N-Heterocyclic Carbene-Catalyzed Enantioselective β-Amination of α-Bromoenals Enabled by a Proton-Shuttling Strategy

Article abstract of DOI:10.1002/ejoc.201800648

An unprecedented enantioselective NHC-catalyzed β-amination of α-bromoenals with o-benzodiamines was developed by utilizing a proton-shuttling strategy. This formal [4+3] annulation protocol yielded the corresponding 1,5-benzodiazepines in high yields with excellent enantioselectivities. The obtained optically active 1,5-benzodiazepines as building blocks and pharmacophores should be useful in the synthesis of other valuable molecules or in drug discovery.

Full text of DOI:10.1002/ejoc.201800648

A Journal of
Accepted Article
Title: N-Heterocyclic Carbene-catalyzed Enantioselective beta-
Amination of alfa-Bromoenals Enabled by a Proton-Shuttling
Strategy
Authors: Jian Wang and ming lang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800648
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800648
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10.1002/ejoc.201800648
European Journal of Organic Chemistry
COMMUNICATION
N-Heterocyclic Carbene-catalyzed Enantioselective -Amination
of -Bromoenals Enabled by a Proton-Shuttling Strategy
Ming Lang and Jian Wang*
Dedication ((optional)
carbonyls. First, the competing reaction (amide bond formation)
between nitrogen nucleophile and acyl azolium moiety; Second,
the relatively weak electrophilicity of the -carbon atom of α,β-
unsaturated acyl azoliums; Third, the high pKa value of NH
bond in nitrogen nucleophile.
Abstract: An unprecedented enantioselective N-heterocyclic
carbene-catalyzed-amination of -bromoenals with o-
benzodiamines was developed by utilizing a proton-shuttling strategy.
This formal [4+3] annulation protocol yielded number of
corresponding 1,5-benzodiazepines in high yields with excellent
enantioselectivities. The obtained optically active 1,5-
a
Scheme 1. Strategies for NHC-catalyzed -functionalization and
biologically important 1,5-benzodiazepines.
benzodiazepines as building blocks and pharmacophores should be
useful in the synthesis of other valuable molecules or drug discovery.
Introduction
-amino carbonyls are important and valuable building
blocks in organic synthesis.[1] The asymmetric aza-Michael
addition to -unsaturated carbonyl substrates is arguably one
of the most straightforward methods for their installation.[2]
However, most relevant approaches are limited to the use of
chiral starting materials, chiral auxiliaries, or stoichiometric
amounts of chiral ligands.[3] Taking into account the
environmental and economic impacts,[4] therefore the
development of catalytic strategies for asymmetric synthesis of
-amino carbonyls continues to be an important objective.
Over the past decade, asymmetric N-heterocyclic carbene
(NHC) catalysis has led substantial advances in synthetic
chemistry.[5] Extensive research has shown that chiral NHC
organic catalysts could activate carbonyls to form a catalytic
amount of NHC-bounded active intermediates (e.g. Breslow
intermediate,[6] acyl anion equivalent,[5a, 7] homoenolate,[8] etc[5]),
which subsequently reacted with another counterpart to deliver
target molecules. Recently, NHC-bounded α,β-unsaturated acyl
azolium intermediatbecae[9] received a lot of attention mainly
because of its extensive use in conjugate addition reactions
(Scheme 1a, I). Oxidation of the NHC-bounded homoenolate[10]
or addition of NHC to -bromoenals[11] or α,β-unsaturated
esters[12] have become the robust methods to synthesize α,β-
unsaturated acyl azolium intermediates. Despite
a lot of
synthetic reports with regard to α,β-unsaturated acyl azoliums,
carbon synthons are the most popular nucleophiles in these
reactions. It is worth mentioning that only a very few examples of
nitrogen nucleophiles have been explored to react with α,β-
unsaturated acyl azoliums.[13] Specifically, to the best of our
knowledge, only two examples belong to asymmetric -carbon
CN bond formation of carbonyls. In 2013, Hui et al. realized
that 2′-aminophenylenone as nitrogen resource could be utilized
in an NHC-catalyzed cascade reaction.[14a] Later on, the group of
Chi reported an elegant NHC-catalyzed [3+2] reaction by use of
activated hydrazine as nitrogen resource (Scheme 1b).[14b] On
the basis of above results, we speculate that three factors might
prevent the development of asymmetric amination of
Herein, we report a novel NHC-catalyzed [3+4] annulation
of -bromoenals in presence of o-aryleneamines as nitrogen
resources (Scheme 1c).[15] The valued product 1,5-
benzodiamine as pharmacophoreis widely spread in
pharmaceuticals such as lofendazam, triflubazam and
pirenzepine (Scheme 1d).[16] It is well known that the
enantioselective construction of seven-membered ring has
always been a challenging task caused by disfavored entropy
and transannular strain.[17] While a weak nitrogen nucleophile is
[*]
M. Lang and Prof. Dr. J. Wang
School of Pharmaceutical Sciences, Key Laboratory of Bioorganic
Phosphorous Chemistry & Chemical Biology (Ministry of Education)
Tsinghua University, Beijing, 100084 (China)
E-mail: wangjian2012@tsinghua.edu.cn
Homepage: http://wangj.med.tsinghua.edu.cn/
[**] Supporting information for this article is available on the WWW
under http://dx.doi.org
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10.1002/ejoc.201800648
European Journal of Organic Chemistry
COMMUNICATION
catalyst loading were evaluated subsequently (Table 1, entries
915). We were pleased to find that a combination of catalyst H
(5 mol %) and K3PO4 (1.1 equiv) in methyl phenyl ether (1.0 mL)
could rapidly afford product 3a in excellent yield without any
influence on the enantioselectivity (Table 1, entry 15, 99%, 98%
ee, 2 h).
used (note: the pKa value of NH in o-aryleneamines is roughly
30.6)[18], the difficulty of the reaction will increase dramatically.
To resolve this issue, we propose to use proton-shuttling
strategy[19], which could create a well-organized hydrogen-
bonding network and facilitate the proton transfer from
substrate to product via a proton-shuttle promoter. Eventually
the unfavorable cleavage of neutral NH bond can be avoided.
Having the optimal conditions in hand, we sought to explore
the scope of the -bromoenal components. As shown in Table 2,
a diverse array of electron-donating and -withdrawing -
bromoenals with multiple substituents (e.g. methyl, methoxyl,
fluoro, bromo) performed well in this transformation. The
corresponding products were observed in high yields with
excellent enantioselectivities (3b−3g). When the phenyl ring was
replaced by naphthalene or heterocyclic ring in -bromoenals,
the corresponding products were still obtained in high yields with
excellent enantioselectivities (3h−3j). It is worth highlighting that
this method was compatible with various β-alkyl -bromoenals,
giving the corresponding products in high yields and
enantioselectivities (3k−3n). The absolute configuration of 3c
was confirmed by X-ray single crystal analysis and other
products were assigned by analogy (for more details, see the
Supporting Information).[24]
Results and Discussion
Table 1. Optimization of the reaction conditions.[a]
Table 2. Scope of -bromoenals.[a]
Entry
NHC cat.
Base
Solvent
ee [%][b]
Yield
[%][c]
< 5
< 5
< 5
63
< 5
< 5
< 5
82
< 5
20
91
92
< 5
99
1
2
3
4
5
6
7
8
A
B
C
D
E
F
G
H
H
H
H
H
H
H
H
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Et3N
K2HPO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Toluene
MeCN
PhOMe
PhOMe
-
-
-
76
-
-
-
98
-
98
98
97
-
9
10
11
12
13
14[d]
15[e]
98
98
99
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), NHC cat. (10 mol %),
base (0.22 mmol), THF (1.0 mL), room temperature, 3 h. [b] The enantiomeric
excesses (ee) were determined by HPLC with a chiral column. [c] Yield of
isolated product. [d] Cat. H (10 mol %), 0.5 h. [e] Cat. H (5 mol %), 2 h.
Initial investigation commenced with o-benzodiamine 1a and
-bromoenal 2a as model substrates. Key results are briefly
summarized in Table 1. Given the significance of structural
diversification on the success of a given catalytic transformation,
examining various catalyst structures is essential. Chiral
triazolium catalysts AH were screened initially. Only a trace
amount of product 3a was formed by use of widely explored
indanol-derived triazolium catalyst AC[20] (Table 1, entries 1).
When catalyst L-leucine-derived triazolium D[21] was used, the
corresponding 3a was achieved in a moderate yield with a
moderate ee (Table 1, entry 4). Switching to triazolium E, the
reactivity was found to be decreased dramatically (Table 1, entry
5). It was evident that catalyst F[22] with
a bulky tert-
butyldimethylsilyl (TBS) side chain, showed no catalytic activity
(Table 1, entry 6). To further understand the importance of
catalyst scaffold, a morpholinone-derived triazolium catalyst
G[23a] was next tested, but no reaction was observed (Table 1,
entry 7). Gratifyingly, an enhanced result was achieved in
presence of morpholinone-derived triazolium catalyst H[23b] with
an N-Mes substituent (Table 1, entry 8, 98% ee, 82% yield). To
further satisfy the catalytic performance, solvent, base, and
[a] Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), cat. H (5 mol %), K3PO4
(0.22 mmol), PhOMe (1.0 mL), room temperature, 25 h.
We then moved on to explore the substrate scope of o-
arylenediamines. From the results presented in Table 3 we can
see that all chosen substrates reacted with 2a to give desired
products in high yields and preserved enantiopurities. Various
electron-withdrawing functionalities tethered on the 4-position of
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[a] Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), cat. H (5 mol %), K3PO4
(0.22 mmol), PhOMe (1.0 mL), room temperature, 1.514 h. [b] The relative
configuration of isomers was determined by NOESY.
o-arylenediamines including halogen, trifluoromethyl, ester and
cyano group were well tolerated in current reaction to give the
corresponding products (Table 3, 4a4f). However, these
reactions gave two regioisomers with a ratio ranged from 1:1 to
1:5. o-Arylenediamines tolerated electron-donating substituents
on the 4-position were also examined. Almost equal amounts of
two regioisomers were achieved, but overall chemical yields and
enantioselectivities remained satisfactory (Table 3, 4g4i). Next,
4,5-disubstituted o-benzendiamines were investigated. No
matter if substrates have electron-donating or electron-
withdrawing substituents, all reactions furnished the
corresponding products in good chemical yields and excellent
enantioselectivities (Table 3, 4j4n). We last turned our attention
to the impacts of other substituted patterns. Pleasingly, the
reactions of 3-methyl, 3-methoxyl, 3,5-dimethyl or 3-methyl-4-
bromo o-benzendiamine gave the corresponding 4o-4r both with
excellent enantioselectivities and regioselectivities. The
structures of these regioisomers were determined by their
NOESY spectra. Finally, the reaction of naphthalene-2,3-
diamine as substrate also gave the corresponding product 4s in
95% yield with 99% ee.
Scheme 2. Gram scale synthesis and synthetic elaboration.
In addition, a gram-scale synthesis (5 mmol) was carried out
under standard conditions and afforded 3a in an excellent yield
and enantioselectivity (Scheme 2, 1.1 g, 92% yield, 98% ee, eq
(1)). Furthermore, a new 1,5-benzodiazepine derivative 5 could
be readily prepared from 3a via a LiAlH4 reduction (Scheme 2,
eq (2)).
Table 3. Scope of o-arylenediamines.[a,b]
Scheme 3. Postulated mechanism.
The origins of stereo-selectivity of this reaction are
rationalized by the postulated mechanism illustrated in Scheme
3. The addition of NHC pre-catalyst H to -bromoenal 1a
generates an NHC-bounded -unsaturated acyl azolium
intermediate I,[9] which subsequently reacts with 1a to give
adduct II. Owing to the high pKa values of aryl amines, fully
deprotonating under weak base K3PO4 or free NHC carbene
seems not possible.[19] Presumably, the hydrogen-bonding
network will facilitate the 1,3-proton transfer in the process of
nucleophilic addition of aryNH2 to intermediate I (Path a). o-
Benzenediamine 2a not only works as nucleophile and also
plays a role as proton-shuttle. In absence of strong evidences,
path b cannot be completely ruled out. In path b, external base,
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10.1002/ejoc.201800648
European Journal of Organic Chemistry
COMMUNICATION
such as K3PO4 or NHC catalyst, also can work as proton-shuttle
to facilitate the proton transfer (see III). Finally, intramolecular
lactamization of II or III furnishes the product 3a and release the
NHC catalyst. To further elaborate mechanism, several control
experiments were conducted. As shown in Scheme 4, 1a reacts
with 2a in the presence of a relatively strong base, such as DBU
or TEA, giving almost no 3a (eq. (3)). This indicates that DBU or
TEA may quench the reaction by interacting with proton to form
a parallel, non-selective proton source ammonium. When mono-
or dual-protected 1,2-benzendiamines 58 react with 2a, no
reaction is observed (eq. (4) and eq. (5)). In principle, the amino
group can both functionalize as nucleophile, hydrogen-bonding
donor and hydrogen-bonding acceptor. These functions made
1,2-benzendiamine 1a both an nucleophile and a proton-shuttle.
Protection of arylNH2 will allow 1a to lose their functions and
poison the reaction.
Keywords: proton-shuttling • aza-Michael addition • asymmetric
catalysis • N-hetereocyclic carbene • [4+3] annulation
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Conclusions
In summary, an unprecendented enantioselective NHC-
catalyzed -amination of -bromoenals has been established.
This [4+3] annulation protocol allows the rapid assembly of 1,5-
benzodiazepine pharmacophores from simple and readily
available starting materials under mild conditions. High yields
and excellent enantioselectivities were achieved by using a
chiral triazolium NHC catalyst. The intellectual concerns of this
novel strategy are concentrated on the proton transfer, which is
critical and potentially problematic for this annulation. In
comparison with reported asymmetric hydrogenation or
reduction method to build optically active 1,5-benzodiazepines,
our protocol provides a concise and modular scheme. Further
investigations regarding both expansion of the substrate scope
and other NHC-catalyzed proton-shuttling reactions are currently
underway in our laboratory.
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Acknowledgements
Generous financial supports for this work are provided by: the
National Natural Science Foundation of China (21672121), the
“Thousand Plan” Youth program of China, the Tsinghua
University, the Bayer Investigator fellow, the fellowship of
Tsinghua-Peking centre for life sciences (CLS).
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Conflict of interest
The authors declare no conflict of interest.
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10.1002/ejoc.201800648
European Journal of Organic Chemistry
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Ming Lang and Jian Wang*
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catalyzed
N-Heterocyclic Carbene-
Enantioselective -
Amination of -Bromoenals Enabled
by a Proton-Shuttling Strategy
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