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ACS Catalysis
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activity and enantioselectivity (95% yield, 88% ee, entry 9,
Table 2).
With these reaction conditions identified, our attention
enantioselectivity. The best level of stereocontrol was obtained
for aromatic aldehydes with an ortho substituent. Furthermore,
the scalability of the newly investigated method was proven
with a 1.0ꢀmmol scale experiment and the recycling of the
catalyst was illustrated.
turned to examination of the scope of catalytic asymmetric
condensation/amine addition cascade reaction. The reactions
were carried out using catalyst 1j under the optimized condiꢀ
tions and the results are summarized in Table 3. All reactions
proceeded in generally excellent yields with good to excellent
enantioselectivities. The influence of the aldehyde substrates
was first investigated. Either electronꢀwithdrawing or ꢀ
donating substituents (ꢀBr, ꢀNO2, ꢀCl, ꢀOMe, ꢀOCH2Oꢀ) on the
phenyl group of aromatic aldehydes could be well tolerated,
affording their desired products 4aꢀl. It is noteworthy that difꢀ
ferent positionꢀsubstituent on the the phenyl group of aromatic
aldehydes appears to have a remarkably effect on the enantiꢀ
oselectivity. We found that the best level of stereocontrol was
obtained for aromatic aldehydes with an ortho substituent,
such as 4b (98%ee), 4d (95%ee), 4f (98%ee), 4g (96%ee) and
4i (94%ee). The 1ꢀnaphthyl bearing substrate also led to prodꢀ
uct 4m in 99% yield and 97% ee, while 2ꢀnaphthyl bearing
substrate only gave product 4n in 89% yield and 89% ee.
When a cyclohexyl substituent was introduced, the reaction
ran smoothly, affording the product 4o in 98% yield and 84%
ee. We further expanded the scope of this cascade reaction to
substituted 2ꢀaminobenzamide. Reaction of 1ꢀnaphthaldehyde
and orthoꢀchlorobenzaldehyde with 5ꢀiodoꢀ2ꢀaminobenzamide,
which can participate in subsequent transformations such as
crossꢀcoupling reactions, gave the corresponding 2,3ꢀ
dihydroquinazolinone 4p and 4q in good yields with excellent
ees.
ASSOCIATED CONTENT
Supporting Information.
Experimental procedures and characterization of the products.
This material is available free of charge via the Internet at
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AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: lxfok@zju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the National Natural Foundation of China (21272202
and J1210042) and the Fundamental Research Funds for the Cenꢀ
tral Universities for financial support.
REFERENCES
(1) (a) Chinigo, G. M.; Paige, M.; Grindrod, S.; Hamel, E.;
Dakshanamurthy. S.; Chruszcz, M.; Minor, W.; Brown, M. L. J.
Med. Chem. 2008, 51, 4620. (b) Okumura, K.; Oine, T.; Yamada,
Y.; Hayashi, G.; Nakama, M. J. Med. Chem. 1968, 11, 348. (c)
Bonola, G.; Da Re, P.; Magistretti, M. J.; Massarani, E.; Setnikar,
I. J. Med. Chem. 1968, 11, 1136. (d) Russel, H. E.; Alaimo, R. J.
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in, J. I.; Chan, P. S.; Bailey, T.; Katocs, A. S.; Venkatesan, A. M.
Bioorg. Med. Chem. Lett. 1994, 4, 1141.
The absolute stereochemistry of product 4c, obtained by usꢀ
ing the catalyst (S)ꢀ1j, was determined to be S by comparison
of its optical rotation with the literature data.3b Thus, a possible
transition state of this reaction is proposed in Figure 2. It is
clear that the enantioselectivity is determined by the step of
intramolecular amidation of imine. SPINOLꢀphosphoric acid
(S)ꢀ1j as a bifunctional organocatalyst brings together two
groups (amine and imine) through hydrogen bonding. In this
model, the amine attacks the imine from the Si face preferenꢀ
tially due to less steric hindrance, resulting in the Sꢀ
stereoisomer.
(2) Uzunov, D. P.; Zivkovich, I.; Pirkle, W. H.; Costa, E.; Guidotti,
A. J. Pharm. Sci. 1995, 84, 937.
(3) (a) Cheng. X; Vellalath. S; Goddard, R; List, B. J. Am. Chem.
Soc. 2008, 130, 15786. (b) Rueping, M.; Antonchick, A. P.;
Sugiono, E.; Grenader, K. Angew. Chem., Int. Ed. 2009, 48, 908.
(c) Cheng, D. J.; Tian, Y.; Tian, S. K. Adv. Synth. Catal. 2012,
354, 995. (d) Prakash, M.; Kesavan, V. Org. Lett. 2012, 14, 1896.
(4) For recent reviews of chiral phosphoric acid catalysis, see: (a)
Terada, M. Synthesis 2010, 1929. (b) Akiyama, T. Chem. Rev.
2007, 107, 5744. (c) Kampen, D.; Reisinger, C. M.; List, B. Top.
Curr. Chem. 2010, 291, 395. (d) Rueping, M.; Kuenkel, A.;
Atodiresei, I. Chem. Soc. Rev. 2011, 40, 4539. (e) Terada, M.
Chem. Commun. 2008, 4097. (f) Yu, J.; Shi, F.; Gong, L. Z. Acc.
Chem. Res. 2011, 44, 1156. (g) You, S.; Cai, Q.; Zeng, M. Chem.
Soc. Rev. 2009, 38, 2190. (h) Yu, X.; Wang, W. Chem.–Asian J.
2008, 3, 516.
(5) For selected examples of the application of chiral phosphoric
acid catalysis, see: (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe,
K. Angew. Chem., Int. Ed. 2004, 43, 1566. (b) Uraguchi, D.; Teꢀ
rada, M. J. Am. Chem. Soc. 2004, 126, 5356. (c) Rowland, G.;
Zhang, H. Rowland, E.; Chennamadhavuni, S.; Wang, Y.; Antilꢀ
la, J. C. J. Am. Chem. Soc. 2005, 127, 15696. (d) Hoffmann, S.;
Seayad, A. M.; List, B. Angew. Chem., Int. Ed. 2005, 44, 7424.
(e) Magnus, R.; Sugiono, E.; Azap C.; Theissmann, T.; Bolte, M.
Org. Lett., 2005, 7, 3781. (f) Storer, R. I.; Carrera, D. E.; Ni, Y.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84. (g) Liu,
H.; Cun, L.ꢀF.; Mi, A.ꢀQ.; Jiang,Y. Z; Gong, L. Z. Org. Lett.
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Figure 2. Possible transition state of the reaction
In summary, we have developed an efficient and practical
protocol
to
synthesize
optically
active
2,3ꢀ
dihydroquinazolinones by chiral SPINOLꢀphosphoric acidꢀ
catalyzed asymmetric condensation/amine addition cascade
sequence of 2ꢀaminobenzamides and aldehydes. Following
this methodology, a series of 2,3ꢀdihydroquinazolinones were
obtained in excellent yields (up to 99%) with good to excellent
ees (up to 98%) at room temperature. In addition, we found
that different positionꢀsubstituent on the the phenyl group of
aromatic aldehydes appears to have a remarkably effect on the
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