Application of selective palladium-mediated functionalization of the pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine heterocyclic system for the total synthesis of variolin B and deoxyvariolin B

Article abstract of DOI:10.1002/ejoc.201000599

The reaction of protected 3-bromo-2-(bromomethyl)-4-methoxypyrrolo[2,3-b] pyridine and tosylmethyl isocyanide (TosMIC) afforded a pyrido[3′, 2′:4,5]pyrrolo[1,2-c]pyrimidine derivative in good yield. This compound was transformed through installation of the pyrimidine moiety in the C5 position, hydrolysis, and decarboxylation in an advanced intermediate for the total or formal synthesis of the naturalalkaloid variolin B. Reaction of 3-bromo-2-(bromomethyl)-4-chloropyrrolo[2,3-b]pyridine with N-tosylmethyl dichloroformimide as a synthetic TosMIC equivalent afforded trihalo-substituted pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine. This compound was used in a new total synthesis of the alkaloid variolin B by selective and sequential C-N, C-C, and C-O palladium-mediated functionalization at the C9, C5, and C4 positions of the pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine system. A formal synthesis of deoxyvariolin B is also described by using the same synthetic strategy. A new synthesis for deoxyvariolin B and the natural product variolin B was achieved by selective and sequential palladium-mediated functionalization of di- or trihalo-substituted pyrido[3′,2′:4,5] pyrrolo[1,2-c]pyrimidine.

Full text of DOI:10.1002/ejoc.201000599

FULL PAPER
DOI: 10.1002/ejoc.201000599
Application of Selective Palladium-Mediated Functionalization of the
Pyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidine Heterocyclic System for the Total
Synthesis of Variolin B and Deoxyvariolin B
Alejandro Baeza,[a] Javier Mendiola,[a] Carolina Burgos,*[a] Julio Alvarez-Builla,[a] and
Juan J. Vaquero*[a]
Dedicated to Professor Benito Alcaide on the occasion of his 60th birthday
Keywords: Cross-coupling / Total synthesis / Natural products / Heterocycles
The reaction of protected 3-bromo-2-(bromomethyl)-4-meth-
oxypyrrolo[2,3-b]pyridine and tosylmethyl isocyanide
(TosMIC) afforded a pyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidine
derivative in good yield. This compound was transformed
through installation of the pyrimidine moiety in the C5 posi-
tion, hydrolysis, and decarboxylation in an advanced inter-
mediate for the total or formal synthesis of the natural
alkaloid variolin B. Reaction of 3-bromo-2-(bromomethyl)-4-
chloropyrrolo[2,3-b]pyridine with N-tosylmethyl dichloro-
formimide as a synthetic TosMIC equivalent afforded trihalo-
substituted pyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidine. This
compound was used in a new total synthesis of the alkaloid
variolin B by selective and sequential C–N, C–C, and C–O
palladium-mediated functionalization at the C9, C5, and C4
positions of the pyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidine sys-
tem. A formal synthesis of deoxyvariolin B is also described
by using the same synthetic strategy.
Introduction
In 1994, Munro and Blunt reported the isolation and
structure of the variolins, a family of alkaloids isolated from
the Antarctic sponge Kirtpatrickia varialosa[1] (1–3, Fig-
ure 1). In addition to being one of the rare examples of
a natural product containing the pyrrolo[1,2-c]pyrimidine
system [the other example is the alkaloid hinckdentine
(4)[2] isolated from the bryozoan Hincksinoflustra denticul-
ata[3]], it was claimed that variolins have antiproliferative
activity against P388 murine leukemia cells.[1] An in vitro
screening also showed variolin B to be highly active as an
antiviral agent (Herpes simplex Type I, polio Type I).
Three total syntheses of variolin B have been reported to
date. The first total synthesis was reported by Morris.[4] In
this convergent synthesis the tricyclic system is formed from
pre-existing pyridine and pyrimidine rings by using the pos-
sibilities offered by a highly symmetrical key intermediate.
The two other total syntheses of variolin B were reported
by Molina[5] and Alvarez,[6] respectively, and in these cases
the tricyclic core was obtained in a linear route starting
from 7-azaindole (1H-pyrrolo[2,3-b]pyridine).
Figure 1. Structures of variolins and hinckdentine.
theses incorporate the oxygen substituent on the pyridine
ring. However, the amino functionality at C9 is introduced
at relatively early stages in the approaches of Molina and
Alvarez, but in the Morris synthesis this amino group is
incorporated in an advanced intermediate. The pyrimidine
substituent at C5 is the last substituent to be introduced in
both the Alvarez and Molina routes – albeit by using dif-
ferent strategies – whereas in the Morris approach this het-
erocyclic substituent can be viewed as a starting material.
View this journal online at
Regarding the functionality present in the natural alka-
loid, some of the starting compounds in the three total syn-
[a] Departamento de Química Orgánica, Universidad de Alcalá,
28871-Alcalá de Henares, Madrid, Spain
Fax: +34-91-8854660
E-mail: juanjose.vaquero@uah.es
wileyonlinelibrary.com
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In addition, some of these approaches have also been
employed for the synthesis of deoxyvariolin B[7] and some
variolin B derivatives and analogs in the search for com-
pounds with improved cytotoxic activity.[8] In this context,
the three reported methods employed in the synthesis of the
core nucleus scarcely explored the introduction of chemical
diversity at the C4 position (oxygen functionality), with the
Morris synthesis having the best potential to introduce alk-
yl- and arylamino substituents at C9 and the Alvarez syn-
thesis for aryls and heteroaryls at C5.
Our synthetic strategy for variolin B was based on our
initial studies on azolopyrimidine syntheses,[9] which al-
lowed the development of a new route for the construction
of the heterocyclic core of variolins from an appropriately
substituted 7-azaindole through its reaction with tosylme-
thyl isocyanide (TosMIC).[10] Herein we describe in detail
our synthetic studies towards the synthesis of variolins,
which have led to a conceptually different convergent ap-
proach to variolin B and deoxyvariolin B.[11] Our approach
is well suited not only for the synthesis of the natural alka-
loid but also for the eventual structural modification of the
natural product by using sequential palladium-mediated C–
N, C–C, and C–O coupling reactions for the installation of
key structural substituents on a trihalo-substituted pyr-
ido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidine, which is a key inter-
mediate.
Scheme 1. Reaction of some N-protected 2-bromomethylazaindoles
and TosMIC under basic conditions.
on the isocyanide group would lead to cyclization and 1,2-
elimination of p-toluenesulfinic acid to afford 7a. This un-
expected result was clearly very convenient because our ini-
tial strategy to variolins could be easily adapted to achieve
a key tricyclic intermediate (Figure 2) by the simple intro-
duction of an oxygenated functionality at C4 in the starting
azaindole. Thus, our retrosynthetic strategy to synthesize
variolin B is shown in Figure 2.
Results and Discussion
Our initial studies towards the synthesis of variolin B
were started as an extension of the reaction of TosMIC with
azole carboxaldehydes[9] to develop an easy and straightfor-
ward route to the pyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidine
system, the core heterocycle of variolins. However, this ini-
tial approach was abandoned when it was found that the
required starting azaindole was not able to produce the de-
sired tricyclic system.[10b]
The failure of this initial strategy led us to examine the
reaction of an N-protected 2-bromomethylazaindole and
TosMIC under basic conditions on the assumption that the
product of the nucleophilic substitution would be stable
enough for further transformation into the corresponding
pyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidine derivative after de-
Figure 2. Retrosynthetic analysis for variolin B.
The total synthesis of 2 started from 7-azaindole (8;
protection. Some attempts with N-phenylsulfonyl-protected Scheme 2), which was transformed into 4-methoxy-7-azain-
3-bromo-2-bromomethyl-7-azaindole 5a (Scheme 1) were dole (9) by following a literature procedure via 4-chloro-7-
unsuccessful to obtain the desired tricyclic intermediate 6.
azaindole.[12] Subsequent steps to 5c were a modified route
The alternative protection of the azaindole derivative as regarding those optimized for the preparation of 5b and
the methyl carbamate afforded the N-protected bro- began with the initial deprotection of 10b and subsequent
momethyl compound 5b. This derivative cleanly reacted protection as the N-methoxycarbonyl carbamate to supply
with TosMIC under phase-transfer (PTC) conditions 11.
(TBAI/NaOH/CH2Cl2) to afford the unexpected methyl 5-
The bromination of 11 in dichloromethane with the use
bromopyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidine-7-carboxyl- of NBS (2 equiv.; optimized reactions conditions) gave 5c
ate (7a) in 65% yield. The mechanism proposed[10] to ac- in 77% yield. Azaindole derivative 5c reacted with TosMIC
count for the formation of 7a involves initial nucleophilic in a two-phase system (NaOH/CH2Cl2) in the presence of
substitution of TosMIC on the bromomethylpyrrole fol- TBAI as a phase-transfer catalyst to afford key tricyclic
lowed by intramolecular transfer of the methoxycarbonyl compound 7b in an initial 61% yield, which was improved
protecting group. Subsequent attack of the pyrrole nitrogen to 79% by conducting the reaction at low temperature
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Total Synthesis of Variolin B and Deoxyvariolin B
These and further studies on model compounds allowed
us to prepare two advanced intermediates, 19 and 20, by
following the synthetic route shown in Scheme 3. Removal
of the ester group in 7b required hydrolysis of the methyl
ester, which was attempted under different conditions. The
best yield was obtained by using LiOH in aqueous THF. On
the basis of our previous results, decarboxylation of highly
insoluble acid 13 was achieved by prolonged heating in di-
phenyl ether, but under these conditions, debromination
was also promoted and 14 was isolated as the major prod-
uct. Other attempts to promote decarboxylation resulted in
either no reaction (Cu/quinoline) or extensive decomposi-
tion (KOH/MeOH, NaOH/toluene). Adsorption of com-
pound 13 on silica gel and heating under microwave irradia-
tion led to recovery of unaltered starting material at low
power and decomposition at high power or after prolonged
irradiation times.
Scheme 2. Optimized synthesis of key tricyclic compound 7b from
azaindole 8.
(–10 °C) and by only partial purification by column
chromatography (the compound is extremely polar) for iso-
lation of the product. It is noteworthy that in the course of
our experiments to improve the initial yield we were able
to detect compound 12. The structure of this acid strongly
supports the previously proposed mechanism to rationalize
the formation of the tricyclic methoxycarbonyl esters from
the bicyclic precursors.
Transformation of key intermediate 7b into the natural
alkaloid required the removal of the methoxycarbonyl
group at C7, the functionalization of the pyrido[3Ј,2Ј:4,5]-
pyrrolo[1,2-c]pyrimidine system at C9 and C5, and the de-
protection of the oxygen functionality. Removal of the pro-
tecting and ester groups and the introduction of the pyr-
imidine moiety at C5 seemed feasible on the basis of pub-
lished results and our own studies.[13] However, direct
introduction of the amino substituent at C9 of a pyrido-
[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidine was unprecedented.
Consequently, our efforts were focused on exploring the
feasibility of the amination reaction on C9. Previous studies
on model compounds[10b] showed that the C9 position can
be selectively metalated but that the metalated intermediate
was highly reactive, producing a mixture of dimeric com-
pounds. This situation precluded the possibility of achiev-
ing appropriate functionalization of this position through a
precursor with an amino group. It was also reported in
same work that the ester group could be removed from the
model compound by hydrolysis followed by thermal decar-
boxylation,[13] although small amounts of the debrominated
compound were also formed. In this work, additional stud-
ies on similar models showed that some primary amines
were able to produce a nucleophilic attack on both the ester
group and the C9 position of the tricyclic derivatives. How-
ever, no satisfactory results were obtained in the presence
of ammonia.
Scheme 3. Synthesis of advanced intermediates 19 and 20.
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We envisaged that if the pyrimidine ring was incorpo- mediated C–N, C–C, and C–O coupling reactions for the
rated at C5 before decarboxylation, the desired compound installation of key structural substituents.
should be obtainable without going through intermediate
13. On the basis of this analysis, we attempted to transform
7b into the corresponding 5-trialkylstannylderivative 15a by
treatment with tBuLi followed by chlorotrimethylstannane
in the hope that the behavior of the pyrido[3Ј,2Ј:4,5]pyr-
rolo[1,2-c]pyrimidine system would resemble that of 3-
bromo-7-azaindoles, which were transformed into the cor-
responding stannanes by Alvarez and co-workers by using
these standard conditions.[14] However, compound 7b did
not react and all attempts resulted in recovery of the start-
ing material or formation of homocoupling products. Sim-
ilar results were obtained on attempting to convert 7b into
the corresponding boronic acid derivative 15b to be used as
a partner in a Suzuki–Miyaura coupling.[15]
To achieve the biaryl connection between 7b and the pyr-
imidine moieties we turned our attention to pyrimidinyl-
Figure 3. Retrosynthetic analysis for variolin B.
stannane 16, which was first reported by Undheim and co-
workers[16] and later employed by the Alvarez group (65%)
Three bromomethylpyridopyrroles (5b–d) were chosen as
model substrates to test the heterocyclization reaction.
Compounds 5d (X = Cl) and 5b (X = H) should afford the
corresponding advanced precursors for variolin B and its
deoxy analog, respectively (Scheme 4). On the other hand,
methyl 2-bromomethyl-4-methoxypyrrolo[2,3-b]pyridin-1-yl
carboxylate (5c; X = OMe) was also chosen as a starting
azaindole, as we envisaged that a methoxy group in the C4
in the synthesis of deoxyvariolin B.[7] In our hands, 16 was
prepared in 90% yield by simple slow addition of the stan-
nane (Sn2Me6) to 4-iodo-2-methylthiopyrimidine. The cou-
pling reaction between 7b and 16 proceeded in acceptable
yields (53%) when tetrakis(triphenylphosphane)palla-
dium(0) was used as the catalyst in toluene. Under more
polar conditions, the yield was improved and 17 was ob-
tained in 73% yield, the optimum value, in a mixture of
toluene/MeOH (20:1).
position of the tricycle would prove very convenient for the
synthetic strategy if variolin B was not feasible from 5d.
Coupled compound 17 was selectively hydrolyzed to acid
18 and subsequent decarboxylation in refluxing Ph2O pro-
vided, as predicted, desired intermediate 19 or 20 in accept-
able yields depending on the heating conditions. These in-
termediates could be used in a formal or in a new total
of synthesis of variolin B. Unfortunately, extensive studies
showed that neither 19 nor 20 could be transformed into
a previously reported intermediate or the natural alkaloid
because all attempts to incorporate the amino group in the
C9 position failed.
In spite of the disappointing results obtained from these
studies, we envisaged that the strategy for building the tricy-
clic system might still serve for the synthesis of variolin if
we were able to find a reagent suitable for the heterocycliz-
ation reaction to give the pyrimidine nucleus and for the
incorporation of some functionality at C9 that could be
transformed into the amino group. Such an intermediate
would have general structure 21, and as a result, our rea-
gents of choice were the TosMIC synthetic equivalent repre-
sented by tosylmethylimines 22,[17] with the general struc-
ture represented in Figure 3. Thus, of the different possibil-
ities for 22 (Y = Cl, Br, OMe, SMe) our choices were 22a
Scheme 4. Synthesis of the di- or trihalo-functionalized pyr-
ido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidines.
(Y = Cl) and 22b (Y = Br), as any of these N-tosylmethyl
dihaloformimides would enable a conceptually different ap-
proach to variolin B on the basis of the synthesis of a tri-
The reaction of 5b–d with 22a,b failed under different
halo-substituted pyrido[3Ј,2Ј:4,5]-pyrrolo[1,2-c]-pyrimidine. homogeneous conditions (DBU/CH2Cl2, NEt3/CH2Cl2,
This approach is well suited not only for the synthesis of iPr2NEt, 14% NaOH), and phase-transfer catalyst (PTC)
this alkaloid but also for the eventual structural modifica- conditions were necessary to obtain intermediates 21a,c, al-
tion of the natural product by using sequential palladium- beit in moderate yields. Derivative 21b could not be ob-
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Total Synthesis of Variolin B and Deoxyvariolin B
tained under these conditions. Moreover, N-tosylmethyl di-
bromoformimide (22b) was prone to bromine loss to regen-
erate TosMIC, which reacted with 5d to give the previously
described[10b] methyl 5-bromo-4-chloropyrido[3Ј,2Ј:4,5]pyr-
rolo[1,2-c]pyrimidin-7-yl carboxylate (7c) in 30% yield.
In the search for the optimal conditions it was observed
that compound 21a was not formed on using more concen-
trated NaOH (30%), and unexpected compound 23a was
isolated in 5% yield. This result was very convenient in
terms of our ultimate goal, the total synthesis of variolin,
as it circumvents the need to remove the methoxycarbonyl
group. Consequently, we studied this heterocyclization pro-
cess further to find a set of appropriate conditions to obtain
23a–c in a synthetically useful yield. The best results were
obtained for 23a (58% yield) under phase-transfer condi-
tions in the two-phase system LiOH (30%)/CH2Cl2, with
tetrabutylammonium chloride (TBACl) as the catalyst at
room temperature.[18] The use of a less lipophilic base such
as NaOH and/or other phase-transfer catalysts did not im-
prove the yield. Under these optimal conditions, com-
pounds 23b and 23c were obtained in 31 and 58% yield,
respectively.
The mechanistic proposal for the formation of com-
pounds 21 and 23 is shown in Scheme 5. Although the for-
mation of 21 can be explained by a mechanism similar to
that proposed for the reaction between 5b and TosMIC
(Scheme 1),[10a] the first step in the formation of 23 is also
likely to involve the nucleophilic substitution of 22a on the
corresponding bromomethylpyrrole (5b, X = H; 5c, X =
OMe; 5d, X = Cl). Subsequent deprotection of the azolic
pyrrole under phase-transfer conditions, cyclization by at-
tack of the pyrrole nitrogen on the chloroimine, and 1,2-
elimination of p-toluenesulfinic acid would afford tricyclic
derivatives 23 Support for this mechanism was provided by
the unsuccessful attempts to transform 21 into 23 under the
reaction conditions described (Scheme 5).
Scheme 5. Proposed mechanism for the formation of compounds
21 and 23.
At this stage, the completion of the synthesis of vari-
olin B would involve either of the intermediates 23b or 23c
obtained from 5c or 5d, respectively. Compound 23b has
the advantage of the presence of the methoxy substituent at
the C4 position but the drawback associated with the lower
yield in which it was obtained when compared to 23c (31
vs. 58%). The approach from 23c (X = Cl) offered not only
the potential synthesis of the alkaloid but also the versatil-
ity required for eventual structural modification of the nat-
ural product at the C4 position.
Figure 4. Functionalization of
[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidine through palladium-mediated re-
actions.
a trihalo-substituted pyrido-
As
a result, trihalo-substituted pyrido[3Ј,2Ј:4,5]pyr-
rolo[1,2-c]pyrimidine 23c was the intermediate chosen for new total or formal synthesis of deoxyvariolin B. Function-
the installation of the key structural substituents on the va- alization at the C5 position with the appropriate pyrimid-
riolin core system through a conceptually different ap- inyl moiety by using the palladium methodology was pre-
proach based on sequential palladium-mediated C–N, C–C, viously shown to be successful for pyrido[3Ј,2Ј:4,5]pyr-
and C–O coupling reactions (Figure 4).
rolo[1,2-c]pyrimidine derivative 7b (Scheme 3). As a conse-
Prior to undertaking the total synthesis of variolin B, di- quence, we focused on exploring the conversion of 23a into
halo-substituted pyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidine amino derivative 24a (Scheme 6) by simple nucleophilic dis-
23a was employed as a model compound to explore the placement of the chloride substituent in the C9 position.
introduction of the aminopyrimidine moiety at C5 and the Different experiments were carried out in the presence of
amino substituent at C9. It is worth noting that the success- ammonium hydroxide, sodium amide, and some aliphatic
ful introduction of these two substituents would lead to a amines, but this substitution reaction proved to be inappro-
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priate for our purposes, with substitution products formed (2-biphenyl)di-tert-butylphosphane followed by treatment
in very low yields. Consequently, we turned our attention of the reaction mixture with acid. The best yield (89%) was
to the palladium-promoted C–N bond formation developed obtained by using a slight excess of LiHMDS (1.2 equiv.)
by Buchwald and Hartwig.[19]
and Ph3SiNH2 (1.2 equiv.) in THF at room temperature
(16 h) or under reflux (12 h). Prior to the reaction of 24a
with pyrimidinyl stannane 26, prepared according to the
procedure reported by Alvarez and co-workers[6a] it was
necessary to protect the amino group and this was achieved
by using acetic anhydride under reflux. Protected derivative
25a was obtained in 73% yield and this could not be im-
proved by using other conditions due to the formation of
the diacetylated byproduct, which proved difficult to isolate
and purify. Compound 25a could not be prepared directly
from 23a by using a palladium- or copper-catalyzed amid-
ation reaction under standard reaction conditions.[20]
The coupling reaction between 25a and 26 was attempted
under the conditions reported previously[6a] [Pd2(dba)3/
PPh3/LiCl/CuI, dioxane, heat] but these were not appropri-
ate for the coupling reaction, and starting material 25a was
recovered unaltered and extensive decomposition of 26 oc-
curred. A broad study was undertaken to find a suitable set
of conditions for the synthesis of 27a, including the use of
electronically rich and bulky phosphanes [PCy3, PtBu3, (2-
biphenyl)di-tert-butylphosphane], more polar solvents
(DMSO, DMF), and other fluoride sources (CsF, TBAF).
However, all attempts proved unsuccessful and the deacety-
lated product and/or the starting material were recovered.
This failure led us to consider the use of diiodo or bro-
moiodo azaindoles 29 and 30, respectively (Scheme 6) as
partners in the coupling reaction on the assumption that
the higher reactivity would lead to success in the coupling
process.
After some experimentation, it was found that 30 could
not be prepared through the procedure used for the synthe-
sis of 5c (Scheme 2), as the attempted radical halogenation
of intermediate 28 failed with NIS and ipso-substitution
compound 5b was formed when NBS was employed as a
brominating agent.[21] Therefore, we chose a debromina-
tion–iodination strategy to obtain the desired intermedi-
ate.[22] Thus, under the conditions shown in Scheme 6, de-
sired intermediate 31a was obtained in 72% yield from 25a.
As this intermediate is the same as that obtained by Alvarez
and co-workers in their synthesis of deoxyvariolin B,[6a] we
had achieved a formal synthesis of this variolin B analog.
The total synthesis of variolin B was continued by trans-
forming trihalo-substituted pyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]
pyrimidine 23c into the C9-aminated derivative with lithium
bis(trimethylsilyl)amide/triphenylsilylamine
(LiHMDS/
Ph3SiNH2) as the ammonia source in the presence of
Pd2(dba)3. This process gave 25c after protection of the
amino group (Scheme 7). As the attempted C–C coupling
reaction between 25c and 26 did not give the expected cou-
Scheme 6. Formal synthesis of deoxivariolin B.
Our initial results showed that 23a can be converted se- pling product it was also necessary to prepare the corre-
lectively into 9-aminopyrido[3Ј,3Ј:4,5]pyrrolo[1,2-c]pyrim- sponding iodo derivative 31c by the same debromination–
idine (24a) by using triphenylsilylamine (Ph3SiNH2) as an iodination process used on 25a. Fortunately, 31c reacted
ammonia equivalent in the presence of lithium bis(trime- with the pyrimidyl stannyl reagent 26 to afford the expected
thylsilyl)amide (LiHMDS) by using 2 mol-% of tris(diben- coupling product 27c, after deprotection of both amino
zylideneacetone)dipalladium(0) [Pd2(dba)3] and 4 mol-% of groups.
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Total Synthesis of Variolin B and Deoxyvariolin B
Conclusions
In summary, we have developed a new heterocyclization
method for constructing the tricyclic pyrido[3Ј,2Ј:4,5]-
pyrrolo[1,2-c]pyrimidine system, the core heterocyclic nu-
cleus of variolin alkaloids, by reaction of appropriate bro-
momethylazaindole derivatives with tosylmethyl isocyanide
(TosMIC) or tosylmethylimines (TosMIC synthetic equiva-
lent). The advanced intermediate obtained in the reaction
with TosMIC could not be transformed into the natural
alkaloid due to a problem associated with the introduction
of the C9 amino functionality. In contrast, the approach
based on the reaction of bromomethylazaindoles and N-
tosylmethyl dichloroformimide as the key step allowed the
synthesis of dihalo- and trihalopyrido[3Ј,2Ј:4,5]pyrrolo[1,2-
c]pyrimidine derivatives, which were transformed into a pre-
viously reported advanced intermediate in the total synthe-
sis of deoxyvariolin B and into the natural product vari-
olin B by three successive palladium-promoted cross-cou-
pling reactions. We are currently investigating the behavior
of variolin B and some analogs obtained by these strategies
as selective DNA binders.
Scheme 7. Total synthesis of variolin B (2).
Experimental Section
General Remarks: All reactions were carried under an atmosphere
of argon and by using solvents that were dried by routine pro-
cedures. Column chromatography was performed by using silica
gel (60 F254, 70–200 µm) as the stationary phase. IR spectra were
determined on KBr pellets. NMR spectra were obtained at 200,
300, or 500 MHz (1H) and 50, 75, or 125 MHz (13C). Chemical
shifts are reported in ppm relative to tetramethylsilane. Microwave
Having obtained compound 27c, we turned our attention
to the introduction of the oxygen functionality in the C4
position. It was reported that diamino derivative 27c could
be transformed into the C4 methoxy derivative by reaction
with sodium methoxide in MeOH/THF. However, this
transformation required heating at 90 °C for 40 h and the
best yield was 41%.[8c] Consequently, we decided to explore experiments were performed in sealed reaction vessels using a mi-
crowave oven CEM-Discovery (IR monitoring temperature). Com-
pounds 9[12] and 22a/b[17] were synthesized according to previously
reported procedures. The following compounds have been de-
scribed previously: 4-methoxy-1-(phenylsulfonyl)pyrrolo[2,3-b]-
pyridine,[24] 3-iodo-2-methyl-1-(phenylsulfonyl)pyrrolo[2,3-b]pyr-
idine,[25] 2,[4a] N-(pyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidin-9-yl)acet-
amide,[6a] 31a,[6a] 27c,[8d] 7b,[10a] 7c,[10b] and 10a.[10b]
the functionalization of the C4 position under milder condi-
tions through a palladium-promoted C–O coupling reac-
tion. Although this reaction has rarely been used in hetero-
cyclic chemistry, several examples are known in which it has
been applied to aryl halides by using Ni or Pd as cata-
lysts.[23] Thus, before attempting the C–O functionalization
on 27c we tested the feasibility of this unprecedented het-
erocyclic reaction on a commercially available 2-methyl-4-
chloroquinoline model. Furthermore, our choice of nucleo-
philic partner for the coupling reaction was sodium tert-
butoxide (NaOtBu) because the tert-butyl group could be
more easily removed than the methyl group to generate the
required hydroxy substituent at C4.
4-Methoxy-1-(phenylsulfonyl)pyrrolo[2,3-b]pyridine:[24] To a solu-
tion of azole 9[12] (7.52 g, 50.85 mmol) and benzyltriethylammon-
iun chloride (TEBACl, 0.30 g, 1.32 mmol) in CH2Cl2 (100 mL) was
added powdered NaOH (6.35 g, 159 mmol). The solution was co-
oled to 0 °C and benzenesulfonyl chloride (7.14 mL, 55.93 mmol)
was added dropwise. The mixture was stirred at 0 °C for 4 h and
then warmed to room temperature. The resulting mixture was fil-
tered through Celite and washed with CH2Cl2, and the solvent was
The best results for the model substrate (65% yield) were
obtained by irradiating the reaction mixture in a microwave evaporated under reduced pressure. The residue was purified by
chromatography (silica gel; hexane/EtOAc, 7:3) to yield the product
oven with a reaction time of 2 min at 300 W power by using
a mixture of toluene/tBuOH as solvent, Pd2(dba)3 (5 mol-
%), and (2-biphenyl)di-tert-butylphosphane (10 mol-%).[11]
It is noteworthy that experiments with a Ni catalyst and
other alkoxides failed to improve this yield. Compound 27c
was subjected to the optimized conditions found for the C–
O coupling reaction on the model quinoline substrate to
afford tert-butoxy derivative 32, which was converted with-
out isolation into variolin B in 48% yield by removal of the
tert-butyl group under acidic conditions (Scheme 7).
(11.57 g, 79%) as a white powder. M.p. 149–151 °C. IR (KBr): ν =
˜
1581, 1493, 1367, 1297, 1143 cm–1. 1H NMR (300 MHz, CDCl3):
3
δ = 3.91 (s, 3 H, OMe), 6.59 (d, J = 5.6 Hz, 1 H), 6.64 (d, JH,H
=
3
3.8 Hz, 1 H, 3-H), 7.50–7.40 (m, 3 H), 7.54 (d, JH,H = 3.8 Hz, 1
H, 2-H), 8.16–8.11 (m, 2 H), 8.28 (d, J = 5.6 Hz, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 55.5, 100.8, 102.7, 112.8, 123.9, 127.7,
128.9, 133.8, 138.2, 146.9, 148.7, 159.7 ppm. MS (EI): m/z (%) =
288 (31) [M]+, 224 (75), 223 (67), 147 (57), 117 (91), 77 (100).
C14H12N2O3S (288.33): calcd. C 58.32, H 4.20, N 9.72; found C
58.34, H 4.21, N 9.71.
Eur. J. Org. Chem. 2010, 5607–5618
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5613

A. Baeza, J. Mendiola, C. Burgos, J. Alvarez-Builla, J. J. Vaquero
4-Methoxy-2-methyl-1-(phenylsulfonyl)pyrrolo[2,3-b]pyridine (10b): Methyl 3-Bromo-2-bromomethyl-4-methoxypyrrolo[2,3-b]pyridine-1-
FULL PAPER
4-Methoxy-1-(phenylsulfonyl)pyrrolo[2,3-b]pyridine
(7.81 g,
carboxylate (5c): Powdered NBS (7.12 g, 40 mmol) was added to a
solution of N-methyl carbamate protected 11 (4.40 g, 20 mmol) in
CH2Cl2 (200 mL), and the mixture was stirred at room temperature
until the starting material had been consumed (as monitored by
TLC, 48 h). The solvent was evaporated under reduced pressure,
and the residue was purified by chromatography (silica gel; CH2Cl2/
acetone, 98:2) to yield 5c (5.82 g, 77%) as a yellow solid. M.p. 171–
27.13 mmol) was dissolved in THF (290 mL) under an argon atmo-
sphere, and the solution was cooled to –30 °C. Then, LDA (2  in
THF, 27.1 mL, 54.2 mmol) was added dropwise, and the mixture
was stirred at –30 °C for 40 min. After this time, methyl iodide
(10.13 mL, 162 mmol) was added, and the mixture warmed to
room temperature and stirred at room temperature for 6 h. The
reaction mixture was quenched with NH4Cl, extracted with
CH2Cl2, dried with anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was purified by chromatography (sil-
ica gel; hexane/EtOAc, 7:3) to give 10b (8.11 g, 99%) as a yellow
172 °C. IR (KBr): ν = 1739, 1578, 1449, 1394, 1295, 1093 cm–1. 1H
˜
NMR (200 MHz, CDCl3): δ = 3.96 (s, 3 H, OMe), 4.12 (s, 3 H,
3
OMe), 5.02 (s, 2 H, CH2), 6.67 (d, JH,H = 5.7 Hz, 1 H, 5-H), 8.36
3
(d, JH,H = 5.7 Hz, 1 H, 6-H) ppm. 13C NMR (50 MHz, CDCl3):
powder. M.p. 99–101 °C. IR (KBr): ν = 1562, 1452, 1375, 1292,
δ = 24.0, 54.8, 55.8, 98.1, 101.6, 110.1, 131.6, 148.2, 148.5, 150.2,
˜
4
1164 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.69 (d, JH,H
=
160.4 ppm. MS (EI): m/z (%) = 381, 379, 377 (53, 100, 50) [M]+.
4
0.9 Hz, 3 H, Me), 3.91 (s, 3 H, OMe), 6.36 (q, JH,H = 0.9 Hz, 1 C11H10Br2N2O3 (378.02): calcd. C 34.95, H 2.67, N 7.41; found C
H, 3-H), 6.60 (d, J = 5.7 Hz, 1 H), 7.57–7.42 (m, 3 H), 8.12–8.10 35.01, H 2.67, N 7.43.
(m, 2 H), 8.25 (d, J = 5.7 Hz, 1 H) ppm. 13C NMR (75 MHz,
Methyl 5-Bromo-4-methoxypyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]-pyrimid-
CDCl3): δ = 16.3, 55.4, 101.1, 102.9, 111.6, 127.4, 128.8, 133.6,
ine-7-carboxylate (7b): A mixture of 5c (0.378 g, 1 mmol), TosMIC
135.9, 139.3, 145.6, 150.8, 158.5 ppm. MS (EI): m/z (%) = 302 (11)
(0.220 g, 1.1 mmol), and TBAI (0.080 g, 0.2 mmol) in CH2Cl2
(7 mL) and sodium hydroxide (15% in H2O, 7 mL) was stirred at
–10 °C for 17 h. Then, the reaction mixture was poured into water
[M]+, 238 (34), 161 (100), 131 (58), 77 (74). C15H14N2O3S (302.35):
calcd. C 59.59, H 4.67, N 9.27; found C 59.59, H 4.67, N 9.24.
and extracted with CH2Cl2. The organic phase was washed with
brine, dried (MgSO4), and concentrated under reduced pressure,
providing a crude that was treated with acetone and filtered to
afford 7b (0.250 g). The filtrate was concentrated under reduced
pressure, and the residue was purified by chromatography (silica
gel; CH2Cl2/acetone, 9:1) to give other 0.015 g of 7b as a bright
4-Methoxy-2-methylpyrrolo[2,3-b]pyridine: To
a solution of 1-
(phenylsulfonyl) derivative 10b (3.02 g, 10 mmol) in MeOH/H2O
(3:1, 170 mL) was added K2CO3 (6.90 g, 50 mmol), and the mixture
was heated to reflux for 16 h. Afterward, the solution was allowed
to cool to room temperature. Methanol was removed in vacuo, and
the resulting suspension was partitioned between water and ethyl
acetate. Organic layers were combined and dried (Na2SO4). After
filtration, the filtrate was concentrated under reduced pressure to
give a crude product, which was purified by chromatography (silica
gel; CH2Cl2/acetone, 9:1) to yield the product (1.60 g, 99%) as a
yellow powder. Yield: 79%. M.p. 256–257 °C. IR (KBr): ν = 1711,
˜
1568, 1468, 1437, 1352, 1324, 1294, 1225, 1013 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 4.01 (s, 3 H, OMe), 4.07 (s, 3 H, OMe),
3
6.86 (d, JH,H = 5.5 Hz, 1 H, 3-H), 8.23 (d, J = 1.5 Hz, 1 H), 8.42
3
(d, JH,H = 5.5 Hz, 1 H, 2-H), 9.44 (d, J = 1.5 Hz, 1 H) ppm. 13C
white powder. M.p. 207–209 °C. IR (KBr): ν = 1602, 1334, 1298,
˜
1269 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 2.38 (s, 3 H, Me),
NMR (125 MHz, CDCl3): δ = 53.0, 56.1, 82.7, 102.0, 112.3, 116.4,
128.9, 135.5, 137.7, 141.2, 147.0, 160.8, 165.0 ppm. MS (EI): m/z
(%) = 337, 335 (100, 97) [M]+, 322, 320 (46, 45), 320 (45), 57 (93).
C13H10BrN3O3 (336.15): calcd. C 46.45, H 3.00, N 12.50; found C
46.41, H 3.02, N 12.51.
3
3.95 (s, 3 H, OMe), 6.15 (s, 1 H, 3-H), 6.57 (d, JH,H = 5.6 Hz, 1
H, 5-H), 7.92 (d, 3JH,H = 5.6 Hz, 1 H, 6-H), 11.50 (br. s, NH) ppm.
13C NMR (50 MHz, [D6]DMSO): δ = 13.5, 56.0, 96.4, 98.7, 103.4,
124.1, 135.4, 143.7, 145.2 ppm. MS (EI): m/z (%) = 162 (100)
[M]+, 147 (49), 119 (56). C9H10N2O (162.19): calcd. C 66.65, H
6.21, N 17.27; found C 66.63, H 6.24, N 17.26.
5-Bromo-4-methoxypyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidine-7-
carboxylic Acid (13): To a solution of ester 7b (0.336 g, 1.0 mmol)
in THF/H2O (4:1, 5 mL) was added LiOH·H2O (63 mg, 1.5 mmol),
and the reaction mixture was stirred at room temperature for 12 h.
Then the reaction mixture was concentrated, water was added, and
the aqueous solution was neutralized with 1  HCl. The solid thus
obtained was filtered and washed with water and Et2O/hexane to
afford 13 (0.274 g, 85%) as a yellow powder that was used without
Methyl
4-Methoxy-2-methylpyrrolo[2,3-b]pyridine-1-carboxylate
(11): LiHMDS (1  in THF, 8.4 mmol, 8.4 mL) was added to a
solution of 4-methoxy-2-methylpyrrolo[2,3-b]pyridine (1.234 g,
7.62 mmol) in dry THF (25 mL) under an atmosphere of argon at
–78 °C, and the mixture was stirred at the same temperature for
20 min. Then, the mixture was warmed to room temperature over
a period of 2 h. The mixture was cooled again to –78 °C, methyl
chloroformate (0.7 mL, 8.4 mmol) was added dropwise, stirring was
continued for 2 h at –78 °C, and then the reaction was warmed to
room temperature, stirring at the same temperature until the start-
ing material had been consumed (as monitored by TLC, 12 h). The
mixture was treated with NH4Cl and extracted with EtOAc, and
the combined layer was washed with brine and dried (Na2SO4).
The solvent was evaporated, and the crude product was purified by
chromatography (silica gel; EtOAc) to yield 11 (1.41 g, 84%) as a
further purification. M.p. Ͼ260 °C. IR (KBr): ν = 3630, 3449,
˜
1719, 1570, 1435, 1324, 1285, 1224, 1014 cm–1. 1H NMR
3
(300 MHz, [D6]DMSO): δ = 4.06 (s, 3 H, OMe), 7.18 (d, JH,H
=
5.6 Hz 1 H, 3-H), 7.99 (s, 1 H), 8.50 (d, 3JH,H = 5.6 Hz, 1 H, 2-H),
9.53 (s, 1 H) ppm. MS (EI): m/z (%) = 323, 321 (100, 99) [M]+,
279, 277 (76, 81), 264, 262 (69, 69).
4-Methoxypyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidine (14): From acid
13 (0322 g, 1.0 mmol) and without further purification, the re-
sulting yellow powder was suspended in Ph2O (5 mL), and the mix-
white solid. M.p. 88–90 °C. IR (KBr): ν = 3368, 1736, 1569, 1442, ture was heated at 260 °C and stirred for 4 h at this temperature.
˜
1
1288, 1080 1269 cm–1. H NMR (200 MHz, CDCl3): δ = 2.51 (s, 3 The residue was washed with hexane/EtOAc (1:1) to yield com-
H, Me), 3.86 (s, 3 H, OMe), 4.00 (s, 3 H, OMe), 6.28 (s, 1 H, 3- pound 14 (38 mg, 19%), which was isolated as an orange powder.
3
3
1
H), 6.55 (d, JH,H = 5.8 Hz, 1 H, 5-H), 8.20 (d, JH,H = 5.8 Hz, 1
H, 6-H) ppm. 13C NMR (50 MHz, CDCl3): δ = 16.5, 53.8, 55.3,
100.7, 102.0, 111.9, 124.1, 136.0, 145.3, 146.9, 158.3 ppm. MS (EI):
M.p. 178–181 °C. IR (KBr): ν = 2922, 1571, 1308, 1029 cm–1. H
˜
NMR (300 MHz, CDCl3): δ = 4.05 (s, 3 H, OMe), 6.61 (s, 1 H),
6.81 (d, J = 5.4 Hz, 1 H), 7.23 (d, J = 6.9 Hz, 1 H), 7.53 (d, J =
m/z (%) = 220 (77) [M]+, 205 (53), 161 (97), 133 (100). C11H12N2O3 6.9 Hz, 1 H), 8.35 (d, J = 5.4 Hz, 1 H), 9.49 (s, 1 H) ppm. MS (EI):
(220.23): calcd. C 59.99, H 5.49, N 12.72; found C 60.00, H 5.49,
N 12.73.
m/z (%) = 199 (100) [M]+, 184 (68). C11H9N3O (199.21): calcd. C
66.32, H 4.55, N 21.09; found C 66.58, H 5.78, N 20.98.
5614
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5607–5618

Total Synthesis of Variolin B and Deoxyvariolin B
Methyl 5-(2Ј-Methylthiopyrimidin-4-yl)-4-methoxypyrido[3Ј,2Ј:4,5]- General Procedure for the Preparation of Methyl Pyrido[3Ј,2Ј:4,5]-
pyrrolo[1,2-c]pyrimidine-7-carboxylate (17): To a suspension of 7b
(50 mg, 0.149 mmol) in toluene/MeOH (20:1, 1 mL) was added
stannane 16 (48 mg, 0.164 mmol) and Pd(PPh3)4 (1.7 mg,
0.0015 mmol), and the reaction mixture was heated to reflux for
14 h. Then, the reaction mixture was filtered through Celite,
washed with CH2Cl2, and concentrated under reduced pressure,
and the residue was treated with Et2O. The solid obtained was fil-
tered to afford 17 (41.1 mg, 73%) as a bright yellow powder. M.p.
pyrrolo[1,2-c]pyrimidine Carboxylates 21a,c: To a mixture of the
corresponding bromoazole 5b or 5d (1.0 mmol) was added N-tosyl-
methyl dichloroformimide (22a; 0.210 g, 1.1 mmol), the phase-
transfer catalyst in CH2Cl2 (0.1 mmol in 10 mL), and NaOH (15%
in H2O, 10 mL), and the reaction mixture was stirred at room tem-
perature for 5 h. Then, water (10 mL) was added, and the two lay-
ers were separated. The aqueous layer was extracted with CH2Cl2.
The combined organic layer was washed with brine and dried with
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
217–218 °C. IR (KBr): ν = 3561, 1735, 1570, 1439, 1346, 1328 cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 2.69 (s, 3 H, Me), 4.01 (s, 3 H, sure to give crude 21a,c, which was purified by chromatography on
OMe), 4.07 (s, 3 H, OMe), 6.96 (d, J = 5.5 Hz, 1 H), 7.56 (d, J = silica gel to yield the pure compounds.
5.3 Hz, 1 H), 8.49 (d, J = 5.5 Hz, 1 H), 8.52 (d, J = 5.3 Hz, 1 H),
Methyl 5-Bromo-9-chloropyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidine-7-
9.17 (d, J = 1.3 Hz, 1 H), 9.65 (d, J = 1.3 Hz, 1 H) ppm. 13C NMR
carboxylate (21a): Starting from 5b (0.348 mg, 1.0 mmol), 22a
(75 MHz, CDCl3): δ = 14.2, 53.1, 55.9, 102.8, 111.3, 117.0, 118.9,
(1.1 mmol), and Bu3NMeCl (24 mg), and after purification by
chromatography (CH2Cl2/hexane, 95:5), 21a (146 mg, 43%) was
128.3, 132.3, 137.6, 138.1, 142.8, 146.8, 156.4, 160.2, 160.8, 164.8,
171.8 ppm. MS (EI): m/z (%) = 381 (100) [M]+, 351 (37), 321 (18),
obtained as a yellow powder. M.p. 185–187 °C. IR (KBr): ν = 1721,
˜
291 (24), 276 (9). C18H15N5O3S (381.42): calcd. C 56.68, H 3.96,
N 18.36; found C 56.69, H 3.96, N 18.37.
1561, 1441, 1395, 1110 cm–1. 1H NMR (300 MHz, CDCl3): δ =
4.01 (s, 3 H, OMe), 7.58 (dd, J = 8.2, 4.6 Hz, 1 H), 8.16 (d, J =
8.2 Hz, 1 H), 8.24 (s, 1 H, 6-H), 8.70 (d, J = 4.6 Hz, 1 H) ppm. 13
C
5-(2Ј-Methylthiopyrimidin-4-yl)-4-methoxypyrido[3Ј,2Ј:4,5]pyrrolo-
[1,2-c]pyrimidine-7-carboxylic Acid (18): To a solution of ester 17
(57 mg, 0.149 mmol) in THF/H2O (4:1, 5 mL) was added
LiOH·H2O (9.2 mg, 0.22 mmol), and the reaction mixture was
stirred at room temperature for 12 h. Then, the reaction mixture
was concentrated, water was added, and the aqueous solution was
neutralized with 1  HCl. The solid thus obtained was filtered and
washed with water and Et2O/hexane to afford 18 (52 mg, 95%) as
a brown powder that was used without further purification. M.p.
NMR (75 MHz, [D6]DMSO): δ = 53.2, 84.9, 97.1, 121.8, 128.6,
132.0, 135.2, 136.9, 138.4, 147.7, 164.5 ppm. MS (DIP-CI, NH3):
m/z (%) = 344, 342, 340 (25, 100, 80) [M + 1]+. C12H7BrClN3O2
(340.57): calcd. C 42.32, H 2.07, N 12.34; found C 42.14, H 2.12,
N 12.30.
Methyl 5-Bromo-4,9-dichloropyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimid-
ine-7-carboxylate (21c): Starting from 5d (0.383 g, 1.0 mmol), 22a
(1.1 mmol), and Bu3NMeCl (24 mg), and after purification by
chromatography (CH2Cl2/hexane, 95:5), 21c (154 mg, 43%) was ob-
Ͼ250 °C. IR (KBr): ν = 3415, 1719, 1567, 1442, 1344, 1103,
˜
1016 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 2.62 (s, 3 H, Me),
4.05 (s, 3 H, OMe), 7.29 (d, J = 5.9 Hz, 1 H), 7.70 (d, J = 5.4 Hz,
1 H), 8.57 (d, J = 5.9 Hz, 1 H), 8.62 (d, J = 5.4 Hz, 1 H), 9.03 (s,
1 H), 9.72 (s, 1 H), 13.40 (br. s, 1 H, OH) ppm.
tained as a yellow powder. M.p. Ͼ250 °C (dec.). IR (KBr): ν =
˜
1725, 1634, 1557, 1466, 1372, 1185 cm–1 1H NMR (300 MHz,
.
3
CDCl3): δ = 4.01 (s, 3 H, OMe), 7.45 (d, JH,H = 4.8 Hz, 1 H, 3-
H), 8.27 (s, 1 H, 6-H), 8.41 (d, 3JH,H = 4.8 Hz, 1 H, 2-H) ppm. 13
C
5-(2Ј-Methylthiopyrimidin-4-yl)-4-methoxypyrido[3Ј,2Ј:4,5]pyrrolo-
[1,2-c]pyrimidine (19): A suspension of acid 18 (37 mg, 0.1 mmol)
in Ph2O (0.5 mL) was heated at 260 °C for 6 h. Then the reaction
mixture was filtered through silica gel by using Ph2O as solvent.
The crude product was purified by column chromatography
(CH2Cl2/acetone, 95:5) to afford 19 (18.5 mg, 57%) as a yellow
NMR (75 MHz, CDCl3): δ = 53.9, 89.1, 102.3, 114.3, 121.9, 122.3,
129.0, 131.1, 132.7, 137.4, 146.3, 167.9; 3 ppm. MS (DIP-CI, NH3):
m/z (%) = 378, 376, 374 (7, 14, 9) [M + 1]+, 318 (83), 279 (32), 102
(93), 86 (100). C12H6BrCl2N3O2 (375.01): calcd. C 38.43, H 1.61,
N 11.21; found C 38.29, H 1.70, N 11.18.
General Procedure for the Preparation of Azolopyrimidines 23a–c:
A mixture of bromomethylazole 5b–d (2.8 mmol), N-tosylmethyl
dichloroformimide (22a; 0.821 g, 3.1 mmol), TBACl (80 mg,
0.28 mmol) in CH2Cl2 (30 mL), and 30 % LiOH (30 mL) was
stirred at room temperature for 5 h. The reaction mixture was
poured into water (20 mL), the two layers were separated, and the
aqueous layer was extracted with CH2Cl2. The organic phase was
washed with brine, dried (Na2SO4), filtered, and concentrated un-
der reduced pressure to give a crude product, which was purified
by chromatography on silica gel to yield pure compounds 23a–c.
powder. M.p. 170–172 °C. IR (KBr): ν = 3423, 1561, 1439,
˜
1358 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.64 (s, 3 H, Me),
4.05 (s, 3 H, OMe), 6.93 (d, J = 5.5 Hz, 1 H), 7.51 (d, J = 5.5 Hz,
1 H), 7.81 (d, J = 6.8 Hz, 1 H), 8.24 (dd, J = 6.8, 1.6 Hz, 1 H),
8.41 (d, J = 5.5 Hz, 1 H), 8.47 (d, J = 5.5 Hz, 1 H), 9.63 (d, J =
1.6 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.2, 55.7,
102.7, 109.0, 111.8, 114.1, 116.9, 133.8, 138.4, 139.8, 141.9, 145.1,
146.6, 155.8, 157.4, 160.3 ppm. MS (EI): m/z (%) = 323 (100)
[M]+, 290 (43), 251 (25). C16H13N5OS (323.38): calcd. C 59.43, H
4.05, N 21.66; found C 59.45, H 4.06, N 21.65.
5-Bromo-4-chloropyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidine (23a):
Chromatography: hexane/EtOAc (8:2). Yield: 58%; yellow solid.
4-Hydroxy-5-(2Ј-methylthiopyrimidin-4-yl)pyrido[3Ј,2Ј:4,5]pyrrolo-
[1,2-c]pyrimidine (20): A suspension of acid 18 (37 mg, 0.1 mmol)
in Ph2O (0.5 mL), following the same procedure described for 19
and after heating at 320 °C for 6 h, 20 (15 mg, 48%) was obtained
M.p. Ͼ250 °C (dec.). IR (KBr): ν = 3066, 1616, 1587, 1495, 1388,
˜
1
1005 cm–1. H NMR (300 MHz, CDCl3): δ = 7.29 (d, J = 6.4 Hz,
1 H), 7.51 (d, J = 6.4 Hz, 1 H), 7.52 (dd, J = 8.0, 4.6 Hz, 1 H),
8.10 (dd, J = 8.0, 1.5 Hz, 1 H), 8.61 (dd, J = 4.6, 1.5 Hz, 1 H) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 82.5, 110.3, 121.3, 122.2,
127.1, 129.5, 134.0, 136.3, 139.3, 143.5 ppm. MS (DIP-CI, NH3):
m/z (%) = 286, 284, 282 (25, 100, 80) [M + 1]+. C10H5BrClN3
(282.53): calcd. C 42.51, H 1.78, N 14.87; found C 42.39, H 1.72,
N 14.98.
as a yellow powder. M.p. 159–160 °C. IR (KBr): ν = 3378, 2924,
˜
1
1582, 1442, 1311 cm–1. H NMR (300 MHz, CDCl3): δ = 2.64 (s,
3 H, Me), 6.93 (d, J = 5.4 Hz, 1 H), 7.40 (d, J = 5.4 Hz, 1 H), 7.71
(d, J = 6.9 Hz, 1 H), 7.96 (d, J = 6.9 Hz, 1 H), 8.29 (d, J = 5.4 Hz,
1 H), 8.50 (d, J = 5.4 Hz, 1 H), 9.69 (s, 1 H), 14.44 (s, 1 H,
OH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.2, 101.9, 109.0,
110.8, 111.7, 112.2, 133.6, 137.9, 139.6, 141.7, 143.1, 146.4, 157.2,
158.6, 160.3 ppm. MS (API, ESI+): m/z = 310 [M + 1]+, 308 [M –
1]+. C15H11N5OS (309.35): calcd. C 58.24, H 3.58, N 22.64; found
C 58.26, H 3.54, N 22.65.
5-Bromo-9-chloro-4-methoxypyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimid-
ine (23b): Chromatography: CH2Cl2/acetone (95:5). Yield: 31%;
yellow solid. M.p. 250 °C (dec.). IR (KBr): ν = 1609, 1566, 1492,
˜
Eur. J. Org. Chem. 2010, 5607–5618
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5615

A. Baeza, J. Mendiola, C. Burgos, J. Alvarez-Builla, J. J. Vaquero
95:5) provided the debrominated derivative (18 mg, 80%) as a yel-
FULL PAPER
1296, 1001, 820 cm–1. H NMR (300 MHz, CDCl3): δ = 4.06 (s, 3
1
H, OMe), 6.85 (d, J = 5.5 Hz, 1 H), 7.26 (d, J = 6.4 Hz, 1 H), 7.45 low powder. M.p. 158–160 °C (ref.[6a] 160–161 °C).
(d, J = 6.4 Hz, 1 H), 8.45 (d, J = 5.5 Hz, 1 H) ppm. 13C NMR
3-Iodo-2-methyl-1-(phenylsulfonyl)pyrrolo[2,3-b]pyridine:[25] To
(75 MHz, CDCl3): δ = 55.9, 79.9, 101.8, 110.8, 112.3, 130.1, 132.7,
a
solution of 10a[10b] (1.0 g, 3.67 mmol) in CH2Cl2 (20 mL) was
added NIS (1.65 g, 7.36 mmol), and the mixture was stirred at
room temperature for 48 h. Then, the solvent was removed under
reduced pressure, and the residue was purified by chromatography
(silica gel; hexane/EtOAc, 8:2) to afford the product (1.34 g, 92%)
135.3, 139.9, 144.9, 159.9 ppm. MS (DIP-CI, NH3): m/z (%) = 316,
314, 312 (25, 100, 80) [M + 1]+. C11H7BrClN3O (312.55): calcd. C
42.27, H 2.26, N 13.44; found C 42.17, H 2.11, N 13.51.
5-Bromo-4,9-dichloropyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidine (23c):
Chromatography: hexane/EtOAc (8:2). Yield: 58%; yellow solid.
of as a white powder. M.p. 147–148 °C. IR (KBr): ν = 1578, 1547,
˜
1
M.p. Ͼ 250 °C (dec.). IR (KBr): ν = 3070, 1634, 1553, 1475, 1268,
1449, 1368, 1259, 1176 1005 cm–1. H NMR (200 MHz, CDCl3): δ
˜
1
1172 cm–1. H NMR (300 MHz, CDCl3): δ = 7.35 (d, J = 6.6 Hz, = 2.82 (s, 3 H, Me), 7.19 (dd, J = 7.7, 4.8 Hz, 1 H), 7.44–7.58 (m,
1 H), 7.50 (d, J = 5.1 Hz, 1 H), 7.58 (d, J = 6.6 Hz, 1 H), 8.45 (d,
J = 5.1 Hz, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 80.8,
110.6, 122.1, 128.9, 130.0, 133.5, 135.1, 135.9, 136.8, 142.5 ppm.
MS (APCI): m/z (%) = 322, 320, 318, 316 (8, 46, 100, 61)
[M + 1]+. C10H4BrCl2N3 (316.97): calcd. C 37.89, H 1.27, N 13.26;
found C 37.80, H 1.31, N 13.28.
4 H), 8.13 (d, J = 7.1 Hz, 2 H), 8.37 (dd, J = 4.8, 1.5 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 17.3, 68.6, 119.9, 124.7, 127.9,
129.3, 129.5, 134.3, 138.7, 139.2, 145.2, 148.5 ppm. MS (DIP-CI,
NH3): m/z (%)
C14H11IN2O2S (398.22): calcd. C 42.23, H 2.78, N 7.03; found C
41.52, H 2.79, N 6.98.
= 399 (100) [M +
1]+, 277 (7), 258 (8).
5-Bromopyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidin-9-amine (24a): To a
mixture of 23a (0.282 g, 1.0 mmol), triphenylsilylamine (0.330 g,
1.2 mmol), Pd2(dba)3 (18 mg,0.02 mmol), and (2-biphenyl)di-tert-
butylphosphane (12 mg, 0.04 mmol) in dry THF (10 mL) was
added LiHMDS (1.0  in THF, 1.2 mL, 1.2 mmol) under an atmo-
sphere of dry argon. The reaction mixture was stirred at room tem-
perature for 16 h. The reaction mixture was poured into water and
extracted with CH2Cl2. The combined organic layer was washed
with brine, dried with anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. Purification by chromatography (sil-
ica gel; CH2Cl2/acetone, 9:1) provided 24a (0.234 g, 89%) as an
3-Iodo-2-methylpyrrolo[2,3-b]pyridine: To a solution of 1-benzene-
sulfonyl-3-iodo-2-methylpyrrolo[2,3-b]pyridine (3.98 g, 10 mmol) in
MeOH (130 mL) and water (43 mL) was added K2CO3 (6.91 g,
50 mmol), and the suspension was heated at reflux for 10 h. Then,
the reaction mixture was concentrated under reduced pressure, di-
luted with water (20 mL), and extracted with EtOAc. The com-
bined organic layer was dried with anhydrous Na2SO4 and concen-
trated under reduced pressure. Purification by chromatography (sil-
ica gel; hexane/EtOAc, 8:2) provided the product (1.80 g, 70%) as
a white powder. M.p. 169–171 °C. IR (KBr): ν = 1608, 1586, 1401,
˜
1277, 1046 cm–1. 1H NMR (200 MHz, CDCl3): δ = 2.48 (s, 3 H,
Me), 7.09 (dd, J = 7.7, 4.8 Hz, 1 H), 7.62 (d, J = 7.7 Hz, 1 H), 8.21
orange powder. M.p. 205–207 °C. IR (KBr): ν = 3317, 1659, 1613,
˜
1571, 1390, 1121, 759 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.72 (d, J = 4.8 Hz, 1 H), 10.41 (br. s, 1 H, NH) ppm. 13C NMR
(d, J = 6.7 Hz, 1 H), 7.42 (dd, J = 8.1, 4.4 Hz, 1 H), 7.43 (d, J = (50 MHz, CDCl3): δ = 14.9, 56.1, 116.6, 124.6, 128.6, 138.5, 141.8,
6.7 Hz 1 H), 8.02 (dd, J = 8.1, 1.5 Hz, 1 H), 8.34 (dd, J = 4.4, 149.0 ppm. MS (APCI): m/z (%) = 259 (100) [M + 1]+, 133 (11).
1.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 78.6, 100.2,
120.0, 126.0, 128.3, 129.2, 130.1, 133.5, 135.6, 140.2 ppm. MS
(DIP-CI, NH3): m/z (%) = 265, 263 (94, 100) [M + 1]+, 184 (12).
C10H7BrN4 (263.10): calcd. C 45.65, H 2.68, N 21.30; found C
45.51, H 2.58, N 21.48.
C8H7IN2 (258.06): calcd. C 37.23, H 2.73, N 10.86; found C 37.20,
H 2.71, N 10.84.
Methyl 3-Iodo-2-methylpyrrolo[2,3-b]pyridine-1-carboxylate (28):
LiHMDS (1  in THF, 8.4 mL, 8.4 mmol) was added to a
solution of methyl 3-iodo-2-methylpyrrolo[2,3-b]-pyridine (1.97 g,
7.62 mmol) in dry THF (25 mL) under an atmosphere of argon at
–78 °C. The reaction mixture was stirred at this temperature for
20 min, and it was then warmed to room temperature over a period
of 2 h. When the reaction mixture turned red it was cooled again
to –78 °C and methyl chloroformate (0.7 mL, 8.4 mmol) was added
dropwise and stirring was continued for 1 h at –78 °C. Then the
reaction was warmed to room temperature and stirred for a further
4 h. The mixture was quenched with NH4Cl and extracted with
EtOAc, and the combined organic layer was washed with brine and
N-(5-Bromopyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidin-9-yl)acetamide
(25a): A suspension of 24a (0.263 g, 1.0 mmol) in acetic anhydride
(15 mL) was heated under reflux for 30 min. Then, the solvent was
eliminated under reduced pressure to yield a dark oil, which was
treated with a saturated NaHCO3 solution, and the mixture was
extracted with CH2Cl2, dried with anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. Purification by chromatog-
raphy (silica gel; CH2Cl2/acetone, 95:5) provided 25a (0.223 g,
73%) as an orange solid. M.p. 202–203 °C. IR (KBr): ν = 3016,
˜
1700, 1619, 1574, 1398, 1007, 944 cm–1. 1H NMR (300 MHz, dried (Na2SO4). The solvent was evaporated, and the crude product
CDCl3): δ = 2.62 (s, 3 H, Me), 7.00 (d, J = 6.6 Hz, 1 H), 7.46 (dd,
J = 8.1, 4.8 Hz, 1 H), 7.59 (d, J = 6.6 Hz, 1 H), 8.04 (dd, J = 8.1,
1.5 Hz, 1 H), 8.42 (dd, J = 4.8, 1.5 Hz, 1 H), 12.59 (br. s, 1 H,
NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 26.6, 80.1, 100.5,
105.6, 120.7, 122.6, 127.4, 134.1, 138.3; 141.1, 142.7, 170.5 ppm.
was purified by chromatography (silica gel; CH2Cl2/acetone, 9:1) to
give 28 (1.98 g, 82%) as a white powder. M.p. 118–119 °C. IR
(KBr): ν = 1741, 1576, 1556, 1449, 1397, 1255 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 2.72 (s, 3 H, Me), 4.10 (s, 3 H, MeO), 7.23
(dd, J = 7.9, 4.8 Hz, 1 H), 7.63 (dd, J = 7.9, 1.5 Hz 1 H), 8.39 (dd,
MS (DIP-CI, NH3): m/z (%) = 307, 305 (100, 100) [M + 1]+, 263 J = 4.8, 1.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.7,
(22). C12H9BrN4O (305.14): calcd. C 47.24, H 2.97, N 18.36; found
C 47.29, H 3.02, N 18.31.
54.6, 68.1, 118.9, 119.8, 124.9, 129.35, 139.5, 145.2, 148.4 ppm. MS
(DIP-CI, NH3): m/z (%) = 317 (100) [M + 1]+; 282 (9). C10H9IN2O2
(316.10): calcd. C 38.00, H 2.87, N 8.66; found C 38.12, H 2.73, N
8.68.
N-(Pyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidin-9-yl)acetamide:[6a]
A
solution of TTMSS (49 mg, 0.2 mmol), AIBN (33 mg, 0.2 mmol),
and 25a (31 mg, 0.1 mmol) in dry THF (1.5 mL) was slowly added
(3 h) to an additional dry THF (2 mL) at 70–80 °C (bath tempera-
ture). The resulting reaction mixture was stirred for 12 h at this
temperature. Evaporation of the solvent under reduced pressure
and purification by chromatography (silica gel; CH2Cl2/acetone,
N-(5-Iodopyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidin-9-yl)acetamide
(31a):[6a] To a cold solution (0 °C) of N-(pyrido[3Ј,2Ј:4,5]pyrrolo-
[1,2-c]pyrimidin-9-yl)acetamide (23 mg, 0.1 mmol) in CH2Cl2
(3 mL) was added NIS (25 mg, 0.11 mmol), and the mixture was
stirred at this temperature for 1 h. Removal of the solvent under
5616
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5607–5618

Total Synthesis of Variolin B and Deoxyvariolin B
reduced pressure and purification by chromatography (silica gel;
CH2Cl2/acetone, 9:1) provided iodo derivative 31a (32 mg, 90%) as
a yellow powder. M.p. 160–161 °C (ref.[6a] 163–164 °C).
pyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidin-9-yl)acetamide
(26 mg,
0.1 mmol) in CH2Cl2 (3 mL) was added NIS (25 mg, 0.11 mmol),
and the mixture was stirred at this temperature for 1 h. Removal
of the solvent under reduced pressure and purification by
chromatography (silica gel; CH2Cl2/acetone, 9:1) yielded pure 31c.
N-(5-Bromo-4-chloropyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidin-9-yl)
amine: A solution of LiHMDS (1.0  in THF, 1.2 mL, 1.2 mmol)
was added dropwise to a mixture of azolopyrimidine 23c (0.317 g,
1.0 mmol), triphenylsilylamine (0.330 g, 1.2 mmol), Pd2(dba)3
(18 mg, 0.02 mmol), and (2-biphenyl)di-tert-butylphosphane
(12 mg, 0.04 mmol) in dry THF (10 mL) under an atmosphere of
dry argon. The resulting mixture was stirred at room temperature
for 16 h and then poured into water and extracted with CH2Cl2.
The organic phase was washed with brine, dried (Na2SO4), and
concentrated under reduced pressure to give a crude product, which
was purified by chromatography (silica gel; CH2Cl2/acetone, 9:1) to
Yield: 90%; yellow solid. M.p. 157–159 °C. IR (KBr): ν = 3021,
˜
1678, 1561, 1325, 1192 cm–1. 1H NMR (300 MHz, CDCl3): δ =
2.63 (s, 3 H, Me), 7.05 (d, J = 6.7 Hz,1 H), 7.44 (d, J = 5.3 Hz, 1
H), 7.65 (d, J = 6.7 Hz,1 H), 8.27 (d, J = 5.3 Hz, 1 H), 12.64 (br.
s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 26.7, 46.5,
108.0, 120.5, 121.7, 136.9, 138.5, 138.8, 140.2, 140.5, 142.9,
170.6 ppm. MS (ESI): m/z (%) = 389, 387 (99, 100) [M + 1]+.
C12H8ClIN4O (386.58): calcd. C 37.28, H 2.09, N 14.49; found C
36.92, H 2.01, N 14.87.
yield the pure compound (21 mg, 71%) as an orange solid. M.p.
5-(2-Aminopirimidin-4-yl)-4-hydroxypyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]-
pyrimidin-9-amine (2):[4a] A solution of 31c (39 mg, 0.1 mmol),
stannane 26 (60 mg, 0.2 mmol), Pd2(dba)3 (5 mg, 0.006 mmol),
PPh3 (3 mg, 0.012 mmol), LiCl (12 mg, 0.3 mmol), and CuI (1 mg,
0.006 mmol) in dioxane (1 mL) was heated at reflux for 1.5 h. The
solvent was eliminated under reduced pressure, and the residue was
treated with hydrogen chloride–methanol solution (5 mL) and
heated again to reflux for 1 h. Then, the reaction mixture was con-
centrated under reduced pressure, and the residue was treated with
CH2Cl2 (1 mL). The organic phase was extracted with HCl (4 ),
and the two phases were separated. The aqueous phase was basified
with powdered Na2CO3 and extracted with CH2Cl2, and the com-
bined organic phase was dried with anhydrous Na2SO4 and concen-
trated under reduced pressure. The residue was purified by
chromatography (silica gel; CH2Cl2/MeOH, 9:1) to provide diamine
27c (15 mg, 48%) as a yellow powder, which was used in the next
step.[8d] A solution of 27c (16 mg, 0.05 mmol), Pd2(dba)3 (2.5 mg,
0.0025 mmol), di-tert-butylphenylphosphane (1 mg, 0.005 mmol),
and NaOtBu (10 mg, 0.1 mmol) in toluene/tBuOH (5:1, 2 mL) in
a sealed reaction vessel and under a dry argon atmosphere was
irradiated in a microwave oven (CEM-Discovery) at 150 °C and
300 W (IR monitoring temperature) for 2 min. The solvent was
evaporated, and the residue was dissolved in hydrogen chloride–
methanol solution (2 mL) at room temperature for 30 min. Then,
the reaction mixture was basified with 30% aqueous NH4OH, satu-
rated with solid NaCl, extracted with CH2Cl2, and dried (Na2SO4).
After evaporation of CH2Cl2, the residue was purified by
chromatography (silica gel; CH2Cl2/MeOH, 9:1) to yield pure 2
(48%). Yellow solid. M.p. Ͼ300 °C (dec.). 1H NMR (300 MHz,
1
189–190 °C. IR (KBr): ν = 3311, 1658, 1475, 1377 cm–1. H NMR
˜
(300 MHz, CDCl3): δ = 6.77 (d, J = 6.8 Hz, 1 H), 7.37 (d, J =
5.3 Hz, 1 H), 7.47 (d, J = 6.8 Hz, 1 H), 8.16 (d, J = 5.3 Hz, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 77.4, 100.7, 121.3, 126.6,
128.1, 129.2, 130.2, 135.2, 139.6, 140.9 ppm. MS (DIP-CI, NH3):
m/z (%) = 301, 299, 297 (33, 100, 71) [M + 1]+, 219 (19).
C10H6BrClN4 (297.54): calcd. C 40.37, H 2.03, N 18.83; found C
40.32, H 2.08, N 18.89.
N-(5-Bromo-4-chloropyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidin-9-yl)-
acetamide (25c): A suspension of N-(5-bromo-4-chloropyrido-
[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidin-9-yl)amine (0.297 g, 1 mmol) in
acetic anhydride (15 mL) was heated to reflux for 30 min. After-
ward, the mixture was allowed to cool to room temperature. The
solvent was removed in vacuo, and the resulting oil was basified
with a saturated solution of NaHCO3 in water and extracted with
CH2Cl2. The organic layers were combined and dried (Na2SO4).
After filtration, the filtrate was concentrated under reduced pres-
sure to give a crude product, which was purified by chromatog-
raphy (silica gel; CH2Cl2/acetone, 95:5) to yield pure compound
25c. Yield: 72%; orange solid. M.p. 230–233 °C. IR (KBr): ν =
˜
3018, 1708, 1640, 1532, 1345, 1108 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 2.63 (s, 3 H, Me), 7.07 (d, J = 6.6 Hz, 1 H), 7.46 (d,
J = 5.3 Hz, 1 H), 7.64 (d, J = 6.6 Hz, 1 H), 8.28 (d, J = 5.3 Hz, 1
H), 12.56 (br. s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ =
25.9, 78.0, 105.1, 118.3, 120.9, 134.5, 135.6, 138.7, 139.8, 140.6,
141.7, 169.8 ppm. MS (DIP-CI, NH3): m/z (%) = 343, 341, 339 (21,
100, 80) [M + 1]+, 299 (38). C12H8BrClN4O (339.58): calcd. C
42.44, H 2.37, N 16.50; found C 42.39, H 2.48, N 16.53.
3
CDCl3): δ = 6.79 (d, JH,H = 5.7 Hz, 1 H, 3-H), 7.00 (br. s, 2 H,
3
3
N-(4-Chloropyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidin-9-yl)acetamide:
A solution of TTMSS (49 mg, 0.2 mmol), AIBN (33 mg,
0.2 mmol), and 25c (34 mg, 0.1 mmol) in THF (1.5 mL) was added
dropwise with the use of a syringe pump over the course of 3 h to
an additional amount of THF (2 mL) at 80 °C (bath temperature).
Stirring was maintained at the same temperature for a further 12 h.
The solution was concentrated, and the crude mixture was purified
by chromatography (silica gel; CH2Cl2/acetone, 95:5) to yield the
pure product. Yield: 83 %; yellow solid. M.p. 150 °C (dec.). IR
NH2), 7.13 (d, JH,H = 5.5 Hz, 1 H, 5Ј-H), 7.24 (d, JH,H = 6.7 Hz,
3
3
1 H, 6-H), 7.63 (d, JH,H = 6.7 Hz, 1 H, 7-H), 8.15 (d, JH,H
5.7 Hz, 1 H, 2-H), 8.26 (d, JH,H = 5.5 Hz, 1 H, 6Ј-H), 8.50 (br. s,
=
3
1 H), 9.70 (br. s, 1 H), 16.04 (s, 1 H) ppm.
Acknowledgments
The authors acknowledge support of this work from Ministerio
de Ciencia e Innovación (project CTQ2008/04313) and Instituto
de Salud Carlos III (Red de Investigación Renal, REDinREN,
RD06/0016/0016) and grants from the Ministerio de Educación y
Ciencia (A.B. and J.M.).
(KBr): ν = 3153, 1710, 1588, 1205 cm–1 1H NMR (300 MHz,
.
˜
CDCl3): δ = 2.65 (s, 3 H, Me), 6.67 (s, 1 H, 5-H), 7.02 (d, J =
6.6 Hz, 1 H), 7.45 (d, J = 5.3 Hz, 1 H), 7.57 (d, J = 6.6 Hz, 1 H),
8.31 (d, J = 5.3 Hz, 1 H), 12.80 (s, 1 H, NH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 27.7, 89.5, 107.7, 120.0, 122.8, 126.6, 129.1,
135.9, 137.0, 140.2, 169.6 ppm. MS (DIP-CI, NH3): m/z (%) = 263,
261 (32, 100) [M + 1]+. C12H9ClN4O (260.68): calcd. C 55.29, H
3.48, N 21.49; found C 55.38, H 3.31, N 21.41.
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Munro, S. Parkin, H. Hope, Tetrahedron 1994, 50, 3987–3992;
b) G. Trimurtulu, D. J. Faulkner, N. B. Perry, L. Ettouati, M.
Litaudon, J. W. Blunt, M. H. G. Munro, G. B. Jameson, Tetra-
hedron 1994, 50, 3993–4000.
N-(4-Chloro-5-iodopyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidin-9-yl)-
acetamide (31c): To
a cold solution (0 °C) of N-(4-chloro-
Eur. J. Org. Chem. 2010, 5607–5618
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5617

A. Baeza, J. Mendiola, C. Burgos, J. Alvarez-Builla, J. J. Vaquero
FULL PAPER
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Published Online: August 24, 2010
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