Synthesis and properties of seven-to nine-membered ring nitrogen heterocycles. Cyclic amidines and cyclic amidinium salts

Medium-sized ring nitrogen heterocycles are an important class of compound which occurs in a range of natural and synthetic products. This review summarizes the current methods for the synthesis and chemical properties of cyclic amidines and cyclic amidinium salts of medium-sized rings (n= 2-4) with a fully saturated backbone


Introduction
Monocyclic medium-sized ring nitrogen heterocycles are an extremely important class of compounds which occur in a range of natural and synthetic products.The term "medium-sized ring" is usually applied to cyclic compounds having eight to eleven members; 1 however, seven-and twelve-membered rings are frequently included.
The present review will therefore focus on the synthesis and the main properties of medium-sized cyclic amidines and cyclic amidinium salts (I and II, n= 2-4).

Synthesis of Cyclic Amidines
Synthetic methods of medium-sized cyclic amidines are generally extensions of the methods employed for lower homologous cycles such as imidazolines and tetrahydropyrimidines.Literature data on the higher homologues, 1,3-diazepines, diazocines and diazonines, are scarce.
There are basically two methods for the synthesis of cyclic medium-sized amidines which involve acyclic compounds as precursors (Scheme 1) : Method A: from 1,n-alkylenediamines as precursors Method B: from -aminoamides as precursors Scheme 1

Synthesis of amidines from 1,n-alkylenediamines (Method A)
The construction of the amidine nucleus involves the coupling of a 1,n-diamine with an appropriate condensation partner that provides the C-2 of the amidine ring.The synthesis of tetrahydro-1,3-diazepines and hexahydro-1,3-diazocines from tetramethylenediamines (putrescine) and pentamethylenedimine (cadaverine) was the first class of methods developed in chemistry.Generally, this method was applied to the synthesis of cyclic amidines C-2-substituted with alkyl or aryl groups but without N-substitution.
Cyanides can be an adequate source of C-2.Oxley et al. have described the synthesis of some 2substituted tetrahydrodiazepines 1 in good yields from a mixture of a nitrile and tetramethylenediamine/ tetramethylenediammonium bistoluene-p-sulfonate at 200 o C (Scheme 2). 54The practical limitation of this method appears to be that ocurring with the synthesis of tetrahydrodiazepines, since attempts to produce hexahydrodiazocines and diazonines (I, n= 3,4) by condensation of penta-and hexamethylenediamines or their salts with cyanides, resulted in a mixture from which no homogeneous solid derivative could be isolated.

Scheme 2
Johnson and Woodburn have used more electrophilic nitriles for the synthesis of cyclic amidines of five to seven members.Thus, the authors accomplished the reaction between trifluoroacetonitrile with aliphatic diamines to yield carboxamidines and, where n = 0-2, with cyclic amidines as well. 55The reactions with tetramethylenediamine yielded carboxamidine as the major product but only 6 % of the cyclic compound, namely 2-trifluoromethyl-4,5,6,7-tetrahydro-1H-1,3-diazepine 2, was isolated (Scheme 3).On the other hand, penta-and hexa-methylenediamine only produced carboxamidines when treated with trifluoroacetonitrile.

Scheme 4
The use of catalysts has, in some cases, improved the results of reactions of diamines with nitriles.In 1974, three 1,3-diazepines containing -alkoxybenzyl groups on C-2, with potential hypoglycemic and natriuretic activity, were synthesized using 2-alkoxy-2-arylacetonitriles as source of C-2. 57The conversion of the nitrile into the corresponding amidine was readily accomplished by heating the reaction mixture with an excess of diamine using a few drops of CS 2 as catalyst.
Forsberg et al. have published the lanthanide(III)-catalyzed addition of amines to nitriles for the construction of amidines. 58Ln 3+ ions activate nitriles through a predominantly electrostatic ion-dipole interaction.This interaction enhances polarization of the cyano group, thereby facilitating the attack by the nucleophilic amine.The reactions are quite facile and progress to completness (yields 75-95%) when equimolar amounts of amine and nitrile are heated with 1 mol % Ln 3+ for 24 h.By means of this strategy, 2methyl, ethyl and phenyl 1H-4,5,6,7-tetrahydro-1,3-diazepines 4 could be synthesized (Scheme 5).

Scheme 5
As activated equivalents of carboxylic acids, imidic esters (imidates), have been used in the synthesis of cyclic amidines.The reaction of an imidic ester with alkylendiamines generally requires milder reaction conditions than those in which the corresponding nitriles are employed.Sahyun et al. have obtained among other cyclic amidines 2-chloro-and 2-hydroxy-alkyltetrahydro-1,3-diazepines 5,6 from the corresponding imidic ester hydrochlorides.The compounds were subsequently transformed into esters 7 with antispasmodic activity (Scheme 6). 22RKAT USA, Inc Cl - Cl - RCOOH 6 5 7

Scheme 13
In 2009, Wilhelm et al. synthesized a tetrahydro-1,3-diazepine 15 containing a bicyclic core derived from camphor from 1,3-diamino-1,2,2-trimethylcyclopentane, which is a compound easily obtained from camphor that is a very useful material to construct chiral compounds.The method involves the N-alkylation of the camphoric diamine followed by reaction with triethyl orthoformate.Alkyl halides have also been used as source of C-2.The 3-substituted 5-(chloromethyl)-1,2,4-oxadiazole reacts with putrescine in the presence of sulfur as dehydrogenating agent to yield 2-heteroaryltetrahydro-1,3diazepines 17 (Scheme 16). 70,71 Scheme 16 Bieraugel has studied the carbon unit transfer from cyclic amidinium salts to bifunctional nucleophiles as -diaminoalkanes. 72,34Thus, protonated 4,5,6,7,8,9-hexahydro-1,3-diazonine 18 was obtained using an imidazolinium salt as C-2 donor to hexamethylenediamine (Scheme 17).The process results from the ability of such imidazolinium salt to transfer a formyl equivalent to a variety of nucleophiles.However, the product was only characterized by 1 H-NMR through the presence of the N = CH signal at 8.00 ppm.Recently Simion et al. have reported an unexpected synthesis of the same diazonine 19 using hexamethylenediamine and dimethylformamide as source of C-2. 73The cyclization was explained as a twostep process involving formylation and subsequent intramolecular condensation (Scheme 18).

Scheme 18
The usefulness of this process has been demonstrated through the synthesis of two other nitrogencontaining macroheterocycles (Scheme 19).

Synthesis of amidines from -aminoamides (Method B)
This general method involves the cyclodehydration of N-aryl-N'-acylalkylenediamines 20 to the corresponding cyclic amidine by heating with a cyclizing agent.The proposed mechanism is given below.This is a general method for the synthesis of five to eight-membered N-aryl substituted cyclic amidines, and the variations depend on the synthetic route to generate the precursor aminoamide and the cyclizing agent used (Scheme 20).

Scheme 22
However, when the aryl group of the N-arylalkylenediamine is not substituted or when it is substituted with electron donor or slightly electron withdrawing groups, the reaction with acyl chlorides under Schotten-Baumann conditions led to the corresponding N,N'-diacyl derivatives. 32Selective monoacylation was achieved using aliphatic carboxylic acid anhydrides working at 0 o C in a biphasic system (Cl 3 CH/aqueous Na 2 CO 3 ) 75 or working in homogeneous phase with DCM as solvent and TEA as acceptor of hydrogen chloride at -10 o C (55-60%). 32nother suitable synthetic strategy to obtain the precursor aminoamides 20 involves the synthesis of N-4halobutyl or N-5-halopentylbenzamides 22 as key synthetic intermediates and subsequent reaction with amines (Method B-2).Attempts to obtain the haloalkylamides 22 by acylation of the corresponding haloalkylamines in basic medium have failed, because in such reaction medium intramolecular aminolysis occured. 33Conversely, 4-chlorobutyl-and 5-chloropentyl-benzamides could be obtained by reaction of Nbenzoylpyrrolidine or piperidine with phosphorus pentachloride by the von Braun reaction (Scheme 23). 76The subsequent reaction with arylamines leads to the expected aminoamides 20 (R 1 = Ar). 31,77A drawback of this strategy is that the procedure is restricted to N-acyl derivatives without -hydrogens. 769][80] The synthesis of medium-sized cyclic amidines through the cyclization of aminoamides was first reported in 1977 (Table 1, entries 1-6), 74 when a series of 1,2-diaryl-1,3-diazepines and diazocines having a nitrophenyl substituent on N-1 were synthesized through the ring closure of the corresponding N-nitroaryl-N'-aroyltetra-and penta-methylenediamines, respectively, employing a chloroform solution of PPE or phosphorus oxychloride as cyclizing agent for the synthesis of diazepines and neat PPE to obtain the corresponding diazocines.Similarly in 2000 Hedrera et al. synthesized 1,3-diazepines employing the same cyclizing agent (Table 1, entries 7-10). 33,35 X=Cl,Br 22 20

Scheme 23
Table 1.Synthesis of -aminoamides and their cyclization conditions Cyclization conditions Yield (%) Ref.In general, cyclization reactions usually required long reaction times and high temperatures, resulting in lower product yields in some cases.The traditional methods have been modified to improve their efficiency, optimizing the routes of synthesis with the use of new technologies.Microwave irradiation has emerged as an efficient technique for reagent activation in organic reactions.The remarkable advantages of this methodology are the simple experimental procedures, high yields of products, short reaction times, mild conditions and easy work-ups.][85][86][87] Using this methodology, Orelli et al. have presented a simple and efficient microwave-based protocol for the synthesis of cyclic amidines through an PPE-promoted cyclodehydration of N-aryl-N'-acylalkylenediamines, using a modified domestic microwave 81 (Table 1, entries 11-15).Employing microwave heating and a chloroformic solution of PPE, 1-aryl-1,3-diazepines and diazocines could be obtained with satisfactory (240 W, 2.5 min and 320 W, 6 min respectively.) The microwave-assisted ring closure of N-aryl-N'-acyltetramethylenediamine derivatives promoted by PPE allowed the synthesis of 1-aryl-2-alkyl-1,3-diazepines (Table 2, entries 16-23). 75The cyclodehydration was © ARKAT USA, Inc carried out in a Monowave 300 monomode reactor.The reactions were completed in 8 min at 100°C with 63-90% yield.Under similar conditions, however, considerably lower yields of homologous 1-(4-methylphenyl)-2alkyl-1,3-diazocine were obtained (Table 1, entry 24). 75Alternatively, the use of PPSE as cyclodehydrating agent under solvent-free conditions in the microwave-assisted ring closures of N-acyl-N'arylpentamethylenediamines allowed obtaining acceptable yields of 1-aryl-2-alkyldiazocines (Table 1, entries 25-33). 82On the other hand, 1,2-diarylderivatives of 1,3-diazepines and diazocines were obtained by cyclization of either the corresponding N-aryl-N'-aroyltetra-or penta-methylenediamine (Table 1, entries 34-38). 31,32

Scheme 24
Upon comparing the basicity of the seven and eight-membered 1,2-diaryl substituted cyclic amidines (n=2,3) with that of the lower amidine (n=0,1), it was observed that basicity decreases in the order tetrahydropyrimidines (n=1) > tetrahydrodiazepines (n=2) > hexahydrodiazocines (n=3) > imidazolines. 35,36,74his phenomenon was attributed to the possible torsion of the seven and eight-membered rings that may result in a less favored delocalization of the amidinium charge, and consequently in a decrease in basicity.
The effects of the sustituents on the N-1 aryl, were analyzed in a series of 1-aryl-2-phenyltetrahydrodiazepines. 35,36

Nucleophilic character
Like other cyclic amidines, [88][89][90][91] 1-substituted tetrahydrodiazepines and hexahydrodiazocines have a strong nucleophilic character due to the N-3 lone electron pair.33]35 Since the reaction is a typical S N 2 displacement, it is adequate for the introduction of primary alkyl groups (Scheme 25).

Hydrolysis
1,2-Diaryltetrahydrodiazepines and hexahydrodiazocines are resistant to acid hydrolysis due to the high stability of the amidinium ion. 36However, due to their amidinic nature, they are hydrolyzed in alkaline solutions affording N-acyl derivatives of the corresponding tetra-and pentamethylenediamines.The observed regioselectivity was analyzed in the light of the stereoelectronic control theory (Scheme 26). 35,36N:

Scheme 26
The resistance of cyclic amidines to alkaline hydrolysis depends on the cycle size.A comparison of halflives of 1,2-diaryl derivatives has demonstrated that the degree of stability is: imidazolines (n=0) < tetrahydropyrimidines (n=1) << tetrahydrodiazepines (n=2) < hexahydrodiazocines (n=3). 74The greater stability of the larger rings was attributed to conformational factors that prevent the attack of the nucleophile OH -on C-2.

Synthesis of Cyclic Amidinium Salts
As indicated above (3.2) cyclic amidinium salts are typical salts where the cation is resonance-stabilized and the positive charge can be delocalized either on the nitrogen atoms or on the C-2 (Scheme 25).As in the case of cyclic amidines, the methods of synthesis for cyclic amidinium salts of medium size, are in general, extensions of the methods employed for lower cyclic amidinium salts.These methods employ both cyclic and acyclic compounds as precursors.

Synthesis of amidinium salts from acyclic precursors
The treatment of N,N'-disubstituted -alkanediamines with trialkyl orthoesters in the presence of a source of protons and anions (ammonium tetrafluoroborate, ammonium hexafluorophosphate, ammonium chloride), leads to the corresponding cyclic amidinium salts.The drawback of this method is that it is not applicable to acid-sensitive substrates.This method employing alkyl orthoformates as C-1 building block is the method of choice for obtaining 2-unsubstituted salts (R 2 = H, Scheme 28), which are important as NHC precursors.

Scheme 28
The synthetic routes for obtaining the precursor diamines vary according to the nature of the linking backbone, the nitrogen substituents and the presence of chirality.This issue has been extensively addressed by César et al. 92 The first report on the synthesis of seven-membered cyclic amidinium salts dates from 1991, when Saba et al. 93 prepared a series of cyclic amidinium salts by the reaction of trialkyl orthoesters with various N,N'-dialkyl--alkanediamines in the presence of ammonium tetrafluoroborate or hexafluorophosphate.Among others, 2-methyl, 2-ethyl and 2-isopropyl substituted tetrahydro-1,3-diazepinium salts were obtained.

© ARKAT USA, Inc
Several diazepinium salts were synthesized later to be used as precursors in the synthesis of sevenmembered N-heterocyclic carbenes (NHC).In this sense, Iglesias et al. have obtained 1,3-dicyclohexyl derivatives 27 through the reaction of N,N'-dicyclohexylputrescine with triethyl orthoformate in the presence of ammonium hexafluorophosphate. 94 The diamine was obtained in high yields by condensation of 1,4diaminobutane followed by reduction of the formed di-imine with sodium borohydride.Overall yields of 70% after recrystallization were obtained for the formation of the amidinium salt (Scheme 29).Çetinkaya et al. have reported the synthesis of 1,3-dibenzyl and 1,3-diheteroarylmethyl diazepinium salts with good yields. 95,96More recently, Wilhelm et al. has reported the synthesis of 1,3-dibenzyl and 1,3-di-phenylethyl)diazepinium salts to be employed as organocatalysts 97 Diazepinium salts embedded in a rigid bicyclic system containing a core derived from camphor 28 were obtained by cyclization of 1,3-diamino-1,2,2trimethylcyclopentane (camphoric diamine) with triethyl orthoformate. 68These salts were employed as precursors of enantiopure NHCs (Scheme 30).

Scheme 30
Employing a similar methodology, Newman et al. have synthetized salts containing aryl groups bearing electron donor groups as precursors of tridentate ligands. 98,99n 2005, a method was patented in which orthoesters were used as precursors to prepare cationic polymers bearing cyclic non-aromatic units containing an amidinium group, such as tetrahydrodiazepinium salts, among others. 100One strategy to introduce a cyclic amidinium group into a side chain of the polymer is either to start out from a polymer which bears an orthoester group 29, preferably an ethyl orthoester, in the side chain and allow it to react with an N,N'-dialkyl-α,ω-alkanediamine, or to start out from a polymer which bears the diamine function 30 in the side chain and allow it to react with an orthoester, preferably an ethyl orthoester (Scheme 31).

Scheme 31
In the same patent, polymers in which cyclic amidinium cations are located in the main chain and are linked to it via C atoms are described.Thus, for example, the reaction of polyamine with an orthoester leads to the formation of polymers 31 eight-membered rings (cyclic diazocinium ions) in the main chain (Scheme 32).

Scheme 32
The reaction of an N,N'-disubstituted amidine with an ,-dihalo compound in basic medium has been successfully used for the synthesis of N,N'-diaryl substituted cyclic amidinium salts 32.From a mechanistic point of view, in the basic medium the deprotonation of the amidine 33 generates an 1,3-diazaallyl anion, which reacts with a dielectrophile such as the ,-dihalo compound (Scheme 33).

Scheme 33
Thus, 2-unsubstituted tetrahydrodiazepinium salts have been synthesized by Cavell through the reaction of the appropriate N,N'-diarylformamidine with 1,4-diiodobutane in refluxing acetonitrile in the presence of a mild base such as potassium carbonate. 101,102The reaction proceeds rapidly for the larger ring sizes and less congested amidines.Formamidine precursors are easily obtained through the reaction of triethyl orthoformate with anilines.This synthetic strategy has been especially employed for N-substituted ARKAT USA, Inc compounds bearing bulky aryl groups (Scheme 34).This method has been used with good results for the synthesis of seven-membered salts with different N-aryl substituents. 103

Scheme 34
Similarly, Nechaev et al. have synthesized six-and seven-membered ring salts with bulky aryl groups by reaction of neat N,N'-diarylformamidine with 1,4-dibromobutane in the presence of diisopropylethylamine (DIPEA). 107,108This method has recently been extended to the synthesis 1,3-dialkyl diazepinium salts. 109The formamidine precursor was obtained through the reaction of the alkyl amine with triethyl orthoformate and one equivalent of acetic acid.
Asymmetrically 1,3-substituted rings 34 may be generated in good to high yields using a formamidine obtained by a step-wise reaction sequence. 106During the synthesis of the seven-membered salts containing a pyridine substituent 35, an alternative ring closure, via of the pyridine ring nitrogen, was observed, giving rise to a novel ionic fused ring product 36 (Scheme 35

Synthesis of amidinium salts from cyclic precursors
One of the method involves the dehydrogenation of cyclic aminals (Scheme 37).
Page 307

Scheme 37
The cyclic aminal 37 is commonly obtained from the corresponding -diaminoalkane and an aldehyde.Formaldehyde is used as C-1 building block to obtain 2-unsubstituted salts.In this method, the cyclization step requires neutral conditions, therefore, it is applicable to acid-sensitive substrates.Probably, for these reasons, Iglesias et al. 94 have used this route for the synthesis of a seven-membered ring salt 38 containing a strained 5,6-dioxolane moiety using NBS as a dehydrogenating agent (Scheme 38).Similarly, Wilhelm 97 has reported the synthesis of analogous 1,3-dibenzyl derivatives using NBA as dehydrogenating agent.
The synthesis of 1,3-dibenzyltetrahydrodiazepinium and hexahydrodiazociniun salts 39 through the dehydrogenation of aminals with NBS has recently been described (Scheme 39). 31s mentioned in Section 3.2, the alkylation of 1-substituted cyclic amidines affords the corresponding cyclic amidinium salts (Scheme 25).Since the reaction is a typical S N 2 displacement, it is adequate for the introduction of primary alkyl groups, being a method of choice for the synthesis of asymmetrically substituted salts.Thus, series of 1,2-diaryl-3-methyl-1H-4,5,6,7-tetrahydro-1,3-diazepinium iodides have been obtained through the reaction of the corresponding diazepines with methyl iodide in anhydrous THF under reflux, obtaining yields of 81-90 % in reaction times of 1-2 h. 33,35More recently, this methodology has been optimized by the use of MW irradiation, the reaction times were dramatically decreased (3-6 min) using a Microwave Digestion System in chloroform solution at 90 o C and 400 W. 31 However, when the reaction of 1,3-diazocines were conducted under the same conditions, the major product obtained was the corresponding hexahydrodiazocine hydrohalide. 32The protonation of the amidine could be avoided by using a mixture of DCM-DMSO (10:1) as solvent.Working under reflux conditions with conventional heating, 2-4 h were required for total © ARKAT USA, Inc conversion (71-95%), while the reaction times were reduced to 6-15 min when MW irradiation was employed (85-96% yields). 31,32These compounds are of special interest due to their electron richness.Consequently, they have been widely applied as ligands in transitionmetal catalysts and organometallic chemistry, [111][112][113][114][115] and as organocatalysts in their own right (Scheme 41). 116-

Scheme 41
In particular, tetrahydrodiazepinium salts have been synthesized to be employed as precursors of ring expanded NHCs (RE-NHCs), which are stronger -donating ligands. 120Structurally, they also have unique features: the saturated seven-membered ring is flexible, highly twisted, which provides an opportunity to design novel chiral ligands, and of considerable interest due to the large heterocyclic rings with large N-C NHC -N angles.Key features of these ligands are the presence of an increased basicity and a a high "steric" pressure on the metal center with respect to the more traditional five-membered NHCs.
Different bases have been employed to generate ER-NHCs: KN(SiMe 3 ) 2 (potassium hexamethyldisilylamide, KHMDS) in THF; [101][102][103]106,109,121 LiN(iPr) 2 (lithium diisopropylamide, LDA) in toluene, 101 t-BuOK in water/DMF, 96,104,105,122 Ag 2 O (silver oxide) in DCM 102,107 and potassium carbonate. 95 In some ases, seven-membered free carbenes have been isolated and characterized.102,108,121 However, they are generally obtained as metal complexes by direct reaction of the in situ generated carbenes with suitable metal salts.6,105,122 Other complexes with Pt, 104 Au, 123 Rh and Ir, 98,103,106,109 have also been reported.Seven-membered NHC complexes of Cu and Pd have been obtained by transmetallation of the corresponding NHC-Ag (I) complex with suitable metal salts.107,108 © ARKAT USA, Inc The use of seven-NHC metal complexes in catalytic transformations have provided encouraging results.The first example has been reported by Cetinkaya et al., who demonstrated that in situ generated 1,3dibenzyltetrahydrodiazepin-2-ylidene palladium complexes are very effective in Suzuki-Miyaura coupling reactions of deactivated aryl chlorides. 95Since then, seven-membered NHC complexes have been tested for catalytic transformations such as the Heck type cross-coupling, 96,105,122 Suzuki type reactions, 10,99 hydration of internal alkynes, 123 hydrosilylation, 99,104 catalytic hydrogenation 106 and transfer hydrogenation. 124,125he important results achieved with complexes bearing expanded ring NHC ancillary ligands in catalytic transformations have been attributed to the strong binding of the electron-rich carbene to the metal center that helps the metal retain its ligand, which provides the compound a longer catalyst life time, thus affording enhanced activity 106,126 Cavell et al. have reported the synthesis of the first eight-membered ring (diazocanylidene) NHCs 43 (8-NHCs) through the reaction of the corresponding cyclic amidinium salt 44 with KHMDS. 110In general, the free RE-NHCs could be isolated, and in one case, the molecular structure was elucidated.Rh complexes 45, 46 have been formed through the treatment of the in situ formed free carbene with the appropriate Rh precursor complex.Silver complexes 47 have been prepared through direct reaction of Ag 2 O with the diazocanylidinium salts (Scheme 42).

Scheme 42
Key features of these novel RE-NHCs are the extreme steric strain they impose on the metal center and their high electron donor capacity, being some of the most basic NHCs currently available.

Adduct formation.
In some cases, the reaction of 1,3-diazepinium salts with alkoxides leads to the addition products (2-alkoxyaminals).In this sense, while the 1,3-dicyclohexyl salt 48 reacts with strong bases affording the expected NHC 49, the corresponding adduct 50 was obtained when the salt was treated with potassium tert-butoxide in toluene (Scheme 43).

Scheme 43
Similarly, the adduct (7-dipp)(H)(OMe) 51 has been obtained by the reaction of equimolar amounts of the salt and NaOMe in absolute THF (Scheme 44).Attempts to obtain the NHC by vacuum thermolysis have failed.).][129] Wilhelm et al. have reported the application of several cyclic amidinium salts as catalysts in the ring opening of epoxides (Scheme 45). 97They tested four 1,3-diazepinium salts (52-55) and their activity was compared with the imidazolinium salt 56 (Figure 2).While the salt 56 displayed very low catalytic activity (12%), diazepinium salts 53 and 55 gave the product in 78% and 99% yield, respectively.These results were attributed to the special geometry of the 1,3-diazepinium cation which does not allow the planar conformation to be kept, thus the positive charge is less delocalized over the NCN atoms.Instead, there is a better delocalization of the positive charge in the planar sp 2 -centered imidazoline scaffold in the imidazolinium salts.The camphor-based salt 52 and the salt 54, with a larger steric environment around the amidinium unit, gave yields of only 24% and 38%, respectively.

34 35 36 Scheme 35
110mploying this method, Cavell et al. have recently synthesized the first eight-membered cyclic amidinium salts to be employed as NHC precursors (Scheme 36).The reaction was slow but yields were good (75%).110