Trifluoromethylation of Unactivated Alkenes with Me3SiCF3 and N-Iodosuccinimide

Article abstract of DOI:10.1021/acs.orglett.9b00332

A novel approach to the trifluoromethylation of unactivated alkenes is presented. This reaction is promoted by N-iodosuccinimide (NIS) under visible light irradiation without the need for photocatalysts. The mild conditions allow the direct synthesis of u

Full text of DOI:10.1021/acs.orglett.9b00332

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Trifluoromethylation of Unactivated Alkenes with Me3SiCF3 and
N‑Iodosuccinimide
Xinkan Yang and Gavin Chit Tsui*
Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR
S
* Supporting Information
ABSTRACT: A novel approach to the trifluoromethylation of unactivated
alkenes is presented. This reaction is promoted by N-iodosuccinimide (NIS)
under visible light irradiation without the need for photocatalysts. The mild
conditions allow the direct synthesis of useful trifluoromethylated (E)-alkenes
from readily available alkene feedstocks with excellent functional group
tolerability. In addition, using easy-to-handle and commercial Me3SiCF3
instead of gaseous CF3I as the CF3 source is highly attractive for industrial-
scale applications.
electrophilic CF3 radical from trifluoromethyl iodide (CF3I)
(Scheme 1a). This radical then adds to an alkene 1 to give the
nactivated alkenes are among the most abundant
1
Uchemical feedstocks in organic synthesis.
They are
readily available in bulk quantities at low costs from
petrochemical and renewable resources and possess a
characteristic reactivity profile. For this reason, alkene
functionalization has become the staple method for construct-
ing new carbon−carbon bonds.2 Direct trifluoromethylation of
unactivated alkenes is a powerful tool for introducing the
trifluoromethyl group into organic molecules (C−CF3 bond
formation). Despite enormous progress in the field of
trifluoromethylation methodology,3 this area remains under-
developed. Pioneering work on copper-catalyzed trifluorome-
thylation of terminal alkenes allowed the efficient construction
of allylic C−CF3 bonds.4 Hydrotrifluoromethylation of
unactivated alkenes was also achieved by photoredox catalysis
and other conditions to provide a net addition of “H−CF3”
across the double bond.5,6 In view of the importance of
organofluorine compounds for pharmaceutical, agrochemical,
and material applications,7 the development of new methods
for the synthesis of trifluoromethylated molecules directly from
simple alkenes is of high relevance.
Scheme 1. Vinylic Trifluoromethylation of Unactivated
Alkenes
Vinylic trifluoromethylation of unactivated alkenes is unique
for creating a Csp2−CF3 bond in the product, which
constitutes a formal vinylic C−H bond functionalization that
is distinct from other trifluoromethylation processes.4−6 The
resulting trifluoromethylated alkenes are not only key
structural motifs in drug candidates7 but also synthetically
useful substrates for C−F bond activations.8 Typically these
compounds were prepared from prefunctionalized alkenes via
cross-coupling-type reactions9 with the limitations of poor
atom economy and moderate E/Z selectivity. Significant
improvement was brought about by visible light photoredox
catalysis to directly convert unactivated alkenes to alkenyl-CF3
products with excellent E-selectivity under mild conditions.10
In the seminal report,10a a Ru-based photocatalyst was
employed in a reductive quenching cycle to generate an
trifluoromethylated secondary carbon radical. An additional
base DBU was required to act as both a reductive quencher
and a base for hydrogen iodide elimination leading to the final
alkenyl-CF3 product 2. The choice of CF3I as the CF3 radical
source was universal in the photocatalytic alkene trifluor-
omethylation.10,11 Despite its utility and low cost, using CF3I
(gas, bp = −22.5 °C) in a routine operation and on an
industrial scale can be challenging.12 We herein report an
alternative protocol for generating the CF3 radical from
Ruppert-Prakash reagent (Me3SiCF3, liquid, bp = 54−55
°C),13 a formal CF3 anion equivalent, in the presence of N-
iodosuccinimide (NIS) and visible light (Scheme 1b). This
Received: January 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00332
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
redox-neutral approach does not require photocatalysts and
alleviates the use of gaseous CF3I.
increased to 53% (entry 4), which is in contrast with the
excellent yields obtained by similar photoredox catalysts with
CF3I.10a Silver(I) salts are known activators for NIS,17a yet
adding a catalytic amount of AgNO3 did not change the yield.
However, using 1.2 equiv significantly enhanced the yield
(73%); a larger excess was not useful (entries 5−7). Various
other silver(I) salts were also tested and were found to be
inferior to AgNO3, except AgOAc, which gave same results
(entry 8). Considering the wider commercial availability and
less hazardous nature of AgOAc, we decided to continue the
optimization with AgOAc. Silver was unique in this reaction,
and other metal salts such as CuCl, FeCl2, and FeCl3 only gave
traces of products along with unreacted starting materials even
though FeCl3 has been shown to activate NIS in iodination
reactions.16,17b We also varied the amounts of Me3SiCF3/
NaOAc, and 4.0 equiv of each was optimal. Solvent screening
revealed that DMSO was more suitable than DMF due to the
complete inhibition of hydrotrifluoromethylated side products
(entries 9−10). Other less polar solvents including 1,4-
dioxane, dichloromethane, toluene, and diethyl ether led to
poor solubilities of the reaction mixture. In DMSO, only 2.0
equiv of NIS were needed to achieve the same yield (entries
11−12). Extensive screening of the initiator for Me3SiCF3 was
carried out16 showing that carboxylates were superior in this
reaction compared to other commonly used initiators such as
carbonate10a and fluoride.10c For instance, sodium benzoate
and potassium/lithium acetate all gave similar yields as sodium
acetate. However, reactions carried out without NaOAc (even
using larger excess of AgOAc) caused sharp decreases in yield
(entries 13−14). Irradiation was crucial for the reaction. The
reactivity was dramatically reduced without light (8% yield),
even after heating at 80 °C (13% yield, entry 15).16 The
reaction parameters did not seem to have significant impact on
the E/Z-selectivities; in all cases, the E-alkene predominated.
By applying the optimized conditions to readily available
unactivated alkenes 1, a library of trifluoromethylated alkenes 2
were rapidly generated in one step with good E-selectivities
(Scheme 2). The advantages of the mild conditions (room
temperature and no strong oxidant) were reflected in the
excellent functional group tolerance. Ester derivatives (2a−n)
bearing electron-donating/electron-withdrawing aromatic sub-
stituent groups (2b−g), aryl halides (2h−k), and heteroaryl
groups (2l−n) were shown to be compatible. Phenol
derivatives (2o−p) containing ketone and aldehyde function-
alities mainly gave the desired products despite the fact that
these carbonyl groups are highly susceptible to nucleophilic
additions13c,d by Me3SiCF3.18 Aryl iodide (2q) and boronate
(2r), which are useful cross-coupling partners, were also
tolerated. Gram-scale synthesis of 2q was also feasible with
recovered unreacted starting material (94% yield brsm).
Phthalimide derivatives (2s−t),18 benzyl and silyl ethers
(2u−v), were suitable substrates. However, in cases where
good leaving groups are present in the substrates (1w OTs, 1x
Br), the major products obtained were the succinimide
derivatives (2w−x) via SN2 displacements. A shorter carbon
chain analog (2y vs 2a) was obtained with a somewhat lower
yield and E/Z ratio. An allylbenzene derivative gave a mixture
Oxidative allylic trifluoromethylation,14a hydrotrifluoro-
methylation,14b and fluorotrifluoromethylation14c of unacti-
vated alkenes using Me3SiCF3 have been successfully
developed by Qing’s group. These processes were transition-
metal-mediated and required a strong oxidant such as
PhI(OAc)2 for the presumable generation of CF3 radical
from CF3 anion. To the best of our knowledge, vinylic
trifluoromethylation of unactivated alkenes with Me3SiCF3 is
unknown. We decided to circumvent this limitation by
employing a common inexpensive reagent N-iodosuccinimide
for its two roles: (1) as a mild oxidant; (2) as an iodine source
for the iodotrifluoromethylated intermediate10a,d prior to
elimination. The hypothesis includes the base of known NIS-
promoted oxidative transformations under visible light;15
however, whether NIS is capable of generating the CF3 radical
from Me3SiCF3 remained unclear from the outset.
We chose the unactivated alkene 1a in the optimization
studies for its higher boiling point and ease of preparation.
Excess Me3SiCF3 (CF3 source) and NaOAc (initiator) were
adopted based on related trifluoromethylation condi-
tions.14b,13c,d Various reaction parameters were subsequently
screened (Table 1),16 and the initial results showed that, under
Table 1. Optimization Studies for NIS-Promoted
Trifluoromethylation of Alkene 1a with Me3SiCF3
a
entry
x
additive (equiv)
solvent
yield % (E/Z)
1
2
3
4
5
6
7
8
3.0
4.0
5.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.0
1.0
2.0
2.0
2.0
none
none
none
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
38 (94:6)
62 (92:8)
42 (93:7)
53 (93:7)
38 (93:7)
73 (93:7)
74 (92:8)
73 (93:7)
33 (96:4)
76 (93:7)
76 (93:7)
37 (94:6)
30 (94:6)
15 (93:7)
13 (92:8)
Ru(bpy)3Cl2·6H2O (0.025)
AgNO3 (0.2)
AgNO3 (1.2)
AgNO3 (2.0)
AgOAc (1.2)
AgOAc (1.2)
AgOAc (1.2)
AgOAc (1.2)
AgOAc (1.2)
AgOAc (1.2)
AgOAc (5.2)
AgOAc (1.2)
9
10
11
12
13
14
b
b
c
15
a
Yield and E/Z ratio were determined by 19F NMR analysis of the
crude mixture versus an internal standard (benzotrifluoride).
b
c
Without NaOAc. No irradiation, at 80 °C.
irradiation with blue LED at room temperature in DMF with
3.0 equiv of NIS, the corresponding trifluoromethylated alkene
product 2a was formed in 38% yield and good E/Z-selectivity
(94:6) (entry 1). Increasing the equivalents of NIS gave a
higher yield (62%), but no further improvement was achieved
with increased equivalents (entries 2−3). In these experiments,
we also observed small amounts (4−6%) of hydrotrifluoro-
methylated products that were difficult to separate from 2a.
Substituting NIS with NBS, NCS, or I2 gave no conversion at
all. Next, additive effects were explored. We first added the Ru-
based photocatalyst and found that the yield was only
10a
of alkenyl-CF3 (36%, 19F NMR, E/Z = 94:6) and allyl-CF3
(8%, 19F NMR) products. The longer carbon chain epoxide
(2z), ester (2aa), and amide (2ab) were all tolerated.
Oxidation of aliphatic alcohols such as 1ac catalyzed by
AgOAc in the presence of NIS and light is known,15a yet in our
reaction this substrate was chemoselectively converted to 2ac
B
DOI: 10.1021/acs.orglett.9b00332
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Scope of Trifluoromethylated Alkenes 2
a
General conditions: 1 (0.3 mmol), NIS (0.6 mmol), AgOAc (0.36 mmol), Me3SiCF3 (1.2 mmol), NaOAc (1.2 mmol), DMSO (3.0 mL), under
b
argon. The E/Z ratio was determined by 19F NMR analysis of the crude mixture. Larger excess of AgOAc (0.45 mmol) was used to inhibit side
product formation. Used 1.51 g (5.0 mmol) of 1q, DMSO (0.2 M). Recovered starting material.
c
d
in a good yield as the sole product. Even carboxylic acid 2ad
was compatible, which is rarely employed in the usually basic
conditions involving Me3SiCF3. These protecting-group-free
approaches for directly accessing functionalized trifluorome-
thylated alkenes are useful for enhancing step economy. It is
worth noting that Ag-catalyzed trifluoromethylation of arene
C−H bonds with Me3SiCF3 in DMSO at room temperature
has been reported,19a yet our reactions were devoid of any aryl-
CF3 side products which was likely due to the absence of
strong oxidants such as PhI(OAc)2. Styrene derivatives were
unreactive under these conditions. Such limitation also existed
in previously reported photocatalytic methods.10a,d,20 Finally,
late-stage trifluoromethylation of natural product derivatives
was achieved to install tethered trifluoromethylated alkene
units to the estrone (2ae), umbelliferone (2af), flavone (2ag),
and quinine (2ah) cores.21 This strategy allows the selective
placement of the CF3 group in bioactive molecules in the last
step which will be highly attractive for medicinal chemistry
research.7
Mechanistic studies were subsequently carried out to gain
more insights into the reaction. Subjecting 1a to preformed
AgCF322 in the presence of NIS with irradiation did not afford
any product 2a (eq 1), thus ruling out the presence of AgCF3
in the reaction mixture.
Cyclohexene also reacted under standard conditions to form
the trisubstituted alkenyl-CF3 product 6a, while at the same
time producing the anti-iodotrifluoromethyl product 6b, which
could not undergo HI elimination for alkene formation (eq
3).10a
Furthermore, we employed substrate 7, a radical clock4a in
the reaction to probe the radical mechanism (eq 4).
Cyclopentane derivatives 8a and 8b were obtained mainly,
which can be explained by the 5-exo-trig cyclization of the
radical species 7′ after the C−CF3 bond-forming event.
Ultimately an alkyl iodide should be formed at a primary
carbon, which either underwent SN2 displacement with
succinimide to give 8a or HI elimination to give alkene 8b.16
Another radical clock cyclopropane 9 was also used providing
exclusively the ring-opened products 10a (HI elimination
product) and 10b (SN2 displacement product) (eq 5), which
should derive from the initial radical intermediate 9′.16 These
studies strongly support the addition of a CF3 radical to the
alkene resulting in a carbon-based radical species such as 7′ or
9′.23
Using a deuterium-labeled substrate 3 in standard conditions
(cf. Scheme 2) gave the desired product 4 with one retained
deuterium (eq 2). No significant amount of deuterated
succinimide 5 was observed thus suggesting that succinimide
may not be the base for D-I elimination.
C
DOI: 10.1021/acs.orglett.9b00332
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Letter
nation process forming less soluble AgI and driving the
reaction forward, which also explains why stoichiometric
amounts of silver are required (cf. Table 1, entries 5−6) and a
weaker base acetate is equally effective. The dual roles of the
reagents in this system are most intriguing: (1) acetate acting
as both an initiator for Me3SiCF3 and a base for HI
elimination; (2) NIS acting as both an oxidant for CF3
anion and an iodine radical source; (3) silver(I) salt acting
as both an activator for NIS and a facilitator for dehydro-
halogenation. The impact of such a multifunctional system is a
highly streamlined process without the need for an extra
oxidant/reductant.
In conclusion, we have developed a new approach toward
trifluoromethylation of unactivated alkenes, which allows the
rapid generation of a wide array of synthetically useful and
pharmaceutically important trifluoromethylated alkenes with
high E-selectivities. Compared to other methods,10,14 this
protocol has the following advantages: (1) using easy-to-
handle Me3SiCF3 instead of gaseous CF3I as the CF3 source;
(2) using NIS as a mild oxidant instead of PhI(OAc)2; (3)
direct access of the alkenyl product 2 from 1 without separately
adding a base to the iodotrifluoromethyl intermediate C; (4)
using a visible light source (commonly available and cheap
blue LED) without precious metal photocatalysts. Further
investigation of the combination of NIS and light for alkene
activation is ongoing in our laboratory.
Based on these studies and literature examples, we propose
the following mechanism to rationalize product formation
(Scheme 3). Light promotes the cleavage of the N−I bond of
Scheme 3. A Plausible Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00332.
Experimental procedures and characterization data for
all new compounds (PDF)
NIS resulting in an iodine radical.15 This process is further
enhanced synergistically by the complexation of NIS (complex
A) with a silver(I) salt which acts as a Lewis acid.17a,16 The
optimization studies clearly showed the benefits of adding
AgOAc and using light (cf. Table 1, entries 1, 8, and 15).
Meanwhile, a CF3 anion is generated from Me3SiCF3 and
NaOAc, which is effectively oxidized to the CF3 radical. Such
type of oxidation has been described using a strong oxidant
PhI(OAc)2;14b,c however in our case, the N−I bond cleavage
process couples with this oxidation step conveniently resulting
in the formation of a succinimide anion.24 No extra oxidant is
required. Addition of the electron-deficient CF3 radical to
alkene 1 affords the trifluoromethylated secondary carbon
radical B.10a,d Radical clock experiments supported the
existence of this radical intermediate (cf. eqs 4−5). Rapid
recombination of radical B with the iodine radical leads to the
iodotrifluoromethyl intermediate C,25 as evidenced by the
detection of compound 6b (cf. eq 3). The displacement
products 8a and 10b also provided support for the presence of
alkyl iodides (cf. eqs 4−5). Finally, intermediate C undergoes
E2 elimination of HI to predominantly generate the E-alkene
product 2.10a Here we propose acetate acting as the base,
instead of succinimide, due to its higher concentration in the
reaction system (large excess of NaOAc) and the absence of
significant amounts of deuterated succinimide 5 (cf. eq 2). A
stronger base DBU has been employed for such elimination;10a
in our case, the silver(I) salt can facilitate the dehydrohaloge-
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gctsui@cuhk.edu.hk.
ORCID
Gavin Chit Tsui: 0000-0003-4824-8745
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Research Grants Council of
Hong Kong (CUHK 24301217) and the Chinese University of
Hong Kong (the Faculty Strategic Fund for Research from the
Faculty of Science and the Direct Grant for Research). We also
thank the Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences for funding.
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added to the reaction with 1a, no conversion was observed and no
significant amount of TEMPO-CF3 was detected. Separate H NMR
(7) For reviews, see: (a) Muller, K.; Faeh, C.; Diederich, F. Science
̈
2007, 317, 1881. (b) Purser, S.; Moore, P. R.; Swallow, S.;
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Nature 2011, 473, 470. (e) Wang, J.; Sanchez-Rosello, M.; Acena, C.;
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del Pozo, J. L.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu,
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(8) For selected examples, see: (a) Huang, Y.; Hayashi, T. J. Am.
Chem. Soc. 2016, 138, 12340. (b) Kojima, R.; Akiyama, S.; Ito, H.
Angew. Chem., Int. Ed. 2018, 57, 7196. (c) Gao, P.; Yuan, C.; Zhao, Y.;
Shi, Z. Chem. 2018, 4, 2201. (d) Fujita, T.; Fuchibe, T. K.; Ichikawa,
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(9) For selected examples, see: (a) Liu, T.; Shen, Q. Org. Lett. 2011,
13, 2342. (b) Cho, E. J.; Buchwald, S. L. Org. Lett. 2011, 13, 6552.
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1
studies revealed that NIS was not compatible with TEMPO and
underwent decomposition in the presence of TEMPO and, therefore,
could not convert 1a to 2a. See the SI for details.
(10) (a) Iqbal, N.; Choi, S.; Kim, E.; Cho, E. J. J. Org. Chem. 2012,
77, 11383. (b) Choi, W. J.; Choi, S.; Ohkubo, K.; Fukuzumi, S.; Cho,
E. J.; You, Y. Chem. Sci. 2015, 6, 1454. (c) Kim, S.; Park, G.; Cho, E.
J.; You, Y. J. Org. Chem. 2016, 81, 7072. (d) Nguyen, J. D.; Tucker, J.
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133, 4160. (e) Wallentin, C.-J.; Nguyen, J. D.; Finkbeiner, P.;
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(11) Besides alkene trifluoromethylation, CF3I is also commonly
used for trifluoromethylation of heterocycles and α-trifluoromethyla-
tion of carbonyl compounds under photoredox catalysis; see:
(a) Iqbal, N.; Choi, S.; Ko, E.; Cho, E. J. Tetrahedron Lett. 2012,
53, 2005. (b) Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2009, 131, 10875. (c) Pham, P. V.; Nagib, D. A.;
MacMillan, D. W. C. Angew. Chem., Int. Ed. 2011, 50, 6119 For a
recent example of iodotrifluoromethylation of unactivated alkenes
using CF3I and catalyzed by chloride ions, see: . (d) Beniazza, R.;
(24) The presence of succinimide is evidenced by products 2w/2x
(cf. Scheme 2) and 8a/10b (cf. eqs 4−5) via SN2 displacement of the
leaving group by the succinimide nucleophile.
(25) Zhang, Z.; Stateman, L. M.; Nagib, D. A. Chem. Sci. 2019, 10,
1207.
E
DOI: 10.1021/acs.orglett.9b00332
Org. Lett. XXXX, XXX, XXX−XXX