Highly enantioselective synthesis of 2,3-dihydroquinazolinones through intramolecular amidation of imines

Article abstract of DOI:10.1021/ol300518m

Enantioselective synthesis of 2,3-dihydroquinazolinones (DHQZs) was accomplished using readily available Sc(III)-inda-pybox as the catalyst. This is the first report on the metal catalyzed asymmetric intramolecular amidation of imines to synthesize DHQZs.

Full text of DOI:10.1021/ol300518m

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1896–1899
Highly Enantioselective Synthesis of
2,3-Dihydroquinazolinones through
Intramolecular Amidation of Imines
Muthuraj Prakash and Venkitasamy Kesavan*
Department of Biotechnology, Bhupat and Jyothi Mehta School of Biosciences Building,
Indian Institute of Technology Madras, Chennai 600036, India
vkesavan@iitm.ac.in
Received February 29, 2012
ABSTRACT
Enantioselective synthesis of 2,3-dihydroquinazolinones (DHQZs) was accomplished using readily available Sc(III)-inda-pybox as the catalyst.
This is the first report on the metal catalyzed asymmetric intramolecular amidation of imines to synthesize DHQZs.
Pharmacologically active heterocycles/intermediates which
possess a chiral center are increasingly being synthesized in a
stereoselective manner in recent years.1 Nitrogen containing
heterocycles are an integral part of many drug molecules or
physiologically active natural products and/or synthetic mol-
ecules. One such heterocycle is 2,3-dihydroquinazolinone
(DHQZ-1) which contains a cyclic aminal chiral center.
DHQZ is a privileged scaffold because of its extensive
pharmacological activities including antibacterial, antifertil-
ity, antitumor, antifibrilatory, vasodilatory, antifungal, and
analgesic efficacy.2
Regardless of various methods that are available to
synthesize DHQZs as racemates,3 enantioselective synthe-
sis of 2,3-DHQZs is not easily achieved since the aminal
stereocenter is sensitive to racemization.4 Development of
synthetic methodology to synthesize S-enantiomers is very
much wanted because they are more potent antiprolifera-
tive agents than R-enantiomers.4 The reported higher
anticancer activity of S-enantiomer is possible only if
racemization of DHQZs does not occur under physiologi-
cal conditions (pH ≈ 7.0À7.4). Catalytic asymmetric
synthesis of 2,3-DHQZ has been a challenge for a long
(1) (a) Agranat, I.; Caner, H.; Caldwell J. Nat. Rev. Drug Discovery
2002, 1, 753. (b) Kasprzyk-Hordern, B. Chem. Soc. Rev. 2010, 39, 4466.
(c) Agranat, I.; Wainschtein, S. R. Drug Discovery Today 2010, 15, 163.
(2) (a) Russel, H. E.; Alaimo, R. J. J. Med. Chem. 1972, 15, 335. (b)
Cooper, E. R. A.; Jackson, H. J. Reprod. Fert. 1973, 34, 445. (c) Neil,
G. L.; Li, L. H.; Buskirk, H. H.; Moxley, T. E. Cancer Chemother. Rep.
1972, 56, 163. (d) Kuo, S. C. H.; Lee, Z.; Juang, J. P.; Lin, Y. T.; Wu,
T. S.; Chang, J. J.; Lednicer, D.; Paull, K. D.; Lin, C. M.; Hamel, E.; Lee,
K. H. J. Med. Chem. 1993, 36, 1146. (e) Hamel, E.; Lin, M.; Plowman,
C. J.; Wang, H. K.; Lee, K. H.; Paull, K. D. Biochem. Pharmacol. 1996,
51, 53. (f) Hour, M. J.; Huang, L. J.; Kuo, S. C.; Xia, Y.; Bastow, K.;
Nakanishi, Y.; Hamel, E.; Lee, K. H. J. Med. Chem. 2000, 43, 4479. (g)
Bonola, G.; Da Re, P.; Magistretti, M. J.; Massarani, E.; Setnikar, I.
J. Med. Chem. 1968, 11, 1136. (h) Levin, J. I.; Chan, P. S.; Bailey, T.;
Katocs, A. S.; Venkatesan, A. M. Bioorg. Med. Chem. Lett. 1994, 4,
1141. (i) Xu, Z.; Zhang, Y.; Fu, H.; Zhong, H.; Hong, K.; Zhu, W.
Bioorg. Med. Chem. Lett. 2011, 21, 4005.
(3) For selected references for the synthesis of 2,3-DHQZ, see: (a)
Chen, J. X.; Wu, H.; Hua, Y.; Su, W. K. Chin. Chem. Lett. 2007, 18, 536.
(b) Chen, J.; Wu, D.; He, F.; Liu, M.; Huayue, D.; Ding, J.; Su, W.
Tetrahedron Lett. 2008, 49, 3814. (c) Allameh, S.; Heravi, M. M.;
Hashemi, M. M.; Bamoharram, F. F. Chin. Chem. Lett. 2011, 22, 131
and references therein.
(4) Chinigo, G. M.; Paige, M.; Grindrod, S.; Hamel, E.;
Dakshanamurthy, S.; Chruszcz, M.; Minor, W.; Brown, M. L. J. Med.
Chem. 2008, 51, 4620.
(5) (a) Xu, C.; Sreekumar, V.; Richard, G.; Benjamin, L. J. Am.
Chem. Soc. 2008, 130, 15786. (b) Rueping, M.; Antonchick, A. P.;
Sugiono, E.; Grenader, K. Angew. Chem., Int. Ed. 2009, 48, 908.
r
10.1021/ol300518m
Published on Web 03/29/2012
2012 American Chemical Society

various mechanistically different asymmetric transforma-
tions with a wide variety of Lewis acids.6À8 Initial attempts
were made to prove our hypothesis by screening ligands
5 and 6 with various metal salts. Intramolecular amidation
of imine formed between 2-aminobenzamide (2) and benz-
aldehyde (3) was carried out at 25 °C with various Lewis
acids such as Cu(I)OTf, Cu(OTf)2, or Zn(OTf)2 (5 mol %)
and 10 mol % of ligand 5 or 6 in the presence of powdered
Scheme 1. Enantioselective Synthesis of DHQZ 4a
˚
4 A molecular sieves in dichloromethane. It was observed
that DHQZ 4a was isolated in very low yields (10À20%)
with no chiral induction. Since these attempts were not
successful, we turned our attention to pybox ligand com-
plexes with rare metal triflates. The catalytic efficiency of
these complexes as Lewis acids is well demonstrated in the
literature.9,10 We were delighted to observe that pybox
6/Sc(OTf)3 catalyzed the intramolecular amidation of
imine with great efficiency and with an enantiomeric excess
of 34% (Table 1, entry 1). Encouraged by this observation,
we sought to identify the suitable pybox ligand to enhance
the enantioselectivity of this transformation. Valinol,
phenylalaninol, phenyl glycinol, and 1,1-diphenyl valinol
derived pybox ligands 7À10, respectively, failed to
time.5 List et al.5a and Rueping et al.5b developed meth-
odologies for enantioselective synthesis of DHQZs using
chiral Brønsted acids. The first method5a worked well only
for linear aliphatic aldehydes or R-unbranched aldehydes,
and poor enantioselectivity was observed for R-branched
aldehydes including aromatic aldehydes. The method by
Rueping et al. lacks substrate diversity. Except for these
chiral Brønsted acid catalyses, there is no other catalytic
method available to the best of our knowledge for the
asymmetric synthesis of DHQZs. That stimulated us to
develop a high yield metal catalyzed enantioselective
intramolecular amidation of imines to synthesize 2,3-
dihydroquinazolinones. To circumvent the racemization
of an aminal stereocenter, we sought to activate the imine
formedbythe reaction between2-aminobenzamide (2) and
benzaldehyde (3) through a chiral Lewis acid catalyst.
We hoped that a suitable chiral Lewis acid would
mediate intramolecular amidation of imines to form en-
antiomerically pure 2,3-DHQZ 4a (Scheme 1). Although
there are many chiral ligands that can be employed for
Lewis acid mediated catalysis, we initially selected bis-
(oxazoline) 5 and pyridine bis(oxazoline) 6 for evaluation
because they are renowned for their ability to catalyze
Table 1. Evaluation of Box and Pybox Ligands in Lewis Acid
Catalyzed Enantioselective Synthesis of 2,3-Dihydroquinazoli-
nonea 4a
entry
ligand
metal
yield (%)b
ee (%)c,d
1
6
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Yb(OTf)3
Y(OTf)3
90
80
82
89
90
94
72
65
60
93
34 (R)
racemic
16 (R)
36 (R)
30 (R)
84 (S)
76 (S)
64 (S)
racemic
98 (S)
2
7
3
8
4
9
5
10
11
11
11
11
11
6
7
8
9
10e
La(OTf)3
Sc(OTf)3
a Reactions were carried out using 300 μmol of 2-aminobenzamide
(2), 360 μmol of benzaldehyde (3), 5 mol % of Lewis acid, 10 mol % of
˚
ligand, and powdered 4 A molecular sieves at 25 °C in CH2Cl2 for
6À48 h. b Isolated yields. c Enantiomeric excess were determined on a
chiral stationary phase. d Absolute configuration of the product is
indicated in the parentheses. e Lewis acid/Ligand ratio (1:2.5 mol %)
was used.
(6) For selected references of box catalyzed reactions, see: (a) Evans,
D. A.; Woerpel, A. K.; Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc.
1991, 113, 726. (b) Desimoni, G.; Faita, G.; Jorgenen, K. A. Chem. Rev.
2006, 106, 3561. (c) Xu, X.; Hu, W.-H.; Doyle, M. P. Angew. Chem., Int.
Ed. 2011, 50, 6392 and references therein.
(7) For selected references of pybox, see: (a) Nishiyama, H.; Sakaguchi,
H.; Nakamura, T.; Horlhata, M.; Kondo, M.; Itoh, K. Organometallics
1989, 8, 846. (b) Evans, D. A.;Murry, J. A.;Kozlowski, M. C.J. Am. Chem.
Soc. 1996, 118, 5814. (c) Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev.
2003, 103, 3119. (d) Poisson, T.; Yamashita, Y.; Kobayashi, S. J. Am.
Chem. Soc. 2010, 132, 7890. (e) Hanhan, N. V.; Sahin, A. H.; Chang, T. W.;
Fettinger, J. C.;Franz, A. K.Angew. Chem., Int. Ed. 2010, 49, 744. (f) Singh,
P. K.; Singh, V. K. Org. Lett. 2010, 12, 80. (g) Zeng, T.; Yang, L.; Hudson,
R.;Song, G.;Moores, A. R.;Li, C.-J.Org. Lett. 2011, 13, 442. (h) Gutierrez,
E. G.; Wong, C. J.; Sahin, A. H. Org. Lett. 2011, 13, 5754 and references
therein.
(9) (a) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L.
Chem. Rev. 2002, 102, 2227. (b) Luo, S.; Zhu, L.; Talukdar, A.; Zhang,
G.; Mi, X.; Cheng, J.-P.; Wang, P. G. Mini-Rev. Org. Chem. 2005, 2, 177.
(c) Burai, R.; Ramesh, C.; Shorty, M.; Curpan, R.; Bologa, C.; Sklar,
L. A.; Oprea, T.; Prossnitz, E. R.; Arterburn, J. B. Org. Biomol. Chem.
2010, 8, 2252 and references therein.
(10) For selected applications of Scandium pybox, see: (a) Desimoni,
G.; Faita, G.; Guala, M.; Pratelli, C. J. Org. Chem. 2003, 68, 7862. (b)
Liang, G.; Trauner, D. J. Am. Chem. Soc. 2004, 126, 9544. (c) Evans,
D. A.; Wu, J. J. Am. Chem. Soc. 2005, 127, 8006. (d) Evans, D. A.; Aye,
Y. J. Am. Chem. Soc. 2006, 128, 11034. (e) Comelles, J.; Pericas, A.;
Moreno-Manas, M.; Vallribera, A.; Drudis-Sole, G.; Lledos, A.;
Parella, T.; Roglans, A.; Garcia-Granda, S.; Roces-Fernandez, L.
J. Org. Chem. 2007, 72, 2077. (f) Desimoni, G.; Faita, G.; Toscanini,
M.; Boiocchi, M. Chem.;Eur. J. 2008, 14, 3630. (g) Hanhan, N. V.;
Ball-Jones, N. R.; Tran, N. T.; Franz, A. K. Angew. Chem., Int. Ed. 2011,
50, 1 and references therein.
(8) For synthesis of box and pybox, see: (a) Gupta, A. D.; Bhuniya,
D.; Singh, V. K. Tetrahedron 1994, 50, 13725. (b) Cornejo, A.; Fraile,
J. M.; Garcia, J. I.; Gil, M. J.; Martinez-Merino, V.; Mayoral, J. A.;
Pires, E.; Villalba, I. Synlett 2005, 15, 2321.
Org. Lett., Vol. 14, No. 7, 2012
1897

improve the enantioselectivity of the reaction (entries
2À5). It is important to note that, in all these reactions,
DHQZ 4a was observed to possess an R-configuration.
Since S-amino alcohol derived pybox ligands yielded the
R-stereoisomerof DHQZ4a, we evaluated the efficiency of
the scandium(III)-(1R,2S)-Inda-pybox 11 catalytic system
in the asymmetric synthesis of DHQZ 4a to obtain the S-
stereoisomer. Asweexpected theS-stereoisomer of DHQZ
4a formed under the reaction conditions with very good
enantioselectivity (84% ee, entry 6). Scandium(III) triflate
was found to be the most suitable metal partner since
reactions catalyzed by other rare earth metal triflates such
as Yb(OTf)3, Y(OTf)3, and La(OTf)3 in combination with
(1R,2S)-Inda-pybox 11 did not improve either the yield or the
enantioselectivity (entries 7À9). Screening of various solvents
identified dichloromethane or chloroform as the most suit-
able reaction medium in which remarkable enantioselectivity
was obtained. When ethanol was used as the reaction
medium, complete racemization of the product occurred.
To optimize the catalyst loading, we lowered the metal to
1 mol % and increased the ligand ratio to 2.5 times, i.e.,
2.5 mol % for efficient complex formation. We hoped that
this would suppress the synthesis of DHQZ 4a catalyzed by
metal alone which in turn will enhance the enantioselectivity.
Indeed DHQZ 4a was obtained in 98% ee, with a catalyst
loading of 1 mol % of Sc(OTf)3 and 2.5 mol % of Inda-pybox
11 under standard reaction conditions (entry 10). Thus we
have achieved the first metal catalyzed synthesis of 2,3-
dihydroquinazolinone 4a in quantitative yield and admirable
enantioselectivity with a catalytic loading of 1 mol % at
ambient temperature. With these optimized conditions in
hand, we extended the scope of our methodology in synthe-
sizing various optically pure 2,3-dihydroquinazolinones.
Benzaldehyde and 2-naphthaldehyde underwent cycli-
zation with 2-aminobenzamide (2) with ease and in ex-
cellent enantioselectivity to afford DHQZs 4a and 4b
respectively (Table 2, entries 1 and 2). The presence of
fluorine on benzaldehyde at either the meta or para posi-
tion did not have any bearing on the outcome of the
transformation. Fluorine containing DHQZs 4c and 4e
(entries 3 and 5) were obtained in superior yield and
enantioselectivity. The steric effect of a bromine atom
contributed to the diminished enantioselectivity in the case
of m-bromobenzaldehyde (3d) (entry 4). A similar steric
effect was not observed when p-bromobenzaldehyde (3f)
was treated with 2-aminobenzamide (2) to afford DHQZ
4f (entry 6) with excellent enantioselectivity (94% ee). The
presence of an electron withdrawing nitrile group, as well
as ethyl and phenyl substituents in the para-position of
benzaldehyde, is well tolerated in synthesizing DHQZs
4gÀ4i. These DHQZs were obtained in high yields and
with enantiomeric excess ranging from 86 to 96% (entries
7À9). Although a moderate enantioselectivity was ob-
served for aliphatic aldehydes at ambient temperature,
lowering the temperature to À20 °C resulted in the desired
asymmetric induction. DHQZs 4jÀ4l were obtained in
very good yields (80À85%) by reacting respective alde-
hydes 3jÀ3l with 2-aminobenzamide (2) at À20 °C. The
asymmetric induction observed (86À92% ee) in these
aliphatic aldehydes was comparable to that in aromatic
aldehydes (entries 10À12). In all of these experiments the
S-enantiomer was obtained as the major product. We
further expanded the scope of our methodology to 3,4-
disubstituted benzaldehydes and substituted 2-aminoben-
zamides (Figure 1). It is evident from Figure 1 that 3,4-
disubstituted benzaldehydes are very well tolerated sub-
strates under the protocol. The presence of a hydroxyl
group and electron donating groups did not hamper the
catalytic efficiencyof the scandium(III)-inda-pyboxsystem
in the intramolecular amidation of imines. 2,3-Dihydro-
quinazolinones 4mÀ4p were synthesized under optimized
reaction conditions in admirable yields and enantioselec-
tivities (90À92% ee). Similarly substitution on 2-amino-
benzamide did not have any negative influence on the
enantioselectivity. Reaction of 4-phenylbenzaldehyde with
5-chloro and 5-OCF3 substituted 2-aminobenzamides
gave rise to corresponding 2,3-dihydroquinazolinones 4q
and 4r in quantitative yields.
Table 2. Substrate Scope of Scandium(III)-Inda-Pybox Catalyst
in Enantioselective Synthesis of 2,3-Dihydroquinazolinonesa
entry
DHQZ (4aÀl) R =
yield (%)b
ee (%)c
1
C6H5 (4a)
94
92
91
94
92
90
88
95
91
86
80
85
98
98
98
80
90
94
90
96
86
92
86
86
2d
3
2-naphthyl (4b)
m-F-C6H4 (4c)
m-Br-C6H4 (4d)
p-F-C6H4 (4e)
p-Br-C6H4 (4f)
p-CN-C6H4 (4g)
p-Ph-C6H4 (4h)
p-C2H5-C6H4 (4i)
n-C6H13 (4j)
4
5
6
Encouraged by this success, we proceeded to highlight
the efficiency of our catalytic system in synthesizing 2,3-
dihysdroquinazolinone 4sby reacting4-phenylbenzaldehyde
with 2-amino-N-phenylbenzamide. DHQZs derived from
2-amino-N-phenylbenzamide are potent anti-inflammatory
and analgesic agents.11 The scandium(III)-inda-pybox
system catalyzed the intramolecular amidation of imines
to form dihydroquinazolinone 4s in 95% yield and with an
7
8
9
10e
11e
12e
n-C3H7 (4k)
Ph-C2H4 (4l)
a Reactions were carried out using 300 μmol of 2-aminobenzamide
2, 360 μmol of benzaldehyde 3, 1 mol % of metal, 2.5 mol % of pybox
˚
11, at rt in CH2Cl2 and powdered 4 A molecular sieves for 6À48 h.
b Isolated yields. c Enantiomeric excess were determined by HPLC on a
chiral stationary phase. d Structure of 4b was ascertained by single
crystal XRD. e Reactions were carried out at À20 °C.
(11) (a) Kozhevnikov, Y. V.; Smirrnova, N. N.; Zalesov, V. S.;
Gradel, I. I. Pharm. Chem. J. 1981, 15, 403. (b) Sadanandam, Y. S.;
Ram Mohan Reddy, K.; Bhaskar Rao, A. Eur. J. Med. Chem. 1987, 22,
169–173.
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Org. Lett., Vol. 14, No. 7, 2012

of the reactant with the metal complex in Si face, which
results in the formation the S-stereoisomer (Figure 2).
Figure 2. A plausible mechanistic pathway. Si-face approach;
less sterically hindered and more favored. Coordinating triflate
anions are not shown for clarity purposes.
In summary, we developed the first metal catalyzed
highly enantioselective synthesis of 2,3-dihydroquinazoli-
nones through intramolecular amidation of imines in
very good yields. The scandium(III)-inda-pybox catalyst
provided remarkable catalytic activation of 2-amino-
N-phenylbenzamide to afford the corresponding 2,3-
dihydroquinazolinone with very good enantioselectivity.
Further application of our methodology in synthesizing
enantiomerically pure 2,3-dihydroquinazolinones by condens-
ing 2-amino-N-arylbenzamides and 2-amino-N-alkylbenz-
amides with various aldehydes is currently being investigated.
Figure 1. Efficient enantioselective synthesis of 2,3-dihydro-
quinazolinones using scandium(III)-inda-pybox.
Acknowledgment. We acknowledge DBT (BT/PR/
10064/AGR/36/30/07), Government of India, New Delhi
for financial support. Prakash thanks CSIR for a research
fellowship. Wethank Dr. Babu Varghese for XRD and Dr.
M. S. Moni for NMR analysis at SAIF-IIT Madras.
enantiomeric excess of 82%. It is important to highlight
here that there is no prior report in the literature in
synthesizing optically pure 2,3-DHQZ from 2-amino-N-
phenylbenzamide.
A plausible mechanism for the stereochemical outcome
of the product can be explained by a model proposed
by Evans et al.12 The reaction may proceed through a more
favored Si face attack rather than an unfavored Re face
attack since less steric hindrance is expected in the approach
Supporting Information Available. Detailed experimen-
tal procedures and characterization data by 1H, 13C
NMR for all compounds and chiral HPLC analysis of
all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(12) Evans, D. A.; Fandrick, K. R.; Song, H.-J.; Scheidt, K. A.; Xu,
R. J. Am. Chem. Soc. 2007, 129, 10029.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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