General synthesis of 8-aryl-2-tetralones

Article abstract of DOI:10.1021/jo060688j

Two alternative routes are described for the synthesis of 8-aryl-2-tetralones (1). Route A starts from α-tetralone 3 and involves 3 or 4 steps, with the selective Na-EtOH reduction of 1-aryl-7-methoxynaphthalenes 2 being the key step. The exclusive reduct

Full text of DOI:10.1021/jo060688j

General Synthesis of 8-Aryl-2-tetralones
M. Carmen Carren˜o,* Marcos Gonza´lez-Lo´pez, Alfonso Latorre, and Antonio Urbano*
Departamento de Qu´ımica Orga´nica (C-I), UniVersidad Auto´noma, Cantoblanco, 28049 Madrid, Spain
carmen.carrenno@uam.es; antonio.urbano@uam.es
ReceiVed March 30, 2006
Two alternative routes are described for the synthesis of 8-aryl-2-tetralones (1). Route A starts from
R-tetralone 3 and involves 3 or 4 steps, with the selective Na-EtOH reduction of 1-aryl-7-methoxy-
naphthalenes 2 being the key step. The exclusive reduction of the A ring of naphthalenes 2 occurs when
the aryl group at C-1 has no substituent at the ortho positions, affording tetrahydronaphthalenes 11.
Reduction of the B ring of 2 becomes the major process when the aryl fragment has two substituents at
the ortho positions, affording 8-aryl-2-tetralones 1 as the major component. Route B involves 5 steps
starting from 2-tetralone 5, with the key step being the Suzuki coupling with triflate 4. This approach
allows the synthesis of 8-aryl-2-tetralones 1 with no substituent at the ortho positions of the aryl fragment
and with naphthalene and anthracene rings at C-8.
Introduction
substances, 2-tetralones are often very expensive and much more
difficult to synthesize. In addition, preparation of 2-tetralones
has long been hampered either by poor yields or by difficulty
in finding accessible starting materials.
The most frequently employed methods for the preparation
of 2-tetralones4 involve 1,2-transposition of the carbonyl group
of 1-tetralones,5 reduction of substituted 2-methoxy-naphtha-
lenes, followed by hydrolysis of the resulting enol ethers,6
cyclization of the diazoketones,7 and the Friedel-Crafts reaction
of the aromatic acyl chlorides with olefins.2c-d,3c,8
Substituted 2-tetralones have played an important role in
organic synthesis as a result of their high reactivity and
suitability as starting materials for a wide range of synthetic
heterocyclic compounds,1 pharmaceuticals2 with biological
activities, and other useful properties, as well as precursors of
several natural products and their derivatives.3
However, unlike their congeners, the 1-tetralones, which are
inexpensive, easy to prepare, and commercially available
(1) Recent examples: (a) Herrera, A.; Mart´ınez-Alvarez, R.; Chioua, M.;
Chatt, R.; Chioua, R.; Sa´nchez, A.; Almy, J. Tetrahedron 2006, 62, 2799-
2811. (b) Jha, A.; Beal, J. Tetrahedron Lett. 2004, 45, 8999-9001. (c) Li,
D.; Zhao, B.; Sim, S.-P.; Li, T.-K.; Liu, A.; Liu, L. F.; LaVoie, E. J. Bioorg.
Med. Chem. 2003, 11, 521-528. (d) Wang, X.-Z.; Yao, Z.-J.; Liu, H.;
Zhang, M.; Yang, D.; George, C.; Burke, T. R. Tetrahedron 2003, 59,
6087-6093.
(2) Recent examples: (a) Fisher, M. J.; Backer, R. T.; Husain, S.; Hsiung,
H. M.; Mullaney, J. T.; O’Brian, T. P.; Ornstein, P. L.; Rothhaar, R. R.;
Zgombick, J. M.; Briner, K. Bioorg. Med. Chem. Lett. 2005, 15, 4459-
4462. (b) Shefali; Srivastava, S. K.; Husbands, S. M.; Lewis, J. W. J. Med.
Chem. 2005, 48, 635-638. (c) Wheeler, W. J.; O’Bannon, D. D.; Swanson,
S.; Gillespie, T. A.; Varie, D. L. J. Labelled Compd. Radiopharm. 2005,
48, 149-164. (d) Youngman, M. A.; Willard, N. M.; Dax, S. L.; McNally,
J. J. Synth. Commun. 2003, 33, 2215-2227. (e) Gemma, S.; Butini, S.;
Fattorusso, C.; Fiorini, I.; Nacci, V.; Bellebaum, K.; McKissic, D.; Saxenac,
A.; Campiani, G. Tetrahedron 2003, 59, 87-93.
(3) Recent examples: (a) Zhu, H.; Tu, P. Synth. Commun. 2005, 35,
71-78. (b) Tririya, G.; Zanger, M. Synth. Commun. 2004, 34, 3047-3059.
(c) Silveira, C. C.; Machado, A.; Braga, A. L.; Lenardao, E. J. Tetrahedron
Lett. 2004, 45, 4077-4080. (d) Barolo, S. M.; Lukach, A. E.; Rossi, R. A.
J. Org. Chem. 2003, 68, 2807-2811. (e) Renaud, J. L.; Dupau, P.; Hay,
A.-E.; Guingouain, M.; Dixneuf, P. H.; Bruneau, C. AdV. Synth. Catal. 2003,
345, 230-238.
(4) Reviews: (a) Silveira, C. C.; Braga, A. L.; Kaufman, T. S.; Lenardao,
E. J. Tetrahedron 2004, 60, 8295-8328. (b) Schner, V. F.; Przhiya-
glovskaya, N. M. Russ. Chem. ReV. 1966, 35, 523-531.
(5) (a) Banerjee, A. K.; Vera, W. J.; Laya, M. S. Synth. Commun. 2004,
34, 2301-2308. (b) Chen, F.; Feng, X.; Qin, B.; Zhang, G.; Jiang, Y. Synlett
2003, 558-560. (b) Alcock, L. J.; Mann, I.; Peach, P.; Wills, M.
Tetrahedron: Asymmetry 2002, 13, 2485-2490. (c) Parker, M. H.; Chen,
R.; Conway, K. A.; Lee, D. H. S.; Luo, C.; Boyd, R. E.; Nortey, S. O.;
Ross, T. M.; Scorr, M. K.; Reitz, A. B. Bioorg. Med. Chem. 2002, 10,
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10.1021/jo060688j CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/26/2006
4956
J. Org. Chem. 2006, 71, 4956-4964

Synthesis of 8-Aryl-2-tetralones
SCHEME 1. Retrosynthesis of 8-Aryl-2-tetralones
Results and Discussion
Two retrosynthetic routes were envisaged for the desired
8-aryl-2-tetralones 1 (Scheme 1). The first one (route A)
involved the Na/EtOH reduction of the corresponding 7-meth-
oxy-1-arylnaphthalenes 2, which, in turn, could be formed from
the commercially available R-tetralone 3 by introduction of the
aryl substituent at the required position and aromatization. Two
alternative ways could be used to place the 8-aryl group from
3: addition of an aryl Grignard, followed by dehydration of
the resulting carbinol or metal-catalyzed cross-coupling reaction
between an aryl organometallic species and the enol triflate
derived from ketone 3.
In the second approach (route B), we considered a Pd-
catalyzed cross-coupling reaction of the triflate 4 as the key
step to introduce the desired aryl substitution at the C-8 of the
protected tetralone. Compound 4 could be easily accessible from
commercially available 2-tetralone 5, by carbonyl protection,
ether cleavage, and formation of the triflate.
We first investigated the Na/EtOH reduction of 2-methoxy-
naphthalenes (route A),12 initially described by Cornforth et al.,13
because this strategy had been successfully applied by us for
the selective synthesis of differently substituted 8-alkyl-2-
tetralones from the corresponding 8-alkyl-2-methoxynaphtha-
lenes.9a,14 It is well-known that metal-mediated reductions15 of
naphthalenes bearing electron-releasing substituents at C-1 occur
at the unsubstituted aromatic ring, whereas electron-withdrawing
groups at C-1 direct the reduction to the same ring.16 Before
our study, the ring selectivity of the reduction of 1-aryl-
substituted naphthalenes had been only reported for 1-phenyl-
naphthalene itself, which, upon treatment with Na and ammonia,
afforded exclusively the products resulting from the reaction
of the naphthalene ring bearing the phenyl substituent.17 The
effect of the presence of alkyl or alkoxy substituents on the
aryl ring at C-1 of 1-aryl-7-methoxynaphthalenes 2 on the
selectivity of the reduction remained unknown.
Synthesis of 8-Aryl-2-tetralones (Route A). The retrosyn-
thetic route A depicted in Scheme 1, first required the introduc-
tion of the aromatic substituent at C-1 of the commercially
available 7-methoxy-1-tetralone (3). From the two possible
alternatives, we initially chose the route based on the addition
of differently substituted aryl Grignard reagents 6 to R-tetralone
3 (Scheme 2).18
In connection with a program devoted to the synthesis of
polyaromatic compounds such as helicenes,9 we needed to
prepare several 8-aryl-2-tetralones (1 in Scheme 1) bearing
different substituents at the aryl moiety. On revising the
literature, we found that the synthesis of 8-aryl-2-tetralones had
been only addressed using the carbanion-induced condensation
of differently substituted 2H-pyran-2-ones with a 1,4-cyclohex-
anedione monoketal.10 Although different substituents were
admitted in the 2H-pyran-2-ones, the necessary starting materials
were not easily accessible.
We thus decided to explore the reduction of 7-methoxy-1-
arylnaphthalenes 2 as a route to the required 8-aryl-2-tetralones
1, after hydrolysis of the resulting enol ether. The presence of
different aromatic rings at the C-1 position of the starting
naphthalenes 2, required to know the ring selectivity of the
process (Scheme 1). The study of the Na/EtOH reduction of
compounds 2 bearing differently substituted phenyl groups at
C-1 allowed us to synthesize a few 8-aryl-2-tetralones with one
or two susbtituents at the ortho position of the 8-aryl group
with yields ranging from 29 to 60%.11 Looking for an improved
and more general access to these targets, we thought of a
different strategy starting from 2-tetralones bearing at the C-8
position a substituent that enabled the introduction of the 8-aryl
moiety at the final steps. We now report a full account of our
results, which allowed the synthesis of 1 using both alternative
strategies.
(6) (a) Hirayama, Y.; Ikunaka, M.; Matsumoto, J. Org. Process Res. DeV.
2005, 30-38. (b) Banerjee, A. K.; Vera, W. J. J. Chem. Res. 2004, 135-
136. (c) Cheung, A. W.-H.; Danho, W.; Swistok, J.; Qi, L.; Kurylko, G.;
Rowan, K.; Yeon, M.; Franco, L.; Chu, X.-J.; Chen, L.; Yagaloff, K. Bioorg.
Med. Chem. Lett. 2003, 13, 133-137. (d) Jha, A.; Dimmock, J. R. Can. J.
Chem. 2003, 81, 293-296. (e) Taber, D. F.; Neubert, T. D.; Rheingold, A.
L. J. Am. Chem. Soc. 2002, 124, 12416-12417.
(7) (a) Li, D.; Zhao, B.; Sim, S.-P.; Li, T.-K.; Liu, A.; Liu, L. F.; LaVoie,
E. J. Bioorg. Med. Chem. 2003, 11, 3795-3805. (b) Makhey, D.; Li, D.;
Zhao, B.; Sim, S.-P.; Li, T. K.; Liu, A.; Liu, L. F.; LaVoie, E. J. Bioorg.
Med. Chem. 2003, 11, 1809-1820. (c) Maguire, A. R.; O’Leary, P.;
Harrington, F.; Lawrence, S. E.; Blake, A. J. J. Org. Chem. 2001, 66, 7166-
7177.
(8) (a) Oishi, S.; Kang, S. U.; Liu, H.; Zhang, M.; Yang, D.; Deschamps,
J. R.; Burke, T. R., Jr. Tetrahedron 2004, 60, 2971-2977. (b) Kusumoto,
T.; Saito, Y.; Nagashima, Y.; Negishi, M.; Takehara, S.; Iwashita, Y.;
Takeuchi, K.; Takatsu, H. Mol. Cryst. Liq. Cryst. 2004, 411, 155-161. (c)
Gray, A. D.; Smith, T. P. J. Org. Chem. 2001, 66, 7113-7117.
(9) (a) Carren˜o, M. C.; Gonza´lez-Lo´pez, M.; Urbano, A. Chem. Commun.
2005, 611-613. (b) Carren˜o, M. C.; Garc´ıa-Cerrada, S.; Urbano, A. Chem.s
Eur. J. 2003, 9, 4118-4131. (c) Carren˜o, M. C.; Garc´ıa-Cerrada, S.; Urbano,
A. Chem. Commun. 2002, 1412-1413. (d) Carren˜o, M. C.; Garc´ıa-Cerrada,
S.; Urbano, A. J. Am. Chem. Soc. 2001, 123, 7929-7930.
Thus, the reaction between 3 and p-tolylmagnesium bromide
6a took place in ethyl ether at room temperature to give an
(12) Soffer, M. D.; Bellis, M. P.; Gellerson, H. E.; Stewart, R. A. Org.
Synth. 1952, 32, 97-100.
(13) Cornforth, J. W.; Cornforth, R. H.; Robinson, R. J. Chem. Soc. 1942,
689-691.
(14) (a) Carren˜o, M. C.; Garc´ıa-Cerrada, S.; Sanz-Cuesta, M. J.; Urbano,
A. Chem. Commun. 2001, 1452-1453. (b) Carren˜o, M. C.; Enr´ıquez, A.;
Garc´ıa-Cerrada, S.; Sanz-Cuesta, M. J.; Urbano, A. Unpublished results.
(15) Birch, A. J. J. Chem. Soc. 1944, 430-436.
(16) (a) Harvey, R. G. Synthesis 1970, 36, 161-172. (b) Rabideau, P.
W. Tetrahedron 1989, 45, 1579-603. (c) Rabideau, P. W.; Marcinow, Z.
Org. React. 1992, 42, 1-334.
(17) (a) Rabideau, P. W.; Marcinow, Z. J. Org. Chem. 1990, 55, 3812-
3816. (b) Eisenbraun, E. J.; Melton, R. G.; Flanagan, P. W.; Hamming, M.
C.; Keen, G. W. Prepr. Am. Chem. Soc., DiV. Pet. Chem. 1971, 16, B43-
B50.
(18) For other examples of additions of aryl Grignard reagents to
R-tetralones, see: (a) Alcock, N. J.; Mann, I.; Peach, P.; Wills, M.
Tetrahedron: Asymmetry 2002, 13, 2485-2490. (b) Schneider, M. R.;
Schiller, C. D. Arch. Pharm. 1990, 323, 17-21. (c) Laus, G.; Tourwe, D.;
Van Binst, G. Heterocycles 1984, 22, 311-331. (d) Adam, G.; Andrieux,
J.; Plat, M. Tetrahedron 1982, 38, 2403-2410. (e) Bindal, R. D.; Durani,
S.; Kapil, R. S.; Anand, N. Synthesis 1982, 405-407.
(10) (a) Ram, V. J.; Agarwal, N.; Saxena, A. S.; Farhanullah; Sharon,
A.; Maulik, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 1426-1437. (b)
Ram, V. J.; Agarwal, N.; Farhanullah. Tetrahedron Lett. 2002, 43, 3281-
3283.
(11) Part of this work was previously communicated: Carren˜o, M. C.;
Gonza´lez-Lo´pez, M.; Latorre, A.; Urbano, A. Synlett 2005, 1601-1605.
J. Org. Chem, Vol. 71, No. 13, 2006 4957

Carren˜o et al.
SCHEME 2. Synthesis of Dihydronaphthalenes 8a-d from
Aryl Grignard Additions on r-Tetralone 3
SCHEME 3. Synthesis of Dihydronaphthalenes 8d-h from
Suzuki Coupling between Boronic Acids 10d-h and Enol
Triflate 9
intermediate carbinol 7a, which was directly transformed into
4-(p-tolyl)-6-methoxy-1,2-dihydronaphthalene (8a) by treatment
with 35% HCl (73% yield for the two steps, Scheme 2).
Dihydronaphthalenes 8b and 8c were similarly obtained by
reaction of 3 with 4-methoxyphenylmagnesium bromide (6b)
or the 2,4-dimethoxyphenyl derivative 6c, in 86 and 72% overall
yields, respectively. Nevertheless, when the reaction of 3 was
carried out with the Grignard reagent 6d, bearing a bulky ethyl
substituent at the ortho position, compound 8d was formed in
a poor 20% yield. Moreover, when the reagent of choice was
2,4,6-trimethylphenylmagnesium bromide, no reaction was
observed, even at higher temperatures (refluxing Et2O) or in
the presence of several Lewis acids such as BF3‚OEt2 or
Yb(OTf)3.19
With these results in hand, we decided to evaluate the
synthetic alternative pathway to dihydronaphthalenes 8, on the
basis of the metal-catalyzed cross-coupling reaction between
the enoltriflate derived from 3 and an aryl organometallic
species. Among the different organometallic reagents available
in the synthetic arsenal, we decided to use boronic acids20 as a
result of their accessibility and the excellent results achieved
in their cross-coupling reactions even with sterically hindered
derivatives.21
The synthesis of 6-methoxy-4-[(trifluoromethanesulfonyl)-
oxy]-1,2-dihydronaphthalene 922 was carried out from the
reaction of R-tetralone 3 with N-phenyl-bis(trifluoromethane-
sulfonamine) (Tf2NPh) at -78 °C in the presence of a 0.5 M
solution of potassium hexamethyldisilazane (KHMDS) in THF,
in 96% yield (Scheme 3). All cross-coupling reactions were
performed under the experimental conditions reported by Suzuki
et al. [Pd(PPh3)4, Ba(OH)2‚8H2O, DME/H2O, 80 °C]21 using
commercially available boronic acids 10d-h, except in the case
of 10g, which was prepared as previously described.23
Thus, the reaction between enol triflate 9 and 2-ethylphenyl
boronic acid (10d), under the above-mentioned conditions,
furnished in only 40 min dihydronaphthalene 8d with an
excellent 94% yield (Scheme 3), enhancing the poor 20% yield
obtained using the Grignard reagent addition to 3, as indicated
in Scheme 2. Under the same experimental conditions, the cross-
coupling reactions of compound 9 with differently substituted
aryl boronic acids 10e-h, bearing one or two substituents at
the ortho positions of the aryl moiety, took place in short
reaction times (15-120 min), affording the corresponding
dihydronaphthalenes 8e-h with yields ranging from 70 to 97%
(Scheme 3). It is worth mentioning the excellent 90% yield
achieved in the preparation of compound 8h, which could not
be synthesized using the Grignard addition strategy.
Once the dihydronaphthalenes 8a-h were prepared, the
synthetic sequence toward the desired 8-aryl-2-tetralones (Scheme
1) required the full aromatization of the dihydroaromatic ring
of 8a-h to the corresponding 1-aryl-7-methoxynaphthalenes
2a-h. This was easily achieved using 2,3-dichloro-5,6-dicy-
anoquinone (DDQ) as the oxidant agent.
Thus, the reaction of dihydronaphthalene 8a with 1.2 equiv
of DDQ in CH2Cl2 afforded, after 15 min at room temperature,
1-(4-methylphenyl)-7-methoxynaphthalene (2a) in 71% yield
(Scheme 4). Under the same experimental conditions, 1-aryl-
7-methoxynaphthalenes 2b-g, bearing different substituents at
the aryl moiety (Scheme 4), were obtained from the corre-
sponding dihydronaphthalenes 8b-g in good to excellent yields
(80-97%).
With 1-arylnaphthalenes 2a-g in hand, we undertook the
study of the selectivity of their reductions with Na-EtOH. All
reactions were performed by adding an excess of sodium (6 or
7 pieces of ca. 0.5 cm) to a solution of the corresponding 1-aryl-
7-methoxynaphthalene 2 in refluxing EtOH until the disappear-
ance of all starting material (followed by TLC). Heating the
external bath to 100 °C was essential to attain good results.
After consumption of the excess of sodium, the resulting mixture
(19) (a) Molander, G. A.; Burkhardt, E. R.; Weinig, M. J. Org. Chem.
1990, 55, 4990-4991. (b) Hattori, T.; Date, M.; Sakurai, K.; Morohashi,
N.; Kosugi, H.; Miyano, S. Tetrahedron Lett. 2001, 42, 8035-8038.
(20) (a) Suzuki, A. Modern Arene Chemistry, Wiley-VCH: New York,
2002; pp 53-106. (b) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-
2483. For examples of cross-coupling reactions between enol triflates and
boronic acids and derivatives, see: (c) Miyashita, K.; Sakai, T.; Imanishi,
T. Org. Lett. 2003, 5, 2683-2686. (d) Basil, L. F.; Nakano, H.; Frutos, R.;
Kopach, M.; Meyers, A. I. Synthesis 2002, 2064-2074. (e) Pal, K. Synthesis
1995, 1485-1487.
1
was treated with 35% HCl and investigated by H NMR.
The reduction of 1-(p-tolyl)-7-methoxynaphthalene (2a),
under the above conditions, gave rise exclusively to 1-(p-tolyl)-
(21) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207-210.
(22) Scheiper, B.; Bonnekessel, M.; Krause, H.; Fuerstner, A. J. Org.
Chem. 2004, 69, 3943-3949.
(23) Bringmann, G.; Goetz, R.; Keller, P. A.; Walter, R.; Boyd, M. R.;
Lang, F.; Garcia, A.; Walsh, J. J.; Tellitu, I.; Bhaskar, K. V.; Kelly, T. R.
J. Org. Chem. 1998, 63, 1090-1097.
4958 J. Org. Chem., Vol. 71, No. 13, 2006

Synthesis of 8-Aryl-2-tetralones
SCHEME 4. Synthesis of Naphthalenes 2a-h by
Aromatization of Dihydronaphthalenes 8a-h with DDQ
SCHEME 6. Ring Selectivity in the Na-EtOH Reduction of
1-(2,4-Dimethoxyphenyl)-7-methoxynaphthalene 2c
identified as 1-(2,4-dimethoxyphenyl)-7-methoxy-1,2,3,4-tetra-
hydronaphthalene 11c, proceeding from the over-reduction of
the A ring of 2c, and 8-(2,4-dimethoxyphenyl)-3,4-dihydro-
2(1H)-naphthalenone (1c), which was formed after the reduction
of the B ring of 2c, followed by acidic hydrolysis of the initially
formed vinyl ether intermediate Z. Compounds 11c and 1c could
be isolated pure in 50 and 29% yields, respectively, after
chromatographic separation.
SCHEME 5. Exclusive Na-EtOH Reduction of the A Ring
of Naphthalenes 2a,b
To evaluate if the variation observed in the selectivity of the
process was due to the presence of two electron-donating groups
or to the existence of a OMe substituent at the ortho position
of the 1-aryl group in 2c, we performed the reduction of 1-(2-
ethylphenyl)-7-methoxynaphthalene (2d). In this case, the phenyl
substituent at C-1 possesses a bulkier ethyl group at the ortho
position, but the electronic density of the aryl ring in 2d is
smaller if compared with the 2,4-dimethoxy-substituted phenyl
ring in 2c. Under the typical reduction conditions (Table 1, entry
4), naphthalene 2d gave rise to a 50:50 mixture of tetrahy-
dronaphthalene 11d and â-tetralone 1d, both being isolated pure
in 36% yield. This result seemed to indicate that the presence
of a bulky substituent at the ortho position of the aryl ring at
C-1 could favor the ring B reduction of the naphthalene
derivative, enhancing the ratio of the desired 2-tetralone in the
final mixture.
This assumption was confirmed after reduction of compound
2e, bearing an isopropyl group at the ortho position of the 1-aryl
substituent, which afforded a 40:60 mixture of compounds 11e
and 1e, isolated in 20 and 45% yields, respectively (Table 1,
entry 5). In this case, the reduction of the B ring of naphthalene
2e was favored, thus confirming that the steric hindrance at the
ortho positions of the aryl group at C-1 was playing an essential
role in defining the ring selectivity of the process. An identical
result was observed when 7-methoxy-1-(2,4,6-trimethoxyphen-
yl)naphthalene (2f), with two methoxy groups at the ortho
positions of the phenyl moiety at C-1, was submitted to the
reduction conditions. In this case (Table 1, entry 6), a 28% yield
of 1-(2,4,6-trimethoxyphenyl)-7-methoxy-1,2,3,4-tetrahydronaph-
thalene (11f) and a 32% yield of the corresponding 2-tetralone
1f were obtained after chromatographic separation of the initially
formed 40:60 mixture of compounds.
7-methoxy-1,2,3,4-tetrahydronaphthalene (11a) in 62% yield
(Scheme 5). Compound 11a was probably formed from the
initial reduction of the A ring of 2a, bearing the p-tolyl
substituent, to the corresponding 1,4-dihydroaromatic intermedi-
ate X (Scheme 5), isomerization of the double bond to derivative
Y, and over-reduction of the conjugate double bond formed.
The intermediate formation of 1,2-dihydrotetralins had been
already recognized in Birch reductions.24 The ring selectivity
observed by us was not unexpected because Rabideau et al.16a
had shown that the Na-NH3 reduction of 1-phenylnaphthalene
afforded exclusively the product resulting from the reduction
of the naphthalene ring bearing the phenyl substituent.
When 7-methoxynaphthalene 2b, bearing a p-methoxyphenyl
substituent at C-1, was submitted to the typical reduction
conditions, we obtained 1-(p-methoxyphenyl)-7-methoxy-1,2,3,4-
tetrahydronaphthalene (11b), also proceeding from the over-
reduction of the A ring of 2b, as the exclusive product, which
was isolated in 71% yield (Scheme 5). This result indicated
that the presence of a more electron-donating substituent had
no influence on the ring selectivity of the process.
With the aim of further increasing the ratio of the B ring
reduction of 1-aryl-7-methoxynaphthalenes 2 and, as a conse-
quence, the yield of the 8-aryl-2-tetralones 1, we performed the
reduction of 7-methoxy-1-(2,4-dimethoxy-6-methylphenyl)naph-
thalene 2g, bearing a methoxy and a methyl group at the ortho
positions of the aryl substituent at C-1 (Table 1, entry 7). In
Nevertheless, reduction of compound 2c, possessing two
methoxy groups at the ortho and para positions of the phenyl
group at C-1 (Scheme 6) gave a 70:30 mixture of two products
(24) Birch, A. J. Q. ReV., Chem. Soc. 1950, 4, 69-93.
J. Org. Chem, Vol. 71, No. 13, 2006 4959

Carren˜o et al.
TABLE 1. Ring Selectivity in the Na-EtOH Reductions of
1-Aryl-7-methoxynaphthalenes 2a-h
FIGURE 1. 1H NMR spectra of tetrahydronaphthalene 11g at different
temperatures.
this case, a 25:75 mixture of tetrahydronaphthalene 11g (22%
isolated yield) and â-tetralone 1g (60% yield) was formed.
Finally, the best result, referred to the B ring selective Na-
EtOH reduction of compounds 2, was achieved from derivative
2h, bearing two methyl groups at the ortho positions of the aryl
moiety at C-1 (Table 1, entry 8). In this case, a 15:85 mixture
of 1-(2,4,6-trimethylphenyl)-7-methoxy-1,2,3,4-tetrahydronaph-
thalene (11h) and 8-(2,4,6-trimethylphenyl)-2-tetralone (1h) was
formed from which both compounds could be isolated in 8 and
54% yields, respectively.
It is worth mentioning that in the 1H NMR spectrum (CDCl3)
of tetrahydronaphthalene 11g, bearing an aryl substituent at C-1
with a methoxy and a methyl group at the ortho positions,
several broad nonwell-resolved signals appeared (Figure 1). This
could probably be due to the presence of atropisomers A and
B, caused by a restricted rotation around the C1′(sp2) aryl-C4-
(sp3) single bond.25 When a solution of 11g in C2D2Cl4 was
heated at 390 °K, the broad signals observed for H1 (δ ) 4.90
and 4.20 ppm), OMe (o) (δ ) 3.80 and 3.40 ppm), and Me
(δ ) 2.18 and 1.98 ppm), at room temperature, coalesced to a
multiplet at 4.50 ppm, a singlet at 3.58 ppm, and a singlet at
2.08 ppm, respectively (Figure 1).
This type of restricted rotation about a C(sp3)-C(sp2) bond
had also been observed for similar conveniently functionalized
systems such as 9-arylfluorenes,26 9-aryltriptycenes,27 9-aryl-
xanthenes,28 and 9-aryl-9,10-dihydroanthracenes.29
1
The comparison of the H NMR data of the three tetrahy-
dronaphthalenes 11f-h, possessing an aryl group at C-1 with
two substituents at the ortho positions, suggested three different
situations. Compound 11f, bearing two methoxy groups, must
have a free rotation around the C(sp3)-C(sp2) bond at room
temperature, because both OMe groups are equivalent and
appear at the same chemical shift (3.65 ppm; Figure 2). In the
1H NMR spectrum of 11h, with two bulkier ortho methyl groups
at the aryl substituent at C-1, two different signals for the two
nonequivalent methyl groups could be observed at 2.26 and 1.79
ppm, respectively (Figure 2). This could be due to a restricted
(26) Ford, W. T.; Thompson, T. B.; Snoble, K. A. J.; Timko, J. M. J.
Am. Chem. Soc. 1975, 97, 95-100.
(27) Nakamura, M.; Oki, M. Bull. Chem. Soc. Jpn. 1975, 48, 2106-
2111.
(28) Nakamura, M.; Oki, M. Bull. Chem. Soc. Jpn. 1980, 53, 2977-
2980.
(25) Eliel, E. L.; Wilen, S. H.; Doyle, M. P. In Basic Organic
Stereochemistry; Wiley: New York, 2001; p 629.
(29) Rabideau, P. W.; Govindarajan, U. J. Org. Chem. 1989, 54, 988-
990.
4960 J. Org. Chem., Vol. 71, No. 13, 2006

Synthesis of 8-Aryl-2-tetralones
FIGURE 3. Extended conjugation of intermediates I (R1 ) R2 ) H)
favoring exclusive reduction of the A ring of 1-arylnaphthalenes 2a,b.
FIGURE 2. 1H NMR data of tetrahydronaphthalenes 11f and 11h,
suggesting free or restricted rotation of the aryl ring at C-1.
SCHEME 7. Mechanistic Proposal for the Na-EtOH
Reduction of 1-Aryl-7-methoxynaphthalenes 2a-h
FIGURE 4. Steric inhibition of the resonance in intermediates I
(R1 ) R2 * H) favoring reduction of the B ring of 1-arylnaphthalenes
2f-h through intermediates II.
The stabilization of the negative charge or the electron situated
at C-1 in species I•- or I2- is possible if the aryl group is situated
in the same plane with respect to the dihydronaphthalene moiety
to allow delocalization (Scheme 7 and Figure 3).
This situation is optimal in the intermediates of type I bearing
a p-methyl (resulting from 2a) or a p-methoxy substitution (from
2b) at the aryl group at C-1, without substituents at the ortho
positions, which allows the extended conjugation (Figure 3).
Further protonation of such species, followed by evolution
through the intermediates shown in Scheme 5, accounts for the
exclusive formation of tetrahydronaphthalenes 11a,b.
rotation about the C(sp3)-C(sp2) bond at room temperature.
Finally, as indicated above, in the case of derivative 11g, with
a methyl and a methoxy ortho groups, a partially restricted
rotation around the C(sp3)-C(sp2) must occur at room temper-
1
ature, because a broadening of several signals in the H NMR
When a small substituent such as an OMe group is introduced
at the ortho position of the C-1 aryl group (compound 2c), a
nonnegligible 30% of evolution through the B ring reduction is
also observed (Scheme 6). If the ortho substituent is an ethyl
group (compound 2d), there is no selectivity in the reduction
of the A or B rings (50:50 mixture of 11d and 1d, Table 1,
entry 4). These results could be a consequence of the higher
volume of the ortho ethyl substituent, which could force the
C-1 aryl fragment out of the plane, thus inhibiting the resonance
stabilization of intermediates I. In such a situation, the B ring
reduction through evolution of intermediates II becomes
competitive. The bulkier isopropyl substituent present in the
aryl group at C-1 of 2e could be in the origin of the slight but
significant inversion of the ring selectivity reduction observed
in favor of the B ring (40:60 mixture of 11e and 1e, Table 1,
entry 5). Going down in the results shown in Table 1, the
preference for the A ring reduction in compounds 2f-h
decreased significantly when increasing the number or the size
of the ortho substituents in the aryl group at C-1. These
observations are in agreement with the increasing steric inhibi-
tion of the resonance due to the presence of two ortho
substituents in the aryl fragment at C-1 of naphthalenes 2, which
force the disposition of this group out of the plane, destabilizing
intermediates I and favoring the B ring reduction of naphthalenes
2f-h to give compounds 1 as majors (Figure 4).
spectrum is observed as a consequence of the presence of two
atropisomeric species A and B (Figure 1).
Mechanistic Proposal. The mechanism of the Birch and
related metal-alcohol processes has been extensively studied
both from the experimental and from the theoretical points of
view.30 The reduction of the aromatic ring is thought to begin
by the formation of a radical anion by electron transfer from
the metal. After protonation by the alcohol, the resulting radical
is further reduced to a carbanion by a second electron transfer
from the metal. Finally, a second proton is transferred from the
alcohol to this anion. In the case of polynuclear arenes, a second
electron addition to the initially formed radical anion may take
place to produce a dianion.16c,31 In both cases, the first
protonation is the rate-determining step. The structure of the
final metal-mediated reduction product will be defined by the
site of protonation of the radical anion or the dianion, which,
in turn, will be the position of the highest electron density.16a
In the case of the reduction of naphthalenes 2a,b, the selective
formation of tetrahydronaphthalenes 11a,b, resulting from the
exclusive reduction of the A ring, must be a consequence of
the intermediate formation of the radical anion I•- or dianion
I
2-, which must be favored over the analogues II•- and II2-
.
(30) Carey, F. A.; Sundberg, R. J. In AdVanced Organic Chemistry, Part
B: Reactions and Synthesis, 4th ed.; Kluwer: Norwell, MA, 2000.
(31) Rabideau, P. W.; Burkholder, E. G. J. Org. Chem. 1978, 43, 4283-
4288.
Moreover, when the radical or the negative charge is located
at C-1 of the A ring (intermediates I in Figure 4), the steric
J. Org. Chem, Vol. 71, No. 13, 2006 4961

Carren˜o et al.
hindrance due to the presence of ortho substituents R1 and R2
in the orthogonal aryl fragment at C-1, could also inhibit or
cause their protonation to be more difficult, which also would
favor the B ring reduction process.
SCHEME 8. Synthesis of 8-Aryl-2-tetralones 1a,i-n from
2-Tetralone 5
Synthesis of 8-Aryl-2-tetralones (Route B). Although the
above synthetic strategy allowed us to show that the ring
selectivity of the Na-EtOH reduction of 1-aryl-7-methoxynaph-
thalenes 2 could be modulated by the substitution pattern at
the 1-aryl fragment, from the synthetic point of view, the
preparation of 8-aryl-2-tetralones 1 by this route presented
serious drawbacks. First, although â-tetralones 1c-h could be
isolated pure, they were always obtained as mixtures with the
corresponding 4-aryl-6-methoxy-1,2,3,4-tetrahydronaphthalenes
11c-h. Moreover, this method did not allow the synthesis of
the simplest 8-aryl-2-tetralones 1a,b without substituents at the
ortho positions of the 8-aryl moiety. On the other hand, the
synthesis of 8-naphthyl-substituted 2-tetralones 1 by this strategy
appeared complicated by the competitive reduction of both
naphthalene fragments under the Na-EtOH reductive conditions
employed.
Therefore, with the aim of describing a more general method
to access to 8-aryl-2-tetralones 1, we turned our attention to
the synthetic alternative pathway proposed in Scheme 1 as Route
B. The starting material in this approach could be a preformed
2-tetralone, such as 5, bearing at C-8 a methoxy group, which
could be easily transformed into the aryl moiety present in
derivatives 1.
Thus, the initial protection of commercially available 8-meth-
oxy-2-tetralone (5) as dioxolane, afforded compound 1232 in
nearly quantitative yield (Scheme 8). Demethylation of 12
proved to be very difficult under various aryl methyl ether
cleavage protocols33 as a result of the presence of the sensitive
acetal moiety. After considerable experimentation, success was
achieved using lithium diphenylphosphide,34 prepared in situ
from diphenylphosphine and n-butyllithium, in refluxing THF
for 24 h. Under these conditions, compound 12 furnished phenol
13 in 77% yield. The corresponding triflate 4, necessary for
the introduction of the aryl groups by Suzuki coupling, was
prepared from 13 by a reaction with trifluoromethanesulfonic
anhydride in the presence of pyridine in 90% yield (Scheme
8).
With triflate 4 in hand, we performed the introduction of the
aryl groups at the desired position by Suzuki coupling using
differently substituted aryl boronic acids 10 (Scheme 8). For
these reactions, we used two phenyl boronic acids with no
substituents at the ortho positions, 10a and 10i, one derivative
with a phenyl group at the ortho position, 10j, three naphthyl
boronic acids with different substitutions at the naphthalene ring,
10k-m, and, finally, one derivative bearing an anthracenyl
moiety, 10n. All cross-coupling reactions were performed under
the experimental conditions described by Suzuki et al.21 [Pd-
(PPh3)4, Ba(OH)2‚8H2O, DME, reflux], slightly modified, using
commercially available arylboronic acids 10a,i-k, or previously
described derivatives 10l,35 10m,36 and 10n.37 Under these
conditions, biaryls 14a,i-l were obtained in excellent yields
(80-98%), after flash chromatography. Nevertheless, when
more hindered arylboronic acids such as 10m and 10n were
used, low yields of the corresponding biaryls were obtained
using the above-mentioned procedure. In these cases, the
application of the experimental conditions reported by Tanaka
et al.38 [Pd(PPh3)4, Cs2CO3, toluene/EtOH/H2O, 90 °C] for the
Suzuki coupling with triflate 4, furnished biaryls 14m and 14n
in 63 and 84% yields, respectively (Scheme 8).
(32) (a) Cordi, A. A.; Lacoste, J.-M.; Descombes, J.-J.; Courchay, Ch.;
Vanhoutte, P. M.; Laubie, M.; Verbeuren, T. J. J. Med. Chem. 1995, 38,
4056-4069. (b) Lee, S.; Frescas, S. P.; Nichols, D. E. Synth. Commun.
1995, 25, 2775-2780. (c) Turner, R. B.; Miller, R. B.; Lin, J.-L. J. Am.
Chem. Soc. 1968, 90, 6124-6130.
Finally, the treatment of derivatives 14a,i-n with 35% HCl
at 0 °C (Scheme 8) afforded 8-aryl-2-tetralones 1a,i-n with
(33) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999.
(35) Castanet, A.-S.; Colobert, F.; Broutin, P.-E.; Obringer, M. Tetra-
hedron: Asymmetry 2002, 13, 659-665.
(34) (a) Ireland, R. E.; Walba, D. M. Organic Syntheses; Wiley &
Sons: New York, 1988; Collect. Vol. No. VI, pp 567-570. For more recent
references, see: (b) Wipf, P.; Jung, J.-K. J. Org. Chem. 2000, 65, 6319-
6337. (c) Ohira, S.; Kuboki, A.; Hasegawa, T.; Kikuchi, T.; Kutsukake, T.;
Nomura, M. Tetrahedron Lett. 2002, 43, 4641-4644. (d) Zheng, S.-L.; Yu,
W.-Y.; Xu, M.-X.; Che, Ch.-M. Tetrahedron Lett. 2003, 44, 1445-1447.
(e) Moriarty, R. M. J. Org. Chem. 2004, 69, 1890-1902.
(36) Ford, A.; Sinn, E.; Woodward, S. J. Chem. Soc., Perkin Trans. 1
1997, 927-934.
(37) (a) Suzuki, K.; Seno, A.; Tanabe, H.; Ueno, K. Synth. Met. 2004,
143, 89-96. (b) Li, Z. H.; Wong, M. S.; Tao, Y.; D’Iorio, M. J. Org. Chem.
2004, 69, 921-92.
(38) Yoshikawa, S.; Odaira, J.; Kitamura, Y.; Bedekar, A. V.; Furuta,
T.; Tanaka, K. Tetrahedron 2004, 60, 2225-2234.
4962 J. Org. Chem., Vol. 71, No. 13, 2006

Synthesis of 8-Aryl-2-tetralones
lene (9; 1.0 g, 3.2 mmol) in DME (20 mL) and H2O (4 mL). The
reaction mixture was heated at 80 °C with vigorous stirring for the
time indicated in each case, cooled to room temperature, and filtered
over Celite. After extraction with CH2Cl2, workup, and flash
chromatography, the corresponding pure 4-aryl-6-methoxy-1,2-
dihydronaphthalene 8d-h was obtained.
General Procedure for the Aromatization of Dihydronaph-
thalenes. Synthesis of 1-Aryl-7-methoxynaphthalenes 2a-h.
Method C. To a solution of the corresponding 6-methoxy-4-aryl-
1,2-dihydronaphthalene 8a-h (2.6 mmol) in CH2Cl2 (50 mL) at
room temperature was added DDQ (711 mg, 3.1 mmol, 1.2 equiv).
The reaction mixture was stirred for 15 min and washed with a
saturated aqueous solution of sodium bicarbonate. After workup
and flash chromatography, pure 1-aryl-7-methoxynaphthalenes
2a-h were obtained.
General Procedure for the Na-EtOH Reductions. Synthesis
of 1-Aryl-7-methoxy-1,2,3,4-tetrahydronaphthalenes, 11a-h,
and 8-Aryl-2-tetralones, 1c-h. Method D. To a solution of the
corresponding 1-aryl-7-methoxynaphthalene 2a-h (0.7 mmol) in
EtOH (35 mL) heated at 100 °C, under argon, was added 6 or 7
pieces of Na of about 0.5 cm in length, and during the reaction
time, the same amount of Na was maintained in the reaction media.
The mixture was vigorously stirred at 100 °C for the time indicated
in each case, quenched with EtOH, and cooled to room temperature.
When the Na had completely disappeared, H2O was slowly added,
the mixture was cooled to 0 °C, and 35% HCl was added dropwise
until acidity was reached. After extraction with CH2Cl2, washing
with sodium bicarbonate, and workup, the corresponding mixture
of 1-aryl-7-methoxy-1,2,3,4-tetrahydronaphthalenes, 11a-h, and
8-aryl-2-tetralones, 1c-h, were obtained, which were separated by
flash chromatography.
good to excellent yields (71-99%), demonstrating the generality
of this synthetic methodology for the efficient preparation of
8-aryl-â-tetralones bearing different substitution at the aryl
moiety at C-8.
Conclusions
We have reported two complementary strategies to synthesize
8-aryl-substituted 2-tetralones. When the 8-aryl groups bear a
bulky ortho substituent or two ortho substitutents, the method
of choice was based on the use of 1-aryl-7-methoxy naphtha-
lenes 2 as precursors. Their selective Na-EtOH reductions
occurred preferentially at the methoxy-substituted B ring to give
a 1,4-dihydro-2-methoxy-8-arylnaphthalene derivative, which,
after in situ acidic hydrolysis, gave rise to the corresponding
8-aryl-2-tetralones. The study of the Na-EtOH reduction of
several 1-aryl-7-methoxynaphthalenes 2 has shown the influence
of the different substitutions at the 1-aryl moiety on the ring
selectivity of the process. The other route to 8-aryl-2-tetralones
used a Suzuki coupling between triflate 4 and differently
substituted aryl boronic acids as the key step to the targets. This
strategy allowed us to prepare derivatives with phenyl rings at
C-8 with no substituent at the ortho positions, as well as
2-tetralones bearing aryl groups at C-8 with more than one ring
(naphthalene or anthracene moieties).
Experimental Section
General Procedure for the Addition of Aryl Grignard
Reagents. Synthesis of 4-Aryl-6-methoxy-1,2-dihydronaphtha-
lenes 8a-c. Method A. A solution of the corresponding com-
mercially available aryl bromide (11.2 mmol, 2.6 equiv) in dry ethyl
ether (9 mL) was added to magnesium turnings (177 mg, 7.3 mmol,
1.8 equiv) at 60 °C under argon. After the disappearance of all
magnesium (ca. 3-7 h), the reaction was cooled to room temper-
ature, and a solution of commercially available 7-methoxy-2-
tetralone (3; 752 mg, 4.3 mmol) in dry ethyl ether (20 mL) was
added. The reaction mixture was stirred for the time indicated in
each case, quenched with NH4Cl, and extracted with Et2O. After
workup, the residue was dissolved in 10 mL of CH2Cl2, and 35%
HCl was slowly added at 0 °C until acidity was reached. The
mixture was stirred for 30 min, extracted with CH2Cl2, and washed
with sodium bicarbonate. After workup and flash chromatography,
the corresponding pure 4-aryl-6-methoxy-1,2-dihydronaphthalene
8a-c was obtained.
6-Methoxy-4-trifluoromethanesulfonyloxy-1,2-dihydronaph-
thalene (9). To a solution of commercially available 7-methoxy-
1-tetralone (3; 1.50 g, 8.51 mmol) and N-phenyl-bis(trifluoromethane-
sulfonimide) (3.33 g, 9.36 mmol) in dry THF (80 mL) was slowly
added a solution of 0.5 M KHMDS in THF (18.7 mL, 9.36 mmol)
at -78 °C under argon. The mixture was stirred for 1.5 h and
quenched with H2O at -78 °C. After warming to room temperature,
workup, and flash chromatography (eluent CH2Cl2/hexane 1:4),
compound 922 was obtained as a colorless oil, in 96% yield: 1H
NMR δ 2.48 (m, 2H), 2.80 (t, J ) 8.1 Hz, 2H), 3.80 (s, 3H), 6.03
(t, J ) 4.3 Hz, 1H), 6.80 (dd, J ) 2.7 and 8.7 Hz, 1H), 6.92 (d,
J ) 2.7 Hz, 1H), 7.09 (d, J ) 8.6 Hz, 1H); 13C NMR δ 22.6, 25.8,
55.2, 107.1, 114.3, 118.3, 118.1 (q, J ) 319 Hz), 128.1, 128.6,
129.5, 146.2, 158.6; MS (EI) m/z (%) 115 (29), 147 (81), 173 (22),
175 (66), 308 (M+, 100); HRMS (EI) calcd for C12H11O4F3S (M+),
308.0330; found, 308.0323.
8-Methoxy-2-[spiro-(1,3-dioxolyl)]tetralin (12)32 In a two-
necked round-bottom flask equipped with a stirring bar and a
Dean-Stark trap, commercially available 8-methoxy-2-tetralone (5;
1.1 g, 6.3 mmol) and p-toluenesulfonic acid (1.8 mg) were added,
and the mixture was purged with N2. Then benzene (14 mL) and
ethylene glycol (0.70 mL, 12.6 mmol) were added, and the mixture
was refluxed for 4 h. The solution was cooled, poured into a solution
of saturated aqueous sodium carbonate, and extracted with ether.
After workup, the crude was filtered over silica gel to obtain
compound 12 as a white solid in 99% yield: mp 96-96 °C (lit32a
1
124-125 °C, lit32c 51.5-52 °C); H NMR δ 1.93 (t, J ) 6.8 Hz,
2H), 2.87 (s, 2H), 2.98 (t, J ) 6.8 Hz, 2H), 3.8 (s, 3H), 4.03 (m,
4H), 6.65 (d, J ) 8.1 Hz, 1H), 6.75 (d, J ) 7.5 Hz, 1H), 7.10 (m,
1H); 13C NMR δ 28.1, 31.5, 33.5, 55.2, 64.5, 107.0, 108.4, 120.7,
123.3, 126.4, 136.5, 157.3.
8-Hydroxy-2-[spiro-2-(1,3-dioxolyl)]tetralin (13). To a solution
of diphenylphosphine (1.0 mL, 6 mmol) in THF (5.2 mL) was added
a solution of 2.5 M n-butyllithium in hexane (2.3 mL, 5.8 mmol).
The resulting red anion was stirred for 30 min, and a solution of
compound 12 (870 mg, 3.9 mmol) in THF (10.3 mL) was added.
The reaction mixture was refluxed for 24 h, cooled in an ice bath,
and quenched with a saturated aqueous ammomium chloride
solution. Ether was added and, after workup and flash chromatog-
raphy (eluent AcOEt/hexane 1:5), compound 13 was obtained as a
colorless oil in 77% yield: 1H NMR δ 1.93 (t, J ) 6.5 Hz, 2H),
2.87 (s, 2H), 2.98 (t, J ) 6.5 Hz, 2H), 4.04 (m, 4H), 4.65 (s, 1H),
6.57 (d, J ) 8.1 Hz, 1H), 6.72 (d, J ) 8.1 Hz, 1H), 6.99 (t, J ) 8.1
Hz, 1H); 13C NMR δ 28.1, 31.6, 33.3, 64.5, 108.4, 112.0, 120.8,
121.4, 126.5, 137.0, 153.5; MS (EI) m/z (%) 91 (45), 105 (21),
120 (36), 134 (55), 162 (50), 206 (M+, 100); HRMS (EI) calcd for
C12H14O3 (M+), 206.0943; found, 206.0943.
8-(Trifluoromethanesulfonyl)oxy-2-[spiro-2-(1,3-dioxolyl)]tet-
ralin (4). To a solution of compound 13 (499 mg, 2.4 mmol) in
CH2Cl2 (4 mL) and pyridine (2 mL) at 0 °C was added trifluo-
romethanesulfonic anhydride (884 mg, 0.52 mL, 3.1 mmol). The
reaction mixture was stirred at 5 °C overnight and quenched by
pouring into a cold saturated aqueous sodium carbonate solution.
After workup and flash chromatography (eluent AcOEt/hexane 1:5),
General Procedure for the Suzuki Coupling Reaction. Syn-
thesis of 4-Aryl-6-methoxy-1,2-dihydronaphthalenes 8d-h.
Method B. To a mixture of the corresponding arylboronic acid
10d-g (3.5 mmol, 1.1 equiv), Pd(PPh3)4 (74 mg, 2% mol), and
Ba(OH)2‚8H2O (1.5 g, 4.8 mmol, 1.5 equiv) was added a solution
of 6-methoxy-4-trifluoromethanesulfonyloxy-1,2-dihydronaphtha-
J. Org. Chem, Vol. 71, No. 13, 2006 4963

Carren˜o et al.
compound 4 was obtained as a colorless oil in 90% yield: 1H NMR
δ 1.96 (t, J ) 6.8 Hz, 2H), 2.99 (s, 2H), 3.05 (t, J ) 6.8 Hz, 2H),
4.04 (m, 2H), 7.08-7.22 (m, 3H); 13C NMR δ 29.1, 32.3, 34.7,
65.6, 108.3, 119.4, 119.6 (q, J ) 319 Hz), 128.1, 129.0, 129.4,
140.0, 149.3; MS (EI) m/z (%) 91 (20), 105 (12), 119 (11), 133
(16), 161 (23), 205 (100), 338 (M+, 27); HRMS (EI) calcd for
C12H13O5SF3 (M+), 338.0436; found, 338.0446.
solution of the corresponding 8-aryl-2-[spiro-2-(1,3-dioxolyl)]-
tetralin 14a or 14i-n (0.07 mmol, 1 equiv) in CH2Cl2 (1 mL) at 0
°C was added 35% HCl until pH ) 1. The resulting mixture was
stirred at room temperature for the time indicated in each case,
and more CH2Cl2 was added. After workup and filtration over silica
gel, the corresponding pure 8-aryl-2-tetralones 1a or 1i-n were
obtained.
General Procedure for the Suzuki Coupling Reactions.
Synthesis of 8-Aryl-2-[spiro-2-(1,3-dioxolyl)]tetralins 14a and
14i-l. Method E. To a mixture of the corresponding arylboronic
acid 10a or 10i-l (0.21 mmol, 2.4 equiv), Pd(PPh3)4 (10.4 mg, 10
mol %), and Ba(OH)2‚8H2O (see each individual case) was added
a solution of compound 4 (30 mg, 0.09 mmol, 1 equiv) in DME
(1.5 mL). The reaction mixture was heated at 80 °C with vigorous
stirring for the time indicated in each case, cooled to room
temperature, and filtered over Celite. After extraction with CH2Cl2,
workup, and flash chromatography, the corresponding pure com-
pounds 14a or 14i-l were obtained.
Acknowledgment. We thank Ministerio de Ciencia y
Tecnolog´ıa (Grant CTQ2005-02095/BQU) and Comunidad
Auto´noma de Madrid/Universidad Auto´noma de Madrid (Grant
08/PPQ/002) for financial support and Comunidad Auto´noma
de Madrid for a fellowship to M.G.L.
Supporting Information Available: General experimental
paragraph, experimental procedures, characterization data, and
copies of 1H and 13C NMR spectra for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
General Procedure for the Deprotection of the Ketal Moiety.
Synthesis of 8-Aryl-2-tetralones 1a and 1i-n. Method F. To a
JO060688J
4964 J. Org. Chem., Vol. 71, No. 13, 2006