A two-stage iterative process for the synthesis of poly-oxazoles

Article abstract of DOI:10.1021/ol051244x

(Chemical Equation Presented) Methodology has been developed to prepare bis-oxazoles via a two-stage iterative process. The sequence begins with C ₂-chlorination of a lithiated oxazole using hexachloroethane. Generation of the C₂-C

Full text of DOI:10.1021/ol051244x

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3351-3354
A Two-Stage Iterative Process for the
Synthesis of Poly-oxazoles
Jeffery M. Atkins and Edwin Vedejs*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
edVed@umich.edu
Received May 26, 2005
ABSTRACT
Methodology has been developed to prepare bis-oxazoles via a two-stage iterative process. The sequence begins with C2-chlorination of a
lithiated oxazole using hexachloroethane. Generation of the C2 C4 bond by SNAr substitution with TosMIC anion, followed by conversion to
−
′
the heterocycle in a one-pot reaction with glyoxylic acid monohydrate, affords the desired bis-oxazole in good yield and purity. The two-stage
process allows for efficient synthesis of a tris-oxazole and the first iterative preparation of a tetra-oxazole.
Potentially repeatable methods have been used to assemble
the C2-C4′ linked bis-oxazole and tris-oxazole subunits of
marine natural products and related structures.1-13 With the
recent discovery of the macrocyclic C2-C4′ linked hepta-
oxazole telomestatin 1,14 these techniques may benefit from
further refinement and comparison with new options for
iterative oxazole assembly.
Among the prior methods that have been used to prepare
tris-oxazoles, Panek’s approach using an adaptation of the
Hantzsch oxazole synthesis is probably the most efficient in
terms of overall yield (ca. 80%) and number of steps (three)
per iteration.6 This procedure appends each new oxazole by
elaborating a C4-carboxamido group of an existing oxazole.
The carboxamido carbon becomes C2′ in the new oxazole
ring, and the order of events corresponds to a “clockwise”
strategy for assembly of an oligo-oxazole chain with respect
to the telomestatin structure (Figure 1). Several other iterative
(1) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604.
(2) Doyle, K. J.; Moody, C. J. Tetrahedron 1994, 50, 3761.
(3) Barrett, A. G. M.; Kohrt, J. T. Synlett 1995, 5, 415.
(4) Vedejs, E.; Luchetta, L. M. J. Org. Chem. 1999, 64, 1011.
(5) Chattopadhyay, S. K.; Pattenden, G. Synlett 1997, 12, 1342.
(6) Liu, P.; Celatka, C. A.; Panek, J. S. Tetrahedron Lett. 1997, 38, 5445.
(7) Magnus, P.; McIver, E. G. Tetrahedron Lett. 2000, 41, 831.
(8) Wipf, P.; Methot, J.-L. Org. Lett. 2001, 3, 1261.
(9) Celatka, C. A.; Panek, J. S. Tetrahedron Lett. 2002, 43, 7043.
(10) Yamada, S.; Shigeno, K.; Kitagawa, K.; Okajima, S.; Asao, T. PCT
Int. Appl. WO 2002048153 A1 20020620, 2002; Chem. Abstr. 2002, 137,
47050.
(11) Endoh, N.; Tsuboi, K.; Kim, R.; Yonezawa, Y.; Shin, C. Hetero-
cycles 2003, 60, 1567.
(12) Coqueron, P.-Y.; Didier, C.; Ciufolini, M. A. Angew. Chem., Int.
Ed. 2003, 42, 1411.
(13) (a) Nicolaou, K. C.; Bella, M.; Chen, D. Y. K.; Huang, X. H.; Ling,
T. T.; Snyder, S. A. Angew. Chem., Int. Ed. 2002, 41, 3495. (b) Nicolaou,
K. C.; Rao, P. B.; Hao, J. L.; Reddy, M. V.; Rassias, G.; Huang, X. H.;
Chen, D. Y. K.; Snyder, S. A. Angew. Chem., Int. Ed. 2003, 42, 1753. (c)
Burgett, A. W. G.; Li, Q.; Wei, Q.; Harran, P. G. Angew. Chem., Int. Ed.
2003, 42, 4961. (d) Magnus, P.; Mciver, E. G. Tetrahedron Lett. 2000, 41,
831. (e) Bagley, M. C.; Hind, S. L.; Moody, C. J. Tetrahedron Lett. 2000,
41, 6897.
Figure 1. Telomestatin.
(14) (a) Shin-ya, K.; Wierzba, K.; Matsuo, K.; Ohtani, T.; Yamada, Y.;
Furihata, K.; Hayakawa, Y.; Seto, H. J. Am. Chem. Soc. 2001, 123, 1262.
(b) Kim, M.-Y.; Vankayalapati, H.; Shin-ya, K.; Wierzba, K.; Hurley, L.
H. J. Am. Chem. Soc. 2002, 124, 2098.
approaches for a clockwise strategy are known (append to
C4-CO2R or C4-CN).2,7,12 Convergent alternatives have also
been reported involving oxazole synthesis by cyclization of
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© 2005 American Chemical Society
Published on Web 06/22/2005

a nitrogen-linked bis-oxazole intermediate (C4-[C2′-N-
C4′]-C2′′ connected in an amide group).5,10,11 In principle,
this method can be repeated, but the need for several
protection-deprotection steps results in a lengthy sequence,
as reported for the assembly of the telomestatin macrocycle
(>40 steps overall).10 We are aware of only one iterative
approach to oligo-oxazoles that operates in the “counter-
clockwise” mode and appends each new oxazole unit at
preexisting oxazole C2. This method relies on an LDA-
induced Chan rearrangement, and has been used to prepare
a tris-oxazole containing phenyl or tert-butyl groups at the
C5 position of each oxazole ring.8 Alternatives that can be
used to access C5-unsubstituted oligo-oxazoles would be
needed to prepare telomestatin analogues. As described
below, this problem can be addressed using a route that
involves activation and coupling of C2-unsubstituted ox-
azoles.
intercepts the cyclic tautomer (Table 1).21 Despite the
dominant presence of 3,20,22 good yields of 2-chlorooxazoles
were obtained. Athough the formation of 4-chlorooxazole
might have been expected,4 this was not observed using the
latent chlorine source. However, yields did increase by
5-15% using longer reaction times (42 h), suggesting that
there may be more to the mechanism than simply trapping
2.
Table 1. Trapping of 2-Lithiooxazoles with Hexachloroethane
To Form 2-Chlorooxazole
Formation of a C-C bond at C2 of oxazole poses a
significant synthetic challenge. In principle, this can be done
by reacting C2-metalated oxazoles with carbon electro-
philes,15,16 or by displacing a C2 leaving group using carbon
nucleophiles. Oxazoles activated by the introduction of Cl
at C2 have been shown to undergo palladium-mediated
Suzuki coupling17 and to react with deprotonated alcohols
and amines quite effectively.18a,b However, there are only
limited examples of stabilized carbon nucleophiles reacting
with activated oxazoles to form C-C bonds at C2 via an
SNAr reaction.18b,c Displacement of the C2 chloride with a
carbon nucleophile that can be converted into a new oxazole
unit was envisioned as a route for bis- and poly-oxazole
synthesis.
a Base ) BuLi. b Base ) LiHMDS.
Prior to this work, relatively few 2-chlorooxazoles were
known in the literature. Construction of these compounds
was typically achieved via the oxazolone or oxazole-2-thione
using POCl3/pyridine19a,b or PCl5,19c or from the amino-
oxazole under Sandmeyer conditions.17 2-Chlorooxazoles had
also been generated by trapping a 2-lithiooxazole-BH3
complex with hexachloroethane.15 However, we have re-
cently found that borane complexation prior to generating
the lithiooxazole is not necessary for chlorination at C2. Even
though lithiation of oxazoles results in the ring-opened
enolate isonitrile valence bond tautomer 3,20 reaction of the
equilibrium mixture of 2 and 3 with hexachloroethane
Generation of the 2-lithiooxazole intermediate occurred
readily upon the low-temperature addition of BuLi to the
C4 phenyl substituted oxazole 4a in THF. The C2 chlorinated
oxazole 5a was isolated in good yield and purity after
addition of hexachloroethane and stirring for 18 h at room
temperature. Similar successful results were seen with aryl,
alkyl, and heteroaryl functionalities at oxazole C5 (entries
2-4, Table 1). Sensitive functionality on the starting oxazole,
such as the C5 ethyl ester in 4e, was tolerated if LiHMDS
was used instead of BuLi. The products 5a-e were readily
purified by column chromatography on silica gel, provided
that the excess hexachloroethane was removed by flushing
the column with hexanes before eluting the product.
(15) Vedejs, E.; Monahan, S. D. J. Org. Chem. 1996, 61, 5192.
(16) For coupling with oxazol-2-ylzinc chlorides, see: (a) Anderson, B.
A.; Becke, L. M.; Booher, R. N.; Flaugh, M. E.; Harn, N. K.; Kress, T. J.;
Varie, D. L.; Wepsiec, J. P. J. Org. Chem. 1997, 62, 8634. (b) Anderson,
B. A.; Harn, N. K. Synthesis 1996, 5, 583. For coupling with 2-stanylox-
azole, see: (c) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini,
P. Synthesis 1987, 8, 693.
With a simple procedure in hand for chlorination at
oxazole C2, the next problem was to introduce functionality
that can be used to assemble a new oxazole. The key finding
(17) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2003, 5, 2911. (b)
Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2002, 4, 2905. (c) Young, G.
L.; Smith, S. A.; Taylor, R. J. K. Tetrahedron Lett. 2004, 45, 3797.
(18) (a) Padwa, A.; Cohen, L. A. J. Org. Chem. 1984, 49, 399. (b)
Gompper, R.; Effenberger, F. Chem. Ber. 1959, 92, 1928. (c) Yamanaka,
H.; Ohba, S.; Sakamoto, T. Heterocycles 1990, 31, 1115.
(19) (a) Gompper, R. Chem. Ber. 1956, 89, 1748. (b) Lee, L. F.;
Schleppnik, F. M.; Howe, R. K. J. Heterocycl. Chem. 1985, 22, 1621. (c)
Haviv, F.; Ratajczyk, J. D.; DeNet, R. W.; Kerdesky, F. A.; Walters, R. L.;
Schmidt, S. P.; Holms, J. H.; Young, P. R.; Carter, G. W. J. Med. Chem.
1988, 31, 1719.
(21) It may be relevant that CCl4 or trichloroacetyl chloride have been
reported as electrophilic chlorine sources to generate 2-chlorothiazole via
halogen-metal exchange. See: (a) Boga, C.; Del Vecchio, E.; Forlani, L.;
Todesco, P. E. J. Organomet. Chem. 2000, 601, 233. (b) Boga, C.; Del
Vecchio, E.; Forlani, L.; Milanesi, L.; Todesco, P. E. J. Organomet. Chem.
1999, 588, 155.
(22) (a) Chinchilla, R.; Najera, C.; Yus, M. Chem. ReV. 2004, 104, 2667.
(b) Schroeder, R.; Schoellkopf, U.; Blume, E.; Hoppe, I. Justus Liebigs
Ann. Chem. 1975, 3, 533. (c) Jacobi, P. A.; Ueng, S.; Carr, D. J. Org.
Chem. 1979, 44, 2042. (d) Hodges, J. C.; Patt, W. C.; Connolly, C. J. J.
Org. Chem. 1991, 56, 449. (e) Whitney, S. E.; Rickborn, B. J. Org. Chem.
1991, 56, 3058.
(20) Hilf, C.; Bosold, F.; Harms, K.; Marsch, M.; Boche, G. Chem. Ber.
1997, 130, 1213.
3352
Org. Lett., Vol. 7, No. 15, 2005

was the observation that deprotonated tosylmethyl isocyanide
(TosMIC)23 is capable of displacing the C2 chloride via SNAr
substitution. Thus, conversion to the isonitrile 6a occurred
upon addition of 5a to 1.5 equiv of TosMIC anion, generated
by deprotonation with 3.5 equiv of NaH in DMF at 0 °C
(Scheme 1). An excess of base was required for complete
Using the one-pot procedure, good yields of bis-oxazoles
8a-f were obtained from 2-chlorooxazoles 5a-f (Table 2).
Table 2. One-Pot Formation of [2,4′]-Bis-oxazoles
Scheme 1. Stepwise and One-Pot Routes to Bis-oxazole 8a
reaction because TosMIC anion deprotonates the intermediate
6a. Consumption of 5a and conversion to 6a were confirmed
by ESI-MS after 90 min. Subsequent addition of glyoxylic
acid monohydrate and K2CO3 resulted in formation of the
bis-oxazole 8a (72% isolated after 12 h at rt) via fragmenta-
tion of an intermediate oxazoline 7. One prior example of a
similar sequence involving a substituted TosMIC anion
addition to glyoxylic acid with fragmentation to an oxazole
has been reported by Sisko et al., along with several examples
of the analogous imidazole synthesis from glyoxylic acid
imines.24
The best results for the one-pot conversion from 5a to 8a
were obtained in DMF. Lower yields resulted in DMSO or
THF, or with NaHMDS or LiH as the base, but attempted
deprotonation of 6a with BuLi/THF gave extensive decom-
position.25 Lower efficiency was also encountered in a
stepwise sequence. If desired, 6a could be isolated (52%)
after the first stage, prior to addition of the glyoxylic acid,
but 6a could not be completely separated from unreacted
TosMIC, and decomposed on standing. Although the partially
purified 6a could be converted to the bis-oxazole 8a upon
addition of glyoxylic acid/K2CO3 in DMF, the yield was only
59%.
a 1.1 equiv of TosMIC. b 1.5 equiv of TosMIC.
For entry 2 and entries 4-6, conversion to the isonitrile was
complete within 1.5 h at 0 °C after the addition of 5 to
deprotonated TosMIC. Cyclization to the bis-oxazoles 8b
and 8d-f occurred as before (12 h, rt, glyoxylic acid/
K2CO3). The conversion of 5c to 6c was sluggish at 0 °C,
but was complete after 5 h at rt. The reaction could also be
perfomed at 75 °C for entries 1-4, but the lower temperature
was necessary for entries 5 and 6 due to decomposition of
the isonitrile intermediates 6e and 6f.
The bis-oxazole 8b was chosen to prove the viability of
poly-oxazole synthesis using an iterative version of this
technique (Scheme 2). Generation of the lithiooxazole by
low-temperature addition of BuLi to 8b and trapping with
hexachloroethane gave 2-chlorinated bis-oxazole 9 in 76%
yield. The first attempt to convert 9 to the tris-oxazole 10
proceeded in only 52% yield, and decomposition of the
isonitrile intermediate was evident from the dark color during
TosMIC coupling. However, lowering the reaction temper-
ature to -42 °C for the SNAr step improved the isolated
yield of 10 to 64%. As long as the temperature was kept
below -10 °C, the solution mantained a light yellow color
and decomposition of the bis-oxazole derived TosMIC
intermediate was minimized.
(23) For reviews of TosMIC and R-metalated isocyanides, see: (a) van
Leusen, A. M.; van Leusen, D. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 7, p 4973.
(b) Scho¨llkopf, U. Angew. Chem., Int. Ed. Engl. 1977, 16, 339. (c) Tandon,
V. K.; Rai, S. Sulfur Rep. 2003, 24, 307. (d) Do¨mling, A.; Ugi, I. Angew.
Chem., Int. Ed. 2000, 39, 3169. (e) Hoppe, D. Angew. Chem., Int. Ed. Engl.
1974, 13, 789. (f) Marcaccini, S.; Torroba, T. Org. Prep. Proced. Int. 1993,
25, 141.
(24) Sisko, J.; Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen, A.; Olsen,
M. A. J. Org. Chem. 2000, 65, 1516.
(25) A half-life of ca. 15 min has been reported for TosMIC and NaH/
DME. (van Leusen, A. M.; Wildeman, J.; Oldenziel, O. H. J. Org. Chem.
1977, 42, 1153.) We have found that TosMIC anion is substantially more
stable in DMF as the solvent.
To further extend the oxazole chain, the sequence was
repeated from 10, allowing isolation of 2-chloro tris-oxazole
11 (72%), and tetra-oxazole 12 (46%). Construction of the
Org. Lett., Vol. 7, No. 15, 2005
3353

Scheme 2. Synthesis of Tetra-oxazole 12
tris-oxazole 10 proceeds in 39% yield over four isolated
constitutes a two-stage iterative process for the incorporation
of additional oxazole rings leading to bis-, tris-, and tetra-
oxazoles.
intermediates from 4b. Thus, the tetra-oxazole 12 was
obtained in 13% overall yield via six isolated intermediates
from 4b.
In conclusion, methodology has been developed that
assembles poly-oxazoles starting from a C2-unsubstituted
oxazole. Direct chlorination of 2-lithiooxazoles with hexa-
chloroethane in THF provides a selective, general protocol
for preparation of 2-chlorooxazoles. Subsequent SNAr-type
substitution with deprotonated TosMIC forms an isonitrile
intermediate that affords the corresponding [2,4′]-bis-oxazole
upon reaction with glyoxylic acid monohydrate in the one-
pot mode. Repetition of the chlorination and coupling steps
Acknowledgment. This work was supported by the
National Institutes of Health (CA17918).
Supporting Information Available: Experimental details
and spectroscopic data for compounds 5c-e, 8a-f, and
9-12. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL051244X
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Org. Lett., Vol. 7, No. 15, 2005