Stable and Persistent Acyclic Diaminocarbenes with Cycloalkyl Substituents and Their Transformation to β‐Lactams by Uncatalysed Carbonylation with CO

Abstract

Four new acyclic diaminocarbenes (ADACs), viz. [(cyclo‐CnH2n−1)2N]2C (n=5–7) and iPr2N‐C‐N(cyclo‐C6H11)2, were synthesised by reacting the corresponding formamidinium hexafluorophosphates with NaN(SiMe3)2. Their nucleophilicities and electrophilicities were respectively judged from the 1JCH values determined for the N2CH unit of the corresponding formamidinium cations and from the 77Se NMR chemical shifts of the selenourea derivatives obtained from the reaction of elemental selenium with the corresponding ADACs. An ambiphilic profile essentially identical to that of the “Alder carbene” (iPr2N)2C was found in each case. Similar to the latter carbene, the new ADACs undergo a well‐defined thermal decomposition by β‐fragmentation, affording an alkene and a formamidine. The stabilities of [(cyclo‐CnH2n−1)2N]2C depend strongly on the value of n, following the order 6>5>7, with the latter congener being too unstable for isolation. [(cyclo‐C6H11)2N]2C shows no thermal decomposition at room temperature in solution and is thus significantly more stable than (iPr2N)2C. The stability of iPr2N‐C‐N(cyclo‐C6H11)2 is intermediate between that of (iPr2N)2C and [(cyclo‐C6H11)2N]2C, its β‐fragmentation selectively affording propene and iPrN=CH‐N(cyclo‐C6H11)2. [(cyclo‐CnH2n−1)2N]2C (n=5–7) react readily with CO under mild conditions, selectively affording trisubstituted spirocyclic β‐lactam derivatives with an antimicrobial activity spectrum similar to that of penicillin G.

Recent Advances in the Synthesis of Spiro‐β‐Lactams and Spiro‐δ‐Lactams

“…Siemeling et al reported a metal-free synthetic methodology for the synthesis of racemic spiro-βlactam derivatives 85 by exploring the reactivity of acyclic diaminocarbenes 84, containing cycloalkyl substituents and using carbon monoxide as building block (Scheme 22). [39] The acyclic diaminocarbenes 84 were synthesized from secondary amines (cyclo-C n H 2n-1 ) 2 NH (n = 5, 6, 7). The amines were formylated with formic acid followed by the reaction with oxalyl chloride (28) to give the corresponding Vilsmeyer complex.…”

The reaction of a particularly electrophilic acyclic diaminocarbene with carbon monoxide: formation of β- and γ-lactams

“…Steric strain appears to be slightly Fig. 3), as has been observed before for closely related compounds [18,19]. In contrast to this, the tetrachloridoferrate(III) anion of [cis-1H][FeCl 4 ] is not involved in hydrogen bonding.…”

“…The structure of [2H]Cl is very similar to that of other hydrochlorides of amino-substituted β-lactams [18,19]. Steric strain in the cation is indicated by the fact that N2 exhibits unusually long bonds to its carbon atoms, ranging from 1.520(3) to 1.572(3) Å (average value 1.554 Å).…”

“…Scheme 1 summarises the outcome of the carbonylation of iPr 2 N-C-TMP and gives a plausible mechanistic explanation, which is based on our previous work with related bulky ADACs (vide supra) [18,19,21]. It is interesting that this carbonylation affords products belonging to two prominent classes of bioactive compounds.…”

“…Owing to their ambiphilic profile, CAACs are suitable for the activation of fundamentally important small molecules like ammonia and carbon monoxide at room temperature or below [16,17]. We recently found that ADACs, too, react with CO under very mild conditions [18][19][20][21], which is perfectly plausible in view of the similar electronic profiles of CAACs and ADACs [15,22]. The primary carbonylation product of an ADAC is the corresponding diaminoketene (R 2 N) 2 C=C = O, which is a transient species too unstable for isolation [23][24][25].…”