1,1,7,7-Tetramethyl-9-azajulolidine (TMAJ), which theoretical studies have suggested as a highly active DMAP analog, was synthesized for the first time. The catalytic activity of TMAJ was confirmed by the acetylation reactions of various tert-alcohols. TMAJ showed much higher catalytic activity than DMAP and one of the highest activity levels among the conventional DMAP analogs. These experimental results were in good agreement with the previous theoretical studies

Chu, MengYue

Karanjit, Sangita

Kasai, Tomoyo

Nakayama, Atsushi

Namba, Kosuke

Saitoh, Arisa

Tsutsumi, Tomohiro

Tokushima University Institutional Repository

1 Tetrahedron Letters journal  homepage:  www.e lsevier .com  Synthesis and evaluation of 1,1,7,7-tetramethyl-9-azajulolidine (TMAJ) as a highly active derivative of N,N-dimethylaminopyridine Tomohiro Tsutsumi, Arisa Saitoh, Tomoyo Kasai, MengYue Chu, Sangita Karanjit, Atsushi Nakayama and Kosuke Namba∗ Graduate School of Pharmaceutical Sciences and Research Cluster on “Innovative Chemical Sensing”, Tokushima University, 1-78-1 Shomachi, Tokushima 770-8505, Japan ——— ∗ Corresponding author. Tel.: +81-88-633-7293; fax: +81-88-633-9575; e-mail: namba@tokushima-u.ac.jp N,N-Dimethylaminopyridine (DMAP) is one of the most widely used organocatalysts in the field of organic chemistry.1 In particular, DMAP is the most common catalyst for condensation reactions of various alcohols, amines, and so on. Thus, the development of more active derivatives of DMAP has been a subject of intensive research.2 The catalytic activity of DMAP analogs tends to increase with the electron-donating properties of the 4-substituent, and 4-pyrolidinopyridine (PPY) has been used as a more reactive analog than DMAP.3 In 2003, Steglich et al. reported that bis-six-membered DMAP analog 9-azajulolidine (9-AJ), synthesized according to Yamanaka’s procedure,4 showed about six times the catalytic activity of DMAP in the esterification reaction of a tertiary alcohol.5 After that report, Han’s group improved the synthesis of 9-AJ6 and developed an aza-analog that is slightly better than 9-AJ.7 Wong’s group also reported the improved synthesis of 9-AJ and its application to the post-Ullmann reaction.8 Moreover, various aza-analogs of 9-AJ were developed as highly nucleophilic pyridines.9 In these ways, cyclic analogs of DMAP have been intensively studied. Among them, the bis-six-membered analogs have exhibited the highest catalytic activity so far. On the other hand, Zipse et al. vigorously investigated the catalytically most active DMAP derivatives by computational studies.10 They reported that 1,1,7,7-tetramethyl-9-azajulolidine 1 (TMAJ), the tetramethylated analog of 9-AJ, forms the most stable acylpyridinium cation intermediate next to the Fu’s ferrocene analog11 in various DMAP analogs.10a However, although various derivatives of 9-AJ have been developed so far, TMAJ (1), which was suggested to be the most efficient DMAP analog, has not yet been synthesized. The main reason for this is probably the difficulty of synthesizing 1. In particular, the introduction of quaternary carbon centers to the neighboring position of the pyridine ring is generally difficult. For example, the Friedel-Crafts-type reaction is not suitable for the pyridine ring because pyridine is an electron-deficient aromatic ring. The intramolecular radical cyclization reactions and the Heck reactions were likely to preferentially proceed with 5-exo cyclizations. On the other hand, we recently reported theconcise synthesis of quinolizidine alkaloid (+)-epilupinine.12 As 1also includes the quinolizidine skeleton, we considered that oursynthetic method for quinolizidine alkaloids can be applied to thesynthesis of 1. Herein, we report the first synthesis of TMAJ (1)and assess its ability as an acylation catalyst.Figure 1. Structures of DMAP analogs Our synthesis of (+)-epilupinine was achieved by the cascade reaction of 2. Treatment of 2 with PhSH and L-proline induced sequential reactions consisted of a removal of nosyl group, condensation of the resulting secondary amine with either ART ICLE  INFO  AB ST R ACT  Article history: Received Received in revised form Accepted Available online 1,1,7,7-Tetramethyl-9-azajulolidine (TMAJ), which theoretical studies have suggested as a highly active DMAP analog, was synthesized for the first time. The catalytic activity of TMAJ was confirmed by the acetylation reactions of various tert-alcohols. TMAJ showed much higher catalytic activity than DMAP and one of the highest activity levels among the conventional DMAP analogs. These experimental results were in good agreement with the previous theoretical studies. 2009 Elsevier Ltd. All rights reserved. Keywords: N,N-Dimethylaminopyridine 1,1,7,7-Tetramethyl-9-azajulolidine Acylation catalyst Quinolizidine alkaloid Cascade reaction © 2020. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/The published version is available via https://doi.org/10.1016/j.tetlet.2020.152047.Tetrahedron Letters 2 aldehyde, and an intramolecular asymmetric Mannich reaction to give 3. Subsequent direct addition of NaBH4 and methanol to the reaction mixture afforded (+)-epilupinine in one step from 2 (Scheme 1a). Based on this quinolizidine-forming reaction, we designed 4 possessing tetramethyl groups and exomethylene moiety as the precursor of a similar cascade reaction that would afford quinolizidine compound 5. The pyridine formation using aldehyde and exomethylene moiety as a foothold would afford TMAJ (1) (Scheme 1b).  Scheme 1. Synthesis of (+)-epilupinine and synthetic plan of 1. Reaction conditions; (a) PhSH, L-proline, Cs2CO3, CHCl3, 0 °C. (b) NaBH4, MeOH, 0 °C to rt.  We synthesized the cascade reaction precursor 4. Starting with commercially available 6, the conjugate addition of the allyl group followed by hydrolysis and decarboxylation afforded carboxylic acid 7. The carboxylic acid moiety was reduced to alcohol 8, and the resulting hydroxy group was converted into the tosylate group as a leaving group to give 9. Next, commercially available o-nosylamide was treated with 2.0 equiv of 9 as an alkylating reagent to afford double-alkylated product 10 in 70% yield. After ozonolysis of 10, treatment of the resulting dialdehyde 11 with 1.0 equiv of formalin under basic conditions afforded the desired cascade reaction precursor 4 (Scheme 2).  Scheme 2. Synthesis of the cascade reaction precursor 4.  Having prepared the cascade reaction precursor, we tried the cascade reaction of 4. Treatment of 4 with PhSH and K2CO3 in methanol for the removal of the nosyl group initially afforded reactive secondary amine 12. Then, when the reaction was extended for a long time, the desired 5 gradually appeared as a single diastereomer.13 The reaction leading to 5 probably consisted of the hemiaminal formation with the aldehyde on the enal side (12→13) and the generation of iminium cation (13→14) followed by the intramolecular Mannich reaction (14→5). Although the desired quinolizidine skeleton 5 was obtained in this cascade reaction, the yield of 5 had to be improved for further conversion. The main reason for the low yield and long reaction time is that the 1,4-addition reaction leading to 15 (path b) and the other hemiaminal formation leading to 16 (path c) compete with the desired hemiaminal formation, and these undesired reactions take precedence over the desired path a (Scheme 3).  The reaction mainly afforded 15 and 16 at the beginning, and then 5 was gradually obtained through equilibrium.14 Thus, we needed to suppress the undesired paths b and c to increase the yield of 5.  Scheme 3. The reaction pathway of the cascade reaction leading to 5.   It was difficult to modify the olefin moiety to suppress path b despite our efforts. On the other hand, the unconjugated aldehyde was convertible into silyl enol ether 17 for the suppression of path c. A similar reaction of 17 increased the yield of 5 to 47%, although the reaction time was longer due to the unavoidable path b and the stability of TIPS enol ether. Indeed, it was confirmed that the 1,4-addition product was generated mainly in the early stage, and that the isolated 1,4-adduct was returned to enal under the reaction conditions. On the other hand, TBS enol ether instead of the TIPS group converted readily back to aldehyde before the removal of the nosyl group in the reaction conditions.  Scheme 4. Cascade reaction of silyl enol ether 17.  With a sufficient amount of 5 in hand, we attempted the syn-thesis of TMAJ (1). Treatment of 5 with O-methylhydroxyamine afforded O-methyloxime 18 in excellent yield. We next applied the Polonovski reaction to introduce another double bond into 18.15 The tertiary amine of 18 was oxidized by mCPBA to give N-oxide 19. Subsequent treatment of crude 19 with trifluoroacetic anhydride afforded the desired enamine 20, along with inseparable regioisomers 20a and 20b. Although the desired 20 was a minor product, it was considered that major regioisomers 20a and 20b could also be isomerized to the desired isomer 20.16 Therefore, a mixture of the three isomers was heated to 150 °C by microwave irradiation, and the desired TMAJ (1) was obtained in 36% yield from 18.  3  Scheme 5. Synthesis of TMAJ (1)  Having established the synthesis of 1, we evaluated its catalytic activity. The acetylation reaction of unreactive tertiary alcohol 21 with acetic anhydride was adopted for the activity test according to the conventional evaluation of DMAP analogs. The progress of the reaction in the presence of 10 mol % of DMAP analogs as catalysts was observed by 1H NMR spectroscopy. The yields of acetate 22 were plotted over a time course as shown in Figure 2. In comparison with DMAP and PPY, bis-six-membered analogs showed much higher catalytic activity. In particular, TMAJ (1) had the highest catalytic activity, ca. 1.5 times higher than 9-AJ.5,17 These experimental results supported the theoretical studies reported by Zipse et al.10a       Figure 2. Time course of yield in the acetylation reaction of 21 using 10 mol % of DMAP analog catalyst: DMAP (▲), PPY (◆), 9-AJ (■), and TMAJ (●).  Finally, the acetylation reactions of various tert-alcohols using TMAJ as a catalyst were examined (Table 1). The reaction of aliphatic alkynyl alcohol 23 proceeded smoothly to give the desired acetate in 83% yield, while the use of DMAP significantly decreased the yield (entry 1). The reactions of alkenyl alcohol 24 and alkyl alcohol 25 also smoothly catalyzed by TMAJ (1) (entries 2 and 3). The reaction time was prolonged in the order of alkyl, alkenyl, and alkynyl group, reflecting the steric hindrance of these substituents. The reaction of tert-alcohol at the α-position of ketone 26 also gave the acetate in good yield, i.e., TMAJ accelerated the reaction in the tert-alcohol possessing strong electron with-drawing groups (entry 4). The case of cyclic trialkyl tert-alcohol 27 similarly gave the desired acetates in much higher yields than DMAP (entry 5). In addition, the reaction of diol 28 with 4.0 equiv of acetic anhydride afforded the corresponding diacetate in good yield (entry 6). Throughout, TMAJ (1) showed much higher catalytic activity than DMAP.  Table 1. Comparison of DMAP and TMAJ in reactions of various tert-alcohols.   aNMR yield using pyrazine as an internal standard. b4.0 equiv of Ac2O and 6.0 equiv of NEt3 were used. In conclusion, we achieved the first synthesis of TMAJ (1), which has been proposed as a highly active DMAP analog in theoretical studies. The catalytic activity of 1 was actually confirmed by the acetylation reaction of various tert-alcohols, and 1 showed much higher catalytic activity than DMAP and one of the highest activity levels among the conventional DMAP analogs. These experimental results were in good agreement with the previous theoretical studies. TMAJ (1) is expected to be widely used as an efficient catalyst for acylation reactions and various other reactions such as carbamylation, silylation, Tetrahedron Letters 4 sulfonylation, lactonization, and so on. For this purpose, the synthesis of 1 still needs several improvements regarding the number of steps, the yields, and the reaction time of the cascade reaction. In addition, chiral DMAP analogs have recently been developed and successfully applied to asymmetric syntheses.18 Our synthesis of 1 can be applied to the development of novel chiral DMAP analogs that possess chiral centers at the 1- and 7-positions instead of a dimethyl group. Although the cascade reaction needs dimethyl groups so far, we are currently undertaking the improvement of the cascade reaction so that the reaction can be applied not only to the large-scale synthesis of TMAJ (1) but also to the development of novel chiral DMAP analogs. Acknowledgments This work was partially supported by JSPS KAKENHI Grant Numbers JP16H01156 in Middle Molecular Strategy, JP18H04416, and JP19H02851. We acknowledge Tokushima University for their financial support of the Research Clusters program of Tokushima University (No. 1802001). T.T. is grateful to Nagai Memorial Research Scholarship from the Pharmaceutical Society of Japan (N-206305) for young scientists.  References and notes 1. (a) W. 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Synthesis and evaluation of 1,1,7,7-tetramethyl-9-azajulolidine (TMAJ) as a highly active derivative of N,N-dimethylaminopyridine

Synthesis and evaluation of 1,1,7,7-tetramethyl-9-azajulolidine (TMAJ) as a highly active derivative of N,N-dimethylaminopyridine

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