Synthesis of polycyclic aromatics from a diiodosultine by Suzuki-miyaura cross-coupling and Diels-Alder reaction

Article abstract of DOI:10.3987/COM-10-S(E)63

A convergent synthesis of polycyclic aromatic compounds by the application of Suzuki-Miyaura cross-coupling and Diels-Alder reaction as key steps is described. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-S(E)63

HETEROCYCLES, Vol. 82, No. 2, 2011
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HETEROCYCLES, Vol. 82, No. 2, 2011, pp. 1663 - 1668. © The Japan Institute of Heterocyclic Chemistry
Received, 20th June, 2010, Accepted, 9th September, 2010, Published online, 10th September, 2010
DOI: 10.3987/COM-10-S(E)63
SYNTHESIS
OF
POLYCYCLIC
AROMATICS
FROM
A
DIIODOSULTINE BY SUZUKI-MIYAURA CROSS-COUPLING AND
DIELS-ALDER REACTION†
Sambasivarao Kotha* and Milind Meshram
Department of Chemistry, Indian Institute of Technology-Bombay, Mumbai,
400076, India. Fax: (+91)-22-2572-3480; phone: (+91)-22-2576-7160; e-mail:
srk@chem.iitb.ac.in
Abstract – A convergent synthesis of polycyclic aromatic compounds by the
application of Suzuki-Miyaura cross-coupling and Diels-Alder reaction as key
steps is described.
Functionalized polycyclic aromatic systems have found a variety of applications in chemical and
pharmaceutical sciences. Linearly fused polycyclic compounds are used as organic semiconductors and
luminescence materials. Highly substituted naphthalene derivatives are useful in designing organic
electronic materials.1 To functionalize aromatic systems, the Suzuki-Miyaura (SM) cross-coupling
reaction is the one of the efficient method.2 Now, we report a new strategy for assembling polycyclic
aromatic compounds via the application of the Diels-Alder (DA) reaction of highly functionalized sultine
derivatives which are generated via SM cross-coupling. The required sultine building block 3 for DA
reaction is prepared by using rongalite as a solfoxylate dianion equivalent.3 The detailed strategy is
shown in Figure 1.
Figure 1. Our strategy toward the synthesis of polycyclic compounds
R
R
R
R
I
I
O
S
O
S
O
O
1
2
3
†This paper is dedicated to Prof. Dr. Albert Eschenmoser on the occasion of his 85th birthday.

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HETEROCYCLES, Vol. 82, No. 2, 2011
Toward the synthesis of polycyclics, the known diiodosultine 33 was employed (Scheme 1). To this end,
compound 3 was prepared from readily available starting material such as o-xylene 4. Thus, treatment
of o-xylene 4 with periodic acid in presence of acetic acid and concentrated sulfuric acid afforded 1,2-
diiodo-4,5-dimethylbenzene as a white solid in 34% yield which was further subjected to radical
bromination reaction (side-chain bromination) using NBS in presence of catalytic amount of benzoyl
peroxide as a radical initiator to generate 1,2-diiodo-4,5-bis(bromomethyl)benzene 5 as a white solid in
73% yield (Scheme 1).3-5
1. H5IO6, AcOH, H2SO4,
5 h, 70 °C, 34%
SO2 Na+
-
Me
Me
I
I
I
I
HO
Br
Br
O
S
6
2. NBS, (Bz)2O2, CCl4,
73%.
TBAB, DMF, 0 °C-rt
6 h, 69%
O
4
5
3
Scheme 1. Synthesis of 5,6-diiodo-1,4-dihydro-2,3-benzoxathiin-3-oxide 3
Having the dibromo compound 5 in our hand, the next goal was to prepare sultine derivative 3. To this
end, dibromide 5 was reacted with rongalite 6 in presence of tetrabutylammonium bromide as
phase-transfer catalyst, and the desired diiodosultine 3 was obtained in 69% yield as a white solid. Next,
the diiodosultine 3 was subjected to SM cross-coupling with (Ph3P)4Pd and PEPPSI catalysts. Under the
examined conditions, however, no cross-coupling product was obtained. At higher temperature
(~80 °C) sultine derivatives rearrange to sulfone derivatives, and therefore, it is desirable to perform the
coupling reaction at lower temperature to avoid sulfone formation during the coupling sequence. Later,
we found that in the presence of a Buchwald ligand 78-9 (Figure 2) in combination with palladium catalyst
9 was suitable for the cross-coupling reaction. Treatment of the sultine derivative 3 with phenylboronic
acid 8a under the conditions gave the cross-coupling product 2a in 26% yield. Along similar lines,
3-(trifluoro-methyl)phenylboronic acid 8b furnished the cross-coupling product 2b in 31% yield (Scheme
2).5-7
PCy2
iPr
iPr
iPr
Figure 2. Electron-rich Buchwald ligand 7

HETEROCYCLES, Vol. 82, No. 2, 2011
1665
Ar B(HO)
2 , Pd2(dba)3,
I
I
Ar
Ar
8a-b
O
S
9
O
S

Na2CO3, THF, toluene, H2O, 60 C
O
O
3
7
2a, Ar = Ph, 26%
2b
, Ar = 3-CF3-Ph, 31%
Scheme 2. Synthesis of SM cross-coupling products 2a-b
The next task was the realization of the DA reaction with the sultine derivatives 2. In this regard, we
previously found that the DA reaction starting with various sulfone derivatives5 and dimethyl
acetylenedicarboxylate (DMAD) 10 under different conditions (toluene reflux and o-dichlorobenzene
reflux) failed to deliver the desired cycloadducts. Due to this reason we chose the sultine building block
2 which is expected to undergo DA reaction at lower temperature. Toward this goal, the coupling
product 2b was reacted with DMAD 10 under toluene reflux conditions to give the cycloadduct 11 as a
white solid in 67% yield.
Similarly, the sultine 2b was treated with another dienophile,
1,4-naphthaquinone 12 under the same reaction conditions to give the corresponding cycloadduct 13.
Later, the DA products 11 and 13 were directly subjected to aromatization sequence using DDQ. Thus,
treatment of DA adducts 11 and 13 with DDQ in refluxing toluene afforded the corresponding aromatized
compounds 1a-b in 78% and 41% respectively (Scheme 3).
Ar
Ar
CO2Me
Ar
CO2Me
Ar
Ar
DMAD 10, toluene,
DDQ, toluene
O
S
reflux, 30 h, 67%
reflux, 42 h, 78%
CO2Me
O
Ar
1a
CO2Me
O
O
2b
2b
11
13
Ar = 3-CF3-Ph
Ar
Ar
Ar
Ar
Ar
Ar
12
1,4-naphthaquinone
,
DDQ, toluene
O
S
reflux, 5 days,
two-steps 41%
toluene, reflux, 24 h
O
O
O
1b Ar = 3-CF3-Ph
Scheme 3. Synthesis of functionalized polycyclic aromatics 1a-b
We have demonstrated a convergent route for the synthesis of polycyclic compounds via SM
cross-coupling and DA reaction as key steps. Here, rongalite is used to prepare the required sultine
derivative.
EXPERIMENTAL PROCEDURE
Preparation of the cross-coupling product (2a)

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To a solution of diiodosultine 3 (50 mg, 0.12 mmol) in THF (2 mL) and toluene (2 mL) were added
phenylboronic acid 8a (75 mg, 0.6 mmol), phosphine-ligand 7 (6 mg, 0.01 mmol) under N2 and then a
solution of sodium carbonate (64 mg, 0.6 mmol) in H2O (2 mL) was added. The resultant mixture was
degassed for 15 min, and later tris(dibenzylideneacetone)dipalladium(0) 9 (2 mg, 0.001 mmol) was added.
Then, the reaction mixture was heated at 60 ºC for 15 h. At the completion of the reaction (TLC
monitoring), the reaction mixture was quenched with H2O (5 mL) and then extracted with EtOAc (3 × 10
mL), the organic layer was washed with aqueous sodium hydrogencarbonate solution (10 mL), dried over
anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude product
obtained was purified by column chromatography. Elution of the column with 6% EtOAc/petroleum
ether mixture gave 2a as a white solid (10 mg, 26%). mp 168-170 °C. IR (thin film): 3057, 3024,
2924, 1479, 1107, 1023, 763, 700 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.29 (s, 1H, ArH), 7.27 (s, 1H,
ArH), 7.20-7.22 (m, 6H, ArH), 7.09-7.12 (m, 4H, ArH), 5.41 (d, J = 13.5 Hz, 1H), 5.07 (d, J = 13.6 Hz,
1H), 4.46 (d, J = 15.5 Hz, 1H), 3.68 (d, J = 15.5 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 141.2, 140.5,
132.4, 132.1, 129.9, 129.8, 128.2, 127.8, 127.0, 124.9, 62.6, 56.3. HRMS (TOF MS ES+): m/z: (M+H)
calcd. for C20H17O2S: 321.0942; found: 321.0949.
Preparation of the cross-coupling product (2b)
To a solution of diiodosultine 3 (100 mg, 0.24 mmol) in THF (3 mL), toluene (3 mL) were added
3-(trifluoromethyl)phenylboronic acid 8b (213 mg, 1.14 mmol), phosphine-ligand 7 (10 mg, 0.02 mmol)
under N2 and then a solution of sodium carbonate (127 mg, 1.1 mmol) in H2O (1.5 mL) was added. The
resultant reaction mixture was degassed for 15 min, and later tris(dibenzylideneacetone)dipalladium(0) 9
(4 mg, 0.003 mmol) was added. Then, the reaction mixture was heated at 60 ºC for 15 h. At the
completion of the reaction (TLC monitoring), the reaction mixture was quenched with H2O (10 mL) and
then extracted with EtOAc (3  10 mL), washed with aqueous sodium hydrogencarbonate solution (15
mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude product
obtained was purified by column chromatography. Elution of the column with 6% EtOAc/petroleum
ether mixture gave 2b (33 mg, 31%) as a white solid. mp 120-122 °C. IR (thin film): 3004, 2924,
1537, 1454, 1275, 1260, 1021, 764, 749 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.51 (s, 1H, ArH), 7.49 (s,
1H, ArH), 7.35-7.31 (m, 6H, ArH), 7.25-7.22 (m, 2H, ArH), 5.43 (d, J = 14.0 Hz, 1H), 5.10 (d, J = 14.0
Hz, 1H), 4.45 (d, J = 15.5 Hz, 1H), 3.73 (d, J = 15.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 140.6,
139.6, 139.1, 133.3, 133.1, 132.1, 131.0, 130.7, 128.9, 127.7, 126.6, 126.0, 124.1, 62.3, 55.8. HRMS
(TOF MS ES+): m/z: (M+H) calcd. for C22H15O2F6S: 457.0697; found: 457.0693.
Preparation of the DA adduct (11)

HETEROCYCLES, Vol. 82, No. 2, 2011
1667
To a solution of the coupling product 2b (42 mg, 0.093 mmol) in dry toluene (10 mL) was added DMAD
10 (0.04 mL, 0.32 mmol) was added. Then, the reaction mixture was refluxed for 30 h under N2. At
the completion of the reaction (TLC monitoring), the solvent was removed at reduced pressure to deliver
the crude product which was purified by silica-gel column chromatography. Elution of the column with
10% EtOAc/petroleum ether mixture gave the desired cycloaddition product (33 mg, 67%) as a white
solid. 1H NMR (400 MHz, CDCl3): δ 8.33 (s, 1H, ArH), 8.01 (s, 1H, ArH), 7.55-7.46 (m, 2H, ArH),
7.34-7.29 (m, 6H, ArH), 3.85 (s, 6H, 2-OMe), 3.82 (s, 4H, 2-CH2). 13C NMR (100 MHz, CDCl3): δ
168.1 [C=O], 141.2, 138.0, 133.3, 133.1, 132.1, 130.5, 130.1, 129.6, 128.7, 126.7, 123.8, 52.7, 31.3.
The DA adduct was directly subjected to aromatization reaction without further purification.
To a solution of DA adduct 11 (30 mg, 0.057 mmol) in toluene (10 mL) was added DDQ (26 mg, 0.1
mmol) in small portions, and then refluxed for 42 h. At the completion of the reaction (TLC
monitoring), the reaction mixture was quenched with water, and extracted with EtOAc (3  10 mL).
The organic layer was washed with aqueous 2% KOH solution, water, brine and dried over anhydrous
Na2SO4, filtered. Evaporation of the solvent at reduced pressure gave the crude product which was
purified by silica-gel column chromatography. Elution with 10% EtOAc/petroleum ether mixture gave
the desired product 1a (24 mg, 78%) as a white solid. mp 148-150 ºC. IR (thin film): 3054, 2986,
1712, 1605, 1421, 1265, 896, 740 cm-1. 1H NMR (400 MHz, CDCl3): δ 8.33 (s, 2H, ArH), 8.01 (s, 2H,
ArH), 7.55-7.53 (m, 2H, ArH), 7.42-7.34 (m, 6H, ArH), 3.98 (s, 6H, 2-OMe). 13C NMR (100 MHz,
CDCl3): δ 168.0 [C=O], 140.7, 140.2, 133.2, 133.0, 131.0, 130.7, 130.4, 130.1, 129.6, 128.9, 126.8, 124.3,
53.0. HRMS (TOF MS ES+): m/z: (M+H) calcd. for C28H19O4F6: 533.1176; found: 533.1188.
Aromatization of the DA adduct (13)
To a solution of coupling product 2b (30 mg, 0.093 mmol) in dry toluene (10 mL) was added
1,4-naphthaquinone 12 (14.7 mg, 0.093 mmol). Then, the reaction mixture was refluxed for 24 h under
N2. At the completion of the reaction (TLC monitoring), the solvent was removed at reduced pressure to
deliver the crude cycloaddition product 13 as a yellow solid which was subjected to DDQ oxidation
without further purification.
To a solution of the DA adduct 13 (56 mg, 0.057 mmol) in dry toluene (10 mL) was added DDQ (26 mg,
0.1 mmol) in portionwise, and then the reaction mixture was refluxed for 5 days. At the completion of
the reaction (TLC monitoring), the reaction mixture was quenched with water, and extracted with EtOAc
(3  10 mL). The organic layer was washed with aqueous 2% KOH solution, water, brine and dried
over anhydrous Na2SO4, filtered. Evaporation of the solvent at reduced pressure gave the crude product
which was purified by silica-gel column chromatography. Elution with 10% EtOAc/petroleum ether
mixture gave the desired product 1b (41% two-steps) as a yellow solid. mp >260 °C. IR (thin film):

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HETEROCYCLES, Vol. 82, No. 2, 2011
3031, 1668, 1589, 1577, 715, 701 cm-1. 1H NMR (400 MHz, CDCl3): δ 8.95 (s, 2H, ArH), 8.44-8.41 (m,
2H, ArH), 8.20 (s, 2H, ArH), 7.87-7.85 (m, 2H, ArH), 7.58-7.56 (m, 2H, ArH), 7.44 (s, 2H, ArH),
7.42-7.34 (m, 4H, ArH). 13C NMR (100 MHz, CDCl3): δ 182.9 [C=O], 141.1, 140.6, 134.7, 134.6,
134.5, 133.1, 131.8, 130.8, 129.6, 129.0, 127.7, 126.8, 124.5, HRMS (TOF MS ES+): m/z: (M+H) calcd.
for C32H17O2F6: 547.1111; found: 547.1133.
ACKNOWLEDGEMENTS
We thank CSIR (New Delhi) for generous financial support of our research activities. We also thank to
SAIF Mumbai for recording the spectral data. Milind Meshram thank CSIR (New Delhi) for the award
of a research fellowship. SK thank DST for the award of JC Bose fellowship.
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