Full text of DOI:10.1016/j.tetlet.2018.06.007

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One-pot synthesis of hydrazine derivatives from aldehydes via radical addition
reactions
Ji Hye Kim, Doo Ok Jang
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S0040-4039(18)30736-6
https://doi.org/10.1016/j.tetlet.2018.06.007
TETL 50045
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Tetrahedron Letters
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31 May 2018
3 June 2018
Please cite this article as: Hye Kim, J., Ok Jang, D., One-pot synthesis of hydrazine derivatives from aldehydes via
radical addition reactions, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.06.007
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Tetrahedron Letters
One-pot synthesis of hydrazine derivatives from aldehydes via radical addition
reactions
Ji Hye Kim and Doo Ok Jang
Department of Chemistry, Yonsei University, Wonju 26493, Republic of Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A one-pot procedure for the synthesis of hydrazine derivatives from aldehydes via radical
addition reactions was developed. Lewis acids promoted both the condensation between
aldehydes and benzhydrazide, and the alkyl radical addition to the C=N bond of hydrazones,
affording moderate-to-high yields of hydrazine derivatives. The present process provides a tin-
free radical, sustainable, and eco-friendly synthetic method.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
One-pot
Radical
Aldehyde
Hydrazine
———
 Corresponding author. Tel.: +82-33-760-2261; fax: +82-33-760-2261; e-mail: dojang@yonsei.ac.kr

2
Tetrahedron Letters
1. Introduction
employed in both the preparation of imine derivatives and radical
addition reactions, and the large reactivity difference between the
C=N and C=O bonds towards radical addition reactions, a one-
pot multi-component procedure was designed for the synthesis of
hydrazines from aldehydes via radical addition reactions. One-
pot multi-component reactions are sustainable and eco-friendly
synthetic methods that form more than one bond in a single step
and generate minimal waste.10
The hydrazine scaffold is a common skeleton in biologically
active compounds.1 Hydrazine derivatives are frequently
employed as precursors of various heterocyclic compounds.2
They also serve as protected amines, which are transformed to
amines by N‒N bond cleavage.3 However, hydrazines, including
structurally simple alkyl hydrazines are difficult to synthesize
directly from hydrazine, affording low yields and complex
mixtures of products.4 One of the most reliable methods to
prepare hydrazine derivatives is the nucleophilic addition to
hydrazones.5 However, strong nucleophiles such as
organometallic compounds are required due to the intrinsically
low reactivity of hydrazones. The use of organometallic reagents
promotes the deprotonation of α-hydrogens, thus, requires
anhydrous conditions and often results in side reaction products.
2. Results and discussions
Zn(ClO4)2.6H2O is known to promote the condensation
between aldehydes and hydrazine,11 and a mixture of THF and
(CH2Cl)2 has been reported as the optimal solvent system for
radical reactions.12 Bearing these facts in mind, we examined the
one-pot radical addition reaction to hydrazones employing
benzaldehyde, benzhydrazide, ethyl iodide, and diphenylsilane in
the presence of Zn(ClO4)2.6H2O in THF:(CH2Cl)2 (v/v, 1:1) at
room temperature. A solution of triethylborane was added
portion-wise to the reaction mixture to maintain chain conditions,
affording the ethyl-added product 2a in 40% yield (Table 1, entry
1). A variety of Lewis acids such as ZnCl2, SnCl2, Mg(ClO4)2,
MgBr2, In(OTf)3, Sc(OTf)3, and Yb(OTf)3 were screened (entries
2‒8). It was found that Sc(OTf)3 and Yb(OTf)3 catalyzed the
reaction efficiently to give the ethyl-added product 2a in 76%
and 78% yields, respectively (Table 1, entries 7 and 8). Due to
their high reactivity and inertness toward air and water, Sc(OTf)3
and Yb(OTf)3 have been previously used as efficient Lewis acid
catalysts in organic reactions.13 Subsequently, various solvents
were screened for the Yb(OTf)3-catalyzed reaction such as
CH2Cl2, THF, (CH2Cl)2, and MeOH (entries 9‒12). Nevertheless,
the combination of THF and (CH2Cl)2 (v/v, 1:1) turned out to be
the best choice of the solvent.
These problems can be avoided by employing radical
reactions. Radical species are neutral, and thus, are not affected
by moisture. It has been shown that radical reactions can be
performed in aqueous conditions.6 Recently, we found that
radical reactions proceed smoothly “on water” conditions with a
significant solvent effect of water.7 In addition, radical reactions
provide several advantages over ionic reactions including high
chemoselectivity and low tendency of rearrangement reactions.
It has been reported that radicals add to C=N bond of imine
derivatives, including N-acyl hydrazones,8a-d N,N-dialkyl
hydrazones,8e-g O-benzyl oximes,8h-o N-tosyl imines,8p-s N-acyl
imines,8t N-Boc-imines,8u and N-tert-butanesulfinyl imines.8v
Some imine derivatives require Lewis acids to promote the
radical addition reactions due their low reactivity.9
Generally, imine derivatives are prepared by the condensation
of aldehydes with hydrazine derivatives in the presence of Lewis
acids. Furthermore, radical additions to C=N bonds are more
feasible than that to C=O bonds. Considering that Lewis acids are
Table 1. Screening of reaction conditions for the one-pot synthesis of 2a from benzaldehyde 1a
entry
catalyst
solvent
Et3B (equiv)a
time (h)
yield (%)b
1
Zn(ClO4)2.6H2O
ZnCl2
THF:(CH2Cl)2 (v/v, 1:1)
THF:(CH2Cl)2 (v/v, 1:1)
THF:(CH2Cl)2 (v/v, 1:1)
THF:(CH2Cl)2 (v/v, 1:1)
THF:(CH2Cl)2 (v/v, 1:1)
THF:(CH2Cl)2 (v/v, 1:1)
THF:(CH2Cl)2 (v/v, 1:1)
THF:(CH2Cl)2 (v/v, 1:1)
CH2Cl2
3.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
4.5
2.5
2.5
4.5
28
20
20
20
20
20
20
20
36
20
20
36
40
62
46
55
67
45
76
78
64
52
50
54
2
3
SnCl2
4
Mg(ClO4)2
MgBr2
5
6
In(OTf)3
Sc(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
7
8
9
10
11
12
(CH2Cl)2
THF
MeOH
b
a0.5 equiv of triethylborane (1 M solution in THF) was added every 4 h. Isolated yield
Under the optimized reaction conditions, the radical addition
of various alkyl iodides was investigated. The results are
presented in Table 2. The reaction with 10 equiv of isopropyl
iodide afforded the isopropyl-added product 2b in 59% yield
(Table 2, entry 1). Upon increasing the amount of isopropyl
iodide to 30 equiv, the yield of the addition product 2b increased
to 80% (entry 2). A similar tendency was observed in the reaction
with cyclohexyl iodide. Thus, the reaction with 10 equiv of

cyclohexyl iodide gave the corresponding addition product 2c in
63% yield, while the reaction with 30 equiv afforded 2c in 81%
yield (entries 3 and 4, respectively). The lower yields of addition
product using 10 equiv of alkyl iodides was attributed to the
competition reaction between the alkyl radical and ethyl radical,
which is produced from triethylborane. The reaction with tertiary
alkyl iodides took place smoothly to give the corresponding
addition products in moderate-to-high yields (entries 5 and 6).
The addition of a primary radical was examined using n-octyl
iodide affording 64% isolated yield (entry 7).
3
4
5
6
7
2-F-C6H4
4-Cl-C6H4
3-Cl-C6H4
2-Cl-C6H4
2-Br-C6H4
1d
1e
1f
3.5
3.5
3.0
3.5
4.0
28
28
24
28
32
3c
3d
3e
3f
70
84
73
71
68
1g
1h
3g
4-NO2-
C6H4
8
9
1i
1j
3.5
4.0
28
32
3h
3i
60
56
4-MeO-
C6H4
Table 2. Synthesis of hydrazine derivatives from 1a with
various alkyl iodides
10
11
12
13
4-Et-C6H4
cHex
1k
1l
3.5
2.5
28
20
24
24
3j
3k
3l
-
71
81
60
NR
nOct
1m 3.0
1n 3.0
tBu
a0.5 equiv of triethylborane (1 M solution in THF) was added every 4 h.
bIsolated yield.
entry R (equiv)
Et3B (equiv)a time (h) product yield (%)b
A plausible mechanism for the synthesis of hydrazine
derivatives from aldehydes via radical addition reactions is
depicted in Scheme 1. Yb(OTf)3 promotes the condensation of
the aldehyde with benzhydrazide, producing a hydrazone. The
ethyl radical that is formed by the reaction of Et3B with O2 reacts
with the alkyl halide to generate an alkyl radical. This radical
then adds to the C=N bond of the hydrazone to form a radical
intermediate. The radical addition reaction is also assisted by
Yb(OTf)3. The radical intermediate abstracts a hydrogen from
Ph2SiH2 to give the final product.
1
2
3
4
5
6
7
iPr (10)
3.5
3.5
2.5
3.0
3.5
3.0
28
28
20
24
28
24
24
2b
2b
2c
2c
2d
2e
2f
59
80
63
81
79
69
64
iPr (30)
cHex (10)
cHex (30)
tBu (30)
1-Ad (30)
n-Oct (30) 3.0
a0.5 equiv of triethylborane (1 M solution in THF) was added every 4 h.
bIsolated yield.
Subsequently, the scope and limitations of the reaction with
respect to the aldehyde substrate were investigated. Reactions
using isopropyl iodide were performed with various aldehydes
under the optimized reaction conditions. The results are
summarized in Table 3. Aryl aldehydes bearing a halogen group
such as fluorine and chlorine at the 4-position gave high yields of
isopropyl-added products (Table 3, entries 1 and 4). Instead,
halide substituents at the 2-position gave lower yields (entries 3,
6, and 7). The drop in the yield might be caused by the steric
hindrance of the halide near the reaction site. Aryl aldehydes
bearing a strong electron-donating or electron-withdrawing group
showed a deteriorating effect on the outcome of the radical
addition reaction to the C=N bond (entries 8 and 9). The aliphatic
aldehyde cyclohexyl aldehyde gave the corresponding addition
product in high yield, instead n-octyl aldehyde, which is an
aliphatic aldehyde with a long chain, provided a lower yield
(entries 11 and 12, respectively). The reaction with tert-butyl
aldehyde did not proceed, possibly due to high steric hindrance.
Scheme 1. Plausible mechanism of the one-pot procedure for
the synthesis of hydrazines from aldehydes via radical
addition reactions
3. Conclusions
We have developed a one-pot procedure for the synthesis of
hydrazine derivatives from aldehydes via a radical addition
reaction. Lewis acids promoted the condensation between various
aldehydes and benzhydrazide, and the alkyl radical addition to
the C=N bond of hydrazones. The present process is a tin-free
radical reaction using non-toxic diphenylsilane as the radical
chain carrier and hydrogen source, providing a sustainable and
eco-friendly synthetic method.
Table 3. Synthesis of hydrazine derivatives from various
aldehydes via isopropyl radical addition
Typical experimental procedure for the synthesis of hydrazine
derivatives: A solution of triethylborane (0.25 mL, 0.25 mmol, 1
M solution in THF) was added to a solution of aldehyde (0.50
mmol), benzhydrazide (0.50 mmol, 78 mg), diphenylsilane (0.50
mmol, 0.09 mL), and alkyl halide (15 mmol) in the presence of
Yb(OTf )3 (0.125 mmol, 77.5 mg) in (ClCH2)2/THF (v/v, 1:1) (5
mL) at room temperature. Further triethylborane (0.25 mL, 1 M
solution in THF) was added every 4 h and air was injected
Et3B
time
(h)
yield
(%)b
entry
R
product
(equiv)a
1
2
4-F-C6H4
3-F-C6H4
1b
1c
3.5
3.0
28
24
3a
3b
82
76

4
Tetrahedron
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Acknowledgments
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
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5

Tetrahedron
6
Graphical
Abstr
One-pot synthesis of hydrazine derivatives
from aldehydes via radical addition reactions
Leave this area blank for abstract info.
Ji Hye Kim and Doo Ok Jang

7
Highlights



A one-pot procedure for the synthesis of hydrazine derivatives.
Alkyl radical addition to the C=N bond of hydrazones.
A tin-free radical, sustainable, and eco-friendly synthetic method.
7