A cascade reaction consisting of Pictet-Spengler-type cyclization and Smiles rearrangement: Application to the synthesis of novel pyrrole-fused dihydropteridines

Article abstract of DOI:10.1021/ol0629364

(Chemical Equation Presented) Tandem Pictet-Spengler-type cyclization and Smiles rearrangement have been discovered in the synthesis of pyrimidine-fused heterocycles. The reaction of 4-chloro-5-pyrrol-1-ylpyrimidine amino aldehyde with an amine under an a

Full text of DOI:10.1021/ol0629364

ORGANIC
LETTERS
2007
Vol. 9, No. 5
765-767
A Cascade Reaction Consisting of
Pictet Spengler-Type Cyclization and
−
Smiles Rearrangement: Application to
the Synthesis of Novel Pyrrole-Fused
Dihydropteridines
Jinbao Xiang, Lianyou Zheng, Feng Chen, Qun Dang, and Xu Bai*
The Center for Combinatorial Chemistry and Drug DiscoVery, Jilin UniVersity,
75 Haiwai Street, Changchun, Jilin 130012, P. R. China
xbai@jlu.edu.cn
Received December 4, 2006
ABSTRACT
Tandem Pictet
The reaction of 4-chloro-5-pyrrol-1-ylpyrimidine amino aldehyde with an amine under an acidic condition yielded the Pictet
cyclization product diazepine, which readily underwent Smiles rearrangement to give a novel pyrrolo[1,2-f]pteridine derivative.
−
Spengler-type cyclization and Smiles rearrangement have been discovered in the synthesis of pyrimidine-fused heterocycles.
−Spengler-type
Pyrimidine moiety, as a structural component of several key
biomolecules, has been widely employed in the design of
biologically active agents. Its fused bicyclic analogues,
pteridines, have also been reported to exhibit a variety of
biological activities and constitute the backbones of several
marketed drugs. For example, methotrexate (MTX) is used
as an antitumor agent and triamterene as a diuretic. In
addition, some pteridine derivatives exhibit potent inhibitory
activity against biological targets such as dihydrofolate
reductase,1 adenosine kinase,2 neuronal nitric oxide synthase,3
cAMP-specific phosphodiesterase,4 mycobacterial FtsZ,5 and
hepatitis C virus NS5B RNA-dependent RNA polymerase.6
Although there are a few examples of pteridine scaffolds,
few reports exist describing the synthesis of pyrrolo[1,2-f]-
pteridines.7
As a part of our ongoing interest in novel pyrimidine-
fused heterocycles,7b,8 we sought efficient methodologies to
construct novel fused heterocyles. Tandem reactions are
efficient strategies in organic synthesis, since they enable
(4) Merz, K. H.; Marko, D.; Regiert, T.; Reiss, G.; Frank, W.; Eisenbrand,
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Bai, X. Chem. J. Chinese UniV. 2006, 27, 1869.
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Chem. 2005, 7, 474. (b) Liu, J.; Dang, Q.; Wei, Z.; Zhang, H.; Bai, X. J.
Comb. Chem. 2005, 7, 627. (c) Yang, J.; Che, X.; Dang, Q.; Wei, Z.; Bai,
X. Org. Lett. 2005, 7, 1541. (d) Fu, R.; Xu, X.; Dang, Q.; Bai, X. J. Org.
Chem. 2005, 70, 10810. (e) Che, X.; Zheng, L.; Dang, Q.; Bai, X.
Tetrahedron 2006, 62, 2563. (f) Zheng, L.; Xiang, J.; Dang, Q.; Guo, S.;
Bai, X. J. Comb. Chem. 2005, 7, 813. (g) Zheng, L.; Xiang, J.; Dang, Q.;
Guo, S.; Bai, X. J. Comb. Chem. 2006, 8, 381. (h) Liu, J.; Dang, Q.; Wei,
Z.; Shi, F.; Bai, X. J. Comb. Chem. 2006, 8, 410. (i) Fu, R.; Xu, X.; Dang,
Q.; Chen, F.; Bai, X. Org. Lett. 2007, 9, 571-574.
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McCormack, J. J. J. Med. Chem. 1977, 20, 1215. (b) Rosowsky, A.; Cody,
V.; Galitsky, N.; Fu, H.; Papoulis, A. T.; Queener, S. F. J. Med. Chem.
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10.1021/ol0629364 CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/06/2007

multiple transformations via a series of cascade reactions.9
Consequently, they have found wide application in the prepa-
ration of complex molecules. For example, several interesting
nitrogen-containing natural products have been synthesized
using tandem reactions.9b,10 The success of tandem reactions
provides the impetus to new synthetic strategies that combine
existing reactions into a single operationsnew tandem
reactions. Pictet-Spengler cyclization reactions8e-g,11 have
been widely used for C-C bond formation to build various
nitrogen ring systems. Another important reaction often
reported in the synthesis of condensed heterocyclic systems
is the Smiles rearrangement.12
Scheme 2. Tandem Pictet-Spengler-Type Cyclization/Smiles
Rearrangement
We envisioned that a tandem Pictet-Spengler-type cy-
clization and Smiles rearrangment may be feasible with
potential application to the synthesis of pyrrolo[1,2-f] peridine
derivatives outlined in Scheme 1. Reaction of 4-chloro-5-
Scheme 1. Design of a Tandem Pictet-Spengler Cyclization/
Smiles Rearrangement
pine 4.10a was formed. Diazepine 4.10a was not stable and
quickly underwent Smiles rearrangement to produce the
expected pteridine derivative 5.10a at ambient temperature.
The initial Pictet-Spengler-type product could be intercepted
if the reaction time was kept short. Thus, after 12 min of
reaction between aldehyde 3a and p-toluidine, a careful
isolation afforded 26% of diazepine 4.10a, whereas the same
reaction but with prolonged reaction time to ensure complete
conversion of diazepine 4.10a gave the desired pteridine
5.10a in 58% yield. To unambiguously identify the structures
of these products, X-ray structures of both products 4.10a
and 5.10a (Figure 1) were obtained. These experiments
pyrrol-1-ylpyrimidine amino aldehyde and an amine via a
Pictet-Spengler-type cyclization reaction provides a diaze-
pine intermediate which then readily undergoes a Smiles
rearrangement to give the six-membered ring dihydropteri-
dine analogue.
To test the feasibility of the above design, compound 2a
was prepared and reacted with p-toluidine as depicted in
Scheme 2 (R1 ) Bn, R2 ) p-Me-Ph). Clauson-Kaas
reaction13 of 4,6-dichloro-5-aminopyrimidine and 2,5-di-
methoxytetrahydrofuran gave 4,6-dichloro-5-pyrrol-1-ylpy-
rimidine 1 in good yield. Nucleophilic substitution of
pyrimidine 1 by N-benzylglycinol afforded 2a in excellent
yield. Amino alcohol 2a was then oxidized under conditions
of the Parikh-Doering oxidation14 to give the corresponding
aldehyde 3a, which readily cyclized to give hydroxydiazepine
6a during purification on a silica gel column. However, when
crude aldehyde 3a was treated with p-toluidine under Pictet-
Spengler cyclization reaction conditions, the desired diaze-
Figure 1. X-ray structures of compounds 4.10a and 5.10a.
exemplified the feasibility of the proposed novel sequence
of Pictet-Spengler-type cyclization/Smiles rearrangement
and its utility in the synthesis of novel heterocycles.
The scope of this new cascade reaction was investigated
with pyrimidines 3 (a, R1 ) Bn or b, R1 ) Me) and various
amines, and the results are summarized in Table 1.
(9) (a) Winkler, J. D. Chem. ReV. 1996, 96, 167. (b) Parsons, P. J.;
Penkett, C. S.; Shell, A. J. Chem. ReV. 1996, 96, 195. (c) Denmark, S. E.;
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2001, 57, 2065.
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Chem., Int. Ed. 2006, 45, 620.
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Dinsmore, C. J.; Zartman, C. B.; Baginsky, W. F.; O’Neill, T. J.; Koblan,
K. S.; Chen, I.-W.; McLoughlin, D. A.; Olah, T. V.; Huff, J. R. Org. Lett.
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As evidenced in Table 1, moderate to good yields (21-
62%) of the desired product 5 could be obtained considering
766
Org. Lett., Vol. 9, No. 5, 2007

Pictet-Spengler-type cyclization product, while an o-MeO
substitution did generate the desired product 5.6a (entry 6).
These results suggest that the Smiles rearrangement stage
of this tandem reaction is sensitive to electronic effects at
the ortho position. This reaction appears to tolerate various
functional groups in the aromatic amine, such as electron-
donating groups (m- and p-methyl or -methoxy) and electron-
withdrawing groups (m- and p-halo or -nitro).
In conclusion, a novel methodology involving tandem
Pictet-Spengler-type cyclization and Smiles rearrangement
was reported. The utility of this reaction sequence has been
demonstrated by the synthesis of novel pyrrolo[1,2-f]pteridine
derivatives. This new method complements existing pteridine
chemistry, thus allowing access of additional new pteridine
analogues. Exploration of this new strategy in the synthesis
of other interesting molecules is currently underway.
Table 1. Synthesis of 5,6-Dihydropyrrolo[1,2-f]pteridinesa
entry
R2
product
timeb (h)
yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Med
n-Bu
Bn
cyclohexyl
i-Pr
5.1a
5.2a
5.3a
5.4a
5.5a
5.6a
5.7a
4.8a
48
20
30
42f
48f
96
16
18
18
16
18
20
20
20
22
14f
24f
72
20
96
30 (12)e
32
34
35 (5)e
42
61
40
86
31
58
55
64
38
62
50
32
43
o-MeO-Ph
p-MeO-Ph
o-Me-Ph
m-Me-Ph
p-Me-Ph
Ph
o-Cl-Ph
m-Cl-Ph
p-Cl-Ph
p-F-Ph
o-NO2-Ph
p-NO2-Ph
BnOg
5.9a
5.10a
5.11a
4.12a
5.13a
5.14a
5.15a
4.16a
5.17a
5.18a
5.10b
5.14b
Acknowledgment. This work was supported by grants
from the China Natural Science Foundation (20572032 and
20232020) and Changchun Discovery Sciences, Ltd.
21
51
36
p-Me-Ph
p-Cl-Ph
Supporting Information Available: Experimental de-
1
tails, H and 13C NMR, and LC-MS-ELSD spectra for key
a Reactions were conducted at room temperature unless otherwise
specified. b Reaction time from 3 to 5 or 4. c Overall yield (three steps)
from alcohol 2 and isolated via flash chromatography. d Methylamine
alcohol solution (27-32%) was used. e The numder in parentheses repre-
sents the isolated yield of hydroxydiazepine 6. f Refluxed. g O-Benzylhy-
droxylamine hydrochloride was used in absence of TFA.
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0629364
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that these yields represent overall yields for three reactions.
Both aromatic and aliphatic amines can be employed for this
tandem reaction. The yields were higher with an aromatic
amine (entries 6, 7, 9-11, 13-15, 17, 19, and 20) compared
to the ones with an aliphatic or benzyloxy amine. On the
other hand, a substituent at the meta position of the aromatic
amine led to lower yields of the final product 5 (entries 9
and 13) compared to its corresponding para-substituted
analogue (entries 10 and 14). Substitution at the ortho
position of the aniline (entries 8, 12, and 16) only led to the
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Org. Lett., Vol. 9, No. 5, 2007
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