Synthesis of functionalized naphthalenes from substituted 1-methoxybenzocyclobutenes

Full text of DOI:10.1021/jo951978v

J . Org. Chem. 1996, 61, 2885-2887
2885
Sch em e 1
Syn th esis of F u n ction a lized Na p h th a len es
fr om Su bstitu ted
1-Meth oxyben zocyclobu ten es
Neil G. Andersen,† Shawn P. Maddaford, and
Brian A. Keay*
Department of Chemistry, University of Calgary,
Calgary, Alberta, Canada, T2N 1N4
Sch em e 2
Received November 7, 1995
Multisubstituted naphthalene rings can be difficult to
prepare by conventional electrophilic aromatic substitu-
tion reaction(s), since regiochemical control can be
problematical.1-3 Thus, new or improvements on known
methods for the preparation of multisubstituted naph-
thalene rings are useful since substituted naphthalene
rings are often found in natural products.4 In particular,
one of our synthetic routes5 toward the pentacyclic poly-
ketides halenaquinone6 and xestoquinone7 prompted this
study. We report herein a simple improvement in the
synthesis of naphthalene rings having an ortho or para
arrangement of methoxy groups in one ring using a sub-
stituted 1-methoxybenzocyclobutene as an o-quinodimeth-
ane precursor with acetylenic dienophiles (Scheme 1).
It is well known that o-quinodimethanes have been
used as intermediates toward the synthesis of function-
alized naphthalene rings.8 However, if the starting
material is a benzocyclobutenol (1), the o-quinodimethane
intermediate may undergo a competing [1,5]-hydrogen
rearrangement rather than the desired cycloaddition
reaction. While attempting to synthesize some multi-
functionalized naphthalene rings, we found that com-
pound 19 in the presence of 3-bromopropynoic acid (5,
Scheme 2) formed both 2,5-dimethoxy-6-methylbenzal-
dehyde (19, Scheme 3), presumably resulting from a [1,5]-
hydrogen shift, and the unexpected ester 3; compound 8
was not detected in the reaction mixture. In an attempt
to alleviate the formation of ester 3, compound 1 was
refluxed in toluene with methyl 3-bromopropynoate (6);10
however, after 24 h a complex mixture of products was
obtained in which the major product was identified as
bromide 4. These two results indicated that the alcohol
group in 1 could be an interfering factor in the cycload-
dition reaction.
To test this hypothesis, 1,3,6-trimethoxybenzocy-
clobutene (2) was prepared from 1 in quantitative yield
according the procedure of Wallace et al.11 and used as
the Diels-Alder precursor.12 Thermolysis of 2 in reflux-
ing anhydrous toluene under an atmosphere of N2 with
ethyl 3-bromopropynoate (7) provided a disappointing 5%
yield of naphthalene 9 plus aldehyde 19. The yield of
compound 9 was improved to 65% when compounds 2
and 7 were refluxed in anhydrous toluene in the presence
of 4 Å molecular sieves, the remainder being aldehyde
19. The formation of aldehyde 19 could be suppressed
by the addition of solid K2CO3 or MgCO3 to the reaction
mixture; however, the yield of 9 was not improved.
Interestingly, 1,4,5-trimethoxybenzocyclobutene (10)13
reacted smoothly with dienophile 7 to provide naphtha-
lene 13 in 82% yield (entry 3, Table 1).
Since compound 2 could be used to successfully prepare
naphthalene 9, we investigated using methoxybenzocy-
clobutenes 2 and 10 with a variety of acetylenic dieno-
philes. Refluxing compound 2 or compound 10 with a
variety of acetylenic dienophiles in toluene (8 h, N2)
provided naphthalenes 11-15 in good to excellent yield
(Table 1). The reaction is quite general and tolerates a
variety of functional groups on the acetylenic dienophile.
As expected, the more electron poor dienophiles gave rise
to higher yields.
The reactions listed in Table 1 did not require the
addition of 4 Å molecular sieves, potassium, or magne-
sium carbonate to effect a successful reaction. We feel
that the difference in the reaction conditions needed for
2 to react with ethyl 3-bromopropynoate (7) when com-
pared to the examples listed in Table 1 can be explained
as follows. Due to steric hindrance between the adjacent
methoxy groups, o-quinodimethane 16 forms and reacts
slower than o-quinodimethane 20 (Scheme 3).9 Inter-
† Awarded one of four Alfred Bader Awards (Canadian Society of
Chemistry) for this work as a senior undergraduate student in 1995.
(1) Loudon, G. M. Organic Chemistry, 3rd ed.; Benjamin/Cummings
Publishing Co., Inc.: Redwood City, CA, 1995; pp 1173-1177.
(2) March, J . Advanced Organic Chemistry, 3rd ed.; J ohn Wiley and
Sons: New York, 1985; pp 460-461 and references therein.
(3) Griffin, R. W., J r.; Gass, J . D.; Berwick, M. A.; Shulman, R. S.
J . Org. Chem. 1964, 29, 2109. Nishino, H.; Kajikawa, S.; Hamada, Y.;
Kurosawa, K. Tetrahedron Lett. 1995, 36, 5753. Shishido, K.; Yamahs-
hita, A.; Hiroya, K.; Fukumoto Tetrahedron Lett. 1989, 30, 111.
(4) Faulkner, D. J . Nat. Prod. Rep. 1995, 12, 223. Ward, R. S. Nat.
Prod. Rep. 1995, 12, 183. Ward, R. S. Nat. Prod. Rep. 1993, 10, 1.
(5) Cristofoli, W.; Keay, B. A. Synlett 1994, 625.
(6) Isolation: Roll, D. M.; Scheuer, P. J .; Matsumotao, G. K.; Clardy,
J . J . Am. Chem. Soc. 1983, 105, 6177. Synthesis: Harada, N.; Sugioka,
T.; Ando, Y.; Uda, H.; Kuriki, T. J . Am. Chem. Soc. 1988, 110, 8483.
(7) Isolation: Nakamura, H.; Kobayashi, J .; Kobayashi, M.; Ohi-
zumi, Y.; Hirata, Y. Chem. Lett. 1985, 713. Synthesis: Harada, N.;
Sugioka, T.; Uda, H.; Kuriki, T. J . Org. Chem. 1990, 55, 3158. Formal
synthesis: Kanematsu, K.; Soejima, S.; Wang, G. Tetrahedron Lett.
1991, 32, 4761.
(11) Azadi-Ardakani, M.; Hayes, R.; Wallace, T. W. Tetrahedron
1990, 46, 6851.
(12) Although 1-methoxybenzocyclobutene has been reported to
undergo the [4 + 2] cycloaddition reaction via the o-quinodimethane
with olefins, we were surprised to find that substituted 1-methoxy-
benzocyclobutenes have not been used as Diels-Alder precursors,
see: (a) Arnold, B. J .; Sammes, P. G.; Wallace, T. W. J . Chem. Soc.,
Perkin Trans. 1 1974, 409. (b) Moss, R. J .; Rickborn, B. J . Org. Chem.
1984, 49, 3694. (c) Takahashi, Y.; Kochi, J . K. Chem. Ber. 1988, 121,
253. (d) Zhang, X.; Foote, C. S. J . Org. Chem. 1994, 59, 5235.
(13) 4,5-Dimethoxybenzocyclobuten-1-ol was prepared according to
Charlton, J . L.; Koh, K.; Plourde, G. L. Can. J . Chem. 1990, 68, 2028
and methylated according to the procedure reported by Wallace et al.11
(8) Charlton, J . L.; Alauddin, M. M. Tetrahedron 1987, 43, 2873.
(9) Azadi-Ardakani, M.; Wallace, T. W. Tetrahedron 1988, 44, 5939.
(10) Commercon, A.; Normant, J . F.; Villieras, J . Tetrahedron 1980,
36, 1215.
0022-3263/96/1961-2885$12.00/0 © 1996 American Chemical Society

2886 J . Org. Chem., Vol. 61, No. 8, 1996
Notes
Ta ble 1. P r ep a r a tion of Na p h th a len es fr om Su bstitu ted
1-Meth oxyben zocyclobu ten es
MeOH to acetylene 7 followed by the elimination of HBr
to form ethyl 3-methoxypropynoate (18). Methanol is
formed when the Diels-Alder adduct 17 aromatizes to
form ester 9 (Scheme 3, eq 1). The increase in the yield
of 9 in the presence of 4 Å molecular sieves is presumably
due to the absorption of most of the MeOH resulting in
a decrease in HBr production; however, due to the high
temperature (110 °C) some of the MeOH is released and
some HBr is formed (Scheme 3, eq 2) which results in
the formation of some aldehyde 19 (Scheme 3, eq 3). The
addition of solid carbonate removes the HBr completely
resulting in no aldehyde formation. The lower reactivity
of 16 (when compared to 20) results in a poorer yield of
9 (when compared to 13) due to decomposition of 16 via
other pathways. The reaction of 16 with dimethyl
acetylenedicarboxylate is higher yielding, presumably,
due to the increased reactivity of the latter.
We have shown that substituted 1-methoxybenzocy-
clobutenes can be used successfully as precursors for the
preparation of some functionalized naphthalenes.
Exp er im en ta l Section
Meth od s a n d Ma ter ia ls. 3,6-Dimethoxybenzocyclobuten-
1-ol (1),9 4,5-dimethoxybenzocyclobuten-1-ol,13 1,3,6-trimethoxy-
benzocyclobutene (2),11 and methyl 3-bromopropynoate (6)10 were
prepared according to literature procedures. All melting points
are uncorrected. Elemental analyses were obtained by Dorthy
Fox at The University of Calgary.
3-Br om op r op yn oic Acid (5). Freshly distilled propiolic acid
(0.63 g, 9.0 mmol) was dissolved in dry THF (10 mL) and added
dropwise to a solution of LHMDS (5.32 g, 22.5 mmol) in THF
(40 mL) at -78 °C. The reaction mixture was stirred at -78 °C
for 20 min and then warmed to 0 °C for a further hour. The
solution was then cooled to -78 °C and Br2 (0.47 mL, 9.2 mmol)
added dropwise over a period of 10 min. The resulting solution
was extracted with EtOAc (5 × 25 mL). The combined organic
extracts were washed with saturated Na2S2O3 (25 mL), dried
(Na2SO4), and concentrated in vacuo to afford a dark brown oil
which later crystallized. Recrystallization from ethyl acetate-
petroleum ether gave the title compound as light brown needles
(63%): mp 76-78 °C (lit.14 76-78 °C); 1H NMR (CDCl3, 200
MHz) δ 10.6-9.8 (bs, 1H, CO2H); 13C NMR (CDCl3, 50 MHz) δ
55.20, 72.27, 155.31; mass spectrum, 150/148 (88, M•+), 133/131
(95, M•+ - OH), 106/104 (100, M•+ - CO2).
Sch em e 3
Eth yl 3-Br om op r op yn oa te (7). Ethyl propiolate (1.8 g, 18.3
mmol) was dissolved in dry acetone (20 mL) and treated with
N-bromosuccinimide (3.6 g, 20.2 mmol) and a catalytic amount
of AgNO3. After 2 h at ambient temperature, the mixture was
quenched with water (20 mL) and filtered. The filtrate was
extracted with hexanes, and the combined organic extracts were
washed with 10% HCl (2 × 20 mL), dried (Na2SO4), and
concentrated in vacuo to afford a clear oil which later crystallized
(85%): mp 21-22 °C; 1H NMR (CDCl3, 200 MHz) δ 1.31 (t, 3H,
OCH2CH3), 4.22 (q, 2H, OCH2CH3); 13C NMR (CDCl3, 50 MHz)
δ 14.0, 52.5, 62.5, 73.0, 152.5; HRMS calcd for C3OBr: 132.9120/
130.9135 (M+ - OCH2CH3), found: 132.9127/130.9132.
1,4,5-Tr im eth oxyben zocyclobu ten e (10). Compound 10
was prepared in 94% yield from 4,5-dimethoxybenzocyclobuten-
1-ol13 according to the procedure reported for preparation of
compound 2:11 bp 86-93 °C, 0.1 mmHg; 1H NMR (CDCl3, 200
MHz) δ 3.03 (dd, 1H, J trans ) 2 Hz, J gem ) 13.5 Hz, H2), 3.35
(dd, 1H, J cis ) 4 Hz, J gem ) 13.5 Hz, H2), 3.47 (s, 3H, OMe), 3.86
(s, 3H, OMe), 3.87 (s, 3H, OMe), 4.91 (dd, 1H, J trans ) 2 Hz, J cis
) 4 Hz, H1), 6.73 (s, 1H), 6.83 (s, 1H); 13C NMR (CDCl3, 50 MHz)
δ 37.4, 55.7, 56.0, 56.2, 76.3, 106.9, 107.3, 134.2, 136.9, 149.7,
151.5; HRMS calcd for C11H12O3: 194.0947, found: 194.0943.
Eth yl 3-Br om o-5,8-d im eth oxy-2-n a p h th oa te (9). A mix-
ture of benzocyclobutene 2 (60 mg, 0.31 mmol) and ethyl
3-bromopropynoate (109 mg, 0.62 mmol) in dry toluene (1.5 mL)
was refluxed in the presence of 4 Å molecular sieves under a
nitrogen atmosphere for 24 h. The mixture was filtered and
mediate 16, therefore, has more time to be protonated
by an acid source thereby forming aldehyde 19. The
proton source could be HBr formed by the addition of
(14) Straus, F.; Kollek, L.; Heyn W. Ber. 1930, 63, 1868.

Notes
J . Org. Chem., Vol. 61, No. 8, 1996 2887
concentrated in vacuo to afford a dark orange oil. The crude
material was purified by column chromatography with silica gel
(9:1 hexanes/EtOAc) and purified by distillation (bp 140 °C/0.1
mmHg) (65%): IR (KBr) 1712 cm-1 (CdO); 1H NMR (CDCl3, 200
MHz) δ 1.46 (t, 3H, J ) 7.1 Hz, CO2CH2CH3), 3.96, 3.97 (s, 3H
each, 2 × OMe), 4.45 (q, 2H, J ) 7.1 Hz, CO2CH2CH3), 6.73 and
6.80 (ABq, 2H, J ) 8.6 Hz, H6 and H7), 8.50 (s, 1H, H4), 8.66 (s,
1H, H1); 13C NMR (CDCl3, 50 MHz) δ 14.3, 55.8, 55.7, 61.6, 104.3,
106.4, 117.6, 124.3, 126.3, 127.5, 128.1, 129.6, 148.3, 149.7, 166.6;
mass spectrum, 338/340 (100, M•+), 323/325 (88, M•+ - CH3).
Anal. Calcd for C15H15BrO4: C, 53.12; H, 4.46. Found: C, 53.13,
H, 4.51.
NMR (CDCl3, 100 MHz) δ 52.5, 56.0, 106.7, 126.9, 128.3, 129.6,
151.5, 166.4; mass spectrum, 304 (74, M•+), 273 (100, M•+
-
OCH3). Anal. Calcd for C16H16O6: C, 63.15; H, 5.30. Found:
C, 62.66, H, 5.41.
Eth yl 3-Br om o-6,7-d im eth oxy-2-n a p h th oa te (13). A mix-
ture of benzocyclobutene 10 (137 mg, 0.7 mmol) and ethyl
3-bromopropynoate (250 mg, 1.4 mmol) in dry toluene (1.5 mL)
was refluxed under a nitrogen atmosphere for 24 h. The crude
mixture was filtered, concentrated in vacuo, and recrystallized
from CH2Cl2/hexanes to afford the title compound as long, light
brown needles (82%): mp 128-129 °C; IR (KBr) 1712 cm-1
1
(CdO); H NMR (CDCl3, 400 MHz) δ 1.45 (t, 3H, J ) 7.14 Hz,
Dim eth yl 5,8-Dim eth oxy-2,3-d in a p h th oa te (15). A mix-
ture of benzocyclobutene 2 (130 mg, 0.67 mmol) and dimethyl
acetylenedicarboxylate (670 mg, 4.7 mmol) in dry toluene (1.0
mL) was refluxed under a nitrogen atmosphere for 24 h. The
crude mixture was filtered, concentrated in vacuo, and recrystal-
lized from CH2Cl2/hexanes to afford the title compound as yellow
cubes (95%): mp 127-128 °C; IR (KBr) 1716 cm-1 (2 × CdO);
1H NMR (CDCl3, 200 MHz) δ 3.96 (s, 6H, 2 × OMe), 3.98 (s, 6H,
2 × OMe), 6.84 (s, 2H, H6 and H7), 8.62 (s, 2H, H1 and H4); 13C
NMR (CDCl3, 50 MHz) δ 52.6, 55.8, 106.1, 124.3, 126.2, 128.2,
149.7, 168.4; mass spectrum, 304 (90, M•+), 289 (100, M•+ - CH3),
273 (23, M•+ - OCH3). Anal. Calcd for C16H16O6: C, 63.15; H,
5.30. Found: C, 62.86, H, 5.30.
N,5,8-Tr im eth oxy-N-m eth yl-2-n a p h th a m id e (11). A mix-
ture of benzocyclobutene 10 (118.5 mg, 0.61 mmol) and N-
methoxy-N-methylpropynamide (173 mg, 1.53 mmol) in dry
toluene (1.5 mL) was refluxed under a nitrogen atmosphere for
24 h. The crude mixture was filtered, concentrated in vacuo,
and recrystallized from CH2Cl2/hexanes to afford the title
compound as light brown plates (72%): mp 123-124 °C; IR (KBr)
1637 cm-1 (CdO); 1H NMR (CDCl3, 400 MHz) δ 3.40 (s, 3H,
NCH3), 3.57 (s, 3H, NOCH3), 3.99, 4.00 (s, 3H each, 2 × OMe),
7.12 and 7.15 (s, 1H each, H5 and H8), 7.62, 7.68 (ABq, 2H, J )
8.0 Hz, H2 and H3), 8.08 (s, 1H, H1); 13C NMR (CDCl3, 100 MHz)
δ 34.0, 55.9, 61.0, 106.0, 107.0, 123.6, 125.8, 127.2, 128.2, 129.6,
130.4, 149.9, 150.7, 170.1; mass spectrum, 275 (8, M•+), 215 (100,
M•+ - N(OMe)Me), 187 (18, M•+ - C(O)N(OMe)Me). Anal.
Calcd for C15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C,
64.67; H, 6.18; N, 4.98.
CO2CH2CH3), 4.01, 4.02 (s, 3H each, 2 × OMe), 4.45 (q, 2H, J )
7.14 Hz, CO2CH2CH3), 7.03, 7.14 (s, 1H, H5 and H8), 7.98 (s,
1H, H4), 8.22 (s, 1H, H1); 13C NMR (CDCl3, 100 MHz) δ 14.3,
55.9, 56.0, 61.4, 104.9, 106.6, 115.4, 127.0, 131.7, 127.2, 130.6,
131.2, 150.30, 151.8, 166.3; mass spectrum, 338/340 (100, M•+),
310/312 (14, M•+ - C2H4), 293/295 (71, M•+ - Et). Anal. Calcd
for C15H15BrO4: C, 53.12; H, 4.46. Found: C, 53.38; H, 4.67.
Eth yl 6,7-Dim eth oxy-2-n a p h th oa te (14). A mixture of
benzocyclobutene 10 (26.4 mg, 0.14 mmol) and ethyl propiolate
(67 mg, 0.68 mmol) in dry toluene (1.0 mL) was refluxed under
a nitrogen atmosphere for 24 h. The crude mixture was filtered,
concentrated in vacuo, and recrystallized from CH2Cl2/hexanes
to afford the title compound as clean white prisms (93%): mp
1
103-104 °C; IR (KBr) 1712 cm-1 (CdO); H NMR (CDCl3, 400
MHz) δ 1.45 (t, 3H, J ) 7.12 Hz, CO2CH2CH3), 4.02, 4.04 (s, 3H
each, 2 × OMe), 4.43 (q, 2H, J ) 7.12 Hz, CO2CH2CH3), 7.15,
7.23 (s each, 1H, H5 and H8), 7.72 (d, 1H, J 34 ) 8.84 Hz, H4),
7.95 (dd, 1H, J 34 ) 8.84 Hz, J 13 ) 1.70 Hz, H3), 8.47 (d, 1H, J 13
) 1.70, H1); 13C NMR (CDCl3, 100 MHz) δ 14.4, 55.9, 60.9, 106.1,
107.4, 124.0, 126.3, 129.2, 126.1, 128.3, 131.9, 150.0, 151.3, 167.0;
mass spectrum, 260 (100, M•+), 245 (8, M•+ - CH3), 232 (26, M•+
- C2H4), 215 (76, M•+ - OEt); HRMS calcd for C15H16O4:
260.1029, found: 260.1049.
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council of Canada and the
University of Calgary for financial support. We also
thank Human Resources Development Canada for a
SEED grant (to N.G.A.).
Dim eth yl 6,7-Dim eth oxy-2,3-d in a p h th oa te (12). A mix-
ture of benzocyclobutene 10 (90 mg, 0.46 mmol) and dimethyl
acetylenedicarboxylate (197 mg, 1.4 mmol) in dry toluene (1.5
mL) was refluxed under a nitrogen atmosphere for 24 h. The
crude mixture was filtered, concentrated in vacuo, and recrystal-
lized from CH2Cl2/hexanes to afford the title compound as clean
white prisms (84%): mp 177-178 °C; IR (KBr) 1724 cm-1 (CdO);
1H NMR (CDCl3, 400 MHz) δ 3.94 (s, 6H, 2 × OMe), 4.02 (s, 6H,
2 × OMe), 7.17 (s, 2H, H5 and H8), 8.09 (s, 2H, H1 and H4); 13C
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 7, 10, and 14 (6 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
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J O951978V