Diastereoselective Trifluoromethylation of Chiral α,β-Unsaturated N-tert-Butanesulfinyl Ketimines with Ruppert-Prakash Reagent: Asymmetric Synthesis of α-Tertiary Trifluoromethyl Allylic Amines

Article abstract of DOI:10.1002/adsc.201800625

The diastereoselective trifluoromethylation of chiral α,β-unsaturated N-tert-butanesulfinyl ketimines with Ruppert-Prakash reagent (TMSCF₃) has been attained, which provided a convenient and straightforward method for the asymmetric synthesis of structurally diverse α-tertiary trifluoromethyl allylic amines in high yields and with excellent diastereoselectivities (dr up to > 99:1). The stereochemical outcome of the present diastereoselective trifluoromethylation of the α,β-unsaturated N-tert-butanesulfinyl ketimines suggested that a cyclic six-membered transition state is involved in the reaction, which is remarkably different from that of the trifluoromethylation of N-tert-butanesulfinyl aldimines. (Figure presented.).

Full text of DOI:10.1002/adsc.201800625

Title: Diastereoselective Trifluoromethylation of Chiral α,β-Unsaturated
N-tert-Butanesulfinyl Ketimines with Ruppert-Prakash Reagent:
Asymmetric Synthesis of α-Tertiary Trifluoromethyl Allylic Amines
Authors: Peng Liu, Zhong-Liang Lei, Ying-Ying Peng, Zhen-Jiang Liu,
Feng-Qun Zhu, Jin-Tao Liu, and Fanhong Wu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800625
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10.1002/adsc.201800625
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Diastereoselective Trifluoromethylation of Chiral α,β-
Unsaturated N-tert-Butanesulfinyl Ketimines with Ruppert-
Prakash Reagent: Asymmetric Synthesis of α-Tertiary
Trifluoromethyl Allylic Amines
Peng Liu,a,† Zhong-Liang Lei,a,† Ying-Ying Peng,a Zhen-Jiang Liu,a,b,* Feng-Qun Zhu,a
Jin-Tao Liu,b and Fanhong Wua,*
a
School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai
201418, China
Fax: (+86)-21- 60877231; phone: (+86)-21- 60877227; e-mail: zjliu@sit.edu.cn; wfh@sit.edu.cn
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
b
345 Lingling Road, Shanghai 200032, China
These authors contributed equally to this work.
†
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Huang independently reported a single case of the
chiral α,β-unsaturated N-tert-butanesulfinyl ketimines with synthesis of a chiral α-tertiary trifluoromethyl allylic
Abstract. The diastereoselective trifluoromethylation of
Ruppert-Prakash reagent (TMSCF3) has been attained,
which provided a convenient and straightforward method
for the asymmetric synthesis of structurally diverse α-
tertiary trifluoromethyl allylic amines in high yields and
with excellent diastereoselectivities (dr up to > 99:1). The
stereochemical outcome of the present diastereoselective
trifluoromethylation of the α,β-unsaturated N-tert-
butanesulfinyl ketimines suggested that a cyclic six-
membered transition state is involved in the reaction, which
amine from different CF3-substituted ketimines,
which involved multiple steps and resulted in low
yields.[4] More recently, our group developed a
general and efficient method for the asymmetric
synthesis of structurally diverse
α-tertiary
trifluoromethyl allylic amines by the regioselective
addition of organolithium reagents to chiral
trifluoromethyl α,β-unsaturated N-tert-butanesulfinyl
ketimines (Scheme 1, eq. a).[5] However, the use of
organolithium reagents is known to make the reaction
is
remarkably
different
from
that
of
the
trifluoromethylation of N-tert-butanesulfinyl aldimines.
Keywords: Allylic compounds; Trifluoromethylation;
Fluorine; Ketimines; Ruppert-Prakash reagent
Chiral trifluoromethylated allylic amines are an
important structural motif because of their versatile
synthetic utility as chiral building blocks in the
synthesis of pharmaceuticals and agrochemicals.[1]
Their versatility can be attributed to the presence of
the strongly electron withdrawing trifluoromethyl
group which can tune the basicity of amines and thus
enhance the lipophilicity, metabolic stability and
bioactivity of a target drug molecule.[2] Therefore,
great efforts have been devoted to their asymmetric
synthesis.[3-6] However, most of the reported methods
focus on the preparation of chiral α-secondary
trifluoromethyl allylic amines.[3] Due to the lack of
efficient methods for the highly stereoselective
construction of tetrasubstituted carbon stereogenic
centers with a trifluoromethyl group, strategies for
the asymmetric synthesis of α-tertiary trifluoromethyl
allylic amines are very rare. Recently, Ohshima and
Scheme 1. Methods for the asymmetric synthesis of α-
tertiary trifluoromethyl allylic amines.
1
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10.1002/adsc.201800625
Advanced Synthesis & Catalysis
process considerably tedious and this severely
restricts their application in such processes. In
addition, our group also developed several efficient
methods for the stereoselective synthesis of
functionalized α-tertiary trifluoromethyl allylic
amines.[6] Nevertheless, the direct asymmetric
synthesis of α-trifluoromethyl allylic amines bearing
a tetrasubstituted carbon stereogenic center is highly
sought after, but remains a significant challenge in
organic synthesis.
Table 1. Optimization of the Reaction Conditions.a)
En
1
T / Yield 3a:3a′
(%)b) (dr)c)
try Initiator (equiv.) Solvent oC
1d) TMAF
1.5 -25 43
2d) TMAFf) 3.0
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DMF
Toluene
DCM
Et2O
THF
THF
THF
THF
THF
THF
THF
THF
90:10
86:14
92:8
92:8
93:7
93:7
The
stereoselective
nucleophilic
trifluoromethylation of imines provides one of the
most convenient and straightforward approach for the
synthesis of chiral α-trifluoromethyl amines.[7]
Although the stereoselective trifluoromethylation of
aldimines has been extensively investigated,[8] the
corresponding asymmetric trifluoromethylation of
ketimines still remains a formidable challenge.[9] The
difficulties in the nucleophilic trifluoromethylation of
ketimines are ascribed to the relatively lower
reactivity of ketimines as compared to aldimines, and
the low thermal stability and nucleophilicity of
-10 28
-25 61
3d) CsFf)
4d) CsFf)
5d) CsFf)
6d) CsFf)
3.0
3.0
4.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
0
0
0
0
77
83
100
100h) 93:7
7
CsF
8d) CsF
9e) CsF
10 CsFg)
11 CsF
12 CsF
13 CsF
14 CsF
15 TMAF
16 TBAF
17 KF
-10 100
-20 74
94:6
95:5
93:7
-
-
trifluoromethylated carbanion CF3 (referred to as the
“negative fluorine effect” proposed by Hu and co-
workers[10]). In addition, a minor steric discrimination
of the substituents on a ketimine and the existence of
its E and Z isomers render the differentiation of the
stereotopic faces of the ketimine more difficult.
Recently, Chen and Xu reported the first asymmetric
trifluoromethylation of “double” activated ketimines
derived from isatins and N-tert-butanesulfinamide.[9a]
0
0
0
0
0
0
0
0
0
0
0
0
0
60
NRi)
29
96:4
88:12
93:7
88:12
60:40
-
5
18
42
However,
the
reactions
gave
very
low
8
diastereoselectivities (generally 2:1 dr or lower). To
the best of our knowledge, there are no reports on the
asymmetric trifluoromethylation of α,β-unsaturated
N-tert-butanesulfinyl ketimines[11] which is more
challenging compared to the corresponding reaction
with nonconjugated ketimines. This is primarily due
to their ambident electrophilic character which results
into a competition between the 1,2- and 1,4-addition
reactions.[12] As a continuation of our interest in the
chemistry of chiral α,β-unsaturated N-tert-
butanesulfinyl ketimines,[5-6] we report herein the first
NRi)
NRi)
75
18 CuF2
19 tBuOK
-
93:7
-
20 NaOAc 5.0
21 Cs2CO3 5.0
NRi)
12
NRi)
88:12
-
22 K2CO3
5.0
a) 1.1 equiv. of initiator relative to that of 2a was used and
the reaction time was 5 h unless stated otherwise. b) Yields
were determined by 19F NMR spectroscopy using C6H5CF3
as internal standard. c) Diastereomeric ratio was determined
by 19F NMR spectroscopic analysis of the crude reaction
mixture. d) The reaction time was 12 h. e) The reaction time
was 24 h. f) 2.0 equiv. of initiator was used. g) 0.5 equiv. of
highly
regio-
and
diastereoselective
trifluoromethylation of chiral α,β-unsaturated N-tert-
butanesulfinyl ketimines with the Ruppert-Prakash
reagent (TMSCF3) (Scheme 1, eq. b). The reaction
proceeds solely via a 1,2-addition mechanism,
affording the corresponding α-tertiary trifluoromethyl
allylic amines in good to high yields and with
excellent diastereoselectivities.
h)
CsF was used. 98% of isolated yield was obtained after
i)
flash chromatography. NR = No reaction. TMAF =
tetramethylammonium
fluoride,
TBAF
=
We began our investigations by examining the
feasibility of the asymmetric trifluoromethylation of
α,β-unsaturated N-tert-butanesulfinyl ketimine 2a
with the Ruppert-Prakash reagent (TMSCF3, 1).
TMAF, which was previously reported to be an
tetrabutylammonium fluoride.
90:10), but low yield (43%) (Table 1, entry 1).
Increasing the amount of TMAF and TMSCF3,
meanwhile elevating the reaction temperature had no
effect on the reaction yield or the diastereoselectivity
(Table 1, entry 2). It is well-known that the choice of
an appropriate initiator is critical in the
trifluoromethylation reactions with TMSCF3.[7a,d]
Remarkably, the use of CsF instead of TMAF as the
efficient
initiator
in
the
asymmetric
trifluoromethylation of aldimines,[8b-c] was initially
selected to activate the TMSCF3 for the
trifluoromethylation of ketimine 2a. The reaction was
found to proceed smoothly, giving only the 1,2-
adduct and a good diastereoselectivity (3a:3a′ =
2
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10.1002/adsc.201800625
Advanced Synthesis & Catalysis
Table 2. The Direct Asymmetric Trifluoromethylation of α,β-Unsaturated N-tert-Butanesulfinyl Ketimines 2 with
TMSCF3 1.a)
Entry
1
R1
R2
Product
3a+3a′
3b+3b′
3c+3c′
3d+3d′
3e+3e′
3f+3f′
3g+3g′
3h+3h′
3i+3i′
Yield (%)b)
100 (98)
100 (97)
86 (80)
3:3′ (dr)c)
93:7
2
Ph
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
2
4-NO2C6H4
4-ClC6H4
4-PhC6H4
4-MeOC6H4
2-Furyl
t-Bu
Ph
> 99:1
90:10
95:5
3
Ph
4
Ph
100 (95)
57 (50)
5
Ph
95:5
6
Ph
91 (86)
73:27
98:2
7
Ph
100 (94)
80 (78)
8
Ph
4-MeOC6H4
4-ClC6H4
4-MeC6H4
2-Furyl
95:5
9
Ph
100 (94)
82 (78)
93:7
10
11
12
Ph
94:6
2j
2k
2l
3j+3j′
3k+3k′
3l+3l′
Ph
78 (70)
94:6
70 (65)
93:7
13
14
96 (90)
87 (84)
98:2
98:2
2m
2n
3m+3m′
3n+3n′
a)
b)
In all cases, 5.0 equiv. of TMSCF3 (1) and 1.1 equiv. of CsF were used.
Yield was determined by 19F NMR
spectroscopy using C6H5CF3 as internal standard. Isolated yield in the brackets. c) Diastereomeric ratio was determined by
19F NMR spectroscopic analysis of the crude reaction mixture.
initiator dramatically improved the yield, while
imparting high diastereoselectivities (Table 1, entries
3-10). Gratifyingly, when 1.1 equiv. of CsF and 5.0
equiv. of TMSCF3 were used for the reaction at 0 C
for 5 h, a quantitative yield determined by 19F NMR
spectroscopy (98% isolated yield after flash
chromatography) and high diastereoselectivity
(3a:3a′ = 93:7) were obtained (Table 1, entry 7).
Decreasing the amount of CsF to 0.5 equiv. or
performing the reaction at -20 C resulted in a
significant reduction of the yield (Table 1, entries 9-
10). Among the solvents tested, THF was proven to
be the best solvent for this reaction (Table 1, entries 7
and 11-14). A further evaluation of the various Lewis
3
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10.1002/adsc.201800625
Advanced Synthesis & Catalysis
base initiators indicated that CsF proved be the
optimal one for this trifluoromethylation, although
tBuOk was also found to promote the reaction
efficiently (Table 1, entries 7 and 15-22). It is worth
noting that the use of 5.0 equiv. of TMSCF3 is
essential for obtaining high yields of the addition
product (Table 1, entries 4-8).
Having identified the optimal reaction conditions
(Table 1, entry 7), the substrate scope and generality
of the direct asymmetric trifluoromethylation reaction
was then investigated with a wide range of
electronically and sterically diverse α,β-unsaturated
N-tert-butanesulfinyl ketimines 2.[13] As shown in
Table 2, the regio- and diastereoselective
trifluoromethylation reaction of α,β-unsaturated
ketimines 2 proved to be surprisingly general. All the
reactions took place readily in a 1,2-addition manner
Figure 1. Proposed transition state for the CsF-mediated
direct trifluoromethylation of α,β-unsaturated N-tert-
butanesulfinyl ketimines with TMSCF3..
unsaturated N-tert-butanesulfinyl ketimines (Scheme
1, eq. a),[5] the direct trifluoromethylation of
nonfluorinated α,β-unsaturated N-tert-butanesulfinyl
ketimines produced the opposite R configuration
products predominantly for the newly created
stereogenic center by using the same configured N-
tert-butanesulfinyl amide (Scheme 1, eq. b), thus
providing an alternative and complementary method
for the asymmetric synthesis of either stereoisomer of
α-tertiary trifluoromethyl allylic amines. Based on the
observed diastereofacial selectivity, it is proposed
that a cyclic six-membered transition state is formed,
wherein the bulky tert-butyl group preferentially
adopts an equatorial position and the trifluoromethide
ion preferably attacks the less hindered Si face of the
and
afforded
the
corresponding
α-tertiary
trifluoromethyl allylic amines in good to high yields
and with excellent diastereoselectivities. The
electronic properties of the substituents on the phenyl
ring of 2 did not have any significant effect on the
stereochemical outcome of the reaction (Table 2,
entries
trifluoromethylation of ketimine 2e gave only a
moderate yield, which is believed to be
1-5
and
8-10).
However,
the
a
consequence of the decreased reactivity of the
ketimine 2e due to the presence of the strong
electron-donating effect of para-methoxy substituent
(Table 2, entry 5). The heteroaryl substituted
α,β-unsaturated ketimines
2
(Figure 1). The
ketimines
are
also
tolerated
in
the
the
stereocontrol mode of the current diastereoselective
trifluoromethylation of the α,β-unsaturated ketimines
is completely opposite to the previously reported
nucleophilic fluoroalkylation of N-tert-butanesulfinyl
aldimines (nonchelation controlled mode),[8a-d,11,17]
but similar to that of the previous precedents for the
indirect mono- and difluoromethylation of N-tert-
butanesulfinyl ketimines.[18] However, the exactly
underlying reaction pathway of the diastereoselective
trifluoromethylation of α,β-unsaturated ketimines 2
depicted in this study is still elusive.
trifluoromethylation
reaction;
however,
trifluoromethylation of ketimine 2f, where R1 is a
furyl substituent, resulted in
a
moderate
diastereoselectivity (Table 2, entries 6 and 11). The
alkyl substituted ketimine 2g was also suitable for
this trifluoromethylation reaction, affording the
corresponding product 3g in high yield and with
excellent diastereoselectivity (96% de) (Table 2,
entry 7). However, the trifluoromethylation of β-alkyl
substituted ketimines (R2 = alkyl) was very complex
and no product formation could be observed. This is
mainly because of the basicity of the CF3 anion.[14] It
is evident that the substitution at the α-position of
ketimine 2l by a methyl group has no influence on the
diastereoselectivity of the reaction (Table 2, entry 12).
It is worth mentioning that the synthetically versatile
propargylic amines[15] and homoallylic propargylic
In summary, we have successfully developed the
first direct asymmetric trifluoromethylation of α,β-
unsaturated N-tert-butanesulfinyl ketimines with the
Ruppert-Prakash reagent. The reaction is highly
regio- and diastereoselective. A variety of structurally
diverse chiral α-tertiary trifluoromethyl allylic amines
can be obtained in good to high yields and with
excellent diastereoselectivities using this reaction
scheme, thus providing an alternative and
complementary method to our previously developed
protocol.[5] These α-tertiary trifluoromethyl allylic
amines represent potentially useful structural motifs
amines5 which bear
a
tetrasubstituted carbon
stereogenic center with a trifluoromethyl group can
also be obtained by the trifluoromethylation of the
α,β-acetylenic ketimines 2m and 2n in high yields
and with excellent diastereoselectivities (Table 2,
entries 13-14).
The absolute configuration of the product 3a was
assigned as (Rs, R) upon the removal of the N-
sulfinyl group under acidic conditions, followed by
the comparison of the optical rotation with that of a
known compound.[5,16] The absolute configurations of
the products 3b–n were assigned by analogy. It
should be noted that comparing to the addition of
organolithium reagents to trifluoromethyl α,β-
for the synthesis of
a
variety of bioactive
compounds.[5] The stereocontrol mode of the present
diastereoselective trifluoromethylation of the α,β-
unsaturated ketimines suggested the involvement of a
cyclic six-membered transition state in the reaction.
This is in sharp contrast to the previously reported
nucleophilic
trifluoromethylation
of
N-tert-
butanesulfinyl aldimines. Further studies to clarify
the reaction mechanism and expand the substrate
4
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10.1002/adsc.201800625
Advanced Synthesis & Catalysis
scope of this methodology are currently in progress in
our laboratory.
Science 2007, 317, 1881; g) T. Furuya, A. S. Kamlet, T.
Ritter, Nature 2011, 473, 470; h) M. Morgenthaler, E.
Schweizer, A. Hoffmann-Röder, F. Benini, R. E.
Martin, G. Jaeschke, B. Wagner, H. Fischer, S. Bendels,
D. Zimmerli, J. Schneider, F. Diederich, M. Kansy, K.
Müller, ChemMedChem 2007, 2, 1100.
Experimental Section
General
trifluoromethylation
butanesulfinyl ketimines 2 with TMSCF3 1
procedure
for
the
asymmetric
N-tert-
[3] a) Z.-J. Liu, J.-T. Liu, Chem. Commun. 2008, 5233; b)
M. Kawatsura, S. Terasaki, M. Minakawa, T. Hirakawa,
K. Ikeda, T. Itoh, Org. Lett. 2014, 16, 2442; c) G. K. S.
Prakash, M. Mandal, G. A. Olah, Org. Lett. 2001, 3,
2847; d) N. T. N. Tam, G. Magueur, M. Ourévitch, B.
Crousse, J.-P. Bégué, D. Bonnet-Delpon, J. Org. Chem.
2005, 70, 699; e) S. D. Kuduk, C. N. D. Marco, S. M.
Pitzenberger, N. Tsou, Tetrahedron Lett. 2006, 47,
2377; f) S. Fries, J. Pytkowiz, T. Brigaud, Tetrahedron
Lett. 2005, 46, 4761; g) S. Fustero, J. García Soler, A.
Bartolomé, M. Sánchez Roselló, Org. Lett. 2003, 5,
2707; h) G. Magueur, B. Crousse, D. Bonnet-Delpon,
Eur. J. Org. Chem. 2008, 1527.
of
α,β-unsaturated
In a glove box, α,β-unsaturated N-tert-butanesulfinyl
ketimines (R)-2 (0.1 mmol) and CsF (0.11 mmol) were
added to a reaction tube that is equipped with a stirring bar.
The tube was capped with a septum and taken out. Under
an atmosphere of N2, THF (2.0 mL) was added and the
mixture was stirring for 10 minutes at 0oC. Next, TMSCF3
1 (0.5 mmol) was added by syringe and the reaction
solution was stirred at 0oC for 5 h then quenched with
saturated aqueous NH4Cl solution (2 mL). The resulting
mixture was extracted with EtOAc (10 mL x 3). The
combined organic solution was dried over Na2SO4. After
the removal of volatile solvents under vacuum, the crude
product was further purified by silica gel column
chromatography (petroleum ether / EtOAc = 5:1 as eluent)
to give product 3.
[4] a) K. Morisaki, M. Sawa, J.-y. Nomaguchi, H.
Morimoto, Y. Takeuchi, K. Mashima, T. Ohshima,
Chem. Eur. J. 2013, 19, 8417; b) Y. Yang, Y. Huang,
F.-L. Qing, Tetrahedron Lett. 2013, 54, 3826.
Acknowledgements
Financial support from the National Natural Science Foundation
of China (Nos. 21102093, 21472126, 21672151), the
Science and Technology Commission of Shanghai Municipality
(No. 15DZ1942203), the Innovation Program of Shanghai
Municipal Education Commission (No. 14YZ144), Chemical
Engineering and Technology (Perfume and Aroma Technology)
of Shanghai Plateau Discipline and Shanghai Institute of
Technology (No. XTCX2016-5) is gratefully acknowledged.
[5] P. Liu, Z.-J. Liu, F. H. Wu, Adv. Synth. Catal. 2015,
357, 818.
[6] a) F. Zhang, Z.-J. Liu, J.-T. Liu, Org. Biomol. Chem.
2011, 9, 3625; b) X.-M. Yuan, J. Xu, Z.-J. Liu, X.-J.
Yang, L.-M. Wang, Y. Zhang, X.-Y. Yang, X.-P. He,
J.-T. Liu, J. Fluorine Chem. 2012, 144, 102; c) P. Li, M.
Jiang, J.-T. Liu, Chin J Chem. 2014, 32, 1003.
[7] a) X. Liu, C. Xu, M. Wang, Q. Liu, Chem. Rev. 2015,
115, 683; b) X. Yang, T. Wu, R. J. Phipps, F. D. Toste,
Chem. Rev. 2015, 115, 826; c) see ref. 2c; d) J.-A. Ma,
D. Cahard, J. Fluorine Chem. 2007, 128, 975; e) G. K.
S. Prakash, M. Mandal, J. Fluorine Chem. 2001, 112,
123; f) R. P. Singh, J. M. Shreeve, Tetrahedron 2000,
56, 7613; g) G. K. S. Prakash, A. K. Yudin, Chem. Rev.
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5
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10.1002/adsc.201800625
Advanced Synthesis & Catalysis
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6
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10.1002/adsc.201800625
Advanced Synthesis & Catalysis
UPDATE
Diastereoselective Trifluoromethylation of Chiral
α,β-Unsaturated N-tert-Butanesulfinyl Ketimines
with Ruppert-Prakash Reagent: Asymmetric
Synthesis of α-Tertiary Trifluoromethyl Allylic
Amines
Adv. Synth. Catal. Year, Volume, Page – Page
Peng Liu,a,† Zhong-Liang Lei,a,† Ying-Ying Peng,a
Zhen-Jiang Liu,a,b,* Feng-Qun Zhu,a Jin-Tao Liu,b
Fanhong Wua,*
7
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