Intramolecular heck reaction on bromobenzyloxy-substituted chromenes: Formation of chelated ketones

Article abstract of DOI:10.1080/00397911.2012.655358

Heck reaction on 2-bromobenzyloxy-substituted 4H-chromene derivatives using Pd(OAc)2 in Aliquat 336 and N,N-dimethylformamide mixture leads to intramolecular heteroannulation along with hydrolysis, affording chelated 6H-benzo[c]chromen-2-yl ketones. The m

Full text of DOI:10.1080/00397911.2012.655358

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Intramolecular Heck Reaction
on Bromobenzyloxy-Substituted
Chromenes: Formation of Chelated
Ketones
Amarendra Patra a & Tanusri Mahapatra a
a Department of Chemistry, University of Calcutta, University
College of Science and Technology, Calcutta, India
Accepted author version posted online: 17 May 2012.Version of
record first published: 06 Mar 2013.
To cite this article: Amarendra Patra & Tanusri Mahapatra (2013): Intramolecular Heck Reaction on
Bromobenzyloxy-Substituted Chromenes: Formation of Chelated Ketones, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:11, 1602-1609
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Synthetic Communications1, 43: 1602–1609, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.655358
INTRAMOLECULAR HECK REACTION ON
BROMOBENZYLOXY-SUBSTITUTED CHROMENES:
FORMATION OF CHELATED KETONES
Amarendra Patra and Tanusri Mahapatra
Department of Chemistry, University of Calcutta, University College of
Science and Technology, Calcutta, India
GRAPHICAL ABSTRACT
Abstract Heck reaction on 2-bromobenzyloxy-substituted 4H-chromene derivatives using
Pd(OAc)2 in Aliquat 336 and N,N-dimethylformamide mixture leads to intramolecular
heteroannulation along with hydrolysis, affording chelated 6H-benzo[c]chromen-2-yl
ketones. The method offers Pd(0)-catalysis and regioselectivity in product formation.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Aliquat 336; chelated ketones; intramolecular Heck cyclization; Pd(0) catalysis
INTRODUCTION
In recent days, ligandless Heck reaction in ionic liquid (IL) catalyzed by simple cat-
alysts such as PdCl2 or Pd(OAc)2 has been widely studied and found to be preparatively
significant for the formation of C-C bonds in a variety of organic compounds.[1–10] Its
intramolecular version undoubtedly becomes an efficacious methodology for the syn-
thesis of annulated heterocycles. In this context, it is worth noting that though somewhat
extensive work has been performed on ligand-demanding intramolecular processes,[11–21]
reported data on ligandless intramolecular processes is scanty and still there is much
more left to do.[22–25] The intramolecular version of the Heck reaction promoted in ionic
liquid is our prime interest for the construction of annulated heterocycles.
Received November 15, 2011.
Address correspondence to Amarendra Patra, Department of Chemistry, University of Calcutta,
University College of Science and Technology, 92 Acharya Prafulla Chandra Road, Calcutta 700009,
India. E-mail: amarendra.patra@gmail.com
1602

REGIOSELECTIVE FORMATION OF CHELATED KETONES
1603
Figure 1. 6H-Benzo[c]chromene derivatives.
4H-Chromene derivatives have been found to exhibit important biological and
pharmacological activities.[26–30] With the thought that further heteroannulation
may diversify their potential biological and pharmacological behavior, we opted
for the synthesis of 6H-benzo[c]chromene derivatives (Fig. 1). Herein we report
the results of our study of Pd(0)-catalyzed ligand-free Heck cyclization on
7-hydroxy-4H-chromene derivatives in IL Aliquat 336.[31–36]
RESULTS AND DISCUSSION
We used newly synthesized 7-(2-bromobenzyloxy)-4H-chromene derivatives
2a–e as starting materials, which were produced via the classical technique by
refluxing with 2-bromobenzyl bromide dissolved in anhydrous acetone in the pres-
ence of anhydrous K2CO3 (Scheme 1).[25]
7-Hydroxy-4H-chromene derivatives 1a–e were synthesized by dimethylamino-
pyridine (DMAP)–catalyzed condensation of resorcinol, malononitrile, and aromatic
aldehydes in water under microwave irradiation. Compounds 2a–e were susceptible
to Pd(0)-catalyzed Heck cyclization when heated with Pd(OAc)2 (10 mol%) along
Scheme 1. Synthesis of 7-(2-bromobenzyloxy)-4H-chromene derivatives. (Figure is provided in color
online.)

1604
A. PATRA AND T. MAHAPATRA
Scheme 2. Intramoleculer Heck cyclization of 7-(2-bromobenzyloxy)-4H-chromene derivatives. (Figure is
provided in color online.)
with NaHCO3 (anhydrous) and Aliquat 336 (0.12 mmol) in anhydrous N,N-dimethyl
formamide (30 mL) under stirring in an argon atmosphere for a period of 10–12 h
(Scheme 2). The reaction mixture was diluted with water and extracted with dichloro-
methane. After evaporating the organic layer, actual products were isolated via pre-
parative thin-layer chromatography (TLC) method. It is interesting to find that the
final products were not the expected heteroannulated 4H-chromene derivatives
but instead chelated 6H-benzo[c]chromen-2-yl ketones 3a–e in reasonable yield
(Table 1). Initial screening of the reaction conditions using substrate 2a revealed that
between Pd(OAc)2 and PdCl2, Pd(OAc)2 was the most suitable catalyst for this reac-
tion. Only 10 (mol%) of this catalyst was sufficient to induce the intramolecular coup-
ling reaction. With PdCl2 as catalyst, no coupling product was produced at all. We have
also examined other reaction variables. Various bases, for example, KOAc, NaOAc,
and NaHCO3, can be used in this reaction while keeping the reaction media same.
However, the reaction is much cleaner and yield of the product was modest to
good (58–75%) in the presence of NaHCO3. With KOAc or NaOAc, the same reac-
tion occurred, affording heteroannulated chelated ketones in 50–55% yield. The
reaction rate was temperature dependent. While it took 12 h to yield 70% of 3a at
80 ꢀC, the reaction time can be shortened (10 h) by raising the reaction temperature
to 100 ꢀC without any compromise in product yield. With further increase of
temperature, no significant yield improvement of the product was observed. While
increasing the reaction temperature seemed to improve the reaction, the temperature
range was limited by the boiling point of dimethylformamide (DMF). Thus we chose
the optimal reaction temperature to be between 100 and 120 ꢀC. Raising the
temperature above 120 ꢀC gave no significant yield improvement of the product.
We have studied the effect of increasing Aliquat 336, taking 2a as substrate. Use
of 0.12 mmol of IL is sufficient to bring about a reasonable yield of product.

REGIOSELECTIVE FORMATION OF CHELATED KETONES
1605
Table 1. Synthesis of pyrano-fused chelated hydroxy ketones
Temp.
(ꢀC)
Time
(h)
Yielda
(%)
Mps (obs.)
(ꢀC)
Entry
Substrate 2
Product 3
1
100
10
70
98
2
110
12
75
176
3
4
5
110
120
120
12
14
12
72
58
70
170
110
158
aYields of pure isolated product.
We also carried out the model study using 2a with Pd(OAc)2 (10 mol%)
and NaHCO3 in different normal solvents [dichloromethane (DCM), MeCN, and
N,N-DMF] without using IL. In DCM and MeCN, no reaction occurred. In N,N-
DMF, reaction occurred but the yield of the product 3a remained very poor
(Table 2). We have thus used N,N-DMF and Aliquat 336 together as reaction media.
The structures of the newly synthesized compounds received support from
extensive NMR studies along with high-resolution mass spectroscopy (HRMS)
1
whereever necessary. The appearance of a singlet signal in the H spectrum of all
the compounds in the region above d 12.0 clearly indicated the presence of chelated

1606
A. PATRA AND T. MAHAPATRA
Table 2. Result of different solvents with NaHCO3 as base
Product (3a)
DCM
MeCN
N,N-DMFa
N,N-DMF þ ILa
Time (h)
No reaction
No reaction
10%
70%
10
aYields of pure isolated product.
hydroxyl proton. In addition, the presence of a signal in the region ꢁd 200.0 for
quaternary carbon in the 13C spectrum also supported that it was a chelated hydroxy
ketone. Moreover, the presence of two singlets in the 1H spectrum of all the
compounds in the regions d 7.97–8.17 and 6.62–6.94 clearly indicated that the pro-
ducts obtained were linearly fused heterocycles, not its angular analog. Hence, the
reaction was regioselective too. The relatively downfield signal was attributed to
an aromatic proton ortho to the carbonyl, whereas the upfield signal was correlated
to the aromatic proton in between two O-atoms. In the products 3b and 3c, appear-
ance of a meta coupled doublet at d 7.36 (J ¼ 1.5 Hz) and 8.17 (J ¼ 2.1 Hz), respect-
ively, which are multiple bond correlated with carbonyl carbon signal respectively at
d 199.2 and 199.0, established that intramolecular cyclization in the second aromatic
ring is also regioselective. Thus the formation of the other regioisomer for 3b (Fig. 2)
was discarded.
It is noteworthy that this kind of chelation stabilizes the heavily substituted
ketones and forces these to be coplanar. The proposed mechanism for this annu-
lation process includes oxidative addition of 7-(2-bromobenzyloxy)-4H-chromene
derivatives to Pd(0), which were in turn produced in situ by the reduction of the
Pd(II) catalyst precursor, forming an aryl-palladium intermediate, which on addition
to the double bond produces a r-allylpalladium intermediate and subsequent
b-hydrogen elimination completes the catalytic cycle.[25] The hydrolysis of annulated
4H-chromene derivatives to chelated 6H-benzo[c]chromen-2-yl ketones possibly
occurs during workup with DCM-H2O. This is in contrast to the result of acidic
and alkaline hydrolysis of 2-amino-4-aryl-3-cyano-4H-benzochromenes to 4-aryl-
3-cyano-3,4-dihydrobenzopyran-2-ones.[37] The plausible mechanism (Scheme 3)
Figure 2. Regioisomer of 3b. (Figure is provided in color online.)

REGIOSELECTIVE FORMATION OF CHELATED KETONES
1607
Scheme 3. Plausible mechanism of formation of chelated 6H-benzo[c]chromen-2-yl ketones from
annulated 4H-chromene derivatives. (Figure is provided in color online.)
includes a 1,3-prototropic shift of H atom at C-4 of 4, producing 5, which on sub-
sequent attack by H2O molecules generates 6. The 4-H is acidic because of its
dibenzylic-allylic nature and in the presence of aliquat [Cl-NþCH3[(CH2)7CH3]3]
the direction of the 1,3-prototroic shift in 4 can be accounted for if one considers
the electrostatic association of Qþ (quaternaryammonium ion) with the NH2 group,
making the latter less electron donating.[38,39] The driving force for a subsequent step
=
is the good leaving aptitude of NH2CH CHCN due to the presence of complemen-
tary functionalities (NH2 and CN) and association with quaternaryammonium ions
(Qþ), whereby 6 produces chelated hydroxy ketones 3.
In summary, our effort to heteroannulate 7-(2-bromobenzyloxy)-4H-chromene
derivatives successfully extended the Pd(0)-catalyzed intramolecular Heck cycliza-
tion to the synthesis of a new series of heteroannulated chelated hydroxy ketones.
Being ligand-free, this process is much less resource demanding. Yields are modest
to good. Moreover, operational simplicity, mildness of reaction condition, and high
degree of regioselectivity makes an improved procedure for the preparation of
pyrano-fused chelated hydroxy ketones of complex framework.
EXPERIMENTAL
Melting points were recorded on a Toshniwal apparatus. Infrared (IR) spectra
were recorded on a Perkin-Elmer Fourier transform (FT) IR-RXI spectro-
1
photometer using KBr pellets. H (300 MHz), 13C (75 MHz), and 2-D [correlation
spectroscopy (COSY), heteronuclear single quantum correlation (HSQC), hetero-
nuclear multiple quantum correlation (HMQC), and heteronuclear multiple bond
correlation (HMBC)] NMR spectra were recorded on a Bruker AV 300 Supercon
NMR spectrometer in a 5-mm broadband observe (BBO) probe using CDCl3 or
dimethylsulfoxide (d6-DMSO) as solvent. High-resolution mass spectra were taken
on a Qtof Micro YA 263 spectrometer.
Compound 3a: Mp 98 ꢀC; IR (KBr): nmax 3437, 1599, 1492, 1447, 1162,
1
762 cmꢂ1; H NMR (300 MHz, CDCl3): d 5.20 (2H, s, 6-H2), 6.64 (1H, s, 4-H),

1608
A. PATRA AND T. MAHAPATRA
7.13 (1H, br. d, J ¼ 7.1 Hz, 7-H), 7.24 (1H, ddd, J ¼ 7.4 Hz, 7.3 Hz, 1.4 Hz, 8-H), 7.30
(1H, ddd, J ¼ 7.4 Hz, 7.3 Hz, 1.5 Hz, 9-H), 7.40 (1H, br. d, J ¼ 7.5 Hz, 10-H), 7.55
(2H, br. t, J ¼ 8.5 Hz, 30-H, 50-H), 7.63 (1H, br.t, J ¼ 8.4 Hz, 40-H), 7.72 (2H, br.
d, J ¼ 8.1 Hz, 20-H, 60-H), 7.97 (1H, s, 1-H), 12.47 (1H, s, chelated OH); 13C
NMR (75 MHz, CDCl3): d 68.8 (CH2, C-6), 105.6 (CH, C-4), 114.7 (C, C-10b),
114.8 (C, C-2), 121.2 (CH, C-10), 124.7 (CH, C-7), 127.4 (CH, C-8), 128.5 (2CH,
C-30, C-50), 128.8 (CH, C-9), 128.9 (C, C-10a), 129.0 (CH, C-1), 129.1 (2CH, C-20,
C-60), 129.7 (C, C-6a), 131.8 (CH, C-40), 1þ38.3 (C, C-10), 161.7 (C, C-4a), 165.6
=
(C, C-3), 200.3 (C, C O). HRMS: m=z, M H (%), Found: 303.1011 (90). Calcd.
for C20H15O3: 303.1021.
SUPPLEMENTARY DATA
Experimental details; spectral data; copies of 1H, 13C, and 2-D (COSY, HSQC,
and HMBC) NMR spectra; and copies of HRMS are incorporated in the
Supplementary Data file available online.
ACKNOWLEDGMENTS
We thank the CAS Instrumentation Centre, Department of Chemistry,
University of Calcutta, India, for spectral data and the University Grants
Commission, New Delhi, and University of Calcutta, Calcutta, for financial assistance.
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