Trifluoromethylation of allylsilanes under copper catalysis

Article abstract of DOI:10.1002/chem.201201707

Branched allylic CF₃ products are accessible by copper-catalyzed trifluoromethylation of allylsilanes with the Togni reagent I. The silyl group is critical to control the outcome of this reaction because in its absence, a product of addition be

Full text of DOI:10.1002/chem.201201707

COMMUNICATION
DOI: 10.1002/chem.201201707
Trifluoromethylation of Allylsilanes under Copper Catalysis
Satoshi Mizuta,[a] Oscar Galicia-Lꢀpez,[a] Keary M. Engle,[a] Stefan Verhoog,[a]
Katherine Wheelhouse,[b] Gerasimos Rassias,[b] and Vꢁronique Gouverneur*[a]
Medicinal chemists commonly incorporate a trifluorometh-
yl group into druglike molecules to enhance binding selec-
tivity, improve metabolic stability and increase lipophilici-
ty.[1] To date, various methods are available for the introduc-
tion of the CF3 group onto functionalized arenes and hetero-
arenes.[2] Numerous catalytic trifluoromethylation reactions
of ketones or aldehydes have also been developed, leading
to the formation of Csp3–CF3 bonds, including elegant asym-
metric variants.[3] The construction of Csp3–CF3 stereogenicity
from poorly activated substrates is less common. In this con-
text, the direct selective installation of a CF3 group on an al-
lylic position remains a challenging synthetic problem.[4] Iso-
lated examples of Pd-catalyzed trifluoromethylation of allyl-
stannanes with CF3I[5] and Cu-mediated nucleophilic tri-
fluoromethylation of allyl bromide using the Ruppert–Pra-
kash reagent (CF3SiMe3) are known,[6] giving linear allylic
CF3 products. Recently, Buchwald,[7] Wang,[8] and Liu[9] and
their co-workers reported that terminal alkenes are amena-
ble to allylic trifluoromethylation under copper catalysis,
a reaction also affording linear allylic CF3 products with
very good control over E:Z geometry. Access to branched
acyclic allylic CF3 products has not been demonstrated, and
only two branched cyclic products have been prepared
ty of the proximal alkene and to dictate the regiochemistry
of the fluorination. Based on these principles and the availa-
bility of various electrophilic trifluoromethylating re-
agents[11] (e.g., hypervalent iodine reagents I and II,[12] and
the sulfonium salts III[13] and IV[14]), we describe herein
a copper-catalyzed trifluoromethylation reaction to prepare
various branched allylic CF3 products from allylsilanes
(Figure 1).
ꢀ
through application of this C H functionalization methodol-
ogy.[7–9] To address this synthetic challenge, we reasoned that
we could access allylic CF3 products using alkenes tempora-
rily activated with a regiodirecting silyl group. Since our
first report in 2003, we have demonstrated that a diverse
range of allylic fluorides are accessible upon electrophilic
fluorination of allylsilanes under very mild conditions and
have found that this reaction is broad in scope and tolerant
of various functional groups.[10] The presence of the allylic
trimethylsilyl group is essential to increase the nucleophilici-
Figure 1. Trifluoromethylation of allylsilanes.
Preliminary experiments with the model substrate 1a
served to demonstrate that the trifluoromethylation of
a silyl-activated alkene could be a valid route to access the
allylic CF3 product 2a. The trifluoromethylation of trimeth-
yl(2-phenylallyl)silane (1a) with Togniꢀs reagent I was suc-
cessfully performed in methanol at 708C in the presence of
20 mol% of CuCl. Compound 2a was isolated in 70% yield.
In the absence of CuCl, no reaction took place. A control
experiment with a-methylstyrene established that the trime-
thylsilyl (TMS) group is critical to induce allylic trifluorome-
thylation. When this structurally related non-silylated pre-
cursor was allowed to react under the same conditions as
1a, adduct 3 was isolated in 36% yield with only 4% of the
desired product 2a (Scheme 1).
[a] Dr. S. Mizuta, O. Galicia-Lꢁpez, K. M. Engle, S. Verhoog,
Prof. V. Gouverneur
Chemistry Research Laboratory
University of Oxford
12, Mansfield Road, Oxford OX1 3TA (UK)
E-mail: veronique.gouverneur@chem.ox.ac.uk
[b] Dr. K. Wheelhouse, Dr. G. Rassias
Medicines Discovery & Development
GlaxoSmithKline R&D
With this result in hand, we next examined the trifluoro-
methylation of allylsilane (Z)-1b, a substrate that would po-
tentially lead to the allylic product 2b featuring Csp3–CF3
stereogenicity. Our optimization study is presented in
Table 1.[15] In the absence of catalyst, no reaction took place
Gunnels Wood Road
Stevenage SG1 2NY (UK)
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under http://dx.doi.org/10.1002/chem.201201707.
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tion was predominant with [(CH3CN)4Cu]PF6 . We next ex-
amined the effect of the CF3 source. Under CuCl catalysis,
3,3-dimethyl-1-(trifluoromethyl)-1,2-benzodioxole, reagent
II (also developed by Togni), was less efficient than I, and
both sulfonium salts III (Umemotoꢀs reagent) and IV (Shi-
bataꢀs reagent) led to decomposition of the starting material
(Table 1, entries 8–10). For the copper-catalyzed reactions
using reagent I, methanol was identified as the best solvent
(Table 1, entries 11–13). Further optimization revealed that
the reaction was not progressing significantly after 2 h,
likely due to the thermal decomposition of Togniꢀs reagent I
over extended period of time (Table 1, entry 14).[16] Shorter
reaction time favored trifluoromethylation over competitive
protodesilylation.
Scheme 1. Evidence for TMS-driven allylic trifluoromethylation.
Table 1. Optimization study for the trifluoromethylation of 1b.
A series of Lewis acids were tested as alternative catalysts
for this reaction.[17] Trifluoromethylation of 1b took place in
the presence of 20 mol% of SnCl4 in dichloromethane fur-
nishing 2b in 44% yield, while no reaction took place with
BF3 Et2O (Table 1, entries 15 and 16). Pleasingly, the inex-
pensive and green catalyst FeACHTNUGTRENUNG(OAc)2 led to 2b in similar
.
Entry Catalyst
Additive Solvent/time “CF3”[a] Yield
[%][b]
1
–
–
–
–
–
–
–
–
–
–
–
–
–
MeOH/12 h
MeOH/20 h
MeOH/20 h
MeOH/2 h
MeOH/20 h
MeOH/17 h
MeOH/20 h
MeOH/20 h II
MeOH/20 h III
MeOH/20 h IV
I
I
I
I
I
I
I
NR[c]
53
50
14
17
yield to that obtained with CuCl (52%, Table 1, entry 17).
With the aim of suppressing protodesilylation, the reaction
was carried out in the presence of a base. Significant im-
provement was observed when the copper-catalyzed reac-
tion was performed in the presence of iPr2NEt or Et3N
(Table 1, entries 18 and 19). Since the presence of iPr2NEt
led to a complex reaction mixture under FeII catalysis
(Table 1, entry 20), we performed subsequent reactions in
methanol using 20 mol% CuCl, and 1.2 equivalents of
Togniꢀs reagent I at 708C with or without iPr2EtN depend-
ing, in part, on the sensitivity of the substrate to protodesily-
lation (Table 2).
Several trends emerge upon examining the impact of
para-aryl substitution for allylsilanes 1c, 1e, and 1g–j on the
efficiency of the reaction. Electron-releasing groups typical-
ly led to higher chemical yields than electron-withdrawing
groups. This reactivity profile held for 1c–e (Table 2, en-
2
3
CuCl
CuI
[d]
4
5
6
[Cu
CuTc
[(MeCN)4Cu]PF6
G
U
23
12
7
8
9
10
11
12
CuCl2
CuCl
CuCl
CuCl
CuCl
CuCl
29
[e]
–
–
[e]
DMF/20 h
DMAc/
I
I
34
13
20 h[f]
13
14
15
CuCl
CuCl
SnCl4
–
–
–
iPrOH/20 h
MeOH/2 h
CH2Cl2/
24 h[g]
I
I
I
17
53
44
.
16
BF3 Et2O
–
CH2Cl2/
I
NR[c]
24 h[g]
17
18
19
20
Fe
CuCl
CuCl
(OAc)2
–
MeOH/2 h
MeOH/2 h
I
I
I
I
52
61
75
11
Et3N
iPr2EtN MeOH/2 h
iPr2EtN MeOH/2 h
tries 1–3) and the branched products 2g–2l featuring Csp3–
FeACHTUNGTRENNUNG(OAc)2
CF3 stereogenicity (Table 2, entries 5–10 and 17). The gener-
ation of branched allyl CF3 products bearing substitution on
the g-position required the use of an excess of Togniꢀs re-
agent I (2 equiv) and iPr2EtN (2 equiv) to maximize the
yields (Table 2, entries 5–10 and 17). The reaction tolerates
the presence of a pyridine ring (42% yield for 2 f, Table 2,
entry 4), and pleasingly, the 2-naphtyl and 2-styryl substitut-
ed products 2l and 2m were isolated with yields above 80%
(Table 2, entries 11 and 12). A significant drop in yield was
observed for the more substituted allyl CF3 product 2o
(Table 2, entry 13). For this substrate, the addition of base
did not prove to be beneficial. The branched cyclic trifluoro-
methylated product 2p was isolated in 50% yield (Table 2,
entry 14) but the reaction did not proceed with the cyclic al-
lylsilane 1q, which is disubstituted at the g-position (Table 2,
entry 15). Allylic quaternary Csp3–CF3 stereogenicity there-
fore does not appear to be within the scope of this method.
Secondary and primary alkyl groups are tolerated on the b-
position with yields around 40% (Table 2, entries 16 and
[a] The structures of reagents I, II, III, and IV are given in Figure 1.
[b] Yield of isolated product. [c] No reaction, with recovery of 1b. [d] Re-
action performed with 2.0 equivalents of reagent I. [e] Decomposition.
[f] DMAc=dimethylacetamide. [g] Reaction performed at room temper-
ature.
(Table 1, entry 1). Various CuI/II salts led to product forma-
tion with Togniꢀs reagent I but were not equally efficient
(Table 1, entries 2–7). The reaction of allylsilane 1b with
CuCl in methanol gave the branched product 2b in 53%
yield after 20 h (Table 1, entry 2). 2-Phenylbutene resulting
from protodesilylation was observed in the crude reaction
mixture but this side product could be separated by careful
purification with silica gel column chromatography. CuI was
a competent catalyst (Table 1, entry 3) but [Cu
ACHTUGNRTNE(NUNG OTf)]2C6H6,
CuTc (copper(I)-thiophene-2-carboxylate),
ꢀ
[(CH3CN)4Cu]PF6 and CuCl2 gave 2b in significantly lower
yields (Table 1, entries 4–7). Fluoride-induced protodesilyla-
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Trifluoromethylation of Allylsilanes
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Table 2. Copper-catalyzed trifluoromethylation of 1c–t.[a,b]
in favor of the anti diastereomer 2t (d.r.=4.6:1). In previous
work, we have shown that a structurally related allylsilane
subjected to electrophilic fluorination led to an advanced in-
termediate of an 1a-fluoro vitamin D3 analogue with a simi-
lar sense and level of diastereocontrol (d.r.=3:1 in favor of
the anti isomer).[19] Further experimentation revealed that
allylsilanes lacking an alkyl or aryl group at the b-position
are unreactive.[15] The stabilization offered by the b-substitu-
ent is therefore essential for the trifluoromethylation
to proceed.
Entry
Allylsilane
Product
Yield [%][c,d]
1
1c
2c
2d
2e
2 f
2g
2h
2i
74
2
1d
1e
1 f
1g
1h
1i
70
59
42
40
40
17
3[e]
Mechanistically, the superior reactivity of the para-substi-
tuted 2-aryl allylsilanes featuring electron-releasing groups
could be attributed to the intermediacy of a benzylic carbo-
4
5[f]
6[f]
7[f]
ꢀ
cation following C CF3 bond formation (E or C, see
Scheme 4); however, a similar reactivity pattern would also
be expected if the reaction proceeded via an electrophilic
CF3 radical species. Silicon has the ability to stabilize effi-
ciently b-carbocations (29–30 kcalmolꢀ1)[20] through sSiꢀC!p
hyperconjugation and to a lesser degree b-carboradicals
(2.6–4.5 kcalmolꢀ1).[21] A pathway involving radical species
is consistent with our findings and is certainly possible
under copper-catalysis.[22] To gain further insight into the re-
8[f]
1j
2j
6
action
mechanism,
2,2,6,6-tetramethyl-1-piperidinyloxy
9[f]
1k
1l
2k
2l
42 (86)
48 (96)
83
(TEMPO) was allowed to react with one equivalent of allyl-
silane (Z)-1b and 1.2 equivalents of the hypervalent iodine-
AHCTUNGTREG(NNUN III) reagent I in the presence of 20 mol% CuCl. Under
10[f]
11
these conditions, we recovered the starting material 1b
along with trace amounts of 2b and of the TEMPO–CF3
adduct (diagnostic signal at d=ꢀ55 ppm in the 19F NMR
spectrum).[15] These experimental results provide supportive
evidence that a CF3 radical may be involved as a reactive
species in the reaction mechanism. To investigate this fur-
ther, we next subjected the cyclopropane radical clock 4 to
our standard reaction conditions (Scheme 2). This transfor-
1m
2m
12
1n
1o
2n
2o
84
13[g]
38 (57)
14
1p
1q
1r
1s
2p
2q
2r
2s
50 (68)
trace
42
15[h]
16
17[f]
40 (58)
18[i]
1t
2t
44 anti/syn=4.6:1[j]
[a] Reaction conditions: allylsilane (1 equiv), CuCl (20 mol%), CF3 re-
agent I (1.2 equiv) in MeOH at 708C for 2 h on a 0.25–0.5 mmol scale.
[b] 1g–1l, 1o, and 1s were used as mixture of Z/E isomers (Z major).
[c] Yield of isolated product. [d] Numbers in parentheses refer to yields
based on recovery of allylsilane. [e] 1.4 equivalents of reagent I.
[f] 2.0 equivalents of the CF3 reagent I and 2.0 equivalents of iPr2EtN.
[g] Reaction time 12 h. [h] Reaction time 24 h. [i] Reaction time 3 h.
[j] The d.r. was determined by 19F NMR analysis of the crude product.
Scheme 2. Trifluoromethylation of the cyclopropane radical clock 3.
mation led to a complex but tractable mixture of products.
The trifluoromethylated cyclopropane 5 was isolated in
10% yield along with the ring-opened (bis)trifluoromethy-
lated product 6 (8%), and the methoxy adduct 7 (9%).
Trace amounts of the diene 8 and the (bis)trifluoromethylat-
ed methoxy adduct 9 could also be detected. The presence
of the trifluoromethylated cyclopropane 5 and the ring-
17). We also explored the trifluoromethylation of allylsilane
1t possessing a stereogenic center proximal to the site of tri-
fluoromethylation.[18] The reaction proceeded in 44% yield
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opened adduct 7 trapped with methanol indicates that
a silyl-stabilized b-carbocation is a plausible intermediate
undergoing either rapid desilylation or ring opening fol-
lowed by intermolecular capture with the solvent. The for-
mation of product 6 is however consistent with a radical
pathway involving CF3 radical addition followed by ring
opening leading to a trifluoromethylated benzylic radical
species possibly sequestered by a second CF3 radical.
To investigate the fate of the silyl group, we carried out
the trifluoromethylation using cyclic allylsilane 10. This is
a conformationally restricted substrate that does not possess
the requisite coplanarity of the involved orbitals for s–p hy-
perconjugative vertical stabilization. Interestingly, the reac-
tion took place under CuCl catalysis with the formation of
the allylic CF3 product 11, which clearly indicates that the
silyl group is trapped with methanol (Scheme 3).[23]
in the trifluoromethylated benzylic radical intermediate B
further stabilized by the proximal silyl group. Oxidation of
B with either CuII or I gives intermediate C, a carbocationic
species that is more stabilized by the b-silyl group than B.
Subsequent desilylation with methanol[23] gives the desired
allylic CF3 product 2b. A mechanism with the CuI catalyst
acting as a Lewis acid could also be operative. Upon activa-
tion of I leading to cationic active species D, electrophilic
trifluoromethylation of allylsilane can take place affording
intermediate C either directly or via reductive elimination
from the l3-iodane species E.[24] Both the cationic and the
radical mechanisms could operate in parallel, progressing at
different rates.
In summary, we have developed an allylic trifluoromethy-
lation of allylsilanes,[25] a method allowing access to various
branched cyclic and acyclic allylic CF3 products including
compounds featuring Csp3–CF3 stereogenicity. A preliminary
analysis suggests that the mechanism is complex and in-
volves multiple reaction pathways featuring radical and/or
cationic intermediates. Current efforts focus on further ex-
amining the mechanistic details of this reaction to expand
its scope and efficiency.
Scheme 3. Trifluoromethylation of the cyclic allylsilane 10.
Experimental Section
Taken together, this collection of data leads us to propose
the reaction pathways detailed in Scheme 4.
Representative protocol for trifluoromethylation of allylsilanes: A 5mL
vial containing a magnetic stir bar was charged with allylsilane 1a
(47.6mg, 0.25mmol) and CuCl (5.0mg, 20mol%). Then MeOH (0.5mL)
and Togniꢀs trifluoromethylating reagent I (0.3mmol) were added under
argon, and the reaction mixture was stirred for 2h at 708C. Saturated
aqueous NaHCO3 was then added at room temperature. After extraction
with diethyl ether, the combined organic phases were washed with dis-
tilled water and brine, then dried over MgSO4, and concentrated in
vacuo. After silica-gel column chromatography, 2a (32.6mg, 70% yield)
was obtained as a colorless oil.
Acknowledgements
The authors thank the European Union (grant PIIF-GA-2010–274903 to
S. M.), the CONACyT Mexico Program (grant 205456 to O. G. L.), the
Skaggs-Oxford Scholarship Program and NSF GRFP (predoctoral fellow-
ships to K. M.E.), the EPSRC, and GSK (industrial studentship to S. V.)
for generous funding. We are most grateful to Prof. N. Shibata for provid-
ing a sample of reagent IV and Dr T. Yamamoto for early experiments.
Keywords: allylsilanes · copper · homogeneous catalysis ·
radicals · trifluoromethylation
Scheme 4. Suggested mechanism.
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Angew. Chem. Int. Ed. 2011, 50, 9120–9123.
[8] J. Xu, Y. Fu, D.-F. Luo, Y.-Y. Jiang, B. Xiao, Z.-J. Liu, T.-J. Gong, L.
Liu, J. Am. Chem. Soc. 2011, 133, 15300–15303.
[9] X. Wang, Y. Ye, S. Zhang, J. Feng, Y. Xu, Y. Zhang, J. Wang, J. Am.
Chem. Soc. 2011, 133, 16410–16413.
[22] For a review on Cu-catalyzed reactions via SET: C. Zhang, C. Tang,
N. Jiao, Chem. Soc. Rev. 2012, 41, 3464–3484.
[23] Trapping with Clꢀ is possible followed by substitution with metha-
nol.
[10] a) B. Greedy, J.-M. Paris, T. Vidal, V. Gouverneur, Angew. Chem.
2003, 115, 3413–3416; Angew. Chem. Int. Ed. 2003, 42, 3291–3294;
b) M. C. Pacheco, V. Gouverneur, Org. Lett. 2005, 7, 1267–1270;
c) M. Tredwell, K. Tenza, M. C. Pacheco, V. Gouverneur, Org. Lett.
2005, 7, 4495–4497; d) M. Tredwell, V. Gouverneur, Org. Biomol.
Chem. 2006, 4, 26–32; e) S. Thibaudeau, R. Fuller, V. Gouverneur,
Org. Biomol. Chem. 2004, 2, 1110–1112; f) Y.-h. Lam, C. Bobbio,
I. R. Cooper, V. Gouverneur, Angew. Chem. 2007, 119, 5198–5202;
Angew. Chem. Int. Ed. 2007, 46, 5106–5110.
[24] For a similar reductive elimination, see reference [17].
[25] Very recently, Sodeoka has reported a similar reaction: R. Shimizu,
H. Egami, Y. Hamashima, M. Sodeoka, Angew. Chem. 2012, 124,
4655–4658; Angew. Chem. Int. Ed. 2012, 51, 4577–4580.
[11] For reviews, see: a) N. Shibata, A. Matsnev, D. Cahard, Beilstein J.
Org. Chem. 2010, 6, No. 65; b) Y. Macꢅ, E. Magnier, Eur. J. Org.
Chem. 2012, 2479–2494.
Received: April 5, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!

V. Gouverneur et al.
Homogeneous Catalysis
S. Mizuta, O. Galicia-Lꢀpez,
K. M. Engle, S. Verhoog,
K. Wheelhouse, G. Rassias,
V. Gouverneur* ............... &&&& — &&&&
Branched allylic CF3 products are
accessible by copper-catalyzed
trifluoroACTHNUTRGNEmNUG ethylation of allylsilanes
with the Togni reagent I. The silyl
group is critical to control the outcome
of this reaction because in its absence,
a product of addition between the
alkene and the Togni reagent is
Trifluoromethylation of Allylsilanes
under Copper Catalysis
formed preferentially. The reaction is
inhibited with 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) and is likely
to operate via multiple reaction path-
ways.
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www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!