Multicomponent reactions, applications in medicinal chemistry & new modalities in drug
discovery
Konstantinidou, Markella
DOI:10.33612/diss.111908148
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Konstantinidou, M. (2020). Multicomponent reactions, applications in medicinal chemistry & new modalities in drug discovery. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.111908148
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CHAPTER
4
beta-
CARBOLINONE ANALOGUES FROM THE UGI
SILVER MINE
This chapter is published
Rudrakshula Madhavachary,† Naganaboina Naveen,† Yuanze Wang, Qian Wang,
Markella Konstantinidou and Alexander Dömling † the authors contributed equally
European Journal of Organic Chemistry 2018, 24, 3139 – 3143 DOI: 10.1002/ejoc.201800557
ABSTRACT
Here we describe a facile, tandem synthetic route for β-carbolinones, a class of natural products of high biological significance. Commercially available building blocks yield highly diverse analogues in just two simple steps.
INTRODUCTION
Synthetic strategies to obtain natural products, and analogues/skeletons thereof, are at the very heart of synthetic organic chemistry.[1] Approaches achieving atom economy are highly sought after,
offering various advantages, such as minimization of waste, time and resources. Multicomponent reaction chemistry is such a group of synthetic transformations allowing via short synthetic routes, access to large libraries of analogues of many different scaffolds from common building blocks, finally minimizing waste, time and resources.[2] Natural products containing the β-carbolinone
scaffold show diverse biological and pharmacological activities,[3] such as anticancer, inhibition
of human leukocyte elastase, and the modulation of effects associated with depression, anxiety disorders and muscle spasms, just to name a few.[4]
Conventional methods toward the synthesis of β-carbolinone analogues require multiple steps, including complicated steps to prepare starting materials.[5] To access this significant
scaffold recent methods such as dehydrogenative annulations,[6a] intramolecular Heck,[6b] and
cycloisomerization[6c] were established. Recently, a silver-catalyzed oxidative cyclization of
propargylamide-substituted indoles towards phosphorated indoloazepinones was described.[6d]
On the other hand, Ugi-adducts are easily accessible, however, transforming such adducts into potentially biologically active molecules remains challenging, even in light of considerable recent advances.[7] In particular, the use of propargylamine as an amine source in Ugi reactions is limited
to date. Recently, propargylamine was used as the amine component in an Ugi reaction, and via a three-step synthesis using palladium catalyzed cyclization resulted in aza-polyheterocycles.
[7b] Moreover, Eycken and co-workers developed a gold-catalyzed approach for the synthesis
of cyclopentapyridinones and spirocyclopentapyridinones using propargylamine as an amine source.[7c] The same group, recently described a gold-catalyzed synthesis of pyrrolopyridines and
azepinoindoles starting from propargylamines.[7d] Chauhan and co-workers described interesting
β-carbolinone and indolo-pyrazinone analogues based on an Ugi-four-component reaction (Ugi-4CR) with aminodimethylacetal as amine source. However, this reaction requires stoichiometric amounts of p-TSA and it produces a side product along with the β-carbolinones.[8] Synthesis of
oxopyrazino[1,2-a] indoles was developed by Shafiee group using potassium tert-butoxide, in which cyclization takes place at the more nucleophilic nitrogen of the Ugi product, resulting in oxopyrazino[1,2-a]indoles (Scheme 1). [9]
Although the above methods are useful, there is still room for improvement regarding the establishment of a mild synthetic approach with high diversity for the β-carbolinone scaffold.
Scheme 1. Synthesis of carbolinones: present and previous work.
Here, our aim is to use propargylamine in Ugi four-component reactions followed by a tandem/ sequential AgOTf-catalyzed carbocyclization of the Ugi-products towards β-carbolinone analogues. In this synthetic approach, 6-exo-dig carbocyclization takes place to form the six-membered indole annulated pyrido-1-one in fair to very good yields.
RESULTS AND DISCUSSION
Isocyanide-based multicomponent reactions (IMCRs) have attracted a lot of attention, due to the fact that versatile functional groups can be introduced in the MCR adducts, which can undergo further condensations or cyclization reactions leading to an array of structurally diverse scaffolds.
[10]
In this study, starting from the Ugi-4CR of propargylamine 1a as an amine source, benzaldehyde
2a, indole-2-carboxylic acid 3a and tert-butyl isocyanide 4a in methanol at room temperature
resulted to the corresponding Ugi adduct 5a in a good yield of 83% after 12 h. With compound 5a in hand, we were keen to investigate the intramolecular hydroarylation. The initial investigation with Al(OTf)3 (20 mol%) in CH3CN at 75 °C gave the desired product 6a but in a low yield of 21%, whereas no product was detected with CuI, p-TSA, TfOH, KOTf, and NaOTf. On the other hand, the usage of ZnCl2 as Lewis-acid catalyst (20 mol%) led to an isolated yield of 6a in 40%. The application of catalysts like Sn(OTf)2, In(OTf)3, Zn(OTf)2 in the reaction at 75 °C gave the isolated yield of 42%, 56%, and 56% respectively. Finally, the yield was increased to 75% when the reaction was carried out in the presence of AgOTf (20 mol%) at 75 °C (Table 1, entry 11). After selecting the catalyst, we extensively screened different solvents to achieve the best conditions. A one-pot
cyclization was also explored since it could add considerable value to our synthetic approach. To our delight, using methanol as a solvent for 12 h at room temperature for the Ugi reaction and then adding AgOTf (20 mol%) and heating the reaction mixture to 75 °C for 3 h was proven to be the best condition (Table 1, entry 15).
Table 1. Optimization of the intramolecular hydroarylation.[a, b]
No. Catalyst (20 mol%) Solvent Product 6a (yield)[a, b]
1 p-TSA CH3CN nd 2 CuI CH3CN nd 3 TfOH CH3CN nd 4 Al(OTf)3 CH3CN 21% 5 KOTf CH3CN nd 6 NaOTf CH3CN nd 7 ZnCl2 CH3CN 40% 8 Sn(OTf)2 CH3CN 42% 9 In(OTf)3 CH3CN 56% 10 Zn(OTf)2 CH3CN 56% 11 AgOTf CH3CN 75% 12 AgOTf Toluene 52% 13 AgOTf Acetone 67% 14 AgOTf MeOH 76% 15 AgOTf MeOH 69% [c] 16 AgNO3 MeOH 57%
[a] The Ugi reaction was carried out using 1a (1.0 mmol), 2a (1.0 mmol), 3a (1.0 mmol) and 4a (1.0 mmol) in MeOH for 12 h at rt.
Pure product 5a was subjected to cyclization under indicated catalysis in a sealed tube with an indicated solvent for 3 h at 75
oC. [b] Isolated yield. [c] Reaction was carried out one-pot (Ugi reaction followed by cyclization)
With the optimized one-pot reaction conditions in hand, the scope of the “Ugi-4CR/cyclization” reaction was further investigated by reacting propargylamine with different aldehydes/ketones, isocyanides and indole-2-carboxylic acid in methanol followed by AgOTf catalyzed cyclization to furnish the corresponding β-carbolinone library 6a-v (Table 2). All the substrates 1, 2, 3 and 4 led to the expected β-carbolinone products 6a-v in 49-77% yields in one-pot. Substituted benzyl isocyanides with electron-donating groups like p-methoxy (4b), 3,4,5-trimethoxy (4d) reacted
smoothly with 65 and 63 % yields, respectively. Electron withdrawing substituents like cyano and chloro reacted nicely to give the cyclized products in good yields (6c, 6e). The commercially available 5-chloro substituted indole-2-carboxylic acid (3i) reacted to give the expected product
6i in 59 % yield. Similarly, 2,6-dimethyl benzyl isocyanide and aliphatic branched isocyanides also
furnished the different β-carbolinone products in good yields. Table 2 clearly indicates that there are no electronic or steric effects on the outcome of the reaction.
Table 2. Synthesis of β-carbolinones: variation in isocyanide part.[a,b]
[a] The reactions were run using 1a (1.0 mmol), 2a (1.0 mmol), 3 (1.0 mmol) and 4a-i (1.0 mmol) in MeOH as solvent for 12-24 h at
rt. After the Ugi reaction, AgOTf (20 mol%) followed by extra MeOH was added to the reaction mixture and the whole mixture was heated to 75 oC for 3 h in a sealed tube. [b] Isolated yield.
After successfully demonstrating the one-pot cyclization reactions with different isocyanides, we then focused on different aldehydes and ketones. As shown in Table 3, also, in this case, the
one-pot approach results in very good yields. For instance, in case of ortho/para bromo substituted benzaldehydes, the corresponding products were obtained in 77 % and 67 % yields respectively, which unlocks interesting opportunities for further functionalization of the bromo-products via palladium catalysis (Table 3, 6j, 6k). Furthermore, keeping in mind the intriguing physicochemical properties of fluoro and trifluoromethyl substituents, we performed the reactions with 2l, 2m and 2n to get the desired products in good yields (6l, 6m, 6n). Strong +M groups, as well as –M groups containing benzaldehydes, reacted well to give fair yields (6p, 6q, 6r, 6s, 6t). Even the aliphatic aldehyde (2u) efficiently reacted to give 70% yield of expected cyclized product 6u. It is worth mentioning that the cyclic ketone (2v) reacted without any interruption to obtain decent yield (6v).
[a] The reactions were run using 1a (1.0 mmol), 2 (1.0 mmol), 3a (1.0 mmol) and 4a (1.0 mmol) in MeOH as solvent for 12-24 h at
rt. After Ugi-reaction, AgOTf (20 mol%) followed by extra MeOH was added to the reaction mixture and the whole mixture was heated to 75 oC for 3 h in a sealed tube. [b] Isolated yield.
A plausible mechanism of the cyclization path was explained based on the previous reports as shown in Scheme 2. [11] After getting the Ugi adduct, silver attacks the alkyne to give the
intermediate A, which undergoes a 6-exo-dig cyclization to give intermediate B, which upon rearomatization/protodemetalation gives the β-carbolinone product 6.
Scheme 2. Anticipated mechanistic pathway for 6-exo-dig cyclization reaction.
As already mentioned, β-carbolinones possess diverse biological activities. In 2011, Bracher et. al. [12]
reported derivatives of 7,8-dichloro-1-oxo-β-carbolinones, which were based on the alkaloid bauerine C and showed kinase inhibitory activity. A co-crystal structure with DAPK3 was obtained shedding light into the molecular interactions and indicating an unusual, non-ATP mimetic binding mode. Using the PDB code 3BHY, we were interested in docking our β-carbolinone derivatives. Interestingly, we observed a good overlap of the indole parts with the original ligand and our compounds fitted nicely into the pocket. Although in the original crystal structure, the two chloro substituents of the indole ring participate in halogen bonds, this feature is missing
from our derivatives. However, in our case, the indole rings are oriented in a similar manner and the amide moieties of the side chains were able to form hydrogen bonds. Halogen bonds are weaker than the hydrogen bonds that we observed while docking the compounds and we thus hypothesize that these compounds could have potential as kinase inhibitors (Figure 1).
Figure 1. Docking poses. Up left: Overlap of compound 6p (yellow sticks) with the ligand (green sticks) of
PDB 3BHY. Up right: hydrogen bonds (black dots) of compound 6p (yellow sticks) with Lys141 and Ser21
(cyan sticks). Below: 2D structures of ligand of PDB 3BHY and compound 6p.
CONCLUSIONS
To sum up, we have successfully established a mild and facile one-pot procedure for the synthesis of β-carbolinones, starting from commercially available starting materials. Diversity can be achieved mainly through the isocyanide and the aldehyde component and to a smaller extent the indole-carboxylic acid. Regarding potential applications, docking studies indicate that these types of derivatives could be useful as kinase inhibitors.
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EXPERIMENTAL SECTION
General experimental procedures
Procedure A (General procedure for the synthesis of β-carbolinones 6 in one-pot): In a
seal-tube, to the stirred solution of propargylamine 1 (1.0 mmol) in methanol (1.0 ml), was added aldehyde/ketone 2 (1.0 mmol). The mixture was stirred for 10 min at rt. Then isocyanide 4 (1.0 mmol) followed by indole-2-carboxylic acid 3 (1.0 mmol) was added to the solution. The reaction mixture was stirred at rt overnight and the reaction was monitored by TLC. After completion of Ugi-reaction, the reaction was continued for cyclization under AgOTf-catalysis. The mixture was diluted to 0.3 M with MeOH and 20 mol% of AgOTf was added as a catalyst and the seal-tube was closed with a screw cap. The reaction mixture was heated to 75 oC for 3 h. After completion
of the cyclization, the mixture was evaporated under reduced pressure and diluted with DCM, washed with saturated aqueous NH4Cl, dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography using petroleum ether/ethyl acetate (6:4) to afford the product 6.
N-(tert-butyl)-2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenyl
acetamide (6a)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6a (267 mg, 69 %) as white semi-solid. 1H NMR (500 MHz, DMSO-d
6) δ 12.08 (s, 1H), 8.37 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.48 – 7.40 (m, 3H), 7.30 (d, J = 7.7 Hz, 2H), 7.24 – 7.12 (m, 1H), 6.97 (s, 1H), 6.78 (s, 1H), 3.33 (s, 1H), 2.41 (s, 3H), 1.31 (s, 9H). 13C NMR (126 MHz, DMSO-d 6) δ 167.7, 154.9, 139.9, 138.0, 129.4, 129.0, 128.6, 126.9, 126.5, 125.0, 123.6, 122.8, 122.7, 120.2, 113.0, 110.1, 59.5, 51.2, 28.8, 17.1. MS (ESI) m/z 388.20 (M+H)+, calcd for C
24H26N3O2: 388.20, HRMS (ESI) calculated for C24H26N3O2
[M+H]+: 388.2020; found: 388.2020.
N-(4-methoxybenzyl)-2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenyl
acetamide (6b)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6b (293 mg, 65 %) as yellow semi-solid. 1H NMR (500 MHz, CDCl 3) δ 10.83 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.64 (s, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.42 – 7.30 (m, 6H), 7.27 (s, 1H), 7.23 – 7.11 (m, 3H), 6.98 (s, 1H), 6.74 – 6.60 (m, 2H), 4.56 (dd, J = 14.7, 5.9 Hz, 1H), 4.41 (dd, J = 14.7, 5.1 Hz, 1H), 3.65 (s, 3H), 2.51 (s, 3H). 13C NMR (126 MHz, CDCl 3) δ 168.4, 158.8, 155.2, 139.9, 135.8, 129.9, 129.1, 129.0, 128.8, 128.5, 126.5, 125.4, 123.9, 122.8, 122.6, 122.5, 120.1, 114.0, 113.8, 113.4, 60.8, 55.1, 43.3, 17.1. MS (ESI) m/z 452.20 (M+H)+, calcd for C
28H26N3O3: 452.19, HRMS
(ESI) calculated for C28H26N3O3 [M+H]+: 452.1969; found: 452.1968. N H N O O NH N H N O O NH O
4
N-(4-cyanobenzyl)-2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenyl
acetamide (6c)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6c (272 mg, 61 %) as white solid. 1H NMR (500 MHz,
DMSO-d6) δ 12.15 (s, 1H), 9.24 (t, J = 6.0 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.84 – 7.75 (m, 2H), 7.58 (d, J = 8.3 Hz, 1H), 7.51 – 7.40 (m, 6H), 7.38 – 7.28 (m, 2H), 7.20 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 6.77 (d, J = 1.3 Hz, 1H), 4.60 – 4.36 (m, 2H), 2.42 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 168.9, 155.0, 145.4, 139.9, 136.7, 132.7, 132.7, 129.4, 129.0, 128.6, 127.0, 126.6, 124.3, 123.7, 122.8, 122.7, 120.3, 119.3, 113.1, 110.8, 110.1, 60.4, 42.7, 17.1. MS (ESI) m/z 447.43 (M+H)+,
calcd for C28H23N4O2: 447.18, HRMS (ESI) calculated for C28H23N4O2 [M+H]+: 477.1816; found: 477.1815. 2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenyl-N-(3,4,5-trimethoxy benzyl)acetamide (6d)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6d (321 mg, 63 %) as white solid. 1H NMR (500 MHz,
CDCl3) δ 10.87 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.79 (t, J = 5.9 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.44 – 7.30 (m, 6H), 7.27 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 1.3 Hz, 1H), 6.47 (s, 2H), 4.67 (dd, J = 15.0, 6.6 Hz, 1H), 4.35 (dd, J = 15.1, 5.2 Hz, 1H), 3.76 (s, 3H), 3.66 (s, 6H), 2.50 (s, 3H). 13C NMR (126 MHz, CDCl 3) δ 168.6, 155.3, 153.3, 139.9, 137.0, 135.6, 133.9, 129.0, 128.9, 128.7, 126.8, 126.5, 125.4, 123.7, 122.8, 122.6, 120.2, 113.4, 104.4, 104.2, 61.0, 56.4, 55.9, 55.4, 43.8, 17.1. MS (ESI) m/z 512.22 (M+H)+, calcd for C
30H30N3O5:
512.22, HRMS (ESI) calculated for C30H30N3O5 [M+H]+: 512.2180; found: 512.2180.
N-(4-chlorobenzyl)-2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenyl
acetamide (6e)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6e (318 mg, 70 %) as yellow solid. 1H NMR (500 MHz,
CDCl3) δ 10.44 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.45 – 7.39 (m, 1H), 7.37 (s, 5H), 7.24 – 7.20 (m, 1H), 7.16 – 7.08 (m, 5H), 6.92 (s, 1H), 4.60 – 4.34 (m, 2H), 2.52 (s, 3H). 13C
NMR (126 MHz, CDCl3) δ 168.5, 155.2, 139.8, 136.3, 135.3, 133.2, 129.1, 129.0, 128.9, 128.8, 128.6, 126.9, 126.5, 125.5, 123.8, 122.9, 122.7, 120.3, 113.6, 112.5, 61.1, 43.1, 17.1. MS (ESI) m/z 456.71 (M+H)+, calcd for C
27H23ClN3O2: 456.15, HRMS (ESI) calculated for C27H23ClN3O2
[M+H]+: 456.1473; found: 456.1473. N H N O O NH C N N H N O O NH O O O N H N O O NH C l
2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)-N-phenethyl-2-phenyl acetamide (6f)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6f (291 mg, 67 %) as white solid. 1H NMR (500 MHz, CDCl 3) δ 11.30 (s, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.44 – 7.40 (m, 1H), 7.39 – 7.34 (m, 5H), 7.25 – 7.20 (m, 1H), 7.14 – 7.05 (m, 6H), 6.88 (s, 1H), 6.65 (t, J = 5.9 Hz, 1H), 3.75 – 3.63 (m, 1H), 3.63 – 3.51 (m, 1H), 2.81 (t, J = 6.6 Hz, 2H), 2.52 (s, 3H). 13C NMR (126 MHz, CDCl 3) δ 168.4, 155.3, 140.1, 138.4, 135.5, 129.1, 128.9, 128.7, 128.6, 128.5, 126.7, 126.7, 126.4, 125.4, 123.5, 122.9, 122.6, 120.2, 113.7, 112.8, 61.4, 40.9, 35.5, 17.1. MS (ESI) m/z 436.41 (M+H)+, calcd for C
28H26N3O2: 436.20.
2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenyl-N-(2,4,4-trimethyl pentan-2-yl)acetamide (6g)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6g (323 mg, 73 %) as yellow semi-solid. 1H NMR (500 MHz, CDCl 3) δ 11.82 (s, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.53 – 7.47 (m, 2H), 7.47 – 7.37 (m, 4H), 7.25 – 7.17 (m, 2H), 6.98 (d, J = 1.3 Hz, 1H), 6.40 (s, 1H), 2.56 (s, 3H), 1.91 – 1.64 (m, 2H), 1.52 (s, 3H), 1.49 (s, 3H), 0.91 (s, 9H). 13C NMR (126 MHz, CDCl 3) δ 167.2, 155.5, 140.2, 136.2, 129.1, 129.0, 128.6, 126.9, 126.5, 125.1, 123.6, 122.9, 122.5, 120.0, 113.4, 112.9, 61.6, 56.1, 52.3, 31.5, 31.4, 28.9, 28.6, 17.2. MS (ESI) m/z 444.19 (M+H)+, calcd for C
28H34N3O2: 444.26, HRMS (ESI) calculated for
C28H34N3O2 [M+H]+: 444.2646; found: 444.2644.
N-(2,6-dimethylphenyl)-2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenylacetamide (6h)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6h (308 mg, 71 %) as white solid. 1H NMR (500 MHz, DMSO-d
6) δ 12.21 (s, 1H), 10.02 (s, 1H), 8.14 – 7.97 (m, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.56 – 7.51 (m, 4H), 7.51 – 7.47 (m, 1H), 7.46 – 7.41 (m, 1H), 7.23 – 7.17 (m, 1H), 7.12 – 7.02 (m, 4H), 6.73 (d, J = 1.3 Hz, 1H), 2.42 (s, 3H), 2.14 (s, 6H). 13C NMR (126 MHz, DMSO-d 6) δ 167.4, 155.0, 139.9, 136.1, 135.8, 135.0, 129.9, 129.6, 129.3, 128.2, 127.1, 126.6, 124.0, 123.8, 122.8, 122.7, 120.3, 113.0, 110.7, 105.9, 61.2, 18.6, 17.2. MS (ESI) m/z 436.25 (M+H)+, calcd for C
28H26N3O2: 436.20, HRMS
(ESI) calculated for C28H26N3O2 [M+H]+: 436.2020; found: 436.2018.
N H N O O NH Ph N H N O O NH N H N O O NH
4
N-(tert-butyl)-2-(6-chloro-4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenylacetamide (6i)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6i (248 mg, 59 %) as white solid. 1H NMR (500 MHz, CDCl 3) δ 11.96 (s, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.48 – 7.38 (m, 6H), 7.18 – 7.10 (m, 2H), 6.87 (s, 1H), 6.51 (s, 1H), 2.42 (s, 3H), 1.38 (s, 9H). 13C NMR (126 MHz, CDCl 3) δ 167.6, 155.6, 138.4, 136.1, 129.3, 129.1, 128.9, 127.8, 126.7, 125.4, 124.6, 124.3, 123.6, 121.7, 113.9, 113.1, 61.6, 52.2, 28.8, 17.1. MS (ESI) m/z 422.31 (M+H)+, calcd for C
24H25ClN3O2: 422.16, HRMS (ESI) calculated for C24H25ClN3O2 [M+H]+: 422.1630;
found: 422.1628.
2-(4-bromophenyl)-N-(tert-butyl)-2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)acetamide (6j)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6j (358 mg, 77 %) as white solid. 1H NMR (500 MHz, CDCl 3) δ 11.25 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 7.7 Hz, 2H), 7.42 (t, J = 7.2 Hz, 1H), 7.30 (d, J = 10.1 Hz, 2H), 7.22 (t, J = 6.9 Hz, 1H), 7.12 (s, 1H), 6.89 (s, 1H), 6.51 (s, 1H), 2.55 (s, 3H), 1.41 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 167.2, 155.4, 140.0, 135.3, 132.2, 130.5, 126.7, 125.4, 123.7, 122.9, 122.8, 122.7, 120.2, 113.5, 112.6, 60.3, 52.2, 28.7, 17.1. MS (ESI) m/z 466.18 (M+H)+, calcd
for C24H25BrN3O2: 466.11, HRMS (ESI) calculated for C24H25BrN3O2 [M+H]+: 466.1125; found: 466.1124. 2-(2-bromophenyl)-N-(tert-butyl)-2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)acetamide (6k)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6k (311 mg, 67 %) as white solid. 1H NMR (500 MHz, CDCl 3) δ 12.25 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.58 (t, J = 7.0 Hz, 2H), 7.39 (t, J = 7.7 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.26 – 7.19 (m, 2H), 7.11 (t, J = 7.6 Hz, 1H), 6.64 (s, 1H), 6.60 (s, 1H), 2.46 (s, 3H), 1.40 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 167.3, 155.5, 140.4, 135.7, 133.8, 130.6, 130.4, 127.9, 127.0, 126.4, 125.7, 125.1, 122.7, 122.7, 122.3, 119.9, 113.5, 113.3, 62.4, 52.1, 28.6, 17.2. MS (ESI) m/z 466.13 (M+H)+, calcd for C
24H25BrN3O2: 466.11, HRMS (ESI) calculated for C24H25BrN3O2 [M+H]+: 466.1125;
found: 466.1125. N H N O O NH C l N H N O O NH Br N H N O O NH Br
N-(tert-butyl)-2-(2,4-difluorophenyl)-2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]
indol-2-yl)acetamide (6l)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6l (258 mg, 61 %) as yellow solid. 1H NMR (500 MHz, CDCl 3) δ 12.00 (br, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.63 – 7.58 (m, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.38 – 7.31 (m, 1H), 7.21 – 7.15 (m, 1H), 6.97 (t, J = 8.4 Hz, 2H), 6.90 (s, 1H), 5.81 (br s, 1H), 2.56 (s, 3H), 1.37 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 166.4, 162.90 (d, J = 6.9 Hz), 160.90 (d, J = 7.0 Hz), 155.3, 140.4, 131.31 (d, J = 10.5 Hz), 126.9, 126.8, 125.1, 122.8, 122.4, 122.1, 120.3, 114.7, 113.4, 112.4, 112.2, 67.2, 52.2, 28.7, 17.4. MS (ESI) m/z 424.19 (M+H)+, calcd for C
24H24F2N3O2: 424.19, HRMS (ESI) calculated
for C24H24F2N3O2 [M+H]+: 424.1831; found: 424.1830.
N-(tert-butyl)-2-(3-fluorophenyl)-2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)acetamide (6m)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6m (303 mg, 75 %) as semi-solid. 1H NMR (500 MHz, CDCl 3) δ 11.15 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.42 – 7.32 (m, 2H), 7.23 – 7.13 (m, 3H), 7.11 – 7.02 (m, 2H), 6.93 – 6.86 (m, 1H), 6.42 (s, 1H), 2.57 – 2.49 (m, 3H), 1.39 (s, 9H). 13C NMR (126 MHz, CDCl 3) δ 167.2, 163.1 (d, J = 247.4 Hz), 155.5, 140.1, 138.7 (d, J = 7.3 Hz), 130.7 (d, J = 8.2 Hz), 126.8, 125.5, 124.5 (d, J = 2.9 Hz), 123.8, 123.1, 122.8, 120.4, 116.0 (d, J = 22.7 Hz), 115.7 (d, J = 21.0 Hz), 113.6, 112.7, 60.6, 52.3, 28.8, 17.2. MS (ESI) m/z 406.21 (M+H)+, calcd for C
24H25FN3O2: 406.19,
HRMS (ESI) calculated for C24H25FN3O2 [M+H]+: 406.1925; found: 406.1924.
N-(tert-butyl)-2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)-2-(2-(trifluoromethyl)phenyl)acetamide (6n)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6n (273 mg, 60 %) as yellow oil. 1H NMR (500 MHz, CDCl 3) δ 11.80 (br, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.69 – 7.57 (m, 2H), 7.51 (t, J = 7.5 Hz, 1H), 7.49 – 7.43 (m, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.27 – 7.21 (m, 1H), 7.14 (t, J = 7.5 Hz, 1H), 6.83 (s, 1H), 6.19 (s, 1H), 2.52 (s, 3H), 1.34 (s, 9H). 13C NMR (126 MHz, CDCl 3) δ 167.4, 155.4, 140.3, 134.1, 132.5, 130.5, 129.7, 129.5, 129.1, 127.3, 127.17 (q, J = 5.6 Hz), 126.5, 125.2, 122.5 (m), 120.1, 113.5, 113.1, 59.6, 52.2, 28.5, 17.3. MS (ESI) m/z 456.22 (M+H)+, calcd for C
25H25F3N3O2: 456.19, HRMS (ESI) calculated for C25H25F3N3O2
[M+H]+: 456.1893; found: 456.1893. N H N O O NH F F N H N O O NH F N H N O O NH F3C
4
N-(tert-butyl)-2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)-2-(p-tolyl)
acetamide (6o)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6o (292 mg, 73 %) as white solid. 1H NMR (500 MHz, CDCl 3) δ 11.82 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.72 – 7.56 (m, 1H), 7.42 – 7.28 (m, 3H), 7.22 – 7.08 (m, 4H), 6.88 (s, 1H), 6.56 (s, 1H), 2.48 (s, 3H), 2.34 (s, 3H), 1.40 (s, 9H). 13C NMR (126 MHz, CDCl 3) δ 168.0, 155.6, 140.3, 138.5, 133.4, 129.8, 129.0, 126.9, 126.4, 125.3, 124.0, 122.9, 122.5, 119.9, 113.1, 112.9, 61.0, 52.0, 28.8, 21.3, 17.2. MS (ESI) m/z 402.20 (M+H)+, calcd for C
25H28N3O2: 402.22, HRMS (ESI)
calculated for C25H28N3O2 [M+H]+: 402.2176; found: 402.2173.
N-(tert-butyl)-2-(4-hydroxyphenyl)-2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)acetamide (6p)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6p (209 mg, 52 %) as white solid. 1H NMR (500 MHz, DMSO-d
6) δ 12.04 (s, 1H), 9.64 (s, 1H), 8.23 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.16 – 7.08 (m, 2H), 6.86 – 6.77 (m, 3H), 6.73 (d, J = 1.3 Hz, 1H), 2.41 (s, 3H), 1.29 (s, 9H). 13C NMR (126 MHz, DMSO-d 6) δ 168.2, 157.8, 154.9, 139.9, 130.5, 127.8, 127.0, 126.4, 125.0, 123.6, 122.8, 122.7, 120.2, 116.1, 113.0, 109.8, 59.5, 51.0, 28.9, 17.2. MS (ESI) m/z 404.24 (M+H)+, calcd for C
24H26N3O3: 404.20, HRMS (ESI) calculated for C24H26N3O3 [M+H]+: 404.1969;
found: 404.1967.
N-(tert-butyl)-2-(4-methoxyphenyl)-2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)acetamide (6q)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6q (317 mg, 76 %) as white semi-solid. 1H NMR (500 MHz, CDCl 3) δ 10.85 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.46 – 7.33 (m, 3H), 7.19 (t, J = 7.5 Hz, 1H), 7.05 – 6.92 (m, 2H), 6.92 – 6.81 (m, 2H), 6.17 (s, 1H), 3.82 (s, 3H), 2.51 (s, 3H), 1.39 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 168.0, 159.9, 155.5, 140.0, 130.6, 128.1, 126.9, 126.6, 125.3, 124.0, 123.2, 122.8, 120.2, 114.6, 112.9, 112.7, 60.7, 55.5, 52.2, 28.8, 17.3. MS (ESI) m/z 418.21 (M+H)+,
calcd for C25H28N3O3: 418.21, HRMS (ESI) calculated for C25H28N3O3 [M+H]+: 418.2125; found: 418.2124.
N H N O O NH Me N H N O O NH OH N H N O O NH OMe
2-(benzo[d][1,3]dioxol-5-yl)-N-(tert-butyl)-2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b] indol-2-yl)acetamide (6r)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6r (262 mg, 61 %) as white solid. 1H NMR (500 MHz, CDCl 3) δ 11.65 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.44 – 7.36 (m, 1H), 7.23 – 7.12 (m, 2H), 7.01 – 6.92 (m, 3H), 6.80 (d, J = 8.0 Hz, 1H), 6.64 (s, 1H), 6.02 – 5.93 (m, 2H), 2.55 (s, 3H), 1.44 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 167.7, 155.4, 148.3, 147.9, 140.2, 129.8, 126.8, 126.4, 125.3, 123.7, 122.8, 122.6, 120.0, 113.2, 112.9, 112.7, 109.3, 108.7, 108.6, 101.4, 60.8, 52.0, 28.8, 17.2. MS (ESI) m/z 432.23 (M+H)+, calcd for C
25H26N3O4: 432.19, HRMS (ESI) calculated for C25H26N3O4 [M+H]+:
432.1918; found: 432.1916.
N-(tert-butyl)-2-(4-cyanophenyl)-2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)acetamide (6s)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6s (226 mg, 55 %) as white semi-solid. 1H NMR (500 MHz, CDCl 3) δ 10.23 (s, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.54 – 7.42 (m, 4H), 7.26 – 7.23 (m, 1H), 6.99 (s, 1H), 6.92 – 6.84 (m, 1H), 6.34 (s, 1H), 2.55 (s, 3H), 1.39 (s, 9H). 13C NMR (126 MHz, CDCl 3) δ 166.7, 155.3, 141.5, 139.8, 132.8, 129.4, 127.2, 126.6, 125.5, 123.6, 123.2, 123.0, 120.8, 118.4, 114.1, 112.5, 60.6, 52.5, 28.8, 17.2. MS (ESI) m/z 413.19 (M+H)+, calcd for C
25H25N4O2: 413.20, HRMS (ESI)
calculated for C25H25N4O2 [M+H]+: 413.1972; found: 413.1971.
N-(tert-butyl)-2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)-2-(4-nitrophenyl)
acetamide (6t)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6t (306 mg, 71 %) as yellow solid. 1H NMR (500 MHz, CDCl 3) δ 10.43 (s, 1H), 8.21 (d, J = 8.3 Hz, 2H), 8.07 (d, J = 8.0 Hz, 1H), 7.62 – 7.49 (m, 3H), 7.45 (t, J = 7.5 Hz, 1H), 7.26 – 7.21 (m, 1H), 7.06 (s, 1H), 6.91 (s, 1H), 6.43 (s, 1H), 2.55 (s, 3H), 1.40 (s, 9H). 13C NMR (126 MHz, CDCl 3) δ 166.6, 147.9, 143.4, 139.9, 129.6, 127.2, 124.2, 123.6, 123.1, 123.0, 120.8, 114.4, 112.6, 60.5, 52.6, 28.7, 17.2. MS (ESI) m/z 434.18 (M+H)+, calcd for C
24H25N4O4: 433.19, HRMS (ESI) calculated for C24H25N4O4 [M+H]+: 433.1870; found: 433.1869. N H N O O NH O O N H N O O NH C N N H N O O NH NO2
4
N-(tert-butyl)-4-methyl-2-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)
pentanamide (6u)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6u (256 mg, 70%) as white solid. 1H NMR (500 MHz, DMSO-d
6) δ 12.01 (br, 1H), 8.07 (d, J = 8.2 Hz, 1H), 8.01 (s, 1H), 7.62 – 7.53 (m, 1H), 7.46 – 7.38 (m, 1H), 7.25 (s, 1H), 7.22 – 7.13 (m, 1H), 5.90 – 5.74 (m, 1H), 2.56 (s, 3H), 2.05 – 1.91 (m, 1H), 1.83 – 1.70 (m, 1H), 1.34 – 1.28 (m, 1H), 1.26 (s, 9H), 0.88 (d, J = 7.0 Hz, 3H), 0.87 (d, J = 6.5 Hz, 3H). 13C NMR (126 MHz, DMSO-d 6) δ 170.0, 154.9, 139.8, 127.1, 126.4, 124.1, 123.5, 122.8, 120.1, 113.0, 110.4, 54.3, 50.8, 40.3, 28.9, 24.9, 23.5, 21.6, 17.1. MS (ESI) m/z 368.24 (M+H)+, calcd for C
22H30N3O2: 368.23, HRMS (ESI) calculated for
C22H30N3O2 [M+H]+: 368.2333; found: 368.2332.
N-(tert-butyl)-1-(4-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)cyclopentane-1-carboxamide (6v)
Synthesized according to procedure A in 1.0 mmol scale, afforded 6v (178 mg, 49 %) as white solid. 1H NMR (500 MHz, CDCl 3) δ 12.22 (s, 1H), 8.25 – 8.07 (m, 2H), 7.66 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.08 (s, 1H), 5.87 (s, 1H), 3.06 – 2.91 (m, 2H), 2.71 (s, 3H), 2.40 – 2.29 (m, 2H), 2.06 – 1.92 (m, 2H), 1.88 – 1.78 (m, 2H), 1.21 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 172.0, 155.7, 140.5, 128.3, 126.9, 124.5, 122.4, 122.1, 121.0, 120.1, 113.9, 113.4, 75.7, 51.0, 36.6, 28.6, 23.8, 17.5. MS (ESI) m/z 366.22 (M+H)+, calcd for C
22H28N3O2: 366.22,
HRMS (ESI) calculated for C22H28N3O2 [M+H]+: 366.2176; found: 366.2172, HRMS (ESI) calculated for
C22H27N3O2Na [M+Na]+: 388.1995; found: 388.1991.
Docking procedure
All the synthesized β-carbolinones were converted to 2D-structures with OpenBabel.[s1] Conformers
were generated with Moloc.[s2] The conformers were subsequently docked in the crystal structure
with PDB code 3BHY [s3] using Moloc. The poses were visualized with Pymol, [s4] which was also
used to create the docking figure.
N H N O O NH N H N O O NH
REFERENCES
[s1] N.M. O’Boyle, M. Banck, C.A. James, C. Morley, T. Vandermeersch, G.R. Hutchison, J. Cheminform.
2011, 3, 33 – 47.
[s2] P.R. Gerber, K. Müller, J. Comput. Aided Mol. Des. 1995, 9, 251 – 268.
[s3] K. Huber, L. Brault, O. Fedorov, C. Gasser, P. Filippakopoulos, A. N. Bullock, D. Fabbro, J. Trappe, J. Schwaller, S. Knapp, F. Bracher, J. Med. Chem. 2012, 55, 403 – 413.
[s4] The PyMOL Molecular Graphics System, Version 1.3 Schrödinger, LLC
