Kinetic Resolution of Benzylamines via Palladium(II)-Catalyzed C-H Cross-Coupling

Article abstract of DOI:10.1021/jacs.6b04660

A Pd(II)-catalyzed enantioselective C-H cross-coupling of benzylamines via kinetic resolution has been achieved using chiral mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) ligands. Both chiral benzylamines and ortho-arylated benzylamines are obtained in high enantiomeric purity. The use of a readily removable nosyl (Ns) protected amino group as the directing group is a crucial practical advantage. Moreover, the ortho-arylated benzylamine products could be further transformed into chiral 6-substituted 5,6-dihydrophenanthridines as important structural motifs in natural products and bioactive molecules.

Full text of DOI:10.1021/jacs.6b04660

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Article
Kinetic Resolution of Benzylamines via
Palladium(II)-Catalyzed C–H Cross-Coupling
Kai-Jiong Xiao, Ling Chu, Gang Chen, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b04660 • Publication Date (Web): 01 Jun 2016
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Kinetic Resolution of Benzylamines via Palladium(II)-
Catalyzed C–H Cross-Coupling
Kai-Jiong Xiao, Ling Chu, Gang Chen, Jin-Quan Yu*
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Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA
92037
*yu200@scripps.edu
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Abstract. A Pd(II)-catalyzed enantioselective C−H cross-coupling of benzylamines via kinetic resolution
has been achieved using chiral mono-N-protected -amino-O-methylhydroxamic acid (MPAHA) ligands.
Both chiral benzylamines and ortho-arylated benzylamines are obtained in high enantiomeric purity. The
use of a readily removable nosyl (Ns) protected amino group as the directing group is a crucial practical
advantage. Moreover, the ortho-arylated benzylamine products could be further transformed into chiral
6-substituted 5,6-dihydrophenanthridines as important structural motifs in natural products and bioactive
molecules.
1. Introduction
Enantiopure -branched amines are highly important structural motifs found prevalent in many
natural products and biologically active compounds. In particular, chiral ortho-arylated benzylamines are
known to be medicinally important motifs with a wide range of biological activities including CYP450
3A inhibition, -secretase modulation, and FVIIa inhibition (Figure 1).1 Consequently, a plethora of
methods for the asymmetric synthesis of chiral amines have been developed.2 Among them, asymmetric
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addition of carbanions to aldimines/ sulfinimines,3 asymmetric reduction/ hydrogenation of ketimines/
enamines/ enamides,4 and asymmetric hydroamination of alkenes are most extensively investigated.5
Despite these impressive advances, the enzymatic kinetic resolution and classical resolution via
diastereomeric salt formation are still frequently used in manufacturing.6 Notably, non-enzymatic kinetic
resolution of amines by acylation catalysts remains a significant challenge (Scheme 1a).7
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Figure 1. Bioactive compounds containing ortho-arylated benzylamines.
Considering the limited success of kinetic resolution of amines via acylation, we envisioned that
kinetic resolution of racemic benzylamines via a palladium(II)-catalyzed enantioselective C−H cross-
coupling8 would be appealing, as this approach will give access to both chiral benzylamines and ortho-
arylated benzylamines. Despite significant progress in the development of enantioselective C−H
functionalization reactions via desymmetrization,9-12 enantioselective C−H activation reactions through a
kinetic resolution process are rare.13 Recently enantioselective C−H iodination14 and enantioselective
C−H olefination15 via kinetic resolution were achieved utilizing Pd(II) coordinated with mono-N-
protected amino acid (MPAA) ligand as the catalyst.9,14,15 To the best of our knowledge, kinetic resolution
via palladium-catalyzed enantioselective C−H cross-coupling has not been demonstrated to date. The
elementary steps of C−H cross-coupling are fundamentally different from that of the C−H iodination14
and enantioselective C−H olefination,15 which suggests that the development of a different chiral ligand
may be necessary. From the viewpoint of synthetic utility, enantioselective C−H cross-coupling affords
highly valuable chiral bis-aryl compounds. Herein, we report a Pd(II)-catalyzed highly enantioselective
C−H cross-coupling/ kinetic resolution of racemic benzylamines with arylboronic acid pinacol esters
using a chiral mono-N-protected -amino-O-methylhydroxamic acid (MPAHA) ligand (Scheme 1b).
Notably, the amino moiety protected by the commonly used nosyl (Ns) group is used as the directing
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group, representing a practical advantage in synthetic applications. In contrast to traditional acylative
kinetic resolution, this asymmetric reaction not only separates two enantiomers of racemic benzylamines,
but also installs a new carbon-carbon bond,16 thereby providing a valuable method for the preparation of
chiral ortho-arylated benzylamines.
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Scheme 1. Kinetic Resolution of Racemic Benzylamines.
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2. Results and Discussion
We initiated our studies by exploring the enantioselective C−H cross-coupling/ kinetic resolution of
racemic nosyl (Ns) protected 1-(2-methylphenyl)ethanamine 1a. Guided by our previous conditions for
C−H cross-coupling of triflyl-protected amines,17 the reaction of 1a with para-
methoxycarbonylphenylboronic acid pinacol ester was carried out in the presence of 10 mol% Pd(OAc)2,
30 mol % Boc-L-Ala-OH, 3.0 equiv of Na2CO3, 2.0 equiv of Ag2CO3, 0.4 equiv of DMSO and 5.0 equiv
of H2O in t-AmylOH at 50 °C. We were pleased to find that the desired cross-coupled product 2aa and
the recovered starting material 1a were obtained with 58% ee and 93% ee respectively, corresponding to
a selectivity factor (s)18 of 12 (Table 1, entry 1). Encouraged by this result, a variety of commercially
available Boc protected amino acid ligands with different side chains were screened (entries 2-5). Boc-L-
Phe-OH (L1) gave the best s-factor of 19 (entry 5). However, further tuning the N-protecting group only
led to the decreased selectivities (entries 6 and 7). Influenced by our previous observation that conversion
of the carboxylic acid in MPAA ligand to hydroxamic acid can be beneficial to enantioselective C−H
activation reactions,9e a series of mono-N-protected -amino-o-methylhydroxamic acid (MPAHA)
ligands were investigated. This effort led to a significant improvement with Boc-L-Leu-NHOMe (L8)
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giving an excellent s-factor of 73 (entry 8). Replacing Boc with Cbz and Fmoc only gave inferior results
(entries 9 and 10, s = 47 and 29, respectively). Further tuning the side chains revealed that Boc-L-Phe-
NHOMe (L14) gave the best s-factor of 77 (entries 11-14). Notably, increasing the ligand loading to 20
mol% gave a similar s-factor albeit a decreased conversion (entry 15). Most likely, excessive ligand can
lead to the formation of Pd(II) complexes coordinated to two MPAHA ligands which will prevent
substrate binding. When the temperature was raised to 55 °C, the s-factor was slightly decreased to 68
(entry 16). The absolute configuration of 2aa was determined to be R by X-ray crystallographic analysis
(Figure 2), thus providing important information for the establishment of a stereo-model in the kinetic
resolution process through C−H activation.
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Table 1. Reaction Optimizationa
aReaction conditions: rac-1a (0.1 mmol), 4-(CO2Me)Ph-BPin (1.0 equiv), Pd(OAc)2 (10 mol%), ligand (30 mol%),
Ag2CO3 (2.0 equiv), Na2CO3 (3.0 equiv), BQ (0.5 equiv), H2O (5.0 equiv), DMSO (0.4 equiv), t-AmylOH (0.5 mL), N2,
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50 °C, 15 h. Calculated conversion, C = eeSM/(eeSM+eePR). Determined by chiral HPLC analysis. Selectivity (s) =
ln[(1–C)(1–eeSM)]/ln[(1–C)(1+eeSM)]. eUsing 15 mol% ligand. fUsing 20 mol% ligand. gRun at 55 °C.
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Figure 2. X-ray crystal structure of 2aa.
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With the optimized reaction conditions in hand, we next investigated the scope of the arylboronic
acid coupling partner. To our delight, the enantioselective C−H cross-coupling of racemic benzylamine
1a with a variety of arylboronic acid pinacol esters proceeded smoothly to provide the desired products
with excellent s-factor values (Table 2). The reaction with para-methoxycarbonylphenylboronic acid
pinacol ester provided 47% yield of the arylated product 2aa in 91% ee, accompanied with 46% yield of
recovered 1a in 96% ee (s = 77). Fluoro- and trifluromethyl-substituted phenylboronic acid pinacol esters
were also suitable coupling partners, affording the corresponding products with s-factor values ranging
from 96 to 107 (2ab-2ad). Functional groups such as aryl chlorides (2ae, s = 100), nitriles (2af, s = 67),
and ketones (2ag, s = 73) were well tolerated. Coupling partners containing electron-donating methyl and
methoxy groups also performed well and gave the cross-coupled products in excellent selectivity factors
(2ah and 2ai, s = 103 and 98, respectively). In general, the structures of the organoboronic acids do not
have significant impact on the s-factor, which is consistent with the enantioselectivity being determined
by the C–H activation step.
Table 2. Scope of Arylboronic Acid Coupling Partnersa,b
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aReaction conditions: rac-1a (0.2 mmol), Ar-BPin (1.0 equiv), Pd(OAc)2 (10 mol%), L14 (15 mol%), Ag2CO3 (2.0
equiv), Na2CO3 (3.0 equiv), BQ (0.5 equiv), H2O (5.0 equiv), DMSO (0.4 equiv), t-AmylOH (0.5 mL), N2, 50 °C, 15 h.
bIsolated yield; Calculated conversion, C = eeSM/(eeSM+eePR). Enantiomeric excess (ee) was determined by chiral HPLC
analysis; Selectivity (s) = ln[(1–C)(1–eeSM)]/ln[(1–C)(1+eeSM)].
We then examined the amine scope of the kinetic resolution process. We were pleased to find that
our protocol was tolerant of a variety of substituents on the phenyl ring, giving the corresponding products
in high enantioselectivities (Table 3). Both electron-withdrawing (2b-2f) and electron-donating (2g)
benzylamines were reactive. The chloride-containing substrates were also suitable for this
enantioselective cross-coupling (2c, 2f and 2h), although the 2,4-dichlorinated substrate gave a slightly
decreased conversion of 43% (2h, s = 75). While the reaction with ortho- and meta-substituted substrates
provided only the mono-arylated products, the reaction of para-substituted and unsubstituted substrates
gave a mixture of mono- and di-arylated products (2i and 2j, s = 87 and 72, respectively). A series of
different alkyl-substituted amines were also subjected to the reaction conditions. Primary alkyl-substituted
substrates afforded excellent s-factor values (2k and 2l, s = 72 and 122, respectively). The secondary
cyclopropyl-substituted amine 1m proceeded smoothly with an s-factor of 100, but bulkier isopropyl-
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substituted substrate 1n led to a decrease in conversion (C = 38%, s = 93). The results obtained with
substrates 1k-n containing the same meta-chloro phenyl group suggests that the size of alkyl chain has
moderate effect on enantioselectivity with the longest chain butyl group affording the highest s-factor.
This trend is consistent with the stereomodel proposed for kinetic resolution via C–H olefination enabled
by an analogous chiral MPAA ligands.15 The reaction with racemic -amino acid 1o also produced the
arylated product in high enantioselectivity, albeit with a reduced s-factor of 34. Importantly, this
enantioselective C−H activation method can also be applied to prepare chiral -amino alcohols (2p, s =
95), an important class of molecules with broad applications as chiral synthons and chiral auxiliaries in
asymmetric synthesis.19 Comparison between substrates 1o and 1p containing the same ortho-chloro
phenyl group indicates that sterically hindered alkyl chain gives better enantioselectivity.
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Table 3. Scope of Benzylamine Substratesa,b
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aReaction conditions: rac-1 (0.2 mmol), Ar-BPin (1.0 equiv), Pd(OAc)2 (10 mol%), L14 (15 mol%), Ag2CO3 (2.0 equiv),
Na2CO3 (3.0 equiv), BQ (0.5 equiv), H2O (5.0 equiv), DMSO (0.4 equiv), t-AmylOH (0.5 mL), N2, 50 °C, 15 h. bIsolated
yield; Calculated conversion, C = eeSM/(eeSM+eePR). Enantiomeric excess (ee) was determined by chiral HPLC analysis;
Selectivity (s) = ln[(1–C)(1–eeSM)]/ln[(1–C)(1+eeSM)]. cConversion was determined by crude 1H-NMR.
To demonstrate the synthetic utility of this enantioselective C−H activation reaction, a gram-scale
experiment was carried out using racemic 1f under the optimal reaction conditions. The cross-coupled
product 2f was obtained in 45% yield with 94% ee, and the recovered starting material 1f was isolated in
42% yield with 91% ee (Scheme 2a). Importantly, the nosyl protecting group was readily removed under
mild conditions (Scheme 2b). Moreover, the arylated product 2f was further transformed into 6-substituted
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5,6-dihydrophenanthridine 4 without loss of optical activity by an NIS-mediated ring-closure (Scheme
2c). It should be noted that 6-substituted 5,6-dihydrophenanthridines are important structural units in
natural products and biologically active molecules.20
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Scheme 2. Synthetic Applications.
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3. Conclusion
In conclusion, we have developed an unprecedented kinetic resolution process for nosyl-protected
benzylamines via Pd(II)-catalyzed enantioselective C−H cross-coupling. This approach allows for rapid
preparation of both chiral benzylamines and ortho-arylated benzylamines in high enantioselectivities. The
use of Ns-protected amines as substrates is an important practical advantage for synthetic applications. In
addition, NIS-mediated ring-closure of enantioenriched ortho-arylated benzylamines provides a
convenient access to the highly valuable chiral 6-substituted 5,6-dihydrophenanthridines. Currently, the
incompatibility of this reaction with heterocyclic substrates is a limitation that remains to be overcome.
4. Experimental Section
General Procedure for Kinetic Resolution of Benzylamines via Palladium(II)-Catalyzed C–H Cross-
coupling: Substrate rac-1 (0.2 mmol, 1.0 equiv), Pd(OAc)2 (0.1 equiv), L14 (0.15 equiv), Ar-BPin (1.0
equiv), Ag2CO3 (2.0 equiv), Na2CO3 (3.0 equiv), BQ (0.5 equiv), DMSO (0.4 equiv), H2O (5.0 equiv)
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and t-AmylOH (1.0 mL) were added into a 10 ml sealed tube. The reaction vessel was evacuated and
backfilled with nitrogen (×3). The reaction mixture was heated to 50 °C for 15 h under vigorous stirring.
After being cooled to room temperature, the reaction mixture was diluted with EtOAc and filtered through
a pad of Celite, eluting with EtOAc. The filtrate was concentrated under vacuum and the resulting residue
was purified by preparative TLC using EtOAc/hexanes as the eluent to produce the desired product. The
ee value was determined on a Hitachi LaChrom HPLC system using commercially available chiral
columns as described below.
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Acknowledgements. We gratefully acknowledge The Scripps Research Institute and the NIH (NIGMS,
2R01GM084019) for financial support.
Supporting Information Available. Detailed experimental procedures, characterization of new
compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
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Wang, X.-C.; Moore, C. E.; Rheingold, A. L.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 16344. (e)
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(g) Hyster, T. K.; Knörr, L.; Ward, T. R.; Rovis, T. Science 2012, 338, 500. (h) Ye, B.; Cramer, N.
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(18) The selectivity factor (s) = (rate of fast-reacting enantiomer) / (rate of slow-reacting enantiomer)
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