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alkene 2k was also applicable to give the corresponding g-lactam
(3s) in 77% yield (Table 3, entry 10).
The success in synthesis of g-lactams prompted us to
investigate other nitrogen heterocycles such as pyrroles. We
have designed a,b-unsaturated ketones as substrates for the
construction of a pyrrole ring. When the reaction of 1a with an
a,b-unsaturated ketone derivative (5) was examined under
similar reaction conditions to the g-lactam synthesis, dihydro-
pyrrole (6) was obtained in 64% yield (Scheme 2a). Encouraged
by this result, we have successfully developed one-pot synthesis
of pyrroles by oxidation of dihydropyrroles (Scheme 2b). After
photoreactions of a-silyl secondary amines (1a and 1i) with 5,
subsequent treatment of the resulting mixture with 2 equiv.
of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) at room
temperature for 30 min gave the corresponding tri- and tetra-
substituted pyrroles (7a and 7b) in high yields.
Scheme 3 Plausible reaction pathways.
cyclization of C (E = CO2Et) affords g-lactams, while oxidation of
dihydropyrroles (D) formed by dehydration condensation of C
(E = COCH3) gives pyrroles.
To obtain mechanistic insight, some additional experiments were
carried out. At first, the quantum yield of the reaction of 1a with 2a
was determined to be 0.13. The value is in the common range of the
photoredox reactions which proceed by a sequential redox process.8
Next, we monitored the photoreaction of 1a with 2a by GC-MS
because isolation of the primary products without an aqueous
work-up was not possible due to the high boiling point of NMP.
GC-MS analyses indicate that the reaction mixture includes
hexamethyldisiloxane and 3a0 (see Table 1 for the structure of
3a0). This result shows that the trimethylsilyl group was captured
by adventitious water8,10 and 3a0 is the primary product in the
reaction system. Separately, we carried out the reaction of 1a
with 2a in the presence of a small amount of water (NMP/H2O =
25/1), where 3a was obtained in 86% yield. This result indicates
that the additional water did not affect the yield of g-lactam.
Based on the experimental results, the reactions are considered
to proceed via a reaction pathway similar to the previously reported
sequential redox pathway, as shown in Scheme 3.8 At first, single
electron oxidation of a-silyl secondary amines 1 by a photo-excited
catalyst (*cat) occurs. Then, a-aminoalkyl radicals (A) are formed
along with generation of trimethylsilyl cations.10 The trimethylsilyl
cation is captured by adventitious water in the reaction system
to give hexamethyldisiloxane and protons. Addition of A to
a,b-unsaturated carbonyl compounds 2 affords the corresponding
radical intermediates (B). The reduction of B13 by a reduced catalyst
(catꢀ)14 and subsequent protonation give g-aminocarbonyl com-
pounds (C) as primary products. Subsequently, base-mediated
In summary, we have developed a novel reaction system for
generation and utilization of a-aminoalkyl radicals derived from
secondary amines. The a-aminoalkyl radicals were successfully
applied toward addition to a,b-unsaturated carbonyl compounds
and subsequent cyclization into nitrogen heterocycles such as
g-lactams and pyrroles. We believe that the method described
here provides a useful approach for syntheses of various nitrogen
heterocycles, which are useful in pharmacological science.
Further investigations on scope of substrates and mechanistic
details are now under way.
We thank the Funding Program for Next Generation World-
Leading Researchers (GR025) and Grants-in-Aid for Scientific
Research (Nos. 26288044, 26620075, 26105708, and 26870120)
from the Japan Society for the Promotion of Science (JSPS) and the
Ministry of Education, Culture, Sports, Science and Technology of
Japan (MEXT).
Notes and references
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Stuttgart, 2005, p. 647; (b) D. StC. Black, in Science of Synthesis, ed.
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2 (a) B. Nay, N. Riache and L. Evanno, Nat. Prod. Rep., 2009, 26, 1044;
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3 (a) S. Das, J. S. D. Kumar, K. Shivaramayya and M. V. George, J. Photochem.
Photobiol., A, 1996, 97, 139; (b) S. Das, J. S. D. Kumar, K. Shivaramayya and
M. V. George, J. Chem. Soc., Perkin Trans. 1, 1995, 1797; (c) R. C. Cookson,
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5 A. G. Fallis and I. M. Brinza, Tetrahedron, 1997, 53, 17543.
6 (a) J. Wang, P. Li, P. Y. Choy, A. S. C. Chan and F. Y. Kwong,
ChemCatChem, 2012, 4, 917; (b) D. Enders, C. Wang and
J. X. Liebich, Chem. – Eur. J., 2009, 15, 11058.
´
7 (a) D. Harakat, J. Pesch, S. Marinkovic and N. Hoffmann, Org.
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Biomol. Chem., 2006, 4, 1202; (b) A. Bauer, F. Westkamper,
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Scheme 2 One-pot syntheses of dihydropyrrole (6) and pyrroles (7a and 7b).
8902 | Chem. Commun., 2014, 50, 8900--8903
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