Visible-Light-Mediated Aerobic Tandem Dehydrogenative Povarov/Aromatization Reaction: Synthesis of Isocryptolepines.

A metal-free, photoinduced aerobic tandem amine dehydrogenation/Povarov cyclization/aromatization reaction between N-aryl glycine esters and indoles leads to tetracyclic 11H-indolo[3,2-c]quinolines under mild conditions and with high yields. The reaction can be performed by using molecular iodine along with visible light, or by combining an organic photoredox catalyst with a halide anion. Mechanistic studies reveal that product formation occurs through a combination of radical-mediated oxidation steps with an iminium ion or N-haloiminium ion [4+2]-cycloaddition, and the N-heterocyclic products constitute new analogues of the antiplasmodial natural alkaloid isocryptolepine.

Introduction

The Povarov reaction (i.e., the aza‐Diels–Alder reaction of imines with electron‐rich alkenes) is a classical and versatile method for the synthesis of polysubstituted tetrahydroquinolines,1 and the pivotal imine [4+2]‐cycloaddition can be catalyzed by a range of Brønsted or Lewis acids.2 In recent years, dehydrogenative Povarov reactions have been developed (Scheme 1 a), in which an amine‐to‐imine oxidation precedes the imine [4+2]‐cycloaddition, followed by aromatization to quinoline products. These protocols typically involve the use of metal catalysts like CuI and CuII salts as well as FeII and AuI and AuIII complexes, along with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone (DDQ), organic peroxides, or O2 as the stoichiometric oxidants.3 A thermal double dehydrogenative variant of the Povarov reaction, including the parallel oxidation of an alkane as the precursor to the alkene 2 π component, has also been introduced,4 and Huo et al. remarkably could achieve such a process using the metal‐free system of CBr4 and PPh3 (Scheme 1 b).5 In the arena of photochemistry, Li and Zhang developed a dual photoredox and Lewis acid catalyzed dehydrogenative Povarov reaction between glycine esters and styrenes (Scheme 1 c),6 and later they also demonstrated the use of Eosin Y as an organic photocatalyst for the dehydrogenation of glycine esters in the Brønsted acid mediated cycloaddition with dihydrofuran.7 A single example of an aerobic photoinduced CuII‐mediated reaction has also been reported.8

Scheme 1

Methods for the tandem dehydrogenative Povarov/aromatization reaction.5, 6 NHPI=N‐hydroxyphthalimid, DDQ=2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone, TBHP=tert‐butyl hydroperoxide, PC=photocatalyst.

We report here the tandem amine dehydrogenation/imine [4+2]‐cycloaddition/aromatization of glycine esters with indoles. We developed two photoinduced aerobic and metal‐free variants of this reaction, either using I2 with blue light irradiation, or employing a system combining an organic photoredox catalyst with a source of halide anion X− and visible light (Scheme 1 d). 11H‐Indolo[3,2‐c]quinoline products were obtained under mild conditions and with yields up to 99 %. These tetracyclic compounds possess the core structure of the natural alkaloid isocryptolepine from the West African flowering plant Cryptolepis sanguinolenta, which shows antimalarial activity against Plasmodium falciparum.9 Therefore, new derivatives of isocryptolepine have been of ongoing interest in medicinal chemistry research.10

Results and Discussion

Initially, we observed that reacting p‐anisidinyl glycine ester 1 a with N‐Boc‐indole (2 a) (Boc=tert‐butoxycarbonyl) in the presence of small amounts of molecular iodine and oxygen under blue light irradiation led to the aromatic N‐Boc‐protected 11H‐indolo[3,2‐c]quinoline‐6‐carboxylate 4 a in a mixture with the Boc‐deprotected derivative 4 a′, and the reaction was subsequently optimized as shown in Table 1, method A (see also Table S1, Supporting Information). Using 10 mol % of I2 in MeCN under air led to a combined yield of cycloadducts 4 a,4 a′ of 38 % after 48 h (Table 1, entry 1). When the same reaction was performed in the dark, the dihydro‐11H‐indolo[3,2‐c]quinoline 3 a was formed in 12 % yield along with 5 % of product 4 a. The intermediacy of 3 a in the reaction was soon confirmed because its conversion to 4 a,4 a′ increased with prolonged reaction time. Increasing quantities of I2 and oxygen both improved the yields of 4 a and 4 a′ (Table 1, entries 3–5), and using 50 mol % of I2 under O2 atmosphere fully converted indole 2 a within 48 hours, to give compound 4 a in a high yield of 70 % after chromatography, along with 22 % of its Boc‐deprotected congener 4 a′. Br2 could be used in place of I2 (Table S1, Supporting Information); however, this resulted in lesser conversion and a markedly decreased selectivity. Under the optimum conditions, no conversion occurred in the absence of I2 and just 14 % in the absence of O2, whereas in the case of p‐anisidinyl glycine ester 1 a, some product formation was also observed in the dark, which can be attributed to the particular ease of autoxidation of the highly electron‐rich substrate 1 a. By comparison, the analogous dark reaction of the much less activated p‐toluidinyl glycine ester 1 b gave only trace amounts of the corresponding product 4 b (<5 %) (Table S1, Supporting Information). Employing N‐tosylindole (2 b) in the reaction with 1 a under the optimum conditions, none of the corresponding indolo[3,2‐c]quinolines could be detected. Using N‐acetylindole (2 c), its cycloadducts were formed in only 14 % combined yield, whereas 1H‐indole (2 d) underwent decomposition to undefined products (entry 6).

Table 1

Reaction optimization.[a]

Entry	R1	Conditions	Conv. 2 a [%][b]	3 [%][c]	4/4′ [%][c]
method A
1	OMe	10 mol % I2, air, MeCN, 48 h	38	0	36:2
2	“	10 mol % I2, air, MeCN, 48 h, no light	22	12	5:0
3	“	20 mol % I2, air, MeCN, 48 h	38	8	21:8
4	“	50 mol % I2, air, MeCN, 48 h	82	8	56:26
5	“	50 mol % I2, O2, MeCN, 48 h	100	0	74:26 (70[d]:22[d])
6	OMe	N‐tosylindole (2 b), N‐acetylindole (2 c), 1H‐indole (2 d)	n.d.[e]	14 % cycloadducts from 2 c only
method B
7	OMe	1 mol % Acr+‐Mes⋅ClO4, 10 mol % TBAI, O2, MeCN, 48 h	0	0	0:0
8	“	1 mol % TPP⋅BF4, 10 mol % TBAI, O2, MeCN, 48 h	0	0	0:0
9	“	1 mol % TPP⋅BF4, 10 mol % TBAI, O2, HFIP/DCE, 48 h	48	0	0:48
10	“	2 mol % TPP⋅BF4, 10 mol % TBAI, O2, HFIP/DCE, 48 h	68	12	22:30
11	“	1 mol % TPP⋅BF4, 10 mol % TBAI, O2, HFIP/DCE, 72 h	74	12	10:52 (55[d,f])
12	Me	1 mol % TPP⋅BF4, 10 mol % TBAI, O2, HFIP/DCE, 72 h	80	3	20:56 (75[d,f])

[a] Reactions performed on 0.10 mmol scale of 2 a, irradiation with 36 W blue compact fluorescent lamp (CFL), λ=(450±50) nm. [b] Conversion determined by 1H NMR spectroscopic analysis. [c] Yield determined by 1H NMR spectroscopy against CH2Br2 as internal standard. [d] Yield of isolated products after chromatography. [e] n.d.=not determined. [f] Reaction mixture treated with TFA before isolation. Acr+‐Mes= 9‐Mesityl‐10‐methylacridinium, TPP⋅BF4=triphenylpyrylium tetrafluoroborate.

“

“

“

“

50 mol % I

74:26 (

“

“

“

“

1 mol % TPP

20:56 (

We subsequently aimed at developing an alternative photoorganocatalytic variant of the reaction (Table 1, method B), which potentially would allow replacement of I2 by the iodide anion. Although Fukuzumi's catalyst11 along with a catalytic quantity of tetrabutylammonium iodide (TBAI) under O2 in MeCN slowly converted glycine ester 1 a to the corresponding imine (56 % conversion after 48 h), no cycloaddition products were detected (entry 7). The same reaction with the triphenylpyrylium (TPP+) cation as the organic photocatalyst gave a similar result, however, with quantitative conversion of 1 a to the imine. Using 1 mol % of TPP⋅BF4 and 10 mol % of TBAI in the protic solvent mixture of hexafluoroisopropanol (HFIP) and dichloroethane (DCE), conditions similar to those previously used by Muñiz et al. for photocatalytic Hofmann–Löffler‐type reactions,12 glycine ester 1 a and N‐Boc‐indole (2 a) were converted into the Boc‐deprotected aromatic cycloadduct 4 a′ with 48 % yield after 48 h (Table 1, entry 9). After further experimentation (Table 1, entries 10 and 11 and Table S1, Supporting Information), the best conditions were using 1 mol % of TPP⋅BF4 with irradiation for 72 h, to give 4 a′ as the major product with 52 % yield, accompanied by 10 % of N‐Boc‐protected compound 4 a. To generate a single product, the reaction mixture was subsequently treated with trifluoroacetic acid (TFA), to furnish compound 4 a′ in an isolated yield of 55 % after chromatography. Using glycine ester 1 a, a maximum conversion of indole 2 a of 74 % was obtained under these conditions; however, in the case of p‐toluidinyl‐substituted 1 b, we demonstrated that despite incomplete conversion of 2 a of 80 % (Table 1, entry 12), an isolated yield as high as 75 % for compound 4 b′ could be achieved. Further, we found that tetrabutylammonium bromide (TBABr) could be used in place of TBAI (Table S1, Supporting Information).

The scope of the visible‐light‐mediated tandem dehydrogenative Povarov/aromatization reaction is depicted in Scheme 2. Using method A, various donor‐substituted N‐aryl glycine esters 1 a–1 f were employed in the reaction giving rise to clean and quantitative conversion of N‐Boc‐indole (2 a) in all cases. The indolo[3,2‐c]quinoline products 4 a–4 f were isolated in high yields of 59–85 %, along with minor quantities of their N‐deprotected analogues 4 a′–4 f′ (9–35 %), which were readily separated by column chromatography.13 Using method B, compounds 4 a′–4 f′ were obtained in 55–75 % yield after treatment of the crude product mixtures with TFA. Notably, the N‐phenyl glycine ester 1 g did not provide the products 4 g,4 g′ under the conditions of method A (aromatic iodination of the aniline ring occurred), but using method B, derivative 4 g′ was prepared in 37 % yield. Further, acceptor‐substituted glycine esters like the 4‐trifluoromethylphenyl and 4‐cyanophenyl derivatives 1 h and 1 i did not react when employed under conditions A. However, by using the photocatalyst TPP⋅BF4 with a halide anion, this limitation could be overcome. Thus, product 4 h′ was formed in 17 % yield with TPP+/TBAI, and with a significantly improved yield of 52 % with TBABr in place of TBAI. In the case of 4‐cyanophenyl glycine ester 1 i, the best result was achieved by using the photocatalyst along with tetrabutylammonium chloride (TBACl), to furnish product 4 i′ in 54 % yield.

Scheme 2

Reaction scope. Yields after chromatography. Method A: 50 mol % I2, O2, hv 450 nm, MeCN, RT, 48 h. Method B: 1 mol % TPP⋅BF4, 10 mol % TBAI, O2, hv 450 nm, HFIP/DCE, RT, 72 h, then TFA, 50 °C, 6 h.

In addition to N‐Boc‐indole (2 a), N‐Boc‐5‐bromoindole (2 e) as well as the 5‐ and 7‐methoxylated N‐Boc‐indoles 2 f and 2 g were used, giving rise to polysubstituted indoloquinolines 4 j,4 j′–4 l,l′. Further, 2‐methyl‐N‐Boc‐indole (2 h) was successfully employed, leading to the cycloadducts 4 m and 4 n with 59 and 31 % yields, respectively, but using I2 only. Finally, benzofuran (5) was identified as another viable 2 π component, to generate the benzofuro[2,3‐c]quinoline‐6‐carboxylates 6 a–6 c in yields of 42–94 %, and the observed reversal of regioselectivity in these cycloaddition reactions was unambiguously confirmed by the single‐crystal X‐ray structure of compound 6 c.13 Again, products 6 a–6 c were accessible only under the conditions of method A. We further attempted to use N‐Boc‐pyrrole (7) and benzothiophene (8) in the reaction; however, no cycloaddition occurred and both substrates were mostly recovered. The reaction between glycine ester 1 a and 5‐cyano‐N‐Boc‐indole (2 i) was also not feasible.

With regard to the reaction mechanism, we conducted the control experiments summarized in Scheme 3. The reaction to form products 4 a,4 a′ starting from glycine ester 1 a and N‐Boc‐indole (2 a) could also be promoted by N‐iodosuccinimide (NIS) with blue light irradiation, whereas almost no conversion occurred in the dark, which proved the contribution of radical intermediates (Scheme 3 a). Additionally, the standard reaction between 1 a and 2 a using I2 was largely quenched in the presence of an equimolar amount of 2,2,6,6‐tetramethylpiperidine N‐oxide (TEMPO) (Scheme 3 b). Although no cycloaddition occurred, 56 % of the imine 9 a was formed, indicating its role as a key intermediate. The same experiment under the conditions of method B also showed radical quenching, even though to a slightly lesser extent (compare with Table 1, entry 11).

Scheme 3

Mechanistic control experiments.

Imine 9 a, derived from glycine ester 1 a by dehydrogenation, was generally present in all crude reaction mixtures as evident from NMR spectroscopic analysis. When glycine ester 1 a was reacted alone, imine 9 a was generated exclusively, both under the conditions of methods A and B. As shown in Scheme 3 c (and Table S2, Supporting Information), we reacted imine 9 a with indole 2 a under various conditions. Although irradiation of imine 9 a in MeCN under O2 with indole 2 a alone gave no conversion, its reactions under both conditions of methods A and B delivered the products 3 a, 4 a, and 4 a′. In order to establish which species actually activates imine 9 a in the [4+2]‐cycloaddition, we added hydroiodic acid (HI), NIS as well as I2, to find that the cycloaddition occurred in all cases, even in the dark. These results showed that the imine could be activated by a number of alternative pathways, including protonation by HI to the iminium ion (9‐H) as well as N‐iodination with NIS or I2 to give the N‐iodoiminium ion (9‐I), and possibly also by halogen bonding activation of 9 in a complex 9⋅I under these model conditions.14

However, when using HI, NIS, and I2 under irradiation, a further significant increase in conversion was observed, which proved an additional strong contribution of light‐induced radical pathways in the subsequent oxidation steps to the final products 4 a,4 a′. Finally, in order to rule out a conceivable reaction pathway consisting of a tandem cross‐dehydrogenative coupling (CDC) between glycine ester 1 a and indole, followed by 6 π‐electron cyclization and aromatization, we subjected the independently prepared CDC products 10 a and 10 b to the typical conditions of method A (Scheme 3 d). These reactions however did not generate products 3 and 4,4′, but the deeply rearranged15 6H‐indolo[2,3‐b]quinoline‐11‐carboxylates 11 a and 11 b were formed as the only products and isolated in moderate yields of 38 and 48 %, respectively; their constitution being confirmed by single‐crystal X‐ray analysis of product 11 b.13

On the basis of our observations, we propose the mechanism depicted in Scheme 4. Under the conditions of method A, photolysis of I2 generates the iodine radical I., which abstracts a hydrogen atom from glycine ester 1, to give HI and the α‐amino radical 12, which is trapped by O2. The resulting peroxyl radical can react with another molecule of glycine ester 1 in a chain propagation step.5a Elimination of H2O2 from hydroperoxide 13 gives the imine 9, which undergoes a Brønsted acid mediated [4+2]‐cyclization with HI followed by 1,4‐hydrogen shift, and a fast oxidation mediated by I. and O2 leads to the dihydroquinoline 3. The regeneration of the I2 catalyst can occur through the reaction between HI and H2O2.16 Conversely, using TPP+ and X− (method B), photoelectron transfer (PET) between the excited‐state catalyst (E*red=+2.55 V vs. the standard calomel electrode (SCE))17 and glycine esters 1 (E ox ranging from +0.82 to +1.59 V vs. SCE)18 generates the radical cation 14, which can react with superoxide to give the imine 9. In the protic medium, the major product‐forming pathway similarly is the acid‐mediated [4+2]‐cycloaddition and oxidation to 3; however, control experiments showed that the presence of the halide ion X− contributes to 30–35 % of total conversion to products 3 and 4 (Table S1, Supporting Information), indicating the existence of a second minor reaction pathway. We propose that PET between PC* and HX generates X2,19, 20 which in the presence of trace amounts of H2O gives hypohalite,12 to convert imine 9 into the N‐haloiminium ion 14. The subsequent [4+2]‐cyclization followed by elimination of HX leads to intermediate 3. The final comparatively slow oxidation of 3 gives the aromatic product 4, which undergoes N‐Boc‐deprotection by HX, the rate of which depends on the actual acid concentration under the reaction conditions A or B. Generally, the protic medium of method B also facilitates an autoxidative product formation in the case of highly electron‐rich glycine esters like 1 a or 1 b; this is however much less pronounced for less activated and acceptor‐substituted systems. In the presence of TPP+, all incident light is absorbed by the photocatalyst.

Scheme 4

Proposed mechanism.

The orientation of the C3‐nucleophilic indole 2 and imine 9 in the [4+2]‐cycloaddition is polarity‐matched, yet it also avoids a steric clash between the N‐Boc‐group of the indole and the carboethoxy function of the imine; such steric hindrance does not occur in cycloadditions with benzofuran (5), which reacts through a regioisomeric orientation, which is also in agreement with its higher charge density at C2.21 The failure of benzofuran (5) to undergo the imine [4+2]‐cycloaddition under conditions B likely results from a competing photoelectron transfer to the excited photocatalyst (E ox of 5 = +1.20 V vs. SCE)22 impeding further conversion, and which evidently does not occur with N‐Boc‐indole (2 a).

Conclusion

We developed two metal‐free protocols for the photoinduced aerobic tandem amine dehydrogenation/Povarov cyclization/aromatization reaction between N‐aryl glycine esters and indoles as well as benzofuran, to furnish the corresponding aromatic [4+2]‐cycloadducts with high selectivity and yield. The indolo[3,2‐c]quinoline products resemble new analogues of the antimalarial natural alkaloid isocryptolepine, and thus they may be of value in medicinal research.

Experimental Section

Typical procedures: synthesis of compounds 4 b and 4 b′

Method A: In a 10 mL crimp cap vial, N‐aryl glycine ester 1 b (40.2 mg, 208 μmol) and N‐Boc‐indole (2 a, 22.6 mg, 104 μmol) were dissolved in MeCN (3.50 mL). I2 (13.2 mg, 52.0 μmol) was added, and the vial was sealed and fitted with an O2‐balloon (with the septum pierced by a needle). The mixture was irradiated between two blue CFL lamps (2×18 W, 450±50 nm) with rapid stirring for 48 h. The mixture was poured into NaHCO3 (aq.) and Na2S2O3 (aq.) followed by extraction with EtOAc (3×). The combined organic layers were dried with Na2SO4, filtered, and evaporated to dryness. Column chromatography (silica, Et2O/heptane 1:1) furnished compounds 4 b (35.8 mg, 85 %) and 4 b′ (4.4 mg, 14 %).

Method B: In a 10 mL crimp cap vial, N‐aryl glycine ester 1 b (44.1 mg, 228 μmol), N‐Boc‐indole (2 a, 24.8 mg, 114 μmol), TBAI (4.2 mg, 11.0 μmol), and TPP⋅BF4 (0.5 mg, 1.0 μmol) were dissolved in DCE (1.90 mL) and HFIP (1.90 mL). The vial was sealed and fitted with an O2‐balloon (with the septum pierced by a needle). The mixture was irradiated between two blue CFL lamps (2×18 W, 450±50 nm) with rapid stirring for 72 h. TFA (169 μL, 2.21 mmol) was added, and the mixture was stirred at 50 °C for 6 h. The mixture was poured into NaHCO3 (aq.) and Na2S2O3 (aq.) followed by extraction with EtOAc (3×). The combined organic layers were dried with Na2SO4, filtered, and evaporated to dryness. Column chromatography (silica, Et2O/heptane 1:1) furnished 4 b′ (26.0 mg, 75 %).

Compound 4 b: Colorless solid; m.p. 103 °C; R f=0.57 (Et2O/heptane 1:1); 1H NMR (600 MHz, CDCl3): δ=1.56 (t, 3 J=7.2 Hz, 3 H, CH3), 1.72 (s, 9 H, tBu), 2.62 (s, 3 H, Ar‐CH3), 4.70 (q, 3 J=7.2 Hz, 2 H, CH2), 7.45 (ddd, 4 J=1.1 Hz, 3 J=7.2, 8.2 Hz, 1 H, 8‐H), 7.54–7.60 (m, 2 H, 3‐H, 9‐H), 8.07 (s, 1 H, 1‐H), 8.21 (dt, 4 J=0.9 Hz, 3 J=8.4 Hz, 1 H, 10‐H), 8.23 (d, 3 J=8.6 Hz, 1 H, 4‐H), 8.44 ppm (dt, 4 J=1.0 Hz, 3 J=7.9 Hz, 1 H, 7‐H); 13C NMR (150 MHz, CDCl3): δ=14.5 (q, CH3), 22.4 (q, Ar‐CH3), 28.1 (q, tBu), 62.6 (t, CH2), 85.8 (s, tBu), 114.4 (d, C‐10), 117.1 (s, C‐6a), 119.1 (s, C‐4a), 123.0 (s, C‐6b), 123.4 (d, C‐7), 123.8 (d, C‐1), 124.0 (d, C‐8), 127.7 (d, C‐9), 130.8 (d, C‐4), 131.2 (d, C‐3), 136.9 (s, C‐2), 140.3 (s, C‐10a), 141.1 (s, C‐11a), 144.2 (s, C‐6), 144.9 (s, C‐11b), 150.9 (s, NCO), 167.1 ppm (s, CO2R); IR: = 2980, 2935 (=C−H, −C−H), 1740 (CO), 1250 (C=C), 1150, 1095, 750 cm−1; HRMS (ESI+): m/z calcd C24H24N2O4 [M+H]+: 405.1809, found: 405.1825.

Compound 4 b′: Colorless solid; m.p. 276 °C (dec.); R f=0.57 (Et2O/heptane 3:1); 1H NMR (600 MHz, [D6]acetone): δ=1.50 (t, 3 J=7.2 Hz, 3 H, CH3), 2.62 (s, 3 H, Ar‐CH3), 4.62 (d, 3 J=7.1 Hz, 2 H, CH2), 7.35 (ddd, 4 J=1.1 Hz, 3 J=7.1, 8.2 Hz, 1 H, 8‐H), 7.52 (ddd, 4 J=1.2 Hz, 3 J=7.1, 8.2 Hz, 1 H, 9‐H), 7.65 (dd, 4 J=1.9 Hz, 3 J=8.5 Hz, 1 H, 3‐H), 7.73 (dt, 4 J=1.0 Hz, 3 J=8.2 Hz, 1 H, 10‐H), 8.12 (d, 3 J=8.5 Hz, 1 H, 4‐H), 8.30–8.34 (m, 1 H, 1‐H), 8.53 (dd, 4 J=1.0 Hz, 3 J=8.2 Hz, 1 H, 7‐H), 11.9 ppm (s, 1 H, NH); 13C NMR (150 MHz, [D6]acetone): δ=14.7 (q, CH3), 21.9 (q, Ar‐CH3), 62.2 (t, CH2), 112.5 (d, C‐10), 113.4 (s, C‐6a), 118.4 (s, C‐4a), 121.5 (d, C‐1), 121.7 (d, C‐8), 122.3 (s, C‐10a), 124.2 (d, C‐7), 126.9 (d, C‐9), 131.0 (d, C‐4), 131.6 (d, C‐3), 138.2 (s, C‐2), 140.5 (s, C‐6b), 142.2 (s, C‐11a), 143.8 (s, C‐11b), 145.6 (s, C‐6), 168.1 ppm (s, CO2R); IR: =2972 (=C−H, −C−H), 1720 (C=O), 1588 (C=N, C−N, NH), 1299, 1239, 1175, 816, 739 (C−H) cm−1; HRMS (ESI+): m/z calcd C19H16N2O2 [M+H]+: 305.1290, found: 305.1292.

Conflict of interest

The authors declare no conflict of interest.

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