Kannan Muruganab,
Murugan Chinnapattuab,
Fazlur-Rahman Nawaz Khan*b and
Pravin S. Iyer*a
aDepartment of Medicinal Chemistry, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560 024, India. E-mail: praviniyer@yahoo.com; Tel: +91 9900081547
bChemistry Division, School of Advanced Sciences, VIT University, Vellore 632014, India. E-mail: Nawaz_f@yahoo.co.in
First published on 15th April 2015
We herein discuss the synthesis of novel benzoxaborinin-4-one from substituted isatins and 2-acetyl phenylboronic acid. Furthermore, we have demonstrated the application of these boronic acids to synthesize indolin-2-ones (Z isomer) regioselectively using Suzuki–Miyaura reaction.
Spiro cyclic compounds are finding increasing application in drug discovery, owing to their conformational restriction and structural novelty.4 Specifically, cyclic spiro 2-oxindole derivatives obtained from isatin, occur in many natural products such as spirotryprostatins A, horsfiline, etc.5 The synthetic spiro 2-oxindole derivative such as NITD605 is currently in clinical development for malaria (Fig. 1).6 In the course of our research, we became interested in the synthesis of a novel spiro boronic acid and its application in the area of medicinal and synthetic organic chemistry.
We used isatin as the key building block due to its presence in many fused bioactive heterocyclic compounds.7 Benzoxaborole, an important class of boronic acids was synthesized from 2-formylphenylboronic acid.8
The benzoxaborole derivatives were synthesised by reducing the aldehyde group with sodium borohydride and followed by condensation (Fig. 2). We envisioned that spirocyclic boron compounds could be synthesized by the condensation of isatin with acetyl phenyl boronic acid.
Entry | Solvent | Reagent | Temp (°C) | Time (h) | Yieldb (%) |
---|---|---|---|---|---|
a 5-Chloro-1-methylindoline-2,3-dione (1 mmol), 2-acetylphenylboronic acid (1.1 mmol) and solvent (4 ml) in Supelco vial.b Isolated yield after column chromatography. | |||||
1 | EtOH | — | 90 | 16 | 20 |
2 | EtOH | — | 90 | 24 | 35 |
3 | MeOH | — | 90 | 24 | 15 |
4 | Hexanol | — | 120 | 16 | 10 |
5 | THF | — | 70 | 16 | 0 |
6 | DMF | — | 120 | 16 | 0 |
7 | Toluene | — | 110 | 16 | 0 |
8 | EtOH | — | r.t | 16 | 0 |
9 | EtOH | — | 100 | 16 | 56 |
10 | EtOH | — | 120 | 16 | 63 |
11 | EtOH | TEA | 120 | 16 | 0 |
12 | EtOH | AcOH | 120 | 16 | 0 |
13 | EtOH | PTSA | 120 | 16 | 0 |
Mechanistically, we believe that the reaction begins with the nucleophilic attack of 2-acetyl boronic acid on isatin resulting in the formation of tertiary alcohol intermediate (IV) which upon dehydration affords the intermediate (V). Cyclisation of the boronic acid onto the activated double bond yielded a diastereoisomeric mixture of products (VI). 3-Acetyl boronic acid yielded no product under these conditions, suggesting that boron group at 2 position promotes enolization of the acetyl group (Fig. 3).
To explore the applicability of the synthesized boronic acids, we attempted a cross coupling reaction under Suzuki–Miyaura conditions. Initially, we examined the Suzuki coupling reaction of compound 1d with 4-iodochlorobenzene in presence of 2% Pd(PPh3)4, NaHCO3 and DME/water solvent mixture (5:
1) at 90 °C (Table 3, Entry 1). Gratifyingly, the reaction afforded the indolin-2-one product 2a in 20% yield. The structure of the coupled product was established by spectroscopic analysis and single crystal XRD study. The structure and conformation (Z isomer) of product 2a were unambiguously determined by single crystal X-ray analysis (Fig. 4). Indolin-2-one compounds have demonstrated useful biological activity as tyrosine kinase inhibitor,9 selective plasmodial CDK inhibitors,10 human transglutaminase-2 inhibitors11 and antifouling/antibacterial agent.12 Interestingly on omission of water, the reaction did not yield any product (Entry 2). The best yield was observed using 10% Pd catalysts at 90 °C in DME/water for 5 min (Entry 3). DME/water proved to be the best solvent (Entry 3–6) and optimum base was NaHCO3 (Entry 3, 7 and 8).
Entry | Catalyst | Base | Solvent | Temp (°C)/time (min) | Yieldb (%) |
---|---|---|---|---|---|
a All reaction were performed with 1d (1 mmol), 4-iodochlorobenzene (1.3 mmol) and base (1.5 mmol) and solvents (5![]() ![]() |
|||||
1 | 5% Pd(PPh3)4 | NaHCO3 | DME![]() ![]() |
90/15 | 45 |
2 | 5% Pd(PPh3)4 | NaHCO3 | DME | 90/120 | 0 |
3 | 10% Pd(PPh3)4 | NaHCO3 | DME![]() ![]() |
90/5 | 65 |
4 | 10% Pd(PPh3)4 | NaHCO3 | Ethanol![]() ![]() |
90/5 | 27 |
5 | 10% Pd(PPh3)4 | NaHCO3 | THF![]() ![]() |
65/5 | 10 |
6 | 10% Pd(PPh3)4 | NaHCO3 | Dioxane![]() ![]() |
100/5 | 50 |
7 | 10% Pd(PPh3)4 | Na2CO3 | DME![]() ![]() |
90/5 | 55 |
8 | 10% Pd(PPh3)4 | K2CO3 | DME![]() ![]() |
90/5 | 48 |
All cyclic boronic acid derivatives were successfully transformed into the respective products in moderate yields (Table 4). We found that only the Z isomer was formed in the reaction indicating high regioselectivity. Mechanistically, we believe that the reaction first undergoes Suzuki–Miyaura reaction resulting in a boronic acid intermediate that further undergoes E2 elimination reaction leading to indolin-2-one product (Fig. 5). The regioselectivity can be understood from the geometries for E2 elimination reaction. The Z isomer resulting from the less hindered transition state of boronic acid intermediate is the more favoured isomer.
Entry | R1 | R2 | Ar | Product | Yieldb (%) |
---|---|---|---|---|---|
a All reaction were performed with benzoxaborinin-4-one (1 mmol), Ar–X (1.3 mmol) and base (1.5 mmol) and solvents (5![]() ![]() |
|||||
1 | F | CH3 | ![]() |
2a | 65 |
2 | F | CH3 | ![]() |
2b | 57 |
3 | F | CH3 | ![]() |
2c | 46 |
4 | H | H | ![]() |
2d | 62 |
5 | H | H | ![]() |
2e | 35 |
6 | H | CH3 | ![]() |
2f | 65 |
7 | H | CH3 | ![]() |
2g | 43 |
8 | Cl | CH3 | ![]() |
2h | 55 |
9 | Cl | CH3 | ![]() |
2i | 41 |
10 | Br | CH3 | ![]() |
2j | 42 |
11 | CH3 | CH3 | ![]() |
2k | 51 |
Footnote |
† Electronic supplementary information (ESI) available. CCDC 1057094. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra05755h |
This journal is © The Royal Society of Chemistry 2015 |