From racemic alcohols to enantiopure amines: Ru-catalyzed diastereoselective amination

Article abstract of DOI:10.1021/ja5058482

A commercially available ruthenium(II) PNP-type pincer catalyst (Ru-Macho) promotes the formation of α-chiral tert-butanesulfinylamines from racemic secondary alcohols and Ellmans chiral tert-butanesulfinamide via a hydrogen borrowing strategy. The formation of α-chiral tert-butanesulfinylamines occurs in yields ranging from 31% to 89% with most examples giving >95:5 dr.

Full text of DOI:10.1021/ja5058482

Communication
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Open Access on 08/29/2015
From Racemic Alcohols to Enantiopure Amines: Ru-Catalyzed
Diastereoselective Amination
Nathan J. Oldenhuis, Vy M. Dong,* and Zhibin Guan*
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025, United States
S
* Supporting Information
been achieved to date, by Zhao and co-workers.8 However, this
ABSTRACT: A commercially available ruthenium(II)
PNP-type pincer catalyst (Ru-Macho) promotes the
formation of α-chiral tert-butanesulfinylamines from
racemic secondary alcohols and Ellman’s chiral tert-
butanesulfinamide via a hydrogen borrowing strategy.
The formation of α-chiral tert-butanesulfinylamines occurs
in yields ranging from 31% to 89% with most examples
giving >95:5 dr.
Ir-catalyzed method is limited to the synthesis of chiral
anilines.8 Guided by previous studies using Ru−pincer
complexes,4,9 we proposed that racemic alcohol 2 (Scheme
2) would undergo oxidation by Ru−pincer complex 3a to form
Scheme 2. Mechanistic Proposal Featuring Hydrogen
Borrowing via a Ruthenium(II) Pincer Complex
ecause of the high value of α-chiral amines in both
B
medicinal and synthetic chemistry, there is a need to
develop more efficient methods for the stereoselective
construction of C−N bonds.1 Since its discovery in 1997,
Ellman’s sulfinamide has become a widely used reagent for the
synthesis of α-chiral primary amines, with many industrially
relevant applications.2,3 Considering the high practicality of this
ammonia equivalent, we sought a catalytic method for the
diastereoselective N-alkylation of Ellman’s sulfinamide (1)
using readily available secondary alcohols 2 (Scheme 1).4,5 This
Scheme 1. Diastereoselective Amination: Proposed Catalytic
Strategy (One Step) versus the Conventional Approach
(Three Steps)
ketone 4 and Ru hydride 3b. Ketone 4 would undergo
condensation with sulfinamide 1 to form the sulfinylimine 5.10
Hydrogenation of imine 5 via Ru hydride 3b would proceed
with high and predictable diastereoselectivity to generate the α-
chiral sulfinylamine 6.10 To achieve this novel alkylation, we
recognized the challenge of identifying a catalyst that would
favor hydrogen transfer over competing pathways (e.g.,
acceptorless dehydrogenation).11,12 Moreover, the Ru catalyst
would need to tolerate H2O as the main byproduct.
To test our hypothesis, we investigated the coupling of
sulfinamide 1 and racemic alcohol 1-phenylethanol (2b) with a
number of Ru−pincer complexes (Table 1). A few structurally
related pincer complexes, including Milstein’s catalyst 3c (entry
1) as well as catalysts 3d and 3f (entries 2 and 3), showed no
desired reactivity, even though these catalysts are known to
activate both C−N and C−O bonds.11,13 In a previous study,14
we discovered that Ru-Macho (3f)15 acts as an efficient catalyst
formal nucleophilic substitution would transform racemic
alcohols into enantiopure amines and generate water as the
only byproduct. Herein we describe a Ru-catalyzed approach
that overcomes the need for stoichiometric reagents and
achieves in a single operation what traditionally requires three
chemical steps (i.e., oxidation, condensation using Ti(OEt)4,
and then reduction), as shown in Scheme 1.
The direct amination of alcohols has been demonstrated with
Received: June 12, 2014
various catalysts,6,7 but only one stereoselective amination has
© XXXX American Chemical Society
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dx.doi.org/10.1021/ja5058482 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Optimization of Reaction Conditions for the
Formation of N-tert-Butanesulfinylamines
Table 2. Variation of Secondary Alcohols Used in
Diastereoselective Amination
Reaction conditions: 0.5 mmol of 2b, 0.5 mmol of 1, 1 mol % 3, 15
a
mol % base, 0.5 mL of toluene, 110 °C, 8 h. Conversion measured by
GC with a known amount of dodecane standard.
for the dehydrogenative synthesis of amides and imines from
alcohols and amines. We envisioned that this complex could
potentially act as a hydrogen-transfer catalyst to afford the
desired product. Indeed, Ru-Macho afforded α-chiral sulfinyl-
amine 6 in 71% conversion (entry 4). By further tuning the
reaction parameters, we identified the optimal conditions to be
the use of toluene as the solvent and KOH as the base at 120
°C (89% conversion; entry 10). The transformation occurs
efficiently using only 1 mol % catalyst.
With this protocol in hand, we transformed a variety of
racemic alcohols into optically active amines. (Table 2).16 The
reaction conditions do not epimerize the chiral sulfinamide, and
the expected enantiomer was produced after coupling with an
achiral alcohol (entry 1). Both electron-donating and electron-
withdrawing groups on the β-phenyl group relative to the
amine could be incorporated (73−89% yield, >95:5 dr; entries
3−7). Fluoro-containing amines were obtained in good yields
(73−89%) with high diastereocontrol (>95:5 dr) (entries 5 and
6). Next, we found that chiral pyridyl derivatives (6h−j) could
Reaction conditions: 0.5 mmol of 1, 0.5 mmol of 2, 1 mol % Ru-
a
Macho, 15 mol % KOH, 0.5 mL of toluene, 120 °C. Isolated yields.
b
c
1
Determined by H NMR analysis. Determined by polarimetry.
B
dx.doi.org/10.1021/ja5058482 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
be generated in 55−80% isolated yield with high diaster-
eoselectivity (>95:5 dr) (entries 8−10). A racemic alcohol
bearing a larger aromatic substituent, such as the 2-naphthyl
group (entry 11) underwent coupling in 84% yield with >95:5
dr. When the aryl group was substituted for saturated
hydrocarbon chains (entries 12 and 13), a drop in
diastereoselectivity (75:25 and 70:30 dr, respectively) was
observed, but the reaction yield remained between 71 and 81%
(6l and 6m, respectively). Our observations are in agreement
with those of previous studies by Ellman and others, who found
that reduction of sulfinylimines proceeds with lowered
diastereocontrol when the β-substituents are similar in
size.2,17 We propose that the lower diastereocontrol in entries
12 and 13 is due to the similar steric bulk of a methyl group and
an n-butyl or −(CH2)2Ph group.18 In contrast, an alcohol with
a isopropyl substituent (entry 14) was shown to form the
corresponding sulfinylamine with higher diastereoselectivity
(>95:5) as a result of the greater steric difference in the
corresponding substituents (6n).19
The synthesis of α-chiral amines bearing a β-methyl group is
challenging to achieve because of the low diastereocontrol in
the conventional addition of MeLi to N-tert-butylsulfinylaldi-
mine.2,3 In contrast, our method is most effective for the
construction of amines bearing a β-methyl group (Table 2,
entries 2−14). Ru-Macho appears to be sensitive to the steric
bulk at the β-position on the sulfinylimine intermediate during
hydrogen transfer (5 in Scheme 2). For example, lower isolated
yields are encountered when bulkier groups were placed at the
β-position on both sides of the alcohol (31−36%; entries 15
and 16), but the diastereoselectivities remain high (>95:5 dr)
(6o and 6p). We found that more bulky substrates (e.g., a tert-
butyl-substituted alcohol or ortho-arylated alcohol) show no
reactivity under these conditions (entries 17 and 18).
ACKNOWLEDGMENTS
■
Z.G. is thankful for the financial support received from the U.S.
National Institutes of Health (DK098446) and the U.S.
National Science Foundation (CHE-1012422). V.M.D. is
thankful for the financial support received from the U.S.
National Institutes of Health (GM105938).
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ASSOCIATED CONTENT
■
S
* Supporting Information
Substrate preparation and 1H and 13C NMR spectra and
characterization data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
dongv@uci.edu
zguan@uci.edu
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Notes
The authors declare no competing financial interest.
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