Facile preparation of benzo[4,5]thieno[2,3-b]pyridines and naphtho[b-4,5]thieno[2,3-b]pyridines via the reaction of Barton esters and benzynes

Article abstract of DOI:10.1021/jo016407j

Titled compounds were prepared in a one-pot synthesis by generating symmetrically substituted benzyne intermediates by the diazotization of anthranilic acids in the presence of Barton esters. Unsymmetrically substituted aryne either gave mixtures of regioisomers or failed. However, nitro and methyl derivatives of titled compounds could be obtained as single products using appropriately substituted Barton esters.

Full text of DOI:10.1021/jo016407j

J . Org. Chem. 2002, 67, 3409-3411
3409
F a cile P r ep a r a tion of Ben zo[4,5]th ien o[2,3-b]p yr id in es a n d
Na p h th o[b-4,5]th ien o[2,3-b]p yr id in es via th e Rea ction of Ba r ton
Ester s a n d Ben zyn es
U. Narasimha Rao and Ed Biehl*
Department of Chemistry, Southern Methodist University, Dallas, Texas 75275
ebiehl@mail.smu.edu
Received December 26, 2001
Titled compounds were prepared in a one-pot synthesis by generating symmetrically substituted
benzyne intermediates by the diazotization of anthranilic acids in the presence of Barton esters.
Unsymmetrically substituted aryne either gave mixtures of regioisomers or failed. However, nitro
and methyl derivatives of titled compounds could be obtained as single products using appropriately
substituted Barton esters.
Sch em e 1
The chemistry of 1,2-arynes is accepted today as an
important addition to synthetic design.1 These intermedi-
ates have been used as versatile precursors in a number
of synthetic reactions. The arynes are powerful electro-
philic intermediates, whose substituted derivatives can
undergo regioselective additions2 with a variety of nu-
cleophiles.3 These properties have been used in the
synthesis of a number of heterocycles and polynuclear
hydrocarbons with substitution patterns not easily ob-
tained from standard aromatic substitution methods.4
Additionally, the dienophilic nature of the arynes have
been exploited in [2 + 2] and [4 + 2] cycloaddition
reactions with enes and dienes.5
Although the nature of the singlet and triplet electronic
states of ortho-, meta-, and para-benzynes6 and their
reactivity in the gas phase7 have been investigated, very
little has been reported on the involvement of free
radicals in aryne reactions in solution. Two of these
studies indicated that aryne reacted with tertiary amines8
and diaryl sulfides9 to give nitrogen and sulfur ylides,
respectively, by the usual nucleophilic addition pathway.
However, chemical-induced dynamic nuclear polarization
was observed in these intermediates (using1H NMR
techniques), which indicated these initially formed aryne
adducts underwent a free-radical dissociation-recombina-
tion rearrangement via a radical-pair intermediate to the
observed products. Other studies have suggested that
benzyne reacts with highly strained polycyclics10 and
vinylcyclopropanes11 via diradical intermediates.
Recently, benzyne was found to undergo 1,4 addition
reactions with 2-pyridylcarboxylate-pyridones to give
1-(2-acylphenyl)-2-pyridones.5 These novel results sug-
gested that a study of reaction of the corresponding sulfur
derivatives, such as the O-acyl derivatives of thiohydrox-
amic esters (Barton esters)12 with arynes under similar
conditions might be worthy of study. Since Barton esters
are known to be photolabile precursor of carbon radicals,
it was of interest to see if radicals may be involved in
these reactions.
Anthranilic acid aryne precursors (1a -f) and Barton
esters (3a -d ) chosen for study are shown in Figure 1.
The reactions were run under subdued lighting in order
to moderate the decomposition of 3a -d . As shown in
Scheme 1, benzyne (2a ), generated from anthranilic acid
(1a ), and 3,4,5,6-tetraphenylbenzyne (2b ), generated
(1) For reviews see: Hoffman, R. W. In Dehydrobenzene and
Cycloalkynes; Academic: New York, 1967. Biehl, E. R.; Khanapure,
S. P. Acc. Chem. Res. 1989, 22, 275. Reinecke, M. G. Tetrahedron 1982,
38, 427.
(2) Roberts, J . D.; Vaughan, C. W.; Carlsmith, L. A.; Semenow, D.
A. J . Am. Chem. Soc. 1956, 78, 611.
(3) Roberts, J . D.; Semenow, D. A.; Simmons, H. E.; Carlsmith, L.
A. J . Am. Chem. Soc. 1956, 58, 601.
(4) Biehl, E. R. In Advances in Nitrogen Heterocycles; Moody, C. J .,
Ed.; J AI Press Inc: New York, 2000; Vol. 4, pp 251-293. Escudero,
S.; Dolores, P.; Guitan, P.; Castedo, L. Tetrahedron Lett. 1997, 38, 5375
and references therein.
(5) See: Rayabarapu, D.; Majumdar K. K.; Sambaiah, T.; Cheng C.-
H. J . Org. Chem. 2001, 66, 3646 and references therein.
(6) See: Clark, A. E.; Davidson, E. R. J . Am. Chem. Soc. 2001, 123,
10691 and references therein.
(7) For example, see: Guo, Y.; Grabowski, J . J . J . Am. Chem. Soc.
1991, 113, 5923.
(8) Lepley, A. R.; Becker, R. H.; Guimanini, A. G. J . Org. Chem.
1971, 36, 1222.
(9) Iwamura, H.; Iwamura, M.; Nishida, T.; Yoshida, M.; Najayama,
J . Tetrahedron Lett. 1971, 1, 63.
(10) Gassman, P. C.; Richmond, G. D. J . Am. Chem. Soc. 1970, 92,
2090.
(11) Usieli, V.; Sarel, S. J . Org. Chem. 1973, 38, 1703..
(12) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Chem. Commun.
1983, 939. Barton, D. H. R.; Blundell, P.; J aszberenyi, J . C. Tetrahe-
dron 1992, 48, 7121
10.1021/jo016407j CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/17/2002

3410 J . Org. Chem., Vol. 67, No. 10, 2002
Rao and Biehl
F igu r e 1.
Ta ble 1. Yield s of Com p ou n d s 4a -l
the known nucleophilicity of sulfur, it is possible that
Barton esters would react with benzyne, perhaps by SET.
to give a radical intermediate. CIDNIP results from a
previous sulfur/aryne study9 are consistent with such an
intermediate. Barton esters are used to provide a radical
source by the regeneration of the pyridine ring in the
special version of the J ulia synthesis.13 We are carrying
out studies on elucidating the mechanism of this reaction.
Irrespective of the mechanism, this arynic reaction
provides a convenient method for preparing sulfur- and
nitrogen-containing tricylic and tetracyclic heterocycles,
which competes well with the two most commonly used
multistep syntheses.14,15 Although compounds such as 4
are rare, they have been found to be annulated NADH
models with very good activity under mild laboratory
conditions.16 Furthermore, they are of pharmaceutical
interest due to their isosterism with indolopyridines.17
R1
R2
R3
R4
R5
R6
yield,%
a
b
c
d
e
f
g
h
i
H
H
H
H
Ph
Ph
Ph
Ph
H
H
H
H
H
H
52
55
52
56
23
27
21
18
49
48
51
51
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
H
Me
H
H
H
Me
H
4
H
Me
H
H
H
Me
NO2
H
Ph
Ph
Ph
Ph
CHdCH
CHdCH
CHdCH
CHdCH
Ph
Ph
Ph
Ph
CHdCH
CHdCH
CHdCH
CHdCH
H
Me
NO2
H
H
Me
NO2
j
k
l
H
H
H
H
H
H
from 3,4,5,6-tetraphenyl derivative 1b, were found to
react with Barton esters (3a -d ) to give benzo- (4a -d )
and 5,6,7,8,-tetraphenybenzol[4,5]thieno[2,3-b]pyridines
(4e-h ), respectively.
The low yields (shown in Table 1) of 4e-h (21-32%)
probably reflect steric effects and the low solubility of 1b
in methylene chloride solvent. In addition, 2,3-naph-
thalyne (2c), generated from 3-amino 2-naphtholic acid
(1c), was found to react with esters 3a -d to provide
naphtho[b-4,5]thieno[2,3-b]pyridines (4i-l) in modest
yields. The unsymmetrical 3-methylbenzyne (2d ), gener-
ated from 3-methylanthranilic acid (1d ), reacted with the
unsubstituted Barton ester 3a nonregioselectively to yield
a 1:1 mixture of 5- and 8-methylbenzo[4,5]thieno[2,3-b]-
pyridine that resisted separation by usual chromato-
graphic techniques. Similar treatment of 3-methoxy- (1e)
and 4,5-dimethoxyantranilic acids (1f) with ester 3a gave
complex mixture of unidentifiable compounds. The im-
portance of steric effects in these reactions was further
demonstrated by the fact that replacement of the N-
acetate group with N-pivaloate in the Barton ester
resulted in depressed yields (∼20%).
Exp er im en ta l Section
Gen er a l Da ta . Melting points are uncorrected with respect
to stem correction. IR spectra were recorded on a FTIR
1
spectrometer, and the H and 13C NMR spectra were recorded
on a 400-MHz multinuclear NMR spectrometer; chemical
shifts were referenced to TMS as internal standard.. Elemental
analyses were obtained from SMU Analytical Services Labo-
ratories. With the exception of 5,6,7,8-tetraphenylanthranilic
acid (1b), the anthranilic acids (1a ,c, and d ) were obtained
from commercial sources. Compounds 1b18 and Barton esters
3a -d 13 were prepared by literature procedures. Barton esters
were stored in an ambered bottle in a refrigerator, and
glassware was heated at 125 °C in an oven overnight prior to
use. All benzyne reactions were done under an atmosphere of
dry O2-free N2 via balloon.
Gen er a l Syn t h esis of Com p ou n d s 4a -l. All reactions
were carried out under subdued lighting. A solution of an-
thranilic acid (1, 1.0 mmol) dissolved in 5 mL of acetone was
added dropwise over 45-60 min to a refluxing mixture
containing Barton ester (3, 1.0 mmol) and isoamylnitrite (3.0
mmol) in 10 mL of dichloromethane. The resulting solution
was refluxed for an additional 3 h. Then, the solution was
cooled to room temperature, and the solvent was evaporated
to give crude product mixture. The mixture was purified by
silica gel chromatography with a mixture of 5% ethyl acetate
The structures of 4b-l were ascertained by 1H and 13C
NMR spectroscopy, as well as MS and elemental analy-
ses. The structures of 4i and 4f were further confirmed
by single-crystal X-ray crystallography. The X-ray data
reveal that the 4-methyl group in the tetraphenyl deriva-
tive 4f is located across from the cavity of the 5-phenyl
ring, which is perpendicular to the benzo ring. Conse-
quently, the proton chemical shift of the 4-methyl group
in 4f occurs at a chemical shift (δ ) 1.51 ppm) lower than
that (δ ) 2.98 ppm) of the 4-methyl group in 4b. Similar
differences in chemical shifts of the 4-H in in the 3-methyl
derivatives 4g (δ ) 6.49 ppm) and 4c (δ ) 8.18 ppm) are
also observed.
(13) Barton, D. H. R.; Tachdjian, C. Tetrahedron 1992, 48, 7109.
(14) Monnet, M. O.; Fauret, O.; Levacher, V.; Dupas, G.; Bourgui-
gnon, J .; Qu’eguiner, G. Tetrahedron 1992, 48, 831.
(15) Degl’Innocenti, A. D.; Funicello, M.; Scafoto, P.; Spagnolo, P.;
Zanirato, P. J . Chem. Soc., Perkin Trans. 1 1996, 2561.
(16) Levacher, V.; Boussad, N.; Dupas, G.; Bourguignon, J .;
Qu’eguiner, G. Heterocycl. Chem. 1989, 26, 1029.
(17) Roques, B. P.; Prange, T.; Oberlin, R. Org. Magn. Reson. 1977,
9, 185.
(18) Qiao, X.; Padula, M. A.; Ho, D. M.; Vogelaar, N. J .; Schutt, C.
E.; Pascal, R. J . Am. Chem. Soc. 1996, 118, 741.
There is insufficient data upon which to propose a
mechanism for this reaction. However, on the basis of

Benzo[4,5]- and Naphtho[b-4,5]thieno[2,3-b]pyridines
J . Org. Chem., Vol. 67, No. 10, 2002 3411
in hexane as eluent to give the desired product (4). The
physical properties of 4 are given below.
3-Nitr o-5,6,7,8-tetr a p h en ylben zo[4,5]th ien o[2,3-b]p yr i-
d in e (4h ). Colorless solid, mp 260-263 °C; Rf ) 0.35 (hexane/
ethyl acetate ) 9:1). 1H NMR (DMSO-d6): δ 6.70-7.35 (m, 17
H), 7.48 (d, J ) 8.80 Hz, 1 H), 7.58 (d, J ) 8.80 Hz, 1 H), 7.75
(d, J ) 8.80 Hz, 1 H), 8.16 (dd, J ) 9.00, 2.6 Hz, 1 H). 9.20 (d,
J ) 2.4 Hz, 1 H). 13C NMR (DMSO-d6): δ 122.71, 124.61,
125.96, 127.17, 128.18, 128.31, 129.45, 130.12, 131.46, 131.70,
133.78, 135.71, 143.10, 145.00, 168.22. Anal. Calcd for
C35H22N2O2S: C, 78.63; H, 4.15; N, 5.24. Found: C, 78.70; H,
4.2-; N, 5.30.
Naph th o[b-4,5]th ien o[2,3-b]pyr idin e (4i). Colorless solid,
mp 190-191 °C; Rf ) 0.26 (hexane/ethyl acetate ) 9:1). 1H
NMR (CDCl3): δ 7.39 (d,d, J ) 7.8, 4.7 Hz, 1 H), 7.54 (m, 2
H), 7.93 (d, J ) 7.1 Hz, 1 H), 8.01 (d, J ) 7.6 Hz, 1 H), 8.28 (s,
1 H), 8.42 (dd, J ) 7.9, 1.7 Hz, 1 H), 8.56 (s, 1 H), 8.64 (dd, J
) 4.7, 1.5 Hz, 1 H). 13C NMR (CDCl3): δ 199.53, 120.88, 121.07,
125.49, 126.48, 127.13, 128.32, 128.95, 129.29, 130.86, 132.56,
132.85, 135.75, 148.95, 162.89. MS(EI) m/z 235 (M+ 100), 117
(5), 104 (4). Anal. Calcd for C15H9NS (235.305): C, 76.56; H,
3.86; N, 5.95. Found: C, 76.60; H, 3.98; N, 5.88.
Ben zo[4,5]th ien o[2,3-b]p yr id in e (4a ). Colorless solid, mp
75-76 °C (lit.15 73-74 °C).
4-Meth ylben zo[4,5]th ien o[2,3-b]p yr id in e (4b). Light tan
solid, mp 75-77 °C; Rf ) 0.21 (hexane/ethyl acetate ) 9:1).
1
IR (KBr): 3054, 2955, 1571, 1552, 1440, 738, 572 cm-1
.
H
NMR (CDCl3): δ 2.79 (s, 3 H), 7.08 (d, J ) 4.8 Hz, 1 H), 7.42-
7.45 (m, 2 H), 7.82 (d, J ) 9.2 Hz, 1 H), 8.16 (d, 9.2 Hz, 1 H),
8.42 (d, J ) 4.8 Hz, 1 H). 13C NMR (CDCl3): δ 21.6, 121.0,
122.9, 124.6, 125.2, 126.6, 128.0, 133.8, 137.9, 143.3, 147.4.
Anal. Calcd for C12H29NS (199.05): C, 72.33; H, 4.55; N, 7.03.
Found: C, 72.31; H, 4.63; N, 7.10. MS(EI): m/z 199 (M+, 100),
171 (10), 154 (5).
3-Meth ylben zo[4,5]th ien o[2,3-b]p yr id in e (4c). Viscous
liquid; Rf ) 0.18 (hexane/ethyl acetate ) 19:1). 1H NMR
(CDCl3): δ 2.54 (s, 3 H), 7.48-7.51 (m, 2 H), 7.87 (d, J ) 7.19,
1 H), 8.10 (d, J ) 6.8 Hz, 1 H), 8.18 (s, 1 H), 8.49 (s, 1 H). 13C
NMR (CDCl3): 18.4, 121.9, 123.01, 124.6, 127.3, 129.0, 129.1,
132.6, 138.4, 149.3, 159.0. MS(EI): m/z 199 (M+, 100), 171-
(10), 127 (5). Anal. Calcd for C12H9NS (199.05): C, 72.33; H,
4.55; N, 7.03. Found: C, 72.38; H, 4.60; N, 7.02.
3-Nitr oben zo[4,5]th ien o[2,3-b]p yr id in e (4d ). Colorless
solid, mp 210-211 °C; Rf ) 0.46 (hexane/ethyl acetate ) 9:1).
IR (KBr): 3068, 1580, 1571, 1512, 1338, 892, 771, 645, 586.
1H NMR (CDCl3):: δ 7.59-7.67 (m, 2 H), 7.95 (d,d J ) 6.4 Hz,
1.2 Hz, 1 H), 8.25 (d,d J ) 7.2, 2.0 Hz, 1 H), 9.14 (d, J ) 2.4
Hz, 1 H), 9.48 (d, J ) 2.4 Hz, 1 H). 13C NMR (CDCl3): 121.8,
122.2, 123.1, 124.13, 126.4, 127.2, 129.9, 136.4, 140.1, 141.3,
164.6. Anal. Calcd for C11H6N2O2S (230.24): C, 57.38; H,
2.62: N, 12.17. Found: C, 57.45; H, 2.66; N, 12.22.
4-Meth yln a p h th o[b-4,5]th ien o[2,3-b]p yr id in e (4j). Col-
orless solid, mp 163-165 °C; Rf ) 0.58 (hexane/ethyl acetate
) 4:1). IR (KBr): 3052, 2921, 1595, 1551, 1425, 1370. 1199.
1
875, 740, 474 cm-1. H NMR (CDCl3): δ 2.98 (s, 3 H), 7.16 (d,
J ) 4.9 Hz, 1 H), 7.50-7.55 (m, 2 H), 7.90 (d, J ) 7.84 Hz, 1
H), 8.01 (d, J ) 7.8 Hz, 1 H), 8.29 (s, 1 H), 8.47 (d, J ) 4.8 Hz,
1 H), 8.69 (s, 1 H). 13C NMR (CDCl3): δ 21.9, 120.9, 122.3,
124.7. 125.3, 126.6, 126.8, 128.7. 130.9, 132.0, 133.5, 135.8.
143.7, 148.0, 162.9. MS m/z 249 (M+, 100), 221 (10), 124 (15).
Anal. Calcd for C16H11NS (249.33): C, 77.07; H, 4.45; N, 5.62.
Found: C, 77.10; H, 4.44; N, 5.62.
5,6,7,8-Tetr aph en ylben zo[4,5]th ien o[2,3-b]pyr idin e (4e).
Colorless solid, mp 330-332 °C; Rf ) 0.36 (hexane/ethyl
acetate ) 9:1). IR (KBr): 3056. 1600, 1552, 1497, 1384, 698,
3-Meth yln a p h th o[b-4,5]th ien o[2,3-b]p yr id in e (4k ). Col-
orless solid, mp 145-147 °C; Rf ) 0.36 (hexane/ethyl acetate
) 19:1). 1H NMR (CDCl3): δ 2.53 (s, 3 H), 7.50-7.57 (m, 2 H),
7.91 (d, J ) 5.3 Hz, 1 H), 8.0 (d, J ) 7.4 Hz, 1 H), 8.21 (d, J )
1.0 Hz, 1 H), 8.25 (s, 1 H), 8.48 (d, J ) 1.1 Hz, 1 H), 8.52 (s, 1
H). 13C NMR (CDCl3): δ 18.5, 120.8, 121.1, 125.5, 126.5, 127.2,
128.4, 129.2, 129.3, 129.7, 130.9, 132.6, 132.9, 136.3, 149.5,
159.7. MS(EI) m/z 249 (M+, 100), 221 (5), 124 (7), 110 (5). Anal.
Calcd for C16H11NS (249.33): C, 77.07; H, 4.45; N, 5.62.
Found: C, 77.02; H, 4.40; N, 5.69.
3-Nitr on a p h th o[b-4,5]th ien o[2,3-b]p yr id in e (4l). Rf )
0.35 (hexane/ethyl acetate 9:1). 1H NMR (CDCl3): δ 7.50-7.70
(m, 2 H), 7.96 (d, J ) 6.7 Hz, 1 H), 8.10 (d, J ) 7.6 Hz, 1 H),
8.35 (s, 1 H), 8.71 (s, 1 H), 9.18 (d, J ) 1.6 Hz, 1 H), 9.45 (d,
J ) 1.12 Hz, 1 H). 13C NMR (DMSO-d6): δ 122.71, 124.61,
125.96, 127.17, 128.18, 128.31, 129.45, 130.12, 131.46, 131.70,
133.78, 135.71, 143.10, 145.00, 168.22. Anal. Calcd for
1
569, 417 cm-1. H NMR (CDCl3): δ 6.76 (dd, J ) 8.3, 1.5 Hz,
1 H), 6.86-6.91 (m, 10 H), 6.95-6.98 (dd, J ) 4.6, 1.5.Hz, 1
H), 7.24-7.36 (m, 10 H), 8.49 (dd, J ) 4.60, 1.51. 1 H). 13C
NMR (DMSO-d6): δ 119.80, 126.26, 126.44, 127.22, 127.37,
128.09, 128.83, 129.19, 130.27, 130.26, 130.41, 130.49, 131.62,
131.78, 132.32, 135.80, 138.35, 138.77, 139.69, 139.74, 139.86,
140.14, 140.19, 148.29, 162.49. Anal. Calcd for C35H23NS
(489.16): C, 85.86; H, 4.73; N, 2.86. Found: C, 85.93; H, 4.78;
N, 2.93.
4-Meth yl-5,6,7,8-tetr a p h en ylben zo[4,5]th ien o[2,3-b]p y-
r id in e (4f). Colorless solid, mp 290-292 °C; Rf ) hexane/ethyl
acetate ) 9:1). 1H NMR (CDCl3): δ 1.46 (s, 3 H), 6.73-6.85
(m, 2 H), 6.83-6.85 (m, 2 H), 6.87-6.92 (m, 7 H), 7.05-7.07
(m, 2 H), 7.12-7.14 (m, 3 H), 7.25-7.31 (m, 5 H), 8.37 (d, J )
4.7 Hz, 1 H). 13C NMR (CDCl3): δ 22.6, 122.3, 125.4, 125.7,
126.6, 126.7, 127.5, 127.7, 128.2, 130.0, 130.2, 131.1, 131.7,
131.8, 135.5, 127.9, 139.4, 139.7, 139.8, 140.1, 131.9, 145.2,
147.1, 163.0. Anal. Calcd for C36H25NS (503.17): C, 85.85; H,
5.00; N, 2.78. Found: C, 85.90; H, 4.98; N, 2.83.
C
15H8N2O2S (280.30): C, 62.47; H, 2.88; N, 9.99. Found: C,
62.59; H, 2.93; N, 10.07.
Ack n ow led gm en t. This work was sponsored in part
by a grant from the Robert A. Welch Foundation,
Houston, TX.
3-Meth yl-5,6,7,8-tetr a p h en ylben zo[4,5]th ien o[2,3-b]p y-
r id in e (4g). Colorless solid, mp 252-254 °C; Rf ) hexane/
1
ethyl acetate ) 19:1). H NMR (CDCl3): δ 2.14 (s, 3 H), 6.49
(d, J ) 1.4 Hz, 1 H), 6.89-6.90 (m, 10 H), 7.23-7.35 (m, 10
H), 8.34 (d, J ) 1.6 Hz, 1 H). 13 C NMR (CDCl)3: δ 18.6, 125.6,
125.8, 126.7, 127.3, 127.4, 128.2, 128.5, 130.0, 130.2, 130.3,
131.4, 132.8, 135.6, 137.8, 139.0, 139.5, 139.6, 139.6, 139.8,
148.6, 159.9. Anal. Calcd for C36H25NS (503.17): C, 85.85; H,
5.00; N, 2.78. Found: C, 85.78; H, 4.96; N, 2.85.
Su p p or tin g In for m a tion Ava ila ble: X-ray diffraction
data for compounds 4f and 4i. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O016407J