2019-12-26 08:46:06
Jin Qiao,+a Xiuwen Jia,+a Pinyi Li,a Xiaoyan Liu,a Jingwei Zhao,a Yu Zhou,b, c
Jiang Wang,b, c Hong Liu,b, c,* and Fei Zhaoa,* a Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics,
Chengdu University, 168 Hua Guan Road, Chengdu 610052, People’s Republic of China
E-mail: [email protected] b State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, Peoples Republic of China
E-mail: [email protected] c University of Chinese Academy of Sciences, No.19 A Yuquan Road, Beijing 100049, Peoples Republic of China
These authors contributed equally to this work.
Manuscript received: November 6, 2018; Revised manuscript received: January 5, 2019;
Version of record online: January 29, 2019
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201801494
Introduction
Gold catalysts have attracted considerable attention[1] in cascade reactions because of their outstanding performance in activating alkynes,[2] alkenes,[3] allenes,[4] etc. Remarkably, alkynoic acids (AAs) are
widely employed as building blocks in gold-catalyzed cascade reactions to construct nitrogen-containing heterocyclic compounds (NCHCs) since Dixon’s pioneering work (Scheme 1a).[5] They revealed that linear aliphatic AAs underwent a cascade reaction smoothly with amine nucleophiles (ANs) carrying a nucleophilic C atom to provide indole- or pyrrole-fused heterocycles under the catalysis of Au(PPh3)Cl/AgOTf. Soon afterwards, the group of Patil further broadened the substrate scope of this cascade reaction using a similar catalytic system (Scheme 1b).[6] They proved cyclic aromatic AA, namely 2-ethynylbenzoic acid, and ANs carrying a nucleophilic N atom were also suitable substrates. In our ongoing efforts to develop facile approaches for the construction of nitrogen-containing heterocyclic scaffolds via gold catalysis,[7] we herein extensively study the cascade reaction between diverse AAs and ANs, and develop a much more general and efficient catalytic system, which tolerates a much more
broader substrate scope of AAs and ANs, and therefore allows the rapid construction of NCHC library with scaffold diversity and molecular complexity (Scheme 1c). We found the combination of Au(PPh3)
Cl, which acts as a Lewis acid catalyst to activate the carbon-carbon triple bonds of AAs, and a Brønsted acid, namely CF3CO2H, allows diverse linear aliphatic AAs as well as various cyclic aromatic AAs react well with broader ANs carrying a nucleophilic C/N/O atom to assemble indole/pyrrole/thiophene/benzene/naphthalene/pyridine-based NCHCs with a large diverse scaffolds. The extraordinarily broad substratescope of this catalytic system significantly widens the application of the cascade reactions between AAs and ANs in the assembly of nitrogen-containing heterocycles.
On the other hand, indole-fused skeletons are highly valuable scaffolds because they are widely found in bioactive natural products[8] and pharmaceutical agents.[9] Hence, they are considered as one of the most prominent privileged structures[10] in drug development. As a result, methods for the generation of indole-fused frameworks have captured wide attention. Tremendous efforts have been made[11,12] to develop efficient protocols to assemble these frameworks to provide potentially useful scaffolds for drug screening. Apparently, one-pot cascade reactions featuring simple operation and multiple bond formation in a single one chemical process are much more efficient and convenient for the furnishment of these complex scaffolds as compared with multistep synthesis. Despite the remarkable achievements made, the construction of indole-fused multi-ring architectures in high selectivity and efficiency from simple starting materials through a one-pot cascade process
still represents a significant synthetic challenge. As part of our interests in the synthesis of indole-fused heterocycles,[13] here we aim to develop a highly selective cascade reaction between 1,3 unsubstituted 2-(1H-indol-2-yl)ethanamines and AAs to assemble novel indole-fused skeletons. As shown in Scheme 2, we expected that AAs could undergo intramolecular cyclization motivated by proper metal catalysts to give the enol lactone A (path a) or B (path b) due to the C1/C2 regioselectivity of the AAs.[5] The following aminolysis of A or B by 1,3-unsubstituted 2-(1Hindol-2-yl)ethanamines could produce A’ or B’. Then A’ or B’ would undergo an iminium ion formation/nucleophilic cyclization sequence to provide four possible scaffolds A1 (path a1), A2 (path a2), B1 (path b1), and B2 (path b2) owing to the C3/N1 site selectivity of the indole ring. The main challenge of this process is to achieve high levels of chemoselectivity including C1/C2 regioselectivity and C3/N1 site selectivity to generate a single skeleton in high efficiency. In this paper, we report the highly selective and efficient construction of the novel A1 scaffold through gold catalysis. To the best of our knowledge, 1,3-unsubstituted 2-(1H-indol-2-yl)ethanamines are employed for the first time to react with AAs to achieve highly selective tandem reactions, thus affording the novel indole-fused framework A1. More importantly, the gold catalytic system was proved to be compatible with various ANs and diverse AAs, and was successfully employed for the rapid construction of an indole/pyrrole/thiophene/benzene/naphthalene/pyridine-based NCHC library with scaffold diversity and molecular complexity.
The hit rates of most of current combinatorial libraries in high-throughput screening (HTS) are far from satisfactory. This is because the scaffold diversity of these libraries, which contain similar molecular
skeletons decorated with different substituents, is too limited to possess a wide chemical space. In recent years, skeletal diversity of a compound library is well recognized to be much more important than the appendices in HTS. Since compound libraries featuring a high degree of scaffold diversity can effectively improve the occupation of chemical space to increase the hit rates for various biological targets.[14] Apart from scaffold diversity, drug-like properties are equally important. As a library created with little consideration of drug-like properties may suffer from more absorption, distribution, metabolism, excretion, and toxicity (ADMET) problems during the drug development process.[15] Therefore, a high-quality and valuable compound library should display scaffold diversity as well as good drug-like properties. Undoubtfully, privileged-substructure-based diversity-oriented synthesis (pDOS) offers a powerful strategy to construct high-quality compound libraries because privileged structures exhibit inherent affinity for diverse biological targets and ubiquitously exist in natural and pharmaceutical products.[16] However, the development of robust processes to generate diverse scaffolds embedded with privileged structures remains a challenge and is highly demanding for drug screening. We herein introduce an efficient protocol, which allows the rapid access to the pDOS library of NCHCs encompassing molecular complexity, scaffold diversity, and drug-like properties. More importantly, two potent compounds with good antiproliferative activities were identified from this library.
Results and Discussion
Initial screening experiments were carried out with 2- (1H-indol-2-yl)ethanamine (1 a) and 4-pentynoic acid (2 a) as model substrates to optimize the reaction conditions including catalysts and solvents (Table 1). A variety of metal complexes (5 mol%) as Lewis acid catalysts were screened in toluene in a sealed tube at 120 8C for 24 h at first. It turned out that AuCl was more effective than other metal species such as Pd, Cu, Ag, Ni, Co, and Pt catalysts (entries 1–11). A high yield of 3 a (85%) with excellent C1/C2 regioselectivity and high C3/N1 site selectivity (90:10) were obtained with AuCl (entry 11). Then a series of Au catalysts were explored (entries 12–17). Isomers 3 a2 and 3 a3, which derive from the 6-endo ring closure intermediate of 2 a, were not observed in these cases.
Among them, Au(PPh3)Cl showed the highest catalytic performance and C3/N1 site selectivity (>99:1) (entry 14). Subsequently, a further screening of solvents (entries 18–23) revealed the transformation was strongly influenced by the solvents used. DCE turned out to be the best choice for this reaction resulting in almost quantitative yield (96%) with excellent C1/C2 regioselectivity and C3/N1 site selectivity (>99:1) (entry 19). In addition, Brønsted acids such as HOAc, TFA and HOTf were also tested as the catalysts (entries 24–26), but none of them could catalyze this transformation. They alone could not promote this reaction even when a stoichiometric amount (1 equivalent) of them was used. By contrast, control experiments showed that Au(PPh3)Cl played a crucial and indispensable role in this cascade reaction (entry 27).
In this way, the optimum results were obtained when 2-(1H-indol-2-yl)ethanamine (0.25 mmol) and 4-pentynoic acid (0.3 mmol) were treated with 5 mol% of Au(PPh3)Cl in DCE in a sealed tube at 1208C for 24 h. With the optimal conditions established, we then investigated the scope of this method. Firstly, we examined the reactions of various substituted 2-(1Hindol-2-yl)ethanamines 1 with 2 a. As shown in Scheme 3, the reactions of 2-(1H-indol-2-yl)ethanamines bearing electron-donating (5-OMe, 5-Me) or electron-withdrawing groups (5-F) appeared to be reactive and afforded the corresponding products 3 b–3 d in high yields. It should be noted that the reaction of 2-(5-fluoro-1H-indol-2-yl)ethanamine with 2 a was sluggish under standard conditions because the C3 nucleophilicity was weakened by the fluorine. An improved two-step one-pot procedure, in which a Brønsted acid, namely CF3CO2H, was added to accelerate the formation of iminium ion, well addressed this issue. Similar results were also observed when the reactions were carried out with other AAs such as 5-hexynoic acid, 2-ethynylbenzoic acid, 2-(2-ethynylphenyl)acetic acid and 2-hexyl-4-pentynoic acid. This may be attributed to the relatively lower reactivities of these AAs. Nevertheless, these AAs underwent the tandem reactions smoothly to produce the desired products 3 e–3 k in 70–96% yields under improved conditions. In addition to terminal AAs, internal AAs were also tested as the reaction substrates. However, we found the reaction between 5-phenylpent-4-ynoic acid and 1 a was not active, and the desired product 3l was obtained in a low yield (15%). This may be ascribed to the lower reactivities of internal carbon-carbon triple bonds caused by steric hindrance as compared with terminal ones. We hypothesized the addition of silver salts, which can increase the catalytic activity of Au(PPh3)Cl,[1o] would be able to activate the internal carbon-carbon triple bonds of terminally substituted AAs to solve this problem. Therefore, several silver complexes such as AgBF4, AgOTf, and AgSbF6 were added and screened. Pleasingly, AgBF4 was found to be the most efficient silver additive, with which product 3l was produced in a good yield (67%) at a higher temperature. Similarly, other internal AAs such as 6-phenylhex-5-ynoic acid, 2-(phenylethynyl)benzoic acid, 2-(2-(phenylethynyl)phenyl)acetic acid or 2-(hex-1-yn-1-yl) benzoic acid also reacted well with 1 a under the catalysis of Au(PPh3)Cl/AgBF4/CF3CO2H to afford the desired products 3m–3 p in moderate to good yields. We also made our efforts to achieve the synthesis of 3 q from 2-(2-(hex-1-yn-1-yl)phenyl)acetic acid. Unfortunately, a complex reaction mixture was obtained and only a trace amount of 3 q was detected by LC-MS. Notably, excellent C1/C2 regioselectivity of AAs and C3/N1 site selectivity of the indole ring were observed in all examples, providing the corresponding novel indole-fused scaffolds presented by 3 a–3 p with high efficiency. The excellent C3/N1 site
selectivity of the indole ring may be attributed to the stronger nucleophilicity of C3 than that of N1, whose nucleophilicity is reduced by the aromatic ring.[17,18] As a result, indole C3 instead of indole N1 attacked the iminium ion intermediate in priority to give the C3-cyclization products selectively.
Further experiments under the standard or improved reaction conditions demonstrated that the protocol could be extended to the reactions of various AAs with diverse ANs containing an indole moiety, such as 2-(1H-indol-3-yl)ethanamines, 2-(1H-indol-1-yl)ethanamines, 3-(1H-indol-1-yl)propan-1-amines and 2-(1H-indol-1-yl)anilines, to generate a variety of indole-fused scaffolds. In general, all the corresponding NCHCs embedded with an indole motif were obtained in moderate to high yields (Scheme 4). Specifically, 2-(1H-indol-3-yl)ethanamines reacted smoothly with anyone of 4-pentynoic acid, 5-hexynoic acid, 2-ethynylbenzoic acid, 2-(2-ethynylphenyl)acetic acid and 2-hexyl-4-pentynoic acid, providing the desired products 5 aa–5 ai in 61–94% yields. Similarly, 2-(1H-indol-1-yl)ethanamines were also found to be suitable substrates. Their reactions with various AAs worked well to afford the corresponding products 5 aj–5 ax in 46–92% yields. To our delight, 3-(1Hindol-1-yl)propan-1-amines were well tolerated and converted into the polycyclic products 5 ay–5 ba embedded with a seven-membered ring in good yields.
This further highlights the efficiency of this approach because the generation of seven-membered ring analogues is less favored on energetics and dynamics in cascade reactions. Gratifyingly, this process could also be applicable to 2-(1H-indol-1-yl)anilines, which underwent this transformation successfully to give more rigid compounds 5 bb–5 bd in 62–89% yields. It should be noticed that the indole-fused polycyclic scaffolds presented by 3 a–3 q and 5 aa–5 bd are considered as valuable heterocycles in view of their frequent occurrence in biologically active natural products and drugs.[19] Pleasingly, other 2-aryl-ethanamines such as 2-(1Hpyrrol-2-yl)ethanamine, 2-(1H-pyrrol-1-yl)ethanamine, 2-(thiophen-3-yl)ethanamine, 2-(thiophen-2-yl) ethanamine and 2-(3,4-dimethoxyphenyl)ethanamine also turned out to be suitable substrates for this cascade process. They reacted well with AAs to afford the desired NCHCs with high selectivity and moderate to high yields (Scheme 5). For example, the reaction of 2-(1H-pyrrol-2-yl)ethanamine with 2-ethynylbenzoic acid took place smoothly and selectively, producing the C3 ring closure product 7 a instead of N1 ring closure product 7 a’. Likewise, 2-(thiophen-3 yl)ethanamine underwent this transformation with various AAs in a highly selective manner, providing the C2 ring closure products rather than C4 closure ones (7 c–7 e). Similarly, the ring closure site occurred at the less-hindered position selectively in the reactions of 2-(3,4-dimethoxyphenyl)ethanamine with AAs (7 h–7 j).
Based on these results, we could conclude that, when two or more nucleophilic sites exist in the final cyclization step, the stronger and less-hindered nucleophilic site tends to attack the iminium ion with strict priority to afford the corresponding ring closure products. The applicability of this cascade reaction in ANs 8 bearing another nucleophilic heteroatom (O, N) was also well studied and established. As shown in Scheme 6, the reactions of 2-aminobenzoic acid/3-amino-2-naphthoic/2-aminonicotinic acid with diverse AAs worked smoothly to give the desired products 9 a–9 g in 35–94% yields. Even (2-aminophenyl)methanol could react with AAs to provide the products 9 h–9i, albeit with lower yields. It is worth noting that the aniline N played as the nucleophile which attacked the enol lactone intermediate, and the amide N played as the nucleophile which attacked the iminium ion when 2-aminobenzamide was employed as the bisnucleophile to react with 4-pentynoic acid, thus leading
to the formation of 9 j selectively instead of 9 j’. Similar results have been observed in the reactions of 2-aminobenzamide with other AAs such as 2-hexyl-4-pentynoic acid, 5-hexynoic acid, 2-ethynylbenzoic acid, and 2-(2-ethynylphenyl)acetic acid, affording the single kind of products with high selectivity (9 k–9 n).
To our delight, positive results were also observed when 2-amino-N-methylbenzamide and AAs weresubjected to the reaction conditions, and the corresponding products 9 o–9 r were obtained in 38–91%
yields. Despite the lower yields, benzene-1,2-diamine was also found to be a suitable substrate, which could be converted into the desired products 9 s–9 t. Interestingly, in the reaction of 2 (aminomethyl)aniline with 4-pentynoic acid, the more nucleophilic amine N rather than the aniline N displayed as the nucleophile to attack the enol lactone intermediate in the first step. As a result, the aniline N could only display as the nucleophile to attack the iminium ion in the final cyclization step, thus affording 9 u selectively instead of 9 u’. Similarly, 9 v was obtained as the only product
in 43% yield when 2-(aminomethyl)aniline and 2-ethynylbenzoic acid were used as the starting materials. From the above results, we could come to a conclusion that the more nucleophilic N is generally
involved in the first ring-opening of enol lactone intermediate, while the less nucleophilic N is normally involved in the final cyclization step when bisnucleophiles carrying two nitrogen atoms are employed as the substrates. Briefly, these findings further broadened the substrate scope of the methodology.
Thus, the cascade reactions between various ANs and diverse AAs rapidly created a library of indole/pyrrole/thiophene/benzene/naphthalene/pyridinebased NCHCs with scaffold diversity and molecular complexity. It should be noted that two rings and three new bonds were formed efficiently in a single one step to give the NCHCs bearing a quaternary carbon center. It is also worth noting that lots of the scaffolds in this paper are reported for the first time and turn out to be novel nitrogen-containing heterocyclic frameworks. Such a divergent synthesis of heterocycles is evidently appealing and promising in diversity oriented synthesis because it provides a platform to assemble thousands of NCHCs with scaffold diversity in an efficient manner.
To further illustrate the practicality of this methodology, the cascade reaction between 1 a and 2 a was carried out on a gram scale under optimal conditions. Impressively, the desired product 3 a was obtained in 90% yield (Scheme 7a). In addition, the reported potent a1A-adrenoceptor antagonists[7g] 5 ag–1, 5 ah–1, 5 ai–1 were prepared easily via a simple reduction of the corresponding precursors in our library (Scheme 7b). Besides, a pharmacological screening of these NCHCs in this library to evaluate their inhibitory activities against human cancer cell lines A549 and HL60 resulted in the identification of two potent compounds 3 g and 9 k, which exhibited moderate to good inhibition activities as compared with the positive control Adriamycin (Table 2). These aspects further highlight the advantages and potential applications of our approach.
Furthermore, mechanistic studies were performed to probe the reaction mechanism. When 2-ethynylbenzoic acid (2 c) or 2-(2-ethynylphenyl)acetic acid (2 d) was subjected to the standard conditions without ANs, the corresponding enol lactone 2 c–1 or 2 d–1, whose structure was confirmed by 1 H NMR, 13C NMR and HRMS, was isolated as the product (Scheme 8a and 8b). In addition, the aminolysis product 3m–1 of the enol lactone derived from 6-phenylhex-5-ynoic acid 2 g in the reaction of 1 a and 2 g was isolated in 52% yield, and the treatment of 3m–1 with TFA in DCE at 140 8C for 4 h provided the target product 3m in a high yield (Scheme 8c). These results suggest that the enol lactone species is likely to be involved in this cascade reaction. Besides, the reaction of 1 a with the commercially available enol lactone C could afford the desired product 3 a with or without Au(PPh3)Cl. A higher yield was obtained in the presence of Au(PPh3) Cl as compared with catalyst-free conditions (Scheme 8d).
This indicates that the gold catalyst may not only catalyze the formation of enol lactone intermediate, but also catalyze the iminium ion formation. Based on the above mechanistic study results, we proposed a plausible catalytic cycle (Scheme 9). The complexation of the Au catalyst to the alkyne moiety of AAs gives intermediate D1, which undergoes intramolecular exo cyclization to afford the vinylgold intermediate D2. Then the protodemetalation of D2 occurs to provide the key enol lactone intermediate D3 with the release of the Au catalyst. The subsequent aminolysis of D3 by ANs produces intermediate D4.
Then the coordination of the Au catalyst to the carbonyl of D4 takes place to generate intermediate D5, which undergoes a sequential nucleophilic addition and iminium ion formation to yield intermediate D7. The final nucleophilic cyclization of D7 provides the products and regenerates the Au catalyst. In brief, two catalytic cycles were involved in the proposed reaction mechanism. The Au catalyst could catalyze the formation of enol lactone as well as the iminium ion intermediate. Besides, CF3CO2H could accelerate the formation of iminium ion intermediate to promote this cascade reaction.
Conclusion
In summary, we empolyed 1,3-unsubstituted 2-(1Hindol-2-yl)ethanamines for the first time to react with AAs to achieve gold-catalyzed highly selective cascade reaction to furnish novel indole-fused skeletons. More importantly, this gold catalytic system has been successfully used for the rapid construction of an indole/pyrrole/thiophene/benzene/naphthalene/pyridine-based NCHC library with scaffold diversity and molecular complexity by employing various ANs and diverse AAs as the scaffold-building reagents.
This synthetic protocol exhibits valuable features of readily available inputs, operational simplicity, extraordinarily broad substrate scope, good to high yields, excellent selectivity, high bond-forming efficiency, and step economy. In addition, two potent compounds with good antiproliferative activities were identified from this library, highlighting the potential and value of this strategy. Considering the large presence of NCHCs in natural and pharmaceutical products, the approach presented here is very promising as it could provide a rapid and powerful tool to construct a library of thousands of NCHCs with a large diverse scaffolds. Further bioactivity studies of this library are currently in progress in our laboratory, and we expect these valuable nitrogen-containing heterocycles embedded with privileged structures may find more pharmaceutical applications.
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2,5-Difluoro-4-methoxybenzoic acidCatalog No.:AA007E32 CAS No.:1060739-01-6 MDL No.:MFCD11847151 MF:C8H6F2O3 MW:188.1282 |
2-Amino-4-chloro-5-(trifluoromethyl)phenolCatalog No.:AA0096WC CAS No.:1060757-37-0 MDL No.:MFCD24646161 MF:C7H5ClF3NO MW:211.5689 |
(S)-Fmoc-2-amino-5-(N'-Pbf-N''-trifluoroethyl-guanidino)-pentanoic acidCatalog No.:AA009623 CAS No.:1060769-47-2 MDL No.:MFCD18782822 MF:C36H41F3N4O7S MW:730.7935 |
(S)-Fmoc-2-amino-5-[(N'-Pbf-N''-Boc-amino)-guanidino]-pentanoic acidCatalog No.:AA008WZZ CAS No.:1060769-54-1 MDL No.:MFCD18782823 MF:C39H49N5O9S MW:763.8995 |
(S)-Fmoc-2-amino-5-[(N'-Pbf-N''-tert-butoxy)-guanidino]-pentanoic acidCatalog No.:AA008X2F CAS No.:1060769-55-2 MDL No.:MFCD18782824 MF:C38H48N4O8S MW:720.8747 |
Methyl 5-bromo-2-(methylsulfonyl)pyrimidine-4-carboxylateCatalog No.:AA009940 CAS No.:1060795-14-3 MDL No.:MFCD11100780 MF:C7H7BrN2O4S MW:295.1105 |
2-Ethoxy-5-(4h-1,2,4-triazol-4-yl)anilineCatalog No.:AA007E29 CAS No.:1060796-06-6 MDL No.:MFCD11505340 MF:C10H12N4O MW:204.2285 |
6-(4H-1,2,4-Triazol-4-yl)picolinic acidCatalog No.:AA007VU7 CAS No.:1060796-15-7 MDL No.:MFCD11053897 MF:C8H6N4O2 MW:190.1588 |
2-cyanopyridine-3-sulfonyl chlorideCatalog No.:AA01BE0E CAS No.:1060801-06-0 MDL No.:MFCD13188945 MF:C6H3ClN2O2S MW:202.6182 |
3-bromo-N,N-dimethylpyridin-2-amineCatalog No.:AA0095GY CAS No.:1060801-39-9 MDL No.:MFCD13188970 MF:C7H9BrN2 MW:201.0638 |
6-Chloro-N,N-dimethylpyridin-2-amineCatalog No.:AA0093IV CAS No.:1060801-42-4 MDL No.:MFCD13188973 MF:C7H9ClN2 MW:156.6128 |
6-(Aminomethyl)-n,n-dimethylpyridin-2-amineCatalog No.:AA01A2J3 CAS No.:1060801-43-5 MDL No.:MFCD13188974 MF:C8H13N3 MW:151.2089 |
2-(N-Methylaminomethyl)-5-methylpyridineCatalog No.:AA00HAO5 CAS No.:1060801-52-6 MDL No.:MFCD13188986 MF:C8H12N2 MW:136.1943 |
3-Fluoro-5-methoxypyridineCatalog No.:AA007E28 CAS No.:1060801-62-8 MDL No.:MFCD13185606 MF:C6H6FNO MW:127.1163 |
6-Chloro-5-methoxypyridine-3-carbaldehydeCatalog No.:AA00HAO6 CAS No.:1060801-67-3 MDL No.:MFCD13189003 MF:C7H6ClNO2 MW:171.5810 |
5-Methoxypyridine-3-sulfonyl chlorideCatalog No.:AA0096S5 CAS No.:1060801-85-5 MDL No.:MFCD13189017 MF:C6H6ClNO3S MW:207.6347 |
5-TRIFLUOROMETHYL-PYRIDINE-3-SULFONYL CHLORIDECatalog No.:AA0092WJ CAS No.:1060802-03-0 MDL No.:MFCD13189030 MF:C6H3ClF3NO2S MW:245.6067 |
5-Chloropyridine-3-sulfonyl chlorideCatalog No.:AA008UA5 CAS No.:1060802-18-7 MDL No.:MFCD13189042 MF:C5H3Cl2NO2S MW:212.0538 |
5-Bromo-2-chloropyridine-4-carbaldehydeCatalog No.:AA007E27 CAS No.:1060802-23-4 MDL No.:MFCD11847346 MF:C6H3BrClNO MW:220.4511 |
5-Bromo-4-chloronicotinaldehydeCatalog No.:AA00HAO8 CAS No.:1060802-24-5 MDL No.:MFCD13189052 MF:C6H3BrClNO MW:220.4511 |
5-Bromo-4-chloropicolinic acidCatalog No.:AA007VU6 CAS No.:1060802-25-6 MDL No.:MFCD13189053 MF:C6H3BrClNO2 MW:236.4505 |
2,2,2-Trifluoro-1-(3-fluoropyridin-2-yl)ethanoneCatalog No.:AA0096RI CAS No.:1060802-41-6 MDL No.:MFCD13189065 MF:C7H3F4NO MW:193.0984 |
5-Fluoropyridine-3-Sulfonyl ChlorideCatalog No.:AA008WFY CAS No.:1060802-49-4 MDL No.:MFCD13189070 MF:C5H3ClFNO2S MW:195.5992 |
6-Bromo-1,2-benzisoxazoleCatalog No.:AA00HAOA CAS No.:1060802-88-1 MDL No.:MFCD06659634 MF:C7H4BrNO MW:198.0168 |
5-IODO-1H-BENZIMIDAZOLE-2-AMINECatalog No.:AA008T5Y CAS No.:1060803-19-1 MDL No.:MFCD06659791 MF:C7H6IN3 MW:259.0471 |
5-Cyanopyridine-3-sulfonyl chlorideCatalog No.:AA00953T CAS No.:1060804-15-0 MDL No.:MFCD13189095 MF:C6H3ClN2O2S MW:202.6182 |
[3-(benzyloxy)pyridin-4-yl]methanamineCatalog No.:AA01BA4Y CAS No.:1060804-47-8 MDL No.:MFCD13189117 MF:C13H14N2O MW:214.2631 |
5-HydroxynicotinaldehydeCatalog No.:AA003MQ4 CAS No.:1060804-48-9 MDL No.:MFCD13189119 MF:C6H5NO2 MW:123.1094 |
2-Chloro-5-hydroxyisonicotinaldehydeCatalog No.:AA0093WY CAS No.:1060804-53-6 MDL No.:MFCD13189121 MF:C6H4ClNO2 MW:157.5545 |
2-Chloro-5-hydroxyisonicotinic acidCatalog No.:AA003GW8 CAS No.:1060804-57-0 MDL No.:MFCD13189124 MF:C6H4ClNO3 MW:173.5539 |
6-Bromo-4-methylnicotinic acidCatalog No.:AA0094PE CAS No.:1060804-74-1 MDL No.:MFCD13189138 MF:C7H6BrNO2 MW:216.0320 |
methyl[(4-methylpyridin-3-yl)methyl]amineCatalog No.:AA01BGGO CAS No.:1060804-84-3 MDL No.:MFCD13189144 MF:C8H12N2 MW:136.1943 |
1-(4-Methylpyridin-3-yl)ethanamineCatalog No.:AA01A44D CAS No.:1060805-01-7 MDL No.:MFCD13189155 MF:C8H12N2 MW:136.1943 |
(4-Methoxypyridin-3-yl)methanamineCatalog No.:AA00955D CAS No.:1060805-04-0 MDL No.:MFCD13189160 MF:C7H10N2O MW:138.1671 |
6-Bromo-4-methoxypicolinic acidCatalog No.:AA00HAOD CAS No.:1060805-13-1 MDL No.:MFCD13189165 MF:C7H6BrNO3 MW:232.0314 |
6-chloro-4-(trifluoromethyl)pyridine-2-carbaldehydeCatalog No.:AA01BTGZ CAS No.:1060805-47-1 MDL No.:MFCD13189193 MF:C7H3ClF3NO MW:209.5530 |
2-[4-(trifluoromethyl)pyridin-2-yl]ethan-1-amineCatalog No.:AA01BBSD CAS No.:1060805-59-5 MDL No.:MFCD11848105 MF:C8H9F3N2 MW:190.1657 |
4-Bromo-6-chloronicotinaldehydeCatalog No.:AA008YBY CAS No.:1060805-64-2 MDL No.:MFCD13189209 MF:C6H3BrClNO MW:220.4511 |
4-Bromo-6-chloropicolinic acidCatalog No.:AA008VQP CAS No.:1060805-66-4 MDL No.:MFCD13189210 MF:C6H3BrClNO2 MW:236.4505 |
1-(4-Bromopyridin-2-yl)ethanoneCatalog No.:AA008WMC CAS No.:1060805-69-7 MDL No.:MFCD13189212 MF:C7H6BrNO MW:200.0326 |
4-Chloro-6-methylnicotinic acidCatalog No.:AA007VU4 CAS No.:1060805-95-9 MDL No.:MFCD11520850 MF:C7H6ClNO2 MW:171.5810 |
6-bromo-2-methylpyridine-3-carboxylic acidCatalog No.:AA008ZRQ CAS No.:1060805-97-1 MDL No.:MFCD13188658 MF:C7H6BrNO2 MW:216.0320 |
3-(2-methylpyridin-3-yl)propan-1-amineCatalog No.:AA01DX6S CAS No.:1060806-37-2 MDL No.:MFCD13188694 MF:C9H14N2 MW:150.2209 |
4-Bromo-2-methoxynicotinaldehydeCatalog No.:AA00HAOH CAS No.:1060806-59-8 MDL No.:MFCD13188725 MF:C7H6BrNO2 MW:216.0320 |
4-Chloro-6-methoxypyridine-3-carboxylic acidCatalog No.:AA00994Q CAS No.:1060806-60-1 MDL No.:MFCD13188727 MF:C7H6ClNO3 MW:187.5804 |
6-bromo-2-methoxypyridine-3-carboxylic acidCatalog No.:AA009559 CAS No.:1060806-62-3 MDL No.:MFCD13188730 MF:C7H6BrNO3 MW:232.0314 |
4-Fluoro-2-methoxynicotinic acidCatalog No.:AA003ALR CAS No.:1060806-71-4 MDL No.:MFCD13188735 MF:C7H6FNO3 MW:171.1258 |
[(6-methoxypyridin-2-yl)methyl](methyl)amineCatalog No.:AA018RRM CAS No.:1060806-94-1 MDL No.:MFCD13188748 MF:C8H12N2O MW:152.1937 |
1-(6-Methoxypyridin-3-yl)cyclopropanecarboxylic acidCatalog No.:AA01DMC6 CAS No.:1060807-02-4 MDL No.:MFCD13188756 MF:C10H11NO3 MW:193.1992 |
1-(2-Methoxy-pyridin-4-yl)-cyclopropanecarboxylic acidCatalog No.:AA00HAOJ CAS No.:1060807-03-5 MDL No.:MFCD13188757 MF:C10H11NO3 MW:193.1992 |
2,2,2-trifluoro-1-(6-methoxypyridin-2-yl)ethanamineCatalog No.:AA01BRK3 CAS No.:1060807-19-3 MDL No.:MFCD13188767 MF:C8H9F3N2O MW:206.1651 |
1-(2-METHOXYPYRIDIN-4-YL)ETHANAMINECatalog No.:AA009698 CAS No.:1060807-28-4 MDL No.:MFCD13188773 MF:C8H12N2O MW:152.1937 |
2-Chloro-6-(trifluoromethyl)isonicotinaldehydeCatalog No.:AA0084C5 CAS No.:1060807-47-7 MDL No.:MFCD13188805 MF:C7H3ClF3NO MW:209.5530 |
4-Chloro-6-(trifluoromethyl)nicotinaldehydeCatalog No.:AA008VNP CAS No.:1060807-48-8 MDL No.:MFCD13188806 MF:C7H3ClF3NO MW:209.5530 |
4-Bromopyridine-2-sulfonyl chlorideCatalog No.:AA0084C4 CAS No.:1060808-87-8 MDL No.:MFCD11847757 MF:C5H3BrClNO2S MW:256.5048 |
6-Bromo-4-chloronicotinic acidCatalog No.:AA003A2Y CAS No.:1060808-92-5 MDL No.:MFCD13189219 MF:C6H3BrClNO2 MW:236.4505 |
6-Amino-4-chloronicotinic acidCatalog No.:AA008YC1 CAS No.:1060808-94-7 MDL No.:MFCD13189221 MF:C6H5ClN2O2 MW:172.5691 |
4-Fluoro-2-formylpyridineCatalog No.:AA008Z04 CAS No.:1060809-18-8 MDL No.:MFCD13189242 MF:C6H4FNO MW:125.1005 |
2-Chloro-4-fluoropyridine-3-carbaldehydeCatalog No.:AA01EA48 CAS No.:1060809-21-3 MDL No.:MFCD13189245 MF:C6H3ClFNO MW:159.5455 |
6-Bromo-4-fluoronicotinic acidCatalog No.:AA0084C3 CAS No.:1060809-33-7 MDL No.:MFCD13189252 MF:C6H3BrFNO2 MW:219.9959 |
4-Amino-2-bromonicotinic acidCatalog No.:AA009563 CAS No.:1060809-71-3 MDL No.:MFCD13189282 MF:C6H5BrN2O2 MW:217.0201 |
2-Bromo-6-methylnicotinic acidCatalog No.:AA0092CT CAS No.:1060810-09-4 MDL No.:MFCD13189307 MF:C7H6BrNO2 MW:216.0320 |
3-Chloro-6-methoxypicolinaldehydeCatalog No.:AA00HAOP CAS No.:1060810-35-6 MDL No.:MFCD13189327 MF:C7H6ClNO2 MW:171.5810 |
2-Bromo-6-methoxynicotinaldehydeCatalog No.:AA0084C1 CAS No.:1060810-41-4 MDL No.:MFCD13189331 MF:C7H6BrNO2 MW:216.0320 |
4-Chloro-6-(trifluoromethyl)nicotinic acidCatalog No.:AA008WQC CAS No.:1060810-66-3 MDL No.:MFCD13188812 MF:C7H3ClF3NO2 MW:225.5524 |
4-Bromo-6-(trifluoromethyl)picolinic acidCatalog No.:AA008Z0U CAS No.:1060810-68-5 MDL No.:MFCD13188813 MF:C7H3BrF3NO2 MW:270.0034 |
4-Hydroxy-6-(trifluoromethyl)nicotinic acidCatalog No.:AA008WVU CAS No.:1060810-79-8 MDL No.:MFCD28138139 MF:C7H4F3NO3 MW:207.1068 |
1-(2-(Trifluoromethyl)pyridin-4-yl)ethanoneCatalog No.:AA007VU1 CAS No.:1060810-86-7 MDL No.:MFCD11847720 MF:C8H6F3NO MW:189.1345 |
1-(2-(Trifluoromethyl)pyridin-4-yl)ethanamineCatalog No.:AA00JSIY CAS No.:1060811-09-7 MDL No.:MFCD13188839 MF:C8H9F3N2 MW:190.1657 |
2-(Trifluoromethyl)-3-pyridinesulfonyl chlorideCatalog No.:AA00J28N CAS No.:1060811-16-6 MDL No.:MFCD13188846 MF:C6H3ClF3NO2S MW:245.6067 |
6-Bromo-4-chloronicotinaldehydeCatalog No.:AA008YC2 CAS No.:1060811-24-6 MDL No.:MFCD13188856 MF:C6H3BrClNO MW:220.4511 |
2-bromo-6-chloroisonicotinic acidCatalog No.:AA00952U CAS No.:1060811-26-8 MDL No.:MFCD13185792 MF:C6H3BrClNO2 MW:236.4505 |
2-AMino-6-broMo-isonicotinic acidCatalog No.:AA00955P CAS No.:1060811-29-1 MDL No.:MFCD13188859 MF:C6H5BrN2O2 MW:217.0201 |