Enantioselective Trichloromethylation of MBH-Fluorides with Chloroform Based on Silicon-assisted C-F Activation and Carbanion Exchange Induced by a Ruppert-Prakash Reagent

Article abstract of DOI:10.1002/anie.201508574

Enantioselective trichloromethylation of Morita-Baylis-Hillman (MBH)-type allylic fluorides with chloroform (HCCl₃) under organocatalysis was achieved with high to excellent enantioselectivities. Silicon-assisted C-F bond activation by a Rupper

Full text of DOI:10.1002/anie.201508574

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201508574
German Edition: DOI: 10.1002/ange.201508574
Organocatalysis
Enantioselective Trichloromethylation of MBH-Fluorides with
À
Chloroform Based on Silicon-assisted C F Activation and Carbanion
Exchange Induced by a Ruppert–Prakash Reagent
Takayuki Nishimine, Hiromi Taira, Etsuko Tokunaga, Motoo Shiro, and Norio Shibata*
Abstract: Enantioselective trichloromethylation of Morita–
Baylis–Hillman (MBH)-type allylic fluorides with chloroform
(HCCl3) under organocatalysis was achieved with high to
À
excellent enantioselectivities. Silicon-assisted C F bond acti-
vation by a Ruppert–Prakash reagent and direct activation of
HCCl3 by a carbanion exchange process with trifluoromethyl
(CF3) carbanion generated in situ from the Ruppert-Prakash
reagent realized the direct asymmetric trichloromethylation at
a stereogenic allylic positon, without any help from transition
metal catalysis, and under very mild conditions. Pre-activation
of HCCl3 was not required. This method was extended to the
Scheme 1. Direct enantioselective trichloromethylation of MBH-type
fluorides 1 with HCCl3 based on a silicon-assisted C F bond activation
and a carbanion exchange process by Me3SiCF3 and related asymmet-
ric transformations.
À
direct enantioselective introduction of other C H compounds
À
such as alkyne, arene, indene, and FBSM without any pre-
activation under a metal-free system.
[1]
À
T
he cleavage/activation of carbon–fluorine (C F) bonds
[2]
À
and the direct activation of carbon–hydrogen (C H) bonds
importantly, this method was widely applied for the direct
À
followed by sequential chemical transformations have been
asymmetric introduction of other C H compounds 3, such as
substantial challenges for chemists in recent decades. Many
alkyne 3a, fluorobenzene, 3b, indene 3c, and fluorobisphe-
nylsulfonylmethane (3d, FBSM) without any pre-activation
by a carbanion exchange process by CF3 carbanion under the
same reaction conditions to furnish 4 in good yields with high
enantioselectivities.
À
À
kinds of C F and C H bond activations have been achieved
under transition metal catalysis.[1,2] In this context, we are
À
interested in the development of methods for C X bond
activation/cleavage under mild conditions, without using
transition metals. Herein, we realize this idea, including the
More than 5000 organohalogen compounds are found in
nature, and many of them show remarkable biological
activities.[3] The majority of naturally occurring organohal-
ogen compounds consists of organic chlorides, thus the
development of an efficient synthetic methodology for
organochlorine compounds is of great importance.[4] Among
many organochlorine compounds, we are interested in the
trichloromethylated compounds, since the importance of the
trichloromethyl (CCl3) group in natural products and biolog-
ically active molecules has been addressed.[5] Moreover, they
have been widely used as valuable intermediates in organic
synthesis.[6] Although there have been many reports on
trichloromethylation reactions,[7] enantioenriched trichloro-
methylated compounds attract less attention than others such
as racemic compounds, and the method for direct enantiose-
lective trichloromethylation is extremely rare.[8] In recent
years, we reported the enantioselective reactions of MBH-
acetates,[9a] carbonates,[9b] and fluorides[9c] with fluoromethy-
lated nucleophiles under organocatalysis providing allylic
monofluoro- and trifluoromethylated compounds in high
yields with high enantioselectivities.[9] During our research of
the trifluoromethylation of MBH-fluorides 1 with Me3SiCF3,
we accidently noticed that allylic trichloromethylated com-
pounds 2 were obtained predominantly instead of trifluor-
omethylated ones when the reaction was carried out in
chloroform, HCCl3.
À
À
À
cleavage of C F and C H bonds, following asymmetric C C
bond formation at a stereogenic carbon center using fluorine
chemistry, exemplified by an enantioselective catalytic tri-
chloromethylation of Morita–Baylis–Hillman (MBH)-type
À
allylic fluorides with chloroform (HCCl3). Silicon-assisted C
F bond activation of MBH-allylic fluorides 1, followed by
À
direct activation of the C H bond of HCCl3 (that is,
a carbanion exchange process by an in situ generated
trifluoromethyl (CF3) carbanion), is key for this transforma-
tion (Scheme 1). The reaction requires neither organometal-
lics nor strong bases, but instead relies upon catalytic amount
of cinchona alkaloids and the Ruppert–Prakash reagent
(trifluoromethyl)trimethylsilane (Me3SiCF3). A variety of
allylic trichloromethylated compounds 2 were obtained in
high to excellent enantioselectivities up to 97% ee. More
[*] T. Nishimine, H. Taira, E. Tokunaga, Prof. Dr. N. Shibata
Department of Frontier Materials, Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya, 466-8555 (Japan)
E-mail: nozshiba@nitech.ac.jp
Dr. M. Shiro
Rigaku Corporation
3-9-12 Matsubara-cho, Akishima, Tokyo, 196-8666 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201508574.
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Table 1: Optimization of the reaction conditions and substrate generality
for direct trichloromethylation of MBH substrates.
Table 2: Direct enantioselective trichloromethylation with HCCl3 using
Me3SiCF3.[a,b,c]
Run 1, 5 X, Ar
Me3SiCF3 Conditions Product Yield
(X equiv)
[%][a]
1
2
3
4
5
6
7
8
9
10
1a
5a
5b
1a
1a
1a
1b
1e
1 f
F, Ph
1.2
1.2
1.2
2.0
3.0
–
3.0
3.0
3.0
3.0
À608C/3 h
RT/24 h
RT/24 h
2a
2a
2a
2a
2a
2a
2b
2e
2 f
65
0[b]
13
77
92
NR
98
88
87
83
OAc, Ph
OBoc, Ph
F, Ph
F, Ph
F, Ph
F, 4-CH3C6H4
F, 4-BrC6H4
F, 4-CF3C6H4
F, 2-Naphthyl
À608C/3 h
À608C/3 h
RT/24 h
À608C/3 h
À608C/3 h
À608C/3 h
À608C/3 h
1h
2h
[a] Isolated yield. [b] SN2’ adduct of acetate (OAc) was obtained.
We thus started our investigation of allylic trichlorome-
thylation of MBH-fluoride 1a with Me3SiCF3 in HCCl3
(Table 1). The allyl fluoride 1a was smoothly converted into
the corresponding trichloromethylated compound 2a in
HCCl3 in the presence of a catalytic amount of 1,4-
diazabicyclo[2.2.2]octane (DABCO) at À608C after 3 h
(65%, run 1). It was obvious that HCCl3 is a source of the
CCl3 unit. We next attempted the same reaction using MBH
acetate 5a, but the acetate adduct was observed instead of 2a
(run 2). Although MBH carbonate 5b was converted into 2a,
the yield was low (13%) at room temperature for 24 h (run 3).
Using further amounts of Me3SiCF3 (2.0–3.0 equiv) improved
the yield of 2a to 77–92% (runs 4,5). In contrast, the reaction
did not proceed in the absence of Me3SiCF3 (run 6). These
results indicate that an in situ generated CF3 carbanion likely
[a] Reactions were carried out using 1 (0.2 mmol), Me3SiCF3 (2.0 equiv)
and (DHQD)2PHAL (10 mol%) in HCCl3 (1.0m) unless otherwise noted.
[b] Isolated yield. [c] Determined by HPLC analysis. [d] (DHQD)2PHAL
(20 mol%). [e] (DHQ)2PHAL was used instead of (DHQD)2PHAL.
at the ortho-, meta-, or para-position of aromatics were
smoothly converted into the enantioenriched trichloromethy-
lated compounds (S)-2b–d in high yields with up to 95% ee.
Bromide, and an electron-withdrawing group, such as a CF3
and NO2, were also accepted as a substituent on the benzene
ring to provide the corresponding CCl3 products (S)-2e–g in
high yields with high enantioselectivities. The sterically
demanding naphthyl substrate 1h could also be transformed
into the desired CCl3 product 2h in 84% yield with 90% ee. A
series of bulkier ethyl or tert-butyl esters of MBH-fluorides
1i–k were also converted into the corresponding CCl3
compounds (S)-2i–k with excellent ee values up to 97%,
even though a higher loading of organocatalyst, 20 mol% of
(DHQD)2PHAL, was required to improve the reactivity of
tert-butyl esters 1j–k. The opposite enantiomer, (R)-2a, was
also accessed in 91% yield with 77% ee, when the pseudo
enantiomer of the catalyst, (DHQ)2PHAL, was used instead
of (DHQD)2PHAL. The absolute configuration of 2e was
unambiguously S, assigned by X-ray crystallographic analysis
of corresponding isoxazoline derivative (1S,2S)-6 (see below,
and Scheme 2); the absolute stereochemistry of the other
CCl3-products 2 was tentatively assumed to be S by analogy.
We next applied a one-pot synthesis of the biologically
À
acts as a base to activate the C H of HCCl3 to furnish a CCl3
carbanion.[10]
A
similar C H activation process using
À
Me3SiCF3 was recently reported by two independent groups
for C H activation of CH2Cl2[11] and arenes;[12] however, they
À
require a stoichiometric amount of ammonium fluorides[11] or
0.5 equivalents of metal fluorides.[12] Our process is truly an
organocatalytic reaction. This allylic trichloromethylation
reaction was also successfully applied to a variety of MBH
fluorides 1b,e,f, and h, and the desired trichloromethylated
compounds 2b,e,f, and h were obtained in high yields within
a short period (entries 7–10).
Encouraged by these results, we advanced to the enantio-
selective variant of this transformation. After a brief survey of
the reaction conditions, including asymmetric catalysts, tem-
peratures, the amount of Me3SiCF3, and reaction concentra-
tions, the optimal conditions were established (Supporting
Information, Tables S1,S2). Thus, 1a was treated with
2.0 equivalents of Me3SiCF3 in the presence of 10 mol% of
(DHQD)2PHAL under a concentration of 1.0m in HCCl3,
and the desired product (S)-2a was obtained in 97% yield
with an excellent ee value of 94% after 120 h at À608C. The
results and substrate generality are summarized in Table 2.
MBH-fluorides 1 having an electron-donating methyl group
attractive chiral trichloromethylated spiro-isoxazoline[13]
6
from p-bromo substituted MBH fluoride 1e (Scheme 2).
Namely, treatment of 1e with Me3SiCF3 in HCCl3 under the
conditions mentioned above for 120 h provided 2e, which was
360
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Scheme 2. One-pot synthesis of trichloromethylated spiro-isoxazoline 6
from 1e.
directly reacted with N-hydroxybenzimidoyl chloride without
purification in a 1,3-dipolar cycloaddition reaction to furnish
chiral trichloromethylated isoxazoline 6 in 75% overall yield
with 79:21 d.r. The enantiopurities of both isomers 6 were
retained with or above > 90% ee. X-ray crystallographic
analysis of the major isomer of 6 revealed that the absolute
stereochemistry is (1S,2S)-6.[19]
Figure 1. A proposed reaction mechanism consisting of three impor-
À
tant steps: i) C F bond activation, ii) carbanion exchange of CF3 to
We finally assessed the potential of this silicon-assisted
direct enantioselective allylic substitution reaction of MBH
CCl3, and iii) enantioselective SN2’ addition.
À
fluorides 1 with other non-pre-activated C H compounds
2
À
À
such as H C(sp) (alkyne 3a), H C(sp ) (arene 3b and indene
3
À
3c), and H C(sp ) (FBSM 3d). After brief optimization of
SiMe3. It should be noted that the CF3 carbanion rapidly
[11,16]
abstracts H+ from the surrounding chloroform, H CCl3,
À
the reaction conditions, we succeeded in obtaining the desired
allylic substitution products 4a–d in moderate to good yields
with high enantioselectivities under a non-metallic system
(Scheme 3). The stereochemistries of 4 were determined by
rather than its direct nucleophilic attack on the alkene moiety
of ammonium salts I, resulting in a new ion pair of CCl3
carbanion and cationic intermediates I, with the release of
stable fluoroform, HCF3. The enantioselective nucleophilic
trichloromethylation by CCl3 carbanion to the ammonium
salts I by a secondary SN2’ process proceeds to give the
enantioenriched CCl3-products 2. A similar reaction mecha-
À
nism could be considered for the direct activation of other C
H compounds 3,[12,17] although the competitive trifluorome-
thylation to 7 was observed in this case.
In summary, we have developed an efficient protocol for
the enantioselective allylic trichloromethylation reaction of
MBH-type fluorides[18] by metal-free, silicon-assisted C F
À
À
bond activation and direct C H activation of chloroform,
HCCl3 by a carbanion exchange process with CF3 carbanion,
using the Ruppert–Prakash reagent, Me3SiCF3. This trans-
formation affords a wide range of chiral trichloromethylated
compounds in high yields with high enantioselectivities.
Direct enantioselective trichloromethylation is rare, and to
our knowledge, this is the first example of the use of
chloroform for an enantioselective trichloromethylation reac-
À
Scheme 3. Direct enantioselective allylic substitution reactions with R
H compounds using Me3SiCF3. A) (DHQD)2 PHAL (20 mol%) in
CH2Cl2 (1.0m); B) (DHQD)2PHAL (10 mol%) in CH2Cl2 (0.5m);
C) (DHQD)2AQN (10 mol%) in CH2Cl2 (0.5m); D) (DHQD)2AQN
(10 mol%) in CH2Cl2 (0.5m).
À
tion. The direct asymmetric introduction of other C H
compounds such as alkyne, arene, indene, and FBSM without
pre-activation was also achieved under the same reaction
conditions.
comparisons with reported data.[9,14] Although the corre-
sponding expected trifluoromethylated product 7a[9] was also
obtained as a by-product, greater optimization of the reaction
conditions is required to achieve higher conversion.
A plausible reaction mechanism for the asymmetric allylic
substitution reaction of MBH fluorides 1 mediated by
Me3SiCF3 is shown in Figure 1. This transformation starts
Acknowledgements
This research is partially supported by the Platform Project
for Supporting in Drug Discovery and Life Science Research
from the Ministry of Education, Culture, Sports, Science and
Technology (MEXT), the Japan Agency for Medical
Research and Development (AMED), the Advanced Cata-
lytic Transformation (ACT-C) from the Japan Science and
À
with the activation of the strongest C F bond of allyl fluoride
1 by the silicon atom of Me3SiCF3.[9,15] An ion pair of cationic
intermediate I and a CF3 carbanion should be generated by an
SN2’ addition of the chiral tertiary amine catalyst at the
À
terminal alkenyl position of 1 with the release of stable F
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Foundation.
Keywords: C-F activation · fluorine · organocatalysis · silicon ·
trichloromethylation
How to cite: Angew. Chem. Int. Ed. 2016, 55, 359–363
Angew. Chem. 2016, 128, 367–371
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http://www.chemicalize.org/). These data support the hypothesis
that anion exchange is reasonable between RH and CF3 anion.
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362
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Angewandte
Communications
Chemie
[18] The use of MBH-type chlorides and bromides instead of MBH-
[19] CCDC 1419720 contains the supplementary crystallographic
fluorides 1 failed because MBH-type chlorides are too unstable
to be prepared, and MBH-type bromides are isomerized to
internal alkenes or react by an SN2’ reaction to provide internal
alkenes. These facts clearly show the advantage of MBH-
fluorides. See; M. Y. Shandala, S. M. Kalil, M. S. Al-Dabbagh,
Tetrahedron 1984, 40, 1195 – 1198; K. H. Kim, S. Lee, J. Lee, M. J.
Go, J. N. Kim, Tetrahedron Lett. 2013, 54, 5739 – 5743; M.-L. Yao,
G. W. Kabalka, D. W. Blevins, M. S. Reddy, L. Yong, Tetrahe-
dron 2012, 68, 3738 – 3743.
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre.
Received: September 13, 2015
Revised: October 1, 2015
Published online: October 21, 2015
Angew. Chem. Int. Ed. 2016, 55, 359 –363
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