Divergent syntheses of 2-aminonicotinonitriles and pyrazolines by copper-catalyzed cyclization of oxime ester

Article abstract of DOI:10.1021/ol500094w

Copper-catalyzed cyclization of an oxime ester toward divergent heterocycle synthesis is reported. Oxime ester serves as an enamine precursor to cyclize with malononitrile and aldehydes for access to 2-aminonicotinonitriles in a one-pot reaction, while cyclizing with N-sulfonylimines leads to synthesis of pyrazolines.

Full text of DOI:10.1021/ol500094w

Letter
pubs.acs.org/OrgLett
Divergent Syntheses of 2‑Aminonicotinonitriles and Pyrazolines by
Copper-Catalyzed Cyclization of Oxime Ester
Qifan Wu, Yan Zhang, and Sunliang Cui*
Institute of Materia Medica and College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058,
P. R. China
S
* Supporting Information
ABSTRACT: Copper-catalyzed cyclization of an oxime ester
toward divergent heterocycle synthesis is reported. Oxime
ester serves as an enamine precursor to cyclize with
malononitrile and aldehydes for access to 2-aminonicotinoni-
triles in a one-pot reaction, while cyclizing with N-
sulfonylimines leads to synthesis of pyrazolines.
Scheme 1
ivergent synthesis allows the rapid entry to structurally
Ddiverse compounds from the same starting material and
therefore has been a popular and useful tool in the discovery of
bioactive molecules and functional materials.1 The success of
divergent synthesis requires precise control of the chemo- and
regioselectivity and a careful selection of the reaction
conditions, guided by an understanding of the reactivity of
intermediates and substrates.2 So far, transition-metal-catalyzed
cyclization has emerged as a powerful and distinct approach in
the divergent synthesis of nitrogen-containing heterocycles.3
Recently, copper-catalyzed cyclization of oxime esters for
heterocycle synthesis has been developed.4 For example,
Yoshikai reported pioneering work on the modular synthesis
of pyridines using oxime esters and enals through synergistic
copper/iminium catalysis (Scheme 1).5 Jiang reported excellent
work on the synthesis of pyrroles and imidazo[1,2-a]pyridines
by copper-catalyzed cyclization of oxime esters with alkynes
and pyridines (Scheme 1), respectively.6 In those cases, the
copper(I) catalyst presumably plays a role in reducing the
oxime N−O bond to be an iminyl radical, which is further
reduced by another copper(I) to an iminyl copper(II) which
tautomerizes to the nucleophilic copper(II) enamide.2−4
Therefore, oxime esters serve as enamine precursors in the
presence of copper catalysts and definitely serve as an
inspiration in heterocycle synthesis.
In the course of our research on metal-catalyzed cyclization
for access to heterocyles,7 we found that N−O bond cleavage
would occur for O-pivaloyl hydroxylamine in the presence of a
transition metal7a,b under conditions that were compatible with
those in copper-catalyzed cyclization of oxime esters.
Consequently, we envisioned that O-pivaloyl oxime esters
would exhibit dramatically active reactivity under copper
catalysis and give rise to enamine species. We also envisioned
that further cyclization with electrophilic 2-benzylidenemaloni-
trile and N-sulfonylimine would deliver interesting heterocycles.
Herein, we report divergent syntheses of 2-aminonicotinoni-
triles and pyrazolines via copper-catalyzed cyclization of oxime
esters (Scheme 1).
We initially commenced our study by investigating the
multicomponent reaction of O-pivaloyl acetophenone oxime
1a, benzaldehyde 2a, and malonitrile 3, since 2-benzylidene-
malonitrile could easily be formed from benzaldehyde and
malonitrile in one-pot.8 To our delight, the reaction delivered
Received: January 11, 2014
Published: February 26, 2014
© 2014 American Chemical Society
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Letter
a
the desired 2-aminonicotinonitrile product 4a in 25% yield
when CuCl was used as a catalyst (Table 1, entry 1). A
Scheme 2. Synthesis of 2-Aminonicotinonitriles
a
Table 1. Reaction Condition Optimization.
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), 3 (0.4 mmol),
b
additive, solvent (2 mL), argon, 6−8 h. Yields of isolated products.
screening of Cu(I) catalysts showed that CuI was optimal
(Table 1, entries 2 and 3). Interestingly, the addition of
piperidine dramatically increased the yield to 69% (Table 1,
entry 4), and a survey of solvents revealed that CH3CN and
DMSO were inferior (Table 1, entries 5 and 6), while
increasing the temperature to 80 °C led to a slightly lower
yield (Table 1, entry 7).
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), 3 (0.4 mmol), CuI
(20 mol %), piperidine (20 mol %), DCE (2 mL), argon, 6−8 h.
With the data in hand, we next investigated the scope of this
reaction involving various oxime esters and aldehydes. As
shown in Scheme 2, various benzaldehydes, regardless of the
electron-donating or electron-withdrawing group on the
aromatic ring, were broadly tolerated, giving the products in
moderate-to-good yield (4b−j, 45−79%). Valuable functional
groups such as methyl, methoxy, trifluoromethyl, cyano, bromo,
and chloro were also present in the products. Heterocyclic
aldehydes like furan-2-aldehyde, thiophene-3-aldehyde, and
pyridine-3-aldehyde also performed well in this transformation
to produce the products in good yield (4k−m, 62−77%).
Variation of the oxime esters, with differential substitution on
the aromatic ring, showed that they reacted smoothly to afford
the 2-aminonicotinonitriles in moderate yield (4n−p, 44−
56%), while heterocyclic oxime esters with furan, thiophene,
and indole skeletons also were applicable in this transformation,
affording the products in moderate yield (4q−s, 43−68%).
Interestingly, when polysubstituted oxime esters including a
cyclic scaffold were used, this transformation proceeded
smoothly to generate polycyclic products in moderate-to-
good yield (4t−z, 43−76%). 2-Aminonicotinonitriles are
important components of pharmaceuticals, with antifungal,9
A2A adenosine receptor antagonist10 and prion protein
inhibitory activity.11 The classical synthesis of 2-amino
nicotinonitriles relies on amination of 2-unsubstituted pyridines
with sodium amide (Chichibabin reaction), which suffers from
the limitation of low yield and narrow scope.12,13 Therefore,
this method represents an expedient approach toward the
construction of 2-aminonicotinonitriles.
Since oxime esters successfully acted as enamine precursors,
we next established the copper-catalyzed cyclization scope of
oxime esters with N-sulfonylimines to gain access to N-
sulfonylpyrazolines, through integration of enamine formation
and oxidative cyclization.14−16 By changing the reaction
conditions, using 2 equiv of CuCl and 20 mol % Cu(OAc)2
as additives, the reaction of oxime esters and N-sulfonylimines
performed in DMSO at 100 °C could deliver the N-
sulfonylpyrazoline product 6 successfully (for detailed reaction
optimization, see the Supporting Information). As depicted in
Scheme 3, various N-sulfonylimines, regardless of electron-
donating or electron-withdrawing groups on the aromatic ring,
were applicable in this cyclization generating N-sulfonylpyrazo-
line products in moderate-to-excellent yield (6a−e, 42−97%),
with functional groups like methyl, methoxy, chloro, and nitro.
The naphthyl- and dihydrocinnamyl-tethered N-sulfonylimines
also performed well in this transformation producing the
corresponding products in moderate-to-good yield (6f,g, 46−
78%). Variation of the oxime esters showed that differential
substitution on the aromatic ring of the oxime ester proceeded
well to produce the products in moderate-to-good yield (6h−l,
53−82%). Interestingly, when the saccharin-derived cyclic N-
sulfonylimine was used, this cyclization produced the fused
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a
lonitrile B to give C. Then an intramolecular addition takes
place to form D, and a further oxidation of D with copper(II)
furnishes E and regenerates the copper(I). Lastly, the
isomerization of E leads to aromatic 2-aminonicotinonitrile 4.
With respect to N-sulfonylpyrazoline formation, copper(II)
enamide A undergoes Michael addition to the activated N-
sulfonylimine 5 to form F, which is converted to the copper−
chelate complex G. The following oxidative cyclization of G
under air provides the N-sulfonyl pyrazoline 6.15,16 This
cyclization excludes the regeneration of copper(I) and therefore
demands the stoichiometric use of CuCl.
Scheme 3. Synthesis of N-Sulfonylpyrazolines
In conclusion, we have documented the divergent syntheses
of 2-amino nicotinonitriles and pyrazolines via the copper-
catalyzed cyclization of oxime esters. Our results disclose that
pivaloyl oxime esters convert to copper enamides in the
presence of copper(I), which can undergo either Michael
addition to 2-benzylidenemalonitrile or oxidative cyclization
with N-sulfonylimines. Further studies and extensions of this
protocol are in progress.
ASSOCIATED CONTENT
* Supporting Information
■
S
a
Reaction conditions: 1 (0.2 mmol), 5 (0.4 mmol), CuCl (0.4 mmol),
Experimental procedures, and spectral data for products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Cu(OAc)2 (20 mol %), DMSO (2 mL), under air for 8 h.
pyrazoline product 6m in 54% yield. The scope was also
extended to heterocyclic oxime esters, thus providing access to
functionalized pyrazolines (6n and 6o). N-Sulfonylpyrazolines
represent a core structure in many biologically active
compounds, with progesterone receptor antagonist,17 anti-
microbial agent,18 and monoamine oxidase inhibitory activ-
ities.19 Therefore, this method provides a simple and expedient
approach for the straightforward assembly of these compounds.
Based on these results and literature precedents, a plausible
mechanism for this cyclization toward divergent heterocycles is
proposed in Scheme 4. For 2-aminonicotinonitrile synthesis,
the pivaloyl oxime ester 1 is converted to a copper(II) enamide
A, in the presence of copper(I) catalyst. Michael addition then
occurs between A and the in situ generated 2-benzylidenema-
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: slcui@zju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21202143), the Fundamental Research
Funds for the Central Universities (2013QNA7014), and
Zhejiang University.
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