Regioselective palladium cross-coupling of 2,4-dihalooxazoles: Convergent synthesis of trisoxazoles

Article abstract of DOI:10.1021/jo800121y

(Chemical Equation Presented) A regioselective Suzuki-Miyaura cross-coupling of 2,4-dihalooxazoles followed by a Stille coupling has been successfully developed. The procedure affords convergent syntheses of trisoxazoles in high yield and in a minimum num

Full text of DOI:10.1021/jo800121y

lenging reaction that has appeared only rarely in the literature.
The first example was reported in 1995 by Barrett, using a Stille
coupling to prepare a bisoxazole in an approach to the natural
product Hennoxazole A.7 Since that time, bisoxazole synthesis
has been reported by Vedejs using a Negishi coupling8 and by
our own group9 and that of Inoue10 using the Suzuki-Miyaura
reaction of oxazoyl boronate esters. Inoue has recently extended
this work to the production of some challenging pentakis and
hexakis polyoxazole structures.11 However, the linearity of this
approach combined with a lengthy preparation of a common
boronic ester intermediate necessarily restricts its scope. Given
recent developments in azole cross-coupling reactions,12 we were
interested in developing our own method based on a convergent
approach to the synthesis of trisoxazoles.
Regioselective Palladium Cross-Coupling of
2,4-Dihalooxazoles: Convergent Synthesis of
Trisoxazoles
Emmanuel Ferrer Flegeau,† Matthew E. Popkin,‡ and
Michael F. Greaney*,†
School of Chemistry, UniVersity of Edinburgh, Joseph Black
Building, King’s Buildings, West Mains Road, Edinburgh EH9
3JJ, U.K, and Chemical DeVelopment, GlaxoSmithKline, Old
Powder Mills, Tonbridge, Kent TN11 9AN, U.K.
michael.greaney@ed.ac.uk
2,4-Diiodooxazoles 3, known in the literature from work of
Vedejs,8 would be expected to undergo preferential oxidative
addition of Pd0 at the more reactive C2 position, followed by
Suzuki-Miyaura cross-coupling with an oxazol-4-ylboronate
2 (Scheme 1). The C4-I bond would be left intact for a second
cross-coupling with a 2-metallo-oxazole 4, forming the trisox-
azole 1. Selective cross-coupling on dihaloazoles is a well
precedented strategy but has yet to be applied to polyoxazole
synthesis.13
ReceiVed January 18, 2008
A regioselective Suzuki-Miyaura cross-coupling of 2,4-
dihalooxazoles followed by a Stille coupling has been
successfully developed. The procedure affords convergent
syntheses of trisoxazoles in high yield and in a minimum
number of steps.
SCHEME 1. Cross-Coupling Strategy for the Synthesis of
Trisoxazoles
Naturally occurring polyoxazoles commonly display a 2-4
substitution pattern, a consequence of their biosynthetic as-
sembly from serine residues.1 In certain natural products, such
as telomestatin2 or ulapualide A,3 three or more successive C2-
C4′ linked polyoxazoles are present rather than single oxazole
units. These compounds have fascinating structures, show a wide
range of biological properties, and therefore make ideal targets
for the synthetic chemist.4
A plethora of methods have been developed for the construc-
tion of C2-C4′ linked polyoxazoles. Although these methods
differ greatly in their synthetic strategy, they share a common
linear approach, involving a high number of consecutive steps
each time an oxazole ring needs to be introduced.5,6 An
alternative approach is to employ the palladium-catalyzed cross-
coupling of appropriately functionalized oxazole units, a chal-
We elected to break down the proposed regioselective
trisoxazole synthesis into two parts, examining each C-C bond
formation separately on monoiodooxazoles to define the reaction
parameters, prior to using the diiodooxazoles 3. Accordingly,
we began by examining a simplified version of the proposed
Suzuki-Miyaura reaction, using 2-phenyl-oxazol-4-yl boronate
ester 2a and 2-iodo-5-phenyloxazole 5, both of which can be
prepared in multigram quantities8,10 (Table 1). Standard Suzuki-
Miyaura conditions at 100 °C in DMF produced dioxazole 6 in
49% yield (entry 1). Milder conditions such as those developed
by Liebeskind14 and Fu15 gave a complex mixture of products
that could not be separated (entries 2 and 3 respectively). It
† University of Edinburgh.
‡ GlaxoSmithKline.
1294. (d) Chattopadhyay, S. K.; Biswas, S. Tetrahedron Lett. 2006, 47,
7897-7900. (e) Marson, C. M.; Saadi, M. Org. Biomol. Chem. 2006, 4,
3892-3893. (f) Atkins, J. M.; Vedejs, E. Org. Lett. 2005, 7, 3351-3354.
(g) Deeley, J.; Pattenden, G. Chem. Comm. 2005, 797-799.
(7) Barrett, A. G. M.; Kohrt, J. T. Synlett 1995, 415-416.
(8) Vedejs, E.; Luchetta, L. M. J. Org. Chem. 1999, 64, 1011-1014.
(9) Ferrer Flegeau, E.; Popkin, M. E.; Greaney, M. F. Org. Lett. 2006,
8, 2495-2498.
(1) (a) Jin, Z.; Li, Z.; Huang, R. Nat. Prod. Rep. 2002, 19, 454-476.
(b) Lewis, J. R. Nat. Prod. Rep. 2002, 19, 223-258.
(2) Shin-ya, K.; Wierzba, K.; Matsuo, K.; Ohtani, T.; Yamada, Y.;
Furihata, K.; Hayakawa, Y.; Seto, H. J. Am. Chem. Soc. 2001, 123, 1262-
1263.
(3) Rosener, J. A.; Scheuer, P. J. J. Am. Chem. Soc. 1986, 108, 846-
847.
(4) Yeh, V. S. C. Tetrahedron 2004, 60, 11995-12042.
(5) Review: Riego E.; Herna´ndez, D.; Albericio, F.; AÄ lvarez, M.
Synthesis 2005, 1907-1922.
(10) Araki, H.; Katoh, T.; Inoue, M. Synlett 2006, 555-558.
(11) Araki, H.; Katoh, T.; Inoue, M. Tetrahedron Lett. 2007, 48, 3713-
3717.
(6) Recent examples: (a) Herna´ndez, D.; Vilar, G.; Riego, E.; Librada,
M.; Can˜edo, L. M.; Cuevas, C.; Albericio, F.; AÄ lvarez, M. Org. Lett. 2007,
9, 809-811. (b) Pattenden, G.; Ashweek, N. J.; Baker-Glenn, C. A. G.;
Walker, G. M.; Yee, J. G. K. Angew. Chem. In. Ed. 2007, 46, 4359-4363.
(c) Chattopadhyay, S. K.; Biswas, S.; Pal, B. K. Synthesis 2006, 8, 1289-
(12) Schnu¨rch, M.; Flasik, R.; Khan, A. F.; Spina, M.; Mihovilovic, M.
D.; Stanetty, P. Eur. J. Org. Chem. 2006, 3283-3307.
(13) Schro¨ter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245-2267.
(14) Savarin, C.; Liebeskind, L. S. Org. Lett. 2001, 3, 2149-2152.
(15) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295-4298.
10.1021/jo800121y CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/12/2008
J. Org. Chem. 2008, 73, 3303-3306
3303

TABLE 1. Suzuki-Miyaura Coupling between Oxazol-4-ylboronate 2a and 2-Iodo-5-phenyloxazole 5a
entry
time
2 h
4 days
4 days
20 min
20 min
20 min
solvent
DMF
THF
THF
dioxane/H2O
DMF
DMF
palladium source
base
K2CO3
none
KF
Na2CO3 2M
K2CO3
K2CO3
temperature
100 °C
rt
rt
150 °C, microwave
150 °C, microwave
150 °C, microwave
additives
yield of 6 (%)b
49
complex mixture
complex mixture
34
79
87
1
2
3
4
5
6
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3
PdCl2(PPh3)2
Pd(PPh3)4
Pd2(dba)3
none
CuTC (1.1 equiv)
[(tBu)3PH]BF4 (0.1 equiv)
none
none
PCy3 (0.1 equiv)
a Conditions: 1.1 equiv of 2a, 1 equiv of 5, 3 equiv of base, 5 mol % of Pd, 3 mL of solvent. b Isolated yields.
TABLE 2. Stille Coupling between Oxazol-2-ylstannane 4a and 4-Iodo-5-phenyloxazole 7a
entry
time
solvent
palladium sourcea
base
temperature
reflux
additives
yield of 8 (%)b
1
2
3
4
5
2 days
3 h
5 min
2 h
DME
NMP
NMP
NMP
NMP
PdCl2(PPh3)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
none
CsF
CsF
none
KF
none
42
traces
complex mixture
35
rt
[(tBu)3PH]BF4 (0.12 equiv)
[(tBu)3PH]BF4 (0.12 equiv)
TFP (0.1 equiv) and Cu2O (1 equiv)
[(tBu)3PH]BF4 (0.2 equiv) and
Cu2O (1 equiv)
150 °C, microwave
100 °C
rt
4 days
traces
6
2 days
4 days
20 min
5 min
NMP
NMP
DMF
DMF
Pd2(dba)3
None
Pd2(dba)3
Pd2(dba)3
none
none
none
none
rt
rt
TPF (0.2 equiv) and Cu(OAc)2 (1 equiv)
CuTC (1.5 equiv)
PCy3 (0.1 equiv)
26
traces
54
7
8c
9d
150 °C, microwave
150 °C, microwave
PCy3 (0.1 equiv)
87
a 5 mol % of Pd. b Isolated yields. c 1.5 equiv of stannane 4a was used. d 3 equiv of stannane 4a was used.
was quickly found that the use of microwave irradiation not
only shortened reaction times but also increased the yields
dramatically, a combination of Pd2(dba)3 (5 mol %) with PCy3
(10 mol %) in DMF giving the desired product 6 in an excellent
87% isolated yield (entry 6). With a good yield of the Suzuki-
Miyaura coupling in hand, we turned out attention to the second
cross-coupling. We settled on a Stille coupling as the method
of choice,16 given that oxazol-2-ylstannanes are known nucleo-
philes in Pd-catalyzed oxazole cross-coupling reactions.17
We synthesized oxazol-2-ylstannane 4a by trapping 5-phe-
nyloxazole with n-BuLi at -78 °C and quenching the reaction
mixture with Bu3SnCl. The resulting stannane did not store well
and was best used freshly prepared.18 The optimization results
for the Stille reaction are shown in Table 2. Standard conditions
provided a moderate yield of 8 after 2 days reflux in DME (entry
1). Milder Stille catalyst systems were not effective for this
substrate: Fu’s (tBu)3PHBF4 salt15 used at room temperature,
under microwave irradiation or in combination with Cu2O, only
led to complex mixtures or slow reaction rates (entries 2, 3, 5,
and 8). The ligand trifurylphosphine (TFP) in combination with
Pd2(dba)3 and Cu2O gave a modest 35% of isolated 8, but a
slow reaction rate if combined with Cu(OAc)2 (entries 4 and 6,
respectively). Liebeskind’s copper-mediated Stille coupling19
gave a slow reaction rate in our system (entry 7). After
considerable optimization, we realized that higher yields could
be achieved if higher loadings (3 equiv) of stannane 4a where
used in the reaction. Hence, the best of all combinations
appeared to be same catalyst system used for the Suzuki-
Miyaura coupling in Table 1: Pd2(dba)3 (5 mol %) and PCy3
(10 mol %) in DMF and under microwave irradiation gave an
excellent 87% yield of isolated 8 (entry 9).
To merge the two reactions into a trisoxazole synthesis, we
synthesized diiodooxazole 3a according to Vedejs’ selective C-4
iodination8 procedure followed by C2 iodination using 1,2-
diiodoethane.18 As planned, the Suzuki-Miyaura coupling was
regioselective for C2 and gave the desired dioxazole 9 in 46%
isolated yield when using Pd2(dba)3/PCy3 (50% yield if Pd-
(PPh3)4 was used) (Scheme 2). Careful analysis of the crude
reaction mixture by HPLC and LC-MS revealed the formation
of trimer 10 (presumably the Pd-catalyzed product of the
reaction between 9 and starting material 2a), 11 (protodebor-
onation of 2a), and 12 (homo-coupled 2a) as side products.
We sought to reduce the formation of unwanted trisoxazole
10 by modifying the diiodo compound 3a. Thus, we envisaged
that if a Br atom would be selectively placed at C4 instead of
I, oxidative addition on newly formed 9 would be diminished
and therefore the yield should be improved. No examples exist
in the literature of hybrid dihalooxazoles. We successfully
managed to selectively brominate 5-phenyloxazole20 13 on C-4
(16) In agreement with Inoue (ref 11), attempts at oxazole C2 borylation
for potential Suzuki-Miyaura coupling have not been successful.
(17) (a) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P.
Synthesis 1987, 693-696. (b) Krebs, O.; Taylor, R. J. K. Org. Lett. 2005,
7, 1063-1066.
(19) Allred, D. G.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748-
2749.
(18) See Supporting Information for details.
3304 J. Org. Chem., Vol. 73, No. 8, 2008

SCHEME 2. Regioselective Coupling between Oxazol-4-yl-
boronate 1 and 2,4-Diiodooxazole 2
SCHEME 5. Stille Couplings for the Formation of
Trisoxazoles
DMPU and cooled to -78 °C. LHMDS (1 M in THF, 55 mL, 55.0
mmol, 1.6 equiv) was added slowly with a syringe. The reaction
mixture was stirred 1 h at -78 °C, and then neat bromine (2.1 mL,
41.37 mmol, 1.2 equiv) was added dropwise to the reaction mixture,
which was stirred for an additional 30 min at -78 °C. The reaction
mixture was then poured into a mixture of TBME (200 mL) and
aqueous Na2S2O3 (10%, 200 mL) at room temperature. The two
layers were separated, and the organic phase was washed three times
with distilled water, dried over magnesium sulfate, and concentrated
in vacuo. The residue was purified by flash chromatography
(hexanes/TBME 10:0.5 to 10:1) and gave the desired bromooxazole
14 (5.32, 69% yield) as a white solid. Mp ) 60-61 °C. 1H NMR
(360 MHz, CDCl3) δ 7.37-7.86 (3H, m), 7.86 (1H, s), 7.92-7.95
(2H, m). 13C NMR (90 MHz, CDCl3) δ 110.9 (quat), 125.5 (CH),
126.7 (quat), 128.8 (CH), 129.1 (CH), 146.7 (quat), 149.6 (CH).
HRMS (ESI) calculated for C9H6BrNO 223.9705, found 223.9709.
2-Iodo-4-bromo-5-phenyloxazole 15. Synthesized using Vedejs’
protocol8 with minor modifications. 4-Bromo-5-phenyloxazole 14
(5.00 g, 22.32 mmol, 1 equiv) was dissolved in 70 mL of dry THF
and cooled to -78 °C. LHMDS (1 M in THF, 27 mL, 27 mmol,
1.21 equiv) was added slowly, and the reaction mixture stirred for
1 h at -78 °C. Then, solid 1,2-diiodoethane (7.62 g, 26.78 mmol,
1.2 equiv) was added, and the reaction mixture allowed to warm
to room temperature. After 10 min complete consumption of the
starting material was observed by HPLC, and the reaction was
quenched with a mixture of TBME (200 mL) and aqueous Na2S2O3
(10%, 200 mL). The two layers were separated, and the organic
phase washed three times with distilled water, dried over magnesium
sulfate, and concentrated in vacuo to give an orange solid which
was recrystallized from toluene to afford the desired dihalooxazole
SCHEME 3. Synthesis of 2-Iodo-4-bromo-5-phenyloxazole
15 via Selective C4 Bromination on 5-Phenyloxazole
SCHEME 4. Regioselective Coupling between Oxazol-4-yl-
boronate 2a and 2,4-Dihalooxazole 15
using a modification of Vedejs’ procedure,8 obtaining 4-bromo-
5-phenyloxazole 14 in a good 69% yield after column chro-
matography. Then, iodination using LHMDS and 1,2-diiodo-
ethane gave the desired dihalooxazole 15 in excellent yield (86%
after recrystallization) (Scheme 3).
Initial attempts at regioselective Suzuki-Miyaura coupling
of 15 with 2a using Pd2(dba)3/PCy3 produced the dioxazole 16
in a disappointing 21% yield. However, a switch to Pd(PPh3)4
proved effective, producing the bromo dioxazole 16 in a very
good 81% yield (Scheme 4). This result points to the ability of
the bulkier and electron-rich PCy3 ligand to facilitate oxidative
addition, eroding the selectivity in our system.
Finally, we were pleased to observe clean formation of the
desired trisoxazoles using the optimized Stille coupling condi-
tions developed previously. Trisoxazole 17 was obtained in 60%
yield from iodide 9 and stannane 4a and 75% yield using the
bromide 16. Coupling was also successful for the simple
stannane 4b, producing trisoxazole 18 in 73% yield using the
same procedure (Scheme 5).
To conclude, we have developed a novel and regioselective
Suzuki-Miyaura reaction for the synthesis of 2,4-bisoxazoles
followed by a second palladium-catalyzed Stille coupling, which
has produced trisoxazole structures. The method is convergent
and avoids the synthesis of complicated precursors giving a high
level of complexity in a minimum number of steps.
1
15 (6.70 g, 86% yield) as a white solid. Mp ) 104-106 °C. H
NMR (360 MHz, CDCl3) δ 7.37-7.48 (3H, m), 7.85-7.88 (2H,
m). 13C NMR (90 MHz, CDCl3) δ 99.3 (quat), 112.5 (quat), 125.3
(CH), 125.9 (quat), 128.7 (CH), 129.4 (CH), 153.1 (quat). HRMS
(ESI) calculated for C9H5NOBrI 348.8594, found 348.8597.
4-Bromo-5,2′-diphenyl-[2,4′]bisoxazole 16. A 5 mL microwave
vial was charged with oxazol-4-ylboronate 2a10 (72 mg, 0.27 mmol,
1.2 equiv), 2-iodo-4-bromo-5-phenyloxazole 15 (77 mg, 0.22 mmol,
1 equiv), Pd(PPh3)4 (13 mg, 5 mol %), K2CO3 (92 mg, 0.66 mmol,
3 equiv), and anhydrous DMF (1 mL). The microwave vial was
then sealed, and the resulting mixture was stirred at room
temperature for about 5 min before irradiation at a preselected
temperature of 150 °C in a Smith synthesizer for 10 min. The vial
was then cooled with air jet cooling, opened, and poured into a
mixture of Et2O (20 mL) and brine (20 mL). The organic phase
was separated, and the aqueous layer extracted twice with Et2O.
The organic layers were combined, dried over MgSO4, and filtered.
The organic solvent was removed in vacuo, and the residue was
purified by flash column chromatography (silica, hexane/EtOAc
9:1) to give the coupled product 16 (65 mg, 81% yield) as a white
1
solid. Mp ) 149-152 °C. H NMR (360 MHz, CDCl3) δ 7.36-
Experimental Section
7.50 (6H, m), 8.00-8.02 (2H, m), 8.13-8.15 (2H, m), 8.31 (1H,
s). 13C NMR (90 MHz, CDCl3) δ 112.3 (q), 125.5 (CH), 126.3 (q),
126.5 (q) 126.8 (CH), 128.6 (CH), 128.8 (CH), 128.9 (CH), 130.9
(q), 131.1 (CH), 138.7 (CH), 146.2 (q), 153.7 (q), 162.8 (q). HRMS
(ESI) calculated for C18H11N2O2Br 365.9998, found 366.0001.
5, 5′, 2′′-Triphenyl-[2, 4′, 2′, 4′′] teroxazole 17. A 5 mL
microwave vial was charged with dioxazole 16 (100 mg, 0.27 mmol,
4-Bromo-5-phenyloxazole 14. Synthesized using Vedejs pro-
tocol8 with modifications. 5-Phenyloxazole20 13 (5.00 g, 34.47
mmol, 1 equiv) was dissolved in 50 mL of dry THF and 40 mL of
(20) Prepared according to: Van Leusen, A. M.; Hoogenboom, B. E.;
Siderius, H. Tetrahedron Lett. 1972, 23, 2369-2372.
J. Org. Chem, Vol. 73, No. 8, 2008 3305

1 equiv), oxazol-4-ylstannane 3 (354 mg, 0.82 mmol, 3 equiv), Pd2-
(dba)3 (12 mg, 5 mol %), PCy3 (8 mg, 10 mol %), and anhydrous
DMF (1 mL). The microwave vial was then sealed, and the resulting
mixture stirred at room temperature for 5 min before irradiation at
a preselected temperature of 150 °C in a Smith synthesizer for 15
min. The vial was then cooled with air jet cooling, opened, poured
into a mixture of saturated aqueous KF (30 mL) and EtOAc (30
mL), and stirred for 30 min. After this time the organic layer was
separated and the aqueous layer was extracted twice with EtOAc.
The organic layers were combined, dried over Mg2SO4, and filtered
through celite. The solvent was removed in vacuo, and the residue
was purified by flash column chromatography (silica doped with
10% KF, hexane/Et2O 6:4) to give the coupled product 17 (88 mg,
2-(tributylstannyl)oxazole17 (314 mg, 0.82 mmol, 3 equiv), Pd2-
(dba)3 (12 mg, 5 mol %), PCy3 (8 mg, 10 mol %), and 1 mL of
anhydrous DMF. The crude product was purified by flash chro-
matography (silica, hexane/EtOAc 8:2) to give the desired product
1
18 (63 mg, 60% yield) as a white solid. Mp ) 179-182 °C. H
NMR (360 MHz, CDCl3) δ 7.32 (1H, s), 7.44-7.52 (6H, m), 7.79
(1H, s), 8.14-8.17 (m, 2H), 8.35-8.37 (2H, m), 8.44 (1H, s). 13
C
NMR (90 MHz, CDCl3) δ 125.4 (quat), 126.4 (quat), 126.8 (CH),
126.9 (quat), 127.5 (CH), 128.3 (CH), 128.5 (CH), 128.8 (CH),
129.8 (CH), 131.1 (CH), 131.1 (quat), 138.8 (CH), 139.1 (CH),
149.9 (quat), 154.0 (quat), 155.8 (quat), 162.7 (quat). HRMS (ESI)
calculated for C21H13N3O3 355.0951, found 355.0949.
1
75% yield) as a yellow oil. H NMR (360 MHz, CDCl3) δ 7.42-
Acknowledgment. We thank the University of Edinburgh
and GSK for funding, Professor Mark Bradley for the use of a
Smith synthesizer, and EPSRC mass spectrometry center at the
University of Swansea.
7.54 (10H, m), 7.74 (2H, dd, J1 ) 1.3 Hz, J2 ) 8.4 Hz), 8.17-
8.20 (2H, m), 7.74-8.32 (2H, m), 8.47 (1H, s). 13C NMR (90 MHz,
CDCl3) δ 123.3 (CH), 124.4 (CH), 125.5 (quat), 126.5 (quat), 126.9
(CH), 127.1 (quat), 127.6 (quat), 127.7 (CH), 128.5 (CH), 128.6
(CH), 128.9 (CH), 128.9 (CH), 129.9 (CH), 131.1 (CH), 138.0
(quat), 139.2 (CH), 150.1 (quat), 151.6 (quat), 154.2 (quat), 155.0
(quat), 162.8 (quat). HRMS (ESI) calculated for C27H17N3O3
431.1264, found 431.1266.
Supporting Information Available: Full characterization of
novel compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
5′, 2′′,-Diphenyl-[2,4′;2′,4′′]teroxazole 18. Prepared as for
compound 17 from bisoxazole 16 (100 mg, 0.27 mmol, 1 equiv),
JO800121Y
3306 J. Org. Chem., Vol. 73, No. 8, 2008