Organic Letters
Letter
Scheme 3
ASSOCIATED CONTENT
* Supporting Information
■
S
Synthesis of compounds 1a−x, 2, 3, 4a−e, experimental details,
additional spectra, and X-ray crystal structure details for 1a, 1p,
and 4a (CIF). This material is available free of charge via the
AUTHOR INFORMATION
Corresponding Author
■
*Tel: 886-4-2359-7613. Fax: 886-4-2359-0426. E-mail: yang@
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Ministry of Science and Technology of the
Republic of China, Taiwan, for financially supporting this
research under Contract No. MOST 102-2113-M-029-004-MY2.
marin and thiophenecarbaldehyde) to afford the intermediate 13.
The subsequent hydrolysis of the iminium 13 gives the free amine
14. Final intramolecular nucleophilic acyl substitution to open
the lactone ring on the coumarin moiety by the amine nearby
furnishes the product lactam 4a. Since at least 3 equiv of
thiophenecarbaldehyde are needed for the formation of the
iminium 13, this mechanism supports the observation that the
formation of 4a is favored when a higher concentration of
aldehyde is present in the reaction. It is worth mentioning that
this readily available pyrrolizinone 4 can presumably serves as a
precursor for efficient synthesis of some naturally occurring and
biologically important pyrrolizidine alkaloids (necine bases).13
Our studies demonstrate that the azomethine ylide inter-
mediates, generated via microwave-promoted decarboxylative
coupling of proline and aromatic aldehyde, can undergo proton-
mediated isomerization to the enamine 7 or 9. The enamine can
then proceed to two different products via two different
pathways, depending upon the concentration and size of the
aldehyde present in the reaction. First, the enamine 7 can
undergo conjugate addition to 8 and subsequent cyclization to
yield pyrano[2,3-b]pyrrole 1. Second, the enamine 9 can
condense with aldehyde and then followed by conjugate addition
to 12 to afford pyrrolizinone 4. Pyrano[2,3-b]pyrrole 1 is formed
exclusively when 2 equiv of aldehyde is present in the reaction,
whereas pyrrolizinone 4 is favored predominantly when 4 equiv
of thiophene or furan carbaldehyde is present. Thus, we have
discovered a new mode of reactivity for azomethine ylides other
than the well-documented [3 + 2] cycloaddition and
protonation/nucleophilic addition. This MCR synthetic strategy
represents one of the few methods of the preparation of α,β-
difunctionlized amines via decarboxylation of secondary α-amino
acids.14
REFERENCES
■
(1) (a) Strecker, A. Liebigs Ann. Chem. 1862, 123, 363. (b) Schonberg,
A.; Moubasher, R. Chem. Rev. 1952, 50, 261.
(2) For example, see: (a) Yan, Y.; Wang, Z. Chem. Commun. 2011,
9513. (b) Mao, H.; Wang, S.; Yu, P.; Lv, H.; Xu, R.; Pan, Y. J. Org. Chem.
2011, 76, 1167.
(3) Rizzi, G. P. J. Org. Chem. 1970, 35, 2069.
(4) For selected reviews, see: (a) Padwa, A., Ed. 1,3-Dipolar
Cycloaddition Chemistry; Wiley: New York, 1984; Vol. 1, p 817.
(b) Padwa, A., Ed. 1,3-Dipolar Cycloaddition Chemistry; Wiley: New
York, 1984; Vol. 2, p 704. (c) Padwa, A.; Pearson, W. H. Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles
and Natural Products; Wiley: Chichester, U.K., 2002; Vol. 59, p 940.
(d) Najera, C.; Sansano, J. M. Curr. Org. Chem. 2003, 7, 1105.
(e) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765. (f) Pandey, G.;
Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484.
(5) (a) Bi, H.-P.; Zhao, L.; Liang, Y.-M.; Li, C.-J. Angew. Chem., Int. Ed.
2009, 48, 792. (b) Bi, H.-P.; Chen, W.-W.; Liang, Y.-M.; Li, C.-J. Org.
Lett. 2009, 11, 3246.
(6) Bi, H.-P.; Teng, Q.; Guan, M.; Chen, W.-W.; Liang, Y.-M.; Yao, X.;
Li, C.-J. J. Org. Chem. 2010, 75, 783.
(7) For a recent review, see: Seidel, D. Org. Chem. Front. 2014, 1, 426.
(8) Zhang, C.; Seidel, D. J. Am. Chem. Soc. 2010, 132, 1798.
(9) (a) Lin, C. H.; Jhang, J. F.; Yang, D. Y. Org. Lett. 2009, 11, 4064.
(b) Lin, C. H.; Chen, J. R.; Yang, D. Y. J. Comb. Chem. 2010, 12, 119.
(c) Li, K. T.; Lin, Y. B.; Yang, D. Y. Org. Lett. 2012, 14, 1190.
(10) (a) Grigg, R.; Idle, J.; McMeekin, P.; Vipond, D. J. Chem. Soc.,
Chem. Commun. 1987, 49. (b) Zotova, N.; Franzke, A.; Armstrong, A.;
Blackmond, D. G. J. Am. Chem. Soc. 2007, 129, 15100.
(11) (a) Orsini, F.; Pelizzoni, F.; Forte, M.; Destro, R.; Gariboldi, P.
Tetrahedron 1988, 44, 519. (b) Zotova, N.; Franzke, A.; Armstrong, A.;
Blackmond, D. G. J. Am. Chem. Soc. 2007, 129, 15100.
(12) (a) Shi, D. Q.; Wang, Y. H.; Lu, Z. S.; Dai, G. Y. Synth. Commun.
2000, 30, 713. (b) Jin, T. S.; Zang, J. S.; Wang, A. Q.; Li, T. S. Synth.
Commun. 2005, 35, 2339. (c) Das, B.; Thirupathi, P.; Reddy, K. R.;
Ravikanyh, B.; Nagarapu, L. Catal. Commun. 2007, 8, 535. (d) Ilangovan,
A.; Muralidharan, S.; Sakthivel, P.; Malayappasamy, S.; Karuppusamy, S.;
Kaushik, M. P. Tetrahedron Lett. 2013, 54, 491.
In summary, we have reported a metal- and catalyst-free
synthesis of multifunctionalized pyrano[2,3-b]pyrrole, pyrano-
[2,3-b]pyridine, and pyrrolizinone derivatives via a pseudo-four-
component coupling of proline/pipecolic acid, 2 or 4 equiv of
aldehyde, and 1,3-diketone in 1,4-dioxane under microwave
irradiation. We also found that the product distributions of 1 and
4 can be controlled by varying the concentration and size of the
aromatic aldehyde added into the reaction. Further applications
of this MCR to the synthesis of some biologically active natural
products as well as potential functional materials are currently
underway.
(13) (a) Liddell, J. R. Nat. Prod. Rep. 2002, 19, 773. (b) Dreger, M.;
Stanisławska, M.; Krajewska-Patan, A.; Mielcarek, S.; Mikołajczak, P. L.;
Buchwald, W. Herba Polym. 2009, 55, 127.
(14) During the preparation of this manuscript, a “redox-neutral α,β-
difunctionalization of cyclic amines” was reported; see: Chen, W.; Kang,
Y. K.; Wilde, R. G.; Seidel, D. Angew. Chem., Int. Ed. 2014, 53, 5179.
5693
dx.doi.org/10.1021/ol5027574 | Org. Lett. 2014, 16, 5690−5693