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Summer Research Fellowship Programme of India's Science Academies

Synthesis of derivatives of Cinnamaldehyde using Wittig Reaction

Sowmya Shree R

Summer Research Fellow, Indian Institute of science, Indian Institute of science, CV Raman Rd, Bengaluru, Karnataka 560012

Dr Akkattu T. Biju

Department of Organic Chemistry, Indian Institute of Science, Indian Institute of science, CV Raman Rd, Bengaluru, Karnataka 560012

Abstract

Even after 60 years of the discovery of Wittig reaction by Georg Wittig and co-workers lot more research is going on this topic till date. Formation of carbon – carbon bond is quite a difficult job, very less reactions have been successful in this, in which Wittig reaction is one of the most important tool in both synthetic organic chemistry and in synthesis of natural products.

Wittig reaction is the reaction in which carbonyl group and phosphonium ylide react together to form carbon-carbon double bond in desired position. Ylides are classified into three different types – non-stabilized ylides, semi stabilized ylides and stabilized ylides. In this project we have used stabilized ylide to prepare α-β unsaturated carbonyl compounds (commonly called enals). This preparation can be done in single step (generally for electron withdrawing group or electronically neutral group present in β-aryl ring) or three steps (generally for electron donating group) based on the stereochemistry of the product that we need as this wittig reactions give stereo specific products.

Abbreviations

Abbreviations
 DCMDichloromethane
CH3CN Acetonitrile
EtOAc  Ethyl Acetate
 THF Tetrahydrofuran
 equiv Equivalent
 h Hour
 rt room temperature
 mmolMillimole 
mol Mole 
NMR Nuclear Magnetic Resonance 
s  Singlet
d  Doublet
m  Multiplet
dd  Doublet of doublet
 TLC Thin Layer Chromatography

INTRODUCTION

Wittig reaction is mainly used for olefination reaction, in this reaction carbonyl compounds (aldehyde and ketone) and phosphorous ylide salts(4) are reacted together to form carbon-carbon double bond at desired position and phosphonium oxide as by-product with the intermediate oxaphosphetane(6). Based on the stability of ylides in air they are classified into non stabilized, semi stabilized and stabilized ylides. Wittig reactions are famous not only for carbon-carbon bond formation but also known for its stereo specific products, based on which kind of above three ylides are used. In general non stabilized ylides give alkenes with Z configuration, stabilized ylides give alkenes with E configuration and semi stabilized ylides are not so selective for particular isomer(7). However we cannot stick on to this strictly as this is more general rule.

    Scope

    This Wittig reaction is extensively used in both synthetic organic chemistry lab and in manufacturing of natural products(8) (e.g. - vitamin A, brevetoxin B, sphingolipids, macrolides and pyrenes). Here I have used Wittig reactions with stabilized ylides to prepare α-β unsaturated compounds (particularly various cinnamaldehyde derivatives). This preparation can be done in single step (generally for electron withdrawing group or electronically neutral substitution R1) or three steps (generally for electron donating group on R') based on the stereochemistry of the product that we need as the Wittig reactions give stereo specific products.

    LITERATURE REVIEW

    These cinnamaldehydes are very much important as they have great scope in synthetic organic chemistry which I have mentioned above. I prepared these cinnamaldehyde using the procedures and the methodologies followed in previously available protocols which I have cited in the references.

     

    Information

    I have prepared 14 different cinnamaldehyde derivatives (Table 1). Since we are concerned about the stereochemistry of the enals that we prepare, for electron withdrawing and electronically neutral groups we are using single step synthesis and three step synthesis for electron donating groups.

    Summary

      METHODOLOGY

      Synthesis of Electron withdrawing and neutral substituted enals: These enals are synthesized using this single step synthesis, as the R group is electron withdrawing and neutral in this case. This follows the below procedure.

      To 1 equivalent of Substituted Benzaldehyde and 1.5 equivalent of aldehydic ylide is added in acetonitrile (solvent) and refluxed at 85˚C over night(5).

        Synthesis of Electron Donating Substituted enals: These are synthesized using this three-step procedure as R group is electron donating in nature. This follows the below procedure.

        Step 1: Wittig reaction

        1equivalent of Substituted benzaldehyde and 1.2 equivalent ester ylide is taken in DCM and stirred for 12 h at room temperature(3).

          Step 2: Reduction of ester group to alcohol

          To a stirred solution of ester in DCM, DIBAL-H was added drop wise over 30 mins at -78˚C. Then the reaction was stirred for 4hrs when TLC full conversion occurs. The mixture was quenched with Rochelle salt (potassium and sodium tartarate) and stirred for overnight, precipitate will be dissolved, the phases were separated, and aqueous layer was extracted with DCM(2).

            Step 3: Oxidation of alcohol into aldehyde.

            A solution of alcohol in (1,4)- dioxane, DDQ was added to the solution and contents was stirred at room temperature for 30 mins, then the reaction mixture was filtered for the removal of DDQ-H. Solvent was evaporated in vacuum and resulting residue was purified by flash chromatography(1).

              RESULTS AND DISCUSSION

              Following the general procedure, the above (Table 1) cinnamaldehyde derivatives were prepared. Electronically different substituent at the 4-position of aldehyde gives moderate to good yield. Substituent at 3-position and 2-position of the aldehyde and disubstituted aldehyde also gives moderate to good yield.

              Synthesis and Characterization of cinnamaldehyde Derivatives:

              (E)-3-(4-chlorophenyl)acrylaldehyde (1):

                (E)-3-(4-bromophenyl)acrylaldehyde (2):

                  (E)-3-(p-tolyl)acrylaldehyde (3):

                    (E)-3-(4-fluorophenyl)acrylaldehyde (4):

                      (E)-3-(4-(trifluoromethyl)phenyl)acrylaldehyde (5):

                        (E)-3-(2-chlorophenyl)acrylaldehyde (6):

                          (E)-3-(2-fluorophenyl)acrylaldehyde (7):

                            (E)-3-(2-bromophenyl)acrylaldehyde (8):

                              (E)-3-(o-tolyl)acrylaldehyde (9):

                                (E)-3-(3-chlorophenyl)acrylaldehyde (10):

                                  (E)-3-(3-bromophenyl)acrylaldehyde (11):

                                    (E)-3-(3-nitrophenyl)acrylaldehyde (12):

                                      (E)-3-(3,4-dichlorophenyl)acrylaldehyde (13):

                                        (E)-3-(3,4-dimethoxyphenyl)acrylaldehyde (14):

                                          SPECTROSCOPIC DATA

                                                                      CONCLUSION

                                                                      In conclusion I have prepared 14 electronically different substituted cinnamaldehyde derivatives and characterized those derivatives. These cinnamaldehyde derivatives are very much important feedstock for different catalytic reactions. I have learned to handle chemicals and how to do characterization of synthesized organic compounds and some technique which followed in organic chemistry lab.

                                                                      REFERENCES

                                                                      1.      Porey, A.; Santra, S.; Guin, J. J. Org. Chem. 2019, 84, 5313.

                                                                      2.      Rao, S.; Kapanaiah, R.; Prabhu, k. R. Advanced Synthesis and Catalysis. 2019, 361, 1301.

                                                                      3.      Krayer, M.; Ptaszek, M.; Kim, H.; Meneely, K. R.; Fan, D.; Secor, K.; Lindsey, J. S. J. Org. Chem. 2010, 75, 1016.

                                                                      4.      Wube, A. A.; Hufner, A.; Thomaschitz, C.; Blunder, M.; Kollnoser, M.; Bauer, R.; Bucar, F. Bioorg. Med. chem. 2011, 19, 1, 567.

                                                                      5.      Challa, C.; Vellekkatt, J.; Ravindran, J.; Lankalapalli, R. S. Org. Biomol. Chem. 2014, 12, 8588.

                                                                      6.      Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 98, 863.

                                                                      7.      Byrne, P.; Gilheany, D. G. Chem. Soc. Rev. 2013, 42, 6670.

                                                                      8.      Rocha, D. H. A.; Pinto, D. C. G. A.; Silva, M. S. Eur. J. Org. Chem. 2018, 2443.

                                                                      ACKNOWLEDGEMENTS

                                                                      First of all, I am grateful to Indian Academy of Sciences, for providing me the opportunity under summer research fellowship programme and for the fellowship amount.

                                                                      Then I would like to thank Indian Institute of Science for providing the place for work and my guide Dr Akkattu T Biju, Department of Chemistry, IISC, Banglore, for his support and guidance.

                                                                      I also thank my labmates who are pursuing their Ph.D in IISC as they taught me lab techniques, handling chemicals and how to do characterization of synthesized organic compounds in organic chemistry lab.

                                                                      At last but not the least, I would like to thank my family and friends for their love and support.

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