Wittig olefination and thiol mediated 7-endo-trig radical cyclization: novel synthesis of oxepin derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.10.134

Thiophenol-mediated 7-endo radical cyclization for the synthesis of seven-membered cyclic ethers is described. This method can be successfully applied to synthesize various benzoxepin derivatives, which are present in many natural products as building blo

Full text of DOI:10.1016/j.tetlet.2008.10.134

Tetrahedron Letters 50 (2009) 228–231
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Wittig olefination and thiol mediated 7-endo-trig radical
cyclization: novel synthesis of oxepin derivatives
*
K. C. Majumdar , Abu Taher
Department of Chemistry, University of Kalyani, Kalyani 741 235, WB, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Thiophenol-mediated 7-endo radical cyclization for the synthesis of seven-membered cyclic ethers is
described. This method can be successfully applied to synthesize various benzoxepin derivatives, which
are present in many natural products as building blocks. Alkenyl radicals are generated from easily avail-
able terminal alkynes and thiophenol.
Received 20 September 2008
Revised 23 October 2008
Accepted 28 October 2008
Available online 31 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Wittig reaction
Thiophenol
7-endo reaction
Oxepin derivatives
The synthesis of medium- and large-sized cyclic ethers annu-
lated with aromatic ring is a challenging problem to organic chem-
ists due to their presence in many bioactive natural products.1 The
seven-membered benzoxepin moiety is found in many natural
products, for example, heliannuol C,1c heliannuol D,2 plumbagic
acid lactones,3 pterulone,4 heliannuol B, and radulanins A, E, and
H.5 Besides, oxepin is an important structural subunit present in
biologically active naphthoxepin derivatives6 which have been
used as antipsychotic drugs. These biological activities encouraged
many research groups to synthesize these compounds.
oxa-heterocycles are also obtained by the application of ‘direct-
ortho-metalation-olefin-metathesis’ strategy10 and ‘[3+3] cycliza-
tion-olefin-metathesis’ strategy.11 Roy et al. reported the synthesis
of benzoannulated medium-sized cyclic ethers in moderate yields
using titanocene(III) chloride (Cp2TiCl)-mediated radical cycliza-
tion of epoxides.12 Recently, we have also reported13 the synthesis
of eight-membered cyclic ethers. There are several examples for
the construction of eight-membered cyclic ethers by radical cycli-
zation.12a,13,14 To our knowledge, there are only few examples in
the literature12b,15 for the construction of seven-membered cyclic
ethers by radical cyclization. Thiophenol is an efficient reagent16
for carrying out radical cyclization. These reasons have prompted
us to undertake a study on the synthesis of oxepin derivatives by
Several methodologies were developed for the construction of
medium-sized oxacycle rings including ring-closing metathesis
(RCM),7 Heck reaction,8 and radical cyclization.9 Benzo-fused
Figure 1. Single X-ray crystal structure of compound 4a.
* Corresponding author. Tel.: +91 033 25827521; fax: +91 033 2582 8282.
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.2008.10.134

K. C. Majumdar, A. Taher / Tetrahedron Letters 50 (2009) 228–231
229
CHO
R3
CHO
R1
R2
OH
R4
R1
R2
O
R1
R2
O
(i)
(ii)
R4
R4
R3
R3
2a-f
1a-f
3a-f
a. R1, R3, R4 = H, R2 = Me
b. R1, R3, R4 = H, R2 = Br
c. R1, R4 = Me, R2, R3 = H
d. R1 = Me, R2 = Cl, R3, R4 = H
e. R1, R3 = Me, R2, R4 = H
f. R1, R2 = 5,6-C4H4 (phenylene)
Scheme 1. Reagents and conditions: (i) propargyl bromide, anhydrous K2CO3, acetone, reflux, 3 h; (ii) PPh3MeI, nBuLi, THF, 0 °C–rt, 1 h.
Table 1
Table 2
Optimization of sulfanyl radical addition cyclization of 3a
Sulfanyl radical addition cyclization of 3(a–f) to 4(a–f)a
Entry
Starting material (3)
Product (4)
Yieldb (%)
88
O
O
H
O
O
H
SPh
Me
Me
AIBN (equiv)
1
4a
3a
SPh
Me
Me
Entry
PhSHa (equiv)
Solventb
Yield (%)
4a
3a
1
2
3
4
5
6
7
8
9
1.5
1.5
1.5
1.5
2.0
1.0
0.5
0.5
1.0
1.5
1.5
1.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.0
1.0
0.5
0.5
C6H6
t-BuOH
MeCN
EtOH
C6H6
C6H6
C6H6
C6H6
C6H6
C6H6
C6H6
C6H6
88
16
0
O
O
H
2
3
82
72
0
SPh
Br
Br
57
32
17
12
15
21
0
4b
3b
Me
O
Me
O
10
11
12
H
0
SPh
a
Me
4c
Me
3c
All reactions were carried out at 80 °C.
All reactions were carried out for 2 h.
b
O
O
H
thiophenol-mediated radical cyclization. Herein, we report the re-
sults (Fig. 1).
4
78
76
86
SPh
Cl
Cl
Me
4d
Me
3d
The required radical precursors 3a–f were prepared in moder-
ate to good yields by the Wittig reaction of substrate 2a–f. The Wit-
tig reagent was prepared from PPh3MeI in dry THF in the presence
of nBuLi at 0 °C for about 1 h. The Wittig precursors 2a–f were in
turn obtained by refluxing hydroxy-aldehyde 1a–f with propargyl
bromide in dry acetone in the presence of anhydrous K2CO3 and a
catalytic amount of NaI17 (Scheme 1).
Substrate 3a when subjected to radical cyclization in the pres-
ence of thiophenol (1.5 equiv) and AIBN (1.5 equiv) as radical initi-
ator in refluxing benzene under a nitrogen atmosphere for 2 h gave
4a18 in 88% yield. The optimized condition for thiophenol-medi-
ated radical cyclization was established through a series of exper-
iments, in which sequential changes were made in the amount of
thiophenol and radical initiator (AIBN) and also by changing the
solvent used for the reaction with the substrate 3a (Table 1).
Among the various solvents used, benzene was proven to be
superior than t-BuOH, MeCN, and EtOH. When t-BuOH was used,
only 16% cyclized product was obtained keeping the residual start-
ing material intact. The use of MeCN, EtOH as solvents did not give
any cyclized product.
O
Me
Me
O
H
5
SPh
Me
Me
3e
4e
PhS
H
O
6
O
3f
4f
a
All reactions were carried out using the optimized reaction conditions.
Isolated yields.
b
The use of more thiophenol than the requisite amount
(1.5 equiv) causes a lower yield of the cyclized product (entry 5).
This may be due to the formation of an adduct of thiophenol with
the terminal carbon atom of the alkyne. The use of thiophenol in
lower concentrations also decreases the yield of cyclized products
(entries 6–8).
The amount of AIBN played a vital role in this radical cyclization
reaction. When 1.5 equiv of AIBN was used, a characteristic yield
(12–88%, entries 5–7) of the cyclization product was obtained,
and the maximum yield was obtained when 1.5 equiv of thiophe-
nol was used. The use of 1 equiv of AIBN and varying the thiophe-

230
K. C. Majumdar, A. Taher / Tetrahedron Letters 50 (2009) 228–231
nol concentration reduced the yield of the cyclized product, and
the reaction became extremely slow (entries 8 and 9). No reaction
occurred when 0.5 equiv of AIBN was used (entries 11 and 12). A
stoichiometric amount of AIBN with respect to thiophenol was re-
quired to complete the reaction indicating that the chain process is
not very efficient under the reaction conditions. This inefficiency
can be explained by the dimerization of the thiyl radicals, but
when a stoichiometric amount of AIBN was used, free thiyl radical
was generated from either thiophenol or disulfides, which brought
about the cyclization reaction.
We had earlier reported13 the synthesis of benzoxocine deriva-
tives by thiol-mediated radical cyclization, where ortho-C-allylated
prop-2-ynyl substrates were utilized for the 8-endo-trig cyclization
to occur. It is difficult to form a seven-membered ring by the afore-
said protocol. Here, the ortho-vinyl prop-2-ynyl ethers have been
designed to achieve the exclusive endo-trig cyclization with the
advantage of forming the stable benzylic radical intermediate.
Other available methods7,21 for the synthesis of benzoxepin in-
volve Pd-catalyzed reactions and ring-closing metathesis, which
require costly reagents and complicated reaction conditions.
In conclusion, we have developed a useful protocol for the syn-
thesis of benzoxepin derivatives, which are an important core
structure of many naturally occurring bioactive compounds via
sulfanyl radical addition cyclization. The procedure applied here
is mild, less toxic, and less expensive. Finally, the products bear a
phenylthio substituent that offers many opportunities for further
transformation.16b,i,22
The other substrates 3b–f were also treated under this opti-
mized condition to afford the oxepin products 4b–f in 72–86%
yields. The results are summarized in Table 2.
The structure of thiophenol-mediated cyclization products 4
has been determined from their spectral data and single crystal
XRD data.19 The compounds 4 were found to be a seven-membered
cyclic ether having an exocyclic double bond, and the stereochem-
istry of the exocyclic double bond of compound 4 was found to be
Z, where –SPh and the new C–C bond formed are cis to each other.
Both the 6-exo-trig and 7-endo-trig modes of cyclizations are
favorable, according to Baldwin’s rule,20 to give the products 4
and 5 (Scheme 2). It is remarkable to note that here 7-endo cycliza-
tion has occurred to afford the oxepin derivative 4.
The mechanistic rationalization for the formation of product 4
by sulfanyl radical addition cyclization is depicted in Scheme 3. Ini-
tially, the phenyl sulfanyl radical generated from thiophenol and
AIBN adds to the terminal alkyne moiety to form the corresponding
vinyl radical intermediate 6. This vinyl radical intermediate 6 may
undergo a 7-endo-trig intramolecular cyclization with the adjacent
alkene to form the radical intermediate 9 which, on abstraction of a
proton from thiophenol, leads to the formation of product 4. The
predominant formation of product 4 may be explained not only
by the stability of the secondary alkyl radical 9 as opposed to that
of the primary alkyl radical 7 but also by the stability of the ben-
zylic radical 9 (extended conjugation) which is perhaps the driving
force that allowed the reaction to follow pathway a. Alternatively,
pathway b, a 6-exo-trig cyclization process followed by 1,2-alkenyl
migration via a cyclopropyl methyl radical 8 (neophyl rearrange-
ment), would also lead to the same product.
Acknowledgments
We thank the CSIR (New Delhi) and DST (New Delhi) for the
financial assistance. We thank Professor A. T. Khan, Indian Institute
of Technology, Guwahati, for the XRD data of 4a. One of us (A.T.) is
grateful to the CSIR (New Delhi) for the fellowship received.
References and notes
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SPh
Path b
6-exo-trig
O
O
O
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SPh
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PhSH
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X
3
6
7
SPh
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Me SPh
7-endo-trig
Path a
Neophyl
rearrangement
O
.
O
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H
H
PhSH
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SPh
SPh
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4
9
8
stable
Scheme 3. Mechanism of sulfanyl radical addition cyclization reaction.

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