Kinetic resolution of primary allylic amines via palladium-catalyzed asymmetric allylic alkylation of malononitriles

Article abstract of DOI:10.1039/c5ob00671f

A range of primary allylic amines were resolved with selectivity factors of up to 491 through [Pd(allyl)Cl]₂/(S)-BINAP-catalyzed and mesitylsulfonyl hydrazide-accelerated asymmetric allylic alkylation of malononitriles involving enantioselectiv

Full text of DOI:10.1039/c5ob00671f

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Kinetic resolution of primary allylic amines via
palladium-catalyzed asymmetric allylic alkylation
of malononitriles†
Cite this: Org. Biomol. Chem., 2015,
13, 5367
Received 5th April 2015,
Accepted 8th April 2015
Yong Wang, Ya-Nan Xu, Guo-Sheng Fang, Hong-Jian Kang, Yonghong Gu* and
Shi-Kai Tian*
DOI: 10.1039/c5ob00671f
www.rsc.org/obc
A range of primary allylic amines were resolved with selectivity closed. Enzymatic acylative kinetic resolution has allowed the
factors of up to 491 through [Pd(allyl)Cl]2/(S)-BINAP-catalyzed and synthesis of enantioenriched primary allylic amines, mainly
mesitylsulfonyl hydrazide-accelerated asymmetric allylic alkylation α-aryl allylamines, in moderate to excellent ee.13 In 2011,
of malononitriles involving enantioselective C–N bond cleavage Seidel and coworkers disclosed a chiral thiourea/aminopyri-
under aerobic conditions. Moreover, the reaction proved useful for dine-catalyzed acylative kinetic resolution of unsymmetrical
the asymmetric synthesis of α-branched allyl-substituted malono- primary allylic amines with s factors of up to 20.14 Notably,
nitriles with high enantiopurity.
Itoh and coworkers reported a kinetic resolution of tertiary
allylic amines having α-phenyl and γ-trifluoromethyl groups
with s factors of up to 19 via palladium-catalyzed asymmetric
α-to-γ isomerization.15 In connection with our long-standing
interest in exploring the synthetic utilities of C–N bond clea-
vage,2,16 we have developed a new strategy for the catalytic
kinetic resolution of primary allylic amines through enantio-
selective substitution of the NH2 group under mild conditions
with s factors of up to 491.
To develop an efficient kinetic resolution of primary allylic
amines, we started our investigation by establishing a set of
mild conditions for direct substitution of the NH2 group.
Prompted by our recent studies on the removal of the NHNH2
group from sulfonyl hydrazides,17 particularly in its oxidative
coupling with primary allylic amines,2d we proposed a sulfonyl
hydrazide-accelerated allylic alkylation reaction of malono-
nitriles with primary allylic amines.2c As outlined in Scheme 1,
when a primary allylic amine is treated with a malononitrile
and a sulfonyl hydrazide in the presence of a palladium cata-
lyst and an acid, the NH2 group would prefer to be displaced
by the sulfonyl hydrazide because of its higher nucleophilicity
relative to the malononitrile. The resulting disubstituted
Enantioenriched allylic amines serve as versatile building
blocks for the synthesis of important compounds such as aza-
heterocycles, amino alcohols, amino acids, and therapeutic
agents.1 Moreover, direct substitution of enantioenriched
allylic amines has emerged as a powerful approach to afford
chiral functionalized alkenes.2 Enantioenriched allylic amines
are generally prepared via asymmetric imine additions,3 allylic
amination,4 Overman rearrangement,5 and aza-Morita–Baylis–
Hillman reaction.6 Among these approaches, only a few asym-
metric allylic amination reactions directly provide enantio-
enriched primary allylic amines, which are, in fact, limited to
terminal or symmetrical ones.7 Alternatively, direct access to
enantioenriched primary allylic amines has been developed
via resolution of the corresponding racemic mixtures, which,
however, has received much less attention relative to that of
other primary alkylamines.8,9 In this regard, classic resolution
via diastereomeric crystallization with chiral acids proves
useful in affording enantioenriched primary allylic amines,
albeit the process requires one equivalent of a chiral reagent
and frequently suffers from poor yields because of repeated
crystallization.2a,b,10 Moreover, a chiral acylating agent in a
stoichiometric amount has enabled kinetic resolution of
terminal primary allylic amines with selectivity factors (s =
kfast/kslow) of up to 34.11,12 On the other hand, catalytic enantio-
selective acylation of primary allylic amines has also been dis-
Department of Chemistry, University of Science and Technology of China, Hefei,
Anhui 230026, China. E-mail: ygu01@ustc.edu.cn, tiansk@ustc.edu.cn;
Tel: (+86) 551-6360-0871
†Electronic supplementary information (ESI) available: General information,
experimental procedures, characterization data, and copies of 1H NMR and 13C
NMR spectra and HPLC traces. See DOI: 10.1039/c5ob00671f
Scheme 1 Proposed sulfonyl hydrazide-accelerated allylic alkylation.
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hydrazine B would be oxidized quickly to give diazene C,
which is a highly reactive allylic compound and would
undergo palladium-catalyzed substitution with the malono-
nitrile. While a sulfinic acid (R3SO2H) would be generated
in this step as well as through oxidation of the sulfonyl
hydrazide,2d its coupling with π-allylpalladium complex A, an
intermediate generated either in the first step or in the last
step, was expected to proceed more slowly due to its lower
nucleophilicity relative to the malononitrile.
The allylic alkylation reaction of malononitrile 2a with
racemic primary allylic amine rac-1a was selected to test
our hypothesis (Scheme 2). In the presence of [Pd(allyl)Cl]2
(1 mol%) and racemic BINAP (4 mol%), the reaction proceeded
very sluggishly in dioxane under air at room temperature. In
sharp contrast, addition of a sulfonyl hydrazide (1.2 equiv.)
dramatically accelerated the reaction to yield malononitrile
Scheme 3 Allylic alkylation with enantioenriched primary allylic
amines.
rac-4a. Moreover, we were able to minimize the formation of of sulfonyl hydrazide 3d (0.6 equiv.), [Pd(allyl)Cl]2 (1 mol%),
sulfone rac-5 by changing the structure of the sulfonyl hydra- and (S)-BINAP (4 mol%) proceeded smoothly in dioxane under
zide. To our delight, mesitylsulfonyl hydrazide (3d) was identi- air at room temperature to give malononitrile 4a in 38% yield
fied as the best additive, the use of which gave malononitrile and 80% ee together with the recovered enantioenriched
rac-4a in 90% yield with 96 : 4 α/γ selectivity and complete primary allylic amine 1a in 40% yield and 92% ee, corres-
retention of the E-alkene geometry.18
ponding to an s factor of 29 for the kinetic resolution (Table 1,
To investigate the stereochemistry, we treated highly entry 1).19 Addition of 5 Å molecular sieves improved the
enantioenriched primary allylic amine 1a with malononitrile enantioselectivity of the kinetic resolution with an s factor of
2a, sulfonyl hydrazide 3d, [Pd(allyl)Cl]2, and optically active 42 (entry 2). The use of a palladium(II) source such as
(S)-BINAP (Scheme 3). The reaction proceeded sluggishly Pd(OAc)2, PdCl2, or Pd(NO3)2 led to lower enantioselectivity for
under air at room temperature and gave malononitrile ent-4a the kinetic resolution, and in contrast, the reaction failed to
in only 3.3% yield (determined by 1H NMR) with complete take place when using a palladium(0) source such as Pd2(dba)3
retention of the configuration. In sharp contrast, replacement (entries 3–6). Chiral phosphorus ligands L2–7 were evaluated
of amine 1a with its enantiomer ent-1a led to the formation of and only axially chiral bisphosphine ligands L2 and L3 were
malononitrile 4a in 94% yield with complete retention of the capable of promoting the reaction but gave lower enantio-
configuration. These results allowed us to conclude that the selectivity (entries 7–9). Replacing dioxane with some other
stereochemistry was controlled by the substrate rather than by common organic solvents gave lower enantioselectivity or even
the reagent and that the in situ-generated π-allylpalladium led to sluggish reactions (entries 10–13). Finally, portionwise
complexes, A1 and A2, would not isomerize to each other addition of sulfonyl hydrazide 3d was found to give the best
under the above conditions. Importantly, the dramatically result: s = 49 (entry 14).20
different reaction rates (kfast/kslow = 28) for the two enantio-
meric substrates encouraged us to develop an efficient kinetic kinetic resolution of various racemic primary allylic amines
resolution process for primary allylic amines.
with malononitriles (Table 2). In general, the asymmetric
Under the optimized reaction conditions, we conducted the
To our delight, the reaction of racemic primary allylic allylic alkylation reaction of malononitriles with unsymmetri-
amine rac-1a with malononitrile 2a (0.6 equiv.) in the presence cal primary allylic amines having α-alkyl and γ-aryl groups pro-
ceeded with excellent α selectivity and complete retention of
the E-alkene geometry and the racemic primary allylic amines
were efficiently resolved with s factors ranging from 32 to 491
(entries 1–6, 8–13, and 17–20).21 In contrast, moderate enantio-
selectivity was observed in the kinetic resolution of primary
allylic amines when both the α- and γ-substituents are either
aryl or alkyl groups (entries 7 and 15). Moreover, the kinetic
resolution process was successfully extended to a primary
allylic amine having a γ-alkenyl group as well as an α-aryl allyl-
amine with good enantioselectivity (entries 14 and 16). In the
above cases, the regioselectivity was determined by the steric
and electronic properties of the α- and γ-substituents, and the
reaction preferred to occur at the allylic position having less
steric hindrance and/or leading to a higher degree of conju-
Scheme 2 Survey of sulfonyl hydrazides.
5368 | Org. Biomol. Chem., 2015, 13, 5367–5371
gation. Nevertheless, the reaction became sluggish with a
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Table 1 Optimization of reaction conditionsa
Yieldb (%)
eed (%)
Entry
[Pd]
L
Solvent
1a
4a
α/γc (4a)
1a
4a
se
1f
2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
Pd(OAc)2
PdCl2
Pd(NO3)2
L1
L1
L1
L1
L1
L1
L2
L3
Lh
L1
L1
L1
L1
L1
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
THF
CH2Cl2
Toluene
Solventi
Dioxane
40
42
72
27
34
—
35
34
—
47
48
58
—
43
38
40
13
41
54
0
46
41
Trace
37
35
26
Trace
41
96 : 4
96 : 4
94 : 6
95 : 5
94 : 6
—
96 : 4
96 : 4
—
96 : 4
96 : 4
96 : 4
—
92
95
34
99
97
—
99
99
—
65
80
43
—
95
80
84
87
70
73
—
56
61
—
84
66
92
—
86
29
42
20
28
26
—
17
20
—
22
11
37
—
49
3g
4g
5g
6
Pd2(dba)3
7
8
9
10
11
12
13
14j
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
96 : 4
a Conditions: rac-1a (0.30 mmol), 2a (0.18 mmol), 3d (0.18 mmol), [Pd] (1 mol%), L (4 mol%), ms (30 mg), air, solvent (1.8 mL), rt, 24 h.
b Isolated yield. c Determined by 1H NMR analysis of the crude product. d Determined by chiral HPLC. e s = ln[(1 − C)(1 − ee1a)]/ln[(1 − C)(1 +
ee1a)], where C = ee1a/(ee1a + ee4a).12 f Without ms. g [Pd] (2 mol%) was used. h L4–7. i MeCN, DMF, DMSO, or EtOH. j 3d was added three times
in 8 h.
cyclic primary allylic amine, such as 3-aminocyclohexene, and without the malononitrile and that, in sharp contrast, signifi-
with a primary allylic amine having a β-substituent, such as cant erosion of enantiopurity was observed for secondary
(E)-3-amino-2-methyl-1-phenyl-1-butene.
allylic amine 1eb (from 70% ee to 50% ee). These results indi-
The enantioenriched primary allylic amines obtained from cate that the π-allylpalladium complex generated from an
the above process underwent enantiospecific allylic alkylation allylic amine having a bulkier leaving amino group would iso-
of malononitriles under the same reaction conditions but merize more readily via Pd–Pd-exchange under the standard
using racemic BINAP instead of (S)-BINAP as the ligand reaction conditions.23 Definitely, the isomerization contributes
(Scheme 4). Such transformation provided facile access to the greatly to the lower enantioselectivity for the kinetic resolution
enantiomers of malononitriles 4 (as listed in Table 2) in good of secondary and tertiary allylic amines relative to primary
yields with excellent ee. Importantly, the enantioselective ones. On the other hand, the reaction of a secondary or a ter-
kinetic resolution along with the enantiospecific substitution tiary allylic amine would give a primary or a secondary amine,
complemented the scope for the asymmetric synthesis of rather than gaseous ammonia in the case of a primary allylic
α-branched allyl-substituted malononitriles with high amine, as the byproduct, which would stay in the reaction
enantiopurity.2c,19
mixture and decrease the enantioselectivity in the subsequent
When the kinetic resolution process was extended to sec- allylic alkylation through coordination with the palladium
ondary and tertiary allylic amines, the reaction provided lower atom and/or deprotonation of the malononitrile.24
enantioselectivity relative to that with primary ones
In summary, we have developed a new and efficient strategy
(Scheme 5).15,22 Furthermore, we found that the enantiopurity for the catalytic kinetic resolution of primary allylic amines
of primary allylic amine 1e (94% ee, Table 2, entry 5) remained via enantioselective C–N bond cleavage. A range of primary
unchanged under the standard reaction conditions but allylic amines were resolved with s factors of up to 491 through
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Table 2 Kinetic resolution of primary allylic aminesa
[Pd(allyl)Cl]2/(S)-BINAP-catalyzed and mesitylsulfonyl hydra-
zide-accelerated asymmetric allylic alkylation of malononitriles
under air at room temperature or at 50 °C. Moreover, the reac-
tion proved useful for the asymmetric synthesis of α-branched
allyl-substituted malononitriles with high enantiopurity.
We are grateful for the financial support from the National
Natural Science Foundation of China (21472178, 21232007 and
21172206), the National Key Basic Research Program of China
(2014CB931800), and the Natural Science Foundation of Anhui
Province of China (1408085MB24).
Yieldb (%)
eed (%)
Entry R1, R2, R3
1
4
α/γc (4)
1
4
se
1
2
3
4
Et, Ph, Ph
Me, Ph, Ph
43
42
39
44
42
56
35
51
42
48
41
41
41 96 : 4 95
54 >99 : 1 97
48 94 : 6 90
45 93 : 7 96
44 95 : 5 94
21 90 : 10 60
86 49
79 33
94 100
94 127
93 98
94 60
60 8.2
96 128
88 53
84 40
90 60
73 32
95 124
69 13
46 5.4
(CH2)3Me, Ph, Ph
(CH2)7Me, Ph, Ph
(CH2)2Ph, Ph, Ph
CH2CHvCH2, Ph, Ph
Ph, Ph, Ph
Et, 4-MeOC6H4, Ph
Et, 4-FC6H4, Ph
Et, 4-ClC6H4, Ph
Et, 4-NCC6H4, Ph
Me, 2-naphthyl, Ph
5
Notes and references
6
7f
8
57
—
70
45 98 : 2 85
48 97 : 3 93
49 96 : 4 94
49 97 : 3 91
51 >99 : 1 99
47 99 : 1 91
37 >99 : 1 80
41 >99 : 1 70
52 <1 : 99 89
50 96 : 4 93
36 95 : 5 80
37 94 : 6 67
45 93 : 7 80
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9
10
11
12
13
14
15
16f
17g
18g
19g
20g
Et, benzo[b]thien-2-yl, Ph 42
Me, (E)-PhCHvCH, Ph
Me, cyclohexyl, Ph
Ph, H, Ph
(CH2)2Ph, Ph, 2-furyl
(CH2)2Ph, Ph, 2-naphthyl 40
(CH2)2Ph, Ph, CuCTMS 30
(CH2)2Ph, Ph, CO2 Bu
40
42
37
37
—
—
93 94
99 491
94 65
87 35
t
36
a Conditions: rac-1 (0.30 mmol), 2 (0.18 mmol), 3d (0.18 mmol), [Pd-
(allyl)Cl]2 (1 mol%), (S)-BINAP (4 mol%), ms (30 mg), air, dioxane
1
(1.8 mL), rt, 24 h. b Isolated yield. c Determined by H NMR analysis of
the crude product. d Determined by chiral HPLC. e s = ln[(1 − C)(1 −
ee1)]/ln[(1 − C)(1 + ee1)], where C = ee1/(ee1 + ee4).12 f 3d (10 mol%) was
used and the reaction was run for 4 h. g The reaction was run at 50 °C.
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Scheme 4 Enantiospecific allylic alkylation.
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Scheme 5 Kinetic resolution of secondary and tertiary allylic amines.
5370 | Org. Biomol. Chem., 2015, 13, 5367–5371
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active ligand instead of the corresponding racemic one
{[Pd(allyl)Cl]2 (2 mol%) and (S)-BINAP (4 mol%) in
dichloromethane under nitrogen at room temperature},2c
the reaction of racemic primary allylic amine rac-1a with
malononitrile 2a gave malononitrile 4a in 35% yield and
64% ee together with the recovered enantioenriched
primary allylic amine 1a in 55% yield and 42% ee, corres-
ponding to an s factor of 6.8 for the kinetic resolution.
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