Effects of B2pin2 and PCy3 on copper-catalyzed trifluoromethylation of substituted alkenes and alkynes with the Togni reagent

Article abstract of DOI:10.1016/j.tet.2014.12.077

The copper-catalyzed oxytrifluoromethylation of phenylacetylenes and C-H trifluoromethylation of quinones were studied. It was found that both reactions are accelerated by B₂pin₂ and PCy₃ additives. The two reactions have different substituent effects. The oxytrifluoromethylation is faster in the presence of electron-donating groups, while the C-H trifluoromethylation is faster with electron-withdrawing substituents. The Hammett plot for oxytrifluoromethylation gave a ρ value of -0.76 indicating electron demand in the rate determining step of the reaction. According to the absolute value of ρ the reaction probably does not proceed through a rate determining formation of a carbocation intermediate. The kinetic isotope effect measurements indicate that in C-H trifluoromethylation of quinones the cleavage of the C-H bond is not the rate determining step of the reaction.

Full text of DOI:10.1016/j.tet.2014.12.077

Tetrahedron 71 (2015) 922e931
Contents lists available at ScienceDirect
Tetrahedron
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Effects of B2pin2 and PCy3 on copper-catalyzed trifluoromethylation
of substituted alkenes and alkynes with the Togni reagent
*
€
ꢀ
ꢀ
ꢀ
Par G. Janson, Nadia O. Ilchenko, Alberto Diez-Varga, Kalman J. Szabo
Department of Organic Chemistry, Stockholm University, SE-106 91 Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 October 2014
Received in revised form 6 December 2014
Accepted 22 December 2014
Available online 30 December 2014
The copper-catalyzed oxytrifluoromethylation of phenylacetylenes and CeH trifluoromethylation of
quinones were studied. It was found that both reactions are accelerated by B2pin2 and PCy3 additives. The
two reactions have different substituent effects. The oxytrifluoromethylation is faster in the presence of
electron-donating groups, while the CeH trifluoromethylation is faster with electron-withdrawing
substituents. The Hammett plot for oxytrifluoromethylation gave a
demand in the rate determining step of the reaction. According to the absolute value of
r
value of ꢀ0.76 indicating electron
r
the reaction
Keywords:
Catalysis
Trifluoromethylation
Substituent effects
Hammett plot
Quinones
probably does not proceed through a rate determining formation of a carbocation intermediate. The
kinetic isotope effect measurements indicate that in CeH trifluoromethylation of quinones the cleavage
of the CeH bond is not the rate determining step of the reaction.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
The development of new methods for trifluoromethylation re-
actions has become an attractive and competitive field in organic
synthesis.1e10 The reason is two-fold: (i) an increased demand by
the pharmaceutical and agrochemical industries to access a large
variety of CF3 derivatives, which have very useful pharmacological
and pharmacokinetic properties;11 and (ii) the appearance of new
safe, easily handled reagents for selective introduction of the CF3
group (see examples in Fig. 1).12e14 Functionalization, including
difunctionalization of alkenes has been a very active field in tri-
fluoromethylation reactions.1e3 Oxytrifluoromethylation of alkenes
and alkynes attracted a particularly broad attention. Independent
studies by Sodeoka,15 Loh16 and our group17 have presented the
first copper-catalyzed oxytrifluoromethylation of alkenes and al-
kynes using the Togni,1,18 and related reagents,14 1aec. These
studies have been followed by excellent work on copper-catalyzed
intramolecular oxytrifluoromethylation by Buchwald19 and Liang20
and the difunctionalization based trifluoromethylation processes
have been extended to carbon,16,21e24 nitrogen,25 and other sub-
stituents26,27 as well. A related addition/elimination type of re-
action for CeH functionalization of alkenes has also been reported
and studied.15,16,28e31
Fig. 1. Safe, easy to handle trifluoromethylation reagents for difunctionalization based
trifluoromethylation of alkenes and alkynes.
Useful metal-free trifluoromethylation approaches involving
photocatalysis or organocatalysis for oxytrifluoromethylation and
related difunctionalization reactions were reported by Nagano,32
Studer,33 Akita,34 Masson35 and other groups.26,36e40 As shown
above a large number of excellent publications have appeared in
the past years on development of new difunctionalization methods
but the systematic studies of additive and substituent effects have
received somewhat less attention.
In two previous studies, we have shown that catalytic amounts
of bispinacolato diboron (B2pin2) 4 have an acceleration effect on
trifluoromethylation processes.21,29 This is particularly interesting,
as the formation of borylation products was not observed. We
postulated21,29 that B2pin2 undergoes transmetallation with the Cu-
catalyst and thus Bpin serves as a spectator ligand accelerating the
trifluoromethylation. As far as we know, our observation was the
first one, which indicated that Bpin ligand is able to accelerate
ꢀ
* Corresponding author. E-mail address: kalman@organ.su.se (K.J. Szabo).
http://dx.doi.org/10.1016/j.tet.2014.12.077
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

P.G. Janson et al. / Tetrahedron 71 (2015) 922e931
923
a catalytic reaction without subsequent CeB bond formation. In-
terestingly, in a recent publication Zhang and co-workers41 re-
ported that the B2pin2 effect can also be exploited for use in the
copper-catalyzed aminofluorination of styrenes.
Of course, traditional ligands/additives also efficiently accelerate
trifluoromethylation reactions.19,22,24,26,28,42 We have found21 that
PCy3 also accelerate similar trifluoromethylation reactions as
B2pin2. In addition, the reaction rates of the oxy-
trifluoromethylation of unsaturated substrates17,21 (Scheme 1) and
the related trifluoromethylation of quinones29 (Scheme 2) show
a significant substituent dependence, which is also modulated by
B2pin2 additive. Therefore, we decided to study the effects of B2pin2
and (the traditional) PCy3 on the trifluoromethylation reactions. As
In each reaction we employed 1.5 equiv of 1a relative to the alkyne
substrates 2 in order to obtain measurable rates even for the less
reactive substrates and compensate for the partial decomposition/
disproportionation of the Togni reagent 1a in the presence of
copper-catalyst (CuTc). The progress of the trifluoromethylations
was followed by 1H NMR spectroscopy. We also calculated the initial
rates of the reactions relative to the oxytrifluoromethylation of
phenylacetylene 2a (Figs. 2e4).
explicit substrates, we choose phenylacetylene derivatives
2
(Scheme 1) and quinones 3 (Scheme 2), which according to our
earlier studies displayed significant substituent effects.17,29 We
have particularly focused on the extent of acceleration of the re-
actions by B2pin2 and PCy3 as a function of the substituent effects.
We have also studied the possible rate determining steps of the
processes by Hammett plot for the oxytrifluoromethylation of al-
kynes and carried out measurements of the kinetic hydrogen iso-
tope effects for the trifluoromethylation of quinones.
Fig. 2. Progress of the oxytrifluoromethylation (Scheme 1) without additives. Legends:
(
)
phenylacetylene 2a, 1.0;
( ) p-methoxyphenylacetylene 2b, 7.6; ( ) p-nitro-
phenylacetylene 2c, 0.4. The relative initial rates are given in italics.
Scheme 1. Trifluoromethylation of phenylacetylenes.
Scheme 2. Trifluoromethylation of quinones.
2. Results and discussion
Fig. 3. Progress of the oxytrifluoromethylation (Scheme 1) with 10 mol % of B2pin2 (4)
as additive. Legends: ( ) phenylacetylene 2a, 1.0; ( ) p-methoxyphenylacetylene 2b,
6.6; ( ) p-nitrophenylacetylene 2c, 1.0. The relative initial rates are given in italics.
2.1. Reactions of phenylacetylenes
It was found that the initial rate of trifluoromethylation of
methoxyphenylacetylene 2b (Scheme 1) was about eight times
faster than for the parent 2a (Fig. 2) indicating that the electron-
donating OMe substituent accelerates the overall process. On the
other hand the nitro derivative 2c reacted more slowly than the
other acetylene derivatives, showing that in the presence of an
electron-withdrawing group the trifluoromethylation is slow. Upon
addition of B2pin2 the trifluoromethylation reaction of nitro-
phenylacetylene 2c is significantly accelerated and its
In order to get comparable data for the above reactions (Schemes
1 and 2), we had to change the optimized reaction conditions re-
ported for the synthetically useful oxytrifluoromethylation and the
CeH trifluoromethylation. In the present study the reaction condi-
tions and the catalyst were chosen to get a homogenous reaction
mixture for all processes. Therefore, we chose copper thiophene
carboxylate (CuTc) as the catalyst (10 mol %) and CDCl3 as solvent,
which enabled monitoring the reactions with 1H NMR spectroscopy.

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P.G. Janson et al. / Tetrahedron 71 (2015) 922e931
oxytrifluoromethylation of phenylacetylene derivatives 2a,b (Figs.
2e4). The substituent effects on the trifluoromethylation of qui-
nones without additives are relatively weak. However, when B2pin2
(4) was added all reactions are accelerated (Fig. 7). The largest ac-
celeration in the initial rates occurs for the dichloro derivative 3b
but the parent BQ (3a) is also trifluoromethylated faster than in the
absence of B2pin2. Dichloro derivative 3b reacts about twice as fast
as 3a. Conversely, the methoxy derivative 3c and naphthoquinone
3d react much slower than 3a and 3b. Accordingly, the substituent
effects for the CeH trifluoromethylation and the oxy-
trifluoromethylation (cf. Figs. 3 and 7) are the opposite, as using
B2pin2. The addition of PCy3 (5) has a similar, but not identical,
accelerating effect as B2pin2 (Fig. 8).
Fig. 4. Progress of the oxytrifluoromethylation (Scheme 1) with 10 mol % of PCy3 (5) as
additive. Legends: ( ) phenylacetylene 2a, 1.0; ( ) p-methoxyphenylacetylene 2b, 1.1;
(
) p-nitrophenylacetylene 2c, 1.2. The relative initial rates are given in italics.
oxytrifluoromethylation is about as fast as for the parent 2a (Fig. 3).
Surprisingly, when PCy3 is used as additive the processes for 2b,c
are decelerated and the relative initial rates are similar.
In order to get insight on the substituent effects on the rate
determining step of the oxytrifluoromethylation of phenyl-
acetylenes, we constructed a Hammett plot for 2aee with using spþ
values (Fig. 5). Although the correlation is fair (r2¼0.902)
r<0 in-
dicates increased electron demand in the rate determining step of
the reaction. The value of
r
is ꢀ0.76 indicating that the TS is mildly
resonance stabilized. The Hammett data for the reactions carried
out in the presence of B2pin2 are more scattered (r2¼0.777) than for
the reactions without any additive. However, the lower absolute
Fig. 6. Progress of the CeH trifluoromethylation (Scheme 2) of quinones without
additives. Legends: ( ) 1,4-benzoquinone 3a, 1.0; ( ) 2,6-dichloro-1,4-benzoquinone
3b, 1.0; ( ) 2,6-dimethoxy-1,4-benzoquinone 3c, 0.3; ( ) 1,4-naphthoquinone 3d 0.4.
The relative initial rates are given in italics.
value of
r
(ꢀ0.54) indicates that the reaction is less sensitive to the
resonance stabilization of the substituents in the presence of B2pin2
than in its absence.
Fig. 7. Progress of the CeH trifluoromethylation (Scheme 2) of quinones with 10 mol %
of B2pin2 as additive. Legends: ( ) 1,4-benzoquinone 3a, 1.0; ( ) 2,6-dichloro-1,4-
Fig. 5. Hammett plots for the copper-catalyzed oxytrifluoromethylation of alkynes
(Scheme 1). Legends (
) no additive ꢀ0:76sþp þ 0:14; ; r2¼0.902, (
) 10 mol %
benzoquinone 3b, 1.8;
( ) 2,6-dimethoxy-1,4-benzoquinone 3c, 0.2; ( ) 1,4-
2
sþ
naphthoquinone 3d, 0.5. The relative initial rates are given in italics.
B2pin2 (4) ꢀ0:54 þ 0:28; r ¼0.777.
p
When PCy3 was applied as additive, the trifluoromethylation of
naphthoquinone 3d and the methoxy BQ derivative 3c were ac-
celerated to about the same extent but less than for 3a and 3b
(Fig. 8). The acceleration of the trifluoromethylation of BQ (3a) is
2.2. Reactions of benzoquinone derivatives
Under the same reaction conditions the trifluoromethylation of
benzoquinone 3a (Figs. 6e8) is much slower than the

P.G. Janson et al. / Tetrahedron 71 (2015) 922e931
925
naphthoquinone 3d. Synthesis of tetradeutero benzoquinone de-
rivative 3a-d4 and mono deuterobenzoquinone derivative 3d-d was
carried out using a modified literature procedure by Tashiro and co-
workers43 (Scheme 3).
Fig. 8. Progress of the CeH trifluoromethylation (Scheme 2) of quinones with 10 mol %
of PCy3 as additive. Legends: 1,4-benzoquinone 3a, 1.0; 2,6-dichloro-1,4-
benzoquinone 3b, 3.0; 2,6-dimethoxy-1,4-benzoquinone 3c, 0.4; 1,4-
naphthoquinone 3d, 0.3. The relative initial rates are given in italics.
(
)
( )
(
)
( )
stronger with PCy3 than with B2pin2 suggesting that the two ad-
ditives probably influence different reaction steps. The oxy-
trifluoromethylation (Scheme 1) usually proceeds faster than the
CeH trifluoromethylation (Scheme 2). In the absence of any addi-
tives the initial rates follow the 2a[3a order (Fig. 9) indicating
Scheme 3. Synthesis of deuterated quinones.
The trifluoromethylation reactions of 3a and 3a-d4 were moni-
tored by 19F NMR instead of 1H NMR since the trifluoromethylated
product 7a-d3 has no protons. Because of the different signalenoise
ratio in the 1H NMR (Fig. 6) and 19F NMR (Fig. 10) the initial part
(NMR yield <5%) of the curves obtained for trifluoromethylation of
3a is slightly different. The rates measured by 19F NMR for the
deuterated and non-deutereted substrates (for 3a and 3a-d4, re-
spectively) are nearly identical in 12 h indicating that there is no
deuterium isotope effect in trifluoromethylation using 1a and CuTc
catalyst at 40 ꢁC (Scheme 2). In order to ensure that slight changes
of the reaction conditions (and substrate) do not alter the deute-
rium isotope effect, we carried out competitive measurements
using 3a and 3a-d4 under the same reaction conditions employed29
in the previous synthetic studies using stoichiometric amounts of
that the electron deficient
p-system of BQ is less reactive in tri-
fluoromethylation than the double and triple bond of styrene and
phenylacetylene derivatives.
Fig. 9. Comparison of the progress of the oxytrifluoromethylation (Scheme 1) and CeH
trifluoromethylation (Scheme 2) without additives. Legends:
yphenylacetylene 2a, ( ) 1,4-benzoquinone 3a.
( ) p-methox-
2.3. Study of the possible deuterium isotope effect for the
CeH trifluoromethylation of quinones
The CeH trifluoromethylation of quinones involves cleavage of
a CeH bond, which could be the rate determining step of the
process. To explore this mechanistic possibility, we have studied
the kinetic isotope effects for trifluoromethylation of BQ 3a and
Fig. 10. Progress of the CeH trifluoromethylation of quinones (Scheme 2) followed by
19F NMR. Legends:
(
)
1,4-benzoquinone 3a,
(
)
2,3,5,6-tetradeutero-1,4-
benzoquinone 3a-d4.

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P.G. Janson et al. / Tetrahedron 71 (2015) 922e931
Table 1
CuCN to mediate the trifluoromethylation (Scheme 4). We did not
observe any kinetic isotope effect in this process either. Finally we
studied the relative rate of proton and deuterium replacement in
3d-d (Scheme 5). These two processes also occurred at about the
same rate. Considering the above results, we conclude that the CeH
bond cleavage is not rate determining in CeH trifluoromethylation
of quinones.
Copper-catalyzed CeH trifloromethylation and oxytrifluoromethylationa
Entry
Substrate
Product
Yieldb (%)
1
50
2
3
55
53
Scheme 4. Intermolecular competitive trifluoromethylation between 1,4-
benzoquinone and its deuterated analog.
4
5
54
44
6
7
54
65
Scheme 5. Intramolecular competitive trifluoromethylation in mono-deuterated
naphthoquinone 3d-d.
2.4. Synthetic utility of the improved reaction conditions
In our original communication,17 we described the tri-
fluoromethylation of alkynes without using B2pin2 or other addi-
tives. These reactions required relatively high temperatures and
a long reaction time, which led to extensive decomposition/dis-
proportionation of 1a. Some substrates with electron-withdrawing
substituents (such as 2d and f) and sensitive functional groups
(such as 2h) could not be trifluoromethylated at all. Using 10 mol %
Ar¼2-iodophenyl.
a
A mixture of 2 (0.1 mmol), 1a (0.15 mmol), CuTc (10 mol %), and B2pin2
(10 mol %) in CDCl3 (0.5 mL) was stirred for 18 h at 60 ꢁC.
b
Isolated yield.
can be easily and selectively performed using 1a, CuTc catalyst in
the presence of 10 mol % B2pin2 (entries 6 and 7). Interestingly the
regioselectivity under these conditions and with MTO are different,
in particular for the indole derivative 9b.
t
of B2pin2 as additive halogenated (2d and 2f) and Bu substituted
(2e) substrates reacted smoothly (Table 1, entries 1e3). The rela-
tively mild conditions allowed the trifluoromethylation of sub-
strates with oxidation sensitive groups (entries 4 and 5), such as
NMe2 (2g) and Bpin (2h). The relatively low yield (44%) obtained for
7h is mainly due to purification losses. Product 7h (entry 5) is
a useful substrate for a subsequent SuzukieMiyaura coupling.44,45
CeH trifluoromethylation of benzofuran and indole derivatives
has previously been performed using zinc and methyltrioxo-
rhenium (MTO) as catalyst using 1a as CF3 source by Togni and co-
workers.46,47 Furthermore, Sanford and co-workers48 reported ox-
idative trifluoromethylation of the B(OH)2 derivative of 9a using
Langlois’ reagent. We have now found that the reaction with 9a,b
2.5. Plausible mechanisms
The above studies shed light to the effects of additives and
substituent effects on the oxytrifluoromethylation reaction of al-
kenes and alkynes, as well as to related CeH trifluoromethylation
reactions of benzoquinone derivatives. Thus, at least a plausible
mechanism including the role of additives 4 and 5 and the sub-
stituent effects on the rate of trifluoromethylation can be
presented.

P.G. Janson et al. / Tetrahedron 71 (2015) 922e931
927
It is reasonable to assume that the oxytrifluoromethylation
(Scheme 1) and CeH trifluoromethylation reactions (Scheme 2)
have similar or identical initial steps for addition of the CF3 group to
suggests that the two functionalities (CF3 and ArCOO) are in-
troduced in two separate steps (such as 11/12/16/6). Alter-
natively, one can also speculate that the reductive elimination to 15
has a prohibitively high barrier, and therefore adduct 14 reversibly
decomposes to 2 and 11 and product 6 is formed by a 12/16/6
sequence.
In vinyl radical 12 the unpaired electron is likely trans to both
the aryl and the CF3. The next step is recombination of radical 12
and the doublet complex 13 to give 16, in which the formal oxi-
dation state of the Cu-atom is þ3. The last step is a reductive
elimination to give the observed E-product 6 and regenerate the
catalyst 10. Based on the Hammett plot (Fig. 5) we suggest that the
reductive elimination is the rate determining step of the process. A
facile reductive elimination of 16 requires a high electron density
on the carbon atom adjacent the Cu(III) center. Thus reduction of
Cu(III) in 16 to Cu(I) in 10 is certainly accelerated by the resonance
effects of electron donating Z groups, such as OMe in 2b. Therefore,
the
p-system of the substrate. The main differences are in the
closing steps, as the oxytrifluoromethylation is terminated by ad-
dition of an iodobenzoate group, while the trifluoromethylation of
quinones involves CeH cleavage.
2.5.1. Oxytrifluoromethylation of alkynes. A plausible mechanism
for the oxytrifluoromethylation of phenylacetylenes in the pres-
ence of B2pin2 is given in Fig. 11. The initial step is probably
transmetallation of B2pin2 with the Cu(I) catalyst to give CueBpin
complex 11. A similar process was first described and studied by
Sadighi and co-workers49 and a possible transmetallation of Cu(I)
complexes and 4 was invoked for many Cu-catalyzed borylation
reactions.50e55 In the present study, we did not observe any bor-
ylation of our substrates. The acceleration effect probably arises
from the strong
s
-donation of the Bpin ligand to copper.50e52 The
the negative
reductive elimination.
r
value (
r¼ꢀ0.76) is in line with the rate determining
electron-rich Cu-atom in 10 may undergo efficient oxidative addi-
tion with 1a to form Cu(III) complex 11. Many previous studies have
shown15,17,21,29,56 that the copper-catalyzed trifluoromethylation
reactions with 1a are inhibited by radical traps, for example,
TEMPO. This indicates that the reaction proceeds via CF3 radicals.
We suggest that complex 11 may undergo homolytic cleavage of the
CueCF3 bond. This process does not necessarily involve formation
of a free CF3 radical but perhaps leads to transfer of a CF3 radical to
the alkyne group in 2 affording radical species 12. The driving force
of the CF3 transfer could be formation of the stable Cu(II)
complex 13.
Alternatively, instead of a 16/6þ10 reductive elimination,
a rate determining single electron oxidation (SET) of 12 by Cu(II)
complex 13 is also possible. This process would result in the for-
mation of a benzyl cation of 12. However, the relatively small
value obtained does not justify a rate determining formation of
a benzyl cation. We obtained a
-value of ꢀ0.76 (Fig. 5), which is
much lower than expected for a reaction proceeding via rate
determining formation of a carbocation (e.g., benzyl cation) in-
termediate, such as an SN1 process57 (typical
-value is about ꢀ5).
The extent of the substituent effects in oxytrifluoromethylation can
r-
r
r
r
Fig. 11. Plausible mechanism for the copper-catalyzed oxytrifluoromethylation of phenylacetylenes with 1a in the presence of B2pin2. Ar¼2-iodophenyl.
An alternative pathway involving insertion of 11 to the triple
bond of 2 affording a singlet adduct 14 is unlikely (Fig. 11). This
insertion would proceed via a syn mechanism and then the re-
ductive elimination of the benzoate would give product 15, in
which the CF3 and benzoate groups are in Z relationship. Yet,
Sodeoka15 and we17 have shown that E-product 6 forms, which
be similar to the electronic effects of the electron donating sub-
stituents in SN2 reactions (typical
carbocation intermediates does not form but there is still a signifi-
r
-value is about ꢀ1), in which
cant electron demand the transition state.
The strong
s-electron donor Bpin may influence at least two
reaction steps: (i) increasing the aptitude of oxidative addition of 10

928
P.G. Janson et al. / Tetrahedron 71 (2015) 922e931
to 1a; (ii) possibly stabilizing the radical state of 13, and thus trigger
the homolytic cleavage of the CueCF3 bond in 11 promoting the CF3
transfer to 2.
to relatively high reactivity (Fig. 7). The bulky and less efficient p-
acceptor quinones, such as 3c,d, coordinate poorly and therefore
their reactivity is low.
The boryl group has one of the best radical stabilization effects
via the so called ‘captodative effect’.58 On the other hand, the re-
ductive elimination step is not facilitated by the Bpin ligand, which
may explain that the trifluoromethylation of electron-rich alkynes,
such as 2b is not accelerated significantly by 4. Acceleration effects
by PCy3 (5) can likely be explained in a similar way, since PCy3 (like
The semiquinone type structure in 18 can efficiently delocalize
the unpaired electron. For sake of clarity only two resonance
structures (18 and 180) are given in Fig. 12. A recombination of Cu(II)
complex 13 and semiquinone 18 (via its oxygen atom) would lead
to formation of 19, which may then undergo intermolecular
deprotonation involving reduction of the formally Cu(III) central
atom. The intermolecular deprotonation restores the conjugation of
quinone in 7, which could be the driving force of the reaction and
may explain the absence of deuterium isotope effect (Schemes 4
and 5). Again, the electronic effects of the Bpin and PCy3 ligands
Bpin) is a very efficient
s-donor, and thus may influence the re-
action in the steps i and ii. However, PCy3 is more bulky and more
sensitive to oxidation than Bpin and therefore the efficiency of the
acceleration of 4 and 5 could be different.
are probably similar. Both ligands are strong
s-donors and thus
2.5.2. CeH trifluoromethylation of quinones. A plausible mecha-
nism of the CeH trifluoromethylation of quinones (3) in the pres-
ence of 4 is given in Fig. 12. Formation of catalyst 10 proceeds by
transmetallation of CuTc with B2pin2 as for the oxy-
trifluoromethylation (Section 2.5.1). The next step is oxidative ad-
dition of 1a to 10, which is followed by coordination of 3.
increase the coordination ability of 3 to Cu(III) in complex 17. The
bulkiness of PCy3 could also be beneficial to increase the migration
aptitude of CF3 to the quinone substrate affording semiquinone 18.
3. Conclusions
Benzoquinone 3 has a more electron deficient
p-system than
We have shown that B2pin2 and PCy3 have an accelerating effect
in the oxytrifluoromethylation of phenylacetylenes 2 and the CeH
trifluoromethylation of benzoquinone derivatives 3. The two re-
phenylacetylenes 2 and therefore a direct addition of an electro-
philic CF3 radical to the double bond is unlikely. However, co-
ordination to the electron-rich Cu(III) complex formed after
oxidative addition with 1a would reduce the electron deficiency of
actions
have
opposite
electron
demands.
The
oxy-
trifluoromethylation of phenylacetylenes are accelerated in the
the p-system of 3, and thus increase the aptitude for the transfer of
t
presence of electron donating substituents (OMe, Bu) in the para
the electrophilic CF3 radical. Accordingly, migration of the CF3
radical from Cu to the double bond of the coordinated 3 in 17 would
allow formation of semiquinone 18 and Cu(II)-complex 13 (Fig. 12).
We have shown59 that electron-withdrawing substituents strongly
position and decelerated by electron-withdrawing ones (NO2). The
r
value from the Hammett plot is ꢀ0.76 indicating an increased
electron demand in the TS of the rate determining step. However,
the extent of resonance stabilization is relatively small, and there-
fore the reaction probably does not proceed via rate determining
formation carbocation (benzyl cation) intermediates. The CeH tri-
fluoromethylation of quinones does not show a deuterium isotope
effect indicating that the CeH bond cleavage is not rate de-
termining. The trifluoromethylation of quinones is faster in the
presence of an electron-withdrawing substituent (such as Cl) than
with electron donating substituents (such as OMe, naph-
thoquinone). We reasoned that this could be the consequence of
rate determining coordination of quinones to the Cu-catalyst. This
increase the
p-coordinating ability of quinones to transition metals.
The -coordinating ability of benzoquinones is, of course, also very
p
sensitive to steric effects. Supposing that this coordination is the
rate determining step the high reactivity of the chloro derivative 3b
and the parent BQ 3a can be explained.
The coordinating ability of 3a,b can be particularly improved
when s-donor Bpin is also coordinated in 17, which probably leads
coordination likely reduces the electron deficiency of the p-system
of the quinone allowing the addition of the electrophilic CF3 radical.
The Bpin ligand is less bulky and less oxidation sensitive than
bulky phosphines such as PCy3, which apparently has similar
electronic effects. We believe that the above study contributes to
the better understanding of the oxidative trifluoromethylation re-
actions and inspire development of new highly reactive catalyst
systems.
4. Experimental section
4.1. General information
Hypervalent iodine reagent 1a was prepared according to lit-
erature procedures.12,13 Deuterated quinones 3a-d4 and 3d-d were
synthesized according to a modified literature procedure (see be-
low). All other compounds and solvents were obtained from com-
mercial suppliers and used without further purification. All
reactions were performed under air using non-dried solvents un-
less otherwise stated. 1H NMR, 13C NMR, and 19F NMR spectra were
recorded in CDCl3, or CD3OD on 400 or 500 MHz instruments. All 1H
NMR spectra are measured relative to the signals for residual CHCl3
(7.26 ppm) or CH3OH (3.31 ppm) and all 13C NMR spectral data are
reported relative to CDCl3 (77.16 ppm) or CD3OD (49.00). For 19F
NMR,
a,a,a-trifluorotoluene was used as an internal standard
Fig. 12. Plausible mechanism for the copper-catalyzed CeH trifluoromethylation of
benzoquinone derivatives in the presence of B2pin2. Ar¼2-iodophenyl.
(ꢀ63.7 ppm). HRMS data were recorded on a micrOTOF instrument

P.G. Janson et al. / Tetrahedron 71 (2015) 922e931
929
using ESI or APCI technique. All column chromatography was per-
formed using silica gel (35e70 m).
is no longer yellow). The combined organic layers (yellow-brown)
were washed twice with water then dried over MgSO4, filtered, and
evaporated. The products were used in the next step without fur-
ther purification. Oxidation of deuterated hydroquinones (step 3 in
Eq. 4). To a 25 mL round flask equipped with a stirring bar were
added SiO2 (600 mg) and dichloromethane (5 mL), the mixture was
stirred at room temperature. Over the suspension was added
dropwise a solution of NaIO4 (0.7 mL, 1.3 equiv, 0.65 M) in water.
After 5 min, hydroquinone (0.3 mmol, 1 equiv) dissolved in diethyl
ether (1.0 mL) was added. The mixture was stirred for 1 h during
which it became red-orange. After that the suspension was filtered
and concentrated under reduced pressure. The products were pu-
rified by silica gel column chromatography (DCM/pentane 2:1). N.B.
The products easily sublimate in high vacuum.
m
4.2. General procedure for kinetic NMR experiments
All kinetic NMR data were acquired on a 500 MHz spectrometer.
The reactions were monitored with 1H NMR. The exception was
2,6-dichloro-1,4-benzoquinone 3b for which 19F NMR was used for
the monitoring. CuTc (0.5 mg, 0.0025 mmol, 10 mol %) and hyper-
valent iodine reagent 1a (11.9 mg, 0.0375 mmol, 1.5 equiv) were
weighed into an NMR tube under air. Additives (0.0025 mmol,
10 mol %) were added (B2pin2 under air, PCy3 inside a glovebox
under argon) and the tube was fitted with a plastic cap (rubber
septum for reactions performed with PCy3). The probe of the NMR
spectrometer was heated to 40 ꢁC. Immediately before inserting the
reaction tube into the spectrometer 0.5 mL of a stock solution
(0.05 M for substrate and 0.05 M internal standard in CDCl3) was
injected by syringe. The first spectrum was recorded 5 min after
insertion of the tube into the spectrometer. The NMR yields are
4.5. Procedure for determining KIE by intermolecular com-
petitive trifluoromethylation (Scheme 4)
To a 3 mL vial were added copper cyanide (9.0 mg, 0.1 mmol,
1 equiv), B2pin2 (1.3 mg, 0.005 mmol, 5 mol %), 1a (31.6 mg,
0.1 mmol, 1 equiv), 1,4-benzoquinone 3a (10.8 mg, 0.1 mmol,
1 equiv), 2,3,5,6-tetradeutero-1,4-benzoquinone 3a-d4 (11.2 mg,
0.1 mmol, 1 equiv), and CDCl3 (0.5 mL). The reaction mixture was
stirred at 40 ꢁC for 18 h. The crude reaction mixture was centri-
fuged, the solution was transferred to an NMR tube, and the solvent
was evaporated slowly at low temperature (N.B. 3a and 7a may
easily sublimate). Finally the NMR tube was refilled with a 1:1
mixture of MeOH/MeOD-d4 and the 1H and 2H NMR were run. The
conversion was determined for both the protonated and the deu-
terated quinones. The KIE was determined as the ratio con-
version(proton)/conversion(deuterium)¼1.08.
based on using hexamethylbenzene (1H NMR) or
a,a,a-tri-
fluorotoluene as internal standards (19F NMR). The product yields
were calculated as the sum of the yield of mono-and bistri-
fluoromethylated products for 2,6-dichloro-1,4-benzoquinone 3b
and as the sum of the yield of the ketone and the enol ester (for the
oxytrifluoromethylation of terminal alkynes, when the enol ester
form 6 underwent partial hydrolysis).
4.3. General procedure for trifluoromethylation and oxy-
trifluoromethylation reactions (Table 1)
To a 3 mL vial was added CuTc (1.9 mg, 0.01 mmol, 10 mol %),
B2pin2 (2.5 mg, 0.01 mmol, 10 mol %), 1a (47.4 mg, 0.15 mmol,
1.5 equiv), substrate (0.1 mmol, 1 equiv), and 0.5 mL of CDCl3. The
reaction mixture was stirred for 18 h at 60 ꢁC. The products were
purified by silica gel column chromatography.
4.6. Procedure for determining KIE by intramolecular com-
petitive trifluoromethylation
The reaction of 2-deutero-1,4-naphthoquinone 3d-d was per-
formed according to the above quinone CeH trifluoromethylation
procedure. After 18 h the crude reaction mixture was centrifuged,
the solution was transferred to an NMR tube and the solvent was
slowly evaporated at room temperature. The NMR tube was refilled
with a 1:1 mixture of MeOH/MeOH-d4 and analyzed by 1H and 2H
NMR. The KIE was determined as the ratio conversion(proton)/
conversion(deuterium)¼1.11.
4.4. Synthesis of deuterated quinone dervatives 3a-d4 and
3d-d
The synthesis of 3a-d4 and 3d-d was carried out by a slightly
modified literature procedure of Tashiro and co-workers.43 Re-
duction of quinones to the corresponding hydroquinones (step 1 in Eq.
4). To a 500 mL round bottom flask were added halogenated qui-
none 8 (5 mmol, 1 equiv), sodium dithionite (8.8090 g, 50 mmol,
10 equiv), diethyl ether (250 mL), and water (75 mL). The flask was
equipped with a stirring bar and stirred at room temperature for
30 min during which the top layer was decolorized slightly. The
organic layer was separated and washed with brine (3ꢂ100 mL).
The aqueous layer was extracted with diethyl ether (3ꢂ100 mL). All
organic layers were combined and dried over MgSO4, filtered, and
evaporated. The products were used in the next step without fur-
ther purification. Halide-deuterium exchange (step 2 in Eq. 4). To an
oven-dried 10 mL double-necked round bottom flask, equipped
with a stirring bar was added halogenated hydroquinone (1 mmol,
1 equiv). The flask was equipped with rubber septa, evacuated, and
refilled with argon. A solution of NaOD (4.0 mL, 10% in D2O) was
added and the flask was placed in a water bath at room tempera-
ture. Raney nickel (100 mg for each equivalent of halogen atom) is
added slowly in small portions over a period of 30 min. This op-
eration was carried out under an argon stream. The flask was placed
in an oil bath and heated at 60 ꢁC for 1 h. Bubbles could be observed
over the suspension. After 1 h the flask was allowed to cool to room
temperature and the contents were then filtered through Celite and
washed with water. The colorless solution turns dark brown during
this operation. The solution was acidified with HCl (10%) until pH 1,
then extracted with diethyl ether (10ꢂ15 mL, until the organic layer
4.7. (E)-3,3,3-Trifluoro-1-(4-bromophenyl)prop-1-en-1-yl 2-
iodobenzoate (6d)
Synthesized according to the general procedure (see general
procedure for trifluoromethylation and oxytrifluoromethylation
reactions). The product was isolated by column chromatography
(pentane/diethyl ether 19:1) as a colorless oil (50%). 1H NMR
(400 MHz, CDCl3):
d
8.05 (dd, JHH¼8.0, 1.0 Hz, 1H), 7.92 (dd, JHH¼7.9,
1.5 Hz, 1H), 7.58e7.54 (m, 2H), 7.48e7.42 (m, 3H), 7.22 (ddd,
JHH¼7.9, 7.5, 1.6 Hz, 1H), 5.98 (q, JHF¼7.8 Hz, 1H); 19F NMR (376 MHz,
CDCl3):
d
ꢀ55.75 (d, JHF¼7.8 Hz, 3F); 13C NMR (100 MHz, CDCl3):
d
163.3, 156.0 (q, JCF¼6.3 Hz), 142.2, 134.0, 132.7, 131.9, 131.8, 131.2,
130.3 (q, JCF¼1.8 Hz), 128.3, 125.3, 122.4 (q, JCF¼269.3 Hz), 110.9 (q,
JCF¼36.2 Hz), 95.0; HRMS (ESI): m/z calcd for [C16H979BrF3IO2þNa]þ
518.8675, found 518.8684.
4.8. (E)-3,3,3-Trifluoro-1-(4-tert-butylphenyl)prop-1-en-1-yl
2-iodobenzoate (6e)
Synthesized according to the general procedure. The product
was isolated by column chromatography (pentane/DCM 5:1) as
a colorless oil (55%). 1H NMR (400 MHz, CDCl3):
d
8.05 (dd, JHH¼8.0,

930
P.G. Janson et al. / Tetrahedron 71 (2015) 922e931
1.0 Hz, 1H), 7.96 (dd, JHH¼7.8, 1.7 Hz, 1H), 7.52 (d, JHH¼8.4 Hz, 2H),
7.45 (td, JHH¼7.5, 1.1 Hz, 1H), 7.42 (d, JHH¼8.7 Hz, 2H), 7.21 (ddd,
JHH¼7.9, 7.5, 1.7 Hz, 1H), 5.92 (q, JHF¼7.9 Hz, 1H), 1.32 (s, 9H); 19F
108.3 (q, JCF¼3.1 Hz); HRMS (APCI): m/z calcd for [C9H5F3O]þ
186.0287, found 186.0279.
NMR (376 MHz, CDCl3):
(100 MHz, CDCl3):
d
ꢀ55.58 (d, JHF¼7.9 Hz, 3F); 13C NMR
4.13. 5-Bromo-1-methyl-3-(trifluoromethyl)-1H-indole (6j)
d
163.4, 157.1 (q, JCF¼6.5 Hz), 154.0, 142.1, 133.8,
133.0, 131.9, 129.2, 128.4 (q, JCF¼1.8 Hz), 128.3 125.4, 122.7 (q,
JCF¼268.7 Hz), 109.7 (q, JCF¼36.1 Hz), 95.1, 35.0, 31.3; HRMS (ESI):
m/z calcd for [C20H18F3IO2þNa]þ 497.0196, found 497.0187.
Synthesized according to the above general procedure. The
product was isolated by column chromatography (pentane) as
a colorless oil (65%). 1H NMR (400 MHz, CDCl3):
d
7.80 (d,
JHH¼1.8 Hz, 1H), 7.44 (dd, JHH¼8.9, 1.8 Hz, 1H), 7.25 (ad, JHH¼8.8 Hz,
1H), 6.88e6.86 (m,1H); 19F NMR (376 MHz, CDCl3):
ꢀ59.90 (s, 3F);
13C NMR (100 MHz, CDCl3):
4.9. (E)-3,3,3-Trifluoro-1-(4-fluorophenyl)prop-1-en-1-yl 2-
iodobenzoate (6f)
d
d
137.3 (q, JCF¼1.6 Hz) 133.6, 128.4 (q,
JCF¼37.3 Hz), 127.6, 127.3, 124.8, 121.2 (q, JCF¼268 Hz), 114.0, 111.5,
103.8 (q, JCF¼4.0 Hz), 101.8, 31.1 (q, JCF¼2.0 Hz); HRMS (APCI): m/z
calcd for [C10H779BrF3N]þ 276.9708, found 276.9706.
Synthesized according to the general procedure. Isolated by
column chromatography (pentane/diethyl ether 40:1) as a colorless
oil (53%). 1H NMR (400 MHz, CDCl3):
d
8.05 (dd, JHH¼7.9, 1.1 Hz, 1H),
7.92 (dd, JHH¼7.8, 1.7 Hz, 1H), 7.61e7.55 (m, 2H), 7.45 (td, JHH¼7.6,
1.1 Hz, 1H), 7.21 (td, JHH¼7.7, 1.7 Hz, 1H), 7.14e7.07 (m, 2H), 5.97 (q,
Acknowledgements
JHF¼7.7 Hz, 1H); 19F NMR (376 MHz, CDCl3):
ꢀ55.79 (d, JHF¼7.8 Hz,
d
The authors thank 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).
3F), e108.99 to ꢀ109.08 (m, 1F); 13C NMR (100 MHz, CDCl3):
d 164.0
(d, JCF¼251.5 Hz), 163.4 (q, JCF¼0.9 Hz), 162.7, 156.1 (q, JCF¼6.3 Hz),
142.2, 133.9, 132.8, 131.9, 130.9 (dq, JCF¼8.7, 1.8 Hz), 128.38 (d,
JCF¼3.6 Hz), 128.30, 122.5 (q, JCF¼269.2 Hz), 115.7 (d, JCF¼22.1 Hz),
110.6 (q, JCF¼36.1 Hz), 95.0; HRMS (ESI): m/z calcd for
[C16H9F4IO2þNa]þ 458.9476, found 458.9475.
Supplementary data
The NMR spectra of the products are given. This material is
available free of charge via the Internet at http://pubs.acs.org.
Supplementary data associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2014.12.077.
4.10. (E)-3,3,3-Trifluoro-1-(4-dimethylaminophenyl)prop-1-
en-1-yl 2-iodobenzoate (6g)
Synthesized according to the above general procedure. The
product was isolated by column chromatography (pentane/DCM
References and notes
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d 8.05 (dd,
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Synthesized according to the above general procedure. The
product was isolated by column chromatography (pentane/diethyl
ether 9:1) as a colorless oil (44%). 1H NMR (400 MHz, CDCl3):
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134.67, 133.9, 132.7, 131.9, 128.3, 127.8 (q, JCF¼1.7 Hz), 122.5 (q,
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