A lewis acid catalyzed annulation to 2,1-benzisoxazoles

Article abstract of DOI:10.1021/jo5015432

We report here a new, atom economical annulation to 2,1-benzisoxazole scaffolds via the BF₃·Et₂O-catalyzed reaction of glyoxylate esters and nitrosoarenes. The developed method represents a convergent route to this compound class from previously unexplored inputs and provides a range of 2,1-benzisoxazoles in moderate to high yields under convenient conditions. Along with exploration of substrate scope, initial mechanistic investigation through ¹⁸O labeling and the synthesis of a reaction intermediate provides evidence for an unusual umpolung addition of glyoxylates to nitrosobenzenes with high O-selectivity, followed by a new type of Friedel-Crafts cyclization.

Full text of DOI:10.1021/jo5015432

Article
pubs.acs.org/joc
Open Access on 08/26/2015
A Lewis Acid Catalyzed Annulation to 2,1-Benzisoxazoles
Kate D. Otley and Jonathan A. Ellman*
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520-8107, United States
S
* Supporting Information
ABSTRACT: We report here a new, atom economical annulation to 2,1-
benzisoxazole scaffolds via the BF3·Et2O-catalyzed reaction of glyoxylate esters
and nitrosoarenes. The developed method represents a convergent route to
this compound class from previously unexplored inputs and provides a range
of 2,1-benzisoxazoles in moderate to high yields under convenient conditions.
Along with exploration of substrate scope, initial mechanistic investigation
through 18O labeling and the synthesis of a reaction intermediate provides
evidence for an unusual umpolung addition of glyoxylates to nitrosobenzenes
with high O-selectivity, followed by a new type of Friedel−Crafts cyclization.
oxygen is incorporated into the isoxazole ring rather than the
oxygen from the aldehyde partner. A novel reaction pathway is
proposed based upon the observed oxygen incorporation,
substrate scope, and product regioselectivity. The proposed
mechanism is supported by the independent synthesis and
transformation of a putative reaction intermediate.
INTRODUCTION
■
In addition to their application as scaffolds in a number of
biologically active compounds,1,2 2,1-benzisoxazoles serve as
useful intermediates in organic synthesis.2 Of particular note is
the reductive cleavage of the benzisoxazole N−O bond to give
2-aminophenyl ketones, which have been widely employed in
the synthesis of important pharmaceuticals and materials such
as 1,4-benzodiazepines and quinolines.2,3
Our lab recently reported the synthesis of indazoles via the
reversible Rh(III)-catalyzed addition of azobenzene C−H
bonds to aldehydes, followed by intramolecular nucleophilic
displacement of the hydroxyl group and aromatization (Figure
1A).4 We reasoned that 2,1-benzisoxazoles might also be
RESULTS AND DISCUSSION
■
In our initial efforts to couple nitrosobenzene and ethyl
glyoxylate, we employed the catalyst system that we had
previously successfully applied to indazole synthesis:
[Cp*RhCl2]2 as a precatalyst and AgSbF6 as a chloride
abstractor (entry 1, Table 1).4 We were encouraged by the
20% yield of desired product, but before carrying out additional
optimization experiments, we first performed control reactions
wherein the two constituents of the catalyst system were
evaluated separately (entries 2 and 3). To our surprise, AgSbF6
alone was capable of catalyzing the reaction (entry 3). We,
therefore, chose to explore the competence of a series of
inexpensive Lewis acids in affording the desired 2,1-
benzisoxazole products (entries 4−6). Because of its low cost
and the promising initial results, we focused our efforts on
development of the transformation with BF3·Et2O as the Lewis
acid. Examination of catalyst loading showed 10 mol % of BF3·
Et2O to be ideal, with reduced yields obtained at significantly
higher or lower loading (entries 6−9). Extended reaction times
resulted in higher conversion (entry 10), as did an increase in
the reaction temperature to a gentle reflux (entry 11). A
number of aprotic and protic solvents of varying polarity were
investigated, but all were inferior to dichloromethane and
dichloroethane (data not shown). Inversion of the reaction
stoichiometry brought the yield to 70% (entry 12).
Conveniently, the reaction proved amenable to scale up (1
mmol) with setup on the benchtop giving a 79% isolated yield
(entry 13).
Figure 1. (A) Previous indazole synthesis from azobenzenes. (B) New,
Lewis acid catalyzed annulation to give benzisoxazoles from nitro-
sobenzenes.
prepared by the Rh(III)-catalyzed coupling of isoelectronic
nitrosobenzenes and aldehydes, two inputs that had not
previously been applied to benzisoxazole synthesis (Figure
1B).2,5,6 However, in our exploration of this approach, we
uncovered an unprecedented Lewis acid catalyzed annulation
that generated 2,1-benzisoxazoles from nitrosobenzenes and
glyoxylate esters. The reaction can readily be performed on the
benchtop under practical conditions with 10 mol % of BF3·
Et2O as the Lewis acid. Subjecting 18O-labeled substrates to the
reaction conditions clearly establishes that the nitrosoarene
Received: July 11, 2014
© XXXX American Chemical Society
A
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a
Table 1. Optimization of Reaction Conditions
c
entry
catalyst (mol %)
time (h)
temperature (°C)
1a:2a
yield (%)
b
1
[Cp*RhCl2]2 (5)/AgSbF6 (20)
[Cp*RhCl2]2 (5)
AgSbF6 (20)
24
24
24
24
24
24
24
24
24
48
48
48
48
110
110
110
rt
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
2:1
2:1
20
0
b
2
b
3
29
31
0
4
5
FeCl3 (20)
AlCl3 (20)
rt
6
BF3·Et2O (40)
BF3·Et2O (20)
BF3·Et2O (10)
BF3·Et2O (5)
BF3·Et2O (10)
BF3·Et2O (10)
BF3·Et2O (10)
BF3·Et2O (10)
rt
15
22
32
29
40
63
70
79
7
rt
8
rt
9
rt
10
11
12
rt
reflux
reflux
d
e
13
reflux
a
b
c
Conditions: 0.40 mmol limiting reagent in CH2Cl2 (0.05 M), in glovebox. DCE as solvent. Determined by GC relative to tetradecane as an
d
e
internal standard. Conditions: 1a (2.0 mmol) and 2a (1.0 mmol) in CH2Cl2 (0.05 M), outside glovebox. Isolated yield.
Having established efficient conditions for the BF3·Et2O-
catalyzed transformation, the reaction scope was examined
using a variety of substituted nitrosobenzenes (Table 2).
Electron-neutral (3a), electron-rich (3b−3g, 3l−3n), and even
modestly electron-deficient (3h−3k) aromatics reacted effi-
ciently. However, the site of substitution of the electronegative
chloro group was crucial for reaction success. While 3-
nitrosochlorobenzene provided the benzisoxazole 3h in good
yield, the regioisomeric 4-nitrosochlorobenzene gave only trace
product. This pronounced sensitivity to the placement of the
chloro group is consistent with an electrophilic aromatic
substitution reaction pathway where electronegative halogen
substituents are known to be deactivating but, due to resonance
stabilization, also strongly ortho-/para-directing.
ab c
, ,
Table 2. Examination of Substrate Scope
Substitutions at the para and meta positions of the aromatic
ring were well-tolerated. In contrast, 2-nitrosotoluene resulted
in <10% yield of the desired benzisoxazole (not shown). The
regioselectivity of the transformation was examined by
employing a number of meta-substituted nitrosoarenes. While
only moderate regioselectivity was observed for alkyl and
chloro groups (3d, 3e, 3h, 3i), a fluoro substituent at the meta
position provided significantly higher regioselectivity, with the
major site of addition being that most remote from the fluoro
group (3j, 3k). Reaction with a meta-methoxy group resulted in
a single regioisomer (3m, 3n). Notably, a single benzisoxazole
regioisomer was also observed from reaction with 2-nitro-
sonaphthalene (3l). This result parallels the regioselectivity
observed in electrophilic aromatic substitution reactions.7
While other glyoxylate esters react efficiently under the
optimized conditions (3o), less electrophilic aldehydes such as
benzaldehyde did not give 2,1-benzisoxazole products.
We next aimed to shed light on the reaction mechanism by
employing an 18O labeling study to determine the origin of the
oxygen in the isoxazole product. First, 18O-enriched 4-tert-
butyl-nitrosobenzene (4) was prepared and subjected to the
reaction conditions to give benzisoxazole 5 (eq 1). The 18O-
a
Conditions: nitrosoarene (2.0 mmol), aldehyde (1.0 mmol), BF3·
b
Et2O (10%) in CH2Cl2 (0.05 M). Isolated yield of all regioisomers
after silica gel chromatography. Ratio of regioisomers determined by
c
1H NMR of crude product. Isolated as an inseparable mixture of
nitrosobenzene was generated by oxidation of the correspond-
ing aniline with H218O2 in the presence of a diphenyldiselenide
regioisomers.
B
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catalyst, and 18O incorporation into the nitroso product was
confirmed by GCMS analysis.8 In order to work with the low
concentrations of aqueous H218O2 that are commercially
available,9 we opted to label 4-tert-butyl-nitrosobenzene for
this study to alleviate issues with nitrosobenzene sublimation
on a small scale. Importantly, reaction of the 18O-labeled
nitrosoarene with ethyl glyoxylate resulted in almost complete
incorporation of the 18O label in the 2,1-benzisoxazole product
5 as determined by LCMS analysis (eq 1).10
To verify that the isoxazole oxygen originates from
nitrosobenzene, a control reaction was conducted with 18O-
labeled ethyl glyoxylate. Labeling of the glyoxylate ester was
achieved by exchange with H218O. Because ethyl glyoxylate not
only readily hydrates and oligomerizes but also poorly ionizes,
direct GCMS and LCMS analyses were not effective for
accurately quantitating the extent of 18O labeling of the ethyl
glyoxylate. Instead, the 18O-labeled glyoxylate was subjected to
Sakurai allylation with allyltrimethylsilane to give alcohol 7 for
which a high level of 18O incorporation was confirmed by
LCMS analysis (eq 2).11 Notably, when the labeled glyoxylate 6
to provide adduct 10. This step is consistent with previously
reported O-selective nucleophilic additions of carbon nucleo-
philes, including silyl enol ethers, to Lewis acid activated
nitrosoarenes.12 The O-selectivity is postulated to result from
coordination of the nitroso nitrogen to the Lewis acid to
increase electrophilicity at oxygen.12−14 Although the proposed
umpolung reactivity of the glyoxylate ester upon hydration does
not have direct precedent, it is highly analogous to the acid-
catalyzed addition of glyoxylate-derived silyl ketene acetals to a
variety of electrophiles, including carbonyls and alkyl halides.15
Following dehydration of addition product 10 to regenerate the
carbonyl 11, an intramolecular Friedel−Crafts cyclization gives
bicyclic intermediate 12, which provides the 2,1-benzisoxazole
product 3 upon aromatization.
To test this mechanistic pathway, we prepared Boc derivative
13 that, upon acidic Boc cleavage, should provide intermediate
11, with the only difference being a proton in place of BF3.
Indeed, upon treatment of 13 with trifluoroacetic acid, 2,1-
benzisoxazole 3a was observed as the major reaction product
(eq 4). The acid not only removed the Boc group but
presumably also promoted Friedel−Crafts cyclization. The
yield of 3a from 13 is limited by a competing Bamberger
rearrangement to give the 4-aminophenol side product in 20%
yield.16 We also explored cyclization of the less electrophilic
benzoate analogue of pyruvate 13. However, upon acid
treatment, benzisoxazole was not detected, and 4-aminophenol
and benzoic acid from competing Bamberger rearrangement
were instead observed as the sole reaction products.
was subjected to the reaction conditions, minimal 18O
incorporation was observed in benzisoxazole 8 by LCMS (eq
3). Taken together, the results of the described labeling
experiments clearly establish that the isoxazole oxygen
originates from the nitrosoarene partner rather than from the
aldehyde.
We propose a mechanism shown in Scheme 1 that is based
on the 18O incorporation experiments and the clear parallel
between this reaction and electrophilic aromatic substitutions in
terms of substrate reactivity and regioselectivity. Enol 9b is
proposed to add to the nitroso oxygen upon activation with BF3
CONCLUSION
■
A practical annulation to give 2,1-benzisoxazoles from
previously unexplored inputs has been developed. A range of
electron-neutral, electron-rich, and modestly electron-deficient
nitrosobenzenes serve as efficient inputs for the reaction. On
the basis of mechanistic studies that include 18O labeling,
substrate scope and regioselectivities, and preparation of a
putative reaction intermediate, the reaction likely proceeds by
an unusual BF3·Et2O-catalyzed umpolung addition of glyox-
ylates to nitrosobenzenes with high O-selectivity. A new type of
Friedel−Crafts cyclization then occurs, followed by aromatiza-
tion to give the desired 2,1-benzisoxazole products. Studies are
currently underway to capitalize on the uncovered novel
reactivity to access other heterocyclic motifs.
Scheme 1. Proposed Reaction Mechanism
EXPERIMENTAL SECTION
■
General Experimental Methods. Unless otherwise indicated, all
reactions were set up under an inert atmosphere (N2) using flame-
dried glassware. Dichloromethane and all other solvents were purified
by elution through a column of activated alumina under N2 before use.
Triethylamine was distilled from CaH2 under nitrogen immediately
before use. Dichloromethane-d2, benzene-d6, acetone-d6, and chloro-
form-d were all used as received. Unless otherwise noted, all reagents
were purchased from commercial sources and used without further
purification. Products and starting materials were visualized on TLC
using UV or by staining with KMnO4. NMR chemical shifts are
reported in ppm relative to CDCl3 (7.26 ppm 1H and 77.16 ppm 13C),
1
C6D6 (7.16 ppm H), (CD3)CO (29.84 ppm 13C), or CD2Cl2 (5.32
C
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1
ppm H and 54.00 ppm 13C). Trifluoroacetic acid (−76.55 pm in
hexanes/dichloromethane (20:1). The product 1i (0.74 g, 20% yield)
was obtained as a white solid. (mp: 66−68 °C). IR (film) 3089, 2930,
1917, 1580, 1480, 1380, 1249, 1215, 1049, 869, 824, 766, 703, 555
CDCl3) was used as an external standard for determining 19F NMR
chemical shifts. For IR spectra, only partial data are provided. Melting
points are reported uncorrected. High-resolution mass spectra
(HRMS) and low-resolution mass spectra (LRMS) data for the
benzisoxazole products were obtained using electrospray ionization
(ESI) on a time-of-flight (TOF) mass spectrometer. HRMS data for
the nitrosoarene starting materials were obtained using an APGC ion
source. GC analysis was performed using an Agilent J&W HP-5
column (5%-phenyl)-methylpolysiloxane.
Ethyl Glyoxylate (2a). Purification of ethyl glyoxylate was adapted
from a literature procedure.17 A 50% technical solution of ethyl
glyoxyate in toluene (purchased form Aldrich) was purified by flash
chromatography on silica gel (hexanes/ethyl acetate 20:1 to 1:1) and
then distilled through a vacuum-jacketed vigereux column under N2
(90 °C, 60 mmHg) to give a pale yellow oil. The freshly distilled ethyl
glyoxylate was stored under N2 in a Schlenk flask at −20 °C and
warmed to ambient temperature before use.
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.91 (dd, J = 8.0, 1.8 Hz, 1H),
7.71 (d, J = 1.8 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 2.47 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 165.1, 144.8, 136.0, 131.7, 121.1, 120.2,
20.9; HRMS (APGC/[M + H]+) calcd. for C7H7ClNO+: 156.0211.
Found: 156.0220.
1-Fluoro-3-nitrosobenzene (1j). The general procedure was
followed with 3-fluoro-benzeneamine (2.7 g, 24 mmol, 1.0 equiv)
with purification by silica gel chromatography eluting using hexanes/
ether (10:1). The product 1j (2.1 g, 67% yield) was obtained as a
white solid. (mp: 52−56 °C) IR (film) 3060, 3039, 1602, 1479, 1446,
1
1412, 1392, 1234,1144, 1011, 905, 830, 782, 691, 519, 479 cm−1; H
NMR (500 MHz, CDCl3) δ 8.17 (dt, J = 7.8, 1.0 Hz, 1H), 7.70 (td, J =
8.0, 5.3 Hz, 1H), 7.48−7.40 (m, 1H), 7.16 (dt, J = 8.3, 2.1 Hz, 1H);
13C NMR (126 MHz, CDCl3) δ 165.9 (d, J = 4.7 Hz), 163.3 (d, J =
251.8 Hz), 131.3 (d, J = 7.7 Hz), 122.3 (d, J = 22.4 Hz), 121.2 (d, J =
2.7 Hz), 103.7 (d, J = 22.6 Hz); 19F NMR (376 MHz, CDCl3) δ
−106.95 (q, J = 7.6 Hz); HRMS (APGC/[M + H]+) calcd. for
C6H5FNO+: 126.0350. Found: 126.0356.
Benzyl Glyoxylate (2b). Benzyl glyoxyate was prepared according to
a literature procedure18 and purified by distillation using a Kugelrohr
apparatus (95 °C, 20 mmHg) to give a yellow oil.
BF3·Et2O Catalyst. Boron trifluoride diethyl etherate was purchased
from Aldrich and purified according to a literature procedure.19 The
reagent was stored under N2 in a Schlenk flask at −20 °C and warmed
to ambient temperature before use.
2-Fluoro-1-methyl-4-nitrosobenzene (1k). The general procedure
was followed with 3-fluoro-4-methyl-benzeneamine (2.0 g, 16 mmol,
1.0 equiv) with purification by silica gel chromatography eluting using
hexanes/ether (20:1). The product 1k (1.4 g, 63% yield) was obtained
as a green oil. IR (neat) 3073, 1593, 1502, 1478, 1400, 1226, 1184,
Nitrosoarenes (1). Nitrosobenzene, which was used to prepare 3a
and 3o, is commercially available. The nitrosoarenes used to prepare
2,1-benzisoxazoles 3b,20 3c,21 3d,22 3e,23 3g,24 and 3m20 were
prepared according to the cited recently published methods.
General Procedure for the Preparation of Nitrosoben-
zenes.25 In a round-bottom flask equipped with a stir bar, the
indicated aniline (3.7−24 mmol, 1.0 equiv) was dissolved in CH2Cl2
(0.26 M) and added to a solution of oxone (11−72 mmol, 3.0 equiv)
in water (0.60 M). The reaction mixture was stirred at room
temperature with vigorous stirring. After 4 h, the reaction mixture was
extracted with CH2Cl2 (3 × 1 mL/mmol aniline), dried over MgSO4,
and concentrated under reduced pressure. Purification by silica gel
column chromatography provided the indicated nitrosobenzene.
1-Isopropyl-3-nitrosobenzene (1e). The general procedure was
followed with 3-isopropyl-benzeneamine (2.7 g, 20 mmol, 1.0 equiv)
with purification by silica gel chromatography eluting using hexanes/
ether (15:1). The product 1h (1.3 g, 45% yield) was obtained as an
1
1065, 879, 821, 784, 745 cm−1; H NMR (400 MHz, CDCl3) δ 8.08
(dd, J = 7.9, 1.7 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.11 (dd, J = 9.2, 1.7
Hz, 1H), 2.37 (d, J = 2.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
165.7 (d, J = 4.8 Hz), 161.6 (d, J = 250.6 Hz), 134.1 (d, J = 18.2 Hz),
132.2 (d, J = 4.8 Hz), 121.5, 103.2 (d, J = 23.0 Hz), 15.5 (d, J = 3.5
Hz); 19F NMR (376 MHz, CDCl3) δ −115.82 (ddd, J = 9.6, 7.3, 2.4
Hz); HRMS (APGC/[M + H]+) calcd. for C7H7FNO+: 140.0506.
Found: 140.0512.
1-Chloro-2-methoxy-4-nitrosobenzene (1n). The general proce-
dure was followed with 4-chloro-3-methyoxy-benzeneamine (1.0 g, 6.4
mmol, 1.0 equiv) with purification by silica gel chromatography eluting
using hexanes/ether (20:1). The product 1n (0.52 g, 48% yield) was
obtained as a pale yellow solid (mp: 115−120 °C). IR (film) 3093,
1
2935, 1583, 1482, 1281, 1245, 1030, 768, 690 cm−1; H NMR (500
MHz, CDCl3) δ 8.08 (dd, J = 8.2, 2.0 Hz, 1H), 7.73 (d, J = 8.2 Hz,
1H), 6.86 (d, J = 1.9 Hz, 1H), 3.97 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 164.9, 156.0, 131.6, 131.3, 120.7, 98.1, 56.5; HRMS
1
amorphous tan paste. H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 7.7
+
(APGC/[M + H]+) calcd. for C7H7ClNO2 : 172.0160. Found:
Hz, 1H), 7.73 (s, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.53 (t, J = 7.6 Hz,
1H), 3.18−2.91 (m, 1H), 1.32 (d, J = 6.9 Hz, 6H); 13C NMR (126
MHz, CDCl3) δ 166.7, 150.6, 134.1, 129.3, 119.3, 118.7, 34.1, 23.9.
The analytical data for this compound are consistent with previously
reported data.26
1-2-3-Trimethyl-5-nitrosobenzene (1f). The general procedure was
followed with 3,4,5-trimethyl-benzeneamine (0.50 g, 3.7 mmol, 1.0
equiv) with purification by silica gel chromatography eluting using
hexanes/ether (20:1). The product 1f (0.14 g, 25% yield) was
obtained as a pale blue solid. (mp: 36−39 °C). IR (film) 3082, 2915,
1793, 1590, 1511, 1482, 1415, 1343, 1260, 1092, 965, 901, 747, 701
cm−1; 1H NMR (500 MHz, CDCl3) δ 7.55 (s, 2H), 2.42 (s, 6H), 2.25
(s, 3H); 13C NMR (126 MHz, CDCl3) δ 165.7, 144.9, 137.7, 120.5,
20.8, 16.6; HRMS (APGC/[M + H]+) calcd. for C9H12NO+:
150.0913. Found: 150.0920.
172.0163.
2-Nitrosonaphthalene (1l).28 In a round-bottom flask positioned in
a water bath at ambient temperature, NOBF4 (174 mg, 1.49 mmol,
1.03 equiv) was added in one portion, with vigorous stirring, to a white
slurry of potassium naphthalene-2-trifluoroborate (340 mg, 1.45
mmol, 1.00 equiv) in acetonitrile (4.40 mL, 0.330 mL). The reaction
mixture immediately turned black and was stirred for 20 s before the
addition of H2O (20 mL) and then CH2Cl2 (20 mL). The reaction
mixture was extracted with CH2Cl2 (3 × 20 mL). The organic layers
were combined, dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude material was purified by SiO2 column
chromatography eluting with hexanes/ethyl acetate (4:1) to give 1l
(34.0 mg, 14.9% yield) as a tan solid (mp: 58−63 °C). IR (film) 3089,
1
3054, 2925, 1596, 1425, 1381, 1347, 868, 814, 751, 566 cm−1; H
1-Chloro-3-nitrosobenzene (1h). The general procedure was
followed with 3-chloro-benzeneamine (3.1 g, 24 mmol, 1.0 equiv)
with purification by silica gel chromatography eluting using hexanes/
ether (20:1). The product 1h (2.0 g, 60% yield) was obtained as a
white solid (69−73 °C, lit.27a 72−73 °C). 1H NMR (500 MHz,
CDCl3) δ 8.06 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.66−7.60
(m, 2H); 13C NMR (126 MHz, CDCl3) δ 165.2, 136.2, 135.1, 130.9,
121.6, 118.9. The analytical data for this compound are consistent with
previously reported data.27b
NMR (500 MHz, CDCl3) δ 9.52 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H),
7.90 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.76−7.71 (m, 1H),
7.71−7.66 (m, 1H), 7.01 (dd, J = 8.9, 1.8 Hz, 1H); 13C NMR (126
MHz, CDCl3) δ 164.0, 137.5, 136.7, 133.2, 131.3, 130.7, 129.3, 128.3,
127.9, 108.5; GCMS (EI/[M]+) calcd. for C10H6NO+: 157.1. Found:
157.1.
General Procedure for the BF3·Et2O-Catalyzed 2,1-Benzisox-
azole Synthesis. In a flame-dried Schlenk flask equipped with a stir
bar, ethyl glyoxylate (90−110 mg, 0.88−1.1 mmol, 1.0 equiv) was
dissolved in CH2Cl2 (0.067 M) under an atmosphere of N2. To the
solution was added BF3·Et2O (13−15 mg, 0.088−0.11 mmol, 0.10
equiv), followed by a solution of the indicated nitrosobenzene (1.8−
2-Chloro-1-methyl-4-nitrosobenzene (1i). The general procedure
was followed with 3-chloro-4-methyl-benzeneamine (3.4 g, 24 mmol,
1.0 equiv) with purification by silica gel chromatography eluting using
D
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2.2 mmol, 2.0 equiv) in CH2Cl2 (0.40 M). The Schlenk flask was
equipped with a reflux condenser under positive N2 pressure and
placed in a temperature-controlled oil bath set to 45 °C. After 48 h, the
flask was removed from the oil bath and cooled to ambient
temperature. The mixture was pushed through a plug of SiO2 with
EtOAc and then concentrated under reduced pressure. The crude
reaction product was purified via silica gel column chromatography to
afford the indicated product.
3.04 (p, J = 6.9 Hz, 1H), 1.47 (t, J = 7.1 Hz, 3H), 1.29 (d, J = 6.9 Hz,
6H); 13C NMR (101 MHz, CDCl3) major regioisomer δ 156.7, 152.9,
149.4, 147.2, 140.8, 127.4, 119.1, 111.3, 63.3, 34.3, 24.4, 14.3; HRMS
+
(ESI/[M + H]+) calcd. for C13H16NO3 : 234.1125. Found 234.1146.
Ethyl 4,5,6-Trimethylbenzo[c]isoxazole-3-carboxylate (3f). The
general procedure was followed with ethyl glyoxylate (95.0 mg, 0.931
mmol, 1.00 equiv) and 1,2,3-trimethyl-5-nitrosobenzene (1f) (278 mg,
1.86 mmol, 2.00 equiv). Purification via silica gel column
chromatography eluting with hexanes:ethyl acetate (8:1) afforded 3f
(98 mg, 44% yield) as a white solid (mp: 119−123 °C). IR (film)
2982, 1726, 1537, 1373, 1287, 1231, 1197, 1157, 1027, 881, 857, 781,
652, 627 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 4.53 (q, J
= 7.1 Hz, 2H), 2.51 (s, 3H), 2.39 (s, 3H), 2.30 (s, 3H), 1.48 (t, J = 7.1
Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 157.0, 152.1, 149.6, 137.7,
136.3, 135.1, 120.0, 119.2, 63.2, 21.5, 15.9, 14.4, 13.0; HRMS (ESI/[M
Ethyl Benzo[c]isoxazole-3-carboxylate (3a). The general proce-
dure was followed with ethyl glyoxylate (110 mg, 1.08 mmol, 1.00
equiv) and nitrosobenzene (1a) (230 mg, 2.16 mmol, 2.00 equiv).
Purification via silica gel column chromatography eluting with
hexanes:ethyl acetate (4:1) afforded 3a (165 mg, 79% yield) as a
very pale, pink solid (mp: 94−96 °C). IR (film) 3078, 2976, 1731,
1606, 1545, 1476, 1451, 1373, 1310, 1207, 1153, 1105, 1016, 947, 853,
1
765, 752, 625 cm−1; H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 8.0
+
+ H]+) calcd. for C13H16NO3 : 234.1125. Found 234.1109.
Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.52 (t, J = 7.3 Hz, 1H), 7.45 (t, J =
7.3 Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H); 13C
NMR (126 MHz, CDCl3) δ 156.6, 152.9, 151.0, 140.6, 128.2, 125.9,
122.2, 111.8, 63.4, 14.3; HRMS (ESI/[M + H]+) calcd. for
Ethyl 4,6-Dimethylbenzo[c]isoxazole-3-carboxylate (3g). The
general procedure was followed with ethyl glyoxylate (95.0 mg,
0.931 mmol, 1.00 equiv) and 1,3-dimethyl-5-nitrosobenzene (1g) (251
mg, 1.86 mmol, 2.00 equiv). Purification via silica gel column
chromatography eluting with hexanes:ethyl acetate (4:1) afforded 3g
(66 mg, 32% yield) as an off-white solid (mp: 78−80 °C). IR (film)
2925, 1729, 1625, 1547, 1446, 1368, 1307, 1290, 1212, 1155, 1129,
1111, 1024, 958, 848, 637 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.46
(s, 1H), 7.12 (s, 1H), 4.54 (q, J = 7.1 Hz, 2H), 2.54 (s, 3H), 2.44 (s,
3H), 1.48 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 156.9,
152.8, 148.8, 140.5, 135.9, 130.6, 121.8, 119.0, 63.2, 21.6, 15.3, 14.4;
+
C10H10NO3 : 192.0655. Found: 192.0661.
Ethyl 5-Methylbenzo[c]isoxazole-3-carboxylate (3b). The general
procedure was followed with ethyl glyoxylate (102 mg, 1.00 mmol,
1.00 equiv) and 4-methyl-1-nitrosobenzene (1b) (242 mg, 2.00 mmol,
2.00 equiv). Purification via silica gel column chromatography eluting
with hexanes:ethyl acetate (8:1) afforded 3b (154 mg, 75% yield) as a
pale pink solid (mp: 81−84 °C). IR (film) 2989, 1729, 1599, 1541,
1371, 1313, 1245, 1218, 1163, 1112, 1022, 857, 814, 780, 605 cm−1;
1H NMR (400 MHz, CD2Cl2) δ 7.73 (d, J = 8.3 Hz, 1H), 7.47 (m,
1H), 7.36−7.21 (m, 1H), 4.49 (q, J = 7.1 Hz, 2H), 2.52 (s, 3H), 1.45
(t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 156.7, 152.4,
151.3, 139.2, 138.5, 127.4, 121.5, 111.7, 63.3, 22.2, 14.3; HRMS (ESI/
+
HRMS (ESI/[M + H]+) calcd. for C12H14NO3 : 220.0968. Found
220.0953.
Ethyl Chlorobenzo[c]isoxazole-3-carboxylates (3h and 3h′). The
general procedure was followed with ethyl glyoxylate (110 mg, 1.08
mmol, 1.00 equiv) and 1-chloro-3-nitrosobenzene (1h) (304 mg, 2.16
mmol, 2.00 equiv). Purification via silica gel column chromatography
eluting with hexanes:ethyl acetate (5:1) afforded 3h (129 mg, 52%
yield) as a tan solid and 3h′ (40.3 mg, 16% yield) as an off-white solid.
Characterization for ethyl 6-chlorobenzo[c]isoxazole-3-carboxylate (3h,
major): (mp: 79−80 °C). IR (film) 3067, 2984, 1734, 1601, 1546,
1472, 1449, 1371, 1305, 1210, 1159, 1113, 1053, 1012, 921, 852, 828,
+
[M + H]+) calcd. for C11H12NO3 : 206.0812. Found 206.0805.
Ethyl 5-(tert-Butyl)benzo[c]isoxazole-3-carboxylate (3c). The
general procedure was followed with ethyl glyoxylate (102 mg, 1.00
mmol, 1.00 equiv) and 4-tert-butyl-1-nitrosobenzene (1c) (326 mg,
2.00 mmol, 2.00 equiv). Purification via silica gel column
chromatography eluting with hexanes:ethyl acetate (4:1) afforded 3c
(178 mg, 72% yield) as a yellow solid (mp: 45−47 °C). IR (film)
2962, 2909, 2875, 1741, 1621, 1547, 1368, 1302, 1192, 1152, 1112,
1016, 954, 930, 859, 829, 779, 659 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.76 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.49 (dd,
J = 8.6, 1.7 Hz, 1H), 4.51 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H),
1.35 (s, 9H); 13C NMR (126 MHz, (CD3)2CO) δ 157.0, 153.8, 153.3,
152.0, 139.3, 124.6, 121.8, 109.0, 63.3, 36.1, 31.8, 14.4; HRMS (ESI/
1
704, 636 cm−1; H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 2.0 Hz,
1H), 7.60 (d, J = 8.8 Hz, 1H), 7.50 (dd, J = 8.8, 2.1 Hz, 1H), 4.56 (q, J
= 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3)
δ 156.3, 154.0, 149.5, 141.6, 131.6, 128.84, 122.03, 112.74, 63.66,
+
14.30; HRMS (ESI/[M + H]+) calcd. for C10H9ClNO3 : 226.0265.
Found 226.0285. Characterization for ethyl 4-chlorobenzo[c]isoxazole-3-
carboxylate (3h′, minor): (mp: 84−86 °C). IR (film) 3003, 1742, 1610,
1549, 1471, 1444, 1375, 1310, 1252, 1197, 1140, 1109, 1018, 963, 854,
+
[M + H]+) calcd. for C14H18NO3 : 248.1281. Found 248.1255.
1
787, 734, 634 cm−1; H NMR (600 MHz, CDCl3) δ 7.79 (d, J = 8.1
Ethyl 6-Methylbenzo[c]isoxazole-3-carboxylate (3d). The general
procedure was followed with ethyl glyoxylate (110 mg, 1.08 mmol,
1.00 equiv) and 1-methyl-3-nitrosobenzene (1d) (260 mg, 2.16 mmol,
2.00 equiv). Purification via silica gel column chromatography eluting
with hexanes:ethyl acetate (4:1) afforded 3d and 3d′ (150 mg, 67%
yield) as an inseparable mixture of two regioisomers in a ratio of 2.6:1
as a pale yellow solid. IR (film) 2994, 2914, 1730, 1606, 1545, 1475,
1375, 1343, 1309, 1298, 1208, 1157, 1113, 1014, 952, 854, 809, 781,
758, 635 cm−1; 1H NMR (600 MHz, CDCl3) major regioisomer δ 7.65
(s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 4.55 (q, J =
7.1 Hz, 2H), 2.50 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H); 13C NMR (151
MHz, CDCl3) major regioisomer δ 156.7, 152.9, 149.3, 140.8, 136.0,
129.7, 121.8, 111.2, 63.4, 21.7, 14.4; HRMS (ESI/[M + H]+) calcd. for
Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 4.57 (q, J =
7.1 Hz, 2H), 1.50 (t, J = 7.1 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ
156.1, 153.2, 147.7, 141.7, 128.4, 126.6, 120.7, 117.2, 63.7, 14.3;
+
HRMS (ESI/[M + H]+) calcd. for C10H9ClNO3 : 226.0265. Found
226.0294.
Ethyl Chloro-5-methylbenzo[c]isoxazole-3-carboxylate (3i and
3i′). The general procedure was followed with ethyl glyoxylate (102
mg, 1.00 mmol, 1.00 equiv) and 2-chloro-1-methyl-4-nitrosobenzene
(1i) (310 mg, 2.00 mmol, 2.00 equiv). Purification via silica gel
column chromatography eluting with hexanes:ethyl acetate (5:1)
afforded 3i (121 mg, 51% yield) as a pale pink solid and 3i′ (68 mg,
28% yield) as a pale orange solid. Characterization for ethyl 4-chloro-5-
methylbenzo[c]isoxazole-3-carboxylate (3i, major): (mp: 110−115 °C).
IR (film) 3071, 2997, 1737, 1595, 1544, 1448, 1370, 1297, 1247, 1158,
+
C11H12NO3 : 206.0812. Found 206.0803.
Ethyl 6-Isopropylbenzo[c]isoxazole-3-carboxylate (3e). The gen-
eral procedure was followed with ethyl glyoxylate (110 mg, 1.08 mmol,
1.00 equiv) and 1-isopropyl-3-nitrosobenzene (1e) (321 mg, 2.16
mmol, 2.00 equiv). Purification via silica gel column chromatography
eluting with hexanes:ethyl acetate (4:1) afforded 3e and 3e′ (211 mg,
84% yield) as an inseparable mixture of two regioisomers in a ratio of
4:1 as a red solid. IR (film) 2973, 2953, 2869, 1738, 1606, 1553, 1461,
1
1109, 1007, 950, 851, 781, 691, 650, 626, 509 cm−1; H NMR (500
MHz, CDCl3) δ 7.86 (s, 1H), 7.52 (s, 1H), 4.55 (q, J = 7.2 Hz, 2H),
2.52 (s, 3H), 1.48 (t, J = 7.2 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
156.4, 153.4, 149.8, 139.7, 137.2, 132.2, 121.9, 113.0, 63.5, 21.4, 14.3;
+
HRMS (ESI/[M + H]+) calcd. for C11H11ClNO3 : 240.0422. Found
240.0414. Characterization for ethyl 6-chloro-5-methylbenzo[c]isoxazole-
3-carboxylate (3i′, minor): (mp: 85−86 °C). IR (film) 3086, 2994,
2943, 1744, 1592, 1551, 1479, 1365, 1330, 1297, 1246, 1202, 1135,
1107, 1030, 943, 854, 809, 633, 599 cm−1; 1H NMR (600 MHz,
1
1367, 1294, 1228, 1154, 1108, 1016, 957, 853, 802, 658 cm−1; H
NMR (400 MHz, CDCl3) major regioisomer δ 7.69 (d, J = 1.3 Hz, 1H),
7.54 (d, J = 8.6 Hz, 1H), 7.41−7.37 (m, 2H), 4.53 (q, J = 7.2 Hz, 2H),
E
dx.doi.org/10.1021/jo5015432 | J. Org. Chem. XXXX, XXX, XXX−XXX

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CDCl3) δ 7.66 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 4.56 (q, J
= 7.1 Hz, 2H), 2.54 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H); 13C NMR (151
MHz, CDCl3) δ 156.2, 152.8, 148.2, 139.6, 136.9, 128.5, 119.7, 116.6,
(film) 2978, 2944, 2843, 1733, 1608, 1550, 1485, 1434, 1366, 1311,
1257, 12222, 1151, 1105, 1022, 959, 850, 803, 779, 643, 554, 529
1
cm−1; H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 9.0 Hz, 1H), 7.29
+
63.5, 19.7, 14.3; HRMS (ESI/[M + H]+) calcd. for C11H11ClNO3 :
(d, J = 2.5 Hz, 1H), 7.12 (dd, J = 9.0, 2.6 Hz, 1H), 4.54 (q, J = 7.2 Hz,
2H), 3.87 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 158.3, 156.6, 153.5, 145.8, 141.6, 118.2, 112.1, 103.7, 63.3,
240.0422. Found 240.0395.
Ethyl 6-Fluorobenzo[c]isoxazole-3-carboxylate (3j and 3j′). The
general procedure was followed with ethyl glyoxylate (102 mg, 1.00
mmol, 1.00 equiv) and 1-fluoro-3-nitrosobenzene (1j) (150 mg, 2.00
mmol, 2.00 equiv). Purification via silica gel column chromatography
eluting with hexanes:ethyl acetate (4:1) afforded 3j and 3j′ (80 mg,
38% yield) as an inseparable mixture of two regioisomers in a ratio of
14:1 as a pale yellow solid. IR (film) 3074, 2922, 2852, 1734, 1608,
1553, 1473, 1448, 1437, 1369, 1346, 1302, 1262, 1221, 1148, 1114,
+
56.1, 14.3; HRMS (ESI/[M + H]+) calcd. for C11H12NO4 : 222.0761.
Found 222.0751.
Ethyl 5-Chloro-6-methoxybenzo[c]isoxazole-3-carboxylate (3n).
The general procedure was followed with ethyl glyoxylate (102 mg,
1.00 mmol, 1.00 equiv) and 1-chloro-2-methoxy-4-nitrosobenzene
(1n) (342 mg, 2.00 mmol, 2.00 equiv). Purification via silica gel
column chromatography eluting with hexanes:ethyl acetate (4:1)
afforded 3n (114 mg, 45% yield) as a tan solid (mp: 115−120 °C). IR
(film) 3101, 3077, 2970, 2951, 1733, 1603, 1544, 1469, 1437, 1375,
1320, 1278, 1226, 1149, 1042, 1018, 991, 954, 863, 837, 779, 694, 627,
546 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.70 (s, 1H), 7.34 (s, 1H),
4.55 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H); 13C
NMR (126 MHz, CDCl3) δ 156.2, 154.1, 153.6, 144.9, 140.0, 124.7,
113.2, 103.3, 63.4, 56.9, 14.3; HRMS (ESI/[M + H]+) calcd. for
1
1016, 962, 884, 854, 808, 779, 637, 512 cm−1; H NMR (400 MHz,
C6D6) major regioisomer δ 7.25 (dd, J = 8.1, 2.6 Hz, 1H), 6.76 (dd, J =
9.0, 4.3 Hz, 1H), 6.62 (td, J = 9.1, 2.6 Hz, 1H), 4.01 (q, J = 7.1 Hz,
2H), 0.93 (t, J = 7.1 Hz, 3H); 13C NMR (151 MHz, CDCl3) major
regioisomer δ 160.7 (d, J = 243.5 Hz), 156.3, 154.4, 147.4 (d, J = 1.0
Hz), 141.4 (d, J = 13.3 Hz), 116.7 (d, J = 26.8 Hz), 112.5 (d, J = 10.0
Hz), 108.2 (d, J = 25.4 Hz), 63.6, 14.30; 19F NMR (376 MHz, CDCl3)
δ −116.16 (td, J = 8.5, 4.1 Hz); HRMS (ESI/[M + H]+) calcd. for
+
C11H11ClNO4 : 256.0371. Found 256.0378.
+
18O Labeling Studies. Synthesis of 1-(tert-Butyl)-4-(nitroso)-
benzene (18O) (4).8 In an oven-dried one dram vial with a Teflon cap,
cooled to room temperature in a desiccator, diphenyldiselenide (0.97
mg, 3.1 μmol, 0.10 equiv) and 4-(tert-butyl)aniline (5.0 μL, 31 μmol,
1.0 equiv) were dissolved in CHCl3 (100 μL, 0.31 M). Finally, a 2.5%
aqueous solution of 18O-labeled hydrogen peroxide9 (100 mg, 65.8
μmol, 2.10 equiv) was added, and the reaction mixture was stirred
vigorously in a water bath at ambient temperature under an
atmosphere of air for 5 h. The reaction mixture was extracted with
CHCl3 (3 × 0.5 mL) and concentrated under reduced pressure. The
crude mixture was purified via SiO2 column chromatography, eluting
with hexanes/dichloromethane (4:1) to give 1-(tert-butyl)-4-nitro-
sobenzene-(18O) (4) as a yellow-green oil (0.5 mg, 10% yield). GCMS
(EI/[M]+) calcd. for C10H13N18O+: 165.1. Found: 165.1.
C10H9FNO3 : 210.0561. Found 210.0569.
Ethyl Fluoro-5-methylbenzo[c]isoxazole-3-carboxylate (3k and
3k′). The general procedure was followed with ethyl glyoxylate (110
mg, 1.08 mmol, 1.00 equiv) and 2-fluoro-1-methyl-4-nitrosobenzene
(1k) (300 mg, 2.16 mmol, 2.00 equiv). Purification via silica gel
column chromatography eluting with hexanes:ethyl acetate (8:1)
afforded 3k (182 mg, 73% yield) as a pale pink solid and 3k′ (5 mg,
2% yield) as an orange solid. Characterization for ethyl 6-fluoro-5-
methylbenzo[c]isoxazole-3-carboxylate (3k, major): (mp: 100−104 °C).
IR (film) 3036, 2925, 1731, 1601, 1546, 1460, 1375, 1318, 1280, 1215,
1
1143, 1098, 1026, 1006, 865, 782, 631, 512 cm−1; H NMR (500
MHz, CDCl3) δ 7.49 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 6.1 Hz, 1H),
4.55 (q, J = 7.1 Hz, 2H), 2.44 (d, J = 2.3 Hz, 3H), 1.49 (t, J = 7.2 Hz,
3H); 13C NMR (126 MHz, CDCl3) δ 159.5 (d, J = 242.9 Hz), 156.4,
153.7, 147.4, 139.3 (d, J = 13.5 Hz), 127.4 (d, J = 21.7 Hz), 113.0 (d, J
= 5.8 Hz), 107.4 (d, J = 26.7 Hz), 63.4, 15.9 (d, J = 4.5 Hz), 14.3; 19F
NMR (376 MHz, CDCl3) δ −118.88 (tt, J = 6.0, 2.6 Hz); HRMS
BF3·Et2O-Catalyzed Reaction with 1-(tert-Butyl)-4-(nitroso)-
benzene (18O) (eq 1). In a N2-filled glovebox, a solution of ethyl
glyoxylate (2a) in CH2Cl2 (0.025 M, 59 μL, 1.5 μmol, 1.0 equiv) was
added to 1-(tert-butyl)-3-(nitroso)benzene-18O (4) (0.50 mg, 2.9
μmol, 2.0 equiv) in an oven-dried one dram vial with a Teflon cap. To
the reaction mixure was added BF3·Et2O (0.02 μL, 0.2 μmol, 0.1
equiv). The vial was capped tighly, removed from the glovebox, and
placed into a temperature-controlled oil bath set to 40 °C with stirring
for 48 h. The reaction solution was cooled to ambient temperature,
pushed through a SiO2 plug with ethyl acetate, and concentrated under
reduced pressure. A reaction yield was determined by GC using
tetradecane as an external standard (14%). The crude reaction mixture
was purified by prep-TLC with hexanes/ethyl acetate (3:1), and
product was collected as a fluorescent band at Rf 0.68. LCMS (ESI/[M
+ H]+) calcd. for C14H18NO218O+: 250.1324. Found: 250.1253.
Ethyl 2-(Oxo-18O)acetate (6). In a flame-dried 5 mL Schlenk flask
under positive N2 pressure, ethyl glyoxylate (2a) (52.5 mg, 0.514
mmol, 1.00 equiv) was dissolved in H218O (262 mg, 13.1 mmol, 25.5
equiv).29 The solution was stirred in an ambient temperature water
bath under N2 for 12 h. After 12 h, the mixture was frozen with liquid
N2 and then placed onto the lyophilizer to remove water. Ethyl 1-
(oxo-18O)acetate (6) was recovered after lyophilization for 4 h (20 mg,
38% yield).
+
(ESI/[M + H]+) calcd. for C11H11FNO3 : 224.0717. Found 224.0690.
Characterization for ethyl 4-fluoro-5-methylbenzo[c]isoxazole-3-carbox-
ylate (3k′, minor): (mp: 95−98 °C). IR (film) 2926, 1739, 1602, 1561,
1506, 1469, 1369, 1306, 1256, 1232, 1171, 1076, 1012, 954, 819, 777,
693, 607, 540 cm−1; 1H NMR (600 MHz, C6D6) δ 7.24 (d, J = 8.2 Hz,
1H), 6.58 (t, J = 7.3 Hz, 1H), 4.00 (q, J = 7.1 Hz, 1H), 1.95 (s, 1H),
0.92 (t, J = 7.2 Hz, 2H); 13C NMR (151 MHz, CD2Cl2) δ 156.5 (s),
153.3 (s), 145.9 (d, J = 251.1 Hz), 142.1 (d, J = 1.0 Hz), 139.1 (d, J =
12.0 Hz), 129.0 (d, J = 3.1 Hz), 125.4 (d, J = 12.5 Hz), 117.4 (d, J =
4.8 Hz), 63.8 (s), 14.8 (d, J = 3.2 Hz), 14.5 (s); 19F NMR (376 MHz,
C6D6) δ −138.26 (dq, J = 6.8, 2.3 Hz); HRMS (ESI/[M + H]+) calcd.
+
for C11H11FNO3 : 224.0717. Found 224.0746.
Ethyl Naphtho[2,1-c]isoxazole-1-carboxylate (3l). The general
procedure was followed with ethyl glyoxylate (90.0 mg, 0.882 mmol,
1.00 equiv) and 2-nitroso-naphthalene (1l) (276 mg, 1.76 mmol, 2.00
equiv). Purification via silica gel column chromatography eluting with
hexanes:ethyl acetate (5:1) afforded 3l (79 mg, 37% yield) as a red
solid (mp: 90−92 °C). IR (film) 3055, 2976, 2909, 1729, 1654, 1582,
1537, 1374, 1322, 1247, 1204, 1145, 1023, 815, 754, 636, 561 cm−1;
1H NMR (500 MHz, CDCl3) δ 8.38 (d, J = 8.2 Hz, 1H), 7.99 (d, J =
8.1 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.68
(m, 1H), 7.63 (m, 1H), 4.59 (q, J = 7.2 Hz, 2H), 1.52 (t, J = 7.2 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 156.6, 152.3, 147.7, 137.5,
133.2, 128.9, 127.6, 127.4, 127.1, 121.2, 120.5, 119.4, 63.3, 14.4;
Trapping of 6 To Give Ethyl 2-(Hydroxyl)pent-4-enoate-2-18O (7)
(eq 2).11 In the same flame-dried 5 mL Schlenk flask used for the
preparation of 6, under positive N2 pressure, 18O-ethyl glyoxyate (6)
(18 mg, 0.17 mmol, 1.0 equiv) was dissolved in CH2Cl2 (0.86 mL,
0.20 M). Allyltrimethylsilane (60 μL, 0.35 mmol, 2.0 equiv) was added
to the solution, which was then cooled to 0 °C. BF3·Et2O (40 μL, 0.35
mmol, 2.0 equiv) was added dropwise over 15 min. The reaction
mixture was stirred at 0 °C for 15 min before warming slowly to
ambient temperature and stirring for an additional 2 h in an ambient
temperature water bath. The reaction was quenched with a saturated
solution of NH4Cl (1.2 mL), extracted with CH2Cl2 (3× 1.5 mL),
washed with brine (3× 1.5 mL), dried over Na2SO4, filtered, and
+
HRMS (ESI/[M + H]+) calcd. for C14H12NO3 : 242.0812. Found
242.0787.
Ethyl 6-Methoxybenzo[c]isoxazole-3-carboxylate (3m). The
general procedure was followed with ethyl glyoxylate (102 mg, 1.00
mmol, 1.00 equiv) and 1-methoxy-3-nitrosobenzene (1m) (274 mg,
2.00 mmol, 2.00 equiv). Purification via silica gel column
chromatography eluting with hexanes:ethyl acetate (2:1) afforded
3m (115 mg, 52% yield) as a pale pink solid (mp: 80−83 °C). IR
F
dx.doi.org/10.1021/jo5015432 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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concentrated under reduced pressure to give 7 as a pale yellow oil
(20.2 mg, 80%). LCMS (ESI/[M + H]+) calcd. for C7H13O218O+:
147.0902. Found: 147.0956.
ACKNOWLEDGMENTS
■
This work was supported by the NIH (GM069559). We
gratefully acknowledge Prof. Seth B. Herzon for helpful
discussions regarding plausible reaction mechanisms.
BF3·Et2O-Catalyzed Reaction with Ethyl 2-(Oxo-18O)acetate (3a)
(eq 3). In a flame-dried 10 mL Schlenk flask under positive N2
pressure, 18O-ethyl glyoxylate (6) (20 mg, 0.20 mmol, 1.0 equiv) was
dissolved in CH2Cl2 (3 mL). A solution of nitrosobenzene (1a) (43
mg, 0.40 mmol, 1.0 equiv) in CH2Cl2 (1 mL) was added to the
reaction mixture, followed by BF3·Et2O (2.8 μL, 0.020 mmol, 0.10
equiv). The Schlenk flask was fitted with a reflux condenser under
positive N2 pressure and placed in a temperature-controlled oil bath
set to 45 °C. After stirring at a gentle reflux for 48 h, the reaction
mixture was cooled to ambient temperature, pushed through a SiO2
plug with ethyl acetate, and concentrated under reduced pressure. The
crude mixture was purified via SiO2 column chromatography eluting
with hexanes/ethyl acetate (4:1) to give a pale pink solid (34 mg, 88%
REFERENCES
■
(1) For examples of biologically relevant 2,1-benzisoxazoles, see:
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application, see: (a) Elguero, J. In Comprehensive Heterocyclic
Chemistry; Katrizky, A. R., Rees, C. W., Eds.; Pergamon Press: New
+
yield). LCMS (ESI/[M + H]+) cacld. for C10H10NO3 : 192.0655.
Found: 192.0873.
York, 1984; Vol. 4, p 167. (b) Grunanger, P.; Vita-Finzi, P. In The
̈
Preparation of N-Boc-O-acylphenylhydroxylamine and Con-
version to 2,1-Benzisoxazole. Ethyl 2-(((tert-Butoxycarbonyl)-
(phenyl)amino)oxy)-2-oxoacetate (13). In a flame-dried round-
bottom flask, N-Boc-phenylhydroxylamine30 (1.0 g, 4.8 mmol, 1.0
equiv) was dissolved in THF (50 mL, 0.10 M) under a N2 atmosphere
and cooled to 0 °C. Triethylamine (1.3 mL, 9.6 mmol, 2.0 equiv) was
added dropwise, and the reaction mixture was stirred at 0 °C for 15
min before dropwise addition of ethyl oxalyl chloride (1.2 mL, 5.7
mmol, 1.2 equiv). A white gas evolved, and the reaction mixture
warmed slowly to rt over 1.5 h. After stirring for an additional 6 h in a
rt water bath, the reaction mixture was diluted with ether (20 mL) and
washed with saturated NaHCO3 (2 × 25 mL), water (2 × 25 mL), and
brine (2 × 25 mL). The organic layer was dried over MgSO4, filtered,
and concentrated under reduced pressure to give a yellow oil (1.43 g,
97%). IR (neat) 2981, 2939, 1803, 1750, 1730, 1596, 1492, 1346,
Chemistry of Heterocyclic Compounds; Taylor, E. C., Weissberger, A.,
Eds.; Wiley Inc.: New York, 1991; Vol. 49, Chapter 2, p 123. (c) Silva,
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1
1300, 1157, 1094, 1004, 852, 747, 692 cm−1; H NMR (500 MHz,
CDCl3) δ 7.45 (d, J = 7.7 Hz, 2H), 7.38 (t, J = 7.9 Hz, 2H), 7.29 (t, J =
7.3 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.50 (s, 9H), 1.39 (t, J = 7.1 Hz,
3H); 13C NMR (126 MHz, CDCl3) δ 156.3, 152.1, 139.8, 129.1,
128.0, 124.8, 121.1, 84.3, 63.9, 28.1, 14.0; LRMS (ESI/[M + H]+)
+
calcd. for C16H19NO6 : 310.1. Found: 310.1.
Deprotection of N-Boc-O-acylphenylhydroxylamine To Give 3a
(eq 4). In a flame-dried round-bottom flask, 13 (124 mg, 0.400 mmol,
1.00 equiv) was dissolved in CH2Cl2 (12 mL, 0.030 M) with 3 Å MS
and cooled to 0 °C under N2. TFA (0.80 mL, 10 mmol, 26 equiv) was
added dropwise with stirring at 0 °C, and the reaction mixture slowly
warmed to rt over 1.5 h. After stirring for an additional 6.5 h in a rt
water bath, the crude reaction mixture was washed with water (2 × 20
mL) and brine (2 × 20 mL), dried over Na2SO4, and concentrated.
The crude mixture was purified by SiO2 column chromatography
eluting with hexanes/ethyl acetate (4:1) to give 3a as a white solid (32
(5) Few annulations to 2,1-benzisoxazoles have been reported. (I)
For reactions of nitroarenes and benzyl cyanide, see: (a) For a seminal
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31, 1. (II) Annulations of 2-nitrobenzaldehyde and arenes are of very
narrow scope and have seen very limited use; see: (c) Kliegl, A. Chem.
Ber. 1908, 41, 1845. (d) Tan
1443.
(6) Additional routes to 2,1-benzisoxazoles: (a) Smith, P.; Brown, B.;
Putney, R. J. Am. Chem. Soc. 1953, 75, 6335. (b) Musso, H.; Schroder,
̂ ̂
asescu, I. Bull. Soc. Chim. Fr. 1926, 39,
̈
1
mg, 42%). H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 8.0 Hz, 1H),
́
H. Chem. Ber. 1965, 98, 1562. (c) Boduszek, B.; Halama, A.; Zon, J.
7.67 (d, J = 8.3 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.46 (t, J = 7.7 Hz,
1H), 4.56 (q, J = 7.1 Hz, 2H), 1.50 (t, J = 7.1 Hz, 3H); 13C NMR (126
MHz, CDCl3) δ 156.6, 152.9, 151.0, 140.7, 128.3, 125.9, 122.3, 111.9,
63.4, 14.3.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Spectral data for all compounds shown in Table 2 and LCMS
traces for the labeling studies described in eqs 1−3. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(8) Zhao, D.; Johansson, M.; Backvall, J. E. Eur. J. Org. Chem. 2007,
4431.
̈
AUTHOR INFORMATION
■
(9) Purchased from Sigma-Aldrich (2.3−2.5 aqueous solution, ≥ 90%
Corresponding Author
*E-mail: jonathan.ellman@yale.edu (J.A.E.).
18O, lot no. TA0895V).
(10) Yield determined by GC relative to tetradecane. The low yield
relative to unlabeled reactions is likely the result of difficulty in
purifying the 18O-nitroso starting material on a small scale.
Notes
The authors declare no competing financial interest.
G
dx.doi.org/10.1021/jo5015432 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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dx.doi.org/10.1021/jo5015432 | J. Org. Chem. XXXX, XXX, XXX−XXX