Synthesis of benzisoxazolines by the coupling of arynes with nitrones

Article abstract of DOI:10.1021/jo2025064

A variety of substituted benzisoxazolines have been synthesized by the [3 + 2] cycloaddition of nitrones and arynes. The reaction scope is broad, the reaction conditions are mild, and the process tolerates a variety of functional groups.

Full text of DOI:10.1021/jo2025064

Article
pubs.acs.org/joc
Synthesis of Benzisoxazolines by the Coupling of Arynes with
Nitrones
Chun Lu, Anton V. Dubrovskiy, and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
S
* Supporting Information
ABSTRACT: A variety of substituted benzisoxazolines have
been synthesized by the [3 + 2] cycloaddition of nitrones and
arynes. The reaction scope is broad, the reaction conditions are
mild, and the process tolerates a variety of functional groups.
benzyne precursor failed to improve the yield significantly
INTRODUCTION
■
(Table 1, entries 2 and 3). Another fluoride ion source,
TBAF,11 was also examined (Table 1, entries 4 and 5). By
utilizing 2.0 equiv of 1a and 4.0 equiv of TBAF in THF (Table
1, entry 5), a high yield of the corresponding benzisoxazoline
(92%) was obtained. These reaction conditions, however,
turned out not to be suitable for other nitrones, probably
because of the relatively rapid rate of benzyne generation. In
order to better control the rate of benzyne generation, differing
amounts of CsF in THF were examined, since CsF has limited
solubility in THF, thus reducing the rate of benzyne generation
(Table 1, entries 6−9). Using 2.0 equiv of 1a and 5.0 equiv of
CsF at 65 °C in THF, a 93% yield of the desired cycloadduct
was produced (Table 1, entry 7). Using reduced amounts of the
benzyne precursor (1.6 equiv) and CsF (4.0 equiv) still
afforded a high 91% yield (Table 1, entry 8).
Benzisoxazoline is a critical subunit in pharmaceuticals with
important biological and pharmacological activities, including
antimicrobial activity against Salmonella paratyphi, Proteus
vulgaris, Xanthomonas spp., Fusarium solanii, and Botrytis
cinerea.1 Benzisoxazolines can also be important synthetic
intermediates for the preparation of more complex molecules.2
Much effort has been devoted to the synthesis of this
heterocyclic ring system.3
Since a convenient approach to aryne generation by the
fluoride-induced 1,2-elimination of o-(trimethylsilyl)aryl tri-
flates was first reported,4 highly electrophilic arynes have been
employed extensively in recent years for the construction of
many heteroaromatic structures.5 Our group has recently
reported that simple nucleophilic reactions,6 annulation
reactions,7 and a variety of 1,3-dipolar cycloadditions8 provide
useful new synthetic routes to a variety of heterocycles,
generally affording excellent yields under mild reaction
conditions. In a continuation of our work on the reactions of
arynes with dipoles, we have investigated the cycloaddition
reactions of nitrones and arynes. During this project, related
work was communicated by other groups.9 However, that work
generally involved less convenient reaction conditions and
aryne precursors, such as n-BuLi-promoted halogen exchange of
o-haloaryl triflates under low temperatures9b and PhI(OAc)2/
TfOH-promoted generation of benzynes from benzobisoxadi-
siloles.9c More importantly, the authors failed to examine the
scope and effect of various functional groups on their processes.
Herein, we wish to report our more detailed and extensive
results on the 1,3-dipolar cycloaddition reaction of nitrones and
arynes generated from o-silylaryl triflates to afford a wide variety
of substituted benzisoxazolines.10
Using the optimal conditions shown in Table 1, entry 8, the
scope and limitations of this methodology have been examined.
Various substituted nitrones have been examined in this
reaction, and the results are summarized in Table 2.
Excellent yields have been obtained from both N-alkyl (Table
2, entries 2−5) and N-benzyl-substituted nitrones (Table 2,
entries 1 and 6−9). The results suggest that the steric effect of
substituents on the carbon of the nitrone double bond are
significant. Lower yields are observed for the substrates with
more steric hindrance on the carbon of the C−N double bond.
For example, 2e, which has two methyls on the carbon of the
C−N double bond (Table 2, entry 5), and 2h, which has an
ortho-methoxy-substituted phenyl on that carbon (Table 2,
entry 8), both give lower yields. The process has also been
applied to N-aryl-substituted nitrone 2j (Table 2, entry 10),
which affords a high 92% yield of benzisoxazoline 3j.
Nitrones with a variety of functionally substituted phenyl
groups on the nitrone carbon have been examined under our
optimal conditions (Table 2, entries 11−19). Many functional
groups are well tolerated, including ester, cyano, amino,
halogen, and other groups. Nitrones with electron-donating
RESULTS AND DISCUSSION
■
We optimized the reaction conditions for the reaction of the
unsubstituted benzyne precursor o-(trimethylsilyl)phenyl tri-
flate (1a) and N-benzylidenebenzylamine N-oxide (2a) (Table
1). Employing acetonitrile as the solvent and 3.0 equiv of CsF
as the fluoride source provides the desired benzisoxazoline 3a
in a 60% yield (Table 1, entry 1). Adding more CsF or more
Received: December 16, 2011
Published: February 13, 2012
© 2012 American Chemical Society
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Table 1. Optimization Studies of the Reaction between o-(Trimethylsilyl)phenyl Triflate (1a) and N-Benzylidenebenzylamine
a
N-Oxide (2a)
b
entry
benzyne (equiv)
CsF (equiv)
solvent
temp (°C)
time (h)
% yield of 3a
1
2
3
4
5
6
7
8
9
1.2
1.2
2.0
1.2
2.0
1.2
2.0
1.6
1.6
3.0
4.0
3.0
MeCN
MeCN
MeCN
THF
rt
rt
24
24
24
24
24
24
14
14
24
60
65
56
45
92
68
93
91
83
rt
c
2.0 TBAF
rt
c
4.0 TBAF
THF
45
65
65
65
65
3.0
5.0
4.0
3.0
THF
THF
THF
THF
a
b
c
All reactions were conducted on a 0.25 mmol scale in 5 mL of solvent for 24 h. Yields of products isolated by column chromatography. 1 M
TBAF in THF solution.
groups tend to result in lower yields (Table 2, entries 15 and
16) than nitrones with electron-withdrawing groups (Table 2,
entries 11−14), presumably because of the reduced electro-
philicity of the carbon−nitrogen double bond due to the
presence of such groups (see the later mechanistic discussion).
Nitrone 2q also afforded a relatively low yield of 57%, mainly
because of the steric hindrance produced by the ortho-methoxy
group (Table 2, entry 17). Because of the presence of the
additional carbon−carbon double bond in 2s, the reaction was
not as clean as that of other substrates but still produced a good
yield (Table 2, entry 19).12 Several cyclic nitrones have also
been examined, and moderate yields have been obtained (Table
2, entries 21−23).
CONCLUSIONS
■
In conclusion, we have developed a facile and general method
for the synthesis of substituted benzisoxazolines by the 1,3-
dipolar cycloaddition of arynes and nitrones under mild
reaction conditions, which provides excellent yields. A variety
of functional groups are well tolerated in this process, allowing
further synthesis of more complicated molecules.
EXPERIMENTAL SECTION
General Methods. The H and 13C NMR spectra were recorded
■
1
at 300 and 75.5 MHz or 400 and 100 MHz, respectively. All melting
points are uncorrected. High resolution mass spectra were recorded
using EI at 70 eV. All reagents were used directly as obtained
commercially unless otherwise noted. All reactions were carried out in
oven-dried glassware and monitored by thin layer chromatography
(SiO2, hexanes or hexanes/EtOAc). THF was distilled over Na. The
silylaryl triflate 1a, CsF, TBAF solution (1 M in THF), and acetonitrile
were purchased from Sigma-Aldrich. 4,5-Dimethyl-substituted silylaryl
triflate 1b, 4,5-dimethoxy-substituted silylaryl triflate 1c and 4,5-
difluoro-substituted silylaryl triflate 1d were prepared according to a
literature procedure.13
Noncommercially Available Compounds. Noncommercially
available starting materials were prepared according to literature
procedures.14
(2-Methoxyphenylmethylene)benzylamine-N-oxide (2h). Light
yellow solid: mp 78−79 °C; H NMR (300 MHz, CDCl3) δ 9.28
After a variety of substituted nitrones were examined, the
behavior of various aryne precursors was studied in this reaction
(Table 3).
Symmetrical dimethyl- (1b), dimethoxy- (1c), and difluoro-
substituted (1d) benzyne precursors have been employed
under our optimal reaction conditions with nitrone 2f. All of
these substrates generated comparable but lower yields than
benzyne itself. Similar results have been observed before in
other reaction systems.6 The unsymmetrical methoxy-sub-
stituted benzyne precursor 1e provided benzisoxazoline 3fe as a
single regioisomer in a 75% yield. Two possible mechanisms for
this process are proposed in Scheme 1 on the basis of the
experimental results and previous experience.8
Following the formation of benzyne induced by fluoride from
benzyne precursor 1e, a [3 + 2] cycloaddition can occur.
Nucleophilic attack of the oxygen anion of 2f on benzyne,
quickly followed by cyclization of 3fe′, can be envisioned as a
mechanistic alternative. The significant steric and electronic
effects of the substituents on the carbon−nitrogen double bond
of the nitrone on the reaction results are consistent with both
of these proposed mechanisms. The steric hindrance arising
from the substituent on the carbon of the C−N double bond
(see the results of entries 5, 8, and 17 in Table 2) is expected to
disfavor the cycloaddition of 2f to 3fe or the cycloaddition of
3fe′ to 3fe. Furthermore, the presence of electron-withdrawing
substituents on the phenyl group present on the carbon of the
C−N double bond (see the results of entries 12−16 in Table 2)
would be expected to increase the electrophilicity of the C−N
double bond in 3fe′, producing higher yields of the products.
1
(dd, J = 7.8, 1.5 Hz, 1H), 7.96 (s, 1H), 7.51−7.26 (m, 7H), 6.99 (t, J =
8.1 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 5.05 (s, 2H), 3.83 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 157.0, 133.9, 131.7, 129.1, 128.9, 128.8,
128.8, 120.8, 119.7, 109.8, 71.7, 55.6; HRMS (EI) calcd for
C15H15NO2 241.1103, found 241.1101.
(3-Nitrophenylmethylene)benzylamine-N-oxide (2i). Yellow solid:
1
mp 142−144 °C; H NMR (300 MHz, CDCl3) δ 9.04 (s, 1H), 8.57
(d, J = 7.8 Hz, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.57−7.41 (m, 7H), 5.11
(s, 2H); 13C NMR (75 MHz, CDCl3) δ 148.2, 133.8, 132.8, 132.1,
132.0, 129.6, 129.5, 129.5, 129.2, 124.7, 123.1, 71.9; HRMS (EI) calcd
for C14H12N2O3 256.0848, found 256.0843.
(5-Bromo-2-methoxyphenylmethylene)phenylamine-N-oxide
(2q). Yellow solid: mp 135−137 °C; H NMR (300 MHz, CDCl3) δ
9.66 (d, J = 2.7 Hz, 1H), 8.33 (s, 1H), 7.78−7.74 (m, 2H), 7.51−7.46
(m, 4H), 6.79 (d, J = 9.0 Hz, 1H), 3.86 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 156.5, 149.6, 134.6, 131.1, 130.1, 129.3, 128.2, 121.9, 121.7,
113.6, 111.7, 56.1; HRMS (EI) calcd for C14H12NO2Br 305.0051,
found 305.0049.
1
(4,5-Dimethoxy-3-iodophenylmethylene)phenylamine-N-oxide
(2r). Yellow solid: mp 162−164 °C; H NMR (300 MHz, CDCl3) δ
1
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a
Table 2. Cycloadditions of Benzyne with Nitrones
Table 3. Investigation of Different Arynes in the Coupling
Reaction with Nitrone 2f
a
a
Unless otherwise stated, all reactions have been carried out on a 0.25
mmol scale, with 1.6 equiv of benzyne precursor 1a and 4.0 equiv of
b
CsF in 5 mL of THF at 65 °C for 14 h. Yields of products isolated by
column chromatography.
Scheme 1. Possible Mechanisms
8.60 (d, J = 1.5 Hz, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.82 (s, 1H), 7.75−
7.72 (m, 2H), 7.45 (m, 3H), 3.92 (s, 3H), 3.89 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 152.2, 150.8, 148.9, 132.8, 132.3, 130.2, 129.3, 128.8,
121.7, 112.5, 92.0, 60.7, 56.1; HRMS (EI) calcd for C15H14NO3I
383.0018, found 383.0014.
Representative Procedure for the Cycloaddition of Arynes
and Nitrones. An oven-dried 6-dram vial equipped with a stir bar was
charged with 0.25 mmol of the nitrone, 0.40 mmol (1.6 equiv) of the
aryne precursor, and 1.00 mmol (152 mg, 4.0 equiv) of CsF, followed
by 5 mL of dry THF. The vial was sealed and placed in an oil bath at
65 °C for about 14 h. The resulting mixture was cooled and
concentrated under vacuum to yield the crude product, which was
purified by flash chromatography on silica gel with ethyl acetate/
hexanes or dichloromethane/hexane as the eluent.
a
Unless otherwise stated, all reactions have been carried out on a 0.25
2-Benzyl-3-phenyl-2,3-dihydrobenzo[d]isoxazole (3a). White
mmol scale, with 1.6 equiv of benzyne precursor 1a and 4.0 equiv of
CsF in 5 mL of THF at 65 °C for 14 h. Yields of products isolated by
column chromatography.
b
1
solid (65.5 mg, 91%): mp 94−95 °C; H NMR (400 MHz, CDCl3)
δ 7.43 (s, 2H), 7.39−7.28 (m, 8H), 7.23 (t, J = 7.7 Hz, 1H), 7.04 (d, J
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= 7.5 Hz, 1H), 6.93 (t, J = 7.4 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 5.37
(s, 1H), 4.41 (d, J = 13.3 Hz, 1H), 4.18 (d, J = 13.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 156.3, 140.7, 136.6, 129.5, 129.1, 129.0,
128.8, 128.7, 128.2, 128.0, 127.9, 124.5, 121.7, 117.6, 108.4, 72.9, 63.0;
HRMS (EI) calcd for C20H17NO 287.1310, found 287.1304.
7.09−6.85 (m, 7H), 6.74 (d, J = 9.0 Hz, 2H), 6.62 (t, J = 6.0 Hz, 1H),
6.53−6.49 (m, 1H), 6.43 (dd, J = 6.0, 3.0 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 150.6, 138.6, 136.5, 131.5, 129.9, 129.5, 129.1, 127.7,
127.2, 122.8, 121.1, 118.3, 110.2, 108.9, 99.3; HRMS (EI) calcd for
C19H15NO 273.1154, found 273.1152.
3-(2-Chlorophenyl)-2-phenyl-2,3-dihydrobenzo[d]isoxazole (3k).
2-Butyl-3-phenyl-2,3-dihydrobenzo[d]isoxazole (3b). Colorless oil
1
1
White solid (69.2 mg, 90%): mp 74−76 °C; H NMR (300 MHz,
(55.7 mg, 88%): H NMR (300 MHz, CDCl3) δ 7.45−7.33 (m, 5H),
CDCl3) δ 7.54 (d, J = 6.0 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.29−7.15
(m, 5H), 7.08 (dt, J = 9.0, 3.0 Hz, 2H), 6.99 (t, J = 9.0 Hz, 1H), 6.92−
6.87 (m, 1H), 6.82−6.79 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
150.3, 142.3, 135.3, 134.4, 133.5, 131.0, 130.3, 129.6, 128.8, 127.6,
122.7, 121.4, 121.3, 117.5, 110.5, 109.2, 95.6; HRMS (EI) calcd for
C19H14NOCl 307.0764, found 307.0769.
7.22 (t, J = 6.0 Hz, 1H), 7.00 (d, J = 6.0 Hz, 1H), 6.93−6.87 (m, 2H),
3.27 (m, 1H), 3.01 (m, 1H), 1.78−1.71 (m, 2H), 1.51−1.38 (m, 2H),
0.95 (t, J = 6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 156.1, 140.8,
129.5, 129.0, 128.1, 128.0, 124.1, 121.3, 108.0, 74.5, 59.6, 30.0, 20.6,
14.1; HRMS (EI) calcd for C17H19NO 253.1467, found 253.1463.
2-tert-Butyl-3-phenyl-2,3-dihydrobenzo[d]isoxazole (3c). White
1
2-Phenyl-3-(4-trifluoromethylphenyl)-2,3-dihydrobenzo[d]-
solid (60.2 mg, 95%): mp 94−96 °C; H NMR (300 MHz, CDCl3)
1
isoxazole (3l). White solid (79.4 mg, 93%): mp 86−88 °C; H NMR
δ 7.43−7.26 (m, 5H), 7.14 (d, J = 9.0 Hz, 1H), 6.90 (d, J = 6.0 Hz,
1H), 6.83−6.79 (m, 2H), 5.61 (s, 1H), 1.20 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 156.4, 144.1, 130.0, 128.8, 127.6, 127.5, 123.8, 120.9,
106.9, 67.2, 61.2, 29.9, 25.7; HRMS (EI) calcd for C17H19NO
253.1467, found 253.1468.
(300 MHz, CDCl3) δ 7.66 (t, J = 9.6 Hz, 4H), 7.32−7.24 (m, 2H),
7.13−7.01 (m, 4H), 6.94−6.79 (m, 4H); 13C NMR (75 MHz, CDCl3)
δ 150.4, 142.6, 142.4, 134.6, 129.8, 127.7, 126.2, 126.2, 126.1, 126.1,
123.3, 121.6, 118.4, 110.8, 109.1, 98.4; HRMS (EI) calcd for
C20H14NOF3 341.1027, found 341.1032.
2-Octyl-3-heptyl-2,3-dihydrobenzo[d]isoxazole (3d). Colorless oil
1
3-(4-Carbomethoxyphenyl)-2-phenyl-2,3-dihydrobenzo[d]-
(74.8 mg, 90%): H NMR (300 MHz, CDCl3) δ 7.21−7.09 (m, 2H),
1
isoxazole (3m). White solid (74.2 mg, 90%): mp 118−120 °C; H
6.91 (t, J = 7.3 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 4.09 (dd, J = 7.7, 5.3
Hz, 1H), 3.02 (dd, J = 13.2, 6.5 Hz, 1H), 2.79−2.58 (m, 1H), 1.70−
1.66 (m, 4H), 1.49−1.17 (m, 20H), 0.88 (t, J = 6.4 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 156.2, 129.3, 128.6, 123.9, 121.1, 108.4,
70.0, 60.4, 36.8, 32.1, 29.8, 29.7, 29.5, 29.5, 27.8, 27.6, 26.0, 22.9, 14.3;
HRMS (EI) calcd for C22H37NO 331.2875, found 331.2878.
NMR (300 MHz, CDCl3) δ 8.06 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.1
Hz, 2H), 7.27 (t, J = 7.5 Hz, 2H), 7.10 (m, 3H), 7.02 (t, J = 7.5 Hz,
1H), 6.92−6.79 (m, 4H), 3.90 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
166.8, 150.5, 143.1, 142.5, 134.7, 131.5, 130.4, 129.7, 127.3, 123.2,
121.5, 121.4, 118.5, 110.5, 109.0, 98.6, 52.4; HRMS (EI) calcd for
C21H17NO3 331.1208, found 331.1215.
2-Isopropyl-3,3-dimethyl-2,3-dihydrobenzo[d]isoxazole (3e).
3-(4-Cyanophenyl)-2-phenyl-2,3-dihydrobenzo[d]isoxazole (3n).
1
Light brown oil (37.6 mg, 79%): H NMR (300 MHz, CDCl3) δ
1
White solid (65.7 mg, 88%): mp 105−108 °C; H NMR (300 MHz,
7.21−7.15 (m, 2H), 6.92 (t, J = 6.0 Hz, 1H), 6.81 (d, J = 9.0 Hz, 1H),
4.05 (t, J = 6.0 Hz, 1H), 3.03 (m, 1H), 2.68 (m, 1H), 1.71 (m, 4H),
1.01 (td, J = 9.0, 6.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 156.3,
129.0, 128.7, 123.9, 121.1, 108.3, 71.2, 62.3, 29.5, 21.0, 12.0, 10.3;
HRMS (EI) calcd for C12H17NO 191.1310, found 191.1308.
CDCl3) δ 7.72−7.65 (m, 4H), 7.30 (t, J = 7.5 Hz, 2H), 7.12−7.03 (m,
4H), 6.94−6.79 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 150.3, 143.5,
133.0, 129.8, 128.0, 123.5, 121.7, 121.7, 118.6, 118.5, 113.7, 111.0,
109.2, 98.2; HRMS (EI) calcd for C20H14N2O 298.1106, found
298.1106.
2-Benzyl-3-(4-methoxyphenyl)-2,3-dihydrobenzo[d]isoxazole
3-(4-Methylthiophenyl)-2-phenyl-2,3-dihydrobenzo[d]isoxazole
1
(3f). White solid (71.2 mg, 90%): mp 121−123 °C; H NMR (300
1
(3o). White solid (61.8 mg, 77%): mp 82−84 °C; H NMR (300
MHz, CDCl3) δ 7.46−7.31 (m, 5H), 7.26−7.20 (m, 3H), 7.02 (d, J =
6.0 Hz, 1H), 6.95−6.86 (m, 4H), 5.34 (s, 1H), 4.38 (d, J = 12.0 Hz,
1H), 4.18 (d, J = 12.0 Hz, 1H), 3.81 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 159.6, 156.4, 136.7, 132.6, 129.5, 129.2, 129.2, 129.0, 128.6,
127.8, 124.3, 121.6, 114.2, 108.3, 72.5, 62.6, 55.5; HRMS (EI) calcd
for C21H19NO2 317.1416, found 317.1420.
MHz, CDCl3) δ 7.45 (d, J = 9.0 Hz, 2H), 7.29−7.23 (m, 4H), 7.12−
7.08 (m, 3H), 7.00 (t, J = 9.0 Hz, 1H), 6.90−6.83 (m, 1H), 6.80−6.76
(m, 3H), 2.46 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 150.5, 142.5,
140.8, 135.2, 130.2, 129.6, 127.7, 126.7, 122.8, 121.2, 121.1, 118.4,
110.1, 108.9, 98.9, 15.7; HRMS (EI) calcd for C20H17NOS 319.1031,
found 319.1034.
2-Benzyl-3-(3-methoxyphenyl)-2,3-dihydrobenzo[d]isoxazole
3-[4-(Dimethylamino)phenyl]-2-phenyl-2,3-dihydrobenzo[d]-
isoxazole (3p). Light brown oil (58.3 mg, 74%): 1H NMR (300 MHz,
CDCl3) δ 7.40 (d, J = 8.7 Hz, 2H), 7.29−7.20 (m, 3H), 7.16−7.08 (m,
3H), 6.98 (t, J = 7.2 Hz, 1H), 6.86 (td, J = 6.0, 3.0 Hz, 1H), 6.79−6.77
(m, 2H), 6.70 (d, J = 9.0 Hz, 2H), 2.96 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 151.7, 150.7, 142.5, 129.6, 129.4, 128.4, 125.8, 122.5, 120.9,
120.7, 118.4, 112.4, 109.6, 108.7, 99.6, 40.6; HRMS (EI) calcd for
C21H20ON2 316.1576, found 316.1583.
3-(5-Bromo-2-methoxyphenyl)-2-phenyl-2,3-dihydrobenzo[d]-
isoxazole (3q). White solid (54.6 mg, 57%): mp 73−75 °C; 1H NMR
(300 MHz, CDCl3) δ 7.55 (d, J = 3.0 Hz, 1H), 7.43 (dd, J = 6.0, 3.0
Hz, 1H), 7.27 (t, J = 6.0 Hz, 2H), 7.19−7.16 (m, 2H), 7.11−7.08 (dd,
J = 9.0, 3.0 Hz, 2H), 7.00 (t, J = 9.0 Hz, 1H), 6.90 (td, J = 6.0, 3.0 Hz,
1H), 6.85 (s, 1H), 6.80 (dd, J = 9.0, 3.0 Hz, 2H), 3.89 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 156.7, 150.5, 142.8, 134.3, 133.7, 130.8,
129.6, 128.4, 122.6, 121.4, 121.2, 117.4, 113.5, 113.2, 111.0, 109.1,
93.4, 56.3; HRMS (EI) calcd for C20H16NO2Br 381.0364, found
381.0368.
3-(4,5-Dimethoxy-3-iodophenyl)-2-phenyl-2,3-dihydrobenzo[d]-
isoxazole (3r). Light brown oil (80.3 mg, 70%): 1H NMR (300 MHz,
CDCl3) δ 7.55 (d, J = 3.0 Hz, 1H), 7.33 (d, J = 6.0 Hz, 2H), 7.16−7.05
(m, 6H), 6.93 (td, J = 9.0, 6.0 Hz, 1H), 6.83 (t, J = 6.0 Hz, 2H), 6.70
(s, 1H), 3.85 (s, 3H), 3.83 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
153.2, 150.3, 150.2, 142.6, 136.3, 134.8, 129.7, 129.5, 123.3, 121.4,
118.6, 111.4, 110.6, 109.0, 98.4, 92.9, 60.6, 56.2; HRMS (EI) calcd for
C21H18NO3I 459.0331, found 459.0320.
1
(3g). White solid (63.0 mg, 79%): mp 69−72 °C; H NMR (300
MHz, CDCl3) δ 7.46 (d, J = 6.0 Hz, 2H), 7.41−7.32 (m, 3H), 7.83 (m,
2H), 7.29−7.21 (m, 2H), 7.07 (d, J = 6.0 Hz, 1H), 6.96−6.83 (m,
5H), 5.36 (s, 3H), 4.42 (d, J = 12.0 Hz, 1H), 4.18 (d, J = 12.0 Hz, 1H),
3.77 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.0, 156.3, 142.2,
136.5, 129.8, 129.5, 129.1, 128.8, 128.6, 127.9, 124.4, 121.6, 120.2,
113.8, 113.3, 108.3, 72.7, 62.9, 55.4; HRMS (EI) calcd for C21H19NO2
317.1416, found 317.1422.
2-Benzyl-3-(2-methoxyphenyl)-2,3-dihydrobenzo[d]isoxazole
1
(3h). White solid (51.8 mg, 65%): mp 71−73 °C; H NMR (300
MHz, CDCl3) δ 7.46 (d, J = 6.0 Hz, 2H), 7.38−7.19 (m, 8H), 6.95−
6.86 (m, 4H), 5.89 (s, 1H), 4.37 (d, J = 15.0 Hz, 1H), 4.18 (d, J = 15.0
Hz, 1H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 156.7, 156.4,
137.1, 129.6, 129.4, 128.9, 128.9, 128.5, 127.6, 124.8, 121.6, 121.1,
110.4, 108.5, 66.4, 63.5, 55.5; HRMS (EI) calcd for C21H19NO2
317.1416, found 317.1419.
2-Benzyl-3-(3-nitrophenyl)-2,3-dihydrobenzo[d]isoxazole (3i).
White solid (57.1 mg, 69%): mp 118−120 °C; 1H NMR (300
MHz, CDCl3) δ 8.11 (dd, J = 6.0, 3.0 Hz, 2H), 7.62 (d, J = 6.0 Hz,
2H), 7.49−7.25 (m, 8H), 7.09 (d, J = 9.0 Hz, 1H), 6.97 (d, J = 9.0 Hz,
1H), 6.91 (d, J = 9.0 Hz, 1H), 5.44 (s, 1H), 4.50 (d, J = 12.0 Hz, 1H),
4.13 (d, J = 12.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 156.2, 148.1,
143.3, 135.7, 133.7, 129.8, 129.8, 129.6, 128.8, 128.2, 127.3, 124.4,
123.0, 122.6, 122.1, 108.8, 71.5, 63.2; HRMS (EI) calcd for
C20H16N2O3 332.1161, found 332.1166.
2,3-Diphenyl-2,3-dihydrobenzo[d]isoxazole (3j). Light brown oil
2-Phenyl-3-(E-2-phenylethenyl)-2,3-dihydrobenzo[d]isoxazole
1
(62.7 mg, 92%): H NMR (300 MHz, CDCl3) δ 7.19−7.15 (m, 2H),
(3s). Light brown oil (42.1 mg, 56%): 1H NMR (300 MHz, CDCl3) δ
2282
dx.doi.org/10.1021/jo2025064 | J. Org. Chem. 2012, 77, 2279−2284

The Journal of Organic Chemistry
Article
7.48−7.43 (m, 3H), 7.38−7.28 (m, 6H), 7.09−7.05 (m, 2H), 6.92−
6.72 (m, 4H), 6.48−6.38 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
150.9, 142.8, 135.3, 131.5, 129.6, 129.3, 128.8, 128.7, 127.3, 125.4,
122.9, 121.2, 121.1, 118.5, 110.8, 108.9, 99.1; HRMS (EI) calcd for
C21H17ON 299.1310, found 299.1305.
347.1521, found 347.1521. Note: In the 1D-NOE experiment, a
correlation of 5.37 (s, 1H) to 3.75 (s, 3H). but not to 6.57 (d, J = 8.0
Hz, 1H) or 6.51 (d, J = 8.2 Hz, 1H), is observed. This would not be
the case if the compound 3fe were the other regioisomer.
2-(4-Methoxyphenyl)-3-phenyl-2,3-dihydrobenzo[d]isoxazole
ASSOCIATED CONTENT
■
1
(3t). White solid (48.6 mg, 64%): mp 118−120 °C; H NMR (300
S
* Supporting Information
MHz, CDCl3) δ 7.53 (dd, J = 6.0, 3.0 Hz, 2H), 7.36 (t, J = 3.0 Hz,
1H), 7.03 (d, J = 9.0 Hz, 2H), 6.82−6.74 (m, 6H), 6.64 (s, 1H), 3.71
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 156.4, 150.4, 138.6, 136.9,
135.6, 129.9, 128.9, 127.6, 122.6, 121.3, 120.3, 114.8, 108.9, 108.4,
100.5, 55.6; HRMS (EI) calcd for C20H17NO2 303.1259, found
303.1255.
5,12-Dihydro-6H-[1,2]benzisoxazolo[3,2]isoquinoline (3u). White
solid (36.4 mg, 65%): mp 69−72 °C; 1H NMR (300 MHz, CDCl3) δ
7.37 (d, J = 9.0 Hz, 1H), 7.29 (t, J = 9.0 Hz, 1H), 7.22−7.09 (m, 4H),
6.90−6.83 (m, 2H), 5.80 (s, 1H), 3.36−3.30 (m, 2H), 3.00−2.77 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 156.7, 134.1, 133.5, 129.1, 128.8,
128.6, 127.2, 127.0, 126.9, 123.6, 121.6, 108.7, 65.7, 49.9, 26.9; HRMS
(EI) calcd for C15H13NO 223.0997, found 223.1003.
1H and 13C NMR data for compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: larock@iastate.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Institute of General Medical Sciences
(GM070620 and GM079593) and the National Institutes of
Health Kansas University Center of Excellence in Chemical
Methodology and Library Development (P50 GM069663) for
their generous financial support. Thanks are also extended to
Dr. Feng Shi, Dr. Shilpa Worlikar, and Dr. Donald Rogness for
preparation of the benzyne precursors.
7,10a-Dimethylpyrido-8,9,10-trihydro[1,2]benzisoxazole (3v).
1
Colorless oil (30.5 mg, 60%): H NMR (300 MHz, CDCl3) δ 7.13
(t, J = 6.0 Hz, 1H), 7.03 (d, J = 9.0 Hz, 1H), 6.87 (t, J = 6.0 Hz, 1H),
6.78 (d, J = 9.0 Hz, 1H), 3.22 (m, 1H), 1.63−1.51 (m, 9H), 1.41 (d, J
= 9.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 155.5, 136.9, 128.0,
121.0, 120.8, 108.0, 65.6, 54.0, 33.3, 26.3, 22.8, 20.3, 19.3; HRMS (EI)
calcd for C13H17NO 203.1310, found 203.1306.
10a-Methyl-7,8,9,10-tetrahydropyrido[1,2]benzisoxazole (3w).
1
Colorless oil (30.4 mg, 64%): H NMR (300 MHz, CDCl3) δ 7.19
REFERENCES
■
(d, J = 9.0 Hz, 1H), 7.07 (d, J = 6.0 Hz, 1H), 6.97 (t, J = 6.0 Hz, 1H),
6.89 (d, J = 9.0 Hz, 1H), 3.39 (m, 1H), 2.64 (td, J = 9.0, 6.0 Hz, 1H),
2.29 (m, 1H), 1.86 (m, 1H), 1.65−1.51 (m, 3H), 1.35 (s, 3H), 1.35−
1.23 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 157.2, 133.4, 128.2,
121.8, 121.7, 110.0, 67.0, 52.7, 32.8, 30.0, 23.5, 20.5; HRMS (EI) calcd
for C12H15NO 189.1154, found 189.1149.
2-Benzyl-3-(4-methoxyphenyl)-2,3-dihydro-5,6-dimethylbenzo-
[d]isoxazole (3fb). Yellow solid (62.0 mg, 72%): mp 121−123 °C; 1H
NMR (300 MHz, CDCl3) δ 7.43−7.26 (m, 5H), 7.18 (d, J = 8.4 Hz,
2H), 6.85 (d, J = 9.0 Hz, 2H), 6.78 (s, 1H), 6.68 (s, 1H), 5.25 (s, 1H),
4.35 (d, J = 13.0 Hz, 1H), 4.12 (d, J = 13.0 Hz, 1H), 3.79 (s, 3H), 2.25
(s, 3H), 2.17 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.5, 154.8,
137.5, 136.8, 133.2, 129.7, 129.6, 129.5, 129.1, 128.6, 127.7, 126.5,
125.1, 114.1, 109.3, 72.3, 62.8, 55.5, 20.5, 19.6; HRMS (EI) calcd for
C23H23NO2 345.1729, found 345.1721.
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2-Benzyl-5,6-dimethoxy-3-(4-methoxyphenyl)-2,3-dihydrobenzo-
1
[d]isoxazole (3fc). Light brown oil (66.2 mg, 70%): H NMR (300
MHz, CDCl3) δ 7.42−7.27 (m, 5H), 7.16 (d, J = 9.0 Hz, 2H), 6.86 (d,
J = 9.0 Hz, 2H), 6.53 (d, J = 9.0 Hz, 2H), 5.27 (s, 1H), 4.35 (d, J =
12.0 Hz, 1H), 4.14 (d, J = 15.0 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H),
3.77 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.6, 150.8, 150.3,
144.5, 136.8, 132.8, 129.5, 129.4, 128.6, 127.8, 118.7, 114.2, 107.9,
93.6, 73.0, 62.8, 57.0, 56.4, 55.5; HRMS (EI) calcd for C23H23NO4
377.1627, found 377.1620.
2-Benzyl-5,6-difluoro-3-(4-methoxyphenyl)-2,3-dihydrobenzo[d]-
isoxazole (3fd). Light brown oil (36.3 mg, 41%): 1H NMR (300 MHz,
CDCl3) δ 7.40−7.31 (m, 6H), 7.20 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 9.0
Hz, 2H), 6.77 (t, J = 9.0 Hz, 1H), 6.66 (dd, J = 9.0, 6.0 Hz, 1H), 5.27
(s, 1H), 4.34 (d, J = 12.0 Hz, 1H), 4.16 (d, J = 12.0 Hz, 1H), 3.82 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 159.9, 136.2, 129.4, 129.3, 128.7,
128.0, 114.4, 112.7, 112.4, 98.3, 98.0, 72.5, 62.5, 55.5; HRMS (EI)
calcd for C21H17NO2F2 353.1227, found 353.1230.
2-Benzyl-4-methoxy-3-(4-methoxyphenyl)-2,3-dihydrobenzo[d]-
1
isoxazole (3fe). Colorless oil (64.8 mg, 75%): H NMR (600 MHz,
CDCl3) δ 7.44 (d, J = 7.0 Hz, 2H), 7.36 (t, J = 7.3 Hz, 2H), 7.32 (t, J =
7.2 Hz, 1H), 7.22 (t, J = 8.1 Hz, 1H), 7.12 (d, J = 8.7 Hz, 2H), 6.80 (d,
J = 8.7 Hz, 2H), 6.57 (d, J = 8.0 Hz, 1H), 6.51 (d, J = 8.2 Hz, 1H),
5.37 (s, 1H), 4.39 (d, J = 12.8 Hz, 1H), 4.05 (d, J = 12.9 Hz, 1H), 3.77
(s, 3H), 3.75 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.9, 157.9,
156.6, 136.3, 132.9, 130.4, 129.5, 128.5, 128.4, 127.7, 115.1, 113.7,
104.1, 101.8, 69.3, 63.0, 55.5, 55.2; HRMS (EI) calcd for C22H21NO3
(11) 1 M TBAF in THF solution.
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2284
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