(dpmmcs) (12) ............................................ 155
1H spectrum for U(NBu’)2(dpmmeS) (26) ................................................ 156
1 t mes

H spectrum for U(NBu )2(dpm )(dmpe) (27) .................................... 157
31 t mes

P spectrum for U(NBu )2(dpm )(dmpe) (27) ................................... 158
'H spectrum for U(NBu’)2(THF)2(dpm) (28) ......................................... 159
13c spectrum for Ti(NMe2)2(NHMe2)(pyrr3’5_CF3)2 (19) in CDC13 ....l60

5

'H spectrum for Ti(NMe2)2(NHMe2)pyrr3’ 4'33» (19) in CDC13 ....... 161

xii

Boc
Butbipy
Cod
dap
szpm
GC/F ID
THF
DME

dmpe

CS

prrrm

prn} ,S—C F 3

prrr4—CF3

prlTtol

szpmmes

szpm3,5—CF3

3-dpm3’5—CF3

3-dme6F3

3_prn_3,5—CF 3

LIST OF ABBREVIATIONS

tert-butyloxycarbonyl

4,4’-di-tert-butyl-2,2’-bipyridine

1,5- cyclooctadiene
2-((dimethyamino)methyl)pyrrolyl
5,S-dimethyldipyrrolylmethane

Gas Chromotography Flame Ionization Detector
tetrahydrofuran

1 ,2-dimethoxyethane

bis(dimethylphosphino)ethane
2-(mesityl)pyrrole
2-(3,5-bis(tn'fluoromethyl)phenyl)pyrrole
2-(4-(trifluoromethyl)phenyl)pyrrole
2-p-toly1-1H-pyrrole
5,5'-(propane-2,2-diyl)bis(2-mesityl-pyrrole)

5,5'-(propane-2,2-diyl)bis(2-(3,5-
bis(trifluoromethyl)phenyl)pyrrole)

5,5'-(propane-2,2-diyl)bis(3-(3,5-
bis(trifluoromethyl)phenyl)pyrrole)

5,5'-(propane-2,2-diy1)bis(3 -mesity1-pyrrole)

3-(3,5-bis(t1ifluoromethyl)phenyl)pyrrole

xiii

C6F5

3-prrr 3-(perfluorophenyl)pyrrole

prrr 2-023 -4-C6F5 2-(3 ,5-bis(trifluoromethyl)phenyl)-4-(perfluorophenyl)pyrrole
Hchm I ,1 -bis(a-pyrrolyl)cyclohexane

Hztmcpm 1 , 1 -bis(a-pyrrolyl)-3 ,3 ,5 ,5-tetramethylcyclohexane

TFA trifluoroacetic acid

RT room temperature

EtOAc ethyl acetate

xiv

Scheme 1.1

Scheme 1.2

Scheme 1.3

Scheme 1.4

Scheme 1.5

Scheme 1.6

Scheme 1.7

Scheme 2.1

Scheme 2.2

Scheme 2.3

Scheme 2.4

Scheme 2.5

Scheme 2.6

Scheme 2.7

Scheme 3.1

Scheme 3.2

LIST OF SCHEMES

Comparison between condensation and titanium-catalyzed

hydroamination methodologies ................................................................... 1
Bergman mechanism for hydroamination ................................................... 4
Hydroamination results with Ti(NMez)4 (3) as catalyst ............................. 5
Hydroamination/hydrosilylation by Ti(NMe2)2(Cp-SiMe2-NBut) (6) ...... 6
Synthesis of Hgdpma and Ti(NMe2)2(dpma) (8) ....................................... 9
Synthesis of szpm and Ti(NMe2)2(dpm) (9) ......................................... 11
Proposed 3-component coupling reaction mechanism involving a
primary amine, alkyne, and isonitrile ....................................................... 16
Synthesis of szpm and Ti(NMe2)2(dpm (9) .......................................... 22
Proposed mechanism for titanium-catalyzed alkyne hydroamination ...... 24
Chauvin mechanism for olefin metathesis ................................................ 24
Synthesis of szpmmes, szpm3’5_CF3, Ti(NMe2)2(dpmmes) (12), and
Ti(NMe2)2(dpm3’5'CF3) (13) .................................................................... 27
Synthesis of Ti(NMe2)2(pyrrm"s)2 (15) and

. 3,5-CF3
T1(NMe2)2(pyrr )2 (l4) .................................................................. 30
Reaction conditions for kinetic studies ..................................................... 33

Synthesis of Ti(NMe2)2(pyrr4'CF3)2 (l6) and

Ti(NMe2)2(pyrrt°l)2 (17) .......................................................................... 37
Smith borylation followed by Suzuki coupling to prepare 3-substituted

pyrroles ..................................................................................................... 60
Synthesis of 3-prrr3’5-CF3 and 3-prrrC6F5 ........................................ 61

Scheme 3.3

Scheme 3.4

Scheme 3.5

Scheme 4.1

Scheme 4.2

Scheme 4.3

Scheme 5.1

Scheme 5.2

Scheme 6.1

Scheme 6.2

C6F5

Possible pyrrolyl crossover in the reaction of prrr and
Ti(NMez)4 (3) ........................................................................................... 64
Synthesis of 2-(3,5-bis(trifluoromethyl)phenyl)-4-

. 2-CF3-4C6F5
(perfluorophenyl)pyrrole and T1(NMe2)3(pyr ) (20) ............. 66
Conditions for kinetic study ...................................................................... 67
Synthesis of 3-aryl pyrroles ...................................................................... 83
Synthesis of 3-H2dpm3’5_CF3, 3-H2dme6F3,
Ti(NMe2)2(NHMe2)(dpm3’5'CF3) (22) and
Ti(NMe2)2(NHMe2)(dme6F3) (23) ........................................................ 85
Reaction conditions for kinetic study ....................................................... 88
Synthesis of szpm and Ti(NMe2)2(dpm) (9) ........................................ 105

Synthesis of Hchm, Hztmcpm, Ti(NMez)2(cpm) (24) and
Ti(NMe2)2(tmcpm) (24) .......................................................................... 107

Exchange of imido ligand in U(NBut)2(THF)2I2 and
U(NBu’)2(0PPh3)212 123

uuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuu

Synthesis of U(NBu’)2(THF)2(I)(pyrrmes) (29) ...................................... 132

xvi

CHAPTER 1
Titanium pyrrolyl catalysts in C—N bond formation

1.1 Introduction

The synthesis of C—N bonds is a significant process in organic chemistry. While a
typical method for their preparation is the condensation of an amine or hydrazine with a
ketone or aldehyde, titanium-catalyzed hydroamination is an attractive alternative when
the desired product is not readily prepared using current carbonyl methodologies. While
both methods are effective in preparing Simple irnine products, titanium-catalyzed
hydroamination offers great synthetic utility in the selective generation of a variety of
nitrogen containing products.

For example, the selective syntheis of a,B-unsaturated imines from the reaction of
an (LB-unsaturated ketone with a primary amine can be problematic. Competing Michael
addition reactions can lead to a mixture of products which can make isolation difficult.
However, titanium-catalyzed hydroamination of a 1,3-enyne with a primary amine yields
the desired product selectively without unwanted by-products (Scheme 1.1).

0 NR RHN O RHN - NR
+ NH2R + +
R2 R2 R2 R2
R R

R1 1 1 ‘l

. NR
_ [TI]
__ R, + NHZR =
Hz

92

 

ll

 

Scheme 1.1 Comparison between condensation and titanium-catalyzed

hydroamination methodologies.

In addition to the synthesis of or,B-unsaturated imines, new methodologies in the
synthesis of pyrroles, hydrazones, pyrimidines, and a,B-unsaturated B-iminoamines have
been developed which use titanium-catalyzed hydroamination (vide infia). The
development of titanium catalysts to carry out these transformations often use the
hydroamination of alkynes with primary amines as a method for evaluating the efficacy
of catalyst design.

While there are a plethora of titanium catalysts known to hydroaminate alkynes
with primary amines, the development of catalysts through ancillary ligand studies to
improve the substrate scope and enhance catalyst activity is an area of intense research.
This chapter takes a cursory look at ancillary ligands for titanium catalysts with the main
focus being on the enhancement of titanium pyrrolyl complexes towards the development

of C—N bond forming reactions.

1.2 Hydroamination with titanium Cp complexes

Cyclopentadienyl (Cp) ligands are some of the most heavily studied ancilliaries
for transition metals. Fittingly, some of the first reported examples of hydroamination
with titanium catalysts were ligated with Cp-based ligands.l

Titanium-catalyzed hydroamination is believed to operate through a similar
mechanism as the zirconocene-based system elucidated by Bergman and co-workers
(Scheme 1.2).2 A primary amine is a restriction of the Bergman mechanism for
hydroamination and it is assumed that all the titanium catalysts in this chapter operate via
this mechanism.

The first step in the catalytic cycle is the generation of a reactive metal imido
species (A) which is formed from protonylsis of the precatalyst M—R bond. Introduction
of an alkyne coordinates to A to yield complex B which undergoes a [2 + 2]-
cylcoaddition to yield a azarnetallacyclobutene intermediate (C). Coordination of free
primary amine to C in solution gives complex D which undergoes prontonlysis of the M—
C bond to give bis(amido) metal complex E. Further protonation from the amide
regenerates the active catalyst A and yields the imine product.

Chart 1.1 Cp based titanium catalysts

Ti Me
,Tif—‘NAr ( )2
(1) Doye
(2)
Bergman3 Doye4

NAr

R L M n
R [1" ( )2 R=alkyl,amido

l l 122:;

 

Fl R Ar
R / N.Ar Ill
' H—>MIL1
ML n
ArHN’ H"
E R 3

,l. l

:81 13 ,Ar

I I N

MlLln | I

13 ==" Mil-In
NHZAI' NHzAl‘ R
D

C

Scheme 1.2 Bergman mechanism for hydroamination

The groups of Doye and Bergman have pioneered Cp-based titanium catalysts,
which have been shown to be fairly general catalysts for alkyne hydroamination (Chart
1.1).4 Bergman and co-workers revealed that TiszMez undergoes
cyclopentadienyl/amide ligand exchange, which enhances the reactivity towards alkyne

hydroamination.

1.3 Hydroamination with titanium amido complexes

Since the first reports of hydroamination with titanium Cp catalysts, many groups
have explored the use of amido ancillary ligands in hopes of generating more reactive
catalysts and expanding the substrate scope. Odom reported that commercially available
Ti(NMe2)4 (3) was a general hydroamination catalyst for aryl primary amines and alkynes
(Scheme 1.3).5

Scheme 1.3 Hydroamination results with Ti(NMe2)4 (3) as catalyst.

10% Ti(NMez)4 (3) _ NPh
75 °C, toluene R, “2

 

 

NH2Ph + R, : R,
R1, R2 = (Bun, H), (Et, El), 87 - 92 %
(Ph,H)

Shortly after that report, Bergman and co-workers reported the hydroamination of
amino allenes and amino alkynes with sulfonamido ancillary ligands on titanium (Chart
1.2).‘5 It is also worthy to note, that the ligation of these chelating sulfonamido ligands on
zirconium are relatively good asymmetric intramolecular alkene hydroamination catalysts
with good yields and moderate ee’s.7

Chart 1.2 Titanium sulfonamido complexes

9

so2 so2
N N
\
0’ \TI(NM92)2 0’ TI(NM92)2
.. / -., /
Iv bl!
so, 802
(4) (5)

Doye and co-workers reported a chelated Cp/amido titanium complex capable of

hydroaminating an alkyne, followed by direct reduction via hydrosilylation with the same

titanium precatalyst (Scheme 1.4).8 This synthetic procedure allows for the production of

secondary amines in a one-pot procedure, without having to use stoichmetric amounts of

conventional reducing agents like NaBHgCN or LiAlH4.

Scheme 1.4 Hydroamination/hydrosilylation by Ti(NMe2)2(Cp-SiMe2-NBut) (6).

\
\Si\ /TI(NM62)2

 

 

N
””2” /|\ (6) “I IT'l
N’ I
+ ; )l\/R
_ n2 3 PhSiHs

methanol
piperdine

 

1.4 Hydroamination with titanium amidate complexes

The Schafer group has prepared a class of amidate titanium complexes capable of
intermolecular hydroamination (Figure 1.1).9 The development of electron deficient
amidate ligands on titanium resulted in decreased catalytic performance and unexpected
ligand reactivity.lo There is supporting evidence that a more Lewis acidic metal center
may facility greater hydroamination reactivity (vide infia).

Figure 1.1 Titanium amidate complex
0 .
(Ph—<< #TKNEtzlz
N 2

(7)

The strategy of using fluorine groups on the phenyl group rendered the arene
susceptible to nucleophilic attack by primary amines at elevated temperatures. This
resulted in the formation of HF during catalysis, which decomposed the catalyst
(Equation 1.1). This observation shows there should be a judicious choice of electron-

vvithdrawing substituents when selecting an ancillary ligand for titanium-catalyzed

 

hydroamination.
i i
. “9:9 “1:9
F F
NHZR + fl Pri A > E, Pri + HF (1.1)
F F F F
F F

1.5 Hydroamination with titanium pyrrolyl complexes

Using deprotonated pyrroles as ancillary ligands is nothing new in transition
metal chemistry. However, pyrrolyl ligands have seen increased attention as ancillaries in
the field of catalysis. Among the many fields of catalysis, titanium catalyzed C—N and C—

C bond forming reactions have probably been the largest application of pyrrolyl

ligands. 12d

Unlike many alkoxide, amide, or Cp ligands, pyrrole is not a strongly n—donating
ligand. The nitrogen lone pair is delocalized around the ring to maintain aromaticity,
which directly competes with rt-donation to the metal center (The aromatic stabilization
energy for pyrrole is ~21 kcal/mmol).11 This decreased it-donation to the metal center
results in a more Lewis acidic metal center that has proven useful in a variety of catalytic
systems.12

One can easily draw analogies between the Bergman mechanism for
hydroamination and the Chauvin mechanism for olefin metathesis. Both mechanisms
include metal-ligand multiple bond intermediates and [2+2] cycloaddition processes with
unsaturated substrates. One of the results from Schrock’s olefin metathesis studies was
that the reactivity increased in his (I0 molybdenum catalysts as the metal center was made
more Lewis acidic.13 Applying the same principle towards titanium catalysts for
hydroamination using pyrrole-based ancillary ligands could be fruitful given the
similarities in mechanisms and that pyrroles are weak rc—donors. The increased Lewis
acidity of the metal could result in stronger metal-alkyne binding, facilitating the [2+2]
cycloaddition. In addition, the Bronsted acidity of a coordinated amine increases upon

coordination to a metal center, which may speed up the rate-limiting protonolysis step. '4

The first reported example of a pyrrolyl-based titanium catalyst for
hydroamination was Ti(NMe2)2(dpma) (8), where dpma is N,N-di(pyrrolyl-a-methyl)-N—
methylamine.15 szpma is readily prepared by reaction of 2 equivalents of pyrrole, 2
equivalents of formaldehyde, and an equivalent of methyl ammonium hydrochloride
generating the ligand in good yield. szpma can be placed on titanium by transamination
with Ti(NMe2)4 (3) to yield precatalyst 8 in excellent yield (Scheme 1.5).

Scheme 1.5 Synthesis of szpma and Ti(NMe2)2(dpma) (8).

H

.0

 

+ / NH HN \
O > / N \
2 EtOH/HZO, 55 °C, 4 h l
H’ILH 73%
szpma
+
MeNH2°HC|

95% Ti(NMe2), (3)

 

A
‘

NMBZ

/|
N Ti— NMe2

/ ”(Mt

/ Me

Ti(NMez)2(dpma) (8)

The hydroamination of aniline and l-hexyne is carried out in 6 h at 75 °C with 8
at 10 mol% catalyst loading.l6 Complex 8 is a relatively good catalyst for the
hYdroamination of aryl and alkyl amines with alkynes (Table 1.1). While most of the
reactions could be carried out at 75 °C with moderate reaction times, higher temperatures

were required for more difficult substrates.

Table 1.1 Representative hydroamination results with 10 mol% Ti(NMe2)2(dpma)

 

 

 

 

 

 

 

 

 

 

(8).
Selectivity
Time (h) at % Yield at (M: anti-M)
Amine Alkyne 75°C [130°C] 75°C [130°C] at 75 °C [130 °C]
PhNH2 Bu" _—_-_- H 6 90 50:1
Ph 2 H 8 41 3.6:1
Ph 2 Me 144[24] 99 [96] 1:24 [1:19]
Et 2 Et 72 63
Ph 2 Ph 72 [74] 31[99]
CyNHz Ph : H 20 50 1:6
Ph : M9 95 I29] trace [99] 1:4
Et—-=-_:——Et 72 [24] 3 [57]
Ph : Ph 72 [241 0[701

The dpma ligand architecture bears pyrrolyl ligands with an r] l,r]‘-coordination in

the solid state and in solution when bound to titanium. To date, this is the only bonding

hapticity observed for the dpma ligand. Even though Ti(NMe2)2(dpma) (8) was a

relatively good hydroamination catalyst, alterations in ligand design to create a more

Lewis acidic metal were explored. The most logical modification to the dpma ligand was

removal of the donor amine in the dpma backbone, which lead to the use of

dipyrrolylmethanes as ligands.

A variety of dipyrrolylmethanes can be prepared by reacting pyrrole with

aldehydes or ketones in the presence of a catalytic amount of a Lewis or Branstead acid. '7

The neat reaction of pyrrole and acetone with a catalytic amount of trifluoroacetic acid

(TFA) yields 5,5-dimethyldipyrrolylmethane, szpm. Reacting szpm with Ti(NMe2)4

(3) affords Ti(NMe2)2(dpm) (9) (Scheme 1.6).

10

 

 

Scheme 1.6 Synthesis of szpm and Ti(NMe2)2(dpm) (9).

H No
25 IN 0 10%TFA N [,1 Ti(NMe2)4(3) \
D + \f T \ I l / -2HNM82 : / N/TKNMGZ)?

szpm

 

 

TI(NM92)2(de) (9)

The solid-state structure of 9 has the pyrrolyls 111,715 -bound; however, in solution

the 1H NMR spectrum shows equivalent pyrrolyls, indicative of fast pyrroyl exchange on
the NMR timescale. Using line shape analysis and spin saturation transfer experiments,
our group has been able to place a barrier for pyrrolyl exchange at ~10 kcal/mol."”19
Ti(NMe2)2(dpm) (9) catalyzes the reaction of aniline and l-hexyne famously in

~5 minutes with a modest 5 mol% catalyst loading. The reaction of aniline and l-hexyne

is so rapid and exothermic that the reaction vessel is hot to the touch and refluxes the

reagents, which results in the low yield for Entry 1 in Table 1.2.19

11

Table 1.2 Representative hydroamination results with Ti(NMe2)2(dpm) (9) as the

 

 

 

 

 

 

 

 

 

catalyst.
Selectivity
Amine Alkyne Conditions °/. Yield (M: anti-M)
PhNHz Bu : H 5%, 25 °C,5min 57 4011
Ph : H 5%, 25 °C,5min 41 3.6:1
Ph : Me 5%, 50 °C,6h 83 50:1
Et—z—Et 5%, 50 °C, 24 h 94
Ph : Ph 5%, 75 °C, 24h 34
CvNHz Ph : H 5%, 25 °C,1o min 54 1.621
Ph : Me 5%, 75°C, 24h 93 11:1
Et : Et 10%, 75 °C, 48h 73
ph : ph 10°/o,100°C,48h 72

The results in Table 1.2 show that 9 is a good catalyst for the hydroamination of
alkyl and aryl amines with alkynes and much more reactive than Ti(NMe2)2(dpma) (8). A
kinetic study comparing the various ligand architectures of 8, 9, and Cp-derived pyrrolyl
complex (10), shows that the dipyrrolylmethane framework is quite a bit faster relative to

the other pyrrole-based ligand frameworks (Table 1.3).

12

Table 1.3 Rate constants for Ti(NMe2)2(dpma) (8), Ti(NMe2)z(dpm) (9),

Ti(NMe2)2(pyrr-Cp) (10) for the hydroamination of aniline and l-phenylpropyne.

 

 

Me 0.. .
10 NH2Ph + / 10/ catalyst (0 05 M) ; NPh Ph
Ph toluene, 75 °C
5 M 0.5 M

d[1 -phenylpropyne]

 

 

 

    
 

= kobst
dt
Entry Precatalyst kobs x 10'6 s" a
NM62
1 éii—NMez (a) 11m
/ ”X l
. / "'N‘Me
N0
2 \
/T|(NM92)2 (9) [157]
/ N
I. 10 1
3 /TI(NM82)2 ( I

a Values in brackets are with chlorobenzene as solvent.

Complex 9 was about 20 times faster than Ti(NMe2)2(dpma) (8) and about a 100
times faster than 10. It was proposed that Ti(NMe2)2(dpm) (9) can more readily access
the nlml-isomer than 10, accounting for the increase in catalysis rate.

Expanding the scope of hydroamination to include 1,3-enyne substrates allows for
the synthesis of cult-unsaturated imines, which can be difficult to prepare from a purely

organic synthesis approach of reacting a primary amine with an (LB-unsaturated ketone.

13

Using titanium-catalyzed hydroamination avoids the competing Michael addition

products which can occur in the latter procedure.

   

\
/TI(NM82)2 CY\N

___ |
NHQCY + Qfi-_— > (1 .2)
100°C,PhCL5ll

73%:

 

Complex 9 can conveniently hydroaminate a 1,3-enyne in 5 h at 100 °C (Equation
1.2).20 Catalyst 9 showed good reactivity with less reactive alkyl amines; however, due to
the rapidity of hydroamination, 9 was problematic with sensitive substrates where
potential side reactions could occur (i.e. terminal alkynes). Ti(NMe2)2(dap)2 (11) where
dap is a-(dimethylaminomethyl)pyrrole proved to be the optimal catalyst for highly
reactive substrates (Table 1.4). Catalyst 11 is prepared by reacting 2 equivalents of Hdap

with Ti(NMe2)4 (3) (Equation 1.3).21

 

TMez
\ Nlu \\
H NMe2 ZTiQMez
2 N + Ti(NM32)4 950/ 7: me I NMeg (1'3)

\ l (3) ° N

\ /
Hdap ,
TI(NM92)2(daP)2 (11)

14

Table 1.4 Respresentative hydroamination results with Ti(NMe2)2(dap)2 (11) at

 

 

10 mol% catalyst loading.
Amine 1,3-enyne Conditions % Yield Product
NPh
PM”? O—z 50 °C 16 h 88 O_<
NPh
>.—_— 50 °C, 44 n 64
>—:‘:—Ph 130 °C, 19 h 70 \ NP“
Ph
NC
CvNHz 0‘: 50 °C, 24 h 78 W y
NCy
>—_—: 50 °C, 43 h 73

The ability to make new C—N bonds using hydroamination is a desirable
alternative when the condensation of carbonyls with amines is problematic. The
development of well-defined pyrrolyl-based catalysts provides the organic chemist with

another synthetic tool to prepare a variety of imine products. In addition to imine
a

products, new methodologies have been established for preparing pyrroles,22 indoles,9

and hydrazones9 via titanium-catalyzed reactions.

15

1.6 Iminoamination

Development of the hydroamination reaction to yield more elaborate imine
products offers more potential in preparing valuable C—N containing products with
broader applications. To expand on the scope of products obtained from the
hydroamination mechanism, our group developed a new 3-component coupling reaction
involving the coupling of a primary amine, alkyne, and isonitrile in a single synthetic step
catalyzed by a titanium pyrrolyl complex. The result is the formal irninoamination of an
alkyne, which is not readily achievable using current carbonyl methodologies. The
mechanism for the coupling is shown in Scheme 1.7.

Scheme 1.7 Proposed 3-component coupling reaction mechanism involving a

primary amine, alkyne, and isonitrile.

NR NHR3
R1
my R
a, i. \,
[Ti] 2
NHZR K \
R R1
~ R R
'1‘ \ R ‘N 1
III] 2 I I
\ [TI] R
N~R3 2

cans,
Ti(NMe2)2(dpma) (8) catalyzes the coupling effectively allowing for the

production of a,B-unsaturated B-iminoamines (Table 1.5).23 One of the two identifiable
by-products is an imine product fiom hydroamination of the alkyne by the primary
amine. The other by-product is an N,N-disubstituted-formamidine, which results from the

coupling of the primary amine with isonitrile. Altogether, the by-products are typically

16

found in less than 15% yield.

The regioselectivities of the 3-component coupling reaction with catalyst 8 are
similar to the reported regioselectivies of the hydroamination reaction.5 It is worthy to
note that the coupling does not take place in the absence of the catalyst and even the by-
products are not observed. Also, simple treatment of the hydroamination product with
isonitrile in the presence of the catalyst results in no formation of the 3-component
coupling product, therefore the azametallacyclobutene must be present to result in the
formation of desired coupling product.

Table 1.5 Results of 3-component coupling with Ti(NMe2)2(dpma) (8) at 10

mol% catalyst loading at 100 °C in toluene.

 

Amine Alkyne lsonitrile % Yield PIOdUCt

PhNH2 anne- czN-Bu‘ 77 Bu'HNMNPh

Me '— Ph csN—Bu‘ 72

 

CyNH2 Bu"

(1.2 : 1)
Catalyst 9 is also a very good 3-component coupling catalyst and works with a
variety of alkynes and aniline derivatives. Moreover, our group has expanded the
applications of the 3-component coupling reaction and developed new syntheses for

quinolines, pyrimidines, and pyrazoles from the 3-component coupling product.24

17

1.7 Conclusion

The field of titanium-catalyzed hydroamination has seen an explosion of research
since the first reported example of a titanium catalyst carrying out the hydroamination of
an alkyne and a primary amine.16 The development of well-defined pyrrolyl-based
titanium catalysts has led to new methodologies in ON bond forming reactions. Because
so many of the applications listed are based on the hydroamination catalytic cycle, the
hydroamination of alkynes can be used as a method for evaluating the efficacy of new
catalyst designs. The following chapters discuss the investigation of elaborating the
pyrrolyl framework in order to produce more reactive hydroamination catalysts with

potential applications in multi-component coupling reactions.

18

1.8 References
1. Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc. 1992, 114, 1708.

2. (a)Baranger, A.M.; Walsh, P. J.; Bergman, R. G. J. Am. Chem. Soc. 1993, 115, 2753.
(b) Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc. 1992, 114, 1708.
(c) Duncan, A. P.; Bergman, R. G. Chem. Rec. 2002, 2, 431. ((1) Le, S. Y.; Bergman,
R. G. Tetrahedron 1995, 51, 4255. (e) Polse, J. L.; Andersen, R A.; Bergman, R. G. J.
Am. Chem. Soc. 1998, 120, 13405.

3. Johnson, J. S.; Bergman, R.G. J. Am. Chem. Soc., 2001, 123, 2923.

4. Heutling, A.; Pohlki, F .; Doye, S. Chem. Eur. J. 2004, 10, 3059.

5. Shi, Y.; Ciszewski, J. T.; Odom, A. L. Organometallics, 2001, 20, 3967.

6. Ackerman, L.; Bergman, R. G. Loy, R. N. J. Am. Chem. Soc. 2003, 125, 11956.
8. Watson, D. A. ; Chieu, M.; Bergman, R. G. Organometallics, 2006, 25, 4731.

8. Heutling, A.; Frauke Pohlki, F.; Igor Bytschkov, I.; Doye, S. Angew. Chem. Int. Ed.
2005, 44, 2951.

9. (a) Zhang, Z.; Schafer, L. L. Org. Lett, 2003, 5, 4733. (b) Li, C.; Thomson, R. K.;
Gillon, B.; Patrick, B. O.; Schafer, L. L. Chem. Commun. 2003, 2462 (0) Thomson, R.
K.; Zahariev, F. B; Zhang, Z.; Patrick, B. 0.; Wang, Y.A.; Schafer, L. L. Inorg.
Chem, 2005, 44, 8680.

10. Bexrud, J. A.; Li. C.; Schafer, L. L. Organometallics, 2007, 26, 6366.

11. March, J. Advanced Organic Chemistry, Wiley-Interscience, New York, 4th ed., 1996,
45.

12. (a) Saeed, 1.; Katao, S.; Nomura, K. Organometallics, 2009, 28, 111. (b) Hock A. S.;
Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc., 2006, 128, 16373. (c) Mazet, C.;
Gade, L. H. Organometallics, 2001, 20, 4144. (d) Odom, A. L. Dalton T rans., 2005,
225 and references therein. (e) Schouteeten, S.; Allen, 0. R.; Haley, A. D. ;. Ong, G.
L.; Jones, G. D.; Vicic, D. A. J. Organ. Chem. 2006, 4975.

13. Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.; O’Regan, M.
J. Am. Chem. Soc. 1990, 112, 3875.

14. Fulton, J. R.; Sklenak, S.; Bouwkamp, M. W.; Bergman, R. G. J. Am. Chem. Soc.
2002, 124, 4722.

15. Harris, S.A.; Ciszewski, J. T.; Odom, A.L. Inorg. Chem, 2001, 40, 1987.

19

16. Cao, C.; Ciszewski, J. T.; Odom, A.L. Organometallics, 2001, 20, 5011.

17. (a) Littler, B. J .; Miller, M. A.; Hung, C. H.; Wagner, R. W.; O’Shea, D. F.; Boyle, P.
D.; Lindsey, J. S. J. Org. Chem. 1999, 64, 1391. (b) Patchanita T. P.; Bhise, A. D.;
Taniguchi, M.; Lindsey J. S. J. Org. Chem, 2006, 71, 903.

18. Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.; Odom, A. L. Chem. Commun. 2003, 586.

19. Swartz, D.L.; Odom, Dalton Trans. 2008, 4254.

20. Cao, C.; Li, Y.; Shi, Y.; Odom, A. L. Chem. Comm. 2004, 2002.

21. For Ti(NMe2)2(dap)2 as a hydrohydrazination catalyst see (a) Cao, C. Shi, Y.; Odom,
A.L. Org. Lett, 2002, 4, 2853. (b) Banerjee, S.; Shi, Y.; Cao, C.; Odom, A.L. J.
Organo. Chem. 2005, 5066.

22. Ramanathan, B.; Keith, A. J.; D. Armstrong D.; Odom, A.L. Org. Lett, 2004, 6,
2957.

23. Cao, C.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2002, 125, 2880.

24. Majumder, S.: Odom, A. L.; manuscripts in preparation.

20

CHAPTER 2

Synthesis, structure, and hydroamination kinetics of 2,2’-diaryldipyrrolylmethane
and bis(Z-arylpyrrolyl)titanium complexes

2.1 Introduction

The generation of new carbon-nitrogen bonds is a significant process in organic
chemistry. The most atom economical process for the generation of amines and imines is
through hydroamination, which is the formal addition of an N—H bond across an
unsaturated C—C bond. Many natural products and pharmaceutical drugs contain C—N
bonds; therefore these heteroatom molecules offer pharmaceutical applications as well as
other industrial applications in the way of dyes, detergents, and fungicides.l Pyrrolyl-
ligated titanium complexes provide very reactive catalysts for hydroamination. This
chapter discusses 2,2’-diaryldipyrrolylmethane and bis(2-arylpyrrolyl)titanium
complexes as competent hydroamination catalysts and gauges the efficacy of their design

through kinetic studies.

21

2.2 Titanium Pyrrolyl Hydroamination
Titanium-catalyzed intermolecular hydroamination has been widely studied and
has led to new methodologies in the synthesis of imines,2 hydrazones,3 indoles,2

5 tautomers of 1,3-dimines,6 and tautomers of 1,3-

pyrroles,4 unsaturated imines,
iminohydrazones.7 In addition, a variety of nitrogen containing heterocycles have been
synthesized by intramolecular cyclization.8 There are many ancillary ligands on titanium

known to mediate these types of transformations. The ligands employed include

0 l

alkoxides,9 amides,1 amidates,l and pyrroles.12 Pyrrolyl-ligated titanium complexes
provide very reactive catalysts capable of extremely fast hydroamination.

Perhaps the most active precatalyst known for simple alkyne hydroamination as
of 2008 was a dipyrrolylmethane-ligated titanium complex Ti(NMe2)2(dpm) (9), where
dpm is 5,5-dimethyldipyrrolylme1hane. The dipyrrolylmethane ligand is readily prepared
from acetone and pyrrole in the presence of trifluoroacetic acid (TFA). The ligand can
then be placed on titanium by transamination with Ti(NMe2)4 (3) to yield the precatalyst
in good yields (Scheme 2.1).l3

Scheme 2.1. Synthesis of szpm and Ti(NMe2)2(dpm) (9).

H HN \ 5 ‘
o H ___. ' \
min, /

53% / 90.,3 _ N (9)

szpm TilNM92)2(de) (9)

 

 

The use of pyrrole-based ancillary ligands offers several advantages compared to
other architectures. First, pyrroles can be easily manipulated into multidenate ligands by a
standard set of condensation reactions that take advantage of the nucleophilic nature of

the pyrrole ring. Therefore, several classes of ligands can be synthesized in a small

22

number of steps (e.g. Mannich reaction) with a vast degree of steric and electronic
variance. Secondly, pyrroles are relatively weak 1t donors compared to their alkoxide or
amide counterparts due to the nitrogen lone pair delocalization by its participation in the
ring’s aromaticity. This decreased donation to titanium results in a more Lewis acidic
metal center.

Titanium-catalyzed hydroamination is believed to operate through a smiliar
mechanism as the Bergman mechanism for hydroamination elucidated by Bergman and
co-workers using a zirconocene-based system (Scheme 2.2).14 The first step in the
catalytic cycle is the generation of a reactive titanium imido species (A). Introduction of
an alkyne coordinates to A which undergoes a [2 + 2]-cylcoaddition to yield a
azametallacyclobutene intermediate (B). Coordination of free primary amine to B in
undergoes prontonlysis of the Ti—C bond to give bis(amido) titanium complex C. Further
protonation from the amide regenerates the active catalyst A and yields the imine
product.

Applying the steady-state approximation to the intermediates in the mechanism

shown in Scheme 2.2, the following rate law can be derived (Equation 2.1).

k k k alk ne catal st
v= 1231 V II V] (2.1)

k-,(k2+k3 [amine])

 

23

Scheme 2.2 Proposed mechanism for titanium-catalyzed alkyne hydroamination

NAr
Ft, R2 LnTl(NHAl')2
u NH2Ar
k1 k1
R
/1 ’Ar er a
N
l
Fl
A 2
k4 k-2 k2
Rt R, ,Ar
N
R2 / N’Ar )E'l’iLn
,TiLn F12
ATHN B
C
W
NH2Ar

One can easily draw connections between the Group-4 Hydroamination Mechanism for

alkyne hydroamination and the Chauvin mechanism for olefin metathesis (Scheme 2.3).

Scheme 2.3. Chauvin mechanism for olefin metathesis
R R M=CH2 R
\ ___. 7/ F \K
R M
“[1 D
I R R G
Fl /—_—
\§\‘ M=/
R H

Both mechanisms are known to include metal-ligand multiple bond intermediates
(A and F). Another key step is the [2 + 2]-cyclization between the C—C unsaturated bond

24

and the metal ligand multiple bond (B and G). Detailed olefin metathesis studies done by
Schrock and co-workers found that increasing the Lewis acidity of d0 metal centers led to
an increase in catalysis rates.15

Given the similarities in mechanism and the known improvement in catalyst
activity in (10 Schrock carbenes bearing electron deficient alkoxides on Lewis acidic metal
centers, it is expected that decreasing the donor ability of the pyrrole ligands could have a
positive effect on catalyst reactivity. This chapter describes the effects on structure and
catalysis 2-aryl substituents have on the dpm framework. Complexes containing 2-aryl
bis(pyrrolyl) ligands were also synthesized to evaluate the effect the linker in the dpm

framework has on structure and catalysis.

25

2.3 Hydroamination kinetics with titanium dipyrrolylmethane derivatives

The selective generation of 2-arylpyrroles can be achieved by the seminal
methodology established by Sadighi and co-workers (Equation 2.1).16 This technique
allows for the production of 2-arylpyrroles on multigram scales. For this study, I wanted

to investigate pyrroles of varying electronic and steric profiles.

RZP

 

RP [PdI/ Pit—C cat. )1
U + Zl'lClg + Ar-X - MAr (2.1)

THF, 60 - 100 °C ’

For this study, I prepared 2-Ar-pyrroles where Ar = 4-(CF3)C6H4, 4-(CH3)C6H4,
3,5-(CF3)2C6H3, and 2,4,6-(CH3)3C6H2. The typical procedure for the synthesis of
dipyrrolyhnethanes involves the use of a large excess of pyrrole with respect to the
aldehyde or ketone (Scheme 2.1). However, in the preparation of 2-substituted dpm
derivatives, pyrrole is the limiting reactant with excess acetone as the electrophile. The
reaction is smoothly catalyzed by TFA to produce the ligands in good yield. The initial
5,5-dimethyldipyrrolylmethane derivatives prepared were 2,9-[3,5-(CF3)2C6H3]-5,5-

3,5-CF3

dimethyldipyrrolylmethane (szpm ) and 2,9-[2,4,6-(CH3)3C6H2]—5,5-

dimethyldipyrrolylmethane (szpmmes). These complexes were then reacted with

Ti(NMe2)4 (3) to yield the corresponding dipyrrolylmethane metal complexes,

3,5—CF3

Ti(NMe2)2(dpmmes) (12) and Ti(NMe2)2(dpm ) (13) (Scheme 2.4).

26

Scheme 2.4 Synthesis of szpmmes, szpm3’5‘cp3, Ti(NMe2)2(dpmmes) (12), and

TiCNMe2)2(dpm3’5'CF3) (13).

\21

 

0 10°/ TFA O H "N \
+ 25 /U\ 1h, RT. neat t I N
68% /

H 2dpmmes

. Ti(NMe2)., (3)
3° 4 0512, so °c
18 n
- 2 l-iNMc2

 

Ti(NM°2)2(dem°s) (12)

27

CF3

 

H
N o
10% TFA
+ 25 =
W /u\ 3 h, RT, neat
72°/o

CF3

 

92% 0E12. T

 

Ti(NM62)2(dpm3'5‘CF3) (13)

Single crystal X-ray diffraction shows that the pyrrole rings are in a 111,115

conformation in the solid state for both Ti(NMez)2(dpmmes) (12) and Ti(NMe2)2(dpm3’5

CF3) (13). The crystal structure of 13 is shown in Figure 2.1. This is similar to previous

studies carried out by our group and the Love group on Ti(NMe2)2(dpm) (1).17 The
pyrrole rings in Ti(NMe2)2(dpm) (9) are in an minis-conformation in the solid state as
well. In cold solutions on the NMR timescale, resonances consistent with the solid state
structure are observed. As the solution warms, resonances for the til-pyrrolyl and 115-
pyrrolyl coalesce, and the fast exchange limit is reached well before room temperature.
The barrier for pyrrolyl ligand exchange was measured at 10 kcal/mol using line shape
analysis.4 It is believed that the pyrrolyl exchange occurs through a 111,111-isomer.18 The

28

magnitude for the barrier of pyrrolyl ligand exchange and the mechanism for

isomerization are consistent with other known pyrrolyl isomerizations in the literature.19

F(l3l) _

2Q -... F(153) N2 '-
F(l5|) 5‘.)

 

a, ‘3 . T‘
‘5?" I v/y _
F(152) N13) 0.4 a
t. -
F(232)
F(233)I'
?? a,”
1‘ .: F(252)
F031) I-d '4‘
F(251) H253)

Figure 2.1 ORTEP structure from single-crystal X-ray diffraction of
Ti(NMe2)2(dpm3’5'CF3) (13). Selected bond distances (A) and angles (deg): Ti—N(3)
1.875(5), Ti-N(4) 1.892(5), Ti-N(2) 2.048(5), Ti-N(1) 2.400(6); N(4)-Ti-N(3) 107.1(2),
N(4)-Ti-N(2) 102.6(2), N(3)-Ti-N(2) 104.8(2).

Detailed NMR studies were carried out on 12 and 13 to investigate pyrrolyl
exchange. Consistent with previous results, 12 and 13 Show resonances for equivalent
pyrrolyls at room temperature, indicative of rapid n',n5-isomerization. Cooling the
solutions to —60 °C showed no difference in the 1H NMR spectrum. Parkin and Tanski
have reported that increased sterics lower the barrier for pyrrolyl exchange.18 These
results are consistent with their findings, and assuming a pyrrolyl isomerization is taking

place, one can place a maximum on the pyrrolyl exchange barrier of 5 kcal/mol.

29

To investigate the effect of removing the methylene linker in the dpm architecture

on catalysis, I synthesized two bis(pyrrolyl) derivatives bearing the same aryl

3,5-CF3

substituents. Ti(NMe2)2(pyrr ) (14) and Ti(NMe2)2(pyrrmes)2 (15) were prepared by

3,5-CF3

reacting two equivalents of prrrmes and prrr with Ti(NMe2)4 (3) to give the

corresponding metal complexes (Scheme 2.5).
The solid-state structures for 14 and 15 are shown in Figures 2.2 and 2.3. Both
structures show both pyrroles in an nlznl-binding mode. Cooling solutions to —60 °C in

the NMR probe showed no new resonances in the baseline.

Scheme 2.5 Synthesis of Ti(NMe2)2(pyrrmeS)2 (15) and Ti(NMe2)2(pyrr3’5'CF3)2

 

 

(14).
F330 CFS
H CF3
N
2 I/ + Ti(NMe2)4 r
0512. RT. 6h (MeaNiaTi N \
CF 3 38%
3 -2HNM62 — 2
Ti(NM62)2(pyr3'5'CF3)2 (14)
H
2 N .
I / + TI(NM62)4 T

3 74%
- 2 HNMe2

OEt2, 60 °C, 40 h (MeszTitN \ )
2

TI(NM92)2(PYrm°s)2 (15)

30

 

Figure 2.2 ORTEP structure from single-crystal X-ray diffraction on
TiCNMez)2(pyrrm°s)2 (15). Selected bond distance (A) and angles (deg): Ti-N(3) 1.844(4),
Ti-N(4) = 1.865(4), Ti-N(2) 1.971(4), Ti-N(1) 2.007(4); N(3)-Ti-N(4) 109.3(2), N(3)-Ti-
N(2) 107.5(2), N(4)-Ti-N(4) 109.3(2), N(3)-Ti-N(1) 112.0(2), N(4)-Ti-N(1) 114.1(2),
N(2)-Ti-N(1) 105.2(2).

With these complexes in hand, I set out to answer several questions. First, how
would sterics in the 2-position affect the catalysis rate? Second, how does the linker
affect the catalysis rate? Third, can it be shown experimentally that electron-withdrawing
substituents increase the catalytic activity as proposed in the Introduction?

To test the kinetic viability of these complexes, I chose a standard set of reaction
conditions (Scheme 2.6). The reactions were run pseudo-first order in aniline. Aniline
was chosen because it has a large catalyst scope and runs at a reasonable rate compared to
other amines. The limiting reagent was l-phenylpropyne. This alkyne was chosen for a

couple of reasons.

31

First, it has good regioselectivity with most catalysts and runs at a reasonable rate.
Second, an internal alkyne was required due to the rapidity of hydroamination with
terminal alkynes with catalysts like Ti(NMe2)2(dpm) (9). In addition to testing the
kinetics of the titanium dpm derivatives, I also wanted to compare Ti(NMe2)4 (3), which
serves as a very reasonable hydroamination catalyst as well, but is generally limited in

substrate scope to aryl amines and can oligomerize terminal alkynes.

F(252)
F(253) 1., .. 1 _

F(25 1’)

F(23l) _ . . ,_ r
“-1 .v ”1- 12)
'. F 233
F(232) 3’ ( )-
f) ‘41 é "‘3,
F053) ‘.

”1

F052) "' s ,

x vi

F(l5l)

,9, F032)

F(l31) .‘5

F(l33) ‘

Figure 2.3 ORTEP structure from single-crystal X-ray diffraction on
Ti(NMe2)2(pyrr3’5'CF3)2 (14) Selected bond distances (A) and angles (deg): Ti-N(1)
1.989(4), Ti-N(2) 2.011(4), Ti-N(3) 1.855(4), Ti-N(4) 1.848(4), N(4)-Ti-N(3) 108.88(17),
N(4)-Ti-N(l) 114.72(16), N(3)-Ti-N(1) 107.32(l6), N(4)-Ti-N(2) 107.97(16), N(3)-Ti-

N(2) 1100.69(16), N(1)-Ti-N(2) 107.3605).

32

These complexes were evaluated based on Ti(NMe2)2(dpm) (9). Complex 9
catalyzes the reaction to completion efficiently in less than 4 hours at 75 °C with a rate
constant of 1976 i 130 ><10'7 s". Often, catalytic reactions Show a first-order dependence
in catalyst concentration, which is true in this case. Changes in catalyst concentration
track linearly with the rate constant (Figure 2.4).

Scheme 2.6 Reaction conditions for kinetic studies

 

Me °. .
10 NH2Ph + / 10 / catalyst 0 05 M > NPh Ph
Ph toluene-d8, 75 °C
5 M 0.5 M

d[1 -phenylpropyne]
dt

 

= kobst

Figure 2.4 Plot of catalyst concentration of 9 versus pseudo first-order rate

constant for kinetic reaction conditions.

2000 . .
l

1800.

 

16WI

14W'r

1200 1

km x 10'7 S'1

1000»

 

—y III £11.73 '0 51848)! R8 0.99951

 

l 1 A

0.02 0.025 0.03 0.035 0.04 0.045 0.05 0.055

[91 M

33

While most of the catalysts were quite regioselective, monitoring the reaction by
disappearance of l-phenylpropyne was preferential due to possible rate inconsistencies
by measuring the formation of products which may include the other regioisomer. The
comparison of these catalysts by relative reaction rate was measured by kobs. A
representative plot of the disappearance of ln[l-phenylpropyne] versus time with
TiCNMe2)2(dpm) (9) as the catalyst is shown in Figure 2.5.

Figure 2.5 Representative plot of ln[l-phenylpropyne] vs time with complex 9 as

 

 

 

the hydroamination catalyst.
05 -
—y = 0.56599 - 0.21074x R: 0.99946
.1 _
E -1.5 .
E
>5 . _
E 2
.fl
9‘
3' -2.5 _
.3 ._
.35 I I r l l l 1
0 2 4 6 8 1O 12 14

Time X 103 (s).
The results of this kinetic study are shown in Table 2.1 for catalysts 9 and 12 - 15.
The errors are based on 99% confidence level, with at least three repeated runs. The
average error in rate constants was ~10% and varied from as little as 4% to as much as
20%.

34

Table 2.1 Observed rate constants for catalysts Ti(NMe2)2(dpm) (9),

TiINMethdpmm“) (12). TiINMe2)2(dpm3’5‘CF3) (13). TitNMenztpyt-P’S‘CBh (14),

 

 

Ti(NMe2)2(pyrrmes)z (15).
Entry Catalysta kobs (x 10-7 3")"

1 Ti(NMe2)2(dpm) 1976 :1: 130
9

2 Ti(NMe2)2(dpm3’5_CF3) 780 a 30
13

3 Ti(NMe2)2(dpmmes) 403 a: 80
12

4 Ti(NMe2)2(pyrr3'5‘CF3)2 1275 a 72
14

5 TiCNMe2)2(pyn-mes) 769 a: 30
15

 

3 Conditions are shown in Scheme 2.6. bAll errors are at the 99% confidence

limit with at least three repeated runs.

35

It is quite clear to see from Table 2.1 that substitution on the 2-position of the
dpm architecture results in a significant decrease in reaction rate. This decrease in rate
can be attributed to increased sterics of the dpm framework near the substrate binding
site. Comparatively, the unlinked bis(pyrrolyl) complexes still had a slower rate than
Ti(NMe2)2(dpm) (9), but showed a faster rate than their linked dpm derivaties by ~1.5
times. A possible explanation for the increase in hydroamination reaction rate for the
unlinked pyrrolyl catalysts is their ability to rotate their bulky substiuents away from the
substrate binding site unlike the dpm derivatives, leading to a more open metal center.
While each of the dpm derivatives and bis(pyrrolyl) catalysts bearing an electron
withdrawing substituent resulted in faster rates, these examples do not allow the

separation of steric and electronic factors.

As a result, two additional catalysts were prepared Ti(NMe2)2(py1-r4'CF3

) (16) and
Ti(NMez)2(pyrrt°l)2 (17) that differ only in the donor ability of the substituent in the 4-

position of the aromatic group. The pyrroles, 2-(4-(trifluoromethyl)phenyl)pyrrole

(prrr4'CF3) and 2-(4-tolyl)pyrrole (l-lpyrrtOI), were synthesized using Sadighi’s protocol

(Equation 2.1). The pyrroles were then placed on titanium by transamination with

Ti(NMez)4 (3) to give the corresponding metal complexes (Scheme 2.7).

36

Scheme 2.7 Synthesis of Ti(NMe2)2(pyrr4'CF3)2 (16) and Ti(NMe2)2(pyrr‘°')2 (17).

CF3
CF + Ti(NM62)4 =
a 0512, 25°C. 36 h. (MegN)2Ti<CN \ )
3
2

 

N
:\ ZI

 

Ti(NMe2)2(pyr“CF3)2 (16)
37%
H
N
2 W + Ti(NM62)4 =
3 OEt2,60°C, 24 h. (MeZN)2Ti~CN \ )
— 2
TiINMeaialpyr‘°')2 <17)
45%

Catalysts l6 and 17 were tested under the same kinetic conditions as shown in

Scheme 2.6. Table 2.2 shows the comparison of the bis(pyrrolyl) catalysts.

Ti(NMez)2(pyrrt°l)2 (17) had a rate constant of 880 a 20 x 10'7 s", while

Ti(NMez)2(pyrr4-CF3)2 (16) gave a rate constant of 1255 d: 145 X 10'7 s". It is clear to see

that there is a dramatic difference in rate with the donor ability in the para position on the

3,5—CF3

arene. Ti(NMe2)2(pyrr )2 (14) had a rate constant of 1275 i 72 x 10'7 5", similar to

that of Ti(NMe2)2(pyrr4—CF3)2(16). The position of the electron-withdrawing substituent

on the arene may have a significant effect on rate. While one may expect

3,5—CF3

Ti(NMe2)2(pyrr )2 (14) to have a significantly higher rate than Ti(NMez)2(pyrr4_

37

CB); (16) due to the increase of electron-withdrawing substituents, it seems to be offset

by the position of the substitution.
Table 2.2 Comparison of rate constants for hydroamination of the bis(pyrrolyl)

catalysts. Errors are at the 99% confidence limit.

 

 

Entry Catalysta kobs (x 10'7 s")b
1 Ti(NMe2)2(pyrr3’5'CF3)2 1275 a 72
14
2 Ti(NMcz)2(pyrrmes)2 769 :t 30
15
3 Ti(NMe2)2(pyrr4—CF3)2 1255 a 145
16
. t l
4 Tl(NMCz)2(py1T 0 )2 880 :1: 20
17

a Conditions are shown in Scheme 2.6. bAll errors are at the 99% confidence

limit with at least three repeated rims.

38

One possible complication with the bis(pyrrolyl) catalysts is disproportionation
reactions to generate a mixture of mono(pyrrolyl) and t1is(pyrrolyl) catalysts. This raises
the question as to whether the mono(pyrrolyl) or the bis(pyrrolyl) complexes are the
actual catalysts carrying out the reaction. There were many attempts to prepare and
isolate mono(pyrrolyl) precatalysts, but these lead to impure mixtures. I attempted to
study the kinetics of the mono(pyrrolyl) species by generating the complex in situ from
TiCNMe2)4 (3) and prrr derivatives, but large variations in rate constant rendered these

results unreliable. To investigate the possibility of crossover of the pyrrolyl ligands an

5——CF3)2 (l4) and

experiment was carried out in a C6D, solution of Ti(NMe2)2(pyrr3’
Ti(NMe2)2(pyrrmes)2 (15) in a 1:1 ratio at 75 CC in the NMR probe. After several hours

new resonances in the 1H NMR spectrum could be observed, which are presumably due

to pyrrolyl crossover (Equation 2.2).

F,C CF,
/
N /
(MGZNhTi‘CN \ > + (MezNthVCN \ > 0606' 75 0C : (MGZN)2T1< (2.2)
2 — 2 F C

 

N \
3 \

CF,
While there is no definitive answer as to whether the mono(pyrrolyl) or

bis(pyrrolyl) or a mixture of both are carrying out the catalysis, it can be said that the
active species is not Ti(NMe2)4 (3) or a species not containing the pyrrolyl ligand.
Throughout all the catalyses no free prrr resonances were observed in the 1H NMR
spectrum, therefore the maximum amount of Ti(NMe2)4 (3) that can be generated is half
the amount of the concentration in our kinetic studies. Because the rate scales linearly
with catalyst concentration, full disproportionation to Ti(NMe2)4 (3) and Ti(pyrr)4 would

39

give a rate constant of 433 X 10'7 5‘, half the Ti(NMe2)4 (3) rate under our standard
conditions. Since all of the catalysts are faster than this, it can be said definitively that

Ti(NMez)4 (3) is not the active species.

40

2.4 Conclusion

Using readily available 2-substituted pyrroles, a route to 2,9-
diaryldipyrrolylmethanes has been developed where the synthesized pyrroles can be used
as the limiting reagent in condensation with acetone. Placing these new ligands on
titanium is readily accomplished by reaction with Ti(NMe2)4 (3), and the resulting
complexes show haul-coordination of the dipyrrolylmethane in the solid state. However,
the barrier for pyrrolyl exchange in these substituted dipyrrolylmethanes is quite low and
is below what could be measured by variable temperature 1H NMR spectroscopy.

Catalysis with these new dpm complexes was slower than with unsubstituted 9,
which are assigned to steric inhibition by the bulky groups near the substrate-binding site.
Consistent with this, simple bis(pyrrolyl) complexes without the methylene linker and
with the same substituents show faster catalysis rates, which is likely due to free rotation
of the steric bulk away from the substrate binding site in the bis(pyrrolyl) derivatives.
Using these bis(pyrrolyl) catalysts, I were able to show experimentally that
hydroamination activity can be increased by adding electron-withdrawing groups to
pyrrolyl substituents.

Comparison of various catalyst architectures shows that the pyrrolyl catalysts are
quite rapid. It should be noted that this does not necessarily imply that these catalysts are
superior for any particular application. The “best” catalyst for any particular application
is a function of availability, selectivity, and activity with a particular set of substrates. For
example, the fastest catalyst studied here, 9, is a poor catalyst for some applications, e.g.
hydrohydrazination,20 and the only catalyst studied that leads to any product for others,

e.g. the synthesis of 1-phenyl-2,5-dibenzylpyrrolyl from 1,6-diphenyl-l,5-hexadiyne and

41

aniline.8 The aim is to optimize the activity of the most promising catalysts for these
reactions, which my current results suggest are the dipyrrolylmethane complexes of
titanium, especially Ti(NMe2)2(dpm) (9). From these experiments, I am discovering what
electronic features and steric profiles encourage these useful C—N bond forming

reactions.

42

2.4 Experimental

General Considerations. All manipulations of air sensitive compounds were
carried out in an MBraun drybox under a purified nitrogen atmosphere. Anhydrous ether
was purchased from Columbus Chemical Industries Inc., and pentane and toluene was
purchased fiom Spectrum Chemical Mfg. Corp., were purified by sparging with dry N2,
then water was removed by running through activated alumina systems purchased from
Solv—Tek. Hexanes and ethyl acetate were purchased from Mallinckodt-Baker Inc., and
reagent grade acetone was purchased from Fisher Scientific and distilled from CaSO.t
under N2 and stored over 4A molecular sieves. Trifluoroacetic acid was purchased from
Aldrich and used as received. Aniline was purchased from Matheson, Coleman and Bell
Mfg. and was distilled twice from calcium hydride under vacuum. l-phenylpropyne was
purchased from GFS Chemical, vacuum distilled, and then passed over two columns of

neutral alumina. Ti(NMe2)4 (3)21 was prepared using the literature procedures. 2-(2,4,6-

t1imethylphenyl)-lH-pyrrole (prrrmes) and 2-[3,5-bis(trifluoromethyl)phenyl]-1H-

3,5-CF3

pyrrole (prrr ) were synthesized according to literature methods.23 Deuterated

solvents were dried over purple sodium benzophenone ketyl (C6D6) or phosphoric
anhydride (CDCl3) and distilled under a nitrogen atmosphere. Deuterated toluene 7 was
dried by passing it over two columns of neutral alumina. 1H and '3C spectra were
recorded on Inova-300 or VXR-500 spectrometers. All spectra were referenced internally
to residual protiosolvent ('H) or solvent (BC) resonances. 1H and 13C assignments were
confirmed when necessary using two-dimensional lH——'H and lH—BC correlation NMR

experiments. Chemical shifts are reported in ppm and coupling constants reported in Hz.

43

General Considerations for X-Ray Diffraction. Crystals grown from concentrated
solutions at —35 °C quickly were moved from a scintillation vial to a microscope slide
containing Paratone N. Samples were selected and mounted on a glass fiber in wax and
Paratone. The data collections were carried out at a sample temperature of 173 K on a
Bruker AXS platform three—circle goniometer with a CCD detector. The data were
processed and reduced utilizing the program SAINTPLUS supplied by Bruker AXS. The
structures were solved by direct methods (SHELXTL v5.1, Bruker AXS) in conjunction
with standard difference Fourier techniques.

General Procedure for Kinetics. All manipulations were done in an inert
atmosphere drybox. In a 2 mL volumetric flask was loaded the catalyst (10 mol %, 0.1
mmol), aniline (0.931 g, 911 ,uL, 10 mmol), l—phenylpropyne (0.116 g, 125 ”L, 1 mmol),
and ferrocene (0.056 g, 0.3 mmol) as an internal standard. The solution was then diluted
to 2 mL with deuterated toluene. An ample amount of solution (~0.75 mL) was put into a
threaded J. Young NMR tube that was sealed with a cap and then wrapped with Teflon
tape. The tube was then removed from the drybox and heated at 75 °C in the NMR
spectrometer. The relative l-phenylpropyne versus ferrocene concentration was
monitored as a function of time. The fits are to the exponential decay of the starting

material using the scientific graphing programs Origin or KaleidaGraph. The exact

expression used to fit the data was Y, = YOo + (Y0 - Yoo) exp-“b5! where Y = [1-
phenylpropyne] at time = t (Yr), infinity (Yoo), or initial (Yo). The variables Yoo, Y0, and

kobs were optimized in the fits.22

44

Synthesis of 2-(4-methylphenyl)-lH-pyrrole (prrrml)

(D
Q/ Z’:F”
0_cr

Under an atmosphere of dry nitrogen a threaded Schlenk tube was loaded with
sodium pyrrole (4.69 g, 52.6 mmol), Zan (7.17 g, 52.6 mmol) and a stirbar. To that
same vessel was added of THF (40 mL) slowly (caution: exothermic). After 10 min,
Pd(OAc)2 (20 mg, 0.5 mol%) and 2-(di-tert-butylphosphino)biphenyl (26 mg, 0.5 mol%)
were added to the Schlenk tube. The tube was then capped, taken from the dry box, and
connected to a Schlenk line. Under a continuous flow of nitrogen the screw cap was
removed, and 4-bromotoluene quickly was added. The screw cap was replaced after
addition. The headspace in the Schlenk tube was evacuated and then placed in a 100 °C
oil bath for 24 h. After 24 h, the tube was removed from the oil bath and allowed to cool
to room temperature. The cap was removed, and the solution was transferred to a
separatory funnel. The tube was rinsed with OH; (30 mL) and of H20 (30 mL), which
were then added to the separatory funnel. The aqueous layer was extracted with OH; (3 X
50 mL); the combined organic layers were collected and dried over MgSO4. The solution
was then filtered and concentrated in vacuo. Purification of the crude product was
accomplished by column chromatography on silica gel using an eluting solution of
hexaneszethyl acetate (9:1) to yield an white solid (1.44 g, 54%). mp. 145 °C. 1H NMR
(500 MHz, CDC13): 8.2 (br s, 1 H, H“), 7.37 (d, Jun = 8.46 Hz, 2 H, H3 or H“), 7.18 (d,
JHH = 8.07 Hz, 2 H, H8 or H“), 6.82 (m,1 H, H°, Hb or H“), 6.50 (m, 1 H, H“, Hb or H“),
6.31 (m, 1 H, H“, H“, or H“), 2.39 (s, 3 H, H). 13c {‘H}NMR (125 MHz,CDC13): 135.85
(ci or c“), 132.19 (ci or C“), 129.97 (0‘), 129.50 (0“ or C“), 123.77 (ch or c“), 118.42

45

(C“, C“ or C“), 109.90 (C“, Cc or C“), 105.31 (C°, C“, or C“), 21.38 (C’). Elemental

Analysis (Experimental) Calc. C: (84.10) 84.04, H: (7.02) 7.05, N:(8.66) 8.91.

46

F3

Synthesis of 2-(4-trifluoromethylphenyl)-lH-pyrrole (prrrw )

Ha
FC.
31 \ '0
d

Under an atmosphere of dry nitrogen, a threaded Schlenk tube was loaded with
sodium pyrrole (3.6 g, 40.4 mmol), ZnClz (5.5 g, 40.4 mmol) and a stirbar. To that vessel
was added 32 mL of THF slowly (caution: exothermic). Afier 10 min, Pd(OAc)2 (15 mg,
0.5 mol%) and 2-(dicyclohexylphosphino)biphenyl (24 mg, 0.5 mol%) were added to the
Schlenk tube. The screwcap was replaced, and the tube was removed from the dry box
and connected to a Schlenk line. Under a continuous flow of nitrogen the screwcap was
removed and 4-bromobenzotrifluoride (3 g, 13 mmol) quickly was added. The screwcap
was replaced, and the headspace in the tube was evacuated. The tube was then placed in a
80 °C oil bath where it was allowed to react for 20 h. After the reaction was complete, the
tube was removed from the oil bath and allowed to cool to room temperature. The cap
was removed, and the solution was transferred to a separatory funnel. The tube was
rinsed OH; (30 mL) and H20 (30 mL), which were then added to the separatory funnel.
The aqueous layer was extracted with OEtz (3 X 50 mL); the combined organic layers
were collected and dried over MgSO4. The solution was then filtered and concentrated in
vacuo. Purification of the crude product was accomplished by column chromatography
on silica gel using an eluting solution of hexaneszethyl acetate (9:1) to yield a white solid
(2.53 g, 90%). mp. 158 °C. 1H NMR (500 MHz, CDC13): 8.46 (br s, l H, H“), 7.59 (d,
Jun = 7.73 Hz, 2 H, H“), 7.53 (d, Jun = 7.73 Hz, 2 H, H“), 6.91 (m, 1 H, H“: H“, or H“),
6.62 (m, 1 H, H“, H°, or H“), 6.33 (m, 1 H, H“, H“, or H“). 13C {‘H} NMR (125 MHz,

CDC13): 135.91 (Cf), 130.6 (C'), 127.85 (q, JCF = 33 Hz, C“), 125.92 (q, JCF = 33 Hz, C“),

47

124.29 (q, Jcp = 272 Hz, C“), 123.58 (C8) , 120.1 (C“, C“, or C“), 110.65 (C“, C“, or C“),
107.7 (Cc, Cd, or Cb). Elemental Analysis (Experimental) Calc. C: (62.22) 62.56, H:
(3.54) 3.82, N: (6.51) 6.67.

Caution! The lithium pyrrolide of 2-(4-(trifluoromethyl)pheny1)pyrrole (prrr4-
CF3) was recently prepared in our laboratory by addition of n-butyllithium to prrr4-
CF3, which allowed apparent production of the desired lithium salt. This compound,
Li(pyrrCF3), was found to be explosive in the solid state under an inert atmosphere. It is
likely that o-CFg-aryl pyrrolides can undergo a similar decomposition. Consequently,
extreme caution should be used if alkali-metal salts are produced of aryl-substituted
pyrroles containing CF 3 groups in the ortho or para positions of the arene.23 It is
unknown if the same decomposition can occur in an explosive manner in solution as well,
but we also urge caution with solutions of such compounds. We have produced the
lithium salts of pyrroles containing m-CF3-aryl groups on numerous occasions, and, thus

far, these have not undergone the same explosive decomposition.

48

Synthesis of 2,9-bis[3,5-bis(trifluoromethyl)phenyl]-5,5-dimethyldipyrrolylmethane

(szpms’wm)

 

A l-neck 14/20 25 mL round-bottom flask was charged with 2-[3,5-
bis(trifluoromethyl)phenyl]-lH-pyrrole (0.4 g, 1.4 mmol) and acetone (2.08 g, 36 mmol).
The flask then was sealed with a septum. The solution was stirred at room temperature
while degassed under a flow of argon. After 15 min, trifluoroacetic acid (0.4 g, 3.6 mmol)
was added via syringe. The solution was allowed to stir for 3 h under an argon
atmosphere. The reaction was quenched with ~15 mL of 0.1 M NaOH solution. The
resulting mixture was transferred to a separatory funnel where the aqueous layer was
extracted with EtZO (2 x 15 mL). The combined organic layers were dried over MgSO4
and filtered. The solvent was removed in vacuo to give a purple oil. The oil was then
tritrated with pentane to yield a pink solid (0.311 g, 72%). mp. 130 °C. 1H NMR (500
MHz, CDC13): 8.11 (br s, 2 H, H“), 7.73 (s, 4 H, H‘), 7.6 (s, 2 H, H'), 6.6 (m, 2 H, H“ or
H“), 6.2 (m, 2H, H“ or H“), 1.76 (s, 6 H, H“). 13C {‘H}NMR (125 MHz, CDCl3): 141.64
(C“ or C“), 134.4 (C“ or C“), 132.18 (q, Jcp = 31.94 Hz, C’), 129.03 (C“), 123.28 (q, Jcp =
272 Hz, C"), 123.15 (q, Jcp = 2.54 Hz, C‘), 119.1 (q, JCF = 3.91 Hz, C'), 108.64 (C“ or C‘),
107.09 (C° or Cf), 35.83 (C’), 29.09 (Cd). Elemental Analysis (Experimental) Calc. C:

(54.63) 54.19, H: (3.14) 3.03, N: (4.52) 4.68.

49

Synthesis of 2,9-bis(2,4,6,-trimethylphenyl)-5,5-dimethyldipyrrolylmethane

CS

(szpmm )

 

A l-neck 14/20 25 mL round-bottom flask was charged with 2-(2,4,6—
trimethylphenyD-lH-pyrrole (0.25 g, 1.3 mmol) and acetone (1.96 g, 33 mmol) then
sealed with a septum. The solution was stirred at room temperature while degassed under
a flow of argon. After 15 min, trifluoroacetic acid (0.384 g, 3.3 mmol) was added via
syringe. The solution was allowed to stir for 1 h. The reaction was quenched with ~15
mL of 0.1 M NaOH solution. The resulting mixture was transferred to a separatory funnel
where the aqueous layer was extracted with B20 (2 X 15 mL). The combined organic
layers were dried over MgSO4 and filtered. The solvent was removed in vacuo to give an
orange oil. The oil was then tritrated with pentane to yield an orange solid. (0.187 g,
68%). mp. 115 °C. 1H NMR (500 MHz, CDC13): 7.57 (br s, 2 H, H‘), 6.89 (s, 4 H, H"),
6.09 (app t, JHH = 2.87 Hz, 2 H, H“ or H‘), 5.88 (app t, JHH = 5.86 Hz, 2 H, H“ or H‘), 2.2
(s, 6 H, H'“), 2.0 (s, 12 H, H“ ), 1.6 (s, 6 H, H“). 13C {‘H}NMR (125 MHz, CDCl;):
138.54 (C', C“, or C“), 138.31 (C', C“, or C“), 137.38 (C', C“, or C“), 130.83 (C“ or C“),
128.76, 127.98 (C‘), 107.5 (Ce or Cf), 103.4(C° or C’), 35.30 (C°), 28.95 (C’), 20.99 (Cm),
20.52 (C’). Elemental Analysis (Experimental) Cale: C, (84.85) 84.83, H: (8.37) 8.35, N:

(6.78) 6.82.

50

Synthesis of Ti(NMe2)z(dpmmes) (12):

 

Under an atmosphere of dry nitrogen, a threaded pressure tube was loaded with
Ti(NMe2)4 (3) (0.316 g, 1.4 mmol), szpmmes (0.578 g, 1.4 mmol), and E120 (8 mL).

The pressure tube was sealed with a Teflon screw cap, taken out of the dry box, and put
in a 50 °C oil bath, where it was lefl to react for 18 h. The pressure tube was then
removed from the oil bath and taken back into an atmosphere of dry nitrogen, where the
volatiles were removed in vacuo to yield an orange oily solid. Crystallization from
pentane yielded an orange solid (0.225 g, 30%). mp. 155 °C (dec). 1H NMR (500 MHz,
CDC13): 6.80 (s, 4 H, H"), 6.37 (d, Jun = 2.80 Hz, 2 H, Hf or H’), 6.28 (d, JHH = 2.77 Hz,
2 H, Hf or H°), 2.59 (s, 12 H, H“), 2.23 (s, 6 H, H”), 2.18 (s, 12 H, H“), 1.94 (s, 6H, H“).
l3C {‘H} NMR (125 MHz, CDCl3) 159.15 (C“), 138.38 (Ci or C'), 138.26 (Ci or C'),
136.27 (C“ or C8), 132.54 (C8 or C“), 128.52 (C‘), 113.70 (C“ or C“), 107.01 (C“ or Cf),
47.45 (C'), 39.26 (C’), 30.15 (Cm), 21.67 (C’), 20.92 (C°). After many attempts at
elemental analysis, satisfactory results were not obtained. 1H and 13 C NMR spectra are

included in the Appendix to demonstrate purity.

51

Synthesis of Ti(NMe2)z(dpm3’5'CF3) (13):

 

Under an atmosphere of dry nitrogen a vial was loaded with Ti(NMe2)4 (3) (0.131
g, 0.584 mmol) in EtzO (3 mL). In a 20 mL scintillation vial was loaded 2,9-bis[3,5-
bis(trifluoromethyl)phenyl]-5,5-dimethyldipyrrolylmethane (0.350 g, 0.584 mmol) in
OEtz (3 mL). The solutions were put into a cold well where they sat until nearly frozen.

3'5”“ was added to the cold solution of 3. The solution

To a thawing solution of szpm
was stirred at room temperature for 4 h. Volatiles were removed in vacuo to yield an
orange solid (0.395 g, 92%). mp. 150 °C (dec). 1H NMR (300 MHz, CDC13): 7.96 (s, 4
H, H‘), 7.63 (s, 2 H, H'), 6.55 (d, JHH = 3.19 Hz, 2 H), 6.44 (d, Jun = 3.18 Hz, 2 H), 2.6 (s,
12 H, H“), 1.8 (s, 6 H, H“). ”C {'H} NMR (125 MHz, CDC13): 162.84 (C“), 138.18 (C8
or C8), 138.04 (C“ or C8), 131.17 (q, Jcp = 33.6 Hz, C“), 126.26 (q, C“), 119.55 (q, Jcp =
3.7 Hz, C'), 110.22 (CC or C‘), 109.53 (C“ or C‘), 45.88 (Cm), 39.67 (0529.33 (C“).

Elemental Analysis (Experimental) Calc. C: (50.45) 50.84, H: (3.75) 3.85, N: (7.48) 7.65.

52

Synthesis of Ti(NMe2)2(pyrrmes)z (15):

k
(MGZN)2 \

T
I
N
/
C

   

Under an atmosphere of dry nitrogen a threaded pressure tube was loaded with
Ti(NMe2)4 (3) (0.075 g, 0.334 mmol), prrimes (0.124 g, 0.667 mmol), and EtzO (5 mL).

The pressure tube was then sealed with a Teflon screwcap and wrapped with Teflon tape.
The pressure tube was then taken out of the dry box and put into a 60 °C oil bath for 40 h.
Afier 40 h, the pressure tube was taken back into an atmosphere of dry nitrogen, and the
volatiles were removed in vacuo to yield a yellow solid (0.125 g, 74%). mp. 160 °C
(dec). 1H NMR (500 MHz, CDC13): 6.83 (s, 4 H, H“), 6.81 (m, 2 H, H“, H“, or H“), 6.19
(m, 2 H, H“, H“ or H0, 5.91 (m, 2 H, H“ ,H“, or H“), 2.77 (s, 12 H, H"), 2.28 (s, 6H, H“),
2.1 (s, 12 H, H8). ”C {H} NMR (125 MHz, CDC13): 139.2 (C‘), 137.54 (C‘, C“, or C“),
136.85 (C‘, C“, or C“), 134.65 (C‘, C“, or C“), 127.6 (C“), 123.09 (C', C“, or C'), 108.6 (C'
C“ or C“), 108.3 (C“, C“, or C“), 44.14 (C'), 21.04 (C“), 20.36 (C8). Elemental Analysis

(Experimental) Cale. C: (70.98) 71.42, H: (8.01) 7.99, N: (10.97) 11.10.

53

Synthesis of Ti(NMe2)2(pyrr3'5'C”)2 (14)

l
(MGZN)2\
1'1 CF3

Nd .
bc 19

SF“ 2

Under an atmosphere of dry nitrogen, a 20 mL scintillation vial was loaded with

Ti(NMe2)4 (3) (0.150 g, 0.669 mmol) in OEtz (3 mL). A separate vial was loaded
prrr3’5_C123 (0.372 g, 1.33 mmol) in OEtz (5 mL). prrr3’5‘CF3 was then added to the vial

containing 3 at room temperature. The solution was allowed to stir at room temperature
for 6 h. Crystallization from pentane yielded the bis(pyrrolyl) as an orange solid (0.175 g,
38%). m.p. 86 °C (dec). 'H NMR (500 MHz, CDCh): 7.74 (s, 4 H, H‘), 7.61 (s, 2 H, H“),
6.89 (m, 2 H, H“, H“, or H“), 6.48 (m, 2 H, H“, H“, or H“), 6.25 (m, 2 H, H“, H“, or H“),
3.0 (s, 12 H, H“). ”C {‘H} NMR (125 MHz, CDCh): 138.88 (C“), 137.70 (C“), 131.62 (q,
.10: = 33 Hz, C8), 126.63 (C“, C“, or C“), 125.96 (C‘), 123.35 (JCF = 273 Hz, C“), 119.1
(C‘), 111.86 (C“, C“, or C“), 111.20 (C“, C“, or C“), 44.53 (C“). Elemental Analysis

(Experimental) Calc. C: (48.48) 48.57, H: (3.53) 3.49, N: (7.78) 8.09.

54

Synthesis of Ti(NMe2)2(pyrr4'CF3)2 (l6)

(MeN).
2 2;”
N i
I/de hcfi
bc 9

Under an atmosphere of dry nitrogen, a 20 mL scintillation vial was loaded with
Ti(NMe2)4 (3) (0.061 g, 0.272 mmol), prrr4_CF3 (0.115 g, 0.544 mmol), CB; (3 mL),

and a stir bar. The vial was then capped and allowed to stir for 36 h at room temperature.
The volatiles were removed in vacuo to yield an orange oil. Crystallization from pentane
yielded an orange solid (0.069 g, 45%). mp. 72 °C. 1H NMR (500 MHz, CDCl3): 7.47 (d,
Jun = 7.88 Hz, 4 H, H8), 7.45 (d, JHH = 7.89 Hz, 4 H, Hf ), 7.00 (m, 2 H, H“), 6.36 (m, 2
H, H“ , H“, or H“), 6.27 (m, 2 H, H“, H“ or H“), 3.16 (s, 12 H, H“). ”C {‘H} NMR (125
MHz, CDC13): 140.43 (C“), 139.50 (C“), 127.64 (q, Jcp = 33 Hz, C“), 126.56 (C‘), 126.51
(C“, C“, or C“), 125.12 (q, Jcp = 11.78 Hz, C8), 124.31 (q, Jcp = 272 Hz, C“), 111.07 (C“,
C“, or C“), 109.86 (C“, C“, or C“), 44.68 (C“). Elemental Analysis (Experimental) Calc. C:

(55.83) 56.13, H: (5.11) 4.71, N: (10.29) 10.07

55

Synthesis of Ti(NMez)2(pyrrt°l)2 (17):

a
(“'92le
Ti
. 9 N b
I e
1—<l:>_§\:"c
d

Under an atmosphere of dry nitrogen a threaded pressure tube was loaded with

2

prrrml (0.115 g, 0.732 mmol), Ti(NMe2)4 (2) (0.082 g, 0.366 mmol), GB; (3 mL), and

a stirbar. The pressure tube was then sealed with a Teflon screwcap and then wrapped
with Teflon tape. The tube was removed from the dry box and placed in a 60 °C oil bath,
where it was left to react for 24 h. After the reaction was complete, it was taken back into
an atmosphere of dry nitrogen. The reaction mixture was transferred to a 20 mL
scintillation vial where the volatiles were concentrated in vacuo to yield an orange oil.
Crystallization from pentane yielded an orange solid (0.060 g, 37%). mp. 71 °C. 1H
NMR (500 MHz, CDC13): 7.18 (d, Jun = 7.68 Hz, 4 H, Hh or H“), 7.04 (d, Jun = 7.77, 4
H, H“ or H8), 6.90 (m, 2 H, H“, H“, or H“), 6.27 (m, 2 H, (H“, H“, or H“), 6.18 (m, 2 H, H“
,H“, H“), 2.99 (s, 12 H, H“), 2.29 (s, 6 H, H“). ”C {'H} NMR (125 MHz, CDCl;): 141.11
(C‘), 135.53 (C’), 134.57 (C“), 128.82 (C“ or C8), 126.97 (C“ or C8), 125.67 (C“), 110.05
(C“, C°’ or C“), 107.68 (C“ ,C“ or C“), 44.68 (C“), 21.10 (C“). Elemental Analysis

(Experimental) Calc. C: (69.53) 69.94, H: (7.60) 7.19, N: (12.17) 12.49.

56

2.5 References

1.

10.

11.

12.

13.

14.

15.

Chenier, P.J. Survey of Industrial Chemistry, John Wiley & Sons, New York, 1986;
82.

(a) Zhang, Z.; Schafer, L. L. Org. Lett. 2003, 5, 4733. (b) Cao, C.; Ciszewski, J. T.;
Odom, A. L. Organometallics, 2001, 20, 5011.

(a) Cao, C.; Shi, Y.; Odom, A. L. Org. Lett. 2002, 4, 2853. (b) Khedkar, V.; Tillack,
A.; Michalick, M.; Beller, M. Tetrahedron Lett. 2004, 45, 3123. (c) Ackerman, L.;
Born, R. Tetrahedron Lett. 2004, 45, 9541. (d) Khedkar, V.; Tillack, A.; Michalik,
M.; Beller, M. Tetrahedron 2005, 61, 7622.

Cao, C.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2003, 125, 2880.

C30, C.; Li, Y.; Odom, A. L. Chem. Commun. 2004, 2002.

C30, C.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2003, 125, 2880.

Banerjee, S.; Shi, Y.; Cao, C.; Odom, A.L. J. Organomet. Chem. 2005, 690, 5066.
Majumder, S.; Odom. A. L. Organometallics, 2008, 27, 1174.

Khedkar, V.; Tillack, A.; Beller, M. Org. Lett. 2003, 5, 4767.

Shi, Y.; Ciszewski, J. T.; Odom, A. L. Organometallics, 2001, 20, 3967.

Bexrud, J. A.; Li, C.; Schafer, L. L.Organometallics, 2007, 26, 6366.

Swartz, D.L.; Odom. A.L. Organometallics, 2006, 26, 625.

Littler, B.J.; Miller, M.A.; Hung, C. H.; Wagner, R.W.; O’Shea, D.F.; Boyle, P.D.;
Lindsey, J. S. J. Org. Chem. 1999, 64, 1391.

(a)Baranger, A.M.; Walsh, P. J.; Bergman, R. G. J. Am. Chem. Soc. 1993, 115, 2753.
(b) Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc. 1992, 114,
1708. (c) Duncan, A.P.; Bergman, R. G. Chem. Rec. 2002, 2, 431. ((1) Le, S. Y.;
Bergman, R. G. Tetrahedron 1995, 51, 4255. (e) Polse, J. L.; Andersen, R. A.;
Bergman, R. G. J. Am. Chem. Soc. 1998, 120, 13405.

Schrock, R. R.; Murdzek, J. S.; Bazan G. C.; Robbins, J.; DiMare, M.; O’Reagan, M.

J. Am. Chem. Soc. 1990, 112, 3875.

16. Reith, R. D.; Mankad, N. P.; Calimano, E.; Sadighi, J. P. Org. Lett. 2004, 6, 3981.

17. A. Novak, A. J. Blake, C. Wilson and J. B. Love, Chem. Commun., 2002, 2796.

57

18. Shi, Y; Hall, C.; Ciszewski, J. T.; Cao, C.; Odom. A.L. Chem. Commun., 2003, 586.
19. Tanski, J. M.; Parkin, G. Organometallics 2002, 21, 587.

20. Banerjee, S.; Odom, A. L. unpublished results.
21. Bradley, D. C.; Thomas, I.M.; J. Chem. Soc., 1960, 3859.

22. Espenson, J. H. Chemical Kinetics and Reaction Mechanisms; McGraw-Hill: New
York, 1995.

23. A similar caution has been issued by Wigley and co-workers concerning Li-4-
CF 3C6Hs, which likely undergoes a similar decomposition: Weller, K. J .; Gray, S. D.;
Briggs, P. M.; Wigley, D. E. Organometallics 1995, 14, 5588.

58

CHAPTER 3

Synthesis, structure, and hydroamination reactivity of electron
deficient titanium complexes bearing bis- and mono(pyrrolyl) ligands

3.1 Introduction

Pyrrole-based ancillary ligands on titanium are a useful class of compounds

I 2

known to participate in catalytic hydroamination, iminoarnination, and
hydrohydrazination.3 In the previous chapter, I reported that placing aryl-substituents on
the 2-position of the pyrrolyl provided effective catalysts for the hydroamination of
primary amines and alkynes. Using these bis(2-arylpyrrolyl) titanium catalysts, I was able.
to show experimentally that hydroamination activity can be increased by adding electron-
withdrawing groups to the pyrrolyl ligand, however the addition of sterically hindered
groups in these positions inhibits access to the metal center negatively affecting catalysis
rates.4

In an attempt to increase the hydroamination activity of these bis(pyrrolyl)
titanium catalysts, moving electron-withdrawing substituents from the 2—position to the 3-
position of the pyrrole may provide greater access to the binding site resulting in

enhanced hydroamination activity. This chapter discusses the synthesis and

hydroamination catalysis of 3-arylpyrrolyl titanium complexes.

59

3.2 Results and Discussions

The synthesis of 3-arylpyrroles can be achieved by the seminal methodology
established by Smith and co-workers, which begins with an iridium-catalyzed reaction of
N-Boc-pyrrole with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (HBpin) to generate 3-
(pinacolboryl)-N-Boc-pyrrole. The aryl group is then installed by Suzuki cross-coupling
to generate 3-aryl pyrroles on multi-grarn scales (Scheme 3.1).5

Scheme 3.1 Smith borylation followed by Suzuki coupling to prepare 3-
substituted pyrroles. (Cod = 1,5-cyclooctadiene, Butbipy = 4,4'-di-tert-butyl-2,2'-

bipyridine, Boc = tert-butyl-carboxylate).

Boc H 1.5% [Ir(OMe)(Cod)]2 Boc

EN) + 1.5 O’ on 3% Butbipy : Q
/ N Hexane, 60 °C, 12 h

85 A: Pro

HBpin O><K

[Pd]/Phosphine
Ar—X, Base

[5)

Ar

 

C6F5
)

Using the above methodology 1 was able to synthesize 3-C6F5 (3-prrr and

3,5—(CF3)C6H3 (3-prrr3’5'CF3) pyrroles in 53% and 76% isolated yields (Scheme 3.2).

3,5—CF3

Reacting 3-prrr with half an equivalent of Ti(NMe2)4 (3) yields

60

Ti(NMe2)2(NHMe2)(pyrr3’5_CF3)2 (19) in 76% yield (Equation 3.1). Single crystal X-Ray
diffraction on 19 shows that the pyrrolyls are nlznl-bound in the solid-state taking on a

pseudo trigonal-bipyramidal geometry (tbp). A structure for 19 is shown in Figure 3.1.

 

 

Scheme 3.2 Synthesis of 3-prrr3’5_CF3 and 3-prrrC6F5.
[13°C 3' 2.5% Pd(PPh3)4 3°C
1.5 K3PO4
I / + 1‘ \ /
Bpin DME, 80 °C
F30 CF88 36 h F30
, ICF3170 °C
C:/ /; 76 A 20 min
300 3' 1% Pd(PPh3)4 {3°C
F F 1.5 K3PO4
I / + > F \ /
Bpin DME, 100 °C
F F 8 d F
F F

53/° 170°C
/° 20min

Consequently, moving the aryl groups from the 2-position to the 3-position on the
pyrrole reduces sterics around the metal center allowing for the retention of

dimethylamine. As expected the longest Ti—N bond distance is from the dimethylamine

61

ligand, 2.248(4) A, which sits in the axial position trans to one of the pyrrolyl ligands.
The average Ti—N(NMe2) bond distance is 1.867 A, while the average pyrrolyl Ti—N
bond distance is 2.075 A. These bond distances are quite similar to previously reported

derivatives.4

(57 ,3 Run/___}
"“5, F(231) *— 2 "in; F233
5A" "L ." ( )
N“ a i
x, . 1“
a". ‘ ‘ i ( "‘"
9 Ti ‘i' a. l

w 3, .- F:(252)
G : 11 >
F033) r, ’1 F(253)
77"“ F031) F(251)
“’1. 7““: -

a,

1) “‘ F(152)
F(151)

Figure 3.1 ORTEP structure from single crystal X-ray diffraction on
Ti(NMe2)2(NHMe2)(3-pyr3’5'CF3)2 (19) with thermal ellipsoids at 50% probability level.
Selected bond distances (A) and angles (deg). Ti-N(1) 2.098(4), Ti-N(2) 2.053(5), Ti-
N(3) 1.862(5), Ti-N(4) 1.873(5), Ti-N(5) 2.248(4), N(1)-Ti-N(2) 87.89(18), N(2)-Ti-N(3)
116.7(2), N(3)-Ti-N(4) 111.9(2), N(4)-Ti-N(5) 90.21(18), N(2)-Ti-N(4) 130.8(2), N(2)-
Ti-N(5) 81.54(17), N(3)-Ti-N(5) 91.33(18), N(1)-Ti-N(3) 99.01(19), N(1)-Ti-N(4)
87.89(18), N(1)-Ti-N(5) 167.72(18).

The 1H spectrum of 19 at room temperature is inconsistent with the solid-state

structure showing equivalent pyrrolyls. This is indicative of a rapid isomerization on the

62

NMR timescale. Cooling solutions of 19 in CDC13 to —60 °C in the NMR probe produces
a rather complex lH Spectrum. Small peaks in the aromatic region present in the room
temperature lH spectrum, which were presumed to be impurities, intensify at —60 °C in
the 1H spectrum and the aromatic peaks associated with the pyrrolyls of 19 split into new
resonances. New peaks also appear in the methyl region and the methyl peaks associated
with the dimethylamine ligand begin to split as well. Due to the complexity of the 1H
spectrum at —60 °C a definitive structural assignment of the peaks in the spectrum was
not possible. One possible explanation for this behavior is that there could be additional
isomers of 19 in solution causing the complexity of the 1H spectrum at room temperature

as well as at depressed temperatures.

 

NHM62 CF
3
H MeZN...,,,l. SQ

2 | N + Ti(NM92)4 , M92” | 01:3

/ OEtz, 25 °C, 6 h N
CF3
F30 “3

F30

Ti(NMez)2(NHMez)(3-pyrr 3M“) (19)
Surprisingly, reacting 2 equivalents of 3-prrrC‘SFS with Ti(NMe2)4 (3) does not
seem to yield a single metal complex Ti(NMe2)2(NHMe2)(per6F5)2 or
Ti(NMe2)2(NHMe2)2(per6F5)2. The 1H NMR spectrum of the orange solid obtained from
the reaction mixture is rather perplexing. Integration of the peaks did not correspond to a
single metal complex. Variable temperature 1H NMR experiments were carried out in
toluene-d3 proved to be fairly informative. An increase in temperature in the NMR probe

results in new resonances in the baseline of the 1H spectrum as well as significant shifts

63

in the methyl groups assigned to NMe2 groups. One possible explanation for this

C6F5

behavior is that upon formation of Ti(NMe2)2(NHMe2)n(pyr )2, it disproportionates to

yield a mixture of mono- and 1ris(pyrrolyl) complexes (Scheme 3.3) and pyrrolyl

crossover is occurring at elevated temperatures. Attempts to isolate a single metal

complex from the reaction of 3-prrrC6F5 and Ti(NMe2)4 (3) via crystallization were

successful. Single crystals of Ti(NMe2)2(NHMe2)(pyrrC6F5)2 were grown from a

OEt2/pentane solution at -—35 °C, proving that Ti(NMe2)2(NHMe2)(pyrrC6F5)2 is formed at

 

low temperatures.
Scheme 3.3 Possible pyrrolyl crossover in the reaction of prrrC‘SF5 and
Ti(NMe2)4 (3).
K1
4 \ / ,t 2 Ti(NM62)4 = 2 Ti(NMez)2(NHMez)n(pyr°°F5)2
F
(3)
F F n
F F
Ti(NMez)(NHMe2)n
T(NM92)3(NHM92)11 '1‘
N \ /
F
F \ / +
F
F
F F F
F F F 3

The reaction of aniline and l-phenylpropyne under pseudo-first order reaction
conditions at 75 °C with 19 as the catalyst, results in the reaction being ~10% complete
after 10 h. One possible explanation for the slow catalysis may be that pyrrolyl crossover
is occurring at elevated temperatures, similar to the process depicted in Scheme 3.3. This

assertion warrants further investigation.

64

F(451) «1 12(453)

 

.. 41f'f’.F(452) C.
,5
H430 ..,. f) -
’5." .- m’ _ “Q
. ‘__ of", v",
\; \”"
F(432) T1 2‘: g;
C
F(433) (381141 '1'“
y)
-; F(2)
4 ._..,,
1.13““ F(3)

 

F14)

Figure 3.2 ORTEP structure from Single crystal X-ray diffraction on
ri(NMe2)3(pyr2'CF3‘4C“F5) (20) with thermal ellipsoids at 50% probability level. Selected
bond distances (A) and angles (deg). Ti-N(1) 1.865(4), Ti-N(2) 1.861(5), Ti-N(3)
1.865(5), Ti—N(4) 2.074(5), N(1)-Ti-N(2) 106.7(2), N(2)-Ti-N(3) 108.3(2), N(3)-Ti-N(4)
1 17.09(1 9), N(2)-Ti-N(4) 1 10.2(2), N(1)-Ti-N(4) 106.35(19).

In an attempt to reduce amine coordination, pyrrolyl crossover and also to
increase the hydroamination activity, I prepared 2-(3,5-bis(trifluoromethyl)pheny1)-4-

(perfluorophenyl)pyrrole and the corresponding titanium complex (Scheme 3.4).

65

Scheme 3.4 Synthesis of 2-(3,5-bis(1rifluoromethyl)phenyl)-4-

(perfluorophenyl)pyrrole (prnlcm'cm) and Ti(NMe2)3(pyr2'C““’4C8“8) (20).

 

 

F30
Boc H 1.5% [lr(OMe)(Cod)]2 OF“
N 0’8 t - 8°C
1 ‘ 3% Bu blpy a N
+ .5 O a
F30 \ / N Hexane.60°C,18h \ /
95% Bpin CFs
HBpin
100°C 1. Pd(PPh3)4. K3PO4
DME 2. areal:5
8d
CF3
Boc
165°C,10min \ /
20% CSFS CFS

 

Tl(NM62)4 (3)

£12
86 %

 

Ti(NMe2)3(pyr2-CF34C6F5) (20)
Reacting 1 equivalent of prrlg'CFM‘C6F5 with Ti(NMe2)4 (3) generates
Ti(NMe2)3(pyr2'CF3'4C6F5) (20) in 86% yield. A structure of 20 is shown in Figure 3.2.

The synthesis of Ti(NMe2)2(pyr2'CF3'4C6F5)2 would have been preferential, but

2-CF3-4C6F 5

reacting two equivalents of prr with Ti(NMe2)4 (3) produces only the

66

2-CF3-4C6F5

mono(pyrroyl) titanium complex. Attempts to prepare Ti(NMe2)2(pyr )2 by salt

2-CF3-4C6F5

metathesis through the reaction of 2 equivalents of Lipyr with Ti(NMe2)2Cl2

yielded only the mono(pyrrolyl) complex as well.

Complex 20 is a very competent hydroamination catalyst carrying out the reaction
of l-phenylpropyne and aniline in less than 6 hours at 75 °C. Reintroducing sterics in the
2-position of the pyrrolyl in 20 proved advantageous in preparing a much more reactive
catalyst compared to 19.

Complex 20 was the first mono(pyrrolyl) titanium complex I had prepared and

isolated since working with these pyrrolyl titanium complexes. I wanted to evaluate the
hydroamination reactivity of 20 relative to Ti(NMe2)2(pyrrmes)2 (13), a bis(pyrrolyl)

titanium catalyst from Chapter 2, as well as Ti(indenyl)2Me2 (21) which has been shown
by Doye and co-workers to be a fairly general alkyne hydroamination catalyst, through
kinetic studies.6 The conditions for the kinetic study are Shown in Scheme 3.5

Scheme 3.5 Conditions for kinetic study

Me 10% catalyst 0.05 M NPh

10 NH2Ph + é :
Ph/ toluene-d8, 100 °C )k/ Ph

 

5M 0.5M

d[1 -pheny| propyne]
dt

= kobst

 

Both 20 and Ti(NMe2)2(pyrrmes)2 (l3) carry out the reaction of aniline and 1-

phenylpropyne effectively at 75 °C. While Ti(indenyl)2Me2 (21) was active at 75 °C, the
results were inconsistent at this temperature, which was apparently due to a catalyst

activation period. Assuming that there was an activation problem, I incubated the catalyst

67

with the aniline portion at 100 °C prior to alkyne addition. However, this still did not
result in good reproducibility of the kinetics under these conditions. Consequently, I ran
the reactions with Ti(indenyl)2Me2 (21) at 100 °C, which afforded plots that reliably fit to
first-order kinetics. The results of the kinetic study are shown in Table 3.1. The errors are
at the 99% confidence limit and based off as least three repeated runs and range from as
little as 7% to as much as 27%.

The results in Table 3.1 suggest that the pyrrolyl framework is quite effective

relative to other catalyst architecture. Comparison of Ti(indenyl)2(Me)2 (21) with

Ti(NMe2)2(pyrrmes)2 (13) under identical conditions reveals that this pyrrolyl catalyst is

about a factor of 4 times faster for these substrates. Complex 20 was significantly faster

than Ti(Indenyl)2(Me)2 (21), which resulted in catalysis about 8 times faster, and was

twice as fast as Ti(NMe2)2(pyrrmes) (13).

68

Table 3.1 Comparison of Ti(NMe2)2(pyr2‘CF3‘4C6F5) (20), Ti(NMe2)2(pyrrmeS)2

(l3), and Ti(indenyl)2Me2 (21).

 

Entry Catalysta

kobs (x10'7 5-1)

 

 

2
(MegN)2T'1~<N \ >
2
l3
3 Ti(Indenyl)2Me2
21

7366 :1: 2002

888 m 61

3888 i 764

 

69

3.3 Conclusion
Using the seminal C—H activation/borylation work by Smith and co-workers

followed by Suzuki coupling, two new 3-substituted pyrroles were synthesized as well as

3,5—CF3

a 2,4-disubstituted pyrrole. Placing 3-prrr on titanium is readily accompliShed by

reaction with Ti(NMe2)4 (3). The decreased sterics of the 3-substituted pyrrole compared

to the 2-substituted derivative results in an increased coordination number with retention
. . . 3,5—CF3
of HNMe2. However, subjectlng T1(NMe2)2(pyrr )2(NHMe2) (19) to the

hydroamination of aniline and 1-phenylpropyne resulted in extremely slow catalysis.

The reaction of 2 equivalents of 3-prrrC6F5 with Ti(NMe2)4 (3) does not yield the
anticipated bis(pyrrolyl) complex. Variable temperature experiments on the orange solid
from the reaction mixture suggest ligand exchange is occurring to give a mixture of
titanium complexes that are relatively hydroamination inactive.

While the bis(3-arylpyrrolyl) titanium complex resulted in disappointing catalysis,

fast hydroamination kinetics were achieved with Ti(NMe2)3(pyrr2'CF3'4'C6F5) (20). The
comparison of 20 relative to Ti(NMe2)2(pyrrmeS)2 (13) and Ti(indenyl)Me2 (21) under

identical reaction conditions shows that the 20 is significantly faster than the bis(pyrrolyl)
complex 13 and the Cp-based system 21. Whether the faster rates with 20 are due to
electronic factors resulting from the different ligand architecture or steric constraints, or a
combination of the two effects is currently unknown, which is subject of ongoing
scrutiny.

The further optimization of these 3-aryl pyrroles towards the synthesis of more

reactive titanium catalysts is addressed in the following chapter.

70

3.4 Experimental

General Considerations: All manipulations of air sensitive compounds were
carried out in an MBraun drybox under a purified nitrogen atmosphere. Anhydrous ether
was purchased from Columbus Chemical Industries Inc. Pentane and toluene were
purchased from Spectrum Chemical Mfg. Corp. These were purified by sparging with dry
N2, then dried by running through activated alumina systems purchased from Solv-Tek.
Hexanes and ethyl acetate were purchased from Mallinckodt Baker Inc. Pinacolborane
was purchased fi'om BASF and was used as received. N-Boc-pyrrole was vacuum
distilled and stored under a purified nitrogen atmosphere over molecular sieves. Di-tert-
butyl-dicarbonate (Boc anhydride) was purchased from Oakwood Chemical and was used
as received. Aniline was purchased from Matheson Coleman and Bell Mfg. and was
distilled twice from calcium hydride under vacuum. l-phenylpropyne was purchased

from GF S Chemical, distilled under vacuum, and then passed over two columns of

neutral alumina. Ti(NMe2)4,7 2-[3,5-bis(trifluoromethyl)phenyl]-1H-pyrrole (prrr3’5’
C173)? and Ti(indenyl)2(Me)210 were synthesized according to literature methods.

Deuterated solvents were dried over purple sodium benzophenone ketyl (C6D6) or
phosphoric anhydride (CDCl3) then distilled under a nitrogen atmosphere. Deuterated
toluene was dried by passing it through two columns of neutral alumina. 1H and 13C
spectra were recorded on Inova-300 or VXR-SOO spectrometers. All spectra were
referenced internally to residual protiosolvent (H) or solvent (13C) resonances.

General Considerations for X—Ray Diffraction. Crystals grown from concentrated
solutions at —35 °C quickly were moved fi'om a scintillation vial to a microscope slide

containing Paratone N. Samples were selected and mounted on a glass fiber in wax and

71

Paratone. The data collections were carried out at a sample temperature of 173 K on a
Bruker AXS platform three-circle goniometer with a CCD detector. The data were
processed and reduced utilizing the program SAINTPLUS supplied by Bruker AXS. The
structures were solved by direct methods (SHELXTL v5.1, Bruker AXS) in conjunction
with standard difference Fourier techniques.

General Procedure for Kinetics. All manipulations were done in an inert
atmosphere drybox. In a 2 mL volumetric flask was loaded the catalyst (10 mol %, 0.1
mmol), aniline (0.931 g, 911 14L, 10 mmol), l-phenylpropyne (0.116 g, 125 uL, 1 mmol),
and ferrocene (0.056 g, 0.3 mmol) as an internal standard. The solution was then diluted
to 2 mL with deuterated toluene. An ample amount of solution (~0.75 mL) was put into a
threaded J. Young tube that was sealed with a cap and then wrapped with Teflon tape.
The tube was then removed from the drybox and heated at 75 or 100 °C in the NMR
spectrometer. The relative l-phenylpropyne versus ferrocene concentration was
monitored as a function of time. The fits are to the exponential decay of the starting

material using the scientific graphing programs Origin or KaleidaGraph. The exact

kObst where Y = [1-

expression used to fit the data was Y, = Yoo + (Yo - Yoo) exp-

phenylpropyne] at time = t (Y t), infinity (Yoo), or initial (Yo).8 The variables 1’00, Y0, and

kobs were optimized in the fits.

72

Synthesis of 3-(3,5-bis(trifluoromethyl)phenyl)-lH-pyrrole (3-prrr3HF3)

\ZI

CF3
F3C

Under an atmosphere of dry N2, tetrakis(triphenylphosphine)palladium (0.817 g, 0.07
mmol) was loaded into a 20 mL scintillation vial in DME (5 mL). To the same vial was
added 3,5-bis(trifluoromethyl)bromobenzene (4 g, 13.69 mmol), and the two were stirred
10 min before being transferred to a Schlenk tube. To the Schlenk tube was added 3-
(pinacolboryl)-N-Boc-pyrrole (3.9 g, 13.31 mmol) in DME (10 mL). Finally, K3P04
(5.31 g, 19.97 mmol) was added. The tube was capped, taken out the dry box, and
connected to a Schlenk line. The headspace of the Schlenk tube was removed, and the
vessel was placed in a 100 °C oil bath for 24 h. When the reaction was complete as
judged by GC-FID, the solution was transferred to a separatory funnel. The tube was
rinsed with OEt2 (30 mL) and H20 (30 mL). The solution was extracted with OEt2 (2 x
50 mL). The combined organic layers were collected and dried over MgSO4. The
solution was filtered and volatiles were removed in vacuo to yield a viscous oil. The oil
was then transferred to a threaded Schlenk tube equipped with a stirbar. Then it was
placed under a continuous flow of N2. The reaction vessel was heated in an oil bath at
170 °C with stirring for ~ 20 min. The black solution was then run through a plug of
silica gel with methylene chloride (500 mL). The volatiles were removed in vacuo to
yield a white solid (2.81 g, 76%). M.p. 106-109 °C lH NMR(CDC13, 500 MHz): 8.37 (br

s, 1 H), 7.90 (s, 2 H), 7.65 (s, 1 H), 7.18 (m, 1 H), 6.87 (q, 1 H), 6.58 (m, l H). 13C {'H}

73

NMR (CDC13, 125 MHz): 138.04, 131.81 (q, Jcp = 31.51 Hz), 124.85 (dd), 123.77 (q, 1cF
= 277.72 Hz), 122.53, 119.78, 118.77 (sept., Jcp = 4.63 Hz), 115.74, 106.63. Anal.

(Found) Calcd: C, (51.63) 51.29; H, (2.53) 2.33; N, (5.02) 5.03.

74

Synthesis of 3-(perfluorophenyl)-lH-pyrrole

H
N
l /

Under an atmosphere of dry N2, tetrakis(triphenylphosphine)palladium (0.107 g, 0.092
mmol) was loaded into a 20 mL scintillation vial in DME (5 mL). To the same vial was
added pentafluorobromobenzene (2.2 g, 8.9 mmol), and the two were stirred 10 min
before being transferred to a Schlenk tube. To the tube was added 3-(pinacolboryl)-N-
Boc-pyrrole (2.63 g, 8.98 mmol) in DME (10 mL). Finally, K3PO4 (3.58 g, 13.46 mmol)
was added. The tube was capped, taken out the dry box, and connected to a Schlenk line.
The headspace was removed, and the vessel was placed in a 100 °C oil bath for 8 d.
When the reaction was complete as judged by GC-F ID, the tube was rinsed with OEt2 (30
mL) and H20 (30 mL). The solution was transferred to a separatory funnel and extracted
with OEt2 (2 x 50 mL). The combined organic layers were collected and dried over
MgSO4. The solution was then filtered and the volatiles removed in vacuo to yield a
viscous oil. The oil was then transferred to a threaded Schlenk tube equippedwith a
stirbar. Then it was placed under a continuous flow of N2. The reaction vessel was
heated in an oil bath at 170 °C with stirring for ~ 20 min. The black solution was then
run through a plug of Silica gel with methylene chloride (500 mL). The volatiles were
removed in vacuo to yield a white solid (1.1 g, 53%). M.p 48-51 °C. 1H NMR (CDC13,
500 MHz): 8.46 (s, 1 H), 7.29 (s, 1 H), 6.89 (app s, 1H), 6.68 (app s, 1 H). ”C {'H}

NMR (CDCl3, 125 MHz) 6 145.10-144.08 (m), l43.05—142.98 (111), 13941-13929 (m),

75

13899-13888 (m), 137.41-137.29 (m), 137.18-36.93 (m), 119.48 (t, Jcp = 6.81 Hz),
118.43, 111.23-110.01 (m), 109.34 (t, Jcp = 5.98 Hz). Anal. (Found) Calcd: C, (51.37)

51.52; H, (1.72) 1.73; N, (5.85) 6.01.

76

Synthesis of Ti(NMezh(3-pyrr3’5'CF3)2(NI-1Me2) (19)

NHM92
CF3
MezNuuh'll‘NS/Q
Me N’| -" 01:3
N
\ /
CF3
F3C

Under an atmosphere of dry N2, 3-prr3’5'CF3 (0.283 g, 1.01 mmol) was loaded into a 20
mL scintillation vial in OEt2 (3 mL). In a separate vial was loaded Ti(NMe2)4 (3) (0.113

g, 0.506 mmol) in OEt2 (3 mL). The two vials were capped and put into a cold well,

3 5—CF3

where they sat until frozen. 3-prrr ’ was added to the vial containing 3 and the

solution was allowed to warm to room temperature where it was left to stir for 6 h. After
6 h the solution was concentrated in vacuo to yield a red oil. The oil was then triturated
with pentane to yield a red solid. The solid was crystallized from pentane to yield
Ti(NMe2)2(NHMe2)(pyrr3’5.C173 )2 as a red solid (0.285 g). Due to probable isomerization
of 19 in solution, the 1II and '3C spectra recorded were not consistent with the solid

structure. See Appendix for 1H and '3 C spectra for 19.

77

Synthesis of 2-(bis(trifluoromethyl)phenyl)-4-pentafluorophenyl-pyrrole

 

Under an atmosphere of dry N2, [Ir(OMe)(Cod)]2 (0.1g, 0.151 nnnol) was loaded into a

20 mL scintillation vial with hexane (4 mL) and HBpin (1.92 g, 15 mmol) and stirred for

10 min prior to the addition of Butbipy (0.081 g, 0.302 mmol) which was then stirred for

another 10 min. To the same vial was added N-Boc-Z-(3,5-
(bistrifluoromethyl)phenyl)pyrrole (3.8 g, 10 mmol) in hexane (5 mL). The resulting
reaction mixture was then transferred to a Schlenk tube, sealed, taken out of the dry box,
and put in a 60 °C oil bath for 36 h. After the reaction was complete by GC-FID, the
crude mixture was run through two plugs of silica gel with copious amounts methylene
chloride. The volatiles were removed in vacuo to yield a clear oil. Trituration with
pentane yielded and N-Boc-2-(3,5-(bistrifluoromethyl)phenyl)-4-pinacolboryl-pyrrole
compound as a white solid. The product was used without any further purification. Under
an atmosphere of dry N2, a 20 mL scintillation vial was loaded with Pd(PPh3)4 (0.140 g,
0.120 mmol) in DME (5 mL), BrC6F5 (0.632 g., 2.57 mmol), and N-Boc-2-(3,5-
(bistrifluoromethyl)phenyl)-4-pinacolboryl-pyrrole (1.18 g., 2.33 mmol). The solution
was transferred to a Schlenk tube, sealed, removed from the dry box, and connected to a
Schlenk line. Under a continuous flow of N2, the cap was removed, K3POa was added to

the vessel, and the vessel was quickly capped. The headspace in the Schlenk tube was

78

evacuated and the tube was heated in an oil bath at 100 0C for 8 d. After 8 d the reaction
mixture was transferred to a separatory funnel. The tube was rinsed with H20 (30 mL)
and EtOAc (30 mL). The solution was extracted with EtOAc (3 x 30 mL). The combined
organic layers were collected and dried over MgSOs. The volatiles were removed in
vacuo to yield a viscuous oil. The oil was transferred to a Schlenk tube and placed in a
165 °C oil bath for 10 min under a continuous flow of N2. After 10 min the crude
mixture was run through a plug of silica with methylene chloride (500 mL). The volatiles
were removed in vacuo to yield a pale pink solid. Crystallization from pentane yielded
the product as a pale pink solid (0.2, 19.2 %). M.p 146-149 °C. 1H NMR (500 MHz,
CDCl;): 9.01 (br s, 1 H), 7.90 (s, 2 H), 7.72 (s, 1 H), 7.42 (s, 1 H), 7.06 (s, 1 H). ”C {‘H}
NMR (125 MHz, CDC13): 133.75, 132.52 (q, JCF = 33.9 Hz), 129.79, 123.18 (q, IQ}? = 276
Hz), 123.8-123.58 (m), 122.12, 122.14-121.9 (m), 120.19-119.5 (m), 111.88, 110.9-
110.05 (m), 109.1-108.85 (m). Anal. (Found) Calcd: C, (48.11) 48.56; H, (1.27) 1.36; N,

(3.22) 3.15.

79

Synthesis of Ti(NMez)3(pyr2-CF3-4-C6F5

) (20)

 

Under an atmosphere of dry N2, Ti(NMe2)4 (3) (0.05 g, 0.223 mmol) was loaded into a 20
mL scintillation vial in OEt2 (2 mL). In a separate vial was loaded 2-(3,5-
(bistrifluoromethyl)phenyl)-4-pentafluoropheny pyrrole (0.1 g, 0.223 mmol) in OEt2 (2
mL). The vials were placed in a cold well where that sat until frozen. While still cold,
prrrZ'CF3'4'C6F5 was added to the vial containing 3. The solution was allowed to stir at
room temperature for ~18 h. The following day the volatiles were removed in vacuo to
yield a yellow solid. Crystallization from OEt2/pentane yielded the title compound as a
yellow solid (0.12 g 86%). M.p 76-79 °C. 1H NMR (500 MHz, CDC13) 7.85 (2 H, S),
7.70 (1 H, s), 7.37 (1 H, s), 6.80 (1 H, s), 3.13 (18 H, s). ”C {‘H} NMR (125 MHz,
CDC13): l45.1-l44.80 (m), 142.98-142.5 (m), 138.45, 139.05-138.73 (m), 137.51- 136.97
(in), 131.46 (q, Jcp = 33 Hz), 131.47-131.25 (m), 126.88 (q, Jcp = 3.5 Hz), 126.75, 123.55
(q, Jcp = 273 Hz), 119.41-119.21 (m), 111.60-111.49 (m), 110.82-110.67 (m), 43.74.

Anal. (Found) Calcd: C, (46.25) 46.17; H, (3.73) 3.71; N, (8.86) 8.97.

80

3.5 References

1.

9.

(a) Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.; Odom, A. L. Chem. Commun. 2003, 5,
586. (b) Cao, C.; Li, Y.; Shi, Y.; Odom, A.L. Chem. Commun, 2004, 17, 2002. For
some recent reviews on hydroamination see: (a) Odom, A. L. Dalton Trans. 2005,
225. (b) Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem Rev.,
2008, 108, 3795.

Cao, C.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2003, 125, 2880.

. Banerjee, S.; Barnea, E.; Odom, A. L. Organometallics, 2008, 27, 1005.

Swartz II, D. L.; Odom. A. L. Organometallics, 2006, 25, 6125.

. For some additional reports on iridium catalyzed borylation/coupling reactions see.

(a) Paul, S.; Chotana, G. A.; Holmes, D.; Reichle, R. C.; Maleczka, R. E.; Smith III,
M.R. J. Am. Chem. Soc. 2006, 128, 15552. (b) Holmes, D.; Chotana, G. A.;
Maleczka, R. E.; Smith III, M. R. Org. Lett. 2006, 8, 1407. (c) Chotana, G. A.; Rak,
M. A.; Smith III, M. R. J. Am. Chem. Soc. 2005, 127, 10539. (d) Boebel, T.A.;
Hartwig, J. F . Organometallics, 2008, 27, 6013. (e) Ishiyama, T.; Takagi, J.; Ishida,
K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc., 2002, 124, 390.

Heutling, A.; Pohlki, F.; Doye, S. Chem. Eur. J. 2004, 10, 3059.
Bradley, D. C.; Thomas, I. M. J. Chem. Soc. 1960, 3859.

Espenson, J. H. Chemical Kinetics and Reaction Mechanisms; McGraw-Hill: New
York, 1995.

Rieth, R. D.; Mankad, N. P.; Calimano, E.; Sadighi, J. P. Org. Lett. 2004, 6, 3981.

10. Balboni, D.; Carnurati, 1.; Prini, G.; Resconi, L. Inorg. Chem. 2001, 40, 6588.

81

CHAPTER 4
Synthesis, structure, and hydroamination kinetics of 3,3’-diaryldipyrrolylmethane
titanium complexes

4.1 Introduction

Dipyrrolylmethane ligands on titanium are effective catalysts for the
hydroamination of primary amines and alkynes as well as iminoamination.l The fastest
hydroamination catalyst in the literature as of 2008 was Ti(NMe2)2(dpm) (9), where dpm
is 5,5-dimethyldipyrroly1methane (Figure 4.1).2 The previous chapters have discussed the
approaches taken to alter the dpm framework to improve catalyst reactivity with hopes of
generating more reactive catalysts and applying them to multi-component coupling
reactions. However, every attempt to prepare a catalyst more active than 9 has been

unsuccessfiil.

N

N/Ti(NMe2)2
/

Ti(NMe2)2(dpm) (9)

Figure 4.1 Solid-state structure of Ti(NMe2)2(dpm) (9).

Putting sterics on the 2-position of the dpm framework results in decreased
hydroamination reactivity, which is attributed to steric inhibition near the substrate
binding site.2 In the same report, it was shown experimentally with bis(pyrrolyl) titanium
catalysts, that the hydroamination reactivity increases with electron-withdrawing
substituents. Moving sterics from the 2-position to the 3—position on the dpm framework
could result in faster catalysis than Ti(NMe2)2(dpm) (9). This chapter discusses the
synthesis, structure, and hydroamination kinetics of 3,3’-diaryldipyrrolylmethane

titanium complexes.

82

4.2 Results and discussions

The synthesis of 3-arylpyrrole complexes is greatly enabled by contributions from
Smith and co-workers who demonstrated the selective generation of 3-(pinacolboryl)-N-
Boc-pyrrole, which can then be coupled with aryl halides using a palladium catalyst.
(Scheme 4.1).3

Scheme 4.1 Synthesis of 3-aryl pyrroles.

 

 

Boc
Boc Pd lPhos hine
U N l 1 p Boc
[Ir] | / Ar—X, Base N
+ t = Q
BPin
H Ar

0
\
’m

HBPin

Using this synthetic procedure I prepared 3-(3,5-(CF3)-C6H3) PYITOIC (3-HPYIT3’5—

CF3) and 3-(2,4,6-(F)3-C6H2) pyrroles (3-prrrC6F3

) to use as starting materials for 3-
substituted dpm derivatives. The decision to use these two pyrroles was driven by a few

initial results. First, it was shown experimentally that electron-withdrawing substituents

on pyrrolyl ligands increase hydroamination catalysis rates. Therefore, the ligands'should

3,5—CF3

be electron deficient. Second, a comparison of Ti(NMe2)2(pyrr ) (14), which has

two CF3 groups in the meta positions of the arene, and Ti(NMe2)2(pyrr4'CF3)2 (16), which

has one CF 3 group in the para position on the arene, had similar catalysis rates (Table
4.1). For that reason, I wanted to see what effect placing electron-withdrawing groups at

the ortho and para positions had on the catalysis activity.

83

Table 4.1 Comparison of hydroamination catalysis rate constants

3,5—CF 3

Ti(NMe2)2(pyrr )2 (14) and Ti(NMe2)2(pyrr4'CF3)2 (16) from Chapter 2. The

reaction conditions are shown in Scheme 4.4. Rates are at the 99% confidence level with

at least 3 repeated runs.

 

 

Entry Catalyst kobs (x104 S-l)
F,c CF,
1 1275 :t 72
(Me,N),Ti N \
f — )2
14

CF,
2 1255 :t 145
(MepN)2Tl~CN \ >
— 2
16

The usual procedure for the synthesis of 2,2’-diaryldipyrrolylmethanes involves
the neat reaction of 2-aryl pyrroles in excess acetone with a catalytic amount of
trifluoroacetic acid (TFA). However, using these reaction conditions with 3-aryl pyrroles
did not yield the corresponding 3,3’-diary1dipyrrolylmethane derivatives. Switching to a

Lewis acid, InC13, catalyzes the reaction of 3-ary1 pyrroles and acetone to yield two new
3,3’-diaryldipyrroly1methanes, 3-H2dpm3’5_CF3 and 3-H2dpmc‘5F3 in 76% and 14%

isolated yields. These complexes react with Ti(NMe2)4 (3) to yield two new titanium

84

3,5—CF3 C6133)

precatalysts, Ti(NMe2)2(NHMe2)(dpm ) (22) and Ti(NMe2)2(NHMe2)(dpm

(23) in 92% and 86% crystallized yields (Scheme 4.2).

  

 

 

 

Scheme 4.2 Synthesis of 3-H2dpm3’5—CF3, 3-H2dme6F3,
. 3,5—CF3 . C6F3
T1(NMe2)2(NHMe2)(dpm ) (22) and T1(NMe2)2(NHMe2)(dpm ) (23).
CFs CF,
ll 0 40/ l Cl 0
°° n 3 F C
+ excess 4, s
' / A 40 °C, 18 h CF,
74%
CF, H
F30 3-H2dpm3'5‘CF3
3-prrr3-5'CF3
Ti(NMez)4 (3)
92% 0512
N O 10/ l Cl
00 n 3
+ excess ..
' / 2K 40 °C, 18 h
F 43%
F
F
Ci-prrrc’fiF3
Ti(NM92)4 (3)
860/0 OEt2
12 h

Ti(NM82)2(NHM62)(dme6F3) (23)

85

The solid-state structure of 22 has a pseudo trigonal bipyramidal (tbp) geometry
with the pyrrolyls 111,1]1-bound. The 1H NMR spectrum is consistent with the solid-state
structure showing equivalent pyrrolyls. There is a broad Singlet at 2.61 ppm in the 1H
spectrum that integrates to 6 hydrogens, which are assigned to the methyl groups on
dimethylamine. As expected, the longest Ti-N bond length is for the dimethylamine
ligand at 2.135(17) A, which sits in the equatorial plane.

Attempts to grow X-ray quality crystals of 23 are currently underway. The 'H
NMR Spectrum of 23 is similar to 22, showing equivalent pyrrolyls and a broad singlet at
2.49 ppm corresponding to 6 hydrogens, which are assigned to the methyl groups on a

coordinated dimethylamine.

86

H532) F(531)

F(551),,. '
F(553) . 8'
3 ~‘ "“‘F(533)
‘13 a
F(552) 1' ,,

Q
Q
Q 0
1:“(433) . . 321,045,)

“185131 ‘5 1'
,6, ( )F(451’

Figure 4.2 Solid-state structure of Ti(NMe2)2(NHMe2)(3-dpm3’5_CF3) (22) from

single crystal X-ray diffraction. Selected bond distances (A) and bond angles (deg): Ti-
N(1) 1.931(18), Ti-N(2) 1.826(13), Ti-N(3) 2.135(17), Ti-N(4) 2.051(9), Ti-N(5)
2.067(9), N(1)-Ti-N(2) 109.6(9) N(2)-Ti-N(3) 97.7(7), N(3)-Ti-N(4) 84.8(5), N(4)-Ti-
N(5) 82.3(4), N(2)-Ti-N(4) 108.8(6), N(2)-Ti-N(5) 102.8(5), N(3)-Ti-N(5) 158.4(6),
N(1)-Ti-N(3) 87.2(7), N(1)-Ti-N(4) 141.4(8), N(1)-Ti-N(5) 92.2(6).

To test the kinetic ability of these catalysts compared to Ti(NMe2)2(dpm) (9),
precatalysts 22 and 23 were tested under the kinetic conditions reported in Chapter 2
(Scheme 4.3).2 In addition to running the reactions at 75 °C in toluene-d3 in the NMR

probe, they were also run at 75 °C in a reaction calorimeter.4’5 The disappearance of the

87

 

l-phenylpropyne starting material versus time was used to fit the first-order equations as
measured by 1H NMR spectroscopy. Alternatively, integrated heat flow versus time, t,
divided by the total heat of reaction would be used to give the percent conversion, which
also fit well to first order equations.6 The methods were consistent with each other,
producing the same rate for each catalyst. The results of the kinetic studies on compounds
9, 22, and 23 are shown in Table 4.2. The errors are based of at least three repeated runs
and are at the 99% confidence level. The errors varied from as little as 7% to as much as
10%.
Scheme 4.3 Reaction conditions for kinetic study

Me 10% catalyst 0.05 M NPh

 

 

10 NH2Ph + é 4,
Ph/ toluene-d8, 75 °C /u\/ Ph
5 M 0.5 M
d 1- hen ro ne
1 P th'P DY l = kobst

From the data in Table 4.2, 3-aryl substitution on the dpm results in an increase in
rate constant by a factor of about 3.5. As anticipated, adding electron-withdrawing groups“
without increasing steric congestion around the metal results in catalysis faster than
Ti(NMe2)2(dpm) (9). The reaction of aniline and l-phenylpropyne is smoothly catalyzed

by 22 and 23 in ~1 h with rate constants of (6963 s 582) and (6225 a 614) x 10‘7 s“.

88

Table 4.2. Representative catalysis rates for Ti(NMe2)2(dpm) (9),

 

 

Ti(NMe2)2(NHMe2)(3-dpm3’5“CF3) (22) and Ti(NMe2)2(NHMe2)(3-dme6F3) (23).
Entry cataIYSt kObS (X104 S-l)a
1
Ti(NMe2)2(dpm) 1976 :l: 130
9
2 Ti(NMe2)2(NHMe2)(3-dpm3’5_CF3) 6963 :1: 582
22
3 Ti(NMe2)2(NHMe2)(3-dme6F3) 6225 t 614
23

a Errors are based at 99% confidence level with at least 3 repeated runs.

89

4.3 Conclusions

Using readily prepared 3-substituted pyrroles, a route to 3,3’-
diaryldipyrrolylmethanes has been developed where the synthesized pyrroles can be used
as the limiting reagent in condensation with acetone. Placing these new ligands on
titanium is readily accomplished by reaction with Ti(NMe2)4 (3), and the resulting
complexes Show nl,nl-coordination of the dipyrrolylmethane in the solid-state. The
increased electrophilic nature of the metal center allows for dimethylamine retention.

Catalysis with these new complexes was faster than the dpm parent complex 9,
suggesting that electron-withdrawing groups increase hydroamination reactivity.
However, strategic positioning of the electron-withdrawing groups did not result in a
significant difference in catalysis rate, which can be attributed to the choice of electron-
withdravving substiuents. While CF3 and F are good o-withdrawing groups, it is possible
for F to be a rt-donor negating some of the electron-withdrawing ability. Investigations
are currently underway with using just CF 3 substitution in ortho/para positions on the

arene to see if there is a Significant difference in catalysis rate.

90

 

4.4 Experimental

General Considerations: All manipulations of air sensitive compounds were
carried out in an MBraun drybox under a purified nitrogen atmosphere. Anhydrous ether
was purchased from Columbus Chemical Industries Inc. Pentane and toluene were
purchased from Spectrum Chemical Mfg. Corp., were purified by sparging with dry N2,
then dried by running through activated alumina systems purchased from Solv-Tek.
Hexanes and ethyl acetate were purchased from Mallinckodt Baker Inc. Pinacolborane
was purchased from BASF and was used as received. 1-bromo-3,5-
bis(trifluoromethyl)benzene and 2-bromo-l,3,5-trifluorobenzene were purchased from
Matrix Scientific and dried by passed over a column of neutral alumina. N-Boc-pyrrole
was purchased from Aldrich, vacuum distilled, and stored under a purified nitrogen
atmosphere over molecular sieves. Aniline was purchased from Matheson Coleman and
Bell Mfg. and was distilled twice from calcium hydride under vacuum. l-phenylpropyne
was purchased from GFS Chemical, distilled under vacuum, and then passed over two
columns neutral alumina. Ti(NMe2)4,7 was synthesized according to the literature
procedure. Deuterated solvents were dried over purple sodium benzophenone ketyl
(C5D6) or phosphoric anhydride (CDC13) then distilled under a nitrogen atmosphere.
Deuterated toluene was dried by passing it through two columns of neutral alumina. 1H
and 13 C spectra were recorded on Inova—300 or VXR-500 spectrometers. All spectra were
referenced internally to residual protiosolvent ('H) or solvent (13C) resonances.

General Considerations for X-ray Crystallography: Crystals grown from
concentrated solutions in pentane at —35 °C were moved quickly from a scintillation vial

to a microscope slide containing Paratone N. Samples were selected and mounted on a

91

glass fiber in wax and Paratone. The data collections were carried out at a sample
temperature of 173 K on a Bruker AXS platform three-circle goniometer with a CCD
detector. The data were processed and reduced utilizing the program SAINTPLUS
supplied by Bruker AXS. The structures were solved by direct methods (SHELXTL v5.1,
Bruker AXS) in conjunction with standard difference Fourier techniques.

General Considerations for Kinetics: All manipulations were done in an inert
atmosphere drybox. In a 2 mL volumetric flask was loaded the catalyst (10 mol%, 0.1
mmol), aniline (0.931 g, 911 11L, 10 mmol), l-phenylpropyne (0.116 g, 125 11L, 1 mmol),
and ferrocene (0.056 g, 0.3 mmol) as an internal standard. The solution was then diluted
to 2 mL with deuterated toluene. An ample amount of solution (~0.75 mL) was put into a
threaded J. Young tube that was sealed with a cap and then wrapped with Teflon tape.
The tube was then removed from the drybox and heated at 75 °C in the NMR
spectrometer. The relative I-phenylpropyne versus ferrocene concentration was
monitored as a function of time.

For kinetics by reaction calorimetry, the same amounts of reagents were used. The
solution was added to the reaction vial and sealed with a Teflon cap minus 1-
phenylpropyne. The vial was taken out of the dry box and put in the calorimeter at 75 °C.
Once the solution had reached 75 °C, the alkyne was added via syringe. The progress of
the reaction was monitored by heat as a function of time, and the kinetic rates were
verified by 1H NMR spectroscopy.

The fits are to the exponential decay of the starting material or exponential growth

of the heat using the scientific graphing programs Origin or KaleidaGraph. The exact

_ t
expression used to fit the data was Y, = Yo, + (Y0 - Yoo)exp kObs where Y = [1-

92

 

phenylpropyne] at time = t (Y 1), infinity (1’00), or at the start of the reaction (Y0).8 The

variables Yoo, Y0, and kobs were optimized in the fits.

93

Synthesis of 3-(3,5-bistrifluromcthylphenyl-lH-pyrrole) (3-prrr3’5'CF3)

\ZI

CF3
F30

Under an atmosphere of dry N2 an oven dried 250 mL Schlenk tube was loaded with a
stirbar, Pd(PPh3)4 (0.536 g, 0.464 mmol) in DME (10 mL), 3,5-
bis(trifluoromethyl)phenylbromobenzene (4.54 g, 15.5 mmol) and N-Boc-3-
pinacolborylpyrrole (4.54 g, 15.5 mmol) in DME (20 mL). To that same vessel was
added K3PO4 (6.16 g, 23.15 mmol). DME (7 mL) was used to wash the sides of the tube.
The tube was then capped, removed from the drybox, and placed in an oil bath at 85 °C
for 18 h. After the reaction was complete as judged by GC-FID, the reaction mixture was
transferred to a separatory funnel with H20 (100 mL). The aqueous layer was extracted
and washed with ethyl acetate (3 x 75 mL). The combined organic layers were combined
and dried with MgSO4_ The volatiles were removed in vacuo to yield a viscous brown oil.
The oil was then transferred to that same 250 mL Schlenk tube with l-butanol (35 mL)
and K3PO4 (6 g, 23 mmol). The solution was then heated in an oil bath at 100 °C for 18 h.
The resulting solution was then transferred to a separatory funnel with H20 (75 mL)
water. The aqueous layer was extracted and washed with ethyl acetate (3 x 75 mL). The
combined organic layers were collected and dried with MgSOa. The volatiles were
removed in vacuo to yield a viscous brown oil. The product was then purified by column
chromatography on basic alumina with an elution of hexaneszethyl acetate (4:1) to yield

the product as an off white solid. The product was purified further by sublimation to give

94

a bright white solid (2.7 g, 62.5 %). lH NMR(CDC13, 500 MHz): 8.37 (br s, l H), 7.90
(s, 2 H), 7.65 (s, 1 H), 7.18 (m, 1 H), 6.87 (q, l H), 6.58 (m, 1 H). ”C {‘H} NMR
(CDC13, 125 MHz): 138.04, 131.81 (q, 1,, = 31.51 Hz), 124.85 (dd), 123.77 (q, JCF =
277.72 Hz), 122.53, 119.78, 118.77 (sep., 1c, = 4.63 Hz), 115.74, 106.63. Anal. (Found)

Calcd: C, (51.63) 51.29; H, (2.53) 2.33; N, (5.02) 5.03.

95

 

 

C8F6

Synthesis of 3-(2,4-bis(trifluoromethyl)phenyl)-lH-pyrrole (prr )

\ZI

CF,

CF3
Under an atmosphere of dry N2, a 200 mL Schlenk tube was loaded with 3-
(pinacolboryl)-N-Boc-pyrrole (4.86 g, 16.5 mmol), K3P04 (anhydrous) (3.51 g, 16.5
mmol), Pd2(dba)3 (0.216 g, 0.236 mmol) biphenyl-2-yldicyclohexylphosphine (0.165 g,
0.471 mmol) and a stirbar. The Schlenk tube was capped, removed from the drybox, and
connected to a Schlenk line. The headspace was evacuated and back filled with N2. The
cap was removed quickly under a continuous flow of N2 and replaced with a septum. A
60 mL syringe containing t-amyl alcohol (30 mL) and 1-bromo-2,4-
bis(trifluoromethyl)benzene (3.46 g, 11.8 mmol) was inserted into the septum with the
needle extending below the neck of the Schlenk tube, and the solution was added. The
septum and needle were removed quickly, and the tube was sealed with a screwcap. The
headspace was evacuated and filled with N2. This procedure was repeated 6 times. The
Schlenk tube was then placed in a 100 °C oil bath for 18 h. Once the reaction was
complete as judged by GC-FID, K3P04 (3 g, 14 mmol) and Bu"OH (OH) were added.
The reaction mixture was allowed to reflux for an additional 2 h at 100 °C. After the
deprotection, the resulting solution was poured into a separatory funnel with H20 (100
mL) and ethyl acetate (50 mL). The water layer was washed and extracted with ethyl
acetate (3 x 75 mL). The combined organic layers were collected and dried over MgSOa.

The volatiles were removed in vacuo to give a viscous red oil. The product was then

96

purified by column chromatography on silica gel using an elutant of CH2Cl2zhexanes
(7:3). This was followed by a second column on silica gel with hexaneszethyl acetate
(7:3) as elutants to give the product as a pale orange solid (2.6 g, 76%). M.p 27 - 30 °C
1H NMR (CDC13, 500 MHz): 8.35 (br s, l H), 7.99 (s, 1 H), 7.75 (d, 1 H, Jim = 8.14 Hz),
7.62 (d, 1 H, JHH = 8.14 Hz), 7.00 (s, 1H), 6.87-6.85 (m, 1 H), 6.45 (app s, 1 H). ”C {‘H}
NMR (CDC13, 125 MHz): 140, 132.79, 128.28 (q, Jcp = 33 Hz), 128.34 (q, Jcp = 30 Hz),
128.14-128.05 (m), 123.87 (q, Jcp = 278 Hz), 123.77 (q, Jcp = 271 Hz), 123.66-123.49
(m), 120.93, 118.30, ll7.91-117.83 (m), 10988-10983 (m). Anal. (Found) Calcd: C,

(51.26) 51.63; H, (2.42) 2.53; N, (4.87) 5.02.

97

 

Synthesis of 3-(2,4,6-trifluorophenyl)—lH-pyrrole (3-prrrC6F3)

Under an atmosphere of dry N2 a 200 mL Schlenk tube was loaded with 3-(pinacolboryl)-
N-Boc-pyrrole (4.16 g, 14.2 mmol), K3PO4 (anhydrous) (2.81 g, 13.2 mmol), Pd2(dba)3
(0.156 g, 0.173 mmol), biphenyl-2-yldicyclohexylphosphine (0.119 g, 0.346 mmol) and a
stirbar. The Schlenk tube was capped, removed from the drybox, and connected to a
Schlenk line. The headspace was evacuated and back filled with N2. The cap was
removed quickly under a continuous flow of N2 and replaced with a septum. A 60 mL
syringe containing t-amyl alcohol (30 mL) and 2-bromo-1,3,5-trifluorobenzene (2 g, 9.5
mmol) was inserted into the septum with the needle extending below the neck of the
Schlenk tube, and the solution was added. The septum and needle were removed quickly,
and the tube was sealed with a screwcap. The headspace was evacuated and filled with
N2. This procedure was repeated 6 times. The Schlenk tube was then placed in a 100 °C
oil bath for 18 h. Once the reaction was complete as judged by GC-FID, K3P04 (2 g, 9.4
mmol) and Bu"OH (8 mL) were added. The reaction mixture was refluxed for an
additional 2 h at 100 °C. After the deprotection, the resulting solution was poured into a
separatory firnnel with H20 (50 mL) and ethyl acetate (50 mL). The water layer was
washed and extracted with ethyl acetate (3 x 75 mL). The combined organic layers were
collected and dried over MgSOa. The volatiles were removed in vacuo to give a viscous

red oil. The flask containing the oil was connected to the Schlenk line and kept under

98

 

vacuum for 24 h. The product was then purified by column chromatography on silica gel
using of CH2Cl2zhexanes (7:3) as elutants. A second column on silica gel with of
hexaneszethyl acetate (4:1) as elutants gave the product as an off white solid, (0.958 g,
52%). 1H NMR (CDC13, 500 MHz): 8.38 (br s, 1 H), 7.28-7.27 (m, 1 H), 6.90-6.78 (m, 1
H), 6.77-6.71 (m, 3 H). 13C {H} NMR (CDC13, 125 MHz): 161.14-160.65 (m), 159.16-
158.69 (m), 118.74 (app t), 117.89, 110.76, 109.40 (app t), 100.54-100.09 (m). Anal.

(Found) Calcd: C, (60.50) 60.92; H, (3.14) 3.07; N, (6.84) 7.10.

99

Synthesis of 5,5'{propane-2,2-diyl)bis(3-(3,5-bis(trifluoromethyl)phenyl)-1H-

pyrrole) (3-H2dpm3’5'CF3)

 

An oven dried pressure tube was loaded with 3-(3,5-bistrifluromethylphenyl-lH-pyrrole)
(2.33 g, 8.35 mmol), acetone (13 mL, 10.27 g, 176 mmol), and a stirbar. To that tube was
added InC13 (0.3 g, 1.3 mmol). The tube was then capped and placed in an oil bath at 40
°C for 24 h. Once the reaction was complete as judged by 1H NMR spectroscopy, the
solution was transferred to a 250 mL round bottom flask, and the volatiles were removed
in vacuo. The resulting solid was put into a solution of hexaneszCH2Cl2 (7:3) (~35 mL).
A column was made using hexanes:CH2Cl2 (7:3). Once the crude mixture was loaded
onto the column, it was flashed with hexanes until spots appeared on the TLC plate. Once
material started appearing on TLC the elutant was changed to hexaneszCH2Cl2 (7:3).
Once the desired product appeared by TLC, the elutant was changed to just CH2Cl2 until
all the product had been collected. The fractions were collected, and the volatiles were
removed in vacuo to yield the product as a white solid, (1.9 g, 76 %) lH NMR (CDC13,
500 MHz): 8.03 (br S, 2 H), 7.87 (s, 4 H), 7.62 (s, 2 H), 7.06 (q, 2 H), 6.45 (q, 2 H), 1.74
(s, 6 H). ”C {'H} NMR (CDC13, 125 MHz): 140.67, 138.13, 132.09 (q, J,F = 32.14 Hz),
124.88, 123.77 (q, Jcp = 272.73 Hz), 122.46, 118.99 (pent, JCF = 4.11 Hz), 115.61,
102.73, 35.85, 29.19. Anal. (Found) Calcd: C, (53.88) 54.14; H, (3.31) 3.03; N, (4.51)

4.68.

100

Synthesis of 5,5'-(propane—Z,Z-diyl)bis(3-(2,4,6-trifluorophenyl)-lH—pyrrole) (3-

szme6F3)

 

A threaded pressure tube was charged with InCl3 (0.107 g, 0.0484 mmol), 3-(2,4,6-
trifluorophenyl)—lH-pyrrole (0.952 g, 0.483 mrnol), acetone (2.80 g, 3.55 mL, 4.83
mmol), and a stirbar. The tube was capped and placed in a 40 °C oil for 18 h. Once the
reaction was complete as judged by 1H NMR spectroscopy, the solution was transferred
to a 100 mL round bottom flask, where the volatiles were removed in vacuo to yield a
viscous orange oil. The product was purified by column chromatography on silica gel
using hexaneszethyl acetate (85:15) as elutants. The product was obtained as an off white
solid, (0.450 g, 43 %). 1H NMR (500 MHz, CDC13): 7.09 (s, 2H), 7.07-7.06 (m, 2 H),
6.75-6.65 (m, 4 H), 6.55-6.53 (m, 2 H). 13C {H} NMR (125 MHz, CDC13): 161.12-
160.67 (m), 159.12-158.72 (m), 138.68, 118.37 (1), 110.42, 110.05-109.83 (111), 105.12-
105.01 (m), 100.63-100.15 (m), 35.35, 28.96. Anal. (Found) Calcd: C, (63.11) 63.60; H,

(3.58) 3.31; N, (6.17) 6.48

101

 

Synthesis of Ti(NMe2)2(NHMe2)(3-dpm3’5‘C”) (22)

 

3,5—CF3

Under an atmosphere of purified N2, a vial was loaded with 3-H2dpm (0.503 g,

0.841 mmol) in OEt2 (3 mL). A separate vial was loaded with Ti(NMe2)4 (3) (0.188 g,
0.840 mmol) in OEt2 (3 mL). The two vials were placed in the cold well where they sat

3,5-CF3

until frozen. To the thawing solution, 3-H2dpm was added to the vial containing 3.

The solution was allowed to stir overnight. The next day, the volatiles were removed
under reduced pressure to give a red oil. The oil was triturated with pentane thrice to give
the product as a bright orange solid. The solid was crystallized from OEt2/pentane to
yield the title compound as an orange solid, (0.602 , 92%). 1H NMR (CDC13, 500 MHz):
7.83 (s, 4 H), 7.53 (s, 2 H), 7.07 (s, 2 H), 6.40 (s, 2 H), 3.37 (s, 12 H), 2.61 (br s, 6 H),
1.72 (s, 6 H). 13C {'H} NMR (CDC13, 125 MHz): 154.05 (m), 138.8, 131.5 (q,Jcp = 34
Hz), 124.4, 123.8 (q, Jcp = 270 Hz), 122.2, 121.8, 117.6, 100.9, 46.8, 40.5, 38.2, 31.1.

Anal. (Found) Calcd: C, (50.75) 50.98; H, (4.89) 4.54; N, (9.04) 9.01.

102

 

Synthesis of Ti(NMe2)2(NHMe2)(3_dme6F3

) (23)

 

Under an atmosphere of purified N2, a vial was loaded with 3-H2dpmc6F3 (0.130 g, 0.3

mmol) in OEt2 (3 mL). A separate vial was loaded with Ti(NMe2)4 (3) (0.067 g, 0. mmol)
in OEt2 (3 mL). The two vials were placed in the cold well, where they sat until frozen.

To the thawing solution, 3-H2dmeéF3

was added to the vial containing 3. The solution
was allowed to stir overnight. The next day the volatiles were removed under reduced
pressure to give a red oil. The oil was triturated with pentane twice to give the product as
a bright orange solid. The solid was crystallized from OEt2/pentane to yield the title
compound as an orange solid, (0.157 g, 86%). M.p 110-112 °C. 1H NMR (CDCl3, 500
MHz): 7.32 (s, 2 H), 6.72-6.64 (m, 6 H), 6.63 (s, 2 H), 3.24 (s, 12 H), 2.49 (br s, 6 H),

1.73 (s, 6 H).

103

4.5 References

1.

(a) Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.; Odom, A. L. Chem. Commun. 2003,
586. (b) Ramanathan, B.; Keith, A.J.; D. Armstrong D.; Odom, A.L. Org. Lett., 2004,
6, 2957. (c) Majumder, S.: Odom, A.L.; manuscripts in preparation.

2. Swartz, D.L.; Odom, A.L. Organometallics, 2006, 26, 6125.

3.

(a) Tse M.K.; Cho, J-Y.; and Smith, 111 MR. Org. Lett., 2001, 3, 2831. (b) Paul, S.;
Chotana, G.A.; Holmes, D.; Reichle, R.C.; Maleczka, R.E.; Smith 111, MR. J. Am.
Chem. Soc. 2006, 128, 15552.

. For a nice review on kinetics obtained using reaction calorimetry see. Blackmond, D.

G. Angew. Chem, Int. Ed. 2005, 44, 4302.

. For some additional reports on reaction calorimetry used in catalysis see. (a) Antonio

Jinu C. F.; Mathew, J. S.; Blackmond, D. G.; Ind. Eng. Chem. Res, 2007, 46, 8584.
(b) Mathew, J. S.; Klussmann, M.; Iwamura, H.; Valera, F.; Futran, A.; Emanuelsson,
E.A.C.; Blackmond, D. G.; J. Org. Chem, 2006, 71, 4711. (c) Blackmond, D. G.;
Ropic, M.; Stefinovic, M. Org. Process Res. Dev., 2006, 10, 457. (d) Shekhar, S.;
Ryberg, P.; Hartwig, J. F.; Mathew, J. S.; Blackmond, D. G.; Strieter, E. R.;
Buchwald, S. L. J. Am. Chem. Soc., 2006, 128, 3584.

6. Blackmond, D.G.; Rosner, T.; Pfaltz, A. Org. Process Res. Dev., 1999, 3, 275.

7. Bradley, D.C.; Thomas, I.M.; J. Chem. Soc., 1960, 3859.

8. Espenson, J. H. Chemical Kinetics and Reaction Mechanisms; McGraw-Hill: New

York, 1995.

104

 

CHAPTER 5

Effects of 5,5-substitution on dipyrrolylmethane ligand isomerization

5.1 Introduction

Dipyrrolylmethane ligands on titanium provide catalysts capable of extremely
fast hydroamination of alkynes with primary amines 2and very efficient catalysts for
iminoamination.3 One of the most commonly employed dipyrrolylmethane derivatives
is prepared from acetone and pyrrole in the presence of trifluoroacetic acid.4 The
product 5,5-dimethyldipyrrolylmethane (H2dpm) can be placed on titanium by
transamination with Ti(NMe2)4 (3) to provide Ti(NMe2)2(dpm) (9) (Scheme 5.1). 1’2

Scheme 5.1 Synthesis of H2dpm and Ti(NMe2)2(dpm) (9).

H o 10/ TFA ”N \ Ti(NMe) (a)
on 24
2° = = T' NM
U + )K 5min°,/ RT [H 01:12 / N/ '( e,),
N/ 90% ,

H2dpm T1(NMe2)2(dpm) (9)

 

 

In the solid state and in solution, 9 has a structure where the two pyrrolyl
substituents are inequivalent. One of the pyrrolyl rings adopts an 115-geometry, and the
other is til-bound. However, at room temperature in the 1H NMR spectrum the two
pyrroles appear equivalent due to fast exchange on the timescale of this spectroscopy.

Our research group previously reported the barrier for pyrrolyl exchange as AGI ~ 10

heal/mol.l

105

 

1,3 diaxial interactions

Figure 5.1 Use of 1,3-diaxial interactions to affect dipyrrolylmethane
isomerizations barriers.

The most likely mechanism for pyrrole exchange is conversion of both rings to
an Til-geometry} Methods for altering this barrier may provide clues for the active
species in catalyses and allow control of complex structure.

Previously,6 we have reported that altering the pyrrolyl ligand by placing aryl-
substituents in the 2-position of the dpm framework lowers the barriers associated
with pyrrolyl exchange, presumably by sterically destabilizing the 115-bonding mode.7
In fact placing a 3,5-bis(trifluoromethyl)phenyl or mesityl group in the 2-position of
the pyrrole lowers the pyrrolyl exchange barriers below what can be measured by
variable temperature NMR (<5 kcal/mol). However, addition of sterically hindered
groups in these positions hinders access to the metal center as well, affecting catalysis

{31637

106

 

Scheme 5.2 Synthesis of H2cpm, H2tmcpm, Ti(NMe2)2(cpm) (24) and

 

Ti(NMe2)2(tmcpm) (24).
0 Ft
Ll “(>9 10% TFA R R R
excess IL) + > H H
/ R R N N
\ I l /

H: Hchm, 43%
Me: Hztmcpm, 24%

Ti(NMez)4
o t,

 

 
    
 

/Ti’\"NM62
NM62

/

Z

R = H: T1(NM62)2(Cpm) (24)
R = Me: Ti(NMez)2(tmcpm) (25)

In an attempt to alter the pyrrolyl isomerization rates without blocking access to
the metal I explored the use of substituents in the dpm backbone. The strategy was to use
1,3-diaxial interactions within a cyclohexyl ring to stabilize the 115-bonding mode by
sterically inhibiting pyrrolyl-ring rotation (Figure 5.1). The steric interaction will be with
the axial pyrrolyl substituent, which will prefer to be in the 115-bonding mode allowing it
to present one side of the its-system to the cyclohexyl substituents rather than the larger
ring edge. By using gem-disubstitution, the 1,3-diaxial interactions are required
regardless of which ring is bound through the rr-face. The Size of R should affect the ease
with which the 115-bound ring can rotate to obtain the rill-bonding mode.

This chapter discusses the synthesis of 1,1-bis(a-pyrrolyl)cyclohexane ligands,

their titanium complexes, and the barriers for pyrrolyl exchange. The barriers were

107

determined using the Eyring method with kinetics from variable temperature spin
saturation magnetization transfer NMR spectroscopy. Consequently, the enthalpic and
entropic effects of this substitution were determined. All this data will be compared

with the Simple dimethyl compound 9.

108

 

5.2 Ligand Isomerization Study

I examined two cyclohexyl-dpm derivatives, which were easily prepared using
commercially available cyclohexanone and 3,3,5,5-tetramethylcyclohexanone as
shown in Scheme 5.2. The 1,1-bis(a-pyrrolyl)cyclohexane (H2cpm) and 1,1-bis(a-
pyrrolyl)-3,3,5,5-tetramethylcyclohexane (H2tmcpm) compounds were prepared in
43% and 24% isolated yields. The transamination reactions with Ti(NMe2)4 (3) and
both of these cyclohexyl derivatives occurs in high yields to provide R = H
Ti(NMe2)2(cpm) (24) and R = Me Ti(NMe2)2(tmcpm) (25).

The structure of the tetramethylcyclohexyl complex was determined by X-ray
diffraction. An ORTEP diagram is shown in Figure 5.2. The metric parameters around
titanium are quite similar to previously reported derivatives."2 The cyclohexyl group
has the expected chair-conformation with the iris-pyrrolyl in the more sterically
favorable axial position. This conformation puts the two axial methyl groups directly

over the ins-pyrrolyl.

109

 

 

 

 

Figure 5.2 ORTEP diagram of the X-ray diffraction model for Ti(NMe2)2
(trncpm) (25). Ellipsoids at the 50% probability level. Hydrogens are omitted for clarity.
Selected bond distances (A) and angles (°): Ti(1)-N(1) 2.292(2), Ti(1)-N(2) 2.023(1),
Ti(l)-N(3) 1.901(1), Ti(1)-N(4) 1.895(2); N(4)-Ti(1)-N(3) 103.49(6), N(4)-Ti(1)-N(2)

107.01(6), N(3)-Ti(1)—N(2) 101.47(6).

The increased steric interaction between the axial cyclohexane substituent and
the 115-pyrrolyl Jr-face raises the barrier for pyrrolyl exchange as can be seen in the 1H
spectrum at room temperature. There is significant line broadening in the room
temperature lH spectrum, which indicates that the coalesense point is nearly reached
at this tempertature. Cooling a solution of 24 in CDCl3 to —40 °C provided a spectrum
of the 111,115 -complex. The 1H NMR spectra of 24 at room temperature and at —40 °C

is shown in Figure 5.3.

110

 

 

Variable temperature spin-saturation magnetization transfer was used to
determine the barriers for pyrrolyl equilibration for Ti(NMe2)2(dpm) (9),
Ti(NMe2)2(cpm) (24), and Ti(NMe2)2(tmcpm) (25). As an example, the Eyring plot
for Ti(NMe2)2(tmcpm) (25) is shown in Figure 5.4.

Figure 5.3. 1H spectra of 24 at room temperature and —40 °C in CDC13.

25 °C

 

 

‘
I
..
4
1

d
J
4
1
q

C

q

u-
N-J
—

—40 °C

 

 

 

 

lll

 

 

Figure 5.4 Eyring plot of pyrrolyl exchange in Ti(NMe2)2(tmcpm) (25).

I —y-m.107-M.OI RIO“

.3’ ......... ..........1.z--.
0.” 0.0030 0.004 0.0041 0.0042 GM

1”

 

 

The plot in Figure 5.4 is of ln(k/1') versus UT and is used with the Eyring
Equation (Equation 5.1), where k3 = Boltzmann constant and R is the gas constant, to

determine the activation parameters under the usual assumptions of Transition State

Theory.8 Consequently, the slope (m) can be used to determine AHI using Equation
5.2, and the intercept (b) can be used to determine ASI using Equation 5.3.
ln(.]_(. AS: + In .k_B _ E
T R 11 RT (5'1)
Ali!“t a-me (5.2)

A51 -R[b-ln(kTB)] (5.3)

The parameters for the pyrrolyl exchange in compounds 9, 24, and 25 can be
found in Table 5.1. The enthalpic barriers increase from approximately 12 kcal/mol to
over 17 kcal/mol for 9, 24, and 25 reflective of the greater steric interactions on

attempting to rotate the 115-pyrrolyl substituent during the exchange in the

112

 

 

tetramethylcyclohexyl complex.

Table 5.1 Parameters for pyrrolyl exchange for 9, 24, and 25 at 25 °C.

 

 

AH“ As“ AG“
(kcal/mol) (cal/mol0K) (kcal/mol)

Ti(NMe2)2(dpm) 1 1.8 5 .2 10.3
(9)

Ti(NMe2)2(cpm) 14.1 5.1 12.6
(24)

Ti(NMe2)2(tmcpm) 17.2 12.7 13.4
(25)

 

 

The entropic parameters are the same, small and positive, for the 5,5-
dimethyldipyrrolyl 9 and cyclohexyldipyrrolyl 24 during the exchange. The
tetramethyl complex 25 shows a substantial increase in AS1 to 13 cal/mOIOK, which is
quite a large positive value for a unimolecular process. The increase in entropy in the
transition state suggests that the ground state is highly ordered. This may be due to
the single preferred conformation when one of the pyrroles is in the ins-conformation
as opposed to the more conformationally flexible nl-conformation where neither chair
conformer will be strongly favored and any C—C rotations difficult in the 111,115-
conforrner will be more readily allowed.

AS Shown in Table 5.1, the difference in exchange barriers between 9 and 24
are largely enthalpic and presumably caused by the 1,3-diaxial interactions. In
contrast, the difference in barriers between, 9 and 25, is more complex. The enthalpic
barrier to reach the transition state for exchange is ~5 kcal/mol higher for 3, but the

entropic term reduces the overall barrier to 13.4 kcal/mol.

113

 

 

5.3 Conclusion

Cyclohexyl substituents in the backbone of the dipyrrolylmethane ligand can
be used to affect pyrrolyl exchange barriers. The difference in sterics for the 115-
pyrrolyl and til-pyrrolyl groups can be used to alter this barrier. While placing gem-
dimethyl groups on the 3-carbon of the cyclohexyl ring increases the enthalpic cost to
pyrrolyl exchange substantially (increased ~50% relative to 9), the entropic factor for
sterically hindered 25 cancels some of the enthalpic increases. Consequently, the free
energy barrier only increased by a modest 3 kcal/mol using this strategy.

All three of these compounds were evaluated for catalysis using the same
hydroamination test conditions used previously.6 All three exhibited the same rate for
catalysis, indicating that altering the isomerization barriers to the level possible here
did not affect the catalysis rates, which is consistent with the rate limiting step not
being associated with this isomerization. This is not unexpected as barriers associated
with the isomerization are relatively small for this titanium system.

The same methodology used here may prove useful to study pyrrolyl coordination
effects in systems where the isomerization has a much larger enthalpic barrier. In
addition, this strategy using cyclohexane-based dipyrrolylmethanes potentially could be
used to control complex chirality by using asymmetric cyclohexane substituents in

systems with a larger tendency to stay in the 111,115 -coordination mode.

114

5.4 Experimental

General Considerations: Anhydrous ether was purchased from Columbus
Chemical Industries Inc., and pentane and toluene was purchased from Spectrum
Chemical Mfg. Corp., were purified by sparging with dry N2, then water was removed
by running through activated alumina systems purchased from Solv-Tek. Hexanes and
ethyl acetate were purchased from Mallinckodt-Baker Inc. Reagent grade
cyclohexanone and 3,3,5,5-tetramethylcyclohexanone were purchased from Acros
Organics and used as received. Pyrrole was purchased from TCI, was refluxed with
sodium, distilled under nitrogen, and then was stored in a purified nitrogen glove box.
Ti(NMe2)49 was prepared using a modification of the literature procedure. Deuterated
solvents were dried over purple sodium benzophenone ketyl (C6D6) or phosphoric
anhydride (CDC13) and distilled under a nitrogen atmosphere. 1H and 13 C spectra were
recorded on a VXR-SOO spectrometers. All spectra were referenced internally to
residual protiosolvent ('H) or solvent (13C) resonances. Chemical shifts are reported
in ppm, and coupling constants are reported in Hz. Typical coupling constants are not
reported.

Procedure for Spin Saturation Transfer Experiments: The spin saturation
transfer experiments were carried out using the method described by Kresge and co-
workers.10 The dimethylamido resonances were observed in the spin saturation
transfer experiments. In order to correct for decoupler spill-over, off-resonance
irradiation was carried out on the opposite side of the observation peak relative to the
dimethylamido resonance being irradiated.

General Considerations for X-Ray Diffiaction: Crystals grown from

115

 

 

concentrated toluene solutions at —35 °C were moved quickly from a scintillation vial
to a microscope slide containing Paratone N. Samples were selected and mounted on a
glass fiber in wax and Paratone. The data collections were carried out at a sample
temperature of 173 K on a Bruker AXS platform three-circle goniometer with a CCD
detector. The data were processed and reduced utilizing the program SAINTPLUS
supplied by Bruker AXS. The structures were solved by direct methods (SHELXTL

v5.1 , Bruker AXS) in conjunction with standard difference Fourier techniques.

116

 

 

Synthesis of l,1-bis(a.-pyrroly1)cyclohexane (H2cpm)

H H

\ I \ /

An oven dried 100 mL round bottom flask was charged with cyclohexanone (1 g, 10
mmol) and pyrrole (17 g, 253 mmol) and capped with a septum. The solution was
then degassed with argon for 10 min. Trifluoroacetic acid (0.116 g, 1 mmol) was
added via syringe. The reaction mixture was allowed to stir for 15 min under an argon
atmosphere before being quenched with a 0.1 M NaOH (30 mL) solution. The
solution was then transferred to a separatory funnel. It was extracted with OEt2 and
the aqueous layer was washed with OEt2 (2 X 30 mL). The combined organic layers
were dried with MgSOs and subjected to rotary evaporation to yield a viscous brown
oil. The excess pyrrole was removed by distillation under vacuum (~l torr). The
product was purified by column chromatography on silica gel with an eluant of
hexaneszethyl acetate (7:3) to yield a white solid, (0.928 g, 43%). M. p. 104-106 °C.
1H NMR (CDC13, 500 MHz): 7.61 (br s, 2 H), 6.58-6.55 (m, 2 H), 6.18-6.13 (m, 2 H),
6.13-6.11 (m, 2 H), 2.12-2.07 (m, 4 H), 1.62-1.53 (m, 4 H), 1.52-1.45 (m, 2 H). 13C
{H} NMR (125 MHz, CDC13): 137.81, 116.67, 107.78, 104.30, 39.77, 37.123, 25.91,

22.74. Anal. Found (Calc.) C: 78.21 (78.46); H: 8.91 (8.47); N: 12.83 (13.07).

117

 

Synthesis of l,l-bis(a-pyrrolyl)-3,3,5,5-tetramethylcyclohexane (H2tmcpm)

H n

\ I \ /

An oven dried 100 mL round bottom flask was charged with 3,3,5,5-
tetramethylcyclohexanone (1.0 g, 6.5 mmol) and pyrrole (9.3 g, 138 mmol) and
capped with a septum. The solution was then degassed with argon for 10 min.
Trifluoroacetic acid (0.074 g, 0.65 mmol) was added via syringe. The reaction
mixture was allowed to stir for 15 min under an atmosphere of argon before being
quenched with 0.1 M NaOH (30 mL) solution. The solution was then transferred to a
separatory funnel and was extracted with OEt2. The aqueous layer was washed with
OEt2 (2 X 30 mL). The combined organic layers were dried with MgSO4 and
subjected to rotary evaporation to yield a viscous brown oil. The excess pyrrole was
removed by distillation under vacuum (~1 torr). The product was purified by column
chromatography on silica gel with an eluant of hexaneszethyl acetate (7:3) to yield a
white solid, 0.426 g (24%). M. p. 83-85 °C. 1H NMR (CDC13, 500 MHz): 7.65 (br s, 2
H), 6.55 (dd, 2 H, JHH = 2.5 Hz, JHH =1.5 Hz), 6.13-6.07 (m, 4 H), 2.00 (s, 4 H), 1.27
(s, 2 H), 0.94 (s, 12 H). 13C {'H} NMR (CDCI3 125 MHz): 138.7, 116.4, 107.7, 104.0,
51.9, 47.9, 39.5, 32.7, 31.7. Anal. Found (Calc.) C: 80.17 (79.95); H: 9.94 (9.69); N:

10.46 (10.36).

118

Synthesis of Ti(NMe2)2(cpm) (24)

   

/T'<'NM92
NM92

All manipulations were carried out in an inert atmosphere dry box filled with purified
dinitrogen. A 20 mL scintillation vial was loaded with Ti(NMe2)4 (3) (0.222 g., 0.991
mmol) and 2 mL of ether. In a separate vial was loaded H2cpm (0.212 g., 0.991
mmol) in 2.5 mL of ether. The two vials were placed in a liquid nitrogen cooled cold
well where they sat until frozen. To a thawing solution, H2cpm was added to
Ti(NMe2)4 (3). The solution was allowed to warm to room temperature where it was
left to react for 18 h. The volatiles were removed under reduced pressure, which
provided the compound in pure form as judge by NMR and elemental analysis. M. p.
126-130 °C (dec). 1H NMR (CDCl3, 500 MHz, 25 °C) 6 7.01 (br s, 2 H), 6.41 (br s, 2
H), 6.30 (br s, 2 H), 3.24 (s, 12 H), 2.19 (br s, 4 H), 1.51 (br s, 6 H). 1H NMR (CDC13,
500 MHz, —40 °C): 7.25 (app 8, 1 H), 6.83 (app s, 1 H), 6.78 (app s, 1 H), 6.73 (app 8,
1 H), 6.11 (S, 1 H), 5.93 (S, 1 H), 3.34 (s, 6 H), 3.15 (s, 6 H) 2.76 (d, 1 H, JHH = 12
Hz), 2.29 (d, 1 H, JHH = 14 Hz), 1.87 (app t, 1 H, JHH = 15 Hz), 1.79 (app t, ‘1 H, JHH =
8.5 Hz), 1.56-1.72 (m, 3 H), 1.42-1.56 (m, 1 H), 1.28-1.40 (m, 1 H), 1.18-1.26 (m, 1
H). 13C NMR {1H} (CDC13, 125 MHz, —40 °C): 163.35, 160.79, 126.54, 123.97,
118.13, 115.33, 106.27, 100.67, 48.12, 47.32, 43.93, 38.81, 37.62, 25.60, 23.37,

23.26. Anal. Found (Calcd.) C: 61.91 (62.07); H: 8.49 (8.10); N: 15.62 (16.08).

119

 

 

Synthesis of Ti(NMe2)2(tmcpm) (25)

 

All manipulations were carried out in an inert atmosphere dry box filled with purified
dinitrogen. In a 20 mL scintillation vial was loaded Ti(NMe2)4 (3) (0.195 g, 0.869
mmol) and 2 mL of ether. In a separate vial was loaded H2tmcpm (0.270 g, 0.870
mmol) and 2.5 mL of ether. The two vials were placed in the cold well where they sat
until frozen. To a thawing solution of Ti(NMe2)4 (3) was added H2tmcpm. The
solution was allowed to warm to room temperature, where it was left to react for 18 h.
The volatiles were removed under reduced pressure, which provided the compound in
pure form as judged by NMR and-elemental analysis. M. p. 174-177 °C (dec). 1H
NMR (CDC13, 500 MHz, 25 °C): 6 6.97 (br s, 2 H), 6.37 (br s, 4 H), 3.24 (br s, 12 H),
2.6-1.6 (br s, 4 H), 1.25 (s, 2 H), 0.92 (br s, 12 H). 1H NMR (CDC13, 500 MHz, —40
°C): 7.19 (app s, 1 H), 6.77-6.75 (m, 3 H), 6.11 (t, 1 H, JHH = 2.6 Hz), 5.88 (dd, 1 H,
JHH = 1.83 Hz, JHH = 1.09 Hz), 3.35 (S, 6 H), 3.12 (s, 6 H), 2.85 (d, 1 H, JHH = 14.0
Hz), 2.29 (d, 1 H, JHH = 15.0 Hz), 1.73 (d, 1 H, JHH = 15.0 Hz), 1.63 (d, 1 H, JHH =
14.0 Hz), 1.23 (br s, 2 H), 1.00 (s, 3 H), 0.93 (s, 3 H), 0.90 (s, 3 H), 0.63 (s, 3 H). ”C
{'H} NMR (CDC13, 125 MHz) (—40 °C): 166.21, 162.59, 126.09, 123.93, 117.15,
115.16, 106.31, 101.06, 51.89, 50.05, 49.45, 48.16, 47.25, 43.43, 37.10, 35.82, 32.14,
31.91, 29.97, 27.40. Anal. Found (Calcd.) C: 65.13 (65.34); H: 8.91 (9.23); N: 13.62

(13.85).

120

u—
1'

 

5.5 References

H

. Y. Shi, C. Hall, J. T. Ciszewski, C. Cao, A. L. Odom Chem. Commun. 2003, 586.

2. For some additional reports of dipyrrolylmethane ligands on transition metals see (a)
A. Novak, A. J. Blake, C. Wilson, J. B. Love Chem. Commun., 2002, 2796 (b) S.
Majumder, A. L. Odom Organometallics, 2008, 1174 (c) J. B. Love, P. A. Salyer, A.
S. Bailey, C. Wilson, A. J. Blake, E. S. Davies, D. J. Evans Chem. Commun, 2003,
1390.

3. Majumder, S.; Odom, A.L. submitted.

4. Littler, B. J.; Miller, M. A.; Hung, C. H.; Wagner, R. W.; O’Shea, D. F.; Boyle, P. D.;
Lindsey J. S. J. Org. Chem, 1999, 64, 1391.

5. For a recent computational study on pyrrolyl isomerization see Dias, A. R.; Ferreira,
A. P.; Veiros, L. F. Comptes Rendus Chimie, 2005, 8, 1444.

6. Swartz II, D. L.; Odom, A. L. Organometallics, 2006, 25, 6125.
7. Tanski, J. M.; Parkin, G. Organometallics 2002, 21 , 5 87.

8. B. K. Carpenter, Determination of Organic Reaction Mechanisms, John Wiley &
Sons: New York, 1984.

9. D. C. Bradley, 1. M. Thomas,J. Chem. Soc. 1960, 3859.

10. C. L. Perrin, J. D. Thoburn, J. Kresge, J. J. Am. Chem. Soc. 1992, 114, 8800.

121

 

CHAPTER 6

Uranium (VI) bis(imido) pyrrolyl complexes: synthesis, structure, and reactivity

6.1 Introduction

The metal-ligand multiple bond functional group has played a significant role in
transition metal synthetic organometallic chemistry and catalysis.1 This functionality has
been far less developed for actinides. Since its discovery, the most widely studied metal
ligand multiple bond in actinide chemistry is the uranyl ion, UO22+. The reactivity of the
uranyl ion has been generally limited to equitorial coordination sites due to the high
degree of thermodynamic stability and kinetic inertness of the U—0 bond.2 Therefore,
uranyl analogues are highly attractive to expand on the reactivity associated with metal
ligand multiple bonds in actinides as well as investigate f-orbital involvement in bonding.
Until the recent work done by Boncella and co-workers in developing a dependable
synthetic strategy for uranium bis(imido) analogues,3 the understanding of the extent to
which the f-orbitals participate in U-element multiple bonding was limited to the uranyl
ion and a hand full of uranium imido complexes.4

Analysis of chemical bonding using density functional theory (DF T) On uranium
bis(irnido) complexes suggests that there is a significant amount of covalency in the U—N
bond, which goes against the paradigm of the actinide elements being highly ionic in
nature.5’6 The 6 orbitals involved in bonding in U(NMe)2I2(THF)2, 0,, 0,, two as and mu,
are the same types involved in the uranyl ion, although the ordering differs, which is
partly due to the higher electronegativity of the oxygen atom and larger involvement of

the 6p orbital in uranyl.“7

122

 

 

Unlike uranyl, the U—N multiple bond in U(NBut)2(THF)2I2 is not kinetically

inert. The U—N bond can undergo [2+2]-cycloaddition with aryl isocyanates to yield an
array of uranium (bis)imido derivatives,8 as well react with B(C6F5)3°(H2O) to yield an
uranium oxo imido complex (Scheme 6.1).9 Interestingly, the addition of OPPh3 forces

the iodide ligands trans.

Scheme 6.1 Exchange of imido ligand in U(NBut)2(THF)2I2 and

 

 

 

t
U(NBu )2(OPPh3)2lz.
\rL/ O
THF\||/| 3(Cerla' ”20 THRfl/I OPPh, Ph3P°;U\/'
/U\ ’ THF/“\I ’ ' || OPPhs
THF || 1 N
A A
Ar
i ll
Ph3PO\ /1 Ph3P0\ ,1
U ArN=C=O
l/“\OPPh3 e l/||\0PPh3

2, )1
Among the many ancillary ligands employed in organoactinide chemistry, the

most common are Cp-based ligands. Burns and Amey reported a cis-imido uranium

complex U(115-C5Me5)2(NPh)2,4c while Boncella and co-workers reported U(ns-
C5H5)2(NBut)2 with the irnidos in a cis-geometry. They also prepared a mono-Cp based
system in U(NBu’)2(dmpe)l(n“-C,H,) with the imido ligands trans.”

Similar to Cp, pyrrolyl ligands can adopt bonding modes of n5 or n' (Chart 6.1).

Marks and co-workers reported a tetrakis(pyrrolyl) uranium complex where 3 of the

123

 

 

pyrrolyls are nl-bound and the other is 115-bound.ll The fluxional behavior of pyrroles
involving interchanging n'- and 115-coordination in their bonding hapticities is common in
transition metals. Similarly at elevated temperatures the pyrrolyls interchange rapidly on
the NMR timescale between 715- and nl-bound in Marks’ uranium pyrrolyl complex.ll

Our group has reported titanium ligated dipyrrolylmethanes as effective catalysts
for hydroamination and multi-component coupling reactions.12 Pyrrolyl ligands have
proven to be a useful class of ancillary ligands for transition metals,13 whereas their
employment in actinide chemistry is relatively scarce and to the best of my knowledge
there are no reports of dipyrrolylmethane ligands on uranium. I wanted to investigate the
scope of dipyrolyhnethane ligands as suitable ancillary ligands for uranium. This chapter
discusses the synthesis, structure, and reactivity of uranium bis(imido) dipyrrolylmethane
complexes.

Chart 6.1 Possible bonding modes of pyrrolyl and dipyrrolylmethane ligands to

one metal center.

 

124

 

6.2 Uranium bis(imido) dipyrrolylmethane complexes

Encouraged by our previous results of pyrrolyl ligands supporting metal ligand
multiple bonds on transition metals I sought to prepare novel uranium bis(imido)
dipyrrolyhnethane complexes. 1 was intrigued to investigate the bonding modes the
ligand may adopt given the reports of Parkin and Tanski and our own research group that

increased sterics lower the barrier for pyrrolyl exchanged”l4 Therefore, I thought to use

a 2,2’-di(aryl)dipyrrolylmethane (H2dpmmes), where dpmmes is 2,2’-bis(mesityl)-5,5-
dimethyldipyrrolyhnethane. The ligation of the dpmme:S on titanium shows pyrrolyls
bound-111,115 in the solid state!” While the pyrrolyl groups in Ti(NMe2)2(dpmmes) (13)

are inequivalent in the solid-state, the 1H NMR is indicative of fast pyrrolyl exchange on

the NMR timescale!“ I was interested to see if dpmmes would exhibit this same

fluxional behavior in uranium bis(imido) complexes and what ground-state geometry it

would have in the solid-state.

Given the wonderful synthetic utility of U(NBut)2(THF)2I2 in preparing a plethora
of uranium bis(irnido) derivatives, it was the practical synthon of choice in preparing
dipyrrolylmethane uranium bis(imido) complexes. The addition of K2dpmmes to a stining

orange solution of U(NBut)2(THF)2I2 in THF provides a black solution, from which

U(NBut)2(dpmmeS) (26) can be isolated as a black solid (Equation 6.1). Single crystals of

26 grown from hexane at -—35 °C were suitable for X-ray diffraction. The structure of 26

is shown in Figure 6.1.

125

 

 

1 o 0

I e
THF H I + / NK KN \ THF, 25 °C,12h
/ \ 600/0

 

 

U(NBu'laldpmmesl 1261

Complex 26 has C2-symmetry with the pyrrolyls bound-715,1)5 in the solid state.
The ability of the dpmmes ligand to adopt an n5,n5-binding mode may be partly due to the
sheer size of the uranium atom relative to the Size of transition metals.

The geometry of the dpmmes ligand forces the imido ligands cis with U-N bond
lengths of 1.930(4) A and 1.946(4) A respectively. The average U-N(imido) bond length
is significantly longer than the bond lengths found in U(NBut)2(THF)2I2 which is
probably due to an electronic effect.3 The average U-N(imido) bond length is similar to
the bond lengths found in 115,115-bound U(NBut)2(C5H5)2, although the N-U-N imido
angle in 26 is 116.06(15)°, which is significantly larger than the N-U-N imido bond angle

CS

in U(NBut)2(C5H5)2 (N-U-N = 103.4(3)°), This can be attributed to the chelated dpmm

ligand.”

126

.3‘.‘

'2.-
t}; 5'
‘ a T” (‘I‘
\ \
‘\\-
’ r
\V
t
' at
.. ;- f-J
'.
u . I
“ U ' 1.
a l
‘ I ‘3 . ‘
v ’5 r--'
I.
.' Q .
o "‘1 _, '
I D 1 J
~ 11121
’1
-_ "‘
V
-' ‘ _
- ‘ ' N ("t
r‘ " 4-
.1...

Figure 6.1 ORTEP structure of U(NBut)2(dpmmes) (26) from single crystal X-ray

diffraction. Selected bond distances (A) and angles (deg): U-N(1) 1.930(4), U-N(2)
1.946(4), U-N(3) 2.575(4), U-N(4) 2.592(4), N(1)-U-N(2) 116.06(15), N(1)-U-N(3)
91.90(14), N(1)-U-N(4) 131.47(13), N(2)-U-N(3) 130.79(13), N(2)-U-N(4) 94.11(14),
N(3)-U-N(4) 95.72(12).

Uranium imidos are known to undergo [2+2]-cycloaddition to yield imido
dervatives as well as react with B(C6F5)3'H2O to produce an oxo imido uranium
speciess’l0 Attempts to take advantage of this known reactivity with previously reported
uranium imidos, showed disappointing imido reactivity in 26, usually resulting in
decomposition. Complex 26 is also sensitive to solvent. Leaving 26 in a solution of THF
for extended periods of time resulted in decomposition as well, resulting in protio-ligand

and new uranium resonances in the 1H NMR spectrum. Unfortunately, the only solvent to

CS

facilitate the production of 26 from U(NBut)2(THF)2(I)2 and K2dpmm was THF,

therefore particular attention to reaction times was required. Attempts to isolate the

127

 

uranium decomposition product were unsuccessful.

To probe the coordination chemistry of 26, a handful of Lewis bases were
examined (i.e. pyridine, OPPh3, and dmpe). Most bases examined yielded no clean
isolable products, however a reaction of 26 with dmpe, (dmpe = 1,2-
biS(dimethylphosphino)ethane), in toluene yields U(NBu’)2(dpm"'°s)(dmpe) (27)
(Equation 6.2). A structure for 27 is shown in Figure 6.2. The addition of dmpe to 26
forces the imidos trans, and the increased sterics around the metal center forces the
dpmm“ ligand to adopt an n'ml-binding mode resulting in 27 taking on a pseudo-

octahedral geometry.

 

Figure 6.2 ORTEP structure of U(NBu’)2(dpm‘“es)(dmpc) (27) from single
crystal X-ray diffraction. Selected bond distances (A) and angles (deg): U-N(1)
1.865(15), U-N(2) 1.857(14), U-N(3) 2.393(15), U-N(4) 2.431(15), U-P(l) 3.043(6), U-
p(2) 3.116(6), N(1)-U-N(2) 165.9(6), N(1)-U-N(3) 9710(6), N(1)-U-N(4) 98.2(6), N(2)-

U-N(3) 92.7(6), N(2)-U-N(4) 91.4(6), N(3)-U-N(4) 93.1(5), N(2)-U-P(1) 84.1(5), N(1)-

128

 

 

U-P(1) 84.5(5), N(3)-U-P(1) = 169.4(4), N(4)-U-P(1) = 97.0(4), N(2)-U—P(2) = 80.6(5),
N(1)-U-P(2) 87.3(5), N(3)-U-P(2) 102.2(4), N(4)-U-P(2) 163.0(4), P(1)-U-P(2)
67.39(15).

The average imido bond length in 27 is 1.861 A, which is Similar to the average
bond lengths found in U(NR)2(THF)(I)2.5 The N-U-N imido bond angle, 165.9(6)°, in 27
deviates from the ideal bond angle of an octahedral complex of 180°, which is likely due

to steric effects. The average U-P bond distance of 3.079 A is longer than the bond

distance in U(NBut)2(dmpe)(n5-C5H5)2 (U-P average = 2.99 A), the only structurally

characterized other uranium (VI) complex supported by the dmpe ligand.10 The 1H NMR

spectrum of 27 shows an extremely broad singlet at 3.35 ppm, assigned to the ortho-

methyl groups on dpmmes, which could possibly be due to hindered rotation about

pyrrolyl-mestiyl bond (See Appendix for the 1H spectrum of 26 and 27); however,
fluxional behavior could also explain this phenomena. This broad singlet is also seen in

complex 26.

\l/

r—\ _ ‘N,..,N’
+ —P\ ,P— Tol.,25 °C,18 11v :Pfi‘f: (6.2)
47% 4\

U(NBu')2(dpmm°s)(dmpe) (27)

 

 

26

I also investigated the use of the sterically smaller ligand 5,5-

dimethyldipyrrolylmethane (H2dpm). The dry addition of K2dpm to a stirred dilute

orange stining solution of U(NBut)2(THF)2(I)2 in THF affords U(NBut)2(THF)2(dpm)

129

(28) as a red solid, which can be isolated in 42% using this synthetic procedure (Reaction
6.3). Crystallization of 28 from THF/hexane resulted in the growth of crystals suitable for
X-ray diffraction. A structure of 28 is shown if Figure 6.3. The dilute reaction conditions
for the production of 28 were required due to the low solubility of K2dpm, which resulted

in slightly longer reaction times.

i 1,“

H I \
THF>U< + / NK KN \ : N>U<THF (63)
THF H ' / \ THF, 25°C, 24h ,N H THF '
N 42% N

“c 4

U(NBu’lalTHFlaldpml (28)

 

The pyrrolyls in the dpm ligand in 28 adopt an 111,1] l-bonding mode. The 1H NMR
spectrum is consistent with the solid-state structure of 28 with the pyrrolyls being
equivalent. The average imido bond length in 28 is 1.856(6) A which is similar to the
bond length found in 27 and other U(NR)2(THF)2(I)2 complexes.5 The imido bond angle
in 28 is nearly linear with a bond angle of 172.8(3)°. The average U-N(pyrrolyl) bond
length of 2.356(6) A is similar to the U-N(pyrrolyl) average bond length in 28, while the
average U-O bond length in 28 is also similar to previously reported U-O bond lengths in

U(NR)2(THF)2(I)2 complexes.

130

‘\

N(2) ‘: .4“-

. _

a;

 

V
\é.

Figure 6.3 ORTEP structure of U(NBut)2(dpm)(THF)2 (28) from single crystal X-

ray diffraction. Selected bond distances (A) and angles (deg): U-N(1) 1.856(6), U-N(2)
1.856(7), U-N(3) 2.356(6), U-N(3A) 2.356(6), U-(Ol) 2.461(4), U-O(1A) 2.461(4),
N(1)-U-N(2) 172.8(3), N(2)-U-N(3A) 91.52(19), N(1)-U-N(3A) 94.23( 19), N(2)-U-N(3)
91.52(19),

Complex 28 did not show the same sensitivity to solvent and temperature as 26.

Extended time in THF did not result in any new resonances is the 1H NMR spectrum.

I also investigated the use of a 2-mesityl pyrrole (prrrmcs) as an ancillary

ligand. Reacting 2 equivalents of prrrmes with U(NBut)2(TI-IF)2(I)2 did not afford the

bis(pyrrolyl) uranium complex, instead a mono(pyrrolyl) uranium complex,

131

U(NBut)2(THF)2(I)(pyrrmeS) (29) was produced and structurally characterized by X-ray
diffraction (Scheme 6.2). The structure of 29 is shown in Figure 6.4.

Scheme 6.2 Synthesis of U(NBu’)2(THF)2(l)(pyrrm°S) (29).

it

 

N
K
THF\“/| N H \
u 2 _ HF u N
THF/”\l I / X ' a )2” ——
N N 2

N
THF\U/THF
’ N

U(NBu‘MTHFhUXpynmesl (29)

 

 

The 1H NMR Spectrum of the reaction mixture showed free prrrmes peaks in the
baseline in addition to a uranium complex. There were several attempts to reproduce 29
by reacting 1 equivalent of prrrmes with U(NBut)2(THF)2(I)2, but they yielded no

isolable products resembling the structure of 29. It is possible that the production of
bis(2-mesitylpyrolyl) uranium complex disproportionates to give a mixture of

mono(pyrrolyl) and other uranium complexes.15

132

 

 

n‘u
.-
O I

 

{a D

&

Figure 6.4 ORTEP structure of U(NBu‘)2(pyrrm°S)(THF),(l) (29) from single

crystal X-ray diffraction. Selected bond distances (A) and angles (deg): U-N(1) 1.849(3),
U-N(2) 1.841(3), U-N(3) 2.385(3), U-(Ol) 2.467(3), U-O(2) 2.437(3), U-I 3.0721(4),
N(1)-U-N(2) 175.06(13), N(2)-U-N(3) 91 .41(12), N(1)-U-N(3) 92.69(12).

Complex 29 takes on a pseudo-octahedral geometry with the pyrroyl bonded n' in
the solid state and imido ligands trans with a U-N bond angle of 175.06° and an average
U-N bond distance of 1.844 A, which are similar to previously reported
U(NR)2(THF)2(I)2 complexes. The average U-I and U-O bond distances are similar to

previously reported complexes as well.5

133

6.3 Conclusion
In summary, a series of novel uranium bis(irnido) dipyrrolylmethane complexes

have been prepared by reacting the potassium salt of the dipyrrolylmethane ligand with
t
U(NBu )2(THF)2(I)2-

Binding the dpmmes ligand to uranium results in the ligand adopting an 115,115-

coordination forcing the imido ligands cis. U(NBut)2(dpmmes) (26) showed disappointing

reactivity towards alkynes, ketones, and isocyanates which typically resulted in
decomposition. However, reacting 26 with one equivalent of dmpe, resulted in dmpe
coordination. The increased steric interaction forced the imido ligands to adopt a trans
geometry and pushed the dipyrrolylmethane ligand to an nlml-bonding mode.

Ligation of the dpm ligand to uranium resultd in a Six coordinate complex with
the imido ligands trans and the dipyrrolylmethane ligand adopting an nlml-binding
mode. The possibility of fluxional behavior in 26 and 27 warrant further investigation.

These findings show that dipyrrolyhnethanes support uranium(VI) bis(imido)
complexes. In addition, the ability to take advantage of a dipyrrolylmethane ligand that
adopts an 115,115-bonding mode may prove useful in producing uranium bis(imido)
complexes with the imido ligands in a cis-geometry that can be used in catalytic

hydroamination reactions and other organoactinide catalysis.

134

 

 

6.4 Experimental

General Considerations. All manipulations of air sensitive compounds were
carried out in an MBraun drybox under a purified nitrogen atmosphere. Anhydrous
solvents were purchased from Acros Organics and were used as received. Deuterated
solvents were dried over purple sodium benzophenone ketyl (C6D6) or phosphoric

anhydride (CDC13) and distilled under a nitrogen atmosphere and stored over molecular

mes 13a

sieves. U(NBut)2(THF)2(I)2,5 H2dpm , and H2dpm]6 were synthesized according to

literature procedures. 1H and '3 C spectra were recorded on Bruker-300 spectrometers. All
spectra were referenced internally to residual protiosolvent (1H) or solvent (13 C)
resonances. 1H and 13C assignments were confirmed when necessary using two-
dimensional lH—lH and lH—13C correlation NMR experiments. Chemical shifts are

reported in ppm and coupling constants reported in Hz.

135

Synthesis of U(NBut)2(dpmmes) (26)

 

Under an atmosphere of dry N2, a 20 mL scintillation vial was loaded with
U(NBut)2(THF)2(I)2 (1.24 g, 1.59 mmol) in THF (8 mL). In a separate vial was K2dpm":s

(0.886 g, 1.59 mmol) in THF (6 mL). Both vials were put into the freezer where they sat

for ~30 minutes. After that time, K2dpmmes was added to the vial containing

U(NBut)2(THF)2(I)2. The solution was allowed to stir overnight at room temperature. The

following day the solution was filtered through a pipette filter with a thin pad of celite.
The volatiles were removed by vacuum to give a viscous black oil. The oil was stirred in
hexamethyldisiloxane (8 mL) for 8 h, after which the solution was filtered through a
pipette filter. The solid remaining on the pipette filter was dissolved in toluene and put
back into the vial containing the original solution. The volatiles were removed by vacuum
to a black solid. The solid was triturated with hexane to give UmBu')2(dpmm°‘) as a black
solid, (0.750 g 60%). 1H NMR (C6D6, 300 MHz): 7.03 (s, 4H), 6.31 (app s, 2 H), 5.68

(app s. 2H), 3.56 (br s, 12 H), 2.32 (s, 6 H), 2.24 (s, 6 H), 0.49 (s, 18 H).

136

Synthesis of U(NBu’),(dpm"'°’)(drnpe) (27)

Under an atmosphere of dry N2, a 20 mL scintillation vial was loaded with

U(NBut)2(dpmmes) (0.075 g, 0.0951 mmol) in toluene (3 mL). To that vial was added

dmpe (0.014 g, 0.0951 mmol). The solution was allowed to stir overnight. The next day
the volatiles were removed in vacuo to give a black solid. The solid was dissolved in a
minimal amount of hexane and put into the freezer to crystallize. The following day thin
black needles were deposited on the side of vial. The crystals were dried in vacuo to give
the title compound as a black solid, (0.047 g. 47%) 1H NMR (C6D6, 300 MHz): 7.01 (s, 4
H), 6.37 (app s, 2 H), 3.36 (br s, 12 H), 2.44 (br s, 6 H), 2.26 (s, 6 H), 1.21 (br s, 4 H),

0.99 (br s, 12 H), 0.45 (s, 18 H).

137

 

 

Synthesis of U(NBut)2(dpm)(THF)2 (28)
\l/
‘N\IUI /THF
,N””“THF
N

Under an atmosphere of dry N2, a 20 mL scintillation vial was loaded with
U(NBut)2(THF)2(I)2 (0.050 g, 0.064 mmol) in THF (5 mL). To that vial was added

K2dpm (0.016 g, 0.064 mmol) dry. The solution was allowed to stir for 24 hours, after
which it had turned deep red in color. The following day the solution was filtered through
a pipette filter with a thin pad of celite. The volatiles were removed in vacuo to give a
deep red solid. The solid was dissolved in THF and layered with an equal amount of
hexane and put in the freezer to crystallize. The following day, red crystals were
deposited on the side of the vial. The crystals were then dried to give the product as a red
solid, (0.018 g 42%). 1H NMR (C6D6, 300 MHz):7.37 (app s, 2 H), 7.22 (app S, 2 H),

6.59 (app s, 2 H), 3.61 (s, 4 H), 1.76 (s, 6 H), 1.41 (s, 4 H), 1.38 (s, 18 H).

138

Synthesis of U(NBu’),(dpm)(dmpe) (30)

Under an atmosphere of dry N2, a 20 mL scintillation vial was loaded with

U(NBut)2(THF)2(dpm) (0.050 g, 0.072 mmol) in toluene (2 mL). To that vial was added

dmpe (0.0108 g, 0.072 mmol). The solution was allowed to stir overnight. The following
day the volatiles were removed in vacuo to yield a red solid. The solid was dissolved in a
minimal amount of THF and layered with an equal amount of hexane and put in the
freezer to crystallize. Crystals formed as deep red blocks. The crystals were dried to give
a deep red solid, 0.020 g (44 %). 1H NMR (C7D3, 300 MHz) 5: 7.59 (app s, 2 H), 6.87
(app s, 2 H), 6.45 (app s, 2 H), 1.98 (app 3, 4 H), 1.36 (s, 12 H), 1.27 (s, 18 H). 31P NMR

(C7Dg, 300 MHz) 8: 79.57.

139

 

6.5 References
1. Mayer, J.M.; Nugent, W.A. Metal Ligand Multiple Bonds, Wiley, New York, 1988.

2. Morss, L. R.; Edelstein, N. M.; Fuger, J. The Chemistry of the Actinide and
Transactinide elements, 3rd ed.; Springer Netherlends, New York, 2006, Vol 1.

3. Hayton, T. W.; Boncella, J. M.; Palmer, P. D.; Scott, B. L.; Batista, E. R.; Hay, P. 1.
Science, 2005, 310, 1941.

4. (a) Amey, D. S. J.; Burns, C. J.; Smith, D. C. J. Am. Chem. Soc. 1992, 114,10068 (b)
Amey, D. S. J.; Burns, C. J. J. Am. Chem. Soc. 1995, 117, 9448. (c) Warner, B. P.;
Scott, B. L.; Burns, C. J. Angew. Chem, Int. Ed 1998, 37, 959. (d) Cramer, R. E.;
Edelmann, F .; Mori, A. L.; Roth, S.; Gilje, J. W.; Tatsumi,K.; Nakamura, A.
Organometallics 1988, 7, 841. (e) Ariyaratne, K. A. N. S.; Cramer, R. E.; Gilje, J. W.
Organometallics 2002, 21, 5799.

 

5. Hayton, T. W.; Boncella, J. M.; Scott, B. L.; Batista, E.R., Hay, P. J. J. Amer. Chem.
Soc., 2006, 128, 10549.

6. Kaltsoyannis, N. Inorg. Chem. 2000, 39, 6009.

7. For an explanation of the “pushing from below” mechanism see. (a) Pepper, M.;
Bursten, B. E. Chem. Rev. 1991, 91, 719. (b) Tataumi, K.; Hoffrnann, R Inorg. Chem.
1980, 19, 2656.

8. Spencer, L. P.; Yang, P.; Scott, B. L. Batista, E. R.; Boncella, J.M. J. Amer. Chem.
Soc. 2008, 130, 2930.

9. Hayton, T. W. Boncella, J. M.; Scott, B.L. Batista, E.R. J. Amer. Chem. Soc. 2006,
128, 12622.

10. Spencer, L. P.; Gdula, R. L.; Hayton, T. W.; Scott, B. L.; Boncella, J. M. Chem.
Comm. 2008, 4986.

11. Marks, T.J. Acc. Chem. Res. 1976, 9, 223.

12. (a) Swartz II, D. L.; Odom, A.L. Organometallics, 2006, 26, 6125. (b) Majumder, S.;
Odom, A.L; manuscript in preparation.

13. (a) A. Novak, A. J. Blake, C. Wilson, J. B. Love Chem. Commun., 2002, 2796 (b) S.
Majumder, A. L. Odom Organometallics, 2008, 1174 (c) J. B. Love, P. A. Salyer, A.
S. Bailey, C. Wilson, A. J. Blake, E. S. Davies, D. J. Evans Chem. Commun, 2003,
1390.

140

 

14. Tanski, J .M.; Parkin, G. Organometallics 2002, 21 , 587.

15. Spencer, L.P. personal communication.

16. Littler, B. J.; Miller, M. A.; Hung, C. H.; Wagner, R. W.; O’Shea, D. F.; Boyle, P.
D.; Lindsey, J. S. J. Org. Chem. 1999, 64, 1391.

141

APPENDIX A

Kinetic reaction plots for selected catalysts in Chapter 2

Figure Al.l Representative plot of [l-phenylpropyne] versus time with 10 mol%

Ti(NMe2)2(dpmmeS) (12) at 75 °C.

 

 

0.05- I
k = 369 x 10-7 s-1
5 “-04“ R2 = 0.99573
g 0.03- '
E 0.02-1
0.01 -
l l I l f l l l
0 2 4 6 8 10 12
Tlme (h)

142

Figure A1.2 Representative plot of [l-phenylpropyne] versus time with 10 mol%

Ti(NMe2)2(dpm3'5‘CF3) (13) at 75 oC.

 

 

 

0.05-
k = 777 X 10'7 S'l
0.04-1 2 =
2 . R 0.99942
E 0.03-
: 002-1
0.01 -
01“) I I V 1 ' 1 l
O 2 4 6 8
Time (h)

143

Figure Al.3 Representative plot of [l-phenylpropyne] versus time with 10 mol%

3,5—CF3

Ti(NMe2)2(pyrr )2 (14) at 75 °C.

k = 1297 X 10"7 S"1

2
E 00,, j R2 = 0.99746

 

 

144

Figure Al.4 Representative plot of [l-phenylpropyne] versus time with 10 mol%

Ti(NMe2)2(pyrrmes)2 (15) at 75 °C.

k = 805 X 10’7 S‘1

  

 

R2 = 0.99966

[1-phenylpropynel M
'8

0.01 - \h

 

0.“)

 

o-
.s
N
w
J.
01
a)
\l

145

Figure A1.5 Representative plot of [l-phenylpropyne] versus time with 10 mol%

Ti(NMe2)2(pyrr4‘CF3)2 (16) at 75 °C.

0055.
““5“: k = 1188 x 10-7 s-1
0.045-1
. 2::
mm R 0.99418

 

thenylpropynelM
g. i

0.015 -

0.010 -

 

 

00 05 10 15 20 25 30 35 4o
Thnean

146

Figure Al.6 Representative plot of [l-phenylpropyne] versus time with 10 mol%

Ti(NMe2)2(pyrrt°l)2 (17) at 75 °C.

 

 

°'°5‘ 1: = 897 x 10-7 s-1
,_,,_ R2 = 0.99932
2 \
5 0.034
E 0.02-
0.01 -
K“
o'm l l l r ’ l l r l
0 1 2 4 5 6

147

APPENDIX B

Kinetic plots for selected catalysts in chapter 3

Figure 81.] Representative plot of [l-phenylpropyne] versus time with 10 mol%

Ti(NMe2)2(pyrrmeS)2 (15) at 100 °C.

 

 

0.05- n
k = 4383 X 10’7 S‘1

°‘°“ R2 = 0.99784
3 .
E 0.03-
E 0.02-
:- 0.01- \k\

0.00-

00 0r2 ' 0'4 0'6 0TB 1:0 112 1'4 f1‘6
T1me(h)

148

 

Figure B1.2 Representative plot of [l-phenylpropyne] versus time with 10 mol%

Ti(indenyl)2(Me)2 (21) at 100 oC.

   
  

 

 

0.05-
k = 830 x 10-7 s-1
0.041 I
E. 1 R2 = 0.98799
g 0.03-
E 0.02-
0.01 - I
a I I
o'm I l l l I ‘ l l
0 1 2 3 4 5
Time (h)

149

 

 

Figure Bl.3 Representative plot of [l-phenylpropyne] versus time with 10 mol%

Ti(NMe)3(pyr2'CF3'4C6F5) (20) at 100 °C.

005-1 I\
\ k = 7200 x 10-7 s-1

0.04- '
. \ R2 = 0.99751

0.03- \

11mm] M
/
1r
/

0.01 - \k

0.00 -

 

 

0 500.1000'1gmf2600'25'00'3dm1
T1me(sec)

1

150

 

 

APPENDIX C

Kinetic plots for selected catalysts in chapter 4

Figure Cl.l Representative plot of [l-phenylpropyne] versus time with 10 mol%

3,5—CF3

Ti(NMe)2(3-dpm ) (22) at 75 °C.

0.05 - q

1 \ k= 6400 x 10-7 s-1
0.04-
R2 = 0.99848

0.03 A

“WWI M

0.01 -

 

0.00 .

 

151

 

Figure Cl.2 Representative plot of [l-phenylpropyne] versus time with 10 mol%

Ti(NMe)2(3-dme6F3) (23) at 75 °C.

0.05 - I

- \\ k = 6700 X 10‘7 S‘1
0.04-
\ R2 = 0.99874

0.03 -1

[l-Phenylpmpynel M
/J’
x-
/

\.\
I

 

o-m 'ITI‘I'ITI'I‘I'I'I
-500 0 5001000150020002500300035004000
Tlme(sec)

 

152

Figure Cl.3 Representative plot of % conversion versus time with 10 mol%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Ti(NMe)2(3-dpm3’5—CF3) (22) at 75 °C using reaction calorimetry.
100 ,. K , 1::
K" ,. L7)”, I
-. Q: "’i
C V/
80 Q/
975 y = M1+(M3-M1)*exp(-(M2*M0))
,5 6° Value Error
g 6 ___m1 _____105.13 _ 2.0908
g - m2 K000066566 ”4323895
“3 m3 -7.4384 2.6543
°\ 40 C .
Chlsq 166.89 NA
R 0.99547 NA
20
1/
o L)
o 1000 2000 3000 4000 5000 6000

Times (sec)

153

7000

APPENDIX D

NMR spectra for selected compounds

Figure 131.1 lH spectrum for Ti(NMe2)2(dpmmeS) (12).

 

 

 

 

 

 

154

Figure Dl.2 13 C spectrum for Ti(NMe2)2(dpmmes) (12).

 

 

 

 

 

 

 

 

 

 

‘1 0". '''''''''''' V'T' "77 "Y' "" VVII 'TYj '7'. ‘U‘T vrfr "" "" YYYT vv1‘r
r I I I l l I l I r T [ r I I 1 1 1

 

155

Figure Dl.3 lH spectrum for U(NBut)2(dpmmes) (26).

va.
mmm.

mmm.

vow.

oam.

mmo.
ova.

Nell!
blllllll

 

 

 

"V I V

VIIIITWIIY'

2

I'VITVIVVV

F l

 

8.2.

Bum

N56

 

NW:

0

1 lil

SN

1

 

and

 

156

Figure Dl.4 lH spectrum for U(NBut)2(dpmmes)(dmpe) (27).

 

 

 

 

 

 

 

 

 

 

Fl 15151 ii iii if“:

 

 

 

 

 

 

 

 

 

157

' Figure Dl.5 31P spectrum for U(NBu')2(dpmmeS)(dmpe) (27).

\D
H
0‘

c
("‘1
\D

 

 

158

Figure D1.6 lH spectrum for U(NBu’)(THF)2(dpm) (28).

0mm.
mHv.
wa.

mam.

Nam.

wvH.
ONN.

PMP.

 

 

 

 

 

 

 

159

3,5—CF3

Figure Dl.7 '3 C spectrum for Ti(NMe2)2(NHMe2)(pyrr )2 (19) in CDC13.

 

 

 

 

 

 

 

 

 

 

 

I I I I I I I I V I I T I I I I ' 1 I fir I I I I I I r I I I I I I I I I 1 I I I V I r I I T I I I I Y I I I I I I I I Y I I I I l T r I I Ifir
150 100 130 120 110 100 90 IO 70 ‘0 50 40 3O 20 pp-

160

Figure Dl.8 lH spectrum for Ti(NMe2)2(NHMe2)(pyrr3’S-CF3» _(19) in CDC13.

 

 

 

 

 

161