An unexpected N-heterocyclic carbene-catalyzed annulation of enals and nitroso compounds

Full text of DOI:10.1021/jo802515g

of d1-nucleophiles. Addition reactions involving this kind of acyl
anions are called a1-d1 Umpolung which can be found in benzoin
condensation6 and the Stetter reaction.7
An Unexpected N-Heterocyclic
Carbene-Catalyzed Annulation of Enals and
Nitroso Compounds†
In contrast to the a1-d1 Umpolung, the NHC-catalytic Um-
polung of R,ꢀ-unsaturated aldehydes generates d3-nucleophiles
which show homoenolate reactivity, and thus constitute an a3-
d3 Umpolung. The first applications of the homoenolate
intermediate involving the formation of γ-butyrolactones by the
reaction of enals and aldehydes were reported by Glorius and
Bode simultaneously.8 Employing a similar strategy, Bode
described NHC-catalyzed γ-lactam formation via direct annu-
lation of enals and imine.9 Scheidt disclosed the NHC-catalyzed
amination of the d3-nucleophiles with diazene to afford pyra-
zolidinones as a single regioisomer.10 The formal [3+3]
homoenolate cycloaddition with 1,3-dipoles such as azomethine
imine and nitrone delivering bicyclic pyridazinone products and
γ-amino ester derivatives respectively was also reported by
Scheidt.11 Ying reported the NHC-catalytic reaction of direct
amidation of aldehyde with nitroso compounds for the synthesis
of N-arylhydroxamic acids. They also reported NHC-catalyzed
addition of R,ꢀ-unsaturated aldehydes to nitrosobenzene fol-
lowed by an acid-catalyzed esterification of the intermediate
Limin Yang, Bin Tan, Fei Wang, and Guofu Zhong*
DiVision of Chemistry and Biological Chemistry, School of
Physical & Mathematical Sciences, Nanyang Technological
UniVersity, Singapore 637371, Singapore
guofu@ntu.edu.sg
ReceiVed NoVember 11, 2008
The N-heterocyclic carbene (NHC)-catalyzed annulation of
enals with nitroso compounds in the presence of DBU in
THF has been described. Unexpected seven-membered
4-azalactones were formed according to a process involving
a 1,2-Bamberger-type rearrangement.
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The carbon-nitrogen bond-forming reactions play an out-
standing role in chemical transformations.1 To date, the
discovery of new catalytic methods for carbon-nitrogen bond
formation still remains a challenge in the continuing develop-
ment of efficient, sustainable chemical processes. In the past
decade, the inversion of the classical reactivity (Umpolung) has
provided unusual synthetic avenues for target molecules.2
N-Heterocyclic carbenes (NHCs), due to their unique electronic
characteristics, not only promote development of new organo-
metallic processes,3 but also act as Umpolung catalysts in
organocatalytic reactions,4 and as reagents in multicomponent
coupling reactions.5 The polarity reversal of carbonyl units
generates carbonyl or acyl anions which represent a useful class
† Dedicated to Professor Dr. Richard A. Lerner on the occasion of his 70th
birthday.
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Xia, C. G. Eur. J. Org. Chem. 2005, 633. (d) Beller, M.; Seayad, J.; Tillack, A.;
Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368. (e) Hultzsch, K. C. AdV. Synth.
Catal. 2005, 347, 367. (f) Ma, J.-A. Angew. Chem., Int. Ed. 2003, 42, 4290. (g)
Magriotis, P. A. Angew. Chem., Int. Ed. 2001, 40, 4377. (h) Khramov, D. M.;
Bielawski, C. W. Chem. Commun. 2005, 39, 4958. (i) Khramov, D. M.;
Bielawski, C. W. J. Org. Chem. 2007, 72, 9407.
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P.; Lingen, B.; Baumann, M.; Pohl, M.; Muller, M. J. Am. Chem. Soc. 2002,
124, 12084. (b) Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326. (c) Gong,
J. H.; Im, Y. J.; Lee, K. Y.; Kim, J. N. Tetrahedron Lett. 2002, 43, 1247. (d)
Lapworth, A. J. Chem. Soc. 1903, 83, 995. (e) Breslow, R.; Kim, R. Tetrahedron
Lett. 1994, 35, 699. (f) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407. (g)
Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743.
(10) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 2740.
(11) (a) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 5334. (b)
Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2008, 130,
2416.
1744 J. Org. Chem. 2009, 74, 1744–1746
10.1021/jo802515g CCC: $40.75 2009 American Chemical Society
Published on Web 01/26/2009

TABLE 1. Optimization of Annulation of Enal 1a and
4-Nitrosotoluene 2ca
TABLE 2. NHC-Catalytic Annulation of Enal 1a and Nitroso
Compoundsa
entry
catalyst
solvent
base
yieldb (%)
1
2
3
4
5
6
7
8
I
II
THF
THF
THF
THF
DCM
DCM
THF
toluene
Et2O
THF
THF
DBU
DBU
DBU
DBU
t-BuOK
DBU
t-BuOK
DBU
DBU
DBU
DBU
NDc
ND
30
68
56
42
51
53
55
III
IV
IV
IV
IV
IV
IV
IV
IV
9
10d
11e
42
41
a Unless other specified, all of the reactions were carried out with 1a
(0.15 mmol, 1.5 equiv) and 2c (0.10 mmol, 1.0 equiv) in the presence of
20 mol % of catalyst and base in solvent (0.5 mL) at -5 °C. b Isolated
yields. c Not detected. d At room temperature (23 °C). e The ratio of 1a
and 2c is 1.0:1.1.
a Unless otherwise specified, all of the reactions were carried out with
1a (0.15 mmol, 1.5 equiv) and 2 (0.10 mmol, 1.0 equiv) in the presence
of 20 mol % of catalyst and base in solvent (0.5 mL) at -5 °C.
b Isolated yields.
leading to the N-PMP protected ꢀ-amino acid esters via 1,4-
Bamberger-type rearrangement.12
Herein we report a NHC-catalyzed annulation of enals and
4-nitrosotoluene to afford unexpected seven-membered 4-aza-
lactone derivatives by way of the intramolecular 1,2-Bamberger-
type rearrangement.
was used (Table 2, entry 3). Annulation of 4-bromocinnamal-
dehyde with nitrosobenzene (2a) and 2-nitrosotoluene (2b)
afforded the corresponding seven-membered 4-azalactones 3aa
and 3ab in yields of 53% and 48%, respectively (Table 2, entries
1 and 2) and the X-ray crystal structure of 3ab was shown in
the Supporting Information. The more electron donating sub-
stituted nitroso compounds, for example, 4-methoxylnitrosoben-
zene, cannot proceed with reaction and just the starting enal
was recovered due to the rapid formation of azoxy(methoxy-
benzene). The electron withdrawing substituted nitroso com-
pounds such as 4-chloronitrosobenzene cannot give any of the
product due to their poor reactivity.
Our studies began with an initial experiment of 4-bromocin-
namaldehyde (1a) and 4-nitrosotoluene (2c) catalyzed by a NHC
catalyst generated from imidazolium salts III. To our surprise,
an unexpected seven-membered 4-azalactone 3a was isolated.
We then investigated the NHC-catalyzed enal-nitroso annulation
by using different imidazolium and thiazolium salts. Thiazolium
catalyst I did not afford the desired product; only trace amounts
of undesired direct amidation products and azoxytoluene were
observed (Table 1, entry 1). While bisalkyl imidazolium salts
II proved to be unreactive (Table 1, entry 2), the N-heterocyclic
carbenes generated in situ from bisarylimidazolium salts IV
exhibited high catalytic activity toward 4-azalactone formation
(Table 1, entry 4). And we were very pleased to find that the
benzoin condensation, Stetter reaction, and homo addition of
aldehyde to the Umpoled enal were sufficiently suppressed due
to the high reactivity of the nitroso compounds.
Hence, we chose IV as the most promising catalyst to
optimize the conditions. Further optimization of the reaction
conditions revealed that the reaction temperature and ratio of
reactants played critical roles in the reaction. Optimized reaction
conditions were found when 1.5 equiv of 4-bromocinnamalde-
hyde (1a) and nitrosobenzene were added to catalyst IV and
DBU at -5 °C in 0.2 M THF. This gave 3a in 68% yield.
Under the optimized reaction conditions, we investigated the
reaction of other nitroso compounds such as nitrosobenzene (2a)
and 2-nitrosotoluene (2b). Our results are summarized in Table
2. The best yield (68%) was obtained when 4-nitrosotoluene
Annulation of 4-bromocinnamaldehyde with nitrosobenzene
(2a) and 2-nitrosotoluene (2b) afforded the corresponding seven-
membered cyclic 4-azalactones 3aa and 3ab in yields of 53%
and 48%, respectively (Table 2, entries 1 and 2).
It was observed that a variety of functionalized R,ꢀ-
unsaturated aldehydes and 4-nitrosotoluene gave the respective
substituted 4-azalactones in moderate to good yields under our
reaction conditions. It was discovered that enal substrates with
an electron-withdrawing substituent on the aromatic ring provide
better results. Highest yield was obtained with 4-nitrocinnama-
ldehyde (Table 3, entry 7). It appeared that the position of the
substituents on the aromatic rings also has an effect on the result
(Table 3, entries 1, 4, and 5). We noticed that para-substituted
R,ꢀ-unsaturated aldehydes gave higher yields than ortho- or
meta-substituted R,ꢀ-unsaturated aldehydes. For example, 2-bro-
mocinnamaldehyde gave a lower yield. Even the naphthyl,
hetero aryl groups also participated in this process to give the
expected products in good yields (Table 3, entries 9-11).
(13) (a) Bamberger, E. Chem. Ber. 1894, 27, 1548. (b) Stahl, M. A.; Kenesky,
B. F.; Berbee, R. P. M.; Richards, M.; Heine, H. W. J. Org. Chem. 1980, 45,
1197. (c) Ratnam, K. J.; Reddy, R. S.; Sekhar, N. S.; Kantam, M. L.; Deshpande,
A.; Figueras, F. Appl. Catal. A 2008, 348, 26.
(12) (a) Seayad, J.; Patra, P. K.; Zhang, Y.; Ying, J. Y. Org. Lett. 2008, 10,
953. (b) Wong, F. T.; Patra, P. K.; Seayad, J.; Zhang, Y.; Ying, J. Y. Org. Lett.
2008, 10, 2333.
J. Org. Chem. Vol. 74, No. 4, 2009 1745

TABLE 3. NHC-Catalytic Annulation of Enals and
4-Nitrosotoluenea
isoxazolidinone 9. Isoxazolidinone 9 then undergoes 1,2-
Bamberger-type rearrangement to its presumably more stable
form 3 instead of the 1,4-Bamberger rearrangement reported
by Ying.12a,13 This could be ascribed to the blocking of the
4-position on the nitroso compound, the steric hindrance for
the oxygen atom to attack 4-position, and the instability of the
corresponding 1,4-Bamberger-type rearrangement product. Thus,
the carboxylate nucleophile prefers to attack the 2-position of
the imino quinone intermediate 11 during the Bamberger-type
rearrangement. The carboxyl oxygen atom attacks the 2-position
of the phenyl ring affording the very reactive intermediate 12,
which is followed by the tautomerization to the desired product
3. The mechanism also provides a possible explanation to the
failure of annulation reaction involving electron withdrawing
substitutents on nitroso compounds such as 4-chloronitrosoben-
zene: the positive charge may not be efficiently stabilized by
the electron withdrawing group and the absence of stabilizing
group of nitrosobenzene results in a lower yield to the
1,2-Bamberger-type rearrangement product.
In summary, we have developed a concise annulation of enals
and 4-nitrosotoluene catalyzed by N-heterocyclic carbene af-
fording the unexpected seven-membered 4-azalactones in mod-
erate to high yields (up to 81%) and electron-withdrawing
substituents on the aromatic ring of R,ꢀ-unsaturated aldehydes
favor the annulation reaction. The mechanism involves a 1,2-
Bamberger-type rearrangement to the unexpected outcome.
N-Heterocyclic carbenes as organocatalysts represent a mine
for new discoveries in preparative chemistry.
entry
Ar
3
yield (%)b
1
2
3
4
5
6
4-BrC6H4
4-ClC6H4
4-FC6H4
3a
3b
3c
3d
3e
3f
3g
3h
3i
68
69
66
58
50
76
81
71
60
65
64
55
45
3-BrC6H4
2-BrC6H4
4-CF3C6H4
4- O2NC6H4
2- O2NC6H4
1-naphthyl
2-thienyl
2-furyl
7
8c
9
10
11
12
13
3j
3k
3l
C6H5
4-CH3C6H4
3m
a All of the reactions were carried out with 1a (0.15 mmol, 1.5 equiv)
and 2 (0.10 mmol, 1.0 equiv) in the presence of 20 mol % of III and
DBU at -5 °C in THF (0.5 mL). b Isolated yields. c The reaction was
carried out in 0.1 M THF.
SCHEME 1. Proposed Mechanism
Experimental Section
4-(4-Bromophenyl)-4,5-dihydro-8-methylbenzo[b][1,4]oxazepin-
2(3H)-one (3a). To a solution of 1,3-bis(2,6-diisopropylphenyl)imi-
dazolium chloride (IV, 8.5 mg, 0.02 mmol, 0.2 equiv) in THF (0.5
mL) was added DBU (3 µL, 0.02 mmol, 0.2 equiv). After the
mixture was stirred for 5 min, (E)-3-(4-bromophenyl)acrylaldehyde
(1a, 0.15 mmol, 1.5 equiv) and 4-nitrosotoluene (2c, 0.1 mmol,
1.0 equiv) were added. The mixture was then stirred at -5 °C.
After the reaction was complete, the purification by flashed column
chromatography on neutral aluminum oxide (eluent: n-hexane/ethyl
acetate ) 10:1) afforded the seven-membered 4-azalactone product
(3a, 68% yield): white solid (mp 120-122 °C). 1H NMR (400 MHz,
CDCl3) δ 7.49 (d, J ) 8.4 Hz, 2H), 7.25 (d, J ) 8.7 Hz, 2H), 6.95
(s, 1H), 6.93 (d, J ) 8.0 Hz, 1H), 6.78 (d, J ) 7.6 Hz, 1H), 4.93
(t, J ) 6.4 Hz, 1H), 3.41 (br, 1H), 2.94 (dd, J ) 6.2 Hz, J ) 12.7
Hz, 1H), 2.81 (dd, J ) 6.7 Hz, J ) 12.7 Hz, 1H), 2.33 (s, 3H). 13
C
NMR (100 MHz, CDCl3) δ 168.6 (Cq, CO), 145.0 (Cq), 141.8
(Cq), 134.2 (Cq), 132.6 (Cq), 132.2 (CH), 127.9 (CH), 126.9 (CH),
122.8 (CH), 122.4 (Cq), 120.9 (CH), 62.9 (CH), 39.1 (CH2), 20.8
(CH3). HRMS (ESI) calcd for C16H1479BrNO2 + H, m/z 332.0286,
found 332.0278.
Acknowledgment. Research support from the Ministry of
Education in Singapore (ARC12/07, No. T206B3225) and
Nanyang Technological University (URC, RG53/07 and SEP,
RG140/06) is gratefully acknowledged. We thank Dr. Yongxin
Li from Nanyang Technological University for the X-ray
crystallographic analysis.
For this unusual reaction outcome, we proposed the following
mechanism (Scheme 1). The addition of imidazolin-2-ylidene
to R,ꢀ-unsaturated aldehyde form a zwitterionic structure 4,
which can tautomerize to the conjugated Breslow intermediate
5. The intermediate 5 can give rise to a more reactive
homoenolate 6. This in turn attacks the 4-nitrosotoluene as a
d3-nucleophile under formation of intermediate 7. The tautomer-
ization of 7 to the acylimidazolium 8 is followed by an
intramolecular attack of the amino-oxygen atom at the carbonyl
unit, which regenerates the catalyst and forms the five-membered
Supporting Information Available: Experimental procedure,
characterization spectra, and X-ray crystallographic data (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO802515G
1746 J. Org. Chem. Vol. 74, No. 4, 2009