Highly diastereoselective synthesis of optically pure trifluoromethyl- substituted imidazolidine, oxazolidine and thiazolidine

Article abstract of DOI:10.1016/j.tetlet.2010.11.061

Optically pure trifluoromethylated imidazolidine, oxazolidine, and thiazolidine derivatives were synthesized through double Michael addition of chiral amino amides, amino acids, or amino alcohols to an easily available trifluoromethyl building block methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate. These reactions occurred highly diastereo-selectively (up to 99:1) in good yields (65-96%) under mild conditions.

Full text of DOI:10.1016/j.tetlet.2010.11.061

Tetrahedron Letters 52 (2011) 349–351
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly diastereoselective synthesis of optically pure trifluoromethyl-substituted
imidazolidine, oxazolidine and thiazolidine
⇑
Honghai Zhang, Qilong Shen, Long Lu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Optically pure trifluoromethylated imidazolidine, oxazolidine, and thiazolidine derivatives were synthe-
sized through double Michael addition of chiral amino amides, amino acids, or amino alcohols to an easily
available trifluoromethyl building block methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate. These reactions
occurred highly diastereo-selectively (up to 99:1) in good yields (65–96%) under mild conditions.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 28 September 2010
Revised 4 November 2010
Accepted 12 November 2010
Available online 18 November 2010
Heterocycles including saturated cyclic compounds and aro-
matic analogs form the backbone of important molecules of life
and a framework on which biologically active molecules are
based.1 Introduction of trifluoromethyl group into heterocycles is,
therefore, an area of considerable current interest due to the un-
ique physical properties of the trifluoromethyl group.2 It is well
established that the incorporation of the trifluoromethyl group
into ‘drug like’ molecules may lead to enhanced binding selectivity,
higher lipophilicity, and/or increased metabolic stability.3 While
significant progress has been made in the synthesis of trifluorom-
ethylated aromatic heterocycles,4 methods for the synthesis of tri-
fluoromethyl-substituted saturated heterocycles have been much
less documented.5,6 Moreover, the construction of optically active
trifluoromethyl-substituted quaternary stereogenic center in a
saturated heterocycle such as imidazolidine,8 oxazolidine9, and
thiazolidine10 has been rarely reported.5,7 Saigo reported that tri-
fluoro-substituted oxazolidine was selectively obtained from the
reaction of (S)-phenylglycinol with 4,4,4-trifluoro-3-oxobutanoate
in the presence of 3 equiv of acetic acid, however, only one exam-
ple was reported. The scope of the reaction was not investigated
and the absolute configuration of the trifluoromethyl containing
quaternary carbon center was not determined.11 Yamanaka re-
ported that polyfluoro-2-alkynoic acids readily underwent the se-
quence of inter- and intramolecular Michael addition with a
variety of bifunctional azanucleophiles, to give trifluoromethyl-
substituted imidazolidine, thiazolidine and oxazolidine derivatives
in moderate to good yields. However, the azanucleophiles used in
this study were achiral and the heterocycles obtained were race-
mic mixtures.12
oxazolidine, and thiazolidine through double Michael addition of
chiral amino amides, amino acid, or amino alcohol to an easily
available trifluoromethyl building block methyl (Z)-2-bromo-
4,4,4-trifluoro-2-butenoate 1. Imidazolidine, oxazolidine, and thia-
zolidine are important structural motifs frequently encountered in
natural products, pharmaceuticals, and agrochemicals.
In 2004, we reported that treatment of methyl (Z)-2-bromo-
4,4,4-trifluoro-2-butenoate 1 with diethyl malonate in the pres-
ence of NaH as base gave stereospecifically trifluoromethyl-substi-
tuted cyclopropane in good yields.13 The reaction was initiated by
the Michael addition of carbanion to 1, followed by a proton trans-
fer from C1 to C3 and intramolecular nucleophilic substitution to
Br
F C
3
Br
H
F C
3
CO Me
2
F C
3
CO Me
2
CO Me
2
E
E
E
E
E
E
E
E=CO Et
2
CO Me
2
CF
3
E
F C
MeO C
2
3
N
F C
3
Br
CO Me
N
HN
HN
2
O
O
1
2
3
O
N
NH
Br
H
Br
CO Me
2
CO Me
2
In this Letter, we report an approach for the efficient prepara-
tion of optically pure heterocycles containing trifluoromethyl-
substituted quaternary carbon stereocenter, such as imidazolidine,
CO Me
F C
3
2
F C
3
F C
HN
3
HN
HN
HN
HN
HN
O
O
T3
T1
T2
O
⇑
Corresponding author. Tel./fax: +86 21 54925197.
E-mail address: lulong@mail.sioc.ac.cn (L. Lu).
Scheme 1. Possible pathways for the reaction of methyl (Z)-2-bromo-4,4,4-
trifluoro-2-butenoate 1 with nucleophiles.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.061

350
H. Zhang et al. / Tetrahedron Letters 52 (2011) 349–351
Table 1
mides occurred in good yields (over 83%) and with excellent
diastereoselectivities (dr >96:4). Chlorine substitution at C3 of
Reactions of building block 1 with L-prolinamide under various conditions
O
NH
L
-prolinamide gave slightly lower diastereoselectivity (Table 2, en-
try 6). Not only -prolinamides reacted with 1 to afford the imidaz-
olidine, -prolinol or 4-chloroprolinol also reacted with 1 to give
O
NH2
F3C
Br
CO2Me
L
Base
+
L
N
N
H
Solvent
CO2Me
the corresponding oxazolidine in high yield and excellent diastere-
oselectivity (Table 2, entries 7 and 8). Even hindered diphenyl-
F3C
1
3
substituted
(Table 2, entry 9).
L-proline proceeded with high diastereoselectivity
Entry
Base
Solvent
Yielda
1
2
3
4
5
6
7
8
NaH
KHMDS
DBU
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
THF
THF
THF
THF
Toluene
DMSO
Dioxane
DMF
26
—
—
52
75
50
72
85b
Encouraged by the results of prolinamides and prolinols react-
ing with 1, other amino alcohols were explored under the similar
reaction conditions. Reactions of a number of amino alcohols with
1 occurred in good yield with excellent diastereoselectivity when
the solvent was switched to acetonitrile. These results were sum-
marized in Table 3. For example, phenyl substituted amino alco-
hols reacted with 1 to give the corresponding CF3-substituted
oxazolidine in 66% with 99:1 selectivity (Table 3, entry 3). It is
a
Isolated yield.
dr = 99:1 as determined by 19F NMR of the crude mixture.
b
Table 2
Reaction of 1 with substituted L-prolinamide and L-prolinol
X1
R1
+
X1
X2HR2
R1
X2R2
F3C
Br
Cs2CO3
DMF
N
N
H
F3C
CO2Me
CO2Me
1
3
Entry
X1
X2
R1
R2
Product
Yielda (%)
drb
1
2
3
4
5
6
7
8
9
O
O
O
O
O
O
NH
NH
NH
NH
NH
NH
O
H
H
H
H
H
Cl
H
Cl
H
H
Bn
3a
3b
3c
3d
3e
3f
3g
3h
3i
85
95
92
96
92
83
80
71
91
99:1
98:2
99:1
97:3
98:2
96:4
99:1
99:1
99:1
p-C6H4CH3
(CH2)3CH3
p-OMeC6H4
Bn
—
H, H
H, H
Ph, Ph
O
O
—
—
a
Isolated yields.
Determined by 19F NMR.
b
Table 3
Synthesis of trifluoromethylated oxazolidine and thiazolidine derivatives
R2
Figure 1. The ORTEP view of 3a.
R1
HN
R1
COOMe
Br
Cs2CO3
CH3CN
R2
X
+
H2N
F3C
afford the cyclopropane. Based on these observations, we predicted
that if a dinucleophile such as prolinamide is used under similar
conditions, a [4,3,0] bicyclic trifluoromethyl heterocycle 2 would
X
F3C
COOMe
5
4
1
Entry
R1
R2
X
Product
Yielda (%)
drb
be obtained (Scheme 1). However, when 1 was treated with L-pro-
1
2
3
CH(CH3)2
Bn
Ph
H
H
H
OH
OH
OH
5a
5b
5c
73
65
66
99:1
99:1
99:1
linamide in the presence of NaH at room temperature, no expected
heterocycle 2 was isolated. Instead, a new [3,3,0] heterocycle imi-
dazolidine derivative 3 containing a quaternary carbon was iso-
lated in 26% yield (Table 1, entry 1). When other bases such as
KHMDS or DBU were used, a number of unidentified fluorinated
products with little or none of heterocycle 2 or 3 were obtained.
In contrast, reaction conducted with Cs2CO3 as the base afforded
imidazolidine 3 in high yield (Table 1, entry 5). Finally, DMF was
found to be the best solvent with respect to diastereoselectivity
and yield. The diastereoselectivity of the product was determined
by 19F NMR analysis of the crude reaction mixture. The absolute
configuration of compound 3a was determined by X-ray diffraction
of a single crystal of 3a (Fig. 1).14
H
N
4
H
OH
5d
70
97:3
S
5
6
7
H
Ph
Me
OH
OH
OH
5e
5f
5g
70
78
71
98:2
98:2
99:1
Ph
COOMe
8
9
OH
SH
5h
5i
76
70
99:1
99:1
COOMe
H
a
Reactions of substituted
L-prolinamides with 1 were summa-
Isolated yields.
Determined by 19F NMR.
b
rized in Table 2. Reactions of N-alkyl or aryl substituted
L-prolina-

H. Zhang et al. / Tetrahedron Letters 52 (2011) 349–351
351
COOMe
Supplementary data
Cs2CO3
DMF
+
(1)
O
N
Br
N
H
OH
Supplementary data (all experimental procedures and spectro-
scopic data of new compounds) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2010.11.061.
Me
Me
5
COOMe
COOMe
Cs2CO3
DMF
References and notes
N
+
(2)
O
N
H
Br
OH
F3C
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Scheme 2. Parallel reactions of
L
-prolinol with 5 and 1.
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chael reaction occurs to provide the final product oxazolidines in
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In conclusion, we have developed a highly diastereoselective
synthesis of optically pure trifluoromethylated imidazolidine, oxa-
zolidine, and thiazolidine derivatives from methyl (Z)-2-bromo-
4,4,4-trifluoro-2-butenoate through double Michael reaction.
These heterocycles containing a trifluoromethyl-substituted qua-
ternary carbon center are otherwise unaccessible. Furthermore,
through parallel reactions of L-prolinol and substrate 5 with build-
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ing block 1, we concluded that trifluoromethyl group enhances the
acidity of the methylene proton neighbor to CF3 group, conse-
quently, facilitates the formation of intermediate T3 and the sec-
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Acknowledgments
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14. CCDC 793449 & 793450 contains the supplementary crystallographic data for
the compound 3a and 4c reported in this Letter. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif or pm application to CCDC, 12 Union
The authors gratefully acknowledge the financial support from
the National Natural Science Foundation of China (Grant Number
29825104 and 29632003), the project of Application of Nuclear
Techniques in Agriculture (200803034), the Key Program of Na-
tional Natural Science Foundation of China (20632070), the Na-
tional Basic ResearchProgram of China (2010CB126103), and the
SIOC startup fund (QS) for financial support.
Road, Cambridge CB2
deposit@ccdc.cam.ac.uk].
1
EZ, UK [fax: +44 1223/336 033; email: