Reaction of bromomethylazoles and tosylmethyl isocyanide. A novel heterocyclization method for the synthesis of the core of marine alkaloids variolins and related azolopyrimidines

Article abstract of DOI:10.1021/jo0358168

A novel and efficient synthesis of the pyrido[3′,2′:4,5] pyrrolo[1,2-c]pyrimidine system, the heterocyclic core of the variolin family of marine alkaloids, is described. The route involves the reaction of 3-bromo-2-(bromomethyl)pyrrolo[2,3-b]pyridine and tosylmethyl isocyanide (TosMIC) under phase-transfer conditions. This unprecedented reaction was also used to synthesize a series of new methoxycarbonyl azolopyrimidines by reaction of TosMIC with bromomethylindoles, bromomethylbenzimidazole, and bromomethylpyrazole. Hydrolysis and decarboxylation of 5-bromo-7- methoxycarbonylpyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine obtained by this heterocyclization process and installation of the pyrimidine moiety in the C5 position open an alternative approach to complete a total synthesis of variolin B.

Full text of DOI:10.1021/jo0358168

Rea ction of Br om om eth yla zoles a n d Tosylm eth yl Isocya n id e. A
Novel Heter ocycliza tion Meth od for th e Syn th esis of th e Cor e of
Ma r in e Alk a loid s Va r iolin s a n d Rela ted Azolop yr im id in es
J avier Mendiola, Alejandro Baeza, J ulio Alvarez-Builla, and J uan J . Vaquero*
Departamento de Qu´ımica Orga´nica, Universidad de Alcala´, 28871-Alcala´ de Henares, Madrid, Spain
juanjose.vaquero@uah.es
Received December 15, 2003
A novel and efficient synthesis of the pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine system, the heterocyclic
core of the variolin family of marine alkaloids, is described. The route involves the reaction of
3-bromo-2-(bromomethyl)pyrrolo[2,3-b]pyridine and tosylmethyl isocyanide (TosMIC) under phase-
transfer conditions. This unprecedented reaction was also used to synthesize a series of new
methoxycarbonyl azolopyrimidines by reaction of TosMIC with bromomethylindoles, bromometh-
ylbenzimidazole, and bromomethylpyrazole. Hydrolysis and decarboxylation of 5-bromo-7-meth-
oxycarbonylpyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine obtained by this heterocyclization process and
installation of the pyrimidine moiety in the C5 position open an alternative approach to complete
a total synthesis of variolin B.
In tr od u ction
We previously reported a novel synthesis of pyrrolo-
[1,2-c]pyrimidine and some derivatives based on the
reaction of tosylmethyl isocyanide (TosMIC) with 2-pyr-
role carboxaldehydes.1 This method provided a simple
and efficient route to the target system, which could be
obtained in 40% overall yield (compared to 1% for the
previously reported procedure2).
This heterocyclic system, although rare in nature, is
present in the marine alkaloid hinckdentine (1)ssome
analogues of which have cataleptogenic activity.3,4 The
ring system is also present in the variolins, a family of
alkaloids isolated from the antarctic sponge Kirkpatrickia
varialosa, which have antitumor and antiviral activity5
(Figure 1).
These latter alkaloids, particularly variolin B (3), have
attracted the attention of several groups that have been
involved in the total synthesis of this alkaloid. All of the
approaches described to date involve the construction of
the pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine as one of the
key steps of the synthetic strategy. The first total
synthesis of variolin B was reported by Morris,6 who
F IGURE 1. Structure of hinckdentine and variolins.
prepared the highly functionalized core 8 in three steps
from the commercially available 2-methylthiopyrimidine
(5) (Scheme 1). Molina7 completed the synthesis of the
tricyclic system using a sequential approach. In this total
synthesis the 4-methoxypyridine (6) was converted into
the appropriate 7-azaindole by an indole synthesis in-
volving a nitrene insertion process. Subsequent formation
of the pyrimidine ring was achieved by a carbodiimide-
mediated cyclization process. In the most recently re-
ported total synthesis, Alvarez8 prepared the tricyclic
system from 4-methoxy-7-azaindole (7), which is func-
tionalized with an appropriate aminoethyl side chain,
followed by formation of the third ring with concomitant
* To whom correspondence should be addressed. Fax: 34-91-
8854660.
(1) M´ınguez, J . M.; Vaquero, J . J .; Garc´ıa Nav´ıo, J . L.; Alvarez-
Builla, J . Tetrahedron Lett. 1996, 37, 4263.
(2) Wong, J . L.; Brown, M. J .; Rapoport, H. J . Org. Chem. 1965, 30,
2398.
(3) Blackman, A. J .; Hambly, T. W.; Picker, K.; Taylor, W. C.;
Thirasasana, N. Tetrahedron Lett. 1987, 28, 5561.
(4) (a) Billimoria, A. D.; Cava, M. P. J . Org. Chem. 1994, 59, 6777.
(b) Liu, Y.; McWhorter, W. W. J . Am. Chem. Soc. 2003, 125, 4240.
(5) (a) Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J . W.; Munro,
M. H. G.; Parkin, S.; Hope, H. Tetrahedron 1994, 50, 3987. (b)
Trimurtuhu, G.; Faulkner, D. J .; Perry, N. B.; Ettouati, L.; Litaudon,
M.; Blunt, J . W.; Munro, M. H. G.; J ameson, G. B. Tetrahedron 1994,
50, 3993.
(7) Molina, P.; Fresneda, P. M.; Delgado, S. J . Org. Chem. 2003,
68, 489.
(8) Ahaidar, A.; Fernandez, D.; Danelon, G.; Cuevas, C.; Manza-
nares, I.; Albericio, F.; J oule, J . A.; Alvarez, M. J . Org. Chem. 2003,
68, 10020.
(6) Anderson, R. J .; Morris, J . C. Tetrahedron Lett. 2001, 42, 8697.
10.1021/jo0358168 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/29/2004
4974
J . Org. Chem. 2004, 69, 4974-4983

Reaction of Bromomethylazoles and Tosylmethyl Isocyanide
SCHEME 1. Syn th etic Str a tegies for th e Tr icyclic
Cor e of Va r iolin B
SCHEME 2
SCHEME 3
introduction of a protected amino group. Two syntheses
of deoxyvariolin B9 and several patents that focus on the
preparation of analogues of variolin B10 are also based
on these methodologies for the construction of the pyrido-
[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine system.
SCHEME 4
In the work described here we present a detailed
account of our studies on the synthesis of the heterocyclic
core of variolins.11 Our synthetic approach, which is
complementary to the efforts described to date, employs
a 2-bromomethyl-7-azaindole for the construction of the
pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine system through
an unprecedented reaction with TosMIC.12 The method
has been extended to different bromomethyl substituted
azoles and has allowed the preparation of a novel series
of heterocyclic systems.
Resu lts a n d Discu ssion
7-azaindole-2-carboxaldehyde (12) with TosMIC to afford
the expected 3-tosylpyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimi-
dine (13), which could subsequently be converted into the
desired variolin core by an apparently simple desulfony-
lation (Scheme 3).
The 7-azaindole-2-carboxaldehyde 12 was prepared by
a literature procedure.15 However, all attempts to prepare
the tricyclic compound 13 only afforded complex reaction
mixtures in which the oxazole derivative 17 could be
detected but could not be isolated presumably due to its
instability. When the 2-indolecarboxaldehyde (15)16 was
tested, the resulting undesired oxazole 1816 was also the
dominant product, despite the fact that indole 15 is a far
more electron-rich system than its 7-aza analogue 12
(Scheme 4).
The results described above seem to preclude the use
of our initial approach to tricycle 14, and so we decided
to examine the reaction of an N-protected 2-bromo-
methylazaindole with TosMIC under basic conditions in
the hope that the product of the nucleophilic substitution
would be sufficiently stable for further transformation
into the corresponding pyrido[3′,2′:4,5]pyrrolo[1,2-c]py-
rimidine derivative after deprotection.
Although the cyclocondensation reaction between al-
dehydes and TosMIC has proven to be particularly useful
in oxazole synthesis,13 we found that in the presence of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) the pyrrole NH
competes with the oxygen to furnish 3-tosylpyrrolo[1,2-
c]pyrimidines (10) in yields of up to 60% (Scheme 2). This
method allowed the synthesis of pyrrolo[1,2-c]pyrimidine
(11, R1 ) H) with a significant reduction in the number
of steps and constitutes the best reported procedure to
date for the synthesis of pyrrolo[1,2-c]pyrimidines.1,14
Given the ease of formation of the pyrrolo[1,2-c]-
pyrimidine nucleus, we envisaged a simple and straight-
forward strategy for the synthesis of the pyrido-
[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine system 14. The syn-
thesis would depend on an efficient condensation of
(9) (a) Anderson, R. J .; Morris, J . C. Tetrahedron Lett. 2001, 42, 311.
(b) Alvarez, M.; Ferna´ndez, D.; J oule, J . A. Tetrahedron Lett. 2001,
42, 315.
(10) (a) Mercedes, A.; Bleda, D.; Puentes, J . L. PCT Int. Appl. WO
02/12240 (C07D 471/14), Feb 14, 2002. (b) Morris, J . C.; Anderson, R.
J .; Remuin˜an, M.; Manzanares, I. Int. Appl. WO 02/04447 (C07D 471/
14), J anuary 2002. (c) Remuin˜an, M.; Gonzalez, J . J .; del Pozo, C.;
Francesch, A.; Cuevas, C.; Manzanares, I. PCT Int. Appl. WO 03/
006457 (C07D 401/06), J anuary 2003.
The route started from commercially available 7-aza-
indole 7a (Scheme 5). Treatment of 7a with phenylsul-
(11) Mendiola, J .; Minguez, J . M.; Alvarez-Builla, J .; Vaquero, J . J .
Org. Lett. 2000, 2, 3253.
(12) van Leusen, A. M.; Wildeman, J .; Oldenziel, O. H. J . Org. Chem.
1977, 42, 1153.
(13) Lamberth, C. J . Prakt. Chem. 1998, 3293.
(15) Desabre, E.; Coudret, S.; Meheust, C.; Me´rour, J .-Y. Tetrahe-
dron 1997, 53, 3637.
(14) Minguez, J . M.; Vaquero, J . J .; Alvarez-Builla, J .; Castan˜o, O.;
Andre´s, J . L. J . Org. Chem. 1999, 64, 7788.
(16) Saikachi, H.; Kitagawa, T.; Sasaki, H.; van Leusen, A. M. Chem.
Pharm. Bull. 1982, 30, 4199.
J . Org. Chem, Vol. 69, No. 15, 2004 4975

Mendiola et al.
SCHEME 5
SCHEME 6
fonyl chloride produced the protected azaindole 19a in
87% yield.15 This compound was then methylated (LDA/
THF/MeI) to give 20a in 96% yield.15 The attempted
selective bromination of 20a under radical conditions
[NBS/(BzO)2 or NBS/AIBN] afforded in all cases variable
mixtures of the desired 2-bromomethyl-7-azaindole, 3-bro-
mo-2-methyl-7-azaindole, and 3-bromo-2-bromomethyl-
7-azaindole depending of the conditions. A change in the
protecting group of the 7-azaindole (Boc and CO2Me)
afforded similar results. We therefore decided to promote
a sequential electrophilic and radical bromination to
obtain the dibromo compound 22a and use this azaindole
derivative as a good model to test the reaction with
TosMIC. The electrophilic bromination of 20 (NBS/CCl4,
rt) afforded the 3-bromo-7-azaindole 21a in 67% yield.
Subsequent radical bromination of 21a [NBS/(BzO)2]
gave the dibromo derivative 22a in 81% yield. The
reaction of 22a with TosMIC under phase transfer
conditions (TBAI/NaOH/CH2Cl2) to prevent the formation
of the disubstituted compound17 afforded the desired
product 23. Unfortunately the yield was only 37% in the
best case and unreacted starting materials and the
dialkylated derivative 24 (15%) were also isolated from
the reaction mixture. Both, 23 and 24 are unstable
compounds and all attempts to transform 23 into the
tricyclic intermediate 25 failed under the conditions for
deprotection because of decomposition of 23. We there-
fore considered the protection of 7a as a carbamate
hoping that removal of such a protecting group under
acidic conditions would preserve the stability of the
product, 2-methyl-7-azaindole. However, the introduction
of the methyl substituent on C-2 proved troublesome on
both the N-Boc- and N-methyl carbamate 7-azaindoles
with decomposition or deprotection observed during the
attempted methylation under conditions similar to those
employed for 20a .
carbonyl chloride and subsequent radical bromination
(Scheme 6). Having obtained azaindole 28a , we proceeded
to test its reaction with TosMIC under the phase transfer
conditions employed to optimize the formation of 23.
Bromomethyl compound 28a reacted cleanly, but 30a
was not formed under these reaction conditions. A new,
yellow fluorescent product formed and was unambigu-
ously identified as 5-bromopyrido[3′,2′:4,5]pyrrolo[1,2-c]-
pyrimidine-7-carboxylic acid methyl ester (29a , 65%
yield) (Scheme 6).
This result was unexpected but was also very conve-
nient in terms of our ultimate goalsthe synthesis of the
variolin core and variolins themselves. Indeed, the syn-
thesis of the tricyclic compound 29a could be easily
adapted to prepare a key intermediate by simply intro-
ducing the hydroxy functionality at C-4 in the starting
azaindole 7a .
The mechanism proposed to account for the formation
of 29a involves initial nucleophilic substitution of TosMIC
on the bromomethypyrrole followed by intramolecular
transfer of the methoxycarbonyl protecting group. Sub-
sequent attack of the pyrrole nitrogen on the isocyanide
Finally, the desired intermediate 28a was obtained by
deprotection of 21a followed by reaction with methoxy-
(17) van Leussen, A. M.; Bouma, R. J .; Possel, O. Tetrahedron Lett.
1975, 40, 3487.
4976 J . Org. Chem., Vol. 69, No. 15, 2004

Reaction of Bromomethylazoles and Tosylmethyl Isocyanide
SCHEME 7
under the phase transfer conditions. For example, in 28b
the heterocyclization process clearly competes with depro-
tection atom and the deprotected compound is isolated
as the main reaction product. On the other hand, in the
reaction of 28a significant amounts of the deprotected
compound were not observed. This difference in yield is
associated with the presence of the electron-withdrawing
substituent (4-choro) in 28b which presumably favors the
deprotection of this substrate. A similar effect of the
electron-withdrawing group on the yield is observed on
comparing substrates 28c and 28e. In the cases of
benzimidazole and pyrazole, their more electron-deficient
nature when compared with indole would account for the
lower yields of 29f and 29g when compared with 29c.
With some of these substrates, we also observed that the
temperature of the reaction has a significant effect on
the deprotection and azolopyrimidine yield. For example,
at room temperature 29a is isolated in only 40-45%
yield. However, in the case of bromomethylindoles 28c-e
(Table 1, entries 3-5) the temperature had little effect
on the yield of the reaction (29c-e).
Although this heterocyclization method allowed the
preparation of different bicyclic and tricyclic heterocycles,
it seems limited to azole chemistry. For example, the
attempted reaction of TosMIC with N-Boc-protected
2-bromomethylpyrrolidine18 resulted in the formation of
complex reaction mixtures. We also proved that the use
of a bulkier carbamate such as Boc in those substrates
that gave low or moderate yields of the azolopyrimidine
did not improve the yields. As an example, the N-Boc-
protected benzimidazole 28h afforded the tricyclic de-
rivative 29h in 40% yield.
The method described above is very advantageous in
the context of our synthetic interest in variolins and can
give the heterocyclic core of these alkaloids in a cascade
process. However, any attempt at the total synthesis of
such a compound would involve the appropriately sub-
stituted pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine hetero-
cycle, the removal of the methyl ester group, the func-
tionalization of the C5 position bearing the bromine atom
with an appropriate pyrimidine ring, and the introduc-
tion of the amino group in C9 position. For this purpose,
the tricyclic derivatives 29a was considered a good model
to test all these heterocyclic transformations.
First, we studied the formation of the corresponding
carboxylic acid 31a from 29a and the subsequent decar-
boxylation reaction. The ester hydrolysis was carried out
under three different sets of basic conditions: K2CO3/
MeOH-H2O, KOH/MeOH, and LiOH/THF-H2O. The
pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine substrate (29a )
was hydrolyzed under all the conditions tested, but it
decomposes to a great extent in KOH/MeOH. With either
K2CO3 or LiOH at room temperature, 31a was obtained
in excellent yield (Scheme 9).
Initial attempts to promote decarboxylation of the
highly insoluble acid 31a under standard conditions
resulted in either no reaction (Cu/quinoline) or extensive
decomposition (KOH/MeOH, NaOH/toluene). When the
substrate was adsorbed on silica gel and heated under
microwave irradiation 31a was recovered unaltered at
group would lead to cyclization and 1,2-elimination of
p-toluenesulfinic acid would afford the azolopyrimidine
derivative 29a (Scheme 7).
The success of this unusual and unprecedented het-
erocyclization led us to study the general scope of this
reaction. Therefore, in addition to the 7-azaindole 28a ,
a range of different azoles were prepared in an attempt
to explore the behavior of different heterocycles in this
cyclization reaction. Two 7-azaindoles, three indoles,
3-methylpyrazole, benzimidazole, and imidazole were
transformed into the bromomethylazoles 28b-h by fol-
lowing the general procedure shown in Scheme 8. Each
azaindole was protected as a benzenesulfonamide, meth-
ylated, brominated under electrophilic conditions, depro-
tected and finally protected as a carbamate to afford
substituted azaindoles 27a ,b. Commercially available
methyl indoles 7c-e were transformed into 27c-e by
protection as methyl carbamates followed by electrophilic
bromination. Radical bromination of indole and azaindole
derivatives afforded the corresponding dibromocom-
pounds 28a -e. Commercially available pyrazole 7f,
benzimidazole 7g, and imidazole 7h were protected as
methyl carbamates and brominated under radical condi-
tions to give substrates 28f,g,i.
Table 1 shows the various bromomethylazoles 28a -i
prepared according to the conditions detailed in Scheme
8. All these substrates were then reacted with TosMIC
under the same conditions as for 28a and these reactions
produced the corresponding azolopyrimidines 29b-i. The
results summarized in Table 1 indicate that the hetero-
cyclization process proceeded in moderate or good yields
-the only exception being the bromomethylimidazole 28i
(Table 1, entry 8), which decomposed extensively under
phase transfer conditions. A range of different homoge-
neous conditions were tested for this substrate but only
in THF/Et3N were traces of the imidazopyrimidine 29i
detected.
(18) (a) Kawara, A.; Taguchi, T. Tetrahedron Lett. 1994, 47, 8805.
(b) Mori, M.; Washioka, Y.; Urayama, T.; Yoshiura, K.; Chiba, K.; Ban,
Y. J . Org. Chem. 1983, 48, 4058.
In all cases, the isolated yield seems to be closely
related to the resistance of the substrate to deprotection
J . Org. Chem, Vol. 69, No. 15, 2004 4977

Mendiola et al.
SCHEME 8
low power and decomposition was observed upon increas-
ing the power or irradiation time. On the basis of our
previous results in the synthesis of pyrrolo[1,2-a]pyrim-
idines,1,14 decarboxylation was finally achieved by heating
(12 h) in diphenyl ether (250 °C). However, under these
conditions the yields were moderate or low (23-35%).
Longer reaction times resulted in lower yields due to
decomposition and formation of debrominated products.
Similar results were found with the pyrimido[1,6-a]indole
29c although in this case better yields were obtained.
This likely reflects the greater stability of 29c and 31c
to basic conditions and heating.
Our strategy for the introduction of the pyrimidine
moiety in the C5 position initially focused on the prepa-
ration of a boronic acid or stannane from 29a and a
subsequent Suzuki or Stille reaction. However, all our
efforts to prepare the organometallics failed, likely by the
instability of the organolithium intermediate and/or the
organometallics themselves. We therefore considered the
coupling of 29a and an appropriate stannane or boronic
acid to achieve the required C5 substitution on this
pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine. We proved that
29a reacted with (3-methylthiopyrimidinyl)trimethyltin19
in the presence of Pd(PPh3)4 producing the cross-coupling
product 33 in a 63% yield when the reaction was carried
out in toluene/MeOH (20:1).
1,2-dibromoethane or 1,2-dibromotetrachlorethane in
THF at -78 °C. The only compounds isolated from this
attempted functionalization of the C9 position were
dimers 35 and 36. The mixture 35/36 is slowly oxidized
on standing or with NBS, yielding 36 in a 64% yield.
Con clu sion s
Variolins are a class of marine alkaloids characterized
by a highly functionalized pyrido[3′,2′:4,5]pyrrolo[1,2-c]-
pyrimidine system. The heterocyclic core of these alka-
loids has been prepared by reaction of 3-bromo-2-
bromomethylpyrrolo[2,3-b]pyridine and tosylmethyl iso-
cyanide (TosMIC). This efficient and novel reaction was
also used to synthesize a new series of methoxycarbony-
lazolopyrimidines. The 5-bromo-7-methoxycarbonylpy-
rido[3′,2′:4,5]pyrrolo[1,2-c]-pyrimidine obtained by this
heterocyclization process was subjected to hydrolysis and
decarboxylation and functionalized at the C5 position
with an appropriately substituted pyrimidine ring. These
heterocyclic transformations are key elements to com-
plete a formal or total synthesis of variolin B, a target
that is currently one of our goals.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried under Ar and
using solvents that were dried by routine procedures. Col-
Finally, we turned our attention to the C9 position.
Based on our earlier studies on the reactivity of the
pyrrolo[1,2-c]pyrimidine,14 we attempted the metalation
of this position and subsequent quenching with a source
of electrophilic bromine. After many experiments we were
unable to obtain the desired 1-bromo derivative 34 using
different lithium bases (LDA, t-BuLi, and LHMDS) and
umn chromatography was performed using silica gel (60 F254
,
70-200 µm) as the stationary phase. All melting points are
uncorrected. IR spectra were determined on films. NMR
spectra were obtained at 200, 300, or 500 MHz (1H) and 50 or
75 MHz (13C). Chemical shifts are reported in ppm relative to
tetramethylsilane. The 8-chloropyrrolo[2,3-b]pyridine 7b, 7-aza-
indole-2-carboxaldehyde 12, and 2-methyl-1-phenylsulfonylpyr-
rolo[2,3-b]piridine 20a was synthesized according to the
previously reported procedures.
(19) (a) Majeed, A. J .; Antonsen, Ø.; Benneche, T.; Undheim, K.
Tetrahedron 1989, 45, 993. (b) Alvarez, M.; Ferna´ndez, D.; J oule, J .
A. Tetrahedron Lett. 2001, 42, 315.
P r epar ation of 3-Br om o-2-m eth yl-1-ph en ylsu lfon ylpyr -
r olo[2,3-b]p yr id in e (21a ). To a solution of 20a (7.14 g, 26.3
4978 J . Org. Chem., Vol. 69, No. 15, 2004

Reaction of Bromomethylazoles and Tosylmethyl Isocyanide
TABLE 1. Azolop yr im id in es 29 fr om 2-Br om om eth yla zoles 28 a n d TosMIC
a
TosMIC (1.1 mmol), Bu4N+I- (0.2 mmol), CH2Cl2, aq NaOH.
mmol) in CCl4 (250 mL) was added NBS (4.68 g, 26.3 mmol),
and the mixture was stirred at room temperature for 12 h.
Afterward, the succinimide was removed by filtration, the
solution was concentrated to dryness, and the residue was
chromatographed on a silica gel column using hexane/ethyl
acetate (9:1) as eluent to give 21a (6.18 g, 67% yield). Mp:
134-135 °C (white solid). IR (KBr) νmax: 2902, 1638, 1583,
1561, 1375, 1183 cm-1. 1H NMR (200 MHz, CDCl3) δ: 2.75 (s,
3H); 7.20 (dd, 1H, J ) 7.7, 4.8 Hz); 7.60-7.40 (m, 3H); 7.69
(dd, 1H, J ) 7.7, 1.6 Hz); 8.18-8.10 (m, 2H); 8.42 (dd, 1H, J
) 4.8, 1.6 Hz). 13C NMR (50 MHz, CDCl3) δ: 14.3; 97.4; 119.5;
121.6; 127.2; 127.6; 129.0; 134.0; 135.3; 138.9; 144.9; 147.4.
MS (EI) m/z (relative intensity): 352 (12); 350 (M+, 12); 288
(22); 286 (22); 211 (31); 209 (32); 77 (100). Anal. Calcd for
C14H11BrN2O2S: C, 47.88; H, 3.16; N, 7.98. Found: C, 47.84;
H, 3.17; N, 7.95.
3-Br om o-2-br om om eth yl-2-m eth yl-1-ph en ylsu lfon ylpyr -
r olo[2,3-b]p yr id in e (22a ). A mixture of 21a (0.70 g, 1.99
mmol), 4 mg of benzoyl peroxide, and NBS (2 mmol) in 20 mL
of CCl4 was heated at reflux temperature for 2.5 h. Then the
reaction mixture was allowed to cool to room temperature and
filtered and the solvent evaporated under reduced pressure.
The residue was chromatographed on silica gel using hexane/
EtOAc (9:1) as eluent yielding 0.69 g of 22a (81%) as a yellow
solid. Mp: 149-150 °C. IR (KBr) νmax: 1394, 1378, 1297, 1177,
1088 cm-1 1H NMR (300 MHz, CDCl3) δ: 5.21 (s, 2H); 7.25
.
(dd, 1H, J ) 7.9, 5.1 Hz); 7.52-7.47 (m, 2H); 7.61-7.57 (m,
1H); 7.78 (dd, 1H, J ) 7.9, 1.5 Hz); 8.45-8.40 (m, 2H); 8.49
J . Org. Chem, Vol. 69, No. 15, 2004 4979

Mendiola et al.
SCHEME 9
(dd, 1H, J ) 5.1, 1.5 Hz). 13C NMR (50 MHz, CDCl3) δ: 22.8;
101.0; 119.9; 120.8; 126.0; 128.5; 128.8; 128.9; 133.0; 134.4;
138.2; 146.7. EM (EI) m/z (relative intensity): 430 (M+, 2);
351 (13); 349 (13); 141 (48); 77 (100). Anal. Calcd for
mmol) was added dropwise. The mixture was stirred at 0 °C
for 15 min and then allowed to warm to room temperature.
The resulting mixture was filtered over Celite and washed with
CH2Cl2 and the solvent evaporated under reduced pressure.
The residue was chromatographed on silica gel. N-Phenylsul-
fonyl azaindoles were isolated using hexane/EtOAc as eluent.
C
14H10Br2N2O2S: C, 39.10; H, 2.34; N, 6.51. Found: C, 39.16;
H, 2.32; N, 6.50.
Rea ction of 22a w ith TosMIC. To a mixture of 22a (340
mg, 0.79 mmol), TosMIC (154 mg, 0.79 mmol), and TBAI (58
mg, 0.15 mmol) in CH2Cl2 (15 mL) a 30% aqueous solution of
NaOH (15 mL) was added, and the resulting mixture was
vigorously stirred at -10 °C for 2 h. Then the reaction mixture
was diluted with water and extracted with CH2Cl2, the organic
phase waswashed with a saturated solution of NaCl and dried
(Na2SO4), and the solvent was evaporated under reduced
pressure. The residue was chromatographed on silica gel to
provide 159 mg (37%) of 23 (hexane/EtOAc, 7:3) and 94 mg
(15%) of 24 (hexane/EtOAc, 1:1).
Meth yla tion of P yr r olo[2,3-b]p yr id in es. N-Phenylsul-
fonyl azaindoles (5.0 mmol) were dissolved in THF (25 mL)
under an argon atmosphere, and the solution was cooled to
-30 °C. Then LDA (10.0 mmol, 2 M, THF) was added dropwise
and the mixture stirred at -30 °C for 40 min. After this time,
methyl iodide (30 mmol) was added, and the mixture was
allowed to warm to room temperature and stirred at room
temperature for 3-16 h. The reaction mixture was quenched
with NH4Cl, extracted with CH2Cl2, and dried (Na2SO4) and
the solvent evaporated under reduced pressure. The residue
was chromatographed on silica gel using variable mixtures of
hexane,EtOAc as eluent to give the corresponding methyl
N-phenylsulfonyl azaindoles.
Electr op h ilic Br om in a tion . Gen er a l P r oced u r e. A mix-
ture of the azole (5 mmol) and NBS (5 mmol) was stirred in
CCl4 (50 mL) at room temperature for 12 h. Then the
succinimide was filtered off and washed with CCl4, and the
combined organic phases wereevaporated under reduced pres-
sure. The residue was chromatographed on silica gel using
hexane/EtOAc as eluent to give pure brominated compounds.
Dep r otection of P yr r olo[2,3-b]p yr id in es. To a solution
of the N-phenylsulfonyl azaindole (2.15 mmol) in MeOH/H2O
(170 mL, 3:1 v/v) was added K2CO3 (6.45 mmol) and the
mixture heated to reflux temperature. The resultant solution
was stirred for 7 h at reflux temperature. Afterward, the
solution was allowed to cool to room temperature. Methanol
was removed in vacuo, and the resulting suspension was
partioned between water and ethyl acetate. Organic layers
were combined and dried (Na2SO4). After filtration, the filtrate
3-Br om o-2-(2′-isocya n yl-2′-t osylet h yl)-1-p h en ylsu lfo-
n ylp yr r olo[2,3-b]p yr id in e (23). Unstable pale yellow solid.
1
Mp: 160-163 °C dec. H NMR (300 MHz, CDCl3) δ: 2.49 (s,
3H); 3.91 (dd, 1H, J ) 14.4 Hz, J ) 11.1 Hz); 4.08 (dd, 1H, J
) 14.4 Hz, J ) 3.7 Hz); 5.41 (dd, 1H, J ) 11.1 Hz, J ) 3.7
Hz); 7.27 (dd, 1H, J ) 8.1, 4.8 Hz); 7.29-7.27 (m, 1H); 7.59-
7.44 (m, 3H); 7.62-7.55 (m, 1H); 7.78 (dd, 1H, J ) 8.1, 1.6
Hz); 7.97 (d, 2H, J ) 8.2 Hz); 8.09 (d, 2H, J ) 7.3 Hz); 8.48
(dd, 1H, J ) 4.8, 1.6 Hz).
1,3-Bis(3-br om o-1-ph en ylsu lfon ylpyr r olo[2,3-b]pyr idin -
2-yl)-2-isocya n yl-2-tosylp r op a n e (24). Brown powder. Un-
stable at room temperature. 1H NMR (300 MHz, CDCl3) δ:
2.47 (s, 3H); 4.27 (d, 2H, J ) 15.5 Hz); 4.48 (d, 2H, J ) 15.5
Hz); 7.16 (dd, 2H, J ) 8.0, 4.7 Hz); 7.47-7.30 (m, 8H); 7.70
(dd, 2H, J ) 8.0, 1.4 Hz); 7.89 (d, 4H, J ) 8.2 Hz); 8.12 (m,
2H); 8.39 (dd, 2H, J ) 4.7, 1.4 Hz).
Gen er a l P r oced u r es for t h e P r ep a r a t ion of 27a -h .
P r ot ect ion of P yr r olo[2,3-b]p yr id in es 7a ,b a s N-Ben -
zen esu lfon a m id e. To a solution of the azole 7a ,b20 (5.0 mmol)
and benzyltriethylammoniun chloride (0.13 mmol) in CH2Cl2
(10 mL) was added powdered NaOH (15.62 mmol). The
solution was cooled to 0 °C, and phenylsulfonyl chloride (6.25
(20) Clark, B. A. J .; Patrick, J . J . Chem. Soc., Perkin Trans. 1 1974,
2270.
4980 J . Org. Chem., Vol. 69, No. 15, 2004

Reaction of Bromomethylazoles and Tosylmethyl Isocyanide
was concentrated to dryness and the residue was chromato-
graphed on a silica gel column using hexane/EtOAc (1:1) as
eluent.
1-Meth oxycar bon yl-2-m eth ylben zim idazole (27g). Chro-
matography CH2Cl2/acetone 9:1 (0.43 g, 96%). Mp: 122-124
°C (pale yellow solid). IR (KBr) νmax: 1758, 1636, 1457, 1355,
1210 cm-1 1H NMR (200 MHz, CDCl3) δ: 2.79 (s, 3H); 4.06
.
P r otection a s N-Meth ylca r ba m a tes. Gen er a l P r oce-
d u r e for Azoles 27a -g,i. LiHMDS in THF (2.61 mmol, 2.6
mL, 1 M) was added to a solution of the azole (2.35 mmol) in
dry THF (8 mL) under argon at -78 °C, and the mixture was
allowed to warm to room temperature over a period of 2 h.
The mixture was cooled again to -78 °C, methyl chloroformate
(0.22 mL, 2.61 mmol) was added dropwise, stirring was
continued for 2 h at -78 °C, and then the reaction was allowed
to warm to room temperature. The mixture was treated with
NH4Cl, extracted with ethyl acetate, and the combined layers
were washed with brine and dried (Na2SO4). The solvent was
evaporated, and the crude product was chromatographed on
a silica gel column using hexane/EtOAc as eluent.
(s, 3H); 7.30-7.23 (m, 2H); 7.63 (dd, 1H, J ) 7.1, 2.0 Hz); 7.85
(dd, 1H, J ) 6.0, 2.2 Hz). 13C NMR (50 MHz, CDCl3) δ: 18.1;
54.1; 108.8; 114.6; 119.1; 124.3; 132.6; 142.0; 150.9; 153.0. MS
(EI) m/z (relative intensity): 191 (M+ + 1, 100); 147 (18). Anal.
Calcd for C10H10N2O2: C, 63.15; H, 5.30; N, 14.73. Found: C,
63.11; H, 5.32; N, 14.80.
2-Meth yl-1-m eth oxyca r bon ylim id a zole (27i). Chroma-
tography CH2Cl2/acetone 9:1 (0.17 g, 51% yield, pale yellow
1
oil). H NMR (200 MHz, CDCl3) δ: 2.49 (s, 3H); 3.84 (s, 3H);
6.67-6.69 (m, 1H); 7.17-7.19 (M, 1H). MS (EI) m/z (rela-
tive intensity): 82 (100), 81 (47), 54 (34). Anal. Calcd for
C6H8N2O2: C, 51.42; H, 5.75; N, 19.99. Found: C, 51.15; H,
5.37; N, 19.81.
3-Br om o-1-m et h oxyca r b on yl-2-m et h ylp yr r olo[2,3-b]-
p yr id in e (27a ). Chromatography hexane/EtOAc 6:4 (0.56 g,
89% yield). Mp: 114-115 °C (white solid). IR (KBr) νmax: 1732,
1564, 1446, 1394, 1314, 1257 cm-1. 1H NMR (300 MHz, CDCl3)
δ: 2.66 (s, 3H); 4.10 (s, 3H); 7.23 (dd, 1H, J ) 7.7, 4.6 Hz);
7.76 (dd, 1H, J ) 7.7, 1.5 Hz); 8.43 (dd, 1H, J ) 4.6, 1.5 Hz).
13C NMR (50 MHz, CDCl3) δ: 14.4; 54.0; 96.6; 119.0; 121.4;
127.7; 135.4; 144.5; 146.7; 150.8. MS (EI) m/z (rela-
tive intensity): 271 (98); 269 (M+ + 1, 100). Anal. Calcd for
2-Meth yl-1-ter t-bu toxyca r bon ylben zym id a zole (27h ).
2-Methylbenzimidazole (503 mg, 3.81 mmol) was dissolved in
20 mL of CH2Cl2, and triethyamine (0.5 mL, 3.81 mmol),
(dimethylamino)pyridine (0.38 mmol), and Boc2O (7.62 mmol)
were added to the solution. Water (20 mL) was added, and
the organic phase was washed with brine and dried (Na2SO4).
The organic phase was filtered and concentrated under
reduced pressure yielding 0.88 g of 2-methyl-N-tert-butoxy-
carbonylbenzymidazole. 99% yield. Mp: 275-278 °C dec (pale
yellow solid). IR (KBr) νmax: 1751, 1561, 1453, 1352, 1095, 748
cm-1. 1H NMR (300 MHz, CDCl3) δ: 1.66 (s, 9H); 2.77 (s, 3H);
C
10H9BrN2O2: C, 44.63; H, 3.77; N, 10.41. Found: C, 44.61;
H, 3.36; N, 10.38.
3-Br om o-4-ch lor o-1-m eth oxycar bon yl-2-m eth ylpyr r olo-
[2,3-b]p yr id in e (27b). Chromatography hexane/EtOAc 8:2
(0.55 g, 77% yield). Mp: 146-148 °C (white solid). IR (KBr)
7.26-7.23 (m, 2H); 7.62-7.59 (m, 1H); 7.87-7.84 (m, 1H). 13
C
NMR (75 MHz, CDCl3) δ: 17.5; 27.1; 84.2; 113.7; 118.2; 122.9;
123.0; 131.9; 141.1; 147.9; 152.1. MS (ES) m/z (relative
intensity) 233 (M + H+, 100); 255 (M + Na+, 42). Anal. Calcd
for C13H16N2O2: C, 67.22; H, 6.94; N, 12.06. Found: C, 67.20;
H, 6.95; N, 12.05.
ν
max: 1734, 1575, 1550, 1440, 1376, 1285, 1190 cm-1. 1H NMR
(200 MHz, CDCl3) δ: 2.62 (s, 3H); 4.19 (s, 3H); 7.20 (d, 1H, J
) 5.3 Hz); 8.24 (d, 1H, J ) 5.3 Hz). 13C NMR (50 MHz, CDCl3)
δ: 14.5; 54.5; 94.2; 115.9; 120.5; 128.8; 137.0; 141.3; 142.2;
144.8 MS (EI) m/z (relative intensity): 305 (18); 303 (M++1,
18); 167 (100). Anal. Calcd for C10H8BrClN2O2: C, 39.57; H,
2.66; N, 9.23. Found: C, 39.51; H, 2.68; N, 9.24.
Ra d ica l Br om in a tion . Gen er a l P r oced u r e for Azoles
28a -i. In a typical procedure, powdered NBS (1.78 g, 10 mmol)
and benzoyl peroxide (20 mg) were added to a solution of the
N-methyl carbamate protected azole (10 mmol) in CCl4 (100
mL), and the mixture was stirred and heated at reflux
temperature. The succinimide formed was filtered off, and the
solvent was evaporated under reduced pressure. The residue
was chromatographed on a silica gel column to yield pure
compounds 28a -i (yields are referred to the radical bromi-
nation step).
3-Br om o-1-m eth oxycar bon yl-2-m eth ylin dole (27c). Chro-
matography hexane/EtOAc 9:1 (0.48 g, 92% yield). Mp:
1
75-77 °C (lit.21 mp 75-76 °C). H NMR δ: 2.65 (s, 3H); 4.09
(s, 3H); 7.28-7.34 (m, 2H); 7.43 (m, 1H); 8.08 (m, 1H).
3,6-Dibr om o-5-m eth oxy-1-m eth oxyca r bon ylca r bon yl-
2-m eth ylin d ole (27d ). Chromatography hexane/EtOAc 9:1
(0.67 g, 76%). Mp: 136-137 °C (white solid). IR (KBr) νmax
:
1736, 1464, 1435, 1365, 1210, 1109 cm-1. H NMR (200 MHz,
CDCl3) δ: 2.53 (s, 3H); 3.88 (s, 3H); 3.96 (s, 3H); 6.81 (s, 1H);
8.19 (s, 1H). 13C NMR (50 MHz, CDCl3) δ: 14.7; 53.7; 56.1;
99.2; 99.7; 108.5; 119.6; 128.1; 128.4; 135.0; 151.0; 152.1. MS
(EI) m/z (relative intensity): 379 (42); 377 (M+, 86); 375 (43);
63 (32); 59 (100). Anal. Calcd for C12H11Br2NO3: C, 38.23; H,
2.94; N, 3.71. Found: C, 38.30; H, 2.97; N, 3.68.
1
3-Br om o-2-br om om eth yl-1-m eth oxyca r bon ylp yr r olo-
[2,3-b]p yr id in e (28a ). Chromatography hexane/EtOAc 9:1
(3.17 g, 91% yield). Mp: 147-148 °C (yellow solid). IR (KBr)
1
ν
max: 1739, 1576, 1436, 1402, 1319, 1255 cm-1. H NMR (300
MHz, CDCl3) δ: 4.05 (s, 3H); 4.97 (s, 2H); 7.20 (dd, 1H, J )
7.9, 4.8 Hz); 7.75 (dd, 1H, J ) 7.9, 1.6 Hz); 8.45 (dd, 1H, J )
4.8, 1.6 Hz). 13C NMR (50 MHz, CDCl3) δ: 23.5; 54.7; 100.4;
119.7; 121.0; 128.3; 133.8; 147.0; 147.3; 150.2. MS (EI) m/z
(relative intensity): 351 (39); 349 (M+ + 1, 80); 347 (41); 269
(99); 267 (100). Anal. Calcd for C10H8Br2N2O2: C, 34.52; H,
2.32; N, 8.05. Found: C, 34.60; H, 2.32; N, 8.01.
5-Ch lor o-1-m et h oxyca r b on yl-2-m et h ylin d ole (27e).
Chromatography hexane/EtOAc 8:2 (0.42 g, 59%). Mp: 49-50
°C (white solid). IR (KBr) νmax: 1738, 1459, 1371, 1317, 1210,
1
1094, 1069 cm-1. H NMR (200 MHz, CDCl3) δ: 2.59 (s, 3H);
4.04 (s, 3H); 6.25 (s, 1H); 7.16 (dd, 1H, J ) 8.9, 2.1 Hz); 7.37
(d, 1H, J ) 2.1 Hz); 7.97 (d, 1H, J ) 8.9 Hz). 13C NMR (50
MHz, CDCl3) δ: 16.6; 53.4; 107.6; 116.3; 118.9; 123.1; 128.2;
130.6; 134.5; 139.0; 152.0. MS (EI) m/z (relative intensity): 226
(34); 224 (M+ + 1, 100). Anal. Calcd for C11H10ClNO2: C, 59.07;
H, 4.51; N, 6.26. Found: C, 59.00; H, 4.50; N, 6.28.
3-Br om o-2-b r om om et h yl-4-ch lor o-1-m et h oxyca r b on -
ylp yr r olo[2,3-b]p yr id in e (28b). Chromatography hexane/
EtOAc 8:2 (2.47 g, 65% yield). Mp: 160-161 °C (yellow solid).
IR (KBr) νmax: 1735, 1618, 1560, 1438, 1381, 1284 cm-1 1H
.
NMR (300 MHz, CDCl3) δ: 4.17 (s, 3H); 5.06 (s, 2H); 7.26 (d,
1H, J ) 5.3 Hz); 8.37 (d, 1H, J ) 5.3 Hz). MS (EI) m/z (relative
intensity): 385 (32); 384 (11); 383 (M+ + 1, 75); 305 (31); 303
(100); 301 (74). Anal. Calcd for C10H7Br2ClN2O2: C, 31.41; H,
1.84; N, 7.32. Found: C, 31.32; H, 1.84; N, 7.34.
3-Br om o-2-b r om om et h yl-1-m et h oxyca r b on ylin d ole
(28c). Chromatography hexane/EtOAc 95:5 (3.33 g, 96% yield).
Mp 119-120 °C (lit.21 mp 118-119 °C). 1H NMR (300 MHz,
CDCl3) δ: 4.11 (s, 3H); 5.05 (s, 2H); 7.30-7.35 (m, 1H);
7.37-7.44 (m, 1H); 7.50-7.53 (m, 1H); 8.08-8.11 (m, 1H).
2-Br om om eth yl-3,6-d ibr om o-5-m eth oxy-1-m eth oxyca r -
bon ylin d ole (28d ). Chromatography hexane/EtOAc 98:2 (0.91
4-Br om o-1-m eth oxycar bon yl-3,5-dim eth ylpyr azole (27f).
Chromatography CH2Cl2/acetone 9:1 (0.53 g, 96%); mp 102-
104 °C (white solid). IR (KBr) νmax 1749, 1438, 1374, 1347,
1297, 1064 cm-1 1H NMR (200 MHz, CDCl3) δ 2.24 (s,3H);
.
2.50 (s,3H); 4.00 (s,3H). 13C NMR (50 MHz, CDCl3) δ 11.9; 12.3;
53.9; 100.1; 141.3; 148.9; 150.4 MS (EI): m/z (relative in-
tensity) 233 (M+ + 1, 6); 189 (100); 187 (99). Anal. Calcd for
C7H9BrN2O2: C, 36.07; H, 3.89; N, 12.02. Found: C, 36.08; H,
3.87; N, 12.05.
(21) Nagarathnam, D. Synthesis 1992, 743.
g, 20% yield). Mp: 175-176 °C (yellow solid). IR (KBr) νmax
:
J . Org. Chem, Vol. 69, No. 15, 2004 4981

Mendiola et al.
1
1738, 1616, 1440, 1362, 1290, 1214 cm-1. H NMR (300 MHz,
1.2 Hz); 8.61 (dd, 1H, J ) 4.6, 1.4 Hz); 9.55 (d, 1H, J ) 1.2
Hz). 13C NMR (50 MHz, CDCl3) δ: 53.1; 85.0; 116.0; 121.7;
122.0; 128.2; 130.3; 136.3; 138.0; 139.8; 145.1; 164.8. MS (EI)
m/z (relative intensity): 306 (99); 304 (M+,100); 249 (43); 248
(40); 247 (44); 246 (36). Anal. Calcd for C12H8BrN3O2: C, 47.08;
H, 2.63; N, 13.73. Found: C, 47.13; H, 2.62; N, 13.76.
CDCl3) δ: 3.96 (s, 3H); 4.11 (s, 3H); 5.02 (s, 2H); 6.93 (s, 1H);
8.33 (s, 1H). 13C NMR (50 MHz, CDCl3) δ: 24.4; 54.1; 56.2;
100.3; 103.3; 111.0; 120.2; 127.7; 129.2; 133.1; 150.1; 152.6.
MS (EI) m/z (relative intensity): 457 (8); 455 (M+, 8), 378 (48),
376 (100), 374 (47), 59 (59). Anal. Calcd for C12H10Br3NO3: C,
31.61; H, 2.21; N, 3.07. Found: C, 31.59; H, 2.21; N, 3.08.
3-Br om o-2-b r om om et h yl-5-ch lor o-1-m et h oxyca r b on -
ylin d ole (28e). Chromatography hexane/EtOAc 95:5 (3.74 g,
98% yield). Mp: 138-139 °C (white solid). IR (KBr) νmax: 2953,
5-Br om o-4-ch lor o-7-m eth oxyca r bon ylp yr id o[3′,2′:4,5]-
p yr r olo[1,2-c]p yr im id in e (29b). Chromatography hexane/
EtOAc 8:2 (0.09 g, 27% yield). Mp: 195-196 °C (yellow solid).
1
IR (KBr) νmax: 2924, 1713, 1444, 1356, 1260, 1098. H NMR
1
1742, 1637, 1439, 1375, 1207, 1072 cm-1. H NMR (300 MHz,
(300 MHz, CDCl3) δ: 4.06 (s, 3H); 7.55 (d, 1H, J ) 5.0 Hz);
8.33 (s, 1H); 8.47 (d, 1H, J ) 5.0 Hz); 9.56 (s, 1H). 13C NMR
(50 MHz, CDCl3) δ: 53.2; 116.2; 121.1; 122.5; 123.9; 125.9;
128.2; 128.6; 130.0; 138.0; 144.6; 158.4. MS (EI) m/z (relative
intensity) 344 (24); 342 (100); 341 (26); 340 (M+ + 1, 77). Anal.
Calcd for C12H7BrClN3O2: C, 42.32; H, 2.07; N, 12.34. Found:
C, 42.25; H, 2.07; N, 12.37.
CDCl3) δ: 4.11 (s, 3H); 5.00 (s, 2H); 7.31 (dd, 1H, J ) 9.0, 2.1
Hz); 7.47 (d, 1H, J ) 2.1 Hz); 8.00 (d, 1H, J ) 9.0 Hz). 13C
NMR (50 MHz, CDCl3) δ: 24.0; 54.4; 103.1; 117.1; 119.4; 126.9;
129.1; 129.9; 133.9; 134.2; 150.8. MS (EI) m/z (relative
intensity): 381 (14); 304 (25); 303 (12); 302 (100); 300 (75);
132 (34); 127 (26); 59 (51). Anal. Calcd for C11H8Br2ClNO2: C,
34.64; H, 2.11; N, 3.67. Found: C, 34.70; H, 2.10; N, 3.68.
4-Br om o-5-br om om eth yl-3-m eth yl-1-m eth oxyca r bon -
ylp yr a zole (28f). Chromatography CH2Cl2 (2.93 g, 94% yield).
Mp 75-76 °C (white solid). IR (KBr) νmax: 1759, 1637, 1480,
5-Br om o-3-m e t h oxyca r b on ylp yr im id o[1,6-a ]in d ole
(29c). Chromatography hexane/EtOAc 1:1 (0.27 g, 89% yield).
Mp: 260-261 °C (yellow solid). IR (KBr) νmax: 1729, 1456,
1372, 1217, 1095 cm-1. 1H NMR (300 MHz, CDCl3) δ: 4.02 (s,
3H); 7.59-7.52 (m, 2H); 7.82 (d, 1H; J ) 7.6 Hz); 8.03 (d, 1H;
J ) 7.8 Hz); 8.25 (s, 1H); 9.14 (s, 1H). 13C NMR (50 MHz,
CDCl3) δ: 53.0; 87.9; 111.0; 116.4; 120.1; 124.4; 126.0; 128.4;
129.0; 130.7; 135.8; 138.4; 165.2. MS (EI) m/z (relative
intensity: 307 (96); 305 (M+ + 1, 100); 254 (45); 226 (51). Anal.
Calcd for C13H9BrN2O2: C, 51.17; H, 2.97; N, 9.18. Found: C,
51.09; H, 2.98; N, 9.17.
1445, 1352, 1297, 1149 cm-1 1H NMR (300 MHz, CDCl3) δ:
.
2.28 (s, 3H); 4.10 (s, 3H); 4.79 (s, 2H). 13C NMR (50 MHz,
CDCl3) δ: 12.6; 19.8; 55.2; 103.5; 140.9; 149.4; 151.7. MS (EI)
m/z (relative intensity): 312 (M+, 7); 310 (4); 233 (50); 231 (51);
65 (100), 63 (49). Anal. Calcd for C7H8Br2N2O2: C, 26.95; H,
2.58; N, 8.98. Found: C, 27.01; H, 2.58; N, 8.98.
2-Br om om e t h yl-1-m e t h oxyca r b on ylb e n zim id a zole
(28g). Chromatography CH2Cl2 (1.39 g, 52% yield). Mp:
120-121 °C (pale yellow solid). IR (KBr) νmax: 1756, 1605, 1539,
5,8-Dibr om o-7-m eth oxy-3-m eth oxyca r bon ylp yr im id o-
[1,6-a ]in d ole (29d ). Chromatography CH2Cl2 (0.23 g, 56%
yield). Mp: 279-280 °C (yellow solid). IR (KBr) νmax: 1737,
1453, 1357, 1320, 1292 cm-1 1H NMR (300 MHz, CDCl3) δ:
.
1
4.14 (s, 3H); 4.94 (s, 2H); 7.38-7.24 (m, 2H); 7.74-7.71 (m,
1H); 7.79-7.89 (m, 1H). 13C NMR (50 MHz, CDCl3) δ: 24.7;
54.7; 115.0; 120.4; 124.9; 125.9; 132.7; 141.7; 150.1; 150.4 MS
(EI) m/z (relative intensity): 271 (97); 269 (M+ + 1, 100); 189
(99). Anal. Calcd for C10H9BrN2O2: C, 44.63; H, 3.37; N, 10.41.
Found: C, 44.75; H, 3.38; N, 10.40.
1637, 1560, 1542, 1449 cm-1. H NMR (300 MHz, DMSO-d6)
δ: 3.88 (s, 3H); 3.99 (s, 3H); 7.16 (s, 1H); 7.95 (s, 1H); 8.89 (s,
1H); 9.67 (s, 1H). 13C NMR (50 MHz, DMSO-d6) δ: 52.9; 56.6;
84.8; 98.8; 109.0; 113.8; 123.0; 128.4; 130.8; 134.9; 140.1; 153.7;
164.3. MS (EI) m/z (relative intensity): 417 (49); 415 (M+ + 1,
100); 414 (40); 413 (50). Anal. Calcd for C14H10Br2N2O3: C,
40.61; H, 2.43; N, 6.77. Found: C, 40.53; H, 2.43; N, 6.76.
5-Br om o-7-ch lor o-3-m eth oxyca r bon ylp yr im id o[1,6-a ]-
in d ole (29e). Chromatography hexane/EtOAc 8:2 (0.20 g, 58%
yield). Mp: 218-219 °C (yellow solid). IR (KBr) νmax: 1731,
1655, 1446, 1098 cm-1. 1H NMR (300 MHz, CDCl3) δ: 4.08 (s,
3H); 7.48 (d, 1H; J ) 9.0 Hz); 7.81 (s, 1H); 7.98 (d, 1H, J ) 9.0
Hz); 8.24 (s, 1H); 9.12 (s, 1H). MS (EI) m/z (relative inten-
sity): 343 (27); 342 (19); 341 (100); 340 (30); 339 (M+ + 1, 77);
338 (16). Anal. Calcd for C13H8BrClN2O2: C, 45.98; H, 2.37; N,
8.25. Found: C, 46.03; H, 2.37; N, 8.23.
2-Br om om e t h yl-1-t er t -b u t oxyca r b on ylb e n zym id a -
zole (28h ). Chromatography hexane/EtOAc (8:2) (1.18 g, 38%
yield). Mp 76-77 °C (pale yellow solid). IR (KBr) νmax: 1741,
1547, 1458, 1206, 754 cm-1. 1H NMR (300 MHz, CDCl3) δ: 1.75
(s, 9H); 4.95 (s, 2H); 7.39-7.34 (m, 2H); 7.72 (dd, 1H, J ) 7.2,
1.8 Hz); 7.97 (dd, 1H, J ) 7.5, 1.2 Hz). 13C NMR (75 MHz,
CDCl3) δ: 24.1; 26.9; 85.5; 114.2; 119.4; 123.7; 124.7; 132.3;
140.7; 147.0; 149.4. MS (ES) m/z (relative intensity): 311 (M+,
98), 313 (M + 2, 100). Anal. Calcd for C13H15BrN2O2: C, 50.18;
H, 4.86; N, 9.00. Found: C, 50.18; H, 4.85; N, 9.03.
2-Br om om et h yl-1-m et h oxyca r b on ylim id a zole (28i).
Chromatography CH2Cl2 (0.24 g, 11% yield). Mp: 94-95 °C
5-Br om o-2-m eth yl-5-m eth oxyca r bon ylp yr a zolo[1,3-c]-
p yr im id in e (29f). Chromatography hexane/EtOAc 1:1 (0.12
1
(white solid). IR (KBr) νmax: 1772, 1430, 1295, 1190 cm-1. H
g, 44% yield). Mp: 180-181 °C (white solid). IR (KBr) νmax:
1
NMR (300 MHz, CDCl3) δ: 4.03 (s, 3H); 4.82 (s, 2H); 6.96-
6.98 (m, 1H); 7.40-7.42 (m, 1H). MS (EI) m/z (relative
intensity): 220 (19); 218 (M+, 20); 149 (24); 139 (27), 94 (100).
Anal. Calcd for C6H7BrN2O2: C, 32.90; H, 3.22; N, 12.79.
Found: C, 32.81; H, 3.21; N, 12.82.
Gen er a l P r oced u r e for th e Rea ction of 28a -h w ith
TosMIC. P r ep a r a tion of 29a -h . A mixture of the bromo-
methyl derivative 28 (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 solution (7 mL) was stirred at the temper-
ature indicated in Table 1. After the appropriate reaction time
(20 min to 2 h), the reaction mixture was poured into water
and extracted with CH2Cl2. The organic phase was washed
with brine, dried (Na2SO4), and concentrated under reduced
pressure, providing a crude that was chromatographed on
silica gel to yield compounds 29a -h .
1724, 1616, 1532, 1470, 1337, 1277, 1204 cm-1. H NMR (300
MHz, CDCl3) δ: 2.48 (s, 3H); 3.99 (s, 3H); 8.17 (s, 1H); 9.08 (s,
1H). 13C NMR (50 MHz, CDCl3) δ: 12.6; 53.1; 90.1; 114.3;
136.9; 138.5; 140.2; 155.0; 164.3. MS (EI) m/z (relative
intensity): 272 (97); 270 (M+ + 1, 100). Anal. Calcd for
C9H8BrN3O2: C, 40.02; H, 2.99; N, 15.56. Found: C, 39.97; H,
3.00; N, 15.58.
3-Meth oxycar bon ylpyr im ido[1,6-a ]ben zim idazole (29g).
Chromatography EtOAc (0.09 g, 41% yield). Mp: 190-191 °C
(white solid). IR (KBr) νmax: 1735, 1638, 1513, 1458, 1243 cm-1
.
1H NMR (300 MHz, CDCl3) δ: 4.05 (s, 3H); 7.70-7.51 (m, 2H);
8.10-8.01 (m, 2H); 8.43 (s, 1H); 9.39 (s, 1H). 13C NMR (50
MHz, CDCl3) δ: 53.3; 111.1; 115.9; 121.0; 124.2; 127.8; 139.0;
141.2; 145.2; 149.3; 151.1; 164.4.MS (EI) m/z (relative inten-
sity): 227 (M+, 100); 169 (93); 168 (75); 102 (63). Anal. Calcd
for C12H9N3O2: C, 63.43; H, 3.99; N, 18.49. Found: C, 63.39;
H, 4.00; N, 18.45.
5-Br om o-7-m et h oxyca r b on ylp yr id o[3′,2′:4,5]p yr r olo-
[1,2-c]p yr im id in e (29a ). Chromatography CH2Cl2/acetone
95:5 (0.20 g, 65% yield). Mp: 208-209 °C (yellow solid). IR
3-t er t -Bu t oxyc a r b on ylp yr im id o[2,3-a ]b e n zym id a -
zole (29h ). Chromatography hexane/EtOAc 6:4 (0.11 g, 40%
(KBr) νmax: 1732, 1637, 1618, 1567, 1523, 1439, 1286 cm-1
.
yield). Mp: 164-165 °C (pale yellow solid). IR (KBr) νmax:
1H NMR (300 MHz, CDCl3) δ: 4.04 (s, 3H); 7.57 (dd, 1H, J )
8.1, 4.6 Hz); 8.15 (dd, 1H, J ) 8.1, 1.4 Hz); 8.26 (d, 1H, J )
1729, 1519, 1251, 1097, 762 cm-1. 1H NMR (300 MHz, CDCl3)
δ: 1.64 (s, 9H); 7.38 (td, J ) 8.2, 1.5 Hz); 7.50 (td, J ) 8.2, 1.0
4982 J . Org. Chem., Vol. 69, No. 15, 2004

Reaction of Bromomethylazoles and Tosylmethyl Isocyanide
Hz); 7.88 (d, 1H, J ) 8.2 Hz); 7.94 (d, 1H, J ) 8.2 Hz); 8.21 (d,
1H, J ) 1.5 Hz); 9.30 (d, 1H, J ) 1.5 Hz). 13C NMR (75 MHz,
CDCl3) δ: 28.4; 83.5; 111.5; 115.5; 121.1; 124.3; 128.7; 139.4;
143.3; 145.5; 147.0; 163.1; 176.4. MS (ES) m/z (relative
intensity): 270 (M + 1, 100). Anal. Calcd for C15H15N3O2: C,
66.90; H, 5.61; N, 15.60. Found: C, 66.92; H, 5.61; N, 15.59.
Gen er a l P r oced u r e for th e Hyd r olysis a n d Deca r -
boxyla tion of 29a ,c. To a solution of 29a ,c (1.0 mmol) in THF/
H2O (4:1 v/v) was added LiOH‚H2O (63 mg, 1.5 mmol), and
the mixture was stirred at room temperature. Afterward, the
THF was removed in vacuo, water was added (5 mL), and the
solution was acidified with 1 N HCl (pH ) 5). The yellow solid
formed was filtered, washed with water, and dried in vacuo
to give the corresponding acids 31a ,c. These acids, without
further purification, were suspended in Ph2O (5 mL), and the
mixture was heated at 260 °C and stirred for 4 h at this
temperature. The residue was chromatographed on a silica gel
column using hexane/EtOAc 1:1 as eluent to yield compounds
32a ,c.
7.60 (dd, 1H, J ) 8.2, 4.4 Hz); 8.57 (d, 1H, J ) 5.4 Hz); 8.72-
8.62 (m, 2H); 9.23 (d, 1H, J ) 1.5 Hz); 9.73 (d, 1H; J ) 1.5
Hz). 13C NMR (75 MHz, CDCl3) δ: 14.4; 53.2; 105.7; 113.0;
118.3; 120.8; 122.4; 129.9; 133.7; 138.5; 141.4; 145.1; 157.3;
160.2; 164.7; 173.2. MS (ES) m/z (relative intensity): 351 (M+,
100); 291 (75); 246 (41). Anal. Calcd for C17H13N5O2S: C, 58.11;
H, 3.73; N, 19.93. Found: C, 58.14; H, 3.71; N, 19.94.
Self-Con d en sa tion of 29a . Syn th esis of 36. To a solution
of 29a (50 mg, 0.16 mmol) in dry THF (30 mL) was added 1 M
LiHMDS in THF (0.17 mL, 0.17 mmol) under argon at -78
°C, and the solution was stirred at this temperature for 1 h.
Then 1,2-dibromoethane (0.12 mL, 1.28 mmol) was added, and
stirring was continued for 12 h at -78 °C. The reaction mixture
was quenched with a saturated solution of NH4Cl and ex-
tracted with CH2Cl2 (2 × 30 mL). The organic phase was dried
with Na2SO4 and evaporated under reduced pressure and the
residue chromatographed on silica gel (hexane/EtOAc, 1:1)
yielding 38 mg of a mixture of 35 and 36. The mixture 35/36
was dissolved in 3 mL of CH2Cl2, NBS (14 mg, 0.08 mmol)
was added, and the solution was stirred at room temperature
for 4 h. Afterward, it was concentrated under reduced pressure
and the dark orange residue was purified by chromatography
on silica gel (hexane/EtOAc, 1:1) yielding 31 mg (64%) of the
dimeric compound 36 as a orange solid. The same result was
obtained when the reaction was carried out in the absence of
1,2-dibromoethane. Mp: 290-293 °C dec. IR (KBr) νmax: 1725;
1565; 1436; 1413; 1235; 764 cm-1. 1H NMR (300 MHz, CDCl3)
δ: 3.99 (3H, s), 7.20 (1H, dd, J ) 8.05, J ) 4.59), 7.85 (1H, d,
J ) 4.59), 7.98 (1H, d, J ) 8.05), 8.50 (1H, s). 13C NMR (75
MHz, CDCl3) δ: 53.9; 85.97; 117.018; 120.94; 121.75; 127.65;
131.39; 136.03; 140.00; 141.98; 145.05; 164.80. MS (ES) m/z
(relative intensity): 614 (M + 4+, 18); 612 (M + 2+, 37); 610
(M+, 100). Anal. Calcd for C24H14BrN6O4: C, 47.24; H, 2.31;
N, 13.77. Found: C, 46.98; H, 2.33; N, 13.73.
5-Br om opyr ido[3′,2′:4,5]pyr r olo[1,2-c]pyr im idin e (32a).
Yield: 11.6 mg, 29%. Mp: 139-140 °C (pale brown solid). IR
(KBr) νmax: 3415, 3055, 1614, 1570, 1420, 1325, 1224, 1192
cm-1. 1H NMR (300 MHz, CDCl3) δ: 7.26 (dd, 1H, J ) 6.7, 1.5
Hz); 7.50 (dd, 1H, J ) 8.0, 4.7 Hz); 7.68 (d, 1H, J ) 6.7 Hz);
8.06 (dd, 1H, J ) 8.0, 1.3 Hz); 8.49 (dd, 1H, J ) 4.7, 1.3 Hz);
9.50 (d, 1H, J ) 1.5 Hz). Anal. Calcd for C10H6BrN3: C, 48.42;
H, 2.44; N, 16.94. Found: C, 48.40; H, 2,41; N, 16.93.
5-Br om op yr im id o[1,6-a ]in d ole (32c). Yield: 44.4 mg,
55%. Mp: 149-150 °C (pale brown solid). IR (KBr) νmax: 1606,
1452, 1352, 1214 cm-1 1H NMR (300 MHz, CDCl3) δ: 7.28
.
(dd, 1H, J ) 6.6, 1.4 Hz); 7.47-7.42 (m, 1H); 7.58-7.53 (m,
1H); 7.61 (d, 1H, J ) 6.8 Hz); 7.78 (d, 1H, J ) 7.9 Hz); 7.99 (d,
1H, J ) 8.4 Hz); 9.14 (d, 1H, J ) 1.4 Hz). 13C NMR (75 MHz,
CDCl3) δ: 82.0; 110.3; 111.3; 119.0; 122.3; 125.2; 127.5; 128.6;
131.2; 136.2; 138.6. MS (EI) m/z (relative intensity): 249 (99);
247 (M+, 100); 167 (52). Anal. Calcd for C11H7BrN2: C, 53.49;
H, 2.86; N, 11.33. Found: C, 53.47; H, 2.86; N, 11.34.
Ack n ow led gm en t. We acknowledge support of this
work from the Plan Nacional de Investigacio´n Cient´ıfica,
Desarrollo e Innovacio´n Tecnolo´gica, Direccio´n General
de Investigacio´n, Ministerio de Ciencia y Tecnolog´ıa,
through project BQU2002-03578 and grants from the
Ministerio de Educacio´n y Ciencia (J .M. and A.B.).
5-(2-Methylthiopyrimidin-4-yl)pyrido[3′,2′:4,5]pyrrolo[1,2-c]-
pyrimidine-7-carboxylic Acid Methyl Ester (33). The ester 29a
(50 mg, 0.163 mmol) was dissolved in 2 mL of toluene/MeOH
(20/1) under argon. Pd(PPh3)4 (10%) and (2-methylthiopyri-
midin-4-yl)trimethyltin (0.180 mmol) were added, and the
mixture was heated at 110 °C. Afterward, the reaction mixture
was filtered through Celite and washed with CH2Cl2, and the
combined organic layers were concentrated under reduce
pressure. The residue was chromatographed on silica gel
(CH2Cl2/acetone 95:5) yielding 36 mg (63%) of the coupled
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
mental procedures for the synthesis and characterization data
for all intermediate compounds shown in Schemes 8 and 9.
This material is available free of charge via the Internet at
http://pubs.acs.org.
compound. Mp: 235-236 °C (yellow solid). IR (KBr) νmax
:
3453, 1712, 1556, 1437, 1365, 1336, 1181. 1H NMR (300 MHz,
CDCl3) δ: 2.73 (s, 3H); 4.04 (s, 3H); 7.41 (d, 1H, J ) 5.4 Hz);
J O0358168
J . Org. Chem, Vol. 69, No. 15, 2004 4983