Br?nsted Acid Catalyzed Functionalization of Aromatic Alcohols through Nucleophilic Substitution of Hydroxyl Group

Article abstract of DOI:10.1021/acs.joc.5b02849

The hydroxyl groups of naphthol and tautomerizable phenol derivatives have been substituted by O-, S-, N-, and C-centered nucleophiles under solvent-free reaction conditions. The products are generated in good to excellent yields. para-Toluenesulfonic acid exhibits the best catalytic activity compared to other Bronsted acids. Experimental observations suggest that the reaction proceeds through the intermediacy of the keto tautomer of naphthol. Nucleophilic addition to the carbonyl group followed by elimination of water generates the desired product. The present methodology provides access to substituted naphtho[2,1-b]furan derivatives. The products generated using N-centered nucleophiles can be further transformed to important classes of organic molecules such as benzocarbazole and imidazole derivatives.

Full text of DOI:10.1021/acs.joc.5b02849

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Article
Brønsted Acid-Catalyzed Functionalization of Aromatic
Alcohols through Nucleophilic Substitution of Hydroxyl Group
Abhishek Kumar Mishra, and Srijit Biswas
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02849 • Publication Date (Web): 02 Feb 2016
Downloaded from http://pubs.acs.org on February 2, 2016
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Brønsted Acid-Catalyzed Functionalization of Aromatic Alcohols through
Nucleophilic Substitution of Hydroxyl Group
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Abhishek Kumar Mishra and Srijit Biswas*
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Division of Molecular Synthesis and Drug Discovery, Centre of Bio-Medical Research,
SGPGIMS Campus, Raebareli Road, Lucknow 226014, India
Email: srijit.biswas@cbmr.res.in
Table of content graphic:
Abstract
The hydroxyl groups of naphthol and tautomerizable phenol derivatives have been substituted
by O-, S-, N-, and C-centered nucleophiles in a solvent free reaction condition. The products
are generated in good to excellent yields. para-Toluenesulfonic acid exhibits the best
catalytic activity compared to other Brønsted acids. Experimental observations suggest that
the reaction proceeds through the intermediacy of the keto tautomer of naphthol.
Nucleophilic addition to the carbonyl group followed by elimination of water generates the
desired product. The present methodology provides access to substituted naphtho[2,1-b]furan
derivatives. The products generated using N-centered nucleophiles can be further transformed
to important classes of organic molecules such as benzocarbazole and imidazole derivatives.
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Introduction
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Nucleophilic aromatic substitution (SNAr) and cross-coupling reactions are useful for
functionalizing many aromatic compounds.1 Most of these reactions use aryl halides that give
salt by-products, a source of atom inefficiency.2 Recent improvements of these reactions still
have drawbacks such as costly reagents and catalysts, atom inefficiency, and low reactivity
with many nucleophiles.3 Our research is devoted to finding efficient means of
functionalizing phenols through aryl C–OH bond cleavage, which is difficult because of the
stability of carbon-oxygen bond.4a
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Scheme 1: Recent Reports of Biaryl Formations Through Aryl C-OH Bond Cleavage
In recent times, cross-coupling methods have been developed where phenols are
functionalized through the cleavages of aryl C–OH bonds (Scheme 1A–C).4 These methods
generally require in situ functional group interconversion (FGI) of the aryl C–OH
functionality and are applicable only for biaryl synthesis. A general method to functionalize
aryl C–OH bonds by nucleophilic substitution would be desirable because the transformation
would not require prefunctionalization of the hydroxyl group, and water would be generated
as the only by-product. Also, access to variety of functional derivatives could be achieved
employing different types of nucleophiles.
Acid-mediated thiolation of naphthols and aryl diols through nucleophilic substitution of the
aryl C–OH bond have been previously reported.5 Hardy and co-workers developed a novel
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method in which the hydroxyl group of 2-naphthol was replaced by thioglycolic acid and
other S- centered nucleophiles.5a Large amounts of catalyst (30–60 mol%) were required to
achieve high yields of the desired products. Thongpanchang and co-workers subsequently
developed a protocol to synthesize bisthioalkylarenes from aryl diols and thiols using 50
mol% catalyst and a large excess of thiol.5b Nakazawa and co-workers also demonstrated a
reaction of naphthols with alkyl and arylthiols employing 2 equivalents of triflic acid to
synthesize naphthyl thioethers.5c These methods5 are limited to the synthesis of aryl
thioethers. Very recently, Takai and co-workers developed a method where bismuth triflate
was successfully employed in nucleophilic substitution of aryl C–OH bonds by O- and S-
centered nucleophiles (Scheme 2A).6 There remain some limitations such as use of heavy
metal catalysts and applicability only for O- and S- centered nucleophiles. Moreover,
secondary alcohols did not work as nucleophiles in the desired reaction.
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Scheme 2: Catalytic Nucleophilic Substitution of Aryl C-OH Bond
We report herein a straightforward method of nucleophilic substitution of aryl C–OH bonds
by a variety of O-, S-, N-, and C-centered uncharged nucleophiles (Scheme 2B). Catalytic
amounts of para-toluenesulfonic acid (p-TSA) were found to be suitable for this
transformation. Best results were observed by executing the reaction in solvent free reaction
conditions. Importantly, the present protocol allows direct access to substituted naphtha[2,1-
b]furan derivatives and precursors of valuable target molecules such as benzocarbazole and
imidazole derivatives.
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Results and Discussion
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We first sought to make alkyl-naphthyl ethers via nucleophilic substitution of the naphthyl
C–OH bond by aliphatic alcohols (dehydrative etherification). We chose 2-naphthol (1a) as
the electrophile and a secondary alcohol, 2-heptanol (2a), as the nucleophile. Aryl ethers
derived from secondary alcohols cannot be prepared by traditional Williamson synthesis
because of low reactivity and undesired side reactions.7 Moreover, a secondary alcohol was
reported not to take part in the bismuth-catalyzed naphthyl-alkyl ether formation reaction6
and in a stoichiometric version of the etherification reaction.8 Several Brønsted acids
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Table 1. Optimization of Reaction Conditionsa
entry catalyst (mol%)
solvent
yield (%)b
3a
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18c
4a
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p-TSA·H2O (10) toluene
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CH3SO3H (10)
Bi(OTf)3 (10)
toluene
toluene
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p-TSA·H2O (10)
CH3SO3H (10)
76 (72)d
22c
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neat
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aReaction conditions: 1a (1.0 mmol), 2a (3.0 mmol) and catalyst was taken in 1.5 mL solvent. The reaction mixture was
purged with nitrogen and stirred at 120 °C for 48 hours in a closed 5 mL reaction vial. The residue was used directly for
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purification and GCMS analysis. GC conversion, calculated with respect to 1a. Formation of complex mixture with full
consumption of starting materials. dIsolated yield within the parenthesis.
such as, para-toluenesulfonic acid (p-TSA), methanesulfonic acid (CH3SO3H), phosphinic
acid (H3PO2), acetic acid (AcOH), sulfanilic acid (H2NC6H4SO3H), triflic acid (CF3SO3H)
and trifluoroacetic acid (CF3CO2H) were tested and p-TSA was found to give 53% of the
desired ether 3a in toluene (Table 1, entry 1). Methanesulfonic acid generated a small amount
of the desired product under the same reaction conditions (Table 1, entry 2). All other
Brønsted acid catalysts and bismuth triflate (Table 1, entry 3)6 did not generate the desired
product (see SI for a detailed optimization table including solvent screening and amounts of
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nucleophile). Symmetrical ether 4a, resulting from dehydration of 2a was formed as by-
product in different conditions (Table 1). The best result was observed by running the
reaction using 3 equiv. of 2a at 120 °C for 48 h without using any solvent, which generated
the desired product 3a in 72% isolated yield (Table 1, entry 4). Other Brønsted acid catalysts
that were inactive in toluene did not give better results in solvent free reaction conditions (see
SI for details), but a marginal improvement of the conversion was observed for
methanesulfonic acid (Table 1, entry 5).
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The optimized reaction conditions were applied to a variety of electrophiles and nucleophiles
to synthesize the products through nucleophilic substitution of naphthyl C–OH bonds (Table
2). Primary alcohols, such as 1-hexanol (2b) and 1-heptanol (2c) reacted smoothly with 2-
naphthol (1a) and generated the substitution products, 3b and 3c, respectively, in nearly
quantitative yields (Table 2, entries 2–3). Importantly, only 5 mol% catalyst and 24 h reaction
time was sufficient for complete conversion. A gram scale reaction employing 1a and 2b was
also carried out using 2 g of 1a, which generated the product 3b in 93% yield under the same
reaction conditions (see experimental section for details). Selective mono-naphthylation was
observed using ethane-1,2-diol (2d) as nucleophile to generate the product 3d in 80% yield
(Table 2, entry 4). Homo-allylic alcohol (2e) also reacted with 2-naphthol (1a) to furnish the
product 3e in 81% yield (Table 2, entry 5). Phenol (2f) also served as nucleophile under the
optimized reaction conditions and reacted with 1a to generate the product 3f in 62% yield
(Table 2, entry 6). The protocol was also found to be general with respect to various S-, C-,
and N-centered nucleophiles. Thiophenol (2g) reacted with 1a and generated the
corresponding thioether 3g in 96% yield in the presence of 5 mol% p-TSA (Table 2, entry
7).5 The N-centered nucleophile, such as aniline (2h), also worked well to produce the
secondary amine
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Table 2. Substrate Scope in Catalytic Nucleophilic Substitution of Naphthyl C–OH
Bondsa
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aReaction conditions: Unless otherwise mentioned, 1 (1.0 mmol), 2 (3.0 mmol) and catalyst (0.05 mmol) were purged with
nitrogen and stirred at 120 °C for 24 h in a closed 5 mL reaction vial. The residue was used directly for purification and
GCMS analysis. Yields are optimized and refer to pure and isolated products, calculated with respect to 1. Yield of gram
scale reaction is given within the parenthesis (see experimental section for details). 0.1 mmol catalyst, 48 h. 0.1 mmol
catalyst, 6 mmol nucleophile, 48 h. d0.2 mmol catalyst, 200 °C, 48 h. e80 °C, 48 h. f0.1 mmol catalyst, 160 °C, 48 h.
b
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3h in 73% yield (Table 2, entry 8). 4-Substituted aniline derivatives such as 4-fluoroaniline
(2i) and p-anisidine (2j) also reacted smoothly with 1a to generate the products 3i and 3j in
76% and 71% yields, respectively (Table 2, entry 9–10). 2-Aminopyridine (2k) also reacted
with 2-naphthol (1a) at elevated reaction temperature to furnish the product 3k in 62% yield
(Table 2, entry 11). N-Methylindole (2l) served as a C-centered nucleophile to generate 3-
substituted indole derivative 3l in 50% yield (Table 2, entry 12). The generality of the present
methodology was investigated using a variety of substituted naphthol derivatives. 3-Bromo-
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2-naphthol (1b) and 6-bromo-2-naphthol (1c) reacted with 2b to afford the desired ethers 3m
and 3n in 81% and 90% yields, respectively (Table 2, entries 13–14). The reaction was
selective towards the naphthyl C–OH functionality and substitution of naphthyl C–Br bonds
was not observed at C3 or C6 positions of 1b and 1c, respectively. 6-Methoxy-2-naphthol
(1d) reacted with primary alcohol 2b as well as hindered secondary alcohol 2a and produced
the desired products 3o and 3p in 73% and 76% yields, respectively, via selective
nucleophilic substitution of the naphthyl C–OH bond (Table 2, entries 15–16). The
heterocyclic naphthol derivative, quinolin-6-ol (1e), was less reactive and did not react with
primary alcohols. However, 1e reacted with aniline (2h) at elevated reaction temperature to
generate the product 3q in 61% yield (Table 2, entry 17). Under the same reaction conditions,
4-fluoroaniline (2i) and p-anisidine (2j) also reacted with 1e to generate the heterocyclic
products 3r and 3s in 70% and 63% yields, respectively (Table 2, entry 18–19). 1-Naphthol
(1f) was found to be an equally efficient electrophile in the present reaction. Thus, 94%
formation of 3t was observed by the reaction between 1f and 1-hexanol (2b) (Table 2, entry
20). A mixture of mono- and di-etherification was observed when naphthalene-1,5-diol (1g)
was employed as electrophile to generate 3u1 and 3u2 in 20% and 76% yields, respectively
(Table 2, entry 21).
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To further extend the substrate scope, phenol derivatives were employed as electrophile in the
present nucleophilic substitution reaction (Table 3). Unfortunately, unsubstituted phenol did
not produce any desired product, but led to a complex mixture of Friedel-Crafts alkylation
products. Gratifyingly, the two poly-phenols, resorcinol (1h) and phloroglucinol (1i),
smoothly underwent the reaction. Steric effect of the nucleophile had a pivotal role. Thus,
selective mono-ether formation was observed when resorcinol (1h) was subjected to reaction
with 1-hexanol (2b) producing 3v in 72% yield (Table 3, entry 1). Di-ether 3w was formed
by the reaction between phloroglucinol (1i) and 1-hexanol (2b) in 80% yield (Table 3, entry
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Table 3. Substrate Scope in Catalytic Nucleophilic Substitution of Phenyl C–OH Bondsa
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aReaction conditions: Unless otherwise mentioned, 1 (1.0 mmol), 2 (3.0 mmol) and catalyst (0.1 mmol) were purged with
nitrogen and stirred at 120 °C for 48 h in a closed 5 mL reaction vial. The residue was used directly use for purification and
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GCMS analysis. Yields are optimized and refer to pure and isolated products, calculated with respect to 1. 6.0 mmol
nucleophile. c0.2 mmol catalyst, 10 mmol nucleophile, 1.5 mL toluene as solvent. d0.2 mmol catalyst, 6 mmol nucleophile.
2). Under similar reaction conditions, phloroglucinol (1i) reacted with 2-heptanol (2a), which
is a hindered secondary alcohol, to generate the ether 3x in 60% yield through selective
mono-etherification of the substrate (Table 3, entry 3). All the three hydroxyl groups of
phloroglucinol (1i) were substituted by aniline (2h) to generate the product N1,N3,N5-
triphenylbenzene-1,3,5-triamine (3y) in 70% yield (Table 3, entry 4). 4-Fluorophenol (1j)
was a less reactive substrate and only 23% of the product 3z was formed when 1j was
subjected to reaction with 1-hexanol 2b (Table 3, entry 5).
The present methodology served for the synthesis of naphtho[2,1-b]furan derivatives in one
step (Scheme 3). Naphthofuran derivatives are found in a large number of biologically
important natural products.9 Under the optimized reaction conditions, naphtho[2,1-b]furan 4a
was formed in 60% yield by the reaction between propargyl alcohol 2m and 2-naphthol 1a
(Scheme 3A). The reaction took place through nucleophilic substitution of the naphthyl C–
OH bond followed by in situ Claisen rearrangement and cyclo-isomerization. 2-Naphthol
derivatives having bromo-substituents at two different positions also reacted at the hydroxyl
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function under the present reaction conditions. Thus, 3- bromo- and 6-bromo-2-naphthols (1b
and 1c respectively) reacted with
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Scheme 3: Synthesis of Naphtho[2,1-b]furan Derivatives
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propargyl alcohol 2m to afford the bromo-substituted naphtha[2,1-b]furan derivatives 4b and
4c in 57% and 50% yields, respectively (Scheme 3A). For further applications, the aryl C–Br
bonds of the products 4b and 4c enable transformation to functionalized derivatives.10
A
different mechanism was found to operate when phenyl substituted secondary propargylic
alcohol 2n was employed instead of primary propargyl alcohol 2m (Scheme 3B). Due to the
stabilization of the benzylic carbocation,11 2n formed the carbocation, which alkylated the C1
position of 1a.12 In situ aryl-oxylation followed by isomerisation generated the phenyl
substituted naphtho[2,1-b]furan derivative 4d in 61% yield (Scheme 3B). Similar reactivity
was observed when methyl substituted secondary propargylic alcohol 2o was used instead of
2n. Thus, 4e was generated in 52% yield when subjected to reaction with 1a through a similar
alkylation and in situ aryl-oxylation / isomerisation mechanism (Scheme 3B). This
observation indicated that the reaction reported in scheme 3B occurred with both benzylic
and secondary alkyl carbocations.
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Scheme 4: Synthesis of Benzocarbazole and Imidazopyridine Derivative
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The present protocol also provides useful precursors for synthesizing benzocarbazoles and
imidazopyridines (Scheme 4). Benzocarbazole derivatives are used in material science,
including the construction of organic electro-emission diodes (OED).13 The product 3h
obtained via nucleophilic substitution of hydroxyl group of ß-naphthol (1a) by aniline (2h)
(Table 2, entry 8) was converted to 7H-benzo[c]carbazole 3y in 30% yield when treated with
20 mol% Pd(OAc)2 and 2 equivalents of Cu(OAc)2 through a dehydrogenative C–C coupling
reaction (Scheme 4A). The reaction also occurred when electron withdrawing 4-fluoro and
electron donating 4-methoxy substituents were present in the phenyl ring (3i and 3j
respectively). Thus, compound 3i and 3j obtained by the reaction of 2-naphthol (1a) with 4-
fluoroaniline (2i) and p-anisidine (2j), respectively (Table 2, entries 9–10), underwent
dehydrogenative coupling reactions under same reaction conditions to generate the fluoro-
and methoxy- substituted 7H-benzo[c]carbazole derivatives 4g and 4h in 31% and 38%
yields, respectively (Scheme 4B). In a similar way, product 3i obtained by the reaction
between 2-naphthol (1a) by 2-aminopyridine (2k) could be transformed to the synthetically
and pharmaceutically relevant imidazopyridine14 derivative (4i) by a reported method
(Scheme 4B).15
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Scheme 5: Mechanistic Investigations
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Experiments outlined in Scheme 5 were performed in order to probe the reaction mechanism.
2-Naphthol (1a) was treated with 3 equiv. of 99.8% D2O in the presence of 5 mol% p-TSA
catalyst at 60 °C for 24 h in dry 1,2-dichloroethane solvent. Selective deuterium
incorporation (70%) was observed exclusively at the C1-position of 1a to produce 1a-D
(Scheme 5A). Similarly, selective deuterium incorporation (70%) at C2-position was
observed when 1-naphthol (1f) was subjected to reaction with D2O under the same reaction
conditions to generate 1f-D (Scheme 5B).16 These experimental outcomes imply keto-enol
tautomerization of the naphthols during the course of the reaction. To exclude the possibility
of in situ formation of tosylate (OTs), substrate 1k was prepared and isolated in a separate
step. When 1k was subjected to react with 2b under identical reaction conditions, no reaction
occurred and unreacted 1k was recovered quantitavely even after 72 h (Scheme 5C). This
experiment ruled out the possibility of in situ functionalization group interconversion of aryl
C–OH to aryl C–OTs followed by ipso substitution. All the experimental observations are in
line if the keto-tautomer of the electrophile would have formed during the course of the
reaction.
Based on the experimental outcomes and taking into account the theoretical work reported by
Ellervik and co-workers,17a a plausible mechanism is proposed considering the etherification
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reaction between 2-naphthol 1a and 1-hexanol 2b (Scheme 6). The first step is the
tautomerization of 2-naphthol 1a to the keto form B through formation of a complex (A).
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Scheme 6: Plausible Mechanism
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Complex A is roughly thermo-neutral as calculated in Ellervik’s report with a relative energy
of ΔH (ΔG) = 1 (15) kJ mol-1.17a From A, a concerted mechanism proposed by Ellervik would
operate. Thus, in complex A, the acidic proton of the catalyst protonates the C1 centre of 1a
whereas, one of the oxo groups of the catalyst abstracts the proton from the hydroxyl group18
to form the keto tautomer B17b through a cyclic transition state A‡. The relative energy of the
transition state A‡ is reported as ΔH‡
(ΔG‡calcd) = 42 (64) kJ mol-1.17a Nucleophile 2b
calcd
attacks the electrophilic carbonyl carbon of B to produce the addition product C, which upon
elimination of water and regeneration of the catalyst produces the desired substitution product
3b. Overall, the reaction undergoes via an addition-elimination mechanism, rather than the
traditional SNAr mechanism.
Conclusion: We report a simple strategy for catalytic nucleophilic substitution of the
hydroxyl groups of aryl alcohols by O-, S-, N-, and C-centered uncharged nucleophiles. Pre-
activation or pre-functionalization of the hydroxyl group is not required and catalytic amount
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of para-toluenesulfonic acid (p-TSA) is sufficient to selectively activate the aryl C–OH bond.
Experimental studies and previously reported theoretical work suggests that formation of the
keto-tautomer of the aryl alcohol occurs in the first step. Nucleophilic addition to the
carbonyl group of the keto-tautomer followed by water elimination generates the substitution
products, mostly in high yields. The reaction does not require any organic reaction medium
and water is formed as the only by-product. As application, the present protocol allows a
direct access to substituted naphtha[2,1-b]furan derivatives and benzocarbazole and
imidazole derivatives.
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Experimental Section:
1
General Considerations: H and 13C NMR spectra were recorded with a 400 MHz
spectrometer as solutions in CDCl3. Chemical shifts are expressed in parts per million (ppm,
δ) and are referenced to CHCl3 (δ = 7.28 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
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doublet of triplates, td = triplet of doublet, and br. s. = broad singlet. C 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 = 77.0 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 Al plate, which was analyzed with iodine
1
and/or uv light, H NMR analysis, and GC / GCMS analysis of crude reaction mixture. All
reactions were executed with oven-dried glassware under nitrogen atmosphere.
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Representative experimental procedure for the synthesis of 2-(Heptan-2-yloxy)naphthalene
(3a):
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Catalyst p-TSA·H2O (19 mg, 10 mol%), 2-Naphthol 1a (144 mg, 1.0 mmol) and 2-heptanol
2a (349 mg, 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 48 h. After
completion of the reaction (by TLC, GC or NMR), the crude was directly purified by silica-
gel (230–400 mess) column chromatography (flash) using 2% (v/v) ethyl acetate / hexane
solution to afford the desired product 3a as a colourless liquid (174 mg, 0.72 mmol, 72%). 1H
NMR (400 MHz, CDCl3): δ = 0.93–0.97 (m, 3 H), 1.35–1.40 (m, 4 H), 1.41 (dd, J=6.04, 1.01
Hz, 3 H), 1.45–1.58 (m, 2 H), 1.63–1.73 (m, 1 H), 1.77–1.92 (m, 1 H), 4.56 (sxt, J = 5.99 Hz,
1 H), 7.10–7.22 (m, 2 H), 7.29–7.40 (m, 1 H), 7.41–7.51 (m, 1 H), 7.68–7.83 (m, 3 H) ppm;
13C NMR (101 MHz, CDCl3): δ = 14.0, 19.6, 22.6, 25.2, 31.8, 36.4, 73.8, 108.3, 119.8, 123.4,
126.2, 126.6, 127.6, 128.8, 129.4, 134.6, 156.0 ppm; HRMS (ESI) calcd. for C17H23O
[M+H]+ m/z 243.1743 found m/z 243.1730.
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2-(Hexyloxy)naphthalene (3b):19
p-TSA·H2O (10 mg, 5 mol%), 2-Naphthol 1a (144 mg, 1.0 mmol) and 1-hexanol 2b (306 mg,
3.0 mmol) were treated as described for the synthesis of 3a for 24 h to obtain 3b as a
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colorless liquid (223 mg, 0.98 mmol, 98%). H NMR (400 MHz, CDCl3): δ = 0.90–1.06 (m,
3 H), 1.44 (dq, J = 7.27, 3.62 Hz, 4 H),1.50–1.65 (m, 2 H), 1.83–1.98 (m, 2 H), 4.13 (t, J =
6.55 Hz, 2 H), 7.12–7.26 (m, 2 H), 7.39 (ddd, J = 8.06, 6.92, 1.13 Hz, 1 H), 7.50 (ddd, J =
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8.18, 6.92, 1.26 Hz, 1 H), 7.71–7.87 (m, 3 H) ppm; C NMR (101 MHz, CDCl3): δ = 14.0,
22.6, 25.8, 29.2, 31.6, 68.0, 106.5, 119.0, 123.4, 126.2, 126.7, 127.6, 128.9, 129.3, 134.6,
157.1 ppm.
2-(Heptyloxy)naphthalene (3c):
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p-TSA·H2O (10 mg, 5 mol%), 2-Naphthol 1a (144 mg, 1.0 mmol) and 1-heptanol 2c (348
mg, 3.0 mmol) were treated as described for the synthesis of 3b to obtain 3c as a colourless
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liquid (237 mg, 0.98 mmol, 98%). H NMR (400 MHz, CDCl3): δ = 0.93 (t, J = 6.80 Hz, 3
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H), 1.22–1.46 (m, 6 H), 1.46–1.62 (m, 2 H), 1.79–1.96 (m, 2 H), 4.10 (t, J = 6.55 Hz, 2 H),
7.10–7.22 (m, 2 H), 7.34 (ddd, J = 8.06, 6.92, 1.13 Hz, 1 H), 7.45 (td, J = 7.55, 1.26 Hz, 1 H),
7.69–7.83 (m, 3 H) ppm; 13C NMR (101 MHz, CDCl3) δ = 14.1, 22.6, 26.1, 29.1, 29.2, 31.8,
68.0, 106.5, 119.0, 123.4, 126.3, 126.7, 127.6, 128.8, 129.3, 134.6, 157.1 ppm; HRMS (ESI)
calcd. for C17H23O [M+H]+ m/z 243.1743 found m/z 243.1730.
2-(Naphthalen-6-yloxy)ethanol (3d):20
p-TSA·H2O (10 mg, 5 mol%), 2-Naphthol 1a (144 mg, 1.0 mmol) and ethane-1,2-diol 2d
(372 mg, 6.0 mmol) were treated as described for the synthesis of 3b to obtain 3d as a reddish
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oil (150 mg, 0.80 mmol, 80%). H NMR (400 MHz, CDCl3); δ = 2.20 (br. s., 1 H), 4.02 (br.
s., 2 H), 4.14–4.25 (m, 2 H), 7.10–7.22 (m, 2 H), 7.34 (t, J = 7.55 Hz, 1 H), 7.44 (t, J = 7.55
Hz, 1 H), 7.74 (q, J = 8.73 Hz, 3 H) ppm; 13C NMR (101 MHz, CDCl3) δ = 61.4, 69.1, 106.8,
118.7, 123.8, 126.4, 126.7, 127.6, 129.1, 129.5, 134.4, 156.5 ppm.
2-(But-3-enyloxy)naphthalene (3e):21
p-TSA·H2O (10 mg, 5 mol%), 2-Naphthol 1a (144 mg, 1.0 mmol) and but-3-en-1-ol 2e (216
mg, 3.0 mmol) were treated as described for the synthesis of 3b to obtain 3e as a colorless
liquid (160 mg, 0.81 mmol, 81%). 1H NMR (400 MHz, CDCl3) δ = 2.57–2.70 (m, 2 H), 4.17
(t, J = 6.80 Hz, 2 H), 5.09–5.30 (m, 2 H), 5.99 (ddt, J = 17.12, 10.32, 6.67, 6.67 Hz, 1 H),
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7.10–7.22 (m, 2 H), 7.31–7.41 (m, 1 H), 7.41–7.50 (m, 1 H), 7.66–7.85 (m, 3 H) ppm. C
NMR (101 MHz, CDCl3): δ = 33.6, 67.1, 106.6, 117.2, 118.9, 123.5, 126.3, 126.7, 127.7,
128.9, 129.3, 134.4, 134.5, 156.8 ppm.
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2-Phenoxynaphthalene (3f):3e
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p-TSA·H2O (10 mg, 5 mol%), 2-Naphthol 1a (144 mg, 1.0 mmol) and phenol 2f (282 mg, 3.0
mmol) were treated as described for the synthesis of 3b to obtain 3f as a colorless oil (136
mg, 0.62 mmol, 62%). 1H NMR (400 MHz, CDCl3) δ = 7.14 (d, J = 7.81 Hz, 2 H), 7.20 (t, J
= 7.43 Hz, 1 H), 7.29–7.55 (m, 6 H), 7.76 (d, J = 8.06 Hz, 1 H), 7.88 (dd, J = 8.31, 4.03 Hz, 2
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H) ppm; C NMR (101 MHz, CDCl3) δ = 114.1, 119.1, 120.0, 123.4, 124.7, 126.5, 127.1,
127.7, 129.8, 129.8, 130.1, 134.3, 155.1, 157.1 ppm.
(Naphthalen-6-yl)(phenyl)sulfone (3g):22
p-TSA·H2O (10 mg, 5 mol%), 2-Naphthol 1a (144 mg, 1.0 mmol) and benzenethiol 2g (330
mg, 3.0 mmol) were treated as described for the synthesis of 3b to obtain 3g as a colorless oil
(227 mg, 0.96 mmol, 96%). 1H NMR (400 MHz, CDCl3): δ = 7.31–7.35 (m, 1 H), 7.35–7.42
(m, 2 H), 7.42–7.48 (m, 2 H), 7.49 (dd, J = 4.03, 1.76 Hz, 1 H), 7.51–7.59 (m, 2 H), 7.74–
7.83 (m, 2 H), 7.83–7.89 (m, 1 H), 7.89–7.96 (m, 1 H) ppm; 13C NMR (101 MHz, CDCl3): δ
= 126.2, 126.5, 127.0, 124.4, 127.7, 128.7, 128.8, 129.2, 129.8, 130.9, 132.2, 132.9, 133.7,
135.8 ppm.
N-Phenylnaphthalen-2-amine (3h):23
p-TSA·H2O (19 mg, 10 mol%), 2-Naphthol 1a (144 mg, 1.0 mmol) and aniline 2h (279 mg,
3.0 mmol) were treated as described for the synthesis of 3a to obtain 3h as a pale yellow solid
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(160 mg, 0.73 mmol, 73%). H NMR (400 MHz, CDCl3): δ = 5.89 (br. s., 1 H), 7.10 (t, J =
7.30 Hz, 1 H), 7.16–7.34 (m, 3 H), 7.42 (t, J = 7.81 Hz, 3 H), 7.46–7.57 (m, 2 H), 7.75 (d, J =
13
8.31 Hz, 1 H), 7.79–7.90 (m, 2 H) ppm; C NMR (101 MHz, CDCl3): δ = 111.5, 118.2,
120.0, 121.3, 123.4, 126.4, 126.4, 127.6, 129.1, 129.4, 134.5, 140.7, 142.8 ppm.
N-(4-Fluorophenyl)naphthalen-2-amine (3i):24
p-TSA·H2O (19 mg, 10 mol%), 2-Naphthol 1a (144 mg, 1.0 mmol) and 4-fluoroaniline 2i
(333 mg, 3.0 mmol) were treated as described for the synthesis of 3a to obtain 3i as a grey
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solid (180 mg, 0.76 mmol, 76%). H NMR (400 MHz, CDCl3): δ = 5.75 (br. s., 1 H), 6.96–
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7.11 (m, 2 H), 7.11–7.23 (m, 3 H), 7.30–7.39 (m, 2 H), 7.45 (t, J = 7.15 Hz, 1 H), 7.67 (d, J =
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8.17 Hz, 1 H), 7.71–7.83 (m, 2 H) ppm; C NMR (101 MHz, CDCl3): δ = 110.3, 115.9,
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116.1, 119.3, 121.0, 121.0, 123.3, 126.3, 126.5, 127.6, 128.9, 129.3, 134.6, 138.7, 141.6,
157.0, 159.4 ppm.
N-(4-Methoxyphenyl)naphthalen-2-amine (3j):24
p-TSA·H2O (19 mg, 10 mol%), 2-Naphthol 1a (144 mg, 1.0 mmol) and 4-methoxyaniline 2j
(369 mg, 3.0 mmol) were treated as described for the synthesis of 3a to obtain 3j as a brown
solid (177 mg, 0.71 mmol, 71%). 1H NMR (400 MHz, CDCl3): δ = 3.86 (s, 3 H), 5.69 (br. s.,
1 H), 6.87–6.99 (m, 2 H), 7.14 (dd, J = 8.80, 2.35 Hz, 1 H), 7.17–7.23 (m, 2 H), 7.25 (d, J =
2.35 Hz, 1 H), 7.27–7.33 (m, 1 H), 7.36–7.46 (m, 1 H), 7.63 (d, J,=,7.63 Hz, 1 H) 7.75 (dd, J
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= 8.22, 4.11 Hz, 2 H) ppm; C NMR (101 MHz, CDCl3): δ = 55.6, 108.7, 114.7, 118.8,
122.5, 122.8, 126.2, 126.4, 127.6, 128.5, 129.1, 134.8, 135.5, 142.9, 155.5 ppm.
N-(Naphthalen-6-yl)pyridin-2-amine (3k):25
p-TSA·H2O (38 mg, 20 mol%), 2-Naphthol 1a (144 mg, 1.0 mmol) and 2-aminopyridine 2k
(282 mg, 3.0 mmol) were treated as described for the synthesis of 3a at 200°C to obtain 3k as
a yellowish solid (136 mg, 0.62 mmol, 62%). 1H NMR (400 MHz, CDCl3): δ = 6.81 (br. s., 1
H), 7.03 (d, J = 8.31 Hz, 1 H), 7.35–7.53 (m, 3 H), 7.56 (t, J = 7.68 Hz, 1 H), 7.76–7.91 (m, 4
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H), 8.30 (s, 1 H) ppm; C NMR (101 MHz, CDCl3): δ = 108.5, 115.2, 115.4, 121.3, 124.2,
126.4, 127.0, 127.6, 129.0, 129.9, 134.3, 137.8, 138.1, 148.3, 156.0 ppm.
1-Methyl-3-(naphthalen-6-yl)-1H-indole (3l):26
p-TSA·H2O (19 mg, 10 mol%), 2-Naphthol 1a (144 mg, 1.0 mmol) and 1-methyl-1H-indole
2l (393 mg, 3.0 mmol) were treated as described for the synthesis of 3a to obtain 3l as brown
liquid (128 mg, 0.50 mmol, 50%). 1H NMR (400 MHz, CDCl3): δ = 3.90 (s, 3 H), 7.23–7.33
(m, 1 H), 7.33–7.41 (m, 2 H), 7.42–7.58 (m, 3 H), 7.81–7.99 (m, 4 H), 8.11 (d, J = 7.81 Hz, 1
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2-Bromo-3-(hexyloxy)naphthalene (3m):
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p-TSA·H2O (19 mg, 10 mol%), 3-bromonaphthalen-2-ol 1b (223 mg, 1.0 mmol) and 1-
hexanol 2b (306 mg, 3.0 mmol) were treated as described for the synthesis of 3a to obtain 3m
as a colorless oil (248 mg, 0.81 mmol, 81%). 1H NMR (400 MHz, CDCl3): δ = 0.80–1.01 (m,
3 H), 1.30–1.47 (m, 4 H), 1.57 (q, J = 7.05 Hz, 2 H), 1.79–2.00 (m, 2 H), 4.14 (t, J = 6.55 Hz,
2 H), 7.15 (s, 1 H), 7.29–7.40 (m, 1 H), 7.40–7.51 (m, 1 H), 7.58–7.76 (m, 2 H), 8.08 (s, 1 H)
ppm; 13C NMR (101 MHz, CDCl3): δ = 14.0, 22.6, 25.7, 29.0, 31.5, 69.1, 107.4, 113.9, 124.3,
126.5, 126.5, 126.7, 129.3, 132.1, 133.5, 153.1 ppm; HRMS (ESI) calcd. for C16H20BrO
[M+H]+ m/z 307.0692 found m/z 307.0696.
2-Bromo-6-(hexyloxy)naphthalene (3n):6
p-TSA·H2O (10 mg, 5 mol%), 6-bromonaphthalen-2-ol 1c (223 mg, 1.0 mmol) and 1-hexanol
2b (306 mg, 3.0 mmol) were treated as described for the synthesis of 3b to obtain 3n as a
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colorless oil (276 mg, 0.90 mmol, 90%). H NMR (400 MHz, CDCl3): δ = 0.96 (t, J = 6.55
Hz, 3 H), 1.40 (m, 4 H), 1.47–1.60 (m, 2 H), 1.81–1.93 (m, 2 H), 4.07 (t, J = 6.55 Hz, 2 H),
7.10 (s, 1 H), 7.15–7.22 (m, 1 H), 7.51 (d, J = 8.56 Hz, 1 H), 7.60 (d, J = 8.56 Hz, 1 H), 7.66
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(d, J = 9.06 Hz, 1 H), 7.93 (s, 1 H) ppm; C NMR (101 MHz, CDCl3): δ = 14.0, 22.6, 25.8,
29.1, 31.6, 68.0, 106.4, 116.8, 120.1, 128.3, 128.4, 129.5, 129.6, 129.9, 133.1, 157.4 ppm.
2-(Hexyloxy)-6-methoxynaphthalene (3o):
p-TSA·H2O (10 mg, 5 mol%), 6-methoxynaphthalen-2-ol 1d (174 mg, 1.0 mmol) and 1-
hexanol 2b (306 mg, 3.0 mmol) were treated as described for the synthesis of 3b at 80°C to
obtain 3o as a colorless oil (188 mg, 0.73 mmol, 73%). 1H NMR (400 MHz, CDCl3): δ = 0.94
(t, J = 6.55 Hz, 3 H), 1.30–1.45 (m, 4 H), 1.46–1.57 (m, 2 H), 1.79–1.93 (m, 2 H), 3.92 (s, 3
H), 4.07 (t, J = 6.55 Hz, 2 H), 7.05–7.20 (m, 4 H), 7.65 (dd, J = 8.56, 5.29 Hz, 2 H) ppm; 13C
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NMR (101 MHz, CDCl3): δ = 14.0, 22.6, 25.8, 29.3, 31.6, 55.3, 68.0, 106.0, 106.9, 118.8,
119.2, 128.0, 128.1, 129.6, 129.8, 155.6, 156.0 ppm; HRMS (ESI) calcd. for C17H23O2
[M+H]+ m/z 259.1693 found m/z 259.1684.
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2-(Heptan-2-yloxy)-6-methoxynaphthalene (3p):
p-TSA·H2O (19 mg, 10 mol%), 6-methoxynaphthalen-2-ol 1d (174 mg, 1.0 mmol) and 2-
heptanol 2a (349 mg, 3.0 mmol) were treated as described for the synthesis of 3a to obtain 3p
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as a colorless oil (207 mg, 0.76 mmol, 76%). H NMR (400 MHz, CDCl3): δ = 0.92 (t, J =
6.67 Hz, 3 H), 1.31–1.40 (m, 7 H), 1.41–1.69 (m, 3 H), 1.72–1.89 (m, 1 H), 3.92 (s, 3 H),
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4.48 (sxt, J = 6.04 Hz, 1 H), 7.07–7.18 (m, 4 H), 7.59–7.70 (m, 2 H) ppm; C NMR (101
MHz, CDCl3): δ = 14.0, 19.7, 22.6, 25.3, 31.8, 36.5, 55.3, 74.0, 105.9, 109.0, 118.8, 120.1,
128.1, 129.6, 129.8, 154.5, 156.1 ppm; HRMS (ESI) calcd. for C18H25O2 [M+H]+ m/z
273.1849 found m/z 273.1849.
N-Phenylquinolin-6-amine (3q):27
p-TSA·H2O (19 mg, 10 mol%), quinolin-6-ol 1e (145 mg, 1.0 mmol) and aniline 2h (279 mg,
3.0 mmol) were treated as described for the synthesis of 3a at 160°C to obtain 3q as a reddish
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solid (134 mg, 0.61 mmol, 61%). H NMR (400 MHz, CDCl3): δ = 6.19 (br. s., 1 H), 7.02–
7.09 (m, 1 H), 7.19–7.26 (m, 2 H), 7.29–7.40 (m, 4 H), 7.44 (dd, J = 9.06, 2.52 Hz, 1 H), 7.95
(d, J = 8.31 Hz, 1 H), 8.01 (d, J = 9.06 Hz, 1 H), 8.73 (d, J = 2.77 Hz, 1 H) ppm; 13C NMR
(101 MHz, CDCl3): δ = 109.3, 119.0, 121.5, 122.1, 123.0, 129.5, 129.6, 130.5, 134.4, 141.7,
142.1, 144.3, 147.5 ppm.
N-(4-Fluorophenyl)quinolin-6-amine (3r):
p-TSA·H2O (19 mg, 10 mol%), quinolin-6-ol 1e (145 mg, 1.0 mmol) and 4-fluoroaniline 2i
(333 mg, 3.0 mmol) were treated as described for the synthesis of 3q to obtain 3r as a brown
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solid (167 mg, 0.70 mmol, 70%). Melting point range: 70–72 °C; H NMR (400 MHz,
CDCl3): δ = 6.18 (br. s., 1 H), 7.00–7.11 (m, 2 H), 7.11–7.23 (m, 3 H), 7.29–7.40 (m, 2 H),
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7.84–8.07 (m, 2 H), 8.61–8.79 (m, 1 H) ppm; 13C NMR (101 MHz, CDCl3): δ = 107.8, 116.0,
116.3, 121.5, 122.0, 122.1, 122.7, 129.7, 129.9, 134.8, 137.8, 137.8, 142.7, 143.4, 146.9,
157.5, 159.9 ppm; HRMS (ESI) calcd. for C15H12FN2 [M+H]+ m/z 239.0979 found m/z
239.0976.
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N-(4-Methoxyphenyl)quinolin-6-amine (3s):27
p-TSA·H2O (19 mg, 10 mol%), quinolin-6-ol 1e (145 mg, 1.0 mmol) and 4-methoxyaniline
2j (369 mg, 3.0 mmol) were treated as described for the synthesis of 3q to obtain 3s as a
brown solid (158 mg, 0.63 mmol, 63%). 1H NMR (400 MHz, CDCl3) δ = 3.85 (s, 3 H), 5.89
(br. s., 1 H), 6.82–7.02 (m, 2 H), 7.11 (d, J=2.52 Hz, 1 H), 7.15–7.25 (m, 2 H), 7.25–7.37 (m,
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2 H), 7.91 (d, J=8.56 Hz, 1 H), 7.98 (d, J=9.06 Hz, 1 H), 8.68 (s, 1 H) ppm; C NMR (101
MHz, CDCl3) δ = 55.5, 106.7, 114.8, 121.4, 122.1, 123.4, 129.8, 130.2, 134.3, 134.6, 143.5,
143.7, 146.7, 156.0 ppm.
1-(Hexyloxy)naphthalene (3t):6
p-TSA·H2O (10 mg, 5 mol%), 1-naphthol 1f (144 mg, 1.0 mmol) and 1-hexanol 2b (306 mg,
3.0 mmol) were treated as described for the synthesis of 3b to obtain 3t as a colorless liquid
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(214 mg, 0.94 mmol, 94%). H NMR (400 MHz, CDCl3) δ = 0.95–1.08 (m, 3 H), 1.40–1.48
(m, 4 H), 1.56–1.69 (m, 2 H), 1.92–2.02 (m, 2 H), 4.18 (t, J = 6.42 Hz, 2 H), 6.85 (dd, J =
7.55, 1.01 Hz, 1 H), 7.35–7.50 (m, 2 H), 7.50–7.63 (m, 2 H), 7.79–7.95 (m, 1 H), 8.32–8.47
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(m, 1 H) ppm; C NMR (101 MHz, CDCl3) δ = 14.0, 22.6, 25.9, 29.3, 31.6, 68.1, 104.5,
119.9, 122.1, 125.0, 125.8, 125.9, 126.3, 127.4, 134.5, 154.9 ppm.
5-(Heptyloxy)naphthalen-1-ol (3u1):
p-TSA·H2O (10 mg, 5 mol%), naphthalene-1,5-diol 1g (160 mg, 1.0 mmol) and 1-heptanol
2c (696 mg, 6.0 mmol) were treated as described for the synthesis of 3b to obtain 3u1 as a
colorless oil (49 mg, 0.20 mmol, 20%). 1H NMR (400 MHz, CDCl3): δ = 0.92 (t, J = 6.67 Hz,
3 H), 1.29–1.49 (m, 6 H), 1.54–1.68 (m, 2 H), 1.86–2.01 (m, 2 H), 4.14 (t, J = 6.42 Hz, 2 H),
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5.23 (s, 1 H), 6.86 (t, J = 7.18 Hz, 2 H), 7.31 (t, J = 8.06 Hz, 1 H), 7.40 (t, J = 8.06 Hz, 1 H),
7.73 (d, J = 8.31 Hz, 1 H), 7.90 (d, J = 8.56 Hz, 1 H) ppm; 13C NMR (101 MHz, CDCl3) δ =
14.1, 22.6, 26.2, 29.1, 29.3, 31.8, 68.2, 105.2, 109.3, 113.4, 114.7, 125.0, 125.3, 127.1, 151.2,
154.8 ppm; HRMS (ESI) calcd. for C17H23O2 [M+H]+ m/z 259.1693 found m/z 259.1691.
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Obtained as colourless oil 3u2 (271 mg, 0.76 mmol, 76%). H NMR (400 MHz, CDCl3) δ =
0.94 (t, J = 8.0 Hz, 6 H), 1.29–1.47 (m, 12 H), 1.55–1.62 (m, 4 H), 1.91–1.98 (m, 4 H), 4.14
(t, J = 8.0 Hz, 4 H), 6.85 (d, J = 7.81 Hz, 2 H), 7.38 (t, J = 8.06 Hz, 2 H), 7.88 (d, J = 8.56
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Hz, 2 H) ppm; C NMR (101 MHz, CDCl3) δ = 14.1, 22.6, 26.3, 29.1, 29.3, 31.8, 68.2,
105.2, 114.0, 125.0, 126.8, 154.7 ppm.
3-(hexyloxy)phenol (3v):29
p-TSA·H2O (19 mg, 10 mol%), resorcinol 1h (110 mg, 1.0 mmol) and 1-hexanol 2b (612 mg,
6.0 mmol) were treated as described for the synthesis of 3a to obtain 3v as a colorless oil
(140 mg, 0.72 mmol, 72%). 1H NMR (400 MHz, CDCl3) δ = 0.95 (t, J = 6.29 Hz, 3 H), 1.34–
1.42 (m, 3 H), 1.42–1.54 (m, 2 H), 1.71–1.86 (m, 2 H), 3.94 (t, J = 6.67 Hz, 2 H), 6.42–6.50
(m, 2 H), 6.53 (d, J = 8.31 Hz, 1 H), 7.14 (t, J = 8.44 Hz, 1 H) ppm; 13C NMR (101 MHz,
CDCl3) δ = 14.0, 22.5, 25.6, 29.1, 31.5, 68.1, 102.2, 107.1, 107.8, 130.1, 156.6, 160.4 ppm.
3,5-Bis(hexyloxy)phenol (3w):
p-TSA·H2O (19 mg, 10 mol%), benzene-1,3,5-triol 1i (126 mg, 1.0 mmol) and 1-hexanol 2b
(612 mg, 6.0 mmol) were treated as described for the synthesis of 3v to obtain 3w as a white
semi solid (235 mg, 0.80 mmol, 80%). 1H NMR (400 MHz, CDCl3): δ = 0.93 (t, J = 6.55 Hz,
6 H), 1.30 (br. s., 1 H), 1.32–1.40 (m, 8 H), 1.40–1.54 (m, 4 H), 1.68–1.85 (m, 4 H), 3.90 (t, J
= 6.55 Hz, 4 H), 6.05 (s, 2 H), 6.10 (s, 1 H) ppm; 13C NMR (101 MHz, CDCl3): δ = 13.9,
22.5, 25.6, 29.1, 31.5, 68.1, 94.3, 94.8, 157.3, 161.0 ppm. HRMS (ESI) calcd. for C18H31O3
[M+H]+ m/z 295.2268 found m/z 295.2260.
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5-(Heptan-2-yloxy)benzene-1,3-diol (3x):30
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p-TSA·H2O (38 mg, 20 mol%), benzene-1,3,5-triol 1i (126 mg, 1.0 mmol) and 2-heptanol 2a
(1.16 g, 10.0 mmol) in 1.5 mL dry toluene were treated as described for the synthesis of 3b to
obtain 3x as a white solid (134 mg, 0.60 mmol, 60%). 1H NMR (400 MHz, CDCl3): δ = 0.88
(t, J = 6.55 Hz, 3 H), 1.24 (d, J = 6.04 Hz, 3 H), 1.26–1.34 (m, 5 H), 1.36–1.44 (m, 1 H),
1.45–1.58 (m, 1 H), 1.60–1.77 (m, 1 H), 4.24 (sxt, J = 5.94 Hz, 1 H), 5.95 (s, 1 H), 6.01 (s, 2
H) ppm; 13C NMR (101 MHz, CDCl3): δ = 14.0, 19.6, 22.6, 25.1, 31.7, 36.3, 74.4, 95.7, 96.2,
157.4, 160.2 ppm.
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N1,N3,N5-Triphenylbenzene-1,3,5-triamine (3y):31
p-TSA·H2O (38 mg, 20 mol%), benzene-1,3,5-triol 1i (126 mg, 1.0 mmol) and aniline 2h
(558 mg, 6.0 mmol) were treated as described for the synthesis of 3a to obtain 3y as a brown
solid (246 mg, 0.70 mmol, 70%). 1H NMR (400 MHz, CDCl3): δ = 5.65 (br. s., 3 H), 6.36 (s,
3 H), 6.96 (t, J = 7.30 Hz, 3 H), 7.11 (d, J = 8.31 Hz, 6 H), 7.23–7.34 (m, 6 H) ppm; 13C
NMR (101 MHz, CDCl3): δ = 98.9, 118.7, 121.2, 129.3, 142.7, 145.3 ppm.
1-Fluoro-4-(hexyloxy)benzene (3z):6
p-TSA·H2O (19 mg, 10 mol%), 4-fluorophenol 1j (112 mg, 1.0 mmol) and 1-hexanol 2b (306
mg, 3.0 mmol) were treated as described for the synthesis of 3a to obtain 3z as a reddish
liquid (45 mg, 0.23 mmol, 23%). 1H NMR (400 MHz, CDCl3): δ = 0.86–0.98 (t, J = 8.0 Hz, 3
H), 1.29–1.42 (m, 4 H), 1.42–1.54 (m, 2 H), 1.70–1.84 (m, 2 H), 3.93 (t, J = 6.55 Hz, 2 H),
6.79–6.88 (m, 2 H), 6.92–7.02 (m, 2 H) ppm; 13C NMR (101 MHz, CDCl3): δ = 14.0, 22.6,
25.7, 29.2, 31.6, 68.6, 115.3, 115.4, 115.6, 115.8, 155.2, 155.2, 155.9, 158.3 ppm.
2-Methylnaphtho[2,1-b]furan (4a):32
p-TSA·H2O (10 mg, 5 mol%), ß-Naphthol 1a (144 mg, 1.0 mmol) and prop-2-yn-1-ol 2m
(168 mg, 3.0 mmol) were treated as described for the synthesis of 3b for 12 h to obtain 4a as
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a brown oil (109 mg, 0.60 mmol, 60%). H NMR (400 MHz, CDCl3) δ = 2.59 (s, 3 H), 6.90
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(d, J = 4.00 Hz, 1 H), 7.45–7.53 (m, 1 H), 7.54–7.73 (m, 3 H), 7.95 (d, J = 8.06 Hz, 1 H),
8.09 (d, J = 8.31 Hz, 1 H) ppm; 13C NMR (101 MHz, CDCl3) δ = 14.2, 101.7, 112.0, 123.4,
123.7, 124.1, 124.2, 125.9, 127.4, 128.6, 130.2, 151.9, 154.7 ppm.
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4-Bromo-2-methylnaphtho[2,1-b]furan (4b):
p-TSA·H2O (10 mg, 5 mol%), 3-bromonaphthalen-2-ol 1b (223 mg, 1.0 mmol) and prop-2-
yn-1-ol 2m (168 mg, 3.0 mmol) were treated as described for the synthesis of 4a for 12 h to
obtain 4b as a yellowish solid (149 mg, 0.57 mmol, 57%). Melting point range: 147–149 °C;
1H NMR (400 MHz, CDCl3) δ = 2.62 (s, 3 H), 6.95 (s, 1 H), 7.44–7.52 (m, 1 H), 7.54–7.61
(m, 1 H), 7.73–7.90 (m, 2 H), 8.04 (d, J=8.06 Hz, 1 H) ppm; 13C NMR (101 MHz, CDCl3) δ
= 14.3, 102.6, 104.6, 123.5, 125.0, 125.4, 125.7, 126.2, 126.4, 127.8, 131.2, 148.7, 155.7
ppm; HRMS (ESI) calcd. for C15H12BrO3 [M+OAc]– m/z 318.9975 found m/z 318.9995.
7-Bromo-2-methylnaphtho[2,1-b]furan (4c):33
p-TSA·H2O (10 mg, 5 mol%), 6-bromonaphthalen-2-ol 1c (223 mg, 1.0 mmol) and prop-2-
yn-1-ol 2m (168 mg, 3.0 mmol) were treated as described for the synthesis of 4a for 12 h to
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obtain 4c as a yellowish solid (131 mg, 0.50 mmol, 50%). H NMR (400 MHz, CDCl3) δ =
2.58 (s, 3 H), 6.85 (s, 1 H), 7.49–7.59 (m, 1 H), 7.59–7.66 (m, 2 H), 7.95 (d, J=8.22 Hz, 1 H),
8.09 (d, J=1.76 Hz, 1 H) ppm; 13C NMR (101 MHz, CDCl3) δ = 14.2, 101.6, 113.1, 117.8,
122.7, 125.2, 129.0, 130.6, 131.4, 152.0, 155.3 ppm.
2-Methyl-1-phenylnaphtho[2,1-b]furan (4d):34
p-TSA·H2O (10 mg, 5 mol%), ß-Naphthol 1a (144 mg, 1.0 mmol) and 1-phenylprop-2-yn-1-
ol 2n (396 mg, 3.0 mmol) were treated as described for the synthesis of 4a to obtain 4d as a
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brown oil (158 mg, 0.61 mmol, 61%). H NMR (400 MHz, CDCl3) δ = 2.46 (s, 3 H), 7.29–
7.35 (m, 1 H), 7.41 (td, J = 7.49, 1.13 Hz, 1 H), 7.44–7.59 (m, 5 H), 7.62–7.75 (m, 2 H), 7.79
(d, J = 8.31 Hz, 1 H), 7.94 (d, J = 8.06 Hz, 1 H) ppm; 13C NMR (101 MHz, CDCl3) δ = 12.3,
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112.0, 118.9, 122.3, 123.2, 124.0, 124.5, 125.6, 127.5, 127.9, 128.6, 128.8, 130.5, 130.7,
134.2, 151.2, 151.2 ppm.
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p-TSA·H2O (10 mg, 5 mol%), ß-Naphthol 1a (144 mg, 1.0 mmol) and but-3-yn-2-ol 2o (210
mg, 3.0 mmol) were treated as described for the synthesis of 4a to obtain 4e as a reddish oil
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(102 mg, 0.52 mmol, 52%). H NMR (400 MHz, CDCl3): δ = 2.50 (s, 3 H), 2.59 (s, 3 H),
7.48 (t, J=7.05 Hz, 1 H), 7.52–7.63 (m, 2 H), 7.63–7.70 (m, 1 H), 7.96 (d, J=8.06 Hz, 1 H),
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8.41 (d, J=8.06 Hz, 1 H) ppm; C NMR (101 MHz, CDCl3): δ = 11.4, 11.7, 111.7, 112.1,
123.0, 123.2, 123.7, 123.9, 125.7, 128.7, 128.9, 130.6, 149.9, 151.2 ppm.
7H-benzo[c]carbazole (4f):36
Pd(OAc)2 (23 mg, 10 mol%), Cu(OAc)2 (182 mg, 1.0 mmol) and N-phenylnaphthalen-2-
amine 3h (219 mg, 1.0 mmol) was refluxed in 3 mL dry acetonitrile for 24 h. Pd(OAc)2 (23
mg, 10 mol%) and Cu(OAc)2 (182 mg, 1.0 mmol) was added and the reaction was continued
for another 24 h. After completion of the reaction, acetonitrile was evaporated and the residue
was purified by flash column chromatography to obtain 4f as a reddish brown oil (65 mg,
0.30 mmol, 30%). 1H NMR (400 MHz, CDCl3): δ = 7.42 (t, J = 7.43 Hz, 1 H), 7.45–7.54 (m,
2 H), 7.60 (d, J = 8.06 Hz, 1 H), 7.65 (d, J = 8.81 Hz, 1 H), 7.68–7.77 (m, 1 H), 7.89 (d, J =
8.56 Hz, 1 H), 8.03 (d, J = 8.31 Hz, 1 H), 8.47 (br. s., 1 H), 8.60 (d, J = 7.81 Hz, 1 H), 8.81
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(d, J = 8.06 Hz, 1 H) ppm; C NMR (101 MHz, CDCl3): δ = 104.5, 111.1, 112.6, 120.2,
122.0, 123.0, 123.2, 124.0, 124.3, 126.9, 127.4, 129.2, 129.2, 129.9 ppm.
10-Fluoro-7H-benzo[c]carbazole (4g):37
Pd(OAc)2 (46 mg, 20 mol%), Cu(OAc)2 (364 mg, 2.0 mmol) and N-(4-
fluorophenyl)naphthalen-2-amine 3i (237 mg, 1.0 mmol) was refluxed as described for the
synthesis of 4f to obtain 4g as a brown solid (73 mg, 0.31 mmol, 31%). 1H NMR (400 MHz,
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CDCl3): δ = 7.22 (td, J = 8.88, 2.39 Hz, 1 H), 7.39–7.55 (m, 2 H), 7.62 (d, J = 8.81 Hz, 1 H),
7.74 (t, J = 7.68 Hz, 1 H), 7.89 (d, J = 8.81 Hz, 1 H), 8.02 (d, J = 8.06 Hz, 1 H), 8.22 (dd, J =
10.07, 2.27 Hz, 1 H), 8.42 (br. s., 1 H), 8.66 (d, J = 8.31 Hz, 1 H) ppm; 13C NMR (101 MHz,
CDCl3): δ = 107.4, 107.6, 111.4, 111.5, 112.1, 112.4, 112.6, 122.8, 123.2, 127.1, 128.1,
129.1, 129.2, 129.7, 134.7, 138.3, 156.7, 159.1 ppm.
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10-Methoxy-7H-benzo[c]carbazole (4h):38
Pd(OAc)2 (46 mg, 20 mol%), Cu(OAc)2 (364 mg, 2.0 mmol) and N-(4-
methoxyphenyl)naphthalen-2-amine 3j (249 mg, 1.0 mmol) was refluxed as described for the
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synthesis of 4f to obtain 4h as a deep green solid (94 mg, 0.38 mmol, 38%). H NMR (400
MHz, CDCl3): δ = 4.05 (s, 3 H), 7.15 (dd, J=8.81, 2.27 Hz, 1 H), 7.48–7.53 (m, 2 H), 7.64 (d,
J=8.56 Hz, 1 H), 7.74 (ddd, J=8.31, 7.05, 1.26 Hz, 1 H), 7.87 (d, J=8.56 Hz, 1 H), 8.00–8.06
(m, 2 H), 8.36 (br. s., 1 H), 8.73 (d, J=8.56 Hz, 1 H); 13C NMR (101 MHz, CDCl3): δ = 56.2,
105.1, 111.6, 112.7, 113.5, 115.3, 122.8, 122.9, 124.4, 126.8, 127.4, 129.1, 129.2, 129.9,
133.4, 137.8, 154.4 ppm.
Gram Scale Experiment between 2-Naphthol (1a) and 1-Hexanol (2b): Catalyst p-
TSA·H2O (132 mg, 5 mol%), 2-Naphthol 1a (2.00 g, 13.87 mmol) and 1-hexanol 2b (4.25 g,
41.62 mmol) were taken in a 10 mL reaction vial under nitrogen atmosphere. The cap of the
vial was closed and the reaction mixture was stirred at 120 °C for 12 h in an oil bath. After
completion of the reaction (GCMS), the crude was directly purified by silica-gel (230–400
mess) column chromatography (flash) using 2% (v/v) ethyl acetate / hexane solution to afford
the desired product 2-(hexyloxy)naphthalene 3b as a colourless liquid (2.95 g, 12.90 mmol,
93%).
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Acknowledgement
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SB thanks DST-Inspire programme, Govt. of India for financial support and Faculty Award
(DST/INSPIRE/04/2013/000017). AM thanks DST-Inspire for his project fellowship. We are
thankful to Prof. Ganesh Pandey for his generous supports and Centre of Bio-Medical
Research (CBMR) for infrastructural and financial assistances. We also thank Dr.
Chattopadhaya for helpful discussions; Prof. Roy, Dr. Baishya and Mr. Ajay for their helps in
NMR; Mr. Prashant and Mr. Durgaprasad for HRMS; and Ms. Ranjana for melting point
determinations. We are extremely thankful to the corresponding reviewers for their valuable
comments and suggestions.
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Supporting Information Available
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Optimization table, compound characterization checklist, and copies of H and C NMR
Spectra. This material is available free of charge via the Internet at http://pubs.acs.org.
References and Footnotes
(1) For selected examples, see: ac ic ter ripps ran- u , M.; Zhu, H.; Huang, B.;
Cui, J.; Sutton, S. C. Org. Lett. 2012, 14, 3886.
(2) Mare, P. B. D. L. Electrophilic halogenations; Cambridge University Press: New York, 1976.
(3) For selected examples, see: (a) Maiti, D.; Buchwald, S. L. J. Org. Chem. 2010, 75, 1791. (b) Larsson, P.-
F.; Correa, A.; Carril, M.; Norrby P.–O.; Bolm, C. Angew. Chem., Int. Ed., 2009, 48, 5691. (c) Buchwald S. L.;
Bolm, C. Angew. Chem., Int. Ed., 2009, 48, 5586. (d) Maiti, D.; Buchwald, S. L. J. Am. Chem. Soc., 2009, 131,
17423. (e) Bistri, O.; Correa, A.; Bolm, C. Angew. Chem., Int. Ed., 2008, 47, 586. (f) Shelby, Q.; Kataoka, N.;
Mann, G.; Hartwig, J. F. J. Am. Chem. Soc., 2000, 122, 10718.
(4) (a) Yu, D. –G.; Li, B. –J.; Zheng, S. –F.; Guan, B. –T.; Wang, B. –Q.; Shi, Z. –J. Angew. Chem. Int. Ed.
2010, 49, 4566. (b) Yu, D. –G. Shi, Z. –J. Angew. Chem. Int. Ed. 2011, 50, 7097. (c) Ackermann, L.; Pospech, J.;
Potukuchi, H. K. Org. Lett. 2012, 14, 2146.
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