Further Insights into the Exhaustive Grignard Tetramethylation of <I>N</I>-benzylphthalimide

Viraj Chathuranga Jayawardena

doi:doi:10.11648/j.ijsts.20231106.14

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Further Insights into the Exhaustive Grignard Tetramethylation of N-benzylphthalimide

Viraj Chathuranga Jayawardena

Published in International Journal of Science, Technology and Society (Volume 11, Issue 6)

Received: 4 April 2023 Accepted: 21 April 2023 Published: 26 December 2023

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Abstract

1,1,3,3-tetramethylisoindolin-2-yloxyl (TMIO) is one of the most versatile isoindoline nitroxides due to the applications and a variety of important advantages it possesses. TMIO had been prepared previously by few different approaches, but none of these produced good yields due to the involvement of higher number of steps in the synthetic pathway. The most common pathway used to prepare TMIO involves the treatment of N-benzylphthalimide with methylmagnesium halide (MeMgX), followed by deprotection and oxidation. This Grignard approach remains the most effective when it comes to the synthesis of TMIO due to the higher overall yield obtained (36%) and the involvement of only four steps. However, the major yield limiting step in this route is the reaction between N-benzylphthalimide and MeMgX. The limited yield of this step is a mystery for 40 years due to some unknown reasons. Therefore, the author had decided to mechanistically investigate the aforesaid reaction with the aim of searching the reasons that lead to the limited yield. Analysis of the Grignard reaction mixture through a novel aqueous work-up (that was different to published Griffiths’ work-up) demonstrates the formation of five products including the target, N-benzyl-1,1,3,3-tetramethylisoindoline. Two of them among five products are recognized to be dead-end, while other two did not involve in improving the yield of the target although they both appear to be intermediates on the pathway to form the target. According to the findings of this study, it is finally concluded that a range of potential reactions and the formation of numerous side products could be the possible reasons for the low yield of the Grignard step.

Published in	International Journal of Science, Technology and Society (Volume 11, Issue 6)
DOI	10.11648/j.ijsts.20231106.14
Page(s)	215-238
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

Isoindoline, Nitroxide, Work-up

References

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[2]	Kielty, P., Chalmers, B. A., Farràs, P., Smith, D. A. and Aldabbagh, F., 2021. Visible light activated benzimidazolequinone alkoxyamines of 1, 1, 3, 3-tetramethylisoindolin-2-yloxyl (TMIO). European Journal of Organic Chemistry, 2021(48), pp.6652-6657.
[3]	Verderosa, A. D., Hawas, S., Harris, J., Totsika, M. and Fairfull-Smith, K. E., 2022. Isothiazolone–Nitroxide Hybrids with Activity against Antibiotic-Resistant Staphylococcus aureus Biofilms. ACS omega, 7(6), pp. 5300-5310.
[4]	Zhu, Y. L., Shen, Y. C., Liu, F., Chen, S., Yan, G. P., Liang, S. C., Zhang, Y. F. and Wu, Y. G., 2021. Dual-modal fullerenol probe containing glypican-3 monoclonal antibody for electron paramagnetic resonance/fluorescence imaging. Fullerenes, Nanotubes and Carbon Nanostructures, 29(4), pp.280-287. doi: 10.1080/1536383X.2020.1839055.
[5]	Larin, A. C., Pfrunder, M. C., Mullen, K. M., Wiedbrauk, S., Boase, N. R. and Fairfull-Smith, K. E., 2023. Synergistic or antagonistic antioxidant combinations–a case study exploring flavonoid-nitroxide hybrids. Organic & Biomolecular Chemistry, 21 (8), pp. 1780-1792.
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[8]	Griffiths, P. G., Rizzardo, E. and Solomon, D. H., 1982. Quantitative studies on free radical reactions with the scavenger 1, 1, 3, 3-tetramethylisoindolinyl-2-oxy. Tetrahedron Letters, 23 (12), pp. 1309-1312.
[9]	P. G. Griffiths, P. G., Moad, G., Rizzardo, E. and Solomon, D. H., 1983. Synthesis of Radical Scavenger 1,1,3,3-Tetramethylisoindolin-2-yolxyl. Australian Journal of Chemistry, 36, pp.397-401. doi: 10.1071/CH9830397.
[10]	Jayawardena, V. C., Fairfull-Smith, K. E. and Bottle, S. E., 2013. Improving the Yield of the Exhaustive Grignard Alkylation of N-Benzylphthalimide. Australian Journal of Chemistry, 66(6), pp. 619-625.
[11]	Manske, R. H. F., 1932. Organic Syntheses by Oxidation with Metal Compounds. Organic Syntheses, 12, pp. 10-11.
[12]	He, Z. and Yudin, A. K., 2006. Palladium-catalyzed oxidative activation of arylcyclopropanes. Organic Letters, 8(25), pp. 5829-5832. doi: 10.1021/ol062476e.
[13]	Kundu, N. G. and Khan, M. W., 2000. Palladium-catalysed heteroannulation with terminal alkynes: a highly regio-and stereoselective synthesis of (Z)-3-Aryl (alkyl) idene isoindolin-1-ones. Tetrahedron, 56(27), pp. 4777-4792.
[14]	Hansson, C. and Wickberg, B., 1973. Preparation of enamines by addition of Grignard reagents to N, N-dialkylformamides. The Journal of Organic Chemistry, 38(17), pp. 3074-3076.
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[16]	Jayawardena, V.C., 2014. Synthesis of heterocyclic nitroxides with an improved yield by investigating the tetraalkylation of N-benzylphthalimide (Doctoral dissertation, Queensland University of Technology).

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APA Style

Jayawardena, V. C. (2023). Further Insights into the Exhaustive Grignard Tetramethylation of N-benzylphthalimide. International Journal of Science, Technology and Society, 11(6), 215-238. https://doi.org/10.11648/j.ijsts.20231106.14

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ACS Style

Jayawardena, V. C. Further Insights into the Exhaustive Grignard Tetramethylation of N-benzylphthalimide. Int. J. Sci. Technol. Soc. 2023, 11(6), 215-238. doi: 10.11648/j.ijsts.20231106.14

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AMA Style

Jayawardena VC. Further Insights into the Exhaustive Grignard Tetramethylation of N-benzylphthalimide. Int J Sci Technol Soc. 2023;11(6):215-238. doi: 10.11648/j.ijsts.20231106.14

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@article{10.11648/j.ijsts.20231106.14,
  author = {Viraj Chathuranga Jayawardena},
  title = {Further Insights into the Exhaustive Grignard Tetramethylation of N-benzylphthalimide},
  journal = {International Journal of Science, Technology and Society},
  volume = {11},
  number = {6},
  pages = {215-238},
  doi = {10.11648/j.ijsts.20231106.14},
  url = {https://doi.org/10.11648/j.ijsts.20231106.14},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijsts.20231106.14},
  abstract = {1,1,3,3-tetramethylisoindolin-2-yloxyl (TMIO) is one of the most versatile isoindoline nitroxides due to the applications and a variety of important advantages it possesses. TMIO had been prepared previously by few different approaches, but none of these produced good yields due to the involvement of higher number of steps in the synthetic pathway. The most common pathway used to prepare TMIO involves the treatment of N-benzylphthalimide with methylmagnesium halide (MeMgX), followed by deprotection and oxidation. This Grignard approach remains the most effective when it comes to the synthesis of TMIO due to the higher overall yield obtained (36%) and the involvement of only four steps. However, the major yield limiting step in this route is the reaction between N-benzylphthalimide and MeMgX. The limited yield of this step is a mystery for 40 years due to some unknown reasons. Therefore, the author had decided to mechanistically investigate the aforesaid reaction with the aim of searching the reasons that lead to the limited yield. Analysis of the Grignard reaction mixture through a novel aqueous work-up (that was different to published Griffiths’ work-up) demonstrates the formation of five products including the target, N-benzyl-1,1,3,3-tetramethylisoindoline. Two of them among five products are recognized to be dead-end, while other two did not involve in improving the yield of the target although they both appear to be intermediates on the pathway to form the target. According to the findings of this study, it is finally concluded that a range of potential reactions and the formation of numerous side products could be the possible reasons for the low yield of the Grignard step. 
},
 year = {2023}
}

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TY  - JOUR
T1  - Further Insights into the Exhaustive Grignard Tetramethylation of N-benzylphthalimide
AU  - Viraj Chathuranga Jayawardena
Y1  - 2023/12/26
PY  - 2023
N1  - https://doi.org/10.11648/j.ijsts.20231106.14
DO  - 10.11648/j.ijsts.20231106.14
T2  - International Journal of Science, Technology and Society
JF  - International Journal of Science, Technology and Society
JO  - International Journal of Science, Technology and Society
SP  - 215
EP  - 238
PB  - Science Publishing Group
SN  - 2330-7420
UR  - https://doi.org/10.11648/j.ijsts.20231106.14
AB  - 1,1,3,3-tetramethylisoindolin-2-yloxyl (TMIO) is one of the most versatile isoindoline nitroxides due to the applications and a variety of important advantages it possesses. TMIO had been prepared previously by few different approaches, but none of these produced good yields due to the involvement of higher number of steps in the synthetic pathway. The most common pathway used to prepare TMIO involves the treatment of N-benzylphthalimide with methylmagnesium halide (MeMgX), followed by deprotection and oxidation. This Grignard approach remains the most effective when it comes to the synthesis of TMIO due to the higher overall yield obtained (36%) and the involvement of only four steps. However, the major yield limiting step in this route is the reaction between N-benzylphthalimide and MeMgX. The limited yield of this step is a mystery for 40 years due to some unknown reasons. Therefore, the author had decided to mechanistically investigate the aforesaid reaction with the aim of searching the reasons that lead to the limited yield. Analysis of the Grignard reaction mixture through a novel aqueous work-up (that was different to published Griffiths’ work-up) demonstrates the formation of five products including the target, N-benzyl-1,1,3,3-tetramethylisoindoline. Two of them among five products are recognized to be dead-end, while other two did not involve in improving the yield of the target although they both appear to be intermediates on the pathway to form the target. According to the findings of this study, it is finally concluded that a range of potential reactions and the formation of numerous side products could be the possible reasons for the low yield of the Grignard step. 

VL  - 11
IS  - 6
ER  -

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Viraj Chathuranga Jayawardena

National Institute of Fundamental Studies, Kandy, Sri Lanka

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APA Style

Jayawardena, V. C. (2023). Further Insights into the Exhaustive Grignard Tetramethylation of N-benzylphthalimide. International Journal of Science, Technology and Society, 11(6), 215-238. https://doi.org/10.11648/j.ijsts.20231106.14

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ACS Style

Jayawardena, V. C. Further Insights into the Exhaustive Grignard Tetramethylation of N-benzylphthalimide. Int. J. Sci. Technol. Soc. 2023, 11(6), 215-238. doi: 10.11648/j.ijsts.20231106.14

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AMA Style

Jayawardena VC. Further Insights into the Exhaustive Grignard Tetramethylation of N-benzylphthalimide. Int J Sci Technol Soc. 2023;11(6):215-238. doi: 10.11648/j.ijsts.20231106.14

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@article{10.11648/j.ijsts.20231106.14,
  author = {Viraj Chathuranga Jayawardena},
  title = {Further Insights into the Exhaustive Grignard Tetramethylation of N-benzylphthalimide},
  journal = {International Journal of Science, Technology and Society},
  volume = {11},
  number = {6},
  pages = {215-238},
  doi = {10.11648/j.ijsts.20231106.14},
  url = {https://doi.org/10.11648/j.ijsts.20231106.14},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijsts.20231106.14},
  abstract = {1,1,3,3-tetramethylisoindolin-2-yloxyl (TMIO) is one of the most versatile isoindoline nitroxides due to the applications and a variety of important advantages it possesses. TMIO had been prepared previously by few different approaches, but none of these produced good yields due to the involvement of higher number of steps in the synthetic pathway. The most common pathway used to prepare TMIO involves the treatment of N-benzylphthalimide with methylmagnesium halide (MeMgX), followed by deprotection and oxidation. This Grignard approach remains the most effective when it comes to the synthesis of TMIO due to the higher overall yield obtained (36%) and the involvement of only four steps. However, the major yield limiting step in this route is the reaction between N-benzylphthalimide and MeMgX. The limited yield of this step is a mystery for 40 years due to some unknown reasons. Therefore, the author had decided to mechanistically investigate the aforesaid reaction with the aim of searching the reasons that lead to the limited yield. Analysis of the Grignard reaction mixture through a novel aqueous work-up (that was different to published Griffiths’ work-up) demonstrates the formation of five products including the target, N-benzyl-1,1,3,3-tetramethylisoindoline. Two of them among five products are recognized to be dead-end, while other two did not involve in improving the yield of the target although they both appear to be intermediates on the pathway to form the target. According to the findings of this study, it is finally concluded that a range of potential reactions and the formation of numerous side products could be the possible reasons for the low yield of the Grignard step. 
},
 year = {2023}
}

Copy | Download

TY  - JOUR
T1  - Further Insights into the Exhaustive Grignard Tetramethylation of N-benzylphthalimide
AU  - Viraj Chathuranga Jayawardena
Y1  - 2023/12/26
PY  - 2023
N1  - https://doi.org/10.11648/j.ijsts.20231106.14
DO  - 10.11648/j.ijsts.20231106.14
T2  - International Journal of Science, Technology and Society
JF  - International Journal of Science, Technology and Society
JO  - International Journal of Science, Technology and Society
SP  - 215
EP  - 238
PB  - Science Publishing Group
SN  - 2330-7420
UR  - https://doi.org/10.11648/j.ijsts.20231106.14
AB  - 1,1,3,3-tetramethylisoindolin-2-yloxyl (TMIO) is one of the most versatile isoindoline nitroxides due to the applications and a variety of important advantages it possesses. TMIO had been prepared previously by few different approaches, but none of these produced good yields due to the involvement of higher number of steps in the synthetic pathway. The most common pathway used to prepare TMIO involves the treatment of N-benzylphthalimide with methylmagnesium halide (MeMgX), followed by deprotection and oxidation. This Grignard approach remains the most effective when it comes to the synthesis of TMIO due to the higher overall yield obtained (36%) and the involvement of only four steps. However, the major yield limiting step in this route is the reaction between N-benzylphthalimide and MeMgX. The limited yield of this step is a mystery for 40 years due to some unknown reasons. Therefore, the author had decided to mechanistically investigate the aforesaid reaction with the aim of searching the reasons that lead to the limited yield. Analysis of the Grignard reaction mixture through a novel aqueous work-up (that was different to published Griffiths’ work-up) demonstrates the formation of five products including the target, N-benzyl-1,1,3,3-tetramethylisoindoline. Two of them among five products are recognized to be dead-end, while other two did not involve in improving the yield of the target although they both appear to be intermediates on the pathway to form the target. According to the findings of this study, it is finally concluded that a range of potential reactions and the formation of numerous side products could be the possible reasons for the low yield of the Grignard step. 

VL  - 11
IS  - 6
ER  -

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