Palladium-mediated C-N, C-C, and C-O functionalization of azolopyrimidines: a new total synthesis of variolin B

Article abstract of DOI:10.1016/j.tetlet.2008.04.063

A new total synthesis of the alkaloid variolin B is achieved by a selective and sequential palladium-mediated functionalization of a trihalo-substituted pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine. This intermediate is obtained by a new heterocyclization reaction between an appropriate bromomethyl azaindole and N-tosylmethyl dichloroformimide. The methodology may be effective for the synthesis of some analogs by substitution on the relatively unexplored C4 and C9 positions of the alkaloid.

Full text of DOI:10.1016/j.tetlet.2008.04.063

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 4073–4077
Palladium-mediated C–N, C–C, and C–O functionalization
of azolopyrimidines: a new total synthesis of variolin B
a
b
a,
*
Alejandro Baeza , Javier Mendiola , Carolina Burgos ,
Julio Alvarez-Builla a, Juan J. Vaquero a,*
a Departamento de Qu´ımica Orga´nica, Universidad de Alcala´, 28871 Alcala´ de Henares, Madrid, Spain
b Centro de Investigacio´n Lilly, Avenida de la Industria 30, 28108 Alcobendas, Madrid, Spain
Received 25 January 2008; revised 4 April 2008; accepted 9 April 2008
Available online 12 April 2008
Abstract
A new total synthesis of the alkaloid variolin B is achieved by a selective and sequential palladium-mediated functionalization of a
trihalo-substituted pyrido[30,20:4,5]pyrrolo[1,2-c]pyrimidine. This intermediate is obtained by a new heterocyclization reaction between
an appropriate bromomethyl azaindole and N-tosylmethyl dichloroformimide. The methodology may be effective for the synthesis of
some analogs by substitution on the relatively unexplored C4 and C9 positions of the alkaloid.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Variolin B; Total synthesis; Palladium-mediated C–N, C–C and C–O; Pyrido[30,20:4,5]pyrrolo[1,2-c]pyrimidine; N-tosylmethyl dichloro-
formimide
Variolin B is a member of a family of marine alkaloids
isolated from an extremely rare Antarctic sponge, Kirkpat-
rickia varialosa.1 The potent antitumoral activity found for
variolin B and some analogs and the fact that the natural
compound is no longer available from its natural source
have led to several groups to develop the total syntheses
of the natural alkaloid.1,2 From the three reported total
syntheses, those of Molina3 and Alvarez4 used a similar
strategy to build up the tricyclic heterocyclic core, with
the pyrimidine ring being constructed by an annelation
method on the 7-azaindole system. In the strategy
described by Morris5 the tricyclic system is formed from
pre-existent pyridine and pyrimidine rings using the possi-
bilities offered by a highly symmetrical key intermediate.
Regarding the functionality present in the alkaloid, the
three total syntheses incorporate the oxygen substituent
on the pyridine ring in some of the starting compounds.
However, the amino functionality at C9 is introduced in
relatively early stages in the approaches of Molina and
Alvarez, but in the Morris synthesis this group is incorpo-
rated in an advanced intermediate. The pyrimidine substi-
tuent at C5 is the last substituent to be introduced in
both the Alvarez and the Molina routes—albeit using dif-
ferent strategies—while in the Morris approach this hetero-
cyclic substituent can be viewed as a starting material.
Me
H2N
N
+
OH
R
5
_
R =
R =
Variolin A (1)
4
N
3
2
O
6
N
7
N
N
H2N
1
N8
Variolin B (2)
Variolin D (3)
9
H2N
N
*
Corresponding authors. Tel.: +34 1 8854761; fax: +34 1 8854686
R = CO2Me
(J.J.V.).
Fig. 1. Structure of the variolin alkaloid family.
E-mail address: juanjose.vaquero@uah.es (J. J. Vaquero).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.063

4074
A. Baeza et al. / Tetrahedron Letters 49 (2008) 4073–4077
OR
N
OR
N
Br
Br
Br
TosMIC
PTC
N
N
CO2R
N
OR
O
13
X
N
Br
12
Br
X
N
N
Br
OR
O
7
2
N
+
CO2R
N
Z
z
Ts
N
Z
14
11
Scheme 1. Approach and retrosynthesis for variolin B.
However, the reported methods employed in the synthesis
of this nucleus scarcely explored the introduction of chem-
ical diversity at C4 position (oxygen functionality),2c,dwith
the Morris synthesis having the best potential to introduce
alkyl- and aryl-amino substituents at C9 and the Alvarez
synthesis for aryls and heteroaryls at C5 (Fig. 1).
(heterocyclic core of variolins). This makes the approach
well suited not only for the synthesis of this alkaloid
but also for the eventual structural modification of the nat-
ural product using sequential palladium-mediated C–N,
C–C, and C–O coupling reactions for the installation of
key-structural substituents.
In this Letter we wish to disclose a conceptually different
approach to variolin B that is based on the synthesis of a
trihalo-substituted pyrido[30,20:4,5]-pyrrolo[1,2-c]pyrimidine
Our initial strategy for the synthesis of the heterocyclic
core of variolin B was based on an unprecedented reaction
between a protected 4-alkoxy-3-bromo-2-bromomethyl-7-
X
Br
N
N
11a
CO2Me
N
Cl
14a: X= Cl (43%)
14b: X = OMe (0%)
MeBu3NCl
CH2Cl2
X
Br
Br
Cl
Br
NaOH (15%)
N
N
CO2Me
7a: X = Cl
11b
7b: X = OMe
N
N
TBACl
CH2Cl2
15
CO2Me
N
11a
LiOH
(30%)
X
Palladium-mediated
C-O bond formation
Br
N
Palladium-mediated
C-C bond formation
N
Cl
N
Cl
Br
N
8a: X = Cl (58%)
8b: X = OMe (31%)
Palladium-mediated
C-N bond formation
N
N
8a
Cl
Scheme 2. Synthesis of the trihalo-functionalized pyrido[30,20:4,5]pyrrolo[1,2-c]pyrimidine 8a.

A. Baeza et al. / Tetrahedron Letters 49 (2008) 4073–4077
4075
azaindole 12 and tosylmethylisocyanide (TosMIC) under
phase transfer conditions.6 This allowed the efficient
preparation of the appropriately substituted pyrido-
[30,20:4,5]pyrrolo[1,2-c]pyrimidine carboxylate7 (Scheme 1).
However, from the resulting intermediate 13 the total
synthesis of variolin B could not be achieved because all
attempts to carry out the amination at the C9 position
failed.
We envisaged that this strategy for building up the tricy-
clic system might serve for variolin synthesis if we were able
to find a reagent suitable for the heterocyclization reaction
leading to the pyrimidine nucleus and for the incorporation
of some functionality at C9 that could be transformed into
the amino group. As this intermediate should have the gen-
eral structure 14, our reagents of choice were tosylmethyl-
imines 11 with the structure represented in Scheme 1.
As noted above, our original strategy was to construct a
trihalo-functionalized pyrido[30,20:4,5]pyrrolo[1,2-c]pyrimi-
dine that could be used for variolin B through sequential
palladium-catalyzed coupling reactions. Thus, from the dif-
ferent possibilities for 11 (Z = Cl, Br, OMe, SMe) our
choices were 11a (Z = Cl) and 11b (Z = Br). These N-
tosylmethyl dihaloformimides were prepared on a multi-
gram scale by improving the literature procedure8 (see Sup-
plementary data).
Two 4-substituted 3-bromo-2-bromomethylpyrrolo-
[2,3-b]pyridin-1-yl methyl carboxylates (7a: X = Cl; 7b:
X = OMe)7 were also chosen as starting azaindoles for
the reaction with 11a,b, as we envisaged that a methoxy
group in the C4 position of the tricycle would prove very
convenient for the synthetic strategy if variolin B were
not feasible from 7a.
Table 1
Optimization of the C–O coupling reaction on 2-methyl-4-chloroquinoline (16)
OC(Me)3
Cl
NaO t-Bu (2 eq)
N
Me
N
Me
17
16
Entry
Catalyst
Phosphine
Conditions
17 Yield (%)
1
2
—
—
BINAP
Toluene, 110 °C
Toluene, 110 °C
NR
NR
Pd2(dba)3 (10%)
3
4
5
6
7
8
9
Pd2(dba)3 (10%)
Pd2(dba)3 (10%)
Ni(cod)2 (10%)
Pd2(dba)3 (5%)
Pd2(dba)3 (5%)
Pd2(dba)3 (5%)
Pd2(dba)3 (5%)
Toluene, 110 °C, 20 h
Traces
43
tBu2P
tBu2P
tBu2P
tBu2P
tBu2P
tBu2P
tBu2P
Toluene, 150 °C, sealed vessel, 20 h
Toluene, 150 °C, sealed vessel, 20 h
Toluene, 150 °C, MW, 150 W, 5 min
Toluene/t-BuOH, 150 °C, MW, 150 W, 5 min
Toluene/t-BuOH, 150 °C, MW, 300 W, 2 min
MeCN, 150 °C, MW, 300 W, 2 min
NR
34
64
65
13
10
11
Pd2(dba)3 (5%)
Pd2(dba)3 (5%)
dppf
BINAP
Toluene/t-BuOH, 150 °C, MW, 300 W, 2 min
Toluene/t-BuOH, 150 °C, MW, 300 W, 2 min
12
41

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A. Baeza et al. / Tetrahedron Letters 49 (2008) 4073–4077
Initial results showed that the reaction of 7a,b and 11a,b
and C9 using the palladium methodology was previously
shown to be successful in this pyrido[30,20:4,5]pyrrolo[1,2-
c]pyrimidine system.4,9 As a result, the key step of this
approach to variolin B was the formation of the C–O bond
at the C4 position.
The C–O coupling reaction has rarely been used in het-
erocyclic chemistry, although several methods are known
in which it has been applied to aryl halides using Ni or
Pd as catalysts.10 Thus, before attempting the C–O func-
tionalization on 8a we decided to test the feasibility of this
unprecedented heterocyclic reaction on a commercially
available 2-methyl-4-chloroquinoline model 16. The reac-
tion of 16 and sodium tert-butoxide (NaOt-Bu) was
attempted in the presence of several catalysts and ligands
at different temperatures. The results obtained are summa-
rized in Table 1.
Initial experiments showed that in the absence of the
palladium catalyst, the reaction failed (entry 1, Table 1)
and only when the reaction was carried out in toluene in
the presence of tris(dibenzylideneacetone) dipalladium (0)
[Pd2(dba)3] at 150 °C in a sealed vessel for 20 h (entry
4) was 17 obtained in moderate yield (43%). Under
similar conditions, catalyst bis(1,5-cyclooctadiene)nickel(0)
[Ni(cod)2] proved to be unsuccessful (entry 5). In order to
find milder conditions that should be more appropriate
for the variolin B synthesis, we attempted this coupling
failed under different homogeneous conditions [DBU/
CH2Cl2, NEt3/CH2Cl2, i-Pr2NEt, 14% NaOH], and
phase-transfer catalyst (PTC) conditions were necessary
to obtain intermediate 14a (X = Cl, Scheme 2). Moreover,
N-tosylmethyl dibromoformimide 11b was prone to lose
bromine to regenerate TosMIC, which reacted with 7a to
give the previously described 5-bromopyrido[30,20:4,5]pyr-
rolo[1,2-c]pyrimidin-7-yl methyl carboxylate 15.7
In the search for the optimal PTC conditions, a number
of catalysts for the reaction of 7a,b and 11a were screened.
In a precedent report,9 it was found that compound 14a
was not formed on using higher concentrations of NaOH
(30%) and the unexpected compound 8a was isolated
instead. This result was very convenient since it circum-
vents the need to remove the methoxycarbonyl group from
14a. Therefore, we concentrated our efforts on finding a set
of appropriate conditions to obtain 8a, with the optimized
conditions shown in Scheme 2. It is worth noting
that, under the optimal conditions found for 8a, pyr-
ido[30,20:4,5]pyrrolo[1,2-c]pyrimidine 8b (X = OMe) is
obtained in only 31% yield (Scheme 2).
The completion of the synthesis of variolin B involved
intermediate 8a, from which the natural product might be
obtained by three successive palladium-promoted cross-
coupling reactions (Scheme 2). Functionalization in C5
Cl
1) LiHMDS/THF, -78ºC
Ref. 7
2) ClCO2Me
Me
N
N
N
N
86%
H
H
5
4
Cl
Cl
Cl
N
Br
NBS (2.2 eq)
CH2Cl2
Ts
N
Cl
Br
11a
Me
LiOH (30%)/CH2Cl2
N
N
75%
N
TBACl
58%
OMe
OMe
O
6a
Cl
O
7a
SnMe3
1. Pd2(dba) 3 (5%)/THF
Phosphine (10%)
Br
N
Cl
N
R
1.
LiHMDS/Ph3SiNH2
N
NHAc
N
N
Pd2(dba)3, PPh3
LiCl, CuI, dioxane
2. MeOH/HCl
48%
2. Ac2O
51%
N
N
Cl
N
8a
AcHN
R = Br
R = l
9a
9b
1. AIBN/TTMSS/THF
2. NIS/CH2Cl2
75%
N
NH2
Cl
N
1. NaOtBu (2 eq)
Pd2(dba)3 (5%)/phosphine (10%)
N
Toluene /
t
-BuOH
Variolin B (2)
N
2. H2O/HCl
N
48%
H2N
10
Scheme 3. Total synthesis of variolin B.

A. Baeza et al. / Tetrahedron Letters 49 (2008) 4073–4077
4077
reaction using microwave heating. The best results (65%
yield) were obtained using a mixture of toluene/t-BuOH
as solvent, Pd2(dba)3 (5 mol %) and (2-biphenyl)di-t-butyl-
phosphine (10 mol %), with a reaction time of only 2 min at
300 W power (entry 8). Under these conditions, further
experiments with other ligands and solvents failed to
improve on this yield.
associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2008.04.063.
References and notes
1. (a) Trimurtulu, G.; Faulkner, D. J.; Perry, N. B.; Ettouati, L.;
Litaudon, M.; Blunt, J. W.; Munro, M. H. G.; Jameson, G. B.
Tetrahedron 1994, 50, 3993–4000; (b) Perry, N. B.; Ettouati, L.;
Litaudon, M.; Blunt, J. W.; Munro, M. H. G.; Parkin, S.; Hope, H.
Tetrahedron 1994, 50, 3987–3992.
2. (a) Fresneda, P. M.; Delgado, S.; Francesch, A.; Manzanares, I.;
Cuevas, C.; Molina, P. J. Med. Chem. 2006, 49, 1217–1221; (b)
Simone, M.; Erba, E.; Damia, G.; Vikhanskaya, F.; Di Francesco, A.
The overall synthesis of intermediate 8a from 7-azain-
dole 4, and its conversion into variolin B are shown in
Scheme 3. The amination reaction at the C9 position was
carried out with the system lithium bis(trimethyl-
silyl)amide/triphenylsilylamine (LiHMDS/Ph3SiNH2) as
the ammonia source in the presence of Pd2(dba)3. This gave
9a after protection of the amino group. According to pre-
vious reports for a related system,4 the attempted C–C cou-
pling reaction between 9a and the appropriate N-(4-
trimethylstannylpyrimidin-2-yl)acetamide did not give the
expected coupling product 10 after a large number of
experiments with different catalysts, ligands, and condi-
tions-most of which resulted in the recovery of 9a or its
decomposition. To enhance the low reactivity of 9a, it
was transformed into the corresponding iodo-derivative
by a debromination–iodination process to give 9b in 75%
yield. Fortunately, 9b did react with the pyrimidyl stannyl
compound to afford the expected coupling product 10,
after deprotection of both amino groups, albeit in moder-
ate yield.11 Finally, 10 was converted into variolin B by
the introduction of the t-butoxy group in the C4 position
using the same optimized conditions found for the C–O
bond formation in 16 followed by the removal of the t-
butyl protecting group under acid conditions.
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In conclusion, we have developed a new convergent
synthesis of variolin B starting from the commercially
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available 7-azaindole. From this,
a trihalo pyrido-
[30,20:4,5]pyrrolo[1,2-c]pyrimidine was obtained as the key
intermediate by a new heterocyclization reaction between
an appropriate bromomethyl azaindole and N-tosylmethyl
dichloroformimide. From this intermediate, the natural
product was obtained by three successive palladium-pro-
moted cross-coupling reactions.
10. (a) Thutewohl, M.; Schirok, H.; Bennabi, S.; Figueroa-Perez, S.
Synthesis 2006, 629–632; (b) Anderson, K. W.; Ikawa, T.; Tundel, R.
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11. Although the 3-iodo-2-methylpyrrolo[2,3-b]-pyridin-1-yl methyl car-
boxylate, an analogue of 6a with iodo in C-3, could be prepared, all
attempts to obtain the diiodo analogue of 7a using NIS failed.
Unexpectedly, the reaction of 3-iodo-2-methylpyrrolo[2,3-b]pyridin-1-
yl methyl carboxylate with NBS afforded 3-bromo-2-bromomethyl-
pyrrolo[2,3-b]pyridin-1-yl methyl carboxylate, likely by an ipso-
substitution proccess in C-3 position.12
Acknowledgments
The authors acknowledge financial support from the
´
Spanish Ministerio de Educacion y Ciencia (project
CTQ2005/011060/BQU), Comunidad de Madrid (CAM),
´
and Universidad de Alcala (UAH) (project CCG-UAH/
´
SAL-0660) and a grant from the Ministerio de Educacion
y Ciencia (A.B.).
Supplementary data
´
´
12. Burgos, C.; Delgado, F.; Garcıa-Navıo, J. L.; Izquierdo, M. L.;
Experimental procedures and characterization data for
Alvarez-Builla, J. Tetrahedron 1995, 51, 8649–8654.
compounds 5-11 and intermediates. Supplementary data