Microwave promoted amination of 3-bromoisoxazoles

Article abstract of DOI:10.1016/j.tetlet.2004.02.135

This Letter describes the amination of 3-bromoisoxazoles by a nucleophilic aromatic substitution reaction. We have found 3-bromoisoxazoles to be inert to substitution under thermal conditions, however, the employment of phosphazene bases under microwave i

Full text of DOI:10.1016/j.tetlet.2004.02.135

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3189–3191
Microwave promoted amination of 3-bromoisoxazoles
Jane E. Moore,a Daniel Spinksb and Joseph P. A. Harritya,*
aDepartment of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
bDepartment of Medicinal Chemistry, Organon Laboratories Ltd., Newhouse, Lanarkshire ML1 5SH, UK
Received 27 January 2004; accepted 27 February 2004
Abstract—This Letter describes the amination of 3-bromoisoxazoles by a nucleophilic aromatic substitution reaction. We have
found 3-bromoisoxazoles to be inert to substitution under thermal conditions, however, the employment of phosphazene bases
under microwave irradiation facilitates the amination process and allows the corresponding 3-aminoisoxazoles to be isolated in
moderate yield.
Ó 2004 Elsevier Ltd. All rights reserved.
We have recently uncovered a regioselective method for
the construction of highly substituted aromatic boronic
esters through a series of cycloaddition reactions of
alkynylboronates.1 In particular, we have found that
fully substituted isoxazoles can be assembled with the
boronate moiety in the 4-position and that these
undergo efficient Suzuki coupling reactions. In an effort
to broaden the synthetic utility of these intermediates,
we opted to investigate some cycloaddition reactions of
bromonitrile oxide in the hope that we could elaborate
at C-4 through cross-coupling reactions and at C-3 by
substitution with an appropriate nucleophile (Scheme
1).2 In the context of the latter transformation, whilst a
small number of alkoxide substitution reactions had
been reported, the corresponding amination process
appeared to be much less general. Specifically, the direct
substitution process was limited to 3-chlorobenzisoxaz-
oles3 whereas substitution of 3-chloroisoxazoles
required a multistep sequence including pre-activation
of the isoxazole ring.4 We decided to examine the fea-
sibility of direct nucleophilic aromatic substitution of
3-bromoisoxazoles and report herein our preliminary
findings.
We initiated our studies by preparing a relatively simple
isoxazole and this was carried out by conducting a [3þ2]
cycloaddition reaction of in situgenerated bromonitrile
oxide with 1-hexyne. We were pleased to find that this
reaction proceeded efficiently to furnish the 3,5-disub-
stituted isoxazole 1a together with a small quantity of its
regioisomer 1b (Scheme 2).
We next turned our attention to the amination reaction
and decided to employ piperidine in our optimisation
studies, the results are summarised in Table 1. We began
by examining thermally promoted amination reactions
and were disappointed to find that 1a was inert to
substitution by piperidine under a range of conditions.
For example, heating the reaction mixture in a sealed
reactivial and in the presence of a nucleophilic catalyst
or the employment of inorganic bases failed to furnish
any of the desired aminoisoxazole 2 (entries 1–3). The
surprisingly sluggish nature of this substitution reaction
prompted us to consider alternative means for promot-
ing the amination process.5 In this context, microwave
Cross-
Coupling
Br
S Ar
N
O
O
O
B
R
Br
N
B O
+
N
O
R
O
Br
Br
Bu-n
Scheme 1.
OH
Br
N
n-Bu
+
Bu-n
KHCO , DME
3
N
N
Br
O
O
50 °C, 16 h, 98%
1a:1b - 8:1
Keywords: Isoxazoles; Microwave irradiation; BEMP; Amination.
* Corresponding author. Tel.: +44-0114-222-9496; fax: +44-0114-222-
9346; e-mail: j.harrity@shef.ac.uk
1a
1b
Scheme 2.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.135

3190
J. E. Moore et al. / Tetrahedron Letters 45 (2004) 3189–3191
Table 1
Table 2
Br
R2N
Br
+
R2NH
N
+
N
N
Bu-n
O
Bu-n
N
O
N
Bu-n
O
N
H
1a
3-6
Bu-n
O
1a
Entry Conditions
2
Entry
1
Substrate
Additivea
Yield
Additive
Yield (%)
BEMP
ps-BEMP
3; 40%
3; 55%
Me
Bn
NH
NH
1
2
3
4
106 °C, 92 ha;b
106 °C, 72 ha
DMF, 153 °C, 120 h
5% DMAP
KOH
Ag2CO3
0
0
BEMP
ps-BEMP
4; 42%
4; 59%
2
3
4
0
57
MW, MeCN, 200 °C, 15 min ps-BEMP
BEMP
ps-BEMP
5; 30%
5; 38%
2-MeOC6H4
NH
NH
a Piperidine used as solvent.
b Reactions heated in a sealed reactivial.
BEMP
ps-BEMP
6; 20%
6; 37%
O
a BEMP mediated reactions were run at 180 °C, MW, for 30 min and
ps-BEMP mediated reactions were run at 200 °C, MW, for 15 min.
(MW) reactors have recently been reported to facilitate
nucleophilic aromatic substitution reactions.6 Addi-
tionally, N-alkylation processes of weakly acidic amines
have been shown to proceed efficiently in the presence of
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-
1,3,2-diazaphosphorine (BEMP).7 We therefore specu-
lated that the conversion of 1a to 2 would be feasible if
the process were run under microwave conditions8 in the
presence of phosphazene base. Accordingly, we sub-
jected a mixture of 1a, piperidine and 1.1 equiv of
polymer supported BEMP (ps-BEMP) to microwave
irradiation at 200 °C in acetonitrile and were pleased to
find that 3-aminoisoxazole 2 was produced in 57% yield
after only 15 min.
Having successfully uncovered conditions to carry out
the amination of 3-bromoisoxazoles our final goal was
to incorporate this technique in sequence with our
alkynylboronate cycloaddition process. As outlined in
Scheme 3, [3þ2] cycloaddition of bromonitrile oxide
with the alkynylboronate proceeded smoothly to furnish
the desired boronic ester as a single regioisomer that
underwent efficient cross-coupling to provide isoxazole
8. Unfortunately, employment of the microwave pro-
moted amination conditions provided 3-aminoisoxazole
9 in a disappointing 30% yield (70% recovery of 8), likely
because of the increased steric demands at C-4.10 More
pleasingly however, we had previously shown that
3-bromoisoxazoles could be substituted by methoxide
under thermal conditions albeit over extensive reaction
times.2 However, the use of microwave irradiation pro-
duced 3-methoxyisoxazole 10 in high yield but in a sig-
nificantly reduced reaction time.
This encouraging result prompted us to investigate the
microwave promoted reaction further. We briefly
examined the substitution reaction of a series of cyclic
amines in the presence of BEMP and ps-BEMP and
found that these conditions furnished the appropriate
2-aminoisoxazoles, albeit in moderate yields. Notably
however, the mass balance of isoxazole material con-
sisted of starting bromide 1a that was readily recovered
after column chromatography. Therefore the moderate
yields reported in Table 2 are a consequence of low
reaction conversion and not compound decomposition.
We have found that ps-BEMP provides optimum yields
of amination product over solution phase BEMP. This
is likely due to the fact that the former reagent can be
heated at 200 °C whereas the latter base is restricted to
reaction temperatures of 180 °C.9
In conclusion, we have demonstrated that the amination
reaction of 3-bromoisoxazoles is promoted by micro-
wave irradiation in the presence of phosphazene bases.
Notably, the reactions do not take place under thermal
conditions and whilst the corresponding 3-aminoisox-
azoles are generated in only moderate yield, the reac-
tions are clean and starting isoxazole can be efficiently
recovered.
O
B
n-Bu
O
B O
Ph-I
Br
Ph
Bu-n
OH
Br
O
Br
N
10 mol% PdCl (dppf)
2
K PO , dioxane, 85 °C
KHCO , DME
N
3
4
3
Br
N
O
Bu-n
98%
50 °C, 16 h, 44%
O
7
8
Ph
Br
Ph
Bu-n
MeO
Ph
N
N
N
N
Bu-n
Bu-n
O
O
O
9
8
10
KOH, MeOH, 65 °C, 3 d; 66%
MW, KOH, MeOH, 160 °C,
60 min.; 70%
MW, Piperidine, MeCN,
BEMP, 180 °C, 90 min.; 30%
Scheme 3.

J. E. Moore et al. / Tetrahedron Letters 45 (2004) 3189–3191
3191
6. Li, W.; Yun, L.; Wang, H. Synth. Commun. 2002, 32,
€
Acknowledgements
2657; For an excellent review see: Lidstrom, P.; Tierney,
J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225.
7. (a) Schwesinger, R.; Wiharedt, J.; Schlemper, H.; Keller,
M.; Schmitt, D.; Fritz, H. Chem. Ber. 1994, 127, 2435; (b)
Xu, W.; Mohan, R.; Morrissey, M. M. Bioorg. Med.
Chem. Lett. 1998, 8, 1089; (c) Habermann, J.; Ley, S. V.;
Scott, J. S. J. Chem. Soc., Perkin Trans. 1 1999, 1253.
8. Microwave promoted reactions were carried out using an
Emryse Optimiser EXP instrument with ‘Fixed Hold
Time’ set to ‘Off ’ and ‘Absorption Level’ set to ‘High’.
Representative experimental procedure: The starting bromo-
isoxazole 1a (0.20 g, 0.98 mmol) was weighed into a
microwave process vial. ps-BEMP (0.45 g, 1.0 mmol),
acetonitrile (0.5 mL) and piperidine (0.97 mL, 9.8 mmol)
were added sequentially. The vial was sealed and irradi-
ated in the microwave (200 °C, 900 s, 9 bar). The vial was
cooled to room temperature and the ps-BEMP filtered off.
The filtrate was concentrated in vacuo and purified by flash
column chromatography (eluting solvent 4:1:0.1
heptane:ethyl acetate:triethylamine) to give aminoisoxaz-
ole 2 as a yellow oil wt. 0.120 g, 57% yield. 1H NMR
(400 MHz, CDCl3): d 0.93 (3H, t, J ¼ 7:28 Hz), d 1.33–
1.48 (2H, m), d 1.56–1.68 (8H, m), d 2.61 (2H, t,
J ¼ 7:53 Hz), d 3.22–3.31 (4H, m), d 5.6 (1H, s). 13C
NMR (62.9 MHz, CDCl3) d: 13.7, 22.2, 24.2, 25.1, 26.8,
We gratefully acknowledge funding from the EPSRC
and Organon and Dr. Mark York for helpful discus-
sions.
References and notes
1. (a) Davies, M. W.; Johnson, C. N.; Harrity, J. P. A. Chem.
Commun. 1999, 2107; (b) Davies, M. W.; Johnson, C. N.;
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M. W.; Wybrow, R. A. J.; Johnson, C. N.; Harrity, J. P.
A. Chem. Commun. 2001, 1558.
2. Moore, J. E.; Goodenough, K. M.; Spinks, D.; Harrity,
J. P. A. Synlett 2002, 2071.
3. Amination reactions of 3-chlorobenzisoxazole derivatives
have been reported: (a) Yevich, J. P.; New, J. S.; Smith, D.
W.; Lobeck, W. G.; Catt, J. D.; Minielli, J. L.; Eison, M.
S.; Taylor, D. P.; Riblet, L. A.; Temple, D. L. J. Med.
Chem. 1986, 29, 359; (b) Boeshagen, H. Chem. Ber. 1967,
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69, 70; (d) Villalobos, A.; Blake, J. F.; Biggers, C. K.;
Butler, T. W.; Chapin, D. S.; Chen, Y. L.; Ives, J. L.;
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1995, 6, 321.
29.49, 29.7, 48.3, 91.8, 167.5, 173.3 ppm. FT-IR: (mmax
/
CHCl3) 1448 (s), 1505 (m), 1613 (s), 1698 (m), 2858 (s),
2931 (s) cmꢀ1. HRMS (EIþ): calcd for C12H20N2O
208.1576, found: 208.1572.
4. Sugai, S.; Sato, K.; Kataoka, K.; Iwasaki, Y.; Tomita, K.
Chem. Pharm. Bull. 1984, 32, 530.
5. Attempts at transition metal catalysed amination reactions
failed and starting material was recovered in all cases. For
a review of Pd-catalysed amination reactions see: Hartwig,
J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
9. The microwave reactor would not tolerate heating reac-
tion mixtures containing solution phase BEMP to tem-
peratures >180 °C because of the high pressures generated
inside the reaction vessel.
10. ps-BEMP was found to decompose over the extended
reaction times required for conversion of 8 into 9.