Copper-Catalyzed Aldol Reaction of Vinyl Azides with Trifluoromethyl Ketones

Article abstract of DOI:10.1021/acs.orglett.9b02616

A novel and efficient aldol reaction of readily available vinyl azides with trifluoromethyl ketones by copper catalysis is developed. The reaction is proposed to go through a nucleophilic trapping of vinyl azides with trifluoromethyl ketones as a trifluor

Full text of DOI:10.1021/acs.orglett.9b02616

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Aldol Reaction of Vinyl Azides with
Trifluoromethyl Ketones
Zhenhua Liu, Zhihai Zhang, Guangyu Zhu, Yiqin Zhou, Lin Yang, Wen Gao,* Lili Tong, and Bo Tang*
College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for
Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong
Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan 250014, P. R. China
S
* Supporting Information
ABSTRACT: A novel and efficient aldol reaction of readily available
vinyl azides with trifluoromethyl ketones by copper catalysis is
developed. The reaction is proposed to go through a nucleophilic
trapping of vinyl azides with trifluoromethyl ketones as a
trifluoromethyl source, leading to the assembly of diverse
trifluoromethylated compounds under mild conditions in satisfactory
yield.
Scheme 1. Synthesis of Fluorine-Containing Compounds
with Vinyl Azides
ecause of the impressive physical and chemical properties
B
of the fluorine moiety,1 the fluorine-containing com-
pounds prevail in pharmaceuticals, agrochemicals, and
materials with exclusive lipophilicity, binding interactions,
and bioavailability.2 The trifluoromethyl (CF3) group, in
particular, appears to have broad applications in pharmaceut-
icals such as efavirenz (anti-HIV),3 sorafenib (anticancer),4
mefloquine (antimalaria),5 and fluralaner (insecticide).6 More-
over, radiotracers labeled with 18F are widely used as positron
emission tomography (PET) agents.7 In the past several years,
the emergence of relative-abundance trifluoromethyl precur-
sors8 has substantially inspired the progress of trifluoromethyl
moiety insertion into organic molecules. With the underlined
importance of the CF3 motif, the development of chemical
diversity for the efficient, selective, and mild incorporation of a
trifluoromethyl scaffold into diverse interesting frameworks still
receives growing attention in organic synthesis.
Vinyl azides as multifaceted substrates are highly versatile
synthons to furnish new avenues for the synthesis of appealing
valuable molecules,9 and they have been regarded as emerging
functionalized alkenes along with the convenient preparation
method via the hydroazidation of alkynes.9b In particular as
good radical acceptors, vinyl azides readily react with fluorine-
containing radicals to generate the corresponding fluorine-
substituted compounds. For example, Chiba and coworkers10
realized a trifluoromethylation reaction of vinyl azides by using
Me3SiCF3 as CF3 precursors to access α-trifluoromethyl azines,
which could be smoothly transformed into valuable α-CF3
ketones in a second step (Scheme 1a). Visible-light irradiation
was also successful for the synthesis of trifluoromethylated
ketones with vinyl azides and CF3SO2Na.11 Chiba12a and
Liu12b further extended this trifluoromethylation strategy by
adjusting the reaction conditions, thus producing diverse
trifluoroethyl isoquinoline derivatives in one pot (Scheme 1b).
Recently, Liu’s group13 reported an elegant base-promoted
fluoridation protocol with selectfluor as a fluorine precursor to
efficiently afford α-fluoroketones from vinyl azides (Scheme
1c). An innovative trifluoromethylation of vinyl azides was
disclosed by Bi’s group,14 along with C- to N-center remote
arene migration (Scheme 1d). In this regard, the exploration of
a general and concise methodology for constructing more
Received: July 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02616
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
diverse trifluoromethylated molecules with a new trifluor-
omethyl reagent and vinyl azides remains to be highly
impending and appealing. Taking advantage of our recent
efforts on the discovery of novel reactions with vinyl azides,15
herein we report an incorporation reaction of the trifluor-
omethyl group with readily available vinyl azides and
inexpensive trifluoromethyl ketones as a CF3 source,16 which
successfully provides a facile access for the convenient
synthesis of diverse trifluoromethyl-containing tertiary alcohol
products under operationally simple conditions in good to
excellent yield (Scheme 1e).
resulted in a poor reactivity for the trifluoromethylated product
(Table 1, entries 16 and 17).
The optimal reaction conditions in hand prompted us to
investigate the reactivity of vinyl azides for the construction of
target products (Scheme 2). In general, a battery of
a
Scheme 2. Scope of Vinyl Azides
At the outset of a copper-catalyzed template for the
preparation of tertiary alcohol products bearing a trifluor-
omethyl group, our initial endeavors with 1a and 2a as model
substrates were evaluated. Fortunately, the expected product
3a was observed, albeit in a moderate yield when the reaction
was conducted in the presence of CuI at 40 °C in DMSO
solvent (Table 1, entry 1). By using some control experiments
a
Table 1. Optimization of the Reaction Conditions
a
Conditions:1 (0.5 mmol), 2a (0.6 mmol), CuI (0.075 mmol), PPh3
entry
[M]
sol.
yield (%)
(0.5 mmol), and PMDETA (1.0 mmol) in DMSO (1 mL) at 40 °C
1
2
3
4
5
6
7
8
CuI
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DCE
64
0
under air for 6−10 h. Yields of isolated products.
b
CuI
CuI
CuBr
0
trifluoromethyl-substituted products 3a−t were obtained in
good to high yield under standard conditions regardless of
whether the electron-rich or -deficient aryl group was attached
to the vinyl azide substrates. For example, vinyl azides were
well tolerated, thus yielding the products 3b−k in 83−96%
yield with both electron-donating and -withdrawing substitu-
tions at the para position. Additionally, the absolute
configuration was unequivocally verified by obtaining the
crystal structure of product 3j (CCDC: 1938448). By
switching the para-substituted group to the meta or ortho
position, this methodology could smoothly enable the
synthesis of products 3l−n in satisfactory yield. Replacing
the phenyl ring with a naphthyl or thienyl unit was also suitable
and exhibited good compatibility with this transformation,
leading to the corresponding products 3o,p in good yield. As
the challenging substrates, aliphatic vinyl azides had no major
influence on the efficiency of the trifluoromethyl incorporation
process to offer the products 3q,t in good yield.
The examination of the scope with respect to the
trifluoromethyl ketones was continued under the Cu(II)-
enhanced reaction conditions (Scheme 3). The position and
the electron-deficient effect of the Br atom in substrate 2 were
checked and had a marginal effect on providing the
corresponding products 4a,b with an intact halogen atom for
further modification. The introduction of different substitution
patterns such as methyl and methoxyl groups smoothly
afforded the products 4c,d in 88 and 86% yield, respectively.
The highly substituted products 4e−g were also allowed in
75−86% yield. The direct trifluoromethylation reaction could
be further expanded to the substrates with a thienyl ring and
delivered good reactivity for the synthesis of the corresponding
aldol product 4h. Unfortunately, aliphatic trifluoromethyl
ketone 2i failed to give the product 4i.
c
0
61
trace
90
Cu(CH3CN)4BF4
Cu(OAc)2
NiCl2
Pd(OAc)2
Ag2CO3
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
67
9
trace
trace
58
trace
72
10
11
12
13
14
15
16
17
EtOH
toluene
CH3CN
DMF
DMSO
DMSO
70
trace
trace
trace
d
e
a
Conditions: 1a (0.5 mmol), 2a (0.6 mmol), CuI (0.075 mmol),
PPh3 (0.5 mmol), PMDETA (1.0 mmol) in solvent (1 mL) at 40 °C
b
under air for 8 h. Yields of isolated products. Without PPh3 (1.0
c
d
e
equiv). Without PMDETA (2.0 equiv). At r.t. At 70 °C. PMDETA,
pentamethyldiethylenetriamine.
(Table 1, entries 2−4), we confirmed that the copper catalyst,
PPh3, and PMDETA acted as the indispensable factors in
favoring the construction of target product 3a. Subsequently,
the optimization studies focused on other metal salts such as
CuBr, Cu(CH3CN)4BF4, Cu(OAc)2, NiCl2, Pd(OAc)2, and
Ag2CO3 in DMSO solvent. An 8 h reaction showed that
Cu(OAc)2 gave an improved yield of the expected product 3a
(Table 1, entries 5−10). Then, the screening of alternative
solvents revealed that DMSO could efficiently facilitate the
yield of the desired transformation (Table 1, entries 11−15).
Eventually, we tested the appropriate reaction temperature for
the standard template to access the trifluoromethylation
procedure. Reducing or increasing the reaction temperature
Considering the excellent universality of our template, the
large-scale reaction between 1a and 2a was also successfully
B
DOI: 10.1021/acs.orglett.9b02616
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Reaction Scope of Trifluoromethyl Ketones
Scheme 5. Mechanistic Investigations
a
Conditions:1a (0.5 mmol), 2 (0.6 mmol), CuI (0.075 mmol), PPh3
(0.5 mmol), PMDETA (1.0 mmol) in DMSO (1 mL) at 40 °C under
air for 6−10 h. Yields of isolated products.
Scheme 6. Possible Mechanism for the Reaction
implemented under mild conditions to generate product 3a in
85% yield, thus reinforcing the operability and practicability of
this reaction (Scheme 4). Product 3a was further derivatized
for valuable CF3 alkene17 3a′ with E/Z isomers in 82% yield
under the acid-mediated conditions.
Scheme 4. Large-Scale Synthesis and Further
Transformations
the copper intermediate B with the concomitant release of N2
under standard conditions (path a). Another possible active
intermediate A′,20 generated from A in the presence of PPh3
and trace H2O in the system, underwent nucleophilic addition
with 2a to give intermediate B (path b). Direct protonation of
imine copper B with trace amounts of H2O in the system could
further afford imine species C, along with the release of the
Cu2+ ion. Species C was finally converted to product 3a by the
hydrolysis reaction, and the Cu2+ ion continued the engage-
ment in the next catalytic cycle.
In summary, we have developed a Cu(II)-catalyzed
incorporation of CF3 moiety protocol to conveniently
constitute various trifluoromethylated tertiary alcohols from
readily available feedstocks. This novel conversion is deduced
to involve an electrophilic trapping of trifluoromethyl ketones
by using vinyl azides as the electron-rich partner under mild
conditions. Simple conditions, a high reaction efficiency, and a
broad substrate scope are achieved in this versatile approach. A
possible mechanism is also elucidated by preliminary control
studies. Further exploitations of vinyl azides in organic
synthesis are currently underway.
Preliminary control studies were conducted to probe more
insight into the reaction mechanism. First, the radical
inhibition experiments were performed by the addition of
butylated hydroxytoluene (BHT) or 2,2,6,6-tetramethylpiper-
idinyloxyl (TEMPO) as a free-radical quencher, successfully
producing product 3a in 68 and 79% yield, respectively
(Scheme 5 a). These observations indicated that the CF3
moiety could be implanted into the final product in an ionic
manner rather than by a radical pathway.18 Next, the
assumptive intermediates 5−7 and the replacement of vinyl
azide 1a were introduced into the standard conditions
(Scheme 5b−d). However, no intermediates were converted
to the desired trifluoromethylation product 3a. This proved
that the above intermediates were not involved in the standard
reaction. Moreover, vinyl azide 1a could be transformed into
acetophenone in the presence of a copper catalyst in the
reported literature.9a,b Therefore, we used acetophenone 8
instead of vinyl azide 1a as a coupling partner for the
optimized trifluoromethylation reaction (Scheme 5e), whereas
product 3a was not formed, suggesting the absence of
acetophenone 8 during the present process.
ASSOCIATED CONTENT
* Supporting Information
■
S
On the basis of the above control experiments and precedent
reports,9,15 a plausible mechanism for the incorporation of the
trifluoromethyl reaction is illustrated in Scheme 6. First, vinyl
azide 1a complexed with Cu(II) to generate a N-diazoenamine
copper species A,19 which was subsequently well-suited for
trapping the electrophile 2a by nucleophilic addition to form
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02616.
Typical experimental procedure and characterization for
all products (PDF)
C
DOI: 10.1021/acs.orglett.9b02616
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
Letter
364, 1170. (b) Miller, P. W.; Long, N. J.; Vilar, R.; Gee, A. D.
Synthesis of 11C, 18F, 15O, and 13N Radiolabels for Positron Emission
Tomography. Angew. Chem., Int. Ed. 2008, 47, 8998.
CCDC 1938448 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Reactions of Ketone Donors with Aryl Trifluoromethyl Ketone
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: gaowen@sdnu.edu.cn (W.G.).
*E-mail: tangb@sdnu.edu.cn (B.T.).
ORCID
Bo Tang: 0000-0002-8712-7025
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(9) (a) Banert, K. In Organic Azides: Syntheses and Applications;
Brase, S., Banert, K., Eds.; Wiley: Chichester: U.K., 2010. (b) Fu, J.;
This work was supported by the National Natural Science
Foundation of China (21535004, 91753111, 21927811,
21605097, 21775092, 21976112), the Key Research and
Development Program of Shandong Province
(2018YFJH0502), the Natural Science Foundation of
Shandong Province of China (ZR2016BQ01, ZR2018JL008),
and the China Postdoctoral Science Foundation
(2017M610442, 2019M650168).
̈
Zanoni, G.; Anderson, E. A.; Bi, X. α-Substituted Vinyl Azides: an
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(c) Hu, B.; DiMagno, S. G. Reactivities of Vinyl Azides and their
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Annulation of Diazoenals and Vinyl Azides: Direct Synthesis of
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