A facile synthesis of 3-substituted-2-aminothiophenes and 1,3-disubstituted-2-methylthiopyrroles

Article abstract of DOI:10.1021/jo001159x

Electron-rich 3-functionalized-2-aminothiophenes 6 and 1,3-disubstituted-2-methylthiopyrroles 10 were synthesized from substituted allyl benzotriazoles 2 and isothiocyanates 3 via condensation and subsequent heterocyclization.

Full text of DOI:10.1021/jo001159x

2850
J . Org. Chem. 2001, 66, 2850-2853
A F a cile Syn th esis of 3-Su bstitu ted -2-a m in oth iop h en es a n d
1,3-Disu bstitu ted -2-m eth ylth iop yr r oles
Alan R. Katritzky,* Xiaojing Wang, and Anna Denisenko
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Katritzky@chem.ufl.edu
Received J uly 31, 2000
Electron-rich 3-functionalized-2-aminothiophenes 6 and 1,3-disubstituted-2-methylthiopyrroles 10
were synthesized from substituted allyl benzotriazoles 2 and isothiocyanates 3 via condensation
and subsequent heterocyclization.
In tr od u ction
C(3) position; (ii) cyclizations of [3 + 2] products from
1-lithiomethoxyallene and c-hexyl isothiocyanate or meth-
yl isothiocyanate, these gave 2-ethylthio-3-methoxy-N-
cyclohexylpyrrole or 2-methylthio-3-methoxy-N-meth-
ylpyrrole in 11% or 54% yield, respectively.15a,b
Following our use of benzotriazole-stabilized carban-
ions for the preparation of pyrroles16 and furans,17 we
now report the synthesis of 3-functionalized-2-amino-
thiophenes and 1,3-disubstituted-2-methylthiopyrroles
via [3 + 2] component cyclizations.
Cycloadditions are powerful synthetic tools.1 Recently,
novel routes to important heterocycles, including 2-ami-
nothiophenes and 2-alkylthiopyrroles, were developed on
the basis of cyclizations of intermediates formed from
unsaturated carbanions and isothiocyanates.2
Since the first reported preparation of 2-amino-
thiophene,3 the synthesis of functionalized amino-
thiophenes has been studied extensively.4 Four main
synthetic approaches have been applied, three of which
utilize preexisting thiophene rings: (i) reduction of nitro-5
or nitroso-thiophenes,6 (ii) Beckmann, Schmidt,7 or Cur-
tius rearrangements8 of thiophenecarboxylic acid deriva-
tives, and (iii) nucleophilic displacements in mercapto-9
or iodo-thiophenes10 with amines. Route (iv), ring closure
reactions from non thiophene starting materials, is less
developed for the preparation of simple 2-aminothiophenes.
To the best of our knowledge, the only described examples
reported are based on the use of (a) methyl N-phenyl-2-
alkenimidothioates,11 (b) metalated ynamines or allenic
amines,12a,b and (c) lithiated 1-alkynes or allenes.13
Approaches to 3-substituted-2-(alkylthio)pyrroles, es-
pecially those with an electron-donating 3-substituent,
are rather limited. The two main routes are (i) cycliza-
tions of [3 + 2] products from acyl- or nitro-ketene S,N-
acetals and bromoacetaldehyde acetal,14a,b a highly re-
giospecific reaction which is limited to products containing
an electron-withdrawing substituent (acyl or nitro) at the
Resu lts a n d Discu ssion
1. Syn th esis of 3-Su bstitu ted -2-a m in oth iop h en es.
1-Allylbenzotriazole (1) (Scheme 1) was functionalized by
the sequential addition of a solution of n-BuLi and
quenching the resulting anion with various electro-
philes18 which gave 1-(1-alkylprop-2-enyl)benzotriazoles
2a -f (Scheme 1) in excellent yields. The use of n-BuLi
at a low-temperature prevents the isomerization of the
compound 1.18
Intermediate 2g (Scheme 2) was obtained by one-step
condensation of acrolein diethyl acetal with benzotriazole
in refluxing hexanes for 18 h,19 followed by purification
of the crude product by flash column chromatography
which allowed for the separation of the Bt1 and Bt2
isomers (for the structures of Bt1 and Bt2, see Scheme
1).
Treatment of intermediates 2a -e,g with n-BuLi and
subsequent condensation reactions with various isothio-
cyanates 3u -x (see Table 1) followed by the addition of
saturated aqueous ammonium chloride at -78 °C gave
the expected thioamides 4 (accompanied by the regio-
isomers 5, Scheme 1). Isolation of derivative 4a u (Table
(1) Dell, C. P. J . Chem. Soc., Perkin Trans. 1 1998, 3873.
(2) Trofimov, B. A. J . Heterocycl. Chem. 1999, 36, 1469.
(3) Stadler, O. Chem. Ber. 1885, 18, 1490.
(4) Norris, R. K. Aminothiophenes and Their Derivatives. In
Thiophene and Its Derivatives; Gronowitz, S., Eds.; J ohn Wiley and
Sons: New York, 1986; Part Two, p 631.
(5) Steinkopf, W.; Ho¨pner, T. Liebigs Ann. Chem. 1933, 174.
(6) Abramenko, P. I.; Zhiryakov, V. G. Khim. Geterotsikl. Soedin.
1970, 1624.
(7) Hurd, C. D.; Moffat, J . J . Am. Chem. Soc. 1951, 73, 613.
(8) Galvez, C.; Garcia, F. J . Heterocycl. Chem. 1981, 18, 851.
(9) von Hartmann, H.; Scheithauer, S. J . Prakt. Chemie 1969, 311
(5), 827.
(14) (a) Kumar, A.; Ila, H.; J unjappa, H. J . Chem. Soc., Chem.
Commun. 1976, 593. (b) Gupta, A. K.; Chakrasali, R. T.; Ila, H.;
J unjappa, H. Synthesis 1989, 141.
(15) (a) Nedolya, N. A.; Brandsma, L.; Trofimov, B. A. Chem.
Heterocycl. Compd. (N.Y.) 1996, 32, 781. (b) Nedolya, N. A.; de Lang,
R.-J .; Brandsma, L.; Trofimov, B. A. Russ. J . Org. Chem. 1997, 33,
776.
(16) Katritzky, A. R.; Chang, H.-X.; Verin, S. V. Tetrahedron Lett.
1995, 36, 343.
(17) Katritzky, A. R.; Wu, H.; Xie, L.; Rachwal, S.; Rachwal, B.;
J iang, J .; Zhang, G.; Lang, H. Synthesis 1995, 1315.
(18) Katritzky, A. R.; Li, J .; Malhotra, N. Liebigs Ann. Chem. 1992,
843.
(10) King, F. D.; Walton, D. R. M. J . Chem. Soc., Chem. Commun.
1974, 256.
(11) Schaumann, E.; Fittkau, S. Synthesis 1985, 172.
(12) (a) Brandsma, L.; Vvedensky, V. Y.; Nedolya, N. A.; Tarasova,
O. A.; Trofimov, B. A. Tetrahedron Lett. 1998, 39, 2433. (b) De J ong,
R. L. P.; Brandsma, L. J . Organomet. Chem. 1986, 316, C21.
(13) Tarasova, O. A.; Klyba, L. V.; Vvedensky, V. Y.; Nedolya, N.
A.; Trofimov, B. A.; Brandsma, L.; Verkruijsse, H. D. Eur. J . Org.
Chem. 1998, 253, 3.
(19) Katritzky, A. R.; Feng. D.; Lang, H. J . Org. Chem. 1997, 62,
4131.
10.1021/jo001159x CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/29/2001

Synthesis of 3-Substituted-2-aminothiophenes
J . Org. Chem., Vol. 66, No. 8, 2001 2851
Sch em e 1
a
For the significance of 4, 5, and 6, see Table 1.
Ta ble 1. P r ep a r a tion of 3-Su bstitu ted -2-a m in oth iop h en es 6
crude 4 + 5
entrya
R1
R2
C6H5
C6H5
3-FC6H4
C6H5
yield (%)
ratio 4:5
isolated 6 yield (%)b
starting materials
a u
bu
bv
cu
d x
ew
Et
106
112
102
111
102
99
1.6:1
6:1
5.8:1
1.7:1
1.3:1
4:1
50
80
69
41
25
54
2a , 3u
2b, 3u
2b, 3v
2c, 3u
2d , 3x
2e, 3w
2-ClC6H4CH2
2-ClC6H4CH2
n-C6H13
CH2dCHCH2
2-FC6H4CH2
4-ClC6H4
4-MeOC6H4
a
The lettering system for 4, 5, and 6 follows that the first letter is the same as in the starting material 2, the second letter is the same
b
as in the starting material 3, eg, 2a + 3u f [4a u + 5a u ] f 6a u . Isolated yields of compounds 6 based on starting materials 2.
low. However, with benzyl groups as the substituents R1
(4bu ,bv,ew ), the regioselectivities were higher. Particu-
larly, with ethoxy as R1 group, only R-isomer 4gu
Sch em e 2
1
(Scheme 2) was observed from crude H and 13C NMR
spectra. This is presumably due to the electron-with-
drawing ability of the oxygen atom upon the stabilization
of R-carbanion generated. Intermediates 5 (Scheme 1)
were not isolated due to their instability on silica gel
during column chromatography purification.
Although compounds 4 can be isolated as described
above, thioamides 4 undergo partial decomposition (simi-
lar to 5) upon flash column chromatography on silica gel
and therefore were conveniently directly converted with-
out purification into the desired 3-substituted-2-ami-
nothiophenes 6 by anhydrous ZnBr2-promoted cycliza-
tion. It is noteworthy that only the R isomers 4 were
cyclized, while the γ isomers 5 were unchanged. This
simplified significantly the purification procedure for the
final products, since 5 (ca Rf: 0.01 with ethyl ether:
pentane ) 1:10) are far more polar than 6 (ca Rf: 0.5
with ethyl ether:pentane ) 1:10). After removal of the
benzotriazole generated in situ with sodium hydroxide
solution, the expected products 6 (Table 1) were obtained
as oils in 25-80% overall yields after quick flash column
chromatography. Due to the relative instability of
thienylamines,14 we encountered problems for elemental
CHN analyses for the compounds 6d x,ew .
1) by recrystallization from Et2O and identification of two
ethylenic hydrogens [4.61 ppm (d, 1H) and 5.29 ppm (d,
1H)] and an acidic proton (9.8-10.1 ppm, 1H) by 1H NMR
demonstrated the occurrence of an R-substitution reac-
tion at 1-(1-ethylprop-2-enyl)benzotriazole 2a . In addition
1
to the characteristic peaks for 4a u from crude H NMR,
the observation of a doublet (3.9 ppm, 2H), a triplet (6.3
ppm, 1H), and another broad singlet (10.1-10.2 ppm,
1H), demonstrated the presence of the corresponding
γ-regioisomer 5a u (Scheme 1). Similarly, intermediates
5bu ,bv,cu ,d x,ew were also observed in the crude 1H
NMR spectra. The ratios of 4 vs 5 deduced from the crude
1H NMR spectra are reported in Table 1. For those with
simple R1 substituents such as alkyl groups (4a u ,cu ) or
allyl group (4d x), the regioselectivities were relatively
A variety of substituents was investigated for 6. Simple
alkyl (6a u ,cu ), benzyl (6bu ,bv,ew ), allyl (6d x), and
ethoxy (6gu ) groups were successfully utilized as sub-

2852 J . Org. Chem., Vol. 66, No. 8, 2001
Ta ble 2. Syn th esis of In ter m ed ia tes 9 a n d P r od u cts 10
Katritzky et al.
9
10
entrya
R1
R2
yield (%)b
mp (°C)
methodc
yield (%)d
yield (%)e
gu
gv
gw
gx
gy
gz
d u
fu
EtO
EtO
EtO
EtO
EtO
EtO
Ph
71
60
80
63
59
75
63
65
112.5-112.8
113-115
104-106
78-79
78-81
93-94
oil
A
A
A
A
A
A
B
C
65
59
f
33
38
21
33
39
85
79
f
76
94
75
79
78
3-FC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
2-ClC6H4
Ph
CH2dCHCH2
n-C3H7
Ph
oil
a
b
The lettering system of 9 and 10 follows the pattern: 2g + 3u f 9gu f 10gu . Isolated yield based on 2. c Reaction conditions for
converting intermediates 9 into products 10; A: ZnBr2, dry CH2Cl2, reflux; B: ZnBr2, dry toluene, reflux; C: AlCl3, 1,2-dichloroethane,
reflux. Isolated yield based on 9. e GC yield. f Not obtained.
d
Sch em e 3
crude NMR spectra disclosed only single regioisomers
9gu -gz. Compounds 2d ,f where R1 is an alkyl group also
gave 9d u ,fu in reasonable yields. Though regioisomers
of 9d u ,fu were observed, they were easily separated from
9d u ,fu by column chromatography. The reaction of
benzoyl chloride and allyl chloride with the thiolate 7 was
not successful.
Cyclizations readily occurred for 9gu ,gv,gx-gz with
ZnBr2 in dry methylene chloride under reflux for 1 h to
provide 10gu ,gv,gx-gz (Table 2). The GC yields of the
crude products are high. Isolated yields after column
chromatography are moderate because of the instability
of the electron-rich pyrroles. For 9gw , which has a
4-methoxyphenyl group as R2, no desired product was
obtained, presumably because 10gw , if generated, de-
composes due to the low stability. The attempted cycliza-
tion of compound 9d u using anhydrous ZnBr2 in dry
methylene chloride or in 1,2-dichloroethane failed, prob-
ably because the allyl group is much less electron-
donating than the methoxy group. Nevertherless, 9d u
was successfully cyclized with anhydrous ZnBr2 in re-
fluxing dry toluene to give 10d u in good GC yield (79%).
Product 10fu decomposed in refluxing toluene, but, AlCl3
in refluxing 1,2-dichloroethane successfully cyclized 9fu
into the pyrrole 10fu .
In summary, the present work provides facile synthe-
ses of relatively unstable novel 2-aminothiophenes 6
without needing purification of the intermediates and of
2-methylthiopyrroles 10 both starting from easily acces-
sible 1-allylbenzotriazole (1), which complement known
literature methods. Although the proposed procedure is
sensitive to the substitution in the N-allylbenzotriazole
intermediates, the expected products are typically ob-
tained in about 50% overall yields under mild reaction
conditions.
a
For the significance of 9 and 10, see Table 2.
stituents in the 3-position. Electron-withdrawing (3v,x)
and electron-donating (3w ) groups in the aromatic ring
of aryl isothiocyanates were also scanned during the
preparation of products 6bv,d x,ew (Scheme 1). The
reactions were not greatly affected by the nature of a
substituent from the point of view of the total yields. The
low regioselectivities in the case of 6a u ,cu ,d x are be-
lieved to be caused by the substituent R1 group. As
expected, the final product 6ew is less stable than 6bv
and 6d x due to the presence of the more electron-rich
methoxy group. Since 3-alkoxythiophenes with primary
or secondary amino groups at the 2-position generally
show low stability,2 the aminothiophene obtained from
1-(2-ethoxyprop-2-enyl)benzotriazole (Scheme 2) was im-
mediately converted to the methylated analogue 6gu by
quantitative N-methylation with methyl iodide; the
product 6gu was isolated in 43% yield.
2. Syn t h esis of 1,3-Disu b st it u t ed -2-m et h ylt h io-
p yr r oles. During the cyclizations discussed above, the
corresponding pyrrole analogues, such as 8 (Scheme 3),
were not detected. However, 3-substituted-2-(methylthio)-
1-phenyl-1H-pyrroles 10 were obtained when anions 7
were S-methylated in situ, and the intermediate 2-sub-
stituted-3-butenimidothioates 9 were cyclized with Lewis
acids. During these cyclizations, no formation of quino-
lines 11 was observed.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e P r ep a r a tion of 1-(1-Alk yl-
p r op -2-en yl)-1H-ben zotr ia zoles 2a -f. A solution of n-BuLi
(1.47 M, 6.8 mL, 10.2 mmol) was added at -78 °C under argon
atmosphere to a prechilled solution of allylbenzotriazole (1)
(1.59 g, 10 mmol) in dry THF (50 mL). After 20 min, the
electrophile of choice (10.2 mmol) was added dropwise, and
the resulting mixture was allowed to react until complete
conversion of the starting material was achieved (TLC control).
Saturated solution of NH4Cl (40 mL) was added, and the
reaction was allowed to reach rt. The aqueous layer was
extracted by Et2O (3 × 30 mL), and the combined organic
layers were dried (Na2SO4), filtered, and concentrated under
reduced pressure. The crude reaction mixture was then
subjected to purification on flash column chromatography on
silica gel (pentane/Et2O:2/1) to give the desired 2 as pure
product.
Intermediates 9 were obtained in good yields and
purified (Table 2). The condensations between 2g and
3u -z gave 9gu -gz with very high regioselectivities. The

Synthesis of 3-Substituted-2-aminothiophenes
J . Org. Chem., Vol. 66, No. 8, 2001 2853
1-(1-Eth ylp r op -2-en yl)-1H-1,2,3-ben zotr ia zole (2a ): Col-
orless oil; H NMR δ 0.88 (t, J ) 7.4 Hz, 3H), 2.16-2.39 (m,
2H), 5.17-5.28 (m, 3H), 6.12-6.23 (m, 1H), 7.34 (t, J ) 7.1
Hz, 1H), 7.44 (t, J ) 8.0 Hz, 1H), 7.55 (d, J ) 8.3 Hz, 1H),
8.07 (d, J ) 8.3 Hz, 1H); 13C NMR δ 10.4, 26.7, 63.8, 109.9,
117.6, 119.8, 123.5, 126.7, 132.3, 135.5, 146.0. Anal. Calcd for
tography on silica gel (pentane/Et2O:10/1) to afford compounds
1
6 and 10 as pure products.
3-Eth yl-2-p h en yla m in oth iop h en e (6a u ): Yellow oil; H
1
NMR δ 1.13 (t, J ) 7.4 Hz, 3H), 2.46 (q, J ) 7.4 Hz, 2H), 5.10
(br s, 1H), 6.64 (d, J ) 8.2 Hz, 2H), 6.77 (t, J ) 7.4 Hz, 1H),
6.85 (d, J ) 5.5 Hz, 1H), 6.99 (d, J ) 5.8 Hz, 1H), 7.16 (t, J )
7.5 Hz, 2H); 13C NMR δ 14.5, 20.6, 113.6, 118.9, 120.8, 127.0,
129.1, 137.6, 139.0, 147.1. Anal. Calcd for C12H13NS: C, 70.89;
H, 6.44; N, 6.89. Found: C, 70.51; H, 6.58; N, 7.25.
C
11H13N3: C, 70.56; H, 7.00; N, 22.44. Found: C, 70.33; H,
7.26; N, 22.89.
1-(1-Hexylp r op -2-en yl)-1H-1,2,3-ben zotr ia zole (2c): Col-
1
orless oil; H NMR δ 0.82 (t, J ) 6.9 Hz, 3H), 1.11-1.30 (m,
3-[(2-C h lo r o p h e n y l)m e t h y l]-2-p h e n y la m in o t h io -
8H), 2.12-2.21 (m, 1H), 2.28-2.37 (m, 1H), 5.18 (d, J ) 17.1
Hz, 1H), 5.29 (d, J ) 16.9 Hz, 1H), 5.34-5.39 (m, 1H), 6.12-
6.23 (m, 1H), 7.34 (t, J ) 7.1 Hz, 1H), 7.44 (t, J ) 8.0 Hz, 1H),
7.56 (d, J ) 8.4 Hz, 1H), 8.06 (d, J ) 8.3 Hz, 1H); 13C NMR δ
13.7, 22.2, 25.7, 28.4, 31.2, 33.3, 62.2, 109.9, 117.4, 119.7, 123.5,
126.7, 132.2, 135.7, 146.0. Anal. Calcd for C15H21N3: H, 8.70;
N, 17.27. Found: H, 8.90; N, 16.98.
1
p h en e (6bu ): Colorless oil; H NMR δ 3.91 (s, 2H), 5.20 (s,
1H), 6.69-6.74 (m, 3H), 6.80 (t, J ) 7.1 Hz, 1H), 6.96 (d, J )
5.8 Hz, 1H), 7.10-7.20 (m, 5H), 7.30-7.32 (m, 1H); 13C NMR
δ 31.2, 114.0, 119.3, 120.7, 126.8, 127.6, 127.7, 129.2, 129.4,
130.5, 133.6, 133.9, 137.9, 139.5, 146.6. Anal. Calcd for C17H14
-
ClNS: C, 68.10; H, 4.71; N, 4.67. Found: C, 67.71; H, 4.64; N,
5.04.
Gen er a l P r oced u r e for th e P r ep a r a tion of Th ioa m id es
4 (Sch em e 1) a n d Bu ten im id oth ioa tes 9 (Sch em e 3). 1-(1-
Alkylprop-2-enyl)-1H-benzotriazoles 2a -g (4 mmol) were dis-
solved in dry THF (30 mL) under argon atmosphere. The
resulting solutions were cooled to - 78 °C before the addition
of a solution of n-BuLi in hexane (1.52 M, 2.6 mL, 4 mmol).
After 10 min, the isothiocyanate of choice (4.1 mmol) was
introduced. Then the mixtures were allowed to react for 30
min for compounds 4 before treatment with saturated aqueous
NH4Cl (30 mL). In the case of 9, after 30 min, methyl iodide
(3 equiv) was added, and the mixture was allowed to warm to
room temperature overnight before treatment with saturated
aqueous NH4Cl (30 mL). Once separated from the organic
layers, the aqueous layers were extracted with Et2O (3 × 20
mL). The combined organic layers were dried (Na2SO4),
filtered, and concentrated under reduced pressure. Compounds
4 admixed with isomers 5 were used in the next step without
purification. Compounds 9 were purified by pentane/Et2O (3/
1) on silica gel.
3-E t h oxy-2-(m et h ylt h io)-1-p h en yl-1H-p yr r ole (10gu ):
Colorless oil; 1H NMR δ 1.42 (t, J ) 6.9 Hz, 3H), 2.02 (s, 3H),
4.10 (q, J ) 7.1 Hz, 2H), 6.03 (d, J ) 3.3 Hz, 1H), 6.77 (d, J )
3.2 Hz, 1H), 7.31-7.45 (m, 5H); 13C NMR δ 15.1, 20.1, 66.6,
97.3, 107.6, 121.6, 126.0, 126.9, 128.6, 139.7, 151.3. Anal. Calcd
for C13H15NOS: C, 66.92; H, 6.48; N, 6.00. Found: C, 66.73;
H, 6.69; N, 6.35.
1-(4-Ch lor op h en yl)-3-et h oxy-2-(m et h ylt h io)-1H -p yr -
r ole (10gx): White microcrystals, mp 40.0-42.0 °C; 1H NMR
δ 1.42 (t, J ) 6.8 Hz, 3H), 2.02 (s, 3H), 4.10 (q, J ) 6.81 Hz,
2H), 6.04 (d, J ) 3.0 Hz, 1H), 6.75 (d, J ) 3.3 Hz, 1H), 7.31 (d,
J ) 8.7 Hz, 2H), 7.39 (d, J ) 8.7 Hz, 2H); 13C NMR δ 15.1,
20.2, 66.6, 97.8, 107.6, 121.6, 127.2, 128.8, 132.7, 138.2, 151.6.
Anal. Calcd for C13H14ClNOS: C, 58.31; H, 5.27; N, 5.23.
Found: C, 58.15; H, 5.35; N, 5.15.
3-Allyl-2-m eth ylth io-1-p h en yl-1H-p yr r ole (10d u ): Col-
orless oil; 1H NMR δ 1.95 (s, 3H), 3.43 (d, J ) 6.6 Hz, 2H),
5.01-5.02 (m, 1H), 5.09-5.16 (m, 1H), 5.95-6.09 (m, 1H), 6.19
(d, J ) 3.0 Hz, 1H), 6.92 (d, J ) 2.7 Hz, 1H), 7.34-7.47 (m,
5H); 13C NMR δ 20.6, 31.8, 109.4, 114.7, 120.8, 124.5, 126.4,
127.1, 128.6, 129.6, 138.1, 140.0. Anal. Calcd for C14H15NS:
C, 73.32; H, 6.59; N, 6.11. Found: C, 72.99; H, 6.68; N, 6.38.
P r ocedu r e for th e P r epar ation of N-(3-Eth oxyth ioph en -
2-yl)-N-su bstitu ted Am in es (6gu , Sch em e 2). Compound
6gu was first prepared similarly to the other derivatives 6 and
further methylated before purification as follows. The crude
product was dissolved in dry DMF (30 mL) under argon
atmosphere before the introduction of sodium hydride (60%
in mineral oil, 0.8 g, 20 mmol). The resulting solution was
allowed to react for 10 min, methyl iodide (1.25 mL, 20 mmol)
was added, and the mixture was stirred for 5 h at room
temperature. After addition of water (10 mL), the reaction was
extracted with Et2O (3 × 30 mL), and the combined organic
layers were dried (Na2SO4), filtered, and concentrated under
reduced pressure. The crude reaction mixture was purified by
flash column chromatography on silica gel (pentane/Et2O:20/
1) to afford compound 6gu as a pure product.
Meth yl 2-(1H-1,2,3-ben zotr ia zol-1-yl)-2-eth oxy-N-p h en -
yl-3-bu ten im id oth ioa te (9gu ): White microcrystals, mp
1
112.5-112.8 °C; H NMR δ 1.04 (t, J ) 6.6 Hz, 3H), 2.15 (br
s, 3H), 2.50-2.80 (m, 1H), 3.56-3.61 (m, 1H), 5.75 (d, J ) 10.7
Hz, 1H), 5.90 (d, J ) 17.5 Hz, 1H), 6.00-6.20 (m, 2H), 6.80-
7.00 (m, 3H), 7.14 (dd, J ) 11.0, 17.6 Hz, 1H), 7.38 (dd, J )
7.4, 7.4 Hz, 1H), 7.53 (dd, J ) 7.9, 7.9 Hz, 1H), 7.87 (d, J )
8.2 Hz, 1H), 8.01 (d, J ) 8.3 Hz, 1H); 13C NMR δ 14.6, 14.7,
59.3, 94.2, 111.8, 117.6, 119.6, 119.8, 123.0, 124.2, 127.6, 128.1,
132.0, 132.3, 146.2, 147.9, 163.1. Anal. Calcd for C19H20N4OS:
C, 64.75; H, 5.72; N, 15.90. Found: C, 64.42; H, 5.80; N, 15.87.
Met h yl
2-(1H -1,2,3-b en zot r ia zol-1-yl)-N-(4-ch lor o-
p h en yl)-2-eth oxy-3-bu ten im id oth ioa te (9gx): White mi-
1
crocrystals, mp 78.0-79.0 °C; H NMR δ 1.04 (t, J ) 6.8 Hz,
3H), 2.17 (s, 3H), 2.69 (br s, 1H), 3.51-3.65 (m, 1H), 5.76 (d,
J ) 11.7 Hz, 1H), 5.90 (d, J ) 17.4 Hz, 1H), 6.10 (br s, 2H),
6.94 (br s, 2H), 7.12 (dd, J ) 11.1, 17.4 Hz, 1H), 7.39 (t, J )
8.1 Hz, 1H), 7.53 (t, J ) 8.4 Hz, 1H), 7.85 (d, J ) 8.1 Hz, 1H),
8.04 (d, J ) 8.4 Hz, 1H); 13C NMR δ 14.5, 14.9, 59.3, 94.1,
111.6, 118.9, 119.9, 120.0, 124.2, 124.3, 127.7, 128.0, 131.9,
132.0, 146.2, 146.5, 165.4. Anal. Calcd for C19H19ClN4OS: C,
58.98; H, 4.95; N, 14.48. Found: C, 59.16; H, 5.09; N, 14.48.
Gen er a l P r oced u r e for th e P r ep a r a tion of Th iop h en es
6 (Sch em e 1) a n d P yr r oles 10 (Sch em e 3). The crude
reaction mixtures 4a u ,bu ,bv,cu ,d x,ew (2 mmol) or pure
compounds 9gu ,gv,gx,gy,gz (2 mmol) were dissolved in dry
CH2Cl2 (30 mL) under argon atmosphere, and anhydrous
ZnBr2 (1.2 g, 5 mmol) was added. Similarly, 9d u (2 mmol) or
9fu (2 mmol) was dissolved in dry toluene (30 mL) or
1,2-dichloroethane (30 mL) with ZnBr2 or AlCl3, respectively,
under reflux. The resulting solutions were allowed to react
under reflux for 24 h (for 4a u ,bu ,bv,cu ,d x, ew , 9d u ,fu ) or 1
h (for 9gu ,gv,gx-gz) until the complete conversion of the
starting material was observed (TLC control). After addition
of aqueous NaOH solution (2 M, 30 mL), the aqueous layers
were separated from the organic layers and extracted with
Et2O (2 × 20 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated under reduced pressure.
The crude mixtures were purified by flash column chroma-
3-Eth oxy-2-p h en yl(m eth yl)a m in oth iop h en e (6gu ): Col-
orless oil; 1H NMR δ 1.25 (t, J ) 7.1 Hz, 3H), 3.25 (s, 3H),
4.03 (q, J ) 7.1 Hz, 2H), 6.76-6.80 (m, 4H), 6.97 (d, J ) 6.0
Hz, 1H), 7.18-7.25 (m, 2H); 13C NMR δ 15.3, 40.4, 66.8, 113.6,
118.1, 118.3, 119.7, 128.8, 129.9, 149.1, 150.2. Anal. Calcd for
C
13H15NOS: C, 66.92; H, 6.48; N, 6.00. Found: C, 66.97; H,
6.65; N, 6.30.
Ack n ow led gm en t. We thank Dr. Christophe Chas-
saing and Dr. Sergey Denisenko for their help with this
work.
Su p p or tin g In for m a tion Ava ila ble: 1H, 13C NMR spec-
tra, and elemental analyses or HRMS for compounds 2b,d -f,
4a u , 9gv,gw ,gy,gz,d u ,fu , 6bv,cu ,d x,ew , and 10gv,gy,gz,fu .
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O001159X