Transition-metal-free trifluoromethylaminoxylation of alkenes

Article abstract of DOI:10.1002/anie.201202623

No transition metal! Fluorinated hypervalent-iodine reagents react with TEMPONa in the presence of an alkene under mild conditions to give the corresponding perfluoroalkylaminoxylation products. These radical addition/trapping reactions occur with high st

Full text of DOI:10.1002/anie.201202623

Angewandte
Chemie
DOI: 10.1002/anie.201202623
Trifluoromethylation
Transition-Metal-Free Trifluoromethylaminoxylation of Alkenes**
Yi Li and Armido Studer*
The trifluoromethyl group is a privileged chemical entity
found in many drugs and drug candidates in medicinal
chemistry.[1] Introduction of a CF3 group leads to changes in
the chemical and physical properties of a potential drug
candidate. For example, the solubility and lipophilicity are
altered, leading to compounds that show better membrane
permeability and increased bioavailability. Fluorinated com-
pounds often show increased metabolic stability because they
have higher resistance towards oxidative degradation. It is
À
therefore important to develop novel methods for C CF3
bond formation. Transition-metal-mediated or -catalyzed[2–10]
and radical[11,12] aromatic trifluoromethylation have been
studied intensively recently. However, the trifluoromethyla-
tion of alkenes, in particular unactivated alkenes, is valuable
but highly challenging.[13] Nucleophilic CF3 reagents[14] do not
react with unactivated alkenes and electrophilic CF3 reagents
react only with electron-rich double bonds (metal enolates,
Scheme 1. Radical trifluoromethylation of alkenes with the Togni
reagent 1.
silyl enol ethers, and enamines).[15,16] Radical chemistry
should be well suited for the trifluoromethylation of alkenes
because the CF3 radical reacts rapidly with various olefinic
acceptors.[17–22] We herein describe easy-to-conduct, transi-
tion-metal-free radical trifluoromethylations of alkenes using
the commercially available hypervalent-iodine–CF3 reagent
1 (Togni reagent).[15]
reagent (TEMPONa) into an oxidizing reagent (TEMPO). In
synthesis, such redox behavior is usually reserved for tran-
sition metals.[28] Surprisingly, TEMPONa has not found any
À
application as a SET reagent in synthesis and the N O bond
The Buchwald[23] and Wang[24] groups showed that reagent
1[15] can be used as a clean source of the CF3 radical for the
trifluoromethylation of alkenes. These trifluoromethylations
rely on Cu catalysis and experimental evidence for the
involvement of free CF3 radicals was provided. Based on
these results, we planned to use the readily available sodium
aminoalkoxide 2 as a single-electron-transfer (SET) reagent
for reduction of hypervalent-iodine–CF3 reagent 1 to gener-
ate the CF3 radical along with the corresponding persistent
TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl) radical[25,26]
and o-IC6H4CO2Na. Addition of the CF3 radical to an
alkene and subsequent selective trapping steered by the
“persistent radical effect”[27] (oxidation of the C radical) with
TEMPO should eventually provide the corresponding tri-
fluoromethylated product 3 (Scheme 1).
in alkoxyamines of type 3 is readily cleaved with Zn in acetic
acid[25,26] to give products of formal trifluoromethylhydro-
xylation. Such trifluoromethyl-substituted alcohols are not
directly accessible by epoxide opening with nucleophilic CF3
reagents.[29]
Careful reaction optimization revealed that the trifluoro-
methylation is best conducted in THF at high concentration.
TEMPONa was readily generated in situ by stirring commer-
cially available TEMPO with sodium in the presence of
naphthalene (see the Supporting Information). The TEM-
PONa solution (1.2 equiv, THF) was slowly added by syringe
pump to a solution of the alkene (5 to 10 equiv) and
1 (1 equiv) in THF at room temperature (RT). Results of
the trifluoromethylation of various alkenes are summarized in
Table 1 and Scheme 2.
À
À
The process comprises the formation of a C C and a C O
bond and the organic reagent 2 is transformed from a reducing
Styrene and styrene derivatives were readily trifluorome-
thylated and the corresponding products 3a–h were isolated
in good yields (Table 1, entries 1–8).[30] For styrene we showed
that reaction worked equally well on a large scale and 3a was
isolated in 83% yield (0.86 g). A side product in these radical
trifluoromethylations was TEMPOCF3 resulting from the
direct trapping of the CF3 radical with TEMPO. However, the
in situ generation of TEMPO ensures a low concentration of
the nitroxide during the reaction which suppresses the
formation of TEMPOCF3. Under the applied conditions
telomerization was not observed. The ortho-iodobenzoic acid
sodium salt formed as a by-product from 1 was easily removed
by basic extraction, and TEMPOCF3 was removed by simple
[*] Dr. Y. Li, Prof. Dr. A. Studer
Organisch-Chemisches Institut
Westfꢀlische Wilhelms-Universitꢀt
Corrensstrasse 40, 48149, Mꢁnster (Germany)
E-mail: studer@uni-muenster.de
[**] We thank the Alexander von Humboldt foundation for supporting
our work (stipend to Y.L.) and Prof. Dennis Curran for helpful
comments on this manuscript.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202623.
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Table 1: Radical trifluoromethylaminoxylation of terminal alkenes (for
structures see Scheme 1, R3 =H).
trifluoromethylaminoxylation of the electron-poor methyl-
acrylate afforded 3n in low yield (Table 1, entry 14). In
contrast, the reaction with the electron-rich butyl vinyl ether
was more efficient, and 3o was isolated in 75% yield (Table 1,
entry 15). Changing the electronic properties of the acrylate
by introducing an additional methyl group at the alkene, such
as in methyl methacrylate, led to an improved yield and 3p
was obtained in 53% yield (Table 1, entry 16). This example
shows that formation of quaternary C centers is possible (see
also 3q and 3r; Table 1, entries 17 and 18).
Entry
R1
R2
Compound
Yield [%][a]
1
2
3
4
5
6
7
8
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
84
72
65
62
82
75
56
67
73
53
76
58
65[b]
27
75
53
45
71
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
4-BrC6H4
b-naphthyl
C6F5
4-pyridyl
(CH2)2Ph
(CH2)3CH3
(CH2)3Br
(CH2)4OH
(CH2)2(CHOCH2)
CO2CH3
OBu
We switched to internal alkenes as substrates to study the
diastereoselectivity[31] of the trifluoromethylaminoxylation
(Scheme 2). The selectivity of the reactions was determined
9
10
11
12
13
14
15
16
17
18
1
by H NMR analysis of the crude products. b-Methylstyrene
reacted with high regioselectivity (20:1) to give regioisomer
3s as the major product in 61% yield. Product 3s was formed
with a diastereoselectivity of 8.3:1 and the assignment of the
relative configuration was based on the allylic A[1,3] strain
model.[32] As expected, trans- and cis-b-methylstyrene deliv-
ered the same product ratio. The diastereoselectivity was even
better for cyclic systems. Dihydronaphthalene, indene, and
benzofuran reacted with excellent selectivity (> 98:2) to give
the corresponding products 3t, 3u, and 3z (41–77% yield).
The trifluoromethylaminoxylation of cyclohexene was also
highly selective (see 3v). The transformation of dihydropyran
provided 3w as the major regioisomer (44% yield) with
complete trans selectivity along with the other regioisomer in
7% yield (not shown in Scheme 2). Norbornene reacted with
complete exo selectivity for the initial CF3-radical addition
and perfect trans selectivity in the TEMPO-trapping step
(3y). Moderate diastereoselectivity was obtained in the
transformation of 2,3-dimethylbutadiene (3aa).
CO2CH3
C6H5
CH2CH3
CH3
CH3
CH2CH3
[a] Yields of isolated products. [b] Obtained as a 1:1 mixture of
diastereoisomers.
We also tested whether the trifluoromethylaminoxylation
can be used to “open and close” a cascade reaction compris-
ing an additional typical radical step such as a 5-exo
cyclization. Indeed, the trifluoromethylaminoxylation of
bisallyl ether gave tetrahydrofuran 4 in 62% yield as a 3.6:1
mixture of cis/trans isomers along the noncyclized product
3ab in 14% yield (Scheme 2). Despite this useful result, this
experiment clearly showed that the fast trapping of the
intermediate radical with TEMPO in the cascade process
lowers the yield of 4. To remedy this problem, we tested the
bulky sodium aminoalkoxide 5 as a SET reagent for the
generation of CF3 radicals from 1 (Scheme 3). Salt 5 can be
generated from TEMPO congener 6, which in turn was
readily prepared on a large scale in analogy to the synthesis of
TEMPO.[33] C-centered radicals react with very bulky nitro-
xides significantly slower than with TEMPO.[34] Importantly,
also the undesired direct CF3-trapping reaction will be
suppressed and higher yields for radical trifluoromethylamin-
oxylation should be obtained.
We were pleased to observe that the reaction of 5 with
alkenes gave adduct yields that were generally 10 to 25%
higher than those of the analogous TEMPONa-mediated
processes (compare Table 1, Scheme 2 and Scheme 3). Hence,
trifluoromethylation of styrene with 5 afforded 7a in 93%
yield. Aliphatic unactivated alkenes underwent addition/
trapping reaction in good yields (see 7b and 7c). Benzofuran
and indene reacted with excellent diastereoselectivities (7d
Scheme 2. Diastereoselective trifluoromethylation.
evaporation. A substrate containing an aryl bromide group,
which is susceptible to reaction with transition metals, was
tolerated (3e; Table 1, entry 5). Electronic effects exerted by
the aryl substituent as judged by comparing yields were not
that pronounced in the styrene series and also 4-vinylpyridine
afforded the trifluoromethylaminoxylation product 3h in
good yield (Table 1, entry 8). Trifluoromethylation of the
pyridine ring did not occur. Pleasingly, reactions with non-
activated aliphatic terminal alkenes delivered the targeted
products 3i–m in good yields and neither the terminal
bromide (3k) nor the epoxide (3m) interfered with the
trifluoromethylation (Table 1, entries 9–13). Not surprisingly,
considering the electrophilic nature of the CF3 radical,
2
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trifluoromethylhydroxylate the steroidal allylether 10 to give
alcohol 11 in 57% overall yield.
Finally, we showed that our novel method is not restricted
to trifluoromethylation. The hypervalent-iodine reagent 12
bearing a C2F5 substituent was prepared using commercially
available TMSCF2CF3 in analogy to the synthesis of 1.[15] We
were pleased to find that 12 reacted cleanly with TEMPONa
and styrene to give the corresponding addition/trapping
product 13 in 86% yield (Scheme 5).
In conclusion, we have introduced a novel approach for
the radical trifluoromethylation of alkenes. We found that
TEMPONa, which is readily generated from commercially
available TEMPO and sodium, is a useful SET reagent for
generation of CF3 radicals from the Togni reagent 1. In these
Scheme 3. Trifluoromethylation of various alkenes with 5 and 1.
and 7e) and b-pinene underwent the addition/fragmentation/
trapping reaction to give 7 f (with TEMPONa,[35] 7 f–TEMPO
was formed in 37% yield, not shown).
Although we expect that the trifluoromethylated com-
pounds bearing the bulky TEMPO moiety will be tested in
À
medicinal chemistry, we consider the corresponding N O-
cleaved b-trifluoromethyl-substituted secondary alcohols as
À
major targets. The N O bond in alkoxyamines 3 and 7 was
Scheme 5. Pentafluoroethylation of styrene.
readily cleaved with Zn in acetic acid under mild conditions
(RT). The corresponding alcohols 8 were isolated in high
yields (89–94%, Scheme 4 and the Supporting Information).
It was also practicable to run the trifluoromethylation/
cleavage reactions without purifying the intermediate alkoxy-
amines. Examples for these two-step processes are also given
in Scheme 4. Piperidine 9 which formed during cleavage can
be recovered in high yield (up to 96%). Recovery of the
transformations TEMPONa first acts as a mild organic
reducing reagent (SET) for the generation of C radicals
along with formation of the TEMPO radical, which then acts
as an oxidant for trapping the C radicals. The in situ
generation of TEMPO ensures a low concentration of the
nitroxide during the reaction, which is the key for the
successful intermolecular addition of the CF3 radical and
TEMPO-trapping reaction. The trifluoromethylations are
easy to conduct, occur under mild conditions, and show
a broad substrate scope. Excellent diastereoselectivity was
obtained for the trifluoromethylaminoxylation of cyclic
alkenes. Product alkoxyamines can be reduced under mild
conditions to give the corresponding b-trifluoromethylated
secondary alcohols. Yields could be further improved upon
switching to a bulky nitroxide as the trapping reagent.
À
Importantly, the piperidine moiety released during N O
bond cleavage could be recovered in high yield. The method is
also applicable for pentafluoroethylation of an alkene.
Received: April 4, 2012
Published online: && &&, &&&&
Publication delayed on request of the authors.
Keywords: radicals · single-electron transfer ·
.
synthetic methods · TEMPO · trifluoromethylation
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Chemie
Communications
Trifluoromethylation
Y. Li, A. Studer*
&&&& — &&&&
Transition-Metal-Free
Trifluoromethylaminoxylation of Alkenes
No transition metal! Fluorinated hyper-
valent-iodine reagents react with TEM-
PONa in the presence of an alkene under
mild conditions to give the corresponding
perfluoroalkylaminoxylation products.
These radical addition/trapping reactions
occur with high stereoselectivity using
commercially available reagents, and the
product alkoxyamines are readily trans-
formed into the corresponding alcohols.
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