Unexpected ring-expansion of 1,2-benzisoxazol-3-ones

Article abstract of DOI:10.1016/j.tetlet.2011.10.027

A novel and unexpected ring-expansion reaction of 1,2-benzisoxazol-3-ones is identified. The scope of this reaction is exemplified and the proposed mechanism is also implicated in another degradation process. This reaction also represents a new method for accessing the 4H-1,3-benzoxazin-4-one skeleton.

Full text of DOI:10.1016/j.tetlet.2011.10.027

Tetrahedron Letters 52 (2011) 6775–6778
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Unexpected ring-expansion of 1,2-benzisoxazol-3-ones
⇑
Steven A. Raw , Anne M. O’Kearney-McMullan, Mark A. Graham
Medicines Evaluation Chemistry, Pharmaceutical Development, AstraZeneca, Charter Way, Macclesfield SK10 2NA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 July 2011
Revised 13 September 2011
Accepted 7 October 2011
Available online 14 October 2011
A novel and unexpected ring-expansion reaction of 1,2-benzisoxazol-3-ones is identified. The scope of
this reaction is exemplified and the proposed mechanism is also implicated in another degradation pro-
cess. This reaction also represents a new method for accessing the 4H-1,3-benzoxazin-4-one skeleton.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ring-expansion
1
1
,2-Benzisoxazol-3-one
,3-Benzoxazin-4-one
Vilsmeier
Microwave-assisted synthesis
The construction and subsequent functionalisation of densely-
substituted and/or unusual heterocyclic skeleta is a recurrent
theme in industrial and academic research groups alike. Further-
more, there is a growing desire within the pharmaceutical industry
As part of an ongoing research programme, we had reason to
investigate the functionalisation of polysubstituted 1,2-benzisox-
azoles containing a protected aldehyde moiety. To this end, we at-
tempted a microwave-mediated chlorination of a 1,2-benzisoxazol-
3-one containing a reasonably robust pinacol acetal 1b. ‘Standard’
1
to access hitherto unexplored chemical space. Increasingly there-
fore, synthetic chemists might expect to encounter individual sub-
strates, or even classes of substrates, which do not perform well in
otherwise standard methodologies. The research described herein
highlights this point, albeit on a relatively common heterocyclic
skeleton.
conditions using POCl
3
with or without a solvent (e.g., acetonitrile)
O
Cl
POCl3
The 1,2-benzisoxazole motif is a common pharmacophore and,
as such, is found in a wide range of pharmaceutically active com-
HN
O
N
O
microwave,
50 °C, 2 h
2
1
pounds. Due to this biological importance, construction and sub-
1a
2
a, 94%
sequent functionalisation of 1,2-benzisoxazoles has attracted
3
,4
much interest. One of the more common methods used for func-
O
tionalisation at the 3-position is chlorination of the corresponding
4
Morpholine,
MeCN,
1
,2-benzisoxazol-3-one followed by reaction with a nucleophile
N
(
e.g., see Scheme 1).
N
As can be seen in this example, however, the conditions used
microwave,
130 °C, 1 h
O
are often quite harsh. Indeed, it appears that chlorination of the
isoxazol-3-one unit in general is a difficult transformation. For
example, as well as the microwave-mediated chemistry outlined
above, Andersen and Begtrup found it necessary to develop highly
acidic thermal conditions to accomplish chlorination of 4,5,6,7-
3
a, 84%
Scheme 1. Functionalisation of a 1,2-benzisoxazol-3-one.4a
3 3 4
tetrahydroisoxazolo[4,5-c]pyridin-3-ones (POCl , H PO and pyrid-
inium hydrochloride at reflux).5 As one might expect, neither
methodology lends itself to application in the presence of sensitive
functionality.
O
Cl
N
R
POCl , Pyr.HCl,
R
3
H
O
O
Cl
Cl
PO
3
4
HN
O
microwave,
O
100 °C, 0.5 h
1b
2b, 27%
⇑
Corresponding author.
E-mail address: steven.raw@astrazeneca.com (S.A. Raw).
Scheme 2. Chlorination of an acetal-bearing 1,2-benzisoxazolone.
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.027

6
776
S. A. Raw et al. / Tetrahedron Letters 52 (2011) 6775–6778
resulted in no conversion. When the more forcing acidic conditions
developed by Andersen and Begtrup were attempted, the only
product isolated from this reaction was 3-chloro-1,2-benzisoxazole
derivative 2b in which the pinacol acetal had been transformed into
a gem-dichloromethyl moiety (Scheme 2).
Table 1
Substrate scope of the ring-expansion8
Entry
Substrate
Product
Yield (%)
51
O
O
O
A subsequent survey of the literature identified only one exam-
N
N
HN
O
1
ple of the chlorination of a 2-oxoazacycle bearing a pendant acetal
6
unit. This employed a Vilsmeier POCl
3
/DMF reagent system, a
1c
common alternative when confronted with stubborn substrates.
When we applied these milder conditions to our densely-func-
tionalised substrate 1b, we were pleased to observe relatively clean
4b
O
O
N
conversion by HPLC to a new product which then crystallized di-
HN
O
1
2
3
4
5
6
57
76
rectly from the reaction mixture. However, analysis by LCMS,
H
N
N
O
1
3
and C NMR spectroscopy was inconsistent with the desired 3-
chloro-1,2-benzisoxazole. The product was identified as 2-(dimeth-
1
a
4c
O
7
ylamino)-4H-1,3-benzoxazin-4-one derivative 4a (Scheme 3).
O
Given the intrinsic incompatibility of our substrate with com-
mon chlorination methodologies, we did not pursue this strategy
any further in terms of target molecule delivery. Nevertheless,
we were keen to understand if this unexpected ring-opening reac-
tion pathway observed was specific to our densely-substituted 1,2-
benzisoxazol-3-one 1b or if it was a general effect. To this end, we
subjected a range of 1,2-benzisoxazol-3-ones to the general reac-
N
HN
O
F
O
F
F
F
1
d
1
4d
O
O
O
8
N
N
HN
tion conditions and, in all cases, we found the predominant reac-
24
O
tion pathway to be that leading to the ring-expanded 4H-1,3-
benzoxazin-4-one products 4. The results are summarized in Table
Cl
N
N
Cl
e
4
e
1. As can be seen, the ring-opening pathway appears to be general
O
O
O
O
O
to 1,2-benzisoxazol-3-ones (entries 1–4). It is noteworthy that 7-
methyl-1,2-benzisoxazol-3-one (1a) gives the corresponding 4H-
HN
1
,3-benzoxazin-4-one 4c (entry 2) as this substrate furnishes the
a
O
OMe
OMe
expected 3-chloro-1,2-benzisoxazole (2a) when reacted with neat
4
a
O
O
3
POCl (Scheme 1). The mechanism also operates when 1,2-iso-
5
a
6
a
xazol-3-ones 5a,b are employed (entries 5 and 6), though we found
the corresponding 4H-1,3-oxazin-4-one products 6a,b were unsta-
ble to isolation and consequently were only detected using analyt-
ical methods. We then went on to investigate the fate of the related
O
N
HN
b
O
1
,2-benzisothiazol-3-one 7 and indazol-3-one 9 skeleta under
N
5
b
these conditions. Neither appeared susceptible to such a ring-
expansion mechanism: the 1,2-benzisothiazol-3-one furnished
the expected 3-chloro-1,2-benzisothiazole 8 (entry 7) and the
indazol-3-one 9 did not react under these conditions (entry 8).
Having examined the substrate-scope in terms of the heterocy-
clic component, we also investigated the performance of a range of
6
b
O
Cl
7
8
HN
N
83
—
S
S
7
8
O
O
HN
HN
Cl
R
N
N
O
Bn
9
Bn
O
R
N
9
POCl ,DMF,
X
O
O
3
toluene
O
O
HN
a
Product confirmed by LC–MS and 2D NMR spectroscopy, not isolated or
purified.
O
20 °C, 0.5 h
1
b
b
Product visible as a minor component, confirmed by LC–MS and GC–MS only.
O
O
N+
R
O
O
N
Cl
H
N
O
R
R
4a, 21%
N
O
1
,2 eq. POCl3,
.2 eq. R NCHO,
Cl
N
O
O
O
1
H
O
O
2
toluene
N
HN
O
60 °C,10 min
F
2
R N
F
O
O
O
F
F
R
O
O
O
H
N
N
1d
NR =pyrrolidine, 4f, 78%
2
N
Cl
Cl
O
H
O
NR =piperidine, 4g, 67%
2
N
NR =morpholine, 4h, 62%
2
Scheme 3. Unexpected ring-expansion to a 4H-1,3-benzoxazin-4-one.
Scheme 4. Alternative N-formyl amines in the ring-expansion.8

S. A. Raw et al. / Tetrahedron Letters 52 (2011) 6775–6778
6777
formamides in this methodology. The results are summarized in
Scheme 4. As shown, in addition to N,N-dimethylformamide
In summary, we have identified a new ring-expansion11 of 1,2-
benzisoxazol-3-ones mediated by Vilsmeier reagents which results
in the incorporation of the N-formylamine moiety into the N–O
bond furnishing 4H-1,3-benzoxazin-4-ones 4. We have shown this
mechanism to be general to a range of 1,2-benzisoxazol-3-ones 1,
1,2-isoxazol-3-ones 5 and N-formylamines. Further, we have ob-
served this mechanistic pathway operating in other activated
1,2-benzisoxazole systems, such as 10.
(Table 1), N-formyl-pyrrolidine, -piperidine and -morpholine all
performed well under standard conditions to furnish the corre-
sponding 4H-1,3-benzoxazin-4-one products 4f–h, in good yields.
The mechanism we propose for this ring-expansion is outlined
in Scheme 3. Though we have no experimental evidence (e.g., iso-
lated intermediates, kinetics, etc.), this proposal is based on a sim-
ilar mechanism outlined for 1,2-oxazolin-5-ones.10 Further, we
have shown the implicit intermediacy of the Vilsmeier species
The primary focus for this communication was to highlight the
difficulties encountered when applying apparently standard meth-
odology to unusual heterocyclic systems and to describe the new,
unexpected ring-expansion pathway of 1,2-benzisoxazol-3-ones.
We acknowledge that this work does not represent a powerful
new methodology for the construction of 4H-1,3-benzoxazin-4-
ones 4 as the prerequisite 1,2,-benzisoxazol-3-one substrates 1
are often difficult to access themselves. Nevertheless, this work
does represent a new approach to the 4H-1,3-benzoxazin-4-one
ring system, which itself appears to be underexploited in the
chemical space and, as such, suffers from a paucity of synthetic
(
rather than, for instance, a sequential chlorination/ring-opening
sequence or some nucleophilic attack of DMF) by exposing 1,2-
benzisoxazol-3-one 1d and 3-chloro-1,2-benzisoxazole 2c to
‘
3
‘dummy’’ reactions containing no POCl (Scheme 5). Neither of
these reactions returned even traces of the 4H-1,3-benzoxazin-4-
one product 4d, both resulting in no detectable reaction of the
substrate.
We have one final cautionary tale relating to this unexpected
ring-expansion mechanism: in an unrelated piece of work, we
were attempting a palladium-catalysed cross-coupling of 1,2-ben-
zisoxazol-3-yl trifluoromethanesulfonate (10). We were cognizant
of the risk associated with ring-opening of the aryl palladium inter-
mediate to yield o-hydroxybenzonitrile. However, after complete
consumption of 10, neither this byproduct nor the desired 3-aryl-
1
2
approaches.
Acknowledgements
The authors would like to thank Dr. Anthony W. T. Bristow for
QTOF LCMS analysis and Dr. Steven R. Coombes and Dr. Andrew
Phillips for NMR spectroscopic analysis and interpretation (all of
Pharmaceutical Development, AstraZeneca).
1
,2-benzisoxazole were observed. We eventually discerned that,
with DMF as the reaction solvent, trifluoromethanesulfonate 10
was participating in the same ring-expansion mechanism to give
4
b in 30% isolated yield (Scheme 6). As shown, we propose transfer
of the triflate group from 10 to DMF to give a Vilsmeier-type imin-
ium species which then mediates a ring-expansion via a mecha-
nism analogous to that outlined in Scheme 3.
References and notes
1
2
.
.
Pitt, W. R.; Parry, D. M.; Perry, B. G.; Groom, C. R. J. Med. Chem. 2009, 52, 2952.
The patent and academic literature yields many examples of pharmacologically
active 1,2-benzisoxazoles. To exemplify, we cite some of the literature we read
whilst conducting this work: Anticoagulants: (a) Lee, Y.-K.; Parks, D. J.; Lu, T.;
Thieu, T. V.; Markotan, T.; Pan, W.; McComsey, D. F.; Milkiewicz, K. L.; Crysler,
C. S.; Ninan, N.; Abad, M. C.; Giardino, E. C.; Maryanoff, B. E.; Damiano, B. P.;
Player, M. R. J. Med. Chem. 2008, 51, 282–297; Anti-inflammatory: (b) Pettus, L.
H.; Xu, S.; Cao, G.-Q.; Chakrabarti, P. P.; Rzasa, R. M.; Sham, K.; Wurz, R. P.;
Zhang, D.; Middleton, S.; Henkle, B.; Plant, M. H.; Saris, C. J. M.; Sherman, L.;
Wong, L. M.; Powers, D. A.; Tudor, Y.; Yu, V.; Lee, M. R.; Syed, R.; Hsieh, F.;
Tasker, A. S. J. Med. Chem. 2008, 51, 6280–6292; Antipsychotic: (c) 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., Jr. J. Med. Chem. 1986, 29, 359–369.
O
DMF
microwave,
HN
O
F
O
1
60 °C, 2 h
1
d
F
N
X
3. For examples of recent advances, see: (a) Dubrovskiy, A. V.; Larock, R. C. Org.
Lett. 2010, 12, 1180–1183; (b) Spiteri, C.; Sharma, P.; Zhang, F.; MacDdonald, S.
J. F.; Keeling, S.; Moses, J. E. Chem. Commun. 2010, 46, 1272–1274. and
references cited therein; (c) Spiteri, C.; Mason, C.; Zhang, F.; Ritson, D. J.;
Sharma, P.; Keeling, S.; Moses, J. E. Org. Biomol. Chem. 2010, 8, 2537–2542. and
references cited therein.
4. For example, see: (a) Smith, J. A.; Le, G.; Jones, E. D.; Deadman, J. Future Med.
Chem. 2010, 2, 215–224; (b) Yamada, A.; Spears, G.; Hayashida, H.; Tomishima,
M.; Ito, K.; Imanishi, M. Int. Patent WO 01/87845; Chem. Abstr. 2001, 135,
N
O
F
Cl
N
F
4
d
DMF/toluene
microwave,
O
F
1
60 °C, 1 h
2
c F
Scheme 5. Functionalised benzisoxazoles under ‘‘dummy’’ conditions.
371759.
5.
6.
7.
Andersen, K.; Begtrup, M. Acta Chem. Scand. 1992, 46, 1130–1132.
Annis, G. D.; Int. Patent WO 06/124657; Chem. Abstr. 2006, 146, 7979.
Kokel, B.; Menichi, G.; Hubert-Habart, M. Tetrahedron Lett. 1984, 25, 3837–
3840.
Het-H, Pd(OAc) ,
TfO
N
2
Het
N
PPh , K CO
3
8. General procedure: The substrate was dissolved or suspended in toluene (or
3
2
acetonitrile where specified below) and DMF (2.5 equiv) or formamide
X
X
(
1.2 equiv) was added. Under an atmosphere of nitrogen, POCl
was added dropwise to control any exotherm. The mixture was either stirred at
0 °C or warmed in an Emrys Optimizer microwave reactor (see below) until
complete reaction was observed by HPLC. The mixture was cooled when
necessary and poured into saturated K CO solution. The solid product was
then isolated by vacuum filtration and drying in vacuo at 40 °C.
3
(1.2 equiv)
DMF, 125 °C, 1 h
O
O
1
0
2
O
2
3
N
N
1
4
a—20 °C, 30 min; 4b—60 °C, 40 min; H NMR (400 MHz, DMSO-d
s), 3.19 (3H, s), 7.38 (1H, ddd, J = 7.7, 7.3, 1.1 Hz), 7.42 (1H, ddd, J = 8.4, 1.0,
.3 Hz), 7.70 (1H, ddd, J = 8.4, 7.3, 1.7 Hz), 7.88 (1H, ddd, J = 7.7, 1.7, 0.3 Hz). MS
6
): 3.12 (3H,
4b, 30%
N
O
0
HO
+
1
As in Scheme 3
3
(ESI) m/z 191 [M+H ]; 4c—60 °C, 20 min; H NMR (400 MHz, CDCl ): 2.38 (3H,
s), 3.24 (3H, s), 3.26 (3H, s), 7.21 (1H, dd (app. t), J = 7.6 Hz) , 7.40 (1H, ddq (app.
dsext.), J = 7.6, 0.8 Hz) , 7.59 (1H, ddq, J = 7.6, 0.8, 0.5 Hz). MS (ESI) m/z 205
O
O
+
1
[
M+H ]; 4d—20 °C, 30 min; H NMR (400 MHz, DMSO-d
6
): 3.14 (3H, s), 3.18
N
N+
+
(3H, s), 7.44 (1H, ddd, J = 10.4, 8.9, 7.0 Hz), 7.71 (1H, ddd, J = 8.9, 5.7, 2.3 Hz). MS
TfO
N
HN
1c
+
1
(
ESI) m/z 227 [M+H ]; 4e—60 °C, 20 min; H NMR (400 MHz, CDCl
3
): 3.23 (3H,
H
O
O
TfO
H
s), 3.26 (3H, s), 7.26 (1H, d, J = 1.9 Hz), 7.32 (1H, dd, J = 8.4, 1.9 Hz), 8.05 (1H, d,
+
1
J = 8.4 Hz). MS (ESI) m/z 225/227 [M+H ]; 4f—20 °C, 30 min; H NMR (400 MHz,
DMSO-d ): 1.88–2.02 (4H, m), 3.52 (2H, app. t, J = 6.6 Hz), 3.63 (2H, app. t,
Scheme 6. Ring-expansion as another side reaction.
6

6
778
S. A. Raw et al. / Tetrahedron Letters 52 (2011) 6775–6778
10. Beccalli, E. M.; Marchesini, A. J. Org. Chem. 1987, 52, 3426–3434.
J = 6.6 Hz), 7.44 (1H, ddd, J = 10.4, 9.0, 7.0 Hz), 7.72 (1H, ddd, J = 9.0, 5.7, 2.3 Hz).
MS (ESI) m/z 253 [M+H ]; 4g—60 °C, 10 min; H NMR (400 MHz, DMSO-d
1
J = 8.9, 5.7, 2.3 Hz). MS (ESI) m/z 267 [M+H ]; 4h—60 °C, 10 min; H NMR
(
(
3
characterised unambiguously by H and C NMR spectroscopy and various 2D
correlation experiments and also by QTOF and HRMS analysis (+1.4 ppm).
Unfortunately, this data cannot be disclosed at this point. Observed data and
those previously described for compounds 4b and 8 were in agreement.
(a) Selva, A.; Gaetani, E. Org. Mass. Spectrom. 1973, 7, 327–328; (b) Tanikawa,
H.; Ishii, K.; Kubota, S.; Sasanuma, T.; Yagai, S.; Kitamura, A.; Karatsu, T.
Heterocycles 2010, 81, 659–674.
+
1
6
):
11. During the preparation of this manuscript, we encountered a single reference
to the transformation of 5b into 6b under similar conditions: Jones, G.;
Stanforth, S. P. In Paquette, L. A., Beak, P., Ciganek, E., Curran, D., Czarnik, A. W.,
Denmark, S. E., Hegedus, L., Kelly, R. C., Overman, L. E., Roush, W., Smith, A. B.,
III, White, J. D., Eds.; Organic Reactions; John Wiley & Sons: New York, 1997;
Vol. 49,. Chapter 1 This appears simply as a table entry and cites Tomita, K.;
Murakami, T. Jpn. Kokai Tokkyo Koho JP 54020504, 1979; Chem Abstr. 1979, 91,
157755b. Unfortunately, we have thus far been unable to obtain a copy of the
original document.
.64 (6H, br s), 3.71 (4H, br s), 7.44 (1H, ddd, J = 10.5, 8.9, 7.0 Hz), 7.70 (1H, ddd,
+
1
400 MHz, DMSO-d
1H, ddd, J = 8.9, 5.7, 2.3 Hz). MS (ESI) m/z 269 [M+H ]; 6a—MeCN, 60 °C,
0 min; 6b—60 °C, 20 min. The structure of proprietary compound 4a was
6
): 3.73 (8H, br s), 7.45 (1H, ddd, J = 10.5, 8.9, 7.1 Hz), 7.73
+
1
13
7
9
12. In July 2011, a a
SciFinderÒ database search using compound 4b as
9
.
substructure unit returned only 26 individual references. The same search
performed in Reaxys returned only 19 individual references.
Ò