Synthesis of substituted 6H-benzo[c]chromenes: A palladium promoted ring closure of diazonium tetrafluoroborates

Article abstract of DOI:10.1016/j.tetlet.2012.10.038

A highly efficient palladium-catalysed phenyl diazonium tetrafluoroborate participation of C-H activation ring closure protocol has been developed. A series of 6H-benzo[c]chromenes have been synthesized by intramolecular cyclization of ortho diazonium sal

Full text of DOI:10.1016/j.tetlet.2012.10.038

Accepted Manuscript
Synthesis of substituted 6H-benzo[c]chromenes: A palladium promoted ring
closure of diazonium tetrafluoroborates
Jing Zhou, Liangzhu Huang, You-Qiang Li, Zhen-Ting Du
PII:
S0040-4039(12)01795-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2012.10.038
TETL 42000
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
20 July 2012
19 September 2012
9 October 2012
Please cite this article as: Zhou, J., Huang, L., Li, Y-Q., Du, Z-T., Synthesis of substituted 6H-benzo[c]chromenes:
A palladium promoted ring closure of diazonium tetrafluoroborates, Tetrahedron Letters (2012), doi: http://
dx.doi.org/10.1016/j.tetlet.2012.10.038
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1
Tetrahedron Letters
journal homepage: www.elsevier.com
Synthesis of substituted 6H-benzo[c]chromenes: A palladium promoted ring closure
of diazonium tetrafluoroborates
Jing Zhou, Liangzhu Huang, You-Qiang Li, Zhen-Ting Du*
College of Science, Northwest A&F University, Yangling 712100, Shaanxi Province, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A highly efficient palladium-catalysed phenyl diazonium tetrafluoroborate participation of C-H
activation ring closure protocol has been developed. A series of 6H-benzo[c]chromenes have
been synthesized by intramolecular cyclization of ortho diazonium salts tetrafluoroborate of
benzyloxyphenyl (Method A) or phenoxymethyl phenyl diazonium (Method B). The
transformation allows the synthesis of 6H-benzo[c]chromenes with a wide variety of functional
groups and substitution patterns from simple and easily accessible precursors.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
6H-benzo[c]chromene
palladium-catalysed
diazonium salt
Development of drug-like heterocyclic compounds from
simple and facile substrates is one of the emerging areas in
modern synthetic chemistry. The benzochromene ring is an
important heteroaromatic system found in many natural products
and bioactive molecules1. Especially, 6H-benzo[c]chromene is a
structural scaffold which can be found in natural product such as
cannabinol2, whose analogues show antiemetic3, analgesic4, and
anticonvulsant5 properties and leading compound such as
selective progesterone receptor modulators (SPRMs)6 (Figure 1).
specific structures 11(Scheme 1, Path C). However, a general,
regioselective approach to generate 6H-benzo[c]chromenes with
a
wide functional group tolerance from readily available
precursors is still lacking. More specifically, access to highly
halo substituted 6H-benzo[c]chromenes is particularly limited.
Our research group has been devoted to searching new
heterocyclic structures which serve as potential bioactive
compounds in agriculture12. Recently we disclosed the palladium-
catalysed intramolecular coupling of diazonium salts and its
application to the synthesis of dibenzofurans12b. On the basis of
these results, we envisioned taking advantage of a palladium-
catalysed diazonium salts as a new means to prepare heterocyclic
structures which would overcome the lack of classical methods.
Herein, we describe a convenient and efficient procedure for the
synthesis of highly substituted 6H-benzo[c]chromenes by Pd-
catalysed C-H activation of diazonium salts in moderate to good
yields.
Figure 1. Typical compounds of 6H-benzo[c]chromenes
Generally, the classical methods for the synthesis of 6H-
benzo[c]chromenes can be divided two different methodologies
(Scheme 1). One is an intramolecular biaryal formation of
phenylbenzyl ether such as Suzuki-Miyaura7, Negishi, Kumada-
Corriu and Hiyama coupling 8(Scheme 1, Path A). The other is an
intramolecular SN2 reaction of a preset biphenyl to construct the
middle ring 9(Scheme 1, Path B). However, these approaches
usually present significant limitations in terms of substituents that
can be introduced, the substitution pattern, or regioselectivety.
The novel C-H functionalization of phenylbenzyl ether strategies
have been described in recent years10 where simple arenes are
used in place of the organometallic component. As a matter of
fact, the functionalization of aromatic C-H bonds have become
one of the most efficient strategies in the synthesis of the
universal existence of aromatic functionalities in nature and other
M Br
Biaryal formation
Path A
O
O
Path B
intramolecular SN2
OH
O
LG
X
Path C
C-H activition
O
O
M=B(OR)2, SnR3, SiR3; LG=Leaving group; X=Halogen
Scheme 1. Pathways of synthesis of 6H-benzo[c]chromene
As shown in Scheme 2, a variety of diazonium substrates were
prepared according to literature, through the etherification of

2
Tetrahedron
corresponding phenols and benzyl halide 13a,b, reduction by
tolerated(Table 2), including chloro (Table 2, entries 3, 7, 11) and
bromo (entries 2, 8, 12). The transformation described herein
allows the synthesis of corresponding 6H-benzo[c]chromenes in
68-83% yields. Moreover, the presence of either electron-
withdrawing or electron-donating groups on the benzyl does not
hinder the reaction (entries 13-14). Access to halo 6H-
benzo[c]chromenes is particularly noteworthy as synthetic routes
to such compounds are rare, which can be functionalized to other
moieties or subjected by cross coupling reaction. Thus, all the
SnCl2 dihydrate and diazonation in the presence of sodium nitrite
and HBF4 in good overall yields. Different substituents on the
benzyl, including alkyl and halo moieties, as well as several
functional groups, are tolerated in the substrates preparations.
13c
products in our reactions listed in Table
2 were easily
characterized on the basis of physical and spectral data and also
by comparison with authentic samples. The ORTEP of 2h was
shown in Figure 2.
Table 2. Pd(OAc)2 catalysed cyclization 2-
(benzyloxy)benzenediazonium tetrafluoroborate (Method A)
entry
1, 2
2-phenoxybenzenediazonium
tetrafluoroborate
Isolated
yield
Scheme 2. The preparation of substrates for cyclization in Method A
and Method B.
With these diazonium substrates tetrafluoroborates in hand,
we next tested six-membered ring formation by palladium-
catalysed cyclization. In contrast to Pd(PPh3)4 and
Pd(CH3CN)2Cl2, Pd(OAc)2 (Table
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
j
k
l
m
n
R1 =H, R2=H
R1 =H, R2=Br
R1 =H, R2=Cl
75
68
70
76
75
80
72
71
78
83
76
72
48
83
R1 =H, R2=CH3
R1=CH3, R2=H
R1=CH3, R2= CH3
R1=CH3, R2= Cl
R1=CH3, R2= Br
R1 =t-Bu, R2=H
R1 =t-Bu, R2= CH3
R1 =t-Bu, R2= Cl
R1 =t-Bu, R3= Br
R1 =H, R2=OMe
R1 =COOEt, R2=H
1, entries 4, 9-10) provided higher yields in same conditions.
The choice of the base also plays a crucial role. In comparison
with organic bases, the inorganic ones were more effective for
the preparation of 6H-benzo[c]chromene (Table 1, entries 4-8).
Our studies subsequently showed that the reaction solvent seems
to be crucial to this reaction. Acetone and DMF were found to be
less productive, whereas ethanol can improve the yield markedly
(Table 1, entries 1-3). It is worth pointing out that when
acetonitrile was used, the highest yield was obtained (Table 1,
entry 4). We believe that nonproton solvents are beneficial in this
process in that they can suppress the denitrification to arene.
Finally, we set up the optimum reaction conditions that are
acetonitrile as solvent, 5% molar ratio Pd(OAc)2 as catalyst,
150% molar ratio K2CO3 as base at refluxing temperature (Table
1, entry 4).
9
10
11
12
13
14
Table 1. Screening of reaction conditions for the cyclization of 2-
(benzyloxy)benzenediazonium tetrafluoroborate
Figure 2. OPTEP drawing of the crystal structure of 2h
Ent
ry
1
2
3
4
5
6
7
Catalyst
Base
Solvent
Temperatur
e (oC)
100
Yield
(%)a
<5
58
0
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(CH3CN)2Cl2
K2CO3
K2CO3
K2CO3
K2CO3
none
Na2CO3
Cs2CO3
Et3N
DMF
EtOH
The alternative pathway to 6H-benzo[c]chromenes was also
studied (Scheme 2, Method B). The diazonium moieties were
changed to another phenyl rings (Scheme 1, Method B), thus an
extension of the synthetic approach to 6H-benzo[c]chromenes
can also be furnished. As the results in Table 3 indicate, seven
6H-benzo[c]chromenes can be obtained smoothly in all cases in
50-68% yield. The transformation also allowed the synthesis of
6H-benzo[c]chromenes bearing different halogen sources in good
yields (Method B).
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
Acetone
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
75
30 b
45
40
<5
48
60
8
9
10
K2CO3
K2CO3
a: isolated yield. b: the reaction is slow.
Table 3. Pd(OAc)2 catalysed cyclization phenoxymethyl phenyl
diazonium tetrafluoroborate (Method B)
Under this optimized reaction conditions, the scope of Pd-
catalysed cyclization of 2-(benzyloxy)benzenediazonium
tetrafluoroborate was explored for the synthesis of substituted
6H-benzo[c]chromenes. A variety of functional groups were

3
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at doi 10.1016/j.tetlet.2012.10.038.
References and notes
entry
3, 4
phenoxymethyl
diazonium
tetrafluoroborate
R1=H
R1 =4-F
R1 =4-Cl
R1 =4-Br
R1 =4-CH3
R1=2-CH3
phenyl Isolated
yield
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A plausible mechanism of the intramolecular cyclization is
proposed in Scheme 3. The beneficial effect of diazonium salt led
us to consider its mechanism as Palladium-catalysed tandem
denitrification/C-H Activation12b, 14. First, Pd (II) was firstly
reduced to Pd (0) by reducing reagent. Then an oxidative
addition to the diazonium salt gave intermediate I and evolved a
nitrogen. Finally, A C-H insertion of Pd formed seven-membered
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15. General procedure for the preparation of 6H-benzo[c]chromenes from
of ortho diazonium salts using Pd(OAc)2: At argon, a suspension of ortho
diazonium salts corressponding (5 mmol) in acetonitrile (20 ml), catalytic
In conclusion, an extremely efficient Pd-catalysed protocol for
the
synthesis
of
6H-benzo[c]chromenes
from
2-
phenoxybenzenediazonium or phenoxymethyl phenyl diazonium
tetrafluoroborate has been developed. This transformation is
distinguished by its mild conditions, allowing the tolerance of a
wide variety of functional groups, especially halogen functional
groups tolerance. Further work is in progress to broaden the
scope of this methodology.
Pd(OAc)2
(56mg, 0.25mmol) and (1.0 g, 7.5mmol) K2CO3 was refluxed
for 2-6 hours. The mixtures were evaporated under vacuum and the
residue was purified by column chromatography on silica gel eluting
with a mixture of petroleum ether and ethyl acetate to give 6H-
benzo[c]chromenes.
16. Selected spectrum data of 2h: 1H NMR (500 Hz, CDCl3): δ = 7.84 (s, 1
H), 7.50 (s, 1 H), 7.41 (d, 1 H, J = 8 Hz), 7.12 (d, 1 H, J = 8 Hz), 7.02(d,
1 H, J = 8 Hz), 6.95 (d, 1 H, J = 8 Hz), 5.04 (s, 2 H), 2.41 (s, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 152.7, 132.4, 131.6, 130.9, 130.3,
130.2, 126.3, 125.0, 123.8, 122.4, 121.4, 117.2, 68.0, 21.0 ppm.
Acknowledgments
Financial support from the Fundamental Research Funds for
the Central Universities in NWSUAF (No. QN2009048) and the
National Natural Science Foundation of China (20802058) is
greatly appreciated.

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Synthesis of Substituted 6H-benzo[c]chromenes: A Palladium
promoted Ring closure of diazonium tetrafluoroborates
Jing Zhou, Liang-Zhu Huang, You-Qiang Li, Zhen-Ting Du
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