The use of sulfur ylides in the synthesis of 3-alkyl(aryl)thio-4- trifluoromethylpyrroles from mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates

Article abstract of DOI:10.1016/j.tetlet.2012.03.130

In this report, we describe a new method for the synthesis of densely functionalized pyrroles. Reaction of mesoionic 1,3-oxazolium-5-olates with various S-ylides proceeds via nucleophilic addition followed by opening of the oxazole ring and subsequent cyclization to multisubstituted pyrroles bearing both a trifluoromethyl and alkyl(aryl)thio group at 3- and 4-positions.

Full text of DOI:10.1016/j.tetlet.2012.03.130

Tetrahedron Letters 53 (2012) 2782–2785
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The use of sulfur ylides in the synthesis of 3-alkyl(aryl)thio-4-trifluoromethyl-
pyrroles from mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates
⇑
Ryosuke Saijo, Masami Kawase
Faculty of Pharmaceutical Sciences, Matsuyama University, Matsuyama, Ehime 790-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In this report, we describe a new method for the synthesis of densely functionalized pyrroles. Reaction of
mesoionic 1,3-oxazolium-5-olates with various S-ylides proceeds via nucleophilic addition followed by
opening of the oxazole ring and subsequent cyclization to multisubstituted pyrroles bearing both a
trifluoromethyl and alkyl(aryl)thio group at 3- and 4-positions.
Received 20 February 2012
Revised 24 March 2012
Accepted 30 March 2012
Available online 4 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrole
Trifluoromethyl
Sulfur ylide
Mesoion
We recently described a convenient synthesis of 3-trifluorom-
ethylpyrroles 1 by the Wittig reaction of mesoionic 4-trifluoroace-
tyl-1,3-oxazolium-5-olates 2.1 These novel ring transformations of
2 into 1 occur via an initial attack of the phosphorus (P)-ylide on
the C-2 position of the ring. Then, the reaction involves the decar-
boxylation followed by the elimination of triphenylphosphine
oxide to afford the pyrroles (1).
It is known that sulfur (S)-ylides, which are conveniently gener-
ated by the treatment of sulfonium salts with base, have proven to
be a versatile nucleophilic agents.2 Their reactions with aldehydes
or ketones give epoxides, which are known as the Corey–Chaykov-
sky (CC) reaction.3
In addition, we recorded therein the unusual formation of the
product introduced by thioalkyl(aryl) group in the CC reactions.
Only limited examples of the CC reaction of S-ylides have been thus
far reported as a synthon of alkylthio(methyl) anion equivalent.6
On the basis of our previous study on the reaction of 2 with
P-ylides,1 treating 2a with the S-ylide, methylenedimethylsulpho-
rane, generated from trimethylsulfonium iodide (2.4 mol equiv)
using n-BuLi (2.2 mol equiv) at À20 °C, and subsequently treatment
with AcOH at 80 °C provided the 4-trifluoromethyl-1-methyl-3-
methylthio-2-phenylpyrrole 3a in 70% yield (Table 1, entry 1). In
addition, 4-trifluoromethyl-1-methyl-2-phenylpyrrole 1a was also
isolated in 8% yield as a by-product. These two compounds 1a and
3a were identical with the authentic samples prepared by the con-
densation of 2a with Ph3P = CHSMe and Ph3P = CH2, respectively.1
Without the addition of AcOH as the second step, the reaction
did not work and no product was detected by TLC, which indicated
that the second step was essential for the reaction.
The effects of the base on the yield of 3a were briefly investi-
gated. n-BuLi, which had proven useful in an earlier study,1 gave
good yields of 3a under our standard conditions (Table 1, entry
1), while neither t-BuOK nor phosphazene base (P4 base)7 medi-
ated the reaction to a synthetically useful degree (entries 2 and
3). Much weaker base, DBU failed to give the pyrrole product at all.
Next, three different S-ylides generated from the sulfonium salts,
such as phenyldimethylsulfonium BFÀ4 , S-methyltetrahydrothi-
ophenium iodide, and S-methylhexahydrothiopyrylium iodide,
were employed to probe the scope of the reaction (Table 2). Me2PhS+
BFÀ4 showed the expected pyrrole 3b by the reaction of 2a in a mod-
erate yield (entry 1). Next, the reactions of 2a with two cyclic sulfo-
nium ethylides, generated from S-methyltetrahydrothiophenium
Mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates 2 are easily
prepared from N-acyl-N-alkyl-a-amino acids in a one step through
the cyclodehydration by trifluoroacetic anhydride followed by
trifluoroacetylation at C-4 position of an intermediary mesoionic
1,3-oxazolium-5-olate and are useful synthons for trifluoro-
methyl-substituted heterocycles.4
As a continuation of our studies on the synthetic potential of
mesoionic 2, and owing to the increasing importance of trifluoro-
methyl-containing heterocycles in biology, pharmacology, and
industrial applications,5 we decided to investigate their reactions
of mesoionic oxazoles 2 with S-ylides. This paper is devoted to
the behavior of 2 with S-ylides from the comparison with the reac-
tion of 2 with P-ylides; herein, efficient syntheses of multiple
substituted pyrroles with a trifluoromethyl and thioalkyl (aryl)
groups are reported.
⇑
Corresponding author. Tel.: +81 89 9267098; fax: +81 89 9267162.
E-mail address: kawase@cc.matsuyama-u.ac.jp (M. Kawase).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.130

R. Saijo, M. Kawase / Tetrahedron Letters 53 (2012) 2782–2785
2783
Table 1
mesoionic ring on the reaction were investigated. The reaction is
efficient in both 3-alkyl- and 3-aryl-substituted mesoionic com-
pounds (entries 1–6), in which 3-alkyl compounds 2a and d–f
afforded the better yields. However, 2-alkyl-substituted mesoionic
compounds 2c gave slightly lower yields compared to 2-aryl-
substituted compounds 2a, d, e, and f, except 2b. Therefore, 3-al-
kyl-2-aryl-substituted mesoionic oxazoles would afford the better
yields than 2,3-diaryl and 2-alkyl-3-aryl compounds.
Conditions tested for the reactions
-
1) Me3S+I , base,
solvent, 10 h
MeS
Ph
CF3
CF3
COCF3
Me
+
N
+
Ph
-
N
Me
N
Me
3a
2) AcOH, 80°C,
10 h
O
Ph
O
2a
Base
1a
Solvent
Condition 1a
Yield (%)
On the basis of the experimental results and the previous
report,1 a plausible mechanism of the present reaction could be
described as shown in Scheme 1. The anion of the S-ylide initially
attacks at an electrophilic carbon center in a nucleophilic addition
reaction: the first step is the same as the case of the reactions of
P-ylides with carbonyl compounds.9 Thus, initial nucleophilic at-
tack of the ylide on C-2 of 2 gave rise to an adduct 4 which is con-
verted into 5 via a proton transfer. Then, equilibration gives a ylide
6 which seems to be stable in an aprotic solvent, and the driving
force for the decarboxylation of 6 to 7 in protic solvent such as
AcOH is probably due to the electron-donating nitrogen and the
electron-withdrawing trifluoromethyl ketone. Intramolecular
cyclization of 7 leads to 8. A nucleophilic attack of iodide ion on
the methyl group of the dimethylsulfonium substituent in the
intermediate of 8 involves loss of MeI to afford an intermediate
9, which undergoes aromatization to provide the pyrrole 3.
On the other hand, the intermediate 8 competes with loss of
Me2S=O resulting in the formation of product 1.
The difference of the reactivity between S- and P-ylides is sug-
gested to be mainly due to the differing leaving group ability of the
respective onium groups.10 The nucleophilic attack of the oxygen
to phosphorus occurs to form the P–O bond, due to the greater
affinity of phosphorus for oxygen, in which an intermediate in
the reaction of 2 and P-ylides decomposed by thermal elimination
of Ph3P = O to afford the pyrrole 1.1
In conclusion, we have developed a novel application of S-ylides
of the general preparation of not readily accessible and syntheti-
cally valuable 3-alkyl(aryl)thio-4-trifluoromethylpyrroles from
easily available mesoionic compounds. Readily available starting
materials and simple synthetic procedures make this method very
attractive and convenient for the synthesis of multisubstituted
3a
1a
1
n-BuLi
t-BuOK
P4-tBu
DBU
THF
DMF
THF
THF
À20 °C to rt
0 °C to rt
70
16
4
8
0
3
NR
2
3
4
À20 °C to rt
0 °C to rt
NR
a
2.4 equiv of sulfonium salt and 2.2 equiv of base were used.
and S-methylhexahydrothiopyrylium iodides, afforded 3-(4-
iodobutylthio)- (3c) or 3-(5-iodopentylthio)pyrrole 3d which were
obtained in moderate yields, respectively (entries 2 and 3). The for-
mation of 3c and 3d indicated that the 3-substituents of the pyrrole
depend on the counteranion of the sulfonium ions. Changing the
counteranion of the sulfonium salt from IÀ to BF4À gave the pyrrole
product bearing 3-(4-acetoxybutylthio) group in a low yield (22%).
The co-addition of AcONa in second step increased the yield (entry
4). The acetoxy group was derived from the additive acetic acid.
When (CF3)2CHOH instead of AcOH was used as the additive in
the second step, the 3-substituent was 4-(1,1,1,3,3,3-hexafluoro-
propan-2-yloxy)butylthio group indicating that the 3-substituent
depends on the additive in the second step (entry 5). Apparently,
the iodide salt of the sulfonium precursor is more likely to produce
a significant amount of iodoalkylthio-substituted pyrrole product
compared with other counteranion salts (entries 2, 4 and 5), because
IÀ is more nucleophilic than acetate anion, (CF3)2CHOÀ and BF4
.
À
These results indicated that in the reactions of Me3S+IÀ, iodometh-
ane could be generated as a side product.
With the optimized conditions in hand,8 the scope of the reac-
tion substrates was briefly investigated. The results are summa-
rized in Table 3. First, the substituents on C2 and N3 of the
Table 2
Reaction of mesoionic oxazole 2a with various S-ylides
R3
CF3
CF3
COCF3
Me
1) S+, n-BuLi, THF, 10 h
+
N
+
Ph
Ph
-
N
Me
N
Me
2) additive, 80 °C, 10 h
O
Ph
O
2a
3
1a
Entry
S+
R3
Condition
Additive
Yield (%)
3
1a
À
1
2
Me2PhS+BF4
SPh
À78 °C to rt
À20 °C to rt
AcOH
AcOH
3b (54)
0
–S(CH2)4I
–S(CH2)5I
3c (45)
10
6
I
S
Me
I
3
À20 °C to rt
AcOH
3d (53)
S
Me
4
5
–S(CH2)4OAc
À20 °C to rt
À20 °C to rt
AcOHa
3e (35)
3f (45)
0
0
BF4
BF4
S
Me
–S(CH2)4OCH(CF3)2
(CF3)2CHOHb
S
Me
a
Plus 3 equiv AcONa.
Plus 3 equiv CsF.
b

2784
R. Saijo, M. Kawase / Tetrahedron Letters 53 (2012) 2782–2785
Table 3
Reaction of various mesoionic oxazoles 2 with S-ylides
R3
R2
CF3
CF3
R1
COCF3
1) S+, n-BuLi, THF, 10 h
+
N
+
R2
-
R2
N
2) AcOH, 80 °C, 10 h
O
N
O
R1
R1
2
3
1
Entry
S+
2
R1
R2
R3
Condition
Yield (%)
3
1
1
2
3
4
5
6
7
Me3S+IÀ
Me3S+IÀ
Me3S+IÀ
Me3S+IÀ
Me3S+IÀ
Me3S+IÀ
Me2PhS+BF4
2a
2b
2c
2d
2e
2f
Me
Ph
Ph
Bn
Bn
Ph
Ph
Me
Ph
PMP
Ph
SMe
SMe
SMe
SMe
SMe
SMe
SPh
À20 °C to rt
À20 °C to rt
À20 °C to rt
À20 °C to rt
À20 °C to rt
À20 °C to rt
–78 °C to rt
3a (70)
3g (41)
3h (48)
3i (64)
3j (60)
3k (63)
3l (55)
1a (8)
1b (20)
1c (1)
1d (17)
1e (20)
1f (12)
1b (0)
PMB
Ph
À
2b
Ph
O
O
R1
N
R1
O
proton
R1
keto-enol
tautomer
+ -
CF3
OH
N
CF3
-
+
transfer
Me2SCH2
N
CF3
-
R2
R2
O
O
-
O
R2
O
O
CH
CH2
2
+
+
SMe2
SMe2
5
4
O
R1
-
(b)
R1
CF3
R1
+
+
N..
CF3
-
N
(a)
H+
N
CF3
OH
R2
O
R2
O
O
-
R2
MeI
-
CO
-
2
-
H
+
+
H2C
S
CH
(a)
SMe2
Me
Me
-
I
+
SMe2
(b)
7
8
CF3
6
R2
N
R1
R1
R1
CF3
MeS
R2
+
+
-
-
N
N
CF3
OH
1
R2
CF3
R2
N
H O
-
2
H
R1
SMe
SMe
9
3
10
Scheme 1. Proposed mechanistic pathway.
pyrroles with a trifluoromethyl and alkylthio or phenylthio group.
Furthermore, the 3-substituents of the pyrrole product depend on
what counterion of the sulfonium salts was employed as the S-
ylide precursor.
References and notes
1. Saijo, R.; Hagimoto, Y.; Kawase, M. Org. Lett. 2010, 12, 4776.
2. (a) Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37, 611; (b) Appel, R.;
Hartmann, N.; Mayr, H. J. Am. Chem. Soc. 2010, 132, 17894.
The 2- or 5-substituted pyrroles are easily synthesized by
aromatic electrophilic substitution, whereas a special strategy is
necessary to obtain 3- or 4-substituted pyrroles.11 Furthermore,
pyrroles bearing electron-donor substituents are not very stable
and rather limited. The alkylthio-substituted pyrroles are not as of-
ten reported as the pyrroles bearing electron-withdrawing
substituents.12
3. (a) Johnson, A. W.; LaCount, R. B. J. Am. Chem. Soc. 1961, 83, 417; (b) Corey, E. J.;
Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867; (c) Corey, E. J.; Chaykovsky, M. J.
J. Am. Chem. Soc. 1965, 87, 1353.
4. (a) Gribble, G. W. Mesoionic Oxazoles In The Chemistry of Heterocyclic
Compounds, ‘‘Oxazoles Synthesis, Reactions, and Spectroscopy’’; Taylor, E. C.,
Wipf, P., Eds.; John Wiley & Sons: Hoboken, 2003; Vol. 60, p 473. Part A; (b)
Kawase, M.; Koiwai, H. Chem. Pharm. Bull. 2008, 56, 433.
5. Petrov, V. A. Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and
Applications; John Wiley & Sons: Hoboken, 2009.
6. (a) Peng, Y.; Yang, J.-H.; Li, W-D. Z. Tetrahedron 2006, 62, 1209; (b) Date, S. M.;
Singh, R.; Ghosh, S. K. Org. Biomol. Chem. 2005, 3, 3369; (c) Roush, W. R.; Russo-
Rodriguez, S. J. Org. Chem. 1987, 52, 603.
Therefore, it is important to note that we have developed a sim-
ple and regiospecific synthetic procedure for the preparation of
new 3-alkyl(aryl)thio-substituted 4-trifluoromethylpyrroles.
7. P4 base is 1-tert-butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)
-phosphoranylidenamido]-2k5,4k5-catenadi(phosphazene).
8. General procedure for the reactions of S-ylides with 2: To a stirred suspension of
Acknowledgments
sulfonium salt (1.2 mmol) in THF (2 mL) at À20 °C, was added n-BuLi (690
lL,
1.1 mmol), and the mixture was stirred for 30 min under atmosphere of argon.
To the mixture at À20 °C was added a solution of 2 (0.5 mmol) in THF (3 mL).
The reaction mixture was allowed to be warmed to rt and stirred for an
additional 10 h. To the mixture was added AcOH (2 mL), and the whole was
heated at 80 °C for a further 10 h. After workup with 10% aq Na2CO3, the
Financial support in the form of a Grant-a-Aid for Scientific Re-
search (C)(Kawase No. 20590114) from the Japan Society for the
Promotion of Science (JSPS) is greatly acknowledged.

R. Saijo, M. Kawase / Tetrahedron Letters 53 (2012) 2782–2785
2785
mixture was extracted with AcOEt (Â3). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue
was purified by column chromatography and preparative TLC (silica gel,
hexane/AcOEt 9:1) to give the products 1 and 3.
11. Muzalevskiy, V. M.; Shastin, A. V.; Balenkova, E. S.; Haufe, G.; Nenajdenko, V. G.
Synthesis 2009, 23, 3905.
12. (a) Yin, G.; Wang, Z.; Chen, A.; Gao, M.; Wu, A.; Pan, Y. J. Org. Chem. 2008, 73,
3377; (b) Zanatta, N.; Schneider, J. M. F.; Schneider, P. H.; Wouters, A. D.;
Bonacorso, H. G.; Matrtins, M. A. P.; Wessjohann, L. A. J. Org. Chem. 2006, 71,
6996; (c) Katritzky, A. R.; Wang, X.; Denisenko, A. J. Org. Chem. 2001, 66, 2850.
9. (a) Volatron, F.; Eisenstein, O. J. Am. Chem. Soc. 1987, 109, 1; (b) Maryanoff, B. E.;
Reitz, A. B. Chem. Rev. 1989, 89, 863.
10. (a) Aggarwal, V. K.; Harvey, J. N.; Robiette, R. Angew. Chem., Int. Ed. 2005, 44,
5468; (b) Vedejs, E.; Marth, C. F. J. Am. Chem. Soc. 1990, 112, 3905.