Regioselective synthesis of quinolone-annulated sulfur heterocycles by aryl radical cyclization

Article abstract of DOI:10.1016/j.tetlet.2005.07.151

The tin hydride-mediated cyclizations of a number of sulfides and sulfones under mild, neutral conditions, have been investigated accompanied by some amount of β-scission product for sulfides. The sulfides were derived from 4-mercaptoquinolone and 2-bromobenzyl bromides by phase transfer catalyzed reaction and the corresponding sulfones were prepared by treatment of the sulfides with m-CPBA at room temperature. The sulfides and the corresponding sulfones were then reacted with ⁿBu₃SnH-AIBN to give regioselective quinolone-annulated sulfur heterocycles.

Full text of DOI:10.1016/j.tetlet.2005.07.151

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6655–6658
Regioselective synthesis of quinolone-annulated sulfur
heterocycles by aryl radical cyclization
K. C. Majumdar,* P. P. Mukhopadhyay and A. Biswas
Department of Chemistry, University of Kalyani, Kalyani 741 235, West Bengal, India
Received 13 May 2005; revised 22 July 2005; accepted 29 July 2005
Abstract—The tin hydride-mediated cyclizations of a number of sulfides and sulfones under mild, neutral conditions, have been
investigated accompanied by some amount of b-scission product for sulfides. The sulfides were derived from 4-mercaptoquinolone
and 2-bromobenzyl bromides by phase transfer catalyzed reaction and the corresponding sulfones were prepared by treatment of the
sulfides with m-CPBA at room temperature. The sulfides and the corresponding sulfones were then reacted with nBu3SnH-AIBN to
give regioselective quinolone-annulated sulfur heterocycles.
Ó 2005 Published by Elsevier Ltd.
Aryl radical cyclizations have been developed as a pow-
erful method for constructing carbon–carbon bonds in
organic synthesis.1 These radical cyclization protocols
commonly have several advantages over non-radical
methods, for example, the radical cyclization can be car-
ried out in neutral organic solutions. We have previously
synthesized several novel heterocyclic systems contain-
ing sulfur by sigmatropic rearrangements.2 During our
studies, we observed the unusual formation of [6,6]pyr-
anothiopyrans during the second Claisen rearrangement
step.3 The oxygen- and nitrogen-containing radical
cyclizations have been studied intensively. However,
an examination of the literature revealed only a few
examples of the synthesis of sulfur-based heterocycles
via radical methods. These include cyclizations where
the sulfur functionality is in a hexenyl chain at the 3-4
and 4-positions5 and an example of a sulfonylated radi-
cal in the 2-position,6 but these reactions were not regio-
selective. Several useful radical cyclizations with a sulfur
functionality located a- to the radical centre have also
been reported, however, these yielded a cyclic product
with the sulfur external to the ring.7 We have recently
succeeded in the regioselective synthesis of [6,6] cyclic
compared to hydrogen abstractions. The rate of b-scis-
sion9 of the product radicals is high when the C-centred
radical released is tertiary or resonance stabilized.9b
However, when a highly electron-withdrawing SO2
group is attached to the radical centre, it confers consid-
erable stability (lowers the energy of the SOMO) to the
intermediate radical and prevents the b-scission with an
increase in the product yield. It was observed that alkyl
radical cyclization predominantly gave the smaller five-
membered ring rather than the larger six-membered ring
owing to the stereoelectronically more favourable transi-
tion state during 5-exo-cyclization although it resulted in
an unstable primary radical intermediate. For stabilized
radicals,10 this preference is found to be reversed. A
study of the cyclization of R-sulfenyl-, R-sulfinyl- and
R-sulfonyl-5-hexenyl and 5-methyl-5-hexenyl radicals
revealed a unique contrast in the mode of ring closure
of the radicals.11 In this context, we undertook a study
on the radical cyclization of the sulfides 3a–d, sulfones
4a–d and sulfoxides 5a,b. Here we report the results.
The starting materials 4-(20-bromobenzylsulfanyl)-1-
alkyl-1H-quinolin-2-ones 3 (X = S) were prepared in
80–85% yield by the phase transfer catalyzed alkylation
of 4-mercaptoquinolone 1 with either 2-bromobenzyl
bromide (2a) or 2-bromo-5-methoxybenzyl bromide
(2b) in chloroform and 1% aq NaOH solution in the
presence of benzyltriethylammonium chloride (BTEAC)
at room temperature for 3 h. The other starting
materials 4-(20-bromobenzylsulfonyl)-1-alkyl-1H-quino-
lin-2-ones 4 (X = SO2) were synthesized from the
n
sulfur heterocycles by Bu3SnH mediated cyclization.8
b-Scission is a competitive side reaction for thiyl radicals
Keywords: Heterocyclic compounds; Sulfur heterocycles; Organotin
reagent; 4-Mercaptoquinolone; b-Scission; 6-endo-Trig.
*
Corresponding author. Tel.: +91 33 2582 7521; fax: +91 33 2582
8282; e-mail: kcm_ku@yahoo.co.in
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.07.151

6656
K. C. Majumdar et al. / Tetrahedron Letters 46 (2005) 6655–6658
R2
Br
SH
S
Br
Br
R1
R2 Yield (%)
85
i
+
CH3
H
3a
3b
3c
O
R2
O
N
R1
N
R1
CH3 OCH3 83
C2H5 85
C2H5 OCH3 80
H
3d
1a R1 = CH3
1b R1 = C2H5
2a R2 = H
ii
iii
2b R2 = OCH3
R2
R2
O
O
S
S
O
Br
Br
R1
CH3
R2 Yield (%)
98
H
4a
4b
O
O
CH3 OCH3 97
C2H5 98
C2H5 OCH3 96
N
N
R1
4c
4d
H
R1
R2 Yield (%)
90
CH3 OCH3 92
R1
CH3
H
5a
5b
Scheme 1. Reagents and conditions: (i) 1% aq NaOH–CHCl3, BTEAC, 3 h, rt; (ii) m-CPBA (2 equiv), CH2Cl2, stirring, 3–4 h, rt; (iii) m-CPBA
(1 equiv), CH2Cl2, stirring, 1 h, 0–5 °C.
corresponding sulfides by treatment with m-CPBA at
room temperature (Scheme 1).
strates 3b–d and 4b–d were also treated similarly with
nBu3SnH and AIBN to give exclusively the [6,6]thiopyr-
anopyridone derivatives 6b–d,f,g in 60–88% yields
(Scheme 2).
Compounds 3 and 4 were characterized from their ele-
mental analyses and spectroscopic data. The IR spec-
trum of compound 4a showed characteristic S@O
stretching frequencies at mmax 1305 (sym.) and 1137
(asym.) cmꢀ1. The two proton singlet due to –SCH2 pro-
tons of 3a at d 4.36 was shifted by 0.39 ppm downfield in
4a. The substrate 3a was refluxed in dry degassed C6H6
We attempted to extend this reaction to 4-(20-
bromobenzylsulfinyl)-1-alkyl-1H-quinolin-2-ones (5a,b),
but the starting materials decomposed and no cyclized
products were obtained.
n
under a nitrogen atmosphere with Bu3SnH in the pres-
The formation of a six-membered sulfur heterocyclic
ring in products 6 along with small amounts of b-scis-
sion products can be best explained by the addition of
a hydrogen radical to the intermediate radical 9, which
in turn is formed from the aryl radical 8 by a Ô6-endoÕ
ring closure. An alternative route, via Ô5-exoÕ ring clo-
sure to generate spiro heterocyclic radical14 10 with a
subsequent neophyl rearrangement15 has also been con-
sidered (Scheme 3).
ence of AIBN as an initiator for 1 h to give the cyclic
product 6a12 (yield 65%) accompanied by a small quan-
tity of the b-scission product. We were able to separate
the b-scission product in the case of compound 3b
(12%). The b-scission is controlled by conversion of
the sulfide to the sulfone. Exposure of the sulfone 4a
to nBu3SnH under the same conditions as described
above afforded the cyclized sulfone 6e13 (X = SO2) in
90% yield. The structures of the compounds
6
1
(X = S,SO2) were readily elucidated by H NMR spec-
troscopy, which a exhibited one proton doublet at d
4.21 (J = 4 Hz) and another one proton doublet at d
4.42 (J = 4 Hz) due to ring junction protons Hd and
Hc, respectively, for 6a (X = S) where as the same two
protons resonated at d 4.44 (J = 6 Hz) and d 4.54
(J = 6 Hz), respectively, for 6e (X = SO2). The stereo-
chemistry of the ring fusion of the cyclic system can be
surmised from the molecular model (Dreiding Model),
which shows a strain free cis-arrangement and also from
the small coupling constants 6a (X = S, J = 4 Hz) and
6e (X = SO2, J = 6 Hz). The 13C spectrum of 6
(X = S,SO2) also supported the proposed structure.
The 13C NMR chemical shifts as well as the multiplicity
of compound 6 was established by a DEPT experiment.
There are eleven carbons carrying hydrogen atoms, one
CH3, one CH2 and nine CH moieties. The mass spectra
of compounds 6a and 6e showed molecular ion peaks at
m/z = 281 and 313 (M+), respectively. The other sub-
However, the 5-exo-cyclization to form the spiro hetero-
cyclic radical 10 followed by a neophyl rearrangement is
highly unlikely with the present systems. It is known
that b-fragmentation of alkyl thiyl radicals is very
fast16 (>108 sꢀ1) compared to neophyl-type rearrange-
ments, which are much slower9a (about 103–104 sꢀ1).
Therefore, neophyl rearrangement of radical 10 cannot
compete with the b-fragmentation reaction, which
would lead to another product. The other reason is that
the intermediate tertiary radical 9 is more stable than the
spiro heterocyclic radical 10. Inspection of molecular
models indicate that the radical intermediate 9 should
be more stable due to excellent overlapping of the
p-orbital of the radical centre with the neighbouring aro-
matic p-system and also due to the greater polarization of
the sulfur atom.17 The stabilized conformational intermedi-
ate radical 9 gives preferably cis-products, the usual
reduced product and the dihydro heterocyclic ring is iso-
lated in good yield. All the starting materials gave the

K. C. Majumdar et al. / Tetrahedron Letters 46 (2005) 6655–6658
6657
R2
3
R2
2
Me
R2
2a
1X
X
N
4
SH
Hc
12
9
6a
Br
5
8b
2b
11
10
6b
6
Hd
+
7
O
O
8a
O
N
R1
8N
R1
R1
3. X = S
4. X = SO2
6
7 (10-15%)
X
R1
R2 Yield(%)
65
X
R1
SO2 CH3
SO2 CH3 OCH3 88
R2 Yield(%)
6a
6b
6c
6d
S
S
S
S
CH3
H
6e
H
90
CH3 OCH3 63
C2H5 65
C2H5 OCH3 60
6f
H
SO2
SO2
C2H5
H
85
6g
6h
C2H5 OCH3 80
Scheme 2. Regents and conditions: nBu3SnH, AIBN, benzene, reflux, 1–4 h.
R2
R2
R2
X
N
X
X
.
Br
O
.
5-exo
N
R1
3, 4
O
O
N
R1
R1
8
10
6-endo
Neophyl
Rearrangement
R2
R2
X
X
Hc
.
.
+H
Hd
O
N
R1
O
N
R1
9
6
β-scission
R2
.
Me
R2
R2
Me
S
SH
S
.
+H
Bu3SnH
O
N
R1
O
O
N
R1
N
R1
7
12
11
Scheme 3.
reduced six-membered heterocyclic ring regioselectively
thank the DST (New Delhi) for providing a UV–vis
spectrophotometer and FT-IR spectrometer under the
DST-FIST programme.
n
via Bu3SnH mediated cyclization.18 The methodology
described here is mild and interesting by its simplicity.
Acknowledgements
Supplementary data
We thank the CSIR (New Delhi) for financial assistance.
Two of us (P.P.M. and A.B.) are thankful to CSIR
(New Delhi) for Senior Research Fellowships. We also
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.07.151.

6658
K. C. Majumdar et al. / Tetrahedron Letters 46 (2005) 6655–6658
(CDCl3, 75.5 MHz): dC = 30.1 (C-2), 30.27 (–NCH3), 40.7
References and notes
(C-6b), 47.7 (C-6a), 115.3 (C-9), 123.1 (C-12), 124.9
(C-8b), 126.5 (C-11), 127.7 (C-6), 128.2 (C-4), 128.3
(C-3), 129.0 (C-5), 132.2 (C-10), 132.5 (C-2a), 133.0
(C-2b), 139.8 (C-8a), 168.2 (C-7). MS: m/z = 281 (M+).
UV (EtOH): kmax = 211, 216, 233, 359 nm. Anal. Calcd
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72.79, H, 5.20, N, 5.27.
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.
1H NMR (CDCl3, 300 MHz): dH = 3.44 (s, 3H, –NCH3),
4.33 (d, J = 15 Hz, 1H, –SO2CH), 4.42 (d, J = 15 Hz, 1H,
–SO2CH), 4.44 (d, J = 6 Hz, 1H, –CCHd), 4.54 (d,
J = 6 Hz, 1H, –CCHc), 7.13 (m, 3H, ArH), 7.34 (m, 5H,
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IR (KBr): mmax = 753, 1602, 1674, 2923 cmꢀ1 1H NMR
.
(CDCl3, 300 MHz): dH = 3.45 (s, 3H, –NCH3), 3.88 (d,
J = 16 Hz, 1H, –SCH), 4.06 (d, J = 16 Hz, 1H, –SCH),
4.11 (d, J = 4 Hz, 1H, –CCHd), 4.42 (d, J = 4 Hz, 1H,
–CCHc), 7.06 (m, 2H, ArH), 7.20 (m, 6H, ArH). 13C NMR