Scheme 1. Proposed Mechanism for Benzofuran Formation
activation of a vinyl sulfoxide by trifluoroacetic anhydride6
In the series with sulfoxide 9, we commonly found that,
while the benzofuran was the only product formed, signifi-
cant quantities of the two starting materials remained after
the workup. Hence, a number of variations were pursued1
in a search for conditions that would force the reaction to
go to completion. The reaction may indeed be conveniently
carried out briefly at room temperature, but even at this
temperature the reaction did not go to completion.
to form 5 at -40° C, as in the ortho-thioalkylation of
phenols.7 The addition of the phenol presumably forms a
sulfoxonium intermediate, 6, probably in equilibrium with
the related neutral or O-protonated trifluoroacetoxysulfurane.
The intermediate then reacts cleanly and rapidly at -40 °C
to give the dihydrobenzofuran 7. Product 7 usually aroma-
tizes spontaneously to the benzofuran 8 in cases with R1 )
H. When the reaction is complete, the acids are neutralized
by quenching with triethylamine and the products isolated
by chromatography.
In experiments using 9 with 12b (p-cresol), 13b was
formed essentially quantitatively except for unreacted starting
materials, and these were easily separated by chromatogra-
phy. Racemization at sulfur apparently intervenes, since
racemic 13b was formed from nonracemic sulfoxide 9.
Extended reaction times at any temperature caused decom-
position of the product 13b as shown in Scheme 2.
Trifluoroacetylation of the phenol only occurs after quench-
ing with base, and no other byproducts were observed by
The original strategy was aimed at the synthesis of
morphinans, and so the first and major studies were carried
out at reduced temperature on various phenols 12 with the
sulfoxide 9, to form the model dihydrobenzofurans 13, as
o
NMR or TLC, at -40 C or at room temperature. Nucleo-
philic attack by the phenol at the â-position of the sulfoxide
was not observed.
Attempts to drive the reaction to completion using excesses
of reagents failed, with excesses of p-cresol simply promoting
the decomposition of 13b as outlined above. A number of
Table 1. Reaction of Sulfoxides and Phenols
entry
sulfoxide
phenol
product
methoda
% yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
9
9
9
9
9
12b
12b
12c
12d
12e
12g
12h
12a
12c
12e
12j
12c
12e
12i
12a
12b
12e
13b
13b
13c
13d
13e
13g
13h
14a
14c
14e
14j
15c
15e
15i
19a
19b
19e
B
C
B
B
B
A
A
B
B
B
B
B
B
B
A
C
A
55 (100)
55 (100)
52 (100)
0
35 (62)
41
9
9
21
10
10
10
10
11
11
11
18
18
18
22 (63)
33 (68)
21 (36)
31
19
37
34
39
22
40
exemplified in Table 1. The sulfoxides 9-11 were readily
prepared from the corresponding ketones via their enol
thioethers,8 oxidized with MCPBA at low temperatures.9
(6) For other examples of the activation of alkenyl sulfoxides by TFAA,
see: (a) Craig, D.; Daniels, K.; MacKenzie, A. R. Tetrahedron Lett. 1990,
31, 6441-6444. (b) Brichard, M.-H.; Janousek, Z.; Merenyi, R.; Viehe, H.
G. Tetrahedron Lett. 1992, 33, 2511-4.
a Method A: reactants mixed at -78 °C and then warmed to 0 °C and
quenched at -78 °C. Method B: reactants mixed at -40 °C ending with
slow phenol addition (1.5 h), followed by 2 h stirring and quenching at
-40 °C. Method C: reactants mixed at 25 °C and left only 5 min before
quenching. b Yields after isolation by flash chromatography. Yields in
parentheses allow for recovered starting materials.
(7) (a) Burdon, M. G.; Moffatt, J. G. J. Am. Chem. Soc. 1965, 87, 4656-
4658. (b) Pfitzner,.K. E.; Marino, J. P.; Olofson, R. A. J. Am. Chem. Soc.
1965, 87, 4658-4659. (c) Gassman, P. G.; Amick, D. R. J. Am. Chem.
Soc. 1978, 100, 7611-7619. (d) Lee, T. V. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: London, 1991; Vol.
7, pp 292-309.
(8) Labiad, B.; Villemin, D. Synthesis 1989, 143-4.
2730
Org. Lett., Vol. 2, No. 18, 2000