A Rapid Synthesis of Chiral Allylic Amines via Microwave-assisted Asymmetric Alkenylation of N-Tosyl Aldimines Catalyzed by Rhodium/Chiral Diene Complexes

Article abstract of DOI:10.1002/jccs.201600888

A method providing expeditious access to chiral allylic amines via a Rh(I)/bicyclo[2.2.1]heptadiene-catalyzed enantioselective alkenylation of N-tosyl aldimines with potassium alkenyltrifluoroborates under microwave irradiation is described. The rate of the asymmetric 1,2-addition reaction, conducted in the presence of 1 mol % of the catalyst, was significantly enhanced as compared to when the standard heating method was applied while still providing the corresponding products without decrease in enantioselectivity.

Full text of DOI:10.1002/jccs.201600888

JOURNAL OF THE CHINESE
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Article
A Rapid Synthesis of Chiral Allylic Amines via Microwave-assisted Asymmetric
Alkenylation of N-Tosyl Aldimines Catalyzed by Rhodium/Chiral Diene Complexes
a
Balraj Gopula,a Hao-Wei Zeng,a Ping-Yu Wu,b Julian P. Henschkeb and Hsyueh-Liang Wu
*
aDepartment of Chemistry, National Taiwan Normal University, Taiwan, Republic of China
bScinoPharm, Taiwan Science-Based Industrial Park, Taiwan, Republic of China
(Received: December 29, 2016; Accepted: March 9, 2017; DOI: 10.1002/jccs.201600888)
A method providing expeditious access to chiral allylic amines via a Rh(I)/bicyclo[2.2.1]hepta-
diene-catalyzed enantioselective alkenylation of N-tosyl aldimines with potassium alkenyltrifluoro-
borates under microwave irradiation is described. The rate of the asymmetric 1,2-addition
reaction, conducted in the presence of 1 mol % of the catalyst, was significantly enhanced as com-
pared to when the standard heating method was applied while still providing the corresponding
products without decrease in enantioselectivity.
Keywords: Microwave irradiation; Chiral allylic amine; Enantioselective.
INTRODUCTION
Optically active amines are prevalent in natural
employed in a stoichiometric amount. Subsequent to
this, the asymmetric Rh(I)-catalyzed 1,2-addition of
potassium aryl or alkenyltrifluoroborates without
recourse to a chiral auxiliary was reported, but only N-
sulfonylketimines8,9 and benzoxathiazine-2,2-dioxides9
were reported as substrates. Recently, we reported the
first example of the catalytic asymmetric 1,2-addition of
potassium alkenyltrifluoroborates to simple N-tosyl aryl
aldimines, derived from tosyl amide and arylalde-
hydes.10 Rh(I) catalysts comprising chiral bicyclo[2.2.1]
heptadiene ligands 1 have often proved to be highly
enantioselective in this transformation (Scheme 1).
Despite the high selectivity and versatility of this
method, extended reaction times were generally
required to effect full conversion even though the reac-
and synthetic molecules with biological and pharmaco-
logical activity. Consequently, the development of effi-
cient synthetic methods for their preparation has been
an important part of synthetic organic chemistry.1 In
particular, the synthesis of chiral allylic amines has
attracted considerable attention because of the wide-
spread existence of this moiety in compounds of interest
and because of the synthetic versatility of the olefinic
group.2 Pd- or Ir-catalyzed enantioselective substitution
reactions of amino nucleophiles with allylic electro-
philes have often been employed to produce optically
active allylic amines.3 Further, rearrangement of allylic
imidates in the presence of Pd catalysts proceed in a
highly enantioselective manner to furnish allylic
amines.4 While chiral allylic amines can be synthesized
by a number of other useful methods5 including the
enantioselective addition of alkenylboronic acids to in
situ generated iminium salts or imines catalyzed by
organocatalysts, known as the asymmetric Petasis
reaction,6 the Rh(I)-catalyzed diastereoselective alkeny-
lation reaction of chiral N-tert-butanesulfimines with
alkenylboronic nucleophilic donors has emerged as a
preferred approach to chiral allylic amines.7 Although
operating in a highly selective manner, the chirality-
inducing N-tert-butanesulfinyl moiety must be
ꢀ
tion was conducted at 100 C. The use of microwave
irradiation11 in transition-metal-catalyzed reactions has
enabled very short reaction times while not causing any
loss of stereoselectivity as compared to the thermal ver-
sion of the reactions.12,13 More recently, we have
achieved the microwave-assisted 1,4-conjugate addition
reaction of alkenylboronic acids to a cyclopentenone
for the synthesis of prostaglandins.14 Based on this and
our previously established results, the enantioselective
alkenylation of N-tosyl aryl and heteroaryl aldimines
catalyzed by rhodium/chiral diene catalysts under
microwave irradiation is reported here.
*Corresponding author. E-mail: hlw@ntnu.edu.tw
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Article
Gopula et al.
[RhCl(1a)]2
(3.0 mol% of Rh)
R2
more rapid, the yield was inferior as compared to that
of the thermal version of the reaction (92%).10 A very
similar result was obtained under microwave irradia-
tion after 3 h when conducted in the presence of 3 mol
% of the Rh(I)/1a catalyst generated in situ from
1.5 mol % of [RhCl(C2H4)2]2 and chiral diene 1a (entry
2). While the addition product was obtained in only
35% yield and 94% ee using the catalyst comprising
diene ligand 1b (entry 3), the reaction carried out in
the presence of the Rh(I)/1c catalyst afforded allylic N-
Ts-amine 4aa in 72% yield with 95% ee (entry 4).
R2
NHTs
Ar
Ts
N
BF3K
+
R1
R1
MeOH (5 equiv)
toluene, 100 °C
H
Ar
R3
R3
(2.0 equiv)
73–97% yield
72–>99.5% ee
Ar
Ar
1a : Ar = 4-CF3-C6H4
1b : Ar = C6H5
1c : Ar = 4-NO2-C6H4
Scheme 1. Enantioselective alkenylation under ther-
mal reaction conditions.
ꢀ
RESULTS AND DISCUSSION
When employing the Rh(I)/1c catalyst at 200 C, prod-
Initially, to confirm that the Rh(I)/chiral diene
catalysts functioned in the microwave-irradiated reac-
tion as in the thermal counterpart, the optimal reaction
parameters obtained from the thermally heated reac-
tions were adopted (Table 1).10 The addition of potas-
sium styryltrifluoroborate (2a) to benzaldimine (3a), in
the presence of 1.5 mol % of the preformed [RhCl
(1a)]2 complex, was carried out under microwave irra-
diation at 100ꢀC, exclusively providing (E)-4aa in 70%
yield and 93% ee after 1 h (entry 1). Although much
uct 4aa was isolated in 94% yield with 95% ee after
only 1 h of irradiation (entry 5). Increasing the amount
of MeOH or raising the reaction temperature to
250 ꢀC (entries 6–8) provided no improvement upon
that of entry 5. Performing the reaction in the presence
of 2 or 1 mol % of the Rh(I)/1c catalyst prepared in
situ from 1 or 0.5 mol %, respectively, of [RhCl
(C2H4)2]2 resulted in no erosion of the enantioselectiv-
ity, but a slight decrease in yield was observed in the
latter case (entry 10).
Table 1. Rh(I)-catalyzed asymmetric alkenylation under microwave irradiation
Entrya
1 (x mol % of Rh)
MeOH (y equiv)
Temp (ꢀC)
Time (h)
Yield (%)b
Ee (%)c
1d
2
3
4
5
6
7
8
1a (3)
1a (3)
1b (3)
1c (3)
1c (3)
1c (3)
1c (3)
1c (3)
1c (2)
1c (1)
5
5
5
5
5
10
20
20
5
100
100
100
100
200
200
200
250
200
200
1
3
3
3
1
1
1
0.5
1
1
70
66
35
72
94
91
94
99
94
79
93
92
94
95
95
93
93
92
94
95
9
10e
5
a Reaction conditions: 2a (0.250 mmol), 3a (0.125 mmol), [RhCl(C2H4)2]2, (1.87 μmol, 1.5 mol %), ligand 1 (4.50 μmol, 3.6 mol
%), MeOH (0.63 mmol), toluene (2.0 mL), reactions were carried out under N2 in a CEM (Discover and Explorer SP)
microwave reactor.
b Isolated yield.
c Determined by chiral HPLC on an OD-H column.
d Preformed [RhCl(1a)]2 was used.
e The reaction was performed in a 0.25 mmol scale of compound 3a.
2
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Chiral Allylic Amine Synthesis
Table 2. Substrate scope of Rh(I)-catalyzed asymmetric alkenylation under microwave irradiation
Entrya
2
Ar
Time (h)
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2e
2e
2e
2e
2f
C6H5 (3a)
2-F-C6H4 (3b)
4-F-C6H4 (3c)
2-Cl-C6H4 (3d)
2,4-Cl2-C6H3 (3e)
2-Me-C6H4 (3f)
3-Me-C6H4 (3g)
4-Me-C6H4 (3h)
4-MeO-C6H4 (3i)
C6H5 (3a)
1
2
2
2
2
1
2
1
2
1
1
2
1
1
1
1
1
1
1
2
2
2
2
2
1
1
79 [(S)-4aa]
40 [(S)-4ab]
78 [(S)-4ac]
55 [(S)-4ad]
67 [(S)-4ae]
87 [(S)-4af]
85 [(S)-4ag]
74 [(S)-4ah]
94 [(S)-4ai]
92 [(S)-4ba]
88 [(S)-4ca]
74 [(S)-4da]
95 [(S)-4ea]
95 [(S)-4ef]
91 [(S)-4eh]
95 [(S)-4ej]
80 [(S)-4ek]
96 [(S)-4fa]
96 [(S)-4ga]
90 [(S)-4gf]
92 [(S)-4gh]
89 [(S)-4ha]
91 [(S)-4hf]
94 [(S)-4hh]
95 [(S)-4ia]
95 [(R)-4ja]
95
86
94
93
89
94
95
93
90
92
94
90
93
97
94
95
94
97
95
94
95
96
90
96
90
98
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
C6H5 (3a)
C6H5 (3a)
C6H5 (3a)
2-Me-C6H4 (3f)
4-Me-C6H4 (3h)
2-Furyl (3j)
2-Thienyl (3k)
C6H5 (3a)
2g
2g
2g
2h
2h
2h
2i
C6H5 (3a)
2-Me-C6H4 (3f)
4-Me-C6H4 (3h)
C6H5 (3a)
2-Me-C6H4 (3f)
4-Me-C6H4 (3h)
C6H5 (3a)
2j
C6H5 (3a)
a General reaction condition: N-tosyl aldimines 3 (0.250 mmol), 2 (0.50 mmol), [RhCl(C2H4)2]2 (1.25 μmol, 1 mol% of Rh),
ligand 1c (3.0 μmol, 1.2 mol%), MeOH (1.25 mmol) in toluene (4 mL), reactions were carried out under N2 in a CEM (Discover
and Explorer SP) microwave reactor.
b Isolated yield.
c Determined by HPLC on a chiral stationary phase.
The scope of the microwave-assisted alkenylation
reaction was investigated based on the optimal reaction
conditions identified for the asymmetric addition of potas-
sium styryltrifluoroborate (2a) to imine (3a) established in
Table 1 (entry 10). The reactions of trifluoroborate 2a
with aldimines 3b–3e derived from halogenated aldehydes
furnished the addition products 4ab–4ae in 40–78% yield
with 86–94% ee (Table 2, entries 2–5). While the elec-
tronic and/or steric effects caused by the presence of
ortho-chloro or ortho-fluoro substituents might have
accounted for the observed lower chemical yield and
selectivity of entries 2 and 4, the use of ortho-tolyl sub-
strate 3f offered the addition product 4af in 87% yield
with 94% ee (entry 6). Good to high yields and
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Article
Gopula et al.
ꢀ
enantioselectivities were observed for aldimines bearing
alkyl and electron-donating substituents (entries 7–9).
Enantioselective addition of 1,2-disubstituted alkenyltri-
fluoroborates with aryl or alkyl substituents (2b, R1 = 4-
Me-C6H4; 2c, R1 = 4-F-C6H4; 2d, R1 = CH2OH) to
imine 3a produced the reaction adducts 4ba–4da in
74–92% yield with 90–94% ee (entries 10–12). Similarly,
trisubstituted potassium alkenyltrifluoroborates (2e, R1 =
R3 = Me; 2f, R1–R3 = (CH2)3; 2g, R1–R3 = (CH2)4)
were good reaction partners, allowing the rapid prepara-
tion of enantio-enriched trisubstituted allylic amines 4ea–
4gh with high enantio-enrichment (entries 13–21, 80–96%
yield, 93–97% ee), including, notably, (E)-chiral allylic
amines harboring cyclopentyl (4fa) and cyclohexenyl
(4ga) moieties. The (E)-1,3,3-trisubstituted allylic amines
4ha, 4hf, and 4hh (R1 = CO2Me, R2 = Me, R3 = H) were
obtained in 89–94% yield and with 90–96% ee from the
asymmetric reaction of alkenyltrifluoroborate 2h, which
bears an ester group at the β-position of the nucleophile
(entries 22–24). Crucially, in the thermally heated version
of the reaction using the diene ligand 1a, reaction times of
144–240 h were required for this trifluoroborate, probably
due to lower nucleophilicity resulting from the electron-
withdrawing carbonyl substituent. By contrast, the
microwave-irradiated reaction required only 2 h for a
similar conversion. Chiral allylic amine 4ia harboring (Z)-
stereochemistry was prepared with 90% ee from the addi-
tion of potassium cis-propenyltrifluoroborate 2i in 95%
yield, but no cis to trans double-bond isomerization
was detected even though the reaction was irradiated at
microwave reactor at 200 C. After thin-layer chroma-
tography (TLC) indicated that consumption of imines
3 was complete, the reaction mixture was cooled to
room temperature, diluted with Et2O (30 mL), and
washed with saturated NaHCO3(aq) (10 mL) and then
with brine (10 mL). The organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified over silica
gel eluting with 8:2 (v/v) hexanes/EtOAc to furnish the
alkenylation products 4.
CONCLUSIONS
The asymmetric 1,2-addition reaction of various
potassium alkenyltrifluoroborates with N-Ts aldimines
under microwave irradiation was realized. The enantio-
selective transformation proceeded effectively within
1–2 h in the presence of 1 mol % of a Rh(I)-catalyst,
generated in situ from a Rh(I) dimer precursor and
diene ligand 1c, in a good to highly stereoselective man-
ner to provide a diverse range of optically active di-,
tri-, and tetra-substituted chiral allylic amines. By
contrast, the previously reported10 thermal version of
the reaction required between 15 and 240 h to reach
similar levels of conversion using diene ligand 1a.
ACKNOWLEDGMENTS
Financial support from Ministry of Science and
Technology, Republic of China (102-2113-M-003-006-
MY2 and 104-2628-M-003-001-MY3), and National
Taiwan Normal University is gratefully acknowledged.
ꢀ
200 C (entry 25). Finally, the enantioselective alkenyla-
tion of imine 3a with potassium 3-methyl-2-buten-
yltrifluoroborate (2j) provided the tetra-substituted allylic
amine 4ja in 95% yield and with 98% ee (entry 26) in just
1 h. This is to be compared with the 20 h required when
applying the thermal version of the reaction using diene
ligand 1a.
Supporting information
Additional supporting information is available in
the online version of this article.
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