Lactams Chlorosulfonyl isocyanate

AT-Unsubstituted azetidin-2-ones are versatile intermediates in the preparation of a variety of novel /3-lactam containing systems. They are usually made either by reductive dechlorosulfonylation of alkene/chlorosulfonyl isocyanate cycloadducts cf. Section 5.09.3.3.2), which... 

Substituted azocine systems are much more stable than the parent compound, and 2-methoxy derivatives have been intensively examined. Starting from cyclohexa-1,4-diene (3), a [2 + 2] cycloaddition with chlorosulfonyl isocyanate, followed by removal of the chlorosulfonyl group, leads to the /3-lactam 4, which can be transformed by O-methylation with Meerwein s salt into the corresponding imidate. Monobromination with A-bromosuccinimide and subsequent treatment with base results in a methoxyazabicyclo[4.2.0]octatriene derivative, which spontaneously isomerizes to 2-methoxyazocine (5).13,14... 

The reactive compound chlorosulfonyl isocyanate (ClSOaNCO, forms P-lactams even with unactivated alkenes, as well as with imines, allenes, conjugated dienes, and cyclopropenes. With microwave irradiation, alkyl isocyanates also... 

Simple allenes can also react with chlorosulfonyl isocyanate (CSI) to afford a-alky-lidene-/l-lactams 8 and 2-carboxamido-l,3-butadienes 9 [8],... 

Allenes react with isocyanates to give the a-alkylidene-/Mactams. The highly reactive chlorosulfonyl isocyanate (CSI) is often used. Initial nucleophilic attack of the central allenic carbon atom to the central isocyano carbon atom produces an allylic cation intermediate, which cyclizes to the /i-lactam. 

Lactams substituted only in the 3 position cannot be prepared by the present procedure, since the lactam formed has the nitrogen of the chlorosulfonyl isocyanate attached to the more highly substituted carbon atom of the olefinic double bond in Markownikoff fashion. 2-Azetidinones substituted in the 3 position only have been prepared by Grignard reagent-catalyzed cyclizations of esters of appropriately substituted /3-amino acids.4,5... 

On the pages which follow, general methods are illustrated for the synthesis of a wide variety of classes of organic compounds including acyl isocyanates (from amides and oxalyl chloride p. 16), epoxides (from reductive coupling of aromatic aldehydes by hexamethylphosphorous triamide p. 31), a-fluoro acids (from 1-alkenes p. 37), 0-lactams (from olefins and chlorosulfonyl isocyanate p. 51), 1 y3,5-triketones (from dianions of 1,3-diketones and esters p. 57), sulfinate esters (from disulfides, alcohols, and lead tetraacetate p. 62), carboxylic acids (from carbonylation of alcohols or olefins via carbonium-ion intermediates p. 72), sulfoxides (from sulfides and sodium periodate p. 78), carbazoles... 

Moricini and Kelly [75] have reported the synthesis of spiro-fi-lactams 6 containing an exocyclic double bond (Scheme 2) by the 1,2-dipolar cycloaddition of symmetrically/unsymmetrically substituted allene 4 with chlorosulfonyl isocyanate 5 in ether. 

Georgiev et al. [82] have described the preparation of novel adamantine-spiro-heterocyclic (3-lactams 34, 35, and 40. Grignard reaction of 2-adamantanone 31 with benzylmagnesium halide provided the compound 32, which on further dehydration afforded corresponding analogs 33. Condensation reaction of compound 33 with chlorosulfonyl isocyanate in ether afforded spiro-(3-lactams 34 and cycloaddition with chlorosulfonyl isocyanate resulted in the formation of spiro product 35 (Scheme 10). 

Starting from the commercially available (+)-3-carene, the cycloaddition of chlorosulfonyl isocyanate [228] has been reported to furnish the enantiomeric (3-lactam in a regio- and stereoselective manner [229]. Treatment of the (3-lactam with di-ferf-butyl dicarbonate resulted in iV-Boc (3-lactam, that could be readily opened under mild conditions (Scheme 104). 

The reaction of chlorosulfonyl isocyanate with 1,4-cycloesadiene [304] was previously reported to provide [3-lactams in quantity. More recently, these CSI-derived building blocks have been reported to be modified in various [3-lactams bearing at C-3 and C-4 protected polar substituents (I, II and III, Fig. 25), [305]. 

Scheme 38 Formation of chiral [S-lactams (155) from chlorosulfonyl isocyanate (148) and homochiral enol ethers (154)...

Here are typical reactions of difnethyl ketene to give a cyclobutanone and chlorosulfonyl isocyanate to give a p-lactam. 

When we wish to make (3-lactams by the alternative addition of an isocyanate to an alkene, a substituent on nitrogen is again required, but for quite a different reason. Because alkenes are only moderately nucleophilic, we need a strongly electron-withdrawing group on the isocyanate that can be removed after the cycloaddition, and the most popular by far is the chlorosulfonyl group. The main reason for its popularity is the commercial availability of chlorosulfonyl isocyanate. It reacts even with simple alkenes. 

Graf [103] originally proposed a two-step mechanism for the cycloaddition of chlorosulfonyl isocyanate to alkenes. This leads to the 1,4-dipole shown in Eq. (5-35), which can then ring close to give a y9-lactam (and as by-product an unsaturated amide via a proton shift from R or R to N ). Moriconi [104], on the other hand, has proposed a nearly concerted, thermally allowed +, j2a] cycloaddition, probably initiated by a r-complex formation, and proceeding through the dipolar activated complex shown in the lower part of Eq. (5-35). 

W-C4H9) [106, 107]. Ab initio MO calculations have shown that the [2 - - 2] cycloaddition between cis- or Jraw-alkenes and isocyanates to yield y9-lactams takes place by a concerted mechanism in the gas phase, with retention of the alkene configuration in the product. However, increasing solvent polarity contributes to the asynchronicity of the reaction to such an extent that the mechanism changes from a concerted to a two-step process involving a zwitterionic intermediate, with a consequent loss of alkene stereospecificity, as observed in the reaction between chlorosulfonyl isocyanates and vinyl ethers [794]. 

Chlorosulfonyl isocyanate reacts with a wide range of alkenes under mild conditions to produce 3-lactams (25) accompaniedby variable but usually minor amounts of open-chain adducts (26 Scheme 27). In most cases, 3-lactams and open-chain products are formed independently. Thus N-chlorosulfonyl amide by-products are not formed by further reaction of N-chlorosulfonyl-3-lactams. 

An alternative route to chiral p-lactams was provided by reactions of electron-deficient isocyanates with chiral nucleophilic alkenes such as vinyl ethers or vinyl acetates. Chlorosulfonyl isocyanate (CSI), a commonly used reactive isocyanate [34], undergoes stereospecific 5-yn-addition to alkenes. The chlorosulfonyl group can subsequently be reductively removed from the nitrogen atom. It has been shown that reactions between CSI and (Z)- and ( )-alkenyl ethers stereoselectively give cA-3,4-disubstituted azetidinones from (Z)-olefins and tmns-3,4-... 

SCHEME 10.13 Formation of (3-lactams on reaction with chlorosulfonyl isocyanate (CSI) with sugar vinyl ethers. 

However, treatment of benzocyclooctatetraene (3) with chlorosulfonyl isocyanate (CSI) at 82 °C for three hours followed by hydrolysis of the resulting Af-(chlorosulfonyl)lactam with aqueous sodium hydroxide in acetone gave via a benzotropylium cation 4, the 2,3-benzo-7-azabicyclo[4.2.2]deca-2,4,9-trien-8-one 5 in 82% yield. 

When bicyclopropylidene reacted with chlorosulfonyl isocyanate the ) -lactam 17 resulting from [2 + 2] cycloaddition was a minor product. The main product was 5-chlorosulfonyl-7-methylene-5-azaspiro[2.4]heptan-4-one (16). ... 

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