Benzylidene succinimides as 3C synthons for the asymmetric tandem Mannich reaction/transamidation of cyclic trifluoromethyl ketimines to obtain F3C-containing polycyclic dihydroquinazolinones

Article abstract of DOI:10.1039/d0cc08131k

By taking advantage of benzylidene succinimides as a new class of 3C synthons, a highly diastereo- and enantioselective tandem Mannich reaction/transamidation has been established by reacting them with cyclic trifluoromethylN-acyl ketimines. Using aCinchonaalkaloid-derived squaramide as the catalyst, the tandem reaction proceeded smoothly under mild conditions and afforded a range of F₃C-containing chiral polycyclic dihydroquinazolinones with excellent results (up to 99% yield, all cases >20?:?1 dr, up to 99% ee).

Full text of DOI:10.1039/d0cc08131k

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Benzylidene succinimides as 3C synthons
for the asymmetric tandem Mannich reaction/
transamidation of cyclic trifluoromethyl ketimines
to obtain F3C-containing polycyclic
dihydroquinazolinones†
Cite this: Chem. Commun., 2021,
57, 2927
Received 15th December 2020,
Accepted 4th February 2021
DOI: 10.1039/d0cc08131k
a
Xia-Yan Zhang,‡abc Pei-Hao Dou,‡abc Wen-Ya Lu,abc Yong You,
Jian-Qiang Zhao,
a
a
Zhen-Hua Wang *a and Wei-Cheng Yuan
*
rsc.li/chemcomm
By taking advantage of benzylidene succinimides as a new class of 3C
Cyclic trifluoromethyl N-acyl ketimines have attracted
synthons, a highly diastereo- and enantioselective tandem Mannich tremendous attention from synthetic chemists because they
reaction/transamidation has been established by reacting them with can react with different types of nucleophiles in a catalytic
cyclic trifluoromethyl N-acyl ketimines. Using a Cinchona alkaloid- asymmetric manner for the direct construction of
derived squaramide as the catalyst, the tandem reaction proceeded F3C-containing chiral dihydroquinazolinone derivatives.5,6
smoothly under mild conditions and afforded a range of F3C-containing In this research area, the asymmetric transformations developed
chiral polycyclic dihydroquinazolinones with excellent results (up to to date have been largely restricted to the one-step addition
99% yield, all cases 420 : 1 dr, up to 99% ee).
reaction to the electrophilic cyclic trifluoromethyl N-acyl keti-
mine substrates (Scheme 1).5 However, only limited examples
Dihydroquinazolinones are ubiquitous and important hetero- employing cyclic trifluoromethyl N-acyl ketimine substrates for
cyclic ring systems found in many bioactive compounds and the asymmetric tandem reaction to obtain chiral polycyclic
pharmaceuticals.1 Extensive efforts have been devoted to the dihydroquinazolinones have been reported (Scheme 1).6 There-
development of efficient strategies for the synthesis of diverse fore, considering the potential biological significance of trifluor-
dihydroquinazolinone derivatives.2 Among these multifarious omethyl substituted chiral dihydroquinazolinones in medicinal
structures, the dihydroquinazolinone skeletons containing an and organic chemistry,3 the development of a novel catalytic
F3C-functionality at the C4-position are particularly important, asymmetric tandem reaction involving cyclic trifluoromethyl
largely because they are embedded indispensably in several N-acyl ketimine is still an attractive research topic.
significant drug molecules, such as DPC 961 and DPC 083.3
Meanwhile, because benzylidene succinimides contain both
Nevertheless, it is well accepted that installing an F3C-group nucleophilic and electrophilic sites, asymmetric reactions with
into a lead compound will not only result in structurally novel them as distinctive and useful synthons have attracted special
molecules, but also generally improve its lipophilicity, bioavail- attention, and many new synthetic strategies involving benzy-
ability, and metabolic stability.4 Along this line, the exploration lidene succinimides for the asymmetric reaction have been
of effective and direct methods to construct molecular scaffolds discovered.7–9 Originally, benzylidene succinimides are usually
containing both an F3C-functionality and dihydroquinazoli- selected as nucleophilic 1C synthons for the synthesis of chiral
none chemotypes should have a promising prospect in the maleimides and succinimides (Scheme 2a).7 Nevertheless,
research and development of new drugs.
benzylidene succinimides can also act as 2C synthons (as
dipolarophiles) for the 1,3-dipolar cycloaddition reaction with
azomethine ylides (Scheme 2b).8 In addition, benzylidene
a Institute for Advanced Study, Chengdu University, Chengdu 610106, China.
E-mail: yuanwc@cioc.ac.cn, wangzhenhua@cdu.edu.cn
b National Engineering Research Center of Chiral Drugs, Chengdu Institute of
Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
c University of Chinese Academy of Sciences, Beijing, 100049, China
† Electronic supplementary information (ESI) available: Experimental proce-
dures, spectral data of new compounds, and crystallographic data. CCDC
2046051 and 2046067. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/d0cc08131k
Scheme 1 Catalytic asymmetric reaction types of cyclic trifluoromethyl
N-acyl ketimines.
‡ These authors contributed equally to this work.
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Table 1 Optimization of reaction conditionsa
Entry
Cat.
Solvent
Time (h)
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
A
B
C
D
B
B
B
B
B
B
B
B
MTBE
MTBE
MTBE
MTBE
CH2Cl2
DCE
TCE
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
16
24
24
16
16
16
16
16
16
16
16
24
99
96
84
85
99
58
42
91
99
94
68
98
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
72
94
93
82
94
90
92
94
96
98
98
98
Scheme 2 Catalytic asymmetric transformations of benzylidene succini-
mides and our synthetic strategy in this work.
8
9e
succinimides can be used as allyl-like 3C synthons in the
asymmetric tandem annulation reaction (Scheme 2c). Despite
this elegant progress, we still believe that exploiting innovative
methods with benzylidene succinimides as a new class of
synthons for the construction of structurally neoteric chiral
molecules is quite attractive and is a meaningful topic of
research. In this context, a careful literature survey reveals that
the possible involvement of benzylidene succinimides as both
nucleophiles and transamidation reagents has not yet been
realized (Scheme 2d), even though they belong to a typical class
10ef
11efg
12egh
a
Unless otherwise noted, the reactions were carried out with 1a
(0.10 mmol), 2a (0.12 mmol) and 20 mol% catalyst in the solvent
b
(1.0 mL) at room temperature for the specified time. Isolated yields.
c
d
e
Determined by 1H NMR. Determined by chiral HPLC. 3 Å MS
f
g
(50.0 mg) was added. Run at 0 1C. 5 mol% catalyst was used.
h
The reaction was conducted at 0 1C for 12 h and then continued at
room temperature for 12 h. TCE = 1,1,2,2-tetrachloroethane.
of imide compounds and the succinimide moiety enables the molecular sieves (MS) led to an improved outcome (entry 9).
transamidation reaction.10
Lowering the temperature resulted in further increase of the ee
As a continuation of our research on the exploration of value (up to 98% ee, entry 10). Reducing the catalyst loading
asymmetric reactions involving benzylidene succinimides and from 20 mol% to 5 mol%, the reaction was influenced
cyclic trifluoromethyl N-acyl ketimines,5i,6c,7c we recently found obviously to give 3aa only in 68% yield, although the enantio-
that a series of F3C-containing chiral polycyclic dihydroquina- selectivity remained constant (entry 11). Ultimately, we found
zolinones can be obtained by the reaction of benzylidene that running the reaction for 12 h at 0 1C and then for another
succinimides and cyclic trifluoromethyl N-acyl ketimines via a 12 h at room temperature could afford 3aa in 98% yield with
tandem Mannich reaction/transamidation (Scheme 2, the lower 98% ee (entry 12).
part). It is worth noting that this represents the first example
With the optimized conditions (Table 1, entry 12) in hand,
of benzylidene succinimides serving as a new class of 3C the scope of benzylidene succinimides 1 was examined
synthons, including the nucleophilic ability of the allylic site (Table 2). The electro-neutral 1a could react smoothly with 2a
and a sequential transamidation reaction. Herein, we wish to to give 3aa in 95% yield with 420 : 1 dr and 98% ee (entry 1).
report our research results on this subject.
A variety of mono-substituted benzylidene succinimides 1b–l
Our initial investigation began with the reaction of 1a and 2a bearing different groups on the phenyl were investigated;
in methyl tert-butyl ether (MTBE) at room temperature. As regardless of substituent positions on the benzene ring and
shown in Table 1, with the Cinchona alkaloid-derived thiourea their electronic properties, the reactions proceeded well
A as the catalyst, the reaction proceeded smoothly and afforded and afforded the corresponding products 3ba–la in good to
the polycyclic dihydroquinazolinone 3aa in 99% yield with excellent yields (81–99%) with excellent stereoselectivities
72% ee (entry 1). To our delight, the Cinchona alkaloid-derived (420 : 1 dr and 96–98% ee) (entries 2–12). The di-substituted
squaramide catalysts B–D gave higher ee than catalyst A (entries 1m was also used as a substrate to give 3ma in 81% yield with
2–4 vs. entry 1). Particularly, using catalyst B, 3aa could be 99% ee (entry 13). Heteroaromatic substituted 1n and 1o were
obtained in 96% yield with 420 : 1 dr and 94% ee after 24 h successfully employed to react with 2a, giving 3na and 3oa in
(entry 2). The solvent screening revealed that CH2Cl2 was the excellent yields (entries 14 and 15). In addition, 2-naphthyl
best choice for the reaction, providing 3aa in 99% yield with substituted 1p was also tolerable in the current catalytic system,
94% ee after 16 h (entry 5 vs. entries 6–8 and 2). Adding 3 Å providing 3pa in excellent yield (entry 16). When replacing the
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Table 2 Substrate scope of benzylidene succinimides 1a
Table 3 Substrate scope of cyclic trifluoromethyl N-acyl ketimines 2
Entry R1/R2
1
3/Yieldb (%) drc
eed (%)
1
2
3
4
5
6
7
8
Ph/Boc
1a
1b
1c
1d
1e
1f
1g
1h
1i
3aa/95
3ba/95
3ca/88
3da/99
3ea/99
3fa/98
3ga/99
3ha/95
3ia/81
3ja/98
3ka/99
3la/99
420 : 1 98
420 : 1 98
o-MeC6H4/Boc
o-MeOC6H4/Boc
o-FC6H4/Boc
o-ClC6H4/Boc
o-BrC6H4/Boc
m-MeC6H4/Boc
m-ClC6H4/Boc
p-MeC6H4/Boc
p-MeOC6H4/Boc
p-ClC6H4/Boc
p-BrC6H4/Boc
420 : 1 98
420 : 1 97
420 : 1 96
420 : 1 97
420 : 1 98
420 : 1 96
420 : 1 98
420 : 1 97
420 : 1 97
420 : 1 96
420 : 1 99
420 : 1 97
420 : 1 97
420 : 1 97
420 : 1 99
420 : 1 97
420 : 1 95
9
10
11
12
13
14
15
16
17
18
19
1j
1k
1l
m,p-(MeO)2C6H3/Boc 1m 3ma/81
2-Thienyl/Boc
2-Furyl/Boc
2-Naphthyl/Boc
CH3CH2CH2/Boc
Ph/CO2Et
1n
1o
1p
1q
1r
3na/91
3oa/96
3pa/95
3qa/74
3ra/99
3sa/99
As to the reaction conditions, see the footnote of Table 2. a Run for 5 days.
b
Run for 24 h at 0 1C and then at room temperature for another 24 h.
Ph/Ac
1s
To demonstrate the synthetic utility of the present method, a
gram-scale synthesis of 3aa was performed under the standard
reaction conditions.12 The reaction proceeded smoothly to
produce 3aa in a synthetically useful yield with excellent dr
and ee values (Scheme 3). Synthetic transformations of 3aa
were also conducted to further demonstrate the synthetic
potential. The treatment of 3aa with TFA led to the removal
of the Boc group to give 4 with excellent results. Through the
oxidative removal of the PMB group with ceric ammonium
nitrate (CAN), 3aa was transformed into 5 in 63% yield and
without erosion of diastereo- and enantioselectivity in the trans-
formation. In addition, a palladium-catalyzed C–C bond coupling
a
The reactions were carried out with 1 (0.1 mmol), 2a (0.12 mmol), 3 Å
MS (50.0 mg), and 5 mol% B in 1.0 mL of CH2Cl2 at 0 1C for 12 h, and
b
c
then at room temperature for 12 h. Isolated yields. Determined by
1H NMR. Determined by chiral HPLC.
d
aromatic group with an aliphatic substituent, the reaction also
occurred well and afforded 3qa in good yield with 420 : 1 dr
and 99% ee (entry 17). Moreover, replacing the Boc-group with
an EtO2C or Ac group, the corresponding 1r and 1s were also
used as substrates to yield 3ra and 3sa, respectively, in 99%
yield with excellent dr and ee values (entries 18 and 19).
However, benzylidene succinimides substituted with electron-
donating groups, such as Me-, Ph-, and Bn-groups, could not be
applied as feasible substrates for the current reaction system.
Next, the substrate cyclic trifluoromethyl N-acyl ketimines
2 bearing varied substituents were examined (Table 3). In
general, all the reactions of 2b–g with 1a gave the products
3ab–ag as virtually pure stereoisomers (all cases 420 : 1 dr). On
replacing the chlorine substituent in substrate 2a with an
electron-donating (Me–, PMB–) or electron-withdrawing
(F–, F3C–) substituent, there was no obvious influence on the
reactivity and enantioselectivity, providing products 3ab–ae in
81–98% yields with 93–98% ee. When the R4 group was a
benzyl or 2-bromobenzyl group, the desired products 3af and
3ag also could be obtained in excellent yields. Notably,
replacing the F3C-group on the cyclic ketimine with phenyl,
the reaction for 3ah did not occur. This example suggests that
F3C as a strong electron-withdrawing group plays an impor-
tant role in the tandem Mannich reaction/transamidation.
The relative and absolute configuration of 3aa was deter-
mined by X-ray crystallographic analysis. The configurations
of other compounds 3ba–sa and 3ab–ag were assigned by
analogy.11
Scheme 3 Gram-scale reaction and derivatization of 3aa. Reaction
conditions: (a) TFA (10.0 equiv.), CH2Cl2, r.t.; (b) CAN (2.0 equiv.), MeCN/
H2O (9/1), 0 1C to r.t.; and (c) Cs2CO3 (2.0 equiv.) in the reflux 1,4-dioxane
at 101 1C, 2 h.
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The authors are grateful for financial support from the
National Key R&D Program of China (2018YFC0807301-3) and
the National Natural Science Foundation of China (21871252,
21801026, and 21801024).
Conflicts of interest
The authors declare no competing financial interest.
Notes and references
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Scheme 4 Plausible mechanism towards the asymmetric tandem
Mannich reaction/transamidation.
¨
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The desired Suzuki coupling product was not obtained, but the
reaction provided quinazoline-2,4(1H,3H)-dione 6 in 64% yield.
The structure of compound 6 was also verified by X-ray
crystallography.11 As to this reaction, we presumed that 3aa was
probably hydrolyzed under the basic conditions in the Cs2CO3
mixture and thus decomposed to compound 6. To confirm this
analysis conclusion, we further conducted the reaction by stirring
the mixture of 3aa with Cs2CO3 in refluxing 1,4-dioxane at 101 1C
for 2 h. As expected, 3aa could be readily converted to 6 and was
isolated in 70% yield.12
According to our experimental observations and previous
studies on the related asymmetric reaction of cyclic trifluoromethyl
N-acyl ketimines with organocatalysis,5,6 a plausible mechanism for
the organocatalytic asymmetric tandem Mannich reaction/transa-
midation is proposed in Scheme 4. The a-deprotonation of benzy-
lidene succinimide 1a by the tertiary amine moiety of catalyst B
generates dienolate 1a, which can coordinate to the ammonium
center of the chiral catalyst through hydrogen bonding. Synchro-
nously, the cyclic trifluoromethyl N-acyl ketimine 2a could be
activated by the dual-hydrogen bonding of the squaramide moiety.
In the stereochemical environment of the transition state structure
TS-1, the a-carbon center of dienolate 1a from the Re-face attacks
the Si-face of cyclic trifluoromethyl N-acyl ketimine 2a, generating
the Mannich addition product Int-1. Subsequently, the inter-
mediate product Int-1 undergoes an intramolecular transamidation
to form the desired chiral dihydroquinazolinone 3aa with stereo-
specific configuration.
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11 CCDC 2046067 (3aa) and 2046051 (6)†.
In conclusion, a highly diastereo- and enantioselective tandem
Mannich reaction/transamidation of benzylidene succinimides
and cyclic trifluoromethyl N-acyl ketimines has been developed.
Using a Cinchona alkaloid-derived squaramide as the catalyst, a
wide variety of F3C-containing chiral polycyclic dihydroquinazoli-
none compounds could be obtained smoothly in high yields
(up to 99%) with excellent stereoselectivities (all cases 420 : 1 dr,
up to 99% ee) under mild reaction conditions. It is worth
mentioning that, in the developed protocol, benzylidene succini-
mides can serve as a new class of 3C synthons to enable a catalytic
asymmetric tandem reaction via an unprecedented pathway.
12 See the ESI† for details.
2930 | Chem. Commun., 2021, 57, 2927À2930
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