Bicyclic system fused

A number of papers have been published on the chemistry and biological activity of 1,5-benzothiazepines containing an additional bicyclic system fused to different positions of the seven-membered ring. Tetracyclic indolo-, benzofuro-, pyrazolopyrido-, quino-, benzopyrano-, benzothio-pyrano-, quinazolino-, and quinoxalino-l,5-benzothiazepines are known. 

It is possible to prepare pyrimidines from other heteromonocyclic compounds by a variety of processes, or from fused heterobicyclic systems which already contain a pyrimidine ring by preferentially degrading the unwanted second ring. In the latter case, the bicyclic system may best be made from a pyrimidine in the first place, occasionally even from the self-same pyrimidine to which it reverts on degradation. Such syntheses may be of interest but are certainly not of any utility. 

Whereas in all previously mentioned inverse cycloaddition reactions [h]-fused pyrido annelated systems are formed, some reactions are described which lead to [c]-pyridine annelated bicyclic systems. 5-(Butynylthio)pyrimidines (R = Ph, NHCOCH3) give on heating at 180°C in nitrobenzene 5-R-2,3-dihydrothieno[2,3-c]pyridines (89T803). 5-Propynyloxymethylpyrimidines also readily undergo cycloaddition into l,3-dihydrofuro[3,4-c]pyridines (89T5151) (Scheme 39). Considerable rate enhancements were observed with quaternized pyrimidinium salts. Whereas... 

Fused bicyclic systems are those in which two rings share two and only two atoms. In such systems there is no new principle. The fusion may be cis or trans, as illustrated by cis- and /ran -decalin. However, when the rings are small enough, the trans configuration is impossible and the junction must be cis. The smallest trans junction that has been prepared when one ring is four-membered is a four-five... 

Of the possible 10 bicyclic systems containing one bridgehead nitrogen and two extra nitrogen atoms, 1 1 in each ring, nine are known. One new system, pyrimido[l,6-A]pyridazine (system 1 in Table 1), has been reported since CHEC-II(1996) <1996CHEC-II(8)633>. The number of known tricyclic benzo-fused systems is 16. 

Of the possible 16 pyridazino-, pyrimido-, and pyrazino-oxazines, 10 are known with 19 benzo-fused derivatives. Literature over the past 10 years reports 10 bicyclic and 9 tricyclic systems and these are shown in Table 2. Of the possible 16 N-bridgehead pyridazino-, pyrimido-, and pyrazino-thiazines, 7 are known along with 13 benzo-fused derivatives. In this review five bicyclic and four tricyclic systems are discussed and these are shown in Table 3. One bicyclic system has been reported with a Se heteroatom and this is shown in Table 4. 

A wide range of ring sizes have been synthesized, from the very small [1.1.0] fused ring systems to the macro-bicyclic systems. The reactivity and synthesis of the fused ring systems is reviewed first followed by the nonfused compounds. As the synthetic methods used to produce the various examples in this class of compounds were well reviewed in CHEC-II(1996), the synthetic methods section, Section 12.12.8, will outline selected types of compound within this group that have received more attention over the review period. 

CHEC-II(1996) comprehensively outlines the most commonly used synthetic approaches applied to these types of bicyclic compounds of phosphorus, arsenic, antimony, and bismuth <1996CHEC-II(8)863>. The six classes of compounds listed in this section have received considerable attention over the review period and as such the principal synthetic methods for these compounds are discussed. Schoth et al. <2000CCR101> have reviewed the use of fluorinated 1,3-diketones, 2-trifluoroacetylphenols, and their derivatives in the synthesis of phosphorus compounds. Included in this review is the use of these reagents for the synthesis of various [3.3.1] nonfused and [3.3.0] fused phosphorus bridgehead bicyclic systems. 

The products of these [4 + 2 + 2]-reactions have a high level of molecular complexity, which has been used to advantage in exploring the conversion of the [4 + 2 + 2]-cycloadducts into commonly encountered ring systems. Zeise s dimer, for example, has been employed to carry out a skeletal rearrangement, as illustrated in Scheme 61, producing fused and bridged bicyclic systems found in several natural product families. 

In the first step, borane coordinates to the nitrogen atom in oxazaborolidine 79b from the less hindered side of the fused bicyclic system, resulting in the... 

The number of methods available for the synthesis of bicyclic systems containing two fused five-membered rings with one bridgehead nitrogen can be summarized in a few general reactions dehydrative ring closure, oxidative Schiff base cyclization, and base-induced closure (Scheme 3). One-pot reactions involving precursor synthesis followed by cyclization are also known. 

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). 

Intramolecular electron transfer initiated cyclization reaction of 7V-allyliminium salt systems may also generate 3-pyrrolidinyl ethers or alcohols in monocyclic and bridged or fused bicyclic systems (e.g. equations 63 - 65)122,123. 

In contrast, in the formation of the hydroazulene ring of bulnesol (23) Marshall and Partridge [11] started from a bridged system (21) to arrive, through an intermediate carbocation 22, at the fused bicyclic system 23 (Scheme 7.10). 

A base-promoted reaction between L-threitol and tetraethylene glycol di-tosylate afforded (165) the chiral bis(15-ctown-5) derivative l-146 as well as the trans-fused bicyclic system l-147 containing 15-crown-5 and 17-crown-5 rings. These constitutional isomers, which were separated chromatographically, were characterized by preparing l-147 unequivocally by a stepwise route from 2,3-O-isopropylidene-L-threitol. 

Bicyclic systems 146 have been further elaborated into other natural productlike structures by acid-promoted rearrangement, which affords fused tricyclic systems [125], or by ring-opening/ring-closing metathesis processes [123, 126], after installing allyl groups into the structure. 

Some related cyclic scaffolds, such as the azepines, were obtained by Ugi-4CR/ RCM combinations (Fig. 5a) [61], and fused benzodiazepine/triazole frameworks were derived from sequential Ugi-4CR/alkyne-azide dipolar cycloaddition (Fig. 5b) [62]. Both are considered as interesting (3-tum mimics. Similarly, bicyclic systems featuring fused DKP rings (Fig. 5c) have been reported to mimic the ten-membered pseudo-cycle of type 1 (3-tums [63, 64]. 

The strongly colored planar fused bicyclic system (25) is quinonoid with distinctly alternating bond lengths 1.33-1.35 A and 1.42-1.44 A. A strong 7r-stacking interaction in the molecule (28) between tolyl and phenanthroline planes is evident (interplane distance is 3.3 A), as well as between tolyl and cyclopentadienyl planes (the distance is 3.61 A) which results in columns of stacked molecules. 

The intramolecular cycloadditions of cychc nitronates have received much more attention. The cyclic nitronate structure provides three basic modes of intramolecular cycloaddition (Fig. 2.15). Attachment of the tether to the C(3) position of the nitronate results in the formation of a sprro system (sprro mode). However, if the tether is appended to the C(4) position of the nitronate, the dipolar cycloaddition yields a fused ring system (fused mode). Finally, if the tether is attached at any other point of the cyclic nitronate, the cycloadducts obtained will consist of bicyclic structures (bridged mode). 

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