Electrophilic trifluoromethylation by copper-catalyzed addition of CF 3-transfer reagents to alkenes and alkynes

Article abstract of DOI:10.1021/ol3011419

Regio- and stereoselective Cu-catalyzed addition of the above hypervalent iodine reagent to alkynes and alkenes was achieved. In the presence of CuI, the reaction is suitable to perform trifluoromethyl-benzoyloxylation and trifluoromethyl-halogenation of

Full text of DOI:10.1021/ol3011419

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2882–2885
Electrophilic Trifluoromethylation by
Copper-Catalyzed Addition of CF3-
Transfer Reagents to Alkenes and Alkynes
,†
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Par G. Janson, Ibrahim Ghoneim, Nadia O. Ilchenko, and Kalman J. Szabo*
Department of Organic Chemistry, Stockholm University, SE-106 91 Stockholm,
Sweden
kalman@organ.su.se
Received April 27, 2012
ABSTRACT
Regio- and stereoselective Cu-catalyzed addition of the above hypervalent iodine reagent to alkynes and alkenes was achieved. In the presence of CuI,
the reaction is suitable to perform trifluoromethyl-benzoyloxylation and trifluoromethyl-halogenation of alkenes and alkynes. Electron-donating
substituents accelerate the process, and alkenes react faster than alkynes emphasizing the electrophilic character of the addition reaction.
Trifluoromethylated compounds have highly desirable
physical, physiological, and pharmacokinetic properties,
which renders them important synthetic targets in phar-
maceutical and agrochemical industries.1 A high demand
for structurally diverse trifluoromethylated compounds
requires development of new synthetic methods for selec-
tive formation of CÀCF3 bonds in organic substrates.1a,2
Reagents 1aÀb together with 1c have been extensively
used in CÀH functionalization based trifluoromethylation
reactions.2hÀl Commonly used strategies for introduction of
a CF3 group are based on substitution reactions (including
CÀH functionalization);2d,fÀq however there are a few
examples of addition reactions as well (Scheme 1).2t,v,3aÀ3c
It was shown3a that CuI and CF3I, in the presence of Zn
powder, undergo addition to alkynes, which after hydrolysis
gives vinyl-CF3 derivatives. Kumadaki and co-workers2t,v,3b
have shown that R,β-unsaturated ketones react with
CF3I in the presence of Et2Zn and catalytic amounts of
RhCl(PPh3)3 (Scheme 1), which can be employed for R-
trifluoromethylation of keto groups. Furthermore, S-tri-
fluoromethyl xanthates efficiently add to alkenes without
metal catalysis in a radical process.3c There are also several
examples for introduction of polyfluoroalkyl3d,e and tri-
fluormethylphosphate3f groups to CÀC multiple bonds.
We have now found that hypervalent iodine 1a under-
goesanaddition reaction withbothalkynes(2) and alkenes
(3) in the presence of a CuI catalyst affording vinyl-CF3 (4)
and alkyl-CF3 products (5À6) respectively. The reaction
proceeds with excellent regio- (4À5) and stereoselectivity
(4). An advantage of this approach is that use of gaseous
and rather costly reagent CF3I could be replaced by 1a and
that not only a trifluoromethyl but also another function-
ality could be introduced to the substrates. Furthermore,
this addition reaction represents one of the most atom
Figure 1. Electrophilic CF3 transfer reagents.
The appearance of highly reactive yet easily handleable
trifluoromethylating reagents inspired the development of
many new procedures. Togni and co-workers2nÀr,u devel-
oped the synthesis and use of easily accessible hypervalent
iodine reagents 1a and 1b (Figure 1), which are efficient
electrophilic CF3 transfer reagents.2jÀl,nÀr,u
† Home page: http://www.organ.su.se/ks/.
(1) (a) Pacheco, M. C.; Purser, S.; Gouverneur, V. Chem. Rev. 2008,
108, 1943. (b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
€
Chem. Soc. Rev. 2008, 37, 320. (c) Muller, K.; Faeh, C.; Diederich, F.
Science 2007, 317, 1881.
r
10.1021/ol3011419
Published on Web 05/21/2012
2012 American Chemical Society

economical4 applications of reagent 1a. The addition
reaction of 1a to alkynes 2aÀe requires relatively high
temperatures (typically 80À100 °C) and usually catalytic
amounts (10 mol %) of CuI. The isolated yield for the
reaction of phenyl acetylene 2a is about the same with
catalytic (entry 1) and stoichiometric amounts (entry 2) of
CuI. However, in the case of anisyl derivative 2b the yield
dropped substantially when the reaction was conducted
with 10 mol % CuI (entry 3) instead of a stoichiometric
amount (entry 4). Because of the limited thermostability of
1a, heating of the reaction mixture for extended times
decreased the yield. Therefore, using microwave condi-
tions was found to be beneficial in several cases (e.g.,
entries 5 and 7). The reactions usually proceed cleaner
and with better yields, when the substrates have electron
supplying substituents. For example, we obtained a better
yield with anisyl derivative 2b and methoxy naphthyl
substrate 2d than with nitro phenyl acetylene 2c.
Scheme 1. Examples for Trifluoromethylation by Addition to
CarbonÀcarbon Double and Triple Bonds (Ar = 2-Iodo-
phenyl)
Furthermore, silyl acetylene 2e could easily be func-
tionalized to give 4e, probably due to the presence of the
electron donating silyl functionality. In this case micro-
wave conditions gave the best yields. When the reac-
tion was conducted by traditional heating for extended
times, the yield dropped due to the decomposition of
product 4e. The addition reactions proved to be highly
regio- and stereoselective. The presented trifluoro-
methyl styrene derivatives 4aÀe are isolated as single
isomers. Although, the crude mixture contained some
unidentified byproducts, we could not find any evidence
for the formation of other regio- or stereoisomers.
Authentic synthesis (see Supporting Information) of 4b
has shown that the addition of 1a across the triple bond
occurs with trans selectivity.
Alkenes, such as 3aÀe, also undergo smooth addition
reactions with 1a using copper catalysis. In these reactions
the corresponding trifluoromethyl alkanes 5aÀe are formed
with high regioselectivity. Similarly to alkynes the reaction
proceeds with higher yield and more cleanly for electron-
rich styrenes. The addition reaction is relatively tolerant of
steric effects, as both para methoxy (3a) and ortho methoxy
styrene (3b) could be efficiently functionalized.
However, the reaction is faster for 3a than for 3b (see
below). Disubstituted alkene 3e also undergoes trifluoro-
methyl-benzoyloxylation reaction to give tertiary alcohol
derivative 5e. This process is more sluggish than the
reaction of the analog styrene derivatives and requires
microwave heating to proceed with high yield (Table 1,
entry 13). Not only styrene derivatives but also vinyl
sulfide (3d) and silane (3f) substrates undergo addition
reactions. Vinyl sulfide 3d reacted similarly to styrenes
3aÀc and 3e to give the expected trifluoromethyl benzoate
product 5d. However, vinyl silane 3f showed a surprising
reactivity. At elevated temperatures 3f and 1a with a
catalytic or stoichiometric amount of CuI gave a complex
mixture of products. On the other hand, when the reaction
was conducted at 20 °C with a stoichiometric amount of
CuI, compound 6awas formedinhighyield and selectivity.
In this reaction an iodide functionality was introduced
instead of an iodobenzoate. Furthermore, when CuI was
replaced by CuBr a bromination of the silylated carbon
occurred (entry 14) affording 6b. Thus, in the presence of a
silyl substituent the trifluoromethyl-benzoyloxylation re-
action of alkenes can be switched to a trifluoromethyl-
halogenation process further extending the synthetic poten-
tial of the above methodology.
(2) (a) Gouverneur, V. Science 2009, 325, 1630. (b) Grushin, V. V.
Acc. Chem. Res. 2009, 43, 160. (c) Sato, K.; Tarui, A.; Omote, M.; Ando,
A.; Kumadaki, I. Synthesis 2010, 1865. (d) Nagib, D. A.; MacMillan,
D. W. C. Nature 2011, 480, 224. (e) Parsons, A. T.; Buchwald, S. L.
Nature 2011, 480, 184. (f) Watson, D. A.; Su, M.; Teverovskiy, G.;
Zhang, Y.; Garcıa-Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science
´
2009, 325, 1661. (g) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.;
Watson, D. A.; Buchwald, S. L. Science 2010, 328, 1679. (h) Wang, X.;
Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3648. (i) 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. (j) Wang, X.; Ye, Y.; Zhang, S.; Feng,
J.; Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, 133, 16410. (k)
Parsons, A. T.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 9120. (l)
Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 4986.
(m) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.;
Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108,
14411. (n) Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem., Int. Ed.
2007, 46, 754. (o) Koller, R.; Stanek, K.; Stolz, D.; Aardoom, R.;
Niedermann, K.; Togni, A. Angew. Chem., Int. Ed. 2009, 48, 4332. (p)
€
Niedermann, K.; Fruh, N.; Vinogradova, E.; Wiehn, M. S.; Moreno, A.;
Togni, A. Angew. Chem., Int. Ed. 2011, 50, 1059. (q) Tomashenko, O. A.;
ꢀ
Escudero-Adan, E. C.; Martınez Belmonte, M.; Grushin, V. V. Angew.
´
Chem., Int. Ed. 2011, 50, 7655. (r) Zanardi, A.; Novikov, M. A.; Martin,
E.; Benet-Buchholz, J.; Grushin, V. V. J. Am. Chem. Soc. 2011, 133,
20901. (s) Prakash, G. K. S.; Krishnan, H. S.; Jog, P. V.; Iyer, A. P.;
Olah, G. A. Org. Lett. 2012, 14, 1146. (t) Sato, K.; Omote, M.; Ando, A.;
ꢁ
Kumadaki, I. Org. Lett. 2004, 6, 4359. (u) Matousek, V.; Togni, A.;
Bizet, V.; Cahard, D. Org. Lett. 2011, 13, 5762. (v) Sato, K.; Yuki, T.;
Yamaguchi, R.; Hamano, T.; Tarui, A.; Omote, M.; Kumadaki, I.;
Ando, A. J. Org. Chem. 2009, 74, 3815. (w) Weng, Z.; Li, H.; He, W.;
Yao, L.-F.; Tan, J.; Chen, J.; Yuan, Y.; Huang, K.-W. Tetrahedron 2012,
68, 2527. (x) Chu, L.; Qing, F.-L. Org. Lett. 2012, 14, 2106. (y) Parsons,
A. T.; Senecal, T. D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2012, 51,
2947.
(3) (a) Kitazume, T.; Ishikawa, N. J. Am. Chem. Soc. 1985, 107, 5186.
(b) Sato, K.; Omote, M.; Ando, A.; Kumadaki, I. Org. Synth. 2009, Coll.
Vol. 11, 336. (c) Bertrand, F.; Pevere, V.; Quiclet-Sire, B.; Zard, S. Z. Org.
Lett. 2001, 3, 1069. (d) Fuchikami, T.; Ojima, I. Tetrahedron Lett. 1984,
25, 303. (e) Uneyama, K.; Kitagawa, K. Tetrahedron Lett. 1991, 32,
3385. (f) Yang, Z. Y.; Burton, D. J. J. Org. Chem. 1992, 57, 4676.
(4) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259.
Org. Lett., Vol. 14, No. 11, 2012
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Table 1. Electrophilic Trifluoromethylation of Alkynes and
Alkenes by Copper-Mediated Addition of 1aa
Figure 2. Competitive trifluoromethyl-benzoyloxylation experi-
ment to explore the electronic effects on the reactivity.
the substituent effects we performed competitive trifluoro-
methyl-benzoyloxylation reactions. When a mixture of 2b
and 2a was reacted with 1a and a stoichiometric amount of
CuI a 1:0.5 mixture of 4b and 4a was formed (Figure 2).
This shows that 2b reacts about twice as fast as 2a. This
acceleration is clearly due to the electron-donating effect of
the methoxy substituent in 2b. We have also compared the
rates of reaction of 2b and 3a. These experiments showed
that alkene 3a undergoes trifluoromethyl-benzoyloxyla-
tion four times as fast as alkyne 2b under the same reaction
conditions. These simple competitive reactions strongly
indicate the electrophilic nature of the copper-catalyzed
addition of 1a. A similar competitive experiment was
performed to assess the steric effects of the substrates.
Competitive trifluoromethyl-benzoyloxylation of 3a
and 3b showed that para-substituted substrate 3a re-
acted about three times as fast as its ortho-substituted
counterpart 3b.
We have also studied the effects of the counterions on
copper. It was found that CuCl, CuBr, and CuOAc give
results similar to those of CuI (except entries 14À15);
however the yields are usually higher with CuI. Interest-
ingly, CuPF6(MeCN)4 successfully applied in allylic CÀH
trifluoromethylation2k with 1a performed very poorly
under the above reaction conditions. Chloroform and
dichloroethane proved to be the best solvents; however
in many reactions chloroform gave cleaner crude products
and thus better yields than dichloroethane. It is interesting
to note that, in methanol, the preferred solvent in the CÀH
trifluoromethylation with 1a,2j,k only traces of the product
was formed. Reagents 1b and 1c proved to be much less
reactive and selective in the addition reactions. Using 1c
with stoichiometric and catalytic amounts of copper gave
no products at all. Reagent 1b reacted with 3f; however the
reaction mixture was very complex and contained only
traces of 6a. Interestingly, Huang and co-workers2w have
shown that the copper-catalyzedreaction of 1bwithphenyl
acetylene derivatives (such as 2) in the presence of base
and phenanthroline leads to formation of trifluoromethyl
acetylene derivatives. Thus, instead of addition (entries
1À7) CÀH trifluoromethylation occurs. The iodobenzoate
group can easily be removed from the product by standard
hydrolysis (Figure 3). When the benzoate product 5a
formed from 3a and 1a (entry 8) was hydrolyzed
(without purification) by K2CO3, alcohol 7 was obtained
in 77% overall yield.
a Unless otherwise stated copper(I) iodide (0.01 mmol, 10 mol %), 1a
(47.4 mg, 0.15 mmol, 1.5 equiv), and substrate 2or 3(0.10 mmol) were reacted
in chloroform (0.5 mL) for the indicated times and temperatures. b Reaction
conditions: temperature/time = °C/h. c Ar = 2-iodo-phenyl. d Isolated yield
(%).e Stoichiometric amount (0.10 mmol) of CuI was used. f The reaction was
conducted under microwave irradiation. g 0.10 mmol of CuBr was used.
As mentioned above the electron-donating groups seem
toacceleratethereaction. Inordertogainmoreinsight into
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Org. Lett., Vol. 14, No. 11, 2012

addition of TEMPO, (2,2,6,6-tetramethyl-piperidin-1-yl)-
oxyl, which is a well-known radical scavenger. Thus, it was
suggested that the reaction follow a radical mechanism
involving single electron transfer (SET) steps. Several
other mechanistic studies on the transfer of the trifluoro-
methyl group from 1aÀc to organic substrates suggest a
radical and SET mechanism.2j,k,x,5a Our preliminary me-
chanistic studies also show that TEMPO inhibits the
addition of 1a to CÀC multiple bonds, for example to 3a
(entry 9). Furthermore, formation of 4aÀe by trans addi-
tion of 1a across the triple bond of 2aÀe (entries 1À8)
suggests a two-step process. All these findings indicate that
the allylic CÀH functionalization and the presented addi-
tion reaction might have a similar mechanism involving
trifluoromethyl radical intermediates. Another alternative
isthat1aoxidizes the Cu(I) catalyst toforma Cu(III)ÀCF3
complex.2i,k Hypervalent iodine reagents are known to
easily oxidize transition metals, even Pd(II), to higher
oxidation states.5bÀh Exploration of the mechanistic de-
tails of the addition reaction is an ongoing project in our
laboratory.
Figure 3. Hydrolysis of 5a to β-trifluoromethyl alcohol 7.
The reaction conditions of the above addition process
and some of the reported copper-catalyzed allylic CÀH
trifluoromethylation reactions2iÀk are rather similar.
When substrates with allylic CÀH bonds (such as 8) were
reacted with 1a under the usual catalytic conditions an
inseparable mixture of several products were formed. Both
allylic trifluoromethylation (9) and addition (10) products
could be detected (by 1H NMR and MS) as main compo-
nents in this reaction mixture (Figure 4).
In summary, we have shown that hypervalent iodine 1a
undergoes Cu-catalyzed addition to alkenes and alkynes.
The reaction proceeds with high regio- and stereoselectiv-
ity. In the case of vinyl silane substrate 3f, trifluoromethyl-
halogenation takes place instead of the expected benzoy-
loxylationprocess(entries 14À15). The addition reaction is
accelerated by electron-donating substituents, and alkenes
react faster than alkynes under identical reaction condi-
tions. The described reaction is suitable for the synthesis
of new trifluoromethyl substances, which are important
synthetic targets in pharmaceutical and agrochemical
industries1,6 using inexpensive substrates (2À3) and easily
handleable CF3 source 1a.
Figure 4. Reaction with substrates containing allylic CÀH bond.
This suggests that the allylic CÀH trifluoromethylation
with hypervalent iodines (1) and the above presented
addition reaction take place via similar reaction intermedi-
ates. In fact, an addition elimination type mechanism for
the Cu-catalyzed allylic CÀH functionalization using 1c as
the CF3 source.2i,k,x Formation of addition byproducts in
allylic CÀH trifluoromethylation reactions conducted in
the presence of hypervalent iodines was also reported.2x,y
Currently, the mechanism of the CÀH functionalization
process is also unclear. Wang and co-workers2j studying
the mechanism of allylic CÀH trifluoromethylation by 1a
(cf. Figure 4) have found that the reaction is inhibited by
Acknowledgment. The authors are thankful for the
financial support of the Swedish Research Council (VR)
and the Knut och Alice Wallenbergs Foundation via the
Center of Molecular Catalysis at Stockholm University
(CMCSU).
Supporting Information Available. Detailed experimen-
tal procedures and compound characterization data are
given. This material is available free of charge via the
Internet at http://pubs.acs.org.
ꢀ
(5) (a) Mace, Y.; Pradet, C.; Popkin, M.; Blazejewski, J.-C.; Magnier,
E. Tetrahedron Lett. 2010, 51, 5388. (b) Lyons, T. W.; Sanford, M. S.
Chem. Rev. 2010, 110, 1147. (c) Dick, A. R.; Hull, K. L.; Sanford, M. S.
J. Am. Chem. Soc. 2004, 126, 2300. (d) Powers, D. C.; Geibel, M. A. L.;
Klein, J. E. M. N.; Ritter, T. J. Am. Chem. Soc. 2009, 131, 17050. (e)
Powers, D. C.; Ritter, T. Nat. Chem. 2009, 1, 302. (f) Ariafard, A.;
Hyland, C. J. T.; Canty, A. J.; Sharma, M.; Brookes, N. J.; Yates, B. F.
Inorg. Chem. 2010, 49, 11249. (g) Pilarski, L. T.; Selander, N.; Bose, D.;
Szabo, K. J. Org. Lett. 2009, 11, 5518. (h) Selander, N.; Willy, B.; Szabo,
K. J. Angew. Chem., Int. Ed. 2010, 49, 4051.
(6) Ding, Y.; Huang, X. Heteroatom. Chem. 2003, 14, 304.
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The authors declare no competing financial interest.
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