benzene systems in one chemical operation. These com-
pounds can be easily transformed to many other 1,4-
disubstituted-2,3-di(trifluoromethyl)benzenes, thus providing
a general synthesis of this class of biologically attractive
compounds.
As illustrated in Scheme 1, the 2-heteroatom-substituted
furan would undergo a Diels-Alder reaction with 2 to give
cycloadduct 3. We envisioned that the 2-hetero substituent
would donate electrons along the X-C-O bonds in cyclo-
adduct 3 and promote the opening of the 7-oxa bridge to
form unstable intermediate 4. A self-assisted deprotonation
of the H4 would lead to an aromatization to form phenoxide
5, which after protonation would give 4-functionalized 2,3-
di(trifluoromethyl)phenol 6.11-16
tion of the reaction at a series of temperatures (60, 82, and
100 °C) revealed that BOC deprotection occurred at 120 °C
but did not occur at 82 °C. The cycloaddition reaction was
incomplete when run at 60 °C (for 15 h). No solvent effect
was observed among THF, acetonitrile, and benzene. Thus,
when 1a was heated with 2 in a pressure tube in benzene at
82 °C for 5 h, evaporation of the solvent gave essentially
pure desired carbamate 6a (Table 1/entry1). Further purifica-
Table 1. Diels-Alder Reactions of Hexafluoro-2-butyne with
2-Heterosubstituted Furans
entrya
1, XR
product
yieldb
1
2
3
4
5
6
1a , NHBOC
1b, OCH3
1c, OTMS
1d , OCO2CH3
1e, O2CC(CH3)3
1f, Sn(Bun)3
6a
92%
87%
93%
100%
98%
100%
3b/6b
3c/6c
3d c
3ec
3fc
Scheme 1
a All reactions were performed in benzene at 82 °C (entries 1-5) or at
110 °C (entry 6) for 5-15 h. b Isolated yields based on furans used. c No
1
rearrangement to 6 was detected by H NMR over 2 months at 25 °C.
tion by recrystallization followed by flash chromatography
of the mother liquor afforded a 92% yield of analytically
pure sample. As shown in Table 1/entry 2, the Diels-Alder
reaction of 2-methoxyfuran 1b with 2 furnished either 3b
or 6b depending on the isolation method. After heating 1b
with 2 in benzene or THF at 82 °C for 6 h, removal of the
solvent afforded pure 3b. 3b is stable for storage at -30 °C
for at least 1 month and slowly rearranged to phenol 6b with
a half-life of about 2 days at 25 °C. To remove trace amounts
of solvent present in the volatile product, 3b was distilled
under vacuum (0.4 mmHg) at 25 °C. Surprisingly, complete
conversion to compound 6b was observed within 10 min.
Perhaps self-solvation stabilizes 3b as a bicyclic molecule,
whereas such self-stabilization is lost in the gas state. The
cycloaddition of 2-trimethylsilyloxyfuran 1c with 2 in
benzene or THF initially gave a 93% yield of pure bicyclic
compound 3c. 3c was more stable than 3b and could be
distilled without aromatization at 35 °C. Complete conversion
of 3c to 6c took 2 months at room temperature as the neat
material. However, this rearrangement is accelerated on silica
gel, giving exclusively 6c during flash chromatography. Less
electron-donating substituents such as methyl carbonate
(entry 4) and pivaloyloxy groups (entry 5) failed to promote
the rearrangement of 3d or 3e at room temperature, even
with assistance of 1% HCl in aqueous THF. Only bicyclic
products 3d and 3e were isolated in 100 and 98% yields,
respectively. To introduce a tributylstannyl functionality at
position-4 of 6 for Stille-type coupling reactions, tributyl-
stannylfuran 1f was subjected to the Diels-Alder reaction.
7-Oxabicyclic tin derivative 3f was isolated in quantitative
yield as a stable compound (entry 6). An attempt to convert
3f into the corresponding phenol, using BF3‚OEt2 as a
catalyst, provided a mixture of materials. Clearly, the ease
of rearrangement of 3 to 6 is on the order of NHBOC >
In an initial experiment, when hexafluoro-2-butyne 2 was
heated with readily available furan 1a (XR ) NHBOC)16 in
THF at 120 °C for 18 h, neither desired phenol 6a nor
cycloadduct 3a was observed. A careful chromatography of
the crude reaction mixture furnished 6% of 4-amino-2,3-di-
(trifluoromethyl)phenol (6, XR ) NH2) along with other
unidentified side products. Obviously, cleavage of the BOC
protecting group occurred under these conditions. Examina-
(5) Weis, C. D. J. Org. Chem. 1962, 27, 3693.
(6) Abubakar, A.; Booth, B.; Tipping, A. J. Fluorine Chem. 1991, 55,
189.
(7) Nishida, M.; Hayakawa, Y.; Matsui, M.; Shibata, K.; Muramatsu,
H. J. Heterocycl. Chem. 1991, 28, 225.
(8) Nishida, M.; Hayakawa, Y.; Matsui, M.; Shibata, K.; Muramatsu,
H. J. Heterocycl. Chem. 1992, 29, 113.
(9) Barton, T.; Wulff, W. J. Am. Chem. Soc. 1979, 101, 2735.
(10) Hussmann, G.; Wulff, W.; Barton, T. J. Am. Chem. Soc. 1983, 105,
1263.
(11) For a recent review on synthetic application of furan Diels-Alder
chemistry, see: Kappe, C.; Murphree, S.; Padwa, A. Tetrahedron 1997,
53, 14179.
(12) Wong, H.; Ng, T.; Wong, T.; Xing, Y. Heterocycles 1984, 22, 875.
(13) Wong, H.; Ng, T.; Wong, T. Heterocycles 1983, 20, 1815.
(14) Balthazor, T.; Williams, E. Synth. Commun. 1992, 22, 1023.
(15) Brownbridge, P.; Chan, T. Tetrahedron Lett. 1980, 21, 3423.
(16) Padwa, A.; Dimitroff, M.; Waterson, A.; Wu, T. J. Org. Chem. 1997,
62, 4088.
3346
Org. Lett., Vol. 2, No. 21, 2000