C-C bond formation by radical cyclization: Facile syntheses of [6,6]pyranothiopyrans and [6,6]pyridothiopyrans

Article abstract of DOI:10.1002/jhet.220

(Chemical Equation Presented) 4-Chloromethylthiopyrano[3,2-c][1]benzopyran- 5-(2H)-ones were refluxed with o-bromophenols in acetone in the presence of anhydrous potassium carbonate and sodium iodide to afford a number of 4-aryloxymethylthiopyrano[3,2-c][

Full text of DOI:10.1002/jhet.220

1324
CAC Bond Formation by Radical Cyclization: Facile Syntheses
of [6,6]Pyranothiopyrans and [6,6]Pyridothiopyrans
Vol 46
K. C. Majumdar,* S. Sarkar, P. Pal, and S. Muhuri
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
*E-mail: kcm_ku@yahoo.co.in
Received October 26 2008
DOI 10.1002/jhet.220
Published online 11 November 2009 in Wiley InterScience (www.interscience.wiley.com).
4-Chloromethylthiopyrano[3,2-c][1]benzopyran-5-(2H)-ones were refluxed with o-bromophenols in ac-
etone in the presence of anhydrous potassium carbonate and sodium iodide to afford a number of 4-ary-
loxymethylthiopyrano[3,2-c][1]benzopyan-5-(2H)-ones in 72–79% yields. These compounds were
refluxed with tri-n-butyltin hydride and azobisisobutyronitrile in dry benzene for 7–8 h to give [6,6]pyr-
anothiopyrans in 76–84% yields with good diastereoselectivity. Similarly, [6,6]pyridothiopyrans were
also synthesized in 70–75% yields with excellent diastereoselectivity.
J. Heterocyclic Chem., 46, 1324 (2009).
INTRODUCTION
[6,6]pyranothiopyrans by the application of sequential
Claisen rearrangement followed by pyridine hydrotribro-
mide-mediated regioselective 6-endo cyclization. We
have also reported some successful 6-endo aryl radical
cyclizations by tri-n-butyltin hydride-mediated radical
reaction [16]. In continuation of our studies, we became
interested to examine the viability of synthesizing the
[6,6]pyranothiopyran ring system by tri-n-butyltin
hydride-induced radical cyclization of appropriate sub-
strates (3a–f).
In recent years, radical cyclization has emerged as a
valuable tool for the construction of carbo- and hetero-
cyclic compounds, including natural products [1]. An
understanding of the kinetic and the structural informa-
tion of these reactive intermediates paved the way for
the development of modern synthetic radical chemistry
[2]. There has been continuing enhanced interest in
recent years in the synthesis of coumarin derivatives
largely on account of their occurrence in nature [3,4]
and biological activity [5] viz., anthelmintic, hypnotic,
insecticidal, antifungal activities, anticoagulant effect on
blood, and diuretic properties. During our work on the
synthesis of heterocycles by the application of sigma-
tropic rearrangements [6], we recently observed the
unusual formation of [6,6]pyranopyrans in case of
substrates containing 5-hydroxypyrimidines [7] and 3-
hydroxycoumarin [8], in the second Claisen rearrange-
ment step. The generation and subsequent reactions of
radicals formed from aryl halides using tri-n-butyltin
hydride and azobisisobutyronitrile (AIBN) are now well
established [9]. However, literature reveals only a few
examples of heteroaryl radicals [10–13]. Aryl radical cy-
clization normally has a high 5-exo:6-endo ratio indicat-
ing stronger preference for exo cyclization compared to
the alkyl radicals. However, this preference is found to
be reversed in cyclizations involving stabilized radicals
[14]. Recently, we have reported [15] the synthesis of
RESULTS AND DISCUSSION
4-Chloromethylthiopyrano[3,2-c][1]benzopyran-5-(2H)-
ones (1a–b) were refluxed with o-bromophenol in ace-
tone in the presence of anhydrous potassium carbonate
and sodium iodide to afford a number of 4-aryloxyme-
thylthiopyrano[3,2-c][1]benzopyran-5-(2H)-ones
(Scheme 1).
(3a–f)
Compounds (3a–f) were characterized from their ele-
mental analyses and spectral data. IR spectrum of com-
pound 3a showed carbonyl absorption at 1690 cmꢀ1
.
1
The high-field (300 MHz) H NMR spectrum of com-
pound 3a exhibited two proton doublet at d 3.48 for
ASCH2, two proton doublet at d 5.18 for AOCH2, one
proton triplet at d 6.35 for the vinylic proton among
other signals for aromatic protons.
The substrate 3a was refluxed in dry benzene under
nitrogen atmosphere with tri-n-butyl tin hydride and
C
V
2009 HeteroCorporation

November 2009
CAC Bond Formation by Radical Cyclization: Facile Syntheses of
[6,6]Pyranothiopyrans and [6,6]Pyridothiopyrans
1325
Scheme 1. Reagents and condition: K2CO3, NaI, dry acetone, reflux 3–5 h.
AIBN for 7 h to afford cyclic product 4a in 80% yield
as an inseparable diastereoisomeric mixture (3:1), which
The starting materials for our study 4-arylamino-
methyl-7-methyl thioyrano[3,2-c]pyran-5-ones 7a–e were
synthesized from 4-chloromethyl-7-methyl-thiopyr-
ano[3,2-c]pyran-5-ones 5 and various substituted o-bro-
moanilines 6a–e in refluxing acetone in the presence
of anhydrous K2CO3 and catalytic amount of NaI
(Scheme 3).
1
was determined by H, 13C, COSY, and NOESY experi-
1
ments. H NMR spectrum of the product 4a displayed
peaks for two ASCH2 protons at d 3.23 and 3.33, two
AOCH2 protons at d 3.88 and 4.70, and two ring junc-
ture protons at d 3.25 and 3.75 along with eight aro-
matic protons (d 6.91–7.76) for the major diaster-
eoisomer, whereas minor diastereoisomer displayed
peaks at d 3.05 and 3.74 for two ASCH2 protons, d
3.93 and 5.67 for two AOCH2 protons, and d 3.17 and
3.42 for two ring juncture protons. IR spectrum of com-
pound 4a also showed carbonyl absorption at 1700
cmꢀ1. The generality of the reaction was tested by sub-
jecting five other substrates 3b–f under the same reac-
tion condition to give products 4b–f in 76–84% yields
(Scheme 2).
Substrate 7a was refluxed in benzene with tributyl tin
(IV) hydride in the presence of azoisobutyronitrile
(AIBN) for 5 h to give compound 8a (70%), which was
characterized from its elemental analysis and spectro-
scopic data. The IR spectrum of the compound 8a
showed peaks at 3387 and 1682 cmꢀ1 for secondary
NAH group and carbonyl group, respectively. The high-
1
field H NMR (500 MHz) spectrum of the product 8a
displayed peaks for two ASCH2 protons at d 2.90 and d
3.02, two ring juncture protons at d 3.09 and d 3.65,
and two ANCH2 protons at d 3.19 and 3.33. The mass
spectrum of the compound 8a also displayed a molecu-
lar ion peak at m/z 286 (Mþ þ 1). Encouraged by this
result, other substrates 7b–e were also similarly treated
to give tetracyclic heterocycles 8b–e in 70–75% yields
(Scheme 4).
In the course of our studies on the application of sig-
matropic rearrangements for the synthesis of heterocy-
clic compounds, we have already noted the formation of
several [6,6]pyranopyran and [6,6]pyranothiopyran ring
systems [17] using sequential Claisen rearrangements.
However, we failed to synthesize [6,6]pyridothiopyran
ring system using the Claisen rearrangement. The afore-
said results motivated us to investigate the synthesis of
[6,6]pyridothiopyran ring system by tributyl tin hydride-
mediated aryl radical cyclization.
Substrates 3b and 3c also gave diastereomeric mix-
tures [18] (2.5:1 and 2:1, respectively) under similar
reaction conditions, whereas substrates 3d–f and 7a–e
with Bu3SnH and AIBN in refluxing benzene gave the
Scheme 2. Reagents and condition: Bu3SnH, AIBN, dry benzene, under N2, reflux 7–8 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1326
K. C. Majumdar, S. Sarkar, P. Pal, and S. Muhuri
Vol 46
Scheme 3. Reagents and reaction condition: K2CO3, NaI, dry acetone, reflux 4–5 h.
cyclized products 4d–f and 8a–e, respectively, with
explained by the generation of an aryl radical 9 in the
tri-n-butyltin hydride and azobisisobutyronitrile-medi-
ated reaction. The aryl radical 9 may undergo cycliza-
tion by two different modes, a 6-endo trig cyclization to
afford the heterocyclic radical 11 (pathway a) or a 5-exo
trig cyclization to give the spiroheterocyclic radical [20]
10 (not isolated, pathway b). The possibility of the for-
mation of heterocyclic radical 11 via spirocyclic radical
10 by a neophyl rearrangement [21] cannot be ruled out
(Scheme 5).
1
100% diastereoselectivity. The high-field H NMR (500
MHz) of the compound 8a showed the two ring juncture
protons at d 3.09–3.12 (dt, 1H, J ¼ 12.1, 3.5 Hz) and d
3.65–3.69 (dt, 1H, J ¼ 11.5, 3.6 Hz). The low coupling
constants (J ¼ 3.5 and 3.6 Hz) for the ring juncture pro-
tons indicate cis-stereochemistry of the ring juncture.
The cis-stereochemistry of the ring juncture is also sup-
1
ported by the comparison of the H NMR data of simi-
lar compounds published earlier [17]. The stereochemis-
try at the ring juncture can also be surmised from the
molecular models (Dreiding model), which shows a
strain free cis-arrangement.
It is known that radical cyclizations leading to six-
membered rings are usually less general than cyclization
leading to five-membered rings. The six-membered ring
forming reactions are also slower than five-membered
ring forming reactions and are subject to competitive
formation of reduced uncyclized by-products. However,
appropriately substituted 5-hexenyl radicals are known
to undergo 6-endo cyclization to give six-membered
rings. Our noteworthy observation is that the usual oxi-
dation [13] does not occur at the present instance, and
the dihydro compounds are isolated in excellent yield
with good diastereoselectivity. It is also interesting
to note that six-membered heterocyclic rings are regiose-
lectively formed in all the cases. This is an attractive
and simple methodology for the synthesis of [6,6]pyra-
nothiopyran and [6,6]pyridothiopyran ring systems.
It was already established [19] that very high level of
diastereoselectivity (>50:1) could be obtained when the
concentration of the reactants is reduced from 0.1 to
0.01 M. This observation has been attributed to the re-
versibility of the cyclization and decreased availability
of the Bu3SnH. However, no significant change in dia-
stereoselectivity was observed when the substrates 3a–c
n
were treated with Bu3SnH and AIBN in refluxing ben-
zene under a very dilute condition. Therefore, the reason
behind the reduced diastereoselectivity in case of 3a–c
over the other is not clear.
The formation of products 4a–f and 8a–e from the
substrates 3a–f and 7a–e, respectively, may easily be
EXPERIMENTAL
Scheme 4. Reagents and reaction condition: Bu3SnH, AIBN, dry ace-
tone, under N2, reflux 5–8 h.
Melting points were determined in an open capillary and are
uncorrected. IR spectra were recorded on a Perkin-Elmer
L120-000A spectrometer (mmax in cmꢀ1) on KBr disks. UV
absorption spectra were recorded in EtOH on a Shimadzu UV-
1
2401PC spectrophotometer (kmax in nm). H NMR (300 MHz,
500 MHz) and 13C NMR (125 MHz) spectra were recorded on
a Bruker DPX-300 and Bruker DPX-500 spectrometer in
CDCl3 (chemical shift in d) with TMS as an internal standard.
1H NMR and 13C NMR spectra were recorded at the Indian
Institute of Chemical Biology, Kolkata and Bose Institute,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
CAC Bond Formation by Radical Cyclization: Facile Syntheses of
[6,6]Pyranothiopyrans and [6,6]Pyridothiopyrans
1327
Scheme 5
Kolkata. Silica gel [(60–120 mesh), Spectrochem, India] was
used for chromatographic separation. Silica gel G [E-Merck
(India)] was used for TLC. Petroleum ether refers to the frac-
tion boiling between 60 and 80ꢁC.
C19H13BrO3S: C, 56.85%; H, 3.24%; Found C, 56.91%; H,
3.57%.
Compound 3b. Yield 79%; yellow solid; m.p. 138ꢁC;
UV(EtOH) kmax: 209, 246, 355 nm; IR(KBr) mmax: 1690,
The starting materials (1a,b) and 5 for this study were pre-
pared according to our earlier published procedure [22,23].
General procedure for the preparation of compound
3a–f. Compound (1a, b) (1 mmol) was refluxed with several
o-bromophenols (2a–c) (1 mmol) in acetone (100 mL) in the
presence of anhydrous potassium carbonate (1g) and catalytic
amount of NaI for 3–5 h. The reaction mixture was then
cooled, filtered, and the solvent was removed. The residual
mass was subjected to column chromatography over silica gel
using petroleum ether–ethylacetate (19:1) as eluant to give
compounds 3a–f, which were then recrystallized from
chloroform.
1600, 1270 cmꢀ1 1H NMR (500 MHz): d 2.34 (s, 3H,
;
ACH3), 2.38 (s, 3H, ACH3), 3.49 (d, 2H, J ¼ 6 Hz, ASCH2),
4.97 (d, 2H, J ¼ 1 Hz, AOCH2), 6.39–6.41 (tt, 1H, J ¼ 1, 6
Hz, ¼CH), 7.29–7.32 (m, 4H, ArH), 7.51–7.55 (m, 1H, ArH),
7.83–7.85 (m, 1H, ArH); Anal. Calcd. for C21H17BrO3S: C,
58.74%; H, 3.96%; Found C, 59.05%; H, 3.61%.
Compound 3c. Yield 74%; yellow solid; m.p. 136ꢁC;
UV(EtOH)kmax: 218, 240, 336 nm; IR(KBr) mmax: 1700, 1600,
1
1240 cmꢀ1; H NMR (500 MHZ): d 2.43 (s, 3H, ACH3), 3.46
(d, 2H, J ¼ 6 Hz, ASCH2), 5.20 (d, 2H, J ¼ 1 Hz, AOCH2),
6.34–6.35 (tt, 1H, J ¼ 1,6 Hz, ¼CH), 6.83–7.61 (m, 7H,
ArH); Anal. Calcd. for C20H15BrO3S: C, 57.83%; H, 3.61%;
Found C, 58.04%; H, 3.73%.
Compound 3a. Yield 75%; yellow solid; m.p. 90ꢁC; UV(E-
tOH)kmax: 214, 243, 371 nm; IR(KBr) mmax: 1690, 1600, 1260
Compound 3d. Yield 72%; yellow solid; m.p. 94ꢁC; UV(E-
tOH)kmax: 221, 243, 375 nm; IR(KBr) mmax: 1700, 1590, 1290
cmꢀ1
;
1H NMR (500 MHz): d 3.48 (d, 2H, J ¼ 6 Hz,
ASCH2), 4.99 (d, 2H, J ¼ 1 Hz, AOCH2), 6.38–6.42 (tt, 1H,
J ¼ 1, 6 Hz, ¼CH), 7.17–7.23 (m, 3H, ArH), 7.29–7.37 (m,
4H, ArH), 7.50–7.61 (m, 1H, ArH); Anal. Calcd. for
cmꢀ1 1H NMR (300 MHz): d 2.26 (s, 3H, ACH3), 3.46 (d,
;
2H, J ¼ 6 Hz, ASCH2), 5.16 (d, 2H, J ¼ 1 Hz, AOCH2),
6.31–6.35 (tt, 1H, J ¼ 1, 6 Hz, ¼¼CH), 6.84–6.87 (m, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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K. C. Majumdar, S. Sarkar, P. Pal, and S. Muhuri
Vol 46
ArH), 7.02–7.05 (m, 1H, ArH), 7.29–7.35 (m, 3H, ArH), 7.51–
7.57 (m, 1H, ArH), 7.82–7.85 (m, 1H, ArH); Anal. Calcd. for
C20H15BrO3S: C, 57.83%; H, 3.61%; Found C, 57.98%; H,
3.47%.
(d, 1H, J ¼ 8.12 Hz), 6.96–6.98 (dd, 1H, J ¼ 8, 1.68 Hz),
7.33 (d, 1H, J ¼ 1.68 Hz). UV (EtOH) kmax ¼ 356, 248, 205
nm. Anal. Calcd. for C18H18NO2SBr: C, 55.10%; H, 4.59%;
N, 3.57%; Found C, 54.80%; H, 4.89%; N, 3.28%.
Compound 7e. Yield: 75%; Solid, m.p. 110ꢁC; IR
Compound 3e. Yield 75%; yellow solid; m.p. 122ꢁC;
UV(EtOH)kmax: 216, 245, 359 nm; IR(KBr) mmax: 3300, 1680,
1
(KBr)mmax: 1711, 1495 cmꢀ1; H NMR (CDCl3, 500 MHz) dH
1590, 1250 cmꢀ1 1H NMR (500 MHz): d 2.26 (s, 3H,
;
1.17–1.20 (t, 3H, J ¼ 7.59 Hz), 2.18 (s, 3H), 2.52–2.57 (q,
2H, J ¼ 7.57 Hz), 2.62 (s, 3H, ANMe), 3.25–3.26 (d, 2H, J ¼
5.99 Hz), 4.16 (s, 2H), 5.96–5.99 (m, 2H), 6.94–6.96 (d, 1H, J
¼ 8.12 Hz), 7.0–7.02 (dd, 1H, J ¼ 8.15, 1.9 Hz), 7.35 (d, 1H,
J ¼ 1.9 Hz). UV (EtOH) kmax¼ 359, 299, 249, 215 nm. Anal.
Calcd. for C19H20NO2SBr: C, 56.16%; H, 4.93%; N, 3.45%;
Found C, 56.36%; H, 4.63%; N, 3.15%.
General procedure for the preparation of compounds
4a–f and 8a–e by radical cyclization. A suspension of the
compound 3a (0.5 mmol), nBu3SnH (0.075 mL), and AIBN
(0.5–0.6 mol equiv) in dry benzene (7–10 mL) were refluxed
for 7–8 h under N2 atmosphere. The solvent was evaporated
under reduced pressure. The residue was dissolved in 10 mL
of ether and stirred with 10 mL of 10% aqueous potassium flu-
oride for 45 min. The white precipitate separated by filtration
and the aqueous phase was extracted with CHCl3 (3 ꢂ 10
mL). The combined organic extract was washed with brine
and dried (Na2SO4). The residual mass after removal of the
solvent was subjected to column chromatography over silica
gel using pet-ether–ethyl acetate (19:1) as eluant to give
cyclized products 4a, which were then recrystallized from
chloroform–petroleum ether. Similarly, other compounds 4b–f
and 8a–e were also synthesized.
Compound 4a. Yield 80%; white solid; m.p. 140ꢁC; UV
(EtOH) kmax: 219, 279 nm; IR (KBr) mmax: 2900, 1700, 1195
cmꢀ1, 1H NMR (CDCl3, 500 MHz): Major diastereomer: d 3.23
(t, 1H, J ¼ 11.4 Hz, ASCH2), 3.25 (dt, 1H, J ¼ 3.6, 10.5 Hz,
ring juncture), 3.33 (dd, 1H, J ¼ 2.4 Hz, 12.6 Hz, SCH2), 3.75
(dt, 1H, J ¼ 3.1, 11.4 Hz, ring juncture), 3.88 (t, 1H, J ¼ 10.5
Hz, OCH2), 4.70 (dd, 1H, J ¼ 3.08, 10.8 Hz, OCH2), 6.88–6.97
(m, 2H, ArH), 7.28–7.35 (m, 2H, ArH), 7.51–7.57 (m, 3H,
ArH), 7.74–7.76 (m, 1H, ArH); 13C NMR (125 MHz, CDCl3):
at 29.6, 31.7, 32.4, 64.5, 114.9, 117.7, 120.7, 121.2, 124.0,
124.5, 129.3, 130.1, 130.2, 130.6, 132.2, 149.9, 151.3, 154.7,
and 159.5; MS m/z 322 (Mþ); Anal. Calcd. for C19H14O3S: C,
70.81%; H, 4.35%; Found C, 71.02%; H, 4.43%. Minor diaster-
eomer: 1H NMR (CDCl3, 500 MHz): d 3.05–3.07 (m, 1H),
3.17–3.20 (m, 1H), 3.42–3.45 (m, 1H), 3.74–3.76 (m, 1H),
3.93–3.96 (m, 1H), 5.66 (dd, 1H, J ¼ 3.4 Hz, 10.46 Hz); 13C
NMR (125 MHz, CDCl3): d 28.7, 37.5, 38.8, and 69.
ACH3), 2.43 (s, 3H, ACH3), 3.45 (d, 2H, J ¼ 6 Hz, ASCH2),
5.16 (d, 2H, J ¼ 1 Hz, AOCH2), 6.30–6.33 (tt, 1H, J ¼ 1, 6
Hz, ¼¼CH), 6.84–6.86 (d, J ¼ 9 Hz, 1H, ArH), 7.01–7.03 (dd,
1H, J ¼ 2.5, 9 Hz, ArH), 7.21–7.26 (m, 1H, ArH), 7.32–7.34
(m, 2H, ArH), 7.60 (s, 1H, ArH); Anal. Calcd. for
C21H17BrO3S: C, 58.74%; H, 3.96%; Found C, 58.60%; H,
4.19%.
Compound 3f. Yield 73%; yellow solid; m.p. 168ꢁC; UV(E-
tOH)kmax: 212, 240, 326 nm; IR(KBr) mmax: 1720, 1700, 1230
1
cmꢀ1; H NMR (500 MHz): d 2.24 (s, 3H, ACH3), 2.26 (s, 3H,
ACH3), 2.43 (s, 3H, ACH3), 3.48 (d, 2H, J ¼ 6 Hz, ASCH2),
5.00 (d, 2H, J ¼ 1 Hz, AOCH2), 6.38–6.42 (t, 1H, J ¼ 6 Hz,
¼¼CH), 7.19–7.61 (m, 5H, ArH); Anal. Calcd. for C22H19BrO3S:
C, 59.59%; H, 4.29%; Found C, 59.70%; H, 4.06%.
General procedure for the synthesis of compounds
7a–e. Compound 5 (1 mmol) was refluxed with several o-bro-
moanilines (6a–e) (1 mmol) in dry acetone (100 mL) in the
presence of anhydrous potassium carbonate (1 g) and catalytic
amount of NaI for 4–5 h. The reaction mixture was cooled, fil-
tered, and the solvent was removed. The residual mass was
subjected to column chromatography over silica gel using pe-
troleum ether–ethylacetate (19:1) as eluant to give compounds
7a–e.
Compound 7a. Yield: 80%; Solid, m.p. 170ꢁC; IR
(KBr)mmax: 3410, 1698, 1596, 1497 cmꢀ11 H NMR (CDCl3,
400 MHz) dH 2.21 (s, 3H), 3.27–3.28 (d, 2H, J ¼ 5.8 Hz),
4.38 (s, 2H), 5.76–5.79 (t, 1H, J ¼ 5.8 Hz), 5.99 (s, 1H),
6.49–6.53 (t, 1H, J ¼ 7.42 Hz), 6.59–6.61 (d, 1H, J ¼ 8 Hz),
7.09–7.12 (t, 1H, J ¼ 7.5 Hz), 7.35–7.37 (d, 1H, J ¼ 8.04
Hz). UV (EtOH) kmax¼ 361, 302, 245, 209 nm. Anal. Calcd.
for C16H14NO2SBr: C, 52.75%; H, 3.85%; N, 3.85%; Found
C, 52.45%; H, 3.55%; N, 3.65%.
Compound 7b. Yield: 80%; Gummy mass. IR (KBr)mmax
:
3399, 1698, 1492 cmꢀ1 1H NMR (CDCl3, 400 MHz) dH 2.18
(s, 3H), 2.21 (s, 1H), 3.26–3.28 (d, 2H, J ¼ 5.8 Hz), 4.36 (s,
2H), 5.75–5.78 (t, 1H, J ¼ 5.86 Hz), 5.99 (s, 1H), 6.50–6.52
(d, 1H, J ¼ 8.2 Hz), 6.90–6.92 (dd, 1H, J ¼ 8.24, 1.32 Hz),
7.20–7.21 (d, 1H, J ¼ 1.16 Hz). UV (EtOH) kmax¼ 302, 243,
208 nm. Anal. Calcd. for C17H16NO2SBr: C, 53.96%; H,
4.23%; N, 3.70%; Found C, 53.66%; H, 4.53%; N, 3.40%.
Compound 7c. Yield: 75%; Solid, m.p. 125–130ꢁC; IR
(KBr)mmax: 3391, 1699, 1594 cmꢀ1 1H NMR (CDCl3, 500
MHz) dH 1.15–1.18 (t, 3H, J ¼ 7.58 Hz), 2.22 (s, 3H), 2.47–
2.52 (q, 2H, J ¼ 7.58 Hz), 3.28–3.29 (d, 2H, J ¼ 5.88 Hz),
4.36–4.37 (d, 2H, J ¼ 1.09 Hz), 5.77–5.79 (t, 1H, J ¼ 5.87
Hz), 5.99 (s, 1H), 6.56–6.58 (d, 1H, J ¼ 8.26 Hz), 6.94–6.96
(dd, 1H, J ¼ 8.26, 1.98 Hz), 7.23–7.24 (d, 1H, J ¼ 1.99 Hz).
UV (EtOH) kmax¼ 303, 246, 209 nm. Anal. Calcd. for
C18H18NO2SBr: C, 55.10%; H, 4.59%; N, 3.57%; Found C,
55.40%; H, 4.49%; N, 3.27%.
Compound 4b. Yield 76%; white solid; m.p. 198ꢁC; UV
(EtOH) kmax: 215, 279 nm; IR (KBr) mmax: 2910, 1700, 1190
cmꢀ1, 1H NMR (CDCl3, 500 MHz): Major diastereomer: d 2.19
(s, 3H, ACH3), 2.28 (s, 3H, ACH3), 3.20 (t, 1H, J ¼ 11.2 Hz,
ASCH2), 3.24 (dt, 1H, J ¼ 3.4, 10.8 Hz, ring juncture proton),
3.34 (dd, 1H, J ¼ 2.6, 12.4 Hz, ASCH2), 3.72 (dt, 1H, J ¼ 3.2,
11.2 Hz, ring juncture proton), 3.90 (t, 1H, J ¼ 10.8 Hz,
AOCH2), 4.68 (dd, 1H, J ¼ 2.6, 11.8 Hz, AOCH2), 6.84–
6.89(s, 2H, ArH), 7.32–7.61 (m, 2H, ArH), 7.73–7.76 (m, 2H,
ArH); MS m/z 350 (Mþ); Anal. Calcd. for C21H18O3S: C,
72.0%; H, 5.14%; Found C, 72.25%; H, 5.43%. Minor diaster-
eomer: 1H NMR (CDCl3, 500 MHz): d 2.99–3.22 (m, 3H),
3.73–3.87 (m, 2H), 5.64 (dd, 1H, J ¼ 3.5, 10.7 Hz).
Compound 7d. Yield: 80%; Solid, m.p. 120ꢁC; IR
Compound 4c. Yield 82%; white solid; m.p. 182ꢁC; UV
(EtOH) kmax: 219, 280 nm; IR (KBr) mmax : 2915, 1710, 1190
cmꢀ1, 1H NMR (CDCl3, 300 MHz): Major diastereomer: d 2.43
1
(KBr)mmax: 1711, 1493 cmꢀ1; H NMR (CDCl3, 400 MHz) dH
2.17 (s, 3H), 2.24 (s, 3H), 2.61 (s, 3H, ANMe), 3.23–3.25 (d,
2H, J ¼ 6.04 Hz), 4.15 (s, 2H), 5.92–5.95 (m, 2H), 6.89–6.91
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
CAC Bond Formation by Radical Cyclization: Facile Syntheses of
[6,6]Pyranothiopyrans and [6,6]Pyridothiopyrans
1329
Compound 8c. Yield: 75%; Solid, m.p. 200ꢁC; IR
(s, 3H, ACH3), 3.26 (t, 1H, J ¼ 11.4 Hz, ASCH2), 3.27 (dt, 1H,
J ¼ 3.4, 10.7 Hz, ring juncture proton), 3.35 (dd, 1H, J ¼ 2.5,
12.2 Hz, ASCH2), 3.74 (dt, 1H, J ¼ 3.5, 11.4 Hz, ring juncture
proton), 3.87 (t, 1H, J ¼ 10.7 Hz, AOCH2), 4.64 (dd, 1H, J ¼
2.6, 10.2 Hz, AOCH2), 6.88–6.97 (m, 3H, ArH), 7.14–7.35 (m,
3H, ArH), 7.51(s, 1H, ArH); MS m/z 336 (Mþ); Anal. Calcd.
for C20H16O3S: C, 71.43%; H, 4.76%; Found C, 71.62%; H,
4.83%. Minor diastereomer: 1H NMR (CDCl3, 300 MHz): d
3.00–3.22 (m, 3H), 3.88–3.93 (m, 2H), 5.62 (dd, 1H, J ¼ 3.4,
10.4 Hz).
(KBr)mmax: 3386, 1693, 1545 cmꢀ1 1H NMR (CDCl3, 500
;
MHz) dH 1.17–1.20 (t, 3H, J ¼ 7.58 Hz), 2.19 (s, 3H), 2.50–
2.55 (q, 2H, J ¼ 7.57 Hz), 2.92–2.95 (dd, 1H, J ¼ 13.11, 2.49
Hz), 2.99–3.03 (t, 1H, J ¼ 11.4 Hz), 3.06–3.09 (dt, 1H, J ¼
12.14, 3.5 Hz), 3.19–3.24 (t, 1H, J ¼ 12.63 Hz), 3.31–3.34
(dt, 1H, J ¼ 10.98, 4.0 Hz), 3.64–3.66 (dt, 1H, J ¼ 11.44,
3.68 Hz), 3.91 (brs, 1H, NAH), 5.80 (s, 1H), 6.47–6.49 (d,
1H, J ¼ 8.63 Hz), 6.88–6.89 (m, 2H). MS: m/z ¼ 314 (M þ
1); UV (EtOH) kmax¼ 309, 257, 232, 210 nm. Anal. Calcd.
For C18H19NO2S: C, 69.01%; H, 6.07%; N, 4.47%; Found C,
69.31%; H, 5.87%; N, 4.19%.
Compound 4d. Yield 82%; white solid; m.p. 182ꢁC; UV
(EtOH) kmax: 220, 279 nm; IR (KBr) mmax : 2900, 1700, 1196
cmꢀ1 1H NMR (CDCl3, 300 MHz): d 2.29 (s, 3H, ACH3),
,
Compound 8d. Yield: 70%; Solid, m.p. 162ꢁC; IR
1
(KBr)mmax: 1694, 1463 cmꢀ1; H NMR (CDCl3, 500 MHz) dH
3.19 (dd, 1H, J ¼ 2.4, 11.2 Hz, ASCH2), 3.26–3.34 (m, 2H),
3.69 (dt, 1H, J ¼ 3.5, 11.0 Hz, ring juncture proton), 3.78 (t,
1H, J ¼ 10.5 Hz, AOCH2), 4.61 (dd, 1H, J ¼ 2.1, 10.0 Hz,
AOCH2), 6.78–7.00 (m, 3H, ArH), 7.27–7.34 (m, 2H, ArH),
7.51–7.56 (m, 1H, ArH), 7.73 (d, J ¼ 7.8 Hz, 1H, ArH); MS
m/z 336 (Mþ); Anal. Calcd. for C20H16O3S: C, 71.43%; H,
4.76%; Found C, 71.59%; H, 4.62%.
2.19 (s, 3H), 2.23 (s, 3H), 2.97–3.01 (t, 1H, J ¼ 11.09 Hz),
3.03–3.07 (m, 1H), 3.14–3.19 (t, 1H, J ¼ 12.54 Hz), 3.43–3.47
(dt, 1H, J ¼ 10.83, 4.19 Hz), 3.48–3.51 (ddd, 1H, J ¼ 11.25,
3.9, 1.3 Hz), 5.80 (s, 1H), 6.53–6.55 (d, 1H, J ¼ 8.37 Hz),
6.88–6.89 (d, 1H, J ¼ 1.78 Hz), 6.95–6.97 (dd, 1H, J ¼ 8.31,
1.84 Hz). 13C NMR (125 MHz, CDCl3): 19.8, 20.6, 30.9, 31.0,
35.8, 39.3, 50.7, 104.3, 111.8, 112.9, 123.2, 125.9, 129.5,
130.4, 143.8, 151.9, 158.0, 161.7. MS: m/z ¼ 314 (M þ 1);
UV (EtOH) kmax ¼ 309, 260, 208 nm. Anal, Calcd. for
C18H19NO2S: C, 69.01%; H, 6.07%; N, 4.47%; Found C,
69.29%; H, 6.28%; N, 4.25%.
Compound 4e. Yield 84%; white solid; m.p. 208ꢁC; UV
(EtOH) kmax: 219, 280 nm; IR (KBr) mmax: 2900, 1690, 1220
cmꢀ1, 1H NMR (CDCl3, 300 MHz): d 2.29 (s, 3H, ACH3), 2.43
(s, 3H, ACH3), 3.18–3.29 (m, 3H), 3.72 (dt, 1H, J ¼ 3.4, 10.7
Hz, ring juncture proton), 3.77 (t, 1H, J ¼ 10.5 Hz, AOCH2),
4.60 (dd, 1H, J ¼ 3.2, 10.4 Hz, AOCH2), 6.77–7.01 (m, 3H,
ArH), 7.20–7.24 (m, 1H, ArH), 7.32 (dd, 1H, J ¼ 1.6, 8.3 Hz,
ArH), 7.51 (s, 1H, ArH); MS m/z 350 (Mþ); Anal. Calcd. for
C21H18O3S: C, 72.0%; H, 5.14%; Found C, 72.17%; H, 5.25%.
Compound 4f. Yield 77%; white solid; m.p. 214ꢁC; UV
(EtOH) kmax: 219, 278 nm; IR (KBr) mmax : 2910, 1690, 1210
Compound 8e. Yield: 70%; Solid, m.p. 140ꢁC; IR
1
(KBr)mmax: 1700, 1463 cmꢀ1; H NMR (CDCl3, 500 MHz) dH
1.18–1.21 (t, 3H, J ¼ 7.59 Hz), 2.19 (s, 3H), 2.51–2.56 (q,
2H, J ¼ 7.59 Hz), 2.88–2.90 (ddd, 1H, J ¼ 12.8, 3.16, 2.0
Hz), 2.91 (s, 3H), 2.98–3.02 (t, 1H, J ¼ 11.08 Hz), 3.05–3.08
(dt, 1H, J ¼ 12.08, 3.4 Hz), 3.15–3.20 (t, 1H, J ¼ 12.53 Hz),
3.43–3.47 (dt, 1H, J ¼ 10.87, 4.2 Hz), 3.49–3.52 (ddd, 1H, J
¼ 11.2, 2.76, 1.2 Hz), 5.81 (s, 1H), 6.56–6.58 (d, 1H, J ¼
8.34 Hz), 6.90–6.91 (d, 1H, J ¼ 1.87 Hz), 6.98–7.00 (dd, 1H,
J ¼ 8.4, 1.99 Hz). MS: m/z ¼ 328 (M þ 1); UV (EtOH)
kmax ¼ 308, 262, 231, 208 nm. Anal. Calcd. For C19H21NO2S:
C, 69.72%; H, 6.42%; N, 4.28%; Found C, 69.45%; H, 6.22%;
N, 4.50%.
cmꢀ1 1H NMR (CDCl3, 300 MHz): d 2.18 (s, 3H, ACH3),
,
2.26 (s, 3H, ACH3), 2.43 (s, 3H, ACH3), 3.13–3.30 (m, 3H),
3.66–3.71 (dt, 2H, J ¼ 3.6, 10.7 Hz, ring juncture proton),
3.76 (t, 1H, J ¼ 10.6 Hz, AOCH2), 4.66 (dd, 1H, J ¼ 2.1,
10.3 Hz, AOCH2), 6.84–6.87 (d, 2H, J ¼ 9 Hz, ArH), 7.20–
7.23 (m, 1H, ArH), 7.32–7.34 (m, 1H, ArH), 7.52 (s, 1H,
ArH); MS m/z 364 (Mþ); Anal. Calcd. for C22H20O3S: C,
72.53%; H, 5.49%; Found C, 72.71%; H, 5.25%.
Compound 8a. Yield: 70%; Solid, m.p. 218ꢁC; IR
Acknowledgment. The authors thank the CSIR (New Delhi) for
financial assistance. They are thankful to Dr. A. Dutta of the Me-
dicinal Chemistry Department, University of Kansas for spectral
analyses of compound 4a. Three of them S.M., S.S., and P.P. are
grateful to the CSIR for their Research Fellowships.
(KBr)mmax: 3387, 1682, 1539 cmꢀ1 1H NMR (CDCl3, 500
;
MHz) dH 2.18 (s, 3H), 2.90–2.94 (ddd, 1H, J ¼ 12.9, 3.2, 2.1
Hz), 3.02–3.06 (t, 1H, J ¼ 11.4 Hz), 3.09–3.12 (dt, 1H, J ¼
12.1, 3.5 Hz), 3.19–3.24 (t, 1H, J ¼ 12.6 Hz), 3.33–3.37 (dt,
1H, J ¼ 11.02, 4.1 Hz), 3.65–3.69 (dt, 1H, J ¼ 11.5, 3.6 Hz),
4.02 (brs, 1H, NAH), 5.81 (s, 1H), 6.51–6.53 (dd, 1H, J ¼ 8.04,
0.76 Hz), 6.64–6.67 (dt, 1H, J ¼ 7.32, 1.12 Hz), 7.02–7.06 (m,
2H). MS: m/z ¼ 286 (M þ 1); UV (EtOH) kmax¼ 306, 255,
232, 209 nm. Anal. Calcd. for C16H15NO2S: C, 67.37%; H,
5.26%; N, 4.91%; Found C, 67.67%; H, 4.96%; N, 5.21%.
REFERENCES AND NOTES
[1] (a) Giese, B. Radicals in Organic Synthesis: Formation of
Carbon-Carbon Bonds; Pergamon: New York, 1986; (b) Curran, D. P.
Synthesis 1988, 417; (c) Jasperse, C. P.; Curran, D. P.; Fevig, T. L.
Chem Rev 1991, 91, 1237; (d) Renaud, P.; Sibi, M., Eds. Radicals in
Organic Synthesis, Vol. 1, 2; Wiley-VCH: Weinheim, 2001; (e)
Majumdar, K. C.; Basu, P. K. Heterocycles 2002, 57, 2413.
Compound 8b. Yield: 75%; Solid, m.p. 210ꢁC; IR (KBr)mmax
:
3392, 1684, 1539 cmꢀ1; 1H NMR (CDCl3, 300 MHz) dH 2.18 (s,
3H), 2.23 (s, 3H), 2.90–2.97 (m, 1H), 3.00–3.08 (m, 2H), 3.17–
3.25 (t, 1H, J ¼ 12.35 Hz), 3.30–3.34 (m, 1H), 3.62–3.66 (d, 1H,
J ¼ 11.17 Hz), 3.90 (brs, 1H, NAH), 5.81 (s, 1H), 6.45–6.47 (d,
1H, J ¼ 7.77 Hz), 6.85–6.87 (d, 1H, J ¼ 7.63 Hz), 6.87 (s, 1H).
13C NMR (125 MHz, CDCl3): 19.8, 20.7, 30.8, 31.0, 35.2, 42.0,
104.3, 112.9, 115.0, 121.9, 126.8, 129.3, 130.5, 141.7, 151.7,
158.0, 161.7. MS: m/z ¼ 300 (M þ 1); UV (EtOH) kmax ¼ 308,
257, 232, 208 nm. Anal. Calcd. for C17H17NO2S: C, 68.23%; H,
5.69%; N, 4.68%; Found C, 68.53%; H, 5.39%; N, 4.98%.
[2] (a) Baldwin, J. E. J Chem Soc Chem Commun 1976, 734;
(b) Cekovic, Z. Tetrahedron Lett 1972, 13, 749; (c) Curran, D. P.;
Chang, C. T. J Org Chem 1989, 54, 3140; (d) Studer, A.; Amerin, S.
Synthesis 2002, 835.
[3] (a) Dean, F. M. Naturally Occurring Oxygen Ring Com-
pounds; Butterworths: London, 1963; (b) Murray, R. D. H.; Mendez,
J.; Brown, S. A. The Natural Coumarins, Occurance, Chemistry and
Biochemistry; Wiley Interscience: New York, 1982; (c) Wawzonek, S.
In Heterocyclic Compounds; Elderfield, R. C., Ed.; Wiley: New York,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1330
K. C. Majumdar, S. Sarkar, P. Pal, and S. Muhuri
Vol 46
1951; Vol. 2, p 176; (d) Staunton, J. In Comprehensive Organic Chem-
istry; Sammes, P. G., Ed.; Pergamon Press: Oxford, 1979; Vol. 4, p
646; (e) Hepworth, J. D. In Comprehensive Heterocyclic Chemistry;
Boulton, A. J., Mckillop, A., Eds.; Pergamon Press: Oxford, 1984;
Vol. 3, p 1799.
[13] Rosa, A. M.; Lobo, A. M.; Branco, P. S.; Prabhakar, S.;
Pereira, A. M. D. L. Tetrahedron 1997, 55, 269.
[14] (a) Ishibashi, H.; Kato, I.; Takeda, Y.; Kogure, M.; Tamura,
O. Chem Commun 2000, 1527; (b) Ponaras, A. A.; Zaim, O. Tetrahe-
dron Lett 2000, 41, 2279.
[4] (a) Soine, T. J Pharm Sci 1964, 53, 231; (b) Lauger, V. P.;
Martin, H.; Muller, P. Helv Chim Acta 1994, 27, 892; (c) Deana, A.
A. J Med Chem 1983, 26, 580; (d) Gordon, M.; Grover, S. H.;
Stothers, J. B. Can J Chem 1973, 51, 2092.
[15] Majumdar, K. C.; Kundu, U. K.; Ghosh, S. K. Org Lett
2002, 4, 2629.
[16] (a) Majumdar, K. C.; Mukhopadhyay, P. P. Synthesis 2003,
99; (b) Majumdar, K. C.; Mukhopadhyay, P. P. Synthesis 2003, 920;
(c) Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P.; Sarkar, S.;
Ghosh, S. K.; Biswas, P. Tetrahedron 2003, 59, 2151; (d) Majumdar,
K. C.; Sarkar, S. Synth Commun 2004, 34, 2873; (e) Majumdar, K.
C.; Debnath, P.; Chattopadhyay, S. K. Synth Commun 2008, 38, 1768;
(f) Majumdar, K. C.; Biswas, A.; Mukhopadhyay, P. P. Synthesis
2003, 2385; (g) Majumdar, K. C.;Mukhopadhyay, P. P.; Biswas, A.
Tetrahedron Lett 2005, 46, 6655.
[5] (a) Feur, G. In Progress in Medicinal Chemistry; Ellis, G.
P., West, G. B., Eds.; North-Holland Publishing Company: New York,
1974; (b) Kitagawal, H.; Iwaki, R.; Yanagi, B.; Sato, T. J Pharm Soc
Jpn 1956, 76, 186; (c) Burger, A. In Burger’s Medicinal Chemistry;
Wolff, M. E., Ed.; Wiley Interscience: New York, 1995.
[6] Majumdar, K. C.; Balasubramanium, K. K.; Thyagarajan,
B. S. J Heterocycl Chem 1973, 10, 159.
[7] Majumdar, K. C.; Das, U. J Org Chem 1998, 63, 9997.
[8] Majumdar, K. C.; Chatterjee, P.; Saha, S. Tetrahedron Lett
1998, 39, 7147.
[17] (a) Majumdar, K. C.; Pal, A. K. J Sulfur Chem, in
press; (b) Majumdar, K. C.; Kundu, N. J Heterocycl Chem 2008,
45, 1039.
[9] (a) Ishibashi, H.; Ohata, K.; Niihara, M.; Sato, T.; Ikeda,
M. J Chem Soc Perkin Trans 1 2000, 547; (b) Parsons, A. F.; Wil-
liams, D.A. J. Tetrahedron 2000, 56, 7217.
[18] (a) Majumdar, K. C.; Muhuri, S. Synthesis 2006, 2725; (b)
Majumdar, K. C.; Jana, M. Synth Commun 2007, 37, 1735.
[19] (a) Enholm, E. J.; Prasad, E. J.; Kinter, K. S. J Am Chem
Soc 1991, 113, 7784; (b) Enholm, E. J.; Kinter, K. S. J Org Chem
1995, 60, 4850.
[10] (a) Shankaran, K.; Solan, C. P.; Snieckus, V. Tetrahedron
Lett 1985, 26, 6001; (b) Solan, C. P.; Cuevas, J. C.; Quesnelle, C.;
Snieckus, V. Tetrahedron Lett 1988, 29, 4685; (c) Jones, K.; Willkin-
son, J. A. J Chem Soc Chem Commun 1992, 1767.
[20] Ishibashi, H.; Kawanami, H.; Nakagawa, H.; Ikeda, M.
J Chem Soc Perkin Trans 1 1997, 2291.
[11] (a) Snieckus, V. Bull Soc Chim Fr 1988, 67; (b) Har-
rowven, D. C.; Browne, R. Tetrahedron Lett 1994, 35, 3501.
[12] (a) Tsuge, O.; Hatta, T.; Tsuchiyama, H. Chem Lett 1998,
155; (b) Fiumana, A.; Jones, K. Tetrahedron Lett 2000, 41, 4209; (c)
Sundberg, R. J.; Cherney, R. J. J Org Chem 1990, 55, 6028.
[21] Abeywickrema, A. N.; Beckwith, A. L. J.; Gerba, S. J Org
Chem 1987, 52, 4072.
[22] Majumdar, K. C.; Ghosh, S. K. Tetrahedron Lett 2002, 43, 2115.
[23] Majumdar, K. C.; Kundu, U. K.; Ghosh, S. J Chem Soc
Perkin Trans 1 2002, 2139.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet