Selective Synthesis of N-Acylnortropane Derivatives in Palladium-Catalysed Aminocarbonylation

The aminocarbonylation of various alkenyl and (hetero)aryl iodides was carried out using tropane-based amines of biological importance, such as 8-azabicyclo[3.2.1]octan-3-one (nortropinone) and 3α-hydroxy-8-azabicyclo[3.2.1]octane (nortropine) as N-nucleophile. Using iodoalkenes, the two nucleophiles were selectively converted to the corresponding amide in the presence of Pd(OAc)2/2 PPh3 catalysts. In the presence of several iodo(hetero)arenes, the application of the bidentate Xantphos was necessary to produce the target compounds selectively. The new carboxamides of varied structure, formed in palladium-catalyzed aminocarbonylation reactions, were isolated and fully characterized. In this way, a novel synthetic method has been developed for the producing of N-acylnortropane derivatives of biological importance.


Introduction
Amide functionality can be found in numerous pharmaceutically, biologically active and agrochemical molecules [1][2][3], and its formation has been deeply studied [4,5]. There are several ways of introducing acyl functionality into simple model compounds or skeletons of practical importance. The application of conventional acylating agents is well known and is referenced in reviews [6], handbooks, and even textbooks [7]. Activated carboxy compounds are widely used acylating agents producing the desired amide derivative in the presence of amines. Acyl azides [8], anhydrides [9][10][11], as well as esters [12,13] can be successfully used in the formation of amide bond. The most efficient and widely-used method among the conventional amide synthesis is the reaction with acyl chlorides and amines [14][15][16][17][18]. Despite of the widespread use of acyl chlorides in amide synthesis, it has to be noted that acyl chlorides have significant limitations (e.g., hydrolysis, racemization, cleavage of protecting groups) [6]. Due to the importance of amides, several novel methods have also been developed for their synthesis [19][20][21][22].
When the hundreds of examples of aminocarbonylation reactions are surveyed, we might conclude that great variety of aryl/alkenyl halides/triflates were investigated as substrates in the presence of simple primary or as secondary amines as N-nucleophiles. However, a relatively small number of investigations are focused on the "opposite" reaction, i.e., applying amines of practical (for instance, pharmaceutical) importance and palladiumacyl intermediates formed in situ from relatively simple aryl or alkenyl halide by oxidative addition followed by carbon monoxide insertion. The palladium(II)-acyl species can be considered as highly reactive acylating agents [50][51][52].
Considering the fact that the palladium-catalyzed aminocarbonylation reactions have been widely applied to build-up amide functionality in several bioactive compounds and natural products, this method has been chosen to produce novel N-acylnortropane derivatives in our research. The high selectivity, the mild reaction conditions, and the tolerance of wide range of functional groups make also more applicable the palladium-catalyzed aminocarbonylation for the synthesis of our target compounds than the conventional acylating methods.
The tropane-based derivatives have great importance in chemistry, which have been indicated by their wide-ranging use. The synthesis of N-substituted nortropinones via reactivity umpolung of tropinone has been carried out by Willand et al. [53]. The role of twist-boat conformers in hydride reduction of tropinone has been investigated computationally and compared with experiments [54]. The diastereoselective acetylation of 6,7-dihydroxytropinones has been investigated in enzyme-catalyzed reaction [55]. Recently, a tropine-based ionic liquid was used for the resolution of racemic amino acids [56].
To the best of our knowledge, only just a few aromatic or α,β-unsaturated N-acyl nortropane derivatives can be found in the literature [62,63], and the using of nortropinone and nortropine as nucleophiles in aminocarbonylation has not been mentioned. It has to also be noted that the tropane-based derivatives have enormous biological relevance [64]. As a part of our long-standing interest in the investigation of the fine details of aminocarbonylation, we decided to investigate of use of tropane-derived nucleophiles in aminocarbonylation.
Considering the behavior of the two nortropane-based nucleophiles, used in the reactions, decreased reactivity was observed in the case of nortropinone (a): the starting substrates (1)(2)(3)(4)(5) were completely converted into the target carboxamides in substantially longer reaction times (4-24 h). This phenomenon can be explained by the different conformation of the two nucleophiles. We believe that the different reactivity of the two secondary amines is due to steric factors. That is, the close to perfect chair conformation of nortropine is highly distorted when an sp 2 carbon (that is, keto functionality) is introduced into the ring. This distortion could result in different reactivities both in the amine activation step toward the formation of the Pd-amide intermediate, and also in the product-forming step, where the acyl-amide-palladium(II) complex undergoes reductive elimination.

Aminocarbonylation of Iodoarenes (6-10) in the Presence of Tropane-Based Nucleophiles (a, b)
After completing the reactions with the above mentioned iodoalkene substrates, we turned our attention to the investigation of aminocarbonylation of iodoarene compounds in the presence of nortropinone (a) and nortropine (b). (6) The aminocarbonylation of iodobenzene (6) was carried out in the presence of nortropin one (a) and nortropine (b) under different reaction conditions to find to optimal parameters for the further investigations (Scheme 2). Pd(OAc) 2 was used as the catalyst precursor, and the influence of ligand, CO pressure, and temperature on the reactivity and selectivity was investigated.
Performing the reactions in the presence of PPh 3 at 1 bar of CO, it can be seen, that the conversion was very low both at 50 and 70 • C ( Figure 1). Using elevated carbon monoxide pressure (40 bar), 55% conversion was detected after 24 h. Under high pressure conditions, the corresponding 2-keto-carboxamide (6a') was also formed due to the second carbon monoxide insertion. The ratio of amide (6a): ketoamide (6a') type products was 56:44. Based on our previous results [72], the PPh 3 was changed to the bidentate Xantphos to reach complete conversion in sort reaction time. Surprisingly, under atmospheric conditions, only 60 % conversion was observed after 24 h in a selective reaction towards the corresponding carboxamide (6a). Higher conversion (73%) was detected under elevated CO pressure (40 bar) and the ratio of 6a:6a' was 39:61. Increasing the temperature to 70 • C, the target carboxamide (6a) was synthesized selectively after 6 h under atmospheric conditions ( Figure 1).
The optimization study was also performed in the reaction on iodobenzene (6) with nortropine (b) under aminocarbonylation conditions (Scheme 3). Performing the reactions in the presence of PPh 3 both under atmospheric and 40 bar CO pressure, after 24 h, the conversion was just 80% and 76%, respectively. After 24 h stirring, the ratio of the amide (6b):ketoamide (6b') type products was 66:34 under atmospheric CO pressure, while the chemoselectivity was shifted toward 6b' at 40 bar (73%). Changing the PPh 3 to the bidentate Xantphos, as we expected, the iodobenzene was completely converted after 2 h at 50 • C, producing the target carboxamide (6b) selectively ( Figure 2). It has to be also mentioned, comparing the reactions of both nortropine-based nucleophile, that the nortropinone (b) showed higher reactivity than the nortropinone under same reaction conditions.

Aminocarbonylation of Nortropane Derivatives (a, b) in the Presence of Iodoalkenes (1-5) and Iodoarenes (6-11) under High Carbon Monoxide Pressure
In a typical experiment Pd(OAc) 2 , triphenylphosphine or Xantphos, iodoalkene (1)(2)(3)(4)(5) or iodo-(hetero)arene (6-11) and tropane-based nucleophile (a, b) and triethylamine were used in the same amount as above and were dissolved in 10 mL of DMF under argon in a 100 mL autoclave. The atmosphere was changed to carbon monoxide, and the autoclave was pressurized to the given pressure with carbon monoxide (caution: high pressure carbon monoxide should only be used with adequate ventilation (hood) using CO sensors as well). The reaction was conducted for the given reaction time upon stirring at 50 • C. After the given reaction time, the reaction mixture was cooled to room temperature, and the autoclave was carefully depressurized in a well-ventilated hood. The product mixture was analyzed by GC and GC-MS. The work-up of the reaction mixture was identical to that discussed for the atmospheric experiments.

Conclusions
In summary, nortropane-based nucleophiles (nortropinone (a), nortropine (b)) can be used as N-nucleophiles in palladium-catalyzed aminocarbonylation. In the presence of simple iodoalkenes, as well as biologically important skeletons possessing iodoalkene functionality, the target carboxamide derivatives have been produced exclusively by using Pd(OAc) 2 /PPh 3 catalysts. The iodobenzene has shown lower reactivity than the iodoalkene substrates using the above-mentioned catalysts. Thus, increasing the carbon monoxide pressure (40 bar), the chemoselectivity has been shifted toward the corresponding 2-ketocarboxamide formed due to the double CO insertion, but the conversion was still not complete after 48 h reaction time. Changing the triphenylphosphine to the bidentate Xantphos, the target carboxamide has been formed selectively under mild reaction conditions (1 bar of CO, 50-70 • C). Using these optimized reaction conditions, we have been able to synthesize various N-acylnortropane derivatives in the presence of iodo-(hetero)arenes in aminocarbonylation reactions. The new carboxamide derivatives were isolated in moderate to good yields (51-92%), and they were fully characterized.
It can be stated that the palladium-catalyzed aminocarbonylation provides an efficient tool for the "acylation" of amines possessing biologically important skeletons. It is based on the good acylating ability of the palladium(II)-acyl species formed during the catalytic cycle of the aminocarbonylation. In this way, important carboxamides could be synthesized that cannot be produced by using conventional organic synthetic methods.
Supplementary Materials: 1 H and 13 C NMR spectra of the products synthesized in this work are available online.