Synthesis of 4- and 4,5-Functionalized Imidazol-2-Ylidenes from a Single 4,5-Unsubstituted Imidazol-2-Ylidene

Abstract

Using the nucleophilicity of NHCs and aNHCs, as well as the leaving group ability of the former, the carbon-carbon double bond of imidazol-2-ylidenes can be readily mono- and di-functionalized. These results provide also a new light on the formation of abnormal carbene adducts from classical unsaturated NHCs.

Since the discovery by Arduengo et al. of the stable 1,3-diadamantyl imidazol-2-ylidene (1, R = Ad),^1,2 a myriad of the so-called unsaturated N-heterocyclic carbenes (NHCs) has been prepared, and numerous applications have been found.³ Because of the commonly practiced synthetic routes, most unsaturated NHCs feature an unsubstituted carbon-carbon double bond or alternatively alkyl or aryl groups are placed at the 4 and 5 positions.⁴ The rare exceptions are imidazol-2-ylidenes annulated to a quinone derivative (A)⁵ or a heterocycle (such as B and C),⁶ the oxazoline-derivatives (D, E),⁷ and NHCs featuring one (F, G)⁸ or two (H)⁹ heavier main group elements.

Interestingly, it has been shown that the substituents at the carbon-carbon double bond have a dramatic influence on the electronic properties of the carbene center. For example, the dichlorinated derivatives H are exceptionally stable, and are certainly the only carbenes that can be handled in air.^9a Therefore, practical synthetic strategies, allowing the access to symmetrically and unsymmetrically 4- and 4,5-functionalized imidazol-2-ylidenes are highly desirable. Herein we report a convenient route to a variety of these compounds from a single precursor, namely a 4,5-unsubstituted imidazol-2-ylidene of type 1 (Ar = 2,6-diisopropylphenyl, Dipp).¹⁰ In addition, the mechanism of formation of the so-called abnormal carbene-adducts is discussed.

The syntheses of NHCs A–E follow classical methods, using precursors already featuring the desired backbone. In contrast, NHCs F–H are obtained in a single operation from the corresponding 4,5-unsubstituted NHCs of type 1. The latter results are reminiscent of the discovery by Crabtree that 2-pyridylmethylimidazolium salts react with IrH₅(PPh₃)₂ to give a complex in which the imidazole ring bound the “wrong way” at C5 and not at C2 (Scheme 1, top).¹¹ The mechanism of formation of C5-bound adducts is still obscure, whether a transition metal is involved or a main group elements as in F–H.¹² These adducts correspond to a formal rearrangement of imidazol-2-ylidene 1 into its isomeric C5-deprotonated imidazolium, a so-called abnormal carbene (aNHC), followed by addition of the electrophile, and finally deprotonation at C-2. However, the rearrangement of 1 is very unlikely since it is well established that the isomeric aNHC is some 70–80 kJmol⁻¹ higher in energy, corresponding to a pKa value for the C5- proton (~ 33) 9 units higher than that for the C2 proton in the parent imidazolium salt;¹³ moreover, a 1,3-hydrogen shift would certainly be energetically costly.¹⁴ Therefore, it is clear that the formation of aNHCs can only be favored if the C2-position is protected, and indeed we have recently shown that aNHC 2 can be prepared and even isolated (Scheme 1, bottom).¹⁵

Scheme 1.

With the aim of tuning the electronic properties of aNHCs, we chose to vary the C2-substituent, using NHC 1 (Ar = Dipp) as a starting material. Addition of one equivalent of benzoyl chloride to 1 cleanly afforded the corresponding adduct 3a. However, deprotonation of 3a with potassium hexamethyldisilazide at −78 °C did not lead to the expected aNHC 2a, but to its isomeric NHC 4a, which was isolated in 64% yield (Scheme 2). Its structure was determined unambiguously by single crystal X-ray diffraction (Fig. 2). A plausible mechanism to rationalize these results involves the deprotonation of 3a with formation of aNHC 2a as a fleeting intermediate. The latter then acts as a nucleophile toward 3a, generating the bis-adduct 5a along with 1. NHC 1 can act as a nucleophile towards the former leading to the observed 4-substituted NHC 4a, and regenerating the starting material 3a. To confirm the viability of this hypothesis, stable aNHC 2 was added to the 2-benzoyl imidazolium 3a, and indeed the formation of the penta-substituted imidazolium salt 5b was observed along with NHC 1. Then, imidazolium salt 5a, prepared by addition of benzoyl chloride to 4a, was reacted with 1, which led to C5-substituted imidazol-2-ylidene 4a and C2-substituted imidazol-2-ylidene 3a.

Scheme 2.

Figure 2.

Molecular structures of 4a (left) and 4f (right) in the solid state (hydrogen atoms are omitted for clarity; ellipsoids are drawn at 50% probability). Selected bond lengths [Å] and angles [°]; 4a: N1-C2 1.372(8), N3-C2 1.351(8), N3-C4 1.389(8), N1-C5 1.380(8), C4–C5 1.366(10), C4–C6 1.464(9), C6-O1 1.229(7), N1-C2-N3 101.9(5), 4f: N3-C2 1.3695(15), N1-C2 1.3714(15), N1-C5 1.3848(15), N3-C4 1.4071(14), C4–C5 1.3510(17), C4-P1 1.8124(12), N3-C2-N1 101.31(9).

The scope of this reaction is quite general as shown in Scheme 3. A variety of C4-functionalized NHCs 4a–f were prepared in moderate to good isolated yields (not optimized). Of special interest, both electron-withdrawing and -donating groups can be used to functionalize the carbon-carbon double bond of NHCs.

Scheme 3.

These results prompted us to investigate the possibility of using the same synthetic strategy to place two functional groups at the carbon-carbon double bond. As a proof of principle, 4-diphenylphosphino-NHC 4f was treated with benzoyl chloride, affording the 2-benzoyl-4-diphenylphosphino-imidazolium salt 6 (86% yield). Subsequent treatment with hexamethyldisilazide gave the 4-benzoyl-5-diphenylphosphino imidazol-2-ylidene 7 in 51% isolated yield (Scheme 4).

Scheme 4.

When combined with the recent discovery of modular syntheses of N,N′-unsymmetrically substituted imidazolium salts,⁴ these results pave the way for the preparation of NHCs with virtually any substitution pattern. Particularly appealing is the possibility of placing strong electron-withdrawing groups, such as trifluoromethane sulfonyl, which should decrease the σ-donor and increase the π-acceptor ability of NHCs. Moreover, these results provide a new light on the formation of abnormal carbene adducts from classical unsaturated NHCs.

Figure 1.

Imidazol-2-ylidenes 1 and its derivatives A–H featuring C4 and/or C5 substituents different from H, alkyl, and aryl groups.