Debrominative cyclization

Incineration of a collection of polymers with 10 different kinds of brominated flame retardants has been studied under standardized laboratory conditions using varying parameters including temperature and air flow. Polybrominated diphenyl ethers like the deca-, octa-, and pentabromo compounds yield a mixture of brominated dibenzofurans while burning in polymeric matrices. Besides cyclization, debromination/hydrogenation is observed. Influence of matrix effects and burning conditions on product pattern has been studied the relevant mechanisms have been proposed and the toxicological relevance is discussed. 

During incineration of 1 in the polymeric matrix debromination/hydrogenation occur in addition to cyclization process. Tetrabrominated dibenzofuran isomers are the most abundant products formed in the temperature range between 300° or 400° (Figure 6 shows Br-composition at 300° - 800°C). Incineration at 400°C gives tetrabromo-benzofurans in yields up to 13 % (Fig. 6). Besides of PBDF, brominated dibenzodioxins are also formed, but to a much lesser extent (30-90 ppm) (ref. 11). 

Metljylcoumarone has been prepared by the cyclization of ethyl a-phenoxyacetoacetate followed by hydrolysis and decarboxylation of the resulting ethyl 3-methylcoumarilate,3 4 by debromination and rearrangement of 3,4-dibromo-4-methyl-coumarin to 3-methylcoumarilic acid followed by decarboxylation,4-6 by cyclization of phenoxyacetone with concentrated sulfuric acid,6 and by treatment of 3-coumaranone with methyl-magnesium iodide followed by dehydration of the resulting car-binol.7... 

Treatment of 122 with (R,R)-tartrate crotyl-boronate (E.R.R)-W 1 provides the alcohol corresponding to 123 with 96% stereoselectivity. Benzylation of this alcohol yields 123 with 64% overall yield. The crude aldehyde intermediate obtained by ozonolysis of 123 is again treated with (Z,R,R)-111 (the second Roush reaction), and a 94 5 1 mixture of three diastereoisomers is produced, from which 124 can be isolated with 73% yield. A routine procedure completes the synthesis of compound 120, as shown in Scheme 3-44. Heating a toluene solution of 120 in a sealed tube at 145°C under argon for 7 hours provides the cyclization product 127. Subsequent debromination, deacylation, and Barton deoxygenation accomplishes the stereoselective synthesis of 121 (Scheme 3-44). 

Pd(Ph3P)4 and Et3N in refluxing acetonitrile to form the intramolecular Heck cyclization product 152 [125]. The mechanism is akin to that of the Mori-Ban indole synthesis (see page 24). In another case, the intramolecular Heck cyclization of enamidone 153 with a pendant thienylbromide moiety furnished the 6-trig-endo product, indolizine 154, in 63% yield, along with the debrominated enamidone 155 in 37% yield [126],... 

Coupling of 834 with 783 gave 835, which cyclized to 836 (92MI8). However, treatment of the sodium salt of 839 with 783 afforded a mixture of two major positional isomers of nucleosides. The reaction is thermodynamically controlled. At room temperature the N-1 isomer predominates, whereas formation of the N-7 isomer increases with an increase in temperature. Debromination of the mixture gave 840 and 841, which could be separated. 

Trans acylations have been encountered in the acylation of 2-acylthiophenes. Thus the action of benzoyl chloride on 2-acetylthiophene in presence of excess A1C13 has led to a complex mixture, from which 2-benzoyl-, 2,4-dibenzoyl- and 2,5-dibenzoyl-thiophene were isolated (73ZOR1959). Other examples of ipso acylation including acyl-debromination and acyl-de-r-butylation have been recorded. Unexpected products have been reported in some intramolecular cyclizations. Thus cyclization of the acid (103) leads to (104) and not (105) (63AHCHH). Acid-catalyzed cyclization of ylidene-malononitriles has been reported (75JOC1840). Yields are in the range 30-60% (Scheme 19). 

The cyclization of a number of chalcone dibromides to flavones has been achieved by treatment with pyridine (81JOC638). It is thought that the reaction may proceed through debromination and dehydrobromination to the chalcone and bromochalcone, respectively (Scheme 166). The formation of pyridine perbromide would account for the nuclear brominated flavones which sometimes accompany the flavone (63CB913). 

Fused tetracyclic biaryl-2-azetidinones have been prepared by the radical cyclization of aryl /3-lactam-tethered haloarenes. Azetidin-2-one 504, having an extra radical acceptor on C-3, underwent radical cyclization with tributyltin hydride to give the biaryl-2-azetidinone 505 in a low yield, with debrominated 3-phcnoxyA-phcnyl-l -(/ -methoxy-phenyl)-2-azetidinone as the main product (60% yield) (Equation 82). But when the azetidinones 506 (Rz = R6 = H) bearing an extra link (O) on the radical precursor at C-3 or N-l of the /3-lactam ring were treated with tributyltin hydride, the expected cyclization products 507 were obtained. If azetidinones 506 (Rz = OMe, or Me R6 = H, OMe, or Me) were treated in the same way then the tetracyclic azetidinones 508 were produced (Equation 83) <2005T7894>. 

Stereoselective synthesis of (+ )-botryodiplodin was carried out by a radical cyclization of dibromoacetal (203) containing an allene group, with Bu3SnH initiated by Et3B, through the 5-exo-trig cyclization, and the subsequent debromination with bulky... 

Subsequent exposure of geminal dibromide 62 to BU3S11H provided the desired ester 63 via a stereocontrolled cyclization-debromination tandem sequence. Finally, Barbier-Wieland degradation and hydrogenolytic debenzylation of ester 63 afforded 5a-carba-D-fructofuranose 64 in excellent yields. In a preliminary enzymological study, its 6-phosphate derivative showed to be an interesting substrate for the enzymes of the glycolysis pathway. 

The closure of the 4,5-epoxide bridge during synthesis of compounds with structures related to morphine has been the subject of several investigations. Schopf 50,51 was the first to achieve the closure of dihydrothebainone (13) in high yield, by dibromination followed by debromination effected with alkali. When the corresponding isomorphinan-6-one (i.e., B/C trans-dihydrothebainone) was treated in a similar manner, cyclization was less efficient/52 This pathway was employed during early syntheses of both metopon<53) (74, Scheme 2.12) (p. 36) and morphine/5 ... 

The halolactonization reaction can be utilized to synthesize enantiomerically pure ot-hydroxy acids. In fact, cyclization of the (S)-/V-(a,/ii-unsaturated acyl)proline 1, prepared by the condensation of ( S )-pi oline and ( )-2-methyl-2-butenoyl chloride in 86 % yield, proceeds stereoselec-tively. The halolactonization, carried out by stirring the unsaturated amide with an equivalent of jY-bromosuccinimide in dimethylformamide for 20 hours, provides the bromolactone 2 in 84% yield and a diastereomeric ratio of 94.5 5.5. Debromination with tributyltin hydride in benzene affords the crude lactone 3 which is hydrolyzed with 36% hydrochloric acid at reflux to give (R)-2-hydroxy-2-methylbutanoic acid (4)1,2,4b. 

Attempts to enforce the morphine type of coupling have so far been unsuccessful. XXIXa cyclizes at C2 with debromination [153]. XXIXb [149,153] and XXIXc,d [157] lead to cleavage at Cl in XXIXe,f the C2 ring closure is hardly hindered and I or Br is replaced in an ipso substitution [149,153] XXIXg, however, in which the C2 and C6 coupling are identical, forms 35-55% of the cyclization product [151,153]. 

Alternatively, a,a -dibromo ketones are reductively debrominated with concomitant cyclization by [Cr(C0)4N0][PPN] at -78 or — 95°C in dichloromethane. This method is particularly suited for NMR tube scale experiments, but is limited to tri- and tetrasubstituted cyclopropanones. Bicyclo[1.1.0]butanones are also accessible by this synthetic procedure which utilizes 1,3-elimination of two bromine atoms from 2,4-dibromocyclobutanones. ... 

Bromoquinolines behave in the Suzuki reaction similarly to simple carbocyclic aryl bromides and the reaction is straightforward. Examples include 3-(3-pyridyl)-quinoline 80 from 3-bromoquinoline 58 and 3-pyridylboronic acid 79 [36] and 3-phenyl-quinoline 83 from substituted 3,7-dibromoquinoline 81 and (2-pivaloylaniinophenyl)boronic acid 82 [37]. Notice that the combination of potassium carbonate and ethanol resulted in debromination at the C(7) position (but the combination of sodium carbonate and methanol left the C(7) bromide intact). It was speculated that the debromination arose from a second palladium insertion, followed by hydrolysis of the intermediate. Further manipulations of biaryl 83 delivered an interesting ll//-indolo[3,2-c]quinoline 84. The result is particularly intriguing since the cyclization of the azide is regioselective which is not usually the case in the pyridine series [38]. 

Total syntheses of ( )-capaurine (194 R1 = R2 = R4 = R5 = Me, R3 = OH),209 ( )-isocorybulbine (195 R1 = Me, R2 = R3 = H, R4 = R5 = OMe),202 ( )-kikemanine (194 R1 = R2 = R4 = Me, R3 = R5 = H),210 and ( )-0-methylcaseadine (202)211 have been reported. In all cases, conventional routes involving Bischler-Napieralski cyclization to form benzylisoquinoline derivatives and subsequent insertion of the C(8)-carbon by reaction with formaldehyde were adopted. A further example of para-activation by an ethoxycarbonyl-amino-function for the Bischler-Napieralski reaction may be noted.211 In the synthesis of capaurine, the presence of the bromo-function in compound (203) forced the Mannich reaction with formaldehyde to produce the tetracyclic derivative (204) rather than the normally more favourable mode of cyclization para to the hydroxy-group. Debromination was effected at a later stage with zinc powder in 50 % acetic acid solution.209... 

Two DHPs were obtained from tetramethoxystilbene [279]. Substitution by a nitro group in the meta or para position reduces distinctly [82], Saltiel et al. have questioned whether the values may be erroneous [105], On the basis of quenching measurements with azulene they proposed additional routes for bromostilbenes from c via excited states of DHP which may relax back to 3c or c. A consequence of a higher value of for the mechanism of cis -> tram isomerization is that the ratio of c decaying to the trans isomer may have to be reexamined. For trans-ct-bromostilbene and the / -phenyl substituted derivatives several photoreactions (e.g., debromination) compete with photocyclization [475]. Interestingly, no evidence for photocyclization could be found for several fluorinated stilbenes [481]. Rotamers can be distinguished in the cyclization of c/s-2,2 -DNE [482],... 

A variety of y-lactams are prepared by 5-exo or 5-endo cyclization of a-haloamides depending on the substrate [4, 5]. Dimethylbromoacetanilide 4 reacted smoothly with nickel powder-acetic acid in 2-propanol to give the bromolactam 5 in 68% yield together with debrominated lactam 6 (23%). However, when 2-propanol was replaced by cyclohexane, a poorer hydrogen donor, bromide 5 was the sole product (85%). 

The synthesis of hepialone (928), the principal sex pheromone produced by the male moth Hepaialus californicus, relies on (7 )-1,2-epoxybutane (925) as the source of chirality (Scheme 136) [204]. Epoxide 925 is in turn synthesized from (7 )-malic acid by reduction of the THP derivative 921b with lithium aluminum hydride and conversion of diol 922 to ditosylate 923 and then dibromide 924. Removal of the protecting group followed by base-catalyzed cyclization results in epoxide formation. Debromination of the primary bromide with tri-n-butyltin hydride affords the desired oxirane 925. 

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