Synthesis of α,β-unsaturated γ-amino esters with a quaternary center by ruthenium-catalyzed codimerization of N-acetyl α-arylenamines and acrylates

Abstract

Ruthenium-catalyzed highly selective codimerization of N-acetyl α-arylenamines with ethyl acrylates is reported. This codimerization reaction provides a new efficient method for the synthesis of α,β-unsaturated γ-amino esters with a quaternary center.

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α,β-Unsaturated γ-amino esters are very useful intermediates and building blocks in organic synthesis.¹ They can be found in various bioactive natural products and drug molecules, such as miraziridine A, a novel cysteine protease inhibitor from the marine sponge Theonella aff. mirabilis,² and AG7088, a rhinovirus protease inhibitor for treatment of the common cold ³ (Fig. 1). More importantly, α,β-unsaturated γ-amino esters can serve as precursors for the preparation of γ-amino acids, which are key ingredients in pharmaceuticals.⁴ α,β-Unsaturated γ-amino esters are usually prepared from N-protected α-amino aldehydes by Witting-type olefination reactions.⁵ Direct catalytic syntheses of α,β-unsaturated γ-amino esters are very limited. The reported catalytic methods include the palladium-catalyzed rearrangement of α-sulfonimidoyl β,γ-unsaturated esters,⁶ the palladium-catalyzed insertion of α-diazoesters into vinyl halides and trapping with amines,⁷rhodium- and palladium-catalyzed ring opening of vinyl epoxides with amines and azide,⁸ and Lewis acid-catalyzed N–H insertions of methyl styryldiazoacetate with aniline.⁹ However, the efficiencies of these methodologies, especially in the preparation of the α,β-unsaturated γ-amino esters with a quaternary center, are unsatisfied. Therefore, the development of highly efficient and atom-economic catalytic methods for the synthesis of α,β-unsaturated γ-amino esters is highly desired.

Fig. 1 Bioactive molecules containing the α,β-unsaturated γ-amino acid/ester moiety.

Transition metal-catalyzed selective codimerization of two different alkenes, for example hydrovinylation, is a very important and highly atom-efficient olefin-forming reaction, and has been the subject of extensive study.¹⁰ Recently, we studied codimerizations of α-substituted vinylarenes with ethylene (hydrovinylation) and obtained olefin products with a quaternary center in high yields and high chemoselectivities¹¹ This result encouraged us to investigate the codimerization of N-acetylenamines with functionalized alkenes to generate polyfunctionalized alkenes. In this communication, we report the codimerization of N-acetyl α-arylenamines with acrylates catalyzed by a ruthenium complex RuHCl(CO)(PCy₃)₂, producing α,β-unsaturated γ-amino esters with a quaternary center in high yields (Scheme 1).¹²

Scheme 1 The codimerization of N-acetyl α-arylenamines with acrylates.

The codimerization reaction was initially performed under the standard conditions for the hydrovinylation of N-acetylenamines.^11d The reaction of N-(1-phenylvinyl)acetamide (1a) with 2.0 equivalents of ethyl acrylate (2a) in the presence of 5 mol% of catalyst RuHCl(CO)(PCy₃)₂ and 5 mol% of additive AgOTf in DCE at 65 °C produced α,β-unsaturated γ-amino ester (E)-3a in 85% yield accompanied by a small amount (∼5%) of by-product formed from the dimerization of 1a (Table 1, entry 1). On increasing the amount of ethyl acrylate (2a) from 2.0 to 5.0 equivalents, the reaction became faster (reaction time changed from 40 h to 3.5 h) and the yield of 3a increased to 96% (entry 2). However, changing the ruthenium catalyst to RuH₂(CO)(PPh₃)₃ or [Ru(p-cymene)Cl₂]₂/PPh₃, which are efficient for the addition of olefinic C–H bonds of α,β-unsaturated ketones/esters to olefins,^12a–d led only to dimerization of 1a. The reaction temperature strongly influenced reaction rate. Lowering the reaction temperature to 45 °C and 25 °C decreased the reaction rate and gave lower yields (entries 7 and 8 vs. entry 2). Solvent screening experiments revealed that dichloroethane (DCE) was the best reaction medium, and coordinating solvents such as N,N-dimethylformamide (DMF) afforded no desired product. Trifluoromethanesulfonic acid anion (OTf⁻) was demonstrated to be the counteranion of choice for the catalyst, albeit that the codimerization of 1a and 2a proceeded well with other counteranions such as BF₄⁻, PF₆⁻, SbF₆⁻, and BAr_F⁻ (entries 12–15). The reaction can be carried out at 2 mol% of catalyst load, yielding codimerization product 3a in 80% yield with 86% conversion (entry 16).

Table 1 Reaction conditions optimization for the codimerization of 1a and 2a^a

Entry	Catalyst	Additive	Solvent	Temp./°C	Time/h	Conv. (%)	Yield (%)^b
a Reaction conditions: 0.01 mmol of [Ru] catalyst, 0.01 mmol of additive, 0.2 mmol of 1a, 1.0 mmol of 2a (5 eq.), 3 mL of solvent, 20 h. b Isolated yield. c 2 equivalents of 2a. d 15 mol% of PPh3, 30 mol% of NaHCO2. e 2 mol% catalyst.
1^c	RuHCl(CO)(PCy3)2	AgOTf	DCE	65	40	>97	85
2	RuHCl(CO)(PCy3)2	AgOTf	DCE	65	3.5	100	96
3	RuH2(CO)(PPh3)3	None	DCE	65	20	27	None
4	RuH2(CO)(PPh3)3	None	Toluene	140	20	41	None
5^d	[Ru(p-cymene)Cl2]2/PPh3	NaHCO2	Toluene	140	20	25	None
6	RuHCl(CO)(PPh3)3	AgOTf	DCE	65	20	13	None
7	RuHCl(CO)(PCy3)2	AgOTf	DCE	45	19	100	90
8	RuHCl(CO)(PCy3)2	AgOTf	DCE	25	72	92	86
9	RuHCl(CO)(PCy3)2	AgOTf	Toluene	65	20	76	33
10	RuHCl(CO)(PCy3)2	AgOTf	DMF	65	20	8	0
11	RuHCl(CO)(PCy3)2	AgOTf	Dioxane	65	20	51	47
12	RuHCl(CO)(PCy3)2	AgBF4	DCE	65	20	100	86
13	RuHCl(CO)(PCy3)2	AgPF6	DCE	65	20	63	60
14	RuHCl(CO)(PCy3)2	AgSbF6	DCE	65	20	100	91
15	RuHCl(CO)(PCy3)2	NaBArF	DCE	65	20	82	77
16^e	RuHCl(CO)(PCy3)2	AgOTf	DCE	65	40	86	80

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A variety of N-acetyl α-arylenamines 1 was studied under the optimal reaction conditions. The electronic property of the α-arylenamine substrate has a strong effect on the reaction rate and the yield of α,β-unsaturated γ-amino ester product. Substrates containing an electron-donating group at the para- or meta-position of the phenyl ring of the α-arylenamine showed high reaction rates and high yields (Table 2, entries 2, 3 and 8). Substrates having an electron-withdrawing group exhibited slow reaction rates, however the yields of the codimerizations are still high (entries 4–7). The reaction was also sensitive to the steric effect of the substituents on the substrates. ortho-Substitution on the ring of the α-arylenamine substrate led to a slower reaction and a lower yield, especially N-acetyl-α-(2-methylphenyl)enamine gave only 22% yield and 53% conversion (entry 9). Substrate α-(2-naphthyl)enamine also gave the desired codimerization product in high yield. The R group of the acrylate has little impact on the reaction except in the case of the very bulky ^tBu (2c), which resulted in a low reaction rate, although the yield of the reaction was kept at 88%.

Table 2 Codimerization of N-acetyl α-arylenamines with acrylates catalyzed by RuHCl(CO)(PCy₃)₂^a

Entry	Ar	R	Product	Time/h	Conv. (%)	Yield (%)^b
a The reaction conditions were the same as those in Table 1, entry 2. For details of operation and analysis, see ESI. b Isolated yield.
1	C6H5	Et	3a	3.5	100	96
2	4-MeC6H4	Et	3b	3.5	100	91
3	4-MeOC6H4	Et	3c	2.5	100	90
4	4-FC6H4	Et	3d	20	100	85
5	4-ClC6H4	Et	3e	12	100	90
6	4-BrC6H4	Et	3f	12	100	93
7	3-BrC6H4	Et	3g	12	100	87
8	3-MeC6H4	Et	3h	4	100	88
9	2-MeC6H4	Et	3i	20	53	22
10	2-MeOC6H4	Et	3j	14	100	83
11	2-Naphthyl	Et	3k	8	100	95
12	C6H5	Me	3l	3	100	92
13	C6H5	^t Bu	3m	20	95	88

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The codimerization reaction of N-vinylacetamide (4) with ethyl acrylate (2a) was also studied (Scheme 2). When the reaction was performed with 5 mol% catalyst codimerization products 5 and 6 were obtained in 46% and 38% yield, respectively. By adding another 5 mol% catalyst to the reaction mixture, compound 5 was converted to compound 6. If 10 mol% catalyst was directly used in the beginning, the reaction gave only compound 6. These results showed that the reaction may produce compound 5 first, which is isomerized to the more stable compound 6 in the presence of catalyst RuHCl(CO)(PCy₃)₂/AgOTf. The reaction of N-vinylacetamide with ethyl acrylate produced β,γ-unsaturated β-amino ester 5, instead of the expected α,β-unsaturated γ-amino ester, indicating that the reaction might proceed via a different mechanism.^11d

Scheme 2 Codimerization of N-vinylacetamide (4) and ethyl acrylate (2a).

To demonstrate the utility of the codimerization products, α,β-unsaturated γ-amino esters, as key intermediates in organic synthesis, we converted 3a to tricyclic compound 10, which is the structural motif in natural products of the Erythrina alkaloids group.¹³ The α,β-unsaturated γ-amino ester 3a was hydrogenated over Pd/C catalyst to give saturated γ-amino ester 7 in quantitative yield. Treatment of the γ-amino ester 7 with LHMDS, followed by reaction with ethyl 2-bromoacetate, gave the substituted 2-pyrrolidinone 8 in 81% yield. Cyclization of 8 under acidic conditions, followed by a reduction with Pd/C under hydrogen, afforded the tricyclic compound 10 (Scheme 3). This study provided a new efficient approach to the synthesis of pyrroloisoquinoline-type tricyclic compounds with a quaternary center.

Scheme 3 Synthesis of tricyclic compound 10.

In conclusion, we have developed an efficient ruthenium-catalyzed codimerization of N-acetyl α-arylenamines with acrylates. The new reaction provides convenient access to α,β-unsaturated γ-amino esters with a quaternary center. Further studies on this reaction, especially in searching for efficient chiral ligands to accomplish chiral induction, are in progress in our laboratory.

Acknowledgements

We thank the National Natural Science Foundation of China, the National Basic Research Program of China (973 Program) (2010CB833300), and the “111” project (B06005) of the Ministry of Education of China for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Detailed experimental procedures, and the analysis data of new compounds. See DOI: 10.1039/c1ob06412f

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