Copper-catalyzed intramolecular trifluoromethylation of N -benzylacrylamides coupled with dearomatization: Access to CF 3-containing 2-azaspiro[4.5]decanes

Article abstract of DOI:10.1021/ol501054c

Copper-catalyzed intramolecular trifluoromethylation of N-benzylacrylamides coupled with dearomatization was achieved and used to regiospecifically construct a variety of trifluoromethylated 2-azaspiro[4.5]decanes bearing adjacent quaternary stereocenters under mild conditions in moderate to excellent yields.

Full text of DOI:10.1021/ol501054c

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Intramolecular Trifluoromethylation of
N‑Benzylacrylamides Coupled with Dearomatization: Access to
CF3‑Containing 2‑Azaspiro[4.5]decanes
Guifang Han, Yuxiu Liu, and Qingmin Wang*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Collaborative Innovation
Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: Copper-catalyzed intramolecular trifluorome-
thylation of N-benzylacrylamides coupled with dearomatiza-
tion was achieved and used to regiospecifically construct a
variety of trifluoromethylated 2-azaspiro[4.5]decanes bearing
adjacent quaternary stereocenters under mild conditions in
moderate to excellent yields.
Scheme 1. Metal-Catalyzed Trifluoromethylation of Alkenes
he trifluoromethyl group is of interest in pharmaceutical
T
chemistry, agrochemistry, and materials science because
introducing a trifluoromethyl group to small organic molecules
can dramatically enhance chemical and metabolic stability, as
well as lipophilicity.1 Thus, the development of efficient methods
for selectively introducing a trifluoromethyl group into organic
molecules is a hot topic in modern organic chemistry.2
Transition-metal-mediated direct difunctionalization of alkenes
involving the simultaneous formation of C−CF3 and C−O, C−
N, or C−C bonds was recently reported to be effective for the
construction of polyfunctional molecules.3−5 For example,
catalytic electrophilic allylic trifluoromethylation of terminal
alkenes has been reported,6 and an intramolecular oxy-
trifluoromethylation that yields trifluoromethylated epoxides,
cyclic ethers, and lactones has been elaborated.3d,4b The Wu,5d
Sodeoka,5g and Tu5e research groups independently demon-
strated that Cu(I) and Fe(II) catalyze carbotrifluoromethylation
of α,α-diaryl allylic alcohols via trifluoromethylation coupled
with 1,2-aryl migration to afford β-trifluoromethyl ketones. Cu/
Pd-catalyzed aryltrifluoromethylation of terminal alkenes with
Togni’s reagent as the CF3 source yields compounds with
conjugated rings as the main product.5 Meanwhile, the Nevado
group reported the metal-free catalytic aryltrifluoromethylation
of activated alkenes to achieve trifluoromethylated isoquinoline-
diones, spirobicycles, oxindoles, and α-aryl-β-trifluoromethyla-
mides with high regioselectivity.5k The trifluoromethyl cation or
a radical species has been suggested as an intermediate, but the
detailed mechanisms of these reactions have not been elucidated.
Dearomatization reactions provide a powerful strategy for the
synthesis of ring systems from readily available aromatic
compounds.7 The dearomatization of phenols to cyclohexadie-
nones is of particular interest, and numerous such dearomatiza-
tions have been used in complex total syntheses.8 For example,
Pettus9 reported the first total synthesis of (+)-rishirilide B by
dearomatization of resorcinol derivatives, and Nicolaou10
synthesized (−)-platensimycin through oxidative dearomatiza-
tion of a phenolic substrate with concomitant C−C bond
formation. Research on the synthesis of spirocyclic frameworks,
which are found in a wide variety of biologically active natural
products and pharmaceuticals, is ongoing in our laboratory, and
the spirocyclic framework could be obtained by trifluoromethy-
lation of a benzyl-substituted alkene coupled with C−C bond
formation when a hydroxyl group or methoxy group was present
at the para position of the aromatic ring,5k despite the existence
of a pathway to afford the conjugated ring product or other
byproducts.11 Herein, we describe copper-catalyzed intra-
molecular trifluoromethylation of N-benzylacrylamides coupled
with dearomatization in the presence of Togni’s reagent (Scheme
1).
We optimized the reaction conditions using N-(4-hydroxy)-
benzylacrylamide (2a)12 as a model substrate (Table 1). We
Received: April 10, 2014
Published: June 5, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/ol501054c | Org. Lett. 2014, 16, 3188−3191

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope of Copper-Catalyzed
Trifluoromethylation/Dearomatization
a
b
entry
catalyst
ligand
solvent
yield (%)
1
CuI
CuI
1,4-dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1,4-dioxane
DCE
20
65
0
2
Bipy
Bipy
Bipy
Bipy
Bipy
Bipy
3
4
CuCl
52
75
61
5
[Cu(MeCN)4]PF6
Cu(OAc)2
CuBr
6
c
7
92 (85)
8
CuBr
93
72
91
87
72
95
99
9
CuBr
10
11
12
13
14
CuBr
d
CuBr
CHCl3
CuBr
DMF
CuBr
EtOH
DMSO
CuBr
a
Reaction conditions: 2a (0.2 mmol), 1 (0.4 mmol), catalyst (0.02
mmol), ligand (0.02 mmol), solvent (2 mL), 80 °C, 24 h, under N2.
b
Determined by 19F NMR analysis with (trifluoromethyl)benzene as
c
an internal standard. The value in parentheses was isolated yield.
d
Reaction temperature, 60 °C. Bipy = 2,2′-bipyridyl.
initially examined the reaction of 2a with Togni’s reagent (1) as
the source of CF3 and CuI as the catalyst and found that reaction
in 1,4-dioxane at 80 °C afforded the desired trifluoromethyl-
containing product, 2-azaspiro[4.5]decane 3a, in 20% yield as
determined by 19F NMR spectroscopy (entry 1). Encouraged by
this result, we investigated whether the yield could be improved
by addition of a ligand; fortunately, we found that the addition of
2,2′-bipyridyl and the use of CH3CN as the solvent increased the
yield to 65% (entry 2). The copper catalyst was essential; no
reaction occurred in the absence of CuI (compare entries 2 and
3). Various copper catalysts were then evaluated. The use of
CuCl, [Cu(MeCN)4]PF6, or Cu(OAc)2 lowered the yield
(entries 4−6), whereas CuBr gave 3a in 92% yield as indicated
by 19F NMR (isolated yield, 85%; entry 7). With the ideal copper
catalyst in hand, we discovered that a ligand was unnecessary for
the high yield (entry 8). We then screened various organic
solvents in reactions without a ligand and found that the solvent
did not strongly influence the yield: reactions in 1,4-dioxane,
DCE, CHCl3, DMF, and EtOH all gave satisfactory yields
(entries 9−13). When the reaction was conducted in DMSO, the
starting material was completely converted after 24 h at 80 °C,
and the yield of the desired product was nearly quantitative
(entry 14).
Using the optimized reaction conditions (Table 1, entry 14),
we investigated the substrate scope with a wide range of
substituted N-benzylacrylamides (Scheme 2). First we focused
on the N-substituent (R2). Substrates with n-butyl and cyclohexyl
substituents, more bulky isopropyl and tert-butyl substituents,
and even a 1-adamantanyl substituent, all afforded the
corresponding 2-azaspiro[4.5]decanes 3a−e in excellent yields.
Substrate 2f, which was substituted with the methyl ester of
glycine, cyclized efficiently to give 3f in 85% yield. When R2 was a
benzyl group, there were two aromatic rings in the substrate; we
nevertheless obtained 3g exclusively, which indicates that the
phenolic hydroxyl group is essential for the spiro cyclization. The
structure of 3g could be unequivocally assigned by X-ray
a
Reactions were carried out with CuBr (10 mol %) and 1 (2 equiv) in
degassed DMSO at 80 °C under N2. Isolated yields are provided.
diffraction analysis.13 When R2 was a phenyl group, desired
product 3h was obtained in 50% yield, along with a 10% yield of
conjugated-ring byproduct 3h′; this result provided some insight
into the reaction mechanism. Next, we turned our attention to
the substituents on the aromatic ring (R1). Substrates with
electron-donating CH3 and OMe groups or electron-with-
drawing F, Cl, or Br atoms afforded desired products 3i−n in
good to excellent yields. When the substituents were
axisymmetric with respect to the phenolic hydroxyl group,
corresponding 2-azaspiro[4.5]decanes 3i−k were obtained
exclusively; nonaxisymmetric substrates gave pairs of diaster-
eomers in an approximately 1:1 ratio. When the phenol was
replaced with a naphthol, the desired product 3o was also
obtained as two diastereomers in 55% yield. Finally, we
investigated the reaction of a monosubstituted olefin (R3 = H),
which was previously reported not to undergo reaction leading to
the conjugated-ring product;5 however, we obtained desired
product 3p in 81% yield, and its structure was unequivocally
determined by X-ray diffraction analysis.13 Expecting carbotri-
fluoromethylation and subsequent formation of a six-membered
ring, we subjected 2q to the standard reaction conditions, but
unfortunately, the expected product 3q was not detected by 19
NMR.
To further explore the applications of this reaction system, we
extended it to stable, easy-to-prepare substrates with various
substituents (R4) on the phenol O atom (Table 2). As expected,
even when the phenol O atom was masked with a methyl group
F
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Organic Letters
Letter
Table 2. Copper-Catalyzed Trifluoromethylation/
Dearomatization of Substrates with Masked Phenol Groups
Scheme 3. Mechanistic Investigation
a
addition of 200 mol % of TEMPO (Scheme 3a). Similar results
were obtained with BHT (Scheme 3b). These results clearly
point toward a radical mechanism. However, when the reaction
in the presence of TEMPO was followed by 19F NMR, the
corresponding TEMPO−CF3 adduct was not detected, which
suggests that some species other than CF3 radical might form at
the outset of the process. In addition, when R2 was Ph (Scheme
2), the reaction gaves pirocyclic product 3h and the conjugated-
ring product 3h′, which suggests that the two products maybe
form from the same intermediate during the initial stage of the
reaction.
On the basis of these results and previously reported
results,3−5 we propose the mechanism illustrated in Scheme 4.
Scheme 4. Proposed Reaction Mechanism
a
Reactions were carried out with CuBr (10 mol %) and 1 (2 equiv) in
degassed EtOH at 80 °C under N2. Isolated yields are provided.
(substrate 2r), the tandem cyclization occurred and afforded
spirocyclic product 3b in 63% yield rather than the conjugated-
ring product (isoquinolinone, entry 1). Note that the reaction
was carried out in EtOH rather than DMSO because complete
conversion took longer in DMSO. Even monosubstituted olefin
2s (R3 = H) furnished corresponding product 3s in moderate
yield (entry 2). Substrates 2t, 2u, and 2v, which bear
triphenylmethyl, tert-butyldimethylsilyl, and acetyl protecting
groups respectively, were good substrates, affording spirocyclic
compounds in moderate to excellent yields (entries 3−5).
Substrate 2w, which bears an electron-donating OMe group at
the ortho position of the aromatic ring, afforded 3w in 75% yield
as a 1:2 mixture of diastereomers (entry 6). However, 2x which
has an electron-withdrawing nitro group, gave unsatisfactory
results (entry 7).
To gain insight into the reaction mechanism, we performed
several control experiments. The trifluoromethylation reaction of
1 and 2a was conducted under the standard conditions in the
presence of various amounts of a radical scavenger, either 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) or 2,6-di-tert-butyl-4-
methylphenol (BHT). In the presence of 50 mol % of TEMPO,
the yield of 3a dropped to 79% as determined by 19F NMR. In the
presence of 100 mol % of TEMPO, the yield decreased further to
41%, and the reaction was almost completely shut down by the
In the first step, Cu(I) reacts with 1 to generate highly reactive
CF3Cu(II)-containing radical I, which reacts with 2 to form a
radical species with a C(sp3)−CF3 bond (II). The carbon-
centered radical undergoes thermodynamically controlled 5-exo
cyclization onto the phenol ring to give spiro intermediate III,5k
rather than a 6-endo cyclization leading to the isoquinolinone.14
Radical III is then oxidized by Cu(II) to oxonium ion IV or the
corresponding protonated species. Oxonium ion IV is trans-
formed into 3 either in the reaction medium or during workup,
and Cu(I) is released to participate in the next reaction cycle.
When R2 is Ph, there is an alternative pathway: radical II-h may
undergo 5-endo cyclization, oxidation, and deprotonation to give
oxindole VI (e.g., 3h′). The possibility of the mechanism to
proceed via a nucleophilic attack of electron-rich aryl ring to
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Organic Letters
Letter
(c) Yasu, Y.; Koike, T.; Akita, M. Org. Lett. 2013, 15, 2136. (d) Lin, J. S.;
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acrylamide involved carbocation intermediate to afford 3h′
cannot be excluded.5b,c,k
In summary, we developed a copper-catalyzed cascade
reaction involving trifluoromethylation of substituted N-
benzylacrylamides, 5-exo cyclization, and dearomatization. This
reaction allows regiospecific construction of trifluoromethylated
spirocyclohexadienones bearing adjacent quaternary stereo-
centers under mild conditions in good to excellent yields.
Because of the wide substrate scope and operational simplicity,
this reaction should be useful for medicinal chemistry and other
applications. We are working on developing an asymmetric
variant in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures, copies of H 13C and 19F
■
S
1
NMR spectra for compounds 2a−x, 3a−q, 3h′, 3s, and 3w. This
material is available free of charge via the Internet at http://pubs.
acs.org.
(6) (a) Parsons, A. T.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50,
9120. (b) Shimizu, R.; Egami, H.; Hamashima, Y.; Sodeoka, M. Angew.
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K. M.; Verhoog, S.; Wheelhouse, K.; Rassias, G.; Gouverneur, V.
Chem.Eur. J. 2012, 18, 8583. (d) Xu, J.; Fu, Y.; Luo, D. F.; Jiang, Y. Y.;
Xiao, B.; Liu, Z. J.; Gong, T. J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 15300.
(e) Wang, X.; Ye, Y. X.; Zhang, S. N.; Feng, J. J.; Xu, Y.; Zhang, Y.; Wang,
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wangqm@nankai.edu.cn, wang98@263.net.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(7) (a) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123.
We are grateful to the National Key Project for Basic Research
(2010CB126100), the National Natural Science Foundation of
China (21132003, 21121002, 21372131), and the Specialized
Research Fund for the Doctoral Program of Higher Education
(20130031110017) for generous financial support for our
programs.
(b) Pape, A. P.; Kaliappan, K. P.; Kundig, E. P. Chem. Rev. 2000, 100,
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2917. (c) Ortiz, F. L.; Iglesias, M. J.; Fernan
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dez, I.; Sanchez, C. M.;
Gomez, G. R. Chem. Rev. 2007, 107, 1580. (d) Rousseaux, S.; García-
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(12) For detailed experimental procedures and characterization of
starting materials, see the Supporting Information.
(13) CCDC 982991 (3g) and CCDC 982990 (3p) contain
supplementary crystallographic data for this paper. These data can be
free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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