A direct route to 2-alkyl-4-carbethoxy-5-vinyloxazoles

Article abstract of DOI:10.1016/j.tetlet.2010.06.130

The reaction of an α-chloroglycinate ester with the dimethylaluminum acetylide derivative of phenyl propargyl ether provides the corresponding 5-vinyloxazole in 40-50% yield.

Full text of DOI:10.1016/j.tetlet.2010.06.130

Tetrahedron Letters 51 (2010) 4699–4701
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A direct route to 2-alkyl-4-carbethoxy-5-vinyloxazoles
*
Jianmin Zhang, Marco A. Ciufolini
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, Canada V6T 1Z1
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of an
a-chloroglycinate ester with the dimethylaluminum acetylide derivative of phenyl
Received 11 May 2010
Revised 16 June 2010
Accepted 28 June 2010
Available online 3 July 2010
propargyl ether provides the corresponding 5-vinyloxazole in 40–50% yield.
Ó 2010 Elsevier Ltd. All rights reserved.
An ongoing program in this laboratory centers on the synthesis
of oxazole-containing natural products1 through the application of
the oxazole-forming reaction shown in Scheme 1.2 This technique
methyl propargyl ether reacts with 3 to furnish some 10 as a minor
product (ca. 20%) that accompanied the ‘normal’ oxazole 9 (40–
60%).2
involves the reaction of a readily available
a
-chloroglycinate ester,
Initial attempts to enhance the formation of 10 aimed to induce
elimination of MeOH from 9 by the action of strong base (tBuOK/
DMSO or LDA. The COOR group activates the C-5 methylene for
deprotonation).19 All these efforts met with failure: in most cases,
base treatment had no effect on 9. This suggested that in all likeli-
hood the events responsible for the generation of 10 occur prior to
the formation of 9. A mechanistic possibility is that the intermedi-
ate alkynylglycinate 11 undergoes in situ conversion into a mixture
of 12 (product of alkyne–allene isomerization) and 13 (product of
MeOH elimination; Scheme 3). An ensuing electrocyclic process
then yields 9 from 12 and 10 from 13. If this were the case, then
the replacement of the OMe group in 10 with a better nucleofuge
would favor the formation of cumulene 13, ergo that of 10.
A summary of experiments designed to probe the foregoing
hypothesis appears in Scheme 4. Dimethylaluminum acetylides de-
rived from methyl or benzyl propargyl ether reacted with test sub-
strate 3a to give 10a in an identical 21% yield. Oxazole 10a is an
important building block in an ongoing synthetic study. The yield
of 10a dropped to a disappointing 13% with the Me2Al derivative
3, with a dimethylaluminum acetylide, 5, leading to an alkynylgly-
cinate ester, 6. While the latter is isolable, its propensity to under-
go cycloisomerization to an oxazole is such that one may
conveniently allow it to advance to 7 in situ. The process thus com-
bines the conversion of propargylic amides into oxazoles3 with the
considerably more facile cycloisomerization of alkynylglycinate
esters.4
We note that the isomerization of propargylamides to oxazoles
has more recently been induced through the agency of Au5 and Pd6
catalysis. In addition, an ‘oxidative’ variant of the process has been
devised, in which a hypervalent iodine reagent triggers the conver-
sion of propargylamides into 5-hydroxymethyl oxazole deriva-
tives.7 Of course, the continuing search for such diverse avenues
to oxazoles reflects the importance of these heterocycles in natural
products8 and medicinal chemistry.9
The objectives of our own research made it desirable to achieve
the direct conversion of 3 into a 4-carbethoxy-5-vinyloxazole. It
should be noted that 5-alkenyloxazoles in general are scantily doc-
umented in the literature. Known methods for their synthesis
encompass Pd-mediated coupling reactions,10 hydride reduction
of 5-acyloxazoles followed by dehydration of the resulting alco-
hols,11,12 Peterson reaction of 5-(trimethylsilyl)methyl-oxazoles,13
‘long range Pummerer cyclization’ of appropriate sulfur-substi-
tuted propargylamides,14 olefin metathesis of preformed 5-alke-
nyloxazole substrates,15 and Wittig reaction of 5-formyloxazoles.16
The 5-vinyloxazole system is particularly rare, a mere 17 exam-
ples thereof having been recorded in the CAS database as of this
writing.17 A route to 5-vinyloxazoles lacking a 4-COOR substituent
was devised by Wipf in the form of a base-promoted conversion of
propargylamides 7 into 8 (Scheme 2).18 In accord with this prece-
dent, we found that the dimethylaluminum acetylide derived from
O
X
O
OHC–COOEt
R1
SOCl2
Me2Al
N
H
COOEt
R1 NH2
1
2
3
X = OH
X = Cl
BuLi, then
Me2AlCl
R2
R2
4
5
R2
R2
COOEt
combine
O
O
R1
N
R1
N
H
COOEt
7
6
* Corresponding author. Tel.: +1 604 822 2419; fax: +1 604 822 8710.
E-mail address: ciufi@chem.ubc.ca (M.A. Ciufolini).
Scheme 1. An oxazole-forming reaction (Ref. 2).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.130

4700
J. Zhang, M. A. Ciufolini / Tetrahedron Letters 51 (2010) 4699–4701
Table 1
OMe
R2
5-Vinyloxazoles obtained by the new procedure
O
N
NaH
O
Cl
O
N
Me2Al
R1
O
R2 ° COOR
R
OPh
R2
(ref 18)
R
N
H
COOEt
R1
N
H
COOEt
Yielda (%)
8
3
10
7
OMe
Entry
R
OMe
Me2Al
b
c
d
e
f
Me
cyclo-C6H11
Ph
41
50
36
39
41
<10%
O
N
O
N
R1
R1
3
+
(ref 2)
COOEt
COOEt
10
Bn
9
PhSCH2
(E)-Ph–CH@CH
g
Scheme 2. 5-Alkenyloxazoles via isomerization–elimination of propargylamides.
a
Yield of chromatographically purified vinyloxazoles.
of propargyl chloride, apparently due to facile degradation of the
organometallic agent. Inspired by the work of Schweitzer,20 we
then tested a phenoxy nucleofuge. Happily, lithiation (n-BuLi) of
phenyl propargyl ether, transmetallation to Me2AlCl, and reaction
of the resultant with 3a afforded 10a as the sole product in 55%
yield after chromatography.
The successful preparation of 10a may be regarded as a major
application of the new route to 5-vinyloxazoles, given the pro-
jected usefulness of structurally related heterocycles in medicinal
(e.g., preparation of peptidomimetics) and natural product (assem-
bly of key subunits of various antibiotic substances) chemistry.
Accordingly, included herein are detailed procedures for its prepa-
ration accompanied by full characterization data.21
Additional examples of the new 5-vinyloxazole synthesis from
the known2,22,23 chloroglycinates 3b–d and 3f–g appear in Table 1.
In most cases, the sole discernible product of these reactions was
10, but occasionally, traces (<10%, not characterized) of a byprod-
uct, probably an oxazole of the type 9, were also observed. The
low yield obtained with 3g is consistent with previous observa-
tron-withdrawing substituents) gave disappointing results. This
was apparently due to the lability of the resulting aluminum acet-
ylides. For instance, experiments involving 4-chlorophenyl propar-
gyl ether and 2,4,6-trichlorophenyl propargyl ether in lieu of
phenyl propargyl ether afforded the target vinyloxazoles in sub-
stantially diminished yields (ca. 15–20%). Consequently, such a line
of research was pursued no further.24
In summary, the use of an acetylenic alane derived from phenyl
propargyl ether permits the direct conversion of chloroglycinates 3
into 5-vinyloxazoles 10 in synthetically useful yield. Applications
of this chemistry in synthesis are being evaluated and will be de-
scribed in due course.
Acknowledgments
Financial support from the CRC program, CFI, BCKDF, NSERC,
CIHR, the University of British Columbia and MerckFrosst Canada
is gratefully acknowledged.
tions indicating that chloroglycinates arising from a,b-unsaturated
amides are poor substrates for the present oxazole-forming
process.22
Supplementary data
Attempts to further improve the reaction by enhancing the
nucleofugal aptitude of the phenoxy segment (introduction of elec-
Supplementary data (experimental procedures, characteriza-
tion data, 1H and 13C and NMR spectra of the new compounds)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.06.130.
OMe
COOEt
O
N
O
N
bases
R1
R1
References and notes
COOEt
10
9
1. Reviews: (a) Yeh, V. S. C. Tetrahedron 2004, 60, 11995; (b) Blunt, J. W.; Copp,
B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2006,
23, 26; (c) Jin, Z. Nat. Prod. Rep. 2003, 20, 584; (d) Jin, Z. Nat. Prod. Rep. 2009,
26, 382.
OMe
OMe
base
[ ? ]
+
2. Coqueron, P. Y.; Didier, C.; Ciufolini, M. A. Angew. Chem. Int. Ed. 2003, 42, 1411.
3. (a) Nilsson, B. M.; Hacksell, Uli. J. Heterocycl. Chem. 1989, 26, 269; (b) Nilsson, B.
M.; Vargas, H. M.; Ringdahl, B.; Hacksell, U. J. Med. Chem. 1992, 35, 285.
4. (a) Nagao, Y.; Kweon, K.; Sano, S.; Kakegawa, H.; Lee, W. S.; Shimizu, H.; Shiro,
M.; Katunuma, N. Tetrahedron Lett. 1996, 37, 861; (b) Sano, S.; Shimizu, H.; Kim,
K.; Lee, W. S.; Shiro, M.; Nagao, Y. Chem. Pharm. Bull. 2006, 54, 196.
5. Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett. 2004, 6, 4391.
6. Leading references: (a) Arcadi, A.; Cacchi, S.; Cascia, L.; Fabrizi, G.; Marinelli, F.
Org. Lett. 2001, 3, 2501; (b) Merkul, E.; Müller, T. J. J. Chem. Commun. 2006,
4817; (c) Bacchi, A.; Costa, M.; Gabriele, B.; Pelizzi, G.; Salerno, G. J. Org. Chem.
2002, 67, 4450; (d) Beccalli, E. M.; Borsini, E.; Broggini, G.; Palmisano, G.;
Sottocornola, S. J. Org. Chem. 2008, 73, 4746; (e) Saito, A.; Iimura, K.; Hanzawa,
Y. Tetrahedron Lett. 2010, 51, 1471.
7. Saito, A.; Matsumoto, A.; Hanzawa, Y. Tetrahedron Lett. 2010, 51, 2247.
8. (a) Turchi, I. J.; Dewar, M. J. S. Chem. Rev. 1975, 75, 389; (b) Wasserman, H. H.;
McCarthy, K. E.; Prowse, K. S. Chem. Rev. 1986, 86, 845; (c) Wipf, P. Chem. Rev.
1995, 95, 2115.
9. Examples: (a) Ok, H. O.; Reigle, L. B.; Candelore, M. R.; Cascieri, M. A.; Colwell, L.
F.; Deng, L.; Feeney, W. P.; Forrest, M. J.; Hom, G. J.; Mac Intyre, D. E.; Strader, C.
D.; Tota, L.; Wang, P.; Wyvratt, M. J.; Fisher, M. H.; Weber, A. E. Bioorg. Med.
Chem. Lett. 2000, 10, 1531; (b) Dalvie, D. K.; Kalgutkar, A. S.; Khojasteh- Bakht,
S. C.; Obach, R. S.; O’Donnell, J. P. Chem. Res. Toxicol. 2002, 15, 269; (c) Zhang, J.;
Huitema, C.; Niu, C.; Yin, J.; James, M. N. G.; Eltis, L. D.; Vederas, J. C. Bioorg.
Chem. 2008, 36, 229.
O
O
O
R1
N
COOEt
11
Scheme 3. Possible mechanism of 5-vinyloxazole formation.
R1
N
COOEt
R1
N
COOEt
H
H
H
12
13
O
Cl
yield (%)a
Z
N
H
COOEt
Me2Al
PhtN
Z
21
21
13
55
OMe
OBn
Cl
3a
O
COOEt
N
OPh
PhtN
10a
Scheme 4. Effect of nucleofuge Z on the yield of 10a.

J. Zhang, M. A. Ciufolini / Tetrahedron Letters 51 (2010) 4699–4701
4701
10. (a) Sakamoto, T.; Nagata, H.; Kondo, Y.; Shiraiwa, M.; Yamanaka, H. Chem.
Pharm. Bull. 1987, 35, 823; (b) Jeong, S.; Chen, X.; Harran, P. G. J. Org. Chem.
1998, 63, 8640; (c) Li, J.; Jeong, S.; Esser, L.; Harran, P. G. Angew. Chem. Int. Ed.
2001, 40, 4765; (d) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2002, 4, 2905; (e)
Booker, J. E. M.; Boto, A.; Churchill, G. H.; Green, C. P.; Ling, M.; Meek, G.;
Prabhakaran, J.; Sinclair, D.; Blake, A. J.; Pattenden, G. Org. Biomol. Chem. 2006,
4, 4193; See also: (f) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2003, 5, 2911.
11. Lechel, T.; Lentz, D.; Reissig, H.-U. Chem. Eur. J. 2009, 15, 5432.
12. Examples of elimination from 5-(1-alkoxyethyl)oxazoles: appear also in:
Hashmi, A. S. K.; Weyrauch, J. P.; Kurpejovic, E.; Frost, T. M.; Michlich, B.;
Frey, W.; Bats, J. W. Chem. Eur. J. 2006, 12, 5806.
13. Chau, J.; Zhang, J.; Ciufolini, M. A. Tetrahedron Lett. 2009, 50, 6163.
14. Xu, G.; Chen, K.; Zhou, H. Synthesis 2009, 3565.
15. (a) Hoffmann, T. J.; Rigby, J. H.; Arseniyadis, S.; Cossy, J. J. Org. Chem. 2008, 73,
2400; (b) Besselièvre, F.; Piguel, S.; Mahuteau-Betzer, F.; Grierson, D. S. Org.
Lett. 2008, 10, 4029; (c) Verrier, C.; Hoarau, C.; Marsais, F. Org. Biomol. Chem.
2009, 7, 647. and literature cited therein.
7.79–7.75 (m, 4H), 5.56 (d, 1H, J = 6.9), 5.44 (d, 1H, J = 6.9), 4.47 (d, 1H, J = 11.3),
4.44 (d, 1H, J = 11.2), 4.29–4.24 (m, 6H), 2.87–2.83 (m, 2H), 1.27 (t, 6H, J = 7.1),
1.11 (d, 6H, J = 6.5), 0.86 (d, 6H, J = 6.5). 13C: 169.7, 169.5, 169.4, 169.3, 168.4,
134.5, 131.2, 123.8, 72.5, 72.3, 62.5, 27.6, 27.5, 19.7, 19.5, 19.4, 13.9. ESIMS:
349 [M+H]+, 371 [M+Na]+). A solution of this material (ca. 5 mmol) and SOCl2
(15 mmol) in CH2Cl2 (15 mL) was stirred overnight under argon at rt, then the
mixture was evaporated to dryness to leave a residue of 1.8 g of essentially
pure a
-chloroglycinate, 1:1 mixture of diastereomers, in quantitative yield (1H:
8.56 (d, 1H, J = 9.5), 8.35 (d, 1H, J = 9.5), 7.93–7.88 (m, 4H), 7.80–7.77 (m, 4H),
6.24 (d, 2H, J = 9.5), 4.50 (d, 1H, J = 11.2), 4.48 (d, 1H, J = 11.2), 4.39–4.22 (m,
4H), 2.93–2.79 (m, 2H), 1.35 (q, 3H, J = 7.2), 1.33 (q, 3H, J = 7.2), 1.12 (d, 3H,
J = 6.7), 1.10 (d, 3H, J = 6.7), 0.88 (d, 3H, J = 6.7), 0.87 (d, 3H, J = 6.7)). This
reactive substance was not thoroughly characterized and it was used without
further purification. Commercial n-BuLi (1.6 M in hexanes, 3.3 mL, 5.3 mmol)
was added to a THF (8 mL) solution of phenyl propargyl ether (0.7 g, 5.3 mmol)
at ꢀ78 °C, under Ar. The mixture was stirred at ꢀ78 °C for 20 min, then it was
warmed up to 0 °C and dimethylaluminum chloride (1.0 M in hexanes, 5.3 mL,
5.3 mmol) was added. The mixture was stirred at 0 °C for 1 h, then was
16. Chandrasekhar, S.; Sudhakar, A. Org. Lett. 2010, 12, 236.
17. Examples are provided in Refs. 2, 10d, 11, 12, 16. See also: (a) Maquestiau, A.;
Flammang, R.; Ben Abdelouahab, F. B. Heterocycles 1989, 29, 103; (b) Emeric, G.;
Gary, S.; Gerusz, V.; Gourlaouen, N.; Hartmann, B.; Huser, N.; Lachaise, H.; Le
Hir De Fallois, L.; Perez, J.; Wegmann, T. PCT Int. Appl. WO 2001002385 A1
20010111, 2001.; (c) Bacque, E.; Barriere, J. C.; Puchault, G. Fr. Demande FR
2001-16856 20011226, 2003.; (d) Reissig, H.-U.; Lechel, T. Ger. Offen. DE
102008049431 A1 20100401, 2010.
18. (a) Wipf, P.; Rahman, L. T.; Rector, S. R. J. Org. Chem. 1998, 63, 7132; See also:
(b) Wipf, P.; Aoyama, Y.; Benedum, T. E. Org. Lett. 2004, 6, 3593.
19. Cornwall, P.; Dell, C. P.; Knight, D. W. J. Chem. Soc., Perkin Trans. 1 1991, 2417.
See Ref. 23 for a discussion.
20. Schweitzer, E. E.; Bach, R. D. Org. Synth. Coll. Vol. V, 1145, and refs cited therein.
21. Synthesis of 10a. A solution of N-phthaloyl valinamide (1.2 g, 5.0 mmol) and
ethyl glyoxylate (50% w/w in toluene, 1.3 g, 6.5 mmol) was refluxed overnight,
whereupon TLC (30% EtOAc/hexanes) indicated complete conversion of the
starting amide into the hydroxyglycinate. The mixture was concentrated in
vacuo, and the residue was triturated with 30% EtOAc in hexanes to yield 1.7 g
transferred over 15 min (syringe) to a solution of a-chloroglycinate (1.8 g,
5.0 mmol) in THF (6 mL), kept at rt. The resulting mixture was stirred at rt for
4 h; then it was diluted with CHCl3, filtered through silica gel (elution with
EtOAc), and concentrated in vacuo. Purification of the residue (flash
chromatography on silica gel; 0.5% Et3N in 20% EtOAc/hexanes) afforded
1.0 g (55%) of 10a, as a colorless oil, ½a D22
= ꢀ50.4 (c 0.6, CHCl3). IR: 1770, 1720,
ꢁ
1639, 1563. 1H: 7.80 (dd, 2H, J = 5.5, 3.1), 7.69 (dd, 2H, J = 5.5, 3.1), 7.11 (dd, 1H,
J = 17.7, 11.4), 5.94 (d, 1H, J = 17.7), 5.51 (d, 1H, J = 11.4), 5.13 (d, 1H, J = 10.3),
4.32 (q, 2H, J = 7.1), 3.16–3.04 (m, 1H), 1.32 (t, 3H, J = 7.1), 1.08 (d, 3H, J = 6.7),
0.93 (d, 3H, J = 6.7). 13C: 167.3, 161.6, 159.3, 154.2, 134.3, 131.5, 127.4, 123.5,
122.0, 120.7, 61.2, 54.1, 28.5, 20.4, 19.3, 14.3. HRMS: calcd for C20H20N2O5Na
M+Na+, 391.1270; found, 391.1268.
22. Zhang, J.; Ciufolini, M. A. Org. Lett. 2009, 11, 2389.
23. Zhang, J.; Polishchuk, E. A.; Chen, J.; Ciufolini, M. A. J. Org. Chem. 2009, 74, 9140.
24. In particular, no propargyl ethers of ortho- or para-nitrophenols were
investigated, because previous research had shown that alkynes displaying
nitro groups anywhere in the molecule fail to produce well-behaved
(>99% crude yield) of the corresponding
a
-hydroxyglycinate, 1:1 mixture of
dimethylaluminum acetylides. For
Dissertation, Université Claude Bernard Lyon I, 2001.
a
discussion see: Coqueron, P.-Y.
diastereomers (1H: 8.29 (d, 1H, J = 6.5), 8.15 (d, 1H, J = 6.5), 7.89–7.87 (m, 4H),