Formation of -Fused Systems

A logical extension of the synthetic strategy underlying our solid-phase approach toward 1,5-benzothiazepinones was to replace the P-mercapto acids (cysteine, penicillamine) by a-mercapto acids, such as mercaptoacetic acid 54a or thiolactic acid 54b. This change would facilitate access to the corresponding [6,6]-fused systems, i.e. l,4-benzothiazin-3-ones57. As with the benzothiazepines, no solid-phase synthesis of benzothiazines has been reported to date. 

The literature contains several references to reductive cyclizations producing cyclic hydroxamic acids like those described above, though not in solid-phase chemistry. We showed that this reaction competes well with lactam formation. The relative extent of these two reaction pathways is highly dependent on the presence and the nature of other heteroatoms and substituents around the ring system as well as on the conditions used to effect the reduction. 

From a pharmaceutical discovery perspective, it could be fruitful to embark on a library synthesis using cyclic hydroxamic acid templates. There are several reports describing interesting bioactivities for such compounds, particularly as inhibitors of metal-dependent enzymes. However, only three a-mercapto acid monomers are currently available from commercial sources hence the structural diversity of products that could be easily prepared is limited. Several approaches to introducing additional points of diversity into the benzothiazinone scaffold are currently under investigation. 

Some 30 benzyl bromides, allyl bromide, and different esters of bro-moacetic acid were found to work well in the A (4)-alkylation reaction. Benzyl chlorides, a-bromo acetophenones, as well as unactivated alkyl bromides, however, did not give satisfactory results. 

To summarize this section, several research groups have effectively exploited parallels between S Ar strategies leading to [6,7]- and [6,6]-ben-zofused heterocycles and have described complementary reaction protocols suitable for generating diverse combinatorial libraries of benzothiazin-3-ones and quinoxalin-2-ones. 

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Stereoselective intermolecular [2- -2]-photocycloaddition reactions of unsaturated heterocycles with formation of fused systems 98S683. 

Stereocontrolled synthesis and recyclizations of C-acetylenylglycosides in the presence of dicobalt hexacarbonyl with formation of fused saturated 0-heterocyclic systems 98CC2665. 

In reducing media, a synthetically useful variation of the Smiles rearrangement, which leads to the formation of fused ring systems, has been observed (equation 77)251. In this reaction, rearrangement is followed by displacement of the sulfinate anion by a nucleophilic o -substituent. 

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 . 

Iodine-transfer cyclization. Irradiation of unsaturated a-iodo carbonyl compounds in the presence of a hexaalkylditin (5-10%) can result in isomerization to cyclic y-iodo carbonyls.1 The reaction is very slow in the absence of an initiator. Thus under these conditions 1 isomerizes to a mixture of 2 and 3 in which 2 predominates. The reaction is particularly useful for formation of fused bicyclic systems (4 - 5). 

This article deals with the chemistry of carbazoles, and except for their formation from carbazoles as illustrations of the chemistry of carbazoles, it specifically excludes that of 1,2,3,4-tetrahydro-, 1,2,3,4,4a,9a-hexahydro-, 1,2,3,4,5,6,7,8-octahydro carbazoles, etc., because from the viewpoint of chemical reactivity, these are indoles, anilines, pyrroles, and so on. This article also excludes carbazoles with additional fused aromatic or heteroaromatic rings, again except for the formation of such systems as illustrations of carbazole reactivity. The physical and spectroscopic properties are not covered. 

Having a cyano group and an amino group ortho to each other on a ring is another system that has led to the formation of fused pyrimidine ring systems. In this case, an aminopyrimidine is the result. Compound 42 in Scheme 5 is one such structure. Treatment of 42a with formamide leads to the amino derivative 43 <1999PS(155)175>. Alternatively 42b provides 44 after treatment with triethyl orthoformate followed by hydrazine <1999PS(155)175>. 

The preparation of fused nitrogen heterocycles such as pyrrolizidines, indolizidines, quinolizidines, pyrrolidinoazocines and piperidinoazocines by the RCM of appropriate dienes (equation 38), is another case where presence of a ring assists the RCM reaction. However, when n = 7 (with x = 1), the C=C bonds, separated by 11 single bonds, are too far apart for RCM to occur. Applications of this general strategy are in prospect for the formation of fused nitrogen heterocyclic systems in problems of alkaloid synthesis240. 

The /V-acylaminals 136 can serve as substrates for the formation of fused azepinone derivatives on treatment with a catalytic amount of TiCh, although the reaction is sensitive to the nature of the R group. Thus, 138 was obtained from 136 (R = CH2OAc), but with R = Me in 136, the 6,6-fused system 137 resulted (Scheme 18) <1999TL7939>. 

For the period 1995-2006, the formation of fused-ring thietanes from three-membered rings is exclusively confined to the transformation of oxiranes fused to complex ring systems. It was reported <1997PS389> that the 5- y-acetyl-2,3-epoxide derived from D-xylose 116 was easily converted to 2-oxa-6-thia-bicyclo[3.2.0]heptane 117 by the action of sodium acetate (Equation 34). 

Figure 4. Section of the pseudobinary phase diagram of the sulfuric acid SLP catalytic material. The data were taken from Ref. 16. The data points were derived from anomalies of the conductivity versus temperature curves of the respective mixtures. At the high compositional resolution and in the range of the global eutectic, the formation of a vanadate-sulfato complex causes the local maximum in the solidus curve. It is noted that extreme precision in the experimental procedures was necessary to derive this result illustrating the characteristic of fused systems that compound formation can well occur in the molten state.

Also, the one pot reaction of heterocyclic bis-iminophosphoranes with one or two equivalents of aryl isocyanates leads to selective formation of fused heterocycles. For example, from the pyrazole derivative 17 either [l,3]-diazepines 18 or tricyclic ring systems 19 are formed. The latter reaction involves an intramolecular [2-1-2] cycloaddition of both carbodiimide substituents. ... 

The formation of fused anthraquinone systems in a two-stage photoreaction between 2-bromo-3-methoxy-1,4-naphthoquinone and 1,1-diarylethylenes is well established, and the reaction has been extended to include 1-(heteroaryl)-1-phenylethylenes (e.g., 149). In general the preferred mode of ring-closure follows... 

This type of ring formation, via acylation was used for the formation of fused three ring systems, which were then ring-opened for the introduction of the alkyl side chain on the oxazepine (31) (Scheme 11)<89JMC2178>. 

An interesting example of a domino reaction used in a sohd-phase strategy was reported by Meldal et al. [26], wherein the formation of fused (5-5), (5-6), (6-5), and (6-6) bicyclic ring systems was targeted using a common N-acyhminium... 

Carbon-hydrogen bond activation by transition metals has found its way to becoming an important aspect of organic synthesis. Metals have been found to break C-H bonds and then participate in follow-up reactions, oftentimes insertions of olefins or alkynes, that permit functionalization of a substrate or the formation of fused-ring systems. As this chemistry is developed, it is clear that selectivity in C-H bond activation is a critical issue that must be controlled to make a given functionalization reaction valuable. 

The synthesis of fused and polycyclic derivatives of quinoxalines will not be dealt with in this chapter, except those cases where the formation of these systems occurs in one pot. This implies either the condensed parent compounds or the compounds capable, besides constructing a quinoxaline system, to annulate separate rings on various sides under the reaction conditions. 

Only relatively few examples of interesting target molecules containing rings are known. These include caryophyllene (E.J. Corey, 1963 A, 1964) and cubane (J.C. Barborak, 1966). The photochemical [2 + 2]-cycloaddition applied by Corey yielded mainly the /ranr-fused isomer, but isomerization with base leads via enolate to formation of the more stable civ-fused ring system. 

BeryUium reacts with fused alkaU haUdes releasing the alkaU metal until an equUibrium is estabUshed. It does not react with fused haUdes of the alkaline-earth metals to release the alkaline-earth metal. Water-insoluble fluoroberyUates, however, are formed in a fused-salt system whenever barium or calcium fluoride is present. BeryUium reduces haUdes of aluminum and heavier elements. Alkaline-earth metals can be used effectively to reduce beryUium from its haUdes, but the use of alkaline-earths other than magnesium [7439-95-4] is economically unattractive because of the formation of water-insoluble fluoroberyUates. Formation of these fluorides precludes efficient recovery of the unreduced beryUium from the reaction products in subsequent processing operations. 

True electrophilic substitution is very difficult in pyridopyridazines. For example, the [3,4-d] parent (286) is inert to hot 65% oleum (68AJC1291), and although formation of a 3-bromo derivative (308) was reported in the [2,3-d] series, it seems to have arisen by an addition-elimination reaction via the dibromide (309) (69AJC1745). Attempted chlorination led to ring opening. A similar effect was observed in the [3,4-d] system, where an 8-bromo derivative was obtained (77BSF665), and in iV-oxides of the pyrido[2,3-c]pyridazine and fused pyridazino[3,4-c]isoquinoline series (72JHC351). The formation of (311) from (310)... 

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