Journal of the American Chemical Society
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Thus, Rolipram is now made available in only three steps from
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inexpensive 2ꢀpyrrolidinone.
R. F.; Karady, S.; Abramson, N. L.; Douglas, A. W. J. Org. Chem.
1993, 58, 3384. (d) Matsuo, J.ꢀi.; Aizawa, Y. Tetrahedron. Lett. 2005,
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(8) For DDQꢀmediated desaturation of γ,γꢀdialkylsubstituted lactams, see:
Bhattacharya, A.; DiMichele, L. M.; Dolling, UꢀH.; Douglas, A. W.;
Grabowski, E. J. J. J. Am. Chem. Soc. 1988, 110, 3318.
(9) Weber, B.; Scharer, N.; Muller, B. W. U.S. Patent App 2006/0281949
A1, Dec 14, 2006.
Interestingly, the phthalimide-protected amide was recognized
4
as an underutilized surrogate for various carboxylic acid deriva-
23
tives (Scheme 4d). For example, ester (7), free primary amide
2
4
(
8), carboxylic acid (9) and thioester (10) can be efficiently obꢀ
tained in a single step from linear conjugate amide 4b.
In summary, as an essential step towards direct βꢀC−Cꢀforming
functionalization of lactams, we have developed an amide desatuꢀ
ration method that operates under acidic conditions at room temꢀ
perature. The merge of soft enolization with palladium catalysis
should have a broad implication on functionalization of other less
enolizable carbonyl compounds. Detailed mechanistic studies
through kinetic measurements and identification of key intermediꢀ
ates are ongoing to eventually enable using catalytic Lewis pairs.
Development of direct βꢀarylation of lactams will be focused in
the future work.
(
10) Chen, Y. F.; Turlik, A.; Newhouse, T. R. J. Am. Chem. Soc. 2016,
38, 1166.
1
(
11) For seminal discoveries, see: (a) Lehnert, W. Tetrahedron Lett. 1970,
11, 4723. (b) Mukaiyama, T.; Inoue, T. Chem. Lett. 1976, 559. (c) Evꢀ
ans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.
12) When this manuscript was in preparation, a ketone dehydrogenation
method through a stepwise generation of boron enolates was reported,
see: Sakamoto, Y.; Amaya, T.; Suzuki, T.; Hirao, T. Chem. Eur. J.
2016, 22, 18686.
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(
(
13) (a) Hama T.; Liu, X. X.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem.
Soc. 2003, 125, 11176. (b) Liu, X. X.; Hartwig, J. F. J. Am. Chem. Soc.
2
004, 126, 5182.
ASSOCIATED CONTENT
(14) Abiko, A. In Boron Enolate Chemistry; Coca, A., Eds.; Boron
Reagents in Synthesis; American Chemical Society: 2016, 1236, 123ꢀ
Supporting Information Experimental procedures; specꢀ
tral data. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
71.
(15) Use of B(C
on using catalytic B(C
6
F
5
)
3
has also been attempted. For a recent elegant work
to enolize a range of carbonyl compounds
6 5 3
F )
for enantioselective αꢀamination, see: Shang, M.; Wang, X.; Koo, S.
M.; Youn, J.; Chan, J. Z.; Yao, W.; Hastings, B. T.; Wasa, M. J. Am.
Chem. Soc. 2017, 139, 95.
16) Use of Ac as the PG gave a complex reaction mixture, likely due to a
competing enolization on the Ac methyl group. Use of Ts as the PG
gave no conversion of the lactam, likely due to the weak chelation efꢀ
fect of the sulfonyl group.
17) Voleva, V. B.; Prokofeva, T. I.; Belostotskaya, I. S.; Komissarova, N.
L.; Ershov, V. V. Russian Chem. Bull. 1998, 47, 1952.
(18) Chen, Y. F.; Turlik, A.; Newhouse, T. R. J. Am. Chem. Soc. 2015,
137, 5875.
19) Takaya, Y.; Ogasawara, M.; Hayashi, T.; J. Am. Chem. Soc. 1998,
AUTHOR INFORMATION
(
Corresponding Author
Notes
(
The authors declare no competing financial interests.
ACKNOWLEDGMENT
(
We thank University of Chicago for a startup fund. G.D. is a Searle Scholꢀ
ar and Sloan fellow. M.C. thanks Shanghai Institute of Organic Chemistry
and Jiangsu Aosaikang Pharmaceutical Co., Ltd. for a postdoc fellowship.
Mr. Chengpeng Wang is acknowledged for checking the experiments.
1
20, 5579.
(
20) Behenna, D. C.; Liu, Y. Y.; Yurino, T.; Kim, J. M.; White, D. E.;
Virgil, S. C.; Stoltz, B. M. Nature. Chem. 2012, 4, 130.
(
21) (a) Lowe, J. A. L.; Archer, R. L.; Chapin, D. S.; Cheng, J. B.; Helꢀ
weg, D.; Johnson, J. L.; Koe, B. K.; Lebel, L. A.; Moore, P. F.; Nielsen,
J. A.; Russo, L. L.; Shirley, J. T. J. Med. Chem. 1991, 34, 624. (b)
Myeku, N.; Clelland, C. L.; Emrani, S.; Kukushkin, N. V.; Yu, W. H.;
Goldberg, A.; Duff, K. E. Nat. Med. 2016, 22, 46.
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(
(
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