Silver(I) salts as useful reagents in pyrazole synthesis

This account provides a survey on the synthesis of a huge variety of pyrazole-containing molecules by 1,3-dipolar cycloadditions promoted by silver(I) salts. The data on this subject are listed in a systematic way according to the type of the cycloaddition involved, with an emphasis to improvements with respect to reactions performed in the presence of the usual organic basic agents.


Introduction
Due to its wide occurrence in the field of heterocyclic chemistry, 1 the pyrazole ring constitutes a relevant synthetic target in both academia and industry.In fact, such a heterocyclic moiety represents the core structure of a number of drugs, 2 including the widely prescribed Celebrex and Viagra. 3Among the various synthetic routes which are amenable for the preparation of substituted pyrazoles, 4 the cycloadditive method occupies a prominent place due to its versatility in the construction of complex heterocycles. 5To this respect, 1,3-dipolar species which have been traditionally exploited in pyrazole synthesis are diazocompounds 6 and nitrilimines. 7These latter are well-known labile intermediates 8 which are generated in situ in the presence of the dipolarophile as beautifully described from early works by Huisgen. 9The classical way followed in order to generate the nitrilimine implies the base-promoted dehydrohalogenation of the corresponding hydrazonoyl halides.This step is usually carried out in homogeneous conditions by using an organic base fully soluble in the reaction medium, which involves deprotonation of the NH group and subsequent loss of the halide ion. 7The aim of the present account is to describe the synthesis of pyrazole-containing molecules by means of an 1,3-dipolar cycloaddition as the key step, in which the generation of the reactive species is promoted by a non-conventional basic agent, namely silver(I) salts, in heterogeneous conditions.

Intermolecular cycloadditions
An early report describing the behaviour of silver(I) carbonate as an efficient enhancer of hydrazonoyl halides reactivity was concerned to the synthesis of cyclopropa[c]cinnolines by way of an 1,7-electrocyclisation of N-(2-vinylphenyl)-substituted nitrilimines. 10he application of such reagent to the intermolecular nitrilimine cycloaddition were first exploited onto allylic alcohols as dipolarophiles (Scheme 1). 11The expected pyrazolinic cycloadducts 3 and 4 were obtained with low combined yields (10-28%) with respect to the similar reaction between allyl alcohol and diphenylnitrilimine (80%). 12These results may appear, prima facie, disappointing.However, the formation of open-chain products 5 gave some useful mechanistic insights about the reaction occurring between 1 and 2 in the presence of silver(I) carbonate.
As a rationalisation, it was proposed the mechanistic picture illustrated in the Scheme 2. Due to the well-known ability of the silver ion to facilitate the heterolysis of the carbon-halogen bond, 13 it was envisaged the initial formation of the nitrilium ion A. This intermediate can then evolve following alternative pathways: (i) proton elimination to generate the nitrilimine intermediate B, (ii) electrophilic attack to the π bond of the alkenol 2 to form the new carbocation C. The pinacol-type rearrangement of the latter 14 gave the carbonyl derivatives 5, whose formation have no precedent in the base-promoted reactions of hydrazonoyl halides with alkenols. 15

Scheme 2
Open-chain products similar to 5 were also found in the silver(I) carbonate-promoted reaction between hydrazonoyl chlorides and homoallylic or homopropargylic alcohols, 16 thus further supporting the above mechanistic picture.As a common drawback, however, it should be pointed out that cycloaddition yields were low and a number of side-products were always formed.Furthermore, the cycloadditions were not regioselective when R 1 and R 2 were other than hydrogens.This unappealing behaviour was avoided using trimethylsilyl homoallylethers 7a and 7b as dipolarophiles in the presence of silver(I) acetate (Scheme 3). 17The major cycloadducts 8 and 9 were highly preferred, being the regioisomeric ratio between 90:10 and 92:8.Further removal of the trimethylsilyl group from the latter cycloadducts with TBAF gave unprotected 4-(1-hydroxy)ethyl-4,5-dihydropyrazoles with good overall yield (59-65%).Cyclopropane derivatives 10 are unusual products whose formation can be ascribed to the multi-step ionic mechanism depicted in the Scheme 3. Electrophilic attack from the nitrilium-like ion to the C=C double bond of 7 gave the new carbocation D. Proton loss from the latter intermediate and subsequent ring closure gave cyclopropane derivatives 10.

Scheme 3
The use of silver(I) carbonate as an unconventional basic agent has been exploited in the cycloaddition between nitrilimines and (arylsulfonyl)allene 11 (Scheme 4). 18The choice of silver(I) carbonate in the place of more common organic bases, like triethylamine 19,20 comes from the following considerations: (i) the allene → acetylene isomerisation is suppressed in the current reaction conditions; (ii) room temperature and heterogeneous reaction medium allow a smooth generation of the nitrilimine, so minimising the degradative processes of the 1,3-dipole.From a mechanistic standpoint, it is likely that the final pyrazoles 12 and 13 would originate from the first-formed cycloadducts E and F, respectively, via 1,3-prototropic shift. 19,21The formation of the sulfinic ester intermediates 14 can be rationalised by invoking a [2,3]sigmatropic rearrangement of cycloadduct G via a sulfur-to-oxygen bond migration. 22It needs to be added that, due to the HOMO-nitrilimine control of the cycloaddition, electron-rich nitrilimines (entries a-c,f) gave better results, while the cycloaddition pathway appeared impervious with electron-poor nitrilimines (entries d,e).The computational aspects of this reaction have been investigated by means of DFT reactivity indices. 23itrilimine cycloadditions to partially saturated heterocycles as (hetero)dipolarophiles are attractive reactions since it is possible to synthesise complex tri-, tetra-and pentacyclic heterocycles which are not easy to obtain by other routes.
The C=N bond of the furo [3,4-c]pyrazoline 16 is able to react with hydrazonoyl chlorides in the presence of both silver(I) carbonate or silver(I) acetate giving the tricyclic compounds 17 with 2-32% yield (Scheme 5). 24The better results were obtained with silver(I) acetate, since some amount of the oxidation product 18 was always formed in the presence of silver(I) carbonate.This behaviour is not surprising in the light of the known oxidising ability of silver(I) carbonate. 25Notwithstanding these low cycloaddition yields, it has to be underlined that by performing the above reactions in the presence of triethylamine no noticeable reaction occurred onto the C=N bond of 16.   26 The competitive formation of products due to the nitrilimine attack at different dipolarophilic sites has been observed, and the experimental evidence was discussed by taking into account electronic features of the reactive species as well as their steric encumbrance.Since the known antibiotic activity of 2-azetidinone-based heterocycles 27 and the anti inflammatory features of some pyrazolines, 28 some compounds which brings together these heterocyclic fragments have been synthesised.The key step was an efficient nitrilimine cycloaddition to racemic 2-azetidinones 20 and 21 promoted by silver(I) acetate.Although not regioselective (regioisomeric ratio between 80:20 and 83:17), the cycloaddition to compound 20

Intramolecular cycloadditions
The most prominent features of intramolecular 1,3-dipolar cycloadditions 31 are related to the linkage between the reacting groups, which allows the simultaneous formation of two annulated (or fused) rings.Furthermore, the entropic advantage due to intramolecularity 32 works to improve the reactivity of the dipolarophilic fragment.
As far as intramolecular nitrilimine cycloadditions are concerned, the effect of the basic species used to generate these intermediates plays a key role in the whole process.The presence of triethylamine or very strong bases (e.g.sodium hydride) often cause the fast and irreversible generation of the nitrilimine which can force intermolecular processes leading to resinous materials.The effectiveness of silver(I) salts in a heterogeneous medium is the consequence of the very slow generation of the nitrilimine intermediate, which mimics high-dilution conditions favouring intramolecular over intermolecular pathways.
The following sections will be illustrated according to the length of the tether joining the reactive groups, i.e. to the size of the ring to which the pyrazole nucleus is annulated.

Formation of pyrazoles annulated to a five-or six-membered ring
Acetylenic α-diazoketones 22 bearing gem-dimethyl substituents in the α'-position were capable to undergo intramolecular cycloaddition in the presence of silver(I) carbonate or silver(I) oxide giving the corresponding bicyclic pyrazoles (Scheme 8). 33This behaviour was somewhat surprising since no trace of the expected Wolff rearrangement product was observed.However, bicyclic pyrazole derivatives were isolated with 35 to 55% yields depending on the silver(I) salt only in the presence of the mentioned gem-dimethyl substitution, which finds a rationale in terms of steric effects on conformational energies in the transition state.Despite their propensity for substitution rather than addition reactions, various fivemembered heteroaromatics can behave as dipolarophiles in intramolecular cycloadditions of 1,3dipoles. 34Plausibly, the high energy barrier due to the loss of aromaticity is overcome by favourable entropic contributions working in intramolecular reactions. 32Intramolecular nitrilimine cycloaddition onto a thiophene, 35 furan, 36 and isoxazole 37 ring (Scheme 9) were described as a synthetic route to a number of tricyclic pyrazoline derivatives.All these cycloadditions work well only in the presence of silver(I) salts, while the use of triethylamine as the base did not produce any appreciable reaction.In the case of the thiophene and isoxazole dipolarophiles the formation of diadducts 24, 25 and 27 can be ascribed to a sequential intraintermolecular cycloaddition pathway.

Scheme 9
The examples described above involve intramolecular reactions in which the dipolarophile is linked to the C terminus of the 1,3-dipole.Only one recent report deals with the behaviour of Nsubstituted nitrilimines in which the thiophene ring acts as the dipolarophile (Scheme 10). 38The formation of the cycloadduct 28 have been rationalised on the basis of the corresponding transition state optimised at the B3LYP/cc-pVDZ level.

Formation of pyrazoles annulated to a medium-sized ring
Pyrazoles annulated with a seven-, 39 eight-, 39 nine- 40,41 and ten- 40,41 membered ring have been synthesised by nitrilimine cycloaddition onto a terminal C≡C bond in the presence of silver(I) carbonate (Scheme 11).Partially unsaturated analogues of the latter cycloadducts have been obtained under the same reaction conditions from the corresponding hydrazonoyl chlorides bearing an ethylenic dipolarophile. 42,43For the sake of comparison, some of the starting hydrazonoyl chlorides were found very slow to react with triethylamine or similar bases even in more severe conditions. 44 2 CO 3

Formation of pyrazoles annulated to a large-sized ring
A number of strategies have been devoted to the synthesis of macrocyclic systems, including that based upon a multiple 1,3-dipolar cycloaddition sequence.This latter approach has been pioniered by Garanti and co-workers in a 1975 paper which describes the formation of macrocyclic compounds using intermolecular followed by intramolecular cycloadditions of nitrile oxides bearing an alkenyl dipolarophile. 45The synthesis of a variety of (1,5)pyrazolophanes 42,43,46 can be accomplished by treating a suitably functionalised hydrazonoyl chloride with silver(I) carbonate (Schemes 12 and 13).Of course, the intermolecular plus intramolecular cycloaddition sequence is competitive with the direct intramolecular cycloaddition, and the predominance of one pathway over the other is dependent on the length and the rotational freedom of the tether joining the reactive groups.

Scheme 13
Here again, the presence of a common base like triethylamine did not produce any appreciable result since large amounts of tarry material were usually formed.The intermolecularintramolecular cycloadditive protocol promoted by silver(I) carbonate was also applied to Csubstituted nitrilimines as precursors of bis-(3,5)pyrazolophanes. 47 Following the multiple cycloadditive macrocyclisation between bis-nitrile oxides and bifunctional dipolarophiles introduced by Kim and co-workers, 48 it was reported a version of the same methodology based upon the double cycloaddition between bis-hydrazonoyl chlorides and ARKAT USA, Inc.
bis-dipolarophiles in the presence of silver carbonate as the basic agent (Scheme 14). 49acrocyclic products 35 and 36 were obtained with good combined yields (36-59%).

Stereoselective cycloadditions
Due to the utility of enantiopure pyrazolines in organic synthesis and some interesting applications of related products, stereoselective cycloadditions of nitrilimines have become useful in the last few years, and the subject have been recently reviewed. 50Much of the examples discussed above actually involves stereoselective cycloadditions, although onto racemic substrates.The aim of this paragraph is to present the behaviour of silver(I) salts-promoted nitrilimine cycloadditions towards stereoselectivity in the synthesis of enantiopure heterocycles.For this reason the discussion will be restricted to cover cycloadditions in which the product(s) is optically active.

Scheme 15
In contrast to the above examples, nitrilimine cycloadditions to limonene derivatives (1S)-(-)perillyl alcohol and (S)-(-)-perillaldehyde resulted as site-and regioselective but not stereoselective processes. 51he behaviour of nitrilimines towards a series of enantiopure acrylamides 41 was investigated in the presence of several basic agents, namely triethylamine, (-)-sparteine and silver(I) acetate 52 (Scheme 16).The diastereoisomeric ratio ranges between 58:42 and 83:17 depending upon the chiral auxiliary connected to the α,β-unsaturated dipolarophile.The best results, obtained with acrylamides 41c and 41e, possibly reflect the lower conformational flexibility of the latter two substrates compared to 41a, 41b and 41d.The base and the presence of salts as LiCl and (AcO) 2 Mg, which were investigated as potential complexating agents, exerted little or no influence on cycloaddition diastereoselectivity.

Intramolecular stereoselective cycloadditions
Due to their versatility, intramolecular nitrilimine cycloadditions constitute a powerful approach to a wide range of heterocyclic systems. 53Furthermore, the products arising from these processes are generally complex polycyclic, annulated, and fused ring heterocycles that are difficult to prepare by any other method.From these preliminary remarks, it can be argued that a way which allows the synthesis of the mentioned products in the enantiopure form should be highly desirable.
As far as the synthesis of pyrazoles annulated to a five-membered ring is concerned, it may be recalled that the construction of the furo [3,4-c]pyrazole skeleton belongs to the first success of the intramolecular nitrilimine cycloaddition methodology. 54The first case of asymmetric induction in such reactions promoted by silver(I) carbonate was reported in 1999, 55 giving rise to a mixture of enantiopure cycloadducts 42 and 43 (Scheme 17).Since the intramolecular cycloaddition of nitrilimines 44 occurred with a lower degree of diastereoselectivity, 56 it is apparent that better results are obtained if the pre-existing stereocentre is placed in the αposition to the ethylenic dipolarophile or the 1,3-dipole (closer to the reaction site).

Scheme 17
A further example of pyrazoline annulated to a five-membered ring is given by the tricyclic β-lactam 47, which was obtained with full stereoselectivity. 57RKAT USA, Inc.

Scheme 18
Annulated [1,4]benzodiazepines represent valuable synthetic targets due to their well-known pharmacological activity as hypnotics and sedatives. 580][61] Anyway, this stereochemical outcome is worth noting because the distance between the pre-existing and the newly-formed stereocentres is rather large.

Scheme 20
The sequential inter-intramolecular cycloadditions of nitrilimine 49 (Schemes 21) gave the enantiopure pyrazolophane 50. 63This macrocyclic compound have been obtained as a single diastereoisomer, possibly due to the asymmetric induction of the pre-existing stereocentre reinforced by some kind of coordination between the silver ion and the ethereal oxygens of the reactants.

1
Formation of pyrazoles annulated to a five-or six-membered ring 3.2 Formation of pyrazoles annulated to a medium-sized ring 3.3 Formation of pyrazoles annulated to a large-sized ring 4. Stereoselective cycloadditions 4.1 Intermolecular stereoselective cycloadditions 4.2 Intramolecular stereoselective cycloadditions