Palladium(II)-catalyzed enantioselective synthesis of α- (trifluoromethyl)arylmethylamines

Article abstract of DOI:10.1021/ol401862g

Trifluoromethylacetaldimines, generated in situ from the corresponding N,O-acetals, undergo 1,2-addition of arylboroxines under palladium(II) catalysis to generate a variety of α-(trifluoromethyl)arylmethylamines with good to high enantioselectivity (up to 97% ee). The pyridine-oxazolidine (PyOX) class of ligands was found to be particularly suitable for this transformation, which proceeds without exclusion of ambient air and moisture.

Full text of DOI:10.1021/ol401862g

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Palladium(II)-Catalyzed
Enantioselective Synthesis of
r‑(Trifluoromethyl)arylmethylamines
Thomas Johnson and Mark Lautens*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto,
Ontario, Canada M5S 3H6
mlautens@chem.utoronto.ca
Received July 3, 2013
ABSTRACT
Trifluoromethylacetaldimines, generated in situ from the corresponding N,O-acetals, undergo 1,2-addition of arylboroxines under palladium(II)
catalysis to generate a variety of R-(trifluoromethyl)arylmethylamines with good to high enantioselectivity (up to 97% ee). The pyridine-oxazolidine
(PyOX) class of ligands was found to be particularly suitable for this transformation, which proceeds without exclusion of ambient air and moisture.
The transition-metal-catalyzed addition of organoboron
reagents to imines has emerged as a versatile method for the
preparation of diversely substituted amines in an enantio-
selective fashion.1 Among the catalytic systems capable
of effecting this transformation, complexes of rhodium(I)
with chiral dienes or phosphorus-based ligands have most
often been employed.1,2 In comparison, there are few reports
featuring the use of the less expensive palladium(II) as the
catalyst for this transformation.3
In view of the prevalence of organofluorine com-
pounds in medicinal chemistry, as well as the occurrence
of R-(trifluoromethyl)amines in several biologically active
molecules,4 we sought to develop an enantioselective
method for the synthesis of this class of compounds.
Herein, we report that readily available N,O-acetals of
trifluoroacetaldehyde react with arylboroxines and a
Pd(II)/(S)-PyOX complex to afford enantioenriched sec-
ondary amines.
Much recent interest in trifluoromethylated amines
can be associated with their use as amide bond isosteres,
with a recent report of a cathepsin K inhibitor drug
candidate.5 Previous reports on the asymmetric synthesis
of R-(trifluoromethyl)amines are in the fields of catalytic
hydrogenation of imines,6 cinchona alkaloid-catalyzed
isomerization of trifluoromethylated imines,7 and nucleophilic
(4) (a) Lim, J.; Taoka, B.; Otte, R. D.; Spencer, K.; Dinsmore, C. J.;
Altman, M. D.; Chan, G.; Rosenstein, C.; Sharma, S.; Su, H.-P.;
Szewczak, A. A.; Xu, L.; Yin, H.; Zugay-Murphy, J.; Marshall, C. G.;
Young, J. R. J. Med. Chem. 2011, 54, 7334–7349. (b) O’Shea, P. D.;
Chen, C.-Y.; Gauvreau, D.; Gosselin, F.; Hughes, G.; Nadeau, C.;
Volante, R. P. J. Org. Chem. 2009, 74, 1605–1610. (c) Zhang, N.; Ayral-
Kaloustian, S.; Nguyen, T.; Afragola, J.; Hernandez, R.; Lucas, J.;
Gibbons, J.; Beyer, C. J. Med. Chem. 2007, 50, 319–327. (d) Grunewald,
G. L.; Caldwell, T. M.; Li, Q.; Criscione, K. R. J. Med. Chem. 1999, 42,
3315–3323.
(5) Black, W. C.; Bayly, C. I.; Davis, D. E.; Desmarais, S.; Falgueyret,
J. P.; Leger, S.; Li, C. S.; Masse, F.; McKay, D. J.; Palmer, J. T.; Percival,
M. D.; Robichaud, J.; Tsou, N.; Zamboni, R. Bioorg. Med. Chem. Lett.
2005, 15, 4741–4744.
(6) (a) Chen, M. W.; Duan, Y.; Chen, Q.-A.; Wang, D.-S.; Yu, C.-B.;
Zhou, Y. G. Org. Lett. 2010, 12, 5075–5077. (b) Henseler, A.; Kato, M.;
Mori, K.; Akiyama, T. Angew. Chem., Int. Ed. 2011, 50, 8180–8183. (c)
Gosselin, F.; O’Shea, P. D.; Roy, S.; Reamer, R. A.; Chen, C.; Volante,
R. P. Org. Lett. 2006, 7, 355–358.
(7) (a) Liu, M.; Li, J.; Xiao, X.; Xie, Y.; Shi, Y. Chem. Commun. 2013,
49, 1404–1406. (b) Wu, Y.; Deng, L. J. Am. Chem. Soc. 2012, 134, 14334–
14337.
(1) (a) Ramadhar, T. R.; Batey, R. A. In Boronic Acids: Preparation
and Applications in Organic Synthesis, Medicines and Materials; Hall,
D. G., Ed.; Wiley-VCH: Weinheim, Germany, 2011; Vol. 2, pp 427ꢀ477. (b)
Sun, Y.-W.; Zhu, P.-L.; Xu, Q.; Shi, M. RSC Adv. 2013, 3, 3153–3168.
(c) Marques, C. S.; Burke, A. J. ChemCatChem 2011, 3, 635–645.
(2) Selected recent examples: (a) Jung, H. H.; Buesking, A. W.;
Ellman, J. A. J. Org. Chem. 2012, 77, 8541–8548. (b) Nishimura, T.;
Noishiki, A.; Tsui, G. C.; Hayashi, T. J. Am. Chem. Soc. 2012, 134,
5056–5059.
(3) (a) Chen, J.; Lu, X.; Lou, W.; Ye, Y.; Jiang, H.; Zeng, W. J. Org.
Chem. 2012, 77, 8541–8548. (b) Marques, C. S.; Burke, A. J. Eur. J. Org.
Chem. 2010, 9, 1639–1643. (c) Dai, H.; Lu, X. Tetrahedron Lett. 2009, 50,
3478–3481. (d) Ma, G. N.; Zhang, T.; Shi, M. Org. Lett. 2009, 11, 875–
878. (e) Dai, H.; Lu, X. Org. Lett. 2007, 9, 3077–3080.
r
10.1021/ol401862g
XXXX American Chemical Society

additions to fluorinated or nonfluorinated imines (Figure 1).8
Despite these important developments, asymmetric addi-
tion to imines generally relies on N-activating groups that
are cleavable under particularly harsh conditions8c,d or on
chiral auxiliaries.8a,b,12
Table 1. Optimization of the Reaction Conditionsa
entry
Pd source
solvent
DCE
yield (%)b
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
73 (77)c
DCM
63
51
ꢀ
TFT
dioxane
toluene
acetonitrile
DCE
ꢀ
ꢀ
71
ꢀ
d
Pd2(dba)3
DCE
a Reaction conditions: N,O-acetal (0.20 mmol, 1 equiv); phenylbor-
oxine (0.20 mmol, 1 equiv); Pd source (0.010 mmol, 5 mol %); BiPy
(0.012 mmol, 6 mol %); solvent (1.1 mL); under air. b Yield of isolated
product after flash chromatography. c 2.5 mmol scale reaction. d Control
experiment with a Pd(0) source.
Figure 1. Previous examples of R-(trifluoromethyl)amine synthe-
sis by asymmetric addition to imines.
We began our work examining the racemic addition
to aniline-derived N,O-acetal 1a using phenylboroxine
(Table 1). At the outset, we observed that a catalytic
amount of Pd(OAc)2 along with 2,20-bipyridine (BiPy) as
a ligand furnished the desired amine 2a in good yield, using
DCE as the solvent (Table 1, entry 1). DCM and trifluoro-
toluene (TFT) could also be used, albeit with diminished
yields (Table 1, entries 2 and 3); other common solvents
were ineffective (Table 1, entries 4ꢀ6). It was also observed
that Pd(TFA)2 could be employed with similar results as
with Pd(OAc)2 (Table 1, entry 7). In a control experiment,
Pd2(dba)3 led to no observable product by 19F NMR
analysis of the reaction mixture (Table 1, entry 8). Under
the optimized contidions, the reaction could effectively be
scaled up to a 2.5 mmol scale (Table 1, entry 1).
afforded increasing levels of enantioselectivity with in-
creasing steric bulk of the R side chain (Table 2, entries
5ꢀ8). As the analogue bearing a tert-butyl side chain (L8)
yielded the desired amine with highest enantioselectivity
(92% ee), it was selected to examine the scope of the
reaction (Table 3).
Table 2. Screening of Chiral Ligandsa
Although commercial phenylboronic acid was used in
our preliminary experiments, it was found that different
lots gave inconsistent results. In fact, the boroxine/boronic
acid/water ratio of such samples can vary from batch to
batch and over time.9 We hypothesized that dehydrating
the boronic acids to their corresponding boroxines would
circumvent the problem. Indeed, the use of boroxines
enabled completely reproducible results.10
We then turned our attention to finding an appropriate
chiral ligand for this reaction. A number of privileged
structures were screened under our optimized conditions:
while BOX (L1-L2) or PyBOX (L3-L4) ligands were un-
suitable (Table 2, entries 1ꢀ4), pyridine-oxazoline (PyOX)
ligands (L5-L8)3c were compatible with the reaction and
(8) (a) Xu, J.; Liu, Z.-J.; Yang, X.-J.; Wang, L.-M.; Chen, G.-L.; Liu,
J.-T. Tetrahedron 2010, 66, 8933–8937. (b) Truong, V. L.; Pfeiffer, J. Y.
Tetrahedron Lett. 2009, 50, 1633–1635. (c) Kawai, H.; Kusuda, H.;
Nakamura, S.; Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2009, 48,
6324–6327. (d) Lauzon, C.; Charette, A. B. Org. Lett. 2006, 8, 2743–
2745.
a Reaction conditions: N,O-acetal (0.20 mmol, 1 equiv); phenylbor-
oxine (0.20 mmol, 1 equiv); Pd(OAc)2 (0.010 mmol, 5 mol %); ligand
(0.012 mmol, 6 mol %); solvent (1.1 mL); under air. b Yield of isolated
product after flash chromatography. c Determined by HPLC on a chiral
stationary phase. See Supporting Information for details.
(9) Boronic acids trimerize to form boroxines upon standing, with
release of water. See Boronic Acids: Preparation and Applications in
Organic Synthesis, Medicines and Materials; Hall, D. G., Ed.; Wiley-VCH:
Weinheim, Germany, 2011; pp 1ꢀ123.
(10) For examples of the use of boroxines in 1,2-addition reactions,
see ref 2.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 1. Removal of the Amine PMP Groupa
Table 3. Pd(II)-Catalyzed Enantioselective Synthesis of
R-(Trifluoromethyl)aminesa
a Step 1: MeCN/H2O (1:1), rt, 16 h. See Supporting Information for
details.
electron-neutral or moderately electron-rich boroxines
reacted to give the desired amines in high yield and
enantioselectivity (Table 3, entries 10ꢀ12). Boroxines with
a more electron-donating substituent reacted equally well
but with diminished enantiocontrol (Table 3, entries 13
and 14). However, the switch to a substrate bearing a 3-Br
substituent restored a high level of enantioselectivity
(Table 3, entry 13 vs 16). A fluorinated boroxine was also
tolerated but necessitated a longer reaction time to reach
complete conversion (Table 3, entry 15). Under our opti-
mized conditions, other electron-poor boroxines (e.g.,
3-chlorophenyl, 4-(acetyl)phenyl) and anortho-substituted
boroxine (2-methyl) did not display any reactivity.
The p-methoxyphenyl (PMP) group of R-(trifluoro-
methyl)amine 2b could be removed under modified litera-
ture conditions (Scheme 1).11 Oxidative cleavage followed
by workup and acidification furnished the hydrochloride
salt (S)-3 in 67% yield. The absolute stereochemistry was
assigned by comparison of the optical rotation with that
found in the literature ([R]D25 = þ26.5 (c = 0.65, MeOH))
for 94% ee.12
a Reaction conditions: N,O-acetal (0.20 mmol, 1 equiv); boroxine
(0.20 mmol, 1 equiv); Pd(OAc)2 (0.020 mmol, 10 mol %); ligand (0.024
mmol, 12 mol %), solvent (1.1 mL); under air. b Yield of isolated product
after flash chromatography. c Enantiomeric excesses determined by
HPLC on a chiral stationary phase. d Reaction ran on a 1 mmol scale.
e L6 was used. f Reaction time was 48 h.
The influence of substituents on the N-aryl ring was
studied. Notably, all reactions were performed without
rigorous exclusion of air and moisture. Using phenylbor-
oxine as the nucleophile, N,O-acetals bearing electron-rich
or neutral aryl rings gave good to high yields of product
(77ꢀ85%) (Table 3, entries 1, 2, and 8) with the exception
of dioxolane-bearing amine 2c, generated in lower yield
(59%) (Table 3, entry 3). Substrates with moderately
electron-deficient aromatic rings furnished products in
comparable yields (75ꢀ86%) (Table 3, entries 4ꢀ7). How-
ever, introduction of a nitro group at the 4 position shut
down reactivity (Table 3, entry 9). In all of the successful
examples, high enantioselectivity was achieved with the
exception of ortho-substituted product 2h (63% ee). Inter-
estingly, in the latter case, switching to the less hindered
ligand L6 proved beneficial as the ee increased to 71%.
The scope of boroxines was then studied with an N,O-
acetal bearing a 4-MeO aryl substituent. It was found that
In summary, a Pd(II)-catalyzed enantioselective synthe-
sis of R-(trifluoromethyl)arylmethylamines has been de-
veloped, starting from readily available N,O-acetals of
trifluoroacetaldehyde. A variety of fluorinated benzyl-
amines could be synthesized in up to 97% ee and 91%
yield. Efforts are underway to extend this reaction to the
addition of other classes of nucleophiles.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada (NSERC) and
Merck for anIndustrialResearch Chair, and the University
of Toronto for financial support. T.J. thanks NSERC for a
CGS-M scholarship. Mr. Ken-Loon Choo (University of
Toronto) is thanked for experimental assistance.
Supporting Information Available. Detailed experimen-
tal procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) Verkade, J. M M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.;
Alsters, P. L.; van Delft, F. L.; Rutjes, F. P. J. T. Tetrahedron Lett. 2006,
47, 8109–8133.
(12) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem., Int.
Ed. 2001, 40, 589–590.
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
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