Tartrate-derived iminophosphorane catalyzed asymmetric hydroxymethylation of 3-substituted oxindoles with paraformaldehyde

Abstract

The enantioselective synthesis of 3-hydroxymethyl-2-oxindoles was achieved through organocatalysis by a tartrate-derived chiral iminophosphorane in 81–98% yields and up to 94% ee under mild conditions. Of note is that readily available and easily usable paraformaldehyde was employed as a hydroxymethylation C1 unit in the reaction.

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Oxindole, a well-known scaffold, has been found in a number of medicinally important compounds.¹ Because of the structural diversity and biological activities of oxindole based small molecules, such as NSC635473, YK-4-279, donaxaridine, convolutamydine A, dioxibrassinin, SU11248 (Sutent) etc. (Fig. 1), they have continued to attract the attention of chemists and pharmacologists.² Therefore, inspired by the pharmaceutical importance and the synthetic value of oxindole derivatives, intense efforts have been made toward the construction of enantiomerically enriched chiral 3,3-disubstituted oxindoles in recent years.³

Fig. 1 Examples of biologically active oxindole-based molecules.

On the other hand, the hydroxymethylation reaction, one of the most important reactions in organic synthesis due to its rich chemistry of functional group conversion with the hydroxyl group, is a powerful and atom-economical one-carbon extension method.⁴ In this regard, catalytic asymmetric hydroxymethylations of silyl enolates,⁵ α-cyanopropionates,⁶ β-keto esters⁷ and ketones⁸ have been intensively investigated in the last decade.⁹ Particularly, in 2010, Kobayashi et al. tried one example of enantioselective hydroxymethylation of N-Boc-3-methyl-2-oxindole with formalin (37% formaldehyde in aqueous solution) using a chiral bipyridine–Sc^III complex, which gave the desired product in 59% yield with 82% ee (Scheme 1).^8c Subsequently, Yuan and co-workers reported a bifunctional thiourea-catalyzed asymmetric hydroxymethylation of N-Boc-oxindoles using paraformaldehyde, and the adducts were afforded in 80–99% yields and 5–91% ee.^8d Since then, the Feng group described an enantio-selective synthesis of 1,3-bis(hydroxymethyl)-2-oxindoles with formalin, in up to 93% yield and 99% ee by using a recyclable Nd^III–N,N′-dioxide complex.^8e Interestingly, Bisai and co-workers employed this strategy involving a thiourea catalyzed enantioselective hydroxymethylation reaction for the total synthesis of both spiro(pyrrolidinyl-oxindole) and hexahydropyrrolo[2,3-b]indole alkaloids.^8f However, there are still some limitations in terms of the substrate scope and enantioselectivity in the asymmetric hydroxymethylation of 3-disubstituted-2-oxindoles using these catalytic systems. Recently, chiral Brønsted base catalysis has achieved great advances in the growing branch of asymmetric organocatalysis.^10,11 As such, given the abundant availability and ready diversification of tartaric acid and its derivatives thereof, we have developed a novel family of chiral iminophosphoranes featuring a tartrate-derived skeleton (Fig. 2); these iminophosphoranes showed remarkable catalytic activity toward the asymmetric chlorination of 3-substituted oxindoles.^11b To further expand the utility of this library of iminophosphoranes, herein we describe the asymmetric hydroxymethylation of 3-substituted oxindoles with paraformaldehyde as a useful C1 unit in high yields (81–98%) and excellent stereocontrol (up to 94% ee).

Scheme 1 Established asymmetric hydroxymethylation of 3-substituted oxindoles.

Fig. 2 The iminophosphorane catalysts used in this work.

Initially, we studied the hydroxymethylation of N-Boc-3-benzyloxindole 1a with paraformaldehyde 2 to optimize the reaction conditions and catalysts at room temperature (Table 1). Firstly, given the easy availability of iminophosphorane 4a (Fig. 2), we used 4a as the catalyst (10 mol%) to screen various solvents. In chlorinated solvents, dichloromethane (DCM) or 1,2-dichloroethane (DCE), the reaction afforded excellent yields and moderate ee values in 15 hours (Table 1, entries 1 and 2, 97% yield and 46% ee, 98% yield and 43% ee, respectively). In polar solvents, although high yields were obtained, the enantiomeric excess was quite low. For example, when the reaction was conducted in acetone (Table 1, entry 3), methanol (MeOH) (Table 1, entry 4) or acetonitrile (MeCN) (Table 1, entry 5), it could afford 85–98% yields but only 19% ee, 12% ee, or −5% ee, respectively. Next, screening of non-polar solvents revealed that not only excellent yields could be obtained, but also the enantiomeric excess was significantly improved (Table 1, entries 6–9, 91–95% yields, 73–88% ee). Mesitylene was demonstrated to be superior to the other solvents; it could provide the desired product 3a in 95% yield and 88% ee (Table 1, entry 9). Regarding the formaldehyde reactant, we also tried formalin as an aldehyde source instead of (CH₂O)_n in mesitylene solution, even though the yield was still excellent, 96%, the enantiomeric excess was obviously decreased to 67% (Table 1, entry 10).

Table 1 Optimization of the reaction conditions^a

Entry	Cat. 4	Solvent	Yield^b (%)	ee^c (%)
a Reaction conditions: 1a (0.1 mmol, 1.0 equiv.) and catalyst 4 (10 mol%) were dissolved in solvent (2 mL), then 2 (3 equiv.) was added into the stirring solution at 25 °C. After 15 h, the solution mixture was purified directly by silica gel column chromatography to afford product 3a. b Isolated yield. c Enantiopurity of the products was determined by HPLC analysis using a chiral column with hexane/isopropanol as the solvent. d Formalin (25 μL, 3 equiv.) was used instead of (CH2O)n. e A pre-made HCl salt of 4a was used. f 5 mol% of 4g was used. g 1 mol% of 4g was used and the reaction time was 30 h.
1	4a	DCM	97	46
2	4a	DCE	98	43
3	4a	Acetone	85	19
4	4a	MeOH	89	12
5	4a	MeCN	98	−5
6	4a	n-Hexane	91	73
7	4a	Cyclohexane	92	83
8	4a	Toluene	93	76
9	4a	Mesitylene	95	88
10^d	4a	Mesitylene	96	67
11	4b	Mesitylene	88	73
12	4c	Mesitylene	89	72
13	4d	Mesitylene	85	90
14	4e	Mesitylene	98	89
15	4f	Mesitylene	97	92
16	4g	Mesitylene	98	94
17	4h	Mesitylene	97	38
18	4i	Mesitylene	96	87
19	4j	Mesitylene	97	−95
20^e	4a·HCl	Mesitylene	Trace	N.D.
21^f	4g	Mesitylene	90	94
22^g	4g	Mesitylene	91	95

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With mesitylene as the optimal solvent, we were pleased to discover that all iminophosphoranes 4 (Fig. 2) bearing diverse aryl groups could catalyze the direct hydroxymethylation of 3-benzyl substituted oxindole 1a with paraformaldehyde, providing 3a in good yields with a quaternary stereocenter as shown in Table 1, entries 11–17. When 4b (Ar = 4-FC₆H₄) or 4c (Ar = 4-ClC₆H₄) was used as the catalyst, comparable results were obtained (Table 1, entries 11 and 12, 88% yield and 73% ee, 89% yield and 72% ee, respectively). However, when 4d (Ar = 4-PhC₆H₄) was applied in the reaction, both the yield and enantiomeric excess were slightly increased (Table 1, entry 13, 85% yield, 90% ee) compared to the result of 4a (Table 1, entry 9). Furthermore, the catalytic performance of the alkyl-substituted Ar group of iminophosphoranes was exploited in the model reaction, and the desired product 3a was achieved in excellent yields, and the enantiomeric excess was increased along with the bulk of alkyl chains substituted at the C4 position of the Ar group (Table 1, entries 9, 14–16, 95–98% yield, 88–94% ee). In particular, catalyst 4g was superior to the other catalysts 4a–f in terms of enantioselectivity (Table 1, entries 16 vs. 9, 11–15). In sharp contrast, catalyst 4h, bearing 3,5-dimethylphenyl groups, provided excellent yield but low ee (Table 1, entry 17, 97% yield, 38% ee). The ketal moiety of the iminophosphorane catalyst 4i with a cyclohexanone unit afforded 96% yield of 3a together with 87% ee (Table 1, entry 18). Additionally, as the enantiomer of catalyst 4g, catalyst 4j was employed to this reaction and it afforded the product with 97% yield and −95% ee (Table 1, entry 19 was compared with entry 16). Notably, when the HCl salt of 4a was employed as the catalyst, only trace 3a was observed by thin-layer chromatography (Table 1, entry 20). The enantioselectivity did not decrease at all with the decline of catalytic loading, and we could obtain 95% ee even in the case of 1 mol% 4g as the catalyst but the reaction rate slowed down (Table 1, entries 21 and 22).

Having established the optimal reaction conditions, we then explored the generality of the substrate scope by varying the structure of N-Boc-protected oxindoles 1 as summarized in Table 2. A wide array of oxindoles were proved to be suitable substrates. For example, an electron-rich (3b, 96% yield, 93% ee, and 3c, 92% yield, 93% ee) or electron-poor (3j, 95% yield, 90% ee) group substituted at the C5 position or 4-methyl (3d, 90% yield, 93% ee), 4-methoxyl (3e, 97%, 91% ee), 4-flouro (3k, 95%, 91% ee) substituted on the 3-benzyl group were accommodated in this reaction. In addition, oxindoles bearing both electron-rich and electron-poor groups on the aryl rings respectively were also well tolerated (3f–i, 85–95% yields, 89–92% ee). However, the difluoro-substituted or 7-fluoro-substituted oxindoles such as 3m, 3n and 3o were not well compatible with this method (Table 2). C3-aliphatic substituents led to moderate to good enantioselectivity despite the good yields (3p–r, 81–92% yield, 65–86% ee). It is noteworthy that, in the case of 3-phenyl oxindole 1s as the substrate, the corresponding adduct 3s was obtained in 30% ee which however has been the best result so far in comparison with a previous report (95% yield, <5% ee with a bifunctional thiourea–tertiary amine as the catalyst).^8d

Table 2 Substrate scope of 3-substituted oxindoles^a

a Conditions: 1 (0.1 mmol, 1.0 equiv.),and cat. 4g (0.005 mmol, 5 mol%) were added to a tube with mesitylene (2 mL) and a magnetic stirrer at 25 °C, then 2 (0.3 mmol, 3.0 equiv.) was added to the stirring solution. After stirring for 24 h at 25 °C, the reaction mixture was purified directly by silica gel column chromatography to yield product 3. The ee of product 3 was determined by chiral HPLC analysis.

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The stereochemical rationale for our hypothesized catalytic hydroxymethylation process in the presence of iminophosphorane is shown in Fig. 3. Oxindole 1 would be initially deprotonated by chiral iminophosphorane 4 which is known as a Brønsted base, the resulting chiral phosphonium and enolate of 1 could form a structured ion pair (I) and activate the nucleophile 1, allowing the highly stereoselective addition to formaldehyde (electrophile) and giving the enantioenriched adducts 3.

Fig. 3 Mechanism hypothesis for the asymmetric hydroxymethylation.

In conclusion, we have developed a new catalytic asymmetric approach for the hydroxymethylation of 3-substituted oxindoles. With the suitable choice of a chiral tartrate-derived iminophosphorane catalyst, a range of various substituted oxindoles bearing quaternary stereocenters were synthesized with high efficiency (81–98% yield) and good to excellent enantioselectivity (up to 94% ee). Further investigations on this catalytic system by using iminophosphoranes to produce important compounds are currently underway in our laboratory.

Acknowledgements

This work was supported by grants from the National Nature Science Foundation of China (NSFC no. 21472213, 21202186), as well as by Croucher Foundation (Hong Kong) in the form of a CAS-Croucher Foundation Joint Laboratory Grant. This research program was performed under the auspices of Professor Henry N. C. Wong, whom we thank for helpful discussions and generous support.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6qo00074f

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