Reaction of 2-(2,2,2-Trifluoroethylidene)-1,3-dithiane 1-Oxide with ketones under pummerer conditions and its application to the synthesis of 3-Trifluoromethyl-Substituted five-membered heteroarenes

Article abstract of DOI:10.1002/anie.200906774

(Figure Presented) Easy as pie: With the aid of triflic anhydride, the title reaction resulted in nucleophilic attack of the carbonyl oxygen atom onto the activated cationic sulfur center and subsequent [3,3]-sigmatropic rearrangement (see scheme). The pr

Full text of DOI:10.1002/anie.200906774

Communications
DOI: 10.1002/anie.200906774
Synthetic Methods
Reaction of 2-(2,2,2-Trifluoroethylidene)-1,3-dithiane 1-Oxide with
Ketones under Pummerer Conditions and Its Application to the
Synthesis of 3-Trifluoromethyl-Substituted Five-Membered
Heteroarenes**
Takayuki Kobatake, Suguru Yoshida, Hideki Yorimitsu,* and Koichiro Oshima*
The Pummerer rearrangement is an important method for the
synthesis of a-substituted alkyl sulfides from alkyl sulfoxides,
and is widely used in organic synthesis. Recently, the extended
use of aryl sulfoxides in Pummerer chemistry has attracted
increasing attention, especially in the field of synthesis of
complex heterocycles.[1,2] On the other hand, the extended
Pummerer reactions of 1-alkenyl sulfoxides have been much
less investigated.[3]
In general, 1-alkenyl sulfoxide reacts with a nucleophile at
the 2-position under Pummerer conditions (Scheme 1). Our
Scheme 2. Unsuccessful Tf2O-mediated reaction of 1a with silyl
enolate.
which was formed by direct nucleophilic substitution at the
cationic sulfur atom. In addition, an attempt to use 1-
phenylvinyl triflate instead of the enolate resulted in no
trace of the products and 48% of unchanged 1a was
recovered.
Scheme 1. Typical behavior of 1-alkenyl sulfoxide under Pummerer
conditions.
We then turned our attention to acetophenone itself—
research group has recently developed 2-(2,2,2-trifluoroethyl-
idene)-1,3-dithiane 1-oxide (1a; see Scheme 2) as a trifluoro-
methyl-containing substrate for Pummerer chemistry.[4] We
envisioned that 1a would react with silyl enolate[5] at the 2-
position in the usual fashion to provide 2a. In turn, 2a would
be a promising precursor of generally unavailable 2-trifluoro-
methyl-1,4-diketones[6] en route to potentially useful yet
difficult-to-synthesize 3-trifluoromethyl five-membered het-
eroaromatic compounds.[7] However, the case proved to be
rather complicated. Treatment of 1a with the trimethylsilyl
enolate of acetophenone with the aid of trifluoromethane-
sulfonic anhydride (Tf2O) afforded a complex mixture, even
after extensive optimization (Scheme 2). The mixture indeed
contained the expected product 2a and its hydrolyzed form
3a (albeit in less than 30% combined yield), as well as ylide 4,
instead of the corresponding enolate—even though use of a
carbonyl group as a nucleophile in the Pummerer reaction has
not been reported. Our working hypothesis is outlined in
Scheme 3. The reagent Tf2O would preferentially activate the
Scheme 3. Our working hypothesis.
sulfoxide moiety of 1a over the carbonyl group of acetophe-
none. Regioselective nucleophilic attack of acetophenone
would then take place at the cationic sulfur atom.[4] The
resulting vinyl vinyloxy sulfonium species would undergo
rapid [3,3]-sigmatropic rearrangement at a low temperature
to eventually form a carbon–carbon bond between the
trifluoromethylated carbon atom and the a-carbon atom of
acetophenone.
[*] T. Kobatake, Dr. S. Yoshida, Prof. Dr. H. Yorimitsu,
Prof. Dr. K. Oshima
Department of Material Chemistry, Graduate School of Engineering
Kyoto University, Kyoto-daigaku Katsura
Nishikyo-ku, Kyoto 615-8510 (Japan)
Fax: (+81)75-383-2438
E-mail: yori@orgrxn.mbox.media.kyoto-u.ac.jp
oshima@orgrxn.mbox.media.kyoto-u.ac.jp
[**] This work was supported by Grants-in-Aid for Scientific Research
and GCOE Research from JSPS. S.Y. acknowledges JSPS for financial
support.
To our delight, treatment of 1a[8] with acetophenone
(2 equiv) in the presence of Tf2O (2 equiv)[9] in nitroethane at
À408C for 30 minutes cleanly afforded a mixture of adducts
2a and 3a after aqueous workup. The crude mixture was
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906774.
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subsequently subjected to acidic hydrolysis and yielded 3a as
the sole product in 73% overall yield (Table 1, entry 1).
The wide scope of ketones used is exemplified in Table 1
and [Eqs. (1) and (2)]. Acetophenone derivatives having a
primary product was unstable enough to undergo hydrolysis
upon aqueous workup. Another enolizable ketone, a-tetra-
lone, reacted as smoothly as other methyl ketones shown in
Table 1 and Equation (4).
Table 1: Reactions of 1a with various methyl ketones.
The trifluoromethyl group of 1a plays an important role in
this reaction. The heptafluoropropyl group of 1b proved to be
as efficient as a trifluoromethyl group [Eq. (5)]. However,
Entry
R
3
Yield of 3 [%]
1
2
3
4
5
6
7
8
9
Ph
3a
3b
3c
3d
3e
3 f
3g
3h
3i
73
69
40
77
70
81
66
71
64
p-MeC6H4
o-MeC6H4
p-PhC6H4
p-ClC6H4
p-BrC6H4
p-MeOC6H4
p-MeO2CC6H4
tBu
treatment of 1c or 1d bearing a phenyl or methyl group under
the same reaction conditions yielded a complex mixture. The
trifluoromethyl group would give moderately reactive mono-
cationic intermediate A ample chance to react with the
ketone by preventing the formation of much more reactive
dicationic intermediate B (Scheme 4).[10] Acyclic sulfoxide 1e
also reacted with a ketone in a similar manner, albeit in lower
yield [Eq. (6)].
functional group at the para position reacted smoothly
(entries 2, and 4–8). The electronic nature of the substituents
had little effect on the reaction efficiency (entries 5–8),
however, an ortho substituent retarded the reaction
(entry 3). The reactions of aliphatic ketones such as pinaco-
lone (entry 9) and 3-pentanone [Eq. (1)] gave good yields.
Interestingly, unsymmetrical aliphatic ketone, 3-methyl-2-
butanone, underwent regioselective transformation to pre-
dominantly yield 6a bearing a quaternary carbon atom
[Eq. (2)]. The carbon–carbon bond formation in the reaction
Scheme 4. Inhibitive effect of the CF3 group on the formation of
dicationic intermediate.
To clarify the effect of the CF3 group of 1a and the
reaction mechanism, we performed DFT calculations on the
CF3-containing putative intermediates A and B and their
CH3-analogues C and D (Figure 1). The calculations were
performed by using the Spartanꢀ04 program.[11] All the
structures were optimized and the energies were obtained at
the B3LYP/6-31G* level.[12] The energies determined with
aqueous solvation—used as a model for solvation with polar
nitroethane—were obtained by the SM5.4 procedure.[13]
Intermediate A can take two stable conformations Aeq and
Aax, in which the TfO group is located at either the equatorial
of 2,4-pentanedione proceeded at the 3-position selectively
[Eq. (3)]. Secondary product 7 was obtained without the
treatment of hydrochloric acid because the corresponding
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Scheme 5. Transformation of 3a and 5 into CF3-substituted 1,4-dike-
tones and five-membered heteroaromatic compounds. Reagents and
conditions: a) MeI (2 equiv), iPr2EtN (2 equiv), acetone, 258C, 8 h,
80%; b) [PdCl2(PPh3)2] (10 mol%), EtZnI (2 equiv), toluene, reflux,
12 h, 65%; c) p-TsOH·H2O (1.1 equiv), toluene, reflux, 10 h, 75%;
d) Lawesson’s reagent (2.4 equiv), 1,2-dichloroethane, 258C, 8 h, 62%;
e) nBuNH2 (2 equiv), Ti(OiPr)4 (1.5 equiv), toluene, reflux, 10 h, 81%;
f) MeI (2 equiv), iPr2EtN (2 equiv), acetone, 258C, 8 h, 78%; g) [PdCl2-
(dppf)] (10 mol%), (2-thienyl)ZnI·LiCl (5.6 equiv), toluene, 08C, 1 h,
87%, d.r.=3:2; h) [PdCl2(dppf)] (10 mol%), PhZnI·LiCl (3 equiv),
toluene, 08C, 1 h, 93%, d.r.=3:2; i) p-TsOH·H2O (1.1 equiv), toluene,
reflux, 8 h, 82%; j) Lawesson’s reagent (2.4 equiv), 1,2-dichloroethane,
608C, 8 h, 47%; k) nBuNH2 (4 equiv), Ti(OiPr)4 (3 equiv), toluene,
258C, 4 h, 83%. dppf=1,1’-bis(diphenylphosphanyl)ferrocene, Ts=
4-toluenesulfonyl.
Figure 1. DFT calculations for the putative intermediates.
and a subsequent [3,3]-sigmatropic rearrangement. The
present reaction greatly expands the scope of nucleophile in
the Pummerer reaction.
and axial position, respectively. Dicationic intermediate B is
calculated to be much more unstable than Aeq and Aax by 43.8
and 44.8 kcalmolÀ1, respectively, with aqueous solvation.
Thus, the departure of TfOÀ would never take place via an
SN1-type process at À408C but may proceed via an SN2-type
mechanism. The CF3 group would destabilize the dicationic
intermediate B. On the other hand, dication D is calculated to
be less stable than the CH3-analogues Ceq and Cax by 16.2 and
18.4 kcalmolÀ1, respectively, with aqueous solvation. The
formation of D is much more likely than that of B and can
occur at low temperatures. These calculations support the
reaction mechanism in Scheme 3 and Scheme 4.
The products are precursors of generally unavailable 2-
trifluoromethyl-1,4-diketones en route to 3-trifluoromethyl-
furans, -thiophenes, and pyrroles of latent use. The new
protocol provides the only access to fully substituted 3-
trifluoromethyl five-membered heteroaromatics. The trifluor-
omethyl group of 1a not only play an important role in the
success of the new Pummerer process but will undoubtedly
lead to heteroaromatic products with interesting chemical,
biological, and physical properties.
Trifluoromethylated arenes play important roles in medic-
inal, agricultural, and material sciences.[14] The unusual
chemical properties of a trifluoromethyl unit often render
the synthesis of trifluoromethylated arenes difficult, and the
development of reliable routes to trifluoromethylated arenes
has been eagerly anticipated.[15]
Thiol esters 3a and 5 have proved to be versatile
precursors of 3-trifluoromethylfurans, -thiophenes, and -pyr-
roles (Scheme 5). Methylation of the mercapto groups of 3a
and 5 and subsequent cross-coupling reactions of the resulting
thiol esters with organozinc reagents[16–18] yielded 2-trifluoro-
methyl-1,4-diketones 11 and 12, respectively. Classic Paal–
Knorr condensation[19] of 11 and 12 afforded a diverse range
of highly substituted 3-trifluoromethyl five-membered
heteroaromatics 13 and 14, which would be difficult to
synthesize by the conventional methods.[7]
Experimental Section
Typical procedure for the reaction of 1a with ketone in the presence
of Tf2O (Table 1, entry 1): Trifluoromethanesulfonic anhydride
(0.067 mL, 0.40 mmol) was added to a solution of acetophenone
(0.047 mL, 0.40 mmol) in C2H5NO2 (2 mL) and 1a (43.2 mg,
0.20 mmol) under argon at À788C, and the reaction mixture was
stirred for 30 min at À408C. The mixture was poured into saturated
aqueous NaHCO3 (10 mL), and the product was extracted with
CHCl3 (20 mL ꢁ 3). The combined organic layer was dried over
anhydrous Na2SO4 and concentrated in vacuo. The crude residue was
dissolved in MeOH (2 mL) and water (1 mL). Aqueous HCl (11m,
0.18 mL, 2.0 mmol) was added, and the whole mixture was heated at
reflux for 2 h. The mixture was diluted with H2O (10 mL) and
extracted with EtOAc (10 mL ꢁ 3). The combined organic layer was
dried over anhydrous Na2SO4 and concentrated in vacuo. The crude
residue was purified by chromatography on silica gel (eluent: toluene/
n-hexane = 3:2) and provided S-(3-mercaptopropyl) 4-oxo-4-phenyl-
2-trifluoromethylbutanethioate (3a, 49.1 mg, 0.147 mmol, 73%).
Typical procedure for the synthesis of 2-trifluoromethyl-1,4-
diketone (Scheme 5, steps f and g): Iodomethane (0.47 mL,
7.6 mmol) and iPr2EtN (1.3 mL, 7.6 mmol) were added to a solution
of 5 (1.14 g, 3.78 mmol) in acetone (5 mL). The resulting reaction
In summary, we have devised a novel Pummerer trans-
formation using ketones as substrates. The transformation
includes a new combination of nucleophilic attack of the
carbonyl oxygen atom onto the activated cationic sulfur atom
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mixture was stirred for 8 h at 258C. The mixture was poured into H2O
(10 mL) and extracted with EtOAc (10 mL ꢁ 3). The combined
organic layer was dried over anhydrous Na2SO4 and concentrated
in vacuo. The crude residue was purified by chromatography on silica
gel (eluent: n-hexane/EtOAc = 10:1) and provided (S)-(3-methyl-
thiopropyl) 3-methyl-4-oxo-2-trifluoromethylhexanethioate (0.933 g,
2.95 mmol, 78%).
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A
solution of (S)-(3-methylthiopropyl) 3-methyl-4-oxo-2-
trifluoromethylhexanethioate (63.3 mg, 0.20 mmol) in toluene
(2.0 mL) was added to [PdCl2(dppf)] (16.3 mg, 0.02 mmol) under
argon. After the mixture was cooled to 08C, (2-thienyl)ZnI·LiCl
complex (1.06 mL, 1.12 mmol, 1.06m in THF) was added, and the
resulting reaction mixture was stirred for 30 min. The mixture was
poured into aqueous HCl (1m, 10 mL) and extracted with EtOAc
(10 mL ꢁ 3). The combined organic layer was dried over anhydrous
Na2SO4 and concentrated in vacuo. The crude residue was purified by
chromatography on silica gel (eluent: n-hexane/EtOAc = 10:1) and
provided 3-methyl-1-(2-thienyl)-2-trifluoromethyl-1,4-hexanedione
(12a, 48.1 mg, 0.173 mmol, 87%).
Typical procedure for the Paal–Knorr condensation (Scheme 5,
step k): A solution of 12a (55.7 mg, 0.20 mmol), nBuNH2 (0.080 mL,
0.80 mmol), and Ti(OiPr)4 (0.18 mL, 0.60 mmol) in toluene (2 mL)
was stirred for 4 h at 258C. Water (10 mL) was added to the reaction
mixture, and the product was extracted with EtOAc (10 mL ꢁ 3). The
combined organic layer was dried over anhydrous Na2SO4 and
concentrated in vacuo. The crude residue was purified by chroma-
tography on silica gel (eluent: n-hexane/EtOAc = 20:1) and provided
1-butyl-5-ethyl-4-methyl-2-(2-thienyl)-3-trifluoromethylpyrrole (14c,
52.5 mg, 0.166 mmol, 83%).
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[8] The geometry of the double bond does not matter. Treatment of
the Z isomer of 1a also gave virtually the same result.
[9] The use of both 1.2 equivalents of acetophenone and Tf2O
resulted in moderate conversion. Trifluoromethanesulfonic
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Received: December 1, 2009
Published online: February 23, 2010
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Keywords: heterocycles · ketones · Pummerer rearrangement ·
sulfoxides · triflic anhydride
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