Thiophenol-mediated intramolecular radical cyclization: an efficient method for the synthesis of benzoxocine derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.07.030

A new, efficient, high yielding method for the synthesis of benzoxocine derivatives has been developed via a thiophenol-mediated intramolecular 8-endo radical cyclization. This method allowed the synthesis of the backbone of several sesquiterpenes.

Full text of DOI:10.1016/j.tetlet.2008.07.030

Tetrahedron Letters 49 (2008) 5597–5600
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Tetrahedron Letters
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Thiophenol-mediated intramolecular radical cyclization: an efficient
method for the synthesis of benzoxocine derivatives
*
Krishna C. Majumdar , K. Ray, P. Debnath, P. K. Maji, N. Kundu
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new, efficient, high yielding method for the synthesis of benzoxocine derivatives has been developed
via a thiophenol-mediated intramolecular 8-endo radical cyclization. This method allowed the synthesis
of the backbone of several sesquiterpenes.
Received 27 May 2008
Revised 2 July 2008
Accepted 5 July 2008
Available online 9 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Thiophenol
Benzoxocines
8-endo Trig
Tandem cyclization
The search for new methods for the construction of organic
molecules from simple starting materials is an ongoing challenge
for organic chemists. The synthesis of medium and large ring
ethers, especially those annulated with aromatic rings such as ben-
zoxepines and benzooxocines, is of current interest due to their
presence in a large number of bioactive natural products.1 Some
examples of natural products containing the 3,4,5,6-tetrahydro-
2H-benzo[b]oxocine core structure include helianane,2 heliannuols
RCM.9 Langer et al. reported the synthesis of 2,5-benzoxepins
and 5,6-dihydro-2H-benzo[b]oxocines by the combination of
[3+3] cyclizations and RCM.10 However, general cost effective
methods for the synthesis of these ring systems under mild reac-
tion conditions are scarce.
Intramolecular radical cyclization reactions have been devel-
oped for carbon–carbon bond formation, and represent a powerful
tool in modern synthetic chemistry.11 Although tin hydride medi-
ated radical reactions have been used for the synthesis of medium-
sized oxacycles,12 there are many drawbacks13 associated with
such tin-based radical reactions. It is therefore not surprising that
many groups have started research programs directed towards tin-
free radical chemistry.14,15 Recently, Naito et al.16 explored a new,
efficient, tin-free carbon–carbon bond forming process based on
sulfanyl radical17,18 addition and cyclization. In our earlier study,19
we reported a novel, high yielding protocol for the construction of
medium-sized cyclic ethers by thiophenol-mediated tandem radi-
cal addition–cyclizations of various enyne systems. The success of
this methodology prompted us to undertake a further study on
thiophenol-mediated radical cyclizations towards the synthesis
of benzoxocine derivatives which would provide a procedure for
the construction of the benzoxocine skeleton present as a basic
structural moiety in a number of natural sesquiterpenes.
The radical precursors 2a–g required for the present investiga-
tion were synthesized in 88–96% yields by refluxing 2-allyl phenols
with propargyl bromide in dry acetone in the presence of
anhydrous K2CO3 (Scheme 1). The 2-allyl phenols were in turn pre-
pared by Claisen rearrangement of the corresponding allylphenyl
ethers.
A
and K,3,4 and protosappanine B.5 Sevaral 5,6-dihydro-2H-
benzo[b]oxocines are found in heliannuols G and H,2 specionine
and sophoroside A.6 The characteristic phytotoxic activity and
the unique structural features enshrined in these compounds have
made them attractive targets for synthesis.7
OH
HO
HO
X
O
O
O
H
Helianane
Heliannuol H
Heliannuol A, X =
OH
Heliannuol K, X = O
Snieckus reported the synthesis of benzene-fused oxygen
heterocycles by combination of directed-ortho-metalation and ring
closing metathesis (RCM).8 A number of benzo[b]oxepin and
benzo[b]oxocine natural products were also prepared based on
* Corresponding author. Tel.: +91 33 2582 7521; fax: +91 33 25828282.
E-mail address: kcm_ku@yahoo.co.in (K. C. Majumdar).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.030

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K. C. Majumdar et al. / Tetrahedron Letters 49 (2008) 5597–5600
Table 1
R1
R4
R1
Thiophenol-mediated radical cyclizations of 2b–g to 3b–ga
R2
R3
O
R2
R3
OH
(i)
Entry
Starting material 2
Product 3
Yield (%)
76
H
H
H3C
O
R4
2a-g
O
1a-g
(88-96%)
H3C
SPh
SPh
2a. R1 = R4 = H, R2 = CH3, R3 = Cl
2b. R1 = R3 = H, R2 = R4 = CH3
2c. R1 = R2 = R4 = H, R3 = CH3
2d. R1 = R2 =CH3, R3 = R4 = H
2e. R1= R3 = CH3, R2 = R4 = H
2g. R1 = R2 = R3 = H, R4 = CH3
2f. R1 = R2 = R3 = H, R4 = Cl
1
2b
CH3
3b
CH3
O
O
Scheme 1. Synthesis of starting materials. Reagents and conditions: (i) propargyl
bromide, dry acetone, K2CO3, reflux, 4–6 h.
2
3
85
82
H3C
H3C
H3C
H3C
2c15b
CH3
3c
The alkenyl radicals were generated by the addition of phen-
ylsulfanyl radicals to the terminal alkynes and their efficiency in
tandem cyclizations were examined. Initially, substrate 2a was
studied under different conditions.
CH3
H
H
O
O
SPh
SPh
A diastereomeric mixture of the corresponding vinyl sulfanyl-
phenyl adduct was formed in 82%, when a 0.1 M solution of 2a,
PhSH (atmosphere, 2 equiv) and AIBN (2 equiv) was refluxed in
dry t-butanol for 4 h under a nitrogen atmosphere however, no
cyclization product was detected. The failure of cyclization led us
to consider changing the solvent. After surveying the reaction con-
ditions using 2a as precursor, we found that using 0.01 M benzene
solution was effective for the radical cyclization which gave as 82%
of cyclized product 3a20 (Scheme 2). Under these reaction condi-
tions, formation of the reduced vinyl adduct was not observed.
Interestingly, the amount of initiator played a crucial role in this
process. The use of 2 equiv of AIBN was required for completion of
the reaction and to obtain the high yields of the cyclized products.
With 1 equiv of AIBN, the reactions were extremely slow and gave
lower yields of the cyclization product (37%); with 0.5 equiv of
AIBN, no reaction occurred. Dimerization of thiyl radicals leading
to diphenyl disulfide could explain this inefficiency. The use of a
stoichiometric amount of AIBN allows regeneration of the phen-
ylsulfanyl radicals from either thiophenol or disulfide. Changing
the solvent to the higher boiling toluene did not improve the yield
of product further.
2d
CH3
3d
CH3
O
O
4
5
80
H3C
H3C
2e
3e
H
H
O
O
72 (3:2)b
SPh
SPh
2f
Cl
3f
Cl
O
O
6
78 (3:2)b
2g
CH3
3g
CH3
a
Isolated yield.
Diastereometric ratio determined from the 1H NMR spectrum.
b
The stereochemistry of the exocyclic double bond in 3a was
found to be exclusively E on the basis of an NOE correlation
between the methylene (–OCH2) resonance at d = 4.46 ppm and
the exocyclic proton at d = 5.90 ppm. The stereochemical outcome
of the reaction is difficult to understand. Naito et al. obtained a
mixture of isomers and the main stereoisomer was the one in
which the SPh group and the new C–C bond were anti to each
other. In our earlier work,19 we obtained exclusively the Z-isomer
where the SPh group and newly formed C–C bond were anti to each
other. The reason for the E-selectivity is not clear at present.
In order to examine the versatility of this intramolecular addi-
tion–cyclization reaction, enynes 2b–g were reacted under the
optimized conditions and after column chromatography, afforded
benzoxocines 3b–g in 72–85% yields. The results are summarized
in Table 1. When the substrates 2a–e were treated with AIBN
and PhSH in refluxing benzene, cyclization proceeded with 100%
diastereoselectivity. However, reaction of substrates 2f and 2g hav-
ing an ortho substituent with respect to the allyl group, under
similar conditions, resulted in a diastereomeric mixture of cyclized
products 3f and 3g in 72% and 78% yields, respectively. The
products were isolated as diastereomeric mixtures in the ratios
3:2, which were not separable by column chromatography.
The 8-endo radical cyclization was further extended for the
synthesis of naphthyl annulated oxocine derivative 3h. Here, it is
important to note that under the above optimized conditions,
substrate 2h15b gave the cyclized product 3h in 55% yield along
with recovered starting material (35%). However, when the reac-
PhS
H
H
O
H3C
O
O
(i)
H3C
Cl
O
(i)
SPh
Cl
2a
2h
3a (82%)
3h (88%)
Scheme 2. Thiophenol-mediated radical cyclization. Reagents and conditions: (i)
Scheme 3. Sulfanyl radical cyclization onto a naphthalene moiety. Reagents and
PhSH (2 equiv), AIBN (2 equiv), benzene, reflux.
conditions: (i) PhSH (2 equiv), AIBN (2 equiv), toluene, reflux.

K. C. Majumdar et al. / Tetrahedron Letters 49 (2008) 5597–5600
5599
.
O
SPh
O
O
SPh
.
b
SPh
a
7--exo-trig
Path b
.
4
2
6
7
8-endo-trig
Neophyl
rearrangement
a
Path
H
H
O
O
O
PhSH
SPh
SPh
.
SPh
.
5
3
Scheme 4. Mechanism of the sulfanyl radical addition–cyclization reaction.
6. (a) Nohara, T.; Kinjo, J.; Furusawa, J.; Sakai, Y.; Inoue, M. Phytochemistry 1993,
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tion was carried out in refluxing toluene with PhSH (2 equiv) and
AIBN (2 equiv), the 8-endo cyclized product was obtained in 88%
yield (Scheme 3).
The proposed mechanism of the thiophenol-mediated reaction
is depicted in Scheme 4. The phenylsulfanyl radical, generated
from thiophenol and AIBN, adds to the terminal alkyne of enyne
2 to form vinyl radical 4. The high E-selectivity of double bond
formation may be explained by the trapping of the intermediary
vinyl radical 4 (via as 8-endo-trig mode, path a) from the opposite
face, followed by hydride radical transfer from thiophenol to the
radical intermediate 5 to afford product 3. An alternative pathway
(path b), a 7-exo cyclization process followed by 1,2-alkenyl migra-
tion via a cyclopropyl methyl radical 7 (neophyl rearrangement)
would also lead to the same product 3. This may be an indication
that the reaction is proceeds via a ring expansion process (Scheme
4, path b), that is ring opening of the cyclopropylmethyl radical
intermediate may be stereoselective.
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In conclusion, we have developed a new and efficient method
for the synthesis of benzoxocine derivatives 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 for the syn-
thesis of benzoxocine derivatives. Moreover, during the cyclization
process, a phenylthio moiety is incorporated into the final prod-
ucts. This functionalization is particularly attractive for further
transformation of the products.21 The application of this strategy
for the synthesis of benzoxepine and benzoxocine related natural
products is currently underway in our laboratory.
15. (a) Mandal, S. K.; Roy, S. C. Tetrahedron Lett. 2006, 47, 1599; (b) Mandal, S. K.;
Roy, S. C. Tetrahedron 2007, 63, 11341.
Acknowledgements
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Bradley, M. Tetrahedron Lett. 2003, 44, 503; (d) Fernandez, M.; Alonso, R. Org.
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We thank the CSIR (New Delhi) and the DST (New Delhi) for
financial assistance. Two of us (P.D. and K.R.), and one of us
(P.K.M.), are thankful to the CSIR and UGC (New Delhi), respec-
tively, for their fellowships.
References and notes
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20. All new compounds reported here gave satisfactory spectroscopic and/or
analytical data. Data for compound 3a: Yield: 82%; solid; mp: 88–90 °C
(petroleum ether); IR (KBr):
m ;
= 2937, 1582, 1457, 1255, 1024 cmÀ1 1H NMR
(CDCl3, 500 MHz): dH 1.76–1.81 (m, 2H), 2.32 (s, 3H), 2.44 (t, J = 6.1 Hz, 2H),
2.83 (t, J = 5.9 Hz, 2H), 4.46 (s, 2H), 5.90 (s, 1H), 6.82 (d, J = 8.5 Hz, 1H),

5600
K. C. Majumdar et al. / Tetrahedron Letters 49 (2008) 5597–5600
6.96–6.98 (m, 2H), 7.14–7.17 (m, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.21–7.25
Araujo, N. C.; Korshin, E. E.; Bickley, J. F.; Ward, S. A.; Bray, P. G.; Pasini, E.;
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(m, 2H) ppm; 13C NMR (CDCl3, 125 MHz): 16.7, 26.4, 27.4, 32.2, 82.3,
120.4, 125.5, 126.8, 128.1, 129.1, 129.4, 130.7, 135.2, 136.2, 137.8, 140.5,
156.0 ppm. HRMS: m/z calcd for C19H19ClOSNa [M+Na]+: 353.0743; found:
353.0742.
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