Metalation of 4-oxazolinyloxazole derivatives. A convenient route to 2,4-bifunctionalized oxazoles.

Article abstract of DOI:10.1021/jo010762s

The synthesis of an array of 5-phenyloxazole derivatives bearing a variety of hydroxyalkyl groups at the C-2 position of the heterocyclic nucleus and possessing a formyl or a carboxyl function at C-4 is reported. These bifunctionalized compounds have been efficiently prepared by addition of carbonylated electrophiles to the 2-lithio derivative of 5-phenyloxazole preliminarily equipped with an oxazoline unit at the 4-position of the oxazole nucleus. It is demonstrated that this protocol offers a double advantage since it suppresses the troublesome electrocyclic ring-opening reaction and allows access to the target compounds by simple chemical transformation of the oxazoline ring system.

Full text of DOI:10.1021/jo010762s

J . Org. Chem. 2002, 67, 3601-3606
3601
Meta la tion of 4-Oxa zolin yloxa zole Der iva tives. A Con ven ien t
Rou te to 2,4-Bifu n ction a lized Oxa zoles
Axel Couture,*,† Pierre Grandclaudon,† Christophe Hoarau,† J ose´phine Cornet,‡
J ean-Pierre He´nichart,‡ and Raymond Houssin‡
Laboratoire de Chimie Organique Physique, UPRES A-CNRS 8009, Universite´ des Sciences et
Technologies de Lille, F-59655 Villeneuve d’Ascq Cedex, France, and Institut de Chimie Pharmaceutique
Albert Lespagnol, Universite´ de Lille 2, EA 2962, 3 rue du Professeur Laguesse, B.P. 83,
F-59006 Lille, France
axel.couture@univ-lille.fr
Received J uly 27, 2001
The synthesis of an array of 5-phenyloxazole derivatives bearing a variety of hydroxyalkyl groups
at the C-2 position of the heterocyclic nucleus and possessing a formyl or a carboxyl function at
C-4 is reported. These bifunctionalized compounds have been efficiently prepared by addition of
carbonylated electrophiles to the 2-lithio derivative of 5-phenyloxazole preliminarily equipped with
an oxazoline unit at the 4-position of the oxazole nucleus. It is demonstrated that this protocol
offers a double advantage since it suppresses the troublesome electrocyclic ring-opening reaction
and allows access to the target compounds by simple chemical transformation of the oxazoline
ring system.
Ta ble 1. Ta r get Com p ou n d s 1a -c a n d 2c,d
In tr od u ction
As a part of a program designed to prepare new metallo
enzyme inhibitors potentially useful as anticancer drugs,
we were recently interested in the synthesis of 5-phenyl-
oxazole derivatives 1a -c and 2c,d (Table 1) bearing a
variety of hydroxyalkyl groups at the C-2 position of the
heterocyclic nucleus and equipped with a formyl or
carboxyl function at C-4.
The emergence of oxazoles as a major class of hetero-
cycles1 that can be exploited for transformation into more
complex heterocycles, for their considerable utility as
latent functional group equivalents,2 and for their pres-
ence in a number of interesting and biologically active
products3 has stimulated considerable effort in the
development of new synthetic approaches to polysubsti-
tuted and diversely substituted models.4 Paradoxically,
many specific, simple examples remain difficult to pre-
pare. This is notably the case of oxazoles functionalized
at both the 2- and the 4-positions with differing oxidation
states of the appending carbon atoms, which have yet to
find important applications in the synthesis of more
complex natural products.5 Classical and most of the long
standing synthetic methods leading to substituted ox-
azoles involve ring-forming reactions.6 However, they
compd
X
R1
R2
1a
1b
1c
2c
2d
CHO
CHO
CHO
COOH
COOH
Ph
H
H
CH3(CH2)7
(CH2)5
(CH2)5
(CH3)2CHCH2
H
genuinely lack universality and are generally inadequate
for the synthesis of models carrying specific substituents,
namely sensitive functional groups, on the basic oxazole
nucleus. More recently, alternative methods based upon
the sequential metalation of the different sites of the
heteroring unit have gained interest from the scientific
community and are currently the object of intensive
synthetic endeavors.7
Resu lts a n d Discu ssion
A contentious issue in the elaboration of the diversely
functionalized 5-phenyloxazoles 1 and 2 was judging the
proper order for the tailored introduction of the func-
* To whom correspondence should be addressed. Fax +33-(0)3 20
33 63 09.
(5) (a) Williams, D. R.; Clark, M. P. Tetrahedron Lett. 1999, 40, 2291.
(b) Liu, P.; Panek, J . S. Tetrahedron Lett. 1998, 39, 6143. (c) Meyers,
A. I.; Lawson, J . P.; Walker, D. G.; Linderman, R. J . J . Org. Chem.
1986, 51, 5111. (d) Breuilles, P.; Uguen, D. Tetrahedron Lett. 1998,
39, 3149.
(6) (a) Iddon, B. Heterocycles 1994, 37, 1321. (b) Hartner, F. W.
Oxazoles. In Comprehensive Heterocyclic Chemistry II; Katritzky, A.
R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996;
Vol. 6, pp 262-318. (c) Turchi, I. J . In Heterocyclic Compounds; Turchi,
I. J ., Ed.; J . Wiley: New York, 1986; Vol. 45. (d) Lee, J . C.; Hong, T.
Tetrahedron Lett. 1997, 38, 8959. (e) Gilchrist, T. L. Adv. Heterocycl.
Chem. 1987, 41, 41.
† Universite´ des Sciences et Technologies de Lille.
‡ Universite´ de Lille 2.
(1) (a) Lipshutz, B. H.; Hungate, R. W. J . Org. Chem. 1981, 46, 1410.
(b) Wipf, P. Chem. Rev. 1995, 95, 2115. (c) Zhao, Z.; Scarlato, G. R.;
Armstrong, R. W. Tetrahedron Lett. 1991, 32, 1609.
(2) (a) Hutchings, R. H.; Meyers, A. I. J . Org. Chem. 1996, 61, 1004.
(b) Wasserman, H. H.; McCarthy, K. E.; Prowse, K. S. Chem. Rev. 1986,
86, 845.
(3) (a) Pattenden, G. J . Heterocycl. Chem. 1992, 29, 607. (b) Michael,
J . P.; Pattenden, G. Angew. Chem., Int. Ed. Engl. 1993, 32, 1. (c) Lewis,
J . R. Nat. Prod. Rep. 1995, 12, 135.
(4) (a) Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J . J . Chem.
Soc., Perkin Trans. 1 1998, 591. (b) Cardwell, K. S.; Hermitage, S. A.;
Sjolin, A. Tetrahedron Lett. 2000, 41, 4239. (c) Pei, W.; Li, S.; Nie, X.;
Li, Y.; Pei, J .; Chen, B.; Wu, J .; Ye, X. Synthesis 1998, 1298.
(7) (a) Williams, D. R.; Brooks, D. A.; Meyer, K. G.; Pagel, M.
Tetrahedron Lett. 1998, 39, 8023. (b) Shafer, C. M.; Molinski, T. F. J .
Org. Chem. 1998, 63, 551. (c) Shafer, C. M.; Molinski, T. F. Tetrahedron
Lett. 1998, 39, 2903.
10.1021/jo010762s CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/01/2002

3602 J . Org. Chem., Vol. 67, No. 11, 2002
Couture et al.
Sch em e 1
Sch em e 3
Sch em e 2
tionalities on the oxazole heterocyclic nucleus. Within
this context, it initially appeared that a convenient route
to the desired materials 1 and 2 would involve a double
sequence of metalation-functionalization of the parent
5-phenyloxazole 4. This initial conceptual approach was
guided by several observations recorded by previous
workers on the metalation of oxazoles8 in conjunction
with the known ease of the preparation of 5-aryl-
substituted oxazoles,9 which suggested the simple retro-
synthetic Scheme 1 (path a). Schematically, the synthesis
entailed the generation of the carbinol derivative 3, which
might have been obtained by hydroxyalkylation of the
parent oxazole 4 via its 2-metalated derivative.8d Sequen-
tial protection followed by metalation at the 4-position
of the heterocyclic nucleus and final connection of the
appropriate functionality should complete the synthesis
of the desired compounds 1 and 2. Literature precedent
gave support to the feasibility of such an approach. The
C-2 proton of an oxazole is thermodynamically more
acidic than the ortho proton of the phenyl ring in 410 and
particularly more than the C-4 proton of the heteroring
unit.11 If C-2 and C-5 are blocked, direct metalation at
C-4 can be reasonably expected so that we should be able
to sequentially functionalize an intact 5-phenyloxazole
in the desired manner. It was, however, anticipated that
this strategy would be fraught with difficulties associated
with the erratic nature of the metalation processes.7c
Indeed, attempts to trap 2-lithiooxazoles with electro-
philes must contend with the complication due to the
presence of valence bond tautomers 5 and 6 (Scheme 2),
which can react at the enolate oxygen as well as car-
bon,6,8,12 even though this problem has been partly solved
recently by the elegant method of Vedejs.13 Nevertheless,
using aromatic aldehydes as electrophiles, variable yields
of the normal carbinol adducts have been reported.8c,e
Above all, the well-known acidity of 2R-methyl protons,8a,14
especially when activated by two aromatic rings, e.g., 3
(R1 ) H, R2 ) aryl), could interfere with the second
metalation step since the different CH bonds of oxazole
itself and its alkyl derivatives differ considerably in
acidity. It is generally believed that the relative acidities
follow the trend 2 > 2R > 5 > 4. Finally, the 4-deproto-
nation of 2,5-disubstituted oxazoles can be complicated
by competing reactions, namely addition of the lithiated
base to the imine bond of the oxazole ring.15 Considering
then that this strategy would be doomed to failure, we
decided to adopt the alternative synthetic tactic depicted
in the retrosynthetic Scheme 1 (path b). We opted to
introduce specific carbon electrophiles at the 2-position
of the oxazole nucleus by metalation of a 5-phenyloxazole
precursor 8 pre-equipped at the 4-position with a protec-
tive group (PG) liable to give access to the desired
functionalities of 1 and 2.
Critical to the success of this strategy then was the
ability to identify a masked carboxaldehyde or carboxylic
acid synthon that was capable not only of retaining the
required functionalities but also of surviving and, if
possible, facilitating the metalation step. For this pur-
pose, we initially chose the readily accessible 4-carb-
ethoxy-5-phenyloxazole (9). The first metalation experi-
ments followed literature precedent settling the optimal
conditions for the formation of the 2-lithio derivative 10.8a
Thus, the 4,5-disubstituted oxazole 9 was deprotonated
with LTMP at -78 °C in THF to give a deep red solution
that became amber in color on addition of benzaldehyde
and that was stirred overnight with gradual warming
(Scheme 3). Deuterium quenching studies revealed that
the metalation reaction was complete within 5 min and
that the only detectable product was the 2-deuterated
(8) (a) Whitney, S. E.; Rickborn, B. J . Org. Chem. 1991, 56, 3058.
(b) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P. J .
Org. Chem. 1987, 52, 3413. (c) Hodges, J . C.; Patt, W. C.; Connolly, C.
J . J . Org. Chem. 1991, 56, 449. (d) Schro¨der, R.; Scho¨llkopf, U.; Blume,
E.; Hoppe, I. Liebigs Ann. Chem. 1975, 533. (e) Kozikowski, A. P.;
Ames, A. J . Org. Chem. 1980, 45, 2548.
(9) Van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron
Lett. 1972, 2369.
(10) Meyers, A. I.; Lawson, J . P. Tetrahedron Lett. 1981, 22, 3163.
(11) Levin, J . I.; Weinreb, S. M. J . Org. Chem. 1984, 49, 4325.
(12) (a) J acobi, P. A.; Ueng, S.; Carr, D. J . Org. Chem. 1979, 44,
2042. (b) Howe, R. K.; Lee, L. F. Eur. Pat. Appl. 27 020; Chem. Abstr.
1981, 95, 80933. (c) Crowe, E.; Hossner, F.; Hughes, M. J . Tetrahedron
1995, 51, 8889.
(14) (a) Wasserman, H. H.; Gambale, R. J .; Pulwer, M. J . Tetrahe-
dron 1981, 37, 4059. (b) Pridgen, L. N.; Shilcrat, S. C.; Lantos, I.
Tetrahedron Lett. 1984, 25, 2835.
(15) (a) Turchi, I. J . In Oxazoles; Turchi, I. J ., Ed.; Wiley: New York,
1986; Chapter 1. (b) Vedejs, E.; Grissom, J . W. J . Org. Chem. 1988,
53, 1876.
(13) Vedejs, E.; Monahan, S. D. J . Org. Chem. 1996, 61, 5192.

Metalation of 4-Oxazolinyloxazole Derivatives
J . Org. Chem., Vol. 67, No. 11, 2002 3603
Sch em e 4
Sch em e 5a
derivative 11 in which the oxazole ring had remained
intact. Somewhat surprisingly and disappointingly, no
trace of the carbinol adduct 12 could be detected in the
reaction mixture that had been treated with benzalde-
hyde. All that was present were major amounts of
recovered 9. We assumed that the absence of formation
of the desired carbinol adduct 12 might not be due to the
simple lack of reactivity between the formal carbanion
10 and benzaldehyde, an unprecedented phenomenon,
but that a more complex and circuitous mechanism may
be involved. This peculiar behavior could tentatively be
rationalized by involving a reaction between the aromatic
aldehyde and the open-chain tautomer lithio R-isocyano
enolate 13 (or 14) to form the hemiacetal 16.8c Rapid
hydrolysis of this isocyanoacetic acid derivative during
workup then should regenerate the parent oxazole 9
(Scheme 3). The available evidence was suggestive of an
extremely rapid and almost irreversible conversion of 10
to 13 favored by the relative stability of enolate 13 with
a coordinated lithium species such as 15 playing a
contributing role in this reaction pathway.
Having been thwarted in attempts to use ester 9 as a
precursor for the target compounds 1 and 2, we then
opted to modify the temporary protecting auxiliary
involved in the original retrosynthetic route (Scheme 1,
path b) in order to achieve the challenging 2-hydroxy-
alkylation of the oxazole precursor 8. The installation of
the oxazoline unit at the 4-position of the oxazole
framework originated from the following premises: (i)
the oxazoline ring system is easily accessible from the
readily available carboxylic acid derivative,2a (ii) it not
only survives treatment with alkyllithium reagents but
also facilitates diverse metalation processes,16 (iii) it can
easily be converted to formyl,17 carboxyl,18 and equally
nitrile19 functionalities; (iv) in particular, it could be
anticipated that the lithio anion reactivity should be
reversed in favor of the 2-lithio intermediate 18 (Scheme
4) (kinetic effect) and that the reactivity of the ring-
opening enolate 19, compared to 15 should be notably
decreased (thermodynamic effect). We then embarked on
the synthesis of the 4-(4,4-dimethyloxazolin-2-yl)-5-phen-
yloxazole (17). The assemblage of this heterobicyclic
compound was readily accomplished by initial saponifica-
tion of ester 9 to afford acid 20 (Scheme 5). Conversion
into the corresponding acid chloride and sequential
treatment with 2-methyl-2-aminopropanol and thionyl
chloride ensured the formation of the oxazoline ring and
thus completed the synthesis of the target compound 17.
Exposure of the heterobicyclic compound 17 to n-BuLi
(1 equiv) at -78 °C in THF (15 min) furnished an orange
solution that was immediately quenched with a variety
a
Reagents and conditions: (a) NaOH, EtOH, H2O, rt, 12 h; (b)
(i) SOCl2, (ii) HOCH2C(CH3)2NH2, CH2Cl2, NEt3, rt, 3 h, (iii) SOCl2,
rt, 4 h; (c) (i) n-BuLi, THF, -78 °C, 15 min, (ii) electrophile, (iii)
-78 °C to rt, 1 h, (iv) NH4Cl saturated, H2O; (d) (i) n-BuLi, THF,
-78 °C, 15 min, (ii) (CH2CO)2O, (iii) rt, 3 h, (iv) NH4Cl saturated,
H2O.
Ta ble 2. Rea ction of 17 w ith Differ en t Electr op h iles
yield
entry
electrophile
PhCHO
CH3(CH2)7CHO
cyclohexanone
R1
R2 product (%)
1
2
3
4
5
6
Ph
H
H
21a
21b
21c
21d
21e
21f
64
48
56
51
67
34
CH3(CH2)7
(CH2)5
(CH3)2CHCH2CHO (CH3)2CHCH2
H
H
H
Ph(CH2)2CHO
(CH2O)2CH-
(CH2)2CHO
(CH2CO)2O
Ph(CH2)2
(CH2O)2CH(CH2)2
7
21g
22
of carbonyl compounds to afford solely and exclusively
products of electrophilic substitution at C-2 21a -g
(Scheme 5). Gratifyingly, no complications due to nucleo-
philic addition to the imine subunit of either of the two
heterocycles15,20 or opening of the oxazole were detected.
A variety of electrophiles that can participate in the
coupling reaction and a representative series of com-
pounds that have been prepared by this method are
presented in Table 2, where it may be seen that this
simple procedure affords very satisfactory yields of the
hydroxyalkylation products 21a -g. Examination of Table
2 deserves some comment. The method is compatible with
a wide variety of carbonyl compounds since the reaction
can be indiscriminately performed with aromatic (Table
2, entry 1) and aliphatic (Table 2, entries 2, 4, 5, 6)
aldehydes but equally with enolizable ketones (Table 2,
entry 3) and succinic anhydride (Table 2, entry 7) albeit
in moderate yield. It also allows incorporation of diverse
functionalities on the pendant chain at C-2, which can
be interesting for further synthetic planning (Table 2,
entries 6 and 7). The adoption of the oxazoline protecting
auxiliary for the latent functionalities was rewarded
here: the carboxylic acid function was easily retrieved
by conversion to the methiodide and removal of the
oxazolinium moiety by alkaline hydrolysis20 as exempli-
(16) Snieckus, V. Chem. Rev. 1990, 90, 879.
(17) Barner, B. A.; Meyers, A. I. J . Am. Chem. Soc. 1984, 106, 1865.
(18) Meyers, A. I.; Temple, D. L.; Nolen, R. L.; Mihelich, E. D. J .
Org. Chem. 1974, 39, 2778.
(19) Carini, D. J .; Duncia, J . V.; Aldrich, P. E.; Chiu, A. T.; J ohnson,
A. L.; Pierce, M. E.; Price, W. A.; Santella, J . B., III; Wells, G. J .;
Wexler, R. R.; Wong, P. C.; Yoo, S. E.; Timmermans, P. B. M. W. M. J .
Med. Chem. 1991, 34, 2525.
(20) Meyers, A. I.; Gabel, R.; Mihelich, E. D. J . Org. Chem. 1978,
43, 1372.

3604 J . Org. Chem., Vol. 67, No. 11, 2002
Couture et al.
Sch em e 6a
internal standard. Elemental analyses were performed by the
CNRS microanalysis center. CH2Cl2 and DMF were distilled
from CaH2 and stored over 3 Å molecular sieves. THF was
distilled over sodium benzophenone before use.
Ma ter ia ls. The 5-phenyloxazole-4-carboxylic acid ethyl
ester (9)8d [13C NMR (CDCl3) δ 161.8, 155.4, 149.1, 130.4,
128.35, 128.3, 126.6, 126.5, 61.3, 14.1] and 3-([1,3]dioxolan-2-
yl)propanal23 were synthesized according to previously re-
ported procedures.
5-P h en yloxa zole-4-ca r boxylic Acid (20). A solution of
NaOH (5.7 g, 142.0 mmol) in water (10 mL) was added to a
solution of 5-phenyloxazole-4-carboxylic acid ethyl ester (9,
20.5 g, 94.4 mmol) in EtOH (200 mL), and the reaction mixture
was then stirred at 20 °C for 12 h. The reaction mixture was
concentrated to dryness in vacuo, and aqueous HCl (3N, 100
mL) was added. The resulting precipitate was filtered and
dried in vacuo to afford 16.0 g (91%) of 20 as a white solid
that was recrystallized from AcOEt: mp 166-168 °C; IR (KBr)
3136, 1710 cm-1; 1H NMR (DMSO-d6) δ 7.50 (m, 3H), 8.00 (m,
2H), 8.55 (s, 1H), 13.20 (s, 1H); 13C NMR (DMSO-d6) δ 162.9,
153.8, 150.7, 130.2, 128.5, 128.3, 126.8 (two peaks overlapping).
Anal. Calcd for C10H7NO3: C, 63.49; H, 3.73; N, 7.40. Found:
C, 63.36; H, 3.65; N, 7.24.
4-(4,4-Dim eth yloxazolin -2-yl)-5-ph en yloxazole (17). Com-
pound 20 (10 g, 52.9 mmol) was stirred with thionyl chloride
(70 mL) at reflux for 3 h. Excess thionyl chloride was removed
in vacuo to give the corresponding acid chloride which was
then dissolved in CH2Cl2 (100 mL) and added to a mixture of
2-methyl-2-aminopropanol (5.6 g, 63 mmol) and triethylamine
(7 g, 70 mmol) in CH2Cl2 (50 mL) at 0 °C. The mixture was
stirred for 3 h at room temperatur,e and the organic layers
were washed with HCl (1 M), water, and brine, dried over
MgSO4, and concentrated in vacuo to afford a crude residue
that was dissolved in CH2Cl2 (50 mL) and then slowly added
to thionyl chloride (40 mL) at 0 °C. The resulting solution was
stirred at room temperature for 4 h, and thionyl chloride was
removed in vacuo. HCl (1 M, 10 mL) was added to the residue,
and the resulting solution was washed with ether. The aqueous
fraction was made basic with aqueous NaOH (10%) and
extracted with Et2O (3 × 50 mL). The ether solution was
washed with brine, dried over MgSO4, and concentrated under
vacuum. The residual solid was recrystallized from cyclohex-
ane to give a white crystalline solid (8.3 g, 65%): mp 68-70
a
Reagents and conditions: (a) (i) CH3I, rt, 12 h, (ii) NaOH (2
N), H2O; (iii) H3O+; (b) (i) HMDS, I2 (cat.), CH2Cl2, (ii) Na2S2O3;
(iii) NaHCO3 saturated, H2O; (c) (i) CH3I, rt, 12 h, (ii) NaBH4,
THF-MeOH (4:1), (iii) NH4Cl saturated, H2O, (iv) silica gel,
CH2Cl2 (5% H2O), rt, 2 h; (d) Bu4NF, THF, -20 °C, 5 min.
fied by the attainment of 2a -d and particularly of the
target 2-hydroxyalkylated 4-oxazole carboxylic acids 2c
and 2d (Scheme 6). The synthesis of the formyl deriva-
tives 1a -d proved a little more problematic than we had
anticipated. Indeed, this required protection of the pen-
dant hydroxy function in 21a -d prior to generation of
the formyl functionality. The operation was therefore
performed by applying Meyers protocol17,18 to the O-
silylated compounds 22a -d .21 Reduction and subsequent
treatment with silica gel22 caused release of the formyl
function, while sparing the silyl protection and final
desilylation of the intermediate 23a -d resulted in the
generation of the target bifunctional compounds 1a -d ,
including the target compounds 1a -c, with satisfactory
yields (Scheme 6).
In summary, the synthetic strategy outlined in this
paper provides a convenient and efficient synthesis of
suitably 2,4-bifunctionalized 5-phenyloxazoles. We have
notably demonstrated that incorporation of the oxazoline
unit at the 4-position of an oxazole nucleus allows
addition of a wide variety of carbonylated electrophiles
via the 2-lithio derivative and suppresses the troublesome
electrocyclic ring opening reaction. It also demonstrates,
if still necessary, the remarkable potential of the oxazo-
line ring system mainly exploited thus far in nucleophilic
aromatic substitutions and in ortho-directed metalation
reactions.
1
°C; IR (KBr) 1650 cm-1; H NMR (CDCl3) δ 1.39 (s, 6H), 4.10
(s, 2H), 7.41-7.44 (m, 3H), 7.90 (s, 1H), 8.07-8.10 (m, 2H);
13C NMR (CDCl3) δ 156.5, 151.9, 149.3, 129.8, 128.3, 127.9,
127.1, 124.3, 79.1, 68.0, 28.3. Anal. Calcd for C14H14N2O2: C,
69.40; H, 5.82; N, 11.55. Found: C, 69.33; H, 5.91; N, 11.33.
Gen er a l Meth od for P r ep a r a tion of [4-(4,4-Dim eth yl-
oxa zolin -2-yl)-5-p h en yloxa zol-2-yl] Alcoh ols 21a-f. A so-
lution of n-BuLi (7.75 mL, 12.4 mmol, 1.6 M solution in
hexane) was added dropwise, at -78 °C under Ar, over a period
of 20 min, to a stirred solution of 4-(4,4-dimethyloxazolin-2-
yl)-5-phenyloxazole (17, 3.0 g, 12.4 mmol) in THF (30 mL). The
solution was stirred for 15 min at this temperature, and a
solution of the appropriate electrophile (12.4 mmol) in THF
(5 mL) was added by syringe. The reaction was allowed to
warm to room temperature over a period of 1 h and then
treated with saturated aqueous NH4Cl (40 mL). The mixture
was extracted with Et2O (3 × 50 mL), and the combined
organic phases were washed with HCl (1 M, 3 × 10 mL). The
aqueous fraction was made basic by treatment with aqueous
NaOH (10%) and then extracted with Et2O (3 × 50 mL). The
combined organic phases were washed with brine, dried over
MgSO4, and concentrated under vacuum to an oily residue that
was purified by flash column chromatography on silica gel,
using a MeOH/CH2Cl2 mixture (5:95) as eluent, and finally
recrystallized.
1-[4-(4,4-Dim eth yloxa zolin -2-yl)-5-p h en yloxa zol-2-yl]-
1-p h en ylm eth a n ol (21a ): white solid; mp 176-179 °C
1
(AcOEt); IR (KBr) 3189, 1655 cm-1; H NMR (CDCl3) δ 1.40
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. Infrared
spectra were recorded in a KBr pellet. 1H and 13C NMR spectra
were recorded at 300 and 75 MHz, respectively, with TMS as
(21) Karimi, B.; Golshani, B. J . Org. Chem. 2000, 65, 7228.
(22) Cahiez, G.; Lepifre, F.; Ramiandrosoa, P. Synthesis 1999, 2138.
(23) Lucchesini, F. Tetrahedron 1992, 48, 9951.

Metalation of 4-Oxazolinyloxazole Derivatives
J . Org. Chem., Vol. 67, No. 11, 2002 3605
(s, 6H), 4.10 (s, 2H), 6.01 (s, 1H), 7.30-7.43 (m, 6H), 7.45-
7.53 (m, 2H), 7.90-7.98 (m, 2H); 13C NMR (CDCl3) δ 163.2,
156.1, 152.4, 139.1, 129.7, 128.6, 128.4, 128.2, 128.1, 127.1,
126.6, 79.2, 69.7, 67.7, 28.2. Anal. Calcd for C21H20N2O3: C,
72.33; H, 5.74; N, 8.04. Found: C, 72.23; H, 5.86; N, 8.31.
Calcd for C18H18N2O5: C, 63.10; H, 5.25; N, 8.18. Found: C,
62.94; H, 5.44; N, 8.23.
Gen er a l Meth od for P r ep a r a tion of th e F or m yl De-
r iva tives 1a -d . A solution of 1,1,1,3,3,3-hexamethylsilazane
(HMDS, 0.81 g, 5 mmol) in CH2Cl2 (10 mL) was added
dropwise over a period of 5 min to a stirred solution of alcohols
21a -d (6 mmol) and I2 (1.5 mg, 0.06 mmol) in CH2Cl2 (25 mL)
under Ar. The solution was stirred for 3 h, and finely powdered
Na2S2O3 (1.5 g, portion wise) was then added. The mixture
was stirred for an additional 30 min, and the white solid was
then filtered off and washed twice with CH2Cl2 (2 × 10 mL).
The solution was concentrated in vacuo to afford a crude
residue that was stirred with CH3I (10 mL) for 24 h. Excess
CH3I was removed under vacuum, and the resulting yellow
foam was dissolved in THF/MeOH (10 mL, 4:1) and treated
with NaBH4 (345 mg, 9 mmol, portionwise) over a period of
15 min. Stirring was maintained during 2 h at room temper-
ature followed by addition of saturated aqueous NH4Cl (10
mL). The mixture was stirred for an additional 2 h and then
extracted with Et2O (3 × 30 mL). The combined organic phases
were washed with water and brine and dried (MgSO4).
Concentration under vacuum left a crude residue that was
dissolved in a suspension of silica gel (10 g) in CH2Cl2 (25 mL)
with a few drops of water, and the mixture was vigorously
stirred at room temperature overnight. Filtration and removal
of the solvent under vacuum followed by purification by column
chromatography on silica gel with CH2Cl2 as eluent delivered
1-[4-(4,4-Dim eth yloxa zolin -2-yl)-5-p h en yloxa zol-2-yl]-
1
n on a n -1-ol (21b): yellow oil; IR (KBr) 3351, 1661 cm-1; H
NMR (CDCl3) δ 0.86 (t, J ) 7.0 Hz, 3H), 1.20-1.28 (m, 12H,
CH2), 1.40 (s, 6H), 1.83-1.89 (m, 2H), 4.09 (s, 2H), 4.84 (t, J
) 6.5 Hz, 1H), 7.40-7.44 (m, 3H), 8.10-8.13 (m, 2H); 13C NMR
(CDCl3) δ 164.4, 156.7, 152.0, 129.7, 128.3, 128.0, 127.5, 79.2,
67.7 (two peaks overlapping), 35.6, 31.8, 30.9, 29.4, 29.3, 28.3,
25.0, 22.6, 14.1. Anal. Calcd for C23H32N2O3: C, 71.84; H, 8.39;
N, 7.29. Found: C, 71.76; H, 8.31; N, 7.33.
1-[4-(4,4-Dim eth yloxa zolin -2-yl)-5-p h en yloxa zol-2-yl]-
cycloh exa n ol (21c): white solid; mp 119-120 °C (hexane/
1
toluene); IR (KBr) 3356, 1662 cm-1; H NMR (CDCl3) δ 1.36
(s, 6H), 1.49-2.05 (m, 10H), 4.06 (s, 2H), 7.32-7.41 (m, 3H),
8.00-7.98 (m, 2H); 13C NMR (CDCl3) δ 167.2, 156.7, 151.7,
129.6, 128.8, 128.3, 127.4, 124.3, 79.1, 70.7, 67.8, 36.3, 28.3,
25.1, 21.6. Anal. Calcd for C20H24N2O3: C, 70.57; H, 7.11; N,
8.23. Found: C, 70.49; H, 7.0; N, 8.31.
1-[4-(4,4-Dim eth yloxa zolin -2-yl)-5-p h en yloxa zol-2-yl]-
3-m eth ylbu ta n -1-ol (21d ): white solid; mp 93-95 °C (cyclo-
hexane); IR (KBr) 3354, 1660 cm-1; 1H NMR (CDCl3) δ 0.95-
1.01 (m, 6H), 1.40 (s, 6H), 1.70-1.95 (m, 3H), 4.10 (s, 2H),
4.98-5.01 (m, 1H), 7.39-7.41 (m, 3H), 8.03-8.06 (m, 2H); 13
C
1
the silylated compounds 23a -d , which were identified by H
NMR (CDCl3) δ 164.7, 156.8, 152.0, 129.7, 128.3 (two peaks
overlapping), 128.0, 127.2, 79.2, 67.8, 65.9, 44.4, 28.3, 24.3,
23.1, 21.8. Anal. Calcd for C19H24N2O3: C, 69.42; H, 7.31; N,
8.52. Found: C, 69.20; H, 7.45; N, 8.33.
NMR spectroscopy [e.g. 23c (CDCl3) δ 0.00 (s, 9H), 1.19-1.60
(m, 4H), 1.67-1.85 (m, 2H), 1.92-2.25 (m, 4H), 7.50-7.52 (m,
3H), 8.10-8.14 (m, 2H), 10.10 (s, 1H)]. Compounds 23a -d
were used directly in the next step without further purification.
Thus compounds 23a -d were dissolved in THF (10 mL) and
treated with Bu4NF (6.6 mL, 6.6 mmol of 1 M solution in THF)
at -20 °C for 5 min. Removal of excess reagents left an oily
residue that was finally purified by flash column chromatog-
raphy on silica gel with a mixture MeOH/CH2Cl2 (5:95) as
eluent.
1-[4-(4,4-Dim eth yloxa zolin -2-yl)-5-p h en yloxa zol-2-yl]-
3-p h en ylp r op a n -1-ol (21e): white solid; mp 107-110 °C
1
(cyclohexane); IR (KBr) 3361, 1654 cm-1; H NMR (CDCl3) δ
1.40 (s, 6H), 2.20-2.31 (m, 2H), 2.75-2.92 (m, 2H), 4.10 (s,
2H), 4.89 (t, J ) 6.5 Hz, 1H), 7.10-7.30 (m, 5H), 7.40-7.51
(m, 3H), 7.95-8.03 (m, 2H); 13C NMR (CDCl3) δ 164.3, 156.8,
152.1, 141.1, 129.7, 128.5, 128.4, 128.3, 128.1, 127.2, 126.0,
124.2, 79.2, 67.7, 66.6, 37.0, 31.3, 28.3. Anal. Calcd for
2-(H yd r oxyp h en ylm et h yl)-5-p h en yloxa zole-4-ca r b a l-
d eh yd e (1a ): yellow oil; IR (KBr) 3251, 1692 cm-1; 1H NMR
(CDCl3) δ 6.03 (s, 1H), 7.32-7.42 (m, 4H), 7.45-7.54 (m, 4H),
7.96-8.00 (m, 2H), 10.05 (s, 1H); 13C NMR (CDCl3) δ 184.6,
163.4, 156.8, 138.6, 131.4, 129.0, 128.9, 128.1, 127.7, 126.6,
126.0, 70.0. Anal. Calcd for C17H13NO3: C, 73.11; H, 4.69; N,
5.01. Found: C, 73.16; H, 4.52; N, 5.09.
C
23H24N2O3: C, 73.38; H, 6.42; N, 7.42. Found: C, 73.05; H,
6.45; N, 7.39.
1-[4-(4,4-Dim eth yloxa zolin -2-yl)-5-p h en yloxa zol-2-yl]-
3-([1,3]d ioxola n -2-yl)p r op a n -1-ol (21f): white solid; mp 92-
94 °C (cyclohexane); IR (KBr) 3374, 1661 cm-1 1H NMR
;
(CDCl3) δ 1.39 (s, 6H), 1.82-2.20 (m, 4H), 3.78-4.00 (m, 4H),
4.10 (s, 2H), 4.85-5.03 (m, 2H), 7.42-7.52 (m, 3H), 7.97-8.09
(m, 2H); 13C NMR (CDCl3) δ 164.0, 156.7, 153.1, 129.7, 128.3,
128.1, 127.1, 103.8, 79.2, 67.8, 67.4, 64.9, 65.0, 29.5, 29.2, 28.3.
Anal. Calcd for C20H24N2O5: C, 64.50; H, 6.50; N, 7.52.
Found: C, 64.49; H, 6.79; N, 7.22.
2-(1-Hyd r oxyn on yl)-5-p h en yloxa zole-4-ca r ba ld eh yd e
1
(1b): yellow oil; IR (KBr) 3275, 1688 cm-1; H NMR (CDCl3)
δ 0.84 (t, J ) 6.8 Hz, 3H), 1.21-1.25 (m, 12H), 1.92-2.00 (m,
2H), 4.90 (t, J ) 6.8 Hz, 1H), 7.46-7.81 (m, 3H), 7.98-8.01
(m, 2H), 10.03 (s, 1H); 13C NMR (CDCl3) δ 184.6, 164.9, 156.5,
133.8, 131.3, 129.0, 127.7, 126.1, 67.4, 35.4, 31.8, 29.4, 29.3,
29.2, 25.0, 22.6, 14.1. Anal. Calcd for C19H25NO3: C, 72.35; H,
7.99; N, 4.44. Found: C, 72.21; H, 8.05; N, 4.52.
P r epar ation of 4-[4-(4,4-Dim eth yloxazolin -2-yl)-5-ph en -
yloxa zol-2-yl]-4-oxobu ta n oic Acid (21g). A solution of
n-BuLi (1.25 mL, 2.0 mmol, 1.6 M solution in hexane) was
added dropwise by syringe, at -78 °C under Ar, to a solution
of compound 17 (0.48 g, 2.0 mmol) in THF (10 mL). The purple
solution was stirred at this temperature for an additional 15
min, and solid succinic anhydride (0.21 g, 2.0 mmol) was added
at once. The cyclic anhydride dissolved slowly as the solution
turned from purple to orange. Stirring was continued for 3 h
at room temperature, and the solution was then treated with
saturated aqueous NH4Cl (40 mL). The mixture was extracted
with Et2O (3 × 20 mL), and the combined organic phases were
washed with aqueous NaOH (10%, 20 mL). The aqueous
fraction was made acidic (pH 3) with citric acid (10%) and then
extracted with Et2O (3 × 20 mL). The organic layer was then
washed with water and brine and dried (MgSO4). The dried
extract was concentrated in vacuo to afford a crude residue
that was finally purified by recrystallization from AcOEt:
white solid (150 mg); mp 188-190 °C; IR (KBr) 3226, 1726,
1707, 1660 cm-1; 1H NMR (DMSO-d6) δ 1.30 (s, 6H), 2.65 (t, J
) 6.6 Hz, 2H), 3.30 (t, J ) 6.6 Hz, 2H), 4.15 (s, 2H), 7.54-
2-(1-Hyd r oxycycloh exyl)-5-p h en yloxa zole-4-ca r ba ld e-
h yd e (1c): yellow oil; IR (KBr) 3250, 1685 cm-1 1H NMR
;
(CDCl3) δ 1.56-1.66 (m, 4H), 1.72-1.82 (m, 2H), 1.92-1.98
(m, 2H), 2.08-2.15 (m, 2H), 7.46-7.53 (m, 3H), 8.02-8.06 (m,
2H), 10.07 (s, 1H); 13C NMR (CDCl3) δ 185.0, 166.9, 156.2,
133.9, 129.0, 128.8, 128.4, 126.3, 70.8, 36.4, 25.1, 21.7. Anal.
Calcd for C16H17NO3: C, 70.83; H, 6.32; N, 5.16. Found: C,
70.92; H, 6.44; N, 5.08.
2-(1-H yd r oxy-3-m et h ylb u t yl)-5-p h en yloxa zole-4-ca r -
ba ld eh yd e (1d ): yellow oil; IR (KBr) 3281, 1687 cm-1 1H
;
NMR (CDCl3) δ 0.99 (d, J ) 6.0 Hz, 6H), 1.77-1.96 (m, 3H),
4.98 (t, J ) 8.4 Hz, 1H), 7.46-7.54 (m, 3H), 7.98-8.05 (m, 2H),
10.05 (s, 1H); 13C NMR (CDCl3) δ 184.6, 165.1, 156.5, 133.9,
131.3, 129.0, 127.7, 126.2, 65.9, 44.3, 24.4, 23.1, 21.9. Anal.
Calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C,
69.68; H, 6.54; N, 5.28.
Gen er a l Meth od for P r ep a r a tion of Acid Der iva tives
2a -d . A mixture of alcohol 21a -d (3 mmol) in CH3I (10 mL)
was stirred for 24 h at room temperature. CH3I was then
removed under vacuum, and the yellow foam obtained was
treated by aqueous NaOH (2 M, 25 mL) over 48 h. The mixture
was first washed with Et2O (3 × 20 mL), and the aqueous
7.56 (m, 3H), 8.10 (dd, J ) 2.5, 7.6 Hz, 2H), 12.35 (s, 1H); 13
C
NMR (DMSO-d6) δ 192.7, 174.2, 164.0, 156.4, 155.2, 130.9,
128.8, 128.5, 128.4, 126.2, 79.6, 67.9, 33.9, 33.7, 28.2. Anal.

3606 J . Org. Chem., Vol. 67, No. 11, 2002
Couture et al.
1
fraction was made acidic by treatment with aqueous HCl (2
M) and then extracted with Et2O (3 × 20 mL). The combined
organic phases were washed with brine, dried (MgSO4), and
evaporated to give a white solid that was recrystallized from
hexane/toluene.
2-(Hyd r oxyp h en ylm eth yl)-5-p h en yloxa zole-4-ca r boxy-
lic a cid (2a ): white solid; mp 194 °C dec; IR (KBr) 3291, 1692
cm-1; 1H NMR (CDCl3) δ 6.19 (s, 1H), 7.23-7.47 (m, 6H), 7.56-
7.58 (m, 2H), 8.22-8.31 (m, 2H), 13.12 (s, 1H); 13C NMR
(CDCl3) δ 167.4, 162.4, 149.0, 140.0, 133.2, 129.0, 128.4, 128.2,
127.7, 127.4, 126.5, 67.8. Anal. Calcd for C17H13NO4: C, 69.15;
H, 4.44; N, 4.74. Found: C, 69.31; H, 4.50; N, 4.98.
2-(1-Hyd r oxyn on yl)-5-p h en yloxa zole-4-ca r boxylic a cid
1693 cm-1; H NMR (DMSO-d6) δ 1.33-1.43 (m, 4H), 1.66-
1.69 (m, 2H), 1.80-1.84 (m, 2H), 1.96-2.03 (m, 2H), 7.44-
7.54 (m, 3H), 7.96-8.00 (m, 2H), 13.10 (br s, 1H); 13C NMR
(DMSO-d6) δ 166.2, 163.2, 153.4, 130.0, 128.4, 128.2, 127.0,
126.9, 69.0, 35.7, 24.9, 21.6. Anal. Calcd for C16H17NO4: C,
66.89; H, 5.96; N, 4.67. Found: C, 66.95; H, 6.11; N, 4.58.
2-(1-H yd r oxy-3-m et h ylb u t yl)-5-p h en yloxa zole-4-ca r -
boxylic a cid (2d ): white solid; mp 145-146 °C; IR (KBr)
3380, 1685 cm-1 1H NMR (DMSO-d6) δ 0.90-0.93 (m, 6H),
;
1.68-1.77 (m, 3H), 4.71 (br. s, 1H), 7.49-7.52 (m, 3H), 7.99-
8.03 (m, 2H), 13.10 (br s, 1H); 13C NMR (DMSO-d6) δ 164.9,
163.8, 155.4, 130.4, 128.5, 128.4, 126.6, 65.8, 44.3, 24.4, 23.0,
21.9. Anal. Calcd for C15H17NO4: C, 65.44; H, 6.22; N, 5.09.
Found: C, 65.36; H, 6.15; N, 5.14.
(2b): white solid; mp 129-130 °C; IR (KBr) 3375, 1688 cm-1
;
1H NMR (CDCl3) δ 0.84 (m, 3H), 1.21-1.45 (m, 12H), 1.62-
1.90 (m, 2H), 5.83 (br. s, 1H), 7.45-7.65 (m, 3H), 7.90-8.05
(m, 2H), 13.12 (s, 1H); 13C NMR (CDCl3) δ 163.9, 163.1, 153.2,
129.9, 128.4, 128.1, 127.2, 127.0, 65.6, 35.4, 31.8, 29.4, 29.3,
29.2, 25.0, 22.6, 13.9. Anal. Calcd for C19H25NO4: C, 68.86; H,
7.60; N, 4.23. Found: C, 68.76; H, 7.45; N, 3.96.
Ack n ow led gm en t. We wish to acknowledge helpful
discussions and advice from Dr. T. G. C. Bird (Zeneca
Pharma).
2-(1-Hyd r oxycycloh exyl)-5-p h en yloxa zole-4-ca r boxy-
lic a cid (2c): white solid; mp 141-142 °C; IR (KBr) 3350,
J O010762S