Azolium salt, deprotonation

Two general routes are normally employed for the generation of free 77-heterocyclic carbenes 5. These are (1) the deprotonation of azolium salts of types 1 and 2 or (2) the reductive desulfurization of thiones 3 and 4 (Fig. 4) [1]. Most of the free NHCs are obtained by deprotonation of the azolium salts at the C2 position of the heterocycle with a suitable base like NaH, KOf-Bu, or DMSO/NaH in THF [8] or liquid ammonia... 

In the case of azolium salts with acidic substituents the use of a sterically demanding base like KHMDS is required for a selective deprotonation at C2. 

Fig. 4 Preparation of free A-heterocyclic carbenes by deprotonation of azolium salts or by desulfurization of the corresponding thiones...

The two most common methods for the synthesis of complexes with NHC ligands are the reaction of a free carbene (a) or its enetetramine dimer (b) with a suitable metal precursor or the in situ deprotonation of an azolium salt (c) depicted in Fig. 8 using diaminocarbenes with five-membered heterocycles as examples. 

Metal complexes with M-heterocyclic carbene ligands were known long before the first stable NHCs were isolated. Wanzlick [5] and Ofele [6] demonstrated as early as 1968 that NHC complexes can be obtained by in situ deprotonation of azolium salts in the presence of a suitable metal complex without prior isolation of the free NHC ligand (Fig. 1). In these cases a ligand of the metal complex precursor (acetate or hydride) acted as a base for the deprotonation of the imidazolium cation. This method has been successfully transferred to other metal precursors containing basic ligands like [Pd(OAc)2] [97] and [(cod)lr(p-OR)2lr(cod)] [98, 99]. Alternatively, an external base such as NaOAc, KOf-Bu or MHMDS (M = Li, Na, K) can be added for the deprotonation of the azolium salt [100]. In general, the in situ deprotonation of azolium salts appears as the most attractive method for the preparation of NHC complexes as it does not require the isolation of the reactive free carbene or its enetetramine dimer. 

The carbene transfer reaction from silver NHC complexes has developed into a standard procedure for the synthesis of NHC complexes. This versatile procedure was introduced by Lin et al. in 1998 [102]. It is based on the preparation of silver NHC complexes which are obtained in good yield by the in situ deprotonation of azolium salts with silver oxide (Fig. 9). Depending on the counter ions present in the azolium salt and the steric demand of the N,N -substituents, complexes 25a-25c... 

The formation of complexes with abnormal carbene ligands is controlled by steric, electronic, and kinetic effects as well as by the counter ion present in the azolium salt [145-148]. In selected cases the base used for the deprotonation of the azolium salt [149, 150] also plays a significant role. Crabtree et al. demonstrated in a detailed study that A-pyridyl functionalized imidazolium salts react with... 

The most common way to prepare N-heterocyclic carbenes is the deprotonation of the corresponding azolium salts, like imidazolium, triazolium, tetrazolium, pyrazolium, benzimidazolium, oxazolium or thiazolium salts or their partly saturated pendants, with the help of suitable bases. The pJCa value of imidazolium and benzimidazolium salts was determined to be between 21 and 24, which puts them right in between the neutral carbonyl carbon acids acetone and ethyl acetate [41,42], Arguably, imidazolium-based carbenes have proven to be especially versatile and useful and their synthesis should be discussed in more detail. The synthesis of imidazolium salts has been developed over many decades and numerous powerful methods exist [43]. 

In Situ Deprotonation of Azolium Salt with a Base. 93... 

Abstract The manuscript describes the methods that are most often used in the preparation of N-heterocyclic carbene (NHC) complexes. These methods include (1) insertion of a metal into the C = C bond of bis(imidazolidin-2-ylidene) olefins (2) use of carbene adducts or protected forms of free NHC carbenes (3) use of preformed, isolated free carbenes (4) deprotonation of an azolium salt with a base (5) transmetallation from an Ag-NHC complex prepared from direct reaction of an imidazolium precursor and Ag20 and (6) oxidative addition via activation of the C2 - X (X = Me, halogen, H) of an imidazolium cation. 

The in situ deprotonation of an azolium salt to produce the desired NHC has the advantage that the carbene does not have to be isolated, thus simplifying the reaction workups when the aim is preparation of the metal complex. This avoids the handling of the free NHCs, which most of the times are air-and moisture-sensitive. Two types of azolium in situ deprotonation reactions can be found in the literature, depending on the deprotonation process employed (i) addition of an external base and (ii) use of metal complexes with basic ligands. 

Initially, a solution of cinnamaldehyde and 4-chlorobenzaldehyde in tetrahydrofuran (THF) was treated with different azolium salts under basic conditions (Scheme 6). The use of thiazolium salt 4 resulted in no formation of the desired y-butyrolactone, only benzoin products were formed. In contrast, using the NHC IMes [l,3-di(2,4,6-trimethyl-phenyl)imidazol-2-ylidene generated in situ from the salt IMesHCl by deprotonation], y-butyrolactone 3a was isolated in 53% yield and a 80 20 cisltrans ratio. This different outcome might be explained by the increased steric demand of IMes compared to 4 (Scheme 7). Most likely, IMes reversibly adds to the aldehyde groups of both substrates resulting in the intermediates la and 2a. Whereas the mesityl groups shield the former aldehyde carbon in both intermediates, the conjugate position of 2a is still accessible and can add to the electrophilic aldehyde. 

Deprotonation of an azolium salt with a strong base renders the free carbene which can then be reacted with a suitable transition metal complex to yield the transition metal carbene complex. In many cases, the NHC is not isolated, but prepared in situ prior to adding the metal complex. 

The deprotonation of an azolium salt to form a carbene requires a base. This base can be supplied as the anion of a transition metal compound, in which case the azolium salt is deprotonated in situ and the carbene formed coordinates to the metal generating the NHC transition metal complex. This method works best if a coordinating anion, such as bromide or iodide, is suppUed with the azolium salt. 

Note The strong M-NHC bond facilitates deprotonation of the azolium salt enabling the use of weak anionic bases like acetate. 

The interesting electronic properties of NHC and their azolium precursors can be seen in the H- and C-NMR spectra for the and atoms. Since the W atom of an azolium salt is essentially acidic, the corresponding chemical shift will be observed downfield, typically at 5 = 8-11 ppm (see Figure 1.22). There is a correlation between the proton chemical shift and the ease of deprotonation [50]. The precursor of the acyclic carbene bis-(diisopropylamino)carbene, A, A, A ,A -tetraisopropylformamidinium chloride has a proton chemical shift of 5 = 7.60 ppm [118], significantly upheld of the normal range for azolium salts. 

Since the synthesis of NHC TM complexes was initially achieved by in situ formation of NHC from azolium salt in the presence of base followed by coordination to a metal center, a simpler procedure would be useful. In 1996, Arduengo reported the synthesis of Hg(IDM)2 (128) from Hg(OAc)2 and IDM HCl salt. The mechanism of this reaction is depicted in Scheme 21. Dissociation of one acetate ligand generates [Hg(OAc)]+ (126) and the mildly basic acetate anion drives the deprotonation of the imidazohum salt. Thus, the newly formed NHC coordinated promptly (126) and led to [(IDM)Hg(OAc)]+ (127). 

Direct acylation of AT-protected imidazole involves formation of an AT-acyl azolium salt, which is then deprotonated at C-2 followed by rearrangement of the acylazolium ylide to the 2-acylated imidazole (for mechanism and a number of applications, see CHEC-II(1996)). An example is shown in Scheme 82 N-acylation of imidazole 350 followed by 2-deprotonation of the azolium cation, then migration of the acyl group to C-2 gives product 351 <2005JME2154>. 

Sometimes the presence of a basic ligand, such as an acetoxy or alkoxy group, will cause deprotonation of the azolium salt. Equation 10.24 shows this variation of in situ generation of an NHC followed by complexation 42... 

Acylation of 1-methylimidazole at C-2 takes place via the azolium salt which deprotonates to form an ylide, and then rearranges <84TL1715,86CHE587). This reaction has similarities to the Regel acylation process (see CHEC-I). In the presence of excess aromatic aldehyde, instead of the usual... 

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