Application of directed metallation in synthesis. Part 3: Studies in the synthesis of (±)-semivioxanthin and its analogues

Article abstract of DOI:10.1016/S0040-4020(02)01599-5

The synthesis of several analogues of (±)-semivioxanthin including five thiophene analogues, using directed metalation are reported. The strategy consisted of the synthesis of functionalized naphthalene or benzo[b]thiophene as building blocks followed by

Full text of DOI:10.1016/S0040-4020(02)01599-5

Tetrahedron 59 (2003) 1339–1348
Application of directed metallation in synthesis. Part 3: Studies in
the synthesis of (6)-semivioxanthin and its analoguesq
*
Sukanta Kamila, Chandrani Mukherjee, Sasanka S. Mondal and Asish De
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700-032, India
Received 10 May 2002; revised 8 November 2002; accepted 5 December 2002
Abstract—The synthesis of several analogues of (^)-semivioxanthin including five thiophene analogues, using directed metalation are
reported. The strategy consisted of the synthesis of functionalized naphthalene or benzo[b]thiophene as building blocks followed by
annelation of the pyrone. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Our aim was to develop a common strategy towards the
synthesis of racemic semivioxanthin and its analogues and
we intended to use for this purpose, the methodology of
heteroatom directed ortho-metallation8 commonly termed
‘directed metallation’. The use of directed metallation in
organic synthesis has been amply reviewed.8 One of the
many ramifications of this methodology is its usefulness in
the annelation of a ring on to an existing aromatic or
heteroaromtic core, of which there are many examples8–10
including those reported from this laboratory. While
designing the analogues, the principal structural features
of the natural product viz. the linear naphthopyrone
skeleton, oxygenated substituents in the aromatic rings
and the methyl substituent in the lactone ring were meant to
be preserved while allowing variations of the positions of
the oxygenated functionalities and replacement of each of
the benzene rings in turn with thiophene, following the
general principle of bioisosterism.11 A preliminary
account10 of our work was published earlier.
Semivioxanthin (1) is a naturally occurring linear naphtho-
pyrone with a stereogenic centre at C-3. Both of its
enantiomeric forms occur in nature and have antifungal
properties. (þ)-Semivioxanthin has 3-R configuration and
was isolated2 from the culture filtrate of Penicillium
citreoviride while the other isomer was isolated3 from
Cryptospirosis abietina and, in addition to being fungicidal,
is a defoliant3 and also possesses abscisic3 properties.
Although its biological activities make it an interesting
synthetic target, there are only a few reports on synthetic
studies on semivioxanthin and its analogues. Racemic
semivioxanthin was synthesized by Yamaguchi4 and
Deshpande5 using a polyketide approach and condensation
of a pyrone with a polysubstituted benzene, respectively.
More recently Deshpande6 obtained 35% yield of (2)-
semivioxanthin during the synthesis of (þ)-orthosporine.
Tatsuta and Nakata7 reported the conversion of one of the
products of intramolecular aldolisation of a polyketide
lactone to the linear naphthopyrone (2) related to semi-
vioxanthin.
2. Results and discussion
It was envisaged to synthesize suitably functionalized
naphthalene or benzo[b]thiophene as building blocks
followed by annelation of the pyrone ring through acid
mediated cyclization of an ortho-allyl tertiary benzamide.
This strategy was fairly successful in most of the cases,
except the two reported below. Thus our attempt to obtain
the natural product, as envisaged in Scheme 1, met with
limited success.
q For Part 2 see Ref. 1.
Commercially available dimethylresorcilic acid (3) was
converted into its diethylamide (4) followed by regio-
selective introduction of an allyl group ortho- to the amide
function by metallation-transmetallation,12,13 under care-
fully controlled conditions. Use of s-BuLi even slightly in
Keywords: semivioxanthin; naphthopyrone; benzothienopyrone; directed
metallation.
*
Corresponding author. Tel.: þ91-33-473-4971x246/253; fax: þ91-33-
473-2805; e-mail: ocad@mahendra.iacs.res.in
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01599-5

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S. Kamila et al. / Tetrahedron 59 (2003) 1339–1348
Scheme 1. Reagents: (i) SOCl2/benzene/reflux/N,N-diethylamine, (ii) s-BuLi (2.2 equiv.)/THF/CuBr–Me2S/2788C, (iii) Allyl bromide(2 equiv.), (iv) LDA
(1.5 equiv.)/THF/2788C or MeLi (2 equiv.)/THF/08C, (v) NaH/THF/ClCONEt2, (vi) s-BuLi/TMEDA/THF/2788C/ClCONEt2, (vii) 6N HCl/reflux.
excess of 2.2 equiv. led to a mixture containing the
undesired regioisomer 6. Cyclisation of 5 to 1-hydroxy-
6,8-dimethoxynaphthalene (7) with LDA or MeLi14 was
easily accomplished. Its conversion to the O-carbamate (7a)
by reacting with N,N-diethylcarbamyl chloride under
standard reaction conditions (K2CO3/acetone or NaH/
THF) was, however, disappointing. The extremely poor
yield of 7a (8%) made it unsuitable as an intermediate for
the three subsequent steps proposed in Scheme 1 and all our
attempts to increase the yield of 7a were unsuccessful.
Analogues 23 and 29 of semivioxanthin (Schemes 3 and 4),
were, however, successfully synthesized by the same type of
route. In both the cases the O-carbamate functions in the
naphthalenic intermediates are free from any steric
interaction with methoxy substituents in the peri-position.
In Scheme 3 the two hydroxy functions of 1,5-dihydroxy-
naphthalene 18 were sequentially converted to methoxy and
O-carbamate. The resulting compound 19 underwent
selective deprotonation ortho- to the O-carbamate function
under standard directed metallation conditions (s-BuLi/
TMEDA/THF/2788C). The deprotonated species under-
went anionic ortho-Fries rearrangement when left at room
temperature for 12 h and the resulting salicylamide was
subjected to O-methylation to afford 20. Alternatively the
deprotonated species could be quenched with N,N-diethyl-
carbamylchloride to afford 21. Attempts to introduce an
allyl function ortho- to the tertiary amide in 20 led to an
intractable mixture containing among others N,N-diethyl-1-
allyloxy-5-methoxy-2-carboxamide, presumably resulting
A similar problem was encountered during the synthesis of
the analogue 17 of semivioxanthin starting from guiacol
(11) (Scheme 2) because of the poor conversion of 15 to the
key intermediate 16 (10%). The O-carbamate 12 underwent
smooth anionic ortho-Fries rearrangement15 and subsequent
O-methylation, introduction of allyl function ortho- to the
amide group followed by cyclisation afforded 15 in
reasonable yield.
Scheme 2. Reagents: (i) NaH/THF/ClCONEt2/rt, (ii) s-BuLi/TMEDA/THF/2788C, (iii) K2CO3/MeI/acetone, (iv) s-BuLi/THF/CuBr–Me2S/2788C, (v) Allyl
bromide (2.5 equiv.), (vi) LDA (1.5 equiv.)/THF/2788C or MeLi (2 equiv.)/THF/08C.

S. Kamila et al. / Tetrahedron 59 (2003) 1339–1348
1341
Scheme 3. Reagents: (i) K2CO3 (1.2 equiv.)/MeI(1.1 equiv.)/acetone/reflux, (ii) NaH/THF/ClCONEt2/rt, (iii) s-BuLi/TMEDA/THF/2788C,
(iv) s-BuLi/TMEDA/THF/2788C/ClCONEt2, (v) s-BuLi/THF/CuBr–Me2S/2788C, (vi) Allyl bromide, (vii) 6N HCl/reflux/36 h.
from demethylation and subsequent O-allylation. An allyl
group was successfully introduced ortho- to the tertiary
amide function in 21 and the resulting compound 22 was
cyclized.16
salicylamide which was converted to the OMOM derivative
26 (R¼MOM). Introduction of allyl function ortho- to the
tertiary amide group in 26 (R¼MOM) was not possible
because of the hydrolysis of the OMOM function and
subsequent O-allylation. The deprotonated species
generated from 25 was quenched with N,N-diethyl-
carbamylchloride to afford 27 in 69% yield. Introduction
of allyl function ortho- to the tertiary amide group in 27
afforded 28 which was subsequently cyclized with hot HCl.
The O-carbamate function was hydrolysed during cycliza-
tion as in the previous case and the crude phenolic
compound was O-methylated to afford 29.
The drastic reaction conditions needed for cyclization16
(heating under reflux with 6N HCl for 36 h) resulted in the
hydrolysis of the O-carbamate and the somewhat labile
phenolic compound was O-methylated to afford 23 in 61%
yield.
The synthesis of 29 (Scheme 4) started from 6-methoxy-1-
tetralone (24) which was converted into the O-carbamate
25. Deprotonation ortho- to the O-carbamate function took
place under standard directed metallation conditions and
subsequent anionic ortho-Fries rearrangement generated the
The thiophene analogues 36, 42, 49, 50 and 55 of
semivioxanthin were also synthesized (Schemes 5–8) in
which the A and B rings of the natural product were
Scheme 4. Reagents: (i) Br2/CCl4, (ii) Li2CO3/LiBr/DMF/K,17 (iii) NaH/THF/ClCONEt2/rt, (iv) s-BuLi/THF/TMEDA/2788C, (v) NaH/THF/MOMCl,
(vi) s-BuLi/TMEDA/THF/ClCONEt2, (vii) s-BuLi/THF/CuBr–Me2S, (viii) Allyl bromide, (ix) 6N HCl/reflux/55 h, (x) K2CO3/MeI/acetone.

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S. Kamila et al. / Tetrahedron 59 (2003) 1339–1348
Scheme 5. Reagents: (i) NaH/THF/ClCONEt2, (ii) s-BuLi/TMEDA/THF/2788C, (iii) K2CO3/MeI/acetone, (iv) s-BuLi/TMEDA/THF/2788C/TBDMSCl,
(v) s-BuLi/THF/2788C/CuBr–Me2S, (vi) Allyl bromide, (vii) 6N HCl/reflux/55 h. (viii) K2CO3/MeI/acetone.
Scheme 6. Reagents: (i) NaH/THF/ClCONEt2/rt, (ii) s-BuLi(2.5 equiv.)/TMEDA/THF/2788C2rt, (iii) K2CO3 (1.2 equiv.)/Acetone/MeI, (iv) s-BuLi
(2.5 equiv.)/CuBr–Me2S/ Allyl bromide (3 equiv.)/THF, (v) 6N HCl/reflux/ 51 h.
Scheme 7. Reagents: (i) s-BuLi/TMEDA/THF/2788C/ClCONEt2, (ii) s-BuLi/THF/2788C/CuBr–Me2S, (iii) Allyl bromide, (iv) 6N HCl/reflux/56–60 h, (v)
K2CO3/MeI/acetone.

S. Kamila et al. / Tetrahedron 59 (2003) 1339–1348
1343
Scheme 8. Reagents: (i) SOCl2/benzene/diethylamine/reflux, (ii) K2CO3/acetone/MeI, (iii) s-BuLi/THF/2788C/ CuBr–Me2S/allyl bromide, (iv) 6N
HCl/reflux/39 h.
replaced in turn by thiophene. Readily available function-
alized benzo[b]thiophenes1 were used as starting materials
in these syntheses. In the analogues 36 and 42, ring A
comprised thiophene while in the analogues 49, 50 and 55
ring B comprised thiophene.
4. Experimental
4.1. General
Commercially available solvents were distilled prior to use.
Light petroleum ether (bp 60–808C) was used for column
chromatography. Anhydrous sodium sulfate was used as
drying agent. THF, n-hexane, cyclohexane were dried by
In the first step of the synthesis of 36 (Scheme 5),
4-hydroxybenzo[b]thiophene18 (30) was converted into its
O-carbamate (31). The latter was subjected to anionic ortho-
Fries rearrangement followed by O-methylation of the
resulting salicylamide. After silyl protection of the free
a-position of the thiophene ring,7 an allyl function was
introduced in the 6-position of 33 through usual sequences.
Demethylation with concomittant desilylation was observed
during cyclisation of 34 (hot 6N HCl, 55 h) and the slightly
labile phenolic cyclized product 35 was characterized as its
methyl ether 36.
the usual sodium-benzophenone-ketyl method. H and 13C
1
NMR spectra (300 MHz) were recorded in CDCl3 solution
on Bruker DPX-300 spectrometer. Chemical shifts (d) are
expressed in ppm using tetramethylsilane as internal
standard. Coupling constant (J) values are given in Hz.
Melting points (uncorrected) were recorded in open
capillaries on a hot stage apparatus. IR spectra were
recorded on a FTIR-8300, SHIMADZU spectrometer, for
solids in potassium bromide discs and for liquids by placing
a thin layer of the sample between two potassium bromide
discs. n-BuLi and s-BuLi were prepared in our laboratory by
reacting lithium dispersion with 1-chlorobutane in n-hexane
(in the case of n-BuLi) or 2-chlorobutane in cyclohexane (in
the case of s-BuLi). Molecularisation of lithium was done
either by heating the lithium in heavy paraffin liquid and
then vigorous stirring with a mechanical stirrer or under
sonication.
Compounds 42, 49, 50 and 55 were synthesized following
the same synthetic methodology (Schemes 6–8) starting
from 7-hydroxybenzo[b]thiophene1 (37), 4-methoxy-
benzo[b]thiophene (43),1,19 4,6-dimethoxybenzo[b]thio-
phene (44)1 and 5-hydroxybenzo[b]thiophene-2-carboxylic
acid (51),20 respectively. The tricyclic phenolic compound
42 obtained from the cyclization of 41 was notably stable in
contrast to similar compounds reported in this paper and did
not need conversion to its methyl ether for characterization.
The yield of compound 50 (49%) can be calculated from the
peak heights in the NMR spectrum [dH (300 MHz, CDCl3)
6.31 (1H, d, J¼2.07 Hz, C-8), 6.08 (1H, d, J¼2.07 Hz, C-6),
5.09–5.11 (1H, m, C-3), 3.68 (3H, s, –OMe), 3.64 (3H, s,
–OMe), 3.51–3.30 (2H, m, C-4), 1.42 (3H, d, J¼6.10 Hz,
–CH3). The IR spectrum showed carbonyl absorption at
1720 cm21]. However trace impurities present along with
this product which could not be separated thereby prevent-
ing the preparation of analytically pure sample.
4.1.1. N,N-Diethyl-2,4-dimethoxybenzamide (4). The acid
(3) (3.2 g, 0.0018 mmol), thionyl chloride (HAZARD)
(7.8 mL) and dry benzene (HAZARD) (100 mL) were
heated at reflux under stirring for 2 h. Solvent and excess
thionyl chloride were removed under vacuum and the crude
acid chloride (3.6 g, 0.0018 mmol) was dissolved in
benzene (40 mL). Diethylamine (5.6 mL, 0.0054 mmol) in
dry benzene (15 mL) was added to the reaction mixture at
08C, under magnetic stirring. After the addition was
complete, the reaction mixture was stirred for 2 h at 08C
and then 8 h at room temperature. After removal of benzene
under reduced pressure, the residue was extracted with
dichloromethane. The organic layer was thoroughly washed
with 5% sodium hydrogencarbonate, then with 5% HCl and
finally with water. Removal of solvent after drying the
organic layer afforded 4 which was purified by column
chromatography (ethyl acetate–light petroleum (1:9)).
Colorless viscous liquid (3.6 g, 87%); (Found: C, 65.84;
H, 8.15; N, 5.95. C13H19O3N requires C, 65.82; H, 8.01; N,
5.90%]; nmax (CHCl3) 1614 cm21; dH (300 MHz, CDCl3)
7.05 (1H, d, J¼8 Hz, C-6), 6.42 (1H, dd, J¼2.1, 8 Hz, C-5),
6.39 (1H, d, J¼2.1 Hz, C-3), 3.74 (3H, s, –OMe), 3.72 (3H,
s, –OMe), 3.48 (2H, q, J¼7.2 Hz, –CH2CH3), 3.10 (2H, q,
3. Conclusion
This work is another demonstration of the effectiveness of
the methodology of directed metallation as a synthetic tool,
which enabled us to synthesize a number of analogues of
semivioxanthin, designed through variation of its structure
permissible under the general principle of bioisosterism.
Work is currently in progress towards the synthesis of the
natural product and overcoming the difficulties in the
synthesis of analogues 10 and 17.

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S. Kamila et al. / Tetrahedron 59 (2003) 1339–1348
J¼7.2 Hz, –CH2CH3), 1.16 (3H, t, J¼6.9 Hz, –CH2CH3),
0.98 (3H, t, J¼6.9 Hz, –CH2CH3); dC (300 MHz, CDCl3)
167.7, 160.1, 155.4, 127.2, 118.6, 103.5, 97.4, 54.3, 54.2,
41.7, 37.8, 12.8, 11.7.
4.1.5. N,N-Diethyl-1-carbamyloxy-3-allyl-5-methoxy-
naphthalene-2-carboxamide (22). Purified by column
chromatography (ethyl acetate–light petroleum (2:3)).
Gummy liquid (85%); [Found: C, 69.68; H, 8.0; N, 6.8.
C24H32O4N2 requires C, 69.9; H, 7.76; N, 6.79%]; nmax
(CHCl3) 1708, 1629 cm21; dH (300 MHz, CDCl3) 8.01 (1H,
s, C-4), 7.36 (1H, dd, J¼8.4, 7.5 Hz, C-7), 7.28 (1H, d,
J¼8.4 Hz, C-8), 6.8 (1H, d, J¼7.5 Hz, C-6), 6.12–5.9 (1H,
m, –CH2–CHvCH2), 5.2–5.13 (2H, m, –CH2–
CHvCH2), 3.97 (3H, s, –OMe), 3.1–3.6 {10H, m,
4.1.2. N,N-Diethyl-5-methoxybenzo[b]thiophene-2-car-
boxamide (53). 5-Hydroxybenzo[b]thiophene-2-carboxa-
mide was prepared from 5-hydroxybenzo[b]thiophene-2-
carboxylic acid in the same way as 4. The hydroxy group of
the carboxamide (1.8 g, 0.000718 mmol) was methylated by
the usual procedure (K2CO3/acetone/MeI) to afford com-
pound 53 which was purified by column chromatography
(ethyl acetate–light petroleum (1:3)). Pale yellow gummy
liquid (1.7 g, 88%); (Found: C, 63.79; H, 6.26; N, 5.16.
C14H17O2NS requires C, 63.85; H, 6.51; N, 5.31%); nmax
(KBr) 1620 cm21; dH (300 MHz, CDCl3) 7.69 (1H, d,
J¼9 Hz, C-7), 7.41 (1H, s, C-3), 7.24 (1H, d, J¼2.4 Hz,
C-4), 7.04 (1H, dd, J¼2.4, 9 Hz, C-6), 3.87 (3H, s, –OMe),
3.56 (4H, q, J¼6 Hz, –CH2CH3), 1.27 (6H, t, J¼9 Hz,
–CH2CH3); dC (300 MHz, CDCl3) 164.2, 157.6, 139.7.
138.8, 132.4, 123.9, 122.8, 116.1, 106.0, 55.4, 42.0, 14.0.
–CH2–CHvCH2,
CH3)2}, 1.0–1.3 {12H, m,
–OCON(CH2CH3)2,
–CON(CH2-
–OCON(CH2CH3)2,
–CON(CH2CH3)2}; dC (300 MHz, CDCl3) 167.4, 155.5,
153.8, 143.5, 136.5, 133.8, 128.8, 128.0, 126.8, 126.7,
120.1, 117.2, 114.4, 105.0, 55.9, 43.2, 42.7, 42.5, 38.6, 37.7,
14.7, 13.9, 13.8, 13.1.
4.1.6. N,N-Diethyl-1-carbamyloxy-3-allyl-6-methoxy-
naphthalene-2-carboxamide (28). Purified by column
chromatography (ethyl acetate–light petroleum (3:7)).
Viscous liquid (73%); [Found: C, 69.87; H, 7.74; N, 6.76.
C24H32O4N2 requires C, 69.9; H, 7.76; N, 6.79%]; nmax
(CHCl3) 1721 cm21; dH (300 MHz, CDCl3) 7.60 (1H, d,
J¼9 Hz, C-8), 7.46 (1H, s, C-4), 7.11 (1H, dd, J¼2.4, 9 Hz,
C-7), 7.06 (1H, d, J¼2.4 Hz, C-5), 5.9–6.12 (1H, m,
–CH2–CHvCH2), 5.06–5.26 (2H, m, –CH2–CHvCH2),
3.89 (3H, s, –OMe), 3.1–3.6 {10H, m, –CH2–CHvCH2,
–OCON(CH2CH3)2, –CON(CH2CH3)2}, 1.01–1.32 {12H,
m, –OCON(CH2CH3)2, –CON(CH2CH3)2}; dC (300 MHz,
CDCl3) 167.4, 158.7, 153.8, 143.9, 136.4, 135.9, 135.3,
126.2, 124.7, 123.9, 122.3, 119.5, 117.3, 105.9, 55.7, 43.1,
42.7, 42.5, 38.6, 37.4, 14.7, 14.0, 13.8, 13.1.
4.1.3. N,N-Diethyl-2,4-dimethoxy-6-allylbenzamide (5).
s-BuLi (2.2 equiv., 4.6 mL) was slowly added by syringe to
a solution of the substrate (1 g, 0.000421 mmol) in dry THF
(10 mL) at 2788C followed by CuBr–Me2S (2 equiv.,
1.7 g) after 1 h. The temperature of the reaction mixture was
allowed to rise between 2108C to 2158C and kept at that
temperature for 30 min. After cooling the reaction mixture
to 2788C allylbromide (2 equiv., 0.73 mL) was added.
After 1 h at 2788C the reaction mixture was allowed to
attain room temperature and filtered through a pad of silica
gel which was washed with ethyl acetate. The organic layer
was washed with water and dried. Removal of solvent
afforded 5 which was purified by column chromatography
(ethyl acetate–light petroleum (1:4)). Colorless gummy
liquid (0.88 g, 76%); (Found: C, 69.38; H, 8.40; N, 5.01.
C16H23O3N requires C, 69.31; H, 8.30; N, 5.05%); nmax
(CHCl3) 1631 cm21; dH (300 MHz, CDCl3) 6.27 (1H, d,
J¼2.0 Hz, C-5), 6.22 (1H, d, J¼2 Hz, C-3), 5.76–5.85 (1H,
m, –CH2–CHvCH2), 4.92–5.01 (2H, m, –CH2–
CHvCH2), 3.67 (3H, –OMe), 3.65 (3H, s, –OMe), 2.96–
3.35 {6H, m, –CH2–CHvCH2, –CON(CH2CH3)2}, 1.12
{3H, t, J¼7.1 Hz, –CON(CH2CH3)2}, 0.91 {3H, t,
J¼7.1 Hz, –CON(CH2CH3)2}; dC (300 MHz, CDCl3)
167.9, 160.5, 156.4, 138.7, 136.2, 118.9, 116.2, 105.5,
96.1, 55.3, 55.1, 42.6, 38.3, 37.1, 13.6, 12.6. This
procedure is followed for the synthesis of all other allyl
compounds.
4.1.7. N,N-Diethyl-4-methoxy-6-allyl-2-tert-butyl-
dimethylsilyl[1]benzo[b]thiophene-5-carboxamide (34).
Purified by column chromatography (ethyl acetate–light
petroleum (2:3)). Gummy liquid (69%); [Found: C, 66.35;
H, 8.3; N, 3.17. C22H33O2NSSi requires C, 66.14; H, 8.44;
N, 3.35%]; nmax (KBr) 1624 cm21; dH (300 MHz, CDCl3)
7.52 (1H, s, C-3), 7.51 (1H, s, C-7), 5.93–6.02 (1H, m,
–CH2–CHvCH2), 5.09–5.16 (2H, m, –CH2–CHvCH2),
3.99 (3H, s, –OMe), 3.62 {2H, q, J¼7.2 Hz, –CON(CH2-
CH3)2}, 3.35–3.46 (2H, m, –CH2–CHvCH2), 3.14 {2H, q,
J¼7.2 Hz, –CON(CH2CH3)2}, 1.31 {3H, t, J¼7.2 Hz,
–CON(CH2CH3)2}, 1.04 {3H, t, J¼7.2 Hz, –CON(CH2-
CH3)2}, 0.97 {9H, s, –Si(CH3)2C(CH3)3}, 0.36 (6H, s,
–Si(CH3)2C(CH3)3}; dC (300 MHz, CDCl3) 167.8, 150.3–
114.0, 62.4, 43.2, 38.8, 37.1, 26.1, 13.6, 12.8, 25.2.
4.1.8. N,N-Diethyl-5-allyl-7-methoxy-2-trimethylsilyl-
benzo[b]thiophene-6-carboxamide (41). Purified by
column chromatography (ethyl acetate–light petroleum
(3:7)). Colorless viscous oil (72%); [Found: C, 64.10; H,
7.83; N, 3.9. C20H29O2NSSi requires C, 64.00; H, 7.73; N,
3.73%]; nmax (CHCl3) 1629 cm21. dH (300 MHz, CDCl3)
7.44 (1H, s, C-3), 7.41 (1H, s, C-4), 5.88–5.97 (1H, m,
–CH2–CHvCH2), 5.01–5.11 (2H, m, –CH2–CHvCH2),
4.04 (3H, s, –OMe), 3.25–3.46 {6H, m, –CH2–CHvCH2,
–CON(CH2CH3)2}, 1.03 {3H, t, J¼9 Hz, –CON(CH2-
CH3)2}, 1.29 {3H, t, J¼6 Hz, –CON(CH2CH3)2}, 0.38
{9H, s, –Si(CH3)2C(CH3)3}. dC (300 MHz, CDCl3) 150.3,
145.6, 139.0, 136.0, 134.2, 132.8, 127.8, 125.7, 117.8,
116.4, 62.4, 42.8, 39.1, 36.8, 16.6, 13.6, 12.5, 0.1.
4.1.4. N,N-Diethyl-2,3-dimethoxy-6-allylbenzamide (14).
Purified by column chromatography (ethyl acetate–light
petroleum (1:3)). Gummy liquid (72%). (Found: C, 69.30;
H, 8.26; N, 5.00. C16H23O3N requires C, 69.31; H, 8.30; N,
5.05%); nmax (CHCl3) 1632 cm21; dH (300 MHz, CDCl3)
6.93 (1H, d, J¼8.4 Hz, C-5), 6.84 (1H, d, J¼8.4 Hz, C-6),
5.89–5.92 (1H, m, –CH2–CHvCH2), 5.03–5.11 (2H, m,
–CH2–CHvCH2), 3.84 (3H, s, –OMe), 3.81 (3H, s,
–OMe), 3.07–3.77 {4H, m, –CON(CH2CH3)2}, 1.24 {3H,
t, J¼7.2 Hz, –CON(CH2CH3)2}, 1.06 {3H, t, J¼7.2 Hz,
–CON(CH2CH3)2}; dC (300 MHz, CDCl3) 167.4, 150.7,
144.4, 136.6, 131.9, 128.8, 124.8, 115.9, 112.1, 61.3, 55.6,
42.8, 38.4, 36.2, 13.6, 12.5.

S. Kamila et al. / Tetrahedron 59 (2003) 1339–1348
1345
4.1.9. N,N-Diethyl-3-allyl-4-methoxybenzo[b]thiophene-
2-carboxamide (47). Purified by column chromatography
(ethyl acetate–light petroleum (2:3)). Gummy liquid (81%);
[Found: C, 67.19; H, 6.67; N, 4.8. C17H21O2NS: C, 67.32;
H, 6.93; N, 4.62%]; nmax (CHCl3) 1623 cm21; dH
(300 MHz, CDCl3) 7.3 (1H, d, J¼8 Hz, C-7), 7.2 (1H, dd,
J¼8, 7.8 Hz, C-6), 6.69 (1H, d J¼7.8 Hz, C-5), 5.93–6.02
(1H, m, –CH2–CHvCH2), 4.85–4.97 (2H, m, –CH2–
CHvCH2), 3.84 (3H, s,–OMe), 3.23–3.71 {6H, m,
–CH2–CHvCH2, –CON(CH2CH3)2}, 1.01–1.21{6H, m,
–CON(CH2CH3)2}; dC (300 MHz, CDCl3) 164.5, 156.2,
140.5, 136.5, 132.6, 129.6, 127.7, 125.4, 114.3, 114.2,
104.5, 54.7, 33.3, 12.6.
CDCl3) 168.3, 152.6, 144.7, 132.4, 124.6, 118.7, 112.5,
61.4, 55.7, 42.9, 38.8, 13.9, 12.8.
4.1.13. N,N-Diethyl-1,5-dimethoxynaphthalene-2-car-
boxamide (20). Prepared in the same way as before.
Purified by column chromatography (ethyl acetate–light
petroleum (1:3)). Gummy liquid (35%); [Found: C, 70.86;
H, 7.31; N, 4.87. C17H21O3N requires C, 70.8; H, 7.3; N,
4.8%]; nmax (CHCl3) 1633 cm21; dH (300 MHz, CDCl3)
8.04 (d, 1H, J¼8.6 Hz, C-4), 7.72 (d, 1H, J¼8.2 Hz, C-8),
7.44 (1H, dd, J¼8.0, 8.2 Hz, C-7), 7.29 (1H, d, J¼8.6 Hz,
C-3), 6.86 (1H, d, J¼8.0 Hz, C-6), 4.07 (3H, s, –OMe), 3.9
(3H, s, –OMe), 3.43 {4H, q, J¼6.6 Hz, –CON(CH2CH3)2},
1.16 {6H, t, J¼7.14 Hz, –CON(CH2CH3)2}; dC (300 MHz,
CDCl3) 169.5, 156.0, 151.9, 129.3, 127.4, 126.9, 126.9,
124.2, 118.7, 114.9, 105.1, 63.1, 55.9, 43.4, 39.5, 14.4, 13.2.
4.1.10. N,N-Diethyl-3-allyl-4,6-dimethoxybenzo[b]thio-
phene-2-carboxamide (48). Purified by column chroma-
tography (ethyl acetate–light petroleum (3:7)). Yellowish
viscous liquid (75%); [Found: C, 64.9; H, 7.1; N, 4.6.
C18H23O3NS: C, 64.86; H, 6.9; N, 4.2%]; nmax (CHCl3)
1631 cm21; dH (300 MHz, CDCl3) 6.75 (1H, d, J¼1.9 Hz,
C-7), 6.32 (1H, d, J¼1.9 Hz, C-5), 5.88–6.0 (1H, m,
–CH2–CHvCH2), 4.84–4.96 (2H, m, –CH2–CHvCH2),
3.8 (3H, s, –OMe), 3.78 (3H, s, –OMe), 3.16–3.70 {6H, m,
–CH2–CHvCH2, –CON(CH2CH3)2}, 0.97–1.18 {6H, m,
–CON(CH2CH3)2}; dC (300 MHz, CDCl3) 171.1, 159.4,
157.5, 142.4, 137.5, 133.5, 131.2, 129.2, 115.1, 97.0, 96.6,
56.0, 55.7, 34.0, 30.1, 11.3.
4.1.14. N,N-Diethyl-1-methoxymethylene-6-methoxy-
naphthalene-2-carboxamide (26). Purified by column
chromatography (ethyl acetate–light petroleum (1:4)).
Colorless viscous liquid (78%); [Found: C, 68.41; H, 7.35;
N, 4.48. C18H23O4 requires C, 68.13; H, 7.25; N, 4.41%];
n
max (CHCl3) 1627 cm21; dH (300 MHz, CDCl3) 8.15 (1H,
d, J¼8.1 Hz, C-8), 7.53 (1H, d, J¼8.4 Hz, C-3), 7.29 (1H, d,
J¼8.4 Hz, C-4), 7.19 (1H, dd, J¼2.5, 9.1 Hz, C-7), 7.12
(1H, d, J¼2.5 Hz, C-5), 5.19 (2H, s, –OCH2OCH3), 3.92
(3H, s, –OCH2OCH3), 3.5 (3H, s, –OMe), 3.1–3.5 {4H, m,
–CON(CH2CH3)2}, 1.28 {3H, t, J¼7.2 Hz, –CON(CH2-
CH3)2}, 1.03 {3H, t, J¼7.2 Hz, –CON(CH2CH3)2}; dC
(300 MHz, CDCl3) 169.6, 158.9, 149.7, 136.7, 125.8, 125.0,
124.6, 124.0, 123.7, 119.6, 106.2, 101.0, 58.2, 55.7, 43.5,
39.5, 14.4, 13.3.
4.1.11. N,N-Diethyl-3-allyl-5-methoxybenzo[b]thio-
phene-2-carboxamide (54). Purified by column chroma-
tography (ethyl acetate–petroleum ether (3:7)). Gummy
liquid (69%); [Found: C, 67.35; H, 6.98; N, 4.79.
C17H21O2NS: C, 67.32; H, 6.93; N, 4.62%]; nmax (CHCl3)
1624 cm21; dH (300 MHz, CDCl3) 6.67 (1H, d, J¼9 Hz,
C-7), 7.19 (1H, d, J¼2.4 Hz, C-4), 7.03 (dd, 1H, J¼2.4,
9 Hz, C-6), 6.11–5.92 (1H, m, –CH2–CHvCH2), 4.81–
5.92 (2H, m, –CH2–CHvCH2), 3.87 (3H, s, –OMe),
3.49–3.62 {6H, m, –CH2–CHvCH2, –CON(CH2CH3)2},
4.1.15. N,N-Diethyl-4-methoxybenzo[b]thiophene-5-car-
boxamide (32). Purified by column chromatography (ethyl
acetate–light petroleum (1:3)). Colorless liquid (68%);
[Found: C, 63.65; H, 6.61; N, 5.45. C14H17O2NS requires C,
63.85; H, 6.51; N, 5.31%]; nmax (CHCl3) 1635 cm21; dH
(300 MHz, CDCl3) 7.78 (1H, d, J¼8.7 Hz, C-6), 7.46 (1H,
d, J¼5.4 Hz, C-3), 7.13 (1H, d, J¼5.4 Hz, C-2), 7.03 (1H, d,
J¼8.7 Hz, C-7), 3.88 (3H, s, –OMe), 3.45 {4H, q,
J¼7.8 Hz, –CON(CH2CH3)2}, 1.64 {6H, t, J¼6.9 Hz,
–CON(CH2CH3)2}; dC (300 MHz, CDCl3) 167.8, 150.4,
145.6, 139.0, 132.9, 127.9, 125.7, 117.9, 116.5, 62.4, 38.5,
36.8, 12.8, 12.1.
1.25 {6H, t, J¼6 Hz,
–CON(CH2CH3)2}; dC
(300 MHz, CDCl3) 164.7, 157.5, 139.7, 134.8, 133.1,
131.7, 131.2, 123.0, 116.3, 115.0, 105.1, 55.4, 42.2, 31.6,
13.1.
4.1.12. N,N-Diethyl-2,3-dimethoxybenzamide (13). To a
well stirred solution of TMEDA (4 mL, 1.5 equiv.) and THF
(50 mL), s-BuLi (13.45 mL, 1.5 equiv.) was added at
2788C. Stirring was continued for 40 min when an yellow
colour developed. Compound 12 (4 g, 0.00179 mmol) in
THF (10 mL) was then added to it at that temperature. The
reaction mixture was allowed to attain room temperature
and kept at that temperature for 16 h. Usual work up
afforded the hydroxy compound which was sufficiently pure
for the next step. This crude phenolic compound (3.34 g,
0.001497 mmol) was methylated using K2CO3 (2.5 g,
1.2 equiv.) and methyl iodide (4.7 mL, 5 equiv.). Purified
by column chromatography (ethyl acetate: petroleum ether
(3:17)). Pale yellow liquid (1.57 g, 45%); [Found: C, 65.80;
H, 8.18; N, 6.1. C13H19O3N requires C, 65.79; H, 8.07; N,
5.90%]; nmax (CHCl3) 1627 cm21; dH (300 MHz, CDCl3),
7.07 (1H, dd, J¼6, 9 Hz, C-5), 6.9 (1H, dd, J¼3, 9 Hz, C-6),
6.80 (1H, dd, J¼3, 6 Hz, C-4), 3.88 (3H, s, –OMe), 3.85
(3H, s, –OMe), 3.16 {4H, q, J¼6 Hz, –CON(CH2CH3)2},
1.14 {6H, t, J¼6 Hz, –CON(CH2CH3)2}; dC (300 MHz,
4.1.16. N,N-Diethyl-7-methoxy-2-trimethylsilylben-
zo[b]thiophene-6-carboxamide (40). Purified by column
chromatography (ethyl acetate–light petroleum (3:7)).
Colorless gummy liquid (68%); [Found: C, 61.00; H,
7.56; N, 4.19. C17H25O2NSSi requires C, 60.89; H, 7.46; N,
4.17%]; nmax (CHCl3) 1596 cm21; dH (300 MHz, CDCl3)
7.55 (1H, d, J¼8.1 Hz, C-5), 7.46 (1H, s, C-3), 7.19 (1H, d,
J¼8.1 Hz, C-4), 4.05 (3H, s, –OMe), 3.50 {4H, q, J¼6 Hz,
–CON(CH2CH3)2}, 1.15 {6H, t, J¼9 Hz, –CON(CH2-
CH3)2}, 0.39 (9H, s, –SiMe3); dC (300 MHz, CDCl3) 153.7,
146.6, 144.0, 142.7, 136.6, 131.5, 120.6, 117.1, 62.4, 42.9,
42.6, 14.8, 13.8, 0.1.
4.1.17. N,N-Diethyl-4-methoxy-2-tert-butyldimethylsilyl-
benzo[b]thiophene-5-carboxamide (33). Synthesized from
32 following the general procedure using tert-butyl-
dimethylsilylchloride (TBDMSCl) as electrophile. Purified

1346
S. Kamila et al. / Tetrahedron 59 (2003) 1339–1348
by column chromatography (ethyl acetate: light petroleum
(3:7)). Colorless viscous liquid (58%); [Found: C, 63.94; H,
8.04; N, 3.81. C20H31NO2Ssi requires C, 63.61; H, 8.28; N,
3.71%]; nmax (CHCl3) 1630 cm21; dH (300 MHz, CDCl3)
7.63 (1H, d, J¼8.4 Hz, C-6), 7.59 (1H, s, C-3), 7.18 (1H, d,
J¼8.4 Hz, C-7), 4.02 (3H, s, –OMe), 3.64 {2H, q,
J¼7.8 Hz, –CON(CH2CH3)2}, 3.16 {2H, q, J¼7.8 Hz,
–CON(CH2CH3)2}, 1.30 {3H, t, J¼6.9 Hz, –CON(CH2-
CH3)2}, 1.04 {3H, t, J¼6.9 Hz, –CON(CH2CH3)2}, 0.98
{9H, s, –Si(CH3)2C(CH3)3}, 0.37 {6H, s, –Si(CH3)2-
C(CH3)3}; dC (300 MHz, CDCl3) 167.7, 150.2, 145.3,
139.2, 132.9, 127.7, 125.5, 117.3, 115.5, 62.4, 38.4, 36.3,
12.7, 12.1, 25.2.
was converted to O-carbamate by usual procedure. Purifi-
cation of the reaction mixture by column chromatography
(ethyl acetate–petroleum ether (1:9)) afforded 19 as a
yellow solid (76%), mp 65–668C; [Found C, 70.41; H, 6.98;
N, 5.11. C16H19O3N requires C, 70.32; H, 6.95; N, 5.12%];
n
max (KBr) 1708 cm21; dH (300 MHz, CDCl3) 8.11 (1H, d,
J¼8.4 Hz, C-2), 7.37–7.50 (3H, m, C-3, C-4, C-7), 7.29
(1H, dd, J¼7.8, 1 Hz, C-8), 6.82 (1H, d, J¼7.2 Hz, C-6), 4.0
(3H, s, –OMe), 3.52 {4H, q, J¼9 Hz, –OCON(CH2CH3)2},
1.3 {6H, t, J¼6 Hz, –OCON(CH2CH3)2}; dC (300 MHz,
CDCl3) 155.9, 154.7, 147.6, 129.0, 127.3, 126.7, 125.1,
119.2, 113.9, 104.6, 55.9, 42.7, 42.4, 14.9, 13.8.
4.1.21. N,N-Diethyl-1-carbamyloxy-6-methoxynaphtha-
lene (25). Compound 25 was synthesized from com-
4.1.18. N,N-Diethyl-1-carbamyloxy-2-methoxybenzene
(12). Compound 11 (5 g, 0.004 mmol) was converted to
the corresponding O-carbamate by the usual procedure
using NaH (2.4 g, 1.5 equiv.), ClCONEt2 (5.06 mL,
1 equiv.). Purified by column chromatography (ethyl
acetate: light petroleum (1:9)); Gummy liquid (7.9 g,
88%); [Found: C, 64.32; H, 7.81; N, 4.94. C12H17O3N
requires C, 64.57; H, 7.62; N, 6.27 %]; nmax (CHCl3)
1686 cm21; dH (300 MHz, CDCl3) 7.06 (2H, dd, J¼1.4,
9.0 Hz, C-6, C-7), 6.87 (2H, dd, J¼1.4, 9 Hz, C-3, C-4),
3.72 (3H, s, –OMe), 3.36 {4H, q, –CON(CH2CH3)2}, 1.21
{6H, t, –CON(CH2CH3)2}; dC (300 MHz, CDCl3) 152.4,
150.1, 139.1, 124.4, 121.6, 118.8, 116.7, 54.0, 40.5, 40.3,
11.7.
mercially
available
6-methoxy-a-tetralone
(24).
Bromination (with CuBr) and dehydrobromination (with
Li2CO3/LiBr/DMF) afforded the 6-methoxy-1-hydroxy-
naphthalene as white solid (87%). The hydroxy compound
(4.16 g, 0.0024 mmol) was converted to O-carbamate by the
usual procedure as described earlier with NaH (1.43 g,
1.5 equiv.) and freshly distilled N,N-diethylcarbamyl-
chloride (4.35 mL, 1.2 equiv.) and THF as solvent. Crystal-
lisation with ether–petroleum ether afforded 25 as an
yellowish solid (5.9 g, 90%), mp 83–858C; [Found: C,
70.35; H, 6.79; N, 4.88. C16H19O3N requires C, 70.32; H,
6.95; N, 5.12%]; nmax (CHCl3) 1629 cm21; dH (300 MHz,
CDCl3) 7.81 (1H, d, J¼8.9 Hz, C-8), 7.58 (1H, d, J¼8.0 Hz,
C-4), 7.4 (1H, dd, J¼7.8, 8 Hz, C-3), 7.11–7.17 (3H, m,
C-2, C-5, C-7), 3.9 (3H, s, –OMe), 3.51 {4H, q, J¼9 Hz,
–OCON(CH2CH3)2}, 1.30 {6H, t, J¼6 Hz, –OCON(CH2-
CH3)2}; dC (300 MHz, CDCl3) 173.2, 160.1, 158.6, 137.6,
125.8, 124.8, 120.8, 118.1, 116.7, 108.8, 106.1, 55.7, 42.6,
13.8.
4.1.19. N,N-Diethyl-1-carbamyloxy-7,8-dimethoxy-
naphthalene (16). Prepared in the same way as 12. Purified
by column chromatography (ethyl acetate–light petroleum
(3:7)); Yellowish oil (10%); [Found: C, 67.0; H, 6.83; N,
4.41. C17H21O4N requires C, 67.32; H, 6.93; N, 4.62 %];
n
max (CHCl3) 1694 cm21; dH (200 MHz, CDCl3) 7.59 (2H,
d, J¼8.6 Hz, C-2, C-4), 7.52 (2H, dd, J¼7.5, 8.6 Hz, C-3,
C-5), 7.10 (1H, d, J¼7.5 Hz, C-6), 3.93 (3H, s, –OMe), 3.88
(3H, s, –OMe), 3.52 {4H, q, J¼6 Hz, –OCON(CH2CH3)2},
1.23 {6H, t, J¼9 Hz, –OCON(CH2CH3)2}; dC (300 MHz,
CDCl3) 154.8, 149.6, 146.3, 143.1, 131.8, 125.8, 124.4,
123.3, 120.4, 115.5, 61.1, 56.7, 42.2, 41.6, 13.9, 13.2.
4.1.22. N,N-Diethyl-4-carbamyloxybenzo[b]thiophene
(31). Prepared in the same way as 12. Purified by column
chromatography (ethyl acetate–light petroleum (1:9)).
Colorless viscous liquid (82%); [Found: C, 62.56; H, 6.37;
N, 5.72. C13H15O2NS requires C, 62.62; H, 6.06; N, 5.61%];
n
max (KBr) 1700 cm21; dH (300 MHz, CDCl3) 7.76 (1H, d,
J¼8.1 Hz, C-5), 7.38 (2H, dd, J¼2, 8 Hz, C-6, C-7), 7.24
(1H, d, J¼5.02, C-3), 7.07 (1H, d, J¼5.02, C-2), 3.66–3.2
{4H, m, –OCON(CH2CH3)2}, 1.54–1.10 {6H, m,
–OCON(CH2CH3)2}.
4.1.20. N,N-Diethyl-1-carbamyloxy-5-methoxynaphtha-
lene (19). Potassium carbonate (3.87 g, 1 equiv.) was added
to a solution of the compound 18 (4.5 g, 0.0028 mmol) in
dry acetone (20 mL). After stirring for 3 h the mixture was
cooled to 08C and methyl iodide (1.4 mL, 8 equiv.) in dry
acetone (10 mL) was added drop wise at that temperature.
After stirring for 2 h at 08C and 10 h at room temperature,
the mixture was filtered, the solvent was removed under
reduced pressure and the residue was poured into crushed
ice. After extraction with diethyl ether, the organic layer
was washed with water and removal of solvent afforded
compound 19 which was purified by column chromato-
graphy (ethyl acetate–light petroleum (3:7)). Low melting
white solid (1.71 g, 40%); [Found: C, 69.81; H, 7.02; N,
5.10. C16H19O3N requires C, 70.32; H, 6.95; N, 5.12%];
4.1.23. N,N-Diethyl-7-carbamyloxy-2-trimethylsilyl-
benzo[b]thiophene (38). Prepared in the same way as
compound 12. Purified by column chromatography (ethyl
acetate–light petroleum (1:3)), light yellow oil (79%);
[Found: C, 59.78; H, 7.06; N, 4.42. C16H23O2NSSi requires
C, 59.81; H, 7.16; N, 4.36%]; nmax (CHCl3) 1625 cm21; dH
(300 MHz, CDCl3) 7.53 (1H, d, J¼7.8 Hz, C-6), 7.36 (1H, s,
C-3), 7.24 (1H, dd, J¼7.8, 7.5 Hz, C-5), 7.08 (1H, d,
J¼7.5 Hz, C-4), 3.39 {4H, q, J¼7.8 Hz, –OCON(CH2-
CH3)2}, 1.20 {6H, t, J¼9 Hz, –OCON(CH2CH3)2}, 0.28
{9H, s, –Si(CH3)3}; dC (300 MHz, CDCl3) 153.7, 146.5,
143.9, 142.7, 136.6, 131.5, 125.5, 120.6, 117.1, 42.8, 42.5,
14.7, 13.8, 0.1.
n
max (KBr) 3360 cm21. dH (300 MHz, CDCl3) 7.84 (1H, d,
J¼8.1 Hz, C-4), 7.74 (1H, d, J¼8.0 Hz, C-8), 7.39 (1H, dd,
J¼7.8, 8.1 Hz, C-3), 7.29 (1H, dd, J¼7.8, 8 Hz, C-7), 6.82
(2H, d, J¼7.8 Hz, C-6, C-8), 4.0 (3H, s, –OMe); dC
(300 MHz, CDCl3) 155.0, 154.3, 147.5, 128.0, 127.3, 125.7,
125.5, 119.1, 113.4, 105.6, 56.9. The free hydroxy group
4.1.24. N,N-Diethyl-1-carbamyloxy-5-methoxynaphtha-
lene-2-carboxamide (21). To a well stirred solution of
TMEDA (1.1 mL, 1.5 equiv.), s-BuLi (3.92 mL, 2.5 equiv.)

S. Kamila et al. / Tetrahedron 59 (2003) 1339–1348
1347
in THF (10 mL) at 2788C compound 19 (1 g,
0.00044 mmol) was added. After stirring the reaction
mixture for 40 min at 2788C, freshly distilled N,N-
diethylcarbamylchloride (0.9 mL, 1.5 equiv.) was added
and stirring was continued at that temperature for 1 h. After
which it was allowed to attain room temperature and was
stirred for further 12 h at that temperature. Usual work up
with diethyl ether afforded compound 21 which was purified
by column chromatography with ethyl acetate: petroleum
ether (1:3) as eluant. Viscous liquid (62%); [Found: C,
67.84; H, 7.72; N, 7.48. C21H28O4N2 requires C, 67.74; H,
7.52; N, 7.52%]; nmax (CHCl3) 1732, 1714 cm21; dH
(500 MHz, CDCl3) 8.16 (1H, d, J¼8.5 Hz, C-4), 7.43 (2H,
d, J¼6 Hz, C-7, C-8), 7.3 (1H, d, J¼8.5 Hz, C-3), 6.84 (1H,
dd, J¼4.2, 4.5 Hz, C-6), 3.99 (3H, s, –OMe), 3.47 {8H, q,
J¼6 Hz, –OCON(CH2CH3)2, –CON(CH2CH3)2}, 1.21
{12H, t, J¼7.2 Hz, –OCON(CH2CH3)2 –CON(CH2-
CH3)2}; dC (300 MHz, CDCl3) 168.4, 155.8, 153.9, 143.7,
129.6, 128.2, 127.5, 127.0, 122.7, 120.3, 114.4, 105.1, 56.0,
43.2, 42.7, 42.7, 39.0, 14.8, 14.2, 13.8, 13.0. Compound 27,
45 and 46 were synthesized in the same way.
reflux for 36 h with 6N HCl. After cooling, saturated
solution of ammonium chloride was added and the reaction
mixture was extracted with dichloromethane. The organic
phase was washed with water, dried and the solvent
evaporated. The crude residue consisting of the labile
phenolic cyclization product was methylated with methyl
iodide in hot dry acetone in the presence of anhydrous
potassium carbonate. After filtering the reaction mixture,
the filtrate was washed with water, dried, the solvent
evaporated and the residue purified by column chromato-
graphy (ethyl acetate–light petroleum (2:3)). Low melting
white solid (61%); [Found: C, 70.71; H, 6.15. C16H16O4
requires C, 70.58; H, 5.88%]; nmax (KBr) 1714 cm21; dH
(300 MHz, CDCl3) 7.8 (1H, d, J¼8 Hz, C-9), 7.75 (1H, s,
C-5), 7.36 (1H, dd, J¼7.5, 8.1 Hz, C-8), 6.87 (1H, d,
J¼7.5 Hz, C-7), 4.59–4.65 (1H, m, C-3), 4.1 (3H, s,
–OMe), 4.0 (3H, s, –OMe), 3.04–3.07 (2H, m, C-4), 1.51
(3H, d, J¼4.5 Hz, –CH3); dC (300 MHz, CDCl3) 155.3,
134.9, 126.6, 116.4, 115.7, 115.5, 107.3, 107.0, 76.9, 63.7,
56.1, 37.0, 21.1.
4.1.29. 3,4-Dihydro-3-methyl-7,10-dimethoxy-1-oxo-1H-
naphtho[2,3-c]pyran (29). Purified by column chromato-
graphy (ethyl acetate–light petroleum (2:3)). Low melting
white solid (67%); [Found: C, 70.87; H, 5.98. C16H16O4
requires C, 70.58; H, 5.88%]; nmax (KBr) 1714 cm21; dH
(300 MHz, CDCl3) 8.2 (1H, d, J¼9.2 Hz, C-9), 7.26 (1H, s,
C-5), 7.16 (1H, dd, J¼2.5, 9 Hz, C-8), 7.03 (1H, d,
J¼2.5 Hz, C-6), 4.61–4.63 (1H, m, C-3), 4.1 (3H, s,
–OMe), 3.9 (3H, s, –OMe), 3.0 (2H, d, J¼6.6 Hz, C-4),
1.51 (3H, d, J¼6.33 Hz, –CH3); dC (300 MHz, CDCl3)
163.5, 160.9, 154.9, 138.9, 136.6, 126.4, 123.7, 120.1,
119.3, 105.6, 74.7, 63.7, 55.8, 36.9, 21.1.
4.1.25. N,N-Diethyl-1-carbamyloxy-6-methoxynaphtha-
lene-2-carboxamide (27). Purified by column chromato-
graphy (ethyl acetate–light p etroleum (1:3)). Gummy
liquid (69%); [Found: C, 67.78; H, 7.58; N, 7.59.
C21H28O4N2 requires C, 67.74; H, 7.52; N, 7.52%]; nmax
(CHCl3) 1629 cm21; dH (300 MHz, CDCl3) 7.77 (1H, d,
J¼9.1 Hz, C-8), 7.6 (1H, d, J¼8.4 Hz, C-3), 7.29 (1H, d,
J¼8.4 Hz, C-4), 7.18 (1H, dd, J¼2.5, 9.1 Hz, C-7), 7.12
(1H, d, J¼2.5 Hz, C-5), 3.89 (3H, s, –OMe), 3.45 {8H, q,
J¼6.9 Hz, –OCON(CH2CH3)2, –CON(CH2CH3)2}, 1.2
{12H, t, J¼7.1 Hz, –OCON(CH2CH3)2, –CON(CH2-
CH3)2}; dC (300 MHz, CDCl3) 168.4, 158.7, 153.9, 144.2,
136.3, 125.5, 124.8, 124.3, 124.0, 123.9, 120.1, 106.2, 55.7,
43.2, 42.7, 42.7, 39.0, 14.8, 14.2, 13.8, 13.0.
4.1.30. 3,4-Dihydro-3-methyl-9-methoxy-1-oxo-1H-
[1]benzothieno[5, 6-c]pyran (36). White crystals (ether–
light petroleum) (85%), mp 105–1068C; [Found: C, 63.05;
H, 4.95. C13H12O3S requires C, 62.86; H, 4.87%]; nmax
(KBr) 1707 cm21; dH (300 MHz, CDCl3) 7.56 (1H, d,
J¼5.4 Hz, C-8), 7.45 (1H, s, C-5), 7.39 (1H, d, J¼5.4 Hz,
C-7), 4.72–4.79 (1H, m, C-3), 4.1 (3H, s, –OMe), 3.02 (2H,
d, J¼5.7 Hz, C-4), 1.52 (3H, d, J¼6.3 Hz, –CH3); dC
(300 MHz, CDCl3) 158.9, 146.2, 136.4, 134.8, 126.9, 122.0,
116.3, 113.2, 96.5, 74.7, 63.3, 36.9, 21.0.
4.1.26. N,N-Diethyl-4-methoxybenzo[b]thiophene-2-car-
boxamide (45). Purified by column chromatography (ethyl
acetate–light petroleum (1:3)). Waxy solid (71%); [Found:
C, 64.0; H, 6.37; N, 5.16. C14H17O2NS requires C, 63.85; H,
6.51; N, 5.31%]; nmax (CHCl3) 1618 cm21; dH (300 MHz,
CDCl3) 7.65 (1H, s, C-3), 7.41 (1H, d, J¼8 Hz, C-7), 7.3
(1H, dd, J¼8, 8.6 Hz, C-6), 6.74 (1H, d, J¼8.6 Hz, C-5), 3.9
(3H, s, –OMe), 3.5 {4H, q, J¼7.08 Hz, –CON(CH2CH3)2},
1.2 {6H, t, J¼7.1 Hz, –CON(CH2CH3)2}; dC (300 MHz,
CDCl3) 164.6, 155.9, 142.0, 136.8, 130.0, 127.1, 121.3,
116.4, 114.9, 104.8, 55.8, 42.0, 14.2.
4.1.31. 3,4-Dihydro-3-methyl-5-methoxy-1-oxo-1H-
[1]benzothieno[2,3-c]pyran (49). White crystals (CCl4–
petroleum ether) (68%), mp 136–1408C; [Found: C, 63.1;
H, 5.1. C13H12O3S requires C, 62.9; H, 4.8%]; nmax (KBr)
1708 cm21; dH (300 MHz, CDCl3) 7.71 (1H, d, J¼8.7 Hz,
C-8), 7.14–7.08 (2H, m, C-6, C-7), 4.84–4.94 (1H, m, C-3),
3.9 (3H, s –OMe), 2.89–3.19 (2H, m, C-4), 1.63 (3H, d,
J¼6.24 Hz, –CH3); dC (300 MHz, CDCl3) 157.8, 142.4,
137.9, 136.0, 124.6, 119.2, 105.1, 76.9, 55.6, 30.5, 20.9.
4.1.27. N,N-Diethyl-4,6-dimethoxybenzo[b]thiophene-2-
carboxamide (46). Yellow crystals (ether–light petroleum)
(72%), mp 110–1118C; [Found: C, 61.52; H, 6.51; N, 4.81.
C15H19O3NS requires C, 61.43; H, 6.48; N, 4.77%]; nmax
(KBr) 1604 cm21; dH (300 MHz, CDCl3) 7.55 (1H, s, C-3),
6.86 (1H, d, J¼1.6 Hz, C-7), 6.38 (1H, d, J¼1.6 Hz, C-5),
3.9 (3H, s, –OMe), 3.86 (3H, s, –OMe), 3.57 {4H, q,
J¼7.08 Hz, –CON(CH2CH3)2}, 1.27 {6H, t, J¼7.08 Hz,
–CON(CH2CH3)2}; dC (300 MHz, CDCl3) 164.4, 160.3,
156.4, 143.3, 134.4, 124.7, 121.4, 96.5, 96.1, 56.1, 55.8,
42.7, 14.1.
4.1.32. 3,4-Dihydro-3-methyl-6-methoxy-1-oxo-1H-
[1]benzothieno[2,3-c]pyran (55). White crystals (62%)
(CCl4–petroleum ether), mp 128–1308C; [Found: C, 63.12;
H, 5.2. C13H12O3S requires C, 62.9; H, 4.8%]; nmax (KBr)
1701 cm21; dH (300 MHz, CDCl3) 7.78 (1H, d J¼8.7 Hz,
C-8), 7.19 (1H, d, J¼2.4 Hz, C-5), 7.15 (1H, dd, J¼2.4,
8.7 Hz, C-7), 4.87–4.94 (1H, m, C-3), 3.9 (3H, s, –OMe),
2.89–3.20 (2H, m, C-4), 1.6 (3H, d, J¼6.0 Hz, –CH3); dC
4.1.28. 3,4-Dihydro-3-methyl-6,10-dimethoxy-1-oxo-1H-
naphtho[2,3-c]pyran (23). Compound 22 was heated at

1348
S. Kamila et al. / Tetrahedron 59 (2003) 1339–1348
3. Yada, H.; Sate, H.; Toshima, H.; Dewra, M.; Ichihara, A.
Biosci. Biotechnol. Biochem. 2001, 65, 484.
4. Yamaguchi, M.; Hasabe, K.; Minami, T. Tetrahedron Lett.
1986, 27, 2401.
(300 MHz, CDCl3) 158.4, 142.4, 137.9, 136.0, 124.6, 119.2,
105.1, 76.9, 56.0, 30.8, 21.2.
4.1.33. 3,4-Dihydro-3-methyl-9-hydroxy-1-oxo-1H-
[1]benzothieno[6,5-c]pyran (42). White solid (63%)
(CCl4–light petroleum), mp 137–1388C; [Found: C,
61.42; H, 4.1. C12H10O3S requires C, 61.53; H, 4.27%];
5. Deshpande, V. H.; Khan, R. A.; Rai, B.; Ayyangar, N. R.
Synth. Commun. 1993, 23, 2337.
6. Deshpande, V. H.; Rai, B.; Khan, R. A. Tetrahedron 1996, 52,
7159.
n
max (KBr) 1710 cm21; dH (300 MHz, CDCl3) 11.92 (1H, s,
–OH), 7.6 (1H, d, J¼6 Hz, C-6), 7.34 (1H, d, J¼6 Hz, C-7),
7.17 (1H, s, C-5), 4.72–4.79 (1H, m, C-3), 3.02 (2H, d,
J¼9 Hz, C-4),1.59 (3H, d, J¼6.0 Hz, –CH3); dC (300 MHz,
CDCl3) 158.9, 146.2, 136.4, 134.8, 126.4, 122.0, 116.3,
113.2, 96.5, 7.7, 36.9, 21.0.
7. Tatsuta, K.; Kojima, N. M.; Chino, M.; Kawazoe, S.; Nakata,
M. Tetrahedron Lett. 1993, 34, 4961.
8. Snieckus, V. Chem. Rev. 1990, 90, 879.
9. Mondal, S. S.; Samanta, S. S.; Deb, C.; De, A. J. Chem. Soc.,
Perkin Trans. 1 1998, 2559.
10. Kamila, S.; Mukherjee, C.; De, A. Tetrahedron Lett. 2001, 42,
5955.
Acknowledgements
11. Canno, J. G.; 5th ed. Burger’s Medicinal Chemistry and Drug
Discovery, Wolff, M. E., Ed.; Wiley: New York, 1995; Vol. 1.
p 783.
Financial assistance from the Council of Scientific and
Industrial Research (New Delhi) (Project No.
01(1573)/99/EMR-11) which also provided a fellowship to
S. K (Project) and S. S. M. (JRF and SRF NET), is gratefully
acknowledged. Thanks are due to Dr Ganesh Pandey,
Deputy Director, National Chemical Laboratory, Pune for
the technique of preparing s-BuLi under the hot and humid
Indian climate and also for providing us initially with a
generous quantity of the reagent and to Dr V. S. Giri and Dr
R. Mukherjee for some of the NMR spectra.
12. Sibi, M. P.; Jalil Miah, M. A.; Snieckus, V. J. Org. Chem.
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