Nucleophilic trifluoromethylation of arylidene Meldrum's acids

Article abstract of DOI:10.1016/j.tetlet.2009.03.188

A method for the trifluoromethylation of arylidene Meldrum's acids using Me₃SiCF₃ followed by transformation of the initial products to CF₃-substituted esters and alcohols is described. The sequence of reactions is perform

Full text of DOI:10.1016/j.tetlet.2009.03.188

Tetrahedron Letters 50 (2009) 2998–3000
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Tetrahedron Letters
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Nucleophilic trifluoromethylation of arylidene Meldrum’s acids
*
Artem A. Zemtsov, Vitalij V. Levin, Alexander D. Dilman , Marina I. Struchkova, Pavel A. Belyakov,
Vladimir A. Tartakovsky
N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky Prospect 47, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for the trifluoromethylation of arylidene Meldrum’s acids using Me3SiCF3 followed by transfor-
mation of the initial products to CF3-substituted esters and alcohols is described. The sequence of reac-
tions is performed without isolation of intermediate compounds furnishing the final products in good
overall yields.
Received 27 January 2009
Revised 17 March 2009
Accepted 27 March 2009
Available online 2 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Arylidene Meldrum’s acids
Michael reaction
Trifluoromethylation
O
O
The Ruppert–Prakash reagent (Me3SiCF3) has found widespread
application as a convenient source of trifluoromethyl carbanions
allowing for the facile introduction of the CF3 group into organic
molecules.1 While nucleophilic trifluoromethylations of C@O and
C@N bonds have received considerable attention,2–4 addition of
the CF3 carbanion to electron-deficient alkenes (the Michael reac-
tion) has remained virtually unexplored.5 Furthermore, conven-
CN
CO2Et
Ph
Ph
Ph
O
CN
—9.42
CO2Et
—20.55
O
E-parameter
—9.15
Figure 1. Electrophilicity E-parameters according to Mayr’s scale.
tional
a,b-unsaturated aldehydes and ketones were reported to
undergo trifluoromethylation with Me3SiCF3 preferentially at the
OAc
carbonyl group.6,7
Me
Me
Si Me
CF3
Recently, we demonstrated that arylidenemalononitriles can be
readily trifluoromethylated under mild conditions.8 At the same
time, nucleophilic addition to arylidenemalonates was unsuccess-
ful8 and likely to be associated with their low electrophilicity, as
is supported by Mayr’s reactivity scale (Fig. 1).9
We proposed that switching from malonates to the arylidene
derivatives of Meldrum’s acid (2,2-dimethyl[1,3]dioxane-4,6-
dione) possessing a reactive C@C bond, would allow easy nucleo-
philic trifluoromethylation. We also hoped that addition of the
CF3 carbanion would take place selectively at the alkene double
bond leaving the carbonyl groups intact.
O
O
CF3
O
O
O
Me3SiCF3
NaOAc
Ar
O
O
O
Ar
O
DMF, 2 h
O
Ar
O
O
1a, Ar = 4-MeOC6H4
CF3
O
O
O
CF3
O
H3O
aq. HCl
100-120 °C, 1 h
Ar
2a
O
Ar
OH
3a
Compound 1a, derived from anisaldehyde and Meldrum’s acid,
was selected as a model substrate, and its trifluoromethylation
with Me3SiCF3 was studied (Scheme 1). The reaction was carried
out in DMF using sodium acetate as the basic activator. To achieve
complete conversion of 1a the process had to be performed at
elevated temperature (50 °C) and a stoichiometric amount of
NaOAc (1.5 equiv) was required.10
Scheme 1.
Acidic aqueous work-up provided a crude sample of compound
2a. However, decomposition of 2a occurred upon chromatographic
purification, which may be associated with the enhanced electro-
philicity of the carbonyl groups. Therefore, the 1,3-dioxane 2a
was hydrolyzed with concomitant decarboxylation by heating
the reaction mixture with aqueous hydrochloric acid. The carbox-
ylic acid 3a was isolated in 98% yield after purification by basic/
acidic extractions.
* Corresponding author. Fax: +7 499 135 53 28.
E-mail address: adil25@mail.ru (A.D. Dilman).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.188

A. A. Zemtsov et al. / Tetrahedron Letters 50 (2009) 2998–3000
2999
Conventional column chromatography of acid 3a proved to be
problematic due to significant tailing. In this regard, we decided
to perform further transformation of the acids into esters and alco-
hols. It would also be desirable that the overall procedure starting
from 1 would not require purification of the intermediate products.
This seemed feasible since trifluoromethylation and decarboxyl-
ation proceed cleanly.
Thus, the crude acid 3a was either converted to methyl ester 4a
by alkylation or reduced to alcohol 5a in 88–90% overall yields
based on starting material 1a (Table 1, entries 1 and 2). Under
the optimized conditions, a variety of arylidene derivatives were
utilized for the trifluoromethylation reaction (Table 1). Substrates
obtained from para- and ortho-substituted aldehydes, as well as
when an alkylidene substrate synthesized from cyclohexanone
and Meldrum’s acid was tested in this process, only traces of prod-
uct were detected.
Trifluoromethylation of compound 1m followed by stan-
dard decarboxylation and esterification gave hydroxy-substi-
tuted product 7 (Scheme 2). This product was formed even
with 2.5 equiv of the silicon reagent thereby suggesting that
elimination of the methoxy group does not occur during
the trifluoromethylation step, but upon further acidic
treatment.
In summary, a convenient protocol for the synthesis of CF3-
substituted derivatives based on the Michael addition of a trifluo-
romethyl carbanion to arylidene Meldrum’s acids has been devel-
oped. The trifluoromethylation reaction proceeds under mildly
basic conditions and subsequent transformations of the 1,3-diox-
ane-4,6-diones provide esters or alcohols in good overall yields.11
The reported method for the synthesis b-CF3-substituted esters is
complementary to the approach based on conjugate addition of
non-fluorinated nucleophiles to trifluorocrotonates,12 with the
present method enabling the direct introduction of fluorinated
fragments.
from
a,b-unsaturated and heteroaromatic aldehydes, gave good
yields of products 4 and 5.
In the case of alkylidene substrates that contain acidic hydro-
gens adjacent to the double bond, reduced yields of products were
observed. For example, compound 1l furnished ester 4l in only 62%
yield along with non-trifluoromethylated ester 6 (Scheme 2). The
formation of ester 6 can be explained by deprotonation of 1l by
the CF3 carbanion at the trifluoromethylation stage. Similarly,
Table 1
Trifluoromethylation of arylidene Meldrum’s acids
CF3
O
MeI
Ar
Ar
OMe
OH
K2CO3
O
4
a) 1.5 eq. Me3SiCF3
1.5 eq. NaOAc
CF3
O
Ar
O
Ar
OH
DMF, 50 °C, 2 h
O
O
3
CF3
b) aq. HCl, 100-120 °C, 1 h
1
NaBH4
BF3·OEt2
5
Entry
Ar
1
Product
Yield of 4 or 5a (%)
1
2
3
4
5
4-MeOC6H4
4-MeOC6H4
Ph
4-O2NC6H4
4-ClC6H4
2-MeOC6H4
3,4,5-(MeO)3C6H2
4-Me2NC6H4
1-Naphthyl
(E)-Ph-CH@CH
2-Thienyl
1a
4a
5a
4b
4c
4d
4e
4f
5g
4h
4i
88
90
76
83
88
81
85
88
75
74
75
66
1a
1b
1c
1d
1e
1f
1g
1h
1i
6
7
8b
9
10
11
12
1j
1k
4j
4k
2-Furyl
a
Overall yield of isolated product starting from 1.
Reaction was performed with 2 equiv of Me3SiCF3 and 2 equiv of NaOAc at 70 °C for 5 h.
b
O
a) 1.5 eq. Me3SiCF3, 1.5 eq. NaOAc
CF3
O
O
DMF, 50 °C, 2 h
O
+
OBn
4l 62%
OBn
b) aq. HCl, 100-120 °C, 1 h
c) BnBr, K2CO3
O
O
21%
6
1l
CF3
O
O
O
O
2.5 eq. Me3SiCF3
1.5 eq. NaOAc
CF3
O
aq. HCl, 100-120 °C
then BnBr, K2CO3
MeO
O
MeO
O
HO
OBn
DMF, 50 °C, 2 h
O
O
1m
7
64%
Scheme 2.

3000
A. A. Zemtsov et al. / Tetrahedron Letters 50 (2009) 2998–3000
Chem. 2003, 68, 7747; (c) Sosnovskikh, V. Ya.; Usachev, B. I.; Sevenard, D. V.;
Acknowledgments
Röschenthaler, G.-V. J. Fluorine Chem. 2005, 126, 779; (d) Sosnovskikh, V. Ya.;
Usachev, B. I.; Permyakov, M. N.; Sevenard, D. V.; Röschenthaler, G.-V. Russ.
Chem. Bull. 2006, 55, 1687.
This work was supported by the Russian Academy of Sciences
(Program # 18), Ministry of Science, Russian Foundation for Basic
Research (Project 08-03-00428), and the Russian Science Support
Foundation.
6. Singh, R. P.; Kirchmeier, R. L.; Shreeve, J. M. Org. Lett. 1999, 1, 1047.
7. Trifluoromethylation of enones in combination with bulky aluminum reagents
was studied, but the yields of the products of conjugate addition were
moderate, see: Sevenard, D. V.; Sosnovskikh, V. Ya.; Kolomeitsev, A. A.;
Königsmann, M. H.; Röschenthaler, G.-V. Tetrahedron Lett. 2003, 44, 7623.
8. Dilman, A. D.; Levin, V. V.; Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V. A.
Tetrahedron Lett. 2008, 49, 4352.
9. (a) Kaumanns, O.; Lucius, R.; Mayr, H. Chem. Eur. J. 2008, 14, 9675; (b)
Kaumanns, O.; Mayr, H. J. Org. Chem. 2008, 73, 2738; (c) Lemek, T.; Mayr, H. J.
Org. Chem. 2003, 68, 6880.
Supplementary data
Supplementary data associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2009.03.188.
10. When the reaction was performed with 0.2 equiv of NaOAc at 50 °C, only 17%
conversion of starting substrate was observed. This suggests that the anion,
which is formed after nucleophilic addition of the CF3 group to 1a, does not
activate Me3SiCF3.
References and notes
11. General procedures. Trifluoromethylation: Silane Me3SiCF3 (222 lL, 1.5 mmol)
1. For reviews on the chemistry of Me3SiCF3, see: (a) Prakash, G. K. S.; Yudin, A. K.
Chem. Rev. 1997, 97, 757; (b) Prakash, G. K. S.; Mandal, M. J. Fluorine Chem.
2001, 112, 123; (c) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613.
2. For addition to C@O bonds, see: (a) Prakash, G. K. S.; Panja, C.; Vaghoo, H.;
Surampudi, V.; Kultyshev, R.; Mandal, M.; Rasul, G.; Mathew, T.; Olah, G. A. J.
Org. Chem. 2006, 71, 6806; (b) Kawano, Y.; Kaneko, N.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 2006, 79, 1133; (c) Mizuta, S.; Shibata, N.; Akiti, S.; Fujimoto, H.;
Nakamura, S.; Toru, T. Org. Lett. 2007, 9, 3707; (d) Fustero, S.; Albert, L.; Acena, J.
L.; Sanz-Cervera, J. F.; Asensio, A. Org. Lett. 2008, 10, 605.
and NaOAc (123 mg, 1.5 mmol) were added to a solution of 1 (1.0 mmol) in dry
DMF (2 mL) at room temperature. The reaction mixture was stirred at 50 °C for
2 h, cooled to room temperature, and quenched with aq HCl (2 mmol, 280 lL of
an aq 7 M solution). The resulting mixture was stirred at 100–120 °C for 1 h,
cooled to room temperature, and diluted with water (10 mL). The aqueous
phase was extracted with Et2O (3 Â 5 mL), the combined organic phase was
filtered through Na2SO4, and the solvents were removed under vacuum. The
residue was dried in vacuum (ca. 1 mmHg) to remove AcOH to give a crude
sample of acid 3.
3. For addition to C@N bonds, see: (a) Prakash, G. K. S.; Mandal, M.; Olah, G. A.
Synlett 2001, 77; (b) Prakash, G. K. S.; Mogi, R.; Olah, G. A. Org. Lett. 2006, 8,
3589; (c) Kirij, N. V.; Babadzhanova, L. A.; Movchun, V. N.; Yagupolskii, Y. L.;
Tyrra, W.; Naumann, D.; Fischer, H. T. M.; Scherer, H. J. Fluorine Chem. 2008,
129, 14; (d) Nelson, D. W.; Owens, J.; Hiraldo, D. J. Org. Chem. 2001, 66, 2572.
4. For results from our group, see: (a) Dilman, A. D.; Arkhipov, D. E.; Levin, V. V.;
Belyakov, P. A.; Korlyukov, A. A.; Struchkova, M. I.; Tartakovsky, V. A. J. Org.
Chem. 2007, 72, 8604; (b) Dilman, A. D.; Arkhipov, D. E.; Levin, V. V.; Belyakov,
P. A.; Korlyukov, A. A.; Struchkova, M. I.; Tartakovsky, V. A. J. Org. Chem. 2008,
73, 5643; (c) Levin, V. V.; Kozlov, M. A.; Song, Y.-H.; Dilman, A. D.; Belyakov, P.
A.; Struchkova, M. I.; Tartakovsky, V. A. Tetrahedron Lett. 2008, 49, 3108; (d)
Levin, V. V.; Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V. A.
Eur. J. Org. Chem. 2008, 5226.
Esterification: The crude acid 3 was dissolved in dry DMF (2 mL) and was
treated with MeI (125 lL, 2 mmol) and K2CO3 (276 mg, 2 mmol). The mixture
was stirred for 1 h at room temperature, diluted with water (10 mL), and the
aqueous phase was extracted with Et2O/hexanes (1:1, 3 Â 5 mL). The combined
organic phase was filtered through Na2SO4, the solvents were removed under
vacuum, and the residue was purified by column chromatography.
Reduction: A solution of crude acid 3 in dioxane (2.0 mL) at 0 °C was treated
with BF3ÁOEt2 (317
lL, 2.5 mmol) and NaBH4 (114 mg, 3.0 mmol). The mixture
was stirred at 50 °C for 1.5 h and quenched by dropwise addition of water
(10 mL). The aqueous phase was extracted with Et2O (3 Â 5 mL), the combined
organic phase was filtered through Na2SO4, the solvents were removed under
vacuum, and the residue was purified by column chromatography.
12. (a) Shinohara, N.; Haga, J.; Yamazaki, T.; Kitazume, T.; Nakamura, S. J. Org.
Chem. 1995, 60, 4363; (b) Konno, T.; Tanaka, T.; Miyabe, T.; Morigaki, A.;
Ishihara, T. Tetrahedron Lett. 2008, 49, 2106; (c) Gestmann, D.; Laurent, A. J.;
Laurent, E. G. J. Fluorine Chem. 1996, 80, 27; (d) Yamazaki, T.; Shinohara, N.;
Kitazume, T.; Sato, S. J. Fluorine Chem. 1999, 97, 91.
5. Only specific substrates, such as perfluoroalkyl-substituted chromones and
quinolones, were trifluoromethylated, see: (a) Sosnovskikh, V. Ya.; Sevenard, D.
V.; Usachev, B. I.; Röschenthaler, G.-V. Tetrahedron Lett. 2003, 44, 2097; (b)
Sosnovskikh, V. Ya.; Usachev, B. I.; Sevenard, D. V.; Röschenthaler, G.-V. J. Org.