One-step formation both of C-N and of C-O bonds of N-alkoxyamides through NHC-catalyzed three-component reactions of enals, nitrosoarenes, and enones

Article abstract of DOI:10.1002/ejoc.201200525

NHC-catalyzed three-component reactions of α,β-unsaturated aldehydes (enals), nitrosoarenes, and α,β-unsaturated ketones (enones) were studied. The reactions proceeded through a cascade aza-benzoin condensation/oxo-Michael addition sequence to produce N,O-bisfunctionalized N-hydroxylacrylamides in moderate to good yields. This work not only provides an efficient method for the one-step formation both of the C-N and of the C-O bonds in N-alkoxyamides, but also advances the application of NHC organocatalysis in the field of multicomponent reactions. NHC-catalyzed three-component reactions of α,β-unsaturated aldehydes (enals), nitrosoarenes, and α,β-unsaturated ketones (enones) proceeded through a cascade aza-benzoin condensation/oxo-Michael addition sequence to produce N,O-bisfunctionalized N-hydroxylacrylamides in moderate to good yields. Copyright

Full text of DOI:10.1002/ejoc.201200525

Job/Unit: O20525
/KAP1
Date: 25-07-12 10:31:51
Pages: 7
FULL PAPER
DOI: 10.1002/ejoc.201200525
One-Step Formation both of C–N and of C–O Bonds of N-Alkoxyamides
through NHC-Catalyzed Three-Component Reactions of Enals, Nitrosoarenes,
and Enones
Zhong-Xin Sun[a] and Ying Cheng*[a]
Keywords: Synthetic methods / Multicomponent reactions / Domino reactions / Cascade reactions / Carbenes / Enones /
Enals / Nitrosoarenes
NHC-catalyzed three-component reactions of α,β-unsatu-
rated aldehydes (enals), nitrosoarenes, and α,β-unsaturated
ketones (enones) were studied. The reactions proceeded
through a cascade aza-benzoin condensation/oxo-Michael
droxylacrylamides in moderate to good yields. This work not
only provides an efficient method for the one-step formation
both of the C–N and of the C–O bonds in N-alkoxyamides,
but also advances the application of NHC organocatalysis in
addition sequence to produce N,O-bisfunctionalized N-hy- the field of multicomponent reactions.
documented in the literature, and multicomponent reac-
Introduction
tions (MCRs) incorporating NHCs have also been well ex-
plored,[8] studies on NHC-catalyzed MCRs are very ra-
re.[9,10a]
Reactions catalyzed by N-heterocyclic carbenes (NHCs)
have emerged as an exceptionally fruitful research area in
organic chemistry in recent years.[1] Most NHC-catalyzed
reactions are initiated by umpolung of electrophilic alde-
hyde carbonyl groups into nucleophiles through the action
of a heterocyclic carbene. The interactions between NHCs
and saturated aldehydes or aryl aldehydes to form Breslow
intermediates belong to the a1–d1 class of umpolung (a1 to
d1 umpolung) according to the terminology of Seebach.[2]
The classical examples of reactions of this type are benzoin
reactions between d1-nucleophiles and aldehydes[1,3] or
Stetter reactions between d1-nucleophiles and Michael ac-
ceptors.[1,4] The action of NHCs on α,β-unsaturated alde-
hydes (enals), on the other hand, generally results in the
formation of homoenolate intermediates that can be re-
garded as d3-nucleophiles and thus constitute a3–d3 umpo-
lung. The homoenolate intermediates produced from α,β-
unsaturated aldehydes and NHCs, for example, acted as
carbon nucleophiles at the β-positions of carbonyls to react
with aldehydes or ketones leading to the formation of γ-
butyrolactones,[5] whereas the homoenolates of α,β-unsatu-
rated aldehydes reacted with imines to produce γ-lactams.[6]
NHC-catalyzed homoenolate annulations of α,β-unsatu-
rated aldehydes (enals) with α,β-unsaturated ketones (en-
ones) generally formed cyclopentane skeletons to afford cy-
clopentenes, cyclopentanols, or cyclopentanones.[7] Al-
though numerous NHC-catalyzed reactions have been
In recent years a few NHC-catalyzed reactions between
carbonyl compounds and nitrosoarenes have been reported;
these provided an efficient method for the formation of car-
bon-nitrogen bonds.[11–12] For instance, whereas Breslow in-
termediates derived from aldehydes and NHCs reacted with
nitrosoarenes leading to the direct amidation of aldehydes
to provide N-arylhydroxamic acids,[10a] the NHC-catalyzed
cascade reactions between o-vinylarylaldehydes and ni-
trosoarenes produced 2,3-benzoxazin-4-one derivatives.[10b]
On the other hand, the homoenolate intermediates pro-
duced from α,β-unsaturated aldehydes and NHCs under-
went cascade nucleophilic additions and intramolecular cy-
clizations with nitrosoarenes to afford isoxazolidin-5-one
products or intermediates, which could further convert into
isoxazol-5-ones, β-amino acid esters, or benzo[b][1,4]ox-
azepin-2-ones.[11] NHC-catalyzed reactions between ketenes
and nitrosoarenes proceeded through formal [2+2] cycload-
ditions to produce oxazetidinones.[12]
We have been interested in the reactivity of N-heterocy-
clic carbenes and their versatility in organic syntheses for
many years.[13] Recently our attention was drawn to NHC-
catalyzed reactions.[10b,14] NHC organocatalysis has only
rarely been utilized in promoting multicomponent reac-
tions, so we considered that the development of NHC-cata-
lyzed multicomponent reactions could be of great impor-
tance for the establishing of highly efficient synthetic meth-
ods. We were intrigued by multicomponent reactions of en-
als, enones, and nitroso compounds in terms of various pos-
sible reaction pathways, and envisioned that the reactions
could lead to interesting multifunctional compounds. Here
[a] College of Chemistry, Beijing Normal University,
Beijing, 100875, China
Fax: +86-10-58805558
E-mail: ycheng2@bnu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200525.
Eur. J. Org. Chem. 0000, 0–0
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Z.-X. Sun, Y. Cheng
FULL PAPER
we report our investigation into three-component reactions tion of 5b in 63% yield (Table 1, Entry 6). Increases in the
of α,β-unsaturated aldehydes, nitrosoarenes, and α,β-unsat- equivalents of 1a or 2b all decreased the yield of major
urated ketones, which provide an efficient one-pot method product 5b, whereas utilization of 2 equiv. of enone 3a gave
for the synthesis of N,O-bisfunctionalized N-hydroxylacryl- yields of 5b and 6a very similar to those of the reaction in
amides.
the presence of 1.5 equiv. of enone 3a (Table 1, Entries 2, 7–
10). Use of lower or higher reaction temperatures, of other
solvents (including acetonitrile, THF, dioxane, and benz-
ene), and of other bases (such as tBuOK, Cs2CO3, NaH,
and Hünig’s base) all caused reduced yields of product 5b
(Table 1, Entries 11–20).
Results and Discussion
Initially, the reaction of cinnamaldehyde (1a, Table 1), 1-
methyl-4-nitrosobenzene (2b), and 1-phenylprop-2-en-1-one
(3a) (1a/2b/3a 1:1:1.5) catalyzed by different NHCs 4Ј
Because the use of larger excesses of enone 3a did not
(20 mol-%, generated in situ from the corresponding azol- significantly improve the yield of major product 5b,
ium salts 4 with a base) in dry dichloromethane was exam- 1.5 equiv. of enones 3 were employed in other reactions, to
ined at 25–30 °C. It was found that triazole carbenes 4aЈ, save starting materials. The scope of the reaction under the
4bЈ, and 4cЈ could promote this reaction to produce 5b in optimized conditions was studied by use of a variety of sub-
54%, 73%, and 30% yields, respectively, along with 11– stituted α,β-unsaturated aldehydes 1, nitroso compounds 2,
25% yields of by-product 6b (Table 1, Entries 1–3). In con- and α,β-unsaturated ketones 3 (Table 2). It was found that
trast, when the reaction was performed under the same con- the reaction showed tolerance for the substituents attached
ditions but in the presence of imidazole carbene 4cЈ or thi- to cinnamaldehydes 1. All cinnamaldehydes 1a–1e, substi-
azole carbene 4dЈ it was inefficient.
tuted either with electron-donating or with electron-with-
The reaction conditions with catalysis by triazole carbene drawing groups, reacted with 1-methoxy-4-nitrosobenzene
4bЈ were further optimized by variation of catalyst loadings, (2c) and 1-phenylprop-2-en-1-one (3a) to produce 3-aryl-N-
ratios of starting materials, temperature, solvents, and bases (p-methoxyphenyl)-N-(3-oxo-3-phenylpropoxy)acrylamides
used to generate the carbene catalyst. In dichloromethane, 5 in 63–72% yields, along with 9–24% yields of 3-aryl-N-
halving the catalyst loading to 10 mol-% led to the forma- hydroxyl-N-(p-methoxyphenyl)acrylamides 6 (Table 2, En-
Table 1. Optimization of the reaction conditions.
Entry
1a/2b/3a
NHC
precursor 4
mol-%
of 4
Base
Solvent
Temperature
[°C]
Time
[h]
Yield [%]
5b
6b
1
2
3
4
5
6
7
1:1:1.5
1:1:1.5
1:1:1.5
1:1:1.5
1:1:1.5
1:1:1.5
1:1:1
1.5:1:1
1:1.5:1
1:1:2
1:1:1.5
1:1:1.5
1:1:1.5
1:1:1.5
1:1:1.5
1:1:1.5
1:1:1.5
1:1:1.5
1:1:1.5
1:1:1.5
4a
4b
4c
4d
4e
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
20
20
20
20
20
10
20
20
20
20
20
20
20
20
20
20
20
20
20
20
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
tBuOK
Cs2CO3
NaH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
THF
dioxane
benzene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
25–30
25–30
25–30
25–30
25–30
25–30
25–30
25–30
25–30
25–30
0
reflux
25–30
25–30
25–30
25–30
25–30
25–30
25–30
25–30
4
2
5
5
5
2
2
2
2
2
12
2
2
2
2
2
2
2
2
2
54
73
30
4
23
11
25
14
19
17
18
16
19
10
19
20
13
34
25
21
33
25
33
22
12
63
49
64
62
74
64
59
66
44
52
53
34
11
38
14
8
9
10
11
12
13
14
15
16
17
18
19
20
DIPEA
2
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C–N and C–O Bond Formation by NHC-Catalyzed MCR
tries 3, 10–13). On the other hand, although all nitrosoar-
The structures of products were elucidated on the basis
enes 2 and enones 3 substituted with anisyl, tolyl, phenyl, of spectroscopic data and microanalysis. The NMR spectra,
or halophenyl groups reacted with cinnamaldehyde (1a) mass data, and elemental analyses indicated that the major
smoothly to produce compounds 5 in 54–73% yields products 5 are 3-aryl-N-aryl-N-(3-oxo-3-arylpropoxy)acryl-
(Table 2, Entries 1–4, 6–8), the three-component reactions amides derived from the 1+1+1 addition of enals 1 with
either with 1-nitro-4-nitrosobenzene (2e) or with 1-(4-ni- nitroso compounds 2 and enones 3, whereas the minor
trophenyl)prop-2-en-1-one (3e) as one of the reactants did products 6 are 3-aryl-N-aryl-N-hydroxylacrylamides that
not form products 5 or 6 (Table 2, Entries 5 and 9). The are adducts of 1 with 2. To identify the products beyond
inefficiency of the nitro-substituted nitrosobenzene 2e or doubt, the structure of 5i was also determined by single-
enone 3e in the three-component reactions with enals 1 was crystal X-ray diffraction analysis.[15]
probably due to their instability in the presence of triazole
A cascade mechanism for these three-component reac-
carbene and DBU. Because the products 5 were presumably tions is proposed (Scheme 1). Unlike in most NHC-cata-
derived from the addition of by-products 6 to enones 3, lyzed reactions of α,β-unsaturated aldehydes, in which the
promotion of the transformation of compounds 6 to com- enals are believed to be converted into homoenolate inter-
pounds 5 was attempted, variously by utilization of more mediates and to act as γ-carbon nucleophiles, here the α,β-
enones 3 or base (DBU), prolongation of reaction time, or unsaturated aldehydes 1 are believed to form Breslow inter-
elevation of reaction temperature. However, none of them mediates 7 with NHC and to behave as α-carbon nucleo-
could improve the yields of 5. After the occasional discov- philes toward nitrosoarenes 2 to produce intermediates 8.
ery that products 5 would undergo base-catalyzed elimi- Proton shifting from C–OH to N–OH, accompanied by the
nation to give products 6 and enones 3 in the presence of elimination of the NHC moiety from 8, would produce
DBU, we realized that the formation of 5 from 6 and 3 is products 6. With catalysis by a base such as DBU or tri-
actually a reversible process. We were therefore now able to azole carbene 4Ј, oxo-Michael addition of N-hydroxylacryl-
understand why byproducts 6 could not be totally trans- amides 6 to α,β-unsaturated ketones 3 would afford prod-
formed into products 5 under the reaction conditions.
ucts 5. N-Heterocyclic carbenes have been reported to cata-
lyze conjugate additions of alcohols to α,β-unsaturated
ketones,[16] and we have also verified the transformation of
compounds 6 into 5 by treatment of 6 with enones 3 in the
presence of DBU. These studies support our mechanism.
Theoretically, the Breslow intermediates derived from α,β-
unsaturated aldehydes and NHCs could undergo Michael
addition to α,β-unsaturated ketones to form 1,4-diketones
(Stetter reaction). Additionally, cinnamaldehydes 1 have
been reported to form homoenolate intermediates with an
imidazole carbene, afterwards undergoing Michael addition
with α,β-unsaturated ketones to produce cyclopentanols.[7b]
However, no such products derived from enals 1 and enones
3 were isolated from this three-component reaction. Exami-
nation of the reaction behavior between α,β-unsaturated al-
Table 2. Reactions of enals 1, nitrosoarenes 2, and enones 3 under
the optimized conditions.
Entry
1
Ar1
2
X
3
Ar2
Yield [%]
1
2
3
4
5
6
7
8
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1b p-MePh
2a
2b
2c
2d
2e
2c
2c
2c
2c
2c
H
Me
OMe
Cl
NO2
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
3a Ph
3a Ph
3a Ph
3a Ph
5a [54], 6a [15]
5b [73], 6b [11]
5c [72], 6c [9]
5d [54], 6d [27]
–
3a Ph
3b p-MePh
3c p-MeOPh 5f [67], 6f [18]
3d p-BrPh
3e p-NO2Ph
3a Ph
3a Ph
3a Ph
5e [64], 6e [15]
5g [58], 6g [13]
–
5i [67], 6i [24]
5j [64], 6j [17]
5k [71], 6k [15]
5l [63], 6l [18]
9
10
11
12
13
1c p-MeOPh 2c
1d p-BrPh 2c
1e p-NO2Ph 2c
3a Ph
Scheme 1. Proposed mechanism.
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Z.-X. Sun, Y. Cheng
FULL PAPER
7.4 Hz, 1 H, ArH), 7.47 (t, J = 7.8 Hz, 2 H, ArH), 7.33–7.43 (m,
6 H, ArH, C=CH), 7.21 (d, J = 8.2 Hz, 2 H, ArH), 4.40 (t, J =
5.8 Hz, 2 H, CH2), 3.36 (t, J = 6.6 Hz, 2 H, CH2), 2.37 (s, 3 H,
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 196.6, 165.5, 143.9,
136.8, 136.6, 136.2, 135.3, 133.5, 129.8, 129.5, 128.8, 128.7, 128.3,
dehydes 1 and α,β-unsaturated ketones 3 in the absence of
nitrosoarenes 2 under the same conditions as used in the
three-component reactions showed that the interaction of
enals 1 with enones 3 was actually inefficient under our
reaction conditions.
128.1, 123.7, 117.4, 69.1, 36.5, 21.0 ppm. IR: ν = 1689, 1669,
˜
1627 cm–1. HRMS (ESI): calcd. for C25H24NO3 [M
386.1756; found 386.1750.
+
H]+
Conclusions
N-Hydroxy-N-(p-tolyl)cinnamamide (6b): This compound was ob-
tained in 11% yield (28 mg); m.p. 160–161 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.75 (d, J = 15.6 Hz, 1 H, HC=C), 7.39–7.41 (m, 2 H,
ArH), 7.32–7.33 (m, 5 H, ArH), 7.26 (d, J = 9.1 Hz, 2 H, ArH),
6.51 (d, J = 15.2 Hz, 1 H, C=CH), 2.42 (s, 3 H, CH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 161.7, 142.7, 139.2, 135.3, 134.8,
In summary, we have studied NHC-catalyzed three-com-
ponent reactions of α,β-unsaturated aldehydes, nitrosoar-
enes, and α,β-unsaturated ketones. The reactions proceeded
by cascade aza-benzoin condensations between α,β-unsatu-
rated aldehydes and nitrosoarenes, followed by oxo-Michael
additions of the N-hydroxylacrylamide to the α,β-unsatu-
rated ketones to produce N,O-functionalized N-hydroxylac-
rylamides in moderate to good yields. This work not only
provides an efficient method for the one-step construction
of both C–N and C–O bonds of N-alkoxyamides, but also
advances the application of NHC organocatalysis in the
field of multicomponent reactions.
129.9, 128.8, 128.0, 126.4, 115.4, 21.2 ppm. IR: ν = 3130, 1638,
˜
1587, 1575 cm–1. HRMS (ESI): calcd. for C16H16NO2 [M + H]+
254.1181; found 254.1185.
N-(p-Methoxyphenyl)-N-(3-oxo-3-phenylpropoxy)cinnamamide (5c):
This compound was obtained in 72% yield (292 mg); m.p. 97–
1
98 °C. H NMR (400 MHz, CDCl3): δ = 7.97 (d, J = 7.4 Hz, 2 H,
ArH), 7.76 (d, J = 15.7 Hz, 1 H, HC=C), 7.61 (br, 2 H, ArH), 7.58
(t, J = 7.3 Hz, 1 H, ArH), 7.47 (d, J = 7.8 Hz, 2 H, ArH), 7.45 (t,
J = 8.5 Hz, 2 H, ArH), 7.33–7.41 (m, 4 H, ArH, C=CH), 6.93 (d,
J = 8.9 Hz, 2 H, ArH), 4.40 (t, J = 5.8 Hz, 2 H, CH2), 3.83 (s, 3 H,
OCH3), 3.36 (t, J = 5.8 Hz, 2 H, CH2) ppm. 13C NMR (100 MHz,
CDCl3): δ = 196.8, 158.7, 143.8, 136.6, 135.2, 134.9, 133.5, 131.6,
129.8, 128.8, 128.7, 128.3, 128.1, 127.9, 117.3, 114.3, 69.0, 55.6,
Experimental Section
General: Melting points were determined with a Reliant YRT-3
melting point apparatus. 1H NMR (400 MHz) and 13C NMR
(100 MHz) were recorded in the indicated solvents. J values are
reported in Hz. IR spectra were recorded with an AVATAR 360
FT-IR spectrometer. Mass spectra were recorded with a Surveyor
MSQ Plus (ESI) instrument and elemental analyses were performed
with a GMBH Vario EL instrument. Column chromatography was
performed with 200–300 mesh silica gel. The NHC precursors
4a,[17] 4b,[18] 4c,[19] 4d,[18] and 4e[18] were prepared by literature
methods.
36.6 ppm. IR: ν = 1689, 1650, 1613 cm–1. MS (ESI): m/z = 402 [M
˜
+ H]+. C25H23NO4: C 74.79, H 5.77, N 3.49; found C 74.47, H
5.90, N 3.29.
N-Hydroxy-N-(p-methoxyphenyl)cinnamamide (6c): This compound
was obtained in 9% yield (24 mg); m.p. 140–141 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.74 (d, J = 15.6 Hz, 1 H, HC=C), 7.32–
7.40 (m, 8 H, ArH), 6.99 (d, J = 8.7 Hz, 2 H, ArH), 6.43 (d, J =
15.3 Hz, 1 H, C=CH), 3.87 (s, 3 H, OCH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 161.5, 160.2, 142.6, 134.7, 130.1, 130.0,
General Procedure for the Reactions of α,β-Unsaturated Aldehydes
1, Nitrosoarenes 2, and α,β-Unsaturated Ketones 3: An α,β-unsatu-
rated aldehyde 1[20] (1 mmol), a nitrosoarene 2[21] (1 mmol), an α,β-
unsaturated ketone 3[22] (1.5 mmol), and an N,N-dimethyl-1,2,4-tri-
azolium salt (0.2 mmol) were mixed in dry dichloromethane
(12 mL) under nitrogen at 25–30 °C. DBU (0.2 mmol) was then
added, and the mixture was stirred at about 25 °C for 4–6 h. The
solvent was removed under vacuum and the residue was chromato-
graphed on a silica gel column with elution with a mixture of petro-
leum ether and ethyl acetate (10:1 to 2:1) to afford the correspond-
ing products 5 and 6.
128.8, 128.7, 128.0, 115.0, 114.6, 55.6 ppm. IR: ν = 3119, 1641,
˜
1592, 1578 cm–1. HRMS (ESI): calcd. for C16H16NO3 [M + H]+
270.1130; found 270.1132.
N-(p-Chlorophenyl)-N-(3-oxo-3-phenylpropoxy)cinnamamide (5d):
This compound was obtained in 54% yield (219 mg); m.p. 125–
126 °C. 1H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 7.3 Hz, 2
H, ArH), 7.80 (d, J = 15.7 Hz, 1 H, HC=C), 7.68 (d, J = 6.2 Hz,
2 H, ArH), 7.60 (t, J = 7.5 Hz, 1 H, ArH), 7.56 (d, J = 8.8 Hz, 2
H, ArH), 7.48 (t, J = 7.8 Hz, 2 H, ArH), 7.33–7.44 (m, 6 H, ArH,
C=CH), 4.41 (t, J = 5.6 Hz, 2 H, CH2), 3.37 (d, J = 5.6 Hz, 2 H,
CH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 196.3, 165.8, 144.9,
137.4, 136.5, 135.1, 133.6, 131.6, 130.1, 128.9, 128.81, 128.76,
N-(3-Oxo-3-phenylpropoxy)-N-phenylcinnamamide (5a): This com-
pound was obtained in 54% yield (203 mg); m.p. 113–114 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 7.3 Hz, 2 H, ArH), 7.80
(d, J = 15.7 Hz, 1 H, HC=C), 7.65 (d, J = 6.7 Hz, 2 H, ArH), 7.57–
7.60 (m, 3 H, ArH), 7.47 (t, J = 7.8 Hz, 2 H, ArH), 7.37–7.44 (m,
6 H, ArH, C=CH), 7.26 (d, J = 8.3 Hz, 1 H, ArH), 4.42 (t, J =
5.8 Hz, 2 H, CH2), 3.37 (t, J = 5.8 Hz, 2 H, CH2) ppm. 13C NMR
(100 MHz, CDCl3): δ = 196.6, 165.7, 144.3, 138.8, 136.6, 135.2,
133.5, 129.9, 128.9, 128.8, 128.7, 128.3, 128.1, 126.6, 123.2, 117.3,
128.4, 128.1, 123.9, 116.9, 69.4, 36.4 ppm. IR: ν = 1685, 1655,
˜
1614 cm–1. MS (ESI): m/z = 428 [M + Na]+. C24H20ClNO3
(405.88): calcd. C 71.02, H 4.97, N 3.45; found C 70.70, H 5.12, N
3.29.
N-(p-Methoxyphenyl)-N-[3-oxo-3-(p-tolyl)propoxy]cinnamamide
(5e): This compound was obtained in 64% yield (266 mg); m.p.
105–106 °C. 1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.1 Hz,
2 H, ArH), 7.76 (d, J = 15.7 Hz, 1 H, HC=C), 7.61 (br, 2 H, ArH),
7.44 (d, J = 8.1 Hz, 2 H, ArH), 7.36–7.40 (m, 4 H, ArH, C=CH),
7.25 (d, J = 7.8 Hz, 2 H, ArH), 6.94 (d, J = 8.6 Hz, 2 H, ArH),
4.39 (t, J = 5.8 Hz, 2 H, CH2), 3.83 (s, 3 H, OCH3), 3.33 (t, J =
5.8 Hz, 2 H, CH2), 2.41 (s, 3 H, CH3) ppm. 13C NMR (100 MHz,
69.3, 36.5 ppm. IR: ν = 1684, 1667, 1620 cm–1. HRMS (ESI): calcd.
˜
for C24H22NO3 [M + H]+ 372.1591; found 372.1591.
N-(3-Oxo-3-phenylpropoxy)-N-(p-tolyl)cinnamamide (5b): This
compound was obtained in 73% yield (281 mg); m.p. 75–76 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 7.2 Hz, 2 H, ArH), 7.78 CDCl3): δ = 196.4, 165.6, 158.6, 144.4, 143.7, 135.3, 134.2, 131.6,
(d, J = 15.7 Hz, 1 H, HC=C), 7.62 (br, 2 H, ArH), 7.58 (t, J = 129.8, 129.40, 129.35, 128.7, 128.2, 125.9, 117.3, 114.2, 69.1, 55.6,
4
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Pages: 7
C–N and C–O Bond Formation by NHC-Catalyzed MCR
36.4, 21.7 ppm. IR: ν = 1683, 1650, 1613 cm–1. MS (ESI): m/z =
(E)-N-Hydroxy-N,3-bis(p-methoxyphenyl)acrylamide (6j): This
compound was obtained in 17% yield (51 mg); m.p. 166–167 °C.
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 15.6 Hz, 1 H,
HC=C), 7.36 (d, J = 8.6 Hz, 2 H, ArH), 7.35 (d, J = 8.6 Hz, 2 H,
ArH), 6.98 (d, J = 8.8 Hz, 2 H, ArH), 6.84 (d, J = 8.8 Hz, 2 H,
ArH), 6.30 (d, J = 14.7 Hz, 1 H, C=CH), 3.87 (s, 3 H, OCH3), 3.81
(s, 3 H, OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.9,
161.1, 160.1, 142.3, 130.2, 129.6, 128.6, 127.5, 114.6, 114.2, 112.4,
˜
416 [M + H]+. C26H25NO4 (415.49): calcd. C 75.16, H 6.06, N 3.37;
found C 74.72, H 5.95, N 3.22.
N-(p-Methoxyphenyl)-N-[3-(p-methoxyphenyl)-3-oxopropoxy]-
cinnamamide (5f): This compound was obtained in 67 % yield
1
(289 mg); m.p. 132–133 °C. H NMR (400 MHz, CDCl3): δ = 7.96
(d, J = 8.8 Hz, 2 H, ArH), 7.75 (d, J = 15.7 Hz, 1 H, HC=C), 7.60
(br, 2 H, ArH), 7.34–7.45 (m, 6 H, ArH, C=CH), 6.94 (d, J =
8.9 Hz, 2 H, ArH), 6.92 (d, J = 8.8 Hz, 2 H, ArH), 4.39 (t, J =
5.8 Hz, 2 H, CH2), 3.86 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 3.30
(t, J = 5.8 Hz, 2 H, CH2) ppm. 13C NMR (100 MHz, CDCl3): δ =
195.2, 163.8, 158.6, 143.7, 135.3, 131.6, 130.4, 129.8, 128.7, 128.3,
55.6, 55.4 ppm. IR: ν = 3114, 1640, 1589, 1568 cm–1. HRMS (ESI):
˜
calcd. for C17H18NO4 [M + H]+ 300.1236; found 300.1234.
(E)-3-(4-Bromophenyl)-N-(p-methoxyphenyl)-N-(3-oxo-3-phenyl-
propoxy)acrylamide (5k): This compound was obtained in 71%
yield (348 mg); m.p. 144–145 °C. 1H NMR (400 MHz, CDCl3): δ
= 7.98 (d, J = 7.7 Hz, 2 H, ArH), 7.69 (d, J = 15.0 Hz, 1 H,
HC=C), 7.59 (t, J = 7.2 Hz, 1 H, ArH), 7.43–7.52 (m, 8 H, ArH,
C=CH), 6.94 (d, J = 7.9 Hz, 2 H, ArH), 4.39 (brs, 2 H, CH2), 3.84
(s, 3 H, OCH3), 3.34 (brs, 2 H, CH2) ppm. 13C NMR (100 MHz,
CDCl3): δ = 196.7, 158.7, 142.4, 136.5, 134.2, 133.6, 132.0, 131.4,
129.7, 128.7, 128.1, 125.7, 124.0, 118.1, 114.3, 68.8, 55.6, 36.5 ppm.
126.0, 117.4, 114.2, 113.9, 69.2, 55.54, 55.46, 36.2 ppm. IR: ν =
˜
1679, 1659, 1619 cm–1. HRMS (ESI): calcd. for C26H26NO5 [M +
H]+ 432.1811; found 432.1802.
N-[3-(p-Bromophenyl)-3-oxopropoxy]-N-(p-methoxyphenyl)-
cinnamamide (5g): This compound was obtained in 58 % yield
1
(284 mg); m.p. 140–141 °C. H NMR (400 MHz, CDCl3): δ = 7.82
(d, J = 8.5 Hz, 2 H, ArH), 7.75 (d, J = 15.6 Hz, 1 H, HC=C), 7.59
(d, J = 8.5 Hz, 2 H, ArH), 7.58 (br, 2 H, ArH), 7.35–7.43 (m, 6 H,
ArH, C=CH), 6.94 (d, J = 8.9 Hz, 2 H, ArH), 4.39 (t, J = 5.7 Hz,
2 H, CH2), 3.84 (s, 3 H, OCH3), 3.31 (t, J = 5.6 Hz, 2 H, CH2) ppm.
13C NMR (100 MHz, CDCl3): δ = 195.8, 165.5, 158.8, 143.8, 135.3,
135.2, 132.0, 131.5, 130.3, 129.9, 129.6, 128.8, 128.2, 121.7, 117.3,
IR: ν = 1677, 1655, 1616 cm– 1. HRMS (ESI): calcd. for
˜
C25H23BrNO4 [M + H]+ 480.0810; found 480.0811.
(E)-3-(p-Bromophenyl)-N-hydroxy-N-(p-methoxyphenyl)acrylamide
(6k): This compound was obtained in 15% yield (54 mg); m.p. 167–
168 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 10.81 (brs, 1 H,
OH), 7.40–7.70 (m, 8 H, ArH, CH=CH), 6.97 (d, J = 8.9 Hz, 2 H,
ArH), 3.77 (s, 3 H, OCH3) ppm. 13C NMR (100 MHz, DMSO): δ
= 164.0, 156.8, 140.3, 134.7, 134.1, 131.9, 129.8, 123.0, 120.7, 119.3,
114.3, 68.8, 55.5, 36.5 ppm. IR: ν = 1686, 1647, 1611 cm–1. HRMS
˜
(ESI): calcd. for C25H23BrNO4 [M + H]+ 480.0810; found
480.0813.
113.6, 55.3 ppm. IR: ν = 3114, 1641, 1587, 1573 cm–1. HRMS
(E)-N-(p-Methoxyphenyl)-N-(3-oxo-3-phenylpropoxy)-3-(p-tolyl)-
acrylamide (5i): This compound was obtained in 67 % yield
˜
(ESI): calcd. for C1.6H15BrNO3 [M + H]+ 348.0235; found
348.0231.
1
(278 mg); m.p. 124–125 °C. H NMR (400 MHz, CDCl3): δ = 7.97
(d, J = 7.5 Hz, 2 H, ArH), 7.74 (d, J = 15.7 Hz, 1 H, HC=C), 7.58
(t, J = 7.4 Hz, 1 H, ArH), 7.42–7.55 (m, 6 H, ArH, C=CH), 7.19
(d, J = 7.7 Hz, 2 H, ArH), 6.94 (d, J = 8.9 Hz, 2 H, ArH), 4.40 (t,
J = 5.8 Hz, 2 H, CH2), 3.83 (s, 3 H, OCH3), 3.36 (t, J = 5.8 Hz, 2
H, CH2), 2.38 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ
= 196.8, 165.7, 158.6, 143.8, 140.1, 136.6, 133.5, 132.5, 131.7, 129.5,
129.5, 128.7, 128.3, 128.1, 126.1, 116.2, 114.3, 69.0, 55.6, 36.6,
(E)-N-(p-Methoxyphenyl)-3-(p-nitrophenyl)-N-(3-oxo-3-phenyl-
propoxy)acrylamide (5l): This compound was obtained in 63% yield
(294 mg); m.p. 169–170 °C. H NMR (400 MHz, CDCl3): δ = 8.24
1
(d, J = 8.8 Hz, 2 H, ArH), 7.99 (d, J = 7.2 Hz, 2 H, ArH), 7.82
(brs, 2 H, ArH), 7.77 (d, J = 15.9 Hz, 1 H, HC=C), 7.60 (t, J =
7.4 Hz, 1 H, ArH), 7.44–7.52 (m, 5 H, ArH, C=CH), 6.96 (d, J =
9.0 Hz, 2 H, ArH), 4.41 (t, J = 5.6 Hz, 2 H, CH2), 3.85 (s, 3 H,
OCH3), 3.34 (t, J = 5.6 Hz, 2 H, CH2) ppm. 13C NMR (100 MHz,
CDCl3): δ = 196.7, 165.0, 158.5, 148.1, 141.6, 140.8, 136.4, 133.8,
131.0, 128.9, 128.8, 128.1, 125.3, 124.0, 122.0, 114.3, 68.7, 55.5,
21.5 ppm. IR: ν = 1681, 1655, 1615 cm–1. MS (ESI): m/z = 438 [M
˜
+ Na]+. C26H25NO4 (415.49): calcd. C 75.16, H 6.06, N 3.37; found
C 74.91, H 5.71, N 3.16.
36.3 ppm. IR: ν = 1681, 1651, 1616, 1509 cm–1. HRMS (ESI):
(E)-N-Hydroxy-N-(p-methoxyphenyl)-3-(p-tolyl)acrylamide (6i):
˜
calcd. for C25H23N2O6 [M + H]+ 447.1556; found 447.1567.
This compound was obtained in 24% yield (68 mg); m.p. 161–
1
162 °C. H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 15.6 Hz, 1
(E)-N-Hydroxy-N-(p-methoxyphenyl)-3-(p-nitrophenyl)acrylamide
(6l): This compound was obtained in 18% yield (60 mg); m.p. 185–
186 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 10.93 (brs, 1 H,
OH), 8.25 (d, J = 7.8 Hz, 2 H, ArH), 7.99 (brs, 2 H, ArH), 7.72
(d, J = 15.6 Hz, 1 H, HC=C), 7.59 (brs, 3 H, ArH, C=CH), 6.99
(d, J = 8.6 Hz, 2 H, ArH), 3.78 (s, 3 H, OCH3) ppm. 13C NMR
(100 MHz, DMSO): δ = 163.5, 156.8, 147.6, 141.4, 139.1, 134.5,
H, HC=C), 7.29 (d, J = 8.6 Hz, 2 H, ArH), 7.22 (d, J = 7.9 Hz, 2
H, ArH), 7.06 (d, J = 7.9 Hz, 2 H, ArH), 6.91 (d, J = 8.8 Hz, 2 H,
ArH), 6.31 (d, J = 15.3 Hz, 1 H, C=CH), 3.80 (s, 3 H, OCH3), 2.27
(s, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.8, 160.1,
142.6, 140.3, 132.0, 130.3, 129.5, 128.6, 127.9, 114.6, 114.0, 55.6,
21.4 ppm. IR: ν = 3117, 1636, 1592 cm–1. HRMS (ESI): calcd. for
˜
C17H18NO3 [M + H]+ 284.1287; found 284.1289.
129.0, 124.0, 122.8, 120.7, 113.7, 55.3 ppm. IR: ν = 3196, 1642,
˜
(E)-N,3-Bis(p-methoxyphenyl)-N-(3-oxo-3-phenylpropoxy)acryl-
amide (5j): This compound was obtained in 64% yield (276 mg);
m.p. 109–110 °C. 1H NMR (400 MHz, CDCl3): δ = 7.97 (d, J =
7.4 Hz, 2 H, ArH), 7.72 (d, J = 15.7 Hz, 1 H, HC=C), 7.58 (t, J =
7.4 Hz, 1 H, ArH), 7.55 (br, 2 H, ArH), 7.42–7.49 (m, 4 H, ArH),
6.93 (d, J = 9.0 Hz, 2 H, ArH), 6.87–6.91 (m, 3 H, ArH, C=CH),
4.39 (t, J = 5.8 Hz, 2 H, CH2), 3.84 (s, 3 H, OCH3), 3.83 (s, 3 H,
OCH3), 3.35 (t, J = 5.8 Hz, 2 H, CH2) ppm. 13C NMR (100 MHz,
CDCl3): δ = 196.8, 161.1, 158.6, 143.5, 136.6, 133.5, 131.8, 129.9,
129.5, 128.7, 128.1, 128.0, 126.1, 121.6, 118.9, 114.8, 114.2, 68.9,
1602, 1594, 1522, 1509 cm–1. HRMS (ESI): calcd. for C16H15N2O5
[M + H]+ 315.0981; found 315.0974.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H NMR and 13C NMR spectra of products 5 and
6, excluding those byproducts without full characterization.
Acknowledgments
55.5, 55.4, 36.6 ppm. IR: ν = 1688, 1651, 1601 cm–1. HRMS (ESI):
This work was supported by the National Natural Science Founda-
tion of China (NSFC) (grant numbers 20832006 and 21172021),
˜
calcd. for C26H26NO5 [M + H]+ 432.1811; found 432.1819.
Eur. J. Org. Chem. 0000, 0–0
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/KAP1
Date: 25-07-12 10:31:51
Pages: 7
Z.-X. Sun, Y. Cheng
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Received: April 21, 2012
Published Online: ᭿
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20525
/KAP1
Date: 25-07-12 10:31:51
Pages: 7
C–N and C–O Bond Formation by NHC-Catalyzed MCR
Multicomponent Reactions
NHC-catalyzed three-component reactions
of α,β-unsaturated aldehydes (enals), ni-
trosoarenes, and α,β-unsaturated ketones
(enones) proceeded through a cascade aza-
benzoin condensation/oxo-Michael ad-
dition sequence to produce N,O-bis-
functionalized N-hydroxylacrylamides in
moderate to good yields.
Z.-X. Sun, Y. Cheng* ....................... 1–7
One-Step Formation both of C–N and of
C–O Bonds of N-Alkoxyamides through
NHC-Catalyzed Three-Component Reac-
tions of Enals, Nitrosoarenes, and Enones
Keywords: Synthetic methods / Multicom-
ponent reactions / Domino reactions / Cas-
cade reactions / Carbenes / Enones / Enals /
Nitrosoarenes
Eur. J. Org. Chem. 0000, 0–0
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7