Preparation of 4,5-dihydronaphth[2,1-c]isoxazoles from dilithiated 2-tetralone oxime and select esters

Article abstract of DOI:10.1080/00397910701820228

Dilithiated 2-tetralone oxime, prepared in excess lithium diisopropylamide, was condensed with aromatic esters, such as methyl 4-methoxybenzoate, followed by cyclization of the C-acylated intermediate with aqueous acid to give dihydronaphthisoxazoles, 4,5

Full text of DOI:10.1080/00397910701820228

Synthetic Communicationsw, 38: 713–722, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701820228
Preparation of 4,5-Dihydronaphth[2,1-c]
isoxazoles from Dilithiated 2-Tetralone
Oxime and Select Esters
Emily Choi, John D. Knight, Maria D. Malatanos,
J. Matthew Rhett, Matthew J. Walters, S. Patrick Dunn,
and Charles F. Beam
Department of Chemistry and Biochemistry, College of Charleston,
Charleston, South Carolina, USA
Abstract: Dilithiated 2-tetralone oxime, prepared in excess lithium diisopropylamide,
was condensed with aromatic esters, such as methyl 4-methoxybenzoate, followed by
cyclization of the C-acylated intermediate with aqueous acid to give dihydronaphth-
isoxazoles, 4,5-dihydronaphth[2,1-c]isoxazoles.
Keywords: acylation–cyclization, dianion, dihydronaphthisoxazole, regioselectivity
INTRODUCTION
Isoxazoles and 4,5-dihydroisoxazoles constitute a very important group of
heterocyclic compounds because of their use in other syntheses, their stand-
alone potential with selectively bonded halogens and pendant groups, their
interest for spectral and theoretical studies, and their biological and other
application potential.[1]
There is ongoing interest in the methods of preparation of isoxazole
and isoxazole-containing compounds. The condensation–cyclization of b-
dicarbonyl compounds with hydroxylamine is one of the oldest and best
documented synthetic methods, even though there is the probability for two
Received in the USA September 14, 2007
Address correspondence to Charles F. Beam, Department of Chemistry and Bio-
chemistry, College of Charleston, Charleston, SC 29424, USA. E-mail: beamc@
cofc.edu
713

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E. Choi et al.
isomers forming when unsymmetrical b-dicarbonyl compounds are
employed.[2] The preparations involving the 1,3-dipolar cycloaddition of
nitrile oxides with alkenes or alkynes is usually regiospecific, and it is a
leading method for the preparation of unsymmetrical 3,5-disubstituted isoxa-
zoles and 4,5-dihydroisoxazoles (2-isoxazolines).[3] Another method initiated
by the Hauser research group is always regiospecific, and it has been sub-
sequently developed and expanded by others.[4] It involves 1,4-dilithiated
oximes of C(a)-aldehydes and ketones, which undergo condensation–cycliza-
tion with a variety of electrophilic reagents. The original account employed
a variety of C(a)-ketone oximes, such as those made from substituted
acetophenones, 1-tetralone, deoxybenzoin, diphenylacetone, and cycloalka-
nones. These entry compounds were dilithiated with n-butyllithium at 08C
followed by a Claisen-type condensation with predominantly aromatic
esters, then cyclization with dilute hydrochloric acid. The effective molar
ratios of reagents were oxime/n-butyllithium/ester 1:2:0.5). Even though
the yields of products were based on the ester, multigram quantities of
products were readily obtained after recrystallization from common
solvents. Other electrophilic reagents employed were aromatic carboxylic
acid chlorides, which underwent di-C-acylation then cyclization to 4-acyl-
isoxazoles,[5] diethyl oxalate to biisoxazoles,[6] and aromatic nitriles to
also afford another regiospecific synthesis of unsymmetrical isoxazoles
(oxime/n-butyllithium/nitrile 1:2:1).[7] The condensations with aromatic
esters and nitriles are an unequivocal method for the preparation of 3,5-di-
substuted unsymmetrical isoxazoles. The C-acylated precyclization inter-
mediate formed during the condensation step (or condensation to an imine
followed by hydrolysis to the ketone) has the five atoms in place that will
make up the five-membered isoxazole ring. A single bond is formed
during acid cyclization. Olofson et al. were able to improve the yields of
select 5-alkylisoxazoles by lithiating the oxime with n-butyllithium at Dry
Ice/acetone temperature 2788C or 08C, followed by condensation–cycliza-
tion with N,N-dimethylcarboxylic acid amides, including dimethylforma-
mide (DMF) and a couple of N,N-dimethylbenzamides (oxime/base/
amide 1:2:1).[8] Because N,N-dimethylamides have the potential for lithia-
tion of the N-methyl hydrogen, thus interfering with the reaction, Nitz
et al. condensed-cyclized dilithiated oximes at 08C with N-methoxy-N-
methylalkylamides (oxime/n-butyllithium/amide 1:2:0.83)[9] to place an
alkyl group in the 5-position of the isoxazole ring. Lithium diisopropylamide
(LDA) used instead of n-butyllithium permitted a change in the ratio of the
reagents (oxime/LDA/ester 1:3:1)[10] and increased the quantity of isoxa-
zoles prepared where the yield is based on the oxime. The residual diisopro-
pylamine resulting from the initial deprotonation process was easily
removed during the workup. The trace amounts of diisopropylamine and
THF that remained did not impede the crystallization of products from
common solvents. This change in amount of and type of strong base
resulted in additional oxime dianion-type investigations, involving an

Preparation of 4,5-Dihydronaphth[2,1-c]isoxazoles
715
Figure 1. Fused-ring isoxazoles and pyrazoles.
abundance of readily available esters and related compounds such as car-
boxylic acid anhydrides, both general and specific.
Although the preparation of substituted isoxazoles has been extensively
investigated, there has been an expansion of these studies to include fused-
ring isoxazoles. The fused-ring compounds germane to this report are illustrated
in Fig. 1. They include 4,5-dihydronaphth[2,1-c]isoxazoles,[8] the focus of this
investigation, and 4,5-dihydronaphth[1,2-c] isoxazoles prepared by others.[11]
Some of our specific projects have focused on 1- and 2-tetralone oximes
and hydrazones because of their applications for ligand preparations and bio-
logical studies, especially in agriculture. The synthons using dilithiated
1-tetralone oximes and esters for the preparation of 4,5-dihydronaphth[1,2-
c]isoxazoles were very straightforward,[12] along with projects involving
dilithiated 1-tetralone phenylhydrazones or carboalkoxyhydrazones[13] with
esters for the preparation of 4,5-dihydro-2H-benz[g]indazoles (Fig. 1). The
preparations of 4,5-dihydro-2H-benz[e]indazoles involving condensation–
cyclization of dilithiated 2-tetralone phenylhydrazone[14] or carbomethoxy-
hydrazones[15] with aromatic esters were more challenging, yet successful,
but resulted in lower yields for 4,5-dihydrobenz[e]indazoles (Fig. 1) in direct
comparison to analogous compounds prepared from 1-tetralone hydrazones.
The use of dilithiated 2-tetralone oxime 1 has proven to be the greatest
challenge regarding condensations with certain electrophilic reagents. Nitz
et al. were unable to condense dilithiated 2-tetralone oxime 2 and diphenyl-
acetone oximes with the specialty amides,[9] but Hoskin and Olofson were
successful with the condensation of dilithiated 2-tetralone oxime 2 with a
more electrophilic carbocation salt solution made from trifluoromethanesulfo-
nic acid and DMF, which resulted in the first and apparently only example of a
4,5-dihydronaphth[2,1-c]isoxazole.[8] They attributed these results to dimin-
ished reactivity of these stabilized dianions (intermediate 2, Scheme 1).
RESULTS AND DISCUSSION
During the current investigation, 2-tetralone oxime 1 was dilithiated to 2 with
excess LDA, which was followed by condensation with select aromatic esters
to give C-acylated intermediates 3, which were not isolated but cyclized

716
E. Choi et al.
Scheme 1. 4,5-Dihydronaphth[2,1-c]isoxazoles.
directly with aqueous hydrochloric acid to afford all-new fused-ring 4,5-dihydro-
naphth[2,1-c]isoxazoles 4a–i. Dihydronaphthisoxazoles 4a–i were prepared in
14–64% yield, with an average yield of 34%. Even with the lower yield
products, multigram quantities of them can be prepared after modest scale up
followed by routine recrystallization. The yields 4a–i may be attributed to
several factors in addition to a less reactive or unreactive carbanion–enolate
type system, 2. Also, 2-tetralone oxime is more challenging to prepare, and it is
less stable than 1-tetralone oxime. The varying stability of this entry compound
plus varied challenges in handling probably have an effect on the overall yield
of products. The success of these reactions is apparently due to the choice of
base, LDA. Diisopropylamine resulting from the twofold deprotonation of
oximes with LDA is available for coordination with lithium of the multiple
anion-type system and/or resulting intermediates involved in the condensation
process, which is not the situation with n-butyllithium alone. Even though
aromatic esters are not especially reactive electrophilic reagents, the combination
of LDA/THF at 08C for dilithiation gives an active enough 1,4-dianion-type
system to condense with them. Our investigations with tetramethylethylenedi-
amine (TMEDA) with this dianion-type system have been limited, and we did
not detect any benefit from its use. Also, the characterization of each product
was straightforward, with no anomalies.

Preparation of 4,5-Dihydronaphth[2,1-c]isoxazoles
717
CONCLUSIONS
Every compound prepared and reported here is new, and they may be difficult
to prepare by other routes or procedures. They are an initial part of the
synthons of a less-known group of fused-ring isoxazoles that have potential
for overall continued study and development. The general reaction sequence
from 2-tetralone to the product may not represent optimal conditions for the
preparation of a particular dihydronaphthisoxazole, but multigram quantities
of readily purified product can be obtained.
EXPERIMENTAL
Melting points were obtained with a Mel-Temp II melting-point apparatus in
open capillary tubes and are uncorrected. FT-IR spectra were obtained with a
Nicolet Impact 410 FT-IR or a Mattson Genesis II FT-IR with Specac Golden
Gate Accessory. NMR spectra were obtained with a Varian Associates
1
Mercury Oxford spectrometer, 300 MHz for H and 75 MHz for 13C, and
chemical shifts are recorded in d ppm downfield from an internal tetramethyl-
silane (TMS) standard. Combustion analyses were performed by Quantitative
Technologies, Inc., Whitehouse, NJ.
General Procedure for Preparation of 4,5-Dihydronaphth[2,1-
c]isoxazoles (4a–i)
(Ratio of reagents: oxime/LDA/ester 1:3:1; for 4d, 1:4:1.) In a typical
reaction sequence, LDA (0.048 mol) was prepared by the addition of 30 mL
(or 40.0 mL for 4d) of 1.6 M n-butyllithium (0.048 mol or 0.063 mol for
4d) to a three-neck, round-bottomed flask (e.g., 500 mL), equipped with a
nitrogen inlet tube, a side-arm addition funnel (e.g., 125 mL), and a
magnetic stir bar. The flask was cooled in an ice bath, and 4.88 g (or 6.41 g
for 4d) (0.048 mol or 0.063 mol for 4d) of diisopropylamine (Aldrich
Chem. Co., 99.5%), dissolved in 25–30 mL of dry tetrahydrofuran (THF)
(sodium/benzophenone–ketyl), was added from the addition funnel at a
fast dropwise rate during 5 min (08C, N2). The solution was stirred at 08C
for an additional 15–20 min and then treated via the addition funnel with
2.42 g (0.0150 mol) of 2-tetralone oxime dissolved in 35–45 mL of THF.
The addition time was 5 min. After 45–60 min of dilithiation at 08C,
0.0158 mol of ester, dissolved in 25–35 mL of THF, was added to the
dilithiated intermediate, and the solution was stirred for 1–1.5 h (08C, N2).
Finally, 100 mL of 3 M hydrochloric acid was added, and the two-phase
mixture was well stirred and heated under reflux for 30–45 min. At the end
of this period, the mixture was poured into a large flask containing ice (ca.
100 g) followed by 100 mL of solvent-grade ether. The mixture was then

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E. Choi et al.
neutralized with solid sodium bicarbonate, and the layers were separated. The
aqueous layer was extracted with ether (2 Â 75 mL), and the organic fractions
were combined, evaporated, and recrystallized.
Data
1-(3,4,5-Trimethoxy)phenyl-4,5-dihydronaphth[2,1-c]isoxazole (4a)
Condensation–cyclization of 2 with methyl 3,4,5-trimethoxybenzoate
afforded 4a, (3.24 g, 64% yield), mp 125–1278C (methanol): IR,
1
1595 cm21; H NMR (CDCl3) d ppm 2.97–3.04 (m. 4H, CH2CH2), 3.86
(s, 6H, OCH3), 3.94 (s, 3H, OCH3), 7.05 (s, 2H, ArH), 7.17–7.21, 7.22–
7.32, and 7.69–7.72 (m, 4H, ArH); 13C NMR (CDCl3) d ppm 21.3, 29.6,
56.5, 61.3, 105.1, 111.5, 123.9, 124.6, 127.0, 128.0, 129.2, 136.4, 139.8,
153.7, 162.8, and 163.1. Anal. calcd. for C20H19NO4: C, 71.20; H, 5.67; N,
4.15. Found: C, 71.20; H, 5.66:, N, 4.07.
1-(3,4-Dimethoxyphenyl)-4,5-dihydronaphth[2,1-c]isoxazole (4b)
Condensation–cyclization of 2 with methyl 3,4-dimethoxybenzoate afforded
4b (1.72 g, 36% yield), mp 129–1318C (methanol): IR, 1624 cm21; 1H NMR
(CDCl3) d ppm 2.96–3.03 (m. 4H, CH2CH2), 3.89 (s, 3H, OCH3), 3.96 (s, 3H,
OCH3), 6.96–6.99, 7.15–7.31, 7.40–7.44, 7.64–7.67 (m, 7H, ArH); 13C
NMR (CDCl3) d ppm 21.3, 29.7, 56.2, 56.3, 110.7, 111.0, 111.4, 121.0,
121.3, 124.3, 127.1, 127.7, 128.2, 129.1, 136.3, 149.3, 150.8, and 163.0.
Anal. calcd. for C19H17NO3: C, 74.25; H, 5.57; N, 4.56. Found: C, 74.17;
H, 5.61; N, 4.46.
1-(4-Methoxyphenyl)-4,5-dihydronaphth[2,1-c]isoxazole (4c)
Condensation–cyclization of 2 with methyl 4-methoxybenzoate afforded 4c
1
(1.16 g, 28% yield), mp 111–1148C (methanol): IR, 1604 cm21; H, NMR
(CDCl3) d ppm 2.97–3.01 (m. 2H, CH2), 3.72 (m, 2H, CH2), 3.88 (s, 3H,
OCH3), 7.00–7.03, 7.17–7.26, 7.58, 7.73–7.76 (m, 8H, ArH); 13C NMR
(CDCl3) d ppm 21.3, 29.7, 55.6, 110.9, 114.5, 121.2, 124.2, 127.2, 127.6,
128.2, 129.0, 129.5, 136.2, 161.3, and 163.1. Anal. calcd. for C18H15NO2:
C, 77.95; H, 5.45; N, 5.05. Found: C, 77.86; H, 5.56; N, 4.89.
1-(4-Hydroxyphenyl)-4,5-dihydronaphth[2,1-c]isoxazole (4d)
Condensation–cyclization of 2 with lithium methyl 4-hydroxybenzoate
afforded 4d (0.553 g, 14% yield), mp 246–2498C (methanol): IR, 3100,
1626 cm21 1H NMR (DMSO-d6) d ppm 2.87–3.01 (m, 4H, CH2CH2),
;
6.94–6.96, 7.17–7.60 (m, 8H, ArH), and 10.16 (s, 1H, ArOH); 13C NMR

Preparation of 4,5-Dihydronaphth[2,1-c]isoxazoles
719
(CDCl3) d ppm 21.1, 29.0, 110.5, 116.6, 119.1, 123.9, 127.6, 127.9, 128.1,
129.6, 129.9, 136.5, 160.5, 162.8, and 163.3. Anal. calcd. for C17H13NO2:
C, 77.55; H, 4.98; N, 5.32. Found: C, 77.38; H, 5.05; N, 5.13.
1-(4-Iodophenyl)-4,5-dihydronaphth[2,1-c]isoxazole (4e)
Condensation–cyclization of 2 with ethyl 4-iodobenzoate afforded 4e (2.30 g,
41% yield), mp 124–1268C (methanol): IR, 1630 cm21; 1H NMR (CDCl3) d
ppm 2.87–3.03 (m, 4H, CH2CH2), 7.09–7.26 (m, 3H, ArH), 7.47–7.50
(m, 3H, ArH), 7.77 (d, 2H, ArH, J ¼ 8.1 Hz); 13C NMR (CDCl3) d ppm
20.8, 29.2, 96.6, 111.9, 123.9, 126.9, 127.2, 127.7, 127.8, 128.8, 129.0,
135.0, 138.9, 161.3, and 162.8. Anal. calcd. for C17H12INO: C, 54.72; H,
3.24; N, 3.75. Found: C, 54.95; H, 3.18; N, 3.58.
1-(4-Bromophenyl)-4,5-dihydronaphth[2,1-c]isoxazoles (4f)
Condensation–cyclization of 2 with ethyl 4-bromobenzoate afforded 4f
1
(1.42 g, 29% yield), mp 117–1208C (methanol): IR, 1626 cm21; H NMR
(CDCl3) d ppm 2.97–3.01 (m, 4H, CH2CH2), 7.27–7.29, 7.62–7.70
(m, 8H, ArH); 13C NMR (CDCl3) d ppm 21.2, 29.5, 112.2, 124.8, 127.2,
127.5, 127.6, 128.0, 128.1, 129.1, 129.5, 132.2, 132.6, 136.4, and 163.1.
Anal. calcd. for C17H12BrNO: C, 62.60; H, 3.71; N, 4.29. Found: C, 62.98;
H, 3.64; N, 4.01.
1-(4-Chlorophenyl)-4,5-dihydronaphth[2,1-c]isoxazoles (4g)
Condensation–cyclization of 2 with methyl 4-chlorobenzoate afforded 4g
1
(1.99 g, 47% yield), mp 116–1188C (methanol): IR, 1636 cm21; H, NMR
(CDCl3) d ppm 2.98–3.07 (m, 4H, CH2CH2), 7.23–7.31, 7.47–7.54, 7.75–
7.78 (m, 8H, ArH); 13C NMR (CDCl3) d ppm 21.2, 29.6, 112.1, 124.2,
127.2, 127.3, 127.6, 128.0, 129.1, 129.2, 129.5, 136.4, 136.5, 161.7, and
163.1. Anal. calcd. for C17H12ClNO: C, 72.47; H, 4.29; N, 4.97. Found: C,
72.25; H, 4.39; N, 4.67.
1-(3-Chlorophenyl)-4,5-dihydronaphth[2,1-c]isoxazoles (4h)
Condensation–cyclization of 2 with methyl 3-chlorobenzoate afforded 4h
(1.10 g, 26% yield), mp 91–948C (methanol): IR, 1636 cm21 1H NMR
;
(CDCl3) d ppm 2.95–3.06 (m, 4H, CH2CH2), 7.16–7.81 (m, 8H, ArH); 13C
NMR (CDCl3) d ppm 21.2, 29.6, 112.5, 124.4, 126.0, 127.4, 127.5, 127.9,
128.0, 128.2, 130.5, 130.6, 135.2, 136.4, 161.3, and 163.1. Anal. calcd. for
C17H12ClNO: C, 72.47; H, 4.29; N, 4.97. Found: C, 72.35; H, 4.29; N, 4.92.

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E. Choi et al.
1-(4-Methylphenyl)-4,5-dihydronaphth[2,1-c]isoxazoles (4i)
Condensation–cyclization of 2 with methyl 4-methylbenzoate afforded 4i
1
(0.982 g, 25% yield), mp 122–1258C (methanol): IR, 1629 cm21; H NMR
(CDCl3) d ppm 2.44 (s, 3H, CH3), 2.98–3.01 (m, 4H, CH2CH2), 7.17–7.31,
7.68–7.71 (m, 8H, ArH); 13C NMR (CDCl3) d ppm 21.2, 21.7, 29.6, 111.4,
125.8, 127.0, 127.6, 127.9, 128.0, 129.0, 129.8, 136.2, 140.7, and 162.9.
Anal. calcd. for C18H15NO: C, 82.73; H, 5.79; N, 5.36. Found: C, 80.50: H,
5.39; N, 4.51.
ACKNOWLEDGMENTS
We thank the following sponsors: the Research Corporation, the National
Science Foundation (Grants CHE 9708014 and 0212699) for Research at
Undergraduate Institutions, the United States Department of Agriculture
(NRICGP 2003-35504-12853), and Donors of the Petroleum Research
Fund, administered by the American Chemical Society. J. D. Knight
received a stipend from the College of Charleston, Summer Undergraduate
Research Forum, SURF-2006.
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