A direct preparation of silyl oxazoles: A dramatic chemoselectivity difference between R3SiOTf and R3SiCl

Article abstract of DOI:10.1016/S0040-4039(01)02342-5

General, highly selective silylation conditions for the ambident oxazole anion (isocyano enolate) have been found. The chemoselectivity between O-silylation and C-silylation changed from <1:99 to >99:1 upon switching from R₃SiCl to R₃

Full text of DOI:10.1016/S0040-4039(01)02342-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 935–938
A direct preparation of silyl oxazoles: a dramatic
chemoselectivity difference between R3SiOTf and R3SiCl
Ross A. Miller,* Randi M. Smith,† Sandor Karady and Robert A. Reamer
Process Research and Development, Merck Research Laboratories, PO Box 2000 Rahway, NJ 07065, USA
Received 30 October 2001; revised 6 December 2001; accepted 7 December 2001
Abstract—General, highly selective silylation conditions for the ambident oxazole anion (isocyano enolate) have been found. The
chemoselectivity between O-silylation and C-silylation changed from <1:99 to >99:1 upon switching from R3SiCl to R3SiOTf.
© 2002 Elsevier Science Ltd. All rights reserved.
Oxazoles are common heterocycles in a wide variety of
natural products possessing biological activity and also
are widely used intermediates for functional group
transformations.1 Preparation of 2-substituted oxazoles
via C-2 lithiation and quenching with an electrophile
has been studied extensively but proved to be less
straightforward than with typical arylmetallated spe-
cies.2 The C-2 oxazole anion has a well-documented
mobile equilibrium between 2a and 2b that has compli-
cated the subsequent reactions (Fig. 1).3
plexes.5 C-2 Silyl oxazoles react in the ring-closed form
and have been shown to couple with aldehydes, acyl
iminium salts and acid chlorides.6 Previous prepara-
tions of C-2 silyloxazoles involved a two-step process of
initial O-silylation to give 3a followed by a thermal 1,5
silyl migration to the C-2 silyloxazole 3b. Unfortu-
nately, this process has not proved general for other
oxazole substrates and has limited their use in
syntheses.7,8
As part of the synthetic efforts to support a drug
Creative solutions to this mobile equilibrium problem
have included pre-complexation of the oxazole with
borane4 and transmetallation to the organozinc com-
development program at Merck, a synthesis of a gem-
dimethylamino substituted pyridyl oxazole
6 was
needed (Fig. 2).9 One option for synthesizing 6 was an
Li
N
LiO
O
O
nBuLi
N
N
R1
R1
R1
R2
2a
R2
2b
R2
1 R1, R2 = H
TMSCl
TMS
N
1,5 Si shift TMSO
O
N
R1
R1
ref. 5
R2
3b
R2
3a
Figure 1.
* Corresponding author. Tel.: 732-594-1358; e-mail: ross miller@merck.com
–
† Merck Research Laboratories UNCF Summer Intern. Present address: Xavier Univerity of Louisiana, New Orleans LA, USA.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02342-5

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R. A. Miller et al. / Tetrahedron Letters 43 (2002) 935–938
C-silyl compound. Finally, when TBSOTf (entries 9
and 10) was added to the magnesiated or lithiated
oxazole, complete C-2 silylation within the limits of
detection was observed. This dramatic reversal of selec-
tivity has not been previously reported in the literature
to the best of our knowledge, and prompted examina-
tion of the scope and mechanism of this unexpected
highly selective silylation.
ipso-substitution of an iminium species 5 onto the
silyloxazole 4a. In order to explore this route, a practi-
cal synthesis of the silyloxazole 4a was required.
As expected using Dondoni’s methodology for prepar-
ing C-silyloxazoles, metallation of compound 7 fol-
lowed by quenching with R3SiCl gave exclusive
O-silylation (4b). However, all attempts to effect ther-
mal isomerization to 4b were unsuccessful. Only desily-
lation or no reaction at all was observed under a variety
of conditions, including thermal as well as acid or base
catalysis.
In order to test the generality of this silylation duality,
several other oxazole substrates and different silylating
reagents were examined. As can be seen from Table 2,
the size of the silylation reagent did not affect the
partition between O- and C-silylation, with TMS, TBS
and TIPS chlorides and triflates showing equally selec-
tive results (>99:1 selectivity, entries 1, 3–5 and 10). As
the trimethylsilyl oxazoles proved to be completely
unstable to water and the TBS derivatives only mar-
ginally stable, only the TIPS derivatives were prepared
for each of the oxazoles (8, 12,10 1, 13) tested. The
tri-isopropylsilyloxazoles were very stable to aqueous
workups and column chromatography, and purification
without the extensive decomposition seen with the
other derivatives was possible. Benzoxazole (13) metal-
lation led to a aromaticity-stabilized isocyano pheno-
late anion, and might have been predicted to give only
O-silylation regardless of silylation reagent. However,
selective differential (O,C) silylation occurred with both
the triflate and the chloride (entries 18 and 19) in line
The initial silylation conditions were then investigated
with the goal of altering the product ratio (Table 1).
The metallation of the pyridyl oxazole was achieved
chemoselectively with a variety of bases as evidenced by
deuterium labeling studies, using isopropylmagnesium
chloride, LDA, nBuLi or potassium t-butoxide.
Greater than 90% deuterium incorporation was
observed for each base. Upon quenching the various
metallated oxazoles with TBSCl, no change in the
relative O/C ratios were observed. Even premixing
TBSCl with the oxazole, followed by slow LDA addi-
tion, gave complete O-silylation within the limits of
detection. The presence or absence of TMEDA did not
affect the O/C ratio. Some change in selectivity
occurred with the potassium isocyano enolate, yet large
amounts of enolsilyl ether still contaminated the desired
R1 R2
N
SiR3
O
R1 R2
O
N
O
+
OTf
N
O
N
N
N
4a
5
6
Figure 2.
Table 1.
TBS
TBS
N
A) THF, nBuLi
OoC
O
O
O
MeO
N
MeO
N
MeO
+
B) TBSX
0 to RT
N
N
N
7
4a
4b
Entry
Base
Solvent
THF
THF (1 equiv. TMEDA)
THF
Temp. (°C)
Silylating reagent
Ratio (4a:4b)
1
2
3
4
5
6
7
8
nBuLi
nBuLi
LDA
LDA
iPrMgCl
KOtBu
KOtBu
iPrMgCl
iPrMgCl
nBuLi
−5
−5
−5
−5
−5
−20
0
−5
−5
−5
TBSCl
TBSCl
TBSCl
Inverse TBSCl
TBSCl
TBSCl
TBSCl
TBSOTf
TBSOTf
TBSOTf
B1:99
B1:99
B1:99
B1:99
B1:99
THF
THF (1 equiv. TMEDA)
THF
THF
THF/DMPU (2:1)
THF
2.4:1
1:1
1:3
9
10
\99:1
\99:1
THF (1 equiv. TMEDA)

R. A. Miller et al. / Tetrahedron Letters 43 (2002) 935–938
937
Table 2.
R3
R2
R3
A) THF, nBuLi
O
O
O
N
OoC
N
R1
N
R1
R1
+
B) R3X
0 to RT
R2
R2
10 a-g
11 a-g
Entry
Oxazole
Silylating conditionsc
Major product
Ratio (10:11)
\99:1
Yielda
93
1
8 (R1=Ph, R2=H)
TBSOTf
10a
2
3
4
5
6
7
8
9
8
8
8
8
8
8
8
8
8
8
TBSOTf (1 equiv. TMEDA)
TBSCl
11a
10b
11b
10b
11b
10c
10c
11c
11c
B1:99
\99:1
B1:99
\99:1
B1:99
\99:1
\99:1
B1:99
B1:99
96
TIPSOTfd
95b
95
TIPSCl
TIPSOTf (LiCl added)
TIPSCl (LiOTf added)
TMSOTf (−60°C)
TMSOTf (−5°C)
TMSCl
NA
NA
90
NA
92
10
11
TMSCl then 0.2 equiv. TMSOTf
NA
12
13
14
15
12 (R1=H, R2=Ph)
TBSOTf
TBSCl
10d
11d
10e
11e
\99:1
B1:99
\99:1
B1:99
87
12
12
12
90
TIPSOTfd
TIPSCl
91b
96
16
17
18
1 (R1=H, R2=H)
1
13
TIPSOTfd
TIPSCl
10f
11f
10g
\99:1
B1:99
\99:1
94b
94
TIPSOTfd
90b
O
H
N
19
13
TIPSCl
11g
B1:99
93
a Ratios and yields determined on the crude reaction mixture by NMR using an internal standard.
b Isolated yields.
c Standard conditions were addition of 1.05 equiv. nBuLi (1.6 M) to an inerted and cooled (−5 to −10°C) solution of the oxazole in THF (0.33
M), followed by addition of 1.05 equiv. silylation reagent at −5°C.
d TIPOTf purchased from Aldrich contained approx 10% of diisopropyl-n-propylsilyltriflate.
Li
Li
Li
TMSOTf
O
O
O
TMS
N
N
R1
N
R1
R1
R2
R2
R2
2a
2b
TMSCl
TMS
3d
TMS
O
O
N
R1
N
R1
R2
3b
R2
3a
Figure 3.
with the other oxazoles. Parent oxazole11 1 gave selec-
tive O- and C-silylations as well (entries 16 and 17)
with no detectable isomer either case.12
Conceptually, several different pathways can be pro-
posed to explain the observed C-silyl product (3b, Fig.
3). With silyltriflates, C-silylation could occur directly

938
R. A. Miller et al. / Tetrahedron Letters 43 (2002) 935–938
on the closed-form oxazole anion (2a), present in small
quantities, though undetectable on the NMR
timescale.13 Alternatively, C-silylation of the open-form
a-isocyano enolate (2b) could occur followed by ring-
closure (Fig. 3, 3d). The observed products are reversed
from HSAB theory of O/C ambident enolate alkyla-
tions, whereby hard electrophiles react on oxygen.14
Lastly, O-silylation could occur giving 3b followed by a
1,5-silyl migration promoted by silyltriflate. However,
this last pathway seems unlikely since adding silyltri-
flate to the enolsilyl ethers or adding lithium triflate to
a quenched or unquenched crude TBSCl reaction (entry
7, Table 2) did not alter the ratios. Also, attempted
isomerization of O-silyl to C-silyl with TBSOTf at rt or
elevated temperatures failed as well. Mechanistic details
of this unexpectedly clean C-silylation await further
experimental efforts.
5. (a) Crowe, E.; Hossner, F.; Hughes, M. J. Tetrahedron
1995, 32, 8889; (b) Harn, N. K.; Gramer, C. J.; Ander-
son, B. A. Tetrahedron Lett. 1995, 52, 9453; (c) Hilf, C.;
Bosold, F.; Harms, K.; Marsch, M.; Boche, G. Chem.
Ber./Recueil 1997, 130, 1213.
6. (a) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.;
Pedrini, P. J. Org. Chem. 1987, 52, 3413; (b) For a review
of the preparation and reactivity of silicon and tin oxa-
zoles, see: Dondoni, A.; Fantin, G.; Fogagnolo, M.;
Mastellari, A.; Medici, A.; Negrini, E.; Pedrini, P. Gazz.
Chim. Ital. 1988, 211–231.
7. Whitney, S. E.; Rickborn, B. J. Org. Chem. 1991, 56,
3058.
8. Although C-2 tin oxazoles can be prepared directly, due
to the known toxicity of these reagents as well as limited
stability, they have not been widely used. Dondoni, A.;
Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P. Syn-
thesis 1987, 693.
9. Miller, R. A.; Karady, S.; Marcune, B., manuscript in
In conclusion, a novel preparation of C-2 silyloxazoles
has been found. The generality, selectivity and yields
are superior to the existing literature methods and
should therefore find use in various applications.
preparation
10. Whitney, S. E.; Rickborn, B. J. Org. Chem. 1991, 56,
3058. The two-step procedure reported in this paper was
modified slightly by adding 1.5 equiv. of ammonium
acetate in acetic acid slowly over 30 min, resulting in
higher ratios of the oxazole versus imidazole by-product
(2:1 versus 1:1).
Acknowledgements
11. Shafer, C. M.; Molinski, T. Heterocycles 2000, 53, 1167.
Small quantities are also commercially available from
Lancaster.
The support of Dr. Paul J. Reider is also gratefully
acknowledged.
12. General procedure: To a dry solution of the oxazole 1 (66
uL, 1.0 mmol) in 3 ml THF (water content less than 200
ug/mL as measured by Karl Fisher titration), under a
nitrogen atmosphere and cooled to −20 to −30°C, was
slowly added 1.05 mmol nBuLi (650 uL, 1.6 M in hex-
anes). The anion solution was warmed to 0 to −5°C and
then either silyl triflate or chloride was added to the
anion solution. The mixture was then warmed to room
temperature and aged 20 min. The mixture was then
diluted with water and isopropylacetate, the layers cut
and the organic solution concentrated to dryness. Com-
pound 10f 1H NMR (600.13 MHz, CDCl3) l 7.82 (s, 1H),
7.21 (s, 1H), 1.41 (septet, J=7.6 Hz, 3H), 1.14 (d, J=7.6
Hz, 18H); 13C NMR (150.92 MHz, CDCl3) l 168.7,
References
1. For reviews of oxazole syntheses and/or reactions, see: (a)
Turchi, I. J.; Dewar, M. J. S. Chem. Rev. 1974, 75, 389;
(b) Turchi, I. J. In Heterocyclic Compounds; Turchi, I. J.,
Ed.; Wiley & Sons: New York, 1986; Vol. 45, Chapter 1;
(c) Rickborn, B. Org. React. 1998 223–630. For examples
of oxazole-containing natural products, see: (d) Vedejs,
E.; Barda, D. A. Org. Lett. 2000, 2, 1033 and references
cited therein; (e) Kozikowski, A. P.; Ames, A. J. Org.
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Chem. Soc. 1978, 100, 7748; (g) Liotta, D.; Saindane, M.;
Ott, W. Tetrahedron Lett. 1983, 24, 2473; (h) Whitney, S.
E.; Winters, M.; Rickborn, B. J. Org. Chem. 1990, 55,
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2. (a) Hodges, J. C.; Patt, W. C.; Connolly, C. J. J. Org.
Chem. 1991, 56, 449; (b) Pridgen, L. N.; Shilcrat, S. C.
Synthesis 1984, 1048; (c) Anderson, B. A.; Harn, N. A.
Synthesis 1996, 583; (d) Harn, N. A.; Gramer, C. J.;
Anderson, B. A. Tetrahedron Lett. 1995, 36, 9453.
3. In fact, 2a was not observed on the NMR time scale: (a)
Schroder, R.; Schollkopf, U.; Blume, E.; Hoppe, I.
Liebigs Ann.Chem. 1975, 533; (b) Crowe, E.; Hossner, F.;
Hughes, M. J. Tetrahedron 1995, 32, 8889; (c) Hilf, C.;
Bosold, F.; Harms, K.; Marsch, M.; Boche, G. Chem.
Ber./Recueil 1997, 130, 1213; (d) Hodges, J. C.; Pratt, W.
C.; Connolly, C. J. J. Org. Chem. 1991, 56, 449.
1
140.4, 126.6, 18.3, 11.0 Compound 11f H NMR (399.87
MHz, CDCl3) l 6.43 (br d, J=4.0 Hz, 1H), 5.02 (d,
J=4.0 Hz, 1H), 1.15 (m, 21H); 13C NMR (100.55 MHz,
CDCl3) l 166.2, 145.3, 95.0 (t, JN14–C13=12.8 Hz), 17.3,
11.7.
13. The NMR of lithiated oxazole 2b (R1=Ph) was consis-
tent with other published studies of metallated oxazoles
shown to be exclusively in the open isocyanoenolate form
(2b, R1=Ph): 1H NMR (399.87 MHz, d8-THF) l 7.68
(m, 2H), 7.15 (m, 3H), 5.20 (s, 1H); 13C NMR (100.55
MHz, d8-THF) l 169.3, 164.6, 144.0, 129.22, 129.19,
127.5, 83.5. Magnesiation of 7 in THF/DMPU at 0°C
gave the following data consistent with an open form
1
isocyanoenolate anion: H NMR (500.13 MHz, d8-THF)
l 8.38 (s, 1H), 8.11 (s, 1H), 7.98 (br s, 1H), 5.45 (s, 1H),
3.90 (br s, 3H); 13C NMR (125.76 MHz, d8-THF) l
164.1, 162.9, 156.9, 139.4, 138.6, 138.0, 117.9, 83.8, 56.6,
see Refs. 5a and 5c.
14. Carey, F. A.; Sundberg, R. J. Advanced Organic Chem-
istry; Plenum Press: New York, 1983; pp. 21–24.
4. Vedejs, E.; Monahan, S. D. J. Org. Chem. 1996, 61, 5192.