Copper-catalyzed direct C-H trifluoromethylation of quinones

Article abstract of DOI:10.1021/ol4016095

An efficient and practical methodology has been developed to introduce the CF₃ group onto quinones through Cu(I)-catalyzed direct C-H trifluoromethylation of quinones.

Full text of DOI:10.1021/ol4016095

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper-Catalyzed Direct CꢀH
Trifluoromethylation of Quinones
Xi Wang, Yuxuan Ye, Guojing Ji, Yan Xu, Songnan Zhang, Jiajie Feng,
Yan Zhang,* and Jianbo Wang*
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory
of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, Peking University, Beijing 100871, China
yan_zhang@pku.edu.cn; wangjb@pku.edu.cn
Received June 7, 2013
ABSTRACT
An efficient and practical methodology has been developed to introduce the CF3 group onto quinones through Cu(I)-catalyzed direct CꢀH
trifluoromethylation of quinones.
Quinones can transfer electrons and protons and, thus,
behave like redox centers.1 Many natural products contain
quinone subunits.2 Moreover, molecules bearing a qui-
none framework have been widely applied in the realm
of material sciences, pharmaceuticals, and biochemistry.2
Quinone derivatives are also used as versatile oxidizing
reagents, ligands, and synthons in organic synthesis.3
On the other hand, the trifluoromethyl group is valu-
able in the fields of pharmaceuticals, agrochemicals, and
material sciences.4 Due to the unique properties of CF3-
containing compounds including high electronegativity,
lipophilicity, metabolic stability, and bioavailability, it is
highly significant to develop efficient methods to introduce
the trifluoromethyl group onto organic molecules.5 The
traditional pathway to CF3-bearing building blocks is a
Swarts-type process, which requires exhaustive chlorination,
followed by chlorine/fluorine exchange under harsh reac-
tion conditions.6 Modern trifluoromethylation strategies
are based on transition-metal-catalyzed or -mediated cross-
coupling reactions5,7 and radical trifluoromethylations.8,9
(6) Swarts, F. Bull. Soc. Chim. Belg. 1892, 24, 309.
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R. H. Naturally Occurring Quinones IV; Blackie Academic: London, 1997.
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10.1021/ol4016095
XXXX American Chemical Society

Although remarkable progress has been made on the
trifluoromethylation of various types of organic com-
pounds, methods that introduce the CF3 group onto
quinones are still very limited. The few reported methods
currently available for CF3-containing quinone synthesis
all need multiple synthetic steps, which usually include
reduction, protection, bromination, trifluoromethylation,
and deprotection/oxidation (Scheme 1).10 To the best of
our knowledge, direct CꢀH trifluoromethylation of qui-
nones is not known in the literature.
initially applied to allylic trifluoromethylation of olefins
using electrophilic trifluoromethylation reagents (Togni
reagent and Umemoto regent), reported by Buchwald,11
Liu,12 and our group13 (Scheme 2a), although a different
reaction mechanism may operate. Following these reports,
various metal-catalyzed trifluoromethylation reactions
or related reactions with electrophilic trifluoromethyla-
tion reagents have been documented.14 In all these reports,
the trifluoromethyl radical adds to an electron-rich
double bond. Inspired by the radical trifluoromethylation
of heteroarenes recently reported by MacMillan9a and
Baran,9b,d in which the CF3 radical also adds to electron-
deficient hetero aromatic systems, we conceived that the
CF3 radical may also add to electron-deficient double bond
of quinones. Herein we report that the catalytic trifluor-
omethylation shown in Scheme 2a indeed works with
quinones. This transformation represents the first catalytic
direct trifluoromethylation of quinones (Scheme 2b).15
Scheme 1. Known Method for Trifluoromethylation of Quinone
Scheme 2. Direct CꢀH Trifluoromethylation of Quinones
An interesting recent development in radical trifluoro-
methylation is that electrophilic trifluoromethylation re-
agents (CF3þ) undergo single-electron-transfer (SET)
reduction by a Cu(I) catalyst, followed by a radical process
and then back electron transfer to regenerate the Cu(I)
catalyst. This type of Cu(I)-catalyzed process has been
(8) For reviews, see: (a) Studer, A. Angew. Chem., Int. Ed. 2012, 51,
8950. (b) Ye, Y.; Sanford, M. S. Synlett 2012, 23, 2005. (c) Liu, H.; Gu,
Z.; Jiang, X. Adv. Synth. Catal. 2013, 355, 617.
(9) (a) Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224.
(b) 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. (c) Ye, Y.; Lee, S. H.; Sanford, M. S. Org. Lett. 2011, 13, 5464.
(d) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder, E. D.; Dixon, D. D.;
At the outset of this investigation, vitamin K 1awas used
as the substrate to screen the reaction conditions for
possible direct CꢀH trifluoromethylation. A trace amount
of trifluoromethylated product 3a was detected by treat-
ment of 1a with Togni reagent 2a16,17 in the presence of
20 mol % of CuCl in MeOH at 80 °C (Table 1, entry 1).
After preliminary solvent screening (Table 1, entries 2ꢀ6),
we identified that the reaction in t-BuOH at rt afforded
the desired product in 72% GC yield (Table 1, entry 6). We
also examined mixed solvents (Table 1, entries 7ꢀ9), and
the conversion was slightly improved using a solvent
mixture of t-BuOH/DCM (1:1, v/v)(Table 1, entry 8).
A range of temperature was then screened. The yield could
be further increased at elevated temperature (Table 1,
ꢀ
Rodriguez, R. A.; Baxter, R. D.; Herle, B.; Sach, N.; Collins, M. R.;
Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95.
€
(10) (a) Hunig, S.; Bau, R.; Kemmer, M.; Meixner, H.; Metzenthin,
T.; Peters, K.; Sinzger, K.; Gulbis, J. Eur. J. Org. Chem. 1998, 335.
(b) Tuyen, N. V.; Kesteleyn, B.; De Kimpe, N. Tetrahedron Lett. 2002,
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58, 121. (c) Lanfranchi, D. A.; Belorgey, D.; Muller, T.; Vezin, H.;
Lanzerd, M.; Davioud-Charvet, E. Org. Biomol. Chem. 2012, 10, 4795.
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9120.
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Gong, T. J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 15300.
(13) Wang, X.; Ye, Y.; Zhang, S.; Feng, J.; Xu, Y.; Zhang, Y.; Wang,
J. J. Am. Chem. Soc. 2011, 133, 16410.
(14) (a) Parsons, A. T.; Senecal, T. D.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2012, 51, 2947. (b) Shimizu, R.; Egami, H.; Hamashima,
Y.; Sodeoka, M. Angew. Chem., Int. Ed. 2012, 51, 4577. (c) Mizuta, S.;
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Galicia-Lopez, O.; Engle, K. M.; Verhoog, S.; Wheelhouse, K.; Rassias,
(15) While the manuscript was under preparation, a Cu-mediated
trifluoromethylation of quinones was reported online. See: Ilchenko,
ꢀ
N. O.; Janson, P. G.; Szabo, K. J. Chem. Commun. 2013, 49, DOI:
10.1039/C3CC43357A.
G.; Gouverneur, V. Chem.;Eur. J. 2012, 18, 8583. (d) Zhu, R.;
Buchwald, S. L. J. Am. Chem. Soc. 2012, 134, 12462. (e) Yasu, Y.;
Koike, T.; Akita, M. Angew. Chem., Int. Ed. 2012, 51, 9567. (f) Li, Y.;
Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8221. (g) Mizuta, S.; Engle,
K. M.; Verhoog, S.; Galicia-Lopez, O.; O’Duill, M.; Medebielle, M.;
Wheelhouse, K.; Rassias, G.; Thompson, A. L.; Gouverneur, V. Org.
Lett. 2013, 15, 1250. (h) Yasu, Y.; Koike, T.; Akita, M. Org. Lett. 2013,
15, 2136. (i) Egami, H.; Shimizu, R.; Kawamura, S.; Sodeoka, M.
Angew. Chem., Int. Ed. 2013, 52, 4000. (j) Mizuta, S.; Verhoog, S.;
Engle, K. M.; Khotavivattana, T.; O’Duill, M.; Wheelhouse, K.;
(16) (a) Eisenberger, P.; Gischig, S.; Togni, A. Chem.;Eur. J. 2006,
12, 2579. (b) Niedermann, K.; Welch, J. M.; Koller, R.; Cvengros, J.;
Santschi, N.; Battaglia, P.; Togni, A. Tetrahedron 2010, 66, 5753. (c)
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Niedermann, K.; Fruh, N.; Senn, R.; Czarniecki, B.; Verel, R.; Togni, A.
Angew. Chem., Int. Ed. 2012, 51, 6511.
(17) For related electrophilic trifluoromethylation reagents, see:
(a) Noritake, S.; Shibata, N.; Nakamura, S.; Toru, T.; Shiro, M. Eur.
J. Org. Chem. 2008, 3465. (b) Matsnev, A.; Noritake, S.; Nomura, Y.;
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B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Direct CꢀH Trifluoromethylation of Quinonesa
Table 1. Optimization of Direct CꢀH Trifluoromethylation of
Quinonea
entry
cat.
þCF3
solvent
t (°C)
yieldb
1
2
3
4
5
6
7
8
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuI
CuI
CuI
CuI
CuTcd
CuTc
CuCl2
ꢀ
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2c
2d
2a
2a
MeOH
DMF
DCM
i-PrOH
2-methyl-2-butanol
t-BuOH
t-BuOH/CH2Cl2 (3:1)
t-BuOH/CH2Cl2 (1:1)
t-BuOH/CH2Cl2 (1:3)
t-BuOH/CH2Cl2 (1:1)
t-BuOH/CH2Cl2 (1:1)
t-BuOH/CH2Cl2 (1:1)
t-BuOH/CH2Cl2 (1:1)
t-BuOH/CH2Cl2 (1:1)
t-BuOH/CH2Cl2 (1:1)
t-BuOH/CH2Cl2 (1:1)
t-BuOH/CH2Cl2 (1:1)
t-BuOH/CH2Cl2 (1:1)
t-BuOH/CH2Cl2 (1:1)
80
25
25
25
25
25
25
25
25
55
75
55
55
55
55
55
55
55
55
trace
trace
58%
29%
64%
72%
71%
74%
59%
79%
80%
84%c
72%
no
9
10
11
12
13
14
15
16
17
18
19
no
trace
trace
40%
trace
a Reaction conditions: quinone (0.2 mmol, 1.0 equiv), electrophilic
trifluoromethylation reagent (0.4 mmol, 2.0 equiv), catalyst (20 mol %),
solvent (1 mL), 12 h. b GC yield. c The isolated yield is 83%. d CuTc =
(thiophene-2-carbonyloxy)copper.
a Reaction conditions: quinone 1 (0.2 mmol, 1.0 equiv), 2a (0.4 mmol,
2.0 equiv), CuI (20 mol %), t-BuOHꢀCH2Cl2 (1:1, v/v,1.0 mL), 55 °C,
entries 10, 11). 3a could be obtained in 84% isolated yield
when CuI was employed instead of CuCl, and no hydro-
quinone byproducts were detected (Table 1, entry 12).
Replacing 2a with 2b led to a slight decline in the yield
(Table 1, entry 13). The reaction was totally shut down
when CuI/Umemoto reagent 2c or CuI/Umemoto reagent
2d was used (Table 1, entries 14, 15). A trace product was
observed by using CuTc/Umemoto reagent 2c and CuTc/
Umemoto reagent 2d (Table 1, entries 16, 17). Finally,
CuCl2 only showed moderate efficiency (Table 1, entry18),
and a control experiment showed that a copper catalyst
was necessary in this reaction (Table 1, entry 19).
With the optimized reaction conditions in hand, we then
proceeded to study the scope of this reaction. As shown in
Scheme 3, a number of quinone derivatives underwent
smooth trifluoromethylation under optimal conditions.
High reactivity was observed with naphthoquinones bear-
ing either electron-rich or -deficient arene substituents
(3bꢀe). The sensitive chlorine and bromine at the β-position
of naphthoquinone, which would be vulnerable in Pd-
catalyzed transformations, was compatible with the reac-
tion conditions. These halide functional groups are valuable
because they can be used in further transformations.
b
c
12 h. Isolated yield. Based on 19F NMR analysis using 4-CF3O-
C6H4OCF3 as an internal standard. d Quinone 1 (0.4 mmol, 2.0 equiv),
2a (0.2 mmol, 1.0 equiv). e quinone 1 (0.5 mmol, 2.5 equiv), 2a (0.2 mmol,
1.0 equiv). f 50 mol % CuI was used.
Notably, naphthoquinone bearing a N-methyl aniline sub-
stituent also worked well, providing 3h in decent yield.
The yield of 3i was based on 2a, and excess 1,4-naphtho-
quinone was necessary to avoid further trifluoromethyla-
tion of product 3i. 1,4-Anthraquinone 1j exhibited low
efficiency due to its low solubility. Monotrifluoromethy-
lated benzoquinone 3k was obtained in 72% yield (based
19F NMR analysis). Benzoquinone fused with an aliphatic
ring also reacted successfully with 2a to give 3l in accep-
table yield. Trifluoromethylation of trimethylbenzoqui-
none showed moderate efficiency and yielded 3m in 52%
yield. The yield of 3m could be increased to 65% with
a high catalyst loading (50%). Benzoquinones bearing
methoxy and aryl groups were also employed, affording
corresponding trifluoromethyl products 3n and 3o in
moderate yield, respectively.
To gain insight into the reaction mechanism, we have
designed a series of experiments (Scheme 4). First, we
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Experiments for Mechanistic Study
Scheme 5. Mechanistic Rationale
found that no reaction occurred when 1a was treated with
stoichiometric CuI in the absence of Togni reagent 2a,
which indicatesthatCuIcannot be oxidized bythe quinone
substrates. In order to probe possible radical intermedi-
ates, the trifluoromethylation reaction was then conducted
under the standard conditions in the presence of different
amounts of radical scavenger TEMPO (2,2,6,6-tetramethyl-
1-piperidinyloxy).13 When adding 20 mol % TEMPO, 3a
was diminished to 57% yield (19F NMR), while the TEM-
POꢀCF3 adduct was formed in 18% yield as estimated by
19F NMR analysis. In the presence of 1.0 equiv of TEMPO,
the 19F NMR yield of 3a was further decreased to 31%,
while the TEMPOꢀCF3 adduct yield increased to 61%.
The reaction was almost shut down by adding 2.0 equiv
of TEMPO. However, no TEMPOꢀquinone adducts were
detected in these experiments.
Scheme 6. Attempted Trifluoromethylation with Electron-
Deficient Double Bond
Furthermore, acid catalysts, including BF3 Et2O, AuCl3,
3
TiCl4, FeCl3, and CF3CO2H (TFA), were employed in
this reaction instead of CuI. TiCl4 and FeCl3 achieved
the conversion, giving 3a in 15% and 31% 19F NMR
yield, respectively. Only trace 3a was observed by using
the expected trifluoromethylation product. Thus, we consider
that the success of this quinone trifluoromethylation method
is largely attributed to the special structure of quinones.
In summary, we have developed a novel and practical
reaction for trifluoromethylated quinone synthesis. In due
course, the C(sp2)ꢀCF3 bond is formed on an electron-
deficient π-system under mild conditions. The reaction
employs cheap copper iodide as the catalyst and the
hypervalent iodine(III) reagent 2a as both the oxidant
and CF3 source. The direct CꢀH functionalization stream-
lines the synthetic routes and has an advantage over
previous methods. Further work will focus on the expan-
sion of the substrate scope and in-depth studies to unam-
biguously establish the reaction mechanism.
BF3 Et2O, AuCl3, and TFA. These results indicate that CuI
does not act as a nonredox acid catalyst to activate the
substrates.
3
Based on these observations, we considered that the
CF3 radical is involved in the transformation (Scheme 5).
At first, Togni reagent 2a is activated by CuI, generating
radical intermediate A. Further decomposition of A af-
fords Cu(II) species B with simultaneous release of the CF3
radical. Notably, it is possible that resulting Cu(II) species
B undergoes a second SET oxidation by 2a to produce
radical intermediate A0. The collapse of A0 produces the
CF3 radical and Cu(III) complex B0. The putative process
is consistent with the fact that the reaction is not quenched
by catalytic TEMPO and that Cu(II) also catalyzes this
transformation (Table1, entry 18). The CF3 radical then
undergoes addition to quinone to give radical C. Oxida-
tion of the radical C regenerates active Cu(I) or Cu(II)
species and forms carbon cation D, which is followed
by deprotonation to complete the trifluoromethylation
process.
Acknowledgment. Supported by 973 Program (No.
2009CB825302) and NSFC (Grant No. 21272010). The
authors thank Mr. Xiaoshen Ma (Peking University) for
helpful suggestions.
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra of all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
Finally, we conceived that this trifluoromethylation
reaction might also be applied to other electron-deficient
double bonds (Scheme 6). However, none of them affords
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX