N-Heterocyclic carbene-catalyzed 1,3-dipolar cycloaddition reactions: A facile synthesis of 3,5-di- and 3,4,5-trisubstituted isoxazoles

Article abstract of DOI:10.1039/c1ob06072d

A first example of organo-N-heterocyclic carbene (NHC) catalyzed click-type fast 1,3-dipolar cycloaddition of nitrile oxides with alkynes was developed for the regioselective synthesis of 3,5-di- and 3,4,5-trisubstituted isoxazoles. Triethylamine (Et

Full text of DOI:10.1039/c1ob06072d

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PAPER
N-Heterocyclic carbene-catalyzed 1,3-dipolar cycloaddition reactions: a facile
synthesis of 3,5-di- and 3,4,5-trisubstituted isoxazoles†
Shravankumar Kankala,a Ravinder Vadde*a and Chandra Sekhar Vasam*b
Received 3rd July 2011, Accepted 30th August 2011
DOI: 10.1039/c1ob06072d
A first example of organo-N-heterocyclic carbene (NHC) catalyzed click-type fast 1,3-dipolar
cycloaddition of nitrile oxides with alkynes was developed for the regioselective synthesis of 3,5-di- and
3,4,5-trisubstituted isoxazoles. Triethylamine (Et3N) was employed as an effective base to generate both
nitrile oxide and the organo-NHC catalyst in situ. This catalytic approach was used to attach a variety
of substituents, including other biologically active fragments, onto the isoxazole ring to selectively
design multinucleus structures. Further, we have also optimized the conditions for Cu(I)-free
Sonogashira cross-coupling to obtain internal alkynes in high yields, which were subsequently used in
cycloaddition. A catalytic cycle is proposed and the remarkable regiocontrol in the formation of
isoxazoles was ascribed to a beneficial zwitterion intermediate developed by the interaction of the
strongly nucleophilic organo-NHC catalyst with alkyne followed by nitrile oxide.
investigations using organocatalysts to accelerate the 1,3-dipolar
Introduction
cycloaddition have been reported. Considering the possible dis-
An early study by Huisgen on 1,3-dipolar cycloaddition of azides
proportionation by metal catalysts and the advantages found with
and alkynes to obtain triazoles1 has generated interest in exploring
the usefulness of other dipoles.2 Of particular interest, 1,3-
dipolar cycloaddition of nitrile oxides (1,3-dipole) with alkynes
(dienophile) has good synthetic value since it produces the
biologically and technologically useful isoxazoles.3 However, the
development of a suitable catalyst is suggested to control the
product regioselectivity and also to activate the inert alkyne
dienophiles (Scheme 1).3a–h
organocatalysts in recent homogeneous catalysis,4 we intend to
develop an effective organocatalyst for 1,3-dipolar cycloaddition.
Probably, a strong Lewis basic organocatalyst would be suit-
able to accelerate the reactivity of terminal/internal alkynes by
forming an active zwitterion and thereby directing regioselective
cycloaddition. The formation of zwitterions (alkenyl ion) in the
stoichiometric/catalytic reactions of Lewis basic nucleophiles,
including NHCs, with alkynes in some organic syntheses has
already been reported.5
Within the context of Lewis base catalysis, N-heterocyclic
carbenes (NHCs) are distinct Lewis base (nucleophilic) organocat-
alysts that have both s basicity and p acidity characteristics.6
Starting from the early investigations on thiamine-derived NHCs
in benzoin,6a and later Stetter reactions,6b the mechanistic diversity
of NHCs depending on their properties has led to the development
of several unprecedented C–C and C–X (X = heteroatom) bond
formations. Indeed the isolation of the first stable NHC by
Arduengo in 19917 from imidazolium salts disclosed their tunable
steric and electronic properties by varying the N-substituents on
the imidazole ring. Further, the imidazolium salts, precursors to
NHCs, are stable and easy to operate.
Scheme 1 1,3-Dipolar cycloaddition of nitrile oxides with terminal
alkynes.
1,3-Dipolar cycloaddition of nitrile oxides with terminal alkynes
catalyzed by Cu(I) (click chemistry) and Ru(II) catalysts is
well established to obtain regioselectively the 3,5-di- and 3,4-
disubstituted isoxazoles, respectively.3a–g The Ru(II) catalysts were
also used in the cycloaddition of internal alkynes to obtain
sterically crowded 3,4,5-trisubstituted isoxazoles.3a However, no
Herein we describe for the first time the usefulness of easily
accessible nucleophilic organo-NHC catalysts in the click-type
1,3-dipolar cycloaddition of nitrile oxides with terminal and
internal alkynes to produce regioselectively (a) 3,5-disubstituted
and (b) sterically crowded 3,4,5-trisubstituted isoxazoles, respec-
tively. Further, we also report the optimization of the conditions
to obtain internal alkynes in high yields by a copper(I)-free
Sonogashira cross-coupling which are required in cycloadditions.
aDepartment of Chemistry, Kakatiya University, Warangal, India.
E-mail: ravichemku@rediffmail.com; Fax: +91-870-2438800; Tel: +91-
9390100594
bDepartment of Chemistry, Satavahana University, Karimnagar, India.
E-mail: vasamcs@yahoo.co.in; Fax: +91-878-2255933; Tel: +91-
9000285433
† Electronic supplementary information (ESI) available: Data of yields
and characterization for 3,5-disubstituted isoxazoles 6f–q. See DOI:
10.1039/c1ob06072d
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Table 1 Results of organo-NHC-catalyzed cycloaddition of terminal
alkyne of isoindole (4a) with nitrile oxides (5a–e)a
Results and discussion
(a) Organo-NHC-catalyzed regioselective synthesis of
3,5-disubstituted isoxazoles
We have employed some newly synthesized isoindole-derived ter-
minal alkynes as partners to nitrile oxide in cycloaddition to derive
multinucleus structures. These new terminal alkynes were obtained
in a two step synthesis (Scheme 2). Firstly, the isoindoles (3a–e)
were obtained by the condensation of o-phthaladehyde (OPA) 2
with o-phenylenediamines (OPDA) (1a–e) via the formation of a
Schiff base. N-Propargylation of isoindoles (3a–e) gave terminal
alkynes of isoindoles (4a–e). Previously, we have reported the
application of OPA as a starting material to synthesize biologically
useful quinazolines, macrocyclic Schiff bases and, in a recent
contribution on organo-NHC-catalyzed benzoin condensation of
OPA–chalcone, napthalenone-type metabolites.6q,8 We now extend
the work to obtain isoindole terminal alkynes for cycloaddition.
Entry
Ar
Product
Time
Yield (%)b
1
2
3
4
5
6
4-OMeC6H4 (5a)
4-OMeC6H4 (5a)
4-MeC6H4 (5b)
2-NO2C6H4 (5c)
4-FC6H4 (5d)
6a
6a
6b
6c
6d
6e
30 h
54 (4 : 1)c
15 min
18 min
20 min
20 min
20 min
95
92
85
90
92
4-ClC6H4 (5e)
a All products were characterized by NMR and mass spectral analysis.
b Isolated yields after column chromatography. c Ratio of 3,5 and 3,4
isomers noted without catalyst. d Fig. 1 R = (i).
Fig. 1 NHC precursors (imidazolium salts) and NHCs.
presence of mild triethylamine (Et3N) base via the deprotonation
of the C2–H proton.
Scheme 2 Synthesis of isoindole terminal alkyne derivatives.
Before the addition of nitrile oxide (5a), the reactivity/stability
of alkyne (4a) was examined in the presence of organo-NHC cata-
lyst of salt (i). There was no indication of possible homocoupling
of alkyne. When the in situ generated nitrile oxide (5a) was added to
alkyne (4a) in the presence of the above organo- NHC catalyst, the
cycloaddition was accomplished quickly, within 15 min under the
conditions mentioned in Table 1, and produced exclusively a single
regioisomer of the corresponding 3,5-disubstituted isoxazole (6a)
in good yields (Table 1, entry 2).
The aforementioned optimized conditions for cycloaddition
were then extended to different nitrile oxides (5b–e) with various
electronic properties. It has been noted that all these reactions
catalyzed by organo-NHC of salt (i) were highly regioselective
towards the 3,5-disubstituted isoxazoles (Table 1). In fact, these
catalytic reactions were found to proceed almost instantaneously
(during the first minute), although an approximate time of 15–
20 min was used. However, a small decrease in yields of isoxazoles
(Table 1, entry 4) could be caused by the presence of an ortho-nitro
group on the nitrile oxide exerting an ortho effect. Although Table
1 describes the results obtained with only organo-NHC catalyst of
salt (i), the organo-NHC catalysts of salts ii–vii can also perform
equally well to produce only 3,5-disubstituted isoxazoles.
After these efforts, we also studied the catalytic cycloaddition of
terminal alkynes (4b–e) with nitrile oxides (5a–c) and noticed the
formation of only 3,5-disubstituted isoxazoles as a sole product in
high yields (see ESI†).
Optimization of conditions for the generation and stabilization
of nitrile oxides is an important issue in cycloaddition. In our
work, the nitrile oxides were generated in situ by the reaction
of hydroximoyl chlorides with triethylamine base at 0–5 ◦C to
limit the dimerisation to furoxans. The hydroximoyl chlorides were
obtained by treating aldoximes with an equimolar amount of N-
chlorosuccinimide in dimethyl formamide at room temperature.9
The stabilized nitrile oxides were then subjected to cycloaddition
with isoindole-derived terminal alkynes under N2 atmosphere. The
details of the reaction and the results are summarized in Table 1.
Firstly, the conditions for cycloaddition were optimized by using
nitrile oxide (5a) and terminal alkyne (4a) as model substrates.
The cycloaddition between 5a and 4a studied without a catalyst
was sluggish (~30 h) and produced a mixture of two regioisomers
of disubstituted (3,4- and 3,5-) isoxazole (entry 1, 54% yield
of combined mixture in ~4 : 1 ratio). In this viewpoint, it was
considered to use a nucleophilic organo-NHC catalyst to enhance
the reactivity of the alkyne and thereby to improve the product
regioselectivity. It is known that the lowest unoccupied orbital
of alkynes (being low in energy) allows reactions with strong
nucleophiles, but not directly with weak nucleophiles. We have
considered the imidazolium salts (i–vii, Fig. 1) as organo-NHC
catalyst precursors in this reaction, which were easily synthesized
by a one pot method reported by Arduengo.10 Our efforts began
with the organo-NHC catalyst generated from salt (i) in the
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Table 2 Results of Pd(II)–NHC-catalyzed synthesis of internal alkynes
(10a–h)a
The catalytic conditions optimized in the above 1,3-dipolar
cycloadditions by organo-NHC catalysts for the regioselective syn-
thesis of 3,5-disubstituted isoxazoles are comparable or relatively
better than those of copper-catalyzed3b–i and microwave-induced
1,3-dipolar cycloadditions11 in terms of the ranges of the isoxazole
yields and reactions times. These are also more facile than
other catalytic methods12 for the synthesis of 3,5-disubstituted
isoxazoles such as (i) base-catalyzed cycloaddition of primary
nitro compounds with terminal alkynes; (ii) palladium-catalyzed
four-component coupling of a terminal alkyne, hydrazine, carbon
monoxide and aryl iodide; (iii) gold-catalyzed cycloisomerization
of a,b-acetylenic oximes; (iv) gold-catalyzed transformation of the
cross-dehydrogenative coupling product of nitrones and terminal
alkynes; (v) silver-catalyzed cyclization of alkynyl oxime ethers.
Regarding the characterization, the formation of 3,5-
disubstituted isoxazoles (6a–q) was conformed by 1H and 13C
NMR and mass spectroscopies (experimental and ESI†). The
absence of 1H NMR signals of terminal alkyne at d = ~2.10,
and emergence of a new signal at d = ~6.20 corresponding to
the 4th C–H proton of isoxazole provides good support for
the cycloaddition forming 3,5-disubstituted isoxazoles. The same
features are reflected in the 13C NMR spectra, where the signal
belonging to the terminal carbon of alkyne disappeared and a
new signal belonging to the 4th C–H ring carbon appeared at d =
~99 after cycloaddition.
Entry
R
R1
Product
Yield (%)b
1
2
3
4
5
6
7
8
C6H5 (7a)
4-Me (9a)
10a
10b
10c
10d
10e
10f
10g
10h
96
92
95
82
90
92
85
94
C4H9 (7b)
9a
HOC2H4 (7c)
9a
7a
7b
7c
7a
7b
4-OMeC6H4 (9b)
9b
9b
2-NO2C6H4 (9c)
9c
a All products were characterized by IR, NMR and mass spectral analysis.
b Isolated yields after column chromatography.
In this respect, the Pd(II)–NHC catalyst generated in situ (see the
Experimental) has catalyzed the Cu(I)-free Sonogashira coupling
of some specific terminal alkynes (7a–c) with aryl iodides (9a–c)
in the presence of pyrrolidine base (milder than even Et3N) and
provided excellent yields of the corresponding internal alkynes
(10a–h) at room temperature (Table 2). The Sonogashira coupling
of this work is very tolerant of other functional groups on terminal
alkynes (7b and c) as indicated by spectral analysis.
Among the various pre-synthesized internal alkynes (10a–h),
we have chosen internal alkynes (10a–d), designed with specific
electronic and steric properties, to conduct cycloaddition with
nitrile oxides (5a–e). Two sets of control cycloaddition experiments
were planned with or without organo-NHC catalyst. In the
absence of catalyst, the cycloaddition of nitrile oxide (5a) studied
with the internal alkynes (10a) and (10c) was very slow, but the
former reaction (10a with 5a) yielded a single regioisomer (Table
3, entry 1) and the latter one (10c with 5a) yielded a mixture of two
regioisomers of trisubstituted isoxazole (Table 3, entry 7) due to
steric factors. This observation reveals the necessity of a catalyst
to improve not only the yields of isoxazole but also to control the
regioselectivity for steric reasons.
Further control experiments were performed by submitting
a 1 : 1 mixture of alkynes (4a) and (4b) to the cycloaddition
with nitrile oxide (5a) to ensure the involvement of the NHC
catalyst in the cycloaddition path. It was found that under
identical reaction conditions, again only the corresponding 3,5-
disubstituted isoxazoles (6a) and (6f) were formed (91% of
combined mixture in ~1 : 1.2 ratios). There was no evidence for
side reactions such as homocoupling or cross-coupling of alkynes.
This result clearly indicates the decisive role of the NHC catalyst
in the cycloadditions.
(b) Organo-NHC-catalyzed regioselective synthesis of sterically
crowded 3,4,5-trisubstituted isoxazoles
To elaborate on the scope of the organo-NHC-catalyzed cycload-
ditions, we have also organized the regioselective synthesis of some
sterically crowded 3,4,5-trisubstituted isoxazoles by employing
some pre-synthesized internal alkynes as partners to nitrile oxides.
Since the nucleophilic organo-NHC catalyst can interact with both
terminal and internal alkyne functions in the same fashion, we have
undertaken this study. It is noticeable that the Sharpless copper
catalyst is not suitable for the cycloaddition of internal alkynes.
First, we gave attention to optimizing the conditions for
synthesis of internal alkynes by Pd(II)-catalyzed Sonogashira
cross-coupling of terminal alkynes with aryl iodides in the
presence of an amine base. According to the original report on
Sonogashira coupling,13 the Pd(II) catalyst needs the support of a
Cu(I) co-catalyst. However, recent investigations recommended
the Cu(I)-free Sonogashira coupling to prevent the possible
oxidative dimerization of terminal alkynes by Cu(I).14 Since NHCs
have also been recognized as strong s-donating ligands, the
metal–NHC complexes have become popular catalysts to process
certain organic transformations, specifically cross-coupling and
metathesis.15
In view of the above information, organo-NHC catalyst of salt
(i) (Fig. 1) was brought into the cycloaddition of the substrates
listed in Table 3. To our delight, the catalytic cycloaddition re-
actions of internal alkynes (10a–d) also occurred instantaneously,
similarly to those terminal alkynes, upon mixing with nitrile oxides
(5a–e) under simple stirring at 0–5 ◦C for a period of 30 min, and
produced selectively 3,4,5-trisubstituted isoxazoles (11a–j) in good
yields (Table 3) by diminishing the steric factors. The result of a
control experiment is also provided (entry 13). It is now clear that
NHC catalysts are involved in the cycloaddition.
We noticed that the results and conditions depicted in Table 3
for the organo-NHC-catalyzed regioselective synthesis of 3,4,5-
trisubstituted isoxazoles are found to be comparable or relatively
better than the previous reports,3a,h,i,16 including (i) Ru(II)-catalyzed
cycloaddition of nitrile oxide with internal alkynes; (ii) sequential
1,3-dipolar cycloaddition and cross-coupling of silicon adducts;
(iii) base-catalyzed cycloaddition of primary nitro compounds
with internal alkynes; (iv) palladium-catalyzed cross-coupling
of 4-iodo-substituted 2,5-dihydroisoxazoles and isoxazoles; (v)
Sonogashira coupling of acid chlorides with terminal alkynes,
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Table 3 Results of organo-NHC-catalyzed cycloaddition of internal
alkynes (10a–d) and nitrile oxides (5a–e)a
undergoes C–O heterocyclization to produce regioselectively the
corresponding isoxazoles.
Conclusions
A facile catalytic approach to synthesize regioselectively both
3,5-di- and 3,4,5-trisubstiututed isoxazoles in high yields was
developed by the nucleophilic organo-NHC-catalyzed 1,3-dipolar
cycloaddition of nitrile oxide with alkynes. To our knowledge, this
is the first effort established with an organocatalyst to process
the cycloaddition of both terminal and internal alkynes. Most
importantly, the NHC catalyst precursors used in this work are
easy to synthesize and operate. Specifically, the multinucleus
structures like isoindole linked disubstituted isoxazoles and ster-
ically crowded trisubstituted isoxazoles can be accessed easily
selectively by this method, which could be useful in biology and
material science. Our method could be an efficient alternative to
Sharpless copper catalyst and Fokin Ru(II) catalyst in the 1,3-
dipolar cycloaddition of nitrile oxide with alkynes. Depending on
the choice of starting materials, this is also an alternative to other
existing catalytic methods.12a,b,16 There have been some reports on
catalyst-free 1,3-dipolar cycloadditions of nitrile oxide to alkyne17
or alkene,18 but these appear to be applicable for specific examples.
Further, we have also disclosed that the combination of Pd(II)–
NHC catalyst and mild pyrrolidine base works well in Cu(I)-free
Sonogashira coupling to obtain internal alkynes in high yields.
We are currently working on the development of cycloaddition
reactions under non-inert conditions using air stable Ag(I)–NHCs
as precursors to provide free organo-NHC catalysts in solution.
The Ag(I)–NHCs were obtained by Lin’s Ag2O method.15f Lewis
basic nucleophiles such as N-oxides, phosphines, quaternary
ammonium salts and tertiary amines are also worthwhile to be
considered in cycloaddition, which will certainly explore new
catalytic paths. Since alkynes, nitro compounds and aldehydes,
and NHCs in the form of thiamine, are also available in nature, our
efforts may also be useful to connect Nature’s chemical reactions.
Entry Internal alkyne (Ar1, R)
Nitrile oxide (Ar) Product Yield (%)b
1
2
4-OMeC6H4 (5a) 11a
4-OMeC6H4 (5a) 11a
2-NO2C6H4 (5c) 11b
24c
96
3
4
5
10a
10a
85
90
92
4-FC6H4 (5d)
11c
4-MeC6H4 (5b) 11d
6
7
10b
4-ClC6H4 (5e)
5a
11e
11f
90
32 (8 : 2)c
8
9
10
10c
10c
5a
5b
5a
11f
11g
11h
94
90
92
11
12
13
10d
5b
5c
5a
11i
11j
92
85
10d
10d + 10c
11f + 11h 86d
a All products were characterized by IR, NMR and mass spectral analysis.
b Isolated yields after column chromatography. c Without NHC catalyst.
d Control experiment (11f = 46% + 11h = 40%)
followed by 1,3-dipolar cycloaddition with nitrile oxide under
dielectric heating; (vi) gold-catalyzed domino reaction of alkynyl
oxime ethers.
Finally, based on the results obtained in our work con-
cerning the regioselective synthesis of both 3,5-di- and 3,4,5-
trisubstiututed isoxazoles including control experiments, a plau-
sible mechanism has been deduced (Scheme 3). The formation
of isoxazoles could occur in a domino fashion in cycloaddition.
According to Scheme 3, the organo-NHC catalyst will interact
first with the alkyne (terminal/internal) and form a zwitterion.
The formation of a zwitterion in the catalytic/stoichiometric
reaction of nucleophiles including NHCs and alkynes has already
been already established.5 The reactive zwitterionic species will
now interact with nitrile oxide through nucleophilic attack and
form another zwitterion via C–C bond formation, which finally
Experimental section
General
All commercially available reagents were used without further
purification. Reaction solvents were dried by standard methods
before use. Purity of the compounds was checked by TLC using
Merck 60F254 silica gel plates. Elemental analyses were obtained
1
with an Elemental Analyser Perkin–Elmer 240 C apparatus. H
and 13C NMR spectra were recorded with a Mercuryplus 400
spectrometer (operating at 400 MHz for 1H and 100.58 MHz for
13C); chemical shifts were referenced to TMS. EI (electron impact)
mass spectra (at an ionising voltage of 70 eV) were obtained using
a Shimadzu QP5050A quadrupole-based mass spectrometer. IR
spectra were recorded with a Perkin-Elmer 881 spectrometer.
General procedure for the synthesis of 3,5-disubstituted isoxazoles
(6a–q). To terminal alkynes 4a–e (1 mmol) and NHC precursor
(i) (5 mol%) in dry DCM (5 ml) under nitrogen atmosphere was
added Et3N (5 mol%). The mixture◦was stirred for 10 min. The
reaction mixture was cooled to 0–5 C and added dropwise to a
solution of benzonitrile oxide 5a–e (1 mmol), generated in situ by
the treatment of triethylamine (1.2 mmol) with the corresponding
Scheme 3 A plausible mechanism for the formation of 3,5-di- and
3,4,5-trisubstituted isoxazoles.
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chlorooximes (1 mmol) in dry DCM (10 ml) over a period of 2 min
while maintaining the temperature between 0–5 ◦C. The reaction
mass was allowed to attain room temperature and stirring was
continued for 20 min. After conversion was complete, the mixture
was quenched by addition of saturated solution of NH4Cl (2 ml)
and diluting with dichloromethane (40 ml). The organic layer was
separated and the aqueous layer extracted with dichloromethane
(2 ¥ 20 ml). The combined organic layers were dried (anhydrous
Na2SO4) and evaporated under reduced pressure to afford a crude
product which was subjected to column chromatography (silica
gel, 60–120 mesh, eluent; n-hexane/EtOAc gradient) to afford
pure products (6a–q).
Butyl-4-methylphenylacetylene (10b). 1H NMR (400 MHz,
CDCl3, 25 C): d = 0.92 (t, 3H, J = 7.3 Hz), 1.28–1.62 (m, 4H),
◦
2.24 (s, 3H), 2.42 (t, 2H, J = 6.9 Hz), 6.94 (d, 2H, J = 8.0 Hz,
Ar-H), 7.24 (d, 2H, J = 8.0 Hz, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3, 25 ◦C): d = 13.82, 19.26, 21.54, 22.19, 31.14, 82.80, 86.22,
120.71, 129.41, 131.94, 138.35 ppm. IR (KBr): = 3140, 3022, 2925,
2140, 1355, 1177, 830 cm-1. MS (EI, 70 eV): m/z (%) = 173 [M
+ H]+. EA calcd (%) for C13H16 (172.10): calcd. C 90.64, H 9.36;
found C 90.32, H 9.26.
4-(4-Methylphenyl)-3-butyn-1-ol (10c). 1H NMR (400 MHz,
CDCl3, 25 ◦C): d = 2.23 (s, 3H), 2.62 (t, 2H, J = 6.5 Hz), 2.68 (br
s, 1H), 3.72 (t, 2H, J = 6.5 Hz), 6.95 (d, 2H, J = 8.0 Hz, Ar-H),
7.20 (d, 2H, J = 8.0 Hz, Ar-H) ppm. 13C NMR (100 MHz, CDCl3,
25 ◦C): d = 21.82, 24.12, 61.50, 82.82, 86.24, 120.75, 129.44, 131.92,
138.30 ppm. IR (KBr): = 3416, 3046, 2925, 2140, 1355, 1177, 830
cm-1. MS (EI, 70 eV): m/z (%) = 161 [M + H]+. EA calcd (%) for
C11H12O (160.03): calcd. C 82.46, H 7.55; found C 82.44, H 7.54.
5-(3-(4-Methoxyphenyl)isoxazol-5-ylmethyl)-5H benzo(4,5)imi-
dazo(2,1a)isoindole (6a). 1H NMR (200 MHz, CDCl3, 25 ◦C):
d = 3.84 (s, 3H), 4.56 (s, 2H), 6.38 (s, 1H◦), 6.94–7.28 (m, 13H, Ar-H)
ppm. 13C NMR (100 MHz, CDCl3, 25 C): d = 56.24, 58.30, 99.06,
109.22, 112.10, 113.42, 117.11, 118.76, 120.95, 124.05, 125.62,
128.22, 128.62, 128.85, 135.52, 150.62, 157.85, 162.44 ppm. MS
(EI, 70 eV): m/z (%) = 394 [M + H]+. EA calcd (%) for C25H19N3O2
(393.15): calcd. C 76.32, H 4.87, N 10.68; found C 76.30, H 4.85,
N 10.65.
4-Methoxydiphenylacetylene (10d). 1H NMR (400 MHz,
◦
CDCl3, 25 C): d = 3.82 (s, 3H), 6.88–6.90 (m, 2H, Ar-H), 7.35–
7.42 (m, 3H, Ar-H), 7.55–7.62 (m, 4H, Ar-H) ppm. IR (KBr): =
3014, 2216, 2029, 1607, 1595, 1273, 1102, 834, 754, 691 cm-1. MS
(EI, 70 eV): m/z (%) = 209 [M + H]+. EA calcd (%) for C15H12O
(208.10): calcd. C 86.51, H 5.81; found C 86.49, H 5.78.
5-(3-(4-Methylphenyl)isoxazol-5-ylmethyl)-5H-benzo(4,5)imi-
dazo(2,1a)isoindole (6b). 1H NMR (200 MHz, CDCl3, 25 ◦C): d =
2.36 (s, 3H), 4.56 (s, 2H), 6.36 (s, 1H), 6.94–7.18 (m, 13H, Ar-H)
ppm. 13C NMR (100 MHz, CDCl3, 25 ◦C): d = 23.56, 58.32, 99.06,
109.22, 112.10, 113.42, 117.24, 118.72, 120.95, 124.05, 125.62,
128.22, 128.62, 128.85, 135.52, 150.62, 157.85, 162.44 ppm. MS
(EI, 70 eV): m/z (%) = 378 [M + H]+. EA calcd (%) for C25H19N3O
(377.15): calcd. C 79.55, H 5.07, N 11.13; found C 79.52, H 5.05,
N 11.10.
Butyl-4-methoxyphenylacetylene (10e). 1H NMR (400 MHz,
CDCl3, 25 ◦C): d = 0.92 (t, 3H, J = 7.3 Hz), 1.28–1.62 (m, 4H), 2.4
(t, 2H, J = 6.9 Hz), 3.82 (s, 3H), 6.92 (d, 2H, J = 8.0 Hz, Ar-H),
7.24 (d, 2H, J = 8.0 Hz, Ar-H) ppm. IR (KBr): = 3140, 3022, 2925,
2140, 1355, 1170, 1050, 830 cm-1. MS (EI, 70 eV): m/z (%) = 189
[M + H]+. EA calcd (%) for C13H16O (188.03): calcd. C 82.94, H
8.57; found C 82.92, H 8.46.
5-(3-(2-Nitrophenyl)-isoxazol-5-ylmethyl)-5H-benzo(4,5)imida-
zo(2,1a)isoindole (6c). 1H NMR (200 MHz, CDCl3, 25 ◦C): d =
4.56 (s, 2H), 6.36 (s, 1H), 6.96-7.48 (m, 13H, Ar-H) ppm. MS (EI,
70 eV): m/z (%) = 409 [M + H]+. EA calcd (%) for C24H16N4O3
(408.12): calcd. C 70.58, H 3.95, N 13.72; found C 70.56, H 3.93,
N 13.70.
4-(4-Methoxyphenyl)-3-butyn-1-ol (10f). 1H NMR (400 MHz,
CDCl3, 25 ◦C): d = 2.62 (t, 2H, J = 6.5 Hz), 2.74 (br s, 1H), 3.72
(t, 2H, J = 6.5 Hz), 3.82 (s, 3H), 6.92 (d, 2H, J = 8.0 Hz, Ar-H),
7.24 (d, 2H, J = 8.0 Hz, Ar-H) ppm. IR (KBr): = 3416, 3046, 2925,
2140, 1355, 1170, 1050, 830 cm-1. MS (EI, 70 eV): m/z (%) = 177
[M + H]+. EA calcd (%) for C11H12O2 (176.06): calcd. C 74.98, H
6.86; found C 74.96, H 6.84.
General procedure for Sonogashira cross-coupling. In a typical
procedure, a suspension of Pd(OAc)2 (0.03 mmol) and NHC
precursor (i) (0.06 mmol) was dissolved in DCM (2 ml). Then,
the indicated amount of the above dichloromethane solution was
added to a mixture of aryl iodides (1 mmol), phenyl acetylenes (1.2
mmol), pyrrolidine (3 mmol) and DCM (5 ml). Then, the mixture
was stirred at room temperature for 2 h to give desired internal
alkyne products. Complete consumption of starting material was
judged by TLC and GC analysis. After, the mixture was filtered and
evaporated, the residue was purified by column chromatography
(silica gel, 60–120 mesh, eluent; n-hexane/EtOAc (8 : 2) gradient)
to afford the desired coupled products (10a–h).
2-Nitrodiphenylacetylene (10g). 1H NMR (400 MHz, CDCl3,
◦
25 C): d = 7.28–7.34 (m, 3H, Ar-H), 7.55–7.61 (m, 3H, Ar-H),
7.74–7.82 (m, 2H, Ar-H) 8.24 (d, 1H, Ar-H) ppm. IR (KBr): =
3100, 3040, 2934, 2048, 1607, 1533, 1236, 1105, 831, 768, 735
cm-1. MS (EI, 70 eV): m/z (%) = 224 [M + H]+. EA calcd (%) for
C14H9NO2 (223.02): calcd. C 75.33, H 4.06, N 6.27; found C 75.31,
H 4.04, N 6.24.
Butyl-2-nitrophenylacetylene (10h). 1H NMR (400 MHz,
◦
CDCl3, 25 C): d = 0.92 (t, 3 H, J = 7.3 Hz), 1.58–1.64 (m, 4H),
2.42 (t, 2 H, J = 6.9 Hz), 7.64–7.82 (m, 3H, Ar-H) 8.21 (d, 1H,
Ar-H) ppm. IR (KBr): = 3040, 2934, 2150, 1607, 1533, 1345, 758
cm-1. MS (EI, 70 eV): m/z (%) = 204 [M + H]+. EA calcd (%)
for C12H13NO2 (203.06): calcd. C 70.92, H 6.45, N 6.89; found C
70.86, H 6.41, N 6.88.
4-Methyl◦diphenylacetylene (10a). 1H NMR (400 MHz,
CDCl3, 25 C): d = 2.52 (s, 3H), 7.10–7.24 (m, 2H, Ar-H), 7.41–
7.50 (m, 3H, Ar-H), 7.60–7.68 (m, 4H, Ar-H) ppm. 13C NMR (100
MHz, CDCl3, 25 ◦C): d = 21.69, 88.90, 89.74, 114.2, 115.6, 123.8,
128.2, 128.5, 131.7, 133.3, 159.9 ppm. IR (KBr): = 3045, 2214,
2038, 1607, 1595, 1168, 1025, 834, 754, 694 cm-1. MS (EI, 70 eV):
m/z (%) = 193 [M + H]+. EA calcd (%) for C15H12 (192.04): calcd.
C 93.71, H 6.29; found C 93.65, H 6.26.
General procedure for the synthesis of 3,4,5-trisubstituted isox-
azoles. To internal alkynes (1 mmol) and NHC precursor (i)
(5 mol%) in dry DCM (5 ml) under nitrogen atmosphere was
added Et3N (5 mol%). The mixture was stirred for 10 min. The
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reaction mixture was cooled to 0–5 ◦C and added dropwise to
a solution of benzonitrile oxide (1 mmol), generated in situ by
the treatment of triethylamine (1.2 mmol) with the corresponding
chlorooxime (1 mmol) in dry DCM (15 ml) over a period of 2 min
while maintaining the temperature between 0–5 ◦C. The reaction
mass was allowed to attain room temperature and stirring was
continued for 30 min. After conversion was complete, the mixture
was quenched by addition of saturated solution of NH4Cl (2 ml)
and diluting with dichloromethane (40 ml). The organic layer was
separated and the aqueous layer extracted with dichloromethane
(2 ¥ 20 ml). The combined organic layers were dried (anhydrous
Na2SO4) and evaporated under reduced pressure to afford a crude
product which was subjected to column chromatography (silica
gel, 60–120 mesh, eluent; n-hexane/EtOAc gradient) to afford
pure products (11a–j).
2H, Ar-H) ppm. IR (KBr): = 2938, 1642, 1527, 1428, 1245, 1258,
1176, 1126, 1062, 934, 902, 838, 788, 736 cm-1. MS (EI, 70 eV):
m/z (%) = 348 [M + Na]+. EA calcd (%) for C20H20ClNO (325.08):
calcd. C 73.72, H 6.19, N 4.30; found C 73.70, H 6.16, N 4.28.
2-(3-(4-Methoxyphenyl)-5-(4-methylphenyl)◦-4-isoxazolyl)-1-etha-
nol (11f). 1H NMR (400 MHz, CDCl3, 25 C): d = 2.32 (s, 3H),
2.52 (t, 2H, J = 6.9 Hz), 3.84 (s, 3H), 3.91 (t, 2H, J = 6.9 Hz),
4.25 (s, 1H), 6.92–7.01 (m, 2H, Ar-H), 7.28–7.32 (m, 2H, Ar-H),
7.44–7.52 (m, 4H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3,
25 ◦C): d = 21.52, 24.22, 56.20, 64.08, 110.82, 115.63, 121.53,
127.41, 128.32, 129.25, 129.96, 138.47, 161.84, 162.28, 165.04
ppm. IR (KBr): = 3422, 2934, 1612, 1527, 1441, 1298, 1258, 1176,
1116, 1062, 948, 902, 838, 788, 736 cm-1. MS (EI, 70 eV): m/z
(%) = 332 [M + Na]+. EA calcd (%) for C19H19NO3 (309.07): calcd.
C 73.77, H 6.19, N 4.53; found C 73.75, H 6.14, N 4.49.
3-(4-Methoxyphenyl)-5-(4-methylphenyl)-4-phenylisoxazole (11a).
1H NMR (400 MHz, CDCl3, 25 ◦C): d = 2.32 (s, 3 H), 3.84 (s, 3H),
6.81–6.86 (m, 2H, Ar-H), 7.12–7.20 (m, 2H, Ar-H), 7.31–7.53
(m, 7H, Ar-H), 7.60–7.68 (m, 2H, Ar-H) ppm. 13C NMR (100
MHz, CDCl3, 25 ◦C): d = 21.84, 54.16, 108.62, 115.23, 121.04,
126.24, 127.53, 127.62, 127.89, 129.42, 130.88, 137.26, 157.20,
159.24, 160.47 ppm. IR (KBr): = 3008, 2844, 1604, 1508, 1428,
1258, 1105, 1063, 942, 838, 742, 736, 684 cm-1. MS (EI, 70 eV):
m/z (%) = 364 [M + Na]+. EA calcd (%) for C23H19NO2 (341.14):
calcd. C 80.92, H 5.61, N 4.10; found C 80.90, H 5.58, N 4.09.
2-(3,5-di(4-Methylphenyl)-4-isoxazolyl)-1-ethanol (11g). 1H
NMR (400 MHz, CDCl3, 25 ◦C): d = 2.32 (s, 6H), 2.52 (t, 2H, J =
6.9 Hz), 3.91 (t, 2H, J = 6.9 Hz), 4.25 (s, 1H), 6.92–7.01 (m, 2H,
Ar-H), 7.28–7.32 (m, 2H, Ar-H), 7.44–7.52 (m, 4H, Ar-H) ppm.
IR (KBr): = 3428, 2934, 1612, 1527, 1441, 1276, 1241, 1176, 1116,
1062, 948, 902, 838, 788, 736 cm-1. MS (EI, 70 eV): m/z (%) = 316
[M + Na]+. EA calcd (%) for C19H19NO2 (293.10): calcd. C 77.79,
H 6.53, N 4.77; found C 77.78, H 6.50, N 4.76.
3,5-di(4-Methoxyphenyl)-4-phenylisoxazole (11h). 1H NMR
(400 MHz, CDCl3, 25 ◦C): d = 3.85 (s, 6H), 6.84–6.92 (m, 4H,
Ar-H), 7.46–7.58 (m, 7H, Ar-H), 7.64–7.72 (m, 2H, Ar-H) ppm.
IR (KBr): = 3005, 2942, 2826, 1614, 1508, 1428, 1275, 1107, 1084,
942, 838, 742, 734, 680 cm-1. MS (EI, 70 eV): m/z (%) = 380 [M
+ Na]+. EA calcd (%) for C23H19NO3 (357.10): calcd. C 77.29, H
5.36, N 3.92; found C 77.28, H 5.33, N 3.90.
5-(4-Methylphenyl)-3-(2-nitrophenyl)-4-phenylisoxazole (11b).
1H NMR (400 MHz, CDCl3, 25 ◦C): d = 2.32 (s, 3 H), 7.12–
7.19 (m, 2H, Ar-H), 7.31–7.53 (m, 8H, Ar-H), 7.61–7.70 (m, 2H,
Ar-H), 8.32 (m, 1 H, Ar-H) ppm. IR (KBr): = 3100, 3080, 2922,
1942, 1508, 1428, 1245, 1063, 932, 836, 786, 736, 680 cm-1. MS (EI,
70 eV): m/z (%) = 379 [M + Na]+. EA calcd (%) for C22H16N2O3
(356.12): calcd. C 74.15, H 4.53, N 7.86; found C 74.13, H 4.50, N
7.85.
5-(4-Methoxyphenyl)-3-(4-methylphenyl)-4-phenylisoxazole (11i).
1H NMR (400 MHz, CDCl3, 25 ◦C): d = 2.34 (s, 3 H), 3.85 (s,
3H), 6.81–6.86 (m, 2H, Ar-H), 7.12–7.20 (m, 2H, Ar-H), 7.31–
7.53 (m, 7H, Ar-H), 7.65–7.70 (m, 2H, Ar-H) ppm. IR (KBr): =
3005, 2942, 1614, 1508, 1428, 1275, 1107, 1084, 942, 838, 742, 734,
680 cm-1. MS (EI, 70 eV): m/z (%) = 364 [M + Na]+. EA calcd (%)
for C23H19NO2 (341.02): calcd. C 80.92, H 5.61, N 4.10; found C
80.90, H 5.60, N 4.09.
3-(4-Fluorophenyl)-5-(4-methylphenyl)-4-phenylisoxazole (11c).
1H NMR (400 MHz, CDCl3, 25 ◦C): d = 2.32 (s, 3 H), 6.93–7.02
(m, 2H, Ar-H), 7.12–7.20 (m, 2H, Ar-H), 7.31–7.53 (m, 7H, Ar-
H), 7.63–7.70 (m, 2H, Ar-H) ppm. IR (KBr): = 3008, 2854, 1602,
1508, 1428, 1245, 1063, 942, 838, 788, 736, 680 cm-1. MS (EI,
70 eV): m/z (%) = 352 [M + Na]+. EA calcd (%) for C22H16FNO
(329.10): calcd. C 80.23, H 4.90, N 4.25; found C 80.21, H 4.89, N
4.22.
5-(4-Methoxyphenyl)-3-(2-nitro◦phenyl)-4-phenylisoxazole (11j).
1H NMR (400 MHz, CDCl3, 25 C): d = 3.85 (s, 3H), 7.12–7.20
(m, 2H, Ar-H), 7.31–7.53 (m, 8H, Ar-H), 7.64–7.70 (m, 2H, Ar-
H), 8.32 (m, 1H, Ar-H) ppm. IR (KBr): = 3100, 3045, 2904, 1613,
1508, 1428, 1275, 1063, 932, 838, 786, 736, 680 cm-1. MS (EI,
70 eV): m/z (%) = 395 [M + Na]+. EA calcd (%) for C22H16N2O4
(372.02): calcd. C 70.96, H 4.33, N 7.52; found C 70.94, H 4.32, N
7.51.
4-Butyl-3,5-di(4-methylphenyl)isoxazole (11d). 1H NMR (400
MHz, CDCl3, 25 ◦C): d = 0.92 (t, 3H, J = 7.5 Hz), 1.41–1.63 (m,
4H), 2.42 (t, 2H, J = 7.2 Hz), 2.32 (s, 6H), 6.94–7.01 (m, 2H,
Ar-H), 7.24–7.31 (m, 2H, Ar-H), 7.44–7.52 (m, 4H, Ar-H) ppm.
13C NMR (100 MHz, CDCl3, 25 ◦C): d = 14.26, 21.34, 21.96,
25.22, 29.14, 31.22, 112.26, 125.43, 126.63, 127.42, 129.34, 130.04,
136.48, 139.48, 159.16, 161.34 ppm. IR (KBr): = 2932, 1638, 1527,
1428, 1245, 1258, 1184, 1126, 1063, 932, 902, 838, 786, 736 cm-1.
MS (EI, 70 eV): m/z (%) = 328 [M + Na]+. EA calcd (%) for
C21H23NO (305.12): calcd. C 82.58, H 7.59, N 4.59; found C 82.56,
H 7.58, N 4.55.
Acknowledgements
The authors thank the University Grant Commission (UGC,
F. No. 34-363/2008(SR)), New Delhi, India for the financial
support. The authors also thank Prof. A.J. Arduengo, University
of Alabama-USA and Prof. I.J.B. Lin, National Dong Hwa
University-Taiwan for their suggestions on NHC chemistry.
4-Butyl-3-(4-chlorophenyl)-5-(4-methylphenyl)isoxazole (11e).
1H NMR (400 MHz, CDCl3, 25 ◦C): d = 0.92 (t, 3H, J = 7.5
Hz), 1.41–1.63 (m, 4H), 2.42 (t, 2H, J = 7.2 Hz), 2.32 (s, 3H),
6.94–7.01 (m, 2H, Ar-H), 7.24–7.31 (m, 4H, Ar-H), 7.44–7.52 (m,
7874 | Org. Biomol. Chem., 2011, 9, 7869–7876
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