Copper-catalyzed cascade cyclization of 1,5-enynes: Via consecutive trifluoromethylazidation/diazidation and click reaction: Self-assembly of triazole fused isoindolines

Article abstract of DOI:10.1039/c6cc07394h

Copper-catalyzed cascade cyclization of 1,5-enynes with two types of hypervalent reagents was developed via consecutive trifluoromethylazidation/diazidation and intramolecular click reaction (CUAAC), providing one-pot self-assembly of triazole fused isoindolines bearing a trifluoromethyl or an azide moiety. Moreover, the construction of a trifluoromethylcyclopropyl unit, which has been considered as a metabolically stable replacement for a tert-butyl moiety and was difficult to access, was also achieved under trifluoromethylazidation conditions. All these reactions exhibited excellent chemoselectivity, good to excellent yields and broad functional group tolerance.

Full text of DOI:10.1039/c6cc07394h

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Copper-catalyzed cascade cyclization of 1,5-enynes via
consecutive trifluoromethylazidation/diazidation and click
reaction: self-assembly of triazole fused isoindolines†
Received 00th January 20xx,
Accepted 00th January 20xx
Liu-Zhu Yu,a Yin Weib and Min Shi*a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
Copper-catalyzed cascade cyclization of 1,5-enynes with two types transition metal catalysts.[4] In particular, alkene
of hypervalent reagents was developed via consecutive difunctionalization using Togni reagent or Zhdankin reagent as
trifluoromethylazidation/diazidation and intramolecular click functional-group transfer reagent to synthesize valuable CF3-
reaction (CUAAC), providing one-pot self-assembly of triazole or N3- containing compounds has made predominant progress.
fused isoindolines bearing a trifluoromethyl or azide moiety. In general, trifluoromethylation of alkenes using hypervalent
Moreover, the construction of trifluoromethylcyclopropyl unit, reagents often simultaneously constructs C (sp3)-CF3 and C-C,[5]
which has been considered as metabolically stable replacement C-O,[6] C-N[7] bonds. In the realm of C-N bonds formation, most
for a tert-butyl moiety and was difficult to be accessed, was also nucleophiles
are
restricted
to
amines.
Recently,
achieved under trifluoromethylazidation conditions. All these trifluoromethylazidation of alkenes using TMSN3 or NaN3 as
reactions exhibited excellent chemoselectivity, good to excellent azide source have been reported by several research groups.
yields and broad functional group tolerance.
For examples, Masson reported the photoredox-catalyzed
trifluoromethylazidation of enecarbamates, allowing access to
various β-trifluoromethyl amines in good yields.[7c] Moreover,
Liu’s group developed a mild copper-catalyzed intermolecular
trifluoromethylazidation of alkenes employing less reactive
Togni reagent I as trifluoromethyl source (Scheme 1a).[7d] Apart
from trifluoromethylazidation of alkenes, Liu and co-workers
also reported a sequential trifluoromethyazidation of alkynes
and photocatalyzed rearrangement process, providing more
convenient access to CF3-containing 2H-azirines (Scheme 1b).[8]
Organofluorines, especially trifluoromethyl groups, play a
prevalent role in pharmaceutical chemistry, agrochemical
chemistry, and medical imaging, due to their apparent
development of unique properties of organic compounds such
as membrane permeability, bioavailability and metabolic
stability,[1] which have stimulated the exploration of
efficacious methodologies to construct C-CF3 bonds.[2] On the
other hand, organoazides have also been widely used in
synthetic intermediates and building blocks in organic
synthesis because of their versatile reactivities and
bioactivities in the synthesis of nitrogen-containing
heterocycles and a variety of probes for the robust azide-
alkyne click chemistry.[3] Therefore, the effective and
convenient approaches for the introduction of both functional
groups are urgently pursued.
Thereafter,
they
also
disclosed
copper-catalyzed
intermolecular trifluoromethylazidation of allenes, thus
affording a series of CF3-containing allyl azides with high yields
and good stereoselectivities.[9] Furthermore, diazidation of
alkenes have represented a powerful tool to generate high-
value chemicals from hydrocarbons.[10] However, until now
most methodologies suffered from high temperature,
explosive azide source (NaN3), narrow substrate scope and
limited types of alkenes. Only recently, Xu’s group discovered a
mild iron-catalyzed diastereoselective olefin diazidation
method using Zhdankin reagent as azide source which
tolerated a broad range of olefins (Scheme 1c).[11] Herein, we
wish to describe a copper-catalyzed cascade cyclization of 1,5-
enynes via consecutive trifluoromethylazidation/diazidation
and click reaction processes, providing novel access to a
variety of structurally valuable triazole fused isoindolines
(Scheme 1d).[12]
Hypervalent iodine compounds have been widely used as
oxidants routinely. Recent years have witnessed their intensive
studies of cyclic hypervalent reagents (λ-3-iodane) in
functional-group transfer reactions in the presence of
a.Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of
Chemistry & Molecular Engineering, East China University of Science and
Technology, Meilong Road No. 130, Shanghai, 200237 (China).
b.State Key Laboratory of Organometallic Chemistry, University of Chinese
Academy of Science, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 345 Lingling Road, Shanghai 200032 China. E-mail:
mshi@mail.sioc.ac.cn
† Electronic Supplementary Information (ESI) available: Experimental procedures,
characterization data of new compounds, and CCDC 1440522 and 1482939. See
DOI: 10.1039/b000000x
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Table 1 Reaction Scope: synthesis of CF3-containing triazole fused isoindolinesa, b
a
Reaction conditions: 1 (0.20 mmol, 1.0 equiv), CuTc (0.01 mmol, 0.05 equiv),
Scheme 1 Trifluoromethylazidation and diazidation of alkenes, alkynes and enynes.
Togni reagent II (0.30 mmol, 1.5 equiv), TMSN3 (0.40 mmol, 2.0 equiv), MeCN (2.0
mL), 50 oC, argon atmosphere for 6 h. b Isolated yield. c Togni reagent I was used
as trifluoromethyl source. d dr = 1 : 0.6.
Upon reaction conditions screening (for the details, see
Table S1 in the Supporting Information), we identified the
optimal reaction conditions for the synthesis of 2a as follows
(Scheme 2): 1a (0.10 mmol, 1.0 equiv), Togni reagent II (0.15
mmol, 1.5 equiv), and CuTc (0.005 mmol, 0.05 equiv) as the
catalyst with TMSN3 (0.20 mmol, 2.0 equiv) under argon
o
atmosphere using MeCN (1.0 mL) as the solvent at 50 C for 6
h.
Scheme 3 Three possible undesired pathways of 3a under trifluoromethylazidation
conditions.
Scheme 2 Optimal reaction conditions for the synthesis of 2a.
Table 2 Reaction Scope: synthesis of trifluoromethylcyclopropyl-containing triazole
fused isoindolinesa, b
Having established the optimal reaction conditions, we
began to investigate the feasibility of reaction scope and the
results are shown in Table 1. When R2 was aryl group, the
reactions proceeded smoothly to give the desired products 2b
and 2c in 89% and 94% yields, respectively. Satisfactorily, nitro-
substituted substrate 1d, was also well tolerated, providing the
desired product 2d in up to 85% yield. For the substrate 1e
with both phenyl rings substituted, the reaction also worked
efficiently to deliver the corresponding product 2e in 87% yield.
When R2 was methyl or heterocyclic group, the reactions also
performed well under current trifluoromethylazidation
conditions to give 2f and 2g in 91% and 90% yields, respectively.
Moreover, internal alkene 1h was also compatible using Togni
reagent I as trifluoromethyl source, thus giving product 2h in
80% yield with 1:0.6 diastereoselectivity. Astoundingly, 2i
without click reaction process was obtained in 90% yield when
R2 was non-substituted, which was probably caused by Thorpe-
Ingold effect, indicating that trifluoromethylazidation of alkene
moiety was the first step of this cascade process.
a
Reaction conditions: 3 (0.2 mmol, 1.0 equiv), CuTc (0.01 mmol, 0.05 equiv),
Togni reagent II (0.30 mmol, 1.5 equiv), TMSN3 (0.40 mmol, 2.0 equiv), MeCN (2.0
mL), 50 oC, argon atmosphere for 6 h. Isolated yield. Trimethylsilyl protected
b
c
d
e
alkyne was used as substrate. Terminal alkyne was used as substrate. Togni
reagent I was used as trifluoromethyl source.
Recently, our group has paid attention to investigate
trifluoromethylation of functional alkylidenecyclopropanes
(ACPs) to construct CF3-containing polycyclic scaffolds.[6h, 6i] We
2 | J. Name., 2012, 00, 1-3
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envisaged whether trifluoromethylcyclopropyl-containing
The success of consecutive trifluoromethylazidation and
triazole fused isoindolines could be achieved utilizing this click reaction of 1,5-enynes to construct triazole fused
newly established synthetic method. However, we faced isoindolines encouraged us to further investigate whether
following challenges: 1) The addition of in-situ generated CF3 Zhdankin reagent was compatible under current conditions
radical could be abstracted by ACP, followed by a successive (Table 3). Gratifyingly, various N3-containing triazole fused
ring-opening process because of highly strained cyclopropane isoindolines 5a
ring and intramolecular cyclization to deliver A [6h, 6i] 2) The aryl group. When R2 was a methyl or a heterocyclic group, the
ring-opening homoallyl radical intermediate was trapped by reactions also proceeded smoothly under current diazidation
alkyne moiety of 1,5-enyne to afford as reported by Liang’s conditions to afford 5e and 5f in 93% and 96% yields,
work;[13] 3)
was also a possible product if ACP was not respectively. Both phenyl rings substituted substrate was also
-
5c were formed in good yields when R2 was an
;
B
C
opened and ACP radical intermediate was trapped by alkyne tolerable, affording product 5d in 83% yield. Moreover,
moiety (Scheme 3). However, we hypothesized that proper internal alkene 1h was also compatible, thereby giving product
control of the stability of alkylidenecyclopropyl radical by 5h in 65% yield with 4:1 diastereoselectivity. Disappointingly,
modulating electronic effect would help us to achieve our goal. ACP tethered substrate was not compatible and the reaction
The most stable electron-deficient CF3-containing ACP radical system was complex. Finally, when R2 was non-substituted,
intermediate (CF3-containing ACP radical > homoallyl radical > only trifluoromethylazidation of alkene moiety occurred to
vinyl radical)[2a,
6d, 14]
can preferentially combine with CuII afford product 5i. The structure of 5a was also confirmed by
complex to give CuIII species, due to captodative effect. single crystal X-ray analysis.[18]
Gratifyingly, trifluoromethylcyclopropyl-containing triazole
Table 3 Reaction Scope: synthesis of N3-containing triazole fused isoindolinesa, b
fused isoindoline 4a was indeed formed in good yield under
optimized conditions (for the details, see Table S2 in the
Supporting Information). Trifluoromethylcyclopropyl group has
been demonstrated as a metabolically stable replacement for
a tert-butyl moiety and the most effective approach to
introduce trifluoromethylcyclopropyl group currently rescues
from preparative trifluoromethylcyclopropyl sulfinate salt
(TFCS-Na) by employing an interrupted Barton decarboxylation
reaction.[15]
R1
N
N3
3R2
R4 R5
R2
R4
R5
N
CuTc (5 mol%)
TMSN3 (2.0 equiv)
O
I
N
N
O
+
R1
MeCN, 50 o
C
R3
R3
Zhdankin reagent
1.2 equiv
1
N3
N3
N
N3
tBu
N
N
N
R
N
N
N
N
N
Ph
5a
R = H, , 87%
R = 2-Me, 5b, 81%
R = 4-Cl, 5c 76%
Cl
N
5e, 93%
5d
, 83%
Ph
N3
N3
Ph
N3
Ph
N
N
N
N
The importance of introducing trifluoromethylcyclopropyl
group and difficulty in obtaining such distinctive group
encouraged us to examine the substrate scope of ACP-
tethered alkynes carefully and the results are shown in Table 2.
When R1 is an aryl group, a variety of arylalkynes were
compatible and the reactions proceeded smoothly to furnish
the corresponding products 4a-4g in good yields ranging from
70% to 86%. The electronic effect and substituent position had
no obvious impact on the reaction efficiency. We were pleased
to obtain desired product 4h in 77% and 38% yields when TMS
alkyne or terminal alkyne were employed as substrates.[16]
N
N
N
N
Ph
Ph
S
N3
N3
5h, 65%c
5g
, complex
5i
, 86%
5f, 96%
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), CuTc (0.01 mmol, 0.05 equiv),
Zhdankin reagent (0.24 mmol, 1.2 equiv), TMSN3 (0.4 mmol, 2.0 equiv), MeCN
(2.0 mL), 50 oC, argon atmosphere for 6 h. b Isolated yield. c d r = 4 : 1.
n
Cyclopropyl and butyl alkynes were also tolerated under such
trifluoromethylazidation conditions, affording 4i and 4j in 89%
and 80% yields, respectively. Then, we investigated the
electronic effect and steric hindrance of R2 when it was an aryl
group: electron-withdrawing substituents provided the desired
products 4m and 4n in 76% and 65% yields, respectively and
substrates with electron-donating ones gave products 4k, 4l,
4o with better yields up to 85% yield. The reaction became
sluggish when the ortho-methyl substituted phenyl was
employed, probably because of steric hindrance. Changing R3
to OMe group or Cl atom, the reactions still worked smoothly
Scheme 4 A plausible mechanism for tandem trifluoromethylazidation/diazidation and
click reaction of 1,5-enynes.
and products 4q-4s were isolated in good yields. Both phenyl
On the basis of the experimental results, control
experiments and previous reports,[8, 9, 11, 13, 19] we concluded
that the radical specie existed during the reaction process (for
the details, see Scheme S1 in the Supporting Information).
Therefore, a plausible mechanism is outlined in Scheme 4.
Initially, X (X = CF3 or N3) radical is released when hypervalent
rings substituted substrate 1t was also tolerated, affording 4t
in 80% yield. When R2 was an alkyl group, the corresponding
product 4u was also obtained, albeit in 64% yield. However,
only trifluoromethylazidation of ACP moiety occurred when R2
was non-substituted, delivering 4v in 52% yield. The structure
of 4a was confirmed by single crystal X-ray analysis.[17]
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reagent is activated by a TMS group,[7d] followed by a single-
electron transfer (SET) process in the presence of CuI catalyst.
The chemoselective addition of X radical onto alkene moiety
forms alkyl radical intermediate II, which is trapped by N3-
coordinated CuII complex to form intermediate III. Afterwards,
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a
reductive elimination process occurs to deliver
trifluoromethylazidation or diazidation product IV. At this
stage, intramolecular click reaction (CUAAC) further occurs
with the assistance of CuI catalyst.
In summary, we have disclosed a mild and convenient
copper-catalyzed
consecutive
trifluoromethylazidation/diazidation and click reaction of 1,5-
enynes with two types of hypervalent reagents, providing
facile access to diverse triazole fused isoindolines bearing a
8
9
trifluoromethyl
or
azide
is
moiety.
Moreover,
under
trifluoromethylcyclopropyl
also obtained
10 a) P. Klahn, H. Erhardt, A. Kotthaus, and S. F. Kirsch, Angew.
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trifluoromethylazidation conditions. A plausible mechanism
has been also proposed on the basis of control experiments
and related literature. Further investigations on expanding the
scope and applications of this method are undergoing in our
laboratory.
We are grateful for the financial support from the National
Basic Research Program of China (973)-2015CB856603, and
the National Natural Science Foundation of China (20472096,
21372241, 21361140350, 20672127, 21421091, 21372250,
21121062, 21302203, 20732008 and 21572052).
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18 The crystal data of 5a have been deposited in CCDC with
number 1482939.
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4 | J. Name., 2012, 00, 1-3
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We have developed a copper-catalyzed one-pot three-
component reaction to provide diverse triazole fused
isoindolines bearing
trifluoromethyl/trifluoromethylcyclopropyl
moiety via
Copper catalyzed cascade cyclization of 1,5-enynes via
consecutive trifluoromethylazidation/diazidation and
click reaction: self-assembly of triazole fused isoindolines
a
or
azidyl
consecutive
R1
R5
R5
R2
R2
N3
R4
N
trifluoromethylazidation/diazidation and click reaction.
F3C
R4
N
[Cu]cat.
CF3
N
[Cu]cat.
N3
N
N
N
R4 R5
R2
+
TMSN3
R
R1
1
I
I
R3
R3
O
O
R3
O
O
trifluoromethylazidation/click reaction
31 examples
diazidation/click reaction
8 examples
yields: up to 96%
yields: up to 94%
Liu-Zhu Yu, Yin Wei and Min Shi*
construction of trifluoromethylcyclopropyl group !
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