Efficient one-pot synthesis of cyclic β-enaminoamides by thermal Wolff rearrangement of cyclic 2-diazo-1,3-dicarbonyls and conversion to uracil derivatives

Article abstract of DOI:10.1016/j.tet.2012.01.060

This paper describes simple and efficient approaches for the preparation of β-enaminoamides through thermal Wolff rearrangement of cyclic diazodicarbonyls followed by trapping with various amines. The synthesized β-enaminoamides were readily converted into uracil derivatives.

Full text of DOI:10.1016/j.tet.2012.01.060

Tetrahedron 68 (2012) 2496e2508
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Efficient one-pot synthesis of cyclic -enaminoamides by thermal Wolff
b
rearrangement of cyclic 2-diazo-1,3-dicarbonyls and conversion to uracil
derivatives
,
b
Pratik Neupane a, Xin Li a, Jae Hak Jung a, Yong Rok Lee a , Sung Hong Kim
*
a School of Chemical Engineering, Yeungnam University, Gyeongsan 712-749, Republic of Korea
b Analysis Research Division, Daegu Center, Korea Basic Science Institute, Daegu 702-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
This paper describes simple and efficient approaches for the preparation of
thermal Wolff rearrangement of cyclic diazodicarbonyls followed by trapping with various amines. The
synthesized -enaminoamides were readily converted into uracil derivatives.
Ó 2012 Elsevier Ltd. All rights reserved.
b-enaminoamides through
Received 5 December 2011
Received in revised form 17 January 2012
Accepted 18 January 2012
Available online 26 January 2012
b
Keywords:
Diazodicarbonyls
b-Enaminoamides
Wolff rearrangement
Uracil
1. Introduction
diazo-1,3-dicarbonyls in the presence of amines and aldehydes or
a,b-unsaturated aldehydes for the formation of oxazinones or a-
Decomposition of diazocarbonyl compounds has been a widely
applied method in organic synthesis.1 Among these, transition
metal-catalyzed cycloaddition of diazocarbonyl compounds to
substrates has become an important method for the synthesis of
a wide variety of heterocyclic compounds.2 Also, the thermal,
photochemical, and transition metal-catalyzed Wolff rearrange-
ment is a well-known and useful reaction for the homologation of
carboxylic acids and for ring contraction.3 Application of such
a phenomenon in terms of biochemical interest includes DNA
spiro-
g
-lactams and pyrazolidinones have also been described.6
O
hν or
O
N2
O
NuH
O
or
microwaves
n
Nu
n
NuH
n=0, 1, 2
Nu= OR, NR2, SR
n=0, 1, 2
cleavage, b
-peptides, and photo-affinity labeling.3 The Wolff rear-
rangement has also achieved commercial importance in the pho-
Scheme 1.
tolithography industry.3
In particular, the ring contraction of cyclic 2-diazo-1,3-
dicarbonyls by thermal or photo Wolff rearrangement followed
Recently, we have been interested in rhodium(II)-catalyzed re-
actions of cyclic diazodicarbonyl compounds with several sub-
strates, such as nitriles, isocyanates, ketones, vinyl ethers, and
by trapping of the transient
a-oxoketene with nucleophiles is
a well-known method for the preparation of
b-keto carbonyl
compounds (Scheme 1).4 Recently, the microwave-assisted Wolff
rearrangement of cyclic 2-diazo-1,3-dicarbonyls in the presence of
halides for the formation of a number of heterocycles7 and
b-
substituted a
-haloenones.8 We have also developed a new meth-
amines to form
b
-keto amides has been reported.5 Also,
odology for the synthesis of oxindoles by rhodium(II)-catalyzed
Wolff rearrangement of diazoquinolinediones.9 In continuation
with our previous studies on the development of a new method-
ology starting from cyclic diazodicarbonyls, in the present work, we
have investigated thermal Wolff rearrangement of cyclic diazo-
microwave-assisted domino multi-component reactions of 2-
* Corresponding author. Tel.: þ82 53 810 2529; fax: þ82 53 810 4631; e-mail
address: yrlee@yu.ac.kr (Y.R. Lee).
dicarbonyls with amines to form a variety of b-enaminoamides. We
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.060

P. Neupane et al. / Tetrahedron 68 (2012) 2496e2508
2497
Table 1
report herein a facile and efficient one-pot preparation of cyclic b-
Thermal reaction of 1 with 1-propylamine under several solvents
enaminoamides starting from cyclic diazodicarbonyl compounds
(Scheme 2). As an application of this methodology, we also report
an efficient conversion of synthesized
ologically interesting uracil derivatives.
b
-enaminoamides to bi-
O
O
NH
NH
N2
O
CH3CH2CH2NH2
solvent
R1
O
O
NH
R1NH2
N2
4
1
R
R
toluene
NH
R1
R
R
Solvent
THF
Acetonitrile
Benzene
Toluene
Temp (ꢀC)
Time (h)
Yield (%)
O
reflux
66
82
80
110
140
12
12
12
6
0
0
0
67
60
Scheme 2.
p-Xylene
6
2. Results and discussion
Although a few synthetic approaches for the preparation of
b
-
enaminoamides have been reported, those synthetic routes have
many reaction steps, harsh reaction conditions, and low yields.10,15
Therefore, there is still a demand for efficient methods that can
efficiently provide five-membered ring b-enaminoamides through
a one-pot reaction.
desired product 9 in 61% yield (entry 5). Reaction with aniline for
5 h produced 10 in 64% yield (entry 6). Similarly, reactions of other
diazodicarbonyls 2e3 with a number of amines formed the desired
products 11e24 in 52e81% yield (entries 7e20). Importantly, these
reactions provided rapid synthetic approaches for the preparation
The starting cyclic diazodiarbonyls 1e3 were prepared by the
diazotransfer reaction of the corresponding cyclic 1,3-dicarbonyls
with tosyl azide or mesyl azide according to the known pro-
cedure (Fig. 1).11 In order to check the reactivity of 2-
of a variety of b-enaminoamides with several substituents on the
five-membered ring.
Interestingly, reaction of 3 with 1 equiv of benzylamine in
refluxing toluene for 4 h provided
(Scheme 3), without any isolation of the desired cyclic
noamide 22 in Table 2. In the 1H NMR spectrum of 25, the methine
proton appeared at 3.14 ppm as a triplet. However, reactions of
b
-keto amide 25 in 80% yield
diazocyclohexane-1,3-dione (1) to form cyclic b-enaminoamide 4,
b-enami-
thermal reactions of 1 with 2.2 equiv of 1-propylamine under
several solvents were first examined (Table 1). When THF, aceto-
nitrile, or benzene was used in refluxing condition at 66 ꢀC, 82 ꢀC,
and 80 ꢀC for 12 h, respectively, only starting material 1 was re-
d
acyclic 2-diazo-1,3-dicarbonyls of 3-diazopentane-2,4-dione and 2-
diazo-1,3-diphenylpropane-1,3-dione with 2 equiv of benzylamine
in refluxing toluene for 5 h did not afford the desired acyclic b-
covered. With toluene at 110 ꢀC for 6 h, the desired
b-enaminoa-
mide 4 was obtained in 67% yield after column chromatography.
However, when the reaction mixture was heated at 140 ꢀC in p-
xylene for 6 h, compound 4 was produced in 60% yield. Support for
the structural assignment of 4 came from its spectroscopic analysis.
In the 1H NMR spectrum of 4, three methylene peaks due to
enaminoamides. In these cases, a mixture of unidentifiable and
decomposed products was obtained.
The formation of 4 can be explained by the mechanism as shown
in Scheme 4. The diazodicarbonyl compound 1 first gives a carbene
intermediate 26 by the loss of nitrogen under thermal reaction
condition.3,4 A 1,2-shift of 26 leads to
a-oxoketene 27, which reacts
cyclopentene ring were apparent at
d
2.51 (t, J¼7.8 Hz), 2.38 (t,
J¼7.2 Hz), and 1.88e1.78 (m), whereas two methylene peaks next to
an amide and an amine showed at 3.24e3.17 and 3.09e3.03 as
multiplets. In the IR spectrum, a carbonyl absorption of amide
with 1-propylamine to give 28. Further reaction of carbonyl group
of 28 with 1-propylamine gives final product 4. Importantly, when
we used 1 equiv of amine as shown in Scheme 3, the desired b-
enaminoamide product was not produced. In view of this result, the
formation of 4 is likely to proceed via the proposed mechanism
excluding other possible pathway through imine formation before
the carbene intermediate formation.
Moreover, to verify this stepwise mechanism, a cross reaction
with two different primary amines was next performed (Scheme 5).
A reaction of 3 with 1 equiv of 1-propylamine and benzylamine in
group was observed at 1630 cmꢁ1
.
O
O
O
N2
O
N2
O
N2
O
refluxing toluene for 6 h afforded
(32%) as an 84:16 ratio of isomers and keto amides 25 (9%) and 31
(7%) together with a trace amount of -enaminoamides 18 and 22,
described in Table 2. The -enaminoamides 29 and 30 were easily
separated from -keto amides 25 and 31 by column chromatogra-
b-enaminoamides 29 and 30
3
1
2
b
b
Fig. 1. Synthesized cyclic diazodicarbonyls.
b
phy, but each individual component was not separable. The ratio of
29 and 30 to 25 and 31 was calculated by integration of the re-
spective protons in the 1H NMR spectra.
In order to increase the usefulness of this methodology, con-
version of synthesized b-enaminoamide 22 to uracil derivative 32
was next attempted (Scheme 6). Uracil derivatives bearing sub-
stituents at positions 5 and 6 display a wide range of biological
activities.12 Reaction of 22 with 1.1 equiv of triphosgene and 5 equiv
of K2CO3 in refluxing toluene for 10 h formed uracil derivative 32 in
52% yield. The structure of 32 was assigned by 1H NMR analysis and
by comparison with previously reported data.13 The methylene
To explore the generality and scope of this methodology, addi-
tional reactions of cyclic diazodicarbonyls 1e3 with several amines
were performed in refluxing toluene. The outcomes of the reaction
are summarized in Table 2. Reaction of 2-diazocyclohexane-1,3-
dione (1) with 1-butylamine for 5 h produced 5 in 53% yield (en-
try 1, Table 2), whereas that with cyclohexanemethylamine formed
6 in 59% yield (entry 2). The 2-phenylethylamine and benzylamine
resulted in the formation of 7e8 in 57 and 83% yield, respectively
(entries 3e4). Reaction of tryptamine with indole moiety was also
successful. Treatment of 1 with tryptamine for 7 h formed the

2498
P. Neupane et al. / Tetrahedron 68 (2012) 2496e2508
Table 2
Additional reaction of cyclic diazodicarbonyls 1e3 with several amines
Entry
Diazodicarbonyl
Amine
Time (h)
Product
Yield (%)
O
NH
NH
1
1-Butylamine
5
53
5
O
NH
NH
2
Cyclohexanemethylamine
7
59
6
O
NH
NH
3
2-Phenylethylamine
6
57
7
O
O
NH
NH
N2
O
4
Benzylamine
5
83
1
8
NH
O
NH
NH
5
Tryptamine
7
61
N
H
9

P. Neupane et al. / Tetrahedron 68 (2012) 2496e2508
2499
Table 2 (continued )
Entry Diazodicarbonyl
Amine
Time (h)
Product
Yield (%)
O
NH
6
Aniline
5
64
NH
10
O
O
NH
N2
O
7
1-Propylamine
8
55
NH
11
2
O
NH
NH
8
1-Butylamine
7
62
12
O
NH
NH
9
Cyclohexanemethylamine
7
52
13
O
NH
NH
14
10
2-Phenylethylamine
8
54
(continued on next page)

2500
P. Neupane et al. / Tetrahedron 68 (2012) 2496e2508
Table 2 (continued )
Entry
Diazodicarbonyl
Amine
Time (h)
Product
Yield (%)
O
NH
NH
11
Benzylamine
7
63
15
H
N
O
NH
NH
12
Tryptamine
7
60
N
16 H
O
NH
NH
13
Aniline
6
55
17
O
O
NH
NH
18
N2
O
14
1-Propylamine
8
65
3
O
NH
15
1-Butylamine
6
63
NH
19

P. Neupane et al. / Tetrahedron 68 (2012) 2496e2508
2501
Table 2 (continued )
Entry Diazodicarbonyl
Amine
Time (h)
Product
Yield (%)
O
NH
16
Cyclohexanemethylamine
2-Phenylethylamine
Benzylamine
7
5
5
59
54
81
NH
20
O
O
NH
NH
17
21
NH
NH
18
22
NH
O
NH
NH
19
Tryptamine
7
61
23
N
H
O
NH
NH
20
Aniline
5
63
24

2502
P. Neupane et al. / Tetrahedron 68 (2012) 2496e2508
wet ethanol at reflux for 12 h gave
a stoichiometric reaction, manganese(III) acetate and copper(II)
acetate mediated oxidations of -enaminoamides to form the cor-
-keto amides have already been reported by the Cossy
b-keto amide 25 in 84% yield. As
b
O
NH2
NH
O
responding
group.15
b
O
(1 equiv.)
N2
O
For the further formation of uracil derivatives bearing sub-
stituents at positions 5 and 6, additional reactions of synthesized
b
-
toluene
reflux
4 h
enaminoamides with triphosgene were carried out in the presence
of K2CO3. The results are summarized in Table 3. Treatment of
compound 8 with 1.1 equiv of triphosgene in refluxing toluene for
10 h formed uracil derivative 34 in 42% yield (entry 1, Table 3),
whereas reactions of compounds 12, 13, 15, 18e20 formed uracil
25
3
80%
Scheme 3.
O
O
O
O
O
NH
H2N
NH
NH
heat
-N2
N2
O
H2N
O
O
-H2O
O
1
27
4
26
28
Scheme 4.
O
O
NH
NH
NH
+
NH
30
29
NH2
(1 equiv.)
32% (29/30 = 84:16)
+
O
NH2
N2
O
O
(1 equiv.)
NH
O
NH
toluene
reflux
O
+
+
O
7%
3
6 h
25 9%
31
O
O
NH
NH
trace
NH
NH
trace
22
18
Scheme 5.
protons of a benzyl group at N-1 appeared at
d
4.94 ppm, whereas
derivatives 35e40 with 40e54% yield (entries 2e7). These re-
those at N-3 showed peak at 5.14 ppm. Selective deprotection of
d
actions provided a rapid synthetic entry to biologically interesting
32 was successfully performed using catalytic transfer hydroge-
nation with ammonium formate over 10% Pd/C to give 33 in 61%
yield.14 The structure of 33 was also confirmed by 1H NMR analysis
and by comparison with the previously reported data.13 In the 1H
NMR spectrum of 33, the methylene protons of a benzyl group at N-
uracil derivatives from the corresponding
In conclusion, a simple and efficient method for the preparation
of a variety of cyclic -enaminoamides starting from readily avail-
able cyclic diazodicarbonyls and amines has been developed. The
key strategy is thermal Wolff rearrangement. Conversion of syn-
b-enaminoamides.
b
1 were not seen, but those at N-3 were apparent at
d
5.02 ppm.
thesized
b-enaminoamides into uracil derivatives was also per-
Importantly, treatment of 22 with p-TsOH as a metal-free catalyst in
formed by reaction with triphosgene in the presence of K2CO3.

P. Neupane et al. / Tetrahedron 68 (2012) 2496e2508
2503
O
O
O
N
N
triphosgene
K2CO3
NH
NH
O
O
HCO2NH4
N
N
toluene
10% Pd/C
MeOH
61%
H
reflux
33
52%
32
22
p-TsOH
84%
EtOH
(wet)
O
NH
O
25
Scheme 6.
3. Experimental section
3.1. General
CDCl3):
d
7.90 (1H, br s), 4.83 (1H, br s), 3.24e3.17 (2H, m),
3.09e3.03 (2H, m), 2.51 (2H, t, J¼7.8 Hz), 2.38 (2H, t, J¼7.2 Hz),
1.88e1.78 (2H, m), 1.56e1.44 (4H, m), 0.93e0.87 (6H, m); 13C
NMR (75 MHz, CDCl3):
d 169.0, 161.6, 93.2, 46.3, 40.6, 31.8, 29.3,
All the experiments were carried out in a nitrogen atmosphere.
Merck precoated silica gel plates (Art. 5554) with a fluorescent
indicator were used for analytical TLC. Flash column chromatog-
raphy was performed using silica gel 9385 (Merck). The 1H NMR
and 13C NMR spectra were recorded on a Bruker Model ARX (300
and 75 MHz, respectively) spectrometer in CDCl3 as the solvent. The
IR spectra were recorded on a Jasco FTIR 5300 spectrophotometer.
The HRMS were carried out at the Korea Basic Science Institute.
24.3, 23.5, 20.7, 11.5, 11.4; IR (KBr): 3352, 2960, 1630, 1525, 1447,
1289, 1144 cmꢁ1; HRMS m/z (Mþ) calculated for C12H22N2O:
210.1732, found: 210.1734.
3.3.2. N-Butyl-2-(butylamino)cyclopent-1-enecarboxamide
(5). A
reaction 1 (138 mg, 1.0 mmol) with 1-butylamine (161 mg,
2.2 mmol) in refluxing toluene for 5 h afforded compound 5
(126 mg, 53%) as an oil; 1H NMR (300 MHz, CDCl3):
d 7.84 (1H, br s),
4.79 (1H, br s), 3.23e3.16 (2H, m), 3.09e3.02 (2H, m), 2.47 (2H, t,
J¼7.5 Hz), 2.34 (2H, t, J¼7.2 Hz), 1.83e1.74 (2H, m), 1.48e1.38 (4H,
m), 1.34e1.24 (4H, m), 0.87e0.81 (6H, m); 13C NMR (75 MHz,
3.2. General procedure for the preparation of substituted b-
enaminoamides (4e24)
CDCl3):
d 169.1, 161.7, 93.2, 44.3, 38.7, 33.3, 32.5, 31.9, 29.3, 20.8,
To a solution of cyclic diazodicarbonyls (1.0 mmol) in toluene
(5 mL) was added amines (2.2 mmol). The resulting mixture was
heated at 110 ꢀC until completion of the reaction as indicated by
TLC. The solvent was removed under reduced pressure to give an
oily residue, which was purified by silica gel column chromatog-
raphy using n-hexane/ethyl acetate (10:1) as eluent to give desired
products.
20.3, 20.1, 14.0, 13.9; IR (neat): 3322, 2955, 1632, 1530, 1453, 1280,
1146 cmꢁ1; HRMS m/z (Mþ) calculated for C14H26N2O: 238.2045,
found: 238.2044.
3.3.3. N-(Cyclohexylmethyl)-2-(cyclohexylmethylamino)cyclopent-1-
enecarboxamide (6). A reaction of 1 (138 mg, 1.0 mmol) with
cyclohexanemethylamine (249 mg, 2.2 mmol) in refluxing toluene
for 7 h afforded compound 6 (188 mg, 59%) as a solid; mp 96e98 ꢀC;
3.3. General procedure for the preparation of uracil
1H NMR (300 MHz, CDCl3):
d 7.98 (1H, br s), 4.87 (1H, br s), 3.07 (2H,
derivatives (32, 34e40)
t, J¼6.6 Hz), 2.91 (2H, t, J¼6.6 Hz), 2.48 (2H, t, J¼7.5 Hz), 2.38 (2H, t,
J¼7.2 Hz), 1.86e1.76 (2H, m), 1.74e1.59 (10H, m), 1.47e1.32 (2H, m),
1.24e1.04 (6H, m), 0.92e0.82 (4H, m); 13C NMR (75 MHz, CDCl3):
To a solution of b-enaminoamides (0.13e0.40 mmol) in toluene
(5 mL) was added potassium carbonate (5 equiv) and triphosgene
(1.1 equiv). The resulting mixture was heated at 110 ꢀC in sealed
tube until completion of the reaction as indicated by TLC. The sol-
vent was removed under reduced pressure and water (25 mL) was
added to the residue, and then extracted with EtOAc (3ꢂ25 mL).
The organic layer was dried over anhydrous MgSO4 and concen-
trated. The residue was purified by column chromatography on
silica gel using n-hexane/ethyl acetate (10:1) as eluent to give de-
sired products.
d 169.1, 161.7, 93.0, 51.3, 45.2, 39.4, 38.4, 31.9, 31.0, 30.9, 29.4, 26.6,
26.5, 26.0, 25.9 20.7; IR (KBr): 3318, 2917, 2851, 2664, 2345, 1741,
1631, 1523, 1447, 1268 cmꢁ1; HRMS m/z (Mþ) calculated for
C20H34N2O: 318.2671, found: 318.2669.
3.3.4. N-Phenethyl-2-(phenethylamino)cyclopent-1-enecarboxamide
(7). A reaction of 1 (138 mg, 1.0 mmol) with 2-phenylethylamine
(267 mg, 2.2 mmol) in refluxing toluene for 6 h afforded com-
pound 7 (191 mg, 57%) as an oil; 1H NMR (300 MHz, CDCl3):
d 8.03
(1H, br s), 7.31e7.16 (10H, m), 4.87 (1H, br s), 3.55e3.49 (2H, m),
3.39e3.32 (2H, m), 2.84e2.78 (4H, m), 2.41 (2H, t, J¼7.5 Hz), 2.28
(2H, t, J¼7.2 Hz), 1.81e1.72 (2H, m); 13C NMR (75 MHz, CDCl3):
3.3.1. N-Propyl-2-(propylamino)cyclopent-1-enecarboxamide (4). A
reaction of 1 (138 mg, 1.0 mmol) with 1-propylamine (130 mg,
2.2 mmol) in refluxing toluene for 6 h afforded compound 4
(141 mg, 67%) as a solid; mp 56e58 ꢀC; 1H NMR (300 MHz,
d
168.7, 161.3, 139.4, 139.0, 128.8, 128.7, 128.5, 128.4, 126.3, 126.2,
93.7, 46.3, 39.9, 38.0, 36.3, 31.5, 28.9, 20.5; IR (neat): 3315, 3026,

2504
P. Neupane et al. / Tetrahedron 68 (2012) 2496e2508
Table 3
Synthesis of uracil derivatives from the corresponding b-enaminoamides
Entry
b
-Enaminoamide
Time (h)
Product
Yield (%)
O
O
N
NH
NH
1
10
42
O
N
34
8
O
O
N
N
NH
NH
O
2
3
4
8
4
5
40
43
52
35
12
O
O
N
NH
O
N
NH
36
13
O
O
O
N
NH
O
N
NH
37
15
O
N
N
NH
NH
O
5
10
45
38
18
O
O
NH
NH
N
N
6
10
43
O
39
19

P. Neupane et al. / Tetrahedron 68 (2012) 2496e2508
2505
Table 3 (continued )
Entry
b
-Enaminoamide
Time (h)
Product
Yield (%)
O
O
N
N
NH
NH
7
4
54
O
40
20
2934, 1630, 1518, 1448, 1276, 748 cmꢁ1; HRMS m/z (Mþ) calculated
1632, 1527, 1267, 1148 cmꢁ1; HRMS m/z (Mþ) calculated for
for C22H26N2O: 334.2045, found: 334.2042.
C18H26N2O: 286.2045, found: 286.2047.
3.3.5. N-Benzyl-2-(benzylamino)cyclopent-1-enecarboxamide (8). A
reaction of 1 (138 mg, 1.0 mmol) with benzylamine (236 mg,
2.2 mmol) in refluxing toluene for 5 h afforded compound 8
3. 3. 9. N -Bu tyl -2-(butylamin o)-4 -phenylcyc lopent-1 -
enecarboxamide (12). A reaction of 2 (214 mg, 1.0 mmol) with 1-
butylamine (161 mg, 2.2 mmol) in refluxing toluene for 7 h affor-
ded compound 12 (195 mg, 62%) as an oil; 1H NMR (300 MHz,
(254 mg, 83%) as an oil; 1H NMR (300 MHz, CDCl3):
d 8.29 (1H, br
s), 7.23e7.12 (10H, m), 5.18 (1H, br s), 4.39 (2H, d, J¼6.0 Hz), 4.25
CDCl3): d 7.94 (1H, br s), 7.32e7.12 (5H, m), 4.78 (1H, br s),
(2H, d, J¼6.6 Hz), 2.43 (2H, t, J¼7.5 Hz), 2.33 (2H, t, J¼7.2 Hz),
3.48e3.36 (1H, m), 3.32e3.18 (2H, m), 3.16e3.04 (2H, m),
3.02e2.93 (1H, m), 2.86e2.79 (1H, m), 2.67e2.59 (1H, m),
2.53e2.47 (1H, m), 1.51e1.41 (4H, m), 1.37e1.28 (4H, m), 0.92e0.82
1.78e1.68 (2H, m); 13C NMR (75 MHz, CDCl3):
d 168.7, 161.8,
139.8, 139.7, 128.7, 128.6, 127.6, 127.2, 127.1, 126.9, 94.3, 48.3, 42.8,
31.8, 29.3, 20.6; IR (neat): 3319, 3028, 2925, 1631, 1515, 1448,
1281, 735 cmꢁ1; HRMS m/z (Mþ) C20H22N2O: 306.1732, found:
306.1731.
(6H, m); 13C NMR (75 MHz, CDCl3):
d
168.8, 160.0, 146.1, 128.6,
126.9, 126.4, 92.4, 44.3, 40.7, 39.9, 38.6, 38.2, 33.3, 32.4, 20.3, 20.0,
14.0, 13.9; IR (neat): 3325, 2954, 1632, 1522, 1445, 1282, 1147 cmꢁ1
;
HRMS m/z (Mþ) calculated for C20H30N2O: 314.2358, found:
3.3.6. N-(2-(1H-Indol-3-yl)ethyl)-2-(2-(1H-indol-3-yl)ethylamino)
314.2356.
cyclopent-1-enecarboxamide (9). A reaction of
1 (138 mg,
1.0 mmol) with tryptamine (352 mg, 2.2 mmol) in refluxing tol-
uene for 7 h afforded compound 9 (251 mg, 61%) as a solid; mp
3.3.10. N-(Cyclohexylmethyl)-2-(cyclohexylmethylamino)-4-
phenylcyclopent-1-enecarboxamide (13). A reaction of 2 (214 mg,
1.0 mmol) with cyclohexanemethylamine (249 mg, 2.2 mmol) in
refluxing toluene for 7 h afforded compound 13 (205 mg, 52%) as
80e82 ꢀC; 1H NMR (300 MHz, CDCl3):
d 8.89 (1H, br s), 8.57 (1H, br
s), 8.24 (1H, t, J¼6.0 Hz), 7.77e7.71 (2H, m), 7.48e7.24 (6H, m), 7.02
(2H, s), 5.25 (1H, t, J¼5.7 Hz), 3.82e3.76 (2H, m), 3.62e3.55 (2H,
m), 3.14e3.06 (4H, m), 2.65e2.59 (2H, m), 2.44e2.39 (2H, m),
a solid; mp 112e114 ꢀC; 1H NMR (300 MHz, CDCl3):
d 7.99 (1H, br s),
7.25e7.10 (5H, m), 4.82 (1H, br s), 3.43e3.32 (1H, m), 3.11e2.98 (2H,
m), 2.93e2.75 (4H, m), 2.61e2.44 (2H, m), 1.72e1.52 (10H, m),
1.44e1.26 (2H, m), 1.19e1.02 (6H, m), 0.90e0.76 (4H, m); 13C NMR
1.96e1.86 (2H, m); 13C NMR (75 MHz, CDCl3):
d 169.2, 161.9, 136.5,
136.4, 127.5, 127.2, 122.7, 122.4, 121.9, 121.8, 119.2, 119.1, 118.7,
118.5, 113.0, 112.4, 111.5, 111.4, 93.6, 45.0, 39.6, 31.9, 29.2, 27.1, 25.9,
20.6; IR (KBr): 3413, 3297, 3058, 2931, 1730, 1626, 1521, 1445, 1276,
1100 cmꢁ1; HRMS m/z (Mþ) calculated for C26H28N4O: 412.2263,
found: 412.2261.
(75 MHz, CDCl3):
d 168.7, 160.1, 145.9, 128.5, 126.8, 126.3, 92.1, 51.2,
45.1, 40.6, 39.9, 39.3, 38.2, 38.1, 30.9, 30.8, 26.5, 26.4, 25.9, 25.8; IR
(KBr): 3323, 3060, 3026, 2922, 2849, 2357, 1738, 1633, 1588, 1521,
1447, 1259, 1181, 1150, 762 cmꢁ1; HRMS m/z (Mþ) calculated for
C26H38N2O: 394.2984, found: 394.2986.
3.3.7. N-Phenyl-2-(phenylamino)cyclopent-1-enecarboxamide
(10). A reaction of 1 (138 mg, 1.0 mmol) with aniline (205 mg,
2.2 mmol) in refluxing toluene for 5 h afforded compound 10
(178 mg, 64%) as a solid; mp 128e130 ꢀC; 1H NMR (300 MHz,
3.3.11. N-Phenethyl-2-(phenethylamino)-4-phenylcyclopent-1-
enecarboxamide (14). A reaction of 2 (214 mg, 1.0 mmol) with 2-
phenylethylamine (267 mg, 2.2 mmol) in refluxing toluene for
8 h afforded compound 14 (222 mg, 54%) as an oil; 1H NMR
CDCl3):
2.83e2.78 (2H, m), 2.59e2.55 (2H, m), 1.94e1.89 (2H, m); 13C NMR
(75 MHz, CDCl3): 166.6, 159.4, 141.1, 138.6, 129.3, 129.0, 123.7,
d 10.37 (1H, br s), 7.47e6.97 (10H, m), 6.71 (1H, br s),
(300 MHz, CDCl3): d 8.05 (1H, br s), 7.28e7.12 (15H, m), 4.79 (1H, br
d
s), 3.49e3.44 (2H, m), 3.33e3.26 (2H, m), 2.99e2.89 (1H, m),
122.9, 120.8, 120.2, 98.5, 33.7, 29.1, 21.7; IR (KBr): 3242, 3044, 2956,
2360, 1596, 1431, 1237, 1144, 754 cmꢁ1; HRMS m/z (Mþ) calculated
for C18H18N2O: 278.1419, found: 278.1421.
2.78e2.74 (4H, m), 2.69e2.56 (2H, m), 2.47e2.31 (2H, m); 13C NMR
(75 MHz, CDCl3):
d 168.7, 160.0, 145.9, 139.5, 139.1, 129.0, 128.9,
128.8, 128.7, 128.6, 128.5, 126.9, 126.5, 126.4, 92.9, 46.5, 40.6, 40.2,
39.8, 38.3, 37.9, 36.4; IR (neat): 3312, 3027, 2928, 1632, 1521, 1451,
1266, 751 cmꢁ1; HRMS m/z (Mþ) calculated for C28H30N2O:
410.2358, found: 410.2356.
3.3.8. 4-Phenyl-N-propyl-2-(propylamino)cyclopent-1-
enecarboxamide (11). A reaction of 2 (214 mg, 1.0 mmol) with 1-
propylamine (130 mg, 2.2 mmol) in refluxing toluene for 8 h
afforded compound 11 (157 mg, 55%) as an oil; 1H NMR (300 MHz,
3.3.12. N-Benzyl-2-(benzylamino)-4-phenylcyclopent-1-
enecarboxamide (15). A reaction of 2 (214 mg, 1.0 mmol) with
benzylamine (236 mg, 2.2 mmol) in refluxing toluene for 7 h
afforded compound 15 (240 mg, 63%) as an oil; 1H NMR (300 MHz,
CDCl3):
d 7.92 (1H, br s), 7.28e7.10 (5H, m), 4.78 (1H, br s),
3.45e3.34 (1H, m), 3.21e3.14 (2H, m), 3.07e3.00 (2H, m),
2.99e2.91 (1H, m), 2.85e2.78 (1H, m), 2.65e2.57 (1H, m),
2.51e2.45 (1H, m), 1.51e1.42 (4H, m), 0.89e0.83 (6H, m); 13C NMR
CDCl3):
d
8.36 (1H, t, J¼6.3 Hz), 7.28e7.07 (15H, m), 5.13 (1H, t,
(75 MHz, CDCl3):
d
168.9, 160.2, 146.1, 128.6, 126.9, 126.4, 92.4, 46.5,
J¼5.7 Hz), 4.44e4.40 (2H, m), 4.29 (2H, d, J¼6.6 Hz) 3.42e3.31 (1H,
40.8, 40.7, 40.0, 38.2, 24.5, 23.6, 11.6, 11.5; IR (neat): 3337, 2961,
m), 2.96e2.78 (2H, m), 2.64e2.45 (2H, m); 13C NMR (75 MHz,

2506
P. Neupane et al. / Tetrahedron 68 (2012) 2496e2508
CDCl3):
d
168.5, 160.4, 145.8, 139.7, 139.5, 128.8, 128.7, 128.6, 127.8,
1632, 1523, 1448, 1272 cmꢁ1; HRMS m/z (Mþ) calculated for
127.4, 127.3, 127.0, 126.9, 126.5, 93.5, 48.4, 43.1, 40.7, 39.9, 38.2; IR
(neat): 3325, 3060, 2926, 1632, 1520, 1449, 1263, 736 cmꢁ1; HRMS
m/z (Mþ) calculated for C26H26N2O:382.2045, found: 382.2043.
C22H38N2O: 346.2984, found: 346.2982.
3.3.18. 4,4-Dimethyl-N-phenethyl-2-(phenethylamino)cyclopent-1-
enecarboxamide (21). A reaction of 3 (166 mg, 1.0 mmol) with 2-
phenylethylamine (267 mg, 2.2 mmol) in refluxing toluene for
5 h afforded compound 21 (196 mg, 54%) as an oil; 1H NMR
3.3.13. N-(2-(1H-Indol-3-yl)ethyl)-2-(2-(1H-indol-3-yl)ethylamino)-
4-phenylcyclopent-1-enecarboxamide (16). A reaction of 2 (214 mg,
1.0 mmol) with tryptamine (352 mg, 2.2 mmol) in refluxing toluene
for 7 h afforded compound 16 (293 mg, 60%) as a solid; mp
(300 MHz, CDCl3):
d
7.91 (1H, t, J¼6.0 Hz), 7.24e7.07 (10H, m), 4.73
(1H, t, J¼5.4 Hz), 3.46e3.39 (2H, m), 3.22e3.20 (2H, m), 2.75e2.68
87e89 ꢀC; 1H NMR (300 MHz, CDCl3):
d
8.12 (1H, br s), 7.99 (2H, br
(4H, m), 2.11 (2H, s), 1.99 (2H, s), 0.95 (6H, s); 13C NMR (75 MHz,
s), 7.61e7.52 (2H, m), 7.33e6.98 (13H, m), 4.93 (1H, br s), 3.64e3.57
(2H, m), 3.45e3.40 (2H, m), 3.31e3.26 (1H, m), 2.99e2.95 (4H, m),
2.87e2.81 (1H, m), 2.69e2.62 (1H, m), 2.51e2.43 (1H, m),
CDCl3): d 169.0, 160.0, 139.6, 139.1, 128.9, 128.8, 128.6, 128.5, 126.4,
126.3, 92.8, 46.4, 46.3, 44.3, 40.1, 38.2, 36.4, 35.5, 29.9; IR (neat):
3325, 3062, 2950, 1633, 1516, 1448, 1282 cmꢁ1; HRMS m/z (Mþ)
calculated for C24H30N2O: 362.2358, found: 362.2361.
2.36e2.30 (1H, m); 13C NMR (75 MHz, CDCl3):
d 168.9, 160.4, 145.8,
136.5,128.6,127.4,127.1,126.9,126.4,122.8,122.3,121.9,121.8,119.3,
119.2,118.8,118.5,113.0,112.4,111.5,111.4, 92.6, 45.1, 40.5, 39.9, 39.5,
37.5, 27.2, 25.9; IR (KBr): 3414, 3053, 2922, 2346, 1740, 1629, 1519,
1445, 1268, 1096, 910, 739 cmꢁ1; HRMS m/z (Mþ) calculated for
C32H32N4O:488.2576, found: 488.2578.
3.3.19. N-Benzyl-2-(benzylamino)-4,4-dimethylcyclopent-1-
enecarboxamide (22). A reaction of 3 (166 mg, 1.0 mmol) with
benzylamine (236 mg, 2.2 mmol) in refluxing toluene for 5 h
afforded compound 22 (271 mg, 81%) as a solid; mp 69e71 ꢀC; 1H
NMR (300 MHz, CDCl3):
(1H, br s), 4.41 (2H, d, J¼5.7 Hz), 4.26 (2H, d, J¼6.6 Hz), 2.28 (2H, s),
2.18 (2H, s), 1.02 (6H, s); 13C NMR (75 MHz, CDCl3):
168.8, 160.3,
139.7, 139.4, 128.5, 127.6, 127.0, 126.9, 126.6, 93.2, 48.1, 46.3, 44.4,
42.8, 35.8, 29.8; IR (KBr): 3351, 3060, 2945, 1628, 1518, 1430, 1259,
612 cmꢁ1; HRMS m/z (Mþ) calculated for C22H26N2O: 334.2043,
found 334.2043.
d 8.24 (1H, br s), 7.29e7.14 (10H, m), 5.06
3.3.14. N,4-Diphenyl-2-(phenylamino)cyclopent-1-enecarboxamide
(17). A reaction of 2 (214 mg, 1.0 mmol) with aniline (205 mg,
2.2 mmol) in refluxing toluene for 6 h afforded compound 17
d
(195 mg, 55%) as an oil; 1H NMR (300 MHz, CDCl3):
d 10.42 (1H, br
s), 7.45e7.25 (2H, m), 7.28e6.95 (11H, m), 6.71 (1H, br s),
6.61e6.58 (2H, m), 3.53e3.42 (1H, m), 3.24e3.15 (1H, m),
2.99e2.91 (2H, m), 2.73e2.67 (1H, m); 13C NMR (75 MHz, CDCl3):
d
166.4, 157.6, 146.2, 144.8, 140.5, 138.3, 129.2, 129.1, 128.8, 128.6,
3.3.20. N-(2-(1H-Indol-3-yl)ethyl)-2-(2-(1H-indol-3-yl)ethylamino)-
126.8, 126.5, 123.5, 123.0, 120.6, 119.9, 118.4, 115.0, 97.1, 41.4, 41.3,
37.4; IR (neat): 3362, 3055, 2922, 2356, 1630, 1499, 1437, 1243,
754 cmꢁ1; HRMS m/z (Mþ) calculated for C24H22N2O: 354.1732,
found: 354.1732.
4,4-dimethylcyclopent-1-enecarboxamide (23). A reaction of 3
(166 mg, 1.0 mmol) with tryptamine (352 mg, 2.2 mmol) in
refluxing toluene for 7 h afforded compound 23 (268 mg, 61%) as
a solid; mp 69e71 ꢀC; 1H NMR (300 MHz, CDCl3):
d 8.56 (1H, br s),
8.23 (1H, br s), 7.90 (1H, t, J¼6.0 Hz), 7.48e7.40 (2H, m), 7.20e6.94
(6H, m), 6.74 (2H, s), 4.88 (1H, t, J¼6 Hz), 3.52e3.46 (2H, m),
3.29e3.23 (2H, m), 2.87e2.76 (4H, m), 2.13 (2H, s), 1.94 (2H, s), 0.89
3.3.15. 4,4-Dimethyl-N-propyl-2-(propylamino)cyclopent-1-
enecarboxamide (18). A reaction of 3 (166 mg, 1.0 mmol) with 1-
propylamine (130 mg, 2.2 mmol) in refluxing toluene for 8 h
afforded compound 18 (155 mg, 65%) as an oil; 1H NMR (300 MHz,
(6H, s); 13C NMR (75 MHz, CDCl3):
d 169.4, 160.6, 136.5, 127.5, 127.1,
122.7, 122.4, 121.9, 121.7, 119.2, 119.1, 118.8, 118.4, 113.0, 112.3, 111.5,
111.4, 92.5, 46.5, 44.9, 44.2, 39.6, 35.5, 29.9, 27.1, 25.9; IR (KBr): 3410,
3285, 2938,1908,1730, 1629, 1521,1445,1279,1100 cmꢁ1; HRMS m/
z (Mþ) calculated for C28H32N4O: 440.2576, found: 440.2579.
CDCl3):
3.06e2.99 (2H, m), 2.33 (2H, s), 2.20 (2H, s), 1.56e1.44 (4H, m), 1.05
(6H, s), 0.93e0.87 (6H, m); 13C NMR (75 MHz, CDCl3):
169.1, 160.0,
d 7.85 (1H, br s), 4.76 (1H, br s), 3.23e3.17 (2H, m),
d
92.1, 46.3, 46.1, 44.3, 40.4, 35.5, 29.8. 24.3, 23.3, 11.4, 11.3; IR (neat):
3323, 2957, 1633, 1526, 1446, 1286, 1168 cmꢁ1; HRMS m/z (Mþ)
calculated for C14H26N2O: 238.2045, found: 238.2044.
3.3.21. 4,4-Dimethyl-N-phenyl-2-(phenylamino)cyclopent-1-
enecarboxamide (24). A reaction of 3 (166 mg, 1.0 mmol) with an-
iline (205 mg, 2.2 mmol) in refluxing toluene for 5 h afforded
compound 24 (193 mg, 63%) as a solid; mp 140e142 ꢀC; 1H NMR
3.3.16. N-Butyl-2-(butylamino)-4,4-dimethylcyclopent-1-
enecarboxamide (19). A reaction of 3 (166 mg, 1.0 mmol) with 1-
butylamine (161 mg, 2.2 mmol) in refluxing toluene for 6 h affor-
ded compound 19 (168 mg, 63%) as an oil; 1H NMR (300 MHz,
(300 MHz, CDCl3):
br s), 2.69 (2H, s), 2.44 (2H, s), 1.18 (6H, s); 13C NMR (75 MHz,
CDCl3): 166.9, 157.7, 140.8, 138.4, 129.1, 128.9, 123.4, 122.7, 120.5,
d 10.41 (1H, br s), 7.51e6.97 (10H, m), 6.71 (1H,
d
CDCl3):
d
7.78 (1H, br s) 4.71 (1H, br s), 3.22e3.15 (2H, m),
119.9, 97.2, 48.1, 43.9, 36.7, 29.5; IR (KBr): 3361, 3055, 2953, 1628,
1500, 1434, 1244, 1182 cmꢁ1; HRMS m/z (Mþ) C20H22N2O: 306.1732,
found: 306.1734.
3.02e2.98 (2H, m), 2.28 (2H, s), 2.15 (2H, s), 1.46e1.36 (4H, m),
1.33e1.24 (4H, m), 1.05 (6H, s), 0.87e0.81 (6H, m); 13C NMR
(75 MHz, CDCl3):
d 169.2, 160.0, 92.2, 46.5, 44.5, 44.1, 38.6, 35.6,
33.3, 32.4, 30.0, 20.2, 19.9, 13.9, 13.8; IR (neat): 3319, 2953, 1633,
1524, 1444, 1282, 1166 cmꢁ1; HRMS m/z (Mþ) calculated for
C16H30N2O: 266.2358, found: 266.2354.
3.3.22. N-Benzyl-4,4-dimethyl-2-oxocyclopentanecarboxamide
(25). A reaction of 3 (166 mg,1.0 mmol) with benzylamine (107 mg,
1.0 mmol) in refluxing toluene for 4 h afforded compound 25
(196 mg, 80%) as an oil; 1H NMR (300 MHz, CDCl3)
d 7.26e7.16 (5H,
3.3.17. N-(Cyclohexylmethyl)-2-(cyclohexylmethylamino)-4,4-
dimethylcyclopent-1-enecarboxamide (20). A reaction of 3 (166 mg,
1.0 mmol) with cyclohexanemethylamine (249 mg, 2.2 mmol) in
refluxing toluene for 7 h afforded compound 20 (204 mg, 59%) as
m), 7.10 (1H, br s), 4.44e4.28 (2H, m), 3.14 (1H, t, J¼9.6 Hz),
2.30e1.95 (4H, m), 1.08 (3H, s), 0.97 (3H, s); 13C NMR (75 MHz,
CDCl3): d 216.3, 167.0, 138.3, 128.8, 127.8, 127.5, 53.9, 53.7, 43.8, 39.4,
34.2, 28.9, 27.9; IR (neat): 3306, 2954, 2357, 1740, 1648, 1537, 1455,
1365, 1232, 1126 cmꢁ1; HRMS m/z (Mþ) calculated for C15H19NO2:
245.1416, found: 245.1414.
a solid; mp 85e87 ꢀC; 1H NMR (300 MHz, CDCl3):
d 7.93 (1H, br s),
4.79 (1H, br s), 3.06 (2H, t, J¼6.6 Hz), 2.88 (2H, t, J¼6.6 Hz), 2.30 (2H,
s), 2.19 (2H, s), 1.80e1.56 (10H, m), 1.44e1.36 (2H, m), 1.20e1.11 (6H,
m), 1.08 (6H, s), 0.96e0.81 (4H, m); 13C NMR (75 MHz, CDCl3):
3.3.23. 2-(Benzylamino)-4,4-dimethyl-N-propylcyclopent-1-
enecarboxamide (29), N-benzyl-4,4-dimethyl-2-(propylamino)cyclo-
pent-1-enecarboxamide (30), N-benzyl-4,4-dimethyl-2-
d
169.2, 160.2, 91.9, 51.1, 46.5, 45.0, 44.4, 39.3, 38.2, 35.6, 30.9, 30.8,
29.9, 26.5, 26.4, 25.9, 25.8; IR (KBr): 3316, 2920, 2854, 2666, 2344,

P. Neupane et al. / Tetrahedron 68 (2012) 2496e2508
2507
oxocyclopentane carboxamide (25), and 4,4-dimethyl-2-oxo-N-pro-
pylcyclopentanecarboxamide (31). A reaction of (166 mg,
1.0 mmol) with 1-propylamine (59 mg, 1.0 mmol) and benzylamine
temperature, water (25 mL) was added and the mixture was
extracted with EtOAc (3ꢂ25 mL). The organic layer was washed
saturated NaHCO3 solution (30 mL), dried over anhydrous MgSO4,
and concentrated. The residue was purified by column chroma-
tography on silica gel using n-hexane/ethyl acetate (10:1) as eluent
to give 25 (62 mg, 84%) as an oil. The spectral data of 25 are the
same as described above.
3
(107 mg,1.0 mmol) in refluxing toluene for 6 h afforded compounds
29 and 30 (92 mg, 32%) as a 84:16 ratio of isomers and
b-keto
amides 25 (22 mg, 9%) and 31 (14 mg, 7%) as a 60:40 ratio of in-
separable mixtures together with a trace amount of
b
-enaminoa-
mides 18 and 22.
Compound 29: 1H NMR (300 MHz, CDCl3):
d
7.85 (1H, br s)
3.3.27. 1,3-Dibenzyl-6,7-dihydro-1H-cyclopenta[d]pyrimidine-
2,4(3H,5H)-dione (34). A reaction of 8 (100 mg, 0.33 mmol) with
triphosgene (107 mg, 0.36 mmol) in refluxing toluene in the
presence of K2CO3 (228 mg,1.65 mmol) for 10 h afforded compound
7.23e7.18 (5H, m), 5.01 (1H, br s), 4.40 (2H, d, J¼5.7 Hz), 3.03e2.96
(2H, m), 2.29 (2H, s), 2.16 (2H, s), 1.49e1.42 (2H, m), 1.05 (6H, s),
0.86 (3H, t, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3):
d 169.1, 160.9,
139.9, 128.7, 127.8, 126.9, 92.1, 46.7, 46.4, 44.5, 43.0, 35.9, 30.1, 24.6,
11.5; HRMS (FAB) m/z (MþHþ) calculated for C18H27N2O: 287.2123,
found: 287.2126.
34 (46 mg, 42%) as an oil; 1H NMR (300 MHz, CDCl3):
d
7.49e7.46
(10H, m), 5.15 (2H, s), 4.97 (2H, s), 2.77e3.69 (4H, m), 2.04e1.94
(2H, m); 13C NMR (75 MHz, CDCl3):
160.7, 154.8, 153.0, 137.2, 136.1,
d
Compound 30: 1H NMR (300 MHz, CDCl3):
d
8.22 (1H, br s),
128.9, 128.8, 128.3, 127.8, 127.4, 126.7, 112.2, 49.3, 44.6, 32.3, 27.7,
21.0; IR (neat): 3328, 3031, 2953, 2359,1695,1656,1482, 1389, 1354,
1075, 1029, 912, 818, 734, 701 cmꢁ1; HRMS m/z (Mþ) calculated for
C21H20N2O2: 332.1525, found: 332.1525.
7.23e7.18 (5H, m), 5.10 (1H, br s), 4.25 (2H, d, J¼6.6 Hz), 3.03e2.96
(2H, m), 2.27 (2H, s), 2.18 (2H, s),1.49e1.42 (2H, m),1.01 (6H, s), 0.86
(3H, t, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3):
d 169.1, 160.9, 139.9,
128.8, 127.9, 127.2, 94.0, 48.3, 46.6, 44.6, 43.1, 35.9, 30.0, 24.3, 11.5;
IR (neat): 3315, 3061, 3029, 2953, 2869,1633,1588,1517,1448,1282,
1168, 734 cmꢁ1; HRMS m/z (FAB) (MþHþ) calculated for C18H27N2O:
287.2123, found: 287.2126.
3.3.28. 1,3-Dibenzyl-6,7-dihydro-1H-cyclopenta[d]pyrimidine-
2,4(3H,5H)-dione (35). A reaction of 12 (70 mg, 0.22 mmol) with
triphosgene (72 mg, 0.24 mmol) in refluxing toluene in the pres-
ence of K2CO3 (152 mg, 1.09 mmol) for 8 h afforded compound 35
Compound 25: These spectral data of 1H NMR, 13C NMR, and IR
are the same as described above. HRMS m/z (FAB) (MþHþ) calcu-
lated for C15H20NO2: 246.1494, found: 246.1492.
(30 mg, 40%) as an oil; 1H NMR (300 MHz, CDCl3):
d 7.34e7.20 (5H,
m), 3.96e3.91 (2H, m), 3.79e3.62 (3H, m), 3.32e3.16 (2H, m),
2.98e2.80 (2H, m), 1.68e1.56 (4H, m), 1.40e1.30 (4H, m), 0.96e0.88
Compound 31: 1H NMR (300 MHz, CDCl3)
d 7.08 (1H, br s),
4.44e4.28 (2H, m), 3.19e3.07 (1H, m), 2.35e1.95 (4H, m), 1.48e1.41
(6H, m); 13C NMR (75 MHz, CDCl3):
d 160.7, 152.8, 152.5, 144.2,
(2H, m), 1.08 (3H, s), 0.98 (3H, s), 0.84 (3H, t, J¼7.5 Hz); 13C NMR
128.8, 126.8, 126.7, 110.7, 46.5, 41.3, 40.4, 35.9, 31.1, 29.8, 20.3, 20.0,
13.8, 13.7; IR (neat): 2956, 2868, 2358, 1696, 1656, 1484, 1364, 1323,
1253, 1188, 1079, 763 cmꢁ1; HRMS m/z (Mþ) calculated for
C21H28N2O2: 340.2151, found: 340.2154.
(75 MHz, CDCl3): d 216.1, 167.8, 53.6, 43.4, 41.2, 39.1, 33.9, 28.6, 27.6,
22.6, 11.3; HRMS m/z (Mþ) calculated for C15H19NO2: 245.1416,
found: 245.1414 and HRMS (FAB) m/z (MþHþ) calculated for
C11H20NO2: 198.1494, found: 198.1497.
3.3.29. 1,3-Bis(cyclohexylmethyl)-6-phenyl-6,7-dihydro-1H-cyclo-
penta[d]pyrimidine-2,4(3H,5H)-dione (36). A reaction of 13
(158 mg, 0.40 mmol) with triphosgene (131 mg, 0.44 mmol) in
refluxing toluene in the presence of K2CO3 (276 mg, 2 mmol) for 4 h
afforded compound 36 (72 mg, 43%) as an oil; 1H NMR (300 MHz,
3.3.24. 1,3-Dibenzyl-6,6-dimethyl-6,7-dihydro-1H-cyclopenta[d]py-
rimidine-2,4(3H,5H)-dione (32). A reaction of 22 (100 mg,
0.30 mmol) with triphosgene (98 mg, 0.33 mmol) in refluxing
toluene in the presence of K2CO3 (207 mg, 1.5 mmol) for 10 h
afforded compound 32 (56 mg, 52%) as an oil; 1H NMR (300 MHz,
CDCl3):
d 7.29e7.15 (5H, m), 3.81e3.69 (2H, m), 3.67e3.55 (1H, m),
CDCl3):
d
7.49e7.14 (10H, m), 5.14 (2H, s), 4.94 (2H, s), 2.53 (4H, s),
162.3, 153.4, 153.0, 137.3,
3.54e3.43 (2H, m), 3.26e3.11 (2H, m), 2.92e2.76 (2H, m), 1.77e1.50
1.10 (6H, s); 13C NMR (75 MHz, CDCl3):
d
(12H, m), 1.22e1.03 (6H, m), 0.99e0.76 (4H, m); 13C NMR (75 MHz,
136.1, 129.1, 128.9, 128.3, 127.8, 126.6, 110.9, 49.1, 46.8, 44.6, 42.4,
37.5, 29.4; IR (neat): 3332, 3031, 2954, 2358, 1697, 1656, 1481, 1389,
1261, 1074, 1028 cmꢁ1; HRMS m/z (Mþ) calculated for C23H24N2O2:
360.1838, found: 360.1840.
CDCl3): d 161.1, 153.2, 152.9, 150.2, 144.1, 128.7, 126.7, 110.5, 52.8,
47.1, 41.3, 10.9, 37.3, 36.3, 35.9, 30.8, 30.7, 26.3, 26.1, 25.8, 25.7; IR
(neat): 2924, 2851, 2356, 1697, 1657, 1482, 1395, 1355, 1268, 1144,
1108, 1078, 762 cmꢁ1; HRMS m/z (Mþ) calculated for C27H36N2O2:
420.2777, found: 420.2780.
3.3.25. 3-Benzyl-6,6-dimethyl-6,7-dihydro-1H-cyclopenta[d]pyrimi-
dine-2,4(3H,5H)-dione (33). A reaction of 32 (100 mg, 0.28 mmol)
with ammonium formate (10 mL of a 0.4 N solution in dry MeOH)
and 10% palladium on charcoal (319 mg) was refluxed for 15 h. The
mixture was filtered through filter paper, and the solid residue was
extensively washed with MeOH (50 mL) and CHCl3 (50 mL). Re-
moval of solvents under reduced pressure and following column
chromatography on silica gel using chloroform/methanol (99:1) as
eluent gave products 33 (46 mg, 61%) as a solid; mp 213e215 ꢀC; 1H
3.3.30. 1,3-Dibenzyl-6-phenyl-6,7-dihydro-1H-cyclopenta[d]pyrimi-
dine-2,4(3H,5H)-dione (37). A reaction of 15 (50 mg, 0.13 mmol)
with triphosgene (43 mg, 0.14 mmol) in refluxing toluene in the
presence of K2CO3 (90 mg, 0.65 mmol) for 5 h afforded compound
37 (28 mg, 52%) as an oil; 1H NMR (300 MHz, CDCl3):
d 7.80e7.41
(15H, m), 5.46 (2H, s), 5.36e5.17 (2H, m), 3.94e3.83 (1H, m),
3.52e3.44 (2H, m), 3.19e3.07 (2H, m); 13C NMR (150 MHz, CDCl3):
d
160.5, 153.3, 153.0, 143.9, 137.2, 135.9, 129.1, 128.9, 128.7, 128.4,
NMR (300 MHz, CDCl3):
7.24e7.18 (3H, m), 5.02 (2H, s), 2.44 (4H, s), 1.11 (6H, s); 13C NMR
(75 MHz, CDCl3): 161.7, 154.1, 151.8, 137.3, 129.2, 128.5, 127.8, 110.8,
46.2, 43.9, 42.4, 38.2, 29.8. IR (KBr): 3247, 3030, 2953, 2861, 1708,
1641, 1531, 1435, 1330, 1261, 1071 cmꢁ1; HRMS m/z (Mþ) calculated
for C16H18N2O2: 270.1368, found: 270.1369.
d
10.10 (1H, br s), 7.40e7.37 (2H, m),
127.9, 127.5, 126.8, 126.7, 126.6, 111.2, 49.3, 44.7, 41.2, 40.4, 36.0; IR
(neat): 3038, 2944, 2344, 2252, 1656, 1482, 1345, 1189, 1080, 912,
733 cmꢁ1; HRMS m/z (Mþ) calculated for C37H24N2O2: 408.1838,
found: 408.1836.
d
3.3.31. 6,6-Dimethyl-1,3-dipropyl-6,7-dihydro-1H-cyclopenta[d]py-
rimidine-2,4(3H,5H)-dione (38). A reaction of 18 (50 mg,
0.21 mmol) with triphosgene (69 mg, 0.23 mmol) in refluxing
toluene in the presence of K2CO3 (145 mg, 1.05 mmol) for 10 h
afforded compound 38 (25 mg, 45%) as an oil; 1H NMR (300 MHz,
3.3.26. N-Benzyl-4,4-dimethyl-2-oxocyclopentanecarboxamide
(25). To a solution of 22 (100 mg, 0.30 mmol) in wet ethanol (5 mL)
was added p-toluenesulfonic acid monohydrate (6 mg). The re-
action mixture was refluxed for 12 h. After cooling to room
CDCl3):
d
3.86 (2H, t, J¼7.5 Hz), 3.62 (2H, t, J¼7.5 Hz), 2.61 (2H, s),

2508
P. Neupane et al. / Tetrahedron 68 (2012) 2496e2508
2.51 (2H, s), 1.68e1.55 (4H, m), 1.17 (6H, s), 0.94e0.88 (6H, m);
13C NMR (75 MHz, CDCl3):
161.3, 153.0, 152.5, 110.4, 48.0,
46.7, 42.8, 42.4, 37.4, 29.6, 22.2, 21.0, 11.4, 11.1; IR (neat):
References and notes
d
1. (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds; Wiley: New York, NY, 1998; (b) Maas, G. An-
gew. Chem., Int. Ed. 2009, 48, 8186.
3356, 2959, 2871, 1697, 1657, 1482, 1366, 1263, 1074, 765 cmꢁ1
;
HRMS m/z (Mþ) calculated for C15H24N2O2: 264.1838, found:
2. (a) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417; (b) Zhu, S.-F.; Chen, C.;
Cai, Y.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2008, 47, 932; (c) Lee, E. C.; Fu, G. C. J.
Am. Chem. Soc. 2007, 129, 12066; (d) Liu, B.; Zhu, S.-F.; Zhang, W.; Chen, C.;
Zhou, Q.-L. J. Am. Chem. Soc. 2007, 129, 5834; (e) Chen, C.; Zhu, S.-F.; Liu, B.;
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C. J. Am. Chem. Soc. 2006, 128, 4594; (g) Rix, D.; Ballesteros-Garrido, R.; Zeghida,
W.; Besnard, C.; Lacour, J. Angew. Chem., Int. Ed. 2011, 50, 7308; (h) Zhang, Z.;
Liu, Y.; Ling, L.; Li, Y.; Dong, Y.; Gong, M.; Zhao, X.; Zhang, Y.; Wang, J. J. Am.
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Lacour, J. Org. Lett. 2011, 13, 1394.
264.1836.
3.3.32. 1,3-Dibutyl-6,6-dimethyl-6,7-dihydro-1H-cyclopenta[d]py-
rimidine-2,4(3H,5H)-dione (39). A reaction of 19 (60 mg,
0.23 mmol) with triphosgene (75 mg, 0.25 mmol) in refluxing tol-
uene in the presence of K2CO3 (159 mg,1.15 mmol) for 10 h afforded
compound 39 (29 mg, 43%) as an oil; 1H NMR (300 MHz, CDCl3):
d
3.90 (2H, t, J¼7.5 Hz), 3.65 (2H, t, J¼7.5 Hz), 2.60 (2H, s), 2.51 (2H, s),
1.64e1.53 (4H, m), 1.38e1.30 (4H, m), 1.17 (6H, s), 0.96e0.89 (6H,
m); 13C NMR (75 MHz, CDCl3)
: 161.2, 152.8, 152.5, 110.5, 46.7, 46.3,
42.5, 41.2, 37.4, 31.1, 29.8, 29.6, 20.2, 20.0, 13.7, 13.6; IR (neat): 3335,
3. Kirmse, W. Eur. J. Org. Chem. 2002, 2193.
d
4. Wentrup, C.; Heilmayer, W.; Kollenz, G. Synthesis 1994, 1219.
5. Presset, M.; Coquerel, Y.; Rodriguez, J. J. Org. Chem. 2009, 74, 415.
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4124.
2955, 1695, 1658, 1482, 1366, 1317, 1255, 1135, 1079, 766 cmꢁ1
;
HRMS m/z (Mþ) calculated for C17H28N2O2: 292.2151, found:
292.2148.
7. (a) Lee, Y. R.; Hwang, J. C. Eur. J. Org. Chem. 2005, 1568; (b) Lee, Y. R.; Suk, J. Y.;
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10. (a) Haight, A. R.; Stuk, T. L.; Menzia, J. A.; Robbins, T. A. Tetrahedron Lett. 1997, 38,
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3.3.33. 1,3-Bis(cyclohexylmethyl)-6,6-dimethyl-6,7-dihydro-1H-cy-
clopenta[d]pyrimidine-2,4(3H,5H)-dione (40). A reaction of 20
(100 mg, 0.29 mmol) with triphosgene (95 mg, 0.32 mmol) in
refluxing toluene in the presence of K2CO3 (200 mg, 1.45 mmol)
for 4 h afforded compound 40 (58 mg, 54%) as an oil; 1H NMR
(300 MHz, CDCl3):
2.59 (2H, s), 2.50 (2H, s), 1.80e1.59 (12H, m), 1.21e1.08 (12H, m),
1.04e0.89 (4H, m); 13C NMR (75 MHz, CDCl3):
161.7, 153.5, 153.2,
d
3.75 (2H, d, J¼3.6 Hz), 3.47 (2H, d, J¼3.6 Hz),
d
110.4, 53.6, 52.9, 47.5, 47.3, 42.6, 37.6, 37.4, 36.5, 31.0, 30.9, 29.7,
26.6, 26.4, 26.0, 25.9; IR (neat): 3053, 2924, 2851, 2358, 1697,
1657, 1480, 1394, 1357, 1314, 1267, 1171, 1142, 1105, 734 cmꢁ1
;
11. (a) Taber, D. F.; Ruckle, R. E., Jr.; Hennessy, M. J. J. Org. Chem. 1986, 51, 4077; (b)
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Chen, C.; Wu, D.; Guo, Z.; Xie, Q.; Reinhart, G. J.; Madan, A.; Wen, J.; Chen, T.;
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HRMS m/z (Mþ) calculated for C23H36N2O2: 372.2777, found:
372.2779.
Acknowledgements
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This work was supported by grant No. RTI04-01-04 from the
Regional Technology Innovation Program of the Ministry of
Knowledge Economy (MKE).
14. Botta, M.; Summa, V.; Saladino, R.; Nicoletti, R. Synth. Commun. 1991, 21, 2181.
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