A base-promoted tandem cycloaddition/air oxidation reaction of electron-deficient conjugated enynes and hydrazines: Synthesis of highly substituted pyrazoles

Full text of DOI:10.1002/chem.201202583

COMMUNICATION
DOI: 10.1002/chem.201202583
A Base-Promoted Tandem Cycloaddition/Air Oxidation Reaction of
Electron-Deficient Conjugated Enynes and Hydrazines: Synthesis of Highly
Substituted Pyrazoles
Xiuzhao Yu[a] and Junliang Zhang*[a, b]
Pyrazoles are important motifs in bioactive molecules
used in the pharmaceutical and agrochemical industries.[1]
Moreover, pyrazoles are used in supramolecular and poly-
mer chemistry, in the food industry, and as cosmetic color-
ings and UV stabilizers.[2] Substituted pyrazoles have also
been used as ligands for transition metal catalyzed reac-
tions.[3] Typical methods for the synthesis of pyrazoles in-
clude approaches based either on the condensation of hy-
drazines with 1,3-dicarbonyl compounds[4] and a,b-unsatu-
rated aldehydes and ketones[5] (Scheme 1a and b) or on the
intermolecular 1,3-dipolar cycloaddition of diazoalkanes and
nitrile imines with alkenes and alkynes (Scheme 1c)[6] The
drawbacks of these protocols, such as poor reactivity and re-
gioselectivity, and the potential hazards associated with det-
onation of the substrates, limit their practical application to
some extent. Although over the years, diverse methodolo-
gies have been developed,[7,8] access to a regioselective and
broadly applicable method for the synthesis of pyrazoles re-
mains challenging. In 2010, Glorius and co-workers[8a] re-
ported a novel method for the preparation of highly substi-
À
À
tuted pyrazoles; the method involved oxidative C C/N N
bond formation using amines, ketones, and nitriles as sub-
strates, although a high reaction temperature and an excess
of oxidant (CuACHTUNGTRENNUNG(OAc)2, 3.0 equiv) were required
(Scheme 1d). Patil and Singh[8b] developed a novel Lewis-
acid-mediated microwave-based hydroamination reaction of
terminal enynes and aryl hydrazines that gives, for example,
3-methyl-4,5-dihydro-pyrazole, which upon Pd/C-catalyzed
dehydrogenative aromatization gives 3-methyl-pyrazole
(Scheme 1e). However, the need for a high reaction temper-
ature and an excess of Lewis acid (3.0 equiv), as well as the
[a] Dr. X. Yu, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry and
Chemical Processes, Department of Chemistry
East China Normal University
3663 N. Zhongshan Road, Shanghai 200062 (P.R. China)
Fax : (+86)21-6223-5039
Scheme 1. Previous work and this work for the synthesis of highly substi-
tuted pyrazoles. DMA=N,N-dimethylacetamide.
E-mail: jlzhang@chem.ecnu.edu.cn
[b] Prof. Dr. J. Zhang
poor functional-group compatibility may limit the use of this
reaction in organic synthesis. Consequently, the develop-
ment of novel, generally applicable, and very efficient meth-
ods for the synthesis of highly substituted pyrazoles under
mild reaction conditions is still highly desirable. Herein, we
report a facile route to highly substituted functionalized pyr-
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032, (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202583.
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Table 1. Screening of reaction conditions for the reaction of enyne 1a
with hydrazine 2a.[a]
azoles through an unprecedented cycloaddition/oxidation re-
action of hydrazines and electron-deficient 1,3-conjugated
enynes (Scheme 1 f).
Recent studies from our research group and that of Hu
have shown that electron-deficient 1,3-conjugated enynes
are good Michael acceptors and can undergo tandem addi-
tion reactions with nucleophiles, thus leading to various acy-
clic and cyclic compounds.[9] However, previous studies have
shown that the carbonyl group of a,b-unsaturated aldehydes
and ketones will react with hydrazines through condensation
followed by cyclization to afford pyrazoles (Scheme 1b).
However, as expected, we found that highly substituted pyr-
azoles that bear functional groups could be efficiently pre-
pared from the corresponding electron-deficient 1,3-enynes
and hydrazines by tandem inter- and intramolecular nucleo-
philic addition and air oxidation. It is notable that ketone
and aldehyde carbonyl groups in the substrate do not under-
go a condensation reaction with hydrazines under the reac-
tion conditions (Scheme 1 f).
To test the feasibility of our proposed tandem reaction,
we conducted a reaction using easily accessible 1,3-enyne
1a[9,10] as a substrate, together with tert-butylhydrazine hy-
drochloride (2a) and Et3N (1.7 equiv) in DMF at room tem-
perature under air atmosphere. To our delight, following a
reaction time of 7 hours, the desired 1-(5-benzyl-1-tert-butyl-
3-phenyl-1H-pyrazol-4-yl)ethanone (3aa) was isolated in
90% yield as a single isomer (entry 1, Table 1). This result
shows that the ketone moiety remains intact following trans-
formation of the substrate, a result that is different from
that of previous work (the hydrazine first reacts with the
ketone moiety), and that air is sufficient to oxidize the inter-
mediate. These results encouraged us to optimize the other
reaction parameters. Various solvents such as THF, DCE,
CH2Cl2, DMSO, and CH3CN were tested; the results
showed that the use of polar solvents benefits the reaction
and when the reaction was conducted in DMA, the product
could be isolated in up to 96% yield (Table 1, entries 2–10).
Notably, with shorter reaction times, allene product 3aa’
was obtained when using some less polar solvents. Subse-
quently, a series of organic and inorganic bases such as
TMEDA, DABCO, DBU, DMAP, NaOH, NaOAc, and
K2CO3 were tested for reactions conducted in DMA. The
results show that in many cases, the use of these bases lead
to high yields of product, except the use of NaOH and
DMAP (Table 1, entries 11–16); the use of K2CO3 gave the
best results (Table 1, entry 17). Finally, we found that de-
creasing the amount of the hydrazine and base to 1.2 and
1.4 equivalents, respectively, does not adversely affect the
reaction outcome (Table 1, entry 18). The structure of the
product was confirmed by X-ray crystallographic analysis of
3aa (Figure 1, top).[11]
Entry
Base
Solvent
Time [h]
Yield [%][b]
3aa 3aa’
1
2
3
4
5
6
7
8
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DMF
THF
DCE
7
20
20
20
20
20
20
9
90 –
74 15
65 26
81 15
68 31
23 54
50 25
71 –
95 –
96 –
95 –
96 –
CH2Cl2
CHCl3
toluene
1,4-dioxane
DMSO
CH3CN
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
9
Et3N
Et3N
9
10
11
12
13
14
15
16
17
18[c]
1.5
3.5
3.3
3.3
24
24
3.3
1.2
1.5
TMEDA
DABCO
DBU
DMAP
NaOH
NaOAc
K2CO3
K2CO3
87 –
65 11
22 39
93 –
97 –
97 –
[a] All reactions were carried out using 1a (0.2 mmol) and 2a (0.3 mmol)
in the presence of base (1.7 equiv) in solvent (2.5 mL), unless otherwise
specified. [b] Yield of isolated product. [c] 1.2 equiv hydrazine and
1.4 equiv base were used. DABCO=1,4-diazabicycloACHTUNTRGNEU[GN 2.2.2]octane,
DBU=1,8-diazabicyclo
[5.4.0]undecen-7-ene,
DCE=dichloroethane,
DMF=N,N-dimethylformamide,
DMAP=4-dimethyl-aminopyridine,
TMEDA=N,N,N’,N’-tetramethyleth-ane-1,2-diamine.
Table 2. Base-promoted tandem reactions of enyne 1a with various hy-
drazines 2.[a]
Entry
Hydrazine 2
Time [h]
Yield [%][b] 3/4
1[c]
2[d]
3
H2NNH2·H2O 2b
TsNHNH2 2c
PhNHNH2 2d
13
30
9
61 3ab
72 3ab
90 (3ad/4ad 10:1)
86 (3ae/4ae 4.9:1)
4[e]
MeNHNH2·H2O 2e
3.5
[a] The reaction was carried out using 1a (0.2 mmol) and hydrazine 2
(0.24 mmol) in the presence of K2CO3 (20 mol%) in DMA (2 mL) unless
otherwise specified. [b] Yield of isolated product. [c] 85 wt.% of
NH2NH2·H2O was used. [d] The product is the same as that obtained
from the reaction of 1a and 2b. [e] 40 wt.% of MeNHNH2·H2O was
used. Ts=p-toluenesulfonyl.
the reaction of tosylhydrazine (2c) with 1a afforded pyra-
zole 3ab in 72% yield rather than the expected 1-Ts pyra-
zole 3ac (Table 2, entry 2). Phenylhydrazine and methylhy-
drazine reacted efficiently with 1a to give the corresponding
pyrazoles in 90% and 86% yields with levels of regioselec-
tivity of 10:1 and 4.9:1, respectively (Table 2, entries 3 and
4).
The scope of this reaction was examined by variation of
the hydrazine component (2b–e; Table 2). Gratifyingly, hy-
drazine hydrate (2b) is a good substrate, the product, pyra-
zole 3ab, being isolated in 61% yield (Table 2, entry 1); this
product should be amenable to further functionalization
through reaction at the NH group. We were surprised that
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Tandem Cycloaddition/Air Oxidation
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reaction conditions (Table 3, entry 7). Notably, cyclic enynyl
ketone 1i gave the corresponding bicyclic pyrazole 3ia in
75% yield as a single isomer [Eq. (1)].
Considering that 1-nonsubstituted pyrazoles are highly
important intermediates in synthesis, we carried out further
screening of reaction conditions. Ultimately, we found that
product 3ab could be isolated as a single isomer in an im-
proved 80% yield when the reaction is conducted in
CH3CN at 408C (Table 4, entry 1). Encouraged by this
Table 4. Reaction of various enynes 1 with hydrazine hydrate 2b.[a]
Entry
EWG/R1/R2 1
Time
[h]
Yield of 3
[%][b,c]
1
2
3
4
5
6
7
8
COMe/Ph/Ph 1a
COMe/4-NCC6H4/Ph 1c
COMe/styryl/Ph 1j
COMe/Ph/4-NO2C6H4 1 f
COMe/Ph/1-cyclohexenyl 1k
COPh/Ph/Ph 1h
4-ClC6H4CO/Ph/Ph 1l
CO2Me/Ph/Ph 1m
CO2Me/Ph/PMP 1n
CO2Me/Ph/1-naphthyl 1o
CO2Me/Ph/n-C4H9 1p
CO2Me/Ph/cyclopropyl 1q
CO2Me/PMP/Ph 1r
CO2Me/4-FC6H4/Ph 1s
CO2Me/PMP/PMP 1t
CO2Me/PMP/1-naphthyl 1u
CN/Ph/Ph 1v
4 (5.5)
1.8 (4)
3.5 (6)
1.5 (4)
3
65 (80)
61 (78)
49 (53)
54 (73)
76
78
72 (84)
95
75
94
55
78
3ab
3bb
3cb
3db
3eb
3 fb
3gb
3hb
3ib
Figure 1. X-ray crystal structures of 3aa (top) and 3jb (bottom).
4
The scope of the reaction was then explored using various
2-(1-alkynyl)-2-alkene-1-ones 1b–h in combination with tert-
butylhydrazine hydrochloride (2a) (Table 3). To our delight,
the use of every tested substrate gave good to excellent
yields of the desired products, although substrates contain-
ing either electron-donating R1 or electron-donating R2
groups required a longer reaction time (Table 3, entries 1
and 4). The reaction of phenyl ketone 1h gave the desired
product 3ha in 93% yield as a single isomer under the same
3.5 (6)
22
10
10
11.5
11
10.5
10
10
8
3.5
9
10
11
12
13
14
15[d]
16[e]
17
18
19
20
3jb
3kb
3lb
95
93
58
97
3mb
3nb
3ob
3pb
3qb
3rb
3sb
3tb
97
COCO2Me/Ph/Ph 1w
COCO2Me/Ph/4-MeC6H4 1x
CHO/Ph/Ph 1y
3.5 (4)
2 (4)
3.5
47 (61)
75 (45)
58
Table 3. Reaction of various enynes 1 with hydrazine 2a.[a]
[a] The reaction was carried out using 1 (0.2 mmol) and 2 (0.24 mmol) in
the presence of K2CO3 (20 mol%) in DMA (2 mL) unless otherwise
specified. [b] Yield of isolated product; [c] Yields in brackets refer to re-
actions conducted in CH3CN as the solvent. [d] Ratio of isomers: 3ob/
4ob=1.7:1. [e] Ratio of isomers: 3pb/4pb=3:1.
Entry
R3/R1/R2 1
Time [h]
Yield [%][b]
3
promising result, the scope of this reaction was explored fur-
ther using various electron-deficient enynes. The following
points are noteworthy:
1
2
3
4
5
6
7
Me/PMP/Ph 1b
4
1
85 3ba
90 3ca
97 3da
88 3ea
84 3 fa
91 3ga
93 3ha
Me/4-NCC6H4/Ph 1c
Me/Ph/1-naphthyl 1d
Me/Ph/PMP 1e
Me/Ph/4-NO2C6H4 1 f
Me/Ph/4-FC6H4 1g
Ph/Ph/Ph 1h
1.8
4
1.2
1.5
1.5
(1) Either DMA or CH3CN can be used as a solvent for the
reactions of 2-(1-alkynyl)-2-alkene-1-ones (Table 4, en-
tries 1–4, 7, 18, and 19).
(2) The presence of various electron-withdrawing groups
such as ketones, esters, cyano, ketoesters, and aldehydes
are well tolerated. We were surprised that the ketone,
[a] The reaction was carried out using 1 (0.2 mmol) and hydrazine 2a
(0.24 mmol) in the presence of K2CO3 (1.4 equiv) in DMA (2 mL) unless
otherwise specified. [b] Yield of isolated product. PMP=para-methoxy-
phenyl.
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J. Zhang and X. Yu
aldehyde, and ketoester groups did not participate in
further condensation reactions; these pyrazoles, which
contain reactive ketone, aldehyde, and ketoester groups
are difficult to prepared using previously established
methods.
In summary, we have developed a simple and efficient
synthetic strategy for preparing pyrazoles based on an un-
precedented tandem cyclization/air oxidation of hydrazines
and electron-deficient 1,3-conjugated enynes under mild re-
action conditions. The presence of a variety of functional
groups, such as ketones, aldehydes, and ketoesters, are toler-
ated in this transformation; these functional groups often
undergo side reactions in many known processes. The reac-
tion is efficient and ꢁgreenꢂ. We anticipate that this method-
ology will find many applications in the fields of synthetic
organic chemistry and pharmaceutical science. The genera-
tion of libraries of pyrazoles and their biological evaluation
is currently being investigated.
(3) Compound 1j, which contains a styryl group (R1), af-
forded the desired pyrazole 3cb in moderate yield; the
reaction was regioselective in that no 1,6-addition prod-
uct was observed (Table 4, entry 3).
(4) In most cases, the reactions give the products as single
isomers, with the exception of 3ob and 3pb, the reac-
tions of which had poor regioselectivity (Table 4, en-
tries 15 and 16).
(5) The structure of the N-nonsubstituted pyrazoles was
confirmed by X-ray crystallographic analysis of 3jb
(Figure 1).[11]
Experimental Section
Typical procedure for the synthesis of pyrazole 3aa (Table 1, entry 18):
K2CO3 (0.28 mmol, 38.6 mg) was added in one portion to a solution of 3-
benzylidene-5-phenylpent-4-yn-2-one (1a; 0.2 mmol, 49.2 mg) and tert-
butylhydrazine hydrochloride (2a; 0.24 mmol, 29.8 mg) in 2.5 mL of
DMA under air at room temperature. After 1.5 h, the enyne 1a was con-
sumed, as determined by TLC analysis. 3 mL of H2O was added to
quench the reaction and the mixture was extracted with diethyl ether.
The combined organic layers were washed with saturated NaCl solution
and dried over MgSO4. After filtration and concentration, the residue
was purified by column chromatography on silica gel (hexane/ethyl ace-
tate 10:1) to give 3aa (64.4 mg, 97% yield) as a white solid. m.p.: 127–
1288C. 1H NMR (400 MHz, CDCl3, 258C, TMS): d=7.55 (d, J=7.2 Hz,
2H), 7.45–7.37 (m, 3H), 7.26 (t, J=7.2 Hz, 2H), 7.17 (t, J=7.2 Hz, 1H),
7.04 (d, J=7.2 Hz, 2H), 4.59 (s, 2H), 2.01 (s, 3H), 1.59 (s, 9H). 13C NMR
(100 MHz, CDCl3, 258C, TMS): d =196.54, 149.96, 143.07, 138.34, 134.29,
129.28, 128.38, 128.32, 128.23, 127.59, 126.08, 121.83, 61.62, 31.84, 30.96,
30.52 ppm; MS (70 eV): m/z (%): 332 (M+, 94.70), 261 (100). HRMS
calcd for C22H24NO3: 332.1889, found: 332.1890.
Notably, when the reaction is scaled-up (12.2 mmol), the
substrates can be used in less excessive amounts without any
reduction in yield [Eq. (2)]. For example, the reaction of
tert-butylhydrazine hydrochloride (2a, 15 mmol) with 2-(1-
alkynyl)-2-alkene-1-one (1a, 12.2 mmol) exposed to air in
DMA was complete within 3.5 hours, thus giving 3.44 grams
of 3ba (85% yield upon isolation). Notably, the bubbling-in
of air is not necessary for the reaction done on a smaller
scale or on a gram scale.
Acknowledgements
One plausible mechanism that accounts for this base-pro-
moted cycloaddition/oxidation reaction is proposed
(Scheme 2). Regioselective nucleophilic conjugate addition
We are grateful to National Natural Science Foundation of China
(20972054), Ministry of Education of China, 973 program
(2011CB808600) for financial support. This research is also supported by
the Program for Professor of Special Appointment (Eastern Scholar) at
Shanghai Institutions of Higher Learning.
Keywords: cycloaddition · enynes · hydrazines · oxidation ·
pyrazoles
Scheme 2. A plausible mechanism for the tandem cycloaddition/oxidation
reaction.
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[11] CCDC 886253ACTHNUTRGENNGU(3aa) and 886254ACHTUNGTRNE(NUNG 3jb) contain the supplementary
crystallographic date for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Date Centre via
www.ccdc.cam.ac.uk/date request/cif.
[12] This intermediate B appears as a new spot on the TLC plate if the
reaction is run under an atmosphere of N2, B rapidly undergo dehy-
drogenative aromatization during the work-up and the attempts to
isolate this compound failed.
Received: July 23, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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J. Zhang and X. Yu
Tandem Reactions
X. Yu, J. Zhang* ............. &&&& — &&&&
A Base-Promoted Tandem Cycloaddi-
tion/Air Oxidation Reaction of Elec-
tron-Deficient Conjugated Enynes and
Hydrazines: Synthesis of Highly
Substituted Pyrazoles
Rapid access: A base-mediated cyclo-
addition/oxidation reaction of hydra-
zines and electron-deficient 1,3-conju-
gated enynes gives pyrazole deriva-
tives, some of which are not easily
accessible by other methods (see
scheme). The reaction conditions are
mild, thus enabling a variety of func-
tional groups to be tolerated.
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www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!