Palladium-catalyzed and KOtBu-promoted Caryl-O alcoholic coupling: An efficient one-pot synthesis of oxygen containing fused rings

Article abstract of DOI:10.1016/j.tetlet.2013.01.062

An efficient one-pot synthetic method has been developed for the synthesis of oxygen containing fused rings from 2′-bromo-biaryl-2-carbaldehyde via tandem reduction followed by palladium-catalyzed and KO^tBu-promoted C_aryl-O_alcoh

Full text of DOI:10.1016/j.tetlet.2013.01.062

Tetrahedron Letters 54 (2013) 1673–1676
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed and KOtBu-promoted Caryl–Oalcoholic coupling: an efficient
one-pot synthesis of oxygen containing fused rings
⇑
Atiur Ahmed, Shubhendu Dhara, Jayanta K. Ray
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot synthetic method has been developed for the synthesis of oxygen containing fused
rings from 20-bromo-biaryl-2-carbaldehyde via tandem reduction followed by palladium-catalyzed and
KOtBu-promoted Caryl–Oalcoholic coupling.
Received 28 November 2012
Revised 10 January 2013
Accepted 12 January 2013
Available online 21 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
6H-Benzo[c]chromene
Tandem reaction
KOtBu
Palladium catalyst
C
aryl–Oalcoholic coupling
Reduction
6H-Benzo[c]chromenes are one of the most important heterocy-
cles because they have been found in several natural products.1
Some important bioactive molecules with these moieties are pre-
sented in Figure 1.2 Now, 6H-benzo[c]chromene on PCC oxidation
will lead to the formation of benzopyranone3 which is a basic unit
of pharmacologically active natural products such as gilvocarcin V,
alternariol, coumestrol, and lamellarin D etc (Fig. 2).4 So it has
drawn our attention to develop a synthetic route for these com-
pounds, starting from simple materials.
OH
OH O
OH
O
O
O
JWH133
cannabinol
cannabinolic acid A
Figure 1. Bioactive molecules containing 6H-benzo[c]chromene moieties.
During the last decade, development of methods for carbon–
heteroatom bond formations by various transition metal catalyzed
cross-coupling has drawn the attention of researchers greatly.5
Among those most are associated with C–N bond formation pro-
cesses, however methods for aromatic C–O bond formations are
also developed.6–8 Aryl alkyl ethers can be synthesized by cop-
per-mediated classical Ullmann reaction.9,10 Buchwald has devel-
oped a methodology for Caryl–O bond formation using modified
Ullmann reaction.11 6H-Benzo[c]chromenes have been synthesized
by many research groups.12–14 Fagnou and co-workers have re-
ported the synthesis via direct arylation12 while Shen’s synthesis
involves the use of palladium-catalyzed intramolecular decarboxy-
lative coupling of arene carboxylic acids/esters with aryl bro-
mides.13 Shi and co-workers used transition metal catalyzed
direct functionalization of aromatic C–H bonds.14
Herein, we report a new efficient one-pot synthesis of 6H-benzo
[c]chromenes. Our strategy is based on Pd(0)-catalyzed and KOtBu-
mediated intramolecular Caryl–Oalcoholic coupling of reduced prod-
uct of 20-bromo-biaryl-2-carbaldehyde in which the reduction of
carbaldehyde and coupling were performed in one-pot. This meth-
odology is more demanding over other existing methodologies,
including low toxicity of boronic acid derivatives, high yields, short
reaction times, and simple materials.
The starting materials 3a–3g for the tandem reactions were pre-
pared by Suzuki–Miyaura cross-coupling15 by the treatment of
2-bromocarboxaldehydes 1a–1g with 2-bromophenylboronic acid
2 in the presence of Pd-catalyst, base, ligand, dry DMF, and heating
conditions (Scheme 1). To determine an optimal condition for the
cross-coupling reaction, 2-bromo-benzaldehyde was taken as the
standard substance. Then a thorough screening was performed
with different combinations of Pd-catalysts and bases (Table 1).
We got an optimal condition when substrate 1a (1 mmol) and 2
(1.2 mmol) were heated at 80 °C in the presence of Pd(OAc)2
(10 mol %), NaOAc (1.5 mmol), and PPh3 (0.25 mmol) in dry DMF
⇑
Corresponding author. Tel.: +91 3222283326; fax: +91 3222282252.
E-mail address: jkray@chem.iitkgp.ernet.in (J.K. Ray).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.062

1674
A. Ahmed et al. / Tetrahedron Letters 54 (2013) 1673–1676
HO
OMeOH
OH O
O
O
N
HO
MeO
MeO
OMe
O
O
O
Me
OH
OH
O
HO
O
O
Me
OH
OH
HO
OH
O
OH
MeO
lamellarin D
coumestrol
alternariol
gilvocarcin V
Figure 2. Pharmacologically active natural products containing benzopyranone moieties.
CHO
CHO
Br
Table 2
Synthesis of various 20-bromo-biaryl-2-carbaldehydes through Suzuki–Miyaura
cross-couplinga
(HO)2B
+
Pd-catalyst, base
Br
3a-3g
ligand, dry DMF
80oC, 3h, Ar
Br
1a-1g
Entry
Substrate
CHO
Product
CHO
Yield (%)
2
Scheme 1. Synthesis of 20-bromo-biaryl-2-carbaldehydes.
1
80
Br
3a
CHO
1a
Br
Table 1
Optimal condition determinationa,b for Suzuki–Miyaura cross-coupling
CHO
Br
2
3
4
5
6
7
78
80
76
79
74
75
CHO
CHO
1b
3b
3c
(HO)2B
+
Br
Pd-catalyst,base
Br
Br
Br
F
CHO
Br
CHO
ligand, dry DMF
80oC, 3h, Ar
F
Br
3a
1a
2
1c
Entry
Catalyst
Ligand
Base
Yieldc (%)
O2N
CHO
Br
CHO
O2N
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
PdCl2
—
Et3N
Et3N
78
75
80
72
75
55
72
68
PPh3
PPh3
PPh3
PPh3
PPh3
—
NaOAc
Na2CO3
Cs2CO3
K2CO3
NaOAc
NaOAc
1d
3d
Br
CHO
CHO
Br
Br
PPh3
1e
3e
a
CHO
CHO
Reagents and conditions: 1a (1 mmol), 2-bromophenylboronic acid (1.2 mmol),
Br
Br
Pd-catalyst (10 mol %), base (1.5 mmol), PPh3 (0.25 mmol), and dry DMF (6 mL)
heated at 80 °C for 3 h.
Br
Br
O
O
b
O
O
3f
CHO
1f
Two-necked round-bottomed flask fitted with condenser was used for reaction.
Yields refer to the isolated yields after purification through column
c
CHO
chromatography.
1g
3g
(6 mL) for 3 h with 80% isolated yield through column
chromatography.
a
Reagents and conditions: All the reactions were carried out under the following
conditions: 1a–1g (1 mmol), 2-bromophenylboronic acid (1.2 mmol), Pd(OAc)2
(10 mol %), NaOAc (1.5 mmol), PPh3 (0.25 mmol), and dry DMF (6 mL) heated at
80 °C for 3 h.
Now with this optimal condition in our hand we performed
cross-couplings with various 2-bromocarbaldehydes 1a–1g to get
3a–3g (Table 2). ortho-Bromonaphthalenecarboxaldehydes 1e–1g
were synthesized from b-tetralones in excellent yields through
Vilsmeier–Haack type reaction followed by DDQ oxidation.16
Compound 3a was taken as the standard substance for one-pot
synthesis of oxygen containing fused rings. At first, it was reduced
with NaBH4 (1.5 mmol) in dry CH3CN (6 mL) at room temperature
for 3 h under Ar atmosphere. Then the reaction mixture was al-
lowed to undergo coupling reaction without isolation of intermedi-
ate alcohol by the addition of KOtBu (2 mmol), Pd(OAc)2 (2 mol %),
and PPh3 (0.25 mmol) and then refluxed for 1 h (Scheme 2). A thor-
ough screening was performed after reduction with different
combinations of Pd-catalysts and bases (Table 3) and we got opti-
mal condition when the reduced product of 3a (1 mmol) was re-
fluxed for 1 h in the presence of Pd(PPh3)2Cl2 (2 mol %), and
KOtBu (2 mmol) with 90% isolated yield through column
chromatography.
CH2OH
CHO
Pd(OAc)2 (2 mol %)
KOtBu (2 mmol)
NaBH4 (1.5 mmol)
CH3CN (6 mL)
r.t. 3h, Ar
O
PPh3 (0.25 mmol)
reflux, 1h, Ar
Br
4a
Br
3a
5a
Scheme 2. Synthesis of oxygen containing fused rings in one-pot.
was –NO2 group, yield of the fused ring compound was dramati-
cally decreased.
From the above observations it can be concluded that the re-
duced products were unable to undergo coupling reactions with
different types of weak bases and various Pd-catalysts. Again, only
a trace amount of coupling product was obtained in the absence of
Pd-catalyst. The proposed mechanistic pathway for this type of
transformation is as per the literature report.17
Substrates 3a–3g were subjected to one-pot synthesis of fused
rings via tandem reduction followed by palladium-catalyzed and
KOtBu-promoted Caryl–Oalcoholic coupling under above optimal con-
dition (Table 4). It has been observed that when the substituent
6H-Benzo[c]chromene on PCC oxidation will lead to the forma-
tion of benzopyranone (Scheme 3).3

A. Ahmed et al. / Tetrahedron Letters 54 (2013) 1673–1676
1675
Table 3
Optimal condition determination for one-pot cyclization after reductiona,b
PCC
CH2Cl2, rt
92 %
CHO
O
O
CH2OH
Pd-catalyst (2 mol %)
base(2 mmol)
3a
NaBH4 (1.5 mmol)
O
6a
CH3CN (6 mL)
r.t. 3h, Ar
O
PPh3 (0.25 mmol)
reflux, 1h, Ar
Br
3a
Scheme 3. PCC oxidation of 6H-benzo[c]chromene.
Br
4a
5a
Entry
Catalyst
Ligand
Base
Yieldc (%)
promoted Caryl–Oalcoholic coupling 18,19 which upon further PCC oxi-
dation will lead to benzopyranones. Thus this methodology can
also be used for the synthesis of various types of chromene, chry-
sene, and benzopyranone based natural products.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Pd(OAc)2
PdCl2
Pd(OAc)2
PdCl2
PPh3
PPh3
PPh3
PPh3
—
—
—
—
—
—
—
—
—
PPh3
PPh3
—
KOtBu
KOtBu
NaOtBu
NaOtBu
KOtBu
NaOtBu
KOtBu
NaOtBu
K3PO4
Na2CO3
Cs2CO3
K2CO3
Et3N
88
85
87
82
90
88
82
80
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Trace
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
—
Acknowledgments
A.A. thanks UGC, New Delhi for fellowship and also CSIR and
DST (New Delhi) for the financial support.
Supplementary data
Na2CO3
K2CO3
KOtBu
Supplementary data (detailed experimental procedures and
spectral data for the compounds 3a, 4a and 5a–5g) associated with
this article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.01.062.
a
Reagents and conditions: (a) 3a (1 mmol), NaBH4 (1.5 mmol), CH3CN (6 mL), rt
reaction for 3 h under Ar. (b) Pd-catalyst (2 mol %), base (2 mmol), PPh3
(0.25 mmol) and refluxed for 1 h under Ar.
b
References and notes
Two-necked round-bottomed flask fitted with condenser was used for
reactions.
c
1. (a) Devlin, J. P. Can. J. Chem. 1975, 53, 343; (b) Devlin, J. P. Can. J. Chem. 1975, 53,
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Gaoni, Y.; Mechoulam, R. J. Am. Chem. Soc. 1971, 93, 217; (e) Bowd, A.; Swan, D.
A.; Turnbull, J. H. J. Chem. Soc., Chem. Commun. 1975, 797; (f) Kogan, N. M.;
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Yields refer to the isolated yields after purification through column
chromatography.
Table 4
One-pot synthesis of oxygen containing fused ringsa
Entry
1
Substrate
Product
Yield (%)
90
CHO
O
5a
3a
Br
CHO
O
6. (a) Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109; (b) Shelby, Q.;
Kataoka, N.; Mann, G.; Hartwig, J. J. Am. Chem. Soc. 2000, 122, 10718; (c) Parrish,
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8. Torraca, K. E.; Huang, X.; Parrish, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001,
123, 10770.
2
3
88
89
5b
3b
3c
Br
F
CHO
F
O
5c
Br
CHO
O2N
O2N
O
9. Ullmann, F. Chem. Ber. 1904, 37, 853.
10. General review: Lindley, J. Tetrahedron 1984, 40, 1433.
4
5
6
7
62
89
84
85
3d
5d
11. (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5499; (b)
Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428–2439; (c) Sawyer, J. S.
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7578–7584; (c) Campeau, L.-C.; Thansandote, P.; Fagnou, K. Org. Lett. 2005, 7,
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Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
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S.; Samanta, S.; Ray, J. K. Tetrahedron Lett. 2010, 51, 5605.
17. Amatore, C.; Jutand, A.; Suarez, A. J. Am. Chem. Soc. 1993, 115, 9532.
18. General procedure for the synthesis of oxygen containing fused rings: Substrates
3a–3h (1 mmol) and NaBH4 (1.5 mmol) were placed in a two-necked round-
bottomed flask fitted with condenser. After the addition of 6 mL CH3CN the
reaction mixture was allowed to react at rt for 3 h under Ar. Then the reaction
mixture was allowed to undergo coupling reaction without isolation of
intermediate alcohol by the addition of KOtBu (2 mmol), and Pd(PPh3)2Cl2
(2 mol %) and then refluxed for 1 h under Ar. It was allowed to cool to rt and
extracted with EtOAc (3 ꢀ 20 mL). Then the organic part was washed with
water and dried over anhydrous Na2SO4. Evaporation of the solvent gave crude
product which was then purified through column chromatography by using
silica gel (60–120 mesh) and pet ether/EtOAc (100:1) as eluent.
Br
CHO
O
5e
Br
3e
CHO
O
Br
Br
5f
3f
CHO
O
O
O
O
O
5g
3g
a
Reagents and conditions: (a) 3a–3g (1 mmol), NaBH4 (1.5 mmol), CH3CN (6 mL),
rt reaction for 3 h under Ar. (b) Pd(PPh3)2Cl2 (2 mol %), KOtBu (2 mmol) and refluxed
for 1 h under Ar.
In conclusion, we have developed a general methodology for the
synthesis of 6H-benzo[c]chromenes and 5H-6-oxa-chrysens via
tandem reduction followed by palladium-catalyzed and KOtBu-

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A. Ahmed et al. / Tetrahedron Letters 54 (2013) 1673–1676
19. Spectral data of representative compounds, 6H-benzo[c]chromene (5a): From 3a
(0.08 g, 1 mmol), NaBH4 (0.017 g, 1.5 mmol), KOtBu (2 mmol), and Pd(PPh3)2Cl2
(2 mol %) in CH3CN (6 mL) at rt to refluxing condition under Ar, product 5a was
obtained as colorless oil in 90% isolated yield (0.05 g) by column
chromatography. Rf = 0.4 (pet. ether/EtOAc = 100:1); 1H NMR (CDCl3,
200 MHz) d = 4.98 (2H, s), 6.86–7.02 (3H, m), 7.07–7.24 (3H, m), 7.54–7.62
(2H, m). 13C NMR (50 MHz in CDCl3) d = 68.6, 117.6, 122.2, 122.3, 123.1, 123.5,
124.8, 127.8, 128.6, 129.6, 130.3, 131.6, 155.0; Elemental analysis: found C,
85.60; H, 5.66. C13H10 requires C, 85.69; H, 5.53.