Design and synthesis of benzosultine-sulfone as a o -Xylylene precursor via cross-enyne metathesis and rongalite: Further expansion to polycyclics via regioselective diels-alder reaction

Article abstract of DOI:10.1021/jo100655c

Benzosultine-sulfone 5 has been prepared as a o-xylylene or o-quinodimethane precursor by utilization of rongalite. Thermal activation of this hybrid molecule 5 has resulted a new sulfone-based building block 6. Building block 5 is a suitable precursor for the synthesis of unsymmetrically functionalized polycyclics through Diels-Alder (DA) chemistry. The dibromosulfone 24 and benzosultine-sulfone 5 has also been used for the synthesis of various sulfone based unnatural α-amino acid (AAA) derivatives.

Full text of DOI:10.1021/jo100655c

pubs.acs.org/joc
DA strategy, we had reported a novel synthetic approach to
Design and Synthesis of Benzosultine-sulfone as a
o-Xylylene Precursor via Cross-enyne Metathesis and
Rongalite: Further Expansion to Polycyclics via
Regioselective Diels-Alder Reaction
various new o-xylylene (o-quinodimethane) intermediatessuch as
73 and 8.4
Sambasivarao Kotha* and Arjun S. Chavan
Department of Chemistry, Indian Institute of Technology,
Bombay, Mumbai 400 076, India
srk@chem.iitb.ac.in
Received April 6, 2010
FIGURE 1. Approaches toward the generation of o-quinodi-
methane 1.
Although the thermal ring opening of benzosulfone5 2,
benzosultine6 3, and benzocyclobutene7 4 generates the
o-xylylene 1, benzosultine 3 opens up at relatively low tem-
perature as compared with the other o-xylylene precursors
such as 2 and 4. Dittmer and co-workers had reported the
synthesis of the sultine derivative (1,4-dihydro-2,3-benzox-
athiin-3-oxide) 3 from o-xylylene dibromide in high yield
under phase-transfer catalyst (PTC) conditions using ronga-
lite. They had also demonstrated the generation of o-xylylene
intermediate 1 at relatively low temperature.8 Generally, sultine
derivatives are prepared from the corresponding R,R0-dibromoxy-
lenes via rongalite at low temperature, and the corresponding
sulfones are prepared by heating the sultines in the absence of
trapping agents in a sealed tube9 or oxidation of corresponding
sulfides.10 On some occasions it was reported that the pyrolysis of
benzosulfone derivatives gave benzocylcobutenes by extrusion
of sulfur dioxide.11 Rongalite (sodium hydroxymethanesulfi-
nate or sodium formaldehyde sulfoxylate) is commercially
available material used in the textile industry as a decolorizing
agent, and it has also been used in organic synthesis.12
Benzosultine-sulfone 5 has been prepared as a o-xylylene or
o-quinodimethane precursor by utilization of rongalite.
Thermal activation of this hybrid molecule 5 has resulted a
new sulfone-based building block 6. Building block 5 is a
suitable precursor for the synthesis of unsymmetrically func-
tionalized polycyclics through Diels-Alder (DA) chemistry.
The dibromosulfone 24 and benzosultine-sulfone 5 has also
been used for the synthesis of various sulfone based unnatu-
ral R-amino acid (AAA) derivatives.
Transient intermediates related to o-quinodimethane (o-QDM)
or o-xylylene1 1 have expanded the Diels-Alder (DA) strategy.2
Diverse approaches toward the generation of 1 either by thermal
(Figure 1) or photochemical means are available. To expand the
In view of our interest in designing polycyclics and un-
usual R-amino acid (AAA) derivatives via rongalite,13 we
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DOI: 10.1021/jo100655c
r
Published on Web 05/24/2010
J. Org. Chem. 2010, 75, 4319–4322 4319
2010 American Chemical Society

Kotha and Chavan
JOCNote
SCHEME 1. Strategies for New o-Xylylene Precursors
SCHEME 3. Preparation of Dimethyl 4,5-Bis(bromomethyl)-
phthalate 18a
SCHEME 2. Symmetrical Bis(o-xylylene) Precursors
aReagents and conditions: (a) Grubbs catalyst (5 mol %), ethylene, DCM,
rt, 48 h; (b) DMAD, toluene, reflux, 24 h; (c) DDQ, benzene, reflux, 30 h
or MnO2, dioxane, reflux, 72 h, 90%; (d) 10 equiv 33% HBr in acetic acid,
DCM, rt, 36 h, 46%; (e) DMAD, benzene, reflux, 24 h; (f) DDQ, benzene,
reflux, 30 h or MnO2, dioxane, reflux, 60 h, 75%; (g) NBS, benzoyl pero-
xide, CCl4, reflux, 7 h, 25%; (h) NBS, benzoyl peroxide, DCE or R,R,R-
trifluorotoluene (0.1 M), 12 h, 73%.
envisioned a hybrid molecule such as benzosultine-sulfone 5 as
a useful building block for the synthesis of densely functiona-
lized unsymmetrical polycycles. For example, by opening the
sultine and sulfone portion of this hybrid molecule 5 in a
stepwise manner at different temperatures and trapping the
resulting o-xylylene intermediate with appropriate dienophiles,
one can generate unsymmetrical polycyclics. It is worth men-
tioning that here the temperature of the reaction is used as
regiocontrol element. In view of these interesting possibilities,
o-xylylene derivatives 6 and 8 are worthwhile targets. More-
over, these building blocks are also useful to generate a library
of sulfone and BCB derivatives respectively. In this regard,
recently we have demonstrated that the transient intermediate
8 can be generated either from 9 or from 10.4 Herein, we report
the synthesis of 5, a potential precursor for sulfone containing
o-xylylene moiety 6 (Scheme 1). It is interesting to note that
various sulfone derivatives can be alkylated by carbanion
chemistry, and then the resulting alkylated sulfones can under-
go DA chemistry with appropriate dienophiles to generate
complex polycyclics.
Chung and co-workers had reported the synthesis of
benzodisultine 12 from the R,R0,R00,R000-tetrabromo durene
11 via rongalite and explored its DA chemistry with various
dienophiles.14 Cava and co-workers had reported the synth-
esis of benzodisulfone 13 by the oxidation of corresponding
disulfide by cold peracetic acid.10 The benzodisulfone 13 on
thermal extrusion of two molecules of sulfur dioxide gives
the benzodicyclobutene 1411 (Scheme 2). Generally, thermal
activation of the sultine 3 generates the o-QDM 1 at around
100 °C and sulfone 2 or cyclobutene 4 derivatives open up at
higher temperature (180-200 °C). Subsequently, we realized
that the o-xylylene intermediate generated from the sultine 3
can be trapped with dienophile containing an AAA moiety
(e.g., methyl 2-acetamidoacrylate).
variety of reaction conditions (e.g., toluene, reflux; toluene, BF3-
etherate, 0 °C; toluene, hydroquinone, reflux; microwave irradia-
tion). Then, we tried the DA reaction of the diene 16a with vari-
ous other dienophiles under different conditions, but none of the
dienophiles gave the required DA adduct. Then, we speculated
that the bulky tosylate group present in the diene 16a may be
responsible for the failure of the DA reaction. To address this
issue, the hydroxyl groups present in but-2-yne-1,4-diol were
protected as acetyl groups, and the cross-enyne metathesis of the
resulting but-2-yne 1,4-diacetate 15b by Grubbs first generation
catalyst in DCM at rt gave the 2,3-dimethylene butane-1,4-
diacetate 16b in good yield.16 Later, the DA reaction of 16b with
DMAD in toluene followed by aromatization with MnO2 in dry
dioxane gave the dimethyl 4,5-bis(acetoxymethyl) phthalate 17.
Next, the diacetate 17 was converted to dimethyl 4,5-bis(bromo-
methyl)phthalate 18 by treating it with 33% HBr in acetic acid at
rt in DCM using the known protocol.17 This reaction gave an
acceptable yield in a small scale reaction; however, in large scale,
poor yield of the desired product along with 4,5-bis(bromo-
methyl)phthalic acid as a side product was observed. Later,
when the 4,5-bis(bromomethyl)phthalic acid was subjected to
acid-catalyzed esterification, dimethyl 4,5-(methoxymethyl)
phthalate was obtained.
Alternatively, the dibromo derivative 18 was also prepared
by the DA reaction of 2,3-dimethyl butadiene 19 and
DMAD in benzene followed by the aromatization of the
resulting DA adduct with DDQ in benzene (or with MnO2 in
dry dioxane) to give the dimethyl 4,5-(dimethyl)phthalate
20.18 Next, benzylic bromination of 20 mediated by NBS in
dry CCl4 involving a radical mechanism gave the expected
dimethyl 4,5-bis(bromomethyl)phthalate 18 in 25% yield.19
Later, it was found that the bromination yield can be
improved by using NBS and benzoyl peroxide as a radical
Toward the synthesis of intricate polycycles and unusual AAA
derivatives, dibromo derivative 18 was identified as a key inter-
mediate (Scheme 3) that can be assembled by the DA reaction of
dimethyl acetylenedicarboxylate (DMAD) and 2,3-dimethylene-
butane-1,4-ditosylate 16a. The required diene 16a was prepared
by cross-enyne metathesis of but-2-yne-1,4-ditosylate15 15a with
Grubbs second generation catalyst in 80% yield. Unfortunately,
the diene 16a did not undergo DA reaction with DMAD under a
(16) (a) Mori, M.; Kinoshita, A.; Sakakibara, N. J. Am. Chem. Soc. 1997,
119, 12388. (b) Diver, S. T.; Smulik, J. A. Org. Lett. 2000, 2, 2271.
(17) Lohier, J.-F.; Wright, K.; Peggion, C.; Formaggio, F.; Toniolo, C.;
Wakselmana, M.; Mazaleyrat, J.-P. Tetrahedron 2006, 62, 6203.
(18) Farooq, O. Synthesis 1994, 1035.
(14) Wu, An.-T.; Liu, W.-D.; Chung, W.-S. J. Chin. Chem. Soc. 2002, 49,
77 (Only one regioisomer (i.e. 12) is shown here. However, two isomers are
reported).
(19) Esser, B.; Bandyopadhyay, A.; Rominger, F.; Gleiter, R. Chem.;
Eur. J. 2009, 15, 3368. (b) Anthony, J. E.; Swartz, C. R.; Landis, C. A.; Parkin,
S. R. Proceeding of SPIE-The international Society for Optical Engineering 2005,
5940 (Organic field-effect transistors IV), 594002/1-594002/12.
(15) Eglinton, G.; Whiting, M. C. J. Chem. Soc. 1950, 3650.
4320 J. Org. Chem. Vol. 75, No. 12, 2010

Kotha and Chavan
JOCNote
SCHEME 4. Preparation of Dibromosulfone 24a
SCHEME 6. Preparation of Sulfone-Based Unusual AAA De-
rivativesa
aReagents and conditions: (a) diethyl acetamidomalonate, K2CO3, MeCN,
12 h, reflux, 62%; (b) (i) ethyl isocyanoacetate, K2CO3, TBAHS, MeCN,
20 h, reflux; (ii) 4-5 drops of conc HCl, EtOH, rt, 9 h; (iii) DMAP, acetic
anhydride, DCM, rt, 24 h, 52% (overall yield).
aReagents and conditions: (a) rongalite, TBAB, DMF, 0 °C to rt, 7 h,
65%; (b) toluene, 100 °C, 7 h, 75%; (c) LiCl, KBH4, THF, reflux, 24 h,
77%; (d) PBr3, benzene, 0 °C to rt, 12 h, 73%.
sulfone side were not successful. We are exploring alternate
conditions in this direction.
Alternatively, the dibromosulfone 24 has also been used
for the synthesis of sulfone-based AAA derivatives 27 and
28.3 When the dibromosulfone 24 was treated with diethyl
acetamidomalonate13g in dry acetonitrile in presence of
K2CO3 as a base, the sulfone based 1, 2, 3, 4-tetrahydroiso-
quinoline-3-carboxylic acid (Tic) derivative 27 was obtained
in good yield. Similarly, treating the dibromosulfone 24 with
ethyl isocyanoacetate21 in dry acetonitrile in the the presence
of base such as K2CO3, gave the coupling product, which on
hydrolysis and protection using acetic anhydride in presence
of DMAP gave the indane based AAA derivative 28. Because
some of the isocyanonitrile derivatives are unstable, its
isolation and characterization was not attempted. The cor-
responding AAA derivative 28 was prepared. These sulfone
derivatives 27 and 28 serve as advanced building blocks for
further synthetic manipulation to design various unusual
AAA derivatives (Scheme 6).
A new methodology has been devised for the synthesis of
benzosultine-sulfone 5, as a useful building block suitable for
DA strategy. This hybrid molecule 5 contains two latent
o-QDM intermediates of different reactivity. The selective
DA reaction at sultine terminus has delivered the sulfone-
based precursors, which may be suitable for the synthesis of
various polycyclics and unusual AAA derivatives.
SCHEME 5. Preparation of Benezosultine-sulfone and Its Re-
gioselective DA Reaction at the Sultine Terminusa
aReagents and conditions: (a) rongalite, TBAB, DMF, 0 °C to rt, 7 h,
55%; (b) DMAD, toluene, reflux, 24 h; (c) MnO2, dioxane, reflux, 72 h,
90%; (d) methyl 2-acetamidoacrylate, toluene, reflux, 24 h.
initiator in 1,2-dichloroethane (DCE) or R,R,R-trifluoroto-
luene (0.1 M solution) (Scheme 3).
When the compound 18 was treated with rongalite in the
presence of PTC such as tetrabutylammonium bromide
(TBAB) in DMF at 0 °C, the sultine derivative 21 was
obtained in good yield. Later the compound 21 was con-
verted to the sulfone derivative 22 by heating in toluene
at 100 °C for 7 h. Based on Anderson’s observation,20 the
reduction of diester containing sulfone 22 was achieved by
using KBH4, LiCl in refluxing THF to generate the corre-
sponding diol 23 in good yield. The dihydroxysulfone 23 was
then treated with phosphorus tribromide in benzene at 0 °C
to deliver the dibromosulfone 24 in 73% yield (Scheme 4).
Next, the dibromide 24 was converted to the desired benzo-
sultine-sulfone 5 by treatment with rongalite in presence of
TBAB in DMF at 0 °C. Having prepared the key building block
5 in 55% yields, next we explored its utility by selective opening
of sultine portion and reacting the resulting o-xylylene inter-
mediate with DMAD and methyl 2-acetamidoacrylate to gen-
erate the corresponding sulfone-based building blocks. When
the benzosultine-sulfone 5was reacted with DMAD in refluxing
toluene, the desired DA adduct was obtained in good yield,
which was further aromatized with freshly activated MnO2 in
dry dioxane to obtain the sulfone-based diester 25 in 90% yield.
Similarly, when the benzosultine-sulfone 5 was reacted with
methyl 2-acetamidoacrylate in refluxing toluene, the desired
tetraline-based AAA derivative 26 was obtained in a moderate
yield (57%) along with rearranged benzodisulfone 13 (40%) as
a side product. These sulfone derivatives 25 and 26 can be
further utilized to design various polycyclics and unusual AAA
derivatives (Scheme 5). Our initial attempts to open up the
Experimental Section
Prepareation of Benzosultine-sulfone 5. To a suspension of
rongalite (2.39 g, 15.5 mmol) in DMF (15 mL) were added TBAB
(501 mg, 1.55 mmol) and 4,5-bis(bromomethyl)benzosulfone 24
(550 mg, 1.55 mmol) at 0 °C, and the stirring was continued for 4 h
at 0 °C. Then, the reaction mixture was brought to rt, and the
stirring was continued for an additional 4 h. After completion
of the reaction (TLC monitoring), the reaction mixture was
diluted with ethyl acetate and washed with water (3-4 times).
The aqueous layer was again extracted with ethyl acetate and
the combined organic layer was washed with brine, dried over
Na2SO4, and concentrated under reduced pressure, and the pro-
duct was purified by silicagel column chromatography. Elutionof
the column with 60% ethyl acetate-petroleum ether gave 5 as a
white solid (203 mg, 51% yield). Rf = 0.26 (silica gel, 60% EtOAc-
petroleum ether). Mp dec at 185-190 °C. 1H NMR (300 MHz,
CDCl3): δ 7.24 (s, 1H), 7.22 (s, 1H), 5.30 (1/2 ABq, J = 14.0 Hz,
1H), 4.97 (1/2 ABq, J = 14.0 Hz, 1H), 4.38 (s, 4H), 4.35 (d, J =
15.6 Hz, 1H), 3.61 (d, J = 15.6 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 134.5, 132.0, 131.4, 127.8, 127.3, 123.6, 62.7, 56.73,
56.71, 56.4. IR (KBr, cm-1): 2924, 2857, 1602, 1314, 1226, 1112,
726. HRMS (Q-Tof) m/z: [M þ Na]þ calcd for C10H10S2O4Na
280.9918, found 280.9908
(20) Anderson, W. K.; Mach, R. H. Synth. Commun. 1986, 16, 911.
(21) Kotha, S.; Halder, S. Synlett 2010, 337.
J. Org. Chem. Vol. 75, No. 12, 2010 4321

Kotha and Chavan
JOCNote
Preparation of 6,7-Bis(carbomethoxy)-2,3-naphthalene-sul-
fone 25. To a solution of benezosultine-sulfone 5 (42 mg, 0.581
mmol) in toluene (15 mL), DMAD (124 mg, 0.827 mmol) was
added under N2 atmosphere, and the reaction mixture was
refluxed for 36 h. After completion of the reaction (TLC
monitoring), the reaction mixture was cooled, and the solvent
was evaporated under reduced pressure. The crude DA adduct
was directly aromatized without any further purification. This
crude DA-adduct was dissolved in dry dioxane (25 mL) and
treated with 70 equiv of MnO2 (970 mg). Then the reaction
mixture was refluxed for 72 h, and the reaction mixture was
filtered through Buchner funnel and washed (2-3 times) with
ethyl acetate. The combined organic layer was concentrated
under reduced pressure, and the product was purified by silica
gel column chromatography.
Elution of the column with 30% ethyl acetate-petroleum
ether gave 25 (40 mg, 90% overall yield). Rf = 0.42 (silica gel,
60% EtOAc-petroleum ether). Mp 226-228 °C. 1H NMR (400
MHz, CDCl3): δ 8.22 (s, 2H), 7.88 (s, 2H), 4.55 (s, 4H), 3.97 (s,
6H). 13C NMR (100 MHz, CDCl3): δ 167.8, 133.1, 132.2, 129.9,
129.7, 126.3, 56.5, 53.1. IR (KBr, cm-1): 2956, 1720, 1458, 1317,
1290, 1126. HRMS (Q-Tof) m/z: [M þ Na]þ calcd for C16H14-
SO6Na 357.0408, found 357.0424
the solvent was removed under reduced pressure. The insoluble
material was washed (2-3 times) with DCM. The DCM fraction
was concentrated and charged on silica gel column chromatog-
raphy. Elution of the column with 70% ethyl acetate-
petroleum ether gave 26 as a white crystalline product (30 mg,
57% yield). Rf = 0.19 (silica gel, 70% EtOAc-petroleum ether).
Mp 238-240 °C. The insoluble material was again washed with
ethyl acetate to obtain the pure benzodisulfone 13 (16 mg, 40%).
1H NMR (400 MHz, CDCl3): δ 7.08 (s, 1H), 7.03 (s, 1H), 5.66 (s,
1H, NH), 4.33 and 4.29 (ABq, J = 16.0 Hz, 4H), 3.76 (s, 3H),
3.35 (1/2 ABq, J = 17.2 Hz, 1H), 3.03 (1/2 ABq, J = 17.2 Hz,
1H), 2.90-2.80 (m, 2H), 2.52-2.48 (m, 1H), 2.18-2.11 (m, 1H),
1.96 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 173.7, 170.4, 136.0,
133.8, 129.6, 129.3, 127.0, 126.5, 57.8, 56.8, 52.9, 37.7, 28.5, 25.4,
23.3. IR (KBr, cm-1): 3297, 2925, 1737, 1651, 1542, 1315, 1238,
1127. HRMS (Q-Tof) m/z: [M þ Na]þ calcd for C16H19NSO5Na
360.0881, found 360.0890.
Acknowledgment. We thank CSIR and DST, New Delhi
for financial support and SAIF, Mumbai for recording the
spectral data. A.C. thanks CSIR, New Delhi for award of the
research fellowship.
Preparation of Sulfone-Based Tetraline AAA Derivative 26. A
solution of benzosultine-sulfone 5 (40 mg, 0.155 mmol) and
methyl 2-acetamidoacrylate (33 mg, 0.233 mmol) in toluene
(10 mL) was refluxed for 24 h. After completion of the reaction
(TLC monitoring), the reaction mixture was brought to rt, and
Supporting Information Available: Detailed experimental
1
procedures and characterization data with copies of H and 13C
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
4322 J. Org. Chem. Vol. 75, No. 12, 2010