A Peterson avenue to 5-alkenyloxazoles

Article abstract of DOI:10.1016/j.tetlet.2009.08.076

The TiCl₄-promoted Peterson olefination of aldehydes with readily available 5-(trimethylsilyl)methyloxazoles furnishes 5-alkenyloxazoles (mostly E-isomers).

Full text of DOI:10.1016/j.tetlet.2009.08.076

Tetrahedron Letters 50 (2009) 6163–6165
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A Peterson avenue to 5-alkenyloxazoles
*
Jaclyn Chau, 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 TiCl4-promoted Peterson olefination of aldehydes with readily available 5-(trimethylsilyl)methylox-
azoles furnishes 5-alkenyloxazoles (mostly E-isomers).
Received 17 June 2009
Revised 21 August 2009
Accepted 24 August 2009
Available online 27 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Ongoing research on the synthesis of oxazole-containing natu-
ral products1 revealed a need for an expeditious route to 2-alkyl-
(E)-5-alkenyl-4-oxazole-carboxylic esters, 1 (Fig. 1). Surprisingly,
the CAS database records only two compounds of this general type,
2 and 3, both of which are described in a patent that reports anti-
viral activity for such structures.2 The scant precedent for struc-
tures 1 reflects a more general lack of information regarding the
synthesis of 5-alkenyl-oxazoles. Such heterocycles have been
primarily obtained by Pd-mediated coupling reactions of 5-haloox-
azoles.3 A recent method for the assembly of 4-alkyl-5-acyloxaz-
oles provides a route to corresponding 5-alkenyl-oxazoles by
carbonyl reduction and dehydration of the intermediate alcohol.4
However, the products thus obtained lack a 4-COOR substituent.
A noteworthy alternative involves the de novo construction of
the heterocyclic framework through cycloisomerization–elimina-
tion of N-propargyl amides 4 (Fig. 2),5 but again, the ensuing 5-
alkenyl-oxazoles lack the desired 4-COOR group. A variant of that
12 are known, and many Wittig reactions with such agents have
been described.10
Alternatively, the chemistry of Ref. 6 provides facile access to 5-
(trimethylsilyl)methyloxazoles such as 19 and 20 (Scheme 1). We
surmised that these could undergo Peterson olefination11 with
aldehydes, thereby affording the desired 1. On the other hand, Pet-
erson reactions with hetero-aromatic donors are quite rare. More-
over, they appear to have been documented only in the pyridine
series.12 Because no examples of like reactions in the oxazole do-
main appear to exist, a feasibility study was carried out but using
19 and 20.
The deprotonation of the foregoing oxazoles occurred regiose-
lectively at the CH2TMS group upon treatment with LDA or LHMDS
(THF, À78 °C, 20–30 min, Scheme 2), as apparent from the virtually
R2
R
O
N
O
N
method leads to 2-alkyl-4-carbalkoxy-5-vinyl oxazoles
6 by
R1
S
cyclization of N-acyl-2-(3-methoxy-1-propynyl) glycinates (4,
Z = COOR3).6 Unfortunately, products 6 are accompanied by vari-
able quantities of 5-(2-methoxyethyl)-oxazoles 7, to the detriment
of overall efficiency. It should be noted that contrary to the case of
the 5-isomers, the chemistry of 2- and 4-alkenyl-oxazoles is fairly
well developed.7
COOR3
COOMe
1
2
R = Me
R = Ph
3
Figure 1. 5-Alkenyloxazoles of interest in this study (1) and recorded examples
thereof (2–3).
Our interest in compounds 1, the paucity of methods for their
assembly, and their biological relevance1,8 induced us to research
a new synthetic route. In principle, the requisite oxazoles could
be prepared through olefination chemistry, and an option in that
respect would be a Wittig reaction of an oxazole-based phosphor-
ane or phosphonate. However, a search of the CAS database
retrieved no record of phospho-oxazole substructures 8 or 9
(Fig. 3). Motif 10 is documented in only seven compounds,9 none
of which are serviceable in the present case. By contrast, more than
100 examples each of 2- and 4-phosphorylmethyl oxazoles 11 and
G
Z = H or alkyl
G = CH2OR2
O
N
O
R1
R1
N
H
Z
(H, Alkyl)
(ref 5)
5
OR3
4
Z = CO2R3
G = CH2OMe
O
O
R1
+
R1
N
CO2R3
COOR3
N
(ref 6)
6
7
* Corresponding author. Tel.: +1 604 822 2419; fax: +1 822 8710.
E-mail address: ciufi@chem.ubc.ca (M.A. Ciufolini).
Figure 2. 5-Alkenyloxazoles via isomerization–elimination of propargylamides.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.076

6164
J. Chau et al. / Tetrahedron Letters 50 (2009) 6163–6165
complete deuteration of the CH2TMS substituent upon a D2O
P
P
O
N
O
N
O
N
P
R
R
quench. The regioselectivity observed in the lithiation of 19 is
unquestionably due to the activating effect of the TMS group. In-
deed, the metallation of 2,4-dimethyloxazole-4-carboxylates is
infamously non-regioselective.13 The resulting organometallics 21
proved to be poor nucleophiles. In particular, they added ineffi-
ciently even to aldehydes. Past experience with similar difficul-
ties1f suggested that the use of a Lewis acid activator of the
carbonyl acceptor might circumvent the problem. Indeed, TiCl4
emerged as an effective promoter of the addition of 21 to both aro-
matic and aliphatic aldehydes. The ensuing reaction afforded a
mixture of E (dominant) and Z isomers of the desired 1, plus vari-
able quantities of adducts 22, which had failed to undergo elimina-
tion. This is not surprising in light of the retarding effect of
oxophilic metal ions on the Peterson elimination of 1,2-silanols.14
A complete conversion of 22 into 1 occurred smoothly upon treat-
ment of such crude mixtures with TsOH in refluxing toluene.15 In
some cases, such a treatment more than doubled the overall yield
of desired 1.
The base of choice for reactions of phenyl substrate 20 was
found to be LDA, while LHMDS was preferred with methyl oxazole
19. The latter base also gave improved yields in the reaction of 20
with PhCHO. It seems imprudent to venture simplistic explana-
tions for such observations. The aldehydes were best introduced
into a cold (À78 °C), preformed solution of 21 in one portion, either
in neat forms (liquids) or as concentrated THF solutions (solids),
immediately followed by the addition of TiCl4 (1 M solution in
CH2Cl2). Aqueous workup and subsequent TsOH treatment of the
crude product afforded oxazoles 1 (E/Z mixtures), which then were
chromatographically purified.16
Table 1 lists the 5-alkenyl-oxazoles obtained through the new
procedure. The first yield column in this table reports the yields
of 1 obtained from a sequence that omitted the TsOH treatment;
the second one tabulates the yields of 1 arising from a preparation
that included such a step. Available data suggest that the reaction
performs adequately with both aliphatic and aromatic aldehydes.
The latter substrates may indifferently carry substitution at the
ortho, meta, and para positions and incorporate electron-donating
or electron-withdrawing groups. Representative heteroaromatic
aldehydes, such as 2-furaldehyde and 2-thienaldehyde, participate
normally in the reaction. Unfortunately, ketones such as acetone
and cyclohexanone failed to combine with 21 even in the presence
of TiCl4. At this time, we are unable to remedy such a limitation.
On a final note, mixtures of E- and Z-isomers of 1 may be
strongly enriched in (E)-alkene (>95% by integration of 1H NMR
spectra) by refluxing in toluene in the presence of a catalytic
amount of I2 (Table 2).17,18
COOR'
8
9
10
O
0 hits
0 hits
7 hits
P
O
N
O
N
P
11
12
> 100 hits
> 100 hits
Figure 3. Oxazole-based Wittig-type reagents recorded in the CAS database.
SiMe3
O
X
O
O
c
a
R
N
H
COOEt
R
NH2
COOEt
R
N
13 R = Me
14 R = Ph
15 R = Me, X = OH
19 R = Me
20 R = Ph
16 R = Ph, X = OH
b
17 R = Me, X = Cl
18 R = Ph, X = Cl
Scheme 1. Reagents and conditions: (a) OHC–COOEt, THF, reflux, 99%; (b) neat
SOCl2, rt, 99%; (c) Me2Al–CC–TMS, THF, 0 °C, 3 h, 45% (chrom.) for 19, 46% (chrom.)
for 20.
Li
b
a
O
N
TMS
R1
19/20
COOEt
21
TMS
R2
R2
O
O
R1
R1
+
c
OH
N
N
COOEt
COOEt
22
1
Scheme 2. Reagents and conditions: (a) LDA or LHMDS (see text), THF, À78 °C, 20–
30 min; (b) R2–CHO, then TiCl4 in CH2Cl2, À78 °C to rt; (c) TsOHÁH2O, toluene, reflux,
40–80% overall.
Table 1
5-Alkenyloxazoles obtained by the new procedure
R2
In summary, we have shown that readily available 5-(trimethyl-
silyl)methyl-oxazole-4-carboxylate esters are useful for the Peter-
son synthesis of (E)-5-alkenyl oxazoles. Applications of this
chemistry to problems in total synthesis will be described in due
course.
O
R1
1
N
COOEt
Entry
Base
R1
R2
Et
Yield%a (E:Z)
Yield%b (E:Z)
1a
1b
1c
1d
1e
1f
1g
1h
1i
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LHMDS
LHMDS
LHMDS
LHMDS
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
50 (9:1)
57 (4:1)
35 (7:3)
40 (1:1)
60 (7:3)
79 (9:1)
71 (7:3)
74 (7:3)
53 (1:1)
74 (6:1)
57 (4:1)
78 (9:1)
50 (4:1)
83 (3:1)
46 (3:2)
46 (E)
Ph–CH2–CH2
4-MeO–C6H4
2-Me–C6H4
4-Cl–C6H4
4-NC–C6H4
3-Me–C6H4
2-Furyl
Table 2
Equilibration of (E/Z)-1 to the (E)-isomer
R2
R2
O
N
toluene,
O
N
R1
R1
refl., cat. I2
COOEt
COOEt
(E)-1
Ph
45 (4:1)
26 (3:2)
38 (E)
1j
1k
1l
Ph–CH2–CH2
4-Cl–C6H4
2-Thienyl
(E / Z)-1
44 (E)
77 (E)
Entry
R1
R2
Initial E/Z ratio
Final E/Z ratio
a
Yield and E/Z isomer ratio of chromatographically purified alkenyloxazoles
obtained from a sequence that omitted the TsOH treatment (see text).
Yield and E/Z isomer ratio (after chromatography) for a sequence that included
the TsOH treatment prior to isolation of the product (see text).
1d
1i
1j
Ph
Ph
Me
2-Me–C6H4
Ph
Ph–CH2–CH2
1:1
3:1
1.5:1
E only detectable
96:4
96:4
b

J. Chau et al. / Tetrahedron Letters 50 (2009) 6163–6165
6165
Lucas, B. S.; Luther, L. M.; Burke, S. D. J. Org. Chem. 2005, 70, 3757; (k) Gonzalez,
M. A.; Pattenden, G. Angew. Chem., Int. Ed. 2003, 42, 1255; (l) Smith, A. B., III;
Friestad, G. K.; Duan, J. J.-W.; Barbosa, J.; Hull, K. G.; Iwashima, M.; Qiu, Y.;
Spoors, P. G.; Bertounesque, E.; Salvatore, B. A. J. Org. Chem. 1998, 63, 7596; (m)
Ogawa, A. K.; DeMattei, J. A.; Scarlato, G. R.; Tellew, J. E.; Chong, L. S.;
Armstrong, R. W. J. Org. Chem. 1996, 61, 6153; (n) Yokokawa, F.; Hamada, Y.;
Shioiri, T. Chem. Commun. 1996, 871; (o) Kellner, K.; Preussler, C.; Schnepp, K.
Phosphorus, Sulfur, Silicon Relat. Elem. 1993, 76, 391; (p) Evans, D. A.; Gage, J. R.;
Leighton, J. L.; Kim, A. S. J. Org. Chem. 1992, 57, 1961; (q) Zhao, Z.; Scarlato, G. R.;
Armstrong, R. W. Tetrahedron Lett. 1991, 32, 1609.
Acknowledgments
We thank the University of British Columbia, the Canada Re-
search Chair Program, BCKDF, NSERC, CIHR, and Merck Frosst Can-
ada for support of our research.
Supplementary data
11. Reviews: (a) Ager, D. J. Org. React. 1990, 38, 1; (b) van Staden, L. F.; Gavestock,
D.; Ager, D. J. Chem. Soc. Rev. 2002, 31, 195; (c) Kano, N.; Kawashima, T. The
Peterson and Related Reactions in Modern Carbonyl Olefination; Wiley-VCH:
Weinheim, Germany, 2004. pp 18–103.
Supplementary data (experimental procedures and spectral
data for all compounds) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2009.08.076.
12. Konakahara, T.; Takagi, Y. Synthesis 1979, 192.
13. Cornwall, P.; Dell, C. P.; Knight, D. W. J. Chem. Soc., Perkin Trans. 1 1991, 2417.
See also Refs. 1d,f..
14. (a) Sato, F.; Uchiyama, H.; Iida, K.; Kobayashi, Y.; Sato, M. J. Chem. Soc., Chem.
Commun. 1983, 921; (b) Reetz, M. T.; Steinbach, R.; Westermann, J.; Peter, R.
Chem. Ber. 1985, 118, 1441.
References and notes
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;
Leading references: (c) Nett, M.; Erol, Ö.; Kehrhaus, S.; Köck, M.; Krick, A.;
Eguereva, E.; Neu, E.; König, G. M. Angew. Chem., Int. Ed. 2006, 45, 3863; (d)
Linder, J.; Blake, A. J.; Moody, C. J. Org. Biomol. Chem. 2008, 6, 3908; (e) Balskus,
E. P.; Horan, R. A. J.; Langner, M.; Ley, S. V. Chem. Eur. J. 2007, 13, 5515; (f)
Zhang, J.; Ciufolini, M. A. Org. Lett. 2009, 11, 2389.
15. Koreeda, M.; Ciufolini, M. A. J. Am. Chem. Soc. 1982, 104, 2308.
16. Representative procedure for the Peterson olefination with 20: preparation of
compound 1a. Commercial n-BuLi solution (1.6 M in hexanes, 230
was added dropwise to a cold (À78 °C) solution of diisopropylamine (50
360 mmol, 1.1 equiv) in dry THF (300 L) under argon. The resultant was stirred
at (À78 °C) for 30 min, then, a dry THF (600 L) solution of 20 (100 mg,
330 mmol, 1.0 equiv) was added dropwise, and the mixture was stirred for
30 min. Neat propionaldehyde (100 L, 1.4 mmol, 4.2 equiv) was added rapidly
in one portion, followed by commercial TiCl4 in CH2Cl2 (1 M, 360 L, 360 mmol),
and the mixture was stirred for 5 h at À78 °C. Deionized H2O (200 L) was
l
L, 1.4 mmol)
lL,
l
l
2. Nan, F.; Zuo, J.; Wang, W.; Wang, G.; Chen, H.; He, P. PCT Int. Appl. 2006, WO
2006097030.
l
3. (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) 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; For a related 5-arylation of 5-halooxazoles see: (e)
Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2003, 5, 2911.
4. Lechel, T.; Lentz, D.; Reissig, H.-U. Chem. Eur. J. 2009, 15, 5432.
5. (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.
6. (a) Coqueron, P. Y.; Didier, C.; Ciufolini, M. A. Angew. Chem., Int. Ed. 2003, 42,
1411; See also (b) Nagao, Y.; Kim, K.; Sano, S.; Kakegawa, H.; Lee, W. S.;
Shimizu, H.; Shiro, M.; Katunuma, N. Tetrahedron Lett. 1996, 37, 861.
7. Leading references: (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 the literature cited therein.
8. Particular b-lactam antibiotics incorporate a 5-alkenyl- oxazole motif: Bennett,
I.; Broom, N. P. J.; Bruton, G.; Calvert, S.; Clarke, B. P.; Coleman, K.; Edmonson,
R.; Edwards, P.; Jones, D.; Osborne, N. F.; Walker, G. J. Antibiot. 1991, 44, 331.
9. Comprehensive bibliography: (a) Krasovitskii, B. M.; Shershukov, V. M. Khim.
Get. Soed. 1977, 611; (b) Penz, G.; Zbiral, E. Chem. Ber. 1985, 118, 4131; (c)
Crimmin, M. J.; O’Hanlon, P.; Rogers, N. H.; Walker, G. J. Chem. Soc., Perkin Trans.
1 1989, 2047.
l
l
cautiously added and the solution was warmed to rt. The mixture was extracted
three times with diethyl ether (20 mL). The combined extracts were washed
with deionized H2O (15 mL), dried (MgSO4), filtered, and concentrated. A toluene
(3 mL) solution of the crude residue plus TsOHÁH2O (63 mg, 330 mmol) was
refluxed for 20 min under Ar, then it was cooled and evaporated. The residue was
partitioned between Et2O (20 mL) and aq satd NaHCO3 solution (10 mL). The
layers were separated and the aqueous layer was extracted with more Et2O
(15 mL). The combined extracts were dried (MgSO4), filtered, and concentrated.
Chromatographic purification of the residue (20% EtOAc in hexane) yielded
71 mg (79%) of 1a, white solid, 9:1 mixture of E- and Z-isomers. 1H (E-isomer):
8.10–8.13 (m, 2H), 7.45–7.48 (m, 3H), 6.98 (dt, J1 = 16.1, J2 = 1.5, 1H), 6.73 (dt,
J1 = 16.1, J2 = 6.5, 1H), 4.45 (q, J = 7.1, 2H), 2.36 (m, 2H), 1.44 (t, J = 7.1, 3H), 1.16 (t,
J = 7.4, 3H); 1H (Z-isomer): 8.10–8.13 (m, 2H), 7.45–7.48 (m, 3H), 6.90 (dt,
J1 = 14.4, J2 = 1.7, 1H), 6.01(dt, J1 = 11.9, J2 = 7.5, 1H), 4.45 (q, J = 7.1, 2H), 2.70 (m,
2H), 1.43 (t, J = 7.1, 3H), 1.19 (t, J = 7.6, 3H); 13C: 162.31, 159.39, 154.46, 140.42,
130.89, 128.70, 126.96, 126.80, 126.51, 114.95, 61.13, 26.26, 14.38, 12.84; IR:
1710.4; HRMS: calcd for C16H17NO3 Na 294.1106, found 294.1100.
Chromatography of the crude Peterson mixture before TsOH treatment had
afforded 1a in only 50% yield. See the Supplementary data for additional details.
17. Dickinson, R. G.; Lotzkar, H. J. Am. Chem. Soc. 1937, 59, 472. and references cited
therein.
18. Representative procedure for the isomerization of mixtures of geometric isomers:
(E)-1i. A toluene (300 mL) solution of a 3:1 mixture of (E)- and (Z)-1i (16 mg,
50 mmol) and a small crystal of I2 (0.6 mg, ca. 5 mol %) was refluxed under Ar
for 18 h. The mixture was diluted with Et2O (20 mL) and washed with aq satd
NaHCO3 solution (10 mL). The aqueous phase was extracted with more Et2O
(15 mL). The combined extracts were dried (MgSO4), filtered, and concentrated
to provide 16 mg (100%) of 1i, as a 96:4 mixture of (E) and (Z)-isomers
(integration of 1H NMR spectrum). White solid, mp 114–116 °C. 1H: 8.17–8.20
(m, 2H), 7.68 (d, 1H, J = 16.4), 7.62–7.33 (m, 9H), 4.49 (q, 2H, J = 7.1), 1.48 (t, 3H,
J = 7.2). 13C: 162.2, 159.9, 154.4, 135.8, 134.5, 131.1, 129.2, 128.9, 128.8, 128.7,
127.3, 127.0, 126.4, 113.2, 61.3, 14.4. See Supplementary data for additional
information.
10. 2-Isomers and Wittig reactions thereof: (a) Pattenden, G.; Ashweek, N. J.;
Baker-Glenn, C. A. G.; Kempson, J.; Walker, G. M.; Yee, J. G. K. Org. Biomol. Chem.
2008, 6, 1478; (b) Smith, A. B., III; Razler, T. M.; Ciavarri, J. P.; Hirose, T.;
Ishikawa, T.; Meis, R. M. J. Org. Chem. 2008, 73, 1192; (c) Nicolaou, K. C.; Snyder,
S. A.; Giuseppone, N.; Huang, X.; Bella, M.; Reddy, M. V.; Rao, P. B.; Koumbis, A.
E.; Giannakak- ou, P.; O’Brate, A. J. Am. Chem. Soc. 2004, 126, 10174; (d)
Wolbers, P.; Misske, A. M.; Hoffmann, H. M. R. Tetrahedron Lett. 1999, 40, 4527;
(e) Williams, D. R.; Clark, M. P. Tetrahedron Lett. 1999, 40, 2291; (f) Paterson, I.;
Arnott, E. A. Tetrahedron Lett. 1998, 39, 7185; (g) Brown, P.; Davies, D. T.;
O’Hanlon, P. J.; Wilson, J. M. J. Med. Chem. 1996, 39, 446; 4-Isomers (h) Li, D.-R.;
Zhang, D.-H.; Sun, C.-Y.; Zhang, J.-W.; Yang, L.; Chen, J.; Liu, B.; Su, C.; Zhou, W.-
S.; Lin, G.-Q. Chem. Eur. J. 2006, 12, 1185; (i) Panchishin, S. Y.; Smolii, O. B.;
Chernega, A. N.; Rusanov, E. B.; Drach, B. S. Russ. J. Gen. Chem. 2005, 75, 518; (j)