Allylic C-H alkylation with a CF3-containing nucleophile

Article abstract of DOI:10.1039/c3cc43120g

Allylic C-H alkylation of allylarenes with dimethyl 2- trifluoromethylmalonate was successfully developed. The reactions were carried out at room temperature in the presence of a catalytic amount of Pd(OAc) ₂/Ph₃P and a stoichiometric amount of 2,6- dimethylbenzoquinone. The reactions avoided defluorination successfully, providing a new method to construct a CF₃-containing all-carbon quaternary center. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc43120g

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Allylic C–H alkylation with a CF3-containing
nucleophile†‡
Cite this: DOI: 10.1039/c3cc43120g
Lun Li, Qing-Yun Chen* and Yong Guo*
Received 26th April 2013,
Accepted 23rd July 2013
DOI: 10.1039/c3cc43120g
www.rsc.org/chemcomm
Allylic C–H alkylation of allylarenes with dimethyl 2-trifluoromethyl- p-allylpalladium intermediate. C–H activation is among the most
malonate was successfully developed. The reactions were carried out at active research topics in current organic chemistry.11 Shi, White
room temperature in the presence of a catalytic amount of Pd(OAc)2/ and Trost et al. have reported several methods for allylic C–H
Ph3P and a stoichiometric amount of 2,6-dimethylbenzoquinone. The alkylation by carbon nucleophiles.12–16 However, it is unknown
reactions avoided defluorination successfully, providing a new method whether the C–H activation protocol can be applied to fluorinated
to construct a CF3-containing all-carbon quaternary center.
nucleophiles to avoid the serious defluorination issue. With this
in mind, we began our research on the first a-CF3-carbanion-
Due to the unique properties of fluorine atom(s), introduction involved allylic alkylation using the C–H activation protocol, to
of a trifluoromethyl group to organic compounds has aroused construct a CF3-substituted all carbon quaternary center which is
wide interest in recent years and the majority of approaches focus an interesting structural motif in drug design (Scheme 1).2c,17
on direct trifluoromethylation.1–3 Trifluoroethylation (CF3CH2–
At first, reaction of 2 with 1.5 equivalents of 1 in the presence of
or CF3CR2–) has been thought as a synthetic challenge because 5% Pd(OAc)2 and 10% Ph3P in NMP for 12 h by using benzo-
b-defluorination competes with the reaction with nucleophiles quinone (BQ) and a balloon of oxygen as the oxidant at 60 1C was
when an a-CF3 carbanion is generated.4 In 2012, Hu et al. reported carried out, giving the allylic C–H alkylated CF3-containing product
a Pd-catalyzed cross-coupling reaction of boronic derivatives with 3a in 38% yield (Table 1, entry 1). We chose Pd(OAc)2 because
CF3CH2I.5 An extensional study of terminal alkynes was reported OAcÀ was reported to be the necessary counter ion for the allylic
very recently.6 At the end of last year, Chen et al. developed a C–H alkyation.16b This was also supported by the fact that no 3a
method to synthesize ArXCHClCF3 (X = O, S) by Cu-mediated was found with the use of Pd(PPh3)2Cl2, (Table 1, entry 2). Later,
reactions of 1,1-dichloro-2,2,2-trifluoroethane (HCFC123) with several phosphine ligands were tested. When using (2-MeOC6H4)3P
phenoxides or thiophenoxides.7 The existence of electron- or (2-furyl)3P, the yield was 23% or 19%, respectively (Table 1,
withdrawing groups in an a-CF3 carbanion can greatly help to entries 3 and 4). Other ligands, such as (c-hex)3P, (4-MeOC6H4)3P,
stabilize the carbanion.4a The generation of b-fluorinated carban- BINAP, XPhos, t-BuPhos, and (C6F5)3P only gave trace amount of 3a
ion is fast and in reversible equilibrium while b-elimination of (Table 1, entries 5–10). Based on the above comparison, Ph3P
HF is slow but irreversible.1c The certain lifetime of the carbanion was thought as a suitable ligand for further screening of the
allows a fast nucleophilic reaction to occur without defluorination.
Based on this rule, a few protocols have been elegantly developed,
including Ir or Ru-catalyzed addition of CF3-containing nucleo-
philes to alkenes4b and Pd-catalyzed allylic alkylation of carbonates
with CF3-containing nucleophiles.8
The Tsuji–Trost reaction was discovered in 1969 and has been
well-developed.9,10 However, in a traditional Tsuji–Trost reaction
a preoxidized allylic substrate is required for ionization to form a
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
P. R. China. E-mail: yguo@sioc.ac.cn; Fax: +86 21 64166128; Tel: +86 21 54925462
† Dedicated to Prof. Jean’ne M. Shreeve on the occasion of her 80th birthday.
‡ Electronic supplementary information (ESI) available: Experimental details and
copies of 1H NMR, 19F NMR and 13C NMR spectra for all products. See DOI:
10.1039/c3cc43120g
Scheme 1 Allylic C–H alkylation protocol.
c
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Table 1 Screening of conditions for allylic C–H alkylationa
Table 2 The substrate scope of alkenes
Entry
Phosphine ligand
Oxidant
T (1C)
Yield of 3ab (%)
1
Ph3P
BQ, O2
BQ, O2
BQ, O2
BQ, O2
BQ, O2
BQ, O2
BQ, O2
BQ, O2
BQ, O2
BQ, O2
BQ, O2
BQ, N2
DMBQ, N2
DMBQ, N2
DMBQ, N2
DMBQ, N2
DMBQ, O2
60
60
60
60
60
60
60
60
60
60
60
60
60
rt
38
0
23
19
Trace
Trace
Trace
Trace
Trace
Trace
51
2c
3
Pd(PPh3)2Cl2
(2-MeOC6H4)3P
(2-Furyl)3P
(c-Hex)3P
(4-MeOC6H4)3P
BINAP
4
5
6
7
8
g
10
11d
12d
13d
14
15e
16f
17
XPhos
t-BuPhos
(C6F5)3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
73
100
100
88
11
36
rt
rt
rt
a
The reactions of 2a with 1.5 equivalents of 1 in the presence of 5 mol%
Pd(OAc)2, 10 mol% phosphine ligand and 1.5 equivalents of quinone
oxidant in NMP were carried out at varied temperatures for 12 h under
b
an oxygen or nitrogen atmosphere. The yields were determined by
c
19F NMR by using benzotrifluoride as an internal standard. Using
d
Pd(PPh3)2Cl2 instead of Pd(OAc)2/Ph3P. The reaction time was 24 h
e
and 3 equivalents of 1 were used. 1 equivalent of 1 was used.
f
1% Pd(OAc)2 and 2% Ph3P were used.
terms of various aryl substituents at the allylic position of
oxidant system. The utilization of three equivalents of 1 and a alkenes and the electronic effect was less essential than the
reaction time of 24 h increased the yield to 51% (Table 1, entry 11). steric effect. In these reactions, we never found branched-
Interestingly, when the reaction was carried out under a nitrogen substituted products probably due to bulkiness of the trifluoro-
atmosphere, the yield was improved to 73% (Table 1, entry 12), methylated nucleophile. This reaction can be applied to
suggesting that the quinone derivative was the true oxidant for the (CF3)2CHCO2Me to give product 4 in 93% yield, but failed with
Pd(0)/Pd(II) regeneration cycle under these conditions. Luckily, CF3CH2CN. In the previous reports,8,18 an allylic alkylation by a
further investigation of oxidants revealed that DMBQ gave a fluorinated nucleophile normally required a preoxidized allylic
quantitative yield of 3a (Table 1, entry 13), even when the substrate, such as carbonate. This report, to the best of our
amount of 1 was 1.5 equivalents and the reaction time was knowledge, is the first example of C–H activation in allylic
shortened to 12 h (Table 1, entry 14). Subsequently, the use of nucleophilic displacement by a fluorinated nucleophile, whose
only one equivalent of 1 gave rise to a decrease in the yield of 3a stability is relatively low because of the innate tendency of
slightly (88% yield) (Table 1, entry 15). When 1% Pd(OAc)2 was defluorination.
used, the yield dropped greatly probably due to generation of
In 2008, Shi,14 White,15 Trost16 and Fristrup11b,19 reported
Pd black to cease the catalytic cycle (Table 1, entry 16). Usually, their creative studies on direct allylic alkylation via the catalysis
the reaction solution was red after the reaction finished, but in of Pd(II), providing much mechanistic evidence for the C–H
the case of entry 16, the color of the solution turned yellow, activation. According to the results mentioned above, a plausible
which also suggested that Pd(OAc)2 was insufficient. Entry 17 mechanism is proposed in Scheme 2. Palladium(II) is ligated to
shows that the yield decreased in the presence of oxygen.
alkene in a reversible way and then a rate-determining C–H
Using the optimal conditions (Table 1, entry 16), we tested activation happens to give the p-allylpalladium complex. The
the scope of alkenes (Table 2). The substrate with one (3a–3j), complex is attacked by the nucleophilic carbanion of 1, affording
two (3k, 3l) or three substituents (3p, 3q) at the phenyl group product 3a and Pd(0). Pd(0) is oxidized to re-generate Pd(II). The
gave a good to excellent yield of the product. The functional C–H activation is hard in the formation of 3r because of the
group with different electron-withdrawing or -donating abilities steric hindrance of two ortho-methyl substituents.
also did not affect the yield significantly (3a–3j). The aryl
The palladium-catalyzed allylic alkylations with a-CF3 con-
substituent could also be thienyl (3n) or naphthyl (3m). taining nucleophiles and preoxidized allylic substrates were
However, the sterically crowded mesitylene derivative 3r was reported.8 Those reactions proceeded through allylpalladium
obtained in a low yield with a low conversion of alkene. Based intermediates similar to the one for allylic C–H alkylation.
on all the examples in Table 2, we found that the allylic C–H Based on the observations of Kitazume and his co-workers,
alkylation with CF3-nucleophile 1 has a wide substrate scope in defluorination of ethyl 3,3,3-trifluoropropionate (CF3CH2CO2Et)
c
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Notes and references
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3 For recent reviews on transition-metal-mediated trifluoromethylation,
see: (a) S. Roy, B. T. Gregg, G. W. Gribble, V.-D. Le and S. Roy,
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15, 936.
Scheme 2 Plausible mechanism.
in palladium-catalyzed allylic alkylations did not occur. In con-
trast, elimination of fluoride with 2-substituted 3,3-difluoro-
propionates (for example HCF2CH(Me)CO2CH2CH2Ph) was found
to give E-fluoroolefins and they thought it might be due to the
fact that the C–F bond length in the CHF2 group is longer than
that of the CF3 group.8a This means that the stability of a nucleo-
phile is essential for a successful reaction without defluorination.
In the decarboxylative allylations of a-trifluoromethyl b-keto
esters reported by Cahard and Shibata, the defluorinations were
not observed.17b The authors thought that this clearly demon-
strated that the allylation proceeded faster than the b-elimination
reaction. In our experiments, because of three electron-withdrawing
groups within 1, the stability of the anion of 1 should be higher
than the ones with two electron-withdrawing groups.4a Thus,
the carbanion of 1 has a longer lifetime and remains intact
before alkylation. Moreover, quinone acts as a proton acceptor
as well as an oxidant for the conversion of Pd(0) to Pd(II).11b
7 X.-J. Tang and Q.-Y. Chen, Org. Lett., 2012, 14, 6214.
8 (a) Y. Komatsu, T. Sakamoto and T. Kitazume, J. Org. Chem., 1999,
64, 8369; (b) T. Konno, M. Kanda, T. Ishihara and H. Yamanaka,
J. Fluorine Chem., 2005, 126, 1517; (c) K. Sato, Y. Yakifuchi, Y. Yoshizawa,
K. Iwase, Y. Shimizu, A. Tarui, M. Omote, I. Kumadaki and A. Ando,
Chem. Pharm. Bull., 2007, 55, 1593; (d) W. Zhang, Y. Zhao, C. Ni,
T. Mathew and J. Hu, Tetrahedron Lett., 2012, 53, 6565; (e) N. Shibata,
K. Fukushi, T. Furukawa, S. Suzuki, E. Tokunaga and D. Cahard,
Org. Lett., 2012, 14, 5366; ( f ) L. Li, D. Huang, Q.-Y. Chen and Y. Guo,
Synlett, 2013, 611.
9 (a) J. Tsuji, Acc. Chem. Res., 1969, 2, 144; (b) B. M. Trost, Tetrahedron,
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This allows the reaction to happen without additional bases 10 (a) J. Tsuji, Palladium Reagents and Catalysts: New Perspectives for the
21st Century, John Wiley & Sons, Ltd., Chichester, UK., 2004, ch. 4p. 431;
(b) B. M. Trost and D. L. Van Vranken, Chem. Rev., 1996, 96, 395;
(c) Handbook of Organopalladium Chemistry for Organic Synthesis,
and leads to a slow generation of the carbanion of 1 and
suppression of defluorination under the optimal conditions.
In the early research on allylic C–H alkylations, White and
Shi always used the bis(sulfoxide) ligand in order to get a good
experimental result.14,15 However, the bis(sulfoxide) ligand is
relatively complex and not common. During our study, Ph3P
was proved to be an excellent ligand and with this ligand we
could conduct our experiment at room temperature and get a
quantitative yield. This result is consistent with the previous
discovery by Trost and his co-workers, where phosphorus-based
ligands successfully promoted allylic C–H alkylation with 1,4-dienes
and allylarenes.16
In summary, we have found a facile method to introduce a
CF3-containing nucleophile to allylarenes through Pd-catalyzed
allylic C–H alkylations, providing a series of aromatic products with
a quaternary carbon center, which may be useful for drug discovery.
This work was financially supported by the National Basic
Research Program of China (973 Program) (No. 2012CB821600),
the National Natural Science Foundation of China (No. 21032006,
21172241) and the Shanghai Science and Technology Commission
(11ZR1445700).
ed. E.-I.Negishi, Wiley-Interscience, New York, 2002.
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292, 195; (b) C. J. Engelin and P. Fristrup, Molecules, 2011, 16, 951.
12 For a palladium(0)-catalyzed allylic C–H alkylation under reducing
conditions, see: L. S. Hegedus, T. Hayashi and W. H. Darlington,
J. Am. Chem. Soc., 1987, 100, 7747.
13 For a copper- and cobalt-catalyzed cross-dehydrogenative-coupling
reaction of allylic C–H bonds and activated methylenes, see: Z. Li
and C.-J. Li, J. Am. Chem. Soc., 2006, 128, 56.
14 S. Lin, C.-X. Song, G.-X. Cai, W.-H. Wang and Z.-J. Shi, J. Am. Chem.
Soc., 2008, 130, 12901.
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c
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