Aerobic ligand-free domino Suzuki coupling - Michael addition reaction catalyzed by in situ generated palladium nanoparticles in water: A general method for the synthesis of benzo[c]chromene derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.12.005

A general method has been developed for the synthesis of benzo[c]chromene derivatives via aerobic ligand-free domino Suzuki coupling and Michael addition reaction catalyzed by in situ generated palladium nanoparticles in water leading to C-C and C-O bond

Full text of DOI:10.1016/j.tetlet.2012.12.005

Tetrahedron Letters 54 (2013) 665–668
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Aerobic ligand-free domino Suzuki coupling—Michael addition reaction
catalyzed by in situ generated palladium nanoparticles in water: a general
method for the synthesis of benzo[c]chromene derivatives
⇑
Atiur Ahmed, Yasin Nuree, 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:
A general method has been developed for the synthesis of benzo[c]chromene derivatives via aerobic
ligand-free domino Suzuki coupling and Michael addition reaction catalyzed by in situ generated palla-
dium nanoparticles in water leading to C–C and C–O bond formations simultaneously.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 26 September 2012
Revised 29 November 2012
Accepted 1 December 2012
Available online 7 December 2012
Keywords:
Benzo[c]chromene
Domino reaction
Suzuki coupling
Michael addition
Palladium nanoparticles
Wittig reaction
Benzo[c]chromenes are very important oxygen containing het-
erocycles because of their presence in a large number of bioactive
molecules as a key structural subunits.1 Figure 1 represents some
important bioactive molecules containing these moieties.2 Utility
of benzo[c]chromenes in photochemical reactions as photoswitch-
es is important.3 For example, 5H-dibenzo[c,g]chromen-3-ol shows
biological activity as an estrogen receptor agonist.4 So develop-
ment of a general route for the synthesis of benzo[c]chromene
skeletons by using readily available starting materials has attracted
researchers over past decades.
atives via domino Suzuki coupling6 followed by intramolecular
Michael addition reaction in water catalysis by metal nanoparticles
that has proven its novelty toward cross coupling since last few
years.7 Recently Liang and his co-workers synthesized these by
palladium-catalyzed annulations of arynes with 2-(2-idophen-
oxy)-1-arylethanones8 and Ferraccioli and co-workers by
palladium- and nobornene-catalyzed reaction of aryl halides, o-
substituted with electron releasing substituents, o-bromophenols,
and activated alkenes,9 Satyanarayana and co-workers by a dom-
ino palladium-catalyzed C–C and C–O bonds formation via dual
O–H bond activation10 and very recently Xu and co-workers by
Palladium catalyst has proven its novelty and versatility toward
the synthesis of fused-heterocycles via C–C bond formation.5 In
continuation of our work on palladium chemistry, we have devel-
oped a methodology for the synthesis of benzo[c]chromene deriv-
palladium-catalyzed tandem reactions of b-(2-bromophenyl)-a,b-
unsaturated carbonyl compounds with 2-hydroxyphenylboronic
acid.4
OH
OH O
OH
O
O
O
O
Cannabinol
Cannabinolic acid A
JWH133
JWH359
Figure 1. Bioactive molecules containing benzo[c]chromene moieties.
⇑
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 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.005

666
A. Ahmed et al. / Tetrahedron Letters 54 (2013) 665–668
Table 2
O
Synthesis of various benzo[c]chromene derivativesa
(1.5eq)
Ph3P
CHO
Br
2
O
O
O
O
DCM, 0 °C-r.t, 3h
Br
75-90 %
HO
Pd(OAc)2, K3PO4
3a-3h
1a-1h
+
TBAB, water
100 °C, 3h
(HO)2B
Br
Scheme 1. Wittig reaction with 2-bromocarboxaldehydes.
3a-3h
4
5a-5h
O
O
O
Entry
Substrate
Product
Yieldb (%)
Br
HO
(HO)2B
Pd(PPh3)4
+
O
O
K3PO4, water
100 oC,3h
80%
3a
O
4
5a
1
90
Br
Scheme 2. Synthesis of benzo[c]chromene derivative.
5a
3a
O
O
Table 1
O
Optimal condition determinationa,b
2
3
4
87
72
78
O
Br
O
O
O
3b
Br
5b
O
O
Br
(HO)2B
catalyst,base
O
O
+
ligand, water
HO
3a
TBAB
4
5a
5c
3c
O
O
Entry
Catalyst
Ligand
Base
Temp (°C)
Yieldc (%)
O
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(OAc)2
PdCl2
—
PPh3
—
—
—
—
—
—
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
Na2CO3
K2CO3
K3PO4
100
100
100
90
100
100
100
90
80
82
90
88
75
55
52
82
Br
5d
3d
O
O
5
6
74
82
O
Br
5e
a
3e
Reagents and conditions: 3a (1 mmol), 2-hydroxyphenylboronic acid
(1.6 mmol),catalyst (10 mol %), base (4 mmol), TBAB (0.5 mmol), and water (6 mL)
heated at 100 °C for 3 h.
Reaction was done in
condenser.
O
O
b
a
two-necked round-bottomed flask fitted with
F
F
O
c
Yields refer to the isolated yields after purification through column
chromatography.
Br
5f
3f
O
O
Herein, we report aerobic ligand-free in situ generated
palladium nanoparticles catalyzed a general methodology for the
synthesis of substituted benzo[c]chromenes by the treatment of
O
O
O
O
7
8
76
78
O
Br
2-hydroxyphenylboronic acid with b-(2-bromoaryl)-a,b-unsatu-
3g
5g
rated carbonyl compounds where C–C followed by C–O bonds are
formed simultaneously in a domino Suzuki coupling followed by
Michael addition fashion in water.
The starting materials for the domino reactions were prepared
by the Wittig reaction. Wittig products 3a–3h were synthesized
in 75–90% by the treatment of 1-(triphenylphosphoranylidene)-
2-propanone 2 with 2-bromocarboxaldehydes 1a–1h in dry DCM
at 0 °C to rt for 3 h (Scheme 1).11
O
Br
O
O
5h
3h
a
Reagents and conditions: all the reactions were carried out under the following
conditions: substrates 3a–3h (1 mmol), 2-hydroxyphenylboronic acid (1.6 mmol),
Pd(OAc)2 (10 mol %), TBAB (0.5 mmol), K3PO4 (4 mmol), water (6 mL) at 100 °C,
reaction time 3 h.
Initially precursor 3a on domino reaction with 2-hydrox-
yphenylboronic acid 4 in the presence of Pd(PPh3)4 catalyst,
K3PO4 as base, and TBAB in water at 100 °C for 3 h yielded
b
Yields were determined after purification through column chromatography.

A. Ahmed et al. / Tetrahedron Letters 54 (2013) 665–668
667
OK+
(HO)2B
O
HO
(HO)2B
O
K3PO4
O
+
Br
(HO)2B
Br
4
3a
Scheme 3. Reaction without Pd catalyst.
benzo[c]chromene derivative 5a in 80% (Scheme 2) where K3PO4
was used as base and stabilizer and TBAB as stabilizer for the pal-
ladium nanoparticles.12,13
observed probably because of steric crowding between bulky
groups (Scheme 3).
From the above observation we can conclude that the
cyclization was completed through Suzuki coupling12 followed
by intramolecular Michael addition reaction (Scheme 4) where 2-
hydroxyphenylboronic acid itself was acting as a reducing agent.15
It was also confirmed by performing blank test stirring a solution
of 2-hydroxyphenylboronic acid with Pd(OAc)2 in water without
adding TBAB, PPh3, and b-(2-bromoaryl)-a,b-unsaturated carbonyl
compound, when the solution turned black immediately indicating
the generation of Pd(0).
The intermediate 6 could never be isolated because of the close
proximity of OÀ ion and b-carbon of unsaturated part and then
intramolecular Michael addition followed immediately after Suzu-
ki coupling.
To get the optimal condition for the synthesis of benzo[c]chro-
mene derivatives in domino fashion a thorough screening with dif-
ferent combinations of Pd catalysts, bases, and temperatures was
examined (Table 1) and we found optimal condition when sub-
strate 3a (1 mmol) and 4 (1.6 mmol) were heated at 100 °C in
the presence of Pd(OAc)2 (10 mol %) and K3PO4 (4 mmol) and TBAB
(0.5 mmol) in water (6 mL) for 3 h with 90% isolated yield and it
was obvious that the reaction was faster and high yielding in the
absence of PPh3.
Keeping the optimal condition in hand this methodology was
successfully applied on various substrates (3a–3h) (Table 2) syn-
thesized from corresponding 2-bromocarboxaldehydes (1a–1h).
Ortho-bromonaphthalenecarboxaldehydes were synthesized from
their corresponding tetralone derivatives in an excellent yield by
using the Vilsmeier–Haack type reaction followed by DDQ oxida-
tion14 to get 1a–1c and 1h.
Several benzo[c]chromene derivatives (5a–5h) were synthe-
sized from 3a–3h with 2-hydroxyphenylboronic acid (4) through
domino Suzuki coupling and intramolecular Michael addition reac-
tion under the optimized condition (Table 2) where cross coupling
was taking place by in situ generated Pd-nanoparticles.12 It was
being observed that substrates 3a–3b from their corresponding
b-tetralones were more reactive and high yielding than others
probably because of transmetalation with less hindered C–Br
bonds that occurred easily, and again peri steric effect between
the unsaturated part and H at C8 made the cross coupled interme-
diates more unstable leading to faster Michael addition reaction.
Next our target was to determine the right sequence for cycliza-
tion and for that we heated 3a with 2-hydroxyphenylboronic acid
4 without Pd catalyst by keeping all others intact. No reaction was
In conclusion we have developed a general methodology16 for
the synthesis of benzo[c] chromene derivatives via ligand-free
domino Suzuki coupling and Michael addition catalyzed by
in situ generated palladium nanoparticles in water by using
2-hydroxyphenylboronic acid starting from 2-bromocarboxaldehy-
des. This is also helpful for the synthesis of benzo[c]chromene con-
taining natural products.
Acknowledgments
A.A. thanks UGC, New Delhi for fellowship and also to D.S.T. for
financial support for the project and creating 400 MHz NMR facility
under the IRPHA programme.
Supplementary data
Supplementary data (experimental procedures and spectral
data for the compounds 3d and 5a–5h) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.12.005.
PdII
OH
K
O
COMe
References and notes
Intramolecular
Michael
+ K3PO4
COMe
B(OH)2
Br
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addition
O
Pd 0
6
COMe
5d
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Pat. CNS Drug Discovery 2009, 4, 118.
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6. (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 3437; (b)
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
COMe
COMe
OK
PdII
BrPdII
7. (a) Roucoux, A.; Schulz, J.; Patin, H. Chem. Rev. 2002, 102, 3757–3778; (b)
Astruc, D.; Lu, F.; Aranzaes, J. R. Angew. Chem., Int. Ed. 2005, 44, 7852–7872; (c)
Astruc, D. Inorg. Chem. 2007, 46, 1884–1894.
8. Li, R. J.; Pi, S. F.; Liang, Y.; Wang, Z. Q.; Song, R. J.; Chen, G. X.; Li, J. H. Chem.
Commun. 2010, 46, 8183.
OH
+ K3PO4
B(OH)2
9. Motti, E.; Faccini, F.; Ferrari, I.; Catellani, M.; Ferraccioli, R. Org. Lett. 2006, 8,
3967.
10. Mahendar, L.; Krishna, J.; Reddy, A. G. K.; Ramulu, B. V.; Satyanarayana, G. Org.
Lett. 2012, 14, 628.
Scheme 4. A plausible mechanism for the synthesis of substituted
benzo[c]chromenes.

668
A. Ahmed et al. / Tetrahedron Letters 54 (2013) 665–668
11. Paul, S.; Gorai, T.; Koley, A.; Ray, J. K. Tetrahedron Lett. 2011, 52, 4055.
12. Saha, D.; Chattopadhyay, K.; Ranu, B. C. Tetrahedron Lett. 2009, 50, 1003–1006.
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as eluent.
Spectral data of representative compounds, 1-(5H-6-oxa-chrysen-5-yl)-propan-2-
one (5a): From 3a (0.05 g, 1 mmol), 2-bromophenylboronic acid 4 (0.04 g,
1.6 mmol), TBAB (0.5 mmol), K3PO4 (4 mmol), and Pd(OAc)2 (10 mol %) in
water (6 mL) at 100 °C for 3 h, product 5a was obtained as yellow solid in 90%
isolated yield (0.047 g); mp 118–120 °C; 1H NMR (CDCl3, 400 MHz) d = 2.23
(3H, s), 2.49 (1H, dd, J1 = 2.0 Hz, J2 = 16.0 Hz), 3.27 (1H, dd, J1 = 10.4 Hz,
J2 = 16.0 Hz), 6.63(1H, dd, J1 = 2.0 Hz, J2 = 10.4 Hz), 7.02 (1H, t, J = 8.0 Hz), 7.12
(1H, t, J = 7.2 Hz), 7.27–7.31 (1H, m), 7.50 (1H, t, J = 7.4 Hz), 7.58 (1H, t,
J = 7.4 Hz), 7.82–7.92 (5H, m). 13C NMR (50 MHz in CDCl3) d = 31.4, 46.6, 71.1,
118.4, 120.5, 122.3, 122.5 (2C), 123.7, 126.2, 126.3, 127.5, 128.0, 128.7, 129.0,
129.1, 130.1, 133.3, 151.4, 206.3; Elemental analysis: found: C: 83.18; H: 5.69.
15. Han, W.; Liu, C.; Jin, Z. Adv. Synth. Catal. 2008, 350, 501–508.
16. General procedure for the synthesis of benzo[c]chromene derivatives: Substrate
3a–3h (1 mmol), 2-hydroxyphenylboronic acid 4 (1.6 mmol), TBAB (0.5 mmol),
K3PO4 (4 mmol), and Pd(OAc)2 (10 mol %) were placed in a two-necked round-
bottomed flask fitted with condenser. After the addition of 6 mL of water the
reaction mixture was heated at 100 °C for 3 h to complete the reaction. Then it
was allowed to cool to rt and extracted with EtOAc (3 Â 20 mL). Then the
organic part was dried over anhydrous Na2SO4 and concentrated in vacuum to
get the crude product which was then purified through column
chromatography by using silica gel (60–120 mesh) and pet ether:EtOAc (5:1)
C
20H16O2 requires C: 83.31; H: 5.59. HRMS (ESI, 70 eV): m/z = 311.1048
[M++Na] (calcd mass for C20H16O2Na: 311.1048 [M++Na]).