A Very Facile SNAr Reaction with Elimination of Methoxide

Full text of DOI:10.1021/jo972351a

4510
J . Org. Chem. 1998, 63, 4510-4514
Ta ble 1. Alk yla tion of In d ole 1
product and yield (%)
A Ver y F a cile SNAr Rea ction w ith
Elim in a tion of Meth oxid e
compd
Ra
methodb
2
3
a
b
b
c
c
d
e
f
CH3
CH3CH2
CH3CH2
A
A
B
A
B
A
A
A
B
C
D
90
45
95
31
95
40
20
14
13
88
78
NA
16
0
14
0
23
24
27
75
0
J ohn W. Huffman,* Ming-J ung Wu, and J ianzhong Lu
H. L. Hunter Laboratory of Chemistry, Clemson University
Clemson, South Carolina 29634-1905
CH3(CH2)2
CH3(CH2)2
CH3(CH2)3
CH3(CH2)4
CH3(CH2)5
CH3(CH2)5
CH3(CH2)5
CH3(CH2)5
Received December 31, 1997
f
f
f
It has been found that 1-alkyl-3-(1-naphthoyl)indoles
are potent agonists for the cannabinoid brain receptor
and the 1-propyl-2-methyl analogue shows selectivity for
the peripheral (spleen) cannabinoid receptor.1,2 In the
course of preparing a series of 3-(4-methoxy-1-naphthoyl)-
indole derivatives designed to be selective agonists for
the peripheral receptor, the reaction of 3-(4-methoxy-1-
naphthoyl)indole (1) with a series of primary alkyl
halides in the presence of KOH in DMSO was carried
out (eq 1). This is an established procedure for the
0
a
Methyl and ethyl iodide were used for alkylation; all others
were bromides. Method A: KOH, DMSO, 80 °C, 18 h. Method
B: KOH, DMSO, 75 °C, 18 h. Method C: KOH, DMSO, 55 °C, 18
h. Method D: KH, DMSO, 80 °C, 1 h.
b
Two mechanistic rationalizations for the formation of
ethers 3 appeared plausible. The first was nucleophilic
ether cleavage by hydroxide to provide a phenoxide which
is subsequently alkylated to provide the ether (3).
A
second possible reaction path was an SNAr reaction with
hydroxide as nucleophile, to provide a phenol, which
would exist as the conjugate base in the presence of KOH
in DMSO. Alkylation of the phenoxide by the alkyl
halide present in the reaction mixture then provides the
corresponding ether (3).
It is generally considered that SNAr reactions which
proceed via apparent direct nucleophilic displacement of
a substituent from the aromatic ring require the presence
of at least one strongly electron withdrawing group;
however, alkoxide is not favored as a leaving group, nor
is hydroxide a particularly effective nucleophile.4 Re-
cently, it has been found that the SNAr displacement of
o-methoxy groups in the naphthalene series by a variety
of nucleophiles, and with several activating groups, is of
considerable synthetic utility.5 Many of these reactions
employ Grignard or organolithium reagents as nucleo-
philes, and simultaneous complexation of the organome-
tallic with the methoxy and the activating group facili-
tates the SNAr reaction. There are also several examples
in which the o-methoxy group was displaced by an
alkoxide.5b There has been one study of the displacement
of methoxide by alkoxide in DMF using methyl 1-meth-
oxy-2-naphthoate and methyl 2-methoxybenzoate as
substrates.6 This displacement proceeds in good yield
with isopropoxide, benzyloxide, and n-butoxide but failed
with tert-butoxide and phenoxide. The reaction was
extended to the methyl esters of 3- and 4-methoxybenzoic
acids. Only the p-methoxy was displaced, and then in a
meager 22% overall yield. These results were rational
N-alkylation of 3-aroylindoles and usually provides the
N-alkylindoles in fair to good yield.1,3 However, in
contrast to expectations, the reaction products were a
mixture of the desired 1-alkyl-3-(4-methoxy-1-naphthoyl)-
indole (2) and a 1-alkyl-3-(4-alkoxy-1-naphthoyl)indole
(3).
As shown in Table 1 (method A) when the alkylation
was carried out at 80 °C with n-alkyl halides from ethyl
through hexyl, mixtures of products were obtained in
yields of 41-90%. In addition to the expected N-
alkylation product, a substantial fraction of the product
was formed by additional replacement of the methoxyl
group by an alkoxyl group. The reaction is very temper-
ature dependent, since a decrease of only 5 °C (method
B) completely suppresses the formation of the O-alkyla-
tion products with the ethyl or propyl halide. However,
n-hexyl bromide provided a 75% yield of hexyl ether 3f
under these conditions. At 55 °C (method C) alkylation
with n-hexyl bromide gave only the N-alkylation product
(2f).
(4) (a) Paradisi, C. Arene Substitution via Nucleophilic Addition to
Electron Deficient Arenes. Comprehensive Organic Synthesis; Perga-
mon Press: Oxford, 1991; Vol. 4, pp 423-450. (b) Bunnett, J . F.; Zahler,
R. E. Chem. Rev. 1951, 49, 273. (c) Peishoff, C. E.; J orgenson, W. L. J .
Org. Chem. 1985, 50, 1056.
(5) (a) Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837. (b)
Hattori, T.; Sakamoto, J .; Hayashizaka, N.; Miyano, S. Synthesis 1994,
199. (c) Hattori, T.; Tanaka, H.; Okaishi, Y.; Miyano, S. J . Chem. Soc.,
Perkin Trans. 1 1995, 235. (d) Hattori, T.; Suzuki, M.; Komuro, Y.;
Miyano, S. J . Chem. Soc., Perkin Trans. 1 1995, 1473.
(6) Hattori, T.; Satoh, S.; Miyano, S. Bull. Chem. Soc. J pn. 1993,
66, 3840.
(1) Huffman, J . W.; Dai, D.; Martin, B. R.; Compton, D. R. Bioorg.
Med. Chem. Lett. 1994, 4, 563.
(2) Showalter, V. M.; Compton, D. R.; Martin, B. R.; Abood, M. E.
J . Pharmacol. Exp. Ther. 1996, 278, 989.
(3) D’Ambra, T. E.; Estep, K. G.; Bell, M. R.; Eissenstat, M. A.; J osef,
K. A.; Ward, S. J .; Haycock, D. A.; Baizman, E. R.; Casiano, F. M.;
Beglin, N. C.; Chippari, S. M.; Grego, J . D.; Kullnig, R. K.; Daley, G.
T. J . Med. Chem. 1992, 35, 124.
S0022-3263(97)02351-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/11/1998

Notes
J . Org. Chem., Vol. 63, No. 13, 1998 4511
ized in terms of stabilization of the intermediate in the
ortho-substitution reaction as a complex with sodium ion.
These authors also note, without explanation, that naph-
thyl systems are more effective substrates for SNAr
reactions than simple benzenoid systems.6 A similar SN-
Ar reaction of a methoxyfluorenone with hydrazine in
ethanol was described recently by Gould et al.7
efficient as that of naphthyl ketones.6 To determine
whether the SNAr reaction of 4-methoxybenzophenone
was actually slower than that of indoles 1 and 2a -g, and
4-methoxy-1-benzoylnaphthalene, competition experi-
ments were carried out in order to determine the relative
rates of these reactions. Reaction of an equimolar
mixture of 4-methoxybenzophenone and 1-benzoyl-4-
methoxynaphthalene in DMSO, in the presence of less
than 1 equiv of potassium ethoxide, gave a 1:1.4 mixture
of 4-ethoxybenzophenone and 1-benzoyl-4-ethoxynaph-
thalene, verifying the suggestion that a naphthalene
substrate undergoes the SNAr reaction faster than a
monocyclic aromatic. A similar competition reaction was
carried out employing 1-benzoyl-4-methoxynaphthalene
and 1-ethyl-3-(4-methoxy-1-naphthoyl)indole (2b). The
ratio of 1-benzoyl-4-ethoxynaphthalene to 1-ethyl-3-(4-
ethoxy-1-naphthoyl)indole (3b) was 20:1, indicating that
the indolyl ketone reacted considerably more slowly than
the benzoyl analogue.
The enhanced SNAr reactivity of 1-benzoyl-4-methoxy-
naphthalene relative to that of 4-methoxybenzophenone
is not surprising. Assuming the usually accepted value
of 61 kcal/mol for the delocalization energy of naphtha-
lene, and 36 kcal/mol for benzene, this corresponds to an
approximate loss of 25 kcal/mol in the formation of the
intermediate from 4-methoxy-1-benzoylnaphthalene and
36 kcal/mol from 4-methoxybenzophenone. These differ-
ences in energy would be reflected in the transition state
energies leading to the intermediates, which would in
turn be reflected in the relative reaction rates. The
decrease in rate for indolyl ketone 2b may be attributed
to stabilization of the carbonyl by electron delocalization
involving the indole nitrogen. 3-Acylindoles have the
properties of vinylogous amides, and this stabilization
would be lost in the formation of the SNAr intermediate.
The facile carbonyl activated displacement of a p-
methoxy in the SNAr reactions of indoles 1 and 2a -g,
and 4-methoxy-1-benzoylnaphthalene with hydroxy as
nucleophile, and methoxy the leaving group, is quite
unusual. Methoxy is a poor leaving group, hydroxy is a
mediocre nucleophile, and the displacement of a para-
substituent in even modest yield with only a ketonic
carbonyl as an activating substituent is apparently
unprecedented. It is, however, known that the use of
polar aprotic solvents such as DMSO favors these reac-
tions.9
Although published data indicated that methoxynaph-
thoylindoles 1 and 2, which are activated only by a single
carbonyl group para to the site of nucleophilic attack,
should not be particularly favorable substrates for SNAr
reactions, studies were undertaken to explore this pos-
sibility. Indole 2f (R ) 1-hexyl) was treated under the
conditions employed for alkylation, using 1-hexanol
rather than an alkyl halide, and gave a mixture of
recovered 2f, ether 3f (R, R′ ) 1-hexyl), and the corre-
sponding phenol (3, N-hexyl, OR ) OH). Similarly,
reaction of 2a (R ) methyl) with potassium pentoxide in
DMSO afforded the SNAr product, (3, N-methyl, O-n-
pentyl) in 43% yield. With potassium ethoxide in DMSO
indole 2b (R ) ethyl) gave a mixture of ether 3b (53%)
and the corresponding phenol (18%). Reaction of 1 with
1-bromohexane using potassium hydride in DMSO, con-
ditions which had been employed earlier for the alkyla-
tion of 3-(1-naphthoyl)pyrrole,8 gave as the only isolable
product the N-alkylation product, 1-hexyl-3-(4-methoxy-
1-naphthoyl)indole (2f), in 78% yield. Although these
experiments indicate that the carbonyl group para to the
methoxy is sufficiently electron withdrawing to permit
an SNAr reaction under very mild conditions, the forma-
tion of phenols in these experiments is consistent either
with nucleophilic ether cleavage or an SNAr reaction with
adventitious water.
To further explore the course of these reactions, a less
complex model system, 1-benzoyl-4-methoxynaphthalene,
was employed. Reaction of this substrate with KOH in
DMSO under the conditions employed for the alkylation
of 1 provided 4-benzoyl-1-naphthol in 53% yield. When
the reaction was repeated using KOH prepared in situ
from potassium hydride and water enriched in 18O
(approximately 10%), mass spectrometry indicated that
the reaction product contained approximately 10% 18O.
These results are clearly consistent only with an SNAr
reaction with hydroxide as the nucleophile and methoxide
as the nucleofuge. Reaction of 1-benzoyl-4-methoxynaph-
thalene with potassium ethoxide prepared in situ from
anhydrous ethanol in DMSO gave 1-benzoyl-4-ethoxy-
naphthalene as the only isolable product in 74% yield.
Sodium ethoxide gave the same product, but in 48% yield.
However, reaction of 1-benzoyl-4-methoxynaphthalene
with potassium phenoxide in DMSO gave only recovered
starting material. Similar SNAr reactions were also
carried out in the benzophenone series; 4-methoxyben-
zophenone with KOH in DMSO gives 4-benzoylphenol,
and with potassium ethoxide in ethanol 4-ethoxyben-
zophenone is obtained. The yields in this series were only
42% and 11%, respectively; however, no effort was made
to optimize them.
On the basis of the results obtained with indoles 1 and
2, 1-benzoyl-4-methoxynaphthalene, and 4-methoxyben-
zophenone, it would appear that SNAr reactions involving
activation by p-carbonyl are more facile than conven-
tional wisdom dictates. The use of a naphthyl ketone as
substrate and DMSO as solvent certainly facilitate the
reaction.
Exp er im en ta l Section
Melting points are uncorrected. Low-resolution mass spectra
were determined at an ionizing voltage of 70 eV. Ether and THF
were distilled from Na-benzophenone ketyl immediately before
use, and other solvents were purified using standard procedures.
Column chromatography was carried out on Universal silica gel
(32-63 µm) using the indicated solvents as eluents. HRMS data
were provided by the Mass Spectrometry Laboratory, School of
Chemical Sciences, University of Illinois.
In agreement with the results of Hattori et al., reaction
of 4-methoxybenzophenone did not appear to be as
(7) Gould, S. J .; Chen, J .; Cone, M. C.; Gore, M. P.; Melville, C. R.;
Tamayo, N. J . Org. Chem. 1996, 61, 5720.
(8) Lainton, J . A. H.; Huffman, J . W.; Martin, B. R.; Compton, D.
R. Tetrahedron Lett. 1995, 36, 1401.
(9) Zoltawicz, J . A. Top. Curr. Chem. 1975, 59, 33.

4512 J . Org. Chem., Vol. 63, No. 13, 1998
Notes
3-(4-Meth oxy-1-n a p h th oyl)in d ole (1). To a solution of 7.2
mL of 2.7 M methylmagnesium bromide in THF (19.3 mmol) at
0 °C was added 1.88 g (16.1 mmol) of indole in 7 mL of dry ether.
The reaction mixture was allowed to warm to room temperature,
and a solution of 4-methoxy-1-naphthoyl chloride (prepared from
3.26 g, 16.1 mmol, of 4-methoxy-1-naphthalenecarboxylic acid
in 6 mL of THF) was added cautiously. The reaction mixture
was heated at reflux with stirring for 1.5 h. After the solution
was cooled to room temperature, saturated aqueous NH4Cl was
added cautiously, and the ether was distilled off. The solid was
collected by filtration and suspended in 30 mL of CH3OH, and
5 mL of 20% aqueous NaOH was added. The suspension was
stirred at reflux for 4 h and cooled to room temperature, and
the solid was collected by filtration. After being dried in vacuo,
there was obtained 2.81 g (58%) of 3-(4-methoxy-1-naphthoyl)-
indole (1) as a pale-yellow solid. Recrystallization from ethyl
acetate/DMSO gave material with the following: mp 270-275
°C: 1H NMR (300 MHz, DMSO-d6) δ 4.03 (s, 3H), 7.02 (d, J )
8.0 Hz, 1H), 7.25-7.30 (m, 2H), 7.52-7.57 (m, 3H), 7.70-7.73
(m, 2H), 8.15-8.18 (m, 1H), 8.20-8.28 (m, 1H), 8.30-8.35 (m,
1H); 13C NMR (75.5 MHz, DMSO-d6) δ 55.9, 103.1, 112.4, 117.4,
121.6, 121.8, 122.1, 123.2, 125.1, 125.5, 125.7, 126.2, 127.3, 128.0,
131.6, 131.9, 156.2, 191.1. Anal. Calcd for C20H15NO2‚1/4H2O:
C, 78.54; H, 5.11; N, 4.58. Found: C, 78.63; H, 5.12, N; 4.60.
Several separate samples of this compound gave consistent
analytical data.
Gen er a l P r oced u r es for th e Alk yla tion of 3-(4-Meth oxy-
1-n a p h th oyl)in d ole. Meth od s A, B, a n d C. To a stirred
solution of 0.390 g (1.3 mmol) of indole 1 and 0.50 g of powdered
KOH in 5 mL of DMSO was added 3 equiv of the appropriate
alkyl halide. The resulting solution was heated to 80 °C (method
A), 75 °C (method B), or 55 °C (method C) and stirred at this
temperature overnight. After the solution was cooled to room
temperature, water was added, and the reaction mixture was
extracted with ethyl acetate. The combined organic layers were
dried (MgSO4) and the solvent removed in vacuo. The residue
was purified by flash chromatography on silica gel using
petroleum ether/ethyl acetate mixtures for elution.
1-P r op yl-3-(4-m eth oxy-1-n a p h th oyl)in d ole (2c): mp 146-
1
147 °C; H NMR (300 MHz, CDCl3) δ 0.88 (t, J ) 7.2 Hz, 3H),
1.82 (sextet, J ) 7.2 Hz, 2H), 4.02 (t, J ) 7.2 Hz, 2H), 4.4 (s,
3H), 6.80 (d, J ) 7.9 Hz, 1H), 7.31-7.37 (m, 3H), 7.40 (s, 1H),
7.48-7.51 (m, 2H), 7.64 (d, J ) 7.9 Hz, 1H), 8.29-8.34 (m, 2H),
8.46-8.49 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ 11.3, 23.6,
48.6, 55.6, 102.1, 109.9, 117.6, 122.0, 122.6, 122.8, 123.4, 125.6,
125.8, 127.2, 127.3, 127.8, 131.4, 132.1, 136.9, 137.5, 157.0, 191.7.
Anal. Calcd for C23H21NO2: C, 80.44; H, 6.16; N, 4.08. Found:
C, 80.42; H, 6.20; N, 3.98.
1-P r op yl-3-(4-p r op oxy-1-n a p h th oyl)in d ole (3c): viscous
1
oil; H NMR (300 MHz, CDCl3) δ 0.88 (t, J ) 7.3 Hz, 3H), 1.54
(t, J ) 7.3 Hz, 3H), 1.82 (sextet, J ) 7.3 Hz, 2H), 1.98 (sextet, J
) 7.3 Hz, 2H), 4.02 (t, J ) 7.1 Hz, 2H), 4.14 (t, J ) 6.4 Hz, 2H),
6.79 (d, J ) 7.9 Hz, 1H), 7.31-7.37 (m, 3H), 7.40 (s, 1H), 7.47-
7.50 (m, 2H), 7.63 (d, J ) 7.9 Hz, 1H), 8.29-8.33 (m, 1H), 8.36-
8.39 (m, 1H), 8.46-8.49 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ
10.7, 11.3, 22.5, 23.0, 48.6, 69.7, 102.8, 109.9, 117.6, 122.1, 122.5,
122.8, 123.3, 125.4, 125.7, 127.2, 127.9, 131.1, 132.1, 136.9, 137.5,
156.5, 191.8; MS (EI) m/z (rel intensity) 371 (100), 328 (60), 312
(25), 300 (66); HRMS calcd for C25H25NO2 371.1885, found
371.1884.
1-Bu tyl-3-(4-m eth oxy-1-n a p h th oyl)in d ole (2d ): mp 143-
1
144 °C; H NMR (300 MHz, CDCl3) δ 0.89 (t, J ) 7.2 Hz, 3H),
1.23-1.33 (m, 2H), 1.72-1.81 (m, 2H), 4.04 (s, 3H), 4.06 (t, J )
7.2 Hz, 2H), 6.81 (d, J ) 7.9 Hz, 1H), 7.32-7.39 (m, 3H), 7.40
(s, 1H), 7.48-7.51 (m, 2H), 7.64 (d, J ) 7.9 Hz, 1H), 8.29-8.35
(m, 2H), 8.45-8.48 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ 13.5,
20.0, 31.8, 46.8, 55.6, 102.1, 109.9, 117.6, 122.0, 122.6, 122.8,
123.4, 125.6, 125.8, 127.3, 127.8, 131.3, 132.1, 136.9, 137.4, 157.0,
191.7. Anal. Calcd for C24H23NO2: C, 80.64; H, 6.49; N, 3.92.
Found: C, 80.52; H, 6.45; N, 3.88.
1-Bu tyl-3-(4-bu toxy-1-n a p h th oyl)in d ole (3d ): viscous oil;
1H NMR (300 MHz, CDCl3) δ 0.88 (t, J ) 7.3 Hz, 3H), 1.04 (t, J
) 7.4 Hz, 3H), 1.21-1.33 (m, 2H), 1.40-1.68 (m, 2H), 1.71-
1.80 (m, 2H), 1.88-1.98 (m, 2H), 4.04 (t, J ) 7.1 Hz, 2H), 4.18
(t, J ) 6.3 Hz, 2H), 6.78 (d, J ) 7.9 Hz, 1H), 7.30-7.36 (m, 3H),
7.39 (s, 1H), 7.47-7.50 (m, 2H), 7.62 (d, J ) 7.9 Hz, 1H), 8.29-
8.32 (m, 1H), 8.35-8.38 (m, 1H), 8.45-8.48 (m, 1H); 13C NMR
(75.5 MHz, CDCl3) δ 13.5, 13.9, 19.4, 20.0, 31.2, 31.8, 46.8, 68.0,
102.8, 109.9, 117.7, 122.1, 122.5, 122.8, 123.3, 125.4, 125.8, 127.2,
127.9, 131.1, 132.2, 136.9, 137.4, 156.5, 191.7; MS (EI) m/z (rel
intensity) 399 (100), 342 (53), 326 (50), 300 (48), 200 (67); HRMS
calcd for C27H29NO2 399.2198, found 399.2188.
Meth od D. To a stirred solution of 0.400 g (3 mmol, 30 wt
%) of KH in 2 mL of DMSO at ambient temperature was added
a solution of 0.300 g (1 mmol) of indole 1 in 2 mL of DMSO,
followed by 3 mmol of the appropriate alkyl halide. The
resulting solution was heated to 80 °C and stirred at this
temperature for 1 h. After the solution was cooled to room
temperature, water was added, and the reaction mixture was
extracted with ethyl acetate. The organic extracts were dried
(MgSO4), and the solvents were evaporated in vacuo. The
residue was purified by flash chromatography on silica gel, using
petroleum ether/ethyl acetate mixtures for elution.
1-P en tyl-3-(4-m eth oxy-1-n a p h th oyl)in d ole (2e): mp 130-
1
131 °C; H NMR (300 MHz, CDCl3) δ 0.83 (t, J ) 6.8 Hz, 3H),
1.21-1.28 (m, 4H), 1.76 (pentet, J ) 7.2 Hz, 2H), 4.00 (s, 3H),
4.01 (t, J ) 6.8 Hz, 2H), 6.77 (d, J ) 7.9 Hz, 1H), 7.30-7.36 (m,
3H), 7.38 (s, 1H), 7.46-7.49 (m, 2H), 7.62 (d, J ) 7.9 Hz, 1H),
8.29-8.34 (m, 2H), 8.46-8.49 (m, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 13.8, 22.1, 28.8, 29.4, 47.0, 55.6, 102.1, 109.9, 117.6,
122.0, 122.5, 122.7, 123.3, 125.5, 125.6, 125.7, 127.1, 127.2, 127.8,
1-Meth yl-3-(4-m eth oxy-1-n aph th oyl)in dole (2a): mp 194-
1
195 °C; H NMR (300 MHz, CDCl3) δ 3.69 (s, 3H), 4.01 (s, 3H),
6.76 (d, J ) 7.9 Hz, 1H), 7.32-7.35 (m, 4H), 7.46-7.49 (m, 2H),
7.60 (d, J ) 7.9 Hz, 1H), 8.26-8.33 (m, 2H), 8.44-8.48 (m, 1H);
13C NMR (75.5 MHz, CDCl3) δ 33.3, 55.6, 102.1, 109.6, 117.2,
122.0, 122.6, 123.5, 125.5, 125.6, 127.1, 127.3, 131.3, 132.1, 137.6,
138.4, 156.9, 191.7. Anal. Calcd for C21H17NO2: C, 79.98; H,
5.42; N, 4.44. Found: C, 79.90; H, 5.50; N, 4.44.
131.3, 132.1, 136.9, 137.4, 156.9, 191.7. Anal. Calcd for C25H25
-
NO2: C, 80.83; H, 6.78; N, 3.77. Found: C, 80.94; H, 6.80; N,
3.71.
1-P en tyl-3-(4-p en toxy-1-n a p h th oyl)in d ole (3e): viscous
1
oil; H NMR (300 MHz, CDCl3) δ 0.84 (t, J ) 7.1 Hz, 3H), 0.97
1-Eth yl-3-(4-m eth oxy-1-n a p h th oyl)in d ole (2b): mp 170-
1
(t, J ) 7.2 Hz, 3H), 1.21-1.31 (m, 4H), 1.41-1.59 (m, 4H), 1.74-
1.81 (m, 2H), 1.90-1.97 (m, 2H), 4.02 (t, J ) 7.1 Hz, 2H), 4.16
(t, J ) 6.4 Hz, 2H), 6.77 (d, J ) 7.9 Hz, 1H), 7.30-7.36 (m, 3H),
7.38 (s, 1H), 7.47-7.50 (m, 2H), 7.62 (d, J ) 7.9 Hz, 1H), 8.30-
8.33 (m, 1H), 8.35-8.38 (m, 1H), 8.46-8.49 (m, 1H); 13C NMR
(75.5 MHz, CDCl3) δ 13.8, 14.0, 22.1, 22.4, 28.4, 28.8, 29.4, 47.0,
68.2, 102.7, 109.8, 117.6, 122.1, 122.5, 122.8, 123.3, 125.4, 125.7,
127.2, 127.9, 131.0, 132.1, 136.9, 137.4, 156.5, 191.7; MS (EI)
m/z (rel intensity) 427 (100), 356 (44), 340 (38), 300 (57); HRMS
calcd for C29H33NO2 427.2511, found 427.2512.
171 °C; H NMR (300 MHz, CDCl3) δ 1.35 (t, J ) 7.3 Hz, 3H),
3.96 (s, 3H), 4.03 (q, J ) 7.3 Hz, 2H), 6.73 (d, J ) 8.0 Hz, 1H),
7.29-7.33 (m, 3H), 7.38 (s, 1H), 7.43-747 (m, 2H), 7.59 (d, J )
8.0 Hz, 1H), 8.29-8.32 (m, 2H), 8.46-8.50 (m, 1H); 13C NMR
(75.5 MHz, CDCl3) δ 14.9, 41.5, 55.5, 102.0, 109.7, 117.6, 121.9,
122.5, 122.7, 123.3, 125.5, 125.6, 127.1, 127.2, 127.7, 131.2, 132.0,
136.7, 156.8, 191.6. Anal. Calcd for C22H19NO2: C, 80.22; H,
5.81; N, 4.25. Found: C, 80.29; H, 5.75; N, 4.23.
1-Eth yl-3-(4-eth oxy-1-n a p h th oyl)in d ole (3b): viscous oil;
1H NMR (300 MHz, CDCl3) δ 1.42 (t, J ) 7.2 Hz, 3H), 1.57 (t, J
) 7.0 Hz, 3H), 4.11 (q, J ) 7.2 Hz, 2H), 4.24 (q, J ) 7.0 Hz, 2H),
6.78 (d, J ) 7.9 Hz, 1H), 7.31-7.37 (m, 3H), 7.42 (s, 1H), 7.47-
7.50 (m, 2H), 7.62 (d, J ) 7.9 Hz, 1H), 8.28-8.31 (m, 1H), 8.35-
8.39 (m, 1H), 8.44-8.48 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ
14.7, 15.1, 41.6, 63.9, 102.8, 109.7, 117.8, 122.1, 122.6, 122.8,
123.4, 125.5, 125.7, 127.2, 127.8, 131.1, 132.1, 136.7, 156.3, 191.8;
MS (EI) m/z (rel intensity) 343 (91), 326 (47), 314 (48), 286 (35),
172 (100); HRMS calcd for C25H21NO2 343.1572, found 343.1573.
1-Hexyl-3-(4-m eth oxy-1-n a p h th oyl)in d ole (2f): viscous
oil; 1H NMR (300 MHz, CDCl3) δ 0.83 (t, J ) 6.7 Hz, 3H), 1.20-
1.30 (m, 6H), 1.73-1.82 (m, 2H), 4.03 (s, 3H), 4.04 (t, J ) 7.2
Hz, 2H), 6.79 (d, J ) 7.9 Hz, 1H), 7.31-7.37 (m, 3H), 7.39 (s,
1H), 7.47-7.50 (m, 2H), 7.63 (d, J ) 7.9 Hz, 1H), 8.29-8.34 (m,
2H), 8.46-8.49 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ 13.9,
22.4, 26.4, 29.7, 31.1, 47.0, 55.6, 102.1, 109.9, 117.6, 122.0, 122.5,
122.8, 123.3, 125.6, 125.7, 127.1, 127.3, 127.8, 131.3, 132.1, 136.9,

Notes
J . Org. Chem., Vol. 63, No. 13, 1998 4513
137.5, 157.0, 191.8; MS (EI) m/z (rel intensity) 385 (100), 368
(44), 314 (59), 228 (59); HRMS calcd for C26H27NO2 385.2043,
found 385.2040.
4-benzoyl-1-naphthol, mp 166-167 °C (lit.11 mp 166-167 °C),
after chromatography (petroleum ether/ethyl acetate 4:1) and
recrystallization from hexanes/ethyl acetate: 1H NMR (300 MHz,
CDCl3) δ 6.79 (d, J ) 7.8 Hz, 1H), 6.90 (s, 1H), 7.43-7.58 (m,
6H), 7.83 (dd, J ) 7.0, 1.4 Hz, 2H), 8.30 (m, 1H), 8.38 (dd, J )
6.5, 2.0 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 106.8, 112.1,
124.6, 125.8, 128.1, 128.3, 130.4, 131.5, 132.6, 133.0, 139.3, 155.3,
197.9; IR (KBr) 1659, 1591 cm-1; MS (EI) m/z 248 (67), 247 (20),
171 (100), 115 (44).
B. Reaction of 0.15 g (0.57 mmol) of 1-benzoyl-4-methoxy-
naphthalene with 0.11 g of KH and 0.055 mL of water in 2.5
mL of DMSO at 95 °C for 20 h, under the conditions described
above, provided 0.13 g (89%) of 4-benzoyl-1-naphthol, mp 166-
167 °C, after chromatography and recrystallization from hex-
anes/ethyl acetate. This material was identical to that described
in part A. When the reaction was carried out under these
conditions, using 0.114 g of 1-benzoyl-4-methoxynaphthalene
and 0.051 mL of water containing approximately 10% 18O for
15 h, the product was identical in all respects except for the MS
(EI) data: m/z 250 (7), 248 (62), 249 (14), 247 (20), 171 (100),
173 (11).
1-Ben zoyl-4-eth oxyn a p h th a len e. To a mixture of 0.15 g
of KH (3.75 mmol) in 2.5 mL of dry ethanol was added 0.15 g
(0.57 mmol) of 1-benzoyl-4-methoxynaphthalene. The reaction
mixture was stirred at reflux for 15 h, cooled, poured into 50
mL of water, and extracted with three portions of ethyl acetate.
The combined extracts were washed with 5% aqueous HCl and
dried (MgSO4), and the solvent was removed in vacuo to give
an oil. Chromatography (petroleum ether/ethyl acetate 25:1)
gave 0.11 g (74%) of product as a yellow oil which failed to
crystallize:12 1H NMR (300 MHz, CDCl3) δ 1.59 (t, J ) 6.9 Hz,
3H), 4.27 (q, J ) 6.9 Hz, 2H), 6.77 (d, J ) 8.2 Hz, 1H), 7.43-
7.60 (m, 6H), 7.83 (d, J ) 6.9 Hz, 2H), 8.38 (dd, J ) 7.4, 2.5 Hz,
2H); 13C NMR (75.5 MHz, CDCl3) δ 14.9, 64.9, 102.6, 122.3,
125.7, 127.8, 127.9, 128.2, 130.2, 131.6, 132.4, 132.6, 139.5, 157.7,
197.3; MS (EI) m/z 276 (100), 247 (33), 199 (37). When the
reaction was repeated with 0.25 g of 1-benzoyl-4-methoxynaph-
thalene, using NaH, there was obtained 0.12 g (42%) of product,
identical in all respect to that described above.
4-Ben zoylp h en ol. Reaction of 0.15 g (0.71 mmol) of 4-meth-
oxybenzophenone with KH and water in DMSO under the
conditions described above gave 0.059 g (48%) of 4-benzoylphe-
nol, mp 136-137 °C (lit.13 mp 132-133.5 °C): 1H NMR (300
MHz, CDCl3) δ 6.93-6.97 (m, 2H), 7.44-7.48 (m, 2H), 7.50-
7.61 (m, 2H), 7.74-7.80 (m, 4H). The 13C NMR was identical
to that reported.14
4-Eth oxyben zop h en on e. Reaction of 0.40 g (1.9 mmol) of
4-methoxybenzophenone with KH in ethanol under the condi-
tions described above gave 0.045 g (11%) of 4-ethoxybenzophe-
none15 as a yellow oil after chromatography (petroleum ether/
ethyl acetate 20:1): 1H NMR (300 MHz, CDCl3) δ 1.45 (t, J )
7.0 Hz, 3H), 4.11 (q, J ) 7.0 Hz, 2H), 6.95 (dd, J ) 8.8, 2.6 Hz,
2H), 7.46 (t, J ) 7.8 Hz, 2H), 7.54 (m, 1H), 7.75 (dd, J ) 7.1, 1.3
Hz, 2H), 7.82 (7.0, J ) 1.7 Hz, 2H); 13C NMR (75.5 MHz, CDCl3)
δ 14.6, 63.7, 114.0, 128.1, 129.6, 129.9, 131.8, 132.5, 138.3, 162.6,
195.5; IR (KBr) 1665, 1608 cm-1; MS (EI) m/z 226 (88), 197 (15),
149 (100). The 13C NMR data were consistent with those
reported by Frahm and Hambloch.16
Com p etition Exp er im en ts. A. Reaction of a mixture of
0.10 g (0.47 mmol) of 4-methoxybenzophenone and 0.12 g (0.47
mmol) of 1-benzoyl-4-methoxynaphthalene with KH and ethanol
under the conditions described above for 0.5 h, followed by
analysis of the crude reaction mixture by GC/MS, indicated that
0.35 equiv of 4-methoxybenzophenone and 0.47 equiv of 1-ben-
zoyl-4-methoxynaphthalene had been converted to the corre-
sponding ethyl ethers.
1-Hexyl-3-(4-h exoxy-1-n a p h th oyl)in d ole (3f): viscous oil;
1H NMR (300 MHz, CDCl3) δ 0.83 (t, J ) 6.7 Hz, 3H), 0.93 (t, J
) 7.1 Hz, 3H), 1.23 (br s, 6H), 1.37-1.42 (m, 4H), 1.50-1.62
(m, 2H), 1.70-1.80 (m, 2H), 1.89-1.98 (m, 2H), 4.02 (t, J ) 7.2
Hz, 2H), 4.15 (t, J ) 6.3 Hz, 2H), 6.76 (d, J ) 7.9 Hz, 1H), 7.30-
7.35 (m, 3H), 7.38 (s, 1H), 7.45-7.51 (m, 2H), 7.61 (d, J ) 7.9
Hz, 1H), 8.30-8.38 (m, 2H), 8.46-8.49 (m, 1H); 13C NMR (75.5
MHz, CDCl3) δ 13.8, 13.9, 22.3, 22.5, 25.9, 26.4, 29.1, 29.6, 31.1,
31.5, 47.0, 68.2, 102.7, 109.8, 117.6, 122.1, 112.5, 122.7, 123.3,
125.4, 125.7, 127.2, 127.9, 131.0, 132.1, 136.9, 137.4, 156.4, 191.7;
MS (EI) m/z (rel intensity) 455 (100), 438 (18), 370 (36), 300 (54);
HRMS calcd for C31H37NO2 455.2824, found 455.2823.
1-Hexyl-3-(4-h exoxy-1-n aph th oyl)in dole (3f) an d 1-Hexyl-
3-(4-h yd r oxy-1-n a p h th oyl)in d ole. To a stirred solution of
0.068 g (0.18 mmol) of 1-hexyl-3-(4-methoxy-1-naphthoyl)indole
(2f) in 2 mL of DMSO was added 0.037 g (0.036 mmol) of
1-hexanol, followed by 0.1 g of powdered KOH. The resulting
solution was heated to 80 °C and stirred at this temperature
for 20 h. After the solution was cooled to room temperature,
water was added, and the reaction mixture was extracted with
ethyl acetate. The combined organic layers were dried (MgSO4),
and the solvent was removed in vacuo. The residue was purified
by flash chromatography (hexanes/ethyl acetate 95:5) to give
0.012 g (15%) of 1-hexyl-3-(4-hexoxy-1-naphthoyl)indole (3f),
0.026 g (38%) of recovered 2f, and 0.025 g (37%) of 1-hexyl-3-
(4-hydroxy-1-naphthoyl)indole as an oil: 1H NMR (300 MHz,
CDCl3) δ 0.84 (t, J ) 6.7 Hz, 3H), 1.18-1.29 (m, 6H), 1.75-1.85
(m, 2H), 4.08 (t, J ) 7.3 Hz, 2H), 6.72 (d, J ) 7.7 Hz, 1H), 7.31-
7.49 (m, 7H), 7.86 (br s, 1H), 8.17-8.27 (m, 2H), 8.43-8.50 (m,
1H); 13C NMR (75.5 MHz, CDCl3) δ 13.9, 22.4, 29.7, 31.2, 47.2,
107.5, 110.0, 117.6, 122.1, 122.8, 123.5, 124.9, 125.3, 125.7, 127.1,
127.8, 130.9, 132.4, 137.1, 138.3, 154.2, 193.0; MS (EI) m/z (rel
intensity) 371 (100), 300 (63), 228 (65), 171 (88); HRMS calcd
for C25H25NO2 371.1885, found 371.1886.
1-Meth yl-3-(4-p en toxy-1-n a p h th oyl)in d ole. To 0.20 g (1.5
mmol, 30 wt %) KH in 6 mL of dry DMSO at ambient
temperature was added 0.40 g (4.6 mmol) of 1-pentanol, followed
by 0.20 g (0.63 mmol) of 1-methyl-3-(4-methoxy-1-naphthoyl)-
indole (2a ). The resulting solution was heated at 80 °C for 6 h.
After the solution was cooled to room temperature, water was
added, and the reaction mixture was extracted with ethyl
acetate. The organic extracts were dried (MgSO4), and the
solvents were evaporated in vacuo. The solid residue was
recrystallized from ethyl acetate/petroleum ether to give 0.10 g
(43%) of 1-methyl-3-(4-pentoxy-1-naphthoyl)indole: mp 147-148
°C; 1H NMR (300 MHz, CDCl3) δ 0.98 (t, J ) 7.2 Hz, 3H), 1.40-
1.62 (m, 4H), 1.98 (pentet, J ) 7.9 Hz, 2H), 3.77 (s, 3H), 4.19 (t,
J ) 6.4 Hz, 2H), 6.80 (d, J ) 7.9 Hz, 1H), 7.33-7.39 (m, 4H),
7.46-7.53 (m, 2H), 7.63 (d, J ) 7.9 Hz, 1H), 8.25-8.31 (m, 1H),
8.32-8.39 (m, 1H), 8.42-8.50 (m, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 14.1, 22.5, 28.4, 28.9, 33.5, 68.3, 102.8, 109.6, 117.6,
122.1, 122.7, 122.8, 123.5, 125.5, 127.0, 127.3, 130.8, 132.0, 137.5,
138.3, 156.5, 191.6. Anal. Calcd for C25H25NO2: C, 80.83; H,
6.78; N, 3.77. Found: C, 80.72; H, 6.76; N, 3.74.
1-E t h yl-3-(4-et h oxy-1-n a p h t h oyl)in d ole a n d 1-E t h yl-3-
(4-h yd r oxy-1-n a p h th oyl)in d ole. Reaction of 0.10 g (0.30
mmol) of 1-ethyl-3-(4-methoxy-1-naphthoyl)indole with KH and
ethanol in DMSO as described above gave 0.033 g (53%) of
1-ethyl-3-(4-ethoxy-1-naphthoyl)indole, identical to that de-
scribed above, and 0.017 g (18%) of 1-ethyl-3-(4-hydroxy-1-
naphthoyl)indole, mp 180-181 °C, after chromatography (hex-
anes/ethyl acetate 95:5) and recrystallization from ethyl acetate/
1
petroleum ether: H NMR (300 MHz, CDCl3) δ 1.42 (t, J ) 7.2
Hz, 3H), 4.13 (q, J ) 7.2 Hz, 2H), 6.63 (d, J ) 7.7 Hz, 1H), 7.30-
7.48 (m, 7H), 8.05 (br s, 1H), 8.15-8.25 (m, 2H), 8.44-8.51 (m,
1H). Anal. Calcd for C21H17NO2: C, 79.98; H, 5.43; N, 4.44.
Found: C, 79.76; H, 5.44; N, 4.35.
(11) Domanska, U. Ind. Eng. Chem. Res. 1990, 29, 470.
(12) Lapkin (Lapkin, I. I. Zh. Obshch. Khim. 1953, 23, 780; Chem.
Abstr. 1954, 48, 3940i) report this compound as a solid, mp 81-82 °C.
(13) Norell, J . R. J . Org. Chem. 1973, 38, 1924.
(14) Shapiro, M. J . Tetrahedron 1977, 33, 1091.
(15) Mndzhoyan (Mndzhoyan, O. L.; Morozova, N. M. Izv. Akad.
Nauk. SSR, Khim. Nauki 1962, 15, 553; Chem. Abstr. 1962, 59, 6287b)
report mp 47-48 °C.
4-Ben zoyl-1-n a p h th ol. A. Reaction of 0.30 g (1.2 mmol) of
1-benzoyl-4-methoxynaphthalene10 under the conditions of method
A for the alkylation of indole 1, employing 0.63 g of KOH in 6
mL of DMSO at 90 °C for 20 h, provided 0.15 g (53%) of
(16) Frahm, A. W.; Hambloch, H. F. Org. Magnet. Reson. 1980, 14,
444.
(10) Fierz-David, H. E.; J accard, G. Helv. Chim. Acta 1928, 11, 1042.

4514 J . Org. Chem., Vol. 63, No. 13, 1998
Notes
B. Reaction of a mixture of 0.11 g (0.47 mmol) of 1-benzoyl-
4-methoxynaphthalene and 0.14 g (0.42 mmol) of indole 2b with
KH as described above indicated that 0.79 equiv of 1-benzoyl-
4-methoxynaphthalene and 0.04 equiv of 2b had been converted
to the corresponding ethyl ethers.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra of
2f, 3b, 3c, 3d , 3e, 3f, and 3, N-hexyl, OH (7 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
Ack n ow led gm en t. This work was supported by
Grant DA03590 from the National Institute on Drug
Abuse.
J O972351A