Palladium mediated bis- and tris-biaryl Heck coupling for the synthesis of heterocycles

Article abstract of DOI:10.1016/j.tetlet.2008.03.118

A simple and straightforward palladium mediated ligand free bis- and tris-biaryl coupling on an unactivated phenylbenzyl ether system to produce hitherto unreported heterocyclic compound is described.

Full text of DOI:10.1016/j.tetlet.2008.03.118

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Tetrahedron Letters 49 (2008) 3419–3422
Palladium mediated bis- and tris-biaryl Heck
coupling for the synthesis of heterocycles
K. C. Majumdar *, S. Chakravorty, N. De
Department of Chemistry, University of Kalyani, Kalyani 741 235, W.B., India
Received 31 January 2008; revised 19 March 2008; accepted 24 March 2008
Available online 28 March 2008
Abstract
A simple and straightforward palladium mediated ligand free bis- and tris-biaryl coupling on an unactivated phenylbenzyl ether
system to produce hitherto unreported heterocyclic compound is described.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Biaryl-coupling; Heck cyclization; Palladium acetate; 2-Bromobenzyl bromide
Recognizing the need for efficient routes to biaryl
compounds, organic chemists have developed an arsenal
Br
of catalytic methods including the Suzuki–Miyaura,
Negishi, Kumada–Corriu, and Hiyama couplings.1,2 The
O
1
direct arylation of electron rich, heteroaromatic rings
has begun to replace these more traditional techniques
in specific case.3–6 In contrast to these advances, the
direct arylation of simple aromatic rings remains a signif-
icant challenge.7–11 The aryl–aryl linkage is found in a
wide range of compounds, from natural products such
as vancomycin12 and aporphine alkaloids13 to important
synthetic compounds such as 1,10-bi-2-naphthol14 and
BINAP.15 Intramolecular aryl–aryl coupling reactions
involving a palladium reagent have been used to synthe-
size many condensed aromatic compounds.16–20 Recently,
we reported the synthesis of condensed heteroaromatic
compounds using biaryl-coupling reactions with palla-
dium reagents.21–23 Phenolates have been shown to
exhibit enhanced reactivity in intramolecular arylation
reactions.24 On the other hand, ethers such as 1, that
lack a phenolate-activating group react poorly and give
mainly the debrominated product.25
Fagnou et al. improved26 the yield of the cyclized prod-
uct by using Pearlman’s catalyst Pd(OH)2/C. Though this
is a heterogeneous system, the actual catalytically active
species is believed to be a soluble Pd derivative. But in this
case, the reaction took sufficiently long time for comple-
tion. They were also able to achieve much better yield of
the cyclized product (above 90%) by using N-heterocyclic
carbene27 and 2-(diphenylphosphino)-2-(N,N-dimethyl-
amino)biphenyl28 as a ligand with Pd(OAc)2 as a catalyst.
Here we report a simple, expedient, and straightforward
ligand free Heck coupling process for bis- and tris-biaryl
coupling.
The Heck precursors 4a–d required for our present
study were synthesized in 80–90% yields by refluxing
resorcinol 2, m-aminophenol 5, and 2,7-dihydroxyna-
phthalene 6 with either 2-bromobenzyl bromide 3a or
2-bromo-3-methoxybenzyl bromide 3b in dry acetone in
the presence of anhydrous potassium carbonate and a
small amount of sodium iodide (Finkelstein conditions)
(Scheme 1).
*
Corresponding author. Tel.: +91 33 2582 7521; fax: +91 33 2582 8282.
E-mail address: kcm_ku@yahoo.co.in (K. C. Majumdar).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.118

3420
K. C. Majumdar et al. / Tetrahedron Letters 49 (2008) 3419–3422
Br
Br
Br
Br
O
O
3a
i
(yield 83%)
4a
R
R
i
HO
OH
Br
2
Br
Br
Br
3b
O
O
OCH3
4b, R= OCH3 (yield 85%)
Reagents and condition: i. dry acetone, anhydrous K2CO3,
NaI, reflux.
Br
Br
Br
Br
O
N
HO
NH2
i
H
5
4c (yield 80%)
Reagents and condition: i. dry acetone, anhydrous K2CO3,
NaI, reflux.
Br
Br
Br
Br
i
HO
OH
O
O
(yield 86%)
4d
6
Reagents and condition: i. dry acetone, anhydrous K2CO3,
NaI, reflux.
Scheme 1.
Precursor 4a, when subjected to intramolecular Heck
reaction in the presence of 10 mol % of Pd(OAc)2 as cata-
lyst KOAc as base and tetrabutylammonium bromide as
promoter in DMF at about 100 °C, afforded linearly fused
bis-cyclized product 8a (Table 1) in 75% yield along with
10% of the monocyclized product. Increasing, the reaction
Table 1
Results are summarized below
Entry
Precursor
Time (h)
Product
Yield (%)
75
Br
Br
1
4
O
O
O
O
O
8a
4a
R
R
H3CO
OCH3
Br
Br
Br
Br
2
3
5
80
77
O
O
O
O
8b
4b, R= OCH3
3.6
N
H
O
N
H
4c
8c

K. C. Majumdar et al. / Tetrahedron Letters 49 (2008) 3419–3422
3421
Yield (%)
70
Table 1 (continued)
Entry
Precursor
Time (h)
Product
Br
Br
4
4
O
O
O
O
4d
8d
Br
O
O
Br
5
4.2
75
O
O
O
O
4e
8e
Br
Br
H3CO
OCH3
O
OCH3
O
Br
O
O
OCH3
6
4
85
O
O
H3CO
8f 29, 30
Br
OCH3
4f 27, 28
temperature did not improve the yield of the bis-cyclized
product. The use of Pd(PPh3)2Cl2 or PdCl2 as catalyst
did not improve the yield of the bis-cyclized product.
Among several aprotic polar solvents examined DMF gave
the highest yield of the product, while DMSO and CH3CN
were found to give lower yields of the products. The effect
of the base was also examined and KOAc was found to be
superior to NEt3 and Cs2CO3. Substrates 4b and 4c, under
the similar conditions gave the corresponding bis-cyclized
product. However, substrate 4d, under similar conditions
gave the bis-cyclized 8d.
Phloroglucinol (1,3,5-trihydroxybenzene), on reaction
with 2-bromobenzyl bromide or 2-bromo-3-methoxy-
benzyl bromide in the presence of acetone, K2CO3, and
NaI gave the 1,3,5-tribenzylated products 4e and 4f
(Scheme 2).
Tribenzylated 4e, when subjected to intramolecular
Heck reaction with 10 mol % of Pd(OAc)2 as catalyst
KOAc as base and TBAB as promoter in DMF at
120 °C gave the tris-cyclized product 8e (Table 1) in 75%
yield in about 4 h. The use of the low boiling solvent
CH3CN did not lead to any tris-cyclized product, instead
the corresponding monocyclized product was obtained.
The reaction temperature plays an important role in the
formation of the tris-cyclized product, on decreasing the
temperature, the yield of tris-cyclized product decreases.
Substrate 4f29,30 gave the corresponding tris-cyclized
product 8f31,32 under similar conditions (Table 1). Usually,
ligand such as PPh3, (o-tolyl)3P is necessary33–36 for
carrying out this type of palladium mediated biaryl Heck
Coupling. However, no ligand was needed for the reactions
reported here.
Br
R
O
OH
Br
R
O
R
O
i
HO
OH
Br
(yield 84%)
4e, R = H
4f, R = OCH3
(yield 90%)
Scheme 2. Reagents and condition: (i) 2-bromobenzyl bromide or 2-bromo-5-methoxybenzyl bromide, dry acetone, anhydrous K2CO3, NaI, reflux.

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K. C. Majumdar et al. / Tetrahedron Letters 49 (2008) 3419–3422
21. Majumdar, K. C.; Pal, A. K.; Taher, A.; Debnath, P. Synthesis 2007,
In conclusion, we have developed a ligand free Heck
1707.
based approach for bis- and tris-biary coupling of unacti-
vated phenylaryl ethers for the regioselective synthesis of
heterocyclic compounds.
22. Majumdar, K. C.; Chattopadhaya, B.; Nath, S. Tetrahedron Lett.
2008, 49, 1609.
23. Majumdar, K. C.; Chattopadhaya, B.; Ray, K. Tetrahedron Lett.
2007, 48, 7633.
24. Hennings, D. D.; Iwasa, S.; Rawal, V. H. J. Org. Chem. 1997, 62, 2.
25. Ames, D. E.; Opalko, A. Tetrahedron 1984, 40, 1919.
26. Parisien, M.; Valette, D.; Fagnou, K. J. Org. Chem. 2005, 70,
7578.
27. Campeau, L.-C.; Thansandote, P.; Fagnou, K. Org. Lett. 2005, 7,
1857.
Acknowledgments
We thank the CSIR (New Delhi) and the DST (New
Delhi) for financial assistance. One of us (S.C.) is thankful
to the CSIR (New Delhi) and (N.D.) is grateful to UGC
(New Delhi) for fellowships.
28. Campeau, L.-C.; Parisien, M.; Leblanc, M.; Fagnou, K. J. Am. Chem.
Soc. 2004, 126, 9186.
29. A mixture of 1,3,5-trihydroxybenzene (1 mmol), 2-bromo-3-methoxy-
benzyl bromide (3.2 mmol), anhydrous K2CO3 (1 g), and NaI (cat.
amount) was refluxed in dry acetone (75 mL) for 16 h. The reaction
mixture was cooled, filtered, and the solvent was removed. The
residual mass was extracted with CH2Cl2 (3 ꢀ 25 mL). The CH2Cl2
extract was washed with water (3 ꢀ 10 mL) and dried (Na2SO4). The
solvent was removed and the residual mass was purified by column
chromatography over silica gel using petroleum ether–ethyl acetate
(9:1) as eluent to afford compound 4f.
References and notes
1. Metal-catalyzed Cross-coupling Reactions; Diedrich, F., Stang, P. J.,
Eds.; Wiley-VCH: New York, 1998.
2. Hassa, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
Rev. 2002, 102, 1359.
3. Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 5274.
4. Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan,
V. Org. Lett. 2004, 6, 1159.
5. Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J. Org. Lett. 2003, 5,
301.
6. Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc.
2002, 124, 5286.
7. Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E.
Angew. Chem., Int. Ed. 2003, 42, 112.
8. Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem.,
Int. Ed. 1997, 36, 1740.
9. Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai, S. J. Am. Chem.
Soc. 2003, 125, 1698.
10. Kametani, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett.
2000, 41, 2655.
11. Oi, S.; Fukita, S.; Inoue, Y. Chem. Commun. 1998, 2439.
12. Rama Rao, A. V.; Gurjar, M. K.; Reddy, L.; Srinivasa Rao, A. Chem.
Rev. 1995, 95, 2135.
13. The Alkaloids; Brossi, A., Ed.; Academic Press: Orlando, 1985; Vol.
24.
14. Rosini, C.; Franzini, L.; Raffaelli, A.; Salvadori, P. Synthesis 1992,
503.
30. Compound 4f: White solid, mp 121–122 °C, yield 90%. IR (KBr):
m
max = 1617, 1596 cmꢁ1 1H NMR (400 MHz, CDCl3): dH = 3.8 (s,
;
9H), 5.05 (s, 6H), 6.31 (s, 3H), 6.74 (dd, 3H, J = 2.9 Hz, 8.72 Hz), 7.11
(d, 3H, J = 2.9 Hz), 7.45 (d, 3H, J = 8.72) ppm. MS (m/z) = 720
(M+), 722 (M++2), 724 (M++4). Anal. Calcd for C30H27Br3O6; C,
49.82; H, 3.76. Found C, 50.00; H, 3.82.
31. A mixture of 4f (100 mg, 0.138 mmol), TBAB (112 mg, 0.34 mmol),
KOAc (20 mg, 0.21 mmol), Pd(OAc)2 (3.1 mg, 1.4 ꢀ 10ꢁ2 mmol) in
dry DMF (5 mL) was heated at 100 °C for 4 h. After completion, the
reaction mixture was poured into water (25 mL) and extracted with
CH2Cl2 (3 ꢀ 15 mL). The CH2Cl2 extract was washed with water
(3 ꢀ 10 mL) and dried (Na2SO4). The solvent was removed and the
residual mass was purified by column chromatography over silica
gel using petroleum ether–ethyl acetate as eluent (9:1) to afford
compound 8f.
32. Compound 8f: White solid, mp 171–172 °C yield 85%. IR (KBr):
m
max = 2833, 1612 cmꢁ1 1H NMR (400 MHz, CDCl3): 3.85 (s, 9H),
;
5.07 (s, 6H), 6.75 (d, 3H, J = 2.6 Hz), 6.91 (dd, 3H, J = 2.7 Hz,
8.8 Hz), 8.19 (d, 3H, J = 8.8 Hz), ppm. 13C NMR (125 MHz, CDCl3):
158.69, 152.47, 133.18, 128.56, 122.13, 113.78, 110.27, 108.50, 69.46,
55.78. HRMS: m/z calcd for C30H24O6 [M+H]+: 481.1646; found:
481.1641. Anal. Calcd for C30H24O6; C, 74.99; H, 5.03. Found: C,
75.09; H, 5.08.
15. Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345.
16. Tsuji, J. Palladium Reagents and Catalyts; John Wiley & Sons: New
York, 2004; pp 176–201.
17. Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry;
Pergamon: Oxford, 2000.
18. Dyker, G. Chem. Ber. 1997, 130, 1567.
19. Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
Rev. 2002, 102, 1359;.
33. Christoph, G.; Buchwald, S. L. Chem. Eur. J. 1999, 5, 3107.
34. Bumagin, N. A.; Bykov, V. V.; Sukhomlinova, L. I.; Tolstaya, T. P.;
Beletskaya, I. P. Organomet. Chem. 1995, 486, 259.
35. Bumagin, N. A.; More, P. G.; Beletskaya, I. P. J. Organomet. Chem.
1989, 371, 397.
20. Echavarren, A. M.; Gomez-Lor, B.; Gonzalez, J.; de Frutos, O.
Synlett 2003, 585.
36. Moreno-Manas, M.; Pleixats, R.; Roglans, A. Synlett 1997,
1157.