Chiral Bronsted acid catalyzed enantioselective intermolecular allylic aminations

Article abstract of DOI:10.1039/c4ob00526k

This paper describes an enantioselective intermolecular allylic amination catalyzed by a chiral Bronsted acid via a possible chiral contact ion pair intermediate. A variety of symmetrical or unsymmetrical allylic alcohols can be smoothly aminated to affor

Full text of DOI:10.1039/c4ob00526k

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Chiral Brønsted acid catalyzed enantioselective
intermolecular allylic aminations†
Cite this: Org. Biomol. Chem., 2014,
12, 4590
Minyang Zhuang and Haifeng Du*
Received 10th March 2014,
Accepted 23rd April 2014
DOI: 10.1039/c4ob00526k
www.rsc.org/obc
This paper describes an enantioselective intermolecular allylic acid catalyzed intramolecular allylic substitution based on the
amination catalyzed by a chiral Brønsted acid via a possible chiral concept of chiral ion-pair catalysis, with the assumption of
contact ion pair intermediate. A variety of symmetrical or unsym- forming a chiral contact ion pair between the carbocation and
metrical allylic alcohols can be smoothly aminated to afford the chiral Brønsted acid anion.8,9 In 2014, Gong and co-workers
desired products in moderate to high yields with good enantio- described the first chiral Brønsted acid catalyzed intermolecu-
selectivities and/or regioselectivities.
lar allylic alkylation of allylic alcohols with 1,3-dicarbonyls.10
Despite these important advances, the asymmetric substi-
tution of allylic alcohols catalyzed by chiral Brønsted acids is
still not well understood.
The substitution reaction of allylic alcohols and their deriva-
tives with diverse nucleophiles, and its asymmetric versions,
has become an extremely useful tool for the construction of
carbon–carbon and carbon–heteroatom bonds. This field has
long been dominated by transition-metal catalysis.1 Allylic
alcohol derivatives, such as allylic carboxylates, carbonates,
and phosphates, are often used as substrates for this trans-
formation.1 However, the direct use of allylic alcohols as sub-
strates with the hydroxyl group as the leaving group and water
as the only side product has been less developed, owing to the
poor leaving ability of the hydroxyl group and the poor tole-
rance of metal catalysts for water.2 Accordingly, various strat-
egies involving the in situ activation of the hydroxyl group and/
or the development of efficient catalysts have been adopted to
improve the reactivity.3,4 In contrast to the intensive studies on
metal catalysis, metal-free allylic substitution, especially for
the asymmetric transformation, has been investigated less.5,6
Brønsted acid catalysis provides a powerful approach for
the metal-free direct substitution of allylic alcohols.7 A variety
of reactions with carbon, oxygen, and nitrogen nucleophiles
have been successfully described using either stoichiometric
or catalytic amounts of Brønsted acids as catalysts.6 However,
chiral Brønsted acid catalyzed asymmetric versions of this
reaction have rarely been reported. In 2011, Rueping and co-
workers reported the first highly enantioselective Brønsted
Recently, our group reported a chiral phosphoramide cata-
lyzed asymmetric 1,2-rearrangement of racemic epoxides for
the synthesis of enantioenriched aldehydes, in which the
contact ion pair of a carbocation and a chiral phosphoramide
anion is likely involved.11 Since the direct intermolecular
amination of allylic alcohols catalyzed by simple achiral
Brønsted acids has already been reported,6e we wish to
examine the chiral Brønsted acid 2 catalyzed asymmetric
allylic amination of alcohols 1 with amines 3 via a proposed
chiral contact ion pair intermediate (Scheme 1). Herein, we
report our preliminary results on this subject.
Initially, we selected the allylic amination of allylic alcohol
1a with p-toluenesulfonamide (3a) as the model reaction to
test the feasibility of chiral Brønsted acid catalysis (Scheme 2).
We were pleased to find that the reaction using chiral phos-
phoramide 2a as a catalyst went cleanly to give the desired
product 4a in 75% yield with 28% ee. Further searching for
more effective catalysts was conducted, and some selected
results are summarized in Scheme 2. Phosphoramide 2b with
strong electron-withdrawing groups cannot improve the
enantioselectivity. Using 2c and 2f containing 1-naphthyl or
9-phenanthrenyl at the 3,3′-positions gave higher ee’s. The bulky
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, China. E-mail: haifengdu@iccas.ac.cn; Fax: +86-10-62554449;
Tel: +86-10-62652117
†Electronic supplementary information (ESI) available: The characterization and
data for the determination of the enantiomeric excess of products along with the
NMR spectra. See DOI: 10.1039/c4ob00526k
Scheme 1 Strategy for asymmetric allylic aminations.
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Table 2 Chiral Brønsted acid catalyzed asymmetric allylic aminationa
Entry
Product 4
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
4a: Ar = Ph
88
82
61
60
77
80
80
63
75
70
85
86
66
62
22
18
4b: Ar = 4-FC6H4
4c: Ar = 4-ClC6H4
4d: Ar = 4-BrC6H4
4e: Ar = 4-MeC6H4
4f: Ar = 3-MeC6H4
4g: Ar = 2-MeC6H4
4h: Ar = 1-naphthyl
Scheme 2 Selected Brønsted acids for asymmetric aminations.12
Table 1 Optimization of reaction conditionsa
a All reactions were carried out with allylic alcohols 1a–h (0.40 mmol),
amine 3a (0.60 mmol), and 2g (0.04 mmol) in CHCl3 (1.0 mL) at
−60 °C for 10 h. b Isolated yield. c The ee was determined by chiral
HPLC.
4). Solvents were found to influence this reaction significantly,
and CHCl3 gave the optimal results (Table 1, entries 4–8).
Various amine nucleophiles were screened for this reaction.
BocNH2 (3b), TfNH2 (3c), and phthalimide (3d) only gave trace
amount of products (Table 1, entries 9–11). In comparison
with p-toluenesulfonamide (3a), similar results were obtained
with the use of amines 3e and 3f as nucleophiles (Table 1,
entries 4 vs. 12 and 13). However, using amine 3g bearing one
methyl group on the nitrogen atom furnished a racemic
product in 93% yield. When a bulky amine 3h was employed
as a nucleophile, the desired product was obtained in 82%
yield with 84% ee (Table 1, entry 15).
Encouraged by the results obtained with phosphoramide
catalyst 2g, the asymmetric allylic amination of various sym-
metrical allylic alcohols with amine 3a was subsequently exam-
ined. As shown in Table 2, a variety of alcohols 1a–h can be
directly aminated to give the desired products 4a–h in 60–88%
yields with 18–86% ee’s. The substituents on the phenyl
groups can influence both reactivity and enantioselectivity.
Unfortunately, alcohols bearing electron-withdrawing substitu-
ents at the meta or ortho position of phenyl groups were not
suitable substrates for this reaction.
Entry
BA (loading)
Amine
Solvent
Yieldb (%)
eec (%)
1
2
3
4
2f (5 mol%)
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3f
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
Toluene
THF
Hexane
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
68
79
75
88
83
38
Trace
50
Trace
Trace
Trace
72
78
93
82
68
69
71
75
51
45
nde
20
nde
nde
nde
72
72
2
2g (5 mol%)
2f (10 mol%)
2g (10 mol%)
2g (10 mol%)
2g (10 mol%)
2g (10 mol%)
2g (10 mol%)
2g (10 mol%)
2g (10 mol%)
2g (10 mol%)
2g (10 mol%)
2g (10 mol%)
2g (10 mol%)
2g (10 mol%)
5
6d
7
8
9
10
11
12
13
14
15
3g
3h
84
a All reactions were carried out with allylic alcohol 1a (0.40 mmol),
amine 3 (0.60 mmol), solvent (1.0 mL) at −60 °C for 10 h unless other
noted. b Isolated yield. c The ee was determined by chiral HPLC.
d Toluene (2.0 mL) was used. e Not determined.
Besides the enantioselectivity, regioselectivity is also a chal-
lenge for the chiral Brønsted acid catalyzed allylic amination
of unsymmetrical allylic alcohols. Hence, the reaction of
various unsymmetrical allylic alcohols 1i–r under the same
conditions was then investigated. As shown in Table 3, all the
phosphoramide 2e led a low yield and ee, in which a side reac- reactions can proceed smoothly to give the corresponding pro-
tion with alcohol 1a itself as a nucleophile was involved. Inter- ducts in 16–87% yields with 3/1–20/1 regioselectivity and
estingly, a novel chiral phosphoramide 2g proved to be 13–94% ee’s.13 It was found that the amination site was mainly
effective for this transformation to give amine 4a in 81% yield determined by the electronic effect, and the reaction occurred
with 65% ee (Scheme 2).
at the carbon adjacent to the electron-rich aryl group owing to
The reaction conditions using phosphoramide 2f and 2g as a carbocation intermediate involved in this process (Table 3,
catalysts were examined to further improve the enantio- entries 1–7, 9, 10). Moreover, the steric hindrance of substitu-
selectivity. Lowering the temperature to −60 °C led to slightly ents on phenyl groups also had an obvious impact on this
higher ee’s (Table 1, entries 1 and 2). By increasing the catalyst reaction. For example, alcohol 1o containing a bulky group
loading to 10 mol%, up to 75% ee was obtained (Table 1, entry gave a low yield but with an excellent regioselectivity (Table 3,
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Table 3 Chiral Brønsted acid catalyzed asymmetric allylic aminationa
Notes and references
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Yieldb
(%)
rr
4 (ee)d
(%)
4′ (ee)d
(%)
Entry
Allylic alcohol 1
(4/4′)c
1
2
1i: Ar1 = 4-MeC6H4
Ar2 = 4-ClC6H4
1j: Ar1 = 4-MeC6H4
Ar2 = 3-ClC6H4
1k: Ar1 = 3-ClC6H4
Ar2 = 4-MeC6H4
1l: Ar1 = Ph
Ar2 = 3-ClC6H4
1m: Ar1 = 4-MeC6H4
Ar2 = 3-BrC6H4
1n: Ar1 = 4-MeC6H4
Ar2 = 2-BrC6H4
1o: Ar1 = 4-MeC6H4
Ar2 = 2,6-Cl2C6H3
1p: Ar1 = 4-FC6H4
Ar2 = 3-ClC6H4
68
70
75
56
87
87
16
63
64
52
4.3/1
8/1
82
66
nde
67
70
13
60
59
76
71
69
nde
68
58
76
94
nde
73
53
55
3
1/8
4
3.5/1
6.7/1
3/1
5
6
7
>20/1
3/1
8
9
1q: Ar1 = 3-MeC6H4
Ar2 = 3-BrC6H4
1r: Ar1 = 2-MeC6H4
Ar2 = 3-BrC6H4
6.9/1
3.8/1
10
a All reactions were carried out with allylic alcohols 1i–r (0.40 mmol),
amine 3a (0.60 mmol), and 2g (0.04 mmol) in CHCl3 (1.0 mL) at
−60 °C for 10 h. b Isolated yield for two regioisomers. c The
regioisomer ratio (rr) was determined by crude 1H NMR. d The ee was
determined by chiral HPLC. e Not determined.
entry 7). However, phenylpropenol 1s and diarylmethanol 1t
were not suitable substrates for the current catalytic system.
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In summary, we have developed the first chiral Brønsted acid
catalyzed asymmetric intermolecular allylic amination of
allylic alcohols. Under the catalysis of phosphoramide 2g, a
variety of optically active allylic amines can be obtained in
16–88% yields with 13–94% ee’s. In particular, for the challen-
ging unsymmetrical allylic alcohols, moderate to high levels of
regioselectivities were achieved. The electronic effect played a
crucial role for the regioselectivity owing to a carbocation inter-
mediate involved in this transformation. Further efforts on
exploring more efficient catalysts and expanding the substrate
scope are underway in our laboratory.
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Acknowledgements
This work was generously supported by the National Basic
Research Program of China (2011CB808600).
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