N-heterocyclic carbene (NHC)-catalyzed direct amidation of aldehydes with nitroso compounds

Article abstract of DOI:10.1021/ol8004276

(Chemical Equation Presented) NHC-catalyzed direct amidation of aldehydes with nitroso compounds is a powerful method for the synthesis of N-arylhydroxamic acids. A variety of aryl, alkyl, alkenyl, and heterocyclic aldehydes were found to give excellent yields of the corresponding N-arylhydroxamic acids. This chemistry was also extended to the synthesis of chiral N-arylhydroxamic acids by kinetic resolution of α-branched aldehydes, a domino amidation-redox amination reaction of acrolein, and a three-component reaction for the synthesis of N-arylaziridines.

Full text of DOI:10.1021/ol8004276

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2333-2336
N-Heterocyclic Carbene (NHC)-Catalyzed
Direct Amidation of Aldehydes with
Nitroso Compounds
Fong Tian Wong, Pranab K. Patra, Jayasree Seayad,* Yugen Zhang,* and
Jackie Y. Ying
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos,
Singapore 138669, Singapore
ygzhang@ibn.a-star.edu.sg; jayasree@ibn.a-star.edu.sg
Received February 25, 2008
ABSTRACT
NHC-catalyzed direct amidation of aldehydes with nitroso compounds is a powerful method for the synthesis of N-arylhydroxamic acids. A
variety of aryl, alkyl, alkenyl, and heterocyclic aldehydes were found to give excellent yields of the corresponding N-arylhydroxamic acids.
This chemistry was also extended to the synthesis of chiral N-arylhydroxamic acids by kinetic resolution of r-branched aldehydes, a domino
amidation-redox amination reaction of acrolein, and a three-component reaction for the synthesis of N-arylaziridines.
N-Heterocyclic carbene (NHC) catalysis is an efficient
method for metal-free carbon-carbon bond formation via
the nucleophilic “Breslow intermediate”1 ii (Scheme 1) or
the homoenolate equivalent species.2 Depending on the
electrophiles, different types of reactions are possible via both
intermediates. Key examples for the former path are benzoin
condensation,3 wherein an aryl aldehyde acts as the elec-
trophile, and Stetter reaction,4 in which a Michael accepter
takes the role. More recent examples include redox reactions
of R-functionalized aldehydes to form the corresponding
esters5 or amides.6 Examples of C-C bond-forming reactions
using a homoenolate equivalent include lactonization,2
cyclopentannulation,7 azannulation,8 etc. We have recently
developed a NHC-catalyzed homoenolate intermediate based
C-N bond formation by the reaction of R,ꢀ-unsaturated
aldehydes with nitrosobenzene forming N-phenylisoxazoli-
din-5-ones.9 These N-phenylisoxazolidin-5-ones were further
converted to the corresponding N-p-methoxyphenyl (N-
PMP)-protected ꢀ-amino acid esters via a simple acid-
catalyzed Bamberger-like rearrangement in a mild one-pot
(2) (a) Burstein, C.; Tschan, S.; Xie, X.; Glorius, F. Synthesis 2006,
2418–2439. (b) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43,
6205–6208. (c) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006,
128, 8418–8419.
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1745.
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124, 10298–10299. (b) Kerr, M. S.; Rovis, T. Synlett 2003, 1934–1936.
(5) (a) Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126–
8127. (b) Reynolds, N. T.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc.
2004, 126, 9518–9519. (c) Reynold, N. T.; Rovis, T. J. Am. Chem. Soc.
2005, 127, 16406–16407. (d) Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7,
3873–3876. (e) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905–908. (f)
Zeitler, K. Org. Lett. 2006, 8, 637–640.
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13797. (b) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798–
13799.
(1) (a) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719–3726. (b) Zeitler,
K. Angew. Chem., Int. Ed. 2005, 44, 7506–7510. (c) Enders, D.; Balensiefer,
T. Acc. Chem. Res. 2004, 37, 534–541, and references therein. (d) Enders,
D.; Niemeier, O.; Henseler, A. Chem. ReV. 2007, 107, 5606–5655, and
references therein. (e) Marion, N.; D´ıez-Gonza´lez, S.; Nolan, S. P. Angew.
Chem., Int. Ed. 2007, 46, 2988–3000, and references therein.
(7) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E. J. Am. Chem. Soc.
2006, 128, 8736–8737.
(8) Sohn, S. S.; Rosen, E. L.; Bode, J. F. J. Am. Chem. Soc. 2004, 126,
14370–14371.
(9) Seayad, J.; Patra, P. K.; Zhang, Y.; Ying, J. Y. Org. Lett. 2008, 10,
953–956.
10.1021/ol8004276 CCC: $40.75
Published on Web 05/14/2008
2008 American Chemical Society

acids have appeared in the literature, mostly involving
acylation of hydroxylamines.17 Other known synthetic
pathways to N-arylhydroxamic acids involve oxidation of
arylacyl amides18 and reaction of aromatic nitroso com-
pounds with oxoacids in the presence of thiamine-dependent
enzymes19 or acidic media.20 Herein we report a very simple
and efficient synthesis of N-arylhydroxamic acids by NHC-
catalyzed amidation of aldehydes21 via acyl anion addition
to aryl nitroso compounds.
Scheme 1
.
Prosposed Amidation of Aldehydes Using
Nitrosobenzene
In our preliminary experiments, we found that benzalde-
hyde and nitrosobenzene reacted rapidly in the presence of
the NHC catalyst generated from the triazolium salt 422 and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), forming N-hy-
droxy-N-phenylbenzamide 3a in excellent yields. No forma-
tion of benzoin was observed under these conditions.
Optimization studies using different imidazolium and tria-
zolium salts indicated that sterically less hindered triazolium
salts provided higher yields of the product (Table 1). The
synthetic protocol. In another recent study, Chan and Scheidt
reported the NHC-catalyzed amination of homoenolates using
diazenes.10
Table 1. Catalyst Optimization
Nitroso compounds exhibit a high reactivity of the nitroso
group.11 The polarization of the nitrogen-oxygen bond,
resembling that of the carbon-oxygen bond in a carbonyl
group, results in susceptibility of the nitroso group to
additions of nucleophiles. By exploiting the higher reactivity
of the nitroso group relative to its carbonyl counterpart
toward nucleophilic attack, we envisaged a possibility that
involved reaction of the intermediate ii with nitrosobenzene-
forming hydroxamic acid instead of acyloin.
The chemistry and biochemistry of hydroxamic acids are
well documented. They are strong metal ion chelators12 and
possess extensive pharmacological, toxicological, and patho-
logical properties.13 Some of them are being examined in
human clinical trials as drugs for the treatment of several
diseases.14 N-Arylhydroxamic acids15 are also known to be
proximate carcinogens16 and demand simple synthetic pro-
tocols. Recently, many synthetic approaches to hydroxamic
entry
catalyst (mol %)
solvent
base
yield (%)a
1
2
3
4
5
6
7
8
9
4 (20)
5 (20)
6a (20)
6b (20)
6c (20)
4 (20)
4 (20)
4 (0.5)
4 (5)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH2Cl2
CH2Cl2
CH2Cl2
DBUb
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
DBU
99
50
trace
55
trace
95
85
99
99
0
(10) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 2740–2741.
(11) (a) Yamamoto, H.; Momiyama, N. Chem. Commun. 2005, 3514–
3525. (b) Zuman, P.; Shah, B. Chem. ReV. 1994, 94, 1621–1641.
(12) (a) Boukhris, S.; Souizi, A.; Robert, A. Tetrahedron Lett. 1996,
37, 179–182. (b) Jung, M. Curr. Med. Chem. 2001, 8, 1505. (c) Armour,
C. A.; Ryan, D. E. Can. J. Chem. 1957, 35, 1454–1460. (d) Chatterjee, B.
Coord. Chem. ReV. 1978, 26, 281–303.
DBU
DBU
10
none
a GC yield. b DBU ) 1,8-diazabicyclo[5.4.0]undec-7-ene.
(13) Maehr, H. Pure Appl. Chem. 1971, 28, 603–636.
only observable side product was traces of azoxybenzene,
which was minimized by optimizing the reaction parameters.
The scope of the reaction was examined by varying the
aldehydes (1a-1q), as well as the nitroso compounds (2a,
2r-2u). As shown in Table 2, a variety of aryl, alkyl,
alkenyl, and heterocyclic aldehydes gave excellent yields
(55-99%) of the corresponding N-arylhydroxamic acids
(3a-3u).
We have also scaled up the synthesis of N-hydroxy-4-
nitro-N-phenylbenzamide, 3c, to a 5 g scale using 0.125 mol
% of catalyst 4. The reaction was rapidly completed within
2 min, resulting in a turnover frequency (TOF) of 24 000
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1984, 25, 97–98. (h) Pokrovskaya, I. E.; Starikova, Z. A.; Eliseeva, L. N.;
Ryabokobylko, Yu. S.; Zhadanov, B. V.; Obodovskaya, A. E.; Olikova,
V. A. Zh. Obsh. Khim. 1990, 60, 2597–2604. (i) Jain, R. K.; Agrawal, Y. K.
J. Chem. Eng. Data 1979, 24, 250–251. (j) Ayyangar, N. R.; Brahme, K. C.;
Kalkote, U. R.; Srinivasan, K. V. Synthesis 1984, 938–941.
2334
Org. Lett., Vol. 10, No. 12, 2008

reacted with the hydroxamate nucleophile (3q) forming the
product 7 and carbene catalyst (Scheme 2).
Table 2. NHC-Catalyzed Synthesis of N-Arylhydroxamic Acids
Scheme 2
.
Prosposed Domino Amidation-Redox Amination of
Acrolein with Nitrosobenzene
yield
entry
R
R1
(%)a
1
2
3
4
5
6
7
8
9
C6H5 (a)
C6H5 (a)
C6H5
C6H5
96
99
99
95
98
89
78
97
99
99
95
96
87
99
80
99
99
93
4-OMeC6H4 (b)
4-NO2C6H4 (c)
4-BrC6H4 (d)
C6H5
1-methyl-1H-imidazol-2- (e) C6H5
C6H5CH(CH3) (f)
C6H5CH2CH2 (g)
C6H11 (h)
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C3H5 (i)
10 n-C4H9 (j)
11 C6H5CHdCH (k)
12 C6H5CHdC(CH3) (l)
13 4-OMeC6H4CHdCH (m)
14 4-NO2C6H4CHdCH (n)
15 3-OMe-4-OTfC6H3CHdCH (o) C6H5
16 EtOOC-CHdCH (p)
17 CH2dCH (q)
18 C6H5
C6H5
C6H5
4-(Me)2NC6H4 (r)
19 C6H5
3,5-Me-4-(OH)C6H2 (s) 55
20 C6H5
21 C6H5
2,6-F2C6H3 (t)
2-MeC6H4 (u)
82
77
a Isolated yields.
A preliminary study on the synthesis of chiral N-arylhy-
droxamic acids23 by kinetic resolution of the R-branched
aldehyde 1f by reaction with nitrosobenzene in the presence
of NHC catalyst derived from the chiral triazolium salt 824
resulted in 48% yield and 68% ee of the product (S)-3f
(Scheme 3).
h-1. The product precipitated as a yellow solid after the
reaction and was obtained by filtration in excellent yields
and purity (Figure 1).
Scheme 3. NHC-Catalyzed Synthesis of Chiral
N-Arylhydroxamic Acids by Kinetic Resolution of R-Branched
Aldehydes
Figure 1. NHC-catalyzed synthesis of N-hydroxy-4-nitro-N-phenyl
benzamide (3c). Scale up of 5 g product (a) before activation of
the catalyst (4, 0.125 mol %), and (b) after reaction completion (in
2 min).
In the case of acrolein (1q), when used in excess to
nitrosobenzene (3 equiv), a novel domino amidation-redox
amination reaction took place, forming the corresponding
N-propionyloxy-N-phenylacrylamide (7) as the major product
(75%).
The applicability of this methodology was also extended
to a three-component, one-step synthesis of N-arylaziridines
by reaction of the aldehyde, nitroso compound, and a Michael
acceptor. The reaction between hydroxamic acids and acrolyl
Here, two catalytic cycles seemed to operate, one forming
the N-arylhydroxamic acid by the reaction of the d1 nucleophile
with the nitroso compound and the second through protonation
of the d3 nucleophile forming the activated ester vii, which then
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Org. Lett., Vol. 10, No. 12, 2008
2335

derivatives forming N-arylaziridines has been reported previ-
ously.25 In our studies, we found that benzaldehyde, ni-
trosobenzene, and acrolyl derivatives 9a-9e reacted in the
presence of the NHC catalyst generated from the triazolium
salt 4 and NaH, forming the corresponding N-arylaziridines
10a-10e in high yields (Table 3).
Table 3. NHC-Catalyzed Three-Component Synthesis of
N-Arylaziridines
In conclusion, we have developed a powerful NHC-
catalyzed amidation of aldehydes with nitroso compounds
to form a variety of N-arylhydroxamic acids. The reaction
can be carried out with catalyst concentration as low as 0.125
mol %. The applicability of the protocol is extended to the
synthesis of chiral N-arylhydroxamic acids by kinetic resolu-
entry
R
R1
yield (%)a
1
2
3
4
5
COOMe (a)
COOtBu (b)
CN (c)
COOMe (d)
COOMe (e)
H
H
H
Me
82
87
71
67
69
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CH2COOMe
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Trans. 1 1979, 2481–2487.
a Isolated yields.
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769.
tion of R-branched aldehydes, a domino amidation-redox
amination reaction of acrolein, and a three-component
synthesis of N-arylaziridines. Further optimization of the
enantioselective variant and elaboration of the scope of the
reaction is underway.
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Acknowledgment. This work was funded by the Institute
of Bioengineering and Nanotechnology (Biomedical Re-
search Council, Agency for Science, Technology and Re-
search, Singapore).
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Supporting Information Available: Experimental pro-
cedures, compound characterization, NMR spectra, HPLC
traces, X-ray crystallography data. This material is available
free of charge via the Internet at http://pubs.acs.org.
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