“…To explore the general utility of this annelation process, we selected two additional two-carbon-atom spaced substrates. Required acids 1,3-dihydrobenzo[ c ]thiophene-1-acetic acid ( 15 ) , and 3,4-dihydro-1 H -2-benzothiopyran-1-acetic acid ( 20 ) 20 are readily converted to the corresponding indole and pyrrole sulfoxides (Schemes 1 and 2). …”
An approach to many-membered ring N,S-heterocycles involving sulfoxide electrophilic sulfenylation
(SES) followed by ring expansion of the derived sulfonium salt intermediate (in situ) is illustrated
for 9- and 10-membered-ring compounds. Treatment of readily prepared sulfoxides 10a, 10b, 18a,
18b, 23a, and 23b with triflic anhydride (pyridine, CH2Cl2, 0 °C) provides heterocycles 13a (65%),
13b (60%), 19a (67%), 19b (67%), 24a (42%), and 24b (80%), respectively. Sulfoxides 5a and 5b,
under several different conditions, give only the Pummerer dehydration products 6a and 6b,
respectively. Diastereomeric sulfoxides 18a‘ and 18b‘, upon treatment with triflic anhydride, do
not produce clean product mixtures or any of the desired heterocyclic products but, upon heating
in toluene, are converted to the more stable isomers 18a and 18b, respectively. Conducting this
isomerization in the presence of 2-mercaptobenzothiazole produces a disulfide indicative of the
intermediacy of a sulfenic acid. However, the importance of sulfenic acid derivatives in the SES
process leading to many-membered ring heterocycles remains to be determined.
“…To explore the general utility of this annelation process, we selected two additional two-carbon-atom spaced substrates. Required acids 1,3-dihydrobenzo[ c ]thiophene-1-acetic acid ( 15 ) , and 3,4-dihydro-1 H -2-benzothiopyran-1-acetic acid ( 20 ) 20 are readily converted to the corresponding indole and pyrrole sulfoxides (Schemes 1 and 2). …”
An approach to many-membered ring N,S-heterocycles involving sulfoxide electrophilic sulfenylation
(SES) followed by ring expansion of the derived sulfonium salt intermediate (in situ) is illustrated
for 9- and 10-membered-ring compounds. Treatment of readily prepared sulfoxides 10a, 10b, 18a,
18b, 23a, and 23b with triflic anhydride (pyridine, CH2Cl2, 0 °C) provides heterocycles 13a (65%),
13b (60%), 19a (67%), 19b (67%), 24a (42%), and 24b (80%), respectively. Sulfoxides 5a and 5b,
under several different conditions, give only the Pummerer dehydration products 6a and 6b,
respectively. Diastereomeric sulfoxides 18a‘ and 18b‘, upon treatment with triflic anhydride, do
not produce clean product mixtures or any of the desired heterocyclic products but, upon heating
in toluene, are converted to the more stable isomers 18a and 18b, respectively. Conducting this
isomerization in the presence of 2-mercaptobenzothiazole produces a disulfide indicative of the
intermediacy of a sulfenic acid. However, the importance of sulfenic acid derivatives in the SES
process leading to many-membered ring heterocycles remains to be determined.
“…The oxidation of 3,5,5-trimethylcyclohexane-l,2-dione (14) in dioxan gave the bridged selenide (1 5) in 6% yield along with small amounts of the elimination product (16), the main product being a polymer-like oil. To the best of our knowledge, (15) is the only reported compound of the 7-selenabibicyclo[2.2. llheptane series.…”
“…A solution of 94 g (0.57 mol) of 3-(4-methylphenyl)propanoic acid (4) [5] in 200 mL of dichloromethane was added portionwise during 2 hours to 2 kg of stirring polyphosphoric acid maintained at 80-90°. After the addition was complete, the mixture was heated for 3 hours.…”
Section: Discussionmentioning
confidence: 99%
“…A mixture of 81.1 g (0.5 mol) of (E)-3-(2-methylphenyl)-2propenoic acid (8) [5], 43.8 mL (0.6 mol) of thionyl chloride, and 400 mL of dichloromethane was heated at reflux for 1 hour. The solution was concentrated to a free-flowing oil that was further concentrated in vacuo overnight at 25°to remove remaining volatiles.…”
“…Polyphosphoric acid ring closure of 3-(4-methylphenyl)propanoic acid (4) [5] was performed by the method of Simchen and Krämer [6], but on a much larger scale to provide indanone 5 in 74% yield [7]. Indanone 5 was then subjected to the Schmidt rearrangement with sodium azide in trichloroacetic acid utilizing the procedure of Tomita and Minami [8] to provide the initial target 1 in 29% yield along with the known isomeric 3,4-dihydro-2(1H)-quinolinone (6) [9,10] in 8% yield following flash silica gel chromatography.…”
Approaches toward the preparative-scale synthesis of target 3,4-dihydro-1(2H)-isoquinolinones 1-3 are presented. Compounds 1 and 2 were prepared via a Schmidt rearrangement on easily obtained indanone precursors, but in low overall yield. A better method to make this class of compounds is exemplified by the large-scale synthesis of 2 via a Curtius rearrangement sequence. Thus, high-temperature thermal cyclization of an in situ formed styryl isocyanate from precursor 8 in the presence of tributylamine gave the corresponding 1(2H)-isoquinolinone (9). Catalytic hydrogenation of 9 provided the desired 3,4-dihydro-5-methyl-1(2H)-isoquinolinone (2) in 65 % overall yield. Similar reduction of a commercially available 5-hydroxy-1(2H)-isoquinolinone precursor 10 followed by an O-alkylation/amination sequence gave target 3 in good overall yield. The route proceeding via the Curtius rearrangement is recommended for large scale synthesis of other 3,4-dihydro-1(2H)-isoquinolinones. Only when deactivating substituents or sensitive functionality within the benzenoid ring render the high temperature ring closure of the intermediate isocyanate inefficient might a Schmidt rearrangement protocol be the method of choice.
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