Catalyst-free three-component reaction to synthesize chiral α-amino phosphine oxides

Abstract

A three-component reaction for high diastereoselective synthesis of chiral α-amino phosphine oxides has been developed and displayed environmentally friendly and atom efficient characteristics. The reaction proceeds smoothly without catalysts or additives.

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Organic phosphorus compounds feature a variety of biological and pharmacological characteristics prevalent in nucleotides and pharmaceuticals. In particular, α-amino phosphine oxides exhibit antitumor, antibacterial,¹ antiviral,² and enzyme inhibiting³ activities, which have been widely applied in agrochemistry.⁴ Phosphine-containing compounds represent the conventional choice of ligands for transition-metal-catalyzed reactions.⁵ As a consequence, researchers in the past decades have expended tremendous effort on building these skeletons;⁶ the three-component reaction among amines, carbonyl compounds, and phosphine oxides – widely known as the Kabachnik–Fields reaction⁸ – for the synthesis of α-aminophosphine oxides in particular has attracted great interest for its step and atom economy.⁷ In 2008, Keglevich's group reported the synthesis of corresponding α-aminophosphonate and α-aminophosphine oxide through microwave irradiation in the absence of solvent or catalyst.⁹ Recently, Wang and co-workers have disclosed a copper-catalyzed three-component decarboxylative coupling in order to synthesize α-aminophosphine oxides between natural α-amino acids, phosphites, or secondary phosphine oxides and aldehyde.¹⁰ Simultaneously, Seidel's group also reported a three-component reaction in which a simple amine could replace the amino acid.¹¹ Despite significant advances in this field, methods that involve three-component reaction under catalyst-free conditions for the synthesis of chiral α-aminophosphine oxides still represent formidable challenges.¹² The construction of C–P bond in particular has created major interest in the field as well as an exciting challenge for us.¹³ The synthesis of chiral α-aminophosphine also represents an important milestone for us.

Indeed, the development of transition-metal-free processes represents a growing trend in chemical synthesis¹⁴ as well as an attractive and beneficial complement to transition-metal-catalyzed transformations. Our protocol demonstrates great advantages. Herein, we report a new three-component reaction to synthesize chiral α-amino phosphine oxides within a system free of catalysts (Scheme 1). This system exhibits several unique features: (1) the reaction requires no catalyst or additives; (2) the reaction demonstrates high regioselectivity and diastereoselectivity and yields 2a as the exclusive product; (3) the process is both environmentally friendly and atom efficient (Fig. 1).

Scheme 1 Different three-component reactions for the synthesis of α-amino phosphonates or α-amino phosphine oxides.

Fig. 1 The absolute configuration determined by the X-ray of 2h.

We set up our research by evaluating the reaction between 1.5 equiv. of (S)-ethyl pyrrolidine-2-carboxylate, 1.5 equiv. of benzaldehyde, and 1.0 equiv. of diphenylphosphine oxide (Table 1). A screening of different solvents showed that toluene was the best choice and the desired product 2a was obtained in 58% yield (Table 1, entry 3). The reaction could be also performed in DCE, DMF, THF, and dioxane respectively; lower yields were observed. Encouraged by these results, we selected toluene as the reaction solvent and further investigated the reaction temperature; results indicated that 110 °C was a more suitable parameter to this reaction (Table 1, entries 6–11). A screening of the additives revealed that the presence of MgSO₄, Na₂SO₄, or 4 Å MS especially decreased the yields of the desired product (Table 1, entries 12–14), and Cs₂CO₃ shut down the reaction entirely (Table 1, entry 12–15). We have also screened the reaction concentration and the ratio of starting materials and found that the reaction concentration of 0.3 mol L⁻¹ and the ratio of 1a : E : H(O)PPh₂ = 1.5 : 1.5 : 1 were the best choice. Through further study we defined optimal reaction conditions by as the use of 1a (1.5 equiv.), diphenylphosphine oxide (1.0 equiv.), (S)-ethyl pyrrolidine-2-carboxylate (1.5 equiv.) in toluene at 110 °C under an argon atmosphere.

Table 1 Optimization of reaction conditions^a

Entry	Solvent	T (°C)	Additive (eq.)	Yield^b (%)
a Reaction conditions: 1a (0.45 mmol, 46 μL), (L)-ethyl pyrrolidine-2-carboxylate (0.45 mmol, 64 mg), diphenylphosphine oxide (0.3 mmol, 60.6 mg), solvent (2.0 mL), additive (50 mol%), at 80 °C (oil-bath temperature), under argon atmosphere for 30 h.b Isolated yield. DCE = 1,1-dichloroethane, DMF = N, N-dimethylformamide, THF = tetrahydrofuran.
1	DCE	80		39
2	DMF	80		31
3	Toluene	80		58
4	THF	80		49
5	Dioxane	80		36
6	Toluene	60		43
7	Toluene	70		52
8	Toluene	90		63
9	Toluene	100		68
10	Toluene	110		78
11	Toluene	120		65
12	Toluene	110	Na2SO4 (0.5)	64
13	Toluene	110	MgSO4 (0.5)	68
14	Toluene	110	4 Å MS (0.5)	59
15	Toluene	110	Cs2CO3 (0.5)	0

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With optimized reaction conditions in hand, we explored different substituted benzaldehydes in order to examine the scope of the substrates. Table 2 lists the results. Reactions proceeded in moderate-to-excellent yields with aromatic aldehydes and tolerated a variety of functional groups (Table 2, entries 2a–2p). Gratifyingly, when we attempted to use benzaldehyde derivatives with both electron-donating and electron-withdrawing groups, all could afford the desired products in good yields with excellent diastereo-selectivity. In particular, when 4-methylbenzaldehyde was used as the reaction partner, the product 2d was obtained in 95% yield with a 95 : 5 dr value. We were delighted to note that the Cl and Br substituent could also be tolerated in optimized reaction conditions. Substrates with a para-substituted Me, Cl, and Br could afford corresponding products in good to excellent yields. However, no desired product was observed with 2-nitrobenzaldehyde (Table 2, entry 2m).

Table 2 The effect of substituents on the benzaldehyde moiety^a

Entry	Ar	Yield^b (%)	dr^c (%)
a Reaction condition: 1a (0.45 mmol, 46 μL), (S)-ethyl pyrrolidine-2-carboxylate (0.45 mmol, 64 mg), diphenylphosphine oxide (0.3 mmol, 60.6 mg) solvent (2.0 mL), at 110 °C (oil-bath temperature), under argon atmosphere for 35 h.b Isolated yield.c Determined by ^1H NMR or ^31P NMR.
2a	Ph	78	>95 : 5
2b	2-MePh	80	>95 : 5
2c	3-MePh	78	>95 : 5
2d	4-MePh	95	>95 : 5
2e	2-ClPh	66	>95 : 5
2f	3-ClPh	76	>95 : 5
2g	4-ClPh	81	>95 : 5
2h	2-BrPh	78	>95 : 5
2i	3-BrPh	83	>95 : 5
2j	4-BrPh	69	>95 : 5
2k	2-OMePh	84	>95 : 5
2l	4-OMePh	77	>95 : 5
2m	2-NO2Ph	0
2n	3-NO2Ph	75	>95 : 5
2o	4-CNPh	68	>95 : 5
2p	3,5-di-OMePh	72	>95 : 5

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In order to further expand the scope of substrates, we tested aliphatic aldehydes. Lower yields and dr values were achieved as a result (Table 3). For example, 2q was obtained in 68% yield with 51 : 49 dr value and 2r was formed in 57% yield with 53 : 47 dr value. Aromatic heterocyclic aldehydes could also give the desired products in moderate yields with good dr values (2s, 2t). Diverse chiral amino acid ester and amines were also readily converted into the desired products in good yields with moderate dr values (2u, 2v). Results indicate that lower dr values were obtained when aliphatic aldehydes were used, and the ratios of two products' configurations were close to 1 : 1. The results shown in Tables 2 and 3 suggest that the diastereoselectivity of the products mainly depend on the steric hindrance that occurs between the chiral ethyl ester of (S)-ethyl pyrrolidine-2-carboxylate and various substituted aromatic aldehydes.

Table 3 The effect of aliphatic aldehydes, aromatic heterocyclic aldehydes, and other chiral amino acid esters or amines^a

Entry	Product	Yield^b (%)	dr^c (%)
a Reaction condition: 1a (0.45 mmol, 46 μL), (S)-ethyl pyrrolidine-2-carboxylate (0.45 mmol, 64 mg), diphenylphosphine oxide (0.3 mmol, 60.6 mg) solvent (2 mL), additive (50 mol%), at 110 °C (oil-bath temperature), under argon atmosphere for 35 h.b Isolated yield.c Determined by ^1H NMR or ^31P NMR.
2q		68	51 : 49
2r		57	53 : 47
2s		60	>95 : 5
2t		76	79 : 21
2u		74	65 : 35
2v		92	74 : 26

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The reaction may proceed via two pathways at the same time. Path A revealed that prior to the condensation of benzaldehyde and diphenylphosphine oxide, diphenylphosphine oxide was activated by forming a weak H-bond between the N atom of (S)-ethyl pyrrolidine-2-carboxylate and O=P–H function^8,15 which leads to the formation of α-hydroxyphosphine oxide 3. Compound 3 was isolated and identified by using NMR (ESI†). In addition, we observed by TLC an obvious decrease in the concentration of compound 3 during the reaction process. Finally, the reaction of α-hydroxyphosphine oxide moiety 3 between (S)-ethyl pyrrolidine-2-carboxylate resulted in dehydration to form the target compound 2a. The other pathway involves the reaction of benzaldehyde and (S)-ethyl pyrrolidine-2-carboxylate (secondary amine), which forms the imine intermediate 4, which then attacked by diphenylphosphine oxide to afford 2a (Scheme 2).

Scheme 2 The proposed possible mechanism for the reaction.

Conclusions

In summary, we have developed a novel method for high diastereoselective syntheses of chiral α-aminophosphine oxides by a three-component reaction in a metal-free system. This reaction could be widely used to prepare a series of chiral α-aminophosphine oxides from chiral amino acid esters or even chiral amines.

Acknowledgements

We are grateful for the NSF (no. 21072079 and 21272100) and Program for New Century Excellent Talents in University (NCET-11-0215) financial support. S. F. Reichard, MA edited the manuscript.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1000068. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra05645k

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