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Novel methods towards synthesis of pyrroles and applications
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Bala Subramanian Ramanathan

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NOVEL METHODS TOWARDS SYNTHESIS OF PYRROLES AND
APPLICATIONS OF TITANIUM MEDIATED

HYDROAMINATION REACTIONS.

BY

BALA SUBRAMANIAN RAMANATHAN

A THESIS
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of
MASTER OF SCIENCE
Department of Chemistry

2005

ABSTRACT

NOVEL METHODS TOWARDS SYNTHESIS OF PYRROLES AND
APPLICATIONS OF TITANIUM MEDIATED HYDROAMINATION

REACTIONS.

BY
BALA SUBRAMANIAN RAMANATHAN

Several new pyrroles have been synthesized by hydroamination of diynes, which
were catalyzed by titanium-based catalysts. The diynes include terminal and
internal diynes, which was not very stable at room temperature. The catalyst
used for this pyrrole synthesis were chelating dipyrrolyl ligands based on N, N-
di(pyrrolyl-0t-methyl)-N-methylamine (dpma) and 5,S-dimethylpyrrolylmethane
(dmpm) catalysts.

Attempt has been made to synthesize vinylpyrroles as an extension of the work on
hydroamination chemistry. The Diels-Alder chemistry of these vinylpyrroles is

also investigated.

ACKNOWLEDGENIENTS

I would like to thank Michigan State University for their generous support. The
writer gratefully appreciates the support of the Department of Chemistry for a
Brubaker Fellowship, as well as the use of instruments and laboratory space.

A special thanks to my advisor Dr Aaron Odom, for his understanding, patience
and constant support throughout my research. He has always been there to help
me whenever I needed it. His constant motivation has helped me a lot through

these years to maintain my focus towards research.

iii

Table of Contents

LIST OF TABLES .......................................................................... vi
LIST OF FIGURES ........................................................................ vii
LIST OF ABBREVIATIONS ............................................................. xi
CHAPTER 1

INTRODUCTION TO HYDROAMINATION ......................................... 1

Introduction .................................................................................. 1

Hydroamination using different metals ................................................... 5
Hydroamiantion using zirconium ........................................................ 13
Hydroamination using titanium .......................................................... 15
Research in the Odom group ............................................................. 28
Synthesis of titanium catalysts ........................................................... 29

Hydroamination with different ligands .................................................. 33
Three-component coupling and applications ........................................... 34
Conclusions ................................................................................. 35
CHAPTER 2

HYDROAMINATION OF

DIYNES ..................................................................................... 36
Introduction ................................................................................. 36
Hydroamination with other metals ....................................................... 39
Baldwin’s rules for ring closure ........ ' .................................................. 41
Synthesis of 1,4 diynes .................................................................... 43
Hydroamination of 1,4-diynes ............................................................ 44
Synthesis of 1,5-diynes ................................................................... 49

Hydroamination of 1,5-diynes ........................................................... 49

Three component coupling of diynes ................................................... 53
Summary .................................................................................... 54
Experimental ................................................................................ 56
General considerations ..................................................................... 56
1-Phenyl-2-butyl-5-methylpyrrole (1) ................................................... 56
l-Benzyl-2-buty1-5—methylpyrrole (2) ................................................... 57
1-Phenyl-2-benzyl-5-methylpyrrole (3) ................................................. 58
1,2-Dibenzyl-5-methylpyrrole (4) ........................................................ 6O
1-(4-methoxybenzyl)-2-Benzyl-5-methyl pyrrole (5) ................................. 61

1-Phenyl-2,5-dimethylpyrrole (6) ........................................................ 62
l-Benzyl-2,5-dimethylpyrrole (7) ........................................................ 63
l-Phenyl-2,5-dibenzylpyrrole (8) ........................................................ 64

iv

CHAPTER 3
USE OF HYDROAMINATION TO GENERATE 2-

VINYLPYRROLES ........................................................................ 65
Introduction .................................................................................. 65
Synthesis of vinylpyrroles ................................................................ 67
Synthesis of 2-vinylpyrroles .............................................................. 68
Synthesis of 3-vinylpyrroles .............................................................. 70
Synthesis of diynes ......................................................................... 71
Hydroamination of diynes ................................................................ 72
Conclusion .................................................................................. 74
Experimental ................................................................................ 75
General considerations ..................................................................... 75
l-Cyclohexenyl-l,4-pentadiyne (9) ...................................................... 75
l-Cyclohexene-3-methyl-l,4-pentadiyne (10) .......................................... 76
1-Phenyl-2,3-dimethyl-5-( l -cyclohexenyl)-pyrrole (1 1) .............................. 78
l-Benzyl-2,3-dimethyl-5-(1-cyclohexenyl)-pyrrole (12) ............................. 79
BIBLIOGRAPHY .......................................................................... 80

List of Tables

Table 2.1 Results for hydroamination of 1,4 and 1,5-diynes with
aromatic amines ............................................................... 55

vi

List of Figures

Figure 1-1 Alkyne hydroamination ........................................................ 2
Figure 1-2 Thermodynamic data comparing hydroamination of

amines and ammonia .......................................................... 3
Figure 1-3 Hydroamination of terminal alkyne with Hg salt .......................... 5
Figure 1-4 Base catalyzed hydroamination of alkynes ................................. 6
Figure 1-5 Hydroamination of alkynes catalyzed by lanthanides ..................... 7
Figure 1-6 Hydroamination of alkynes catalyzed by actinides ........................ 8
Figure 1-7 Hydroamination of alkynes with yttrium amides .......................... 9
Figure 1-8 Hydroamination of alkynes catalyzed by ruthenium complex ........... 9
Figure 1-9 Hydroamination of alkynes catalyzed by rhodium complex ............ 10
Figure 1-10 Hydroamination of alkynes catalyzed by palladium complex. . . . . . ...11
Figure 1-11 Hydroamination of alkynes catalyzed by gold complex ............... 12
Figure 1-12 Hydroamination of alkynes catalyzed by zirconium complex. . . . .....13
Figure 1-13 Bergman’s mechanism for hydroamination for alkynes ................ 14

Figure 1-14 First example of titanium catalyzed hydroamination of alkynes. . 15
Figure 1-15 Synthesis of (i)-monomorine via intramolecular hydroamination. . . 16

Figure 1-16 Synthesis of (+)-preussin via intramolecular hydroamination
catalyzed by titanium ...................................................... 17

Figure 1-17 Hydroamination of alkynes with szTiMez as catalyst ................ 18

Figure 1-18 Hydroamination of alkynes with szTiMez as catalyst and
benzhydrylamine ............................................................ 19

Figure 1-19 Hydroamination of alkynes with Indenyl-based titanium catalyst. . .20

Figure 1-20 Hydroamination using guanidinate ancillary ligands on titanium. . . .21

vii

Figure 1-21 Hydroamination of terminal alkynes using titanocyclopropene-
based catalyst ............................................................... 22

Figure 1-22 Hydroamination of alkynes and allenes with
group-4 bis(sulfonamido) complexes .................................... 24

Figure 1-23 Hydroamination of alkynes with cationic imido
complex of tantalum ....................................................... 25

Figure 1-24 Hydroamination of internal alkynes with titanium
imido complex ............................................................. 25

Figure 1-25 Hydroamination of internal alkynes with titanium tetrachloride. ...26

Figure 1-26 Use of arnidate complexes of group-4 metals
for intramolecular hydroamination ...................................... 27

Figure 1-27 Hydroamination of alkynes with

catalytic amounts of Ti(NMe2)4 ......................................... 28
Figure 1-28 Synthesis of Ti(dpma)(NMe2)2 ........................................... 29
Figure 1-29 Synthesis of Ti(dmpm)(NMe2)2 .......................................... 30
Figure 1-30 Synthesis of Ti(dap)2(NMez)2 ............................................ 32
Figure 1-31 Synthesis of Ti(SC6F5)2(NHl\'Ie2)(NMe2)2 .............................. 32
Figure 1-32 Hydroamination of hydrazines with Ti(dap)2(NMe2)2 ................ 33

Figure 1—33 Hydroamination of alkynes and aryl hydrazines to give
substituted indoles ......................................................... 33

Figure 1-34 Titanium catalyzed 3-component coupling to give
(LB—unsaturated fl-iminoamines ........................................ 34

Figure 2-1a Pyrrole core structure in NSAIDs
and natural products ...................................................... 37

Figure 2-1b Pyrrole core structure in
natural products ........................................................... 38

Figure 2-2 Hydroamination of 1,4 and 1,5-diynes ................................... 39

viii

Figure 2-3 Hydroamination with molybdenum pentacarbonyl .................. 40

Figure 2-4 Palladium catalyzed intramolecular hydroamination and

cyclization ................................................................. 40
Figure 2-5 Another route for cyclization with Pd to yield pyrroles ............ 41
Figure 2-6 Baldwin’s rules for ring closure in 3- to 7-membered rings ........ 42
Figure 2-7 Synthesis of 1,4-diynes .................................................. 43

Figure 2-8 Hydroamination of 1,4-pentadiyne with aromatic

amines ...................................................................... 44

Figure 2-9 Structure of catalysts used in hydroamination of

diynes ...................................................................... 45

Figure 2-10 Hydroamination of l,4-nonadiyne with aromatic

amines .................................................................... 46

Figure 2-11 Hydroamination of 1-phenyl-l,4-pentadiyne with aromatic

amines .................................................................... 46

Figure 2—12 Hydroamination of l-trimethylsilyl-l,4—pentadiyne

with aromatic amines .................................................... 47

Figure 2~13 Hydroamination of 1-phenyl-1,4—hexadiyne

with aromatic amines ................................................... 48

Figure 2-14 Synthesis of 1,6-diphenyl-1,5-hexadiyne ............................. 49

Figure 2-15 Hydroamination of 1,5-hexadiyne

with aromatic amines ................................................... 50

Figure 2-16 Hydroamination of 1,6-diphenyl-1,5-hexadiyne

with aromatic amines ................................................... 50

Figure 2-17 Gevorgyan’s cyclization of 1-imino—2-alkynes

catalyzed by copper .................................................... 51

Figure 2-18 Reaction to verify if the cyclization

is Ti mediated ........................................................

Figure 2-19 Condensation of hex-5-yn-2-one with aniline........................

ix

....52

.53

Figure 2-20 Three-component coupling of diyne

with amine and isonitn'le ................................................ 53
Figure 3-1 Structure of vinylpyrroles .................................................. 65
Figure 3-2 Proposed scheme for synthesis of 2-vinylpyroles ....................... 66

Figure 3-3 Proposed scheme for Diels-Alder reaction of vinylpyrroles. . . . .......67

Figure 34 Synthesis of 1-vinylpyrroles ............................................... 68
Figure 35 Synthesis of 2-vinylpyrroles ............................................... 68
Figure 3-6 Synthesis of 2-vinylpyrroles via Wittig reaction ........................ 69
Figure 3-7 Diels-Alder chemistry of 2-vinylpyrroles ................................ 70
Figure 3-8 Synthesis of 3-vinylpyrroles ............................................... 71
Figure 3-9 Synthesis of diynes for hydroamination ................................. 71

Figure 3-10 Hydroamination of l-Cyclohexenyl-l,4-pentadiyne with
aromatic amines ........................................................... 72

Figure 3-11 Hydroamination of 1-Cyclohexenyl-3-methyl-l,4-pentadiyne
with amines ................................................................ 73

Abbreviations

1 NMP ............................................. N-methyl pyrrolidine

2 dpma .............................................. Di(pyrrolyl-0t-methyl)methylamine
3 dmpm ............................................. 5,5-Dimethylpyrrolylmethane

4 dppm .............................................. 5,5-Di-n-propyldipyrrolylmethane
5 dap ................................................. (x-(Dimethylaminomethyl)pyrrole
6 PMB ................................................ p ~Methoxybenzylamine

7 DMSO ............................................. Dimethylsulfoxide

8 DMAD ............................................. Dimethylacetylenedicarboxylate

xi

Chapter 1

Introduction

Hydroamination is the formal direct addition of an N—H bond to a C-C multiple
bond. Hydroamination of alkynes is a desirable transformation in organic chemistry from
a synthetic point of view as the products are important bulk chemicals, fine chemicals
and building blocks in organic chemistry. This reaction is of potential industrial
importance because every year several million tons of various amines are produced
worldwide, and 80% of pharmaceutical products have C—N bonds (Figure 1-1).1 The
hydroamination reaction is atom economical with 100% efficiency; therefore, efficient
hydroamination processes offer significant economical and environmental benefits
compared to classical methods2 for the synthesis of the mentioned target compounds.
From a thermodynamic point of view, addition of amines or ammonia across alkynes and
olefins is possible since the corresponding reactions are exothermic to thermoneutral in

nature. Some olefin additions to ammonia and amines are close to thermoneutral.

 

 

 

R3 N—R‘
Fl‘ __ “2 + H—N /——;-< Enamine
for R4 = H
NR3
/—< lmine
R‘ R2

Figure 1-1. Alkyne hydroamination

To illustrate this fact, two representative sets of thermodynamic data for the reactions
of ammonia and ethylamine with ethylene are represented in Figure 1-2.3 Not much
information is available on AH° data for addition of ammonia or amines to alkynes.
Therefore, comparison between thermodynamics of amine addition to alkynes versus that
to alkenes is not possible. However, addition of ammonia to acetylene is estimated
(AMI-semiemperical calculations) to be ~63 kJ mol'1 more exothermic than that to
ethylene.1 Regarding this estimation, the hydroamination of alkynes is supposed to be

more favorable than the corresponding hydroamination of alkenes.

””2 AG° = - 14.7 kJ mor1
= + NH3 ‘ ~ __/ AH° = - 52.7 kJ mol‘1

AS° = - 127.3 J mol'1 K'1

 

NHE‘ AG° = - 33.4 kJ mor1

= + [gt—NH2 __ - AH° = - 78.7 kJ mor1
AS° = - 152.2 J mol'1 K"

 

 

Figure 1-2. Thermodynamic data comparing hydroamination of amines and ammonia

A high activation barrier exists for the direct addition of amines across C—C multiple
bonds, which arise from electrostatic repulsion between the electron lone pair at the
nitrogen atom, and the electron rich n—bond of the alkyne or alkene. However, one cannot
achieve hydroamination by increasing the temperature because of the negative reaction
entropy AS° of the amine addition (Figure 1-2), the equilibrium of the reaction is shifted
back to the starting reactants with increasing temperature.4

In contrast to the hydroamination of alkenes, which yields amines, the hydroamination
of alkynes gives enamines and imines (Figure 1-1). These imines and enamines can be
reduced by standard organic procedures to give amines, if those are the desired products.
Alkenes are inexpensive compared to alkynes but the hydroamination of unactivated
alkenes is a challenging problem, and the hydroarrrination of alkenes remains an unsolved
synthetic problem. However, great progress has been achieved in developing
hydroamination procedures for unactivated alkynes in the last couple of years. Since the
above mentioned thermodynamical data suggest that the hydroarrrination of alkynes is
possible more easily than that of alkenes, it is a reasonable approach to develop efficient

catalytic hydroamination protocols for alkynes first and subsequently apply the obtained

knowledge to the related procedures for alkenes. In this context, one could say that
hydroamination of alkynes can be seen as a basis for future hydroamination of alkenes.
HowkS discovered one of the earliest examples of hydroamination reactions in 1954
wherein ammonia and primary amines add to alkenes in the presence of alkali metals or
their hydrides, but the reaction typically requires harsh conditions (175 oC-200 °C, 800-
1000 atm). The yields were poor and often yielded mono and multiple hydroamination
products. Pez6 reported an efficient metal-amide catalyzed addition of diethylamine and
ammonia to ethylene and propylene. Kruse7 reported one of the earliest hydroamination
reactions of alkynes, wherein ammonia added across the carbon-carbon triple bond at
300-350 °C in the presence of silica or alumina catalyst, while amines required zinc or
cadmium acetate catalyst.

Hydroamination of alkynes can either be an intramolecular or intermolecular reaction,
the latter one being the more difficult of the two. This is can be argued in terms of the
entropy decrease going from intramolecular to intermolecular hydroamination. Even
though both the processes involve a decrease in the entropy, the decrease is going to be
more for the intermolecular one compared to the intramolecular hydroamination.

There have been a number of different transition metals used for the hydroamination
procedure, like mercury and thalium salts, alkali metals, lanthanides, actinides,
zirconium, ruthenium, rhodium, palladium, gold complexes and titanium. By way of
introduction and to place titanium-catalyzed reactions in a context, a brief discussion of a

few different hydroamination catalysts is provided.

1.1.1 Hydroamination using Hg and TI salts

Mercury and thallium complexes catalyze reactions involving terminal alkynes.
Hudrlik,8 reported a low yield of the hydroarrrination product, which was an aziridine
enamine, from the reaction of l-octyne and aziridine in presence of mercuric acetate as

the catalyst (Figure 1-3).

A.

W
mm MAW

AN AN

1 N benzene, 020 _ 1
MN 7 NH2

Figure 1-3. Hydroamination of terminal alkyne with Hg salt

 

Another reaction with pyrrolidine and l-octyne was also reported in good yield, to
give a saturated amine but then one had to deal with the problem of formation of an
iminium salt intermediate,9 (for example, addition of mercury or proton to the initial
aminomercuration adduct), which is easily reduced to a saturated amine. The use of
aziridine effectively prevents the formation of the iminium salt because of the strain
involved in generating an sp2 center in a three-membered ring, and hence facilitates
formation of the enamine. Though this is one of the earliest examples of alkyne
hydroamination to give enamines and saturated amines, this procedure is not of
significance, because one would have to deal with using mercury as stoichometric

reactant. However, this example did pave the way for further catalyst development. Even

though one could achieve product formation in this reaction using the procedure by
Barleunga,10 wherein catalytic amount of mercury (H) chloride and acetate were used, the
method is still not desirable due to the precipitation of metallic mercury.

Barleunga,11 further modified this method and used thallium (1H) acetate instead of
mercury (II) complexes for the hydroamination of phenylacetylene with primary aromatic

amine in a stoichometric ratio.

1.1.2 Hydroamination using alkali metals

In 1999, Knochel,12 reported the first base-catalyzed hydroamination of alkynes with
substituted anilines and heterocyclic amines. They reported the hydroamination of
phenylacetylene with diphenylaniline and N-methyl aniline in the presence of catalytic
amounts of CsOH in N1VIP(N-methylpyrrolidine) at 90-120 °C leading to corresponding

enamines in 82% and 46% yield, respectively (Figure 1-4).

  

 

 

/ \ __ t: + H—N CsOH.H20 20 mol /0 >
_ \Fl NMP, 90 -120°C, 12 to 24 h H

Figure 1-4. Base catalyzed hydroamination of alkynes

Recently,13 the same group reported a base-catalyzed intramolecular hydroamination
of 2-(2-alkynyl)anilines to form substituted indoles in 61-90% yield. The cyclization
reaction is fast at room temperature and tolerates several functional groups enabling the
preparation of a variety of polyfunctional indoles. This interesting cyclization was also

extended to various heterocyclic amines such as amino pyridines.

1.1.3 Hydroamination using lanthanides and actinides

Marks,l4 provided the first example, an intramolecular hydroamination of amino
alkynes catalyzed by organolanthanides, Cp'anCH(SiMe3)2 (Ln: La, Nd, Sm, Lu;
Cp'=775—Me5C5) and MeZSiCp"2LnCH(SiMe3)2 (Ln: Nd, Sm; Cp"=775-—Me4C5), which
offers a new route to a diverse variety of heterocycles and natural product skeletons. The
same catalysts also perform intermolecular hydroamination of internal alkynes with

primary amines yielding imines with good percentage yields.15 (Figure 1-5).

H2N
(> ) 10% Cp'anCH(SiMea)2 /N
m r
R — CeHs

R
10% Cp'anCH(SiM93)2 I

NH 7
+ N 2 N\/\

can6

 

 

 

3'.)

R: TMS, Ph, Me

Figure 1.5. Hydroamination of alkynes catalyzed by lanthanides

Eisen,16 provided the first example of catalytic intermolecular hydroamination of
terminal alkynes with aliphatic amines using actinides, such as thorium and uranium
yielding imines and enamines. An interesting aspect to note is that the regioselectivity of
the products can be tuned by the alkyne and the metal used. The uranium-based catalysts

predominantly yield aldimines in 80-90 % yields, whereas the thorium-based catalyst

gives only the ketimines in somewhat poor yields if the alkyne is internal, but for

terminal alkyne the yield is around 80% (Figure 1-6).

 

 

 

 

H R'
R _— H + R'NH2 10% CVZUMGZ > _N/
c.,H(5 or THF
R
R: TMS, Ph, n-BU. t-Bu 85-90%
R': Me, Et
. . NR'
a H + RNH2 10% Cp 2ThMe2 ;
—' CsHa or THF
R

R: H, R': Et yield is around 80%

R: Ph, n-Bu, R': Me, Et yield is around 7-30%

Figure 1.6. Hydroamination of alkynes catalyzed by actinides

Roesky,17 reported the synthesis of mono- and bis(N-iso-propyl-2-(iso-
propylamino)troponiminato)yttrium amides, [(zPr)2ATI]Y[N(SiMe3)2] and
[(i'Pr)2ATI]2Y[N(SiMe3)2] and used it as a catalyst for the intramolecular hydroamination
of cyclic amines. These complexes were the first cyclopentadienyl-free catalysts for the
intramolecular hydroamination reaction. The reaction requires around 2.0 mol% of the
catalyst and goes to completion in less than an hour (Figure 1-7).

Recently Hultzch,18 also reported a yttrium-based catalyst for the intramolecular
hydroamination of alkenes and alkynes. Schafer,19 has also reported a scandium—based

cationic catalyst for the intramolecular hydroamination of alkynes.

2.0 mol % m

/\A benzene. 21 ° C. < 1 h N\
¢ NH2 > R1

R

 

R: Me, Ph R1: Me. 'CH2Ph

m= O (NI/0' Y—N(SiMe3>2
7 N

2

Figure 1.7. Hydroamination of alkynes with yttrium amides

1.1.4 Hydroamination using ruthenium complexes
Ruthenium-catalyzed intermolecular hydroamination was first reported by
Uchimaru,20 wherein phenylacetylene reacted with N—methylaniline in the presence of

Ru3(CO)12 to afford N—methyl—N-(a—styryl) anilines in high yields (Figure 1-8).

 

 

”\H N R
5 %RU3(CO)12 T
R —_ + =
. 70°C. 18 h
R R'
R: CeHs, n'CaH13. CH20Me

R.= CsHs, 4‘CH3005H4, 2'CH3(6'C2H5)CH3. 4°CIC6H4

Figure 1-8. Hydroamination of alkynes catalyzed by ruthenium complex

 

Another example of a RU3(CO)12 catalyzed hydroamination reaction of
phenylacetylene and aromatic amines was provided by Wakatsuki,21 where in the
presence of an additive like NH4PF6(0.3 mol %), gave imines in high yields. In absence

of the additive, a poor yield of 3 % was obtained under the same conditions.

1.1.5 Hydroamination using rhodium complexes

Beller,22 reported a hydroamination reaction of terminal alkynes with substituted
anilines in the presence of cationic rhodium (1) catalyst, Rh[(COD)2]BF4, under very
mild reaction conditions to yield up to 99% of the corresponding imines (Figure 1-9).
Other rhodium complexes like, [Rh(COD)Cl]2, [Rh(COD)(acac)], [Rh(PPh3)3Cl] and
RhCl3.xH20 in combination with different phosphine ligands show no hydroamination
activity.

NF?1

__ [Rh(COD)2]BF4
C6H13—__-: + HQNR1 > C6H13

PCYa

 

R1=CBH5, 2'M9'06H4, 4'M9'06H4, 4'M90'06H4,3'F'CBH4

Figure 1-9. Hydroamination of alkynes catalyzed by rhodium complex

This method was further extended for a one-pot protocol for the synthesis of branched
amines directly from alkynes by in situ addition of organometallic compounds. Messerle

23

and Turner, recently reported an intramolecular hydroamination of alkynes catalyzed by

cationic rhodium and iridium complexes.

10

1.1.6 Hydroamination using palladium complex

Mtiller,24 reported an intramolecular hydroamination of 6—amino-1-hexyne catalyzed
by 1 mol% of Pd(CH3CN)4(BF)2 to generate the intermediate 2-methylene piperidine.
Subsequent 1,3-hydrogen-shift leads to isomerisation of the initially formed enarnine to
the more stable imine to afford 2-methyl-1,2-dehydropiperidine in 67% yield (Figure 1-

10).

23:

 

 

 

NH2 Pd(CH3CN)4(BF4)2>
/\/\/

H

Figure 1-10. Hydroarrrination of alkynes catalyzed by palladium complex

1.1.7 Hydroamination using gold complex

Tanaka and Hayashi,25 recently published a Au (I) catalyzed, [(Ph3P)AuCH3] with
acidic promoters, heteropoly acids in particular to give ketirrrines, with around 80-90%
yield (Figure 1-11). Some of the heteropoly acids used were H3PW12040, H3MoW1204o,
and H4SiW12040, which were particularly effective giving high yields of the ketimines. In

the absence of the acidic promoter the hydroamination did not work nor did the reaction

11

work in absence of the Au catalyst. Some other acidic promoters like ammonium
hexafluorophosphate and tetrafluoroborate were able to activate the alkyne, but gave only
modest yields. A typical example of the reaction between aniline and phenylacetylene,

using 0.2 mol% (Ph3P)AuCH3 and 1 mol% H3PW12040, proceeded to give N-(OL-

methylbenzylidene)aniline in 98% yield.

 

 

\N
1 2 3 0.2 mol % (PhaP)AuCH3 _ l
R — n + R NH2 1 mol % Acidic promoter R2
R1
Solvent free
+
R3
R1=C6H5, 4'FCSH4, 4'8'06H4JI'CGH13, WC3H7 \N

R2:CH3, H, n'CaH7 k/R1
R2

R3: substituted aromatic amines
Figure 1-11. Hydroamination of alkynes catalyzed by gold complex
In these reactions, the products obtained were a mixture of the corresponding imine
and enarnine, the former being the major component. In addition, internal alkynes took

longer reaction times compared to the terminal alkynes and gave moderate yields of 50-

60%.

12

1.1.8 Hydroamination using Group IV complexes

a) Zirconium

In 1992, Bergman26 reported that zirconium bisamides, CpZZr(NHR)2, catalyze the
intermolecular hydroamination of alkynes with sterically hindered primary amines to give

enamines or their tautomeric imines (Figure 1-12).

NHAr
3 % Cp22r(NHAr)2

CGHG, 120°C

 

Ph —_ Ph + ArNHz

 

Ph Ph
Ar: 2,6-dimethylphenyl 60%

Figure 1-12. Hydroamination of alkynes catalyzed by zirconium complex

A transient imido complex, Cp2Zr=NAr is obtained by thermolysis of the biamides,
which undergoes a reversible [2 + 2] cycloaddition with the internal alkyne to provide
azametallacyclobutene (Figure 1-13). The rate-determining step is the a—elimination of
the amine to give the imido complex. Further, the metallacyclobutene reacts with the
amine to form the enamine and Cp2Zr=NAr, beginning the catalytic cycle again. The
addition of alkynes to Cp2Zr=NAr occurs regioselectively to metallacycles, with the
larger alkyne substituent located a to the metal center. The hydrolysis of metallacycles
gives enamines and imines, which are the net result of anti-Markovnikov addition to the

alkyne.

13

 

szzrlNHAr)2 [Cp22r==(NAr)] + ArNH2
H NH Ar h-C—C-Ph
Ph Ph
Ar '
\ pn
”'1 Al
092 r \ N
NHAr Ph CpZZr/ / Ph
Ph
AINHZ

Figure 1-13. Bergman’s mechanism for hydroamination for alkynes

A drawback for this reaction is the slow rate and its limitation of using disubstituted
alkynes. Also, attempts to hydroaminate olefins such as ethylene, allylbenzene and
norbomene with bisarnide Cp2Zr(NHR)2, and corresponding amines with temperatures up
to 160 0C were unsuccessful.

In 1993, Bergman27 reported hydroamination of terminal alkynes with zirconium
bisarnides, CpZZr(NHR)2, followed by hydrolysis to give predominantly the anti—

Markovnikov product.

14

b) Titanium

The earliest example of titanium-catalyzed hydroamination was provided by

Rothwell,28 wherein titanium bis(phenylamido) complex (I) catalyzes the reaction of

aniline and 3-hexyne to give N-phenylimine of 3-hexanone (Figure 1-14). The titanium

phenylamido complex (11) does not show any evidence of hydroarrrination with 3-hexyne

even after heating at 110 0C for days, probably due to pyridine inhibition.

Ar-OIIIII”. ./Ph

TI
Ar'O/ \Ph

Ar“ = 2,6-Ph206H30

+ 2 NHzPh

 

- 2 06:46

Arl'OllllhhT/NHPh

I
Ar'O/ \NHPh

+ 2 W
- NH2Ph

Figure 1-14. First example of titanium catalyzed hydroarrrination of alkynes

Livinghouse29

provided further evidence of titanium-catalyzed hydroamination,

wherein CpTiCl3 catalyzed the intramolecular hydroarrrination of y—aminoalkyne (Figure

1-15). This intramolecular hydroamination results in an imidotitanium-alkyne [2+2]

cycloaddition, which is used in the synthesis of the indolizidine alkaloid (i)-

monomorine.

15

//

i
NH2

m%cmm3

EnN

 

 

 

EsNH+cr

/

 

 

 

Figure 1-15. Synthesis of (:t)-monomorine via intramolecular hydroamination.

Another alkaloid, (+)-Preussin was also synthesized, with a crucial intramolecular
imidotitanium-alkyne [2+2] cycloaddition step, followed by an acyl condensation to give,
(+)-Preussin30 (Figure 1-16). The overall yield for the synthesis was around 35-44%.

31 was the

Another example of intramolecular hydroamination, published by Livinghouse,
synthesis of dihydropyrrole and tetrahydropyridine derivatives by 20 mol%

szTi(CH3)2Cl and Cer(CH3)2Cl catalysts, with a reasonably good yield of 80-90%.

16

\OBn " \\\\OBn -

 

 

 

 

 

R2 = C(Ph)2
H20204/H20l n
0:0,”, R = H : / N '11,,0/
CpTi(CH3)2Cl T_/
I
CI/ \Cl
4 steps
ll
‘s‘OH
u“ "'m
n-C9H19\\\“ : T: ”I
(+)- Preussin

Figure 1-16. Synthesis of (+)-preussin via intramolecular hydroamination catalyzed by
titanium

In 1999 Doye,32 reported an intermolecular hydroamination of alkynes and aromatic
amines with commercially available szTiMez to give amines, obtained by reduction of
enamines and imines, in relatively good yield of 65-80% yield. This hydroamination did
not work well with benzylamine or with terminal alkynes. Replacing the aromatic
substituent on the alkyne with an alkyl group, also leads to a drastic decrease in the yield.
In many cases, the enamines and the imines obtained by hydroamination were hydrolyzed
by silica to give ketones in 70-85% yield (Figure 1-17). For unsymmetrical substituted

alkynes, the hydroamination reactions occur with high regioselectivity

17

1) 3.0 mol % [szTiMezL NHR

O
Ph—=—Ph + RNH2 100 C’ 72 h > /———<
2) LiAIH4, THF

Ph Ph

 

1) 3.0 mol % [szTiMezL
100°C, 72 h R: Ph, p-C5H4, CSF5, 2,6'M9206H3
2) SiOz, CH20I2

 

ll

/ :0
Ph Ph

Figure 1-17. Hydroamination of alkynes with szTiMez as catalyst

The mechanism for this hydroamination is similar to Bergman’s mechanism.33
In 2000 Doye,34 reported an ammonia equivalent in the dimethyltitanocene-catalyzed

intermolecular hydroamination of alkynes by using benzhydrylamine. This procedure

combined with reduction of the initially formed imines, gives primary amines with 70%

yield (Figure 1-18).

18

 

 

‘ N Ph
NH2 3.0 mol % [szTiMez], I
110-12000, 72 h R1
R‘ —_ a2 + = 2
R
Ph Ph
R‘: Aryl, Alkyl
R2: Aryl, Alkyl, H H2, 5 mol %Pd/C

 

Figure 1-18. Hydroamination of alkynes with szTiMez as catalyst and benzhydrylarrrine

This is an improvement over the previously reported work, where only secondary
amines where obtained, by reduction of the imines formed during hydroamination. Also,
initial experiments of alkyne hydroamination using benzylamine as the ammonia
equivalent had limited success, because benzylamine shows a very low reactivity with the
dimethyltitanocene-catalyzed hydroamination reactions. The hydroamination shows good
results with bisaryl alkynes and alkyl aryl alkynes, but the reaction is relatively slow and
requires 72h to proceed to completion. In contrast, the reactions employing bisalkyl
alkynes do not proceed to completion even after 72b. The hydroamination reactions occur
with high regioselectivity for terminal alkynes and alkyl aryl alkynes.

szTiMez-based reactions have also been reported by Doye35 that catalyze the
intramolecular hydroamination and cyclization of aminoalkynes to give five- and six-

membered cyclic imines within 4-6 h. The imines can be subsequently reduced with

19

sodium borohydride and zinc chloride at room temperature to give cyclic amines in 70-
85% yields.

In 2002, Doye36 modified his titanocene-based catalyst by replacing the Cp group
with Cp', i.e. the pentamethylcyclopentadienyl ligand. In his previous paper,33 a
mechanistic study showed that unfavorable equilibria between titanium imido complexes,
imido complex dimers, and bisamides are responsible for the decreased reactivity of
sterically less demanding amines. So, the use of bigger, space-demanding ligands at the
titanium center should result in faster reactions with smaller amines. The hydroamination
carried out by this modified ligand gives excellent results for intermolecular addition of
various sterically less hindered n-alkyl- and benzylamines to internal alkynes with yields
in the typical range of 70-90%. The hydroamination reactions occur with high
regioselectivity giving the anti-Markovnikov products.

Recently, Doye reported a highly active catalyst for the intermolecular
hydroamination of terminal and internal alkynes using catalytic amounts of IndzTiMez as
the catalyst (Ind=Indenyl).37 This catalyst performs hydroamination of internal and
terminal alkynes with primary aryl, tert-alkyl, sec-alkyl and n-alkylamines (Figure 1-19).

Fl2 (Bu
1) 5.0 mol % [lndzTiMez] HN/ /

toluene, 105 ° C, 3-48 h HN
Ph : a1 + RZNHZ #- > + >___\
2) NaBH3CN, ZnCl2 1
1: 1 Ph R
R M6, CaHs, Cng MBOH, 25 0 C, 20 h R Ph

F12: 'Bu. n-propyl, 2,6-dimethylphenyl, C5H9 anti-Mnaarzovnikov Markovnikov
l

 

 

Figure 1-19. Hydroamination of alkynes with Indenyl-based titanium catalyst

20

The major product of hydroamination of terminal arylalkynes is always the anti-
Markovnikov product, whereas alkylalkynes react with arylamines to give the
Markovnikov product.

In 2002 Richeson,38 reported the formation of Ti(IV) terminal imido complex possessing
a guanidinate ancillary ligands, which catalyzes the intermolecular hydroarrrination of
alkynes (Figure 1-20). Terminal alkynes react more rapidly, with higher yields of the
imine than internal alkynes and also less bulky arylamines and aliphatic amines are

effective for the hydroamination of alkynes with the guanidinate-based titanium catalyst.

 

 

Ar'N Ar'N
5.0 mol% [Ti],
_ n . 105°C > \ + > \
R‘ n2 + ArNH2 = R1 R2 R2 31

R1: Phi M9. "'BU Markovnikov anti-Markovnikov
R2: Ph, H, Me Ar= 2,6—M62C6H3

M62N Nip/r

—N I/IIIIII'," r:N\

lTil - Ti=NAr
PH’N /I
>\_/N
MezN iPr

Figure 1-20. Hydroamination using guanidinate ancillary ligands on titanium

The catalyst exhibits reactivity comparable with the szTiMez and Cp2Zr(NHAr)2
catalyst precursors of Doye and Bergman, respectively. It is interesting to note, that
phenylacetylene preferentially undergoes anti-Markovnikov addition, while

hydroamination of l-hexyne generates predominantly Markovnikov products. The

21

authors attribute this complex regioselectivity to the sterics of the bis(guanidinate)
framework.

Beller39 reported the intermolecular hydroamination of terminal alkynes using a
titanocyclopropene-based catalyst to yield the anti-Markovnikov product selectively
(Figure 1-21). Before this communication, the only group that reported intermolecular

hydroamination of terminal alkynes using titanium-based catalysts was the Odom group.

 

 

tBu EU
2.0 mol % [Ti], N/ N/
a 2 H + t-BuNH2 105°C = >___\ + >—
R= Bn, -(CH2)n, (cycIo-C5H9)CH2 H R R
"= 4' 6'8 anti-Markovnikov Markovnikov
> 70 : 1
ltBu

—— 2.0 mol%[T i],
()2 + t-auNH2 105°C > (02

 

\iBu

m]: Cp2Ti(772-Measi0-CSiMe3)

Figure 1-21. Hydroamination of terminal alkynes using titanocyclopropene-based
catalyst

The titanium complexes ([szTi(02—Me3SiCECSiMe3)] and
([szTi(7]2—Me3SiCECPh)] are synthesized by reaction of titanocene dichloride with the
corresponding silylated alkyne. The hydroamination of terminal alkynes with tert-

butylamine in the presence of the catalyst yielded imines with more than 90% yield with

22

a typical reaction time of a day. The reaction gave predominantly anti-Markovnikov
products, except when using aniline, where Markovnikov products are preferentially
observed. For terminal alkynes with shorter alkyl substituents the hydroamination was
complete in two hours. This is the also the first communication wherein
dihydroamination of diynes is reported to give diimines in 90% yield. A further
modification of this reaction to give (Jr-branched amines was reported by Beller40 a year
later, wherein the corresponding hydroaminated products obtained in the above reaction
were treated with a nucleophile, e. g. n-BuLi and PhLi to provide a—branched amines.
Recently Bergman41 reported the use of group-4 bis(sulfonarrrido) complexes in the
intramolecular hydroamination of alkynes and allenes. Odom42 reported better efficiency
of titanium tetrakis(amido) complexes compared to Cp-based species. By replacing the
ligands with electron-withdrawing groups the metal center can be made more electron
deficient and catalytic activity of the titanium metal center can be increased. Bergman
employed electron-withdrawing and sterically demanding bis(sulfonamido) ligands
(Figure 1-22). Replacing the aryl group on the sulfur by trifluoromethyl and methyl
groups yields a new titanium catalyst, which converts aminoallenes selectively to the

corresponding cyclic imines with corresponding yield of more than 80%.

23

O

 

Fl 14
02$ 023
NH \ [NMez
. Et20 Ti
+ Tl(NM92)4 > 'I / \NM
.. -2HNMe ’I/ 92
"’NH 2 'i‘
so2 302
R O R R R
R: Me, H

Figure 1-22. Hydroamination of alkynes and allenes with group-4 bis(sulfonamido)
complexes

Bergman’s group also reported,43 the synthesis of the new neutral and cationic
imidotantalum complexes, which catalytically hydroaminate alkynes. This is the only
group, which has reported hydroarrrination by group-5 transition metals other than
Lorber’s group.“ Cationic group-5 imido complexes are promising as potential
hydroamination catalysts, since these compounds are isoelectronic to the group-4
catalysts. Hydroamination of diphenylacetylene by aniline in the presence of 5 mol%
[(PhCH2)Ta=NCMe3,]+ at 135 °C gave the imine and enamine products in 3:1 ratio in
26% yield (Figure 1-23). An increased yield of 95% was obtained by in situ generation of

[(PhCH2)Ta=NCMe3]+.

24

 

 

5.0 mol °/o [Ta], / /
o N N
R’ _ R2 + PhNH2 CGDSCI' 135 C > \> \>
+
R1 R2 R2 R‘
Markovnikov anti-Markovnikov
Ph + _
[Ta]: Ta=NCMe3 5(Cerl4
Ph

R‘and R2 = Bi and E1, n-Pr and Me, Ph and H, n-Pr and H, Ph and Me

Figure 1-23. Hydroamination of alkynes with cationic imido complex of tantalum

Hydroamination of internal alkynes was slower than terminal ones and
dialkylacetylenes react more slowly than diphenylacetylene. l-phenylpropyne failed to
react or to give hydroamination products. The tantalum imido species also catalyzes an
unusual hydroamination/hydroarylation reaction between norbomene and aniline.

Ackermann,"5 reported the catalytic intermolecular hydroamination of internal alkynes
by TiC14. He also prepared a titanium imido catalyst, obtained by the reaction between

TiCl4 and excess of 'BuNHz in a halogenated solvent, to give [Clz(py)3Ti=N'Bu] (Figure

 

 

1-24).
R1 R‘
N/ HN/
10.0 mol% Cl T1=N‘B : :
R —_ R + R1NH2 [ 2(DY)3 U]: \ +
R = Ph, Et R R R R

R‘ = Ph, 2,6-Me206H3, and ’Bu
Figure 1-24. Hydroamination of internal alkynes with titanium imido complex
This catalyst performs the hydroamination reaction of internal alkynes such as

diphenylacetylene and phenyl substituted internal alkynes with ’BuNHz to give good to

25

moderate yields of the hydroaminated product. On the other hand, a catalytic amount of
TiCl4 performs hydroamination with diphenylacetylene and phenyl-substituted internal
alkynes with different halogen-substituted amines to give over 80% yield of the

hydroaminated product (Figure 1-25).

10.0 mol % TiC|4 N/
toluene 'BuNH \/\
1 — n2 3 I 2

R‘and R2 = Ph and Ph, Ph and Me, ”Pr and "Pr

 

 

 

R3 = Ph, 4‘MeCBH4NH2, 4‘F06H4NH2, 2"CIC6H4NH2, 3,5‘M6206H3NH2
4-Br-2-MeCeH3NH2, 2'ICBH4NH2, 4'Et02CC6H4NH2

Figure 1-25. Hydroamination of internal alkynes with titanium tetrachloride

Furthermore, this methodology proves tolerant to halide substituents on the aromatic
ring of the amine, allowing expansion of this methodology in the one-pot synthesis of
substituted indoles.

Schafer46 reported the preparation and characterization of amidate complexes of both
titanium and zirconium and their application as catalysts for the intramolecular

hydroamination of alkynes. The catalyst was prepared from reacting amide proligands

with Ti(NMez)4 and Zr(NMe2)4 (Figure 1-26).

26

O 0

EN, HCI,RT,1h
/"\ +'BuNH2 3 C2 2 : /u\/’Bu

 

 

Fl Cl R N
H
R: IPr, Ph, 0er
M(NR‘)4, toluene, heat, 14 h
M=Ti, Zr
v R‘: Et, Me
”N /Nt=t‘2
R M\
o NW2
2

Figure 1-26. Use of amidate complexes of group-4 metals for intramolecular
hydroamination

As expected, the titanium analogues prepared from phenyl and iso-propyl proligands
are more active catalysts than their zirconium derivatives. Also, incorporation of
electron-withdrawing substituents on the carbonyl moiety of the amidate ligand
dramatically enhances catalytic activity. Hence, it is observed that pentafluorophenyl
substituent on the titanium amidate ligand does hydroamination in 15 minutes compared
to the alkyl substituted amidate ligand. Hydroamination results show that a catalytic
amount of the titanium amidate complex yields over 90% of the hydroaminated imine
product when the reaction is carried out with l-hexyne and substituted amines.

The reaction predominantly yields the anti-Markovnikov product (>90%) with tert-
butylamine and iso—propy] amine, while with 2,6-dimethylaniline, the Markovnikov
product is favored (>90%). These catalysts also perform intramolecular hydroaminations
of alkynes and can be tuned for intermolecular hydroaminations by modifying the

amidate ligands.

27

1.1.9 Research in the Odom group

Early research, in our lab was aimed towards the use of non-cyclopentadiene based
systems for hydroamination of alkynes, as previously all known titanium based catalysts
were metallocene based. Odom47 published the use of Ti(NMe2)4 as a catalyst for the
hydroamination of alkynes with primary amines such as aniline. The hydroamination
reaction predominantly gave the Markovnikov addition product, which is in contrast to

the catalyst MezTisz that yields the anti-Markovnikov product (Figure 1-27).

 

 

N—Ar Ar
/ N/
10 % T' NM
R _ R' + 3ArNH2 '( 92)“ = + I R
toluene, 75°C '
R' R R
R, R': (Bun, H); (Et, Et); (Ph, H); (Ph, Ph) For R': H : Markovnikov anti-Markovnikov

Figure 1-27. Hydroamination of alkynes with catalytic amounts of Ti(NMe2)4

The ratio of Markovnikov:anti-Markovnikov products varied from 3:1 to >50:1 with
the different substrates examined. The hydroamination is fast and takes around two hours
for l-hexyne but for internal alkynes such as 3—hexyne, it is slow and the yields are
around 80-90%. The reaction works with aromatic amines such as aniline but was low
yielding with benzylamines and alkyl amines such as t-butylarnine.

Further modifications to this catalyst was reported,48 where instead of Ti(NMe2)4 as
the catalyst, Ti(dpma)(NMez)2, where dpma is di(pyrrolyl-oc-methyl)methylamine. The

catalyst is prepared from Ti(NMe2)4 and szpma in near quantitative yield (Figure 1-28).

28

 

H H
N o H N
N N
2 + 2 k.» MeNH2.HCI HOE/”2° = I \ I /
/ H H 55 0, 4h \

szpma 72% yield on 139 scales

1 Ti(NMe2)4

/ NM92
N\ I
/ QRi—NMGQ

|\|I“"N
/ \Me

Ti(NMe2)2(dpma)

Figure 1-28. Synthesis of Ti(dpma)(NMe2)2

szpma is readily prepared in a single step from a Mannich reaction between two
equivalents of pyrrole, two equivalents of formaldehyde and one equivalent of
methylamine hydrochloride.49 The hydroamination of alkynes using Ti(dpma)(NMe2)2 gave
imines in yields up to 90% for some substrates. Some of the catalyses were slow at 75 °C,
giving low conversions after days of reaction time. In general, hydroaminations involving
internal alkynes were slow with alkyl amines, such as cyclohexylamine. By increasing the
temperature to 130 °C, the yields of the products increased after reasonable reaction times.
The hydroamination of l-phenylpropyne has the nitrogen attachment ,6 to the phenyl group
and this is one of the examples where hydroamination using Ti(dpma)(NMe2)2 and
MezTisz gave the same product. The same product is obtained for both the catalysts if
diphenylacetylene is used as a substrate for hydroamination. The selectivity for the
formation of the Markovnikov product is greater if Ti(dpma)(NMe2)2 is used as the catalyst

in hydroamination. Also, hydroamination using amines such as benzylamine and

29

benzhydrylamine is possible with Ti(dpma)(NMe2)2. The reaction times are slow but give
reasonable yields of the products, around 70-90%. Benzhydrylamine shows poor
regioselectivity with the Markovnikov product being favored only 3:1, Benzylamine gives
very high Markovnikov selectivity. These results are in marked contrast to catalysis with
Ti(NMe2)4, where both benzylamine and benzhydrylamine reactions with l-hexyne
displayed poor yields and selectivities under the same conditions.

A new catalyst50 was reported in 2003, which was obtained by reacting Ti(NMe2)4
with 5,5-dimethylpyrrolylmethane (szmpm). Ti(dmpm)(NMe2)2 was prepared in an
attempt to decrease steric constraints and to increase Lewis acidity of the metal center
(Figure 1-29).

Me Me H
N

H O
N i cat TFA I \
25 equiv D + Me Me neat, 5 min. \ /

53%, 59 scale

23:

 

HMe Me H
N N

 
 
 

, Ether, RT, 3 h ‘—NM
+ T'(NM92)4 > '\ 92

\l \/

 

Figure 1-29. Synthesis of Ti(dmpm)(NMe2)2

Because of poor solubility of Ti(dmpm)(NMe2)2 in some common solvents,
Ti(dppm)(NMe2)2 (szppm is 5,5-di-n-propyldipyrrolylmethane) was also prepared from
5,5-di-n-propyldipyrrolylmethane and Ti(NMe2)4. The solid state structure of both

Ti(dppm)(NMe2)2 and Ti(dmpm)(NMe2)2 has one ns—pyrrolyl ligand, while the other is

30

an nl-pyrrole. The hydroamination reaction of terminal alkynes with Ti(dmpm)(NMe2)2
as a catalyst yields the hydroaminated product in 5 minutes at room temperature in
moderate yields of 50-80%. Internal alkynes like 3-hexyne and l-phenylpropyne took
longer times, usually around a day for completion. The Markovnikov product was
selectively obtained for most of the cases, with more than 40:1 ratio of
Markovnikov:anti-Markovnikov products. These catalysts obtained are an order of
magnitude faster compared to the szTi-(Me3SiCECSiMe3) and Ti(dpma)(NMe2)2
catalysts.

Another application of alkyne hydroamination was investigated51 wherein, 1,1-
dialkyl-substituted hydrazines directly added across the multiple bond of unactivated
alkynes to give a new catalytically transformed product. Due to effects associated with
1,1-disubstituted hydrazines, such as chelation effects with both nitrogens of the
hydrazine bonding in the same complex, new catalysts were developed as the regular
catalysts Ti(NMe2)4 and Ti(dpma)(NMe2)2 proved ineffective for hydrohydrazination

(Figure 1-30).

31

NM62

 

 

H H
N 0 o N
I + i + HNMez.HCI 6° (3'2“ =
/ H H \ /
Hdap
NM92
NM92 I
n \ N’IIllgTi.|\|\“\NM62
2 . 95% N/I \NM62
\ / + TI(NMeZ)4 > M32 N
Ti(dap)2(NMez)2

Figure 1-30. Synthesis of Ti(dap)2(NMez)2

The pyrrolyl titanium complex, Ti(dap)2(NMe2)2 was prepared from two equivalents
of oc-(dimethylaminomethyl)pyrrole,52 (Hdap) and Ti(NMe2)4. A second catalyst, five-
coordinate Ti(NMe2)2(SC6Fs)2(NI-11V1e2), was produced from two equivalents of

commercially available pentaflurophenylthiol and Ti(NMe2)4 (Figure 1-31).

 

/F5
F \ NMe
HS 5 2
/\ 65% \ Sm... I.
I + Ti(NMe2)4 > (Ti—NMez
/ s T
\ NHM82
\ Y
/
F5

Ti(SC6F5)2(NHM92)(NMez)2

Figure 1-31. Synthesis of Ti(SC6F5)2(NHMe2)(NMe2)2

32

With Ti(dap)2(NMe2)2 as the catalyst, hydroamination of terminal alkynes by 1,1-
dimethylhydrazine proceeded to completion in a day at 100 °C to yield the imine in 75-
80% yield. This catalyst fails to show any reactivity with symmetrical internal alkynes
such as diphenylacetylene and 3-hexyne with 1,1-dimethylhydrazine although
hydroamination was observed with l-phenylpropyne. With Ti(NMe2)2(SC6F5)2(NHMe2)
as the catalyst for terminal alkynes such as l-hexyne, the results were more or less
consistent with those obtained by Ti(dap)2(NMe2)2 (Figure 1-32).

R1
\
N—

H2 10 % Ti(dap)2(NMe2)2 : _ S;
toluene, N2 N

/ \ R1

R1 _ ll

N
__ [1 + I
N

R1=Bu", Ph

Figure 1-32. Hydroamination of hydrazines with Ti(dap)2(NMe2)2

With Ti(NMe2)2(SC6F5)2(NI-1Mez) as the catalyst, better reactivity is obtained with
internal alkynes such as diphenylacetylene and l-phenylpropyne, with yields of 90% and
22%, respectively. When aryl hydrazines were used, a modification of the Fischer indole

synthesis,53 occurred to give substituted indoles in moderate to high yield (Figure 1-33).

 

 

R3
NH2 10 % “(dap)2(NMez)2 / N/
I Ti(SC6F5)2(NHM82)(NM92)2
R1 __ R2 + N = R2
— toluene, N
Ph/ \Ft" 2 /
1_ n
R _Bu , Ph R3=Ph,Me, R1
H2=H, Ph, M6

Figure 1-33. Hydroamination of alkynes and aryl hydrazines to give substituted indoles

33

To facilitate indole formation, ZnClz was added to some reactions in a one-pot
procedure. Also reported was acetylene hydroaminations by 1,1-disubstituted hydrazines.
Acetylene hydroamination is extremely fast at room temperature, and the reactions were
complete in less than two hours at room temperature.

As an extension of the current work, Odom reported54 a titanium catalyzed three-

component coupling between amines, alkynes, and isonitriles to generate ogfl-unsaturated

,B-iminoamines in moderate to high yields (Figure 1-34).

 

_ 10% Ti(NMe ) (dpma) HL—N NHR3
R‘——_H H N-R2 a — 3 2 2 V
+ 2 + C N R 24 “100 0C \>——/—

R‘=Bu", Ph 92: ph’ Cy R‘

R3: tert—butyl, 1,1,3,3-tetramethylbutane

L __ , _ 10% Ti(NMe ) (dpma) Ph—N NHR3
P I \lle H N-Ph = - 3 2 2fi
1 l + 2 + C N R 24 “.100 °C M

Me Ph

 

 

R3: tert-butyl, 1.1.3.3-tetramethylbutane

Figure 1-34. Titanium catalyzed 3-component coupling to give 01,,6-unsaturated ,6-
immoamrnes

Different isonitriles along with terminal and internal alkynes were tried for three-

component coupling with aniline and cyclohexylamine. The major byproduct in some of

the reactions was formamidine formation, which led to optimized conditions using 1.1 or

1.2 equivalents of isonitriles. The catalyst used for the three component coupling was

Ti(dpma)(NMe2)2 which successfully catalyzed the reactions with aryl and alkyl amines,

34

terminal alkynes and internal alkynes with isonitriles bearing a quaternary alkyl group.
Regioselectivities in the three-component coupling reactions using T i(dpma)(NMez)2 as
catalyst yields results similar to hydroamination. Hydroamination of l-hexyne by
cyclohexylamine results in a 1.6:1 mixture of Markovnikov:anti-Markovnikov products.
Three-component coupling between l-hexyne, cyclohexylamine, and tert—butylisonitrile

results in a 12:1 mixture of separable isomers.

Conclusion

A bunch of transition metals has been presented as catalysts for hydroamination of
alkynes with amines in this chapter. Use of titanium as a catalyst for hydroamination
offers several advantages over other transition metals.

a) Titanium catalysts are cheap and readily available.

b) They are nontoxic compared to some toxic metals like mercury.

c) Titanium catalysts can be readily prepared from existing literature procedures

(1) They are especially applicable to hydroamination of alkynes with primary amines.

35

Chapter 2

Hydroamination of diynes using a titanium catalyst to yield pyrroles has been reported
by Odom.55 Hydroamination of alkynes was discussed in the previous chapter along with
some recent advances in this field by Odom group using inexpensive titanium-based
catalysts. In this chapter, hydroamination of diynes will be presented as a one-pot
synthesis of pyrroles.

Pyrroles are important biologically as they are present in many naturally occurring
alkaloids and some NSAIDs (non-steroidal anti-inflammatory drugs) based on the pyrrole
structure. The early impetus for the study of pyrroles came from degradative work
relating to the structure of two pigments central to life processes: the blood respiratory
pigment (heme) and, the green photosynthetic pigment of plants (chlorophyll).56 Such
degradation led to the formation of mixtures of alkylpyrroles.

NSAIDs can be classified as COX-l or COX-2 drugs (cyclooxygenase-l or-2).57 COX
activities originate from these two distinct and independently regulated enzymes. COX-2
plays a major role in prostaglandin biosynthesis in inflammatory cells
(monocytes/macrophages) and in the central nervous system.58 Some of the NSAIDs that
have a pyrrole as the core structure are Tolmetin Sodium (Tolectin) and Ketorolac
Tromethamine ®(Toradol). Some natural products that include the pyrrole core are

Polycitone A and B, Lamellarin O and Lukianol A (Figure 2-1a and b).

36

HO
Ph / \ O
N OH
O OH O H2N
OH

Ketorolac Tromethamine

O
/
I N
/ O
ONa. 2 H20
Tolectin Sodium

HO

   

H0 Br Br OH HO Br Br OH

Polycitone A Polycitone B

Figure 2-la. Pyrrole core structure in NSAIDs and natural products

37

MeO

OH

M9020

N
\/

00

HO ' OH

 

Lamellarin O Lukianol A

Figure 2-1b. Pyrrole core structure in natural products

2.1.2 Goal of this project
The primary goal of this project was to extend the hydroamination of alkynes to
diynes using the titanium-based catalysts described in the previous chapter, followed by

cyclization to give the hydroaminated product, i.e. a one-pot synthesis of pyrrole (Figure

2-2).

38

 

catalyst \N
k / + H2NR : M
5-endo digi

 

2 catalyst I

Figure 2-2. Hydroamination of 1,4 and 1,5-diynes

There have been quite a few reports in the literature of pyrrole syntheses from imino
alkynes.”61 Some representative examples of these sorts of cyclizations are as follows.
McDonald reported the use of Group VI carbenes for cycloisomerization, of terminal
alkynes tethered to nitrogen nucleophiles. Reaction of N-(t-butoxycarbonyl)-3-butyn-1-
amine with chromium hexacarbonyl/triethylamine N-oxide (in situ formation of

triethylamine-chromium pentacarbonyl) yielded the cycloisomeric enecarbamate (Figure

2-3).

39

oc
NHBoc

(Et3N)Mo(CO)5 (1.0 equiv) N
\ Et3N, EtZO V K fl

H 68%

 

Figure 2-3. Hydroamination with molybdenum pentacarbonyl

Utimoto reported a palladium-catalyzed cyclization reaction of 1-arnino-3-alkyn-2—ols

to yield 2,4-disubtituted pyrroles in good yields (Figure 2-4).

OH R' n
R. R 1 % PdCl2 > D
NH2 R R'

R = n-hexyl and Ph
R = Et, H and t-Bu

 

Figure 2-4. Palladium catalyzed intramolecular hydroamination and cyclization

Another palladium-catalyzed cycloisomerization reaction was reported by Gabriele
and Salerno wherein catalytic amounts of PdClz in conjunction with KCl at 25-100 °C
cycloisomerized (Z)—(2—en-4—ynyl)amine to yield 2,3,4-trisubstituted pyrrole with
DMA(N,N-dimethylacetamide) as the solvent (Figure 2-5).

The hydroamination of 1,4-diynes would yield the 4-iminoalkyne (Figure 2-2) which
could undergo a 5-end0 dig cyclization,62 whereas the 1,5-diynes could undergo a 5-ex0

dig cyclization to yield the pyrrole.

40

 

 

R1
\ / R3 / R4
N
1 % PdCI2, DMA I
NH = /
R1/ 25-100 ° 0
R2
R3
R4 60-90 % yield
8‘ = Bn and H
a? = Et, H and Ph
33 = Me and H
R4 = BU

Figure 2-5. Another route for cyclization with Pd to yield pyrroles

2.1.3 Baldwin Rules for Ring Closure

Baldwin studied several types of cyclization reactions and categorized them as
follows.

Baldwin’s rules are for certain ring closings of 3- to 7-membered rings. These rules
distinguish two types of ring closure, called exo and endo, and three kinds of atoms at the
starred positions: tet for sp3, trig for sp2, and dig for sp (Figure 2-6).

Rule 1. Tetrahedral systems

(a) 3 to 7-Exo-Tet are favored

(b) 5 to 6- Endo-Tet are disfavored
Rule 2. Trigonal systems

(a) 3 to 7-Ex0-Trig are favored

(b) 3 to 5-End0-Trig are disfavored

(c) 6 to 7 - Endo-Trig are favored

Rule 3. Di gonal systems

41

(a) 3 to 4-Exo-Dig are disfavored
(b) 5 to 7- Exo-Dig are favored

(c) 3 to 7- Endo-Dig are favored

 

/’ Em-
" .7

(\IY) > a

 

X
Y
XVY'
Figure 2-6. Baldwin’s rules for ring closure in 3- to 7-membered rings
“Disfavored” does not mean it is not possible, it just means that it is more difficult
than the favored ones. Some exceptions to this rule, have been reported by Trost, Auvray,
and Torres.63 From the Baldwin rules, we can conclude that the cyclization of the imino
alkynes should be a favored process, since both 5-endo dig cyclization and 5-exo dig

cyclization for 1,4-diynes and 1,5-diynes, respectively, are favored for the digonal

systems.

42

2.1.4 Synthesis of 1,4-diynes
The substrates for the hydroamination, i.e. the diynes, were synthesized using
Verkruijsse’s procedure.“"65 The unsymmetrical bis(internal)-l,4-diyne, 1-phenyl-1,4-

hexadiyne was synthesized by the same procedure (Figure 2-7).

 

 

 

 

 

 

1) EtMgBr R
H : R :: CuBr > \\ //
OTs
Fl: Bu", SiMea, H, Ph 60-70 %
1) EtMgBr Ph
H : ph :23: CuBr — j, \\ /

 

0T5 internal diyne

60 °/o

Figure 2-7. Synthesis of 1,4-diynes

2.1.5 Hydroamination 0f 1,4-Diynes

An attempt was made to hydroaminate 1,4-pentadiyne (1a) with 1 equivalent of
aniline using Ti(dpma)(NMe2)2 (A) as the catalyst.66 The major product obtained in the

reaction had a mass consistent with double hydroamination of pentadiyne (Figure 2-8).

43

R

 

10 mol%A N/
k i + H2N—Fi ————X——> I
/
‘8 R=Ph,Bn
Ph\ /Ph
§ ¢ 10 mol%A _ IN HN
+ H2NPh M
1a
major

Figure 2-8. Hydroamination of 1,4-pentadiyne with aromatic amines

Data for the dihydroamination product matched an authentic sample of 2,4-
bis(phenylimino)pentane, which was synthesized by the condensation of 2,4-
pentanedione and aniline using catalytic p-toluenesulfonic acid. This result suggests that
the second hydroamination was faster than both the mono-hydroamination and the S-endo
dig cyclization. Other catalysts like Ti(dmpm)(NMe2)2 (B) and Ti(dap)2(NMez)2 (C) were
also used but to no avail. Increasing the temperature led to oligomerization of the diyne,
and lowering the temperature led to dihydroamination. The structure of the catalysts is as

shown in Figure 2-9.

44

   

NM92

<\—— FNIIH..| Tl' ..11\\\\NM62
_NM92 N/INI \NMez

 

\NMGZ M62
Ti(NMez)2(dpma) Ti(NMeZ)2(dmpm) Ti(dap)2(NMez)2
A B C

Figure 2-9. Structure of catalysts used in hydroamination of diynes

Hydroamination of l,4-nonadiyne (1b) with aniline and benzylamine at 100 ° C with
A as the catalyst led to the corresponding pyrroles in moderate yields (Figure 2-10).
Hydroamination of 1b with aniline gave l-phenyl-2-butyl-5-methylpyrrole (3a) in 55 %
yield. Hydroamination with benzylamine took longer times and also gave a yield of only
35% of 1-benzyl-2-butyl-5-methylpyrrole (3b). The pyrrole product obtained from the
imine cyclization is preferentially the Markovnikov product. Hydroamination of 1-
hexyne with either benzylamine or aniline gives preferentially the Markovnikov product
with A as the catalyst.67 Considering the terminal alkynes used here are not sterically or
electronically different from l-hexyne, the major product expected in all the cases where

a terminal alkyne was present, is the imine resulting from Markovnikov addition.

45

Bun Ph

 

 

/
\ / 10 |°/ A N
\ / + HZN'Ph 100223.241: F I / 5“"
1b
56%
Ph
Bun
\\ / P“ 10 mol%A N
/ + H2N—/ 100°C,48h F I / 3”"
1b 35%

Figure 2-10. Hydroamination of l,4-nonadiyne with aromatic amines

Hydroamination of 1-phenyl—l,4-pentadiyne with either aryl or alkyl amines did not
yield the desired pyrrole with A, B, or C as catalyst (Figure 2-11). The problem could be

a result of diyne oligomerization.

Ph [R
H Ti catalyst N
\ i + H2N-R W11

Fl: Ph,-CH2Ph

Figure 2-11. Hydroamination of 1-phenyl-1,4-pentadiyne with aromatic amines

46

Hydroamination of l-trimethylsilyl-l,4-pentadiyne did not yield any pyrrole products

(Figure 2-12).

R
H /
TMS Ti catalyst N
\\ i + HzN—R + I / TMS
R=Ph, -CH2Ph

Figure 2-12. Hydroamination of l-trimethylsilyl-l,4—pentadiyne with aromatic amines

Hydroamination reactions by titanium have been shown to be sensitive to the size of
the alkyne substrate.68 Hence, replacing the hydrogen on the terminal position of the
diyne by alkyl or aryl groups should significantly slow down the second hydroamination
reaction relative to the 5-end0 dig cyclization as seen in the case of 1a. We successfully
demonstrated this by hydroarninating l-phenyl-l,4-hexadiyne (1c) with B as the catalyst
with aniline, benzylamine, and p-methoxybenzylamine yielding a single isomer (Figure
2—13). Hydroamination of 1c with benzylamine gave 1,2-dibenzyl-5-methylpyrrole (3d)
in 53% yield, while hydroamination of 1c with p-methoxybenzylamine (PMB-NHZ) gave
1-(4-methoxy-benzyl)-2-benzyl-5-methyl pyrrole (3e). This is likely due to selective
hydroamination of the phenyl-bearing alkyne. Hydroamination of similar substrates, e.g.
l-phenylpropyne, occurs with hydroamination B to the phenyl group, which is consistent
with the observed regioselectivity for this diyne substrate. Also, hydroamination of l-

phenylpropyne is generally more facile than dialkyl substituted alkynes, e.g. 3-hexyne.

47

Consequently, it is likely that regioselectivity for this substrate is due to kinetically

favored amination B to the phenyl group of l-phenyl-1,4-hexadiyne.

 

 

 

Ph PMB
Me I
k y 10 mol% B > N Ph
+ HZN-PMB 100 °C, 24 h I /
1c 3e
30%
Ph Ph
\ Me >
ph 10 mol% 8
\ y + H2N—/ 100 °C, 24 h > N Ph
1c I /
53% 3“
Ph Ph
Me 1) 10 mol% B
\ / ‘°°°C' 24" ’ N Ph
+ HZN—Ph 2) 30 mol% Cul. N33. 110 00 I /
1c
62% 3C

Figure 2-13. Hydroamination of l-phenyl-1,4-hexadiyne with aromatic amines

The cyclization of the imine derived from 1c was quite slow after titanium-catalyzed
reaction when the amine substrate was aniline. To finish the cyclization, Gevorgyan’s
procedure using 30 mol% of CuI in the presence of triethylamine at 110 °C was employed
prior to the work-up.69 Interestingly, the addition of copper for the cyclization was only

required for the aniline substrate to give 1-phenyl-2-benzyl-5-methy1 pyrrole (3c) (Figure

48

2-13). The benzylamine and p-methoxybenzylamine (PMB-NHZ) hydroamination

products underwent cyclization to the pyrrole structure in the absence of copper.

2.1.6 Synthesis of 1,5-diynes
1,5-hexadiyne (2a) was bought from GFS chemicals and was distilled and stored in
the glove box prior to hydroamination. l,6-diphenyl-1,5-hexadiyne (2b) was synthesized

by the literature procedure70 (Figure 2-14).

 

__ H 1%: CUI
__f—_ O 0.5% Pd(PPh3)4 —
H : + 2 : _
i-PerH, THF 0
2a

Figure 2-14. Synthesis of 1,6-diphenyl-l,5-hexadiyne

2.1.6 Hydroamination of 1,5-diynes

Hydroamination of 2a proceeds smoothly with aniline using 1 as catalyst, at 75 °C in 6
h to give 1-phenyl-2,5-dimethylpyrrole (31') (Figure 2-15). Hydroamination with
benzylamine takes a longer time for completion and gives 1-benzyl-2,5-dimethylpyrrole
(3g) with A as catalyst. The yields vary from 68% for hydroamination with aniline to
34% with benzylamine. The reaction is clean and does not yield any dihydroamination

products, as is the case with 23.

49

 

an
: Ph\ // . N
I + H2N_ph 10 mol% A _ I“ 5-exo ring I
_ 75 °C, 6 h V /
M

68%

 

PL Ph>
I + HzNjh 10 mol% A = U 5-exo (119 w:
100 °C, 14 h /
M

34%
Figure 2-15. Hydroamination of 1,5-hexadiyne with aromatic amines

Hydroamination of 2b with aniline at 150 °C using A as catalyst yields l-phenyl-2,5-

dibenzylpyrrole pyrrole (3h) in 90% yield after 26 h (Figure 2-16).

 

 

Ph
Bn N/
/ — '9'” 10 l/ A U
mo °o
— + H N-Ph = B"
P“ 2 150°C, 26 h /
2b 90%

Figure 2-16. Hydroamination of 1,6-diphenyl-1,5-hexadiyne with aromatic amines

Treatment of 2b with benzylamine gave no reaction with catalysts A and B. The lack

of reaction with benzylamine probably represents a limitation to the activity of our

current catalysts rather than an inherent problem with the substrate combination.

50

2.1.7 Cyclization of 1,4-diynes

The cyclizations of the imino alkyne to give the pyrrole can occur through several
different routes: however, they are likely to occur through the Baldwin allowed 5-endo
dig and S-exo dig cyclizations It is unlikely that that allene intermediates were involved.
The reason for this is that the 5-endo trig and 5-exo trig cyclizations required for the
allene cyclizations are disfavored. Experimentally, it has been shown by Gevorgyan, that
1-imino-2-alkynes require copper catalysis to be cyclized, which has been suggested to

occur through allene intermediates (Figure 2-17).

 

I Cul(30 mol%) k R2
NEt3/DMA,110°C

R3 R‘

Figure 2-17. Gevorgyan’s cyclization of l-imino-2-alkynes catalyzed by copper

Our aim was to find out whether the cyclization of the iminoalkynes generated in 1,4-
and 1,5-diyne hydroamination was mediated by titanium or was just a thermal process.
Consequently, we sought to generate the imino alkyne in the absence of the transition

metal compound to observe if cyclization would occur under those conditions.

51

The goal was to synthesize 4-nonyn-2-ol from propylene oxide, oxidize it to 4-nonyn-
2-one and perform a schiff base reaction with aniline to give the imino alkyne (Figure 2-

18).

1 .1 Nal04
OH Bun 0.1 Na20r207 O BU"

0 Li——:—eu" 0.05 HN03 _ /
A THF/HMPA ' M 72% TM

80%

 

 

o NHPh NPh NHPh 0 3“"
Mall" + MSU" HZNPh /u\/

Major Minor

ll

Figure 2-18. Reaction to verify if the cyclization is Ti mediated

The reaction did not work, as 4-nonyn-2-one undergoes isomerisation to the allene
intermediate and then undergoes reaction to give the Michael-addition product and its
schiff base analogue. All attempts to protect the alkyne with C02(CO)3 and deprotect it
later, after the condensation with aniline were unsuccessful. The deprotection step

1 which seem to

involves addition of an aqueous solution of ceric ammonium nitrate, 7
lead to complications. While we were not able to isolate the iminoalkyne in the absence
of titanium, they were observed in several instances confirming their intermediacy in the
reactions.
2.1.8 Cyclization of 1,5-diynes

Even though the imine product was not observed in the hydroamination of 1,5-

hexadiyne (2a), it is still likely that the imine is an intermediate. The relevant ketone

derivative of this intermediate, hex-5-yn-2-one (2c), was prepared according to the

52

literature procedure.72 Reaction of the ketone with aniline (Figure 2-19) in the absence of
titanium leads to formation of N-phenyl-2,S-dimethylpyrrole that is spectroscopically

identical to the product of 23 hydroamination with aniline.

Ph

N
refluxing C6H6
+ HZNPh >

k ' /

 

2c

Figure 2-19. Condensation of hex-5-yn-2-one with aniline

2.1.8 3-Component coupling of diynes
Another application, which was attempted, was a multi-component reaction with
73

diynes, in a similar vein as previously shown with alkynes, isonitriles, and amines

(Figure 2-20).

1 R2
R /
N

RI
\\ // + H NB2 + C‘N R3 iminoamination M
2 " " r \
NHR3

Figure 2-20 Three-component coupling of diyne with amine and isonitrile

 

The reaction did not afford the expected product with any of the 1,4 and 1,5-diynes
attempted. Investigation is underway of new catalysts that might facilitate this

transformation.

53

2.1.9 Summary
The results obtained for the hydroamination product are tabulated as follows.
Applications of this new pyrrole synthesis based on alkyne hydroamination are currently
under investigation. It is hoped that this new pyrrole synthesis will complement existing
procedures such as the Paal-Knorr synthesis, at least in circumstances where
unsymmetrical pyrroles are desired. Many unsymmetrical 1,4-diynes can be prepared in
one or two steps from commercially available compounds and may be as or more
accessible than the corresponding unsymmetrical 1,4-diones in some cases. The titanium-
based pyrrole synthesis of 1,2—dibenzyl-5-methylpyrrole (3d) provides an interesting
example for comparison with current and progressing ketone-based methodologies, e.g.,
Paal-Knorr synthesis. Generally, unsymmetrical 1,4-diketones are relatively difficult to
access in a short symmetric sequence. However, the diketone needed for the synthesis of
3d by Paal-Knorr synthesis and its reaction with benzylamine were recently reported.76
The diketone was prepared using a novel Pd-catalyzed procedure from methyl vinyl
ketone and benzylzinc chloride. Overall, 3d was available in 54% yield over two steps.
Using the procedure of Verkruijsse to generate the diyne and titanium hydroamination,
we prepared the unsymmetrical pyrrole 3d in the comparable yield of 41% in two steps.

In addition, we are investigating the use of this new methodology in the synthesis of
pyrroles where application of the Paal-Knorr synthesis may lead to unwanted side
reactions. For example, we are investigating the synthesis of Ot-vinylpyrroles using diyne

hydroamination, which if prepared using mB-unsaturated ketones may have problems

with interfering Michael-addition side reactions.

54

Table 2.1

Tabulated results for hydroamination of 1,4 and 1,5-diynes with aromatic amines

 

 

 

 

 

 

 

 

 

 

diyne amine conditionsa product!"C
(%yield)
Ph
1 31‘ r H NPh A 24 h M9 ”’
Q é 2 ’ Um"
(56)
1b 3“
Ph>
2 HzNBnb A, 48 h Me N
(35) Um"
3b
Ph Me P"
\ / M ’
3 \ / HzNPh 13,3011" ‘3an
(62) /
1c 3c
M ’B n
4 HzNBnb B, 30h e\EN)7BH
(53) /
3d
PMB
c Me “I
5 HzNPMB B. 26h Us"
(30) /
31:
H : Ph
1.. Me .
6 HzNPh A, 75 °C, U...
2,, 6 h, (68) 3f
M .3"
e N
7 HzNBnb A, 14 h 1 Me
/
(34) U 3
L
”In. Bn Nph
3 HzNPh B, 150 °C, 26 Us.
2b h (90) 3h

 

 

 

 

 

55

 

3. Temperature is 100 °C unless otherwise stated. A = 10 mol% Ti(dpma)(NMe2)2, B
= 10 mol% Ti(dmpm)(NMe2)2. b. Bn is benzyl. c. PMB is p-methoxybenzyl. d. CuI

added to aid in cyclization.
General Procedures

Unless otherwise stated, all manipulations were performed in an MBraun drybox
under an atmosphere of purified nitrogen. All solvents were distilled and were stored in
the drybox. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded on
Varian Inova 300 spectrometer at room temperature unless otherwise stated. 1H and 13C
NMR chemical shifts are reported with respect to internal solvent (7.21 ppm and 77.22 (t)
ppm respectively for CDC13). Coupling constants could not measured for the pyrroles due

to the complex nature of the spectra.

Experimental Section.

 

Preparation of I-phenyl-2-butyl-5-methylpyrrole (Entry 1): Under an atmosphere of
dry nitrogen, a threaded-top pressure tube was loaded with toluene (0.416 mL),

Ti(dpma)(NMe2)2 (A) (0.269 g, 0.832 mmol), aniline (757.5 ILL, 8.32 mmol), and 1,4-

56

nonadiyne (1b) (1.00 g, 8.32 mmol). The tube was sealed with a Teflon cap, and the
reaction mixture was heated at 100 °C for 22 h. The volatiles were removed from the
reaction mixture in vacuo, and the residue was subjected to column chromatography
using 300 g of alumina with 7:1 pentanezether as the eluent. The product eluted in the
first fractions in 55% yield (0.98 g, 4.56 mmol). The compound is a yellow viscous oil.
1H NMR (300 MHz, CDCl3): 5 = 7.2-7.6 (m, 5 H, k, l and m), 5.98 (s, 2 H, f and g), 2.06
(s, 3 H, a), 2.38 (t, 2 H, b), 1.44-1.54 (m, 2 H, c), 1.24-1.34 (m, 2 H, d), 0.84 (t, 3 H, e).
l3C{1H} NMR (CDC13): 8 = 139.3 (j), 134.1 (i), 128.5 (k), 128.8 (1), 127.7(m), 122.8 (h),
105.6 (1), 104.6 (g), 31.2 (b), 13.0 (a), 26.8 (c), 22.4 (d), 13.9 (e). Elemental analysis;

Experimental (Calc.), C: 84.01 (84.46); H: 9.17 (8.98); N: 6.53 (6.57). MS (EI) m/z = 213

(W)-

 

Preparation of 1-benzyl-2-butyI-5-methylpyrrole (Entry 2): Under an atmosphere of
dry nitrogen, a threaded-top pressure tube was loaded with toluene (0.416 mL),
Ti(dpma)(NMez)2 (A) (0.269 g, 0.832 mmol), benzylamine (757.5 ILL, 8.32 mmol), and
1,4-nonadiyne (1b) (1.00 g, 8.32 mmol). The tube was sealed with a Teflon cap, and the

reaction mixture was heated at 100 °C for 46 h. The volatiles were removed from the

57

reaction mixture in vacuo, and the residue was subjected to column chromatography
using 300 g of alumina with 7:1 pentanezether as the eluent. The product eluted in the
first fractions in 35% yield (0.66 g, 2.91 mmol). The compound is yellow viscous oil

1H NMR (300 MHz, CDC13): 8 = 6.8-7.4 (m, 5 H, k, l and m), 5.92 (s, 2 H, 1' and g), 5.06
(s, 2 H, n), 2.16 (s, 3 H, a), 2.48 (t, 2 H, b), 1.52-1.64 (m, 2 H, c), 1.30-1.42 (m, 2H, d),
0.84 (t, 3 H, e). '3C{‘H} NMR (CDCl3): 6 = 138.8 0). 133.1 (1), 128.7 (1), 128.0 (h),
126.3 (m), 125.6 (k), 105.5 (f), 104.4 (g), 46.6 (n), 31.1 (b), 26.5 (c), 22.6 (d), 14.0 (c),
12.5 (a). Elemental analysis; Experimental (Calc.), C: 85.07 (84.53); H: 9.67 (9.31); N:

6.00 (6.16). MS (EI) m/z = 227 (W).

 

Preparation of I-phenyl-2-benzyl-5-methylpyrrole (Entry 3): Under an atmosphere of
dry nitrogen, a threaded-top pressure tube was loaded with chlorobenzene (0.324 mL),
Ti(dmpm)(NMe2)2 (B) (0.20 g, 0.648 mmol), aniline (590.0 uL, 6.48 mmol), and 1-
phenylhexa—1,4-diyne (1c) (1.00 g, 6.48 mmol). The tube was sealed with a Teflon cap,
and the reaction mixture was heated at 100 °C for 30 h. The volatiles were removed from
the reaction mixture in vacuo, and the residue was subjected to cyclization‘59 with CuI

(0.370 g, 1.945 mmol), anhydrous N,N-dimethylacetamide (28 mL) and Et3N (14 mL).

58

The mixture was stirred for 110 °C with protection from light for 7 h. The mixture was
cooled to room temperature and poured into water (100 mL). After shaking with pentane
(50 mL), a 3-layer system formed. The lower (water) phase and upper (organic) phase
was thoroughly separated from the middle layer, which contained an emulsion of copper

complexes. The emulsion and water phases were separately extracted with pentane (3 x

30 mL and 1 x, 30 mL respectively). The combined pentane extracts were filtered over
anhydrous NazCO3. The solvent was evaporated under reduced pressure, and the residue
was subjected to column chromatography using 300 g of alumina with 7:1 pentanezether
as the eluent. The product eluted in the first fractions and was distilled at 200 °C (0.8
torr) to give yellow oil in 35% isolated yield (0.56 g, 2.27 mmol). 1H NMR (300 MHz,
CDC13): 5 = 6.9-7.4 (m, 10 H, k, l, m, d, e, and o), 5.89 (s, 1 H, 1' or g), 5.92 (s, 1 H, f or
g), 1.99 (s, 3 H, a), 3.69 (s, 2 H, b). ”q 1H} NMR (CDC13): 6 = 13.1 (a), 33.8 (b), 106.0
(f or g), 107.0 (f or g), 125-132 (k, l, m, d, e, o, h, and i), 139.0 (j), 140.2 (c). Elemental
analysis; Experimental (Calc.), C: 86.60 (87.41); H: 6.93 (6.93); N: 5.68 (5.66). MS (EI)

m/z = 247 (M+).

59

 

Preparation of I,2-dibenzyl-5-methylpyrrole (Entry 4): Under an atmosphere of dry
nitrogen, a threaded-top pressure tube was loaded with chlorobenzene (0.325 mL),
Ti(dmpm)(NMe2)2 (B) (0.20 g, 0.65 mmol), benzylamine (708 uL, 6.49 mmol), and 1-
phenylhexa-l,4-diyne (1c) (1.00 g, 6.49 mmol). The tube was sealed with a Teflon cap,
and the reaction mixture was heated at 100 °C for 30 h. The volatiles were removed from
the reaction mixture in vacuo, and the residue was subjected to column chromatography
using 300 g of alumina with 7:1 pentanezether as the eluent. The product eluted in the
first fractions to give brown oil in 53% (0.90 g, 3.45 mmol) isolated yield. 1H NMR (300
MHz, CDC13): 6 = 6.8-7.4 (m, 10 H, k, l, m, d, e, and o), 5.89 (br s, 1 H, f or g), 5.84 (br
s, 1 H, 1‘ or g), 4.90 (s, 2 H, n), 3.79 (s, 2 H, b), 2.12 (s, 3 H, a). l3C{1H} NMR (CDC13):
8 = 12.5 (a), 33.3 (b), 46.8 (11), 105.6 (f or g), 107.0 (f or g), 125-132 (k, l, m, d, e, 0, h,
and i), 138.5 (j), 139.7 (c). Elemental analysis (Calc.), C: 87.01 (87.31). H: 7.42 (7.33).

N: 4.72 (5.36). MS (EI) m/z = 261 (NF).

60

 

Preparation of 1-(4-methoxybenzyl)-2-benzyl-5-methyl pyrrole (Entry 5): Under an
atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with chlorobenzene
(0.162 mL), Ti(dmpm)(NMe2)2 (B) (0.10 g, 0.32 mmol), 4-methoxybenzylamine (424
uL, 3.24 mmol), and 1-phenylhexa-1,4-diyne (1c) (0.50 g, 3.24 mmol). The tube was
sealed with a Teflon cap, and the reaction mixture was heated at 100 °C for 26 h. The
volatiles were removed from the reaction mixture in vacuo, and the residue was subjected
to column chromatography using 300 g of alumina with 7:1 pentanezether as the eluent.
The product eluted in the first fractions to give brown oil in 35% (0.33 g, 1.14 mmol)
isolated yield. 1H NMR (300 MHz, CDC13): 6 = 6.7-6.9 (m, 4 H, k and l), 7.2-7.4 (m, 5
H, d, e and o), 5.87 (s, 1 H, 1' or g), 5.89 (s, 1 H, f or g), 4.87 (s, 2 H, n), 2.16 (s, 3 H, a),
3.83 (s, 2 H, b), 3.80 (s, 3 H, m). ”q 'H} NMR (CDC13): 6 = 12.5 (a), 33.3 (b), 46.3 (n),
55.3 (m), 105.6 (f or g), 107.0 (f or g), 114.1 (I), 124-132 (k, j, c, d, e, o, h, and i), 139.8
(c), 158.6 (p). Elemental analysis; Experimental (Calc.), C: 82.25 (82.44); H: 7.67 (7.26);

N: 4.46 (4.81). MS (El) m/z = 291 (M).

61

Preparation of Iphenyl-2,5-dimethylpyrrole (Entry 6): Under an atmosphere of dry
nitrogen, a threaded-top pressure tube was loaded with toluene (6.4 mL),
Ti(dpma)(NMe2)2 (A) (0.4135 g, 1.28 mmol), aniline (1,166 ILL, 12.8 mmol), and 1,5-
hexadiyne (23) (1.00 g, 12.8 mmol). The tube was sealed with a Teflon cap, and the
reaction mixture was heated at 75 °C for 6 h. The volatiles were removed from the
reaction mixture in vacuo, and the residue was subjected to column chromatography
using 300 g of alumina and diethyl ether as the eluent. The product eluted in the first
fractions in 68% isolated yield (1.50 g, 8.76 mmol). When solvent was removed, a
colorless liquid was obtained, which solidified on standing. mp. 45-46 °c (lit.75 50 °C).
1H NMR76 (300 MHz, CDC13): 6 = 7.2-7.6 (m, 5 H, d, e, r, g), 5.93 (s, 2 H, c), 2.07 (s, 6
H, a). ‘3C{‘H} NMR77 (300 MHz, coca): 6 = 139.3 (d), 129.3 (1'), 129.0 (b), 128.5 (e),
127.9 (g), 105.9 (c), 13.2 (a). Elemental analysis; Experimental (Calc.), C: 84.37 (84.17);

H: 8.22 (7.65); N: 7.54 (8.18). MS (EI) m/z = 171 (M+).

62

\ /
c
Preparation of 1-benzyl—2,5-dimethylpyrrole (Entry 7): Under an atmosphere of dry
nitrogen, a threaded-top pressure tube was loaded with toluene (6.4 mL),
Ti(dpma)(NMe2)2 (A) (0.4135 g, 1.28 mmol), benzylamine (1390 111., 12.7 mmol), 1,5-
hexadiyne (23) (1.00 g, 12.8 mmol). The tube was sealed with a Teflon cap and heated at
100 °C for 14 h. The volatiles were removed from the reaction mixture in vacuo, and the
residue was subjected to column chromatography using 317 g of alumina with pentane,
then ether as eluents. The product was isolated in 34 % yield (0.80 g, 4.32 mmol) as a
colorless liquid that solidified on standing. mp. 41-42 °C. 1H NMR78 (300 MHz, CDCl3):
8 = 7.5-7.3 (m, 3 H, g and h), 7.00-7.15 (m, 2 H, 1'), 6.03 (s, 2 H, c), 5.16 (s, 2 H, d), 2.30
(s, 6 H, a). l3cl‘H} NMR (300 MHz, CDC13): 6 = 138.7 (e), 128.9 (1’), 128.1 (b), 127.2

(b), 125.8 (g), 105.6 (c), 46.8 (d), 12.6 (a). Elemental analysis; Experimental (Calc.), C:

83.82 (84.28). H: 8.28 (8.16). N: 7.22 (7.56). MS (EI) m/z = 185 (W).

63

 

Preparation of Iphenyl-2,5-dibenzylpyrrole (Entry 8): Under an atmosphere of dry
nitrogen, a threaded-top pressure tube was loaded with chlorobenzene (1.10 mL),
Ti(dmpm)(NMez)2 (B) (0.13 g, 0.43 mmol), aniline (600 11L, 6.58 mmol), and 1,6-
diphenyl-l,5-hexadiyne79 (2b) (1.00 g, 4.34 mmol). The tube was sealed with a Teflon
cap, and the reaction mixture was heated at 150 °C for 26 h. The volatiles were removed
from the reaction mixture in vacuo, and the residue was subjected to column
chromatography using 300 g of alumina with 1:1 pentanezether as the eluent. The product
was recovered in 90% (1.26 g, 3.90 mmol) isolated yield as pale yellow oil. 1H NMR
(300 MHz, CDC13): 8 = 6.6-7.6 (m, 15 H, i, e, j, k, g and f), 5.92 (s, 2 H, b), 3.70 (s, 2 H,
c). 13C{'H} NMR (CDCl3): 8 = 33.7 (c), 107.0 (b), 114.1 (1'), 124-132 (e, d, h, i, j, k, and
a), 139.8 (h), 158.6 (g). Elemental analysis (Calc.), C: 88.73 (89.12). H: 6.62 (6.54). N:

4.16 (4.33). MS (EI) m/z = 323 M).

64

 

Chapter 3

Chapter 2 was an application of the hydroamination of alkynes, which our group has
been pursuing for some years now. We showed an interesting application to the ever-
expanding field of hydroamination of alkynes, by reporting a one-pot synthesis of
substituted pyrroles using a titanium-based catalyst in moderate yields. In this chapter, a
new application of hydroamination of diynes will be discussed, i.e. synthesis of
vinylpyrroles from diynes along with some latest results that we have obtained in this
pursuit. C-Vinylpyrroles, having the A, B structural element, (Figure 3-1) 80 have been
extensively studied as building blocks for the synthesis of various representatives of the

pyrrole family, especially condensed heterocycles related to pyrrole.81

Figure 3-1. Structure of vinylpyrroles

2-Vinylpyrrole structure A is found in molecules of many vital natural compounds

(porphyrins, chlorophylls, vitamin B12, prodigiosins, etc.). 3-Vinylpy1role structural

65

elements B compose molecules of chlorophylls a, b, c, and d (which play a key role in
photosynthesis processes, i.e., photocatalytic transformation of the solar energy) and
haemoglobin (the compound responsible for oxygen transport in mammal organisms). C-
Vinylpyrroles bearing functional groups on the double bond (or those without them) are
highly reactive starting compounds for the targeted synthesis of conjugated and fused
heterocycles similar to natural pyrrole assemblies. Over the past few years, functionalized
C-vinylpyrroles started attracting attention as molecular optical switches, in particular, as
ultra fast ones, for design of photo- and electroconducting materials, nanodevices82 and

also as ligands for new photocatalysts and biologically active complexes.83

3.1.1 Goal of this project
The aim of this project was to extend further the application of hydroamination of

diynes to report one-pot syntheses of vinylpyrroles (Figure 3-2).

H Tl catalyst \ N

% ¢ + R"NH2 = 1"

 

Figure 3-2. Proposed Figure for synthesis of 2-vinylpyroles

Further, the vinylpyrroles obtained can undergo Diels-Alder reaction to give fused

heterocycles in l-step (Figure 3-3)

66

'-_|‘H—_

 

 

- ans

1

R" R"

l. 1
6W8. + REEL—>6 s / R.

Figure 3-3. Proposed Figure for Diels-Alder reaction of vinylpyrroles

3.1.2 Synthesis of vinylpyrroles

3) Synthesis of l-vinylpyrroles

The most extensively developed method for the preparation of l-vinylpyrroles is based
on the heterocyclization of ketoximes with acetylene in a strong base-DMSO system.84
This reaction is called the “Trofimov reaction” and it requires no pyrrole precursors and
starts from cheap and readily available ketones (Figure 3-4). The reaction allows the
preparation of diverse 2-, 2,3- 2,5-, and 2,3,5- substituted 1-vinylpyrroles. The yields
depend on the structure of reactants; with simple ketoximes and unsubstituted acetylene
yields of 70-95% are attained under optimal conditions. General studies show that certain
l-vinylpyrroles are of interest as precursors of neurostimulators; 2-phenyl-1-(l-
propargyloxyethyl)pyrrole derived from 2-phenyl-1-vinylpyrrole, for example, stimulates
motor activity, and increases excitation. There have been some studies done regarding

biological properties of 1-vinylpyrroles, which show promising results.85

67

 

R2

R2
R‘ 0112142
T MOH/DMSO / \ = / \
+ — = “_ >
70120°c R‘ N R‘

 

 

 

NOH N
H

Figure 3-4. Synthesis of l-vinylpyrroles

b) Synthesis of 2-vinylpyrroles

The general synthesis of 2-vinylpyrroles is the base catalyzed condensation of 2-
formylpyrroles with activated methylene (or methyl groups (Figure 3-5). 2-
Formylpyrroles undergo a normal base catalyzed aldol-type condensation with aliphatic,
aromatic and heteroaromatic ketones to yield the correspondingly substituted 2-

vinylpyrroles.86

X

/\ CH2XY_ /\ / y

CHo '
N -H20

X, Y = COR, COZR, CN, N02
Figure 3-5. Synthesis of 2-vinylpyrroles
Another common way to prepare 2-vinylpyrroles is via the Wittig reaction (Figure 3-

6). The Wittig reaction is fairly efficient in conversion of formyl- and acylpyrroles to

corresponding vinylpyrroles.87

68

 

 

H1 = H, Me; R2 = H, Ph, Ac, 00251

Figure 3-6. Synthesis of 2-vinylpyrroles via Wittig reaction

In all the above-described synthesis the yields of the reaction is low and is in between
15-30%.

Some of the Diels-Alder chemistry of 2-vinylpyrroles is as follows. Facile
cycloaddition of 2-vinylpyrroles with a range of dienophiles has been investigated 88

(Figure 3-7).

69

‘l

a

WI /9 __./..

 

 

N |
I | a
R _ R _
M8020 M802C
— 002Me - COzMe
W DMAD C __> / .
N N N
I | I
a _ R _ H

 

 

Figure 3-7. Diels-Alder chemistry of 2-vinylpy1roles

The products tetrahydroindoles and dihydroindoles are formed in a two-step process,
the first being a [41: + 2n] addition and the second step being a [1,3]-sigmatropic

reaction, which restores the aromaticity. The products are obtained in a moderate yield of

54-80%.

c) Synthesis of 3-vinylpyrroles

3-vinylpyrroles are important biologically as they are building blocks in the
preparation of vinyl-substituted porphyrins (proto-, pento-, and spirographisporphyrins)
and bile pigments (bilirubins, bileverdins, etc.) The synthesis of 3-vinylpyrroles is same
as 2-vinylpyrroles, in most of the cases. The most common synthesis is from 3-

fonnylpyrroles and CH acids (Figure 3-8).

70

Me CHO Me

/ \ CH2(C02Et)2; / \ W002“

i ridine
Et02C Et p pe Et02C Et
N N
H H

 

Figure 3-8. Synthesis of 3-vinylpyrroles

In the above example 3-formylpyrrole is condensed with malonic esters catalyzed by
an amine yields the expected 3-[2,2-di(carbboxyvinlepyrroles at low temperature but,
under more vigorous conditions, partial decarboxylation takes place to afford 6(3-

pyrrolyl)acry1ic acids.89

3.1.3 Synthesis of diynes
The diynes were synthesized using a modified literature procedure.90 The diynes used

for hydroamination were synthesized are as follows (Figure 3-9).

1) EtMgBr

H : / 2) CuBr > \\ //

 

Figure 3-9. Synthesis of diynes for hydroamination

71

 

l-ethynylcyclohexene was prepared using standard literature procedures.”

3.1.4 Hydroamination of diynes

a) Hydroamination of l-Cyclohexenyl-1,4-pentadiyne

Hydroamination of l-cyclohexenyl-1,4-pentadiyne (13) using Ti(dpma)(NMe2)2 (A)
as the catalyst with aniline did not yield any 2-vinylpyrrole. Changing the conditions by I
increasing the temperature and by changing the catalyst to Ti(dmpm)(NMe2)2 (B), -

Ti(dap)2(NMe2)2 (C) and Ti(bap)(NMe2)3 (D) also did not yield any products nor did

 

changing the amine substrate (Figure 3-10).

R
10 "/0 TI catalyst N/
+ RNH2 __*, I
I M

18 R: PILBD

Figure 3-10. Hydroamination of l-Cyclohexenyl-l,4-pentadiyne with aromatic amines

b) Hydroamination of 1-Cyclohexenyl-3-methyl-1,4-pentadiyne

We hoped that by introducing a substitution in the skipped position, the substrate
might undergo hydroamination with diynes. Hydroamination of l-cyclohexenyl-3-
methyl-1,4-pentadiyne (1b) with aniline using A as the catalyst gave 1-phenyl—2,3-

dimethyl-5-(1-cyclohexenyl)-pyrrole (23) in only 23% yield. Reaction of 1b with

72

benzylamine using B as the catalyst gave 1-benzyl-2,3-dimethyl-5-(1-cyclohexenyl)-

pyrrole (2b) in a low yield of 8% (Figure 3-11).

\\

k

10 % Ti catalyst
+ RNH2 >

 

. 14'. qr “owl-i!
'0
..

R: Ph, Bn
1b for R: Ph 23% yield

for Fl: Bn 8.0 % yield

 

Figure 3-11. Hydroamination of l-Cyclohexenyl-3-methyl-1,4-pentadiyne with amines

73

Conclusion

An attempt was made to extend the syntheses of pyrroles described in the previous
chapter, to synthesize 2-vinylpyrroles. We have had limited success as far as this goal
was achieved. Probably, we need some more variation in the catalysts that we are
currently using for hydroamination. We have had some success with the 2-vinylpyrroles
that we have synthesized so far. The yields of the reactions are not high and we are
currently trying to optimize the yields. Also, testing of the Diels-Alder adducts for

biological activity is under investigation.

74

 

General Procedures

Unless otherwise stated, all manipulations were performed in an Mbraun drybox under
an atmosphere of purified nitrogen. All solvents were distilled and were stored in the
drybox. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded on Varian
Inova 300 spectrometer at room temperature unless otherwise stated. 1H and 13C NMR
chemical shifts are reported with respect to internal solvent (7.21 ppm and 77.22 (t) ppm
respectively for CDC13). Coupling constants could not be measured due to the complex

nature of the spectra.

Experimental Section.

 

I -Cyclohexenyl-1,4-pentadiyne (Entry 9)

In a l L, 3-necked flask with a stir bar, reflux condenser and dropping funnel under
nitrogen atmosphere were placed l-ethynyl-l-cyclohexene (50.0 g, 0.472 mol) and THF
(300mL). Under cooling in an ice bath, ethyl magnesium bromide (236 ml, 0.472 mol,
2M solution in THF) was added via a canula over a 45minute period. The solution was
refluxed for 1 h. The reaction mixture was cooled in an ice bath. To this solution, copper

(I) bromide (2.73 g) was added. 30 minutes after this addition. 1-Tosyloxy-2-butyne

75

 

I'V‘YI‘. 'Ma‘.

(105.73 g, 0.472 mol) in 150 mL THF was added with vigorous stirring over a period of
30 minutes at 0 °C. During this addition, the temperature of the reaction mixture was kept
between 0 °C and +5 °C. The bath was then removed, and the reaction was stirred
overnight at room temperature. The reaction was quenched with a solution made from 1
L of water and 100 g of ammonium chloride, and 10 g sodium cyanide. The mixture was
stirred over a period 10 minutes. The organic phase was separated and aqueous phase was
extracted with (4 x 50 mL) pentane. The combined organic phase was dried over MgSO4,
and the solvent was removed under reduced pressure. The crude product was purified by
distillation 78 °C (1torr) to yield a pure product in 67% isolated yield (45.54 g, 316.2
mmol). 1H NMR (300 MHz, CDCl3): 8 = 6.00 (s, 1 H, h), 3.20 (s, 1 H, a), 1.60-2.10 (m,
8 H, i, j, k, and l), 2.03 (s, 1 H, d). ‘3C{‘H} NMR (CDC13): 6 = 10.35 (3), 21.73 (1), 22.51

(k), 25.79 (j), 29.35 (I), 68.86 (c), 78.66 (f), 80.00 (b), 82.95 (e), 120.52 (g), 135.02 (h).

I-Cyclohexene-3-methyl-1,4-pentadiyne (Entry 10)

In a 1 L, 3-necked flask with a stir bar, reflux condenser and dropping funnel under
nitrogen atmosphere were placed l-ethynyl-l-cyclohexene (13.33 g, 0.126 mol) and THF
(100mL). Under cooling in an ice bath to this solution was added benzyl magnesium
chloride (63 mL, 0.126 mol, 2M solution in THF) with a dropping funnel over a 10-

minute period. The solution was refluxed for 1 h. The reaction mixture was cooled in an

76

ice bath to 0 °C. To this solution, copper (I) bromide (0.73 g) was added. 30 minutes after
this addition, 3-tosyl-1-butyne (28.17 g, 0.126 mol) in 40 ml THF was added 0 °C with
vigorous stirring over a period of 15 minutes. During this addition, the temperature of the
reaction mixture was kept between 0 °C and +5 °C. The bath was then removed, 150 mL
of dry THF was added to the reaction mixture and was stirred overnight at room
temperature. The reaction was quenched with a solution prepared from 500 mL of water
and 55 g of ammonium chloride, and 10 g sodium cyanide. The mixture was stirred for
30 minutes. The organic phase was separated and aqueous phase was extracted with (2 x
200 mL) pentane. The combined organic phase was dried over MgSO4, and the solvent
was removed under reduced pressure. The crude product was purified by distillation 65
°C (1 torr) to yield a pure product in 59% isolated yield (11.69 g, 74 mmol). 1H NMR
(300 MHz, CDC13): 8 = 6.08 (s, 1 H, i), 3.57 (d, 1 H, b), 1.60-2.10 (m, 8 H, j, k, land m),
2.13 (d, 1 H, e), 1.48 (d, 3 H, a), 1.95 (s, 3 H, m). l3C{‘H} NMR(CDC13): 6 = 18.37 (a),
21.75 (i), 22.58 (I), 25.82 (k), 29.45 (m), 68.42 ((1), 82.57 (g), 84.16 (c), 85.73 (1'), 128.60

(h), 134.90 (i).

77

 

 

Preparation of Iphenyl-2,3-dimethyl-5-(I-cyclohexenyl)-pyrrole (Entry 11): Under
an atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with toluene
(3.17 mL), Ti(dpma)(NMe2)2 (A) (0.21 g, 0.63 mmol), aniline (576 ILL, 6.33 mmol), and
l-cyclohexene-3-methyl-1,4-pentadiyne (1b) (1.00 g, 6.33 mmol). The tube was sealed
with a Teflon cap, and the reaction mixture was heated at 100 °C for 4 h. The volatiles
were removed from the reaction mixture in vacuo, and the residue was subjected to
column chromatography using 300 g of silica gel with 5:1 hexane:dichloromethane as the
eluent. Product 23 eluted in the first fractions in 23% (0.37 g, 1.45 mmol) isolated yield.
1H NMR (300 MHz, CDC13): 8 = 7.0-7.3 (m, 5 H, j, k and l), 5.87 (s, 1 H, b), 5.25 (br s,
1 H, g), 2.16 (s, 3 H, a), 1.58-1.44 (m, 8 H, c and d), 1.95 (s, 3 H, m). ‘3C{‘H} NMR
(CDCl3): 8 = 10.5 (m), 11.2 (a), 22.0-22.90 (b, c and (1), 108.5 (g), 114.2 (i), 125-139 (j,

k, I, f, h, n and b), 138.5 (.1). 140.4 (e).

78

 

Preparation of 1-benzyl-2,3-dimethyl-5-(I-cyclohexenyl)-pyrrole (Entry 12): Under
an atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with toluene
(6.33 mL), Ti(daP)2(NMe2)2 (C) (0.48 g, 1.26 mmol), benzylamine (1380 “L, 12.65
mmol), and 1-cyclohexene-3-methyl-l,4-pentadiyne (1b) (2.00 g, 12.65 mmol). The tube
was sealed with a Teflon cap, and the reaction mixture was heated at 60 °C for 19 h. The
volatiles were removed from the reaction mixture in vacuo, and the residue was subjected
to column chromatography using 300 g of alumina with 5:1 hexane:dichloromethane as
the eluent. Product 2b eluted in the first fractions in 8.3% (0.278 g, 1.05 mmol) isolated
yield. 1H NMR (300 MHz, CDCl3): 8 = 6.80-7.25 (m, 5 H, j, k and l), 5.87 (s, 1 H, b),
5.45 (br s, l H, g), 4.99 (s, 2 H, o), 1.96 (s, 3 H, a), 1.58-1.44 (m, 8 H, c and d), 1.77 (s, 3
H, m). ”c1 1H} NMR(CDC13): 6 = 9.9 (m), 11.2 (3), 220—3010 (b, c and d), 47.80 (0),

107.5 (g), 114.3 (i), 125-139 (j, k, l, f, h, n and b), 139.6 (e).

79

 

 

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