Catalytic asymmetric synthesis of dihydroquinazolinones from imines and 2-aminobenzamides

Article abstract of DOI:10.1002/adsc.201100849

An unprecedented catalytic asymmetric synthesis of aminal-containing heterocyclic compounds has been developed from imines and tethered nitrogen/nitrogen nucleophiles. In the presence of 10mol% of a commercially available chiral phosphoric acid, a range of aromatic, α,β- unsaturated, and aliphatic imines react with 2-aminobenzamides to give dihydroquinazolinones in good to excellent yields and ee. The enantioselectivity is significantly affected by the imine N-substituent through non-bonding interactions with the chiral phosphoric acid and the 2-aminobenzamide. Copyright

Full text of DOI:10.1002/adsc.201100849

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DOI: 10.1002/adsc.201100849
Catalytic Asymmetric Synthesis of Dihydroquinazolinones from
Imines and 2-Aminobenzamides
Dao-Juan Cheng,a Yu Tian,a and Shi-Kai Tiana,*
a
Joint Laboratory of Green Synthetic Chemistry, Department of Chemistry, University of Science and Technology of
China, Hefei, Anhui 230026, Peopleꢀs Republic of China
Fax : (+86)-0551-360-1592; e-mail: tiansk@ustc.edu.cn
Received: October 30, 2011; Revised: December 19, 2011; Published online: April 4, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100849.
Abstract: An unprecedented catalytic asymmetric
synthesis of aminal-containing heterocyclic com-
pounds has been developed from imines and teth-
ered nitrogen/nitrogen nucleophiles. In the presence
of 10 mol% of a commercially available chiral phos-
phoric acid, a range of aromatic, a,b-unsaturated,
and aliphatic imines react with 2-aminobenzamides
to give dihydroquinazolinones in good to excellent
yields and ee. The enantioselectivity is significantly
affected by the imine N-substituent through non-
bonding interactions with the chiral phosphoric acid
and the 2-aminobenzamide.
the presence of carbon, sulfur, or nitrogen nucleo-
philes (Scheme 1).[3,4] Recently, we reported a catalytic
À
À
asymmetric formation of geminal C C/C N s bonds
from imines and tethered carbon/nitrogen nucleo-
philes, wherein the imine N-substituents significantly
affect the reactivity and enantioselectivity.[3] Inspired
by this study, we investigated the reaction of imines
with tethered nitrogen/nitrogen nucleophiles for the
formation of aminal-containing heterocyclic com-
pounds and developed a highly enantioselective syn-
thesis of dihydroquinazolinones (Scheme 1).
Dihydroquinazolinones display a variety of impor-
tant biological and medicinal properties such as anti-
tumor, analgetic, anti-inflammatory, choleretic, antifi-
brillatory, antibiotic, antispermatogenic, and vasodila-
tory efficiency.[5] They are usually prepared from alde-
hydes and 2-aminobenzamides under acidic condi-
tions, and recently List and Rueping reported
remarkable breakthroughs toward the corresponding
asymmetric synthesis using chiral phosphoric acids as
Keywords: aminals; 2-aminobenzamides; carbon-ni-
trogen bond cleavage; dihydroquinazolinones;
imines
A wide variety of nucleophiles undergo additions to the catalysts.[6–8] List et al. obtained excellent enantio-
À
imines by breaking the C N p bonds but delivering selectivity from the reaction of a-unbranched aliphat-
the stronger C N s bonds to the final products. In ic aldehydes with 2-aminobenzamides, but poor enan-
[1]
À
contrast, the transformation of imines has rarely been tioselectivity from the reaction with a-branched ali-
reported through the complete cleavage of C=N phatic aldehydes (e.g., Me2CHCHO: 50% ee) or aro-
bonds. Other than olefination,[2] the C=N bonds of matic aldehydes (e.g., PhCHO: 26% ee).[6a] Rueping
imines can be transformed into geminal s bonds in et al. obtained 80–92% ee from the reaction with
Scheme 1. Transformation of imine C=N bonds into geminal s bonds.
Adv. Synth. Catal. 2012, 354, 995 – 999
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Dao-Juan Cheng et al.
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Scheme 2. Catalytic asymmetric synthesis of dihydroquinazolinones.
para- and/or meta-substituted benzaldehydes and 80%
Table 1. Survey of the imine N-substituents and catalysts.[a]
ee from the reaction with cyclohexanecarboxalde-
ACHTUNGTRENNUNG
hyde.[6b] Our goal was to improve the enantioselectivi-
ty and extend the scope. Reasoning that imines have
additional N-substituents to interact with the acidic
catalysts and 2-aminobenzamides, we replaced the al-
dehydes in the aminal-forming reaction with imines
and found that the modified reaction not only gave
better enantioselectivity in the synthesis of some
known 2-aryl- and 2-alkyldihydroquinazolinones, but
also extended the scope to 2-(2-substituted-phenyl)-,
2-(1- or 2-naphthyl)-, 2-heteroaryl-, and 2-
alkenyldihydroquinACTHNUTRGENUGNazolinones (Scheme 2).
Treatment of N-benzylidene-p-toluenesulfonamide
(1aa) with 2-aminobenzamide (2a) and 10 mol% of
chiral phosphoric acid 4a in chloroform at room tem-
perature resulted in the formation of dihydroquinazo-
linone 3a in 90% yield and with 24% ee (Table 1,
entry 1). Notably, the enantioselectivity is significantly
better than that for the synthesis of the same product
from a previously reported reaction of benzaldehyde
with 2-aminobenzamide (2a) in the presence of cata-
lyst 4a (10% ee).[6b] Encouraged by this result, we
evaluated a range of substituents on the imine nitro-
gen atoms including the sulfonyl, diphenylphosphinyl,
and aryl groups (Table 1, entries 2–20). The reactivity
and enantioselectivity were dramatically affected by
the imine N-substituents, and the N-(1-naphthalene-
sulfonyl) group was identified as the best one, the use
of which led to the formation of dihydroquinazoli-
none 3a with 64% ee (Table 1, entry 9). It is notewor-
thy that the reaction with N-benzylidene-p-methoxy-
ACHTUNGTRENNUNGaniline (1ap) afforded comparable enantioselectivity
(Table 1, entry 16, 63% ee). While deteriorated ee
and/or unsatisfying yields were observed when replac-
ing chloroform with a number of other common or-
ganic solvents,[9] chiral phosphoric acids 4b–f were
able to improve the enantioselectivity significantly
(Table 1, entries 21–25). Taken together, the employ-
ment of commercially available phosphoric acid 4f in
combination with low temperature (À208C) and 3 ꢂ
molecular sieves allowed the synthesis of
[a]
Reaction conditions: imine 1a (0.11 mmol), 2-aminobenz-
AHCTUNGTREGaNNUN mide (2a) (0.10 mmol), catalyst 4 (10 mol%), chloro-
form (2.0 mL), room temperature, 24 h.
Isolated yield.
Determined by chiral stationary phase HPLC analysis.
The reaction was run at À208C for 4 d in the presence of
3 ꢂ molecular sieves (10 mg).
[b]
[c]
[d]
dihydroquinACHTUNGTRENNUNGazolinone 3a with up to 96% ee (Table 1,
entry 26), which is much higher than that reported in
literature (26% ee[6a] and 86% ee[6b]). For further com-
parison, we applied our optimized conditions to the
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Adv. Synth. Catal. 2012, 354, 995 – 999

Catalytic Asymmetric Synthesis of Dihydroquinazolinones from Imines and 2-Aminobenzamides
Table 2. Catalytic asymmetric synthesis of dihydroquinazoli-
nazolinones in good yields and with excellent ee
(Table 2, entries 1–8). It is noteworthy that both elec-
tron-withdrawing and electron-donating groups were
successfully introduced into the heterocyclic products
by employing the imines bearing such groups on the
aromatic rings. For the reaction with a,b-unsaturated
imines, alternative employment of a 2,6-dichloroben-
zenesulfonyl group as the N-substituent afforded
much better enantioselectivity relative to that with
the 1-naphthalenesulfonyl group,[9] and 2-alkenyldihy-
droquinazolinones were obtained with excellent ee
(Table 2, entries 9 and 10). Switching the imine N-sub-
stituents allowed the reaction with aliphatic imines to
afford very good enantioselectivity (Table 2, entries 11
and 12). Moreover, a variety of 2-aminobenzamides
having substituted benzene rings were transformed
into the corresponding dihydroquinazolinones in good
to excellent yields and with excellent ee (Table 2, en-
tries 13–18). When compared to the catalytic asym-
metric synthesis of dihydroquinazolinones from alde-
hydes,[6] the reaction with imines not only significantly
enhances the enantioselectivity by tuning the elec-
tronic and steric properties of the N-substituents, but
also extends the scope to 2-(2-substituted-phenyl)-, 2-
(1- or 2-naphthyl)-, 2-heteroaryl-, and 2-alkenyldihy-
nones.[a–c]
droquinazolinones in
a
highly enantioselective
manner.
[a]
Reaction conditions: imine 1 (0.11 mmol), 2-aminobenz-
1
According to the H NMR spectroscopic analysis,
no reaction occurred between imine 1ai and 2-amino-
benzamide (2a) in deuterated chloroform at room
temperature. The addition of phosphoric acid 4a to
the mixture resulted in the formation of dihydroqui-
nazolinone 3a and 1-naphthalenesulfonamide (by-
product), but no intermediate was observed. Never-
theless, to our delight, ESI-mass (positive mode) spec-
troscopic analysis of the reaction mixture allowed us
to identify tentatively two intermediates, aminal Aa
and imine Ba, and the complexes of 2-aminobenza-
mide (2a) and imine Ba with phosphoric acid 4a ac-
cording to the high resolution mass data (Table 3).[10]
These results suggest that transimination occurs
ACHTUNGTRENNUNGamide 2 (0.10 mmol), phosphoric acid 4f (10 mol%),
chloroform (2.0 mL), À208C (or 108C for entries 3, 5, 7,
8, 13, and 15-18), 1.5–4 d.
[b]
[c]
For entries 1, 9–11, and 14, 3 ꢂ molecular sieves (10 mg)
were used.
The absolute configuration of product 3e was deter-
mined by single crystal X-ray analysis (CCDC 816904;
these data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif), and that of the
rest of new products was assigned by analogy.
Isolated yield.
Determined by chiral stationary phase HPLC analysis.
X=1-naphthalenesulfonyl.
X=p-methoxyphenyl.
X=2,6-dichlorobenzenesulfonyl.
X=p-toluenesulfonyl.
X=2,4,6-triisopropylbenzenesulfonyl.
The ee reported in literature: 26%[6a] and 86%.[6b]
Product 3i was obtained in 83% ee from the reaction
with (E)-PhCH=CHCHO under the same conditions.
The ee reported in literature: 80%.[6b]
[d]
[e]
[f]
[g]
[h]
[i]
[j]
Table 3. Species detected by ESI-mass spectroscopic analy-
sis.
[k]
[l]
[m]
reaction of benzaldehyde with 2-aminobenzamide
(2a) and obtained dihydroquinazolinone 3a in 73%
yield and with 84% ee.
In the presence of 10 mol% of phosphoric acid 4f,
a range of aromatic and heteroaromatic imines,
having an N-(1-naphthalenesulfonyl) or N-(p-meth-
ACHTUNGTRENNUNG
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Scheme 3. Treatment of imine 1ai with 2-aminobenzamide 5 or 7.
Scheme 4. Proposed reaction pathway.
through promotion by the phosphoric acid during the the nonbonding interactions among by-product F (a
reaction.[11]
primary sulfonamide or a primary amine), intermedi-
The primary amine group rather than the primary ate B, and phosphoric acid 4 as tentatively shown in
amide group in 2-aminobenzamide 2 was confirmed complex E.
to undergo transimination with imine 1 at an early
In summary, we have developed, for the first time,
stage of the reaction by treatment of imine 1ai with an efficient catalytic asymmetric synthesis of aminal-
phosphoric acid 4f and a 2-aminobenzamide having containing heterocyclic compounds from imines and
a methyl group either on the amide nitrogen atom or tethered nitrogen/nitrogen nucleophiles. In the pres-
on the amine nitrogen atom (Scheme 3). While the re- ence of 10 mol% of a commercially available chiral
action with secondary amide 5 proceeded in the pres- phosphoric acid, a range of aromatic, a,b-unsaturated,
ence of phosphoric acid 4f at room temperature to and aliphatic imines react with 2-aminobenzamides to
give dihydroquinazolinone 6 in 81% yield and with give dihydroquinazolinones in good to excellent
51% ee, no desired product was obtained from the re- yields and ee. The enantioselectivity is significantly af-
action with secondary amine 7 under the same condi- fected by the imine N-substituent through non-bond-
tions.[12]
ing interactions with the chiral phosphoric acid and
These experiments allow us to propose the follow- the 2-aminobenzamide.
ing reaction pathway for the catalytic asymmetric syn-
thesis of dihydroquinazolinones (Scheme 4). Both
imine 1 and 2-aminobenzamide 2 are activated by
phosphoric acid 4, a bifunctional catalyst acting as
a hydrogen bond donor and acceptor,[8] and an initial
imine addition results in the formation of aminal A.
Elimination of the original imine N-substituent from
aminal A is promoted by phosphoric acid 4, and the
resulting complex, E, undergoes intramolecular imine
addition to give dihydroquinazolinone 3 and releases
phosphoric acid 4. It is clear that the enantioselectivi-
ty is determined by the step of intramolecular imine
addition. The significant influence of the imine N-sub-
Experimental Section
General Procedure for the Catalytic Asymmetric
Synthesis of Dihydroquinazolinones
With molecular sieves: To a flame dried reaction vial
equipped with a magnetic stirring bar were added 3 ꢂ mo-
lecular sieves (10 mg). The molecular sieves were thermally
activated under vacuum for 30 min, and cooled down to
room temperature under nitrogen. To the reaction vial were
added 2-aminobenzamide 2 (0.10 mmol), chiral phosphoric
acid 4f (7.0 mg, 0.010 mmol), and chloroform (2.0 mL). The
stituent on enantioselectivity should be attributable to mixture was stirred at À20 or 108C for 10 min, and imine
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Adv. Synth. Catal. 2012, 354, 995 – 999

Catalytic Asymmetric Synthesis of Dihydroquinazolinones from Imines and 2-Aminobenzamides
1 (0.11 mmol) was added. The resulting mixture was stirred
for 1.5–4 d, and directly charged onto silica gel. The product
was isolated using hexane/chloroform/ethanol (10/10/1) or
hexane/ethyl acetate (2/1) as eluent.
melli, C. Unaleroglu, Tetrahedron 2009, 65, 2043–2050;
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Lett. 2011, 13, 5636–5639.
Without molecular sieves: To a flame dried reaction vial
equipped with a magnetic stirring bar under nitrogen were
added 2-aminobenzamide 2 (0.10 mmol), chiral phosphoric
acid 4f (7.0 mg, 0.010 mmol), and chloroform (2.0 mL). The
mixture was stirred at À20 or 108C for 10 min, and imine
1 (0.11 mmol) was then added. The resulting mixture was
stirred for 1.5–4 d, and directly charged onto silica gel. The
product was isolated using hexane/chloroform/ethanol (10/
10/1) or hexane/ethyl acetate (2/1) as eluent.
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[7] For a pioneering enantioselective synthesis of N,N-ami-
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Chennamadhavuni, Y. Wang, J. C. Antilla, J. Am.
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[9] For details, see the Supporting Information.
[10] Product 3a and imine Ba have the same molecular for-
mula. Nevertheless, distinct relative abundances of the
relevant peaks were observed in the ESI-mass spec-
trum for the mixture of product 3a and phosphoric acid
4a, and this control experiment substantially supports
the formation of imine Ba and its complex with phos-
phoric acid 4a during the reaction of imine 1ai with 2-
aminobenzamide (2a). For details, see the Supporting
Information.
Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (21172206, 20972147,
and 20732006) and the National Basic Research Program of
China (973 Program 2010CB833300).
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Adv. Synth. Catal. 2012, 354, 995 – 999
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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