2
Abstract
Alkynylated five-membered heteroarenes, and in particular azoles, represent a recurring structural motif found in bioactive natural products, pharmaceuticals, and organic materials. These compounds are of great importance either as building blocks or synthetic intermediates and have become increasingly attractive for synthetic organic chemists.1 During this experimental Thesis, an effective strategy for the selective C-5 alkynylation of the imidazole ring was developed. A series of alkynylimidazoles 73 was synthesized starting from 5-unsubstituted imidazoles 71 by employing a one-pot combination of a C-5 halogenation followed by a Sonogashira reaction. Due to the fact that in the last few years there has been great interest in the construction and investigation of fluorophores featuring a π-conjugated backbone, the developed strategy has been employed for the synthesis of imidazole-based chromophores end-capped with electron-donating (EDG) and electron-acceptor (EWG) groups ("push-pull” systems).
An efficient two-step procedure for the synthesis of symmetrically 4,5-disubstituted imidazoles (27) from 4,5-dibromoimidazole (74) was also developed, and some 2-aryl-4,5-bis(arylethynyl)imidazoles (79), which are potential “Y-shaped” chromophores, were prepared Their main fluorescence properties, such as absorption and emission maxima, Stoke’s shift and quantum yield were evaluated. Moreover, a new synthetic strategy involving a sequential C-5/C-4 double alkynylation of C-5/C-4,5-dibromoimidazoles (7C-5/C-4), concerning a site-selective Sonogashira reaction as the first step, was applied to the preparation of unsymmetrically substituted 4,5-dialkynylimidazoles 76, hardly obtainable from different pathways.
The results obtained in the present work are part of an oral communication that will be presented in September 2014 at the XXV Congress of the Italian Chemical Society.
3
List of Abbreviations
AcOH: acetic acid Boc: tert-butoxycarbonyl BODIPY: boron-dipyrromethene Cy: cyclohexyl DABCO: 1,4-diazabicyclo[2.2.2]octane dba: dibenzyldeneacetone DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DIPEA: N,N-diisopropylethylamine DMA: N,N-dimethylaceamide DMAP: 4-(dimethylamino)pyridine DME: dimethoxyethane DMF: N,N-dimethylformamide DMSO: dimethylsulfoxide DPPB: 1,4-bis(diphenylphosphino)butane DPPE: ethylenebis(diphenylphosphine) DPPF: 1,1’-bis(diphenylphosphino)ferrocene dtbpy: ditertbutylpyridine
EDG: electron-donating group EWG: electron-withdrawing group ICT: intramolecular charge transfer NBS: N-bromosuccinimide
PivOH: pivalic acid QY: quantum yield
TBCHD: 2,4,4,6-tetrabromo-2,5-cyclohexadienone THF: tetrahydrofuran TIPS: triisopropylsilyl TIPS-EBX: 1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one Tos: tosyl Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Xphos: 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl
4
Introduction
This work was focused on those compounds featuring an acetylene moiety directly linked to an azole and, in particular, recent studies on the transition metal-catalyzed alkynylation of 1,2-disubstituted-1H-imidazoles will be described.
Due to their rigidity, to their peculiar electronic properties and to the numerous methods available for the introduction and the functionalization of the triple bond, acetylenes have always been one of the most important functional groups in organic chemistry.1 Furthermore, alkynes are also important structural motifs both in material sciences and chemical biology. On the other hand, the imidazole ring represents the structural core of many relevant drugs, such as anti-hypertensive compounds,2 anti-inflammatory3 and anticancer agents,4,5 and of several antimycotic and antimicrobial compounds.6 Moreover, imidazole-based scaffolds have been often used as building blocks in the synthesis of naturally occurring products.7,8
The scientific interest towards alkynyl-substituted imidazoles came from the fact that in the literature many examples of interesting bioactive molecules possessing an alkynyl moiety directly linked to an azole nucleus have been described. Moreover, these compounds have often been used as precursors of other useful biologically active molecules.
For example, a series of 5-alkynyl-1-ß-D-ribofuranosyl-1H-imidazole-4-carboxamides (1,
Figure 1) have been identified as broad-spectrum antiviral agents.9 These compounds are alkynyl-substituted analogues of ribavirin (2), a nucleoside inhibitor used to stop viral RNA synthesis and viral mRNA capping. Ribavirin is an antiviral drug indicated for severe RSV infection, hepatitis C infection and some other viral infections. 5-Ethynyl-1-ß-D-ribofuranosyl-1H-imidazole-4-carboxamide (EICAR, 1a), the most potent congener of the group, showed antiviral potency about 10- to 100- times greater than that of 2. EICAR was also cytostatic for rapidly growing cells, and hence may represent a potential anti-tumor agent, and inhibited vaccinia virus tail lesion formation at doses that are not toxic for the host.
5 A class of alkynylimidazoles of general structure 3 (Figure 2), has been investigated for its anti-inflammatory properties. These 2-aryl-4-(ethynylaryl)-1H-imidazole-5-carbonitriles have been found to be prostaglandin E synthase-1 (mPGES-1)1 inhibitors. Compounds 3 (including compound 3a which is one of the most active) are indeed useful to treat diseases or disorders associated with mPGES-1 activity or in which mPGES-1 contributes to the pathology or to the symptomology of the disease, such as inflammation due to infection, surgery or other trauma.10
Figure 2
Compounds of general formula 4 (Figure 3), structurally very similar to 3, have been found to be metabotropic glutamate receptor antagonists (mGluR5).2
Figure 3
Therefore, compounds 4 have been used in the treatment or prevention of the central nervous system disorders. Such compounds may find their greatest utility in treatment of Alzheimer’s disease, Parkinson’s disease, senile dementia, amyotrophic lateral sclerosis and multiple
1
Prostaglandines are synthesized in human cells from arachidonic acid; some of them, such as prostaglandin E2, are strong inflammatory mediators and induce fever and pain. Other prostaglandines, however, are
known to have many beneficial properties such as the regulation of the contractions and relaxations of smooth muscle tissue or the protection of the gastrointestinal tissue. The enzyme mPGES-1 is responsible of the transformation of prostaglandin H2 into prostaglandin E2, which is a strong pro-inflammatory mediator, but it is not
implied in the synthesis of other important arachidonic acid metabolites. Traditional non-steroidal anti-inflammatory drugs exhibit a non-selective action inhibiting the synthesis of all the arachidonic acid metabolites and, as a consequence, they may cause adverse gastrointestinal effects such as gastrointestinal irritations. The above-mentioned compounds 3, on the contrary, selectively inhibit mPGES-1.
2 In the central nervous system the transmission of stimuli takes place by the interaction of a
neurotransmitter, which is sent out by a neuron, with a neuroreceptor. Glutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of central nervous system functions. The metabotropic glutamate receptor mGluR5 is a glutamate-dependent stimulus receptor. His main role is to activate messengers to regulate gene expression and to release neuro-active compounds. Compounds of general structure 4 have been found to be mGluR5 antagonists.
6 sclerosis.11 The chemical structures of these pharmaceuticals are based on a 4-(heteroarylalkynyl)-1H-imidazole core that may be substituted at their N-1 with different heteroaryl rings such as pyrimidones or pyridazinones (Figure 4).
Compounds 4a-c, bearing a chlorine atom in a meta position in respect to the triple bond, were found to show a strong activity toward central nervous system diseases (Figure 4).
Figure 4
Acetylene-functionalized imidazoles have been widely employed in pharmaceutical chemistry also as chemotherapeutic agents.12
Figure 5
For example, substituted imidazole rings linked to a pyrazolopyridine or an imidazopyridine moiety with an ethynyl bridge (see Figure 5, compounds 5) have been found to be inhibitors of the kinase PDK 1;3 they are used indeed for the treatment of the myeloproliferative disorders (such as leukemia) or cancer.12 Compounds 5, such as compounds 4, have also been found to be useful for the treatment or the prevention of the Alzheimer’s disease.
3
The kinase PDK1 has an important role in the signaling pathways; in fact, this enzyme is critical for transmitting the growth-promoting signals, which are necessary for normal growth factors and hormones development. The activation of some enzymes in tumor cells by PDK 1 has been shown to have multiple upstream effects that promote the disease progression, including suppression of apoptosis and stimulation of tumor cells proliferation, metabolism and angiogenesis. Compounds of general structure 5 are PDK 1 inhibitors and, thus, exhibit anti-tumor activity.
7 Pharmaceutical chemistry is not the only field in which alkynyl-substituted imidazoles have been employed. Alkynyl-substituted imidazoles may have also great importance in material science,13 especially as organic non-linear optic chromophores. In recent years, several papers describing azole-based chromophores have been published.14 Discovering effective fluorescent molecules has been a longstanding goal. In effect, such photoactive molecules find valuable applications as biomolecular probes for the investigation of physicochemical, biochemical and biological systems, sensor elements, and as building blocks for the synthesis of optical materials. Although well-known fluorophores such as fluorescein, rhodamine, BODIPY, and cyanines are currently used in many research fields, they do not always satisfy the criteria of an ideal fluorophore: high absorption coefficient and quantum yield, a large Stokes shift, long lifetime, high chemical and photochemical stability. Therefore, there is a continuing effort in developing new fluorescent dyes.15,16
In the last few years there has been a great interest in the synthesis and investigation of fluorophores featuring a π-conjugated backbone end-capped with electron-donating (EDG) and electron-acceptor (EWG) groups (the so-called "push-pull” systems). This arrangement of functionalities usually provides considerable intramolecular charge transfer (ICT) between the donor and acceptor moieties during electronic transitions and generates low-energy intense absorption.17 The inclusion of heteroaromatic rings in these structures often gives interesting properties to the whole system, such as high polarizability, intense charge transfer upon electronic excitation, chemical inertness and thermal stability; moreover, heteroatoms may act as auxiliary donors or acceptor moieties.18 However, despite the great interest in these classes of alkynyl-substituted azoles, examples of the incorporation of classical π-conjugated spacers such as a C-C triple bond on the C-2 or C-5 position of the imidazole core are scarcely found in the literature.
In 1994, Miller and coworkers reported the synthesis of a variety of azole-based chromophores, of general structure 6.19 However, only one example of a compound containing the imidazole core, i.e. derivative 6a, was described (Figure 6).
Figure 6
Compound 6a is a classical example of a “push-pull” type chromophore, in which the sulfonyl moiety acts as the electron-withdrawing group while the methoxyl function, at the other end, acts as the electron-donating group. These two functional groups are linked by a π–conjugate phenyl-ethynyl-imidazole skeleton. The azole ring was then used in place of classical aromatic substituents, to extend the π-conjugation; this choice, in addition to modify the linear and non-linear properties by increasing the dipole moment, also increase the thermal stability of the whole molecule.19
Chromogenic materials, which are capable of responding to various stimuli (e.g., light, heat, mechanical stress, and chemical stimuli) through a macroscopic optical output, have been
8 widely explored in recent years.20 In this field, in the lab in which the experimental work of this Thesis has been carried out, a pH-sensitive fluorescent dye (compounds 7, Figure 7) having the electron-rich N-methylimidazole core as a key structural feature has been synthesized and dispersed at low loadings in a polystyrene matrix, obtaining a light-responsive polystyrene film.4
Figure 7
Despite their potential attractive properties, to the best of our knowledge no other examples of dyes featuring an alkynyl-imidazole moiety have been synthesized.
Considering the wide range of possible applications of alkynyl-substituted imidazoles, straightforward synthetic protocols are consequently needed. Transition metal-catalyzed cross-coupling reactions involving organic halides and organometallic reagents rank one of the most powerful and reliable processes for the decoration of heterocyclic compounds. This is certainly true also for the synthesis of alkynyl-substituted imidazoles; as a matter of fact, these compounds have been obtained in most cases by transition metal-catalyzed alkynylation reactions. A short list of transition metal-catalyzed approaches to the synthesis of C-alkynylated-1H-imidazoles is reported below, along with some representative examples involving the synthesis of alkynyl-substituted azoles in which the azole is different from imidazole.
4
Once a light beam in the near-UV range was sent to polystyrene/dye films, polystyrene photooxidation likely occurred at the film surface with the formation of carboxylic compounds. These species locally promoted dye protonation, yielding a clear color change of the film emission directly exposed to the beam from blue to green.
9
Alkynylation reactions of azoles
As described in the previous paragraph, functionalized imidazolyl-substituted-alkynes are highly valuable classes of compounds widely used in contemporary organic synthesis. A convenient and versatile method for their preparation would be attractive and could encourage the development and the employment of this useful class of compounds. Alkynylazoles (including alkynylimidazoles) may be generally obtained by transition metal-catalyzed cross-coupling reactions, and the most convenient retrosynthetic disconnection involves the breakage of the Csp-Csp2 bond between the azole ring and the alkynyl moiety. Three different approaches are thus possible for the formation of this bond: a cross-coupling involving a terminal alkyne and an halogenated azole (route A) via a classical Sonogashira-type coupling, a direct heteroaromatic C-H alkynylation involving a 1-haloalkyne and an azole (route B), or an oxidative-type coupling between a 1-alkyne and a non-activated carbon atom of an azole (route C).
Scheme 1
It is right to mention that a fourth approach involving a preformed metallic acetylide could be considered (Scheme 2). Although some examples of this procedure have been reported in literature for the synthesis of the target compounds,21,22 this approach was judged less convenient than those summarized in Scheme 1, which do not require preformed organometallic reagents.
Scheme 2
Despite some examples of disconnections on the opposite end of the triple bond have been reported in literature,23,24 this approach was not considered as useful (Scheme 3).
10 This decision is motivated by the fact that an ethynylazole intermediate would be required; this intermediate may be readily obtained, for example, by metal-mediated alkynylation reactions of the azole ring with silyl-protected acetylenes, followed by subsequent desilylation to achieve the terminal alkynes (Scheme 4). However this approach requires a first disconnection between the azole ring and the triple bond and it was thus considered to be part of route A (Scheme 1).
Scheme 4
The other known procedures for the synthesis of ethynylazoles are laborious and non-convenient.25 These are the reasons why this retrosynthetic pathway was not considered.
Several examples, taken from the literature, concerning the three main synthetic pathways depicted in Scheme 1, are discussed below. The attention here has been mostly focused on those reactions in which a palladium precatalyst is employed; however, some other transition-metals have been used for this kind of reactions.
Although imidazole was chosen as the preferred substrate (this choice is discussed and justified in Chapter 2), literature data about their metal-mediated alkynylation are scarce and some representative examples of alkynylation reactions on different azoles are reported here.
11 1.1.Sonogashira-type alkynylation reactions involving monohalogenated azoles
In literature there are many papers in which a Sonogashira-type reaction is applied to the formation of a C-C bond according to route A. Classically, this procedure consists in a palladium- and copper-mediated cross-coupling between a terminal alkyne and an aryl (pseudo)halide. In order to activate the alkyne to couple, an organic or inorganic base is required (see Appendix A). However some examples in which copper is omitted have been also reported in the literature (Cassar-Heck procedure, see Appendix A); in these cases, however, stronger bases and higher temperatures are generally needed.
In this section some examples concerning the application of this strategy to the synthesis of alkynyl-azoles will be shown.
As a first example the synthesis of the 2,2’-diyne-linked bis-pyrrole 13, whose precursor 10 have been generated by Sonogashira alkynylation of iodo-pyrroles (8) (Scheme 5), was reported here. By a sequential double alkynylation, congeners 12 have also been obtained. This kind of compounds have proven to be key building blocks for the construction of novel porphyrinoids.26
12
Scheme 5
The double alkynylation of the 2,6-bis(pyrazol-1-yl)pyridine system 14 with trimethylsilylacetylene (9a) afforded the bis-alkynylated system 15, useful in coordination chemistry (Scheme 6).27
Scheme 6
2-Bromobenzothiazole (16) may be synthesized from benzothiazole (17) in one step in 82% yield. This induced Mao and coworkers to optimize a protocol for the “one pot” halogenation and subsequent alkynylation of 17 by a classic Sonogashira coupling.28 The authors employed DMF as the solvent and both the reaction steps were found to give good results at room temperature. When triethylamine was employed as the base, 2 mol% PdCl2(PPh3)2 and 7 mol%
CuI were employed in the cross-coupling step. When the sequence involved phenylacetylene (9b), the required derivative 18 was obtained in 99% yield over two steps (Scheme 7).
13
Scheme 7
In 1987 Yamanaka and coworkers examined the palladium-catalyzed reaction of phenylacetylene (9b) with several halogenated 1,3-azoles such as bromothiazoles, bromooxazoles, and iodo-N-methyl-1H-imidazoles. The coupling reactions of bromothiazoles and bromooxazoles under classical Sonogashira conditions [PdCl2(PPh3)2, CuI, Et3N] afforded,
in the first experimental trials, the desired products 19-22 in moderate yields at the C-4 and C-5 positions. Reactions involving the C-2 position afforded products Z in low yields (Scheme 8) while when iodo-N-methylimidazoles were used, the reaction gave unsatisfactory results at any position (Scheme 9).29
Scheme 8
On the basis of these findings, the reaction with trimethylsilylacetylene (9a) was carried out in order to synthesize 1,3-azole derivatives containing an unsubstituted ethynyl group. Only 4- and 5-bromothiazoles could be converted into the corresponding trimethylsilylethynyl compounds in
14 moderate yields, whereas the crude products obtained by reacting 4- and 5-bromooxazoles with 9a resinified during the purification process.
In summary, during initial investigations, regardless of the position of the iodine (C-2, C-4, or C-5) on the imidazole ring, the Sonogashira reaction between an iodo-N-methylimidazole and simple acetylenes gave unsatisfactory results (Scheme 9).29
Scheme 9
In contrast, when diiodoimidazole 26a derived from iodination of 1,2-dimethylimidazole, and 9a were submitted by Seo and coworkers to the classical Sonogashira reaction conditions, the required diyne 27 was isolated in 68% yield (Scheme 10).30
Scheme 10
The same reaction using propargyl-alcohol (9c) gave poorer results, leading to the coupling product in only 17% yield. Compounds 27 bearing diverse alkynyl moieties underwent a facile Bergman cyclization.31,32
15 Yet in contrast with Yamaka’s results, an excellent yield was obtained for the reaction between 5-iodoimidazole 28 and propargyl alcohol (9c), in the absence of CuI, during the preparation of the 5-alkynyl derivate 1b (Scheme 11).33
The adduct was then deprotected to 5-alkynyl-1-β-D-ribofuranosylimidazole-4-carboxamide 1b, an antileukemic and antiviral agent (Figure 1).9 It is noteworthy that when the Sonogashira reaction was conducted in the presence of CuI, the yield dropped to 19%, probably due to alkyne homocoupling.
Scheme 11
This copper-free process possesses significant flexibility and wide applicability, as exemplified by the preparation of 29 from the corresponding 4-iodoimidazole,34 and 3035,36 from the correspondent N-protected 2-bromobenzimidazole (Figure 8).
Figure 8
The synthesis of the natural product keramidine (31) involved a Sonogashira reaction as the key step. Keramidine was isolated from Agelas sponge in 1984 and was found to have interesting biological activities,37 but posed a challenge for its synthesis due to the Z-alkene substitution at the C-5 position of the imidazole ring (Scheme 12). The key step in the efficient six-steps synthesis of 31 involved the Sonogashira reaction of alkyne 9d with the N-protected 4-iodoimidazole 32. Protecting group cleavage via methylation at N-3 of 33 gave 25c. Metalation at C-2 of the imidazole nucleus was followed by quenching with tosyl azide to provide 25d. The synthesis of keramidine was thus competed following Boc removal, amide bond formation with the activated trichloromethyl ketone 34 and double hydrogenation using Lindlar’s catalyst to prepare the amine functionality at C-2 of the imidazole, as well as to establish the required Z-olefin geometry.37
16
Scheme 12
Regioselective functionalization of histidine at the C-2 position of the imidazole ring has been a synthetic challenge. Evans and Bach observed an anomalous phenomenon when diiodide 35 was subjected to standard Sonogashira reaction conditions (Scheme 13).38 When the coupling was performed in the presence of phosphine ligands, adduct 36a was isolated in 52% yield. This interesting reaction thus solved the dual problem of the dehalogenation at the C-4 atom and the bond construction at the C-2 atom in a single operation. When the same reaction was carried out in the presence of Pd(dba)2, phenylacetylene served as a reducing agent to afford the C-2
17
Scheme 13
Bromoimidazoles may also potentially take part in Sonogashira-type couplings, but in the literature there is only one example of this kind of coupling and the yields were lower than those generally obtained with iodoimidazoles. 4-Bromoimidazole 38 underwent a copper-free cross-coupling reaction with 1-hexyne (9e) and N,N-dimethylpent-4-yne-1-amine (9f) to afford the Csp2-Csp coupling products 24c and 24d in 37% and 46% yields, respectively (Scheme 14).39
Scheme 14
The sila-Sonogashira reaction was also investigated for the synthesis of alkynyl-azoles. This kind of reaction is a modification of the classical Sonogashira coupling and consists in the Csp2-Csp cross-coupling between an (hetero)aryl halide and a trialkylsilylacetylene. The trialkylsilyl protecting group is removed in situ to afford the terminal alkyne which undergoes the cross-coupling reaction.40
18 Lecerclé and Taran used a sila-Sonogashira reaction for the synthesis of 2-heteroaryl-1-alkynylphosphonates and heteroarylpropiolates.41 5-Iodo-1-methyl-1H-imidazole (39) was reacted with diethyl ((triisopropylsilyl)ethynyl)phosphonate (40a) and ethyl 3-(triisopropylsilyl)propiolate (40b) giving the required alkynylimidazoles 25e and 25f in 66% and 60% yields, respectively (Scheme 15).
Scheme 15
Kawai and coworkers employed the sila-Sonogashira coupling on 2,5-diiodo-1-methyl-1H-imidazole (41) in a crucial step of their synthesis of phenyleneethynylene-based and thienyleneethynylene-based π-conjugated polymers with imidazole units in the main chain (Scheme 16). This kind of polymers have attracted considerable interest; this was due to the fact that their properties, such as UV- and fluorescence- spectra, can be easily modulated by metal binding, protonation, or quaternization at their N-position.42
19 1.2.Site-selective Sonogashira-type reactions involving polyhalogenated azoles
Sequential and site-selective cross-coupling reactions on polyhalogenated azoles are particularly attractive strategies because they allow the progressive functionalization of the heteroaromatic nuclei starting from a common precursor. When the halogen atoms on the azole are different, the observed selectivity is obviously related to the relative bond dissociation energies of the respective carbon-halogen bonds, which follows the order C-I < C-Br < C-Cl < C-F.43 In contrast, when the halogen atoms are indentical the selective removal of only one halogen atom may be obviously more difficult.44
Several examples of site-selective alkynylations by Sonogashira-type cross couplings involving polyhalogenated aromatic heterocycles have been reported, but examples in which polyhalogenated azoles underwent selective alkynylation reactions are scarcely found in the literature. Among them, the Sonogashira protocol has been used, for example, to install an alkynyl group at the C-2(5) position of polyhalogenated pyrroles. Due to the higher electrophilicity of the C-2(5) position in respect to the C-3(4) position, the tetrabromopyrrole 42 reacted selectively with 2.2 equivalents of phenylacetylene (9b) giving the required compound 43 (Scheme 17).45
Scheme 17
In the Sonogashira reaction with phenylacetylene, the 4,5-diiodoisothiazole 44 reacted selectively at its C-5 position, giving raise to the 4-iodoisothiazole 45 as the only cross-coupling product (Scheme 18).46 Compound 45 underwent a further identical cross-coupling at C-4 to yield the dialkynylisothiazole 46. Similarly, 3,4,5-tribromoisothiazoles (47) also underwent the Sonogashira cross-coupling at its C-5 position (Scheme 18).46
20
Scheme 18
In 2003, Cosford and coworker reported that 2,4-dibromothiazole (48) in the presence of phenylacetylene, PdCl2(PPh3)2, CuI, Et3N in DME at 80 °C can undergo a site-selective
Sonogashira cross-coupling at its C-2 position (Scheme 19).47
Scheme 19
Multiple halogenated oxazoles are not as easily accessible as the corresponding thiazoles.48 While some few examples of other site-selective cross-coupling reaction on imidazoles were reported, the fact that no site-selective Sonogashira coupling reactions have ever been made on polyhalogenated imidazole rings must be reported. Site-selective Suzuki and Stille reactions were, on the contrary, performed on multi-halogenated imidazoles, showing that the order of reactivity generally is C-2 > C-5 > C-4 (Scheme 20).49,50
21 Due to the fact that the site-selectivity is governed by the oxidative addition step of the catalytic cycle,51 and that Suzuki, Stille and Sonogashira reactions share this step, that the reactivity trend for the Sonogashira alkynylation of imidazoles can be argued to follow the same order observed for the other two cross-coupling reactions.
22 1.3.Direct Alkynylations
Recent advances in direct carbon–hydrogen bond activation chemistry provided a complementary method to the classical cross-coupling reactions reported above.52, 53 Metal-catalyzed direct alkynylation of heteroarene C–H bonds with alkynyl halides or pseudohalides (formally named as “inverse” Sonogashira reaction) has recently received much attention as a complementary process to Sonogashira coupling (route B in Scheme 1).54 In this case, the normal reactivity of alkynes is inverted (an umpolung) and halogenoacetylenes (49-51, Figure 9) are the logical first choice as reagents. Nevertheless, the sp hybridization of the triple bond confers a low reactivity to these reagents, and it is only with the development of transition metal-catalyzed reactions that their potential becomes fully evident. Alkynyliodonium salts (52, Figure
9), by contrast, are much more reactive, as the non-classical 4-electrons–3-centers bond present
in these reagents is particularly weak. Consequently, many reaction pathways not accessible with halogenoacetylenes become possible with this class of reagents. Sulfone-substituted alkynes (53,
Figure 9) as electrophilic acetylenes have been less studied, but were found to be demonstrably
superior reagents for the alkynylation of nucleophilic radicals.
Figure 9
As it can be seen from examples shown in next paragraphs, direct alkynylations generally occur at the most nucleophilic carbon of the heteroarene, and as a matter of fact only C-2 direct alkynylations of azoles can be found in literature.
23 The direct alkynylation reaction may be highly attractive especially when the preparation of heteroaryl halides is not convenient or straightforward. The first practical example of this kind of cross-coupling involving an aromatic heterocycle, the sydnone derivative 54, was disclosed by Kalinin et al. in 1992. However, this procedure should be considered a “formal” direct alkynylation because a stoichiometric amount of CuI was employed to generate the organocopper intermediate 55, which then underwent palladium(0)-catalyzed cross-coupling with alkynyl bromides 50 to give alkynyl sydnones 56 (Scheme 21).55
Scheme 21
Later Trofimov and coworkers, who introduced the term “inverse Sonogashira coupling”, reported that a variety of pyrroles and indoles underwent alkynylation promoted by more than stoichiometric amounts of Al2O3 to give C2-alkynylated pyrroles and C3-alkynylated indoles in
good yields (Scheme 22).56 However, in this case the mechanistic pathway does not involve the formation of any organometallic species, but products 59 comes from a Michael addition on alkynyl ketones 58 of the azoles 57, followed by a dehydrobromination.
Scheme 22
In 2007, the first example of a transition-metal-catalyzed direct alkynylation of electron-rich N-fused heterocycles was reported by Gevorgyan et al.57 They showed that in the presence of a palladium catalyst, indolizine (60a), pyrroloquinoline (60b) and pyrrolooxazole (60c) cores may be highly efficiently and regioselectively alkynylated with bromoalkynes 50 bearing a broad range of substituents (Scheme 23).
24
Scheme 23
Gu and Wang applied this chemistry to the direct palladium-catalyzed regioselective C-3 alkynylation of indoles 62 with various aryl- and alkenyl-substituted alkynyl bromides (50,
Scheme 24).58
Scheme 24
An efficient and versatile Pd-catalyzed direct alkynylation of azoles was recently reported by Chang and coworkers.59 The authors employed lithium tert-butoxide as the base and the simultaneous use of palladium(II) acetate and Xantphos was found to achieve the best catalytic system for this reaction. Oxazole (63), thiazole (64) and N-phenylimidazole (65) underwent the coupling reaction at the C-2 position in good yields (Scheme 25).
25
Scheme 25
Other transition-metals catalysts different than palladium-containing ones have been employed in this kind of cross coupling. For example, nickel(0)-catalyzed inverse Sonogashira reactions involving azoles and different alkynyl bromides have been reported by Miura and co-workers;60 a copper(I)-catalyzed direct alkynylation of azoles was, on the other hand, reported by Piguel et al.,61 who performed also a direct alkynylation of azoles with 1,1-dibromo-1-alkenes as electrophiles.62 For example, 1,1-dibromo-2-naphtylethylene (68) was reacted whit 5-phenyloxazole (63b) affording the C-2 coupling product 66c in 81% yield (Scheme 26).
Scheme 26
In place of bromoalkynes, a more reactive benziodoxolone-based hypervalent iodine reagent (TIBS-EBX, 52a, Figure 10) was employed in the gold-catalyzed direct alkynylation of heterocycles.63
26
Figure 10
Brand and coworkers, for example, performed a gold(I)-catalyzed “inverse” Sonogashira-type reactions on indoles and pyrroles (Scheme 27).64,65
Scheme 27
In 2013 a Pd-catalyzed direct alkynylation of indoles was reported; in contrast with all the Au-catalysts, which selectively alkynylate the C-3 position of the indole, palladium species leads the alkynylation at the C-2 position (Scheme 28).66 The reaction worked well with different halogens on various positions on the benzene ring and no inert atmosphere was required.
27 1.4.Direct oxidative alkynylation of azoles
This reaction, unlike the other metal-mediated alkynylation reactions, does not require any pre-functionalized azole or alkyne (route C in Scheme 1). This interesting coupling was first investigated using lead(IV) as a stoichiometric oxidant.67 More recently, the use of a metallic catalyst together with an external oxidant has led to more environmentally friendly conditions.67
The oxidative alkynylation of azoles may be catalyzed by several transition metals: complexes of Pd, Cu, Ni and Fe have in fact been described to be efficient precatalysts.
When palladium is employed, the active catalyst is a Pd(II) species; since at the end of the catalytic cycle the reductive elimination provides a Pd(0) species, a stoichiometric oxidizing agent is then required.
Scheme 29
Generally, in-situ activation of the most nucleophilic position of the azole nucleus and the simultaneous activation of the alkyne are performed using a large amount of a base. While direct coupling between arenes and terminal alkynes is potentially the most attractive route to arylacetylenes, this type of cross-coupling has been greatly challenging, probably due to the difficulties of control the selectivity in the sequential activation of two different carbon– hydrogen bonds.53 Furthermore, the presence of the oxidant promote the homocoupling reaction of the terminal alkyne taking down the yields; the slow addition of alkynes with a syringe pump is almost always required to suppress the undesired diyne formation.
A Pd-catalyzed intermolecular dehydrogenative alkynylation of indoles using 1-alkynes was reported by Li et al. in 2010 (Scheme 30).68 The reaction was found to give the best results when a buffer system composed of 20 mol% Cs2CO3 and 2 equivalents of pivalic acid (PivOH)
was employed in the presence of K2PdCl4 as the precatalyst under an O2 atmosphere.
28 activity than Pd(OAc)2, and, unlike the classical Sonogashira procedure, only a catalytic amount
of base was sufficient to achieve high product yields.
Scheme 30
Not surprisingly, the reaction was proposed to proceed via an alkynylpalladium intermediate which undergoes an electrophilic attack at the C-2 position of indoles to generate an alkynylindol-palladium species upon deprotonation by pivalate. Reductive elimination of the latter intermediate yields the alkynylated indole products and Pd(0) that is reoxidized to Pd(II) by the action of O2 and pivalic acid (Scheme 31).
29 Chang and co-workers found that palladium was also a viable catalyst for the direct alkynylation reaction of azoles (Scheme 32).69 t-BuOLi was employed as the base and high product yields were obtained only when Pd(PPh3)4 catalyst was employed under aerobic conditions.
Scheme 32
In a very interesting work, Murai and Shibahara introduced two different alkynyl groups onto 5-membered heteroarenes.70 This result is very difficult to achieve by conventional Sonogashira coupling because of the low chemo- and regioselectivities of the reaction involving polyhalogenated heteroarenes. The authors developed a widely applicable direct oxidative coupling of azole and terminal alkynes through the use of a combination of Pd and Ag salts and through a carefully controlled dropwise addition of terminal alkynes. Halogen substituents are tolerated on the azole ring, and products can be submitted to subsequent Sonogashira reactions. In conclusion, their catalytic system allowed the authors to easily access imidazo-pyridines and thiazole containing two different alkynyl groups (Scheme 33).
Scheme 33
An important contribution to the direct C–H alkynylation of benzoxazoles was disclosed by Miura et al. in 2010 (Scheme 34).71 A nickel catalyst in combination with a bipyridine ligand was effectively applied to the C-2 alkynylation of benzoxazoles under atmospheric O2. More
30 than stoichiometric amounts of a strong base (t-BuOLi) were required for achieving high coupling efficiency and a slow addition of the alkyne improved product yields. It was proposed that the base deprotonates both the azole and 1-alkynes to generate organolithium species which are subsequently involved in a transmetallation reaction with nickel complexes.
Scheme 34
The above mentioned reaction conditions, with some variations as noted, have been applied to the alkynylation of different azoles (Scheme 35).
Scheme 35
The same group widely explored the copper(I)-mediated oxidative alkynylation of azoles.72,73 Treatment of 2-aryl-1,3,4-oxadiazoles (69) with terminal acetylenes (9) in the presence of CuCl2
and Na2CO3, in N,N-dimethylacetamide (DMA) at 120°C under an O2 atmosphere, provided the
corresponding coupling products alkynyloxadiazoles 70 (Scheme 36). The slow addition technique was essential for reducing the homocoupling side reaction of acetylenes. The direct coupling was compatible with various functions in the terminal alkyne, including a thienyl-substituted acetylene (64c).
31
Scheme 36
Due to its low toxicity and to the fact that it generally does not require coordination with expensive or/and toxic ligands, an iron catalyst would be very attractive. Bobade and coworkers explored the use of iron catalysts in a ligand- and solvent-free oxidative alkynylation of azoles;74 in this reaction, FeCl2 was used in catalytic amounts in the presence of di-tert-butyl peroxide
(t-BuO)2 (Scheme 37).
Scheme 37
Yields resulted generally lower than that of the previous reported methods, but when 5-methylbenzoxazole was coupled with phenylacetylene under solvent-free conditions the required product was isolated in 85% yield.
32 As clearly emerges from the previous paragraphs, alkynyl-substitute azoles and, in particular, imidazoles, are important synthetic targets. According to this fact, the main aim of this experimental Thesis is the design and development of new methods for the efficient and selective preparation of mono- and dialkynylated imidazoles.
In details, as first goal, efforts will be focused on the synthesis of 5-alkynylated imidazoles (73, Scheme 38), starting from imidazoles (71, Scheme 38). Starting from literature data, the monobromination reaction of imidazoles will be reexamined, putting a particular attention on the regioselectivity of this electrophilic aromatic substitution. Then, the reaction conditions for the alkynylation reaction with alkynes will be optimized, and the possibility to carry out a sequential halogenation-alknynylation reaction pathway will be also evaluated (Scheme 38).
Scheme 38
The second goal will be the evaluation of the regioselectivity of the monoalkynylation reaction involving 4,5-dibromoimidazoles (74), and the application of the obtained results to the preparation of symmetrically and unsymmetrically-substituted 4,5-bis-ethynylimidazoles (Scheme 39). The one-pot double bromination-double alkynylation to compounds 27 will be also evaluated.
Scheme 39
Finally, the preparation of imidazole-based chromophores of general structure 77, 78 and 79 (Figure 11), where EDG is an electron-donating group and EWG an electron-withdrawing group (push-pull systems), will be the last goal.
33
34
Results and Discussion
Synthesis of 5-alkynyl-1,2-disubstituted imidazoles.
As described in the Introduction, the first goal of this Thesis was the development of an efficient procedure for the preparation of 5-alkynyl-1,2-disubstituted imidazoles. In order to achieve this target, Sonogashira-type reactions involving 5-bromoimidazoles as the electrophilic coupling partners were chosen (Scheme 40).
Scheme 40
At first, optimized conditions for the regioselective synthesis of 5-bromoimidazoles had to be found due to the fact that this class of compounds is not commercially available, and no efficient synthetic methods have been published before the studies described in this work. To reach this goal the existing literature procedures for the direct C-H bromination of the imidazole nucleus, briefly summarized below, were initially screened, and the results of the subsequent optimization will be summarized. Then, the efforts to optimize the reaction conditions for the alkynylation reaction involving 5-bromoimidazoles and the results obtained in carrying out a one-pot C-5 halogenation-alknynylation sequence will be described.
Direct
C-H
Bromination
of
imidazoles:
literature
procedures.
All the reported literature procedures for the direct bromination of imidazoles evidenced that a good regioselectivity is hardly to achieve, because mixtures of brominated isomers or poly-brominated products are very often obtained. Imidazoles are preferentially brominated at C-4 or C-5 position (C-4 and C-5 positions in N-unsubstituted imidazoles are tautomerically equivalent, while in 1-substituted imidazoles C-5 is slightly more reactive than C-475), C-2 bromination is also possible, and it is difficult to prevent di- and tri-bromination. Substituents on the imidazole ring play an important role too: electron-withdrawing groups decrease the reaction rates while an imidazole substituted with an electron-donor group can be brominated in an easier way.76 The position of the substituent is also important; for example, a methyl group linked at position 1 is only mildly activating, while a 2-methyl substituent quite strongly improves the bromination rate of imidazole rings.76
35 2,4,5-Tribromoimidazoles, and 2,4,5-tribromo-1-substituted imidazoles, can be readily synthesized using a variety of reagents; for example, tribromoimidazole 81 was prepared in good yield simply treating 1H-imidazole (80) with 1.5 equivalents of bromine in CHCl3 (Scheme 41).77
Scheme 41
Good results were also reported when 80 or N-substituted-1H-imidazoles reacted with bromine in different conditions, such as in acetic acid, in acetic acid/sodium acetate,78 in pure water, or in aqueous sodium hydroxide.79
As well as molecular bromine, several other brominating reactants have been employed for a complete halogenation of the imidazole nucleus. For example, Palmer et al. reported that the reaction of 1H-imidazole (80) with an excess of NBS in CCl4 or in N,N-dimethylformamide (DMF)
provided 81 (Scheme 42).80
Scheme 42
2,4,4,6-Tetrabromocyclohexa-2,5-dien-1-one (TBCHD, 82, Figure 12) was also reported as a suitable brominating agent for the synthesis of tribromoimidazoles,81 and N,N’-dibromo-5,5-dimethylhydantoin (83, Figure 12) was employed in high yield reactions that led to 2,4,5-tribrominated imidazoles.82
Figure 12
For example, 2,4,5-tribromo-1H-imidazole (81) was synthesized from 1H-imidazole (80) in 93% yield employing 83 as the brominating agent (Scheme 43).
36
Scheme 43
In a very similar manner, C-substituted imidazoles were easily halogenated at their remaining C-H bonds. For example, 2-alkylimidazoles were readily brominated at their C-4 and C-5 positions with PBr5 (Scheme 44).83
Scheme 44
Even apparently deactivated compounds can be quite easily brominated at vacant ring positions. For example, papers concerning the bromination of 4,5-dicyano-1H-imidazole (85a, Scheme 45),84 2-nitro-1H-imidazole (84a, Scheme 45),80 1-methyl-2-nitro-1H-imidazole (86),85 2-methyl-4-nitroimidazole (87)86 and N2,N5-di-tertbutyl-1-butyl-1H-imidazole-2,5-dicarboxamide (88, Scheme
45), are present in the literature.87
Scheme 45
The reagent Br2-DMF-K2CO3 has been recommended as a general brominating agent for
imidazoles. The bromine-DMF complex is probably the active reagent, while potassium carbonate acts as an HBr scavenger. As an example, Rao and coworkers obtained
4-bromo-5-nitro-2-methyl-37 1H-imidazole (89) from 4-nitro-2-methyl-1H-imidazole (87) in 94% yield using this specific reagent (Scheme 46).88
Scheme 46
A similar reagent (a Br2-DMF-KHCO3 reagent) was employed for the synthesis of
1,2-dialkyl-4-bromo-5-nitroimidazoles 90 (Scheme 47).88
Scheme 47
In contrast with the bromination of all the vacant positions, which easily occurs on the imidazole ring, the selective halogenation of one or two positions of a non-substituted imidazole ring is generally much more difficult to achieve. While an electrophilic bromination is certainly the most employed process for the synthesis of 4- or 5-bromoimidazoles, the general method for the preparation of 2-bromoimidazoles involves the treatment of C-2 unsubstituted imidazoles with a strong base (generally n-butyllithium) followed by a metal-halogen exchange with a brominating reagent such as Br2 or CBr4,89. Some exceptions to this last procedure, however, may be found in
the literature. For example, when 1-methyl-1H-imidazole (91) was treated with cyanogen bromide, the C-2 brominated product (92) was directly obtained in 64% yield (Scheme 48).90
Scheme 48
Palmer and coworkers treated 1H-imidazole (80) with one equivalent of NBS in DMF, achieving a complex mixture of mono-, di-, and tribromo products (Scheme 49). From this mixture, 4-bromoimidazole was isolated in 41% yield.80 Under similar conditions 1-methylimidazole (91) gives mainly its 5-bromo derivative.91
38
Scheme 49
Calò and coworkers tried to achieve a selective bromination of 1H-imidazole (80) employing an equimolar amount of TBCHD (82) as the brominating agent; however, even in this case a complex mixture of mono-, di- and tribrominated imidazoles resulted (Scheme 50).81
Scheme 50
As demonstrated in the previous examples, the selective placement of an halogen atom at the C-4 or C-5 positions of the imidazole ring is very hard to achieve. However, when sub-stoichiometric amounts of N-bromosuccinimide and catalytic amount of K2CO3 were employed using iso-propyl
acetate as the solvent for the halogenations of 1,2-disubstituted imidazoles, the C-5 halogenated products were recovered in high yields (Scheme 51).92
Scheme 51
To the best of our knowledge, this procedure represents the only example reported in the literature in which the regioselective synthesis of 5-bromoimidazoles from 4,5-unsubstituted imidazoles is described. In fact, in many cases, monobromoimidazoles were prepared by polybromination followed by subsequent reduction with sodium sulfite, triphenylphosphine or by metal/halogen
39 exchange reactions. However, the removal of bromine atoms follows the order C-2 > C-5 > C-4, which obviously precludes the possibility to obtain 5-bromoimidazoles (Scheme 52).93,94
40
Synthesis
and
characterization
of
5-bromo-1,2-disubstituted-1H-imidazoles
As shown in the previous paragraph, Frutos and coworkers, reported that the treatment of 1,2-disubstituted imidazoles with one equivalent of N-bromosuccinimide in iso-propyl acetate and in the presence of K2CO3 provides the corresponding 5-bromo derivatives in high yields and high
selectivity.92 These promising results were chosen as the starting point of this study on the halogenation reactions of imidazoles.
At first, a preliminary study concerning halogenation reactions of imidazole (80) and mono-substituted imidazoles, such as 1-methyl-1H-imidazole (91) and 2-methyl-1H-imidazole (84b), was performed employing the reaction conditions reported by Frutos et al.,92 but using ethyl acetate as the solvent instead of the more expensive iso-propyl acetate (this change was considered to have no consequences on the reaction outcome). Moreover, a brief screening of the reaction conditions was carried out in order to check the possibility to perform a selective bromination of N-1 or C-2 unsubstituted imidazoles. The results are summarized in Table 1.
Table 1
Entrya Substrate Brominating Agent Solvent Base T (°C) M-Br : D-Brb 1 91 NBS EtOAc K2CO3 (20 mol%) r.t. 42c:58 2 84b NBS EtOAc K2CO3 (20 mol%) r.t. 23:77 3 80 NBS EtOAc K2CO3 (20 mol%) r.t 44c:37:19d 4 91 NBS DMF - r.t. 33c : 67 5 91 NBS DMF - 0 45c : 55
41 6 91 NBS DMF Piperidine (20 mol%) r.t. 75c : 25 7 91 NBS DMF Piperidine (3 equiv.) r.t. 59: 41 8 91 NBS DMF K2CO3 (20 mol%) r.t. 94c : 6 9c 91 TBCHD DMF - r.t. 69c : 31 10c 91 TBCHD EtOH - r.t. 82c : 18 11c 91 TBCHD DMF - 0°C 50 : 50 12 84b NBS DMF - r.t 42 : 58 13 80 NBS DMF - r.t 49c : 45c : 6d 14 80 NBS DMF K2CO3 (20 mol%) r.t 52c : 43c : 5d
a) All the reactions were carried out with 1 mmol of substate in 5 mL of solvent. b) Chromatographic ratio between all the monobrominated products and all the dibrominated products. c) Almost equimolar mixture of two isomers. d) Tribrominated product (81).
Attempts to brominate selectively 80 and 84b failed, resulting in a mixture of mono-brominated (M-Br) and di-brominated (D-Br) isomers in which all the compounds were obtained in comparable amounts. Moreover, during the reaction of 80 with NBS, also 2,4,5-tribrominated imidazole was formed. Similar negative results were obtained when 91 was employed: although the di-brominated product (D-Br) was often obtained in very low amounts, reactions proceeded with a scarce selectivity leading to an almost equimolar mixture two mono-brominated products (M-Br, very probably the C-2 and the C-5 monobrominated imidazoles) in all cases. This may be attributed to the high reactivity of the C-2 position with respect to the C-4 position in electrophilic substitution reactions.75,76,95
As can be seen in Table 1, unsatisfactory results were observed when the reactions were performed on 91 also employing DMF as the solvent, with or without potassium carbonate (entries 4-5,8, Table 1).
The use of piperidine instead of potassium carbonate (following a modification of a literature procedure in which triethylamine was employed together with NBS for the C-5 bromination of imidazole nuclei)96 did not improve the reaction selectivity (entries 6-7, Table 1). Attempts of selective bromination of 91 were also performed employing
2,4,4,6-tetrabromocyclohexa-2,5-42 dienone (TBCHD, 82) instead of NBS as the brominating agent; however, complex mixtures of mono-brominated and poly-brominated isomers were still achieved (entries 9-11, Table 1).
A single reaction of 84b with NBS was also performed in DMF at room temperature, without any additional additives or bases, and resulted in an almost equimolar mixture of 4(5)-bromo-2-methyl-imidazole and 4,5-dibromo-2-4(5)-bromo-2-methyl-imidazole (entry 12, Table 1). Very similar results were achieved when 1H-imidazole (80) was employed in the reaction with NBS (with or without adding potassium carbonate). In these cases 2,4,5-tribromoimidazole (81) was also formed (entries 13-14, Table 1).
In summary, all the attempts to selectively brominate a N-1 or C-2 unsubstituted imidazole failed. The investigation on selective halogenation reactions was then oriented toward the use of 1,2-disubstituted imidazoles as substrates, and 1,2-dimethyl-1H-imidazole (71a) was chosen as the model.
In order to check the literature protocol, a first attempt of selective bromination of 1,2-dimethyl-1H-imidazole was performed using again reaction conditions identical to those reported by Frutos.92
Scheme 53
As reported in Scheme 53, NBS was employed in a sub-stoichiometric amount (0.95 equivalents) in order to prevent poly-bromination and 20 mol% K2CO3 was employed. Chromatographic analyses
and mass spectrometry confirmed the formation of a single isomer that was successfully isolated in 86% yield. Comparing the result with those obtained by Frutos, the isolated product was supposed to be the desired 5-bromo-1,2-dimethyl-1H-imidazole (72e). However, due to the fact that routinely
1
H or 13C NMR analyses were not sufficient to unambiguously assign the position of the bromine atom, a simple chemical strategy was then employed: 72e was submitted to a lithium/halogen exchange reaction at low temperature and to a subsequent quenching with MeOD (Scheme 54). The isolated product, in which the bromine atom was selectively replaced by a deuterium atom, was analyzed by 1H NMR spectroscopy and the chemical shift of the only remaining ring proton was compared to the chemical shifts of the two ring protons of 71a. The missing signal showed thus the position of the deuterium atom (and, as a consequence, of the bromine atom on the starting compound).
43 As it was hoped for, this transformation confirmed that the hypothesized structure for 71a was correct (Table 2). Table 2 Imidazole H-4 (δ, ppm) H-5(δ, ppm) 1,2-Dimethyl-1H-imidazolea (71a) 6.87 6.77 5-Deutero-1,2-dimethyl-1H-imidazole (d-71) 6.86
-a) Protons assigned by NOE experiments.97
The promising result obtained in the bromination of 71a by applying the Frutos procedure, and the purpose to develop a one-pot bromination/alkynylation pathway, prompted to proceed with the study by examining the bromination of 71a in solvents known to be more suitable with the reactions conditions usually adopted for the Sonogashira alkynylation.98,99 Hence, ethyl acetate was replaced with DMF or acetonitrile. Moreover, the employed base (K2CO3) was considered unnecessary in
this step; its main role consists in the removal of HBr traces whose presence is due to the use of NBS and may affect the selectivity of the reaction,76 but this inconvenient can be easily avoided by using freshly recrystallized NBS. It is important to point out that the absence of any base in this step allowed the selection of the most appropriate base for the subsequent alkynylation reaction. The first attempt of 5-bromination of 71a with NBS in the absence of any added base was then performed using DMF as the solvent, and 5-bromo-1,2-dimethyl-1H-imidazole (72e) was isolated as the only reaction product in a satisfactory 89% yield (Scheme 55). An attempt in acetonitrile was also carried out, and GLC analyses showed that, once again, only the C-5 brominated isomer was formed.
Scheme 55
This efficient optimized base-free bromination protocol was then successfully paired with the alkynylation reaction, as it will be discussed in the next paragraph.
44
Synthesis of 5-alkynyl-1,2-disubstituted imidazoles by one-pot
halogenation/alkynylation reaction sequence
Once optimal conditions for the regioselective C-5 bromination were found, efforts were then devoted to verify the possibility of pairing the halogenation with a Sonogashira-type alkynylation step in order to obtain directly 5-alkynyl-substituted imidazoles form the parent azole derivatives. As starting point the reaction conditions previously employed by our research group for the alkynylation of electron-poor bromoarenes were chosen.20 Hence, to a solution of 5-bromo-1,2-dimethyl-1H-imidazole (72e), obtained from the regioselective bromination of 71a with NBS in DMF at room temperature for 3h, were sequentially added 2 mol% Pd(PPh3)2Cl2, 4 mol% CuI, 3
equiv of triethylamine and 1.1 equiv of phenylacetylene (9b). With great delight, the required 5-alkynylated imidazole 73a was isolated in a satisfactory 58% yield after 3h at 80°C (from 71a). (Scheme 56).100
Scheme 56
Searching for a further improvement of this initial result, a screening of the reaction conditions was performed. In particular, the effect of the base used in the alkynylation step on the outcome of the whole synthetic sequence was evaluated. This screening was carried out at a lower temperature, 50 °C, in order to allow a better comparison of the different reaction conditions (Scheme 57).
Scheme 57
45
Table 3: optimization of the alkynylation step.
Entrya Base Yield of 73ab
1 Et3N 18% 2 DBU - 3 n-BuNH2 26% 4 i-PrEt2N 32% 5 Piperidine 47% (43%) 6c Piperidine - 7d Piperidine 74% (71%)
a) Unless otherwise mentioned the first step (halogenation) was performed using 1.0 mmol of 71a and 0.95 mmol of NBS in 5 mL of DMF; the second step was carried out by adding 1.1 mmol of 9b, 3.0 mmol of the selected base, 4 mol% PdCl2(PPh3)2 and 2 mol% CuI at 50 °C. b) GLC yields were evaluated using biphenyl as internal standard; in
parentheses, isolated yield. c) This reaction was carried out in the absence of CuI. d) The second step was carried out at 80 °C.
As shown in Table 3, lowering the reaction temperature from 80 to 50 °C resulted in a drastic reduction of the yield when Et3N was employed as the base (compare entry 1, Table 2 with Scheme
56), while with DBU no product was obtained (entry 2, Table 2). The use of n-BuNH2 allowed to
raise the yield up to 26% (entry 3, Table 2), and even better yields were obtained when the secondary amines i-PrEt2N (DIPEA) and piperidine were employed (entries 4 and 5, Table 2). The
presence of CuI was proved to be necessary; in fact, no reaction products were obtained when the reaction was carried out using the Pd precatalyst alone (entry 6, Table 2). Finally, rising the reaction temperature of the alkynylation step again to 80 °C allowed us to isolate the required alkynylimidazole 73a in a satisfactory 71% yield.
The good results obtained in the preparation of 73a from 71a and 9b under the experimental conditions reported in entry 7 of Table 2 prompted to extend this efficient procedure to the selective preparation of 5-alkynyl substituted imidazoles 73 starting from 71a and alkynes 9a–i. The results are reported in Table 4.
46
Table 4: Scope of the one-pot halogenation/alkynylation reaction with different alkynes.
Entrya Alkyne t2 (h)b Product Yieldc
1 9b 1 73a 71% 2 9g 2 73b 81% 3 9i 2 73c 68% 4 9j 2 73d 75% 5 9e 3 73e 55%
47 6 9k 3 73f 80% 7d 9a 4 73g 63% 8 9l 3 73h 59% 9d 9m 5 - -
a) All the reactions were performed with 1 mmol of 71a in 5 mL of DMF, unless otherwise stated; the halogenation step was performed at room temperature and the alkynylation step was performed at 80°C. b) After the period of time reported here, the conversion was quantitative. c) Isolated yields. d) The alkynylation step was carried out at 50°C.
As reported in Table 4, aromatic and aliphatic alkynes are able to react with 5-bromo-1,2-dimethyl-1H-imidazole (72e) formed in situ, allowing the isolation of the corresponding 5-alkynyl substituted derivatives in good to satisfactory yields. In details, phenylacetylene (9b) gave the desired product in 71% isolated yield (entry 1, Table 3). The 5-bromo intermediate 72e underwent the alkynylation step in good yield even when electron-donating groups or electron-withdrawing groups were present on the alkyne. Typical aliphatic alkynes such as 1-hexyne (9e) and 1-dodecyne (9k) were efficiently coupled (entries 5 and 6, Table 4) and the reaction worked well also when a typical conjugated enyne, 9j, was employed (entry 4, Table 4). Free hydroxyl group is also well tolerated, as demonstrated by the reaction involving 5-hexyn-1-ol (9l), which gave the required substituted imidazole 73h in a satisfactory 59% isolated yield (entry 8, Table 4). On the contrary, when trimethylsilylacetylene (9a) was employed as the alkyne the reaction was not so efficient due to an extensive desilylation that led to a complex reaction mixture. Fortunately, lowering the reaction temperature to 50°C depleted the desilylation and allowed to recover the desired product 73g in a 63% isolated yield (entry 7, Table 4). An attempt to perform the one-pot bromination/alkynylation reaction employing ethyl propiolate (9m) as the alkyne was also made (entry 9), but only the nucleophilic addition of piperidine on the unsaturated ester occurred.
In order to further expand the scope of this method, several 2-substituted imidazoles were submitted to the optimized one-pot bromination-alkynylation sequence, as summarized in Table 5.
48
Table 5: one-pot bromination/alkynylation of different C-2 substituted 1-methyl-1H-imidazoles.
Entrya Substrate Alkyne Reaction
time (h)b Product Yieldc 1 71b 9b 2 78a 87% 2 71c 9b 24 77a 81% 3 71d 9b 24 77b 74% 4 71c 9g 24 77c 72% 5 71d 9g 24 77d 90%
