Thiol mediated 8-endo-trig radical cyclization: an easy access to medium-sized cyclic ethers

Article abstract of DOI:10.1016/j.tetlet.2007.10.147

An efficient new method for the synthesis of eight-membered heterocycles has been developed via a thiophenol mediated intramolecular 8-endo radical cyclization reaction. Alkenyl radicals are generated from easily available terminal alkynes and thiophenol.

Full text of DOI:10.1016/j.tetlet.2007.10.147

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Tetrahedron Letters 48 (2007) 9124–9127
Thiol mediated 8-endo-trig radical cyclization:
an easy access to medium-sized cyclic ethers
K. C. Majumdar,* P. K. Maji, K. Ray and P. Debnath
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
Received 31 August 2007; revised 15 October 2007; accepted 25 October 2007
Available online 1 November 2007
Abstract—An efficient new method for the synthesis of eight-membered heterocycles has been developed via a thiophenol mediated
intramolecular 8-endo radical cyclization reaction. Alkenyl radicals are generated from easily available terminal alkynes and
thiophenol.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
cient reagent for this purpose. Moreover, during the
cyclization process, a phenylthio moiety is incorporated
into the final cyclized products. This functionalization is
particularly attractive for further transformation of the
products.6a,7b To the best of our knowledge, only one
example of a thiophenol mediated 8-endo-trig radical
cyclization process has been reported.4a In continuation
of our studies on thiophenol mediated radical cycli-
zation reactions for the synthesis of heterocycles,8 we
report our preliminary results, on the thiophenol medi-
ated 8-endo radical cyclizations toward the synthesis of
oxocine-annulated heterocycles.
Several methods1 have been developed for the construc-
tion of medium-sized oxacycle rings including ring-
closing metathesis (RCM). Recently, radical cyclization
reactions have been developed as a potential method
for the synthesis of various types of cyclic compounds
via intramolecular carbon–carbon bond forming pro-
cesses.2 Much attention has been paid to the construc-
tion of five- and six-membered rings by radical
cyclization.2 However, there are problems associated
with the formation of medium-sized rings using the
aforesaid protocol. Several authors were able to prepare
seven-membered ring systems using a tin hydride-
mediated 7-endo-trig cyclization strategy.3 There are
few examples in the literature for the construction of
eight-membered ring systems by radical cyclization.4
Recently, Roy et al.5 described titanocene(III) mediated
8-endo radical cyclization for the synthesis of eight-
membered cyclic ethers. Naito et al.6,7a have explored
a new, efficient carbon–carbon bond forming reaction
based on sulfanyl radical addition and cyclization. These
radical reactions proceed via the formation of a carbon-
centered radical species generated by the addition of a
sulfanyl radical to an unsaturated bond, followed by
intramolecular addition of the resulting carbon-centered
radical to a multiple bond. Thiophenol7 is a very effi-
2. Results and discussions
We chose substrates 3a–e to investigate the generality of
the sulfanyl radical addition–cyclization. The cyclization
precursors 3a,b were prepared by the reaction of com-
pounds 1a,b with propargyl bromide 2 according to an
earlier published procedure9a (Scheme 1). Similarly,
other enyne derivatives 3c–e were also prepared.9b–d
The alkenyl radicals were generated by the addition of
thiophenol to the terminal alkynes and their efficiency
in tandem cyclization reactions were examined. Initially,
substrate 3a was investigated under different conditions.
Benzene, the most common solvent for radical reactions,
was not the best choice for this radical cyclization pro-
cess. The best results were obtained in refluxing t-buta-
nol with slow addition of thiophenol (2 equiv) in the
presence of the radical initiator AIBN. Interestingly,
Keywords: Thiophenol; Oxacycles; 8-endo Trig; Tandem cyclization.
*
Corresponding author. Tel.: +91 33 2582 7521; fax: +91 33 2582
8282; e-mail: kcm_ku@yahoo.co.in
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.147

K. C. Majumdar et al. / Tetrahedron Letters 48 (2007) 9124–9127
9125
O
O
H3C
O
O
R
Br
H3C
O
OH
N
N
+
(i)
N
N
CH3
CH3
R
3a,b9a
R = H
2
1a, R = H
1b, R = CH3
R = CH3
Scheme 1. Reagents and conditions: (i) dry acetone, anhyd K2CO3, reflux, 1.5–2 h.
the amount of the initiator played a crucial role in this
process. The use of 2 equiv of AIBN with respect to
the substrate proved to be the best compromise between
the addition of thiophenol and cyclization, and the
cyclized product 4a was isolated as a crystalline solid
in 83% yield (Scheme 2). A stoichiometric amount of
AIBN with respect to the thiophenol was required for
the reaction to go to completion indicating that the
redical process was not efficient under the reaction
conditions. Dimerization of thiyl radicals leading to
diphenyl disulfide could explain this inefficiency. The
use of a stoichiometric amount of AIBN allows regener-
ation of the thiyl radicals from either thiophenol or
disulfide.10 Changing the solvent to higher boiling tolu-
ene did not improve the yield of the product. The struc-
ture of 4a was confirmed by single crystal X-ray
diffraction11 (Fig. 1) and was characterized as 1,3-di-
methyl-7-[Z-1(phenylsulfanyl)methylidene]-2,3,4,6,7,8,9,
10-octahydro-1H-oxocino[3,2-d]-pyrimidine.
Encouraged by this result, enynes 3b, 3c, and 3d were
treated in a similar manner to afford 4b, 4c, and 4d in
82–85% yields. The results are summarized in Table 1.
To synthesize a spirocyclic compound, we employed
C,C-allyl-propargyl derivative 3e9d which was formed
during the preparation of its isomer 3d. Radical cycliza-
tion of 3e under the above reaction conditions for 2.5 h
afforded spirocarbocycle 4e in 92% yield (Table 1).
The proposed mechanism of the thiophenol mediated
reaction is depicted in Scheme 3. The phenyl thiyl radi-
cal, generated from thiophenol and AIBN, adds to the
terminal alkyne to form vinyl radical 5. This vinyl radi-
cal may undergo an 8-endo trig intramolecular cycliza-
tion with the adjacent alkene to form intermediate
radical 6 which on abstraction of a H radical from thio-
phenol affords product 4.
O
O
SPh
H3C
O
O
O
Table 1. Sulfanyl radical addition and cyclization of 3b–e
H3C
O
N
(i)
N
H
Starting material 3
Product 4
Yield (%)
N
O
O
SPh
H
N
O
H3C
N
H3C
O
O
CH3
CH3
N
82
3a
O
N
4a (83%)
N
CH3
CH3 CH3
CH3
3b9a
Scheme 2. Reagents and conditions: (i) dry t-butanol, PhSH, AIBN,
reflux, 2 h.
4b
H
SPh
O
84
O
O
N
O
CH3
N
3c9b
CH3
4c
PhS
H
O
O
85
N
N
O
Ph
3d9c
N
N
O
O
Ph
4d
O
O
H
92
SPh
N
N
N
N
O
Ph
Ph
3e9d
4e
Figure 1. X-ray crystal structure of compound 4a.

9126
K. C. Majumdar et al. / Tetrahedron Letters 48 (2007) 9124–9127
O
O
H3C
O
O
SPh
H3C
O
O
.
.
N
N
SPh
N
N
CH3
CH3
3a
5
O
SPh
O
N
SPh
O
H3C
O
H3C
O
N
H
N
H
H-SPh
O
N
.
CH3
4a
CH3
6
Scheme 3. Mechanism of the thiophenol-mediated cyclization.
In conclusion, we have developed a new efficient meth-
odology for the synthesis of 8-membered ring ethers
via sulfanyl radical addition–cyclization. Alkenyl
radicals are generated from readily available terminal
alkynes and thiophenol. The procedure presented here
is more economic than other methods.1,5 The reaction
was found to proceed under mild conditions. We believe
that this procedure strongly enhances the synthetic
potential of the addition–cyclization reaction developed
by Naito. Application of this strategy for the synthesis
of natural products is currently underway in our
laboratory.
column chromatography using gradient elution with
ethyl acetate:petroleum ether (1:4) to afford the crystal-
line solid 4a.
3.2. Compound 4a
Yield: 83%; solid; mp: 110–111 ꢁC; IR (KBr): m = 2916,
1715, 1618 cmÀ1
;
1H NMR (CDCl3, 500 MHz):
dH = 1.86–1.98 (m, 2H), 2.45–2.48 (m, 2H), 2.82–2.84
(m, 2H), 3.21 (s, 3H), 3.45 (s, 3H), 4.83 (s, 2H), 5.10
(s, 1H), 7.08 (d, J = 7.4 Hz, 1H), 7.17–7.29 (m,
4H) ppm; 13C NMR (100 MHz): 26.3, 28.3, 29.2, 30.8,
31.8, 67.4, 118.8, 120.1, 127.0, 129.0, 130.4, 131.1,
134.7, 143.4, 151.3, 155.6 ppm; MS: m/z = 344 (M+).
Anal. Calcd for C18H20N2O3S: C, 62.77; H, 5.85; N,
8.13. Found: C, 62.86; H, 5.89; N, 8.19.
3. General procedure for the preparation of
compounds 3a–e
Compounds 3a–e were synthesized according to the
earlier published procedure.
3.3. Compound 4b
9
Yield: 82%; solid; mp: 102–104 ꢁC; IR (KBr): m = 2923,
Compounds 3a,b,9a 3c,9b 3d,9c and 3e9d were reported
earlier.
1717, 1634 cmÀ1
;
1H NMR (CDCl3, 400 MHz):
dH = 0.78 (d, J = 7.0 Hz, 3H), 1.62–1.68 (m, 2H),
1.90–1.95 (m, 1H), 2.16–2.21 (m, 1H), 2.31–2.36 (m,
1H), 2.49 (s, 3H), 3.28 (s, 3H), 3.41 (d, J = 14.2 Hz,
1H), 3.63 (d, J = 14.2 Hz, 1H), 5.08 (s, 1H), 7.15–7.22
(m, 2H), 7.27–7.34 (m, 3H) ppm; 13C NMR
(100 MHz): 14.8, 25.1, 29.1, 29.6, 32.6, 35.4, 68.0,
117.6, 119.7, 127.1, 129.0, 130.1, 131.5, 136.0, 144.6,
151.2, 157.0 ppm; MS: m/z = 358 (M+). Anal. Calcd
for C19H22N2O3S: C, 63.66; H, 6.19; N, 7.82. Found:
C, 63.85; H, 6.30; N, 7.87.
3.1. Typical experimental procedure for radical
cyclization of compounds 3a–e
A deoxygenated solution of thiophenol (2 equiv) in dry
t-butanol was added dropwise to a solution of the
radical precursor 3a (0.29 mmol, 100 mg) in refluxing
anhydrous t-butanol under a nitrogen atmosphere.
The radical initiator AIBN (0.29 mmol, 50 mg) was
added and the mixture was refluxed until complete dis-
appearance of the starting material (TLC). The solvent
was removed under reduced pressure. The residue was
dissolved in CH2Cl2 (10 mL) and stirred with saturated
NaHCO3 solution (10 mL) for 2 h. The aqueous layer
was extracted with CH2Cl2 (3 · 15 mL) and the
combined CH2Cl2 extracts were washed with water
(2 · 20 mL), brine solution (1 · 20 mL), and dried
(Na2SO4). The solvent was evaporated under reduced
pressure. The crude product was purified by silica gel
3.4. Compound 4c
Yield: 84%; solid; mp: 88–90 ꢁC; IR (KBr): m = 2922,
1
1735, 1681 cmÀ1; H NMR (CDCl3, 500 MHz): dH =
1.49–1.64 (m, 2H), 1.74–1.79 (m, 1H), 1.86–1.91 (m,
1H), 2.04–2.10 (m, 1H), 2.43–2.49 (m, 1H), 3.46 (s,
3H), 3.50 (d, J = 13.8 Hz, 1H), 3.86 (d, J = 13.8 Hz,
1H), 5.48 (s, 1H), 6.45 (dd, J = 1.3, 7.6 Hz, 1H), 6.87
(t, J = 7.5 Hz, 1H), 7.01 (d, J = 7.4 Hz, 1H), 7.26–7.35

K. C. Majumdar et al. / Tetrahedron Letters 48 (2007) 9124–9127
9127
(m, 4H), 7.45 (d, J = 7.1 Hz, 2H) ppm; 13C NMR
(125 MHz): 18.4, 26.9, 30.4, 33.0, 42.6, 54.8, 115.7,
122.2, 124.5, 127.2, 128.90, 128.94, 129.1, 129.4, 131.6,
135.8, 137.1, 140.4, 157.5, 194.4 ppm; HRMS: m/z calcd
for C22H21NO2SNa [M+Na]+: 386.1172; found:
386.1191.
Kaptein, B.; Schoemaker, H. E. Tetrahedron 1994, 50,
12415, and references cited therein.
2. (a) Giese, B. Radicals in Organic Synthesis: Formation of
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3.5. Compound 4d
Yield: 85%; solid; mp: 166–168 ꢁC; IR (KBr): m = 2921,
1713, 1678 cmÀ1
;
1H NMR (CDCl3, 500 MHz):
3. (a) Cid, M. M.; Dominguez, D.; Castedo, L.; Vazquez-
Lopez, E. M. Tetrahedron 1999, 55, 5599; (b) Magono, H.;
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Malacria, M. Tetrahedron 1994, 35, 8601; (e) Fidalgo, J.;
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Hollingworth, G. J.; Pattenden, G. Synlett 1996, 643; (d)
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5977.
dH = 1.86–2.02 (m, 2H), 2.23 (t, J = 5.6 Hz, 4H), 3.48
(d, J = 4.6 Hz, 2H), 5.43 (s, 1H), 7.06–7.12 (m, 2H),
7.17–7.24 (m, 3H), 7.30–7.36 (m, 2H), 7.43–7.52 (m,
4H), 8.16 (dd, J = 1.9, 7.6 Hz, 1H), 8.40 (dd, J = 1.9,
4.8 Hz, 1H) ppm; 13C NMR (100 MHz): 19.0, 29.0,
42.3, 60.4, 112.7, 119.2, 124.9, 125.8, 126.6, 127.0,
128.0, 128.4, 128.7, 128.8, 129.4, 129.5, 135.0, 141.0,
149.8, 150.5, 153.9, 172.2 ppm; MS: m/z = 426 (M+).
Anal. Calcd for C26H22N2O2S: C, 73.21; H, 5.20; N,
6.57. Found: C, 73.37; H, 5.16; N, 6.65.
3.6. Compound 4e
5. Mandal, S. K.; Roy, S. C. Tetrahedron Lett. 2006, 47,
1599.
Yield: 92%; solid; mp: 154–156 ꢁC; IR (KBr): m = 2927,
1709, 1657 cmÀ1
;
1H NMR (CDCl3, 400 MHz):
6. (a) Miyata, O.; Muroya, K.; Kobayashi, Y.; Yamanaka,
R.; Kajisa, S.; Koide, J.; Naito, T. Tetrahedron 2002, 58,
4459; (b) Miyata, O.; Ozawa, Y.; Ninomiya, I.; Naito, T.
Tetrahedron 2000, 56, 6199; (c) Miyata, O.; Kajisa, S.;
Ueda, M.; Yamauchi, M.; Naito, T. Chem. Pharm. Bull.
2005, 53, 995; (d) Miyata, O.; Yamanaka, K.; Ueda, M.;
Naito, T. Arkivoc 2003, iii, 220; (e) Naito, T.; Honda, Y.;
Miyata, O.; Ninomiya, I. J. Chem. Soc., Perkin Trans. 1
1995, 19; (f) Miyata, O.; Nishiguchi, A.; Ninomiya, I.;
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6922; (g) Miyata, O.; Nakajima, E.; Naito, T. Chem.
Pharm. Bull. 2001, 49, 213.
dH = 1.20–1.30 (m, 4H), 2.00–2.13 (m, 1H), 2.51–2.57
(m, 1H), 3.06–3.12 (m, 1H), 3.30–3.41 (m, 1H), 5.99 (t,
J = 2.2 Hz, 1H), 7.09–7.13 (m, 1H), 7.15–7.24 (m, 3H),
7.27–7.38 (m, 4H), 7.45–7.52 (m, 3H), 8.27 (d,
J = 6.3 Hz, 1H), 8.43 (d, J = 3.9 Hz, 1H) ppm; 13C
NMR (100 MHz): 29.6, 38.8, 39.2, 44.2, 63.2, 113.0,
119.0, 125.8, 125.9, 127.0, 128.7, 128.8, 128.9, 129.5,
132.2, 136.7, 136.8, 136.9, 149.8, 154.3, 173.7,
194.5 ppm; MS: m/z = 426 (M+). Anal. Calcd for
C26H22N2O2S: C, 73.21; H, 5.20; N, 6.57. Found: C,
73.44; H, 5.33; N, 6.62.
7. (a) Miyata, O.; Naito, T. C.R. Acad. Sci. Paris, Chim.
2001, 4, 401; (b) Lachia, M.; Denes, F.; Beaufils, F.;
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Fernandez, M.; Alonso, R. Org. Lett. 2005, 7, 11; (e)
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53, 5679; (f) Burke, S. D.; Jung, K. W. Tetrahedron Lett.
1994, 35, 5837; (g) Beaufils, F.; Denes, F.; Renaud, P. Org.
Lett. 2004, 6, 2563; (h) Capella, L.; Montevcehi, P. C.;
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L.; Calestani, G.; Leardini, R.; Minozzi, M.; Nanni, D.;
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Carta, P.; Puljic, N.; Robert, C.; Dhimane, A. L.;
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2007, 6, 1061.
Acknowledgments
We thank the CSIR (New Delhi) for financial assistance.
We thank Prof. A. T. Khan, Indian Institute of Techno-
logy, Guwahati, for the XRD data of 4a. Two of us
(P.D. and K.R.), and one of us (P.K.M.), are thankful
to the CSIR and UGC (New Delhi), respectively, for
the fellowships. We thank the DST (New Delhi) for pro-
viding UV–vis and IR spectrometers under the FIST
program.
8. (a) Majumdar, K. C.; Debnath, P.; Maji, P. K. Tetrahedron
Lett. 2007, 48, 5265; (b) Majumdar, K. C.; Debnath, P.;
Alam, S.; Maji, P. K. Tetrahedron Lett. 2007, 48, 7031.
9. (a) Majumdar, K. C.; Maji, P. K.; Rahaman, H.; Roy, B.
Lett. Org. Chem. 2006, 3, 845; (b) Majumdar, K. C.;
Debnath, P.; Samanta, S. Lett. Org. Chem. 2007, 4, 309;
(c) Majumdar, K. C.; Rahaman, H.; Islam, R.; Roy, B.
Tetrahedron Lett. 2006, 47, 2111; (d) Majumdar, K. C.;
Islam, R.; Rahaman, R.; Roy, B. Org. Biomol. Chem.
2006, 4, 2393.
References and notes
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11. CCDC reference no. for the CIF file of compound 4a:
CCDC-658345.