Synthesis of 3,4,5-trisubstituted isoxazoles via sequential [3 + 2] cycloaddition/silicon-based cross-coupling reactions

Article abstract of DOI:10.1021/jo047755z

(Chemical Equation Presented) A [3 + 2] cycloaddition reaction between alkynyldimethylsilyl ethers and aryl and alkyl nitrile oxides to produce isoxazolylsilanols has been developed. The cross-coupling reactions of these heterocyclic silanols with a varie

Full text of DOI:10.1021/jo047755z

reasoned that in this sequential cycloaddition/cross-
coupling process not only would the silicon group influ-
ence the regioselectivity of the cycloaddition but also
would enable further functionalization of the heterocycle
by a palladium-catalyzed, cross-coupling reaction.6 The
development of this process would allow for the synthesis
of a wide array of heterocycles where the substituents
could be selectively varied based on the choice of dipole
or dipolarophile. Subsequent cross-coupling would pro-
vide another point of diversity in the synthesis of the
substituted heterocycles.
Synthesis of 3,4,5-Trisubstituted Isoxazoles
via Sequential [3 + 2] Cycloaddition/
Silicon-Based Cross-Coupling Reactions
Scott E. Denmark* and Jeffrey M. Kallemeyn
Roger Adams Laboratory, Department of Chemistry,
University of Illinois, Urbana, Illinois 61801
denmark@scs.uiuc.edu
Received December 23, 2004
Isoxazoles constitute an important family of five-
membered heterocycles in view of their use in many
natural products syntheses7 and occurrence in pharma-
ceutical agents, such as the COX-2 inhibitor Bextra.8 A
powerful method for the construction of isoxazoles is the
[3 + 2] dipolar cycloaddition between alkynes and nitrile
oxides,9 although regioselective construction of 3,4,5-
trisubstituted isoxazoles is dependent on the substituents
of the dipolarophile.10 An alternative strategy to selec-
tively prepare 3,4,5-trisubstituted isoxazoles is to employ
a placeholder on the alkyne that biases the [3 + 2]
cycloaddition and facilitates the construction of isomer-
ically pure isoxazole. This concept has been reduced to
practice with both tin-11 and boron-substituted12 alkynes
that engage in [3 + 2] dipolar cycloadditions with nitrile
oxides to afford substituted isoxazoles in moderate
selectivities. In these cases, further manipulation of the
newly formed isoxazoles via a Stille13 or Suzuki14 cross-
coupling introduces a third substituent in a controlled
manner, albeit with a limited variety of substituents on
A [3 + 2] cycloaddition reaction between alkynyldimethyl-
silyl ethers and aryl and alkyl nitrile oxides to produce
isoxazolylsilanols has been developed. The cross-coupling
reactions of these heterocyclic silanols with a variety of aryl
iodides affords 3,4,5-trisubstituted isoxazoles. This sequen-
tial process allows for rapid variation of substituents at the
3, 4, and 5 positions of the isoxazole.
Recent reports from these laboratories have described
mild and selective methods for the introduction of silicon
functional groups into carbon frameworks followed by
transformation of these new organosilicon functions into
carbon-carbon bonds by a palladium-catalyzed cross-
coupling reaction.1 This strategy has been demonstrated
for a variety of processes such as the hydrosilylation2a
and silylformylation of alkynes,2b silylation of aryl ha-
lides,3 and ring-closing metathesis of vinyl silyl ethers.4
These methods place the silicon functional group into a
specific environment which is then primed for the cross-
coupling reaction. Other powerful transformations that
could install a silicon group to guide the construction of
useful products are cycloaddition reactions. In the context
of heterocycle synthesis, the [3 + 2] cycloaddition reaction
of alkynylsilanes would provide highly substituted, silicon-
containing five-membered heterocycles from acyclic pre-
cursors. A concern in the synthesis of these heterocycles
is the regioselectivity of the cycloaddition (and conse-
quently the substitution pattern) which is highly depend-
ent on both steric and electronic features of the dipolaro-
phile. Silicon-substituted dipolarophiles undergo the
[3 + 2] cycloaddition with high regioselectivities.5 We
(5) (a) Padwa, A.; Wannamaker, M. W. Tetrahedron 1990, 46, 1145-
1162. (b) Hlasta, D. J.; Ackerman, J. H. J. Org. Chem. 1994, 59, 6184-
6189.
(6) Denmark, S. E.; Baird, J. D. Org. Lett. 2004, 6, 3649-3652.
(7) (a) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Simoni,
D. Synthesis 1987, 857-869. (b) Kotyatkina, A. I.; Zhabinsky, V. N.;
Khripach, V. A. Russ. Chem. Rev. 2001, 70, 641-653.
(8) Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt,
C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.;
Zhang, Y. Y.; Zweifel, B. S.; Seibert, K. J. Med. Chem. 2000, 43, 775-
777.
(9) Jaeger, V.; Colinas, P. A. Nitrile Oxides. In Synthetic Applications
of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and
Natural Products; Padwa, A., Pearson, W. H., Eds.; Chemistry of
Heterocyclic Compounds; Wiley: Hoboken, 2002; Vol. 59, pp 361-472.
(10) (a) Easton, C. J.; Heath, G. A.; Hughes, C. M. M.; Lee, C. K. Y.;
Savage, G. P.; Simpson, G. W.; Tiekink, E. R. T.; Vuckovic, G. J.;
Webster, R. D. J. Chem. Soc., Perkin Trans. 1 2001, 1168-1174.
(b) Pevarello, P.; Amici, R.; Colombo, M.; Varasi, M. J. Chem. Soc.,
Perkin Trans. 1 1993, 2151-2152. (c) Fouli, F. A.; Habashy, M. M.;
El-Kafrawy, A. F.; Youseef, A. S. A.; El-Adly, M. M. J. Prakt. Chem.
1987, 329, 1116-1122. (d) Yedidia, V.; Leznoff, C. C. Can. J. Chem.
1980, 58, 1144-1150.
(11) (a) Sakamoto, T.; Kondo, Y.; Uchiyama, D.; Yamanaka, H.
Tetrahedron 1991, 47, 5111-5118. (b) Kondo, Y.; Uchiyama, D.;
Sakamoto, T.; Yamanaka, H. Tetrahedron Lett. 1989, 30, 4249-4250.
(c) Uchiyama, D.; Yabe, M.; Kameyama, H.; Sakamoto, T.; Kondo, Y.;
Yamanaka, H. Heterocycles 1996, 43, 1301-1304. (d) Hanamoto, T.;
Hakoshima, Y.; Egashira, M. Tetrahedron Lett. 2004, 45, 7573-7576.
(12) (a) Davies, M. W.; Wybrow, R. A. J.; Harrity, J. P. A.; Johnson,
C. N. Chem. Commun. 2001, 1558-1559. (b) Moore, J. E.; Goodenough,
K. M.; Spinks, D.; Harrity, J. P. A. Synlett 2002, 2071-2073.
(13) Mitchell, T. N. In Metal-Catalyzed Cross-Coupling Reactions,
2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004; Vol. 1, pp 125-162.
(1) (a) Denmark, S. E.; Sweis, R. F. In Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-
VCH: Weinheim, 2004; Vol. 1, pp 163-216. (b) Denmark, S. E.; Sweis,
R. F. Acc. Chem. Res. 2002, 35, 835-846. (c) Denmark, S. E.; Sweis,
R. F. Chem. Pharm. Bull. 2002, 50, 1531-1541. (d) Denmark, S. E.;
Ober, M. H. Aldrichim. Acta 2003, 36, 75-85.
(2) (a) Denmark, S. E.; Pan, W. Org. Lett. 2003, 5, 1119-1122.
(b) Denmark, S. E.; Kobayashi, T. J. Org. Chem. 2003, 68, 5153-5159.
(3) Denmark, S. E.; Kallemeyn, J. M. Org. Lett. 2003, 5, 3483-3486.
(4) Denmark, S. E.; Yang, S.-M. Tetrahedron 2004, 60, 9695-9708.
(14) Miyaura, N. In Metal-Catalyzed Cross-Coupling Reactions, 2nd
ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004;
Vol. 1, pp 41-124.
10.1021/jo047755z CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/24/2005
J. Org. Chem. 2005, 70, 2839-2842
2839

TABLE 1. Optimization of [3 + 2] Cycloaddition To
both the dipole and dipolarophile. We surmised that the
[3 + 2] cycloaddition of silicon-substituted alkynes with
nitrile oxides should proceed in a regioselective manner
such that the silicon could facilitate further functional-
ization. In this paper, we report the cycloaddition of aryl-
and alkyl-substituted alkynyldimethylsilyl ethers with
aryl and alkyl nitrile oxides to generate a variety of
differently functionalized 3,5-disubstituted 4-silylisox-
azoles. A silicon-based cross-coupling reaction with aryl
iodides creates a point for further diversification to afford
3,4,5-trisubstituted isoxazoles.
Form 8a and 8b
7,
no. of
interval,a time,a conversion,b
entry equiv additions
h
h
%
8a/8bc
1
2
3
4
2.0
2.0
2.0
1.0
1
2
3
3
2
4
8
5
42
80
91
89
4.1:1
4.3:1
4.7:1
4.5:1
Studies on the [3 + 2] cycloaddition commenced with
the reaction between phenylethynyl silyl ether, 1, and
ethyl nitrile oxide, which was generated in situ from
1-nitropropane, 2, and phenyl isocyanate.15 Most nitrile
oxides must be prepared in situ from stable precursors
to limit dimerization of the dipole.9 Monitoring consump-
tion of 1 and formation of the two possible isomeric
2
2
1
a See the Supporting Information for details. b Consumption of
1 measured by 1H NMR spectroscopy vs hexamethylbenzene as
an internal standard. c As determined by 1H NMR spectroscopy.
1
7 after an additional 2 h interval had a negligible effect
(Table 1, entries 1-3). Gratifyingly, addition of 1.0 equiv
of both KHCO3 and 7 in three portions with a 1 h interval
provided an 89% conversion to 8a and 8b (entry 4). Under
these conditions, cycloaddition of 1 with 7 afforded 8a
and 8b in a 4.6:1 ratio. Hydrolysis of the resulting silyl
ethers afforded silanol 9 in 52% yield as a single isomer.
Likewise, cycloaddition of 5 with 7 produced a 1.8:1 ratio
of the isoxazole isomers with the silyl ether in the 4- and
5-positions, respectively. Subsequent hydrolysis of this
mixture afforded silanol 10 in a 33% yield as a single
isomer (Scheme 3). In both of these cases the 5-sub-
stituted silanol was not isolated.
isoxazoles, 3a and 3b, by H NMR spectroscopy showed
that slow addition of 2 to 1 was required for high con-
version to 3a and 3b. Addition of 2.5 equiv of 2 to 1 over
5 h resulted in 89% conversion, based on the consumption
of 1, and a 3.4:1 mixture of 3a/3b (Scheme 1).
SCHEME 1
Hydrolysis of the mixture of silyl ethers 3 to silanol 4
was effected with 1.0 M aqueous HOAc in CH3CN3 and
afforded 4 in a 49% isolated yield (from 1) as a single
isomer. Only trace amounts of the silanol resulting from
hydrolysis of 3b could be isolated. Similarly, cycloaddition
of 5 with 2 proceeded in a 3.3:1 regioselectivity of the
isoxazole isomers with the silyl ether in the 4 and 5
positions, respectively. Hydrolysis of the crude mixture
of silyl ethers afforded silanol 6 in a 36% yield (from 5)
as a 19:1 mixture of 6 to the 5-substituted silanol
(Scheme 2).
SCHEME 3
To further expand the utility of these cycloadducts, the
cross-coupling reactions of silanols 4, 6, 9, and 10 were
investigated. Initial studies with 4 showed that signifi-
cant amounts of the product of protodesilylation, 11, was
obtained with a variety of base and solvent combinations
(NaO-t-Bu, KOTMS, Cs2CO3, K3PO4 in toluene, THF,
DMF). Fortunately, the amount of 11 could be reduced
by the use of copper salts6 (Table 2). Addition of copper-
(I) iodide had little effect other than to significantly
reduce the rate of the reaction (entries 1 and 2). Changing
the additive to copper(II) salts showed both an increase
in the rate of cross-coupling as well as an improvement
in the ratio of 12 to 11. Copper acetate was superior to
all other salts surveyed in both conversion to 12 and
selectivity (entries 3-5).
To further improve conversion of 4 to 12, the amounts
of base and copper were varied (Table 3). Decreasing the
amount of base resulted in a large increase in the
proportion of 11 (entry 2), whereas increasing the amount
of base to 2.5 equiv resulted in a 97% conversion to 12
in less than 2 h with a high ratio of 12/11. Decreasing
the Cu(OAc)2 loading to 25 mol % resulted in a slower
reaction as well as a lower ratio of 12/11.
SCHEME 2
To further explore substituent effects, the 3-phenyl-
substituted isoxazoles were obtained by cycloaddition of
silyl ethers 1 or 5 with benzonitrile oxide, generated in
situ from chlorooxime 7 and KHCO3 (Table 1). The
addition of equimolar amounts of KHCO3 and 7 to 1
resulted in the formation of isoxazole isomers 8a and 8b
albeit with modest conversion. The yield of 8 could be
improved by the portionwise addition of KHCO3 and 7.
Addition of 2 equiv of both KHCO3 and 7 to 1 in two
portions in a 2 h interval improved the conversion to 8;
however, addition of a third portion of both KHCO3 and
Under these conditions, the cross-coupling reaction of
4 with 4-iodonitrobenzene afforded 12 in a 78% yield
(15) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339-
5342.
2840 J. Org. Chem., Vol. 70, No. 7, 2005

TABLE 2. Effect of Copper Source on the
Cross-Coupling of 4 with 4-Iodonitrobenzene
TABLE 4. Optimization of the Cross-Coupling of 4 with
4-Iodoanisole
entry
T, °C
Cu(OAc)2, equiv
time, h
14,a %
14/11b
entry
copper additive
time, h
12,a %
12/11b
1
2
3
4
5
40
40
60
80
60
1.0
4
24
8
3
8
19
43
75
82
45
1:2.1
2.1:1
2.7:1
2.9:1
3.5:1
0.25
0.25
0.25
0
1
2
3
4
5
none
CuI
CuBr2
Cu(OTf)2
Cu(OAc)2
4
4
4
4
4
47
19
67
74
81
7.9:1
7.7:1
7.5:1
20.0:1
25.8:1
a Measured by 1H NMR spectroscopy vs hexamethylbenzene as
an internal standard. b As determined by 1H NMR spectroscopy.
a Measured by 1H NMR spectroscopy verses hexamethylbenzene
as an internal standard. b As determined by 1H NMR spectroscopy.
TABLE 5. Summary of Cross-Coupling Reactions of 4
and 6
TABLE 3. Optimization of the Amount of Base and
Copper Acetate
silanol
equiv
arylI,
equiv product
yield,a
%
entry NaO-t-Bu, equiv Cu(OAc)2, equiv time, h 12,a
%
12/11b
entry silanol
R′
1
2
3
4
5
2.0
1.2
2.5
2.5
2.5
1.0
4
4
2
4
8
81
45
97
57
90
25.8:1
1.2:1
23.7:1
11.2:1
11.4:1
1
2
3
4
4
4
6
6
1.1
1.1
1.0
1.0
-OMe
-Me
1.0
14
15
16
17
62
61
52
56
1.0
1.0
1.0
0.25
0.25
-OMe
-Me
1.25
1.25
a Yield of analytically pure material.
a Measured by 1H NMR spectroscopy vs hexamethylbenzene as
an internal standard. b As determined by 1H NMR spectroscopy.
TABLE 6. Optimization of Cross-Couplings of 9 with
4-Iodotoluene
SCHEME 4
9,
18,
Cu(OAc)2, 20,a
entry equiv equiv
solvent
equiv
%
20/19b
(Scheme 4). Reaction of 6 with 4-iodonitrobenzene af-
forded 13 in a 57% yield.
1
2
3
4
5
6
1.1
1.1
1.1
1.0
1.0
1.0
1.0
1.0
1.0
1.25
1.5
2.0
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
0.25
0.25
0
44
51
65
72
80
76
1:1.2
1.3:1
1.6:1
2.5:1
3.7:1
3.2:1
Next, the cross-coupling of 4 with an electron-rich aryl
halide, 4-iodoanisole, was investigated. Using same cross-
coupling conditions as above, significant amounts of
protodesilylation product, 11, was observed (Table 4,
entry 1). Decreasing the Cu(OAc)2 loading and increasing
the reaction temperature improved conversion to product
14 while suppressing the formation of 11 (entries 2-4).
Without Cu(OAc)2, the rate of reaction was impractically
slow and the amount of 11 was decreased only slightly
(entry 5).
0
0
0
a Measured by 1H NMR spectroscopy vs hexamethylbenzene as
an internal standard. b As determined by 1H NMR spectroscopy.
of aryl iodide was increased to 1.25 equiv reaction of 6
afforded 16 in 52% yield (entry 3) and 17 in 56% yield
(entry 4).
The cross-coupling reaction of 4 with 4-iodoanisole
afforded 14 in a 62% yield (Table 5, entry 1) whereas the
reaction of 4 with 4-iodotoluene afforded 15 in a 61% yield
(entry 2). The use of silanol 6, in which the 5-substituent
is now a methyl group, resulted in consumption of the
aryl iodide before consumption of 6. When the amount
The cross-coupling of a sterically congested silanol
bearing phenyl substituents at the C(3) and C(5) posi-
tions, substrate 9, was studied. At 80 °C in toluene with
25 mol % of Cu(OAc)2, a large amount of the product from
protodesilylation, 19, was observed (Table 6, entry 1).
Changing the solvent to dioxane resulted in moderate
J. Org. Chem, Vol. 70, No. 7, 2005 2841

TABLE 7. Summary of Cross-Coupling Reactions of 9
and 10
0.2 equiv) in toluene (8.75 mL) was added via syringe pump over
5.5 h. After 6 h, the mixture was cooled to room temperature.
Diethyl ether (20 mL) was added to the yellow reaction mixture,
and the slurry was filtered and eluted with Et2O (3 × 20 mL).
The filtrate was concentrated in vacuo to afford a yellow oil that
was dissolved in CH3CN (115 mL) and treated with a 1.0 M
aqueous HOAc solution (46 mL). The yellow solution was stirred
at room temperature for 2 h. The reaction mixture was trans-
ferred to a separatory funnel with CH2Cl2 (50 mL). After addition
of H2O (50 mL) and brine (50 mL), the aqueous layer was back
extracted with CH2Cl2 (25 mL). Concentration of the combined
organic layers in vacuo afforded the crude silanol. Purification
by column chromatography (SiO2, 60 mm × 15 cm, Florisil,
60 mm × 1 cm, CH2Cl2/acetone 97/3) and then a second column
chromatography (SiO2, 50 mm × 20 cm, Florisil, 60 mm × 1
cm, pentane/Et2O 2/1) followed by trituration of the resulting
light yellow solid using pentane/Et2O (15/1) afforded 1.40 g (49%)
of 4 as a white solid. Data for 4: mp 63-64 °C (pentane/ether);
1H NMR (500 MHz, CDCl3) δ 7.58 (dd, J ) 7.7, 1.6, 2 H, HC(7)),
7.44 (m, 3 H, HC(8), HC(9)), 2.81 (q, J ) 7.6, 2 H, HC(11)), 2.60
(s, 1 H, H(OSi)), 1.33 (t, J ) 7.6, 3 H, H(C12)), 0.29 (s, 6 H,
HC(10)); 13C NMR (126 MHz, CDCl3) δ 175.4 C(5), 168.6 C(3),
130.1 C(7), 129.5 C(6), 128.8 C(8) or C(9), 128.4 C(8) or C(9),
107.8 C(4), 20.9 C(11), 12.9 C(12), 1.8 C(10); IR (film) 3369 (br
s), 2976 (m), 1612 (w), 1558 (m), 1499 (w), 1460 (m), 1445 (m),
1388 (m), 1257 (s), 1073 (w), 879 (s), 825 (s), 770 (s); MS (EI,
70 eV) 247 (49, M+), 233 (20), 232 (100), 214 (27), 186 (13), 137
(19), 128 (21), 105 (12), 77 (47), 75 (29); Rf 0.26 (pentane/Et2O,
2/1) [silica gel, UV]. Anal. Calcd for C13H17NO2Si: C, 63.12; H,
6.93; N, 5.66. Found: C, 63.12; H, 6.98; N, 5.77.
3-Ethyl-4-(4-nitrophenyl)-5-phenylisoxazole (12). In an
oven-dried 5-mL, round-bottom flask containing a magnetic stir
bar were placed NaO-t-Bu (0.240 g, 2.5 mmol, 2.5 equiv) and
Cu(OAc)2 (0.181 g, 1.0 mmol, 1.0 equiv) in a drybox. After
removal of the flask from the drybox, 4-iodonitrobenzene
(0.249 g, 1.0 mmol) and Pd2(dba)3‚CHCl3 (0.052 g, 0.05 mmol,
0.05 equiv) were added. The flask was fitted with an argon inlet
adaptor capped with a septum. Toluene (1.5 mL) was added. The
reaction mixture was heated to 40 °C for 10 min followed by
addition of 4 (0.272 g, 1.1 mmol, 1.1 equiv). After being heated
3 h at 40 °C, the mixture was cooled to room temperature and
was diluted with EtOAc (3 mL). The resulting mixture was
filtered through a SiO2 plug (2 cm × 2 cm) and eluted with
EtOAc (30 mL), and the filtrate was concentrated in vacuo to
afford a yellow oil. Purification of the oil by column chromatog-
raphy (SiO2, 40 mm × 20 cm, CH2Cl2) then (SiO2, 20 mm ×
25 cm, hexanes/EtOAc, 5/1) afforded a yellow solid that was
further purified by recrystallization from hexanes to afford
0.228 g (78%) of 12 as light yellow needles. Data for 12: mp
96-97 °C (hexanes); 1H NMR (500 MHz, CDCl3) δ 8.30
(d, J ) 9.0, 2 H, HC(12)), 7.49 (d, J ) 9.0, 2 H, HC(11)), 7.46
(dt, J ) 6.9, 1.5, 2 H, HC(7)), 7.40 (tt, J ) 7.5, 1.5, 1 H, HC(9)),
7.35 (tt, J ) 7.5, 0.9, 2 H, HC(8)), 2.68 (q, J ) 7.6, 2 H, HC(14)),
1.22 (t, J ) 7.6, 3 H, HC(15)); 13C NMR (126 MHz, CDCl3)
δ 165.6 C(5), 164.0 C(3), 147.6 C(13), 138.0 C(10), 130.8 C(12),
130.3 C(9), 128.9 C(7), 127.12 C(8), 127.09 C(6), 124.3 C(11),
113.7 C(4), 18.9 C(14), 12.0 C(15); IR (KBr) 2977 (w), 1624 (w),
1601 (m), 1519 (s), 1460 (m), 1447 (m), 1425 (w), 854 (s); MS
(EI, 70 eV) 295 (20), 294 (98 M+), 251 (13), 165 (28), 164 (14),
117 (18), 105 (100), 103 (17), 78 (10), 77 (89), 62 (35); Rf 0.73
(CH2Cl2). Anal. Calcd for C17H14N2O3: C, 69.38; H, 4.79; N, 9.52.
Found: C, 69.12; H, 4.78; N, 9.42.
entry
silanol
methoda
R′
product
yield,b %
1
2
3
4
5
6
9
9
A
A
A
A
A
B
-Me
20
21
24
22
23
25
69
68
55
60
63
63
-OMe
-NO2
-Me
9
10
10
10
-OMe
-NO2
a Method A: dioxane, 80 °C. Method B: toluene, 40 °C, 1.0 equiv
of Cu(OAc)2. b Yield of analytically pure material.
improvement, whereas elimination of Cu(OAc)2 alto-
gether further improved the ratio of 20/19 (entries 2 and
3). However, in dioxane, a significant amount of the aryl
iodide homocoupling product was also observed. As was
the case with 6, using 1.5 equiv of aryl iodide improved
the conversion to 20 (entries 4-6).
Employing these conditions in the cross-coupling of 9
and 10 with 4-iodotoluene, 4-iodoanisole, and 4-iodonitro-
benzene afforded the products 20-25 in 55-69% yields
(Table 7). The reactions of both 9 and 10 with 4-iodonitro-
benzene in dioxane resulted in poorer ratios of product
to protodesilylation. The cross-coupling of 10 with 4-io-
donitrobenzene could be improved by carrying out the
reaction in toluene at 40 °C with 1.0 equiv of Cu(OAc)2
to afford 25 in 63% yield (entry 6).
In summary, we have developed sequential [3 + 2]-
cycloaddition and cross-coupling reactions for the prepa-
ration of 3,4,5-trisubstituted isoxazoles. Reaction condi-
tions for the two major classes of nitrile oxide cycload-
ditions were developed for silyl ethers to afford the
4-substituted silanols. Both alkyl and aryl substituents
at the 3- and 5-positions of the isoxazole were selectively
incorporated based on the choices of the dipole and
dipolarophile. The subsequent transformation of the
silanol through a cross-coupling reaction provided a wide
array of 3,4,5-trisubstituted isoxazoles. In the develop-
ment of the cross-coupling reaction conditions, the use
of Cu(OAc)2 effected the rate of the cross-coupling reac-
tion; however, in some cases, Cu(OAc)2 also promoted the
protodesilylation of the silanol. Investigations into the
role of Cu(OAc)2 in the silicon-based cross-coupling
reaction as well as application of the sequential cycload-
dition/silicon-based cross-coupling to other families of
five-membered heterocycles are ongoing.
Experimental Section
Acknowledgment. We are grateful to the National
Institutes of Health (GM 63167) for generous financial
support. J.M.K. thanks the University of Illinois for a
graduate fellowship.
General Experimental Procedures. See the Supporting
Information.
3-Ethyl-4-(dimethylhydroxysilyl)-5-phenylisoxazole (4).
In a 50-mL oven-dried round-bottom flask containing a magnetic
stir bar and equipped with a reflux condenser and a nitrogen
inlet adapter capped with a rubber septum were combined 1
(2.19 g, 11.5 mmol), toluene (8.75 mL), phenyl isocyanate
(6.25 mL, 57.5 mmol, 5.0 equiv), and triethylamine (0.32 mL,
2.3 mmol, 0.2 equiv). This solution was heated to reflux under
an atmosphere of N2. A solution of 1-nitropropane (2.56 mL,
28.75 mmol, 2.5 equiv) and triethylamine (0.32 mL, 2.3 mmol,
Supporting Information Available: Detailed synthetic
procedures as well as full characterization of all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO047755Z
2842 J. Org. Chem., Vol. 70, No. 7, 2005