Three-Component [3+2] Cycloaddition for Regio- and Diastereoselective Synthesis of Spirooxindole-Pyrrolidines

Abstract

1,3-Dipolar cycloaddition of nonstabilized azomethine ylides derived from α-C-H functionalization of tetrahydroisoquinoline for regio- and diastereoselective synthesis of spirooxindole-pyrrolidines is developed. A three-component reaction of readily available cyclic amine, aryl aldehydes, and olefinic oxindoles provides a pot, atom and step economy (PASE) approach for making spiro-heterocyclic compounds with biological interest

Graphical Abstract

Acid additive-promoted regio- and diastereoselective 1,3-dipolar cycloaddition of nonstabilized azomethine ylides with olefinic oxindoles afforded biologically interested spirooxindole-pyrrolidines

Introduction

There are numbers of biologically active natural and synthetic compounds bearing the spirooxindole moiety,^1,2 such as drugs molecules (+)-alstonisine,³ pteropodine,⁴ spirotryprostatin A,⁵ and (+)-limaspermidine (Fig. 1).⁶ Spirooxindole compounds have also been developed as MDM2 inhibitors for the treatment of cancer diseases (Fig. 2).⁷ Among them, the spirooxindole-pyrrolidine compounds C and D were prepared through a two-step synthesis involving 1,3-dipolar [3+2] cycloaddition of stabilized azomethine ylides with olefinic oxindoles.^8,9

Fig. 1.

Bioactive spirooxindole-pyrrolidine derivatives

Fig. 2.

Spirooxindole MDM2 inhibitors and synthesis

α-Amino ester or α-amino acid-based [3+2] cycloadditions of stabilized azomethine ylides^10–13 with olefinic oxindoles, including organocatalyzed asymmetric synthesis, for making spirooxindole-pyrrolidines have been well documented (Scheme 1A).^14,15 Also reported are cycloadditions of piperidine-2-carboxylates (Scheme 1B)¹⁶ and cycloadditions involving both isotins and olefinic oxindoles (Scheme 1C).¹⁷ α-Amino acid-based decarboxylative [3+2] cycloaddition of non-stabilized azomethine ylides^18,19 for spirooxindole derivatives has also been developed (Scheme 1D).²⁰

Scheme 1.

Olefinic oxindole-based 1,3-dipolar cycloadditions for spirooxindole-pyrrolidine

Since cyclic amines could be used to replace α-amino esters or α-amino acids to form ylides through H-transfer at α-C-H of the amines for cycloadditions,^21,22 we envisioned that a new method could be developed for diastereoselective synthesis of spirooxindole-pyrrolidine compounds 1 structurally related to MDM2 inhibitor D (Scheme 1E). It is a [3+2] cycloaddition of olefinic oxindoles with nonstabilized azomethine ylides derived from cyclic amines. The product ring skeleton (in blue colour) and the positions of R and R³ in 1 and the product in Scheme 1B are different. The later one is produced from the cycloaddition of olefinic oxindoles with stabilized ylides derived from piperidine-2-carboxylates.¹⁶ In addition to form different product structure, the new method is a one-pot and three-component reaction with high pot, atom, and step economy (PASE).^23,24

Results and discussion

The development of reaction conditions for the one-pot 1,3-dipolar cycloaddition of non-stabilized azomethine ylides was carried out using 1,2,3,4-tetrahydroisoquinoline (THIQ) 2a, 4-bromobenzaldehyde 3a, and olefinic oxindole 4a as substrates (Table 1). After screening reaction conditions using different Brønsted acid catalysts such as BzOH, AcOH, TFA, K10, and Zeolite YH (entries 1–10), it was found that a reaction of 1.3:1.1:1.0 of 2a:3a:4a with 0.5 equiv of BzOH in EtOH under microwave at 125 °C for 30 min afforded 67% isolated yield of spirooxindole-pyrrolidine 1a with 6:1 dr (entry 5). Reactions with a solid Brønsted acid catalysts such as K10 or Zeolite YH gave product up to 69% LC yield and 4:1 dr (entries 9 and 10). Using MeCN, toluene, or dioxane as a solvent didn’t give better than 77% LC yield (entries 11–13).

Table 1.

Conditions for the one-pot reaction

entry	solvent	cat. (0.5 equiv)	T (°C)	t (min)	1a (%)b	dr
1	EtOH	--	90	45	55	3:1
2	EtOH	BzOH	90	45	61	4:1
3	EtOH	BzOH	150	45	71	6:1
4	EtOH	BzOH	125	45	75	6:1
5	EtOH	BzOH	125	30	77 (63%)	6:1
6	EtOH	BzOH	125	15	68	5:1
7	EtOH	AcOH	125	30	70	6:1
8	EtOH	TFA	125	30	43	4:1
9	EtOH	K10	125	30	63	4:1
10	EtOH	Zeolite YH	125	30	69	2.5:1
11	MeCN	BzOH	125	30	75	4.5:1
12	toluene	BzOH	125	30	46	4:1
13	dioxane	BzOH	125	30	67	6:1

^aMicrowave heating, dr determined by ¹H-NMR.

^bLC yield, isolated yield in parenthesis.

Under the optimized conditions, the scope of the one-pot synthesis was evaluated in the preparation of spirooxindole-pyrrolidines 1 which are structurally related to MDM2 inhibitor D (Table 2). Reactions of different aldehydes 3 and olefinic oxindoles 4 with gave products 1a–k in 39–77% yields and up to 7:1 dr. The results indicate that substituents on benzene of aromatic aldehydes affects the product yield such as 1e (2-F-5-BrC₆H₃, 39% yield). Olefinic oxindoles 4 with different R¹, R² and R³ were conferred for the construction of 1f–k. Most products have an ester group (−CO₂Et) as R³. In the case of ketone (R³ = −COMe), product 1j was formed in 55% yield. However, product 1l (R³ = Ph) was obtained in a trace amount, which was also observed in previously reported [3+2] cycloaddition reactions.²⁰ Reactions of heterocyclic aldehydes gave 1k (furanyl) in 68% yield, but 1m (pyridyl) in a trace amount due to its basicity offsets the Brønsted acid catalyst. Reactions of aliphatic aldehydes resulted products 1n–p as complex diastereomeric mixtures due to aldehydes’ low reactivity and diastereoselectivity.^19b,19e Further extension of the reaction scope by using tetrahydronorharman (THBC) or isoindoline as cyclic amines gave 5a and 6a in 79% and 46% yield, respectively (Scheme 2). The [3+2] cycloaddition adducts generated from 2-azidobenzaldehyde and 2-nitrobenzaldehyde were derivatized by reducing the −NO₂ and −N₃ groups to −NH₂ for lactamization to give highly condensed-polycyclic spirooxindole 7a in 32% and 51% yield, respectively (Scheme 3).

Table 2.

Synthesis of substituted spirooxindole-pyrrolidines 1

^aIsolated yield. Reaction conditions are same as Table 1, entry 5.

Scheme 2.

Reactions using THBC or isoindoline as cyclic amine

Scheme 3.

One-pot synthesis of polycyclic compound 7a

The stereochemistry of the [3+2] cycloaddition products was established by X-ray crystal structure analysis of a representative compound 1a (Fig. 3). On the basis of product structure and stereochemistry, a mechanism for the diastereoselective [3+2] of azomethine ylides with THIQ is proposed in Scheme 4. The condensation of THIQ with an aldehyde leads to the formation of an iminium ion and then an azomethine ylide in form I or II. As it has been reported that carboxylic acid facilitates amine α-functionalization for azomethine ylides cycloaddition.^22a Acid additives could alter the regioselectivity of 1,3-dipolar cycloaddition.²⁵ In this work, addition of BzOH promote the cycloaddition of ylide I with an olefinic oxindole to give spirooxindole-pyrrolidines 1 as a major diastereomer. Cycloaddition of azomethine ylide II for product 1” does not happen. However, this pathway is favourable for the reaction shown in Scheme 1B, which is a cycloaddition of an olefinic oxindole with a stabilized azomethine ylide derivatized from piperidine-2-carboxylate.¹⁶ Those results indicate that the [3+2] cycloadditions of stabilized or non-stabilized ylides have different regioselectivity.

Fig. 3.

X-ray structure of compound 1a

Scheme 4.

Mechanism for cycloaddition of non-stabilized ylides derived from THIQ

Conclusions

In summary, a three-component [3+2] cycloaddition involving cyclic amines such as THIQ, THBC and isoindoline has been developed for diastereoselective synthesis of pyrrolidine-based spiro-polycyclic compounds. Some of the product structures are closely related to reported MDM2 inhibitors. The new method has advantages of high synthetic efficiency, operation simplicity, and only stoichiometric amount water and CO₂ were produced as side-products. The biological test results of the newly synthesized compounds will be reported in due course.