Bicyclic system

Bicyclic Systems.—Spirophosphoranes (107) with X = Et, Ph, NEta, NMePh, OMe, OEt, and OPr have been prepared by the oxidative cycloaddition of dioxaphospholanes to aldehydes (106). The reactions are reversible and compounds containing the anti orientation of X with respect to R are the thermodynamically preferred products.  

A study of the reactions of amines and hydrogenphosphonates with spirophosphoranes (108) revealed that when = COaR addition occurred at the p-carbon of the double bond to give (109) or (110), whereas with R = H, amines added to the a-carbon to give (111). The alcoholysis of the P-C bond in (109) and (110) is reported in the same paper.  

Another example of five-co-ordinate phosphorus bound to a transition metal is provided by the reaction of (112) with (113) to form the spirophosphorane (114) in 91 % yield. The n.m.r. shift at + 67 p.p.m. is very broad (1100 Hz at half height) because of coupling with the manganese nucleus (spin 5/2), but n.m.r. and i.r. data serve to substantiate the structure as five-co-ordinate. 

Further evidence for a biphilic insertion mechanism is derived from a study of the reaction of the bicyclic phosphoramidites (115) and (116) with diethyl peroxide to form (117) and (118), respectively. The strained 1-phosphabi-cyclo[3.3.0]octane (115) reacts much faster than its l-phosphabicyclo[4.4.0]-decane analogue (116), but the opposite reactivity is found towards diphenyl disulphide. At room temperature (116) produced (120) within seconds, presumably via an intermediate phosphonium salt, whereas (115) gave (119) [S 3ip = —19 p.p.m.] after 1 h at 58 °C. As mentioned earlier, the latter appears to be the only phosphorane reported so far with two exocyclic P-S bonds. 

Tetraoxyazaphosphoranes [e.g., (121) and (122)] may be obtained by the reaction of (115) and (116) with trifluoroethoxybenzenesulphenate, and detailed n.m.r. studies suggest that (121) is the major topological isomer in the series derived from (115) whereas (122) predominates in the series from (116). When (116) was 

The synthesis of bicyclic y-lactam-piperazinone derivatives has been reported by Hulme et al. [8b] as an extension of the UDC strategy. Alternatively, the formation of y-lactams by reacting y-keto acids, amines, and isocyanides [89] has been ex- 

Golebiowski et al. reported the solid-phase [92] and the solution-phase [93] syntheses of bycyclic diketopiperazines which were of great interest because their conformation was similar to the type-1 /i-turn motif. A Merrifield hydroxymethyl resin was esterified with a-N-Boc-fi-N-Fmoc-L-diaminopropionic acid and then mono-deprotected at the / -N with piperidine. Ugi-4CR of the resulting resin-bound amine gave the resin-bound adducts 168. Subsequent N-Boc deprotection and intramolecular N-alkylation afforded the ketopiperazines 169. The diketopiperazines 170 were formed via N-Boc amino acid coupling followed by N-Boc deprotection 

As an example, carbons 1 and 2 of methylcyclohexane would be predicted to be found as follows  

Reasonable predictions for the shift values for trans-decalin can be based on the simple substituent effects outlined in Chapter 1 and the stereochemical considerations mentioned above. Thus, the bridgehead carbons would be predicted to absorb at 45.3 (27.3, + 24.0 for three additional P substituents, and -6.0 for a 3 carbon with four p substituents, 43.7 obs.). Similarly, the prediction for C-2 would be 35.3 (27.3 + 8.0), 34.3 observed, and for C-3 would be 27.3 (26.9 obs.) since there are no additional a or P substituents relative to cyclohexane and the y carbons are anti, not gauche. There is a small upfield shift, typically 0.5 for an anti, y carbon, but in most cases this effect is too small to be of significant use in st eochemical predictions. The situation with cis-decalin is more complicated because of the superposition of two equal energy conformations. Nonetheless, the shifts observed are understandable once this factor is combined with stereochemical considerations to be detailed in Chapter 3. 

Substituent M2-OH M2-Me M2-Et M2-COOH M2-COOEt M2-COMe M2- CHOHMe M2-CHO M2-CH20H M2- CHOHMe 

Sadtler Standard Carbon-13 NMR Spectra, Sadder Research Laboratories, Philadelphia, Pa 19104 (1976-1982). 

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The high regioselectivity ( stereoelectronic control ) in the ring cleavage by chlorination of sulfur was anticipated. It had been found before that in corresponding bicyclic systems such as in the scheme below oxidation of the sulfur atom always led to the undesired cleavage of the S—Cg bond. This was rationalized through the observation on molecular models that... 

The silyl enol ethers 209 and 212 are considered to be sources of carbanions. and their transmetallation with Pd(OAc)2 forms the Pd enolate 210. or o.w-tt-allylpalladium, which undergoes the intramolecular alkene insertion and. 1-elimination to give 3-methylcyclopentenone (211) and a bicyclic system 213[199], Five- and six-membered rings can be prepared by this reaction[200]. Use of benzoquinone makes the reaction catalytic. The reaction has been used for syntheses of skeletons of natural products, such as the phyllocladine intermediate 214[201], capnellene[202], the stemodin intermediate 215[203] and hir-sutene [204]. 

Pyridazines with an appropriate side chain attached to the sulfur atom at position 3 can be transformed into bicyclic systems. For example, pyridazinyl /3-ketoalkyl sulfides are cyclodehydrated in sulfuric acid to give thiazolopyridazinium salts, and 3-carboxymethyl-thiopyridazines are transformed by acetic anhydride in pyridine into 3-hydroxythiazolo[3,2-6]pyridazinium anhydro salts (Scheme 52). 

One of the widely used cinnoline syntheses is the transformation of diazotized o-aminoarylethylenes into this bicyclic system (Widman-Stoermer synthesis) (Scheme 69). 

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. 

The thiones are readily desulfurized with Raney nickel to give the corresponding unsubstituted compounds in bicyclic systems in the 2-, 4- and 7-positions, and in tricyclic systems such as (95). The 2-methylthio derivatives may be similarly desulfurized. Thione groups in the 4-position, but not the 2-position, in pyrido-[2,3- f ]- and -[3,2- f]-pyrimidines may be replaced directly with ammonia or amines. 

Krespan ° has prepared a number of macrocycles, having both aza- and oxa-linkages in them, based on the 3,3-dimethyleneoxetane unit (see also Sect. 8.4 and Eq. 8.12). Typically, 3,3-bis(chloromethyl)oxetane is treated with a diol as shown in Eq. (3.40), in the presence of base. Once the bicyclic system is formed, further treatment with other nucleophiles (e.g., ammonia) can lead to opening of the 4-membered ring. 

In bicyclic systems, bridgehead hydrogens are most resistant to replacement by fluorine Cobalt trifluonde converts l//-nonafluorobicyclo[3.2.0]hept-6-ene to... 

The bicyclic amine 11-methyl-l l-azabicyclo[5.3.1]hendecanc (71) provided a model system in which the hydrogens on the equivalent a-tertiary-carbon atoms cannot be trans to the nitrogen-mercury bond in the mercur-ated complex and in which epimerization at these a carbons is impossible (77). This bicyclic system is large enough to accommodate a... 

Taylor has reported a number examples of intramolecular variations directed towards heterocyclic systems.The following two reactions are representative. Intramolecular addition of triazine 79, after loss of nitrogen afforded 80. Alternatively, triazine 81 generated bicyclic systems 82 which could be oxidized to 83. 

Methylpyrido[2,3-d]pyrimidin-2,4(l//,3/7)-dione has also been prepared by this method, which has also been used for the synthesis of other bicyclic systems. ... 

When an azine-nitrogen and a leaving group are in the 2,3-relation to each other in monoaza- and polyaza-naphthalenes, there is a dramatic effect on the reaction rate (for 3-chloroisoquLnoline lO -lO -fold less than for its 1-chloro isomer and for 2-chloroquinoline 200-400-fold less than for 2-chloropyridine) due to restrictions imposed on the resonance stabilization of charge in the transition state by the bicyclic system ... 

The low reactivity (Section IV,B,3,a) of 3-chlorocinnoline compared to that of its isomer 407 is the combined result of decreased activation by an ortho ring-nitrogen and of the effect of the bicyclic system on charge stabilization in 2,3-orientations. The 2-Le-3-aza effect alone is the reason that the reactivity of 3-chlorocinnoline (396) is much lower than that of its benzopyridazine isomer 403. 

Azide-tetrazole isomerism, or valence tautomerism, was not discussed for [5.6]bicyclic systems in the previous survey (76AHCS1). During recent years, this type of ring-chain tautomerism has been extensively studied for both six- and hve-membered heterocyclic azides. Tire tautomerism of [5.5]bicyclic tetrazole systems is covered in Section II,C. We discuss the tautomerism of the six-membered heterocyclic azides in this section. 

Methods for synthesis of saturated seven-member 0-heterocycles and bicyclic systems with 0-bridge 98ACR603. 

The cycloaddition reaction of compound 6 with N-aryl- and N-aralkylazides 23 was also investigated (967(52)7183). Thiadiazabicyclo[3.1.0]hexene derivatives 25 were obtained from the labile triazoline intermediate 24 through nitrogen elimination. This bicyclic system underwent thermal transformation, producing thiadiazine dioxides 26 as the main product together with thiazete dioxides 27 and pyrazoles 28. 

Bicyclic isothiazole dioxides 81 (99JHC(36)161), on treatment with Ai-nucleo-philes such as benzylamine, afforded isothiazole dioxides 82a,b together with a minor amount of compounds 83. Alternatively, 82b could be obtained from 84 by reduction with 1,2-dimethylhydrazine and DBU. By using r-butylamine as the A-nucleophile, due to steric reasons, the formation of the isothiazole dioxide 85 could also be observed followed by transformation in the bicyclic system 86. 

CN/CC replacements were also observed when the pyrimidine ring is part of a bicyclic system. Reaction of quinazoline with active methylene compounds, containing the cyano group (malonitrile, ethyl cyanoacetate, phenylacetonitrile) gave 2-amino-3-R-quinoline (R = CN, C02Et, Ph) (72CPB1544) (Scheme 12). The reaction has to be carried out in the absence of a base. When base is used, no ring transformation was observed only dimer formation and SnH substitution at C-4 was found. 

The bicyclic system quinazoline undergoes intermolecular inverse cycloaddition reactions with enamines RRiNCR2=CHR3 (RRi=(CH2)3, R2 = Ph, R3 = H) yielding 2,3-disubstituted quinolines. 

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... 

The final chapter by Istvan Hermecz (Chinoin, Ltd., Budapest, Hungary) deals with bicyclic systems containing one ring junction nitrogen and one heteroatom and their benzologs, i.e. pyrido-oxazines, pyrido-thiazines, pyrido-pyridazines, pyrido-pyrazines, pyrido-pyrimidines and their analogs. Much of this material has not been reviewed for forty years, during which time immense advances have occurred. 

The intramolecular Sakurai reaction allows for the synthesis of functionalized bicyclic systems. By proper choice of the reaction conditions, especially of the Lewis acid or fluoride reagent used, high stereoselectivity can be achieved, which is an important aspect for its applicability in natural products synthesis. 

When submitted to oxidation by a 2 per cent, solution of permanganate, pinononic acid, CgHj Og, melting at 128° to 129° C., the semi-carbazone of which melts at 204° C. Lastly the constitution of verbenone, as expressed by the above formula, is further confirmed by the fact that the bicyclic system is convertible into a monocyclic system by boiling with 25 per cent, sulphuric acid, with the formation of acetone and 3-methylcyclohexene-(2)-one-(l). This cyclohexenone has been characterised by its semi-carbazone (melting-point 198° C.) and by its conversion into y-acetobutyric acid (melting-point 36° C). The oily liquid, which did not react with sulphite, was submitted to benzoylation after dilution with pyridine. It thus gave rise to a benzoate from which was... 

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