Facile preparation of oxazole-4-carboxylates and 4-ketones from aldehydes using 3-oxazoline-4-carboxylates as intermediates

Article abstract of DOI:10.1021/ol1012789

(Equation Presented). A novel 2-step synthesis of oxazole-4-carboxylates from aldehydes was developed, which is characterized by the utilization of 3-oxazoline-4-carboxylates as synthetic intermediates. The facile preparation of 4-keto-oxazole derivatives from 3-oxazoline-4-carboxylates based on their interesting reactivity toward Grignard reagents is also described.

Full text of DOI:10.1021/ol1012789

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3456-3459
Facile Preparation of
Oxazole-4-carboxylates and 4-Ketones
from Aldehydes using
3-Oxazoline-4-carboxylates as
Intermediates
Kenichi Murai, Yusuke Takahara, Tomoyo Matsushita, Hideyuki Komatsu, and
Hiromichi Fujioka*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity,
1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
fujioka@phs.osaka-u.ac.jp
Received June 3, 2010
ABSTRACT
A novel 2-step synthesis of oxazole-4-carboxylates from aldehydes was developed, which is characterized by the utilization of 3-oxazoline-
4-carboxylates as synthetic intermediates. The facile preparation of 4-keto-oxazole derivatives from 3-oxazoline-4-carboxylates based on their
interesting reactivity toward Grignard reagents is also described.
Oxazole is an important heterocycle, and many oxazole-
containing natural products, such as disorazole A1 and
hennoxiazole A2 (Figure 1), display attractive biological
activities.3 As for their structures, 2,4-disubstituted oxazoles
are found in a number of natural products, and most of the
substituents at the oxazole 4-position are esters and their
derivatives, because naturally occurring oxazoles are con-
sidered to be derived from amino acids such as serine and
threonine.1a
Oxazole-4-carboxylates are recognized as useful interme-
diates and have been used in various total syntheses.1a,4
General synthetic methods for them include the following
3-step procedure: (1) condensation of carboxylic acids with
serine methyl ester to afford amide alcohols, (2) dehydrative
(4) For examples, see: (a) Wipf, P.; Graham, T. H. J. Am. Chem. Soc.
2004, 126, 15346. (b) Hartung, I. V.; Niess, B.; Haustedt, L. O.; Hoffmann,
H. M. R. Org. Lett. 2002, 4, 3239. (c) Hillier, M. C.; Park, D. H.; Price,
A. T.; Ng, R.; Meyers, A. I. Tetrahedron Lett. 2000, 41, 2821. (d) Williams,
D. R.; Brooks, D. A.; Berliner, M. A. J. Am. Chem. Soc. 1999, 121, 4924.
(e) Yokokawa, F.; Asano, T.; Shioiri, T. Tetrahedron 2001, 57, 6311. (f)
Smith, T. E.; Kuo, W.-H.; Balskus, E. P.; Bock, V. D.; Roizen, J. L.;
Theberge, A. B.; Carroll, K. A.; Kurihara, T.; Wessler, J. D. J. Org. Chem.
2007, 73, 142. (g) Lachia, M.; Moody, C. J. Nat. Prod. Rep. 2008, 25, 227.
(h) Custar, D. W.; Zabawa, T. P.; Hines, J.; Crews, C. M.; Scheidt, K. A.
J. Am. Chem. Soc. 2009, 131, 12406. (i) Deeley, J.; Bertram, A.; Pattenden,
G. Org. Biomol. Chem. 2008, 6, 1994. (j) Zhang, J.; Polishchuk, E. A.;
Chen, J.; Ciufolini, M. A. J. Org. Chem. 2009, 74, 9140. (k) Cheung, C.-
M.; Goldberg, F. W.; Magnus, P.; Russell, C. J.; Turnbull, R.; Lynch, V.
(1) (a) Jansen, R.; Irschik, H.; Reichenbach, H.; Wray, V.; Hoefle, G.
Liebigs Ann. Chem. 1994, 759. (b) Hopkins, C. D.; Wipf, P. Nat. Prod.
Rep. 2009, 26, 585.
(2) Ichiba, T.; Yoshida, W. Y.; Scheuer, P. J.; Higa, T.; Gravalos, D. G.
J. Am. Chem. Soc. 1991, 113, 3173.
(3) For recent reviews, see: (a) Yeh, V. S. C. Tetrahedron 2004, 60,
11995. (b) Jin, Z. Nat. Prod. Rep. 2006, 23, 464. (c) Jin, Z. Nat. Prod.
Rep. 2009, 26, 382.
J. Am. Chem. Soc. 2007, 129, 12320
.
10.1021/ol1012789  2010 American Chemical Society
Published on Web 07/07/2010

Scheme 2. This Work
intermediates in contrast to the previous methods that use
2-oxazoline-4-carboxylates. To the best of our knowledge,
this is the first general method that uses aldehydes as starting
materials for oxazole-4-carboxylates.9 Aldehydes are one of
the most popular functional groups and are readily prepared
by a number of methods. The present method shortens the
steps needed to access oxazoles compared with previous
methods. The method can also provide various oxazoles
including biologically active natural products.
Recently, we developed a novel method for obtaining
2-imidazolines via a one-pot condensation-oxidation involv-
ing aldehydes and 1,2-diamines.10 This reaction chemose-
lectively proceeds under mild conditions at a low reaction
temperature (0 °C-rt) with N-bromosuccinimide (NBS).
During the course of our study on the oxidative synthesis of
heterocycles, we examined the one-pot condensation-oxida-
tion of heptanal (1a) and serine methyl ester hydrochloride
(2a) with N-chlorosuccinimide (NCS) in the presence of
DABCO and expected formation of the 2-oxazoline-4-
carboxylate 4a. However, 3-oxazoline-4-carboxylate 3a was
selectively obtained (Scheme 3). Although the one-pot and
stepwise condensation-oxidation of aldehydes and amino
alcohols has been previously reported, these methods pro-
vided 2-oxazolines11 or a mixture of 2-oxazolines and
3-oxazolines.12 On the other hand, this type of reaction using
ester-substituted amino alcohols, such as the serine methyl
ester, and the selective formation of 3-oxazolines has not
Figure 1. Examples of oxazole-containing natural products.
cyclization to obtain 2-oxazolines,5 and (3) oxidation to the
oxazoles (Scheme 1).6 The Robinson-Gabriel-type cycliza-
tion, which includes side-chain oxidation and subsequent
Scheme 1. General Method
cyclodehydration of amide alcohols, is also employed.7,8
Although such transformations are well-developed, they
require 3 steps, and expensive reagents are necessary for
some of the dehydrative cyclizations. Therefore, developing
a novel efficient synthesis of oxazole-4-carboxylates is still
desirable.
In this Letter, we report a novel 2-step synthesis of
oxazole-4-carboxylates from aldehydes (Scheme 2). It in-
volves a one-pot condensation-oxidation of aldehydes and
serine or threonine methyl ester to give 3-oxazoline-4-
carboxylates and then subsequent oxidation to obtain the
oxazole-4-carboxylates. This method is characterized by the
utilization of 3-oxazoline-4-carboxylates as novel synthetic
(8) For recent progress on synthesis of various substituted oxazole
derivatives, see: (a) Williams, D. R.; Fu, L. Org. Lett. 2010, 12, 808. (b)
Ackermann, L.; Barfus¨ser, S.; Pospech, J. Org. Lett. 2010, 12, 724. (c)
Lee, K.; Counceller, C. M.; Stambuli, J. P. Org. Lett. 2009, 11, 1457. (d)
Santos, A.; dos; Ka¨ım, L. E.; Grimaud, L.; Ronsseray, C. Chem. Commun.
2009, 3907. (e) Verrer, C.; Hoarau, C.; Marsais, F. Org. Biomol. Chem.
2009, 7, 647. (f) Flegeau, E. F.; Popkin, M. E.; Greaney, M. F. Org. Lett.
2008, 10, 2717. (g) Besseliev`re, F.; Piguel, S.; Mahuteau-Betzer, F.;
Grierson, D. S. Org. Lett. 2008, 10, 4029. (h) Chudasama, V.; Wilden,
J. D. Chem. Commun. 2008, 3768. (i) Riedrich, M.; Harkal, S.; Arndt, H.-
D. Angew. Chem., Int. Ed. 2007, 46, 2701. (j) Mart´ın, R.; Cuenca, A.;
Buchwald, S. L. Org. Lett. 2007, 9, 5521. (k) Ferrer Flegeau, E.; Popkin,
M. E.; Greaney, M. F. Org. Lett. 2006, 8, 2495. (l) Keni, M.; Tepe, J. J. J.
Org. Chem. 2005, 70, 4211. (m) Coqueron, P.-Y.; Didier, C.; Ciufolini,
M. A. Angew. Chem., Int. Ed. 2003, 42, 1411. (n) Hodgetts, K. J.; Kershaw,
M. T. Org. Lett. 2002, 4, 2905.
(5) (a) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R.
Org. Lett. 2000, 2, 1165. (b) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992,
33, 6267. (c) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907. (d)
Yokokawa, F.; Shioiri, T. Tetrahedron Lett. 2002, 43, 8679. (e) Sakakura,
A.; Kondo, R.; Ishihara, K. Org. Lett. 2005, 7, 1971.
(9) For limited examples of the oxidation of 2-aryl-oxazolidines derived
from aldehydes to give oxazoles, see: Badr, M. Z. A.; Aly, M. M.; Fahmy,
A. M.; Mansour, M. E. Y. Bull. Chem. Soc. Jpn. 1981, 54, 1844.
(10) (a) Fujioka, H.; Murai, K.; Ohba, Y.; Hiramatsu, A.; Kita, Y.
Tetrahedron Lett. 2005, 46, 2197. (b) Fujioka, H.; Murai, K.; Kubo, O.;
Ohba, Y.; Kita, Y. Tetrahedron 2007, 63, 638. (c) Murai, K.; Morishita,
M.; Nakatani, R.; Kubo, O.; Fujioka, H.; Kita, Y. J. Org. Chem. 2007, 72,
8947. (d) Murai, K.; Morishita, M.; Nakatani, R.; Fujioka, H.; Kita, Y.
Chem. Commun. 2008, 4498. (e) Murai, K.; Takaichi, N.; Takahara, Y.;
Fukushima, S.; Fujioka, H. Synthesis 2010, 520.
(6) (a) Williams, D. R.; Lowder, P. D.; Gu, Y.-G.; Brooks, D. A.
Tetrahedron Lett. 1997, 38, 331. (b) Aoyama, T.; Sonoda, N.; Yamauchi,
M.; Toriyama, K.; Anzai, M.; Ando, A.; Shioiri, T. Synlett 1998, 35. (c)
Meyers, A. I.; Tavares, F. Tetrahedron Lett. 1994, 35, 2481. (d) Meyers,
A. I.; Tavares, F. X. J. Org. Chem. 1996, 61, 8207. (e) Tavares, F.; Meyers,
A. I. Tetrahedron Lett. 1994, 35, 6803.
(7) (a) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604. (b) Brain,
C. T.; Paul, J. M. Synlett 1999, 1642. (c) Pulici, M.; Quartieri, F.; Felder,
(11) (a) Schwekendiek, K.; Glorius, F. Synthesis 2006, 2996. (b) Ishihara,
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Org. Lett., Vol. 12, No. 15, 2010
3457

As a result of this screening, NBS was found to be an
effective oxidant, and oxazole 5a was obtained in 84% yield
in the presence of K2CO3. On the other hand, in the presence
of triethylamine, the reaction did not proceed (entry 6).14
With the optimized reaction conditions in hand, the
generality of the reactions for forming 3-oxazolines 3a-3k
and oxazoles 5a-5k was investigated. As shown in Table
2, the yields were uniformly good to excellent. As well as
2a (entries 1 and 2), the threonine methyl ester hydrochloride
(2b) was evaluated (entries 3 and 4). As functional groups,
TBDMSO, TBDPSO, BzO, BnO, MeO, Cbz, and Boc were
found to be tolerant (entries 5-11). For the oxidation of 3
to 5, some modification of the reaction conditions was
Scheme 3. Formation of the 3-Oxazoline-4-carboxylate 3a
been reported. Our result is the first example of the one-pot
condensation-oxidation of such ester-substituted amino
alcohols and aldehydes to selectively afford the 3-oxazolines.
This transformation involves formation of the N,O-acetal
(namely, the oxazolidine), N-chlorination, and subsequent
E2 elimination. In the final step, deprotonation at the
R-position of the ester selectively occurs to give the
3-oxazoline-4-carboxylate 3a.
Table 2. Synthesis of Oxazole-4-carboxylates from Aldehydes
via 3-Oxazoline-4-carboxylatesa b
,
Although 2-oxazolines are useful synthetic intermediates
for oxazoles, there are a few reports on the synthetic utility
of 3-oxazolines.13 Hence, we examined several oxidative
conditions to obtain oxazole 5a from 3-oxazoline 3a. These
results are summarized in Table 1. We first examined the
Table 1. Oxidation of 3-Oxazoline 3a to Oxazole 5a
entry
1
conditions
yield (%)
BrCCl3 (1.2 equiv), DBU (2.0 equiv)/
CH2Cl2, rt, 22 h
no reaction
2
3
4
5
MnO2 (10 equiv)/benzene, reflux, 16 h no reaction
DDQ (2.2 equiv)/toluene, reflux, 14 h
CAN (2.2 equiv)/CH3CN, reflux, 24 h
NBS (1.2 equiv), K2CO3 (1.2 equiv)/
DCE, reflux, 30 min
decomposition
decomposition
84
6
NBS (1.2 equiv), TEA (1.2 equiv)/
DCE, reflux, 6 h
no reaction
combination of BrCCl3 and DBU, which is widely used for
the oxidation of 2-oxazoline-4-carboxylates to oxazoles.
However, this method was not suitable for 3-oxazoline 3a
and resulted in no reaction judged by TLC (entry 1). MnO2
also resulted in no reaction (entry 2). DDQ and CAN resulted
in decomposition of the starting material (entries 3 and 4).
a Conditions (1 to 3): 2 (1.1 equiv), DABCO (3 equiv), and NCS (1.1
equiv). b Conditions (3 to 5): NBS (1.2 equiv) and K2CO3 (1.2 equiv) (unless
otherwise noted). c Additive: MS 4 Å. d Conditions (3 to 5): NIS (2.0 equiv).
e Conditions (3 to 5): NIS (4.0 equiv).
(12) Favreau, S.; Lizzani-Cuvelier, L.; Loiseau, M.; Dun˜ach, E.; Fellous,
R. Tetrahedron Lett. 2000, 41, 9787.
(13) (a) Do¨mling, A.; Bayler, A.; Ugi, I. Tetrahedron 1995, 51, 755.
(b) Hua, D. H.; Khiar, N.; Zhang, F.; Lambs, L. Tetrahedron Lett. 1992,
33, 7751.
3458
Org. Lett., Vol. 12, No. 15, 2010

needed: molecular sieves were added for 5e, 5h, 5i, and 5j;
NIS was used instead of NBS and K2CO3 for 5h and 5i. It
is noteworthy that oxazoles 5f and 5i were synthetic
interemediates for the oxazole-containing natural products
such as hennoxazole A4d and disorazole C.4b Contrary to
the reported methods that needed 3 steps to prepare 5f or 5i
from the corresponding carboxylic acids as shown in Scheme
1, our method was able to provide them from readily
available aldehydes in 2 steps and good yields.
Scheme 5. Preparation of the 4-Keto-oxazole Derivatives
The 3-oxazoline-4-carboxylates have three electrophilic
functional groups that include an ester, an imine, and an N,O-
acetal.15 Therefore, their reactivity with nucleophiles was
of interest. To explore the synthetic utility of the 3-oxazoline-
4-carboxylates, we examined their reaction with Grignard
reagents. When MeMgBr (1.5 equiv) was added to the
solution of 3a at -78 °C and the reaction was quenched at
the same temperature, MeMgBr was found to only react with
the ester of the three possible electrophilic functional groups.
Very interestingly, the methyl ketone 6a was obtained in
92% yield (Scheme 4). We also confirmed the reaction of
a MS 4 Å was added for 8a.
the previous report using the Weinreb amide for 4-keto-
oxazole synthesis.4e
In conclusion, we have developed a novel 2-step approach
for oxazole-4-carboxylates from aldehydes using 3-oxazoline-
4-carboxylates as synthetic intermediates. It was also found
that the interesting reactivity of the 3-oxazoline-4-carboxy-
lates with Grignard reagents provided an easy preparation
of 4-keto-oxazole derivatives. The availability of various
aldehydes and the simplicity of the developed method can
provide broad synthetic options for the synthesis of oxazole
derivatives. Further detailed investigations including the one-
pot transformation of aldehydes to oxazoles,16 and applica-
tions for the total synthesis of natural products are now
underway.
Scheme 4. Reaction of 3a with MeMgBr
Acknowledgment. This work was financially supported
by Grant-in-Aid for Scientific Research (B) and for Young
Scientists (B) from JSPS.
Supporting Information Available: Experimental details
and detailed spectroscopic data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
the ketone 6a with MeMgBr to give the tertiary alcohol 7
(Scheme 4). Therefore, we assumed that a chelated metal
complex intermediate (Scheme 4) could be involved that
would prevent the addition of more than 1 equiv of reagent
to form the alcohol, although further detailed investigations
of the selective formation of the ketone are needed.
OL1012789
(14) The reaction without any base also afforded oxazole 5a; however,
an inseparable byproduct was also produced. The reaction probably
proceeded via bromination of the 5-position of 3-oxazolines or nitrogen
atom and then aromatization. K2CO3 was used as an acid scavenger for
HBr formed in situ.
This interesting reactivity of the 3-oxazoline-4-carbox-
ylates was useful for preparation of the 4-keto-oxazole
derivatives (Scheme 5). Thus, the reaction of 3a and 3c with
MeMgBr or PhMgBr gave the corresponding ketones 6a-6d
in good yields. The following oxidation also successfully
proceeded under NBS/K2CO3 conditions to give the 4-keto-
oxazole derivatives 8a-8d. In the case of compound 6a, the
modified conditions using molecular sieves as an additve
were effective. This transformation was facile compared with
(15) For examples of the reaction of 1,3-oxazolidines with Grignard
reagents, see: (a) Steinig, A. G.; Spero, D. M. J. Org. Chem. 1999, 64,
2406. (b) Yamauchi, T.; Takahashi, H.; Higashiyama, K. Heterocycles 1998,
48, 1813. (c) Wu, M. J.; Pridgen, L. N. J. Org. Chem. 1991, 56, 1340. (d)
Takahashi, H.; Chida, Y.; Yoshii, T.; Suzuki, T.; Yanaura, S. Chem. Pharm.
Bull. 1986, 34, 2071.
(16) Several attempts at the one-pot transformation of aldehydes to
oxazoles have failed at this stage.
Org. Lett., Vol. 12, No. 15, 2010
3459