Deprotonation of benzoxazole and oxazole using lithium magnesates

Article abstract of DOI:10.1021/jo050493w

The first deprotonations of oxazole and benzoxazole using lithium magnesates are described. The reactions occurred in tetrahydrofuran at room temperature using 1/3 equiv of lithium tributylmagnesate. As 2-lithiooxazole and 2-lithiobenzoxazole, lithium tri(2-oxazolyl)magnesate and lithium tri(2-benzoxazolyl)magnesate very rapidly and completely isomerized to the more stable 2-(isocyano)enolate and 2-(isocyano)phenolate type structures, respectively, a result shown by NMR analysis. The isolation of 2-substituted oxazoles and benzoxazoles in medium to good yields after electrophilic trapping was interpreted in two ways: (1) the equilibration between the open and closed structures is faster than the trapping of the open isomers, and the closed isomers are more reactive than the open ones, or (2) the open isomers react with electrophiles in a intramolecular Passerini type reaction. The nonreactivity of the 2-(isocyano)enolate type structure toward anisaldehyde in the absence of lithium bromide makes the intramolecular Passerini type reaction more plausible.

Full text of DOI:10.1021/jo050493w

Deprotonation of Benzoxazole and Oxazole Using Lithium
Magnesates
†
†
,†,‡
†
†
Omar Bayh, Ha c¸ an Awad, Florence Mongin,* Christophe Hoarau, Laurent Bischoff,
†
†
†
§
§
Fran c¸ ois Tr e´ court, Guy Qu e´ guiner, Francis Marsais, Fernando Blanco, Bel e´ n Abarca, and
§
Rafael Ballesteros
Laboratoire de Chimie Organique Fine et H e´ t e´ rocyclique, UMR 6014, IRCOF, CNRS, Universit e´ et INSA
de Rouen, Place E. Blondel, BP 08, 76131 Mont-Saint-Aignan Cedex, France, and Departamento de
Qu ı´ mica Org a´ nica, Facultad de Farmacia, Universidad de Valencia, Avda. Vicente Andr e´ s Estell e´ s s/n,
4
6100 Burjassot (Valencia), Spain
florence.mongin@univ-rennes1.fr
Received March 11, 2005
The first deprotonations of oxazole and benzoxazole using lithium magnesates are described. The
reactions occurred in tetrahydrofuran at room temperature using 1/3 equiv of lithium tributyl-
magnesate. As 2-lithiooxazole and 2-lithiobenzoxazole, lithium tri(2-oxazolyl)magnesate and lithium
tri(2-benzoxazolyl)magnesate very rapidly and completely isomerized to the more stable 2-(isocyano)-
enolate and 2-(isocyano)phenolate type structures, respectively, a result shown by NMR analysis.
The isolation of 2-substituted oxazoles and benzoxazoles in medium to good yields after electrophilic
trapping was interpreted in two ways: (1) the equilibration between the open and closed structures
is faster than the trapping of the open isomers, and the closed isomers are more reactive than the
open ones, or (2) the open isomers react with electrophiles in a intramolecular Passerini type
reaction. The nonreactivity of the 2-(isocyano)enolate type structure toward anisaldehyde in the
absence of lithium bromide makes the intramolecular Passerini type reaction more plausible.
Introduction
More recently, organomagnesium compounds have
been prepared by deprotonation at higher temperatures,
but the uses of such reactions have barely been explored.
The pioneering work of Marxer and Siegrist in 1974
showed EtMgBr was capable of deprotonating 1-phen-
ylpyrazole at the ortho position of the phenyl ring. Eaton
reported in 1989 the deprotonation of both methyl
The preparation of functional heterocycles is an im-
portant synthetic goal because of the multiple applica-
tions of these molecules. Deprotonation using alkyllith-
iums or lithium dialkylamides has been developed as one
of the major tools since lithiated derivatives display a
high reactivity toward many electrophilic functions.
1
4
2
benzoate and N,N-diethylbenzamide with Hauser bases
Nevertheless, this methodology often requires low tem-
peratures, which can be difficult to realize on an indus-
trial scale. In addition, unlike organoboron, organotin,
organozinc, and organomagnesium compounds, organo-
lithiums can hardly be involved in cross-coupling reac-
i
(
Pr
2
NMgBr or TMPMgBr, TMP ) 2,2,6,6-tetramethylpi-
i
peridino) or magnesium diamides (( Pr
Mg). In 1995, Schlecker extended this methodology to
the regioselective magnesiation of pyridine carboxamides
2
N)
2
Mg or TMP
2
-
5
3
6
tions.
and carbamates, alkylmagnesium halides and dialkyl-
magnesiums rarely deprotonating such substrates be-
*
To whom correspondence should be addressed. Phone: + 33 (0) 2
7
cause of easier 1,4-addition reactions. Next, Kondo and
2
3 23 69 31. Fax: + 33 (0) 2 23 23 63 74.
†
Sakamoto described the regioselective magnesiation of
Universit e´ et INSA de Rouen.
Present address: Synth e` se & ElectroSynth e` se Organiques, UMR
‡
6
510, CNRS, B aˆ timent 10A, Universit e´ de Rennes 1, Campus de
Beaulieu, Avenue du G e´ n e´ ral Leclerc, 35042 Rennes Cedex, France.
(4) Marxer, A.; Siegrist, M. Helv. Chim. Acta 1974, 57, 1988-2000.
(5) (a) Eaton, P. E.; Lee, C.-H.; Xiong, Y. J. Am. Chem. Soc. 1989,
111, 8016-8018. See also: (b) Ooi, T.; Uematsu, Y.; Maruoka, K. J.
Org. Chem. 2003, 68, 4576-4578.
(6) (a) Schlecker, W.; Huth, A.; Ottow, E.; Mulzer, J. J. Org. Chem.
1995, 60, 8414-8416. (b) Schlecker, W.; Huth, A.; Ottow, E.; Mulzer,
J. Liebigs Ann. 1995, 1441-1446. (c) Schlecker, W.; Huth, A.; Ottow,
E.; Mulzer, J. Synthesis 1995, 1225-1227.
§
Universidad de Valencia.
(
1) Katritzky, A. R.; Rees, C. W. In Comprehensive Heterocyclic
Chemistry; Boulton, A. J.; McKillop, A., Eds.; Pergamon Press: New
York, 1984; Vol. 2.
(
2) Schlosser, M. In Organometallics in Synthesis, 2nd ed.; Schlosser,
M., Ed.; Wiley: New York, 2002; Chapter I.
3) Stanforth, S. P. Tetrahedron 1998, 54, 263-303.
(
10.1021/jo050493w CCC: $30.25 © 2005 American Chemical Society
5190
J. Org. Chem. 2005, 70, 5190-5196
Published on Web 05/27/2005

Deprotonation of Benzoxazole and Oxazole
SCHEME 1
8
9
9
N-substituted indoles, thiophenes, and thiazole using
(
or in transition metal-catalyzed cross-coupling reactions
with aryl halides. To obtain more information on the
position of the equilibrium between the 2-metalated
benzoxazole or oxazole and the open isomers, the mixed
lithium-magnesium species were analyzed using NMR
spectroscopy.
i
i
i
2 2 2 2
Pr N) Mg, Pr NMgBr, and Pr NMgCl. Nevertheless,
because of the limited reactivity of these bases, an excess,
in general, has to be used to ensure good yields. Pyrrole
rings of numerous 1-phenyldipyrromethanes did not
require a protection step to be deprotonated at the
position adjacent to the nitrogen atom using EtMgBr.10
Ten years after Eaton, Kondo achieved the deproto-
nation of methyl benzoate and other activated benzenes
through the formation of an arylzincate using lithium di-
tert-butyl(2,2,6,6-tetramethylpiperidino)zincate as a base,
a methodology extended to pyridine and its bromo
derivatives, quinoline, isoquinoline, and ethyl thiophen-
Results and Discussion
Although benzoxazole and oxazole can be readily
metalated by alkyllithiums at C2, the 2-metalated species
are in equilibrium with the corresponding lithium phen-
olate and enolate, respectively.17 In addition, NMR stud-
ies have shown the equilibria were completely on the side
of the open isomers.18 From oxazole, depending on the
nature of the electrophile used to trap, 2-substituted
derivatives (e.g. using DMF, benzophenone, and ethyl
formate), 4-substituted derivatives (using more reactive
aldehydes) or acyclic isomers (using oxophilic electro-
2
1
1
ecarboxylates.
Because arylmagnesates react with a wider range of
electrophiles than arylzincates, we have been interested
in deprotonation reactions using lithium magnesates.
Mulvey documented in 1999 the preparation of a mixed-
metal sodium-magnesium macrocyclic amide which
behaves like a template for the site selective dideproto-
nation of benzene and toluene.12 This process cannot be
used, as it is for synthetic purposes because it involves a
large excess of arene (5 mmol out of the 5 mL used are
consumed in the reaction). Richey observed in 2004 that
treating benzene halides with magnesates partially
results in benzyne formation.13 Even if the organometallic
precursors of benzyne have not been intercepted by
electrophiles, the results show magnesates are capable
of abstracting aromatic protons. Very recently, we studied
philes such as TMSCl or D O) are obtained, the acyclic
19
isomers cyclizing during the workup and/or by heating.
The precomplexation of oxazoles with borane proved
efficient to overcome this problem;20 nevertheless, the
reaction has to be carried out at -78 °C. Transmetalation
to the organozinc derivatives favors the ring closure, a
18
result evidenced by NMR studies and attributed to the
strong covalent carbon-zinc bond along with zinc’s low
2
1
oxophilicity, allowing Negishi cross-couplings.
The deprotonation of benzoxazole (1) was attempted
14
15
the deprotonation of fluoro aromatics, chloropyridines,
22
3
using 1/3 equiv of lithium tributylmagnesate (Bu MgLi)
and thiophenes1 using lithium magnesates, the obtained
arylmagnesates being either trapped with electrophiles
or involved in palladium-catalyzed cross-couplings.
Herein, we describe the first deprotonation reactions
of benzoxazole and oxazole using lithium magnesates and
the reactivity of the species obtained toward electrophiles
6
in tetrahydrofuran (THF) at room temperature. Trapping
the intermediate magnesate with heavy water, iodine,
or 4-anisaldehyde afforded the deuterated compound 2a,
the iodide 2b, and the alcohol 2c, respectively, in good
3
yields. Deprotonation of thiophenes using Bu MgLi being
16
favored in the presence of TMEDA, the reaction was
attempted using this additive. Any positive effect was
noted in this case, since the alcohol 2d prepared in the
presence of TMEDA was isolated in a similar yield
(Scheme 1).
(
7) (a) Bonnet, V.; Mongin, F.; Tr e´ court, F.; Qu e´ guiner, G. J. Chem.
Soc., Perkin Trans. 1 2000, 4245-4249. (b) Schlecker, W.; Huth, A.;
Ottow, E.; Mulzer, J. Tetrahedron 1995, 51, 9531-9542.
(
8) Kondo, Y.; Yoshida, A.; Sakamoto, T. J. Chem. Soc., Perkin
Trans. 1 1996, 2331-2332.
9) Shilai, M.; Kondo, Y.; Sakamoto, T. J. Chem. Soc., Perkin Trans.
2001, 442-444.
10) Rao, P. D.; Littler, B. J.; Geier, G. R., III; Lindsey, J. S. J. Org.
Chem. 2000, 65, 1084-1092.
11) (a) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am.
The intermediate magnesate of benzoxazole was next
involved in cross-couplings with various aromatic halides
(
1
(
(
(17) (a) Schr o¨ der, R.; Sch o¨ llkopf, U.; Blume, E.; Hoppe, I. Liebigs
Ann. Chem. 1975, 533-546. Reviews: (b) Gilchrist, T. L. Adv.
Heterocycl. Chem. 1987, 41, 41-74. (c) Rewcastle, G. W.; Katritzky,
A. R. Adv. Heterocycl. Chem. 1993, 56, 155-302. (d) Iddon, B.
Heterocycles 1994, 37, 1321-1346.
(18) (a) Crowe, E.; Hossner, F.; Hughes, M. J. Tetrahedron 1995,
51, 8889-8900. (b) Hilf, C.; Bosold, F.; Harms, K.; Marsch, M.; Boche,
G. Chem. Ber./Recl. 1997, 130, 1213-1221.
(19) Hodges, J. C.; Patt, W. C.; Connolly, C. J. J. Org. Chem. 1991,
56, 449-452.
(20) Vedejs, E.; Monahan, S. D. J. Org. Chem. 1996, 61, 5192-5193.
(21) (a) Anderson, B. A.; Harn, N. K. Synthesis 1996, 583-585. (b)
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,
8634-8639. (c) Reeder, M. R.; Gleaves, H. E.; Hoover, S. A.; Imbordino,
R. J.; Pangborn, J. J. Org. Proc. Res., Dev. 2003, 7, 696-699.
(22) Concerning the use of lithium magnesates, see: Kitagawa, K.;
Inoue, A.; Shinokubo, H.; Oshima, K. Angew. Chem., Int. Ed. 2000,
39, 2481-2483.
Chem. Soc. 1999, 121, 3539-3540. (b) Imahori, T.; Uchiyama, M.;
Sakamoto, T.; Kondo, Y. Chem. Commun. 2001, 2450-2451. (c)
Schwab, P. F. H.; Fleischer, F.; Michl, J. J. Org. Chem. 2002, 67, 443-
4
49. Concerning the deprotonation of substituted benzenes, see: (d)
Uchiyama, M.; Miyoshi, T.; Kajihara, Y.; Sakamoto, T.; Otani, Y.;
Ohwada, T.; Kondo, Y. J. Am. Chem. Soc. 2002, 124, 8514-8515.
(
12) Armstrong, D. R.; Kennedy, A. R.; Mulvey, R. E.; Rowlings, R.
B. Angew. Chem., Int. Ed. 1999, 38, 131-133.
13) Farkas, J., Jr.; Stoudt, S. J.; Hanawalt, E. M.; Pajerski, A. D.;
Richey, H. G., Jr. Organometallics 2004, 23, 423-427.
14) Awad, H.; Mongin, F.; Tr e´ court, F.; Qu e´ guiner, G.; Marsais, F.;
Blanco, F.; Abarca, B.; Ballesteros, R. Tetrahedron Lett. 2004, 45,
697-6701.
15) Awad, H.; Mongin, F.; Tr e´ court, F.; Qu e´ guiner, G.; Marsais, F.
Tetrahedron Lett. 2004, 45, 7873-7877.
(
(
6
(
(
16) Bayh, O.; Awad, H.; Mongin, F.; Hoarau, C.; Tr e´ court, F.;
Qu e´ guiner, G.; Marsais, F.; Blanco, F.; Abarca, B.; Ballesteros, R.
Tetrahedron 2005, 61, 4779-4784.
J. Org. Chem, Vol. 70, No. 13, 2005 5191

Bayh et al.
SCHEME 2
under palladium catalysis using 1,1′-bis(diphenylphos-
SCHEME 3
phino)ferrocene (dppf) as ligand.1
6,23
Moderate to good
yields were obtained when it was subjected to the
reaction with π-deficient substrates such as 2-bromopy-
ridine, 3-bromoquinoline, and 5-bromopyrimidine, giving
the biaryl compounds 3a-c. A lower yield was noted with
less activated 2-bromothiophene (compound 3d). Medium
to good results were recorded with halides of the benzene
series, affording 3e-g, even when a reactive function
such as ester or nitrile was present. The nature of the
halogen of the halide, bromine or iodine, seems to have
little impact on the outcome of the reaction (Scheme 2).
It is of primary interest to ascertain whether the
SCHEME 4
2
-metalated heterocycle is in equilibrium with the cor-
responding 2-(isocyano)phenolate. Since it is impossible
to determine the ratio of 2-metalated to its open coun-
terpart solely from trapping reactions, NMR spectroscopy
1
13
studies were undertaken. Therefore, the H and
JMOD) NMR spectra of the reaction mixture obtained
after the deprotonation step were recorded. The spectra
Figure 1) indicated very clearly that the deprotonation
using 1/3 equiv of Bu MgLi in THF at room temperature
essentially provided the thermodynamically more stable
-(isocyano)phenolate, in particular with JMOD spectra
C
(
cyano)enolate predominated in the equilibrium with the
1
2
-metalated oxazole: the H NMR spectra signals at 6.88
(
and 4.48 ppm (Figure 2c) attributed to the enolate R-H
and â-H atoms, respectively, proved to be close to those
of the corresponding lithio derivative (6.95 and 4.42 ppm,
Figure 2b). 2-Substituted oxazoles were formed in limited
yields, probably due to the crystallization of the depro-
tonated species as its 2-(isocyano)enolate form in the
reaction mixture. As in the benzoxazole series, one can
interpret the formation of 2-substituted oxazoles in two
ways: (1) the closed isomer is more reactive than the
open one, and its consumption displaces the equilibrium,
or (2) the open isomer reacts with electrophiles in an
intramolecular Passerini type reaction, involving the
R-addition of the electrophile site and the nucleophilic
oxygen atom of the enolate to the isocyanide carbon.
Since lithium bromide catalyzes Passerini type reac-
tions,25 its absence from the reaction mixture could give
3
2
signals at 164.5, 164.4, and 116.8 ppm attributed to its
phenolate R-C, isocyanide, and phenolate â-C atoms,
respectively. The isolation of 2-substituted benzoxazoles
after trapping could be explained by a faster equilibration
between the open and closed structures (Scheme 3) than
the quenching of the open isomer, associated with a
greater reactivity of the closed isomer. Note that such
an explanation was proposed to explain the formation of
2
-metalated (benz)oxazoles by trapping the lithio deriva-
18
tives with zinc halides.
Since NMR measurements showed the open species
was the only observable product at room temperature,
an alternative could be an intramolecular Passerini type
2
6
24
information about the mechanism involved. Conse-
quently, the 2-(isocyano)enolate was isolated from the
reaction mixture containing LiBr by filtration and treated
with a THF solution of anisaldehyde. Under these
conditions, no reaction was observed, a result that gives
weight to the Passerini type approach.
reaction of the open isomer with electrophiles, involving
the R-addition of the electrophilic site and the nucleo-
philic oxygen atom of the phenolate to the isocyanide
carbon (Scheme 4).
The reaction was next extended to oxazole (4). Under
the conditions employed for benzoxazole, the iodide 5a
and the alcohol 5b were provided in good yields. Cross-
couplings with 2-bromopyridine and iodobenzene afforded
the expected 2-aryloxazole 6a,b in medium yields (Scheme
Conclusions
3
Benzoxazole was deprotonated using 1/3 equiv of Bu -
5
).
To gain greater understanding of the nature of the
MgLi in THF at room temperature. As 2-lithiobenzox-
azole, lithium tri(2-benzoxazolyl)magnesate very rapidly
and completely isomerized to the more stable 2-(isocy-
ano)phenolate type structure, a result evidenced by NMR
analysis. The isolation of 2-substituted benzoxazoles in
medium to good yields after electrophilic trapping was
1
species in solution after the deprotonation step, the H
NMR spectrum of the reaction mixture was recorded. It
indicated that the thermodynamically more stable 2-(iso-
(
23) Concerning cross-couplings with lithium arylmagnesates, see:
(
a) Dumouchel, S.; Mongin, F.; Tr e´ court, F.; Qu e´ guiner, G. Tetrahedron
Lett. 2003, 44, 3877-3880. (b) Dumouchel, S.; Mongin, F.; Tr e´ court,
F.; Qu e´ guiner, G. Tetrahedron 2003, 59, 8629-8640.
(25) Cuny, G.; G a´ mez-Monta n˜ o, R.; Zhu, J. Tetrahedron 2004, 60,
4879-4885.
(
24) (a) Passerini, M. Gazz. Chim. Ital. 1922, 52, 126-129. (b)
(26) LiBr is present in all the other reaction mixtures since it is
Passerini, M. Gazz. Chim. Ital. 1922, 52, 181-189.
3 2
formed during the synthesis of Bu MgLi from BuLi and MgBr .
5192 J. Org. Chem., Vol. 70, No. 13, 2005

Deprotonation of Benzoxazole and Oxazole
FIGURE 1. 1H and 13C NMR (JMOD) spectra of benzoxazole (1) and the derivatives obtained after deprotonation in THF (rt).
interpreted in two ways: (1) the equilibration between
the open and closed structures is faster than the trapping
of the open isomer, and the closed isomer is more reactive
than the open one, or (2) the open isomer reacts with
electrophiles in a intramolecular Passerini type reaction.
Similar results were observed starting from oxazole.
The non reactivity of the 2-(isocyano)enolate type struc-
ture toward anisaldehyde in the absence of lithium
bromide makes the intramolecular Passerini type reac-
tion more plausible.
J. Org. Chem, Vol. 70, No. 13, 2005 5193

Bayh et al.
FIGURE 2. 1H NMR spectra of oxazole (4) and the derivatives obtained after deprotonation in THF (rt).
SCHEME 5
In conclusion, lithium magnesates are suitable for
hydrogen-magnesium exchange reactions on oxazole and
benzoxazole at room temperature, whereas corresponding
hydrogen-lithium exchanges have generally to be per-
formed at lower temperatures. Compared to the lithio
species, the organometallics here obtained can also either
react with electrophiles, but without recourse to precom-
plexation with borane in the case of oxazole, or undergo
palladium-catalyzed cross-couplings, but without the
transmetalation step.
intermediate species resulting from deprotonation reactions,
the H and JMOD (J-modulated spin-echo experiment) NMR
spectra were recorded at room temperature after addition of
1
8
20% d -THF (to provide a lock signal) to a fraction (0.6 mL) of
the reaction mixture. The deuterium incorporation was de-
1
termined from the H NMR integration values. The main
absorptions of the IR spectra are given.
Starting Materials. THF was distilled from benzophenone/
Na. The water content of the solvents was estimated to be
27
lower than 45 ppm by the modified Karl Fischer method.
Metalation and cross-coupling reactions were carried out under
2 2
dry N . MgBr was freshly prepared in THF using a described
2
8
procedure. Petrol refers to petroleum ether (bp 40-60 °C).
Experimental Section
Unless otherwise noted, the reaction mixture was diluted
General Procedures. The H and 13C NMR spectra were
1
with CH
dried over MgSO
Cl
(50 mL) after the reaction. The organic layer was
, the solvents were evaporated under reduced
2
2
recorded in CDCl
3
at 300 and 75 MHz, respectively. For the
4
5194 J. Org. Chem., Vol. 70, No. 13, 2005

Deprotonation of Benzoxazole and Oxazole
pressure, and the crude product was chromatographed on a
silica gel column (eluent is given in the product description).
56.5 (p, 2C); IR (KBr) ν 3196, 3092, 2937, 2836, 1592, 1565,
1506, 1456, 1418, 1333, 1236, 1139, 1098, 1080, 993, 840, 821,
2
-Deuteriobenzoxazole (2a). BuLi (6.0 mmol) was added
to a solution of MgBr (2.0 mmol) in THF (3 mL) at -10 °C.
After stirring for 1 h at -10 °C, benzoxazole (0.71 g, 6.0 mmol)
was introduced. After 2 h at room temperature, D O (1 mL)
was added and the mixture was stirred for 18 h at room
temperature before addition of water saturated with NH Cl
5
748. Anal. Calcd for C17H17NO (315.33): C, 64.75; H, 5.43;
N, 4.44. Found: C, 64.63; H, 5.35; N, 4.39.
2-(2-Pyridyl)benzoxazole (3a). BuLi (6.0 mmol) was
2
added to a solution of MgBr (2.0 mmol) in THF (3 mL) at -10
2
2
°C. After stirring for 1 h at -10 °C, benzoxazole (0.71 g, 6.0
mmol) was introduced. After 2 h at room temperature, the
mixture thus obtained was added dropwise to a solution of
4
13
1
(
1 mL). Yield: 75% (90% d) (eluent CH
2
Cl
2
). The H and
C
NMR data of this product showed the replacements of 2-H by
2-bromopyridine (0.58 mL, 6.0 mmol) and PdCl
60 µmol) at reflux and the mixture was heated at reflux for
18 h before addition of water saturated with NH Cl (1 mL)
Yield: 76% (eluent: CH Cl /Et O 95:5); mp 109-110 °C (lit.
2
(dppf) (49 mg,
2
1
8
6
1
-D, and 2-CH by 2-CD, respectively; IR (KBr) ν 3431, 3062,
557, 1472, 1455, 1425, 1316, 1291, 1267, 1070, 1014, 874, 829,
4
3
1
00, 759, 729, 668. Anal. Calcd for C
7
H
4
DNO (120.13): C,
2
2
2
2
9
1
9.99; “H”, 4.29; N, 11.66. Found: C, 69.60; “H”, 4.36; N,
108 °C); H NMR δ 8.62 (d, 1H, J ) 4.5 Hz), 8.13 (d, 1H, J )
13
1.27.
2
7.9 Hz), 7.65 (m, 2H), 7.48 (m, 1H), 7.20 (m, 3H); C NMR δ
-Iodobenzoxazole (2b).30 The procedure is as described
160.5 (q), 150.1 (q), 149.4 (t), 145.0 (q), 140.9 (q), 136.2 (t),
1
25.2 (t), 124.7 (t), 124.1 (t), 122.6 (t), 119.8 (t), 110.3 (t); IR
for 2a but using a solution of I
mL) instead of D O (in this case, the reaction mixture was
treated with Na until bleaching): yield 57% (eluent: CH
Cl /petrol 90:10); H NMR δ 7.70 (m, 1H), 7.53 (m, 1H), 7.30
2
(1.5 g, 6.0 mmol) in THF (3
(
KBr) ν 3059, 1553, 1452, 1439, 1347, 1243, 1077, 1039, 934,
11, 762, 740, 703. Anal. Calcd for C12 O (196.21): C,
2
8
8 2
H N
2
S
2
O
3
2
-
1
73.46; H, 4.11; N, 14.28. Found: C, 73.43; H, 4.19; N, 14.33.
2-(2-Pyridyl)oxazole (6a). The procedure is as described
above but using oxazole (0.39 mL) instead of benzoxazole: yield
2
1
3
(
m, 2H); C NMR δ 153.9 (q), 142.5 (q), 125.2 (t), 124.6 (t),
1
19.2 (t), 110.0 (t), 108.2 (q); IR (KBr) ν 3066, 1686, 1648, 1632,
1
575, 1486, 1474, 1447, 1238, 1115, 1077, 743. Anal. Calcd
53% (eluent: CH
1557, 1513, 1461, 1445, 1275, 1148, 1096, 1077, 916, 797, 715.
Anal. Calcd for C O (146.15): C, 65.75; H, 4.14; N, 19.17.
Found: C, 65.69; H, 4.36; N, 18.89. The other analyses were
2 2
Cl ); IR (KBr) ν 3417, 3127, 2190, 1644, 1591,
for C
4.60; H, 1.97; N, 5.75.
-Iodooxazole (5a). The procedure is as described above
7 4
H INO (245.02): C, 34.31; H, 1.65; N, 5.72. Found: C,
3
8 6 2
H N
2
3
2
found identical to those previously described.
but using oxazole (0.39 mL) instead of benzoxazole: yield 70%
1
3-(2-Benzoxazolyl)quinoline (3b).33 The procedure is as
described for 3a but using 3-bromoquinoline (0.83 mL) instead
of 2-bromopyridine: yield 52% (eluent: CH Cl ); mp 184 °C;
2 2
H NMR δ 9.75 (d, 1H, J ) 1.9 Hz), 9.02 (d, 1H, J ) 1.9 Hz),
8.19 (d, 1H, J ) 8.3 Hz), 7.98 (d, 1H, J ) 8.3 Hz), 7.77 (m,
H), 7.65 (m, 2H), 7.42 (m, 2H); C NMR δ 160.4 (q), 150.3
(
2 2
eluent: CH Cl ); yellow oil; H NMR δ 7.77 (s, 1H), 7.10 (s,
13
1
H); C NMR δ 144.8 (q), 129.8 (q), 101.3 (t); IR (KBr) ν 2961,
2
924, 2853, 1731, 1714, 1463, 1454, 1261, 1094, 1022, 801.
1
Anal. Calcd for C
Found: C, 18.16; H, 1.14; N, 6.89.
3
H
2
INO (194.96): C, 18.48; H, 1.03; N, 7.18.
1
3
2
R-(4-Methoxyphenyl)-2-benzoxazolemethanol (2c). The
(
q), 148.4 (q), 148.0 (t), 141.4 (q), 134.9 (t), 131.0 (t), 129.0 (t),
28.4 (t), 127.4 (t), 126.8 (q), 125.4 (t), 124.6 (t), 119.9 (q), 119.9
(t), 110.4 (t); IR (KBr) ν 3021, 1573, 1556, 1491, 1454, 1245,
182, 967, 918, 786, 763, 747, 475. Anal. Calcd for C16
procedure is as described for 2a but using 4-anisaldehyde (0.73
1
2 2 2
mL, 6.0 mmol) instead of D O: yield 70% (eluent: CH Cl /
1
AcOEt 80:20); H NMR δ 7.71 (m, 1H), 7.45 (m, 3H), 7.33 (m,
H), 6.92 (d, 2H, J ) 6.8 Hz), 5.98 (s, 1H), 3.82 (s, 3H), 3.42
1
10 2
H N O
2
1
3
(246.26): C, 78.03; H, 4.09; N, 11.38. Found: C, 77.81; H, 4.11;
(
s, 1H); C NMR δ 166.9 (q), 159.9 (q), 150.9 (q), 140.3 (q),
N, 11.29.
2
1
2
1
1
31.1 (q), 128.3 (t, 2C), 125.2 (t), 124.5 (t), 120.1 (t), 114.2 (t,
C), 110.9 (t), 70.2 (t), 55.3 (p); IR (KBr) ν 3236, 2929, 2836,
612, 1574, 1510, 1456, 1440, 1244, 1177, 1164, 1107, 1067,
-(5-Pyrimidyl)benzoxazole (3c).34 The procedure is as
described for 3a but using 5-bromopyrimidine (0.95 g) instead
of 2-bromopyridine: yield 41% (eluent: CH Cl /AcOEt 80:20);
mp 168 °C; H NMR δ 9.56 (s, 2H), 9.37 (s, 1H), 7.83 (m, 1H),
030, 1002, 972, 864, 840, 819, 749, 596. Anal. Calcd for C15
(255.28): C, 70.58; H, 5.13; N, 5.49. Found: C, 70.21; H,
.52; N, 5.31.
R-(4-Methoxyphenyl)-2-oxazolemethanol (5b). The pro-
cedure is as described above but using oxazole (0.39 mL)
instead of benzoxazole: yield 61% (eluent: CH Cl ); mp 105-
10 °C; H NMR δ 7.54 (s, 1H), 7.33 (d, 2H, J ) 8.7 Hz), 6.98
s, 1H), 6.85 (d, 2H, J ) 8.7 Hz), 5.82 (s, 1H), 4.92 (s, 1H),
13
H -
2
2
1
NO
3
1
3
7
.65 (m, 1H), 7.44 (m, 2H); C NMR δ 159.7 (t), 157.7 (q), 155.1
5
(
(
t, 2C), 150.3 (q), 141.1 (q), 126.1 (t), 125.0 (t), 121.8 (q), 120.3
t), 110.7 (t); IR (KBr) ν 3089, 3042, 2955, 1618, 1567, 1459,
1
436, 1410, 1352, 1307, 1187, 1129, 1064, 1032, 765, 751, 715,
2
2
1
7 3
632, 623. Anal. Calcd for C11H N O (197.19): C, 67.00; H, 3.58;
1
N, 21.31. Found: C, 66.84; H, 3.77; N, 21.07.
(
1
3
2-(2-Thienyl)benzoxazole (3d). The procedure is as de-
scribed for 3a but using 2-bromothiophene (0.49 g) instead of
3
.77 (s, 3H); C NMR δ 164.9 (q), 159.7 (q), 132.3 (t), 131.5
(
(
q), 128.0 (t, 2C), 126.8 (t), 114.1 (t, 2C), 69.7 (t), 55.4 (p); IR
2
2 2
-bromopyridine: yield 30% (eluent: CH Cl /petrol 80:20); mp
KBr) ν 3436, 2961, 2838, 1652, 1611, 1513, 1252, 1173, 1030,
65, 588. Anal. Calcd for C11H11NO (205.22): C, 64.38; H, 5.40;
3
3
5
1
1
02-103 °C (lit. 104.5 °C); H NMR δ 7.92 (dd, 1H, J ) 3.8
7
and 1.1 Hz), 7.74 (m, 1H), 7.56 (m, 2H), 7.35 (m, 2H), 7.20
N, 6.83. Found: C, 64.33; H, 5.42; N, 6.45.
1
3
(
dd, 1H, J ) 4.9 and 3.8 Hz); C NMR δ 159.5 (q), 149.9 (q),
Note that when the 2-(isocyano)enolate was isolated from
the reaction mixture containing LiBr by filtration under an
air-free atmosphere (nitrogen), and treated with a THF
solution of anisaldehyde, no reaction was observed after 18 h
at room temperature.
(27) Bizot, J. Bull. Soc. Chim. Fr. 1967, 151.
(
28) Meth-Cohn, O.; Jiang, H. J. Chem. Soc., Perkin Trans. 1 1998,
737-3745.
29) The fictitious hydrogen percentage (“H”) was calculated as
3
1
(
R-(3,4,5-Trimethoxyphenyl)-2-benzoxazolemethanol
.008(h + 20.027/18.015 × d)/MW, where h and d stand for the number
(
2d). BuLi (6.0 mmol) was added to a solution of MgBr
2
(2.0
of hydrogen and deuterium atoms, respectively, in the cross formula:
mmol) in THF (3 mL) at -10 °C. After stirring for 1 h at -10
C, TMEDA (0.30 mL, 2 mmol) and, 1 h later, benzoxazole (0.71
g, 6.0 mmol) were introduced. After 2 h at room temperature,
,4,5-trimethoxybenzaldehyde (1.2 g, 6.0 mmol) was added and
the mixture was stirred for 18 h at room temperature before
addition of water saturated with NH Cl (1 mL). Yield: 71%
eluent: cyclohexane/AcOEt 70:30); mp 110-112 °C; H NMR
δ 7.68 (m, 1H), 7.48 (m, 1H), 7.32 (m, 2H), 6.77 (s, 2H), 5.97
Schlosser, M.; Choi, J. H.; Takagishi, S. Tetrahedron 1990, 46, 5633-
5
648.
°
(
30) Gillet, J. P.; Sauvetre, R.; Normant, J.-F. Tetrahedron Lett.
1
985, 26, 3999-4002.
3
(
31) Cohen, V. I. J. Heterocycl. Chem. 1979, 16, 13-16.
(32) Reeder, M. R.; Gleaves, H. E.; Hoover, S. A.; Imbordino, R. J.;
4
Pangborn, J. J. Org. Proc. Res., Dev. 2003, 7, 696-699.
(33) Gromov, S. P.; Razinkin, M. A.; Drach, V. S.; Sergeev, S. A.
Russ. Chem. Bull. 1998, 47, 1179-1185.
1
(
(
34) Chandramohan, M. R.; Seshadri, S. Indian J. Chem. 1972, 10,
1
3
(
s, 1H), 4.39 (broad s, 1H), 3.82 (s, 9H); C NMR δ 166.9 (q),
53.9 (q, 2C), 151.3 (q), 140.6 (q), 138.5 (q), 134.8 (q), 125.8
t), 125.0 (t), 120.5 (t), 111.3 (t), 104.1 (t, 2C), 71.0 (t), 61.2 (p),
5
73-576.
1
(35) Royer, R.; Colin, G.; Demerseman, P.; Combrisson, S.; Gheutin,
A. Bull. Soc. Chim. Fr. 1969, 2785.
(
J. Org. Chem, Vol. 70, No. 13, 2005 5195

Bayh et al.
instead of 2-bromopyridine: yield 52% (eluent: CH Cl ); mp
1
(
1
41.6 (q), 129.9 (t), 129.5 (t), 129.2 (q), 127.8 (t), 124.6 (t), 124.3
t), 119.3 (t), 110.0 (t); IR (KBr) ν 3062, 1615, 1570, 1494, 1451,
419, 1245, 1227, 1049, 1007, 852, 794, 760, 743, 716. Anal.
Calcd for C11 NOS (201.24): C, 65.65; H, 3.51; N, 6.96; S,
5.93. Found: C, 65.69; H, 3.34; N, 6.94; S, 15.81.
-Phenylbenzoxazole (3e). The procedure is as described
for 3a but using iodobenzene (0.67 mL) instead of 2-bromopy-
ridine: yield 50% (eluent: CH Cl ). The physical and spectral
data are analogous to those obtained for a commercial sample.
-Phenyloxazole (6b). The procedure is as described above
but using oxazole (0.39 mL) instead of benzoxazole: yield 60%
eluent: CH Cl ). The analyses were found identical to those
previously described.
2
2
3
7
1
198 °C (lit. 197-198 °C); H NMR δ 8.34 (d, 1H, J ) 8.3 Hz),
8.20 (d, 1H, J ) 8.7 Hz), 7.81 (m, 1H), 7.62 (m, 1H), 7.40 (m,
1
3
H
7
2H), 3.97 (s, 3H); C NMR δ 166.2 (q), 161.8 (q), 150.7 (q),
1
41.8 (q), 132.4 (q), 130.9 (q), 130.0 (t, 2C), 127.4 (t, 2C), 125.6
1
(
t), 124.8 (t), 120.2 (t), 110.7 (t), 52.3 (p); IR (KBr) ν 3420, 2954,
2
1454, 1436, 1410, 1278, 1245, 1195, 1110, 1054, 1012, 828, 762,
46, 713. Anal. Calcd for C15 (253.25): C, 71.14; H, 4.38;
7
H11NO
3
2
2
N, 5.53. Found: C, 70.98; H, 4.51; N, 5.32.
-(2-Benzoxazolyl)benzonitrile (3g). The procedure is as
described for 3a but using methyl 4-bromobenzonitrile (1.1 g)
4
2
2 2
instead of 2-bromopyridine: yield 61% (eluent: CH Cl /petrol
38
(
2
2
80:20); mp 204-205 °C (lit. 207-209 °C). The other analyses
3
6
38
are in accordance with those of the literature.
Methyl 4-(2-Benzoxazolyl)benzoate (3f). The procedure
is as described for 3a but using methyl 4-iodobenzoate (1.6 g)
JO050493W
(
37) Terashima, M.; Ishii, M.; Kanaoka, Y. Synthesis 1982, 484-
85.
(38) Kawashita, Y.; Nakamichi, N.; Kawabata, H.; Hayashi, M. Org.
Lett. 2003, 5, 3713-3715.
4
(36) (a) Kashima, C.; Arao, H. Synthesis 1989, 873-874. (b) Crowe,
E.; Hossner, F.; Hugues, M. J. Tetrahedron 1995, 51, 8889-8900.
5196 J. Org. Chem., Vol. 70, No. 13, 2005