Reaction of 2-bromomethylazoles and TosMIC: A domino process to azolopyrimidines. Synthesis of core tricycle of the variolins alkaloids

Article abstract of DOI:10.1021/ol0062087

(matrix presented) A new reaction of N-protected 2-bromomethylazoles and tosylmethyl isocyanide (TosMIC) leading to the preparation of azolopyrimidines is described. This domino sequence was used to synthesize the pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine core of alkaloids variolins from 4-methoxy-2-methylpyrrolo[2,3-b]pyrimidine in two steps.

Full text of DOI:10.1021/ol0062087

ORGANIC
LETTERS
2000
Vol. 2, No. 21
3253-3256
Reaction of 2-Bromomethylazoles and
TosMIC: A Domino Process to
Azolopyrimidines. Synthesis of Core
Tricycle of the Variolins Alkaloids
Javier Mendiola, Jose´ M. Minguez, Julio Alvarez-Builla, and Juan J. Vaquero*
Departamento de Qu´ımica Orga´nica, UniVersidad de Alcala´,
28871-Alcala´ de Henares, Madrid, Spain
juanjose.Vaquero@uah.es
Received June 15, 2000
ABSTRACT
A new reaction of N-protected 2-bromomethylazoles and tosylmethyl isocyanide (TosMIC) leading to the preparation of azolopyrimidines is
described. This domino sequence was used to synthesize the pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine core of alkaloids variolins from 4-methoxy-
2-methylpyrrolo[2,3-b]pyrimidine in two steps.
In 1994, the structure of the variolins, a family of alkaloids
isolated from the sponge Kirtpatrickia Varialosa Kirkpatrick
(Scheme 1), was published.1,2 In addition to being one of
the rare examples of natural products containing the pyrrolo-
[1,2-c]pyrimidine system (the other one example is the
alkaloid hinckdentine3 isolated from the bryozoan Hinck-
sinoflustra denticulata4), it was claimed that variolins have
antiviral and antiproliferative activity against P388 leukemia
cells.2
synthesis of the pyrrolo[1,2-c]pyrimidine nucleus (9),6,7
a
system incorporated in these alkaloids. The method rests in
an efficient condensation of 2-pyrrole carbaldehydes 7 with
tosylmethyl isocyanide (TosMIC) followed by reductive
desulfonilation (Scheme 2).
Our synthetic strategy to synthesize variolins is shown
in antithetic format in Scheme 1 and is centered on the
construction of the key tricyclic precursor 5. We now report
a study in which the pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine
core of variolins and related fused systems are prepared
in a domino reaction from 2-bromomethylazoles 4 and
TosMIC.
A total synthesis of these alkaloids has not yet been
published;5 thus we devised a strategy for their synthesis that
is in part based on our previous reports concerning to a new
Although the cyclocondensation reactions of aldehydes and
TosMIC have been particularly useful in oxazole synthesis,8
we have found that 2-pyrrolecarboxaldehydes reacted with
TosMIC9 in the presence of 1,8-diazabicyclo[5.4.0]undec-
* To whom correspondence should be addressed. FAX: 34-91-8854660.
(1) Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.; Munro, M. H.
G.; Parkin, S.; Hope, H. Tetrahedron 1994, 50, 3987.
(2) Trimurtuhu, G.; Faulkner, D. J.; Perry, N. B.; Ettouati, L.; Litaudon,
M.; Blunt, J. W.; Munro, M. H. G.; Jameson, G. B. Tetrahedron 1994, 50,
3993.
(3) Blackman, A. J.; Hambley, T. W.; Picker, R.; Taylor, W. C.;
Thirasana, N.; Tetrahedron Lett. 1987, 28, 5561.
(4) Billimoria, A. D.; Cava, M. P. J. Org. Chem. 1994, 59, 6777.
(5) For previous reports on variolins synthesis, see: (a) Alvarez, M.;
Ferna´ndez, D.; Joule, J. A. Synthesis 1999, 4, 615. (b) Alvarez, M.;
Ferna´ndez, D.; Joule, J. A. J. Chem. Soc., Perkin Trans. 1 1999, 215.
(6) M´ınguez, J. M.; Vaquero, J. J.; Garc´ıa Nav´ıo, J. L.; Alvarez-Builla,
J. Tetrahedron Lett. 1996, 37, 4263.
(7) M´ınguez, J. M.; Vaquero, J. J.; Garc´ıa Nav´ıo, J. L.; Alvarez-Builla,
J.; Castan˜o, O.; Andre´s, J. L. J. Org. Chem. 1999, 64, 7888.
(8) For references, see: Grigg, R.; Lansdell, M. I. Thornton-Pett, M.
Tetrahedron 1999, 55, 2025.
10.1021/ol0062087 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/26/2000

Scheme 1
Scheme 2
7-ene (DBU), furnishing 3-tosylpyrrolo[1,2-c]pyrimidines 8
in yields up to 60%. On the basis of these results, at the
outset it was envisaged that the intermediate10 5 could be
formed by means of a simple condensation of the appropriate
7-azaindolecarboxaldehyde 3a and TosMIC. This condensa-
tion, however, failed to afford the expected tosyl derivative
5 either under the conditions previously employed for 8 or
under other tested conditions, with the oxazole derivatives
10 being formed not only with 3a but also with the
2-indolecarboxaldehyde 3b, a much more π-excessive system
than its 7-aza analogue (Scheme 2).
Consequently, the cyclocondensation process was tested
with the corresponding N-protected 2-bromomethylazaindole
4 and TosMIC under basic conditions in the hope that the
product of the nucleophilic substitution was stable enough
for further transformation into the corresponding tricyclic
system after deprotection. Initially, N-Boc carbamate was
chosen as the protecting group, but results showed there was
difficulty in the subsequent bromination step. Using the
phenylsulfonyl as the protecting group, the N-protected
7-azaindole was easily brominated with NBS under ionic
and radical conditions, affording the dibromo derivative 11
in a 60% yield. This result was very convenient because with
our strategy the introduction of the 5-substituents present in
variolins requires a 5-halo derivative as a precursor. Reaction
of 11 with TosMIC, however, resulted in mixtures of the
mono- and dialkylated derivatives, the latter being the main
reaction product. When the methyl carbamate was used as
the protecting group, the 3-bromo-2-bromomethylpyrrolo-
[2,3-b]pyridine derivative 4a was obtained in a 82% yield.
Unexpectedly, when 4a was treated with TosMIC, a clean
reaction afforded the 5-bromopyrido[3′,2′:4,5]pyrrolo[1,2-
c]pyrimidine 3-carboxylic acid methyl ester 6a in a 42%
yield, which was improved to 65% by conducting the
reaction in a two-phase medium [CH2Cl2/NaOH (15%)] in
the presence of a phase transfer catalyst (TBAI). Thus, the
same procedure also allowed us to prepare the key tricycle
intermediate 6b in just two steps from the known 4-methoxy-
7-methylpyrrolo[2,3-b]-pyridine.11
Other 2-bromomethylazoles12 were studied in an attempt
to demonstrate the generality of the process,13 with bicyclic
and tricyclic systems 6c-i being obtained in yields shown
in Table 1. In general, yields of the cyclocondensation
(9) (a) Saikachi, H.; Kitigawa, T.; Sasaki, H.; Van Leusen, A. M. Chem.
Pharm. Bull. 1979, 27, 793. (b) Saikachi, H.; Kitigawa, T.; Sasaki, H.; Van
Leusen, A. M. Chem. Pharm. Bull. 1982, 30, 4199.
(10) For the only previous synthesis of this system, see: Capuano, L.;
Schrepfer, H. J.; Mu¨ller, K.; Roos, H. Chem. Ber. 1974, 107, 929.
(11) Girgis, N. S.; Larson, S. B.; Robins, R. K.; Cottam, H. B. J.
Heterocycl. Chem. 1989, 26, 317.
(12) Bromomethylazoles were prepared from commercially available
methylazoles according to a literature procedure: Nagarathnam, D. Synthesis
1992, 743.
(13) Typical procedure: A mixture of the bromomethyl derivative 4
(1.0 mmol), TosMIC (0.22 g, 1.1 mmol), and TBAI (0.08 g, 0.2 mmol) in
CH2Cl2 (7 mL) and aqueous sodium hydroxide (7 mL) was stirred at the
temperature indicated in Table 1. After the appropriate time (20 min-2 h),
the reaction mixture was poured into water and extracted with CH2Cl2. The
organic phase was washed with saturated NaCl solution, dried (Na2SO4),
and concentrated under reduced pressure, providing a crude product that
was purified by flash chromatography (silica gel, hexane/EtOAc) to yield
compounds 6a-i.
3254
Org. Lett., Vol. 2, No. 21, 2000

Table 1. Azolopyrimidines 6 from 2-Bromomethylazoles and TosMIC
a Reactions were conducted in the two-phase system CH2Cl2/NaOH/TBAI except for 6h, which was carried out in THF/triethylamine.
products were moderate to good except for 6c, obtained in
a 27% yield (entry 3), and 6h (entry 8), which was formed
along with a multicomponent mixture. The highly fluorescent
nature of all these derivatives allowed us to identify traces
of 6h in the reaction mixture using thin-layer chromatogra-
phy. The lower yield obtained for 6c when compared with
6a and 6b is probably related to the lower nucleophilicity
of the pyrrole nitrogen in 6c.
Org. Lett., Vol. 2, No. 21, 2000
3255

substitution of TosMIC to the bromomethylazole followed
by intramolecular transfer of the methoxycarbonyl protecting
group. Subsequent cyclization and 1,2-elimination of tolu-
enesulfonate would afford the desired azolopyrimidine
derivative (Scheme 3).
Scheme 3
In summary, an unusual and efficient domino reaction of
2-bromomethyl-7-azaindoles and TosMIC is reported, thus
providing a straightforward preparation of the pyrido[3′,2′:
4,5]pyrrolo[1,2-c]pyrimidine ring system and opening a
simple route for the synthesis of the natural alkaloids,
variolins. This process is also useful for other 2-bromo-
methylazoles with azolopyrimidines being obtained in mod-
erate to good yields.
Acknowledgment. The authors acknowledge support of
this work from the Comisio´n Interministerial de Ciencia y
Tecnolog´ıa (CICYT) through the project SAF98-0093 and
a grant from the Ministerio de Educacio´n y Cultura (J.M.).
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 4 and 6.
This material is available free of charge via the Internet at
http:\\pubs.acs.org.
The mechanism hypothesized to account for this unusual
cyclocondensation reaction involves initial nucleophilic
OL0062087
3256
Org. Lett., Vol. 2, No. 21, 2000