Dichlorocarbene reaction with amines

Secondary amines react readily with dichlorocarbene to yield secondary formamides in good yield [17, 18]. Apparently, the secondary amine coordinates with dichlorocarbene, and after proton transfer a dialkylaminodichloromethane is produced. The latter undergoes basic hydrolysis under phase transfer conditions which evidently stops before appreciable cleavage of the formamide occurs. The reaction is formulated in equation 3.12 and several examples are tabulated in Table 3.5. 

Reaction with chloroform under basic conditions is a common test for primary amines, both aliphatic and aromatic, since isocyanides have very strong bad odors. The reaction probably proceeds by an SnIcB mechanism with dichlorocarbene as an intermediate ... 

When the reaction with substituted benzaldehydes is conducted in the presence of ammonia, the a-amino carboxylic acids are formed [11], The corresponding reaction involving bromoform is less effective and, for optimum yields, the addition of lithium chloride, which enhances the activity of the carbonyl group, is required. In its absence, the overall yields are halved. The reaction of dichlorocarbene with ketones or aryl aldehydes in the presence of secondary amines produces a-aminoacetamides [12, 13] (see Section 7.6). 

When ketones are reacted with dichlorocarbene in the presence of secondary amines, a-aminoacetamides are obtained via the ring opening of the intermediate oxiranes by the amine [19]. Similar products are obtained from the corresponding reactions with aniline and also with aldehydes (see Section 7.4). 

Carbenes insert into the N=N bond of azo compounds and the unstable adducts rearrange spontaneously to produce benzopyrazoles (e.g. Scheme 7.31) [37,38], The reactions of azo compounds with dichlorocarbene is also catalysed by tertiary amines [36] and, under such conditions, azoxyarenes produce the benzimidazoles, presum-... 

Chloroindolizine is formed in a reaction of 2-vinylpyridine with dichlorocarbene (77ACS(B)224). Af,(V-Disubstituted 3-aminoindolizines have been obtained from a reaction of 2-bromopyridine, propanol and secondary amines (79CL24 l). Irradiation of N- phenylpyr-role and N-methyldibromosuccinimide in benzene gave 18% of the indolizine (187) (80CB2884). 

The chemistry of ammonium ylides formed from the reaction of cyclic amines with carbenes was found to be dependent on the ring size of the amine.52 For example, treatment of 1-benzylazetidine (104) with ethyl diazoacetate in the presence of a copper (II) catalyst afforded pyrrolidine 106 in 96% yield. This result is consistent with ammonium ylide formation followed by ring expansion. In contrast, treatment of 1 -phenethylaz-iridine (107) under identical conditions gave the fragmentation product 109 in quantitative yield. Similar results were observed for the reaction of aziridine 107 with dichlorocarbene.53 On the other hand, reaction of 1-phenethylpyrrolidine with ethyl diazoacetate in the presence of a... 

Scheme 5.1 Reaction of secondary amines with dichlorocarbene generated in situ.

Reactions of Enamines.—Hydroboronation of the 2-enamine (397) gave a product (amine-borane adduct ) from which the 3a- and 3 -pyrrolidino-derivatives (398 3a 3)5 = 82 18) were liberated by refluxing methanol. The stereochemistry of this reduction is quite unusual, and not fully explained. Reaction of the 3,5-dienamine (399) with dichlorocarbene led to ring expansion, giving the A-homo-4-chloro-dienone (400). " Condensations of the enamine... 

The dichlorocarbene complex (TPP)Fe(CCl2) is a useful synthetic intermediate forming isocyanide complexes upon reaction with primary amines (Eq. 14) [106]. 

Sol 9. (d) Aldehydes and ketones having a-protons react with secondary amines to form enamines. The enamine formed in the first step undergoes cyclopropanation reaction at the double bond with dichlorocarbene that is generated by a-elimination of HCl from chloroform. This product undergoes ring expansion to furnish 2-chlorocyclohex-2-en-l-one (I). 

The reactions of dichlorocarbene with a variety of olefinic and acetylenic substrates have been discussed in Chap. 2. We wish now to turn our attention to the reactions of this species with a number of other substrates which either are non-olefmic or contain double bonds which do not constitute the major reactive function. The substrates considered here are alcohols, imines, amines, amides, thioethers, and hydrocarbons. With the exception of the latter, all of these species appear to react by initial coordination of the electrophilic carbene with a Lewis basic site. Subsequent reactions attributable to differences in the basic function or involvement with other reactive sites lead to differences in the chemistry of each substrate, and each is therefore considered separately. 

One example of the reaction of dichlorocarbene with a tertiary amine under phase transfer conditions has been reported [20]. 5,7-Diphenyl-1,3-diazaadamantan-6-one is transformed into l,5-diphenyl-N,N-diformylbispidin-9-one in 23% yield. This unusual reaction may be rationalized as follows. Coordination of dichlorocarbene with a nitrogen lone pair yields a zwitterion (VI). Neighboring nitrogen assists fragmentation and the iminium zwitterion VII results. Protonation and hydrolysis of VII followed by dichlorocarbene reaction with the resulting secondary amine yields the bis-formamide VIII. The sequence is formulated in equation 3.13. 

The reaction of dichlorocarbene with primary amides, amidines, thioamides, and aldoximes all yield the corresponding nitriles. N,N-Disubstituted ureas likewise yield the corresponding N,N-disubstituted amine nitrile. This reaction amounts to a dehydration in the case of primary amides, aldoximes, and N,N-disubstituted ureas the elements of hydrogen sulfide are lost from thioamides, and HCN from amidines. 

Reactions of carbenes other than cyclopropanation can also be performed, and recent examples include the ring expansion of five-ring heterocycles, such as the indoles (18), to their six-membered counterparts (19), and the production of formamides from secondary amines (Scheme 7), both with dichlorocarbene. The latter method is of interest because of its relation to the catalysis of dichlorocarbene generation by tertiary amines in two-phase systems. Recent work indicates that such catalysis is possible because the carbene, after generation at the phase boundary, is transferred into the organic phase (to undergo reaction) in the form of the N-ylid adduct (20). 

Also of interest in the preparation of diazoalkanes are the di-azotization of primary amines with activating substituents in the a-position, reaction of hydrazine or hydrazides with dichlorocarbene, diazo-group transfer reactions, the oxidation of hydrazones, and condensation reactions of active methylene compounds. 

The reaction of dihalocarbenes with isoprene yields exclusively the 1,2- (or 3,4-) addition product, eg, dichlorocarbene CI2C and isoprene react to give l,l-dichloro-2-methyl-2-vinylcyclopropane (63). The evidence for the presence of any 1,4 or much 3,4 addition is inconclusive (64). The cycloaddition reaction of l,l-dichloro-2,2-difluoroethylene to isoprene yields 1,2- and 3,4-cycloaddition products in a ratio of 5.4 1 (65). The main product is l,l-dichloro-2,2-difluoro-3-isopropenylcyclobutane, and the side product is l,l-dichloro-2,2-difluoro-3-methyl-3-vinylcyclobutane. When the dichlorocarbene is generated from CHCl plus aqueous base with a tertiary amine as a phase-transfer catalyst, the addition has a high selectivity that increases (for a series of diolefins) with a decrease in activity (66) (see Catalysis, phase-TRANSFEr). For isoprene, both mono-(l,2-) and diadducts (1,2- and 3,4-) could be obtained in various ratios depending on which amine is used. 

The idea that dichlorocarbene is an intermediate in the basic hydrolysis of chloroform is now one hundred years old. It was first suggested by Geuther in 1862 to explain the formation of carbon monoxide, in addition to formate ions, in the reaction of chloroform (and similarly, bromoform) with alkali. At the end of the last century Nef interpreted several well-known reactions involving chloroform and a base in terms of the intermediate formation of dichlorocarbene. These reactions included the ring expansion of pyrroles to pyridines and of indoles to quinolines, as well as the Hofmann carbylamine test for primary amines and the Reimer-Tiemann formylation of phenols. 

Although the extraction of primary amines from a basic medium with chloroform is an inadvisable procedure, on account of the formation of trace amounts of the pungent isonitriles, the specific synthesis of isonitriles by the two-phase reaction of primary amines with chloroform is unreliable. However, the application of the phase-transfer technique [e.g. 1 -5] for the controlled release of dichlorocarbene facilitates the synthesis of isonitriles in relatively high yields (Table 7.12). 

Compared with primary and secondary amines, tertiary amines are virtually unreac-tive towards carbenes and it has been demonstrated that they behave as phase-transfer catalysts for the generation of dichlorocarbene from chloroform. For example, tri-n-butylamine and its hydrochloride salt have the same catalytic effect as tetra-n-butylammonium chloride in the generation of dichlorocarbene and its subsequent insertion into the C=C bond of cyclohexene [20]. However, tertiary amines are generally insufficiently basic to deprotonate chloroform and the presence of sodium hydroxide is normally required. The initial reaction of the tertiary amine with chloroform, therefore, appears to be the formation of the A -ylid. This species does not partition between the two phases and cannot be responsible for the insertion reaction of the carbene in the C=C bond. Instead, it has been proposed that it acts as a lipophilic base for the deprotonation of chloroform (Scheme 7.26) to form a dichloromethylammonium ion-pair, which transfers into the organic phase where it decomposes to produce the carbene [21]. 

Under favourable circumstances, the initially formed /V-ylid reacts further through C-N cleavage. Thus, in the presence of a strong nucleophile, such as a phenoxide anion, the quaternary dichloromethylammonium cation forms an ion-pair with the phenoxide anion (Scheme 7.27), which decomposes to yield the alkyl aryl ether and the /V-formyl derivative of the secondary amine [22, 23]. Although no sound rationale is available, the reaction appears to be favoured by the presence of bulky groups at the 4-position of the aryl ring. In the absence of the bulky substituents, the Reimer-Tiemann reaction products are formed, either through the breakdown of the ion-pair, or by the more direct attack of dichlorocarbene upon the phenoxide anion [22,23],... 

Predictably, the reaction of A V-disubstituted enamines [26-29] and non-conju-gated unsaturated amines with dihalocarbenes results in the exclusive formation of the dihalocyclopropane derivatives (see Section 7.3). Dichlorocarbene inserts into the a-CH bond of Af-alkyldibenzo[6,/]azepines [16], in addition to the expected electrophilic addition to the C=C bond (see Sections 7.2 and 7.3). 

Several iron porphyrin carbenes are known1110 that are obtained by the general reaction of the chloro iron(III) complex with RCX3 (X = Cl, Br) in the presence of iron powder or sodium dithionite as in equation (101). The air sensitivity of the product depends on the nature11111112 of R. Formally these complexes could be described as iron(II) species. They are diamagnetic, and can bond an additional axial ligand. The structure of the dichlorocarbene complex [Fe(TPP)(CCl2)(H20)] has been determined by X-ray methods,1113 which showed a short Fe—C distance of 1.83 A. This complex is reactive and, for instance, with primary amines a coordinated... 

The reaction of allylamines with the source of dichlorocarbene affords products, the structures of which depend on the structure of the starting amine. 

Reimer-Tiemann conversion of phenoxide into ortfto-hydroxybenzaldehyde involves an electrophilic attack by dichlorocarbene (Scheme 5.72). Carbenes also react with primary amines (carbylamine reaction) to give carbylamines (isonitriles) (Scheme 5.73). 

Makosza has argued that the proton transfer occurs at the interface, and that the remainder of the reaction sequence occurs in the bulk organic phase [9]. He has drawn attention to the following facts. First, hydroxide is a harder ion than either trichloromethide or chloride and the latter two would tend to pair with the soft quaternary ion rather than the former. As a consequence, the base concentration in the organic phase should be low. In addition, numerous examples of isotopic (C-D for C-H) exchange are known for weak carbon acids. These exchange reactions are frequently accomplished under biphasic conditions in the absence of a phase transfer catalyst. Finally, the observation that tertiary amines are effective catalysts for the dichlorocarbene... 

Quaternary alkylammonium salts, tertiary amines, and crown ethers have all been utilized as catalysts in the reaction of hydroxide with chloroform to yield dichlorocarbene. The most commonly utilized catalyst has been benzyltriethylammonium chloride (see Sect. 1.7) but other quaternary ammonium chloride catalysts have proved effective. Cetyltrimethylammonium chloride and tricaprylmethylammonium chloride (Aliquat 336) have both been used effectively in the cyclopropanation of simple alkenes. The use of Z e a-hydroxyethyltrialkylammonium hydroxides as phase transfer catalysts results in increased regioselectivity in the addition of dichlorocarbene to olefins [12]. Crown ethers such as dibenzo and dicyclohexyl-18-crown-6 have both been utilized in place of quaternary ammonium compounds. 18-Crown-6 has also been used as a catalyst in the phase transfer thermal decomposition of sodium trichloroacetate to yield dichlorocarbene [13]. 

Dichlorocarbene generated in a two-phase system in the presence of a chiral amine catalyst, reacts with olefins to afford dichlorocyclopropanation products having small optical rotations. The reaction is discussed in terms of steric interactions in the transition state and is analogous to those discussed in section 2.2 and equations 2.9—2.11. 

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