Nucleophilic ipso-Substitution of Aryl Methyl Ethers through Aryl C

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Nucleophilic ipso-Substitution of Aryl Methyl Ethers through Aryl C– OMe Bond Cleavage; an Access to Functionalized Bisthiophenes Abhishek Kumar Mishra, Ajay Verma, and Srijit Biswas J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02701 • Publication Date (Web): 28 Feb 2017 Downloaded from http://pubs.acs.org on March 1, 2017

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The Journal of Organic Chemistry

Nucleophilic ipso-Substitution of Aryl Methyl Ethers through Aryl C–OMe Bond Cleavage; an Access to Functionalized Bisthiophenes Abhishek Kumar Mishra,† Ajay Verma,‡ and Srijit Biswas*,† †

Division of Molecular Synthesis and Drug Discovery, Centre of Bio-Medical Research,

SGPGIMS Campus, Raebareli Road, Lucknow 226014, India ‡

Division of NMR and Metabolomics, Centre of Bio-Medical Research, SGPGIMS Campus,

Raebareli Road, Lucknow 226014, India *E-mail: [email protected]; [email protected] Table of content graphic:

Abstract A metal and solvent free strategy to functionalize aryl methyl ethers through direct nucleophilic substitution of aryl C–OMe bond has been described. A wide range of O, S, N and C-centered uncharged nucleophiles has been successfully employed. Using this protocol, functional derivatives of bisthiophene have been synthesized in a straightforward way. The reactions are highly atom-efficient and generate methanol as the only by-product. Introduction In recent years, C–O electrophiles have received much attention as alternative to aryl halides in aromatic nucleophilic substitution (SNAr) as well as in cross coupling reactions.1,2 Among

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others, the most profound advantages of using C–O electrophiles are the absence of halogenated waste at the final stage of the reaction, easy availability of phenol derivatives than aryl halides, and possibility of further functionalization in presence of halogen at different reactive positions of the electrophile.3 Aryl sulfonates have been the most commonly used C–O electrophile as an alternative to aryl halides due to the ease of C–O bond cleavage.3 However, aryl sulfonates are costly and generate stoichiometric amount of sulphur-containing waste. Due to these disadvantages, in recent reports, aryl sulfonates have been further replaced by simpler aryl esters or aryl carbamates which are also not commercially available and generates considerable amounts of chemical waste.4,5 Contrary to this, aryl methyl ethers are an attractive alternative C–O electrophile because it is the simplest derivative of phenol and generates less amounts of chemical waste when subjected to react with nucleophiles. But, the exceptional inertness of the aryl C–OMe bond of aryl methyl ethers has limited its use as C–O electrophile compared to the other partners, such as, sulfonates, esters or carbamates.6 Thus, functionalization of aryl C–OMe bond by means of cross coupling or aromatic nucleophilic substitution reactions has remained as a challenging transformation. The recent years have witnessed dramatic efforts that involve innovative catalytic techniques to employ aryl–alkyl ethers as C–O electrophiles in cross coupling reactions. Most of the reactions used Scheme 1: Aryl C–OMe Bond Functionalization

highly reactive and stoichiometric organometallic reagents and remain confined towards C–C bond forming reactions (Scheme 1, path A).2 Among the very few carbon-heteroatom bond


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formation reactions, notable is the very recent Ni-catalyzed ipso-borylation of aryl methyl ether reported by Martin and co-workers.7 In addition, Chatani and co-workers also reported Ni-catalyzed amination reaction of aryl methyl ethers through aryl C–OMe bond cleavage (Scheme 1, path B).8 All these methods are very efficient; but use metal catalyst and large excess of ligands and bases that limits the applicability. Lin and co-workers prepared anthracene ethers and thioethers from anthracene methyl ethers employing equivalent amounts of acid.9 However, their methods are limited towards anthryl–methyl ethers and no reactivity was observed even by changing the electrophile to napthyl–methyl ether under the reported reaction conditions.9a Importantly, in a ground breaking work, Li and co-workers discovered a novel and elegant palladium catalyzed strategy of coupling of phenols with amines, where non-derivatized phenols were used directly as the C–O electrophile.10 The reaction occurred via a unique redox mechanism where the amounts of hydrogen source and use of additives had a crucial role to switch the ratios of formation of aryl amines10a and cyclohexyl amine10b products. We have also contributed to this field by developing a general method to functionalize aryl C–OH bonds of naphthols and electron rich phenol systems which essentially took place via ketotautomerization of the naphthols.11 In the present study, we report an operationally simple, metal and solvent free, and catalytic nucleophilic substitution of aryl methyl ethers by different O-, N-, S- and C-centered uncharged nucleophiles to yield functional derivatives, mostly in high yields (Scheme 1, path C). As an application, 3-methoxy thiophene was used in combination of a variety of nucleophiles to develop an elegant synthesis of functionalized bisthiophene derivatives. Results and Discussions



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Table 1. Optimization of Reaction Conditionsa OMe + HO

10 mol% TfOH 5

1a

2a

120 °C, 24 h neat

O 5

+ MeOH

3a

entry

variation from standard conditions

yield of 3ab

1

None

98% (95%c)

2

p-TSA·H2Od instead of TfOHe

52%

3

CH3SO3H instead of TfOH

NRf

4

H3PO2 instead of TfOH

NRf

5

CH3CO2H instead of TfOH

NRf

6

H2NC6H4SO3H instead of TfOH

36%

7

CF3CO2H instead of TfOH

NRf

8

HBr (48% v/v) instead of TfOH

NRf

9

HBr (10 mol%) + TfOH (10 mol%)

94%

10

5 mol% TfOH

65%

11

2 equivalents 2a were used

76%

12

1.5 mL Toluene was used as solvent

62% (92%)g

13

Reaction time was 12 h instead of 24 h

60%

a

Standard reaction condition: 1a (1.0 mmol), 2a (3.0 mmol) and TfOH (10 mol%) was taken stirred at 120 °C for 24 h in a closed 5 mL reaction vial under nitrogen. The residue was used directly for purification and GCMS analysis. b GC yield with respect to 1a. c Isolated yield with respect to 1a. d p-TSA·H2O = para-Toluenesulfonic acid monohydrate. e TfOH = Trifluoromethanesulfonic acid (triflic acid). f NR = No reaction. g Reaction time 72 h.

Considering the importance of naphthyl alkyl ethers in the flavour chemistry12 and drug synthesis,13 the substrates 2-methoxy naphthalene (1a) and 1-hexanol (2a) have been utilized to investigate the formation of naphthyl–hexyl ether through the direct nucleophilic substitution of aryl C–OMe bond of 1a under solvent free reaction conditions. Different Brønsted acids such as para-toluenesulfonic acid (p-TSA), methanesulfonic acid (MeSO3H), phosphinic acid (H3PO2), acetic acid (AcOH), sulfanilic acid (H2NC6H4SO3H), trifluoroacetic acid (CF3CO2H) and trifluoromethanesulfonic acid (TfOH), hydrobromic acid (HBr) and mixture of HBr and TfOH were tested at variable electophile / nucleophile ratios to optimize the reaction parameters. The results are summarized in Table 1. The best result was obtained employing 5 mol% TfOH catalyst and 3 equivalents of 1-hexanol (2a) while running the


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reaction for 24 h at 120 °C to generate the naphthyl hexyl ether 3a in 95% isolated yield without using any external solvents. Using more than 3 equivalents of nucleophile (2a) did not increase the yield of the product (3a). Table 2. Substrate Scopea

a

Reaction conditions: 1 (1.0 mmol), 2 (3.0 mmol), TfOH (10 mol%), and 24 h at 120 °C. b 48 h instead of 24 h. c TfOH (20 mol%), and 48 h at 150 °C.

The optimized reaction conditions were applied to a large variety of electrophile / nucleophile combinations (Table 2). Heptanol (2b) successfully reacted with 2- methoxynaphthalene (1a) to furnish the product 2-(heptyloxy)naphthalene (3b) in 94% yield (entry 2). Functionalized and aromatic O-centered nucleophiles such as 2-methoxyethanol (2c) and phenol (2d) also reacted with 1a to generate the desired ethers 3c and 3d in 56% and 80% yields respectively (entries 3–4). Also, the reaction was found to be quite general with respect to S- and Ncentered nucleophiles. Thus benzenethiol (2e) and aniline (2f) produced the corresponding thioether 3e and secondary amine 3f when subjected to react with 1a under the optimised



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reaction conditions in 98% and 75% yields respectively (entries 5–6), provided, the later reaction was run for 48 h instead of 24 hours in order to complete consumption of the starting electrophile. Aniline having electron donating 4-methoxy or electron withdrawing 4-fluoro substituents also tolerated the reaction conditions. Thus p-anisidine (2g) and 4-fluoroaniline (2h) smoothly reacted with 2-methoxynaphthalene (1a) to furnish the products 3g and 3h in 90% and 76% yields respectively (entries 7–8). Unfortunately, C-centered nucleophile, such as, N-methylindole and thiophene did not produce any desired products when subjected to react with 1a under the present reaction conditions. The effects of substituents at different positions of the electrophile were also examined. Hexanol

(2a)

regioselectively

replaced

the

methoxy

group

of

2-bromo-3-

methoxynaphthalene (1b) under the optimized reaction conditions to generate the product 3i in 53% yield, where no by-product formation via aryl C–Br bond substitution was observed (entry 9). Similarly, aniline (2f) regioselectively reacted with 1b to furnish the product 3j in 93% yield (entry 10). Similar regioselectivity was observed when 2-bromo-6methoxynaphthalene (1c) was employed as electrophile. Thus, 1c reacted with 2a and 2f to generate the products in 82% and 53% yields respectively (entries 11–12). Both the methoxy groups of 2,6-dimethoxynaphthalene (1d) were found to be replaced by hexanol (2a) and phenol (2d) under the optimized reaction conditions to generate the corresponding di-ethers 3m and 3n in 81% and 60% yields respectively (entries 13–14). Importantly, aniline (2f) only replaced one –OMe group of 1d to furnish the product 3o in 60% yield (entry 15). 1Methoxynaphthalene (1e) also exhibited high reactivity when subjected to react with 2a generating the product 3p in 95% yield (entry 16). Mono-substitution of one methoxy group was observed when 1,5-dimethoxynaphthalene (1f) was subjected to react with aniline (2f) furnishing the desired product 3q in 62% yield (entry 17).


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Unfortunately, anisole did not show any reactivity under the present reaction conditions, however, 1,3,5-trimethoxybenzene (1g) successfully took part in the reaction to generate the products 3r and 3s via regioselective substitution of single methoxy group of 1g in 70% and 73% respectively (entries 18–19). Table 3. One Pot Synthesis of Functionalized Bisthiophenesa

a

Reaction conditions: 1h (1.0 mmol), 2 (3.0 mmol), TfOH (10 mol%), 8 h at 120 °C.

As an application, the present methodology was successfully applied towards an efficient synthesis of functionalized bisthiophene derivatives. Aromatics with extended pi- electron conjugations such as, bisthiophene derivatives have recently received considerable attentions for their interesting application as organic electronic materials.14 Under the present reaction conditions, when 3-methoxythiophene (1h) was employed as electrophile, it generated the functionalized bisthiophene derivatives in a straightforward way with methanol as the only side product (Table 3). The reaction occurred in one pot two steps fashion where the first step is the nucleophilic substitution of aryl C–OMe bond to generate the intermediate 5 (Table 3). Following this step, nucleophilic substitution of aryl C–OMe bond of another molecule occurred by the C2 center of intermediate 5 to generate the functionalized bis thiophene derivatives 4. O-Centered nucleophile such as hexanol (2a) and 2-methoxyethanol (2c) efficiently reacted with 1h in presence of 10 mol% TfOH catalyst under solvent free reaction conditions to generate the functional derivatives of bisthiophene 4a and 4b in 52% in 71% yields respectively. Similarly, N-centered nucleophiles such as aniline (2f), 4-methoxyaniline (2g) and 4-fluoroaniline (2h) efficiently reacted with 1h to generate the amine functionalized



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bisthiophene derivatives 4c, 4d and 4e respectively in good to excellent yields (Table 3). The structures of the products 4a–4d were confirmed by 2-D NMR analysis (see SI). Surprisingly, no homodimerization of 1h was detected for all the reactions by NMR and GCMS analysis of the crude reaction mixtures. Table 4. Controlled Synthesis of Substituted Thiophenes through Aryl C–OMe Bond Cleavagea

a

Reaction conditions: 1 (1.0 mmol), 2 (3.0 mmol), TfOH (5 mol%), 2 h at 80 °C. b 5.0 mmol 2a, 10 h at 100 °C.

The formation of bisthiophenes can be controlled by lowering the reaction temperature to 80 °C (Table 4). Thus O-centered nucleophile such as 2a, and, N-centered nucleophiles 2f–2h efficiently reacted with 1h in a controlled way to generate the mono-substituted thiophene derivatives 5a–5d exclusively.15 Notably, 3, 4-dimethoxythiophene (1i), when subjected to react with 2a, generated the di-substituted product 5e in 71% yield at 100 °C. Lowering the reaction temperature or reduction of the reaction time resulted in incomplete conversion of 1i and formation of a mixture of mono and di-substituted (5e) thiophene derivatives. Moreover, when methanol was used as nucleophile and subjected to react with 1h, it generated 3methoxy-2,3'-bithiophene (6a) in lower yield (22%) under identical reaction conditions. Scheme 2. Proof of Intermediacy of 5 for the One Pot Synthesis of 4


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To test the formation of intermediate 5 during the synthesis of bisthiophene derivatives 4, compound 5b was prepared and purified in a separate step. The analytically pure 5b was subjected to react with 1 equivalent of 3-methoxythiophene 1h in presence of 10 mol% TfOH in toluene solvent (Scheme 2). 69% formation of 4c was observed after 8 h. This experiment proves the intermediate formation of substituted thiophene derivatives 5 which finally converted to the bisthiophene derivatives 4 through direct aryl C–OMe bond substitution of the intermediate 5. In the second step 3-methoxythiophene (1h) acted as a C-centered nucleophile via substitution through C2 center of 1h. Scheme 3. Bi and Trimolecular Synthesis of Methoxy Bis and Tris Thiophenes in Different Reaction Conditions

Using 3-methoxythiophene 1h alone gave the opportunity to synthesize either methoxy substituted bisthiophene 6a or tristhiophene 6b in two different reaction conditions through bimolecular and trimolecular reaction mechanisms respectively (Scheme 3). Thus, when 1h was heated at 120 °C in presence of 5 mol% TfOH in toluene, it generated 6a exclusively in 91% yield. Whereas, under solvent free reaction conditions and higher catalyst loading, tristhiophene derivative 6b was formed in 26% yield. Scheme 4. Deuterium Labeling Experiment for Mechanistic Supports D OMe (A)

+ D2 O 1a OMe

(B)

+ D2 O

100 °C, 12 h 1a-D; 67% D at C1 OMe D 10 mol% TfOH, DCE 100 °C, 12 h

1e

(C)

1a or 1e

OMe

10 mol% TfOH, DCE

1e-D; 66% D at C2

+ D2 O

No Catalyst 100 °C, 24 h

No D-incorporation in 1a or 1e



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To focus on the mechanism of the reaction, we have performed deuterium labelling experiments (Scheme 4). 2-Methoxynaphthalene (1a) when subjected to react with deuterated water in presence of the catalyst in dry 1, 2-dichloroethane (DEC), 67% deuterium incorporation was observed at the C1 position only (Scheme 4A). Similarly, for 1methoxynaphthalene (1e), deuterium incorporation was only observed at C2 position (Scheme 4B). The extent of deuterium incorporations were calculated based on 1H NMR spectra (See SI). Importantly, no deuterium incorporation at any positions of 1a or 1e was observed in absence of the catalyst. Scheme 5. Plausible Mechanism of the Reaction

Based on the deuterium exchange experiments, and a previous theoretical report by Ellervik and co-workers which documented the feasibility of complexation between Brønsted acid and naphthols,16 a mechanism has been proposed taking into account the aromatic nucleophilic substitution of aryl C–OMe bond of 2-methoxynaphthalene (1a). In the first step, the catalyst TfOH protonates the C1 center of 1a (Scheme 5). In order to explain the deuterium incorporation exclusively at C1 position of 1a (Scheme 4A), the protonation is supposed to take place via a favoured cyclic transition state A‡. Nucleophilic attack at the C2 centre of the protonated electrophile B followed by elimination of methanol generated the product 3 with the re-generation of the catalyst in the subsequent reaction steps. It is mentionable that a


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Scheme 6: Proposed Mechanism of Bis-thiophene Formations

similar mechanism may have operated in case of the formation of bis-thiophene derivative as described in Table 3 (Scheme 6). Protonation at C2 position of 1h would have occurred to generate the protonated electrophile A. Nucleophilic attack at the C3 position of A leaded to intermediate B which subsequently eliminated methanol to generate 3-Substituted thiophenes (5). In the next step, nucleophilic addition of 5 through C2 center took place at the C3-center of the protonated intermediate A to generate intermediate C. Methanol elimination at the final stage generated the bis-thiophene derivatives 4 with re-generation of the catalyst. The reaction essentially stopped after formation of 5 under a reduced reaction temperature and lower catalyst loading (see Table 4). To further emphasize on the mechanism, a series of kinetic experiments of the reaction were performed at different concentrations of the substrates (1a and 2a) and the catalyst (TfOH). The extent of formations of 3a in different time intervals were observed and calculated by 1H NMR spectroscopy. A 1st order dependence of the rate of the reaction with respect to 1a and TfOH was observed, whereas, the rate was found to be independent (0th order) with respect to 2a (see SI for details). Conclusion We have developed an atom efficient and metal and solvent free method to functionalize aryl C–OMe bonds of aryl-methyl ether. Different O, S, N, and C-centered uncharged



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nucleophiles were successfully employed. Moreover, the present protocol was found to be highly efficient for the straightforward synthesis of substituted bis and tristhiophene derivatives with methanol as the only by-product. Kinetic studies revealed the 1st order dependence of the rate with respect to the electrophile and the catalyst; and 0th order with respect to the nucleophile. Experimental Section General Considerations: 1H and

13

C NMR spectra were recorded with 400 MHz and 800

MHz spectrometers as solutions in CDCl3. Chemical shifts are expressed in parts per million (ppm, δ) and are referenced to CHCl3 (δ = 7.26 ppm) as an internal standard. All coupling constants are absolute values and are expressed in Hz. The description of the signals include: s = singlet, d = doublet, t = triplet, q = quadrate, sxt = sextet, m = multiplet, dd = doublet of doublets, dq = doublet of quadrate, ddd = doublet of doublet of doublets, ddt = doublet of doublet of triplates, td = triplet of doublet, and br. s. = broad singlet. 13C NMR spectra were recorded as solutions in CDCl3 with complete proton decoupling. Chemical shifts are expressed in parts per million (ppm, δ) and are referenced to CDCl3 (δ = 77.16 ppm) as an internal standard. High Resolution Mass Spectral analyses were performed using Q-TOF mass analyzer by ESI method. The molecular fragments in High Resolution Mass Spectra (HRMS) are quoted as the relation between mass and charge (m/z). The routine monitoring of reactions was performed with silica gel pre-coated aluminium plate, which was analyzed with iodine and/or uv light, 1H NMR analysis, and GCMS analysis of crude reaction mixture. All reactions were executed with oven-dried glassware under nitrogen atmosphere. All the 2-D NMR data were acquired using 800 MHz spectrometer equipped with Z-gradient-capable CPTCI cryoprobe at 300K temperature. All the 2-D NMR spectra were processed using TOPSPIN 2.1 software.


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Compounds 3a,11 3b,11 3d,11 3e,11 3f,11 3g,11 3h,11 3i,11 3k,11 3l,17a 3m,17b 3o,17c 3p,11 5a,17d 5b,17e 5e,17f and 6a17g are known and the 1H,

13

C and MS spectral data obtained were in

accordance to that reported in the literature (See ESI for copies of 1H and

13

C NMR spectra

for all compounds; and 2-D NMR spectra of 4a–4e and 6b). The compounds 3c, 3j, 3n, 3q, 3r, 3s, 4a, 4b, 4c, 4d, 4e, 5c, 5d, and 6b are unknown and the full spectral characterization data are supplemented herewith. General Experimental Procedure for the Synthesis of 3a–3s with characterization data of all unknown compounds: Catalyst TfOH (15 mg, 10 mol%), electrophile 1 (1.0 mmol) and nucleophile 2 (3.0 mmol) were taken in a 5 mL VWR reaction vial under nitrogen atmosphere. The cap of the vial was closed and the reaction mixture was stirred at 120 °C for 24 h until otherwise mentioned. After completion of the reaction (monitored by TLC, GCMS or NMR), the crude was directly purified by silica-gel (230–400 mess) column chromatography (flash) using ethyl acetate / hexane solution to afford the desired product 3. 2-(Hexyloxy)naphthalene (3a): Following the general procedure, 3a was obtained as a colorless liquid (219 mg, 0.95 mmol, 95%). The compound 3a is known and the 1H, 13C and MS spectral data obtained were in accordance to that reported in the literature.11 2-(Heptyloxy)naphthalene (3b): Following the general procedure, 3b was obtained as a colorless liquid (227 mg, 0.94 mmol, 94%). The compound 3b is known and the 1H, 13C and MS spectral data obtained were in accordance to that reported in the literature.11 2-(2-methoxyethoxy)naphthalene (3c): Following the general procedure, 3c was obtained as a reddish oil (113 mg, 0.56 mmol, 56%). The compound 3c is unknown and the full spectral characterization data are supplemented herewith. 1H NMR (400 MHz, CDCl3) δ = 3.49 (s, 3



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H), 3.76–3.86 (m, 2 H), 4.20–4.28 (m, 2 H), 7.16 (d, J = 2.44 Hz, 1 H), 7.22 (dd, J = 9.16, 2.44 Hz, 1 H), 7.35 (t, J = 7.63 Hz, 1 H), 7.45 (t, J = 7.32 Hz, 1 H), 7.68–7.81 (m, 3 H) ppm. 13

C NMR (100 MHz, CDCl3) δ = 59.4, 67.4, 71.2, 106.9, 119.2, 123.8, 126.5, 126.9, 127.8,

129.2, 129.5, 134.6. 156.9 ppm. HRMS (ESI) calcd. for C13H14O2 [M+H]+ m/z 203.1067 found m/z 203.1062. 2-Phenoxynaphthalene (3d): Following the general procedure, 3d was obtained as a colorless liquid (176 mg, 0.80 mmol, 80%). The compound 3d is known and the 1H, 13C and MS spectral data obtained were in accordance to that reported in the literature.11 Naphthalen-2-yl(phenyl)sulfane (3e): Following the general procedure, 3e was obtained as a colorless oil (231 mg, 0.98 mmol, 98%). The compound 3e is known and the 1H,

13

C and

MS spectral data obtained were in accordance to that reported in the literature.11 N-Phenylnaphthalen-2-amine (3f): Following the general procedure, 3f was obtained as a yellowish solid (164 mg, 0.75 mmol, 75%), provided the reaction was run for 48 h instead of 24 h. The compound 3f is known and the 1H,

13

C and MS spectral data obtained were in

accordance to that reported in the literature.11 N-(4-Methoxyphenyl)naphthalen-2-amine (3g): Following the general procedure, 3g was obtained as a brown solid (224 mg, 0.90 mmol, 90%). The compound 3g is known and the 1

H, 13C and MS spectral data obtained were in accordance to that reported in the literature.11

N-(4-Fluorophenyl)naphthalen-2-amine (3h): Following the general procedure, 3h was obtained as a reddish solid (180 mg, 0.76 mmol, 76%). The compound 3h is known and the 1

H, 13C and MS spectral data obtained were in accordance to that reported in the literature.11

2-Bromo-3-(hexyloxy)naphthalene (3i): Following the general procedure, 3i was obtained as a yellow oil (163 mg, 0.53 mmol, 53%), provided 20 mol% catalyst was used and the


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reaction was run at 150 °C for 48 h. The compound 3i is known and the 1H,

13

C and MS

spectral data obtained were in accordance to that reported in the literature.11 3-Bromo-N-phenylnaphthalen-2-amine (3j): Following the general procedure, 3j was obtained as an yellowish oil (276 mg, 0.93 mmol, 93%). The compound 3j is unknown and the full spectral characterization data are supplemented herewith. 1H NMR (400 MHz, CDCl3) δ = 6.26 (br. s., 1 H), 7.12 (t, J = 7.05 Hz, 1 H), 7.28–7.33 (m, 3 H), 7.36–7.46 (m, 3 H), 7.54–7.64 (m, 2 H), 7.67 (d, J = 8.06 Hz, 1 H), 8.11 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3) δ = 110.0, 114.5, 120.7, 123.1, 124.0, 126.4, 126.8, 126.9, 129.2, 129.7, 132.0, 133.7, 139.0, 141.7 ppm. HRMS (ESI) calcd. for C16H12BrN [M+H]+ m/z 298.0226 found m/z 298.0223. 2-Bromo-6-(hexyloxy)naphthalene (3k): Following the general procedure, 3k was obtained as yellowish oil (251 mg, 0.82 mmol, 82%). The compound 3k is known and the 1H, 13C and MS spectral data obtained were in accordance to that reported in the literature.11 6-Bromo-N-phenylnaphthalen-2-amine (3l): Following the general procedure, 3l was obtained as yellow oil (158 mg, 0.53 mmol, 53%), provided 20 mol% catalyst was used and the reaction was run at 150 °C for 48 h. The compound 3l is known and the 1H, 13C and MS spectral data obtained were in accordance to that reported in the literature.17a 2,6-Bis(hexyloxy)naphthalene (3m): Following the general procedure, 3m was obtained as a yellow oil (266 mg, 0.81 mmol, 81%). The compound 3m is known and the 1H, 13C and MS spectral data obtained were in accordance to that reported in the literature.17b 2,6-Diphenoxynaphthalene (3n): Following the general procedure, 3n was obtained as a yellowish oil (187 mg, 0.60 mmol, 60%). The compound 3n is unknown and the full spectral characterization data are supplemented. 1H NMR (400 MHz, CDCl3) δ = 7.04–7.06 (m, 2 H),



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7.06–7.09 (m, 2 H), 7.11–7.17 (m, 2 H), 7.24 (d, J = 2.45 Hz, 1 H), 7.26 (m, 1 H), 7.32 (d, J = 2.45 Hz, 2 H), 7.34–7.35 (m, 1 H), 7.35–7.38 (m, 2 H), 7.38–7.40 (m, 1 H), 7.70 (d, J = 8.80 Hz, 2 H) ppm.

13

C NMR (100 MHz, CDCl3) δ = 114.5, 119.1, 120.9, 123.5, 129.1,

130.0, 131.1, 154.4, 157.5 ppm. HRMS (ESI) calcd. for C22H16O2 [M+H]+ m/z 313.1223 found m/z 313.1222. 6-Methoxy-N-phenylnaphthalen-2-amine (3o): Following the general procedure, 3o was obtained as a brown solid (149 mg, 0.60 mmol, 60%), provided 20 mol% catalyst was used and the reaction was run at 150 °C for 48 h. The compound 3o is known and the 1H, 13C and MS spectral data obtained were in accordance to that reported in the literature.17c 1-(Hexyloxy)naphthalene (3p): Following the general procedure, 3p was obtained as a colorless liquid (217 mg, 0.95 mmol, 95%). The compound 3p is known and the 1H, 13C and MS spectral data obtained were in accordance to that reported in the literature.11 5-Methoxy-N-phenylnaphthalen-1-amine (3q): Following the general procedure, 3q was obtained as a brown oil (154 mg, 0.62 mmol, 62%). The compound 3q is unknown and the full spectral characterization data are supplemented herewith. 1H NMR (800 MHz, CDCl3) δ = 4.04 (s, 3 H), 5.93 (br. s., 1 H), 6.88 (d, J = 7.43 Hz, 1 H), 6.94 (t, J = 7.24 Hz, 1 H), 7.01 (d, J = 8.22 Hz, 2 H), 7.25–7.32 (m, 2 H), 7.37–7.46 (m, 3 H), 7.62 (d, J = 8.61 Hz, 1 H), 8.05 (dd, J = 7.63, 1.76 Hz, 1 H) ppm. 13C NMR (200 MHz, CDCl3) δ = 55.7, 104.3, 114.2, 116.8, 117.1, 117.3, 120.4, 125.4, 125.8, 127.0, 129.0, 129.4, 138.5, 145.0, 156.0 ppm. HRMS (ESI) calcd. for C17H15NO [M+H]+ m/z 250.1226 found m/z 250.1230. N-(4-Fluorophenyl)-3,5-dimethoxyaniline (3r): Following the general procedure, 3r was obtained as a deep red oil (173 mg, 0.70 mmol, 70%). The compound 3r is unknown and the full spectral characterization data are supplemented herewith. 1H NMR (800 MHz, CDCl3) δ = 3.75 (s, 6 H), 5.59 (br. s., 1 H), 6.04 (t, J = 2.15 Hz, 1 H), 6.13 (d, J = 2.35 Hz, 2 H), 6.95–


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7.01 (m, 2 H), 7.04–7.11 (m, 2 H) ppm.

13

C NMR (200 MHz, CDCl3) δ = 55.4, 92.6, 95.0,

116.1 (d, 2JC-F = 22.0 Hz), 121.8 (d, 3JC-F = 6.0 Hz), 138.5, 146.3, 158.5 (d, 1JC-F = 240.0 Hz), 161.8 ppm. HRMS (ESI) calcd. for C14H14FNO2 [M+H]+ m/z 248.1081 found m/z 248.1079. 3,5-Dimethoxy-N-(4-methoxyphenyl)aniline (3s): Following the general procedure, 3s was obtained as a brown oil (189 mg, 0.73 mmol, 73%). The compound 3s is unknown and the full spectral characterization data are supplemented herewith. 1H NMR (800 MHz, CDCl3) δ = 3.74 (s, 6 H), 3.80 (s, 3 H), 5.99 (t, J = 2.15 Hz, 1 H), 6.07 (d, J = 1.96 Hz, 2 H), 6.84–6.91 (m, 2 H) 7.06–7.15 (m, 2 H) ppm.

13

C NMR (200 MHz, CDCl3) δ = 55.3, 55.6, 91.7, 94.0,

114.7, 123.2, 135.2, 147.5, 155.7, 161.8 ppm. HRMS (ESI) calcd. for C15H17NO3 [M+H]+ m/z 260.1281 found m/z 260.1278. General Experimental Procedure for the Synthesis of 4a–4e with characterization data of all unknown compounds: Catalyst TfOH (15 mg, 10 mol%), electrophile 1h (1.0 mmol) and nucleophile 2 (3.0 mmol) were taken in a 5 mL VWR reaction vial under nitrogen atmosphere. The cap of the vial was closed and the reaction mixture was stirred at 120 °C for 8 h. After completion of the reaction (monitored by TLC, GCMS or NMR), the crude was directly purified by silica-gel (230–400 mess) column chromatography (flash) using ethyl acetate / hexane solution to afford the desired product 4. 3-(Hexyloxy)-2,3'-bithiophene (4a): Following the general procedure, 4a was obtained as a brown oil (70 mg, 0.26 mmol, 52%). The compound 4a is unknown and the full spectral characterization data are supplemented herewith. 1H NMR (400 MHz, CDCl3) δ = 0.93 (t, J = 6.80 Hz, 3 H), 1.31–1.40 (m, 4 H), 1.44–1.55 (m, 2 H), 1.78–1.89 (m, 2 H), 4.10 (t, J = 6.55 Hz, 2 H), 6.89 (d, J = 5.54 Hz, 1 H), 7.08 (d, J = 5.54 Hz, 1 H), 7.32 (dd, J = 5.04, 3.02 Hz, 1 H), 7.40–7.47 (m, 1 H), 7.62–7.63 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3) δ = 14.2,



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Page 18 of 24

22.7, 25.9, 29.8, 31.7, 71.7, 116.3, 117.8, 119.4, 121.2, 125.2, 126.6, 133.7, 152.9 ppm. HRMS (ESI) calcd. for C14H18OS2 [M+H]+ m/z 267.0872 found m/z 267.0876. 3-(3-Methoxypropoxy)-2,3'-bithiophene (4b): Following the general procedure, 4b was obtained as a brown oil (86 mg, 0.36 mmol, 71%). The compound 4b is unknown and the full spectral characterization data are supplemented herewith. 1H NMR (400 MHz, CDCl3) δ = 3.44 (s, 3 H), 3.72–3.78 (m, 2 H), 4.19–4.25 (m, 2 H), 6.88 (d, J = 5.54 Hz, 1 H), 7.06 (d, J = 5.54 Hz, 1 H), 7.30 (dd, J = 5.04, 3.02 Hz, 1 H), 7.42 (d, J = 5.04 Hz, 1 H), 7.59–7.70 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3) δ = 59.3, 71.0, 71.5, 117.7, 118.3, 119.9, 121.3, 125.3, 126.7, 133.4, 152.4 ppm. HRMS (ESI) calcd. for C11H12O2S2 [M+H]+ m/z 241.0351 found m/z 241.0346. N-Phenyl-[2,3'-bithiophen]-3-amine (4c): Following the general procedure, 4c was obtained as a brown oil (116 mg, 0.45 mmol, 90%). The compound 4c is unknown and the full spectral characterization data are supplemented herewith. 1H NMR (400 MHz, CDCl3) δ = 5.53 (br. s., 1 H), 6.85–6.96 (m, 3 H), 7.12 (d, J = 5.38 Hz, 1 H), 7.24 (d, J = 5.38 Hz, 1 H), 7.28 (s, 1 H), 7.31 (s, 1 H), 7.33–7.38 (m, 1 H), 7.38–7.43 (m, 1 H), 7.46 (dd, J = 2.93, 1.22 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3) δ = 115.2, 119.7, 121.4, 122.7, 124.5, 125.1, 126.3, 127.3, 129.5, 133.7, 136.3, 145.5 ppm. HRMS (ESI) calcd. for C14H11NS2 [M+H]+ m/z 258.0406 found m/z 258.0400. N-(4-Methoxyphenyl)-[2,3'-bithiophen]-3-amine (4d): Following the general procedure, 4d was obtained as a brown oil (103 mg, 0.36 mmol, 72%). The compound 4d is unknown and the full spectral characterization data are supplemented herewith. 1H NMR (400 MHz, CDCl3) δ = 3.78 (s, 3 H), 5.41 (br. s., 1 H), 6.79–6.90 (m, 4 H), 6.98 (d, J = 5.29 Hz, 1 H), 7.15 (d, J = 5.54 Hz, 1 H), 7.29–7.34 (m, 1 H), 7.34–7.38 (m, 1 H), 7.40 (dd, J = 2.77, 1.26 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3) δ = 55.8, 114.9, 118.0, 121.1, 121.3, 122.7,


Page 19 of 24

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124.0, 126.4, 127.4, 134.0, 138.2, 138.9, 154.1 ppm. HRMS (ESI) calcd. for C15H13NOS2 [M+H]+ m/z 288.0511 found m/z 288.0507. N-(4-Fluorophenyl)-[2,3'-bithiophen]-3-amine (4e): Following the general procedure, 4e was obtained as a brown oil (132 mg, 0.48 mmol, 96%). The compound 4e is unknown and the full spectral characterization data are supplemented herewith. 1H NMR (400 MHz, CDCl3) δ = 5.42 (br. s., 1 H), 6.75–6.83 (m, 2 H), 6.88–6.97 (m, 2 H), 6.99 (d, J = 5.38 Hz, 1 H), 7.18 (d, J = 5.38 Hz, 1 H), 7.28 (dd, J = 5.01, 1.34 Hz, 1 H), 7.32–7.37 (m, 1 H), 7.37– 7.42 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3) δ = 116.0 (d, 2JC-F = 22.0 Hz), 116.8 (d, 3JC-F = 8.0 Hz), 121.4, 122.9, 123.8, 124.6, 126.4, 127.3, 133.7, 136.9, 141.7 (d, 4JC-F = 2.0 Hz), 157.2 (d, 1JC-F = 236.0 Hz) ppm. HRMS (ESI) calcd. for C14H10FNS2 [M+H]+ m/z 276.0311 found m/z 276.0305. General Experimental Procedure for the Synthesis of 5a–5d, 6a, 6b with characterization data of all unknown compounds: Catalyst TfOH (8 mg, 5 mol%), electrophile 1h (1.0 mmol) and nucleophile 2 (3.0 mmol) were taken in a 5 mL VWR reaction vial under nitrogen atmosphere. The cap of the vial was closed and the reaction mixture was stirred at 80 °C for 2 h. After completion of the reaction (monitored by TLC, GCMS or NMR), the crude was directly purified by silica-gel (230–400 mess) column chromatography (flash) using ethyl acetate / hexane solution to afford the desired product 5. 3-(Hexyloxy)thiophene (5a): Following the general procedure, 5a was obtained as a light brown liquid (169 mg, 0.92 mmol, 92%). The compound 5a is known and the 1H, MS spectral data obtained were in accordance to that reported in the literature.17d


13

C and


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Page 20 of 24

N-Phenylthiophen-3-amine (5b): Following the general procedure, 5b was obtained as a reddish oil (123 mg, 0.70 mmol, 70%). The compound 5b is known and the 1H, 13C and MS spectral data obtained were in accordance to that reported in the literature.17e N-(4-Methoxyphenyl)thiophen-3-amine (5c): Following the general procedure, 5c was obtained as a reddish oil (123 mg, 0.70 mmol, 70%). The compound 5c is unknown and the full spectral characterization data are supplemented herewith. 1H NMR (400 MHz, CDCl3) δ = 3.79 (s, 3 H), 5.55 (br. s., 1 H), 6.46–6.59 (m, 1 H), 6.84 (d, J = 8.06 Hz, 3 H), 6.99 (d, J = 9.06 Hz, 2 H), 7.23 (dd, J = 4.78, 3.27 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3) δ = 55.8, 103.2, 114.8, 118.9, 122.1, 125.3, 138.0, 143.6, 154.3 ppm. HRMS (ESI) calcd. for C11H11NOS [M+H]+ m/z 206.0634 found m/z 206.0628. N-(4-Fluorophenyl)thiophen-3-amine (5d): Following the general procedure, 5d was obtained as a yellowish oil (176 mg, 0.91 mmol, 91%). The compound 5d is unknown and the full spectral characterization data are supplemented herewith. 1H NMR (400 MHz, CDCl3) δ = 5.62 (br. s., 1 H), 6.66 (dd, J = 3.18, 1.47 Hz, 1 H), 6.89 (dd, J = 5.14, 1.47 Hz, 1 H), 6.95 (s, 2 H), 6.97 (d, J = 2.45 Hz, 1 H), 7.24–7.29 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3) δ = 105.6, 116.0 (d, 2JC-F = 22.0 Hz), 117.6 (d, 3JC-F = 8.0 Hz), 122.5, 125.5, 140.9, 142.4, 157.4 (d, 1JC-F = 237.0 Hz) ppm. HRMS (ESI) calcd. for C10H8FNS [M+H]+ m/z 194.0434 found m/z 194.0426. 3,4-Bis(hexyloxy)thiophene (5e): Following the general procedure, 5e was obtained as a yellowish oil (202 mg, 0.71 mmol, 71%) provided 5 mmol 2a was used and the reaction was run at 100 °C for 10 h. The compound 5e is known and the 1H,

13

C and MS spectral data

obtained were in accordance to that reported in the literature.17f 3-Methoxy-2,3'-bithiophene (6a): Following the general procedure except using 1 mL dry toluene as solvent at 120 °C reaction temperature, 6a was obtained as greenish oil (178 mg,


Page 21 of 24

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0.91 mmol, 91%). The compound 6a is known and the 1H, 13C and MS spectral data obtained were in accordance to that reported in the literature.17g 3'-Methoxy-3,2':5',3''-terthiophene (6b): Following the general procedure, except the reaction temperature was kept at 120 °C, compound 6b was obtained as a greenish oil (72 mg, 0.26 mmol, 26%). The compound 6b is unknown and the full spectral characterization data are supplemented herewith. 1H NMR (400 MHz, CDCl3) δ = 3.97 (s, 3 H), 7.01 (s, 1 H), 7.28–7.34 (m, 2 H), 7.34–7.42 (m, 3 H), 7.54–7.61 (m, 1 H) ppm.

13

C NMR (100 MHz,

CDCl3) δ = 58.9, 113.1, 119.3, 119.6, 125.4, 125.7, 126.6, 126.7, 133.4, 134.1, 135.8, 153.4 ppm. HRMS (ESI) calcd. for C13H10OS3 [M+H]+ m/z 278.9967 found m/z 278.9970. Acknowledgement This work was supported by DST-INSPIRE programme, Govt. of India. SB is thankful to DST for the Faculty Award (DST/INSPIRE/04/2013/000017). AM thanks DST for his fellowship. We are thankful to the Director of CBMR Prof. Ganesh Pandey for his generous supports and infrastructural and financial assistances; Dr. Buddhadeb for valuable scientific discussions, suggestions, and comments; Dr. Smita for her continuous encouragements and proofreading of the manuscript, Dr. Bikash and Mr. Prashant for their helps in NMR and HRMS analyses respectively. Supporting Information Available Compound characterization checklist, copies of 1H,

13

C, and 2-D NMR Spectra, plots of

kinetic experiments. This material is available free of charge via the Internet at http://pubs.acs.org. References and Footnotes



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(9) (a) Lin, C. –H.; Radhakrishnan, K. Chem. Commun. 2005, 504–506. (b) Radhakrishnana, K.; Lin, C. –H. Synlett, 2005, 2179–2182. (10)

(a) Chen, Z.; Zeng, H.; Girard, S. A.; Wang, F.; Chen, N.; Li, C. –J. Angew.

Chem., Int. Ed. 2015, 54, 14487–14491. (b) Chen, Z.; Zeng, H.; Gong, H.; Wanga, H.; Li, C. –J. Chem. Sci. 2015, 6, 4174–4178. (11)

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Less than 5 % formations of 4a–4d were observed by GCMS analysis of the

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