desilylated product 2a in 47% yield,17 which was the same
product as that obtained by the reaction of 1a and Ph3PdCH2.
Table 3. Yields of 1,2-Disubstituted 4-Trifluoromethylpyrroles
The structures of 2 were supported by the spectral data.
1
For example, the H NMR spectrum of 2a exhibited the
signal of C-3 proton at δ 6.37 (d) and C-5 proton at δ 7.01
(s), and other products (2c-h) also had the characteristic
aromatic proton at the almost same position. In the 13C NMR
spectra of 2a, the pyrrole ring carbon atoms C-2, C-3, C-4
and C-5 appear at δ 136, 106 (3JC-F ) 2.4 Hz), 114 (2JC-F
) 37 Hz), and 122 (3JC-F ) 4.9 Hz), respectively. The carbon
product (yield, %)
R1
R2
Ph
Ph
Me
PMP
Ph
Ph
method 1a
method 2a
of CF3 group in 2 appears at around δ 124 ppm (1JC-F
)
entry
1
266 Hz). The ultimate proof of the structure of 2a rests upon
its conversion into the known ethyl 1-methyl-2-phenylpyr-
role-4-carboxylate 3,18 in which the conversion of 2a to 3 is
effected by the treatment with TFA and EtOH in 80% yield.19
The hydrolytic instability of ꢀ-trifluoromethylpyrroles has
recently been reported.7
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
Me
Ph
Ph
Bn
Bn
2a (74)
2c (19)
2d (14)
2e (80)
2a (90)
2c (70)
2d (60)
2e (88)
2f (87)
2g (87)
2h (32)
PMB
Me
1g
t-Bu
2h (3)
A possible mechanism for the formation of 4-trifluorom-
ethylpyrroles 2 is proposed in Scheme 1. Thus, initial
nucleophilic attack of ylide on C-2 of 1 gives rise to an
adduct 4 which is converted to 5 via a proton transfer. Then,
equilibration gives a ylide 6 which seems to be stable in an
aprotic solvent, and the thermal decarboxylation in protic
solvent such as AcOH may be necessary to afford a
phosphonium salt 7. The driving force of the decarboxylation
is probably due to the electron-donating ylide anion and the
electron-withdrawing trifluoromethyl ketone. In the step of
the formation of 8 from 7, the nucleophilic attack of the
carbonyl oxygen to phosphorus occurs to form the P-O
bond, due to the greater affinity of phosphorus for oxygen.
A similar transformation was postulated in the intramolecular
Wittig reaction leading to indole derivatives.20 The last step
involves thermal elimination of triphenylphosphine oxide to
afford the pyrroles 2.
In conclusion, starting from the mesoionic 1 and ylides, a
new, experimentally very simple, and efficient synthesis of
1,2-disubstituted and 1,2,3-trisubstituted ꢀ-trifluorometh-
ylpyrroles has been described. The principal advantage of
using mesoionic oxazoles 1 is the great variety of substituents
available for R1 and R2. Thus, this flexibility in the type of
substituents in 1 will be reflected in the corresponding
substitution of the resulting pyrrole 2. By this methodology,
the 1-, 2- and 3-substituents in the pyrrole ring can be readily
varied simply by choosing the appropiate N-acyl-N-alkylg-
a Method 1: using the conditions in entry 4 of Table 1. Method 2: using
the conditions in entry 3 of Table 2.
Table 4. Yields of 1,2,3-Trisubstituted
4-Trifluoromethylpyrroles
entry
R3
X-
product (yield, %)
1
2
3
4
5
6
7
8
9
H
Me
Pr
Oct
OMe
OMe
SMe
TMS
i-Pr
Ph
Br-
Br-
Br-
Br-
Cl-
Cl-
Cl-
I-
2a (90)
2b (87)
2i (57)
2j (53)
2k (33) + 2i (26)a
2k (45)b
2l (22)
2a (47)c
2m (6)
2n (6)
Br-
10
Br-
c
a R3 ) Pr. b PhLi was used instead of n-BuLi. R3 ) H.
In the reaction of 1a and Ph3P+CH2OCH3 Br- using
n-BuLi as a base, the expected 4-trifluoromethyl-3-methoxy-
1-methyl-2-phenylpyrrole 2k and 4-trifluoromethyl-1-methyl-
2-phenyl-3-propylpyrrole 2i were isolated in 33% and 26%
yields, respectively. The side product 2i was identical
with the product obtained by the reaction of 1a and
Ph3PdCHC3H7 (Table 4, entry 3). It is reported that the
reaction of Ph3P+CH2OCH3 Cl- with n-BuLi produces
Ph2(CH3OCH2)PdCHC3H7, which accounts for the observed
butylidene products of 2i.16 After the brief optimization was
then made by screening of base, solvent, and reaction
temperature, it was determined that use of phenyllithium
instead of n-BuLi as a base led to the production of 2k in a
slight higher chemical yield (45%) (Table 4, entry 6).
Treatment of 1a with Ph3P+CH2Si(CH3)3 I- gave the
(11) Gribble, G. W. Mesoionic Oxazoles. In The Chemistry of Hetero-
cyclic Compounds, Oxazoles: Synthesis, Reactions, and Spectroscopy;
Taylor, E. C., Wipf, P., Eds.; John Wiley & Sons: Hoboken, 2003; Vol.
60, Part A, p 473.
(12) Kawase, M.; Koiwai, H. Chem. Pharm. Bull. 2008, 56, 433.
(13) Kawase, M.; Saito, S.; Kurihara, T. Chem. Pharm. Bull. 2001, 49,
461.
(14) Kawase, M.; Saito, S. Chem. Pharm. Bull. 2000, 48, 410.
(15) Kawase, M.; Koiwai, H.; Kurihara, T. Tetrahedron Lett. 1998, 39,
6189.
(16) Anderson, C. L.; Soderquist, J. A.; Kabalka, G. W. Tetrahedron
Lett. 1992, 33, 6915.
(17) Gilman, H.; Tomasi, R. A. J. Org. Chem. 1962, 27, 3647.
(18) Croce, P. D.; Rosa, C. L. Heterocycles 1988, 27, 2825.
(19) Full details of the conversion of trifluoromethyl group into ester
group will be reported elsewhere.
(20) Miyashita, K.; Kondoh, K.; Tsuchiya, K.; Miyabe, H.; Imanishi,
T. J. Chem. Soc., Perkin Trans. 1 1996, 1261.
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Org. Lett., Vol. 12, No. 21, 2010