Triphenylphosphine-mediated reaction of dialkyl azodicarboxylate with activated alkenes leading to pyrazolines

Abstract

Reaction of the Huisgen zwitterions, derived from triphenylphosphine and azodicarboxylates with activated alkenes has been studied. The reaction of various ethenetricarboxylates and diethyl azodicarboxylate with PPh₃ gave pyrazolines efficiently. This pyrazoline synthesis is also applicable to 2-substituted acrylates such as trimethyl 2-phosphonoacrylate and methyl 2-(trifluoromethyl)acrylate. The possible reaction mechanism was discussed in comparison with the reaction of acetylenedicarboxylate and Huisgen zwitterions. The selective transformation of pyrazoline products have also been performed.

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Introduction

Pyrazoline¹ and its fully conjugated system pyrazole² derivatives are an important class of organic compounds, because they possess a wide range of biological activities. They are also utilized as building blocks in complex molecule synthesis³ and as functional materials.⁴ Various synthetic methods for the construction of pyrazole rings have been reported. For example, the condensation reaction of 1,3-dicarbonyl or α,β-unsaturated carbonyl compounds with hydrazine derivatives has been widely used.⁵ The 1,3-dipolar cycloaddition reaction has also been effectively utilized.⁶ However, general methods for functionalized pyrazoline rings are relatively few. It is desirable to develop new synthetic methods for the construction of diversely substituted pyrazoline rings.

The reaction of dialkyl azodicarboxylates 2 and triphenylphosphine leads to the formation of Huisgen zwitterions A (Scheme 1),⁷ which plays an important role in the Mitsunobu reaction.⁸ Brunn and Huisgen reported that the cycloaddition reaction of the zwitterion A with dimethyl acelylenedicarboxylate afforded pyrazoles.⁹ The reactions of the zwitterion and allenes, which led to pyrazolines and pyrazoles, have been reported.¹⁰

Scheme 1 Reaction of Huisgen zwitterions A with activated alkynes and allenes.^9,10

In addition, reactions of the zwitterion, with phenyl isocyanate, phenylisothiocyanate and ketone derivatives leading to various heterocycles and nitrogen-containing compounds have been studied.^9a,11 However, few cycloaddition reactions of the zwitterion and alkenes leading to pyrazolines have been reported.¹² In this work, cycloaddition reactions of the zwitterion and an activated alkene as a C=C component has been investigated.

Results and discussion

Ethenetricarboxylates 1 function as highly electrophilic Michael acceptors.¹³ It is interesting to develop cycloaddition reactions which lead to highly substituted pyrazoline derivatives. The reaction of ethenetricarboxylate 1a and diethyl azodicarboxylate 2a with 1 equivalent of PPh₃ in ether at room temperature for 18 h gave pyrazoline 3a in 85% yield and quantitative triphenylphosphine oxide (eqn (1), Table 1). The structure of pyrazoline 3a was determined by spectroscopic data and confirmed on the basis of the X-ray analysis (Fig. S1 in the ESI†). The reaction of various ethenetricarboxylates 1b–f and 2a with PPh₃ were also examined. The reaction gave pyrazolines in 58–89% yield. The additional alkene and alkyne groups on the 2-ester moiety in 1e,f did not participate in the cycloaddition reaction, and the products 3e,f were obtained efficiently (Table 1, entries 5–6).

Table 1 Reaction of 1a–f and 2a

Entry	1	R^1	3	Yield (%)
1	1a	^tBu	3a	85
2	1b	Et	3b	86
3	1c	^iPr	3c	76
4	1d	CH2Ph	3d	82
5	1e	CH2CH=CH2	3e	58
6	1f	CH2C≡CH	3f	89

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Ether was used as a standard solvent, based on the reported Mitsunobu reaction conditions.^8a Various solvents were also examined. The reaction of 1a and 2a in benzene, CH₂Cl₂, THF and CH₃CN for 18 h at room temperature gave the pyrazoline product 3a in 55, 62, 66, and 92% isolated yields, respectively. The polar aprotic solvent CH₃CN gave the better yield.¹⁴

Next, various phosphines for the reaction of 1a and 2a were examined (Fig. 1). The reaction with phosphines 8a–e gave the pyrazoline product 3a in 63–93% yields, respectively. The reaction with phosphines 8f–h gave 3a in lower yields. The reaction of phosphines 8i–n did not give 3a. The byproducts, phosphine oxides, from 8e and 8f were removed by washing with 2 M HCl.¹⁵ Failure by using tri-tert-butylphosphine 8i, tri(o-tolyl)phosphine 8l, diphosphines 8h and 8n, and polymer-supported phosphine 8k¹⁶ could be understood by their steric hindrances. Although the reaction of phenylisocyanate, dimethyl azodicarboxylate and trimethyl phosphite 8g was reported to give a cyclized product, 1,2,4-triazolone in good yield,^9b the reaction of 1a and 2a with 8g gave the product 3a in low yield. The reaction with a chiral phosphoramidite 8m¹⁷ did not give the product 3a. Use of phosphine 8j may lead to the decomposition of the starting materials, as alkyl phosphines are more reactive than aryl phosphines. The side reactions may be caused by the possible reactions between alkene 1a and some phosphines, as discussed later.

Fig. 1 Phosphines examined in this study.

The reaction of 1,1-diethyl 2-t-butyl ethenetricarboxylate (1a) and dimethyl and diisopropyl azodicarboxylates 2b–c in the presence of PPh₃ was examined next. However, the reaction gave complex mixtures, possibly consisting of mixed esters 3x (eqn (2)–(3)). In the reaction of 1a and 2b, formation of a trace amount of 2-t-butyl ethenetricarboxylate 1,1-methyl/ethyl mixed ester 1ax was detected. Related ester migration was reported for the reaction of 3-substituted allenoates and dialkyl azodicarboxylate and triphenylphosphine.^10a

The reaction of less reactive diethyl ethylidenemalonate (4a) and 2a with PPh₃ at room temperature in ether for 18 h gave the cycloadduct 5 in 36% yield, along with the remaining starting material 4a (eqn (4)). The reaction at 80 °C in benzene for 18 h gave 5 in 44% yield. Heating at 110 °C in toluene for 18 h decreased the yield of 5 to 36%. At all attempted temperatures, the starting material 4a remained. The reactions of diethyl benzylidenemalonate (4b) or diethyl/methyl maleates (4c), and 2a/2b with PPh₃ gave inseparable mixtures, possibly containing cycloadducts with the starting alkenes at room temperature and higher temperatures (60 °C in THF, 80 °C in benzene). The reactions of methyl acrylate (4d), dimethyl fumarate (4e), maleic anhydride (4f), N-methyl maleimide (4g), diethyl p-nitrobenzylidenemalonate (4h), benzylidene Meldrum's acid (5-benzylidene-2,2-dimethyl-1,3-dioxane-4,6-dione) (4i),¹⁸ benzalmalononitrile (4j), tetracyanoethylene (4k), or tetraethyl ethenetetracarboxylate (4l) and 2a with PPh₃ gave complex mixtures and/or starting materials (Fig. 2). The suitable reactivity of 1,1,2-trisubstituted activated alkenes 1 compared to these 1-, 1,2-, 1,1,2-, and 1,1,2,2-substituted activated alkenes was shown by the efficient cyclization reaction with 2a in the presence of PPh₃.

Fig. 2 Other activated alkenes examined in this study.

1,1-Disubstituted activated alkenes with two electron-withdrawing groups, acrylate derivatives 6, have been examined next (eqn (5), Table 2). Phosphonate¹⁹ and CF₃²⁰ moieties work as electron-withdrawing groups, and they are biologically attractive and also synthetically useful. The reaction of trimethyl 2-phosphonoacrylate (6a) and dimethyl azodicarboxylate (2b) with 1 equivalent of PPh₃ in ether at room temperature for 20 h gave pyrazoline 7a in 80% yield. The reaction of methyl 2-(trifluoromethyl)acrylate (6b) gave pyrazoline 7b in 61% yield. Then, the reaction of tert-butyl 2-(trifluoromethyl)acrylate (6c) and di-tert-butyl azodicarboxylate (2d) with PPh₃ was examined, in order to avoid the mixed ester formation with consideration of the result in eqn (2)–(3). However, the reaction did not give the expected cycloadduct and only gave the complex mixture. On the other hand, the reaction of 6c and 2a with PPh₃ gave pyrazoline 7c as a major product in 71% yield.

Table 2 Reaction of 6a–d and 2a,b

Entry	6	X	R^3	2	R^2	7	Yield (%)
1	6a	PO(OCH3)2	CH3	2b	CH3	7a	80
2	6b	CF3	CH3	2b	CH3	7b	61
3	6c	CF3	^tBu	2a	CH2CH3	7c	71
4	6d	CN	CH2CH3	2a	CH2CH3	7d	44
5	6e	CO2^tBu	^tBu	2a	CH2CH3	7e	72
6	6e	CO2^tBu	^tBu	2b	CH3	7f	72

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The reaction of 2-cyanoacrylate 6d and 2a with PPh₃ gave pyrazoline 7d in lower yield (Table 2, entry 4). Highly reactive di-tert-butyl methylenemalonate (6e) and 2a with PPh₃ was also examined and the reaction gave pyrazoline 7e as a major product in 72% yield. As well, the reaction of 6e and 2b with PPh₃ gave 7f in 72% yield. The reaction of 6e and di-tert-butyl azodicarboxylate (2d) with PPh₃ also gave a complex mixture.

In order to compare the selectivity of dialkyl acetylenedicarboxylate, the reaction of the dimethyl acetylenedicarboxylate and diethyl azodicarboxylate reported by Cookson and Locke was re-examined (eqn (6)).^9b The reaction in ether at room temperature gave the reported pyrazole in 42% yield as a major isolable product, similar to the reported yield (in dioxane, 49% yield). Although unidentified by-product mixture was formed, the formation of mixed ester products could not be confirmed. The reaction of 1a (1 equiv.), 9 (1 equiv.), 2a (1 equiv.), and PPh₃ (1 equiv.) was also attempted. The reaction gave pyrazole 10 as a major isolable product (31%). Formation of 3a was not detected, although possible mixed pyrazoles and starting materials of 1a and 9 might be formed.

The formation of the pyrazoline ring may undergo a similar mechanism to the reaction of zwitterions A and dimethyl acetylenedicarboxylate or allenic esters (Scheme 1).^9,10 To clarify the mechanisms for pyrazoline formation, we carried out density functional theory calculations for the cyclization reactions of the model compounds, trimethyl ethenetricarboxylate (1m), dimethyl azodicarboxylate (2b), and trimethylphosphine (Scheme 2). The structures of intermediates and transition states (TSs) were optimized by B3LYP/6-31G* calculations (Fig.S2 in the ESI†).²¹

Scheme 2 Proposed mechanism for the reaction of model compounds 1m, 2b and trimethylphosphine and B3LYP/6-31G* calculated Gibbs free energies (T = 298.15 K and P = 1 atm).

Conjugate addition of nitrogen of the zwitterion A (generated from 2b and trimethylphosphine) to ethenetricaboxylate 1m gives the stable intermediate Int1 (ΔG° = −1.57 kcal mol⁻¹). The use of highly electrophilic ethenetricarboxylates 1 or 1,1-disubstituted alkenes 6 may facilitate this addition step. The ring closure by nucleophilic attack of the generated malonate anion to the ester group of the azoester gives betaine intermediate Int2. The intermediate Int2 transforms to the oxaphosphetane intermediate Int4.²² Elimination of the phosphine oxide from Int3via a process similar to the Wittig reaction gives the cyclized product 3m.

The betaine intermediate Int2 is in equilibrium with the ylide intermediate Int4 by C–N bond cleavage. The small energy differences of 1m + A, Int1, Int2, Int4 and TS1,2,4) show the process is reversible. This is probably because of the stability of the malonate ester anion Int1. The proposed mechanism may explain the formation of the mixtures in eqn (2)–(3) (Scheme 3). The same ester groups in malonate and azodicaboxylate should be used for synthetic purposes, in order to obtain a single product. Meanwhile, reactions between t-butyl 1,1-disubstituted acrylate esters 6c and 6e and di-t-butyl azodicarboxylate did not give the cyclized products effectively, and the reactions of 6c and 6e with diethyl azodicarboxylate (2a) or dimethyl azodicarboxylate (2b) gave 3-ethoxy pyrazolines 7c and 7e, and 3-methoxy pyrazoline 7f as major products, respectively. Probably the selective reactions arise from steric reasons.

Scheme 3 Proposed mechanism for the formation of the mixture in eqn (2)–(3).

To explain the difference of the reactivity and selectivity between the alkynes and the alkenes, the mechanism for alkynes was also examined using density functional calculations. The calculations for dimethyl acetylenedicarboxylate (9), dimethyl azodicarboxylate (2b), and trimethylphosphine were carried out (Scheme 4). The structures of intermediates and TSs were obtained (Fig. S3 in the ESI†).

Scheme 4 Proposed mechanism for the reaction of 9, 2b and trimethylphosphine and B3LYP/6-31G* calculated Gibbs free energies.

Conjugate addition of the nitrogen of the zwitterion A to dimethyl acetylenedicarboxylate (9) gives the zwitterion intermediate Int1a. Int1a is transformed to the slightly more stable conformational isomer Int1aii, the precursor for cyclization. The ring closure gives the betaine intermediate Int2a. The intermediate Int2a changes to the oxaphosphetane intermediate Int3a.²⁰ Elimination of the phosphine oxide from Int3a gives the cyclized product 10.

For the reaction of ethenetricarboxylate 1m, the phosphine oxide elimination step (Int3 → 3m + Me₃P=O) is rate-determining (TS3, ΔG^‡ = +28.26 kcal mol⁻¹). On the other hand, for the reaction of acetylenedicarboxylate 9, the addition step (9 + A → Int1a) is rate-determining (TS1a, ΔG^‡ = +12.07 kcal mol⁻¹). The activation energy of the phosphine oxide elimination step (Int3a → 10m + Me₃P=O, TS3a, ΔG^‡ = −13.37 kcal mol⁻¹) is much lower than that for ethenetricarboxylate 1m. Therefore, the formation of another intermediate Int4a and the equilibrium between 9 + A, Int1a, Int1aii, Int2a, and Int4a may not be facile. The small activation energy of the phosphine oxide elimination step and the stability of 10 + Me₃P=O indicate the formation of the aromatic pyrazole ring.

The reaction of the mixture of 1a, 9, 2a, and PPh₃ leading to pyrazole 10 as a major product above described, can be understood by equilibrium for ethenetricarboxylate intermediates and the faster pyrazole ring formation.

It has been reported that phosphines react with dimethyl acetylenedicarboxylate (9) or electrophilic olefins.²³ The relative stability of the phosphine-azodicarboxylate intermediate A compared to phosphine-acetylenedicarboxylate B and phosphine-ethenetricarboxylate C intermediates has also been calculated (Scheme 5). Their optimized structures are shown in the ESI† (Fig. S4).

Scheme 5 B3LYP/6-31G* calculated relative energies ΔG° for intermediates A, B, and C. ΔG° is the difference of Gibbs free energies (T = 298.15 K, P = 1 atom) relative to those of 2b, 9, 1m and trimethylphosphine (the reactants separated), respectively.

A is 2.48 kcal mol⁻¹ more stable than the reactants, 2b and trimethylphosphine. As the energy difference shows, facile formation of A may occur and the result agrees with the reported irreversibility of the process.²⁴ On the other hand, intermediates B and C are less stable than their reactants. Although intermediates B and C may form reversibly, the stability of A leads to the selectivity of formation of the cyclized products, pyrazoline 3 and pyrazole 10. However, the possible formation of intermediate B causes the side reactions and lowers the yield of the product 10. The formation of intermediate C might also cause the side reactions for ethenetricarboxylate 1m and phosphines in Fig. 1. The stability of intermediate A may arise from the larger bond energy of P–N (ca. 290 kJ mol⁻¹) than that of P–C (264 kJ mol⁻¹).²⁵

Next, in order to demonstrate the utility of the pyrazolines, transformation of 3a was performed. Alkaline hydrolysis of 3a gave trans-monocarboxylic acid 11 stereoselectively. Treatment of 11 with Me₃SiCHN₂ led to methyl ester 12 in 85% yield (Scheme 6). The trans structures of 11 and 12 were deduced by the coupling constants (5.1–5.3 Hz) between ring protons (C(4)H and C(5)H).²⁶ Interestingly, monocarboxylic acid 11 is unstable at room temperature and gradually becomes decarboxylated to give 13 in CDCl₃ or CHCl₃ in about 3 days quantitatively (from 3a). Monocarboxylic acid 11 was also transformed by heating in ClCH₂CH₂Cl at 80 °C for 18 h to give 13 in 62% isolated yield (from 3a). Facile decarboxylation of 11 occurs most probably because of the existence of a –C=N– moiety in the ring. Thus, selective transformation of pyrazoline 3a to pyrazoline 12 and the unusually ready transformation of the malonate group, C(CO₂Et)₂, to CH₂ have been found. The detailed reaction mechanism for the transformations is under investigation.

Scheme 6 Transformation of pyrazoline 3a.

In summary, the reaction of the Huisgen zwitterions, derived from triphenylphosphine and diethyl azodicarboxylate with activated alkenes afforded highly functionalized pyrazolines. This reaction demonstrates an efficient way to construct potentially useful pyrazolines. The selective transformation of pyrazoline products have been performed. Further study on the transformation of the products to biologically interesting compounds is under investigation.

Experimental section

General methods

¹H chemical shifts are reported in ppm relative to Me₄Si. ¹³C chemical shifts are reported in ppm relative to CDCl₃ (77.1 ppm). ³¹P NMR chemical shifts are reported in ppm relative to 85% H₃PO₄. ¹⁹F chemical shifts are reported in ppm relative to CFCl₃. ¹³C mutiplicities were determined by DEPT and HSQC. Peak assignments are made by 2D COSY, HSQC, NOESY, and HMBC spectra.

Ethenetricarboxylates (1a,^27a1b,c,f,^27b1d,^27c1e^27d) were prepared according to the literature. All procedures using benzene should be carried out in a ventilated hood.

Typical experimental procedure for the preparation of 3, 7 and 10 (Table 1, entry 1)

To a solution of 1a (272.3 mg, 1 mmol) in ether (1 mL) was added diethyl azodicarboxylate 2a (40% in toluene, 0.45 mL, 1 mmol) and PPh₃ (262 mg, 1 mmol). The mixture was stirred for 18 h at room temperature. After removal of the solvent under reduced pressure, the residue was purified by column chromatography over silica gel with hexane–ether as eluent to give 3a (368 mg, 85%) and then with CH₂Cl₂–ether as eluent to give triphenylphosphine oxide (R_f 0.4, CH₂Cl₂–ether = 1 : 1, colorless crystals) quantitatively.

3a: R_f 0.5 (CH₂Cl₂–ether = 4 : 1); colorless crystals; mp 98–100 °C (EtOAc); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.29 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H), 1.45 (s, 9H), 4.21–4.43 (m, 8H), 5.42 (s, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ (ppm) 13.85 (CH₃), 13.94 (CH₃), 14.16 (CH₃), 14.69 (CH₃), 27.86 (CH₃), 62.38 (CH₂), 63.01 (CH₂), 63.38 (CH₂), 67.32 (CH₂), 67.70 (CH), 68.39 (C), 83.18 (C), 152.67 (C), 156.88 (C), 163.81 (C), 164.57 (C), 165.60 (C). Selected HMBC correlations are between δ 5.42 (C(5)H) and δ 68.39 (C(4)), 156.88 (C(3)), between δ 4.21–4.43 (OCH₂) and δ 156.88 (C(3)), and between δ 4.21–4.43 (OCH₂) and δ 152.67 (NCO₂); IR (KBr) 2980, 1739,1636, 1424, 1369, 1347, 1277, 1234, 1152, 1009 cm⁻¹; MS (FAB) m/z 453 ((M + Na)⁺); HRMS M⁺ 430.1948 (calcd for C₁₉H₃₀N₂O₉ 430.1951); Anal. Calcd for C₁₉H₃₀N₂O₉: C, 53.02; H, 7.02; N, 6.51. Found: C, 52.85; H, 6.88; N, 6.43.

3b (86%): R_f 0.6 (CH₂Cl₂–ether = 2 : 1); colorless oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.27 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.27–1.31 (m, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H), 4.12–4.42 (m, 10H), 5.52 (s, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ (ppm) 13.82 (CH₃), 13.94 (CH₃), 14.04 (CH₃), 14.16 (CH₃), 14.64 (CH₃), 62.18 (CH₂), 62.54 (CH₂), 63.17 (CH₂), 63.54 (CH₂), 67.20 (CH), 67.43 (CH₂), 68.42 (C), 152.68 (C), 156.85 (C), 163.86 (C), 164.47 (C), 166.82 (C). Selected HMBC correlations are between δ 5.52 (C(5)H) and δ 68.42 (C(4)) and between δ 4.12–4.42 (OCH₂) and δ 156.85 (C(3)).; IR (neat) 2985, 1747, 1704, 1645, 1469, 1445, 1257, 1028 cm⁻¹; MS (EI) m/z 402 (M⁺, 21), 211 (25), 85 (94), 83 (100%); HRMS M⁺ 402.1638 (calcd for C₁₇H₂₆N₂O₉ 402.1638).

3c (76%): R_f 0.2 (hexane–ether = 1 : 1); colorless oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.24 (d, J = 6.2 Hz, 3H), 1.28 (d, J = 6.2 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.3 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H), 4.20–4.44 (m, 8H), 5.02 (septet, J = 6.2 Hz, 1H), 5.48 (s, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ (ppm) 13.76 (CH₃), 13.88 (CH₃), 14.10 (CH₃), 14.58 (CH₃), 21.50 (CH₃), 21.65 (CH₃), 62.41 (CH₂), 63.01 (CH₂), 63.43 (CH₂), 67.23 (CH), 67.32 (CH₂), 68.41 (C), 70.10 (CH), 152.66 (C), 156.79 (C), 163.69 (C), 164.44 (C), 166.26 (C). Selected HMBC correlations are between δ 5.48 (C(5)H) and δ 68.41 (C(4)), between δ 4.20–4.44 (OCH₂) and δ 156.79 (C(3)), and between δ 5.48 (C(5)H) and δ 152.66 (NCO₂).; IR (neat) 2984, 1746, 1703, 1645, 1469, 1445, 1383, 1330, 1256, 1227, 1106, 1019 cm⁻¹; MS (EI) m/z 416 (M⁺, 41), 329 (21), 257 (94), 211 (80), 139 (100%); HRMS M⁺ 416.1792 (calcd for C₁₈H₂₈N₂O₉ 416.1795); Anal. Calcd for C₁₈H₂₈N₂O₉: C, 51.92; H, 6.78; N, 6.73. Found: C, 51.52; H, 6.69; N, 6.75.

3d (82%): R_f 0.2 (hexane–ether = 1 : 1); colorless oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.17 (t, J = 7.1 Hz, 3H), 1.21 (m, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 4.00–4.43 (m, 8H), 5.15 (d, J = 12.4 Hz, 1H), 5.18 (d, J = 12.4 Hz, 1H), 5.58 (s, 1H), 7.31–7.36 (m, 5H); ¹³C NMR (100.6 MHz, CDCl₃) δ (ppm) 13.79 (CH₃), 13.94 (CH₃), 14.18 (CH₃), 14.55 (CH₃), 62.59 (CH₂), 63.17 (CH₂), 63.57 (CH₂), 67.24 (CH), 67.49 (CH₂), 67.74 (CH₂), 68.47 (C), 128.41 (CH), 128.50 (CH), 128.60 (CH), 134.98 (C), 152.25 (C), 156.91 (C), 163.78 (C), 164.43 (C), 166.69 (C). Selected HMBC correlations are between δ 5.58 (C(5)H) and δ 68.47 (C(4)), 156.91 (C₃).; IR (neat) 2984, 1743, 1645, 1445, 1383, 1331, 1259, 1228, 1176, 1016 cm⁻¹; MS (EI) m/z 464 (M⁺, 13), 273 (23), 160 (41), 91 (100%); HRMS M⁺ 464.1797 (calcd for C₂₂H₂₈N₂O₉ 464.1795).

3e (58%): R_f 0.7 (CH₂Cl₂–ether = 1 : 1); colorless oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.26 (t, J = 7.1 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H), 4.17–4.42 (m, 8H), 4.60 (dddd, J = 13.2, 5.8, 1.4, 1.4 Hz, 1H), 4.66 (dddd, J = 13.2, 5.7, 1.4, 1.4 Hz, 1H), 5.25 (dddd, J = 10.5, 1.3, 1.3, 1.3 Hz, 1H), 5.35 (dddd, J = 17.2, 1.5, 1.5, 1.5 Hz, 1H), 5.56 (s, 1H), 5.90 (dddd, J = 17.2, 1.5, 1.5, 1.5 Hz, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ (ppm) 13.67 (CH₃), 13.79 (CH₃), 14.02 (CH₃), 14.48 (CH₃), 62.44 (CH₂), 63.13 (CH₂), 63.43 (CH₂), 66.49 (CH₂), 67.03 (CH), 67.31 (CH), 68.32 (C), 118.73 (CH₂), 131.12 (CH), 152.51 (C), 156.73 (C), 163.68 (C), 164.27 (C), 166.35 (C). Selected HMBC correlations are between δ 5.56 (C(5)H) and δ 68.32 (C(4)), 156.73 (C(3)).; IR (neat) 2985, 1742, 1704, 1645, 1446, 1383, 1331, 1255, 1186, 1018 cm⁻¹; MS (EI) m/z 414 (M⁺, 64), 257 (66), 211 (84), 139 (100%); HRMS M⁺ 414.1634 (calcd for C₁₈H₂₆N₂O₉ 414.1638); Anal. Calcd for C₁₈H₂₆N₂O₉: C, 52.17; H, 6.32; N, 6.76. Found: C, 51.88; H, 6.45; N, 6.90.

3f (89%): R_f 0.7 (CH₂Cl₂–ether = 1 : 1); colorless crystals; mp 98–100 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.28 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.3 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H), 2.54 (t, J = 2.5 Hz, 1H), 4.21–4.42 (m, 8H), 4.73–4.74 (m, 2H), 5.56 (s, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ (ppm) 13.69 (CH₃), 13.79 (CH₃), 14.02 (CH₃), 14.47 (CH₃), 53.31 (CH₂), 62.54 (CH₂), 63.29 (CH₂), 63.51 (CH₂), 66.84 (CH), 67.39 (CH₂), 68.32 (C), 75.78 (CH), 76.52 (C), 152.42 (C), 156.70 (C), 163.58 (C), 164.18 (C), 166.03 (C). Selected HMBC correlations are between δ 5.56 (C(5)H) and δ 68.32 (C(4)), 156.70 (C(3)).; IR (neat) 3231, 2990, 2125, 1776, 1735, 1640, 1429, 1384, 1350, 1283, 1255, 1225, 1176, 1027, 1008 cm⁻¹; MS (EI) m/z 412 (M⁺, 60), 339 (39), 293 (68), 257 (74), 221 (79), 211 (100%); HRMS M⁺ 412.1481 (calcd for C₁₈H₂₄N₂O₉ 424.1482); Anal. Calcd for C₁₈H₂₄N₂O₉: C, 52.42; H, 5.87; N, 6.79. Found: C, 52.37; H, 5.73; N, 6.78.

5 (44%; reaction conditions, 80 °C/18 h/benzene): R_f 0.7 (CH₂Cl₂–ether = 1 : 1); colorless crystals; mp 48–50 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.288 (t, J = 7.1 Hz, 3H), 1.293 (t, J = 7.3 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.365 (t, J = 7.1 Hz, 3H), 1.374 (d, J = 6.7 Hz, 3H), 4.19–4.41 (m, 8H), 5.16 (d, J = 6.7 Hz, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ (ppm) 13.94 (CH₃), 14.03 (CH₃), 14.21 (CH₃), 14.70 (CH₃), 15.67 (CH₃), 61.10 (CH), 61.97 (CH₂), 62.47 (CH₂), 62.91 (CH₂), 66.87 (CH₂), 69.08 (C), 152.82 (C), 157.26 (C), 164.50 (C), 164.94 (C). Selected HMBC correlations are between δ 5.16 (C(5)H) and δ 69.08 (C(4)), 157.26 (C(3)), between δ 4.19–4.41 (OCH₂) and δ 157.26 (C(3)), and between δ 4.19–4.41 (CO₂CH₂) and δ 152.82 (NCO₂).; IR (KBr) 2984, 1740, 1636, 1444, 1331, 1265, 1056 cm⁻¹; MS (EI) m/z 344 (M⁺, 100), 271 (83), 141 (63%); HRMS M⁺ 344.1584 (calcd for C₁₅H₂₄N₂O₇ 344.1584); Anal. Calcd for C₁₅H₂₄N₂O₇: C, 52.32; H, 7.02; N, 8.13. Found: C, 52.57; H, 7.04; N, 8.09.

7a (80%): R_f 0.4 (CH₂Cl₂–ether = 1 : 1); colorless oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 3.82 (s, 3H), 3.848 (d, J_PH = 4.9 Hz, 3H), 3.852 (s, 3H), 3.88 (d, J_PH = 4.8 Hz, 3H), 4.01 (s, 3H), 4.43 (dd, J_PH = 21.6, J_HH = 12.1 Hz, 1H), 4.55 (dd, J_PH = 14.5, J_HH = 12.1 Hz, 1H). Selected NOEs are between δ 4.43 (C(5)HH) and δ 4.55 (C(5)HH).; ¹³C NMR (100.6 MHz, CDCl₃) δ (ppm) 53.39 (CH₃), 54.07 (CH₃), 54.41 (d, J_PC = 2 Hz, CH₂), 54.60 (d, J_PC = 8 Hz, CH₃), 54.67 (d, J_PC = 7 Hz, CH₃), 58.45 (CH₃), 59.93 (C), 153.27 (C), 158.74 (d, J_PC = 8 Hz, C), 166.22 (d, J_PC = 2 Hz). Selected HMBC correlations are between δ 4.55 (C(5)HH) and δ 59.93 (C(4)), between δ 4.01 (OCH₃), 4.43, 4.55 (C(5)H₂) and δ 158.74 (C(3)), and between δ 3.82 (CO₂CH₃) and δ 153.27 (NCO₂).; ³¹P NMR (161.9 MHz, CDCl₃) δ (ppm) 18.49; IR (neat) 2959, 1742, 1704, 1644, 1463, 1442, 1393, 1262, 1032 cm⁻¹; MS (EI) m/z 324 (M⁺, 52), 265 (26), 215 (100%); HRMS M⁺ 324.0722 (calcd for C₁₀H₁₇N₂O₈P 324.0723).

7b (61%): R_f 0.4 (hexane–ether = 1 : 1); colorless oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 3.85 (s, 3H), 3.88 (s, 3H), 4.01 (s, 3H), 4.34 (d, J = 12.5 Hz, 1H), 4.49 (dq, J_HH = 12.5, J_FH = 0.8 Hz, 1H). Selected NOEs are between δ 4.34 (C(5)HH) and δ 4.49 (C(5)HH).; ¹³C NMR (100.6 MHz, CDCl₃) δ (ppm) 53.25 (q, J_FC = 1.5 Hz, CH₂), 53.57 (CH₃), 54.24 (CH₃), 58.66 (CH₃), 62.48 (C), 122.60 (q, J_FC = 283 Hz, C), 153.14 (C), 156.69 (C), 164.15 (C). Selected HMBC correlations are between δ 4.34, 4.49 (C(5)H₂) and δ 62.48 (C(4)), between δ 4.01 (OCH₃), 4.34, 4.49 (C(5)H₂) and δ 156.69 (C(3)), and between δ 3.85 (CO₂CH₃) and δ 153.14 (NCO₂).; ¹⁹F NMR (376 MHz, CDCl₃) δ (ppm) −70.71; IR (neat) 2961, 1755, 1709, 1653, 1477, 1443, 1401, 1306, 1205, 1135, 1070 cm⁻¹; MS (EI) m/z 284 (M⁺, 89), 225 (65), 181 (71), 161 (76), 123 (74), 59 (100%); HRMS M⁺ 284.0619 (calcd for C₉H₁₁F₃N₂O₅ 284.0620).

7c (71%; including a small amount of impurity): R_f 0.7 (hexane–ether = 1 : 2); colorless oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.33 (t, J = 7.1 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.50 (s, 9H), 4.28 (q, J = 7.1 Hz, 2H), 4.28 (d, J = 12.3 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 4.40 (dq, J_HH = 12.3, J_FH = 0.7 Hz, 1H). Selected NOEs are between δ 4.28 (C(5)HH) and δ 4.40 (C(5)HH).; ¹³C NMR (100.6 MHz, CDCl₃) δ (ppm) 14.10 (CH₃), 14.68 (CH₃), 27.70 (CH₃), 52.83 (q, J_FC = 1.5 Hz, CH₂), 62.40 (CH₂), 63.22 (C), 67.46 (CH₂), 85.29 (C), 122.81 (q, J_FC = 282 Hz, C), 152.74 (C), 156.39 (C), 162.58 (q, J_FC = 1.5 Hz, C). Selected HMBC correlations are between δ 4.28, 4.40 (C(5)H₂) and δ 63.22 (C(4)), between δ 4.36 (OCH₂), 4.28, 4.40 (C(5)H₂) and δ 156.39 (C(3)), and between δ 4.28 (CO₂CH₂) and δ 152.74 (NCO₂).; ¹⁹F NMR (376 MHz, CDCl₃) δ (ppm) −70.64; IR (neat) 2984, 1745, 1648, 1471, 1446, 1373, 1345, 1305, 1206, 1155, 1058 cm⁻¹; MS (EI) m/z 354 (M⁺, 37), 298 (43), 253 (44), 57 (100%); HRMS M⁺ 354.1403 (calcd for C₁₄H₂₁F₃N₂O₅ 354.1403).

7d (44%): R_f 0.3 (hexane–ether = 1 : 1); colorless oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.33 (t, J = 7.1 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H), 1.39 (t, J = 7.1 Hz, 3H), 4.26–4.42 (m, 6H), 4.46 (d, J = 12.0 Hz, 1H), 4.56 (d, J = 12.0 Hz, 1H). Selected NOEs are between δ 4.46 (C(5)HH) and δ 4.56 (C(5)HH).; ¹³C NMR (100.6 MHz, CDCl₃) δ (ppm) 14.00 (CH₃), 14.10 (CH₃), 14.73 (CH₃), 52.29 (C), 56.44 (CH₂), 62.75 (CH₂), 64.82 (CH₂), 68.56 (CH₂), 113.70 (C), 152.66 (C), 154.68 (C), 163.00 (C). Selected HMBC correlations are between δ 4.46, 4.56 (C(5)H₂) and δ 52.29 (C(4)), between δ 4.26–4.42 (OCH₂), 4.46, 4.56 (C(5)H₂) and δ 154.68 (C(3)), and between δ 4.26–4.42 (CO₂CH₂) and δ 152.66 (NCO₂).; IR (neat) 2985, 2253, 1752, 1701, 1654, 1444, 1383, 1317, 1252, 1126, 1095, 1014 cm⁻¹; MS (EI) m/z 283 (M⁺, 70), 211 (41), 183 (43), 138 (91), 110 (100%); HRMS M⁺ 283.1169 (calcd for C₁₂H₁₇N₃O₅ 283.1168).

7e (72%; including a small amount of impurity): R_f 0.7 (CH₂Cl₂–ether = 1 : 1); colorless oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.32 (t, J = 7.1 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H), 1.48 (s, 18H), 4.26 (q, J = 7.1 Hz, 2H), 4.33 (q, J = 7.1 Hz, 2H), 4.40 (s, 2H); ¹³C NMR (100.6 MHz, CDCl₃) δ (ppm) 14.29 (CH₃), 14.80 (CH₃), 27.83 (CH₃), 54.78 (CH₂), 62.12 (CH₂), 66.20 (C), 66.78 (CH₂), 83.75 (C), 153.23 (C), 158.90 (C), 164.93 (C). Selected HMBC correlations are between δ 4.40 (C(5)H₂) and δ 66.20 (C(4)), between δ 4.33 (OCH₂), 4.40 (C(5)H₂) and δ 158.90 (C(3)), and between δ 4.26 (CO₂CH₂) and δ 153.23 (NCO₂).; IR (neat) 2980, 1734, 1636, 1446, 1370, 1285, 1254, 1159 cm⁻¹; MS (EI) m/z 387 (M⁺ + 1, 14), 386 (M⁺, 6), 275 (48), 231 (62), 57 (100%); HRMS M⁺ 386.2054 (calcd for C₁₈H₃₀N₂O₇ 386.2053).

7f (72%; including a small amount of impurity): R_f 0.7 (CH₂Cl₂–ether = 1 : 1); colorless oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.47 (s, 18H), 3.82 (s, 3H), 3.98 (s, 3H), 4.43 (s, 2H); ¹³C NMR (100.6 MHz, CDCl₃) δ (ppm) 27.74 (CH₃), 53.23 (CH₃), 55.02 (CH₂), 58.00 (CH₃), 65.94 (C), 83.95 (C), 153.38 (C), 159.78 (C), 164.66 (C). Selected HMBC correlations are between δ 4.43 (C(5)H₂) and δ 65.94 (C(4)), between δ 3.98 (OCH₃), 4.43 (C(5)H₂) and δ 159.78 (C(3)), and between δ 3.82 (CO₂CH₃) and δ 153.38 (NCO₂).; IR (neat) 2980, 1731, 1641, 1475, 1456, 1394, 1370, 1287, 1257, 1159 cm⁻¹; MS (EI) m/z 358 (M⁺, 9.8), 202 (76), 57 (100%); HRMS M⁺ 358.1730 (calcd for C₁₆H₂₆N₂O₇ 358.1740).

10 (42%): R_f 0.6 (CH₂Cl₂–ether = 1 : 1); colorless crystals; mp 90–92 °C (lit.^9b mp 92.5–93.5 °C); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.43 (t, J = 7.1 Hz, 3H), 1.46 (t, J = 7.1 Hz, 3H), 3.83 (s, 3H), 3.99 (s, 3H), 4.44 (q, J = 7.1 Hz, 2H), 4.49 (q, J = 7.1 Hz, 2H); ¹³C NMR (100.6 MHz, CDCl₃) δ (ppm) 14.11 (CH₃), 14.45 (CH₃), 52.16 (CH₃), 53.62 (CH₃), 65.62 (CH₂), 66.25 (CH₂), 104.51 (C), 141.35 (C), 148.26 (C), 160.81 (C), 160.99 (C), 161.68 (C). Selected HMBC correlations are between δ 4.44 (OCH₂), and δ 161.68 (C(3)), and between δ 4.49 (CO₂CH₂) and δ 148.26 (NCO₂).; IR (KBr) 2982, 1763, 1708, 1591, 1514, 1473, 1378, 1330, 1278, 1059, 1026 cm⁻¹; MS (EI) m/z 300 (M⁺, 21), 269 (15), 213 (34), 196 (41), 181 (49), 168 (100%); HRMS M⁺ 300.0958 (calcd for C₁₂H₁₆N₂O₇ 300.0958).

Preparation of 12

To a solution of 3a (215 mg, 0.5 mmol) in EtOH (0.47 mL) was added dropwise a 50% (wt%) aqueous NaOH solution (43.9 μL) at 0 °C. The resulting solution was stirred for 2 h at room temperature. The EtOH was evaporated, and the remaining solution was diluted with water (2 mL). The aqueous phase was acidified with KHSO₄ and extracted with Et₂O twice. The combined organic extracts were dried (MgSO₄) and evaporated to give crude 11 (169 mg, 100%).

11: R_f 0.6 (CH₂Cl₂–ether = 1 : 1); pale yellow oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.30 (t, J = 7.0 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H), 1.48 (s, 9H), 3.90 (d, J = 5.1 Hz, 1H), 4.19–4.37 (m, 4H), 5.05 (d, J = 5.1 Hz, 1H), 7.84 (bs, 1H); ¹³C NMR (100.6 MHz, CDCl₃) as a mixture with 13, δ (ppm) 14.20 (CH₃), 14.66 (CH₃), 27.91 (CH₃), 53.27 (CH), 62.48 (CH₂), 63.85 (CH), 67.22 (CH₂), 83.34 (C), 153.02 (C), 158.33 (C), 167.77 (C), 169.48 (C). Selected HMBC correlations are between δ 3.90 (C(4)H), 5.05 (C(5)H), 4.19–4.37 (OCH₂) and δ 158.33 (C(3)).; IR (neat) 3307, 2982, 1748, 1641, 1445, 1223, 1154, 1022 cm⁻¹; MS (EI) m/z 330 (M⁺); HRMS M⁺ 330.1430 (calcd for C₁₄H₂₂N₂O₇ 330.1427).

To a solution of crude 11 (prepared from 3a (0.5 mmol)) in methanol (0.2 mL)–benzene (0.8 mL) was added (CH₃)₃SiCHN₂ (ca. 10% hexane solution, 1.5 mL) at room temperature. The mixture was stirred for 30 min at room temperature and concentrated. The residue was purified by column chromatography over silica gel with hexane–ether as eluent to give 12 (145 mg, 85% from 3a).

12: R_f 0.2 (hexane–ether = 1 : 1); colorless crystals; mp 74–76 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.31 (t, J = 7.1 HZ, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.48 (s, 9H), 3.82 (s, 3H), 3.87 (d, J = 5.3 Hz, 1H), 4.23–4.37 (m, 4H), 5.00 (d, J = 5.3 Hz, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ (ppm) 14.26 (CH₃), 14.72 (CH₃), 27.95 (CH₃), 53.36 (CH), 53.41 (CH₃), 62.30 (CH₂), 64.01 (CH), 67.12 (CH₂), 83.18 (C), 152.83 (C), 158.24 (C), 167.26 (C), 167.82 (C). Selected HMBC correlations are between δ 3.87 (C(4)H), 5.05 (C(5)H) and δ 158.33 (C(3)), and between δ 4.23–4.37 (CO₂CH₂) and δ 152.83 (NCO₂).; IR (KBr) 2993, 1742, 1649, 1427, 1376, 1345, 1250, 1237, 1150, 1025, 1013 cm⁻¹; MS (EI) m/z 334 (M⁺, 12), 243 (59), 69 (100%); HRMS M⁺ 344.1578 (calcd for C₁₅H₂₄N₂O₇ 344.1584); Anal. Calcd for C₁₅H₂₄N₂O₇: C, 52.32; H, 7.02; N, 8.13. Found: C, 52.55; H, 7.23; N, 8.12.

Preparation of 13

A solution of crude 11 (prepared from 3a (0.5 mmol)) in ClCH₂CH₂Cl (1 mL) was heated at 80 °C for 18 h. After cooling, the solvent was removed under reduced pressure. The residue was purified by column chromatography over silica gel with hexane–ether as eluent to give 13 (89 mg, 62% from 3a).

13: R_f 0.2 (hexane–ether = 1 : 1); Colorless oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.28 (t, J = 7.1 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H), 1.48 (s, 9H), 2.82 (dd, J = 17.3, 5.4 Hz, 1H), 3.22 (dd, J = 17.3, 12.1 Hz, 1H), 4.18–4.36 (m, 4H), 4.69 (dd, J = 12.1, 5.4 Hz, 1H). Selected NOEs are between δ 3.22 (C(4)HH) and δ 2.82 (C(4)HH), 4.69 (C(5)H); ¹³C NMR (100.6 MHz, CDCl₃) δ (ppm) 14.32 (CH₃), 14.76 (CH₃), 27.94 (CH₃), 35.46 (CH₂), 59.91 (CH), 62.03 (CH₂), 66.26 (CH₂), 82.46 (C), 153.10 (C), 162.39 (C), 169.24 (C). Selected HMBC correlations are between δ 3.22 (C(4)HH), 2.82 (C(4)HH), 4.69 (C(5)H), 4.18–4.36 (OCH₂) and δ 158.10 (C(3)).; IR (neat) 2983, 1743, 1696, 1643, 1439, 1340, 1222, 1156, 1023 cm⁻¹; MS (EI) m/z 286 (M⁺, 41), 230 (25), 185 (98), 113 (100%); HRMS M⁺ 286.1528 (calcd for C₁₃H₂₂N₂O₅ 286.1529).

Acknowledgements

This work was supported by the Ministry of Education, Culture, Sports, Science, and Technology of the Japanese Government. We thank the Nara Institute of Science and Technology (NAIST) and Prof. K. Kakiuchi (NAIST) for mass spectra. We thank Prof. S. Umetani (Kyoto University) for elemental analyses. We also thank Mr M. A. Kahn, Mr M. Takebayashi, and Mr Y. Maitoko (Nara University of Education) for experimental help.

References

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Footnote

† Electronic supplementary information (ESI) available: Crystallographic data, the optimized geometries, and ¹H and ¹³C NMR spectral data. CCDC reference number 877668. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c2ra21249h

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