Base-catalyzed N -N bond cleavage of hydrazones: Synthesis of α-amino ketones

Article abstract of DOI:10.1002/asia.201400037

An efficient Cs₂CO₃-promoted synthesis of α-amino ketones using hydrazines, aldehydes, and α-haloketones as starting materials through a cascade condensation/nucleophilic substitution/N -N bond cleavage route is developed. The carbonyl group plays a key role in this novel N -N bond cleavage process. Breaking good: A novel method of base-catalyzed N -N bond cleavage of hydrazones has been discovered. A variety of α-amino ketones was synthesized using hydrazines, α-haloketones, and benzaldehyde as starting materials through a cascade condensation/ nucleophilic substitution/N -N bond cleavage sequence.

Full text of DOI:10.1002/asia.201400037

COMMUNICATION
DOI: 10.1002/asia.201400037
À
Base-Catalyzed N N Bond Cleavage of Hydrazones: Synthesis of a-Amino
Ketones
Hai-Tao Tang, Yun-Bing Zhou, Yu Zhu, Hong-Chao Sun, Min Lin, and
Zhuang-Ping Zhan*[a]
Abstract: An efficient Cs2CO3-promoted synthesis of a-
amino ketones using hydrazines, aldehydes, and a-haloke-
tones as starting materials through a cascade condensation/
À
nucleophilic substitution/N N bond cleavage route is devel-
À
oped. The carbonyl group plays a key role in this novel N
N bond cleavage process.
À
N N bond cleavage is regarded as a powerful tool in syn-
thetic chemistry, particularly in the cleavage of hydrazones.
Accordingly, considerable effort has been exerted in this
À
field. Previous procedures for the N N bond cleavage of hy-
drazones involve high temperature,[1] an oxidation system,[2]
a stoichiometric amount of strong base such as LiOtBu,[3]
Scheme 1. Our studies on N-substituted hydrazones.
and induction by a nitrogen cation intermediate.[4]
Methods to prepare N-propargylic sulfonylhydrazones in-
volving rearrangement and cyclization have been developed
they are the main skeletons of brephedrone[6] and bupro-
pion.[7] They also serve as useful precursors for preparing
a wide variety of natural products[8] and nitrogen-containing
heterocycles.[9] Accordingly, considerable attention has been
paid to the development of efficient approaches to their syn-
thesis.[10,11] However, secondary a-sulfonylamino ketones 4
cannot be prepared directly from sulfamide and 2-bromoa-
cetophenone.[12] These types of a-amino ketones are con-
structed from the ring-opening of aziridines[10a–d] or the oxi-
dation of allylic amines.[10e] Very recently, the rhodium-cata-
lyzed denitrogenative hydration of N-sulfonyl-1,2,3-triazoles
to a-sulfonylamino ketones was reported by Murakami and
co-workers.[10f] Herein, we report the efficient Cs2CO3-pro-
moted synthesis of a-amino ketones through a novel base-
À
in our previous studies, and products with cleaved N S
bonds have been obtained (Scheme 1).[5] To continue our
studies on N-sulfonylhydrazones, we conducted the reaction
of N-(2-oxoethyl)hydrazones 6 in the presence of a catalytic
amount of a weak base. Interestingly, products with broken
À
À
N N bonds rather than N S bonds were observed. The car-
À
bonyl group may play a key role in this novel N N bond
cleavage process. To our knowledge, carbonyl promotion of
À
N N bond cleavage using a catalytic amount of a weak base
has not yet been reported. Compared with previous proce-
À
dures for the N N bond cleavage of hydrazones, this
method is characterized by high yields, mild reaction condi-
tions, and a broad variety of substrates. This approach is
a new route to a-amino ketones.
À
catalyzed N N bond cleavage process using hydrazines, al-
a-Amino ketones are extremely important scaffolds in
pharmaceuticals and in synthetic organic chemistry, because
dehydes, and a-haloketones as starting materials in one pot.
We initially optimized different parameters of this novel
reaction. Supplies of catalysts and solvents were screened
using 6a as a model substrate (Table 1). We treated 6a in
CH3CN with DMAP (4-dimethylaminopyridine, 10 mol%)
at 808C. Desired product 4a was observed in 93% yield
(Table 1, entry 1). However, when the reaction took place in
solvents such as PhMe, THF, DCE, 1,4-dioxane, DMF, and
PhCl (Table 1, entries 2–7), no improvement was observed
in the yields of 4a. Further optimization suggested that cata-
lysts also served an important function in this reaction.
Using inorganic base such as K2CO3 and Cs2CO3 (Table 1,
entries 10 and 11) significantly shortened the reaction time
and gave almost the same yields as organic base, including
[a] H.-T. Tang, Y.-B. Zhou, Y. Zhu, H.-C. Sun, M. Lin, Prof. Z.-P. Zhan
Department of Chemistry and Key Laboratory for Chemical Biology
of Fujian Province
College of Chemistry and Chemical Engineering
Xiamen University
Xiamen 361005, Fujian (Peopleꢀs Republic of China)
Fax : (+86)592-218-0318
E-mail: zpzhan@xmu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201400037.
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Zhuang-Ping Zhan et al.
Table 1. Optimization of the reaction conditions.[a] Ts=CH3C6H4SO2
Entry Catalyst
Solvent
T [8C]
t
Yield[b] of 4a [%]
1
2
3
4
5
6
7
8
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
PPY[c]
CH3CN
PhMe
THF
DCE
1,4-dioxane 80
80
80
65
80
2 h
2 h
18 h
3 h
3 h
2 h
2 h
1 h
1 h
10 min
5 min
5 min
5 min
24 h
93
87
78
91
90
DMF
PhCl
80
80
80
80
80
80
rt[d]
rt
complex
83
90
92
88
92
CH3CN
9
DABCO[c] CH3CN
10
11
12
13
14
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
none
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
97
96[e]
0
rt
[a] Conditions: 6a (0.5 mmol), catalyst (10 mol%), solvent (5 mL).
[b] Yield determined by NMR spectroscopy using diethyl phthalate as an
internal standard. [c] PPY=4-pyrrolidinopyridine, DABCO=1,4-
diazabicycloACHTUNGTRENNUNG[2.2.2]octane. [d] rt=room temperature. [e] The amount of
catalyst was decreased to 2 mol%.
Scheme 2. Syntheses of a-amino ketones 4 from hydrazines 1, a-haloke-
tones 3, and benzaldehyde 2a in one pot. Unless otherwise noted, all re-
actions were carried out in
a 5 mL flask using 1 (1.1 mmol), 2a
(1.1 mmol), CH3OH (2 mL), reflux, 30 min; CH3OH was then removed, 3
(1 mmol), Cs2CO3 (1.1 equiv), CH3CN (5 mL) were added, room temper-
ature, 5 to 60 min. Yields of isolated product based on 3 are given. Ms=
CH3SO2. [a] The reaction was run at 808C. [b] The product 4k was ob-
tained using 6b as starting material with Cs2CO3 (2 mol%) and CH3CN
(5 mL) at 808C (see the Supporting Information).
DMAP, PPY, and DABCO (Table 1, entries 1, 8, and 9). No-
tably, the reaction occurred very well when Cs2CO3 was
used as a catalyst in CH3CN without heating (Table 1,
entry 12). Furthermore, the reaction was not sluggish when
catalyst loading was decreased to 2 mol% (Table 1,
entry 13). Conversely, the reaction failed without base cata-
lyst (Table 1, entry 14). Thus, after careful screening the op-
timal reaction conditions were determined to be Cs2CO3
(2 mol%) in CH3CN at room temperature (Table 1,
entry 13).
N-(2-oxoethyl)-hydrazones 6 were easily prepared from
sulfonylhydrazones and a-haloketones 3 with a slight excess
of base. Moreover, sulfonylhydrazones were produced from
aldehydes 2 and sulfonylhydrazides 1 without any catalyst in
CH3OH. Considering the operational simplicity, economical
efficiency, and environmental friendliness, we attempted to
perform these reactions (condensation/nucleophilic substitu-
conditions in one pot, but 4k was obtained using 6b as start-
ing material (Scheme 2, 4k). Additionally, a series of a-halo-
ketones was also suitable as starting material for these reac-
tions. Aromatic a-haloketones (R3 =4-BrC6H4) were suc-
cessfully used in these transformations, and the desired
products were obtained in good yields (Scheme 2, 4i and
4j). When we used nonaromatic a-haloketones (R3 =
CH3CH2) and ethyl bromoacetate (R3 =CH3CH2O) as start-
ing materials, the corresponding products were also obtained
in high yields (Scheme 2, 4g and 4h).
As illustrated in Scheme 3, the reaction scope can be ex-
tended to different aldehydes to afford nitriles.[13] Naturally,
several benzaldehydes (R2 =C6H5, 4-BrC6H4, 2-BrC6H4, 4-
CH3OC6H4) reacted well, providing 5a, 5b, 5c, 5 f, and a-
amino ketone 4a in good yields (Scheme 3, 5a, 5b, 5c, and
5 f). Aromatic heterocycle aldehydes such as 2-thiophenecar-
boxaldehyde and fused-ring aldehydes including 1-naphthal-
dehyde were also suitable for the transformations
(Scheme 3, 5d and 5e). Similarly, the conjugated cinnamal-
dehyde reacted smoothly, affording product 5g in 74% yield
(Scheme 3, 5g). The reaction of non-aromatic phenylacetal-
dehyde and pentanal also smoothly occurred to afford the
corresponding products 5h and 5i[14] in moderate yields
(Scheme 3, 5h and 5i).
À
tion/N N bond cleavage) in one pot and successfully ob-
tained the desired products, a-amino ketones 4, in satisfacto-
ry yields (see the Supporting Information).
First, a variety of a-amino ketones 4 were synthesized
using hydrazines 1, a-haloketones 3, and benzaldehyde 2a.
As shown in Scheme 2, both electron-withdrawing and elec-
tron-donating benzenesulfonylhydrazides reacted smoothly,
and the corresponding a-amino ketones 4 were obtained in
good yields (Scheme 2, 4a, 4b, 4d, and 4e). Notably, metha-
nesulfonylhydrazide also survived the reaction conditions
and afforded the product 4c in 81% yield (Scheme 2, 4c).
Methyl hydrazinocarboxylate (R1 =COOCH3) also afforded
the corresponding product in moderate yield (Scheme 2,
4 f). However, the results suggested that benzoylhydrazine
(R1 =PhCO) failed to form 4k under the aforementioned
To evaluate the reaction pathways, a deuterium-labeling
experiment was conducted. Substrate 6c bearing deuterium
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Zhuang-Ping Zhan et al.
Scheme 3. Synthesis of nitriles 5 and a-amino ketone 4a from 1a, 3a and
aldehydes 2 in one pot. Unless otherwise noted, all reactions were carried
out in a 5 mL flask using 1a (1.1 mmol), 2 (1.1 mmol), CH3OH (2 mL),
reflux, 30 min; CH3OH was then removed, 3a (0.5 mmol), Cs2CO3
(1.1 equiv), CH3CN (5 mL) were added, room temperature, 5 to 60 min.
Yields of isolated product based on 3a are given.
Scheme 5. Proposed mechanism.
atoms smoothly transformed into 4l. This reaction indicated
that almost all deuterium atoms were incorporated into the
secondary carbon position of product 4l [Scheme 4, Eq. (1)].
However, the reaction failed when using 6d [Scheme 4,
Eq. (2)]. Therefore, unlike the previous base-promoted
mechanism,[3] we believe that the carbonyl group may play
The efficient three-step reaction sequence is applicable to
a wide range of substrates. A series of a-amino ketones and
nitriles was synthesized. Further development of this meth-
odology is currently in progress.
À
a key role in this novel N N bond-cleavage process.
Based on the above conclusions, a plausible mechanism
for the reactions is summarized in Scheme 5. First, hydra-
Experimental Section
General procedure for synthesis of a-amino ketones (4a–j) and nitriles
(5a–i)
Aldehyde
2 (1.1 mmol) was added to a solution of hydrazine
1 (1.1 mmol) in CH3OH (2 mL), and the mixture was stirred at 658C.
When the reaction was complete (monitored by TLC), the reaction sol-
vent was removed under reduced pressure, and then a-haloketone 3
(1 mmol), Cs2CO3 (1.1 mmol), and CH3CN (5 mL) were added. The reac-
tion mixture was stirred at room temperature and monitored by TLC.
Following reaction completion, the products were purified by column
chromatography (petroleum ether and ethyl acetate).
Scheme 4. Synthesis of a-amino ketones 4 from N-substituted hydrazones
6.
Acknowledgements
zone 7 reacts with a-haloketone 3 under basic conditions to
yield nucleophilic substitution product 6. Then, compound 6
undergoes an enolization reaction/intramolecular cyclization
Financial support from National Natural Science Foundation of China
(No. 21272190) and PCSIRT in University is gratefully acknowledged.
process to generate six-membered ring intermediate
through transition state 8. Second, unstable six-membered
9
Keywords: amino ketones · domino reactions · hydrazones ·
À
N N bond cleavage
À
ring 9 undergoes a 1,2-hydrogen shift/N N bond cleavage/
protonation step to yield intermediate 12. Finally, intermedi-
ate 12 transforms into final products 4 and 5 through rapid
retro-ene type fragmentation.[15]
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ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: January 7, 2014
Revised: January 17, 2014
Published online: && &&, 0000
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Chem. Asian J. 2014, 00, 0 – 0
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

COMMUNICATION
Domino Reactions
Hai-Tao Tang, Yun-Bing Zhou,
Yu Zhu, Hong-Chao Sun, Min Lin,
Zhuang-Ping Zhan*
&&&& — &&&&
À
Base-Catalyzed N N Bond Cleavage
of Hydrazones: Synthesis of a-Amino
Ketones
Breaking good: A novel method of
base-catalyzed N N bond cleavage of
hydrazones has been discovered. A
variety of a-amino ketones was synthe-
sized using hydrazines, a-haloketones,
and benzaldehyde as starting materials
through a cascade condensation/nucle-
À
À
ophilic substitution/N N bond cleav-
age sequence.
5
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Chem. Asian J. 2014, 00, 0 – 0
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ