Synthesis of substituted naphthalenes from α-tetralones generated by a xanthate radical addition-cyclisation sequence

Article abstract of DOI:10.1039/b411158c

A simple, highly efficient and cheap synthesis of substituted naphthalenes is reported. These aromatic compounds can be easily prepared in acidic or basic conditions from α-tetralones, obtained by a xanthate-mediated addition-cyclisation sequence.

Full text of DOI:10.1039/b411158c

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A R T I C L E
Synthesis of substituted naphthalenes from a-tetralones generated by
a xanthate radical addition–cyclisation sequence
Alejandro Cordero-Vargas, Inés Pérez-Martín, Béatrice Quiclet-Sire and Samir Z. Zard*
Laboratoire de Synthèse Organique associé au CNRS, Ecole Polytechnique, 91128 Palaiseau,
France. E-mail: zard@poly.polytechnique.fr
Received 23rd July 2004, Accepted 1st September 2004
First published as an Advance Article on the web 27th September 2004
A simple, highly efficient and cheap synthesis of substituted naphthalenes is reported. These aromatic compounds
can be easily prepared in acidic or basic conditions from a-tetralones, obtained by a xanthate-mediated addition–
cyclisation sequence.
simplicity, cheapness, absence of heavy metals, ease of scale-up
and the possibility of operating under fairly concentrated condi-
tions.
Introduction
Much attention has recently been focused on the regioselec-
tive synthesis of substituted naphthalene derivatives.1 These
compounds constitute the basic skeleton of many biologically
important natural products and pharmaceuticals2 and synthetic
routes to the naphthalene moiety are highly desirable.
Due to their stability, these aromatic compounds react with
difficulty under mild conditions and, on many occasions, the
use of drastic methods results in non-regioselective reactions. In
addition, when regioselectivity exists, it usually depends on the
nature of the substituents already present in the aromatic ring
(electron-withdrawing or electron-donating groups).
In order to circumvent these limitations, we have developed
a simple methodology for the preparation of the naphthalene
skeleton by using the functionalisation of an a-tetralone and its
aromatisation under acidic or basic conditions, independently
of the nature of the substituents in the ring (Scheme 1).
With the aim of accessing substituted naphthalenes, obtained
from modified a-tetralones, we prepared different precursors
through a two-step one-pot protocol using a range of xanthates
and olefins (Table 1). This is in contrast to our earlier work
where the intermediate adduct 3 was isolated.
The selection of vinyl pivalate 2a as the radical trap was not
arbitrary. It was anticipated that the OPiv group could serve as
a leaving group for the aromatisation in acidic media in order to
facilitate the last step of the route. Furthermore, the pivaloxy
group is compatible with a number of useful transformations
as shown below.
One important aspect that emerges from inspection of
the examples in Table 1 is that in principle, practically all of
the positions of the tetralone structure may be functionalised by
the appropriate choice of the initial xanthate and olefin compo-
nents or by subsequent modification of the product. Although
the overall yields of tetralones 4a–4f may seem moderate, it
must be realised that they correspond to two difficult radical
processes: an intermolecular addition to a non-activated olefin
and a ring closure to an aromatic ring. Both of these steps would
have been difficult to perform using other radical methods. As
for substituents on the starting xanthate moiety, both electro-
donating and electron-withdrawing groups are tolerated.
In the case of tetralones 4a, 4b and 4c, we found that addition
of camphorsulfonic acid (CSA) during the ring-closing step was
beneficial and allowed up to 20% increase in yield. Protonation
of the ketone oxygen presumably causes a speeding up of the
radical addition to the aromatic ring.4 In contrast, with 4d and
4f, which contain electron donating groups, the addition of CSA
proved deleterious causing a rapid degradation and a dramatic
lowering of the yield (to about 10%). The reason may be the pre-
mature elimination of the pivaloxy group. Such an elimination is
facilitated by electron releasing substituents.
Preparation of the required naphthalenes was accomplished
starting from these suitably substituted tetralones or by modifi-
cation of the precursors followed by aromatisation under acidic
or basic conditions as summarized in Table 2 and Scheme 3.
The initial experiments were carried out directly on the
tetralones 4a, 4e and 4f (entries 1, 2 and 3) employing p-tolu-
enesulfonic acid (PTSA) in refluxing toluene. We obtained the
corresponding naphthols in good yields, except in the case of
tetralone 4f (entry 3), where a complex mixture of products was
observed.
Scheme 1
It is known that tetralones can be transformed into their cor-
responding aromatic structures by different methods such as
oxidation with DDQ or Pd/C at high temperatures. However,
commercially available tetralones are limited, as well as general
methods to obtain functionalised precursors for the desired
aromatic systems.
Results and discussion
A few years ago, we reported a new method for the prepara-
tion of a-tetralones using xanthate free radical chemistry
(Scheme 2).3
Scheme 2 Radical addition–cyclisation sequence.
Next, a simple, but important functionalisation was made
prior to the aromatisation step. In this way, tetralones 4a, 4c,
4d and 4f were treated with pyridinium bromide perbromide,
to give compounds 7, 9, 12 and 14 respectively, without affect-
ing the pivalate group.5 These compounds were then subjected
directly to different aromatisation processes. Thus, in the case
We had shown that xanthates such as 1 undergo a radical
chain reaction to a great variety of olefinic traps 2 to give ad-
duct 3, which can be used as a starting point for another radical
sequence, in this case, to construct the six-membered ring of
a-tetralone 4. This methodology has important virtues such as
3 0 1 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 1 8 – 3 0 2 5
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 1 Formation of a-tetralones employed like precursorsa
These last two examples illustrate the possibility of creating C–C
bonds next to the carbonyl group in order to obtain more complex
naphthalene structures. In recent times, the synthesis of such struc-
tures has relied heavily on transition metal catalysed processes.8
Naphthylamines can be obtained via the corresponding
Schiff base. For example, when compound 4b was treated with
benzylamine followed by in situ aromatisation of the interme-
diate imine with AlCl3, naphthalene 19a was produced in good
yield (entry 12). When a Fischer indole synthesis was carried out
with the same tetralone 4b, by treatment with phenylhydrazine
in polyphosphoric acid,9 the tetracyclic compound 20 was ob-
tained in 56% yield (entry 13). These types of products have
attracted a great deal of attention from synthetic as well as medi-
cinal chemists because such structures are present in a number
of natural products.10
Xanthate 1
Olefin 2
Product 4
Yieldb (%)
49c
81c
2a
Finally, examples of treatment of the a-tetralones with carbon
nucleophiles and aromatisation are depicted in Scheme 3.
50
2a
52d
2a
2a
54
41
Scheme 3 Aromatisation of compounds derived from tetralones.11
In the first case, starting from the tetralone 4a and apply-
ing a Horner–Emmons reaction, olefin 22 was obtained in
good yield. The aromatisation process was carried out with p-
toluenesulfonic acid to produce naphthalene 23 in 67% yield.
Lithium acetylides could also be added to the tetralone
carbonyl without affecting the pivaloxy group as illustrated by
the efficient synthesis of 24 and 26. Subsequent aromatization
with POCl3/Py gave the corresponding naphthalenes. In these
cases, the usual treatment with PTSA was not satisfactory.
Compound 25 is especially interesting since it contains a reac-
tive propargyl chloride and thus represents a springboard for
numerous subsequent transformations.
In summary, we have described a convergent approach to
naphthalene structures with a diverse pattern of substitution.
The process involves cheap, readily available reagents and is
based on radical chemistry that does not involve the use of heavy
metals such as tin or mercury.
a Reactions were performed with dilauroyl peroxide (DLP) in 1,2-
dichloroethane at reflux. b Global yield of the xanthate radical addi-
tion–cyclisation processes. c Camphorsulfonic acid (CSA) was added
(10 mmol%). d If CSA is added, a rapid degradation is observed.
of 7 and 9 the reaction was carried out under acidic conditions
with PTSA and pyridinium bromide perbromide, respectively,
and the corresponding a-bromonaphthols were produced in
good yields (entries 4 and 5). These compounds are important in
organic synthesis because they are substrates for various transi-
tion metal catalysed reactions and are appropriate precursors for
the generation of benzynes which, although not isolable, act as
dienophiles that can be trapped with dienes in Diels–Alder reac-
tions to give more complex tricyclic compounds.6 Alternatively,
the treatment of tetralones 7 and 12 with Li2CO3 and LiBr in
dimethylformamide gave regioselectively monoprotected naph-
thalenediols 11 and 13 in 57 and 64% yield respectively (entries
6 and 7), but unfortunately, in the case of the tetralone 14, a
complex mixture was obtained (entry 8).
Tetralone 15, which possesses a xanthate group at the carbon
in the a position to the carbonyl group, was obtained in 68%
yield by nucleophilic displacement of the bromine atom in
tetralone 7. The aromatisation was carried out in the presence
of PTSA, and the product 16 was obtained in excellent yield,
resulting from the aromatisation process and nucleophilic ad-
dition of the resulting phenolic oxygen onto the thiocarbonyl
group (entry 9).
When a-bromotetralone 7 was treated with ethyl cyano-
acetate and K2CO3, naphthalene 17 was produced in 51%
yield after acidification with an aqueous citric acid solution
(entry 10).7
In the formation of naphthol 18, advantage was taken of the
nucleophilic character of the a-carbon to the carbonyl group in
the corresponding tetralone to carry out an aldol condensation
with benzaldehyde. The isomerisation of the exocyclic double
bond in the basic medium generates the corresponding naphthol
18 in moderate yield (entry 11).
Experimental
All reactions were carried out under an inert atmosphere. Com-
mercial reagents were used as received without further purifica-
tion. All products were purified by using silica gel SDS 60 C. C.
40–63 or by crystallisation. NMR spectra were recorded in
CDCl3 with TMS as an internal standard at room tempera-
1
ture on a Bruker AMX400 operating at 400 MHz for H and
100 MHz for 13C. Infrared absorption spectra were recorded as
a solution in CCl4 with a Perkin-Elmer 1600 Fourier Transform
Spectrophotometer. Some mass spectra were determined at
70 eV with an AutoSpec Micromass and the others were re-
corded with an HP 5989B mass spectrometer using ammonia as
the reagent gas. Melting points were determined using a Reichert
microscope apparatus and were uncorrected.
Dithiocarbonic acid [2-(2,5-dimethoxy-phenyl)-2-oxo-ethyl] ester
ethyl ester (1c)
To
a cold (0 °C) solution of 2,5-dimethoxy-2-bromo-
acetophenone12 (5 g, 19.29 mmol) in acetone (38.6 mL)
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 1 8 – 3 0 2 5
3 0 1 9

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Table 2 Aromatisation of substituted a-tetralones
Tetralone
Methoda
Product
Yield (%)
1
2
3
4
A
A
A
A
84
74
—
69
—
5
B
C
75
57
6
7
7
8
C
C
64
—
—
9
A
D
90
51
10
7
11
E
32
12
13
F
75
56
4b
G
a METHOD A: Tetralone derivative (1 mmol) in toluene (35 mL) containing p-toluenesulfonic acid (3 mmol) was refluxed using a Dean–Stark
apparatus. METHOD B: Tetralone derivative (1 mmol) in acetic acid (10 mL) containing pyridinium bromide perbromide (1 mmol) was stirred at
room temperature for 1 h. METHOD C: Tetralone derivative (1 mmol) in dry dimethylformamide (6 mL) containing Li2CO3 (2 mmol) and LiBr
(2 mmol) was warmed at 140 °C. METHOD D: To a cold solution of ethyl cyanoacetate (12 mmol) in acetone (2 mL) was added K2CO3 (3 mmol)
and the tetralone (1 mmol) was added at 0 °C. The mixture was stirred at room temperature and then acidified with an aqueous solution of citric acid.
METHOD E: To the tetralone derivative (1 mmol) and benzaldehyde (1.5 mmol) in dry tert-butanol (10 mL) was added t-BuOK (2 mmol) and the
mixture was heated under reflux conditions. METHOD F: Tetralone derivative (1 mmol) in dry toluene (10 mL) containing benzylamine (2 mmol)
was heated under reflux for 3 h. Then, AlCl3 (2 mmol) was added at room temperature and the solution was refluxed for 15 min. METHOD G: Fischer
indole synthesis. The tetralone (1 mmol) was treated with phenylhydrazine (2 mmol) and polyphosphoric acid (2.5 mmol), and the mixture was heated
at 100 °C for 15 min.
3 0 2 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 1 8 – 3 0 2 5

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was added portionwise potassium O-ethylxanthate (3.4 g,
21.22 mmol). The reaction mixture was stirred at 0 °C for
a further 1 h, the solvent was evaporated and the resulting mix-
ture partitioned between water and CH2Cl2. The aqueous phase
was extracted with CH2Cl2, the combined organic extracts were
dried over Na2SO4 and concentrated under reduced pressure.
Recrystallization of the residue from CH2Cl2–petroleum ether
gave xanthate 1c (95% yield) as yellow crystals. mp = 71–72 °C;
mmax/cm−1 1676 (CO), 1223 (S–CS), 1050 (S–CS); dH
(400 MHz) 7.31 (1H, d, J = 3.2 Hz, CH arom), 7.07 (2H, dd,
J = 9.2, 3.2 Hz CH arom), 6.93 (1H, d, J = 9.2 Hz, CH arom),
4.59–4.64 (4H, m, OCH2 and CH2–S), 3.91 (3H, s, OCH3), 3.78
(3H, s, OCH3), 1.39 (3H, dd, J = 7.2, 7.2 Hz, CH3); dC (100 MHz)
213.8 (C, CS), 193.5 (C, CO), 153.8 (C, C–OMe), 153.4 (C,
C–OMe), 126.6 (C, C–CO), 121.3 (CH, CH arom), 114.4 (CH,
CH arom), 113.2 (CH, CH arom), 70.3 (CH2, OCH2), 56.2 (CH3,
OCH3), 55.9 (CH3, OCH3), 47.7 (CH2, CH2–S), 13.8 (CH3); m/z
(CI + NH3) 318 (MH+ + NH3), 301 (MH+).
2-(7-Chloro-4-oxo-1,2,3,4-tetrahydro-1-naphthalenyl)ethyl
acetate (4c)
According to the typical procedure, a solution of xanthate 1b
(3.80 g, 13.8 mmol) and 3-butenyl acetate 2b (3.15 g, 27.6 mmol)
in DCE (14 mL) was treated with DLP. A refluxing solution of
the crude adduct and CSA (0.32 g, 1.4 mmol) in DCE (140 mL)
was then subjected to the described reaction conditions to afford
tetralone 4c as a yellow oil (50%) (silica gel, petroleum ether–
ethyl acetate, 9:1). mmax/cm−1 1745 (O–CO), 1691 (CO); dH
(400 MHz) 7.96 (1H, d, J = 8.0 Hz, CH arom), 7.26–7.30 (2H,
m, 2 × CH arom), 4.15–4.23 (4H, m, CH2–OAc and CH–CH2),
3.06 (1H, m, 1-H), 2.74 (1H, ddd, J = 17.9, 11.6, 5.1 Hz, 3-Ha),
2.60 (1H, ddd, J = 18.0, 5.2, 5.2 Hz, 3-Hb), 2.28 (1H, m, 2-Ha),
2.01 (1H, m, 2-Hb), 2.07 (3H, s, CO–CH3); dC (100 MHz) 196.6
(C, CO), 171.0 (C, O–CO), 148.7 (C, C-7), 139.9 (C, C-CO),
130.2 (CH, C–CH), 129.3 (CH arom), 128.1 (CH arom), 127.5
(CH arom), 62.1 (CH2, CH2–OAc), 42.8 (CH, C-1), 34.9 (CH3,
OC(O)CH3), 34.6 (CH2, C-3), 33.1 (CH2, CH–CH2), 26.7 (C-
2); m/z (CI + NH3) 286 (MH+ + NH3), 284 (MH+ + NH3), 269
(MH+), 267 (MH+); Anal. calcd. for C14H15ClO3: C, 63.04; H,
5.67. Found: C, 62.83; H, 5.73%.
General procedure for the preparation of tetralones 4a–4f
A solution of xanthate (1 mmol) and vinyl pivalate (2 mmol) in
1,2-dichloroethane (DCE) (1 mL) was refluxed for 15 min under
argon. Lauroyl peroxide (DLP) (5 mol%) was then added to the
refluxing solution, followed by additional portions (2.5 mol%
every 90 min). When starting material was completely consumed
the mixture was cooled to room temperature, concentrated
under reduced pressure and the crude mixture, redissolved in
1,2-dichloroethane (10 mL) together with camphorsulfonic acid
(0.1 mmol, when electron-withdrawing groups are present in
the aromatic ring). DLP was then added to the refluxing solu-
tion (20 mol% every hour). When starting material was totally
consumed, the mixture was cooled to room temperature, con-
centrated under reduced pressure and purified by flash column
chromatography (silica gel, petroleum ether–ethyl acetate, a
small layer of basic alumina was placed on the top of the silica
to remove any lauric acid present) to give the final tetralone.
5,8-Dimethoxy-4-oxo-1,2,3,4-tetrahydro-1-naphthalenyl pivalate
(4d)
Obtained from xanthate 1c as a yellow solid (52%) (silica gel,
petroleum ether–ethyl acetate, 4:1). mp 102–103 °C (CH2Cl2–
petroleum ether); mmax/cm−1 1728 (O–CO), 1695 (CO); dH
(400 MHz) 7.06 (1H, d, J = 8.8 Hz, CH arom), 6.97 (1H, d,
J = 9.2 Hz, CH arom), 6.31 (1H, br s, 1-H), 3.86 (3H, s, OCH3),
3.77 (3H, s, OCH3), 2.82 (1H, ddd, J = 15.2, 5.1, 5.1 Hz, 3-Ha),
2.53 (1H, ddd, J = 16.4, 16.4, 4.8 Hz, 3-Hb), 2.33 (1H, dddd,
J = 14.4, 14.4, 2.3, 0.0 Hz, 2-Ha), 2.17 (1H, dddd, J = 14.2, 14.2,
t
3.6, 3.6 Hz, 2-Hb), 1.13 (9H, s, Bu); dC (100 MHz) 197.2 (C,
CO), 177.6 (C, O–CO), 153.4 (C, C–OMe), 150.6 (C, C–OMe),
130.0 (C, C–CO), 122.6 (C, C–CH), 116.8 (CH arom), 113.5 (CH
arom), 63.7 (C-1), 56.5 (CH3, OMe), 56.2 (CH3, OMe), 38.9 (C,
tBu), 34.9 (CH2, C-3), 27.1 (3 × CH3, tBu), 26.9 (CH2, C-2); m/z
(CI + NH3) 307 (MH+), 205 (MH+ − OPiv); Anal. calcd. for
C17H22O5: C, 66.65; H, 7.24. Found: C, 66.32; H, 7.25%.
7-Fluoro-4-oxo-1,2,3,4-tetrahydro-1-naphthalenyl pivalate (4a)
Obtained from xanthate 1a13 as a yellow oil (49%) (silica gel,
petroleum ether–ethyl acetate, 9:1); mmax/cm−1 1732 (O–CO),
1694 (CO), 1148 (O–CO); dH (400 MHz) 7.97 (1H, dd,
J = 8.8, 5.2 Hz, CH arom), 7.12 (2H, m, CH arom), 6.06 (1H, dd,
J = 8.0, 4.0 Hz, 1-H), 2.89 (1H, ddd, J = 20.0, 8.0, 4.0 Hz, 3-Ha),
2.68 (1H, ddd, J = 16.8, 8.0, 4.0 Hz, 3-Hb), 2.42 (1H, m, 2-Ha),
2.24 (1H, m, 2-Hb), 1.25 (9H, s, 3 × Me); dC (100 MHz) 195.4 (C,
Diethyl 5-[(2,2-dimethylpropanoyl)oxy]-2,8-dioxo-5,6,7,8-
tetrahydro-1H-naphtho[2,3-d]imidazole-1,3(2H)-dicarboxylate
(4e)
Obtained from xanthate 1d14 as a white solid (54%) (silica gel,
petroleum ether–ethyl acetate, 8:2), mp 120–123 °C (AcOEt);
mmax/cm−1 1791 (O–CO), 1752 (O–CO), 1731 (O–CO), 1694
(CO); dH (400 MHz) 8.10 (2H, s, 2 × CH arom), 6.36 (1H, dd,
J = 7.2, 4.0 Hz, 5-H), 4.46–4.55 (4H, m, 2 × COOCH2CH3), 2.81
(1H, m, 7-Ha), 2.70 (1H, m, 7-Hb), 2.50 (1H, m, 6-Ha), 2.14 (1H,
m, 6-Hb), 1.47 (6H, dd, J = 15.2, 6.8 Hz, 2 × COOCH2CH3),
1.14 (9H, s, tBu); dC (100 MHz) 195.4 (C, CO), 177.3 (C), 149.6
(2 × C), 147.7 (C), 131.4 (C, C–N), 129.5 (C, C–N), 126.6 (C,
C–CO), 125.1 (CH arom), 123.6 (C, C–CH), 114.5 (CH arom),
1
C-4), 176.3 (C, O–CO), 166.0 (C, C-7, JC–F = 254.6 Hz), 144.5
(C, C–CO), 130.6 (CH, d, 3JC–F = 10.5 Hz, CH arom), 116.4 (CH,
d, 2JC–F = 23.0 Hz, CH arom), 115.5 (C, C–CH), 114.4 (CH, d,
t
2JC–F = 23.0 Hz, CH arom), 68.6 (CH, C-1), 39.1 (C, Bu), 34.7
(CH2, C-3), 28.7 (CH2, C-2), 27.1 (3 × CH3, tBu); m/z (CI + NH3)
282 (MH+ + NH3), 265 (MH+), 164 (MH+ − OPiv); Anal. calcd.
for C15H17O3F: C, 68.17; H, 6.48. Found: C, 68.31; H, 6.65%.
t
7-Chloro-4-oxo-1,2,3,4-tetrahydro-1-naphthalenyl pivalate (4b)
66.8 (CH, C-5), 65.6 (CH3), 64.6 (CH3), 39.0 (C, Bu), 33.6
(CH2, C-7), 27.4 (CH2, C-6), 26.9 (3 × CH3, tBu), 14.1 (2 × CH3,
Obtained from xanthate 1b13 as a yellow solid (81%), (silica gel,
petroleum ether–ethyl acetate, 9:1), mp 76–80 °C (petroleum
ether); mmax/cm−1 1733 (O–CO), 1696 (CO), 1143 (O–CO);
dH (400 MHz) 8.00 (1H, d, J = 8.0 Hz, CH arom), 7.42 (1H, d,
J = 8.0 Hz, CH arom), 7.41 (1H, s, CH arom), 6.05 (1H, dd,
J = 8.0, 4.0 Hz, 1-H), 2.90 (1H, ddd, J = 18.0, 10.0, 4.0 Hz, 3-
Ha), 2.69 (1H, ddd, J = 20.0, 8.0, 4.0 Hz, 3-Hb), 2.41 (1H, m,
2-Ha), 2.26 (1H, m, 2-Hb), 1.25 (9H, s, 3 × Me); dC (100 MHz)
195.3 (C, C-4), 177.3 (C, O–CO), 142.5 (C, C–CO), 139.9 (C,
C-7), 129.9 (C, C–CH), 128.9 (CH arom), 128.6 (CH arom),
2 × CO2Et); m/z (CI + NH3) 464 (MH+ + NH3), 447 (MH+).
1-(2,2-Dimethylpropanoyl)-8-oxo-5,6,7,8-tetrahydro-1H-
benzo[f]indol-5-yl pivalate (4f )
Obtained from xanthate 1e13 as a white solid (41%) (silica gel,
petroleum ether–ethyl acetate, 95:5), mp 149–151 °C (petroleum
ether); mmax/cm−1 1724 (O–CO), 1682 (CO); dH (400 MHz)
8.06 (1H, d, J = 8.0 Hz, CH arom), 7.75 (1H, d, J = 3.6 Hz,
CH arom), 7.63 (1H, d, J = 8.4 Hz, CH arom), 6.63 (1H, d,
J = 3.6 Hz, CH arom), 6.44 (br s, 5-H), 2.98 (1H, ddd, J = 18.4,
12.6, 6.0 Hz, 7-Ha), 2.70 (1H, m, 7-Hb), 2.35–2.49 (2H, m, 6-H2),
t
127.4 (CH arom), 67.9 (CH, C-1), 38.6 (C, Bu), 34.2 (CH2,
C-3), 28.1 (CH2, C-2), 27.1 (3 × CH3, tBu); m/z (CI + NH3) 299
(MH+ + NH3), 297 (MH+ + NH3), 283 (MH+), 281 (MH+), 182
(MH+ − OPiv), 180 (MH+ − OPiv); Anal. calcd. for C15H17O3Cl:
C, 64.17; H, 6.10. Found: C, 64.04; H, 6.25%.
t
t
1.58 (9H, s, Bu), 1.06 (9H, s, Bu); dC (100 MHz) 197.9 (C,
CO), 180.1 (C, N–CO), 177.5 (C, O–CO), 136.0 (C, C–N–Piv),
133.6 (C, C–CO), 130.2 (C, C–C–N), 130.0 (CH arom), 129.3
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 1 8 – 3 0 2 5
3 0 2 1

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(C, C–CH), 123.1 (CH arom), 121.7 (CH arom), 107.1 (CH
arom), 65.8 (CH, C-5), 42.1 (C, N–CO–C(CH3)3), 38.8 (C,
O–CO–C(CH3)3), 32.6 (CH2, C-7), 29.0 (3 × CH3, N–CO–
C(CH3)3), 27.5 (CH2, C-6), 27.1 (3 × CH3, O–CO–C(CH3)3); m/z
(CI + NH3) 387 (MH+ + NH3), 370 (MH+), 268 (MH+ − OPiv).
dd, J = 9.6, 2.4 Hz), 7.29 (1H, ddd, J = 9.2, 9.2, 2.8 Hz), 7.24
(1H, d, J = 8.8 Hz), 6.01 (1H, br s, OH); dC (100 MHz) 162.5
(C), 160.1 (C), 148.4 (C), 134.8 (2 × C), 129.7 (CH), 125.2
3
4
(CH, JCF = 9.2 Hz), 120.6 (CH, JCF = 5.1 Hz), 116.1 (CH,
2JCF = 16.4 Hz), 110.8 (CH, JCF = 20.7 Hz); m/z (CI + NH3)
2
240 (M+ − 1), 257 (M+ − 1 + NH3); m/z (rel intensity) 242 (M+,
11), 240 (M+, 100); HRMS calcd for C10H6FBrO: 241.956558;
found 241.953297. Anal. Calcd. for C10H6FBrO: C, 49.83; H,
2.51. Found: C, 50.26; H, 3.02%.
Aromatisation of substituted a-tetralones
Method A. 6-Fluoro-1-naphthol (5). A solution of tetralone
4a (0.1 g, 0.378 mmol) and of PTSA·H2O (0.21 g, 1.13 mmol)
in 12.5 mL of toluene was refluxed for 3 h with a Dean–Stark
apparatus. When the starting material was totally consumed, the
reaction mixture was allowed to cool to room temperature, neu-
tralised with saturated aqueous Na2CO3, extracted with CH2Cl2,
dried (Na2SO4) and evaporated under reduced pressure. The
residue was purified by flash column chromatography (silica gel,
petroleum ether–ethyl acetate, 9:1) to give naphthol 5 (84%) as
a pale brown solid. mp 112–113 °C (petroleum ether); mmax/cm−1
3605 (OH); dH (400 MHz) 8.21 (1H, dd, J = 10.0, 6.0 Hz, CH
arom), 7.42 (1H, dd, J = 14.0, 6.0 Hz, CH arom), 7.22–7.38
(3H, m, 3 × CH arom), 6.75 (1H, d, J = 4.0 Hz, CH arom); dC
2,2-Dimethyl-propionic acid 3-ethoxythiocarbonylsulfanyl-7-
fluoro-4-oxo-1,2,3,4-tetrahydro-naphthalen-1-yl ester (15). To a
solution of tetralone 4a (0.2 g, 0.75 mmol) in acetic acid (7.5 mL)
at room temperature was slowly added pyridinium bromide
perbromide (0.29 g, 0.91 mmol). The reaction was stirred at
room temperature for 4 h, neutralised with saturated aqueous
Na2CO3, extracted with dichloromethane, dried (Na2SO4) and
evaporated. To a cold solution (0 °C) of the residue in acetone
(1.5 mL) was then slowly added potassium O-ethyl xanthate
(0.13 g, 0.83 mmol). The reaction mixture was stirred at 0 °C for a
further 1 h, the solvent was evaporated and the resulting mixture
partitioned between water and CH2Cl2. The aqueous phase was
extracted with CH2Cl2, the combined organic extracts were dried
over Na2SO4 and concentrated under reduced pressure. Flash
chromatography of the residue (silica gel, petroleum ether–ethyl
acetate, 99:1 to 95:5), gave xanthate 15 (68% overall yield) as a
yellow oil and an inseparable mixture of diastereoisomers (ratio
2:1). mmax/cm−1 1734 (O–CO), 1695 (CO), 1235 (S–CS),
1052 (S–CS); dH (400 MHz) 8.10–8.16 (1H, m, CH arom),
7.12–7.20 (2H, m, 2 × CH arom), 6.23 (1H, dd, J = 10.4,
4.4 Hz, CHb–OPiv), 6.08 (1H, dd, J = 2.8, 2.8 Hz, CHa–OPiv),
5.16 (1H, dd, J = 12.4, 4.8 Hz, CHa–S), 4.87 (1H, dd, J = 13.2,
4.8 Hz, CHb–S), 4.61–4.67 (2H, m, O–CHa and O–CHb), 2.94
(1H, ddd, J = 12.0, 4.8, 4.8 Hz, CH2b), 2.84 (1H, ddd, J = 14.0,
4.0, 4.0 Hz, CH2a), 2.64 (1H, ddd, J = 13.2, 13.2, 2.8 Hz, CH2a),
2.41 (1H, q, J = 11.5 Hz, CH2b), 1.38 (3H, dd, J = 7.2, 7.2 Hz,
CH2–CH3a and CH2–CH3b), 1.30 (3H, s, (CH3b)3), 1.22 (6H,
s, (CH3a)3); dC (100 MHz) 212.5 (CaS), 212.0 (CbS), 190.6
(CaO), 189.9 (CbO), 177.7 (O–CaO and O–CbO), 166.4 (C,
d, Cb–F, 1JCF = 256 Hz), 166.1 (C, d, Ca–F, 1JCF = 255 Hz), 142.4
(Cb–CO), 142.3 (Ca–CO), 131.4 (3 × CH arom), 128.4 (Ca–CH
1
(100 MHz) 161.3 (C, d, JCF = 244.6 Hz, C–F), 151.8 (C, C-1),
3
135.9 (C, d, JCF = 9.3 Hz, C–CH), 127.3 (CH arom), 124.7
3
(CH, d, JCF = 9.2 Hz, CH arom), 121.6 (C, C–C–OH), 120.1
(CH, d, 4JCF = 5.1 Hz, CH arom), 115.5 (CH, d, 2JCF = 25.1 Hz,
2
CH arom), 110.7 (CH, d, JCF = 20.3 Hz, CH arom), 107.9
(CH, d, 5JCF = 2.2 Hz, CH arom); m/z (CI + NH3) 163 (MH+);
m/z (rel intensity) 162 (M+, 100); HRMS calcd for C15H13ClO2:
162.048093; found 162.047009.
Diethyl
5-hydroxy-2-oxo-1H-naphtho[2,3-d]imidazole-
1,3(2H)-dicarboxylate (6). A solution of tetralone 4e (40 mg,
0.09 mmol) and PTSA·H2O (44 mg, 0.23 mmol) in toluene (3 ml)
was stirred at reflux for 2.5 h using a Dean–Stark apparatus.
The reaction mixture was allowed to cool to room temperature,
diluted with a saturated sodium bicarbonate solution, and
extracted with dichloromethane. The combined organic
layers were dried over MgSO4, filtered and concentrated. The
residue was purified by column chromatography (silica gel,
petroleum ether–ethyl acetate, 75:25) to afford compound 6
(23 mg, 74%) as an amorphous solid; mmax/cm−1 3608 (OH),
1797 (CO), 1748(CO), 1714 (CO); dH (400 MHz) 8.22
(1H, d, J = 9.2 Hz), 8.14 (1H, d, J = 9.2 Hz), 7.35–7.37 (2H,
m), 6.84 (1H, m), 6.84 (1H, m), 5.90 (1H, br s, OH), 4.55–4.63
(4H, m, 2 × CH2CH3), 1.51–1.52 (6H, m, 2 × CH2CH3); dC
(100 MHz) 203.9 (C, N–CO2Et), 200.3 (C, N–CO2Et), 190.6 (C,
N–CO–N), 152.1 (C), 150.0 (C), 148.6 (C), 126.8 (CH arom),
122.4 (C), 121.5 (C), 120.0 (CH arom), 114.5 (CH arom), 112.6
(CH arom), 107.9 (CH arom), 65.2 (CH2, CH2CH3), 64.2 (CH2,
CH2CH3), 14.1 (2 × CH3, 2 × CH2CH3); m/z (CI + NH3) 345
(MH+), 362 (M+ + NH3); m/z (rel intensity) 344 (M+, 79), 272
(M+ − 1 − C3H5O2, 30), 200 (100); HRMS calcd for C17H16N2O6:
344.100836; found 344.101677.
2
and Cb–CH), 117.4 (CH, d, JCF = 21.8 Hz, CH arom), 116.4
(CH, d, 2JCF = 22.1 Hz, CH arom), 112.9 (CH, d, 2JCF = 22.9 Hz,
CH arom), 70.8 (O–CH2a and O–CH2b), 67.9 (CHa–OPiv), 67.8
(CHb–OPiv), 54.0 (CHa–S), 52.6 (CHb–S), 38.8 (Ca(CH3)3
and Cb(CH3)3), 36.0 (CH2b), 35.2 (CH2a), 27.2 ((CH3a)3 and
(CH3b)3), 13.8 (CH2–CH2a and CH2–CH3b); m/z (CI + NH3)
385 (MH+), 283 (MH+ − OPiv).
7-Fluoronaphtho[2,1-d][1,3]oxathiole-2-thione (16). Accord-
ing to the general method A, this compound was prepared from
tetralone derivative 15 to give compound 16 (89%) as an orange
solid. mp 157–159 °C (CH2Cl2–petroleum ether); mmax/cm−1 1189
(CS); dH (400 MHz) 8.25 (1H, dd, J = 8.8, 5.6 Hz, CH arom),
7.76 (1H, d, J = 8.4 Hz, CH arom), 7.54 (1H, d, J = 9.6 Hz,
CH arom), 7.47 (1H, d, J = 8.4 Hz, CH arom), 7.43 (1H, d,
J = 8.0 Hz, CH arom); dC (100 MHz) 201.5 (C, CS), 161.3
2-Bromo-6-fluoro-1-naphthol (8). Pyridinium bromide per-
bromide (52 mg, 0.16 mmol) was added to a solution of tetralone
4a (43 mg, 0.16 mmol) in acetic acid (1.6 ml) and the mixture was
then stirred for 2 h at room temperature. It was diluted with
a saturated sodium carbonate solution, and extracted with ethyl
acetate. The combined organic layers were dried, filtered and
concentrated. The residue was dissolved in toluene (5.6 ml) and
PTSA·H2O (91 mg, 0.48 mmol) was added. The solution was
stirred at reflux for 3.5 h using a Dean–Stark apparatus. The re-
action mixture was allowed to cool to room temperature, diluted
with a saturated sodium bicarbonate solution, and extracted
with dichloromethane. The combined organic layers were dried,
filtered and concentrated. The residue was purified by column
chromatography (silica gel, petroleum ether–ethyl acetate,
95:5) to afford compound 8 (26 mg, 69%) as a white solid. mp
60–65 °C (CH2Cl2); mmax/cm−1 3517 (OH); dH (400 MHz) 8.24
(1H, dd, J = 9.2, 5.6 Hz), 7.49 (1H, d, J = 8.8 Hz), 7.39 (1H,
1
(C, d, JCF = 247.0 Hz, C–F), 150.5 (C, C–O), 133.9 (C, d,
3JCF = 9.6 Hz, CH–C–CH), 125.8 (CH arom), 123.9 (CH, d,
3JCF = 9.0 Hz, CH arom), 120.4 (C, C–C–O), 118.8 (CH arom),
118.5 (CH, d, 2JCF = 25.9 Hz, CH arom), 117.3 (C, C–S), 111.9
(CH, d, 2JCF = 26.0 Hz, CH arom); m/z (CI + NH3) 237 (MH+);
m/z (rel intensity) 236 (M+, 12), 176 (M+ − COS, 100); HRMS
calcd for C11H5FOS2: 235.973215; found 235.973385.
7-Fluoro-4-(2-methoxy-2-oxoethylidene)-1,2,3,4-tetrahydro-
1-naphthalenyl pivalate (22). Methyl (diethoxyphosphoryl)-
acetate (0.36 mL, 1.96 mmol) was added dropwise to a cooled
suspension of NaH (80% dispersion in mineral oil, 60 mg,
1.98 mmol) in anhydrous toluene (1.2 mL). The mixture was
then stirred for 1 h at 60 °C to ensure the formation of the ylide.
3 0 2 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 1 8 – 3 0 2 5

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The formed solution was cooled, and a solution of tetralone 4a
(368 mg, 1.39 mmol) in anhydrous toluene (1.2 ml) was added
dropwise. The mixture was refluxed for 3 h, cooled to room tem-
perature, and then washed with cold water and extracted with
dichloromethane. The separated organic layer was dried over
MgSO4, and the solvent was evaporated under reduced pressure.
The crude residue was chromatographed (petroleum ether–ethyl
acetate, 95:5) to yield 22 (272 mg, 61%) as a colourless oil.
mmax/cm−1 1728 (CO), 1605 (CO); dH (400 MHz) complex
mixture of isomers; dC (100 MHz) complex mixture of isomers;
m/z (CI + NH3) 291 (MH+ − 2CH3), 308 (MH+ + NH3 − 2CH3),
323 (MH+ + NH3 − CH3), 338 (MH+ + NH3).
1.5 mmol) and LiBr (0.13 g, 1.5 mmol) were added and the
solution was heated for 30 minutes at 140 °C, cooled to room
temperature, neutralised with saturated aqueous citric acid,
extracted with diethyl ether and the combined organic extracts
were dried and concentrated in vacuo. The residue was purified
by flash column chromatography (silica gel, petroleum ether–
ethyl acetate, 8:2) to give naphthol 13 (64%) as a brown-green
solid. mp 101–104 °C (CH2Cl2–petroleum ether); mmax/cm−1 3358
(OH), 1743 (O–CO); dH (400 MHz) 8.23 (1H, d, J = 8.8 Hz,
CH arom), 8.00 (1H, d, J = 1.2 Hz, CH arom), 7.44 (1H, dd,
J = 8.8, 1.6 Hz, CH arom), 7.19 (1H, d, J = 7.6 Hz, CH arom),
6.75 (1H, d, J = 7.6 Hz, CH arom), 6.55 (1H, s, OH), 4.41 (2H,
dd, J = 7.4, 7.4 Hz, CH2–OAc), 3.29 (2H, dd, J = 7.2, 7.2 Hz,
Ar–CH2), 2.13 (3H, s, OC(O)CH3); dC (100 MHz) 172.2 (O–CO),
151.2 (C–OH), 133.9 (C–Cl), 132.9 (C–CH2), 128.2 (CH arom),
125.7 (CH arom), 123.2 (C–C–OH), 124.6 (CH arom), 122.7 (C–
C–CH2), 122.6 (CH arom), 108.4 (CH arom), 64.9 (CH2–OAc),
31.5 (Ar–CH2), 21.1 (CH3, OC(O)CH3); m/z (CI + NH3) 284
(MH+ + NH3), 282 (MH+ + NH3). Anal. calcd. for C14H13ClO3:
C, 63.52; H, 4.95. Found: C, 63.48; H, 4.92%.
Methyl (6-fluoro-1-naphthyl)acetate (23). According to the
general method A, this compound was prepared from derivative
22 to give compound 23 (67%) as a solid amorphous. mmax/cm−1
1738 (CO), 1634 (CO); dH (400 MHz) 8.01 (1H, dd, J = 5.2,
9.2 Hz, CH arom), 7.74 (1H, d, J = 8.4 Hz, CH arom), 7.44–7.50
(2H, m, 2 × CH arom), 7.38 (1H, d, J = 6.8 Hz, CH arom), 7.32
(1H, m, CH arom), 4.17 (1H, d, J = 14.4 Hz, CH2), 4.15 (1H,
d, J = 14.4 Hz, CH2), 4.06 (3H, s, CH3); dC (100 MHz) 161.6
(C), 134.8 (C), 130.9 (C), 129.1 (C), 127.8 (C), 126.6 (2 × CH
arom), 118.7 (2 × CH arom), 116.6 (2 × CH arom), 61.1 (CH3),
39.4 (CH2); m/z (CI + NH3) 218 (M+), 233 (M+ + NH). m/z
(CI + NH3) 218 (M+), 233 (M+ + NH); m/z (rel intensity) 218
(M+, 15), 159 (M+ − C2H3O2, 100); HRMS calcd for C13H11FO2:
218.074308; found 218.073933.
Method D. Ethyl 2-amino-7-chloronaphtho[1,2-b]furan-3-
carboxylate (17). To a stirred solution of tetralone 4b (0.1 g,
0.35 mmol) in acetic acid (3.5 mL) was added pyridinium bro-
mide perbromide (0.11 g, 0.35 mmol). The mixture was stirred
at room temperature for 15 min, neutralised with saturated
aqueous Na2CO3, extracted with ethyl acetate, dried and con-
centrated. A solution of the residue in acetone (0.7 mL) was then
added to a stirred mixture of ethyl cyanoacetate (0.07 mL, 0.08 g,
0.71 mmol) and K2CO3 (0.15 g, 1.07 mmol) in acetone (0.7 mL)
at 0 °C. The resulting mixture was stirred at room temperature
for a further 4 h and then acidified with saturated aqueous citric
acid, extracted with dichloromethane and the combined organic
extracts were dried over MgSO4 and concentrated in vacuo. The
residue was purified by flash column chromatography (silica
gel, petroleum ether–ethyl acetate, 9:1) to give furan 17 (51%)
as a brown–green solid. mp 192–195 °C (CH2Cl2–petroleum
ether); mmax/cm−1 3486 (NH2), 3365 (NH2), 1682 (O–CO); dH
(400 MHz) 7.98 (1H, d, J = 8.0 Hz, CH arom), 7.97 (1H, s,
CH arom), 7.91 (1H, d, J = 8.4 Hz, CH arom), 7.70 (1H, d,
J = 8.4 Hz, CH arom), 7.49 (1H, dd, J = 8.8, 1.6 Hz, CH arom),
7.30 (2H, s, NH2), 4.36 (2H, ddd, J = 7.1, 7.1, 7.1 Hz, O–CH2),
1.40 (3H, dd, J = 7.0, 7.0 Hz, CH3); dC (100 MHz) 167.0 (C,
O–CO), 166.7 (C, C–CO2Et), 144.0 (C, C–OH), 132.2 (C, C–Cl),
130.4 (C, C–C–CO2Et), 128.9 (CH arom), 128.8 (CH arom),
125.7 (C, C–C–OH), 125.1 (CH arom), 122.2 (CH arom), 122.0
(CH arom), 120.0 (C, C–CH), 86.2 (C, C–NH2), 61.0 (CH2,
O–CH2), 15.9 (CH3); m/z (CI + NH3) 292 (MH+), 290 (MH+);
m/z (rel intensity) 289 (M+, 63), 243 (M+ − C2H6O, 100); HRMS
calcd for C15H12ClNO3: 289.050571; found 289.046883.
Method B. 2-Bromo-5,8-dimethoxy-1-naphthol (10). To a
stirred solution of tetralone 9 (0.2 g, 0.65 mmol) in acetic acid
(6.5 mL) at room temperature was added slowly pyridinium
bromide perbromide (0.21 g, 0.65 mmol). The mixture was
stirred at room temperature for 1 h, neutralised with saturated
aqueous Na2CO3, extracted with CH2Cl2, dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The resi-
due was purified by flash column chromatography (silica gel,
petroleum ether–ethyl acetate, 8:2) to give directly the naphthol
10 (75%) as a brown-green solid. mp 137–138 °C (CH2Cl2–
petroleum ether) (lit.,15 134 °C).
Method C. 7-Fluoro-4-hydroxy-1-naphthyl pivalate (11).
A mixture of residue 7 (29 mg), LiBr (15 mg, 0.17 mmol),
and Li2CO3 (12.5 mg, 0.17 mmol) in dry DMF (0.5 mL) was
stirred at 140 °C for 2 h under nitrogen. The reaction mixture
was cooled to room temperature, poured into dilute HCl and
extracted with ether. The combined organic layers were washed
with water, dried over MgSO4 and concentrated. The residue
was purified by column chromatography (silica gel, petroleum
ether–ethyl acetate, 95:5) to afford compound 11 (13 mg,
60%) as a yellow solid. mp 136–142 °C (AcOEt); mmax/cm−1
3605 (OH); dH (400 MHz) 8.08 (1H, dd, J = 9.2, 5.6 Hz, CH
arom), 7.31 (1H, dd, J = 10.4, 2.8 Hz, CH arom), 7.21 (1H,
ddd, J = 8.4, 8.4, 2.4 Hz, CH arom), 6.96 (1H, d, J = 8.0 Hz,
CH arom), 6.53 (1H, d, J = 8.4 Hz, CH arom), 5.82 (1H, br s,
MethodE. 6-Chloro-2-[3-(2-hydroxyethyl)benzyl]-1-naphthol
(18). To a stirred solution of tetralone 4c (0.1 g, 0.37 mmol) and
benzaldehyde (0.06 mL, 0.56 mmol) in tert-butanol (3.7 mL) was
added potassium tert-butoxide (0.08 g, 0.75 mmol). The resulting
suspension was then refluxed for 8 h, cooled to room tempera-
ture and acidified with saturated aqueous citric acid. The reac-
tion mixture was extracted with ethyl acetate and the combined
organic extracts were dried (Na2SO4) and concentrated in vacuo.
The residue was purified by flash column chromatography (silica
gel, petroleum ether–ethyl acetate, 9:1) to give 18 (32%) as a yel-
low solid. mp 140–141 °C (CH2Cl2–petroleum ether); mmax/cm−1
3601 (OH), 3530 (OH); dH (400 MHz) 8.13 (1H, d, J = 8.8 Hz,
CH arom), 7.94 (1H, d, J = 1.6 Hz, CH arom), 7.41 (1H, dd,
J = 9.0, 1.8 Hz, CH arom), 7.25–7.34 (6H, m, 6 × CH arom),
4.12 (2H, s, CH2–Ph), 3.95 (2H, dd, J = 6.8, 6.8 Hz, CH2–OH),
3.21 (2H, dd, J = 6.6, 6.6 Hz, CH2–CH2–OH); dC (100 MHz)
148.5 (C, C–OH), 138.8 (C, C–Cl), 133.0 (C, C–C–OH), 132.3
(C, C–CH2–Ph), 131.5 (CH arom), 129.2 (2 × CH arom), 128.5
(2 × CH arom), 127.1 (CH arom), 126.0 (CH arom), 125.9 (C,
C–C–CH2), 124.3 (CH arom), 123.9 (C, C–CH2–C), 122.7 (CH
t
OH), 1.50 (9H, s, Bu); dC (100 MHz) 178.1 (C, O–CO), 162.7
(C, C–OH), 160.3 (C, C–OPiv), 149.7 (C, C–F), 128.8 (2 × C),
3
125.5 (CH, JCF = 9.0 Hz, CH arom), 119.1 (CH arom), 115.6
(CH, 2JCF = 25.1 Hz, CH arom), 107.1 (CH arom), 104.8 (CH,
t
t
2JCF = 23.0 Hz, CH arom), 77.2 (C, Bu), 27.4 (3 × CH3, Bu);
m/z (CI + NH3) 263 (MH+), 280 (MH+ + NH3); m/z (rel inten-
sity) 262 (M+, 15), 178 (M+ − 1 − C5H9O, 100); HRMS calcd
for C15H15FO3: 262.100523; found 262.101006. Anal. calcd. for
C15H15FO3: C, 68.69; H, 5.76. Found: C, 68.71; H, 6.05%.
2-(7-Chloro-4-hydroxy-1-naphthyl)ethyl acetate (13). To a
stirred solution of 4c (0.2 g, 0.75 mmol) in acetic acid (7 mL) at
room temperature was added slowly pyridinium bromide per-
bromide (0.24 g, 0.75 mmol). The mixture was stirred at room
temperature for 15 min, neutralised with saturated aqueous
Na2CO3, extracted with ethyl acetate, dried and concentrated.
The residue was then dissolved in DMF (4 mL). Li2CO3 (0.11 g,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 1 8 – 3 0 2 5
3 0 2 3

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arom), 119.7 (C, C–CH2), 63.1 (CH2, CH2–Ph), 36.8 (CH2,
CH2–OH), 35.6 (CH2, CH2–CH2–OH); m/z (CI + NH3) 332
(MH+ + NH3), 330 (MH+ + NH3), 315 (MH+), 313 (MH+).
arom), 7.28 (1H, dd, J = 7.4, 7.4 Hz, CH arom); dC (100 MHz)
141.0 (C), 137.0 (C), 135.1 (C), 132.1 (C), 129.3 (CH arom),
127.6 (CH arom), 126.8 (CH arom), 125.5 (C), 125.3 (CH
arom), 122.6 (CH arom), 121.6 (CH arom), 121.5 (CH arom),
120.5 (CH arom), 120.3 (C), 113.2 (CH arom); m/z (CI + NH3)
254 (MH+), 252 (MH+); Anal. calcd. for C16H10NCl: C, 76.35; H,
4.00. Found: C, 76.54; H, 3.98%.
Method F. N-Benzyl-6-chloro-1-naphthalenamine (19a).
A solution of tetralone 4b (0.1 g, 0.35 mmol) and benzylamine
(0.08 mL, 0.71 mmol) in toluene (3.5 mL) was refluxed in a
system equipped with a Dean–Stark apparatus. The reaction
was monitored by 1H NMR and after 3 h the starting material
was completely consumed. At this point, the reaction mixture
was cooled to room temperature and AlCl3 (0.95 g, 0.71 mmol)
was added to the imine solution. The reaction was refluxed for a
further 15 min, neutralised with saturated aqueous NaHCO3 and
extracted with dichloromethane. The combined organic extracts
were dried over Na2SO4 and concentrated under reduced pres-
sure. Flash chromatography of the residue (silica gel, petroleum
ether–ethyl acetate, 98:2), gave naphthylamine 19a (75%) as a
green–yellow oil. mmax/cm−1 3428 (NH); dH (400 MHz) 7.80 (1H, d,
J = 2.0 Hz, CH arom), 7.75 (1H, d, J = 8.8 Hz, CH arom), 7.36–
7.48 (7H, m, CH arom), 7.18 (1H, d, J = 8.0 Hz, CH arom), 6.64
(1H, d, J = 7.6 Hz, CH arom), 4.68 (1H, br s, NH), 4.50 (2H,
s, CH2–Ph); dC (100 MHz) 143.4 (C, C–NH), 138.8 (C, C–Cl),
135.2 (C, C–C–NH), 131.7 (C, C–CH2), 128.8 (2 × CH arom),
128.0 (CH arom), 127.8 (CH arom), 127.6 (CH arom), 127.3 (CH
arom), 125.4 (CH arom), 121.9 (CH arom), 121.6 (C, C–CH),
116.8 (2 × CH arom), 105.1 (CH arom), 48.6 (CH2, CH2–Ph);
m/z (CI + NH3) 270 (MH+ + NH3), 268 (MH+ + NH3).
Method H. 4-(3-Chloro-1-propynyl)-4-hydroxy-5,8-dimethoxy-
1,2,3,4-tetrahydro-1-naphthalenyl pivalate (24). n-Butyllithium
(0.42 mL, 1.1 M solution in hexanes) was added to 3-chloro-1-
propyne (39 mL, 0.52 mmol) in THF (2 mL), which had been
previously cooled to −78 °C under a nitrogen atmosphere. After
30 min, tetralone 4d (145 mg, 0.47 mmol) dissolved in dry THF
(1 ml) was added dropwise. The reaction was allowed to warm
to room temperature over 3 h. Saturated ammonium chloride
was slowly added to the reaction followed by distilled water,
and the resulting solution was extracted with ether. The organic
fractions were combined, dried over MgSO4, filtered and con-
centrated. The residue was purified by column chromatogra-
phy (silica gel, petroleum ether–ethyl acetate, 85:15) to afford
compound 24 (159 mg, 88%) as a white solid. mp 135–138 °C
(AcOEt); mmax/cm−1 3537 (OH), 1725 (O–CO); dH (400 MHz)
6.93 (1H, d, J = 8.9 Hz, CH arom), 6.77 (1H, d, J = 9.0 Hz,
CH arom), 6.07 (1H, m, 1-H), 5.33 (1H, s, OH), 4.13 (2H, s,
CH2Cl), 3.94 (3H, s, OCH3), 3.73 (3H, s, OCH3), 2.19–2.21 (2H,
t
m), 2.07–2.10 (2H, m), 1.15 (9H, s, Bu); dC (100 MHz) 177.6
(C, CO), 152.4 (C), 151.0 (C), 130.3 (C), 123.0 (C), 112.7 (CH
arom), 109.8 (CH arom), 89.4 (C, CC), 77.3 (C, CC), 67.1
(C, C-4), 63.7 (C, C-1), 56.7 (CH3, OCH3), 55.5 (CH3, OCH3),
38.7 (C, tBu), 32.0 (CH2), 30.6 (CH2), 27.0 (3 × CH3, tBu), 25.7
(CH2); m/z (CI + NH3) 397 (M+ + NH3), 395 (M+ + NH).
Methyl benzyl(6-chloro-1-naphthyl)carbamate (19b). Acetic
anhydride (0.03 mL, 0.03 g, 0.30 mmol) was added to a solu-
tion of 0.027 g (0.10 mmol) of naphthylamine 19a and DMAP
(0.025 g, 0.20 mmol) in CH2Cl2 (1 mL) at 0 °C. The mixture
was stirred for 10 h at room temperature and then partitioned
between water and dichloromethane. The aqueous phase was
extracted with dichloromethane, the combined organic extracts
were dried over Na2SO4 and concentrated under reduced pres-
sure. Flash chromatography of the residue (silica gel, petroleum
ether–ethyl acetate, 9:1) gave acetamide 19b (97%) as a yel-
low oil. mmax/cm−1 1667 (N–CO); dH (400 MHz) 7.88 (1H, d,
J = 2.0 Hz, CH arom), 7.74 (1H, d, J = 8.0 Hz, CH arom), 7.66
(1H, d, J = 8.8 Hz, CH arom), 7.44 (1H, dd, J = 9.0, 1.8 Hz, CH
arom), 7.38 (1H, dd, J = 7.8, 7.8 Hz, CH arom), 7.22–7.23 (3H,
m, 3 × CH arom), 7.16–7.17 (2H, m, 2 × CH arom), 6.96 (1H, d,
J = 7.2 Hz, CH arom), 5.55 (1H, d, J = 14.0 Hz, CH2–Ph), 4.32
(1H, d, J = 14.0 Hz, CH2–Ph), 1.76 (3H, s, CH3); dC (100 MHz)
171.0 (C, N–CO), 139.0 (C, C–N), 137.5 (C, C–Cl), 135.4 (C,
C–C–N), 132.8 (C, C–CH2), 129.4 (2 × CH arom), 128.8 (C,
C–CH), 128.4 (2 × CH arom), 128.4 (CH arom), 127.9 (CH
arom), 127.6 (CH arom), 127.4 (CH arom), 127.1 (CH arom),
126.9 (CH arom), 124.3 (CH arom), 52.6 (CH2, CH2–Ph), 22.3
(CH3); m/z (CI + NH3) 329 (MH+ + NH3), 327 (MH+ + NH3),
312 (MH+), 310 (MH+); m/z (rel intensity) 309 (M+, 13), 267
(M+ − 1 − C2H3O, 14), 91 (100); HRMS calcd for C19H16ClNO:
309.092042; found 309.089706.
5-(3-Chloro-1-propynyl)-1,4-dimethoxynaphthalene (25). To
a cold (0 °C) solution of 24 (0.044 g, 0.11 mmol) in pyridine
(0.1 mL) was added phosphorous oxychloride (0.14 mL,
1.54 mmol) over a 30 min period. The reaction was allowed to
warm to room temperature and stirred for 40 h. The mixture was
poured into ice-water and was extracted with diethyl ether. The
combined organic layers were dried over MgSO4, filtered and
concentrated. The residue was purified by column chromatogra-
phy (silica gel, petroleum ether–ethyl acetate, 9:1) to afford com-
pound 25 (20 mg, 66%) as an amorphous solid. mmax/cm−1 3070,
2931, 1622, 1590, 1462, 1408, 1267, 1238, 1074; dH (400 MHz)
8.26 (1H, d, J = 8.0 Hz, CH arom), 7.46–7.53 (2H, m, 2 × CH
arom), 6.72–6.81 (2H, m, 2 × CH arom), 4.45 (2H, s, CH2Cl),
3.97 (3H, s, OCH3), 3.85 (3H, s, OCH3); dC (100 MHz) 149.8
(C, C–OMe), 148.0 (C, C–OMe), 129.8 (C, C–CC), 129.0 (CH
arom), 125.9 (C), 125.0 (CH arom), 122.4 (CH arom), 117.1
(C), 106.5 (CH arom), 103.5 (CH arom), 94.9 (C, CC), 94.7
(C, CC), 56.5 (OCH3), 55.7 (CH3, OCH3), 29.6 (CH2, CH2Cl);
m/z (CI + NH3) 261 (MH+), 279 (MH+ + NH3); m/z (rel inten-
sity) 261 (M+ + 1, 50), 260 (M+, 28), 246 (100); HRMS calcd. for
C15H13ClO2: 260.060408; found 260.065285.
Method G. 3-Chloro-11H-benzo[a]carbazole (20). A mixture
of tetralone 4b (0.2 g, 0.71 mmol), phenylhydrazine (0.14 mL,
1.4 mmol) and 0.5 g of polyphosphoric acid (PPA) was heated
at 100 °C for 15 min. The mixture was allowed to cool to room
temperature and then partitioned between water and CH2Cl2.
The aqueous phase was extracted with dichloromethane, the
combined organic extracts were dried over Na2SO4 and con-
centrated under reduced pressure. Flash chromatography of
the residue (silica gel, petroleum ether–ethyl acetate, 98:2) gave
compound 21 (56%) as an orange–brown solid. mp 212–214 °C
(acetone–petroleum ether): mmax/cm−1 3604 (NH), 3478 (NH);
dH (400 MHz) 11.35 (1H, s, NH), 8.49 (1H, d, J = 8.8 Hz,
CH arom), 8.27 (1H, d, J = 8.4 Hz, CH arom), 8.18 (1H, d,
J = 7.6 Hz, CH arom), 8.08 (1H, s, CH arom), 7.66 (1H, d,
J = 5.6 Hz, CH arom), 7.64 (1H, d, J = 6.4 Hz, CH arom), 7.69
(1H, d, J = 8.4 Hz, CH arom), 7.44 (1H, dd, J = 7.6, 7.6 Hz, CH
4-Hydroxy-5,8-dimethoxy-4-(phenylethynyl)-1,2,3,4-tetra-
hydro-1-naphthalenyl pivalate (26). n-Butyllithium (0.52 mL,
1.1 M hexanes) was added to ethynylbenzene (0.07 mL,
0.64 mmol) in THF (2.5 mL), which had been previously cooled
to −78 °C under a nitrogen atmosphere. After 30 min, tetralone
4d (178 mg, 0.58 mmol) dissolved in dry THF (1 mL) was added
dropwise. The reaction was allowed to warm to room tempera-
ture and stirred for 3.5 h. Saturated ammonium chloride was
slowly added to the reaction followed by distilled water, and
the resulting solution, extracted with diethyl ether. The organic
fractions were combined, dried over MgSO4, filtered and con-
centrated. The residue was purified by column chromatography
(silica gel, petroleum ether–ethyl acetate, 95:5) to afford com-
pound 26 (151 mg, 65%) as a white solid. mp 50–53 °C (AcOEt);
mmax/cm−1 3540 (OH), 1724 (CO); dH (400 MHz) 7.36–7.38 (2H,
m, 2 × CH arom), 7.26–7.27 (3H, m, 3 × CH arom), 6.94 (1H, d,
3 0 2 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 1 8 – 3 0 2 5

View Article Online
2 A. Gopalsamy, K. Lim, J. W. Ellingboe, B. Mitsner, A. Nikitenko,
J. Upeslacis, T. S. Mansour, M. W. Olson, G. A. Bebernitz,
J = 9.2 Hz, CH arom), 6.78 (1H, d, J = 8.8 Hz, CH arom), 6.12
(1H, br s, 1-H), 5.44 (1H, s, OH), 3.96 (3H, s, OCH3), 3.74 (3H,
s, OCH3), 2.15–2.31 (4H, m, 2-H2, 3-H2), 1.18 (9H, s, Bu); dC
D. Gringberg, B. Feld, F. J. Moy and J. O’Connell, J. Med. Chem.,
2004, 47, 1893–1899; G. Bringmann, W. Saeb, M. Rückert, J. Mies,
M. Michel, V. Mudogo and R. Brun, Phytochemistry, 2003, 62,
631–636, and references cited therein; A. R. Katritzky, G. Zhang
and L. Xie, J. Org. Chem., 1997, 62, 721–725, and references cited
therein; A. I. Meyers and J. J. Willemsen, Tetrahedron Lett., 1996,
37, 791–792; M. Medarde, A. C. Ramos, E. Caballero and J. L.
Lopez, Tetrahedron Lett., 1996, 37, 2663–2666.
3 A. Cordero-Vargas, B. Quiclet-Sire and S. Z. Zard, Org. Lett., 2003,
5, 3717–3719; A. Liard, B. Quiclet-Sire, R. N. Saicic and S. Z. Zard,
Tetrahedron Lett., 1997, 38, 1759–1762. For an earlier mechanisti-
cally similar approach, see B. B. Snider and L. Han, Synth. Com-
mun., 1995, 25, 2337–2347; E. I. Heiba and R. M. Dessau, J. Am.
Chem. Soc., 1972, 94, 2888–2889.
4 F. Gagosz and S. Z. Zard, Org. Lett., 2002, 4, 4345–4348.
5 G. Mehta, R. S. Senaiar and M. K. Bera, Chem. Eur. J., 2003, 9,
2264–2272.
6 For a review of benzines as dienophiles, see R. W. Hoffmann,
Dehydrobenzene and Cycloalkynes, Academic Press, New York, 1967,
pp. 200–239.
7 For nucleophilic substitution, see G. Murineddu, G. Cignarella,
G. Chelucci, G. Loriga and G. A. Pinna, Chem. Pharm. Bull., 2002,
50, 754–759; G. A. Pinna, G. Loriga, G. Murineddu, G. Grella,
M. Mura, L. Vargiu, C. Murgioni and P. L. Colla, Chem. Pharm.
Bull., 2001, 49, 1406–1411.
8 J. Tsuji, Palladium Reagents and Catalysts. Innovations in Organic
Synthesis, Wiley, New York, 1997.
9 For a monograph, see B. Robinson, The Fischer Indole Synthesis,
Wiley, New York, 1983. For reviews, see I. I. Grandberg and V. I.
Sorokin, Russ. Chem. Rev., 1974, 43, 115–128; H. J. Shine, Aromatic
Rearrangements, Elsevier, New York, 1969, pp. 190–207, Ref. 489;
R. J. Sundberg, The Chemistry of Indoles, Academic Press, New
York, 1970, pp. 142–163; B. Robinson, Chem. Rev., 1969, 69, 227–
250; Y. Lihu, Tetrahedron Lett., 2000, 41, 6981–6984.
10 P. K. Mahata, U. K. Venkatesh, S. Kumar, H. Ila and H. Junjappa,
J. Org. Chem., 2003, 68, 3966–3975, and references cited therein;
S. M. Barolo, A. E. Lukach and R. A. Rossi, J. Org. Chem., 2003,
68, 2807–2811 and references cited therein.
t
(100 MHz) 177.6 (C, CO), 152.5 (C), 151.1 (C), 131.6 (2 × CH
arom), 131.1 (C), 128.1 (3 × CH arom), 122.9 (C), 122.8 (C),
112.9 (CH arom), 109.6 (CH arom), 92.2 (C, C-4), 82.9 (C,
CC), 67.6 (C, CC), 63.9 (CH, C-1), 56.7 (CH3, OCH3), 55.4
t
t
(CH3, OCH3), 38.7 (C, Bu), 32.4 (CH2), 27.0 (3 × CH3, Bu),
25.9 (CH2); m/z (CI + NH3), 409 (MH+), 305 (M+ − OPiv).
1,4-Dimethoxy-5-(phenylethynyl)naphthalene (27). To a cold
(0 °C) solution of 26 (31 mg, 0.08 mmol) in pyridine (0.07 mL)
was added phosphorous oxychloride (0.029 ml, 0.31 mmol) over
a 30 min period. The reaction was allowed to warm to room
temperature and stirred for 36 h. The mixture was poured into
ice-water and was extracted with diethyl ether. The combined
organic layers were dried over MgSO4, filtered and concentrated.
The residue was purified by column chromatography (silica gel,
petroleum ether–ethyl acetate, 9:1) to afford compound 27
(15 mg, 67%) as an amorphous solid. mmax/cm−1 2934, 1462,
1407, 1261, 884; dH (400 MHz) 8.26 (1H, d, J = 8.4 Hz), 7.80
(1H, d, J = 7.2 Hz), 7.60–7.62 (2H, m), 7.45 (1H, dd, J = 7.2,
7.2 Hz), 7.32–7.38 (3H, m), 6.85 (1H, d, J = 8.4 Hz), 6.76 (1H,
d, J = 8.4 Hz), 4.01 (3H, s), 3.98 (3H, s); dC (100 MHz) 159.2
(C), 149.8 (C), 133.8 (CH), 131.4 (CH), 128.2 (3 × CH), 127.7
(CH), 127.0 (C), 126.5 (C), 125.8 (C), 124.9 (CH), 122.6 (CH),
117.6 (C), 103.9 (CH), 91.6 (2 × C), 56.9 (CH3), 55.7 (CH3); m/z
(CI + NH3) 306 (MH+ + NH3), 289 (MH+), 274 (MH+ + NH);
m/z (rel intensity) 288 (M+, 100), 273 (M+ − CH3, 58), 258
(M+ − 2 × CH3, 19); HRMS calcd for C20H16O2: 288.115030;
found 288.113342.
Acknowledgements
I. P.-M. thanks the Ministerio de Educación, Cultura y De-
porte (Spain) for a postdoctoral fellowship and A. C.-V. thanks
CONACYT (Mexico) for its generous financial support. The
authors wish to thank Oya Bermek for the preparation of com-
pound 5, and I.P.N.A., C.S.I.C. (Spain) for micromass spectra.
11 METHOD A: like Method A, Table 2. METHOD G: To a cold
solution of substrate (1 mmol) in pyridine (1 ml) was added POCl3
(15.5 mmol) and the reaction was stirred at room temperature.
12 N. P. Buu-Hoi, P. Jacquignon, N. D. Xuong and D. Lavit, J. Org.
Chem., 1954, 19, 1370–1374.
13 N. Legrand, B. Quiclet-Sire and S. Z. Zard, Tetrahedron Lett., 2000,
41, 9815–9818.
14 Xanthate 1d was prepared by S. Seguin, Nouvelles
réactions d’allylation radicalaires, synthése de nouveaux agents
intercalants-alkylants, apparentés aux duocarmycines, par une
voie radicalaire originale, PhD Thesis, 1999, Université Paris-
Sud, pp. 158–159.
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