Palladium-catalyzed cross-coupling in the synthesis of pyridinyl boxazomycin C analogues

Article abstract of DOI:10.1021/jo0510033

Palladium-catalyzed cross-coupling of 2-thiomethylbenzoxazoles with tri-alkylstannyl pyridines efficiently produces pyridinyl boxazomycin C analogues.

Full text of DOI:10.1021/jo0510033

Palladium-Catalyzed Cross-Coupling in the
Synthesis of Pyridinyl Boxazomycin C
Analogues
Chris Richardson,† Gordon W. Rewcastle,*,†
Denton Hoyer,‡ and William A. Denny†
Auckland Cancer Society Research Centre, Faculty of
Medical and Health Sciences, The University of Auckland,
Private Bag 92019, Auckland 1020, New Zealand, and
Pfizer Global Research and Development,
FIGURE 1. Boxazomycins.
Ann Arbor Laboratories, 2800 Plymouth Road,
Ann Arbor, Michigan 48106-1047
of such reagents and offer the promise of introducing
sensitive functional groups without the need for ad-
ditional protection/deprotection sequences or the use of
harsh deprotection conditions. Consistent with this aim
is the use of palladium chemistry, which is tolerant of
many functional groups.
g.rewcastle@auckland.ac.nz
Received May 20, 2005
The Stille cross-coupling reaction continues to enjoy
success in heterocyclic chemistry.3 Recently, 2-chloro-
oxazoles have been shown to be good substrates for a
variety of palladium-catalyzed coupling processes includ-
ing the Stille reaction.4 Trialkyl organostannanes can be
produced by lithiation procedures when quenched with
trialkyltin halides. Because we desired an ester at C-4
in the A-ring of the analogues, we determined that the
preparation of a trialkylstannyl benzoxazole would be
inconsistent with this type of chemistry. On the basis of
these considerations, we decided upon a retrosynthesis
(Figure 2, path B) where the benzoxazole provides the
component for oxidative addition, “the electrophile” (X
) OTf, halogen), and the pyridine ring is functionalized
into an organostannane (Y ) R3Sn) for use in the Stille
reaction.
As part of a model system we chose to work with
2-bromo-3-methoxy-6-methyl-pyridine 2, an easily pre-
pared substrate,5 although in the future we anticipate
using alternative protecting groups that can be removed
more easily than the methyl ether.6 Following lithiation/
quench procedures, 2 could be converted into trimethyl-
(3) and tributylstannyl (4) derivatives in good yields
(Scheme 1). Compound 3 is sensitive to protodestan-
nylation during both an aqueous workup and upon
storage. To circumvent this problem, 3 was used in
coupling reactions without isolation. Compound 4 is less
sensitive and could be purified by chromatography on
alumina and stored without decomposition.
Palladium-catalyzed cross-coupling of 2-thiomethylbenzox-
azoles with tri-alkylstannyl pyridines efficiently produces
pyridinyl boxazomycin C analogues.
The boxazomycins are a class of gram-positive anti-
bacterial agents1 that contain a biaryl bond between the
benzoxazole (AB) and pyrimidine (C) rings (Figure 1). We
were interested in derivatives of boxazomycin C where
the pyrimidine ring was replaced with a 2-substituted
pyridine ring, such as that generalized by structure 1
(Figure 1). Our aim was to develop a synthetic route,
involving mild reaction conditions, that was amenable
to analogue preparation. Accordingly, we desired an ester
at C-4 in the A-ring and flexibility in the protection of
the hydroxyl groups attached to the pyridine ring.
Historically, the synthesis of these types of compounds
has employed a two-step sequence involving reaction of
appropriately substituted aminophenols with aryl car-
boxylic acids or their synthetic equivalents (Figure 2,
path A) to form an amide bond, and then acid-catalyzed
cyclocondensation to form the benzoxazole ring.2 Re-
agents such as polyphosphoric acid (PPA) and pyridinium
p-toluenesulfonate (PPTS) have been used to effect the
ring closure.2 However, using such strongly acidic re-
agents requires substituents to withstand the reaction
conditions unaffected, and such substituents are them-
selves difficult to deprotect. This restricts the choice of
protecting groups and leads to synthetic inflexibility. We
sought an alternative coupling between the AB and C
ring juncture (Figure 2, path B) that would avoid the use
We first examined whether a triflate compound would
be a suitable partner in a Stille cross-coupling reaction.
Adapting methods used for the preparation of the parent
heterocyclic system, 6 was easily produced by reaction
of 57 with 1,1′-carbonyldiimidazole (CDI) in refluxing
THF solution8 and was then reacted with Tf2O in dichlo-
romethane at low temperature (Scheme 2).9 We found
(3) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry: A
Guide for the Synthetic Chemist; Pergamon: Amsterdam, 2000.
(4) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2002, 4, 2905-2907.
(5) Kelly, T. R.; Lang, F. J. Org. Chem. 1996, 61, 4623-4633.
(6) For example, Suto and Turner used LiI in refluxing pyridine to
deprotect the aryl methyl ether; see ref 2.
(7) Angyal, S. J.; Bullock, E.; Hanger, W. G.; Howell, W. C.; Johnson,
A. W. J. Chem. Soc. 1957, 1592-1602.
(8) Nachman, R. J. J. Heterocycl. Chem. 1982, 19, 1545-1547.
* Telephone: +64 9 373-7599 ext. 86147. Fax: +64 9 373-7502.
† University of Auckland.
‡ Pfizer Global Research and Development.
(1) Kusumi, T.; Ooi, T.; Walchi, M. R.; Kakisawa, H. J. Am. Chem.
Soc. 1988, 110, 2954-2958.
(2) Suto, M. J.; Turner, W. R. Tetrahedron Lett. 1995, 36, 7213-
7216.
10.1021/jo0510033 CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/02/2005
7436
J. Org. Chem. 2005, 70, 7436-7438

FIGURE 2. Retrosynthetic disconnections.
SCHEME 1a
SCHEME 3
a Reagents and conditions: (a) (i) n-BuLi, THF, -78 °C; (ii)
R3SnCl, -78 °C f room temperature (rt). R ) Me, 80%; R ) n-Bu
98%.
SCHEME 2. Preparation of Coupling Partnersa
cently, the groups of Lebeskind12 and Guillaumet13
reported palladium-catalyzed, copper-promoted cross-
coupling of such compounds with organostannanes. Start-
ing from 8, the preparation of 10 was easily accomplished
with MeI/K2CO3 in acetone solution. This compound is
stable to storage at room temperature, and its synthesis
is fully consistent with our aim of using mild chemistry
conditions.
For the coupling reaction, we used a protocol where
the trimethylstannyl pyridine is generated in situ, then
the palladium catalyst, copper promoter, and coupling
partner are simply added, and the mixture is refluxed.
This gave the convenience of conducting all operations
in one pot. A copper(I) source is required in the coupling
reaction,12,13 and we first examined the use of CuBr.
Given that this worked well, no other source was inves-
tigated.14 Our preference for the trimethylstannyl deriva-
tive was based upon the byproduct Me3SnCl being water
soluble and able to be removed during an aqueous
workup. In this case, the desired product is ideally set
up to chelate the copper salt, and must be decomplexed
by treatment with EDTA for isolation. Even so, the yield
of coupled product after separation and purification is
very good (83%, Scheme 3).
a Reagents and conditions: (a) CDI, THF, reflux, 69%; (b) Tf2O,
NEt3, DCM, -78 °C f rt; (c) CS2, KOH, EtOH/H2O, reflux, 66%;
(d) PCl5, chlorobenzene, reflux; (e) MeI, K2CO3, acetone, rt, 88%.
that 7 was produced in the reaction with Tf2O but was
prone to reversion to 6 during purification, and thus we
were unable to isolate it.
Our next target was a 2-chloro-benzoxazole and again
we used conditions described for preparation of the
parent compound.10 Starting from 5, compound 9 could
be produced after reaction with potassium xanthate in
ethanol/water and then reaction with PCl5. We found this
material sensitive to moisture with decomposition to 6
upon standing at room temperature, precluding its util-
ity. The sensitivity to water at C-2 of the benzoxazole
ring with an ester present at the 4-position has been
noted before.11
The advantages of using thiomethyl compound 10 are
its stability as compared to the corresponding triflate and
chloro compounds, the more traditional coupling partners
in palladium-catalyzed reactions, and the mild reaction
conditions used to prepare it.
(11) Goldstein, S. W.; Dambek, P. J. J. Heterocycl. Chem. 1990, 27,
335-336.
Our attention then turned to the use of heteroaromatic
thioether compounds as cross-coupling partners. Re-
(12) Egi, M.; Lebeskind, L. S. Org. Lett. 2003, 5, 801-802.
(13) Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guil-
laumet, G. Org. Lett. 2003, 5, 803-805.
(9) Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4,
2485-2488.
(10) Chen, W.-B.; Jin, G.-Y. Heteroat. Chem. 2001, 12, 151-155.
(14) Egi and Lebeskind advocate the use of copper(I) 3-methylsali-
cylate (CuMeSal); see ref 12.
J. Org. Chem, Vol. 70, No. 18, 2005 7437

Methyl 7-Methyl-2-(methylthio)benzoxazole-4-carboxy-
late (10). A mixture of 6 (2.1 g, 9.5 mmol), anhydrous K2CO3 (5
g), and iodomethane (1.0 mL, 16 mmol) in acetone (200 mL) was
stirred rapidly at room temperature for 3 h. The reaction mixture
was filtered over Celite, the filter pad was washed with acetone
(50 mL), and the solvent was removed. The residue was
partitioned between EtOAc (75 mL) and H2O (20 mL), and the
organic phase was further washed with brine (20 mL), dried over
Na2SO4, and concentrated. The residue was purified by silica
gel column chromatography (25% EtOAc in hexanes, Rf 0.50)
and recrystallized from acetone/water to give 2.05 g (88%) of 10
as colorless needles: mp 102-103 °C; 1H NMR (400 MHz, CDCl3)
δ 2.53 (s, 3H), 2.83 (s, 3H), 3.99 (s, 3H), 7.08 (d, J ) 8.1 Hz,
1H), 7.85 (d, J ) 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
14.6, 15.4, 52.2, 118.0, 124.4, 125.5, 126.7, 141.2, 151.7, 165.7,
167.7. Anal. Calcd for C11H11NO3S: C, 55.68; H, 4.67; N, 5.90.
Found: C, 55.67; H, 4.61; N, 5.77.
Methyl 2-(3-Methoxy-6-methylpyridin-2-yl)-7-methyl-
benzoxazole-4-carboxylate (11). A 2.5 M solution of n-BuLi
in hexanes (0.75 mL, 1.88 mmol) was added dropwise over 5
min to 25 (370.4 mg, 1.83 mmol) dissolved in THF (5 mL) at
-78 °C. After a further 5 min, Me3SnCl (480.4 mg, 2.41 mmol)
dissolved in THF (2 mL) was added, the cooling bath was
removed, and the solution was allowed to attain room temper-
ature. CuBr (386.0 mg, 2.69 mmol) was added as a solid before
10 (283.6 mg, 1.20 mmol) and Pd(PPh3)4 (80.7 mg, 5 mol %)
dissolved in THF (5 mL) were added via syringe. The mixture
was then heated to reflux for 1.5 h. After cooling to room
temperature, Na4EDTA (1.2 g) and LiCl (1.1 g) in H2O (5 mL)
were added, and the mixture was refluxed in the air for 5.5 h.
The mixture was filtered through Celite, and the filter pad was
washed with THF (2 × 10 mL). The organic layer was washed
with new EDTA solution (1.2 g in 10 mL of H2O, pH ) 8) and
brine (2 × 10 mL), before being dried over Na2SO4 and
concentrated to dryness. Following silica gel column chroma-
tography (EtOAc, Rf 0.20) and recrystallization (EtOAc), 309.0
mg (83%) of 11 was obtained as colorless blocks: mp 140-142
°C; 1H NMR (400 MHz, CDCl3) δ 2.64 (s, 3H), 2.68 (s, 3H), 4.03
(s, 3H), 4.05 (s, 3H), 7.24 (d, J ) 7.9 Hz, 1H), 7.30 (d, J ) 8.6
Hz, 1H), 7.36 (d, J ) 8.6 Hz, 1H), 7.98 (d, J ) 7.9 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 15.8, 23.4, 52.3, 56.3, 120.0, 120.8,
126.1, 126.6, 126.9, 127.4, 133.9, 140.67, 150.2, 150.6, 154.4,
161.5. 166.1. Anal. Calcd for C17H16N2O4: C, 65.38; H, 5.16; N,
8.97. Found: C, 65.51; H, 5.17; N, 8.91.
In conclusion, palladium-catalyzed cross-coupling chem-
istry has been successfully applied in the model synthesis
of a precursor to pyridinyl boxazomycin C analogues. This
is also an example where thioether compounds provide
an attractive alternative when other coupling partners
cannot be used.
Experimental Section
3-Methoxy-6-methyl-2-(tributylstannyl)pyridine (4). A
2.5 M solution of n-BuLi in hexanes (1.76 mL, 4.40 mmol) was
added dropwise over 5 min to 25 (877.9 mg, 4.35 mmol) dissolved
in THF (11 mL) at -78 °C. After a further 5 min n-Bu3SnCl
(1.20 mL, 4.42 mmol) was added, the cooling bath was removed,
and the solution was allowed to attain room temperature.
Saturated aqueous NH4Cl (2 mL) was added, and the mixture
was stirred vigorously. Ether (30 mL) was added, and the organic
solution was washed with water (10 mL) and brine (10 mL),
dried over Na2SO4, and concentrated. The residue was purified
by chromatography on alumina (hexanes/EtOAc, 100:1) to give
1
4 as a colorless oil, 1.70 g (98%). H NMR (400 MHz, CDCl3) δ
0.88 (t, J ) 7.3 Hz, 9H), 1.10 (m, 6H), 1.33 (m, 6H), 1.55 (m,
6H), 2.49 (s, 3H), 3.74 (s, 3H), 6.86 (d, J ) 8.5 Hz, 1H), 6.91 (d,
J ) 8.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 9.5, 13.2, 23.1,
26.8, 28.6, 54.7, 113.9, 120.8, 150.6, 158.2, 162.7. Anal. Calcd
for C19H35NOSn: C, 55.37; H, 8.56; N, 3.40. Found: C, 55.48;
H, 8.65; N, 3.12.
Methyl 7-Methyl-2-oxo-2,3-dihydrobenzoxazole-4-car-
boxylate (6). A mixture of 57 (2.5 g, 15 mmol) and CDI (4.1 g,
25 mmol) in THF (50 mL) was refluxed with stirring for 2 h.
The reaction mixture was filtered over Celite while hot, the filter
pad was washed with THF (2 × 25 mL), and the solvent was
removed. The residue was partitioned between CHCl3 (150 mL)
and 2 N HCl (75 mL), and the organic layer was further washed
with 2 N HCl (75 mL), water (75 mL), and brine (25 mL), dried
over Na2SO4, and concentrated. The residue was crystallized
from EtOAc to give 2.0 g (69%) of 6 as colorless needles: mp
220-221 °C; 1H NMR (400 MHz, CDCl3) δ 2.43 (s, 3H), 3.97 (s,
3H), 6.96 (d, J ) 8.1 Hz, 1H), 7.62 (d, J ) 8.1 Hz, 1H); 9.2 (br s,
1H); 13C NMR (100 MHz, CDCl3) δ 14.9, 52.4, 110.3, 123.6, 124.3,
125.7, 130.9, 142.6, 154.2, 165.6. Anal. Calcd for C10H9NO4: C,
57.97; H, 4.38; N, 6.76. Found: C, 57.90; H, 4.30; N, 6.67.
Methyl 7-Methyl-2-thioxo-2,3-dihydro-benzoxazole-4-
carboxylate (8). CS2 (2.0 g, 26 mmol) was added dropwise with
stirring to KOH (2.6 g, 46 mmol) dissolved in an ethanol/water
mixture (2.5:1, 35 mL) to give a clear yellow solution. The
hydrochloride salt of 57 (5.0 g, 23 mmol) was added as a solid,
and the mixture was brought to reflux with stirring for 2 h. The
contents were poured into hot water (100 mL), and AcOH (2 mL)
was added to precipitate the product. The yellow solid was
collected by filtration and recrystallized from ethanol/water to
Acknowledgment. This work was financially sup-
ported by Pfizer Global Research and Development. We
thank Dr. Maruta Boyd for NMR assistance.
1
Supporting Information Available: 1H and 13C NMR
spectra for compounds 4, 6, 8, 10, and 11. LC-MS spectra for
compounds 4, 6, 8, 10, 11. This material is available free of
charge via the Internet at http://pubs.acs.org.
give 3.4 g (66%) of 8 as colorless needles: mp 100-102 °C; H
NMR (400 MHz, CDCl3) δ 2.50 (s, 3H), 3.98 (s, 3H), 7.08 (d, J )
8.2 Hz, 1H), 7.71 (d, J ) 8.2 Hz, 1H); 10.40 (br s, 1H); 13C NMR
(100 MHz, CDCl3) δ 15.0, 52.6, 110.4, 125.1, 125.6, 126.2, 131.4,
147.8, 165.1, 180.8. Anal. Calcd for C10H9NO3S: C, 53.80; H,
4.06; N, 6.27. Found: C, 53.67; H, 4.10; N, 6.20.
JO0510033
7438 J. Org. Chem., Vol. 70, No. 18, 2005