Convenient and efficient decarboxylative aldol reaction of malonic acid half esters with trifluoromethyl ketones

Article abstract of DOI:10.1016/j.tetlet.2012.02.053

A convenient and efficient decarboxylative ketone aldol condensation of malonic acid half esters was reported. In the presence of catalytic amount of triethylamine, a series of aromatic and alkyl trifluoromethyl ketones were transformed into the desired adducts in 61-99% yields. In a preliminary experiment, a moderate stereoselectivity was obtained. Direct reduction of the aldol product with LiAlH₄ afforded trifluoromethylated 1,3-diol.

Full text of DOI:10.1016/j.tetlet.2012.02.053

Tetrahedron Letters 53 (2012) 2117–2120
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Convenient and efficient decarboxylative aldol reaction of malonic acid
half esters with trifluoromethyl ketones
⇑
Xiao-Juan Li, Heng-Ying Xiong, Ming-Qing Hua, Jing Nie, Yan Zheng, Jun-An Ma
Department of Chemistry, Tianjin University, Tianjin 300072, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and efficient decarboxylative ketone aldol condensation of malonic acid half esters was
reported. In the presence of catalytic amount of triethylamine, a series of aromatic and alkyl trifluoro-
methyl ketones were transformed into the desired adducts in 61–99% yields. In a preliminary experiment,
a moderate stereoselectivity was obtained. Direct reduction of the aldol product with LiAlH4 afforded tri-
fluoromethylated 1,3-diol.
Received 23 December 2011
Revised 4 February 2012
Accepted 10 February 2012
Available online 17 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Decarboxylative aldol condensation
Malonic acid half esters
Trifluoromethyl ketones
Stereoselectivity
Reduction
Aspiring to imitate the enzymatic activation of malonic acid half
thioesters (MAHTs) in the biosynthesis of polyketides and fatty
acids,1–6 organic chemists have succeeded in developing many
decarboxylative carbon–carbon bond-forming reactions, such as
Claisen condensations,7–12 Mannich reactions,13–17 Michael addi-
tions,18–22 and Knoevenagel transformations.23–27 Among the most
widely used mimic decarboxylative transformations for the con-
struction of carbon–carbon bonds are decarboxylative aldol reac-
tions. A lot of examples of decarboxylative aldol condensations
have been reported;16,28–34 however, in most cases, the use of alde-
hydes to achieve successful results was necessary. Accordingly,
little attention has been paid to exploring ketone compounds as
electrophilic substrates. The lack of progress may be attributed to
the intrinsic poor reactivity of simple ketones. In comparison with
aldehydes, activated ketone electrophiles are necessary for reason-
able reaction rates. One example of decarboxylative ketone aldol
reactions came from Fagnou and co-workers, who reported a
triethylamine-promoted reaction of malonic acid half esters with
Initially, the condensation of malonic acid half thioester 1a with
2,2,2-trifluoroacetophenone 2a was explored as a model reaction.
The reaction did not proceed in toluene at room temperature with
stoichiometric triethylamine. This result prompted us to screen
other solvents including chloroalkanes, esters, ethers, and alcohols.
It was found that this decarboxylative transformation is highly
dependent on the solvent used, and no reaction occurred in most
cases. Tetrahydrofuran (THF) was shown to be the best solvent
for this reaction. Notably, this decarboxylative ketone aldol con-
densation can be carried out in the presence of catalytic triethyl-
amine (10 mol %) for 60 h to afford the desired product in a 95%
yield. In addition, no precautions for the use of inert atmosphere
are required since the reactions can be performed at room temper-
ature in an open flask. Malonic acid half oxyester (MAHO) 1b, when
used instead of malonic acid half thioester 1a, do participate in the
catalytic aldol reaction to give the adduct 3a in a quantitative yield
over a shorter reaction time (16 h). Subsequently, malonic acid half
oxyesters will be employed as the reactants for the generation of
ester enolate equivalents under very mild reaction conditions
(Scheme 1).
With the optimal conditions established, the scope of the reac-
tion was then probed. The results were listed in Table 1.38 For the
MAHOs with electron-withdrawing groups on the aromatic ring, a
relatively prolonged reaction time was required to get high yields
(entries 2 and 3 vs entry 1). For a series of aromatic trifluoromethyl
ketones with electron-withdrawing groups on aromatic rings were
used, the decarboxylative aldol reactions proceeded smoothly to
give the desired adducts 3e–i in 90–98% yields (entries 4–8). How-
ever, the presence of electron-donating substituents on aromatic
a-ketoesters to afford the tertiary alcohol in modest to good
yields.35,36 Nakamura and co-workers disclosed an asymmetric
organocatalytic decarboxylative addition of malonic acids half thi-
oesters to isatins to yield enantiomerically enriched adducts.37 We
recently found that trifluoromethyl ketones are suitable substrates
for this decarboxylative aldol reaction, the products of which are
the precursors of trifluoromethylated 1,3-diols. Herein, we report
our preliminary results on this subject.
⇑
Corresponding author.
E-mail address: majun_an68@tju.edu.cn (J.-A. Ma).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.053

2118
X.-J. Li et al. / Tetrahedron Letters 53 (2012) 2117–2120
O
O
HO
CF3
10 mol% Et3N
F3C
O
O
X
THF, 25 °C
X
OH
1a
X = S
1b X = O
2a
3a
X = S, 95% yield (60 h)
3b X = O, 99% yield (16 h)
Scheme 1. Decarboxylative aldol condensation of malonic acid half esters 1 with 2,2,2-trifluoroacetophenone 2a.
Table 1
Scope of the decarboxylative aldol condensation of malonic acid half ester 1b with trifluoromethyl ketones 2a
O
10 mol% Et3N
THF, 25 °C
O
O
O
OH
F3C
R
Ar
F3C
R
OAr
O
OH
1
2
3
Entry
1
Ketone
Time (h)
16
Product 3
Yieldb (%)
99
O
O
F3C OH
3b
3c
F3C
OPh
O
O
F3C OH
F3C
2
3
4
5
60
60
16
16
OAr1
(Ar1=3-ClC6H4)
99
97
96
93
O
O
F3C OH
OAr2
(Ar2=4-BrC6H4)
F3C
3d
3e
3f
O
O
F3C OH
F3C
OPh
Cl
Cl
O
O
F3C OH
F3C
OPh
F
F
O
O
F3C OH
F3C
OPh
6
7
12
60
3g
3h
96
90
F3C
CF3
O
Cl
O
F3C OH
F3C
OPh
Cl
O
O
F3C OH
F3C
CF3
F3C
OPh
OPh
8
9
12
72
3i
3j
98
95
CF3
CF3
F3C OH
O
O
F3C
Me
Me
O
O
F3C OH
F3C OH
F3C
OPh
OPh
10
11
120
120
3k
3l
61
65
MeO
MeO
OMe
OMe
O
O
F3C

X.-J. Li et al. / Tetrahedron Letters 53 (2012) 2117–2120
2119
Table 1 (continued)
Entry
Ketone
Time (h)
120
Product 3
O
F3C OH
Yieldb (%)
O
OMe
F3C
OPh
12
13
14
15
3m
3n
3o
3p
64
86
80
98
OMe
F3C OH
O
O
16
16
16
F3C
OPh
OPh
O
O
F3C OH
F3C
Ph
Ph
O
O
F3C OH
S
S
F3C
OPh
O
O
F3C OH
16
17
12
12
24
3q
3r
3s
95
98
89
F3C
O
Me
Me
OPh
O
F3C OH
EtO2C
F3C
O
CO2Et
CO2Et
OPh
O
F3C OH
18
EtO2C
F3C
OPh
a
Unless otherwise noted, the reaction was carried out with malonic acid half ester 1b (1.5 mmol) with trifluoromethyl ketones 2 (1.0 mmol) in the presence of trieth-
ylamine (0.1 mmol) in THF (2.0 mL) at 25 °C.
b
Isolated yield.
rings of ketones decreased the reaction rate, and relatively lower
yields were obtained (products 3j–m, entries 9–12). Accordingly,
the decarboxylative aldol reactions worked well with biphenyl,
2-naphthyl, and 2-thiophenyl trifluoromethyl ketones under our
current conditions to give the aldol products 3n–p in good yields
(entries 13–15). In addition, we also investigated the aldol reaction
of the MAHO 1b with alkyl trifluoromethyl ketones, including
1,1,1-trifluoropropan-2-one, ethyl 3,3,3-trifluoro-2-oxopropano-
ate,35 and ethyl 4,4,4-trifluoro-3-oxobutanoate. These electrophilic
ketones are also viable substrates in this decarboxylative transfor-
mation, affording the products 3q–s in 89–98% yields (entries 16–
18). Furthermore, the products derived from the self-condensation
and keto-enol tautomerization of ethyl 4,4,4-trifluoro-3-oxobut-
anoate have not been observed in the reaction system, demonstrat-
ing the mildness and selectivity of MAHOs activation under the
organic base conditions.
ylamine the aldol adduct 5 was obtained in a 92% yield with 57%
de. The described decarboxylative ketone aldol condensation of
malonic acid half esters could also, in principle, be extended to a
catalytic enantioselective reaction. Screening of a series of avail-
able cinchona alkaloids (see Supplementary data) indicated that
(DHQD)2AQN gave the best performance in terms of both the yield
and the enantioselectivity (Scheme 2b).
In addition, these aldol adducts are useful synthetic intermedi-
ates and can be readily transformed into trifluoromethyl-substi-
tuted 1,3-diol derivatives. For example, direct reduction of 3b in
the presence of LiAlH4 gave 4,4,4-trifluoro-3-phenylbutane-1,3-
diol 6 in an 85% isolated yield (Scheme 3).40
O
F3C OH
LiAlH4/THF
F3C OH
OPh
OH
−78 °C to rt,12h
This methodology was further extended to the chiral (S)-1,10-
binaphthyl-2,20-diol-derived malonic acid half ester 4 to illustrate
the application of the decarboxylative ketone aldol reaction
(Scheme 2a).39 We found that in the presence of 10 mol % of trieth-
85%
3b
6
Scheme 3. Synthetic transformation of the aldol adduct 3b into the product 6.
O
OH
O
OH
O
10 mol% Et3N
F3C
OH
a)
THF, 25 °C, 60 h
CF3
OH
5: 92%, 57% de
*
O
O
O
O
2a
4
O
O
HO
CF3
O
10 mol% (DHQD)2AQN
THF, 25 °C, 16 h
b)
F3C
O
*
O
OH
3b
99% yield, 68% ee
1b
2a
Scheme 2. Asymmetric decarboxylative aldol condensation.

2120
X.-J. Li et al. / Tetrahedron Letters 53 (2012) 2117–2120
27. Berrué, F.; Antoniotti, S.; Thomas, O. P.; Amade, P. Eur. J. Org. Chem. 2007, 1743.
In summary, we have developed a decarboxylative ketone aldol
28. Stiles, M.; Wolf, D.; Hudson, G. V. J. Am. Chem. Soc. 1959, 81, 628.
29. Kourouli, T.; Kefalas, P.; Ragoussis, N.; Ragoussis, V. J. Org. Chem. 2002, 67,
4615.
30. Lalic, G.; Aloise, A. D.; Shair, M. D. J. Am. Chem. Soc. 2003, 125, 2852.
31. Orlandi, S.; Benaglia, M.; Cozzi, F. Tetrahedron Lett. 2004, 45, 1747.
32. Magdziak, D.; Lalic, G.; Lee, H. M.; Shair, M. D. J. Am. Chem. Soc. 2005, 127, 7284.
33. Fortner, K. C.; Shair, M. D. J. Am. Chem. Soc. 2007, 129, 1032.
34. Rohr, K.; Mahrwald, R. Org. Lett. 2011, 13, 1878.
35. Blaquiere, N.; Shore, D. G.; Rousseaux, S.; Fagnou, K. J. Org. Chem. 2009, 74,
6190.
reaction of malonic acid half esters by using triethylamine as an
efficient organocatalyst. A series of aromatic and alkyl trifluoro-
methyl ketones were transformed into the aldol adducts in
61–99% yields. In a preliminary experiment, moderate stereoselec-
tivities were obtained. Further improvement of enantioselectivity
of this transformation as well as additional mechanistic studies
are ongoing in our laboratory and will be reported in due course.
36. Schipper, D. J.; Rousseaux, S.; Fagnou, K. Angew. Chem. Int. Ed. 2009, 48,
8343.
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2976.
Acknowledgment
The financial support from the National Natural Science Foun-
dation of China (NSFC) (Nos. 20972110 and 21002068) is gratefully
acknowledged.
38. General procedure for the catalytic decarboxylative aldol reaction of malonic acid
half esters with trifluoromethyl ketones: To
a Schlenk tube were added
monophenyl malonate 1b (270 mg, 1.2 mmol), 1-(4-chlorophenyl)-2,2,2-
trifluoroethanone (208 mg, 1.0 mmol), triethylamine (10 mg, 0.1 mmol), and
THF (2.0 mL). The resulting mixture was stirred at room temperature with a
hole pierced in the septum. After 16 h, the solvent was evaporated in vacuo and
the reaction mixture was directly purified by flash column chromatography
with ethyl acetate/petroleum ether (1/20 to 1/6) to get the white solid (3e,
330.2 mg). 96% yield, mp: 63–65 °C; 1H NMR (400 MHz, CDCl3) d 3.44 (s, 2H),
4.97 (s, 1H), 6.91 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 5.6 Hz, 1H), 7.36–7.46 (m, 4H),
7.63 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 169.8, 149.6, 135.4, 135.2,
129.6, 128.8, 128.0, 126.6, 124.3 (q, JC–F = 284.5 Hz), 121.0, 75.3 (q, JC–
F = 29.5 Hz), 38.7; 19F NMR (376 MHz, CDCl3) d ꢀ80.3 (s, 3F); MS (ESI) m/z
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.02.053.
References and notes
378.7 [M+Cl–H]ꢀ; IR (KBr)
1359, 1235, 1097, 1041, 1163, 970, 794, 686 cmꢀ1
m 3348, 3075, 2946, 2855, 1714, 1600, 1495, 1436,
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39. Procedure for an asymmetric decarboxylative aldol reaction of malonic acid half
ester 4 with 2,2,2-trifluoroacetophenone 2a: To a Schlenk tube were added 4
(186 mg, 0.5 mmol), 2,2,2-trifluoroacetophenone 2a (131 mg, 0.75 mmol),
triethylamine (5.1 mg, 0.05 mmol), and THF (2.0 mL). The resulting mixture
was stirred at room temperature with a hole pierced in the septum. After 60 h,
the solvent was evaporated in vacuo and the reaction mixture was directly
purified by flash column chromatography with ethyl acetate/petroleum ether
(1/20 to 1/4) to get the light yellow solid (5, 231 mg). mp 70–72 °C; yield 92%,
de 57% (determined by 19F NMR); 1H NMR (500 MHz, CDCl3)
d 2.85 (d,
J = 16.5 Hz, 1H), 3.12 (d, J = 16.5 Hz, 1H), 4.48 (s, 1H), 6.94–7.00 (m, 1H), 7.12–
7.14 (m, 1H), 7.20–7.26 (m, 2H), 7.37–7.48 (m, 7H), 7.50–7.53 (m, 2H), 7.88–
8.00 (m, 5H); 13C NMR (125 MHz, CDCl3) d 170.4, 151.7, 147.1, 136.6, 133.5,
133.4, 132.6, 131.6, 131.1, 131.0, 130.9, 129.3, 129.2, 128.7, 128.5, 128.4, 127.9,
127.1, 126.9, 126.6, 126.3, 126.0, 124.6 (q, JC–F = 283.7 Hz), 124.5, 123.9, 121.2,
118.3, 113.3, 75.3 (q, JC–F = 28.9 Hz), 38.5; 19F NMR (376 MHz, CDCl3) d ꢀ80.34
(s, 3F), ꢀ80.58(s, 3F); MS (ESI) m/z 536.5 [M+Cl–H]ꢀ; IR (KBr)
m 3620, 3483,
3060, 2963, 2927, 1735, 1619, 1596, 1508, 1431, 1381, 1206, 1162, 1072, 1023,
974, 816, 750 cmꢀ1
.
40. General procedure for the reduction of the aldol product: To a solution of 3b
(155.0 mg, 0.5 mmol) in 10 mL of THF was added LiAlH4 (19.5 mg, 0.5 mmol) in
one portion at 0 °C. The resultant mixture was stirred over night at room
temperature (monitored by TLC). The mixture was evaporated in vacuum,
added water (5 mL), extracted with dichloromethane (5 mL ꢁ 3), washed with
brine and dried over MgSO4. Concentration and flash chromatography (ethyl
acetate/hexane: 1/15 to 1/5 as eluant) afforded the white solid (6, 93.5 mg, 85%
yield). Mp: 68–70 °C; 1H NMR (400 MHz, CDCl3) d 7.62 (d, J = 7.6 Hz, 2H), 7.45–
7.39 (m, 3H), 4.98 (s, 1H), 3.98–3.95 (m, 1H), 3.73–3.68 (m, 1H), 2.56–2.46 (m,
1H), 2.40–2.31 (m, 1H), 1.99 (t, J = 3.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
137.3, 128.5, 128.4, 126.6, 125.2 (q, J = 283.0 Hz), 78.03 (q, J = 28.2 Hz), 59.5,
35.2; 19F NMR (376 MHz, CDCl3) d ꢀ80.17 (s, 3F); MS (ESI) m/z 242.3 [M+Na–
H]+; IR (KBr)
706 cmꢀ1
m: 3418, 3215, 2970, 2906, 1451, 1267, 1169, 1134, 1038, 977,
.