Study of 1,3,5-Triazine-Based Catalytic Amide-Forming Reactions: Effect of Solvents and Basicity of Reactants

Abstract

Effect of the basic property of reactants (tertiary amine catalysts, a substrate amine, and acid neutralizers) on catalytic dehydrocondensation between a carboxylic acid and an amine by using 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) was studied. The reaction yield was affected by the acid–base equilibrium among reactants. In dichloromethane, a representative aprotic solvent, a strongly basic catalyst gave amides in higher yields than weakly basic catalysts, regardless of the basicity of the acid neutralizer, which is called the proton capture agent (PCA). In contrast, in protic solvents, such as methanol or aqueous methanol, weakly basic catalysts gave amides in somewhat better yields than the strongly basic catalysts. In general, PCAs with weakly basic properties are favorable, because those with strongly basic properties tend to give byproducts arising from the reaction between CDMT and the substrate amine.

Dehydrocondensation to form amides and esters is an essential tool for organic and medicinal chemists, and various dehydrocondensing reagents have been developed for the past several decades.^1,2) Among them, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, Fig. 1), has proven to be useful because of its stability, reactivities, and low synthetic cost.^3–5) In particular, it selectively produces amides from carboxylic acids and amines even in alcoholic or aqueous media.^6–8) Related triazine-based compounds, N-(4,6-dimethoxy-1,3,5-triazin-2-yl)-N,N,N-trialkylammonium chloride (DMT-Ams), which consist of tertiary amines (tert-amine) instead of N-methylmorpholine (NMM), have a similar reactivity for dehydrocondensation.^9–12)

Fig. 1. Structure of DMT-MM and DMT-Am

We found catalytic dehydrocondensation involving the in situ generation of DMT-Am from a stoichiometric amount of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and a catalytic amount of a tert-amine, as summarized in Chart 1.¹³⁾ In this system, the addition of a base, proton capture agent (PCA),¹⁴⁾ which is inert toward CDMT, is essential for the regeneration of the tert-amine from its hydrochloride.

Chart 1. Catalytic Amide-Forming Reaction Involving DMT-Am

From this understanding, we have developed catalytic dehydrocondensing reactions using a tert-amine with a specific functional property, such as molecular recognition.^13,15–19) As functionalized catalysts, we employed an N,N-dimethylglycine ester as a catalytic tert-amine part because of its facile introduction into functional molecules via the ester group and also because of its potent catalytic activity in a protic solvent. However, the details of the choice of catalytic tert-amine parts depending on the reaction conditions have not been described.

Very recently, we have studied the structure–reactivity relationship of tert-amines reacting with CDMT for the generation of DMT-Am, and proposed the gauche β-alkyl group effect.¹²⁾ This effect indicates that a steric environment around the nitrogen atom rather than the basicity of the tert-amines is predominantly correlated with their reactivity. However, we have not investigated the effect of the basicity of tert-amines in a similar steric environment. In addition, because all the reactants (carboxylates, amines, and tert-amines) can exist in an acid–base equilibrium with each other, the reaction can be affected by solvent properties. Here, we report the effects of the basicity of tert-amines and PCAs on the catalytic dehydrocondensations for the preparation of amides in protic and aprotic solvents.

Results and Discussion

Effect of tert-Amine Catalysts and PCAs on the Catalytic Amide-Forming Reaction in Dichloromethane

To examine the effect of catalysts and PCAs on the catalytic amide-forming reaction, we chose 2-phenylpropionic acid (1a) and 2-phenethylamine (2a) as model reactants, both of which possess a primary aliphatic substituent and allow their detection by UV absorption of the phenyl group. Since we were concerned with the side reaction between 2a and CDMT (Chart 1), we determined yields of the resulting amine-substituted product (4a) in addition to the desired amide (3a). On the basis of the reactivity of tert-amines toward CDMT caused by the gauche β-alkyl group,¹²⁾ we employed NMM, N,N-dimethylglycine ethyl ester (DMGE), and N,N-dimethylbutylamine (Me₂NBu) as catalysts, and triethylamine (Et₃N), N,N-diisopropylethylamine (i-Pr₂NEt), N-cyclohexylmorpholine (NCHM), N,N-diethylaniline (PhNEt₂), and sodium bicarbonate (NaHCO₃) as PCAs. DMGE and Me₂NBu would be suitable catalysts for investigation of the effect of their basicity, because they have different basicities and have similar steric environments around the nitrogen atom.²⁰⁾ We confirmed that the tert-amines moiety of PCAs cannot serve as a catalyst because of two or more unavoidable β-gauche alkyl groups (see, Supplemental Table S2).

Table 1 shows the influence of the basicity of the catalysts and PCAs^20–23) on the distribution of the products (3a, 4a) in dichloromethane (CH₂Cl₂), which was chosen as a representative aprotic solvent because it produced the highest yield of 3a among aprotic solvents under stoichiometric conditions (Supplemental Table S1). Me₂NBu gave the highest yield of 3a and the lowest yield of 4a in the presence of every PCA except PhNEt₂. On the other hand, in the case of the NMM or DMGE catalyst, the yield of 4a increased with increasing the basicity of PCAs, whereas the yield of 3a remained moderate regardless of the basicity of the PCAs.

Table 1. Effect of tert-Amine Catalysts and PCAs on the Reaction between 1a and 2a in CH₂Cl₂^a)

PCA	DMGE pKa=7.2b)		NMM pKa=7.4b)		Me2NBu pKa=10.0b)
	3a (%)	4a (%)	3a (%)	4a (%)	3a (%)	4a (%)
NaHCO3 pKa=6.4b)	69	9	76	13	76	3
PhNEt2 pKa=6.6b)	63	8	56	21	56	2
NCHM pKa=8.3b)	76	14	68	26	91	5
Et3N pKa=10.7b)	57	23	53	32	79	5
i-Pr2NEt pKa=11.4b)	63	28	63	27	82	4

a) Yields were determined by ¹H-NMR of the mixture of 3a and 4a after PTLC. b) The pK_a indicates the values of their conjugated acids (refs. 20–23).

Because the precipitation of DMT-Am, which is insoluble in CH₂Cl₂, was not observed during the reactions, the rate of generation of DMT-Am would be slower than that of its consumption.²⁴⁾ Therefore, we believe that the key step in the catalytic amide-forming reaction is the SNAr substitution of CDMT by tert-amine producing DMT-Am. Me₂NBu having a large pK_a value would have a higher nucleophilicity than 2a, as we empirically know that tert-amines generally react with CDMT faster than primary or secondary amines.²⁵⁾ Thus, CDMT is quickly converted into the acyloxytriazine by Me₂NBu catalyst regardless of the basicity of the PCAs (Chart 2a).

Chart 2. Mechanistic Consideration for the Effect of Acid–Base Equilibrium of Reactants on the Products Distribution in CH₂Cl₂

In the case of NMM and DMGE having lower basicities than Me₂NBu, the direct reaction of 2a toward CDMT to give 4a competes with the production of DMT-Am because of the lower nucleophilicities of these catalysts. Hydrogen chloride arising from the reaction of CDMT with either 2a or tert-amines followed by 1a should be captured by unreacted 2a or PCA rather than DMGE and NMM. The use of NaHCO₃, PhNEt₂, or NCHM, whose basicities are sufficiently lower than that of 2a,²⁶⁾ primarily results in the protonation of 2a. The resulting ammonium salt is unreactive with CDMT; therefore, a lesser amount of 4a is produced (Chart 2b). When using Et₃N and i-Pr₂NEt with the basicities comparable with that of 2a, the amount of the reactive non-protonated form of 2a should increase, causing an increased yield of 4a.

Therefore, Me₂NBu with stronger basicity was found to be superior to weakly basic tert-amine catalysts such as NMM and DMGE for the catalytic amide-forming reaction in aprotic solvents. Consequently, the catalytic amide-forming reaction using a combination of Me₂NBu and NCHM proceeds in good yields in common aprotic solvents (Table 2). The yields were comparable to those obtained under stoichiometric conditions, as shown in Supplemental Table S1.

Table 2. Catalytic Amide-Formation Using Me₂NBu and NCHM in Aprotic Solvents^a)

Solvent	CH2Cl2b)	AcOEt	THF	DMSO	CH3CN
3a	91%	89%	84%	87%	80%
4a	5%	2%	8%	8%	6%

a) Yields were determined by ¹H-NMR of the mixture of 3a and 4a after PTLC. b) The data was cited from Table 1.

Catalytic Amide-Forming Reaction in Protic Solvents

We examined the catalytic amide-forming reaction in neutral protic solvents, such as methanol or a 50% aqueous methanol solution (Table 3). In general, the absolute methanol produced higher yields of 3a and lower yields of 4a, than the 50% aqueous methanol solution. In contrast to the reaction in dichloromethane, in an aqueous solvent, weakly basic tert-amine catalysts such as DMGE and NMM produced higher yields of the amide (3a) to some extent compared with Me₂NBu with strong basicity. Again, the basicity of the PCA affected the product yield; in particular, a lower yield of 3a and a significantly higher yield of 4a were obtained when using Et₃N.

Table 3. Effect of tert-Amine Catalysts and PCAs on the Reaction between 1a and 2a in Aqueous and Non-aqueous Methanolic Solvents^a)

Solvent	PCA	DMGE		NMM		Me2NBu
		3a (%)	4a (%)	3a (%)	4a (%)	3a (%)	4a (%)
MeOH	NaHCO3	81	2	77	4	79	3
MeOH	NCHM	74	13	59	9	52	8
MeOH	Et3N	55	19	59	22	55	15
50% aq MeOH	NaHCO3	61	5	72	13	50	8
50% aq MeOH	NCHM	60	14	54	15	47	22
50% aq MeOH	Et3N	38	28	35	28	26	31

a) Yields were determined by ¹H-NMR of the crude product after PTLC.

In protic solvents, particularly in aqueous solvents, the substrates (1a, 2a) should be present as salts such as the ammonium carboxylate because of the stabilization of the ionized structures by solvation (Chart 3a). The resultant ammonium salt of 2a will be in an acid–base dissociation equilibrium with the catalysts and PCAs, and therefore, affects the product distribution. When Et₃N, which has strong basicity, was used as the PCA, the ammonium of 2a can be significantly deprotonated to form the amine, which is reactive toward CDMT. Therefore, the amine-substituted product 4a was produced in a significantly high yield (Chart 3b). In contrast, when weakly basic PCAs, such as NCHM and NaHCO₃, were used, 2a having the strongest basicity among the species in the reaction media should be presents in an ionized state (as the ammonium salt), which causes a decrease in the yield of 4a (Chart 3c).

Chart 3. Mechanistic Consideration for the Effect of Acid–Base Equilibrium of Reactants on the Products Distribution in Aqueous Solvents

With respect to the tert-amine catalysts, NMM and DMGE should be present in a reactive non-protonated form, which results in the smooth formation of DMT-Am whereas Me₂NBu should be present significantly in the protonated form within the reaction mixture (Charts 3d, e). Owing to a smaller population of the reactive non-protonated species of Me₂NBu, a retarded formation of DMT-Am may cause a lower yield of the amide. Thus, a combination of weakly basic catalysts and PCAs was found to be desirable in aqueous methanol. The observed better results in absolute methanol, which were not affected by the basicity of tert-amine catalyst, may be due to the somewhat intermediate polarity of methanol between aprotic and aqueous solvents.

Conclusion

In the catalytic amide-forming reaction using a combination of CDMT and a tert-amine catalyst, we have found that the polarity of solvents and the basicity of the catalysts and PCAs affect the distribution of the products (3a, 4a). A strongly basic catalyst such as Me₂NBu was found to be the superior catalyst in aprotic solvents as compared with weakly basic catalysts such as NMM and DMGE. NMM and DMGE were found to be slightly better than Me₂NBu in protic solvents. Weakly basic PCAs such as NCHM or NaHCO₃ are found to be favorable, regardless of the solvents, because they help to avoid the side reaction between CDMT and substrate amine, which produces undesirable 4a. In addition, controlling the ionization state of the substrates and catalyst was essential in an aqueous solution. In this regard, the advantages of N,N-dimethylglycine esters that we have utilized for tert-amine catalyst in variety of catalytic amide-forming reactions in aqueous solvents have now been well interpreted. Based on these findings, we are now searching for a more effective tert-amine catalysts that can be used in aqueous solvents.

Experimental

General Experimental Procedures

¹H-NMR spectra were recorded on BRUKER DPX400 spectrometer referenced with tetramethysilane (δ 0.00 ppm) as an internal standard. IR spectra were recorded on Nicolet FT-IR AVATAR360. Low- and high resolution mass spectra were recorded on a JEOL Ltd. the Mstation JMS-700 mass spectrometer and Micromass Zq2000 spectrometer. Melting points were determined with a Yanagimoto melting point apparatus and are uncorrected. pK_a values were determined with Metrohm 794 Basic Titrino. Reactions were monitored by thin-layer chromatography carried out on 0.25 mm Merck silica gel plates (60F-254). Column chromatography was performed with Kanto Chemical silica gel 60N (63–210 mm, spherical, neutral). Preparative thin layer chromatography (PTLC) was performed on silica gel 60 F₂₅₄ (Merck). Reagents and solvents were purchased from TCI, Nacalai Tesque, Aldrich, and Wako Pure Chemical Industries, Ltd. and were used without further purification.

General Procedure for Catalytic Amidation

To a solution (2.37 mL) of phenylpropionic acid (1a, 35.6 mg, 0.237 mmol), phenethylamine (2a, 31.6 mg, 0.261 mmol), tert-amine catalyst (0.047 mmol) and base (0.237 mmol) were added CDMT (45.8 mg, 0.261 mmol) at ambient temperature. After stirring overnight, the reaction mixture was poured into a mixture of water and diethyl ether. The organic layer was washed with saturated sodium bicarbonate, 1 M HCl, and brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by PTLC (CHCl₃/MeOH=95/5) to obtain 3a and 4a mixture. The yields were determined by ¹H-NMR.

N-Phenethyl-3-phenylpropanamide (3a)³⁾

Colorless crystals (CH₂Cl₂–hexane). mp 94.5–95.5 °C. IR (KBr) cm⁻¹: 3299, 1635, 1544. ¹H-NMR (CDCl₃) δ: 2.41 (2H, t, J=7.7 Hz), 2.73 (2H, t, J=6.9 Hz), 2.94 (2H, t, J=7.7 Hz), 3.47 (2H, td, J=6.9, 6.0 Hz), 5.37 (1H, br s), 7.15–7.30 (10H, m). MS m/z: 253 (M⁺).

2,4-Dimethoxy-6-(N-phenethylamino)-1,3,5-triazine (4a)¹²⁾

Colorless crystals mp 113.5–114 °C. IR (KBr) cm⁻¹: 3264, 3146, 3020, 2940, 2861, 1643, 1621, 1478, 1462, 1364, 1107, 815. ¹H-NMR (CDCl₃) δ: 2.90 (2H, t, J=6.9 Hz), 3.72 (2H, q, J=6.9 Hz), 3.91 (3H, s), 3.98 (3H, s), 5.49 (1H, br s), 7.18–7.33 (5H, m). HR-MS m/z: Calcd for C₁₃H₁₆N₄O₂; 260.1273 (M⁺), Found; 260.1269 (M⁺).

Acknowledgment

This work was supported partially by a Grant-in-Aid for Science Research (No. 20390007) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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