Synthesis of 2-phenylnaphthalenes from styryl-2-methoxybenzenes

Article abstract of DOI:10.1039/c4cc05151c

A new simple and efficient method for the synthesis of 2-phenylnaphthalenes from electron-rich 1-styryl-2-methoxybenzenes has been described. The reaction proceeds via TFA catalyzed C-C bond cleavage followed by intermolecular [4+2]-Diels-Alder cycloaddition of an in situ formed styrenyl trifluoroacetate intermediate. The quantum chemical calculations identified the transition state for the cycloaddition reaction and helped in tracing the reaction mechanism. The method has been efficiently utilized for synthesis of the phenanthrene skeleton and a naphthalene-based potent and selective ER-β agonist. This journal is

Full text of DOI:10.1039/c4cc05151c

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COMMUNICATION
Synthesis of 2-phenylnaphthalenes from
styryl-2-methoxybenzenes†‡
Cite this: Chem. Commun., 2014,
50, 12076
Ramesh Mudududdla,ab Rohit Sharma,ab Sheenu Abbat,c Prasad V. Bharatam,c
Ram A. Vishwakarma*ab and Sandip B. Bharate*ab
Received 4th July 2014,
Accepted 18th August 2014
DOI: 10.1039/c4cc05151c
www.rsc.org/chemcomm
A new simple and efficient method for the synthesis of 2-phenyl-
naphthalenes from electron-rich 1-styryl-2-methoxybenzenes has been
described. The reaction proceeds via TFA catalyzed C–C bond cleavage
followed by intermolecular [4+2]-Diels–Alder cycloaddition of an in situ
formed styrenyl trifluoroacetate intermediate. The quantum chemical
calculations identified the transition state for the cycloaddition reaction
and helped in tracing the reaction mechanism. The method has been
efficiently utilized for synthesis of the phenanthrene skeleton and a
naphthalene-based potent and selective ER-b agonist.
Fig. 1 Methods for preparation of the 2-phenylnaphthalene scaffold.
The naphthalene scaffold has great utility in synthetic, medicinal
and material chemistry.1 Several natural products (e.g. rifampicin/
rifamycin and gossypol) which possess a naphthalene core in reactions and involve substrates which require either multiple
their structures exhibit promising biological activities.2 2-Phenyl- steps to prepare or a metal-catalyst for their synthesis. In this
naphthalenes have been reported to exhibit potent estrogen communication, we report a new method for direct synthesis of
receptor (ER-b) agonistic activity.1d,e,3 There exist several methods biologically important 2-phenylnaphthalenes from electron-rich
for the preparation of the naphthalene core including [4+2] Diels– 1-styryl-2-methoxybenzenes (Scheme of Table 1). The substrates,
Alder cycloaddition, benzannulation, metal-mediated cyclization, 1-styryl-2-methoxybenzenes, can be easily synthesized in one
rearrangement of strained rings, and Lewis acid-catalyzed intra- step from corresponding commercially available aldehydes and
molecular cyclization reactions.4 For synthesis of the 2-phenyl-
naphthalene scaffold, most of the reports involve the use of a
Table 1 Optimization of reaction conditions
naphthalene core as a starting material. This includes metal-
catalyzed cross-coupling of aryl boron compounds,5 aryl Grignard
reagents6 and aryl halides with existing naphthalene core
structures.2,7 However, very few methods are reported for the direct
construction of 2-phenylnaphthalenes from non-naphthalene starting
materials (Fig. 1).4b, f,g,i–k,8 These methods are metal-catalyzed
Entry Reaction mediuma Temp. (1C) Time (h) Yield of 2ab,c (%)
1
2
3
4
TFA
TFA
rt
1
0.5
1
1
1
0.5
1
1
10
10
6
70
95
72
74
70
94
94
0
80
80
60
a Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine,
Canal Road, Jammu-180001, India. E-mail: sbharate@iiim.res.in,
ram@iiim.res.in; Fax: +91-191-2569333; Tel: +91-191-2569111
b Academy of Scientific & Innovative Research (AcSIR),
50% TFA in ACN
50% TFA in DCM
50% TFA in MeOH 80
50% TFA in H2O
50% TFA in H2O
25% TFA in H2O
25% TFA in H2O
10% TFA in H2O
H2O
5
6d
7
80
80
80
80
80
80
CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, India
c Departments of Pharmacoinformatics and Medicinal Chemistry,
National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar,
Punjab-160062, India
8
9
10
11
50
0
0
† IIIM Publication number IIIM/1694/2014.
a
For a 100 mg reaction, 1 mL solvent used. b Isolated yield. c Yield calcula-
tion is shown in the ESI (Section S8). d Optimized reaction conditions.
‡ Electronic supplementary information (ESI) available: NMR spectra of all
compounds. See DOI: 10.1039/c4cc05151c
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Table 2 Scope of the reaction for various 1-styryl-methoxybenzenes for
synthesis of 2-phenylnaphthalene 2aa
phosphine salts. The method is simple and efficient with wide-
substrate scope, excellent yields and does not require any metal
catalyst.
In continuation of our work on devinylation of 2,4,6-trimethoxy
vinylbenzenes,9 the reaction of 1-styryl-2,4,6-trimethoxybenzene
1a with TFA led to the formation of a new product 2a along with
1,3,5-trimethoxybenzene 3a. The spectral characterization of the
new product 2a revealed it to be 2-phenylnaphthalene. The
formation of product 2a with the release of 1,3,5-trimethoxy-
benzene 3a indicated that the reaction must involve C–C bond
cleavage followed by intermolecular [4+2]-Diels–Alder cycloaddition.
In order to optimize the reaction conditions, and to investigate the
effect of using solvents (rather than only TFA) in the reaction
medium, a series of experiments using 1-styryl-2,4,6-trimethoxy-
benzene (1a) were carried out as shown in Table 1. A brief examina-
tion of variation in the TFA amount in combination with various
organic solvents and water indicated that 50% TFA in water is an
optimum reaction medium producing desired product 2a in
excellent yield. The HPLC analysis of the reaction mixture also
indicated the formation of only products 2a and 3a (Section S7 of
ESI‡). These optimized conditions (Table 1, entry 6) were used
for further reactions.
Next, the effect of the variation in the leaving-group moiety
(methoxybenzene) was studied using different 1-styryl-methoxy-
benzenes 1a–1f as starting materials (Table 2). Like substrate 1a
(entry 1), under optimized reaction conditions, the 2,4,5-trimethoxy
and 2,4-dimethoxy substrates 1b and 1c produced product 2a in
excellent yields (entries 2 and 3). Similarly, the reaction of 1-styryl-2-
methoxybenzene (1d) with TFA also led to the formation of the
desired product 2a; however comparatively less yield was obtained
(entry 4). Interestingly, the reaction does not proceed with
1-styryl-3,4-dimethoxy and 1-styryl-4-methoxybenzenes (1e–1f,
Styryl methoxy-
Entry benzenes 1a–f
Methoxybenzene Yieldb
products 3a–f of 2a (%)
Product 2a
1
2
3
4
5
94
90
87
80
0
6
0
a
Reagents and conditions: styrylbenzene (100 mg), 50% TFA in water
(1 mL), 80 1C, 30 min. Isolated yield.
b
entries 5 and 6), indicating that the presence of an ortho-methoxy in intermediates from the less hindered side. For example, in the
the leaving group moiety is essential for the reaction to proceed. case of 3,4-dimethoxystyryl-2,4,6-trimethoxybenzene (1y), product
Thus, among 2-methoxybenzenes, the following reactivity trend was 6,7,30,40-tetramethoxy-2-phenylnaphthalene 2ta (Table 2, entry 19)
observed: 2,4,6-trimethoxy 4 2,4,5-trimethoxy 4 2,4-dimethoxy 4 was formed. The formation of product 2ta was further confirmed by
2-methoxy.
HMBC correlations (Fig. S1 of ESI‡). Further, the scope of the
Next, the scope of the reaction for various substituted styryl established protocol was investigated for synthesis of phenanthrene
methoxybenzenes (prepared by Wittig reaction of 2,4,6-tri methoxy- scaffolds. Treatment of 2-(2,4,6-trimethoxystyryl)naphthalene 1z with
benzaldehyde with aryl triphenylphosphine salts)10 was investigated TFA led to the formation of 2-(Naphthalen-20-yl)phenanthrene 2u in
with variation in the substitution of the styryl moiety (Table 3). 92% yield. In this reaction, the phenanthrene product 2u was
First the substrates with mono-substituted styryl-2,4,6-trimethoxy- formed selectively over other possible anthracene products (Fig. 2).
benzenes 1g–1s were investigated. The para-substituted styryl-2,4,6-
To understand the mechanism of TFA-mediated synthesis of
trimethoxybenzenes 1g–1n led to the formation of 7,40-disubstituted 2-phenylnaphthalenes from 1-styryl-2-methoxybenzenes, quantum
2-phenylnaphthalenes as products (entries 1–8). The reaction of chemical studies on the reactants, intermediates, products and the
ortho- 1o–1r (entries 9–12) and meta- 1s (entry 13) substituted styryl- important transition states of the reaction path have been carried
2,4,6-trimethoxybenzenes produced the desired 5,20-disubstituted out using B3LYP/6-311+G (d,p) methods. Fig. 3 shows the reaction
2j–2m and 6,30-disubstituted 2n 2-phenylnaphthalene products, scheme with the enthalpy and activation energy values. The first
respectively. In the latter case, the formation of another possible step of the reaction involves the saturation of the double bond in
product (8,30-disubstituted 2-phenylnaphthalene) was not observed, the presence of trifluoroacetic acid. This is an exothermic reaction
which may be due to the fact that the intermolecular cycloaddition (3–4 kcal molꢀ1), leading to two products (the S-isomer is
step occurs from a less-hindered side.
1.37 kcal molꢀ1 more stable than the R-isomer). The next step
Next, reactions of disubstituted styryl-2,4,6-trimethoxybenzenes is the proton-assisted elimination of methoxybenzene to give V
viz. 2,4-, 3,4- and 3,5-disubstituted substrates 1t–1y were investigated (in a trans arrangement), which is an endothermic reaction
(entries 14–19). In these reactions, 2-phenylnaphthalene products requiring about 17.25 kcal molꢀ1. This step is facilitated by
2o–2t were formed via intermolecular cycloaddition of styryl the proton through an intermediate IV. The dimerization step
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Table 3 Scope of the reaction for synthesis of substituted 2-phenyl-
naphthalenesa
Table 3 (continued)
Styryl
2-Phenylnaphthalenes
2b–t
Yieldb
(%)
Styryl
2-Phenylnaphthalenes
2b–t
Yieldb
(%)
Entry
14
methoxybenzenes 1g–y
Entry
1
methoxybenzenes 1g–y
89
89
98
15
2
3
4
5
90
92
97
92
16
17
18
90
89
88
90
6
7
90
90
19
a
Reagents and conditions: styrylbenzene (100 mg), 50% TFA in water
b
(1 mL), 80 1C, 0.5 h. Isolated yield of 2-phenylnaphthalenes.
8
9
99
90
Fig. 2 Synthesis of phenanthrene product 2u.
involves a concerted mechanism with a barrier of 40.58 kcal molꢀ1
and an endothermicity of 9.27 kcal molꢀ1. The non-isolable
intermediate VI is unstable due to a lack of aromaticity and it
quickly rearranges through a 1,3-H-shift to a more stable
10
11
12
87
89
93
intermediate VII, a process which is exothermic by 27.39 kcal molꢀ1
.
Thus, the dimerization process can be considered to be a
thermodynamically favorable process involving a concerted
mechanism and an immediate 1,3-H-shift. The final step of
the formation of the naphthalene ring with a loss of two
molecules of trifluoroacetic acid is also an exothermic reaction
with about 22.84 kcal molꢀ1 energy release. This last step is
probably the driving force, providing thermodynamic stability
due to aromaticity. The overall reaction is exothermic by about
15 kcal molꢀ1 and thus very favorable even though it involves a
13
87
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Fig. 3 Reaction mechanism showing energy calculations at each step.
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Fig. 4 Synthesis of ER-b agonist 2vh. Reagents and conditions: (a) n-BuLi,
THF, 30 min, 0 1C, 92%; (b) 50% TFA in water, 80 1C, 0.5 h, 92%; (c) BBr3,
anhydrous DCM, rt, 3 h, 84%.
transition state for the concerted Diels–Alder reaction with a
barrier of about 40.58 kcal molꢀ1
.
Further, the newly established protocol was utilized for
synthesis of 7,40-dihydroxy-2-phenylnaphthalene 2vh which
has been reported as a potent and selective agonist of estrogen
receptor-b (IC50 44 nM).1d The synthetic scheme for the preparation
of ER-b agonist 2vh is depicted in Fig. 4.
In conclusion, we have developed a new method for the synthesis
of 2-phenylnaphthalenes from 1-styryl-methoxybenzenes. Using
quantum chemical calculations, the mechanism of the reaction
has been established. The utility of the established protocol for
synthesis of the phenanthrene scaffold and the potent naphthalene-
based selective ER-b agonist has been demonstrated.
The authors thank analytical department IIIM for analytical
support. RM, RS and SA are thankful to CSIR, DST and UGC for
research fellowships. Financial support from DST-SERB is
gratefully acknowledged (grant no. SR/FT/CS-168/2011).
Notes and references
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This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 12076--12079 | 12079