N-Methylimidazole as a promising catalyst for the aza-Michael addition reaction of N-heterocycles

Article abstract of DOI:10.1055/s-2007-983816

N-Methylimidazole has been shown to be a promising catalyst for aza-Michael reactions. Various N-heterocycles were introduced to α,β-unsaturated carbonyl compounds employing N-methylimidazole (0.05 equiv) in a highly efficient, rapid and high yielding syn

Full text of DOI:10.1055/s-2007-983816

PAPER
2653
N-Methylimidazole as a Promising Catalyst for the Aza-Michael Addition
Reaction of N-Heterocycles
N
B
-Methylimidazo
o
le-Catalyzed
A
za-M
K
ichael
A
ddition
a
R
eaction of
i
N
-Heterocyc
L
les iu, Qi Wu, Xue Qi Qian, De Shui Lv, Xian Fu Lin*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P.R. of China
Fax +86(571)87952618; E-mail: llc123@zju.edu.cn
Received 25 April 2007; revised 25 May 2007
ferred to the N-methylimidazole as being a co-catalyst for
esterification, aldol, Claisen and other reactions,14 to the
best of our knowledge, little research on N-methylimida-
Abstract: N-Methylimidazole has been shown to be a promising
catalyst for aza-Michael reactions. Various N-heterocycles were
introduced to a,b-unsaturated carbonyl compounds employing
N-methylimidazole (0.05 equiv) in a highly efficient, rapid and high zole itself as a catalyst for organic synthesis, especially for
yielding synthesis of N-heterocyclic derivatives.
the aza-Michael addition, has been published.
Key words: N-methylimidazole, Michael additions, nucleophiles, In this paper, we report the use of N-methylimidazole as
heterocycles, a,b-unsaturated compounds
an efficient catalyst for Michael addition of N-heterocy-
cles to a,b-unsaturated carbonyl compounds to afford the
corresponding 1,4-aducts. Excellent yields in short reac-
Currently, N-heterocycles are attracting increasing atten- tion times were achieved by using microdosage N-meth-
tion due to their bioactivity, in particular, N-heterocyclic ylimidazole catalyst (Scheme 1).
derivatives containing b-amino carbonyl functionalities,
1
which have potential therapeutic activity. Michael addi-
tion is a molecularly economic reaction and among the
most practical and widely used methods for the synthesis
of such b-amino carbonyl compounds. Generally, the use
of strong bases or acids for this reaction would lead to en-
vironmentally hazardous residues and undesirable by-
O
O
Nu
0
.05 equiv N-methylimidazole
Nu-H
+
R
DMSO, 70 °C
R
3a–x
Scheme 1
products. Over the past few years, a great number of alter- The feasibility of our approach was first tested by mixing
native procedures had been reported which avoid such 4-nitroimidazole (1 mmol) and methyl acrylate (1.2
2
harsh conditions. Most aza-Michael reaction protocols equiv) with N-methylimidazole (0.05 equiv) in dimethyl
3
4
employ transition-metal catalysts such as SmI , CeCl ,
sulfoxide (DMSO; 1 mL) at 70 °C for 1 h. A single prod-
2
3
5
6
7
8
9
InCl , Yb(OTf) , Bi(OTf) , Cu(OTf) , LiClO or het- uct was obtained after flash chromatography that was
3
3
3
3
4
1
0
1
13
erogeneous solid acids. Considering the substantial cost characterized by IR, H NMR and C NMR. No byprod-
and high toxicity associated with these metal complex cat- ucts were detected when the reaction was monitored by
alysts, chemists have been investigating novel alterna- TLC and HPLC. We then screened several tertiary
tives. Recently, ionic liquids have been shown to play a amines, all of which had the potential to promote this ad-
significant role in promoting the aza-Michael reaction,11 dition. The results are summarized in Table 1. N-Meth-
however, such liquids are relatively expensive, difficult to ylimidazole was found to be significantly more effective
purify and not easy to obtain. Therefore, efforts to develop than pyridine and slightly more so than triethylamine,
organocatalysts have continued to increase in popularity. DBU and 4-(N,N-dimethylamino)pyridine (DMAP), indi-
Lately, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) has cating that N-methylimidazole was a novel and promising
been used as a mild promoter of the aza-Michael reaction catalyst for aza-Michael addition.
12
of amines with a,b-unsaturated carbonyl compounds.
The results in Table 2 demonstrate not only the action of
Enlightened by the structural similarity of N-methylimi- N-methylimidazole as catalyst, but also its efficient cata-
dazole to the cationic component of imidazole-type ionic lytic ability. The reaction was very sluggish in the absence
liquids, we envisioned that N-methylimidazole could also of N-methylimidazole; only 3.5% yield was obtained after
play a similar role and catalyze the aza-Michael addition one hour (Table 2, entry 1). Even prolonging the reaction
efficiently. In fact we have found preliminary support for to eight hours gave yields of less than 15%. A moderate
this assumption through the successful application of N- yield was achieved using 0.01 equivalent of N-methylim-
methylimidazole as an efficient additive, instead of ionic idazole (Table 2, entry 3). When the amount of N-meth-
liquids, in the enzymatic reaction (acylation of ribavirin ylimidazole was increased to 0.05 equivalents, an
1
3
with divinyl ester). Although several reports have re- excellent yield was achieved (Table 2, entry 4), showing
that this was sufficient for efficient catalysis of the aza-
Michael addition (Table 2, entries 5–7).
SYNTHESIS 2007, No. 17, pp 2653–2659
x
x.
x
x
.
2
0
0
7
Having the optimal conditions in hand, a variety of struc-
turally diverse five-membered N-heterocycles were react-
Advanced online publication: 24.07.2007
DOI: 10.1055/s-2007-983816; Art ID: F07407SS
Georg Thieme Verlag Stuttgart · New York
©

2
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B. K. Liu et al.
PAPER
Table 1 Screening Catalysts for the Michael Addition of 4-Nitroim- ing the reactivity of the conjugate addition. As the carbon
a
idazole to Methyl Acrylate
chain of the alcohol moiety was increased in length, a
slight decrease in yield was observed (Table 3, entries 2–
Entry
Catalyst
Yield (%)b
4
). Reactions with either a-methyl or b-methyl substituted
1
2
3
4
N-methylimidazole
pyridine
98
28
80
91
90
acrylates proceeded significantly more slowly. Highly
prolonged reaction times were required to achieve satis-
factory yields of products in the reactions of 4-nitroimida-
zole with both methyl methacrylate and methyl crotonate
Et N
3
(
Table 3, entries 5 and 6). Apart from the steric hindrance
DBU
of the Michael accepter, that of the Michael donor also
had a subtle influence on the reaction. Compared with 4-
nitroimidazole, 2-methyl-4-nitroimidazole gave slightly
lower yields upon reaction with both methyl vinyl ketone
5
DMAP
a
Reaction conditions: 4-nitroimidazole (1 mmol), methyl acrylate
1.2 mmol) in DMSO (1 mL) containing catalyst (0.05 equiv) at
(
(
Table 3, entries 1 and 7) and methyl acrylate (Table 3,
7
0 °C for 1 h.
Isolated yield.
b
entries 2 and 8), due to the substitution at the 2-position.
A similar observation was also found with 2-methylimi-
dazole and imidazole (Table 3, entries 9–12). Interesting-
ly, lower yields were obtained from reactions between
nucleophiles bearing a 4-nitro group and methyl vinyl ke-
tone than with methyl acrylate; the opposite was found
when substrates without a 4-nitro group were used.
ed with acrylates and methyl vinyl ketone. In all cases, the
imidazole and its derivatives underwent aza-Michael ad-
dition successfully and the products 3a–p were obtained
in good to excellent yields (Table 3). As seen from the
Table 3, 4-nitroimidazole gave superior results, compared
with imidazole (entry 10), in the reaction with methyl
acrylate (entry 2). A competitive experiment using a 1:1
mixture of 4-nitroimidazole and imidazole, as the Michael
donor, with methyl vinyl ketone was designed. The 4-ni-
troimidazole adduct was obtained in 54% yield, with the
imidazole derived product forming in 35%, showing that
the presence of an electron-withdrawing group enhanced
the nucleophilicity and reactivity of the N-heterocycles
O2N
N
O2N
N
O
N
1
NH
equiv
O
0
.05 equiv N-methylimidazole
54%
+
DMSO 70 °C, 1 h
N
1 equiv
N
1
NH
equiv
N
O
(
Scheme 2). Triazole was found to be more reactive than
imidazole, 2-methylimidazole and 4-methylimidazole,
both in the aza-Michael addition to methyl vinyl ketone
35%
Scheme 2
(
(
Table 3, entries 9, 11, 13 and 15) and to methyl acrylate
Table 3, entries 10, 12, 14 and 16). Examination of the
Encouraged by this result, we then examined the general-
ity of this new strategy under identical reaction condi-
tions. The protocol also proved to be effective for more
complicated N-heterocycles such as pyrimidines and pu-
rines and the expected products were formed in good to
excellent yields. Mono-adducts were obtained almost ex-
clusively, in excellent yields, with only traces of the bis-
adducts being detected. In the case of the aza-Michael ad-
dition of 5-fluorouracil to methyl vinyl ketone, 11% bis-
adduct was observed, thus demonstrating its higher reac-
tivity compared to the other two pyrimidines due to the
electron-withdrawing substituent (Table 4, entry 1). Un-
der the same conditions, only 69% yield was obtained af-
ter one hour, when 6-benzylamino-purine was employed.
Two hours were required for the reaction to go to comple-
tion due to the purines lower reactivity (Table 4, entry 4).
Similar results were obtained from reactions between N-
heterocycles and methyl acrylate (Table 4, entries 5–8).
results obtained with a range of acrylates revealed that the
chain length of the ester played a minimal role in govern-
Table 2 Screening the Amount of N-Methylimidazole in the Micha-
a
el Addition of 4-Nitroimidazole to Methyl Acrylate
Entry
N-Methylimidazole (equiv) Yield (%)b
1
2
3
4
5
6
0
3.5
12c
65
98
98
98
98
0
0.01
0.05
0.10
0.20
0.50
7
a
Reaction conditions: 4-nitroimidazole (1 mmol), methyl acrylate
A possible mechanism through which N-methylimidazole
promotes the Michael addition of N-heterocycles to a,b-
unsaturated carbonyl compounds could proceed via ab-
straction of the N–H proton of the N-heterocycle by N3 of
(
1.2 mmol) in DMSO (1 mL) containing N-methylimidazole at 70 °C
for 1 h.
b
Isolated yield.
Reacted for 8 h.
c
Synthesis 2007, No. 17, 2653–2659 © Thieme Stuttgart · New York

PAPER
N-Methylimidazole-Catalyzed Aza-Michael Addition Reaction of N-Heterocycles
2655
Table 3 Michael Addition of Imidazole and its Derivatives to Acrylates and Methyl Vinyl Ketonea
Entry
1
Nucleophile
Acceptor
Time (h)
1
Product
Yield (%)b
94
O2N
O
3a
N
NH
2
3
4
5
O N
O
O
1
1
3b
3c
3d
3e
98
97
96
99
2
OMe
OEt
N
NH
NH
NH
NH
2
O N
N
2
O N
O
O
1
N
OBu
2
O N
12
OMe
O
N
6
7
2
O N
12
1
3f
99
85
N
NH
NH
OMe
2
O N
O
O
3g
N
8
9
2
O N
1
3h
95
N
NH
OMe
O
O
1
1
3i
3j
92
79
N
N
NH
NH
1
0
1
OMe
OMe
1
O
O
1
1
3k
3l
90
76
N
N
NH
NH
1
2
1
3
4
O
O
1
1
3m
3n
92
70
N
NH
NH
1
N
N
OMe
OMe
1
5
6
N
O
O
1
1
3o
3p
99
90
NH
1
N
N
NH
a
Reaction conditions: N-heterocycle (1 mmol), a,b-unsaturated carbonyl compound (1.2 mmol) in DMSO (1 mL) containing N-methylimida-
zole (0.05 equiv) at 70 °C.
b
Isolated yield.
Synthesis 2007, No. 17, 2653–2659 © Thieme Stuttgart · New York

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B. K. Liu et al.
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Table 4 Michael Addition of Pyrimidine and Purine Derivatives to Methyl Vinyl Ketone and Methyl Acrylatea
Entry
1
Nucleophile
Acceptor
Time (h)
1
Product
Yield (%)b
73c
O
O
3q
F
HN
O
N
H
2
3
O
O
O
1
1
3r
3s
84
HN
O
O
N
H
O
83
HN
N
H
4
5
NHBn
O
O
2
1
3t
69d
9
4
N
N
N
N
H
O
3u
86
90
88
84
F
HN
OMe
OMe
OMe
OMe
O
O
N
H
6
7
O
O
O
O
1
1
2
3v
3w
3x
HN
N
H
O
HN
O
N
H
8
NHBn
N
N
N
N
H
a
Reaction conditions: N-heterocycle (1 mmol), a,b-unsaturated carbonyl compound (1.2 mmol) in DMSO (1 mL) containing N-methylimida-
zole (0.05 equiv) at 70 °C.
b
Isolated yield.
Bis-adduct (3y; 11%) was also formed.
Reacted for 1 h.
c
d
the N-methylimidazole (Scheme 3). Such an abstration In conclusion, we have developed a novel strategy for the
would enhance the nucleophilicity of the N-heterocycle Michael addition reaction of N-heterocycles to a,b-unsat-
for addition to electron-deficient alkenes.
urated carbonyl compounds under the catalytic action of
N-methylimidazole. This new methodology constitutes a
straightforward, highly efficient, cheap and green synthe-
sis of b-amino carbonyl compounds. Further applications
of N-methylimidazole for various organic syntheses and
the relationship between N-methylimidazole and ionic
liquids are under investigation.
It is worth noting that current understanding of the role of
ionic liquids in reactions is still in its infancy, although
high polarity is recognized as being the driving force.15
Since imidazole-type ionic liquids are synthesized from
N-methylimidazole, this preliminary investigation of N-
methylimidazole as a catalyst thus provides valuable clues
for further understanding the role of ionic liquids in pro-
moting certain reactions.
1H and 13C NMR spectra were recorded on a Bruker AVANCE
DMX-500 spectrometer at 500 MHz and 125 MHz in CDCl or
3
DMSO-d , respectively. Chemical shifts are reported in ppm (d),
6
Synthesis 2007, No. 17, 2653–2659 © Thieme Stuttgart · New York

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N-Methylimidazole-Catalyzed Aza-Michael Addition Reaction of N-Heterocycles
2657
ESI-MS: m/z = 214 [M + 1].
N
Butyl 3-(4-Nitroimidazol-1-yl)propionate (3d)16a
Colorless solid; mp 48 °C.
N
O
N
+
Nu-H
+
IR (KBr): 1727, 1521, 1488 cm–1.
O
Nu
H
O
N
δ+
1
H NMR (DMSO-d ): d = 7.84 (s, 1 H), 7.51 (s, 1 H), 4.36 (t, J = 6.1
6
O
δ–
Hz, 2 H), 4.12 (t, J = 6.7 Hz, 2 H), 2.86 (t, J = 6.1 Hz, 2 H), 1.60 (m,
2
H), 1.33 (m, 2 H), 0.94 (t, J = 7.4 Hz, 3 H).
1
3
C NMR (DMSO-d ): d = 170.3, 148.9, 136.6, 119.6, 65.7, 43.8,
6
3
5.5, 30.7, 19.2, 13.8.
ESI-MS: m/z = 242 [M + 1].
O
N
N
H
O
Methyl 2-Methyl-3-(4-nitroimidazol-1-yl)propionate (3e)16a
Colorless solid; mp 64–65 °C.
N
N
+
Nu
O
Nu
O
–
1
IR (KBr): 1726, 1527, 1485 cm .
1
H NMR (CDCl ): d = 7.8 (s, 1 H), 7.46 (s, 1 H), 4.32–4.13 (m,
3
2
H), 3.71 (s, 3 H), 2.95 (m, 1 H), 1.28 (d, J = 7.2 Hz, 3 H).
Scheme 3
13
C NMR (CDCl ): d = 173.7, 148.4, 136.8, 119.9, 52.7, 50.4, 41.2,
3
1
5.2.
relative to the internal TMS standard. IR spectra were measured
with a Nicolet Nexus FTIR 670 spectrophotometer. Mass spectra
were obtained by electrospray ionization (ESI) on a Bruker esquire
ESI-MS: m/z = 214.2 [M + 1].
Methyl 3-(4-Nitroimidazol-1-yl)butanoate (3f)16a
Colorless solid; mp 113–114 °C.
3
000 plus mass spectrometer. Melting points were determined using
an XT-4 apparatus and are uncorrected. All chemicals were ob-
tained from commercial suppliers and used without further purifica-
tion.
IR (KBr): 1734, 1543, 1489 cm–1.
1
H NMR (CDCl ): d = 7.85 (s, 1 H), 7.55 (s, 1 H), 4.79 (m, 1 H),
3
3
.68 (s, 3 H), 2.84 (d, J = 6.9 Hz, 2 H), 1.64 (d, J = 7.0 Hz, 3 H).
1
3
Michael Addition; General Procedure
C NMR (CDCl ): d = 170.0, 148.7, 135.4, 117.5, 52.5, 51.8, 42.0,
3
4
-Nitroimidazole (1 mmol) and a,b-unsaturated carbonyl com-
pounds (1.2 mmol) were added to a solution of N-methylimidazole
0.05 equiv) in DMSO (1 mL) and the mixture was shaken at 200
21.5.
ESI-MS: m/z = 214.1 [M + 1].
(
rpm and 70 °C for 1 h. The reaction mixture was purified by flash
column chromatography (silica gel) to obtain the corresponding
Michael adduct.
4
-(2-Methyl-4-nitroimidazol-1-yl)butan-2-one (3g)16b
Yellow solid; mp 87–89 °C.
–
1
IR (KBr): 1706, 1680, 1653 cm .
4
-(4-Nitroimidazol-1-yl)butan-2-one (3a)16a
Yellow solid; mp 65–67 °C.
1
H NMR (DMSO-d ): d = 8.24 (s, 1 H), 4.12 (t, J = 6.7 Hz, 2 H),
6
3
.07 (t, J = 6.7 Hz, 2 H), 2.38 (s, 3 H), 2.10 (s, 3 H).
–
1
IR (KBr): 1741, 1523, 1490 cm .
13
C NMR (DMSO-d ): d = 206.6 145.8, 122.6, 42.8, 41.7, 30.3,
6
1
H NMR (CDCl ): d = 7.82 (d, J = 1.4 Hz, 1 H), 7.49 (d, J = 1.4 Hz,
13.2.
3
1
3
H), 4.32 (t, J = 5.9 Hz, 2 H), 3.02 (t, J = 5.9 Hz, 2 H), 2.21 (s,
ESI-MS: m/z = 275 [M + Na].
H).
1
3
Methyl 3-(2-Methyl-4-nitroimidazol-1-yl)propionate (3h)16a
Yellow liquid.
C NMR (CDCl ): d = 204.3, 148.1, 136.8, 120.1, 43.8, 42.4, 30.2.
3
ESI-MS: m/z = 184 [M + 1].
–
1
IR (neat): 1729, 1508 cm .
Methyl 3-(4-Nitroimidazol-1-yl)propionate (3b)16a
Colorless solid; mp 109 °C.
1
H NMR (CDCl ): d = 7.76 (s, 1 H), 4.25 (t, J = 6.4 Hz, 2 H), 3.72
3
(
s, 3 H), 2.82 (t, J = 6.4 Hz, 2 H), 2.48 (s, 3 H).
–
1
IR (KBr): 1729, 1526, 1485 cm .
1
13
C NMR (CDCl ): d = 173.2, 148.9, 147.8, 123.1, 54.7, 45.0, 36.9,
3
H NMR (CDCl ): d = 7.83 (s, 1 H), 7.51 (s, 1 H), 4.35 (t, J = 6.1
15.5.
3
Hz, 2 H), 3.73 (s, 3 H), 2.86 (t, J = 6.1 Hz, 2 H).
1
ESI-MS: m/z = 214 [M + 1].
3
C NMR (CDCl ): d = 170.5, 148.9, 136.6, 119.7, 52.7, 43.8, 35.3.
3
4
-(Imidazol-1-yl)butan-2-one (3i)16c
ESI-MS: m/z = 200 [M + 1].
Colorless oil.
Ethyl 3-(4-Nitroimidazol-1-yl)propionate (3c)16a
Colorless solid; mp 35–37 °C.
IR (neat): 1715, 1508 cm–1.
1
H NMR (CDCl ): d = 7.48 (s, 1 H), 6.99 (s, 1 H), 6.92 (s, 1 H), 4.22
3
–
1
IR (KBr): 1733, 1519, 1492 cm .
(t, J = 6.4 Hz, 2 H), 2.92 (t, J = 6.4 Hz, 2 H), 2.14 (s, 3 H).
1
13C NMR (CDCl
H NMR (DMSO-d ): d = 7.85 (s, 1 H), 7.51 (s, 1 H), 4.36 (t, J = 6.1
3
): d = 205.2, 137.2, 129.1, 119.0, 44.4, 40.8, 30.1.
6
Hz, 2 H), 4.18 (q, J = 7.1 Hz, 2 H), 2.85 (t, J = 6.1 Hz, 2 H), 1.25 (t,
J = 7.1 Hz, 3 H).
ESI-MS: m/z = 139 [M + 1].
1
3
Methyl 3-(Imidazol-1-yl)propionate (3j)16a
Yellow oil.
C NMR (DMSO-d ): d = 170.2, 148.9, 136.6, 119.7, 61.9, 43.8,
6
3
5.5, 14.3.
Synthesis 2007, No. 17, 2653–2659 © Thieme Stuttgart · New York

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B. K. Liu et al.
PAPER
–
1
1
IR (neat): 1732, 1509 cm .
H NMR (CDCl ): d = 8.17 (s, 1 H), 7.93 (s, 1 H), 4.49 (t, J = 6.3
3
1
Hz, 2 H), 3.69 (s, 3 H), 2.93 (t, J = 6.3 Hz, 2 H).
1
H NMR (CDCl ): d = 7.54 (s, 1 H), 7.05 (s, 1 H), 6.93 (s, 1 H), 4.27
t, J = 6.6 Hz, 2 H), 3.70 (s, 3 H), 2.78 (t, J = 6.6 Hz, 2 H).
3
3
(
C NMR (CDCl ): d = 171.0, 152.2, 143.8, 52.2, 44.9, 34.0.
3
1
3
C NMR (CDCl ): d = 170.3, 136.6, 128.5, 118.2, 51.1, 41.5, 34.9.
ESI-MS: m/z = 156 [M + 1].
3
ESI-MS: m/z = 155 [M + 1].
1
-(Butan-3-one-1-yl)-5-fluorouracil (3q)16e
-(2-Methylimidazol-1-yl)butan-2-one (3k)16c
Colorless solid; mp 142–143 °C.
4
–
1
Colorless oil.
IR (KBr): 1718, 1705, 1684, 1666 cm .
–
1
1
IR (neat): 1715, 1503 cm .
H NMR (DMSO-d ): d = 11.74 (s, 1 H), 8.01 (d, J = 6.8 Hz, 1 H),
6
1
3.77 (t, J = 6.6 Hz, 2 H), 2.86 (t, J = 6.6 Hz, 2 H), 2.10 (s, 3 H).
1
H NMR (CDCl ): d = 6.83 (s, 1 H), 6.78 (s, 1 H), 4.08 (t, J = 6.4
Hz, 2 H), 2.35 (s, 3 H), 2.12 (s, 3 H).
3
3
C NMR (DMSO-d ): d = 207.3, 158.1, 157.9, 150.0, 140.6, 138.8,
6
1
3
131.3, 131.1, 43.9, 41.7, 30.3.
C NMR (CDCl ): d = 205.3, 144.6, 127.4, 119.3, 45.4, 40.2, 30.5,
3
1
3.2.
ESI-MS: m/z = 223 [M + Na].
ESI-MS: m/z = 153 [M + 1].
1
-(Butan-3-one-1-yl)uracil (3r)16e
Colorless solid; mp 111 °C.
Methyl 3-(2-Methylimidazol-1-yl)propionate (3l)16a
Yellow oil.
–
1
IR (KBr): 1708, 1682, 1650 cm .
–
1
1
IR (neat): 1733, 1508 cm .
H NMR (DMSO-d ): d = 11.52 (s, 1 H), 7.41 (d, J = 7.6 Hz, 1 H),
6
1
5.56 (d, J = 7.6 Hz, 1 H), 3.92 (t, J = 7.5 Hz, 2 H), 2.66 (t, J = 7.5
Hz, 2 H), 2.09 (s, 3 H).
H NMR (CDCl ): d = 6.90 (s, 1 H), 6.84 (s, 1 H), 4.16 (t, J = 6.8
Hz, 2 H), 3.69 (s, 3 H), 2.74 (t, J = 6.8 Hz, 2 H), 2.41 (s, 3 H).
3
13C NMR (DMSO-d
5.4, 30.2.
): d = 207.4, 163.5, 151.8, 141.2, 100.2, 41.3,
6
1
3
C NMR (CDCl ): d = 170.6, 144.1, 126.8, 118.6, 51.6, 41.0, 34.8,
3
3
1
2.4.
ESI-MS: m/z = 205 [M + Na].
ESI-MS: m/z = 183 [M + 1].
1
-(Butan-3-one-1-yl)thymidine (3s)16e
4
-(4-Methylimidazol-1-yl)butan-2-one (3m) (Mixture with 5-
Colorless solid; mp 104–105 °C.
Methylimidazolyl Product)
Colorless oil.
–
1
IR (KBr): 1710, 1684, 1650 cm .
–
1
1
IR (neat): 1715, 1500 cm .
H NMR (DMSO-d ): d = 11.20 (s, 1 H), 7.48 (d, J = 1.1 Hz, 1 H),
6
1
3.77 (t, J = 6.8 Hz, 2 H), 2.83 (t, J = 6.8 Hz, 2 H), 2.09 (s, 3 H), 1.73
(
H NMR (CDCl ): d = 7.42 (s, 0.6 H), 7.35 (s, 0.6 H), 6.72 (s, 1 H),
.60 (s, 0.9 H), 4.13 (m, 3 H), 2.88 (m, 3 H), 2.20 (s, 1.5 H), 2.18 (s,
H), 2.16 (s, 1.5 H), 2.15 (s, 3 H).
3
d, J = 1.0 Hz, 3 H).
6
3
1
3
C NMR (DMSO-d ): d = 207.4, 164.8, 151.3, 142.2, 108.6, 43.4,
6
1
3
42.1, 30.3, 12.5.
C NMR (CDCl ): d = 205.4, 205.2, 138.4, 136.9, 136.5, 126.9,
26.8, 115.5, 44.5, 43.9, 41.0, 38.7, 30.8, 13.6, 9.2.
3
1
ESI-MS: m/z = 219 [M + Na].
ESI-MS: m/z = 153 [M + 1].
1
-(Butan-3-one-1-yl)-6-benzylaminopurine (3t)
Methyl 3-(4-Methylimidazol-1-yl)propionate (3n)16a (Mixture
with 5-Methylimidazolyl Product)
Yellow oil.
Colorless oil.
–
1
IR (KBr): 1706, 1680, 1653 cm .
1
H NMR (DMSO-d ): d = 8.20 (s, 1 H), 8.09 (s, 1 H), 7.29 (m, 5 H),
6
–
1
IR (neat): 1732, 1508 cm .
4.65 (s, 2 H), 4.31 (t, J = 6.7 Hz, 2 H), 3.10 (t, J = 6.7 Hz, 2 H), 2.10
1
(s, 3 H).
H NMR (CDCl ): d = 7.44 (s, 0.4 H), 7.38 (s, 0.6 H), 6.75 (s,
3
1
3
0
2
.4 H), 6.62 (s, 0.6 H), 4.17 (m, 2 H), 3.69 (s, 3 H), 2.75 (m, 2 H),
C NMR (DMSO-d ): d = 206.9, 152.8, 141.4, 128.7, 127.7, 127.6,
6
.21 (d, J = 2.1 Hz, 3 H).
127.1, 42.6, 38.5, 30.3.
1
3
C NMR (CDCl ): d = 171.2, 171.0, 138.6, 136.9, 136.4, 126.9,
ESI-MS: m/z = 318 [M + Na].
3
1
15.4, 52.1, 42.3, 40.0, 35.8, 35.3, 13.6, 9.1.
1
-(2-Methoxycarbonylethyl)-5-fluorouracil (3u)16a
Yellow solid; mp 145–146 °C.
ESI-MS: m/z = 183 [M + 1].
4
-(1,2,4-Triazol-1-yl)butan-2-one (3o)16d
IR (KBr): 1729, 1692, 1663 cm–1.
Yellow oil.
1
H NMR (DMSO-d ): d = 7.52 (s, 1 H), 3.97 (t, J = 5.8 Hz, 2 H),
6
–
1
IR (KBr): 1716, 1507, 1375 cm .
3.72 (s, 3 H), 2.79 (t, J = 5.8 Hz, 2 H).
1
13
H NMR (CDCl ): d = 8.13 (s, 1 H), 7.90 (s, 1 H), 4.37 (t, J = 6.1
C NMR (DMSO-d ): d = 172.0, 157.5, 157.3, 149.6, 141.2, 139.2,
3
6
Hz, 2 H), 3.05 (t, J = 6.1 Hz, 2 H), 2.16 (s, 3 H).
130.5, 130.3, 52.5, 45.8, 32.9.
1
3
C NMR (CDCl ): d = 205.3, 152.3, 144.2, 43.9, 42.7, 30.5.
ESI-MS: m/z = 217 [M + 1].
3
ESI-MS: m/z = 162 [M + Na].
1
-(2-Methoxycarbonylethyl)uracil (3v)16a
Colorless solid; mp 127–128 °C.
Methyl 3-(1,2,4-Triazol-1-yl)propionate (3p)16a
Yellow oil.
–
1
IR (KBr): 1733, 1696, 1662 cm .
–
1
IR (neat): 1735, 1507, 1440 cm .
Synthesis 2007, No. 17, 2653–2659 © Thieme Stuttgart · New York

PAPER
N-Methylimidazole-Catalyzed Aza-Michael Addition Reaction of N-Heterocycles
2659
1
H NMR (DMSO-d ): d = 9.03 (s, 1 H), 7.40 (d, J = 7.9 Hz, 1 H),
(2) Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int.
Ed. 1998, 37, 1044.
(3) Reboule, I.; Gil, R.; Collin, J. Tetrahedron Lett. 2005, 46,
6
5
2
.68 (d, J = 7.9 Hz, 1 H), 4.00 (t, J = 5.9 Hz, 2 H), 3.71 (s, 3 H),
.80 (t, J = 5.9 Hz, 2 H).
1
3
7761.
C NMR (DMSO-d ): d = 172.1, 164.0, 151.0, 146.0, 102.0, 52.4,
6
(
4) Bartoli, G.; Bosco, M.; Marcantoni, E.; Petrini, M.; Sambri,
L.; Torregiani, E. J. Org. Chem. 2001, 66, 9052.
5) Loh, T. P.; Wei, L. L. Synlett 1998, 975.
4
5.5, 33.0.
ESI-MS: m/z = 199 [M + 1].
(
(
6) (a) Saha, B.; Das, D.; Banerji, B.; Iqbal, J. Tetrahedron Lett.
1
-(2-Methoxycarbonylethyl)thymidine (3w)16a
2
002, 43, 6467. (b) Enders, D.; Müller, S. F.; Raabe, G.;
Runsink, J. Eur. J. Org. Chem. 2000, 6, 879.
(7) Varala, R.; Alam, M. M.; Adapa, S. R. Synlett 2003, 720.
Colorless solid; mp 120–121 °C.
–
1
IR (KBr): 1735, 1698, 1655 cm .
1
(
8) Wabnitz, T. C.; Spencer, J. B. Tetrahedron Lett. 2002, 43,
891.
9) Azizi, N.; Saidi, M. R. Tetrahedron 2004, 60, 383.
H NMR (DMSO-d ): d = 8.87 (s, 1 H), 7.20 (s, 1 H), 3.96 (t, J = 6.0
6
3
Hz, 2 H), 3.71 (s, 3 H), 2.78 (t, J = 6.0 Hz, 2 H), 1.91 (s, 3 H).
1
(
3
C NMR (DMSO-d ): d = 172.1, 164.6, 151.1, 141.8, 110.6, 52.3,
(10) Shaikh, N. S.; Deshpande, V. H.; Bedekar, A. V.
6
4
5.3, 33.1, 12.5.
Tetrahedron 2001, 57, 9045.
(
11) (a) Ranu, B. C.; Dey, S. S. Tetrahedron 2004, 60, 4183.
b) Fan, X. S.; Hu, X. Y.; Zhang, X. Y.; Wang, J. J. Aust. J.
ESI-MS: m/z = 213 [M + 1].
(
-(2-Methoxycarbonylethyl)-6-benzylaminopurine (3x)16a
Yellow solid; mp 124–125 °C.
Chem. 2004, 57, 1067. (c) Ranu, B. C.; Banerjee, S. Org.
Lett. 2005, 7, 3049. (d) Calo, V.; Nacci, A.; Lopez, L.;
Lerario, V. L. Tetrahedron Lett. 2000, 41, 8977.
12) Yeom, C. E.; Kim, M. J.; Kim, B. M. Tetrahedron 2007, 63,
904.
(13) Liu, B. K.; Wu, Q.; Xu, J. M.; Lin, X. F. Chem. Commun.
2007, 295.
1
–
1
IR (KBr): 3366, 3097, 1724, 1613 cm .
(
1
H NMR (DMSO-d ): d = 8.52 (s, 1 H), 7.87 (s, 1 H), 7.41–7.27 (m,
6
5
H), 6.45 (t, J = 5.4 Hz, 1 H), 4.85 (d, J = 5.4 Hz, 2 H), 4.59 (t,
J = 6.0 Hz, 2 H), 3.63 (s, 3 H), 2.92 (t, J = 6.0 Hz, 2 H).
(
14) (a) Nakatsuji, H.; Morita, J.; Misaki, T.; Tanabe, Y. Adv.
Synth. Catal. 2006, 348, 2057. (b) Hagiwara, H.; Inoguchi,
H.; Fukushima, M.; Hoshi, T.; Suzuki, T. Tetrahedron Lett.
2006, 47, 5371. (c) Iida, A.; Nakazawa, S.; Okabayashi, T.;
Horii, A.; Misaki, T.; Tanabe, Y. Org. Lett. 2006, 8, 5215.
(d) Iida, A.; Nakazawa, S.; Okabayashi, T.; Horii, A.;
Misaki, T.; Tanabe, Y. J. Am. Chem. Soc. 2005, 127, 2584.
(e) Ding, H. F.; Ma, C.; Yang, Y. W.; Wang, Y. G. Org. Lett.
1
3
C NMR (DMSO-d ): d = 171.6, 155.0, 153.4, 140.7, 138.8, 128.9,
6
1
28.0, 127.7, 121.0, 52.3, 42.0, 39.6, 34.2.
ESI-MS: m/z = 312 [M + 1].
1
,3-Di(butan-3-one-1-yl)-5-fluorouracil (3y)
Colorless solid; mp 86–87 °C.
–
1
IR (KBr): 1703, 1675, 1645 cm .
2005, 7, 2125.
1
H NMR (DMSO-d ): d = 8.08 (d, J = 6.6 Hz, 1 H), 3.97 (t, J = 7.5
6
(15) Crowhurst, L.; Lancaster, N. L.; Arlandis, J. M. P.; Welton,
Hz, 2 H), 3.83 (t, J = 6.7 Hz, 2 H), 2.87 (t, J = 6.7 Hz, 2 H), 2.70 (t,
J = 7.5 Hz, 2 H), 2.10 (d, J = 4.3 Hz, 6 H).
T. J. Am. Chem. Soc. 2004, 126, 11549.
(
16) (a) Xu, J. M.; Qian, C.; Liu, B. K.; Wu, Q.; Lin, X. F.
Tetrahedron 2007, 63, 986. (b) Bhujanga Rao, A. K. S.;
Rao, C. G.; Singh, B. B. J. Org. Chem. 1990, 55, 3702.
1
3
C NMR (DMSO-d ): d = 207.2, 157.0, 149.7, 140.1, 138.3, 130.1,
6
1
29.9, 44.9, 41.5, 40.8, 36.9, 30.3.
(
c) Firouzabadi, H.; Iranpoor, N.; Jafari, A. A. Adv. Synth.
ESI-MS: m/z = 293 [M + Na].
Catal. 2005, 347, 655. (d) Kofman, T. P.; Kartseva, G. Y.;
Glazkova, E. Y.; Krasnov, K. N. Russ. J. Org. Chem. 2005,
4
1, 753. (e) Kim, J. C.; Dong, E. S.; Kim, J. A.; Kim, S. H.;
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Synthesis 2007, No. 17, 2653–2659 © Thieme Stuttgart · New York