Tert-Butyl Nitrite-Mediated Domino Synthesis of Isoxazolines and Isoxazoles from Terminal Aryl Alkenes and Alkynes

Article abstract of DOI:10.1021/acs.joc.7b00946

A sequential construction of C-C, C-O, C = N, and C = O bonds from alkenes leading to the direct synthesis of isoxazolines in the presence of tert-butyl nitrite, quinoline, and the Sc(OTf)₃ catalyst in DCE at 80 °C has been accomplished. An unprecedented three consecutive C-H functionalizations of two styrenes are involved in this isoxazoline synthesis. In this radical-mediated reaction, one-half of the aryl alkene is converted into an intermediate 2-nitroketone, which serves as a 1,3-dipolarophile and undergoes cycloaddition with the other half of the unreacted aromatic terminal alkene. The use of an alkyne in lieu of an alkene leads to the formation of isoxazole under identical reaction conditions.

Full text of DOI:10.1021/acs.joc.7b00946

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Article
Tert-Butyl Nitrite Mediated Domino Synthesis of Isoxazolines
and Isoxazoles from Terminal Aryl Alkenes and Alkynes
Prasenjit Sau, Sourav Kumar Santra, Amitava Rakshit, and Bhisma K. Patel
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 18 May 2017
Downloaded from http://pubs.acs.org on May 19, 2017
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TertꢀButyl Nitrite Mediated Domino Synthesis of Isoxazolines and Isoxazoles
from Terminal Aryl Alkenes and Alkynes
Prasenjit Sau, Sourav Kumar Santra, Amitava Rakshit and Bhisma K. Patel*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahatiꢀ781039, India
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Fax: (+91)361ꢀ26909762.
Eꢀmail: patel@iitg.ernet.in
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
ABSTRACT: A sequential construction of C−C, C−O, C=N and C=O bonds from alkenes
leading to the direct synthesis of isoxazolines in the presence of tertꢀbutyl nitrite, quinoline and
o
Sc(OTf) catalyst in DCE at 80 C has been accomplished. An unprecedented consecutive three
3
C−H functionalisations of two styrenes are involved during this isoxazoline synthesis. In this
radical mediated reaction one half of the aryl alkene is converted into intermediate 2ꢀnitro ketone
which serve as a 1,3ꢀdipolarophile and undergo cycloaddition with the other half of unreacted
aromatic terminal alkene. The use of alkyne in lieu of alkene leads to the formation of isoxazole
under an identical reaction condition.
INTRODUCTION
Alkenes are simple organic molecules which have been widely applied in organic synthesis
for the construction of a diverse array of complex molecules. One of the finest approaches to
build such molecules in a single operation is via the direct 1,2ꢀdifunctionalization of alkenes. In
this context, both intra and intermolecular hetero difunctionalization of alkenes have acquired
significant attention. In contrast to intermolecular processes intramolecular difunctionalizations
are more selective and thermodynamically favorable. Despite that, the transition metal catalyzed
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intermolecular difunctionalizations viz. carbohalogenation, dihydroxylation, oxyarylation,
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oxyamination, aminofluorination, aminocyanation, hydroalkylation, carboboration, and other
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difunctionalization are well explored. However, intermolecular difunctionalization of olefins
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using C–H functionalization strategy remain fewer in numbers. In this context, an intermolecular
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Fe(II)ꢀcatalyzed carbonylationꢀperoxidation,
pꢀtoluenesulfonic acid (pTsOH) catalyzed
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oxidative ketoꢀperoxidation, copper or cobalt catalyzed alkylationꢀperoxidation and copper
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catalyzed cycloalkylationꢀperoxidation of olefins have been reported.
Recently, our group has developed a Lewis acid (AlCl ) catalyzed crossꢀdehydrogenative
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coupling between electronꢀdeficient Nꢀheterocycles (quinoline, isoquinoline and quinoxaline)
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and alkylbenzenes for the synthesis of C1 or C2 aroylated Nꢀheterocycles (Scheme 1a). In the
presence of AlCl catalyst electronꢀdeficient Nꢀheterocycles acts as a radical acceptor, which
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·
trapped the in situ generated aroyl radical (ArCO ) obtained from alkyl benzene by the action of
peroxide (TBHP). During the nitration of alkenes using tertꢀbutyl nitrite as a nitrating agent
follows a radical pathway where the in situ generated alkyl radical is trapped by the radical
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scavenger TEMPO (Scheme 1b). Now a query arises if an alkene is treated with tertꢀbutyl
nitrite in the presence of quinoline in lieu of TEMPO, will it offer similar 1,2ꢀdifunctionalized
product (Scheme 1).
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Scheme 1. C−H Functionalization of Alkene to Isoxazoline
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With this assumption, we treated styrene (1) with quinoline (1 equiv.), tertꢀbutyl nitrite
t
o
(
BuONO) (a, 2.0 equiv.) and AlCl catalyst (5 mol%) in 1,2ꢀdichloroethane (DCE) at 80 C. A
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new product was isolated (55%), spectroscopic analysis of which confirmed the structure to be
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6a
phenyl(5ꢀphenylꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone (1a) (Scheme 1c).
The synthesis of
isoxazolines involving three C−H functionalization of two styrenes is unprecedented in the
literature. The newly formed product is devoid of any quinoline moiety however, in its absence
the yield was dropped to12% (Table 1, entry 2) there by suggesting its possible involement as a
base. Isoxazolines, are an important class of heterocycle that have attracted considerable
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7
attention in the field of anticancer research. Some of the important isoxazoline scaffolds
exhibiting potent anticancer properties are 3,5ꢀdiarylꢀisoxazoline linked 2,3ꢀ
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7a
17b
dihydroquinazolinone hybrids, arylisoxazoline containing anthranilic diamides, 3,5ꢀdiarylꢀ
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17c
isoxazoline
linked
pyrrolo[2,1ꢀc][1,4]benzodiazepine
(PBD)
conjugates
and
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dibenzo[b,f]azepinetethered isoxazoline (Figure 1).
Figure 1. Representative Anticancer Isoxazolines
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RESULT AND DISCUSSION
We then look forward to improving the selfꢀcoupling of aryl alkene via C−H
functionalization leading to the formation of isoxazoline by varying other reaction parameters.
Non polar solvents such as pꢀxylene (45%), toluene (43%), chlorobenzene (52%), and
cyclohexane (50%), and polar aprotic solvents such as DMF (34%), and DMSO (<5%) were all
found to be less efficient compared to DCE (55%), (Table 1, entries 3ꢀ8). Other Lewis acid
catalysts such as FeCl (51%) and FeCl (55%) provided comparable yield of (1a), but Cu(OTf)
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3
2
completely failed to give the desired product (Table 1, entries 9−11). When Sc(OTf) (5 mol%)
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was employed in lieu of other catalysts under otherwise identical conditions gave the best yield
of 66% (Table 1, entry 12). No substantial improvement in the yield (68%) was observed when
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the catalyst loading was increased up to 10 mol% (Table 1, entry 13). Replacing the base
quinoline to DBU (54%), DABCO (50%), pyridine (41%) and DMAP (30%) all gave lower yield
of (1a) (Table 1, entries (14−17). The presence of Sc(OTf) is essential for this transformation,
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which is perhaps serving the role of a Lewis acid catalyst to enhance the reactivity of alkene,
because in its absence the reaction just provided 22% yield of (1a) (Table 1, entry 18). Both
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increasing (110 C) and decreasing temperature (60 C) reduced the product yield (Table 1,
entries 19 and 20). The product yield remained unaltered even when the quantity of quinoline
was reduced to 0.5 equiv. After screening various reaction conditions, it was observed that the
t
use of styrene (0.4 mmol), BuONO (2.0 equiv.), Sc(OTf) (5 mol%) and quinoline (0.5 equiv.)
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gave the best yield for this transformation (Table 1, entry 21).
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Table 1. Optimization of the Reaction Conditions
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entry catalyst (mol%)
solvent
DCE
DCE
pꢀxylene
toluene
PhCl
base
yield %
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<5
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AlCl (5.0)
quinoline
ꢀ
3
AlCl (5.0)
3
AlCl (5.0)
quinoline
quinoline
quinoline
quinoline
quinoline
quinoline
quinoline
quinoline
quinoline
quinoline
quinoline
DBU
DABCO
Pyridine
DMAP
quinoline
quinoline
quinoline
quinoline
3
AlCl (5.0)
3
AlCl (5.0)
3
AlCl (5.0)
cyclohexane
DMF
DMSO
DCE
3
AlCl (5.0)
3
AlCl (5.0)
3
FeCl (5.0)
3
0
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2
3
4
FeCl (5.0)
DCE
DCE
DCE
DCE
2
Cu(OTf) (5.0)
2
Sc(OTf) (5.0)
66
68
54
50
41
30
22
39
56
65
3
Sc(OTf) (10.0)
3
Sc(OTf) (5.0)
DCE
3
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Sc(OTf) (5.0)
DCE
DCE
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Sc(OTf) (5.0)
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DCE
DCE
DCE
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c
Sc(OTf) (5.0)
3
d
Sc(OTf) (5.0)
3
e
Sc(OTf) (5.0)
DCE
3
a
Reaction conditions: Styrene (1) (0.4 mmol) and tertꢀbutylnitrite (a) (0.8
mmol) at 80 C. Yield after 5 h. Temperature100 C. Temperature 60 C.
o
b
c
o
d
o
e
Quinoline 0.5 equiv.
Encouraged by this unprecedented selfꢀcoupling of styrenes we further implemented this
strategy to other substrates. Styrenes containing moderately electronꢀdonating groups such as pꢀ
t
Me (2), mꢀMe (3), pꢀ Bu (4), pꢀPh (5) and pꢀCH Cl (6) all provided their corresponding
2
isoxazolines (2a, 60%), (3a, 58%), (4a, 58%), (5a, 54%) and (6a, 58%) in moderate yields
(
Scheme 2). Styrenes having moderately electronꢀwithdrawing substituents such as pꢀCl (7), mꢀ
Cl (8), oꢀCl (9), pꢀBr (10) oꢀBr (11) pꢀF (12), and mꢀF (13), yielded their corresponding
isoxazolines (7a), (8a), (9a), (10a), (11a), (12a) and (13a) in the range of 61−70% (Scheme 2).
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a,b
Scheme 2. Substrate Scope for Synthesis of Isoxazolines
N
O
R
O
Sc(OTf) (5 mol%)
O
3
N
+
O
tBu
quinoline (0.5 equiv.)
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R
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(
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(a)
DCE, 80 C, 5 h
R
(1-18) (a)
Me
tBu
Me
N
N
N
N
O
O
O
O
O
O
O
O
(
1a, 65%)
(2a, 60%)
(3a, 58%)
(4a, 58%)
tBu
Me
Ph
Me
Cl
CH Cl
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Cl
N
N
O
N
N
O
O
O
Cl
O
O
O
O
(
5a, 54%)
(6a, 58%)
(7a, 62%)
(8a, 62%)
Ph
ClH C
Cl
Br
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F
N
O
N
N
N
O
O
O
Br
Cl
Br
O
O
O
O
(
9a, 70%)
Cl
(10a, 61%)
(11a, 67%)
Br
(12a, 66%)
F
CO Et
2
F
NO2
N
N
O
N
O
O
F
O
O
O
(
13a, 63%)
(14a, 72%)
(15a, 68%)
EtO C
2
NO2
Me
Me
Me
Me
N
N
N
N
O
O
Me
O
O
Me
O
O
(
16a, 55%)
(17a, 49%)
(18a, 66%)
N
Me
Me
Me
Me
a
o
b
Reaction conditions: alkene (1ꢀ18) (0.4 mmol), Quinoline (0.2 mmol) and tertꢀbutyl nitrite (a) (0.8 mmol) at 80 C in DCE. Yield after 5 h.
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However, styrene containing strongly electronꢀwithdrawing substituents such as mꢀnitro
(
14) and pꢀCO Et (15) both provided their desired product in similar yields (14a, 72%) and (15a,
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8%). 2,4ꢀDimethyl (16) and 2,4,6ꢀtrimethyl (17) substituted styrenes also reacted successfully
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affording their corresponding isoxazolines (16a, 55%) and (17a, 49%) respectively. Heteroꢀ
aromatic olefin (18) was well tolerated in this transformation giving its product 18a in 66%
yield. No substantial differences in the yield of the products were observed for substrates
possessing either electronꢀdonating or electronꢀwithdrawing substituents. This may be due to the
high reactivity of the reaction intermediates leading to product in this multiꢀstep process.
We envisaged, that the reaction of terminal alkyenes with tertꢀbutyl nitrite is expected to
give similar 2ꢀnitroketone intermediate (SI, Scheme S1), which is expected to undergo a 1,3ꢀ
dipolar cyclo addition with the unreacted alkyne, serving as the dienophile. This strategy was
tested with different alkynes viz. phenylacetylene (19), 3ꢀmethylphenylacetylene (20), 4ꢀtertꢀ
butylphenylacetylene (21), 4ꢀmethoxyphenylacetylene (22), 3ꢀflurophenylacetylene (23) and 4ꢀ
flurophenylacetylene (24) under the exact experimental condition to that of styrene (Scheme 2).
Interestingly, all the substrates yielded their corresponding isoxazoles (19a), (20a), (21a), (22a),
(23a) and (24a) in the range of 34ꢀ53% (Scheme 3) rather than isoxazoline derivatives. This
result is not surprising since in the case of terminal aryl alkyne the unreacted part serving as the
dienophile while the other half forms 2ꢀnitro ketone intermediate which acts as the 1,3ꢀ
dipolarophile (See supporting information, Scheme S1). This method is not successful for
aliphatic alkenes and alkynes as the intermediate radicals obtained are not stable. This protocol is
not successful with internal alkenes or alkynes because during the formation of product loss of
both the terminal protons in alkene and one proton in alkyne are necessary.
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Scheme 3. Substrate Scope for Synthesis of Isoxazoles
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a
Reaction conditions: alkyne (19ꢀ23) (0.5 mmol), Quinoline (0.5 equiv.) and tertꢀbutyl nitrite (a) (1 mmol) at
o
b
80 C in DCE. Yield after 5 h.
To ascertain the source of keto oxygen in product (1a), the reaction of styrene (1) was
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performed in the presence of H O under otherwise identical condition. Incorporation of an O
2
labeled product suggests that water might be the source of oxygen in the keto group (See
supporting information). When the reaction was performed in the presence of a radical scavenger
2
,2,6,6ꢀtetramethylpiperidineꢀ1ꢀoxyl (TEMPO, 1 equiv.) no desired product was observed
however it form a TEMPO adduct along with the formation of βꢀnitro styrene. This result is
15a
consistent with the finding of Maiti et.al. there by confirming the radical nature of the
reaction. To ascertain the intermolecular nature of the coupling an equimolar mixture of two
different styrenes viz. pꢀMe (2) and pꢀCl (7) were reacted under the present experimental
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condition. Detection of four different isooxazolines (Scheme 4) from the H NMR and HRMS
analysis confirms the intermolecular cross coupling of the process (See supporting information).
Scheme 4. Crossover Experiment
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Based on the literature reports, intermediates detected by HRMS study and from the
controlled experiments carried out a plausible mechanism have been proposed (Scheme 5). The
·
.
heterolytic cleavage of tertꢀbutyl nitrite produces a NO radical which is converts to a NO
2
1
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.
radical under the aerobic reaction condition. The nitro radical (NO ) then attacks at the
2
terminal carbon of the olefin to generate a nitroalkane radical intermediate (A'). The nitroalkane
·
radical (A') thus generated couples with another NO radical to give a Cꢀnitroso intermediate
(B'). In the presence of base the Cꢀnitroso intermediate (B') rearranges to a αꢀnitrooxime (C'),
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which is hydrolyzed from the moisture present in the solvent/open atmosphere to 2ꢀ
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nitroacetophenon (I). The intermediate 2ꢀnitroacetophenone tautomerized to a 1,3ꢀdipolar
intermediate (II) in the presence of base. The unreacted styrene serves as the dienophile and
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undergoes cycloaddition with the 1,3ꢀdipolar intermediate (II) to give intermediate (III). Here
Sc(OTf) acts as a Lewis acid catalyst to enhance the reactivity of alkene towards cycloaddition
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reaction. Finally, loss of a water molecule from the intermediate (III) leads to the formation of
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6b,c
final isoxazoline product (1a). Here, quinoline serve as a base
to facilitate tautomerization
and dehydration step of the reaction. Intermediates (C′), (I), (II) and (III) have been detected by
the HRMS analysis of the reaction mixture at various time intervals (See supporting
information). This mechanism successfully accounts for the formation of all the four
isoxazololine products (Scheme 4). Two independent 1,3ꢀdipolar intermediates would be
generated from two different styrenes (2 and 7). Each of this 1,3ꢀdipolar intermediate would
couple with the unreacted styrenes (2 and 7) independently to give four possible products
(
Scheme 4). A similar mechanism for the formation of isoxazole from terminal alkyne can be
proposed. (See supporting information)
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Scheme 5. Proposed Mechanism for Isoxazoline Synthesis
0
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In conclusion, tertꢀbutyl nitrite serves as a convenient N−O source to convert alkenes or
alkynes into intermediate 2ꢀnitro ketone in DCE. The intermediate so generated reacts with the
unreacted alkenes or alkynes via a 1,3ꢀdipolar cycloaddition to afford isoxazolines or
isoxazoles in the presence of quinoline and Sc(OTf) catalyst. In this domino process, C−C,
3
C−O, C=N and C=O bonds are constructed simultaneously. A radical mechanism has been
proposed, where the cleavage of tertꢀbutyl nitrite produce a NO radical. The NO radical is
oxidized to NO radical and a sequential addition of these radicals to styrene produce a Cꢀ
2
nitroso intermediate which is hydrolyzed to a 2ꢀnitroacetophenone. The 2ꢀnitroacetophenone
so generated is tautomerize to a 1,3ꢀdipolar intermediate which undergo cycloaddition with
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unreacted alkene to generate isoxazoline via loss of a water molecule. An analogous
mechanism has been proposed involving alkynes for the generation of isoxazoles.
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EXPERIMENTAL SECTION
General information:
All the reagents were commercial grade and purified according to the established
procedures. Organic extracts were dried over anhydrous sodium sulphate. Solvents were
removed in a rotary evaporator under reduced pressure. Silica gel (60ꢀ120 mesh size) was used
for the column chromatography. Reactions were monitored by TLC on silica gel 60 F254 (0.25
mm). NMR spectra were recorded in CDCl with tetramethylsilane as the internal standard for
3
1
13
H NMR (400 and 600 MHz) and in for C NMR (100 and 150 MHz) CDCl as the internal
3
standard. MS spectra were recorded using ESI mode. IR spectra were recorded in KBr or neat.
General Procedure for the Synthesis of Phenyl(5ꢀphenylꢀ4,5ꢀdihydroisoxazolꢀ3ꢀ
yl)methanone (1a) from Styrene (1) and tertꢀButyl nitrite (a):
To an ovenꢀdried 10 mL round bottom flask fitted with a reflux condenser was added styrene
(1) (42 mg, 0.4 mmol), quinoline (26 mg, 0.2 mmol), tertꢀbutyl nitrite (a) (82 mg, 0.8 mmol),
Sc(OTf) (9.8 mg, 0.02 mmol), and 1, 2ꢀdichloroethane (1.5 mL). The reaction mixture was
3
o
refluxed in an oil bath preheated to 80 C for 5 h. The reaction mixture was cooled to room
temperature, admixed with ethyl acetate (25 mL) and the organic layer was washed with
saturated sodium bicarbonate solution (1 x 5 mL). The organic layer was dried over anhydrous
sodium sulfate (Na SO ), and solvent was evaporated under reduced pressure. The crude product
2
4
so obtained was purified over a column of silica gel (hexane / ethyl acetate, 9.9:0.1) to give pure
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phenyl(5ꢀphenylꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone (1a) (33 mg, yield 65%). The identity and
purity of the product was confirmed by spectroscopic analysis.
1
6a
1
Phenyl(5ꢀphenylꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone (1a): gummy; yield 33 mg, 65%; H
0
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6
7
8
9
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7
8
9
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9
0
NMR (CDCl , 400 MHz) δ 8.24 (d, 2H, J = 7.2 Hz), 7.62 (t, 1H, J = 7.4 Hz), 7.49 (t, 2H, J = 7.8
3
Hz), 7.42−7.35 (m, 5H), 5.79 (dd, 1H, J = 8.8 Hz, J = 2.8 Hz), 3.80 (dd, 1H, J = 11.6 Hz, J =
1
2
1
2
1
3
1
6
.4 Hz), 3.40 (dd, 1H, J = 8.8 Hz, J = 9.2 Hz); C{ H} NMR (CDCl , 100 MHz) δ 186.4,
1 2 3
ꢀ1
1
57.6, 139.8, 135.9, 133.9, 130.5, 129.1, 128.8, 128.6, 126.1, 84.4, 42.0; IR (KBr, cm ) 3063,
3029, 2957, 2926, 2851, 1651, 1598, 1580, 1572, 1494, 1448, 1360, 1250, 1154, 1077, 901, 851,
+
7
91, 756; HRMS (ESI/QꢀTOF) m/z: [M + H] Calcd for C H NO 252.1019; Found 252.1025.
1
6
14
2
1
pꢀTolyl(5ꢀ(pꢀtolyl)ꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone (2a): gummy; yield 33 mg, 60%; H
NMR (CDCl , 400 MHz) δ 8.16 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.6 Hz), 7.27−7.25 (m, 2H),
3
7.20 (d, 2H, J = 8.0 Hz), 5.74 (dd, 1H, J = 8.8 Hz, J = 2.4 Hz), 3.75 (dd, 1H, J = 11.6 Hz, J =
1 2 1 2
13
1
6
.0 Hz), 3.38 (dd, 1H, J = 8.8 Hz, J = 8.8 Hz), 2.43 (s, 3H), 2.36 (s, 3H); C{ H} NMR
1
2
(CDCl , 100 MHz) δ 186.1, 157.7, 144.9, 138.7, 136.9, 133.4, 130.7, 129.7, 129.4, 126.2, 84.4,
3
ꢀ1
4
2.0, 21.9, 21.4; IR (KBr, cm ) 3025, 2952, 2923, 2856, 1647, 1606, 1577, 1516, 1450, 1358,
+
1253, 1185, 1118, 1036, 902, 852, 831, 813, 788, 741; HRMS (ESI/QꢀTOF) m/z: [M + H]
Calcd for C H NO 280.1332; Found 280.1330.
1
8
18
2
1
mꢀTolyl(5ꢀ(mꢀtolyl)ꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone (3a): gummy; yield 31.5 mg, 58%; H
NMR (CDCl , 600 MHz) δ 8.05−8.03 (m, 2H), 7.43 (d, 1H, J = 7.2 Hz), 7.38 (t, 1H, J = 7.5 Hz),
3
7
.29 (t, 1H, J = 7.5 Hz), 7.18−7.15 (m, 3H), 5.74 (dd, 1H, J = 9.0 Hz, J = 2.4 Hz), 3.77 (dd,
1
2
1
H, J = 11.4 Hz, J = 6.0 Hz), 3.39 (dd, 1H, J = 9.0 Hz, J = 9.0 Hz), 2.43 (s, 3H), 2.37 (s, 3H);
1
2
1
2
1
3
1
C{ H} NMR (CDCl , 100 MHz) δ 186.7, 157.7, 139.8, 138.9, 138.4, 136.0, 134.7, 130.9,
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ꢀ1
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6
29.6, 128.9, 128.5, 127.9, 126.8, 123.2, 84.5, 42.1, 21.6, 21.5; IR (KBr, cm ) 3023, 2957, 2924,
855, 1650, 1601, 1575, 1488, 1459, 1426, 1358, 1259, 1213, 1134, 1040, 921, 787, 732, 699,
+
70; HRMS (ESI/QꢀTOF) m/z: [M + H] Calcd for C H NO 280.1332; Found 280.1342.
1
8
18
2
10
11
12
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(
4ꢀ(tertꢀButyl)phenyl)(5ꢀ(4ꢀ(tertꢀbutyl)phenyl)ꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone
(4a):
1
gummy; yield 42 mg, 58%; H NMR (CDCl , 600 MHz) δ 8.18 (d, 2H, J = 8.4 Hz), 7.50 (d, 2H,
3
J = 8.4 Hz), 7.42 (d, 2H, J = 8.4 Hz), 7.30 (d, 2H, J = 8.4 Hz), 5.75 (dd, 1H, J = 9.0 Hz, J = 2.4
1
2
Hz), 3.75 (dd, 1H, J = 11.4 Hz, J = 6.0 Hz), 3.40 (dd, 1H, J = 8.4 Hz, J = 9.0 Hz), 1.35 (s,
1
2
1
2
1
3
1
9
H), 1.32 (s, 9H); C{ H} NMR (CDCl , 150 MHz) δ 186.2, 157.74, 157.72, 151.9, 136.8,
3
ꢀ1
133.4, 130.5, 126.0, 125.7, 84.3, 41.9, 35.4, 34.8, 31.5, 31.3; IR (KBr, cm ) 2963, 2926, 2899,
2
868, 1647, 1605, 1577, 1559, 1462, 1410, 1363, 1268, 1254, 1198, 1108, 1017, 905, 851, 763,
+
7
24; HRMS (ESI/QꢀTOF) m/z: [M + H] Calcd for C H NO 364.2271; Found 364.2270.
24 30
2
[
1,1'ꢀBiphenyl]ꢀ4ꢀyl(5ꢀ([1,1'ꢀbiphenyl]ꢀ4ꢀyl)ꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone (5a): white
o
1
solid; yield 43 mg, 54%; mp 193.4−195.5 C; H NMR (CDCl , 600 MHz) δ 8.37 (d, 2H, J = 8.4
3
Hz), 7.73 (d, 2H, J = 8.4 Hz), 7.65 (dd, 4H, J = 7.8 Hz, J = 4.2 Hz), 7.60 (d, 2H, J = 7.8 Hz),
1
2
7.50 (d, 2H, J = 7.2 Hz), 7.46 (q, 4H, J = 6.4 Hz), 7.42 (t, 1H, J = 7.5 Hz), 7.37 (t, 1H, J = 7.5
Hz), 5.85 (dd, 1H, J = 9.0 Hz, J = 2.4 Hz), 3.85 (dd, 1H, J = 11.4 Hz, J = 6.0 Hz), 3.48 (dd,
1
2
1
2
13
1
1
1
8
H, J = 9.0 Hz, J = 8.4 Hz); C{ H} NMR (CDCl , 150 MHz) δ 185.9, 157.8, 146.6, 141.9,
1 2 3
40.7, 140.0, 138.8, 134.7, 131.2, 129.2, 129.1, 128.6, 127.9, 127.8, 127.5, 127.34, 127.3, 126.7,
ꢀ1
4.3, 42.1; IR (KBr, cm ) 3054, 3029, 2919, 2851, 1647, 1603, 1578, 1559, 1485, 1405, 1157,
+
1006, 905, 851, 836, 763, 753, 738, 689; HRMS (ESI/QꢀTOF) m/z: [M + H] Calcd for
C H NO 404.1645; Found 404.1650.
28
22
2
(4ꢀ(Chloromethyl)phenyl)(5ꢀ(4ꢀ(chloromethyl)phenyl)ꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone (6a):
o
1
white solid; yield 40 mg, 58%; mp. 109.6−112.8 C; H NMR (CDCl , 600 MHz) δ 8.25 (d, 2H,
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J = 8.4 Hz), 7.51 (d, 2H, J = 7.8 Hz), 7.43 (d, 2H, J = 8.4 Hz), 7.36 (d, 2H, J = 8.4 Hz), 5.79 (dd,
1
3
1
H, J = 8.4 Hz, J = 3.0 Hz), 4.63 (s, 2H), 4.59 (s, 2H), 3.79 (dd, 1H, J = 11.4 Hz, J = 6.0 Hz),
1 2 1 2
13
1
.38 (dd, 1H, J = 9.0 Hz, J = 9.0 Hz); C{ H} NMR (CDCl , 150 MHz) δ 185.6, 157.6, 143.2,
1
2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ1
40.0, 138.2, 135.7, 131.0, 129.4, 128.7, 126.5, 84.1, 45.8, 45.5, 42.0; IR (KBr, cm ) 2965,
2923, 2851, 1640, 1607, 1578, 1564, 1444, 1357, 1286, 1256, 1109, 941, 919, 834, 765, 704,
+
6
68, 576, 530; HRMS (ESI/QꢀTOF) m/z: [M + H] Calcd for C H Cl NO 348.0553; Found
1
8
16
2
2
348.0559.
(4ꢀChlorophenyl)(5ꢀ(4ꢀchlorophenyl)ꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone (7a): gummy; yield
1
40 mg, 62%; H NMR (CDCl , 400 MHz) δ 8.21 (d, 2H, J = 8.9 Hz), 7.46 (d, 2H, J = 8.9 Hz),
3
7
.37 (d, 2H, J = 8.2 Hz), 7.29 (d, 2H, J = 8.6 Hz), 5.76 (dd, 1H, J = 8.8 Hz, J = 2.4 Hz), 3.78
1 2
1
3
1
(
dd, 1H, J = 11.6 Hz, J = 6.4 Hz), 3.34 (dd, 1H, J = 8.8 Hz, J = 8.8 Hz); C{ H} NMR
1 2 1 2
(
CDCl , 100 MHz) δ 184.8, 157.5, 140.6, 138.2, 134.8, 131.9, 129.7, 129.3, 129.0, 127.5, 83.8,
3
ꢀ1
4
1.9; IR (KBr, cm ) 2952, 2924, 2851, 1646, 1584, 1493, 1433, 1401, 1367, 1293, 1274, 1258,
+
1157, 1039, 1014, 937, 902, 845, 829, 807, 745, 719, 684; HRMS (ESI/QꢀTOF) m/z: [M + H]
Calcd for C H Cl NO 320.0240; Found 320.0242.
1
6
12
2
2
(3ꢀChlorophenyl)(5ꢀ(3ꢀchlorophenyl)ꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone (8a): gummy; yield
1
4
0 mg, 62%; H NMR (CDCl , 600 MHz) δ 8.22 (s, 1H), 8.15 (d, 1H, J = 7.8 Hz), 7.59 (d, 1H, J
3
= 8.4Hz), 7.44 (t, 1H, J = 7.8Hz), 7.36−7.33 (m, 3H), 7.24−7.23 (m, 1H), 5.77 (dd, 1H, J = 8.4
1
Hz, J = 3.0 Hz), 3.79 (dd, 1H, J = 11.4 Hz, J = 6.0 Hz), 3.36 (dd, 1H, J = 8.4 Hz, J = 9.0
2
1
2
1
2
13
1
Hz); C{ H} NMR (CDCl , 100 MHz) δ 184.8, 157.4, 141.7, 137.2, 135.1, 134.9, 133.9, 130.5,
3
ꢀ1
1
30.4, 129.9, 129.1, 128.7, 126.2, 124.2, 83.7, 41.9; IR (KBr, cm ) 3068, 2952, 2925, 2854,
1653, 1576, 1566, 1479, 1426, 1361, 1276, 1248, 1094, 1160, 1079, 919, 784, 733, 692; HRMS
+
(ESI/QꢀTOF) m/z: [M + H] Calcd for C H Cl NO 320.0240; Found 320.0247.
16
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(
2ꢀChlorophenyl)(5ꢀ(2ꢀchlorophenyl)ꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone (9a): gummy; yield
1
45 mg, 70%; H NMR (CDCl , 600 MHz) δ 7.54 (d, 1H, J = 7.8 Hz), 7.47−7.43 (m, 3H), 7.42 (d,
3
1
H, J = 7.5 Hz), 7.38−7.36 (m, 1H), 7.32−7.28 (m, 2H), 6.15 (dd, 1H, J = 7.8 Hz, J = 3.6 Hz),
1
2
10
11
12
13
14
15
16
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18
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21
22
23
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34
35
36
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38
39
40
41
42
43
44
45
46
47
48
49
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52
53
54
55
56
57
58
59
60
1
3
1
3
.90 (dd, 1H, J = 12.0 Hz, J = 6.0 Hz), 3.23 (dd, 1H, J = 7.8 Hz, J = 10.2 Hz); C{ H} NMR
1
2
1
2
(
CDCl , 150 MHz) δ 188.2, 158.1, 137.8, 137.3, 132.5, 132.4, 132.0, 131.5, 130.5, 130.0, 129.8,
3
ꢀ1
1
27.5, 126.8, 126.6, 82.8, 40.4; IR (KBr, cm ) 3066, 2923, 2849, 1672, 1651, 1578, 1471, 1435,
1369, 1310, 1273, 1245, 1161, 1128, 1056, 1036, 933, 910, 882, 855, 755, 742, 691; HRMS
+
(ESI/QꢀTOF) m/z: [M + H] Calcd for C H Cl NO 320.0240; Found 320.0236.
16
12
2
2
(
4ꢀBromophenyl)(5ꢀ(4ꢀbromophenyl)ꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone (10a): gummy; yield
1
5
0 mg, 61%; H NMR (CDCl , 400 MHz) δ 8.13 (d, 2H, J = 8.0 Hz), 7.64 (d, 2H, J = 8.6 Hz),
3
7.53 (d, 2H, J = 8.0 Hz), 7.23 (d, 2H, J = 8.6 Hz), 5.74 (dd, 1H, J = 8.8 Hz, J = 2.8 Hz), 3.78
1
2
13
1
(
dd, 1H, J = 11.6 Hz, J = 6.0 Hz), 3.34 (dd, 1H, J = 8.8 Hz, J = 9.4 Hz); C{ H} NMR
1 2 1 2
(
CDCl , 100 MHz) δ 185.0, 157.5, 138.7, 134.5, 132.3, 132.03, 132.0, 129.5, 127.8, 122.9, 83.8,
3
ꢀ1
4
1.9; IR (KBr, cm ) 2952, 2924, 2853, 1640, 1578, 1559, 1489, 1409, 1396, 1361, 1274, 1256,
1
153, 1104, 1072, 1010, 941, 919, 904, 842, 824, 793, 744, 679; HRMS (ESI/QꢀTOF) m/z: [M +
+
H] Calcd for C H Br NO 409.9210; Found 409.9215.
16
12
2
2
(2ꢀBromophenyl)(5ꢀ(2ꢀbromophenyl)ꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone (11a): gummy; yield
1
5
5 mg, 67%; H NMR (CDCl , 600 MHz) δ 7.64 (d, 1H, J = 7.8 Hz), 7.60 (d, 1H, J = 7.5 Hz),
3
7
.50 (d, 1H, J = 7.5 Hz), 7.45 (d, 1H, J = 7.8 Hz), 7.42 (t, 1H, J = 7.2 Hz), 7.36 (q, 2H, J = 7.0
Hz), 7.21 (t, 1H, J = 7.7 Hz), 6.11 (dd, 1H, J = 7.2 Hz, J = 4.2 Hz), 3.93 (dd, 1H, J = 12.0 Hz,
1
2
1
13
1
J = 6.0 Hz), 3.21 (dd, 1H, J = 7.8 Hz, J = 9.6 Hz); C{ H} NMR (CDCl , 150 MHz) δ 188.9,
2
1
2
3
1
57.8, 139.5, 139.3, 133.6, 133.2, 132.4, 130.0, 129.9, 128.1, 127.4, 126.8, 121.1, 120.2, 84.8,
ꢀ1
4
0.6; IR (KBr, cm ) 2956, 2924, 2853, 1672, 1576, 1467, 1434, 1368, 1307, 1270, 1243, 1162,
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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5
5
5
5
5
5
5
6
+
1
119, 1047, 1026, 930, 909, 858, 745, 739, 681, 668, 644; HRMS (ESI/QꢀTOF) m/z: [M + H]
Calcd for C H Br NO 409.9210; Found 409.9220.
16 12
2
2
(4ꢀFluorophenyl)(5ꢀ(4ꢀfluorophenyl)ꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone (12a): gummy; yield
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
8 mg, 66%; H NMR (CDCl , 600 MHz) δ 8.33−8.31 (m, 2H), 7.35−7.33 (m, 2H), 7.16 (t, 2H,
3
J = 8.7 Hz), 7.09 (t, 2H, J = 8.7 Hz), 5.76 (dd, 1H, J = 9.0 Hz, J = 2.4 Hz), 3.77 (dd, 1H, J =
1
2
1
1
3
1
11.4 Hz, J = 6.0 Hz), 3.36 (dd, 1H, J = 9.0 Hz, J = 8.4 Hz); C{ H} NMR (CDCl , 150 MHz)
2
1
2
3
δ 184.6, 167.3, 165.6, 163.9, 162.2, 157.6, 135.57, 135.55, 133.41, 133.35, 132.2, 132.18, 128.1,
ꢀ1
1
1
7
28.0, 116.2, 116.1, 115.9, 115.8, 83.9, 42.1; IR (KBr, cm ) 3073, 2957, 2924, 2846, 1642,
598, 1559, 1511, 1439, 1411, 1358, 1299, 1287, 1239, 1156, 1098, 1013, 939, 902, 853, 816,
+
54; HRMS (ESI/QꢀTOF) m/z: [M + H] Calcd for C H F NO 288.0831; Found 288.0825.
1
6
12
2
2
(
3ꢀFluorophenyl)(5ꢀ(3ꢀfluorophenyl)ꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone (13a): gummy; yield
1
36 mg, 63%; H NMR (CDCl , 600 MHz) δ 8.07 (d, 1H, J = 7.8 Hz), 7.95 (d, 1H, J = 9.4 Hz),
3
7
.50−7.46 (m, 1H), 7.39−7.36 (m, 1H), 7.34−7.31 (m, 1H), 7.13 (d, 1H, J = 7.8 Hz), 7.09−7.04
(m, 2H), 5.79 (dd, 1H, J = 8.4 Hz, J = 3.0 Hz), 3.80 (dd, 1H, J = 12.0 Hz, J = 6.0 Hz), 3.37
1
2
1
2
1
3
1
(
dd, 1H, J = 8.4 Hz, J = 9.6 Hz); C{ H} NMR (CDCl , 150 MHz) δ 184.8, 164.1, 163.6,
1 2 3
1
62.5, 161.9, 157.4, 142.4, 137.6, 130.9, 130.8, 130.4, 130.3, 126.5, 126.4, 121.63, 121.61,
ꢀ1
121.1, 120.9, 117.4, 117.2, 115.9, 115.8, 113.2, 113.0, 83.7, 42.0; IR (KBr, cm ) 2958, 2923,
2
851, 1653, 1587, 1484, 1444, 1362, 1260, 1214, 927, 893, 807, 741, 692, 672, 522; HRMS
+
(ESI/QꢀTOF) m/z: [M + H] Calcd for C H F NO 288.0831; Found 288.0836.
16
12
2
2
(
3ꢀNitrophenyl)(5ꢀ(3ꢀnitrophenyl)ꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone (14a): greay solid; yield
o
1
4
9 mg, 72%; mp 92.3−95.9 C; H NMR (CDCl , 600 MHz) δ 9.08 (s, 1H), 8.60 (d, 1H, J = 7.8
3
Hz), 8.47 (d, 1H, J = 7.8 Hz), 8.25−8.22 (m, 2H), 7.72 (t, 2H, J = 7.8 Hz), 7.62 (t, 1H, J = 7.8
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Hz), 5.94 (dd, 1H, J = 9.0 Hz, J = 2.4 Hz), 3.91 (dd, 1H, J = 11.4 Hz, J = 6.6 Hz), 3.43 (dd,
1
2
1
2
1
3
1
1
1
3
H, J = 8.4 Hz, J = 9.0 Hz); C{ H} NMR (CDCl , 150 MHz) δ 183.7, 157.4, 148.8, 141.7,
1 2 3
ꢀ1
36.8, 136.1, 132.0, 130.4, 129.9, 128.1, 125.5, 123.9, 122.5, 121.2, 83.4, 41.8; IR (KBr, cm )
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
124, 3083, 3043, 1653, 1612, 1590, 1534, 1477, 1346, 1256, 1094, 1002, 930, 906, 886, 834,
+
811, 737, 706, 684, 652; HRMS (ESI/QꢀTOF) m/z: [M + H] Calcd for C H N O 342.0721;
16
12
3
6
Found 342.0719.
Ethyl 4ꢀ(3ꢀ(4ꢀ(ethoxycarbonyl)benzoyl)ꢀ4,5ꢀdihydroisoxazolꢀ5ꢀyl)benzoate (15a): gummy; yield
1
5
4 mg, 68%; H NMR (CDCl , 600 MHz) δ 8.28 (d, 2H, J = 8.4 Hz), 8.14 (d, 2H, J = 8.4 Hz),
3
8.07 (d, 2H, J = 8.4 Hz), 7.43 (d, 2H, J = 7.8 Hz), 5.85 (dd, 1H, J = 8.4 Hz, J = 3.0 Hz), 4.41
1
2
(
q, 2H, J = 6.4 Hz), 4.38 (q, 2H, J = 6.4.Hz), 3.83 (dd, 1H, J = 12.0 Hz, J = 6.0 Hz), 3.37 (dd,
1 2
1
3
1
1
H, J = 9.0 Hz, J = 9.0 Hz), 1.42 (t, 3H, J = 6.9 Hz), 1.39 (t, 3H, J = 7.2 Hz); C{ H} NMR
1 2
(
CDCl , 150 MHz) δ 185.5, 166.2, 165.9, 157.5, 144.5, 139.0, 134.9, 131.0, 130.4, 129.7, 125.9,
3
ꢀ1
8
4.0, 61.7, 61.4, 42.0, 14.5, 14.47; IR (KBr, cm ) 3064, 2995, 2979, 2928, 2900, 2848, 1718,
1653, 1613, 1572, 1475, 1444, 1409, 1367, 1284, 1255, 1194, 1126, 1112, 1019, 945, 872, 863,
+
7
62, 727; HRMS (ESI/QꢀTOF) m/z: [M + H] Calcd for C H NO 396.1442; Found 396.1451.
2
2
22
6
(
2,4ꢀDimethylphenyl)(5ꢀ(2,4ꢀdimethylphenyl)ꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone
(16a):
1
gummy; yield 34 mg, 55%; H NMR (CDCl , 600 MHz) δ 7.65 (d, 1H, J = 8.4 Hz), 7.02−7.01
3
(
m, 2H), 6.99−6.96 (m, 3H), 5.87 (dd, 1H, J = 9.0 Hz, J = 2.4 Hz), 3.67 (dd, 1H, J = 12.0 Hz,
1
2
1
J = 5.4 Hz), 3.15 (dd, 1H, J = 8.4 Hz, J = 9.0 Hz), 2.36 (s, 3H), 2.30 (s, 3H), 2.25 (s, 6H);
2
1
2
1
3
1
C{ H} NMR (CDCl , 150 MHz) δ 189.8, 158.5, 142.6, 138.8, 138.3, 135.1, 134.6, 132.5,
3
ꢀ1
1
31.8, 131.3, 127.3, 126.2, 125.2, 82.8, 40.6, 21.7, 21.2, 20.9, 19.4; IR (KBr, cm ) 3020, 2955,
2
924, 2855, 1653, 1612, 1578, 1559, 1500, 1452, 1379, 1311, 1288, 1252, 1236, 1036, 929, 879,
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4
4
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5
5
5
5
5
5
5
5
5
6
+
8
43, 821, 757; HRMS (ESI/QꢀTOF) m/z: [M + H] Calcd for C H NO 308.1645; Found
20
22
2
308.1647.
1
Mesityl(5ꢀmesitylꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone (17a): gummy; yield 33 mg, 49%; H
NMR (CDCl , 600 MHz) δ 6.89 (s, 4H), 6.27 (t, 1H, J = 12.6 Hz), 3.66 (dd, 1H, J = 12.6 Hz, J
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
=
5.4 Hz), 3.29 (dd, 1H, J = 12.0 Hz, J = 5.4 Hz), 2.31 (s, 6H), 2.29 (s, 3H), 2.28 (s, 3H), 2.27
1 2
13
1
(s, 3H), 2.25 (s, 3H); C{ H} NMR (CDCl , 150 MHz) δ 167.5, 156.2, 140.7, 138.8, 136.9,
3
1
35.3, 135.2, 130.8, 130.6, 128.6, 128.5, 126.9, 84.3, 37.7, 21.4, 21.0, 20.2, 19.98, 19.85; IR
ꢀ1
(
KBr, cm ) 3008, 2960, 2923, 2854, 1612, 1579, 1452, 1379, 1311, 1251, 1036, 978, 953, 934,
+
878, 850, 834; HRMS (ESI/QꢀTOF) m/z: [M + H] Calcd for C H NO 336.1958; Found
22
26
2
336.1968.
Pyridinꢀ2ꢀyl(5ꢀ(pyridinꢀ2ꢀyl)ꢀ4,5ꢀdihydroisoxazolꢀ3ꢀyl)methanone (18a): gummy; yield 33 mg,
1
66%; H NMR (CDCl , 600 MHz) δ 8.60−8.57 (m, 2H), 8.41−8.39 (m, 1H), 7.94 (t, 1H, J = 8.1
3
Hz), 7.73 (t, 1H, J = 7.8 Hz), 7.52 (d, 1H, J = 7.8 Hz), 7.47 (t, 1H, J = 6.3 Hz), 7.25−7.23 (m,
1H), 5.78 (dd, 1H, J = 7.2 Hz, J = 4.2 Hz), 3.95 (dd, 1H, J = 11.4 Hz, J = 6.6 Hz), 3.81 (dd,
1
2
1
2
1
3
1
1
H, J = 7.2 Hz, J = 10.2 Hz); C{ H} NMR (CDCl , 150 MHz) δ 159.7, 156.9, 150.3, 149.6,
1
2
3
ꢀ1
1
46.2, 144.4, 138.3, 137.5, 125.32, 125.28, 123.3, 120.9, 82.3, 42.5; IR (KBr, cm ) 2924, 2853,
1640, 1591, 1569, 1468, 1436, 1384, 1287, 1262, 1152, 1095, 1049, 1006, 894, 849, 790, 749,
+
6
68; HRMS (ESI/QꢀTOF) m/z: [M + H] Calcd for C H N O 254.0924; Found 254.0934.
1
4
12
3
2
General Procedure for the Synthesis of Phenyl(5ꢀphenylisoxazolꢀ3ꢀyl)methanone (19a) from
Phenyl acetylene (19) and tertꢀButyl nitrite (a):
To an ovenꢀdried 10 mL round bottom flask fitted with a reflux condenser was added Phenyl
acetylene (19) (51 mg, 0.5 mmol), quinoline (33 mg, 0.25 mmol), tertꢀbutyl nitrite (a) (103 mg, 1
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mmol), Sc(OTf) (12 mg, 0.025 mmol), and 1,2ꢀdichloroethane (1.5 mL). The reaction mixture
3
o
was refluxed in an oil bath preheated to 80 C for 5 h. The reaction mixture was cooled to room
temperature, admixed with ethyl acetate (25 mL) and the organic layer was washed with
saturated sodium bicarbonate solution (1 x 5 mL). The organic layer was dried over anhydrous
sodium sulfate (Na SO ), and solvent was evaporated under reduced pressure. The crude product
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
33
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35
36
37
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40
41
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43
44
45
46
47
48
49
50
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52
53
54
55
56
57
58
59
60
2
4
so obtained was purified over a column of silica gel (hexane / ethyl acetate, 9.9:0.1) to give pure
Phenyl(5ꢀphenylisoxazolꢀ3ꢀyl)methanone (19a) (27 mg, yield 43%). The identity and purity of
the product was confirmed by spectroscopic analysis.
1
6a
Phenyl(5ꢀphenylisoxazolꢀ3ꢀyl)methanone (19a): white solid; yield 27 mg, 43%; mp 78.4−82.9
o
1
C; H NMR (CDCl , 600 MHz) δ 8.36−8.34 (m, 2H), 7.87−7.85 (m, 2H), 7.68−7.66 (m, 1H),
3
13
1
7
1
1
.56−7.50 (m, 5H), 7.06 (s, 1H); C{ H} NMR (CDCl , 150 MHz) δ 186.1, 171.0, 162.7, 135.9,
3
ꢀ1
34.3, 130.96, 130.92, 129.4, 128.8, 126.9, 126.2, 100.5; IR (KBr, cm ) 2953, 2923, 2853, 1655,
577, 1449, 1244, 1146, 1041, 1028, 848, 894, 824, 769, 681, 676, 617; HRMS (ESI/QꢀTOF)
+
m/z: [M + H] Calcd for C H NO 250.0863; Found 250.0860.
16
12
2
1
mꢀTolyl(5ꢀ(mꢀtolyl)isoxazolꢀ3ꢀyl)methanone (20a): gummy; yield 37 mg, 53%; H NMR (CDCl ,
3
600 MHz) δ 8.15 (d, 1H, J = 7.8 Hz), 8.13 (s, 1H), 7.67 (s, 1H), 7.65 (d, 1H, J = 7.8 Hz), 7.47 (d,
1H, J = 7.8 Hz), 7.43 (t, 1H, J = 7.5 Hz), 7.39 (t, 1H, J = 7.5 Hz), 7.30 (d, 1H, J = 7.8 Hz), 7.02
1
3
1
(
s, 1H), 2.46 (s, 3H), 2.45 (s, 3H); C{ H} NMR (CDCl , 150 MHz) δ 186.3, 171.2, 162.7,
3
ꢀ1
135.1, 131.7, 131.2, 129.3, 128.7, 128.2, 126.8, 123.4, 100.4, 21.64, 21.61; IR (KBr, cm ) 2923,
2853, 1665, 1602, 1574, 1444, 1378, 1319, 1290, 1262, 1207, 1158, 1140, 1095, 1055, 941, 841,
+
8
11, 793, 751, 701, 678; HRMS (ESI/QꢀTOF) m/z: [M + H] Calcd for C H NO 278.1176;
18 16
2
Found 278.1180.
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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6
(
4ꢀ(tertꢀButyl)phenyl)(5ꢀ(4ꢀ(tertꢀbutyl)phenyl)isoxazolꢀ3ꢀyl)methanone (21a): gummy; yield 45
1
mg, 50%; H NMR (CDCl , 400 MHz) δ 8.29 (d, 2H, J = 8.4 Hz), 7.79 (d, 2H, J = 8.8 Hz),
3
13
1
7.57−7.52 (m, 4H), 7.00 (s, 1H), 1.372 (s, 9H), 1.365 (s, 9H); C{ H} NMR (CDCl , 100 MHz)
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
δ 185.7, 171.0, 162.7, 158.1, 154.4, 133.4, 130.9, 126.30, 126.29, 126.0, 125.8, 124.2, 99.9, 35.5,
ꢀ1
35.2, 31.3, 31.2; IR (KBr, cm ) 2958, 2923, 2853, 1659, 1606, 1465, 1444, 1363, 1255, 1106,
+
1017, 897, 856, 777; HRMS (ESI/QꢀTOF) m/z: [M + H] Calcd for C H NO 362.2115; Found
2
4
28
2
3
62.2111.
4ꢀMethoxyphenyl)(5ꢀ(4ꢀmethoxyphenyl)isoxazolꢀ3ꢀyl)methanone (22a): white solid; yield 37
2
0
(
o
1
mg, 48%; mp 127.8−130.5 C; H NMR (CDCl , 400 MHz) δ 8.37 (d, 2H, J = 8.8 Hz), 7.78 (d,
3
1
3
1
2H, J = 8.8 Hz), 7.01−6.99 (m, 4H), 6.89 (s, 1H), 3.90 (s, 3H), 3.87 (s, 3H); C{ H} NMR
(CDCl , 100 MHz) δ 184.4, 170.7, 164.6, 162.9, 161.6, 133.4, 128.9, 127.8, 119.8, 114.7, 114.1,
3
ꢀ1
99.2, 55.8, 55.6; IR (KBr, cm ) 2940, 2837, 1658, 1580, 1469, 1190, 895, 737; HRMS (ESI/Qꢀ
+
TOF) m/z: [M + H] Calcd for C H NO 310.1074; Found 310.1070.
1
8
16
4
(3ꢀFluorophenyl)(5ꢀ(3ꢀfluorophenyl)isoxazolꢀ3ꢀyl)methanone (23a): gummy; yield 24 mg, 34%;
1
H NMR (CDCl , 600 MHz) δ 8.19 (d, 1H, J = 7.8 Hz), 8.07−8.05 (m, 1H), 7.64 (d, 1H, J = 7.8
3
13
1
Hz), 7.57−7.48 (m, 3H), 7.39−7.36 (m, 1H), 7.22−7.19 (m, 1H), 7.08 (s, 1H); C{ H} NMR
(CDCl , 100 MHz) δ 183.1, 169.9, 164.4, 164.1, 162.5, 161.9, 161.6, 131.3, 131.2, 130.6, 130.5,
3
128.6, 126.84, 126.81, 122.04, 122.0, 121.6, 121.3, 118.2, 117.9, 117.7, 117.5, 113.4, 113.2,
ꢀ1
101.2; IR (KBr, cm ) 3145, 1655, 1610, 1506, 1450, 1190, 895, 750, 680; HRMS (ESI/QꢀTOF)
+
m/z: [M + H] Calcd for C H F NO 286.0674; Found 286.0670.
16
10
2
2
(4ꢀFluorophenyl)(5ꢀ(4ꢀfluorophenyl)isoxazolꢀ3ꢀyl)methanone (24a): gummy; yield 28 mg, 39%;
1
H NMR (CDCl , 400 MHz) δ 8.44−8.41 (m, 2H), 7.86−7.82 (m, 2H), 7.23−7.18 (m, 4H), 6.99
3
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(
s, 1H); C{ H} NMR (CDCl , 100 MHz) δ 184.1, 170.1, 167.9, 165.6, 165.4, 163.1, 162.6,
3
1
33.8, 133.7, 133.6, 132.22, 132.19, 128.4, 128.3, 123.2, 123.1, 116.8, 116.6, 116.5, 116.2,
ꢀ1
1
15.9, 100.27, 100.25; IR (KBr, cm ) 3135, 2924, 2850, 1654, 1613, 1507, 1446, 1253, 1240,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
1
162, 942, 838, 771; HRMS (ESI/QꢀTOF) m/z: [M + H] Calcd for C H F NO 286.0674;
16
10
2
2
Found 286.0680.
Cross Over Experiment Using Two Styrenes:
To an ovenꢀdried 10 mL round bottom flask fitted with a reflux condenser was added pꢀMe
styrene (2) (24 mg, 0.2 mmol), pꢀCl styrene (7) (28 mg, 0.2 mmol), quinoline (26 mg, 0.2 mmol),
tertꢀbutyl nitrite (a) (82 mg, 0.8 mmol), Sc(OTf) (9.8 mg, 0.02 mmol), and 1,2ꢀdichloroethane
3
o
(
1.5 mL). The reaction mixture was refluxed in an oil bath preheated to 80 C for 5 h. The
reaction mixture was cooled to room temperature, admixed with ethyl acetate (25 mL) and the
organic layer was washed with saturated sodium bicarbonate solution (1 x 5 mL). The organic
layer was dried over anhydrous sodium sulfate (Na SO ), and solvent was evaporated under
2
4
reduced pressure. The crude product so obtained was purified over a column of silica gel (hexane
/ ethyl acetate, 9.9:0.1) to get rid of the non polar impurities. The identities of the products were
1
confirmed by H spectra (See supporting information, Fig. S4) and HRMS spectrum (See
supporting information, Fig. S5).
1
8
H O Labelling Experiment for the Formation of Isoxazoline (1a) From Styrene:
2
To an ovenꢀdried 10 mL round bottom flask fitted with a reflux condenser was added
sequentially styrene (1) (42 mg, 0.4 mmol), quinoline (26 mg, 0.2 mmol), tertꢀbutyl nitrite (a)
18
(82 mg, 0.8 mmol), Sc(OTf) (9.8 mg, 0.02 mmol), H O (8 mg, 0.4 mmol), and 1,2ꢀ
3
2
o
dichloroethane (1.5 mL). The reaction mixture was refluxed in an oil bath preheated to 80 C.
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After completion of the reaction (5 h) the crude product was admixed with ethyl acetate (25 mL)
and the organic layer was washed with saturated sodium bicarbonate solution (1 x 5 mL), dried
over anhydrous sodium sulfate (Na SO ), and evaporated under reduced pressure. The identity of
2
4
0
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9
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the O labeled product was confirmed by HRMS (See supporting information, Fig. S6) and
1
3
1
C{ H} NMR (See supporting information, Fig. S7).
1
8
H O Labelling Experiment for the Formation of Isoxazole (19a) From Phenylacetylene:
2
To an ovenꢀdried 10 mL round bottom flask fitted with a reflux condenser was added
sequentially phenyl acetylene (41 mg, 0.4 mmol), quinoline (26 mg, 0.2 mmol), tertꢀbutyl nitrite
18
(82 mg, 0.8 mmol), Sc(OTf) (9.8 mg, 0.02 mmol), H O (8 mg, 0.4 mmol), and 1,2ꢀ
3
2
o
dichloroethane (1.5 mL). The reaction mixture was refluxed in an oil bath preheated to 80 C.
After completion of the reaction (5 h) the crude product was admixed with ethyl acetate (25 mL)
and the organic layer was washed with saturated sodium bicarbonate solution (1 x 5 mL), dried
over anhydrous sodium sulfate (Na SO ), and evaporated under reduced pressure. The identity of
2
4
1
8
the O labeled product was confirmed by HRMS (See supporting information, Fig. S8)
AUTHOR INFORMATION
Corresponding Author
*E mail: patel@iitg.ernet.in
ACKNOWLEDGMENT
B. K. P acknowledges the support of this research by the Department of Science and
Technology (DST) (SB/S1/OCꢀ53/2013), New Delhi, the Council of Scientific and Industrial
Research (CSIR) (02(0096)/12/EMRꢀII) and MHRD: 5ꢀ5/2014ꢀTSꢀVII and CIF, IIT Guwahati
for instrumental facility.
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Supporting Information Available
The Supporting Information is available free of charge on the ACS Publications website at
http://pubs.acs.org.
Mechanistic investigation, spectral and analytical data of all products (PDF).
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TertꢀButyl Nitrite Mediated Domino Synthesis of Isoxazolines and Isoxazoles from
Terminal Aryl Alkenes and Alkynes
Prasenjit Sau, Sourav Kumar Santra, Amitava Rakshit and Bhisma K. Patel*
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