Phosphine-catalyzed remote β-C-H functionalization of amines triggered by trifluoromethylation of alkenes: One-pot synthesis of bistrifluoromethylated enamides and oxazoles

Article abstract of DOI:10.1002/anie.201412310

An unprecedented phosphine-catalyzed remote β-C-H functionalization of amine derivatives triggered by trifluoromethylation of an alkene with Togni's reagent was disclosed. This reaction proceeded through the highly selective and concomitant activation of

Full text of DOI:10.1002/anie.201412310

Angewandte
Chemie
DOI: 10.1002/anie.201412310
Radical Chemistry
À
Phosphine-Catalyzed Remote b-C H Functionalization of Amine
Triggered by Trifluoromethylation of Alkene: One-Pot Synthesis of
Bistrifluoromethylated Enamides and Oxazoles**
Peng Yu, Sheng-Cai Zheng, Ning-Yuan Yang, Bin Tan,* and Xin-Yuan Liu*
Abstract: An unprecedented phosphine-catalyzed remote b-
À
C H functionalization of amine derivatives triggered by
trifluoromethylation of an alkene with Togniꢀs reagent was
disclosed. This reaction proceeded through the highly selective
and concomitant activation of an unactivated alkene and the b-
À
Csp3 H bond of an amine derivative, providing bistrifluoro-
methylated enamides in excellent yields with good regio-,
chemo-, and stereoselectivity. Furthermore, the newly devel-
oped one-pot protocol provides a facile and step-economical
access to valuable trisubstituted 5-(trifluoromethyl)oxazoles.
Mechanistic studies showed that this reaction may initiate with
a novel phosphine-catalyzed radical trifluoromethylation of
À
Scheme 1. Catalytic functionalization of C H bonds at the b position
of amine.
unactivated alkene via a phosphorus radical cation.
À
T
he increasing importance of trifluoromethyl nitrogen-rich
precursors by employing Pd-catalyzed amine-directed C H
activation (Scheme 1a). Alternatively, Gaunt and co-workers
have championed the use of a four-membered-ring cyclo-
compounds for the synthesis of interesting pharmaceuticals
and biologically active molecules[1] has inspired considerable
À
À
effort to develop expedient methods for C CF3 bond
palladation pathway to activate the b-Csp3 H bond of amines
formation.[2] Among the most direct approaches for the
(Scheme 1a).[5f] Despite these significant achievements in the
field of transition metal catalysis, the exploration of alter-
native, mechanistically distinct catalytic systems for the b-
À
construction of C CF3 bonds is the trifluoromethylation of
alkenes by using Togniꢀs reagent as the CF3 radical source in
the presence of transition metal complexes or organic
oxidants as external initiators through a single-electron-
transfer (SET) process.[3] In our study on the trifluoromethy-
lation of alkenes,[4] we recently reported the approach of using
a radical trifluoromethylation of an olefin to trigger an
À
Csp3 H bond functionalization of amines, especially with
concomitant activation of other unactivated group and
selective installation of different functional groups into
organic compounds under metal-free conditions, has never
been reported (Scheme 1b). However, our proposed reaction
was rather challenging because of the presence of three
unactivated structures including unactivated olefin and two
À
intramolecular 1,5-H radical shift and further C O bond
formation adjacent to amide with a Cu catalyst.[4f] Based on
this mode of activation, we became interested in developing
a novel redox-neutral process involving simultaneous remote
À
a and b-Csp3 H bonds of amine and difficulties in simulta-
neously controlling the regio-, chemo-, and stereoselectivity
associated with the highly reactive CF3 radical intermediate[3]
in the current reaction system.
À
functionalization of the b-Csp3 H bond of an amine derivative
and unactivated alkene (Scheme 1b, path 1). Noteworthy is
À
that selective functionalization of the b-Csp3 H bond of
Given the established capacity of ammonium/phosphorus
radical cations to rapidly undergo a variety of reactions, which
are most generally formed in situ from simple tertiary amine/
phosphine through SET in the presence of various oxidants,[6]
we hypothesized that such compounds in combination with
Togniꢀs reagent could concurrently generate the CF3 radical
and ammonium/phosphorus radical cations through autox-
idation. To our knowledge, this mode of simple organic base
as the catalyst to activate Togniꢀs reagent via a radical cation
intermediate toward direct trifluoromethylation of unacti-
vated alkene has not been reported.[7] Herein, we describe the
first successful development of an unprecedented organo-
amines remains a formidable synthetic challenge.[5] To
address this issue, the group of Yu[5a,b] as well as other
research groups[5c–e] have elegantly demonstrated arylation,
olefination, and alkylation at the b position of amino acid
[*] P. Yu, Dr. S.-C. Zheng, N.-Y. Yang, Prof. Dr. B. Tan, Prof. Dr. X.-Y. Liu
Department of Chemistry
South University of Science and Technology of China
Shenzhen, 518055 (P.R. China)
E-mail: tanb@sustc.edu.cn
liuxy3@sustc.edu.cn
[**] Financial support from the National Natural Science Foundation of
China (grant numbers 21302088 and 21302087) and the National
Basic Research Program of China (2013CB834802) is greatly
appreciated.
À
phosphine-catalyzed remote b-Csp3 H bond functionalization
of amine derivatives triggered by trifluoromethylation of
unactivated alkenes with Togniꢀs reagent involving the
concurrent incorporation of two CF3 groups into the alkene
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201412310.
À
and the remote b-Csp3 H bond of amine in one step
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Table 1: Substrate scope of alkenyl N-ethyl-amides.[a,b,c]
(Scheme 1b, path 1). It is noteworthy that this reaction is an
advantageous alternative to the transition-metal-catalyzed b-
À
Csp3 H bond functionalization of amine derivatives assisted
by a nitrogen-based directing group.[5] Most importantly, this
transformation through a sequential phosphine-catalyzed
bistrifluoromethylation followed by intramolecular cycliza-
tion in a one-pot version, provides a convenient and step-
economical access to diverse trisubstituted 5-(trifluorome-
thyl)oxazoles (Scheme 1b, path 2); such structural motifs are
important components of various biologically active natural
products and medicinal compounds.[8]
We initiated these investigations by examining the reac-
tion of N-(1-(2-allylphenyl)ethyl)benzamide 1a with Togniꢀs
reagent 2a[3a,9] as the model reaction (Scheme 2, Table S1 in
[a] Reaction conditions: 1 (0.2 mmol), Togni’s reagent 2a (2.2 equiv),
DCE (2.0 mL) at 80–1008C for 16 h under argon. [b] Yield of the isolated
product. [c] E/Z ratio was determined by 19 F NMR spectroscopy. [d] 56 h
reaction time. Cbz=carboxybenzyl, Boc=tert-butyloxycarbonyl.
Scheme 2. Initially investigated catalysts and CF3 sources.
use of alkyl groups at the a position of amides did not affect
the product yield and E/Z selectivity. Several substituents,
such as methyl (1o), n-propyl (1p), and tert-butyl (1q) as the
alkyl moiety were well-tolerated. Even 2-chloro-acetamide
remained intact in the reaction and the product 3r was
obtained in 88% yield as a 6:1 mixture of E/Z isomers. The
configuration of 3r was determined to be E by X-ray analysis
(Figure S1).[10] A variety of functional groups including Cbz
(1s) and Boc (1t) were also found to be compatible with the
current reaction system, affording 3s and 3t in 83% and 89%
yield, respectively, with excellent E/Z selectivity. Further-
more, when alkenyl N-n-propyl-amide 1u was used as
substrate, the product 3u was obtained in 72% yield with
1.7:1 E/Z ratio.
Trisubstituted 5-(trifluoromethyl)oxazoles have been
used as important building blocks in pharmaceutically and
agrochemically relevant molecules.[8] However, convergent
one-step or one-pot methods to prepare such skeletons are
rare, and often require the use of highly reactive species or
2,4-disubstituted oxazole precursors with consequent struc-
tural limitations.[8e,f] We reasoned that oxidative cyclization of
trifluoromethyl enamides 3 with an appropriate oxidant may
afford polysubstituted oxazoles.[11] To further simplify the
reaction protocol, we investigated the possibility of the
combination of two distinct reaction sequences to a one-pot
process with minimal extra procedures. After systematic
optimization of different reaction parameters, including
oxidant, additive, solvent, and temperature (Table S2),
a simple one-pot procedure was realized. Compound 1a was
efficiently converted into 3a in the presence of dppBz (P3)
(10 mol%) in DCM under otherwise identical conditions,
followed by an oxidative cyclization with [bis(trifluoroacet-
the Supporting Information). The use of DABCO as the
catalyst in EtOAc promoted the sequential unactivated
À
alkene/remote b-Csp3 H bond difunctionalization reaction of
1a to afford the bistrifluoromethylated product 3a in 71%
yield as a 6:1 mixture of E/Z isomers (Table S1, entry 1).
Based on these findings, we also screened other tertiary
amines and organic solvents and found that DABCO as the
catalyst in dichloroethane (DCE) gave the best result with
93% yield as a 3:1 mixture of E/Z isomers. To further improve
the E/Z selectivity, we changed the tertiary amines to various
phosphines as the catalyst and found that the use of 10 mol%
of bisphosphine such as 1,2-bis(diphenylphosphino)benzene
(dppBz) (P3) under otherwise identical conditions resulted in
a significantly increased E/Z selectivity of up to 17:1 with
88% yield. Notably, a control experiment demonstrated that
the reaction did not occur in the absence of organocatalyst
under the standard conditions.
We next investigated the substrate scope of alkenyl N-
ethyl-amide with diverse substituents (Table 1). A variety of
substrates 1b–1g, bearing electron-donating or electron-
withdrawing groups on the aryl ring at the a position of the
amide group consistently afforded 3b–3g in good yields with
good E/Z selectivity. The introduction of a naphthyl or thienyl
group was compatible with this protocol to form 3h or 3i in
65% yield with excellent E/Z selectivity. In addition, sub-
stituents including methyl (1j, 1k), fluoro (1l), and chloro
(1m) groups at the different positions were compatible to
afford 3j–3m in 80–89% yield with excellent E/Z selectivity.
Further studies show that the geminal-disubstituted alkene 1n
also underwent this reaction to furnish the corresponding
product 3n in 98% yield with 7:1 E/Z ratio. Interestingly, the
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Table 2: Reaction scope.[a]
intermediate. Furthermore, we also performed electrospray
ionization mass spectroscopic analysis (ESI-MS) of a solution
of PPh3 and 2a in a 1:1 ratio in DCE under air. The spectrum
(Figure S3) shows the characteristic signals corresponding to
P(O)Ph3 at m/z 279.0974 ([P(O)Ph3 + H]+) as well as the 2-
iodobenzoate ion at m/z 246.9130, suggesting that Togniꢀs
reagent 2a can oxidize the tertiary phosphine under the
reaction conditions. Additionally, to validate the original
design of the present radical tandem process involving
a phosphine-initiated single-electron transfer, radical trap-
ping experiments were also conducted by employing 2,6-di-
tert-butyl-4-methylphenol (BHT), benzoquinone (BQ), and
1,4-dinitrobenzene. The reaction could be significantly inhib-
ited by these reagents, suggesting that a SET process is
involved in this reaction (Scheme 3).
Entry
R
X
Product
Yield [%][b]
1
2
3
4
5
6
Ph
H
H
H
H
H
Me
Cl
H
H
4a
4b
4 f
4h
4i
4k
4m
4o
4r
73
76
63
46
78
70
60
66
74
4-MeOC6H4
4-BrC6H4
1-naphthyl
2-thienyl
Ph
Ph
Me
ClCH2
7[c]
8[d]
9
[a] Reaction conditions: 1 (0.1 mmol), 2a (2.2 equiv), P3 (10 mol%),
808C; PIFA (2.2 equiv) was added after first step. [b] Yield of the isolated
product. [c] The reaction temperature was 408C for the second step.
[d] PIFA (5.0 equiv) was added in two portions in the second step for
24 h at 608C.
oxy)iodo]benzene] (PIFA) at room temperature to afford 4a
in 73% yield (Table 2, entry 1). A series of substrates
containing electron-donating, or -withdrawing aryl groups
(naphthyl, thienyl, alkyl) at the a position of the amide group,
and even those containing different functional groups on the
aryl rings were well tolerated to afford 4a–4r in 46–78%
yields (Table 2). It is encouraging to note that the present
process is a rather general protocol for the one-pot synthesis
of trisubstituted oxazoles from simple alkenyl N-ethyl-amides
through simultaneous functionalization of three sequential
Scheme 3. Radical trapping experiments.
With regard to a 1,5-H radical shift, the reaction of
deuterium-substituted [D1]-1a was performed under the
standard conditions and the deuterium at the carbon adjacent
to the nitrogen atom completely shifted to the b position of
the alkene in [D1]-3a [Eq. (2), Scheme 4]. Next, a crossover
experiment involving equimolar amounts of [D1]-1a and 1o
showed no incorporation in [D1]-1a and 1o [Eq. (3)]. These
À
À
À
Csp2 H, Csp3 H, and Csp2 H bonds and selective installation of
different functional groups with remarkable precision under
metal-free conditions, which is clearly complementary to the
previous oxidative cyclization of enamides.[11]
To further evaluate the practicality of such process, the
reaction was carried out on a gram scale. There was almost no
influence on the chemical yield (81% yield) [Eq. (1)],
indicating this protocol should be potential for large-scale
chemical production of trisubstituted 5-(trifluoromethyl)ox-
azoles.
To gain more insights into the reaction mechanism,
a series of control experiments was performed. Initially,
31P NMR analysis showed a remarkable downfield shift after
the interaction of dppBz (P3) and Togniꢀs reagent 2a in a 1:10
ratio at 808C for 16 h (Figure S2c). By comparison, the
sample containing P3 and substrate 1a showed no chemical
shift as compared with that of P3 (Figure S2b). These results
clearly indicated that the phosphine catalyst possibly would
not provide significant activation of unactivated alkenes, but
only activate Togniꢀs reagent to generate the CF3 radical
Scheme 4. Control experiments and proposed mechanism.
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results indicated that the current reaction proceeded with an
intramolecular 1,5-H radical shift process. To further inves-
tigate the reaction mechanism in detail, we examined the
reaction of 1a with 2.2 equiv of 2a at 808C for 6 h, which
could afford enamide 5 in 16% yield along with most of 1a
recovered. Subsequent reaction of 5 with 2a with P3 catalyst
gave the final product in 98% yield [Eq. (4)],[12] which clearly
indicated that the reaction should proceed via an intermedi-
ate enamide.
On the basis of the results described above and previous
studies,[4f] a proposed pathway is depicted in Scheme 4.
Initially, the use of phosphine as a SET reagent for the
reduction of 2a would generate the corresponding phospho-
rus radical cation and CF3 radical. The CF3 radical attacks
alkene 1a affording a nascent a-CF3-alkyl radical intermedi-
ate A, followed by 1,5-H radical shift to generate a lower
energy amide-stabilized radical B, with subsequent single-
electron oxidation from 2a and deprotonation, to simulta-
neously afford enamide intermediate 5 and CF3 radical. Next,
the attack of enamide 5 with the CF3 radical generates
intermediate C, followed by single-electron oxidation from
the phosphorus radical cation and then deprotonation, to give
3a. However, phosphine as the dual catalyst to initiate two
distinct catalytic cycles including the formation of enamide 5
through a 1,5-H radical shift triggered by trifluoromethylation
of alkene and of the resultant enamide 5[12] under the current
reaction conditions, could not be excluded at the present
stage. Therefore, rigorous investigations are necessary to
unambiguously elucidate the exact mechanism.
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In summary, we have developed the first phosphine-
catalyzed tandem radical process enabling the highly selective
and concomitant functionalization of alkene and the remote
À
b-Csp3 H bond of amine derivatives, which provides facile
access to bistrifluoromethylated enamides in excellent yields
with good regio-, chemo-, and stereoselectivity under mild
and metal-free conditions. Furthermore, the newly developed
one-pot protocol from alkenyl N-ethyl-amides by simulta-
À
À
neous functionalization of three sequential Csp2 H, Csp3 H,
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À
and Csp2 H bonds provides a facile and step-economical
access to valuable trisubstituted 5-(trifluoromethyl)oxazoles,
thus demonstrating great potential in synthetic and medicinal
chemistry.
Received: December 23, 2014
Published online: && &&, &&&&
Keywords: 1,5-H radical shift · alkenes · radical chemistry ·
.
À
trifluoromethylation · b-C H functionalization
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Communications
Radical Chemistry
P. Yu, S.-C. Zheng, N.-Y. Yang, B. Tan,*
X.-Y. Liu*
&&&& — &&&&
À
Phosphine-Catalyzed Remote b-C H
Functionalization of Amine Triggered by
Trifluoromethylation of Alkene: One-Pot
Synthesis of Bistrifluoromethylated
Enamides and Oxazoles
The radical tandem functionalization of
unactivated alkenes and the remote b-
pot protocol provides facile access to
bistrifluoromethylated enamides as well
as trisubstituted 5-(trifluoromethyl)oxa-
zoles.
À
Csp3 H bond of amine derivatives is
achieved by phosphine catalysis. The one-
6
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Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!