Synthesis of 3-haloisoxazole boronic esters: Novel heterocyclic synthetic intermediates containing independently variable functionality

Article abstract of DOI:10.1055/s-2002-35595

The regioselective cycloaddition reaction of nitrile oxides with alkynylboronates has been exploited in the preparation of 3-bromo- and 3-chloroisoxazolyl-4-boronates. The synthetic potential of these intermediates has been explored through a number of cr

Full text of DOI:10.1055/s-2002-35595

LETTER
2071
Synthesis of 3-Haloisoxazole Boronic Esters: Novel Heterocyclic Synthetic
Intermediates Containing Independently Variable Functionality
Synthesis
aof 3-Halois
n
oxazole
B
oro
e
nic
E
ster
s
E. Moore,a Katharine M. Goodenough,a Daniel Spinks,b Joseph P.A. Harrity*a
a
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK
E-mail: j.harrity@sheffield.ac.uk
b
Department of Medicinal Chemistry, Organon Laboratories Ltd., Newhouse, Lanarkshire, ML1 5SH, UK
Received 3 October 2002
Abstract: The regioselective cycloaddition reaction of nitrile ox-
ides with alkynylboronates has been exploited in the preparation of
3-bromo- and 3-chloroisoxazolyl-4-boronates. The synthetic poten-
tial of these intermediates has been explored through a number of
cross coupling reactions of the boronic ester unit and some repre-
sentative reactions of the heteroaryl halide moiety.
O
B
O
O
X
N O
O
X
R
B
N
R
O
A
A
B
X
B(OR)2 → A
X → B
Key words: regioselective, cycloadditions, Suzuki coupling,
isoxazole
N
N
R
R
O
O
Scheme 1
The development of parallel synthesis for the high
throughput screening of biologically active compounds
has provided much impetus for the design of intermedi-
ates, which may be manipulated in an independent and or-
thogonal manner.1 In terms of synthetic flexibility,
aromatic and heteroaromatic boronic esters are particular-
ly noteworthy. They participate readily in Pd-catalysed
coupling reactions with aryl and vinyl halides (Suzuki
coupling reaction),2 they permit carbon-heteroatom bond
formation to provide amines and ethers3 and they have
also been shown to participate in nucleophilic addition re-
actions to imines, aldehydes and enones.4 We have recent-
ly been investigating a new approach to aryl boronic
esters through the employment of cycloaddition reactions
of alkynylboronates and have found this approach to be
particularly powerful for the concise preparation of these
valuable synthetic intermediates.5 Indeed, we have report-
ed that the [3+2] cycloaddition reaction of nitrile oxides
with alkynylboronates provides a regioselective method
for the synthesis of isoxazole boronic esters.5c Whilst
these compounds proved to be good precursors to further
isoxazole derivatives through Suzuki coupling reactions,
the cycloadducts were limited to a single point of diversity
arising from the boronate functional group. We were
therefore intrigued by the notion of employing an alterna-
tive nitrile oxide substrate which would furnish isoxazoles
with two readily and independently manipulated points
for further elaboration, thus enhancing the diversity of
compounds which may potentially arise from these inter-
mediates (Scheme 1).
3-haloisoxazoles6 and surmised that the utilisation of
alkynylboronates in this process would furnish an isox-
azole with boronic ester and halide groups which would
act as suitable points for further manipulation of the het-
eroaromatic cycloadduct. We therefore initiated our stud-
ies by examining the cycloaddition reaction of
bromonitrile oxide (generated in situ from 1) with 2-phe-
nylethynyl-4,4,5,5-tetramethyl[1,3,2]dioxaborolane 2a,
an air stable and readily prepared crystalline solid, the re-
sults are summarised in Table 1. We initially employed a
slow addition of triethylamine to the reaction mixture in
an effort to generate a low concentration of bromonitrile
oxide (and hence minimise unwanted nitrile oxide dimer-
isation). We were pleased to find that the desired cycload-
dition had taken place and, by analogy to our previous
studies, that a single regioisomer 3a was produced. Un-
fortunately, the product yields could not be raised above
10–15% and from a practical viewpoint; the necessity of
a syringe pump for controlled slow addition limited the
progress of our optimisation studies. With a view to cir-
cumventing these practical problems, we were intrigued
by reports which employed a suspension of a metal bicar-
bonate in a solution of dibromoformaldoxime 1 and
alkyne.7 Presumably, the low basicity and low solubility
of the bicarbonate permits the slow generation of nitrile
oxide and minimises dimerisation. Indeed, the employ-
ment of sodium bicarbonate in CH2Cl2 proved to dramat-
ically enhance the efficiency of the desired cycloaddition
reaction and we were pleased to isolate a 56% yield of 3a.
Finally, after further optimisation we found that heating a
suspension of the substrates in DME at 50 °C in the pres-
ence of KHCO3 resulted in an increased yield of 69% over
a reduced reaction time of 16 h. The employment of
these conditions was also found to provide n-Bu- and Me-
substituted isoxazoles 3b–c as single regioisomers.8 The
regiochemistry of the cycloaddition was established by
We were aware of the ability of bromo- and chloronitrile
oxides to react with alkynes to generate the corresponding
Synlett 2002, No. 12, Print: 02 12 2002.
Art Id.1437-2096,E;2002,0,12,2071,2073,ftx,en;D19402ST.pdf.
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ISSN 0936-5214

2072
J. E. Moore et al.
LETTER
Table 1 Synthesis of Bromoisoxazole Boronic Esters
Table 2 Suzuki Cross-Coupling Reactions
O
O
B
O
R
B
X
R
10 mol% PdCl2(dppf)
OH
X
X
O
O
X
B
O
N
2a-c
K3PO4, Dioxane, 85 °C
R2-X
N
R1
N
R1
O
X
N
O
3b-d
R
O
4-10
1
3a-d
Entry
R1; X
R2X
Yield
Entry
1
R
X
Conditions
Yield
1
2
3
4
5
6
7
8
n-Bu; Br 3b
n-Bu; Br 3b
Me; Br 3c
PhBr
4: 47%
4: 98%
5: 89%
6: 73%
7: 87%
8: 70%
9: 99%
10: 92%
Ph; 2a
Ph; 2a
Ph; 2a
Br
Br
Br
Br
Br
Cl
Et3N, Et2O, 35 °C,
48 h
3a: 14%
Phl
2
3
4
5
6
NaHCO3, CH2Cl2,
25 °C, 72 h
3a: 56%
3a: 69%
3b: 44%
3c: 40%
3d: 44%
Phl
n-Bu; Br 3b
n-Bu; Br 3b
n-Bu; Br 3b
n-Bu; Cl 3d
n-Bu; Cl 3d
p-NO2C6H4I
o-NO2C6H4I
p-MeOC6H4I
Phl
KHCO3, DME,
50 °C, 16 h
n-Bu; 2b
Me; 2c
KHCO3, DME,
50 °C, 16 h
KHCO3, DME,
50 °C, 16 h
p-NO2C6H4I
n-Bu; 2a
KHCO3, DME,
50 °C, 16 h
incorporated in the 3-position from the appropriate nitrile
oxides,5c we were particularly attracted to the installment
of heteroatom containing groups via SNAr reactions. Ac-
cordingly, treatment of bromoisoxazole 4 with methanol-
ic-KOH resulted in smooth conversion to ether 11 in good
yield.12 The corresponding chloride 9 was found to be less
reactive and furnished 11 in lower yield. Unfortunately,
all attempts to introduce amines and thiols by this route
failed and resulted in the return of starting material or de-
composition.13 Finally, we were pleased to find that ester
functionality could be readily introduced at C-3 via the
isoxol-3-one intermediate. Therefore, hydrolysis of 11
followed by benzoylation14 provided ester 12 in good
overall yield (Scheme 2).
X-ray crystallographic analysis of 3a9,10 and was found to
mirror that observed in previous studies in our labora-
tories.5c Unsurprisingly, chloroisoxazole boronic ester 3d
was generated by following the same reaction course.
With a reliable method for the synthesis of 3-haloisox-
azole boronic esters in hand, we turned our attention to the
independent elaboration of both functional groups. In con-
sidering which of these groups to examine first, we felt
that the sensitivity of the isoxazole boronic esters to pro-
todeboronation under basic conditions would thwart most
attempts to manipulate the halide in compounds 3. In con-
trast, we felt confident that we could carry out selective
Pd-catalysed coupling reactions at the isoxazole boronate
whilst avoiding unwanted reactions at the adjacent bro-
mide or chloride by judicious choice of the substrate aryl
halide. As outlined in Table 2, initial attempts to couple
isoxazole 3b with bromobenzene provided a modest yield
of 4 together with minor amounts of protodeboronated
isoxazole as the only identifiable products (entry 1). No-
tably however, the mass balance of this reaction seldom
exceeded 60% and we were unable to clarify the fate of
the remaining isoxazole material. Accordingly, we inves-
tigated the coupling reaction of the more reactive iodo-
benzene and were pleased to observe that the Suzuki cross
coupling reaction took place to provide 4 in an improved
98% yield (entry 2). Examination of similarly activated
systems proved to be successful although notably lower
yields were observed when an electron rich aryl iodide
was employed (entry 6).11
X
MeO
Ph
Bu-n
Ph
Bu-n
KOH
X=Br, 66%
X=Cl, 42%
N
N
MeOH
65 °C, 3 d
O
O
11
Ph
MeO
Ph
1. HBr, AcOH
O
Ph
Bu-n
58%
O
2. PhCOCl, pyr.
Bu-n
N
N
O
11
O
12
Scheme 2
In conclusion, the [3+2] cycloaddition reaction of haloni-
trile oxides with alkynylboronates provides an expedient
route to functionalised isoxazole products. Whilst the Su-
zuki coupling reaction of these intermediates proceeds in
high yield with aromatic iodides, functionalisation of the
3-isoxazolyl halide was found to be more limited. A thor-
ough investigation of the elaboration of these intermedi-
ates is underway and will be described in a full account of
this work.
It now only remained to explore the scope of elaboration
of the remaining isoxazole bromide and chlorides. Given
the relative simplicity with which alkyl/aryl groups can be
Synlett 2002, No. 12, 2071–2073 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Haloisoxazole Boronic Esters
2073
4.24; Br, 24.21. Found: C, 47.33; H, 6.58; N, 4.23; Br, 24.18.
HRMS calcd for C13H22BNO379Br (MH+): 330.0871, Found:
330.0876. HRMS calcd for C13H22BNO381Br (MH+):
332.0851, Found: 332.0847.
Acknowledgement
The authors gratefully acknowledge financial support from the
EPSRC, Organon Laboratories Ltd. and the University of Sheffield.
We also thank Mr. Harry Adams for assistance in obtaining X-ray
data.
(9) The X-ray data for isoxazole 3a has been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 191718.
(10) For X-ray data of related isoxazole boronic esters see:
Harrity, J. P. A.; Adams, H.; Davies, M. W.; Wybrow, R. A.
J.; Johnson, C. N. Acta Cryst. 2002, C58, o168.
References
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(2) For comprehensive reviews, see: (a) Suzuki, A. Pure Appl.
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Rev. 1995, 95, 2457.
(3) (a) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077.
(b) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett.
1998, 39, 2937.
(4) (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997,
119, 445. (b) Ueda, M.; Miyaura, N. J. Org. Chem. 2000, 65,
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(8) Representative experimental procedure for cyclo-
addition reactions: 3-Bromo-5-butyl-4-(4,4,5,5-
tetramethyl-[1,3,2]dioxaborolan-2-yl)-isoxazole 3b: A
solution of 2-hexyn-1-yl-4,4,5,5-tetramethyl-[1,3,2]dioxa-
boralane (0.90 g, 4.32 mmol), dibromoformaldoxime (0.877
g, 4.32 mmol) and KHCO3 (0.866 g, 8.65 mmol) in
dimethoxyethane (5 mL) was stirred for 12 h at 50 ºC. The
reaction mixture was cooled, the residual solid removed by
vacuum filtration and the solvent removed in vacuo.
Purification by flash chromatography eluting with hexane–
EtOAc, (15:1) followed by kugelrohr distillation 110 °C/ 0.4
mmHg gave the title compound as a colourless oil (0.627g,
44% yield). 1H NMR (250 MHz, CDCl3): 0.91 (3 H, t, J =
7.0 Hz), 1.22–1.41 (2 H, m), 1.31 (12 H, s), 1.58–1.73 (2 H,
m), 2.94 (2 H, t, J = 7.0 Hz). 13C NMR (62.9 MHz, CDCl3)
13.5, 22.0, 24.8, 26.8, 30.1, 83.8, 144.5, 183.6. FTIR
(CHCl3/cm–1): 2978 (s), 2934 (s), 2874 (s), 1741 (m), 1589
(s). Anal. calcd for C13H21BNO3Br: C, 47.31; H, 6.41; N,
(11) Representative experimental procedure for Suzuki
coupling reactions: 3-Bromo-5-butyl-4-(2-nitrophenyl)-
isoxazole 7: A solution of boronic ester 3b (0.05 g, 0.15
mmol), PdCl2(dppf) CH2Cl2 (0.012 g, 0.015 mmol), 1-iodo-
2-nitrobenzene (0.075 g, 0.30 mmol) and K3PO4 (0.096 g,
0.45 mmol) in dioxane (1 mL) was stirred at 85 °C under N2
atmosphere for 16 h. The reaction was quenched with
deionised water (10 mL), and allowed to cool to room
temperature. The product was extracted into CH2Cl2 (3 10
mL) and the organic layer washed with saturated brine (10
mL), dried (MgSO4), filtered and the filtrate was
concentrated in vacuo to give a brown solid. Purification by
flash chromatography eluting with hexane–EtOAc (100:1)
gave the title compound as yellow oil (0.043 g, 87% yield).
1H NMR (250 MHz, CDCl3): 0.77 (3 H, t, J = 7.0 Hz),
1.13–1.31 (2 H, m), 1.46–1.61 (2 H, m), 2.61 (2 H, t, J = 7.0
Hz), 7.28 (1 H, dd, J = 7.0 Hz, 7.5 Hz), 7.51–7.73 (2 H, m),
8.10 (1 H, dd, J = 8.0 Hz, 1.0 Hz). 13C NMR (62.9 MHz,
CDCl3) 13.5, 22.1, 25.9, 29.1, 114.8, 123.3, 125.2, 130.2,
133.4, 141.6, 149.1, 171.4. FTIR (CHCl3/cm–1): 2960 (m),
1633 (m), 1601 (m), 1529 (m), 1441 (m). Anal. calcd for
C13H13BrN2O3: C, 48.02; H, 4.03; N, 8.62; Br, 24.57. Found:
C, 48.30; H, 4.12; N, 8.42; Br, 24.66. HRMS calcd for
C13H14N2O379Br (MH+): 325.0188. Found: 325.0189. HRMS
calcd for C13H14N2O381Br (MH+): 327.0168. Found:
327.0165.
(12) Gagneux, A. R.; Häfleger, F.; Geigy, G. R.; Basle, S. A.;
Eugster, C. H.; Good, R. Tetrahedron Lett. 1965, 25, 2077.
(13) Preliminary investigations indicate that 3-haloisoxazoles 4–
10 are relatively unreactive towards Pd-catalysed coupling
reactions, nonetheless, there is substantial scope for the
optimisation of this process and these studies are ongoing in
our labs. In contrast, the introduction of amines by SNAr
reactions has been demonstrated: Yevich, J. P.; New, J. S.;
Smith, D. W.; Lobeck, W. G.; Catt, J. D.; Minelli, J. L. J.
Med. Chem. 1986, 29, 359.
(14) Bauer, L.; Nambury, C. N. V.; Bell, C. L. Tetrahedron 1967,
23, 4395.
Synlett 2002, No. 12, 2071–2073 ISSN 0936-5214 © Thieme Stuttgart · New York