α-amination of nitrogen heterocycles: Ring-fused aminals

Article abstract of DOI:10.1021/ja077473r

Aromatic aminoaldehydes react with cyclic amines to produce ring-fused aminals under thermal conditions. This process is applied to two-step syntheses of the quinazolinone alkaloids deoxyvasicinone and rutaecarpine. Copyright

Full text of DOI:10.1021/ja077473r

Published on Web 12/15/2007
r-Amination of Nitrogen Heterocycles: Ring-Fused Aminals
Chen Zhang, Chandra Kanta De, Rudrajit Mal, and Daniel Seidel*
Department of Chemistry and Chemical Biology, Rutgers, The State UniVersity of New Jersey,
Piscataway, New Jersey 08854
Received September 27, 2007; E-mail: seidel@rutchem.rutgers.edu
Table 1. Variation of the Aminoaldehyde Componenta
The direct functionalization of nitrogen heterocycles offers an
attractive entry to important molecular targets that might otherwise
require lengthy synthetic procedures.1 Here we report a new
R-functionalization reaction of cyclic amines that proceeds without
the involvement of transition metals or other additives (eq 1). In
this redox-neutral condensation reaction, a C-H bond R to a ring
nitrogen is replaced by a C-N bond, concomitant with the
formation of a new ring system.2,3 This thermally promoted reaction
between an aminobenzaldehyde (e.g., 1) and a cyclic amine results
in the formation of a ring-fused aminal (e.g., 2) and thus provides
convenient access to this structural motif.4 The reaction conditions
resemble those used in Friedla¨nder reactions of aminobenzaldehydes
and ketones to form quinolines, in which pyrrolidine is frequently
used as a base promoter.5,6 To our knowledge, aminals have not
previously been reported as side products of these reactions.
A mechanistic hypothesis for aminal formation involves proton
loss from an intermediate iminium ion A upon rearrangement of
the adjacent π-system. The resulting quinoidal intermediate B is
envisioned to undergo a 1,6-hydrogen transfer to form dipolar
intermediate C, which ultimately goes on to final product 2.7,8
Alternatively, intermediate A could be deprotonated by excess
pyrrolidine resulting in the direct formation of intermediate C.9,10
Tables 1 and 2 summarize the scope of this reaction. A range of
aminobenzaldehydes was allowed to react with pyrrolidine (3 equiv)
in ethanol solution at reflux (Table 1). Aminobenzaldehydes with
differing substitution patterns and electronic properties proved to
be suitable substrates, providing products in good yields. Electron-
poor aminobenzaldehydes are particularly reactive, whereas more
electron-rich substrates (Table 1, entries 11 and 12) give products
in good yields after somewhat prolonged reaction times. Hetero-
cyclic aminoaldehydes (Table 1, entries 13 and 14) give ring-fused
aminals in excellent yields. A substituent on the nitrogen atom of
the aminobenzaldehyde is well-tolerated (Table 1, entry 15).
Aminobenzaldehydes were allowed to react with various cyclic
amines (Table 2).11 Piperidine shows diminished reactivity com-
pared with pyrrolidine and provided only 6% yield of product 3
when the reaction was carried out under the original conditions.
Significant improvement was achieved by conducting the reaction
in a sealed tube at 140 °C, leading to the formation of 3 in 67%
yield. The analogous seven- and eight-membered aza-cycles gave
aminals 4 and 5 in 77 and 60% yield, respectively. Amines
possessing benzylic hydrogen atoms R to the ring nitrogen are
particularly good substrates (Table 2, entries 4-6). Reaction of
a Reactions were run on a 1 mmol scale using 3 equiv of pyrrolidine in
ethanol solution (0.25 M) at reflux. b As partial transesterification occurred
in ethanol solution, the reaction was run in a sealed tube in methanol solution
at 100 °C. c The reaction was run in a sealed tube in ethanol solution at
140 °C.
2-methylpyrrolidine with aminobenzaldehyde 1c gave a mixture
of regioisomers. The more substituted regioisomer 9a was the major
product of this reaction, while the minor regioisomer 9b was
obtained as a 2:1 mixture of diastereomers. This latter observation
combined with the notably increased reactivity of benzylic amines
suggests that a 1,6-hydride shift may be operating.8 Further
mechanistic insight is provided by the observation that the reaction
of aminobenzaldehyde 1c with proline gave the same product as
the corresponding reaction with pyrrolidine under identical condi-
tions (Table 2, entry 8). It is well-established that reactions of
aldehydes with proline and other N-alkylated aminoacids form 1,3-
dipolar intermediates upon decarboxylation.12 This finding is
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10.1021/ja077473r CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Variation of the Amine Componenta
are aimed at developing a more detailed mechanistic understanding
of this reaction as well as expanding the scope and exploring related
processes.
Acknowledgment. Financial support from Merck & Co. and
Rutgers, The State University of New Jersey, is gratefully acknowl-
edged. We thank Dr. Tom Emge for crystallographic analysis.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds including X-ray structures
of 2c and 3. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
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a Reactions were run on a 1 mmol scale in ethanol solution (0.25 M) at
reflux. b The reaction was run in a sealed tube in isopropanol solution at
140 °C. c The reaction was run in a sealed tube in ethanol solution at
140 °C.
consistent with the notion that 1,3-dipoles are likely intermediates
in this reaction.
Aminals are found in a number of natural products.13 In addition,
aminals with the general structure 2 represent reduced versions of
quinazolinone alkaloids, compounds that have attracted significant
attention in the synthetic community due to their diverse array of
biological activities.14,15 Selective oxidation of ring-fused aminals
provides rapid access to this structural motif (eqs 4 and 5). In one
additional step, two steps from commercially available materials,
deoxyvasicinone16 and rutaecarpine17 were obtained in 82 and 61%
yield, respectively.
(14) For a review on quinazolinone alkaloids, see: Mhaske, S. B.; Argade, N.
P. Tetrahedron 2006, 62, 9787-9826.
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none alkaloids: Koretskaya, N. I.; Utkin, L. M. Zh. Obshch. Khim. 1958,
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Liu, J.-F.; Ye, P.; Sprague, K.; Sargent, K.; Yohannes, D.; Baldino, C.
M.; Wilson, C. J.; Ng, S.-C. Org. Lett. 2005, 7, 3363-3366. (c) Lee, E.
S.; Park, J.-G.; Jahng, Y. Tetrahedron Lett. 2003, 44, 1883-1886. (d)
Hamid, A.; Elomri, A.; Daich, A. Tetrahedron Lett. 2006, 47, 1777-
1781. (e) Bowman, W. R.; Elsegood, M. R. J.; Stein, T.; Weaver, G. W.
Org. Biomol. Chem. 2007, 5, 103-113.
(17) For selected examples of recent syntheses of rutaecarpine, see: (a)
Mohanta, P. K.; Kim, K. Tetrahedron Lett. 2002, 43, 3993-3996. (b)
Mhaske, S. B.; Argade, N. P. Tetrahedron 2004, 60, 3417-3420. (c)
Harayama, T.; Hori, A.; Serban, G.; Morikami, Y.; Matsumoto, T.; Abe,
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P.; Sivappa, R. Tetrahedron Lett. 2004, 45, 997-999 and also refs 15c-e.
In summary, we have introduced a simple and efficient method
for the synthesis of ring-fused aminals by a mild functionalization
of nitrogen heterocycles. While some aminals are direct precursors
of natural products, others should prove useful for preparing
analogues of these biologically active materials. Ongoing studies
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