2021 Volume 69 Issue 5 Pages 498-502
In this paper, we report the synthesis of N-acyltriazinedione via the unexpected O–N acyl rearrangement of acyloxytriazinone and its utility as an acylating reagent. N-Acyltriazinedione can be isolated by silica gel column chromatography and reacts with amines in the absence of any base to give the corresponding amides in good yields.
The condensation of carboxylic acids and amines using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) involves two steps: the formation of an acyloxytriazine intermediate, which is the rate-determining step in the condensation, and aminolysis1–3) (Chart 1(A)). Recently, we reported that triazinone-based condensing reagent 1X exhibits superior reactivity to DMT-MM because the electrophilicity of 1X is enhanced compared to DMT-MM4) (Chart 1(B)). On the other hand, according to the calculation study of the sequential tautomerization of cyanuric acid to isocyanuric acid5,6) and the studies of triazine-, triazinedione-based benzylating reagents, 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT),7) and 6-(benzyloxy)-1,3-dimethyl-1,3,5-triazine-2,4(1H,3H)-dione (DMBOT),8) the aminolysis of acyloxytriazinone, which is an intermediate derived from 1X, is considered to be faster than that of the corresponding acyloxytriazine. To investigate the reactivity of acyloxytriazinone toward aminolysis, we attempted to isolate it using 1 and carboxylic acids 2 without an amine as a coupling partner (Chart 1(C)). Unexpectedly, N-acyltriazinedione 3, which can be produced via O–N acyl rearrangemment, was obtained and was found to show acylating ability (vide infra). The structure of N-acyltriazinedione was confirmed by X-ray crystallography using 3X-a synthesized with p-bromobenzoic acid 2a9) (Table 1, entry 9). It has been reported that when 2-benzoyloxy-4,6-dimethoxy-1,3,5-triazine is reacted at 100 °C in toluene, benzoyl group and two methyl groups can be transferred to the nitrogen atoms of the triazine ring to produce N-benzoyl-N′,N″-dimethyltriazinedione.10) However, the acylating ability of the product was not referred. Dicyclohexylcarbodiimide (DCC) has been reported to proceed via a similar O–N acyl rearrangement from the O-acylisourea intermediate to form N-acylurea, which does not have an acylating ability.11,12) Several acylating reagents possessing an amide moiety such as N-acylimidazoles,13) N-acylureas,14) N-acylsuccinimides,15,16) and N-acylbenzotriazoles17) have also been reported. However, it is necessary to activate a carboxylic acid by using a condensing reagent to introduce each leaving group. In the case of our new reagent, synthesis of the corresponding acylating reagent is easy because the condensing reagent itself is converted to the leaving group moiety of the amide-type acylating reagent. In this paper, we describe the synthesis and reaction of N-acyltriazinediones.
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a) The yield was not optimized.
To investigate the stability and reactivity of N-acyltriazinedione, we attempted to synthesize N-acyltriazinedione 3 using condensing reagent 1X in the presence of a catalytic amount of N-methylmorpholine (NMM). Moreover, the synthesis via in situ generation of the condensing reagents from chlorotriazinone 1X′ or its analogue 1Y′ possessing dimethylamino group instead of the isopropoxy group by the reaction with 1.2 equivalents (equiv.) of NMM was also investigated (Table 1). The reaction of 3-phenylpropionic acid 2b with 1X, 1X′, and 1Y′ smoothly proceeded to produce 3X-b and 3Y-b in yields of 82, 95, and 77%, respectively (entries 1–3). The reaction of racemic naproxen 2c as a secondary carboxylic acid and bulky adamantane-1-carboxylic acid 2d as a tertiary carboxylic acid proceeded to give the corresponding N-acyltriazinediones 3X-c and 3X-d, respectively, in good yields (entries 4, 5). Aromatic carboxylic acid derivatives 3X-e, 3X-f, and 3X-a were also prepared (entries 6–9).
Acylation of several amines 4 (1.0 equiv.) using N-acyltriazinedione 3 (1.1 equiv.) was conducted without any base in tetrahydrofuran (THF) or MeOH (Table 2). Reaction of 3X-b with 2-phenylethylamine 4a afforded the corresponding amide 5ba in good yield (in THF: 3 h, 84%, in MeOH: 1.5 h, 97%, entries 1, 2). N-Acyltriazinedione with dimethylamino group 3Y-b also gave the product (entry 3). Polar amine 4b and secondary amine 4c afforded the corresponding amides (entries 4 and 5, respectively), whereas aromatic amine 4d did not yield the amide owing to its low nucleophilicity (entry 6). The reaction of N-adamantanoyltriazinedione 3X-d with 4a required a prolonged reaction time (entries 9, 10), whereas the triazinedione composed of a secondary acyl group 3X-c smoothly underwent the reaction with 4a (entries 7, 8). The aromatic amides were obtained when N-acyltriazinediones derived from aromatic carboxylic acids were used (entries 11–15). Methanolysis of N-acyltriazinedione 3X-b was not observed even in the reaction with low-nucleophilic aniline in methanol (entry 6). However, in the presence of N,N-dimethyl-4-aminopyridine (DMAP) and Hünig’s base, O-acylation of benzyl alcohol with N-acyltriazinedione was accomplished in a 71% yield (entry 16).
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a) The reaction was conducted in the presence of DMAP (10 mol%) and N,N-diisopropylethylamine (DIPEA) (1.1 equiv.) at 0 °C.
Storable N-protected amino acid based acylating reagents are desired because the automated peptide synthesis operation can be simplified.17) Therefore, we attempted to synthesize N-acyltriazinedione using benzyloxycarbonyl (Cbz)-phenylalanine 2g. When 2g was reacted with 1X′ and NMM in CH2Cl2 at −40 °C, the desired 3X-g was obtained in a 70% yield with 98%ee (Chart 2(A)). Further investigation of the reaction conditions failed to improve the optical purity (Supplementary Material Table S1). Next, acylation was conducted using 3X-g with 90%ee and alanine methyl ester hydrochloride 4e in the presence of NMM as a proton scavenger (Chart 2(B)). When MeOH was used, the desired dipeptide (5ge) was obtained without loss of the optical purity. Other solvents, such as THF, CH3CN, CH2Cl2, and N,N-dimethylformamide (DMF) resulted in partial racemization, although the yields improved (Supplementary Material Table S2).18) For use as a practical peptide synthesis reagent, further study is needed to improve the yield and optical purity by modification of the substituents on the triazinedione core.
Acylation of 4a using N-benzoyltriazinedione 3X-e requires a longer reaction time (in THF: 5 h, in MeOH: 1.5 h, Table 2, entries 11, 12, respectively) compared with the condensation of benzoic acid 2e and 4a using triazinone-type condensing reagent 1X (in THF with triethylamine: 10 min, in MeOH with NMM: 10 min).4) To investigate if either acyloxytriazinone or N-acyltriazinedione is the true active intermediate in the condensation using 1X, time-course analyses were performed. The reaction was initiated by the addition of 1X to a THF solution of 2e, 4a, and triethylamine (Chart 3(A)). Aliquots of the reaction mixture were withdrawn at appropriate intervals and analyzed by 1H-NMR spectroscopy using coumarin as the internal standard. As a result, 10 min after the initiation of the reaction, product 5ea was observed in a yield of 95%, and reaction was completed at 30 min (triangles). Next, the reaction, which was designed to proceed through N-acyltriazinedione, was also conducted (Chart 3(B)). After the reaction of 2e and 1X for 30 min, at this point, a significant amount of acyloxytriazinone is thought to have been converted to 3X-e by the O–N acyl rearrangement, 4a was added. In contrast to the former reaction, the yield of the latter reaction was obviously lower. Then, 10 min after addition of 4a, product 5ea was observed in a yield of 66%, and it required 3 h to reach 93% yield (dots). These results indicate that when the condensation was carried out using 1X in the presence of a carboxylic acid and an amine, the reaction would proceed via the more reactive initial intermediate acyloxytriazinone.
We found that the initial intermediate, acyloxytriazinone, which was synthesized from triazinone-type condensing reagent 1 and a carboxylic acid, was immediately converted to N-acyltriazinedione 3 via a O–N acyl rearrangement. N-Acyltriazinedione 3 was stable enough to isolate by silica gel column chromatography and can be used as an acylating reagent in protic and aprotic solvents.
NMR (1H-NMR (400, 500 or 600 MHz), 13C-NMR (100 or 150 MHz)) spectra were determined on a JEOL JNM-ECS400 spectrometer, a JEOL JNM-ECZ500R spectrometer, and JEOL JNM-ECS600 spectrometer. Chemical shifts for 1H-NMR are reported as δ values relative to tetramethylsilane as the internal standard for CDCl3, and coupling constants are in hertz (Hz). The following abbreviations are used for spin multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Chemical shifts for 13C-NMR were reported in ppm relative to the center line of a triplet at 77.16 ppm for CDCl3. MS were measured on JMS-T100TD (electrospray ionization-time-of-flight (ESI-TOF)) and JMS-SX102A (FAB). Melting points (mp) were determined on a Yanaco Micro Melting Point Apparatus. Analytical TLC was performed on Merck precoated analytical plates, 0.25 mm thick, silica gel 60 F254. Flash chromatography separations were performed on KANTO CHEMICAL (Tokyo, Japan) Silica Gel 60 N (spherical, neutral, 40–100 mesh) unless otherwise noted. Reagents were commercial grades and were used without any purification unless otherwise noted. All reactions sensitive to oxygen or moisture were conducted under a N2 atmosphere.
This work was partially supported by JSPS KAKENHI Grant No. 19K06995, 17H03970.
The authors declare no conflict of interest.
The online version of this article contains supplementary materials.
