Synthesis of Diazirines

Smith and Knowles (1973) made several 3-H-3-aryldiazirines and suggested that they had several advantages as photoaffinity labeling reagents over the aryl azides and diazo compounds that were then current. These diazirines did not become popular, however, because they are inconvenient to prepare. The situation today is unchanged. 

In a thorough investigation, Smith and Knowles (1975) defined two routes for making 3-H-3-aryldiazirines. In the first an aldehyde is reacted with chloramine and ammonia to give a tricyclic compound that may be oxidized to a diazirine (Fig. 3.22). In the case of 3-H-3-phenyIdiazirine the intermediate may be isolated and converted to the diazirine in 50 % yield (Smith and Knowles, 1975 Bradley et al., 1977) but this failed in the case of other diazirines (p-CH3- p-CH30-) which were however prepared in 

The second preparation also begins with an aldehyde and may be used to make 3-H-3-aryldiazirines with electron withdrawing substituents (Fig. 3.22). The sequence shown is not as forbidding as it appears as all the reactions are carried out in one pot. The yields are low, however (3 to 15%). 

The low yields in these syntheses make purification of the diazirines a difficult task. Preparative TLC was used extensively by Smith and Knowles and this can now be effectively replaced by HPLC or flash chromatography. 

In contrast to 3-H-3-aryldiazirines, adamantane diazirine may be prepared in high yield by a method (Isaev et al., 1973 Bayley and Knowles, 1980) based on a general procedure for dialkyl diazirines devised by Schmitz and Ohme (1961) (Fig. 3.23). Such a convenient synthesis is most attractive but as yet adamantane diazirines further functionalized to allow their attachment to molecules of biological interest, have not been prepared, although this should not be a difficult task. 

Most diazirines are easily obtained from diaziridines. Dialkyldiazirines are simply formed by dehydrogenation of 3,3-dialkyldiaziridines (60AG781). For example, the spirodiazirine (187) can be prepared in 65-75% yield from the diaziridine with silver oxide (6508(45)83). 

By similar procedures diazirines were prepared not only from simple aliphatic ketones but also from hydroxyketones and )3-aminoketones (B-67MI50800), and so were a large number of diazirines from steroidal ketones (65JA2665). Permanganate, bromine, chlorine and hypochlorite were used as oxidants. A one-step preparation of diazirines from ketones like 3-nonanone, ammonia and chlorine has been claimed in a patent (66USP3290289). 3,3-Diazirinedicarboxylic acid derivatives like (286) were obtained directly from oxime tosylates by the action of two moles of O-ethoxyamine (81AG(E)200). 

Syntheses of alkyldiazirines (287) must start from the diazirinotriazolidines (128) formed from an aldehyde, ammonia and (-butyl hypochlorite. Since the three-membered ring in (128) is much more stable towards acids than the five-membered ring (Section 5.08.3.2.2), the diazirines are obtained by acid hydrolysis of compounds (128) in the presence of an oxidant (62CB795). 

The parent compound, cyclic diazomethane , was first obtained from formaldehyde, ammonia and chloramine by dichromate oxidation of the initially formed higher molecular diaziridine-formaldehyde condensation product (61TL612). Further syntheses of (44) started from Schiff bases of formaldehyde, which were treated with either difluoramine or dichloramine to give (44) in a one-pot procedure. Dealkylation of nitrogen in the transient diaziridine was involved (65JOC2108). 

Another one-pot procedure has given chlorodiazirines in many cases. Amidines are reacted with hypochlorite to form, for example, chlorophenyldiazirine (289) from (288) (65JA4396). 

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Graham recently reported a second synthesis of diazirine [Eq, (57)]. The yield reached 62%. 

Synthesis of diazirine. Graham devised a simple method by which it is possible to prepare pure diazirine, a colorless gas, b.p. —14°. The starting material, r-butyl-azoraethine (b.p. 65°), is the product of condensation of /-butylamine with formalde-... 

In 1960, however, Paulsen and, in the following years, Schmitz and Ohme (1961 a-c), and Graham (1962) achieved the first synthesis of diazirine. As Scheme (5-14) shows, they used methods that are completely independent of diazomethane. With ammonia and hydroxylamine-O-sulfonic acid (or NH2CI with an oxidant such as tert-h xiy hypochlorite, -C4H90C1), formaldehyde (for mono-and disubstituted diazirines other aldehydes and ketones, respectively) forms diaziridine (5.61, originally called an isohydrazone), which is then dehydrogenated to diazirine with silver oxide or bichromate (5-14). 

Graham (1962) described a direct one-step synthesis of diazirine by the reaction of difluoroamine (HNF2) with er butyl- or octyl azomethine (H2C=N —R) in CCI4 solution in a vacuum system. A yield of 62<7o was reported without any further information on mechanistic details. It seems that dealkylation and defluorination take place in the transient l-alkyl-2-fluoro-diaziridine (5.62, 5-15). 

It was not their reactivity but their chemical inertness that was the true surprise when diazirines were discovered in 1960. Thus they are in marked contrast to the known linear diazo compounds which are characterized by the multiplicity of their reactions. For example, cycloadditions were never observed with the diazirines. Especially surprising is the inertness of diazirines towards electrophiles. Strong oxidants used in their synthesis like dichromate, bromine, chlorine or hypochlorite are without action on diazirines. Diazirine formation may even proceed by oxidative dealkylation of a diaziridine nitrogen in (186) without destruction of the diazirine ring (75ZOR2221). The diazirine ring is inert towards ozone simple diazirines are decomposed only by more than 80% sulfuric acid (B-67MI50800). 

The chemical inertness of the three-membered ring permitted many conversions of functional groups in diazirines. Esterifications, cleavage of esters and acetals, synthesis of acid chlorides, oxidation of hydroxy groups to carboxyl groups as well as Hofmann alkenation all left the three-membered ring intact (79AHC(24)63). 

Synthesis of steroidal diazirines has led to some biologically active compounds (65JA2665). The observation that diazirines and their parent ketones are identical in smell (B-67MI50800), points to the possibility that a diazirine group may stand for a keto group vis-d-vis a receptor. 

A further synthesis of 1-alkyl-diaziridines is the addition of Grignard compounds to the NN double bond of diazirines [Eq. (35) ]. The... 

Diazirine and several of its 3-substituted homologues, formally cyclic azo compounds, are explosive on heating or impact [1]. The shock-sensitivity of all diazirine compounds and the inadvisability of their handling in the undiluted state have again been stressed [2], In a description of the synthesis of 27 3-(4-substituted)halodiazirines, the need is stressed to handle the compounds at below 30°C to prevent thermal decomposition, or, for the pure compounds, explosion [3],... 

Diazirines are the cyclic isomers of the alphatic diazo compounds. Both the diaziridines and the diazirines are starting materials for the synthesis of alkyl hydrazines. 3,3-Pentamethyl-enediaziridine can be hydrolyzed quantitatively to hydrazine. Methylamine may be substituted for ammonia in the procedure resulting in l-methyl-3,3-pentamethylenediaziridine (m.p. 35-36°, yield 62% of theoretical) and then methyl hydrazine. Use of ethylenediamine leads to ethylene bis-hydrazine via a bifunctional diaziridine (m.p. 143-144°, yield 48% of theoretical). Ammonia can also be replaced by w-propylamine or cydo-hexylamine cyclohexanone by acetone. 

Thermolysis of aryl chloro diazirine (18) in the presence of acetone and a trapping agent such as A -phenylmaleimide gave rise to cycloadducts such as 41. The unstable adduct hydrolyzed during purification resulting in synthesis of bicyclic hemiacetals 42 and 43 as a mixture of endo and exo adducts in 37 and 8% yield, respectively. The exclusive generation of the singlet carbene was confirmed by low-temperature electron spin resonance (ESR) study of the irradiated diazirine. 

On the other hand, the synthesis of Shih and Bayley is based on the C -alkylation of ethyl N-(diphenylmethylene)glycinate by 3-[4-(iodomethyl)phenyl]-3-(trifluoromethyl)-3//-diazirine (57) (Scheme 13). The precursor for the diazirine-containing alkylating reagent is the O-protected benzyl alcohol 53J1251... 

Scheme 13 Synthesis of 4-[3-(Trifluoromethyl)-3/f-diazirin-3-yl]-D,L-phenylalanine According to Shih and Bayley[125l...

A clean and reagent-free generation of highly strained cycloalkynes from bi-3//-diazirin-3-yls has been described.44 A new synthesis of alkynes has been achieved by... 

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