Synthesis of isoxazole conjugates of 1,4-benzodioxane moiety via intermolecular 1,3-dipolar cycloaddition

Article abstract of DOI:10.1080/00397910902838979

1,3-Dipolar cycloaddition was utilized as a tool to conjugate the 1,4-benzodioxane moiety with several biologically active compounds such as steroid, sugar, and other aromatic scaffolds via isoxazole or triazole bridge. The propynyl ether of 2-hydroxymethyl-1,4-benzodioxane underwent 1,3-dipolar cycloadditions smoothly with different in situ generated nitrile oxides in good yields. The triazole conjugate of 1,4-benzodioxane was synthesized via click chemistry. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910902838979

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Synthesis of Isoxazole
Conjugates of 1,4-
Benzodioxane Moiety via
Intermolecular 1,3-Dipolar
Cycloaddition
Vipraja V. Vaidya a , Karuna S. Wankhede a , Susheel
J. Nara a , Manikrao M. Salunkhe b & Girish K. Trivedi
a
a Department of Chemistry , Institute of Science ,
Mumbai, India
b Shivaji University, Vidyanagar , Kolhapur,
Maharashtra, India
Published online: 07 Oct 2009.
To cite this article: Vipraja V. Vaidya , Karuna S. Wankhede , Susheel J. Nara ,
Manikrao M. Salunkhe & Girish K. Trivedi (2009) Synthesis of Isoxazole Conjugates
of 1,4-Benzodioxane Moiety via Intermolecular 1,3-Dipolar Cycloaddition, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:21, 3856-3866, DOI: 10.1080/00397910902838979
To link to this article: http://dx.doi.org/10.1080/00397910902838979
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Synthetic Communications1, 39: 3856–3866, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902838979
Synthesis of Isoxazole Conjugates of
1,4-Benzodioxane Moiety via Intermolecular
1,3-Dipolar Cycloaddition
Vipraja V. Vaidya,1 Karuna S. Wankhede,1 Susheel J. Nara,1
Manikrao M. Salunkhe,2 and Girish K. Trivedi1
1Department of Chemistry, Institute of Science, Mumbai, India
2Shivaji University, Vidyanagar, Kolhapur, Maharashtra, India
Abstract: 1,3-Dipolar cycloaddition was utilized as a tool to conjugate the
1,4-benzodioxane moiety with several biologically active compounds such as
steroid, sugar, and other aromatic scaffolds via isoxazole or triazole bridge.
The propynyl ether of 2-hydroxymethyl-1,4-benzodioxane underwent 1,3-dipolar
cycloadditions smoothly with different in situ generated nitrile oxides in good
yields. The triazole conjugate of 1,4-benzodioxane was synthesized via click
chemistry.
Keywords: 1,4-Benzodioxane, click chemistry, 1,3-dipolar cycloadditions, isoxa-
zole, triazole
INTRODUCTION
1,4-Benzodioxane moiety occurs as a key structure in a number of natural
products. Its natural occurrence and important biological properties have
attracted special attention in the synthetic community. Various examples
of biologically active natural products possessing this moiety are
documented in literature.[1] 1,4-Benzodioxanes have also served as valu-
able synthetic intermediates in various elegant syntheses. In medicinal
Received December 6, 2008.
Address correspondence to Manikrao M. Salunkhe, Shivaji University,
Vidyanagar, Kolhapur 416004, Maharashtra, India. E-mail: mmsalunkhe@
hotmail.com
3856

Isoxazole Conjugates of 1,4-Benzodioxane Moiety
3857
chemistry, the 1,4-benzodioxane moiety has been widely used in the
design of therapeutic agents with a-adrenergic blocking, antigastric,
spasmolytic, antipsychotic, and anxiolytic properties.[2] The compounds
bearing this moiety are well-known antihypertensive, antidepressant,
and anti-inflammatory drugs.[1]
1,3-dipolar cycloaddition is a versatile and an efficient tool that
facilitates the formation of heterocyclic bridges between the different
units to couple them together.[3] By utilizing this characteristic feature
of dipolar cycloaddition reaction, we synthesized conjugates of the
1,4-benzodioxane moiety using a propynyl ether derivative of 1,4-benzo-
dioxane as a dipolarophile and several different dipoles derived from
diverse classes of compounds. To club the benzodioxane scaffold with
other biologically important moieties, we utilized isoxazole, another
versatile heterocycle, as a bridging mediator via 1,3-dipolar cycloaddi-
tion.[4] In this way, we anticipated amalgamating the desirable attributes
of not only the structural motifs that are bridged together but also those
of the bridging entity.
RESULTS AND DISCUSSION
2-Hydroxymethyl-1,4-benzodioxane (1) was synthesized by the reaction
of 1-chloro-2,3-epoxypropane and 1,2-dihydroxybenzene in the presence
of a base. Further, it was subjected to propynylation with propynyl
bromide to yield 2-propynyloxymethyl-1,4-benzodioxane (2) in 81%
yields. Compound 2 was utilized as a dipolarophile in cycloadditions with
different nitrile oxides to generate new cycloadducts (Scheme 1). The
nitrile oxides have been synthesized in situ using oximes, nitro
compounds, and hydroxamoyl chloride as dipole precursors by different
methods.
To standardize the protocol, we initiated our work with the
cycloaddition of benzonitrile oxide with 2 employing the aqueous bleach
Scheme 1. Reagents and conditions: (a) K2CO3, 1-chloro-2,3-epoxypropane,
MeOH, reflux, 8 h; (b) NaH, propynyl bromide, TBABr, THF, 0ꢀC–rt, 5 h.

3858
V. V. Vaidya et al.
method.[5] The reaction successfully yielded the corresponding cycload-
1
duct in 74% yields. In H NMR spectrum, the signal at d 6.58 (s, 1H)
due to an olefinic proton of the isoxazole ring confirmed the formation
of 5-substituted product. With satisfactory preliminary results in this
cycloaddition, we broadened the scope of our study by exploring two
more nitrile oxides. We subjected 4-methoxybenzonitrile oxide and
2,4-dimethoxybenzonitrile oxide generated in situ from 4-methoxybenzal-
doxime and 2,4-dimethoxybenzaldoxime respectively to cycloaddition
with 2 as dipolarophile. The cycloadditions fetched isoxazole conjugates
of 1,4-benzodioxane moiety in 75–76% yields (Table 1, entries 1–3). To
Table 1. 1,3-Dipolar cycloadditions of 2 with different dipoles
Entry
Dipole precursor
Cycloadduct
Yield (%)
74
1
2
3
75
76
4
5
62
60
6
67
7
8
64
75

Isoxazole Conjugates of 1,4-Benzodioxane Moiety
3859
probe the viability of our approach, we synthesized a wide variety of
dipoles. In addition to the method utilizing oximes as precursors, we
utilized another way of accessing nitrile oxides for 1,3-dipolar cyclo-
addition. Upon dehydration in the presence of phenyl isocyanate and
triethyl amine, the nitro compounds are known to give nitrile oxides
(Mukaiyama’s method).[6] This method helped us investigate the higher
alkyl homologs of the dipoles for the cycloaddition. The nitro alkanes
were prepared from reduction of corresponding nitro styrene derivatives.
These nitro styrenes were prepared from corresponding aldehydes
using the Henry reaction with nitromethane and sodium hydroxide.
The treatment of nitro derivatives with 2-propynyloxymethyl-1,4-
benzodioxane in the presence of phenyl isocynate and triethylamine
afforded the corresponding cycloadducts in 60–62% yields (Scheme 2
and Table 1, entries 4 and 5). We also investigated the cycloaddition of
2 with sterically bulky nitrile oxide. The dipole precursor diphenylaceto-
hydroxamoyl chloride was prepared by the treatment of b-nitrostyrene
with AlCl3 in benzene.[7] Upon treatment with triethyl amine, this dipole
precursor generated diphenylacetonitrile oxide (DPANO) in situ, which
underwent cycloaddition with 2-propynyloxymethyl-1,4-benzodioxane
to give the corresponding isoxazole conjugate (Scheme 3 and Table 1,
entry 6) in 67% yields.
After optimization of the protocol for the synthesis of isoxazole
conjugates, we focused on our prime objective, which was to couple the
1,4-benzodioxane moiety with other biologically active compounds. In
that direction, we first chose to prepare a steroidal conjugate of 1,4-
benzodioxane moiety. The steroid nucleus is one of the largest rigid units
readily available with multiple chiral centers. The biological importance
of this structural entity is well documented.[8] Our group had worked with
steroidal nitro derivatives, and we prepared its isoxazole conjugates with
several sugar molecules.[9] Hence, we zeroed in on the nitro derivative
Scheme 2. Reagents and conditions: (a) CH3NO2, NaOH, methanol, 0–5ꢀC;
(b) silica gel, 2-propanol, NaBH4, CHCl3, rt; (c) PhNCO, Et3N, benzene, rt, 24 h.

3860
V. V. Vaidya et al.
Scheme 3. Reagents and conditions: (a) AlCl3 (anhydrous), benzene, rt; (b) Et3N,
ether, rt, 8–10 h.
of 16-dehydropregnenolone acetate (16-DPA). 3b-Acetoxy-16a-nitro-
methyl-5-pregnen-20-one was prepared from 16-DPA employing Michael
addition reaction of nitromethane using 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) as a base. This nitro steroid derivative under Mukaiyama’s
conditions afforded the corresponding steroidal nitrile oxide, which in
the presence of 2 gave cycloadduct-bearing benzodioxane and steroidal
moieties bridged via isoxazole as a linker in good yields (Scheme 4 and
Table 1, entry 7).
Our next endeavor was to couple the sugar moiety to the benzodiox-
ane moiety. However, in this case, triazole was used to anchor two of
them. To achieve this linkage, we utilized the click chemistry approach.
As a prototype of click chemistry, the recent advances of Cu(I)-catalyzed
Huisgen 1,3-dipolar cycloaddition of azides and alkynes affords superior
regioselectivity and almost quantitative transformation under extremely
mild conditions.[10] The carbohydrate azido substrate was synthesized
Scheme 4. Reagents and conditions: (a) CH3NO2, DBU, CH2Cl2, 0ꢀC;
(b) PhNCO, Et3N, benzene, rt, 24 h.

Isoxazole Conjugates of 1,4-Benzodioxane Moiety
3861
Scheme 5. Reagents and conditions: (a) Cu(OAc)2, Na-ascorbate, t-BuOH–H2O
(1:1), rt, 24 h.
from D-glucose. On treatment with copper acetate and sodium ascorbate,
the sugar azide and 2-propynyloxymethyl-1,4-benzodioxane gave
cycloadduct-bearing carbohydrate and benzodioxane bridged via triazole
(Scheme 5 and Table 1, entry 8).[11]
CONCLUSION
In conclusion, we have utilized 1,3-dipolar cycloaddition for the synthesis
of conjugates of 1,4-benzodioxane moiety with aryl compounds and also
biologically active molecules such as steroid and sugar. The methodology
also illustrates the use of different precursors for the generation of
dipoles, which offers a great deal of structural diversity in one part of
the conjugate. Thus, the methodology opens a gateway for conjugation
of different compounds, along with their properties, to a chosen moiety.
EXPERIMENTAL
Melting points were determined on a Laboratory Devices Meltemp II
melting-point apparatus and are uncorrected. Thin-layer chromato-
graphy (TLC) was performed on precoated silica-gel plates. Column
chromatography was performed on silica gel (60–120 mesh). All chemi-
cals used in this study were commercially available.
General Procedure for Cycloaddition (Cycloadducts 3a–c)
A
solution of the aldoxime (dipole precursor) (1.2 mmol),
2-propynyloxymethyl-1,4-benzodioxane (1 mmol), and triethylamine in
methylene chloride (10 mL) was cooled to 0ꢀC. Sodium hypochlorite
(4%, 10 mL) was added dropwise with stirring at 0ꢀC. The reaction

3862
V. V. Vaidya et al.
mixture was warmed to room temperature and stirred for 6–8 h. Upon
disappearance of starting material (TLC), the reaction phases were sepa-
rated, and the aqueous phase was extracted with dichloromethane. The
combined organic layers were washed with brine and dried over sodium
sulfate, and the solvent was evaporated under reduced pressure to yield
crude cycloadduct. The crude product was chromatographed on a
silica-gel column.
General Procedure for Cycloaddition (Cycloadducts 4a–b and 6)
PhNCO (1 mmol) in dry benzene was added dropwise to the solution of
compound 2 (0.55 mmol), dipole precursor (0.55 mmol), and triethyla-
mine in dry benzene (15 mL) at room temperature. The reaction mixture
was stirred for 24 h at rt. The solvent was evaporated under reduced pres-
sure. The residue so obtained was reconstituted in diethyl ether and fil-
tered. The filtrate was washed with water, dried over sodium sulfate,
and concentrated under reduced pressure to yield crude cycloadduct.
The crude product was chromatographed on a silica-gel column.
General Procedure for Cycloaddition (Cycloadduct 5)
Triethylamine (1 mmol) in ether (5 mL) was added dropwise to a stirred
solution of diphenyl acetohydroxamoyl chloride (1 mmol) and compound
2 (2 mmol) maintained at room temperature. The reaction mixture was
allowed to stir for an additional 8–10 h. The residue was removed by
washing with water, and the organic layer was then dried over sodium
sulfate and concentrated. The crude product was chromatographed on
a silica-gel column.
General Procedure for Cycloaddition (Cycloadduct 7)
The compound 2 (0.33 mmol) and sugar azide (0.33 mmol) were dissolved
in a t-BuOH=H2O mixture (2 mL, 1:1). Copper acetate (0.2 equiv.) and
sodium ascorbate (0.4 equiv.) were added, and the mixture was stirred
at room temperature until TLC indicated the disappearance of the
starting materials. The mixture was poured into saturated aqueous
NH4Cl solution, and the product was extracted with EtOAc. The organic
layer was dried over sodium sulfate and filtered, and the solvent was
removed under reduced pressure. The residue was purified by column
chromatography to yield the pure product.

Isoxazole Conjugates of 1,4-Benzodioxane Moiety
3863
Data
2-Propynyloxymethyl-1,4-benzodioxane, 2
Yellow liquid. IR (CHCl3) nmax: 3288, 3044, 2117, 1593, 1268, 1105cmꢁ1
.
1H NMR (300 MHz, CDCl3): d 6.88–6.82 (m, 4H), 4.32–4.20 (m, 4H),
4.05 (dd, 1H, J ¼ 7.0, 11.4 Hz), 3.81–3.69 (m, 2H), 2.47 (s, 1H) ppm.
13C NMR (75 MHz, CDCl3): d 143.12, 142.96, 121.58, 121.39,
117.36, 117.11, 79.07, 75.20, 71.82, 68.25, 65.39, 58.78 ppm. Mass
(DI): Mþ 204.
Cycloadduct 3a
Mp 57–58ꢀC. IR (CHCl3) nmax: 2922, 1590, 1491, 1428, 1262, 1023, 835,
794, 757 cmꢁ1 1H NMR (300 MHz, CDCl3): d 7.81–7.78 (m, 2H),
.
7.46–7.44 (m, 3H), 6.91–6.82 (m, 4H), 6.58 (s, 1H), 4.73 (s, 2H),
4.41–4.28 (m, 2H), 4.11 (dd, 1H, J ¼ 6.9, 11.4 Hz), 3.88–3.76 (m, 2H)
ppm. 13C NMR (75 MHz, CDCl3): d 169.15, 162.44, 143.08, 142.85,
130.12, 128.93, 128.78, 126.81, 121.70, 121.52, 117.37, 117.20, 101.32,
71.94, 69.51, 65.21, 64.44 ppm. Mass (DI): Mþ 323.
Cycloadduct 3b
IR (CHCl3) nmax: 3020, 1641, 1216, 753 cmꢁ1 1H NMR (300 MHz,
.
CDCl3): d 7.73 (d, 2H, J ¼ 8.7 Hz), 6.97 (d, 2H, J ¼ 8.7 Hz), 6.90–6.82
(m, 4H), 6.52 (s, 1H), 4.72 (s, 2H), 4.38–4.27 (m, 2H), 4.10 (dd, 1H,
J ¼ 7.3, 11.4 Hz), 3.84 (s, 3H), 3.84–3.78 (m, 2H) ppm. 13C NMR
(75 MHz, CDCl3): d 168.89, 162.06, 161.09, 143.12, 128.23, 121.71,
121.52, 117.39, 117.21, 114.35, 101.10, 71.97, 69.51, 65.26, 64.48,
55.37 ppm. Mass (DI): Mþ 353.
Cycloadduct 3c
IR (CHCl3) nmax: 3021, 1611, 1520, 1495, 1463, 1215, 1166, 760 cmꢁ1
.
1H NMR (300 MHz, CDCl3): d 7.82 (d, 1H, J ¼ 8.4 Hz), 6.88–6.84 (m,
4H), 6.75 (s, 1H), 6.55–6.53 (m, 2H), 4.70 (s, 2H), 4.35–4.27 (m, 2H),
4.08 (dd, 1H, J ¼ 6.9, 11.4 Hz), 3.84 (s, 3H), 3.82 (s, 3H), 3.86–3.77
(m, 2H) ppm. 13C NMR (75 MHz, CDCl3): d 167.47, 162.33, 159.83,
158.45, 143.09, 142.90, 130.22, 121.63, 121.44, 117.36, 117.15, 110.46,
105.11, 104.67, 98.78, 71.94, 69.32, 65.29, 64.33, 55.51, 55.44 ppm. Mass
(DI): Mþ 383.

3864
V. V. Vaidya et al.
Cycloadduct 4a
IR (CHCl3) nmax: 2922, 1609, 1491, 1428, 1251, 1107, 1030, 835, 750 cmꢁ1
.
1H NMR (300MHz, CDCl3): d 7.38–7.22 (m, 5H), 6.85–6.81 (m, 4H), 6.03
(s, 1H), 4.61 (s, 2H), 4.33–4.23 (m, 2H), 4.06 (dd, 1H, J ¼ 6.9, 11.4Hz),
4.00 (s, 2H), 3.80–3.69 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3): d
168.59, 163.07, 143.03, 142.79, 136.99, 128.76, 126.93, 121.67, 121.47,
117.34, 117.16, 103.17, 71.86, 69.46, 65.17, 64.40, 32.36 ppm. Mass (DI):
Mþ 337.
Cycloadduct 4b
IR (CHCl3) nmax: 3021, 1639, 1513, 1427, 1215, 1107, 1037, 762 cmꢁ1. 1H
NMR (300 MHz, CDCl3): d 7.16 (d, 2H, J ¼ 8.4 Hz), 6.85 (m, 6H), 6.02
(s, 1H), 4.62 (s, 2H), 4.33–4.24 (m, 2H), 4.05 (dd, 1H, J ¼ 6.9, 11.4 Hz),
3.94 (s, 2H), 3.78 (s, 3H), 3.78–3.69 (m, 2H) ppm. 13C NMR (75 MHz,
CDCl3): d 168.50, 163.42, 158.50, 143.04, 142.79, 129.77, 129.01,
121.63, 121.44, 117.31, 117.13, 114.16, 103.07, 71.85, 69.44, 65.17,
64.39, 55.22, 31.47 ppm. Mass (DI): Mþ 367.
Cycloadduct 5
IR (CHCl3) nmax: 2922, 1594, 1491, 1258, 1096, 1041, 794, 750, 702 cmꢁ1
.
1H NMR (300 MHz, CDCl3): d 7.30–7.19 (m, 11H), 6.84–6.83 (m, 3H),
6.10 (s, 1H), 5.58 (s, 1H), 4.62 (s, 2H), 4.31–4.22 (m, 2H), 4.04 (dd,
1H, J ¼ 6.9, 11.4 Hz), 3.77–3.73 (m, 2H) ppm. 13C NMR (75 MHz,
CDCl3): d 168.69, 165.67, 143.05, 142.81, 128.63, 127.05, 121.67,
121.49, 117.33, 117.16, 103.47, 71.88, 69.58, 65.16, 64.49, 48.71 ppm.
Mass (DI): Mþ 413.
Cycloadduct 6
IR (CHCl3) nmax: 2942, 1727, 1704, 1494, 1249, 1033, 753 cmꢁ1. 1H NMR
(300 MHz, CDCl3): d 6.88–6.86 (m, 4H), 6.05 (s, 1H), 5.38 (s, 1H), 4.62
(bs, 3H), 4.30 (m, 2H), 4.08 (dd, 1H, J ¼ 6.9, 11.4 Hz), 3.92 (t, 1H,
J ¼ 9 Hz), 3.79–3.75 (m, 2H), 3.00 (d, 1H, J ¼ 9 Hz), 2.34–2.31 (m, 2H),
2.17 (s, 3H), 2.04 (s, 3H), 1.94–1.77 (m, 3H), 1.61–1.32 (m, 3H),
1.26–1.16 (m, 2H), 1.03 (s, 3H), 0.74 (s, 3H) ppm. 13C NMR (75 MHz,
CDCl3): d 207.70, 170.51, 168.52, 143.06, 142.84, 139.61, 122.08,
121.66, 121.47, 117.35, 117.16, 102.68, 77.86, 73.72, 71.90, 69.49, 69.08,
65.20, 64.41, 55.67, 49.45, 45.07, 38.56, 38.32, 36.91, 36.54, 34.23,

Isoxazole Conjugates of 1,4-Benzodioxane Moiety
3865
31.67, 31.62, 31.55, 29.68, 27.83, 21.41, 20.86, 19.28, 13.65 ppm. Mass
(DI): Mþ 603.
Cycloadduct 7
IR (CHCl3) nmax: 3147, 1455, 1384, 1071 cmꢁ1 1H NMR (300 MHz,
.
CDCl3): d 7.59 (s, 1H), 7.36 (m, 5H), 6.83 (m, 4H), 5.98 (d, 1H,
J ¼ 3.6 Hz), 4.75–4.69 (m, 5H), 4.54–4.47 (m, 3H), 4.29–4.25 (m, 2H),
4.19–3.99 (m, 2H), 3.78–3.75 (m, 2H), 1.43 (s, 3H), 1.31 (s, 3H) ppm.
13C NMR (75 MHz, CDCl3): d 144.47, 143.11, 136.73, 128.68, 128.33,
127.92, 123.83, 121.51, 121.30, 117.33, 117.06, 112.09, 105.18, 81.89,
81.50, 78.75, 71.93, 68.86, 65.40, 64.87, 49.28, 26.66, 26.14 ppm. HRMS:
calcd. for C27H32N3O7 (M þ H) 510.2240; found 510.2238.
ACKNOWLEDGMENTS
We thank the University Grants Commission (UGC) and Defence
Research and Development Organisation (DRDO), New Delhi, for the
financial support. V. V. V. thanks UGC for the award of a fellowship
[F-12–25=(2003)].
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