Cross-coupling reactions of indium organometallics with 2,5-dihalopyrimidines: Synthesis of hyrtinadine A+

Article abstract of DOI:10.1021/ol801393n

(Chemical Equation Presented) The palladium-catalyzed cross-coupling reaction of triorganoindium reagents (R₃In) with 5-bromo-2- chloropyrimidine proceeds chemoselectively, in good yields, to give 5-substituted-2-chloropyrimidines or 2,5-disubstituted pyrimidines using 40 or 100 mol % of R₃In, respectively. Sequential cross-couplings are also performed, in one pot, using two different R₃In. This method was used to achieve the first synthesis of the alkaloid hyrtinadine A. The key step was a two-fold cross-coupling reaction between a tri(3-indolyl)indium reagent and 5-bromo-2-chloropyrimidine.

Full text of DOI:10.1021/ol801393n

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3745-3748
Cross-Coupling Reactions of Indium
Organometallics with
2,5-Dihalopyrimidines: Synthesis of
Hyrtinadine A†
Ángeles Mosquera, Ricardo Riveiros, José Pérez Sestelo,* and
Luis A. Sarandeses*
Departamento de Qu´ımica Fundamental, UniVersidade da Corun˜a,
E-15071 A Corun˜a, Spain
sestelo@udc.es; qfsarand@udc.es
Received June 20, 2008
ABSTRACT
The palladium-catalyzed cross-coupling reaction of triorganoindium reagents (R3In) with 5-bromo-2-chloropyrimidine proceeds chemoselectively,
in good yields, to give 5-substituted-2-chloropyrimidines or 2,5-disubstituted pyrimidines using 40 or 100 mol % of R3In, respectively. Sequential
cross-couplings are also performed, in one pot, using two different R3In. This method was used to achieve the first synthesis of the alkaloid
hyrtinadine A. The key step was a two-fold cross-coupling reaction between a tri(3-indolyl)indium reagent and 5-bromo-2-chloropyrimidine.
The palladium-catalyzed cross-coupling reaction of indium
organometallics with organic electrophiles is a useful
reaction in organic synthesis.1 In this reaction, triorga-
noindium compounds (R3In, alkyl, alkenyl, aryl and
alkynyl) can be efficiently coupled with aryl, benzyl, and
alkenyl halides and triflates. The main features of these
reactions are their high efficiency, versatility, and chemose-
lectivity, where all three organic groups bonded to indium
are efficiently transferred to the electrophile. Additionally,
organoindium reagents can be used in asymmetric cross-
coupling reactions with racemic benzyl halides.1h Despite
these appealing properties and the fact that the cross-
coupling reaction is a fundamental tool in organic
synthesis, the utility of indium organometallics in natural
product synthesis has been demonstrated in only a limited
number of examples.2 In this communication we report
the cross-coupling reactions of R3In with 2,5-dihalopyri-
midines and the application of this method to the synthesis
of hyrtinadine A.
† Dedicated to Professor Antonio Mourin˜o on the occasion of his 60th
birthday.
(2) (a) Lehmann, U.; Awasthi, S.; Minehan, T. Org. Lett. 2003, 5, 2405–
2408. (b) Yanada, R.; Obika, S.; Oyama, M.; Takemoto, Y. Org. Lett. 2004,
6, 2825–2828. (c) Gopalsamuthiram, V.; Wulff, W. D. J. Am. Chem. Soc.
2004, 126, 13936–13937. (d) Yanada, R.; Obika, S.; Kobayashi, Y.;
Inokuma, T.; Oyama, M.; Yanada, K.; Takemoto, Y. AdV. Synth. Catal.
2005, 347, 1632–1642. (e) Mukai, C.; Hirose, T.; Teramoto, S.; Kitagaki,
S. Tetrahedron 2005, 61, 10983–10994. (f) Frenzel, T.; Bruenjes, M.;
Quitschalle, M.; Kirschning, A. Org. Lett. 2006, 8, 135–138. (g) Rega, M.;
Candal, P.; Jime´nez, C.; Rodr´ıguez, J. Eur. J. Org. Chem. 2007, 934–942.
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A. Org. Lett. 2007, 9, 1489–1492. (i) Meyer, A.; Kirschning, A. Synlett
2007, 1264–1268. (j) Sua´rez, R. M.; Martínez, M. M.; Sarandeses, L. A.;
Pe´rez Sestelo, J. Tetrahedron Lett. 2007, 48, 6493–6495.
(1) (a) Pérez, I.; Pérez Sestelo, J.; Sarandeses, L. A. Org. Lett. 1999, 1,
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Sarandeses, L. A. Chem. Commun. 2002, 2246–2247. (d) Pena, M. A.; Pe´rez
Sestelo, J.; Sarandeses, L. A. Synthesis 2003, 780–784. (e) Rodr´ıguez, D.;
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10.1021/ol801393n CCC: $40.75
Published on Web 08/02/2008
2008 American Chemical Society

Scheme 1
.
Retrosynthetic Analysis for Hyrtinadine A
Table 1. Palladium-Catalyzed Cross-Coupling Reactions of
Triorganoindium Reagents with 5-Bromo-2-chloropyrimidine (5)
Hyrtinadine A (1, Scheme 1) is a novel bis-indole
alkaloid with a 2,5-disubstituted pyrimidine nucleus,
recently isolated from an Okinawan marine sponge of the
Hyrtios genus.3 This compound exhibits in vitro cytotoxic
activity against murine leukemia L1210 cells (IC50 1 µg/
mL) and human epidermoid carcinoma KB cells (IC50
3
µg/mL). Structurally related metabolites isolated from the
Hyrtios genus are important biologically active com-
pounds.4
The synthesis of hyrtinadine A was envisaged by a two-
fold cross-coupling reaction between a 3-indolylindium
derivative (2, Scheme 1) and a 2,5-dihalopyrimidine (3).
The 3-indolylindium derivative 2 could be prepared from
a 3-bromoindole (4). This method could also prove useful
for the synthesis of other 2,5-disubstituted pyrimidines,
which are attractive compounds that are of interest in
materials science5 and as intermediates in the synthesis
of pharmaceuticals.6
Before undertaking the synthesis of hyrtinadine A, we
studied the reactivity of R3In in metal-catalyzed cross-
coupling reactions with 2,5-dihalopyrimidines. In general,
cross-coupling reactions with pyrimidines are quite
rare.5b–d,6,7 For this reason, we found it of particular interest
to study the reactivity of R3In with the commercially
available 5-bromo-2-chloropyrimidine (5, Table 1). The
a Isolated yields. b Reaction performed with Pd(dppf)Cl2 (5 mol %) as
catalyst. c Reaction performed with Pd(Ph3P)4 (5 mol %) as catalyst.
different substitution on the pyrimidine ring should allow
monosubstituted pyrimidines by single selective coupling
reactions or 2,5-disubstituted pyrimidines by dicoupling
reactions. Additionally, the high chemoselectivity of R3In
could also allow sequential cross-coupling reactions.1c,f
(3) Endo, T.; Tsuda, M.; Fromont, J.; Kobayashi, J. J. Nat. Prod. 2007,
70, 423–424.
(4) Blunt, J. W.; Copp, B. R.; Hu, W.-P.; Munro, M. H. G.; Northcote,
P. T.; Prinsep, M. R. Nat. Prod. Rep. 2008, 25, 35–94, and previous reviews
in this series.
In our initial experiments we found that the palladium-
catalyzed reaction of triphenylindium (40 mol %) with 5
using Pd(Ph3P)4 (5 mol %) under reflux for 6 h afforded
2-chloro-5-phenylpyrimidine (6) in 81% yield (Table 1,
entry 1). This result shows that R3In transfers the three
groups to the pyrimidine ring and that the C-5 position is
more reactive in cross-coupling reactions. During the
catalyst screening, the best results were obtained using
Pd(Ph3P)4 (5 mol %), although Pd(dppf)Cl2 also gave
satisfactory yields. Other aryl- and heteroarylindium
reagents, such as thiophenyl-, pyridyl-, naphthyl-, and
alkynylindium reagents, also reacted with 5-bromo-2-
chloropyrimidine to afford the corresponding 2-chloro-5-
(5) (a) Gompper, R.; Mair, H.-J.; Polborn, K. Synthesis 1997, 696–718.
(b) Wong, K.-T.; Hung, T. S.; Lin, Y.; Wu, C.-C.; Lee, G.-H.; Peng, S.-
M.; Chou, C. H.; Su, Y. O. Org. Lett. 2002, 4, 513–516. (c) Hughes, G.;
Wang, C.; Batsanov, A. S.; Fern, M.; Frank, S.; Bryce, M. R.; Perepichka,
I. F.; Monkman, A. P.; Lyons, B. P. Org. Biomol. Chem. 2003, 1, 3069–
3077. (d) Wong, K.-T.; Fang, F.-C.; Cheng, Y.-M.; Chou, P.-T.; Lee, G.-
H.; Wang, Y. J. Org. Chem. 2004, 69, 8038–8044.
(6) (a) Ismail, M. A.; Arafa, R. K.; Brun, R.; Wenzler, T.; Miao, Y.;
Wilson, W. D.; Generaux, C.; Bridges, A.; Hall, J. E.; Boykin, D. W. J. Med.
Chem. 2006, 49, 5324–5332. (b) Pe´rez-Balado, C.; Willemsens, A.;
Ormerod, D.; Aelterman, W.; Mertens, N. Org. Process Res. DeV. 2007,
11, 237–240.
(7) (a) Solberg, J.; Undheim, K. Acta Chem. Scand. 1989, 43, 62–68.
(b) Jiang, B.; Yang, C.-G.; Xiong, W.-N.; Wang, J. Bioorg. Med. Chem.
2001, 9, 1149–1154. (c) Schomaker, J. M.; Delia, T. J. J. Org. Chem. 2001,
66, 7125–7128. (d) Large, J. M.; Clarke, M.; Williamson, D. M.; McDonald,
E.; Collins, I. Synlett 2006, 861–864. (e) Ceide, S. C.; Montalban, A. G.
Tetrahedron Lett. 2006, 47, 4415–4418. (f) For a review, see: Fairlamb,
(8) The cross-coupling reaction using alkylindium reagents proceeded
with lower yields and chemoselectivity, requiring longer reaction times.
I. J. S. Chem. Soc. ReV. 2007, 36, 1036–1045
.
3746
Org. Lett., Vol. 10, No. 17, 2008

substituted pyrimidines 7-10 in good yields (62-83%,
Table 1, entries 2-5).8
bromination with NBS at low temperature afforded the
desired 3-bromoindole 18 in a one-pot procedure in 90%
yield.10
The use of a slight excess of R3In (100 mol %) and
longer reaction times (12-18 h) led to the efficient double
cross-coupling, and a variety of symmetrical 2,5-diaryl,
diheteroaryl, and dialkynyl pyrimidines 11-15 were
obtained in good yields (60-95%, Table 1, entries 6-10).
It is remarkable that the two-fold cross-coupling takes
place efficiently with the 2-chloro-substituted pyrimidine.
Usually, cross-coupling reactions at the C-2 position of
pyrimidines are performed using 2-bromo- or 2-iodo-
substituted pyrimidines,5b–d,6 compounds that are not readily
available. In general, the cross-coupling reaction of 2-chlo-
ropyrimidines requires nonconventional catalysts, higher
temperatures, or nonclassical methods.7 On the other hand,
the chemoselectivity shown by triorganoindium reagents is
comparable to the other few organometallics reported.6b,7a,d
At this point we became fascinated by the possibility
of performing chemoselective sequential (one-pot) cross-
coupling reactions, a reaction type that is only known for
Suzuki and indium couplings.1c,f,9 The reaction of 5 with
tri(4-methoxyphenyl)indium (40 mol %) in the presence of
Pd(Ph3P)4 (5 mol %) for 6 h, followed by addition of
triphenylindium (70 mol %), afforded after 12 h the cross-
coupling product 16 in 70% yield (Scheme 2). When the
The lithium-halogen exchange reaction of 18 with
n-BuLi at low temperature, followed by addition of InCl3,
afforded the indolylindium reagent 19 in solution (Scheme
3). The reaction of 19 (100 mol %), with 5-bromo-2-
Scheme 3. Synthesis of Hyrtinadine A (1)
Scheme 2
.
Sequential Palladium-Catalyzed Cross-Coupling
chloropyrimidine (100 mol %) in the presence of
Pd(Ph3P)4 (5 mol %), gave after heating under reflux in
THF for 18 h the 2,5-bis(indolyl)pyrimidine 20 in excel-
lent yield (87%).11
Reaction with 5
With N,N’-di-tert-butyldimethylsilyl-5,5′-dimethylhyr-
tinadine A (20) in hand, the deprotection was assessed
using two alternative routes: removal of the silyl groups
followed by cleavage of the methyl ethers or vice versa.
The initial cleavage of the silyl group with TBAF afforded
an insoluble material that proved difficult to handle.
Alternatively, treatment of 20 with BBr3 at low temper-
ature afforded the dihydroxyindole 21 (72% yield), which
was converted into hyrtinadine A by treatment with TBAF
in 81% yield.
same sequence was performed with tri(2-thiophenyl)indium
and tri(phenylethynyl)indium, compound 17 was obtained
in a satisfactory 57% yield. These reactions are new examples
of the very few reported precedents in sequential cross-
coupling reactions and the first examples involving the use
of R3In with pyrimidines. The high chemoselectivity and the
high atom efficiency shown by the indium reagents are
remarkable and confirm the usefulness of these reagents for
the preparation of a variety of substituted pyrimidines.
After discovering that R3In are efficient reagents for
single, double, and sequential cross-coupling reactions
with 2,5-dihalopyrimidines such as 5, we decided to apply
our method to the synthesis of the natural alkaloid
hyrtinadine A (1, Scheme 1). According to our synthetic
strategy, the first step was the preparation of a function-
alized 3-indolylindium reagent (2) from a 3-bromoindole
(4). In this way, starting from the commercially available
5-methoxyindole, N-silylation with TBSCl followed by
The spectroscopic and analytical data for synthetic
hyrtinadine A were almost identical to those reported by
3
1
Kobayashi et al. The H NMR spectrum is fully consis-
tent, but the 13C NMR spectrum differs in the 112.0-112.6
ppm region, where we observed four peaks instead of the
three signals (4 carbons) reported. This difference can
probably be attributed to the NMR aquisition method or
due to the small amount of the natural product isolated
(1 mg).
In summary, we have shown that indium organometallics are
useful reagents for chemoselective cross-coupling reactions with
(10) (a) Gerasimov, M.; Marona-Lewicka, D.; Kurrasch-Orbaugh, D. M.;
Qandil, A. M.; Nichols, D. E. J. Med. Chem. 1999, 42, 4257–4263. (b)
Amat, M.; Seffar, F.; Llor, N.; Bosch, J. Synthesis 2001, 267–275.
(11) The use of lower amounts of the tri(3-indolyl)indium reagent or
shorter reaction times provided the monocoupling product at the C-5 position
in good yields (75-85%). For further details, see Supporting Information.
(9) Tsvetkov, A. V.; Latyshev, G. V.; Lukashev, N. V.; Beletskaya, I. P.
Tetrahedron Lett. 2002, 43, 7267–7270
.
Org. Lett., Vol. 10, No. 17, 2008
3747

halo(chloro and bromo)pyrimidines. This method was applied
to the first synthesis of the natural product hyrtinadine A using
the palladium-catalyzed cross-coupling reaction of indium
organometallics. The synthesis, which is short and efficient, was
developed in four steps (46% overall yield) from commercially
available 5-methoxyindole. Further applications of this method
in the synthesis of natural products are now under investigation.
thanks the Ministerio de Educacio´n y Ciencia of Spain
for a predoctoral fellowship (FPI) and R.R. thanks the
Xunta de Galicia for a research contract sponsored by the
Isidro Parga Pondal Program.
Supporting Information Available: Experimental pro-
cedures, spectroscopic and analytical data for compounds
prepared, and copies of NMR spectra for compounds
prepared. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We are grateful to the Ministerio de
Educacio´n y Ciencia (Spain, CTQ2006-06166), Univer-
sidade da Corun˜a, and FEDER for financial support. A.M.
OL801393N
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Org. Lett., Vol. 10, No. 17, 2008