Palladium catalyzed vinyltrifluoromethylation of aryl halides through decarboxylative cross-coupling with 2-(trifluoromethyl)acrylic acid

Article abstract of DOI:10.1021/acs.orglett.5b00551

An efficient Pd-catalyzed stereoselective vinyltrifluoromethylation of aryl halides, through decarboxylative cross-coupling with 2-(trifluoromethyl)acrylic acid is described. The ready availability of the starting materials, the high level of functional group tolerance, and excellent E/Z selectivity make this protocol a safe and operationally convenient strategy for efficient synthesis of vinyltrifluoromethyl derivatives.

Full text of DOI:10.1021/acs.orglett.5b00551

Letter
pubs.acs.org/OrgLett
Palladium Catalyzed Vinyltrifluoromethylation of Aryl Halides
through Decarboxylative Cross-Coupling with
2‑(Trifluoromethyl)acrylic Acid
Subban Kathiravan† and Ian A. Nicholls*,†,‡
†Bioorganic & Biophysical Chemistry Laboratory, Linnaeus University Centre for Biomaterials Chemistry, Linnaeus University,
SE-391 82 Kalmar, Sweden
‡Department of Chemistry, BMC, Uppsala University, SE-751 23 Uppsala, Sweden
S
* Supporting Information
ABSTRACT: An efficient Pd-catalyzed stereoselective vinyl-
trifluoromethylation of aryl halides, through decarboxylative
cross-coupling with 2-(trifluoromethyl)acrylic acid is de-
scribed. The ready availability of the starting materials, the
high level of functional group tolerance, and excellent E/Z selectivity make this protocol a safe and operationally convenient
strategy for efficient synthesis of vinyltrifluoromethyl derivatives.
he increase in prevalence of the trifluoromethyl (CF3)
functionality in pharmaceuticals, agrochemicals, paints,
T
liquid crystal displays (LCDs), and polymers can be attributed to
its unique physicochemical properties.1 For example, in
medicinal chemistry, the trifluoromethyl group is introduced
into organic scaffolds in attempts to improve the properties of
bioactive molecules such as metabolic stability, liphophilicity,
and selectivity. Accordingly, selective synthetic methods for the
preparation of trifluoromethylated intermediates or building
blocks are of great importance.2 Most of the current method-
ologies for the introduction of the trifluoromethyl group entail
either costly reagents for innate substitution or preactivated
substrates containing directing groups.3 Despite their practical
importance, these strategies require prefunctionalized substrates,
the preparation of which can often call for tedious functional
group interconversions and often lead to undesired waste
formation. Several new methods for the direct formation of
alkynyl C(sp)−CF3, aromatic C(sp2)−CF3, and aliphatic
compounds with C(sp3)−CF3 have been reported recently,
highlighting the importance of this particular transformation.4−6
Despite significant advancements in this area, there is no
general method for the production of the CF3 group containing
functionalized alkenes. Selective trifluoromethylation of alkenes
through transition metal catalysis is rare (Figure 1). Buchwald
and co-workers reported the synthesis of β-trifluoromethylstyr-
enes through iron catalyzed trifluoromethylation of prefunction-
alized vinylboron derivatives with Togni’s reagent.7 Further-
more, Feng et al. found that reaction of an enamide with CuI/
Togni’s reagent could provide trifluoromethyl substituted olefin
derivatives,8 and photoredox catalysis with a ruthenium complex
for the construction of trifluoromethylated alkenes with CF3I was
also reported.9 While some current methodologies are limited to
specific substrate classes such as heterocycles, electron-deficient
arenes, and phenols,10 others require the use of hazardous
reagents that are mostly available in the gaseous form and which
have corrosive properties.11 The cost and limited availability of
Figure 1. β-Trifluoromethylation reactions (TFMAA = 2-
(trifluoromethyl)acrylic acid, 2).
these reagents combined with poor functional group tolerance
have prompted our interest in developing alternative, more
general, and more sustainable catalytic strategies.12
Herein we report a Pd-catalyzed decarboxylative cross-
coupling between aryl halides and 2-(trifluoromethyl)acrylic
acid (TFMAA, 2) for the highly selective direct synthesis of
diverse olefins.13 To the best of our knowledge, there exists no
example of decarboxylative coupling between acrylic acid and
aryl halides for aryl vinyltrifluoromethylation. The performance
of the present catalytic system allowed us to extend this
methodology to various heterocyclic systems.
Initial experiments were carried out using bromobenzene (1)
as a model substrate, 2-(trifluoromethyl)acrylic acid (2), and 10
mol % of Pd(OAc)2 as a catalyst. Optimization with respect to
bases, solvents, and several additives was explored under these
reaction conditions (Table 1). Initial studies in the presence of
Received: February 24, 2015
Published: March 31, 2015
© 2015 American Chemical Society
1874
DOI: 10.1021/acs.orglett.5b00551
Org. Lett. 2015, 17, 1874−1877

Organic Letters
Letter
carried out under an air atmosphere (entry 13) and afforded the
vinyl-CF3 product in comparable yield to when performed under
nitrogen (entry 11), highlighting a practical advantage of the
method. Subsequent attempts at lower temperature showed that
an excellent yield can be achieved at 105 °C, although a longer
reaction time was required (entry 14). The screening of silver-
based additives, such as silver oxide, silver acetate, silver fluoride,
and silver carbonate, gave modest yields (Table 1, entries 15−
18). Finally, the influence of a base was studied (entries 19−24).
K2CO3 proved superior, though cesium carbonate and sodium
carbonate afforded low yields of the coupled adducts (Table 1,
entries 19 and 20). Reactions with sodium acetate, potassium
acetate, sodium hydroxide, and potassium hydroxide afforded
only trace amounts of products (Table 1, entries 21−24). The
loading of the catalyst could be decreased to 5 mol %; thus, the
optimized conditions can be summarized as Pd(OAc)2 as the
catalyst (5 mol %), additive CuO (1 equiv), bromobenzene (1)
as the substrate (2 equiv), 2-(trifluoromethyl)acrylic acid (2)
(0.5 equiv), and K2CO3 (1 equiv) as the base (Table 1, entry 26).
With the best optimized reaction conditions in hand
(Pd(OAc)2/CuO/K2CO3), we turned our attention to the
evaluation of the substrate scope of the decarboxylative Pd-
catalyzed vinyltrifluoromethylation of aryl halides by Heck type
reaction with acrylic acid (Table 2). Excellent E/Z product ratios
were observed in most cases. Using aryl bromides with either
electron-donating (Table 2, entries 2−3) or electron-with-
drawing groups (Table 2, entries 4−10) at the para-position led
to the formation of the corresponding vinyl-CF3 derivatives in
good to moderate yields in all the cases. Remarkably, a number of
synthetically useful functionalities, including aryl chloride,
bromide, nitrile, aldehyde, and ester groups, were tolerated
under the reaction conditions. Interestingly, aryl bromide
substituted with an N,N-dimethylamino substituent at the
para-position furnished exclusively the E-product (Table 2,
entry 8). In the case of an aryl bromide substituted with an acetyl
group at the para-position the resultant alkene stereoisomers are
inseparable by column chromatography (Table 2, entry 11).
When the 4-bromobiphenyl was used, we were able to isolate
both the pure and mixture of stereoisomers in good yields (Table
2, entry 12). Gratifyingly, this reaction could also be applied to
the synthesis of ethers 3m, albeit in moderate yield (Table 2,
entry 13). Next this reaction was extended with 2-bromonaph-
thalene and found to produce the corresponding vinyl-CF3
derivative in good yield (Table 2, entry 14). In contrast, the 1-
bromonaphthalene was much less reactive under these
conditions (Table 2, entry 15). Although the electrophile
scope was broad, we found that substrates with meta-
functionalization furnished vinyl-CF3 products in high yields,
and with good to moderate E/Z selectivity (Table 2, entries 16−
19). We were pleased to observe that 3,5-dimethyl-1-iodo
benzene (1t) could be utilized, providing similar reaction rates
and excellent E/Z selectivity (Table 2, entry 20). It is significant
to note that this method tolerates substituents at the ortho-
position, as demonstrated by the vinyltrifluoromethylations of
1u−1v, which furnished the corresponding products with
excellent E/Z-selectivities (Table 2, entries 21−22).
Table 1. Pd-Catalyzed Decarboxylative Reaction of Acrylic
Acid and Aryl Halides: Variation of Reaction Conditions
a
b
entry
solvent
DMF
base
additive
(E/Z)
yield (%)
1
2
3
4
5
6
7
8
9
10
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
NaOAc
KOAc
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OPiv)2
Cu(SO3CF3)2
CuO
−
−
−
−
−
−
−
95/5
90/10
−
≥95:5
−
≥95:5
≥95:5
50/50
60/40
−
−
−
−
−
−
−
−
−
0
DMSO
PhMe
xylene
1,2-DCB
mesitylene
p-cymene
NMP
5
9
NR
8
0
0
55
NMP
50
NMP
0
c
11
NMP
92 (89)
12
NMP
−
trace
d
13
e
NMP
CuO
89
14
NMP
CuO
75
15
16
17
18
19
20
21
22
23
24
NMP
AgO
48
NMP
AgOAc
AgF
35
NMP
28
NMP
AgCO3
CuO
18
NMP
4
NMP
CuO
6
NMP
CuO
0
NMP
CuO
0
NMP
NaOH
KOH
CuO
0
NMP
CuO
0
f
25
g
NMP
K2CO3
K2CO3
CuO
0
26
NMP
CuO
−
93 (90)
a
Reactions were performed with 1 mmol of TFMAA (2), 2 mmol of
bromobenzene, 0.1 equiv of Pd(OAc)2, 1 equiv of additive, 2 equiv of
b
base, 1 mL of solvent at 130 °C for 15 h. Yields were determined by
1H NMR using CH2Cl2 as the internal standard. Isolated yields shown
c
d
in parentheses. The reaction was performed under N2. The reaction
e
was performed under air. The reaction was performed at 105 °C for
f
g
48 h. In the absence of Pd(OAc)2. The reaction was conducted on a
0.5 mmol scale with Pd(OAc)2 (5 mol %) and additive (0.5 equiv), in
NMP (1 mL). DMF = dimethylformamide, DMSO = dimethyl
sulfoxide, 1,2-DCB = 1,2-dichlorobenzene, NMP = 1-methyl-2-
pyrrolidinone.
potassium carbonate (2 equiv) and copper acetate (0.2 equiv)
(entries 1−8) showed that N-methyl pyrrolidine (NMP)
effectively facilitated the reaction and 55% of the desired product
was obtained. This improvement is in agreement with the
positive effect of NMP observed in a number of organic
reactions.14 Interestingly, none of the other high boiling point
solvents examined afforded the product in significant yield. It is
important to note that the reaction is highly selective toward the
linear vinyltrifluoromethylation product, as no traces of the
branched isomer formation were detected under these reaction
conditions.
Next, we examined the influence of different additives on the
reaction (Table 1, entries 9−16). It should be noted that
Cu(OPiv)2 and Cu(OTf)2 were less effective than Cu(OAc)2 for
this reaction (Table 1, entries 9−10). Among the oxidants tested,
CuO was the most effective affording the cross-coupled product
in 92% yield (entry 11). The vinyl trifluoromethylation of the
substrate was completely inhibited in the absence of an additive
(entry 12). Interestingly, we found that the reaction can be
After having observed the general reactivity with aryl
bromides, we turned our attention to the reactivity of different
heterocycles to vinyltrifluoromethylation (Table 3). To our
delight, the coupling reaction with both thiophene and pyridine
proceeded in good yield (Table 3, entries 1−2). The reaction was
stereoselective, predominantly affording the E-product of the
corresponding vinyl-CF3. When 6-bromoquinoline was reacted,
1875
DOI: 10.1021/acs.orglett.5b00551
Org. Lett. 2015, 17, 1874−1877

Organic Letters
Letter
Table 2. Scope of Aryl Bromides with 2-
(Trifluoromethyl)acrylic Acid
Table 3. Scope of Heterocyclic Bromides with 2-
(Trifluoromethyl)acrylic Acid
a
a
a
Reactions were performed with 4 (1 equiv), TFMAA (2) (2 equiv),
Pd(OAc)2 (5 mol %), CuO (0.5 equiv), K2CO3 (1 equiv), NMP (1
b
mL) at 130 °C for 15 h. Isolated yields.
lation of 8-bromo-3-methoxyisoquinoline was achieved with a
96% isolated yield, though, surprisingly, with an E/Z-selectivity
of 90:10 (Table 3, entry 6).
To gain mechanistic insights, additional experiments were
performed. When the reaction was conducted in the presence of
a radical scavenger, such as 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT), none of
the decarboxylative vinyl-TEMPO or vinyl-BHT products were
observed (Scheme 1a). These results excluded the possibility of
Scheme 1. Mechanistic Investigations of the
Vinyltrifluoromethylation
vinyl radical formation through decarboxylation and confirmed
the transmetalation of in situ generated vinyl-CF3 and subsequent
reductive elimination. We also found this reaction was
stereoconvergent, as the cis and trans mixture of 4,4,4-
trifluorocrotonic acid (6) yielded the E-isomer as the major
product (Scheme 1b).
Based on the experimental findings presented above we
proposed a mechanism for the aryl vinyltrifluoromethylation
(Scheme 2). After initial formation of organometallic complex B
via oxidative addition, the subsquent entropically favorable
decarboxylation of acrylic acid generates the Pd(II) complex C.15
Finally, reductive elimination affords the product 7 and
regenerates the active catalyst via Cu(II) reoxidation. An
alternative mechanism could involve the direct carbometalation
of 2-(trifluoromethyl)acrylic acid D followed by decarboxylation
a
Reactions were performed with 1 (2 equiv), TFMAA (2) (1 equiv),
Pd(OAc)2 (5 mol %), CuO (0.5 equiv), K2CO3 (1 equiv), NMP (1
mL) at 130 °C for 15 h. Isolated yields.
b
the corresponding product was obtained with moderate E/Z-
selectivity (Table 3, entry 3). Quinolines containing substituents
at both the 2- and 6-positions also underwent the reaction with
excellent stereoselectivity (Table 3, entry 4). Furthermore, the
reaction of 5-bromoisoquinoline afforded good selectivity and a
high yield (Table 3, entry 5). Finally, the vinyltrifluoromethy-
1876
DOI: 10.1021/acs.orglett.5b00551
Org. Lett. 2015, 17, 1874−1877

Organic Letters
Letter
Faeh, C.; Diederich, F. Science 2007, 317, 1881. (e) Purser, S.; Moore, P.
R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (f) Wang,
J.; Sanchez-Rosello, M.; Acena, J. L.; Pozo, C. D.; Sorochinsky, A. E.;
Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432.
(g) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470.
(h) Zhang, C. Adv. Synth. Catal. 2014, 356, 2895. (i) Li, Y.; Studer, A.
Angew. Chem., Int. Ed. 2012, 51, 8221.
Scheme 2. Proposed Catalytic Cycle for Aryl
Vinyltrifluoromethylation (Ar = aryl; X = Br, I; B = base; L =
solvent)
(2) (a) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475.
(b) Ji, Y.; Brueckil, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. A.; Su, S.;
Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108,
14411. (c) Ye, Y.; Sanford, M. S. J. Am. Chem. Soc. 2012, 134, 9034.
(d) Oishi, M.; Kondo, H. Chem. Commun. 2009, 14, 1909. (e) Liu, H.;
Gu, Z.; Jiang, X. Adv. Synth. Catl. 2013, 355, 617. (f) Wang, X.;
Truesdale, L.; Yu, J. Q. J. Am. Chem. Soc. 2010, 132, 3648. (g) Egami, H.;
Sodeoka, M. Angew. Chem., Int. Ed. 2014, 53, 8294.
(3) (a) Herrmann, A. T.; Smith, L. L.; Zakarian, A. J. Am. Chem. Soc.
2012, 134, 6976. (b) Zhang, H.; Chen, P.; Liu, G. Angew. Chem., Int. Ed.
2014, 53, 10174. (c) Besset, T.; Cahard, D.; Pannecoucke, X. J. Org.
Chem. 2014, 79, 413. (d) Alonso, C.; Martinez de Marigorta, E.;
Rubiales, G.; Palacios, F. Chem. Rev. 2015, 115, 1847.
and stereoselective β-hydride elimination of E to afford the
product 7.16
(4) (a) Zhao, T. S. N.; Szabo, K. J. Org. Lett. 2012, 14, 3966. (b) Chu,
L.; Qing, F. L. J. Am. Chem. Soc. 2010, 132, 7262. (c) He, Z.; Zhang, R.;
Hu, M.; Li, L.; Ni, C.; Hu, J. Chem. Sci. 2013, 4, 3478. (d) Serizawa, H.;
Aikawa, K.; Mikami, K. Chem.Eur. J. 2013, 19, 17692. (e) Miyake, Y.;
Ota, S. I.; Shibata, M.; Nakajima, K.; Nishibayashi, Y. Chem. Commun.
2013, 49, 7809. (f) Besset, T.; Poisson, T.; Pannecoucke, X. Chem.
Eur. J. 2014, 20, 16830.
(5) (a) Jiang, X. Y.; Qing, F. L. Angew. Chem., Int. Ed. 2013, 52, 14177.
(b) Lundgren, R. J.; Stradiotto, M. Angew. Chem., Int. Ed. 2010, 49, 9322.
(c) Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2011, 50, 3793. (d) Zhang, B.; Studer, A. Org. Lett. 2014,
16, 1216. (e) Merino, E.; Nevado, C. Chem. Soc. Rev. 2014, 43, 6598.
(f) Seo, S.; Taylor, J. B.; Greaney, M. F. Chem. Commun. 2013, 49, 6385.
(g) Barata-Vallejo, S.; Lantaco, B.; Postigo, A. Chem.Eur. J. 2014, 20,
16806.
(6) (a) Fruh, N.; Togni, A. Angew. Chem., Int. Ed. 2014, 53, 10813.
(b) Miyake, Y.; Ota, S. I.; Shibata, M.; Nakajima, K.; Nishibayashi, Y.
Org. Biomol. Chem. 2014, 12, 5594.
(7) Parsons, A. T.; Senecal, T. D.; Buchwald, S. L. Angew. Chem., Int. Ed.
2012, 51, 2947.
(8) Feng, C.; Loh, T. P. Angew. Chem., Int. Ed. 2013, 52, 12414.
(9) Iqbal, N.; Jung, J.; Park, S.; Cho, E. J. Angew. Chem., Int. Ed. 2014,
53, 539.
(10) (a) Prakash, G. K. S.; Krishnan, H. S.; Jog, P. V.; Iyer, A. P.; Olah,
G. A. Org. Lett. 2012, 14, 1146. (b) Omote, M.; Tanaka, M.; Ikeda, A.;
Nomura, S.; Tarui, A.; Sato, K.; Ando, A. Org. Lett. 2012, 14, 2286.
(c) Veeraraghavan Ramachandran, P.; Mitsuhasi, W. Org. Lett. 2015, 17,
1252.
In conclusion, we have shown that decarboxylative cross-
coupling of 2-(trifluoromethyl)acrylic acid with various aryl
halides provides a new, steroeselective strategy for the
incorporation of the vinyltrifluoromethyl functionality into aryl
bromide containing structures. From a synthetic standpoint, this
transformation is an extremely simple and efficient method for
incorporating the versatile vinyltrifluoromethyl moiety into
target structures, a task that can otherwise require costly reagents
and more difficult handling processes. Unlike some current
methodologies that are limited to specific substrate classes, our
method is amenable to a broad range of functionalities, e.g.
chlorides, esters, ethers, aldehydes, acetyl and nitriles, and even
heterocycles. Importantly, the demonstration of the stereo-
selective nature of the reaction suggests opportunities for further
utilization. Moreover, this new and unusually simple strategy for
the simultaneous incorporation of vinyl and CF3 functionalities is
also of importance due to increasing interest in fluoroorganic
compounds and trifluoromethylating reagents. More detailed
mechanistic studies shall be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures, spectroscopic data (copies of
1H NMR, 13C NMR, 19F NMR, and 13C-APT). This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) (a) Langlois, B. R.; Laurent, E.; Roidot, N. Tetrahedron Lett. 1991,
32, 7525. (b) Cowell, A. B.; Tamborski, C. J. Fluorine Chem. 1981, 17,
345. (c) Kino, T.; Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.; Uraguchi, D.;
Tokuhisa, K.; Yamakawa, T. J. Fluorine Chem. 2010, 131, 98.
(12) (a) Ye, Y.; Lee, S. H.; Sanford, M. S. Org. Lett. 2011, 13, 5464.
(b) Nishida, T.; Ida, H.; Kuninobu, Y.; Kanai, M. Nat. Commun. 2014, 5,
3387. (c) Mejía, E.; Togni, A. ACS Catal. 2012, 2, 521.
(13) For decarboxylative reactions, see: (a) Gooßen, L. J.; Rodriguez,
N.; Gooßen, K. Angew. Chem., Int. Ed. 2008, 47, 3100. (b) Weaver, J. D.;
Recio, A., III; Grenning, A. J.; Tunge, J. A. Chem. Rev. 2011, 111, 1846.
(c) Li, Z.; Cui, Z.; Liu, Z. Q. Org. Lett. 2013, 15, 406−409.
(14) Ackermann, L. Org. Lett. 2005, 7, 3123.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ian.nicholls@lnu.se.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was undertaken with the generous financial
support of the Swedish Research Council (VR, Grants 2006- and
2014-4573), the KK Foundation (Grant 2010-0223), and
Linnaeus University.
(15) For entropy driven decarboxylation, see: Krapcho, A. P.; Glynn,
G. A.; Grenon, B. J. Tetrahedron Lett. 1967, 8, 215.
(16) We thank one of the reviewers for pointing out this possible
alternative mechanism through β-hydride elimination.
REFERENCES
■
(1) (a) Hiyama, T. Organofluorine Compounds: Chemistry and
Applications; Springer-Verlag: Berlin, Heidelberg, and New York,
2000. (b) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH:
Weinheim, Germany, 2004. (c) Ojima, I. Fluorine in Medicinal Chemistry
and Chemical Biology; Wiley-Blackwell: Chichester, 2009. (d) Muller, K.;
̈
1877
DOI: 10.1021/acs.orglett.5b00551
Org. Lett. 2015, 17, 1874−1877