Next Article in Journal
Rate of Homologous Desensitization and Internalization of the GLP-1 Receptor
Previous Article in Journal
A Multifunctional and Possible Skin UV Protectant, (3R)-5-Hydroxymellein, Produced by an Endolichenic Fungus Isolated from Parmotrema austrosinense
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 22
Issue 1
10.3390/molecules22010024
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Literature Survey and Further Studies on the 3-Alkylation of N-Unprotected 3-Monosubstituted Oxindoles. Practical Synthesis of N-Unprotected 3,3-Disubstituted Oxindoles and Subsequent Transformations on the Aromatic Ring

by
Eszter Kókai
1,2,3,
Gyula Simig
2 and
Balázs Volk
2,*
1
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, P.O.B. 91, 1521 Budapest, Hungary
2
Directorate of Drug Substance Development, Egis Pharmaceuticals PLC., P.O.B. 100, 1475 Budapest, Hungary
3
Department of Materials Technology, GAMF Faculty of Engineering and Computer Science, Pallasz Athéné University, P.O.B. 700, 6001 Kecskemét, Hungary
*
Author to whom correspondence should be addressed.
Molecules 2017, 22(1), 24; https://doi.org/10.3390/molecules22010024
Submission received: 5 November 2016 / Revised: 15 December 2016 / Accepted: 17 December 2016 / Published: 26 December 2016
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
The paper provides a comprehensive review of the base-catalysed C3-alkylation of N-unprotected-3-monosubstituted oxindoles. Based on a few, non-systematic studies described in the literature using butyllithium as the deprotonating agent, an optimized method has now been elaborated, via the corresponding lithium salt, for the selective C3-alkylation of this family of compounds. The optimal excess of butyllithium and alkylating agent, and the role of the halogen atom in the latter (alkyl bromides vs. iodides) were also studied. The alkylation protocol has also been extended to some derivatives substituted at the aromatic ring. Finally, various substituents were introduced into the aromatic ring of the N-unprotected 3,3-dialkyloxindoles obtained by this optimized method.

Graphical Abstract

1. Introduction

The biological activity of 1,3-dihydro-2H-indol-2-one (oxindole (1), Figure 1) derivatives and their structural relationship to indoles render these compounds important targets in medicinal and synthetic organic chemistry. Launched drugs possessing an oxindole skeleton are summarized in Figure 1: the dopamine agonist ropinirole (2) for the treatment of Parkinson’s disease and restless legs syndrome; the atypical antipsychotic ziprasidone (3) and two oncology drugs from the tyrosine kinase inhibitor family, sunitinib (4) and the recently launched nintedanib (5). Several other compounds have reached human Phase III [1], Phase II [2] or Phase I [3] clinical trials, and thousands of further oxindole derivatives are or were studied in preclinical testing in various therapeutic fields.
According to the literature, N-unprotected 3-alkyloxindoles 6 can be prepared by condensation of oxindole (1) with ketones or aromatic aldehydes and subsequent reduction of the primarily formed 3-alkylideneoxindoles, 7. However, in the case of aliphatic aldehydes the yields are low because of aldol-type side reactions [4,5,6]. In order to avoid these difficulties, we disclosed an efficient method for the regioselective synthesis of N-unprotected 3-alkyloxindoles 6, based on the Raney nickel (Ra-Ni) induced 3-alkylation of oxindole (1) with primary and secondary alcohols (Scheme 1) [7,8,9].
This reaction involves a reductive alkylation as the key step: Raney nickel acts as the oxidizing agent in the transformation of the alcohol to the corresponding carbonyl compound, then as the catalyst during the reduction of the in situ-formed 3-alkylideneoxindole.
Next we set ourselves the task to develop an efficient method for the 3-alkylation of N-unprotected 3-alkyloxindoles (8, Scheme 2) to give N-unprotected 3,3-dialkyloxindoles 9.
3-Alkyloxindoles 8 have two regiochemically distinct and easily removable protons (N–H, C3–H), thus rendering possible the formation of N- and C3-alkylated products in a deprotonation-alkylation sequence (i.e. alkylation by nucleophilic substitution). In order to find optimal reaction conditions for the regioselective alkylation of 3-alkyloxindoles 8 we first analyzed the results of systematic studies on the alkylation of oxindole (1) described in the literature.
In a systematic study described by Gruda in 1972 [10], alkylation of oxindole (1) with benzyl chloride was carried out in the presence of sodium bases (NaOEt, NaOH). Besides the 3,3-dibenzyl derivative (9a) as the main product (20.2%), 3-benzyl- (8a), 1,3,3-tribenzyl (10a), 1-benzyl- (11) and 1,3-dibenzyloxindole (12) products (13%, 8.1%, 6.5% and 3.6%, respectively) were isolated by chromatographic separation (Scheme 3). It was demonstrated that, in addition to C-alkylation, N-alkylation also occurred under these conditions.
A protection-deprotection approach was described by Reisch et al. for the synthesis of 3-monosubstituted oxindoles [11]. 3-Acetyloxindole (13), easily available from oxindole (1) [12,13], was alkylated in position 3 in low to moderate yield with various alkyl, alkenyl and alkynyl halides(1.0 eq) in the presence of NaH (1.0 eq) (Scheme 4).
The 3-acetyl protecting group increases the acidity of the C3 position, thereby improving selectivity vs. the N1 atom. 3-Alkyl(alkenyl/ alkynyl)-3-acetyloxindoles 14 thus obtained were then hydrolysed with Na2CO3 in EtOH to give 3-monosubstituted derivatives 8, thus rendering the introduction of a second alkyl group into position 3 possible. However, only one representative of this family was described: 3-propargyloxindole was reacted with 3,3-dimethylallylchloride in the presence of NaOEt to give the disubstituted congener 9b in 45% yield. The low yield of 9b may be due to an incomplete selectivity in this step. Nevertheless, this method has several drawbacks: numerous reaction steps, very long reaction times, chromatographic purifications and low overall yield.
In later studies on the 3-alkylation of 3-monosubstituted oxindoles, sodium hydride (1.0–1.1 eq) was used again as the base in the alkylation reaction of 5-fluoro-3-methyloxindole with 2-bromoethyl methyl ether (1.0 eq, 19% yield after purification by high performance liquid chromatography (HPLC) [14], in the 3-methylation (with 2.9 eq MeI) of 3-arylated 7-fluorooxindole (64% yield, 93% purity) [15], and in the reaction of 3-cyclopropyl- or 3-cyclobutyloxindole with MeI (1.0 eq, chromatographic purification, undisclosed yield) [16]. Thus, sodium bases seem to be unsuitable for the high-yielding selective introduction of a second substituent in position C3.
Potassium bases and cesium carbonate also proved to be disadvantageous in several attempted variants: t-BuOK in DMF [17], t-BuOK in tetrahydrofuran (THF) [18], potassium bis(trimethylsilyl)amide in THF [19], KI-K2CO3 in acetone [20,21], KI-K2CO3 in THF [21], K2CO3 in dimethyl acetamide [22,23], and Cs2CO3 in DMF [24].
Use of a lithium base, first described by Kende et al., proved to be a better approach towards selective C3-alkylation [25], Treatment of oxindole (1) with butyllithium (BuLi, 2.0 eq) in the presence of N,N,N′,N′-tetramethylethylenediamine (TMEDA, 2.0 eq) in THF at −75 °C followed by reaction with various alkyl halides at a temperature between −20 °C and room temperature gave varying yields of the 3-monosubstituted (8, from <20% to 72% yield) and 3,3-disubstituted (9, from <20% to 66% yield) products (Scheme 5), the ratio of which depended also on the excess of alkylating agent and on the reaction conditions. Besides the pleasing lack of N-alkylation, the major drawbacks of this BuLi-TMEDA protocol are the limited mono/di selectivity, the need for chromatographic purification, and the fact that bromides (except for benzyl bromide and ethyl bromoacetate) were unreactive, therefore the corresponding iodides, which are less easily available and more expensive, had to be used. Two examples are given also for the second alkylation in position 3 under the same conditions: 3-butyloxindole was alkylated with iodomethylcyclohexane (74% yield) and 3-benzyloxindole with benzyl bromide (87%). It is noteworthy that omission of TMEDA gave poor results in all these reactions.
As demonstrated above, deprotonation with lithium bases offers a more efficient approach towards selective C3-alkylation than alkali metal bases. Since the first step is the formation of a N,C-dianion, attempts for the selective 3-alkylation of 3-monosubstituted oxindoles 8 with less than 2.0 eq BuLi are always low-yielding. Accordingly, 3-ethylation of 3-methyloxindole (1.0 eq BuLi, 3 eq LiCl, 5.0 eq EtI, THF) [26] or 3-propargylation of 3-ethyloxindole (1.2 eq BuLi, 1.0 eq propargyl bromide, THF) [27] gave, after chromatographic purification, 25% and 55% yields, respectively. Use of 2.0 eq BuLi led to better results: 3-methyloxindole was 3-methylated (2.0 eq BuLi, 9.4 eq MeI) in 75% yield after chromatographic purification [28].
The BuLi-TMEDA protocol described by Kende [25] and its slight modifications (2.0–2.5 eq BuLi, 2.0–3.0 eq TMEDA, 1.0–2.2 eq alkyl iodide, THF, −25 °C or −78 °C → r.t.) have been applied by various research groups for the 3-alkylation of 3-monosubstituted oxindoles 8. Nevertheless, in most cases the yields are not disclosed [16,29,30], or low [31,32,33]. Only a few successful applications are described. 3-Methyl-6-methoxyoxindole was 3-methylated with methyl iodide (MeI, 82% yield after flash chromatography) under similar conditions [34]. Instead of alkyl iodides, Jiang et al. used ethyl 2-bromoacetate as the alkylating agent with 60% yield [35].
Our comprehensive literature search did not reveal further systematic studies (other than those demonstrated in Scheme 3, Scheme 4 and Scheme 5) on the synthesis of N-unprotected 3,3-disubstituted oxindoles 9 starting from 3-monosubstituted oxindoles (8). As shown above, due to the biological importance of oxindole derivatives, several research groups applied the above alkylation reactions for the introduction of a second substituent in position 3 of a 3-monosubstituted oxindole 8, albeit, in quite an erratic way.
In the course of our earlier medicinal chemistry studies, selective C3‑alkylation of a small number of 3-alkyloxindole derivatives 8 using α,ω‑dihaloalkanes (2.5 eq) was successfully carried out after deprotonation with BuLi (2.5 eq), resulting in 3-alkyl-3-(ω-haloalkyl)oxindole intermediates (15, Scheme 6) [36,37].
For the sake of completeness it is worth mentioning that, due to the ambident nucleophile character of oxindoles, deprotonation and alkylation can take place not only on C3 or N1, but also on the O2 atom. To the best of our knowledge, C,O- or C,N-dialkylations are not described. On the other hand, selective O-alkylation can take place under certain conditions, although the occurrence of this reaction in the scientific literature is very rare. It can only be carried out using special alkylating agents, e.g., trialkyloxonium tetrafluoroborates [38,39,40,41,42,43,44,45,46].
Apart from regioselectivity issues, a further difficulty during the alkylation of oxindole derivarives is caused by the observation that position 3 of 3-monoalkyloxindoles 8 is prone to oxidation under basic conditions. Bai et al. described the synthesis of a wide range of 1-acetyl-3-hydroxy-3-phenacyloxindole derivatives 16 starting from 1-acetyloxindole (17, Scheme 7) and α-tosyloxyacetophenone (18, R=Ph, X=OTs) in an open vial [47]. In a control experiment, the reaction of 17 and α-tosyloxyacetophenone was carried out under nitrogen atmosphere for 8 h, and the 3-monosubstituted oxindole 19 was obtained (yield is not disclosed). Then the reaction was continued (8 h) by opening the flask, leading to the formation of 3-hydroxy derivative 16, presumably via the corresponding hydroperoxide, the presence of which was proved by electrospray ionization mass spectrometry (ESI-MS). Since the key factor of the suppression of side reactions is the exclusion of atmospheric oxygen, the reductive method elaborated by our research group (Scheme 1) [9] for the synthesis of 3-monoalkyloxindoles 8 is particularly advantageous.

2. Results and Discussion

In the present work we set ourselves the task to carry out a deeper study on the scope and limitations of the deprotonation of 3-monosubstituted oxindoles with BuLi and subsequent alkylation. The advantages of using lithium bases (alkyllithiums, lithium dialkylamides) instead of other alkali metal bases in C-alkylation reactions for deprotonation of C-H acids (e.g., ketones, esters, amides) is well documented [48]. Lithium cation, as the smallest alkali metal ion has a stronger tendency to form O–Li and N–Li bonds with increased covalent character [49], thus inhibiting undesirable O- and N-alkylations. 3-Monosubstituted oxindoles 8, optionally substituted on the aromatic ring, as the starting materials of the present study were synthesized from the corresponding isatins [50].
Based on the lithiation-alkylation protocol using BuLi (2.5 eq) and α,ω-dihaloalkanes (2.5 eq) described earlier [36,37], we now aimed at the optimization and application of this method to alkylation with alkyl halides. First, 3-ethyloxindole (8b, Scheme 8) was used as the model compound for the introduction of a second alkyl group. Despite the complete regioselectivity found in our earlier studies with α,ω-dibromo- and- α-bromo-ω-chloroalkanes [36,37], reaction of 8b with BuLi (2.5 eq) and MeI (2.5 eq) led to a mixture (Table 1, entry 1) of 3-ethyl-3-methyloxindole (9c, 28%) and 3-ethyl-1,3-dimethyloxindole (20a, 55%).
This finding is particularly surprising in the light of the paper of Kende et al. that does not describe N-alkylation side-reactions with alkyl iodides [25]. When using decreased excesses of the reagents (2.2 eq BuLi, 1.2 eq MeI), 3,3-dialkyl product 9c was obtained in 71% yield, while the formation of 1,3,3-trialkyl derivative 20a could not be detected (entry 2). Unexpectedly, alkylation of 8b occurred regioselectively even with 2.5 eq of EtI (73%, entry 3). Change of EtI (2.5 eq) to EtBr (1.2 eq) led to even better results (90%, entry 4), and the reaction was also performed with BnBr (80%, entry 5). Extension of the ethylation (with 1.2 eq EtBr) to derivatives 8b–e substituted on the aromatic ring was also successful (entries 6–8).
Reactions of 3-isopropyloxindole (8f) gave similar results. Alkylation with 2.5 eq MeI was not regioselective, and led to a mixture of 3-isopropyl-3-methyloxindole (9i, 40%, Table 1 entry 9) and 3-isopropyl-1,3-dimethyloxindole (20b, 35%), but use of 1.2 eq MeI afforded uniformly 9i (entry 10). 3-Alkylations could be carried out in a regioselective manner with 1.2 eq EtBr and 1.2 eq BnBr to give the corresponding 3-ethyl (9j) and 3-benzyl (9k) derivatives in 65% and 63% yields, respectively (entries 11–12).
In order to study the role of TMEDA (applied by Kende et al. during the 3-alkylation reactions of oxindole, 1) [25], a control experiment (analogous to that shown in entry 4 of Table 1) was performed with BuLi/TMEDA (2.2/2.2 eq) using 3-ethyloxindole (8b) as the starting material and ethyl bromide (1.2 eq) as the alkylating agent. The reaction gave practically the same yield (88% vs. 90%) therefore, considering also that the elimination of TMEDA necessitates extra steps during the work-up of the reaction mixture, it was not applied in our standard alkylation protocol.
The reactions summarized in Table 1 were strictly performed under inert atmosphere. Prior to the reactions, the flask was made inert by using three consecutive vacuum–argon cycles, and an argon atmosphere was maintained until quenching the reaction. However, during the first series of experiments where a less strict pre-inertization was used, significant amounts of the 3-hydroxy side products were isolated. When starting from 3-isopropyloxindole (8f), the alkylation using 2.5 eq BuLi and 2.5 eq EtBr provided, after work-up a significant amount (23%) of 3-hydroxy-3-isopropyloxindole (21a, Scheme 9), besides the expected 3-ethyl-3-isopropyloxindole (9i, 36%).
The targeted synthesis of the 3-hydroxy derivatives 21a,b was carried out with BuLi (2.5 eq) without alkylating agent and under non-inert conditions with good yields (Scheme 10). The presence of the hydroxy moiety in products 21a,b renders further functionalizations possible thereby making these compounds valuable synthetic building blocks.
As demonstrated among others by two marketed drugs, ziprasidone (3) and sunitinib (4), and some further drug candidates [51], substitution at position 5 of the aromatic ring is of importance in the oxindole family. A possible approach for the synthesis of 5-substituted 3,3-dialkyloxindoles is 3-alkylation of a 5-subsituted 3-monoalkyloxindole. Nevertheless, several moieties (e.g., Br, NO2, ortho-directing groups, etc.) can be incompatible with BuLi-mediated 3-alkylation. Therefore, aromatic substitution reactions were carried out, starting from 3,3-diethyloxindole (9d) as the model compound (Scheme 11). Moreover, further modifications of the primarily obtained compounds 9l–o have also been envisaged.
First, reaction of 9d with sulfuryl chloride in glacial acetic acid at 10–15 °C was carried out to give the 5-chloro congener 9l in 73% yield (Table 2, entry 1). Bromination of 9d was performed with bromine and KBr in aqueous dioxane at 90 °C to give 5-bromo derivative 9m (entry 2) in almost quantitative yield. Nitration of 9d in a mixture of concentrated sulfuric acid and concentrated nitric acid at 0 °C (entry 3) led to 3,3-diethyl-5-nitrooxindole 9n, which was reduced by catalytic hydrogenation on palladium on charcoal to 5-amino derivative 9p. Treatment of starting material 9d with sulfurochloridic acid afforded 5-chlorosulfonyl derivative 9o in 98% yield (entries 4–6). This latter was reacted with ammonia (entry 4), tert-butylamine (entry 5) or morpholine (entry 6) to give the corresponding aromatic sulfonamides 9q–s.
Reaction of 3,3-diethyloxindole (9d) with sulfuryl chloride in glacial acetic acid at 10–15 °C led to selective 5-chlorination. However, at elevated temperatures (60–80 °C), in accordance with our earlier observations with 3-ethyl-3-(ω-haloalkyl)oxindoles 15 [36,37], the 5,7-dichloro derivative 9t was obtained (Scheme 12). Similar chlorination of 3,3-diethyl-6-fluorooxindole 9g resulted in 5,7-dichloro-3,3-diethyl-6-fluorooxindole (9u).

3. Experimental Section

3.1. General Information

All melting points were determined on a Büchi 535 capillary melting point apparatus (Büchi, Flawil, Switzerland) and on an OptiMelt Automated Melting Point System by Stanford Research Systems (Sunnyvale, CA, USA). IR spectra were obtained on a IFS-113v FT spectrometer (Bruker, Billerica, MA, USA). 1H-NMR and 13C-NMR spectra were recorded on a Bruker Avance III (400 and 100 MHz for 1H- and 13C-NMR spectra, respectively) or a Bruker Avance III HD 600 (600 and 150 MHz for 1H and 13C-NMR spectra, respectively) spectrometer (Bruker, Billerica, MA, USA). CDCl3, DMSO-d6 or CD3CN was used as the solvent and tetramethylsilane (TMS) as internal standard. Chemical shifts (δ) and coupling constants (J) are given in ppm and in Hz, respectively. The electron ionization (EI) mass spectra were recorded on a Clarus 560 D mass spectrometer coupled with a Clarus 500 gas chromatograph (Perkin-Elmer, Waltham, MA, USA). The ESI+ mass spectra (MS) were recorded on a LTQ XL mass spectrometer (Thermo Fisher, Waltham, MA, USA) coupled with an AcquityTM UPLC (Waters, Milford, MA, USA). Elemental analyses (EA) were performed on a 2400 analyzer (Perkin-Elmer, Waltham, MA, USA) on a VARIO EL III Model CHN elemental analyzer (Elementar, Langenselbold, Germany) or on an Elementar Vario MICRO cube (CHNS) elemental analyzer (Elementar, Langenselbold, Germany). The chloride and bromide contents were determined by titration. The reactions were followed by analytical thin layer chromatography on silica gel 60 F254 (Merck, Darmstadt, Germany). All unspecified reagents were purchased from commercial sources. Compounds 9a–b, 9d, 20a–b, 21a are known in the literature. Compounds 9c, 9m, 9n, 9p, 21b are mentioned but poorly characterized in the literature, therefore their full characterization is given below. Compounds 9e–l, 9o, 9q–u are new and characterized below.

3.2. General Procedure I for the Synthesis of Compounds 9c–h (and By-Product 20a)

To a mixture of butyllithium in hexane (2.2–2.5 eq, 1.6 M) and THF, the solution of the appropriate 3-alkyloxindole 8b–e in THF was added dropwise at −78 °C under argon atmosphere. Then the appropriate alkyl halide (1.2–2.5 eq) in THF was added dropwise, the acetone-dry ice bath was removed and the reaction mixture was allowed to warm to room temperature. The stirring was continued for further 4 h, the mixture was quenched with ethanol (EtOH) and the solvents were evaporated. The residue crystallized upon treatment with water. It was triturated in water, filtered, washed with water until the pH was adjusted to 7, then washed twice with diisopropyl ether (DIPE) and dried. Analytical samples were obtained by recrystallization from the indicated solvents.
3-Ethyl-3-methyl-1,3-dihydro-2H-indol-2-one (9c) [52]. Method A: This compound was prepared according to the general procedure I using BuLi (4.26 mL, 6.82 mmol, 2.2 eq) in THF (3 mL), 8b (500 mg, 3.10 mmol) dissolved in THF (4 mL), and MeI (232 µL, 528 mg, 3.72 mmol, 2.2 eq) in THF (2 mL). The reaction was quenched with EtOH (1 mL). The product 9c was obtained as pale yellow crystals (386 mg, 71%), m.p. 143–144 °C (hexane-EtOAc), lit. [52] m.p. 143–145 °C. 1H-NMR (600 MHz, CDCl3) δ 8.32 (br s, 1H), 7.21 (dt, J = 7.6, 1.1 Hz, 1H), 7.16 (d, J = 7.3 Hz, 1H), 7.05 (dt, J = 7.5, 0.9 Hz, 1H), 6.92 (dt, J = 7.5, 0.9 Hz, 1H), 1.96–1.93 (m, 1H), 1.81–1.76 (m, 1H), 1.39 (s, 3H), 0.65 (t, J = 7.4 Hz, 3H). 13C-NMR (150 MHz, CDCl3) δ 183.1, 140.5, 134.3, 127.6, 122.9, 122.4, 109.6, 49.4, 31.4, 23.4, 8.9. IR (KBr) ν 1710, 1618 cm−1. MS (ESI): 176.01 [M + H]+. EA Calcd. for C11H13NO (175.23): C, 75.40%; H, 7.48%; N, 7.99%. Found: C, 75.69%; H, 7.36%; N, 7.96%. Method B: This compound was prepared according to the general procedure I using BuLi (4.84 mL, 7.75 mmol, 2.5 eq) in THF (4 mL), 8b (500 mg, 3.10 mmol) dissolved in THF (4 mL), and MeI (0.48 mL, 1.10 g, 7.75 mmol, 2.5 eq) in THF (2 mL). The reaction was quenched with EtOH (2 mL). The residual oil was purified by gradient elution column chromatography using hexane and ethyl acetate (EtOAc) as the eluents to give 9c (150 mg, 28%) as colorless crystals.
3-Ethyl-1,3-dimethyl-1,3-dihydro-2H-indol-2-one (20a) [53]. This compound was prepared according to the general procedure I using BuLi (4.84 mL, 7.75 mmol, 2.5 eq) in THF (4 mL), 8b (500 mg, 3.10 mmol) dissolved in THF (4 mL), and MeI (0.48 mL, 1.10 g, 7.75 mmol, 2.5 eq) in THF (2 mL). The reaction was quenched with EtOH (2 mL). The residual oil was purified by gradient elution column chromatography using hexane and EtOAc as the eluents to give 20a (320 mg, 1.69 mmol, 55%) as a yellow oil.
3,3-Diethyl-1,3-dihydro-2H-indol-2-one (9d) [54]. Method A: This compound was prepared according to the general procedure I using BuLi (9.70 mL, 15.50 mmol, 2.5 eq) in THF (10 mL), 8b (1.00 g, 6.20 mmol) dissolved in THF (8 mL), and ethyl iodide (1.25 mL, 2.71 g, 15.50 mmol, 2.5 eq) in THF (3 mL). The reaction was quenched with EtOH (2 mL). The product 9d was obtained as colorless crystals (855 mg, 73%), m.p. 158–159 °C (hexane–EtOAc), lit. [54] m.p. 166–168 °C. Method B: This compound was prepared according to the general procedure I using BuLi (344 mL, 0.55 mol, 2.2 eq) in THF (100 mL), 8b (40.25 g, 0.25 mol) dissolved in THF (300 mL), and ethyl bromide (22.40 mL, 32.69 g, 0.30 mol, 1.2 eq) in THF (50 mL). The reaction was quenched with EtOH (20 mL). The product 9d was obtained as colorless crystals (42.60 g, 90%).
3-Benzyl-3-ethyl-1,3-dihydro-2H-indol-2-one (9e). This compound was prepared according to the general procedure I using BuLi (4.26 mL, 6.82 mmol, 2.2 eq) in THF (3 mL), 8b (500 mg, 3.10 mmol) dissolved in THF (4 mL), and benzyl bromide (442 µL, 636 mg, 3.72 mmol, 1.2 eq) in THF (2 mL). The reaction was quenched with EtOH (1 mL). The product 9e was obtained as colorless crystals (626 mg, 80%), m.p. 124–125 °C (hexane–EtOAc). 1H-NMR (400 MHz, CDCl3) δ 7.66 (br s, 1H), 7.15–7.11 (m, 2H), 7.05–7.01 (m, 4H), 6.90–6.87 (m, 2H), 6.69–6.67 (m, 1H), 3.13 (d, J = 13.04 Hz, 1H), 3.04 (d, J = 13.05 Hz, 1H), 2.12–2.07 (m, 1H), 1.94–1.89 (m, 1H), 0.66 (t, J = 7.4 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δ 181.1, 141.0, 136.0, 131.4, 130.0, 127.7, 127.6, 126.4, 123.9, 122.0, 109.3, 55.7, 43.8, 30.5, 8.7. IR (KBr) ν 1717, 1474 cm−1. MS (ESI): 252.14 [M + H]+. EA Calcd. for C17H17NO (251.33): C, 81.24%; H, 6.82%; N, 5.57%. Found: C, 80.88%; H, 6.78%; N, 5.57%.
3,3-Diethyl-5-methyl-1,3-dihydro-2H-indol-2-one (9f). This compound was prepared according to the general procedure I using BuLi (8.25 mL, 13.20 mmol, 2.2 eq) in THF (5 mL), 8c (1.05 mg, 6.00 mmol) dissolved in THF (7 mL), and ethyl bromide (537 µL, 784 mg, 7.20 mmol, 1.2 eq) in THF (4 mL). The reaction was quenched with EtOH (2 mL). The product 9f was obtained as colorless crystals (930 mg, 76%), m.p. 155–156 °C (hexane–EtOAc). 1H-NMR (400 MHz, CDCl3) δ 9.53 (br s, 1H), 6.99 (dd, J = 7.9, 1.0 Hz, 1H), 6.92 (s, 1H), 6.84 (d, J = 7.8 Hz, 1H), 2.33 (s, 3H), 1.96–1.82 (m, 2H), 1.81–1.75 (m, 2H), 0.64 (t, J = 7.4 Hz, 6H). 13C-NMR (100 MHz, CDCl3) δ 183.3, 139.3, 132.4, 131.5, 127.8, 123.6, 109.3, 54.9, 30.6, 21.1, 8.6. IR (KBr) ν 3170, 1695 cm−1. MS (EI): 203 [M], 175, 174, 156, 146, 130. EA Calcd. for C13H17NO (203.29): C, 76.81%; H, 8.43%; N, 6.89%. Found: C, 76.95%; H, 8.24%; N, 7.06%.
3,3-Diethyl-6-fluoro-1,3-dihydro-2H-indol-2-one (9g). This compound was prepared according to the general procedure I using BuLi (46.06 mL, 73.70 mmol, 2.2 eq) in THF (30 mL), 8d (6.00 g, 33.50 mmol) dissolved in THF (45 mL), and ethyl bromide (3.00 mL, 4.38 g, 40.20 mmol, 1.2 eq) in THF (10 mL). The reaction was quenched with EtOH (12 mL). The product 9g was obtained as colorless crystals (5.31 g, 77%), m.p. 149–151 °C (hexane–EtOAc). 1H-NMR (400 MHz, CDCl3) δ 8.84 (br s, 1H), 7.04 (dd, J = 8.2, 5.3 Hz, 1H), 6.74 (ddd, J = 9.6, 8.2, 2.4 Hz, 1H), 6.69 (dd, J = 8.8, 2.4 Hz, 1H), 1.97–1.88 (m, 2H), 1.83–1.73 (m, 2H), 0.64 (t, J = 7.4 Hz, 6H). 13C-NMR (100 MHz, CDCl3) δ 183.1, 162.4 (d, J = 243.8 Hz), 142.6 (d, J = 11.8 Hz), 127.7, 123.9 (d, J = 9.5 Hz), 108.6 (d, J = 22.1 Hz), 98.2 (d, J = 27.5 Hz), 54.6, 30.6, 8.6. IR (KBr) ν 3128, 1722, 1140 cm−1. MS (EI): 207 [M], 178, 160, 150, 135, 108. EA Calcd. for C12H14FNO (207.25): C, 69.55%; H, 6.81%; N, 6.76%. Found: C, 69.19%; H, 6.99%; N, 6.92%.
3,3-Diethyl-7-methyl-1,3-dihydro-2H-indol-2-one (9h). This compound was prepared according to the general procedure I using BuLi (3.92 mL, 6.28 mmol, 2.2 eq) in THF (2 mL), 8e (500 mg, 2.85 mmol) dissolved in THF (9 mL), and ethyl bromide (255 µL, 373 mg, 3.42 mmol, 1.2 eq) in THF (2 mL). The reaction was quenched with EtOH (1 mL). The product 9h was obtained as colorless crystals (380 mg, 66%), m.p. 120–121 °C (hexane). 1H-NMR (400 MHz, CDCl3) δ 8.21 (br s, 1H), 7.03–7.01 (m, 1H), 6.99–6.94 (m, 2H), 2.28 (s, 3H), 1.97–1.88 (m, 2H), 1.83–1.74 (m, 2H), 0.63 (t, J = 7.4 Hz, 6H). 13C-NMR (100 MHz, CDCl3) δ 182.4, 140.0, 132.0, 128.9, 122.3, 120.5, 118.4, 55.1, 30.7, 16.5, 8.7. IR (KBr) ν 2966, 1698 cm−1. MS (EI): 203 [M], 175, 174, 156, 146, 130, 115. EA Calcd. for C13H17NO (203.29): C, 76.81; H, 8.43; N, 6.89%. Found: C, 76.87; H, 8.33; N, 7.07%.

3.3. General Procedure II for the Synthesis of Compounds 9i–k (and By-Product 20b)

To a mixture of BuLi in hexane (2.2–2.5 eq, 1.6 M) and THF, the solution of 3-isopropyloxindole (8f) in THF was added dropwise at −78 °C, under argon atmosphere. Then the appropriate alkyl halide (1.2–2.5 eq) in THF was added dropwise, the acetone-dry ice bath was removed and the reaction mixture was allowed to warm to room temperature. The stirring was continued for further 4–6 h. The mixture was quenched with EtOH (2 mL), saturated ammonium chloride solution (10 mL) was added, then it was stirred for 30 min. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous MgSO4, filtered and the solvent was removed in vacuo at 40 °C. The residue crystallized upon treatment with hexane (5 mL), then it was filtered. Analytical samples were obtained by recrystallization from the indicated solvents.
3-Isopropyl-3-methyl-1,3-dihydro-2H-indol-2-one (9i). Method A: This compound was prepared according to the general procedure II using BuLi (4.46 mL, 7.13 mmol, 2.5 eq) in THF (2 mL), 8f (500 mg, 2.85 mmol) dissolved in THF (6 mL), and MeI (213 µL, 485 mg, 3.42 mmol, 1.2 eq) in THF (2 mL). The product 9i was obtained as colorless crystals (300 mg, 56%), m.p. 126–127 °C (hexane–EtOAc). 1H-NMR (600 MHz, CDCl3) δ 8.08 (br s, 1H), 7.26–7.18 (m, 2H), 7.02 (dt, J = 7.6, 1.0 Hz, 1H), 6.90 (d, J = 7.7 Hz, 1H), 2.13 (sp, J = 6.7 Hz, 1H), 1.40 (s, 3H), 1.02 (d, J = 7.0 Hz, 3H), 0.79 (d, J = 7.7 Hz, 3H). 13C-NMR (150 MHz, CDCl3) δ 183.0, 140.5, 133.5, 127.5, 123.8, 122.1, 109.4, 52.0, 35.4, 21.5, 17.5, 17.1. IR (KBr) ν 3185, 1717, 1670 cm−1. MS (ESI): 190.06 [M + H]+. EA Calcd. for C12H15NO (189.26): C, 76.16; H, 7.99; N, 7.40%. Found: C, 75.89; H, 7.72; N, 7.61%. Method B: This compound was prepared according to the general procedure II using BuLi (4.46 mL, 7.13 mmol, 2.5 eq) in THF (2 mL), 8f (500 mg, 2.85 mmol) dissolved in THF (6 mL), and MeI (444 µL, 1012 mg, 7.13 mmol, 2.5 eq) in THF (2 mL). The residual oil was purified by gradient elution column chromatography using hexane and EtOAc as the eluents to give 9i (216 mg, 40%) as colorless crystals.
3-Isopropyl-1,3-dimethyl-1,3-dihydro-2H-indol-2-one (20b) [55]. This compound was prepared according to the general procedure II using BuLi (4.46 mL, 7.13 mmol, 2.5 eq) in THF (2 mL), 8f (500 mg, 2.85 mmol) dissolved in THF (6 mL), and MeI (444 µL, 1012 mg, 7.13 mmol, 2.5 eq) in THF (2 mL). The residual oil was purified by gradient elution column chromatography using hexane and EtOAc as the eluents to give 20b (200 mg, 35%) as yellow oil, lit. [55] m.p. 54 °C. Spectral data are identical with those described in the literature [55].
3-Ethyl-3-isopropyl-1,3-dihydro-2H-indol-2-one (9j). This compound was prepared according to the general procedure II using BuLi (7.85 mL, 12.55 mmol, 2.2 eq) in THF (8 mL), 8f (1.00 g, 5.70 mmol) dissolved in THF (12 mL), and ethyl bromide (0.51 mL, 0.75 g, 6.84 mmol, 1.2 eq) in THF (2 mL). The product 9j was obtained as colorless crystals (0.76 mg, 65%), m.p. 103–104 °C (hexane). 1H-NMR (600 MHz, CDCl3) δ 8.54 (br s, 1H), 7.20 (dt, J = 7.6, 1.2 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 7.03 (dt, J = 7.5, 1.0 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 2.15 (sp, J = 6.8 Hz, 1H), 1.93 (q, J = 7.3 Hz, 2H), 1.01 (d, J = 7.0 Hz, 3H), 0.77 (d, J = 6.8 Hz, 3H), 0.60 (t, J = 7.4 Hz, 3H). 13C-NMR (150 MHz, CDCl3) δ 182.6, 141.6, 131.5, 127.5, 123.9, 122.0, 109.3, 57.6, 35.1, 28.2, 17.5, 17.2, 8.8. IR (KBr) ν 3164, 1717, 1668 cm−1. MS (ESI): 204.06 [M + H]+. EA Calcd. for C13H17NO (203.29): C, 76.81%; H, 8.43%; N, 6.89%. Found: C, 76.91%; H, 8.08%; N, 7.02%.
3-Benzyl-3-isopropyl-1,3-dihydro-2H-indol-2-one (9k). This compound was prepared according to the general procedure II using BuLi (7.85 mL, 12.55 mmol, 2.2 eq) in THF (8 mL), 8f (1.00 g, 5.70 mmol) dissolved in THF (12 mL), and benzyl bromide (0.81 mL, 1.17 g, 6.84 mmol, 1.2 eq) in THF (2 mL). The product 9k was obtained as colorless crystals (0.95 g, 63%), m.p. 133–134 °C (hexane–EtOAc). 1H-NMR (400 MHz, CDCl3) δ 7.38 (br s, 1H), 7.31 (d, J = 6.7 Hz, 1H), 7.12 (dt, J = 7.7, 1.2 Hz, 1H), 7.05–6.97 (m, 4H), 6.83 (dd, J = 7.4, 1.4 Hz, 2H), 6.61 (d, J = 7.7 Hz, 1H), 3.20 (d, J = 13.0 Hz, 1H), 3.17 (d, J = 13.0 Hz, 1H), 2.37 (sp, J = 6.8 Hz, 1H), 1.12 (d, J = 6.9 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H). 13C-NMR (150 MHz, CDCl3) δ 180.8, 141.1, 136.4, 130.7, 129.9, 127.6, 127.5, 126.2, 124.6, 121.8, 109.1, 58.6, 41.5, 35.5, 17.8, 17.4. IR (KBr) ν 3299, 1716, 1678 cm−1. MS (ESI): 266.16 [M + H]+. EA Calcd. for C18H19NO (235.36): C, 81.47%; H, 7.22%; N, 5.28%. Found: C, 81.26%; H, 7.16%; N, 5.25%.

3.4. General Procedure III for the Synthesis of Compounds 21

To a mixture of BuLi in hexane (4.45 mL, 7.13 mmol, 1.6 M) and THF (4.00 mL), the solution of the appropriate 3-alkyloxindole 8b or 8f (2.85 mmol) in THF (2 mL) was added dropwise at −78 °C, under argon atmosphere. The acetone-dry ice bath was removed, the reaction mixture was allowed to warm to room temperature and the apparatus was opened to the air. The stirring was continued for further 2 h, then the solvent was evaporated. The residue was taken up in water and extracted with EtOAc (3 × 15 mL). The organic layer was dried over MgSO4 and evaporated. The solid residue was triturated in DCM (2 mL). The white solid was filtered and dried. Analytical samples were obtained by recrystallization from the mixture of hexane–EtOAc.
3-Hydroxy-3-isopropyl-1,3-dihydro-2H-indol-2-one (21a) [56]. This compound was prepared according to the general procedure III. The product 21a was obtained as colorless crystals (513 mg, 94%), m.p. 170–172 °C (hexane–EtOAc), lit. [56] m.p. 45–50 °C. 1H-NMR (400 MHz, DMSO-d6) δ 10.21 (br s, 1H), 7.23–7.18 (m, 2H), 6.95 (dt, J = 8.5, 1.0 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 5.77 (br s, 1H), 2.06 (sp, J = 6.9 Hz, 1H), 0.96 (d, J = 6.9 Hz, 3H), 0.63 (d, J = 6.8 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6) δ 179.7, 142.4, 130.8, 128.9, 124.8, 121.5, 109.5, 78.5, 35.0, 16.4, 16.0. IR (KBr) ν 3350, 1702 cm−1. MS (ESI): 191.88 [M + H]+. Anal. Calcd. for C11H13NO2 (191.23): C, 69.09%; H, 6.85%; N, 7.32%. Found: C, 68.99%; H, 6.62%; N, 7.42%.
3-Ethyl-3-hydroxy-1,3-dihydro-2H-indol-2-one (21b) [57]. This compound was prepared according to the general procedure III. The product 21b was obtained as colorless crystals (369 mg, 73%), m.p. 124–125 °C (hexane–EtOAc), lit. [48] m.p. 115–116 °C.
5-Chloro-3,3-diethyl-1,3-dihydro-2H-indol-2-one (9l). To a solution of 9d (1.89 g, 10.00 mmol) in acetic acid (20 mL), sulfuryl chloride (1.62 mL, 2.69 g, 20.00 mmol) was added dropwise at 10–15 °C. The reaction mixture was stirred at 10 °C for 3 hours. The reaction mixture was poured onto ice-water (50 g) and stirred for one hour. The precipitate was filtered off, and washed with water until the pH was adjusted to 7. The crude product 9l (2.09 g, 93%) was recrystallized from hexane–EtOAc to give 9l (1.64 g, 73%) as colorless crystals, m.p. 166–167 °C (hexane–EtOAc). 1H-NMR (400 MHz, CDCl3) δ 9.33 (br s, 1H), 7.19 (dd, J = 8.2, 2.1 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 1.97–1.89 (m, 2H), 1.84–1.76 (m, 2H), 0.65 (t, J = 7.4 Hz, 6H). 13C-NMR (100 MHz, CDCl3) δ 182.7, 140.2, 134.3, 127.8, 127.6, 123.4, 110.6, 55.4, 30.6, 8.6. IR (KBr) ν 3133, 1717 cm−1. MS (EI): 223 [M], 195, 194, 166, 159. EA Calcd. for C12H14ClNO (223.70): C, 64.43%; H, 6.31%; N, 7.32%; Cl, 15.85%. Found: C, 64.37%; H, 6.32%; N, 6.21%; Cl, 15.56%.
5-Bromo-3,3-diethyl-1,3-dihydro-2H-indol-2-one (9m) [32]. To a solution of 9d (0.95 g, 5.00 mmol) in dioxane–water (10 mL–5 mL), a mixture of bromine (0.26 mL, 0.80 g, 5.00 mmol) and potassium bromide (1.19 g, 10.00 mmol) in water (10 mL) was added dropwise at 90 °C. After 10 min, water (5 mL) was added dropwise at 90 °C and crystals were precipitated. The reaction mixture was cooled with an ice bath, filtered off and washed with water and hexane. The product 9m was obtained as colorless crystals (1.26 g, 94%), m.p. 165–166 °C (hexane–EtOAc), lit. [32] m.p. 164–165 °C. 1H-NMR (400 MHz, CDCl3) δ 8.76 (br s, 1H), 7.32 (dd, J = 8.2, 2.0 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 1.96–1.86 (m, 2H), 1.81–1.71 (m, 2H), 0.63 (t, J = 7.4 Hz, 6H). 13C-NMR (100 MHz, CDCl3) δ 182.6, 140.7, 134.7, 130.5, 126.2, 115.1, 111.2, 55.4, 30.6, 8.6. IR (KBr) ν 3133, 1719, 1203, 812 cm−1. MS (EI): 267 [M], 239, 160, 159. EA Calcd. for C12H14BrNO (268.15): C, 53.75%; H, 5.26%; N, 5.22%; Br, 29.80%. Found: C, 54.00%; H, 5.40%; N, 5.11%; Cl, 29.37%.
3,3-Diethyl-5-nitro-1,3-dihydro-2H-indol-2-one (9n) [5]. To a solution of 9d (11.06 g, 61.0 mmol) in cc. sulfuric acid (200 mL, 368 g, 3.75 mol), cc. nitric acid (2.6 mL, 3.93 g, 62.0 mmol) was added dropwise at 0 °C, the stirring was continued at room temperature for 2 hours. The precipitate was filtered off, washed with water until the pH was adjusted to 7 and dried. The product 9n was obtained as pale brown crystals (12.40 g, 85%), m.p. 174–176 °C (EtOAc), lit. [5] m.p. 174–176 °C. 1H-NMR (400 MHz, DMSO-d6) δ 11.08 (br s, 1H), 8.20–8.14 (m, 2H), 7.05–7.03 (m, 1H), 1.94–1.89 (m, 2H), 1.79–1.73 (m, 2H), 0.51 (t, J = 7.4 Hz, 6H). 13C-NMR (100 MHz, DMSO-d6) δ 181.3, 149.4, 142.5, 133.3, 125.4, 119.1, 109.3, 54.4, 29.8, 8.6. IR (KBr) ν 1729, 1340 cm−1. MS (ESI): 233.15 (M − H)−. EA Calcd. for C12H14N2O3 (234.26): C, 61.53%; H, 6.02%; N, 11.96%. Found: C, 61.18%; H, 5.93%; N, 12.01%.
3,3-Diethyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl chloride (9o). To sulfurochloridic acid (20 mL, 35.0 g, 300.0 mmol), 9d (4.75 g, 25.0 mmol) was added at 15–20 °C, then the reaction mixture was heated at 60 °C for one hour. After cooling to room temperature the reaction mixture was added dropwise to ice. The precipitate was filtered off, washed with water until the pH was adjusted to 7, then it was washed with hexane and dried. The product 9o was obtained as off-white crystals (6.62 g, 98%), m.p. 186–188 °C (EtOAc). 1H-NMR (600 MHz, CDCl3) δ 9.09 (br s, 1H), 7.98 (dd, J = 8.4, 2.0 Hz, 1H), 7.78 (d, J = 1.9 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 2.04–1.98 (m, 2H), 1.93–1.77 (m, 2H), 0.68 (t, J = 7.4 Hz, 6H). 13C-NMR (150 MHz, CDCl3) δ 182.3, 147.7, 138.3, 134.0, 128.7, 122.0, 109.8, 55.3, 30.5, 8.7. IR (KBr) ν 1729, 1366, 1175 cm−1. MS (EI): 287 [M], 259, 189, 161, 160, 159, 132, 130. EA Calcd. for C12H14ClNO3S (287.76): C, 50.09%; H, 4.90%; N, 4.87%; S, 11.14%; Cl, 12.32%. Found: C, 49.98%; H, 4.93%; N, 4.82%; S, 10.86%; Cl, 12.15%.
5-Amino-3,3-diethyl-1,3-dihydro-2H-indol-2-one (9p) [5]. To a solution of 9n (800 mg, 3.42 mmol) in methanol (10 mL), activated palladium on charcoal (95 mg, 0.80 mmol, 10%) was added and the reaction mixture was placed into an autoclave (volume 70 mL). It was flushed with nitrogen, charged with hydrogen (20 bar) and heated to 70 °C while stirring. After 7 h the mixture was cooled to room temperature, filtered and the solvent was evaporated in vacuo. The residue was triturated in hexane, filtered off and dried. The product 9p was obtained as off-white crystals (610 mg, 87%), m.p. 189–190 °C (EtOH), lit. [5] m.p. 188–190 °C. 1H-NMR (400 MHz, DMSO-d6) δ 9.89 (br s, 1H), 6.52 (d, J = 8.1 Hz, 1H), 6.44 (d, J = 2.2 Hz, 1H), 6.38 (dd, J = 8.1, 2.2 Hz, 1H), 4.66 (br s, 2H), 1.69–1.58 (m, 4H), 0.51 (t, J = 7.3 Hz, 6H). 13C-NMR (100 MHz, DMSO-d6) δ 180.3, 143.7, 132.9, 132.6, 112.7, 110.1, 109.4, 54.1, 30.2, 8.8. IR (KBr) ν 2963, 1684, 1496 cm−1. MS: 204 (M), 175, 157, 147, 132. EA Calcd. for C12H16N2O (204.27): C, 70.56%; H, 7.90%; N, 13.71%. Found: C, 70.05%; H, 7.68%; N, 13.65%.
3,3-Diethyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide (9q). To a solution of 9o (1.35 g, 5.00 mmol) in EtOH (50 mL), ammonium hydroxide solution (5 mL, 74.0 mmol, 25 w/w%) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for one hour. The volatile compounds were removed in vacuo and the crude product was recrystallized from acetic acid (25 mL) to give 9q (0.80 g, 60%) as pale yellow crystals, m.p. 189–190 °C (EtOH). 1H-NMR (400 MHz, DMSO-d6) δ 10.76 (br s, 1H), 7.69 (dd, J = 8.1, 1.8 Hz, 1H), 7.64 (d, J = 1.8 Hz, 1H), 7.20 (s, 2H), 6.98 (d, J = 8.2 Hz, 1H), 1.83–1.71 (m, 4H), 0.53 (t, J = 7.3 Hz, 6H). 13C-NMR (100 MHz, DMSO-d6) δ 181.0, 145.9, 137.6, 132.5, 126.5, 120.8, 108.9, 54.1, 29.9, 8.7. IR (KBr) ν 3334, 1725, 1328, 1172 cm−1. MS (EI): 268 [M], 240, 159, 130. Anal. Calcd. for C12H16N2O3S (268.33): C, 53.71%; H, 6.01%; N, 10.44%; S, 11.95%. Found: C, 53.59%; H, 6.02%; N, 10.37%; S, 11.75%.
N-tert-Butyl-3,3-diethyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide (9r). To a mixture of 9o (2.90 g, 10.10 mmol) and sodium carbonate (1.20 g, 11.32 mmol) in THF (100 mL), tert-butylamine (2.4 mL, 1.68 g, 22.98 mmol) was added at room temperature. The reaction mixture was refluxed for 7 h, then the volatile compounds were removed in vacuo at 40 °C and hydrochloric acid (30 mL, 1.0 M) was added. The aqueous layer was extracted with EtOAc (3 × 15 mL), the combined organic layer was dried over MgSO4 and evaporated. The solid residue was triturated in DEE (5 mL), filtered off and dried. The product 9r was obtained as colorless crystals (2.00 g, 61%), m.p. 202–203 °C (EtOH). 1H-NMR (400 MHz, CD3CN) δ 8.7 (br s, 1H), 7.72 (dd, J = 8.2, 2.0 Hz, 1H), 7.64 (dd, J = 1.8, 0.5 Hz, 1H), 7.01 (dd, J = 8.2, 0.3 Hz, 1H), 5.47 (s, 1H), 1.83 (q, J = 7.5 Hz, 4H), 1.13 (s, 9H), 0.56 (t, J = 7.5 Hz, 6H). 13C-NMR (100 MHz, CD3CN) δ 182.0, 146.9, 138.4, 134.1, 128.6, 123.0, 110.1, 55.6, 54.9, 31.3, 30.3, 9.00. IR (KBr) ν 3231, 1718, 1299, 1144 cm−1. MS (EI): 324 [M], 309, 252, 204, 188, 159. EA Calcd. for C16H24N2O3S (324.44): C, 59.23%; H, 7.46%; N, 8.63%; S, 9.88%. Found: C, 58.91%; H, 7.44%; N, 8.75%; S, 9.69%.
3,3-Diethyl-5-(morpholin-4-ylsulfonyl)-1,3-dihydro-2H-indol-2-one (9s). To a mixture of 9o (2.88 g, 10.0 mmol) and sodium carbonate (1.59 g, 15.0 mmol) in THF (100 mL), morpholine (6.00 mL, 6.06 g, 69.6 mmol) was added at room temperature. The reaction mixture was refluxed for 5 h. The solvent was removed in vacuo at 40 °C and hydrochloric acid (30 mL, 1.0 M) was added. The aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic layer was dried over MgSO4 and evaporated. The solid residue was triturated in DEE (5 mL), filtered off and dried. The product 9s was obtained as colorless crystals (2.58 g, 76%), m.p. 202–203 °C (EtOH). 1H-NMR (400 MHz, CDCl3) δ 8.78 (br s, 1H), 7.67 (dd, J = 8.2, 1.8 Hz, 1H), 7.51 (d, J = 1.7 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 3.78–3.75 (m, 4H), 3.00–2.97 (m, 4H), 2.02–1.96 (m, 2H), 1.88–1.83 (m, 2H), 0.65 (t, J = 7.4 Hz, 6H). 13C-NMR (100 MHz, CDCl3) δ 182.1, 145.8, 133.5, 128.7 (128.68, 128. 67), 122.8, 109.6, 66.1, 55.0, 46.0, 30.6, 8.7. IR (KBr) ν 1741, 1347, 1164 cm−1. MS (ESI): 339.14 [M + H]+. Anal. Calcd. for C16H22N2O4S (338.42): C, 56.79%; H, 6.55%; N, 8.28%; S, 9.47%. Found: C, 56.78%; H, 6.49%; N, 8.34%; S, 9.62%.
5,7-Dichloro-3,3-diethyl-1,3-dihydro-2H-indol-2-one (9t). To a solution of 9d (3.78 g, 20.0 mmol) in acetic acid (40 mL), sulfuryl chloride (4.80 mL, 8.09 g, 60.0 mmol) was added dropwise at room temperature. The mixture was heated to 60 °C for 4 hours. It was cooled to room temperature, then the reaction mixture was poured onto ice–water (50 g). The precipitate thus obtained was filtered off, washed with water until the pH was adjusted to 7, then it was washed with hexane and dried to give 9t (5.00 g, 97%). The crude product 9t was recrystallized from water (80 mL) and EtOH (120 mL) to give 9t (3.48 g, 13.48 mmol, 67%) as colorless crystals, m.p. 177–178 °C (water–EtOH). 1H-NMR (400 MHz, CDCl3) δ 8.08 (br s, 1H), 7.23 (d, J = 1.9 Hz, 1H), 7.01 (d, J = 1.8 Hz, 1H), 2.00–1.91 (m, 2H), 1.82–1.64 (m, 2H), 0.66 (t, J = 7.4 Hz, 6H). 13C-NMR (100 MHz, CDCl3) δ 180.4, 137.8, 135.2, 128.1, 127.4, 122.0, 115.1, 56.5, 30.7, 8.7. IR (KBr) ν 3183, 1725 cm−1. MS (EI): 259, 257 [M], 231, 230, 229, 228, 214, 200, 193, 165, 164. EA Calcd. for C12H13Cl2NO (258.14): C, 55.83%; H, 5.08%; N, 5.43%, Cl, 27.47. Found: C, 55.76%; H, 5.07%; N, 5.41%; Cl, 27.46%.
5,7-Dichloro-3,3-diethyl-6-fluoro-1,3-dihydro-2H-indol-2-one (9u). To a solution of 9g (1.04 g, 5.0 mmol) in acetic acid (30 mL), sulfuryl chloride (2.00 mL, 3.34 g, 25.0 mmol) was added dropwise at room temperature. The mixture was heated to 70–80 °C for 1 h. It was cooled to room temperature, then the reaction mixture was poured onto ice–water (30 g). The precipitate thus obtained was filtered off, washed with water until the pH was adjusted to 7, then it was washed with hexane and dried. The product 9u was obtained as colorless crystals (1.20 g, 87%), m.p. 192–193 °C (hexane–EtOAc). 1H-NMR (400 MHz, CDCl3) δ 9.05 (br s, 1H), 7.05 (d, J = 6.3 Hz, 1H), 2.00–1.94 (m, 2H), 1.81–1.74 (m, 2H), 0.67 (t, J = 7.4 Hz, 6H). 13C-NMR (100 MHz, CDCl3) δ 181.4, 153.5 (d, J = 248.3 Hz), 139.5 (d, J = 2.7 Hz), 128.6 (d, J = 4.2 Hz), 122.7, 115.0 (d, J = 18.7 Hz), 104.6 (d, J = 22.9 Hz), 56.2, 30.6, 8.6. IR (KBr) ν 3085, 1726, 1189, 770 cm−1. MS (EI): 277, 275 [M], 248, 246, 218, 211, 183. Anal. Calcd. for C12H12Cl2FNO (276.14): C, 52.20%; H, 4.38%; N, 5.07%; Cl, 25.68%. Found: C, 52.06%; H, 4.44%; N, 5.16%; Cl, 25.79%.

4. Conclusions

A systematic study of regioselective 3-alkylation reaction of N-unprotected-3-monosubstituted oxindoles was carried out after summarizing the literature of the numerous, albeit sporadic, precedents giving mostly unsatisfactory results. We have now elaborated an optimized method for the 3-alkylation of N-unsubstituted 3-alkyloxindoles by applying butyllithium as the base and alkyl bromides as the alkylating agents. The method has been extended to various alkyl groups in position 3 and various substituents on the aromatic ring. Introduction of new substituents into the aromatic ring of 3,3-diethyloxindole is disclosed. The formation of 3-hydroxylated side-products was investigated and the targeted synthesis of these compounds is also described. Owing to the presence of the unsubstituted nitrogen atom N1 in the title products (and the 3-hydroxy moiety in certain compounds), further functionalizations can also be carried out, thereby making these compounds valuable building blocks in synthetic organic or medicinal chemistry.

Author Contributions

E. K. performed the experiments and compiled the Experimental Section; G. S. and B. V. conceived and designed the experiments, and wrote the further chapters of the paper.

Conflicts of Interest

The authors declare no conflict of interest.

References and Notes

  1. Oxindole derivatives reaching human Phase III clinical trials are as follows: Tenidap, famitinib, linopirdine, flindokalner, satavaptan.
  2. Oxindole derivatives reaching human Phase II clinical trials are as follows: Aplindore, cipargamin, icopezil maleate, amcasertib, adibendan, funapide, NS-1209, semaxanib, indolidan.
  3. Oxindole derivatives reaching human Phase I clinical trials are as follows: SNAP-37889, PF-03382792, CP-126998, henatinib, BI-847325, CFI-400945, tafetinib, XEN-401, SSR-126768A, T-0632, DS-3032b.
  4. Nozoye, T.; Nakai, T.; Kubo, A. (E)- and (Z)-2-Oxoindolin-3-ethylidenes. Chem. Pharm. Bull. 1977, 25, 196–198. [Google Scholar] [CrossRef]
  5. Mertens, A.; Müller-Beckmann, B.; Kampe, W.; Hölck, J.-P.; von der Saal, W. Nonsteroidal cardiotonics. 1. 2-Pyridyl-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-ones, a novel class of cardiotonic agents. J. Med. Chem. 1987, 30, 1279–1287. [Google Scholar] [CrossRef] [PubMed]
  6. Tacconi, G.; Maggi, L.D.; Righetti, P.; Desimoni, G.; Azzolina, O.; Ghislandi, V. (Z)- and (E)-3-Alkylidene-1,3-dihydroindol-2-ones. Influence of configuration on the transmission of the inductive effect to the carbonyl group. J. Chem. Soc., Perkin Trans. 2 1976, 150–154. [Google Scholar] [CrossRef]
  7. Wenkert, E.; Bringi, N.V. A new procedure for forming carbon-carbon bonds. J. Am. Chem. Soc. 1958, 80, 5575–5576. [Google Scholar] [CrossRef]
  8. Wenkert, E.; Bringi, N.V.; Choulett, H.E. Raney nickel-induced alkylation reactions. Acta Chem. Scand. Ser. B 1982, 36, 348–350. [Google Scholar] [CrossRef]
  9. Volk, B.; Mezei, T.; Simig, G. Raney nickel-induced 3-alkylation of oxindole with alcohols and diols. Synthesis 2002, 595–597. [Google Scholar] [CrossRef]
  10. Gruda, I. Formation of N- and C-substituted derivatives during alkylation of indol-2(3H)-one. Can. J. Chem. 1972, 50, 18–23. [Google Scholar] [CrossRef]
  11. Reisch, J.; Müller, M.; Labitzke, H. Synthetic pathways for 3-substituted indol-2-ones. Arch. Pharm. 1984, 317, 639–646. [Google Scholar] [CrossRef]
  12. Horner, L. Syntheses in the oxindole series. Liebigs Ann. Chem. 1941, 548, 117–146. [Google Scholar] [CrossRef]
  13. Wenkert, E.; Bernstein, B.S.; Udelhofen, J.H. A novel conversion of derivatives of oxindoles to indoles. J. Am. Chem. Soc. 1958, 80, 4899–4903. [Google Scholar] [CrossRef]
  14. Shaun, J.; Tetsuro, K.; Katsura, T.; Tsuyoshi, H.; Yasufumi, U. Carbostyril derivative 5-HT1a receptor subtype agonist for treatment of central nervous system disorders. US 2011195954 U.S. Pat. Appl., Nov 21, 2002. Chem. Abstr. 2002, 137, 363096. [Google Scholar]
  15. Karig, G.; Ford, M.J.; Siegel, K.; Schnatterer, S. Method for producing N-sulfonyl-substituted oxindoles. US 2015133660 PCT Intern. Pat. Appl., May 14, 2015. Chem. Abstr. 2012, 157, 165628. [Google Scholar]
  16. Cook, B.N.; Huber, J.D.; Hughes, R.O.; Kirrane, T.M., Jr.; Lasota, C.; Li, X.; Liang, S.; Mugge, I.A.; Zhang, Q. Preparation of bicyclic compounds as modulators of retinoid-related orphan receptor γt (RORγt or RORc). WO 2015035032 PCT Intern. Pat. Appl., Mar 12, 2015. Chem. Abstr. 2015, 162, 425159. [Google Scholar]
  17. Alkylation of a 3-(substituted phenyl)oxindole and related compounds with α,ω-iodochloroalkanes with t-BuOK in DMF is described with undisclosed yields in: Foulon, L.; Goullieux, L.; Pouzet, B.; Le Serradeil, G.; Claudine, V.G. Novel 3-aminoalkyl-1,3-dihydro-2H-indol-2-one derivatives, preparation thereof and therapeutic use thereof. US 2011059955 U.S. Pat. Appl., Mar 10, 2011, also published as WO 2009115685 PCT Intern. Pat. Appl., Sep 24, 2009. Chem. Abstr. 2009, 151, 403108. [Google Scholar]
  18. Alkylation of 3-phenyloxindole with t-BuOK and 1,2-dibromoethane in THF is described in 53% yield in: Kato, K.; Doi, T.; Sugiura, Y.; Kawada, M. Preparation of 3-[2-(4-arylazino)ethyl]-2-indolones and analogs as antiincontinence agents. WO 9802432 PCT Intern. Pat. Appl., Jan 22, 1998. Chem. Abstr. 1998, 128, 140729. [Google Scholar]
  19. 3-Methyl-4-methoxyoxindole was 3-methylated with potassium bis(trimethylsilyl)amide and methyliodide in THF to give the product in 58% yield after laborious work-up, see: Jesudason, C.D.; Sall, D.J.; Stevens, F.C.; Werner, J.A. Preparation of oxindolyloxypropanolamines as β3 adrenergic receptor agonists. WO 0238543 PCT Intern. Pat. Appl., May 16, 2002. Chem. Abstr. 2002, 136, 369605. [Google Scholar]
  20. Reaction of 5-chloro-3-(4-methoxyphenyl)oxindole with benzyl bromide in the presence of K2CO3 and KI in acetone, subsequent work-up by flash chromatography, and preparation of several analogous derivatives in low to moderate yields in a similar manner are described in: Kin-Chun, L.; Sung-Sau, S.; Jing, Z.; Zhuming, Z. Preparation of oxindoles as inhibitors of MDM2-p53 interaction for the treatment of cancer. WO 2006136606 PCT Intern. Pat. Appl., Dec 28, 2006. Chem. Abstr. 2006, 146, 100555. [Google Scholar]
  21. Reaction of 5-(3,5-dimethylisoxazol-4-yl)-3-phenyloxindole with ethyl bromoacetate in the presence of K2CO3 and KI in acetone, and reaction of 5-(3,5-dimethylisoxazol-4-yl)-3-phenyloxindole with 3-bromopropan-1-ol in the presence of K2CO3 and KI in THF, and subsequent work-up by flash chromatography are disclosed in 60% and 41% yields, respectively, in: Bo, R.; Changyou, Z.; Hexiang, W. 5-(3,5-Dimethylisoxazol-4-yl)indolin-2-ones as BRD4 inhibitors and their preparation and use for the treatment of cancer. WO 2014173241 PCT Intern. Pat. Appl., Oct 30, 2014. Chem. Abstr. 2014, 161, 664198. [Google Scholar]
  22. 3-(Substituted phenyl) or 3-methyloxindoles, eventually substituted on the aromatic ring of the oxindole skeleton, are alkylated with K2CO3 and variously substituted benzyl bromides in DMA. Chromatographic purification is necessary, yields are not disclosed, see: Wilson, J.E.; Kurukulasuriya, R.; Reibarkh, M.; Reiter, M.; Zwicker, A.; Zhao, K.; Zhang, F.; Anand, R.; Colandrea, V.J.; Cumiskey, A.-M.; Crespo, A.; Duffy, R.A.; Murphy, B.A.; Mitra, K.; Johns, D.G.; Duffy, J.L.; Vachal, P. Discovery of novel indoline cholesterol ester transfer protein inhibitors (CETP) through a structure-guided approach. ACS Med. Chem. Lett. 2016, 7, 261–265. [Google Scholar] [CrossRef] [PubMed]
  23. 3-Arlyoxindoles are alkylated with K2CO3 and substituted benzyl bromides in DMA. The products are obtained after chromatography in unknown yields, see: Wilson, J.E.; Vachal, P.; Kurukulasuriya, R. 3,3'-Disubstituted indolines as inhibitors of cholesterol ester transfer protein. WO 2015054088 PCT Intern. Pat. Appl., Apr 16, 2015. Chem. Abstr. 2015, 162, 544611. [Google Scholar]
  24. Reaction of 6-bromo-3-methyloxindole with methyl bromoacetate and allyl bromide in the presence of Cs2CO3 in DMF is described, after purification by flash chromatography, in 71% and 51% yields, respectively, in: Chen, G.; Cushing, T.D.; Fisher, B.; He, X.; Li, K.; Li, Z.; McGee, L.R.; Pattaropong, V.; Faulder, P.; Seganish, J.L.; et al. Alkynyl alcohols as kinase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of inflammation and inflammatory disorders. WO 2009158011 PCT Intern. Pat. Appl., Dec 30, 2009. Chem. Abstr. 2009, 152, 119631. [Google Scholar]
  25. Kende, A.S.; Hodges, J.C. Regioselective C-3 alkylations of oxindole dianion. Synth. Commun. 1982, 12, 1–10. [Google Scholar] [CrossRef]
  26. Fensome, A.; Mccomas, C.C.; Melenski, E.G.; Marella, M.A.; Wrobel, J.E. Progesterone receptor modulators comprising pyrrole-oxindole derivatives and uses thereof. US 2006030615 U.S. Pat. Appl., Feb 9, 2006. Chem. Abstr. 2006, 144, 192104. [Google Scholar]
  27. Brittain, W.D.G.; Buckley, B.R.; Fossey, J.S. Kinetic resolution of alkyne-substituted quaternary oxindoles via copper catalysed azide-alkyne cycloadditions. Chem. Commun. 2015, 51, 17217–17220. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Li, Q.; Woods, K.W.; Zhu, G.-D.; Fischer, J.P.; Gong, J.; Li, T.; Gandhi, V.; Thomas, S.A.; Packard, G.; Song, X.; et al. Preparation of pyridine derivatives as protein kinase inhibitors. WO 03051366 PCT Intern. Pat. Appl., Oct 2, 2003. Chem. Abstr. 2003, 139, 69152. [Google Scholar]
  29. For the introduction of identical alkyl groups (Me, Et, Bn) in position 3 of 4-methoxyoxindole (2 eq BuLi, TMEDA, THF), see: Stevens, F.C.; Bloomquist, W.E.; Borel, A.G.; Cohen, M.L.; Droste, C.A.; Heiman, M.L.; Kriauciunas, A.; Sall, D.J.; Tinsley, F.C.; Jesudason, C.D. Potent oxindole based human β3 adrenergic receptor agonists. Bioorg. Med. Chem. Lett. 2007, 17, 6270–6273. [Google Scholar] [CrossRef] [PubMed]
  30. 3-Alkylation (benzylation) of 3-(substituted phenyl)oxindoles with BuLi (2.2 eq), TMEDA (2.2 eq) and alkylating agent (2.2 eq) with chromatographic work-up is described in: Christensen, M.K.; Bjoerkling, F. Preparation of 3-(4-hydroxyphenyl)-indolin-2-ones for the treatment of cancer. WO 2008129075 PCT Intern. Pat. Appl., Oct 30, 2008. Chem. Abstr. 2008, 149, 513691. [Google Scholar]
  31. 3-Ethylation of 3-ethyloxindole with BuLi (2.0 eq), TMEDA (2.0 eq) and EtI (1.0 eq) in 45% yield is described in: Grubb, G.S.; Zhi, L.; Jones, T.K.; Tegley, C.M.; Fensome, A.; Miller, L.L.; Ullrich, J.W.; Bender, R.H.W.; Zhang, P.; Wrobel, J.E.; et al. Preparation of oxospiro[cycloalkane-1,3′-indoline]derivatives and analogs as progesterone receptor antagonists. WO 0066167 PCT Intern. Pat. Appl., Nov 9, 2000. Chem. Abstr. 2000, 133, 350135. [Google Scholar]
  32. Fensome, A.; Zhang, P.; Koko, M.C.; Zhi, L.; Jones, T.K.; Marschke, K.B.; Tegley, C.M. Preparation of thioxospiro[cycloalkane-1,3′-indole]derivatives and analogs as progesterone receptor agonists. WO 0066555 PCT Intern. Pat. Appl., Nov 9, 2000. Chem. Abstr. 2000, 133, 350136. [Google Scholar]
  33. Fensome, A.; Miller, L.L.; Ullrich, J.W.; Bender, R.H.W.; Zhang, P.; Wrobel, J.E.; Zhi, L.; Jones, T.K.; Marschke, K.B.; Tegley, C.M. Preparation of indolinones as progesterone antagonists. WO 0066556 PCT Intern. Pat. Appl., Nov 9, 2000. Chem. Abstr. 2000, 133, 350137. [Google Scholar]
  34. 3-Methylation of 3-methyl-6-methoxyoxindole (2.0 eq BuLi, 2.0 eq TMEDA, 1.14 eq MeI, THF, −78 °C, flash chromatography, 82%) is described in: Jayyosi, Z.; McGeehan, G.M.; Kelley, M.F.; Labaudiniere, R.F.; Zhang, L.; Groneberg, R.D.; McGarry, D.G.; Caulfield, T.J.; Minnich, A.; Bobko, M. Preparation of diaryl carboxylic acids and derivatives as peroxisome proliferator-activated receptor ligands. WO 0064888 PCT Intern. Pat. Appl., Nov 2, 2000. Chem. Abstr. 2000, 133, 335167. [Google Scholar]
  35. Reaction (2.0 eq BuLi, 2.0 eq TMEDA, THF, 25 °C, 60%) of 5-bromo-3-methyloxindole with BrCH2CO2Et (1.0 eq) is described in: Jiang, T.; Kuhen, K.L.; Wolff, K.; Yin, H.; Bieza, K.; Caldwell, J.; Bursulaya, B.; Wu, T.Y.-H.; He, Y. Design, synthesis and biological evaluations of novel oxindoles as HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem. Lett. 2006, 16, 2105–2108. [Google Scholar] [CrossRef] [PubMed]
  36. Volk, B.; Barkóczy, J.; Hegedűs, E.; Udvari, S.; Gacsályi, I.; Mezei, T.; Pallagi, K.; Kompagne, H.; Lévay, G.; Egyed, A.; et al. (Phenylpiperazinyl-butyl)oxindoles as selective 5-HT7 receptor antagonists. J. Med. Chem. 2008, 51, 2522–2532. [Google Scholar] [CrossRef] [PubMed]
  37. Volk, B.; Gacsályi, I.; Pallagi, K.; Poszávácz, L.; Gyönös, I.; Szabó, É.; Bakó, T.; Spedding, M.; Simig, G.; Szénási, G. Optimization of (arylpiperazinylbutyl)oxindoles exhibiting selective 5-HT7 receptor antagonist activity. J. Med. Chem. 2011, 54, 6657–6669. [Google Scholar] [CrossRef] [PubMed]
  38. For methylation using trimethyloxonium tetrafluoroborate, see: Zhou, H.-J.; Wang, J.; Yao, B.; Wong, S.; Djakovic, S.; Kumar, B.; Rice, J.; Valle, E.; Soriano, F.; Menon, M.-K.; et al. Discovery of a first-in-class, potent, selective, and orally bioavailable inhibitor of the p97 AAA ATPase (CB-5083). J. Med. Chem. 2015, 58, 9480–9497. [Google Scholar] [CrossRef] [PubMed]
  39. For ethylation of unsubstituted oxindole using triethyloxonium tetrafluoroborate, see: Harley-Mason, J.; Leeney, T.J. 2-Ethoxyindoles and -indolenines. A case of indole-indolenine tautomerism. Proc. Chem. Soc. Lond. 1964, 368–369. [Google Scholar]
  40. Tóth, F.; Fráter, G.; Ondi, L. Compounds and the use thereof in metathesis reactions. WO 2015155593 PCT Intern. Pat. Appl., Oct 15, 2015. Chem. Abstr. 2015, 163, 585851. [Google Scholar]
  41. Borovik, V.P.; Gatilov, Y.V.; Shkurko, O.P. Reaction of 3-(R-methylidene)-2-ethoxylindolenines with N,N'-binucleophiles. Russ. J. Org. Chem. 2016, 52, 228–234. [Google Scholar] [CrossRef]
  42. For ethylation of 5-chlorooxindole using triethyloxonium tetrafluoroborate, see: Esses-Reiter, K.; Reiter, J. Attempted synthesis of a tenidap isomer and formation of an unexpected stable water adduct. J. Het. Chem. 2000, 37, 927–933. [Google Scholar] [CrossRef]
  43. For ethylation of 3-methyloxindole using triethyloxonium tetrafluoroborate, see: Nakagawa, M.; Hino, T. 2-Ethoxy and 2-ethylthioindoles. Autoxidation and nucleophilic substitutions. Tetrahedron 1970, 26, 4491–4503. [Google Scholar] [CrossRef]
  44. Hino, T.; Nakagawa, M.; Akaboshi, S. 2-Ethoxyindoles and 2-ethylthioindoles: their autoxidation and reactions with piperidine. Chem. Commun. 1967, 656–658. [Google Scholar] [CrossRef]
  45. For O-alkylation with ethyl diazoacetate in the presence of Rh2(OCOCF3)4, see: Busch-Petersen, J.; Corey, E.J. Rhodium(II) catalytic approach to the synthesis of ethers of a minor component in a tautomeric set. Org. Lett. 2000, 2, 1641–1643. [Google Scholar] [CrossRef] [PubMed]
  46. For the introduction of a monofluoromethyl moiety to the oxygen atom using N,N-(dimethylamino)-S-phenyl-S-monofluoromethyloxosulfonium hexafluorophosphate in the presence of tert-butylimino-tris(dimethylamino) phosphorane, see: Nomura, Y.; Tokunaga, E.; Shibata, N. Inherent oxygen preference in enolate monofluoromethylation and a synthetic entry to monofluoromethyl ethers. Angew. Chem. Int. Ed. 2011, 50, 1885–1889. [Google Scholar] [CrossRef] [PubMed]
  47. Bai, M.; You, Y.; Chen, Y.-Z.; Xiang, G.-Y.; Xu, X.-Y.; Zhang, X.-M.; Yuan, W.-C. An unprecedented protocol for the synthesis of 3-hydroxy-3-phenacyloxindole derivatives with indolin-2-ones and α-substituted ketones. Org. Biomol. Chem. 2016, 14, 1395–1401. [Google Scholar] [CrossRef] [PubMed]
  48. Green, J.R. Science of Synthesis; Majewski, M., Snieckus, V., Eds.; Georg Thieme Verlag: Stuttgart-New York, Germany, 2006; Volume 8a, pp. 427–486. [Google Scholar]
  49. Clugston, M.; Fleming, R. Advanced Chemistry; Oxford University Press: Oxford, United Kingdom, 2000. [Google Scholar]
  50. Volk, B.; Simig, G. New one-pot synthesis of 3-alkyl- and 3-(ω-hydroxyalkyl)oxindoles from isatins. Eur. J. Org. Chem. 2003, 3991–3996. [Google Scholar] [CrossRef]
  51. Drug candidates with a 5-substituted oxindole skeleton are as follows: Tenidap, famitinib, and satavaptan (Phase III); cipargamin, amcasertib, adibendan, NS-1209 and indolidan (Phase II).
  52. Takayma, K.; Isobe, M.; Harano, K.; Taguchi, T. A general synthetic route of 3,3-disubstituted 3H-indoles and rearrangement of their acyl chloride adducts. Tetrahedron Lett. 1973, 14, 365–368. [Google Scholar] [CrossRef]
  53. Fan, J.-H.; Zhou, M.-B.; Liu, Y.; Wei, W.-T.; Ouyang, X.-H.; Song, R.-J.; Li, J.-H. Iron-catalyzed oxidative arylmethylation of activated alkenes using a peroxide as the methyl source. Synlett 2014, 25, 657–660. [Google Scholar] [CrossRef]
  54. Hseih, J.-C.; Cheng, A.-Y.; Fu, J.-H.; Kang, T.-W. Copper-catalyzed domino coupling reaction: an efficient method to synthesize oxindoles. Org. Biomol. Chem. 2012, 10, 6404–6409. [Google Scholar] [CrossRef] [PubMed]
  55. Taylor, A.M.; Altman, R.A.; Buchwald, S.L. Palladium-catalyzed enantioselective α-arylation and α-vinylation of oxindoles facilitated by an axially chiral P-stereogenic ligand. J. Am. Chem. Soc. 2009, 131, 9900–9901. [Google Scholar] [CrossRef] [PubMed]
  56. Braudeau, E.; David, S.; Fischer, J.-C. 2-Hydroxyindoxyls. General and novel preparation, properties, and their role in the perphthalic acid oxidation of indoles. Tetrahedron 1974, 30, 1445–1455. [Google Scholar] [CrossRef]
  57. Nakazaki, A.; Mori, A.; Kobayashi, S.; Nishikawa, T. Diastereoselective synthesis of 3,3-disubstituted oxindoles from atropisomeric N-aryl oxindole derivatives. Tetrahedron Lett. 2012, 53, 7131–7134. [Google Scholar] [CrossRef]
  • Sample Availability: Samples of the compounds 9c–u are available from the authors.
Molecules 22 00024 g001 550
Figure 1. Oxindole (1) and marketed drugs with oxindole skeleton (2–5).
Figure 1. Oxindole (1) and marketed drugs with oxindole skeleton (2–5).
Molecules 22 00024 g001
Molecules 22 00024 sch001 550
Scheme 1. Reductive alkylation reactions of oxindole (1) to give 3-alkyloxindoles 6.
Scheme 1. Reductive alkylation reactions of oxindole (1) to give 3-alkyloxindoles 6.
Molecules 22 00024 sch001
Molecules 22 00024 sch002 550
Scheme 2. C3-Alkylation of 3-alkyloxindoles 8.
Scheme 2. C3-Alkylation of 3-alkyloxindoles 8.
Molecules 22 00024 sch002
Molecules 22 00024 sch003 550
Scheme 3. Direct benzylation of oxindole (1) in the presence of sodium hydroxide.
Scheme 3. Direct benzylation of oxindole (1) in the presence of sodium hydroxide.
Molecules 22 00024 sch003
Molecules 22 00024 sch004 550
Scheme 4. Alkylation of oxindole (1) via its sodium salt using a protection-deprotection approach.
Scheme 4. Alkylation of oxindole (1) via its sodium salt using a protection-deprotection approach.
Molecules 22 00024 sch004
Molecules 22 00024 sch005 550
Scheme 5. Direct alkylation of oxindole (1) via its lithium salt.
Scheme 5. Direct alkylation of oxindole (1) via its lithium salt.
Molecules 22 00024 sch005
Molecules 22 00024 sch006 550
Scheme 6. Synthesis of 3-alkyl-3-(ω-haloalkyl)oxindoles.
Scheme 6. Synthesis of 3-alkyl-3-(ω-haloalkyl)oxindoles.
Molecules 22 00024 sch006
Molecules 22 00024 sch007 550
Scheme 7. Synthesis of 1-acetyl-3-hydroxy-3-phenacyloxindole derivatives 16.
Scheme 7. Synthesis of 1-acetyl-3-hydroxy-3-phenacyloxindole derivatives 16.
Molecules 22 00024 sch007
Molecules 22 00024 sch008 550
Scheme 8. Alkylation of 3-ethyloxindoles 8b–e and 3-isopropyloxindole (8f) with various alkyl halides.
Scheme 8. Alkylation of 3-ethyloxindoles 8b–e and 3-isopropyloxindole (8f) with various alkyl halides.
Molecules 22 00024 sch008
Molecules 22 00024 sch009 550
Scheme 9. Ethylation of 3-isopropyloxindole (8f) under insufficiently inert conditions.
Scheme 9. Ethylation of 3-isopropyloxindole (8f) under insufficiently inert conditions.
Molecules 22 00024 sch009
Molecules 22 00024 sch010 550
Scheme 10. 3-Hydroxylation of 3-alkyloxindoles 8b,f.
Scheme 10. 3-Hydroxylation of 3-alkyloxindoles 8b,f.
Molecules 22 00024 sch010
Molecules 22 00024 sch011 550
Scheme 11. Various functionalizations of 3,3-diethyloxindole (9d) on the aromatic ring.
Scheme 11. Various functionalizations of 3,3-diethyloxindole (9d) on the aromatic ring.
Molecules 22 00024 sch011
Molecules 22 00024 sch012 550
Scheme 12. Synthesis of 5,7-dichloro derivatives 9t,u.
Scheme 12. Synthesis of 5,7-dichloro derivatives 9t,u.
Molecules 22 00024 sch012
Table
Table 1. Alkylation reactions of 3-ethyloxindoles 8b–e and 3-isopropyloxindole (8f) with various alkyl halides.
Table 1. Alkylation reactions of 3-ethyloxindoles 8b–e and 3-isopropyloxindole (8f) with various alkyl halides.
Entry8R1R3BuLi (eq)R2X (eq)99 Yield (%)20 Yield (%)
1bEtH2.5MeI (2.5)c28 a55 a (20a)
2bEtH2.2MeI (1.2)c710
3bEtH2.5EtI (2.5)d730
4bEtH2.2EtBr (1.2)d900
5bEtH2.2BnBr (1.2)e800
6cEt5-Me2.2EtBr (1.2)f760
7dEt6-F2.2EtBr (1.2)g770
8eEt7-Me2.2EtBr (1.2)h660
9fi-PrH2.5MeI (2.5)i40 a35 a (20b)
10fi-PrH2.5MeI (1.2)i560
11fi-PrH2.2EtBr (1.2)j650
12fi-PrH2.2BnBr (1.2)k630
a Isolated by flash chromatography.
Table
Table 2. Various functionalizations of 3,3-diethyloxindole (9d) on the aromatic ring.
Table 2. Various functionalizations of 3,3-diethyloxindole (9d) on the aromatic ring.
EntryReagents of Step 1 aProduct of Step 1R4Yield of Step 1 (%)Reagents of Step 2Product of Step 2R5Yield of Step 2 (%)
1SO2Cl29lCl73----
2Br2, KBr9mBr94----
3HNO3, H2SO49nNO285H2/Pd/C9pNH287
4ClSO3H9oSO2Cl98NH39qNH2SO260
5t-BuNH29rt-BuNHSO261
6morpholine9s(morph)SO276
a For Steps 1 and 2, and substituents R4, R5, see Scheme 11.

Share and Cite

MDPI and ACS Style

Kókai, E.; Simig, G.; Volk, B. Literature Survey and Further Studies on the 3-Alkylation of N-Unprotected 3-Monosubstituted Oxindoles. Practical Synthesis of N-Unprotected 3,3-Disubstituted Oxindoles and Subsequent Transformations on the Aromatic Ring. Molecules 2017, 22, 24. https://doi.org/10.3390/molecules22010024

AMA Style

Kókai E, Simig G, Volk B. Literature Survey and Further Studies on the 3-Alkylation of N-Unprotected 3-Monosubstituted Oxindoles. Practical Synthesis of N-Unprotected 3,3-Disubstituted Oxindoles and Subsequent Transformations on the Aromatic Ring. Molecules. 2017; 22(1):24. https://doi.org/10.3390/molecules22010024

Chicago/Turabian Style

Kókai, Eszter, Gyula Simig, and Balázs Volk. 2017. "Literature Survey and Further Studies on the 3-Alkylation of N-Unprotected 3-Monosubstituted Oxindoles. Practical Synthesis of N-Unprotected 3,3-Disubstituted Oxindoles and Subsequent Transformations on the Aromatic Ring" Molecules 22, no. 1: 24. https://doi.org/10.3390/molecules22010024

Article Metrics

Back to TopTop