An annulation route to 1,4-dimethoxynaphthalenes

Article abstract of DOI:10.1055/s-1998-4500

An efficient regiocontrolled synthesis of substituted and annulated 1,4- dimethoxynaphthalenes as precursors for 1,4-naphthoquinone systems has been developed through naphthoannulation route by regioselective 1,2-addition of 2,5-dimethoxybenzylmagnesium chloride to acyclic and cyclic α-oxoketene dithioacetals and subsequent BF₃ · OEt₂ assisted cycloaromatization of the resulting alcohols.

Full text of DOI:10.1055/s-1998-4500

SYNTHESIS
October 1998
1483
An Annulation Route to 1,4-Dimethoxynaphthalenes
Barun K. Mehta,a Okram Barun,a H. Ila,*b H. Junjappa*a
a Department of Chemistry, North Eastern Hill University, Shillong-793003, Meghalaya, India
b Department of Chemistry, Indian Institute of Technology, Kanpur-208016, India
Fax: +91(512)597436; E-mail: hila@iitk.ernet.in
Received 2 February 1998; revised 2 April 1998
Abstract: An efficient regiocontrolled synthesis of substituted
of 2 to oxoketene dithioacetal 1a gave 3a in nearly quan-
titative yield by exclusive 1,2-addition (Table). The alco-
hol 3a underwent smooth BF3•OEt2 assisted cationic cy-
clization in refluxing benzene to afford 1,4-dimethoxy-5-
methylthio-7-methylnaphthalene (4a) in 73% yield (Ta-
ble). It is pertinent to note that the corresponding benzyl-
magnesium chloride adds to oxoketene dithioacetals in se-
quential 1,4- and 1,2-fashion under these conditions yield-
ing naphthalenes with undesirable benzylic side chain
after cyclization.6
and annulated 1,4-dimethoxynaphthalenes as precursors for 1,4-
naphthoquinone systems has been developed through naphthoan-
nulation route by regioselective 1,2-addition of 2,5-dimethoxy-
benzylmagnesium chloride to acyclic and cyclic α-oxoketene
•
dithioacetals and subsequent BF3 OEt2 assisted cycloaromatiza-
tion of the resulting alcohols.
Key words: 1,4-dimethoxynaphthalenes, 1,4-naphthoquinones,
α-oxoketene dithioacetals, 2,5-dimethoxybenzylmagnesium chlo-
ride, naphthaannulation
Regioselective synthesis of highly substituted polynuclear
quinones has attracted considerable attention during past
two decades owing to the presence of this structural moi-
ety in many of the biologically significant natural prod-
ucts.1 Important routes for the construction of 1,4-naph-
thoquinone framework involve Diels–Alder reaction,2
phthalide annulation3 and cycloadditon via arylchromium
carbene complexes4 or phthaloylcobalt complexes.5 In the
present communication, we report a direct and convenient
route for regiospecific elaboration of 1,4-dimethoxy-
naphthalene moiety (as precursors for 1,4-naphthaquino-
ne system) over acyclic and cyclic active methylene ke-
tones by extension of our earlier reported aromatic anne-
lation strategy via α-oxoketene dithioacetals.6
The regiospecific addition-cyclization sequence was elab-
orated to few selected cyclic and acyclic oxoketene dithio-
acetals. Various substituted and condensed 1,4-dimethoxy-
naphthalenes thus obtained under these conditions are list-
ed in the Table. Corresponding dethiomethylated
naphthalenes 7a–b were obtained either by Raney Ni des-
ulfurization of 4a–b or from β-oxodithioacetals 5a–b un-
der similar sequence of reactions.7 Interestingly, the
oxoketene dithioacetal 1d derived from cylohexanone un-
derwent sequential 1,4- and 1,2-addition to afford the al-
cohol 8, which on BF3•OEt2 catalyzed cyclization, afford-
ed the cycloaromatized product 9 in 41% yield (Scheme
2). The yield of 9 was improved to 68% when two equiv-
alents of 2 were used. The desired 1,4-dimethoxy-5,6,7,8-
tetrahydroanthracene (7c) could, however, be obtained by
cycloaromatization of β-oxodithioacetal 5c with 2 under
similar reaction conditions (Table). Finally, the unsubsti-
tuted 1,4-dimethoxynaphthalene 11 could also be synthe-
sized in moderate yield by utilizing β-phenylthioacrolein
(10)9 as 3-carbon 1,3-electrophilic partner with 2,5-
dimethoxybenzyl Grignard reagent in the cyclization se-
quence (Scheme 3).
The overall strategy is shown in Scheme 1. As a key step
for regiospecific synthesis of substituted and annulated
1,4-dimethoxynaphthalenes, we envisaged that the nu-
cleophilic addition of 2,5-dimethoxybenzyl Grignard
reagent8 2 to α-oxoketene dithioacetals 1 followed by
Lewis acid-induced cycloaromatization of the resulting
alcohols 3 may provide a simple and versatile route for
these classes of compounds. In a model study, the addition
Scheme 1
Scheme 2

SYNTHESIS
Papers
1484
In conclusion, the synthetic method presented herein en-
ables direct and effective access to substituted and con-
densed 1,4-dimethoxynaphthalenes from easily available
precursors with vested regiocontrol. The product 1,4-
dimethoxynaphthalenes serve as precursors to naphtho-
quinones by oxidation,10 besides, the methylthio group
could either be removed reductively or elaborated by fur-
ther transformations.11 Studies along these lines are in
progress.
Scheme 3
Table. Synthesis of Substituted and Annulated 1,4-Dimethoxynaphthalenes.
Entry
Starting Material
Alcohol
R1
R2
Product
Yield (%)a
(1, 5)
(3, 6)
1
2
3
1a
1b
1c
3a
3b
3c
Me
Ph
H
4a, R1 = Me; R2 = H
4b, R1 = Ph; R2 = H
4c, R1 = R2 = Me
73
72
47
H
Me
Me
4
5
6
1e
1f
3e
3f
R = HniO
R = MeO
4e, R = H
67
68
63
4f, R = MeO
1g
3g
4g
7
8
9
5a
5b
5c
6a
6b
6c
Me
Ph
H
H
7a, R1 = Me
7b, R1 = Ph
58 (89)
67 (92)
62
7c
a Yield in parenthesis is for Raney Ni desulfurization.

SYNTHESIS
October 1998
1485
Melting points were determined on Thomas Hoover (capillary meth-
od) apparatus and are uncorrected. IR spectra were recorded on a Per-
kin-Elmer 297 and 983 grating spectrophotometer as KBr pellets. 1H
NMR (90 MHz and 300 MHz), 13C NMR (75.43 MHz) spectra were
recorded on either Varian EM-390 or a Bruker-ACF 300 spectrome-
ter. Chemical shifts are reported in δ (ppm) relative to TMS and cou-
pling constants (J) are given in Hertz. Mass spectra were obtained on
a Jeol JMS-D-300 spectrometer. Elemental analyses were carried out
on Hearaus CHN-O-RAPID analyzer.
1H NMR (300 MHz, CDCl3): δ = 2.51 (s, 3 H, SCH3), 3.84 (s, 3 H,
OCH3), 3.89 (s, 3 H, OCH3), 6.67–6.69 (m, 2 Harom), 7.33–7.46 (m, 4
Harom), 7.70–7.73 (m, 2 Harom), 8.21 (s, 1 Harom).
13C NMR (75 MHz, CDCl3): δ = 16.53, 55.78, 56.56, 104.40, 106.46,
116.19, 120.21, 123.33, 127.39, 127.84, 128.76, 137.18, 137.95,
141.26, 150.02, 151.23.
MS: m/z (%) = 310 (M+, 100).
Anal. calcd for C19H18O2S (310.3): C, 73.55; H, 5.84; Found C,
73.87; H, 5.55.
All reactions were conducted in oven dried (120°C) glasswares. The
reactions were monitored by TLC on glass plates coated with silica
gel (Acme's) containing 13% CaSO4 as binder and visualization of
compounds were accomplished by exposure to I2 vapour or by spray-
ing KMnO4 (acidic) solution. Column chromatography was carried
out using Acme's silica gel (60–120 mesh).
1,4-Dimethoxy-6,7-dimethyl-5-(methylthio)naphthalene (4c): white
crystals; mp 136–137°C.
IR (KBr): ν = 1603, 1261, 1216, 1194, 1104 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.32 (s, 3 H, CH3), 2.45 (s, 3 H,
CH3), 2.70 (s, 3 H, SCH3), 3.92 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3),
6.67 (d, J = 8.4 Hz, 1 Harom), 6.82 (d, J = 8.4 Hz, 1 Harom), 8.06 (s, 1
Harom).
Substituted and Annulated 1,4-Dimethoxynaphthalenes 4a–c, 4e–
g, 7a–c, 11; General Procedure:
13C NMR (73 MHz, CDCl3): δ = 18.97, 20.88, 22.00, 55.77, 57.62,
103.16, 108.43, 122.21, 126.15, 126.60, 130.93, 135.28, 141.75,
149.67, 150.45.
To an ice-cooled and stirred solution of 2,5-dimethoxybenzyl magne-
sium chloride [15 mmol, prepared from Mg turnings (1.0 g, 40 mmol)
and 2,5-dimethoxybenzyl chloride (2.77 g, 15 mmol) in Et2O/THF
(1:1, 100mL)] was added dropwise α-oxoketene dithioacetals (1a–c,
1e–g)/β-oxodithioacetals (5a–c) or β-phenylthioacrolein (10) under a
N2 atmosphere. The mixture was stirred further for 45 min (monitored
by TLC) and the temperature was slowly raised to r.t. It was then
poured onto aq satd NH4Cl solution (50 mL), extracted with Et2O (2 ×
50 mL) and the combined Et2O extracts were washed with H2O
(50 mL), dried (Na2S04) and evaporated to give the alcohols 3, 6 and
12 in nearly quantitative yields. The crude alcohols 3, 6 and 12 were
MS: m/z (%) = 262 (M+, 100).
Anal. calcd for C15H18O2S (262.2): C, 68.71; H, 6.91; Found C,
68.98; H, 6.64.
1,4-Dimethoxy-6-methylnaphthalene (7a): pale yellow crystals; mp
49–50°C.
IR (KBr): ν = 1775, 1654, 1264, 1086 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.52 (s, 3 H, CH3), 3.93(s, 3 H,
OCH3), 3.94 (s, 3 H, OCH3), 6.59–6.68 (m, 2 Harom), 7.33 (dd, J =
1.65, 8.5 Hz, 1 Harom), 7.97 (s, 1 Harom), 8.08 (d, J = 8.5 Hz, 1 Harom).
13C NMR (75 MHz, CDCl3): δ = 21.86, 55.62, 55.66, 102.16, 103.23,
120.82, 121.69, 124.47, 126.44, 127.91, 135.57, 149.03, 149.57.
MS: m/z (%) = 202 (M+, 11.4), 201 (66.2), 186 (100).
Anal. calcd for C13H14O2 (202.1): C, 77.24; H, 6.98: Found C, 77.56;
H, 6.68.
•
dissolved in anhyd benzene (100 mL) and treated with BF3 OEt2
(1.5 mL) followed by refluxing for 10–15 min (monitored by TLC).
The mixture, after cooling to r.t., was neutralized with aq satd
NaHCO3 solution (50 mL). The benzene layer was separated, the wa-
ter layer extracted with CHCl3 (3 × 50 mL) and the combined organic
extracts were dried (Na2SO4) and evaporated to give crude residue,
which on column chromatography over silica gel using hexane as elu-
ent gave pure the products 4a–c, 4e–g, 7a–c and 11 (Table). Analyt-
ically pure samples were prepared by recrystallization from hexane.
1,4-Dimethoxy-6-phenylnaphthalene (7b): white crystals; mp 79–
80°C.
IR (KBr): ν = 1671, 1223, 1156, 1088 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.93 (s, 3 H, OCH3), 3.94 (s, 3 H,
OCH3), 6.66 (br s, 2 Harom), 7.34–7.78 (m, 6 Harom), 8.26 (d, J = 8.4
Hz, 1 Harom), 8.44 (d, J = 8.2 Hz, 1 Harom).
Raney Ni Desulfurization of 4a and 4b; General Procedure:
A suspension of 4a (0.2 g, 0.7 mmol) and W-4 Raney Nickel (2.0 g)
in EtOH (20 mL) was stirred at r.t. for 6–8 h (monitored by TLC).
Raney Nickel was filtered, washed with hot EtOH (3 × 10 mL) and
the filtrate was concentrated under reduced pressure. The residue was
diluted with CHCl3 (30 mL), washed with H2O (2 × 25mL), dried and
evaporated to give crude 7a, which was purified by column chroma-
tography over silica gel using hexane as eluent. Under the similar re-
action conditions, 4b was converted to the corresponding sulfur-free
compound 7b.
13C NMR (75 MHz, CDCl3): δ = 55.69, 103.29, 103.62, 119.84,
122.45, 125.28, 125.41, 126.59, 127.21, 127.45, 128.74, 138.44,
141.31, 149.47, 149.73.
MS: m/z (%) = 264 (M+, 14.7), 263 (75.7), 248 (100).
Anal. calcd for C18H16O2 (264.2): C, 81.79; H, 6.10: Found C, 82.01;
H, 6.45.
1,4-Dimethoxy-5,6,7,8-tetrahydroanthracene (7c): white crystals; mp
43–44°C.
IR (KBr): ν = 1601, 1490, 1251, 1180 cm–1.
1H NMR ( 90 MHz, CDCl3): δ = 1.73–2.10 [m, 4 H, (CH2)2], 2.86–
3.16 [m, 4 H, (CH2)2], 3.96 (s, 6 H, 2 OCH3), 6.63 (s, 2 Harom), 8.00
(s, 2 Harom).
1,4-Dimethoxy-7-methyl-5-(methylthio)naphthalene (4a): white crys-
tals; mp 114–115°C.
IR (KBr): ν = 1625, 1380, 1280, 1105 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.46 (s, 3 H, CH3), 2.47 (s, 3 H,
SCH3), 3.89 (s, 3 H, OCH3), 3.92 (s, 3 H, OCH3), 6.66 (s, 2 Harom),
6.97 (br s, 1 Harom), 7.77(br s, 1 Harom).
MS: m/z (%) = 242 (M+, 58.2), 227 (100).
Anal. calcd for C16H18O2 (242.2): C, 79.35; H, 7.49: Found C, 79.66;
H, 7.73.
13C NMR (75 MHz, CDCl3): δ = 16.43, 21.87, 55.80, 56.49, 104.14,
105.39, 117.21, 122.58, 122.76, 127.89, 135.08, 136.24, 149.38,
151.44.
5,6-Dihydro-8,11-dimethoxy-7-(methylthio)benz[a]anthracene (4e):
pale yellow crystals; mp 94–95°C.
MS: m/z (%) = 248 (M+, 100).
Anal. calcd for C14H16O2S (248.2): C, 67.74; H, 6.49; Found C,
67.98; H, 6.75.
IR (KBr): ν = 1605, 1470, 1350, 1300, 1120 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.32 (s, 3 H, SCH3), 2.86 (t, J =
7 Hz, 2 H, CH2), 3.44 (t, J = 7 Hz, 2 H, CH2), 3.93 (s, 3 H, OCH3),
3.94 (s, 3 H, OCH3), 6.67 (d, J= 8.4 Hz, 1 Harom), 6.84 (d, J = 8.4 Hz,
1 Harom), 7.24–7.36 (m, 3 Harom), 7.94 (d, J = 8.3 Hz, 1 Harom), 8.64 (s,
1 Harom).
1,4-Dimethoxy-5-methylthio-7-phenylnaphthalene (4b): pale yellow
crystals; mp 128–129°C.
IR (KBr): ν = 1605, 1478, 1385, 1280, 1125 cm–1.

SYNTHESIS
Papers
1486
13C NMR (75 MHz, CDCl3): δ = 20.88, 28.34, 29.33, 55.77, 57.47,
103.43, 109.16, 117.58, 124.72, 126.59, 126.92, 127.60, 127.67,
130.66, 132.89, 134.91, 138.13, 141.69, 150.36, 150.48.
MS: m/z (%) = 336 (M+, 100).
Anal. calcd for C21H20O2S (336.3): C, 74.96; H, 5.99: Found C,
75.29; H, 6.32.
(1) Thomson, R. H. Naturally Occurring Quinones; 2nd ed.; Aca-
demic Press: New York, 1971; p 111.
Hauser, F. M.; Baghdanov, V.M. Tetrahedron 1984, 40, 4719.
Swenton, J. S.; Freskos, J. N.; Morrow, G.W.; Sercel, A. D.
Tetrahedron 1984, 40, 4625.
Dodd, J. H.; Garigipati, R. S.; Weinreb, S. M. J. Org. Chem.
1982, 47, 4045.
5,6-Dihydro-7-methylthio-3,8,11-trimethoxybenz[a]anthracene (4f):
white needles; mp 86–87°C.
Iwao, M.; Kuraishi, T. Tetrahedron Lett. 1985, 26, 6213.
Kende, A. S.; Rizzi, J.; Riemer, J. Tetrahedron Lett. 1979, 1201.
Parker, K. A.; Kallmerten, J. L. Tetrahedron Lett. 1979, 1197.
Kelly, T. R.; Gillard, J. W.; Jr. Goener, R. N.; Lyding, J. M.
J. Am. Chem. Soc. 1977, 99, 5514
IR (KBr): ν = 1604, 1251, 1233, 1143 cm–1.
1H NMR (90 MHz, CDCl3): δ = 2.33 (s, 3 H, SCH3), 2.60–3.33 [m, 4
H, (CH2)2], 3.86 (s, 3 H, OCH3), 3.99 (s, 6 H, 2 OCH3), 6.50–7.13 (m,
3 Harom), 7.93–8.36 (m, 2 Harom), 8.66 (s, 1 Harom).
Anal. calcd for C22H22O3S (366.3): C, 72.09; H, 6.05: Found C,
72.39; H, 6.39.
(2) Giles, R.G. F.; Roos, G. H. P. J. Chem. Soc., Perkin Trans. 1
1976, 2057.
Trost, B. M.; Pearson, W. H. Tetrahedron Lett. 1983, 24, 269.
Danishefsky, S.; Singh, R. K.; Gammill, R. B. J. Org. Chem.
1978, 43, 379.
9,12-Dimethoxy-8-methylthiobenzo[f]naphtho[2,3-d]thiepine (4g):
white crystals; mp 116–117°C.
Guay, V.; Brassard, P. Tetrahedron 1984, 40, 5039.
(3) Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178.
Kraus, G. A.; Sugimoto, H. Tetrahedron Lett. 1978, 2263.
Kraus, G. A.; Cho, H.; Crowley, S.; Roth, B.; Sugimoto, H.;
Prugh, S. J. Org. Chem. 1983, 48, 3439.
(4) Ellen Boss, M.; Wulff, W. D.; Wilson, K. J. J. Chem. Soc.,
Chem. Commun. 1996, 1863, and references therein.
Wulff, W. D.; Tang, P. C.; McCallum, J.S. J. Am. Chem. Soc.
1981, 103, 7677.
Dotz, K. H.; Pruskil, I.; Muhlemeier, J. Chem. Ber. 1982, 115,
1278.
Semmelhack, M. F.; Bozell, J. J.; Sato, T.; Wulff, W.; Spiess,
E.; Zask, A. J. Am. Chem. Soc. 1982, 104, 5850.
(5) South, M. S.; Liebeskind, L. S. J. Am. Chem. Soc. 1984, 106,
4181.
IR (KBr): ν = 1609, 1257, 1221, 1107 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.42 (s, 3 H, SCH3), 2.58–2.68 (m,
2 H, CH2), 3.13–3.23 (m, 2 H, CH2), 3.93 (s, 3 H, OCH3), 3.96 (s, 3
H, OCH3), 6.75 (d, J = 8.4 Hz, 1 Harom), 6.93 (d, J = 8.4 Hz, 1 Harom),
7.31–7.64 (m, 4 Harom), 8.24 (s, 1 Harom).
13C NMR (75 MHz, CDCl3); δ = 21.73, 30.99, 39.33, 55.80, 57.84,
103.87, 109.82, 123.15, 126.86, 127.12, 128.41, 128.98, 129.23,
129.47, 131.44, 134.62, 140.20, 143.15, 146.86, 150.46, 150.58.
MS: m/z (%) = 368 (M+, 100).
Anal. calcd for C21H20O2S2 (368.3) : C, 68.47; H, 5.47 : Found C,
68.78; H, 5.80.
1,4-Dimethoxy-9-(2',5'-dimethoxybenzyl)-5,6,7,8-tetrahydroan-
thracene (9): white crystals; mp 104–106°C.
IR (KBr): ν = 1617, 1490, 1251, 1216, 1180 cm–1.
1H NMR (90 MHz, CDCl3): δ = 1.60–2.01 [m, 4 H, (CH2)2], 2.66–
3.23 [m, 4 H, (CH2)2], 3.46 (s, 3 H, OCH3), 3.50 (s, 3 H, OCH3), 3.90
(s, 3 H, OCH3), 3.93 (s, 3 H, OCH3), 4.63 [s, 2 H, CH2C6H3(OMe)2],
6.13–6.96 (m, 5 Harom), 8.03 (s, 1 Harom).
Liebeskind, L. S.; Baysdon, S. L.; South, M. S. J. Am. Chem.
Soc. 1980, 102, 7398.
(6) Review: Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron 1990,
46, 5423.
Review: Junjappa, H.; Ila, H. Phosphorous, Sulfur and Silicon
1994, 95-96, 3.
MS: m/z (%) = 392 (M+, 100).
Anal. calcd for C25H28O4 (392.3): C, 76.50; H, 7.19; Found C, 76.87;
H, 7.46.
Suresh, J. R.; Patra, P. K.; Ila, H.; Junjappa, H. Tetrahedron
1997, 53, 14737, and references therein.
Rao, Ch. S.; Singh, O.M.; Ila, H.; Junjappa, H. Synthesis 1992,
1075.
Balu, M.P.; Singh, G.; Ila, H.; Junjappa, H. Tetrahedron Lett.
1986, 27, 117.
1,4-Dimethoxynaphthalene (11): white crystals; mp 82–83°C (Lit.12
mp 84–85°C).
IR (KBr): ν = 1613, 1258, 1204, 1108, 1060 cm–1.
1H NMR (90MHz, CDCl3): δ = 3.90 (s, 6 H, 2 OCH3), 6.86 (s, 2
Harom), 7.46–7.76 (m, 2 Harom), 7.83–8.10 (m, 2 Harom).
Anal. calcd for C12H12O2 (188.1) : C, 76.57; H, 6.43: Found C, 76.89;
H, 6.77.
(7) Rao, Ch. S.; Balu, M.P.; Ila, H.; Junjappa, H. Tetrahedron 1991,
47, 3499, and references therein.
(8) Hart, D.J.; Huang, H.C. J. Am. Chem. Soc. 1988, 110, 1634.
(9) Bakuzis, P.; Bakuzis, M.L.F. J. Org. Chem. 1981, 46, 235.
(10) Rosen, B. I.; Weber, W.P. J. Org. Chem. 1977, 42, 3436.
Syper, L.; Kloc, K.; Mlochowski, J.; Szulc, Z. Synthesis 1979,
521.
We thank Council of Scientific and Industrial Research, New Delhi
for financial support.
Snyder, C.D.; Rapoport, H. J. Am. Chem. Soc. 1972, 94, 227.
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2548.
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Potts, K.T.; Usifer, D. J. Org. Chem. 1985, 50, 1125.
(12) Seitz, U.; Daub, J. Synthesis 1986, 8, 686.