Silver-Catalyzed [3+3] Annulation of Glycine Imino Esters with Seyferth–Gilbert Reagent To Access Tetrahydro-1,2,4-triazinecarboxylate Esters

Abstract

A silver-catalyzed protocol for [3+3] annulation of glycine imino esters with Seyferth–Gilbert reagent was developed. A variety of phosphorylated tetrahydro-1,2,4-triazinecarboxylate esters were synthesized in moderate to good yields and with excellent diastereoselectivities. The dehydrogenation of a tetrahydro-1,2,4-triazine product to the corresponding triazine counterpart was also demonstrated.

Key words

[3+3] annulation - glycine imino esters - Seyferth–Gilbert reagent - triazines - phosphorylation

Phosphorylated nitrogenous heterocyclic compounds are prevalent biologically active compounds in medicinal chemistry,[1] important structural motifs in materials science,[2] and valuable intermediates for synthesizing ligands for catalysis.[3] Among the various methods available for their synthesis, two classes of (diazomethyl)phosphonate esters,[4] the Ohira–Bestmann[5] and the Seyferth–Gilbert reagents,[6] have proven to be versatile reagents for accessing a broad range of phosphorylated five-membered nitrogenous heterocycles,[7] [8] [9] [10] [11] such as pyrazolines,[7] pyrazoles,[8] triazolines,[9] or tetrazoles,[10] through [3+2]-annulation strategies (Scheme [1a]; top). In sharp contrast, the synthesis of phosphorylated six-membered nitrogenous heterocycles based on these two phosphorylated diazomethane reagents remains undeveloped, probably due to a lack of suitable reaction substrates for [3+3] annulations (Scheme [1a]; bottom). Recently, our group[12] and Zhao’s group[13] discovered that glycine imino esters can serve as reliable substrates for the synthesis of functionalized tetrahydro-1,2,4-triazines through Ag-catalyzed annulation with 2-diazo-1,1,1-trifluoroethane (Scheme [1b]; top) or base-promoted annulation with a diazoacetate ester (Scheme [1b]; middle).

Scheme 1 Synthesis of phosphorylated heterocycles by [3+2]- and [3+3]-annulation strategies

As part of our continuing efforts in heterocycle synthesis based on diazomethane moieties,[10] [12] [14] [15] we surmised that such a Ag-catalyzed protocol might also be viable in the synthesis of various six-membered heterocycles by using other diazomethane entities. Here, we describe the implementation of a Ag-catalyzed [3+3]-annulation reaction of glycine imino esters with Seyferth–Gilbert reagent (Scheme [1b]; bottom). This method provides ready access to phosphorylated tetrahydro-1,2,4-triazine carboxylic esters as a novel class of six-membered nitrogenous heterocyclic compounds.

We commenced our study by using methyl 2-[(4-chlorobenzylidene)amino]acetate (1a, 1.5 equiv) and Seyferth–Gilbert reagent (2; 1 equiv, 0.2 mmol) as model substrates (Table [1]). In the presence of DBU as a base additive, 1a underwent annulation with 2 in THF at room temperature in 12 hours, delivering the 1,4,5,6-tetrahydro-1,2,4-triazine-3-carboxylate ester 3a as the desired product (entry 1). On switching the base to Cs₂CO₃ (1 equiv) and adding AgNO₃ as a catalyst, the yield of 3a increased to 56% (entry 2). Neither the use of other carbonate bases nor conducting the reaction at 0 °C gave any 3a (entries 3–5). Additionally, the yield was not enhanced when an excess of the Seyferth–Gilbert reagent was used (entry 6). Subsequently, AgF was found to be the optimal catalyst, slightly enhancing the yield to 57% (entries 7–13). Whereas the use of other solvents did not increase the yield (entries 14–19), a larger scale of the reaction substrates based on 0.3 mmol of 2 resulted in the formation of 3a in 73% yield (entry 20), presumably due to a relative reduction in losses of the very polar triazine product.

Table 1 Optimization of [3+3] Annulation of a Glycine Imino Esters with Seyferth–Gilbert Reagent^a

Entry	Catalyst	Base (equiv)	Solvent	Yieldb (%)	drc
1	none	DBU (0.5)	THF	22	>99:1
2	AgNO3	Cs2CO3 (1)	THF	56	>99:1
3	AgNO3	K2CO3 (1)	THF	0	–
4	AgNO3	Na2CO3 (1)	THF	0	–
5d	AgNO3	Cs2CO3 (1)	THF	0	–
6e	AgNO3	Cs2CO3 (1)	THF	27	>99:1
7	AgOAc	Cs2CO3 (1)	THF	52	>99:1
8	Ag2O	Cs2CO3 (1)	THF	12	>99:1
9	Ag2CO3	Cs2CO3 (1)	THF	43	>99:1
10	AgCl	Cs2CO3 (1)	THF	37	>99:1
11	AgBF4	Cs2CO3 (1)	THF	24	>99:1
12	AgSbF6	Cs2CO3 (1)	THF	30	>99:1
13	AgF	Cs2CO3 (1)	THF	57	>99:1
14	AgF	Cs2CO3 (1)	CH2Cl2	36	>99:1
15	AgF	Cs2CO3 (1)	toluene	42	>99:1
16	AgF	Cs2CO3 (1)	1,4-dioxane	38	>99:1
17	AgF	Cs2CO3 (1)	NMP	46	>99:1
18	AgF	Cs2CO3 (1)	DMF	51	>99:1
19	AgF	Cs2CO3 (1)	DMSO	31	>99:1
20f	AgF	Cs2CO3 (1)	THF	73	>99:1

^a Reaction conditions: 1 (0.3 mmol), 2 (0.2 mmol), Ag catalyst (0.02 mmol), base (0.5–1 equiv), solvent (2 mL), argon atmosphere, 12 h.

^b Isolated yield.

^c Determined by ³¹P NMR spectroscopy of the isolated product; the dr values for the isolated and crude products were identical.

^d The reaction was performed at 0 °C.

^e 1a (1 equiv) and 2 (1.5 equiv) were used.

^f Reaction conditions: 1 (0.45 mmol), 2 (0.3 mmol), AgF (0.03 mmol), Cs₂CO₃ (0.3 mmol), THF (3 mL), argon atmosphere, 12 h.

With the optimized reaction conditions in hand (Table [1], entry 20), we proceeded to study the substrate scope of the annulation of glycine imino esters 1 with Seyferth–Gilbert reagent 2 (Scheme [2]). This protocol permitted annulations with various glycine imino esters 1 bearing electron-withdrawing (3a–h), electron- donating (3i–m), or electron-neutral aryl groups (3n) to afford the corresponding phosphorylated tetrahydro-1,2,4-triazine-carboxylate esters 3. Whereas the use of 1 containing electron-withdrawing aryl groups generally afforded the corresponding products in moderate to good yields, the presence of electron-donating or electron-neutral groups mostly led to the formation of 3 in modest yields. Noteworthily, the diastereoselectivities toward the phosphorylated tetrahydro-1,2,4-triazine products were particularly high, generally ranging from 94:6 to >99:1. In addition, a wide range of functional groups were compatible, including chloro (3a, 3d), bromo (3b), fluoro (3c), ester (3e), nitro (3f), trifluoromethyl (3g), cyano (3h), and dialkylamino groups (3l). Moreover, 2- and 1-naphthyl (3o, 3p) or anthracen-9-yl (3q) groups could be incorporated into the tetrahydro-1,2,4-triazine products. The relative configuration of the phosphorylated 1,2,4-tetrahydrotriazinecarboxylate ester products was further characterized by X-ray crystallographic analysis of 3b.[16]

Scheme 2 Substrate scope of the [3+3] annulation of glycine imino esters with Seyferth–Gilbert reagent. Reagents and conditions: 1 (0.45 mmol), 2 (0.3 mmol), AgF (0.03 mmol), Cs₂CO₃ (0.3 mmol), THF (3 mL), argon atmosphere, 12 h. The dr was determined by ³¹P NMR spectroscopy of the isolated product. ^a 1j (2 equiv) was used.

Interestingly, the triazines formed in Zhao’s protocol and in the present protocol, which contain a 6-ester group and a 6-phosphoryl group, respectively, have different tautomeric structures to those of the products from our previous protocol, which contained a 6-trifluoromethyl group (Scheme [1]). Presumably, the more-electron-withdrawing 6-trifluoromethyl group significantly attracts electron density from the N² atom of the triazine ring, such that this atom does not have sufficient electron density and prefers to be sp³ hybridized to retain sufficient electron density. On the other hand, the 6-ester and 6-phosphoryl groups are less electron-withdrawing, so that the N² atoms of the triazine rings are sufficiently electron-rich to permit the formation of C=N double bonds.

The synthetic utility of our reaction was demonstrated by the dehydrogenation of the tetrahydro-1,2,4-triazine product 3a to give the phosphorylated triazinecarboxylate ester 4 (Scheme [3]). This transformation might serve as an alternative means for preparing a novel class of phosphorylated triazines and their derivatives.

Scheme 3 Transformation of 3a into the triazine derivative 4

Based on previous analogous studies,[12c] a mechanism for Ag-catalyzed [3+3] annulation of glycine imino esters with Seyferth–Gilbert reagent is proposed (Scheme [4]). In the presence of Cs₂CO₃ and the AgF catalyst, the glycine imino ester 1 is deprotonated to form a Ag/Cs-coordinated enolate complex A. Meanwhile, the Seyferth–Gilbert reagent 2 tautomerizes to form 2′, which then undergoes [3+3] annulation with A to form an Ag/Cs-amide intermediate B. The less sterically hindered trans-configuration of the aryl and phosphoryl groups probably results in a favorable chair-form conformation of intermediate B. Subsequently, intermediate B tautomerizes to give a more stable species C through conjugation of the imino group with the ester group. Upon elimination of Ag salt for a subsequent catalytic cycle, the resulting Cs–amide species D is formed. During aqueous workup, the species D is protonated by water to give the desired phosphorylated tetrahydro-1,2,4-triazinecarboxylate ester product 3.

Scheme 4 Proposed mechanism

In conclusion, we have developed a Ag-catalyzed [3+3] annulation of glycine imino esters with Seyferth–Gilbert reagent.[17] A variety of novel phosphorylated tetrahydro-1,2,4-triazinecarboxylate esters were synthesized with exceptional diastereoselectivities. The products can further undergo dehydrogenation to give the triazinecarboxylate esters. Diversifications of the tetrahydrotriazinecarboxylate esters to other functionalized analogues and a study of their biological activities are our future objectives, based on this work.

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• 17 Methyl 5-(4-Aryl)-6-(diethoxyphosphoryl)-1,4,5,6-tetrahydro-1,2,4-triazine-3-carboxylates 3a–q; General Procedure An oven-dried 10 mL Schlenk tube equipped with a stirring bar and capped with a rubber septum was charged with the appropriate glycine imino ester 1 (1.5 equiv, 0.45 mmol), AgF (0.03 mmol, 10 mol %), and Cs₂CO₃ (1 equiv, 0.30 mmol). The tube was evacuated and backfilled with argon three times. THF (1.5 mL) was transferred into the tube under a positive argon pressure by using a syringe. A solution of Seyferth–Gilbert reagent 2 (1 equiv, 0.3 mmol) in THF (1.5 mL) was then transferred into the mixture by syringe under a positive argon pressure, and the mixture was stirred under argon at rt for 12 h. The mixture was finally concentrated in vacuo in a rotary evaporator and the residue was purified by flash chromatography [silica gel, PE–EtOAc then EtOAc–MeOH (20:1)]. Methyl 5-(4-Chlorophenyl)-6-(diethoxyphosphoryl)-1,4,5,6-tetrahydro-1,2,4-triazine-3-carboxylate (3a) Brown solid; yield: 85.6 mg (73%); mp 120–122 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.34–7.29 (m, 2 H), 7.25–7.21 (m, 2 H), 5.73 (s, 1 H), 5.56 (t, J = 2.2 Hz, 1 H), 4.78–4.83 (m, 1 H), 4.11–3.90 (m, 4 H), 3.86 (s, 3 H), 3.21–3.17 (m, 1 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.12 (t, J = 7.1 Hz, 3 H). ³¹P NMR (162 MHz, CDCl₃): δ = 20.08 (p, J = 8.0 Hz). ¹³C NMR (101 MHz, CDCl₃): δ = 162.1, 138.7 (d, J = 4.5 Hz), 136.2, 134.5, 129.0, 128.8, 63.0 (d, J = 6.7 Hz), 62.7 (d, J = 7.0 Hz), 54.2, 53.1, 52.9 (d, J = 154.1 Hz), 16.5 (d, J = 5.9 Hz), 16.3 (d, J = 6.1 Hz). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₂₂ClN₃O₅P: 390.0980; found: 390.0981.