A convenient oxazole C-2 protecting group: The synthesis of 4- and 5-substituted oxazoles via metalation of 2-triisopropylsilyloxazoles

Article abstract of DOI:10.1021/jo051490m

Metalation of oxazoles at the 4 and 5 position was achieved after regioselective C-2 silyl protection. Removal of the protecting group was then accomplished under mild conditions allowing for a straightforward preparation of C-5 monosubstituted and C-4,5

Full text of DOI:10.1021/jo051490m

A Convenient Oxazole C-2 Protecting
Group: The Synthesis of 4- and
5-Substituted Oxazoles via Metalation of
2-Triisopropylsilyloxazoles
Ross A. Miller,* Randi M. Smith,1 and
Benjamin Marcune
Department of Process Research, Merck Research
Laboratories, P.O. Box 2000, Rahway, New Jersey 07065
ross_miller@merck.com
Received July 18, 2005
FIGURE 1. Reactivity of C-2 Lithioxazoles.
of the counterion, solvent, etc.7 Simple, direct C-2 silyla-
tion with silyl chlorides has proven irreproducible and
unusable in synthesis.8 To protect the C-2 position of
oxazoles, multistep strategies that allowed for C-5 meta-
lation of oxazoles which did not start from the C-2 H
oxazoles have been developed, but integration of the
methodology into multistep syntheses is awkward.9 How-
ever, recently we found a dramatic difference in the
reactivity of C-2 metalated oxazoles between silyl triflates
and silyl chlorides that has allowed for selective and
general C-2 silylation (eq 1).10 Herein we report the
extension of our direct C-2 silyl oxazoles synthesis and
its utility as a useful protecting group for C-2 H oxazoles
that allow for simple metalation methodology to prepare
4 and 5 substituted oxazoles.
Metalation of oxazoles at the 4 and 5 position was achieved
after regioselective C-2 silyl protection. Removal of the
protecting group was then accomplished under mild condi-
tions allowing for a straightforward preparation of C-5
monosubstituted and C-4,5 disubstituted oxazoles. The first
practical C-2 protecting group of oxazoles has been demon-
strated.
Transformation of unsubstituted heterocycles to sub-
stituted heterocycles utilizing metalation is a direct way
to regioselectively prepare substituted aromatic or het-
erocyclic compounds. The hallmark of this strategy to
prepare polysubstituted compounds is its simplicity,
generality, and versatility.2 However, successful applica-
tion of this strategy to more complex substrates often
depends on the proper protection of an undesired sub-
stitution site. Protection of undesired reactive sites with
silicon is common practice to avoid chemoselectivity
problems.3 Oxazoles, whose most acidic site is the C-2
position, present a unique challenge for metalation
protecting group strategies due to the unusual behavior
of the C-2 lithio anion.4 The C-2 lithio intermediate 2a
is not observed by NMR, only the ring-opened compound
2b.5
As previously reported, C-2 silylation of oxazole 1 was
accomplished by treatment with n-BuLi followed by
quenching with silyltriflates yielding >99:1 C-silylated
oxazole B versus O-silylated oxazole A. C-2 silyloxazoles
were prepared in a general manner by treatment with a
base such as n-BuLi or i-PrMgCl in THF at low temper-
ature followed by a silyl triflate. Both the TMS and TBS
Nonselective reaction with electrophiles gives mixtures
of products (3a, 3b, and 3c) due to the formation of an
isocyanoenolate 2b (Figure 1).6 The distribution of prod-
ucts is highly dependent on the electrophile, the nature
(6) (a) Schroder, R.; Schollkopf, U.; Blume, E.; Hoppe, I. Liebigs Ann.
Chem. 1975, 533. (b) Reference 5. (c) Hilf, C.; Bosold, F.; Harms, K.;
Marsch, M.; Boche, G. Chem. Ber./Recl. 1997, 130, 1213. (d) Hodges,
J. C.; Pratt, W. C.; Connolly, C. J. J. Org. Chem. 1991, 56, 449.
(7) (a)Vedejs, E.; Monahan, S. D. J. Org. Chem. 1996, 61, 5192. (b)
Hodges, J. C.; Pratt, W. C.; Connolly, C. J. J. Org. Chem 1991, 56,
449. (c) Ikemoto, N.; Miller, R. A.; Fleitz, F.; Liu, J.; Petrillo, D.; Leone,
J.; Laquidara, J.; Marcune, B.; Karady, S.; Armstrong, J. D.; Volante,
R. P. Tetrahedron Lett. 2005, 46, 1867.
(8) Whitney, S. E.; Rickborn, B. J. Org. Chem. 1991, 56, 3058. This
paper reports they were unable to prepare 2-(trimethylsilyl)-4-phen-
yloxazole via the reported literature methodology of O-Si to C-Si
isomerization. See refs 4a and 4b in that paper.
(1) Merck Research Laboratories 2003 UNCF Summer Intern.
(2) For a recent reviews see: Schlosser, M. Angew. Chem., Int. Ed.
2005, 44, 376 and references therein.
(3) Green, T. W.; Wuts, P. G. M. Protecting Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons: New York, 1999.
(4) The pKa of the C-2 H has been estimated to be ∼20. For a general
review of oxazoles see: (a) Turchi, I. J., Ed. Heterocyclic Compounds;
J. Wiley and Sons: New York, 1986. (b) Palmer, D. , Ed. Heterocyclic
Compounds; J. Wiley and Sons: New York, 2003, 2004; Vol. 60, Parts
A and B.
(9) Shafer, C. M.; Molinski, T. F. J. Org. Chem. 1998, 63, 551.
(10) Miller, R. A.; Smith, R. M.; Karady, S.; Reamer, R. A. Tetra-
hedron Lett. 2002, 43, 935.
(5) Crowe, E.; Hassner, F.; Hughes, M. J. Tetrahedron 1995, 32,
8889.
10.1021/jo051490m CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/29/2005
9074
J. Org. Chem. 2005, 70, 9074-9076

TABLE 1. Lithiation and Reaction of TIPS Protected Oxazoles
isolated yields
isolated yields
entry
R1
electrophile
product
R1
R2
of 5
of 6
1
2
H
H
H
H
H
H
H
H
H
H
Ph
Ph
MeI
5a
5b
5c
5d
5e
5f
5g
5h
5i
Me
Et
CHOHPh
TMS
TBS
CH2Ph
Sn(Bu)3
allyl
H
H
H
H
H
H
H
H
H
H
Me
86
94
84
89
93
79
75
75
86
80
89
56
EtI
3
benzaldehyde
TMSCl
TBSCl
benzylbromide
tributyltinchloride
allyl bromidea
benzonitrile
DMF
95
90
4
5
6
7
8
9
COPh
CHO
Ph
92
10
11
12
5j
5k
5l
MeI
benzaldehyde
94b
90
Ph
CHOHPh
a 13% starting material remained. b (a) Possel, O.; van Leusen, A. M. Heterocycles 1977, 7, 77. (b) Brederick, H.; Gompper, R. Chem.
Ber. 1954, 87, 700.
oxazoles showed partial or complete instability to aque-
ous workup and column chromatography; however, the
TIPS (triisopropylsilyl) derivative was observed to be a
stable and practical protecting group throughout non-
acidic aqueous workups and purification.11,12 TIPS ox-
azole 4a was metalated quantitatively and rapidly with
1.1 equiv of n-BuLi at -10 °C as evidenced by >95%
deuterium incorporation post quenching with D2O after
5 min age time. Additionally, reaction of this C-5 lithio
anion with a variety of electrophiles was examined and
the results are shown in Table 1. No instability of the
anion was observed under the conditions of the metala-
tion. Aryllithium reagents can vary in the efficiency with
which they couple with electrophiles.2 In this case, a
variety of electrophiles reacted in high yield with the C-5
lithiated oxazole, including alkyl halides, allyl and benzyl
halides, stannyl chloride, aldehydes, and nitriles. Isola-
tion of the products was simplified over the corresponding
C-2 hydrogen oxazoles, due to significantly lower volatil-
ity and water solubility. The products were purified on
silica gel without any observation of desilylation. Re-
moval of the TIPS protecting group was then carried out
easily with acidic conditions to regenerate the C-2 H
oxazole, using dilute aqueous acid. Alternatively, the
initial reaction mixture could be quenched with acid and
the C-2 H compound directly isolated. In the case of
stannyl compound 5g, competitive C-5 destannylation
was observed. Due to the volatility of the products, 6a,
6b, and 6j were not desilyated.
group was cleanly accomplished without removing the
more stable C-5 TMS substituted oxazole 5d (eq 2).
In conclusion, efficient and direct C-2 protection of
oxazoles with silicon has allowed for systematic func-
tionalization of oxazoles. The 4- and 5-lithio anions were
reactive in high yield with a variety of electrophiles.
Facile deprotection allowed for regeneration of the C-2
unsubstituted oxazoles. This methodology represents the
first general protecting group for the C-2 position of
oxazoles. Application of this protecting group strategy
should find use in a wide variety of synthetic applications
involving oxazoles.
Experimental Section
Phenyl[2-[tris(1-methylethyl)silyl]-1,3-oxazol-5-yl]meth-
anol (5c). In a round-bottom flask was charged dry TIPS oxazole
4a (2.86 gm, 12.7 mmol) and dry THF (42 mL). The solution
was cooled to ca. -30 °C and then nBuLi was slowly added,
maintaining the internal temperature less than -20 °C. After
a 15 min age, benzaldehyde was added and the reaction mixture
was warmed to room temperature over 30 min. The reaction
mixture was quenched with water (15 mL) and isopropyl acetate
(IPAC) (30 mL) and the layers cut. The organic layer was
concentrated and the resulting oil purified by chromatography,
using silica gel and 30% IPAC/heptane as eluent. A white solid
Entries 11 and 12 demonstrate applications of this
protecting group strategy to prepare disubstituted ox-
azoles. Interestingly, selective removal of the C-2 TIPS
1
(3.2 g) was obtained upon evaporation. H NMR (399.87 MHz,
CDCl3) δ 7.42 (m, 5H), 6.93 (s, 1H), 5.93 (s, 1H), 1.39 (septet,
J ) 7.5, 3H), 1.24 (d, J ) 0.9, 18H). 13C NMR (100.56 MHz,
CDCl3) δ 169.0, 154.9, 140.3, 128.6, 128.4, 126.6, 124.1, 68.8,
18.4, 11.0. Theoretical elemental analysis: C 68.83, H 8.82, N
4.22. Found: C 68.92, H 8.91, N 4.22. LRMS calcd 331.2; found
M + H 332.5.
(11) TIPSOTf contained 5-10% of n-propyldiisopropylsilyl triflate,
which complicated the NMR spectrum but not the subsequent chem-
istry. A similar observation about the purity of TIPSOTF was previ-
ously made: Barden, D. J.; Fleming, I. J. Chem. Soc., Chem. Commun.
2001, 2366.
(12) For a thorough review of the triisopropylsilyl group, see:
Rucker, C. Chem. Rev. 2005, 95, 1009.
1,3-Oxazol-5-yl(phenyl)methanol (6c). Compound 5c (1 g)
was dissolved in 10 mL of THF at room temperature. Addition
of 1 mL of 1 M HCl was carried out, followed by a 15 min age.
J. Org. Chem, Vol. 70, No. 22, 2005 9075

The reaction mixture was diluted with 10 mL of IPAC and 5
mL of water and the layers cut. The organic layer was concen-
trated and purified by chromatography, using silica gel and 40%
IPAC/heptane as eluent to obtain 6c. If desired, compound 6c
could be obtained directly without isolation of 5c by quenching
the reaction with 1 N HCl instead of water. 1H NMR (399.87
MHz, CDCl3) δ 7.74 (s, 1H), 7.4 (m, 5H), 6.77 (s, 1H), 5.84 (s,
1H), 3.70 (br s, 1H). 13C NMR (100.55 MHz, CDCl3) δ 153.7,
151.2, 139.9, 128.7, 128.6, 126.6, 123.6, 68.3. Calcd for C10H9-
NO2: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.62; H, 5.09, N,
7.91. Exact mass calcd 175.1; found M + H 176.1.
Supporting Information Available: Full characteriza-
tion of compounds 5a-l, 6c, 6d, 6i, 6k, and 6l. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO051490M
9076 J. Org. Chem., Vol. 70, No. 22, 2005