Novel Semicarbazone-Based Amidoalkylation Reagents : Preparation and Application to the Stereoselective Synthesis of 14-Membered Hexaaza Macrocycles

An efficient general synthesis of hydrazones of 4-(3-oxobutyl)semicarbazones using novel semicarbazone-based amidoalkylation reagents has been developed. The prepared hydrazones were converted under acidic conditions into 14-membered cyclic bis-semicarbazones, 1,2,4,8,9,11hexaazacyclotetradeca-7,14-diene-3,10-diones. Plausible pathway and stereochemistry of the macrocyclization are discussed.


Introduction
Polyaza macrocycles are of considerable importance in various fields of chemistry, biochemistry, medicine, and material science.The unique features of these heterocycles arise from their ability to bind to different inorganic and organic cations, anions, and neutral molecules. 1,2Polyaza macrocycles and their metal complexes possess a wide range of biological activities 3 including anticancer, 4 anti-HIV, 5 antibacterial and antifungal properties. 6The metal complexes also have applications as contrast agents for magnetic resonance imaging, 7 radiopharmaceuticals, 8 sensors, 9 NMR shift reagents, 10 luminescent materials, 9c,10b and catalysis.2d,11 Although a large variety of polyaza macrocycles have been synthesized, the design of new members, particularly tetradentate 14-membered hexaazacycles, is a topic of great interest.Among them, 14-membered 1,2,4,8,9,11-hexaaza macrocycles remain underexploited. 12Recently, we reported a general approach to novel 14-membered cyclic bis-semicarbazones 1 based on the acid-catalyzed cyclization of 4-(3-oxobutyl)semicarbazide hydrazones 2 (Scheme 1). 13Scheme 1. Synthesis of hexaaza macrocycles 1. 13 In contrast to 14-membered 1,2,4,8,9,11-hexaaza macrocycles previously described in the literature, 12 compounds 1 are conformationally more flexible because they possess only two double bonds in the heterocyclic ring.Powder X-ray diffraction analysis 13a and DFT calculations showed that the internal cavity of macrocycles 1 is able to chelate various metal cations through the N1, N4, N8, and N11 atoms.Indeed, the neutral complex of dianion of 1 (R = Ph, R 1 = H) with Ni(II) was obtained, 14 demonstrating that hexaaza macrocycles 1 can serve as novel tetradentate ligands for metal ions.However, progress in this area was hampered by the low availability of macrocycle precursors 2 which were prepared in four steps from ethyl carbamate involving α-amidoalkylation of sodium acetylacetonates with ethyl N-(tosylmethyl)carbamates. The Achilles' heel of the synthesis was the low isolated yields (29-42%) for the substitution of the ethoxy group in β-carbamato ketones 3 on hydrazino fragment due to the harsh reaction conditions (N 2 H 4 , reflux, 20-24 h).13b We hypothesized that hydrazones 2 could be readily prepared from N1-protected semicarbazides following the same strategy.Additionally, treatment of 4-(3-oxobutyl)semicarbazides with hydrazine could give access not only to N1-unprotected semicarbazide hydrazones 2, but N1-protected analogues which could also serve as macrocycle precursors.

Results and discussion
Based on previous experience, 13b,15 the amidoalkylation reagents 4a-d were obtained by the threecomponent condensation of (E)-1-arylidenesemicarbazides 5a-d with the corresponding aromatic aldehydes 6a-d and p-toluenesulfinic acid (7) (Scheme 2).Under optimized reaction conditions (EtOH, rt, 3-8 days, 30-50 mol% excess of 6 and 7), (E)-semicarbazones 4a-d were isolated in 96-99% yield with >95% purity ( 1 H NMR) after filtration of the precipitate formed after reaction completion.It should be noted that the prepared semicarbazones 4a-d represent novel amidoalkylation reagents 16 and can be widely used in organic synthesis. 17Heating compounds 9a-c in EtOH at reflux for 8.5-10 h in the presence of N 2 H 4 •H 2 O (30 equiv.)afforded hydrazones of semicarbazides 10a-c (78-93%) as mixtures of (E)-and (Z)-isomers in ratios of 92:8, 94:4, and 95:5, respectively.Under all conditions tested, MeO-derivative 9d failed to give the desired hydrazone with sufficient purity.Thus, compounds 10a-c, the key precursors of 14-membered hexaaza macrocycles, were prepared in four steps from semicarbazones 5a-c in 71-83% overall yield on a multi-gram scale, while the overall yields of these compounds obtained in four steps from ethyl carbamate (see Scheme 1) were only 22-32%.13b Treatment of semicarbazones 9a-d with N 2 H 4 •H 2 O (30 equiv.) in EtOH at room temperature for 5 h gave mixtures of (E)-and (Z)-hydrazones of (E)-semicarbazones 11a-d in high yield (94-98%), with significant predominance of the (E)-isomer (91-98%).Analogously, a 92:8 mixture of (E)-and (Z)methylhydrazones of (E)-semicarbazone 11e was obtained in 91% yield from the reaction of compound 9a with methylhydrazine.The configurations of the major and minor isomers of compounds 11a,c were unambiguously determined using 1 H, 1 H NOESY experiments in DMSO-d 6 .For the major isomer of 11a,c, a diagnostic NOE was observed between the CH 3 and C=NNH 2 protons, thus indicating the (E)configuration of the C=N double bond in this isomer.Since the 1 H and 13 C NMR spectra of the major isomers of 11a,c and 11b,d,e were similar, we concluded that the major isomers of 11b,d,e also had the (E)-configuration.
Recently, we reported the TsOH-catalyzed transformation of hydrazones 10a-c into hexaaza macrocycles 12a-c (Scheme 4). 13The reaction proceeded smoothly in EtOH or MeCN at room temperature or at reflux to give compounds 12a-c in 85-93% yields as mixtures of trans-and cisisomers whose ratio was dependent on the reaction conditions.Thus, the effective synthesis of the key precursors 10a-c on a multi-gram scale as described herein, provides an improved access to macrocycles 12a-c.Scheme 4. Syntheses of 14-membered hexaaza macrocycles 12a-d.
We found that the macrocyclization of 11a proceeded well in aprotic solvents (Table 1).In MeCN at reflux, under the action of TsOH (0.10 equiv.), a 89:11 mixture of trans-and cis-12a was cleanly formed from semicarbazone 11a in 72% yield (Entry 1).Increasing the concentration of 11a led to an increase in the cyclization stereoselectivity (Entry 2 vs Entry 1).Decreasing the concentration of 11a resulted in a higher yield of 12a and lower reaction stereoselectivity (Entry 7 vs Entry 1).Use of an increased amount of TsOH improved both the selectivity and yield of the cyclization (Entry 2 vs Entry 6).When the reaction of 11a with TsOH was performed in THF, the yield of 12a increased while the stereoselectivity remained unchanged compared with those in MeCN (Entry 2 vs Entry 5).The stereoselective transformation of 11a into 12a was also promoted by the strong acid TFA (Entry 3).However, only a small amount of 12a (14% 1 H NMR estimated yield, trans/cis = 20:80) along with numerous side-products was obtained in the presence of the relatively weak acetic acid (50 equiv., MeCN, reflux, 9 h) (Entry 4).
Previously, we found that the macrocyclization of semicarbazide 10a in the presence of TsOH completed in EtOH at room temperature for 4 h.13b In contrast, the TsOH-catalyzed conversion of 11a into 12a at room temperature was slow.The crude product obtained after treatment of 11a with TsOH (0.10 equiv.) in MeCN (rt, 24 h) contained starting material (3 mol%), macrocycle 12a (42% 1 H NMR estimated yield, trans/cis = 67:33) and unidentified compounds.Thus, under the optimal conditions (Entry 6), macrocycle 12a was obtained in 75% yield as a 97:3 mixture of trans-and cis-isomers.Analogously, reaction conditions were optimized for the transformation of 11b-d into the corresponding macrocycles 12b-d (Table 1).These compounds were prepared in good yields (60-92%) and with excellent trans-selectivity (up to 100%).It is noteworthy, that under the optimal conditions, the stereoselectivity for formation of macrocycles 12 from the hydrazones of semicarbazones 11 was significantly higher than that from the hydrazones of semicarbazides 10. 13b Table 1 shows that the trans-stereoselectivity of the macrocyclization of compounds 11a-d increases with an increase in starting material concentration, reaction time, and catalyst loading.
Therefore, we propose that the reaction of 11a-d initially proceeds rapidly with low diastereoselectivity to give mixtures of cis-and trans-12a-d which is then followed by a slow irreversible transformation of the cis-isomers into the trans-isomers via ring opening by a retro-aza-Michael reaction.Calculations performed at the DFT B3LYP/6-311++G(d,p) level of theory using the PCM solvation model showed that trans-12a was less stable than cis-12a in both MeCN and EtOH solutions (ΔG = 1.67 and 2.08 kcal/mol, respectively; 298 K and 1 atm).The predominant formation of trans-12a-d from 11a-d can be explained by their significantly lower solubility compared with that of cis-isomers; therefore, trans-12a-d completely precipitates from the reaction media resulting in a gradual increase in the transselectivity of the process.The presence of the hydrazone fragment in the starting semicarbazones 11 was proved to be essential for the formation of the macrocycles.Indeed, treatment of 9a with TsOH (0.10 equiv.) in EtOH (2 h) or MeCN (4 h) at reflux resulted in partial decomposition of the starting material to give semicarbazone 5a, benzylideneacetone, and unidentified products without any formation of macrocycle 12a ( 1 H NMR). The starting material was completely recovered after reflux of 9a in EtOH for 3 h in the presence of AcOH (4.06 equiv.).Thus, the experimental data show that the macrocyclization of 11a-e proceeds via nucleophilic attack of the N1 nitrogen atom of one molecule on the electrophilic carbon of the hydrazone moiety of the second molecule after its activation by the catalyst.However, the nucleophilicity of the N1 atom with sp 2 -hybridization is not sufficient for the cyclization.We propose that under the examined reaction conditions, a more nucleophilic sp 3
Acid-catalyzed macrocyclization of N-methylhydrazone 11e could proceed via two possible pathways involving nucleophilic participation of the N1-atom to give macrocycle 12a or the NHMe nitrogen atom to give 2,9-dimethyl derivative of 12a.At reflux for 2.5 h or at room temperature for 96 h in MeCN in the presence of TsOH (0.10 equiv.),compound 11e afforded macrocycle 12a along with various side and intermediate products ( 1 H NMR). Prolonging the reaction time at reflux to 9 h led to predominant formation of 12a (trans:cis = 58:42).No 1 H NMR signals of the 2,9-dimethyl derivative of 12a were observed.
-hybridized nitrogen is generated by the addition of a nucleophile to the C=N double bond, for example, the water from TsOH•H 2 O.A plausible pathway for the TsOH•H 2 O-catalyzed macrocyclization of hydrazones 11a-e is shown in Scheme 5.