Pd(II)-catalyzed ortho-trifluoromethylation of benzylamines

Article abstract of DOI:10.1021/ol402471y

The Pd(II)-catalyzed ortho-C-H trifluoromethylation of benzylamines has been achieved utilizing an electrophilic CF₃ reagent. Additives, such as H₂O and Ag₂O, were found to be crucial for obtaining good yields. This protoc

Full text of DOI:10.1021/ol402471y

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Pd(II)-Catalyzed Ortho-
Trifluoromethylation of Benzylamines
Masanori Miura,† Chen-Guo Feng, Sandy Ma, and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037, United States
yu200@scripps.edu
Received August 28, 2013
ABSTRACT
The Pd(II)-catalyzed ortho-CÀH trifluoromethylation of benzylamines has been achieved utilizing an electrophilic CF3 reagent. Additives, such
as H2O and Ag2O, were found to be crucial for obtaining good yields. This protocol will be useful in medicinal chemistry for the preparation of
ortho-trifluoromethyl-substituted benzylamines.
The incorporation of trifluoromethyl groups in pharma-
ceuticals and biologically active molecules is important to
medicinal chemists because the addition of a trifluoro-
methyl group can improve the metabolic stability and
lipophilicity of such compounds.1 Given such utility, there
has been interest in the development of new methods for the
installation of trifluoromethyl groups onto the aromatic
scaffolds of these important compounds.2 One general
approach toward arene trifluoromethylation is to use tran-
sition metals to forge arene CÀCF3 bonds from prefunc-
tionalized arenes. Currently, arene trifluoromethylation
can be accomplished via copper-catalyzed cross-coupling
of both aryl halides3 and arylboronic acids.4 Palladium-
catalyzed5 and -mediated6 cross-coupling reactions of aryl
halides have also been used to access trifluoromethylated
arenes.
Another approach for arene trifluoromethylation is
centered on the direct conversion of the arene CÀH bond
to a new CÀCF3 bond. One method that has received
recent attention is arene CÀH trifluoromethylation via the
generation of a CF3 radical.7,8 The other method for arene
trifluoromethylation is via transition-metal-catalyzed
CÀH activation. However, there are inherent difficulties
in the development of such a reaction, which stem from the
† Institute for Drug Discovery Research, Astellas Pharma Inc.
(4) Select examples of copper-catalyzed trifluoromethylation of ar-
ylboronic acids: (a) Liu, T.; Shen, Q. Org. Lett. 2011, 13, 2342–2345. (b)
Chu, L.; Qing, F.-L. Org. Lett. 2010, 12, 5060–5063. (c) Senecal, T. D.;
Parsons, A. T.; Buchwald, S. L. J. Org. Chem. 2011, 76, 1174–1176. (d)
Xu, J.; Luo, D.-F.; Xiao, B.; Liu, Z.-J.; Gong, T.-J.; Fu, Y.; Liu, L.
€
(1) (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–
1886. (b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320–330.
(2) (a) Ma, J.-A.; Cahard, D. Chem. Rev. 2004, 104, 6119–6146. (b)
Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214–231. (c)
Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305–321. (d) Roy, S.; Gregg,
B. T.; Gribble, G. W.; Le, V.-D.; Roy, S. Tetrahedron 2011, 67, 2161–
2195. (e) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470–477.
(f) Besset, T.; Schneider, C.; Cahard, D. Angew. Chem., Int. Ed. 2012, 51,
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Chem. Commun. 2011, 47, 4300–4302. (e) Novak, P.; Lishchynsky, A.;
Grushin, V. V. Angew. Chem., Int. Ed. 2012, 51, 7767–7770. (f) Ye, Y.;
Sanford, M. S. J. Am. Chem. Soc. 2012, 134, 9034–9037.
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Buchwald, S. L. Science 2010, 328, 1679–1681.
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4632–4641. (b) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006,
128, 12644–12645.
(3) For select examples of copper-catalyzed trifluoromethylation of
aryl halides, see: (a) Oishi, M.; Kondo, H.; Amii, H. Chem. Commun.
(7) For reviews on radical-mediated trifluoromethylation, see:
Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8950–8959.
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2009, 1909–1911. (b) Knauber, T.; Arikan, F.; Roshenthaler, G.-V.;
Goossen, L. J. Chem.;Eur. J. 2011, 17, 2689–2697. (c) Morimoto, H.;
Tsubogo, T.; Litvinas, N. D.; Hartwig, J. Angew. Chem., Int. Ed. 2011,
50, 3793–3708. (d) Weng, Z.; Lee, R.; Jia, W.; Yuan, Y.; Wang, W.;
Feng, X.; Huang, K. W. Organometallics 2011, 30, 3229–3232. (e)
Zanardi, A.; Novikov, M. A.; Martin, E.; Buchholz, J.-B.; Grushin,
V. V. J. Am. Chem. Soc. 2011, 133, 20901–20913. (f) Tomashenko, O. A.;
(8) For select recent examples, see: (a) Nagib, D. A.; MacMillan,
D. W. C. Nature 2011, 480, 224–228. (b) Ye, Y.; Lee, S. H.; Sanford,
M. S. Org. Lett. 2011, 13, 5464–5467. (c) Hafner, A.; Brase, S. Angew.
Chem., Int. Ed. 2012, 51, 3713–3715. (d) Fujiwara, Y.; Dixon, J. A.;
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´
r
10.1021/ol402471y
XXXX American Chemical Society

unfavorable reductive elimination of an ArÀPdÀCF3
species6 and the lack of appropriate ligands that can
promote both reductive elimination and CÀH activation.
We have reported the first palladium-catalyzed ortho-
trifluoromethylation of 2-phenylpyridines with Umemoto’s
trifluoromethylation reagent9 and have recently expanded
our protocol to include benzoic acid derived N-arylbenza-
mides (Scheme 1).10 We found in these studies that
Cu(II) salts were crucial for forming the arylÀCF3 bonds.
Recently, Shi has also reported a palladium-catalyzed
CÀH ortho-trifluoromethylation of acetanilides with the
Umemoto’s trifluoromethylation reagent.11 Interestingly,
Liu has reported a palladium-catalyzed CÀH trifluoro-
methylation of indoles with the nucleophilic RuppertÀ
Prakash reagent (TMSCF3).12,13 However, despite these
recent reports, the substrate scope of palladium-catalyzed
CÀH trifluoromethylation has yet to encompass the
breadth and utility observed with other arene trifluoro-
methylation methods.
Scheme 1. Pd-Catalyzed CÀH Ortho-Trifluoromethylation
Given the prevalence of the ortho-trifluoromethyl ben-
zylamine moiety in medicinally relevant compounds
(Figure 1),14 it would be desirable to develop a palla-
dium-catalyzed ortho-CÀH trifluoromethylation protocol
for benzylamine substrates. Although there have been
several reports on the palladium-catalyzed ortho-CÀH
carbonylation and olefination of benzyl- and phenethyl
amines,15 the ortho-trifluoromethylation of benzylamines
via palladium-catalyzed CÀH activation is still unknown
to the best of our knowledge. Furthermore, palladium-
catalyzed ortho-functionalization of NÀH-containing
benzylamines has been met with limited success. The only
known example is the palladium(II)-catalyzed CÀH aryla-
tion of both N-unsubstituted and N-methyl-substituted
benzylamines in TFA reported by Daugulis.16 Herein, we
report the palladium-catalyzed ortho-trifluoromethylation
of N-unsubstituted benzylamine derivatives that has a
moderate substrate scope.
Figure 1. Biologically active ortho-trifluoromethylated benzylamines.
(9) Wang, X.; Dai, Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010,
132, 3648–3649.
(10) Zhang, X.-G.; Dai, H.-X.; Wasa, M.; Yu, J.-Q. J. Am. Chem.
Soc. 2012, 134, 11948–11951.
(11) Zhang, L.-S.; Chen, K.; Chen, G.; Li, B.-J.; Luo, S.; Guo, Q.-Y.;
Wei, J.-B.; Shi, Z. J. Org. Lett. 2013, 15, 10–13.
(12) Mu, X.; Chen, S.; Zhen, X.; Liu, G. Chem.;Eur. J. 2011, 17,
6039–6042.
We initiated our studies into the palladium-catalyzed
CÀH ortho-trifluoromethylation of benzylamines by using
conditions adapted from our previous methods.10 To our
delight, subjection of benzylamine 1a with catalytic palla-
dium acetate, 1 equiv of copper acetate, 10 equiv of
trifluoroacetic acid, and electrophilic fluorination reagent
3 yielded the ortho-CF3 adduct in 20% yield after subse-
quent Boc protection (Table 1, entry 1). Increasing the
amount of Cu(OAc)2 to 2 equiv resulted in a beneficial
boost in yield (Table 1, entry 2). This is unsurprising, as we
believe that the copper acetate can scavenge the free
dibenzothiophene released over the course of the reaction,
which can hamperCÀH activation. Decreasing the equiva-
lents of TFA also improved the yield,17 which suggests that
the equilibrium ratio between the free amine and the amine
(13) Other related examples of trifluoromethylation of indoles/
heteroarenes: (a) Shimizu, R.; Egami, H.; Nagi, T.; Chae, J.; Hamashima,
Y.; Sodeoka, M. Tetrahedron Lett. 2010, 51, 5947–5949. (b) Chu, L.;
Qing, F.-L. J. Am. Chem. Soc. 2012, 134, 1298–1304.
(14) (a) Chen, C.; Wu, D.; Guo, Z.; Xie, Q.; Reinhart, G. J.; Madan,
A.; Wen, J.; Chen, T.; Hang, C. Q.; Chen, M.; Chen, Y.; Tucci, F. C.;
Rowbottom, M.; Pontillo, J.; Zhu, Y.-F.; Wada, W.; Saunders, J.;
Bozigiain, H.; Struthers, R. S. J. Med. Chem. 2008, 51, 7478–7485. (b)
Miyata, M.; Kasahara, C.; Asano, T.; Ito, S.; Seki, N.; Kato, Y.;
Morikawa, N.; Nozaki, K.; Nishimura, K.; Akamatsu, H.; Taguchi,
Y.; Yamaguchi, T.; Abe, Y.; Ohkubo, M.; Watanabe, T.; Ohta, M.;
Takeuchi, M. Bioorg. Med. Chem. Lett. 2012, 22, 5681–5684. (c)
Heinrich, T.; Brugger, N.; Josephson, K. PCT Application
WO2013004332 A1, Jan 10, 2013.
(15) (a) Orito, K.; Horibata, A.; Nakamura, T.; Ushito, H.; Nagasaki,
H.; Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Am. Chem. Soc. 2004,
126, 14342–1434. (b) Cai, G.; Fu, Y.; Li, Y.; Wan, X.; Shi, Z. J. Am.
Chem. Soc. 2007, 129, 7666–7673. (c) Li, H.; Cai, G.-X.; Shi, Z.-J. Dalton
Trans. 2010, 39, 10442–10446. (d) Haffemayer, B.; Gulias, M.; Gaunt,
M. J. Chem. Sci. 2011, 2, 312–315.
(17) Other acids, such as AcOH, MsOH, TfOH, and CCl3CO2H,
were also examined, yielding no observed ortho-trifluoromethylated
product.
(16) Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211–5213.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Reaction Optimization
Scheme 2. Substrate Scope of Pd-Catalyzed Ortho-Trifluoro-
methylation of Benzylaminesa,b
Cu(OAc)2
(equiv)
TFA
H2O
Ag2O
yield
(%)a,b
entity
(equiv)
(equiv)
(equiv)
1c
2
1
10
5
0
0
20
2
0
0
44
3c
4d
5d,e
6d
7d
8f
2
5
20
20
20
20
20
56
0
63
2
5
0.15
0.15
0.15
0.15
0.15 Â 2
69
2
5
0
0
5
0
2
0
4
2 Â 2
5
87 (79)g
a Conditions (unless otherwise specified): Substrate (0.1 mmol),
Pd(OAc)2 (10 mol %), Cu(OAc)2 (0.20 mmol), 3 (0.15 mmol), TFA
(0.5 mmol), H2O (2.0 mmol), Ag2O (15 mol %), ClCH2CH2Cl (0.5 mL),
130 °C, 24 h, then Boc2O (0.5 mmol), sat. aq Na2CO3 (2.0 mL), EtOAc
(1.0 mL), 25 °C, 12 h. b The yields were determined by 1H NMR analysis
of the crude products using CH2Br2 as an internal standard. c Reaction
was performed at 110 °C for 48 h. d Reaction was run at 130 °C for 8 h.
e Reaction was performed without Pd(OAc)2. f Conditions for batchwise
addition: (first batch) Substrate 1 (0.1 mmol), Pd(OAc)2 (10 mol %),
Cu(OAc)2 (0.20 mmol), 3 (0.15 mmol), TFA (0.5 mmol), H2O (5.6 mmol,
0.1 mL), Ag2O (15 mol %), ClCH2CH2Cl (1.0 mL), 130 °C, 6 h; (second
batch) Cu(OAc)2, 3 (0.15 mmol), Ag2O (15 mol %), 130 °C, 6 h; then
Boc2O (0.3 mmol), NaOH (5.0 mmol), 1,4-dioxane (1.0 mL), H2O
(1.0 mL), 25 °C, 12 h. g The isolated yield is given in parentheses.
salt is important for the reaction. The previously used
formamide additives10 as promoters were not effective for
this substrate. Our optimization studies also revealed that
the addition of H2O improves both the reaction yield and
total mass balance (Table 1, entry 3). Further intensive
screening for additives revealed that a catalytic amount of
Ag2O gave the product in 69% yield (Table 1, entry 4).18 It
is possible that Ag2O reoxidizes Pd(0) generated from side
pathways. Inthe absence ofPd(OAc)2, Cu(OAc)2, or TFA,
little or no ortho-trifluoromethylation product was ob-
served, indicating that these three reagents are crucial for
reactivity (Table 1, entries 5À7). Monitoring the reaction
a Conditions: (first batch) Substrate
1 (0.1 mmol), Pd(OAc)2
(10 mol %), Cu(OAc)2(0.20 mmol), 3 (0.15 mmol), H2O (5.6 mmol,
0.1 mL), TFA (0.5 mmol), Ag2O (15 mol %), ClCH2CH2Cl (1.0 mL),
130 °C, 6 h; (second batch) Cu(OAc)2, 3 (0.15 mmol), Ag2O (15 mol %),
130 °C, 6 h; then Boc2O (0.3 mmol), NaOH (5.0 mmol), 1,4-dioxane
(1.0 mL), H2O (1.0 mL), 25 °C, 12 h. b The isolated yields are given.
the ortho-trifluoromethylated product in 87% NMR yield
and 79% isolated yield (Table 1, entry 8).20
With these optimized conditions in hand, we surveyed
the substrate scope of this trifluoromethylation reaction
(Scheme 2). Although m-methyl substituted benzylamine
1b yielded ortho-trifluoromethylated product 2b with
a moderate 60% yield, the p-methyl (1c) and unsubsti-
tuted benzylamines (1d) were less reactive, affording their
corresponding ortho-trifluoromethylated products in
poor yields (30% and 24%, respectively).21 An electron-
donating group at the meta-position, such as the methoxy
1
by H NMR revealed that the electrophilic fluorination
reagent 319 was completely consumed while starting ma-
terial remained after 8 h; thus, the reaction was performed
via batchwise addition of 3, Cu(OAc)2, and Ag2O, yielding
(18) Increasing the amount of Ag2O had no further effect on the
reaction yield. Other Ag(I) reagents, such as AgOAc, Ag2CO3, and
Ag(TFA), did not improve the yield.
(20) Without Boc protection, the corresponding free amine was
isolated in 39% yield. Presumably, the excess amount of Cu might be
coordinated with the product, resulting in complications in extraction
during workup and lower overall yield.
(21) The corresponding di-ortho-CF3 adducts were also obtained in
about 3% yield.
(19) Other electrophilic trifluoromethylation reagents, such as
5-(trifluoromethyl)dibenzothiophenium
trifluoromethanesulfonate,
3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (Togni’s Reagent),
and 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one, were also examined
with no improvement in yield.
Org. Lett., Vol. XX, No. XX, XXXX
C

compounds with acceptable yields (45% and 54% yields,
respectively). Notably, N-methyl substituted benzylamine
(1o) also underwent ortho-trifluoromethylation in 76%
yield.
Based on our previous studies, we tentatively propose
a catalytic cycle of our palladium(II)-catalyzed ortho-
trifluoromethylation of benzylamines (Figure 2). We be-
lieve that the first step is palladium(II)-mediated CÀH
cleavage to generate the [ArÀPdII] species, which can
then react with the electrophilic trifluoromethylation re-
agent to form an octahedral PdIV intermediate.22 This
palladium(IV) species can then undergo reductive elimina-
tion to afford the ortho-trifluoromethylation product. It is
worth mentioning that the possibility of a redox neutral,
electrophilic cleavage pathway that proceeds via Pd(II)
cannot be excluded.
In summary, we report a versatile Pd(II)-catalyzedortho-
CÀH trifluoromethylation of N-unsubstituted benzyl-
amines. The addition of H2O and Ag2O proved to be crucial
for this transformation, and ortho-trifluoromethylated ben-
zylamines were obtained with good yields. We anticipate
that this reaction will have widespread applications in
medicinal chemistry to functionalize benzylamines.
Figure 2. Proposed catalytic cycle.
substituent in 2e, afforded the corresponding product in
42% yield while an electron-withdrawing group, such as a
chloride substituent in 2f, yielded the corresponding prod-
uct in 28% yield. However, the introduction of a methyl
group at the ortho-position was found to restore the
reactivity on a meta-chloro substituted benzylamine (1g),
producing the ortho-trifluoromethylated product 2g in
58% yield. Dimethyl- and phenyl-substituted compounds
were also well tolerated, and the corresponding trifluo-
romethylated products were obtained with moderate to
good yields (Scheme 2, 2hÀ2l). R-Substituted benzylamine
derivatives, such as 1m and 1n, were also compatible
substrates for this reaction, providing trifluoromethylated
Acknowledgment. We gratefully acknowledge The
Scripps Research Institute and the U.S. NSF (CHE-
1011898) for financial support. We also thank Astellas
Pharma Inc. for a postdoctoral fellowship to M.M.
Supporting Information Available. Experimental pro-
cedure and characterization of all new compounds
(PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(22) Ye, Y.; Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem.
Soc. 2010, 132, 14682–14687.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX