Synthesis of 2-alkoxymethyl-3-trifluoromethyl-1,4-naphthoquinones

Article abstract of DOI:10.1016/S0040-4020(01)00791-8

2-Alkoxymethyl-3-trifluoromethyl-1,4-naphthoquinones were conveniently synthesized in two steps by treatment of 2-substituted-3-bromo-1,4-dimethoxynaphthalene with CF₃COONa/CuI and subsequent dealkylative oxidation by treatment with cerium(IV) ammonium nitrate.

Full text of DOI:10.1016/S0040-4020(01)00791-8

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 121±127
Synthesis of
2-alkoxymethyl-3-tri¯uoromethyl-1,4-naphthoquinones
Nguyen Van Tuyen, Bart Kesteleyn and Norbert De Kimpep
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure links 653,
B-9000 Ghent, Belgium
Received 26 February 2001;revised 28 June 2001;accepted 26 July 2001
AbstractÐ2-Alkoxymethyl-3-tri¯uoromethyl-1,4-naphthoquinones were conveniently synthesized in two steps by treatment of
2-substituted-3-bromo-1,4-dimethoxynaphthalene with CF3COONa/CuI and subsequent dealkylative oxidation by treatment with
cerium(IV) ammonium nitrate. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results anddiscussion
The synthesis of a series of benzyloxymethyl-, 2-arylethyl-
oxymethyl- and allyloxymethylnaphthalenes 5 bearing an
additional bromo substituent at the 3-position is outlined
in Scheme 1. Reductive methylation of 2-methyl-1,4-
naphthoquinone 1 with tin(II) chloride and HCl (12 M)
with ethanol as solvent at room temperature for 30 min,
followed by alkylation with dimethylsulfate in acetone in
the presence of potassium carbonate gave 1,4-dimethoxy-
naphthalene 2 in 83% yield.16 The bromination of
compound 2 with N-bromosuccinimide in carbon tetrachlor-
ide in the presence of benzoyl peroxide as initiator under
re¯ux for two hours gave 2-bromo-3-bromomethyl-1,4-
dimethoxynaphthalene 3 in 80% yield.17 The alkylation of
dibromonaphthalene 3 was carried out with sodium
alkoxides in tetrahydrofuran to afford compounds 5 in
90±95% yield.18 Allylic and benzylic alcohols 4 were
deprotonated by treatment with NaH in THF at 408C for
30 min, after which the alkoxides were treated with
dibromonaphthalene 3 in the same solvent at 408C for 2 h
to give 2-bromo-3-alkoxymethyl-1,4-dimethoxynaphthalenes
5 (Scheme 1).
The tri¯uoromethyl group (CF3) is an important structural
moiety in diverse classes of bioactive organic molecules.1,2
The C±F bond in ¯uorinated compounds results in an
increased stability and lipophilicity. Because ¯uorine is
the most electronegative element and the van der Waals
radius of ¯uorine is close to that of hydrogen,3,4 the intro-
duction of the CF3 group into organic molecules often
changes their physical, chemical and physiological proper-
ties in a dramatic way, without the introduction of extra
steric demand.5,6 There are many compounds containing
the CF3-moiety that have been used in agrochemicals,7
pharmaceuticals,1,2 polymers and the dye industry.8 For
this reason, many efforts were made to introduce the
tri¯uoromethyl group into different types of organic
molecules.3,4,9 Concerning the quinone system, there are
few literature references reported on the use of tri¯uoro-
methyl-substituted benzoquinones as redox system10 and
as synthon for organic synthesis.11,12 Very recently,
3-bromo- or 3-chloro-2-substituted naphthoquinones have
been reported having interesting biological activities,
including antiplatelet, antiin¯ammatory, antiallergic
activities and inhibitor of human cytomegalovirus
protease.13±15 It would therefore be of interest to have access
to the hitherto unknown tri¯uoromethylated alkoxymethyl-
benzoquinones 7 because such compounds could exert
interesting physiological properties. Accordingly, the
synthesis of 2-substituted-3-tri¯uoromethyl-1,4-naphtho-
quinones is reported here as an effort towards the discovery
of new biologically active naphthoquinones.
The directed introduction of the CF3 group in an electron-
rich environment is an important item in organic chemistry.
However, it is very dif®cult to generate the CF3-cation
chemically, due to the high electronegativity of the tri¯uoro-
methyl group. Recently, the introduction of the CF3 group
on an aromatic ring via the tri¯uoromethyl anion was
performed by substitution of halogens using (tri¯uoro-
methyl)copper. This short-lived intermediate may be
produced either from gaseous CF3I (using an autoclave)
and copper,19 or more conveniently from CF3COONa/CuI
by decarboxylation.10
Keywords: tri¯uoromethylnaphthoquinones;alkoxymethylnaphthoqui-
nones.
p
Corresponding author. Tel.: 132-9-264-59-51;fax: 132-9-264-62-43;
e-mail: norbert.dekimpe@rug.ac.be
The replacement of the bromine with the CF3 group in the
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00791-8

122
N. Van Tuyen et al. / Tetrahedron 58 (2002) 121±127
Scheme 1.
Scheme 2.
Scheme 3.

N. Van Tuyen et al. / Tetrahedron 58 (2002) 121±127
123
aromatic ring of compounds 5a±h is described in Scheme
2.10 Heating of 3-substituted-2-bromo-1,4-dimethoxy-
naphthalenes 5 with CF3COONa, CuI in DMF and toluene
(2:1) at 1708C for 12 h gave tri¯uoromethylnaphthalenes
6a±h in 74±96% yield. The structure of these compounds
was con®rmed mainly on the basis of their 13C NMR
spectra. In the 13C NMR spectra (CDCl3), the CF3-carbon
in all of the tri¯uoromethylated compounds appeared as a
quartet at about 124 ppm with a JC±F of about 274±278 Hz
and a JC±C±F of about 30 Hz for the a-carbon at position 3,
bearing the CF3 substituent.
the residue was poured into water. The hydroquinone pre-
cipitate was ®ltered and dissolved in acetone (150 mL). The
solution was dried (MgSO4), after which potassium
carbonate (44.4 g, 0.32 mol) and dimethyl sulfate (20.1 g,
0.16 mol) was added. Then the reaction mixture was
re¯uxed for 4 h, and afterwards ®ltered. The ®ltrate was
evaporated in vacuo, the residue was dissolved in ether
(200 mL) and aqueous 20% KOH (100 mL). The mixture
was stirred vigorously for 1 h, the organic layer was sepa-
rated and dried (MgSO4). The solvent was evaporated in
vacuo to give naphthalene 2 (5.0 g, 83% yield, white
solid) which was not puri®ed further (purity .96%) and
1
The oxidation of 2-alkoxymethyl-1,4-dimethoxy-3-(tri-
¯uoromethyl)naphthalenes 6 by treatment with 2 equiv. of
cerium(IV) ammonium nitrate (CAN) in acetonitrile and
water at room temperature for 30 min afforded the
corresponding 2-allyloxy-, 2-(4-¯uorophenyl)ethoxy- and
2-benzyloxy-3-tri¯uoromethyl-1,4-naphthoquinones 7a±h.
Although the electron-withdrawing property of the CF3
group in compounds 6a±h was very strong, the dealkylative
oxidation reaction proceeded smoothly with CAN transfer-
ing two electrons of the substrates to Ce41 to give products
7a±h in excellent yield (79±93%). In the 13C NMR spectra
(CDCl3) of the tri¯uoromethylated compounds 7, the CF3
carbon also appeared as a quartet at about 121±127 ppm
with JC±F of about 274±278 Hz. However, in the case of
compound 6d, containing the electron-donating para-
methoxy substituent, an easy transfer of electrons from the
benzyl group to Ce41 occurred, resulting in the formation of
the intermediate 8. This intermediate 8 underwent attack of
water to give hemi-acetal 9, which was then decomposed to
give 2-hydroxymethyl-3-tri¯uoromethyl-1,4-naphthoqui-
none 7d and 4-methoxybenzaldehyde 10. The mechanism
of the reaction is outlined in Scheme 3.
was used as such for the next step. H NMR (CDCl3) d:
8.02±8.11 (2H, m, H-5, H-8), 7.37±7.52 (2H, m, H-6, H-7),
6.57 (1H, s, H-3), 3.93 (3H, s, OMe), 3.84 (3H, s, OMe),
2.43 (3H, s, Me). 13C NMR (CDCl3) d: 151.5 (C-1), 147.0
(C-4), 128.7 (Cquat), 125.6 (Cquat), 125.2 (Cquat), 126.4
and 124.5 (C-6 and C-7), 122.2 and 121.5 (C-5 and C-8),
106.8 (C-3), 61.1 (OMe), 55.5 (OMe), 16.2 (CH3). IR
(NaCl): 1595, 1460, 1355, 1265, 1220, 1120, 955,
770 cm21;MS, m/z (%): 202 (M1, 56), 187 (100), 159 (82).
3.1.2.
2-Bromo-3-(2-bromomethyl)-1,4-dimethoxy-
naphthalene 3. To a solution of 1,4-dimethoxy-2-methyl-
naphthalene 2 (13 g, 0.064 mol) in CCl4 (200 mL) was
added N-bromosuccinimide (NBS) (11.45 g, 0.064 mol).
The reaction mixture was re¯uxed for 2 h, then it was cooled
to 08C. To this mixture was added NBS (11.45 g, 0.064 mol)
and benzoyl peroxide (1.41 g, 0.006 mol) and the reaction
mixture was re¯uxed for 2 h. After cooling of the reaction
mixture to room temperature, succinimide was ®ltered off.
The ®ltrate was washed with aqueous Na2S2O5, 2 M NaOH,
after which the ®ltrate was dried (MgSO4). The solvent was
evaporated in vacuo to give crude product (20.0 g), which
was crystallized from methanol to give 3 (16.0 g, 80%
1
In conclusion, the introduction of the CF3 group into
functionalized naphthoquinones was performed by reaction
of bromonaphthalenes with CF3COONa/CuI through
decarboxylation to 2-substituted-3-tri¯uoromethyl-1,4-
dimethoxynaphthalenes 5a±h. The latter were conveniently
demethylated by oxidation with CAN to give 2-substituted-
3-tri¯uoromethyl-1,4-naphthoquinones 7a±h in excellent
isolated yields.
yield), white powder, mp 83±858C (lit.17 mp 888C). H
NMR (CDCl3) d: 8.05±8.11 (2H, m, H-5, H-8), 7.52±7.59
(2H, m, H-6, H-7), 4.92 (2H, s, CH2±Br), 4.07 (3H, s, OMe),
3.98 (3H, s, OMe). 13C NMR (CDCl3) d: 152.2 (C-1), 150.6
(C-4), 130.1 (Cquat), 129.3 (Cquat), 128.5 (Cquat), 127.8
(C-7), 127.7 (Cquat), 127.0 (C-6), 123.1 (C-5), 122.7 (C-8),
62.8 (OMe), 61.4 (OMe), 28.9 (CH2±Br). IR (KBr): 1565,
1451, 1349, 1261, 1079, 1004, 957, 714 cm21;MS, m/z (%):
362/360/358 (M1, 16), 281/279 (44), 279 (38), 200 (46),
185 (59), 174 (100), 159 (82).
3. Experimental
3.1. General
3.1.3. 2-(4-Benzyloxymethyl)-3-bromo-1,4-dimethoxy-
naphthalene 5a. The preparation of compound 5a is repre-
sentative of all other analogous compounds. A solution of
benzyl alcohol 4a (180 mg, 1.16 mmol) in dry THF (10 mL)
was added to a stirred suspension of NaH (166 mg,
4.15 mmol, 60% dispersion in mineral oil, oil included in
the mixture) at room temperature and this mixture was stir-
red for 45 min.18 Then 2-bromo-3-(2-bromomethyl)-1,4-
naphthalene 3 (300 mg, 0.83 mmol) was added. The reac-
tion mixture was kept at 458C for 2 h. Then, the reaction
mixture was treated with water and extracted with CH2Cl2
(three times). The combined extracts were washed with
water and dried (MgSO4). The solvent was evaporated in
vacuo to give the crude product (350 mg), which was puri-
®ed by ¯ash chromatography on a SiO2 column (hexane/
ethyl acetate 9:1) to give pure product 5a (330 mg, 93%
yield), white powder, mp 72±738C (hexane/ethyl acetate
Melting points were determined on a BuÈchi 535 apparatus.
1H NMR spectra (270 MHz) and 13C NMR spectra
(67 MHz) were recorded with a Jeol JNM-EX 270 NMR
spectrometer. IR spectra were measured with a Perkin
Elmer Model 983 spectrophotometer. Mass spectra were
recorded with a Varian-MAT 112 mass spectrometer
(70 eV).
3.1.1. 1,4-Dimethoxy-2-methylnaphthalene 2.16 To a solu-
tion of 2-methylnaphthoquinone 1 (5.16 g, 0.03 mol) in
absolute ethanol (100 mL) was added dropwise over a
period of 30 min, a solution of tin(II) chloride (19.95 g,
0.1 mol) in 12 M HCl (20 mL). The reaction mixture was
stirred for 30 min, then ethanol was evaporated in vacuo and

124
N. Van Tuyen et al. / Tetrahedron 58 (2002) 121±127
1
9:1). H NMR (CDCl3) d: 7.93±7.91 (2H, m, H-5, H-8),
7.30±7.39 (2H, m, H-6, H-7), 7.22±7.28 (2H, m, H-20,
H-60), 7.12±7.19 (3H, m, H-30, H-40 and H-50), 4.72 (2H,
s, OCH2), 4.55 (2H, s, OCH2±C6H5), 3.82 (3H, s, OMe),
3.80 (3H, s, OMe). 13C NMR (CDCl3) d: 152.6 (C-1), 150.0
(C-4), 138.0 (Cquat), 129.1 (Cquat), 128.3 (Cquat), 128.1
(C-50, C-30), 128.0 (C-60, C-20), 127.7 (Cquat), 127.5 (C-6),
127.2 (C-7), 126.5 (C-40), 122.9 (C-8), 122.3 (C-5), 116.4
(Cquat), 73.0 (OCH2±C6H5), 66.6 (OCH2), 63.7 (OMe),
(11), 121 (40), 99 (36), 57 (42);Anal. C 21H21BrO4: calcd C
60.44%, H 5.07%;Found: C 60.28%, H 5.13%.
3.1.7. 3-Bromo-2-(4-¯uorophenylethoxymethyl)-1,4-di-
methoxynaphthalene 5e. Yield: 90%, white powder, mp
1
62±638C (hexane). H NMR (CDCl3) d: 8.11±8.19 (2H,
m, H-5, H-8), 7.60±7.65 (2H, m, H-6, H-7), 7.16±7.25
(2H, m, H-20 and H-60), 6.91±6.97 (2H, m, H-30 and
H-50), 4.79 (2H, s, OCH2), 4.00 (3H, s, OMe), 3.89 (3H, s,
OMe), 3.77 (2H, m, OCH2CH2), 2.90 (2H, m, OCH2CH2).
13C NMR (CDCl3) d: 161.0 (d, Jˆ245 Hz, CF), 153.2 (C-1),
153.1 (C-4), 152.8 (Cquat), 134.7. (Cquat), 134.6 (Cquat),
130.3 (C-30), 130.2 (C-50), 129.1 (Cquat), 128.5 and 127.5
(C-7, C-6), 124.4 (Cquat), 123.6 and 123.0 (C-5, C-8), 115.1
and 114.8 (C-20, C-60), 71.8 (CH2±CH2±O), 64.3 (OMe),
64.2 (OMe), 63.9 (OCH2), 35.4 (CH2±CH2±O). IR (KBr):
1584, 1513, 1455, 1366, 1220, 1164, 1094, 1009, 829,
759 cm21;MS, m/z (%): 420/418 (M1, 5), 411/409 (24),
403/401 (16), 381/379 (100), 356/358 (64), 341/343 (30),
313 (19), 281 (19), 200 (29), 185 (15), 170 (23);Anal.
C21H20BrFO3: calcd C 62.16%, H 4.81%;Found: C
61.92%, H 4.55%.
61.1 (OMe). IR (KBr): 1578, 1454, 1359, 1005, 748 cm21
;
MS, m/z (%): 388/386 (M1, 43), 203 (38), 202 (67), 201
(100);Anal. C 20H19BrO3: calcd C 62.03%, H 4.95%;Found:
C 62.23%, H 5.06%.
3.1.4.
3-Bromo-2-(4-chlorobenzyloxymethyl)-1,4-di-
methoxynaphthalene 5b. Yield: 95%, white powder, mp
97±988C (hexane). 1H NMR (CDCl3) d: 8.08±8.12 (2H, m,
H-5, H-8), 7.54±7.57 (2H, m, H-6, H-7), 7.33 (4H, m, H-20,
H-60, H-30 and H-50), 4.85 (2H, s, OCH2), 4.65 (2H, s,
OCH2±C6H4), 3.98 (3H, s, OMe), 3.95 (3H, s, OMe). 13C
NMR (CDCl3) d: 152.7 (C-1), 150.2 (C-4), 136.7 (Cquat),
133.4 (Cquat), 129.4 (C-30, C-50), 129.2 (Cquat), 128.4
(C-20, C-60), 127.8 (Cquat), 127.4 (C-7), 126.7 (C-6),
126.3 (Cquat), 123.0 (C-8), 122.5 (C-5), 116.3 (Cquat),
72.1 (OCH2±C6H4), 66.7 (OCH2), 63.9 (OMe), 61.3
(OMe). IR (KBr): 1579, 1451, 1353, 1084, 1006,
754 cm21;MS, m/z (%): 424/422/420 (M1, 24), 201(81),
186 (16), 125 (46), 97 (29), 85 (56), 57 (100);Anal.
C20H18BrClO3: calcd C 56.96%, H 4.30%;Found: C
57.12%, H 4.41%.
3.1.8. 3-Bromo-2-(methylallyloxymethyl)-1,4-dimethoxy-
naphthalene 5f. Yield: 95%, colorless oil. 1H NMR
(CDCl3) d: 8.06±8.12 (2H, m, H-5, H-8), 7.49±7.55 (2H,
m, H-6, H-7), 5.07 (1H, broad s, CvCH2), 4.94 (1H, broad
s, CvCH2), 4.79 (2H, s, OCH2), 4.07 (2H, s, OCH2±C3H5),
3.98 (3H, s, OMe), 3.96 (3H, s, OMe), 1.82 (3H, s, Me). 13C
NMR (CDCl3) d: 152.8 (C-1), 150.2 (C-4), 142.3 (CvCH2),
129.2 (Cquat), 127.9 (Cquat), 127.3 (C-7), 126.8 (Cquat),
126.7 (C-6), 123.0 (C-8), 122.5 (C-5), 116.5 (Cquat), 112.9
(CvCH2), 75.2 (OCH2±C3H5), 66.6 (OCH2), 64.0 (OMe),
61.3 (OMe), 19.78 (Me). IR (NaCl): 1568, 1449, 1356,
1260, 1085, 1030, 1007, 966, 759, 748 cm21;MS, m/z
(%): 352/350 (M1, 17), 265 (12), 251 (10), 201 (30), 201
(54), 141 (30), 77 (49), 71 (48), 57 (100);Anal. C 17H19BrO3:
calcd C 58.13%, H 5.47%;Found: C 57.99%, H 5.39%.
3.1.5. 3-Bromo-2-(4-methylbenzyloxymethyl)-1,4-di-
methoxynaphthalene 5c. Yield: 92%, white powder, mp
1
67±698C (hexane). H NMR (CDCl3) d: 8.06±8.10 (2H,
m, H-5, H-8), 7.51±7.54 (2H, m, H-6, H-7), 7.32 (2H, d,
Jˆ8.1 Hz, H-20 and H-60), 7.14 (2H, d, Jˆ8.1 Hz, H-30,
H-50), 4.83 (2H, s, OCH2), 4.65 (2H, s, OCH2±C6H4),
3.96 (3H, s, OMe), 3.94 (3H, s, OMe), 2.33 (3H, s, Me).
13C NMR (CDCl3) d: 152.7 (C-1), 150.2 (C-4), 137.4
(Cquat), 135.1 (Cquat), 129.2 (Cquat), 129.0 (C-30, C-50),
128.3 (C-20, C-60), 127.9 (Cquat), 127.3 (C-7), 126.8
(Cquat), 126.6 (C-6), 123.0 (C-8), 122.5 (C-5), 116.5
(Cquat), 73.0 (OCH2±C6H4), 66.6 (OCH2), 63.9 (OMe),
61.3(OMe), 21.2 (Me). IR (KBr): 1574, 1441, 1407, 1360,
1075, 1006, 810, 753 cm21;MS, m/z (%): 402/400 (M1,
21), 252 (12), 202 (16), 201 (100);Anal. C 21H21BrO3:
calcd C 62.85%, H 5.27%;Found: C 62.95%, H 5.15%.
3.1.9.
2-(Allyloxymethyl)-3-bromo-1,4-dimethoxy-
naphthalene 5h. Yield: 95%, colorless oil. 1H NMR
(CDCl3) d: 8.07±8.13 (2H, m, H-5, H-8), 7.52±7.57 (2H,
m, H-6, H-7), 6.03 (1H, m, CHvCH2), 5.20±5.41 (2H, m,
CvCH2), 4.83 (2H, s, CH2±O), 4.18 (2H, dt, Jˆ5.9, 1.3 Hz,
OCH2±C3H5), 3.99 (3H, s, OMe), 3.97 (3H, s, OMe). 13C
NMR (CDCl3) d: 152.8 (C-1), 150.2 (C-4), 134.8
(CHvCH2), 129.2 (Cquat), 127.9 (Cquat), 127.3 (C-7),
126.7 (C-6), 123.0 (C-8), 122.5 (C-5), 117.5 (CvCH2),
116.5 (Cquat), 72.0 (OCH2±CHvCH2), 66.6 (OCH2),
64.0 (OMe), 61.3 (OMe);one quaternary carbon was not
visible due to overlap. IR (NaCl): 1570 (CHvCH2), 1455,
3.1.6. 3-Bromo-2-(4-methoxybenzyloxymethyl)-1,4-di-
methoxynaphthalene 5d. Yield: 91%, white powder, mp
70±728C (hexane). 1H NMR (CDCl3) d: 8.07±8.10 (2H, m,
H-5, H-8), 7.52±7.55 (2H, m, H-6, H-7), 7.35 (2H, d,
Jˆ8.6 Hz, H-20 and H-60), 6.88 (2H, d, Jˆ8.6 Hz, H-30,
H-50), 4.82 (2H, s, OCH2), 4.63 (2H, s, OCH2±C6H4),
3.97 (3H, s, OMe), 3.94 (3H, s, OMe), 3.79 (3H, s, C6H4±
1400, 1360 1260, 1085, 1030, 1007, 966, 775, 760 cm21
;
MS, m/z (%): 336/338 (M1, 26), 201 (100), 185 (40), 141
(30), 77 (49);Anal. C 16H17BrO3: calcd C 56.99%, H 5.08%;
Found: C 56.82%, H 5.06%.
13
OMe). C NMR (CDCl3) d: 159.3 (C-40), 152.7 (C-1),
150.2 (C-4), 132.0 (Cquat), 130.4 (Cquat), 129.8 (C-30,
C-50), 129.2 (Cquat), 127.9 (Cquat), 127.3 (C-7), 126.7
(C-6), 123.0 (C-8), 122.5 (C-5), 116.5 (Cquat), 113.8
(C-20, C-60), 72.8 (OCH2±C6H4), 66.5 (OCH), 63.9
(OMe), 61.5 (OMe), 55.3 (C6H4±OMe). IR (KBr): 1613,
1518, 1453, 1358, 1259, 1083, 810, 750 cm21;MS, m/z
(%): 418/416 (M1, 25), 252 (10), 202 (16), 201 (100), 149
3.1.10.
2-(Benzyloxymethyl)-3-tri¯uoromethyl-1,4-di-
methoxynaphthalene 6a. The synthesis of compound 6a
is representative of all other preparation of compounds 6.
A mixture of 2-(benzyloxymethyl)-3-bromo-1,4-dimethoxy-
naphthalene 5a (1.0 g, 2.584 mmol), CF3COONa (701 mg,
5.16 mmol) and CuI (975 mg, 5.16 mmol) was dissolved in
a mixture of DMF (10 mL) and toluene (5 mL).10 The

N. Van Tuyen et al. / Tetrahedron 58 (2002) 121±127
125
reaction mixture was heated at 1708C for 12 h under N2.
Then the mixture was dissolved in CH2Cl2 (100 mL), after
which it was ®ltered. The ®ltrate was washed with HCl
(12 M) and NaHCO3 (5%) and dried (MgSO4). The solvent
was evaporated in vacuo to give the crude product, which
was puri®ed by ¯ash chromatography on a SiO2 column
with hexane/ethyl acetate (9:1) to give product 6a
1H NMR (CDCl3) d: 8.11±8.18 (2H, m, H-5, H-8), 7.53±
7.64 (2H, m, H-6, H-7), 7.32 (2H, dd, J1ˆ8.9 Hz,
J2ˆ2.0 Hz, H-20, H-60), 6.87 (2H, dd, J1ˆ8.9 Hz,
J2ˆ2.0 Hz, H-30, H-50), 4.82 (2H, d, Jˆ1.6 Hz, OCH2),
4.58 (2H, s, OCH2±C6H4), 3.99 (3H, s, OMe), 3.94 (3H, s,
OMe), 3.79 (3H, s, OMe). 13C NMR (CDCl3) d: 159.3
(C-40), 153.9 (C-1), 152.5 (C-4), 132.0 (Cquat), 130.4
(Cquat), 130.3 (Cquat), 129.7 (C-30, C-50), 128.5 (C-7),
127.4 (C-6), 123.7 (C-8), 123.1 (q, Jˆ278 Hz, CF3), 123.0
(C-5), 122.9 (q, Jˆ29.3 Hz, C±CF3), 113.8 (C-20, C-60),
73.0 (OCH2±C6H4), 64.0 (OCH2), 63.8 (OMe), 63.7
(OMe), 55.3 (OMe). IR (NaCl): 1609, 1583, 1509, 1441,
1358, 1294, 1160, 1019 cm21;MS, m/z (%): 406 (M1,
15), 270 (37), 255 (39), 256 (16), 240 (27), 122 (21), 121
(100);Anal. C 22H21F3O4: calcd C 65.02%, H 5.21%;Found:
C 65.23%, H 5.09%.
1
(760 mg, 84% yield), colorless oil. H NMR (CDCl3) d:
8.06±8.18 (2H, m, H-5, H-8), 7.57±7.63 (2H, m, H-6,
H-7), 7.28±7.50 (5H, m, H-20, H-30, H-40, H-50 and H-60),
4.84 (2H, s, OCH2), 4.65 (2H, s, OCH2±C6H5), 3.98 (3H, s,
OMe), 3.94 (3H, s, OMe). 13C NMR (CDCl3) d: 153.1
(C-1), 152.5 (C-4), 138.5 (Cquat), 137.9 (Cquat), 130.4
(Cquat), 129.7 (Cquat), 128.55 and 128.46 (C-6 and C-7),
128.3 and 128.2 (C-20, C-60 and C-30, C-50), 127.7 (C-40),
124.2 (q, Jˆ276 Hz, CF3), 123.7 (C-8), 123.1 (C-5), 122.5
(q, Jˆ29.4 Hz, C±CF3), 73.4 (OCH2±C6H5), 66.9 (OCH2),
64.0 (OMe), 63.8 (OMe). IR (NaCl): 1618, 1590, 1450,
1358, 1293, 1160, 1117, 966, 775 cm21;MS, m/z (%):
376 (M1, 5), 271 (10), 270 (71), 256 (23), 255 (93), 241
(17), 227 (12), 159 (22), 92 (20), 91 (96), 71 (58), 57 (100);
Anal. C21H19F3O3: calcd C 67.20%, H 5.09%;Found: C
67.20%, H 5.18%.
3.1.14. 2-(4-Fluorophenylethoxymethyl)-3-tri¯uoro-
methyl-1,4-dimethoxynaphthalene 6e. Yield: 85%, white
1
powder, mp 110±1118C (hexane). H NMR (CDCl3) d:
8.11±8.19 (2H, m, H-5, H-8), 7.59±7.65 (2H, m, H-6,
H-7), 7.15±7.25 (2H, m, C-20 and H-60), 6.90±6.97 (2H,
m, C-30 and H-50), 4.79 (2H, s, OCH2), 3.99 (3H, s,
OMe), 3.88 (3H, s, OMe), 3.77 (2H, m, OCH2CH2), 2.92
(2H, m, OCH2CH2). 13C NMR (CDCl3) d: 161.5 (d,
Jˆ247 Hz, CF), 153.9 (C-1), 152.8 (C-4), 134.7 (Cquat),
134.6 (Cquat), 130.3 (C-30), 130.2 (C-50), 129.2 (Cquat),
128.6 (C-7), 127.5 (C-6), 124.1 (Cquat), 124.0 (q,
Jˆ278 Hz, CF3), 123.7 (C-8), 123.0 (C-5), 118.5 (q,
Jˆ29.6 Hz, C±CF3), 115.1 (C-20), 114.8 (C-60), 71.8
(OCH2CH2±C6H4), 64.3 (OMe), 64.0 (OMe) 63.8 (OCH2),
35.8 (OCH2CH2C6H4). IR (KBr): 1586, 1504, 1423, 1365,
1296, 1221, 1143, 1097, 1003 cm21;MS, m/z (%): no M1,
379 (62), 268 (18), 267 (100), 239 (10), 200 (70), 185 (12),
200 (70), 186 (12), 123 (19);Anal. C 22H20F4O3: calcd C
64.70%, H 4.94%;Found: C 64.55%, H 4.68%.
3.1.11. 2-(4-Chlorobenzyloxymethyl)-3-tri¯uoromethyl-
1,4-dimethoxynaphthalene 6b. Yield: 89%, white powder,
mp 67±688C (hexane). 1H NMR (CDCl3) d: 8.11±8.18 (2H,
m, H-5, H-8), 7.58±7.64 (2H, m, H-6, H-7), 7.30 (4H, m,
H-30, H-20, H-60 and H-50), 4.84 (2H, s, OCH2), 4.59 (2H, s,
OCH2±C6H4), 3.98 (3H, s, OMe), 3.94 (3H, s, OMe). 13C
NMR (CDCl3) d: 153.2 (C-1), 152.9 (C-4), 136.6 (Cquat),
133.4 (Cquat), 130.3 (Cquat), 129.4 (C-30, C-50), 129.2
(Cquat), 128.6 (C-7), 128.4 (C-20, C-60), 127.5 (C-6),
123.8 (Cquat), 124.5 (q, Jˆ278 Hz, CF3), 123.7 (C-8),
123.0 (C-5), 118.8 (q, Jˆ29.8 Hz, C±CF3), 72.4 (OCH2±
C6H4), 64.0 (OCH2), 63.9 (OMe), 63.7 (OMe). IR (KBr):
1617, 1422, 1362, 1293, 1164, 1012 cm21;MS, m/z (%):
410 (M1, 41), 270 (49), 269 (13), 256 (16), 255 (87), 240
(50), 239 (18), 201 (27), 200 (34), 127 (46), 125 (100);Anal.
C21H18ClF3O3: calcd C 61.40%, H 4.42%;Found: C
61.59%, H 4.49%.
3.1.15. 2-(2-Methylallyloxymethyl)-3-tri¯uoromethyl-
1,4-dimethoxynaphthalene 6f. Yield: 96%, colorless oil.
1H NMR (CDCl3) d: 8.09±8.16 (2H, m, H-5, H-8), 7.53±
7.58 (2H, m, H-6, H-7), 5.03 (1H, s, CvCH2), 4.90 (1H, s,
CvCH2), 4.76 (2H, s, OCH2), 4.02 (2H, s, OCH2±C3H5),
3.96 (6H, s, OMe), 1.79 (3H, s, Me). 13C NMR (CDCl3) d:
153.1 (C-1), 152.9 (C-4), 142.1 (CvCH2), 130.3 (Cquat),
128.8 (Cquat), 128.4 (C-7), 128.0 (Cquat), 127.3 (C-6),
123.5 (C-8), 122.9 (C-5), 122.4 (q, Jˆ278 Hz, CF3), 119.2
(q, Jˆ29.2 Hz, C±CF3), 112.6 (CvCH2), 75.3 (OCH2±
C3H5), 63.7 (OCH2), 63.6 (2±OMe), 19.5 (Me). IR
(NaCl): 1617, 1588, 1451, 1417, 1358, 1294, 1117, 966,
777 cm21;MS, m/z (%): 340 (M1, 45), 284 (10), 270
(43), 269 (28), 202 (41), 200 (47), 196 (23), 136 (23), 134
(20), 99 (40), 91 (96), 77 (48), 57 (100);Anal. C 18H19F3O3:
calcd C 63.52%, H 5.63%;Found: C 63.46%, H 5.68%.
3.1.12. 2-(4-Methylbenzyloxymethyl)-3-tri¯uoromethyl-
1,4-dimethoxynaphthalene 6c. Yield: 74%, white powder,
mp 63±648C (hexane). 1H NMR (CDCl3) d: 8.11±8.18 (2H,
m, H-5, H-8), 7.58±7.63 (2H, m, H-6, H-7), 7.24 (2H, d,
Jˆ11.9 Hz, H-20 and H-60), 7.15 (2H, d, Jˆ11.9 Hz, H-30,
H-50), 4.82 (2H, s, OCH2), 4.61 (2H, s, OCH2±C6H4), 3.98
(3H, s, OMe), 3.94 (3H, s, OMe), 2.33 (3H, s, Me). 13C
NMR (CDCl3) d: 153.2 (C-1), 152.9 (C-4), 137.3 (Cquat),
135.0 (Cquat), 130.4 (Cquat), 129.2 (Cquat), 129.0 (C-30,
C-50), 128.5 (C-7), 128.3 (C-20, C-60), 128.0 (Cquat), 127.4
(C-6), 125.5 (q, Jˆ277 Hz, CF3), 123.7 (C-8), 123.0 (C-5),
120.9 (q, Jˆ29.4 Hz, C±CF3), 73.3 (OCH2±C6H4), 64.0
(OCH2), 63.8 (2£OMe), 21.2 (Me). IR (KBr): 1617, 1457,
1420, 1360, 1295, 1163, 1118, 1015, 781 cm21;MS, m/z
(%): 390 (M1, 38), 255 (59), 240 (25), 202 (24), 200 (19),
156 (8), 135 (10), 91 (28), 85 (24), 77 (25), 71 (39), 57
(100);Anal. C 22H21F3O3: calcd C 67.68%, H 5.42%;
Found: C 67.48%, H 5.62%.
3.1.16.
2-(Allyloxymethyl)-3-tri¯uoromethyl-1,4-di-
methoxynaphthalene 6h. Yield: 96%, colorless oil. 1H
NMR (CDCl3) d: 8.13±8.20 (2H, m, H-5, H-8), 7.57±7.67
(2H, m, H-6, H-7), 5.93±5.99 (1H, m, CHvCH2), 5.33 (1H,
dd, J1ˆ17 Hz, J2ˆ4.6 Hz, CHvCHa), 5.20 (1H, dd,
J1ˆ9.6 Hz, J2ˆ4.6 Hz, CHvCHb), 4.80 (2H, d, Jˆ1.6 Hz,
OCH2), 4.13 (2H, dt, J1ˆ6.9 Hz, J2ˆ2.3 Hz, OCH2), 4.00
(3H, s, OMe), 3.99 (OMe). 13C NMR (CDCl3) d: 153.1
(C-1), 153.0 (C-4), 134.8 (CHvCH2), 130.4 (Cquat),
3.1.13. 2-(4-Methoxybenzyloxymethyl)-3-tri¯uoromethyl-
1,4-dimethoxynaphthalene 6d. Yield: 78%, colorless oil.

126
N. Van Tuyen et al. / Tetrahedron 58 (2002) 121±127
129.3 (Cquat), 128.6 (C-7), 127.5 (C-6), 124.2 (Cquat),
123.7 (C-8), 123.0 (C-5), 124.5 (q, Jˆ279 Hz, CF3), 119.1
(q, Jˆ36 Hz, C±CF3), 117.4 (CHvCH2), 72.1
(OCH2CHvCH2), 64.0 (OCH2), 63.9 (OMe), 63.7 (OMe).
IR (NaCl): 1617, 1584, 1496, 1451, 1416, 1358, 1158, 1118,
967 cm21;MS, m/z (%): 326 (M1, 100), 270 (37), 269 (32),
266 (23), 255 (80), 240 (30), 200 (70), 127 (22), 113 (21), 71
(59);Anal. C 17H17F3O3: calcd C 62.57%, H 5.25%;Found:
C 62.46%, H 5.20%.
(C-1), 180.3 (C-4), 145.8 (Cquat), 137.7 (Cquat), 134.6 (C-
7), 134.3 (C-6), 131.5 (Cquat), 131.0 (Cquat), 129.1 (q,
Jˆ31 Hz, C±CF3), 129.0 (C-30, C-50), 128.3 (C-20, C-60),
128.1 (Cquat), 126.7 (C-8), 126.5 (C-5), 124.6 (d,
Jˆ279 Hz, CF3), 74.0 (OCH2±C6H4), 61.3 (OCH2), 21.0
(3H, s, Me). IR (KBr): 1673 (CvO), 1669 (CvO), 1593,
1350, 1288, 1213, 1141, 801, 728 cm21;MS, m/z (%): no
M1 341 [(M2F)1, 1], 203 (34), 202 (63), 156 (29), 121
(26), 105 (20), 91 (84), 44 (100);Anal. C 20H15F3O3: calcd
C 66.67%, H 4.20%;Found: C 66.55%, H 4.38%.
3.1.17. 2-(Benzyloxymethyl)-3-tri¯uoromethyl-1,4-naph-
phthoquinone 7a. The synthesis of compound 7a is repre-
sentative of all other preparation of compounds 7. To a
solution of 2-(4-benzyloxymethyl)-3-tri¯uoromethyl-1,4-
dimethoxynaphthalene 6a (635 mg, 1.69 mmol) in a
mixture of water (10 mL) and acetonitrile (10 mL) was
added cerium ammonium nitrate (2.8 g, 5 mmol). The reac-
tion was stirred for 15 min at room temperature, then it was
treated with water and extracted with ether. The combined
extracts were washed with water, brine, dried (MgSO4). The
solvent was evaporated in vacuo to give the crude product,
which was puri®ed by ¯ash chromatography on a SiO2
column with hexane/ethyl acetate (9:1) to give compound
3.1.20. 2-(1-Hydroxymethyl)-3-tri¯uoromethyl-1,4-
naphthoquinone 7d. Yield: 79%, yellow powder, mp 91±
1
938C. H NMR (CDCl3) d: 8.06±8.14 (2H, m, H-5, H-8),
7.71±7.84 (2H, m, H-6, H-7), 4.86 (2H, s broad, CH2OH).
13C NMR (CDCl3) d: 183.6 (C-1), 180.4 (C-4), 147.4
(Cquat), 135.1 (C-7), 134.5 (C-6), 134.4 (q, Jˆ5 Hz, C-2),
127.5 (q, Jˆ30 Hz, C±CF3), 127.1 (Cquat), 126.8 (C-5),
126.7 (C-8), 123.9 (q, Jˆ280 Hz, CF3), 61.8 (CH2OH). IR
(KBr): 3500 (OH), 1675 (CvO), 1667 (CvO), 1588, 1458,
1281, 1186, 1142 cm21;MS, m/z (%): 256 (M1, 6), 236
(36), 216 (18), 202 (14), 151 (11), 149 (26), 141 (11), 84
(64), 57 (100);Anal. C 12H7F3O3: calcd C 56.26%, H 2.75%;
Found: C 56.15%, H 2.68%.
1
7a (490 mg, 84% yield), yellow oil. H NMR (CDCl3) d:
8.05±8.09 (2H, m, H-5, H-8), 7.74±7.77 (2H, m, H-6, H-7),
7.22±7.35 (5H, m, H-20, H-60, H-30, H-40 and H-50), 4.71
(2H, s, OCH2), 4.70 (2H, s, OCH2±C6H5). 13C NMR
(CDCl3) d: 183.1 (C-1), 180.4 (C-4), 137.4 (Cquat), 134.7
(C-7), 134.4 (C-6), 131.2 (q, Jˆ31.2 Hz, C±CF3), 131.1
(Cquat), 128.5 (Cquat), 128.4 (C-30, C-50), 128.1 (C-20,
C-60), 128.0 (C-40), 127.4 (q, Jˆ278 Hz, CF3), 126.8 (C-
8), 126.6 (C-5), 126.2 (C quat), 74.2 (OCH2±C6H5), 61.4
(OCH2). IR (NaBr): 1672 (CvO), 1624 CvO), 1591, 1340,
1283, 1179, 1146, 1075, 727 cm21;MS, m/z (%): 346 (M1,
5), 271 (10), 270 (71), 256 (23), 255 (93), 241 (17), 227
(12), 159 (22), 92 (20), 91 (96), 71 (58), 57 (100);Anal.
C19H13F3O3: calcd C 65.90%, H 3.78%;Found: C 65.98%,
H 3.68%.
3.1.21.
2-(4-Fluorophenylethoxymethyl)-3-tri¯uoro-
methyl-1,4-naphthoquinone 7e. Yield: 84%, yellow oil.
1H NMR (CDCl3) d: 8.07±8.15 (2H, m, H-5, H-8), 7.72±
7.77 (2H, m, H-6, H-7), 7.12±7.17 (2H, m, H-60, H-20),
6.85±6.91 (2H, m, H-30 and H-50), 4.68 (2H, s, OCH2),
3.75 (2H, m, OCH2CH2±C6H4), 2.84 (2H, m, OCH2CH2±
C6H4). 13C NMR (CDCl3) d: 183.1 (C-1), 180.5 (C-4), 161
(d, Jˆ244 Hz, CF), 145.0 (Cquat), 135.0 (Cquat), 134.7
(C-7), 134.4 (C-6), 134.2 (Cquat), 134.1 (Cquat), 130.3
(C-5), 130.2 (C-8) 128.9 (q, Jˆ29.6 Hz, C±CF3), 127.5
(q, Jˆ279 Hz, CF3), 126.8 (C-30), 126.6 (C-50), 115.4
(C-20), 114.8 (C-60), 72.6 (OCH2CH2), 61.8 (OCH2), 35.3
(OCH2CH2). IR (NaCl): 1676 (CvO), 1594 (CvO), 1510,
1345, 1286, 1221, 1180, 1149, 1101 cm21;MS, m/z: 378
(M1, 3), 280 (8), 256 (32), 240 (12), 239 (61), 228 (10), 219
(13), 123 (66), 122 (100);Anal. C 20H14F4O3: calcd C
63.50%, H 3.73%;Found: C 63.69%, H 3.68%.
3.1.18. 2-(4-Chlorobenzyloxymethyl)-3-tri¯uoromethyl-
1,4-naphthoquinone 7b. Yield: 85%, yellow powder, mp
67±688C (hexane). 1H NMR (CDCl3) d: 8.08±8.13 (2H, m,
H-5, H-8), 7.77±7.86 (2H, m, H-6, H-7), 7.27 (4H, m, H-30,
H-40, H-60 and H-50), 4.72 (2H, s, OCH2), 4.59 (2H, s,
OCH2±C6H4). 13C NMR (CDCl3) d: 183.1 (C-1), 180.4
(C-4), 145.2 (Cquat), 135.9 (Cquat), 134.9(Cquat), 134.8
(C-7), 134.5 (C-6), 133.8 (Cquat), 130.1 (Cquat), 129.3
(C-30, C-50), 129.2 (q, Jˆ31.5 Hz, C±CF3), 128.6 (C-20,
C-60), 126.9 (C-8), 126.7 (C-5), 125.4 (d, Jˆ279 Hz,
CF3), 73.3 (OCH2±C6H4), 61.5 (OCH2). IR (KBr): 1673
(CvO), 1650 (CvO), 1591, 1284, 1181, 1150, 1087, 809,
725 cm21;MS, m/z (%): no M1, 256 (M2C7H5Cl1, 3), 255
(15), 194 (10), 192 (25), 174 (41), 105 (30), 91 (29), 86 (43),
49 (100);Anal. C 19H12ClF3O3: calcd C 59.94%, H 3.18%;
Found: C 59.65%, H 3.28%.
3.1.22. 2-(2-Methylallyloxymethyl)-3-tri¯uoromethyl-
1,4-naphthoquinone 7f. Yield: 93%, yellow oil. H NMR
1
(CDCl3) d: 8.05±8.09 (2H, m, H-5, H-8), 7.76±7.79 (2H, m,
H-6, H-7), 4.99 (1H, s, CvCH2), 4.92 (1H, s, CvCH2), 4.63
(2H, d, Jˆ1.6 Hz, OCH2), 4.00 (2H, s, OCH2±C3H5), 1.75
(3H, s, Me). 13C NMR (CDCl3) d: 183.0 (C-1), 180.3 (C-4),
145.3 (Cquat), 141.5 (CvCH2), 134.6 (C-7), 134.4 (q,
Jˆ29.4 Hz, C±CF3), 134.3 (C-6), 131.5 (Cquat), 130.9
(Cquat), 126.7 (C-8), 126.5 (C-5), 123.8 (q, Jˆ278 Hz,
CF3), 113.3 (CvCH2), 75.9 (OCH2±C3H5), 60.8 (OCH2),
19.2 (Me). IR (NaCl): 1673 (CvO), 1669 (CvO), 1592
(CvC), 1343, 1284, 1181, 1151 cm21;MS, m/z (%): 310
(M1, 2), 269 (10), 256 (13), 255 (65), 241 (34), 240 (100),
239 (23), 220 (47), 212 (50), 151 (67), 76 (44), 55 (87);
Anal. C16H13F3O3: calcd C 61.94%, H 4.22%;Found: C
61.75%, H 4.28%.
3.1.19. 2-(4-Methylbenzyloxymethyl)-3-tri¯uoromethyl-
1,4-naphthoquinone 7c. Yield: 84%, yellow powder, mp
68±698C (hexane/ethyl acetate 85:15). 1H NMR (CDCl3) d:
8.00±8.04 (2H, m, H-5, H-8), 7.70±7.73 (2H, m, H-6, H-7),
7.16 (2H, d, Jˆ8.1 Hz, H-20 and H-60), 7.03 (2H, d,
Jˆ8.1 Hz, H-30 and H-50), 4.66 (2H, s, CH2), 4.55 (2H, s,
OCH2±C6H4), 2.22 (3H, s, Me). 13C NMR (CDCl3) d: 183.0
3.1.23. 2-(2-Allyloxymethyl)-3-tri¯uoromethyl-1,4-naph-
thoquinone 7h. Yield: 93%, yellow oil. H NMR (CDCl3)
d: 8.10±8.17 (2H, m, H-5, H-8), 7.62±7.84 (2H, m, H-6,
1

N. Van Tuyen et al. / Tetrahedron 58 (2002) 121±127
127
6. Banks, R. E.;Smart, B. E.;Tatlow, J. C. Organo¯uorine
Chemistry, Principles and Commercial Application;Plenum:
New York, 1994.
H-7), 5.85±5.99 (1H, m, CHvCH2), 2.19±2.29 (2H, m,
CHvCH2), 4.68 (2H, d, Jˆ1.6 Hz, OCH2), 4.11 (2H, dt,
J1ˆ2.9 Hz, J2ˆ1.0 Hz, OCH2CHvCH2). 13C NMR
(CDCl3) d: 183.1 (C-1), 180.5 (C-4), 145.5 (Cquat), 134.8
(C-7), 134.5 (C-6), 134.1 (CHvCH2), 131.6 (Cquat), 131.0
(Cquat), 129.5 (q, Jˆ31 Hz, C±CF3), 126.8 (C-8), 126.6
(C-5), 119.9 (q, Jˆ278 Hz, CF3), 118.0 (CvCH2), 72.9
(OCH2CHvCH2), 61.0 (OCH2). IR (NaCl): 1674 (CvO),
7. Yoshika, H.;Nakayama, C.;Matsuo, N. J. Synth. Chem. Jpn
1984, 42, 809.
8. Reynolds, D. W.;Cassidi, P. E.;Johnson, C. G.;Gameron,
M. L. J. Org. Chem. 1990, 55, 4448±4454.
9. Zang, X.;Qing, F. L.;Yang, Y.;Yu, J.;Fu, X. K. Tetrahedron
Lett. 2000, 41, 2953±2955.
10. HuÈnig, S.;Bau, R.;Kemmer, M.;Meixner, H.;Metzenthin, T.;
Peters, K.;Sinzger, K.;Gulbis, J. Eur. J. Org. Chem. 1998,
335±348.
1669 (CvO), 1591 (CvC), 1341, 1284, 1181, 1151 cm21
;
MS, m/z (%): 296 (M1, 4), 292 (4), 256 (8), 255 (60), 240
(22), 221 (15), 207 (25), 151(45), 41 (100);Anal.
C15H11F3O3: calcd C 60.82%, H 3.74%;Found: C 60.61%,
H 3.88%.
11. Blazejewski, J. C.;Dorme, R.;Wakselman, C. J. Chem. Soc.,
Perkin Trans. 1 1997, 1861±1864.
12. Blazejewski, J. C.;Dorme, R.;Wakselman, C. Synthesis 1985,
1120±1121.
Acknowledgements
13. Peter, E.;Cooper, D.;Allen, G.;Slater, M. J.
Chem. 1999, 9, 2863±2866.
Bioorg. Med.
The authors are indebted to the Janssen Research
Foundation for ®nancial support.
14. Lien, J. C.;Huang, L. J.;Wang, J. P.;Teng, C. M.;Lee, K. H.;
Kuo, S. C. Bioorg. Med. Chem. 1997, 12, 2111±2120.
15. Huang, L. J.;Chang, F. C.;Lee, K. H.;Wang, J. P.;Teng,
C. M.;Kuo, S. C. Bioorg. Med. Chem. 1998, 6, 2261±2269.
16. Ansbacher, S.;Fernholz, E.;Dolliver, M. A. J. Am. Chem. Soc.
1940, 62, 155±158.
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