A novel isocyanide-based three-component reaction: A facile synthesis of substituted 2H-pyran-3,4-dicarboxylates

Article abstract of DOI:10.1016/j.tet.2010.08.041

An efficient method for synthesis of 2H-pyran-3,4-dicarboxylates using the three-component reaction of dithiocarbamates, dialkyl acetylenedicarboxylates, and isocyanides in solvent-free conditions is described. In these reactions, synthesis of dithiocarbamates is possibly based on the one-pot reaction of secondary amines, CS₂, and alkyl halides in solvent-free conditions without using a catalyst. The mild reaction conditions and high yields of the reaction exhibit the good synthetic advantage of these methods.

Full text of DOI:10.1016/j.tet.2010.08.041

Tetrahedron 66 (2010) 8464e8467
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel isocyanide-based three-component reaction: a facile synthesis
of substituted 2H-pyran-3,4-dicarboxylates
,
a
b
b
Mohammad A. Khalilzadeh a , Zinatossadat Hossaini , Mohammad M. Baradarani , Adel Hasannia
*
a Department of Chemistry, Islamic Azad University, Qaemshahr Branch, Qaemshahr, Iran
b Department of Chemistry, Faculty of Science, Urmia University, Uremia, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 June 2010
Received in revised form 29 July 2010
Accepted 16 August 2010
Available online 20 August 2010
An efficient method for synthesis of 2H-pyran-3,4-dicarboxylates using the three-component reaction of
dithiocarbamates, dialkyl acetylenedicarboxylates, and isocyanides in solvent-free conditions is de-
scribed. In these reactions, synthesis of dithiocarbamates is possibly based on the one-pot reaction of
secondary amines, CS2, and alkyl halides in solvent-free conditions without using a catalyst. The mild
reaction conditions and high yields of the reaction exhibit the good synthetic advantage of these
methods.
Keywords:
Acetylenic esters
Isocyanide
Ó 2010 Elsevier Ltd. All rights reserved.
Three-component reactions
2H-Pyran-3,4-dicarboxylate
Dithiocarbamates
NR''
CO2R''
O
1. Introduction
R''O2C
Solvent-free
70 oC, 8 h
S
O
NR'2
+
R
+
R'''
N
C
S
R''O2C
R
Multicomponent reactions (MCRs) have been normally used by
synthetic chemists as a basic means to generate molecular diversity
from bifunctional substrates that react repeatedly in an intra-
molecular method.1e4 Devising such types of MCRs that include the
formation of multiple bonds in a single action is one of the main
challenges in new organic synthesis.5e9 They afford a great tool for
the one-pot synthesis of various and complex compounds as well as
small and drug-like heterocycles.10 MCRs that involve isocyanides
are by far the most flexible reactions in terms of scaffolds and
versatile compounds.1e5,11
CO2R''
4
1
2
3
R'''
R''
R
Yield (%) of 4
1,2,3,4
tBu
90
89
92
94
87
89
90
87
a
b
c
CO2Et
CO2Et
Ph
Me
tBu
Et
cyclohexyl
Me
Me
Me
Et
tBu
tBu
tBu
4-Me-Ph
4-NO2-Ph
4-NO2-Ph
d
e
f
g
Here, we describe an efficient synthesis of 2H-pyran-3,4-dicar-
boxylates via the reaction of dithiocarbamates, dialkyl acetylene-
dicarboxylate, and isocyanides under solvent-free conditions at
70 ꢀC (Scheme 1).
tBu
Me
Me
Et
4-NO2-Ph
CO2Et
4-Me-Ph
cyclohexyl
h
i
j
1,1,3,3-tetramethylbutyl
CH2CO2Et
83
85
Ph
CH2CO2Et
Scheme 1. Three-component condensation reactions of isocyanides, activated acety-
2. Result and discussion
lenes, and dithiocarbamates.
As indicated in Scheme 1, dithiocarbamates 1, activated acety-
lenes 2, and isocyanides 3 undergo a smooth 1:1:1 addition
reaction in solvent-free conditions at 70 ꢀC (the activated acety-
lenes and dithiocarbamates are mixed first and then isocyanides is
added) to produce 2H-pyran-3,4-dicarboxylate derivatives 4 in
83e94% yields (Scheme 1).
Structures of compounds 4ae4j were deduced from their IR,
mass, 1H NMR and 13C NMR spectra. The mass spectra of these
compounds displayed molecular ion peaks at the appropriate m/z
values. The 1H NMR spectrum of 4a exhibited a triplet at
d¼1.29
* Corresponding author. E-mail address: mkkalagar@yahoo.com(M.A.Khalilzadeh).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.041

M.A. Khalilzadeh et al. / Tetrahedron 66 (2010) 8464e8467
8465
(3J¼7.2 Hz) for the methyl group and four singlets for the tert-butyl
3. Experimental
3.1. General
(
d 1.27 ppm), methoxy (3.75 and 3.82 ppm), and olefinic (d
6.57 ppm) protons. The proton-decoupled 13C NMR spectrum of 4a
showed 16 distinct resonances in agreement with the proposed
structure. Three singlet resonances at
d
¼160.4, 162.3, and
All chemicals were obtained from commercial sources. Melting
points were measured on a Kofler hot stage apparatus and are un-
corrected.1H NMR and 13C NMR spectrawere obtained with a Bruker
FT-500 spectrometer in chloroform, and tetramethylsilane (TMS)
was used as an internal standard. Mass spectra were recorded with
a Finnigan Mat TSQ-70 spectrometer. Infrared (IR) spectra were ac-
quiredon a Nicollet Magna 550-FTspectrometer. Elemental analyses
for C, H, and N were performed using a Heraeus CHN-O-Rapid ana-
lyzer. These results agreed favorably with the calculated values.
163.8 ppm are observed in the 13C NMR spectrum of 4a, which are
attributed to the carbonyl groups.
Although we have not established the mechanism of the
reaction between the isocyanides and the acetylenic esters in the
presence of the dithiocarbamate derivatives 1, a possible explana-
tion is proposed in Scheme 2. On the basis of the well-established
chemistry of isocyanides,4,12e15 it is reasonable to assume that
compound 5 results from an initial addition of the isocyanide to the
acetylenic ester adds to dithiocarbamate 1 resulting in the forma-
tion of 6, which undergoes cyclization to generate the 2H-pyran-
3,4-dicarboxylate 4aej.
3.2. Typical procedure for the preparation of 2H-pyran-3,4,6-
tricarboxylate (4)
A mixture of dithiocarbamates (2 mmol) and dialkyl acetyle-
nedicarboxylates (2 mmol) was warmed at about 70 ꢀC for 2 h.
Then, the isocyanide (2 mmol) was added slowly. The reaction
mixture was stirred for 6 h at room temperature, and then poured
into water (15 mL). The resulting precipitate was separated by fil-
tration and recrystallized from diethyl ether (Et2O) to afford the
pure title compounds.
R
R'''
O
R'''
N
N
C
1
CO2R''
2 + 3
4
C
CO2R''
- CS2
-R2NH
CO2R''
CO2R''
5
6
Scheme 2. Possible mechanism for the formation of products 4.
3.2.1. 6-Ethyl 3,4-dimethyl-2-(tert-butylimino)-2H-pyran-3,4,6-tri-
carboxylate (4a). White powder, mp 124e127 ꢀC, yield: 0.61 g
(90%). IR (KBr) (nmax/cmꢁ1): 1738, 1732, 1723, 1547 and 1245 cmꢁ1
.
Dithiocarbamates are important compounds due to their nu-
merous biological activities16 and their essential function in agricul-
ture17 and as linkers in solid-phase organic synthesis.18 They are also
used in the rubber industry as vulcanization accelerators.19 S-Alkyl
dithiocarbamates are used as herbicides, insecticides, fungicides, and
in the treatment of cancer.20 Dithiocarbamates 1 in these reactions
were produced from the reactionofalkyl bromides 7, carbondisulfide
8, and secondary amines 9 under solvent-free conditions in excellent
yields (Scheme 3).
1H NMR:
d
¼1.27 (9H, s, Me3C), 1.29 (3H, t, 3J¼7.6 Hz, Me), 3.75 (3H,
s, MeO), 3.82 (3H, s, MeO), 4.32 (2H, q, 3J¼7.6 Hz, CH2O), 6.57 (1H, s,
CH) ppm. 13C NMR:
d
¼14.0 (Me), 29.6 (Me3C), 51.6 (MeO), 52.3
(MeO), 55.3 (CeN), 63.1 (CH2O),117.4 (CH),135.4 (C),143.2 (C),145.4
(C), 149.8 (C]N), 160.4 (C]O), 162.3 (C]O), 163.8 (C]O) ppm. MS:
m/z (%)¼339 (Mþ, 15), 308 (45), 282 (85), 57 (100), 31(86). Anal.
Calcd for C16H21NO7 (339.34): C, 56.63; H, 6.24; N, 4.13. Found: C,
56.58; H, 6.12; N, 4.02%.
3.2.2. Triethyl 2-(tert-butylimino)-2H-pyran-3,4,6-tricarboxylate(4b).
Yellow powder, mp 130e132 ꢀC, yield: 0.65 g (89%). IR (KBr) (nmax
/
S
O
cmꢁ1): 1738, 1735, 1724, 1582 and 1195 cmꢁ1. 1H NMR:
d¼1.26 (9H,
solvent-free
r t., 5 h
R
Br
s, Me3C), 1.29 (3H, t, 3J¼7.3 Hz, Me), 1.32 (3H, t, 3J¼7.3 Hz, Me), 1.36
(3H, t, 3J¼7.4 Hz, Me), 4.13 (2H, q, 3J¼7.3 Hz, CH2O), 4.15 (2H, q,
3J¼7.3 Hz, CH2O), 4.24 (2H, q, 3J¼7.4 Hz, CH2O), 6.64 (1H, s, CH)
+
CS2
R'2NH
+
R'2N
R'
S
R
O
8
7
9
1
ppm. 13C NMR:
d
¼13.8 (Me), 14.1 (Me), 14.3 (Me), 30.2 (Me3C), 55.6
1, 7, 9
a
R
Yield (%) of 1
(CeN), 62.3 (CH2O), 62.6 (CH2O), 63.0 (CH2O), 119.2 (CH), 136.8 (C),
142.6 (C), 145.4 (C), 148.4 (C]N), 161.5 (C]O), 162.8 (C]O), 163.3
(C]O) ppm. MS: m/z (%)¼367 (Mþ, 10), 339 (62), 310 (84), 57 (100),
45 (48). Anal. Calcd for C18H25NO7 (367.39): C, 58.85; H, 6.86; N,
3.81. Found: C, 58.78; H, 6.73; N, 3.75%.
(CH2)4
(CH2)5
(CH2)4
CO2Et
97
95
b
c
CO2Et
Ph
92
93
4-Me-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-Ph-C6H4
4-NO2-C6H4
(CH2)5
(CH2)2O(CH2)2
(CH2)5
d
e
f
90
89
93
96
93
95
89
3.2.3. Dimethyl
carboxylate (4c). Yellow powder, mp 135e137 ꢀC, yield: 0.68 g
(92%). IR (KBr) (nmax/cmꢁ1): 1730, 1725, 1548 and 1278 cmꢁ1 1H
NMR:
2-(cyclohexylimino)-6-phenyl-2H-pyran-3,4-di-
g
(CH2)5
h
i
j
(CH2)4
.
(CH2)2O(CH2)2
(CH2)5
Ph
d
¼1.34 (2H, m, CH2), 1.40 (2H, m, CH2), 1.47 (2H, m, CH2), 1.66
naphthyl
Ph
(2H, m, CH2), 1.84 (2H, m, CH2), 3.75 (3H, s, MeO), 3.79 (1H, m,
NeCH), 3.82 (3H, s, MeO), 6.68 (1H, s, CH), 7.16 (2H, t, 3J¼7.2 Hz,
2CH), 7.30 (1H, t, 3J¼7.5 Hz, CH), 7.63 (2H, d, 3J¼7.4 Hz, 2CH) ppm.
k
Et
Scheme 3. Three-component reactions of phenacyl bromides, disulfide carbon, and
13C NMR:
d¼24.3 (CH2), 24.5 (CH2), 25.5 (CH2), 33.3 (CH2), 33.5
secondary amines.
(CH2), 51.5 (3H, s, Me), 52.4 (3H, s, Me), 56.9 (CeN), 105.8 (CH),
128.3 (2CH), 129.5 (2CH), 131.5 (CH), 134.0 (C), 136.4 (C), 140.6 (C),
155.2 (C]N), 158.6 (C), 163.5 (C]O), 165.9 (C]O) ppm. Anal. Calcd
for C21H23NO5 (369.41): C, 68.28; H, 6.28; N, 3.79. Found: C, 68.32;
H, 6.37; N, 3.84%.
In conclusion, we have developed the most useful and de-
pendable procedure currently available for the synthesis of S-alkyl
dithiocarbamates and 2H-pyran-3,4-dicarboxylate by using low-
cost and readily available starting materials in one pot. This method
represents a simple procedure, uses mild reaction conditions, and
has general applicability.
3.2.4. Dimethyl 2-(tert-butylimino)-6-(4-methylphenyl)-2H-pyran-
3,4-dicarboxylate (4d). Pale yellow powder, mp 143e145 ꢀC, yield:

8466
M.A. Khalilzadeh et al. / Tetrahedron 66 (2010) 8464e8467
0.67 g (94%). IR (KBr) (nmax/cmꢁ1): 1732, 1725, 1557, 1410 and
3J¼7.5 Hz, 2CH), 7.85 (2H, d, 3J¼7.6 Hz, 2CH) ppm. 13C NMR:
¼14.1
d
1127 cmꢁ1. 1H NMR:
d
¼1.25 (9H, s, CMe3), 2.35 (3H, s, Me), 3.78 (3H,
(Me), 21.4 (Me), 50.3 (CH2eN), 51.6 (MeO), 52.4 (MeO), 61.3 (OCH2),
107.4 (CH), 126.3 (2CH), 129.7 (2CH), 134.8 (C), 135.2 (C), 137.3 (C),
142.8 (C), 153.6 (C), 156.5 (C]N), 160.2 (C]O), 162.7 (C]O), 164.3
(C]O) ppm. Anal. Calcd for C20H21NO7 (387.39): C, 62.01; H, 5.46;
N, 3.62. Found: C, 61.96; H, 5.38; N, 3.54%.
s, MeO), 3.83 (3H, s, MeO), 6.42 (1H, s, CH), 7.42 (2H, d, 3J¼7.6 Hz,
2CH), 7.84 (2H, d, 3J¼7.6 Hz, 2CH) ppm. 13C NMR:
¼21.7 (Me), 30.6
d
(CMe3), 51.6 (MeO), 52.4 (MeO), 57.2 (CeN), 108.6 (CH), 125.7 (2CH),
129.3 (2CH), 133.2 (C), 134.5 (C), 137.0 (C), 142.4 (C), 155.2 (C]N),
156.8 (C), 163.8 (C]O), 164.7 (C]O) ppm. Anal. Calcd for
C20H23NO5 (357.40): C, 67.21; H, 6.49; N, 3.92. Found: C, 67.18; H,
6.53; N, 4.02%.
3.2.10. Diethyl 2-(2-ethoxy-2-oxoethylimino)-6-phenyl-2H-pyran-3,4-
dicarboxylate (4j). White powder, mp 144e146 ꢀC, yield: 0.58 g
(85%). IR (KBr) (nmax/cmꢁ1): 1732, 1728, 1725, 1612, 1547, 1385 and
3.2.5. Dimethyl 2-(tert-butylimino)-6-(4-nitrophenyl)-2H-pyran-3,4-
1215 cmꢁ1
.
1H NMR:
d
¼1.23 (3H, t, 3J¼7.4 Hz, Me), 1.26 (3H, t,
dicarboxylate (4e). Yellow powder, mp 152e154 ꢀC, yield: 0.68 g
3J¼7.5 Hz, Me), 1.29 (3H, t, 3J¼7.3 Hz, Me), 4.12 (2H, q, 3J¼7.4 Hz,
OCH2), 4.15 (2H, q, 3J¼7.5 Hz, OCH2), 4.18 (2H, s, CH2), 4.20 (2H, q,
3J¼7.5 Hz, OCH2), 6.52 (1H, s, CH), 7.21 (2H, t, 3J¼7.8 Hz, 2CH), 7.42
(1H, t, 3J¼7.6 Hz, CH), 7.79 (2H, t, 3J¼7.6 Hz, 2CH) ppm. 13C NMR:
(87%). IR (KBr) (nmax/cmꢁ1): 1738, 1732, 1545, 1412 and 1175 cmꢁ1
.
1H NMR:
d
¼1.27 (9H, s, CMe3), 3.80 (3H, s, MeO), 3.85 (3H, s, MeO),
6.48 (1H, s, CH), 7.87 (2H, d, 3J¼8.2 Hz, 2CH), 8.45 (2H, d, 3J¼8.2 Hz,
2CH) ppm. 13C NMR:
d
¼29.8 (CMe3), 52.0 (MeO), 52.6 (MeO), 56.8
d¼13.8 (Me), 14.0 (Me), 14.3 (Me), 52.4 (CH2eN), 60.3 (OCH2), 61.5
(CeN), 107.6 (CH), 125.2 (2CH), 129.8 (2CH), 133.9 (C), 139.7 (C),
142.9 (C), 146.8 (C), 156.4 (C]N), 158.9 (C), 162.4 (C]O), 164.6 (C]
O) ppm. MS: m/z (%)¼388 (Mþ, 15), 357 (54), 266 (52), 120 (85), 57
(100), 31(78). Anal. Calcd for C19H20N2O7 (388.37): C, 58.76; H, 5.19;
N, 7.21. Found: C, 58.68; H, 5.04; N, 7.14%.
(OCH2), 62.0 (OCH2), 108.0 (CH), 128.2 (2CH), 129.5 (2CH), 131.4
(CH), 135.0 (C), 135.8 (C), 142.3 (C), 154.8 (C), 158.5 (C]N), 162.3
(C]O), 163.5 (C]O), 164.8 (C]O) ppm. Anal. Calcd for C21H23NO7
(401.41): C, 62.84; H, 5.78; N, 3.49. Found: C, 62.75; H, 5.69; N,
3.38%.
3.2.6. Diethyl 2-(tert-butylimino)-6-(4-nitrophenyl)-2H-pyran-3,4-
dicarboxylate (4f). Pale yellow powder, mp 154e156 ꢀC, yield:
0.74 g (89%). IR (KBr) (nmax/cmꢁ1): 1730, 1727, 1645, 1548 and
3.3. Typicalprocedureforthepreparationofdithiocarbamate(1)
To a mixture of the alkyl bromide (2 mmol) and carbon disulfide
(4 mmol) in the test tube, amine (4 mmol) was added and stirred at
0 ꢀC for 30 min, then warmed to room temperature and stirring was
continued until the reaction was complete (reaction mixture so-
lidified or monitored by TLC). The reaction was quenched by the
addition of water (10 mL) and was extracted with EtOAc (3ꢂ5 mL),
dried over anhyd Na2SO4, and evaporated to give NMR pure prod-
uct. Further purification in all cases can be achieved by silica gel
column chromatography eluted with n-hexane and ethyl acetate to
afford the pure dithiocarbamate.
1232 cmꢁ1
.
1H NMR:
d
¼1.27 (9H, s, CMe3), 1.31 (3H, t, 3J¼7.4 Hz,
Me), 1.37 (3H, t, 3J¼7.3 Hz, Me), 4.12 (2H, q, 3J¼7.4 Hz, CH2O), 4.25
(2H, q, 3J¼7.3 Hz, CH2O), 6.45 (1H, s, CH), 8.05 (2H, d, 3J¼8.0 Hz,
2CH), 8.37 (2H, d, 3J¼8.0 Hz, 2CH) ppm. 13C NMR:
¼13.8 (Me), 14.2
d
(Me), 30.4 (CMe3), 57.0 (CeN), 61.4 (CH2O), 52.6 (CH2O), 107.5 (CH),
126.0 (2CH), 130.1 (2CH), 140.2 (C), 141.3 (C), 143.0 (C), 146.5 (C),
157.2 (C]N), 157.6 (C), 162.5 (C]O), 165.3 (C]O) ppm. Anal. Calcd
for C21H24N2O7 (416.43): C, 60.57; H, 5.81; N, 6.73. Found: C, 60.49;
H, 5.75; N, 6.68%.
3.2.7. Di(tert-butyl) 2-(cyclohexylimino)-6-(4-nitrophenyl)-2H-pyran-
3,4-dicarboxylate (4g). Yellow powder, mp 147e149 ꢀC, yield: 0.82 g
(90%). IR (KBr) (nmax/cmꢁ1): 1728,1718,1654,1568 and 1258 cmꢁ1. 1H
3.3.1. Ethyl 2-oxo-3-[(pyrrolidinylcarbothioyl)sulfanyl] propanoate
(1a). Pale yellow powder, mp 125e127 ꢀC, yield: 0.51 g (97%). IR
(KBr) (nmax/cmꢁ1): 1738, 1695, 1614, 1531, 1430, 1334, 1194 and
NMR:
d
¼1.32 (2H, m, CH2), 1.38 (2H, m, CH2), 1.45 (2H, m, CH2), 1.65
1157 cmꢁ1
.
1H NMR:
d
¼0.89 (3H, t, 3J¼7.2 Hz, Me), 2.10 (4H, m,
(2H, m, CH2), 1.67 (9H, s, CMe3), 1.71 (9H, s, CMe3), 1.83 (2H, m, CH2),
3.75 (1H, m, NeCH), 6.48 (1H, s, CH), 7.68 (2H, d, 3J¼7.8 Hz, 2CH),
2CH2), 3.77 (2H, t, 3J¼6.8 Hz, CH2), 3.94 (2H, t, 3J¼6.8 Hz, CH2), 4.02
(2H, q, 3J¼7.2 Hz, OCH2), 4.35 (2H, s, CH2) ppm. 13C NMR:
¼13.5
d
7.92 (2H, d, 3J¼7.8 Hz, 2CH) ppm. 13C NMR:
d¼24.5 (CH2), 24.7 (CH2),
(Me), 25.8 (2CH2), 42.6 (CH2), 48.6 (CH2NCH2), 62.0 (OCH2), 160.5
(C]O), 187.6 (C]O), 198.2 (C]S) ppm. MS: m/z (%)¼261 (Mþ, 20),
216 (56), 191 (86), 70 (94), 45(100). Anal. Calcd for C10H15NO3S2
(261.35): C, 45.96; H, 5.78; N, 5.36. Found: C, 45.87; H, 5.67; N,
5.28%.
25.8 (CH2), 28.2 (CMe3), 29.4 (CMe3), 34.3 (CH2), 35.0 (CH2), 57.0
(CeN), 79.2 (CMe3), 82.3 (CMe3), 108.3 (CH), 125.6 (2CH), 129.8
(2CH), 135.8 (C),138.5 (C),142.0 (C),148.3 (C), 154.8 (C]N), 159.2 (C),
163.4 (C]O), 165.7 (C]O) ppm. Anal. Calcd for C27H33NO5 (453.58):
C, 71.50; H, 7.78; N, 3.09. Found: C, 71.45; H, 7.70; N, 2.98%.
3.3.2. Ethyl 2-oxo-3-[(piperidinocarbothioyl)sulfanyl] propanoate (1b).
3.2.8. 6-Ethyl 3,4-dimethyl-2-(1,1,3,3-tetramethylbutylimino)-2H-py-
ran-3,4,6-tricarboxylate (4h). Yellow powder, mp 137e139 ꢀC, yield:
0.69 g (87%). IR (KBr) (nmax/cmꢁ1): 1730, 1722, 1720, 1545, 1425 and
Yellow powder, mp 128e130 ꢀC, yield: 0.50 g (95%). IR (KBr) (nmax
/
cmꢁ1): 1732, 1695, 1595, 1465, 1386, 1248 and 1194 cmꢁ1. 1H NMR:
d
¼1.38 (3H, t, 3J¼7.3 Hz, Me), 1.52e1.63 (6H, m, 3CH2), 3.75 (2H, t,
1167 cmꢁ1. 1H NMR:
d
¼1.03 (9H, s, CMe3), 1.24 (3H, t, 3J¼7.3 Hz, Me),
3J¼7.2 Hz, CH2), 3.94 (2H, t, 3J¼7.2 Hz, CH2), 4.37 (2H,q, 3J¼7.3 Hz,
1.55 (3H, s, Me), 1.56 (3H, s, Me), 1.83 (2H, s, CH2), 3.74 (3H, s, MeO),
OCH2), 4.38 (2H, s, CH2) ppm. 13C NMR:
d¼13.9 (Me), 23.8 (CH2), 25.2
3.82 (3H, s, MeO), 4.23 (2H, q, 3J¼7.3 Hz, Me), 6.84 (1H, s, CH) ppm.
(CH2), 25.9 (CH2), 41.7 (CH2), 52.4 (CH2), 53.8 (CH2), 62.5 (OCH2),
160.56 (C]O), 187.2 (C]O), 193.4 (C]S) ppm. MS: m/z (%)¼275 (Mþ,
15), 230 (45), 191 (52), 45(100). Anal. Calcd for C11H17NO3S2 (275.38):
C, 47.98; H, 6.22; N, 5.09. Found: C, 47.85; H, 6.14; N, 4.96%.
13C NMR:
d
¼13.9 (Me), 29.7 (C), 29.8 (Me), 31.6 (CMe3), 31.9 (Me),
51.5 (MeO), 52.7 (MeO), 55.0 (CH2), 59.2 (CeN), 61.2 (CH2O), 109.4
(CH), 139.0 (C), 141.3 (C), 144.5 (C), 158.4 (C), 160.2 (C]O), 161.3 (C]
O), 163.5 (C]O) ppm. Anal. Calcd for C20H29NO7 (395.45): C, 60.75;
H, 7.39; N, 3.54. Found: C, 60.68; H, 7.32; N, 3.43%.
3.3.3. 2-Oxo-2-phenylethyl1-pyrrolidinecarbodithioate (1c). Pale yel-
low powder, mp 135e137 ꢀC, yield: 0.49 g (92%). IR (KBr) (nmax
/
3.2.9. Dimethyl 2-(2-ethoxy-2-oxoethylimino)-6-(4-methylphenyl)-
2H-pyran-3,4-dicarboxylate (4i). White powder, mp 138e140 ꢀC,
yield: 0.64 g (83%). IR (KBr) (nmax/cmꢁ1): 1738, 1730, 1728, 1624,
cmꢁ1): 1685, 1585, 1457, 1324, 1283 and 1168 cmꢁ1 1H NMR:
.
d
¼1.97e2.03 (2H, m, CH2), 2.09e2.14 (2H, m, CH2), 3.77 (2H, t,
3J¼6.8 Hz, CH2), 3.94 (2H, t, 3J¼6.8 Hz, CH2), 4.92 (2H, s, CH2), 7.48
1557, 1410 and 1127 cmꢁ1. 1H NMR:
d
¼1.30 (3H, t, 3J¼7.2 Hz, Me),
(2H, t, 3J¼7.5 Hz, 2CH), 7.59 (1H, t, 3J¼7.4 Hz, CH), 8.08 (2H, d,
2.35 (3H, s, Me), 3.76 (3H, s, MeO), 3.83 (3H, s, MeO), 4.20 (2H, s,
3J¼7.4 Hz, 2CH) ppm. 13C NMR:
d
¼24.4 (CH2), 26.2 (CH2), 44.5
CH2), 4.28 (2H, q, 3J¼7.2 Hz, OCH2), 6.47 (1H, s, CH), 7.54 (2H, d,
(CH2), 50.8 (CH2), 55.5 (CH2), 128.6 (2CH), 128.9 (2CH), 133.5 (CH),

M.A. Khalilzadeh et al. / Tetrahedron 66 (2010) 8464e8467
8467
136.2 (C), 191.1 (C]O), 193.5 (C]S) ppm. Anal. Calcd for
C13H15NOS2 (265.39): C, 58.84; H, 5.70; N, 5.28. Found: C, 58.90; H,
5.76; N, 5.32%.
d
¼3.77e3.79 (4H, m, 2CH2), 4.08e4.26 (4H, m, 2CH2), 4.92 (2H, s,
CH2), 7.49 (2H, t, 3J¼7.4, 2CH), 7.60 (1H, t, 3J¼7.3 Hz, CH), 8.07 (2H, d,
3J¼7.4 Hz, CH) ppm. 13C NMR:
¼44.8 (CH2), 50.9 (CH2), 51.3 (CH2),
d
66.2 (2CH2), 128.6 (2CH), 128.8 (2CH), 133.6 (CH), 136.2 (C), 193.0
(C]O), 196.0 (C]S) ppm. Anal. Calcd for C13H15NO2 S2 (281.39): C,
55.49; H, 5.37; N, 4.98. Found: C, 55.38; H, 5.28; N, 4.86%.
3.3.4. 2-(4-Methylphenyl)-2-oxoethyl
carbodithioate (1d). White powder, mp 142e144 ꢀC, yield: 0.58 g
(54%). IR (KBr) (nmax/cmꢁ1): 1683, 1586, 1328, 1269 and 1153 cmꢁ1
tetrahydro-1(2H)-pyridine
.
1H NMR:
d
¼1.59e1.73 (6H, m, 3CH2), 2.41 (3H, S, Me), 3.72 (2H, t,
3.3.10. 2-(Naphthyl)-2-oxoethyl
dithioate (1j). White powder, mp 138e140 ꢀC, yield: 0.63 g (95%).
IR (KBr) (nmax/cmꢁ1): 1698, 1583, 1447, 1338 and 1236 cmꢁ1 1H
tetrahydro-1(2H)-pyridinecarbo-
3J¼6.5 Hz, CH2), 3.96 (2H, t, 3J¼6.5 Hz, CH2), 4.90 (2H, s, CH2), 7.83
(2H, d, 3J¼7.6 Hz, 2CH), 7.95 (2H, d, 3J¼7.6 Hz, 2CH) ppm. 13C NMR:
.
d
¼21.4 (Me), 24.4 (CH2), 25.7 (2CH2), 37.8 (CH2), 45.4 (CH2), 50.1
NMR:
d¼1.45e1.73 (6H, m, 3CH2), 3.99e4.29 (4H, m, 2CH2), 5.05
(CH2), 128.7 (2CH), 129.5 (2CH), 132.9 (C), 144.3 (C), 187.3 (C]O),
193.9 (C]S) ppm. Anal. Calcd for C15H19NOS2 (293.44): C, 61.40; H,
6.53; N, 4.77. Found: C, 61.32; H, 6.46; N, 4.65%.
(2H, s, CH2), 7.57 (1H, t, 3J¼7.6 Hz, CH), 7.62 (1H, t, 3J¼7.5 Hz, CH),
7.88 (1H, d, 3J¼7.5 Hz, CH), 7.92 (1H, d, 3J¼7.5 Hz, CH), 8.01 (1H, d,
3J¼7.8 Hz, CH), 8.10 (1H, d, 3J¼7.8 Hz, CH), 8.66 (1H, s, CH) ppm. 13
C
NMR:
d¼24.2 (CH2), 26.0 (2CH2), 45.0 (CH2), 51.7 (CH2), 53.7 (CH2),
3.3.5. 2-(4-Nitrophenyl)-2-oxoethyl tetrahydro-1(2H)-morpholine-
124.2 (CH), 126.8 (CH), 127.8 (CH), 128.5 (CH), 128.7 (CH), 129.9
(CH), 130.4 (CH), 132.5 (C), 133.6 (C), 135.8 (C), 193.5 (C]O), 194.1
(C]S) ppm. Anal. Calcd for C18H19NOS2 (329.47): C, 65.62; H, 5.81;
N, 4.25. Found: C, 65.53; H, 5.74; N, 4.14%.
carbodithioate (1e). Yellow powder, mp 152e154 ꢀC, yield: 0.59 g
(90%). IR (KBr) (nmax/cmꢁ1): 1687, 1564, 1487, 1326 and 1147 cmꢁ1
.
1H NMR:
d
¼3.79e3.82 (4H, m, 2CH2), 4.02e4.30 (4H, m, 2CH2), 4.86
(2H, s, CH2), 8.16 (2H, d, 3J¼7.8 Hz, 2CH), 8.35 (2H, d, 3J¼7.8 Hz,
2CH) ppm. 13C NMR:
d
¼44.0 (CH2), 46.4 (CH2), 52.1 (CH2), 66.6
3.3.11. 2-Oxo-2-phenylethyl1-diethylaminecarbodithioate (1k). Pale
(CH2), 67.0 (CH2), 124.6 (2CH), 129.6 (2CH), 130.8 (C), 142.6 (C), 192.1
(C]O), 195.3 (C]S) ppm. Anal. Calcd for C13H14N2O4S2 (326.38): C,
47.84; H, 4.32; N, 8.58. Found: C, 47.75; H, 4.26; N, 8.47%.
yellow powder, mp 124e126 ꢀC, yield: 0.48 g (89%). IR (KBr) (nmax
/
cmꢁ1): 1694, 1625, 1595, 1454, 1342 and 1126 cmꢁ1 1H NMR:
.
d
¼1.26 (3H, t, 3J¼7.3 Hz, Me), 1.34 (3H, t, 3J¼7.3 Hz, Me), 3.83 (2H, d,
3J¼7.3 Hz, CH2), 4.02 (2H, d, 3J¼7.3 Hz, CH2), 4.90 (2H, s, CH2), 7.48
(2H, t, 3J¼7.5, 2CH), 7.58 (1H, t, 3J¼7.5 Hz, CH), 8.07 (2H, t, 3J¼7.5,
3.3.6. 2-(4-Nitrophenyl)-2-oxoethyl tetrahydro-1(2H)-pyridinecarbo-
dithioate (1f). Yellow powder, mp 158e160 ꢀC, yield: 0.58 g (89%). IR
(KBr) (nmax/cmꢁ1): 1692, 1587, 1423, 1322 and 1285 cmꢁ1. 1H NMR:
2CH) ppm. 13C NMR:
d¼11.5 (Me), 12.6 (Me), 45.0 (CH2), 47.0 (CH2),
50.1 (CH2),128.5 (2CH),128.6 (2CH),133.4 (CH),136.2 (C),193.4 (C]
O), 194.0 (C]S) ppm. Anal. Calcd for C13H17NOS2 (267.40): C, 58.39;
H, 6.41; N, 5.24. Found: C, 58.28; H, 6.32; N, 5.12%.
d
¼1.43e1.71 (6H, m, 3CH2), 3.94 (2H, t, 3J¼6.5 Hz, CH2), 4.10 (2H, t,
3J¼6.5 Hz, CH2), 5.28 (2H, s, CH2), 8.15 (2H, d, 3J¼7.5 Hz, 2CH), 8.33
(2H, d, 3J¼7.5 Hz, 2CH) ppm. 13C NMR:
¼24.5 (CH2), 26.9 (2CH2),
d
45.1 (CH2), 52.7 (CH2), 54.8 (CH2), 124.5 (2CH), 130.5 (2CH), 139.8 (C),
141.6 (C), 189.6 (C]O), 196.4 (C]S) ppm. Anal. Calcd for
C14H16N2O3S2 (324.41): C, 51.83; H, 4.97; N, 8.64. Found: C, 51.75; H,
4.90; N, 8.54%.
References and notes
€
1. Domling, A. Chem. Rev. 2006, 106, 17.
2. Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51.
3. Zhu, J. Eur. J. Org. Chem. 2003, 1133.
4. Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
5. Zhu, J.; Bienayme’, H. Multicomponent Reactions; Wiley-VCH: Weinheim, Ger-
many, 2005.
3.3.7. 2-Biphenyl-2-oxoethyl tetrahydro-1(2H)-pyridinecarbodithio-
ate (1g). Orange powder, mp 136e138 ꢀC, yield: 0.66 g (93%). IR
(KBr) (nmax/cmꢁ1): 1683, 1576, 1388, 1242 and 1147 cmꢁ1. 1H NMR:
€
6. Ngouansavanh, T.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 5775.
7. Laurent, E. K.; Gizolme, M.; Grimaud, L.; Oble, J. Org. Lett. 2006, 8, 4019.
8. Tempest, P. A. Curr. Opin. Drug Discov. 2005, 8, 776.
9. Lu, K.; Luo, T.; Xiang, Z.; You, Z.; Fathi, R.; Chen, J.; Yang, Z. J. Comb. Chem. 2005,
7, 958.
d
¼1.43e1.71 (6H, m, 3CH2), 4.02 (4H, m, 2CH2), 4.95 (2H, s, CH2),
7.41 (2H, t, 3J¼7.4 Hz, 2CH), 7.48 (1H, t, 3J¼7.4 Hz, CH), 7.63 (2H, d,
3J¼7.5 Hz, 2CH), 7.72 (2H, t, 3J¼7.8 Hz, 2CH), 8.16 (2H, d, 3J¼7.8 Hz,
2CH) ppm. 13C NMR:
d¼24.5 (CH2), 26.9 (2CH2), 44.6 (CH2), 51.7
10. Weber, L. Curr. Med. Chem. 2002, 9, 2085.
(CH2), 53.6 (CH2), 126.9 (2CH), 127.2 (CH), 127.6 (2CH), 128.9 (2CH),
129.4 (2CH), 134.9 (C), 139.8 (C), 142.8 (C), 189.9 (C]O), 194.0 (C]
S) ppm. Anal. Calcd for C20H21NOS2 (355.51): C, 67.57; H, 5.95; N,
3.94. Found: C, 67.48; H, 5.87; N, 3.89%.
€
11. Domling, A. Curr. Opin. Chem. Biol. 2002, 6, 306.
12. Ugi, I. Isonitrile Chemistry; Academic: London, 1971.
13. Ugi, I. Angew. Chem., Int. Ed. Engl. 1982, 21, 810.
14. Walborsky, H. M.; Presiasamy, M. P. In The Chemistry of Functional Groups,
Supplement C; Patai, S., Rappaport, Z., Eds.; Wiley: New York, NY, 1983, Chapter
20, p 835.
3.3.8. 2-(4-Nitrophenyl)-2-oxoethyl tetrahydro-1(2H)-pyrrolidine-
15. Marcaccini, S.; Torroba, T. Org. Prep. Proced. Int. 1993, 25, 141.
16. (a) Caldas, E. D.; Hosana Conceicua, M.; Miranda, M. C. C.; Souza, L.; Lima, J. F. J.
Agric. Food Chem. 2001, 49, 4521; (b) Goel, A.; Mazur, S. J.; Fattah, R. J.; Hartman,
T. L.; Turpin, J. A.; Huang, M.; Rice, W. G.; Appella, E.; Inman, J. K. Bioorg. Med.
Chem. Lett. 2002, 12, 767.
17. (a) Chen-Hsien, W. Synthesis 1981, 622; (b) Mizuno, T.; Nishiguchi, I.; Okushi, T.;
Hirashima, T. Tetrahedron Lett. 1991, 32, 6867; (c) Rafin, C.; Veignie, E.; San-
cholle, M.; Postal, D.; Len, C.; Villa, P.; Ronco, G. J. Agric. Food Chem. 2000, 48,
5283.
18. (a) Morf, P.; Raimondi, F.; Nothofer, H.-G.; Schnyder, B.; Yasuda, A.; Wessels, J.
M.; Jung, T. A. Langmuir 2006, 22, 658; (b) McClain, A.; Hsieh, Y.-L. J. Appl. Polym.
Sci. 2004, 92, 218; (c) Bongar, B. P.; Sadavarte, V. S.; Uppalla, L. S. J. Chem. Res.,
Synop. 2004, 9, 450.
carbodithioate (1h). Yellow powder, mp 143e145 ꢀC, yield: 0.59 g
(96%). IR (KBr) (nmax/cmꢁ1): 1695, 1580, 1454, 1325 and 1185 cmꢁ1
.
1H NMR:
d
¼1.98e2.04 (2H, m, CH2), 2.09e2.17 (2H, m, CH2), 3.76
(2H, t, 3J¼7.2 Hz, CH2), 3.91 (2H, t, 3J¼7.2 Hz, CH2), 4.86 (2H, s, CH2),
8.24 (2H, d, 3J¼7.6 Hz, 2CH), 8.34 (2H, d, 3J¼7.6 Hz, 2CH) ppm. 13
C
NMR:
d
¼24.3 (CH2), 26.1 (CH2), 43.9 (CH2), 50.9 (CH2), 55.7 (CH2),
123.9 (2CH), 129.7 (2CH), 140.8 (C), 146.9 (C), 190.3 (C]O), 192.5
(C]S) ppm. Anal. Calcd for C13H14N2O3S2 (310.38): C, 50.31; H,
4.55; N, 9.03. Found: C, 50.38; H, 4.62; N, 9.12%.
19. Nieuwenhuizen, P. J.; Ehlers, A. W.; Haasnoot, J. G.; Janse, S. R.; Reedijk, J.;
Baerends, E. J. J. Am. Chem. Soc. 1999, 121, 163.
20. (a) Ronconi, L.; Marzano, C.; Zanello, P.; Corsini, M.; Miolo, G.; Macca, C.; Tre-
visan, A.; Fregona, D. J. Med. Chem. 2006, 49, 1648; (b) Elgemeie, G. H.; Sayed, S.
H. Synthesis 2001, 1747.
3.3.9. 2-Oxo-2-phenylethyl1-morpholinecarbodithioate (1i). Pale yel-
low powder, mp 130e132 ꢀC, yield: 0.52 g (93%). IR (KBr) (nmax
/
cmꢁ1): 1700, 1690, 1573, 1458, 1322 and 1274 cmꢁ1 1H NMR:
.