Synthesis of 3,4-Disubsituted Isoxazoles via Enamine [3+2] Cycloaddition

Abstract

Enamine-triggered [3+2]-cycloaddition reactions of ­aldehydes and N-hydroximidoyl chlorides in the presence of tri­ethylamine give rise to 3,4-disubstituted isoxazoles upon oxidation of the cycloadduct 3,4,5-trisubstituted 5-(pyrrolidinyl)-4,5-dihydroisoxazoles. This offers a high yielding, regiospecific and metal-free synthetic route for the synthesis of 3,4-disubstituted isoxazoles.

 

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Key words

isoxazole - enamines - 1,3-dipoles - [3+2] cycloaddition

Since Quilico and Claisen reported their methods,[1] [2] synthetic methodologies that manipulate the synthesis of isoxazoles have progressively gained awareness in organic synthesis. As one of the prominent medicinal scaffolds, the isoxazole group is featured in a large number of pharmaceutically important compounds and natural products.[ ³ ] As exemplified in Figure [1], isoxazole compounds I–VI exhibit some biologically and pharmacologically important properties, such as anticancer, antianaphylactic, and antitumor activity.[3] [4]

Although various synthetic methods for isoxazoles synthesis have been developed,[ ⁵ ] regioselective control of isoxazole functionalization is still the main concern. Moreover, synthetic methods that are available for 3,4-disubstituted isoxazoles are currently rather scarce. Known methods either require multiple steps,[ ⁶ ] metal catalyst,[ ⁷ ] or give low yields.[ ⁸ ] Therefore, there is an urgent need to develop an efficient method for the synthesis of 3,4-disubstituted isoxazoles under mild conditions.[ ⁹ ]

Our group has recently reported the use of enamines as dipolarophiles to react with azide compounds to afford substituted 1,2,3-triazole compounds with high levels of regioselectivities.[ ¹⁰ ] Given that enamines formed in situ from aldehydes are regiospecific, we envisioned that cycloaddition of nitrile oxides with enamines may give rise to the corresponding 3,4-disubstituted isoxazoles upon oxidation of the cycloadduct 3,4,5-trisubstituted 5-(pyrrolidinyl)-4,5-dihydroisoxazoles generated in the first step (Scheme [1]). Herein, we wish to report a new metal-free strategy for the facile synthesis of 3,4-disubstituted isoxazoles that is based on this approach.

Figure 1 Selected examples of bioactive isoxazole compounds

Scheme 1 Enamine-promoted [3+2] cycloaddition reaction

Initial experiments were conducted to examine various reaction parameters (Table [1]). Reactions carried out in polar solvents gave low yields, whereas high yields were achieved in less polar solvent (Table [1], entries 1–4 vs. entries 5–7). The substrate ratio 1a/2a/3a indicated that an excess of 2a and 3a facilitated a higher yield (Table [1], entries 12–15), probably due to a competitive self-aldol side reaction. Lowering the concentration of 1a to 0.1 mol/L allowed higher conversion and gave the desired product in 99% yield (Table [1], entry 11). Surprisingly, only one trans-3,4-disubstituted diastereomer was generated.[ ¹¹ ] The ¹H NMR spectrum of the crude product revealed that the diastereomeric ratio (d.r.) was more than 19:1. 

Table 1 Optimization of Reaction Conditions^a

Entry	Solvent	Concn (mol/L)	Ratio			Yield (%)b,f
			1a	2a	3a
1	Toluene	0.5	1.0	4.0	2.2	98
2	Et2O	0.5	1.0	4.0	2.2	97
3	THF	0.5	1.0	4.0	2.2	93
4	CH2Cl2	0.5	1.0	4.0	2.2	98
5	MeCN	0.5	1.0	4.0	2.2	72
6	MeOH	0.5	1.0	4.0	2.2	58
7	Brine	0.5	1.0	4.0	2.2	39
8	CH2Cl2 c	0.5	1.0	4.0	2.2	64
9	CH2Cl2 d	0.5	1.0	4.0	2.2	80
10	CH2Cl2	0.25	1.0	4.0	2.2	95
11	CH2Cl2	0.1	1.0	4.0	2.2	99
12e	CH2Cl2	0.5	1.0	4.0	2.2	90
13	CH2Cl2	0.5	2.0	1.0	2.0	82
14	CH2Cl2	0.5	1.0	4.0	1.2	92
15	CH2Cl2	0.5	1.0	2.0	2.2	93

^a Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (0.8 mmol, 4.0 equiv), 3a (0.44 mmol, 2.2 equiv), Et₃N (0.2 mmol, 1.0 equiv), 0 °C (0.5 h), r.t. (1.5 h).

^b Yield of isolated product after column chromatography and diastereoisomeric ratio (all d.r. > 19:1) were determined by ¹H NMR analysis of the crude mixture.

^c N-Hydroxybenzimidoyl chloride added in one portion.

^d Reaction carried out at 40 °C for 1.5 h instead of room temperature.

^e Without Et₃N.

^f The relative configuration of 4aa (trans-structure) was determined by X-ray crystal analysis.[ ¹¹ ]

We then investigated the use of secondary amines as catalysts (Table [2]). Six other secondary amines were screened and it was found that pyrrolidine 3a gave the best yield (99%; Table [2], entry 1). Reactions with 3c, 3e and 3g did not afford the desired product.

Scheme 2 Substrate scope. ^a Unless specified, see the experimental section for reaction conditions. ^b All d.r. > 19:1.

Having the optimized conditions in hand, we examined the substrate scope of the reaction (Scheme [2]). Reactions between a range of acetaldehydes and N-hydroxyimidoyl chlorides gave good to high yields (77–99%; Scheme [2]). The reaction tolerated a broad range of functional groups on both the acetaldehyde and N-hydroxyimidoyl chloride. Acetaldehydes bearing aliphatic and aromatic groups (Scheme [2], 2a–f and 2i–k) both gave high yields (82–99%; Scheme [2], 4aa–af and 4ai–ak).[12] [13] Examination of a range of N-hydroxyimidoyl chlorides revealed that the reaction also tolerated a wide range of substituents (Scheme [2], 1a–j), including phenyl, heterocyclic, and aliphatic groups, to give the corresponding 3,4,5-trisubstituted dihydroisoxazoles (77–98%; Scheme [2], 4bi–ii and 4ia).

Importantly, 3,4,5-trisubstituted 4,5-dihydroisoxazoles can undergo Cope elimination by addition of m-chloroperoxybenzoic acid (MCPBA) to afford 3,4-disubstituted isoxazoles in high yields [95 and 93%, respectively; Scheme [3], eq. (1) and (2)]. We then examined the feasibility of using a direct one-pot process for the synthesis of isoxazoles from 1a, 2a and 3a [Scheme [3], eq. (3)] and found that 4aa could be obtained in a yield of 83%. However, five equivalents of MCPBA were required to allow the reaction to reach completion. To this end, the development of a more efficient and concise one-pot synthetic method is in progress in our laboratory.

To illustrate the broad synthetic utility of our developed methodology, we undertook the formal synthesis of herpes virus replication inhibitor 7.[ ¹⁴ ] Intermediate 4bi was easily transformed into 5bi through a Cope elimination step (93%; Scheme [4]). Compound 5bi was efficiently reduced to 6bi in the presence of tin(II) chloride (98%; Scheme [4]), and 6bi could be converted into the reported herpes virus replication inhibitor 7 following known methods.[ ¹⁰ ] Consequently, the presented method provides a convenient and high-yielding process for the synthesis of 3,4-disubstituted isoxazoles, which are useful intermediates for drug design and synthesis. Notably, 3,4-disubstituted isoxazoles that were previously accessed through either low-yielding methods or required transition-metal catalysis can now be made through a metal-free, high-yielding reaction under mild conditions.

Table 2 Effect of the Secondary Amine^a

Entry	Amine	Yield (%)b	Entry	Amine	Yield (%)b
1	3a	99	5	3e	–[c]
2	3b	76	6	3f	37
3	3c	–[c]	7	3g	–[c]
4	3d	75

^a Unless specified, see the experimental section for reaction conditions.

^b Yield of isolated product after column chromatography; diastereoisomeric ratio > 19:1.

^c No reaction.

Scheme 3

Scheme 4 Synthesis of herpes virus replication inhibitor 7

Mechanistically, we propose that nitrile oxide D will be generated from N-hydroxyimidoyl chloride A upon treatment with base (Scheme [5]). Enamine E is rapidly generated in situ when acetaldehyde B reacts with secondary amine C. Subsequently, D will undergo an inverse-electron-demand [3+2]-cycloaddition reaction with E, which behaves as a dipolarophile, to form the cycloadduct F. The latter undergoes oxidation to form amine oxide G. Finally, intermediate G will convert into target isoxazole H through subsequent elimination (Scheme [5]).

Scheme 5 Proposed mechanism

Notably, this methodology provides a regioselective route to 3,4-disubstituted isoxazoles. Due to the regiospecific formation of the enamine from acetaldehyde, only one regioisomer is finally formed in the 1,3-dipolar cycloaddition process.

In conclusion, we have described a new synthetic route to 3,4,5-trisubstituted dihydroisoxazole through an enamine-promoted [3+2]-cycloaddition reaction under mild conditions and high regioselectivities. These 3,4,5-trisubstituted dihydroisoxazoles can be rapidly converted into 3,4-disubstituted isoxazoles through a high-yielding Cope elimination step. Further investigations into the applications of this enamine-promoted [3+2] strategy for the synthesis of other important biological scaffolds are underway.

 

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Acknowledgment

The authors acknowledge financial support from the Ministry of Education and National Research Foundation (Singapore) (MOE R143000443112, R143000480112 and NRF-CRP7-2010-03).

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• 12 Synthesis of 4aa–ia; General Procedure: Pyrrolidine 3a (74.5 μL, 0.88 mmol) and Et₃N (53.9 μL, 0.4 mmol) was dissolved in CH₂Cl₂ (4 mL), the mixture was cooled to 0 °C and isovaleraldehyde 2a–i (173.9 μL, 1.6 mmol) was added. Immediately afterwards, N-hydroxybenzimidoyl chloride 1a (62.2 mg, 0.4 mmol) in CH₂Cl₂ (0.2 mL) was added in five portions in five-minute intervals. After complete addition of N-hydroxybenzimidoyl chloride, the reaction mixture was stirred for a further 10 min at 0 °C, after which, it was allowed to warm to r.t. slowly and stirred for another 1.5 h. The reaction was then stopped and the product was purified by flash column chromatography with silica gel (EtOAc–hexane, 10%) to afford 4aa–ia.
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