Enantioselective primary amine catalyzed aldol-type construction of trifluoromethylated tertiary alcohols

Article abstract of DOI:10.1055/s-0033-1341281

It was found that the cinchona-derived primary amines and their combined catalyst systems with chiral organic acid or Lewis acid have been successfully applied in the cross-aldol reaction of trifluoromethyl ketones and aliphatic ketones. Excellent yields

Full text of DOI:10.1055/s-0033-1341281

LETTER
▌1461
letter
Enantioselective Primary Amine Catalyzed Aldol-Type Construction of
Trifluoromethylated Tertiary Alcohols
Asymmetric Primary Amine Catalysis
Wei Yang,a Yu-Ming Cui,a Wei Zhou,a Li Li,*a Ke-Fang Yang,a Zhan-Jiang Zheng,a Yixin Lu,b Li-Wen Xu*a,c
a
College of Material Chemistry and Chemical Engineering, and Key Laboratory of Organosilicon Chemistry and Material Technology of
Ministry of Education, Hangzhou Normal University, Hangzhou 310012, P. R. of China
Fax +86(571)28868918; E-mail: licpxulw@yahoo.com; E-mail: liwenxu@hznu.edu.cn
b
c
Department of Chemistry and Medicinal Chemistry Program, Life Sciences Institute, National University of Singapore, 3 Science Drive 3,
117543 Singapore, Republic of Singapore
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics and University of Chinese Academy
of Sciences, Chinese Academy of Sciences, Lanzhou 730000, P. R. of China
Received: 22.02.2014; Accepted after revision: 07.04.2014
aldol reactions due to difficulty of the differentiation of
the reactive carbonyl face of ketones, including trifluoro-
methyl ketones.6 In fact, there have been only a few re-
sults of the cross-aldol reaction of aliphatic ketones with
Abstract: It was found that the cinchona-derived primary amines
and their combined catalyst systems with chiral organic acid or
Lewis acid have been successfully applied in the cross-aldol reac-
tion of trifluoromethyl ketones and aliphatic ketones. Excellent
yields and good enantioselectivities (up to 89% ee) of the resulting trifluoromethyl ketones.7–12 And besides them, only some
β-trifluoromethyl-β-hydroxy ketones were obtained in the chiral
primary amine catalyzed cross-aldol reaction under different condi-
activated and functionalized ketones, such as isatins and
α-keto phosphonates, could be used in organocatalytic
tions, which also led to both enantiomers of the desired products.
ketone–ketone aldol reactions.13 Therefore, as a starting
This study also demonstrated the importance of synergistic effect of
point, expanding the scope of the organocatalytic cross-
chiral organic acid on the primary amine catalysis.
aldol reaction with two different types of ketones is highly
Key words: tertiary alcohol, primary amine, organofluorine, or-
desirable.
ganocatalysis, cross-aldol reaction
F3C
OH
O
CF3
Me
NH
HO
O
O
O
H
N
N
Organofluorine compounds are playing a key role in phar-
maceuticals, agrochemicals, functional materials, or or-
ganocatalysts.1 The application of organofluorine
compounds is impressively wide to concern all fields of
chemical and material society. Especially, 20% of all
pharmaceuticals and 30% of the top ten best-selling drugs
contain at least one fluorine atom.2 Of particular relevance
is the enantioselective construction of fluorine-containing
building blocks or substructures. In this context, the syn-
thesis of chiral trifluoromethylated molecules stimulated
high interest in the past decade due to the increasing oc-
currence of this motif in a wide range of biologically ac-
tive molecules (Figure 1).3 As a consequence, the
development of new methods for catalytic asymmetric
construction of trifluoromethylated tertiary alcohol is
highly desirable.
Since List and Barba and co-workers4 identified chiral
proline to be an organocatalyst for enantioselective aldol
reactions, asymmetric organocatalysis has become one of
the most powerful carbon–carbon bond-forming reac-
tions.5 Although numerous methods have been reported
for organocatalytic aldol reactions of aromatic aldehydes
with ketones in the past decade, it is still a challenging re-
search topic in the organocatalytic ketone–ketone cross-
CONH2
HO
N
H
O
anticonvulsant
Ph
HN
O
inhibitor of matrix
metalloproteinases
O
HO
CF3
O
O2
S
H
N
CF3
OH
CN
F
ZK-216348
anticancer agent
CF3
Figure 1 Representative biologically active compounds featuring
the motif of trifluoromethylated tertiary alcohol
On the other hand, there are few reports on the aldol reac-
tion of trifluoromethyl ketones probably due to the diffi-
culties in obtaining excellent enantioselectivity with these
ketones. In 2005, Zhang and co-workers7 reported the first
example of a proline-catalyzed cross-aldol reaction of ac-
etone with aryl trifluoromethyl ketones to give tertiary
trifluoromethyl carbinols with only moderate enantiose-
lectivity (up to 64% ee). More recently, several specifical-
ly for asymmetric aldol reaction trifluoromethyl ketones,
designed proline-derived secondary amines with hydro-
gen-bonding groups have been described successfully by
Nakamura,8 Kokotos,9 Gröger and Berkessel10 indepen-
dently, which provide interesting examples in an effort to
broaden the applicability of chiral secondary amine based
organocatalysts. However, few studies demonstrated that
primary amine based enamine catalysis could be effec-
tively used in aldol reaction of trifluoromethyl ketones. In
SYNLETT 2014, 25, 1461–1465
Advanced online publication: 20.05.2014
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6
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5
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4
1
4
3
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0
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DOI: 10.1055/s-0033-1341281; Art ID: st-2014-w0154-l
© Georg Thieme Verlag Stuttgart · New York

1462
W. Yang et al.
LETTER
this regard, Luo and Cheng11 have even reported the pri- tional use of primary amine and other catalysts for
mary amine catalyzed pyruvate aldol reaction of 2,2,2-tri- asymmetric transformations,14–17 we evaluated the cata-
fluoromethyl-1-phenylethanone but demonstrated only lytic activity of QN-NH2 (C4) in the presence of various
moderate enantioselectivity (59% ee). In 2012, Gröger chiral organic acids or Lewis acids. Representative results
and Berkessel10 also found that chiral primary amine cat- have been provided in Table 1. We found the Boc-L-phe-
alysts, such as the cis-cyclohexane-1,2-diamine (DACH)- nylalanine [A1, (S)-2-(tert-butoxycarbonyl)-3-phenylpro-
derived organocatalyst and 9-amino-9-deoxyepiquinine panoic acid)] resulted in better enantioselectivity (71%
gave low catalytic activity and poor enantioselective in- ee) and excellent yield. Then with the combined catalyst
duction (<5% ee, Scheme 1). In fact, chiral primary system of QN-NH2 and Boc-L-phenylalanine, the reaction
amines have been shown to be viable enamine catalysts
that attain a new level of catalysis beyond traditional sec-
Table 1 Optimization of Reaction Conditions in the Cross-Aldol
ondary amine catalysis in many reactions.14,15 Very re-
Reaction of Acetone and 2,2,2-Trifluoromethyl-1-phenylethanonea
cently, we have developed a novel organocatalyst system
with the combination of a cinchona alkaloid derived pri-
O
O
O
HO
catalyst
mary amine and triphenylphosphine for asymmetric
Michael reaction of aliphatic aldehydes with ma-
leimides.15b,16 This dual catalyst system exhibited highly
enantioselective formation of chiral substituted aldehydes
(up to 99% yield, >99% ee) under air atmosphere. Al-
though pioneering studies on organocatalytic aldol reac-
tions of trifluoromethyl ketones have been performed, the
development of highly enantioselective catalytic systems
with a novel mode of activation or a synthetically useful
approach is still a challenging research. Herein, we pres-
ent our studies toward the chiral primary amine catalyzed
aldol reaction of trifluoromethyl ketones for the enanti-
oselective construction of trifluoromethylated tertiary al-
cohols. Detailed studies focused on enantioselectivity
enhancement supported the powerful activity of coopera-
tive catalysis in asymmetric catalysis.
+
CF3
solvent, 12 h
CF3
1a
2a
3a
OMe
NHBoc
COOH
NH2
NH2
N
A1
N
N
N
NHBoc
C2: CD-NH2
C1: QD-NH2
COOH
NH2
A2
NH2
N
N
OH
N
N
COOH
MeO
A3
C4: QN-NH2
C3: CN-NH2
Entry
Catalyst Acid
Solvent
Yield (%)b ee (%)c
O
O
HO
1
2
C1
C2
C3
C4
C4
C4
C4
C4
C4
C4
C4
C1
C1
C1
TFA
TFA
TFA
TFA
A1
toluene
toluene
toluene
toluene
toluene
xylene
<10
94
96
95
94
99
99
99
98
99
98
87
90
90
65 (S)
57 (R)
59 (S)
68 (R)
71 (R)
73 (R)
74 (R)
70 (R)
71 (R)
75 (R)
76 (R)d
77 (S)d
79 (S)
81 (S)d
O
catalyst
+
CF3
CF3
3
Ph
Ph
S
COOt-Bu
COOt-Bu
O
O
4
H2N
N
H
N
S
H
H2N
N
CF3
H
5
80% yield, 5% ee
Berkessel 201210
31% yield, 30% ee
Kokotos 20129
6
A1
Scheme 1 Primary amine catalysts employed in previous reports9,10
7
A1
mesitylene
CH2Cl2
8
A1
Since little success has been achieved for the chiral prima-
ry amine catalyzed aldol reaction of acetone and 2,2,2-tri-
fluoromethyl-1-phenylethanone (Scheme 1),9–12 initial
evaluation of various organocatalysts (Table S1 and S2 of
Supporting Information) and cinchona-derived primary
amine organocatalysts in this reaction was undertaken
(Table 1). As shown in these Tables, four cinchona-
derived primary amines exhibited promising enantiose-
lectivity in this reaction in comparison to that of chiral
amino acids, various cinchona alkaloids, or its derivatives.
From entries 1–4 (Table 1), it is obvious that the presence
of TFA to assist enamine intermediate is necessary. Ex-
cept for QD-NH2 (catalyst C1), these cinchona-derived
primary amines led to high to quantitative yields, but the
enantioselectivity was not satisfactory (57–68% ee). In-
spired by previous work that had focused on the combina-
9
A2
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
10
11
12
13
14
A3
A1
A1
A3
A3
a The reaction was carried out with trifluoromethyl ketone 1a (0.2
mmol) and acetone (10 equiv) in solvent, and chiral primary amine
(10 mol%) and organic acid (10 mol%) were used as described in this
table.
b Isolated yield after column chromatography.
c The ee was determined by chiral HPLC.
d With Al(Oi-Pr)3 (10 mol%) as additive.
Synlett 2014, 25, 1461–1465
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Primary Amine Catalysis
1463
O
medium was studied (entries 6–8, Table 1). Among the
range of solvents tested, mesitylene provided the best re-
sults (entry 7, 74% ee). We then selected mesitylene as
solvent to investigate other organic acids to promote the
primary amine catalysis. Interestingly, when (R)-2-hy-
droxy-2-phenylacetic acid (mandelic acid) was used as a
chiral acid, an excellent yield (99%) and better enantiose-
lectivity (75% ee) were obtained (entry 10). Continuing
with our interest in the combinational use of Lewis acid
and organocatalyst, we utilized Al(Oi-Pr)3 and found that
it could improve the enantioselectivity slightly (entry 11).
Notably, the combinational use of QD-NH2, (R)-2-hy-
droxy-2-phenylacetic acid, and Al(Oi-Pr)3 led to excellent
yield and good enantioselectivity in the reaction (entry
14).
R1
R2
conditions
A or B
O
CF3
R2
R1
+
X
mesitylene
r.t., 12 h
X
O
CF3
2
HO
1
3
X = O, N
conditions A: 10 mol% of QD-NH2, mandelic acid, Al(Oi-Pr)3, S-product
conditions B: 5 mol% of QN-NH2, mandelic acid, R-product
C6H13
O
O
O
CF3
CF3
CF3
HO
HO
HO
3a
3c
3b
A: 90% yield, 81% ee
B: 70% yield, –81% ee
A: 90% yield, 80% ee
B: 64% yield, –76% ee
A: 95% yield, 85% ee
B: 89% yield, –84% ee
Cl
Cl
O
O
O
CF2Br
HO
CF3
CF3
HO
HO
The scope and limitations of the current methodology
were then investigated. With QN-NH2 or QD-NH2 as the
optimal primary amine catalyst, we next explored the
cross-aldol reaction of a variety of trifluoromethyl ke-
tones and aliphatic ketones to prepare various trifluoro-
methylated tertiary alcohols. As shown in Scheme 2, both
enantiomers of the desired product were achieved with
different reaction conditions, and excellent yields and
good enantioselectivities were achieved in most of reac-
tions. When acetone was replaced by other aliphatic ke-
tones, the enantioselectivity and isolated yield of the
corresponding product were also good (for example, up to
85% ee and 95% yield of 3c). And when one of the fluo-
rine atoms was replaced by a bromine atom, the yield
dropped significantly but the enantioselective induction
was still reserved in good level (3d, 75–78% ee under var-
ious conditions). Interestingly, 2,2,2-trifluoro-1-(pyridin-
2-yl)ethanone can also be utilized as a suitable substrate in
this aldol reaction (see 3i and 3j, 81–98% yield under var-
ious conditions). Although the aldol reaction of 2,2,2-tri-
fluoro-1-(pyridin-2-yl)ethanone with acetone led to only
60% ee or 76% ee in the presence of QN-NH2 or QD-NH2,
respectively, 2-butanone gave superior results under both
conditions A and B (98% yield, 89% ee and 84% ee, re-
spectively).
3d
3e
3f
A: 50% yield, 75% ee
B: 68% yield, –78% ee
A: 76% yield, 83% ee
B: 60% yield, –77% ee
A: 96% yield, 84% ee
B: 69% yield, –77% ee
O
O
N
O
CF3
HO
CF3
HO
CF3
HO
3i
3h
3g
A: 67% yield, 67% ee
B: 81% yield, –71% ee
A: 89% yield, 80% ee
B: 56% yield, –74% ee
A: 90% yield, 76% ee
B: 81% yield, –60% ee
Cl
MeO
O
N
O
O
CF3
CF3
CF3
HO
HO
HO
3j
3k
3l
A: 98% yield, 89% ee
B: 98% yield, –84% ee
A: 91% yield, 80% ee
B: 81% yield, –75% ee
A: 72% yield, 65% ee
B: 69% yield, –75% ee
Scheme 2 Direct asymmetric primary amine catalyzed aldol reaction
between ketone and various trifluoromethyl ketones18,19
OMe
F
F
N
O
N
H
F
N
H
N
N
F3C
O
Al
O
N
O
O
MeO
From the above results, the hypothetical transition state
for the enantioselective cross-aldol reaction of trifluoro-
methyl ketones with acetone is shown in Figure 2. Under
the two different reaction conditions, the hydrogen bond-
ing of primary amine derived enamine would play an im-
portant role in the stabilization of transition states. And
the role of Al(Oi-Pr)3 is probably useful in the activation
of trifluoromethyl ketones and the stabilization of the
plausible QD-NH2-derived enamine-based transition
state.
TS-S (QD-NH2 catalysis)
TS-R (QN-NH2 catalysis)
F3C
F3C
OH
OH
S
R
O
O
Figure 2 Hypothetical transition state for the cross-aldol reaction of
trifluoromethyl ketone 1a with acetone under two different reaction
conditions
In summary, in an effort to develop a primary amine cat-
alyzed cross-aldol reaction of trifluoromethyl ketones and
aliphatic ketones, cinchona-derived primary amines were
tested for this model reaction and a combined catalyst sys-
tem derived from chiral primary amine and chiral organic
acid as well as Lewis acid has been successfully devel-
oped in this transformation. Under the optimized reaction
conditions with cinchona-derived primary amine catalyst,
excellent yields and good enantioselectivities (up to 89%
ee) of the resulting β-trifluoromethyl-β-hydroxy ketones
were obtained. This study also demonstrated the impor-
tance of synergistic effect of chiral organic acid on the
primary amine catalysis. Although the present organocat-
alytic route has some limitation in terms of enantioselec-
tivities, the combination of the chiral primary amine
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1461–1465

1464
W. Yang et al.
LETTER
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Acknowledgment
Financial support by the National Natural Science Foundation of
China (NSFC Grant No. 21173064), the Zhejiang Provincial Natu-
ral Science Foundation of China (LR14B0300001, LQ12B02004),
and the Hangzhou Science and Technology Program
(20130533B15 and 20130432B06), is appreciated.
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at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunpfgIpi
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(12) (a) Zheng, Y.; Xiong, H. Y.; Nie, J.; Hua, M. Q.; Ma, J. A.
Chem. Commun. 2012, 48, 4308. (b) Li, X. J.; Xiong, H. Y.;
Hua, M. Q.; Nie, J.; Zheng, Y.; Ma, J. A. Tetrahedron Lett.
2012, 53, 2117.
(13) For recent reviews, see: (a) Adachi, S.; Harada, T. Eur. J.
Org. Chem. 2009, 3661. For selected examples of
organocatalytic ketone–ketone aldol reactions, see:
(17) (a) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.;
Sambri, L.; Melchiorre, P. Org. Lett. 2007, 9, 1403.
(b) Yang, H. M.; Li, L.; Jiang, K. Z.; Jiang, J. X.; Lai, G. Q.;
Synlett 2014, 25, 1461–1465
© Georg Thieme Verlag Stuttgart · New York

LETTER
Xu, L. W. Tetrahedron 2010, 66, 9708. (c) Cai, Y. F.; Yang,
Asymmetric Primary Amine Catalysis
1465
determined by chiral-phase HPLC analysis using a Chiralcel
OD-H column and the indicated eluent systems.
H. M.; Li, L.; Jiang, K. Z.; Lai, G. Q.; Jiang, J. X.; Xu, L. W.
Eur. J. Org. Chem. 2010, 4986. (d) Loh, C. C. J.; Enders, D.
Chem. Eur. J. 2012, 18, 10212. (e) Xu, L. W.; Yang, H. M.;
Shao, Z. H. Multi-Catalyst Systems, In Comprehensive
Enantioselective Organocatalysis: Catalysts, Reactions,
and Applications; Dalko, P. I., Ed.; Wiley-VCH: Weinheim,
2013, 1333–1357. (f) Zhu, L.; Xi, Z. G.; Lv, J.; Luo, S. Z.
Org. Lett. 2013, 15, 4496. (g) Shang, J. Y.; Li, L.; Lu, Y.;
Yang, K. F.; Xu, L. W. Synth. Commun. 2014, 44, 101.
(18) Although fluorine-containing compounds (such as CF3-
containing molecules) might generally be expected to
show significant level of the self-disproportionation of
enantiomers (SDE) via achiral chromatography, we found
no such effect was observed in this work after column
chromatography. In spite of this, special care should be
taken in collecting the entire product after column
(b) General Procedure for Aldol Reaction of Acetone
with Trifluoroacetophenone (Method B): In a typical
experiment, to a solution of QN-NH2 and (R)-mandelic acid
(10 mol%) in mesitylene (0.5 mL), α,α,α-trifluoroaceto-
phenone (0.2 mmol), and acetone (2.0 mmol) were added
subsequently, and the resulting solution was stirred at 35 °C
for 12 h and monitored by TLC. The crude mixture was
directly purified by column chromatography (silica gel,
petroleum ether–EtOAc mixtures) to obtain pure products.
The products were characterized by NMR, GC–MS, and IR
analysis. And the ee values of the aldol products were
determined by chiral-phase HPLC analysis using a Chiralcel
OD-H column and the indicated eluent systems. 5,5,5-
Trifluoro-4-hydroxy-4-phenylpentan-2-one (3a): colorless
liquid. 1H NMR (400 MHz, CDCl3): δ = 7.48 (m, 2 H), 7.29
(m, 3 H), 5.37 (s, 1 H), 3.20 (q, J = 17.2 Hz, 2 H), 2.11 (s, 3
H). 13C NMR (100 MHz, CDCl3): δ = 208.9, 137.3, 128.7,
128.4, 126.1, 125.8 (q, J = 283.3 Hz), 76.1 (d, J = 29.0 Hz),
45.0, 32.0. 19F NMR (376.5 MHz, CDCl3): δ = –80.35 (s). IR
(KBr): 3442.06, 2925.93, 2854.48, 2361.57, 2344.25,
2069.04, 1704.18, 1630.33, 1497.43, 1451.38, 1401.52,
1337.98, 1164.09, 1061.96, 1000.83, 906.86, 765.69,
736.64, 709.62, 633.02, 573.40, 525.79 cm–1. HRMS (ESI):
m/z [M + Na]+ calcd for C11H11F3NaO2: 255.0603; found:
chromatography. For such phenomena, see:
(a) Sorochinsky, A. E.; Aceña, J. L.; Soloshonok, V. A.
Synthesis 2013, 45, 141. (b) Soloshonok, V. A.; Roussel, C.;
Kitagawa, O.; Solochinsky, A. E. Chem. Soc. Rev. 2012, 41,
4180. (c) Han, J.; Nelson, D. J.; Sorochinsky, A. E.;
Soloshonok, V. A. Curr. Org. Synth. 2012, 8, 310.
(19) (a) General Procedure for Aldol Reaction of Acetone
with Trifluoroacetophenone (Method A): To a mixture of
QD-NH2 (10 mol%), (R)-mandelic acid (10 mol%) was
added aluminium isopropoxide (10 mol%), then the solvent
(mesitylene, 0.5 mL), α,α,α-trifluoroacetophenone (0.2
mmol), and acetone (10 equiv, 2.0 mmol) were added
subsequently, and the resulting solution was stirred at 35 °C
for 12 h and monitored by TLC. The crude mixture was
directly purified by column chromatography (silica gel,
petroleum ether–EtOAc mixtures) to obtain pure products.
The products were characterized by NMR, GC–MS, and IR
analysis. And the ee values of the aldol products were
20
255.0616. Method A: 42 mg, 90% yield, 81% ee; [α]D
15.16 (c = 0.30, CHCl3). HPLC analysis: Chiralcel OD-H
column, i-PrOH–hexane, 5:95; flow rate = 1.0 mL/min, λ =
210 nm, tmajor = 14.12 min, tminor= 8.33 min. Method B: 32
mg, 70% yield, 81% ee; [α]D20 – 21.89 (c = 0.80, CHCl3).
HPLC analysis: Chiralcel OD-H column, i-PrOH–hexane,
5:95; flow rate = 1.0 mL/min, λ = 210 nm, tmajor = 7.91 min,
tminor = 13.76 min.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1461–1465

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