Facile regioselective synthesis of benzofuran-annulated six-membered sulfur heterocycles and the occurrence of thermal [1,3] sigmatropic rearrangement

Article abstract of DOI:10.2174/157017811795038368

Thio-Claisen rearrangement of a number of 3-(4-aryloxybut-2-ynlthio) benzofurans has been achieved under very mild conditions to give 2H-benzo[b]thiopyrano[2,3-d]furans. Attempts at further thio-claisen rearrangement resulted in the occurrence of thermal

Full text of DOI:10.2174/157017811795038368

176
Letters in Organic Chemistry, 2011, 8, 176-179
Facile Regioselective Synthesis of Benzofuran-Annulated Six-Membered
Sulfur Heterocycles and the Occurrence of Thermal [1,3] Sigmatropic
Rearrangement
Krishna C. Majumdar*, Sanjay Nath, Buddhadeb Chattopadhyay and Krishanu Ray
Depepartment of Chemistry, University of Kalyani, India
Received September 30, 2010: Revised December 06, 2010: Accepted February 18, 2011
Abstract: Thio-Claisen rearrangement of a number of 3-(4-aryloxybut-2–ynlthio)benzofurans has been achieved under
very mild conditions to give 2H-benzo[b]thiopyrano[2,3-d]furans. Attempts at further thio-claisen rearrangement resulted
in the occurrence of thermal [1s, 3a] sigmatropic shift.
Keywords: Thio-Claisen rearrangement, [3,3] sigmatropic rearrangement, sulfur heterocycles, regioselective cyclization, [1,3]
hydrogen shift.
S
R
S
The Claisen rearrangement since its discovery in 1912 [1]
has become a powerful method for carbon–carbon bond
formation. Much of its current popularity is due to the
subsequent development of a series of new variants as well
as versatile application in the synthesis of various
heterocycles using oxy-, [2] aza-, [3] and thia- [4] Claisen
rearrangement. We have recently reported the regioselective
synthesis [5, 6] of thiopyrano and thieno[3,2-c]coumarins by
the application of the sigmatropic rearrangement. In
continuation of our ongoing research on [3,3] sigmatropic
rearrangement of 4-(4' aryloxy-but-2'-ynylthio)-6-methyl
pyran-2-one, [7] we have recently reported the regioselective
synthesis of [6,6] pyranothiopyran [8]. The synthesis of
sulfur heterocycles by radical cyclization [9] is also a
regioselective but low yielding process due to ꢀ-
fragmentation of the intermediate radical. Here we apply this
simple methodology to different substrates for the formation
of hitherto unreported sulfur heterocycles, 2H-
benzo[b]thiopyrano[2,3-d]furan and its derivatives .
(i)
+
O
O
X
3a-g
R
1
2a-g
a, R = 2,3-Me2C6H3OCH2, X = Cl
b, R = 4-MeC6H4OCH2, X = Cl
c, R = 4-MeOC6H4OCH2, X = Cl
d, R = 2,4-Me2C6H3OCH2, X = Cl
e, R = 2-ClC6H4OCH2, X = Cl
f, R = 3,5-Me2C6H3OCH2, X = Cl
g, R = H, X = Br
Scheme 1. Reagents and conditions (i) BTEAC, 1% NaOH (aq),
CH2Cl2, rt, 20 min.
S
(ii)
3a-g
The starting materials 3-(4-aryloxybut-2-ynlthio)ben-
zofuran (3a-f) and 3-propargylthio benzofuran (3g) were
synthesized in 80-90 % yields by the phase transfer
catalyzed alkylation of 3-(2H)-benzofuranthione (1), with 1-
aryloxy-4-chlorobut-2-yne (2a-f) and propargyl bromide
(2g), respectively, in dichloromethane and 1% aq. NaOH in
the presence of benzyltriethylammonium chloride (BTEAC)
at room temperature for 20 min. (Scheme 1).
O
4a-g
R
Scheme 2. Reagents and conditions (ii) CH2Cl2, reflux, 2h.
The structure of the compound 4a was readily elucidated
by 1H NMR spectroscopy, which exhibited two proton
doublets at ꢀH = 3.65 (J = 5.3 Hz) and another two proton
singlet at ꢀH = 4.93 for S-CH2 and O-CH2 protons
respectively and a one proton triplet at ꢀH = 5.93 (J = 5.3 Hz,
=CH). The 13C-NMR spectrum of 4a also supported the
proposed structure. The mass spectrum of the compound 4a
showed the molecular ion peak at m/z: 322. Similar results
were also obtained from other substrates 4b-g.
However the compounds 3a-g are found to be very
unstable and undergo [3,3] sigmatropic rearrangement at
room temperature. As a result compounds 3a-g could not be
isolated in their pure state. For complete conversion the
o
substrate 3a was refluxed in dichloromethane (bp 39 C) and
the reaction was monitored by TLC. Complete conversion
was achieved in 2 h. to afford the cyclic product 4a [10]
(85% yield) (Scheme 2).
The formation of the products 4a-g may be rationalized
by a [3,3] sigmatropic rearrangement of the propynyl vinyl
sulfides to give allenyl intermediates 5, which may undergo
enolization to form allenyl-ene thiols 6. Allenyl-ene thiols 6
through [1,5] hydrogen shift may give intermediate 7, which
*Address correspondence to this author at the Dept of Chemistry, University
of Kalyani, India; Tel: +91-33-2582-7521: Fax: +91-33-25828282;
E-mail: kcm_ku@yahoo.co.in
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

Facile Regioselective Synthesis of Benzofuran-Annulated
Letters in Organic Chemistry, 2011, Vol. 8, No. 3
177
S
SH
S
.
[3,3]
.
O
O
O
H
6
[1,5] H
shift
R
R
5
3a-g
R
S
S
O
O
R
R
7
4a-g
Scheme 3.
[3, 3]
C
S
OMe
OMe
S
O
(i)
OMe
HO
O
S
[1s, 3a]
O
4c
O
O
8
Scheme 4. Reagents and conditions, (i) 1,2-Dichlorobenzene, reflux, 3h.
may undergo an electrocyclic ring closure to provide the
products 4a-g (Scheme 3).
double bond, giving product 8. The expected [3,3]
sigmatropic rearrangement was not observed (Scheme 4).
The products 4a-f are allyl-aryl ethers and therefore
suitable substrates for the occurrence of a second Claisen
rearrangement. However, this would require higher
temperature than the first [3,3] sigmatropic rearrangement of
compounds 3a-f, as during this rearrangement the aromatic
sextet of the aryl part will be disturbed. At higher
Thermal sigmatropic [1,3] shifts are reported to be rare in
the literature [11]. However, there are recent reports of
thermal [1,3] sigmatropic rearrangement in the case of 2-
crotylthiophene, [12] 1,3-dimethyl-5-(crotylthio)uracil, [13]
4-(prop-2-ynyloxy)quinolin-2[1H]-thiones, [14] and also in
the rearrangement of 3-benzyloxymethylcoumarin to give
hydroxylated-3-benzylcoumarins [15].
o
temperature in refluxing 1,2-dichlorobenzene, (b.p. 180 C)
4c underwent [1,3] hydrogen shift and the endocyclic double
bond of compound 4c was transformed to an exocyclic
Similarly, a [1,3] hydrogen shift is also observed in the
case of 4-(phenylthiomethyl)thiopyrano[3,2-c]chromen-
R2
S
S
SH
R1
Cl
+
R1
S
R2
O
O
O
O
11a-f
9a, R1 = CH3
9b, R1 = H
10a, R2 = 2 - Br
10b, R2 = 4 - CH3
10c, R3 = H
11 R1
R2
a
b
c
d
e
f
CH3 2 - Br
CH3 4 - CH3
CH3
H
H
H
2 - Br
4 - CH3
H
H
Scheme 5. Reagents and conditions, (i) dry acetone, K2CO3, NaI, reflux, 1-1.5 h.

178 Letters in Organic Chemistry, 2011, Vol. 8, No. 3
Majumdar et al.
R2
R2
S
S
R1
S
R1
S
DCB
H
O
O
O
O
11a-f
12a-f
Scheme 6.
R2
R2
S
S
S
S
[1s, 3a]
R1
R1
H
H
O
O
O
O
11a-f
12a-f
Scheme 7.
5(2H)-one derivatives (11a-f). 4-(phenylthiomethyl)thio-
pyrano [3,2-c]chromen-5(2H)-ones were in turn synthesized
by the classical alkylation of 4-(chloromethyl)thiopyrano
[3,2-c]chromen-5(2H)-ones (9a,b) with thiophenols (10a-c)
in refluxing dry acetone in the presence of anhydrous
potassium carbonate and a small amount of sodium iodide
(Finkelstein conditions [16] ) for 1-1.5h (Scheme 5). The
substrates (9a, b) were in turn prepared according to the
earlier published procedure [6].
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publishers
Web site along with the published article.
REFERENCES AND NOTES
[1]
Claisen, L. Über Umlagerung von Phenol-allyläthern in C-Allyl-
phenole. Chem. Ber., 1912, 45, 3157-3166.
[2]
(a) Majumdar, K. C.; De, R. N, Khan, A. T.; Chattopadhyay, S. K.;
Dey, K.; Patra. A. Studies of [3,3] sigmatropic rearrangements:
Rearrangement of 3-(4-p-tolyoxybut-2-ynyloxy)[1]benzopyran-2-
ones. J. Chem. Soc. Chem. Comm., 1988, 777-779. (b)
Subramanian, R. S.; Balasubramanian, K. K. A novel synthesis of
spirochromenes. Tetrahedron Lett., 1989, 30, 2297-2300. (c)
Majumdar, K. C.; Ghosh, S. K. Sequential [3,3] sigmatropic
rearrangement of 7-(4-aryloxybut-2’-ynyloxy)[1]benzopyran-2-
ones. J. Chem. Res. (S), 1994, 462-463; (M), 1994, 2601-2618. (d)
Otter, B .A.; Suluja, S. S.; Fox, J. J. Pyrimidine XII. A propargyl
Claisen rearrangement in the pyrimidine series. Synthesis of furo-
and pyrano[3,2-d]pyrimidines. J. Org. Chem., 1972, 37, 2858-
2864.
Compound (11a) on refluxing in 1,2-dichlorobenzene
(DCB) (b. p 180oC) for about 4-5 h underwent [1,3]
hydrogen shift to produce 4-(phenylthiomethylene)-3,4-
dihydrothiopyrano[3,2-c]chromen-5(2H)-one (12a) (Scheme
6).
The structure of the compound 12a was determined from
its elemental analysis and spectroscopic data. Other
substrates 11(b-f) were similarly treated to give the products
12(b-f) in overall excellent yields (80-96%).
[3]
(a) Kurth, J.; Decker, O. H. W. Enantioselective preparation of 3-
substituted 4-pentenoic acids via the Claisen rearrangement. J. Org.
Chem., 1985, 50, 5769-5775. (b) Majumdar, K. C.; Bhattacharrya,
T. Synthesis of bioactive heterocycles: Sigmatropic rearrangement
The formation of the products 12(a-f) from 11(a-f) may
be rationalized by the occurrence of a [1,3]-hydrogen shift to
afford the products 12(a-f) (Scheme 7).
of
6-N-(4’-aryloxybut-2’-ynyl),
N-methylamino-1,3-
dimethylpyrimidine-2,4-dione. Synthesis, 2001, 1568-1572. (c)
Majumdar, K. C.; Bhattacharrya, T. Studies of bioactive
heterocycles: Amino-Claisen rearrangement of 4-N-(4-aryloxybut-
2-ynyl)N-methyl-aminoicoumarins. Tetrahedron Lett., 2001, 42,
4231-4233. (d) Majumdar, K. C.; Ghosh, S. Studies of sigmatropic
rearrangement: Synthesis of 4-aryloxy-methynlene-1,7-dimethyl-
1,2,3-trihydropyrimidino[3,2-c]pyran-5-ones. Tetrahedron, 2001,
57, 1589-1592. (e) Danishefsky, S. J.; Phillips, G. B. A rapid route
to ergot precursors via aza-Claisen rearrangement. Tetrahedron
Lett., 1984, 25, 3159-3162.
(a) Majumdar, K. C.; Bandyopadhyay, A.; Biswas, A.
Regioselective synthesis of pentacyclic heterocycles by sequential
[3,3] sigmatropic rearrangement of 2-(4’-aryloxybut-2’-ynl-
mercapto)thiochromen-4-ones. Tetrahedron, 2003, 59, 5289-5293.
(b) Majumdar, K. C.; Jana, G. H. Synthesis of linear heterocycles:
Thermal sigmatropic rearrangement of 4-(4-aryloxybut-2-
ynyloxy[1]benzopyran-2-thiones. Synthesis, 2001, 924-928. (c)
Ellwood, A. R.; Mortimer, A. J. P.; Tocher, D. A.; Porter, M. J.
Diastereoselective thia-Claisen rearrangement of pyrrolidinone-
derived ketene N, S-acetals. Synlett., 2008, 2199-2209.
In conclusion, we have successfully performed a thio-
Claisen rearrangement of the prop-2-ynyl vinyl sulfides
using a very mild conditions to afford the tricyclic sulfur
heterocycles. This methodology displays appreciable
regioselectivity. The mildness of the reaction conditions and
high degree of chemoselectivity of the methodology is
notable. This methodology is a general one and is attractive
by its simplicity.
[4]
ACKNOWLEDGEMENTS
We thank the CSIR (New Delhi) for financial assistance
and two of us (B.C and K. R) are thankful to the CSIR (New
Delhi) for their senior research fellowships. We also thank
the DST (New Delhi) for providing UV-VIS spectrometer
under DST-FIST programme.

Facile Regioselective Synthesis of Benzofuran-Annulated
Letters in Organic Chemistry, 2011, Vol. 8, No. 3
179
[5]
[6]
Majumdar, K. C.; Ghosh, S. K. Studies of bioactive heterocycles:
Facile thio-Claisen rearrangement of propargylthio[1]benzopyran-
2-ones. Tetrahedron Lett., 2002, 43, 2115-2117.
ꢀC = 21.6, 25.3, 60.9, 104.7, 106.5, 109.7, 114.8, 117.8, 118.1,
118.2, 120.0, 120.7, 120.75, 120.8, 121.4, 124.0, 133.1, 144.1,
149.1, 151.4. MS: m/z = 322 (M+). Anal. Calcd. for C20H18O2S: C,
74.50; H, 5.63 %. Found: C, 74.74; H, 5.58 %.
Gilchrist, T. L.; Storr, R. C.; In: Organic Reactions and Orbital
Symmetry; Cambridge Univ. Press: Cambridge. 1979, 257.
Mortensen, J.Z.; Hedegward, B.; Lawesson, S. O. Thiophene
chemistry-XVII: Thio-claisen-rearrangement of allyl thienyl
sulphides. Tetrahedron, 1971, 27, 3831-3838.
Majumdar, K. C.; Jana, N. K.; Bandyopadhyay, A.; Ghosh, S. K.
Synthesis of purimidine-annelated heterocycles: Thermal
rearrangement of 1,3-dimethyl-5-(prop-2-enyltho)pyrimidine-2,4-
diones. Synth. Commun., 2001, 31, 2979-2985.
Majumdar, K. C.; Ghosh, M.; Jana, M. Regioselective synthesis of
thieno[2,3-b]quinolin-4(9H)-ones: Occurrence of thermal [1,3]
sigmatropic rearrangement. Synthesis, 2002, 669-673.
Majumdar, K. C.; Saha, S.; De, R. N.; Ghosh, S. K. Sigmatropic
rearrangement of 3-(aryloxymethyl)coumarins: A simple synthesis
of hydroxylated-3-benzylcoumarin. J. Chem. Soc. Perkin Trans. 1.,
1993, 715-718.
(a) Gazith, M.; Noys, R .M. Kinetics of the thermal and
photochemical exchange between benzyl iodide and iodine. J. Am.
Chem. Soc., 1955, 77, 6091-6098. (b) Gardner, I. J.; Noys, R. M.
Effect of substitutents on the radical exchange reaction between
benzyl iodide and iodine. Ibid., 1961, 83, 2409-2418.
Majumdar, K. C.; Chattopadhyay, B.; Nath, S. Regioselective
synthesis of benzofuran-annulated six-membered sulfer
heterocycles by aryl radical cyclization. Synth. Commun., 2007, 37,
2907-2915.
Majumdar, K. C.; Ghosh, S. K. Studies in sulfoxide rearrangement:
Regioselective
synthesis
of
3-(aryloxyacetal)-2,3-
[11]
[12]
dihydrothieno[3,2-c][1]benzopyran-2-ones. Tetrahedron Lett.,
2002, 43, 2123-2125.
[7]
[8]
Majumdar, K. C.; Kundu, U. K.; Ghosh, S. Regioselective
synthesis of heterocycles by sigmatropic rearrangement: Passage to
benzofuro[3,2-c]-6a,11a-dihydro-3,11a-dimethylthiopyranopyran-
1-one. J. Chem. Soc. Perkin Trans 1., 2002, 2139-2140.
Majumdar, K. C.; Kundu, U. K.; Ghosh, S. K. Studies in
sigmatropic rearrangement: Synthesis of [6,6] pyranothiopyran ring
system by sequential Claisen rearrangement and pyridine
hydrotribromide mediated regioselective “6-endo” cyclization.
Org. Lett., 2002, 4, 2629-2631.
Majumdar, K. C.; Biswas, A.; Mukhopadhyay, P. P. Carbon-carbon
bond formation by radical cyclization: Regioselective synthesis of
coumarin-annulated sulfer heterocycles. Synthesis, 2003, 2385-
2389.
[13]
[14]
[15]
[9]
[10]
General procedure for synthesis of 4a: The dichloromethane
solution of 3a was refluxed for 2h. Solvent was evaporated and the
reaction mixture was subjected to column chromatography over
silica gel (60-120 mesh). The column was eluted with petroleum
ether-ethylacetate (99:1) to afford the product 4a.
[16]
[17]
Compound 4a: Yield: 85%, viscous liquid. IR(neat): ꢀmax = 1448,
1
1470, 1583 cm-1. H-NMR (CDCl3, 400 MHz): ꢁH = 2.20 (s, 3H,
ArCH3), 2.30 (s, 3H, ArCH3), 3.65 (d, 2H, J = 5.3 Hz, -SCH2 ),
4.93 (s, 2H, -OCH2), 5.93 (t, 1H, J = 5.3 Hz, =CH), 6.84 (d, 2H, J =
7.8 Hz, ArH), 7.09 (t, 1H, J = 7.8 Hz, ArH), 7.25-7.33 (m, 2H,
ArH), 7.47 (t, 2H, J = 8.7 Hz, ArH). 13C-NMR (CDCl3, 125 MHz):