Kinetic Resolution of Azomethine Imines by Bronsted Acid Catalyzed Enantioselective Reduction

Article abstract of DOI:10.1002/anie.201507548

Azomethine imines are valuable substrates in asymmetric catalysis, and can be precursors to β-amino carbonyl compounds and complex hydrazines. However, their utility is limited because complex and enantioenriched azomethine imines are often unavailable. R

Full text of DOI:10.1002/anie.201507548

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International Edition: DOI: 10.1002/anie.201507548
German Edition: DOI: 10.1002/ange.201507548
Asymmetric Catalysis
Kinetic Resolution of Azomethine Imines by Brønsted Acid Catalyzed
Enantioselective Reduction
Amanda Bongers, Patrick J. Moon, and AndrØ M. Beauchemin*
Abstract: Azomethine imines are valuable substrates in
asymmetric catalysis, and can be precursors to b-amino
carbonyl compounds and complex hydrazines. However,
their utility is limited because complex and enantioenriched
azomethine imines are often unavailable. Reported herein is
a kinetic resolution of N,N’-cyclic azomethine imines by
enantioselective reduction (s = 13–43). This resolution was
accomplished using a Brønsted acid catalyst, and represents the
first example of the asymmetric reduction of azomethine
imines. The pyrazolidinone product (up to 86% ee) and the
recovered azomethine imine (up to 99% ee) can both be used
to access the opposite enantiomers of valuable products.
I
n the past decade, azomethine imines have been intensely
studied in the field of asymmetric catalysis. These versatile
compounds are well known as substrates in 1,3-dipolar
cycloadditions and nucleophilic additions, as well as directing
groups and bifunctional catalysts.[1] In 2003, Shintani and Fu
reported the first example of asymmetric catalysis with
azomethine imines, where they described the enantioselective
cycloaddition of prochiral N,N’-cyclic azomethine imines.[2]
Since this report, there have been many examples of catalytic
stereoselective reactions with N,N’-cyclic azomethine imines
(1; see Scheme 1),[3] thus establishing their value as precursors
to pyrazolidinones, hydrazines, and b-aminocarbonyl com-
pounds. However, because of the difficult synthesis of
structurally diverse azomethine imines, the scope of these
reactions is limited to simple and achiral substrates. While
simple azomethine imines can be synthesized by the con-
densation of pyrazolidinones onto aldehydes, the complex
and ketone-derived 1 are typically inaccessible.[4] There are
only two reports on the access to enantioenriched 1, that is,
the kinetic resolution of a small scope of substrates (Sche-
me 1a).[5] In both cases, the selective cycloaddition of one
enantiomer provides resolution, but at the cost of half the
starting material going to the cycloadduct. These reaction
conditions are only amenable to aldehyde-derived azome-
thine imines, with limited substitutions at C5 and no
substitution at C4. Herein, we report a kinetic resolution of
the complex ketone- and aldehyde-derived 1 by enantiose-
lective reduction (s = 13–43),[6] where both the products and
recovered starting materials are valuable enantioenriched
Scheme 1. Access to enantioenriched azomethine imines.
compounds containing the b-aminocarbonyl motif (Sche-
me 1b).
We recently reported a cycloaddition of simple alkenes
with imino isocyanates, to give azomethine imines (Æ)-1 of
unprecedented complexity.[7,8] Because examples of intermo-
lecular alkene aminocarbonylations are rare,[7,9] and enantio-
selective variants have not been developed,[10] we aimed to
find a general kinetic resolution procedure to resolve these
azomethine imines. An attractive strategy is enantioselective
reduction, to afford two enantioenriched compounds of
opposite stereochemistry and differing simply by their
oxidation state. This approach would provide access to
enantioenriched pyrazolidinones, hydrazines, and b-amino
carbonyl compounds. Azomethine imines are commonly
reduced with hydrides, but to the best of our knowledge
there are no reports of enantioselective reduction.[11] Fur-
thermore, there are only two examples of enantioselective
nucleophilic additions to 1.[3h,i]
[*] A. Bongers, P. J. Moon, Prof. Dr. A. M. Beauchemin
Centre for Catalysis Research and Innovation
Department of Chemistry and Biomolecular Sciences
10 Marie Curie, Ottawa, Ontario, K1N 6N5 (Canada)
E-mail: andre.beauchemin@uottawa.ca
We explored several methods for the enantioselective
reduction of imines, and became interested in chiral phos-
phoric acid catalysis.[12,13] We envisioned that the Brønsted
acid catalyst would activate the dipole at the negative
nitrogen center, and selectively deliver the hydride to one
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507548.
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Table 1: Kinetic resolutions of fluorenone-derived azomethine imines by enantio-
selective reduction.[a]
enantiomer. While chiral phosphoric acids are well-
known for the reduction of imines, the binding mode
of these catalysts with azomethine imines is unique
and has not been shown to provide efficient control
of enantioselective 1,2-additions.[14] After testing
several chiral phosphoric acid organocatalysts,
reducing agents, and reaction conditions (see
Tables S1–S4 in the Supporting Information for
selected optimization data), we identified (R)-TRIP Entry (Æ)-1 (R1, R2)
as an excellent catalyst for selective reduction, with
Cond.[a] t [h] Conv. [%] ee (Yield) [%][b] s[c]
1
2
the Hantzsch ester (4) as a mild reductant (Sche-
1
2
3
4
5
6
7
8
9
(Æ)-1a (H, Ph)
A
A
A
A
A
B
B
6
6
6
16
5
24
24
24
24
54
58
57
55
49
54
53
50
46
96 (45) 73 (41) 38
96 (32) 76 (32) 21
95 (42) 74 (48) 22
95 (43) 77 (43) 29
82 (50) 83 (46) 35
93 (43) 79 (52) 29
95 (45) 74 (45) 43
82 (48) 81 (45) 26
72 (47) 83 (38) 26
me 1b). We first investigated the use of these
reaction conditions with fluorenone-derived azome-
thine imines [(Æ)-1a–h], which are the products of
our alkene aminocarbonylation process (Table 1).[7]
Gratifyingly, several substrates could be resolved
with high selectivity using this catalyst system
(Table 1). Our initial investigations identified reac-
tion conditions (A) which allowed access to several
C5-aryl-substituted azomethine imines (1a–d, 95–
96% ee) and pyrazolidinones (2a–d, 73–77% ee) in
high yields (entries 1–4). When the kinetic resolution
of (Æ)-1d was stopped at lower conversion (entry 5),
the pyrazolidinone 2d was isolated in 83% ee. Bulky
alkyl- and naphthyl-substituted azomethine imines
[(Æ)-1e–h] were less reactive and also sparingly
soluble in toluene, and chlorobenzene was a more
suitable solvent (conditions B; entries 6–9). The
kinetic resolution of the syn-disubstituted (Æ)-1e
(entry 6) proceeded with high selectivity at 808C,
thus the providing azomethine imine 1e (93% ee)
and pyrazolidinone 2e (79% ee). The 2-naphthyl
substituted (Æ)-1 f (entry 7) was also effectively
resolved under these reaction conditions. In contrast,
reactions of the more hindered 1-naphthyl (entry 8)
and cyclohexyl (entry 9) azomethine imines pro-
ceeded with low conversion but with high selectivity
to give 2g (81% ee) and 2h (83% ee), respectively,
and recovered 1g (82% ee) and 1h (72% ee),
respectively. In addition, bulkier fluorenone-derived
azomethine imines could not be resolved, thus
providing no pyrazolidinone product even at ele-
vated temperatures. To address this limitation, we
decided to explore aldehyde-derived azomethine
(Æ)-1b (H, 4-(F)C6H4)
(Æ)-1c (H, 4-(Me)C6H4)
(Æ)-1d (H, 4-(MeO)C6H4)
(Æ)-1d
(Æ)-1e (Me, Ph)
(Æ)-1 f (H, 2-naphthyl)
(Æ)-1g (H, 1-naphthyl)
(Æ)-1h (H, c-C6H11)
B
B[d]
[a] Azomethine imine (0.1–0.2 mmol, 1 equiv), 4 (1.4 equiv). Conditions A: (R)-TRIP
(5 mol%) in toluene (0.02-0.04m) at 608C. Conditions B: (R)-TRIP (10 mol%) in
PhCl (0.01–0.02m) at 808C. Conversion determined from 1H NMR analysis of crude
reaction mixture. [b] The ee value was determined by HPLC using a Diacel ChiralPak
AD-H column. Yield is that of the isolated product. [c] Selectivity factor=kfast/kslow
[d] 2.0 equiv of 4 were used.
Table 2: Kinetic resolution of unsymmetrical azomethine imines by enantioselective
reduction.[a]
Entry
Solvent T [8C] t [h] Conv. [%]
ee (Yield) [%][b]
s[c]
1
2
1
2
(Æ)-1i
(Æ)-1j
(Æ)-1k
(Æ)-1l
(Æ)-1l
PhMe
PhMe
PhCl
PhMe
PhCl
40
60
60
60
60
6
6
6
6
4
57
56
61
63
61
95 (41) 86 (43)
94 (45) 75 (54)
93 (35) 76 (41)
99 (32) 66 (52)
>99 (39) 67 (50)
98 (29)[f]
22
23
13
18
25
3[d]
4
5[e]
6
(Æ)-1m PhCl
80
24
56
85 (37) 78 (51)[g] 13
[a] Azomethine imine (0.1–0.2 mmol, 1 equiv), 4 (1.4 equiv), (R)-TRIP (2.5 mol%)
in toluene (0.025m) or PhCl (0.05m). Conversion determined from 1H NMR analysis
of crude reaction mixture. [b] The ee value was determined by HPLC using a Diacel
ChiralPak AD-H column. Yield is that of the isolated product. [c] Selectivity
factor=kfast/kslow. [d] 5 mol% (R)-TRIP [e] 1 mmole scale. [f] After recrystallization.
[g] Mixture of two diastereomers (2:1); the ee value is that of the major
diastereomer.
=
imines to improve the reactivity of the C N bond
and increase tolerance of bulkier groups at C4 and
C5.
Aldehyde-derived N,N’-cyclic azomethine imines
[(Æ)-1i–l] showed high reactivity towards the reduc-
tion compared to the fluorenone-derived substrates,
thus requiring lower catalyst loading and temper-
atures (Table 2). These kinetic resolutions proceeded
selectively at 40–608C to provide enantioenriched azome-
thine imines (1i–l) and pyrazolidinones (2i–l) in high yields
(entries 1–5). In addition to solving the lack of reactivity
observed with some of the substrates in Table 1, this protocol
allowed us to assign the absolute configuration of the
products (resolved 1i was compared to previous reports).[5]
The benzaldehyde-derived substrates (Æ)-1k and (Æ)-1l were
synthesized by a one-pot net transimidation protocol from the
fluorenone-derived aminocarbonylation products
[Eq. (1)].[15] These azomethine imines were now easily
reduced (entries 3–4), compared to the fluorenone-derived
precursors (e.g. 1g, Table 1, entry 8). The resolution of (Æ)-1l
was effectively scaled up to 1 mmol, thus affording the
azomethine imine in greater than 99% ee (Table 2, entry 5).
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Fortunately, the pyrazolidinone 2l (67% ee) produced in this
experiment could be recrystallized to 98% ee. After separa-
tion, both 1l and 2l [Eq. (2)] underwent reductive ring
opening to give the corresponding b-amino amides in good
yields with no loss in enantiopurity.
Acknowledgments
We thank the University of Ottawa, CCRI, AstraZeneca, and
NSERC (Discovery Grant and Discovery Accelerator Sup-
plement to A.M.B., CGS-D to A.B.) for support of this work.
We also thank Lyanne Betit for her related work on the
transimidation protocol.
Keywords: asymmetric catalysis · azo compounds ·
Brønsted acids · kinetic resolution · reduction
How to cite: Angew. Chem. Int. Ed. 2015, 54, 15516–15519
Angew. Chem. 2015, 127, 15736–15739
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Figure 1. Pre-transition-state complexes for stereoselective reduction of
the azomethine imine (Æ)-1. E=CO2Et.
In summary, we developed a kinetic resolution of complex
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Received: August 12, 2015
Revised: October 7, 2015
Published online: October 30, 2015
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