Catalyst-free and selective trifluoromethylative cyclization of acryloanilides using PhICF3Cl

Article abstract of DOI:10.1039/c9ob00601j

Trifluoromethylation-triggered cyclization of alkenes provides a useful route to CF₃-containing cyclic compounds. Current approaches to generate CF₃-based initiators from a CF₃ source require a catalyst or an activator. This work describes a catalyst-free protocol to innately produce electrophilic CF₃ species from PhICF₃Cl for trifluoromethylative cyclization of acryloanilides. A new domino biscyclization of dienes has been developed leading to trifluoroethylated tetrahydroindenoquinolinones with chemo- and stereo-selectivity.

Full text of DOI:10.1039/c9ob00601j

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DOI: 10.1039/C9OB00601J
ARTICLE
Catalyst-Free and Selective Trifluoromethylative Cyclizations of
Acryloanilides Using PhICF3Cl
Jia Guo,†a Cong Xu,†b Ling Wang,a Wanqiao Huang,a and Mang Wang*a
Received 00th January 20xx,
Accepted 00th January 20xx
Trifluoromethylation-triggered cyclization of alkenes provides a useful route to CF3-containing cyclic compounds. Current
approaches to generate CF3-based initiator from a CF3 source require a catalyst or an activator. This work describes a catalyst-
free protocol to innately produce electrophilic CF3 species from PhICF3Cl for trifluoromethylative cyclizations of
DOI: 10.1039/x0xx00000x
acryloanilides.
A new domino biscyclization of dienes has been developed leading to trifluoroethylated
tetrahydroindenoquinolinones in chemo- and stereo-selectivity.
A. previous work
Trifluoromethyl group is
a
privileged structure in
pharmaceuticals, agrochemicals, and specialty materials.1
Contrastingly, it is extremely absent in nature. The rich and
profound impact aroused by the presence of CF3 fragment have
inspired persistent and intensive efforts to artificially synthesize
CF3-containing molecules.2 In fact, the efficient introduction of
CF3 group into organic frameworks still challenges this field
though a large number of catalytic trifluoromethylation
reactions have been developed. In view of the practicability,
mild and catalyst-free trifluoromethylation methods would be a
synthetically enabling strategy that would dramatically simplify
access to trifluoromethylated compounds.
CF3
CF3 source
O
catalyst or initiator
N
O
N
new and selective cyclization
B. this work
innate, mild, and catalyst-free process
F3C
PhICF3Cl
N
O
CF3
DMF, 50-60 o
C
,
O
N
O
N
Trifluoromethylation-triggered cyclization of alkenes2d-g,3,4 is
a very valuable transformation for accessing CF3-containing
cyclic compounds, which have potential use in developing new
drug candidates and biological probes. Many kinds of
trifluoromethylating reagents have been well utilized for such
cyclizations,3,4 among which trifluoromethylative cyclization of
acryloanilides is an important representative (Scheme 1A).
Togni’s reagents3 is the most widely used CF3 source, which is
generally reduced by a Cu catalyst or a photocatalyst to produce
a CF3 radical for the reaction.2b,2f-g,3a-n Comparatively, the ionic
pathway has been seldom reported, while it has also been
proposed to release an electrophilic CF3 species by the
activation of copper salt or nBu4NI for the cyclizations of
alkenes.3o-r
Scheme 1. Trifluoromethylation-triggered cyclization of
acryloanilides.
In the field of fluorine chemistry, the extreme challenges in
the preparation of unstable aryltrifluoromethyl λ3 -iodanes
(ArICF3X)
have
hindered
their
applications
as
trifluoromethylating agents.5a-d Recently, we prepared PhICF3Cl
by a direct ligand exchange reaction of PhI(OCOCF3)2 , TMSCF3,
and NaCl for the first time6a since 1978 when such kinds of
compounds were defined as fundamentally electrophilic
perfluoroalkylating reagents.5a Compared with neutral and
intramolecularly coordinated CF3-hypervalent iodanes, which
have been developed by Togni’ group afterwards,2b,5e-g
noncyclic PhICF3Cl has been proved to have an iodonium-like
character, which results in an enhanced CF3-transfer ability in a
range of trifluoromethylation reactions.6,7 Taking into
consideration of unique electrophilicity of PhICF3Cl, and of the
important applications of electrophilic cyclizations in
cyclofunctionalizations of alkenes,8 we envisioned an innate
trifluoromethylation-carbocyclization of alkenes by using
PhICF3Cl as the electrophile (Scheme 1B). Herein, we report a
set of catalyst-free trifluoromethylation-cyclizations, in which
all tested acryloanilides are compatible with the catalyst-free
conditions to furnish cyclic compounds bearing a trifluoroethyl
group efficiently. It is noteworthy that a novel bicyclization
a. Address here. Jilin Province Key Laboratory of Organic Functional Molecular
Design & Synthesis, College of Chemistry, Northeast Normal University, 5268
Renmin Street, Changchun (China).
*E-mail: wangm452@nenu.edu.cn
b. National Engineering Laboratory for Druggable Gene and Protein Screening,
School of Life Sciences, Northeast Normal University, 2555 Jingyue Street,
Changchun (China).
† Jia Guo and Cong Xu contributed equally to this work.
Electronic
Supplementary
Information
(ESI)
available:
See
DOI: 10.1039/x0xx00000x
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reaction has been found to afford trifluoroethylated this cyclization could also tolerate other R3 substituent,
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DOI: 10.1039/C9OB00601J
hydroindenoquinolinone derivatives in high chemo- and stereo- including phenyl, hydroxymethyl, acetoxymethyl, and
selectivity when using diene substrates. Obviously, it is the use phthalimidomethyl group. 2u−w were obtained in relatively
of powerful trifluoromethylating agent that allows efficient and lower yields likely due to the steric hindrance of large R3. By
mild trifluoromethylation-triggered cascades.
comparison, our method could not be applied to acryloanilide
with no R3 substituent.
R3
R3
As described above,
a
catalyst-free intramolecular
CF3
DMF, N2
50 oC, 12 h
R1
aryltrifluoromethylation of acryloanilides has been developed
for the first time by using PhICF3Cl as the CF3 reagent.
Encouraged by the easy achievements in trifluoromethylative
cyclization process, we further tested diene substrates 3 with
the aim of making comparison of the reactivity of two olefinic
bonds toward the electrophilic activation of PhICF3Cl. Thus, 3a
+ PhICF3Cl
R1
O
N
O
N
R2
R2
1
2
2a, R1 = H, 87% (98%)
2b,R1 = Me, 82% (96%)
2c,R1 = OMe, 81% (98%)
2d, R1 = F, 91%
2f, R1 = Br, 89%
2g, R1 = I, 87%
2h, R1 = CF3, 82%
2i, R1 = CN, 86% (98%)
2j, R1 = NO2, 70%
R1
CF3
O
N
o
was first treated with PhICF3Cl in DMF at 60 C (Scheme 3).
2e, R1 = Cl, 89%
Interestingly, the reaction worked well and a biscyclization
product, tetrahydroindenoquinolin-6-one 4a, which was
resulted from the preferential activation of styrene olefin bond
by PhICF3Cl at the beginning of the biscyclization, was isolated
in 81% yield. By comparison, the reaction of 3a with Togni II in
CF3
CF3
CF3
O
O
O
+
N
N
N
R1
2k
2k'
2l, R1 = Me, 72%
2m, R1 = Cl, 81%
2k + 2k', 87% (99%, 2k:2k' = 1:2)b
o
DMF at 60 C gave no any product after 12 h. Notably, 4a was
CF3
identified by the X-ray analysis as the syn-6a,11b-disusbtituted
isomer (Figure 1).10
CF3
CF3
O
O
O
N
N
N
Cl
O
O
R2
R1
R2
R1
2o, 81%
2n, 82%
2p, 91%
N
N
R3
DMF, N2
+
PhICF3Cl
Ar2
CF3
60 oC, 12 h
CF3
Ar1
Ar1
CF3
O
O
CF3
O
N
R2
N
N
3
(+/-)-4
2q, R2 = Et, 89%
2r, R2 = Bn, 78%
2s, R2 = Ph, 82%
2u, R3 = HOCH2, 75%
2v, R3 = AcOCH2, 67%
2w, R3 = PhthNCH2, 71%
O
O
O
2t, 40% (60%)
N
N
N
Scheme 2. Catalyst-free trifluoromethylation-acryloanilides. 1
(0.3 mmol), PhICF3Cl (0.45 mmol), DMF (3 mL). Isolated yields.
Yields in brackets are 19F NMR yields using PhCF3 as an internal
R
R
CF3
CF3
CF3
R
(+/-)-4a, R = H, 81% (90%)
(+/-)-4b, R = Me, 84%
(+/-)-4c, R = F, 70%
(+/-)-4e, R = H, 75%
(+/-)-4f, R = Me, 90%
b
standard. The ratio of 2k to 2k was determined by 19F NMR
(+/-)-4g, R = Cl, 51%
(+/-)-4h, R = NO2, 50%
spectroscopy.
(+/-)-4d, R = Br, 72%
O
O
R2
O
N
R1
At first, we examined the electrophilic cyclization of N-
methyl-N-phenylmethacrylamide (1a) using PhICF3Cl as the
electrophile (For screening of reaction conditions, see SI). As
presented in Scheme 2, the desired cyclization product 2a was
N
N
CF3
CF3
F
F3C
(+/-)-4j, R1 = Et, 85%
(+/-)-4k, R1 = nBu, 84%
(+/-)-4l, R1 = Bn, 65%
(+/-)-4m, R2 = CH2OAc, 75%
(+/-)-4n, R2 = CH2OMe, 85%
(+/-)-4o + 5, R2 = H,
o
finally isolated in 87% yield using DMF as the solvent at 50 C
Cl
(+/-)-4i, 45%
under N2. Indeed, the process indicates a very facile route to
CF3-substituted oxindoles, which are important in natural
products and biologically active compounds.9 Thus, we
documented the scope of acryloanilide substrates. It was found
that all tested 1 bearing alkyl, alkoxy, halo, trifluoromethyl,
cyano, and nitro at the different positions of the arene ring
performed well in this intramelocularly catalyst-free
trifluoromethylation-arylation (2b−o). Among them, 1k
afforded an isomeric mixture of 2k and 2k as the products. By
comparison, 1j with a strong electron-withdrawing nitro
substituent gave 2j in a relatively lower yield. When 1p−s with
different N-substituent were tested, 2p−s were also obtained in
high yields. However, the reaction of acryloanilide with free NH
did not give the desired product and the substrate was
recovered in ~90% yield after 12 h. Additionally, we found that
28% (37%) + 30% (42%)
Scheme 3. Catalyst-free trifluoromethylation-biscyclizations of
dienes. 3 (0.3 mmol), PhICF3Cl (0.45 mmol), DMF (3 mL).
Isolated yields. Yields in brackets are 19F NMR yields using PhCF3
as an internal standard.
Figure 1. X-ray structure of (+/-)-syn-4a.
2 | J. Name., 2012, 00, 1-3
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ARTICLE
JOURNAL NAME
Evoked by this fascinating serendipity, we expanded the investigation and a radical cation pathway (see SI) can’t be ruled
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scope of such chemo- and stereo-selective domino cyclization out at this time, based on current expDeOriIm: 1e0n.1t0a3l9/rCe9sOuBlt0s06a0n1dJ
for facile constructions of interesting CF3-containing tetracyclic reference,13 we prefer an ionic process including the activation
compounds.11b Thus, a series of N-(2-vinylphenyl)acrylamides 3 of the olefin bond by PhICF3Cl and the exo-cyclization via an
were synthesized toward the catalyst-free condition. As shown attack of the aryl substituent (see SI).
in Scheme 3, most tested reactions were complete in 12 h
affording (+/-)-syn-4a−n in good yields with well control of both
chemoselectivity and stereoselectivity. The electronic
additive
3a
+
PhICF3Cl
(+/-)-syn-4a
+
N
DMF, 60 oC, 12 h
properties and steric effect of the substituents on the aromatic
rings of 3 have effects on the transformations. 3 with different
N-R1 were suitable substrates to provide the corresponding (+/-
)-syn-4j−l in comparably good results. It should be pointed out
that the R2 was not confined to the methyl group, and the
acetoxymethyl and methoxymethyl group could also be
tolerated to give (+/-)-syn-4m and (+/-)-syn-4n respectively.
However, when amide 3 with phenyl as the R2 substituent was
treated with PhICF3Cl, large amide substrate was recovered
OCF3
TEMPO-CF3
entry additive equiv yield of (+/-)-syn-4a TEMPO-CF3
1
2
3
--
--
90%
90%
57%
--
--
0
BHT
1.5
TEMPO 1.5
Scheme 5. Mechanism studies with radical scavenger. 3a (0.2
mmol), PhICF3Cl (0.3 mmol), DMF (2 mL). 19F NMR yields using
PhCF3 as an internal standard.
along with
a small amount of unidentified mixture.
Comparatively, when 3o without R2 substituent was tested, the
reaction afforded two products in almost equal amounts. One
was the desired cyclization product (+/-)-syn-4o (Scheme 4A)
and the other was trifluoroethylated dihydrobenzoaze-2-
pinone 5, likely resulted from the preferential activation of the
acrylamide moiety by PhICF3Cl (Scheme 4B). Finally, the gram-
scale synthesis of (+/-)-syn-4j with 75% isolated yield under the
optimal reaction conditions demonstrates the practicality of the
transformations.
PhICF3Cl
+
Cl
PhICF3
O
S-trans
O
O
R2
R1
R1
R1
N
R2
N
N
R2
PhICF3
Ar2
CF3
I
Ar1
Ar1
Ar1
Ph
Ar2
2
I
CF3
Ar
Ph
I
II
S-trans-3
(cation with syn-Ar2)
PhICF3
Cl-
O
R1
PhI + HCl
O
R1
O
R2
O
N
H
R2
N
R2
H
R1
N
N
N
O
A. trifluoromethylation-
Ar2
CF3
anti-4
I
bicyclization via preferential
activation of styrene
Ar1
Ar1
[CF3]
Ph
Ar2
CF3
Ar1
PhI
Ar2
not obtained
CF3
CF3
[CF3]-activated 3o
(+/-)-4o, 28% (37%)
I'
II' (cation with anti-Ar2)
(+/-)-4
O
O
CF3
Scheme 6. Trifluoromethylative Rationale for the Observed
syn/anti Stereoselectivity in Products 4.
H
[CF3]
N
N
B. trifluoromethylation-
olefination of acrylamide
When dienes 3 were used, both the chemoselectivity in the
initial activation of the olefin double bond and the
stereoselectivity in biscyclization products could be observed.
As described in Scheme 5,14 [PhICF3]+ prefers to activate more
electron-rich styrene olefin bond of S-trans-3 and a following
trap of the acryloyl substituent furnishes carbocation II or II. It
is found that the carbocation center in II happens to have a syn-
Ar2 group for easy trap along with the elimination of PhI. As a
result, syn-disubstituted 4 are delivered as the main products.
Comparatively, we did not isolate anti-4 from the reaction
mixture in all cases. Besides having a suitable syn-position
between cation center and Ar2 group in intermediate II, the
other factor for the observed high syn/anti stereoselectivity in
4 is likely because better π-π stack of two olefinic bonds in
intermediate I leads to its preferential formation.
5, 30% (42%)
[CF3]-activated 3o
Scheme 4. Trifluoromethylative Cyclization of 3o.
To elucidate the reaction mechanism, control experiments
were performed (Scheme 5 and SI). The reactions of 1a/3a and
PhICF3Cl in the presence of 1.5 equivalents of BHT were
conducted. By the analysis of 19F NMR spectroscopies, 2a/(+/-)-
syn-4a could be obtained, in yields almost comparable to those
obtained under the standard conditions. Comparatively, the
addition of 1.5 equivalents of TEMPO into the reaction mixtures
could not completely suppress the desired reaction and
products 2a/(+/-)-syn-4a was obtained in 41% and 57% yield,
respectively. The corresponding TEMPO-CF3 adduct could not
be detected in this case. The decrease of the reaction yield may
be due to the consumption of oxidative PhICF3Cl for the
formation of oxoammonium salt and hydroxylamine from
TEMPO.12 Although the exact mechanism requires further
In conclusion, we report herein a concise trifluoromethylative
cyclization of a range of acryloanilides. The use of readily
prepared PhICF3Cl as powerful trifluoromethylating agent
enables
a
catalyst-free
process
for
constructing
trifluoroethylated cycles for the first time. Control experiments
This journal is © The Royal Society of Chemistry 20xx
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support the suggested ionic mechanism. Significantly, the (+/-)-Syn-9-fluoro-5,6a-dimethyl-11b-(2,2,2-trifluoroethyl)-5,
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efficiency of this protocol was highlighted by the new 6a,7, 11b-tetrahydro-6H-indeno[2,1-c] qDuOinI:o1l0in.1-063-9o/Cn9eO(B40c0).601J
biscyclization of dienes. Broad substrate scope, mild reaction 76.3 mg, 70% yield. Yellow solid. mp: 152-153 oC. 1H-NMR (600
conditions, and easy operation make the method well-suited for MHz, CDCl3): δ = 7.37 (dd, J = 7.8 Hz, 4.8 Hz, 1H), 7.22 - 7.24 (m,
wide applications in organic synthesis and drug design. Further 1H), 6.99 - 7.03 (m, 3H), 6.95 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 7.8
mechanistic study and synthetic applications of this catalyst- Hz, 1H), 3.44 (s, 3H), 3.07 (d, J = 15.6 Hz, 1H), 2.88 - 2.96 (m, 1H),
free process are currently ongoing in our laboratory.
2.76 (d, J = 15.6 Hz, 1H), 2.64 - 2.72 (m, 1H), 1.36 (s, 3H). 13C-
NMR (151 MHz, CDCl3): δ = 171.7, 162.4 (d, J = 246.4 Hz), 143.2
(d, J = 8.5 Hz), 142.2, 139.4, 129.2, 128.4, 126.0 (q, J = 278.4 Hz),
124.4, 124.3, 123.1, 114.7, 113.5 (d, J = 22.7 Hz), 113.0 (d, J =
22.8 Hz), 53.0, 52.0 (q, J = 1.4 Hz), 44.3, 39.4 (q, J = 27.6 Hz),
30.2, 18.7. 19F-NMR (470 MHz, CDCl3): δ = -60.9 (t, J = 10.7 Hz,
3F), -114.8 - -114.7 (m, 1F). HRMS (ESI): Calcd for [C20H17F4NO,
M+Na]+: 386.1138, measured: 386.1145.
Experimental
Typical procedures for catalyst-free intramolecular
trifluoromethylation biscyclization of dienes (taking 3a as an
example): To a dried polytetrafluoroethene (PTFE) sealed
pressure tube was added 3a (83.2 mg, 0.3 mmol), PhICF3Cl
(138.6 mg, 4.5 mmol) and anhydrous DMF (3.0 mL) in sequence
under N2. After the reaction mixture was stirred at 60 °C for 12
h, PhCF3 was added as the internal standard and the NMR yield
of 4a was calculated from 19F-NMR integrals. Then the mixture
was washed with water and brine, extracted by CH2Cl2. The
combined organic phase was dried over anhydrous MgSO4 and
concentrated under reduce pressure. Residues were purified by
silica column chromatography (eluent: petroleum ether/EtOAc
= 15/1 to 10/1, v/v) to give 4a as a white solid. Characterization
data for Supporting information.
(+/-)-Syn-9-bromo-5,6a-dimethyl-11b-(2,2,2-trifluoroethyl)-5,
6a,7, 11b-tetrahydro-6H-indeno[2,1-c] quinolin-6-one (4d).
91.4 mg, 72% yield. White solid. mp: 112-113 oC. 1H-NMR (600
MHz, CDCl3): δ = 7.47 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.31 (d, J =
7.8 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 6.99 (t, J = 8.4 Hz, 2H), 6.94
(t, J = 7.8 Hz, 1H), 3.44 (s, 3H), 3.07 (d, J = 15.0 Hz, 1H), 2.88 -
2.97 (m, 1H), 2.76 (d, J = 15.6 Hz, 1H), 2.64 - 2.71 (m, 1H), 1.35
(s, 3H). 13C-NMR (151 MHz, CDCl3): δ = 171.5, 145.7, 143.2,
139.4, 129.9, 129.1, 128.7, 128.5, 125.9 (q, J = 278.4 Hz), 124.8,
123.9, 123.2, 121.4, 114.7, 52.8, 52.4 (q, J = 1.4 Hz), 44.0, 39.1
(q, J = 27.6 Hz), 30.2, 18.6. 19F-NMR (565 MHz, CDCl3): δ = -60.8
(t, J= 10.7 Hz). HRMS (ESI): Calcd for [C20H17BrF3NO, M+Na]+:
446.0338, measured: 446.0336.
Characterization data for new products：
(+/-)-Syn-5,6a-dimethyl-11b-(2,2,2-trifluoroethyl)-5,6a,7,11b-
tetrahydro-6H-indeno[2,1-c]quinolin-6-one (4a).
83.9 mg, 81% yield. White solid. mp: 143-144 oC. 1H-NMR (600
MHz, CDCl3): δ = 7.43 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H),
7.19 - 7.24 (m, 3H), 7.04 (dd, J = 7.8 Hz, 1.2Hz, 1H), 6.99 (d, J =
9.0 Hz, 1H), 6.93 (t, J = 7.2 Hz, 1H), 3.45 (s, 3H), 3.19 (d, J = 15.0
Hz, 1H), 2.93 - 3.02 (m, 1H), 2.78 (d, J = 15.0 Hz, 1H), 2.66 - 2.77
(m, 1H), 1.35 (s, 3H). 13C-NMR (151 MHz, CDCl3): δ = 172.2,
146.5, 140.8, 139.5, 129.3, 128.2, 127.5, 126.8, 126.2 (q, J =
276.5 Hz), 125.4, 124.6, 123.4, 123.1, 114.5, 52.7, 52.6 (q, J = 1.4
Hz), 44.4, 39.3 (q, J = 27.3 Hz), 30.1, 18.7. 19F-NMR (565 MHz,
CDCl3): δ = -60.8 (t, J = 10.7 Hz). HRMS (ESI): Calcd for
[C20H18F3NO, M+Na]+: 368.1233, measured: 368.1241.
(+/-)-Syn-3,5,6a-trimethyl-11b-(2,2,2-trifluoroethyl)-5,6a,7,
11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-one (4e).
80.8 mg, 75% yield. White solid. mp: 192-193 oC. 1H-NMR (600
MHz, CDCl3): δ = 7.41 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H),
7.21 (td, J = 7.2 Hz, J = 0.6 Hz, 1H), 7.18 (d, J = 7.2 Hz, 1H), 6.90
(d, J = 7.8 Hz, 1H), 6.79 (s, 1H), 6.74 (d, J = 7.8 Hz, 1H), 3.44 (s,
3H), 3.07 (d, J = 15.6 Hz, 1H), 2.91 - 2.99 (m, 1H), 2.77 (d, J = 15.0
Hz, 1H), 2.64 - 2.71 (m, 1H), 2.30 (s, 3H), 1.34 (s, 3H). 13C-NMR
(151 MHz, CDCl3): δ = 172.4, 146.7, 140.8, 139.3, 138.1, 129.2,
127.4, 126.7, 126.2 (q, J = 278.4 Hz), 125.3, 123.9, 123.3, 121.6,
115.3, 52.7, 52.3 (q, J = 1.7 Hz), 44.4, 39.2 (q, J = 27.5 Hz), 30.1,
21.4, 18.7. 19F-NMR (565 MHz, CDCl3): δ = -60.8 (t, J = 10.7 Hz).
HRMS (ESI): Calcd for [C21H20F3NO, M+Na]+: 382.1389,
measured: 382.1402.
(+/-)-Syn-5,6a,9-trimethyl-11b-(2,2,2-trifluoroethyl)-5,6a,7,
11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-one (4b).
o
1
90.5 mg, 84% yield. Red solid. mp: 175-176 C. H-NMR (600
MHz, CDCl3): δ = 7.31 (d, J = 7.8 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H),
7.13 (d, J = 7.8 Hz, 1H), 7.05 (dd, J = 7.8 Hz, 1.2Hz, 1H), 7.02 (s,
1H), 6.97 (d, J = 8.4 Hz, 1H), 6.93 (t, J = 7.8 Hz, 1H), 3.44 (s, 3H),
3.05 (d, J = 15.0 Hz, 1H), 2.90 - 2.95 (m, 1H), 2.73 (d, J = 15.0 Hz,
1H), 2.63 - 2.71(m, 1H), 2.33 (s, 3H), 1.35 (s, 3H). 13C-NMR (151
MHz, CDCl3): δ = 172.3, 143.7, 140.8, 139.4, 137.4, 129.3, 128.1,
127.4, 126.2 (q, J = 276.6 Hz), 126.2, 124.9, 123.1, 123.1, 114.5,
52.7, 52.2 (q, J = 1.5 Hz), 44.3, 39.4 (q, J = 27.3 Hz), 30.1, 21.2,
18.7. 19F-NMR (565 MHz, CDCl3): δ = -60.9 (t, J = 10.7 Hz). HRMS
(ESI): Calcd for [C21H20F3NO, M+Na]+: 382.1389, measured:
382.1399.
(+/-)-Syn-3,5,6a,9-tetramethyl-11b-(2,2,2-trifluoroethyl)-5,6a,
7, 11b-tetrahydro-6H-indeno[2,1-c] quinolin-6-one (4f).
100.6 mg, 90% yield. White solid. mp: 173-174 ºC. 1H-NMR (600
MHz, CDCl3): δ = 7.29 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 7.2 Hz, 1H),
7.00 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.78 (s, 1H), 6.73 (d, J = 7.8
Hz, 1H), 3.43 (s, 3H), 3.03 (d, J = 15.0 Hz, 1H), 2.88 - 2.96 (m, 1H),
2.71 (d, J = 15.0 Hz, 1H), 2.61 - 2.69 (m, 1H), 2.32 (s, 3H), 2.30 (s,
3H), 1.33 (s, 3H). 13C-NMR (151 MHz, CDCl3): δ = 172.5, 143.9,
140.8, 139.2, 138.0, 137.3, 129.1, 127.3, 126.2 (q, J = 276.6 Hz),
126.1, 123.9, 123.0, 122.1, 115.2, 52.7, 51.9 (q, J = 1.4 Hz), 44.4,
39.3 (q, J = 27.6 Hz), 30.1, 21.4, 21.2, 18.7. 19F-NMR (565 MHz,
CDCl3): δ = -60.8 (t, J = 10.7 Hz). HRMS (ESI): Calcd for
[C22H22F3NO, M+Na]+: 396.1546, measured: 396.1556.
4 | J. Name., 2012, 00, 1-3
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JOURNAL NAME
114.4, 52.6 (q, J = 1.1 Hz), 52.5, 44.7, 39.3 (q, J = 2V7ie.3w AHrtzic)l,e3O7nl.in2e,
18.6, 12.1. 19F-NMR (565 MHz, CDCl3): δ D=O-6I:010.6.10(t3,9J/C=91O0B.0706H0z1)J.
HRMS (ESI): Calcd for [C21H20F3NO, M+Na]+: 382.1389,
(+/-)-Syn-2-chloro-5,6a-dimethyl-11b-(2,2,2-trifluoroethyl)-5,
6a,7, 11b-tetrahydro-6H-indeno[2,1-c] quinolin-6-one (4g).
58.0 mg, 51% yield. White solid. mp: 235-236 oC. 1H-NMR (600 measured: 382.1392.
MHz, CDCl3): δ = 7.42 (d, J = 7.2 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H),
7.26 (t, J = 7.2 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.17 (dd, J = 9.0 (+/-)-Syn-5-butyl-6a-methyl-11b-(2,2,2-trifluoroethyl)-5,6a,7,
Hz, 2.4Hz, 1H), 6.98 (d, J = 1.8 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 11b-tetrahydro-6H-indeno[2,1-c]-quinol-in-6-one (4k).
3.42 (s, 3H), 3.07 (d, J = 15.0 Hz, 1H), 2.92 - 3.00 (m, 1H), 2.79 97.6 mg, 84% yield. White solid. mp: 113-114 oC. 1H-NMR (600
(d, J = 15.0 Hz, 1H), 2.66 - 2.73 (m, 1H), 1.34 (s, 3H). 13C-NMR MHz, CDCl3): δ = 7.43 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H),
(151 MHz, CDCl3): δ = 171.9, 145.8, 140.6, 138.3, 129.2, 128.3, 7.18 - 7.23 (m, 3H), 7.06 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 8.4 Hz,
128.2, 127.9, 127.2, 126.6, 126.0 (q, J = 278.4 Hz), 125.5, 123.3, 1H), 6.91 (d, J = 7.8 Hz, 1H), 3.95 - 4.04 (m, 2H), 3.11 (d, J = 15.0
115.9, 52.6, 52.5 (q, J = 1.5 Hz), 44.3, 39.2 (q, J = 27.4 Hz), 30.3, Hz, 1H), 2.94 - 3.02 (m, 1H), 2.79 (d, J = 15.6 Hz, 1H), 2.65 - 2.72
18.7. 19F-NMR (565 MHz, CDCl3): δ = -60.9 (t, J = 10.7 Hz). HRMS (m, 1H), 1.67 - 1.73 (m, 1H), 1.57 - 1.63 (m, 1H), 1.42 - 1.48 (m,
(ESI): Calcd for [C20H17ClF3NO, M+Na]+: 402.0842, measured: 2H), 1.34 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H). 13C-NMR (151 MHz,
402.0855.
CDCl3): δ = 171.9, 146.7, 140.9, 138.5, 129.7, 128.2, 127.5,
126.8, 126.2 (q, J = 276.6 Hz), 125.3, 124.6, 123.4, 122.8, 114.5,
52.7 (q, J = 1.1 Hz), 52.5, 44.7, 42.5, 39.3 (q, J = 27.2 Hz), 28.9,
(+/-)-Syn-5,6a-dimethyl-2-nitro-11b-(2,2,2-trifluoroethyl)-
5,6a, 7, 11b-tetrahydro-6H-indeno[2,1-c] quinolin-6-one (4h). 20.4, 18.6, 13.9. 19F-NMR (565 MHz, CDCl3): δ = -60.6 (t, J = 10.7
58.8 mg, 50% yield. Yellow solid. mp 152-153 oC. 1H-NMR (400 Hz). HRMS (ESI): Calcd for [C23H24F3NO, M+Na]+: 410.1702,
MHz, CDCl3): δ = 8.11 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.95 (d, J = 2.4 measured: 410.1707.
Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.23 -
7.31 (m, 3H), 7.09 (d, J = 9.2 Hz, 1H), 3.50 (s, 3H), 2.97 - 3.09 (m, (+/-)-Syn-5-benzyl-6a-methyl-11b-(2,2,2-trifluoroethyl)-5,6a,7,
2H), 2.99 - 3.03 (m, 1H), 2.85 (d, J = 15.6 Hz, 1H), 2.70 - 2.82 (m, 11b-tetrahydro-6H-indeno[2,1-c]-quinol-in-6-one (4l).
1H), 1.39 (s, 3H). 13C-NMR (151 MHz, CDCl3): δ = 172.2, 145.1, 82.1 mg, 65% yield. White solid. mp: 137-138 oC. 1H-NMR (600
144.8, 142.9, 140.2, 128.3, 127.7, 126.1, 125.9 (q, J = 278.3 Hz), MHz, CDCl3): δ = 7.45 (d, J = 7.8 Hz, 1H), 7.34 (t, J = 7.8 Hz, 3H),
125.6, 125.3, 124.3, 123.3, 114.8, 52.5 (q, J = 1.5 Hz), 52.5, 44.6, 7.25 - 7.27 (m, 3H), 7.23 - 7.24 (m, 2H), 7.04 - 7.07 (m, 2H), 6.90
39.3 (q, J = 27.8 Hz), 30.6, 18.7. 19F-NMR (470 MHz, CDCl3): δ = - (t, J = 7.8 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.75 (d, J = 16.2 Hz,
60.9 (t, J = 10.3 Hz). HRMS (ESI): Calcd for [C20H17F3N2O3, 1H), 4.69 (d, J = 16.2 Hz, 1H), 3.29 (d, J = 15.0 Hz, 1H), 2.99 - 3.07
M+Na]+: 415.1164, measured: 415.1173.
(m, 1H), 2.93 (d, J = 15.0 Hz, 1H), 2.71 - 2.78 (m, 1H), 1.40 (s,
3H). 13C-NMR (151 MHz, CDCl3): δ = 172.5, 146.6, 140.6, 139.0,
137.4, 129.4, 128.8 (2C), 128.2 (2C), 127.6, 127.1, 126.9, 126.2,
(+/-)-Syn-3-chloro-11-fluoro-5,6a-dimethyl-11b-(2,2,2-tri
fluoroethyl)-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin- 126.2 (q, J = 276.6 Hz), 125.4, 124.4, 123.4, 123.2, 115.4, 52.8,
6-one (4i).
47.3, 44.8 (2C), 39.3 (q, J = 27.5 Hz), 18.6. 19F-NMR (565 MHz,
o
1
53.6 mg, 45% yield. White solid. mp 142-143 C. H-NMR (600 CDCl3): δ = -60.5 (t, J = 10.7 Hz). HRMS (ESI): Calcd for
MHz, CDCl3): δ = 7.19 - 7.25 (m, 3H), 7.03 - 7.06 (m, 1H), 7.01 (d, [C26H22F3NO, M+Na]+: 444.1546, measured: 444.1554.
J = 1.2 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 3.49 - 3.57 (m, 1H), 3.41
(s, 3H), 3.08 (d, J = 15.6 Hz, 1H), 2,79 - 2.87 (m, 2H), 1.40 (s, 3H). (+/-)-Syn-(5-methyl-6-oxo-11b-(2,2,2-trifluoroethyl)-5,6,7,11b-
13C-NMR (151 MHz, CDCl3): δ = 170.2, 159.0 (d, J = 246,0 Hz), tetrahydro-6aH-indeno[2,1-c]-quinolin-6a-yl)methyl acetate
142.9 (d, J = 5.2 Hz), 136.8, 128.9 (d, J = 8.2 Hz), 128.0 (d, J = 3.8 (4m).
Hz), 127.7, 127.6 (q, J = 277.8 Hz), 127.5, 125.9 (d, J = 1.5 Hz), 90.7 mg, 75% yield. White solid. mp: 146-147 oC. 1H-NMR (600
120.4 (d, J = 3.0 Hz), 114.9, 114.4, 114.2, 53.4, 51.5, 44.2, 37.6 MHz, CDCl3): δ = 7.41 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H),
(q, J = 19.9 Hz), 29.3, 17.9. 19F-NMR (565 MHz, CDCl3): δ = -61.0 7.20 - 7.25 (m, 2H), 7.16 (d, J = 7.2 Hz, 1H), 7.08 (d, J = 7.8 Hz,
(t, J = 10.7 Hz, 3F), -119.5 (dd, J = 11.3 Hz, J = 4.5 Hz, 1F). HRMS 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 4.69 (d, J =
(ESI): Calcd for [C20H16ClF4NO, M+Na]+: 420.0749, measured: 12.0 Hz, 1H), 4.45 (d, J = 12.0 Hz, 1H), 3.44 (s, 3H), 3.03 - 3.14
420.0749.
(m, 3H), 2.88 - 2.95 (m, 1H), 1.70 (s, 3H). 13C-NMR (151 MHz,
CDCl3): δ = 170.4, 169.5, 146.3, 139.8, 138.8, 129.1, 128.4,
127.8, 127.0, 126.1 (q, J = 276.5 Hz), 124.8, 124.4, 123.4, 122.8,
114.7, 64.7, 55.9, 52.0 (q, J = 5.4 Hz), 40.4, 39.7 (q, J = 27.8 Hz),
(+/-)-Syn-5-ethyl-6a-methyl-11b-(2,2,2-trifluoroethyl)-5,6a,7,
11b-tetrahydro-6H-indeno[2,1-c]-quinolin-6-one (4j).
100.0 mg, 85% yield. White solid. mp: 125-126 C. Large scale 30.0, 20.3. 19F-NMR (565 MHz, CDCl3): δ = -59.8 (t, J= 10.2 Hz).
o
test gave the product 4j (1.0635 g，75%). H-NMR (600 MHz, HRMS (ESI): Calcd for [C22H20F3NO3, M+Na]+: 426.1287,
1
CDCl3): δ = 7.43 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 7.19 - measured: 426.1296.
7.23 (m, 3H), 7.06 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.91
(d, J = 7.2 Hz, 1H), 4.15 - 4.20 (m, 1H), 4.00 - 4.06 (m, 1H), 3.10 (+/-)-Syn-6a-(methoxymethyl)-5-methyl-11b-(2,2,2-trifluoro
(d, J = 15.0 Hz, 1H), 2.93 - 3.01 (m, 1H), 2.79 (d, J = 15.6 Hz, 1H), ethyl)-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]-quinolin-6-one
2.65 - 2.72 (m, 1H), 1.34 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H). 13C-NMR (4n).
(151 MHz, CDCl3): δ = 171.7, 146.7, 140.8, 138.1, 129.7, 128.2, 95.6 mg, 85% yield. White solid. mp: 181-182 oC. 1H-NMR (600
127.5, 126.8, 126.2 (q, J = 276.6 Hz), 125.3, 124.7, 123.4, 122.9, MHz, CDCl3): δ = 7.34 (d, J = 7.8 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H),
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
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3
(a) X. Liu, C. Xu, M. Wang, Q. Liu, Chem. Rev. 2015, 115, 683;
7.12 - 7.15 (m, 2H), 7.08 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 7.8 Hz,
1H), 6.91 (d, J = 8.4 Hz, 1H), 6.87 (t, J = 7.2 Hz, 1H), 3.74 (d, J =
10.2 Hz, 1H), 3.58 (d, J = 9.6 Hz, 1H), 3.36 (s, 3H), 3.17 (s, 3H),
2.88 - 2.98 (m, 4H). 13C-NMR (151 MHz, CDCl3): δ = 169.5, 145.5,
139.4, 137.9, 128.2, 127.1, 126.5, 125.7, 125.3 (q, J = 278.3 Hz),
123.8, 123.6, 122.0, 122.0, 113.5, 72.8, 58.3, 55.7, 51.1, 39.2,
38.5 (q, J = 27.9 Hz), 29.0. 19F-NMR (565 MHz, CDCl3): δ = -59.6
View Article Online
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E. Merino, C. Nevado, Chem. Soc. Rev. 2014, 43, 6598; (f) G. S.
Sauer, S. Lin, ACS Catal. 2018, 8, 5175; (g) Y. Tian, S. Chen, Q,
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For selected examples using Togni’s reagents, see: (a) R. Zhu,
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F. Gao, C. Yang, G. -L. Gao, L. Zheng, W. Xia, Org. Lett. 2015,
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L.-H. Li, Y.-F. Yang, Y.-Q. Wang, J.-Y. Luo, X.-Y. Liu, Y.-M. Liang,
Chem. Commun. 2013, 49, 5687; (p) H. Egami, R. Shimizu, S.
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For selected examples using other CF3 sources, TMSCF3: (a) X.
Mu, T. Wu, H.-Y. Wang, Y.-L. Guo, G. Liu, J. Am. Chem. Soc.
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Y.-P. Xiong, B. Tan, X.-Y. Liu, Org. Lett. 2014, 16, 504;
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Chem. Commun. 2014, 50, 936; (e) W.-P. Mai, J.-T. Wang, L.-
R. Yang, J.-W. Yuan, Y.-M. Xiao, P. Mao, L.-B. Qu, Org. Lett.
2014, 16, 204; (f) L. Zhang, Z. Li, Z.-Q. Liu, Org. Lett. 2014, 16,
3688; (g) L. Shi, X. Yang, Y. Wang, H. Yang, H. Fu, Adv. Synth.
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Yang, Z. Tan, Eur. J. Org. Chem. 2014, 2014, 3196; (i) W. Wei,
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+
(t, J = 11.3 Hz). HRMS (ESI): Calcd for [C21H20F3NO2, M+Na] :
398.1338, measured: 398,1349.
(+/-)-Syn-5-Methyl-11b-(2,2,2-trifluoroethyl)-5,6a,7,11b-tetra
hydro-6H-indeno[2,1-c]-quinolin-6-one (4o).
o
1
26.1 mg, 28% yield. Red solid. mp: 167-168 C. H-NMR (600
MHz, CDCl3): δ = 7.49 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H),
7.25 (d, J = 9.6 Hz, 3H), 7.17 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 8.4
Hz, 1H), 6.98 (t, J = 7.8 Hz, 1H), 3.51 (dd, J = 15.6 Hz, 7.8 Hz, 1H),
3.44 (s, 3H), 3.33 (q, J = 7.8 Hz, 1H), 2.95 - 3.03 (m, 1H), 2.88 -
2.92 (m, 1H), 2.61 - 2.69 (m, 1H). 13C-NMR (151 MHz, CDCl3): δ
= 169.6, 146.1, 140.7, 139.2, 128.7, 128.4, 127.8, 127.0, 125.8
(q, J = 277.1 Hz), 124.9, 124.6, 123.7, 123.4, 114.9, 51.6, 49.0 (q,
J = 1.5 Hz), 43.5 (q, J = 27.0 Hz), 35.8, 29.6. 19F-NMR (565 MHz,
CDCl3): δ = -60.8 (t, J = 10.7 Hz). HRMS (ESI): Calcd for
[C19H16F3NO, M+H]+: 332.1269, measured: 332.1278.
1-Methyl-5-phenyl-3-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-
benzo[b]azepin-2-one (5).
29.8 mg, 30% yield. Red oil. 1H-NMR (600 MHz, CDCl3): δ = 7.41
- 7.44 (m, 1H), 7.38 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.33 - 7.36 (m,
3H), 7.26 - 7.27 (m, 2H), 7.23 (dd, J = 8.4 Hz, 1.8 Hz, 1H), 7.15 -
7.17 (m, 1H), 5,95 (d, J = 7.2 Hz, 1H), 3.46 (s, 3H), 2.96 - 3.05 (m,
1H), 2.91 - 2.94 (m, 1H), 2.66 - 2.76 (m, 1H). 13C-NMR (151 MHz,
CDCl3): δ = 170.5, 142.3, 140.7, 140.0, 132.6, 130.4, 129.0, 128.7
(2C), 128.4 (2C), 128.1, 128.1, 126.9 (q, J = 275.0 Hz), 124.7,
122.6, 38.5 (q, J = 2.6 Hz), 36.8, 34.1 (q, J = 28.5 Hz). 19F-NMR
(565 MHz, CDCl3): δ = -64.2 (t, J = 10.7 Hz). HRMS (ESI): Calcd for
[C19H16F3NO, M+Na]+: 354.1076, measured: 354.1072.
4
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank National Natural Sciences Foundation of China
(21672032, 21802016) for funding supports of this work.
5
(a) L. M. Yagupolskii, I. I. Maletina, N. V. Kondratenko, V. V.
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1982, 20, 695; (c) T. Umemoto, Y. Kuriu, H. Shuyama, O.
Miyano, S.-I. Nakayama, J. Fluorine Chem. 1986, 31, 37; (d) P.
Eisenberger, The development of new hypervalent iodine
reagents for electrophilic trifluoromethylation. Thesis,
Eidgenossische Technische Hochschule, ETH Zurich (Zurich),
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Eur. J. 2006, 12, 2579; (f) I. Kieltsch, P. Eisenberger, A. Togni,
Angew. Chem., Int. Ed. 2007, 46, 754; (g) L.-L. Chu, F.-L. Qing,
Org. Lett. 2012, 14, 2106.
Notes and references
1
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14 The bis-cyclization of S-cis-3 also furnished syn-4 as main
products. For details, see the Supporting Information.
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