A Convenient Synthesis of 1-Bromo4,5-dimethoxy-7-methylnaphthalene, a Naphthol Derivative Useful for Construction of Naphthylisoquinoline Alkaloids

Full text of DOI:10.1021/jo9713262

8586
J . Org. Chem. 1997, 62, 8586-8588
Sch em e 1
A Con ven ien t Syn th esis of 1-Br om o-
4,5-d im eth oxy-7-m eth yln a p h th a len e,
a Na p h th ol Der iva tive Usefu l for
Con str u ction of Na p h th ylisoqu in olin e
Alk a loid s
Thomas R. Hoye* and Liang Mi
Department of Chemistry, University of Minnesota,
Minneapolis, Minnesota 55455
Received J uly 21, 1997
The anti-HIV agents, michellamines A, B, and C (cf.
1),1 as well as their presumed biosynthetic precursors,
the monomeric korupensamines A and B (cf. 2),2 all
contain a naphthalene ring bearing a 1,8-dioxygenated-
4-aryl-6-methyl substitution pattern. We employed 1-bro-
mo-4,5-dimethoxy-7-methylnaphthalene in our syntheses
of korupensamine C and ancistrobrevine B.3 This struc-
tural motif also is present in other members of this
naphthylisoquinoline family of natural products.4
Sch em e 2
In previous syntheses of various of these natural
products, several strategies have evolved for construction
of the naphthalene subunit. These are summarized in
Scheme 1. The routes (A-C) begin with the com-
mercially available benzene derivatives 3-5, pass through
the indicated intermediates 6-8, and proceed on to the
various protected 4-bromo-1-naphthols 9 in the indicated
number of transformations. Bromonaphthols 9 can be
converted into various arylmetal species (trialkylstan-
(1) (a) Manfredi, K.; Blunt, J . W.; Cardellina, J . H., II; McMahon,
J . B.; Pannell, L. L.; Cragg, G. M.; Boyd, M. R. J . Med. Chem. 1991,
34, 3402. (b) Boyd, M. R.; Hallock, Y. H.; Cardellina, J . H., II; Manfredi,
K. P.; Blunt, J . W.; McMahon, J . B.; Buckheit, R. W., J r.; Bringmann,
G.; Scha¨ffer, M.; Cragg, G. M.; Thomas, D. W.; J ato, J . G. J . Med. Chem.
1994, 37, 1740.
(2) Hallock, Y. F.; Manfredi, K. P.; Blunt, J . W.; Cardellina, J . H.,
II; Schaffer, M.; Gulden, K.-P.; Bringmann, G.; Lee, A. Y.; Clardy, J .;
Francois, G.; Boyd, M. R. J . Org. Chem. 1994, 59, 6349.
(3) Hoye, T. R.; Mi, L. Tetrahedron Lett. 1996, 37, 3097.
(4) (a) Bringmann, G. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1986; Vol. 29, Chapter 3. (b) Bringmann, G.;
Pokorny, F. In The Alkaloids; Cordell, G., Ed.; Academic Press: New
York, 1995; Vol. 46, Chapter 4.
(5) (a) Bringmann, G.; Gotz, R.; Ketter, P. A.; Walter, R.; Henschel,
P.; Schaffer, M.; Stablein, M.; Kelly, T. R.; Boyd, M. R. Heterocycles
1994, 39 (2), 503. (b) Rizzacasa, M. A.; Sargent, M. V. Aust. J . Chem.
1987, 40, 1737.
(6) (a) Hoye, T. R.; Chen, M.; Mi, L.; Priest, O. P. Tetrahedron Lett.
1994, 35, 8747. (b) Hoye, T. R.; Chen, M. Tetrahedron Lett. 1996, 37,
3099.
nane, boronic acid, or zinc) in preparation for palladium-
catalyzed biaryl cross-coupling reactions.
Even though our previous synthesis (route B) was quite
short, the benzyne annulation reaction (cf. 7) reproduc-
ibly proceeds in 20-25% yield. Chromatographic puri-
fication is cumbersome on a large scale (we have prepared
up to multigram quantities of 9a and 9b by this method),
and so we have developed another synthesis that is
efficient (although longer), passes through many crystal-
line intermediates, and is amenable to implementation
on a large scale.
The new synthesis is outlined in Scheme 2. Naphtha-
lene 9a was prepared by this seven-step sequence. A
(7) Hobbs, P. D.; Upender, V.; Liu, J .; Pollart, P. J .; Thomas, D. W.;
Dawson, M. I. J . Chem. Soc., Chem. Commun. 1996, 923.
S0022-3263(97)01326-1 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 24, 1997 8587
methylene chloride and washed with water. The organic layer
was separated and concentrated. Recrystallization of the result-
ing residue in hexanes gave dibromide 1112 (11.9 g, 88%) as white
crystals. Mp: 85-87 °C. 1H NMR (500 MHz, CDCl3): δ 7.45
[d, J ) 9.0 Hz, 1H], 6.99 [d, J ) 3.0 Hz, 1H], 6.74 [dd, J ) 9.0
and 3.0 Hz, 1H], 4.56 [s, 2H], and 3.80 [s, 3H]. 13C NMR (125
MHz, CDCl3): δ 159.1, 137.7, 133.9, 116.5, 116.1, 114.7, 55.5,
and 33.5. Anal. Calcd for C8H8Br2O: C, 34.32; H, 2.88.
Found: C, 34.26; H, 3.04.
4-Br om o-1-m e t h oxy-3-[(p h e n ylsu lfon yl)m e t h yl]b e n -
zen e (12). Dibromide 11 (6.16 g, 22.0 mmol) and sodium
benzenesulfinite (4.69 g, 28.6 mmol) were suspended in 150 mL
of DMF. The mixture, which became homogeneous upon being
heated and stirred, was refluxed for 4 h. DMF was distilled from
the mixture under reduced pressure. The resulting residue was
dissolved in 250 mL of ether. The solution was washed with
water and brine. The organic layer was separated, dried with
sodium sulfate, and concentrated. The residue was recrystal-
lized with hexanes/ethyl acetate to give sulfone 12 (7.80 g, 95%)
as white crystals. Mp: 113-116 °C. 1H NMR (500 MHz,
CDCl3): δ 7.67 [dd, J ) 7.5 and 1.0 Hz, 2H], 7.62 [tt, J ) 7.5
and 1.0 Hz, 1H], 7.46 [t, J ) 7.5 Hz, 2H], 7.30 [d, J ) 9.0 Hz,
1H], 7.00 [d, J ) 3.0 Hz, 1H], 6.75 [dd, J ) 9.0 and 3.0 Hz, 1H],
4.54 [s, 2H], and 3.78 [s, 3H]. 13C NMR (125 MHz, CDCl3): δ
158.8, 138.0, 133.9, 133.4, 129.0, 128.9, 128.8, 117.5, 117.0, 116.3,
61.7, and 55.5. Anal. Calcd for C14H13BrO3S: C, 49.28; H, 3.84.
Found: C, 49.67; H, 3.89.
notable feature is the efficient bis-bromination of m-
methylanisole (10) with NBS in methylene chloride (at
reflux while irradiating with 100 W tungsten incandes-
cent bulbs) to give the monoaryl monobenzyl dibromide
11. It is critical to use irradiation sufficiently intense to
minimize formation of the 4,6-dibrominated analogue, an
event that competes with benzylic bromination if the
latter is slow. The anion formed from the derived sulfone
12 (LDA, -78 °C) adds to methyl crotonate to generate
the diastereomeric sulfones 13r/13â (ratio ) 4:1).8 The
diastereomeric methyl ethers 14 were separated one
time, and the major isomer 14r was cyclized (TFAA, 80
°C)9 to 15r with no loss of configurational control, but
more often the diastereomeric mixture of 14r/â was ring-
closed directly to a mixture of 15r/â. Aromatization by
elimination of sulfinate from the ketosulfones 15 with
potassium tert-butoxide10 was very efficient and the
resulting naphthol 16 could readily be O-methylated to
give the desired naphthalene. The overall yield for this
sequence that converts 10 to 9a was typically between
40 and 50%. Although the largest amount of material
we have prepared at one time with this sequence is ∼3 g
of 9a , the reaction conditions and intermediates are all
easy to handle. In most cases the crude product mixture
is of sufficient purity for carrying into the next reaction,
and if purification is necessary, recrystallization usually
can be used.
(()-(3R*,4S*)- a n d (()-(3R*,4R*)-Meth yl 4-(2-Br om o-5-
m eth oxyph en yl)-3-m eth yl-4-(ph en ylsu lfon yl)bu tan oate (13r
a n d 13â). Diisopropylamine (435 mg, 4.3 mmol) in 10 mL of
anhydrous THF was treated with n-butyllithium (1.7 mL, 4.2
mmol, 2.5 M in hexane) at -78 °C under nitrogen. A solution
of sulfone 12 (1.36 g, 4.0 mmol) in 5 mL of THF was added. The
mixture was stirred at -78 °C for 2 h, methyl crotonate (410
mg, 4.1 mmol) in 5 mL of THF was added, and the mixture was
stirred at -78 °C for 4 h. The mixture was partitioned into
saturated aqueous ammonium chloride and ethyl acetate. The
organic layer was washed with water and brine, dried with
sodium sulfate, and concentrated. Filtration of the residue
through a bed of silica gel with 3:1 hexanes/ethyl acetate gave
esters 13r and 13â (4:1 mixture, 1.51 g, 86%) as a white solid.
1H NMR of 13r (300 MHz, CDCl3, from the mixture): δ 7.59
[dd, J ) 8.5 and 1.0 Hz, 2H], 7.47 [tt, J ) 8.5 and 1.0 Hz, 1H],
7.33 [d, J ) 3.0 Hz, 1H], 7.31 [t, J ) 8.5 Hz, 2H], 7.14 [d, J )
9.0 Hz, 1H], 6.64 [dd, J ) 9.0 and 3.0 Hz, 1H], 4.83 [d, J ) 9.0
Hz, 1H], 3.84 [s, 3H], 3.62 [s, 3H], 3.20 [dddq, J ) 9.0, 9.0, 3.5,
and 6.5 Hz, 1H], 2.45 [dd, J ) 15.5 and 3.5 Hz, 1H], 2.15 [dd, J
) 15.5 and 9.0 Hz, 1H], and 1.44 [d, J ) 6.5 Hz, 3H]. 13C NMR
of 13r (125 MHz, CDCl3, from the mixture): δ 172.0, 159.0,
138.6, 133.4, 133.3, 133.1, 128.5, 128.3, 117.3, 116.6, 115.1, 72.4,
55.7, 51.7, 38.9, 32.3, and 19.1. 1H NMR of 13â (300 MHz,
CDCl3, from the mixture): δ 7.58 [dd, J ) 8.5 and 1.0 Hz, 2H],
7.48 [tt, J ) 8.5 and 1.0 Hz, 1H], 7.37 [d, J ) 3.0 Hz, 1H], 7.32
[t, J ) 8.5 Hz, 2H], 7.15 [d, J ) 9.0 Hz, 1H], 6.65 [dd, J ) 9.0
and 3.0 Hz, 1H], 5.08 [d, J ) 9.0 Hz, 1H], 3.84 [s, 3H], 3.72 [s,
3H], 3.18 [dddq, J ) 9.0, 8.0, 4.0, and 7.0 Hz, 1H], 3.04 [dd, J )
16.0 and 4.0 Hz, 1H], 2.66 [dd, J ) 16.0 and 8.0 Hz, 1H], and
1.01 [d, J ) 7.0 Hz, 3H]. 13C NMR of 13â (75 MHz, CDCl3, from
the mixture): δ 172.2, 158.9, 138.4, 133.4, 133.2, 133.0, 128.6,
128.4, 117.4, 116.5, 115.4, 70.8, 55.6, 51.6, 38.8, 31.3, and 17.9.
In summary we have developed an alternative route
for the preparation of brominated naphthalene deriva-
tives useful for the synthesis of naphthylisoquinoline
alkaloids.11 The sequence presumably can be easily
modified to access other ring-substitution patterns. We
recommend the use of this method of naphthalene
synthesis for instances where large quantities of 9a or
related derivatives may be required.
Exp er im en ta l Section
Gen er a l. Infrared and GC-MS (70 eV) data, obtained for
every compound, are entirely consistent with the indicated
structures but are ordinary. Only the carbonyl and OH stretches
are reported; molecular ions were observed for all compounds
except acids 14r/â.
4-Br om o-3-(br om om eth yl)-1-m eth oxyben zen e (11). N-
Bromosuccinimide (18.7 g, 105 mmol) was added to a solution
of 3-methylanisole (10, 6.11 g, 50 mmol) in 250 mL of anhydrous
methylene chloride. The mixture was refluxed for 4 h while
exposed to light from two 100 W incandescent bulbs that were
placed within 2 cm of the reaction vessel. The resulting mixture
was filtered, and the filtrate was diluted with 200 mL of
(8) The assignment of relative configuration rests on the observation
of a lower field chemical shift for the C(3)-methyl doublet and higher
field shift of the C(2)-methylene resonances in the 1H NMR spectrum
of the major R-isomer compared with the minor â-isomer. We presume
that the 2-bromo-5-methoxyphenyl ring is differentially shielding those
resonances in the dominant conformation about C(3)-C(4) in which
the two methine protons are anti.
IR of the mixture (neat): 1735 cm-1. Anal. Calcd for C19H21
BrO5S: C, 51.71; H, 4.80. Found: C, 51.58; H, 5.20.
-
(()-(3R*,4S*)- a n d (()-(3R*,4R*)-4-(2-Br om o-5-m eth oxy-
p h en yl)-3-m eth yl-4-(p h en ylsu lfon yl)bu ta n oic Acid (14r)
a n d (14â). The mixture of esters 13r and 13â (176 mg, 0.4
mmol) was dissolved in a solution of potassium hydroxide in
methanol (10%, 10 mL) and stirred at room temperature until
TLC showed that complete hydrolysis had occurred. The
mixture was acidified (pH ∼5, 10% aqueous HCl). Most of the
MeOH was removed under reduced pressure, and the residue
was extracted with ethyl acetate. The combined organic layers
were dried with sodium sulfate and concentrated to give acids
14r and 14â (4:1 mixture, 170 mg, 100%) as a white solid.
Recrystallization of the mixture in hexanes/ethyl acetate gave
acid 14r as a white solid: Mp: 167-168 °C. 1H NMR of 14r
(9) Klix, R. C.; Cain, M. H.; Bhatia, A. V. Tetrahedron Lett. 1995,
36, 6413.
(10) On one occasion the ketone 15 was accompanied by some of its
enol trifluoroacetate. This mixture in methylene chloride was stirred
under a layer of aqueous NaOH at room temperature for 24 h to cleave
the enol ester. During this treatment, smooth conversion of the entire
sample to the naphthol 16 was observed, indicating that even mildly
basic treatment is sufficient to eliminate sulfinate and promote the
aromatization.
(11) We have also investigated the synthesis of the O-MOM analogue
9b starting from 4-bromo-1-(methoxymethoxy)-3-methylbenzene by a
route entirely analogous to that depicted in Scheme 2 for the anisole
derivative. On one occasion it was equally successful, including the
Friedel-Crafts cyclization of the O-MOM analogue of the 4-arylbu-
tanoic acid 14r/â. However, that acid-catalyzed cyclization (TFAA) to
produce the O-MOM analogue of the tetralines 15r/â has proven to
be irreproducible.
(12) Breslow, R.; Garratt, S.; Kaplan, L.; LaFollette, D. J . Am. Chem.
Soc. 1968, 90, 4051.

8588 J . Org. Chem., Vol. 62, No. 24, 1997
Notes
(500 MHz, CDCl3): δ 7.59 [dd, J ) 8.0 and 1.0 Hz, 2H], 7.47 [tt,
J ) 8.0 and 1.0 Hz, 1H], 7.32 [t, J ) 8.0 Hz, 2H], 7.32 [d, J )
3.0 Hz, 1H], 7.15 [d, J ) 9.0 Hz, 1H], 6.64 [dd, J ) 9.0 and 3.0
Hz, 1H], 4.84 [d, J ) 9.0 Hz, 1H], 3.83 [s, 3H], 3.20 [dddq, J )
10.0, 9.0, 3.0, and 6.5 Hz, 1H], 2.53 [dd, J ) 16.0 and 3.0 Hz,
1H], 2.18 [dd, J ) 16.0 and 10.0 Hz, 1H], and 1.47 [d, J ) 6.5
Hz, 3H]. 13C NMR of 14r (125 MHz, CDCl3): δ 177.6, 159.1,
138.5, 133.4, 133.2, 132.9, 128.5, 128.4, 117.3, 116.6, 115.0, 72.2,
55.6, 38.7, 32.1, and 19.0. 1H NMR of 14â (500 MHz, CDCl3
from the mixture): δ 7.56 [dd, J ) 8.0 and 1.0 Hz, 2H], 7.48 [tt,
J ) 8.0 and 1.0 Hz, 1H], 7.32 [t, J ) 8.0 Hz, 2H], 7.32 [d, J )
3.0 Hz, 1H], 7.16 [d, J ) 9.0 Hz, 1H], 6.65 [dd, J ) 9.0 and 3.0
Hz, 1H], 5.05 [d, J ) 9.0 Hz, 1H], 3.83 [s, 3H], 3.20 [dddq, J )
9.0, 9.0, 4.0, and 6.5 Hz, 1H], 3.13 [dd, J ) 18.0 and 4.0 Hz,
1H], 2.70 [dd, J ) 18.0 and 9.0 Hz, 1H], and 1.26 [d, J ) 6.5 Hz,
3H]. 13C NMR of 14â (125 MHz, CDCl3, from the mixture): δ
177.4, 159.1, 138.3, 133.5, 133.2, 133.0, 128.6, 128.4, 177.4, 116.5,
115.4, 70.8, 55.7, 38.8, 31.1, and 17.9. IR of the mixture (KBr):
3420-2574 (br), 1709 cm-1. Anal. Calcd for C18H19BrO5S: C,
50.60; H, 4.48. Found: C, 51.07; H, 5.03.
J ) 6.5 Hz, 3H]. 13C NMR of 15â (75 MHz, CDCl3, from the
mixture): δ 194.5, 158.8, 137.6, 137.1, 133.9, 129.2, 129.0, 128.7,
124.7, 115.5, 114.6, 68.6, 56.4, 42.7, 33.0, and 19.2. IR of the
mixture (neat): 1687 cm-1
409.0111, found 409.0101.
. FABMS: calcd for C18H18BrO4S
5-Br om o-8-m eth oxy-3-m eth yl-1-n a p h th a len ol (16). Po-
tassium tert-butoxide (898 mg, 8.0 mmol) and sulfones 15r and
15â (818 mg, 2.0 mmol) were dissolved in 10 mL of anhydrous
THF. The solution was stirred at room temperature for 12 h
and partitioned with 10% aqueous HCl and ether. The organic
layer was concentrated, and the residue was purified by flash
chromatography (9:1 hexanes/ethyl acetate) to give naphthalenol
16 (491 mg, 92%) as a white solid. Mp: 152-153 °C. 1H NMR
(300 MHz, CDCl3): δ 9.30 [s, 1H], 7.55 [d, J ) 8.3 Hz, 1H], 7.47
[bs, 1H], 6.80 [bs, 1H], 6.53 [d, J ) 8.3 Hz, 1H], 4.00 [s, 3H],
and 2.47 [s, 3H]. 13C NMR (75 MHz, CDCl3): δ 156.0, 154.5,
139.6, 134.4, 129.5, 118.0, 114.5, 114.1, 113.5, 56.3, and 21.9.
IR (neat): 3397 cm-1
. Anal. Calcd for C12H11BrO2: C, 53.96;
H, 4.28. Found: C, 53.78; H, 4.28.
1-Br om o-4,5-d im eth oxy-7-m eth yln a p h th a len e (9a ).
A
(()-(3R*,4S*)- a n d (()-(3R*,4R*)-5-Br om o-8-m eth oxy-3-
solution of dimethyl sulfate (945 mg, 7.5 mmol) in 20 mL of
methylene chloride was added to a solution of tetrabutylammo-
nium bromide (1.06 g, 3.3 mmol) and sodium hydroxide (250 mg,
6.2 mmol) in water (15 mL). A solution of naphthalenol 16 (668
mg, 2.5 mmol) in methylene chloride (10 mL) was added. The
resulting two-phase mixture was stirred at room temperature
for 18 h, separated, and extracted with additional methylene
chloride. The combined organic layers were washed with water,
dried with sodium sulfate, and concentrated. The residue was
purified by silica gel flash chromatography (9:1 hexane/ethyl
acetate) to give methylated naphthalene 9a (660 mg, 94%) as a
white solid. Mp: 105-106 °C. 1H NMR (300 MHz, CDCl3): δ
7.63 [d, J ) 9.0 Hz, 1H], 7.61 [d, J ) 1.5 Hz, 1H], 6.76 [d, J )
1.5 Hz, 1H], 6.64 [d, J ) 9.0 Hz, 1H], 3.96 [s, 3H], 3.94 [s, 3H],
and 2.51 [s, 3H]. 13C NMR (75 MHz, CDCl3): δ 157.1, 157.0,
137.9, 134.8, 130.5, 130.4, 119.3, 113.1, 109.1, 105.6, 56.6, 56.4,
and 22.1. Anal. Calcd for C13H13BrO2: C, 55.54; H, 4.66.
Found: C, 55.76; H, 5.00.
m eth yl-4-(p h en ylsu lfon yl)-1-tetr a lon e (15r a n d 15â).
A
mixture of acids 14r and 14â (427 mg, 1.0 mmol) was dissolved
in 20 mL of 1,2-dichloroethane in a screw-capped culture tube,
and trifluoroacetic anhydride (420 mg, 2.0 mmol) was added.
The mixture was refluxed for 12 h and partitioned into saturated
aqueous sodium bicarbonate and methylene chloride. The
organic layer was washed with water and concentrated. Filtra-
tion of the residue through a bed of silica gel with 2:1 hexanes/
ethyl acetate gave cyclized products 15r and 15â (356 mg, 87%)
as a white solid. Pure compound 15r was also obtained from a
similar reaction of acid 14r. Mp of 15r: 181-184 °C. 1H NMR
of 15r (500 MHz, CDCl3): δ 7.64 (m, 3H], 7.54 [d, J ) 9.0 Hz,
1H], 7.46 [m, 2H], 6.95 [d, J ) 9.0 Hz, 1H], 4.80 [dd, J ) 2.0
and 1.0 Hz, 1H], 3.93 [s, 3H], 3.41 [dd, J ) 19.0 and 8.0 Hz,
1H], 3.26 [dddq, J ) 8.0, 2.0, 1.0, and 7.5 Hz, 1H], 2.32 [ddd, J
) 19.0, 1.0, and 1.0 Hz, 1H], and 1.03 [d, J ) 7.5 Hz, 3H]. 13C
NMR of 15r (75 MHz, CDCl3): δ 193.0, 158.6, 137.4, 137.0,
134.1, 129.2, 129.0, 128.5, 124.6, 117.1, 124.8, 69.2, 56.4, 42.1,
26.5, and 21.6. 1H NMR of 15â (300 MHz, CDCl3, as the minor
component in a 4:1 mixture): δ 7.67-7.34 [m, 6H], 6.88 [d, J )
9.0 Hz, 1H], 4.91 [dd, J ) 3.0 and 1.0 Hz, 1H], 3.92 [s, 3H], 3.19
[dd, J ) 21.0 and 14.5 Hz, 1H], 2.70-2.80 [m, 2H], and 1.60 [d,
Ack n ow led gm en t. This research was supported by
Grant CA-60284 awarded by the DHHS.
J O9713262