Copper-mediated C-H trifluoromethylation of quinones

Article abstract of DOI:10.1039/c3cc43357a

Quinones undergo copper-mediated C-H trifluoromethylation reactions using a hypervalent iodine reagent. The reactions have a broad synthetic scope involving naphtho, alkyl, chloro and methoxy quinones.

Full text of DOI:10.1039/c3cc43357a

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Copper-mediated C–H trifluoromethylation of
quinones†
Cite this: Chem. Commun., 2013,
49, 6614
´
´
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Nadia O. Ilchenko, Par G. Janson and Kalman J. Szabo*
¨
Received 6th May 2013,
Accepted 4th June 2013
DOI: 10.1039/c3cc43357a
www.rsc.org/chemcomm
Quinones undergo copper-mediated C–H trifluoromethylation reactions
using a hypervalent iodine reagent. The reactions have a broad synthetic
scope involving naphtho, alkyl, chloro and methoxy quinones.
Quinones are very important intermediates in biological processes,1
such as cell respiration, electron-transfer and transport processes, as
well as in drug discovery, as anticancer,2 antibacterial3 and antimalarial
Fig. 1 Electrophilic trifluoromethylating agents.
agents.4 Furthermore, quinones are also widely used in transition metal gave complex reaction mixtures. By subsequent studies we have found
catalysis as re-oxidants and/or activator ligands.5 Considering the very that addition of bis(pinacolato)diboron, (B2pin2, 5), accelerated the
high importance of these compounds there is obviously significant trifluoromethylation of BQ and substantially increased the reproduci-
interest in finding new synthetic procedures for functionalization bility of the reaction. It is well established6a,e,f,14 that various organo-
of quinones to widen their structural diversity. Excellent procedures boron species perform well as radical activators, which may explain the
have appeared in the literature for functionalization of these species, beneficial effects of 5. Using the optimized standard conditions
including very efficient C–H functionalization methods.6 However, (Scheme 1) 1a and 2a in the presence of CuCN 4 and B2pin2 5 at
introduction of the trifluoromethyl functionality,7 which is also room temperature resulted in CF3–BQ 3a in a clean reaction with high
privileged in medicinal chemistry8 and efficiently modifies the redox yield (Scheme 1, entry 1). Thus, 3a forms with selective vinylic C–H
properties of quinones,9 has received surprisingly little attention.4,9 trifluoromethylation, a process which has very few previous examples in
Recently, useful trifluoromethylation procedures have been pub- the literature.10b,c Using 1b as a CF3 source the reaction proceeds with
lished,10 in which the CF3 group was introduced into alkenes and moderate yield (entry 2) due to formation of unidentified byproducts,
arenes via hypervalent iodine reagents, such as 1a-b (Fig. 1),11 or related while 1c proved to be inefficient (entry 3).
highly oxidized reagents (1c)12 or reaction intermediates.
When the reaction was performed without B2pin2 5 (entry 4),
Most mechanistic investigations connected with these method we could not observe any reaction at room temperature. At
development studies7c,10 have revealed that under oxidative conditions elevated temperature (entry 5) in the absence of 5 reagent 1a
the CF3 functionality is usually transferred in a radical process.13 For was fully consumed, however the yield was low due to formation
example, we found10a that in the oxytrifluoromethylation of alkenes and of byproducts. Under these conditions the reaction also suffered
alkynes hypervalent iodine 1a undergoes homolytic cleavage in the from reproducibility issues.
presence of a Cu-catalyst. In several recent publications6a,b,f involving
Replacement of CuCN with CuOAc, CuCl or CuI led to a drop
C–H functionalization of quinones, the importance of radical processes in the yield (entries 6–8). The reaction did not proceed when
was pointed out. We envisaged that the domains of the oxidative catalytic amounts (entry 9) of CuCN (or other Cu-sources) were
trifluoromethylation and the C–H functionalization of quinones could used but upon addition of stoichiometric amounts (1 equiv.) of
be linked together by trifluoromethylation of quinones via a radical KCN or Bu4N–CN quinone 3a was formed in moderate yields
mechanism. Our preliminary studies indicated that 1a reacts with (entries 10 and 11). This indicates that one equivalent of
benzoquinone (BQ) 2a in the presence of Cu-salts at elevated tempera- cyanide salt is necessary for the formation of CF3–BQ product
tures. However, the reactions suffered from a low reproducibility and 3a. As the cyanide ion may potentially act as a base to abstract a
proton from 2a, we performed the reaction using NaHCO3,
Na2CO3 and Et3N, but these bases proved to be ineffective
(entry 12). Due to the low price of CuCN, we further developed
Department of Organic Chemistry, Stockholm University, SE-106 91 Stockholm,
Sweden. E-mail: kalman@organ.su.se
our process using stoichiometric amounts of CuCN (entry 1),
which also gives a higher yield than that obtained when using
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and compound characterization data. See DOI: 10.1039/c3cc43357a
c
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briefly screened other solvents in place of CDCl3. The reaction in
MeCN and DMF proceeds with poor yields (entries 14 and 15),
while in MeOH, benzene and THF 3a did not form (entry 16).
Subsequently, we studied the synthetic scope of the reaction
using quinones with various substituents (Table 1). Naphthoqui-
none is one of the most important quinone cores in bioactive
molecules, such as in vitamin K and in menadione (2c) based
drugs.1,4 The above methodology worked smoothly for trifluoro-
methylation of naphthoquinone 2b itself and for menadione 2c
(entries 2 and 3). Brominated analog 2d gave trifluoromethyl
derivative 3d (entry 4), which can easily be functionalized further
by cross-coupling reactions to give trifluoromethylated vitamin K
derivatives or other drug molecules. Trifluoro-menadione 3b
is a promising core for antimalarial drugs.4 It was previously
synthesized by Davioud-Charvet and co-workers4 in a four step
synthesis process via a halogenated hydroquinone derivative (see
the synthesis section in the ESI†).9 Using the above procedure 3b
can be prepared from 2b in a single step by C–H functionalization.
Methyl substituted quinone 2e could be converted to the corre-
sponding mono-CF3 derivative 3e using the above standard proce-
dure (entry 5). Using three equivalents of 1a relative to quinone 2e,
bistrifluoromethylated product 3f could be obtained (entry 6).
Scheme 1 Reaction conditions for trifluoromethylation of benzoquinone.
catalytic amounts of CuCN in the presence of other cyanide salts. Dimethyl derivative 2f showed a tendency for formation of a
When CuCN was replaced by KCN (entry 13), 3a did not form mixture of mono- and bistrifluoromethylated products under
confirming that the reaction is copper catalyzed. We have also standard conditions. However, changing the 2f to 1a ratio led to
Table 1 C–H trifluoromethylation of quinonesa
Yieldb
(%)
Yieldb
(%)
Yieldb
(%)
Entry Substrate
1
Product
Entry Substrate
2e
Product
Entry Substrate
11d
Product
89, 73c 6d
50
77
49
63
58
2h
77
53
51
51
64
2
3
4
76
71
67
72
7e
8d
9
12
2f
13
14f
15
5
10e
a
Unless otherwise state quinone 2 (0.1 mmol), 1a (0.15 mmol), B2pin2 (0.005 mmol, 5 mol%) and CuCN (0.1 mmol) in chloroform (0.5 mL) was
b
c
d
stirred at room temperature for 18 h. Isolated yield. The reaction was scaled up 10 times using 1 mmol of BQ, 2a. 0.3 mmol of 1a, 0.2 mmol,
e
CuCN and 0.01 mmol (10 mol%) of 5 were used. Quinone 2 (0.2 mmol), 1a (0.1 mmol), B2pin2 (0.01 mmol) and CuCN (0.2 mmol) were used.
f
B2pin2 (0.02 mmol, 20 mol%) and heating by microwave irradiation at 100 1C for 1 h were used.
c
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redox neutral reaction using the presented C–H trifluoromethylation
method. The reaction is also easily scalable. For example, trifluoro-
methylation of 2a could be scaled up ten times without signifi-
cant change in the yield (Table 1, entry 1). Using this method a
large variety of new interesting CF3–quinones can be accessed for
drug testing and for use as new oxidants/ligands for transition
metal catalyzed processes.
Scheme 2 Inhibition experiment.
selective reactions. Thus, when 2f was used in excess relative to 1a
trifluoromethylated product 3g was obtained (entry 7), while using
1a in excess relative to 2f led to formation of bistrifluoromethylated
product 3h (entry 8). Subsequently, we wished to explore the
substituent effects of quinone derivatives on the selectivity and
reactivity of the process by studying the trifluoromethylation of
chloro (2g–i) and methoxy (2j–l) derivatives. Chlorinated quinones
readily underwent trifluoromethylation reactions (entries 9–12).
Mono-chlorinated derivative 2g gave mono-CF3 product 3i with high
regioselectivity under standard conditions (entry 9). Dichloro deri-
vative 2h showed a similar tendency for bistrifluoromethylation to 2f
under standard conditions. Therefore, we increased the 2h to 1a
ratio to obtain monotrifluoromethylated product 3j (entry 10) and
decreased this ratio to obtain bistrifluoromethylated product 3k
(entry 11), similarly to the procedure applied for 2f (entries 7 and 8)
to increase the selectivity. Interestingly, dichloro substrate 2i gave
only monotrifluoromethylation under the standard conditions (entry
12). Methoxy quinones probably represent the most important class
of bioactive quinone derivatives including ubiquinone and other
antioxidants as well as apoptosis inducers, such as 2l. The stability of
the starting materials (2j–2l) and the products (3m–3o) was lower
than for the other quinones used in this study, which led
to somewhat lower yields. Dimethoxy quinone 2k reacted more
reluctantly than its regioisomer 2j. Therefore, forcing conditions
(100 1C, 1 h) were required to get acceptable yields of 3n, which is the
CF3-derivative of apoptosis initiator 2l (entry 14). The apoptosis
initiator 2l itself could also be trifluoromethylated under our
standard conditions (entry 15) opening a synthetic route to trifluoro-
methylated ubiquinone analogs.
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6616 Chem. Commun., 2013, 49, 6614--6616
This journal is The Royal Society of Chemistry 2013