A facile and convenient synthesis of 3-alkylamino-5-arylthiophenes with a variety of substituents at C-2 and studies of reaction mechanisms

Article abstract of DOI:10.1021/jo991884b

Thioaroylketene S,N-acetals were treated with active methylene compounds including β-keto ester, nitromethane, cyanoacetic acid, p- toluenesulfonylacetone, 4-nitrophenylacetic acid, and diethyl (2- oxopropyl)phosphonate in the presence of mercury(II) acetate in CH₂Cl₂ at room temperature. These reactions gave 3-alkylamino-5-arylthiophenes containing various substituents, which comprised, respectively, alkoxycarbonyl, nitro, cyano, p-toluenesulfonyl, 4-nitrophenyl, and diethylphosphono groups at C-2 in good yields. The reaction of 3-methylamino- 3-methylthio-1-phenylthioxopropene with malonic acid or Meldrum's acid under the same conditions gave 3-methylamino-5-phenylthiophene. Similarly, treatment of 3-methylamino-3-methylthio-1-phenylthioxopropene with various enolizable cyclic ketones such as 4-hydroxy-6-methyl-2-pyrone, homophthalic anhydride, 2-hydroxy1,4-benzoquinone, and 1,3-diethyl-2-thiobarbituric acid gave thieno[3,2-b]pyridin-4-one, thieno[3,2c]isoquinolin-5-one, thieno[3,2- c]benzazepine-1,6-dione, and thieno[3,2-d]pyrimidine-2,4-dione, respectively.

Full text of DOI:10.1021/jo991884b

3690
J . Org. Chem. 2000, 65, 3690-3699
A F a cile a n d Con ven ien t Syn th esis of
3-Alk yla m in o-5-a r ylth iop h en es w ith a Va r iety of Su bstitu en ts a t
C-2 a n d Stu d ies of Rea ction Mech a n ism s
Bo Sung Kim and Kyongtae Kim*
Department of Chemistry, Seoul National University, Seoul 151-742, Korea
Received December 7, 1999
Thioaroylketene S,N-acetals were treated with active methylene compounds including â-keto ester,
nitromethane, cyanoacetic acid, p-toluenesulfonylacetone, 4-nitrophenylacetic acid, and diethyl (2-
oxopropyl)phosphonate in the presence of mercury(II) acetate in CH2Cl2 at room temperature. These
reactions gave 3-alkylamino-5-arylthiophenes containing various substituents, which comprised,
respectively, alkoxycarbonyl, nitro, cyano, p-toluenesulfonyl, 4-nitrophenyl, and diethylphosphono
groups at C-2 in good yields. The reaction of 3-methylamino-3-methylthio-1-phenylthioxopropene
with malonic acid or Meldrum’s acid under the same conditions gave 3-methylamino-5-phenyl-
thiophene. Similarly, treatment of 3-methylamino-3-methylthio-1-phenylthioxopropene with various
enolizable cyclic ketones such as 4-hydroxy-6-methyl-2-pyrone, homophthalic anhydride, 2-hydroxy-
1,4-benzoquinone, and 1,3-diethyl-2-thiobarbituric acid gave thieno[3,2-b]pyridin-4-one, thieno[3,2-
c]isoquinolin-5-one, thieno[3,2-c]benzazepine-1,6-dione, and thieno[3,2-d]pyrimidine-2,4-dione, re-
spectively.
Sch em e 1
In tr od u ction
Recently, we reported a new and useful synthetic
method for 2-acyl- and 2-aroyl-3-alkylamino-5-arylthio-
phenes 2 and 3-alkylamino-5-aryl-2-(ethoxycarbonyl)thio-
phenes 3, which involved the reactions of thioaroylketene
S,N-acetals 1 with 1,3-diketones (X ) COR3, Y ) R4) and
â-keto ester (X ) CO2Et, Y ) Me), respectively, in the
presence of Hg(OAc)2 in CH2Cl2 at room temperature1
(Scheme 1).
We have found that compounds 3 were also formed by
treatment of 1 with diethyl 1,3-acetonedicarboxylate
(X ) CO2Et, Y ) CH2CO2Et), ethyl 3-nitrobenzoyl acetate
(X ) CO2Et, Y ) 3-O2NC6H4), ethyl methanesulfonyl
acetate, methyl phenylsulfinyl acetate, and triethyl
phosphonoacetate under the conditions described above.
Thus, it would be expected that compounds 1 act as
promising starting materials for the synthesis of thiophene
derivatives by introduction of one carbon unit to a C3S
chain.
Ta ble 1. Yield s a n d Meltin g P oin ts of
3-Alk yla m in o-5-a r ylth iop h en e-2-ca r bon itr iles 4 a n d
3-Alk yla m in o-5-a r yl-2-n itr oth iop h en es 5
compd
Ar
R1
Me CN
3-MeOC6H4 Me CN
X
time (h) yielda (%) mpb (°C)
We have extended the foregoing method to a wide
variety of compounds bearing active methylene hydrogen
atoms. The results are described herein.
4a
4b
4c
4d
5a
5b
5c
5d c
Ph
3
69
88
71
89
82
84
80
81
110-111
116-117
95-96
5
3
Ph
Et CN
Me CN
Me NO2
3-ClC6H4
Ph
3-MeOC6H4 Et NO2
3-ClC6H4 Et NO2
4
146-147
180 (sub)
102-103
130-131
128-130
0.5
0.5
0.5
0.5
Resu lts a n d Discu ssion
(A) Syn th esis a n d Str u ctu r es. The reactions of
1a -d with cyanoacetic acid (X ) CN, Y ) OH) (2-3
molar equiv) in the presence of Hg(OAc)2 (1.5 molar
equiv) in CH2Cl2 at room temperature gave 3-alkylamino-
5-arylthiophene-2-carbonitriles 4a -d . The reactions of
1a ,e,f with nitromethane (3 molar equiv) under the same
conditions gave 3-alkylamino-5-aryl-2-nitrothiophenes
5a -c (X ) NO2). Similar reaction of 1b with ethyl
nitroacetate (X ) NO2, Y ) OEt) gave 5d (Scheme 1).
The results are summarized in Table 1.
3-MeOC6H4 Me NO2
a
b
Isolated yields. Recrystallized from a mixture of EtOAc and
n-hexane. c Compound 5d was obtained by treatment of ethyl
nitroacetate under the same conditions as for 5a -c.
Me), 4-nitrophenylacetic acid (X ) 4-O2NC6H4, Y ) OH),
and bis(phenylsulfonyl)methane in the presence of
Hg(OAc)2 afforded the corresponding thiophenes having
4-tosyl (6), 4-nitrophenyl (7), and benzenesulfonyl (8)
(X ) PhSO2) groups at C-2 (Table 2). In addition, the
reaction with diethyl (2-oxopropyl)phosphonate (X )
PO(OEt)2, Y ) Me) under the same conditions gave
diethyl phosphonate 9. However, the reaction with ma-
lonic acid (X ) CO2H, Y ) OH) gave 3-methylamino-5-
Similarly, compound 1a (Ar ) Ph, R1 ) R2 ) Me)
reacted with 4-toluenesulfonylacetone (X ) 4-tosyl, Y )
(1) Kim, B. S.; Choi, K. S.; Kim, K. J . Org. Chem. 1998, 63, 6086.
10.1021/jo991884b CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/18/2000

Synthesis of 3-Alkylamino-5-arylthiophenes
J . Org. Chem., Vol. 65, No. 12, 2000 3691
Ta ble 2. Rea ction s of 1A w ith Active Meth ylen e Com p ou n d s in th e P r esen ce of Hg(OAc)2
a
b
Isolated yields. Recrystallized from a mixture of EtOAc and n-hexane. c Products from ethanolysis.

3692 J . Org. Chem., Vol. 65, No. 12, 2000
Kim and Kim
phenylthiophene (10) (X ) H). Compounds 6, 8, and 9
were liquids, and compound 7 was a recrystallizable
purple red solid.
Cyclic 1,3-diketones, which have enolizable hydrogen
atoms, also undergo analogous reactions to give a variety
of thiophene derivatives, 10-21, which are collected in
Table 2 (entries 6-17).
coupling of 3-thiapentane-1,5-diones;11 copper(I) salt-
promoted reaction of styryl bromides with dibenzoyl
disulfides in a hot aprotic solvent;12 heating R-bromo-
ketones with Lawesson’s reagent in benzene.13 However,
neither of these may be suitable for the synthesis of
3-amino-2-arylthiophenes.
Surprisingly, synthesis of even simple 3-aminothiophene
has been achieved by a limited number of methods such
as Hofmann rearrangement of thiophene-3-carboxamide,2b
Beckman rearrangement of the 3-acetylthiophene oxime,2b
or reduction of 3-nitrothiophene, which is prepared
starting from 3-amino-2-thiophenecarboxylate.14 In ad-
dition, the reaction of â-chlorocinnamonitriles with R-mer-
captoacetic esters in the presence of a base gave 3-ami-
nothiophenes 3 (R1 ) H, X ) CO2Me, CO2Et).15 2-Alkyl-
thio- or 2-arylthiothiophenes may be prepared by reaction
of the lithio derivative with a disulfide.2b However, it
would be difficult to obtain directly 3-alkylamino-2-
arylsulfonylthiophene derivatives such as compounds 6
and 8.
Compounds 13, 15, and 16 belong to the same class of
compounds as compound 2. However, a method for the
synthesis of 2 may not be practicable because of the
difficulty in synthesizing 1,3-diketones giving rise to the
2-ethoxycarbonylbenzoyl group of 13, the 2-hydroxyben-
zoyl group of 15, and the 5-bromo-2-hydroxybenzoyl
group of 16. There is one report which describes the
synthesis of 2-thenoyl-4-ethylphenols from 2-hydroxy-5-
ethylbenzoyl chloride and thiophene in the presence of
AlCl3 in CS2. The reported yields were low (3-49%).16
(B) Rea ction Mech a n ism . The formation of all of the
compounds 4-21 may be explained by the same mech-
anism as that proposed previously for the formation of
compounds 2 and 3, which involved 2,2-disubstituted
3-methylimino-5-phenyl-2,3-dihydrothiophenes 26 as key
intermediates.1 Thus, the mechanism of the reactions
with carbonyl compounds having active methylene hy-
drogen atoms may be described as shown in Scheme 2.
Treatment of compound 1a with Hg(OAc)2 makes com-
plex 22 having an iminothiolester functionality.17 The
electron-deficient imino carbon would be readily attacked
by an enolic carbon to give intermediate 23, which has
an amino group and a methylthio group at the same
carbon atom. Loss of a methanethiol molecule from 23
gives intermediate 24, which undergoes tautomerization
to give intermediate 25. Intramolecular nucleophilic
attack of the enolic carbon to sulfur, concomitant with
the formation of mercury(0) and acetic acid, leads to key
intermediate 26. Subsequent hydrolysis of 26 gives
thiophene derivatives.
The structures of compounds 4-21 were determined
1
on the basis of spectroscopic (IR, H and 13C NMR, MS)
data and elemental analyses. Compounds 4, 5, and 10
may be prepared by methods described in the literature.
However, it may be difficult to access compounds other
than the foregoing, despite the availability of diverse
synthetic methods for thiophene derivatives.2 Treatment
of the sodium salt of ethyl cyanoacetate with phenyl
isothiocyanate gave the salt of the thioamide, which with
bromonitromethane gave 3-amino-2-nitrothiophenes.3 The
method is now known as a practical method for the
synthesis of 3-amino-2-nitrothiophenes. â-Chloro-R-cy-
anocinnamonitrile reacts with alkanethiol in the presence
of K2CO3 to give 2-substituted 3-aminothiophenes in
which the substituents may be CO2Et, MeCO, PhCO, CN,
and NO2.4 Treatment of S-acetylmercaptoacetonitrile
with NaOEt (1 equiv) in EtOH, followed immediately by
the addition of â-substituted acetylenic nitriles at -78
°C, gave 3-amino-5-aryl-(or alkyl)thiophene-2-carboni-
triles.5 There exist other methods which may be useful
for the synthesis of 2-cyano- and 2-nitrothiophenes.2
However, the methods are incompatible with the syn-
thesis of compounds of the type 4 and 5. The formation
of thienylphosphonate has been seldom reported. Rear-
rangement of O,O-diisopropyl-S-(3-thienyl)thiophosphate
to diisopropyl (3-mercapto-2-thienyl)phosphonate (47%)
may be of practical use for synthesis.6 However, the
method is unrelated to the formation of 9.
A number of methods have been used for the synthesis
of 2-arylthiophenes: reaction of 2-thienylcopper with
iodoarenes;7 treatment of 1,4-diketones with phosphorus
sulfide;8 coupling reactions between 2-thienylmetal de-
rivatives and halobenzenes under catalysts;9 reaction of
1,4-diarylbutadiynes with arenemethanethiols in DMSO
in the presence of KOH;10 intramolecular reductive
(2) Refer to the following excellent review: (a) Rajappa, S. In
Comprehensive Heterocyclic Chemistry; Katritzky, A., Rees, C. W., Eds.;
Pergamon Press: Oxford, 1984; Vol. 4, Chapter 3.14, pp 742-861. (b)
Campaigne, E. In Comprehensive Heterocyclic Chemistry; Katritzky,
A., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 4, Chapter
3.15, pp 864-934. (c) Rajappa, S. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A., Rees, C. W., Scriven, E. F., Eds.; Pergamon
Press: Oxford, 1996; Vol. 2, Chapter 2.10, pp 491-605. (d) Nakayama,
J . In Comprehensive Heterocyclic Chemistry II; Katritzky, A., Rees, C.
W., Scriven, E. F., Eds.; Pergamon Press: Oxford, 1996; Vol. 2, Chapter
2.11, pp 608-729.
(3) (a) Fishwick, B. R.; Rowles, D. K.; Rowles, D. K.; Stirling, C. J .
M. J . Chem. Soc., Chem. Commun. 1983, 834. (b) Fishwick, B. R.;
Rowles, D. K.; Stirling, C. J . M. J . Chem. Soc., Perkin Trans. 1 1986,
1171.
(4) Gewald, K.; Hain, U. Monatsch Chem. 1992, 123, 455.
(5) Ren, W.-Y.; Rao, K. V. B.; Klein, R. S. J . Heterocycl. Chem. 1986,
23, 1757.
Thus, compound 6 can be explained by hydrolysis
(path a) of the acetyl group of the intermediate 26a (X )
(11) (a) Nakayama, J . Phosphorus, Sulfur Silicon 1993, 74, 157. (b)
Nakayama, J . Yuki Gosei Kagaku Kyokaishi 1994, 52, 308.
(12) Ogawa, T.; Hotta, S.; Hayami, K.; Suzuki, H. Chem. Lett. 1992,
1947.
(6) Masson, S.; Saint-Clair, J .-F.; Saquet, M. Tetrahedron Lett. 1994,
35, 3083.
(13) (a) Czogalla, C.-D.; Boberg, F. Phosphorus Sulfur 1988, 35, 67.
(b) Boberg, F.; Schulz, J . 15th International Symposium on the Organic
Chemistry of Sulfur, Caen, 1992; Abstract, p 182.
(14) Baker, J . M.; Huddleston, P. R.; Wood, M. L. Synth. Commun.
1995, 25, 3729.
(7) (a) Nilsson, M.; Ullenius, C. Acta Chem. Scand. 1970, 24, 2379.
(b) Nilsson, M.; Ullenius, C. Acta Chem. Scand. 1971, 25, 2428.
(8) Hartough, H. D. Chem. Heterocycl. Compds. 1952, 3, 1.
(9) (a) Kalinln, V. N. Synthesis 1992, 413. (b) Takahashi, K.; Suzuki,
T.; Akiyama, K.; Ikegami,; Fukuzawa, Y. J . Am. Chem. Soc. 1991, 113,
4576. (c) Amatore, C.; J utand, A.; Negri, S.; Fauvarque, J .-F. J .
Organomet. Chem. 1990, 390, 389. (d) Hatanaka, Y.; Fukushima, S.;
Hiyama, T. Heterocycles 1990, 30, 303.
(15) Hartmann, H. Synthesis 1984, 275.
(16) Evans, D.; Cracknell, M. E.; Saunders: J . C.; Smith, C. E.;
Williamson, W. R. N.; Dawson, W.; Sweatman, W. J . F. J . Med. Chem.
1987, 30, 1321.
(17) One reviewer suggested an oxidation of 1 by Hg(OAc)2 to a
disulfide as an intermediate. The disulfide activated by a second
molecule of Hg(OAc)2 might be attacked by the enol.
(10) Freeman, F.; Lu, H.; Rodriguez, E. Tetrahedron Lett. 1993, 34,
1753.

Synthesis of 3-Alkylamino-5-arylthiophenes
J . Org. Chem., Vol. 65, No. 12, 2000 3693
Sch em e 2
4-tosyl, Y ) Me). The formation of 7 may be explained
by the involvement of the intermediate 26b (X )
4-O2NC6H4, Y ) OH), which undergoes decarboxylation
(path a) to give 7. Similarly, the reaction of 1a with ethyl
cyanoacetate (X ) CN, Y ) OEt) (1 molar equiv) under
the same conditions gave 2,3-dihydrothiophene 26c
(96%), which was converted to 4a (84%) during the
chromatographic separation of the reaction mixture. The
formation of 4a via the intermediate 26c indicates that
detachment of an ethoxycarbonyl group in preference to
a cyano group from 26c occurs exclusively. For hydrolysis
of 26c, cleavage of the bond between the carbonyl carbon
and C-2 of the thiophene ring to give directly 4a (path a)
is preferable to hydrolysis of the acyl-oxygen bond to give
intermediate 26d (X ) CN, Y ) OH) (path b). This is
because the driving force for the cleavage of the carbon-
carbon bond of 26c leading to aromatic compound 4a may
be more important than hydrolysis leading to the forma-
tion of 26d .
in 64% and 16% isolable yields, respectively. Compound
27a was readily converted to 3a (91%) in stirred aqueous
THF. The formation of 3a via the intermediate 27a along
with a strong acidic solution (pH < 1) indicates that
hydrolysis of 27a takes place exclusively to eliminate the
methanesulfonyl group. Similarly, compound 3a obtained
from the reactions with active methylene compounds, i.e.,
methyl phenylsulfinyl acetate and triethyl phosphono-
acetate, may be formed via the formation of dihydrothio-
phenes 27b,c, respectively. In this context, one can
deduce the involvement of the intermediates 27d ,e,
leading to compounds 5 and 8, respectively.
The formation of 3-methylamino-5-phenylthiophene
(10) would be explained by the involvement of the
intermediate 26e (X ) CO2H, Y ) OH), which underwent
decarboxylation, leading to 3-aminothiophene-2-carbox-
ylic acid (28) (Scheme 3). This type of 3-aminothiophene-
2-carboxylic acid has never been isolated.14,18 Conse-
quently, a rapid decarboxylation of 28 via 2,3-dihydro-
thiophene 29, a tautomer of 28, would result in compound
10.
In the meantime, treatment of 1a with ethyl meth-
anesulfonyl acetate under the same conditions gave 2,3-
dihydrothiophene 27a along with 3a (Ar ) Ph, R1 ) Me)
The reaction with Meldrum’s acid under the same
conditions gave 10 (47%), the formation of which can be
explained by cleavage of a carbon-carbon bond (path a)
of the intermediate 27f, followed by decarboxylation and
extrusion of acetone (Scheme 3). Alternatively, a series
of reactions of the intermediate 27f, i.e., hydrolysis,
decarboxylation, and extrusion of acetone, can also give
10 (path b).
To obtain information about the cleavage of the bonds,
EtOH was added to the stirred mixture of 1a , Meldrum’s
acid, and Hg(OAc)2 in CH2Cl2 for 10 min. The mixture
was further stirred for 40 min. From the mixture were
isolated 3a (21%) and diester 30 (28%). The result
suggests that both paths a and b are involved in this
reaction.
When 1a was treated with dimedone in CH2Cl2 for 2 h
under the foregoing conditions, followed by addition of a
(18) (a) 3-tert-Butoxyaminothiophene-2-carboxylic acid has been
prepared: Galvez, C.; Garcia, F.; Garcia, J . J . Chem. Res., Synop. 1985,
296. (b) Kirsch, G.; Cagniant, M. D.; Cagniant, P. J . Heterocycl. Chem.
1982, 19, 443.

3694 J . Org. Chem., Vol. 65, No. 12, 2000
Kim and Kim
Sch em e 3
mixture of H2O and THF (1:5), carboxylic acid 11 was
isolated in 52% yield along with an unknown mixture.
However, upon addition of EtOH to the foregoing mix-
ture, compound 31 analogous to 30 was isolated in 72%
yield. The observation can be understood by assuming
the involvement of intermediate 27g which undergoes
either hydrolysis or ethanolysis to give 11 and 31,
respectively.
opening to give trans isomer 33. This is presumably due
not only to the formation of trans isomer being thermo-
dynamically more stable but also to the recovery of
delocalization energy in forming a conjugated system.
Treatment of 1a with 1,3-indandione followed im-
mediately by addition of ethanol gave 2-(2-thenoyl)ben-
zoate 13 (82%) via intermediate 27i. Heating compound
13 in EtOH at reflux did not give the cyclized product
34 (vide infra).
The reaction with tetronic acid under the foregoing
conditions gave an interesting compound, 14 (56%), in
which the alcohol oxygen of an ester is connected to the
R-carbon of carboxylic acid. The reactions with 4-hy-
droxycoumarin and 6-bromo-4-hydroxycoumarin under
the same conditions gave the 2-(2-thenoyl)phenol deriva-
tives 15 and 16, respectively.
The intermediates 27j, 27k , and 27l are involved in
the formation of 14, 15, and 16, respectively. The forma-
tion of 14 suggests that when a keto carbonyl and an
ester carbonyl group are competitive in hydrolysis, hy-
drolysis of the former occurs exclusively, as was previ-
ously demonstrated in the reaction of 1 with â-keto esters
(Scheme 1).1,20 However, the opposite tendency was
observed in the ethanolysis of 4-hydroxycoumarin, namely,
that the treatment of 1a with 4-hydroxycoumarin for 1
min under the foregoing conditions, followed by the
addition of EtOH, gave 2-(ethoxycarbonyl)phenyl 2-thio-
phenecarboxylate 37 (7%) and ethyl carbonate 36 (84%).
The result suggests that, for hydrolysis, a water molecule
attacks predominantly the ester carbonyl carbon of the
dihydrothiophene 27k , followed by extrusion of CO2 to
give 15 (path a). An alternative path, b, showing the
cleavage between the ester carbonyl carbon and phenolic
oxygen is unlikely to be involved since no 3a is isolated
in this reaction. The isolation of 37 from the ethanolysis
reaction mixture indicates that ethanol also attacks the
keto carbonyl carbon (path c). However, an analogous
product, benzoic acid derivative, could not be isolated
from the hydrolysis reaction mixture.
Similarly, treatment of 1a with 4-cyclopentene-1,3-
dione under the foregoing conditions, followed immedi-
ately by addition of ethanol, gave γ-keto-R,â-unsaturated
ester 12 via the intermediate 27h . The stereochemistry
around the double bond of compound 12 should be
retained, as was confirmed by measurement of the
coupling constant between vinyl protons (J HH ) 11.9 Hz).
Interestingly, heating 12 in ethanol at reflux caused the
isomerization to trans isomer 33, whose corresponding
coupling constant was J HH ) 15.2 Hz.19 The isomerization
may be achieved by Michael-type intramolecular addition
of the methylamino group of 12 to R,â-unsaturated ester
to give thienopyrrolidinone 32, which undergoes ring
The formation of 17 could be rationalized on the basis
of the hydrolysis of the ester functionality of intermediate
27m , which resulted in the intermediate 38a (path a,
(19) Williams, D. H.; Fleming, I. Spectroscopic Methods in Organic
Chemistry, 3rd ed.; McGraw-Hill: London, 1980; p 145.
(20) Harbuck, J . W.; Rapoport, H. J . Org. Chem. 1971, 36, 853.

Synthesis of 3-Alkylamino-5-arylthiophenes
J . Org. Chem., Vol. 65, No. 12, 2000 3695
Sch em e 4
Sch em e 5
ethanol attacks the keto carbonyl carbon in preference
to the amide carbonyl carbon. This is presumably due to
the character of the amide carbonyl carbon, which is less
electron-deficient than the keto carbonyl carbon because
of delocalization of the nonbonding electrons on the
nitrogen atom. Similarly, the formation of R-keto ester
20 can be explained by nucleophilic attack of ethanol on
the vicinal carbonyl carbon of the intermediate 27o.
Activation of a dipole-dipole repulsion arising from the
vicinal carbonyl groups may be responsible for selective
ethanolysis.21 It is noteworthy that heating 20, which
bears an ethylbenzoylformate functional group in EtOH
at reflux, leads to thienoazepinedione derivative 34,
whereas heating compound 13, which has an ethyl
benzoate functional group, under the same conditions did
not give 34. The structure of 34 was confirmed by X-ray
crystallographic analysis.
X ) H) (Scheme 4). Decarboxylation of 38b (X ) H)
concomitant with aromatization would give amino-1,3-
diketone 39. This readily undergoes intramolecular cy-
clization to give intermediate 40, dehydration of which
would give 17. However, hydrolysis of 27m leading to
intermediate 41 (path b, X ) H) was ruled out on the
basis of the result that treatment of 1a with 4-hydroxy-
6-methyl-2-pyrone under the same conditions as for the
reaction with 4-hydroxycoumarin involving 27k gave 3a
(Ar ) Ph, R1 ) Me) in 88% yield. This result suggests
that the cleavage of the bond by a nucleophilic attack of
ethanol follows path a to give intermediate 38 (X ) Et),
which undergoes ethanolysis to give 3a . The fashion of
the cleavage of the bond of 27m is in contrast to that
shown by intermediate 27k . The exclusive cleavage of
the bond by path a leading to 38b (X ) Et) may be due
to the driving mechanism for the formation of 1,3-
diketone via enol 38a . However, for the case of the
intermediate 27k , the π-bond corresponding to the car-
bon-carbon double bond of 27m is already part of the
stable phenyl ring so that the double bond would not
provide the driving force for cleavage by path b.
Compound 21 is envisaged to be formed by decarbox-
ylation of the intermediate 42, which is formed by
hydrolysis of intermediate 27p (Scheme 5). However,
methanolysis of intermediate 27p gave two different
products, 43 and 45, depending upon the reaction tem-
perature. Compound 43, which is a type of carbamate,
was formed at room temperature. Heating 43 in MeOH
at reflux afforded 45 in 91% yield, presumably via the
intermediate 44. Methanolysis of 27p at reflux afforded
45 in 43% yield. 3-(2-Hydroxyethyl)thieno[3,2-d]pyrimi-
dine-2,4(1H,3H)-dione, which is analogous to compound
45, was synthesized from 3-amino-2-(methoxycarbon-
yl)thiophene with ethyl chloroformate followed by etha-
nolamine.22
The formation of thienobenzoisoquinolinone 18 could
be achieved via intermediate 35, which undergoes an
intramolecular nucleophilic attack of the imino nitrogen
on the carbonyl carbon by forming a six-membered cyclic
transition state concomitant with decarboxylation to give
the product 18 (96%). The same reaction was performed
in the presence of EtOH to trap the intermediate as an
ester under the same conditions as in Scheme 3. How-
ever, only 18 was obtained in 91% yield.
In conclusion, it has been found that thioaroylketene
S,N-acetals are useful starting materials for the synthesis
of 3-alkylamino-5-arylthiophenes having various substit-
uents at C-2. Since the enol forms of active methylene
compounds participate in the reactions, further study
with a variety of enol ethers are worthwhile, and such
investigations are in progress.
(21) Refer to equilibrium studies of water to ketones: Burkey, T.
J .; Fahey, R. C. J . Am. Chem. Soc. 1983, 105, 868.
(22) Fukumi, H.; Sugiyama, M.; Sakamoto, T. Chem. Pharm. Bull.
1989, 37, 1197.
The formation of N-methyl-N-(2-ethoxycarbonyl)phen-
yl-2-thiophenecarboxamide 19 could be achieved by eth-
anolysis of intermediate 27n . This result indicates that

3696 J . Org. Chem., Vol. 65, No. 12, 2000
Kim and Kim
of mercury(0) and unreacted Hg(OAc)2. The solids were washed
with CH2Cl2. The solution was treated with brine and dried
over MgSO4. After removal of the solvent in vacuo, the residue
was chromatographed on a silica gel column (2 × 20 cm) using
a mixture of EtOAc and n-hexane (1:4). However, compound
5a was eluted with a mixture of CH2Cl2, EtOAc, and n-hexane
(1:1:4), compounds 5b-d and 10 were eluted with EtOAc and
n-hexane (1:2), compounds 7, 9, and 19 were eluted with
EtOAc and n-hexane (1:1), and compound 12 was eluted with
EtOAc and MeOH (9:1). All compounds were recrystallized
from a mixture of EtOAc and n-hexane, except for 15, which
was recrystallized from a mixture of DMSO and Et2O. (ii) As
described in (i), to a mixture of 1, an active methylene
compound, and Hg(OAc)2 in CH2Cl2 was additionally added
EtOH. The mixture was worked up as usual to give ethyl esters
12, 13, 19, 20, 30, 31, 36, and 37. Reaction times, yields, and
melting points of compounds 4 and 5 and compounds 6-21
are summarized in Tables 1 and 2, respectively.
Exp er im en ta l Section
Gen er a l P r oced u r es. NMR spectra were recorded in
CDCl3 with TMS as the internal standard for 1H (300 MHz)
and solvent as the internal standard for 13C (75 MHz), unless
otherwise stated. GC-MS (EI) spectra were obtained at 70
eV. Elemental analyses were determined by the Inter-
University Center for Natural Science Research Facilities,
Seoul National University. Dichloromethane was distilled from
calcium hydride prior to use. Column chromatography was
conducted with silica gel (70-230 mesh, ASTM). Thio-
aroylketene S,N-acetals 1 were prepared by a procedure which
was modified from the literature and described in this section.
Eth yl 3-m eth yla m in o-5-p h en ylth iop h en e-2-ca r boxyl-
a te (3a ) was prepared by the general procedure i from
3-methylamino-3-methylthio-1-phenylthioxopropene (1a ) and
enolizable compounds which are diethyl 1,3-acetonedicarbox-
ylate (X ) CO2Et, Y ) CH2CO2Et), ethyl 3-nitrobenzoyl acetate
(X ) CO2Et, Y ) 3-NO2C6H4), and ethyl methanesulfonyl
acetate in 83%, 89%, and 74% yields, respectively: pale yellow
5-Ar yl-1,2-d ith iole-3-on es 47. A mixture of compounds 46
(127-284 mmol) and sulfur (280-561 mmol) was heated for
2 h at 245-255 °C in a sand bath, and then cooled, followed
by addition of CH2Cl2 (150-200 mL). The mixture was
subsequently filtered. After removal of the solvent, the residue
was recrystallized from a mixture of CH2Cl2 and MeOH (1:1)
to give flesh-colored compounds 47 (40-52%).23a
5-Ar yl-1,2-d ith iole-3-th ion es 48. A solution of 47 (51-103
mmol) and phosphorus pentasulfide (58-135 mmol) in pyri-
dine (200-300 mL) was refluxed for 4 h, and then the mixture
was worked up by the standard literature procedure to give
the compounds 48 (79-88%).23a
5-Ar yl-3-m eth ylth io-1,2-d ith ioliu m Iod id es 49. A solu-
tion of 48 (45-76 mmol) and iodomethane (134-225 mmol)
in acetone (200-250 mL) was stirred for 2 days at room
temperature, filtered, and washed with acetone to give orange-
colored compounds 49 (86-90%).23b
1
solid; mp 55-57 °C; H NMR δ 1.38 (t, J ) 7.2 Hz, 3H), 3.04
(d, J ) 5.2 Hz, 3H), 4.32 (q, J ) 7.2 Hz, 2H), 6.70 (br s, 1H),
6.88 (s, 1H), 7.37-7.44 (m, 3H), 7.64-7.67 (m, 2H); 13C NMR
(CDCl3) δ 15.0, 32.1, 60.3, 98.3, 112.2, 126.4, 129.3, 129.3,
134.1, 150.0, 157.8, 165.4; IR (KBr) 3373, 1650 cm-1; MS m/z
261 (M+, 100). Anal. Calcd for C14H15NO2S: C, 64.34; H, 5.79;
N, 5.36; S, 12.30. Found: C, 64.05; H, 5.81; N, 5.25; S, 12.51.
Met h yl 5-(3-a n isyl)-3-m et h yla m in ot h iop h en e-2-ca r -
boxyla te (3b) was prepared by the general procedure i from
1-(3-anisyl)-3-methylamino-3-methylthiothioxopropene (1b) and
methyl phenylsulfinyl acetate in 89% yield: pale yellow solid;
mp 49-50 °C; 1H NMR δ 3.02 (d, J ) 5.0 Hz, 3H), 3.82 (s,
3H), 3.84 (s, 3H), 6.67 (br s, 1H), 6.85 (s, 1H), 6.90 (dd, J )
7.8, 2.0 Hz, 1H), 7.14 (d, J ) 2.0 Hz, 1H), 7.21-7.34 (m, 2H);
IR (KBr) 3374, 1664 cm-1; MS m/z 277 (M+, 100). Anal. Calcd
for C14H15NO3S: C, 60.63; H, 5.45; N, 5.05; S, 11.56. Found:
C, 60.56; H, 5.48; N, 5.13; S, 11.43.
2-Alk yl-5-a r ylisoth ia zole-3-th ion es 50. To a mixture of
49 (10-57 mmol) and catalytic amounts of iodine in THF
(100-200 mL) at -30 °C was added alkylamine (12-68 mmol),
and the resulting mixture was stirred for 30 min. The reaction
mixture was warmed to room temperature, and extracted with
Et2O (40 mL × 3). After removal of the solvent, chromatog-
raphy of the residue with a mixture of CH2Cl2, EtOAc, and
n-hexane (1:1:2) gave the compounds 50 (47-63%).23c
2-Alk yl-3-a lk ylth io-5-a r ylisoth ia zoliu m Iod id es 51. A
solution of 50 (4.8-24 mmol) and alkyl iodide (20-99 mmol)
in EtOAc (60-150 mL) was stirred for 2 days at room
temperature. The solid formed was filtered and washed with
Et2O to give the yellow compounds 51 (82-88%).23d
1-Alk yla m in o-1-a lk ylth io-3-a r ylth ioxop r op en es 1. To a
solution of 51 (4.4-20 mmol) in EtOH (40-100 mL) was added
NaBH4 (4.8-25 mmol) at room temperature, and the resulting
solution was stirred for 20 min. The reaction mixture was
extracted with Et2O (30 mL × 3). After removal of the solvent,
chromatography of the residue with a mixture of EtOAc and
n-hexane (1:2) gave the compounds 1 (89-93%).23e
Eth yl 5-(3-a n isyl)-3-m eth yla m in oth iop h en e-2-ca r box-
yla te (3c) was prepared by the general procedure i from 1-(3-
anisyl)-3-ethylamino-3-methylthiothioxopropene (1e) and tri-
ethyl phosphonoacetate in 82% yield: pale yellow solid; mp
1
77-78 °C; H NMR gd 1.36 (t, J ) 7.1 Hz, 3H), 3.02 (d, J )
5.1 Hz, 3H), 4.29 (q, J ) 7.1 Hz, 2H), 6.67 (br s, 1H), 6.85 (s,
1H), 6.91 (dt, J ) 8.0, 2.5 Hz, 1H), 7.15 (t, J ) 2.0 Hz, 1H),
7.22-7.33 (m, 2H); IR (KBr) 3376, 1658 cm-1; MS m/z 291 (M+,
100). Anal. Calcd for C15H17NO3S: C, 61.83; H, 5.88; N, 4.81;
S, 11.01. Found: C, 61.76; H, 5.96; N, 4.95; S, 10.89.
3-Meth yla m in o-5-p h en ylth iop h en e-2-ca r bon itr ile (4a )
was prepared by the general procedure i from 1a and cy-
anoacetic acid (X ) CN, Y ) OH): pale yellow solid; 1H NMR
δ 3.03 (d, J ) 5.2 Hz, 3H), 4.54 (br s, 1H), 6.73 (s, 1H), 7.28-
7.63 (m, 5H); IR (KBr) 3356, 2178 cm-1; MS m/z 214 (M+, 100).
Anal. Calcd for C12H10N2S: C, 67.09; H, 4.73; N, 12.92; S,
14.96. Found: C, 67.26; H, 4.70; N, 13.07; S, 14.96.
5-(3-An isyl)-3-m et h yla m in ot h iop h en e-2-ca r b on it r ile
(4b) was prepared by the general procedure i from 1b and
cyanoacetic acid: pale yellow solid; 1H NMR δ 2.96 (d, J ) 5.1
Hz, 3H), 3.76 (s, 3H), 4.51 (br d, J ) 4.5 Hz, 1H), 6.66 (s, 1H)
6.83-6.85 (m, 1H), 6.98-6.99 (m, 1H), 7.04-7.05 (m, 1H),
7.18-7.23 (m, 1H); IR (KBr) 3320, 2182 cm-1; MS m/z 244 (M+,
100). Anal. Calcd for C13H12N2OS: C, 63.91; H, 4.95; N, 11.47;
S, 13.12. Found: C, 63.98; H, 4.96; N, 11.42; S, 13.03.
3-Eth yla m in o-5-p h en ylth iop h en e-2-ca r bon itr ile (4c)
was prepared by the general procedure i from 3-ethylamino-
3-methylthio-1-phenylthioxopropene (1c) and cyanoacetic
Gen er a l P r oced u r e for th e Syn th esis of 2-Su bstitu ted
3-Alk yla m in o-5-a r ylth iop h en es. (i) To a mixture of ketene
S,N-acetal (0.134-0.475 mmol) and an active methylene
compound (0.134-0.476 mmol) in CH2Cl2 (8-20 mL) was
added a slight excess of a molar equivalent of Hg(OAc)2
(0.201-0.712 mmol). The mixture was stirred for an appropri-
ate time (0.5-17 h) at room temperature, followed by filtration
1
(23) (a) Klingsberg, E. J . Am. Chem. Soc. 1961, 83, 2934. (b)
Bo¨ttcher, B.; Lu¨ttringhaus, A. Annalen 1947, 557, 89. (c) Mckinnon,
D. M.; Hassan, M. E.; Chauhan, M. Can. J . Chem. 1974, 52, 1738. (d)
Coustumer, G. L.; Mollier, Y. Bull. Soc. Chim. Fr. 1970, 3076. (e) Kim,
S. H.; Lee, Y. Y.; Kim, K.; Kim, J .-H. Bull. Korean Chem. Soc. 1994,
15, 237.
acid: pale yellow solid; H NMR δ 1.25 (t, J ) 7.2 Hz, 3H),
3.40 (quintet, J ) 7.2 Hz, 2H), 4.52 (br s, 1H), 6.71 (s, 1H),
7.22-7.67 (m, 5H); IR (KBr) 3320, 2180 cm-1; MS m/z 228 (M+,
59.9), 213 (100). Anal. Calcd for C13H12N2S: C, 68.39; H, 5.30;
N, 12.27; S, 14.04. Found: C, 68.46; H, 5.26; N, 12.14; S, 14.14.

Synthesis of 3-Alkylamino-5-arylthiophenes
J . Org. Chem., Vol. 65, No. 12, 2000 3697
5-(3-Ch lor op h en yl)-3-m eth yla m in oth iop h en e-2-ca r bo-
n itr ile (4d ) was prepared by the general procedure i from 1-(3-
chlorophenyl)-3-methylamino-3-methylthiothioxopropene (1d )
and cyanoacetic acid: pale yellow solid; 1H NMR δ 3.05 (d,
J ) 5.2 Hz, 3H), 4.59 (br d, J ) 4.1 Hz, 1H), 6.76 (s, 1H), 7.33-
7.36 (m, 2H), 7.39-7.44 (m, 1H), 7.53 (m, 1H); IR (KBr) 3344,
2176 cm-1; MS m/z 248 (M+, 100). Anal. Calcd for C12H9ClN2-
S: C, 57.95; H, 3.65; N, 11.26; S, 12.89. Found: C, 57.87; H,
3.64; N, 11.22; S, 12.84.
3-Meth ylam in o-2-n itr o-5-ph en ylth ioph en e (5a) was pre-
pared by the general procedure i from 1a and nitromethane:
yellow solid; 1H NMR δ 3.19 (d, J ) 5.3 Hz, 3H), 6.83 (s, 1H),
7.44-7.49 (m, 3H), 7.64-7.68 (m, 2H), 8.07 (br s, 1H); IR (KBr)
3328, 1587 cm-1; MS m/z 234 (M+, 100). Anal. Calcd for
C15H20NO3PS: C, 55.37; H, 6.20; N, 4.30; S, 9.86. Found: C,
55.43; H, 6.24; N, 4.24; S, 9.82.
3-Meth yla m in o-5-p h en ylth iop h en e (10) was prepared by
the general procedure i from 1a and enolizable compounds,
which are malonic acid (X ) CO2H, Y ) OH) (entry 5) and
Meldrum’s acid (entry 6): yellow solid; 1H NMR δ 2.84 (s, 3H),
3.55 (br s, 1H), 5.92 (s, 1H), 6.86 (s, 1H), 7.24-7.40 (m, 3H),
7.54-7.60 (m, 2H); IR (neat) 3392 cm-1; MS m/z 189 (M+, 100).
Anal. Calcd for C11H11NS: C, 69.80; H, 5.86; N, 7.40; S, 16.94.
Found: C, 69.92; H, 5.84; N, 7.31; S, 16.93.
4-(3-Met h yla m in o-5-p h en ylt h en oyl)-3,3-d im et h ylb u -
ta n oic a cid (11) was prepared by the general procedure i from
1a and dimedone: yellow liquid; 1H NMR δ 1.16 (s, 6H), 2.46
(s, 2H), 2.69 (s, 2H), 3.11 (d, J ) 5.2 Hz, 3H), 6.89 (s, 1H),
7.38-7.45 (m, 3H), 7.64-7.67 (m, 2H), 8.53 (br s, 1H), 13.20
(br s, 1H); IR (neat) 3312, 2944, 1718, 1582 cm-1; MS m/z 331
(M+, 40.1), 216 (100). Anal. Calcd for C18H21NO3S: C, 65.23;
H, 6.39; N, 4.23; S, 9.67. Found: C, 65.28; H, 6.41; N, 4.20; S,
9.63.
C
11H10N2O2S: C, 56.39; H, 4.30; N, 11.96; S, 13.69. Found: C,
56.32; H, 4.36; N, 11.95; S, 13.54.
5-(3-An isyl)-3-eth yla m in o-2-n itr oth iop h en e (5b) was
prepared by the general procedure i from 1e and nitrometh-
ane: yellow solid; 1H NMR δ 1.37 (t, J ) 7.2 Hz, 3H), 3.50
(quintet, J ) 7.2 Hz, 2H), 3.86 (s, 3H), 6.79 (s, 1H), 6.99 (dd,
J ) 8.2, 2.3 Hz, 1H), 7.15 (t, J ) 1.8 Hz, 1H), 7.20-7.38 (m,
2H), 8.04 (br s, 1H); IR (KBr) 3328, 1584 cm-1; MS m/z 278
(M+, 100). Anal. Calcd for C13H14N2O3S: C, 56.10; H, 5.07; N,
10.06; S, 11.52. Found: C, 56.23; H, 5.10; N, 10.01; S, 11.44.
5-(3-Ch lor oph en yl)-3-eth ylam in o-2-n itr oth ioph en e (5c)
was prepared by the general procedure i from 1-(3-chlorophen-
yl)-3-ethylamino-3-methylthiothioxopropene (1f) and nitro-
methane: yellow solid; 1H NMR δ 1.39 (t, J ) 7.2 Hz, 3H),
3.52 (quintet, J ) 7.2 Hz, 2H), 6.82 (s, 1H), 7.36-7.44 (m, 2H),
7.49-7.52 (m, 1H), 7.60 (m, 1H), 8.03 (br s, 1H); IR (KBr) 3332,
1585 cm-1; MS m/z 282 (M+, 31.6), 235 (100). Anal. Calcd for
cis-Eth yl 3-(3-m eth yla m in o-5-p h en ylth en oyl)-2-p r op e-
n oa te (12) was prepared by the general procedure i from 1a
1
and 4-cyclopentene-1,3-dione: yellow liquid; H NMR δ 1.23
(t, J ) 7.2 Hz, 3H), 3.06 (d, J ) 5.2 Hz, 3H), 4.20 (q, J ) 7.2
Hz, 2H), 6.16 (d, J ) 11.9 Hz, 1H), 6.73 (d, J ) 11.9 Hz, 1H),
6.87 (s, 1H), 7.39-7.43 (m, 3H), 7.61-7.65 (m, 2H), 8.27 (br s,
1H); IR (neat) 3320, 1720, 1584 cm-1; MS m/z 315 (M+, 27.6),
242 (100). Anal. Calcd for C17H17NO3S: C, 64.74; H, 5.43; N,
4.44; S, 10.17. Found: C, 64.66; H, 5.47; N, 4.39; S, 10.21.
Eth yl 2-(3-m eth ylam in o-5-ph en ylth en oyl)ben zoate (13)
was prepared by the general procedure ii from 1a and 1,3-
indandione: pale yellow liquid; 1H NMR δ 1.94 (t, J ) 7.1 Hz,
3H), 3.10 (d, J ) 5.2 Hz, 3H), 4.24 (q, J ) 7.1 Hz, 2H), 6.91 (s,
1H), 7.32-7.35 (m, 3H), 7.47-7.60 (m, 5H), 8.03 (br d, J )
8.0 Hz, 1H), 8.27 (d, J ) 4.8 Hz, 1H); IR (neat) 3329, 1712,
1590 cm-1; MS m/z 365 (M+, 95.9), 292 (100). Anal. Calcd for
C
12H11ClN2O2S: C, 50.98; H, 3.92; N, 9.91; S, 11.34. Found:
C, 51.02; H, 4.02; N, 9.82; S, 11.36.
5-(3-An isyl)-3-m eth yla m in o-2-n itr oth iop h en e (5d ) was
prepared by the general procedure i from 1b and ethyl
nitroacetate (X ) NO2, Y ) OEt): yellow solid; 1H NMR δ 3.18
(d, J ) 5.2 Hz, 3H), 3.83 (s, 1H), 6.83 (s, 1H), 6.97-6.99 (m,
1H), 7.12-7.13 (m, 1H), 7.20-7.34 (m, 2H), 8.05 (br s, 1H); IR
(KBr) 3330, 1585 cm-1; MS m/z 264 (M+, 100). Anal. Calcd for
C
21H19NO3S: C, 69.02; H, 5.24; N, 3.83; S, 8.77. Found: C,
69.15; H, 5.28; N, 3.80; S, 8.75.
3-Meth yla m in o-5-p h en yl-2-th en oyloxya cetic a cid (14)
was prepared by the general procedure i from 1a and tetronic
1
C
12H12N2O3S: C, 54.53; H, 4.58; N, 10.60; S, 12.13. Found: C,
acid: pale yellow solid; H NMR δ 3.06 (d, J ) 4.8 Hz, 3H),
54.42; H, 4.55; N, 10.55; S, 12.16.
4.67 (s, 2H), 6.79 (d, J ) 4.7 Hz, 1H), 7.18 (s, 1H), 7.37-7.47
(m, 3H), 7.71-7.74 (m, 2H), 12.86 (br s, 1H); IR (KBr) 3376,
1705, 1651 cm-1. Anal. Calcd for C14H13NO4S: C, 57.72; H,
4.50; N, 4.81; S, 11.01. Found: C, 57.67; H, 4.51; N, 4.86; S,
11.09.
3-Meth yla m in o-5-p h en yl-2-(4-tosyl)th iop h en e (6) was
prepared by the general procedure i from 1a and 4-toluene-
sulfonylacetone (X ) 4-tosyl, Y ) Me): colorless liquid; 1H
NMR δ 2.36 (s, 3H), 2.94 (d, J ) 5.1 Hz, 3H), 5.95 (br, d, J )
4.9 Hz, 1H), 6.75 (s, 1H), 7.25 (d, J ) 8.1 Hz, 2H), 7.31-7.37
(m, 3H), 7.50-7.53 (m, 2H), 7.83 (d, J ) 8.1 Hz, 2H); IR (neat)
3392, 1286, 1136 cm-1; MS m/z 343 (M+, 100). Anal. Calcd for
2-(3-Meth yla m in o-5-p h en yl-2-th en oyl)p h en ol (15) was
prepared by the general procedure i from 1a and 4-hydroxy-
1
coumarin: yellow solid; H NMR δ 3.12 (d, J ) 5.3 Hz, 3H),
C
18H17NO2S2: C, 62.95; H, 4.99; N, 4.08; S, 18.67. Found: C,
6.91-6.93 (m, 1H), 6.92 (s, 1H), 7.00 (dd, J ) 8.3, 1.0 Hz, 1H),
7.39-7.43 (m, 4H), 7.67-7.79 (m, 2H), 8.09 (dd, J ) 8.0, 1.7
Hz, 1H), 8.85 (br d, J ) 4.5 Hz, 1H), 11.72 (s, 1H); 13C NMR
δ 32.0, 107.0, 111.4, 118.5, 119.0, 122.6, 126.7, 129.5, 129.5,
130.3, 133.4, 133.9, 154.8, 161.2, 162.0, 188.3; IR (KBr) 3312,
1571 cm-1; MS m/z 309 (M+, 55.9), 189 (100). Anal. Calcd for
63.06; H, 4.94; N, 4.12; S, 18.71.
3-Met h yla m in o-2-(4-n it r op h en yl)-5-p h en ylt h iop h en e
(7) was prepared by the general procedure i from 1a and
4-nitrophenylacetic acid (X ) 4-O2NC6H4, Y ) OH): red solid;
1H NMR δ 2.99 (s, 3H), 4.22 (br s, 1H), 7.03 (s, 1H), 7.35-7.43
(m, 3H), 7.61-7.67 (m, 4H), 8.23 (d, J ) 7.1 Hz, 1H); IR (KBr)
3392, 1581, 1546, 1481, 1312, 1104 cm-1; MS m/z 310 (M+,
100), 280 (94.4). Anal. Calcd for C17H14N2O2S: C, 65.79; H,
4.55; N, 9.03; S, 10.33. Found: C, 65.71; H, 4.75; N, 8.79; S,
10.45.
C
18H15NO2S: C, 69.88; H, 4.89; N, 4.53; S, 10.36. Found: C,
69.75; H, 4.88; N, 4.56; S, 10.39.
4-Br om o-2-(3-m et h yla m in o-5-p h en yl-2-t h en oyl)p h e-
n ol (16) was prepared by the general procedure i from 1a and
6-bromo-4-hydroxycoumarin: yellow solid; 1H NMR δ 3.15 (d,
J ) 5.2 Hz, 3H), 6.89 (d, J ) 8.8 Hz, 1H), 6.93 (s, 1H), 7.43-
7.48 (m, 4H), 7.68-7.72 (m, 2H), 8.18 (d, J ) 2.4 Hz, 1H), 8.88
2-B e n ze n e s u lfo n y l-3-m e t h y la m in o -5-p h e n y lt h io -
p h en e (8) was prepared by the general procedure i from 1a
1
and bis(phenylsulfonyl)methane: colorless liquid; H NMR δ
(br d, J ) 4.5 Hz, 1H), 11.64 (s, 1H); IR (KBr) 3312, 1570 cm-1
;
3.52 (s, 3H), 5.03 (br s, 1H), 6.63 (s, 1H), 7.36-7.66 (m, 7H),
8.02 (d, J ) 8.1 Hz, 2H); IR (neat) 3375, 1554, 1460, 1283,
1132, 1080 cm-1; MS m/z 329 (M+, 100). Anal. Calcd for
MS m/z 389 (M+ + 2, 11.9), 387 (M+, 11.8), 189 (100). Anal.
Calcd for C18H14BrNO2S: C, 55.68; H, 3.63; N, 3.61; S, 8.26.
Found: C, 55.66; H, 3.65; N, 3.65; S, 8.19.
C
17H15NO2S2: C, 61.98; H, 4.59; N, 4.25; S, 19.47. Found: C,
1,2-Dim eth yl-6-p h en ylth ien o[3,2-b]p yr id in -4-on e (17)
was prepared by the general procedure i from 1a and 4-hy-
droxy-6-methyl-2-pyrone: white solid; 1H NMR δ 2.38 (s, 3H),
3.73 (s, 3H), 6.41 (s, 1H), 7.26-7.48 (m, 3H), 7.67 (d, J ) 7.2
Hz, 2H); 13C NMR δ 20.2, 32.1, 112.6, 116.6, 120.3, 126.5,
129.5, 129.6, 133.8, 144.1, 144.2, 147.6, 163.2; IR (KBr) 1635
cm-1; MS m/z 255 (M+, 100). Anal. Calcd for C15H13NOS: C,
70.56; H, 5.13; N, 5.49; S, 12.56. Found: C, 70.50; H, 5.12; N,
5.52; S, 12.61.
61.88; H, 4.65; N, 4.32; S, 19.38.
Dieth yl 3-m eth yla m in o-5-p h en ylth ien ylp h osp h on a te
(9) was prepared by the general procedure i from 1a and
diethyl (2-oxopropyl)phosphonate (X ) PO(OEt)2, Y ) Me):
1
colorless liquid; H NMR δ 1.34 (t, J ) 7.1 Hz, 6H), 2.95 (s,
3H), 4.1 (m, 4H), 6.09 (br s, 1H), 6.90 (d, J ) 4.5 Hz, 1H), 7.31-
7.42 (m, 3H), 7.59-7.63 (m, 2H); IR (neat) 3360, 1564, 1398,
1226, 1018 cm-1; MS m/z 325 (M+, 100). Anal. Calcd for

3698 J . Org. Chem., Vol. 65, No. 12, 2000
Kim and Kim
2-Meth yl-4-p h en ylth ien o[3,2-c]isoqu in olin -1-on e (18)
was prepared by the general procedure i from 1a and homo-
phthalic anhydride: white solid; 1H NMR δ 3.74 (s, 3H), 7.20
(s, 1H), 7.35-7.46 (m, 4H), 7.61-7.66 (m, 4H), 8.44 (d, J )
8.0 Hz, 1H); 13C NMR δ 31.2, 112.1, 115.8, 121.3, 123.0, 125.1,
125.8, 127.9, 128.5, 128.5, 131.6, 131.8, 132.8, 139.7, 143.5,
161.3; IR (KBr) 1634 cm-1; MS m/z 291 (M+, 100). Anal. Calcd
for C18H13NOS: C, 74.20; H, 4.50; N, 4.81; S, 11.01. Found:
C, 74.22; H, 4.50; N, 4.77; S, 11.04.
6.68 (br s, 1H), 6.83 (s, 1H), 7.34-7.45 (m, 3H), 7.61-7.64 (m,
2H); IR (neat) 3376, 1752, 1663, 1570, 1133 cm-1. Anal. Calcd
for C18H21NO5S: C, 59.49; H, 5.82; N, 3.85; S, 8.82. Found: C,
59.57; H, 5.79; N, 3.86; S, 8.74.
E t h yl 4-(3-m et h yla m in o-5-p h en yl-2-t h en oyl)-3,3-d i-
m eth ylbu ta n oa te (31) was prepared by the general proce-
dure ii from 1a and dimedone in 72% yield: pale yellow liquid;
1H NMR δ 1.19 (s, 6H), 1.27 (t, J ) 7.1 Hz, 3H), 2.51 (s, 2H),
2.72 (s, 2H), 3.02 (d, J ) 5.2 Hz, 3H), 4.13 (q, J ) 7.1 Hz, 2H),
6.87 (s, 1H), 7.38-7.43 (m, 3H), 7.64-7.67 (m, 2H), 8.31 (br s,
1H); IR (neat) 3312, 1727, 1600 cm-1; MS m/z 359 (M+, 47.6),
216 (100). Anal. Calcd for C20H25NO3S: C, 66.82; H, 7.01; N,
3.90; S, 8.92. Found: C, 66.78; H, 6.99; N, 3.95; S, 8.98.
N-[2-(Eth oxyca r bon yl)p h en yl]-N-m eth yl-2-(3-m eth yl-
a m in o-5-p h en yl)t h iop h en eca r b oxa m id e (19) was pre-
pared by the general procedure i from 1a and 4-hydroxy-1-
1
methyl-2(1H)-quinolone: colorless liquid; H NMR δ 1.29 (t,
J ) 7.1 Hz, 3H), 2.98 (s, 3H), 3.35 (s, 3H), 4.29 (q, J ) 7.1 Hz,
2H), 6.73 (s, 1H), 7.25-7.33 (m, 5H), 7.37-7.40 (m, 1H), 7.49-
7.51 (m, 1H), 7.60-7.62 (m, 1H), 7.75 (br s, 1H), 7.99-8.01
(m, 1H); 13C NMR δ 14.1, 31.7, 38.5, 61.5, 99.5, 111.1, 125.8,
128.4, 128.7, 128.7, 130.7, 131.7, 132.0, 133.4, 133.7, 143.4,
147.6, 158.5, 166.1; IR (neat) 3328, 1710, 1582 cm-1; MS m/z
394 (M+, 22.1), 216 (100). Anal. Calcd for C22H22N2O3S: C,
66.98; H, 5.62; N, 7.10; S, 8.13. Found: C, 66.92; H, 5.65; N,
7.18; S, 8.10.
E t h yl 2-(3-m et h yla m in o-5-p h en yl-2-t h en oyl)p h en yl-
oxoa cet a t e (20) was prepared by the general procedure ii
from 1a and 2-hydroxy-1,4-naphthoquinone: yellow liquid; 1H
NMR δ 1.18 (t, J ) 7.1 Hz, 3H), 3.10 (d, J ) 5.2 Hz, 3H), 4.17
(q, J ) 7.1 Hz, 2H), 6.94 (s, 1H), 7.40-7.44 (m, 3H), 7.59-
7.70 (m, 4H), 7.75-7.77 (m, 1H), 7.99-7.82 (m, 1H), 8.61 (br
d, J ) 4.8 Hz, 1H); IR (KBr) 3312, 1696, 1584, 1370 cm-1; MS
m/z 393 (M+, 13.4), 320 (100). Anal. Calcd for C22H19NO4S: C,
67.16; H, 4.87; N, 3.56; S, 8.15. Found: C, 67.12; H, 4.85; N,
3.58; S, 8.22.
N-Eth yl-N′-eth yl-N′-(3-m eth yla m in o-5-p h en yl-2-th en o-
yl)th iou r ea (21) was prepared by the general procedure i
from 1a and 1,3-diethyl-2-thiobarbituric acid: yellow liquid;
1H NMR δ 1.19 (t, J ) 7.3 Hz, 3H), 1.30 (t, J ) 7.0 Hz, 3H),
3.10 (d, J ) 4.5 Hz, 3H), 3.66 (m, 2H), 4.40 (q, J ) 7.0 Hz,
2H), 6.86 (s, 1H), 7.41-7.44 (m, 3H), 7.61-7.67 (m, 2H); 13C
NMR δ 14.2, 14.8, 32.1, 41.5, 46.8, 102.4, 111.5, 126.6, 129.5,
130.3, 133.2, 153.5, 161.4, 169.3, 183.0; IR (neat) 3340, 1594,
1509, 1368 cm-1. Anal. Calcd for C17H21N3OS2: C, 58.76; H,
6.09; N, 12.09; S, 18.45. Found: C, 58.65; H, 6.05; N, 12.14; S,
18.52.
2-Cya n o-2-et h oxyca r b on yl-3-m et h ylim in o-5-p h en yl-
2,3-d ih yd r oth iop h en e (26c). A stirred mixture of 1a (52 mg,
0.233 mmol), ethyl cyanoacetate (26 mg, 0.230 mmol), and
Hg(OAc)2 (102 mg, 0.320 mmol) in CH2Cl2 for 1 h was worked
up as usual. The mixture was extracted with ethyl ether (30
mL × 2). Evaporation of the solvent gave the crude compound
26c (64 mg, 96%): colorless liquid; 1H NMR δ 1.34 (t, J ) 7.1
Hz, 3H), 3.44 (s, 3H), 4.36 (q, J ) 7.1 Hz, 2H), 6.68 (s, 1H),
7.44-7.53 (m, 3H), 7.56-7.59 (m, 2H); IR (neat) 2240, 1747,
1632, 1556, 1229, 1018, 761 cm-1; MS m/z 286 (M+, 40.6), 213
(100).
tr a n s-E t h yl 3-(3-Met h yla m in o-5-p h en yl-2-t h en oyl)-2-
p r op en oa te (33). A solution of 12 (42 mg, 0.133 mmol) in
EtOH (15 mL) was heated for 1 day at reflux. Removal of the
solvent in vacuo gave a residue which was chromatographed
(2 × 20 cm) with a mixture of EtOAc and n-hexane (1:4) to
1
give 33 (36 mg, 85%): yellow liquid; H NMR δ 1.35 (t, J )
7.1 Hz, 3H), 3.10 (d, J ) 5.3 Hz, 3H), 4.28 (q, J ) 7.1 Hz, 2H),
6.86 (d, J ) 15.2 Hz, 1H), 6.90 (s, 1H), 7.41-7.46 (m, 3H),
7.48 (d, J ) 15.2 Hz, 1H), 7.66-7.70 (m, 2H), 8.75 (br s, 1H);
IR (neat) 3296, 1715, 1584 cm-1; MS m/z 315 (M+, 27.8), 242
(100). Anal. Calcd for C17H17NO3S: C, 64.74; H, 5.43; N, 4.44;
S, 10.17. Found: C, 64.72; H, 5.47; N, 4.39; S, 10.21.
2-Me t h yl-4-p h e n ylt h ie n o[3,2-c]b e n za ze p in e -1,6-d i-
on e (34). A solution of 20 (22 mg, 0.056 mmol) in EtOH (15
mL) was heated for 2 days at reflux. Removal of the solvent
in vacuo gave a residue which was chromatographed (2 × 20
cm) with a mixture of EtOAc and n-hexane (1:4) to give 34
(11 mg, 61%): white solid; recrystallized from a mixture of
EtOAc and n-hexane; mp 172-173 °C; 1H NMR δ 3.78 (s, 3H),
7.26 (s, 1H), 7.41-7.45 (m, 3H), 7.64-7.68 (m, 2H), 7.72-7.76
(m, 2H), 8.27-8.29 (m, 1H), 8.43-8.47 (m, 1H); 13C NMR δ
38.3, 118.1, 126.5, 128.5, 129.3, 129.7, 130.2, 132.1, 133.0,
133.1, 133.5, 134.3, 135.3, 142.5, 151.9, 167.0, 181.8; IR (KBr)
1634, 1573 cm-1; MS m/z 318 (M+, 100). Anal. Calcd for
C
19H13NO2S: C, 71.45; H, 4.10; N, 4.39; S, 10.04. Found: C,
71.38; H, 4.12; N, 4.36; S, 10.09.
Eth yl 2-(3-m eth ylam in o-5-ph en yl-2-th en oyl)ph en yl car -
bon a te (36) was prepared by the general procedure ii from
1a and 4-hydroxycoumarin in 84% yield: yellow liquid; 1H
NMR δ 1.30 (t, J ) 7.1 Hz, 3H), 3.07 (d, J ) 5.2 Hz, 3H), 4.26
(q, J ) 7.1 Hz, 2H), 6.89 (s, 1H), 7.26-7.36 (m, 5H), 7.45-
7.50 (m, 1H), 7.57-7.65 (m, 3H), 7.48 (br d, J ) 5.1 Hz, 1H);
IR (KBr) 3320, 1762, 1595, 1249 cm-1; MS m/z 381 (M+, 48.2),
292 (100). Anal. Calcd for C21H19NO4S: C, 66.12; H, 5.02; N,
3.67; S, 8.41. Found: C, 66.24; H, 5.05; N, 3.62; S, 8.32.
2-(Eth oxyca r bon yl)p h en yl 2-(3-m eth yla m in o-5-p h en -
yl)th iop h en eca r boxyla te (37) was prepared by the general
procedure ii from 1a and 4-hydroxycoumarin in 7% yield: pale
yellow liquid; 1H NMR δ 1.20 (t, J ) 7.1 Hz, 3H), 3.06 (d, J )
5.2 Hz, 3H), 4.27 (q, J ) 7.1 Hz, 2H), 6.73 (br s, 1H), 6.91 (s,
1H), 7.21-7.43 (m, 5H), 7.58 (td, J ) 7.8, 1.5 Hz, 1H), 7.69
(m, 2H), 8.04 (dd, J ) 7.8, 1.7 Hz, 1H); IR (KBr) 3376, 1720,
1672, 1576 cm-1. Anal. Calcd for C21H19NO4S: C, 66.12; H,
5.02; N, 3.67; S, 8.41. Found: C, 66.06; H, 4.98; N, 3.71; S,
8.51.
2-Eth oxyca r bon yl-2-m eth a n esu lfon yl-3-m eth yla m in o-
5-p h en yl-2,3-d ih yd r oth iop h en e (27a ). A stirred mixture of
1a (43 mg, 0.193 mmol), ethyl (methanesulfonyl)acetate (30
mg, 0.181 mmol), and Hg(OAc)2 (92 mg, 0.289 mmol) in CH2Cl2
for 3 h was worked up as usual. Chromatography (2 × 10 cm)
of the reaction mixture using a mixture of EtOAc and n-hexane
(2:1) gave 3a (8 mg, 16%) and 27a (42 mg, 64%): a colorless
N-Eth yl-N-m eth oxyca r bon yl-N′-eth yl-N′-(3-m eth yla m i-
n o-5-p h en yl-2-th en oyl)th iou r ea (43). To a stirred mixture
of 1a (40 mg, 0.179 mmol), 1,3-diethyl-2-thiobarbituric acid
(39 mg, 0.195 mmol), and Hg(OAc)2 (68 mg, 0.213 mmol) in
CH2Cl2 for 40 min was added MeOH (10 mL). The mixture
was stirred for 10 min and then worked up as usual. Chro-
matography (2 × 10 cm) of the reaction mixture using a
mixture of EtOAc and n-hexane (1:2) gave 43 (32 mg, 44%):
yellow liquid; 1H NMR δ 1.28 (t, J ) 7.0 Hz, 3H), 1.35 (t, J )
7.1 Hz, 3H), 3.08 (d, J ) 5.2 Hz, 3H), 3.72 (m, 2H), 3.80 (q,
J ) 7.0 Hz, 2H), 4.15 (q, J ) 7.1 Hz, 2H), 6.83 (s, 1H), 7.40-
7.43 (m, 3H), 7.60-7.65 (m, 2H); 13C NMR δ 13.1, 14.0, 32.0,
47.9, 48.3, 53.8, 103.6, 111.5, 126.6, 129.5, 130.3, 133.3, 153.4,
1
liquid; H NMR δ 1.30 (t, J ) 7.1 Hz, 3H), 3.39 (s, 3H), 3.47
(s, 3H), 4.35 (q, J ) 7.1 Hz, 2H), 6.78 (s, 1H), 7.42-7.50 (m,
3H), 7.65-7.67 (m, 2H); IR (neat) 1734, 1310, 1141 cm-1; MS
m/z 339 (M+, 3.8), 214 (100). Compound 27a (42 mg, 0.124
mmol) was dissolved in a mixture of THF and H2O (4:1) (5
mL). The pH of the solution was 7 at the beginning. pH ) 2-3
in 24 h, and pH < 0 in 48 h. Evaporation of the solvent gave
3a (29 mg, 58%).
(1-Eth oxyca r bon yloxy-1-m eth yl)eth yl 3-m eth yla m in o-
5-p h en yl-2-th iop h en eca r boxyla te (30) was prepared by the
general procedure ii from 1a and Meldrum’s acid in 28%
154.2, 161.2, 167.6, 187.4; IR (neat) 3344, 1722, 1618 cm-1
.
1
yield: pale yellow liquid; H NMR δ 1.32 (t, J ) 7.1 Hz, 3H),
Anal. Calcd for C19H23N3O3S2: C, 56.27; H, 5.72; N, 10.36; S,
15.81. Found: C, 56.33; H, 5.70; N, 10.28; S, 15.86.
1.97 (s, 6H), 3.01 (d, J ) 5.2 Hz, 3H), 4.19 (q, J ) 7.1 Hz, 2H),

Synthesis of 3-Alkylamino-5-arylthiophenes
J . Org. Chem., Vol. 65, No. 12, 2000 3699
3-Eth yl-1-m eth yl-6-p h en ylth ien o[3,2-d ]p yr im id in e-2,4-
d ion e (45). (i) A solution of 43 (28 mg, 0.069 mmol) in MeOH
(10 mL) was heated for 1 h at reflux, and then the reaction
mixture was worked up as usual. Chromatography (1.5 × 20
cm) of the mixture using a mixture of EtOAc and n-hexane
(1:2) gave 45 (19 mg, 91%). (ii) To a stirred solution of 1a (41
mg, 0.184 mmol), 1,3-diethyl-2-thiobarbituric acid (40 mg,
0.200 mmol), and Hg(OAc)2 (73 mg, 0.229 mmol) in CH2Cl2
for 1 h was added MeOH (10 mL), and the resulting solution
was heated for 1.5 h at reflux. Chromatography (1.5 × 20 cm)
of the reaction mixture as in i gave 45 (23 mg, 43%): white
solid; recrystallized from a mixture of EtOAc and n-hexane;
an Enraf-Nomius CAD 4 diffractometer using graphite-mono-
chromated Mo KR radiation. The structures were inferred by
direct methods and subsequent Fourier maps. Refinements
were carried out by full-matrix least-squares techniques. Non-
hydrogen atoms were anisotropically refined. Atomic scattering
factors were taken from the International Tables for X-ray
Crystallography, Vol IV, 1974. All calculations and drawings
were performed using a Micro VAX II computer with an SDP
system. Atomic coordinates, bond lengths and angles, and
thermal parameters have been deposited at the Cambridge
Crystallographic Data Centre.
1
mp 209-211 °C; H NMR δ 1.29 (t, J ) 7.1 Hz, 3H), 3.62 (s,
Ack n ow led gm en t. We are grateful to the KOSEF
(Project 981-0302-011-2) for financial support of this
work.
3H), 4.12 (q, J ) 7.1 Hz, 2H), 7.10 (s, 1H), 7.43-7.49 (m, 3H),
7.64-7.67 (m, 2H); 13C NMR δ 13.6, 33.2, 37.4, 111.7, 112.2,
126.7, 129.7, 130.3, 133.0, 146.6, 152.1, 153.5, 158.2; IR (KBr)
1683, 1635 cm-1; MS m/z 286 (M+, 100). Anal. Calcd for
C15H14N2O2S: C, 62.92; H, 4.93; N, 9.78; S, 11.20. Found: C,
62.88; H, 4.94; N, 9.87; S, 11.11.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data of 34. This material is available free of charge
via the Internet at http://pubs.acs.org.
X-r a y Cr ysta llogr a p h ic An a lysis of Com p ou n d 34.
Single crystals of 34 were obtained from the concentrated
solutions in EtOAc and n-hexane. The data were collected on
J O991884B