Vincent Lavallo

Homogeneous catalytic hydroamination of alkynes and allenes with ammonia.

Nitrogen–carbon bonds are ubiquitous in products ranging from chemical feedstock to pharmaceuticals. As ammonia is among the least expensive bulk chemicals produced in the largest volume, one of the greatest challenges of synthetic chemistry is to develop atom-efficient processes for the combination of NH3 with simple organic molecules to create nitrogen–carbon bonds. Transition-metal complexes can readily render a variety of N–H bonds reactive enough to undergo functionalization, including those of primary and secondary amines. However, with a few exceptions,[1,2] metals react with ammonia to afford supposedly inert Lewis acid–base complexes, as first recognized in the late 19th century by Werner.[3] Consequently, the homogeneous catalytic functionalization of NH3 remained elusive[4] until the recent discovery by Shen and Hartwig[5] and Surry and Buchwald[6] of the palladium-catalyzed coupling of aryl halides with ammonia in the presence of a stoichiometric amount of a base. An even more appealing process would be the addition of NH3 to carbon–carbon multiple bonds, a process that would occur ideally with 100% atom economy.[7] Although various homogeneous catalysts, including alkali metals,[8] early[9] and late transition metals,[10] and d-[11] and f-block elements,[12] have been used to effect the so-called hydroamination reaction, none of them were reported to be effective when NH3 is used as the amine partner.[13] Herein we report that cationic gold(I) complexes supported by a cyclic (alkyl)(amino)carbene (CAAC)[14] ligand readily catalyze the addition of ammonia to a variety of unactivated alkynes and allenes to provide a diverse array of linear and cyclic nitrogen-containing compounds. We showed recently that the cationic CAAC–gold complex A was very robust and exhibited unusual catalytic reactivity towards alkynes.[15] This discovery prompted us to investigate whether such a complex could activate alkynes sufficiently to enable the addition of NH3.[16] Thus, excess ammonia was condensed into a sealable NMR tube containing A (5 mol%), 3-hexyne, and deuterated benzene. Upon heating to 160 °C for 3.5 h, the clean addition of NH3 afforded the primary imine 2a, the expected tautomer of the corresponding enamine (Table 1).[17] Table 1 Catalytic hydroamination of 3-hexyne with ammonia.[a] Complex A does not have to be isolated; when it was prepared in situ from an equimolar mixture of [(CAAC)AuCl]/KB(C6F5)4 (A1), identical results were obtained. When the related silver complex [(CAAC)AgCl]/KB(C6F5)4 or NH4B(C6F5)4 was used as the catalyst, no reaction was observed, which shows the importance of gold and rules out a Bronsted acid mediated reaction.[18] Finally, as AuCl, AuCl/ KB(C6F5)4, and even [(CAAC)AuCl] do not induce the hydroamination, it is clear that the gold center can only catalyze the addition of NH3 if it is coordinated by the CAAC ligand and rendered cationic by Cl abstraction. To gain insight into the catalytic process, we performed a number of experiments: The addition of excess NH3 to complex A gave the Werner complex B instantaneously; the addition of 3-hexyne (1a; 1 equiv) to complex A gave the η2-bound alkyne complex C instantaneously (Scheme 1). Upon the exposure of a solution of C in benzene to excess NH3, 3-hexyne was immediately displaced from the gold center, and the Werner complex B was isolated in quantitative yield. This result suggests that NH3 does not add to the alkyne through an outer-sphere mechanism. Importantly, when a solution of complex B in benzene was treated at room temperature for 24 h with a large excess of 3-hexyne, the imine complex D was obtained quantitatively, even when the reaction vessel was open to a glovebox atmosphere. This experiment implies that NH3 does not dissociate from the metal by a simple ligand exchange with the alkyne. Therefore, an insertion mechanism, similar to that proposed by Tanaka and co-workers[19] and Nishina and Yamamoto[20] for gold-catalyzed hydroamination with aryl amines, is quite likely. Finally, the addition of excess NH3 to D liberated the imine 2a and regenerated complex B. From the results of these experiments, it can be concluded that the Werner complex B is the resting state of the catalyst. Indeed, B exhibits identical catalytic activity to that of A/A1. Consequently, the robust and readily available complex B (Figure 1)[21] was used in subsequent experiments. Scheme 1 Experiments to probe the reaction mechanism. The results suggest that an insertion process is involved, and that B is the resting state of the catalyst. Figure 1 Molecular structure of complex B in the solid state. (Hydrogen atoms, except those at N1, and the (C6F5)4B anion are omitted for clarity; ellipsoids are drawn at 50% probability). To test the scope of the reaction, the terminal alkyne 1b and the diaryl alkyne 1c were treated with NH3 in the presence of a catalytic amount of complex B (Scheme 2). With 1b, the reaction took place even at 110 °C to afford the Markovnikov imine 2b exclusively in 60% yield. When diphenyl acetylene (1c) was used, the 2-aza-1,3-diene 3c was formed cleanly in 95% yield. The different outcome of the reaction of 1c with respect to the results with substrates 1a,b can be rationalized by the presence of acidic benzylic hydrogen atoms in the imine. These acidic hydrogen atoms favor the formation of the enamine tautomer, which can then react further with a second molecule of the alkyne to afford 3c. Scheme 2 Catalytic hydroamination of various alkynes with ammonia. Nitrogen heterocycles are an important class of compounds that occur widely in natural products and often display potent biological activity. On the basis of the results described above, we attempted the direct synthesis of hetero-cycles from diynes and NH3. When 1,4-diphenylbuta-1,3-diyne (1d) and hexa-1,5-diyne (1e) were used, the corresponding 2,5-disubstituted pyrroles 4d and 4e were produced in 87 and 96% yield, respectively. Both products result from the Markovnikov addition of NH3, followed by ring-closing hydroamination.[22,23] The treatment of the 1,4-diyne 1f with NH3 under similar conditions led to a 3:2 mixture of the five- and six-membered heterocycles 5f and 6f in 88% yield. The six-membered ring 6f arises from two consecutive Markovnikov hydroamination reactions, whereas the formation of 5f involves an anti-Markovnikov addition of NH3 or ring-closing step. To expand the scope of the hydroamination reaction with NH3, we next tested allenes as substrates. When 1,2-propadiene (7a) was used, a mixture of mono- (8a), di- (9a) and triallylamine (10a) was obtained in excellent yield. Allyl amines are among the most versatile intermediates in synthesis and are of industrial importance. For example, the parent compound 8a, which is produced commercially from ammonia and allyl chloride, is used in antifungal preparations and the synthesis of polymers. By varying the NH3/allene ratio it is possible to control the selectivity of this reaction significantly (Table 2). In particular, the parent allylamine (8a) and triallylamine (10a) can be obtained with 86 and 91% selectivity, respectively, and further optimization of the conditions should be possible. The addition of NH3 to 1,2-dienes is not restricted to the parent allene 7a. The dialkyl-substituted derivative 7b was also converted into the corresponding allyl amines 8b–10b, with exclusive addition of the NH2 group at the less-hindered terminus; however the selectivity of this reaction for the mono-, di-, or trisubstituted amine product needs some improvement. Interestingly, even the tetrasubstituted allene 7c underwent hydroamination with ammonia. Probably because of steric factors, a different regioselectivity was observed, and only the monohydroamination product 11C was formed.[24] Table 2 Catalytic hydroamination of allenes with ammonia. The results outlined herein demonstrate that (CAAC)-gold(I) cations readily catalyze the addition of NH3 to non-activated alkynes and allenes. This reaction leads to reactive nitrogen-containing compounds, such as imines, enamines, and allyl amines, and is therefore an ideal initial step for the preparation of simple bulk chemicals, as well as rather complex molecules, as illustrated by the preparation of heterocycles 4–6. This study paves the way for the discovery of catalysts that mediate the addition of ammonia to simple alkenes, a process considered to be one of the ten greatest challenges for catalytic chemistry.[25]

Allene formation by gold catalyzed cross-coupling of masked carbenes and vinylidenes

Addition of a sterically demanding cyclic (alkyl)(amino)carbene (CAAC) to AuCl(SMe2) followed by treatment with [Et3Si(Tol)]+[B(C6F5)4]− in toluene affords the isolable [(CAAC)Au(η2-toluene)]+[B(C6F5)4]− complex. This cationic Au(I) complex efficiently mediates the catalytic coupling of enamines and terminal alkynes to yield allenes and not propargyl amines as observed with other catalysts. Mono-, di-, and tri-substituted enamines can be used, as well as aryl-, alkyl-, and trimethylsilyl-substituted terminal alkynes. The reaction tolerates sterically hindered substrates and is diastereoselective. This general catalytic protocol directly couples two unsaturated carbon centers to form the three-carbon allenic core. The reaction most probably proceeds through an unprecedented “carbene/vinylidene cross-coupling.”

Carbenes As Catalysts for Transformations of Organometallic Iron Complexes

Stretching Carbene Versatility Stable N-heterocyclic carbene (NHC) molecules are versatile catalysts for organic reactions (see the Perspective by Albrecht). Lavallo and Grubbs (p. 559) now show that these molecules can also catalyze organometallic transformations. Specifically, the carbenes induce coupling of monomeric iron olefin complexes to form clusters incorporating three or four bonded iron centers. Initial coordination of carbene to iron may facilitate formation of an iron-iron bond with a second complex. In a related development, Aldeco-Perez et al. (p. 556) prepared an NHC isomer in which the divalent carbon is shifted so that it no longer lies between the nitrogens. The compound forms stable complexes with both gold and CO2. Carbenes that are useful for organic catalysis are shown to promote organometallic reactions as well. Compared with the enormous arsenal of catalysts used to produce organic compounds, complementary species that are able to mediate sophisticated organometallic transformations are virtually nonexistent. We found that stable N-heterocyclic carbenes (NHCs) can mediate unusual organometallic transformations in solution at room temperature. Depending on the choice of NHC initiator, stoichiometric or catalytic reactions of bis(cyclooctatetraene)iron [Fe(COT)2] ensue. The stoichiometric reaction leads to the isolation of a previously unknown mixed-valent species, featuring distinct and directly bonded Fe(0) and Fe(I) centers. In the catalytic process, three iron atoms are fused to afford the tri-iron cluster Fe3(COT)3, which is a hydrocarbon analog of Dewar’s classic Fe3(CO)12 complex. The key step in both of these processes is proposed to involve the NHC’s ability to induce metal–metal bond formation. These NHC-mediated reactions provide a foundation on which to develop future organometallic transformations that are catalyzed by organic species.

Fusing N-heterocyclic carbenes with carborane anions.

Here we describe the fusion of two families of unusual carbon-containing molecules that readily disregard the tendency of carbon to form four chemical bonds, namely N-heterocyclic carbenes (NHCs) and carborane anions. Deprotonation of an anionic imidazolium salt with lithium diisopropylamide at room temperature leads to a mixture of lithium complexes of C-2 and C-5 dianionic NHC constitutional isomers as well as a trianionic (C-2, C-5) adduct. Judicious choice of the base and reaction conditions allows the selective formation of all three stable polyanionic carbenes. In solution, the so-called abnormal C-5 NHC lithium complex slowly isomerizes to the normal C-2 NHC, and the process can be proton-catalyzed by the addition of the anionic imidazolium salt. These results indicate that the combination of two unusual forms of carbon atoms can lead to unexpected chemical behavior, and that this strategy paves the way for the development of a broad new generation of NHC ligands for catalysis.

Comparative Reactivity of Different Types of Stable Cyclic and Acyclic Mono- and Diamino Carbenes with Simple Organic Substrates

A series of stable carbenes, featuring a broad range of electronic properties, were reacted with simple organic substrates. The N,N-dimesityl imidazolylidene (NHC) does not react with isocyanides, whereas anti-Bredt di(amino)carbene (pyr-NHC), cyclic (alkyl)(amino)carbene (CAAC), acyclic di(amino)carbene (ADAC), and acyclic (alkyl)(amino)carbene (AAAC) give rise to the corresponding ketenimines. NHCs are known to promote the benzoin condensation, and we found that the CAAC, pyr-NHC, and ADAC react with benzaldehyde to give the ketone tautomer of the Breslow intermediate, whereas the AAAC first gives the corresponding epoxide and ultimately the Breslow intermediate, which can be isolated. Addition of excess benzaldehyde to the latter does not lead to benzoin but to a stable 1,3-dioxolane. Depending on the electronic properties of carbenes, different products are also obtained with methyl acrylate as a substrate. The critical role of the carbene electrophilicity on the outcome of reactions is discussed.

Insights Into the Carbene Initiated Aggregation of Fe(COT)2

Stable carbenes react with [Fe(cot)_2] in very different ways. Whereas the classical N-heterocyclic carbenes induce the formation of tetra- and trimetallic iron clusters, abnormal NHCs and carbocyclic carbenes (BACs) form mono- and bimetallic iron complexes. Cyclic (alkyl)(amino)carbenes (CAACs) react with [Fe(cot)_2] in a completely different manner, namely through outersphere [4+1] cycloaddition.

Cation reduction and comproportionation as novel strategies to produce high voltage, halide free, carborane based electrolytes for rechargeable Mg batteries

Here we describe the cation reduction and comproportionation as novel routes to synthesize electrolytes for rechargeable Mg-ion batteries. Reduction of the ammonium cation in [HNMe31+][HCB11H111−] with metallic Mg affords the halide free carborane salt [Mg2+][HCB11H111−]2. Comproportionation of [Mg2+][HCB11H111−]2 with MgPh2 affords the novel monocationic electrolyte [MgPh1+][HCB11H111−], which reversibly deposits/strips Mg with a remarkable oxidative stability of 4.6 V vs. Mg0/+2.

Click-like reactions with the inert HCB11Cl11(-) anion lead to carborane-fused heterocycles with unusual aromatic character.

The chlorinated carba-closo-dodecaborate anion HCB11Cl11(-) is an exceptionally stable molecule and has previously been reported to be substitutionally inert at the B-Cl vertices. We present here the discovery of base induced cycloaddition reactions between this carborane anion and organic azides that leads to selective C and B functionalization of the cluster. A single crystal X-ray diffraction study reveals bond lengths in the heterocyclic portion of the ring that are shortened, which suggests electronic delocalization. Molecular orbital analysis of the ensuing heterocycles reveals that two of the bonding orbitals of these systems resemble two of the doubly occupied π-MOs of a simple 5-membered Hückel-aromatic, even though they are entangled in the carborane skeleton. Nucleus independent chemical shift analysis indicates that both the carborane cluster portion of the molecule and the carborane fused heterocyclic region display aromatic character. Computational methods indicate that the reaction likely follows a stepwise addition cyclization pathway.

Isolation of a carborane-fused triazole radical anion.

Outside the cage: A change in the redox properties of a triazole fused to a carborane anion through methylation to form a zwitterion enabled facile chemical reduction of the compound to an isolable triazole radical anion (see structure: C gray, H white, N blue, B brown, Cl green). The radical anion is stabilized by kinetic protection by the chlorinated carborane and the delocalization of spin density throughout the exo-cluster π system.

Synthesis of a hybrid m-terphenyl/o-carborane building block: applications in phosphine ligand design.

A hybrid terphenyl/o-carborane ligand building block is synthesized by the reaction of m-terphenylalkyne with B10H14. This sterically demanding substituent can be installed into ligands, as demonstrated by the preparation of carboranylphosphine. The bulky phosphine reacts with [ClRh(CO)2]2 to produce monophosphine complex ClRhL(CO)2, which subsequently extrudes CO under vacuum to afford the dimeric species [ClRhL(CO)]2. The latter complex does not react with excess phosphine and is resistant toward cyclometalation, which is in contrast to related o-carborane phosphine complexes. Data from a single-crystal X-ray diffraction study are utilized to quantify the steric impact of the ligand via the percent buried volume approach.