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Unusual reactivity of amine-dienophile Michael adducts in polar protic medium-acetic acid
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Unusual reactivity of amine-dienophile Michael adducts in polar protic medium-acetic acid Jesna A , Rani Mathew , Jomon P. Jacob PII: DOI: Reference:
S2405-8300(19)30389-1 https://doi.org/10.1016/j.cdc.2019.100318 CDC 100318
To appear in:
Chemical Data Collections
Received date: Revised date: Accepted date:
29 September 2019 28 November 2019 4 December 2019
Please cite this article as: Jesna A , Rani Mathew , Jomon P. Jacob , Unusual reactivity of aminedienophile Michael adducts in polar protic medium-acetic acid, Chemical Data Collections (2019), doi: https://doi.org/10.1016/j.cdc.2019.100318
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.
Highlights Synthesised a few novel Michael adducts Compare the reactivity of Michael adducts in polar protic media-acetic acid and methanol Michael adducts show high reactivity in polar protic medium-acetic acid
1
Title: Unusual reactivity of amine-dienophile Michael adducts in polar protic medium-acetic acid Authors: Jesna A., Rani Mathew and Jomon P. Jacob* Affiliations: Department of Applied Chemistry, Cochin University of Science and Technology, Kochi682 022, Kerala, India. Contact email: [email protected] Abstract A few novel Michael adducts were synthesised and compared their reactivity in two polar protic solvents: acetic acid and methanol. Upon refluxing in acetic acid, Michael adducts underwent extensive decomposition. Decomposition of Michael adducts is accelerated by the dienophile present in the reaction medium. But in methanol, Michael adducts remained unchaged even in the presence of dienophiles. Graphical abstract
Keywords: Michael Dibenzoylacetylene. Specifications Table Subject area Compounds Data category Data acquisition format Data type Procedure Data accessibility
adduct;
Acetic
acid;
Methanol;
Dimethyl
acetylenedicarboxylate;
Organic Chemistry, Spectroscopy. Michael adducts Spectral, Synthesized. 1 H NMR, 13C NMR, IR, Mass spectra, m.p. Process and analysis. Unusual reactivity of amine-dienophile Michael adducts in polar protic medium-acetic acid Data is provided with this article
1. Rationale
2
We have done a detailed study1-5 of the electron transfer reaction of 9-(N,Ndiisopropylaminomethyl)anthracene1 (1) with suitable electron-deficient acetylenes viz dimethyl acetylenedicarboxylate (DMAD, 2) and dibenzoylacetylene (DBA, 3) in different solvents. In polar protic solvent-methanol (highly polar, but low boiling), the reaction of 1 (0.034 mol) with 2 yielded 9(methoxymethyl)anthracene6,7 (4) and N,N-diisopropylaminomaleate (5) in good yields along with 9methylanthracene (6), 9-anthraldehyde (7) and 9,10-anthraquinone (8) in negligible amounts (Scheme 1)2. But the reaction of 1 (0.034 mol) with another electron-deficient acetylene, dibenzoylacetylene (DBA, 3) in methanol yielded 4 and 2-diisopropylaminodibenzoylethylene (9) with trace amounts of 6, 7 and 8 (Scheme 1)2.
Scheme 1. Reaction of 9-(N,N-diisopropylaminomethyl)anthracene with dienophiles in methanol To study the generality of the reaction, we have done the reaction in polar protic solventglacial acetic acid2 (intermediate polarity and boiling point). We refluxed 0.034 mol solution of 1 with 2 and the result of the reaction was surprising. After 10h, we obtained (anthracen-9-yl)methyl acetate8,9 (10) and 2-(anthracen-9-ylmethyl)dimethyl-3-oxosuccinate (11) along with trace amounts of 6, 7 and 8 (Scheme 2)2. It may be noted here that 5 was not present in detectable amounts in the reaction mixture. Reaction of 0.034 mol solution of 1 with 2 equivalents of 3 was completed in 10h yielded 10, 2-hydroxydibenzoylethylene10 (12) along with trace amounts of 6, 7 and 8 (Scheme 2)2.
Scheme 2. Reaction of 9-(N,N-diisopropylaminomethyl)anthracene with dienophiles in acetic acid Above reactions may proceeded through the same intermediate and was realized from the formation of products 4 and 10. So, we proposed that the above reactions take place through the nucleophilic attack of amine 1 on dienophiles (2/3) in a Michael type addition pathway giving rise to a Michael adduct/ zwitterion11 13a/b. This leads to the weakening and eventual cleavage of C-N 3
bond giving rise to 9-anthracenemethyl cation (14) and 5 or 9 (Scheme 3). 9-Anthracenemethyl cation (14) formed is captured by the solvent to give the correspornding products 4 and 10.
Scheme 3. Mechanism of 1 with 2/3 in polar protic media. If the reaction of 1 with 2/3 in acetic acid, proceeds through the above mechanism, Michael adduct 5/9 should also be generated. With a view to ascertain this possibility, we carried out GC-MS and NMR analyses of the crude product mixture. The results indicated the absence of Michael adducts 5/9 in the reaction mixture. So we concluded that 5 or 9 are either not formed or undergo further transformations under the reaction conditions employed by us. To discount the latter possibility, we treated independently synthesized Michael adducts by supplying same conditions of acetic acid reactions. 2. Procedure 2.1. Materials and method All reactions were carried out using oven dried glasswares. All experiments were performed in distilled and dried solvents by using standard protocols. All starting materials were purchased from either Sigma-Aldrich or Spectrochem Chemicals and were used without further purification. Progress of the reaction and chromatographic separations were monitored by TLC over dried and activated silica gel TLC plates (Aluminium sheets coated with silica gel, E. Merck). Visualisation of TLC plates was acquired by exposure to iodine vapours or UV lamp. Separation and purification of compounds were done by column chromatography using either silica gel (Spectrochem Chemicals, 60-120 mesh) or neutral alumina (Spectrochem Chemicals). The products were further purified by recrystallization from suitable solvent systems. Solvent eluted from the column chromatography was concentrated using Heidolph rotary evaporator. Melting points are uncorrected and were determined on a Neolab melting point apparatus. Infra-red spectra were recorded using Jasco 4100 and ABB Bomem (MB Series) FT-IR spectrometers. The 1H and 13C NMR spectra of noval comounds in CDCl3 were recorded at 400 MHz Bruker Avance III FT-NMR spectrometer with tetramethylsilane (TMS) as internal standard. Chemical shifts (δ) are reported in parts per million (ppm) downfield of TMS. Elemental analysis was performed using Elementar Systeme (Vario EL III). Molecular mass was determined by fast atom bombardment (FAB) using JMS 600 JEOL mass spectrometer. Here we are giving the spectral and analytical data only for novel compounds and the corresponding reference cited for known compounds. 2.2. Common Procedure for the Synthesis of Michael Adducts An equimolar mixture of secondary amine (15-18, 4 mmol) and dienophile (2/3, 4 mmol) in 20 mL of dichloromethane (DCM) was stirred for about 10 minutes at RT. Progress of the reaction was monitored by TLC. When the reaction was complete, solvent was removed under reduced
4
pressure. The Michael adduct (15-18a/b) obtained was purified by passing through a silica gel plug using hexane-DCM mixture. 2.3. Common Procedure for the Reaction of Michael Adducts in Acetic Acid a. With dienophile:A solution (0.15 mol) of Michael adduct (15-18a/b, 1.5 mmol) was refluxed with dienophile (2/3, 3 mmol) in 10 mL acetic acid and the progress of the reaction was monitored by TLC. When the reaction was complete, the reaction mixture was washed with a saturated solution of sodium bicarbonate and extracted with DCM. Organic extracts were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. If there were products other than polymeric material, was purified by column chromatography on silica gel using hexane-ethylacetate mixture. b. Without dienophile:A solution (0.15 mol) of Michael adduct (15-18a/b, 1.5 mmol) was refluxed in 10 mL acetic acid and the progress of the reaction was monitored by TLC. The rate of the reaction was very slow compared to the above reactions. After 10h, the reaction mixture was washed with a saturated solution of sodium bicarbonate and extracted with DCM. Organic extracts were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. If there were products other than the reactant and polymeric material, they were purified by column chromatography on silica gel using hexane-ethylacetate mixture. This reaction was repeated under RT to reduce the polymerization. Decomposition of Michael adducts (15-18a/b) without dienophile (2/3) yielded the same products as in the reaction with dienophile. Only the rates of the reactions are different and hence the product yield. 3. Data, value and validation Michael adducts were synthesised by stirring secondary amine (15-18) and dienophile (2/3) under room temperature (Scheme 4). After 10 minutes we could easily separate the Michael adduct (15-18a/b) in high yield (Chart 1).
Scheme 4. Reaction of secondary amine with dienophiles
Chart 1. List of selected secondary amines and Michael adducts.
5
When the directly synthesized Michael adducts (15-18a/b) were refluxed with two equivalents of DMAD (2) in acetic acid, the reaction was completed in 4h. Michael adducts underwent extensive decomposition and we could not separate any products from the reaction mixtures. Extensive decomposition of Michael adducts to intractable mixture was observed even when the adducts were refluxed with acetic acid in the absence of DMAD (Scheme 5). From these results, we could neither confirm nor rule out the involvement of Michael adducts in the course of the reaction.
Scheme 5. Reaction of Michael adducts (15-17a) in acetic acid. The story is different in the case of fourth adduct 18a. After 4h, the reaction of 18a with DMAD (2) yielded 6, 7 and 8 along with polymeric materials. But here also we could not isolate the amine component. Similar products may be formed in the decomposition of 15-17a, but the products formed are volatile and hence escaped before isolation/detection. We repeated the above procedure using DBA adducts (15-17b). Refluxing Michael adducts (15-17b) with DBA (3) in acetic acid for about 4h results in 2-hydroxydibenzoylethylene (12) and polymerised materials. Michael adduct 18b also reacted in the same way yielded 12, along with 6, 7 and 8. This result shows that 12 is formed from Michael adducts 15-18b.
Scheme 6. Reaction mechanism of 15-17b in acetic acid We have repeated the reactions of 15-18a/b with and without dienophiles, both in thermal and room temperature. Rate of the reactions are very low under above conditions and yielded same products along with unreacted starting materials in different yields. Consequently, it is possible that Michael adducts are generated in the reaction between anthracenemethanamines and DBA but go undetected due to fast decomposition. Furthermore, generation of Michael adducts mandates zwitterion 13b as a possible intermediate in the reaction of 1 with DBA (3). We further argue that what is true for DBA reaction should be true for DMAD reaction as well. Hence, we can safely argue that zwitterion 13a is a possible intermediate in the reaction between 1 and DMAD (2). In addition, we attempted the reactions of 15-18a/b with dienophiles (2/3) in methanol. After14h, we can easily separated the actual amount of Michael adducts 15-18a/b from the reaction mixture. So, there is no reaction between Michael adducts 15-18a/b and dienophiles (2/3) in polar protic medium-methanol. 3.1. 2-hydroxy-1,4-diphenylbut-2-ene-1,4-dione (12) Yellow Solid, Yield 0.19g (54%), mp:- 61-63 °C., IR νmax (KBr):- 3437 cm-1 (O-H), 1677, 1599 cm-1 (C=O), 1265 cm-1 (C-O)., 1H NMR (CDCl3):- 8.15-7.48 (m, 10H), 6.86 (s, 1H)., 13C NMR (CDCl3):- δ 190.5, 187.1, 182.4, 134.3, 134.2, 133.7, 133.5, 130.5, 128.9, 128.7, 127.6, 96.2., MS-FAB:- m/z 253 (M+1), 105., Elemental analysis calculated for C 16H12O3:- C: 76.16, H: 4.80., Found:- C: 76.16, H: 4.79. 3.2. Dimethyl 2-(dimethylamino)maleate (15a) Colourless Solid, Yield 0.16g (91%), mp:- 54-56 °C., IR νmax (KBr):- 1740, 1683 cm-1 (C=O), 1244 cm-1 (C-O)., 1H NMR (CDCl3):- 4.59 (s, 1H), 3.94 (s, 3H), 3.64 (s, 3H), 2.88 (s, 6H)., 13C NMR (CDCl3):- δ 6
168.1, 166.1, 155.2, 84.6, 52.9, 50.8, 39.8., MS-FAB:- m/z 187 (M+), 156, 128., Elemental analysis calculated for C8H13NO4:- C: 51.31, H: 7.00, N: 7.48.,Found:- C: 51.30, H: 7.01, N: 7.49. 3.3. 2-(dimethylamino)-1,4-diphenylbut-2-ene-1,4-dione (15b) Yellow Solid, Yield 0.17g (94%), mp:- 84-86 °C., IR νmax (KBr):- 1652, 1596 cm-1 (C=O)., 1H NMR (CDCl3):- 8.13-7.27 (m, 10H), 5.91 (s, 1H), 2.96 (br s, 6H)., 13C NMR (CDCl3):- δ 186.2, 176.6, 135.9, 135.2, 129.8, 129.0, 128.9, 128.1, 127.7, 93.00, 40.1., MS-FAB:- m/z 279 (M+), 234, 105, 77., Elemental analysis calculated for C18H17NO2:- C: 77.38, H: 6.14, N: 5.02., Found:- C: 77.39, H: 6.15, N: 5.00. 3.4. Dimethyl 2-(3,4-dihydroisoquinolin-2(1H)-yl)maleate (16a) Yellow Viscous Liquid, Yield 0.49g (92%), IR νmax (KBr):- 1739, 1692 cm-1 (C=O), 1150 cm-1 (CO)., 1H NMR (CDCl3):- 7.21-7.14 (m, 4H), 4.76 (s, 1H), 4.31 (s, 2H), 3.86 (s, 3H), 3.56 (s, 3H), 3.38 (t, 2H, J = 6 Hz), 2.86 (t, 2H, J = 5.8 Hz)., 13C NMR (CDCl3):- δ 168.1, 166.1, 154.1, 134.2, 131.8, 128.4, 127.1, 126.7, 126.3, 85.2, 53.1, 50.9, 48.6, 45.5, 29.0., MS-FAB:- m/z 275 (M+)., Elemental analysis calculated for C15H17NO4:- C: 65.43, H: 6.23, N: 5.09., Found:- C: 65.44, H: 6.23, N: 5.09. 3.5. 2-(3,4-dihydroisoquinolin-2(1H)-yl)-1,4-diphenylbut-2-ene-1,4-dione (16b) Yellow Crystals, Yield 0.50g (94%), mp:- 64-66 °C., IR νmax (KBr):- 1675, 1614 cm-1 (C=O)., 1H NMR (CDCl3):- 7.98-7.08 (m, 14H), 6.08 (s, 1H), 4.46-4.58 (br, 2H), 3.45-3.52 (br, 2H), 2.83-2.73 (br, 2H)., 13C NMR (CDCl3):- δ 199.0, 185.9, 159.8, 134.9, 132.4, 130.4, 128.0, 127.1, 127.1, 126.8, 126.3, 125.9, 125.3, 91.9, 48.1, 44.7, 28.7., MS-FAB:- m/z 367 (M+), 132, 105., Elemental analysis calculated for C25H21NO2:- C: 81.72, H: 5.76, N: 3.81., Found:- C: 81.72, H: 5.77, N: 3.81. 3.6. Dimethyl 2-(3,4-dihydroquinolin-1(2H)-yl)maleate (17a) Yellow Viscous Liquid, Yield 0.48g (91%), IR νmax (KBr):- 1741, 1702 cm-1 (C=O), 1147 (C-O)., 1H NMR (CDCl3):- 7.14-7.00 (m, 4H), 5.29 (s, 1H), 3.78 (s, 3H), 3.67 (s, 3H), 3.47 (t, 2H, J = 6.6 Hz), 2.71 (t, 2H, J = 6.2 Hz), 1.99 (quin, 2H, J = 6.4 Hz)., 13C NMR (CDCl3):- δ 167.6, 165.8, 152.3, 139.6, 132.6, 128.5, 126.6, 124.6, 122.1, 93.7, 52.7, 51.1, 48.7, 26.8, 24.1., MS-FAB:- m/z 275 (M+)., Elemental analysis calculated for C15H17NO4:- C: 65.44, H: 6.22, N: 5.09., Found:- C: 65.43, H: 6.23, N: 5.09. 3.7. 2-(3,4-dihydroquinolin-1(2H)-yl)-1,4-diphenylbut-2-ene-1,4-dione (17b) Yellow Crystals, Yield 0.49g (93%), mp:- 68-70 °C., IR νmax (KBr):- 1678, 1617 cm-1 (C=O)., 1H NMR (CDCl3):- 8.03-7.04 (m, 14H), 6.67 (s, 1H), 3.54 (t, 2H, J = 6.2 Hz), 2.74 (t, 2H, J = 6.6 Hz), 1.99 (quin, J = 6.4 Hz)., 13C NMR (CDCl3):- δ 193.8, 187.7, 159.0, 139.6, 138.8, 136.2, 133.2, 132.7, 131.7, 129.2, 128.8, 128.2, 128.1, 127.9, 126.3, 125.4, 124.2, 99.5, 48.4, 26.4, 24.0., MS-FAB:- m/z 279 (M+), 234, 105, 77., Elemental analysis calculated for C25H21NO2:- C: 81.72, H: 5.76, N: 3.81., Found:- C: 81.71, H: 5.76, N: 3.81. 3.8. Dimethyl 2-((anthracen-9-ylmethyl)(butyl)amino)maleate (18a) Off White Solid, Yield 0.97g (92%), IR νmax (KBr):- 1739, 1692 cm-1 (C=O), 1155 cm-1 (C-O)., 1H NMR (CDCl3):- 8.28-7.25 (m, 9H), 4.99 (s, 2H), 4.78 (s, 1H), 3.78 (s, 3H), 3.50 (s, 3H), 2.38 (t, 2H, J = 8.2 Hz), 1.00-1.04 (m, 2H), 0.44-0.54 (m, 2H), 0.16 (t, 3H, J = 7.4 Hz)., 13C NMR (CDCl3):- δ 168.4, 166.3, 154.9, 131.5, 131.3, 129.3, 129.2, 127.1, 125.3, 124.9, 123.6, 85.4, 53.0, 50.9, 47.2, 45.8, 19.6, 13.1., MS-FAB:- m/z 405 (M+), 191., Elemental analysis calculated for C 25H27NO4:- C: 74.03, H: 6.72, N: 3.46., Found:- C: 74.04, H: 6.71, N: 3.47. 3.9. 2-((anthracen-9-ylmethyl)(butyl)amino)-1,4-diphenylbut-2-ene-1,4-dione (18b) Yellow Crystals, Yield 0.99g (94%), mp:- 135-137 °C., IR νmax (KBr):- 1682, 1619 cm-1 (C=O)., 1H NMR (CDCl3):- 8.51-7.36 (m, 19H), 6.50 (br s, 1H), 5.58 (br s, 1H), 2.74-2.47 (br, 2H), 1.47-1.32 (br, 2H), 0.73 (br, 2H), 0.36 (br, 3H)., 13C NMR (CDCl3):- δ 186.9, 139.4, 136.0, 131.4, 131.3, 129.5, 129.3, 128.9, 128.4, 128.2, 127.8, 127.1, 125.3, 124.9, 123.6, 93.7, 19.6, 13.0., MS-FAB:- m/z 497 (M+), 105., 7
Elemental analysis calculated for C35H31NO2:- C: 84.47, H: 6.28, N: 2.82., Found:- C: 84.48, H: 6.29, N: 2.81. 4. Conclusion Hence we concluded that, the reaction between anthracenmethanamines and dienophiles in acetic acid proceed through initial Michael type addition pathway generating zwitterionic intermediates identical to those observed in the methanol reaction. Major difference here is that Michael adducts undergo fast decomposition and hence elude detection in refluxing acetic acid. Decomposition of Michael adducts is accelerated by dienophile present in the reaction medium. Acknowledgements Financial support for this work was provided by DST (PURSE and FIST schemes), UGC (SAP), and Kerala Government. We thank STIC, Kochi for NMR and elemental analysis. We gratefully acknowledge CUSAT and Kerala Government financial support in the form of Research Fellowships.
Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References [1] J. P. Jacob, L. M. Lalu, R. Gopalakrishnan, R. R. Mallia, S. Prathapan, P. A. Unnikrishnan, Facile one-pot method for the synthesis of arylmethanamines, J. Adv. Res. Appl. Chem. Chem. Eng. 1 (2014) 1-9. https://science.adrpublications.in/index.php/ADR-Journal-ChemistryChemEng/article/view/30/0 [2] J. P. Jacob, R. Gopalakrishnan, R. R. Mallia, J. J. Vadakkan, P. A.Unnikrishnan, S. Prathapan, Dramatic solvent and concentration dependence in the reaction of (anthracen‐9‐ yl)methanamines with suitable electron‐deficient acetylenes, J. Phys. Org. Chem. 27 (2014) 884891. https://doi.org/10.1002/poc.3351 [3] T. Devassia, J. P. Jacob, P. A. Unnikrishnan, Single electron transfer vs Diels Alder reaction: A comparative study of the reaction of 1-(anthracen-9-yl)-N,N-dimethylmethanamine and (anthracen-9-ylmethyl)(methyl)sulfane with dibenzoylethylene, Adv. Org. Chem. Lett. 6 (2019) 13‐16. http://www.pubs.iscience.in/journal/index.php/ocl/article/view/898/588 [4] U. Amrutha, A. Jesna, J. P. Jacob, Novel Diels–Alder adducts formed in the reaction between a few anthracenemethanamines and electron deficient dienophiles, Chemical Data Collections 23 (2019) 100266-100272. https://doi.org/10.1016/j.cdc.2019.100266 [5] J. P. Jacob, L. M. Lalu, R. Gopalakrishnan, R. R. Mallia, P. A. Unnikrishnan, S. Prathapan, Ground and excited-state electron-transfer reactions of a few (anthracen-9-yl)methanamines: a comparative study, ARKIVOC vii (2015) 270-283. http://dx.doi.org/10.3998/ark.5550190.p009.340 [6] A. M. Sarotti, M. M. Joullie, R. A. Spanevello, A. G. Suarez, Microwave-Assisted Regioselective Cycloaddition Reactions between 9-Substituted Anthracenes and Levoglucosenone, Org. Lett. 8 (2006) 5561-5564. https://pubs.acs.org/doi/pdf/10.1021/ol062254g
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[7] J. Liu, G.-H. Wei, G. -J. Ping, J. –F. Ma, 9‐(Methoxymethyl)anthracene, Acta Cryst. E. 63 (2007) 04442. https://doi.org/10.1107/S1600536807052324 [8] S. A. Taghavi, M. Moghadam, I. Mohammadpoor-Baltork, S. Tangestaninejad, V. Mirkhani, A. R. Khosropour, Investigation of catalytic activity of high-valent vanadium(IV) tetraphenylporphyrin: A new, highly efficient and reusable catalyst for acetylation of alcohols and phenols with acetic anhydride, Inorg. Chim. Acta 377 (2011) 159-164. https://doi.org/10.1016/j.ica.2011.07.036 [9] F. Shirini, M. A. Zolfigol, A. R. Aliakbar, J. Albadi, Efficient Acetylation of Alcohols, Phenols, and Amines Catalyzed by Melamine Trisulfonic Acid (MTSA), Synth. Commun. 40 (2010) 1022-1028. https://doi.org/10.1080/00397910903029941 [10] S. Sayama, Oxidative Conversion of 3‐Alkoxyfurans to 2‐Hydroxy‐3(2H)‐furanones and 2‐ Hydroxy‐2‐butene‐1,4‐diones with 2,3‐Dichloro‐5,6‐dicyano‐1,4‐benzoquinone (DDQ) or Phenyltrimethylammonium Tribromide (PTAB) in t‐BuOH, Synth. Commun. 37 (2007) 3067-3075. https://doi.org/10.1080/00397910701543036 [11] L. G. Voskressensky, T. N. Borisova, T. A. Vorob'eva, A. I. Chernyshev, A. V. Varlamov, Tandem transformations of tetrahydropyrrolo[3,2-c]pyridines under the action of dimethyl acetylenedicarboxylate. A novel route to pyrrolo[2,3-d]azocines. Russian Chemical Bulletin 54 (2005) 2594-2601. https://link.springer.com/article/10.1007/s11172-006-0162-x
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Unusual reactivity of amine-dienophile Michael adducts in polar protic medium-acetic acid Jesna A , Rani Mathew , Jomon P. Jacob PII: DOI: Reference:
S2405-8300(19)30389-1 https://doi.org/10.1016/j.cdc.2019.100318 CDC 100318
To appear in:
Chemical Data Collections
Received date: Revised date: Accepted date:
29 September 2019 28 November 2019 4 December 2019
Please cite this article as: Jesna A , Rani Mathew , Jomon P. Jacob , Unusual reactivity of aminedienophile Michael adducts in polar protic medium-acetic acid, Chemical Data Collections (2019), doi: https://doi.org/10.1016/j.cdc.2019.100318
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.
Highlights Synthesised a few novel Michael adducts Compare the reactivity of Michael adducts in polar protic media-acetic acid and methanol Michael adducts show high reactivity in polar protic medium-acetic acid
1
Title: Unusual reactivity of amine-dienophile Michael adducts in polar protic medium-acetic acid Authors: Jesna A., Rani Mathew and Jomon P. Jacob* Affiliations: Department of Applied Chemistry, Cochin University of Science and Technology, Kochi682 022, Kerala, India. Contact email: [email protected] Abstract A few novel Michael adducts were synthesised and compared their reactivity in two polar protic solvents: acetic acid and methanol. Upon refluxing in acetic acid, Michael adducts underwent extensive decomposition. Decomposition of Michael adducts is accelerated by the dienophile present in the reaction medium. But in methanol, Michael adducts remained unchaged even in the presence of dienophiles. Graphical abstract
Keywords: Michael Dibenzoylacetylene. Specifications Table Subject area Compounds Data category Data acquisition format Data type Procedure Data accessibility
adduct;
Acetic
acid;
Methanol;
Dimethyl
acetylenedicarboxylate;
Organic Chemistry, Spectroscopy. Michael adducts Spectral, Synthesized. 1 H NMR, 13C NMR, IR, Mass spectra, m.p. Process and analysis. Unusual reactivity of amine-dienophile Michael adducts in polar protic medium-acetic acid Data is provided with this article
1. Rationale
2
We have done a detailed study1-5 of the electron transfer reaction of 9-(N,Ndiisopropylaminomethyl)anthracene1 (1) with suitable electron-deficient acetylenes viz dimethyl acetylenedicarboxylate (DMAD, 2) and dibenzoylacetylene (DBA, 3) in different solvents. In polar protic solvent-methanol (highly polar, but low boiling), the reaction of 1 (0.034 mol) with 2 yielded 9(methoxymethyl)anthracene6,7 (4) and N,N-diisopropylaminomaleate (5) in good yields along with 9methylanthracene (6), 9-anthraldehyde (7) and 9,10-anthraquinone (8) in negligible amounts (Scheme 1)2. But the reaction of 1 (0.034 mol) with another electron-deficient acetylene, dibenzoylacetylene (DBA, 3) in methanol yielded 4 and 2-diisopropylaminodibenzoylethylene (9) with trace amounts of 6, 7 and 8 (Scheme 1)2.
Scheme 1. Reaction of 9-(N,N-diisopropylaminomethyl)anthracene with dienophiles in methanol To study the generality of the reaction, we have done the reaction in polar protic solventglacial acetic acid2 (intermediate polarity and boiling point). We refluxed 0.034 mol solution of 1 with 2 and the result of the reaction was surprising. After 10h, we obtained (anthracen-9-yl)methyl acetate8,9 (10) and 2-(anthracen-9-ylmethyl)dimethyl-3-oxosuccinate (11) along with trace amounts of 6, 7 and 8 (Scheme 2)2. It may be noted here that 5 was not present in detectable amounts in the reaction mixture. Reaction of 0.034 mol solution of 1 with 2 equivalents of 3 was completed in 10h yielded 10, 2-hydroxydibenzoylethylene10 (12) along with trace amounts of 6, 7 and 8 (Scheme 2)2.
Scheme 2. Reaction of 9-(N,N-diisopropylaminomethyl)anthracene with dienophiles in acetic acid Above reactions may proceeded through the same intermediate and was realized from the formation of products 4 and 10. So, we proposed that the above reactions take place through the nucleophilic attack of amine 1 on dienophiles (2/3) in a Michael type addition pathway giving rise to a Michael adduct/ zwitterion11 13a/b. This leads to the weakening and eventual cleavage of C-N 3
bond giving rise to 9-anthracenemethyl cation (14) and 5 or 9 (Scheme 3). 9-Anthracenemethyl cation (14) formed is captured by the solvent to give the correspornding products 4 and 10.
Scheme 3. Mechanism of 1 with 2/3 in polar protic media. If the reaction of 1 with 2/3 in acetic acid, proceeds through the above mechanism, Michael adduct 5/9 should also be generated. With a view to ascertain this possibility, we carried out GC-MS and NMR analyses of the crude product mixture. The results indicated the absence of Michael adducts 5/9 in the reaction mixture. So we concluded that 5 or 9 are either not formed or undergo further transformations under the reaction conditions employed by us. To discount the latter possibility, we treated independently synthesized Michael adducts by supplying same conditions of acetic acid reactions. 2. Procedure 2.1. Materials and method All reactions were carried out using oven dried glasswares. All experiments were performed in distilled and dried solvents by using standard protocols. All starting materials were purchased from either Sigma-Aldrich or Spectrochem Chemicals and were used without further purification. Progress of the reaction and chromatographic separations were monitored by TLC over dried and activated silica gel TLC plates (Aluminium sheets coated with silica gel, E. Merck). Visualisation of TLC plates was acquired by exposure to iodine vapours or UV lamp. Separation and purification of compounds were done by column chromatography using either silica gel (Spectrochem Chemicals, 60-120 mesh) or neutral alumina (Spectrochem Chemicals). The products were further purified by recrystallization from suitable solvent systems. Solvent eluted from the column chromatography was concentrated using Heidolph rotary evaporator. Melting points are uncorrected and were determined on a Neolab melting point apparatus. Infra-red spectra were recorded using Jasco 4100 and ABB Bomem (MB Series) FT-IR spectrometers. The 1H and 13C NMR spectra of noval comounds in CDCl3 were recorded at 400 MHz Bruker Avance III FT-NMR spectrometer with tetramethylsilane (TMS) as internal standard. Chemical shifts (δ) are reported in parts per million (ppm) downfield of TMS. Elemental analysis was performed using Elementar Systeme (Vario EL III). Molecular mass was determined by fast atom bombardment (FAB) using JMS 600 JEOL mass spectrometer. Here we are giving the spectral and analytical data only for novel compounds and the corresponding reference cited for known compounds. 2.2. Common Procedure for the Synthesis of Michael Adducts An equimolar mixture of secondary amine (15-18, 4 mmol) and dienophile (2/3, 4 mmol) in 20 mL of dichloromethane (DCM) was stirred for about 10 minutes at RT. Progress of the reaction was monitored by TLC. When the reaction was complete, solvent was removed under reduced
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pressure. The Michael adduct (15-18a/b) obtained was purified by passing through a silica gel plug using hexane-DCM mixture. 2.3. Common Procedure for the Reaction of Michael Adducts in Acetic Acid a. With dienophile:A solution (0.15 mol) of Michael adduct (15-18a/b, 1.5 mmol) was refluxed with dienophile (2/3, 3 mmol) in 10 mL acetic acid and the progress of the reaction was monitored by TLC. When the reaction was complete, the reaction mixture was washed with a saturated solution of sodium bicarbonate and extracted with DCM. Organic extracts were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. If there were products other than polymeric material, was purified by column chromatography on silica gel using hexane-ethylacetate mixture. b. Without dienophile:A solution (0.15 mol) of Michael adduct (15-18a/b, 1.5 mmol) was refluxed in 10 mL acetic acid and the progress of the reaction was monitored by TLC. The rate of the reaction was very slow compared to the above reactions. After 10h, the reaction mixture was washed with a saturated solution of sodium bicarbonate and extracted with DCM. Organic extracts were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. If there were products other than the reactant and polymeric material, they were purified by column chromatography on silica gel using hexane-ethylacetate mixture. This reaction was repeated under RT to reduce the polymerization. Decomposition of Michael adducts (15-18a/b) without dienophile (2/3) yielded the same products as in the reaction with dienophile. Only the rates of the reactions are different and hence the product yield. 3. Data, value and validation Michael adducts were synthesised by stirring secondary amine (15-18) and dienophile (2/3) under room temperature (Scheme 4). After 10 minutes we could easily separate the Michael adduct (15-18a/b) in high yield (Chart 1).
Scheme 4. Reaction of secondary amine with dienophiles
Chart 1. List of selected secondary amines and Michael adducts.
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When the directly synthesized Michael adducts (15-18a/b) were refluxed with two equivalents of DMAD (2) in acetic acid, the reaction was completed in 4h. Michael adducts underwent extensive decomposition and we could not separate any products from the reaction mixtures. Extensive decomposition of Michael adducts to intractable mixture was observed even when the adducts were refluxed with acetic acid in the absence of DMAD (Scheme 5). From these results, we could neither confirm nor rule out the involvement of Michael adducts in the course of the reaction.
Scheme 5. Reaction of Michael adducts (15-17a) in acetic acid. The story is different in the case of fourth adduct 18a. After 4h, the reaction of 18a with DMAD (2) yielded 6, 7 and 8 along with polymeric materials. But here also we could not isolate the amine component. Similar products may be formed in the decomposition of 15-17a, but the products formed are volatile and hence escaped before isolation/detection. We repeated the above procedure using DBA adducts (15-17b). Refluxing Michael adducts (15-17b) with DBA (3) in acetic acid for about 4h results in 2-hydroxydibenzoylethylene (12) and polymerised materials. Michael adduct 18b also reacted in the same way yielded 12, along with 6, 7 and 8. This result shows that 12 is formed from Michael adducts 15-18b.
Scheme 6. Reaction mechanism of 15-17b in acetic acid We have repeated the reactions of 15-18a/b with and without dienophiles, both in thermal and room temperature. Rate of the reactions are very low under above conditions and yielded same products along with unreacted starting materials in different yields. Consequently, it is possible that Michael adducts are generated in the reaction between anthracenemethanamines and DBA but go undetected due to fast decomposition. Furthermore, generation of Michael adducts mandates zwitterion 13b as a possible intermediate in the reaction of 1 with DBA (3). We further argue that what is true for DBA reaction should be true for DMAD reaction as well. Hence, we can safely argue that zwitterion 13a is a possible intermediate in the reaction between 1 and DMAD (2). In addition, we attempted the reactions of 15-18a/b with dienophiles (2/3) in methanol. After14h, we can easily separated the actual amount of Michael adducts 15-18a/b from the reaction mixture. So, there is no reaction between Michael adducts 15-18a/b and dienophiles (2/3) in polar protic medium-methanol. 3.1. 2-hydroxy-1,4-diphenylbut-2-ene-1,4-dione (12) Yellow Solid, Yield 0.19g (54%), mp:- 61-63 °C., IR νmax (KBr):- 3437 cm-1 (O-H), 1677, 1599 cm-1 (C=O), 1265 cm-1 (C-O)., 1H NMR (CDCl3):- 8.15-7.48 (m, 10H), 6.86 (s, 1H)., 13C NMR (CDCl3):- δ 190.5, 187.1, 182.4, 134.3, 134.2, 133.7, 133.5, 130.5, 128.9, 128.7, 127.6, 96.2., MS-FAB:- m/z 253 (M+1), 105., Elemental analysis calculated for C 16H12O3:- C: 76.16, H: 4.80., Found:- C: 76.16, H: 4.79. 3.2. Dimethyl 2-(dimethylamino)maleate (15a) Colourless Solid, Yield 0.16g (91%), mp:- 54-56 °C., IR νmax (KBr):- 1740, 1683 cm-1 (C=O), 1244 cm-1 (C-O)., 1H NMR (CDCl3):- 4.59 (s, 1H), 3.94 (s, 3H), 3.64 (s, 3H), 2.88 (s, 6H)., 13C NMR (CDCl3):- δ 6
168.1, 166.1, 155.2, 84.6, 52.9, 50.8, 39.8., MS-FAB:- m/z 187 (M+), 156, 128., Elemental analysis calculated for C8H13NO4:- C: 51.31, H: 7.00, N: 7.48.,Found:- C: 51.30, H: 7.01, N: 7.49. 3.3. 2-(dimethylamino)-1,4-diphenylbut-2-ene-1,4-dione (15b) Yellow Solid, Yield 0.17g (94%), mp:- 84-86 °C., IR νmax (KBr):- 1652, 1596 cm-1 (C=O)., 1H NMR (CDCl3):- 8.13-7.27 (m, 10H), 5.91 (s, 1H), 2.96 (br s, 6H)., 13C NMR (CDCl3):- δ 186.2, 176.6, 135.9, 135.2, 129.8, 129.0, 128.9, 128.1, 127.7, 93.00, 40.1., MS-FAB:- m/z 279 (M+), 234, 105, 77., Elemental analysis calculated for C18H17NO2:- C: 77.38, H: 6.14, N: 5.02., Found:- C: 77.39, H: 6.15, N: 5.00. 3.4. Dimethyl 2-(3,4-dihydroisoquinolin-2(1H)-yl)maleate (16a) Yellow Viscous Liquid, Yield 0.49g (92%), IR νmax (KBr):- 1739, 1692 cm-1 (C=O), 1150 cm-1 (CO)., 1H NMR (CDCl3):- 7.21-7.14 (m, 4H), 4.76 (s, 1H), 4.31 (s, 2H), 3.86 (s, 3H), 3.56 (s, 3H), 3.38 (t, 2H, J = 6 Hz), 2.86 (t, 2H, J = 5.8 Hz)., 13C NMR (CDCl3):- δ 168.1, 166.1, 154.1, 134.2, 131.8, 128.4, 127.1, 126.7, 126.3, 85.2, 53.1, 50.9, 48.6, 45.5, 29.0., MS-FAB:- m/z 275 (M+)., Elemental analysis calculated for C15H17NO4:- C: 65.43, H: 6.23, N: 5.09., Found:- C: 65.44, H: 6.23, N: 5.09. 3.5. 2-(3,4-dihydroisoquinolin-2(1H)-yl)-1,4-diphenylbut-2-ene-1,4-dione (16b) Yellow Crystals, Yield 0.50g (94%), mp:- 64-66 °C., IR νmax (KBr):- 1675, 1614 cm-1 (C=O)., 1H NMR (CDCl3):- 7.98-7.08 (m, 14H), 6.08 (s, 1H), 4.46-4.58 (br, 2H), 3.45-3.52 (br, 2H), 2.83-2.73 (br, 2H)., 13C NMR (CDCl3):- δ 199.0, 185.9, 159.8, 134.9, 132.4, 130.4, 128.0, 127.1, 127.1, 126.8, 126.3, 125.9, 125.3, 91.9, 48.1, 44.7, 28.7., MS-FAB:- m/z 367 (M+), 132, 105., Elemental analysis calculated for C25H21NO2:- C: 81.72, H: 5.76, N: 3.81., Found:- C: 81.72, H: 5.77, N: 3.81. 3.6. Dimethyl 2-(3,4-dihydroquinolin-1(2H)-yl)maleate (17a) Yellow Viscous Liquid, Yield 0.48g (91%), IR νmax (KBr):- 1741, 1702 cm-1 (C=O), 1147 (C-O)., 1H NMR (CDCl3):- 7.14-7.00 (m, 4H), 5.29 (s, 1H), 3.78 (s, 3H), 3.67 (s, 3H), 3.47 (t, 2H, J = 6.6 Hz), 2.71 (t, 2H, J = 6.2 Hz), 1.99 (quin, 2H, J = 6.4 Hz)., 13C NMR (CDCl3):- δ 167.6, 165.8, 152.3, 139.6, 132.6, 128.5, 126.6, 124.6, 122.1, 93.7, 52.7, 51.1, 48.7, 26.8, 24.1., MS-FAB:- m/z 275 (M+)., Elemental analysis calculated for C15H17NO4:- C: 65.44, H: 6.22, N: 5.09., Found:- C: 65.43, H: 6.23, N: 5.09. 3.7. 2-(3,4-dihydroquinolin-1(2H)-yl)-1,4-diphenylbut-2-ene-1,4-dione (17b) Yellow Crystals, Yield 0.49g (93%), mp:- 68-70 °C., IR νmax (KBr):- 1678, 1617 cm-1 (C=O)., 1H NMR (CDCl3):- 8.03-7.04 (m, 14H), 6.67 (s, 1H), 3.54 (t, 2H, J = 6.2 Hz), 2.74 (t, 2H, J = 6.6 Hz), 1.99 (quin, J = 6.4 Hz)., 13C NMR (CDCl3):- δ 193.8, 187.7, 159.0, 139.6, 138.8, 136.2, 133.2, 132.7, 131.7, 129.2, 128.8, 128.2, 128.1, 127.9, 126.3, 125.4, 124.2, 99.5, 48.4, 26.4, 24.0., MS-FAB:- m/z 279 (M+), 234, 105, 77., Elemental analysis calculated for C25H21NO2:- C: 81.72, H: 5.76, N: 3.81., Found:- C: 81.71, H: 5.76, N: 3.81. 3.8. Dimethyl 2-((anthracen-9-ylmethyl)(butyl)amino)maleate (18a) Off White Solid, Yield 0.97g (92%), IR νmax (KBr):- 1739, 1692 cm-1 (C=O), 1155 cm-1 (C-O)., 1H NMR (CDCl3):- 8.28-7.25 (m, 9H), 4.99 (s, 2H), 4.78 (s, 1H), 3.78 (s, 3H), 3.50 (s, 3H), 2.38 (t, 2H, J = 8.2 Hz), 1.00-1.04 (m, 2H), 0.44-0.54 (m, 2H), 0.16 (t, 3H, J = 7.4 Hz)., 13C NMR (CDCl3):- δ 168.4, 166.3, 154.9, 131.5, 131.3, 129.3, 129.2, 127.1, 125.3, 124.9, 123.6, 85.4, 53.0, 50.9, 47.2, 45.8, 19.6, 13.1., MS-FAB:- m/z 405 (M+), 191., Elemental analysis calculated for C 25H27NO4:- C: 74.03, H: 6.72, N: 3.46., Found:- C: 74.04, H: 6.71, N: 3.47. 3.9. 2-((anthracen-9-ylmethyl)(butyl)amino)-1,4-diphenylbut-2-ene-1,4-dione (18b) Yellow Crystals, Yield 0.99g (94%), mp:- 135-137 °C., IR νmax (KBr):- 1682, 1619 cm-1 (C=O)., 1H NMR (CDCl3):- 8.51-7.36 (m, 19H), 6.50 (br s, 1H), 5.58 (br s, 1H), 2.74-2.47 (br, 2H), 1.47-1.32 (br, 2H), 0.73 (br, 2H), 0.36 (br, 3H)., 13C NMR (CDCl3):- δ 186.9, 139.4, 136.0, 131.4, 131.3, 129.5, 129.3, 128.9, 128.4, 128.2, 127.8, 127.1, 125.3, 124.9, 123.6, 93.7, 19.6, 13.0., MS-FAB:- m/z 497 (M+), 105., 7
Elemental analysis calculated for C35H31NO2:- C: 84.47, H: 6.28, N: 2.82., Found:- C: 84.48, H: 6.29, N: 2.81. 4. Conclusion Hence we concluded that, the reaction between anthracenmethanamines and dienophiles in acetic acid proceed through initial Michael type addition pathway generating zwitterionic intermediates identical to those observed in the methanol reaction. Major difference here is that Michael adducts undergo fast decomposition and hence elude detection in refluxing acetic acid. Decomposition of Michael adducts is accelerated by dienophile present in the reaction medium. Acknowledgements Financial support for this work was provided by DST (PURSE and FIST schemes), UGC (SAP), and Kerala Government. We thank STIC, Kochi for NMR and elemental analysis. We gratefully acknowledge CUSAT and Kerala Government financial support in the form of Research Fellowships.
Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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