Pd-catalyzed allylic alkylation of CF3-containing esters with three electron-withdrawing groups

Article abstract of DOI:10.1055/s-0032-1318313

Tsuji-Trost reaction (Pd-catalyzed allylic alkylation) of CF ₃-containing esters with three electron-withdrawing groups is reported. The reactions with methyl bis(trifluoromethyl)acetate and dimethyl (trifluoromethyl)malonate were carried out w

Full text of DOI:10.1055/s-0032-1318313

LETTER
▌611
letter
Pd-Catalyzed Allylic Alkylation of CF3-Containing Esters with Three Elec-
tron-Withdrawing Groups
Allylic Alkylation of CF3-Containing Esters
Lun Li, Donghui Huang, Qing-Yun Chen, Yong Guo*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: yguo@sioc.ac.cn
Received: 09.01.2013; Accepted after revision: 04.02.2013
dently applied the same protocol to CF3-containing sul-
Abstract: Tsuji–Trost reaction (Pd-catalyzed allylic alkylation) of
fones in 2012. Although the mechanism of defluorination
CF3-containing esters with three electron-withdrawing groups is re-
control is unclear, a plain explanation could be thought as
that the highly electrophilic allylic palladium complex re-
ported. The reactions with methyl bis(trifluoromethyl)acetate and
dimethyl (trifluoromethyl)malonate were carried out with low-load-
ing catalysts of Pd(0) and XPhos at ambient temperature in THF, acts very fast with the trifluoromethyl carbanion before its
giving the products in high yields. This method efficiently over-
comes the β-defluorination, which is hard to control in the chemical
transformation of α-trifluoromethyl carbanions, and provides versa-
organolithium reagent, exhibits a more covalent nature
tile fluorinated compounds with quaternary carbon centers, which
are highly demanded in drug discovery.
decomposition. Another complementary consideration is
that the carbon–palladium interaction, compared with the
that results in the decrease of the negative charge at the α-
carbon next to the trifluoromethyl group. We are interest-
Key words: fluorine, carbanions, allylation, palladium, homoge-
ed in the use of CF3-containing esters 1 and 2 because of
neous catalysis
the nucleophilic difference arising from three electron-
withdrawing groups around the carbanion generated from
1 or 2 (Figure 1). Moreover, in 2009, Murahashi et al.
have demonstrated Michael addition reactions of 1 and 2
catalyzed by low-valence iridium and ruthenium com-
Because of unique properties of fluorine (small size and
strong electron-withdrawing ability), fluorine has been
widely introduced into medicines, agrochemicals, and
plex, showing the potential use of these two fluorinated
materials.1 Compounds with trifluoromethyl group(s) are
substrates in pharmaceutical and material sciences.5b
highly demanded in drug discovery, and thus recently
Herein, we report our recent discovery of the Pd-catalyzed
many trifluoromethylation methods have been devel-
allylic alkylation of 1 and 2.
oped,2 including those to build a CF3-containing quaterna-
ry carbon center.3 Among those methods, a mild and
previous work
this work
prompt installation of a CH2CF3 and relevant functional
groups is still limited and is thought as a critical challenge
in organofluorine chemistry.4,5 The essence lies in the
problem associated with defluorination of trifluoromethyl
carbanion when an electrophilic reaction is going to occur
at the α-position of the carbanion bearing a trifluorometh-
yl group.
E
E
H
E
H
E
R1
E
E = electron-withdrawing group
examples
CF3
CF3CH2CO2Et
F3C
CO2Me
Introduction of electron-withdrawing group(s), such as ni-
tro, carbonyl, sulfonyl, and phenyl, can stabilize the triflu-
oromethyl carbanion and allow further reaction. But, even
that an elegant control of reaction conditions is crucial. In
1983, Ishikawa and Yokozawa found that alkylation of di-
methyl (trifluoromethyl)malonate in an excess CsF (or
KF) occurred with methyl iodide smoothly (but not effec-
tive with allylic bromide), which demonstrated the diffi-
culty of allylation of trifluoromethyl carbanion under
usual basic conditions.6 In 1999, Kitazume carried out
creatively the allylic alkylation of a CF3-containing ester
by the Tusji–Trost reaction.7a However, the reaction with
different types of trifluoromethylated compounds was not
well developed7 until Mathew, Hu,8 and Shibata9 indepen-
1
PhSO2CH2CF3
Ph
CF3
CO2Me
MeO2C
F3C
SO2Ph
2
Figure 1 Different fluorinated nucleophiles
Initially, we carried out the reaction of 1 with the same
equivalent of cinnamyl carbonate 3a in the presence of
10% Pd(dba)2 and 12.5% BINAP in several solvents (Ta-
ble 1). Among the solvents screened, THF was the best
(Table 1, entry 1 vs. entries 2–5). In some cases (Table 1,
entries 4 and 5), defluorination was indeed observed, and
a lot of signals were found in the 19F NMR spectrum of the
crude reaction mixture. This means that suitable reaction
conditions are needed to avoid defluorination reaction al-
though three electron-withdrawing groups contribute sig-
nificantly to stabilize the CF3 carbanion. Later on, we
SYNLETT 2013, 24, 0611–0614
Advanced online publication: 20.02.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318313; Art ID: ST-2013-W0029-L
© Georg Thieme Verlag Stuttgart · New York

612
L. Li et al.
LETTER
Table 2 Scope of the Reaction of 1 with Carbonatesa
screened ligands and found that 2-dicyclohexylphosphi-
no-2′,4′,6′-triisopropylbiphenyl (XPhos) gave nearly
quantitative products 4a (Table 1, entries 1, 6–8).
Entry
Product
Yield (%)b
83
CO2Me
F3C CF3
Table 1 Screening of Conditions for the Synthesis of Compound 4a
from 1 and 3aa
1
OCO2Me
1
+
4a
CO2Me
F3C CF3
3a
CO2Me
Pd(dba)2
2
3
89
98
t-Bu
ligand, solvent, r.t.
F3C CF3
4a
4b
CO2Me
F3C CF3
Entry
Ligand
Solvent
Yield (%)b
MeO
1
2
3
4
5
6
7
8
BINAP
BINAP
BINAP
BINAP
BINAP
Ph3P
THF
92 (80)
80
4c
CH2Cl2
toluene
DMF
DMSO
THF
OMe
CO2Me
F3C CF3
75
4
91
60c
OMe
40d
4d
CO2Me
F3C CF3
95
5
6
7
91
90
87
XPhos
dppf
THF
97 (83)
60
F
THF
4e
CO2Me
F3C CF3
a Reaction conditions: 1 (0.4 mmol), 3a (0.4 mmol), Pd(dba)2 (0.04
mol), ligand (0.05 mol BINAP/dppf or 0.10 mol Ph3P/XPhos), solvent
(2 mL), 12 h, r.t.
F3C
b Yields were determined by 19F NMR spectroscopy using benzotri-
fluoride as the internal standard, and the isolated yield is given in pa-
rentheses.
4f
CO2Me
F3C CF3
c A new peak appeared at δ = –55 ppm.
d The reaction system was very complex according to the 19F NMR
spectrum of the reaction mixture.
O2N
4g
With the conditions of entry 7 in Table 1, the reaction
scope of carbonates with 1 was tested (Table 2).10 All ar-
omatic substituted carbonates gave good yields of prod-
ucts (Table 2, entries 2–8). The substituent on the aryl ring
included t-Bu (Table 2, entry 2), electron-donating MeO
(Table 2, entry 3), and electron-withdrawing CF3 (Table
2, entry 6), and NO2 (Table 2, entry 7) groups. The reac-
tion was also applied to an anthracenyl-substituted car-
bonate (Table 2, entry 8). The reaction overcame steric
hindrance when two ortho-OMe groups are located on the
aryl ring (Table 2, entry 4). The reactions gave low isolat-
ed yields of 4i and 4j (Table 2, entries 9 and 10) mainly
arising from the volatility of products while high yields
were observed by 19F NMR spectroscopy.
CO2Me
F3C CF3
8
93
4h
CO2Me
F3C CF3
9
35 (90)c
45 (92)c
4i
4j
CO2Me
F3C CF3
10
a Reaction conditions: 1 (0.4 mmol), carbonate (0.4 mmol), Pd(dba)2
(0.04 mmol), XPhos (0.10 mmol), THF (2 mL), 12 h, r.t.
b Isolated yield.
Later, we screened the reaction conditions of 2 with 3a in
several solvents and different loading of catalyst and li-
gand (Table 3). Again, THF and XPhos were the best sol-
vent and the best ligand, respectively. Moreover, 2%
loading of palladium complex gave the best TON (Table
3, entry 6).
c 19F NMR yield.
shown in Table 4. Again, aryl-substituted carbonates gave
The scope was also extended to various carbonates by us- good to excellent results (Table 4, entries 1–8) while the
ing the conditions of entry 6 in Table 3, and the results are
Synlett 2013, 24, 611–614
© Georg Thieme Verlag Stuttgart · New York

LETTER
Allylic Alkylation of CF3-Containing Esters
613
Table 3 Screening of Conditions for the Synthesis of Compound 5a
from 2 and 3aa
Table 4 Scope of the Reaction of Compound 2 with Carbonatesa
Entry
1
Product
Yield (%)b
OCO2Me
2
+
CO2Me
3a
F3C CO2Me
82
CO2Me
Pd(dba)2 (x mol%)
ligand, THF, r.t
5a
F3C CO2Me
5a
CO2Me
F3C CO2Me
Entry
Ligand
x
Yield (%)b
2
3
88
97
t-Bu
1
2
3
4
5
6
7
XPhos
Ph3P
10
10
10
10
5
100 (98)
97
5b
CO2Me
F3C CO2Me
PCy3
0
MeO
t-Bu-XPhos
XPhos
XPhos
XPhos
74
5c
OMe
100
95 (82)
88
CO2Me
2
4
66
F3C CO2Me
OMe
1
a Reaction conditions: 2 (0.4 mmol), 3a (0.53 mmol), Pd(dba)2 (x
mol%), ligand (x mol%), solvent (2 mL), 12 h, r.t.
b Yield were determined by 19F NMR spectroscopy using benzotriflu-
oride as the internal standard, and the isolated yield is given in paren-
theses.
5d
CO2Me
F3C CO2Me
5
6
7
94
85
71
F
5e
CO2Me
alkylated analogues gave lower yields of products (Table
4, entries 9 and 10).
F3C CO2Me
F3C
In conclusion, the Tsuji–Trost reaction has been applied
to two new CF3-containing substrates (1 and 2) with three
electron-withdrawing groups. The mild and efficient reac-
tions with a wide substrate scope provide many products
with a trifluoromethylated quaternary center and may be
applied in the synthesis of druglike molecules.
5f
CO2Me
F3C CO2Me
O2N
5g
Acknowledgment
CO2Me
This work was financially supported by the 973 Program of China
(2012CB821600), Shanghai Science and Technology Commission
(11ZR1445700), and National Natural Science Foundation of China
(No. 21032006, 21172241).
F3C CO2Me
8
91
5h
CO2Me
F3C CO2Me
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
9
59 (71)c,d
17 (53)c,d
5i
5j
Primary Data for this article are available online at
http://www.thieme-connect.com/ejournals/toc/synthesis and can be
CO2Me
cited using the following DOI: 1
i
0.4125/pd0041th.
m
DayrmaPitrmDPayir42.1/5aDprd0y1hr4taZtahenl01
C
hemyr
F3C CO2Me
10
a Reaction conditions: 2 (0.4 mmol), carbonate (0.53 mmol), Pd(dba)2
(2 mol%), XPhos (2 mol%), solvent (2 mL), 12 h, r.t.
b Isolated yield.
References and Notes
(1) (a) Uneyama, K. Organofluorine Chemistry; Blackwell:
Oxford, 2006. (b) Kirsch, P. Modern Fluoroorganic
Chemistry: Synthesis, Reactivity, Applications; Wiley-VCH:
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308. (d) Müller, K.; Faeh, C.; Diederich, F. Science 2007,
317, 1881. (e) Purser, S.; Moore, P. R.; Swallow, S.;
c Conditions: 1.1 equiv of carbonate.
d 19F NMR yield.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 611–614

614
L. Li et al.
LETTER
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
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(10) Typical Procedure for the Preparation of Compound 4
To a solution of Pd(dba)2 (0.04 mmol) and XPhos (0.1
mmol) in THF (2 mL) were added at r.t. under N2
atmosphere, and the mixture was stirred for 30 min at r.t.,
then carbonate (0.4 mmol) was added dropwise under N2
atmosphere. After 10 min, CF3-containing ester 1 or 2 was
added to the mixture dropwise, and the mixture was allowed
to react at r.t. for 12 h. Then the solvent was evaporated
under vacuum. The residue was purified by column
chromatography on silica gel eluting using a mixture of
hexane and CH2Cl2 as eluent.
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(E)-Methyl 5-Phenyl-2,2-bis(trifluoromethyl)pent-4-
enoate (4a)
1H NMR (300 MHz, CDCl3): δ = 7.35–7.24 (m, 5 H), 6.58
(d, J = 15.9 Hz, 1 H), 6.06 (dt, J = 15.9, 7.2 Hz, 1 H), 3.89
(s, 3 H), 3.08 (d, J = 7.2 Hz, 2 H). 13C NMR (100 MHz,
CDCl3): δ = 162.6, 136.5, 135.9, 128.6, 127.9, 126.5, 122.5
(q, JCF = 284 Hz), 120.2, 61.5 (m, JCF = 25 Hz), 53.9, 32.1.
19F NMR (282 MHz, CDCl3): δ = –66.5 (s). IR (neat): 282
3085, 3028, 2961, 1760, 1600, 1496, 1297, 1147, 1025 cm–1.
MS (EI): m/z (%) = 326 (13.71) [M+]. HRMS (EI): m/z calcd
for C14H12O2F6 [M+]: 326.0741; found: 326.0743.
Synlett 2013, 24, 611–614
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