332L Final Project-Spring 2018 Deadlines for Spring 2018 Project Proposal: March 25th at 11:59 PM Project ELN: Three days after you complete your project lab work General Timeline Approximately Mid Semester • Form a project team of two or three members (not larger). • Read the scientific paper included at the end of this document for background information. • Plan the detailed procedure for replicating the synthesis of the following compound described in the scientific paper (compound 4l) and one variation of the original compound using available reagents (listed in this document). Compound 4l • • Ask your TAs (or other 332L TAs, head TA, or course instructor) questions to clarify your understanding of the project. Look at the Project Proposal Guidelines included in this document and write a Project Proposal. Approximately Two Weeks Before Project Work Begins • Submit your project proposal. All team members may submit the same proposal. Your TA will grade and provide feedback within a week. During Project Lab Periods • Perform the work outlined in your proposal. Be sure to implement TA feedback. Record data in your ELN. . Please see guidelines included in this document for details about expectations so that you record all necessary information while you are in the lab. • Please plan to run simultaneous syntheses the first day so the second day can be spent primarily on obtaining 1H NMR as well as spectral interpretation. Your TAs will run samples for you during your second project class period. Third Day After Project Work is Completed • Submit your project ELN by 11:59 PM on the third day after project work is completed. This must be independent work. Please see ELN Guidelines and Rubric included in this document for details about expectations. Grading • • Project Proposal: 40 pts o Submitted as a team ELN for project work: 40 pts o Submitted individually Overview For the past few semesters, 332L students have been participating in a research project involving synthesis of compounds to be tested for antibacterial properties. For your final project you also will be synthesizing multi-ring compounds with the potential to be potent anti-bacterial agents. You will be synthesizing two related compounds. The first compound, 3-[(4-chlorophenyl)-piperidin-1-yl-methyl]-4-hydroxy-chromen-2-one or compound 4l (see structure above), has been synthesized by Mukhopadhyay, et. al. and you are going to try to replicate the synthesis. The second synthesis will be much like the first, except you will vary one of the reactants in order to get a new compound. Introduction The surfacing of bacteria resistant to available antibiotics is causing disturbing public health issues. As such, design and synthesis of organic compounds effective in treatment of these resistant bacteria is of vital importance. Much effort is focused on synthesis of coumarin derivatives. This is due to the prevalence of naturally occurring coumarin derviatives with many medicinal uses as well as the ready availability of coumarin and its reactive tendencies. The type of reaction you will be performing is a multicomponent, one-pot, Mannich reaction. In general, a Mannich reaction involves the condensation of a nonenolizable aldehyde, a primary or secondary amine and an enolizable carbonyl compound: For your first synthesis, you will be using 4-chlorobenzaldehyde for your nonenolizable aldehyde, piperidine for your amine and 4-hydroxycoumarin which has an enol moiety. For your second synthesis, you will again use 4-hyroxycourmarin, but you will choose a different aldehyde and/or amine. Project Planning Your team will need to plan two syntheses: 1. For the first synthesis you must repeat the synthesis of compound 4l from the scientific paper included in this document. The procedure is described in the paper included in this document. You must monitor the reaction as it progresses and you must characterize your product using whatever methods are available in the lab. You will also submit your product for proton spectra using high field NMR. 2. The second synthesis must be a variation of the first. You must choose at least one different starting reagent. You must justify your choice for your variation based on background reading, provide preliminary data and good reasoning. As with the first synthesis, you must monitor the reaction as it progresses and you must characterize your product using whatever methods are available in the lab. You will also submit your product for proton spectra using high field NMR. NOTE: Do not scale up your reaction. Equipment Available for Use Anything normally available in the lab. If you need additional equipment, talk to your TA as soon as possible to see if it can be provided. Reagents Available for Use (Note that this list is NOT the same as in the journal article. USE THIS LIST) • 100% Ethanol and Dichloromethane • 4-hydroxycoumarin • Aldehydes 1. Benzaldehyde 2. p-tolualdehyde 3. p-bromobenzaldehyde 4. p-nitrobenzaldehyde 5. p-ethylbenzaldehyde 6. salicylaldehyde 7. p-hydroxybenzaldehyde 8. p-chlorobenzaldehyde • Amines 1. Morpholine 2. Pyrrolidine 3. Piperidine 4. Allylamine Project Proposal Guidelines Description Basically your proposal is a very detailed pre-lab writing. You need to write the reaction schemes for your two syntheses, a detailed procedure, a list of chemicals being used as well as relevant physical constants and safety hazards. You should have enough detail so that you are ready to start when you enter the lab to work on your project. Include all the sections listed below. Write in your ELN so you can access the document easily during lab. Submit as a PDF using the assignment link provided on Canvas Proposal Sections: 1. Title and Group Members 2. Purpose of Experiment a. Reaction Scheme for synthesis of (compound 4l) b. Reaction Scheme for modified synthesis of new compound 3. Experimental Procedure: a. Replication of synthesis Enough procedural detail must be given so that anyone in your class would be able to repeat what you plan to do. This should include details such as starting amounts of all reagents, solvent and catalyst, and what glassware you plan to use. You must also give details how you plan to monitor, work up and characterize your product. b. Proposed modified synthesis of new compound See Replication of synthesis, above. 4. Chemical Table List chemicals being used as well as formula, relevant physical constants. 5. Safety Analysis: Include all safety and hazard information specific to this project. Hazard information for each chemical being used should be included (from Safety Data Sheets (SDS)). 6. References List any references you use including the provided scientific paper. Use the same format used for references in this document. ELN Guidelines Description Your ELN for your project will be slightly different than for a typical experiment. Please make sure you read and follow the guidelines given below. All work should be done in your ELN. Submit using the link provided on Canvas Sections 1. Title and Group Members. 2. Raw Data and Observations a. This section should serve as your research notebook. Write down actual masses, volumes, etc. that you use. Write down any observations that will help you draw conclusions later. Also, write any changes in procedure from what was written in your proposal. This section must have a timestamp that matches your lab class time. You may have two “Raw Data and Observations” sections in your ELN: one for each class period. 3. Analysis Questions a. Write a mechanism for both your synthesis of compound 4l and synthesis of new compound. b. Give evidence that you monitored your reactions and determined when they were complete. c. Give evidence whether or not purification was necessary and whether or not your final products were pure (other than spectra). d. Give evidence that your products were what you expected based on your reaction scheme. Your key evidence should be your high field proton NMR spectra. You should have at least one other piece of supporting evidence. Your proton NMR spectra must be included in your ELN submission and needs to be interpreted. Draw a structure on the spectra and assign each peak to the corresponding hydrogen(s) in the structure. e. Calculate your percent yield. Show your work to get full credit. 4. Reflective Writing a. Write the same sections you would write for a normal ELN. b. If your one or both of your syntheses were successful, describe this completely in your Explain and Evaluate section. Be sure to tie all evidence together in your explanation. Describe what you have learned about the particular reaction you ran. Whether your reaction was successful or not, discuss the mechanism of the expected reaction and what intermediates formed, what played to role of nucleophile, electrophile and what is the rate determining step. c. If either or both of your syntheses were not successful, carefully examine why in the Explain and Evaluate section and discuss what you would do differently if you had the opportunity to repeat. If both syntheses were successful, discuss what you would do differently to improve yield or cut down on reaction time. d. For the extend section, you may not restate anything from the introduction in this document. Use the internet or look up some of the references given to provide different information. Rubric: 332L Project Proposal Category Excellent Group Members and Title Purpose of Experiment 2 pts Title and Partner(s) are given 10 pts Schemes are given for both syntheses and are correct. A rational based on chemical properties of starting material chosen for second synthesis is given. Procedure: Replication 8pts Complete: Reader could repeat synthesis with provided information. Procedure: Modified Synthesis 8 pts Complete: Reader could repeat synthesis with provided information. Chemical Information and Safety Table 10 pts Each chemical used (including solvents, etc.) is listed along with properties relevant to being able to complete the experiment as well as safety information. 2 pts Complete References (3%) Good/Acceptable Not Used 8 pts Minor changes are necessary for schemes to be complete and correct and/or rational is given, but has minor flaws. 6 pts Minor Omissions: Reader could repeat synthesis but would have to make some assumptions. 6 pts Minor Omissions: Reader could repeat procedure but would have to make some assumptions. 8 pts Minor Omissions Not Used Needs Improvement Unacceptable 1 pt One is missing 6 pts Major changes for reaction schemes are necessary to be complete and correct. Rationale is given, but has significant flaws. 0 pts Both are missing 0 pts Missing 5 pts Major Omissions: Procedure is not repeatable with the provided information. 0 pts Missing 5 pts Major Omissions: Procedure is not repeatable with the provided information. 0 pts Missing 6 pts Major Omissions 0 pts Missing 1 pt Attempt made but has omissions 0 pts Missing Rubric: 332L Project ELN Category Excellent Good/ Acceptable Needs Improvement Missing Group Members and Title TA Points 2 pts Title and Partner(s) are given Not used 1 pt One is missing 8 pts Preparation for project: Student came to lab ready to work and was not overly dependent on TA. Other partner was not doing most of the work. Lab courtesy and Safety: Cleaning up messes, Clean and return shared equipment, Clean balances Close chemical containers, Following instruction especially with regards to safety, Etc. 8 pts Enough detail should be included here that the reader knows what the student did when combined with procedure provided in proposal. Any data should be recorded here such as Rf values, melting points, or anything else relevant. There should be a data section for both project lab periods with appropriate time stamps. 12 pts All analysis questions are answered. Answers are thoughtful, thorough, and sensible. Spectra have product structures drawn and peaks labeled with corresponding hydrogens. Spectral labeling must be easy to read (not too sloppy). Explain and Evaluate 8 pts Successful syntheses are described completely and evidence given based on data. Student described what was learned about Mannich, multicomponent reactions. The mechanisms for the expected reactions are explained in terms of intermediates formed and what role these intermediates play as well as what step is rate determining. Unsuccessful syntheses are examined. If no product was obtained, reasons for lack of success are given as well as a discussion of what would be done differently if student had the opportunity to repeat the reaction. If completely successful, students discuss what could be changed to increase yield and/or reduce reaction time. Extend to Content beyond the Lab: 2 pts Students discuss how what they learned in lab is related to something outside of lab (lecture, reading, news, etc. are possible sources). Material given in the introduction may not be restated. References used should be given. 6 pts TA choice 4 pts TA choice 0 pts Both are missing 0 pts TA choice 6 pts Minor mistakes and/or omissions 4 pts Major mistakes and/or omissions 0 pts Missing 10 pts Minor mistakes and/or omissions 6 pts Major mistakes and/or omissions 0 pts Missing 6 pts Minor mistakes and/or omissions 4 pts Weak or vague explanations are given for success of syntheses and sources of error. 0 pts Missing Not used 1 pt Some attempt made but needs a great deal of work. 0 pts Missing Data and Observations Analysis Questions Reflective Writing Synthetic Communications1, 42: 3077–3088, 2012 Copyright # Taylor & Francis Group, LLC ISSN: 0039-7911 print=1532-2432 online DOI: 10.1080/00397911.2011.575524 CATALYST-FREE, ONE-POT, EXPEDITIOUS SYNTHESIS OF AMINOALKYLNAPHTHOLS AT ROOM TEMPERATURE Chhanda Mukhopadhyay,1 Sunil Rana,1 and Ray J. Butcher2 1 Department of Chemistry, University of Calcutta, Kolkata, India Department of Chemistry, Howard University, Washington, DC, USA 2 GRAPHICAL ABSTRACT Abstract Aminoalkylnaphthols possess several biological and catalytic activities. A methodology has been developed for the multicomponent one-pot synthesis of aminoalkylnaphthols in dichloromethane under catalyst-free conditions at room temperature. The present approach possesses several advantages such as excellent yields, quick reaction time, mild reaction conditions, and very easy purification processes. Thirteen new compounds in addition to six known compounds have been synthesized by this methodology. Keywords Aminoalkylnaphthols; catalyst-free; dichloromethane; one-pot synthesis; room temperature INTRODUCTION Recently, the synthesis of aminoalkylnaphthols has received special attention from the scientific community because of their significant biological[1] and catalytic[2] properties. These compounds, possessing multiple chelating centers, are potent inhibitors of metalloenzymes containing Fe, Cu, Zn, and Co ions as cofactors.[3–6] In addition, these compounds have the ability to act as scavengers of heavy metals (Hg, Cd, Pb, As, Sb).[7,8] They also show potent oxytocic activity.[9] A number of Received February 12, 2011. Address correspondence to Chhanda Mukhopadhyay, Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata 700009, India. E-mail: cmukhop@yahoo.co.in 3077 3078 C. MUKHOPADHYAY, S. RANA, AND R. J. BUTCHER Scheme 1. Synthesis of aminoalkylnaphthols. aminomethylphenols have been reported in the literature[10] as chelating agents in metal-catalyzed asymmetric induction in many reactions. Chiral Mannich bases are frequently used as ligands in a variety of metal-mediated enantioselective carbon–carbon bond formation reactions.[11–17] Such importance of the aminoalkylnaphthols has caused us to pursue a simple and easy method for their synthesis. Since 1900, aminoalkylnaphthols have been synthesized by the three-component condensation of secondary amines, aromatic aldehydes, and naphthols (Scheme 1). In 1900, Mario Betti synthesized aminoalkylnaphthols (so-called Betti bases) for the first time.[18] After a long gap, Katritzky et al. in 1999 reported the synthesis of aminoalkylphenols by benzotriazole methodology using phase-transfer catalysis.[19a] Saidi et al. synthesized the compounds with lithium perchlorate.[19b] Recently, Jha et al have developed the methodology of p-toluene sulfonic acid–catalyzed microwave irradiation.[20] Kumar et al. explored the synthesis by nonionic surfactant-catalysed methodology.[21] In addition to these, a few other methodologies are also available in the literature.[22] RESULTS AND DISCUSSION Most of the earlier procedures for aminoalkylnaphthol synthesis[18–22] suffer from harsh reaction conditions, catalyst nonrecyclability, or a need for column chromatography for further purification. Our main aim was to synthesize aminoalkylnaphthols while avoiding expensive catalysts, using mild reaction conditions, and avoiding time-consuming column chromatography. After a thorough search for proper catalysts and reaction medium for the standard reaction of pyrrolidine, 2-naphthol, and 4-bromobenzaldehyde, we found that dichloromethane at room temperature (25–30
C) proved to be the best reaction medium (Table 1, entry 3), and the product conversion was so high that no additional catalyst was required. This is the most important aspect of our methodology. The workup procedure is also very simple. After the completion of the reaction, checked by thin-layer chromatography (TLC), dichloromethane was pumped out by rotary evaporation. The product was purified by direct crystallization from ethylacetate and petroleum ether (60–80
C), thus avoiding time-consuming column chromatography. This is the second important aspect of our methodology. Once the optimum condition was reached for the model reaction, various aromatic aldehydes and secondary amines were tried for this reaction. Aromatic aldehydes with slightly electron-withdrawing groups yielded the best results, while electron-donating groups slightly decreased the yield. Aromatic aldehydes with SYNTHESIS OF AMINOALKYLNAPHTHOLS 3079 Table 1. Choice of reaction medium for the synthesis of the aminoalkylnaphthols at room temperature taking the standard reaction of 2-naphthol, 4-bromobenzaldehyde, and pyrrolidine Entry 1 2 3 4 5 6 7 8 9 10 Solvents (5 ml) Time (h) Yield (%) (isolated) Methanol Ethanol Dichloromethane Dichloroethane Acetonitrile DMF Water DMSO 1,4-Dioxane THF 2 2 2 2 2 2 2 2 2 2 55 60 92 67 45 55 58 40 35 53 Figure 1. X-ray structural analysis of a single crystal of 2-[(4-chlorophenyl)-piperidine-1-yl-methyl]naphthalen-1-ol (4q) (Table 2, entry 17) showing the crystallographic numbering (CCDC 800110). (Figure is provided in color online.) 3080 C. MUKHOPADHYAY, S. RANA, AND R. J. BUTCHER ortho-substitution also decrease the yield slightly. This may be due to the steric effect. Of the secondary amines, piperidine, pyrrolidine, morpholine, N-methyl piperazine, and dimethylamine were used. In all cases, the yields of the desired products were moderate to excellent. We further extended the scope of the reaction by using 4-hydroxycoumarin and 1-naphthol as nucleophiles in place of 2-naphthol, with good yields. With 1-naphthol, the substitution occurs specifically at the 2-position (and not at 4) because of the stability of the product by intramolecular six-membered hydrogen-bond formation (further evidence in Fig. 1). All the products are well characterized by melting points, infrared (IR), 1H NMR, 13C NMR, and CHN analysis. In 1H NMR, the -NCH2 protons and in 13C NMR, the -NCH2 carbons appear as broad peaks. This is due to electrical quadruple moment of nitrogen. The crystal structure of 1-[(4-bromophenyl)-pyrrolidin1-yl-methyl]-naphthalen-2-ol (Table 2, entry 7) is given in Fig. 2. which shows a strong hydrogen bonding between OH of 2-naphthol and N of the pyrrolidine moiety. The crystal structure of 2-[(4-chlorophenyl)-piperidine-1-yl-ethyl]-naphthalen1-ol (Table 2, entry 17) is given in Fig. 1, which conclusively proves that 1-naphthol reacts through its 2 position. Probably, the mechanism goes through the iminium ion formation followed by the attack of 2-naphthol at the 1-position for the specific reaction shown in Scheme 2. Figure 2. X-ray structural analysis of a single crystal of 1-[(4-bromo-phenyl)-pyrrolidin-1-yl-methyl]naphthalen-2-ol (4g) (Table 2, entry 7) showing the crystallographic numbering (CCDC 791677). (Figure is provided in color online.) SYNTHESIS OF AMINOALKYLNAPHTHOLS 3081 Table 2. Synthesis of the aminoalkylnaphthols at room temperature (25–30
C) Starting materials Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Amines Aldehydes Naphthols Piperidine Piperidine Dimethylamine Piperidine Piperidine Pyrrolidine Pyrrolidine Piperidine Morpholine Morpholine Piperidine Piperidine Piperidine Dimethylamine N-methylpiperazine Piperidine Piperidine Morpholine N-methylpiperazine 4-Chlorobenzaldehyde 4-Bromobenzaldehyde 4-Chlorobenzaldehyde 3,4-dimethoxybenzaldehyde 2-Chlorobenzaldehyde 4-Chlorobenzaldehyde 4-Bromobenzaldehyde 2-Methoxybenzaldehyde 4-Chlorobenzaldehyde 3,4-Dimethoxybenzaldehyde Benzene-1,4-Dialdehyde 4-Chlorobenzaldehyde 3-Nitrobenzaldehyde 4-Chlorobenzaldehyde Benzaldehyde Pyridine-4-aldehyde 4-Chlorobenzaldehyde Benzaldehyde 4-Bromobenzaldehyde 2-Naphthol 2-Naphthol 2-Naphthol 2-Naphthol 2-Naphthol 2-Naphthol 2-Naphthol 2-Naphthol 2-Naphthol 2-Naphthol 2-Naphthol 4-Hydroxycoumarin 4-Hydroxycoumarin 4-Hydroxycoumarin 2-Naphthol 2-Naphthol 1-Naphthol 1-Naphthol 1-Naphthol Products[ref.] (4a–4s) 4a[20] 4b 4c[21] 4d 4e 4f 4g 4h[21] 4i[20] 4j 4k 4l 4m 4n 4o[20] 4p[20] 4q 4r 4s Time (h) Yield (%), isolated 2 2 2 2 3 2 2 2 2 2 2 2 2 2 2 2 2 2 2 95 92 96 84 75 90 92 74 90 83 76 85 78 81 76 78 74 83 82 Scheme 2. Probable mechanism for the formation of aminoalkylnaphthols. 3082 C. MUKHOPADHYAY, S. RANA, AND R. J. BUTCHER CONCLUSION We have developed a very simple, catalyst-free protocol for the synthesis of aminoalkylnaphthols by a one-pot, three-component methodology. The advantages of the methodology include (a) mild catalyst-free reaction condition, (b) shorter reaction time, (c) very easy purification procedure that avoids column chromatography, and (d) applicability to large-scale preparation. EXPERIMENTAL Ethyl acetate, petroleum ether (boiling range 60–80
C), dichloromethane were distilled before use. All the chemicals were purchased from Aldrich Chemical Company and Spectrochem, Pvt. Ltd. (Mumbai, India). Silica gel G with binder from Spectrochem, Pvt. Ltd., Mumbai, India, was used for TLC. 1H and 13C NMR spectra were obtained on a Bruker 300-MHz instrument at 300 and 75 MHz respectively. CDCl3 and dimethylsulfoxied (DMSO-d6) were purchased from Aldrich Chemical Company. Melting points were determined on an electrical melting-point apparatus with an open capillary. IR spectra were recorded on a Perkin-Elmer spectrophotometer RX=FT-IR system. The C-H-N-analyses were carried out on a 2400 series II CHNS analyzer, (Perkin-Elmer, USA). General Experimental Procedure for Aminoalkylnaphthol Formation Aromatic aldehydes (1 mmol), secondary amine (1.1 mmol), (naphthol= 4-OH-coumarin) (1 mmol), and dichloromethane (5 ml) were added in a 25-ml, round-bottomed flask. The resulting mixture was stirred vigorously with a magnetic bar on a magnetic stirrer for 2h at room temperature (25–30
C). The progress of the reaction was monitored by TLC. After the completion of the reaction as checked by TLC, dichloromethane was pumped out by rotary evaporation. The crude product was purified directly by crystallization from ethyl acetate and petroleum ether (60–80
C). Spectral and Analytical Data of the Compounds (4a–4q) In 13C spectra, most of the compounds show one extra peak in the completely saturated carbon region. The nonequivalence of the similar type of carbons may occur because of the restricted rotation of the C-N bond. 1-[(4-Chlorophenyl)-piperidin-1-yl-methyl]naphthalen-2-ol (4a) (Table 2, Entry 1). White solid. Mp 164–166
C (EtOAc), lit.[20] Mp 165–166
C; IR (KBr): 3050, 2939, 2854, 1590, 1475, 1408, 1352, 1262, 1233, 1152, 1091, 942 and 823 cm1; 1 H NMR (300 MHz; CDCl3): dH 13.80 (s, 1H, OH), 7.76 (d, J ¼ 8.4 Hz, 1H, ArH), 7.69–7.58 (m, 2H, ArH), 7.48–7.45 (m, 2H, ArH), 7.38–7.32 (m, 1H, ArH), 7.23–7.17 (m, 3H, ArH), 7.14 (d, J ¼ 9.0 Hz, 1H, ArH), 5.03 (s, 1H, CH), 3.28 (br, 1H, -NCH), 2.62 (br, 1H, -NCH), 2.06–1.50 (m, 8H, -NCH, -CH2); 13 C NMR (CDCl3, 75 MHz): dc 155.4, 138.2, 133.6, 132.1, 130.3, 129.5, 128.9, 128.6, 126.4, 122.4, 120.7, 119.9, 115.7, 71.2, 54.6, 51.9, 26.0 and 24.0. SYNTHESIS OF AMINOALKYLNAPHTHOLS 3083 1-[(4-Bromophenyl)-piperidin-1-yl-methyl]naphthalen-2-ol (4b) (Table 2, Entry 2). White solid. Found: C, 66.79; H, 5.52; N, 3.45%. C22H22BrNO requires C, 66.67; H, 5.60; N, 3.53%. Mp 158–160
C (EtOAc); IR (KBr): 3056, 2937, 2852, 2592, 1589, 1515, 1475, 1449, 1408, 1352, 1261, 1233, 1152, 1079, 1009, 943, 822 and 740 cm1; 1H NMR (300 MHz; CDCl3): dH 13.79 (s, 1H, OH), 7.90 (d, J ¼ 8.7 Hz, 1H, ArH), 7.69–7.61 (m, 2H, ArH), 7.45–7.30 (m, 5H, ArH), 7.23–1.12 (m, 2H, ArH), 4.99 (s, 1H, CH), 3.25 (br, 1H, -NCH), 2.61 ((br, 1H, -NCH), 2.02–1.20 (m, 8H, -NCH, -CH2); 13C NMR (CDCl3, 75 MHz): dc 155.3, 138.7, 132.1, 131.8, 130.6, 129.5, 128.9, 128.6, 126.4, 122.4, 121.7, 120.7, 119.9, 115.6, 71.2, 54.4, 51.9, 25.9 and 23.9. 1-[(4-Chlorophenyl)-dimethylamino-methyl]naphthalen-2-ol (4c) (Table 2, Entry 3). White solid. Mp 128–130
C (EtOAc), lit.[21] Mp 129–131
C; IR (KBr): 3129, 3061, 2976, 2848, 1629, 1462, 1240 and 758 cm1; 1H NMR (CDCl3, 300 MHZ): dH 10.01 (s, 1H, OH), 7.65–7.83 (m, 3H, ArH), 7.50–7.53 (m, 3H, ArH), 7.08–7.45 (m, 4H, ArH), 4.95 (s, 1H, CH), 2.34 (s, 6H, NCH3); 13C NMR (CDCl3, 75 MHz): dC 155.2, 142.4, 131.2, 129.7, 128.9, 128.8, 128.7, 128.5, 127.7, 126.4, 122.4, 121.1, 119.8, 116.3, 72.8 and 41.5. 1-[(3,4-Dimethoxyphenyl)-piperidin-1-yl-methyl]naphthalen-2-ol (4d) (Table 2, Entry 4). White solid. Found: C, 76.59; H, 7.13; N, 3.62%. C24H27NO3 requires C, 76.36; H: 7.21; N; 3.71%. Mp 120–122
C (EtOAc); IR (KBr): 3056, 2934, 2841, 1595, 1513, 1455, 1418, 1355, 1264, 1145, 1027, 942 and 816 cm1; 1H NMR (300 MHz; CDCl3): dH 14.0 (s, 1H, OH), 7.83 (d, J ¼ 8.4 Hz, 1H, ArH), 7.69–7.61 (m, 2H, ArH), 7.35 (t, J ¼ 8.4 Hz, 1H, ArH), 7.24–7.11 (m, 3H, ArH), 7.06 (d, J ¼ 8.1 Hz, 1H, ArH), 6.73 (d, J ¼ 8.1 Hz, 1H, ArH), 5.01 (s, 1H, CH), 3.79 (s, 3H, OMe), 3.77 (s, 3H, OMe), 3.30 (br, 1H, NCH), 2.65 (br, 1H, NCH), 2.20–1.50 (m, 8H, NCH, -CH2); 13C NMR (CDCl3, 75 MHz): dc 155.4, 148.6, 132.3, 132.1, 129.2, 128.8, 128.6, 126.2, 122.2, 121.7, 121.0, 119.8, 116.2, 110.8, 71.7, 54.6, 51.7, 26.0, 24.1. 1-[(2-Chlorophenyl)-piperidin-1-yl-methyl]naphthalen-2-ol (4e) (Table 2, Entry 5). White solid. Found: C, 75.24; H, 6.21; N, 3.88%. C22H22ClNO requires C, 75.09; H, 6.30; N, 3.98%. Mp 136–138
C (EtOAc); IR (KBr): 3060, 2933, 2821, 2607, 1590, 1516, 1447, 1352, 1265, 1239, 1151, 1093, 1033, 978, 821 and 745 cm1; 1 H NMR (300 MHz; CDCl3): dH 14.28 (s, 1H, OH), 7.84 (d, 3J ¼ 8.4 Hz, 1H, ArH), 7.72–7.64 (m, 3H, ArH), 7.42–7.37 (m, 2H, ArH), 7.26–7.09 (m, 4H, ArH), 5.88 (s, 1H, CH), 3.35 (d, J ¼ 11.4 Hz, 1H, NCH), 2.66 (d, J ¼ 10.8 Hz, 1H, NCH), 2.41–2.27 (m, 2H, NCH), 1.78–1.25 (m, 6H, -CH2), 13C NMR (CDCl3, 75 MHz): dc 156.5, 136.9, 134.2, 132.8, 130.9, 129.5, 129.3, 129.1, 128.7, 128.5, 127.9, 126.6, 122.4, 121.2, 120.0, 115.8, 66.2, 54.7, 49.3, 26.3, 25.9 and 24.0. 1-[(4-Chlorophenyl)-pyrrolidin-1-yl-methyl]naphthalen-2-ol (4f) (Table 2, Entry 6). White solid. Found: C: 74.94; H, 5.86; N, 4.06%. C21H20ClNO requires C, 74.66; H, 5.97; N, 4.15%. Mp 118–120
C (EtOAc); IR (KBr): 3059, 2963, 2829, 1592, 1451, 1400, 1347, 1228, 1100, 949, 889, 820 and 741 cm1; 1H NMR (300 MHz; CDCl3): dH 13.69 (s, 1H, OH), 7.92 (d, 3J ¼ 9.0 Hz, 1H, ArH), 7.74–7.63 (m, 2H, ArH), 7.53 (d, 3J ¼ 8.4 Hz, 2H, ArH), 7.37 (dt, 3J ¼ 8.4 Hz and 4 J ¼ 1.5 Hz, 1H, ArH), 7.28–7.20 (m, 3H, ArH), 7.14 (d, 3J ¼ 8.7 Hz, 1H, ArH), 3084 C. MUKHOPADHYAY, S. RANA, AND R. J. BUTCHER 5.07 (s, 1H, CH), 3.50–3.10 (br, 1H, NCH), 2.80–2.10 (m, 3H, NCH), 1.91 (br, 4H, CH2); 13C NMR (CDCl3, 75 MHz): dc 155.4, 139.7, 133.5, 131.6, 129.8, 129.6, 128.9, 128.8, 128.6, 126.4, 122.4, 120.8, 119.9, 116.2, 69.9, 53.3 and 23.3. 1-[(4-Bromophenyl)-pyrrolidin-1-yl-methyl]naphthalen-2-ol (4g) (Table 2, Entry 7). White solid. Found: C, 66.19; H, 5.16; N, 3.76%. C21H20BrNO requires C, 65.98; H, 5.27, N, 3.66%. Mp 140–142
C (EtOAc); IR (KBr): 3068, 2967, 2818, 2568, 1589, 1451, 1407, 1236, 1107, 1010, 951 and 820 cm1; 1H NMR (300 MHz; CDCl3): dH 13.68 (s, 1H, OH), 7.79 (d, 3J ¼ 8.7 Hz, 1H, ArH), 7.70–7.62 (m, 2H, ArH), 7.44 (d, 3J ¼ 8.4 Hz, 2H, ArH), 7.36–7.31 (m, 3H, ArH), 7.20 (t, 3J ¼ 7.5 Hz, 1H, ArH), 7.15 (d, 3J ¼ 8.7 Hz, 1H, ArH), 5.03 (s, 1H, CH), 3.17 (br, 1H, -NCH), 2.70–2.10 (m, 3H, -NCH, -NCH2), 1.77 (s, 4H, -CH2); 13C NMR (CDCl3, 75 MHz): dc 155.4, 140.2, 132.1, 131.7, 130.0, 129.6, 128.8,128.5, 126.4, 122.4, 121.6, 120.7, 119.8, 116.1, 69.9, 53.4 and 23.3. 1-[(2-Methoxyphenyl)-Piperidin-1-yl-methyl]naphthalen-2-ol (4h) (Table 2, Entry 8). White solid. Mp 160–162
C, lit.[21] Mp 160–161
C; IR (KBr): 3135, 3050, 2959, 2849, 1659, 1442, 1242, 742 cm1. 1H NMR (CDCl3, 300 MHz): dH 13.4 (s, 1H, OH), 7.82 (d, J ¼ 8.55 Hz, 1H, ArH), 7.57–7.67 (m, 3H, ArH), 7.28–7.34 (m, 1H, ArH), 7.12–7.22 (m, 3H, ArH), 6.77–6.89 (m, 2H, ArH), 5.89 (s, 1H, CH), 3.99 (s, 3H -OCH3), 3.23–3.30 (m, 1H, -NCH), 2.64–2.71 (m, 1H, -NCH), 2.29–2.40 (m, 2H, -NCH2), 1.71–1.92 (m, 6H, -CH2), 13C NMR (CDCl3, 75 MHz) dc: 23.19, 23.57, 50.13, 54.61, 55.53, 60.74, 110.47, 117.19, 119.95, 121.46, 121,54, 122.20, 126.19, 128.36, 128.52, 128.80, 129.07, 129.29, 129.67, 132.36, 156.19, 156.40. 1-[(4-Chlorophenyl)-morpholin-4-yl-methyl]naphthalen-2-ol (4i) (Table 2, Entry 9). White solid. Mp 130–132
C, lit.[20] Mp 130–131
C; IR (KBr): 3437, 3061, 1621, 1596, 1451, 1383, 1237 and 1118 cm1; 1H NMR (CDCl3, 300 MHz): dH 13.17 (s, 1H, OH), 7.78–7.70 (m, 3H, ArH), 7.57–7.52 (m, 2H, ArH), 7.45–7.40 (m, 1H, ArH), 7.32–7.18 (m, 4H, ArH), 5.14 (s, 1H, CH), 3.72–3.51 (s, 4H, O-CH2), 3.19–3.14 (m, 1H, NCH), 2.55-2.33 (m, 3H, NCH2); 13C NMR (CDCl3, 75 MHz): dc 154.9, 137.4, 134.5, 132.4, 131.1, 130.5, 129.9, 129.5, 129.2, 127.2, 123.3, 121.2, 120.3, 115.0, 71.6, 67.3, 67.1, 54.3 and 51.9. 1-[(3,4-Dimethoxyphenyl)-morpholin-4-yl-Methyl]naphthalen-2-ol (4j) (Table 2, Entry 10). White solid. Found: C, 72.99; H, 6.54; N, 3.66%. C23H25NO4 requires C, 72.80; H, 6.64; N, 3.69%. Mp 68–70
C (EtOAc); IR (KBr): 3058, 2957, 2841, 1595, 1514, 1456, 1413, 1354, 1263, 1143, 1119, 1023, 941, 870, 817 and 749 cm1; 1H NMR (300 MHz; CDCl3): dH 13.16 (s, 1H, OH), 7.84 (d, 3J ¼ 8.7 Hz, 1H, ArH), 7.74–7.64 (m, 2H, ArH), 7.37 (t, 3J ¼ 7.2 Hz, 1H, ArH), 7.24–7.07 (m, 4H, ArH), 6.73 (d, 3J ¼ 8.4 Hz, 1H, ArH), 5.05 (s, 1H, CH), 3.79 (s, 4H, O-CH2), 3.76 (s, 6H, OCH3), 3.05 (br, 1H, NCH), 2.43 (brs, 3H, NCH2); 13C NMR (CDCl3, 75 MHz): dc 154.6, 149.3, 148.8, 132.2, 131.0, 129.3, 128.8, 126.4, 122.5, 121.8, 120.9, 119.6, 115.2, 111.5, 110.9, 71.6, 66.8, 55.7, 55.6 and 51.1. 1,4-Bis[1-f(Piperidin-1-yl)methylg-2-hydroxynaphthyl]benzene (4k) (Table 2, Entry 11). White solid. Found: C, 82.16; H, 7.13; N, 5.10%. C38H40N2O2 requires C, 81.98; H, 7.24; N, 5.03%. Mp 190–192
C (EtOAc); IR SYNTHESIS OF AMINOALKYLNAPHTHOLS 3085 (KBr): 3055, 2930, 2852, 1617, 1514, 1449, 1412, 1357, 1268, 1234, 1152, 1098, 945, 814 and 743 cm1; 1H NMR (300 MHz; CDCl3): dH 13.76 (s, 2H, OH), 7.52 (t, 3 J ¼ 10.2 Hz, 2H, ArH), 7.68–7.59 (m, 4H, ArH), 7.44 (s, 4H, ArH), 7.36–7.24 (m, 2H, ArH), 7.17 (d, 3J ¼ 7.8 Hz, 2H, ArH), 7.11 (d,3J ¼ 9.0 Hz, 2H, ArH), 4.99 (s, 2H, CH), 3.20 (br, 2H, NCH), 2.50–1.30 (m, 18H, NCH, -CH2); 13C NMR (CDCl3, 75 MHz): dc 155.5, 139.2, 132.4, 129.3, 128.8, 128.5, 126.3, 121.1, 119.9, 116.1, 116.1, 71.4, 52.3, 26.0 and 24.1. 3-[(4-Chlorophenyl)-piperidin-1-yl-methyl]-4-hydroxy-Chromen-2-one (4l) (Table 2, Entry 12). White solid. Found: C, 68.41; H, 5.36; N, 3.67%. C21H20ClNO3 requires C, 68.20; H, 5.45; N%. Mp 176–178
C (EtOAc); IR (KBr): 3069, 2950, 2861, 1650, 1605, 1539, 1460, 1414, 1367, 1331, 1275, 1232, 1066, 951 and 758 cm1; 1H NMR (300 MHz; CDCl3): dH 11.14 (s, 1H, OH), 7.84 (d, 3J ¼ 7.5 Hz, 1H, ArH), 7.62 (d, 3J ¼ 8.4 Hz, 2H, ArH), 7.45–7.37 (m, 3H, ArH), 7.22–7.05 (m, 2H, ArH), 5.13 (s, 1H, CH), 3.76 (d, J ¼ 11.7 Hz, 1H, NCH), 2.93 (d, J ¼ 11.4 Hz, 1H, NCH), 2.78–2.69 (m, 1H, NCH), 2.42–2.33 (m, 1H, NCH), 1.90–1.40 (m, 6H, -CH2); 13C NMR (CDCl3, 75 MHz): dc 173.6, 164.0, 154.0, 135.0, 134.7, 131.3, 130.3, 129.2, 124.1, 123.0, 120.6, 116.4, 94.6, 70.3, 53.6, 50.4, 24.3 and 22.4. 4-Hydroxy-3-[(3-nitrophenyl)-piperidin-1-yl-methyl]chromen-2-one (4m) (Table 2, Entry 13). White solid. Found: C, 66.56; H, 5.36; N, 7.27%. C21H20N2O5 requires C, 66.31; H, 5.30; N, 7.36%. Mp 184–186
C (EtOAc); IR (KBr): 3076, 2948, 2863, 1642, 1604, 1535, 1461, 1402, 1348, 1284, 1237, 1072, 953 and 762 cm1; 1H NMR (300 MHz; CDCl3): dH 11.15 (s, 1H, OH), 8.42 (s, 1H, ArH), 8.16 (d, 3J ¼ 8.1 Hz, 1H, ArH), 8.01–7.95 (m, 2H, ArH), 7.53–7.43 (m, 2H, ArH), 7.24–7.18 (m, 2H, ArH), 5.24 (s, 1H, CH), 3.79 (d, J ¼ 10.5 Hz, 1H, NCH), 2.91 (d, J ¼ 9.9 Hz, 1H, NCH), 2.80–2.72 (m, 1H, NCH), 2.462.38 (m, 1H, NCH), 2.00–1.41 (m, 6H, -CH2); 13C NMR (CDCl3, 75 MHz): dc 173.1, 163.8, 154.0, 148.5, 138.6, 134.9, 131.7, 130.3, 124.2, 124.0, 123.3, 116.6, 95.0, 70.2, 54.2, 24.5 and 22.6. 3-[(4-Chlorophenyl)-dimethylamino-methyl]-4-hydroxy-chromen-2-one (4n) (Table 2, Entry 14). White solid. Found: C, 65.79; H, 4.82; N, 4.18%. C18H16ClNO3 requires C, 65.56, H, 4.89; N, 4.25%. Mp 168–170
C (EtOAc); IR (KBr): 3074, 2856, 1647, 1603, 1543, 1467, 1413, 1358, 1319, 1287, 1219, 1139, 1046, 949, 826 and 756 cm1; 1H NMR (300 MHz; DMSO-d6): dH 10.55 (s, 1H, OH), 7.84 (d, 3J ¼ 7.8 Hz, 1H, ArH), 7.66 (d, 3J ¼ 8.4 Hz, 2H, ArH), 7.45–7.35 (m, 3H, ArH), 7.20–7.08 (m, 2H, ArH), 5.26 (s, 1H, CH), 2.67 (s, 6H, NMe2); 13C NMR (DMSO-d6, 75 MHz): dc 173.9, 163.0, 153.7, 152.6, 137.3, 133.0, 130.0, 128.6, 124.4, 124.2, 123.0, 120.0, 115.9, 93.1, 68.9 and 42.0. 1-[(4-Methyl-Piperazin-1-yl)-phenyl-methyl]naphthalen-2-ol (4o) (Table 2, Entry 15). White solid. Mp 140–142
C (EtOAc), lit.[20] Mp 141–142
C; IR (KBr): 3048, 2944, 2840, 2791, 2686, 1593, 1513, 1454, 1415, 1356, 1277, 1238, 1144, 1084 and 1002 cm1; 1H NMR (300 MHz; CDCl3): dH 13.42 (s, 1H, OH), 7.97 (d,3J ¼ 8.7 Hz, 1H, ArH), 7.96–7.77 (m, 2H, ArH), 7.69 (d,3J ¼ 7.2 Hz, 2H, ArH), 7.50 (t, 3J ¼ 7.2 Hz, 1H, ArH), 7.42–7.32 (m, 4H, ArH), 7.27 (d,3J ¼ 8.7 Hz, 1H, ArH), 5.25 (s, 1H, CH), 3.34–2.60 (m, 8H, N-CH2); 2.43 (s, 3H, N-CH3), 3086 C. MUKHOPADHYAY, S. RANA, AND R. J. BUTCHER 13 C NMR (CDCl3, 75 MHz): dc 155.3, 139.5, 132.6, 130.1, 129.3, 129.1, 128.8, 128.6, 128.1, 127.0, 123.0, 121.5, 120.3, 116.0, 71.9, 55.6, 55.3, 53.7, 51.2 and 46.2. 1-(Piperidin-1-yl-pyridin-4-yl-methyl)naphthalen-2-ol (4p) (Table 2, Entry 16). Off-white solid, Mp 184–186
C (EtOAc), lit.[20] Mp 185–186
C; IR (KBr): 3047, 2943, 2825, 2670, 1593, 1513, 1449, 1416, 1356, 1317, 1270, 1230, 1152, 1094, 1032, 945, 869, 815 and 739 cm1; 1H NMR (300 MHz; CDCl3): dH 13.51 (s, 1H, OH), 8.53 (d,3J ¼ 4.5 Hz, 2H, ArH), 7.83 (d,3J ¼ 8.4 Hz, 1H, ArH), 7.75–7.69 (m, 2H, ArH), 7.54 (d,3J ¼ 4.5 Hz, 2H, ArH), 7.43 (dt, 3J ¼ 7.7 Hz and 4J ¼ 1.3 Hz, 1H, ArH), 7.27 (dt, 3J ¼ 6.2 Hz and 4J ¼ 1.6 Hz, 1H, ArH), 7.19 (d,3J ¼ 9.0 Hz, 1H, ArH), 5.09 (s, 1H, CH), 3.28 (brs, 1H, NCH), 2.61–1.69 (m, 3H, NCH), 1.69–1.25 (m, 6H, NCH2CH2 and NCH2CH2CH2),13C NMR (CDCl3, 75 MHz): dc 155.4, 150.1, 148.5, 132.0, 129.9, 129.0, 128.6, 126.6, 123.6, 122.5, 120.4, 119.8, 114.6, 70.7, 53.6, 25.8 and 23.8. 2-[(4-Chlorophenyl)-piperidin-1-yl-methyl]naphthalen-1-ol (4q) (Table 2, Entry 17). White solid. Found: C, 75.35; H, 6.22; N, 3.91%. C22H22ClNO requires C, 75.09, H; 6.30; N, 3.98%. Mp 152–154
C (EtOAc); IR (KBr): 3050, 2930, 2826, 2659, 1628, 1576, 1450, 1380, 1311, 1216, 1150, 1091, 1015, 934, 871, 836, 800 and 753 cm1; 1H NMR (300 MHz; CDCl3): dH 13.27 (s, 1H, OH), 8.33 (d,3J ¼ 7.5 Hz, 1H, ArH), 7.71 (d,3J ¼ 7.5 Hz, 1H, ArH), 7.56–7.05 (m, 7H, ArH), 6.95 (d,3J ¼ 8.4 Hz, 1H, ArH), 4.51 (s, 1H, CH), 2.43 (brs, 3H, NCH), 1.50 (brs, 5H, NCH2-CH2), 1.26 (brs, 2H, NCH2-CH2-CH2). 2-(Morpholin-4-yl-phenyl-methyl)naphthalen-1-ol (4r) (Table 2, Entry 18). Yellow solid. Found: C, 78.75; H, 6.52; N, 4.48%. C21H21NO2 requires C, 78.97; H, 6.63; N, 4.39%. Mp 116–118
C (EtOAc); IR (KBr): 3421, 3052, 2938, 2798, 1631, 1577, 1456, 1387, 1297, 1145, 1007, 854, 804 and 761 cm1; 1H NMR (300 MHz; CDCl3): dH 12.60 (s, 1H, OH), 8.35 (d, 3J ¼ 7.5 Hz, 1H, ArH), 7.73 (dd,3J ¼ 8.1 Hz and 4J ¼ 1.8 Hz, 1H, ArH), 7.53–7.44 (m, 4H, ArH), 7.38–7.24 (m, 4H, ArH), 7.05 (d, 3J ¼ 8.4 Hz, 1H, ArH), 4.52 (s, 1H, CH), 3.88–3.80 (m, 4H, O-CH2), 2.85–2.45 (m, 4H, NCH2), 13C NMR (CDCl3, 75 MHz): dc 151.5, 139.4, 133.7, 128.9, 128.6, 128.1, 127.2, 127.0, 126.2, 125.3, 124.9, 122.3, 119.0, 117.5, 77.0, 66.9 and 52.4. 2-[(4-Bromo-phenyl)-(4-methyl-piperazin-1-yl)-methyl]-naphthalen-1-ol (4s) (Table 2, Entry 19). Yellow solid. Found: C, 64.47; H, 5.55; N, 6.88%. C22H23BrN2O requires C, 64.24; H, 5.64, N: 6.81%. Mp 74–76
C (EtOAc); IR (KBr): 3421, 3052, 2938, 2798, 1631, 1577, 1456, 1387, 1297, 1145, 1085, 1007, 854, 804 and 761 cm1; 1H NMR (300 MHz; CDCl3): dH 12.38 (s, 1H, OH), 8.20 (dd, 3J ¼ 8.1 Hz and 4J ¼ 2.1 Hz, 1H, ArH), 7.62 (dd, 3J ¼ 6.6 Hz and 4J ¼ 2.4 Hz, 1H, ArH), 7.39–7.34 (m, 2H, ArH), 7.31 (d, 3J ¼ 8.7 Hz, 2H, ArH), 7.21 (d, 3 J ¼ 8.7 Hz, 2H, ArH), 7.14 (d, 3J ¼ 8.4 Hz, 1H, ArH), 6.88 (d, 3J ¼ 8.7 Hz, 1H, ArH), 4.35 (s, 1H, CH), 2.41 (brs, 8H, NCH2), 2.23 (s, 3H, NCH3) ; 13C NMR (CDCl3, 75 MHz): dc 151.7, 138.8, 133.8, 132.1, 131.6, 131.5, 130.3, 127.3, 126.7, 126.3, 125.4, 125.1, 122.4, 122.1, 119.1, 117.4, 75.7, 68.3, 55.0 and 45.5. SYNTHESIS OF AMINOALKYLNAPHTHOLS 3087 ACKNOWLEDGMENTS One of the authors (S. R.) thanks the Council of Scientific and Industrial Research, New Delhi, for his fellowship SRF. We thank the CAS Instrumentation Facility, Department of Chemistry, University of Calcutta, for spectral data. 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