Synthesis of Chiral α-Trifluoromethylamines with 2,2,2-Trifluoroethylamine as a "building Block"

Article abstract of DOI:10.1021/acs.orglett.5b03566

The β-isocupreidine, a cinchonine derived alkaloid, catalyzed asymmetric S_N2′-S_N2′ reaction between N-2,2,2-trifluoroethylisatin ketimines and MBH type carbonates was realized in a simple and efficient way. A series of chiral α-trifl

Full text of DOI:10.1021/acs.orglett.5b03566

Letter
pubs.acs.org/OrgLett
Synthesis of Chiral α‑Trifluoromethylamines with 2,2,2-
Trifluoroethylamine as a “Building Block”
Xiaoyuan Li,† Jinhuan Su,† Zhourujun Liu,† Yuanyuan Zhu,† Zhenghao Dong,† Shuai Qiu,† Jiayi Wang,†
Li Lin,† Zhiqiang Shen,‡ Wenjin Yan,*,† Kairong Wang,*,† and Rui Wang*,†,‡,§
†Institute of Pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic, Medical Sciences,
Lanzhou University, Lanzhou 730000, China
‡State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, Peoples Republic of China
§Collaborative Innovation Centre of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
S
* Supporting Information
ABSTRACT: The β-isocupreidine, a cinchonine derived alkaloid, catalyzed asymmetric SN2′−SN2′ reaction between N-2,2,2-
trifluoroethylisatin ketimines and MBH type carbonates was realized in a simple and efficient way. A series of chiral α-
trifluoromethylamines were prepared with excellent yields and stereoselectivities. A subsequent and easy process of deprotection
gave γ-trifluoromethyl-α-methylenelactam in a stereoselective manner.
t is well-known that organofluorine compounds play a
central role in the fields of pharmaceutical and agro-
Much ongoing effort has been devoted to the synthesis of α-
trifluoromethylamine scaffolds, their preparation frequently
hinging on the reductive amination of ketones, the trifluor-
omethylation of imines or ketimines, the biomimetic trans-
amination, and so forth.5 However, most of these approaches
are hampered by the multiple-step preparation of the reactants
as well as the narrow range of products obtained.
I
chemistry.1 Among fluorinated compounds, the trifluoromethyl
group occupies a special position especially when incorporated
at the α-position to nitrogen, with such compounds often
having enhanced lipophilicity and metabolic stability when
present in small molecules.2 Notable drugs containing α-
trifluoromethylamines include Cathepsin cysteine protease
inhibitors, Odanacatib, 3′-Trifluoromethyl Taxoid, Quazepam,
and so on (Figure 1).3 Moreover, such functional scaffolds are
also key motifs of peptidomimetics and peptides with various
interesting biological activities.4 As a consequence, practical
synthetic approaches to α-trifluoromethylamines are attracting
considerable attention.
CF3−CH2−NH2, a simple α-trifluoromethyl amine unit, has
emerged as a CF3-containing synthon through its direct
conversion into the trifluoromethyl diazomethane.6 This
strategy converts this readily available starting material into
many versatile building blocks that can be used to provide a
highly flexible and efficient synthetic route for the asymmetric
synthesis of complex α-trifluoromethylamines.7 As part of our
continuing interest in this area,8 we now report a convenient
method for the construction of chiral α-trifluoromethylamines.
In this regard, N-2,2,2-trifluoroethylisatin ketimines8 were
used as nucleophiles and reacted with MBH carbonates and
their derivatives9 to test our ideas. An initial experiment was
carried out between nonsubstituted N-2,2,2-trifluoroethylisatin
ketimine 1a and MBH carbonate 2a in DCM with DABCO as
catalyst (Table 1, entry 1). Although no enantioselectivity was
observed, a nucleophilic substitution product was obtained in
91% yield and 12:1 dr. In order to confer optical activity on the
product, the quinine alkaloid (C2 (Figure 2), 10 mol %) and
Received: January 4, 2016
Figure 1. Selected drugs bearing α-trifluoromethylamines.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03566
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Organic Letters
Letter
a
Table 1. Screening of Reaction Conditions
Scheme 1. Scale of N-2,2,2-Trifluoroethylisatin Ketimines
and MBH Adducts
a
b
c
d
entry catalyst
solvent
DCM
time (h) yield (%)
dr
ee (%)
1
C1
C2
C3
C4
C5
C5
C5
C5
C5
C5
C5
C5
C5
C5
C5
1
91
50
46
nd
90
64
80
84
81
88
93
92
88
90
91
12:1
19:1
2:1
0
2
DCM
DCM
DCM
DCM
DCM
1,4-dioxane
THF
36
48
72
6
50
9
3
e
4
nd
nd
85
5
11:1
12:1
16:1
18:1
13:1
13:1
16:1
13:1
>20:1
>20:1
>20:1
f
6
6
65
7
4
77
80
67
65
68
85
86
8
5
9
TOL
4
10
11
12
13
14
15
DCE
4
MTBE
EA
18
2
MeCN
MeCN
MeCN
2
f
6
89
a
g
The reaction time required for each substrate is given. The yields of
16
91
the isolated products are reported. The ee values and dr values were
determined by HPLC analysis.
a
Reaction conditions: 1a (0.20 mmol) and 2a (0.22 mmol) in MeCN
(2 mL) with catalyst (0.02 mmol) reacted at room temperature.
b
c
1
Isolated yield. Determined by chiral phase HPLC analysis or H
d
e
NMR. Determined by chiral phase HPLC analysis. No product was
found. Reacted at 0 °C. Reacted at −10 °C.
position. When the substituent was on the 4-position of isatins,
the enantioselectivities of products were better than when the
substituent group was on the 5-position (Scheme 1, 3c and 3d).
The enantioselectivities of 3d and 3e were almost the same
although 4-Cl substituted 3e showed a slightly better yield. An
ethyl group or a tert-butyl in the position of R3 gave product 3f
and 3g in lower enantioselectivities.
f
g
We next focused on the scope of the MBH adducts. As
shown in Scheme 2, increasing the electronegativity of the aryl
4-position of MBH carbonates 2 eroded the enantioselectivities
and diastereoselectivities of the products, showing a decreasing
trend (Scheme 2, 3h, 3i, 3j, 3k, and 3l). However, no obvious
electronic effect was observed at the 3- and 2-position of MBH
carbonates (Scheme 2, 3m, 3n, 3n, 3p, 3q, and 3r). Moreover,
when heterocycle compounds such as thienyl were used as
alternatives to the aryl group of 2, enantio- and diastereose-
lectivities were maintained (Scheme 2, 3s and 3t). Although
longer reaction times were needed, the reactions showed
excellent results when the MBH carbonates derived from 1-
naphthaldehdye, 2-naphthaldehdye, and heliotropin (Scheme 2,
3u, 3v, and 3w). Replacement of the methoxycarbonyl of the
MBH carbonates by a ketone carbonyl lowered the reactivity
and enantioselectivity (Scheme 2, 3x and 3y). In the
purification process via achiral chromatography, no SDE (self-
disproportionation of enantiomers) was observed.11
Figure 2. Catalyst for screening.
(DHQD)2 Phal (C3, 10 mol %) were tested respectively as
DABCO replacements; the former gave product 3a in 50%
yield and 50% ee, and the latter gave a poor result (Table 1,
entries 2−3). The cinchonidine-squaramide (C4, 10 mol %) was
also applied as a catalyst and led to an undesired product
(Table 1, entry 4). The best result was obtained when β-
isocupreidine10 (C5, 10 mol %) was applied, the reaction giving
3a in 90% yield and up to 85% ee after 6 h at room temperature
(Table 1, entry 5). Encouraged by this result, solvents and
temperature were further optimized (Table 1, entries 6−15).
The results revealed that, at −10 °C in combination with C5
(10 mol %) as a catalyst, the reaction between substrates 1a
(0.20 mmol) and 2a (0.22 mmol) in MeCN (2 mL) gave the
chiral product in excellent yield and stereoselectivity after 16 h
(>20:1 dr, 91% ee) (Table 1, entry 15).
As shown in Figure 3, the N-methyl isatin grouping could be
easily removed in the concentrated hydrochloric acid/EtOH.
The remaining product proceeded to undergo a self-cyclization
and was converted into a pharmacophore of α-methylenelac-
tams 4a which are often found in many anticancer drugs due to
its cytotoxic properties.12
Under the optimized conditions, the scope of the N-2,2,2-
trifluoroethylisatin ketimines 1 was examined, with the use of
MBH carbonates, acetates, and tert-butyl ester also being
demonstrated. As shown in Scheme 1, the enantioselectivity of
product 3b, with a methyl on the 5-position of isatin, was
increased compared to product 3c with a bromine at the same
According to the absolute configuration of products 3r and
3u, a possible mechanism of this reaction is proposed. As
shown in Figure 4, β-ICD attacks the MBH carbonate via an
SN2′ process. It behaves as a Lewis base chiral catalyst. This is
followed by another SN2′-type process, with the isatinketimine
1a acting as an active nucleophile.
B
DOI: 10.1021/acs.orglett.5b03566
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Organic Letters
Letter
a
Scheme 2. Scope of MBH Adducts
Figure 3. Deprotection of product 3e.
Figure 4. Possible mechanism of this reaction.
In conclusion, a highly flexible and efficient approach to the
synthesis of chiral α-trifluoromethylamines via β-ICD catalyzed
SN2′−SN2′ reactions between N-2,2,2-trifluoroethylisatin keti-
mines and MBH carbonates has been achieved. A series of
structurally diverse α-trifluoromethylamine compounds were
obtained in excellent yields and stereoselectivities.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03566.
Experimental procedures and characterization of the
products (PDF)
Crystallographic data for compound 3r (CIF)
Crystallographic data for compound 3u (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yanwj@lzu.edu.cn.
*E-mail: wangkr@lzu.edu.cn.
*E-mail: wangrui@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the grants from the National Natural
Science Foundation of China (Nos. 21432003, 21272107,
21272108, 31200584, 91213302, 81573265).
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DOI: 10.1021/acs.orglett.5b03566
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