Synthesis and reactivity of Mannich bases. Part 15: Synthesis of 3-(2-(1-pyrazolyl)ethyl)-1,2-benzisoxazoles

Article abstract of DOI:10.1016/S0040-4020(02)00027-3

Four new Mannich bases derived from ortho-hydroxyacetophenones and containing pyrazoles as amine moieties have been subjected to oximation in alkaline medium. The selective acetylation to the oximino hydroxyl of the resulting oximes led to the corresponding oxime-acetates. These have been transformed via a ring closure reaction in refluxing benzene and in the presence of anhydrous K₂CO₃ into 3-(2-(1-pyrazolyl)ethyl)-1,2-benzisoxazoles, valuable as potential pharmacologically relevant compounds.

Full text of DOI:10.1016/S0040-4020(02)00027-3

TETRAHEDRON
Pergamon
Tetrahedron 58 22002) 1617±1622
Synthesis and reactivity of Mannich bases. Part 15: Synthesis of
3-ꢀ2-ꢀ1-pyrazolyl)ethyl)-1,2-benzisoxazoles
Gheorghe Roman,a,p Eugenia Comanitab and Bogdan Comanitac
aDepartment of Chemistry, Transilvania University, 29 Eroilor Blvd., RO-2200, Brasov, Romania
bDepartment of Organic Chemistry, Gh. Asachi Technical University, 71A Dimitrie Mangeron Blvd., RO-6600, Iasi, Romania
cInstitute for Chemical Process and Environmental Technology, National Research Council of Canada, Montreal Road Campus,
Ottawa, Canada, K1A 0R6
Received 9 October 2001; revised 4 December 2001; accepted 3January 2002
AbstractÐFour new Mannich bases derived from ortho-hydroxyacetophenones and containing pyrazoles as amine moieties have been
subjected to oximation in alkaline medium. The selective acetylation to the oximino hydroxyl of the resulting oximes led to the correspond-
ing oxime-acetates. These have been transformed via a ring closure reaction in re¯uxing benzene and in the presence of anhydrous K2CO3
into 3-22-21-pyrazolyl)ethyl)-1,2-benzisoxazoles, valuable as potential pharmacologically relevant compounds. q 2002 Elsevier Science
Ltd. All rights reserved.
1. Introduction
The earlier successful synthesis9 of 3-22-dialkylamino-
ethyl)-1,2-benzisoxazoles via the cyclization of 3-dialkyl-
amino-1-22-hydroxyphenyl)-1-propanone oxime acetates in
re¯uxing benzene in the presence of anhydrous K2CO3
urged us to investigate the applicability of this procedure
for the generation of other 1,2-benzisoxazoles, this time
bearing a pyrazolylethyl substituent in position 3.
A survey of the recent literature on 1,2-benzisoxazoles
reveals the importance of the above-mentioned heterocyclic
system as a moiety in pharmaceutically signi®cant
compounds. Moreover, studies suggest that 3-substituted
1,2-benzisoxazoles are more likely to display biological
activities. Thus, a series of 1,2-benzisoxazoles-3-carboxa-
mides was evaluated as potential atypical antipsychotic
agents and presented af®nity for serotonergic and dopa-
minergic receptors.1,2 Iloperidone 2HP 873), an 3-aryloxy-
alkylpiperidinyl-1,2-benzisoxazole derivative, was also
shown to exhibit potent antipsychotic-like activity and
ef®ciency against asociality, a negative symptom of schizo-
phrenia.3 Aminoalkyl 2-cyclic amino-2-21,2-benzisoxazol-
3-yl)acetates and their quaternary ammonium salts4 along
with 3-2N-benzylpiperidinylethyl)-1,2-benzisoxazoles5 were
investigated and found to selectively inhibit acetylcholine-
sterase, making them suitable candidates for the palliative
treatment of Alzheimer's disease. A potent inhibitor of
LTB4 binding to human neutrophile belongs to a family
of 3-amino-1,2-benzisoxazoles6 whereas 3-22-thienyl)- or
3-22-imidazolyl)-1,2-benzisoxazoles inhibit arachidonic
acid-induced platelet aggregation.7 Recently, two patents8
have claimed that substituted 3-2aminoalkylamino)-1,2-
benzisoxazoles are useful for the treatment of various
memory dysfunctions and as antidepressants by inhibiting
monoamine oxidase.
2. Results and discussions
The four step reaction scheme leading to 3-22-21-pyrazolyl)-
ethyl)-1,2-benzisoxazoles 5 is presented in Scheme 1.
The starting 1-22-hydroxyphenyl)-3-21-pyrazolyl)-1-propa-
nones 2 were prepared through an amine exchange reaction
between the dimethylamine Mannich bases 1 2R1ˆH or
CH3) derived from ortho-hydroxyacetophenones11,12 and
pyrazoles. As it has been previously shown for the similar
reaction between the same Mannich bases and aryl-
amines,12,13 the displacement of the dimethylamino moiety
was best accomplished by re¯uxing the reactants for 1 h in a
1:1 2v/v) mixture of ethanol and water, that dissolves both
starting materials and allows a facile separation of the
N-alkylated pyrazoles in the end. The resulting emulsion
was cooled with good stirring in a dry ice±acetone
refrigerating mixture in order to obtain the solid compounds
2 2yield 50±84%).
Oximation of N-2ortho-hydroxybenzoylethyl)pyrazoles 2
was conducted in an aqueous alkaline solution in which
these compounds are soluble due to the phenolic hydroxyl
in their structure. As the salts of the pyrazole-containing
Keywords: b-aminoketones; pyrazoles; amine exchange reaction; oximes;
benzisoxazoles.
Corresponding author; e-mail: gh.roman@info.unitbv.ro;
gheorghe_roman@yahoo.com
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020202)00027-3

1618
G. Roman et al. / Tetrahedron 58 02002) 1617±1622
Scheme 1. Three-step synthesis of 3-22-21-pyrazolyl)ethyl)-1,2-benzisoxazoles.
Mannich bases are not as soluble as their analogs bearing a
dialkylamino moiety instead, larger volumes of dilute
NaOH solution should be used. The alkaline medium also
plays a key role in controlling the stereochemistry of the
resulting oximes. It has been shown14 that oximations in an
alkaline medium leads to only one stereoisomer; further-
more, most aryl alkyl ketoximes exhibit a syn-alkyl con-
®guration,15 that is also important in the subsequent
cyclization stage of oxime acetates to 1,2-benzisoxazoles.
The molar ratio Mannich base/hydroxylamine hydro-
chloride/NaOH was 1:2:4. The reaction proceeded smoothly
and with excellent yields 2over 90%) in a homogeneous
medium from which the oximes 3 were separated by adding
acetic acid to the yellow solution of their salts until the pH
reached 7.
pyrazole-containing Mannich base oxime acetate 4b as a
hydrochloride using acetyl chloride as acylating agent did
not led to the expected product, only some unchanged oxime
being recovered. Instead, acetic anhydride proved ef®cient
in the case of Mannich base oximes bearing a pyrazole as
amine moiety, rendering good yields of solid desired oxime
esters. Due to the Mannich base oxime acetates' remarkable
solubility in most organic solvents, severe loss was incurred
during recrystallization.
In the series of common salicylaldehydes and ortho-
hydroxyacetophenones oximes, ring closure to 1,2-benzi-
soxazoles is frequently brought about thermally or in the
presence of a base. Both elevated temperatures18 and highly
alkaline conditions19,20 may cause unwanted secondary
processes such as cyclization to 1,3-benzoxazoles or the
hydrolysis of the oxime esters. The original method
developed for the synthesis of 3-22-dialkylaminoethyl)-
1,2-benzisoxazoles9 from dialkylamine Mannich bases
oxime acetates under moderate reaction conditions mini-
mized the extent of the hydrolysis and prevented 1,3-
benzoxazole formation, making it a suitable alternative for
further approaches in the preparation of other 1,2-benzi-
soxazoles substituted with nitrogen-containing basic
functions. Thus, the ring closure reaction of the pyrazole-
containing Mannich base oxime acetates 4 was effected with
synthetically useful yields in re¯uxing benzene and in the
presence of a mild base 2anhydrous K2CO3). Only small
amounts 23±6%) of oximes 2that could be separated from
the alkaline extract used in the work-up of the organic
phase and identi®ed by their melting points) resulted
from the basic hydrolysis of oxime acetates. The yields of
pure 1,2-benzisoxazoles 5 reduced substantially after
The conversion of oximes 3 into oxime acetates 4 is
recommendable since it is known that oxime esters are
more reactive in cyclizations to 1,2-benzisoxazoles under
less drastic conditions. Mannich base oxime esters have
received little attention. To our knowledge, except for our
earlier works,9,10,16 only one paper deals with the prepara-
tion of several 2-dialkylaminocycloalkanone oxime benzo-
ates as prodrug candidates with cytotoxic activity.17 As
previously reported,16 the synthesis of the Mannich base
oxime acetates can be achieved by selective acetylation
using either acetyl chloride in THF or acetic anhydride. In
the case of dialkylamine Mannich base oximes, acetic
anhydride provided only oily oxime acetates, whereas the
use of acetyl chloride afforded the solid corresponding
oxime acetate hydrochlorides having the advantage to be
easy to handle and purify prior to the ring closure stage. A
preliminary experiment aiming at the preparation of the

G. Roman et al. / Tetrahedron 58 02002) 1617±1622
1619
values of 26±27 ppm recorded for the carbon atom in the
methylene a to the oximino group are typical rather for the
E 2syn-alkyl) isomer than for the Z isomer. The same con-
®guration was retained in the oxime acetates 4 and favored
the ring closure reaction to 1,2-benzisoxazoles 5.
Figure 1. Representation of aromatic protons in the spectra of compounds
2±5.
3. Experimental
Melting points were determined on a Boetius apparatus and
are uncorrected. Elemental analysis was done on a Carlo
Erba 1106 analyzer. IR spectra were recorded on a Specord
M80 spectrophotometer. NMR analyses were performed on
a Varian INOVA or a Varian Gemini instrument. All
chemical shifts are reported in ppm down®eld from tetra-
methylsilane; the coupling constants are given in Hz. Low
resolution mass spectra were recorded on V.G. Micromass
7070 HS instrument, while the high resolution mass spectra
were registered on a Kratos Concept-IIA spectrometer. All
commercially available reagents were used without further
puri®cation.
recrystallization because of these compounds' good
solubility in common organic solvents.
IR spectra of the N-alkylated pyrazoles 2 presented an
)
intense sharp absorption band at about 1650 cm21 2nCvO
as a result of the incorporation of 2-hydroxybenzoylethyl
moiety in their structure. The involvement of the carbonyl
group in an intramolecular hydrogen bond with the neigh-
boring phenolic hydroxyl lowers to 1650 cm21 the value for
the nCvO band, usually situated at 1700±1675 cm21 in other
common acetophenones. The conversion of the keto group
into oximino in compounds 3 led to the substitution of the
intense nCvO band with the medium intense nCvN absorp-
tion band at 1630±1640 cm21. Acetylation of oximes 3 to
oxime acetates 4 resulted in the IR spectra of the latter
compounds in the intense nCvO ester absorption band at
1760±1790 cm21, that could no longer be detected in the
IR spectra of benzisoxazoles 5.
3.1. N-Alkylation of pyrazoles with Mannich bases
derived from ortho-hydroxyacetophenonesÐgeneral
procedure
Mannich base hydrochloride 1 210 mmol) and 2un)substi-
tuted pyrazole 210 mmol) were re¯uxed in 1:1 2v/v)
ethanol±water mixture 212 mL) for 1 h. The oily reaction
product crystallized on cooling. The solid was ®ltered off,
washed with water and recrystallized from ethanol.
1H NMR spectra of Mannich bases 2 displayed the expected
number of protons 2Fig. 1) at typical chemical shift values.
It should be noted the off-set signal given by the phenolic
proton that con®rms its participation to the above-
1
mentioned intramolecular hydrogen bond. The H NMR
3.1.1. 1-ꢀ2-Hydroxyphenyl)-3-ꢀ3,5-dimethylpyrazol-1-yl)-
1-propanone 2a. 2.05 g 284%) of white crystals, mp
91±92 8C; 2Found: C, 68.93; H, 6.37; N, 11.56.
C14H16N2O2 requires C, 68.85; H, 6.55; N, 11.47); nmax
2KBr) 1649 cm21; dH 2300 MHz, CDCl3) 2.20 and 2.28 2s,
3H, ±CH3), 3.59 2t, 2H, Jˆ6.6 Hz, ±COCH2±), 4.36 2t, 2H,
Jˆ6.6 Hz, ±CH2Nr), 5.75 2s, 1H, HF), 6.84±6.89 2m, 1H,
HA), 6.94±6.97 2m, 1H, HC), 7.42±7.48 2m, 1H, HB), 7.72
2dd, 1H, J1,3ˆ1.5 Hz, J1,2ˆ8.1 Hz, HD), 12.07 2s, 1H,
Ar-OH); dC 275 MHz, CDCl3) 10.99 and 13.50 2±CH3),
38.35 and 42.66 2±COCH2CH2Nr), 104.94, 118.46,
119.06, 130.01, 136.62, 139.29, 147.88, 162.31 2aromatic
carbon atoms), 203.73 2sCvO).
spectra of the oximes 3 differed from the proton spectra of
ketones 2 by the additional off-set peak assigned to the
hydroxyl proton in the oximino group. This peak dis-
1
appeared in the H NMR spectra of oxime acetates 4, that
exhibited instead the supplementary singlet in the aliphatic
region due to the methyl protons in the acetyl group. The
absence of the before mentioned singlet in the proton
spectra of 1,2-benzisoxazoles 5, corroborated with the
lack of any signals in the off-set, made certain the success
of the ring closure reaction.
The structure of the synthesized compounds was further
substantiated by 13C NMR spectra. The carbon atom in the
ketonic group of the pyrazole-containing Mannich bases 2
gave a signal at d values higher than 200 ppm; the same
carbon atom in the oximes 3 could be associated with the
signal at near 160 ppm as a result of the oxygen atom
replacement with a nitrogen atom. The 13C NMR spectra
of oximes 3 also gave valuable information on the con-
®guration of these compounds. The d value recorded21 for
the carbon atom in the methylene a to the oximino group of
several acetophenone oximes lies at about 21 ppm in the
case of E 2syn-alkyl) isomer and at approximately 29 ppm
in the case of Z 2syn-aryl) isomer. The same carbon atom in
the E isomer of the dialkylamine Mannich base oximes10,11
gives a signal near 23ppm as a consequence of the deshield-
ing effect of the nitrogen atom in the b-amino moiety. It is
reasonable to admit that the b-N1-pyrazolyl ring in oximes 3
would exert an even greater deshielding effect, so that the d
3.1.2. 1-ꢀ2-Hydroxy-5-methylphenyl)-3-ꢀpyrazol-1-yl)-1-
propanone 2b. 1.79 g 278%) of yellowish crystals, mp
118±119 8C; 2Found: C, 67.97; H, 5.91; N, 12.26.
C13H14N2O2 requires C, 67.82; H, 6.08; N, 12.17); nmax
2KBr) 1648 cm21; dH 2300 MHz, CDCl3) 2.232s, H3,
±CH3), 3.57 2t, 2H, Jˆ6.6 Hz, ±COCH2±), 4.54 2t, 2H,
Jˆ6.6 Hz, ±CH2Nr), 6.18 2t, 1H, Jˆ2.2 Hz, HF), 6.832d,
1H, Jˆ8.5 Hz, HA), 7.232dd, 1H, J1,3ˆ1.7 Hz, J1,2ˆ8.5 Hz,
HB), 7.432d, 1H, Jˆ2.2 Hz, HG), 7.45 2d, 1H, Jˆ2.2 Hz,
HE), 7.48 2d, 1H, Jˆ1.7 Hz, HD), 11.84 2s, 1H, Ar-OH); dC
275 MHz, CDCl3) 20.34 2±CH3), 38.31 and 46.13
2±COCH2CH2Nr), 106.54, 118.12, 118.70, 128.16,
129.40, 129.98, 137.69, 139.60, 160.13 2aromatic carbon
atoms), 202.98 2sCvO); m/z 160.9 2100%), 162.0
2100%), 230.1 211%, M1), 231.1 21.7%, M11); HRMS:
found 230.10432. C13H14N2O2 requires 320.10556.

1620
G. Roman et al. / Tetrahedron 58 02002) 1617±1622
3.1.3. 1-ꢀ2-Hydroxy-5-methylphenyl)-3-ꢀ3,5-dimethyl-
pyrazol-1-yl)-1-propanone 2c. 1.91 g 274%) of white
plates, mp 133±134 8C; 2Found: C, 69.89; H, 7.08; N,
10.63. C15H18N2O2 requires C, 69.76; H, 6.97; N, 10.85);
nmax 2KBr) 1648 cm21; dH 2300 MHz, CDCl3) 2.21, 2.26
and 2.27 2s, 3H, ±CH3), 3.58 2t, 2H, Jˆ6.8 Hz, ±COCH2±),
4.37 2t, 2H, Jˆ6.8 Hz, ±CH2Nr), 5.75 2s, 1H, HF), 6.87 2d,
1H, Jˆ8.4 Hz, HA), 7.27 2m, 1H, HB), 7.48 2d, s, 1H, HD),
11.91 2s, 1H, Ar-OH); dC 275 MHz, CDCl3) 10.97, 13.49
and 20.41 2±CH3), 38.36 and 42.76 2±COCH2CH2Nr),
104.87, 118.11, 118.89, 128.18, 129.73, 137.67, 139.31,
147.85, 160.17 2aromatic carbon atoms), 203.63 2sCvO).
HE), 10.65 2bs, 1H, .N±OH), 11.18 2s, 1H, Ar-OH); dC
275 MHz, CDCl3) 20.532±CH 3), 27.13and 48.52
2±C2vNOH)CH2CH2Nr), 106.02, 116.93, 117.46,
126.95, 127.93, 129.75, 131.17, 139.36, 155.41 2aromatic
carbon atoms), 158.18 2sCvN±).
3.2.3. 1-ꢀ2-Hydroxy-5-methylphenyl)-3-ꢀ3,5-dimethyl-
pyrazol-1-yl)-1-propanone oxime 3c. 1.88 g 269%) of
white crystals, mp 193±194 8C; 2Found: C, 65.77; H,
7.18; N, 15.47. C15H19N3O2 requires C, 65.93; H, 6.96; N,
15.38); nmax 2KBr) 1636 cm21; dH 2300 MHz, CDCl3) 2.21,
2.22 and 2.31 2s, 3H, ±CH3), 3.29 2t, 2H, Jˆ7.4 Hz,
±C2vNOH)CH2±), 4.35 2t, 2H, Jˆ7.4 Hz, ±CH2Nr),
5.80 2s, 1H, HF), 6.79±6.97 2m, 3H, HA, HB and HD),
11.49 2s, 1H, .N±OH), 12.51 2s, 1H, Ar-OH); dC
275 MHz, CDCl3) 10.87, 13.14 and 20.66 2±CH3), 26.57
and 44.81 2±C2vNOH)CH2CH2Nr), 105.43, 116.98,
117.74, 126.74, 127.64, 130.85, 138.94, 147.53, 155.73
2aromatic carbon atoms), 157.52 2sCvN±).
3.1.4. 3-ꢀ4-Bromo-3,5-dimethylpyrazol-1-yl)-1-ꢀ2-hydroxy-
5-methylphenyl)-1-propanone 2d. 1.68 g 250%) of silky
white needles, mp 130±131 8C; 2Found: C, 53.63; H, 5.17;
N, 8.14. C15H17BrN2O2 requires C, 53.41; H, 5.04; N, 8.30);
nmax 2KBr) 1654 cm21; dH 2300 MHz, CDCl3) 2.17, 2.26
and 2.27 2s, 3H, ±CH3), 3.55 2t, 2H, Jˆ6.6 Hz, ±COCH2±),
4.38 2t, 2H, Jˆ6.6 Hz, ±CH2Nr), 6.85 2d, 1H, Jˆ8.6 Hz,
HA), 7.24 2s, 1H, HB), 7.432d, 1H, Jˆ1.5 Hz, HD), 11.80 2s,
1H, Ar-OH); dC 275 MHz, CDCl3) 10.29, 12.31 and 20.45
2±CH3), 38.01 and 43.83 2±COCH2CH2Nr), 93.87, 118.22,
118.78, 128.25, 129.57, 137.55, 137.83, 146.44, 160.24
2aromatic carbon atoms), 203.10 2sCvO).
3.2.4. 3-ꢀ4-Bromo-3,5-dimethylpyrazol-1-yl)-1-ꢀ2-hydroxy-
5-methylphenyl)-1-propanone oxime 3d. 2.64 g 275%) of
yellowish crystals, mp 217±219 8C; 2Found: C, 51.36; H,
4.95; N, 12.11. C15H18BrN3O2 requires C, 51.13; H, 5.11; N,
11.93); nmax 2KBr) 1641 cm21; dH 2300 MHz, d6-DMSO)
2.007, 2.01 and 2.17 2s, 3H, ±CH3), 3.16 2t, 2H,
Jˆ6.9 Hz, ±C2vNOH)CH2±), 4.25 2t, 2H, Jˆ6.9 Hz,
±CH2Nr), 6.74 2d, 1H, Jˆ8.2 Hz, HA), 6.832d, 1H,
Jˆ2 Hz, HD), 7.00 2dd, 1H, J1,3ˆ2 Hz, J1,2ˆ8.2 Hz, HB),
10.95 2bs, 1H, .N±OH), 11.71 2s, 1H, Ar-OH); dC
275 MHz, d6-DMSO) 9.47, 11.87 and 20.05 2±CH3), 26.38
and 45.92 2±C2vNOH)CH2CH2Nr), 92.68, 116.11,
118.60, 127.14, 127.84, 130.60, 136.84, 144.47, 154.56
2aromatic carbon atoms), 157.632 sCvN±).
3.2. Oximation of the pyrazole-containing ketonic
Mannich basesÐgeneral procedure
N-alkylated pyrazole 2 210 mmol) was dissolved in 10%
aqueous NaOH 21.6 g, 40 mmol) and to the stirred solution
hydroxylamine hydrochloride 21.39 g, 20 mmol) in water
25 mL) was added in portions. The mixture was stirred at
room temperature overnight and then 10% aqueous acetic
acid was added dropwise to the cooled solution until the pH
reached 6.5±7.0. The precipitate was ®ltered off and washed
with water. Recrystallization from ethanol afforded pure
oximes 3 in 69±83% yield.
3.3. Preparation of pyrazole-containing Mannich base
oxime acetatesÐgeneral procedure
Mannich base oxime 3 210 mmol) was stirred with a three-
fold amount of acetic anhydride at 40±50 8C until the solid
dissolves. The mixture was then allowed to stay at room
temperature for 2 h. In the case of compounds 4a and 4d,
crystallization occurred on cooling in a freezer and they
were ®ltered and washed with water. Oxime acetates 4b
and 4c were separated by pouring the reaction mixture
into ice-cold water and bringing the pH to 8 with Na2CO3.
The initial oily product turned to a solid that was ®ltered off
and washed with water. Recrystallization from small
volumes of ethanol provided the pure oxime acetates 4 in
52±63% yield.
3.2.1. 1-ꢀ2-Hydroxyphenyl)-3-ꢀ3,5-dimethylpyrazol-1-yl)-
1-propanone oxime 3a. 2.15 g 283%) of pinkish crystals,
mp 205±206 8C; 2Found: C, 64.64; H, 6.74; N, 16.34.
C14H17N3O2 requires C, 64.86; H, 6.56; N, 16.21); nmax
2KBr) 1638 cm21; dH 2300 MHz, CDCl3) 2.05 and 2.11 2s,
3H, ±CH3), 3.16 2t, 2H, Jˆ7.1 Hz, ±C2vNOH)CH2±), 4.15
2t, 2H, Jˆ7.1 Hz, ±CH2Nr), 5.69 2s, 1H, HF), 6.78±6.87 2m,
2H, HA and HD), 7.17±7.26 2m, 2H, HB and HC), 11.29 2s,
1H, .N±OH), 11.79 2s, 1H, Ar-OH); dC 275 MHz, CDCl3)
10.26 and 13.28 2±CH3), 26.78 and 44.32
2±C2vNOH)CH2CH2Nr), 104.65, 116.52, 118.89,
119.00, 127.84, 130.22, 138.37, 146.03, 157.77 2aromatic
carbon atoms), 157.032 sCvN±).
3.3.1. 1-ꢀ2-Hydroxyphenyl)-3-ꢀ3,5-dimethylpyrazol-1-
yl)-1-propanone oxime acetate 4a. 1.35 g 245%) of white
crystals, mp 104±106 8C; 2Found: C, 63.53; H, 6.14; N,
14.12. C16H19N3O3 requires C, 63.78; H, 6.31; N, 13.95);
nmax 2KBr) 1620, 1778 cm21; dH 2300 MHz, CDCl3) 2.19
2s, 3H, ±COCH3), 2.03and 2.17 2s, 3H, ±CH 3), 3.39 2t,
2H, Jˆ6.7 Hz, ±C2vNOCOCH3)CH2±), 4.25 2t, 2H,
Jˆ6.7 Hz, ±CH2Nr), 5.68 2s, 1H, HF), 6.87 2dd, 1H,
J1,3ˆ1.1 Hz, J1,2ˆ7.8 Hz, HA), 7.01 2dd, 1H, J1,3ˆ1.1 Hz,
J1,2ˆ7.8 Hz, HB), 7.24±7.36 2m, 2H, HB and HC), 11.12
2s, 1H, Ar-OH); dC 275 MHz, CDCl3)10.50 and 13.31
2±CH3), 18.94 2±OCOCH3), 27.90 and 45.28
3.2.2. 1-ꢀ2-Hydroxy-5-methylphenyl)-3-ꢀpyrazol-1-yl)-1-
propanone oxime 3b. 1.81 g 274%) of white plates, mp
138±139 8C; 2Found: C, 63.79; H, 6.28; N, 17.04.
C13H15N3O2 requires C, 63.67; H, 6.12; N, 17.14); nmax
2KBr) 1630 cm21; dH 2300 MHz, CDCl3) 2.19 2s, 3H,
±CH3), 3.37 2t, 2H, Jˆ7.2 Hz, ±C2vNOH)CH2±), 4.532t,
2H, Jˆ7.2 Hz, ±CH2Nr), 6.232t, 1H, Jˆ2.2 Hz, HF), 6.78
2d, 1H, Jˆ8.3Hz, H A), 6.82 2s, 1H, HD), 6.97 2dd, 1H,
J1,3ˆ1.6 Hz, J1,2ˆ8.3Hz, H B), 7.432dd, 1H, J1,3ˆ0.6 Hz,
J1,2ˆ2.2 Hz, HG), 7.51 2dd, 1H, J1,3ˆ0.6 Hz, J1,2ˆ2.2 Hz,

G. Roman et al. / Tetrahedron 58 02002) 1617±1622
1621
2±C2vNOCOCH3)CH2CH2Nr), 105.26, 115.86, 118.18,
119.22, 128.18, 132.56, 138.88, 147.88, 158.82
2aromatic carbon atoms), 164.45 2sCvN±), 166.28
2±OCOCH3).
K2CO3 21.38 g, 10 mmol) under re¯ux for 3 h. The suspen-
sion was cooled to room temperature and the solid inorganic
salts were ®ltered away. The organic phase was extracted
with aqueous 10% NaOH, washed with water, dried on
anhydrous Na2SO4. The removal of benzene under reduced
pressure gave an oil that solidi®ed on standing in a freezer.
The solid substances were recrystallized from aqueous
methanol, except for benzisoxazole 5d, when little ethanol
was employed as solvent.
3.3.2. 1-ꢀ2-Hydroxy-5-methylphenyl)-3-ꢀpyrazol-1-yl)-1-
propanone oxime acetate 4b. 1.81 g 263%) of white
needles, mp 76±77 8C; 2Found: C, 62.93; H, 6.14; N,
14.47. C15H17N3O3 requires C, 62.71; H, 5.92; N, 14.63);
n
max 2KBr) 1618, 1762 cm21; dH 2300 MHz, CDCl3) 2.132s,
3H, ±CH3), 2.21 2s, 3H, ±OCOCH3), 3.40 2t, 2H, Jˆ6.5 Hz,
±C2vNOCOCH3)CH2±), 4.40 2t, 2H, Jˆ6.5 Hz, ±CH2Nr),
6.11 2s, 1H, HF), 6.88 2d, 1H, Jˆ8.3Hz, H A), 6.94 2s, 1H,
HD), 7.08 2d, 1H, Jˆ8.3Hz, H B), 7.19 2s, 1H, HG), 7.49 2s,
1H, HE), 10.87 2s, 1H, Ar-OH); dC 275 MHz, CDCl3)
19.01 2±OCOCH3), 20.40 2±CH3), 28.10 and 49.10
2±C2vNOCOCH3)CH2CH2Nr), 105.81, 115.35, 117.97,
127.99, 128.32, 129.50, 133.46, 139.88, 156.42
2aromatic carbon atoms), 164.22 2sCvN±), 166.32
2±OCOCH3).
3.4.1. 3-ꢀ2-ꢀ3,5-Dimethylpyrazol-1-yl)ethyl)-1,2-benzi-
soxazole 5a. 1.06 g 244%) of colorless needles, mp 40±
41 8C; 2Found: C, 69.94; H, 6.44; N, 17.24. C14H15N3O
requires C, 69.71; H, 6.22; N, 17.42); nmax 2KBr)
1624 cm21; dH 2300 MHz, CDCl3) 1.99 and 2.19 2s, 3H,
±CH3), 3.47 2t, 2H, Jˆ7.1 Hz, uC±CH2±), 4.40 2t, 2H,
Jˆ7.1 Hz, ±CH2Nr), 5.66 2s, 1H, HF), 7.17±7.24 2m, 1H),
7.37 2d, 1H, Jˆ8 Hz), 7.45±7.49 2m, 2H); dC 275 MHz,
CDCl3) 10.71 and 13.40 2±CH3), 26.32 and 46.25
2uCCH2CH2Nr), 105.04, 109.66, 121.11, 121.44, 123.28,
129.89, 139.14, 147.94, 156.0 2aromatic carbon atoms),
162.84 2sCvN±).
3.3.3. 1-ꢀ2-Hydroxy-5-methylphenyl)-3-ꢀ3,5-dimethyl-
pyrazol-1-yl)-1-propanone oxime acetate 4c. 1.86 g
259%) of white microcrystals, mp 114±116 8C; 2Found: C,
64.96; H, 6.49; N, 13.51. C17H21N3O3 requires C, 64.76; H,
6.66; N, 13.33); nmax 2KBr) 1621, 1790 cm21; dH
2300 MHz, CDCl3) 2.03, 2.07 and 2.15 2s, 3H, ±CH3),
2.20 2s, 3H, ±OCOCH3), 3.23 2t, 2H, Jˆ6.7 Hz,
±C2vNOCOCH3)CH2±), 4.16 2t, 2H, Jˆ6.7 Hz,
±CH2Nr), 5.70 2s, 1H, HF), 6.82 2d, 1H, Jˆ8.3Hz, H A),
7.05 2s, 1H, HD), 7.12 2d, 1H, Jˆ8.3Hz, H B), 10.432s,
1H, Ar-OH); dC 275 MHz, CDCl3) 7.37, 10.42 and 17.13
2±CH3), 16.39 2±OCOCH3), 26.66 and 41.79
2±C2vNOCOCH3)CH2CH2Nr), 101.84, 113.67, 115.84,
124.89, 126.82, 129.63, 135.64, 143.20, 151.61 2aromatic
carbon atoms), 162.22 2sCvN±), 164.64 2±OCOCH3);
m/z 109.1 2100%), 315.1 25.5%, M1), 316.1 21.1%,
M11); HRMS: found 315.15758. C17H21N3O3 requires
315.1583.
3.4.2. 5-Methyl-3-ꢀ2-ꢀpyrazol-1-yl)ethyl)-1,2-benzisoxa-
zole 5b. 1.18 g 252%) of white plates, mp 59±61 8C;
2Found: C, 68.49; H, 5.89; N, 18.33. C13H13N3O requires
C, 68.72; H, 5.72; N, 18.50); nmax 2KBr) 1627 cm21; dH
2300 MHz, CDCl3) 2.41 2s, 3H, ±CH3), 3.54 2t, 2H,
Jˆ7 Hz, uC±CH2±), 4.632t, 2H, Jˆ7 Hz, ±CH2Nr),
6.18 2t, 1H, Jˆ2.1 Hz, HF), 7.16 2d, 1H, Jˆ1.7 Hz, HD),
7.32 2d, 1H, Jˆ2.1 Hz, HG), 7.34 2dd, 1H, J1,3ˆ1.7 Hz,
J1,2ˆ8.5 Hz, HB), 7.42 2d, 1H, Jˆ8.5 Hz, HA), 7.56 2d,
1H, Jˆ2.1 Hz, HE); dC 275 MHz, CDCl3) 20.99 2±CH3),
26.66 and 49.832 uCCH2CH2Nr), 105.54, 109.36,
120.23, 121.61, 129.89, 131.65, 133.20, 139.89, 155.42
2aromatic carbon atoms), 161.67 2sCvN±).
3.4.3. 5-Methyl-3-ꢀ2-ꢀ3,5-dimethylpyrazol-1-yl)ethyl)-1,2-
benzisoxazole 5c. 1.55 g 261%) of silky white needles, mp
52±54 8C; 2Found: C, 70.32; H, 6.54; N, 16.23. C15H17N3O
requires C, 70.58; H, 6.66; N, 16.47); nmax 2KBr)
1622 cm21; dH 2300 MHz, CDCl3) 1.98, 2.25 and 2.40 2s,
3H, ±CH3), 3.48 2t, 2H, Jˆ7 Hz, uC±CH2±), 4.41 2t, 2H,
Jˆ7 Hz, ±CH2Nr), 5.59 2s, 1H, HF), 7.09 2d, 1H, Jˆ1.7 Hz,
HD), 7.32 2dd, 1H, J1,3ˆ1.7 Hz, J1,2ˆ8.5 Hz, HB), 7.40
2d, 1H, Jˆ8.5 Hz, HA); dC 275 MHz, CDCl3) 10.75, 13.47
and 20.98 2±CH3), 26.42 and 46.52 2uCCH2CH2Nr),
105.08, 109.16, 120.49, 121.71, 131.54, 133.03,
139.35, 147.97, 155.83 2aromatic carbon atoms), 161.59
2sCvN±).
3.3.4. 3-ꢀ4-Bromo-3,5-dimethylpyrazol-1-yl)-1-ꢀ2-hydroxy-
5-methylphenyl)-1-propanone oxime acetate 4d. 2.05 g
252%) of white crystals, mp 128±129 8C; 2Found: C,
51.57; H, 4.90; N, 10.83. C17H20BrN3O3 requires C, 51.77;
H, 5.07; N, 10.66); nmax 2KBr) 1620, 1783cm 21; dH
2300 MHz, CDCl3) 2.04, 2.19 and 2.24 2s, 3H, ±CH3),
2.20 2s, 3H, ±OCOCH3), 3.35 2t, 2H, Jˆ6.5 Hz,
±C2vNOCOCH3)CH2±), 4.31 2t, 2H, Jˆ6.5 Hz,
±CH2Nr), 6.918 2d, 1H, Jˆ8 Hz, HA), 6.9232s, 1H, H ),
D
7.132dd, 1H, J1,3ˆ2 Hz, J1,2ˆ8 Hz, HB), 10.87 2s, 1H,
Ar-OH); dC 275 MHz, CDCl3) 10.01, 12.26 and 20.54
2±CH3), 19.09 2±OCOCH3), 27.79 and 46.85
2±C2vNOCOCH3)CH2CH2Nr), 94.36, 115.41, 118.11,
128.02, 128.41, 133.70, 137.39, 146.68, 156.52
2aromatic carbon atoms), 164.52 2.CvN±), 166.32
2±OCOCH3).
3.4.4. 3-ꢀ2-ꢀ4-Bromo-3,5-dimethylpyrazol-1-yl)ethyl)-5-
methyl-1,2-benzisoxazole 5d. 1.44 g 243%) of white
microcrystals, mp 77±78 8C; 2Found: C, 54.06; H, 4.91;
N, 12.29. C15H16BrN3O requires C, 53.89; H, 4.79; N,
12.57); nmax 2KBr) 1628 cm21; dH 2300 MHz, CDCl3)
1.92, 2.20 and 2.36 2s, 3H, ±CH3), 3.43 2t, 2H, Jˆ7 Hz,
uC±CH2±), 4.41 2t, 2H, Jˆ7 Hz, ±CH2Nr), 6.96 2d, 1H,
Jˆ1 Hz, HD), 7.30 2d, 1H, Jˆ1 Hz, HB), 7.35 2s, 1H, HA); dC
275 MHz, CDCl3) 9.94, 12.20 and 20.94 2±CH3), 26.17 and
47.64 2uCCH2CH2Nr), 94.03, 109.17, 120.08, 121.49,
131.58, 133.10, 137.50, 146.51, 155.40 2aromatic carbon
atoms), 161.54 2sCvN±).
3.4. Cyclization of pyrazole-containing Mannich base
oxime acetates 4 to 1,2-benzisoxazoles 5Ðgeneral
procedure
Oxime acetate 4 210 mmol) was dissolved in benzene
230 mL) and treated with ®nely grounded anhydrous

1622
G. Roman et al. / Tetrahedron 58 02002) 1617±1622
10. Comanita, E.; Popovici, I.; Comanita, B.; Roman, Gh. A.C.H.
Models Chem. 1997, 134, 3 ±13 .
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