PALLADIUM-CATALYZED PMHS REDUCTIONS OF IMINES
By
Maria del Rosario Ivette Amado Sierra

A THESIS
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of
MASTER OF SCIENCE
Chemistry
2011

ABSTRACT
PALLADIUM-CATALYZED PMHS REDUCTION OF IMINES
By
Maria del Rosario Ivette Amado Sierra
We explored the Pd-catalyzed reductions of imines using polymethylhydrosiloxane
(PMHS) in the presence of aqueous KF. This methodology developed by our group facilitates the
reduction of nitrogen-containing functional groups under mild conditions and short reactions
times. To the best of our knowledge, there are no prior reports of imine reductions using
Pd/PMHS/KF. After optimization of the reaction conditions with respect to the PMHS and KF
concentrations, a screening of palladium salts was conducted. This screening proved that
Pd(OAc)2 is the most efficient catalyst for these reductions.
Chemoselective reductions of aromatic imines were achieved in the presence of nitriles,
nitro, fluoride, and chloride substituents. On the other hand ketones, double bonds and bromide
did not survive under these conditions and gave a complex mixture of products.
The addition of PMHS to a Pd(OAc)2 solution result in the formation of polysiloxane
encapsulated Pd-nanoparticles, and we were able to confirm the existence of these nanoparticles
using transmission electron microscopy (TEM). The crucial role of KF was confirmed on these
studies; without addition of KF agglomeration of the Pd-nanoparticles was observed.

ACKNOWLEDGMENTS

The work described in this dissertation would not have been possible without the
guidance, advice and scientific support of my research advisor, Professor. Robert E. Maleczka,
Jr. His strong work ethic and passion for science helped me evolve both as person and as a
scientist.
I would also like to thank the members of my thesis committee Dr. Gregory L. Baker, Dr.
William D. Wulff and Dr. Merlin L. Bruening, for always taking time to assist me with my
scientific endeavors. A note of appreciation goes to the Chemistry Department and staff at MSU,
for providing me with this excellent educational opportunity. I particularly want to thank Dr. Dan
Holmes, for his help and suggestions related to the NMR experiments.
I am especially indebted to the Dr. Maleczka Research Group, for the late nights working
together and their support in the lab. Especially I want to thank Luis S., Luis M., and Monica for
their friendship, as well as useful conversations.
Last but certainly not least, I would like to thank my family, for their unconditional love
and prayers during the years. My parents Teresa and Marino have been exceptionally supportive,
without their help I would have never made it throughout graduate school. I also thank my sister
Magaly and my aunt Julia, for being great friends and always believing in me. Finally, I want to
thank Mohanish, for all his tolerance, encouragement, patience and help even in this difficult
time. I cannot express how deeply I appreciated everything that he has done for me.

iii

TABLE OF CONTENTS

LIST OF TABLES……...…………………………………………………………………............v
LIST OF FIGURES…………………………………………………………………………........vi
LIST OF SCHEMES...……………………………………..........................................................vii
LIST OF ABBREVIATIONS...……………………………………...........................................viii
CHAPTER 1
IMINE REDUCTIONS…………..………….…………………………………….…………..............1
1.1. Introduction…………………………………………………………………………....….1
1.2. PMHS applications and background………………………….……………………………..3
CHAPTER 2
APPLICATIONS OF Pd(OAc)2/PMHS/KF SYSTEM IN THE REDUCTION
OF IMINES....................................................................................……………..............................8
2.1. Optimization of the Pd(OAc)2/PMHS/KF(aq) system.......…………................................8
2.2. Chemoselectivity studies.................……………………..................................................15
2.3. Conclusions........................................................................................................................25
CHAPTER 3
Pd NANOPARTICLE STUDIES.....................................................................................................27
3.1. Introduction……………………………………………………………..........................27
3.2. TEM and EDS studies..…………………………………................................................28
CHAPTER 4
EXPERIMENTAL……………………………………………………………………………….….31
4.1. General Materials and Methods…...…………….............................................................31
4.2. Experimental..........................................................................................................................32
REFERENCES.....……………………………………………………………..............................52

iv

LIST OF TABLES

Table 2.1. Control experiments with the Pd(OAc)2/PMHS/KF system...........................................9
Table 2.2. Screening of different Pd catalysts for imine reduction…….……................................10
Table 2.3. Reduction of imine 24 monitored by NMR and GC analysis…………….……….....19
Table 2.4. Possible hydrogenolysis of the secondary amine 39 with time………......….………....24

v

LIST OF FIGURES

1

Figure 2.1 Comparison of the H-NMR spectrum of imine 17 (top) and secondary
amine 18 (bottom)…………………………………………………………………….…….13
1

1

Figure 2.2 H-NMR spectrum of over reduced m-NO2 imine 44 (top) and H-NMR
spectrum of the crude mixture of secondary amines 45 and 46 (bottom)…………….17
1

Figure 2.3 H-NMR spectrum of chemoselective reduction of imine vs NO2
group……………………………………………………………………….…………..18
1

Figure 2.4 H-NMR spectrum of imine 24 reduction crude at 1 hour…….....….………………….19
1

Figure 2.5 H-NMR spectrum of complex mixture of imine 25 reduction….….………………...20
1

Figure 2.6 Comparison H-NMR spectrum of imine 28 (top) and over reduced
secondary amine 56 (bottom)…………………..………………………...........................22
1

Figure 2.7 Comparison H-NMR spectrum of imine 55 with aniline contamination
(*) (top) and over reduced secondary amine 57 (bottom)……...………………………..23
Figure 3.1 TEM image of Pd nanoparticles using Gatan Digital MSC camera at
X200k magnification……….……………………………………...…………………....27
Figure 3.2 TEM image of reaction mixture of Pd(OAc)2/PMHS in THF/H2O
without KF(aq)………..……..………………………...………………..………................28
Figure 2.4 EDS of normal sample (spectrum top). EDS of coated film without
selecting darker particles (spectrum bottom)..…………....……..…………………….....30

vi

LIST OF SCHEMES

Scheme 1.1 Previous examples of reductions of imines with PMHS………..………………………2
Scheme 1.2 PMHS structure………………………………..………………………….………………3
Scheme 1.3 Previous examples of nitroarenes reductions using silyl hydrides…………………...4
Scheme 1.4 Reduction of nitro compounds with Pd(OAc)2/PMHS/KF(aq).
at room temperature…………..……………….…………………..………….................5
Scheme 1.5 Preliminary Pd(OAc)2/PMHS/KF(aq) nitro reduction………..….……...…….................5
Scheme 1.6 Pd-catalyzed silicon hydride reductions of aromatic and aliphatic nitro
groups……………………….......................................................................................7
Scheme 2.1 Reduction of N-phenyl-4-methoxybenzylideneamine with Pd/PMHS/KF
system…………………………………………………………...……………………...9
Scheme 2.2 Imines prepared for reductive amination (isolated yield)………..………….……….....11
Scheme 2.3 Secondary amines synthesized (isolated yield)…………………...…………….…….15
Scheme 2.4 Potential imine substrates….………...…………………………………………………..21
Scheme 2.5 Secondary amines synthesized for chemoselectivity studies
(isolated yield)………………………….............................................................................25
Scheme 2.6 Proposed imine reduction catalytic cycle…….………….………………..…………….26

vii

LIST OF ABBREVIATIONS

Acac

acetylacetonate

aq

aqueous

CH2Cl2

dichloromethane

Cl2Pd(PPh3)2

dichlorobis(triphenylphosphine)palladium(II)

dba

dibenzylideneacetone

DMF

N,N-dimethylformamide

EDS

energy dispersive spectroscopy

equiv

equivalent

EtOAc

ethyl acetate

g

gram

h

hour

KF

potassium fluoride

Min

minutes

M

molar

mL

milliliter

Mmol

millimole

Pd(OAc)2

palladium (II) acetate

Ph

phenyl

PMHS

polymethylhydrosiloxane

r.b.

round bottom

viii

r.t.

room temperature

TEM

transmission electron microscopy

THF

tetrahydrofuran

ix

CHAPTER 1: IMINE REDUCTIONS

1.1 Introduction
The importance of the amino functionality in the pharmaceutical industry is considerable,
for example secondary amines are vital building blocks for alkaloid and pharmaceutical drug
1

syntheses. Besides synthetic transformations can be fine-tuned to improve currents methods and
obtain target amino compounds of any complexity from relatively simple structures.

One of the most noteworthy pathways for the synthesis of these nitrogen-containing
building blocks is their preparation from readily available imine compounds. Conventional
approaches to obtain secondary amines by reduction of imines usually involve the use of
2

3

reagents that are difficult to handle like NaBH4, LiAlH4, BH3(CH3)2NH/CH3COOH (glacial),
5

6

4

7

Ra-Ni/aluminum isopropoxide/iPr-OH, NH3/Ra-Ni, BH3S(CH3)2. However, these protocols
usually generate copious waste and involve a difficult work up to isolate the desired amine.

Several efforts have also been extended forward the development of asymmetric
8,9a-c

syntheses of secondary amine using chiral catalyst and ligands.

Most recently the use of

reductive amination reactions, a powerful transformation for fragment coupling of ketones or
aldehydes with amines in the presence of a chiral catalyst and a reducing reagent have been
10

increasing.

1,11

Applications of this reaction in both academic research and chemical industries

highlight once again the importance of imines as key intermediates that can provide direct access
to chiral amines.

1

An alternative route applied towards imine reduction is the use of silanes and siloxanes as
12

reducing reagents. Different methods have employed triethylsilane in combination with Zn,
Mo,

13

9a-b

Ti

14

catalysts or metal free conditions.

In the quest for environmentally friendly and

inexpensive procedures, polymethylhydrosiloxane (PMHS) seems to be a safe and economic
hydride source. Consequently several protocols have been reported using PMHS in combination
with Zn,

15a

16

Sn,

Ti,

9a-c

8

8

In, and Cd catalysts, as well as a recent publication in where PMHS is
17

activated only by trifluoroacetic acid.

However, long reactions times, harsh conditions, poor

chemoselectivity or lower yields governs the outcome of the reductions (Scheme 1.1).

N

R2

ZnCl2 (2 mmol)

HN

R2

PMHS
R1
1

2

1 mmol

ether (5 mL)
r.t., 10-20 h, N2

R1

5 mmol

ref 15a
3

50-75%
O
BuSn

N

R4
PMHS
R(H)

R3
4

2

1 mmol

n-Bu

O

3
CH3

10 mol%

EtOH
r.t., 7-20 h, N2

3 mmol

O
H

R-NH2

R4
ref 16
R(H)

R3
5

75-84%
1) TFA, CH2Cl2, rt, 12 h
2) PMHS, rt, 8-10 h

6
1 mmol

HN

7
1.2 mmol

N
H

R
ref 17

8
28-87%

Scheme 1.1 Previous examples of reduction of imines with PMHS
In these methods PMHS is used as an environmentally friendly, non expensive and
readily available reducing agent.

2

1.2 PMHS applications and background
PMHS is a powerful reagent that can perform a wide range of reactions, such as
18

dehalogenation,
esters,

22

19

opening of aziridines,
23

carboxamides,

20

reduction of ketones,
24

and organotin halides and oxides.

double bonds,

21

carboxylic

It is a byproduct of the silicon

industry’s synthesis of cyclicsiloxanes, so it is inexpensive (approximately $7.2 per mol of
hydride).

25

Moreover, PMHS is air and moisture stable (can be stored on the bench for years);

and is assumed to be non-toxic (Scheme 1.2).

Scheme 1.2 PMHS structure

26

PMHS was first synthesized by Sauer
27

developed in the last decades.
Pd,

19,21,28

Zn,

20a-b,29

Cu,

20c-d

Sn,

in 1946; but its applications have largely been
9,22

Several protocols using PMHS in combination with Ti,
20e,24a,30

9,22

Ti,

Zr,

22

Ru,

23

Fe,

31

and I2

32

are highlighted in the

literature. It is also known that PMHS can be activated to a hypercoordinate species with a
20f,24b,33

fluoride source.

Maleczka and co-workers

34

showed that the combination of KF and

PMHS, in ethereal solution, yielded tributyltin hydride from the corresponding tributyltin
chloride.
Another important application of PMHS is in nitro reductions. An attractive route for
those reductions entailed the use of silanes and siloxanes as hydride source. Early examples by

3

35

Lipowitz and Bowman

recounted the used of PMHS with a Pd/C catalyst towards the reduction

of nitrobenzene to aniline. Almost 20 years later, Bulm and Volhardt

36

highlighted again the use

of PMHS to reduce nitrobenzene; using instead a rhodium catalyst for this transfer
hydrogenation reaction (Scheme 1.3). Another successful methodology was reported years later
37

by Brinkman and Miles,

who employed triethylsilane with a Wilkinson’s catalyst for the

reduction of several nitrobenzenes.

Scheme 1.3 Previous examples of nitroarenes reductions using silyl hydrides.

Encouraged by these results, the Maleczka group developed a methodology that
facilitates the reductions of nitrogen-containing functional groups under milder conditions and
shorter reaction times based on Pd-catalyzed reductions using PMHS in presence of aqueous KF
(Scheme 1.4).

4

Scheme 1.4 Reduction of nitro compounds with Pd/PMHS/KF(aq) at room temperature.

The combination of these reagents was initially tested on the hydrodehalogenation of aryl
chlorides.

18b

During those chlorodehalogenation studies, the reduction of the nitro group in 1-

chloro-4-nitrobenzene was also observed (Scheme 1.5). Therefore, nitrobenzene was subjected to
38

the optimized dehalogenation conditions to yield the desired amine.

Scheme 1.5 Preliminary Pd(OAc)2/PMHS/KF(aq) nitro reduction

In order to optimize this nitro reduction; different palladium catalysts, fluoride sources,
38

and siloxanes/silanes were screened using 2-nitrotoluene as the control substrate.

It was found

that the combination of Pd(OAc)2/PMHS/KF(aq) gave the highest yields and shortest reaction
times.
These results highlight the importance of the fluoride source to activate the
PMHS.

18a,33,34

Moreover, the formation of highly activated palladium nanoparticles as reported
5

previously by Chauhan

39

when Pd(OAc)2 and PMHS were combined seems to favor the outcome

of these reductions. This methodology displayed a broad substituent group tolerance independent
of their ring position. Electron-donating and withdrawing groups on the arene were tolerated
affording the aniline products in quantitative yield. Chemoselective reductions of the nitro group
were also observed, in which carboxylic acids, esters, amides, and fluoro substituents survive;
however ketones, nitriles, bromo, chloro, olefins and triple bonds gave side products. Exceptions
to this chemoselectivity are substrates containing sulfur, which is assumed to poison the
38

catalyst.

38

This methodology was extended to heteroaromatic

40

and aliphatic nitro compounds

giving the corresponding anilines and N-hydroxylamines (Scheme 1.6). In the second case the
optimization conditions required exchange of PMHS for a non-polymeric silicon hydride as
triethylsilane and removal of the fluoride source. One-pot reductive conversion of nitroarenes to
amides, carbamates or sulfonamides was also reported by the Malezcka group
42

work, the formation of cyclic nitrones from the reduction of nitroketones.

6

41

and in recent

40

Scheme 1.6 Pd-catalyzed silicon hydride reductions of aromatic and aliphatic nitro groups.

These successful studies on the reduction of nitro compounds using the Pd/PMHS/KF
system sparked our interest to further investigate its application to the synthesis of secondary
amines from the direct reduction of imines. Therefore, the aim of this thesis is to report our
results on imine reductions as well as their advantages of short reaction times, low catalyst
loadings and the formation of Pd nanoparticles that seems to guide the chemoselective outcome
of these reductions.

7

CHAPTER 2: APPLICATION OF Pd(OAc)2/PMHS/KF SYSTEM IN THE REDUCTION
OF IMINES

The methodology developed by Malezcka’s group seems to be hold a great potential for
the reduction of imines. To the best of our knowledge there has been no report of using
Pd(OAc)2/PMHS/KF for this reductive amination. Therefore the reduction of aromatic and
aliphatic imines using the Pd/PMHS/KF system was studied.

2.1 Optimization of the Pd(OAc)2/PMHS/KF(aq) system
Initially N-phenyl-4-methoxybenzylideneamine was obtained in quantitative yield
43

following standards procedures.

The freshly synthesized imine was subjected to our reduction

methodology (Scheme 2.1) and afforded the desired secondary amine in only 30 min. In order to
optimize conditions for this reductive amination, control experiments were run without
Pd(OAc)2 or aqueous KF; however no reaction was observed after 24 h. A similar result was
obtained without PMHS, after 12 hours any reduction of the imine was observed (Table 2.1).
This last result highlights that under our reduction conditions imine hydrolysis is not observed,
so the reaction goes through a hydrogenolysis pathway. On the other hand, the order of addition
was important: mixing the Pd(OAc)2 with the imine solution in THF/KF(aq) followed by
addition of PMHS assured shorter reaction times. Furthermore, the equivalents of PMHS needed
were reduced to 2, and the concentration of KF(aq) to 10 mol%. Finally the addition of 5 mol% of
the Pd(OAc)2 catalyst gave us the best conditions for imine reduction.

8

Scheme 2.1 Reduction of N-phenyl-4-methoxybenzylideneamine with Pd/PMHS/KF system
Table 2.1 Control experiments with the Pd(OAc)2/PMHS/KF(aq) system
Entry

Pd (OAc)2

PMHS

KF

Time

Result

1

5 mol %

2 equiv

10 mol%

30 min

Complete conversion

2

---

2 equiv

10 mol%

24 h

No reaction

3

5 mol%

2 equiv

---

24 h

No reaction

4

5 mol%

---

10 mol%

12 h

No reaction

In order to confirm that Pd(OAc)2 was the best catalyst for these reductions, we tested
different Pd catalysts under the same reaction conditions of PMHS/KF(aq) previously established
(Table 2.2).

Using 5 mol% of each catalyst and 1 mmol of N-phenyl-4-methoxybenzylideneamine, the
1

control reactions were performed and monitored by H-NMR between 30 min and 2 hours. In the
1

first two attempts using Pd(Cl)2 and Pd(CN)2 (entries 1 and 2 on Table 2.2) the H NMR
spectrum of the crude reaction mixture displayed only the signals of the starting material.
Therefore we continued both reactions for an additional 30 min; however no conversion was
observed and the catalyst precipitated after 2 hours in both cases.

9

Table 2.2 Screening of different Pd catalysts for imine reduction
Entry

Catalyst

Time

% conversion

1

Pd(Cl)2

30 min

0

2

Pd(CN)2

30 min

0

3

Pd(PPh3)2(C6H5)Cl

30 min

0

4

Pd(PPh3)2Cl2

30 min

0

5

Pd(NH3)2Cl2

30 min

0

6

Pd2(dba)3

30 min

50

7

Pd black

30 min

50

8

Pd/C activated

30 min

50

9

Pd(OH)2/C

30 min

50

10

Pd(acac)2

30 min

80

When phosphine ligands were employed (entries 3 and 4) no conversion to the desired
amine was observed after 30 min, instead hydrolysis of the imine generated a complicated
1

mixture as judged by H NMR. The same result was observed when Pd(NH3)2Cl2 was used as a
catalyst (entry 5). On the other hand, when Pd2(dba)3, Pd black, Pd/C activated and Pd(OH)2/C
were employed, partial reduction of the imine was observed at 30 min. The secondary amine to
1

imine ratio was 1:1; complete conversion was observed by H NMR after 1 hour (entries 6 to 9).
The last catalyst tested, Pd(acac)2, gave the highest conversion in 30 min. The ratio of secondary

10

amine to imine was 4:1 and the reaction was complete after 45 min. In summary, these findings
confirmed that Pd(OAc)2 was the best catalyst, giving complete conversion in as little as 30 min.
43,44

With these results in hand, several imines where prepared,

not only to study reductive

amination, but also to further investigate the chemoselectivity of this reduction in the presence of
other functional groups such as alkenes, ketones, nitriles, halogens and nitro substituents
(Scheme 2.2).

Scheme 2.2 Imines prepared for reductive amination (isolated yield)

11

H3CO

N

N

N

O2N
27 (87%)

28 (100%)

29 (75%)

N

N
O2N

N

NO2
30 (100%)

NO2

31 (97%)

N
N

32 (91%)

O2N

N

F

O
33 (98%)

34 (97%)

H3CO

N

35 (74%)

N

H3CO
36 (78%)

37 (100%)

Scheme 2.2 (cont’d)

1

The secondary amines were identified by H-NMR, the spectra usually display an imine
proton (N=CH) around 8.4 ppm for the starting material. After reduction, this signal disappears
and a new peak for the methylene protons (NH-CH2) of the secondary amine is observed around
4.3 ppm (Figure 2.1).

12

OCH 3
N
Ha

17

Ha

10

9

8

7

6

5

4

3

2

1

-0

ppm

OCH 3
H
N
H b Hb

18

Hb

10

9

8

7

6

5

4

3

2

1

ppm

1

Figure 2.1 Comparison of the H-NMR spectrum of imine 17 (top) and secondary amine 18
(bottom)

The initial work up for the N-phenyl-4-methoxybenzylideneamine reduction included
addition of ether, which precipitated the catalyst after stirring. A quick filtration of the Pd
through a plug of Celite (top layer) and neutral alumina (bottom layer) gave a high crude

13

recovery; however the yield of product recovered after column chromatography was <50% and
1

some contamination with PMHS was observed by H NMR. To circumvent this problem, a new
work up was attempted in which a mixture of H2O/Et2O (1:1) was added to the crude. After
stirring, the organic phase was separated, dried with MgSO4, filtered and concentrated. The
crude product was dissolved in EtOAc and treated with a 3M HCl solution. The white solids
formed were filtered, washed with EtOAc and dried overnight to give the desired secondary
amine as a hydrochloride salt. The latter was dissolved in a H2O/methanol (1:1) mixture and
NaHCO3 (sat) solution was added. The solution was concentrated under reduced pressure to the
minimum, and then extracted with EtOAc. The organic layers were dried and concentrated to
give the secondary amine in 65%. Optimization of the work up with a shorter acid/base
procedure increased the yield to 80% of N-(4-methoxybenzyl)phenylamine. In this work up, a
mixture of Et2O/1M HCl (1:1) was added and stirred for 10 min. The organic phase was
separated and washed with 1M HCl. Then the aqueous layers were combined, made basic with
addition of KOH(s), and extracted with EtOAc. Finally, the combined organic layers were dried,
filtered and concentrated.

In summary, the secondary amines were successfully synthesized

16,45

and fully

characterized (Scheme 2.3). Reaction times varied between 15 min to 1 hour and the yields
ranged from 48 to 93%.

14

OCH3

H
N

H
N

H
N
H3CO

38 (90%)

H3CO

18 (80%)

N
H

N
H

39 (48%)

N
H

H3CO

40 (91%)

41 (78%)

42 (93%)

H
N

43 (76%)

Scheme 2.3 Secondary amines synthesized (isolated yield)

2.2 Chemoselectivity studies

The second part of this project is concerned with the reactivity of the imine in the
presence of other functional groups. The first substrates selected contained NO2 groups in the
para and meta position of the aniline or benzaldehyde ring. When the electron withdrawing
group was on the meta position, reduction of both functionalities was observed in 1 hour. For mNO2 anilines (imine 31), only the over reduction product (44) was observed; but m-NO2
benzaldehydes (imine 32) gave a 1:1 mixture of the nitro secondary amine (45) and the over
reduction product (46) was recovered after 1 hour (Figure 2.2). Leaving the reaction for longer
times reduced the yield of the desired secondary amine and new signals of aniline become the
major product in the crude mixture. A similar outcome was observed in the reduction of imine

15

1

35, which contains m-NO2 and a fluoro group in the para position of the same ring. The H NMR
spectrum of the crude reaction mixture, showed the reducted imine; however two secondary
amines could be identified. One where the NO2 group survived, and another where over
reduction took place. No dehalogenated product could be identified in the complicated mixture.

Better chemoselectivity was observed when the nitro substituent was at the para position.
Regardless whether the p-NO2 group was on an aniline or benzaldehyde ring, the nitro group
survived the reduction conditions and no over reduced product (47) was observed after one hour
(Figure 2.3). However, some starting imine remained in the reaction. Leaving the mixture for
longer time reduces the yield of the target secondary amine and increase the formation of aniline
derivative.

16

H
N

NH 2
44

8.0

7.5

7.0

6.5

6.0

5.5

H a Ha

5.0

4.5

4.0

ppm

Hb H b
N
H

N
H

Ha

NO2

NH 2

45

1

46

Hb

1

Figure 2.2 H-NMR spectrum of over reduced m-NO2 imine 44 (top) and H-NMR spectrum of
the crude mixture of secondary amines 45 and 46 (bottom)

17

N
H
O2 N
47

8.5

8.0

7.5

7.0

6.5

6.0

5.5

5.0

4.5

ppm

1

Figure 2.3 H-NMR spectrum of chemoselective reduction of imine vs. NO2 group

Chemoselective reduction of the imine was also observed in the presence of nitrile
substituents (imine 23). Impressively, the nitrile group survives the reaction conditions and no
1

primary amine or aldehyde were detected by H NMR.

Previous studies of this methodology in the presence of halogen substituents showed
dehalogenation as a side reaction. However, under the optimized imine reduction conditions no
dehalogenated products where observed in the case of F (imine 24) and Cl (imine 22) containing
1

substrates. In the reduction of imine (24), the H NMR spectrum displayed a complicated
mixture of the starting material (24), the target secondary amine (48) and 4-fluoroaniline (49)
(Figure 2.4). This reaction was also monitored by GC. Injecting known samples of 4fluoroaniline (49) and the starting imine (24), we were able to observe the consumption of the
18

imine (24) and the formation of the target amine (48). However, the increasing formation of 4fluoroaniline (49) with the time, reduced the yield of the secondary amine (48) (Table 2.3).
Table 2.3 Reduction of imine 24 monitored by NMR and GC analysis
Entry

Crude NMR

Imine 24

Secondary Amine

4-fluoroaniline

1

at 30 min

5.3%

80.9%

13.7%

2

at 1 h

4%

79.7%

16.3%

3

at 3 h

1.4%

37.4%

61.1%

Entry

GC analysis

4

at 1 h

1.6%

82.2%

12.2%

5

at 2 h

2.9%

52.8%

44.9%

STANDARD 1H OBSERVE

NH 2

H
N

N

File: home/amadosie2/1-RA-132-F1hour.fid
Pulse Sequence: s2pul

F

F

F

49

48

24

48

48
48

48

24
49

1

Figure 2.4 H-NMR spectrum of imine 24 reduction crude at 1 hour

19

On the other hand, the imine reduction with Br containing substrate (imine 25) displayed
1

a complicated mixture in the H NMR spectrum, where four different compounds could be
identified: two secondary amines (38, 52) and two imines (19, 25) as a consequence of
dehalogenation. Furthermore, hydrolysis of the two imines present in the mixture was also
observed (compounds 50 and 51). Attempts to separate this mixture, even by preparative TLC,
were unsuccessful (Figure 2.5).
Br
N

Br
H
N

N

25

19

52

O

O

H
N

H

H
Br
50

51

25

38

38
52

19
51
50

10

9

8

7

6

5

ppm

1

Figure 2.5 H-NMR spectrum of complex mixture of imine 25 reduction

A limitation of this methodology was observed in the presence of conjugated and nonconjugated double bonds. In the former case, the presence of the conjugated double bond
accelerates the reaction, yielding complete reduction in only 15 min (Figure 2.6). An important

20

observation was that the complete formation of the secondary amine (56) was detected even
before the typical bubbling and color change could be observed. Expecting a different result with
non-conjugated double bonds, three different imines were envisioned as potential substrates
(Scheme 2.4). However inability to purify the substrate and further contamination with aniline
prevented us from employing our reduction methodology. Among these substrates, ketoimine
(55) showed the lowest aniline contamination. To address this issue, fewer equivalents of aniline
were added; however we were unable to obtain a pure product. Nonetheless, we decided to
1

employ this crude mixture for the imine reduction step. Unfortunately, after only 30 min the H
NMR signals of the double bond between 5 and 6 ppm disappeared, and the over reduced
secondary amine (57) was recovered after preparative TLC (Figure 2.7). At this point we cannot
discount the possibility that the excess aniline present serves as an additive that promotes the
reduction of the double bond. Therefore it might be interesting to ascertain whether a reduction
of a non-conjugated double bond can be avoided in the absence of the aniline impurity.

Scheme 2.4 Potential imine substrates

21

N

28

N
H
56

1

Figure 2.6 Comparison H-NMR spectrum of imine 28 (top) and over reduced
secondary amine 56 (bottom)

22

N

55

*
*

*
*

10

9

8

7

6

5

4

5

4

3

2

1

ppm

H
N

57

10

9

8

7

6

3

1

2

1

ppm

Figure 2.7 Comparison H-NMR spectrum of imine 55 with aniline contamination (*) (top) and
over reduced secondary amine 57 (bottom)
23

Continuing our studies on chemoselectivity, reductions of imines in the presence of
1

ketones (imine 33) were carried out. Unfortunately analysis of the crude H NMR spectrum after
30 min displayed a mixture of selective imine reduction (secondary amine) and the over
reduction product (conversion of ketone to alcohol and secondary amine) in a ratio 1:0.3. The
usual work up developed for the isolation of the secondary amines did not allow us to isolate the
alcohol product, therefore optimization of the isolation and purification of these products is still
underway.

Finally, a different result was obtained when N-benzylidene-4-methoxyaniline (imine 20)
was subjected to the reduction conditions. At 30 min, the target secondary amine 39 was
1

observed by H NMR, along with 4-methoxyaniline as an impurity (Table 2.4). The presence of
small quantities of starting imine 20 led us to leave the reaction for another 30 min. Surprisingly,
another compound was detected in the crude mixture but after purification and concentration of
the solvent, only the secondary amine 39, imine 20 and 4-methoxyaniline were recovered. In a
different batch, left for 5 hours, the desired secondary amine 39 was not detected. Instead,
toluene and 4-methoxyaniline were the major components in the mixture, along with a small
percent of starting material. Leaving the reaction overnight let to complete consumption of the
imine, yielding only toluene and 4-methoxyaniline (Table 2.4). These findings suggest the
possibility of hydrogenolysis of the secondary amine 39 with time.

24

Table 2.4 Possible hydrogenolysis of the secondary amine 39 with time
Crude

N-benzylidene-4-

Secondary

NMR

methoxyaniline

amine 39

1

at 30 min

5.8%

2

at 1 h

3
4

Toluene

4-methoxyaniline

44%

9.8%

39.6%

5.1%

37.8%

16%

41.2%

at 5 h

3.7%

---

43.6%

52.7%

at 21 h

---

---

46.8%

53.2%

Entry

2.3 Conclusions
In this dissertation we focused on the reactivity of several imines in the presence of the
Pd(OAc)2/PMHS/KFaq system. This methodology was selective in the presence of nitriles,
fluoride, chloride and p-nitro substituents, yielding the target secondary amine in short reaction
times at room temperature.

Scheme 2.5 Secondary amine synthesized for chemoselectivity studies (isolated yield)

25

Unfortunately ketones, double bonds and bromide did not survive under the optimized
conditions establish for imine reduction. Continued efforts are still underway in order to increase
the chemoselectivity of the reduction, as well as to uncover a better purification process to
remove the excess of PMHS. Moreover, the identification of the gas (bubbles) generated after the
addition of PMHS is another issue to address for future work. If H2(g) is forming during the
reduction, a two-step mechanism can be proposed (Scheme 2.6). In the first step, it is known that
the Si center of the PMHS can be activated by a fluoride source, in our case KF(aq). Then the
active catalyst is generated when Pd(OAc)2 reacts with PMHS/KF forming Pd-PMHS
nanoparticles, evidence of the formation of this encapsulated Pd-polysiloxane nanoparticles was
27

reported previously by Chauhan.

On the second step the imine is reduced to the secondary

amine by palladium catalyzed hydrosilation.

Scheme 2.6 Proposed imine reduction catalytic cycle
26

CHAPTER 3: Pd NANOPARTICLE STUDIES
3.1 Introduction
We observed that the addition of PMHS to a Pd(OAc)2 solution generates polysiloxane
39

encapsulated Pd-nanoclusters as reported previously in the literature.

Conversely, the

mechanism by which the catalytic action of Pd(OAc)2/PMHS/KFaq system functions is
unknown. Using Transmission Electron Microscopy (TEM) to explore the morphology of the
catalyst medium, we were able to confirm the existence of the Pd-nanoparticles (Figure 3.1).
The presence of these nanoparticles could explain the selectivity of this reaction system,
however, the stability and exact composition of these Pd-nanoparticles remains unexplored.

20 nm

Figure 3.1 TEM image of Pd nanoparticles using Gatan Digital MSC camera at
X200k magnification

27

46

3.2 TEM and EDS studies
Samples were prepared under the same reaction conditions without the substrate. One
hour after the addition of PMHS to a solution of Pd(OAc)2/KFaq in THF, an aliquot was taken
from the reaction mixture and added dropwise to a coated copper grid (carbon film support). The
concentration of the sample is about 0.7 mM of the catalyst. Using tweezers, we dispersed the
sample on the grid, but in some areas saturation was observed. TEM images of the catalyst at
high resolution displayed Pd nanoparticles with an average size between 2 to 4 nm (Figure 3.1).
One important finding in this project was the crucial role of the additive KF. When the samples
were prepared without KF solution, agglomeration of the Pd-nanoparticles was observed (Figure
3.2).

200nm

Figure 3.2 TEM image of reaction mixture of Pd(OAc)2/PMHS in THF/H2O
without KF(aq) at X80k magnification

28

X-ray energy dispersive spectroscopy (EDS) gave the chemical composition highlighting
the presence of K, Si, O and Pd. The spectrum collected at different locations confirmed that the
darker particles were the Pd-nanoparticles (Figure 3.3).
In addition, it was possible to confirm the formation of Pd-nanoparticles under the
reaction conditions, furthermore the crucial role of the additive KF was observed.

29

Figure 3.3 EDS of normal sample (spectrum top). EDS of coated film without selecting darker
particles (spectrum bottom).
30

CHAPTER 4: EXPERIMENTAL

4.1 General Materials and Methods
All starting materials were used as received, unless otherwise stated. Diethyl ether and
tetrahydrofuran were distilled from sodium and benzophenone under nitrogen. Toluene was
distilled from calcium hydride. All reactions were carried out in oven-dried or flame dried
glassware under nitrogen atmosphere, unless otherwise stated. All reactions were performed
with magnetic stirring and monitored by 1H-NMR and GC-FID. Palladium (II) acetate purchased
from Strem, anhydrous A.C.S. grade potassium fluoride and polymethylhydrosiloxane (PMHS)
purchased from Sigma-Aldrich were used without purification. Flash chromatography was
performed with silica gel 60 Å (230-400 mesh) purchased from Silicycle, monitored by thinlayer chromatography using 0.25-nm pre-coated silical gel aluminum plates and developed with
uv and/or phosphomolybdeneic acid. Yields refer to chromatographically and spectroscopically
1

pure compounds unless other wise stated. H NMR and

13

C NMR spectra were recorded on
1

either Varian Gemini-300 or Varian VXR-500 spectrometer (300, 500 MHz for H, respectively,
and 75, 125 MHz for

13

C, respectively). Chemical shifts are reported relative to the residue peaks
1

of solvent CDCl3 (δ 7.24 ppm for H and 77.0 ppm for

13

C). TEM sample were acquired at the

Michigan State University Center for Advanced Microscopy using a JEOL 2200FS TEM
microscope.

31

4.2 Experimental
General procedure for imine formation:
Method A: a dried r.b. flask was charged with the corresponding aromatic aldehyde (1.0 mmol),
the appropriate aniline (1.0 mmol) and 10 mL of Ethanol. The reaction mixture was stirred at
1

room temperature and checked by H-NMR until the reaction was finished (usually 24 h). Then
the solvent was removed under reduced pressure and the pure imine was obtained without an
additional purification. For some imines recrystallization was required and it was indicated in
each case.

Method B: a dried r.b. flask was charged with the corresponding aromatic aldehyde (1.0 mmol),
the appropriate aniline (1.0 mmol) and 50 mL of Toluene. The reaction mixture was refluxed at
120 °C for 24 hours using a Dean Strak apparatus. Then the solvent was evaporated in reduce
pressure and the pure imine was obtained.

General procedure for the reduction of aromatic imines to amines:
A dry 25 mL round bottom flask was charged with Pd(OAc)2 (0.05 mmol, 0.011g), an imine (1
mmol) and 5 mL of freshly distilled THF. The flask was sealed, and placed under nitrogen while
stirring. Then a KF(aq) solution (0.1 mmol, 0.1 mL) was added via syringe. This aqueous
solution was previously degassed using vacuum and liquid N2. The nitrogen outlet was replaced
by a balloon filled with N2. After 5 min PMHS (2 mmol, 0.12 mL, 1 mmol is equal to 0.06 mL)
was added dropwise via syringe. Bubble formation is observed and the mixture turns black. The
reaction was stirred for 30 min or until completed conversion as judged by NMR or GC analysis.
Three different work up procedure were employed.
32

Alternate work up procedure I
The reaction mixture was diluted with ether (5 mL). The organic phase was filtrated through a
plug with celite (top layer) and neutral alumina (bottom layer) in a 1 cm diameter column by
flushing with EtOAc. The mixture was then dried over MgSO4 and concentrated. Finally the
crude was purified by silica gel column chromatography.

Alternate work up procedure II
A mixture of 10 mL H2O/Et2O (1:1) was added to the crude, the layers were separated, and the
aqueous layer back extracted with Et2O. After stirring the organic phase was separated, dried
with MgSO4, filter and concentrated. The crude was dissolved in EtOAc and treated with a 3M
HCl solution. The white solids formed were filtered, washed with EtOAc and dried over night to
give the desired secondary amine as hydrochloride salt. The latter was dissolved in a
H2O/methanol (1:1) mixture and NaHCO3 (sat) solution was added. The volume was reduced to
the minimum and extracted with EtOAc (4 x 10 mL), dried and concentrated.

Alternate work up procedure III
Upon addition of 10 mL Et2O/1M HCl (1:1) and stirring for 10 min, the organic phase was
separated and extracted with 1M HCl (3 x 10 mL). Then the aqueous layers were combined,
made basic with addition of KOH(s), and extracted with EtOAc (4x 15 mL). Finally, the organic
layers were dried, filtered and concentrated.

33

Experimental details and spectroscopic data:

N-phenylbenzylideneamine: Using the general procedure for imine formation (Method A) a
1

colorless solid was obtained after recrystallization from hexanes. Yield: 80%. H-NMR (500
MHz, CDCl3): δ = 8.42 (s, 1H, CH-imine), 7.94 (m, 2H, Ar-H), 7.51-7.50 (m, 3H, Ar-H), 7.457.41 (m, 2H, Ar-H), 7.28-7.24 (m, 3H, Ar-H).

13

C NMR (125 MHz, CDCl3): δ = 169.4, 152.1,

136.3, 131.4, 129.2, 128.8, 128.7, 125.9, 120.8.

N-phenylbenzylamine: N-phenylbenzylideneamine (181 mg, 1 mmol) was reduced in 2h,
following the general procedure for imine reduction. The amine was obtained using the work up
1

procedure I and purified by column chromatography. Yield: 90%; H-NMR (500 MHz, CDCl3):

δ = 7.39-7.33 (m, 4H, Ar-H), 7.27 (t, J = 7.0 Hz, 1H, Ar-H), 7.18 (t, J = 7.0 Hz, 2H, Ar-H), 6.72
(t, J = 7.5 Hz, 1H, Ar-H), 6.68 (d, J = 8.5 Hz, 2H, Ar-H), 4.27 (s, 2H, Ar-CH2), 4.07 (s br, 1H, NH).

13

C NMR (125 MHz, CDCl3): δ = 148.1, 139.4, 129.2, 128.5, 127.4, 127.2, 117.5, 112.8,

48.3.

34

N-phenyl-4-methoxybenzylideneamine: Using the general procedure for imine formation
1

(Method A) a white solid was obtained after recrystallization from hexanes. Yield: 100%. HNMR (500 MHz, CDCl3): δ = 8.34 (s, 1H, CH-imine), 7.84 (d, J = 8.5 Hz, 2H, Ar-H), 7.38-7.34
(m, 2H, Ar-H), 7.21-7.16 (m, 3H, Ar-H), 6.97 (d, J = 8.5 Hz, 2H, Ar-H), 3.86 (s, 3H, Ar-OCH3).
13

C NMR (125 MHz, CDCl3): δ = 162.3, 159.7, 152.4, 130.5, 129.3, 129.1, 125.5, 120.9, 114.1,

55.4.

N-(4-methoxybenzyl)phenylamine: N-phenyl-4-methoxybenzylideneamine (211 mg, 1 mmol)
was reduced in 30 min, following the general procedure for imine reduction. The amine was
obtained using the work up procedure III and purified by column chromatography. Yield: 80%;
1

H-NMR (500 MHz, CDCl3): δ = 7.31 (d, J = 9 Hz, 2H, Ar-H), 7.19 (t, J = 7.5 Hz, 2H, Ar-H),

6.90 (d, J = 8.5 Hz, 2H, Ar-H), 6.74 (t, J = 7.5 Hz, 1H, Ar-H), 6.65 (d, J = 9 Hz, 2H, Ar-H), 4.26
(s, 2H, Ar-CH2), 4.00 (s br, 1H, -NH), 3.81 (s, 3H, Ar-OCH3).

13

158.7, 148.2, 131.3, 129.2, 128.7, 117.4, 113.9, 112.7, 55.2, 47.7.

35

C NMR (125 MHz, CDCl3): δ

N-(4-methoxyphenyl)benzylideneamine: Using the general procedure for imine formation
1

(Method A) a yellow solid was obtained. Yield: 98%. H-NMR (500 MHz, CDCl3): δ = 8.50 (s,
1H, CH-imine), 7.91-7.89 (m, 2H, Ar-H), 7.48-7.47 (m, 3H, Ar-H), 7.26 (d, J = 6.5 Hz, 2H, ArH), 6.96 (d, J = 7 Hz, 2H, Ar-H), 3.86 (s, 3H, Ar-OCH3).

13

C NMR (125 MHz, CDCl3): δ =

158.3, 158.2, 144.9, 136.4, 130.9, 128.7, 128.5, 122.1, 114.3, 55.4.

N-benzyl-(4-methoxyphenyl)amine: N-(4-methoxyphenyl)benzylideneamine (211 mg, 1 mmol)
was reduced in 30 min, following the general procedure for imine reduction. The amine was
obtained using the work up procedure III and purified by column chromatography. Yield: 48%;
1

H-NMR (500 MHz, CDCl3): δ = 7.41-7.35 (m, 4H, Ar-H), 7.30-7.27 (m, 1H, Ar-H), 6.81 (d, J

= 7 Hz, 2H, Ar-H), 6.63 (d, J = 7 Hz, 2H, Ar-H), 4.31 (s, 2H, Ar-CH2), 3.86 (s, 1H, -NH), 3.76
(s, 3H, Ar-OCH3).

13

C NMR (125 MHz, CDCl3): δ 142.4, 139.6, 128.5, 127.5, 127.1, 122.1,

114.8, 114.1, 55.7, 49.2.

36

N-(4-chlorophenyl)-benzylideneamine: Using the general procedure for imine formation
1

(Method A) a white solid was obtained after recrystallization from hexane. Yield: 97%. H-NMR
(500 MHz, CDCl3): δ = 8.41 (s, 1H, CH-imine), 7.88-7.86 (m, 2H, Ar-H), 7.48-7.45 (m, 3H, ArH), 7.34 (d, J = 8 Hz, 2H, Ar-H), 7.14 (d, J = 7 Hz, 2H, Ar-H).

13

C NMR (125 MHz, CDCl3): δ

= 160.7, 150.5, 135.9, 131.6, 131.4, 129.2, 128.8, 128.8, 122.1.

N-phenyl-4-chlorobenzylideneamine: Using the general procedure for imine formation a
1

yellow solid was obtained. Yield: 97%. H-NMR (500 MHz, CDCl3): δ = 8.45 (s, 1H, CHimine), 7.88 (d, J = 8 Hz, 2H, Ar-H), 7.48 (d, J = 8 Hz, 2H, Ar-H), 7.43 (t, J = 7.5 Hz, 2H, ArH), 7.29-7.27 (m, 1H, Ar-H), 7.24 (d, J = 8.5 Hz, 2H, Ar-H).
158.7, 151.6, 137.3, 134.7, 129.9, 129.1, 129.0, 126.1, 120.8.

37

13

C NMR (125 MHz, CDCl3): δ =

N-(4-chlorobenzyl)phenylamine: N-phenyl-4-chlorobenzylideneamine (215 mg, 1 mmol) was
reduced in 2 h, following the general procedure for imine reduction. The amine was obtained
1

using the work up procedure I and purified by column chromatography. Yield: 55%; H-NMR
(500 MHz, CDCl3): δ = 7.18-7.13 (m, 4H, Ar-H), 6.75-6.59 (m, 3H, Ar-H), 6.61 (d, J = 8 Hz,
2H, Ar-H), 4.29 (s, 2H, Ar-CH2).

13

C NMR (125 MHz, CDCl3): δ 129.2, 129.1, 129.0, 128.7,

128.6, 120.8, 117.7, 112.8, 47.5.

N-phenyl-4-nitrilebenzylideneamine: Using the general procedure for imine formation
1

(Method A) a yellow solid was obtained. Yield: 90%. H-NMR (500 MHz, CDCl3): δ = 8.51 (s,
1H, CH-imine), 8.03 (d, J = 6.5 Hz, 2H, Ar-H), 7.78 (d, J = 7.5, 2H, Ar-H), 7.44 (t, J = 8 Hz, 2H,
Ar-H), 7.32-7.25 (m, 3H, Ar-H).

13

C NMR (125 MHz, CDCl3): δ = 157.8, 151.0, 139.9, 132.5,

129.2, 129.1, 126.8, 120.9, 118.4, 114.4.

38

N-(4-nitrilebenzyl)phenylamine: N-phenyl-4-nitrilebenzylideneamine (206 mg, 1 mmol) was
reduced in 2 h, following the general procedure for imine reduction. The amine was obtained
1

using the work up procedure I and purified by column chromatography. Yield: 72%; H-NMR
(500 MHz, CDCl3): δ = 7.64 (d, J = 8 Hz, 2H, Ar-H), 7.51 (d, J = 8 Hz, 2H, Ar-H), 7.20 (t, J =
7.5 Hz, 2H, Ar-H), 6.77 (t, J = 7.5 Hz, 1H, Ar-H), 6.61 (d, J = 8 Hz, 2H, Ar-H), 4.41 (s, 2H, ArCH2).

13

C NMR (125 MHz, CDCl3): δ 147.3, 145.4, 132.4, 129.3 (2C), 127.6, 118.8, 118.0,

112.8, 47.9.

N-(4-fluorophenyl)-benzylideneamine: Using the general procedure for imine formation
1

(Method A) a brown solid was obtained. Yield: 100%. H-NMR (500 MHz, CDCl3): δ = 8.42 (s,
1H, CH-imine), 7.88-7.86 (m, 2H, Ar-H), 7.47-7.44 (m, 3H, Ar-H), 7.19-7.17 (m, 2H, Ar-H),
7.08-7.04 (m, 2H, Ar-H).

13

C NMR (125 MHz, CDCl3): δ = 160.1, 160.1, 131.4, 128.7, 128.7,

122.3, 122.2, 115.9, 115.7.

39

N-benzyl-(4-fluorophenyl)amine: N-(4-fluorophenyl)-benzylideneamine (199 mg, 1 mmol) was
reduced in 1 h, following the general procedure for imine reduction. The amine was obtained
1

using the work up procedure II and purified by column chromatography. Yield: 69%; H-NMR
(500 MHz, CDCl3): δ = 7.43-7.39 (m, 4H, Ar-H), 7.35-7.32 (m, 1H, Ar-H), 6.95-6.90 (m, 2H,
Ar-H), 6.62-6.59 (m, 2H, Ar-H), 4.33 (s, 2H, Ar-CH2), 3.96 (s, 1H, -NH).

N-phenyl-4-bromobenzylideneamine: Using the general procedure for imine formation
1

(Method A) a white solid was obtained. Yield: 98%. H-NMR (500 MHz, CDCl3): δ = 8.43 (s,
1H, CH-imine), 7.80 (d, J = 8.5 Hz, 2H, Ar-H), 7.63 (d, J = 8.5 Hz, 2H, Ar-H), 7.42 (t, J = 8.5
Hz, 2H, Ar-H), 7.28-7.22 (m, 3H, Ar-H).

13

C NMR (125 MHz, CDCl3): δ = 158.9, 151.6, 135.1,

132.0, 130.1, 129.1, 126.2, 125.8, 120.8.

40

N-benzylbenzylideneamine: Using the general procedure for imine formation (Method A) a
1

yellow oil was obtained. Yield: 92%. H-NMR (500 MHz, CDCl3): δ = 8.43 (s, 1H, CH-imine),
7.83-7.81 (m, 2H, Ar-H), 7.47-7.44 (m, 3H, Ar-H), 7.39-7.37 (m, 4H, Ar-H), 7.31-7.28 (m, 1H,
Ar-H), 4.87 (s, 2H, Ar-CH2).

13

C NMR (125 MHz, CDCl3): δ = 161.9, 139.2, 130.7, 128.6,

128.5, 128.4, 128.2, 127.9, 126.9, 64.9.

Dibenzylamine: N-benzylbenzylideneamine (195 mg, 1 mmol) was reduced in 2 h, following
the general procedure for imine reduction. The amine was obtained using the work up procedure
1

I and purified by column chromatography. Yield: 76%; H-NMR (500 MHz, CDCl3): δ = 7.407.35 (m, 8H, Ar-H), 7.31-7.28 (m, 2H, Ar-H), 3.90 (s, 1H, -NH), 3.85 (s, 4H, Ar-CH2).
NMR (125 MHz, CDCl3): δ 140.2 (2C), 128.3 (2C), 128.1 (2C), 126.8 (2C), 53.1 (2C).

41

13

C

N-phenyl-4-nitrobenzylideneamine: Using the general procedure for imine formation (Method
1

A) a yellow solid was obtained. Yield: 87%. H-NMR (500 MHz, CDCl3): δ = 8.59 (s, 1H, CHimine), 8.36 (d, J = 8.5 Hz, 2H, Ar-H), 8.11 (d, J = 8.5 Hz, 2H, Ar-H), 7.46 (t, J = 8 Hz, 2H, ArH), 7.34-7.27 (m, 3H, Ar-H).

13

C NMR (125 MHz, CDCl3): δ = 157.3, 150.9, 141.5, 129.4,

129.3, 127.0, 124.0, 120.9, 104.9.

N-(4-nitrobenzyl)phenylamine: N-phenyl-4-nitrobenzylideneamine (226 mg, 1 mmol) was
reduced in 1 h, following the general procedure for imine reduction. The amine was obtained
1

using the work up procedure III and purified by prep. TLC. Yield: 33%; H-NMR (500 MHz,
CDCl3): δ = 8.21 (d, J = 8.5 Hz, 2H, Ar-H), 7.55 (d, J = 8.5 Hz, 2H, Ar-H), 7.19 (t, J = 7.5 Hz,
2H, Ar-H), 6.76 (t, J = 8.4 Hz, 1H, Ar-H), 6.60 (d, J = 8.5 Hz, 2H, Ar-H), 4.49 (s, 2H, Ar-CH2),
4.25 (s, 1H, -NH).

13

C NMR (125 MHz, CDCl3): δ 147.4, 129.4, 129.3, 127.6, 123.9, 123.8,

118.1, 112.8, 47.5.

42

N-1, 3-diphenyl-(E)-2-propenimine: Using the general procedure for imine formation (Method
1

A) an orange solid was obtained. Yield: 100%. H-NMR (500 MHz, CDCl3): δ = 8.32 (d, J = 6.5
Hz, 1H, CH-imine), 7.58 (d, J = 7.5 Hz, 2H, CH=CH), 7.43-7.40 (m, 5H, Ar-H), 7.30-7.18 (m,
5H, Ar-H).

13

C NMR (125 MHz, CDCl3): δ = 161.6, 151.7, 143.9, 135.5, 129.5, 129.1, 128.8,

128.5, 127.4, 126.1, 120.8.

N-1-[(E)-3-phenyl-2-propenyl]phenylamine: N-1, 3-diphenyl-(E)-2-propenimine (207 mg, 1
mmol) was reduced in 15 min, following the general procedure for imine reduction. The amine
1

was obtained using the work up procedure III. Yield: 67%; H-NMR (500 MHz, CDCl3): δ =
7.32-7.29 (m, 2H, Ar-H), 7.27-7.16 (m, 5H, Ar-H), 6.72-6.69 (m, 1H, Ar-H), 6.59 (d, J = 8.5 Hz,
2H, Ar-H), 3.64 (s, 1H, -NH), 3.17 (t, J = 7.5 Hz, 2H, -N-CH2), 2.75 (t, J = 7.5 Hz, 2H, Ar-CH2),
2.01-1.94 (m, 2H, -CH2) .

13

C NMR (125 MHz, CDCl3): δ 148.3, 141.6, 129.2, 129.1 (2C),

128.3 (2C), 125.9, 118.5, 117.1, 115.0, 112.7, 43.3, 33.3, 31.0.

43

N-(4-methoxybenzyl)-benzylideneamine: Using the general procedure for imine formation
1

(Method A) a yellow solid was obtained. Yield: 75%. H-NMR (500 MHz, CDCl3): δ = 8.41 (s,
1H, CH-imine), 7.85-7.84 (m, 2H, Ar-H), 7.47-7.46 (m, 3H, Ar-H), 7.33 (d, J = 8.25 Hz, 2H, ArH), 6.95 (d, J = 8.5 Hz, 2H, Ar-H), 4.83 (s, 2H, Ar-CH2), 3.83 (s, 3H, -OCH3).

13

C NMR (125

MHz, CDCl3): δ = 161.4, 158.6, 136.1, 131.2, 130.5, 129.1, 128.4, 128.1, 113.7, 64.2, 55.1.

N-(4-nitrophenyl)-benzylideneamine: Using the general procedure for imine formation
1

(Method B) a yellow solid was obtained. Yield: 100%. H-NMR (500 MHz, CDCl3): δ = 8.45 (s,
1H, CH-imine), 8.30 (d, J = 9.5 Hz, 2H, Ar-H), 7.96-7.94 (m, 2H, Ar-H), 7.58-7.54 (m, 3H, ArH), 7.27 (d, J = 9 Hz, 2H, Ar-H).

13

C NMR (125 MHz, CDCl3): δ = 162.6, 157.9, 132.4, 129.7,

129.2, 128.9, 128.9, 125.0, 121.2.

44

N-(3-nitrophenyl)-benzylideneamine: Using the general procedure for imine formation
1

(Method A) a white-yellow solid was obtained. Yield: 97%. H-NMR (500 MHz, CDCl3): δ =
8.47 (s, 1H, CH-imine), 8.07 (td, J = 2 Hz, J = 7.5 Hz, 1H, Ar-H), 8.22 (t, J = 2 Hz, 1H, Ar-H),
7.91 (dd, J = 2 Hz, J = 6.5 Hz, 2H, Ar-H), 7.55-7.47 (m, 5H, Ar-H).

13

C NMR (125 MHz,

CDCl3): δ = 162.5, 153.1, 148.9, 135.4, 132.1, 129.8, 129.1, 128.9, 127.5, 120.4, 115.3.

N-benzyl-(3-aminophenyl)amine: N-(3-nitrophenyl)-benzylideneamine (226 mg, 1 mmol) was
reduced in 1 h, following the general procedure for imine reduction. The amine was obtained
1

using the work up procedure III and purified by prep. TLC. Yield: 52%; H-NMR (500 MHz,
CDCl3): δ = 7.39-7.34 (m, 5H, Ar-H), 6.98 (t, J = 7.5 Hz, 1H, Ar-H), 6.15-6.09 (m, 2H, Ar-H),
6.00-5.99 (m, 1H, Ar-H), 4.31 (s, 2H, Ar-CH2), 3.60 (s, 1H, -NH).

45

N-phenyl-3-nitrobenzylideneamine: Using the general procedure for imine formation (Method
1

A) a brown solid was obtained. Yield: 91%. H-NMR (500 MHz, CDCl3): δ = 8.80 (s, 1H, CHimine), 8.59 (s, 1H, Ar-H), 8.38 (d, J = 7.2 Hz, 1H, Ar-H), 8.30 (d, J = 7.8 Hz, 1H, Ar-H), 7.71
(t, J = 8.1 Hz, 1H, Ar-H), 7.48 (t, J = 7.8 Hz, 2H, Ar-H), 7.36-7.29 (m, 3H, Ar-H).

13

C NMR

(125 MHz, CDCl3): δ = 157.1, 150.8, 148.7, 137.8, 134.0, 129.7, 129.2, 126.8, 125.5, 123.4,
120.9.

4-(N-benzylideneamino)acetophenone: Using the general procedure for imine formation
1

(Method B) a white solid was obtained. Yield: 98%. H-NMR (500 MHz, CDCl3): δ = 8.46 (s,
1H, CH-imine), 8.03 (d, J = 8.5 Hz, 2H, Ar-H), 7.94 (dd, J = 1.5 Hz, J = 8 Hz, 2H, Ar-H), 7.547.52 (m, 3H, Ar-H), 7.25 (d, J = 9 Hz, 2H, Ar-H), 2.64 (s, 2H, CH3).

46

N-phenyl-1-napthylideneamine: Using the general procedure for imine formation (Method A) a
1

white solid was obtained. Yield: 97%. H-NMR (500 MHz, CDCl3): δ = 8.64 (s, 1H, CH-imine),
8.22 (s, 1H, Ar-H), 8.19 (d, J = 8.5 Hz, 1H, Ar-H), 7.95 (t, J = 7.5 Hz, 2H, Ar-H), 7.90 (d, J =
7.5 Hz, 1H, Ar-H), 7.60-7.54 (m, 2H, Ar-H), 7.46-7.42 (m, 2H, Ar-H), 7.30-7.27 (m, 3H, Ar-H).
13

C NMR (125 MHz, CDCl3): δ = 160.3, 152.0, 135.0, 133.9, 133.0, 131.2, 129.1, 128.7, 128.6,

127.9, 127.5, 126.6, 125.9, 123.9, 120.9.

N-(1-napthylmethyl)-phenylamine: N-phenyl-1-napthylideneamine (231 mg, 1 mmol) was
reduced in 1 h, following the general procedure for imine reduction. The amine was obtained
1

using the work up procedure I and purified by column chromatography. Yield: 78%; H-NMR
(500 MHz, CDCl3): δ = 7.85-7.83 (m, 4H, Ar-H), 7.52-7.46 (m, 3H, Ar-H), 7.19 (t, J = 7.5 Hz,
2H, Ar-H), 6.74 (t, J = 8 Hz, 1H, Ar-H), 6.70 (t, J = 8 Hz, 2H, Ar-H), 4.52 (s, 2H, Ar-CH2), 4.15
(s, 1H, -NH).

13

C NMR (125 MHz, CDCl3): δ 148.4, 137.2, 133.7, 133.0, 129.5, 128.6, 128.0,

127.9, 126,4, 126.1, 125.9, 125.9, 117.9, 113.2, 48.7.

47

N-phenyl-3-nitro-4-fluorobenzylideneamine: Using the general procedure for imine formation
1

(Method A) an orange solid was obtained. Yield: 74%. H-NMR (500 MHz, CDCl3): δ = 8.64 (d,
J = 8 Hz, 1H, Ar-H), 8.53 (s, 1H, CH-imine), 8..30-8.25 (m, 1H, Ar-H), 7.52-7.43 (m, 3H, ArH), 7.38-7.34 (m, 1H, Ar-H), 7.32-7.27 (m, 2H, Ar-H).

13

C NMR (125 MHz, CDCl3): δ = 155.7,

155.7, 134.8, 134.7, 129.3, 126.9, 126.3, 126.3, 120.8, 119.1, 118.9.

N-phenyl-3,4-dimethoxybenzylideneamine: Using the general procedure for imine formation
1

(Method A) a brown oil was obtained. Yield: 78%. H-NMR (500 MHz, CDCl3): δ = 8.34 (s,
1H, CH-imine), 7.60 (d, J = 2 Hz, 1H, Ar-H), 7.36 (t, J = 8 Hz, 2H, Ar-H), 7.29 (dd, J = 2 Hz, J
= 7 Hz, 1H, Ar-H), 7.19-7.17 (m, 3H, Ar-H), 6.92 (d, J = 8.5 Hz, 1H, Ar-H) 3.94 (s, 3H, OCH3), 3.93 (s, 3H, -OCH3).

13

C NMR (125 MHz, CDCl3): δ = 159.8, 152.3, 152.0, 149.5,

129.6, 129.1, 125.6, 124.4, 120.8, 110.5, 108.9, 56.1, 56.0.

48

N-(3,4-dimethoxybenzyl)phenylamine: N-phenyl-3,4-dimethoxybenzylideneamine (241 mg, 1
mmol) was reduced in 1 h, following the general procedure for imine reduction. The amine was
1

obtained using the work up procedure III. Yield: 91%; H-NMR (500 MHz, CDCl3): δ = 7.21 (t,

J = 7.5 Hz, 2H, Ar-H), 6.95-6.94 (m, 2H, Ar-H), 6.86 (d, J = 9 Hz, 1H, Ar-H), 6.76 (t, J = 7.5
Hz, 1H, Ar-H), 6.68 (d, J = 7.5 Hz, 2H), 4.28 (s, 2H, Ar-CH2), 3.90 (s, 3H, -OCH3), 3.89 (s, 3H,
-OCH3), 3.85 (s, 1H, -NH).

13

C NMR (125 MHz, CDCl3): δ 148.9, 148.1, 148.0, 131.8, 129.1,

119.1, 117.4, 112.7, 111.0, 110.6, 55.8, 55.7, 48.1.

N-phenyl-2,4,6-trimethylbenzylideneamine: Using the general procedure for imine formation
1

(Method A) a white solid was obtained. Yield: 100%. H-NMR (500 MHz, CDCl3): δ = 8.80 (s,
1H, CH-imine), 7.46-7.42 (m, 2H, Ar-H), 7.27-7.23 (m, 1H, Ar-H), 7.21-7.18 (m, 2H, Ar-H),
6.95 (s, 2H, Ar-H), 2.56 (s, 6H, Ar-CH3), 2.34 (s, 3H, Ar-CH3).

13

C NMR (125 MHz, CDCl3): δ

= 160.8, 153.1, 139.7, 138.5, 130.5, 129.7, 129.0, 125.4, 120.6, 21.2, 21.0.

49

N-(2,4,6-trimethylbenzyl)phenylamine: N-phenyl-2,4,6-trimethylbenzylideneamine (223 mg, 1
mmol) was reduced in 1 h, following the general procedure for imine reduction. The amine was
1

obtained using the work up procedure III. Yield: 93%; H-NMR (500 MHz, CDCl3): δ = 7.377.33 (m, 2H, Ar-H), 7.03 (s, 2H, Ar-H), 6.86 (t, J = 7.5 Hz, 1H, Ar-H), 6.79 (d, J = 7.5 Hz, 2H,
Ar-H), 4.32 (s, 2H, Ar-CH2), 3.4 (s, 1H, -NH), 2.48 (s, 6H, Ar-CH3), 2.42 (s, 3H, Ar-CH3).

13

C

NMR (125 MHz, CDCl3): δ 148.5, 137.4, 137.2, 132.1, 129.2, 129.0, 117.1, 112.3, 42.2, 20.8,
19.3.

N-(hexan-2-yl)phenylamine: (E)-N-(hex-5-en-2-ylidene)phenylamine (173 mg, 1 mmol) in a
mixture with aniline (1:4) was reduced in 30 min, following the general procedure for imine
1

reduction. The amine was obtained using the work up procedure I. H-NMR (500 MHz, CDCl3):

δ = 7.13 (t, J = 8 Hz, 2H, Ar-H), 6.63 (t, J = 7 Hz, 1H, Ar-H), 6.55 (d, J = 8 Hz, 2H, Ar-H), 3.43
(q, J = 6 Hz, 1H, -N-CH), 3.4 (s br 1H, -N-H), 1.43-1.29 (m, 6H, CH2), 1.15 (d, J = 6 Hz, 3H,
CH3), 0.88 (t, J = 7 Hz, 3H, CH3).

13

C NMR (125 MHz, CDCl3): δ 147.6, 129.2, 116.6, 113.0,

48.3, 36.8, 28.3, 22.7, 20.7, 14.1.

50

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Gatan Image software, version 3.4, was used for microscope operation. High resolution
images were taken using Gatan Digital Multi-Scan Camera (MSC).

54