Pd-catalyzed reductive cleavage of N-N bond in dibenzyl-1-alkylhydrazine-1,2-dicarboxylates with PMHS: Application to a formal enantioselective synthesis of (R)-sitagliptin

Article abstract of DOI:10.1016/j.tetlet.2015.12.116

An environmentally benign approach involving Pd-catalyzed reductive N-N bond cleavage in dibenzyl-1-alkylhydrazine-1,2-dicarboxylates leading to the synthesis of N-(tert-butoxy)carbamates under very mild conditions has been described. PMHS serves as an inexpensive source of hydride in MeOH/deionized H₂O medium. This protocol has been successfully applied in the formal synthesis of (R)-sitagliptin, an anti-diabetic drug.

Full text of DOI:10.1016/j.tetlet.2015.12.116

Accepted Manuscript
Pd-catalyzed reductive cleavage of N-N bond in dibenzyl-1-alkylhydrazine-1,2-
dicarboxylates with PMHS: application to a formal enantioselective synthesis
of (R)-sitagliptin
Soumen Dey, Sunita K. Gadakh, Brij Bhushan Ahuja, Sanjay P. Kamble,
Arumugam Sudalai
PII:
S0040-4039(15)30532-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.116
TETL 47163
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 November 2015
28 December 2015
30 December 2015
Please cite this article as: Dey, S., Gadakh, S.K., Ahuja, B.B., Kamble, S.P., Sudalai, A., Pd-catalyzed reductive
cleavage of N-N bond in dibenzyl-1-alkylhydrazine-1,2-dicarboxylates with PMHS: application to a formal
enantioselective synthesis of (R)-sitagliptin, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2015.12.116
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Graphical Abstract
Pd-catalyzed reductive cleavage of N-N bond
in dibenzyl-1-alkylhydrazine-1,2-
dicarboxylates with PMHS: application to a
formal enantioselective synthesis of (R)-
sitagliptin
Leave this area blank for abstract info.
Soumen Dey,a Sunita K. Gadakh,a Brij Bhushan Ahuja,a Sanjay P. Kamble,a Arumugam Sudalaia*



Environmentally benign approach
Broad substrate scope
Formation of several useful intermediates for
various drug molecules



No racemization at the chiral centre
Ambient reaction condition
Use of safe, non-toxic, air and moisture stable
PMHS

1
Tetrahedron Letters
Pd-catalyzed reductive cleavage of N-N bond in dibenzyl-1-alkylhydrazine-1,2-
dicarboxylates with PMHS: application to a formal enantioselective synthesis of
(R)-sitagliptin
Soumen Dey,a Sunita K. Gadakh,a Brij Bhushan Ahuja,a Sanjay P. Kamble,a Arumugam Sudalaia*
a[] Chemical Engineering and Process Development Division, National Chemical Laboratory, Pashan Road, Pune, 411008, India. E-mail:
a.sudalai@ncl.res.in; (+91)-20-2590-2174; Fax: +91-02025902676
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An environmentally benign approach involving Pd-catalyzed reductive N-N bond
cleavage in dibenzyl-1-alkylhydrazine-1,2-dicarboxylates leading to the synthesis of
N-(tert-butoxy)carbamates under very mild conditions has been described. PMHS
serves as an inexpensive source of hydride in MeOH/deionized H2O medium. This
protocol has been successfully applied in the formal synthesis of (R)-sitagliptin, an
anti-diabetic drug.
Available online
Keywords:
Envirronmentally benign
Reductive cleavage
PMHS
2009 Elsevier Ltd. All rights reserved.
Hydrazine
Anti-diabetic
Introduction
As a consequence, a number of methods have been developed for
The development of mild and efficient methods for the synthesis
of amine compounds is of great importance, since these are
frequently encountered as drugs in the pharmaceutical
industries.1 Some of the representative examples of the top
selling drugs containing amine as a functional group include (R)-
sitagliptine (anti-diabetic); (S)-benzphetamine (anorectic); (R)-
selegiline, (anti-Parkinson’s disease); and anisomysin (a
psychiatric), shown in Figure 1. Because of the importance of
amine functionnality various methods are known for its
synthesis.2 Among them reduction of nitro/azido compounds,3a
imines,3b oximes3c and cleavage of N-N bonds4 are the most
common approaches. Especially, for the synthesis of chiral amine
functionality, cleavage of N-N bonds of hydrazine groups has
gained much importance in recent times, since these hydrazine
compounds can be easily synthesized with high enantiopurity via
proline catalyzed α-amination reactions of aldehydes.5
N-N bond cleavage in hydrazine based substrates involving
hydrogenation over metals,4a by reduction with aluminium or
boron hydrides,4b by electroreductive process,4c e.g. Na or Li/NH3
or by making use of SmI2 with HMPA as co-solvent4d or by
oxidative cleavage.4e However, these methods have been
associated with certain drawbacks such as lack of reactivity, use
of acidic or basic condition, sluggish reaction conditions as well
as use of hazardous reagents, namely hydrogen. Therefore, the
development of synthetic methodologies to cleave N-N bonds
under mild, neutral reaction conditions leading to the formation
of the primary amino compounds is highly desirable. Recently,
Chandrasekhar et al. have reported reduction of simple aromatic
hydrazines with Pd/C and PMHS.4f However, Pd catalyzed N-N
bond cleavage in chiral benzyloxy carbamate protected hydrazine
is not yet reported. As a part of our program aimed at the
synthesis of various drug molecules using organocatalytic
amination approach, the cleavage of N-N bonds is often required
to get the amine intermediates.6 Herein, we wish to report Pd
catalyzed reductive cleavage of N-N bonds of dibenzyl-1-
alkylhydrazine-1,2-dicarboxylate using polymethylhydrosiloxane
(PMHS) as a hydride source in an environmentally attractive
fashion using H2O/MeOH medium at room temperature, which
makes the present protocol highly favourable in comparison to
previously reported systems (Scheme 1). PMHS is inexpensive,
non-toxic and stable to air and moisture, which makes it an
attractive reducing agent for environmentally benign reductive
processes7 as compared to hazardous aluminium hydrides,
boranes and hydrogen.
Figure 1 Representative examples of top-selling drugs cantaining
amine functionality

2
Tetrahedron
Table 2 Screening of metal saltsa
entry
metal salts
mol %
yields of 2a
(%)b
-
1
2
3
4
5
6
7
8
9
Ni(COD)2
NiCl2.2H2O
Cu(OAc)2.2H2O
Co(NO3)2. 6H2O
PtCl2
5
5
5
5
5
5
5
5
5
Scheme 1 Pd catalyzed reductive N-N bond cleavage
-
-
-
28
20
40
60
80
78
Results and Discussion
In the initial study, dibenzyl-1-(1-hydroxy-3-phenylpropan-2-
yl)hydrazine-1,2-dicarboxylate (1a), as a model substrate, was
subjected to reductive N-N bond cleavage by reacting with 10%
Pd/C, Et3SiH (2 equiv) and Boc2O in MeOH at ambient
temparature, which produced carbamate 2a in 22% yield (entry 1;
Table 1). Screening of many silanes revealed certain variations in
the rate of cleavage of N-N bond (entry 1-4). For example, the
rate of cleavage was found to be highest when we used PMHS (2
equiv), which gave the corresponding carbamate in 40% yield
(entry 5) as compared to other silane sources. The yield of 2a was
considerably improved to 78% when PMHS quantity was further
increased to four equivalents under the same reaction conditions
(entry 6). However, there was no significant increase in yield
observed on increasing the quantity of PMHS to 8 equivalents.
Pd(dba)2
Pd(OAc)2
10% Pd/C
PdCl2
10
PdCl2
10
a
Substrate (5 mmol), Boc2O (5 mmol), PMHS (20 mmol),
MeOH/Deionized water (1:1) (20 mL), 25 oC, 10 h; only variation in
using metal salts; isolated yields after column chromatographic
purification; COD
deneacetone.
b
=
1,5-cyclooctadiene; dba
=
dibenzyli
Table 1 Screening of silane sourcea
After standardizing the reaction condition, we subjected other
hydrazine compounds such as diethyl or diisopropyl-1-
alkylhydrazine-1,2-dicarboxylates to the reaction conditions and
found that no reaction took place, which may be due to the
absence of reducible benzylic group in these substrates.
Table 3 Variation of reaction medium and temperaturea
entry
silanes
equiv
yields of 2a
entry
medium
t (oC) yields of 2a
(%)b
22
(%)b
1
2
3
4
5
6
7
Et3SiH
Et3SiH
PhSiH3
Ph2SiH2
PMHS
PMHS
PMHS
2
4
2
2
2
4
8
1
2
3
4
5
6
MeOH
25
60
25
25
25
25
60
30
50
10
30
86
25
20
15
40
78
70
MeOH
EtOH
DMF
DI waterc
DI waterc
MeOH (1:1)
DI waterc
MeOH (1:1)
a
Substrate (5 mmol), 10 mol% Pd/C, Boc2O (5 mmol), silane,
MeOH/Deionized water (1:1) (20 mL), 25 C, 10 h; b isolated yields
o
/
/
after column chromatographic purification.
Other metal salts and their complexes were also tested (Table 2)
and found that Ni, Cu, and Co salts were ineffective in N-N bond
cleavage (entry 1-4). However, metal salts such as PtCl2,
Pd(dba)2, and Pd(OAc)2 were found effective giving low yields
(28-40%) of carbamate. Surprisingly, the use of PdCl2 (5 mol%)
afforded the best yield (80%) as compared to other Pd sources.
A number of organic solvents could be used to effect this
reduction, as summarized in Table 3. The use of solvents like
CH2Cl2, toluene, Et2O and CH3CN did not catalyze the reaction.
Indeed, protic solvents like EtOH or MeOH with PdCl2 produced
moderate yield of carbamate (55-60%). Surprisingly, the addition
of deionized water in MeOH (1:1) provided the best yield of 2a
(86%). The requirement for water in these reactions could be
indicative of a transfer hydrogenation process where hydrogen
gas is believed to have formed from silicon hydride and water via
σ bond metathesis on palladium.8 However, the yield of
carbamate was reduced (30%), when deionized water was used
alone as solvent. When the temperature of the reaction was
7
60
78
a Substrate (5 mmol), PdCl2 (5 mol %), Boc2O (5 mmol), PMHS (20
mmol), 10 h; only variation in reaction medium and temperature;
isolated yields after column chromatography
deionized water
b
c
;
DI water =
We have then applied the optimized procedure of Pd catalyzed
reductive N-N bond cleavage to a variety of substrates, which
were prepared using α-amination of carbonyl compounds
following literature procedure (Table 4).5 As can be seen, several
chiral dibenzyl-1-alkylhydrazine-1,2-dicarboxylates underwent
reductive cleavage to furnish carbamates in excellent yields (70-
86%). It may be noted that carbamates like 2a-b serve as builing
blocks in various drug molecules.9 The present protocol was
found to be quite effective in the case of different substituted
chiral hydrazines 1c-e. Oxazolidinone 2f was obtained in 80%
yield using this protocol and can be used as chiral auxiliary in
organic synthesis. Again, reductive cleavage of chiral α,β-
o
increased to 60 C, a slightly lowered yield (78%) was observed
in H2O/MeOH medium.

3
unsaturated hydrazide 1g under the standard reaction condition,
led to the formation of lactam 2g in 76% yield. Also, the more
functionalized hydrazine derivatives 1h-i underwent reductive
9
74
cleavage smoothly to produce functionalized carbamates 2h-i in
moderate yields. In all cases studied, the optical purity of each
substrate was found to be preserved in the respective products.
a
Substrate (5 mmol), PdCl2 (5 mol %), Boc2O (5 mmol),
PMHS (20 mmol), MeOH/Deionized water (1:1) (20 mL), 25
oC, 10 h; b isolated yields after column chromatography; c No
Boc2O was used here.
Table 4 Reductive cleavage of N-N bond: Substrate scopea
entry
1
substrates
products
yields (%)b
86
The catalytic cycle for Pd-catalyzed reductive N-N bond
cleavage is shown in Fig. 2 based on literature precedence.10 The
first step of catalytic cycle involves the reduction of PdCl2 with
PMHS to give active metallic Pd(0) species. This is followed by
the oxidative addition of H2 generated by PMHS to Pd(0) leading
to the formation of palladium dihydride reactive species I. Pd(II)
2
83
3
4
70
72
5
72
80
of species I co-ordinates with nitrogen atom of hydrazine to
generate intermediate II followed σ-bond migration that leads to
formation of intermediate III. Subsequent reductive elimination
of III regenerates active metal species Pd(0) for the next catalytic
cycle along with free amine, which was in situ protected with
Boc2O to furnish the carbamate 2.
6c
Figure 2 Proposed catalytic cycle for reductive N-N bond cleavage
Finally, its application was demonstrated in a short, fomal
synthesis of (R)-sitagliptin, an anti-diabetic drug.9c-d Thus,
aldehyde 4 was obtained from commercially available 2,4,5-
76
76
7c
trifluorobenzaldehyde
3
by
a
simple functional goup
manipulation: (i) two carbon homologation with stabilized Wittig
ylide; (ii) hydrogenation of the benzylic C=C bond by 10% Pd/C
over H2 (1 atm); (iii) selective reduction of ester functionality by
DIBAL-H to aldehyde. The aldehyde was subjected to L-proline
catalyzed α-amination reaction to afford α-amino alcohol 1b in
90% yield, which was converted to carbamate 2b following the
present protocol. The transformation of 2b to (R)-sitagliptin is
well established in the literature (Scheme 2).
8

4
Tetrahedron
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C. R.; Rao, J. R. Synlett, 2001, 10, 1561.
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(a) Juhl, K.; Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124, 2420; (b)
Juhl, K..; Gathergood, N.; Jørgensen, K. A. Angew. Chem., Int. Ed.
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Advances, 2015, 5, 21803.
Scheme 2 Formal synthesis of anti-diabetic drug, (R)-sitagliptin
6
(a) Kotkar, S. P.; Sudalai, A. Tetrahedron Lett., 2006, 47, 6813; (b)
Talluri, S. K.; Sudalai, A. Tetrahedron, 2007, 63, 9758; (c)
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Conclusions
In conclusion, we have demonstrated an efficient,
environmentally benign approach to cleave N-N bonds in
7
Lawrence, N. J.; Drew, M. D.; Bushell, S. M. J. Chem. Soc., Perkin
Trans. 1, 1999, 3381.
8
9
Rahaim, Jr., R. J.; Maleczka, Jr. R. E. Org. Lett. 2005, 7, 5087.
(a) Jankovic, J. J. Neurol. Neurosurg. Psychiatry 2008, 79, 368; (b)
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E. W. Diabetes Care, 2006, 29, 2632.
dibenzyl-1-alkylhydrazine-1,2-dicarboxylate to furnish N-
(tert-butoxy)carbamates. The method effectively cleaves N-
N bond in a variety of hydrazine compounds containing a
number of different functional group to their respective
amines, which can be used as building blocks in medicinal
chemistry. The use of polymethylhydrosiloxane (PMHS), an
inexpensive, easy to handle, environmental benign reagent
as reducing agent in our protocol makes it more viable than
other reported methods.
10
(a) Kunai, A.; Sakurai, T.; Toyoda, E. ; Ishikawa, M.; Yamamoto, Y.
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11 Dey, S.; Sudalai, A. Tetrahedron: Asymmetry, 2015, 26, 67.
12
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Acknowledgements
13 Victoria, M. Lett. Org. Chem., 2010, 7, 159.
14 Hale, K. J.; Delissar, V. M.; Manaviazar, S. Tetrahedron Lett., 1992, 33,
7613.
SD, BBA & SKG thank CSIR, New Delhi for the award of senior
research fellowships and CSIR, Indus MAGIC (CSC 0123) and
DST, (No. SR/S1/OC-42/2014) New Delhi for financial support.
The authors are also thankful to Dr. V.V. Ranade, Chair, Chem.
Engg. & Process Develop. for his constant encouragement.
15 Gommermann, N.; Knochel, P. Tetrahedron, 2005, 61, 11418.
Supplementary Material
Supplementary data (1H and 13C NMR spectra for all
compounds, detailed experimental procedures) associated with
this article can be found, in the online version.
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(a) Patai, S. The Chemistry of the Amino Group, Vol. 4; Ed.;
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Graphical Abstract
Pd-catalyzed reductive cleavage of N-N bond in dibenzyl-1-alkylhydrazine-
1,2-dicarboxylates with PMHS: application to a formal enantioselective
synthesis of (R)-sitagliptin
Soumen Dey, Sunita K. Gadakh, Brij Bhushan Ahuja, Sanjay P. Kamble, Arumugam Sudalai*
A one-step Pd-catalyzed direct conversion of dibenzyl-1-alkylhydrazine-1,2-dicarboxylates to
various reactive intermediates using PMHS as a hydride source in an environmentally benign
fashion is described.



Environmental benign approach
Broad substrate scope
Formation of several useful intermediates for
various drug molecules



No racemization at the chiral centre
Ambient reaction condition
Use of safe, non-toxic, air and moisture stable
PMHS