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Summer Research Fellowship Programme of India's Science Academies

Acid catalyzed C-2/C-4 benzylation of phenols with electron rich benzyl alcohols

Anat Ram Sidar

Indira Gandhi National Tribal University Amarkantak, Lalpur 484887 District Anuppur, Madhya pradesh

Faiz Ahmed Khan

Indian Institute of Technology Hyderabad, Kandi 502285 Sangreddy, Karnataka

Abstract

An acid-catalyzed synthesis of benzylated phenols is reported here. Different types of phenol undergoes Para as well as ortho nucleophilic addition selectively with electron-rich benzyl alcohols. A plausible reaction mechanism also proposed where benzyl alcohols with electron-rich at p-OMe position in situ forms para quionmethoxy methide in presence of Lewis acid.

Keywords: C-2/C-4 addition, Friedel-craft reaction, C-C bond formation, phenols, benzyl alcohols

List of abbreviations:-

Ar Aryl
Aq aqueous
cm centimetre
Calcd calculated
Dd                Doublet of doublet
Dt                Doublet of triplet
DCM                   Dichloromethane
1,2-DCE                     1,2 Dichloroethane
Equiv          equivalents
Et ethyl
Fig. figure
Gm gram
H     hexane
Hz Hertz
H hour
HR-MS                                       high-resolution mass spectrum
IR     infrared
Liq liquid
Lit. literature
m multiple
MHz megahertz
Me methyl
Mg Mili gram(s)
Min minute(s)
Mmol     milli mole (s)
M.p Melting point
MS      Molecular sieves
NMR                          Nuclear Magnetic Resonance
PTSA                     p- tolune sulphonic acid
Ph phenyl
Q quartet
Rf            Retention factor
Rt               Room temperature
T triplet
TLC                           thin layer chromatography
TfOH                                 Trifluromethane sulfonic acid

INTRODUCTION

Benzylated phenolic compounds are the core building unit for the design and synthesis of new molecule entities for antiplastic agent.1 A large number of molecule encompass benzylated phenols derivatives are of immense interest as found application on biological, Pharmaceutical and material science.2 Most of the biological relevant Benzylated phenols are C-4 substituted natural product such as phenstatin, isocombretastatin A-4 etc (Figure 1),3 which is used to prevent, inhibit or halt the development of a neoplasm (a tumor) an agent with antineoplastic properties. For example, oxaliplatin (Eloxatin) is an antineoplastic used in the treatment of metastatic colon cancer.

application.tif

    Figure 1. Biologically important natural product

    Apart from this, benzylated phenolic compounds are constantly used as a subunits for the design of supramolecular structures.4 Because of the wide range of application, benzylated phenols were synthesized by using, transition metal-catalyzed cross-coupling of benzyl nucleophiles with aryl halides.5 Alternative methods which being used are most cases reduction of diaryl ketone or benzhydryl by means of hydride donor with TFA or lewis acids.6,7 Disproportionation reactions were also being used for its synthesis.8 The most common method for its synthesis is Friedel-Craft reaction,9 Previously our group also reported the De novo synthesis of biologically important diarymethane from halo cyclohexene derivatives.10 Kaung sung et al also reported nucleophilic substitution of tert butyl alcohol with benzyl alcohol in presence of TiCl4 as reagent.11 Therefore, there is still valuable demand for the formation of benzylated phenols in a simple catalytic system under mild condition. In this direction our group also currently synthesizing benzylated phenols by using ZnBr2 in 1,2-DCE from electron-rich benzyl alcohols and phenols.12 In continuation to this work we further explored the substrate scope to make several derivative of benzylated phenols.

    Result and discussion:- To check the feasibility of the reaction, we carried our reaction by using commercial simple para methoxy benzyl alcohol and Ressorcinol as a reactant in presence of ZnBr2 as a catalyst in 1,2-dichloroethane as a solvent at room temperature under N2 atmosphere, we obtained Benylated phenol product as expected with C-4 benzylation in 92 % yield within 9 h

    (Scheme 1)..

    sch4.tif
      Substrate scope of Phenols

      After having the product in our hand, we treated different types of substituted phenol to p-methoxy benzyl alcohol under similar condition, all obtained as expected with good to very good yield and the result are summarised in (Scheme 1). Benzyl alcohols with electron-donating substituted phenols such as -Me and -OMe ( 3b-3q) afforded product in moderate to good yield (50-92 %). Phenols like 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2k, 2m, 2n when reacted with compound 1 under similar condition we obtained compound (3c-3i, 3k, 3m and 3n) in moderate yield. Similarly, phenols having more electron-rich on its substitution like compound 1b, 1j, 1l, reacted well and obtained in very good yield ( 3b, 3j, 3l, scheme 1)

      allllllllllll_2.tif

        Conclusion :- In conclusion we have described a novel and efficient method to synthesize the Benzylated phenols under normal condition via C-C bond formation at room temperature this methodologies allows to preparation of benzylated phenols under mild condition. Our protocol is simple and reaction proceed via insitu formation of quinomethoxymethide intermediate. We also successfully synthesized the C2-benzylated phenols with moderate to good yield. All substituted phenol derivatives undergoes nucleophilic addition to obtained the desired products in presence of in-expensive Lewis acid.

        Experimental section:- All reaction were carried out by using electronic magnetic stirrer followed by all standard condition and reaction were monitored by Thin layer chromatography and carried out on SRL silica gel GF 254 plates using short wave UV light, then column chromatography purification were performed over silica gel (100-200 acmes), (60-120), after that 1H and 13C NMR spectra were recorded on NMR spectrometer using CDCl3 and DMSO as the solvent and TMS as the internal standard chemical shift are reported in parts per million (ppm) relative to the central peak of the solvent. Multiplicities are indicated as s (singlet), d(doublet), t(triplet), q(quartet), dd(doublet of doublet), m(multiplet) and br(broad) coupling constant J value are given in hertz. Some of the case we have used digital melting point apparatus for confirmation of two solid product both are different or same, all chemical used were purchased commercially and all solvent are used for extraction and chromatographic further purification.

        General procedure for benzylation of phenols with electron-rich benzyl alcohol:- All reaction we were carried out by using 5-10 ml round bottle flask with 4-methoxy benzyl alcohol (0.5 mmol, 69 mg) and phenols (0.5 mmol) were dissolved in 2ml of 1,2- dichloroethane after that ZnBr2 (0.25 mmol, 56 mg) catalytic amount were used under N2 atmosphere. After completion of reaction monitored by TLC for confirmation, then reaction mixture was concentrated under reduced pressure by using rotary evaporator. Then the crude reaction mixture was purified by column chromatography with required amount of solvent (ethyl acetate and Hexane).

        Selected spectral data

        4-(4-methoxybenzyl)-2,3-dimethylphenol (3c)

        3c 50_1.tif

          After the completion of reaction, the reaction mixture was purified by silica gel through silica gel column chromatography (15% of ethyl acetate/Hexane) compound (3c) was obtained (41 mg, 35%) 1H NMR (400 MHz, CDCl3); d = 7.15 (d, J = 8.3 Hz, 2 H), 6.88 - 6.81 (m, 3 H), 6.60 (s, 1 H), 4.54 (br. s., 1 H), 3.88 (s, 2 H), 3.78 (s, 3 H), 2.19 (s, 3 H), 2.17 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 158.1, 151.5, 153.9, 132.2, 131.9, 129.5, 129.0, 128.6, 128.4, 124.2, 117.1, 114.1, 113.9, 55.2, 35.2, 19.4, 18.7.

          2-isopropyl-4-(4-methoxybenzyl)phenol (3d)

          3d 53.tif

            After the completion of reaction, the reaction mixture was purified by silica gel through silica gel column chromatography (15% of ethyl acetate/Hexane) compound (3d) was obtained (68 mg, 53 %) 1H NMR (400 MHz, CDCl3) d = 7.08 (d, J = 8.8 Hz, 2 H), 7.01 (d, J = 2.0 Hz, 1 H), 6.83 - 6.79 (m, 3 H), 6.62 (d, J = 8.3 Hz, 1 H), 3.84 (s, 2 H), 3.77 (s, 3 H), 3.17 (quin, J = 6.8 Hz, 1 H), 1.23 (s, 3 H), 1.21 (s, 3 H). 13C NMR (100 MHz, CDCl3) d = 157.8, 151.1, 134.4, 133.9, 133.8, 129.8, 129.6, 127.0, 126.9, 115.3, 114.3, 113.9, 55.3, 40.4, 27.2, 22.7, 22.6.

            (3) 4-(4-methoxybenzyl)-2-propylphenol (3e)

            3e 52.tif

              After the completion of reaction, the reaction mixture was purified by silica gel through silica gel column chromatography (15 % of ethyl acetate /Hexane) compound (3e) was obtained (65mg 50 %) 1H NMR (400 MHz,CDCl31H NMR (400MHz,CDCl3) d = 7.09 - 7.06 (m, 2 H), 6.92 (d, J = 2.4 Hz, 1 H), 6.86 - 6.80 (m, 3 H), 6.65 (d, J = 7.8 Hz, 1 H), 4.68 (br. s., 1 H), 3.82 (s, 2 H), 3.77 (s, 3 H), 2.55 - 2.50 (m, 2 H), 1.65 - 1.57 (m, 2 H), 0.95 (t, J = 7.3 Hz, 3 H). 13CNMR (100 MHz, CDCl3):δ 157.8, 151.7, 133.9, 133.7, 130.7, 129.5, 128.9, 128.9, 128.3,127.2, 115.2, 114.2, 113.8, 55.2, 40.2, 32.1,

              (4) 2-ethyl-4-(4-methoxybenzyl)phenol (3f)

              3f 54.tif

                After the completion of reaction, the reaction mixture was purified by silica gel through silica gel column chromatography (15% of ethyl acetate/Hexane) compound (3f) was obtained (64 mg, 53 %) 1H NMR (400 MHz, CDCl3)d = 7.15 - 7.09 (m, 2 H), 6.98 (s, 1 H), 6.90 - 6.84 (m, 3 H), 6.68 (d, J = 7.8 Hz, 1 H), 4.97 (br. s., 1 H), 3.87 (s, 2 H), 3.79 (s, 3 H), 2.66 - 2.59 (m, 2 H), 1.24 (dt, J = 1.5, 7.6 Hz, 3 H).13CNMR (100 MHz, CDCl3): δ 157.8, 151.68, 133.9, 133.8, 129.9, 129.8, 129.6, 127.2, 115.15, 114.2, 113.9, 55.3, 40.2, 23.1, 14.1.

                (5) 2-methoxy-6-(4-methoxybenzyl)-4-methylphenol (3g)

                3g 24.tif

                  After the completion of reaction, the reaction mixture was purified by silica gel through silica gel column chromatography (15 % of ethyl acetate /Hexane) compound (3g) was obtained (45mg 34 %) 1H NMR (400 MHz,CDCl3) d = 7.03 (d, J = 8.8 Hz, 2 H), 6.80 (d, J = 8.3 Hz, 2 H), 6.67 (d, J = 8.8 Hz, 2 H), 5.41 (s, 1 H), 3.84 (s, 3 H), 3.80 (s, 2 H), 3.76 (s, 3 H), 2.17 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 153.1, 151.4, 146.5, 145.4, 144.5, 137.1, 134.3, 132.6,128.7, 126.9, 125.5, 121.4, 120.1, 115.0, 114.2, 111.6, 105.82, 41.8, 41.6, 31.2, 29.9,

                  4-(4-methoxybenzyl)-3,5-dimethylphenol (3h)

                  3h 51.tif

                    After the completion of reaction, the reaction mixture was purified by silica gel through silica gel column chromatography (15 % of ethyl acetate /Hexane) compound (3h) was obtained (41mg 35 %) 1H NMR (400 MHz,CDCl3 ); δ 7.12 (s, 1H), 6.97 (d, J = 6.43 Hz, 1H), 6.72-6.67 (m, 4H ), 3.86 (s, 2 H), 3.68 (s, 3 H), 2.22 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 158.1, 151.5, 153.9, 132.2, 131.9, 129.5, 129.0, 128.6, 128.4, 124.2, 117.1, 114.1, 113.9, 55.2, 35.2, 19.4, 18.7,

                    2-(4-methoxybenzyl)-4,5-dimethylphenol (3i)

                    3i 57.tif

                      After the completion of reaction, the reaction mixture was purified by silica gel through silica gel column chromatography (10 % of ethyl acetate /Hexane) compound (3i) was obtained (65mg 58 %) 1HNMR (400 MHz,CDCl3 ); d = 6.97 (d, J = 7.3 Hz, 1 H), 6.82 (d, J = 8.3 Hz, 2 H), 6.72 - 6.66 (m, 2 H), 6.45 (s, 1 H), 3.80 (s, 2 H), 3.68 (s, 3 H), 2.11 - 2.03 (s, 6 H).

                      2-(4-methoxybenzyl)naphthalen-1-ol (3j)

                      9 hydroxy phenols.tif

                        After the completion of reaction, the reaction mixture was purified by silica gel through silica gel column chromatography (10 % of ethyl acetate /Hexane) compound (3j) was obtained (65mg 58 %) 1H NMR (400 MHz,CDCl3) d = 7.89 (d, J = 8.3 Hz, 1 H), 7.75 (d, J = 8.3 Hz, 1 H), 7.64 (d, J = 8.8 Hz, 1 H), 7.41 (ddd, J = 1.5, 6.8, 8.3 Hz, 1 H), 7.32 - 7.26 (m, 1 H), 7.12 - 7.01 (m, 3 H), 6.77 - 6.72 (m, 2 H), 5.19 (s, 1 H), 4.35 (s, 2 H), 3.69 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ , 157.9, 151.2, 133.6, 132.1, 129.5, 129.2, 128.6, 128.4, 126.7, 123.4, 123.2, 118.6, 117.9, 114.2, 55.3, 29.8.

                        4-(tert-butyl)-2-(4-methoxybenzyl)phenol (3k)

                        3k 54.tif

                          After the completion of reaction, the reaction mixture was purified by silica gel through column chromatography (10 % of ethyl acetate /Hexane) compound (3k) was obtained (58 mg, 48 %). 1HNMR (400 MHz, CDCl3 ); δ 7.24-7.21(m, 2H), 7.14-7.09 (m, 1H), 6.83-6.80 (m, 2H), 6.76-6.71(m, 2H), 3.92 (s, 2 H), 3.75 (s, 3H), 1.27-1.26 (s, 9 H). 13C NMR (100 MHz, CDCl3):δ 158.0, 158.03, 153.1, 151.4, 143.7, 143.5, 132.2, 129.6, 129.5, 127.9, 126.8, 126.5, 126.4, 126.2, 115.5, 114.8, 144.1, 55.3, 36.3, 34.1, 31.6, (3C).

                          3-(4-methoxybenzyl)-[1,1'-biphenyl]-4-ol (3l)

                          3l 71.tif

                            After the completion of reaction, the reaction mixture was purified by silica gel through column chromatography (10 % of ethyl acetate /Hexane) compound (3l) was obtained (101mg 70 %) 1H NMR (400 MHz,CDCl3 ); 1H NMR (400 MHz, DMSO-d6) d = 9.62 (s, 1 H), 7.58 (d, J = 7.3 Hz, 2 H), 7.54 - 7.46 (m, 2 H), 7.41 (t, J = 7.6 Hz, 2 H), 7.28 (t, J = 7.3 Hz, 1 H), 7.10 (s, 1 H), 6.90 (d, J = 8.3 Hz, 2 H), 6.84 (d, J = 8.3 Hz, 1 H), 3.70 (d, J = 2.9 Hz, 2 H), 3.53 - 3.44 (m, 3 H). 13C NMR (100 MHz, CDCl3): δ 157.1, 154.7, 140.2, 133.1, 130.9, 129.4, 129.5, 128.7, 128.5, 128.4, 128.7, 128.5, 128.4, 126.3, 125.9, 115.7, 113.7, 113.6, 54, 34.

                            4-methoxy-2-(4-methoxybenzyl)phenol (3m)

                            3m 52.tif

                              After the completion of reaction, the reaction mixture was purified by silica gel through column chromatography (10 % of ethyl acetate /Hexane) compound (3m) was obtained (71 mg, 58 %). 1H NMR (400MHz, CDCl3) d = 7.15 (d, J = 8.8 Hz, 1 H), 6.84 (d, J = 8.8 Hz, 1 H), 6.78 (d, J = 2.0 Hz, 4 H), 6.77 - 6.67 (m, 2 H), 3.92 (s, 2 H), 3.78 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 158.09, 157.9, 153.5, 149.7, 147.8, 147.3, 146.0, 117.8, 116.6, 116.1, 115.0, 114.3, 114.2, 113.7, 56.3, 55.3, 35.6.

                              4-(4-methoxybenzyl)benzene-1,3-diol (3p)

                              3p 92.tif

                                After the completion of reaction, the reaction mixture was purified by silica gel through column chromatography (10 % of ethyl acetate /Hexane) compound (3p) was obtained (104 mg 92%) 1H NMR (400 MHz, CDCl3) d = 7.15 (d, J = 8.8 Hz, 2 H), 6.84 (d, J = 8.8 Hz, 3 H), 6.78 (d, J = 2.0 Hz, 2 H), 3.92 (s, 2 H), 3.78 (s, 3 H).

                                4-(4-methoxybenzyl)phenol (3q)

                                3q.tif

                                  After the completion of reaction, the reaction mixture was purified by silica gel through column chromatography (10 % of ethyl acetate /Hexane) compound (3q) was obtained (98mg 86%) 1H NMR (400 MHz, CDCl3) d = 7.09 - 7.05 (m, 2 H), 7.03 - 6.99 (m, 2 H), 6.84 - 6.80 (m, 2 H), 6.74 - 6.70 (m, 2 H), 5.14 (br. s., 1 H), 3.83 (s, 2 H), 3.77 (s, 3 H), 13C NMR (100 MHz, CDCl3) d = 157.9, 153.8, 133.8, 133.8, 130.0, 129.8, 115.3, 113.9, 55.3, 40.11.

                                  A copy of selected NMR spectrum

                                  1H NMR (400 MHz ) 13CNMR (100 MHz) of 3d in CDCl3

                                  2 5 dimethyl phenols.jpg
                                    2 5 dimethyl 13c.jpg

                                      1H NMR (400 MHz ) 13C NMR (100 MHz) of 3e in CDCl3

                                      2 n propyl phenols.jpg
                                        2 n propyl 13c.jpg

                                          1H NMR (400 MHz ) 13C NMR (100 MHz) of 3g in CDCl3

                                          4 methyl 2 methoxy phenol.jpg
                                            4 methoxy 2 mthoxy phenols 13c.jpg

                                              1H NMR (400 MHz ) 13C NMR (100 MHz) of 3h in CDCl3

                                              2 5 dimethyl phenols.jpg
                                                2 5 dimethyl 13c.jpg

                                                  1H NMR (400 MHz ) 13C NMR (100 MHz) of 3j in CDCl3

                                                  9 hydroxy ph 13c.jpg
                                                    9 hydroxy ph 13c.jpg

                                                      3-(4-methoxybenzyl)-[1,1'-biphenyl]-4-ol (3l)

                                                      4 phenyl phenols.jpg

                                                        4 phenyl phenols  13c.jpg

                                                          4-(4-methoxybenzyl)phenol (3q)

                                                          4 hydroxy methoxy phenol.jpg
                                                            4 hydroxy methoxy phenols.jpg

                                                              DECLARATION

                                                              I hereby declare that the project work entitled “Acid-catalyzed C-2/C-4 benzylation of phenols with electron-rich benzyl alcohol” is a confide record of an original and authentic work done by me under the supervision of Professor Faiz Ahmed Khan, department of chemistry, IIT Hyderabad based on the research work carried out during the IASc-INSA-NASI summer research fellowship problem 2019. I have duly acknowledged all the source used by me in the preparation of this project.

                                                              Acknowledgment

                                                              The internship opportunity I had IIT Hyderabad was a great chance for learning and professional development, therefore I consider myself as a very lucky individual as I was provided with an opportunity to be a part of it, I am also grateful for having a chance to meet so many wonderful people and professionals who led me through this internship period.

                                                              I am using this opportunity to express my deepest gratitude and special thanks to my esteemed guide Prof. Faiz Ahmed Khan, Department of chemistry IIT Hyderabad for his excellent supervision, valuable suggestion and encouragement and allowing me to carry out my project at their esteemed organization, his timely advice, meticulous scrutiny, scientific approach helped me to a very great extent to complete the project.

                                                              My heartfelt thanks and regard to professor M.R.N.MURTHY chairman, joint science Educational panel and Indian academy of science coordinator Mr. C S RAVI KUMAR summer research fellowship program and the entire team of IASc-INSA-NASI summer research fellowship programme. 2019 for giving me lifetime opportunity through this research programme and funding my project

                                                              I would like to express my special thanks to Mr. Tapan Kumar Jena the senior research scholar in the laboratory for his valuable guidance and being a helping hand in my project for his scholarly advice time to time with a lot of patience. and also establishing the initial results for this project.

                                                              I would also like to convey my heartfelt thanks to the other research scholars in my laboratory Mr. Althaf Hussain Mullah, Dr. Kukkamudi Sreenivas, Mr. Shivaji khadake, Mr. Vijay Kumar, Mr. Rameez, Ms. Sarwat Asma Ziya Ahmad and my co-intern Ms. pujhita for their cooperation, support and help at every stage of the project and making it a memorable one

                                                              I am grateful to all the faculty members of the department of chemistry, Indira Gandhi National Tribal University, Amarkantak (Madhya Pradesh) and my heartiest thanks to Prof. Dr. Biswajit Maji faculty in Organic Chemistry of IGNTU.

                                                              In ending of my words I would like to thank god almighty, my parents and friends for their relentless inspiration and worthy evocations, which helped me a lot for the preparation of this project.

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                                                              6) For reduction of benzhydryl see: (a) Wu, X.; Mahalingam, A.K.; Alterman, M. Tetrahedron Lett. 2005, 46, 1501, (b) Ihmels, H.; Meiswinkel, A.; Mohrschladt, C. J.; Otto, D.; Waidelich, M.; Towler, M.; White, R.; Albrecht, M.; Schnurpfeil, A.J. Org. Chem. 2005, 70, 3929; (c) Barda, D. A.; Wang, Z.-Q.; Britton, T. C.; Henry, S. S.; Jagdmann,G. E.; Coleman, D. S.; Johnson, M. P.; Andis, S. L.; Schoepp, D. D. Bioorg. Med. Chem. Lett. 2004, 14, 3099; (d) Okimoto, M.; Takahashi, Y.; Nagata, Y.; Satoh, M.; Sueda, S.; Yamashina, T.Bull. Chem. Soc. Jpn. 2004,77, 1405;

                                                              7)(a) Harig, M.; Neumann, B.; Stammler, H.-G.; Kuck, D. Eur. J.Org. Chem. 2004, 2381; (b) Hatano, B.; Kadokawa, J.-I.; Tagaya, H.Tetrahedron Lett. 2002, 43, 5859;

                                                              8) Homer, J. A.; Sperry, J. Mushroom-derived indole alkaloids. J. Nat. Prod .2017, 80, 2178.

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                                                              10) Babu, K. R.; Khan, F. A. Tetrahedron lett., 2015, 56 4067.

                                                              11) Tsai, C-Yu.; Sung, R.; Zhuang, Bo-Ren.; Sung, K.; Tetrahedron lett., 2010, 66 6869.

                                                              12) Jena, T. K.; Khan, F. A. (Unpublished result).

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