One-pot three-component reaction providing 1,5-benzodiazepine derivatives

Article abstract of DOI:10.1016/j.tet.2008.09.076

The novel one-pot three-component reaction of aromatic aldehydes, 1,2-phenylenediamine, and β-keto esters is described. This reaction involves the γ-selective C-C bond formation of β-keto esters and produces 1,5-benzodiazepine derivatives.

Full text of DOI:10.1016/j.tet.2008.09.076

Tetrahedron 64 (2008) 11034–11040
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot three-component reaction providing 1,5-benzodiazepine derivatives
*
*
Kenichi Murai, Ryo Nakatani, Yasuyuki Kita , Hiromichi Fujioka
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The novel one-pot three-component reaction of aromatic aldehydes, 1,2-phenylenediamine, and b-keto
Received 8 August 2008
Received in revised form
25 September 2008
Accepted 25 September 2008
Available online 7 October 2008
esters is described. This reaction involves the
produces 1,5-benzodiazepine derivatives.
g
-selective C–C bond formation of
b-keto esters and
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
reaction of the intermediate occurs between the imine and
-position of the enamino ester. In this paper, we describe the
g
1,5-Benzodiazepines are some of the important heterocyclic
compounds from the viewpoint of biological activities.1 General
methods for preparing these compounds include the condensa-
one-pot three-component reaction providing 1,5-benzodiazepine
derivatives using 1,2-phenylenediamine in our reaction instead of
ethylenediamine.
tions of 1,2-phenylenediamine with
a,b-unsaturated carbonyl
compounds or
b
-haloketones.2 As the condensation partners, ke-
2. Results and discussion
tones were also used;3 in this case, 1,2-phenylenediamine and
2 equiv of ketones were condensed through an intramolecular
imine–enamine cyclization. Instead of 1,2-phenylenediamine,
o-nitrophenylazide and o-nitroaniline were used in the presence of
a reducing reagent such as SmI2 and TiCl4/Sm.4 In addition, the
condensation of aldehdyes with enamines prepared from 1,2-
phenylenediamine was also reported.1h,5 Although these methods
were useful and the products from each method were not similar, it
is desirable to develop the reaction readily providing divergent 1,5-
benzodiazepine derivatives.
Recently, multi-component reactions have been receiving more
and more attention because of their efficiency and diversity of
products.6 Their utilities were fully realized in the process of drug
discovery7 and the total synthesis of complex natural products.8
Although a great number of such useful reactions have been
reported, the development of a novel multi-component reaction is
still important in the fields of medicinal and organic syntheses.
We have recently reported the novel three-component reaction
The reaction was first examined in detail using 1,2-phenyl-
enediamine (1), methyl acetoacetate (2a), and benzaldehyde (3a).
When all substrates were simultaneously added to p-TsOH, similar
to the previous procedure, the desired product 4a, the g-addition
product, was obtained, though the yield was low. Reactions with
the other acids did not improve the yield (Scheme 1).
NH2
NH2
1 (1.0 eq.)
HN
NH
acid (0.1 eq.)
DCE, reflux
simultaneous
O
O
O
Ph
OMe
2a (1.0 eq.)
OMe
addition
4a:
23% (p-TsOH·H2O)
13% (PPTS)
26% (TFA)
PhCHO
3a (1.0 eq.)
of aromatic aldehydes, ethylenediamine, and
ducing seven-membered 1,4-azepane compounds.9,10 This reaction
is very unique because -keto esters react at the generally unreac-
tive -positions. The reaction mechanism is rationalized as follows.
During the first stage of the reaction, ethylenediamine bridges
the aldehyde and the -ketoesters to form the intermediates
b-keto esters pro-
Scheme 1. First attempts.
b
It was considered that the formation of the intermediate i in-
volving imines and enamino esters was important for producing 4a
in a good yield (Scheme 2). In the case of 1,2-phenylenediamine (1),
methyl acetoacetate (2a), and benzaldehyde (3a), the imine in-
termediate ii was first formed from 1,2-phenylenediamine (1) and
benzaldehyde (3a). If the intermediate i was formed from the imine
intermediate ii with methyl acetoacetate (2a), the desired reaction
would proceed. However, the formation of the intermediate i
g
b
involving imines and enamino esters. Next, the intramolecular
* Corresponding authors.
E-mail address: fujioka@phs.osaka-u.ac.jp (Y. Kita).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.076

K. Murai et al. / Tetrahedron 64 (2008) 11034–11040
11035
seemed to be much slower than the intramolecular cyclization of
the amine to the imine unit of intermediate ii. It is well known that
in the presence of acid catalysts the condensations of 1,2-phenyl-
enediamine (1) and aldehydes produced the benzoimidazole de-
rivatives.11 Actually, the formation of 2-phenyl benzoimidazole and
N-benzyl 2-phenyl benzoimidazole was confirmed in this reaction.
methyl acetoacetate (2a) gave better results (Table 1, entries 1–3).
Based on the results of the reactions in various solvents (DCE, tol-
uene, MeOH, CH3CN, THF, CH2Cl2, CHCl3, and PhCF3), DCE appeared
to be the best solvent (Table 1, entries 2 and 4–10). As the result of
having examined various acids (TFA, TsOH, TfOH, AcOH, PhPO3H,
Cl3CCO2H, p-NO2C6H4CO2H, C6F5CO2H, Zn(OTf)2, Yb(OTf)3, and
Cu(BF4)2), C6F5CO2H appeared to give the best results.12 The addi-
tions of molecular sieves 4 Å or MgSO4 were not effective. Finally,
the ratio of the substrate and reagent was examined once again
and it was concluded that 1.0 equiv of 1,2-phenylenediamine (1)
and benzaldehyde (3a), 1.3 equiv of methyl acetoacetate (2a), and
0.2 equiv of C6F5CO2H gave the best results (Table 2, entry 1).
We then applied the optimized conditions to the synthesis of the
1,5-benzodiazepine derivatives from various aromatic aldehydes us-
ing 1,2-phenylenediamine (1) and methyl acetoacetate (2a) (Table 2).
At first, various benzaldehydes having the substituent at the para
position were examined. Although electron-withdrawing groups
gave much better results, both the electron-donating and electron-
withdrawing groups gave moderate yields (Table 2, entries 2–7). The
resultofusing o-methylbenzaldehyde(3j)indicatedthatthisreaction
was more influenced by steric effects (Table 2, entry 10). It is worth
mentioning that esters and nitriles are tolerant under the optimized
conditions (Table 2, entries 6 and 7). Furthermore, not only various
substituted benzaldehydes (3a–3k), but also 2-naphthaldehyde (3l),
3-furancarboxaldehyde (3m), and 2-thiophenecarboxaldehyde (3n)
were applicable (Table 2, entries 12–14).
2-phenyl benzoimidazole
derivatives
1
+
3a
N
NH2
N
4a
NH
Ph
O
ii
Ph
OMe
Scheme 2. Reaction of intermediate ii.
i
Therefore, we modified the reaction procedure to form the in-
termediate i. Thus, 1,2-phenylenediamine (1) and methyl acetoa-
cetate (2a) were first condensed to form the enamino ester
intermediate iii, and benzaldehyde (3a) was added to the in-
termediate iii to form intermediate i (Scheme 3).
Various
b-keto esters were next examined using 1,2-phenyl-
enediamine (1) and benzaldehyde (3a) (Table 3). Not only benzyl
acetoacetate (2b), but also tert-butyl acetoacetate (2c) having the
acid sensitive tert-butyl ester moiety was tolerant and gave good
results (Table 3, entries 1 and 2). Unfortunately, the reaction using
1
then 3a
H2N
N
+
NH
NH
4a
O
O
2a
Ph
OMe
OMe
iii
i
Table 2
Scheme 3. Modification of reaction procedure.
Reactions with various aldehydes
NH2
1 ) C6F5COOH
(0.2 eq.)
As we expected, the modification of the reaction procedure
improved the yield of the product (Table 1, entry 1). Various con-
ditions concerning the ratio of the reagent, solvent, and acid were
next tested using the improved procedure. Some of the results are
shown in Table 1. The appropriate ratio of the reagents was first
determined. When an equimolar amount of 1,2-phenylenediamine
(1) and benzaldehyde (3a) were used, the reaction with 1.2 equiv of
rt. 4hr
NH2
1 (1.0 eq.)
2) ArCHO (3)
(1.0 eq.)
reflux
HN
Ar
NH
O
O
O
DCE
OMe
2a (1.3 eq.)
OMe
4
Table 1
Entry
ArCHO
Yield (%)
Optimization
X
NH2
CHO
1 ) acid (0.1 eq.)
1
2
3
4
5
6
7
8
X¼H
(3a)
(3b)
(3c)
(3d)
(3e)
(3f)
(3g)
(3h)
(3i)
4a: 68
4b: 57
4c: 66
4d: 66
4e: 61
4f: 59
4g: 57
4h: 54
4i: 58
4j: 34
4k: 51
NH2
rt.
X¼p-MeO
1
2) PhCHO (3a)
reflux
X¼p-Cl
X¼p-Br
HN
Ph
NH
O
O
O
solvent
X¼p-NO2
X¼p-CN
OMe
OMe
4a
2a (x eq.)
X¼p-CO2Me
X¼m-MeO
X¼m-Cl
9
10
11
Entry
Acid
Solvent
x equiv
Yield (%)
X¼o-Me
(3j)
(3k)
1
2
3
4
5
6
7
8
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
DCE
DCE
DCE
1.0
1.2
1.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
37
54
47
Complex
Complex
38
40
41
48
34
27
28
60
X¼o-Cl
CHO
Toluene
MeOH
CH3CN
THF
CH2Cl2
CHCl3
PhCF3
DCE
12
13
14
(3l)
4l: 57
CHO
(3m)
(3n)
4m: 33
4n: 55
9
TFA
TFA
O
10
11
12
13
TsOH
TfOH
C6F5CO2H
DCE
DCE
CHO
S

11036
K. Murai et al. / Tetrahedron 64 (2008) 11034–11040
Table 3
entry 3). The
such as CH3CN (
a-selectivity was also observed in aprotic solvents
Reactions with various b-keto esters
g
/a¼31:69) and THF (
g/a
¼1<:99) (Table 4, entries
4 and 5). These results showed that the polarity of the solvent was
more important because the protic EtOH and aprotic THF gave the
same selectivity.
Entry
b
-Keto ester (2)
Product (4)
Yield (%)
HN
O
O
Ph
NH
3c (1.0 eq.)
OR
O
HN
Ar
C6F5CO2H
NH
HN
Ar
(0.2 eq.)
H2N
NH
+
NH
O
OR
O
solvent
temp.
1a
2a
R¼Bn (2b)
R¼t-Bu (2c)
R¼Bn (4o)
67
73
O
OMe
OMe
OMe
R¼t-Bu (4p)
5
4c (γ−adduct)
Ar = p-ClC6H4
6 (α−adduct)
O
O
OEt
3
d
d
Table 4
Solvent effect
(2d)
Entry
Solvent
Temperature
Time (h)
Ratioa
(g
/a
)
Yield %b (4c, 6)
HN
Ph
1
2
3
4
5
DCE
DCE
EtOH
CH3CN
THF
Reflux
2.5
19
1
17
6
99:<1
89:11
<1:99
31:69
<1:99
59, d
48, d
d, 78
19, 45
d, 70
O
O
rt
rt
rt
rt
NH
4b
OMe
16
O
OMe
(2e)
Ratio was determined from 1H NMR analysis of crude reaction mixtures.
Isolated yield.
a
(4q)
b
HN
Ph
O
The stability of the
tested, because the -adduct was partially formed in DCE at rt but
not under reflux conditions. As shown in Scheme 4, the -adduct 6
was converted to the -adduct 4c at reflux in DCE in the presence of
C6F5CO2H. The -adduct 4c was also formed in EtOH, though the
yield was lower than that in DCE. Interestingly, the -adduct 4c was
formed without the acid catalyst. Based on these results, we con-
sidered that the -adduct 6 was comparatively unstable at higher
temperatures and the -adduct 6 and imine–enaminoester in-
termediate such as i shown in Scheme 3 were both reversible. The
-adduct 4c, which seemed to be thermodynamically stable due to
a-adduct 6 versus the temperature was next
O
NH
a
5b
50
OMe
a
O
g
(2f)
OMe
g
(4r)
g
a
Reactions were carried out under the same condition as Table 2.
First step of reaction was carried out at 50 ꢀC. For details, see Section 4.
b
a
a
ethyl 2-methylacetoacetate (2d) did not work, because of a diffi-
culty in preparation of enamino ester, the intermediate of the re-
action (Table 3, entry 3).13 Although the reaction using methyl
propionylacetate (2e) formed the enamino ester, the yield was low
(Table 3, entry 4). On the other hand, methyl 2-oxocyclopentane-
carboxylate (2f) produced desired compound 4r in a moderate
yield (Table 3, entry 5).14 The reaction was considered to proceed
through the formation of the intermediate i (Scheme 3) and
g
the intramolecular hydrogen bonding between NH and C]O
functions, was then formed. Accordingly, we now think that the
g-selectivity of the one-pot three-component reaction developed
here was mainly due to thermodynamic control. However, further
investigations are required, since it was the fact that
was observed in DCE even at rt.
g-selectivity
g
-addition probably occurred via the corresponding diene form.
Thus the decrease in the yield of the -keto ester (2e) was probably
due to the 1,3-allylic strain of the Z-enolate of the diene form for
intramolecular -addition. This indicates that the easy formation of
the diene intermediate is essential for this transformation.
Lastly, we did several experiments examining the -selectivity.
In a previous paper, the related reaction using the enamino ester,
which was prepared from 1,2-phenylenediamine (1) and ethyl
acetoacetate, was reported.1h Thus the enamino ester and
m-nitrobenzaldehyde were treated with acetic acid in ethanol at rt
to produce the 1,5-benzodiazepine derivative via the addition at
b
g
HN
NH
C6F5CO2H
(0.2 eq.)
HN
NH
O
g
solvent
reflux
O
6
OMe
Cl
OMe
Cl
4c
DCE (30min): 76%
EtOH (40min): 45%
DCE (without acid, 24h): 70%
the
a-position of the enamino ester. Only one substrate was
Scheme 4. Effect of the temperature.
reported in the paper, and the regioselectivity of the reaction of the
enamino ester was distinct from our results. Therefore, we were
very interested in the differences in the selectivity, thus the fol-
lowing experiments with the enamino ester 5 were carried. The
3. Conclusion
solvent effect was first investigated. When
benzaldehyde (3c) were treated with C6F5CO2H in refluxing DCE,
the -adduct 4c was selectively obtained (Table 4, entry 1). At rt, the
-addition was confirmed, but the major product was the -adduct
4c (
¼89:11) (Table 4, entry 2). On the other hand, when EtOH
was used as the solvent, only the -adduct 6 was obtained (Table 4,
5
and p-chloro-
In conclusion, we have developed a novel one-pot three-com-
ponent reaction of aromatic aldehydes, 1,2-phenylenediamine, and
b-keto esters in the presence of a catalytic acid producing 1,5-
benzodiazepine derivatives. The reaction procedure is important
for good yields. Thus, the condensations of 1,2-phenylenediamine
and the b-keto esters to form the enamino esters were essential.
g
a
g
g/a
a

K. Murai et al. / Tetrahedron 64 (2008) 11034–11040
11037
The main feature of this reaction is the
g
-selective C–C bond for-
to give 4c (97.8 mg, 68%). Reaction time for reflux was 2.5 h. Hex-
ane/AcOEt¼4:1 was used as eluent for SiO2 column chromato-
mation of -enamino esters probably due to the thermodynamic
b
control derived from intramolecular hydrogen bonding of the
enamino esters.
graphy. Pale yellow oil; 1H NMR (300 MHz, CDCl3):
d¼10.18 (br s,
1H), 7.32–7.25 (m, 4H), 7.01–6.89 (m, 3H), 6.76 (d, J¼5.1 Hz,1H), 4.84
(dd, J¼7.5, 4.5 Hz, 1H), 4.52 (s, 1H), 3.66 (br s, 1H), 3.66 (s, 3H), 2.63–
4. Experimental section
4.1. General
2.49 ppm (m, 2H); 13C NMR (75.5 MHz, CDCl3):
d
¼170.4, 158.0,
142.8,137.8,133.5,130.2,128.8,127.6,125.0,122.5,122.0,120.9, 84.2,
64.4, 50.3, 39.8 ppm; IR (KBr): 3276, 2252, 1655, 1591, 1490, 1234,
1168 cmꢁ1; HRMS (EI): calcd for C18H17N2O2Cl [M]þ: 328.0978,
found 328.0989.
The 1H NMR spectra were measured by 300 MHz or 270 MHz
spectrometer with tetramethylsilane as the internal standard at
20–25 ꢀC. IR spectra were recorded by a diffuse reflectance mea-
surement of samples dispersed in KBr powder. E. Merck silica gel 60
for column chromatography and E. Merck pre-coated TLC plates,
silica gel F254, for preparative thin-layer chromatography were
used.
4.2.4. Compound 4d
Reaction was carried out according to the typical procedure with
1,2-phenylenediamine (1, 53.9 mg, 0.498 mmol), methyl acetoace-
tate (2a, 70 ml, 0.647 mmol), 4-bromobenzaldehyde (3d, 92.3 mg,
0.497 mmol), and C6F5CO2H (21.2 mg, 0.099 mmol) in DCE (4.9 ml)
to give 4d (122.1 mg, 66%). Reaction time for reflux was 2.5 h.
Hexane/AcOEt¼12:1 was used as eluent for SiO2 column chroma-
tography. Pale yellow amorphous; 1H NMR (300 MHz, CDCl3):
4.2. One-pot three-component reaction
Typical procedure. C6F5CO2H (0.1 mmol) was added to the solu-
d
¼10.10 (br s, 1H), 7.41–7.36 (m, 2H), 7.20–7.15 (m, 2H), 6.94–6.82
tion of 1,2-phenylenediamine (1, 5 mmol) and
b
-keto esters (2,
(m, 3H), 6.70 (d, J¼7.2 Hz, 1H), 4.76 (dd, J¼7.5, 4.5 Hz, 1H), 4.45 (s,
6 mmol) in DCE (5 ml) at rt under N2 and the reaction mixture was
stirred for 4 h. Aldehyde (3, 5 mmol) was added to the solution and
the reaction mixture was stirred under reflux. After the completion
of the reaction (judged from TLC analysis), the reaction mixture was
cooled to rt. Solvent was evaporated in vacuo and residue was
purified by SiO2 column chromatography to afford compound 4.
1H), 3.59 (br s, 1H), 3.59 (s, 3H), 2.58–2.42 ppm (m, 2H); 13C NMR
(67.8 MHz, CDCl3):
d
¼170.3, 157.8, 143.2, 137.7, 131.7, 130.2, 127.9,
125.0, 122.4, 122.0, 121.6, 120.9, 84.2, 64.6, 50.4, 39.9 ppm; IR (KBr):
3352, 3282, 2947, 1651, 1589, 1487, 1435, 1232, 1163 cmꢁ1; HRMS
(EI): calcd for C18H17N2O2Br [M]þ: 372.0473, found 372.0449.
4.2.5. Compound 4e
4.2.1. Compound 4a
Reaction was carried out according to the typical procedure with
1,2-phenylenediamine (1, 53 mg, 0.492 mmol), methyl acetoacetate
Reaction was carried out according to the typical procedure with
1,2-phenylenediamine (1, 37.4 mg, 0.346 mmol), methyl acetoace-
tate (2a, 49 ml, 0.45 mmol), 4-nitrobenzaldehyde (3e, 52.3 mg,
(2a, 69
m
l, 0.639 mmol), benzaldehyde (3a, 50
m
l, 0.492 mmol), and
0.346 mmol), and C6F5CO2H (14.7 mg, 0.069 mmol) in DCE (3.5 ml)
to give 4e (71.9 mg, 61%). Reaction time for reflux was 1.5 h. Hex-
ane/AcOEt¼4:1 and benzene/AcOEt¼50:1 were used as eluent for
SiO2 column chromatography. Pale yellow amorphous; 1H NMR
C6F5CO2H (20.8 mg, 0.098 mmol) in DCE (4.9 ml) to give 4a
(97.8 mg, 68%). Reaction time for reflux was 3 h. Hexane/AcOEt¼3:1
was used as eluent for SiO2 column chromatography. Pale yellow
oil; 1H NMR (300 MHz, CDCl3):
d¼10.22 (br s, 1H), 7.35–7.24 (m,
(300 MHz, CDCl3):
d
¼10.14 (br s, 1H), 8.17 (d, J¼8.4 Hz, 2H), 7.59 (d,
5H), 7.00–6.87 (m, 3H), 6.76 (d, J¼7.8 Hz, 1H), 4.83 (dd, J¼9.0,
4.2 Hz, 1H), 4.60 (s, 1H), 3.70 (br s, 1H), 3.66 (s, 1H), 2.67 (dd, J¼13.8,
9.0 Hz, 1H), 2.54 ppm (dd, J¼13.8, 4.2 Hz, 1H); 13C NMR (67.8 MHz,
J¼8.4 Hz, 2H), 7.04–6.96 (m, 3H), 6.84 (d, J¼7.5 Hz, 1H), 5.04 (m,
1H), 4.40 (s, 1H), 3.79 (br s, 1H), 3.65 (s, 3H), 2.80 (dd, J¼13.5, 4.5 Hz,
1H), 2.48 ppm (dd, J¼13.8, 6.3 Hz, 1H); 13C NMR (67.8 MHz, CDCl3):
CDCl3):
d
¼170.3, 158.4, 144.5, 137.7, 129.6, 128.6, 127.7, 125.9, 124.8,
d¼170.2, 157.4, 151.5, 147.6, 138.2, 130.8, 127.6, 125.3, 123.9, 122.7,
122.3, 121.4, 120.6, 83.6, 65.0, 50.2, 40.2 ppm; IR (KBr): 3279, 2249,
1651, 1645, 1614, 1504, 1232, 1163 cmꢁ1; HRMS (EI): calcd for
C18H18N2O2 [M]þ: 294.1368, found 294.1344.
122.5, 121.3, 84.8, 64.7, 50.6, 39.5 ppm; IR (KBr): 3366, 3279, 2949,
2837, 1666, 1634, 1529, 1439, 1352, 1236, 1170, 1117 cmꢁ1; HRMS
(EI): calcd for C18H17N3O4 [M]þ: 339.1219, found 339.1221.
4.2.2. Compound 4b
4.2.6. Compound 4f
Reaction was carried out according to the typical procedure with
1,2-phenylenediamine (1, 54.5 mg, 0.504 mmol), methyl acetoace-
Reaction was carried out according to the typical procedure with
1,2-phenylenediamine (1, 53 mg, 0.492 mmol), methyl acetoacetate
tate (2a, 71
m
l, 0.655 mmol), 4-methoxybenzaldehyde (3b, 61
ml,
(2a, 69 ml, 0.639 mmol), 4-formylbenzonitrile (3f, 64.5 mg,
0.504 mmol), and C6F5CO2H (21.4 mg, 0.10 mmol) in DCE (5.0 ml) to
give 4b (93.6 mg, 57%). Reaction time for reflux was 6 h. Hexane/
AcOEt¼7:1 and benzene/AcOEt¼9:1 was used as eluent for SiO2
column chromatography. Pale yellow amorphous; 1H NMR
0.492 mmol), and C6F5CO2H (20.8 mg, 0.098 mmol) in DCE (4.9 ml)
to give 4f (92.4 mg, 59%). Reaction time for reflux was 2.5 h. Hex-
ane/AcOEt¼3:1 was used as eluent for SiO2 column chromatogra-
phy. Pale yellow solid; mp 153–155 ꢀC; 1H NMR (300 MHz, CDCl3):
(270 MHz, CDCl3):
d
¼10.13 (br s, 1H), 7.18 (d, J¼10.2, 2H), 6.91–6.77
d
¼10.12 (br s, 1H), 7.61 (d, J¼8.1 Hz, 2H), 7.51 (d, J¼8.1 Hz, 2H), 7.02–
(m, 5H), 6.66 (dd, J¼7.8 Hz, 1H), 4.71 (dd, J¼8.6, 4.1 Hz, 1H), 4.52 (s,
6.94 (m, 3H), 6.79 (d, J¼7.2 Hz, 1H), 5.01–4.91 (m, 1H), 4.40 (s, 1H),
3.69 (br s, 1H), 3.64 (s, 3H), 2.73 (dd, J¼13.8, 4.5 Hz, 1H), 2.45 ppm
1H), 3.71 (s, 3H), 3.59 (br s, 1H), 3.59(s, 3H), 2.61–2.41 ppm (m, 2H);
13C NMR (67.8 MHz, CDCl3):
d
¼171.3,160.0,159.6,138.7,137.8,130.6,
(dd, J¼13.8, 6.9 Hz, 1H); 13C NMR (75.5 MHz, CDCl3):
¼170.3, 157.2,
d
128.0, 125.8, 123.3, 122.3, 121.6, 114.8, 84.6, 65.5, 56.2, 51.3,
41.3 ppm; IR (KBr): 3356, 3275, 2949, 2835, 1659, 1589, 1512, 1439,
1254, 1165 cmꢁ1; HRMS (EI): calcd for C19H20N2O3 [M]þ: 324.1474,
found 324.1471.
149.2, 137.8, 132.5, 130.5, 127.2, 125.2, 122.6, 122.5, 121.1, 118.7, 111.7,
84.7, 64.7, 50.5, 39.3 ppm; IR (KBr): 3348, 3280, 2947, 2227, 1651,
1614, 1589, 1502, 1267, 1232 cmꢁ1; HRMS (EI): calcd for C19H17N3O2
[M]þ: 319.1321, found 319.1321.
4.2.3. Compound 4c
4.2.7. Compound 4g
Reaction was carried out according to the typical procedure with
1,2-phenylenediamine (1, 53 mg, 0.492 mmol), methyl acetoacetate
Reaction was carried out according to the typical procedure with
1,2-phenylenediamine (1, 42.2 mg, 0.390 mmol), methyl acetoace-
(2a, 69
ml, 0.639 mmol), 4-chlorobenzaldehyde (3c, 69.2 mg,
tate (2a, 55
ml, 0.507 mmol), methyl 4-formylbenzoate (3g, 55 ml,
0.492 mmol), and C6F5CO2H (20.8 mg, 0.098 mmol) in DCE (4.9 ml)
0.390 mmol), and C6F5CO2H (16.6 mg, 0.078 mmol) in DCE (3.9 ml)

11038
K. Murai et al. / Tetrahedron 64 (2008) 11034–11040
to give 4g (97.8 mg, 68%). Reaction time for reflux was 3 h. Hexane/
AcOEt¼5:1 was used as eluent for SiO2 column chromatography.
0.41 mmol), and C6F5CO2H (17.1 mg, 0.081 mmol) in DCE (4.0 ml) to
give 4k (67.1 mg, 51%). Reaction time for reflux was 2.5 h. Hexane/
AcOEt¼12:1 was used as eluent for SiO2 column chromatography.
Pale yellow amorphous; 1H NMR (300 MHz, CDCl3):
d¼10.21 (br s,
1H), 7.38 (d, J¼8.4 Hz, 2H), 7.06 (d, J¼8.4 Hz, 2H), 7.01–6.89 (m, 3H),
6.77 (d, J¼7.8 Hz, 1H), 4.85 (dd, J¼8.1, 4.5 Hz, 1H), 4.59 (s, 1H), 3.71
(br s, 1H), 3.67 (s, 3H), 2.67–2.51 (m, 2H), 2.30 ppm (s, 3H); 13C NMR
Pale yellow amorphous; 1H NMR (300 MHz, CDCl3):
d¼10.08 (br s,
1H), 7.70 (d, J¼6.6 Hz, 1H), 7.35 (d, J¼7.2 Hz, 1H), 7.28–7.18 (m, 2H),
7.02–6.89 (m, 3H), 6.82 (d, J¼7.5 Hz, 1H), 5.42–5.38 (m, 1H), 4.47 (s,
1H), 3.68 (br s, 1H), 3.64 (s, 3H), 2.74 (dd, J¼13.8, 4.2 Hz, 1H),
2.57 ppm (dd, J¼6.9, 13.8 Hz, 1H); 13C NMR (67.8 MHz, CDCl3):
(67.8 MHz, CDCl3):
d
¼170.3, 169.3, 158.2, 150.0, 142.0, 137.6, 129.8,
127.1,124.9,122.4,121.8,121.7,120.8, 83.9, 64.5, 50.3, 40.1, 21.1 ppm;
IR (KBr): 3352, 3279, 3196, 2984, 2947, 2837, 1759, 1651, 1614, 1504,
1435, 1369, 1165 cmꢁ1; HRMS (EI): calcd for C20H20N2O4 [M]þ:
352.1423, found 352.1428.
d
¼170.2, 157.9, 141.0, 138.1, 131.5, 130.0, 129.4, 128.7, 127.9, 127.0,
125.0, 122.4, 121.7, 120.7, 84.3, 60.8, 50.3, 37.5 ppm; IR (KBr): 3358,
3277, 3020, 2988, 2947, 1651, 1589, 1504, 1470, 1435, 1270, 1232,
1167 cmꢁ1; HRMS (EI): calcd for C18H17N2O2Cl [M]þ: 328.0978,
found 328.0964.
4.2.8. Compound 4h
Reaction was carried out according to the typical procedure with
1,2-phenylenediamine (1, 48.2 mg, 0.446 mmol), methyl acetoace-
4.2.12. Compound 4l
tate (2a, 63
m
l, 0.579 mmol), 3-methoxybenzaldehyde (3h, 55
m
l,
Reaction was carried out according to the typical procedure with
1,2-phenylenediamine (1, 53 mg, 0.492 mmol), methyl acetoacetate
(2a, 69 ml, 0.639 mmol), 2-naphthaldehyde (3l, 76.8 mg,
0.446 mmol), and C6F5CO2H (19.0 mg, 0.089 mmol) in DCE (4.5 ml)
to give 4h (78.0 mg, 54%). Reaction time for reflux was 4 h. Hexane/
AcOEt¼12:1 was used as eluent for SiO2 column chromatography.
0.492 mmol), and C6F5CO2H (20.8 mg, 0.098 mmol) in DCE (4.9 ml)
to give 4l (96.9 mg, 57%). Reaction time for reflux was 2 h. Hexane/
AcOEt¼4.5:1 was used as eluent for SiO2 column chromatography.
Pale yellow amorphous; 1H NMR (300 MHz, CDCl3):
d¼10.21 (br s,
1H), 7.28–7.23 (m, 1H), 7.01–6.77 (m, 7H), 4.81 (dd, J¼8.7, 4.2 Hz,
1H), 4.61 (s, 1H), 3.78 (s, 3H), 3.72 (br s, 1H), 3.67 (s, 3H), 2.70–
Pale yellow oil; 1H NMR (300 MHz, CDCl3):
d
¼10.25 (br s, 1H), 7.83–
2.52 ppm (m, 2H); 13C NMR (67.8 MHz, CDCl3):
d¼170.4, 159.7,
7.78 (m, 4H), 7.49–7.44 (m, 3H), 7.01–6.93 (m, 3H), 6.78 (d, J¼7.5 Hz,
1H), 4.99 (dd, J¼8.4, 4.2 Hz, 1H), 4.60 (s, 1H), 3.78 (br s, 1H), 3.66 (s,
3H), 2.76 (dd, J¼13.8, 8.4 Hz, 1H), 2.61 ppm (dd, J¼13.8, 4.2 Hz, 1H);
158.5, 146.3, 137.8, 129.74, 127.70, 124.9, 122.4, 121.5, 120.7, 118.2,
113.2, 111.6, 83.8, 65.1, 55.2, 50.3, 40.2 ppm; IR (KBr): 3356, 3281,
2947, 2835, 1651, 1587, 1269, 1232, 1165 cmꢁ1; HRMS (EI): calcd for
C19H20N2O3 [M]þ: 324.1474, found 324.1472.
13C NMR (75.5 MHz, CDCl3):
d
¼170.5, 158.6, 141.9, 137.9, 133.2,
133.0, 129.9, 128.7, 127.9, 127.6, 126.3, 126.0, 125.1, 124.8, 124.1,
122.5, 121.7, 120.9, 83.9, 65.2, 50.3, 39.9 ppm; IR (KBr): 3277, 3057,
2250, 1654, 1627, 1307 cmꢁ1; HRMS (EI): calcd for C22H20N2O2
[M]þ: 344.1525, found 344.1526.
4.2.9. Compound 4i
Reaction was carried out according to the typical procedure with
1,2-phenylenediamine (1, 41 mg, 0.379 mmol), methyl acetoacetate
(2a, 53
ml, 0.493 mmol), 3-chlorobenzaldehyde (3i, 43
ml,
4.2.13. Compound 4m
0.379 mmol), and C6F5CO2H (16.1 mg, 0.076 mmol) in DCE (3.8 ml)
to give 4i (64.0 mg, 51%). Reaction time for reflux was 3.5 h. Hex-
ane/AcOEt¼12:1 was used as eluent for SiO2 column chromato-
graphy. Pale yellow amorphous; 1H NMR (300 MHz, CDCl3):
Reaction was carried out according to the typical procedure with
1,2-phenylenediamine (1, 53 mg, 0.492 mmol), methyl acetoacetate
(2a, 69 ml, 0.639 mmol), 3-furancarboxaldehyde (3m, 43 ml,
0.497 mmol), and C6F5CO2H (20.8 mg, 0.098 mmol) in DCE (4.9 ml)
to give 4m (46.6 mg, 33%). Reaction time for reflux was 3 h. Hexane/
AcOEt¼3.5:1 was used as eluent for SiO2 column chromatography.
d
¼10.19 (br s, 1H), 7.36 (s, 1H), 7.27–7.25 (m, 3H), 7.03–6.90 (m, 3H),
6.80–6.78 (m, 1H), 4.84 (dd, J¼6.6, 2.4 Hz, 1H), 4.55 (s, 1H), 3.68 (br
s, 1H), 3.67 (s, 3H), 2.58–2.42 ppm (m, 2H); 13C NMR (67.8 MHz,
Pale yellow oil; 1H NMR (300 MHz, CDCl3):
d
¼10.18 (br s, 1H), 7.40
CDCl3):
d
¼170.3, 157.8, 146.4, 137.6, 134.4, 130.0, 129.9, 128.0, 126.3,
(d, J¼13.8 Hz, 2H), 6.99–6.94 (m, 3H), 6.77–6.74 (m, 1H), 6.37 (s,
1H), 4.85 (t, J¼6.3 Hz, 1H), 4.66 (s, 1H), 3.68 (s, 3H), 3.56 (br s, 1H),
125.0, 124.2, 122.4, 121.9, 120.8, 84.2, 64.6, 50.4, 39.9 ppm; IR (KBr):
3348, 3283, 2945, 2852, 1651, 1614, 1591, 1497, 1477, 1435, 1275,
1232 cmꢁ1; HRMS (EI): calcd for C18H17N2O2Cl [M]þ: 328.0978,
found 328.0986.
2.58 ppm (d, J¼6.3 Hz, 2H); 13C NMR (75.5 MHz, CDCl3):
¼170.5,
d
158.5, 143.5, 138.7, 137.5, 130.8, 128.8, 125.0, 122.34, 122.31, 121.3,
108.3, 84.0, 56.9, 50.4, 38.9 ppm; IR (KBr): 3280, 2358, 2341, 1652,
1616, 1589, 1498, 1299, 1267, 1165 cmꢁ1; HRMS (EI): calcd for
C16H16N2O3 [M]þ: 284.1161, found 284.1157.
4.2.10. Compound 4j
Reaction was carried out according to the typical procedure with
1,2-phenylenediamine (1, 44.8 mg, 0.414 mmol), methyl acetoace-
4.2.14. Compound 4n
tate (2a, 58
m
l, 0.539 mmol), o-tolualdehyde (3j, 48
m
l, 0.414 mmol),
Reaction was carried out according to the typical procedure with
1,2-phenylenediamine (1, 53 mg, 0.492 mmol), methyl acetoacetate
(2a, 69 ml, 0.639 mmol), 2-thiophenecarboxaldehyde (3n, 46 ml,
and C6F5CO2H (17.6 mg, 0.083 mmol) in DCE (4.1 ml) to give 4j
(43.4 mg, 34%). Reaction time for reflux was 4 h. Hexane/
AcOEt¼12:1 was used as eluent for SiO2 column chromatography.
0.492 mmol), and C6F5CO2H (20.8 mg, 0.098 mmol) in DCE (4.9 ml)
to give 4n (80.9 mg, 55%). Reaction time for reflux was 2.5 h. Hex-
ane/AcOEt¼9:1 was used as eluent for SiO2 column chromatogra-
Pale yellow amorphous; 1H NMR (300 MHz, CDCl3):
d¼10.26 (br s,
1H), 7.53–7.50 (m,1H), 7.25–7.16 (m, 3H), 7.02–6.86 (m, 3H), 6.79 (d,
J¼7.8 Hz,1H), 5.14 (dd, J¼9.0, 3.3 Hz,1H), 4.61 (s,1H), 3.69 (br s,1H),
3.69 (s, 3H), 2.72–2.47 (m, 2H), 2.39 ppm (s, 3H); 13C NMR
phy. Pale yellow amorphous; 1H NMR (300 MHz, CDCl3):
d
¼10.09
(br s, 1H), 7.17–7.13 (m, 1H), 6.94–6.87 (m, 5H), 6.70 (dd, J¼5.4,
2.1 Hz, 1H), 5.10 (t, J¼6.9 Hz, 1H), 4.58 (s, 1H), 3.65 (br s, 1H), 3.60 (s,
3H), 2.59 ppm (d, J¼6.9 Hz, 2H); 13C NMR (67.8 MHz, CDCl3):
(67.8 MHz, CDCl3):
d
¼170.5, 159.0, 142.8, 137.9, 133.9, 130.6, 129.0,
127.5, 126.6, 125.6, 125.0, 122.6, 121.0, 120.4, 83.5, 60.0, 50.4, 39.5,
19.3 ppm; IR (KBr): 3360, 3277, 3020, 2947, 1655, 1616, 1489, 1437,
1304, 1283, 1265, 1231, 1163 cmꢁ1; HRMS (EI): calcd for C19H20N2O2
[M]þ: 308.1525, found 308.1531.
d
¼170.3, 157.8, 148.0, 136.8, 130.9, 126.5, 124.9, 124.4, 123.3, 122.5,
122.2, 121.7, 84.2, 61.0, 50.4, 40.5 ppm; IR (KBr): 3344, 3279, 2947,
2851, 1651, 1614, 1589, 1470, 1435, 1293, 1269, 1232, 1163 cmꢁ1
;
HRMS (EI): calcd for C16H16N2O2S [M]þ: 300.0932, found 300.0937.
4.2.11. Compound 4k
Reaction was carried out according to the typical procedure with
1,2-phenylenediamine (1, 43.7 mg, 0.404 mmol), methyl acetoace-
tate (2a, 57 ml, 0.53 mmol), 2-chlorobenzaldehyde (3k, 46 ml,
4.2.15. Compound 4o
Reaction was carried out according to the typical procedure with
1,2-phenylenediamine (1, 53 mg, 0.492 mmol), benzyl acetoacetate

K. Murai et al. / Tetrahedron 64 (2008) 11034–11040
11039
(2b,110
m
l, 0.639 mmol), benzaldehyde (3a, 50
m
l, 0.492 mmol), and
160.0, 142.9, 136.4, 128.9, 128.4, 127.6, 127.0, 123.0, 120.6, 120.3,
120.1, 95.0, 64.8, 51.1, 50.0, 26.7, 26.0 ppm; IR (KBr): 3340, 2947,
C6F5CO2H (20.8 mg, 0.098 mmol) in DCE (4.9 ml) to give 4o
(122.6 mg, 67%). Reaction time for reflux was 2 h. Hexane/AcOEt¼6:1
was used as eluent for SiO2 column chromatography. Pale yellow oil;
1734, 1655, 1624, 1589, 1261 cmꢁ1
; HRMS (EI): calcd for
C20H20N2O2 [M]þ: 320.1525, found 320.1527. Anal. Calcd for
C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found C, 74.96; H, 6.38; N,
8.75.
1H NMR (300 MHz, CDCl3):
d¼10.23 (br s, 1H), 7.39–7.26 (m, 10H),
7.00–6.87 (m, 3H), 6.76–6.73 (m, 1H), 5.16 (A in ABq, J¼12.6 Hz, 1H),
5.12 (B in ABq, J¼12.6 Hz, 1H), 4.83 (dd, J¼9.0, 4.2 Hz, 1H), 4.67 (s,
1H), 3.69 (br s, 1H), 2.67 (dd, J¼13.8, 9.0 Hz, 1H), 2.53 ppm (dd,
4.3. Studies about g-selectivity
J¼13.8, 4.2 Hz, 1H); 13C NMR (75.5 MHz, CDCl3):
¼169.9, 159.0,
d
144.7, 137.9, 137.0, 129.7, 128.7, 128.4, 127.9, 127.8, 127.76, 126.0,
125.1, 122.5, 121.5, 120.8, 83.8, 65.2, 64.7 40.2 ppm; IR (KBr): 3280,
3030, 2250, 1666, 1633, 1504, 1234, 1167 cmꢁ1; HRMS (EI): calcd for
C24H22N2O2 [M]þ: 370.1681, found 370.1683.
4.3.1. Preparation of 3-[(2-aminophenyl)amino]-2-butemoic acid
methyl ester (5)
The solution of 1,2-phenylenediamine (1, 1.03 g, 9.55 mmol),
methyl acetoacetate (2a, 1.11 g, 9.55 mmol), and AcOH (0.1 ml,
1.7 mmol) in toluene (30 ml) was heated at reflux for 1 h under N2.
Solvent was evaporated in vacuo and residue was purified by SiO2
column chromatography (Hexane/AcOEt¼7:3) to give 5 (1.09 g)
with minor impurity. It was washed with hexane to afford pure 5
(986 mg, 4.78 mmol, 50%) as colorless solid; mp 84 ꢀC; 1H NMR
4.2.16. Compound 4p
Reaction was carried out according to the typical procedure with
1,2-phenylenediamine (1, 53 mg, 0.492 mmol), tert-butyl aceto-
acetate (2c, 106 ml, 0.639 mmol), benzaldehyde (3a, 50 ml,
0.492 mmol), and C6F5CO2H (20.8 mg, 0.098 mmol) in DCE (4.9 ml)
to give 4p (120.4 mg, 73%). Reaction time for reflux was 1 h. Hex-
ane/AcOEt¼6:1 was used as eluent for SiO2 column chromatogra-
(270 MHz, CDCl3):
d
¼9.86 (br s, 1H), 7.08 (ddd, J¼7.0, 7.0, 1.4 Hz,
1H), 6.98 (d, J¼7.0 Hz, 1H), 6.76–6.68 (m, 2H), 4.73 (s, 1H), 3.83 (br s,
2H), 3.66 (s, 3H), 1.81 ppm (s, 3H); 13C NMR (75.5 MHz, CDCl3):
phy. Pale yellow oil; 1H NMR (300 MHz, CDCl3):
d
¼10.20 (br s, 1H),
d
¼170.8, 161.5, 143.4, 128.5, 127.9, 124.6, 118.2, 115.5, 84.6, 50.3,
19.8 ppm; IR (KBr): 3456, 3363, 2365, 1654, 1604, 1267, 1165 cmꢁ1
.
7.34–7.28 (m, 5H), 6.99–6.76 (m, 3H), 6.74 (d, J¼6.0 Hz, 1H), 4.81
(dd, J¼9.9, 3.9 Hz, 1H), 4.58 (s, 1H), 3.66 (br s, 1H), 2.68 (dd, J¼13.8,
9.9 Hz, 1H), 2.45 (ddd, J¼9.9, 3.9, 0.9 Hz, 1H), 1.50 ppm (s, 9H); 13C
Anal. Calcd for C11H14N2O2: C, 64.06; H, 6.84; N, 13.58. Found C,
64.17; H, 6.85; N, 13.51.
NMR (75.5 MHz, CDCl3):
d
¼170.2, 157.8, 145.1, 137.7, 130.1, 128.8,
127.9, 126.0, 124.7, 122.5, 121.5, 120.8, 85.7, 78.6, 65.2, 40.2,
28.5 ppm; IR (KBr): 3275, 2253, 1793, 1652, 1622, 1589, 1477, 1221,
1153 cmꢁ1; HRMS (EI): calcd for C21H24N2O2 [M]þ: 336.1838, found
336.1828.
4.3.2. Compound 6
C6F5CO2H (15.7 mg, 0.074 mmol) was added to the solution of
compound 5 (76.3 mg, 0.370 mmol) and 4-chlorobenzaldehyde (3c,
54.6 mg, 0.370 mmol) in EtOH (3.7 ml) at rt under N2 and the re-
action mixture was stirred for 1 h. After the completion of the re-
action (judged from TLC analysis), the solvent was evaporated in
vacuo and residue was purified by SiO2 column chromatography
(hexane/AcOEt¼5:3) to afford compound 6 (94.7 mg, 78%). Pale
4.2.17. Compound 4q
C6F5CO2H (20.8 mg 0.098 mmol) was added to the solution of
1,2-phenylenediamine (1, 53 mg, 0.492 mmol) and methyl pro-
pionylacetate (2e, 80 ml, 0.637 mmol) in DCE (4.9 ml) at rt under
N2. The reaction mixture was stirred for 1 h at rt and stirred for
3 h at 50 ꢀC. After the reaction mixture was cooled to rt, benzal-
yellow amorphous powder; 1H NMR (270 MHz, acetone-d6):
d¼7.74
(br s, 1H), 7.23–7.20 (m, 2H), 7.16–7.12 (m, 2H), 6.83–6.80 (m, 1H),
6.59–6.51 (m, 3H), 5.80 (d, J¼6.3 Hz, 1H), 5.71 (d, J¼6.3 Hz, 1H), 3.52
(s, 3H), 2.53 ppm (s, 3H); 13C NMR (75.5 MHz, acetone-d6):
d¼169.1,
dehyde (3a, 50 ml, 0.492 mmol) was added to the solution and the
reaction mixture was heated at reflux for 2.5 h. After the reaction
mixture was cooled to rt, solvent was evaporated in vacuo. The
residue was purified by SiO2 column chromatography (hexane/
AcOEt¼4.5:1) to afford compound 4q. Pale yellow oil; 1H NMR
153.0, 144.8, 139.0, 133.3, 132.2, 130.4, 128.8, 123.4, 121.5, 121.3,
120.5, 101.6, 60.7, 51.1, 24.3 ppm; IR (KBr): 3338, 2360, 1676, 1624,
1533, 1274, 1238 cmꢁ1; HRMS (EI): calcd for C18H17N2O2Cl [M]þ:
328.0978, found 328.0975.
(270 MHz, CDCl3):
d
¼10.42 (br s, 1H), 7.38–7.20 (m, 5H), 7.05–6.97
(m, 3H), 6.69–6.66 (m, 1H), 4.81 (s, 1H), 4.41 (d, J¼9.7 Hz, 1H),
Acknowledgements
3.72 (s, 3H), 3.63 (br s, 1H), 2.95–2.89 (m, 1H), 0.90 ppm (d,
J¼9.5 Hz, 1H); 13C NMR (67.8 MHz, CDCl3):
¼170.7, 163.7, 143.8,
d
This work was financially supported by Grant-in-Aid for Scien-
tific Research (A) and Grant-in-Aid for Scientific Research for Ex-
ploratory Research from Japan Society for the Promotion of Science
and by Grant-in-Aid for Scientific Research on Priority Areas
(17035047) from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan. K.M. thanks the Japan Society for the Pro-
motion of Science (JSPS) for a Research Fellowship for Young
Scientists.
137.5, 130.5, 128.6, 127.7, 126.1, 124.8, 122.3, 122.0, 121.3 81.1, 72.7,
50.3, 39.5, 15.9 ppm; IR (KBr): 3344, 3271, 2980, 1651, 1612, 1277,
1169 cmꢁ1; HRMS (EI): calcd for C19H20N2O2 [M]þ: 308.1525,
found 308.1521.
4.2.18. Compound 4r
C6F5CO2H (20.8 mg 0.098 mmol) was added to the solution of
1,2-phenylenediamine (1, 53 mg, 0.492 mmol) and methyl 2-oxo-
cyclopentanecarboxylate (2f, 79 ml, 0.639 mmol) in DCE (4.9 ml) at
rt under N2. The reaction mixture was stirred for 1 h at rt and
stirred for 3 h at 50 ꢀC. After the reaction mixture was cooled to rt,
References and notes
1. For examples, see: (a) Hadac, E. M.; Dawson, E. S.; Darrow, J. W.; Sugg, E. E.;
Lybrand, T. P.; Miller, L. J. J. Med. Chem. 2006, 49, 850–863; (b) Agrawal, V. K.;
Sharma, R.; Khadikar, P. V. Bioorg. Med. Chem. 2002, 10, 3571–3581; (c) Mer-
luzzi, V.; Hargrave, K. D.; Labadia, M.; Grozinger, K.; Skoog, M.; Wu, J. C.; Shih,
C.-K.; Eckner, K.; Hattox, S.; Adams, J.; Rosenthal, A. S.; Faanes, R.; Eckner, R. J.;
Koup, R. A.; Sullivan, J. L. Science 1990, 250, 1411–1413; (d) Merluzzi, V.; Har-
grave, K. D.; Labadia, M.; Grozinger, K.; Skoog, M.; Di Braccio, M.; Grossi, G.;
Romoa, G.; Vargiu, L.; Mura, M.; Marongiu, M. E. Eur. J. Med. Chem. 2001, 36,
935–949; (e) Tranquillini, M. E.; Cassara, P. G.; Werner, W.; Baumgart, J.;
Burckhardt, G.; Fleck, W. F.; Geller, K.; Gutsche, W.; Hanschmann, H.; Mes-
serschmidt, A.; Ro¨mer, W.; Tresselt, D.; Lo¨ber, G. Biophys. Chem. 1990, 35, 271–
benzaldehyde (3a, 50 ml, 0.492 mmol) was added to the solution
and the reaction mixture was heated at reflux for 2.5 h. After the
reaction mixture was cooled to rt, solvent was evaporated in vacuo.
The residue was purified by SiO2 column chromatography (CH2Cl2/
AcOEt¼50:1) to afford compound 4r. Colorless solid; mp 159–
160 ꢀC; 1H NMR (300 MHz, CD2Cl2):
d
¼9.86 (br s, 1H), 7.40–7.32 (m,
5H), 6.92–6.68 (m, 3H), 6.65–6.62 (m, 1H), 4.27 (d, J¼9.9 Hz, 1H),
3.89 (br s, 1H), 3.71–3.70 (m, 3H), 3.28 (m, 1H), 2.55–2.40 (m, 2H),
´
´
276; (f) Tranquillini, M. E.; Cassara, P. G.; Corsı, M.; Curotto, G.; Donati, D.;
Finizia, G.; Pentassuglia, G.; Polinelli, S.; Tarzia, G.; Ursini, A.; van Amsterdam, F.
1.58–1.34 ppm (m, 2H); 13C NMR (75.5 MHz, CD2Cl2):
d
¼168.1,

11040
K. Murai et al. / Tetrahedron 64 (2008) 11034–11040
T. M. Arch. Pharm. Pharm. Med. Chem. 1997, 330, 353–357; (g) Hagishita, S.; Seno,
1999, 811–814; (c) Tjiou, E. M.; Lhoussaine, E. G.; Virieux, D.; Fruchier, A. Magn.
Reson. Chem. 2005, 43, 557–562.
6. For recent reviews, see: (a) Do¨mling, A. Chem. Rev. 2006, 106, 17–89; (b) Banfi,
K.; Kamata, S.; Haga, N.; Ishihara, Y.; Ishikawa, M.; Shimamura, M. Bioorg. Med.
Chem. 1997, 5, 1433–1446; (h) Atwal, K. S.; Bergey, J. L.; Hedberg, A.; Moreland,
S. J. Med. Chem. 1987, 30, 635–640 and references are cited therein.
2. (a) Reid, W.; Stahlhofen, P. Chem. Ber. 1957, 90, 815–824; (b) Reid, W.; Torinus, E.
Chem. Ber. 1959, 92, 2902–2916.
´
L.; Riva, R. Org. React. 2005, 65, 1–140; (c) Ramon, D. J.; Yus, M. Angew. Chem.
2005, 117, 1628–1661; Angew. Chem., Int. Ed. 2005, 44, 1602–1634; (d) Zhu, J. Eur.
J. Org. Chem. 2003, 1133–1144.
3. For examples, see: (a) Zhang, Z.-H.; Yang, S.-T.; Lin, J. Synth. Commun. 2006, 36,
1645–1654; (b) Kodomari, M.; Noguchi, T.; Aoyama, T. Synth. Commun. 2004, 34,
1783–1790; (c) Giri, B. Y.; Devi, B. L. A. P.; Lakshmi, K. V.; Prasad, R. B. N.; Lin-
gaiah, N.; Prasd, P. S. S. Synth. Commun. 2006, 36, 3797–3801; (d) Curini, M.;
Epifano, F.; Marcotullio, M. C.; Rosati, O. Tetrahedron Lett. 2001, 42, 3193–3195;
(e) Jung, D. I.; Choi, T. W.; Kim, Y. Y.; Kim, I. S.; Park, Y. M.; Lee, Y. G.; Jung, D. H.
Synth. Commun. 1999, 29, 1941–1951; (f) Guzen, K. P.; Cella, R.; Stefani, H. A.
Tetrahedron Lett. 2006, 47, 8133–8136; (g) Pozarentzi, M.; Stephanidou-Ste-
phanatou, J.; Tsoleridis, C. A. Tetrahedron Lett. 2002, 43, 1755–1758; (h) Jarikote,
D. V.; Siddiqui, S. A.; Rajagopal, R.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V.
Tetrahedron Lett. 2003, 44, 1835–1838; (i) Bandgar, B. P.; Bettigeri, S. V.; Joshi, N.
S. Synth. Commun. 2004, 34, 1447–1453; (j) Mahajan, D.; Naqvi, T.; Sharma, R. L.;
Kapoor, K. K. Aust. J. Chem. 2008, 61, 159–162; (k) De, S. K.; Gibbs, R. A. Tetra-
hedron Lett. 2005, 46, 1811–1813; (l) Sivamurugan, V.; Deepa, K.; Palanichamy,
M.; Murugesan, V. Synth. Commun. 2004, 34, 3833–3846; (m) Varala, R.; Enu-
gala, R.; Nuvula, S.; Adapa, S. R. Synlett 2006, 1009–1014; (n) Kuo, C. W.; More,
S. V.; Yao, C. F. Tetrahedron Lett. 2006, 47, 8523–8528; (o) Wu, J.; Xu, F.; Zhou, Z.;
Shen, Q. Synth. Commun. 2006, 36, 457–464; (p) Reddy, K. S.; Reddy, C. V.;
Mahesh, M.; Reddy, K. R.; Raju, P. V. K.; Reddy, V. V. N. Can. J. Chem. 2007, 85,
184–188.
7. (a) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A.
Acc. Chem. Res. 1996, 29, 123–131; (b) Shreiber, S. L. Science 2000, 287, 1964–
1969; (c) Werner, S.; Turner, D. M.; Lyon, M. A.; Huryn, D. M.; Wipf, P. Synlett
2006, 2334–2338 and reference sited therein.
8. For examples, see: (a) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.;
Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 6552–6554; (b) Inanaga, K.; Takasu, K.;
Ihara, M. J. Am. Chem. Soc. 2004, 126, 1352–1353; (c) Powell, D. A.; Batey, R. A.
Org. Lett. 2002, 4, 2913–2916.
9. Fujioka, H.; Murai, K.; Kubo, O.; Ohba, Y.; Kita, Y. Org. Lett. 2007, 9, 1687–1690.
10. Related three-component reaction using b-ketoamide was reported: Sotoca, E.;
Constantieux, T.; Rodriguez, J. Synlett 2008, 1313–1316.
11. For examples, see: (a) Curini, M.; Epifano, F.; Montanari, F.; Rosati, O.; Taccone,
S. Synlett 2004, 1832–1834; (b) Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Otokesh, S.;
Baghbanzadeh, M. Tetrahedron Lett. 2006, 47, 2557–2560; (c) Chakrabarty, M.;
Mukherji, A.; Mukherjee, R.; Arima, S.; Harigaya, Y. Tetrahedron Lett. 2007, 48,
5239–5242; (d) Smith, J. G.; Ho, I. Tetrahedron Lett. 1971, 38, 3541–3544.
12. Acidity of C6F5CO2H, see: Moseley, P. G. N. Electrochim. Acta 1980, 25, 1309–1311.
13. Because of the steric hindrances, enamino ester was not formed at rt. When
reaction was carried out at 50 ꢀC, the reaction afforded the complex mixtures
including 2-methyl-1H-benzimidazole, which was probably formed through
retro Claisen condensation type reaction. For examples, see: Wang, Z.-X.; Qin,
H.-L. J. Hetrocycl. Chem. 2005, 42, 1001–1005.
4. (a) Zhong, W.; Zhang, Y.; Chen, X. J. Chem. Res. 2000, 532–534; (b) Zhong, W.;
Zhang, Y.; Chen, X. Tetrahedron Lett. 2001, 42, 73–75; (c) Ma, Y.; Zhang, Y. Synth.
Commun. 2002, 32, 165–169.
5. (a) Matsuo, K.; Tani, I.; Tanaka, K. Chem. Pharm. Bull. 1987, 35, 5024–5027; (b)
Fodili, M.; Amari, M.; Kolli, B.; Robert, A.; Baudy-Floc’h, M.; Le Grel, P. Synthesis
14. The stereochemistry of 4r and 4s was determined by their differential NOE
spectra. Thus NOE between the benzyl proton and homobenzyl proton in each
compound was not observed to show their trans configuration.