NHC-catalyzed O-selective addition of nitrosoarenes with aldehydes

Article abstract of DOI:10.1021/ol4012458

An NHC-catalyzed O-selective addition of nitrosoarenes with aldehydes probably upon a dual-activation mode was developed, generating a variety of O-acyl hydroxylamines without any detectable competing amidation byproducts.

Full text of DOI:10.1021/ol4012458

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
NHC-Catalyzed O‑Selective Addition
of Nitrosoarenes with Aldehydes
Gang Wang,† Xia Chen,† Yi Zhang,†,‡ Weijun Yao,† and Cheng Ma*,†
Department of Chemistry, Zhejiang University, 20 Yugu Road, Hangzhou 310027,
China, and Zhejiang Tianyu Pharmaceutical Co., Ltd., Taizhou, China
mcorg@zju.edu.cn
Received May 4, 2013
ABSTRACT
An NHC-catalyzed O-selective addition of nitrosoarenes with aldehydes probably upon a dual-activation mode was developed, generating a
variety of O-acyl hydroxylamines without any detectable competing amidation byproducts.
Selective transformations of the same starting materials
into two or more different products simply by the choice
of catalyst provide an expedient approach to molecular
diversity synthesis.1 Nitroso compounds are versatile re-
agents utilized as a nitrogen and/or an oxygen source in
organicsynthesis.2 Duetotheir high reactivitybasedonthe
polarization of the NꢀO bond and specific structure by the
equilibration between the monomer and azodioxy dimer,
the control of chemo- and regioselectivity for various
catalytic reactions using nitroso derivatives is a challenge
of fundamental importance.3
N-Heterocyclic carbene (NHC) catalysis has developed
to a powerful tool for chemical synthesis during the past
decade.4 Notably, a variety of NHC-catalyzed reactions of
aldehydes with nitroso compounds, such as amidation,5
cycloaddition,6 and three-component reactions involving
enone components7 have been achieved primarily upon the
nucleophilic attack of Breslow intermediate I or II at the
nitrogen atom of nitroso groups (Scheme 1a).8 Moreover,
Lobo and Prabhakar have also studied a model reaction of
2-(R-hydroxyalkyl)-3,4-dimethylthiazoliums, a precursor
of I, with nitrosoarenes in the presence of base and find the
formation of a mixture of O- and N-acylhydroxylamine
products.9 Heretofore, the catalytic O-selective attack of
Breslow intermediate I on nitroso electrophiles to form
CꢀO bonds remains to be exploited. We envisaged that if
an appropriate Lewis acid/hydrogen-bonding donor could
† Zhejiang University.
‡ Zhejiang Tianyu Pharmaceutical Co., Ltd.
(1) For a recent review, see: Mahatthananchai, J.; Dumas, A. M.;
Bode, J. W. Angew. Chem., Int. Ed. 2012, 51, 10954.
(2) For reviews on nitroso compounds, see: (a) Zuman, P.; Shap, P.
Chem. Rev. 1994, 94, 1621. (b) Soghyuk, L.; Li, C.; Ann, H. W. Chem.
Rev. 2002, 102, 1019. (c) Yamamoto, H.; Momiyama, N. Chem. Com-
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2007, 80, 595. (e) Bodnar, B. S.; Miller, M. J. Angew. Chem., Int. Ed.
2011, 50, 5630.
(3) For reviews on the formation of R-aminooxy and/or R-hydro-
xyamino carbonyl compounds using nitroso electrophiles, see: (a)
Merino, P.; Tejero, T. Angew. Chem., Int. Ed. 2004, 43, 2995. (b) Janey,
J. M. Angew. Chem., Int. Ed. 2005, 44, 4292. (c) Plietker, B. Tetrahedron:
Asymmetry 2005, 16, 3453.
(5) (a) Corbett, M. D.; Corbett, B. R.; Doerge, D. R. J. Chem. Soc.,
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(7) Sun, Z.-X; Cheng, Y. Eur. J. Org. Chem. 2012, 4982.
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ꢀ
Chem. Rev. 2007, 107, 5606. (b) Marion, N.; Dıez-Gonzalez, S.; Nolan,
´
(8) (a) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719. (b) Burstein, C.;
Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205. (c) Sohn, S. S.; Rosen,
E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 14370.
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G.; Smith, A. D. Synthesis 2012, 44, 2295.
ꢀ
(9) Ferreira, L. M.; Marques, M. M. B.; Gloria, P. M.C.; Chaves,
H. T.; Franco, J-P. P.; Mourato, I.; Antunes, J-R. T.; Rzepa, H. S.;
Lobo, A. M.; Prabhakar, S. Tetrahedron 2008, 64, 7759 and references
therein.
r
10.1021/ol4012458
XXXX American Chemical Society

activate the nitrosoarene without disturbing the oxidative
NHC catalysis,10 the O-selective acylation of nitroso
groups would be achieved. Herein, we want to report an
NHC-catalyzed oxidative esterification of aldehydes11
with nitrosoarenes by using thiazolium carbene as a single
dual-activation catalyst12 to realize the selective formation
of O-acyl hydroxylamines (Scheme 1b).
Table 1. Optimization of Reaction Conditionsa
Scheme 1. NHC-Catalyzed Reaction of Aldehydes and
Nitrosoarenes
yieldb (%)
time
entry
C
base
solvent
(h)
3a
3a0
1
C1
C2
C3
C4
C1
C1
C1
C1
C1
C1
C1
K2CO3
K2CO3
K2CO3
K2CO3
t-BuOK
DBU
THF
6
86
53
45
ꢀ
ꢀ
ꢀ
12
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2
THF
6
3
THF
3
4
THF
12
0.5
12
12
12
6
5
THF
77
ꢀ
6
THF
7
Et3N
THF
ꢀ
We began our investigation by examining the reaction
between benzaldehyde (1a) and methyl 4-nitrosobenzoate
(2a) in the presence of K2CO3 and NHC precursors C
(Table 1, entries 1ꢀ4). After assessing four commonly
encountered NHC catalysts, we were delighted to find that
thiazolium salt C113 was the most effective in promoting
the desired CꢀO bond-forming process to furnish O-acyl
hydroxylamine 3a in 86% yield without any detectable
amount of amidation product 3a0.14 In contrast, triazolium
salt C3 gave a mixture of 3a (45%) and 3a0 (12%) as the
product (entry 3). When employing C1 as the precatalyst,
the base played a critical influence on this reaction. Switch-
ing the base to t-BuOK afforded 3a in a diminished yield due
to the decomposition of the product (Table 1, entry 5). In
contrast, when DBU or Et3N was used instead, no produc-
tive reaction was detected by TLC (entries 6 and 7). More-
over, a stoichiometric amount of K2CO3 with respect to 1a is
essential to accomplish this conversion (Table 1, entry 8).
Finally, among those solvents tested, THF was the choice,
as it led to the best result (Table 1, entries 1 and 9ꢀ11).
8c
9
K2CO3
K2CO3
K2CO3
K2CO3
THF
44 (40)d
51
Toluene
CH2Cl2
i-PrOH
10
11e
6
55
12
22
a Unless otherwise noted, a mixture of 1a (0.2 mmol), 2a (0.24 mmol),
catalyst C (10 mol %), K2CO3 (0.2 mmol), and solvent (2 mL) under N2
was stirred at 0 °C. b Isolated yield. c K2CO3 (0.1 mmol). d Recovery of 1a
is in parentheses. e Some unidentified byproducts were formed.
The reactions of a range of aldehydes 1 with nitroso
compound 2a were next examined. As shown in Figure 1,
a set of electron-deficient benzaldehyde derivatives with
various substitution patterns all carried out this reaction
smoothly to form the corresponding products 3bꢀf in
good yields. Picolinaldehyde also readily participated in
this process to give 3g in 91% yield. Unfortunately, those
targeted products derived from aromatic aldehydes bear-
ing an electron-donating group such as 4-methoxybenzal-
dehyde is too fragile under the current reaction conditions,
only furnishing some unidentified byproducts. Gratify-
ingly, aliphatic aldehydes, such as n-octanal and 2-bromo-
cyclopent-1-enecarbaldehyde, were found to be suitable
substrates, and the desired products 3h and 3i were
obtained in 56% and 49% yield, respectively. Finally, in
each case, the current NHC-catalyzed reaction affords
O-acyl products of methyl 4-nitrosobenzoate without any
detectable N-acyl products.
(10) For reviews on oxidative NHC catalysis, see: (a) Sarkar, S. De;
Biswas, A.; Samanta, R. C.; Studer, A. Chem.;Eur. J. 2013, 19, 4664.
(b) Knappke, C. E. I.; Imami, A.; Jacobi vonWangelin, A. ChemCatChem
2012, 4, 937.
(11) For a recent review on oxidative esterification, see: (a) Ekoue-
Kovi, K.; Wolf, C. Chem.;Eur. J. 2008, 14, 6302. For selected examples
upon NHC catalysis, see: (b) Noonan, C.; Baragwanath, L.; Connon,
S. J. Tetrahedron Lett. 2008, 49, 4003. (c) Maki, B. E.; Chan, A.; Phillips,
E. M.; Scheidt, K. A. Tetrahedron 2009, 65, 3102. (d) Rose, C. A.; Zeitler,
K. Org. Lett. 2010, 12, 4552. (e) Guin, J.; De Sarkar, S.; Grimme, S.;
Studer, A. Angew. Chem., Int. Ed. 2008, 47, 8727.
To further explore the scope and synthetic application
of the current NHC-catalyzed O-selective conversion of
(12) For a review on dual activation in NHC catalysis, see: (a) Biju,
A. T.; Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011, 44, 1182. For
pioneering studies on electron-neutral alkenes, see: (b) He, J.; Tang, S.;
Liu, J.; Su, Y.; Pan, X.; She, X. Tetrahedron 2008, 64, 8797. (c) Biju,
A. T.; Wurz, N. E.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 5970.
(13) Lebeuf, R.; Hirano, K.; Glorius, F. Org. Lett. 2008, 10, 4243.
(14) Compound 3a0 was synthesized according to ref 5c. For details
see the Supporting Information.
(15) For the application of N,O-diacyl-N-arylhydroxylamines, see:
(a) Sakurai, T.; Sukegawa, H.; Inoue, H. Bull. Chem. Soc. Jpn. 1985, 58,
2875. (b) Chowdhury, N.; Dutta, S.; Nishitha, B.; Dasgupta, S.; Singh,
N. D. P. Bioorg. Med. Chem. Lett. 2010, 20, 5414. (c) Donohoe, T. J.;
Callens, C. K. A.; Flores, A.; Mesch, S.; Poole, D. L.; Roslan, I. A.
Angew. Chem., Int. Ed. 2011, 50, 10957.
B
Org. Lett., Vol. XX, No. XX, XXXX

hand, while electron-poor or electron-neutral nitrosoarenes
carried out this reaction smoothly, those substrates with an
electron-rich aryl moiety did not work in the reaction.
In addition, isocyanatobenzene and Boc2O were also
suitable acylation reagents instead of acetic anhydride for
this one-pot protocol, giving the corresponding products 5
and 6 in 51% and 56% yield, respectively (eqs 1 and 2).
Figure 1. NHC-catalyzed formation ofO-acyl hydroxylamines3.
Scheme 2. Proposed Catalytic Cycle
Based on the experimental results, a proposed catalytic
cycle is depicted in Scheme 2. Thus, the addition of in situ
generated NHC to aldehydes1 followed by proton transfer
initially forms Breslow intermediates I. The latter nucleo-
philic species I then attack nitrosoarenes 2 at the oxygen
atom to give intermediates IV. The O-selective nature of
this step indicates a transition state of III, which involves a
potential hydrogen-bonding interaction between the posi-
tively polarized proton of the enaminol and the nitrogen
atom of the nitroso group.17 Finally, the zwitterions IV
release the NHC catalyst and give desired O-acyl hydro-
xylamines 3.
Figure 2. Formation of N,O-diacyl-N-arylhydroxylamines 4.
nitrosoarenes, we subsequently investigated a two-step,
one-pot approach to N,O-diacyl-N-arylhydroxylamines.15
Employing acetic anhydride (2 equiv) and DMAP (10 mol %)
as acylation reagents in the second amidation step,16 a set
of aldehydes and other three nitrosoarenes 2bꢀd were
generally well tolerated, giving the desired products 4 in
reasonably good yields (Figure 2). However, due to the
decomposition of corresponding O-acyl hydroxylamine
intermediates, furfural only furnished the targeted product
4d in quite low yield. Intriguingly, isophthalaldehyde had
also successfully been employed in this process to produce
the corresponding product 4j in 45% yield. On the other
In summary, we have described an NHC-catalyzed
O-selectiveaddition of nitrosoarenes with aldehydes, giving
a type of O-acyl hydroxylamines without any detectable
(17) Hydrogen-bonding interaction has been previously proposed for
the organocatalytic O-nitrosoaldol reaction; for selected references, see:
(a) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2003, 125, 10808. (b) Zhong, G. Angew. Chem., Int. Ed. 2003,
42, 4247. (c) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetra-
hedron Lett. 2003, 44, 8293. (d) Momiyama, N.; Torii, H.; Saito, S.;
Yamamoto, H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5374.
(16) For optimization of conditions see the Supporting Information.
Org. Lett., Vol. XX, No. XX, XXXX
C

competing amidation byproducts. Moreover, upon this
reaction, a one-pot approach to various N,O-diacyl-N-
arylhydroxylamines has been developed. It is proposed that
a dual-activation mode of the distinct carbene catalyst
generated from thiazolium salt C1 is critical to achieving
complete O-selectivities in the reaction.
of Ministry of Education, and the Zhejiang Provincial
Natural Science Foundation of China (No. R4110055) is
gratefully acknowledged.
Supporting Information Available. Experimental de-
tails and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support from NSFC (No.
21072166), New Century Excellent Talents in University
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX