Synthesis of 4-arylsulfonylquinolines by double condensation of allyl aryl sulfones with nitroarenes

Article abstract of DOI:10.1002/(SICI)1099-0690(200002)2000:3<521::AID-EJOC521>3.0.CO;2-A

Allyl aryl sulfones 2 react with aryl nitrocompounds 1 in a DBU/MgCl2 system giving the 4-arylsulfonyl quinolines 3. Some mechanistic aspects of the reaction are discussed. Application of this reaction to the formal total synthesis of the natural product (-)-Eupolauramine is described.

Full text of DOI:10.1002/(SICI)1099-0690(200002)2000:3<521::AID-EJOC521>3.0.CO;2-A

FULL PAPER
Synthesis of 4-Arylsulfonylquinolines by Double Condensation of Allyl Aryl
Sulfones with Nitroarenes
[a]
´
Zbigniew Wrobel*
Keywords: Allyl aryl sulfones / Nitroarenes / Condensation reaction / Lewis acids
Allyl aryl sulfones 2 react with aryl nitrocompounds 1 in a
DBU/MgCl2 system giving the 4-arylsulfonyl quinolines 3.
Some mechanistic aspects of the reaction are discussed.
Application of this reaction to the formal total synthesis of
the natural product (Ϫ)-Eupolauramine is described.
dergoes an intramolecular cyclization and aromatization to
give the product 3. This procedure, which was successful for
cinnamyl sulfones (2, R5 ϭ Ar), gave only very poor results
in the case of allyl sulfones (2, R5 ϭ H, alkyl). Further
investigations revealed that 1-nitronaphthalene (1a) reacts
with allyl 4-tolyl sulfone (2a) in the presence of 10 equiv. of
MgCl2 and 5 equiv. of DBU in HMPA to give 4-tolylsulfon-
ylbenzo[h]quinoline (3a) in 48% yield. The reaction is less
effective in other solvents such as N-methylpyrrolidone,
DMF, DMSO, pyridine or acetonitrile. It was also disco-
vered that the amount of MgCl2 can be reduced to 0.625
equiv. Addition of 1.25Ϫ5.0 equiv. of bis(trimethylsilyl)-
acetamide (BIMSA) slightly increased the product yield to
between 55 and 58%. The reaction did not proceed in the
absence of MgCl2. Other salts, such as LiCl, ZnCl2, CuCl
and CaCl2, were found to be ineffective. Of the Lewis acids
tested as catalysts only Ti(iOPr)4 exhibits similar activity to
MgCl2. Its role has however not been explained until now.
There is a probability that chelation of the nitro group oxy-
gens with MgCl2 facilitates both formation of the σH ad-
duct 4 and its further conversion into the nitroso intermedi-
ate 5. This supposition was strongly supported in the reac-
tion of 1a with methyl phenyl acetate (7), where the nitroso
derivative 8 could be isolated as its oxime tautomer 9
(Scheme 2). Oximes similar to 9 (with a cyano instead of
ester group) have been reported by Davis et al. to be formed
in the reaction of aromatic nitro compounds with aryl
acetonitriles in the presence of a base in a protic solvent.[3]
The presence of a protic solvent was essential in the reac-
tion process as it was assumed that it protonates the σH
adduct before its conversion into the nitroso compound via
the loss of a water molecule. In aprotic solvents the forma-
tion of other products was observed. Lewis acids in aprotic
solvents can react in the same manner. In this case the nu-
Introduction
The addition of a nucleophilic agent to an aromatic nitro
compound leads to the σH adduct which can be stabilized
in a variety of ways.[1] One of the stabilization pathways
involves the reduction of a nitro to a nitroso compound
which, being a very reactive intermediate, usually undergoes
further transformations as reported for the reaction of
nitroarenes with arylacetonitriles,[2Ϫ4] cyanide anion,[5] di-
methyl phosphite[6,7] or Grignard reagents.[8] Recently we
reported a new transformation from the reaction of nitroar-
enes and cinnamyl aryl sulfones under the influence of base
and Lewis acid or a silylating agent leading to 2-aryl-4-aryl-
sulfonylquinoline derivatives.[9,10] The reaction probably
proceeds via the mechanistic pathway shown in Scheme1.
Scheme 1. Proposed mechanistic pathway for the reaction of nitro- cleophilic agent enters exclusively at the para position in
arenes with allyl aryl sulfones
relation to the nitro group; hence amine 10 was isolated
after the reduction with Zn in acetic acid without evidence
for the formation of amide 11.
Base-catalysed formation of the σH adduct 4, followed by
the loss of hydroxide anion (probably silane or Lewis acid
mediated), leads to the nitroso compound 5 which un-
A variety of nitroarenes were treated similarly with allyl
aryl sulfones to give the corresponding quinolines in moder-
ate yields (see Table 1). The reaction proceeds effectively
with activated aromatic nitro compounds such as bicyclic
and heterocyclic nitroarenes. Unfortunately, reaction with
[a]
Institute of Organic Chemistry, Polish Academy of Sciences,
ul. Kasprzaka 44/52, PL-01Ϫ224 Warsaw, Poland
E-mail: wrobel@ichf.edu.pl
Eur. J. Org. Chem. 2000, 521Ϫ525
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0203Ϫ0521 $ 17.50ϩ.50/0
521

O. Brosch, T. Weyhermüller, N. Metzler-Nolte
FULL PAPER
3-nitrobenzonitrile, which is supposed to be the most elec-
trophilic of the series, was fast and led only to tars under
the conditions A or B specified in Table 1. However, a re-
verse addition of the substrates and short time of the reac-
tion resulted in formation of 7-cyano-4-(4-methylphe-
nyl)sulfonylquinoline (3m), albeit in low yield.
In the reaction of 4-methoxynitronaphthalene (1b) with
2a, apart from the anticipated quinoline 3g a considerable
amount of 1-hydroxy-5-methoxy-2-methyl-3-tolylsulfonyl-
benzo[g]indole (12), which resulted from five-membered
ring closure, was obtained. This result can be explained on
the base of Scheme 1. The nitroso intermediate 5, with an
unsaturated β,γ double bond, may exist in equilibrium with
its α,β unsaturated isomer 13 via carbanion 6 (Scheme 3).
Both 5 and 13 can give 6 (then 3) when treated with a base,
but an intramolecular cyclization to 12, probably an electro-
cyclic reaction,[11] is possible only from the isomer 13. The
presence of an electron-donating OMe substituent weakens
the electrophilic character of the nitroso group and lowers
the acidity of the whole system thus directing the reaction
towards 12.
Scheme 2. Formation of the nitroso compound 8 in the reaction of
1-nitronaphthalene 1a with methyl phenylacetate (7)
Table 1. Reaction of nitroarenes 1 with allylic sulfones 2 in selected systems
[a]
A: 1 (1 mmol), 2 (1 mmol), MgCl2 (0.625 mmol), BTMSA (2.5 mmol),DBU (5 mmol), HMPA (1.25 mL); B: 1 (1 mmol), 2 (1 mmol),
[b]
[c]
MgCl2 (10 mmol), DBU (5 mmol), HMPA (5 mL); C: like A but 1 ϩ 2 added to other reagents. Ϫ d ϭ days. Ϫ Isolated by column
chromatography. Ϫ Can be improved, see Scheme 4; 14% of 12 was isolated as a by-product.
[d]
522
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Ferrocene-Labeled Amino Acids
FULL PAPER
The acid 3p was obtained almost quantitatively by sub-
jecting 3o firstly to a basic hydrolysis at elevated tempera-
ture (following the procedure elaborated by Peng et al.[14]
)
and then to acidification. This compound has previously
been described in the literature[12,13] and can be trans-
formed into Eupolauramine 14 in four steps.
Experimental Section
General: Melting points are uncorrected. 1H NMR spectra were
recorded with a Varian Gemini (200 M Hz) in [D6]DMSO solu-
tions. Chemical shifts are expressed in ppm with reference to TMS
as an internal standard. Coupling constants are given in Hz. Mass
spectra were obtained with a ADM-604 (ADM Intectra GmbH
Germany). Column chromatography was performed on silica gel
240Ϫ400 mesh (Merck). Reagents were used in commercially avail-
able form. Solvents were purified and dried according to common
procedures. Nitroarenes, allyl phenyl sulfone 2b and methyl phenyl
acetate (7) were commercially available. Sulfones 2a,[15] 2c,[16]
2d,[17] 2e[18] and 2g[10] were prepared according to known pro-
cedures.
Scheme 3. Intramolecular six- versus five-membered ring closure
of the intermediate 6
Reaction of 1-Nitronaphthalene (1a) with Methyl Phenyl Acetate (7):
A mixture of 1-nitronaphthalene (1a) (173 mg, 1 mmol), methyl
phenyl acetate (7) (165 mg, 1.1 mmol) and MgCl2 (238 mg,
2.5 mmol) in HMPA (2.5 mL) was treated with DBU (746 µL,
5 mmol) and stirred for 3 days at room temperature. After pouring
into dilute aqueous acetic acid, extraction with ethyl acetate and
chromatography, oxime 9 was isolated as the main product
(175 mg, 62%) as yellow crystals, m.p. 146Ϫ147°C. Ϫ 1H NMR
showed 2 isomers (2:3 ratio): major: δ ϭ 3.74 (s, 1 H), 6.83Ϫ7.59
(sets of m, 10 H), 8.10Ϫ8.19 (m, 1 H), 11.98 (s, 1 H). Ϫ minor:
δ ϭ 3.79 (s, 1 H), 6.83Ϫ7.59 (sets of m, 10 H), 8.03Ϫ8.09 (m, 1
H), 12.01 (s, 1 H). Ϫ MS m/z (%): 306 (21.2), 305 (100.0), 389
(12.6), 274 (16.5), 256 (17.3), 246 (14.9), 245 (19.5), 230 (14.2), 229
(29.8). Ϫ HRMS C19H15NO3: calcd. 305.1052; found 305.1044.
Bearing in mind that the yields of the present reaction
are moderate, the process may be nevertheless useful in the
chemistry of heterocycles because of its simplicity. To illus-
trate this, a formal total synthesis of the natural product
Eupolauramine[12,13] 14 was performed (Scheme 4).
Oxime 9 (30 mg, 0.1 mmol) and Zn dust (65 mg, 1 mmol) were re-
fluxed in glacial acetic acid (1 mL) for 20 min, then cooled, neu-
tralized cautiously with aq. NaHCO3, extracted with ethyl acetate
and chromatographed to yield amino ester 10 (25 mg, 96%) as or-
ange crystals, m.p. 126Ϫ127°C. Ϫ 1H NMR: δ ϭ 3.66 (s, 3 H),
5.71 (s, 1 H), 5.76 (broad s, 2 H), 6.63 (d, J ϭ 7.9 Hz, 1 H), 6.98
(d, J ϭ 7.9 Hz, 1 H), 7.18Ϫ7.46 (m, 7 H), 7.80Ϫ7.90 (m, 1 H),
8.05Ϫ8.15 (m, 1 H). Ϫ MS m/z (%): 292 (9.1), 291 (41.5), 233
(19.9), 232 (100.0), 230 (13.7), 215 (17.2). Ϫ HRMS C19H17NO2:
calcd. 291.1259; found 291.1259.
Reactions of Nitroarenes with Allyl Sulfones (Table 1). ؊ Procedure
A: A mixture of nitroarene (1 mmol), allyl sulfone (1.1 mmol),
MgCl2 (60 mg, 0.625 mmol) and BTMSA (642 µL, 2.5 mmol) in
HMPA (1.25 mL) was stirred at room temperature for 20 min. then
treated with DBU (746 µL, 5.0 mmol) and stirred at room tempera-
ture for two days. After completion (TLC control) the reaction mix-
ture was placed on the top of chromatography column and sepa-
rated with toluene (entry 1, 8, 9) or hexane/ethyl acetate mixtures
as eluents.
Scheme 4. Formal total synthesis of Eupolauramine
4-Methoxynitronaphthalene (1b) reacts with allyl 4-tolyl
sulfone (2a) to give 6-methoxy-4-(4-methylphenyl)sulfonyl-
benzo[h]quinoline (3g) in 35% yield (which can be increased
to 49% by the addition of two portions of 2a in excess)
together with 16% of 1-hydroxy-5-methoxy-2-(4-methylphe-
nyl)sulfonylbenzo[g]indole (12) as a by-product. Replace-
ment of the 4-tolyl-sulfonyl group by cyano (tetraethylam-
monium cyanide in a toluene/DMF solution at 80°C) led to
Procedure B: A mixture of nitroarene (1 mmol), allyl aryl sulfone
(1.1 mmol) and MgCl2 (952 mg, 10 mmol) in HMPA (5 mL) was
stirred at room temperature for 20 min. then treated with DBU
(746 µL, 5 mmol) and stirred at room temperature for six days.
After pouring onto saturated aq. NH4Cl solution, extraction with
the 4-cyano-6-methoxybenzo[h]quinoline (3o) in 74% yield. ethyl acetate (5 ϫ 20 mL), washing the extract with dil. NaCl solu-
Eur. J. Org. Chem. 2000, 521Ϫ525 523

O. Brosch, T. Weyhermüller, N. Metzler-Nolte
FULL PAPER
tion and drying with MgSO4 the product was isolated by column
chromatography.
(12.3), 284 (16.7), 283 (5.1), 269 (28.3), 268 (74.8), 267 (8.5), 241
(5.2). Ϫ C21H17NO3S (363.10): calcd. C 69.40, H 4.71, N 3.85;
found C 69.34, H 4.54, N 3.81.
Procedure C: A solution of 1f (148 mg, 1 mmol) and 2a (216 mg,
1.1 mmol) in HMPA (2.5 mL) was added within 5 min to a solution
of MgCl2 (60 mg, 0.625 mmol), BTMSA (642 µL, 2.5 mmol) and
DBU (746 µL, 5 mmol) in HMPA (2.5 mL) at room temperature.
After 5 min. stirring the mixture was worked up as in procedure B.
6-Chloro-2-methyl-4-(4-methylphenyl)sulfonylquinoline (3h): Yield
33%, procedure A; fine light brownish crystals, m.p. 188Ϫ189°C
(ethyl acetate). Ϫ 1H NMR: δ ϭ 2.37 (s, 3 H), 2.80 (s, 3 H),
7.44Ϫ7.49 (m, 2 H), 7.84 (dd, J ϭ 9.0, 2.3 Hz, 1 H), 8.09 (d, J ϭ
9.0 Hz, 1 H), 8.21 (s, 1 H), 8.42 (d, J ϭ 2.3 Hz, 1 H). Ϫ MS m/z
(%): 333 (12.5), 332 (6.7), 331 (32.9), 233 (19.3), 232 (100.0), 231
(6.7), 176 (6.4). Ϫ C17H14ClNO2S (331.82): calcd. C 61.53, H 4.25,
N 4.22; found C 61.34, H 4.11, N 3.77.
4-(4-Methylphenyl)sulfonylbenzo[h]quinoline (3a): Yield 60%, pro-
cedure A; yellow powder, m.p. 160Ϫ163°C (1,2-dichloroethane/
1
ethyl acetate). Ϫ H NMR: δ ϭ 2.35 (s, 3 H), 7.45 (app d, J ഠ 8.5
Hz, 2 H), 7.80Ϫ7.84 (m, 2 H), 7.97 (app d, J ഠ 8.5 Hz, 2 H),
8.05Ϫ8.08 (m, 1 H), 8.13 (d, J ϭ 9.2 Hz, 1 H), 8.35 (d, J ϭ 4.6
Hz, 1 H), 8.47 (d, J ϭ 9.2 Hz, 1 H), 9.19Ϫ9.24 (m, 1 H), 9.32 (d,
J ϭ 4.6, 1 H). Ϫ MS m/z (%): 335 (7.3), 334 (22.8), 333 (100.0), 269
(28.0), 268 (38.8), 254 (33.4), 177 (15.0), 151 (21.9). Ϫ C20H15NO2S
(333.41): calcd. C 72.05, H 4.53, N 4.20; found C 71.99, H 4.39,
N 3.87.
4-(4-Methylphenyl)sulfonylpyrido[3,2-h]quinoline (3i): Yield 49%,
procedure A; off white crystals, m.p. 239Ϫ241°C (1,2-dichloro-
1
ethane/ethyl acetate). Ϫ H NMR: δ ϭ 2.36 (s, 3 H), 7.47 (app d,
J ഠ 8.5 Hz, 2 H), 7.85 (dd, J ϭ 8.4, 4.4 Hz, 1 H), 8.00 (app d, J ഠ
8.5 Hz, 2 H), 8.22 (dd, J ϭ 9.6, 0.6 Hz, 1 H), 8.40 (d, J ϭ 4.6 Hz,
1 H), 8.75 (d, J ϭ 9.6 Hz, 1 H), 9.13 (dd, J ϭ 4.4, 1.7 Hz, 1 H),
9.38 (d, J ϭ 4.6 Hz, 1 H), 9.50 (ddd, J ϭ 8.4, 1.7, 0.7 Hz, 1 H). Ϫ
MS m/z (%): 336 (7.5), 335 (22.9), 334 (100.0), 333 (6.8), 271 (7.4),
270 (40.7), 269 (83.5), 268 (6.5), 256 (16.8), 255 (82.1), 179 (15.4),
152 (34.3). Ϫ C19H14N2O2S (334.39): calcd. C 68.24, H 4.22, N
8.31; found C 68.08, H 4.04, N 8.43.
4-Phenylsulfonylbenzo[h]quinoline (3b): Yield 52%, procedure B;
fine yellow crystals, m.p. 153Ϫ156°C (1,2-dichloroethane/hexane).
Ϫ
1H NMR: δ ϭ 7.61Ϫ7.88 (m, 5 H), 8.04Ϫ8.15 (m, 4 H), 8.39
(d, J ϭ 4.6 Hz, 1 H), 8.47 (d, J ϭ 9.3 Hz, 1 H), 9.17Ϫ9.26 (m, 1
H), 9.34 (d, J ϭ 4.6 Hz, 1 H). Ϫ MS m/z (%): 321 (7.2), 320 (21.7),
319 (100.0), 256 (5.2), 255 (26.7), 254 (50.6), 178 (9.7), 166 (7.9),
2-Methyl-4-(4-methylphenyl)sulfonylpyrido[3,2-h]quinoline
(3j):
Yield 27%, procedure A; off white crystals, m.p. 216Ϫ218°C (ethyl
151 (10.9).
319.0666.
Ϫ HRMS C19H13NO2S: calcd. 319.0667; found
1
acetate). Ϫ H NMR: δ ϭ 2.35 (s, 3 H), 2.94 (s, 3 H), 7.46 (app d,
J ഠ 8.5 Hz, 2 H), 7.80 (dd, J ϭ 8.4, 4.4 Hz, 1 H), 7.99 (app d, J ഠ
8.5 Hz, 2 H), 8.12 (d, J ϭ 9.6 Hz, 1 H), 8.35 (s, 1 H), 8.68 (d, J ϭ
9.6 Hz, 1 H), 9.09 (dd, J ϭ 4.4, 1.7 Hz,1 H), 9.47 (ddd, J ϭ 8.4,
1.7, 0.7 Hz, 1 H). Ϫ MS m/z (%): 350 (6.9), 349 (21.3), 348 (81.3),
284 (28.7), 283 (46.2), 270 (21.7), 269 (100.0), 243 (9.9), 193 (19.9),
192 (20.9). Ϫ HRMS C20H16N2O2S: calcd. 348.0933; found
348.0930.
4-(4-Fluorophenyl)sulfonylbenzo[h]quinoline (3c): Yield 43%, pro-
cedure B; fine yellow crystals, m.p. 154Ϫ155°C (ethyl acetate/hex-
ane). Ϫ H NMR: δ ϭ 7.50 (app t, J ഠ 9.0 Hz, 2 H), 7.80Ϫ7.88
(m, 2 H), 8.06Ϫ8.14 (m, 1 H), 8.16Ϫ8.26 (m, 2 H), 8.37 (d, J ϭ
4.6 Hz, 1 H), 8.47 (d, J ϭ 9.3 Hz, 1 H), 9.18Ϫ9.26 (m, 1 H), 9.34
(d, J ϭ 4.6 Hz, 1 H). Ϫ MS m/z (%): 339 (7.2), 338 (21.8), 337
(100.0), 273 (39.5), 272 (71.7), 178 (24.4), 166 (18.5), 151 (32.4), 150
(17.8). Ϫ HRMS C19H12FNO2S: calcd. 337.073; found 337.0582.
1
6-Methoxy-4-(4-methylphenyl)sulfonylpyrido[3,2-b]pyridine
(3k):
Yield 35%, procedure A; off white crystals, m.p. 181Ϫ183°C. Ϫ 1H
NMR: δ ϭ 2.37 (s,3 H), 3.92 (s, 3 H), 7.36 (d, J ϭ 9.2 Hz, 1 H),
7.41 (app d, J ഠ 8.3 Hz, 2 H), 7.88 (app d, J ഠ 8.3 Hz, 2 H), 8.38
(d, J ϭ 9.2 Hz, 1 H), 8.42 (d, J ϭ 4.5 Hz, 1 H), 9.11 (d, J ϭ 4.1
Hz, 1 H). Ϫ MS m/z (%): 313 (1.4), 251 (6.3), 250 (40.4), 249
(100.0), 235 (50.1). Ϫ C16H14N2O3S (314.36): calcd. C 61.13, H
4.49, N 8.91; found C 61.15, H 4.51, N 8.73.
3-Methyl-4-(4-methylphenyl)sulfonylbenzo[h]quinoline (3d): Yield
35%, procedure A; fine yellow crystals, m.p. 142Ϫ145°C. Ϫ 1H
NMR: δ ϭ 2.34 (s, 3 H), 2.95 (s, 3 H), 7.42 (app d, J ഠ 8.5 Hz, 2
H), 7.75Ϫ7.84 (m, 2 H), 7.90 (app d, J ഠ 8.5 Hz, 2 H), 7.99Ϫ8.08
(m, 2 H), 8.75 (d, J ϭ 9.6 Hz, 1 H), 9.13 (s, 1 H), 9.15Ϫ9.22 (m, 1
H). Ϫ MS m/z (%): 349 (7.5), 348 (23.8), 347 (100.0), 284 (12.8),
283 (58.9), 282 (82.1), 269 (21.3), 268 (95.0), 192 (21.3), 190 (19.5).
Ϫ HRMS C21H17NO2S: calcd. 347.0980; found 347.0976. Ϫ calcd.
C 72.60, H 4.93, N 4.03; found 72.05, H 4.53, N 4.10.
6-Methoxy-2-methyl-4-(4-methylphenyl)sulfonylpyrido[3,2-b]pyridine
(3l): Yield 48%, procedure A; off white crystals, m.p. 191Ϫ196°C
(ethyl acetate/hexane). Ϫ 1H NMR: δ ϭ 2.37 (s, 3 H), 2.79 (s, 3
H), 2.89 (s, 3 H), 7.25 (d, J ϭ 9.1 Hz, 1 H), 7.42 (app d, J ഠ 8.5
Hz, 2 H), 7.95 (app d, J ഠ 8.5 Hz, 2 H), 8.26 (d, J ϭ 9.1 Hz, 1
H), 8.31 (s,1 H). Ϫ MS m/z (%): 328 (1.1), 327 (1.8), 265 (7.7), 264
(46.4), 263 (100.0), 250 (8.5), 249 (48.3). Ϫ C17H16N2O3S (328.39):
calcd. C 62.18, H 4.91, N 8.53; found C 62.17, H 4.89, N 8.61.
2-Methyl-4-(4-methylphenyl)sulfonylbenzo[h]quinoline (3e): Yield
1
53%, procedure A; m.p. 178Ϫ181°C (ethyl acetate/hexane). Ϫ H
NMR: δ ϭ 2.34 (s, 3 H), 2.92 (s, 3 H), 7.42 (app. d, J ഠ 8.5 Hz, 2
H), 7.70Ϫ7.84 (m, 2 H), 7.94Ϫ8.08 (m, 4 H), 8.30 (s, 1 H), 8.41 (d,
J ϭ 9.3 Hz, 1 H), 9.15Ϫ9.22 (m, 1 H). Ϫ MS m/z (%): 349 (7.7),
348 (25.3), 347 (100.0). 283 (16.1), 282 (21.9), 269 (7.4), 268 (31.6),
192 (17.3), 191 (11.1), 180 (10.6), 151 (23.3). Ϫ C21H17NO2S
(347.10): calcd. C 72.60, H 4.93, N 4.03; found C 72.66, H 4.75,
N 3.91.
7-Cyano-4-(4-methylphenyl)sulfonylquinoline (3m): Yield 13%, pro-
cedure A; fine pale-pink crystals, m.p. 208Ϫ210°C (ethyl acetate/
1
hexane). Ϫ H NMR: δ ϭ 2.37 (s, 3 H), 7.46 (app d, J ഠ 8.5 Hz,
2 H), 7.98 (app d, J ഠ 8.5 Hz, 2 H), 8.08 (dd, J ϭ 8.9, 1.7 Hz, 1
H), 8.38 (d, J ϭ 4.4 Hz, 1 H), 8.71 (d, J ϭ 8.9 Hz, 1 H), 8.78 (d,
J ϭ 1.7 Hz, 1 H), 9.36 (d, J ϭ 4.4 Hz, 1 H). Ϫ MS m/z (%): 310
(7.1), 309 (21.3), 308 (100.0), 307 (19.9), 245 (13.1), 244 (73.9), 243
(89.2), 230 (17.6), 229 (94.3), 155 (10.3), 153 (18.7), 139 (43.9). Ϫ
HRMS C17H12N2O2S: calcd. 308.0620; found 308.0627. Ϫ calcd.
C 66.22, H 3.92, N 9.08; found C 65.80, H 3.54, N 8.94.
2-Phenyl-4-phenylsulfonylbenzo[h]quinoline (3f): Yield 72%, pro-
cedure A; fine yellow crystals, m.p. 226Ϫ228°C (1,2-dichloro-
ethane), ref.[10] m.p. 227Ϫ228°C.
6-Methoxy-4-(4-methylphenyl)sulfonylbenzo[h]quinoline (3g): Yield
35%, procedure A; m.p. 206Ϫ208°C (ethyl acetate/hexane). Ϫ 1H
NMR: δ ϭ 2.35 (s, 3 H), 4.07 (s, 3 H), 7.34Ϫ7.49 (m, 2 H), 7.63
(s,1 H), 7.79Ϫ7.89 (m. 2 H), 7.94Ϫ8.01 (m, 2 H), 8.20Ϫ8.30 (m, 1
4-(4-Methylphenyl)sulfonylthieno[2,3-b]pyridine (3n): Yield 45%,
H), 8.33 (d, J ϭ 4.7 Hz, 1 H), 9.13 (d, J ϭ 4.7 Hz, 1 H), 9.14Ϫ9.22 procedure A; fine off-white crystals, m.p. 102Ϫ106°C (ethyl acetate/
1
(m, 1 H). Ϫ MS m/z (%): 365 (8.1), 364 (24.2), 363 (100.0), 299 tetrachloromethane). Ϫ H NMR: δ ϭ 2.36 (s, 3 H), 7.42 (app d,
524
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1
J ഠ 8.4 Hz, 2 H), 7.83 (d, J ϭ 6.1 Hz, 1 H), 7.88 (app d, J ഠ 8.4
Hz, 2 H), 8.03 (d, J ϭ 4.9 Hz, 1 H), 8.23 (d, J ϭ 6.1 Hz, 1 H),
Ϫ H NMR: δ ϭ 4.14 (s, 3 H), 7.06 (s, 1 H), 7.81Ϫ7.91 (m, 2 H),
8.09 (d, J ϭ 4.6 Hz, 1 H), 8.23Ϫ8.32 (m, 1 H), 8.96 (d, J ϭ 4.6
8.86 (d, J ϭ 4.9 Hz, 1 H). Ϫ MS m/z (%): 291 (11.2), 290 (17.7), Hz, 1 H), 9.06Ϫ9.15 (m, 1 H). Ϫ MS m/z (%): 235 (17.3), 234
289 (100.0), 225 (12.2), 224 (15.8), 210 (17.8), 139 (87.5). Ϫ HRMS
C14H11NO2S2: calcd. 289.0231; found 289.0239.
(100.0), 233 (16.3), 192 (11.4), 191 (74.9), 165 (5.4), 164 (15.2). Ϫ
HRMS C15H10N2O: calcd. 234.0792; found 234.0785. Ϫ calcd. C
76.91, H 4.30, N 11.96; found C 76.80, H 3.86, N 11.87.
Total Synthesis of Eupolauramine (14). Improved synthesis of 6-
methoxy-4-(4-methylphenyl)sulfonylbenzo[h]quinoline (3g): A mix-
ture of 4-methoxynitronaphthalene (1b) (4.06 g, 20 mmol), sulfone
2a (3.92 g, 20 mmol) and MgCl2 (1.19 g, 12.5 mmol) was stirred in
HMPA (25 mL) and bis(trimethylsilyl)acetamide (12.8 mL,
50 mmol) for 20 min. and then DBU (14.9 mL, 100 mmol) was ad-
ded in one portion. The reaction flask was stoppered and the mix-
ture stirred at room temperature. After 24 h the second portion
of solid sulfone 2a (1.96 g, 10 mmol) was added and the stirring
continued for 24 h. After pouring into aqueous NH4Cl solution
(150 mL), extraction with ethyl acetate (5 ϫ 50 mL), washing the
extracts with dil. NaCl solution (2 ϫ 50 mL), drying with MgSO4
and evaporation of the solvent the residue was treated with hot
toluene (20 mL). After cooling 1.80 g of 3g was filtered off. The
mother liquor was concentrated and chromatographed with toluene
as an eluent to give a further 1.73 g of 3g (total amount 3.53 g,
49%) and 13a (1.21 g, 16%).
6-Methoxybenzo[h]quinoline-4-carboxylic Acid (3p): Following the
procedure described by Peng et al.[14] nitrile 3o (500 mg,
2.136 mmol) was added to a solution of KOH (560 mg, 10 mmol)
in glycerine (4 mL) and heated with stirring at 150°C for 8 h. After
cooling the mixture was diluted with water (5 mL), filtered, the
filtrate acidified with glacial acetic acid (3 mL) and the precipitate
filtered off and dried over P2O5 under vacuum to give acid 3p
(516 mg, 96%): m.p. 262Ϫ265°C (acetic acid) ref.[12] m.p.
266Ϫ267°C (acetic acid). Ϫ 1H NMR and MS spectra were in
agreement with ref.[12]
[1]
M. Makosza, Pol. J. Chem. 1992, 66, 3Ϫ23.
[2]
R. B. Davis, L. C. Pizzini, J. Org. Chem. 1960, 25, 1884Ϫ1888.
[3]
R. B. Davis, L. C. Pizzini, J. D. Benigni, J. Am. Chem. Soc.
1960, 82, 2913Ϫ2915.
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Z. Wrobel, Pol. J. Chem. 1998, 72, 2384Ϫ2388.
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[6]
V. von Richter, Ber. Dtsch. Chem. Ges. 1871, 4, 21.
W. Danikiewicz, M. Makosza, J. Chem. Soc., Chem. Commun.
1985, 1792Ϫ1793.
1-Hydroxy-5-methoxy-2-methyl-3-(4-methylphenyl)sulfonylbenzo-
[7]
[8]
[g]indole (13a): (16%), light brownish powder, m.p. 205Ϫ205°C,
W. Danikiewicz, M. Makosza, J. Org. Chem. 1991, 56,
1283Ϫ1286.
1
dec. (ethyl acetate). Ϫ H NMR: δ ϭ 2.32 (s, 3 H), 2.71 (s, 3 H),
G. Bartoli, M. Bosco, A. Melandri, A. C, Boicelli, J. Org. Chem.
1979, 44, 2087Ϫ2092.
4.01 (s, 3 H), 7.35 (app. d, J ഠ 8.2 Hz, 2 H), 7.37 (s, 1 H), 7.42Ϫ7.49
(m, 1 H), 7.57Ϫ7.65 (m, 1 H), 7.85 (app. d, J ഠ 8.2 Hz, 2 H),
8.16Ϫ8.28 (m, 2 H), 12.63 (s, 1 H). Ϫ MS m/z (%): 367 (8.0), 366
(24.3), 365 (100.0), 286 (6.8), 285 (14.2), 271 (12.3). Ϫ HRMS
C21H19NO3S2: calcd. 365.1086; found 365.1044. Ϫ calcd. C 66.12,
H 5.02, N3.67; found 65.72, H 5.04, N 3.48.
[9]
´
Z. Wrobel, Tetrahedron Lett. 1997, 38, 4913Ϫ4916.
[10]
[11]
[12]
[13]
´
Z. Wrobel, Tetrahedron 1998, 54, 2607Ϫ2618.
´
Z. Wrobel, M. Makosza, Tetrahedron 1997, 53, 5501Ϫ5514.
P. Karuso, W. C. Tyler, Aust. J. Chem. 1984, 37, 1271Ϫ1282.
M. Kawase, Y. Miyake, T. Sakamoto, Tetrahedron 1989, 45,
1653Ϫ1660.
[14]
[15]
[16]
Ch.-T. Peng, T. C. DanielЈs, J. Am. Chem. Soc. 1955, 77,
6682Ϫ6683.
6-Methoxybenzo[h]quinoline-4-carbonitrile (3o): A solution of sul-
fone 3g (910 mg, 2,5 mmol) and tetraethylammonium cyanide
(1.56 g, 10 mmol) in dry toluene (10 mL) and DMF (5 mL) was
stirred and heated to 80°C in a sealed tube for 48 h. After cooling
the reaction mixture was diluted with ethyl acetate (50 mL), washed
with dil. NaCl solution, dried (MgSO4), the solvent evaporated and
product separated by column chromatography to give 435 mg of 3o
(74%) as fine pale-yellow crystals, m.p. 168Ϫ169°C (ethyl acetate).
A. Jonczyk, T. Radwan-Pytlewski, J. Org. Chem. 1983, 48,
910Ϫ912.
H.-S. Dang, B. J. Roberts, J. Chem. Soc., Perkin Trans 1 1996,
13, 1493Ϫ1498.
[17]
[18]
J. K. Crandall, C. Pradat, J. Org. Chem. 1985, 50, 1327Ϫ1329.
P. Kocienski, J. Chem. Soc., Perkin Trans. , 1983, 5, 945Ϫ948.
Received July 8, 1999
[O99412]
Eur. J. Org. Chem. 2000, 521Ϫ525
525