Siloxane-Based Cross-Coupling of Bromopyridine Derivatives: Studies for the Synthesis of Streptonigrin and Lavendamycin

Article abstract of DOI:10.1021/ol0357503

(Equation Presented) Highly functionalized 4-bromopyridines were prepared and found to undergo fluoride-promoted, Pd-catalyzed cross-coupling with aryltrialkoxy-silanes to give sterically demanding biaryls. The 3-nitro-4-bromopyridine derivative coupled i

Full text of DOI:10.1021/ol0357503

ORGANIC
LETTERS
2003
Vol. 5, No. 25
4779-4782
Siloxane-Based Cross-Coupling of
Bromopyridine Derivatives: Studies for
the Synthesis of Streptonigrin and
Lavendamycin
William T. McElroy and Philip DeShong*
Department of Chemistry and Biochemistry, UniVersity of Maryland,
College Park, Maryland 20742
deshong@umd.edu
Received September 11, 2003
ABSTRACT
Highly functionalized 4-bromopyridines were prepared and found to undergo fluoride-promoted, Pd-catalyzed cross-coupling with aryltrialkoxy-
silanes to give sterically demanding biaryls. The 3-nitro-4-bromopyridine derivative coupled in good yield with TBAT (tetrabutylammonium
triphenyldifluorosilicate) to provide a biaryl adduct that serves as a model system for the total synthesis of the antitumor antibiotics streptonigrin
and lavendamycin.
Palladium-catalyzed coupling reactions continue to be widely
employed to form carbon-carbon bonds.1 In particular, the
Scheme 1
Stille2 (organostannane) and Suzuki-Miyaura3 (organobo-
rane) reactions have been exploited to form unsymmetrical
biaryls in the syntheses of numerous natural products.4 Each
of these approaches has its strengths and limitations with
regard to the cross-coupling reaction.
Our laboratory has recently demonstrated that hypervalent
fluorosilicate derivatives can be employed as substrates in
palladium-catalyzed cross-coupling reactions with aryl ha-
lides and triflates, respectively (Scheme 1). Either aryl
siloxane method. In this context, we chose to synthesize the
antitumor antibiotics streptonigrin7,8 (1) and lavendamycin9,10
siloxanes or preformed aryl fluorosilicates (i.e., TBAT) can
be utilized in the coupling process.5,6 A goal of our studies
has been to determine the scope and limitations of the
(5) (a) Correia, R.; DeShong, P. J. Org. Chem. 2001, 66, 7159-7165.
(b) DeShong, P.; Handy, C. J.; Mowery, M. E. Pure Appl. Chem. 2000,
72, 1655-1658. (c) Mowery, M. E.; DeShong, P. Org. Lett. 1999, 1, 2137-
2140. (d) Mowery, M. E.; DeShong, P. J. Org. Chem. 1999, 64, 3266-
3270. (e) Mowery, M. E.; DeShong, P. J. Org. Chem. 1999, 64, 1684-
1688.
(1) (a) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. ReV. 2002, 102, 1359-1469. (b) Tsuji, J. Palladium Reagents and
Catalysts. InnoVations in Organic Synthesis; John Wiley & Sons: New
York, 1995.
(2) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524.
(3) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(4) For some recent examples, see: (a) Inoue, M.; Sakazaki, H.;
Furuyama, H.; Hirama, M. Angew. Chem., Int. Ed. 2003, 42, 2654-2637.
(b) Miyashita, K.; Ikejiri, M.; Kawasaki, H.; Maemura, S.; Imanishi, T. J.
Am. Chem. Soc. 2003, 125, 8238-8243.
(6) For some recent advances in the Pd-catalyzed coupling reactions of
organosilanes, see: (a) Denmark, S. E.; Ober, M. H. Org. Lett. 2003, 5,
1357-1360. (b) Denmark, S. E.; Pan, W. Org. Lett. 2003, 5, 1119-1122.
(c) Hiyama, T.; Shirakawa, E. Top. Curr. Chem. 2002, 219, 61-85. (d)
Denmark, S. E.; Sweis, R. F. Org. Lett. 2002, 4, 3771-3774. (e) Denmark,
S. E.; Sweis, R. F. Chem. Pharm. Bull. 2002, 50, 1531-1541.
10.1021/ol0357503 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/11/2003

pyridine will require development of new methods for the
synthesis of heteroaromatic silicon-based coupling reagents.
Previous studies by Godard and Que´guiner have investigated
an analogous biaryl coupling strategy employing stannane
and boronic acids, and we hoped to overcome some of the
limitations that they encountered using siloxane derivatives.
In this paper, we describe studies directed to the synthesis
of pyridine 5 and related compounds that establish the
viability of the C-4/D-4 coupling strategy.
Scheme 2
Bromopyridines 5 and 11-14 were prepared as sum-
marized in Scheme 3. Ethyl-2-methylacetoacetate (7) was
Scheme 3a
(2) using the siloxane coupling as the key reaction in the
approach (see Scheme 2). A particularly challenging feature
of this approach to the synthesis of streptonigrin is the
sequential coupling of the ring AB and D components to a
fully substituted pyridine component (ring C).11 The coupling
at carbon-4 of the pyridine ring (C-4) to carbon-4 (D-4) of
the D-ring phenyl group will be challenging since it will
result in formation of a highly hindered biaryl derivative.
Similarly, the B-2/C-2 coupling of the quinoline ring to the
a Conditions: (a) NH4OH, Bentonite K-10, 93%; (b) CH2(CO2Et)2,
NaOEt, EtOH, PhCH3, reflux, 69%; (c) NaOH then HCl, 99%; (d)
POBr3, DMF, 110 °C; (e) MeI, Ag2CO3, PhH, 30% from 10; (f)
HNO3, H2SO4, 97%; (g) Fe, EtOH, H2O, cat. HCl, 65%; (h)
BOC2O, cat. DMAP, THF, reflux, then K2CO3, MeOH, 52%.
converted to its enamine 8 upon reaction with NH4OH.
Condensation under basic conditions with diethylmalonate
afforded pyridone 9.12 Hydrolysis of the ethyl ester and
subsequent decarboxylation gave 10 in high overall yield.
(7) (a) Rao, K. V. Cullen, W. P. Antibiot. Annu. 1959-1960, 950-953.
(b) Rao, K. V.; Biemann, R.; Woodward, R. B. J. Am. Chem. Soc. 1963,
85, 2532-2533.
(8) Three total syntheses of streptonigrin have been reported: (a)
Weinreb, S. M.; Basha, F. Z.; Hibino, S.; Khatri, N. A.; Kim, D.; Pye, W.
E.; Wu, T.-T. J. Am. Chem. Soc. 1982, 104, 536-544. (b) Kende, A. S.;
Lorah, D. P.; Boatman, R. J. J. Am. Chem. Soc. 1981, 103, 1271-1273.
Boger, D. L.; Panek J. S. J. Am. Chem. Soc. 1985, 107, 5745-5754.
(9) Balitz, D. M.; Bush, J. A.; Bradner, W. T.; Doyle, T. W.; O’Herron,
F. A.; Nettleton, D. E. J. Antibiot. 1982, 35, 259-265. (b) Doyle, T. W.;
Balitz, D. M.; Grulich, R. E.; Nettleton, D. E.; Gould, S. J.; Tann, C.-H.;
Moews, A. E. Tetrahedron Lett. 1981, 22, 4595-4598.
(11) For examples of Pd-catalyzed couplings to form streponigrin
analogues, see: (a) Pomel, V.; Rovera, J. C.; Godard, A.; Marsais, F.;
Que´quiner, G. J. Heterocycl. Chem. 1996, 33, 1995-2005. (b) Godard,
A.; Rocca, P.; Pomel, V.; Thomas-dit-Dumont, L.; Rovera, J. C.; Thaburet,
J. F.; Marsais, F.; Que´quiner, G. J. Organomet. Chem. 1996, 517, 25-36.
(c) Godard, A.; Marsais, F.; Ple´, N.; Tre´court, F.; Turck, A.; Que´guiner, G.
Heterocycles 1995, 40 1055-1091. (d) Godard, A.; Fourquez, J. M.;
Tamion, R.; Marsais, F.; Que´guiner, G. Synlett 1994, 235-236. (e) Godard,
A.; Rocca, P.; Fourquez, J.-M.; Rovera, J.-C.; Marsais, F.; Que´guiner, G.
Tetrahedron Lett. 1993, 34, 7919-7922. (f) Godard, A.; Rovera, J.-C.;
Marsais, F.; Ple´, N.; Que´guiner, G. Tetrahedron 1992, 48, 4123-4134. (g)
Marsais, F.; Rovera, J.-C.; Turck, A.; Godard, A.; Que´guiner, G. J. Chem.
Soc., Perkin Trans. 1 1990, 2611-2612. (h) Crous, R.; Dwyer, C.;
Holzapfel, C. W. Heterocycles 1999, 51, 721-726. (i) Kimber, M.;
Anderberg, P. I.; Harding, M. M. Tetrahedron 2000, 56, 3575-3581. (j)
Fryatt, T.; Goroski, D. T. Nilson, Z. D.; Moody, C. J.; Beall, H. D. Bioorg.
Med. Chem. Lett. 1999, 9, 2195-2198.
(10) For total syntheses of lavendamycin, see: (a) Behforouz, M.;
Haddad, J.; Cai, W.; Arnold, M. B.; Mohammadi, F.; Sousa, A. C.; Horn,
M. A. J. Org. Chem. 1996, 61, 6552-6555. (b) Molina, P.; Murcia, F.;
Fresneda, P. M. Tetrahedron Lett. 1994, 35, 1453-1456. (c) Behforouz,
M.; Gu, Z.; Cai, W.; Horn. M. A.; Ahmadian, M. J. Org. Chem. 1993, 58,
7089-7091. (d) Ciufolini, M. A.; Bishop, M. J. J. Chem. Soc., Chem.
Commun. 1993, 1463-1464. (e) Rama Rao, A. V.; Chavan, S. P.; Sivadasan,
L. Tetrahedron 1986, 42, 5065-5071. (f) Boger, D. L.; Duff, S. R.; Panek,
J. S.; Yasuda, M. J. Org. Chem. 1985, 50, 5790-5795. (g) Hibino, S.;
Okazaki, M.; Ichikawa, M.; Sato, K.; Ishizu, T. Heterocycles 1985, 23,
261-264. (h) Kende, A. S.; Ebetino, F. H. Tetrahedron Lett. 1984, 25,
923-926.
(12) Seeman, J. I.; Secor, H. V.; Chavdarian, C. G.; Sanders, E. B.;
Bassfield, R. L.; Whidby. J. F. J. Org. Chem. 1981, 46, 3040-3048.
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Replacement of the hydroxyl group with bromine at C-4
proved to be difficult as a result of competitive bromination
at C-2. After surveying a variety of brominating agents and
conditions, it was found that bromide 11 could be obtained
readily by reaction of hydroxypyridone 10 with 0.70 equiv
of POBr3 in DMF.
Table 1. Cross-Couplings of 4-Bromopyridines with Siloxanes
Attempts to couple bromopyridone 11 with siloxane
derivatives using standard coupling protocols failed. It was
believed that the high acidity of the N-H proton was
interfering with the coupling reaction. Thus, pyridone 11 was
O-methylated under standard conditions to afford 2-meth-
oxypyridine 12.13 The nitrogen functionality at C-3 required
for the synthesis of streptonigrin was introduced by treatment
of 12 with HNO3 to generate nitropyridine 13. This com-
pound could be subsequently transformed to its amino
derivative 14 and BOC-protected amine 5 by standard
technology.
Trimethylated pyridine 17 was synthesized to provide an
ortho,ortho′-disubstituted substrate that could be employed
to assess the steric limitations of the coupling reaction.
Comparison of the couplings of pyridine 17 with pyridines
5 and 12-14 should provide information regarding both
steric and electronic effects in this system. In a fashion
analogous to the synthesis of pyridine 12, trimethyl pyridine
17 was prepared as depicted in Scheme 4. Condensation of
Scheme 4a
a No improvement of yield was obtained with higher catalyst loadings.
b 36% reduced pyridine was also obtained (see Scheme 5).
catalyst loading, pyridine 12 coupled with phenyltrimethoxy-
silane in 62% yield. Increasing the catalyst loading from 10
to 20 mol % led to an increase in yield to 97%. To ascertain
if more sterically congested systems could be prepared in a
similar manner, bromopyridine 12 was coupled with o-tolyl
siloxane (entry 2); however, the expected biaryl was obtained
in only 10% yield. Increasing the catalyst loadings as high
as 50 mol % resulted in no improvement in yield. The low
yield in the coupling of the o-tolyl siloxane was surprising
because previously it had been shown that this siloxane
efficiently coupled to a variety of aryl halides.
a Conditions: (a) CH3CH(CO2Et)2, NaOEt, EtOH, PhCH3, reflux,
69%; (b) POBr3, 110 °C, 60%; (c) MeI, Ag2CO3, PhH, 45 °C, quant.
To determine if biaryls possessing two methyl groups in
ortho positions to the biaryl bond could be prepared, 3,5-
dimethyl-4-bromopyridine 17 was allowed to react with
PhSi(OMe)3. Gratifyingly, the coupled product was isolated
in 89% yield (entry 3). Therefore, the reaction is tolerant of
the ortho,ortho′ substitution pattern present in the bromopy-
ridine. Given that 20 mol % catalyst was necessary for
maximum yields, subsequent reactions were performed at
this catalyst loading. As expected on the basis of the results
above, bromopyridine 17 gave a low yield of biaryl product
on reaction with o-tolyl siloxane (entry 4).
amino ester 8 with diethyl methylmalonate gave pyridone
15, which upon heating with neat POBr3 produced bromopy-
ridone 1614 in good yield. Finally, treatment with methyl
iodide yielded 2-methoxypyridine 17.
A major concern of the outlined approach was the steric
tolerance of the coupling reaction. This matter was probed
using a series of 4-bromopyridine derivatives, and the results
are summarized in the Table. 3-H-4-Bromopyridine 12 was
chosen as the initial substrate as it is the least sterically
hindered of the bromopyridines. At a typical (10 mol %)
(13) Shiao, M.-J.; Tarng, K.-Y. Heterocycles 1990, 31, 819-824.
(14) Mittelbach, M.; Schmidt, H.-W.; Uray, G.; Junek, H.; Lamm, B.;
Ankner, K.; Bra¨ndstro¨m, A.; Simonsson, R. Acta Chem. Scand. B 1988,
42, 524-529.
Couplings of more highly functionalized siloxane deriva-
tives were investigated employing bromopyridine 17. The
trisubstituted siloxane corresponding to the intact D ring of
Org. Lett., Vol. 5, No. 25, 2003
4781

streptonigrin was subjected to the coupling conditions, but
no biaryl product was obtained (entry 5). Instead protode-
silylated siloxane was recovered quantitatively. These results
are consistent with previous observations that siloxanes with
heteratoms in the ortho position rapidly underwent protode-
silylation under the reaction conditions. On the other hand,
3,4-methylenedioxy-substituted siloxane (entry 6) underwent
coupling in good yield with 17, indicating that electron-rich
biaryls can be prepared using this technology, provided the
siloxane does not possess a heteroatom in the ortho position.
Streptonigrin and lavendamycin possess an amino function
at C-3 rather than a methyl substituent, and bromopyridine
substrates that had a (nascient) amino group in this position
were investigated. Nitropyridine 13 (R ) NO2) and bro-
mopyridine 17 (R ) Me) have approximately the same steric
environment, and it was anticipated that the nitro analogue
would give the adduct with efficiency comparable to its
methyl counterpart. Coupling of nitropyridine 13 with PhSi-
(OMe)3 provided the expected biaryl in 36% yield. An
additional 36% of debrominated pyridine was isolated also.
Since trimethylated bromopyridine 17 had coupled in excel-
lent yield (entry 3), it is apparent that the lower yields
obtained with the nitropyridine analogue were the result of
electronic rather than steric factors. Reduction of the nitro
group to the amino and urethane derivatives, followed by
coupling with PhSi(OMe)3 (entries 8 and 9) failed to give
biaryl product. The results are comparable to those obtained
by Godard and Que´guiner with boronic acid derivatives and
indicate that electronic effects play a significant role in the
oxidative addition step.11
Scheme 5
demanding substrates can be employed in the coupling
reaction but that electronic effects play a pivotal role in the
coupling process for both the siloxane and pyridine sub-
strates. Coupling of nitropyridine 13 is of particular interest
to the synthesis of streptonigrin (1) and lavendamycin (2)
since this substrate incorporates the requisite nitrogen
functionality at C-3 found in ring C of the natural products.
Studies directed at the synthesis of streptonigrin and laven-
damycin are underway, and the results of these studies will
be reported in due course.
Alternative silicon-based aryl transfer reagents were inves-
tigated in an effort to improve the yield of the coupling
reactions with nitropyridine 13. We had previously demon-
strated that TBAT (tetrabutylammonium triphenyldifluoro-
silicate, 20) was capable of phenyl transfer to a wide range
of aryl halides and triflates.15 We were pleased to find that
TBAT underwent cross-coupling in good yield with bro-
mopyridine 17 (Scheme 5). Notably, none of debrominated
pyridine 19 was obtained under these conditions.
Acknowledgment. We thank the National Cancer Insti-
tute (CA-82169) for generous financial support. We also
thank Dr. Yiu-Fai Lam (NMR) and Noel Whittaker (MS)
for their assistance in obtaining spectral data. This manuscript
is dedicated to Professor Duilio Arigoni on the occasion of
his 75th birthday.
Supporting Information Available: Experimental pro-
cedures and spectral data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, the scope of Pd-catalyzed siloxane couplings
has been extended to include highly functionalized 4-bro-
mopyridines. These studies have demonstrated that sterically
(15) Brescia, M.-R.; DeShong P. J. Org. Chem. 1998, 63, 3156-3157.
OL0357503
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