An Efficient One-Pot Approach to the Construction of Chiral Nitrogen-Containing Heterocycles under Mild Conditions

Article abstract of DOI:10.1021/acs.orglett.5b01772

A new, general, and practical procedure for the highly enantioselective synthesis of functionalized nitrogen-containing heterocycles has been developed. The simple cyclic hemiaminals were directly catalyzed for the first time as nucleophiles in an enamine

Full text of DOI:10.1021/acs.orglett.5b01772

Letter
pubs.acs.org/OrgLett
An Efficient One-Pot Approach to the Construction of Chiral
Nitrogen-Containing Heterocycles under Mild Conditions
Huan-Xi Feng,† Rui Tan,‡ and Yan-Kai Liu*,†
†Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China,
Qingdao 266003, P. R. China
‡School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan 610031, P. R. China
S
* Supporting Information
ABSTRACT: A new, general, and practical procedure for the highly enantioselective
synthesis of functionalized nitrogen-containing heterocycles has been developed. The
simple cyclic hemiaminals were directly catalyzed for the first time as nucleophiles in
an enamine-based asymmetric conjugate addition reaction. The practical approach
recycles the catalyst and solvent which make it possible for large-scale and diversity-
oriented chemical production.
Scheme 1. Structures of Representative Chiral Nitrogen-
Containing Heterocycles and Strategy for Their Synthetic
Modification
hiral nitrogen-containing heterocycles, such as cyclic
Chemiaminal, lactam, and cyclic amine, are the ubiquitous
substructures in numerous natural products and biologically
active compounds.1,2 Especially, lactams also serve as important
building blocks toward the corresponding acyclic amino acids,
such as γ-aminobutyric acids (GABAs), which are used in the
regulation of neurological disorders such as Parkinson’s disease
and epilepsy.3
Consequently, significant efforts have been directed towards
the development of facile access to these intriguing scaffolds.
However, the asymmetric modification, starting from simple
cyclic hemiaminal, lactam, or cyclic amine, is still viewed as a
challenging task. Previously, the asymmetric organocatalytic
approach has offered straightforward access to chiral α-
substituted lactams; however, most cases are limited to the
lactams containing an electron-withdrawing group at the α-
position (Scheme 1, top, left).4 In sharp contrast to the lactams
containing a strongly electron-withdrawing group, the asym-
metric functionalization of α-nonsubstituted lactams represents
a challenging problem due to the higher pKa value of the
corresponding α-protons. Procedures for the asymmetric
functionalization of α-nonsubstituted lactams can be found;
however, they all rely on the use of chiral auxiliaries attached to
the lactam nitrogen atom, and together with a strong base, such
as LDA or n-BuLi, which can generate amide enolates from
lactams to carry out nucleophilic additions at the α-position of
lactams (Scheme 1, top, right).5 Therefore, despite extensive
efforts, the rapid and efficient synthesis of target nitrogen-
containing heterocycles is still a challenging task in the field of
synthetic organic chemistry.
ongoing interest and efforts in the chemistry of lactols,6 we
questioned whether this concept could be shifted to cyclic
hemiaminals. At this point, however, the direct use of cyclic
hemiaminals as nucleophiles is still one of the untested areas of
enamine catalysis;7 this may be ascribed to two significant
challenges: (1) mechanistically validated N-Michael addition
should be avoided8 and (2) suitable conditions should be
identified that would not deactivate the amine catalyst (Scheme
2).9 We report herein the first case, which directly applies the
simple cyclic hemiaminals as nucleophiles in aminocatalytic
reactions providing facile access to C3-functionalized cyclic
Additionally, it is not hard to find that the C3-substituted
cyclic hemiaminals could be used as versatile synthetic
intermediates for the construction of nitrogen-containing
heterocycles (Scheme 1, bottom). In a continuation of our
Received: June 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01772
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Organic Letters
Letter
a clean HPLC separation, we then subjected the crude 4a to the
reduction with Et3SiH/BF3·Et2O in CH2Cl2 at 0 °C for only 10
min, yielding C3-substituted cyclic amine 5a in 84% yield with
94% enantiomeric excess (ee) and 10:1 diastereoselectivity (dr)
in a one-pot procedure (Table 1, entry 2). Moreover, to our
delight, the relative byproduct (Scheme 2, B), which is from the
hypothesized N-Michael reaction, is not observed. Apparently,
a homogeneous condition, when a mixture of CH3CN/H2O
(10% v/v) was used as the solvent, works much more efficiently
(Table 1, entry 3). With these promising results, several other
solvent systems were tried (Table 1, entries 4−6); the mixture
of THF/H2O showed excellent results providing 5a with an
excellent yield and stereoselectivity (Table 1, entry 4).
However, considering both the efficiency and economy of the
reaction system, EtOH/H2O is used as the final solvent system
(Table 1, entry 6). Similar good results were obtained with
other acidic additives (Table 1, entries 7−9). A subsequent
screening of alcohols such as MeOH, i-PrOH, and t-BuOH was
conducted, but no improvements in results were noticed.12
Having established the optimal reaction conditions (Table 1,
entry 6), the scope and generality of this new asymmetric
conjugate addition reaction, with respect to both electrophiles
and nucleophiles, were investigated, the simple cyclic hemi-
aminal 1 was treated with β-nitrostyrene 2 in the presence of 3
(20 mol %) and p-NO2PhCOOH (20 mol %) in a mixture of
EtOH/H2O (10% v/v) at 25 °C. As shown in Scheme 3,
various electron-rich, electron-neutral, or electron-deficient
nitroolefins with different substitution patterns in different
positions of the aromatic ring reacted smoothly with cyclic
hemiaminal 1 affording the final Michael adducts with good to
excellent yields (71−91%) and enantioselectivities (97−99%),
Scheme 2. Hypothesis and Challenges of Simple Cyclic
Hemiaminals Directly Used As Nucleophiles
hemiaminals.10,11 In line with these considerations, our initial
experiments were carried out for the direct C3-functionalization
of the cyclic hemiaminal 1a with β-nitrostyrene 2a under the
best conditions from our previous work.6 Unexpectedly, the
reaction gave no desired product after 48 h with the
commercially available catalyst 3 and toluene as the solvent
(Table 1, entry 1). Consistent with the work of Chen and co-
workers,9 the intermediate A could deactivate the catalyst
(Scheme 2, A), and water may be helpful for catalyst turnover.
Indeed, in the presence of water (10% v/v), 4a was formed
after 24 h, and however, it is not stable enough for analysis. For
a
Scheme 3. Scope of the Reaction
a
Table 1. Optimization of the Reaction Conditions
b
c
d
entry
solvent
toluene
time (h)
yield (%)
dr (%)
ee (%)
1
2
3
4
5
6
48
24
8
−
−
−
toluene/H2O
CH3CN/H2O
THF/H2O
84
80
89
73
87
80
82
88
10:1
14:1
16:1
11:1
13:1
13:1
9:1
94
98
99
98
98
98
98
99
18
8
acetone/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
4
e
7
4
e
8
5
e
9
24
11:1
a
b
See the Supporting Information for more details. For the first step.
c
d
Yield of the isolated major diastereomer of 5a. Determined by Chiral
e
a
HPLC analysis. Acid A2, A3, and A4 were used as acidic additives for
See the Supporting Information for experimental details. Diastereo-
entries 7, 8, and 9, respectively. THF = tetrahydrofuran. TMS =
meric ratios were determined by Chiral HPLC analysis. Yields are of
trimethylsilyl.
the isolated major diastereomer.
B
DOI: 10.1021/acs.orglett.5b01772
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Letter
a
as well as diastereoselectivities (7:1 → 99:1) (5a−5i).
Heteroaromatic nitroolefins 2j and 2k were also viable
substrates, furnishing the corresponding products 5j and 5k
in excellent yields and enantioselectivities. In addition, similar
good results were attained for the nitroalkenes substituted with
N-Boc protected indol or an even bulkier naphthyl group (5l
and 5m). Particularly noteworthy is the excellent enantiose-
lectivity and good yield observed in the case of the less reactive
alkyl nitroolefins, albeit diastereoselectivities were low for both
cases (5n and 5o). Remarkably, the reactions also proceeded
efficiently with the α,β-unsaturated nitroolefin 2p to afford the
corresponding product 5p in 68% yield and 91% ee.
Surprisingly, the cyclic hemiaminal 1q containing a six-
membered ring gave an even higher diastereoselectivity (5q);
however, combination with one more phenyl ring generated
product 5r with much lower diastereoselectivity albeit in good
yield and excellent enantioselectivity. It should be noted that 2-
nitrobenzenesulfonyl (Ns) could also be used as the protecting
group yielding 5s with excellent stereoselectivity and high yield.
It should be noted that the conjugate addition generated
products as a white precipitate, except for 5n and 5o, in the
reaction process under the optimized conditions. Accordingly,
we envisioned a recycling of the organocatalyst to have a more
practical and eco-friendly methodology. Consistent with this
hypothesis, a 0.3 mmol scale reaction of 1a and 2a (0.36 mmol,
1.2 equiv) was investigated as a model, and the final product
was isolated by simple centrifugation.12 The catalyst and the
excess 2a remained in the filtrate. Then, 1a (0.3 mmol) and 2a
(0.36 mmol) were added to the solution for the next cycle of
the conjugate addition. This procedure was repeated several
times with excellent results obtained, and there was only a
marginal loss of reactivity or stereoselectivity after four cycles.
Notably, to our knowledge, this is the first example of recycling
of the unsupported catalyst, diphenylprolinol silyl ether 3, in an
enamine-based asymmetric Michael reaction.13 As the catalyst
was readily recycled and the reaction was scalable, this method
should be suitable for diversity-oriented chemical production.
To highlight the potential of this novel approach, a complete
open−close procedure,9 starting from simple lactam to α-
substituted lactam 6 in one pot, was carried out on a larger
scale, which proceeded smoothly with maintained efficiency
and enantioselectivity as well as diastereoselectivity (Scheme
4). With the crucial intermediate 4a, subsequent subjection to
acid catalysis afforded several highly functionalized heterocyclic
derivatives 7, 8, and 9 with good yield and excellent
stereoselectivity. It is clear that, in our desired Michael adduct,
a nitrogen-containing heterocycle originally occurred, which is
strongly distinguished from the normal enamine-based Michael
reaction.14 According to this salient feature, a range of valuable
skeletons 10, 11, and 12, containing multiple rings or a
polycyclic alkaloid-like molecule, were synthesized in good to
excellent yields via ordinary conditions. Furthermore, removal
of the N-tosyl group was successfully achieved using Na/
Naphthalene at −78 °C delivering the target molecule 13 in
73% yield.
Scheme 4. Synthetic Transformations
a
See the Supporting Information for experimental details. Diastereo-
meric ratios were determined by Chiral HPLC analysis. Yields are of
the isolated major diastereomer. TFA = trifluoroacetic acid. p-TsOH·
H2O = p-toluenesulfonic acid. Ts = p-methylbenzenesulfonyl. DIBAL-
H = diisobutylaluminum hydride.
Scheme 5. Possible Transition State and the X-ray Crystal
Structure of 6
In summary, we have developed a highly efficient organo-
catalytic strategy for the construction of chiral nitrogen-
containing heterocycles. Starting from simple cyclic hemi-
aminals, α-substituted lactams, C3-substituted cyclic amines,
and even more complex heterocycles were obtained in high
yield with excellent stereoselectivity (up to 99% ee, >99:1 dr).
One-pot, mild reaction conditions were used, and the catalyst
and solvent were recyclable. Additionally, the synthetic
potential of this strategy was highlighted by the efficient
synthesis of complex heterocycles possessing two or three
stereogenic centers, which otherwise are difficult to access from
traditional conjugate additions of aliphatic aldehydes with β-
nitrostyrenes. Further synthetic application of this trans-
formation and mechanistic studies are underway in our
laboratory.
The absolute configuration of the product was estimated by
single-crystal X-ray analysis of compound 6 as shown in
Scheme 5.15 According to the excellent stereoselectivity of the
products, we proposed a model that a plausible intermolecular
H-bond and together with the steric hindrance of the aryl and
silyl substituents of the catalyst 3 dominate the stereoselectivity
and catalytic activity on the si-face of enamine.14
C
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Letter
Dixon, D. J.; Xu, P.-F. Chem. - Eur. J. 2010, 16, 3922−3925. (d) Jin, Z.-
C; Yu, F.; Wang, X.; Huang, H.-C; Luo, X.-Y; Liang, X.-M; Ye, J.-X
Org. Biomol. Chem. 2011, 9, 1809−1816. (e) Wang, Y.; Zhu, S.-L; Ma,
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(12) See the Supporting Information for more details.
ASSOCIATED CONTENT
* Supporting Information
Detailed optimization, experimental procedures, spectroscopic
data for all new compounds, and X-ray data (cif) for 6. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01772.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: liuyankai@ouc.edu.cn.
Notes
(13) Bradshaw, B.; Luque-Corredera, C.; Bonjoch, J. Chem. Commun.
2014, 50, 7099−7102.
(14) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int.
Ed. 2005, 44, 4212−4215.
The authors declare no competing financial interest.
(15) CCDC 1403667 contains the supplementary crystallographic
data for this compound. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
ACKNOWLEDGMENTS
■
The authors thank two reviewers for their constructive and
pertinent comments. This work was supported by the NSFC-
Shandong Joint Fund for Marine Science Research Centers
(No. U1406402), National Nature Science Foundation of
China (Nos. 21302156, 81473337, 81274184), and Ocean
University of China (OUC).
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