Addition Of Hypobromous Acid Research Articles

ChemInform Abstract: Addition of Hypobromous Acid to 1‐Phenylcycloalkenes.

AbstractAddition of HOBr, generated in situ by hydrolysis of NBS in DMSO to the title compounds, affords the corresponding 3‐bromo‐2‐phenylcycloalkens as major products.

Addition of hypobromous acid to 1-phenylcycloalkenes

Reaction of 1-phenylcyclooctene and 1-phenylcycloheptene with N-bromosuccinimide (NBS) in aqueous DMSO gives the corresponding 3-bromo-2-phenylcycloalkenes and 2-phenylcycloalk-2-enols in a ratio of 3 : 1. Unlike them, 1-phenylcyclohexene gives a mixture of 3-bromo-2-phenylcyclohexene and 2-bromo-l-phenylcyclohexanol. The oxidation of allylic alcohols with pyridinium chlorochromate afforded the corresponding α,β-unsaturated ketones.

Hydrogen peroxide-or sodium hypochlorite-induced bromination of 1-arylbut-2-enes

Bromination of 1-arylbut-2-enes in the system [HBr or NaBr (KBr)-HX]-H2O2 (or NaOCl) under relatively mild conditions leads to electrophilic addition of bromine or hypobromous acid at the side-chain double bond. Under more severe conditions, the process is accompanied by bromination of the aromatic ring. Treatment of the title compounds with peroxy acids (RCOOH-H2O2) gives the corresponding epoxy derivatives which react with HBr and oxygen-containing nucleophiles to produce α-bromo alcohols, diols, and diol acetates.

Addition reactions at the 16(17) double bond of 3-methoxy-13α-estra-1,3,5(10),16-tetraene

The epoxidation, the addition of hypobromous acid, and the hydroboration of 3-methoxy-13α-estra-1,3,5(10),16-tetraene 1 with diborane, catecholborane, and 9-BBN were investigated in order to determine the stereochemical outcome and to synthesize new 13α-estra-1,3,5(10)-trienes for biological and conformational investigations. It was shown that the sterically demanding reagent 9-BBN participated in a preferred β attack (53% 16βOH 10, 34% 17βOH 8, 13% 16αOH 11). This stereochemical result is in agreement with that from another cis addition reaction, the recently described OsO 4 dihydroxylation of 1 [Steroids 68 (2003) 113]. With smaller reagents such as B 2H 6, catecholborane, or magnesium monoperoxyphthalate, a diminished stereoselectivity was observed with only a slight excess of β attack. The ionic trans addition of hypobromous acid gave two 17-bromo-16-alcohols with 16β,17α ( 4, 76%) and 16α,17β configuration ( 5, 24%) formed by trans cleavage of the 16,17α- and β-bromonium ion at position 16. The same regioselective and stereoselective course was found for the cleavage of the 16α,17α- and 16β,17β-epoxides ( 3 and 2) with hydrazoic acid ( 3→16 βN 3,17αOH 7, 2→16 αN 3,17βOH 6). The stereochemistry of the addition reactions to 1 can be explained in terms of a twist-boat conformation involving the C ring of compound 1. From a synthetic viewpoint the synthesis of the β-epoxide 2 from the bromohydrin 4, the cleavage of this epoxide to 16α-substituted-17β-hydroxy compounds, such as 6, and hydroboration/oxidation with 9-BBN to the hitherto unknown 16β-hydroxy compound 10 are useful procedures. The bromohydrin 5 is the first 13α-steroid with a 17β-bromo substituent. X-ray analysis revealed twist-boat and 16β-envelope conformations for rings C and D, respectively.

ChemInform Abstract: Stereo‐ and Regiocontrol of Electrophilic Additions to Cyclohexene Systems by Neighboring Groups: Participation of Allylic and Homoallylic Ester Groups in Hypobromous Acid Addition to Some 5‐Unsaturated Cholestane Derivatives.

AbstractHypobromous acid addition to some cholestenes such as (I) proceeds with intramolecular participation of the neighboring acetoxy groups.

Steroids 35: Synthesis of 16,16-dimethyl-17β-hydroxysteroids

The reaction of 16-methylene-17-ketosteroids (Ia), (Ic) and (Ie) with methyl magnesium iodide yields 16-methylene-17α-methyl-17β-hydroxysteroids (IIa), (IIb) and (IId). These are subjected to the addition of hypobromous acid and the subsequent anionotropic rearrangement to convert them into 16α-methyl-16β-bromomethyl -17-ketosteroids (Va), (Vb) and (Vd). These were reduced with LiAlH 4 to obtain 16,16-dimethyl-17β-hydroxysteroids (VIa), (VIb) and (VId). Compounds (VIIa) and (VIIe) were selectively deacetylated yielding (VIIb) and (VIId); these were then oxidized and hydrolyzed to convert them into (VIf) and (VIg).

Stereo- and regio-control of electrophilic additions to cyclohexene systems by neighbouring groups: participation of allylic and homoallylic ester groups in hypobromous acid addition to some 5-unsaturated cholestane derivatives

Hypobromous acid addition to 3β,7β-, 3δ,7α-, 3β,7β-, and 3α,7α-diacetoxycholest-5-ene (8)–(11) and 3β,7β,19- and 3β,7α,19-triacetoxycholest-5-ene (12) and (13) involves intramolecular participation of the neighbouring acetoxy group(s). Competing reaction pathways responsible for the product distribution are discussed. The relative importance of steric, electronic (Markownikoff), and stereoelectronic effects has been elucidated. The findings may be used for prediction of the reaction outcome. They also demonstrate that the purposeful introduction of a neighbouring group can direct the addition along the desired route.

ChemInform Abstract: Studies Related to Penicillins. Part 23. Preparation of the N‐Phenylacetyl and N‐Triphenylmethyl Derivatives of (3R,4R)‐3‐Amino‐4‐t‐butylthioazetidin‐2‐one.

AbstractAddition of HOBr (generated in situ) to the diazabicycloheptenone (I) gives the bromohydrin (III) which is partially converted into a mixture of the compounds (IV) and (V), but all attempts to isolate (V) are without avail.

ChemInform Abstract: Participation of Ambident Neighboring Groups in Hypobromous Acid Addition to Some Steroidal Olefins. Competition of Electronic and Stereoelectronic Effects.

AbstractIn the reactions of the steroidal olefins (I)‐(III) with HOBr (generated in situ from N‐bromoacetamide + HClO4), the participation propensity of ambident neighboring groups containing a carbonyl moiety is studied.

Synthesis of some tetrahydrosantonin derivatives with functionalised angular substituents based on remote oxidation

On treatment with lithium di-isopropylamide, the tosylhydrazone (3b) of tetrahydrosantonin (3a) provided the olefin (4) regioselectively, from which the bromohydrin (5) was obtained by the addition of hypobromous acid. Photochemical remote oxidation of (5) was executed in the presence of lead tetraacetate and iodine to give the bromo dilactone (8) as the major product. Tetrahydrosantonin derivatives with functionalised angular substituents (10)–(18) were efficiently derived from (8).

Participation of ambident neighbouring groups in hypobromous acid addition to some steroidal olefins. Competition of electronic and stereoelectronic effects

The participation propensity, in hypobromous acid addition, of various ambident neighbouring groups containing a carbonyl moiety has been studied for steroidal olefins (1)–(3). The carbamoyloxy group (–OCONH2) has been found to be superior to other groups. The relative importance of the electronic (Markownikoff) and stereoelectronic effects in electrophilic additions has also been elucidated. In cases where these effects are dissonant, the neighbouring group participation may alter the regioselectivity of the reaction. A new method of synthesis of unsubstituted carbamates has been developed.

Studies related to penicillins. Part 23. Preparation of the N-phenylacetyl and N-triphenylmethyl derivatives of (3R,4R)-3-amino-4-t-butylthioazetidin-2-one

Addition of hypobromous acid to the alkene moiety of the 6-substituent of (1S, 5R)-3-benzyl-6-(2-methylprop-1-enyl)-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one (7a) was effected by the action of N-bromoacetamide in aqueous acetone. On the basis of 1H n.m.r. spectroscopy, the resultant bromohydrin (14d) was partially converted by triethylamine in deuteriochloroform into a mixture of (1S,5R)-3-benzyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one (7b) and 2-bromo-2-methyl-propanal, but attempts to isolate compound (7b) were without avail.

Synthesis of 19-hydroxyaldosterone and the 3β-hydroxy-5-ENE analog of aldosterone, active mineralocorticoids

19-Hydroxyaldosterone ( 20) and the 3β-hydroxy-5-ene analog of aldosterone (HAA) ( 8) were synthesized from 21-acetoxy-4-pregnene-3,20-dion-20-ethylene ketal-18,11β-lactone ( 2) as follows: the double bond was transposed from the 4,5 to the 5,6-position by enol acetylation to 3, followed by sodium borohydride reduction. Further reduction of the resulting lactone 4a with diisobutylaluminum hydride (DIBAH) furnished the 20-ketal of HAA 6, from which free HAA ( 8) and the 18,21-anhydro compound 7 were obtained by acid treatment. The [ 1H]NMR spectrum of 8 in CDCl 3 showed it to be a mixture of two isomeric forms. Correlation with the known aldosterone-γ-etiolactone ( 10) was established by periodate oxidation of HAA to the corresponding etiolactone 9 followed by chromic acid oxidation. The preparation of 20 was next effected in the following manner: the diacetate 4b was converted into the 6β,19-oxido compound 13b by addition of hypobromous acid followed by the hypoiodite reaction of the bromohydrin 11. Mild saponification of 13b lead to the corresponcling diol 13a, and was followed by selective oxidation to the 3-one 14, readily dehydrobrominated to 15a. Reductive ring opening furnished a mixture of the 19,21-diol 16a and its 5-ene isomer 16b, which was directly converted to the diketal 17. Reduction with DIBAH gave the hemiacetal 18, and hydrolysis of the latter 19-hydroxyaldosterone ( 20) as a water-soluble solid, accompanied by the 18,21-anhydro compound 19. 19-Hydroxyaldosterone exists in CHCl 3 and water as a mixture of mainly two isomers. Periodate oxidation furnished the etiolactone 21. Preliminary results indicate that HAA and 19-hydroxyaldosterone are active mineralocorticoids in the Kagawa bioassay and short-circuit current measurements.

Synthesis of D-norisomorphinans ((±)-[14α]-D-normorphinans)

A synthesis of the D-norisomorphinan ring system is described. Conversion of the initial synthetic target, trans-1,3,4,9,10,10a-hexahydro-6-methoxy-9-oxo-4a(2H)-phenanthrenecarboxamide (10c) into the D-norisomorphinan (6b) proved possible only after removal of the carboxamide ambident functionality. The successful route proceeds via hypobromous acid addition to trans-1,3,4,10a-tetrahydro-6-methoxy-4a(2H)-phenanthrenemethanamine (21) followed by a facile intramolecular cyclization to the D-norisomorphinan (23).

The synthesis of [1,2,3,4- 13C] cortisol

The preparation of [1,2,3,4- 13C] cortisol 21-acetate by total synthesis is described. The 13C labels are introduced in a way analogous to the one described by us previously for the synthesis of testosterone and estradiol. The cortisol dihydroxyacetone side chain was elaborated using known methods. The 11β-hydroxyl function was introduced by addition of hypobromous acid to a 9-double bond followed by reductive debromination. 13C-labeled cortisol can be used as a tracer for the determination of cortisol production rates.

Electrophilic addition to the 5,6-double bond in A-nor-3,5-secosteroids

The stereochemistry of epoxidation, Simmons-Smith methylenation and addition of bromine and hypobromous acid to 5,6-unsaturated A-nor-3,5-secosteroids was studied. The additions proceed from both sides of the molecule and, the β-oriented positively charged intermediate is regularly cleaved under participation by the substituent at C(3) to the corresponding oxa derivative II or to the lactones VI and XI. Cleavage of the cyclopropano derivative XVI with thallium(III) acetate was accompanied by Westphalen rearrangement and lead to the 5-membered lactone XXI. The structures of the products were established by spectral and chemical means and the mechanisms of reactions observed are discussed.

Acetoxyl group as control element in electrophilic addition: Participation by acetoxy group and its competition with other participating groups in hypobromous acid addition to some 5-cholestene derivatives

The 3β-acetoxy cholestene II (with nonparticipating group at the position 19) is known to be attacked with hypobromous acid predominantly from α-site which results in formation of the diaxial bromohydrin XIV. By contrast, inversion of configuration of the 3-acetoxy group leads to a dramatic change in the reaction course: the 3α-acetoxycholestene derivative VIII is preferentially approached by the electrophile from β-site to give the corresponding 5β,6β-bromonium ion XXVII which on cleavage with 6(O)π,n participation by the 3α-acetoxyl yields two products XXIX and XXXI When hydroxy and acetoxy groups can compete in 5(O)n or 6(O)π,n processes, only hydroxyl group participation takes place (IX → XXV and XI → XXXIV). Two acetoxy groups in X compete successfully in 6(O)π,n processes (X → XXXVII + XLI).

Competition of 5(O)n and 6(O)n participation by 19a-substituent in hypobromous acid addition to 2,3- and 5,6-unsaturated 19-homocholestane derivatives

19-Substituted 2,3-unsaturated cholestane derivatives IIIa-IIIc react with hypobromous acid to give the cyclic bromo ether VI as sole or major product arising by cleavage of the 2α,3α-bromoion V with 6(O)n participation by the 19a-group. The 5,6-unsaturated alcohol IVa reacts with hypobromous acid to yield the cyclic bromo ether X as product of 5(O)n participation. Under the same conditions, the methoxy derivative IVb yields two products, X and XI, with violation of Fürst-Plattner rule. In similar manner as in the preceding case, the products arise by cleavage of the bromonium ion IXb with 5(O)n participation by the 19a-methoxyl. In contrast, the 5,6-unsaturated acetoxy derivative IVc reacts without participation via two diastereoisomeric bromonium ions VIIIc and XV to give the corresponding diaxial bromohydrins XVI and XVII which undergo spontaneous cyclization to the epoxides XVIII and XIX. The course of these reactions, comparison with the lower homologs of the type I and II, the role of Markovnikov and Fürst-Plattner rules and capability of the particular functional groups to participate in 5(O)n and 6(O)n processes are discussed.

Neighboring group participation in electrophilic additions: The role of Markovnikov and Fürst-Plattner rule in hypobromous acid addition to 5,6-unsaturated cholestane derivatives

On reaction with hypobromous acid, the unsaturated alcohol IIIa yields the diequatorial bromo epoxide XIX arising from the 5α,6α-bromonium ion XVIIIa on cleavage at C(5) by 19b-hydroxyl group with 6(O)n participation. By contrast, the bromonium ion XVIIIb generated from the unsaturated methyl ether IIIb is cleaved by water as external nucleophile to yield the unstable diaxial bromohydrin XX which undergoes cyclization to the oxirane derivative XXI. A comparison with the reaction course in homologs of the type I and II permits the conclusion that the change in regioselectivity, generally possible outcome of the 5(O)n participation, is only possible for the 6(O)n process if the participating group is a hydroxyl.

Competition of two participating groups in hypobromous acid addition to some 4-cholestene derivatives

Hypobromous acid addition to the 4,5-unsaturated hydroxy acetate VIII results in formation of the cyclic bromo ether XXIXa as a product of 5(O)n participation. Participation by hydroxy group is thus preferred over 5(O)π,n process by acetoxyl. Under the same conditions the 4,5-unsaturated diacetate IX afforded the diaxial bromohydrin XXXI arising from 4α,5α-bromonium ion with 5(O)π,n participation by the 3β-acetoxyl whereas an alternative 6(O)π,n participation by the 19-acetoxyl is not operative. The 3-epimeric diacetate XV reacts with hypobromous acid in a more complex way: the molecule is attacked by the electrophile from both α- and β-sites to give two diastereoisomeric bromonium ions XXXII and XXXIII. The former is simply cleaved with water as an external nucleophile to afford the diaxial bromohydrin XXXIV. The latter undergoes fission both with 5(O)π,n and 6(O)π,n participation: The first route leads to the trans-bromohydrin XXXVI. In the second pathway the acyloxonium ion XXXVII postulated as an intermediate is further cleaved with 6(O)π,n participation by 19-acetoxyl to give the acyloxonium ion XXXVIII, which is trapped by water to yield an unusual cis-bromohydrin XXXIX. The differences in the reaction course are discussed.