A short synthetic route to a hybrid molecule benzosultine-sulfone via [2+2+2] cyclotrimerization using Mo(CO)6

Article abstract of DOI:10.3987/COM-16-S(S)71

Here, we report an improved and short synthetic route to benzosultine-sulfone via [2+2+2] cyclotrimerization as a key step, starting with dipropargyl ether and 1,4-dibromo-2-butyne with an overall yield of 16%.

Full text of DOI:10.3987/COM-16-S(S)71

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HETEROCYCLES, Vol. 95, No. 2, 2017
HETEROCYCLES, Vol. 95, No. 2, 2017, pp. 1204-1210. © 2017 The Japan Institute of Heterocyclic Chemistry
Received, 8th September, 2016, Accepted, 19th January, 2017, Published online, 14th February, 2017
DOI: 10.3987/COM-16-S(S)71
A
SHORT SYNTHETIC ROUTE TO
A
HYBRID MOLECULE
BENZOSULTINE-SULFONE VIA [2+2+2] CYCLOTRIMERIZATION
†
USING Mo(CO)6
Sambasivarao Kotha* and Gaddamedi Sreevani
Department of Chemistry, Indian Institute of Technology-Bombay, Powai,
Mumbai-400076, India, Fax: +91(22)-2572 7152; E-mail: srk@chem.iitb.ac.in
†This paper is dedicated to Professor Dr. Masakatsu Shibasaki on the occasion of
his 70th birthday.
Abstract – Here, we report an improved and short synthetic route to
benzosultine-sulfone via [2+2+2] cyclotrimerization as a key step, starting with
dipropargyl ether and 1,4-dibromo-2-butyne with an overall yield of 16%.
The reactive intermediate o-quinodimethane (o-QDM), also called as o-xylylene (Figure 1, 1a-d), has
attracted much attention of both synthetic and theoretical chemists over the past fifty years.1 o-QDMs
have a remarkable reactivity in Diels‒Alder (DA) reaction and are often used as key building blocks in
the synthesis of polycycles by inter- or intramolecular [4+2] cycloaddition reactions (Scheme 1). To
expand the DA reaction,2 we were interested in generating various o-QDM intermediates with the help of
sultine derivatives involving rongalite chemistry.3
Figure 1. Different structures contributing to o-QDM
Scheme 1. Generation of o-quinodimethane from sultine followed by DA reaction

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Recently, we reported a hybrid molecule benzosultine-sulfone,4 which is a useful building block for the
synthesis of functionalized polycycles. This hybrid molecule can participate in DA reaction in a stepwise
manner by opening the sultine or the sulfone side at different temperatures and the corresponding
o-xylylene intermediate can be trapped with different dienophiles. This approach delivers densely
functionalized polycyclic compounds. We synthesized benzosultine-sulfone 12, by using
but-2-yne-1,4-diacetate 4 as starting material in eight steps and in another sequence, 2,3-dimethylbutadiene
13 and dimethyl acetylenedicarboxylate (DMAD) as starting materials in seven steps with an overall yield
of 7% and 4% respectively (Scheme 2).
Scheme 2. Synthesis of benezosultine-sulfone via cross-enyne metathesis and DA reactions
Recently, we reported [2+2+2] co-trimerization5a of 1,6-diynes with propargyl halides using catalytic
amount of molybdenum hexacarbonyl [Mo(CO)6].5b Now, we realized that the benzosultine-sulfone 12
can be synthesized from the dibromo derivative 15b which can be prepared from dipropargyl ether 16 via
a [2+2+2] cycloaddition reaction using 1,4-dibromo-2-butyne 17b as a co-trimerization partner in less
number of steps (Scheme 3). To this end, we explored an alternate protocol involving [2+2+2]
co-trimerization with the propargyl halides.

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Scheme 3. Retrosynthetic analysis of benezosultine-sulfone
To synthesize 1,3-dihydrobenzofuran derivatives, dipropargyl ether 16 was prepared from propargyl
alcohol 18 and propargyl bromide 17a in the presence of NaOH at 70 oC.6 Further, the diyne 16 was treated
with proprgyl halides under microwave (MW) irradiation conditions using catalytic amount of Mo(CO)6 to
obtain the corresponding halo derivatives 15a-d in moderate yields along with minor amount of self
trimerized product 19. Since, both the starting materials 18 and 17a are readily available even 48% yield
may be acceptable. We believe that the volatile nature of 16 may be responsible for low yield of 15.
Scheme 4. Preperation of benzofuran derivatives via [2+2+2] co-trimerization
The dibromobenzofuran 15b was further utilized towards the synthesis of benzosultine-sulfone 12 which
was previously prepared in our laboratory via cross-enyne metathesis and DA reaction as key steps.4 In this
regard, Mo(CO)6 and 1,4-dibromo-2-butyne 17b with dipropargyl ether 16 gave dibromo derivative 15b,
which was converted into sultine derivative using rongalite. The sultine 20 generated was used for next step
without any further purification and it was rearranged in refluxing toluene to give the corresponding sulfone
derivative 21. Later, we propose to cleave the ether linkage to generate the dibromosulfone 11. Therefore,
the sulfone 21 was treated with PBr3 in dichloromethane at room temperature for 6 h. However, we did not
realize any change in the starting material and it was recovered. So, we changed the reaction conditions and
accordingly, the sulfone derivative 21 was treated with 48% HBr in water and a drop of conc. H2SO4 at
reflux conditions for 3 h, to deliver the desired dibromosulfone 11 with good yield. Then, the
dibromosulfone 11 was further converted to benzosultine-sulfone 12 in the presence of rongalite and TBAB
under standard reaction conditions.4

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Scheme 5. Synthesis of benzosultine-sulfone from 15b
In conclusion, we have shown that the [2+2+2] cyclotrimerization of propargyl halides with sensitive
substrate such as dipropargyl ether 16 and the corresponding 1,3-dihydrobenzofuran derivatives 15a-d
were isolated in a reasonable yield along with the minor amount of self trimerized product 19. We have also
synthesized benzosultine-sulfone 12 in five steps with an overall yield of 16%.
EXPERIMENTAL
All reactions were performed under an argon or nitrogen atmosphere using well-dried reaction flask. All
commercially available products were used as received without further purification. All the solvents used as
reaction media were dried over predried molecular sieves (4 Å) in oven. Column chromatography was
1
performed with silica gel (100-200 mesh) using mixture of petroleum ether and EtOAc as eluent. H and
13C NMR spectral data were recorded on 400 MHz and 100 MHz or 500 MHz and 125 MHz spectrometers
using tetramethylsilane (TMS) as an internal standard and chloroform-d as a solvent. The high resolution
mass spectroscopy (HRMS) was performed using Brucker (Maxis Impact) or Micromass Q-ToF
spectrometer. The melting points recorded are uncorrected.
General procedure for [2+2+2] cyclotrimerization of propargyl halides with dipropargyl ether:
To the solution of dipropargyl ether 16 in dry MeCN taken in a microwave 10 mL tube, propargyl halide
17 (2 eqv.) and Mo(CO)6 (5 mol%) were added and kept in microwave (CEM Discover Microwave) at 90
oC for 15 min. After completion of the reaction (TLC monitoring), the solvent was removed at reduced
pressure and the crude product was purified by silica gel column chromatography (5% EtOAc-petroleum
ether) gave the cyclotrimerization compound 15.
Compound 15a: Brown denser liquid (yield = 50%); 1H NMR (400 MHz, CDCl3) δ 4.52 (s, 2H), 5.10 (s,
13
4H), 7.20 (d, J = 7.56 Hz, 1H) 7.27-7.30 (m, 2H); C NMR (100 MHz, CDCl3) G 33.58, 73.45, 73.54,
121.50, 121.85, 128.46, 137.32, 139.79, 140.19; IR υmax 621, 705, 823, 901, 964, 1047, 1215, 1319, 1365,
1435, 1492, 1766, 2531, 2851 cm-1.

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Compound 15b: White solid (yield = 48%); MP 141-143 oC; 1H NMR (500 MHz, CDCl3) δ 4.68 (s, 4H),
13
5.08 (s, 4H), 7.26 (s, 2H); C NMR (125 MHz, CDCl3) G 30.23, 73.39, 123.86, 136.19, 140.04; IR υmax
607, 740, 895, 959, 1032, 1068, 1176, 1197, 1218, 1309, 1490, 2528, 2867 cm-1.
1
Compound 15c: Colourless liquid (yield = 51%); H NMR (500 MHz, CDCl3) δ 2.60 (s, 2H), 5.10 (s,
4H), 7.21-7.30 (m, 3H); 13C NMR (125 MHz, CDCl3) G 46.31, 73.48, 73.53, 121.42, 121.46, 128.05,
137.04, 139.75, 140.15; IR υmax 676, 722, 825, 904, 1047, 1140, 1260, 1276, 1367, 1436, 1446, 1473,
1491, 2854, 2905 cm-1.
Compound 15d: White solid (yield = 47%); MP 128-130 °C; 1H NMR (500 MHz, CDCl3) δ 4.78 (s, 4H),
13
5.10 (s, 4H), 7.28 (s, 2H); C NMR (125 MHz, CDCl3) G 43.44, 73.41, 123.52, 135.81, 128.05, 140.86;
IR υmax 683, 754, 894, 1034, 1067, 1176, 1258, 1270, 1371, 1473, 2856 cm-1; HRMS (ESI, Q-ToF) m/z:
calculated for C10H10Cl2KO [M+K]+ 254.9740, found: 254.9744.
Compound 19: The spectra of this compound matched with the literature report.7
Synthesis of sultine compound 20: To a solution of dibromide 15b (200 mg, 0.65 mmol) and TBAB
(105 mg, 0.33 mmol) in DMF (5 mL) was added rongalite (771 mg, 6.5 mmol) at 0 °C and the reaction
mixture was stirred at 0 °C for 3 h and at rt for another 3 h. At the conclusion of the reaction (TLC
monitoring), the aqueous layer was extracted with EtOAc and the organic layer was washed with water
(4-5 times) to remove excess of DMF. The solvent was removed under reduced pressure and the crude
product was used for next step without further purification.
Synthesis of sulfone compound 21: The solution of crude sultine compound 20 in toluene (3 mL) was
refluxed for 6 h. After completion of the reaction (TLC monitoring), quenched with water and extracted
with EtOAc. The solvent was removed under reduced pressure and dried under vacuum, crystalline solid
was obtained. The NMR of the crude product was pure, hence used directly for next step. Colourless
o
1
crystalline solid, yield = 65% (from two steps); MP 196-198 C; H NMR (400 MHz, CDCl3) δ 4.36 (s,
13
4H), 5.10 (s, 4H), 7.19 (s, 4H); C NMR (100 MHz, CDCl3) G 56.98, 73.37, 119.02, 130.48, 140.44; IR
υmax 593, 902, 1039, 1097, 1134, 1162, 1220, 1311, 1364, 1395, 1442, 2857, 2920, 2983 cm-1; HRMS
(ESI, Q-ToF) m/z: calculated for C10H10NaO3S [M+Na]+ 233.0243, found: 233.0241.
Synthesis of dibromosulfone compound 11: To the sulfone 21 (50 mg, 0.24 mmol), 48% HBr in water,
and a drop of conc. H2SO4 were added and refluxed for 3 h. After completion of the reaction (TLC
monitoring), water was added and extracted with EtOAc. The solvent was removed under reduced
pressure and the crude product was purified by by silica gel column chromatography (30%
EtOAc-petroleum ether) to obtain the compound 11 (62 mg, 85% yield).
Synthesis of compound 12: Compound 12 was synthesized from compound 11 as reported in the
literature.4

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11 and 12: The spectra of these compounds matched with the literature reports.4
ACKNOWLEDGEMENTS
We thank Department of Science and Technology (DST), New Delhi for the financial support. S. K. thanks
Department of Science and Technology for the award of a J. C. Bose fellowship. And G. S. thanks the
CSIR-New Delhi for the award of research fellowship.
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