Free Radical-Mediated Aryl Amination: Convergent Two- and Three-Component Couplings to Chiral 2,3-Disubstituted Indolines

Abstract

5-exo-trig Cyclization of an aryl radical to the nitrogen of an azomethine is used as the key annulating step in a modular preparation of 2,3-cis- and trans-disubstituted indolines. The precursors are readily prepared by phase transfer catalyzed Michael addition of a glycine Schiff base to a variety of acceptors. When the more reactive alkylidene malonate Michael acceptors are implemented, a one-pot three component coupling is possible. The net result is a convergent [3+2] coupling strategy for the construction of highly functionalized indolines, a substructure occurring in numerous biologically active natural products.

Graphical Abstract

Introduction

The indoline substructure is a recurring structural feature within heterocyclic alkaloid natural products (Chart 1), perhaps second only to the pyrrolidine and piperidine nitrogen heterocycles. Indoline natural products are often both structurally appealing and biological active,⁴ and can range in complexity from relatively simplified fused tricycles like physostigmine,⁵ to the very complex polycycles vinblastine,⁶ aspidospermidine,⁷ ajmaline,⁸ and strychnine.⁹ Indoline heterocycles are also structural components of pharmaceutical small molecules, the angiotensin converting enzyme (ACE) inhibitor Pentopril is largely built upon (S)-indoline-2-carboxylic acid.¹⁰ This template has also spawned the development of ‘natural product-like’ libraries based on an aminoindoline framework.¹¹ Accordingly, this structural diversity has stimulated a wide range of methods aimed at the stereoselective construction^12,13,14 or functionalization¹⁵ of indoline rings. Few of these methods comprise enantioselective annulation methods - perhaps an indication that even modern methods remain inadequate for building certain common chiral heterocycles.¹⁶

Chart 1.

Representative biologically active indoline small molecules.

We have considered the indoline annulation problem ourselves, and recently reported an enantioselective indoline annulation in two steps, leading to enantioenriched 2-substituted indolines.13 The first step of the sequence is an enantioselective phase transfer catalyzed glycine Schiff base alkylation.¹⁷ Free radical-mediated aryl amination immediately follows as an enabling technology in this context, as it delivers the 2-substituted indoline under mild conditions and in protected form for further manipulation. We have since pursued a variation on this theme that targets the 2,3-disubstituted indoline ring system but retains the convergency offered by the basic modular assembly beginning from a glycine Schiff base. We would like to report a convergent synthesis of 2,3-disubstituted indolines (Figure 1, Type I, eq 1) resulting from a straightforward sequence involving conjugate addition and free radical mediated aryl amination. Additional modularity can be obtained by slight operational change to incorporate a third component (Figure 1, Type II, eq 2) by judicious choice of Michael acceptor. Both incarnations utilize the phase transfer catalyzed Michael addition of a protected glycine Schiff base to activated styrene derivatives.^17,18,19 The key annulation step is effected by a free radical reaction in which an aryl radical adds (nonconventionally) to the nitrogen of the azomethine.^{15,20,21,22,23}

Figure 1.

Indoline Annulation via Two- and Three-Component Couplings and Free Radical-Mediated Aryl Amination.

Results and Discussion

Type I: [3+2] Indoline Annulation via Sequential Michael Addition/Free Radical-Mediated Aryl Amination

A variety of Michael acceptors were synthesized from ortho-bromo benzaldehyde by olefination with the appropriate Wittig reagent.²⁴ A 6:1 E:Z ratio of (inseparable) geometric isomers of ethyl cinnamate 1a²⁵ was exposed to glycine Schiff base 2²⁶ using liquid-liquid phase transfer conditions (BnEt₃N^{+ –}Cl, 50% aq NaOH, CH₂Cl₂) (Scheme 1). The resulting adducts were obtained as an 86:14 cis-6a:trans-6a mixture (as depicted) in a combined 94% yield. The adducts were separated by flash chromatography and individually subjected to stannane and initiator (AIBN) to effect the annulation event. Indoline cis-3a was obtained in 65% isolated yield, and the trans-stereoisomer was retrieved in 84% yield. The assigned stereochemistry could be confirmed at this point by NOE measurements on both diastereomers individually. Although no single example was exhaustively optimized, the different concentrations (10 vs. 5 μM) for the cyclization reflect empirically determined, subtle differences in maintaining an efficient propagating radical reaction. Isolated yields may potentially be further improved by finely tuning the stannane addition rate in concert with reaction concentration. Generally, no product of direct reduction is observed in these or subsequent examples.

Scheme 1.

Two Component (Type I) Indoline Synthesis from Cinnamate Precursors (eq 1)^a

^aReagents and conditions: (a) 20 mol% BnEt₃N^{+ –}Cl, 50% aq NaOH, CH₂Cl₂, 25 °C, (94% from 6:1 E-1a:Z-1a; (b) ⁿBu₃SnH, AIBN, C₆H₆, 80 °C (cis-3a: 65%, trans-3a: 84%).

Acrylonitrile derivative 1b provided convenient access to the cis-adduct as well (Scheme 2). In contrast to cinnamates 1a, the geometric isomers of nitrile 1b were readily separated by flash chromatography, thereby allowing measurement of the impact of olefin geometry on addition diastereoselectivity. Michael addition to β-aryl acrylonitrile E-1b using liquid-liquid phase transfer conditions readily occurred to provide the adducts 6b as a separable 87:13 mixture of cis- and trans-diastereomers. Use of Z-1b was equally efficient (89% yield) but substantially less selective (1.4:1 cis:trans). Following chromatographic separation, the adducts 6b were individually cyclized to indolines 3b. Not unexpectedly, cyclization to the fully protected indoline α-amino acids cis-3b and trans-3b transpired as before in 61% and 80% yields, resepectively. Hence, 2,3-cis- and trans-disubstituted indoline α-amino acids are readily prepared in diastereomerically pure form (>95:5) from the corresponding activated styrenes. Diastereoselection is considerably higher in additions to the E-olefins relative to their Z-isomers. These examples establish a baseline efficiency for the two step annulation using an aryl radical cyclization to a benzophenone imine. We anticipate that this step will broadly tolerate substitution of the aryl radical based on our previous studies.13

Scheme 2.

Two Component (Type I) Indoline Synthesis from β-Aryl Acrylonitrile (eq 1)^a

^aReagents and conditions: (a) 20 mol% BnEt₃N^{+ –}Cl, 50% aq NaOH, CH₂Cl₂, 25 °C, (70% from E-1b; 89% from Z-1b (58:42 dr)); (b) ⁿBu₃SnH, AIBN, C₆H₆, 80 °C (cis-3b: 61%, trans-3b: 80%).

Type II: [3+2] Indoline Annulation via Sequential Michael Addition/Alkylation/Free Radical-Mediated Aryl Amination

At room temperature, the rate of phase transfer-catalyzed alkylation is comparable to Michael addition with electrophiles 1a and 1b. We hypothesized that by increasing the electrophilicity of the Michael acceptor, a sequential Michael/alkylation could be effected with phase transfer catalysis in one pot. Use of alkylidene malonates 4a allowed reduction of this strategy to practice (Figure 1, eq 2 and Table 1, eq 3).

Table 1.

Three Component (Type II) Indoline Synthesis (eq 3)^a

^aSee Supporting Information for complete details. Relative stereochemistry measured by NOE difference measurements. Ratios of diastereomers measured by ¹H NMR (400 MHz).

^bIsolated yield of both diastereomers.

^cIsolated yield.

^d>20:1 dr cis-7a→5:1 dr cis-5a; >20:1 dr cis-7e→10:1 dr cis-5e; 10:1 dr cis-7g→2:1 dr cis-5g.

^eA cinchonidine-derived ammonium salt was used.

^fSolid-liquid phase transfer conditions used: solid NaOH (20 equiv), CH₂Cl₂.

^gIndoline intermediate reacts further to unidentified products.

^hStereo-nonselective hydrostannation is competitive with cyclization.Chart 1. Representative biologically active indoline small molecules.

In the absence of an alkylating agent, alkylidene malonate 4a provided an equal amount of cis- and trans-Michael adducts 7a (Table 1, entry 1). Addition of methyl iodide to the basic reaction mixture resulted in the desired sequence of Michael addition/malonate alkylation (Table 1, entry 2). Although the differential rates of Michael addition/alkylation enable addition of the alkylating agent at the beginning of the reaction, the process is fully optimized by adding the alkylating agent to the reaction mixture after stirring for 3–4 hours. In this way, the Michael adduct (7b) is obtained in 94% isolated yield. The stereoisomers were then separated and subjected to free radical conditions to complete the annulation. This step is again highly efficient, producing cis-5b and trans-5b in 80% and 93% isolated yields, respectively.

Alkylation of the intermediate malonate with benzyl bromide resulted in an outcome similar to alkylation with methyl iodide, providing the stereoisomeric Michael adducts in 95% combined yield (Table 1, entry 3). Despite the possibility of 1,5-hydrogen atom transfer from the benzylic carbon to the intermediate aryl radical, cyclization of this inseparable mixture of diastereomers furnished the cyclized products in 82% combined yield with no evidence of aryl radical direct reduction. Moreover, the adduct diastereomeric ratio could be manipulated to favor (10:1) cis-7c through the use of a solid-liquid phase transfer protocol (NaOH-CH₂Cl₂) (Table 1, entry 4). The high selectivity notwithstanding, a more complete picture of the reaction sequence (vide infra) was obtained by generation of both diastereomers using the nonselective liquid-liquid phase transfer conditions.

A variety of different malonate alkylating agents can be used (Table 1, entries 5–9). Allylation with either allyl bromide or methallyl bromide (Table 1, entries 5 and 6 respectively) proceeded to adducts 7d and 7e in 87% and 95% yield. In both cases, the cis- and trans-diastereomers were separable. Whereas trans-7d and trans-7e cyclized uneventfully in 84% and 78% yield, respectively, cyclization of their cis-counterparts was complicated by the generation of several products. Although the exact nature of these products was not ultimately determined, that aryl-nitrogen bond formation occurred was evident from the signature upfield shifts of the aromatic ring protons in the crude reaction mixture. Accordingly, adduct cis-7e in which the vinyl group (a potential radical acceptor via addition) bears additional steric hindrance, allowed isolation of cis-5e in a modest 30% yield. This behavior continued with the activated allyl derivative cis-7f (Table 1, entry 7) in which trans-indoline 5f was obtained in 82% yield, but the cis-isomer was not formed selectively to any measurable extent. Alkylation of the Michael adduct with α-chloro tert-butyl acetate provided malonate derivative 7g in 76% yield. The cis-isomer cyclized to cis-5g in 45% isolated yield, whereas trans-7g produced trans-5g in 85% yield (Table 1, entry 8). Although propargyl electrophiles can be sequenced in the same manner, the cyclization was accompanied by hydrostannation of the terminal alkyne. The examples in Table 1 were not individually optimized for selectivity or yield, so the results provide an indication of the generality of a standard protocol.

Selective Epimerization of the α-Amino Ester Stereocenter: The Azacyclopentenyl Radical Isomerization (ACCRI).

Several of the Michael adducts 7 exhibited a drop in diastereopurity during the indoline annulation step. While this stereochemical erosion was absent or minimal in most cases, cis-7a, cis-7e, and cis-7g were more susceptible to the isomerization, and the observation was most pronounced in the latter two. This epimerization is highly unusual since free radical conditions are exceptionally mild (pH-neutral) and tolerant of a wide range of functionality.²⁷

We have previously described the azacyclopentenyl carbinyl radical isomerization (ACCRI) in enantioenriched indoline α-amino acid system analogous to the indolines described here.²⁸

By extension of those examples in which loss of enantiomeric excess was correlated to the isomerization, loss of diastereopurity from 7 can be explained by the course of events detailed in Scheme 3. This isomerization proceeds from the radical 8 formed by aryl radical addition to the azomethine nitrogen. A key feature of the isomerization is the nucleophilic nature of 8 and the electrophilic character of 9 which, in concert, lower the activation barrier via a polarization effect.²⁹ Using conditions that allow isomerization to compete with direct hydrogen atom transfer to 8 (low effective stannane concentration), the cis-indoline ring can homolytically fragment at the carbon-nitrogen σ-bond. Following a thermodynamically driven σ-bond rotation, the carbon-nitrogen bond reforms to give the trans-isomer. Rotation of one of the carbon-carbon bonds of the chain must occur, in addition to radical inversion, to reach the epimeric indoline radical intermediate.²⁸ This process is consistent with the observation that cis-indolines are more prone to isomerization than their trans-counterparts. It is significant to note that the isomerization can be prevented by several means, including the use of an electron deficient benzophenone imine.28 We were unable to locate the reduction product corresponding to 9, consistent with our determination that the ACCRI favors the ring isomer at equilibrium, and that subsequent chain-terminating hydrogen atom transfer is reasonably fast relative to reduction of the equilibrium concentration of 9.

Scheme 3.

ACCRI Mechanism for α-Amino Ester Epimerization During Cyclization of cis-Michael Adducts

Stereochemical Models for Diastereoselective Michael Additions

The diastereoselection observed in additions of glycine Schiff base 2 to unsaturated esters and nitriles was considerably higher (4:1) when using E-olefins 1b relative to their Z-isomers.³⁰ We rationalize this using purely steric considerations and the two transition states outlined in Figure 2. The first assumption is the intermediacy of an E-enolate derived from the glycine Schiff base due to the steric bias of the large ammonium counterion. In the case of the E-isomer of the Michael adduct, the transition state 10 arising from attack of the enolate on the Re face leads to the trans isomer in the product (trans-6b). This conformational arrangement suffers from nonbonded interactions involving both aryl and nitrile groups. Attack of the enolate on the Si face of the Michael acceptor leads to transition state 11, eventually forming cis-6b. In this transition state, these non-bonded interactions are minimized and therefore would be lower in energy. This is reflected in the observed 87:13 ratio favoring the cis isomer.

Figure 2.

Proposed competing transition states for E-olefin acceptors to rationalize syn-selectivity.

The lower selectivity (58:42 dr) observed for addition to Z-1b might be rationalized by the competition depicted in Figure 3. Addition of the enolate to the olefin Re-face leads to transition state assembly 12. This transition state suffers from nonbonded interactions between the aryl group and the imine. Similarly, Si-face addition of the enolate would lead to transition state 13 in which nonbonded interactions exist between the cyano group, enolate oxygen, and the quarternary ammonium counterion. Therefore, neither transition state would be preferred as they each suffer from torsional strain in the transition state, and this is reflected in the nearly 1:1 ratio of diastereomeric addition products formed.

Figure 3.

Proposed competing transition states for Z-olefin acceptors to rationalize low diastereoselection.

If the interaction between the aromatic ring of the acceptor and azomethine (and its substituents) of the donor in 10 is a destabilizing influence as we postulate, then an increase in the effective size of the aromatic ring might lead to enhanced diastereoselection. We examined this possibility through the use of acceptor 14 (Scheme 4), as the ortho,ortho-disubstitution leads to a nonplanar styene, and a corresponding increase in the steric destabilization in the transition state leading to the trans adduct. Addition to 14 was indeed more diastereoselective, leading solely (>20:1) to cis-15 in 75% yield. The putative transition state 17 describes how the ortho-substituents lead to a nonplanar acceptor, and how its bromine substituents would be best accomodated away from the diphenyl methylene of the azomethine (c.f. 10-11). Cyclization of this intermediate to indoline cis-16 proceeded well, but in moderate yield due to competitive product debromination.

Scheme 4.

Conclusion

In summary, two- and three-component couplings are described here that constitute strategically innovative approaches to the synthesis of 2,3-disubstituted indolines. Diastereoselection is maximized when ortho,ortho-disubstituted activated styrenes are employed in the Michael addition step. The multifunctional nature of the products is enhanced by their orthogonal protection (nitrile or ethyl ester vs. tert-butyl ester, diphenyl methyl amine). Incidentally, we have recently applied this annulation method to the preparation of the indole framework of ambiguine G.³¹ Whereas the free radical-mediated aryl amination step is both efficient and easily manipulated, there remains a need for highly enantioselective direct additions of glycine Schiff base 2 to styrene-derived Michael acceptors.^17,32,33,34 Ultimately, the development of this type of enantioselective reaction in combination with the strategies disclosed here may directly advance the enantioselective construction of complex indoline alkaloids.

Experimental Section

(cis/trans)-2-(Benzhydrylidene-amino)-3-(2-bromo-phenyl)-4,4-bis-ethoxycarbonyl-6-methyl-hept-6-enoic acid tert-butyl ester (cis/trans-7e).

A dichloromethane solution of alkylidene malonate 4a (250 mg, 764 μmol), Schiff base 2 (225 mg, 764 μmol, 0.34 M), methallyl bromide (204 mg, 1.52 mmol), benzyl triethyl ammonium chloride (20 mol%), and 50% aq NaOH (20 equiv) were stirred rapidly at room temperature for 8 hours. The mixture was diluted with ether, and the organic layer was washed with water and dried (MgSO₄). The residue obtained by filtration and concentration was then purified by flash chromatography (neutral alumina, 5% diethyl ether in hexanes) to afford the desired adducts as a separable 1:1 cis:trans mixture and colorless oil (486 mg, 95%). (cis-7e) R_f = 0.28 (20% EtOAc/hexanes); IR (film) 3062, 2978, 1732, 1625, 1190 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.66 (d, J = 8.3 Hz, 2H), 7.52 (dd, J = 8.0, 1.2 Hz, 1H), 7.42–7.39 (m, 3H), 7.35 (d, J = 7.6 Hz, 1H), 7.32–7.28 (m, 2H), 7.23–7.20 (m, 3H), 7.13 (td, J = 7.2, 1.0 Hz, 1H), 7.03 (td, J = 8.0, 1.6 Hz, 1H), 5.20 (d, J = 10.0 Hz, 1H), 4.74 (d, J = 10.0 Hz, 1H), 4.71 (s, 1H), 4.62 (s, 1H), 4.12–4.01 (m, 2H), 3.97–3.92 (m, 2H), 2.92 (d, J = 14.4 Hz, 1H), 2.45 (d, J = 14.4 Hz, 1H), 1.61 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H), 1.09 (t, J = 7.1 Hz, 3H), 0.97 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) ppm 170.8, 170.0, 169.8, 169.2, 142.2, 140.1, 137.8, 136.8, 133.0, 131.0, 130.3, 129.2, 128.7, 128.4, 128.2, 127.8, 126.8, 114.3, 80.7, 68.8, 61.1, 60.9, 60.5, 53.8, 43.4, 27.4, 24.0, 13.9, 13.8; (trans-7e) R_f = 0.23 (20% EtOAc/hexanes); ¹H NMR (400 MHz, CDCl₃) δ 8.27 (dd, J = 8.0, 1.6 Hz, 1H), 7.59 (d, J = 7.1 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.41–7.39 (m, 3H), 7.36 (d, J = 8.0 Hz, 1H), 7.34–7.29 (m, 3H), 7.15–7.12 (m, 2H), 7.09 (td, J = 8.0, 1.6 Hz, 1H), 4.99 (d, J = 4.6 Hz, 1H), 4.70 (s, 1H), 4.62 (d, J = 4.6 Hz, 1H), 4.52 (s, 1H), 4.07–4.04 (m, 3H), 3.89–3.80 (m, 1H), 2.70 (d, J = 1.2 Hz, 2H), 1.59 (s, 3H), 1.22 (s, 9H), 1.15 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) ppm 171.0, 170.12, 170.08, 169.2, 142.1, 139.8, 137.2, 136.6, 133.5, 132.4, 130.4, 129.0, 128.9, 128.7, 128.6, 128.3, 128.03, 128.00, 126.6, 114.7, 81.5, 67.2, 61.3, 61.2, 60.6, 49.5, 42.4, 27.8, 23.6, 13.8; HRMS (EI): Exact mass calcd for C₃₃H₃₃⁷⁹BrNO₆ [M-C₄H₉]⁺, 618.1491. Found 618.1464.

(trans)-2-(1-Benzhydryl-2-tert-butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)-2-(2-methyl-allyl)-malonic acid diethyl ester (trans-5e).

A benzene solution of Michael adduct trans-7e (80 mg, 118 μmol), and ⁿBu₃SnH (144 μL, 534 μmol) in benzene (50 μM) was warmed to 85 °C. AIBN (23 mg, 142 μmol) was then added as a benzene solution by syringe pump over a 4–5 hour period. The solution was refluxed an additional hour, cooled, and concentrated. The residue was treated with a 1:1 (v/v) ether-satd aq KF solution and stirred vigorously until a white precipitate formed. The organic layer was washed with water, dried (MgSO₄), filtered, and concentrated. The residue was then purified by flash chromatography (10% diethyl ether in hexanes), to furnish the indoline as a white solid (55 mg, 78%). mp 131.5–133.5 °C; R_f = 0.34 (20% EtOAc/hexanes); IR (film) 3062, 2978, 1732, 1602 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, J = 7.7 Hz, 2H), 7.41 (d, J = 7.8 Hz, 2H), 7.29–7.27 (m, 3H), 7.23–7.19 (m, 3H), 7.13 (d, J = 7.3 Hz, 1H), 6.82 (t, J = 7.6 Hz, 1H), 6.57 (t, J = 7.5 Hz, 1H), 5.90 (d, J = 8.0 Hz, 1H), 5.58 (s, 1H), 4.78 (s, 1H), 4.69 (s, 1H), 4.28 (d, J = 2.2 Hz, 1H), 4.19–4.07 (m, 3H), 4.00 (d, J = 2.2 Hz, 1H), 3.98–3.94 (m, 1H), 2.96 (d, J = 14.4 Hz, 1H), 2.70 (d, J = 14.4 Hz, 1H), 1.72 (s, 3H), 1.26 (s, 9H), 1.16 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) ppm 171.5, 170.4, 170.3, 151.1, 143.1, 141.8, 140.6, 129.7, 128.7, 128.6, 128.4, 127.9, 127.6, 127.3, 127.1, 126.3, 118.0, 115.2, 109.6, 81.2, 67.5, 67.3, 61.2, 61.1, 42.0, 27.9, 23.8, 14.0, 13.7; HRMS (EI): Exact mass calculated for C₃₇H₄₃⁷⁹BrNO₆ [M]⁺, 597.3090. Found 597.3093. Anal. Calcd for C₃₇H₄₃NO₆: C, 74.35; H, 7.25; N, 2.34. Found: C, 74.39; H, 7.38; N, 2.25.