A Friedel-Crafts cyclization

Thioindoxyls (72) may be obtained by cyclization of the appropriate -arylthioglycolic acid (71) with phosphorus pentoxide (yields are often low315), hydrofluoric acid,106,316 or chlorosulfonic acid,317,318 (method a) Friedel-Crafts cyclization of the corresponding acid chloride (preferably prepared using thionyl chloride319) (method b) is, however, the preferred procedure (Table V). Jf eta-substituted S-aryl-thioglycolic acids afford mixtures of 4- and 6-substituted thioindoxyls.320... 

Selenazoles (72) and methyl salicylate or methyl-o-mercaptobenzoate lead to ethers (77) or thioethers (78). The acid chlorides of (77) and (78) through a Friedel-Craft cyclization afford l-benzoxepino[3,4-d]selenazoles (79) and l-benzothiepino[3,4-d]selenazoles (80), respectively (Scheme 28) (81JHC789). 

A five-membered ring is formed in a Friedel-Crafts cyclization of 92 to give 93 (68T2645). The acid 94 gave ketone 95 on treatment with polyphosphoric... 

Biphcnylyl chlorodithioformate undergoes a Friedel-Crafts cyclization to give a quantitative yield of the thiopyranthione. 

The reaction is a Friedel-Crafts cyclization, as you could have deduced by the simple loss of water. The resulting cation could cychze in two ways, arbitrarily called A and B. Steric hindrance suggests that A would be the more hkely product. 

The synthesis of dihydrobenzothiepinone 80 by a previously reported gold-catalyzed oxidation of sulfoxide-tethered alkyne 77 was the subject of a detailed experimental and theoretical mechanistic study (13JA8512).A theoretical study showed that the previously proposed mechanism involving benzothiepine formation by a Friedel—Crafts cyclization onto an oxo-car-bene 81 is unlikely and that a [3,3]-sigmatropic rearrangement of the first cyclization intermediate 78 is more favorable. 

Alternatively, isatins 1784 can be synthesized from secondary aromatic amines with oxalyl chloride followed by a Friedel-Crafts cyclization [1311]. 

Cydopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcydopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsucdnate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic acid or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

An ingenious synthesis of 1-arylisoindolcs has been developed by Vebor and Lwowski, based upon the reaction of an o-phthalimido-methylbenzophenone (41, R = aryl) with hydrazine (Table IV). The benzophenone is prepared by a Friedel-Crafts reaction with o-phthalimidomethylbenzoyl chloride (40). The mechanism of isoindole formation can be represented sehematically by a sequence involving attack by hydrazine at the imide to give the ring-opened hj drazide (42), followed by cyclization to phthalazine-l,4-dione (44) with displacement of the o-aminomethylbenzophenone (43). Intramolecular condensation of the latter can lead, via the isoindolenine... 

A great many organic quaternary bases can inhibit the action of acetyl choline in organ systems activated by that neurotransmitter and thus possess anticholinergic-antispasmodic activity. One such agent is methantheline bromide (4), used in the treatment of peptic ulcer and as an antispasmodic agent in intestinal disorders. Its synthesis Involves Friedel-Crafts cyclization of o-... 

The cyclization to structurally defined, soluble LPPP takes place in a two-step sequence, consisting of a reduction of the keto group followed by ring closure of the secondary alcohol groups of 28 in a Friedel-Crafts-type alkylation. 

Friedel-Crafts cyclization of the dibasic acid gives thiaxanthone 4. Note that the symmetry of this intermediate assures formation of a single product. Desulfurization by means of Raney nickel leads, finally, to the antiinflammatory agent, ketopirofen... 

The quinolizine derivative 276 was obtained through a Friedel-Crafts acylation reaction onto the C-3 indole position of 275. This precursor was obtained by a sequence comprising a Fischer cyclization leading to 5-methyl-2-(2-pyridyl)indole 274, catalytic hydrogenation, N-alkylation with ethyl bromoacetate, and hydrolysis of the ester group (Scheme 59) <1999FA479>. 

The electron-rich thiophene ring system can be elaborated into complex, fused thiophenes by acid-mediated intramolecular annelation reactions. For example, treatment of alcohol 96 with trimethylsilyl triflate promoted a Friedel-Crafts acylation and subsequent dehydration giving benzo[b]thiophene 97, a potential analgesic <00JMC765>. Treatment of ketone 98 with p-toluenesulfonic acid resulted in the formation of fused benzo[b]thiophene 99 <00T8153>. Another variant involved the cyclization of epoxide 100 to fused benzo[f>]thiophene 101 mediated by boron trifluoride-etherate . 

Oki and his co-workers (177) also found that these halogenated compounds (107) exhibited enormous differences in reactivity when they were treated with Lewis acids. The sc form undergoes a Friedel-Crafts type cyclization in the presence of titanium tetrachloride, which is a weak Lewis acid, whereas the ap form survives these conditions. The latter reacts in the presence of the stronger Lewis acid antimony pentachloride. This difference is apparently caused by a chloro group in proximity to the site where a cationic center develops during the reaction (Scheme 12). 

Finally, the reactions were examined in order to determine their compatibility with the initiation of Friedel-Crafts cyclizations (Scheme 19, Eq. 2). Both the use of an a-stannyl ether and an a-stannyl amide substrates led to cyclized product. 

The Friedel-Crafts cyclization of biphenyl-2-sulfonyl chloride to give dibenzothiophene sulfone has been described (55%) ° however, thermal cyclization in octachloronaphthalene at 250°, under nitrogen, is reported to yield dibenzothiophene itself rather than the sulfone (47%). Reaction of biphenyl compounds with oleum (H2SO4 + SO3) to yield derivatives of dibenzothiophene 5,5-dioxide is widely used for the preparation of dyestuff intermediates (Section VI, E, 2). A typical example is shown in Eq. (3), starting from o-tolidine. ... 

The Pictet-Spengler reaction is the method of choice for the preparation of tetrahydro-P-carbolines, which represent structural elements of several natural products such as biologically active alkaloids. It proceeds via a condensation of a carbonyl compound with a tryptamine followed by a Friedel-Crafts-type cyclization. In 2004, Jacobsen et al. reported the first catalytic asymmetric variant [25]. This acyl-Pictet-Spengler reaction involves an N-acyliminium ion as intermediate and is promoted by a chiral thiourea (general Brpnsted acid catalysis). 

More recently, a catalyst-free aqueous version of this strategy was proposed with simple acyclic 1,3-dicarbonyls, formaldehyde, and styrene or anilines derivatives (Scheme 40) [131], In the first case (Scheme 40), the very reactive 2-methylene-1,3-dicarbonyl intermediate reacts smoothly at 80°C with a variety of substituted styrenes to give the corresponding dihydropyrans in moderate to good yields. Remarkably, when styrenes were replaced by A-ethylaniline, a novel five-component reaction involving twofold excess of both formaldehyde and 1,3-dicarbonyl selectively occurred (Scheme 41). The result is the formation of complex fused pyranoquinolines following a Friedel-Craft alkylation - dehydration sequence to furnish the quinoline nucleus, which suffers the Hetero-Diels-Alder cyclization in synthetically useful yields. 

Two years later, Craig and Robinson attempted an alternative synthesis of 8 with a more symmetrical pathway starting from derivatives of fluoranthene. Cycliza-tion of fluoranthene-7,10-diacetic acid 14 was attempted to produce diketone 15, expected to enolize to the dihydroxycorannulene 16. Unfortunately, several attempts at cyclization failed, including anhydrous hydrofluoric acid, concentrated sulfuric acid, and polyphosphoric acid. Friedel-Crafts cyclization of the corresponding acid chloride of 14 with aluminum or stannic chloride was similarly unsuccessful. However, although Craig and Robinson were not successful, they developed a convenient synthesis of 7,10-disubstituted fluoranthenes which turned out later to be of premium importance in a new, successful synthesis of corannulene. 

As noted earlier, most classical antidepressant agents consist of propylamine derivatives of tricyclic aromatic compounds. The antidepressant molecule tametraline is thus notable in that it is built on a bicyclic nucleus that directly carries the amine substituent. Reaction of 4-phenyl-l-tetralone (18) (obtainable by Friedel-Crafts cyclization of 4,4-diphenyl butyric acid) with methyl amine in the presence of titanium chloride gives the corresponding Schiff base. Reduction by means of sodium borohydride affords the secondary amine as a mixture of cis (21) and trans (20) isomers. The latter is separated to afford the more active antidepressant of the pair, tametraline (20). 

As mentioned in the introduction, recent synthetic developments now allow access to the 1,2-thiazine structure via disconnection type C (Figure 23). This process can be accomplished by a Friedel-Crafts-type cyclization of sulfamoyl chlorides. The initial report of this reaction utilized a stoichometric amount of aluminium chloride promoter <19920PP463>. Recently, however, A -ethyl phenethylsulfamoyl chloride 214 was shown to undergo Friedel-Crafts cyclization to form sultam 215 with just a catalytic amount of In(OTf)3 (Equation 33) <2002SL1928>. 

An anionic equivalent of the Friedel-Crafts cyclization reaction has been developed for the formation of the C /C-5 bond of the 1,2-benzothiazine structure (Equation 35 Table 5) <1997SL1079>. In this reaction, directed metalation of sulfonamide-substituted aromatic systems 233 with an excess of LDA affords aryl lithium species 234 in a regiocontrolled fashion. This intermediate then reacts in situ with a proximal amide to form l,2-benzothiazine-4-one 1,1-dioxides 235. The yields of this transformation appear to be highly dependent upon the substitution pattern in 233. The authors attribute the low yield when = methyl and = H to a-deprotonation of the amide moiety. 

Epoxides can also serve as effective carbocyclization promotors, either through a polyene cyclization, as in the biomimetic epoxy-olefin cyclization of 100 in the presence of boron trifluoride etherate <99CC325>, or by a Friedel-Crafts approach, as exemplified by the cycli-alkylation of arylalkyl epoxides 102 under the influence of solid acid catalysts <99EJOC837>. 

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