The representative electrochemical method of α-amido functionalization is to form iminium ions through the oxidation of carbamate, and the generated iminium ions are trapped by nucleophiles (Shono type oxidation)50, 51 (Scheme 1-27). Since NAI is formed through direct two electron oxidation of carbamate, oxidation occurs at relatively high potential, therefore only limited nucleophiles with high oxidation potentials, such as alcoholic solvents, can react with formed iminium.
Scheme 1-27. Shono oxidation.
In the 1980s, the Yoshida group developed an electroauxiliary strategy. This concept involves introducing a relatively redox active group to lower the oxidation potential of the substrate to prevent overoxidation of coupling partner or desired product. The trimethylsilyl (TMS) substituted carbamate has an oxidation potential of 1.45V, which is 0.5V lower than the non TMS substituted carbamate (Scheme 1-28a)52. The organothio group is effective electroauxiliary that can form NAI intermediates by cleavage of C-S bond and can be functionalized using various carbon nucleophiles such as allylsilane, silyl enol ether, trimethylsilyl cyanide and electron-rich arenes(Scheme 1-28b)53.
Scheme 1-28. Electroauxiliary strategy.
In 1999, Yoshida and coworkers developed "cation pool" strategy to expand the scope of nucleophiles (Scheme 1-29)54. The concept of “cation pool” is NAI cations accumulated through low-temperature electrolysis. The nucleophiles were added to the “cation pool” under nonoxidative conditions. Therefore, easily oxidizable nucleophiles such as allyl silane, silyl enol ether, electron-rich arene, and 1,3-
17
dicarbonyl compound can be applied to the coupling reaction. Additionally, they found that Grignard reagent can be used as a nucleophile in the “cation pool” method55.
Scheme 1-29. Cation pool strategy.
In 2002, Yoshida and coworker demonstrated the novel radical reaction of "cation pools" (Scheme 1- 30)56. Oxidatively generated NAI is reduced by swapping the electrode from the anode to cathode, it converted into N-α radical intermediate, which undergoes radical addition to activated alkene. Most of NAI intermediate reactions proceeded in polar pathway, this new strategy opens the new reactivity of NAI. Giese-type α-amido alkylation was successfully performed via N-α radical intermediate.
Scheme 1-30. The cathodic reduction of cation pool.
They reported an alkyl radical addition reaction to NAI of "cation pool" (Scheme 1-31)57. Hexabutyldistannane is used to abstract iodine radical from alkyl iodide to form alkyl radical. The resulting alkyl radical undergoes radical addition to the NAI to form a radical cation intermediate. It is converted to corresponding product by single electron transfer (SET) with another distannane.
18
Scheme 1-31. Radical addition to cation pool.
In 2007, the Yoshida group developed the reaction of NAI “cation pool” with organometallic compounds (Scheme 1-32)58. Benzyl radicals formed through direct SET between NAI and benzylsilane or benzylstannane undergo the radical addition reaction to NAI. As the interaction between the σ orbital of C-Si and the π orbital of benzene increases, HOMO level increases, which facilitates ET. The reaction efficiency was improved using benzylstannane having a low oxidation potential. The binary system of stoichiometric benzylsilane and catalytic benzylstannane showed new possibilities for the reaction of organometallic compounds.
Scheme 1-32. SET between cation pool and organometallic compound.
In 2020, Tian-Sheng group reported a novel asymmetric Shono cross-coupling reaction (Scheme 1- 33)59. In the Cu/TEMPO cocatalyst system, α-alkynylation was successfully performed with good enantioselectivity. The TEMPO catalyzed hydride transfer produces iminium intermediates that further react with organocopper.
19
Scheme 1-33. NAI formation via hydride transfer.
20
Chapter 2.
Synthesis of Indolopyrans and 2,3- Dihydrofurans based on Oxidative
Cycloaddition
21
2.1 Design for the synthesis of Indolopyrans and 2,3-dihydrofurans
Indole derivatives appear in pharmaceuticals, and indole-fused-polycyclic scaffolds are known to have biological activities such as carbazole and carboline60-62. Indolopyran scaffolds can be found in compounds with anti-inflammatory, anti-cytotoxic, and analgesic activity.
We developed the synthetic method of indolopyran and 2,3-dihydrofuran derivatives based on oxidative cycloaddition (Figure 2-1). (a) Iodine-mediated cross-coupling proceeds with single electron transfer (SET) followed by radical-radical cross-coupling (RRCC)63. The SET occurs in solvent cage, enabling highly selective RRCC. (b) The electrochemical method is the oxidative cycloaddition reaction via hydrogen atom transfer (HAT)33. The subschiometric amount of iodide and O2 are used as HAT mediator and base, respectively.
Figure 2-1. Developed synthetic method toward indolopyran and 2,3-dihydrofuran.
2.2 Iodine-mediated oxidative cross-coupling reaction 2.2.1 Substrate scope
We investigated several bases and oxidants to perform the synthesis of indolopyran 3a, the use of K3PO4
and I2 showed the excellent reactivity. The equimolar amounts of 1a and acetylacetone 2a were successfully transformed into corresponding product 3a in excellent yield, 92% within 10 minutes. With optimized conditions, we performed the reaction with various 1 and active methylene compounds (AMCs) 2 (Table 2-1). Regardless of electronic effect of 1, corresponding products were obtained in excellent to good yield (3a-3f). It turned out that N-H indole 1g was well tolerated, while other substituent groups, including benzyl, aryl, and acetyl diminished the reaction yield (3h-3j). The other AMCs such as electron-rich diketone, ketonitrile, and ketophosphonate, were able to synthesize the desired products in high yield (3k-3m).
After establishing the substrate scope of indolopyran 3, we investigated the reaction between acetylacetone 2a and enamine 4a instead of 1a. To our delight, single diastereomer of 2,3-dihydrofuran 5a was obtained in 75% yield (Table 2-2). Regardless of the electronic properties of the enamine aryl
22 Table 2-1. Substrate scope of indolopyrana.
[a] Reaction conditions: Reactions were performed with 1 (0.10 mmol) and 2 (0.11 mmol) in dry MeCN (0.1 M) under N2. Isolated yield.
ring, the reactions are carried out without affecting reactivity (5a-5g). Instead of acetylacetone 2a, the reaction proceeds smoothly with ketoester, ketosulfone, and ketophosphonate to synthesize the various substituted 2,3-dihydrofurans (5h-5j).
2.2.2 Mechanistic studies
Various control experiments were performed to elucidate the reaction mechanism. First, to investigate the reaction intermediate, 3′a was synthesized and a standard reaction was performed with a half amount of iodine (Scheme 2-1a (i)). It turned out to provide 3a in 97% yield, indicating 3′a is an intermediate in the formation of 3a. Next, using the iodo-substituted diketone 2k in standard reaction, all starting materials were converted to the desired product 3k (Scheme 2-1a (ii)). From this, we found that the reaction proceeds via the iodo-subsitued AMCs.
23 Table 2-2. Substrate scope 2,3-dihydrofuransa.
[a] Reaction conditions: Reactions were performed with 4 (0.10 mmol) and 2 (0.11 mmol) in dry MeCN (0.1 M) under N2. Isolated yield. [b] acetoacetate (1.5 equiv.), iodine (2 equiv.), K3PO4 (5 equiv.).
To investigate the formation of the 1a radical intermediate, the reaction between anion 1′a and the well-known Togni reagent as an electron acceptor was performed (Scheme 2-1b). After 10 minutes, the starting materials were fully converted to CF3 substituted indole 6 and dimer 7, supporting radical intermediate formation.
Scheme 2-1. Mechanistic study of iodine mediated reaction.
24 2.2.3 Proposed mechanism
We could determine the reaction intermediates after several control experiments. The proposed mechanism is shown in Figure 2-2. The cage collapsed SET occurs between 1′a and 2′a to form the corresponding radical intermediates (Figure 2-2a). The highly selective RRCC between radical intermediates forms 3′a which is oxidized to oxatriene 3′′a by iodine. The generated 3′′a undergoes 6π- electrocyclization resulting in 3a.
On the other hand, the RRCC between the 4′′a and 2′′a affords 5′a, which undergoes oxa-Michael addition to generate 2,3-dihydrofuran 5a (Figure 2-2b). The cage collapsed SET between 4′a and 2′a produces the corresponding radical intermediates. The formation of a single diastereomer can be explained by the chair-like transition state TS-5′a of oxa-Michael addition.
Figure 2-2. Proposed reaction mechanism.
25
2.3 Electrochemical hydrogen atom transfer mediated reaction 2.3.1 Reaction optimization
We were interested in whether the oxidative cycloaddition of indolomalonate and enamine proceeds under the electrochemical method. We started the study to find optimal electrolysis conditions using 1a, 2a, and iodide sources. After several screenings, we were able to synthesize 3a in the presence of NaI (Scheme 2-2). Electrolysis at constant voltage mode (3V) using graphite anode and reticulated vitreous carbon (RVC) cathode, and NaBF4 as electrolyte in undivided-cell, afforded the desired product 3a in 77% yield. Due to the decomposition problem of 3a, only a few amounts of product were obtained at constant current mode (7 mA).
Scheme 2-2. Electrochemical synthesis method.
Table 2-3. Reaction optimizationa.
Entry Variation from the standard conditions Yield (%)
1 none 70 (67)b
2c 10 mA 60
3c 3 mA 63
4c 3 V 50
5c 3 V, C (+) | C (-) instead of C (+) | RVC (-) 30
6c 3 V, 1 equiv. of NaI 34
[a] Reaction conditions: Undivided cell, graphite anode, RVC cathode, 4a (0.1 mmol), 2a (0.15 mmol), NaBF4 (0.1 M), MeCN (3 mL). Yield determined by 1H NMR analysis of the crude reaction mixture using 1,1,2-Trichloroethene. [b] Isolated yield. [c] 2a (2 equiv.).
26
The synthesis of 2,3-dihydfuran 5a was demonstrated under electrochemical synthesis (Table 2-3).
Unlike the reaction of 1a, it showed better yield at constant current mode (7 mA). The slightly decreased yield was shown by variation in current (Table 2-3, entry 2 and 3). Only a few amounts of product were synthesized at constant voltage mode (3 V) (Table 2-3, entry 4-6). Due to the increased reaction time at constant voltage mode, 4a was decomposed.
2.3.2 Substrate scope
The scope of substrate was examined under optimized conditions (Table 2-4). The electronic effect of indolomalonate ring was not significant to afford the product (3a-3e). The bromo-substituted pyran 3f was synthesized in good yield, which can be modified with other functional groups. N-aryl and unsubstituted indoles were tolerated in our reaction (3g and 3i). Various types of substituted dihydropyran can be synthesized using 2a as well as other types of coupling partners (3k-3m). The 7- azaindole also participated well in our reaction (3n). For some substrates, additional tert-butyl peroxide was necessary to improve reaction efficiency. The cathodic reduction of tert-butyl peroxide produces the more basic tert-butoxide, which encourages the reaction.
Table 2-4. Substrate scope of indolopyrana.
[a] Reaction conditions: 1 (0.10 mmol) and 2 (0.11 mmol) in MeCN (0.03 M) under Ar. Yields of isolated products are given. [b] With 1.5 equiv of NaI. [c] Di-tert-butyl peroxide was used as an additive (1.0 equiv.).
27
Various 2,3-dihydrofuran derivatives 5 were synthesized in our reaction (Table 2-5). The electron- deficient enamine showed good reactivity to the corresponding 2,3-dihydrofuran (5f and 5g), whereas the electron-rich enamine reacted with moderate to low yield (5b-5d). Similar to the reaction with indole 1, other types of AMCs were also well tolerated (5h and 5i). The reaction with ketophosphonate showed low reactivity (5j).
Table 2-5. Substrate scope 2,3-dihydrofuransa.
[a] Reaction conditions: 1 (0.10 mmol) and 2 (0.15 mmol) in MeCN (0.03 M) under Ar. Yields of isolated products are given. [b] With 2–3 equiv. of the AMC.
2.3.3 Mechanistic studies
To elucidate the reaction mechanism, several control experiments were performed. We found that 3′a is the reaction intermediate using it under standard reaction conditions (Scheme 2-3a). Standard reaction with 3′a provided 90% of 3a. As shown in Scheme 2-3b, indole dimer 7 is provided in 46% yield at 1 V. This suggests that 1a radical is generated under iodide-mediated electrolysis. The cyclic voltammetry study of 1a and iodide (Figure 2-3) show that 1 V is not sufficient to oxidize 1a, but iodide can be oxidized. Therefore, rather than direct anodic oxidation of 1a, iodine radical generates the 1a radical.
28
We proceed with reactions to rationalize the radical formation mechanism of AMCs (Scheme 2-3c).
Electrolysis with 2k under NaI without O2 did not form any dimer 8, however, it was synthesized in O2
bubbled acetonitrile solution in 48% yield. This indicates that O2 produces AMC radicals rather than iodide.
Scheme 2-3. Mechanistic study of electrochemical synthesis.
Figure 2-3. Cyclic voltammetry graph.
2.3.4 Proposed mechanism
The proposed reaction mechanism based on control experiments is described in Figure 2-4. The iodine radical generated by anodic oxidation of iodide proceeds HAT from 1a toward radical intermediate 1′′a.
Concurrently, the cathodic reduction of oxygen produces superoxide radicals that react as base. It deprotonates the proton from 2a to form 2′a and is oxidized toward the radical intermediate 2′′a. The resulting radical species undergo RRCC to afford 3′a. It undergoes HAT with iodine radical followed by oxidation to provide oxatriene 3′′a. The spontaneous 6π-electrocyclization of 3′′a affords 3a.
29
The RRCC between 4′′a and 2′′a followed by oxa-Michael addition affords 2,3-dihydrofuran 5a (Figure 2-4b). Iodine radical and superoxide radical produce radical intermediate 4′′a and 2′′a, respectively. It shares the same mechanism as 3a. The chair-like transition state, in which the aniline group is located at equatorial, proceeds with a diastereoselective reaction.
Figure 2-4. Proposed reaction mechanism.
2.4 Synthetic application
We demonstrated the importance of indolopyran 3 using it in the synthesis of dihydro-ɣ-carboline, which has shown promising bioactivities in preclinical and clinical studies (Scheme 2-4). The dihydro- ɣ-carboline derivatives 9 are synthesized from the corresponding anilines under acidic conditions.
30
Scheme 2-4. Synthetic application.
2.5 Substrate synthesis
Metal-catalyzed dicarbonyl carbenoid insertion affords indolomalonate derivatives 1 (Scheme 2-5a).
We mainly used Cu(hfacac)2, Cu(acac)2, and Rh2(OAc)4 as metal catalysts. The desired indolomalonate derivatives 1 were synthesized in high yield with substituted indole and diazo compound,
The other substrate, enamine derivatives 4 were synthesized based on photocatalysis (Scheme 2-5b).
We used diethyl 2-bromomalonate as C-radical precursor under the photoredox reaction of 14. The enamine derivatives 14 are prepared by reductive amination followed by Michael addition.
Scheme 2-5. Substrate synthesis – Reaction conditions: a) Copper (II) or Rh (II) catalyst, DCE, 60 ̊C, 50-95% b) NaOMe, paraformaldehyde, r.t.; NaBH4, MeOH, reflux, 70-90% c) methyl propiolate, MeOH, 50 ̊C, 80-95% d) Diethyl 2-bromomalonate, Ir(ppy)3, Na2HPO4, sodium ascorbate, Acetone, Blue LED, r.t., 40-60%
2.6 Conclusions
We developed synthetic methods of indolopyran and 2,3-dihydrofuran based on oxidative cycloaddition.
Iodine-mediated reaction is characterized by fast reaction kinetic that proceeds through the cage collapsed SET pathway. The electrochemical synthesis method is mild conditions using iodide without external base or oxidant. Moreover, the starting compounds 1 and 4 could be easily synthesized in short reaction steps in good to moderate yield.
31 2.7 Procedure
General Procedure for iodine-mediated reaction and characterization of dihydropyrano[4,3- b]indoles
To a suspension of carbonyl compound 2 (0.11 mmol, 1.1 equiv.) and K3PO4 (0.5 mmol, 5.0 equiv.) in anhydrous acetonitrile (1 mL, 0.1 M) at room temperature was added indole substrate 1 (0.1 mmol, 1.0 equiv.) dropwise under a nitrogen atmosphere. I2 (0.22 mmol, 2.2 equiv.) was added under nitrogen and the reaction was stirred at room temperature. The reaction mixture was monitored by TLC until indole was consumed, opened to air, quenched with 2-3 drops of 1N Na2S2O3 solution, diluted with ethyl acetate, and filtered over a pad of celite. The pad was rinsed with an additional ethyl acetate, and the combined solutions were concentrated in vacuo. The crude material was purified by column chromatography to give the product.
General Procedure for iodine-mediated reaction and characterization of 2,3-dihydrofurans To a suspension of carbonyl compound 2 (0.11 mmol, 1.1 equiv.) and K3PO4 (0.3 mmol, 3.0 equiv.) in anhydrous acetonitrile at room temperature was added I2 (0.11 mmol, 1.1 equiv.) under a nitrogen atmosphere. Then a solution of enamine 4 (0.1 mmol, 1.0 equiv.) in anhydrous acetonitrile was added under nitrogen and the reaction was stirred at room temperature. The reaction mixture was monitored by TLC until enamine was consumed, opened to air, quenched with 2-3 drops of 1N Na2S2O3 solution, diluted with dichloromethane, and filtered over a pad of celite. The pad was rinsed with an additional dichloromethane, and the combined solutions were concentrated in vacuo. The crude material was purified by column chromatography to give the product.
General Procedure for ElectraSyn and characterization of dihydropyrano[4,3-b]indoles
The indole derivative 1 (0.1 mmol, 1 equiv.), active methylene compound 2 (0.11 mmol, 1.1 equiv.), NaI (0.1 mmol, 1 equiv.), MeCN (3 mL, 0.1 M NaBF4) and a stir bar was added to the vial. The vial was equipped with cap, which graphite as anode and RVC as cathode were installed. The whole cell was undivided cell. The solution was stirred for 10 minutes. A stirring rate was established at 900 rpm.
The cell potential was set to 3.0 V at room temperature. Upon full consumption of indole starting material as determined by thin-layer chromatography analysis, electrolysis was terminated, solvent was removed under reduced pressure. Dried crude mixture was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by
32 flash chromatography.
General Procedure for ElectraSyn and characterization of 2,3-dihydrofurans
The enamine derivative 4 (0.1 mmol, 1 equiv.), active methylene compound 2 (0.15 mmol, 1.5 equiv.), NaI (0.15 mmol, 1.5 equiv.), MeCN (3 mL, 0.1 M NaBF4) and a stir bar was added to the vial. The vial was equipped with cap, which graphite as anode and RVC as cathode were installed. The whole cell was undivided cell. The solution was stirred for 10 minutes. A stirring rate was established at 900 rpm.
The electrolysis was carried out at r.t. using a constant current of 7 mA. Upon full consumption of indole starting material as determined by thin-layer chromatography analysis, electrolysis was terminated, solvent was removed under reduced pressure. Dried crude mixture was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography.
General Procedure (A) for the Dihydropyridines (9)
A solution of pyran 3a (1.0 equiv.) and aniline (1.2 equiv.) in DCE (0.25 M) was treated with AcOH (20 mol%) at room temperature. The reaction mixture was stirred under N2 at reflux. After the completion of reaction, the reaction mixture was diluted with DCM, washed with saturated NaHCO3, dried and concentrated in vacuo. The crude material was purified by flash chromatography.
2.8 Experimental data
Dimethyl 4-acetyl-3,5-dimethylpyrano[4,3-b]indole-1,1(5H)-dicarboxylate (3a)
m.p. 105-110 °C; 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.25 – 7.20 (m, 1H), 7.18 – 7.13 (m, 1H), 3.84 (s, 6H), 3.57 (s, 3H), 2.42 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.55, 167.34, 157.20, 139.00, 131.15, 123.79, 122.06, 121.05, 119.04, 111.29, 109.77, 99.92, 84.82, 53.40, 32.09, 31.73, 18.17; IR (film): 2955, 1748, 1683, 1589, 1273, 1225, 1201, 744, 743 cm-1; HRMS calcd for C19H19NNaO6+ 380.1105, observed 380.1105 [M+Na]+
33
Dimethyl 4-acetyl-8-methoxy-3,5-dimethylpyrano[4,3-b]indole-1,1(5H)-dicarboxylate (3b)
m.p. 100-105 °C; 1H NMR (400 MHz, CDCl3) δ 8.42 (dd, J = 2.3, 0.5 Hz, 1H), 8.11 (ddd, J = 9.1, 2.2, 0.7 Hz, 1H), 7.32 (dd, J = 9.1, 0.5 Hz, 1H), 3.88 (s, 6H), 3.62 (s, 3H), 2.47 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.92, 166.54, 159.00, 142.72, 141.66, 134.52, 123.24, 117.48, 116.31, 110.79, 109.69, 101.45, 84.21, 53.72, 32.73, 32.10, 18.61; IR (film): 2955, 1747, 1680, 1607, 1256, 1233, 1190, 828, 791, 754 cm-1; HRMS calcd for C20H21NNaO7+ 410.1210, observed 410.1210 [M+Na]+
Dimethyl 4-acetyl-8-((tert-butoxycarbonyl)amino)-3,5-dimethylpyrano[4,3-b]indole-1,1(5H)- dicarboxylate (3c)
m.p. 190-195 °C; 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.28 (m, 2H), 7.17 (d, J = 8.8 Hz, 1H), 6.53 (s, 1H), 3.85 (s, 6H), 3.52 (s, 3H), 2.41 (s, 3H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.55, 167.32, 157.19, 153.16, 135.91, 132.32, 131.78, 123.87, 115.36, 111.34, 109.88, 109.06, 99.59, 84.68, 53.49, 32.16, 31.76, 28.40, 18.18; IR (film): 3376, 2960, 1740, 1672, 1582, 1455, 1265, 1232, 1161, 805, 770 cm-1; HRMS calcd for C24H28N2NaO8+ 495.1738, observed 495.1739 [M+Na]+
Dimethyl 4-acetyl-3,5-dimethyl-8-nitropyrano[4,3-b]indole-1,1(5H)-dicarboxylate (3d)
m.p. 190-195 °C; 1H NMR (400 MHz, CDCl3) δ 7.17 (dd, J = 8.9, 0.6 Hz, 1H), 6.91 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.8, 2.5 Hz, 1H), 3.85 (s, 6H), 3.84 (s, 3H), 3.54 (s, 3H), 2.42 (s, 3H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.62, 167.36, 156.93, 155.01, 134.36, 131.56, 124.25, 111.83, 111.35, 110.45, 101.28, 99.51, 84.75, 55.87, 53.39, 32.17, 31.73, 18.15; IR (film): 2961, 1747, 1679, 1600,
34
1514, 1337, 1254, 1200 812, 750, 735 cm-1; HRMS calcd for C19H18N2NaO8+ 425.0955, observed 425.0955 [M+Na]+
Trimethyl 4-acetyl-3,5-dimethylpyrano[4,3-b]indole-1,1,8(5H)-tricarboxylate (3e)
m.p. 190-195 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 1.6 Hz, 1H), 7.80 (dd, J = 8.7, 1.7 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 3.86 (s, 3H), 3.81 (s, 6H), 3.58 (s, 3H), 2.49 (s, 3H), 2.21 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 199.10, 167.29, 167.22, 156.88, 141.19, 132.93, 123.10, 122.91, 122.57, 120.98, 111.60, 111.08, 100.36, 84.37, 54.12, 52.43, 32.77, 32.57, 18.59; IR (film): 2954, 1742, 1667, 1593, 1264, 1151, 810, 764, 743 cm-1; HRMS calcd for C21H21NNaO8 438.1159+, observed 438.1159 [M+Na]+
Dimethyl 4-acetyl-8-bromo-3,5-dimethylpyrano[4,3-b]indole-1,1(5H)-dicarboxylate (3f)
m.p. 110-115 °C; 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 1.9, 0.5 Hz, 1H), 7.28 (dd, J = 8.7, 1.9 Hz, 1H), 7.14 (dd, J = 8.7, 0.5 Hz, 1H), 3.85 (s, 6H), 3.53 (s, 3H), 2.42 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.33, 166.98, 157.86, 137.71, 132.26, 125.33, 124.90, 121.66, 114.47, 111.13, 111.02, 99.23, 84.48, 53.54, 32.26, 31.86, 18.32; IR (film): 2954, 1738, 1693, 1607, 1304, 1196, 1143, 773, 748, 639 cm-1; HRMS calcd for C19H18BrNNaO6+ 458.0210, observed 458.0210 [M+Na]+
Dimethyl 4-acetyl-3-methylpyrano[4,3-b]indole-1,1(5H)-dicarboxylate (3g)
m.p. 175-180 °C; 1H NMR (400 MHz, CDCl3) δ 10.17 (s, 1H), 7.49 (dq, J = 7.7, 0.9 Hz, 1H), 7.36 (dt, J = 8.2, 0.9 Hz, 1H), 7.25 – 7.07 (m, 2H), 3.83 (s, 6H), 2.57 (s, 3H), 2.52 (s, 3H); 13C NMR (100 MHz,
35
CDCl3) δ 197.17, 166.97, 164.69, 136.23, 129.41, 123.63, 121.91, 120.57, 119.33, 111.44, 110.01, 96.59, 85.24, 53.35, 32.18, 21.88; IR (film): 3403, 2962, 1751, 1641, 1273, 1201, 1167, 749, 731 cm-1; HRMS calcd for C18H17NNaO6+ 366.0948, observed 366.0948 [M+Na]+
Dimethyl 4-acetyl-5-benzyl-3-methylpyrano[4,3-b]indole-1,1(5H)-dicarboxylate (3h)
m.p. 160-165 °C; 1H NMR (400 MHz, CDCl3) δ 7.51 – 7.48 (m, 1H), 7.25 (d, J = 1.7 Hz, 1H), 7.24 – 7.18 (m, 3H), 7.16 – 7.13 (m, 2H), 6.96 – 6.92 (m, 2H), 5.21 (s, 2H), 3.86 (s, 6H), 2.21 (s, 3H), 2.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.2, 167.4, 155.9, 138.8, 136.6, 130.6, 128.8, 127.5, 126.2, 124.1, 122.2, 121.2, 119.2, 111.7, 110.5, 100.6, 84.7, 53.4, 48.4, 31.9, 18.5; IR (film): 2952, 1736, 1680, 1597, 1247, 1190, 1167, 795, 740 cm-1; HRMS calcd for C25H24NO6+ 434.1598, observed 434.1598 [M+H]+
Dimethyl 4-acetyl-3-methyl-5-(p-tolyl)pyrano[4,3-b]indole-1,1(5H)-dicarboxylate (3i)
m.p. 160-165 °C; 1H NMR (400 MHz, CDCl3) δ 7.55 – 7.51 (m, 1H), 7.34 – 7.27 (m, 3H), 7.23 – 7.14 (m, 4H), 3.88 (s, 6H), 2.42 (s, 3H), 2.26 (s, 3H), 1.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.93, 167.36, 157.60, 138.67, 138.23, 134.54, 130.52, 130.27, 127.12, 123.95, 122.46, 121.68, 119.11, 111.29, 110.72, 101.46, 84.59, 53.46, 30.76, 21.20, 18.05; IR (film): 2955, 1752, 1686, 1604, 1289, 1211, 1164, 830, 782, 744 cm-1; HRMS calcd for C25H23NNaO6+ 456.1418, observed 456.1418 [M+Na]+
Dimethyl 4,5-diacetyl-3-methylpyrano[4,3-b]indole-1,1(5H)-dicarboxylate (3j)
36
m.p. 140-145 °C; 1H NMR (400 MHz, CDCl3) δ 7.74 – 7.71 (m, 1H), 7.47 – 7.43 (m, 1H), 7.35 – 7.27 (m, 2H), 3.85 (s, 6H), 2.73 (s, 3H), 2.38 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 195.5, 170.1, 166.7, 158.0, 136.5, 131.4, 126.3, 124.6, 124.0, 119.9, 114.4, 113.3, 109.3, 83.7, 53.6, 30.8, 27.0, 18.7; IR (film): 2924, 1746, 1687, 1625, 1290, 1218, 1160, 793, 740 cm-1; HRMS calcd for C20H19NNaO7+ 408.1054, observed 408.1054 [M+Na]+
Dimethyl 4-benzoyl-5-methyl-3-phenylpyrano[4,3-b]indole-1,1(5H)-dicarboxylate (3k)
m.p. 185-190 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 8.2, 1.0 Hz, 2H), 7.78 – 7.74 (m, 2H), 7.57 – 7.53 (m, 1H), 7.45 – 7.40 (m, 1H), 7.31 – 7.26 (m, 3H), 7.25 (d, J = 3.6 Hz, 2H), 7.21 (dd, J = 4.9, 1.2 Hz, 2H), 7.17 (d, J = 8.0 Hz, 1H), 3.91 (s, 6H), 3.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 194.13, 167.75, 152.90, 138.93, 137.60, 133.68, 133.08, 131.15, 129.96, 129.79, 129.64, 128.64, 127.91, 123.47, 122.17, 120.89, 119.50, 109.47, 108.20, 99.16, 85.02, 53.39, 31.66; IR (film): 2955, 1764, 1668, 1613, 1591, 1274, 1241, 1218, 1142, 775, 743 cm-1; HRMS calcd for C29H23NNaO6+ 504.1418, observed 504.1418 [M+Na]+
Dimethyl 4-cyano-5-methyl-3-phenylpyrano[4,3-b]indole-1,1(5H)-dicarboxylate (3l)
m.p. 170-175 °C; 1H NMR (400 MHz, CDCl3) δ 8.14 – 8.10 (m, 2H), 7.57 – 7.50 (m, 4H), 7.36 (d, J = 8.2 Hz, 1H), 7.28 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 7.20 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 4.05 (s, 3H), 3.87 (d, J = 0.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 166.69, 164.68, 138.99, 132.07, 131.11, 129.52, 128.56, 126.77, 123.07, 122.89, 121.42, 119.43, 116.75, 109.71, 99.24, 85.61, 81.15, 53.66, 30.61; IR
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(film): 2215, 1749, 1588, 1567, 1275, 1244, 1223, 1154, 740, 701 cm-1; HRMS calcd for C23H19N2O5+
403.1288, observed 403.1288 [M+H]+
Dimethyl 4-(dimethoxyphosphoryl)-3,5-dimethylpyrano[4,3-b]indole-1,1(5H)-dicarboxylate (3m)
m.p. 145-150 °C; 1H NMR (400 MHz, CDCl3) δ 7.36 (dt, J = 8.0, 1.0 Hz, 1H), 7.31 (dt, J = 8.3, 0.9 Hz, 1H), 7.20 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.12 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 6H), 3.77 (s, 3H), 3.74 (s, 3H), 2.45 (d, J = 2.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.71, 167.50, 167.14, 139.46, 131.60, 131.57, 123.04, 121.90, 120.76, 118.25, 110.13, 100.50, 100.43, 96.09, 94.05, 84.75, 53.46, 52.56, 52.51, 32.98, 21.10, 21.08; IR (film): 2953, 1748, 1608, 1572, 1464, 1284, 1243, 1049, 1025, 756 cm-1; HRMS calcd for C19H23NO8P+ 424.1156, observed 424.1156 [M+H]+
dimethyl 8-acetyl-7,9-dimethylpyrano[3',4':4,5]pyrrolo[2,3-b]pyridine-5,5(9H)-dicarboxylate (3n)
m.p. 115 - 120 °C; 1H NMR (400 MHz, CDCl3) δ 8.29 (dd, J = 4.7, 1.5 Hz, 1H), 7.79 (dd, J = 8.0, 1.5 Hz, 1H), 7.10 (dd, J = 8.0, 4.7 Hz, 1H), 3.85 (s, 6H), 3.70 (s, 3H), 2.47 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.5, 167.0, 157.2, 149.5, 142.7, 131.3, 127.2, 117.1, 116.8, 110.9, 97.3, 84.00, 53.5, 32.1, 30.4, 18.3; HRMS calcd for C18H19N2O6+ 359.1238 observed 359.1238 [M+H]+
Diethyl 2-((2R,3S)-4-acetyl-2-(methoxycarbonyl)-5-methyl-3-(methyl(phenyl)amino)-2,3- dihydrofuran-2-yl)malonate (5a)
Yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.23 (m, 2H), 6.88 (d, J = 8.3 Hz, 2H), 6.81 (t, J = 7.3
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Hz, 1H), 5.75 (s, 1H), 4.35 – 4.30 (m, 1H), 4.25 (s, 1H), 4.23 – 4.10 (m, 3H), 3.55 (s, 3H), 2.64 (s, 3H), 2.39 (s, 3H), 1.85 (s, 3H), 1.28 (d, J = 7.1 Hz, 3H), 1.23 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 194.7, 170.5, 167.6, 166.0, 165.9, 149.3, 129.4, 118.6, 113.5, 111.5, 91.2, 69.2, 62.5, 62.4, 57.0, 52.7, 32.7, 29.4, 15.1, 14.1, 14.0; IR (film):2980, 1728, 1678, 1598, 1434, 1311, 1204, 750, 693 cm-1; HRMS calcd for C23H30NO8+ 447.1966, observed 448.1978 [M+H]+
Diethyl 2-((2R,3S)-4-acetyl-2-(methoxycarbonyl)-5-methyl-3-(methyl(m-tolyl)amino)-2,3- dihydrofuran-2-yl)malonate (5b)
Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.18 – 7.10 (m, 1H), 6.73 – 6.61 (m, 3H), 5.73 (s, 1H), 4.35 – 4.11 (m, 5H), 3.56 (s, 3H), 2.62 (s, 3H), 2.38 (s, 3H), 2.33 (s, 3H), 1.84 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 194.6, 170.2, 167.5, 165.8, 165.8, 149.3, 138.8, 129.0, 119.4, 114.0, 111.4, 110.7, 91.1, 69.0, 62.3, 62.3, 56.8, 52.6, 32.6, 29.4, 21.9, 15.0, 13.9, 13.9; IR (film): 2981, 1728, 1678, 1600, 1495, 1304, 1218, 937, 628 cm-1; HRMS calcd for C24H32NO8+ 461.2122, observed 462.2131 [M+H]+
Diethyl 2-((2R,3S)-4-acetyl-2-(methoxycarbonyl)-5-methyl-3-(methyl(p-tolyl)amino)-2,3- dihydrofuran-2-yl)malonate (5c)
Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.07 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 5.68 (s, 1H), 4.32 (dq, J = 10.6, 7.3 Hz, 2H), 4.25 (s, 1H), 4.18 – 4.10 (m, 2H), 3.58 (s, 3H), 2.61 (s, 3H), 2.38 (s, 3H), 2.26 (s, 3H), 1.84 (s, 3H), 1.28 (d, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 194.6, 170.2, 167.6, 165.8, 165.8, 147.2, 129.7, 127.6, 113.4, 111.4, 91.2, 69.5, 62.3, 62.3, 56.8, 52.6, 32.6, 29.4, 20.3, 14.9, 13.9, 13.9; IR (film):2980, 1728, 1678, 1607, 1434, 1305, 1230, 1202, 806, 631 cm-1; HRMS calcd for C24H32NO8+ 461.2122, observed 462.2092 [M+H]+
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Diethyl 2-((2R,3S)-4-acetyl-2-(methoxycarbonyl)-3-((4-methoxyphenyl)(methyl)amino)-5- methyl-2,3-dihydrofuran-2-yl)malonate (5d)
Yellow oil; 1H NMR (400 MHz, CDCl3) δ 6.84 (d, J = 2.1 Hz, 4H), 5.62 (s, 1H), 4.35 – 4.12 (m, 5H), 3.77 (s, 3H), 3.60 (s, 3H), 2.60 (s, 3H), 2.38 (s, 3H), 1.84 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 194.7, 170.0, 167.7, 165.8, 165.8, 152.5, 143.9, 114.8, 114.6, 111.6, 91.4, 70.3, 62.3, 56.8, 55.6, 52.6, 32.9, 29.5, 14.9, 13.9, 13.9; IR (film):2982, 1728, 1677, 1605, 1435, 1280, 1244, 1202, 818, 633 cm-1; HRMS calcd for C24H32NO9+ 477.2072, observed 478.2090 [M+H]+
Diethyl 2-((2R,3S)-4-acetyl-3-((4-bromophenyl)(methyl)amino)-2-(methoxycarbonyl)-5-methyl- 2,3-dihydrofuran-2-yl)malonate (5e)
Yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 9.2 Hz, 2H), 6.75 (d, J = 9.1 Hz, 2H), 5.70 (s, 1H), 4.32 – 4.12 (m, 5H), 3.57 (s, 3H), 2.59 (s, 3H), 2.38 (s, 3H), 1.86 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 194.1, 170.3, 167.4, 165.7, 165.7, 148.2, 132.0, 115.0, 111.3, 110.5, 91.0, 68.8, 62.4, 62.4, 56.7, 52.7, 32.7, 29.3, 15.0, 13.9, 13.9; IR (film):2979, 1728, 1679, 1608, 1492, 1435, 1308, 1203, 812, 629, 517 cm-1; HRMS calcd for C23H29BrNO8+ 525.1071, observed 526.1065 [M+H]+
Diethyl 2-((2R,3S)-4-acetyl-2-(methoxycarbonyl)-3-((4-
(methoxycarbonyl)phenyl)(methyl)amino)-5-methyl-2,3-dihydrofuran-2-yl)malonate (5f)