2-Phenallyl as a versatile protecting group for the asymmetric one-pot three-component synthesis of propargylamines

Abstract

2-Phenallyl was found to be a versatile protecting group of primary amines for the asymmetric one-pot three-component synthesis of propargylamines which leads to enantiomeric excess of up to 96%; it can be easily removed with a palladium(0)-catalyzed allylic substitution using 1,3-dimethylbarbituric acid as a nucleophile.

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Protecting groups play an important role in synthetic organic synthesis.¹ The allyl group is widely used for the protection of alcohols, amines and carboxylic acids. Allyl groups are stable under both acidic and basic conditions, but can easily be removed by palladium-catalyzed substitution reactions with various nucleophiles.² Recently, we³ and others⁴ have reported a three-component asymmetric reaction of a terminal alkyne, an aldehyde and a secondary amine using copper(I) bromide/Quinap⁵ as the catalytic system leading to enantiomerically enriched propargylamines (Scheme 1).

Scheme 1 Asymmetric three-component synthesis of propargylamines.

In the course of our studies, we have investigated various amine protecting groups. While dibenzylamine leads to the highest enantioselectivity (Scheme 2, 1a, 98% ee), the removal of this group was not possible under mild conditions. Hydrogenation of the dibenzyl protected propargylamines under standard conditions⁶ led to the reduction of the triple bond. Oxidative methods like CAN- or DDQ-oxidations also failed to remove chemoselectively the benzyl group. Extensive decomposition of the starting propargylamine was observed. The allyl group itself can be used as a protecting group during the propargylamine synthesis, but lower % ee are obtained.⁷ To increase the enantioselectivity of this reaction, we have investigated the influence of the steric hindrance of the allylic amine. The use of diallylamine in a test reaction led to the desired amine 1b in only 90% ee compared to 98% ee obtained by the reaction with dibenzylamine (product 1a). Increasing the steric hindrance by the use of bis(methallyl)amine led to the corresponding product 1c in 92% ee. Finally, the use of bis(phenallyl)amine⁸3 provides the propargylamine 2d in 96% ee, which exhibits still a synthetically useful level of selectivity (see Scheme 2).

Scheme 2 Influence of the steric demand in the allyl protecting group.

Furthermore, the bis(phenallyl)amine is easily prepared from commercially available starting materials using standard protocols. Thus, allylic bromination⁹ of α-methylstyrene using NBS at 160 °C furnished the substituted allyl bromide in 70% yield. Nucleophilic substitution with potassium phthalimide in DMF followed by reductive cleavage with hydrazine in MeOH yielded the primary allylamine in 66% yield over two steps.¹⁰ Condensation with 2-phenallyl bromide led to bis(phenallyl)amine 3 in 70% yield.

In order to examine the scope of this new protecting group in the three-component reaction, several aldehydes 4 and alkynes 5 were reacted with 3 in the presence of CuBr/Quinap leading to bis(phenallyl)-protected propargylamines 2 (Scheme 3 and Table 1).

Scheme 3 Asymmetric three-component synthesis of bis(phenallyl)-protected propargylamines.

Table 1 Asymmetric three-component synthesis of bis(phenallyl)-protected propargylamines

Nr.	Aldehyde 4	Alkyne 5	Propargylamine 2	Yield^a (%)	ee ^b (%)
a Isolated yield of analytically pure product. b Enantiomeric excess determined by HPLC using Chiracel OD-H column (n-heptane : i-PrOH).
	R^1CHO
1	4a: R^1: n-Bu	5a: R^2: TMS	2a: R^1: n-Bu; R^2: TMS	86	84
2	4b: R^1: i-Bu	5a	2b: R^1: i-Bu; R^2: TMS	67	90
3	4c: R^1: i-Pr	5a	2c: R^1: i-Pr; R^2: TMS	79	86
4	4d: R^1: s-Pent	5a	2d: R^1: s-Pent; R^2: TMS	67	96
5	4e: R^1: c-Pr	5a	2e: R^1: c-Pr; R^2: TMS	79	84
6	4f: R^1: c-Hex	5a	2f: R^1: c-Hex; R^2: TMS	82	92
7	4g	5a	2g: R^1: (CH2)2(2-F-4-Br-C6H3); R^2: TMS	75	75
8	4h: R^1: (C6H5)2C=CH	5a	2h: R^1: (C6H5)2C=CH; R^2: TMS	83	81
9	4i: R^1: Ph	5a	2i: R^1: Ph; R^2: TMS	67	34
10	4j: R^1: 3-benzothiophene	5a	2j: R^1: 3-benzothiophene; R^2: TMS	58	84
11	4f	5b: R^2: n-Bu	2k: R^1: c-Hex; R^2: n-Bu	82	68
12	4d	5c: R^2: Ph	2l: R^1s-Pent; R^2: Ph	71	70

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With trimethylsilylacetylene (5a), branched and unbranched aliphatic aldehydes lead to the corresponding propargylamines 2a–f in good yields and enantioselectivities (entries 1–6, Table 1). The selectivity increases with the steric demand of the aldehyde. Valeraldehyde (4a) leads to the product 2a with 84% ee (entry 1), isovaleraldehyde (4b) gives 2b with 90% ee (entry 2) and 2-ethylbutyraldehyde (4d) produces the highest selectivity leading to 2d with 96% ee (entry 4). Aldehydes bearing a cyclic substituent like cyclopropyl- and cyclohexylcarbaldehyde afford the desired propargylamines 2e–f in 79–82% yield and 84 and 92% ee, respectively (entries 5–6). The functionalized dihydrocinnamaldehyde 4g also leads to the desired product 2g in good yield but somewhat lower enantioselectivity (75% ee, entry 7). Phenylcinnamaldehyde 4h also participates in the reaction leading to propargylamine 2h with 81% ee (entry 8). Benzaldehyde (4i) leads to the product 2i with only 34% ee (entry 9), whereas 3-benzothiophenaldehyde (4j) gives the desired propargylamine 2j in 84% ee (entry 10). Likewise, other alkynes can be reacted, but the selectivities are lower. Therefore, reaction of 1-hexyne (5b) with cyclohexanecarbaldehyde (4g) and bis(phenallyl)amine (3) leads to the propargylamine 2k in 82% yield and 68% ee (entry 11). Reaction of 2-ethylbutyraldehyde (4d) with amine 3 and phenylacetylene (5c) gives the propargylamine 2l in 71% yield and 70% ee (entry 12).

For the product 1b derived from diallylamine, both allyl groups are readily removed by Guibé's method.^2a We have observed that the more sterically hindered methallyl group (1c) needs more forcing conditions (heating to 60 °C) to achieve full deprotection. In contrast, the bis(phenallyl) groups could be removed efficiently in CH₂Cl₂ at room temperature leading to the corresponding primary propargylamines 6 (Scheme 4, Table 2).

Scheme 4 Deprotection leading to primary amines 6.

Table 2 Removal of the phenallyl groups leading to primary amines 6

Nr.	Propargylamine 2	Primary amine 6	Yield^a (%)	ee (%)
a Isolated yield of analytically pure product.
1	2d: R^1: s-Pent; R^2: TMS	6a: R^1: s-Pent; R^2: TMS	66	96
2	2e: R^1: c-Pr; R^2: TMS	6b: R^1: c-Pr; R^2: TMS	75	84
3	2h: R^1: (C6H5)2C=CH; R^2: TMS	6c: R^1: (C6H5)2C=CH; R^2: TMS	83	81
4	2i: R^1: Ph; R^2: TMS	6d: R^1: Ph; R^2: TMS	77	34
5	2l: R^1: s-Pent; R^2: Ph	6e: R^1: s-Pent; R^2: Ph	90	70

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Various propargylamines 2 can be converted to the corresponding primary amines 6. Thus, the propargylamines 2d–e can be transformed to the amines 6a and 6b in 66–75% yield (entries 1–2, Table 2). Interestingly, the allyl-substituted propargylamine 2h derived from phenylcinnamaldehyde undergoes a selective cleavage of the phenallyl groups leading to the product 6c in 83% yield (entry 3).

Likewise the phenyl-substituted amine 2i was subjected to the deprotection procedure and furnished the benzylamine 6d in 77% yield (entry 4). Finally, deprotection also takes place with the phenylacetylene-substituted amine 2l leading to 6e in very good yield (90%, entry 5).

In summary, we have developed an efficient protecting group for the synthesis of chiral primary propargylamines. Bis(phenallyl)amine is easily prepared and leads to good enantioselectivities (up to 96% ee) in the one-pot three-component synthesis of propargylamines. Furthermore, it can be removed using a Pd⁰-catalyzed allylic substitution with dimethylbarbituric acid leading to chiral primary propargylamines in good yields. This new protecting group should find numerous applications for the preparation of sensitive amines since the deprotection occurs under very mild conditions.

We thank the Fonds der Chemischen Industrie and Merck Research Laboratories (MSD) for financial support. We thank the DFG (SPP 1118 “Sekundäre Wechselwirkungen als Steuerungsprinzip zur gerichteten Funktionalisierung reaktionsträger Substrate”) for a fellowship for N. G. and Chemetall GmbH (Frankfurt) and BASF AG (Ludwigshafen) for generous gifts of chemicals.

Notes and references

1. P. J. Kocienski, Protective Groups, Thieme, Stuttgart, 3rd edn., 2003.
2. (a) For the deprotection using 1,3-dimethylbarbituric acid, see: F. Garro-Helion, A. Merzouk and F. Guibé, J. Org. Chem., 1993, 58, 6109; (b) for the deprotection using thiosalicylic acid, see: S. Lemaire-Audoire, M. Savignac and J. P. Genêt, Tetrahedron Lett., 1995, 36, 1267; S. Lemaire-Audoire, M. Savignac, C. Dupuis and J. P. Genêt, Bull. Soc. Chim. Fr., 1995, 132, 1157; (c) for the deprotection using sulfinic acids, see: M. Honda, H. Morita and I. Nagakura, J. Org. Chem., 1997, 62, 8932.
3. (a) N. Gommermann, C. Koradin, K. Polborn and P. Knochel, Angew. Chem., Int. Ed., 2003, 42, 5763; (b) N. Gommermann and P. Knochel, Chem. Commun., 2004, 20, 2324; (c) H. Dube, N. Gommermann and P. Knochel, Synthesis, 2004, 12, 2015.
4. (a) C. M. Wei and C.-J. Li, J. Am. Chem. Soc., 2003, 125, 9584; (b) S. Sakaguchi, T. Kubo and Y. Ishii, Angew. Chem., Int. Ed., 2001, 40, 2534; (c) L. Shi, Y.-Q. Tu, M. Wang, F.-M. Zhang and C.-A. Fan, Org. Lett., 2004, 6, 1001; (d) C. M. Wei and C.-J. Li, J. Am. Chem. Soc., 2002, 124, 5638; (e) C. M. Wei, Z. G. Li and C.-J. Li, Org. Lett., 2003, 5, 4473; (f) for the preparation of propargylic alcohols see: D. E. Frantz, R. Faessler and E. M. Carreira, J. Am. Chem. Soc., 2000, 122, 1806.
5. (a) J. M. Valk, G. A. Whitlock, T. P. Layzell and J. M. Brown, Tetrahedron: Asymmetry, 1995, 6, 2593; (b) E. Fernandez, K. Maeda, M. W. Hooper and J. M. Brown, Chem. Eur. J., 2000, 6, 1840.
6. W. H. Hartung and R. Simonoff, Org. React., 1953, VII, 263.
7. (a) C. Koradin, K. Polborn and P. Knochel, Angew. Chem., Int. Ed., 2002, 114, 2651; (b) C. Koradin, N. Gommermann and P. Knochel, Chem. Eur. J., 2003, 9, 2797.
8. During the preparation of this manuscript, the 2-phenallyl group was described first by Barluenga, using tert-butyllithium for deprotection: J. Barluenga, F. J. Fananás, R. Sanz, C. Marcos and J. M. Ignacio, Chem. Commun., 2005, 933.
9. For the preparation of [1-(bromomethyl)vinyl]benzene, see: S. F. Reed, J. Org. Chem., 1965, 30, 3258.
10. (a) For the preparation of phenallylamine, see: N. De Kimpe and D. De Smaele, Tetrahedron, 1995, 51, 6465; (b) I. A. McDonald, J. M. Lacoste, P. Bey, M. G. Palfreyman and M. Zreika, J. Med. Chem., 1985, 28, 186.

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Footnote

† Electronic supplementary information (ESI) available: Experimental section. See http://dx.doi.org/10.1039/b507810e

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