Condensation of naphthalenediols with benzene in the presence of aluminum bromide: an efficient synthesis of 5-, 6-, and 7-hydroxy-4-phenyl-1- and 2-tetralones

Article abstract of DOI:10.1016/j.tetlet.2008.04.062

Isomeric 1,5-, 1,6-, 1,7-, 2,6-, and 2,7-naphthalenediols react smoothly with benzene at room temperature in the presence of an excess of aluminum bromide to give 5-, 6-, and 7-hydroxy-4-phenyl-1-tetralones and 5- and 6-hydroxy-4-phenyl-2-tetralones, resp

Full text of DOI:10.1016/j.tetlet.2008.04.062

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Tetrahedron Letters 49 (2008) 3891–3894
Condensation of naphthalenediols with benzene in the presence
of aluminum bromide: an efficient synthesis of 5-, 6-, and
7-hydroxy-4-phenyl-1- and 2-tetralones
Konstantin Yu. Koltunov *
Boreskov Institute of Catalysis, Pr. Akademika Lavrentieva, 5, Novosibirsk 630090, Russia
Novosibirsk State University, Pirogova, 2, Novosibirsk 630090, Russia
Received 19 February 2008; revised 28 March 2008; accepted 9 April 2008
Available online 12 April 2008
Abstract
Isomeric 1,5-, 1,6-, 1,7-, 2,6-, and 2,7-naphthalenediols react smoothly with benzene at room temperature in the presence of an excess
of aluminum bromide to give 5-, 6-, and 7-hydroxy-4-phenyl-1-tetralones and 5- and 6-hydroxy-4-phenyl-2-tetralones, respectively. The
mechanism of these reactions is interpreted in terms of key di- or tri-cationic (superelectrophilic) intermediates.
Ó 2008 Elsevier Ltd. All rights reserved.
OH
O
1. Introduction
ArH (AlkH)
superacid
Tetralones are useful starting materials for the synthesis
of biologically active compounds.1 In particular, hydroxy-
and methoxy-tetralones, despite their considerable cost, are
of significant current interest in pharmaceutical chemistry
for construction of steroid frameworks2 and production
of antidepressants.1,3
Ar (H)
OH
O
ArH (AlkH)
superacid
Ar (H)
X
An efficient route to tetralones is based on the one-step
condensation of 1- and 2-naphthols with benzene and other
aromatic compounds under the influence of aluminum
halides or in the HF–SbF5 superacid medium (Scheme
1).4 Furthermore, the selective ionic reduction of naphthols
by alkanes leads to tetralones under similar conditions
(Scheme 1).5 The mechanism of these reactions was recog-
nized to involve superelectrophilic6 dications formed by
C,C-diprotonation (structures 1 and 2, Scheme 1) as the
key intermediates and a number of analogous dications
have indeed been generated as long-lived species by dissolv-
ing naphthols and/or their derivatives in liquid superacids.7
Moreover, a set of isomeric naphthalenediols was reacted
+
O
X
+
O
+
+
1
2
_
3n
_
3n
X = H or Al Cl or Al Br
n
n
Scheme 1. Reactions of naphthols with arenes (ArH) and alkanes (AlkH).
successfully with cyclohexane in AlBr3–CH2Br2 medium
to afford the corresponding hydroxytetralones (Scheme 2).8
Further, it has been found recently that, in contrast to
1-naphthol, 5-amino-1-naphthol is activated by N,C-dipro-
tonation in superacids and reacts with benzene and cyclo-
hexane under the influence of aluminum halides through
*
Tel.: +7 3833269765; fax: +7 3833308056.
E-mail address: koltunov@catalysis.ru
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.062

3892
K. Yu. Koltunov / Tetrahedron Letters 49 (2008) 3891–3894
Table 1
O
OH
Reactions of naphthalenediols 6a–e with benzene in the presence of AlBr3
at 25 °Ca
cyclo-C H
6
12
HO
HO
AlBr -CH Br
3
2
2
Naphthalenediol
Reaction time (h) Product
Yieldb (%)
OH
OH
O
O
cyclo-C H
6
12
HO
HO
AlBr -CH Br
3
2
2
24
92
Scheme 2. Ionic reduction of naphthalenediols with cyclohexane.
7a
OH
Ph
OH
6a
OH
O
+
O
H
48
48
48
24
83
87
92
85
HO
HO
7b
Ph
O
6b
NH3
+
OH
O
OH
HO
C6H6
Superacid
HO
(cyclo-C6H12
)
Ph (H)
O
H
NH2
NH2
7c
Ph
Ph
6c
+
O
OH
NH3
+
3
HO
HO
HO
HO
6d
7d
7e
Scheme 3.
O
OH
dications 3 to give 5-amino-3-phenyl-1-tetralone and 5-
amino-1-tetralone, respectively, (Scheme 3).9
Therefore, the question about the nature of key electro-
philic intermediates in the case of reactions of naphthalen-
ediols with cyclohexane is still open because of the two
possible methods of activation: C,C-diprotonation result-
ing in dications of types 1 and 2 with the reaction center
at C-4 (similar to 1- and 2-naphthols) or O,C-diprotona-
tion resulting in dications 4 with the reaction center at C-
3 (similar to N,C-diprotonation of 5-amino-1-naphthol).
The latter possibility seemed quite likely based on the
known behavior of naphthalenediols in superacids. Indeed,
when hydroxyl groups are bound to different rings of the
naphthalene system, naphthalenediols undergo exclusively
O,C-diprotonation in HSO3F–SbF5–SO2ClF and HF–
SbF5–SO2ClF media to produce dications 4 and 5
(X = H).10 In addition, similar complexes 4 and 5
Ph
6e
a
The molar ratio of substrate:AlBr3:benzene = 1:3.5:20, magnetic
stirring.
b
Isolated yields of purified products.
phenyl-1- and 2-tetralones. The main aim of the work was
also to determine the regioselectivity of these reactions.
All isomers 6a–e reacted smoothly with benzene in the
presence of a 3.5-fold molar excess of AlBr3 at room temper-
ature to give hydroxyl-4-phenyl-1- and 2-tetralones 7a–e,
respectively (Table 1). Remarkably, compounds 6b and 6c,
which may both be regarded as derivatives of 1- and 2-naph-
thols, reacted similarly to 1-naphthol to give 1-tetralone
derivatives only. This is in accord with the analogous regi-
oselectivity of the ionic hydrogenation of these compounds
by cyclohexane (Scheme 2),8 suggesting the participation
of the same key intermediates. Likewise, no traces of hydro-
xyl-3-phenyl-1-tetralones (considered as possible alternative
products) were detected in the reaction mixtures. The regi-
oselectivity found indicates the predominant involvement
of di- or tri-cationic intermediates 8 or 80 as shown in Scheme
4. Although structure 9 was not detected earlier by NMR
ðX ¼ AlnBrꢀ Þ are produced via the action of AlBr3.10b
3n
However, C,C-diprotonated dications as stronger electro-
philes11 could react predominantly, despite their relatively
low equilibrium concentration.
+
O
X
+
O
X
+
+
H
O
H
O
along with isomeric complexes 4 ðX ¼ AlnBrꢀ Þ,10b the anal-
3n
X
_
3n
X
4
5
ogous complexes were generated in the case of the parent 1-
naphthol and some of its other derivatives.13
X = H or Al Br
n
On the basis of the recognized low reactivity (contribu-
tion) of the O,C-diprotonated dications 4, it can be postu-
lated that similar O,C-diprotonated dications 5 are also
insufficiently strong electrophiles toward benzene. There-
fore, in the case of substrates 6d and 6e, which represent
exclusively derivatives of 2-naphthol, di- or tri-cationic spe-
cies 10 and 100 are suggested as the most probable key
2. Results
Based on this extensive background, a study on the reac-
tivity of isomeric 1,5-, 1,6-, 1,7-, 2,6-, and 2,7-naphthalenedi-
ols (6a–e)12 toward benzene as a model aromatic compound
is reported with the aim of synthesizing hydroxyl-containing

K. Yu. Koltunov / Tetrahedron Letters 49 (2008) 3891–3894
3893
+
+
The resulting mixture was extracted with ether. The
organic phase was dried over anhydrous MgSO4 and con-
centrated in vacuo to obtain the crude product, which was
purified by silica gel column chromatography with ben-
zene–acetone (5:1) to give product 7a (1.37 g, 92%). Mp
173–174 °C (EtOH). HRMS C16H14O2 calcd 238.0994,
+
O
X
O
X
O
X
H
X
+
+
+
H
H
O
O
HO
+
+
X
8'
9
8
+
+
1
O
X
O
X
found 238.0989. H NMR (250.13 MHz, CDCl3) d 2.16–
+
H
+
H
HO
O
5
2.35 (m, 1H), 2.45–2.7 (m, 3H), 4.5–4.6 (m, 1H), 7.03
(d,J 7.9 Hz, 1H), 7.08–7.2 (m, 2H), 7.2–7.34 (m, 4H),
7.77 (d,J 7.9 Hz, 1H). 13C NMR (62.9 MHz, CDCl3) d
31.0, 33.9, 38.4, 119.9, 121.2, 127.3, 128.17, 128.19, 129.0,
131.9, 134.4, 141.5, 153.5, 198.5.
+
+
X
10
10'
_
3n
X = H or Al Br
n
Scheme 4. Proposed key intermediates.
Acknowledgments
intermediates (Scheme 4). A catalytic amount of protic
superacid (HBr–AlnBr3n or H2O–AlnBr3n) which is
required for C-protonation of intermediate species 9 and
5 is normally present in such reaction media due to traces
of water in the starting materials. So, additional saturation
of the reaction mixture with gaseous HBr, which usually
accelerates similar reactions,14 is not needed. Also, careful
protection from atmospheric moisture is not necessary.
It should also be noted that a 3.5-fold molar excess of
AlBr3 is not essential and a decrease in the loading is pos-
sible. This, however, slows down the reaction. Moreover,
the use of less than a ꢁ2.5-fold molar excess of AlBr3 does
not bring about the reaction. Attempts to replace AlBr3 by
AlCl3 were not generally successful as the reactions pro-
ceeded too slowly at room temperature. For example, reac-
tion 6e?7e in the presence of a 3.5-fold molar excess of
AlCl3 proceeded with about 50% conversion in 24 h. This
is probably due to the lack of solubility of the complexes
of diols 6a–e with AlCl3 in benzene. On the other hand,
heating (up to 80 °C) in order to overcome this solubility
problem gave rise to side reactions, which considerably
decreased the yields of 7a–e.
The students of Novosibirsk State University: Kachaylo
K.M., Kovtonyuk L.V., Jechev D.A. and Derevyanko
A.G. are gratefully acknowledged for their contribution
in the experimental work.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.
04.062.
References and notes
1. (a) Williams, M.; Quallich, G. Chem. Ind. 1990, 10, 315; (b) Meyer,
M. D.; Hancock, A. A.; Tietje, K.; Sippy, K. B.; Prasad, R.; Stout, D.;
Arendsen, D. L.; Donner, B. G.; Carroll, W. A. J. Med. Chem. 1997,
40, 1049; (c) Vukics, K.; Fodor, T.; Fischer, J.; Fellegvary, I.; Levai,
S. Org. Proc. Res. Dev. 2002, 6, 82.
2. See, for example: Kim, D. H.; Kim, K.; Chung, Y. K. J. Org. Chem.
2006, 71, 8264. and references cited therein.
3. (a) Souvie, J.-C.; Blanco, I. G.; Thominot, G.; Chapuis, G.; Horvath,
S.; Damien G. U.S. Patent 7,250,531, July 31, 2007; (b) Descamps-
Franßcois, C.; Yous, S.; Chavatte, P.; Audinot, V.; Bonnaud, A.;
Boutin, J. A.; Delagrange, P.; Bennejean, C.; Renard, P.; Lesieur, D.
J. Med. Chem. 2003, 46, 1127. and references cited therein.
4. (a) Methoden der Organischen Chemie; Thomas, H. G., Ed.; Thieme:
Stuttgart, 1976; Vol. 7, p 1710. 2b; (b) Repinskaya, I. B.; Koltunov,
K. Yu.; Shakirov, M. M.; Shchegoleva, L. N.; Koptyug, V. A. Russ.
J. Org. Chem. 1993, 29, 803; (c) Koltunov, K. Yu.; Repinskaya, I. B.;
Shakirov, M. M.; Shchegoleva, L. N.; Koptyug, V. A. Russ. J. Org.
Chem. 1994, 39, 88. and references cited therein.
5. (a) Koltunov, K. Yu.; Subbotina, E. N.; Repinskaya, I. B. Russ. J.
Org. Chem. 1997, 33, 689; (b) Koltunov, K. Yu.; Ostashevskaya, L.
A.; Repinskaya, I. B. Russ. J. Org. Chem. 1998, 34, 1796.
6. (a) Olah, G. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 767; (b) Olah,
G. A.; Klumpp, D. A. Superelectrophiles and Their Chemistry; Wiley:
New York, 2008.
In conclusion, an additional approach to hydroxytetral-
ones is elaborated. The reaction procedures using readily
available naphthalenediols 6a–e are simple and reproduc-
ible. The regioselectivity of the reactions is in contrast
to that of a close derivative, 5-amino-1-naphthol. The
mechanism of these reactions is interpreted in terms of
key superelectrophilic intermediates 8 and 10, analogous
to C,C-diprotonated dications 1 and 2. A study on similar
condensations of 6a–e with various derivatives of benzene
is underway. In addition, their reactivity toward benzene
and cyclohexane in the presence of H-form zeolites instead
of superacids is under investigation.15
3. Typical procedure
7. (a) Repinskaya, I. B.; Shakirov, M. M.; Koltunov, K. Yu.; Koptyug,
V. A. J. Org. Chem. USSR 1988, 24, 1719; (b) Repinskaya, I. B.;
Koltunov, K. Yu.; Shakirov, M. M.; Koptyug, V. A. J. Org. Chem.
USSR 1992, 28, 785.
3.1. 5-Hydroxy-4-phenyl-1-tetralone ð7aÞ
8. Ostashevskaya, L. A.; Koltunov, K. Yu.; Repinskaya, I. B. Russ. J.
Org. Chem. 2000, 36, 1474.
9. Koltunov, K. Yu.; Prakash, G. K. S.; Rasul, G.; Olah, G. A.
Tetrahedron 2002, 58, 5423.
To a solution of AlBr3 (6 g, 22.5 mmol) in benzene
(15 mL) was added 6a (1 g, 6.25 mmol). The resulting solu-
tion was stirred at 25 °C for 24 h, and then poured onto ice.

3894
K. Yu. Koltunov / Tetrahedron Letters 49 (2008) 3891–3894
10. (a) Kamshii, L. P. Author’s Abstract of Thesis for Candidate of
Chemical Sciences, Novosibirsk, 1976.; (b) Kamshii, L. P.; Mam-
atyuk, V. I.; Koptyug, V. A. Zh. Org. Khim. 1974, 10,
2194.
13. Koptyug, V. A.; Andreeva, T. P.; Mamatyuk, V. I. J. Org. Chem.
USSR 1970, 6, 1859.
14. Koltunov, K. Yu.; Prakash, G. K. S.; Rasul, G.; Olah, G. A. J. Org.
Chem. 2007, 72, 7394.
11. For theoretical estimation of the electrophilicity of dications 1, 2 and
3, see Ref. 9 and: Koltunov, K. Yu.; Prakash, G. K. S.; Rasul, G.;
Olah, G. A. J. Org. Chem. 2002, 67, 4330.
12. For the reactivity of 1,4- and 1,3-naphthalenediols toward benzene
and cyclohexane, see Refs. 4a,c,5a.
15. It was recently discovered, that some of the reactions shown in
Scheme
1 can be successfully mediated by HUSY-zeolites: (a)
Koltunov, K. Yu.; Walspurger, S.; Sommer, J. Chem. Commun.
2004, 1754; (b) Koltunov, K. Yu.; Walspurger, S.; Sommer, J. J. Mol.
Catal. A 2006, 245, 231.