Reductive Hydrazination with Trichlorosilane: A Method for the Preparation of 1,1-Disubstituted Hydrazines

Article abstract of DOI:10.1021/acs.orglett.6b00675

A straightforward and facile method has been developed to prepare 1,1-disubstituted hydrazines via Lewis base promoted direct reductive hydrazination. Under the catalysis of hexamethylphosphoramide (HMPA) and N,N-dimethylacetamide (DMAc), respectively, various ketones and aldehydes could react with phenylhdrazines to prepare 1,1-disubstituted hydrazines with good to high yields.

Full text of DOI:10.1021/acs.orglett.6b00675

Letter
pubs.acs.org/OrgLett
Reductive Hydrazination with Trichlorosilane: A Method for the
Preparation of 1,1-Disubstituted Hydrazines
Tao Wang, Xiao Di, Chao Wang,* Li Zhou, and Jian Sun*
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041 China
Graduate School of Chinese Academy of Sciences, Beijing, 10049, China
S
* Supporting Information
ABSTRACT: A straightforward and facile method has been
developed to prepare 1,1-disubstituted hydrazines via Lewis
base promoted direct reductive hydrazination. Under the
catalysis of hexamethylphosphoramide (HMPA) and N,N-
dimethylacetamide (DMAc), respectively, various ketones and
aldehydes could react with phenylhdrazines to prepare 1,1-
disubstituted hydrazines with good to high yields.
Scheme 1. Strategies for the Synthesis of 1,1-Disubstituted
Hydrazines
irect reductive amination (DRA) represents a convenient
Dand straightforward method for the synthesis of amines,
which have seen wide applications in organic synthesis.1−3 The
amines that could be used as effective reactants for DRA
include various primary and secondary alkyl amines,4−6 aryl
amines,7−11 hydroxyl amines,12 and alkoxyl amines.13 As a
special type of amines, hydrazines should in principle also be
good reactants for DRA. To date, however, there have been no
organocatalytic methods reported in the literature that could
implement DRA using hydrazines as reactants, so-called direct
reductive hydrazination (DRH).14 Since hydrazines have two
vicinal amino groups, conceivably, the difficulties confronted
with DRH include the following: (1) the in situ formed
hydrazone intermediate (A, Scheme 1) is normally much more
stable and less reactive than the carbonyl substrates toward
nucleophilic reduction; (2) the regioselectivity is hard to
control if the two amino groups are both active and have
different substitutions. The use of preformed hydrazones and
thus indirect reductive hydrazination (IRH) method could
address these difficulties to some degree, but it needs extra
operations and is less convenient and economic.15−18
Hydrosilylation of unsaturated double bonds by trichlor-
osilane with Lewis base as an activator is a well-known
reduction method.19−22 Its strength has been well demon-
strated by others and us in asymmetric catalysis.23−34 We were
interested in extending the application of this method to DRH.
The chance is that trichlorosilane should preferentially react
with the terminal amino group of hydrazine 2 and leave the
middle amino group to interact with the carbonyl group of 1.
The resulting intermediate B should be highly active toward the
hydrosilylation. Herein, we wish to communicate the results of
our study and present a highly effective new method to
implement DRH using organic Lewis base as promoter and
trichlorosilane as reducing agent, which furnishes the
condensation of various aldehydes and ketones with aryl
hydrazines and reduction in one-pot under mild conditions to
afford 1,1-disubstituted hydrazines as exclusive regioisomers
with good to high yields.
1,1-Disubstituted hydrazines 3 are important organic
synthons used in a various of reactions such as Fisher
indolization for the synthesis of indole and its derivatives.
Kikugawa and co-workers35 reported a four-step method to
Received: March 9, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00675
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Organic Letters
Letter
prepare hydrazines 5. Nishida36 and Garg37 reported a three-
step method for the preparation of hydrazines 3, respectively
(Scheme 1). Although various 1,1-disubstituted hydrazines
could be obtained by these methods, the atom economy of
these methods is very low since multiple synthesis processes are
required. The method we presented in this study should offer a
straightforward new approach to the synthesis of this type of
hydrazines.
Initially, we used the DRH of acetophenone 1a with
phenylhydrazine 2a as the model reaction to test the catalytic
ability of the Lewis bases. Interestingly, the desired product 3a
could be obtained with moderate to good yields in DCM at 0
°C under the catalysis of 1 equiv of the easily available Lewis
bases (Table 1, entries 1−13). A 98% yield could be achieved
could be increased to 93% when the reaction temperature was
increased to 25 °C. After careful investigation, we identified the
best reaction conditions in which the reduction hydrazination
of acetophenone and phenylhydrazine were performed using 10
mol % of HMPA and trichlorosilane (2.0 equiv) in DCM at 25
°C for 12 h.
With the optimized reaction conditions in hand, the scope
and limitations for the substrates of the DRH were investigated
(Figure 1). Both electron-donating and -withdrawing sub-
stitutions at the para position of the phenyl ring of
acetophenone were tolerated (Figure 1, 3a−h). A 84%−96%
yield could be obtained when the para position of the phenyl
ring of acetophenone was substituted with F, Cl, Br, CF3, NO2,
Me, and MeO, respectively. Yields of 92% and 94% could be
Table 1. Exploration of Reaction Conditions for the Direct
a
Reductive Hydrazination
b
entry
solvent
LB (equiv)
temp (°C)
yield (%)
1
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
CCl4
TMEDA (1.0)
2,6-lutidine (1.0)
pyridine (1.0)
TEA (1.0)
0
0
57
36
76
26
47
60
64
98
60
60
38
62
47
38
60
60
26
71
57
81
81
78
93
38
24
2
3
0
4
0
5
DIPEA (1.0)
DMAP (1.0)
Ph3PO (1.0)
HMPA (1.0)
DMF (1.0)
0
6
0
7
0
8
0
9
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
DMAc (1.0)
imidazole (1.0)
HMDS (1.0)
PPh3 (1.0)
0
0
0
0
HMPA (1.0)
HMPA (1.0)
HMPA (1.0)
HMPA (1.0)
HMPA (1.0)
HMPA (1.0)
HMPA (0.5)
HMPA (0.2)
HMPA (0.1)
HMPA (0.1)
HMPA (1.0)
HMPA (1.0)
0
0
DCE
0
toluene
MeCN
THF
0
0
0
DCM
DCM
DCM
DCM
DCM
DCM
0
0
0
25
−20
−40
a
Unless noted otherwise, reactions were carried out with ketone (0.20
mmol), hydrazine (0.20 mmol), and HSiCl3 (2.0 equiv) in 1.0 mL of
b
solvent for 12 h. Isolated yield. Tetramethylethylenediamine
(TMEDA), triethylamine (TEA), N,N-diisopropylethylamine
(DIPEA), 4-dimethylaminopyridine (DMAP), hexamethylphosphor-
amide (HMPA), dimethylacetamide (DMAc), bis(trimethylsilyl)amine
(HMDS).
when 1 equiv of hexamethylphosphoramide (HMPA) was
added as catalyst. Dichloromethane was found to be the best
solvent for the reaction. The solvent was changed to CHCl3,
CCl4, DCE, toluene, MeCN, and THF, and all of them caused a
lower yield of the desired product 3a (Table 1, entries 14−19).
When the amount of HMPA was reduced to 10 mol %, the
yield of the product 3a dropped to 78%. However, the yield
Figure 1. Direct reductive hydrazination of ketone. Unless noted
otherwise, reactions were carried out with ketone (0.20 mmol),
hydrazine (0.22 mmol), HMPA (0.02 mmol), and HSiCl3 (2.00 equiv)
in 1.0 mL of solvent at 25 °C for 12 h. Isolated yield based on ketone.
B
DOI: 10.1021/acs.orglett.6b00675
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Organic Letters
Letter
obtained also, respectively, when 1-acetylnaphthalene and 2-
acetylnaphthalene were used as the substrate in the reaction.
Moreover, the methyl group of the acetophenone could also
be replaced with other groups such as Et, n-Pr, i-Pr, n-Bu, and
n-heptyl. The desired product 3k−o could be obtained with
74%−98% yields when these substrates were used in the
reaction. Yields of 86% and 98% could be obtained when the
methyl group of the acetophenone was replaced with
cyclohexyl and cyclopropyl, respectively. 1-Tetralone and 1-
indanone could also be used in the reaction to prepare the
corresponding product 3r and 3s with 81% and 89% yield.
Benzophenone, 4,4′-difluorobenzophenone, and 4-chloro-
benzophenone are all good substrates for the reaction. The
desired product could be obtained with 97%−98% yields when
these substrates were used in the reaction. Aliphatic ketones
such as acetylcyclohexane and pentan-3-one could also be used
as substrates for the reaction, and yields of 80% and 72% were
obtained, respectively, when they were used in the reaction.
Furthermore, substituted phenylhydrazines such as (4-
chlorophenyl)hydrazine, (4-fluorophenyl)hydrazine, and (4-
nitrophenyl)hydrazine could also be used in the reaction. The
desired products 3y, 3z, and 3aa could be obtained with 83%,
82%, and 92% yields, respectively.
We next tested whether aldehyde could be used as good
substrate in the DRH reaction to prepare the corresponding
product under the existing reaction conditions. However, no
desired product 5a could be detected when phenylaldehyde was
used in the reaction under the existing reaction conditions.
Most of the phenylaldehydes were reduced to phenylmethanol
or converted to the hydrazone intermediate, which could not be
reduced by trichlorosilane. We found the reduction of aldehyde
by trichlorosilane could be reduced by decreasing the reaction
temperature, and the formation of hydrazone could be
efficiently inhibited by premixing phenylhydrazine with
trichlorosilane. Thus, in order to get a higher yield of the
desired product, we tried to add phenyl aldehyde to the mixture
of trichlorosilane and phenylhydryzine at lower temperature.
Gratifyingly, the desired product 5a could be isolated with 13%
yield under the catalysis of 1 equiv of HMPA at −40 °C, and
58% yield could be obtained when the amount of HMPA was
increased to 5 equiv. The yield of product 5a could be further
increased to 87% when 5 equiv of DMAc was used to replace
HMPA (Figure 2).
Figure 2. Direct reductive hydrazination of aldehyde. Aldehyde (0.20
mmol) was added to the solution of hydrazine (0.22 mmol), DMAc
(1.00 mmol), and HSiCl3 (2.00 equiv) in 1.0 mL of solvent at −40 °C
for 24 h. Isolated yield based on aldehyde.
have moderate to high activity. The desired product 3a could
be obtained with 93% yield and 74% ee when the bis-
sulfinamide catalyst 638 was used.
With the reaction conditions in hand, the substrate scope of
the aldehyde was investigated (Figure 2). Both electron-
donating and -withdrawing substitution at the meta and para
positions of the phenyl ring of phenylaldehyde were tolerated.
The desired products could be obtained with 72%−84% yields
when the meta and para positions of the phenyl ring were
substituted with electron-withdrawing groups such F, Cl, CF3,
and NO2, respectively (5b−d,f−j). Yields of 80% and 71%
could be obtained, respectively, when the meta and para
positions of the phenyl ring were substituted with MeO. The
desired products could be obtained with 82% and 65% yields
when α- and β-naphthaldehyde were used, respectively.
Aliphatic aldehydes such as 3-phenylpropanal, cyclohexanecar-
boxaldehyde, and heptanal could also be used as good
substrates for the reaction, and the desired products could be
obtained with good yields (5p−r).
In conclusion, an efficient method to prepare 1,1-
disubstituted phenylhydrazine by Lewis base catalyzed direct
reductive hydrazination has been reported. Under the catalytic
effects of Lewis bases, trichlorosilane could be used as a
powerful reducing agent to furnish the DRH reaction between a
wide range of aryl/alkyl ketones/aldehyde and phenyl-
hydrazines to obtain the desired products with good to high
yields. On the basis of the results of the existing method and
the literature data, we hypothesize the terminal NH2 of the
In order to develop the chiral version of the DRH reaction,
chiral Lewis bases, which have been proven to be very useful
catalysts in asymmetric hydrosilylation of imine and enamine in
our previous work, were tested. We found the tested catalysts
C
DOI: 10.1021/acs.orglett.6b00675
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phenylhydrazines was blocked under the reaction conditions by
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ASSOCIATED CONTENT
* Supporting Information
■
(22) Orlandi, M.; Tosi, F.; Bonsignore, M.; Benaglia, M. Org. Lett.
2015, 17, 3941−3943.
S
(23) Liu, X. W.; Yan, Y.; Wang, Y. Q.; Wang, C.; Sun, J. Chem. - Eur.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00675.
(24) Wang, Z. Y.; Wang, C.; Zhou, L.; Sun, J. Org. Biomol. Chem.
2013, 11, 787−797.
Experimental details, analytical data, and NMR spectra
(PDF)
(25) Liu, X. W.; Wang, C.; Yan, Y.; Wang, Y. Q.; Sun, J. J. Org. Chem.
2013, 78, 6276−6280.
(26) Wang, C.; Wu, X. J.; Zhou, L.; Sun, J. Org. Biomol. Chem. 2015,
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AUTHOR INFORMATION
Corresponding Authors
■
(27) Ye, J.; Wang, C.; Chen, L.; Wu, X.; Zhou, L.; Sun, J. Adv. Synth.
Catal. 2016, 358, 1042.
(28) Jiang, Y.; Chen, X.; Hu, X. Y.; Shu, C.; Zhang, Y. H.; Zheng, Y.
S.; Lian, C. X.; Yuan, W. C.; Zhang, X. M. Adv. Synth. Catal. 2013, 355,
1931−1936.
*E-mail: wangchao@cib.ac.cn.
*E-mail: sunjian@cib.ac.cn.
Notes
(29) Zheng, Y. S.; Xue, Z. Y.; Liu, L. X.; Shu, C.; Yuan, W. C.; Zhang,
X. M. Org. Biomol. Chem. 2013, 11, 412−415.
(30) Hu, X. Y.; Zhang, M. M.; Shu, C.; Zhang, Y. H.; Liao, L. H.;
Yuan, W. C.; Zhang, X. M. Adv. Synth. Catal. 2014, 356, 3539−3544.
(31) Pan, W.; Deng, Y.; He, J. B.; Bai, B.; Zhu, H. J. Tetrahedron
2013, 69, 7253−7257.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the Western Light
Talents Training Program of Chinese Academy of Sciences, the
National Natural Science Foundation of China (Project Nos.
21272227 and 21402185).
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