Enantioselective Reaction between 2-(Cyanomethyl)azaarenes and N-Boc-amino Sulfones

Article abstract of DOI:10.1021/acs.orglett.8b02205

A series of 2-(cyanomethyl)azaarenes containing benzothiazole or benzoxazole were designed and synthesized for asymmetric α-functionalization with N-Boc-amino sulfones. The Mannich adducts were obtained in high yields with good diastereo- and enantioselectivities. Aryl-substituted amino sulfones were tolerated under the current conditions, and the reaction can be performed on gram scale in good results.

Full text of DOI:10.1021/acs.orglett.8b02205

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Reaction between 2‑(Cyanomethyl)azaarenes and
N‑Boc-amino Sulfones
Kezhou Wang,†,§,∥ Chao Chen,*,‡,∥ Xihong Liu,† Dan Li,† Tianyu Peng,† Xin Liu,† Dongxu Yang,†
and Linqing Wang*,†
†Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou
UniversityLanzhou 730000, China
‡Guangdong Provincial Key Laboratory of Nano-Micro Materials Research, School of Chemical Biology & Biotechnology, Peking
University Shenzhen Graduate School, Shenzhen 518055, China
§The College of Ecological Environment and Resources, Qinghai Nationalities University, Xining 810007, China
S
* Supporting Information
ABSTRACT: A series of 2-(cyanomethyl)azaarenes containing benzo-
thiazole or benzoxazole were designed and synthesized for asymmetric α-
functionalization with N-Boc-amino sulfones. The Mannich adducts were
obtained in high yields with good diastereo- and enantioselectivities. Aryl-
substituted amino sulfones were tolerated under the current conditions,
and the reaction can be performed on gram scale in good results.
Scheme 1. Alkylazaarenes in Construction of α-Quaternary
Stereocenters
itrogen-containing aromatic heterocycles (azaarenes) are
Nimportant building motifs in chiral biological pharma-
ceuticals and agrochemicals. Thus, it would be highly valuable
to construct adjacent stereocenters in enantioenriched
compounds containing azaarenes. Compared with the well-
established asymmetric Friedel−Crafts reactions for building
chiral azaarene skeletons, especially with enamine-containing
azaarenes such as indoles or pyrroles,1 the catalytic
enantioselective reactions employing substrates containing
azaarene-embedded imine structures are relatively less
developed.2 To date, there are representative methods to
accomplish these chiral compounds; these reactions can be
divided into two classes: one is catalytic asymmetric reactions
on the basis of functions on alkenylazaarenes, including
reduction, boration, or additions;3−5 the other is 2-alkylazaar-
enes toward nucleophilic additions or allylic alkylations under
catalytic asymmetric systems.6,7 In this context, by analyzing
the established documented methods, it is observed that there
are still limited studies on constructing α-quaternary stereo-
centers in building imine-embedded azaarene-containing
systems. In 2016, Palomo and co-workers reported an excellent
asymmetric carbo- and hetero-α-functionalization of 2-
cyanomethylazaarene N-oxides; pyridine and pyrazine were
utilized in this mild and direct system (Scheme 1, a).8 Here, we
design and synthesize benzothiazole- or benzoxazole-contain-
ing nucleophiles and apply them in the asymmetric α-
functionalization with N-carbamoyl imines generated in situ
(Scheme 1, b).9
progress). In the initial screening process, C3 was selected for
studying the effects of different bases (Table 1, entries 3−12,
and SI). It was observed that bases influence the reaction
obviously, and Na3PO4·12H2O showed relatively better results.
Further selection processes identified C4 as the optimal
catalyst,10 leading to the desired addition product 3a in
satisfactory results (Table 1, entry 13).
Having the optimal conditions in hand, next we explored the
generality of amino sulfones. As the results illustrate in Table 2,
various aryl- amino sulfones, including mono- or polysub-
stituted aryl rings with different electron properties, reacted
Initial experiments studied the reaction between benzothia-
zolyl nuclephile 1a and amino sulfone 2a catalyzed by a series
of well-developed bifunctional hydrogen-bond catalysts (Table
1; see the Supporting Information (SI) for detailed screening
Received: July 15, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02205
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Table 1. Optimization Process of the Reaction
Table 2. Substrate Scope with Respect to N-Boc-amino
a
Sulfones
b
c
d
entry
C
base
K2CO3
K2CO3
K2CO3
KF·2H2O
LiOH·H2O
Na2CO3
Li2CO3
CH3COONa
CH3COOK
K3PO4·3H2O
Na3PO4·12H2O
Na2HPO4
Na3PO4·12H2O
Na3PO4·12H2O
Na3PO4·12H2O
Na3PO4·12H2O
Na3PO4·12H2O
Na3PO4·12H2O
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
C1
C2
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C4
C5
C4
C4
C4
C4
96
97
94
93
95
92
3:1
3:1
7:1
6:1
3.5:1
15:1
35
38
63
57
39
61
94
93
95
96
88
96
93
90
88
8:1
15:1
15:1
15:1
2:1
9:1
8:1
3:1
4:1
51
63
65
9
10
11
12
13
14
15
16
17
18
68
<10
94
89
61
85
47
e
f
g
89
<10
3:1
h
a
Reactions were carried out with 1a (0.10 mmol), 2a (0.12 mmol),
catalysts (0.02 mmol, 20 mol %), and bases (0.12 mmol) in toluene
b
(0.8 mL) and H2O (0.2 mL) at room temperature for 48 h. Isolated
c
1
yields were reported. The dr were determined by H NMR analysis.
d
e
f
g
h
Analyzed by chiral HPLC. In hexane. In DCM. In Et2O. Carried
out at 0 °C.
with heterocyclic arenes under direct and mild conditions,
leading to the desired chiral benzothiazolyl amino products in
excellent yields with moderate to good selectivities. However,
the current conditions were not suitable to alkylamino
sulfones; only trace amounts of product could be detected
under the bifunctional catalytic system (Table 2, entry 14), and
the related direct reaction with prepared N-Boc-imines also
failed with some of the substrates. Moreover, the absolute
configuration of the adduct was determined by X-ray
crystallographic analysis of 3c.
a
Reactions were carried out with 1a (0.10 mmol), 2 (0.12 mmol), C4
(0.02 mmol, 20 mol %), and Na3PO4·12H2O (0.12 mmol) in toluene
b
(0.8 mL) and H2O (0.2 mL) at room temperature for 48 h. Isolated
c
1
yields were reported. The dr were determined by H NMR analysis.
d
Analyzed by chiral HPLC.
Furthermore, different aza-arene containing nucleophiles
were synthesized and introduced into the reaction conditions
with amino sulfone 2a (Scheme 2). A series of alkyl-substituted
benzothiazolyl nucleophiles were obtained and applied in the
Mannich reaction, and the desired addition amines were
obtained smoothly with good yields and enantioselectivities.
Moreover, a benzoxazolyl-substituted substrate was also
synthesized with similar methods and carried out under the
optimal conditions, leading to the corresponding adduct 3v in
91% yield, 15:1 dr, and 86% ee values. Notably, the 4-
methylthiazolyl nucleophile was also compatible with the
current method and generated the Mannich adduct 3w in 90%
yield with 89% ee (Scheme 2).
However, frankly, some azaarene substrates failed to
generate the desired Mannich adducts under the current
conditions; the examples we tried are listed in Scheme 3,
including pyridinyl, aryl-substituted thiazolyl, and benzoimida-
zolyl nucleophiles, which were not compatible and only led to
a trace amount of the addition products even at 60 °C.
B
DOI: 10.1021/acs.orglett.8b02205
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
metric Mannich reactions. The reaction can be performed
directly with amino sulfones under mild conditions in the
presence of a well-developed bifunctional hydrogen-bond
catalyst. Aryl-substituted imine precursors are good substrates
with optimal conditions, and benzothiazole and benzoxazole
are well tolerated azaarenes in the designed nucleophiles.
There are still limitations of the current methods with regard
to substrate scope, and further work investigating different
catalytic strategies to more broad scope with respect to imines
and azaarenes is underway in our laboratory.
Scheme 2. Substrates Scope with Respect to Azaarenes
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02205.
Experimental procedures, characterization of all com-
pounds, and detailed information on our mechanistic
studies (PDF)
Accession Codes
CCDC 1856394 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chenchao@pkusz.edu.cn.
*E-mail: lqwang@lzu.edu.cn.
ORCID
Linqing Wang: 0000-0001-5922-1332
Author Contributions
∥K.W. and C.C. contributed equally to this work.
Notes
Scheme 3. Unsuccessful Azaarene Nucleophiles of the
Reaction Conditions
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NSFC (21602091, 21432003,
81473095) and the Fundamental Research Funds for the
Central Universities (lzujbky-2018-kb11, lzujbky-2017-19,
lzujbky-2017-118).
Finally, the current method was performed on gram scale
and led to the adduct in similar results under optimal
conditions, as expected (Scheme 4, 3n, 86% yield, 16:1 dr,
89% ee).
In summary, we have synthesized a series of novel 2-
cyanomethylazaarenes and applied them in catalytic asym-
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