Pd(0)-catalyzed intramolecular Heck reaction: A general route for fused oxepine derivatives

Article abstract of DOI:10.1080/00397911.2016.1142566

A simple and facile approach for the synthesis of various structurally different tricyclic bent oxepine frameworks from a readily accessible precursor has been introduced. The synthesis of substituted oxepine derivative involved Pd(0)-catalyzed Heck reaction. This methodology enriches the literature for the large ring formation.

Full text of DOI:10.1080/00397911.2016.1142566

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Pd(0) Catalyzed Intramolecular Heck Reaction: A
General Route for Fused Oxepine Derivatives Pd(0)
Catalyzed Intramolecular Heck Reaction
Arup Kumar Adak, Arabinda Mandal, Susanta Kumar Manna, Suresh Kumar
Mondal, Akash Jana, Dipesh Ghosh, Debasish Kundu, Shubhankar Samanta
& Jayanta K. Ray
To cite this article: Arup Kumar Adak, Arabinda Mandal, Susanta Kumar Manna, Suresh Kumar
Mondal, Akash Jana, Dipesh Ghosh, Debasish Kundu, Shubhankar Samanta & Jayanta K. Ray
(2016): Pd(0) Catalyzed Intramolecular Heck Reaction: A General Route for Fused Oxepine
Derivatives Pd(0) Catalyzed Intramolecular Heck Reaction, Synthetic Communications, DOI:
10.1080/00397911.2016.1142566
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1142566
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Date: 22 February 2016, At: 02:05

Pd(0) catalyzed intramolecular Heck reaction: A general route for fused oxepine
derivatives Pd(0) Catalyzed intramolecular Heck reaction
Arup Kumar Adak1, Arabinda Mandal1, Susanta Kumar Manna1, Suresh Kumar Mondal1,
Akash Jana1, Dipesh Ghosh2, Debasish Kundu3, Shubhankar Samanta1, Jayanta K. Ray4
1Department of Chemistry, Haldia Government College, Haldia, India 2Vivekananda
Mission Mahavidyalaya, Haldia, India 3Department of Chemistry, Indian Association for
the Cultivation of Science, Jadavpur, Kolkata, India 4Department of Chemistry, Indian
Institute of Technology, Kharagpur, India
Corresponding author Shubhankar Samanta , E-mail: chemshubha@gmail.com, Jayanta
K. Ray E-mail: jkray@chem.iitkgp.ernet.in
Supplemental data for this article can be accessed on the publisher’s website.
Abstract
A simple and facile approach for the synthesis of various structurally different tricyclic
bent oxepine frameworks from readily accessible precursor has been introduced. The
synthesis of substituted oxepine derivative involved Pd (0) catalyzed Heck reaction. This
methodology enriches the literature for the large ring formation.
KEYWORDS: oxepine, Heck reaction, large ring, exo-trig, cyclization
INTRODUCTION
Seven-membered oxacycles has been the topic of recent interest because of their
occurrence in natural products, used in polymers, and pharmacological applications.[1]
1

The benz[b]oxepine ring system both medicinally and pharmacogenically are important
due to their anti-mycrobacterial, antifungal and anticancer activity.[2] Examples of
naturally occurring natural products are monocyclic zoapatanol, tricyclic bent ptaeroxylin
and linear oxepino[3,2-g]chromone.[3] Few more examples are gathered in Fig. 1. Another
biologically active compound pacharin was isolated from plant Bauhinia purpurea which
shows significant inhibition to cancer cell growth.[4] Similar type of natural active
compound radulanins H and E isolated from Radula perrottetii also consist of oxepine
subunit.[4] The oxepine ring has been prepared through C-C bond formation or via the
coupling with a heteroatom which proceeds through the C-Y bond formation.[5] Among
them palladium catalyzed intramolecular C-C bond formation is the versatile method for
the synthesis of heterocyclic and carbocyclic molecules.[6] The cyclization of unsaturated
substrate using an intramolecular Heck reaction promoted by palladium species is of
fundamental importance for the designing of vast array of cyclic natural products.[7] Oh et
al. has been synthesized oxacycles from haloene-ynes using palladium catalyst reductive
cyclization.[8] A platinum-catalyzed medium size ring formation with significant yield
was described by Dyker and co-workers.[9] Alternative routes have also been developed
for these ring systems based on ring expansion, ring closing metathesis, reductive
intramolecular cyclization with SmI2, and several other methods.[10] Although numerous
methods have been developed by several groups over the years, synthetic methods for the
construction of medium-sized carbocycles and heterocycles are still challenging and
deserve further exploration because of the unfavourable entropy and enthalpic reasons.
[11]
2

RESULT AND DISCUSSION
Based on the previous report, [1-10] utilizing an oxepine ring system as the subunit of
natural products, we have developed a new method via palladium-catalyzed
intramolecular reaction of O-homoallylated derivatives of bromo alcohol. In preceding
communication, we have described the synthesis of fused pyran ring system by
intramolecular Heck reaction (Scheme 1).[12] Recently, our group synthesized pentalogin
and its related natural product using similar methodology (Scheme 1).[13] In this
connection, we wish to communicate our findings for the formation of oxepine
derivatives from O-homoallylated derivatives of bromo alcohol.
Initially, we targeted to synthesize O-homoallylated derivatives by treating with bromo
alcohol with 4-bromobutene but we were unable to get the Heck precursor of oxepine
derivatives. Changing our strategy by converting bromoalcholos 3 to bromomethylvinyl
bromide derivatives 4, which on treatment with but-3-en-1-ol and sodium hydride in THF
at 0°C to produce O-homoallylated derivatives 5 (Scheme 2). Similarly the O-
homomethyl allylated compound 6 was synthesized by the reaction of 3-Methyl-but-3-en-
1-ol with bromomethyl vinyl bromide in the presence of sodium hydride in THF at 0 0C.
Pivotal role of catalyst, base and ligand on the heck reaction has been well explored in
the literature.[14] To standardized the reaction condition, experiments were performed in
which the reaction parameters such as catalyst, base, solvents were varied for model
substrate 5a (Schematic representation in Table 1). The exo-trig cyclization takes place in
the presence of Pd(OAc)2, PdCl2, PdCl2(PPh3)2 , Pd(PPh3)4 and Pd2(dba)3 (Table 1,
3

entries 1-10). In absence of external ligand PPh3 the yield was decreased substantially
(Table 1, entries 5-7) whereas Pd(OAc)2 with added PPh3 increased the yield to 80%
(Table 1, entry 1). This is because of oxidative addition of C-Br bond to the Pd(0)
complex facilitated by exogenous PPh3. Moreover, the yield of Heck reaction was also
studied by varying bases. We have investigated the role of different bases such as
Cs2CO3, Na2CO3, K2CO3 and Et3N (Table 1, entries1, 6-8) for this cyclization process.
Among the carbonate bases, the cesium salt is stronger base and has a higher solubility in
DMF. Consequently, β-H elimination in catalytic cycle in Heck reaction becomes more
promising in presence of cesium carbonate and should provide much higher yield than
other carbonate bases. This explanation was supported by the experimental observation
where the intramolecular Heck cyclisation in presence of Cs2CO3 afforded a good yield
of oxepine derivative with higher rate compared to sodium and potassium carbonate. On
the other hand, Et3N gave very poor yield in presence of Pd(OAc)2 because of sterically
hindered transition state during β-H elimination. Alternatively, commonly used solvents
in heck reaction are DMF, acetonitrile and dioxane. Among the solvents, dioxane, instead
of DMF, failed to produce satisfactory yield of 7a under this condition (entry 2).
Unfortunately, acetonitrile as solvent was incompetent for cyclisation of 5a even after 12
h heating at 80 0C (entry 3). Hence the optimum condition for the reaction was Pd(OAc)2,
PPh3, Cs2CO3 and TBAC (tetrabutylammonium chloride) in DMF at 80 oC (Table 1).
Using optimum condition (Table 1, entry 1), the intramolecular Heck reaction was
performed with O-homoallylated products to afford fused seven member oxacycles with
excocyclic double bond 7 in 43-80 % yield. The reaction works well with both aromatic
4

and vinyl system and can tolerate substituted benzene ring. The more electron rich
aromatic ring afforded oxepine derivative in lower yield as oxidative addition of Pd(0) to
C-Br bond becomes more difficult and as a result Z = H precursors (5a and 5g) produce
better yield than the substituted derivatives (5b-5f and 5h-5l). Beside electron donating
substituent, we have also tested this cyclization for electron withdrawing substituent to
aromatic ring. The Z = -NO2 group did not furnish any cyclised product whereas Z = -Br
provided our desired product 7l with noticeable influence on yield (43%) and reaction
time. Here, difficulty in solubility was responsible for significantly lower yield of
cyclized product. The ease of oxepine derivatives formation in presence of electron
donating or electron withdrawing substituent on aryl ring depends either by stabilization
of Ar-Pd(II)-X complex or insertion of alkene system in the catalytic cycle of Heck
reaction.[15] However, in case of compound 5j only one isomeric product 7j was obtained
in 60% yield (Table 2).
The mechanism for oxepine derivative formation via intramolecular Heck rection is well
documented in literature.[16] This process involves initial oxidative addition of a L2Pd(0)
catalyst to afford a σ-arylpalladium(II) complex of 5a. Intramolecular coordination of an
alkene and subsequent formation of carbon-carbon bond by syn addition provide a σ-
alkylpalladium(II) intermediate, which readily undergoes β-hydride elimination to release
the oxepine derivative 7a. Conversion of the hydridopalladium(II) complex to the active
L2Pd(0) catalyst by base completes the catalytic cycle.
5

The isomeric product for 7j can be explained from the mechanistic point of view in the β-
H elimination step of intramolecular Heck reaction (Scheme 4). Steric influence plays a
crucial in the reductive elimination of HBr from alkyl Pd (II) complex.[17] The distance
between large Pd (II) complex and Ar-H atom is significant to minimised steric
interaction in substrates 7a-e, 7g-h & 7k compared to 7j. Additionally, similar type
substrate 7f does not enjoy steric interaction as Sp3 C-H and Pd (II) complex adopts a
preferred conformation by which it gives normal Heck product 7f. Therefore, 7j
undergoes syn rearrangement to produce less crowded 7j" intermediate which obtained
thermodynamically stable isomeric product 7j.
In previous report we have successfully prepared tetrcyclic derivatives via palladium
catalyzed C-H activation process from O-methylallyted derivatives of 3.[12] To obtain
such type of C-H activation product, when the substrate 6 was subjected to Heck reaction
under identical condition, we did not get the desired product 8 as shown in Scheme 5.
This can be explained by the formation of strained five membered ring during C-H
activation (Scheme 5).
CONCLUSION
In summary, we have developed a general methodology for the synthesis of oxepine
derivatives via intramolecular Heck reaction which will enrich the literature for large ring
formation. Further studies are underway to synthesis of bioactive molecules bearing
oxepine units for future communication.
6

EXPERIMENTAL
Typical Experimental Procedure For Heck Reaction (7)
Compounds (7, 1equiv.), Pd(OAc)2 (10 mol%), PPh3 (0.25 equiv.), Cs2CO3 (1.2 equiv.),
DMF (6 mL) were placed in a two neck round bottom flask. After degassing with N2, the
mixture was heated to 80-85 oC for 4-5h. After cooling the reaction mixture was diluted
with cold water and extracted with ether (20 mL x 3) and dried (Na2SO4). The solvent
was evaporated and the crude product was purified by preparative thin layer
chromatography.
1-Methylene-5, 6, 7, 9, 10, 11-Hexahydro-8-Oxa-Cyclohepta[A]Naphthalene (7a)
Colourless Liquid, 1H NMR (CDCl3, 400 MHz) δ: 2.22 (t, 2H, J = 8.0Hz), 2.62 (t, 2H, J
= 6.0Hz,), 2.76 (t, 2H, J = 8.0Hz), 3.90 (t, 2H, J = 6.0Hz), 4.30 (s, 2H), 5.00 (s, 1H), 5.35
(s, 1H), 7.12-7.18 (m, 3H), 7.36 (d, 1H, J = 6.8Hz). 13C NMR (CDCl3, 50 MHz) δ: 27.8,
28.3, 39.4, 71.5, 74.4, 116.8, 125.3, 126.1, 126.5, 127.1, 134.3, 135.6, 135.9, 135.9,
144.4. IR max (CHCl3, cm-1) 2985, 2844, 1625, 1540. HRMS calcd for C15H16O
[M++H]: 213.1281, found: 213.1285.
SUPPORTING INFORMATION
Electronic supplementary information (ESI) (1H and 13C spectra of representative
compounds) for this article and can be accessed on the publisher’s website.
ACKNOWLEDGEMENT
7

Financial support from DST (SB/FT/CS-189/2012) and chemistry department of Haldia
Govt. College is gratefully acknowledged. We are specially thanks to department of
chemistry IIT kharagpur and the other faculty members of Haldia Govt. College.
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Table 1 Intramolecular Heck cyclization of O-homoallylated derivative by using different
type of bases, catalysts and solventa
Entry Catalyst
Base
Time Yield (%) of 7a
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Cs2CO3
Cs2CO3
5
80
6
63b
0c
Cs2CO3 12
Cs2CO3 10
48
PdCl2(PPh3)2 Cs2CO3 12
55d
33d
39d
45
Pd(PPh3)4
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Cs2CO3 12
Cs2CO3 10
Na2CO3
K2CO3
Et3N
8
8
9
47
50
[a]Reagent and conditions: Substrate (1 equiv.), Catalyst (10 mol %), Base (1.2 equiv.),
PPh3 (0.25 equiv.), TBAC (1.5 equiv.), DMF, 80 oC; [b]Dioxane solvent; [c]Acetonitrile
solvent; [d]Reaction was performed without PPh3.
11

Table 2 Synthesis of oxepine derivatives via Pd-catalyzed intramolecular heck coupling[a]
[a] Reagent and conditions: Reactant 5a-5k (1 equiv.), Pd(OAc)2 (10 mol %), Cs2CO3
(1.2 equiv.), PPh3 (0.25 equiv.), TBAC (1.5 equiv.), DMF, 80 0C, 4hrs; [b] 5 hrs time
was required; [c] 12 hrs time was required.
12

Scheme 1. Synthesis of different oxacycles by Heck reaction
13

Scheme 2. Preparation of intramolecular Heck precursor
14

Scheme 3. Proposed mechanism of oxepine derivative formation
15

Scheme 4. Mechanistic overview for isomerisation in Heck reaction.
16

Scheme 5. Pd (0) catalyzed C-H activation
17

Figure 1. Biologically active compounds of oxepine ring system
18