Highly regioselective organocatalyzed synthesis of pyrazoles from diazoacetates and carbonyl compounds

Article abstract of DOI:10.1002/chem.201300047

A general, organocatalytic inverse-electron-demand [3+2] cycloaddition reaction between a range of carbonyl compounds and diazoacetates has been developed. This reaction is catalyzed by secondary amines as a "green promoter" to generate substituted pyrazoles with high levels of regioselectivity. It is noteworthy that this [3+2] cycloaddition reaction proceeds efficiently at room temperature with a simple and inexpensive catalyst. Considering the large variety and ready availability of the starting materials (e.g. ketones, β-ketoesters, β-diketones, and aldehydes), as well as the operational simplicity of this process, a convenient, practical, and highly modular pyrazole synthesis has been developed. We believe that this work will arouse more research interest in the organocatalytic synthesis of other biologically active heterocycles. Such studies are currently underway in our laboratory. Dipoles apart: In situ formed enamines react with diazoacetates under mild conditions to afford the corresponding polysubstituted pyrazoles in good-to-excellent yields through an inverse-electron-demand 1,3-dipolar cycloaddition process (see scheme). Copyright

Full text of DOI:10.1002/chem.201300047

FULL PAPER
DOI: 10.1002/chem.201300047
Highly Regioselective Organocatalyzed Synthesis of Pyrazoles from
Diazoacetates and Carbonyl Compounds
Lei Wang,[a] Jiayao Huang,[a] Xiaojie Gong,*[b] and Jian Wang*[a]
Abstract: A general, organocatalytic
inverse-electron-demand [3+2] cyclo-
addition reaction between a range of
carbonyl compounds and diazoacetates
has been developed. This reaction is
catalyzed by secondary amines as a
“green promoter” to generate substi-
tuted pyrazoles with high levels of re-
gioselectivity. It is noteworthy that this
[3+2] cycloaddition reaction proceeds
efficiently at room temperature with a
simple and inexpensive catalyst. Con-
sidering the large variety and ready
availability of the starting materials
(e.g. ketones, b-ketoesters, b-diketones,
and aldehydes), as well as the opera-
tional simplicity of this process, a con-
venient, practical, and highly modular
pyrazole synthesis has been developed.
We believe that this work will arouse
more research interest in the organoca-
talytic synthesis of other biologically
active heterocycles. Such studies are
currently underway in our laboratory.
Keywords: cycloaddition ·
enamines · nitrogen heterocycles ·
organocatalysis · pyrazoles
Introduction
Pyrazole is widely found as the core structure in a large vari-
ety of compounds that possess important agrochemical and
pharmaceutical activities[1] and the recent successful discov-
ery of pyrazole-based anti-inflammatory COX-II inhibitor
and insecticide Fipronil have amplified the importance of
pyrazoles to even a greater extent.[1,2a–c] In addition, the pyr-
azole scaffold has been found in many other important phar-
maceutical compounds, such as Celecoxib (1),[2d] Doramapi-
mod (2, p38 MAP kinase inhibitor),[2e] anti-diabetic agent
3,[2g] and anti-tumor agent 4[2f] (Figure 1). Among the vari-
ous synthetic routes to pyrazoles, the 1,3-dipolar cycloaddi-
tion reaction[3] between a diazo compound and an alkyne
(Scheme 1a) and the cyclocondensation reaction of a hydra-
zine with a 1,3-dicarbonyl compound (Scheme 1b) are two
of most frequently used.[4–5] However, the use of carcinogen-
ic hydrazines and toxic transitional metals, as well as the
somewhat-limited substrate scope and uncontrollable regio-
selectivity, greatly decrease the attractiveness of these ap-
proaches.[6]
Figure 1. Examples of pharmaceutical drugs that are based on a pyrazole
scaffold.
Scheme 1. Two general approaches to polysubstituted pyrazoles.
Although the 1,3-dipolar cycloaddition reaction between
electron-rich diazo compounds and alkynes is known,[7] the
development of efficient processes that use electron-defi-
cient diazo compounds is much less reported,[8] which has
been attributed to the increased HOMO(dipolarophile)–
[a] L. Wang, J. Huang, Prof. Dr. J. Wang
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
Fax : (+65)6516-1691
LUMOACTHNUTRGENU(GN dipole) energy gap between the diazo compounds
and the alkynes.[9] One common method to generate pyra-
zole rings involves the incorporation of either Lewis acids or
transition metals to lower the LUMO of the alkyne dipolar-
ophiles (Scheme 2).[10] Another attractive, but less common,
complementary strategy is the HOMO-raising activation of
the alkynes through the formation of metal acetylides. For
example, in 2007, Qi and Ready reported a mild copper-pro-
moted cycloaddition reaction between diazocarbonyl com-
E-mail: chmwangj@nus.edu.sg
[b] Prof. X. Gong
Medical School of Dalian University
Jinzhou District, Dalian, Liaoning 116622 (P.R. China)
E-mail: gongxiaojie@dlu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300047.
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Table 1. Optimization of the reaction parameters.[a]
[a] Reaction conditions: Compound 1a (0.2 mmol), compound 2a
(0.4 mmol), DMSO (0.4 mL), RT. [b] Catalyst I (20 mol%), 5 h. [c] Cata-
lyst I (10 mol%), 12 h. [d] Catalyst I (5 mol%), 72 h. [e] Compound 2a
(0.2 mmol). [f] Compound 2a (0.6 mmol).
Scheme 2. This work employs enamines as active synthetic intermediates,
thus facilitating the inverse-electron-demand cycloaddition reaction to
generate pyrazoles at room temperature.
pounds and acetylides.[11a] Later, Liang and co-workers re-
ported a ZnII-catalyzed intermolecular cycloaddition reac-
tion between various a-diazocarbonyl compounds and ter-
minal alkynes.[11b] To the best of our knowledge, no such or-
ganocatalytic cycloaddition reaction to achieve the target
pyrazole by raising the HOMO of the dipolarophile has
been performed.
proving the catalysis. When the reaction was carried out in
DMSO, the reactivity was positively influenced, thereby
leading to the desired product (3aa) in 87% yield.[14] Other
solvents, such as toluene, MeCN, 1,2-dichloroethane (DCE),
CHCl3, THF, MeOH, isopropanol (IPA), dimethylacetamide
(DMA), DMF, and 1,4-dioxane, significantly retarded the
chemical yield (<5–64%, Table 1). Lowering the catalyst
loading to 5 mol% resulted in a longer reaction time (90%
yield after 72 h), whilst changing the ratio of compounds 1a/
2a from 1:1 to 1:3 had a slightly beneficial effect on the effi-
cacy of the reaction (71% and 87% yield, respectively;
Table 1). Finally, the best compromise was achieved when
performing the cycloaddition reaction at room temperature
with 10 mol% of second amine II and a 1:2 ratio of com-
pounds 1a/2a in DMSO.
With the optimized reaction conditions in hand, we inves-
tigated the reactions between a variety of ketones and ethyl
diazoacetate (1a), catalyzed by second amine I (10 mol%)
at room temperature; the results are summarized in Table 2.
Interestingly, among the various ketones that were exam-
ined, cyclic ketones (six- to eight-membered rings) appeared
to be the substrates of choice and gave their corresponding
products in good-to-excellent yields under standard condi-
tions (3aa–aj, 75–96% yield, 12–10 h; Table 2). The highest
yield was obtained with cycloheptanone, which afforded the
corresponding isolated pyrazole (3ai) in 96% yield
(Table 2). Notably, unsymmetrical cyclic ketones afforded
high levels of regioselectivity. For example, the reaction of
3,3-dimethylcyclohexanone led to a single regioisomer (3af,
Table 2), in which the heterocycle was furthest from the
gem-dimethyl group, owing to steric reasons. On the other
hand, 4,4-dimethylcyclohexanone furnished pyrazole 3ae
(Table 2), which was an isomer of compound 3af. In this
case, the regioselectivity can be explained by the cycloaddi-
tion reaction occurring with most-stabilized enamine. Sym-
metrical and unsymmetrical acyclic ketones 3ak and 3al
both gave good yields of their corresponding products under
Results and Discussion
During the course of our study on intermolecular cycloaddi-
tion reactions between carbonyl compounds and diazoace-
tates, we made an interesting observation (Scheme 2), that
is, that the in situ formed enamine (versus the metal acety-
lide) could promote the cycloaddition reaction to achieve
the target pyrazole ring. We envisioned that this reaction
may constitute an unusual organocatalytic HOMO-raising-
type inverse-electron-demand (IED) 1,3-dipolar cycloaddi-
tion process.[12–13] In addition, this efficient synthetic proce-
dure could start from simple and readily available starting
materials, that is, carbonyl compounds and diazoacetates.
Moreover, high conversions could be achieved at room tem-
perature.
Initial experiments were conducted by using cyclohexa-
none (2a) and ethyl diazoacetate (1a) in the presence of
various amine catalysts (10 mol%), such as primary amines
(VIII and IX), secondary amines (I,II, III, IV, and V), and
tertiary amines (VI and VII). Among the catalysts that were
tested (Table 1), we found that 1,4-diazabicycloACHTNUTRGNE[NUG 2.2.2]octane
(DABCO, VII) was more effective than triethyl amine (VI)
in the reaction and afforded the product in 31% yield. As
indicated in Table 1, primary and secondary amines showed
higher reactivity than tertiary amines. Finally, pyrrolidine (I)
was identified as the most-effective catalyst for this transfor-
mation. Further optimization of the standard reaction pa-
rameters revealed that the solvent was a crucial factor in im-
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Highly Regioselective Organocatalyzed Synthesis of Pyrazoles
Table 2. Substrate scope of the ketones.[a]
FULL PAPER
To further indicate the gener-
ality and potential of our ap-
proach, other types of carbonyl
compounds (e.g. aldehydes)
were explored in the reactions
with diazoacetates 1a–c. How-
ever, catalyst I only afforded
slow conversions under our pre-
vious optimized conditions. Fi-
nally, after further optimizing
the reaction parameters, acyclic
secondary diethyl amine (IV)
was identified as the best cata-
lyst in the reaction between di-
azoacetates and aldehydes. As
shown in Table 4, the corre-
sponding adducts (3) were ob-
tained in moderate-to-excellent
yields (51–96%).
A
certain
level of variation was possible
in the side-chain of the carbon-
yl group. For example, straight-
chain aldehydes of different
lengths were tolerated, thus af-
fording their corresponding cy-
[a] Reaction conditions: Compound 1a–c (0.2 mmol), compound 2a–n (0.4 mmol), DMSO (0.4 mL), catalyst I
(10 mol%), RT. [b] 808C.
the same conditions (Table 2). Pleasingly, phenones, such as
acetophenone and propiophenone, were both reactive and
afforded their corresponding products (3am and 3an) in
good yields, although a higher reaction temperature was re-
quired (77% and 71% yield, 808C, 24 h, respectively;
Table 2). Two other diazoacetates (1b and 1c, Table 1) were
also explored and both afforded good yields of their corre-
sponding products (3ba and 3ca, respectively) under the
standard conditions (Table 2). Moreover, the regioselective
cycloaddition reactions between diazoacetate and enami-
noesters and enaminones that were formed in situ from acti-
vated ketones (b-ketoesters, b-diketones), with a catalytic
amount of secondary amine I, were investigated. Notably,
ketones that contained simple functional groups (e.g., b-
ester and b-ketone groups, 3ao–ar) could also be successful-
ly employed in this reaction (Table 3), thus achieving similar
results to those that were obtained with their general ketone
counterparts (81–91% yield, 8–12 h; Table 3).
cloadducts in good-to-high yields (76–94%, 18–40 h;
Table 4). Pleasingly, substituted aldehydes 3ai’ and 3am’
also gave good yields (80% and 74% yield, respectively;
Table 4). Moreover, our catalytic reaction was also applica-
ble to functionalized aldehydes. Aldehydes that contained
an aromatic ring, a heteroatom, or alkenyl motifs (3aj’–ap’)
were tolerated under these conditions (51–81% yield;
Table 4).
To further illustrate the unique specificity of the catalysts
in this reaction, we conducted competition experiments. As
shown in Scheme 3, propionaldehyde (2a’) reacted with
ethyl diazoacetate (1a) much faster than 3-pentanone (2l)
in the presence of acyclic secondary diethyl amine IV as a
catalyst, thereby affording compound 3aa’ as the sole prod-
uct in 49% yield. On the contrary, propionaldehyde (2a’)
reacted with ethyl diazoacetate (1a) much more slowly than
3-pentanone (2l) in the presence of cyclic secondary amine I
as the catalyst, thus affording compound 3al as the sole
product in 55% yield (Scheme 4). Moreover, this reaction
was not only limited to ethyl di-
azoacetate; methyl and benzyl
diazoacetates (3bc’ and 3cc’)
Table 3. Substrate scope of the 1,3-dicarbonyl compounds.[a]
were similarly tolerated in the
cycloaddition reaction (96%
and 86% yield, respectively;
Table 4).
Having confirmed the broad
scope of carbonyl compounds
that could be tolerated in this
reaction, we sought to apply
this method to the synthesis of
[a] Reaction conditions: Compound 1a (0.2 mmol), compound 2o–r (0.4 mmol), DMSO (0.4 mL), catalyst I
(10 mol%), RT. [b] Diastereomeric ratio (d.r.) was determined by NMR spectroscopy to be >20:1 in all cases. GPR 109a-agonist 9[15] in only
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X. Gong, J. Wang et al.
Table 4. Substrate scope of the aldehydes.[a]
nal (2c’) with diethylamine
(IV). Enamine 4 acts as the
electron-rich olefinic partner
and reacts with deuterated
benzyl
diazoacetate
(1d)
through an inverse-electron-
demand 1,3-dipolar cycloaddi-
tion process to access inter-
mediate 5. Notably, this cyclo-
addition process demonstrates a
high regioselectivity, which can
lead to the direct introduction
of a diverse set of substituents
onto the pyrazole scaffold. In-
termediate 5 can be converted
into either intermediate 6 or 8
after tautomerization, triggered
by a 1,3-hydride shift, but it
seems unreasonable for the
generation of the product
(3dc’). A subsequent and selec-
À
tive C H1 bond-breaking may
induce the formation of the key
[a] Reaction conditions: Compound 1a–c (0.2 mmol), compound 2a’–q’ (1.0 mmol), DMSO (0.4 mL), catalyst
IV (20 mol%), RT. [b] 408C.
Scheme 3. Competition experiments. Reaction conditions: 1a (0.2 mmol),
2a’ (0.2 mmol), 2l’ (0.2 mmol), DMSO (0.4 mmol), Cat. (20 mol%),
room temperature, 12 h.
Scheme 4. A concise synthesis of GPR 109a-agonist 9.
Scheme 5. Postulated mechanism.
two steps (Scheme 4). First, ethyl diazoacetate (1a) was
treated with 2-pentanone (2v), followed by the addition of
catalyst I (10 mol%) to furnish intermediate pyrazole 3av in
75% yield (Scheme 4 and the Supporting Information). Sub-
sequent hydrolysis caused intermediate pyrazole 3av to be
converted into the target compound, GPR 109a-agonist 9, in
a moderate 53% yield (Scheme 4).
Our postulated reaction pathway is summarized in
Scheme 5. Although the reaction mechanism is unclear at
this stage, we believe that the sequence is triggered by the
generation of enamine 4 through the condensation of penta-
zwitterionic intermediate (7). To confirm our hypothesis of
À
a selective C H bond-breaking, we conducted a deuterium-
labeling experiment (Scheme 6).[16] The enamine-promoted
cycloaddition reaction with a-deuterated benzyl diazoace-
tate (1d) yielded compound 3dc’ without any deuterium in-
corporation onto the pyrazole ring, which supporting our
À
proposed selective breaking of the C H1 bond (Scheme 6).
À
We envision that the C H1 bond is activated by the adjacent
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Highly Regioselective Organocatalyzed Synthesis of Pyrazoles
FULL PAPER
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Scheme 6. Postulated mechanism.
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À
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step followed by tautomerization leads to the generation of
the final product (3dc’).
Conclusion
A general, organocatalytic, inverse-electron-demand [3+2]
cycloaddition reaction between a range of carbonyl com-
pounds and diazoacetates has been developed. This reaction
is catalyzed by secondary amines as a “green promoter” to
generate substituted pyrazoles with high levels of regioselec-
tivity. It is noteworthy that this [3+2] cycloaddition reaction
proceeds efficiently at room temperature with a simple and
inexpensive catalyst. Considering the large variety and
ready availability of the starting materials (e.g. ketones, b-
ketoesters, b-diketones, and aldehydes), as well as the op-
erational simplicity of this process, a convenient, practical,
and highly modular pyrazole synthesis has been developed.
We believe that this work will arouse more research interest
in the organocatalytic synthesis of other biologically active
heterocycles. Such studies are currently underway in this
laboratory.
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(2a, 0.4 mmol, 2.0 equiv), ethyl diazoacetate (1a, 0.2 mmol, 1.0 equiv),
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10:1 then 4:1) to afford the desired product (3aa, 32 mg, 87% yield) as a
pale-yellow oil. 1H NMR (500 MHz, CDCl3): d=4.35 (q, J=7.5 Hz, 2H),
2.74 (t, J=6.2 Hz, 2H), 2.68 (t, J=6.2 Hz, 2H), 1.80–1.74 (m, 4H),
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Acknowledgements
Financial support from the National University of Singapore and the
SingaACHTUNGTRENNUNGpore Ministry of Education (Grant Nos R14300480112 and
R143000443112) are greatly appreciated.
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[16] For the further details of the deuterium-labeling experiments, see
the Supporting Information.
Received: January 6, 2013
Revised: February 19, 2013
Published online: && &&, 0000
[14] CCDC-857248 (3aa) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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Highly Regioselective Organocatalyzed Synthesis of Pyrazoles
FULL PAPER
Organocatalysis
L. Wang, J. Huang, X. Gong,*
J. Wang* ....................... &&&& — &&&&
Highly Regioselective Organocata-
lyzed Synthesis of Pyrazoles from
Diazoacetates and Carbonyl
Compounds
Dipoles apart: In situ formed enamines
react with diazoacetates under mild
conditions to afford the corresponding
polysubstituted pyrazoles in good-to-
excellent yields through an inverse-
electron-demand 1,3-dipolar cycloaddi-
tion process (see scheme).
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!