- Email: [email protected]
An efficient pseudo-seven component reaction for the synthesis of fully-substituted furans containing pseudopeptide based on the union of multicomponent reactions
Journal Pre-proofs An efficient pseudo-seven component reaction for the synthesis of fully-substituted furans containing pseudopeptide base on the union of multicomponent reactions Mohammad Taghi Nazeri, Reza Mohammadian, Hassan Farhid, Ahmad Shaabani, Behrouz Notash PII: DOI: Reference:
S0040-4039(19)31199-2 https://doi.org/10.1016/j.tetlet.2019.151408 TETL 151408
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
1 October 2019 12 November 2019 14 November 2019
Please cite this article as: Nazeri, M.T., Mohammadian, R., Farhid, H., Shaabani, A., Notash, B., An efficient pseudo-seven component reaction for the synthesis of fully-substituted furans containing pseudopeptide base on the union of multicomponent reactions, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151408
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 Ltd.
An efficient pseudo-seven component reaction for the synthesis of fullysubstituted furans containing pseudopeptide base on the union of multicomponent reactions Mohammad Taghi Nazeri,a Reza Mohammadian,a Hassan Farhid,a Ahmad Shaabani,a Behrouz Notasha a
Faculty of Chemistry, Shahid Beheshti University, G.C., P.O. Box 19396-4716, Tehran, Iran
Abstract An atom, step, and energy economic approach based on the union of multicomponent reactions (MCRs) is reported to create higher-order MCRs with unique possibilities for complexity generation of fully-substituted furan derivatives containing pseudopeptidic groups. The unprecedented seven component reaction resulting from implementation of this strategy, provides very complex and valuable scaffolds with several diversity points and up to ten novel bond formations in a one-pot process. This new protocol has proven to be an appropriate green method for the synthesis of biologically relevant furans with extraordinary functional-group from readily available starting materials.
Keywords: Furans; Multicomponent reactions; Pseudopeptide
Corresponding author. Tel.: +982129902800; e-mail: [email protected]
1
Introduction The union of MCRs is a strategy for the rational design and discovering novel MCRs by combining two or more different types of MCRs in a single-pot process, which was firstly introduced by Dömling and Ugi in 1993.1 Significant efforts have been manifested for investigation of various aspects of this novel strategy in drug discovery and pharmaceutical sciences.2 The key point in this strategy is the presence of orthogonal reactivity of functional groups in the product of the primary MCR, which provides the occurrence of the secondary MCR.3 The orthogonal reactivity of functional groups in sequential MCRs avoids the use of protective groups, multiple work-up and increase efficiency in organic synthesis. Over the past 25 years, research in this area has been rising and an incredible range of novel and valuable scaffolds has been produced.4 Nevertheless, the true combination of MCRs in a one-pot manner is generally not possible due to limitations which are arises from experimental procedure, required (de)protection steps and solvent incompatibilities between two MCRs.3 Therefore, with these limitations, designing novel approaches that combine two or more MCRs in one-pot process, which display solvent compatibilities without (de)protection steps would be beneficial. Furans have been known as the important classes of five membered heterocycles, which can be broadly found in many biologically active compounds and natural products.5 Among them, fullysubstituted furans have found widespread application in agrochemicals, chemical industry, functional materials, biological studies, and pharmaceuticals (Figure 1).6 In addition, the peptidesfused heterocyclic skeletons in one structure have been discovered in various biologically occurring compounds.6c, 7
2
Figure 1. Substituted furan derived natural products and drugs
For these reasons, the investigation of novel and more efficient methods for the synthesis of mono, di-, tri-, and fully-substituted furans remain a challenge in combinatorial chemistry.8 Nowadays, several well-established modern methods such as iodocyclization,9 intramolecular cyclization of allenes, propargylic alcohols and alkyne catalyzed by Cu, Ru, Au, Ag, Pd, and Zn,10 transitionmetal-catalyzed vinylic C−H activation/[4 + 2] o-annulation of α-aryl enones,11 and iron-catalyzed oxidative C−H functionalization of internal olefins (Scheme 1) are reported for producing substituted furans.12 However, some of these methods are not economically feasible due to the expensive catalyst and the purification process. In this regard, one of the most attractive traditional methods for the synthesis of furan derivatives is multicomponent reactions. In addition, to the best of our knowledge, in modern methods for the synthesis of biologically active furans containing sequential peptide groups is rarely precedent in the literature.5b Antonchick’s work13
Gao’s work11 3
Yu’s work14
Scheme 1. Transition-metal-catalyzed synthesis of substituted furans
In this aspect and also as a part of our ongoing studies about the synthesis of valuable organic scaffolds using MCRs,15 herein, we wish to report an atom, step, and energy economic approach based on the union of MCRs to achieve higher-order MCRs with unique possibilities for complexity generation of fully-substituted furan derivatives containing pseudopeptidic groups in a one-pot process (Scheme 2). This new protocol which is based on two recently reported MCRs,16 demonstrates extraordinary functional-group and solvent compatibilities.
Scheme 2. Union of MCRs for the synthesis of fully-substituted furans
Results and discussion Initially, we focused on the introduction of a carboxylic acid function on a pseudopeptidic scaffold produced by the primary MCR and using it as one of the starting materials of the secondary MCR. Thus, the reaction of Meldrum's acid 1, 4-nitrobenzaldehyde 2a, and cyclohexyl isocyanide 3a in equal mixture of water and acetonitrile at 70 ˚C led to a clean conversion to form intermediate A.16 Subsequently, a one-pot combination with dimethyl acetylenedicarboxylate (DMAD) 4b, and two 4
equivalents of cyclohexyl isocyanide 3a at the same initial temperature in an Ugi-type 4CR17 afforded 5d after 10 h with overall yield 75% (Scheme 3).
Scheme 3. Pseudo-seven component reaction for synthesis of the fully-substituted furans
For facilitating the procedure, we attempted to use three equivalents of cyclohexyl isocyanide in the initial step for the synthesis of the compound 5d. The results showed that the addition of three equivalents of cyclohexyl isocyanide at the beginning of the reaction did not change the reaction process. Accordingly, two methods have been reported here for the synthesis of fully-substituted furans 5. For the compounds, which have the same isocyanide components in their structures, three equivalents of a one kind isocyanide were used at the first MCR (method A). While, for the synthesis of scaffolds with diverse isocyanide components, isocyanides were added in a sequential fashion (method B). Having found suitable conditions for the synthesis of fully-substituted furan via the pseudo-seven component reaction, we investigated wide range of substrates (Figure 2). Various aldehydes, isocyanides and acetylenic esters were examined, and in all of the cases good yields were obtained. As shown in Figure 2, a broad other reactive reagent could be employed without significantly effect on the yield of the product of fully-substituted furans.
5
6
Figure 2. Substrate scope for synthesis of fully-substituted furans
Structure of compounds 5a-p was confirmed by their analytical and spectral data. For example, the mass spectra of 5a displayed the molecular ion peak at 602 for M+ consistent with the molecular 7
structure. The IR spectrum of 5a displayed characteristic absorption bands at 3320, 1720 and 1600 cm-1 due to NH and C=O stretching vibrations, respectively. The 1H NMR spectrum of 5a (mixture of rotamers) consisted of signals for the tert-butyl groups (δ= 1.23−1.37 ppm, 27H); three signals with multiple splitting for CH2 (δ= 2.33 ppm, dd, J = 16.8, 7.0 Hz, 0.6H; δ= 2.66-2.86 ppm, m, 1H and δ= 3.25 ppm, dd, J = 16.8, 7.0 Hz, 0.4H); OCH3 (δ= 3.69-3.87 ppm, m, 6H) and CH benzylic (δ= 3.98 ppm, dd, J = 9.2, 4.8 Hz, 1H), and; two broad peaks for the NH groups (δ= 5.66-5.71 ppm, bs, 1H and 6.89 ppm, bs, 1H) and two multiplets for aromatic protons (7.45-753 and 8.108.17 ppm, 4H). The 13C NMR spectrum of 5a (mixture of rotamers) also revealed characteristic signals at 172.47, 172.18, 170.35, 165.03, 164.92, 163.26 and 163.09 due to the presence of various amide and ester groups. Unambiguous evidence for the proposed structure of 5f was finally obtained by single-crystal X-ray-diffraction analysis (Figure 3).
Figure 3. X-ray crystal structure of compound 5f.
The proposed mechanism for the formation of fully-substituted furans 5 is shown in Scheme 4. It is well known that the aromatic aldehyde 2 underwent Knoevenagel condensation with Meldrum’s
8
acid 1 furnishing the corresponding intermediate B.17-18 Iminolactone C was resulted from [1+4] cycloaddition reaction of the isocyanide 3 with intermediate B. In the following, removal of acetone and -CO2H group accompanied with the nucleophilic attack of water led to the acid A.17 The
zwitterionic
intermediate
generated
in-situ
from
the
reaction
of
dialkyl
acetylenedicarboxylates 4 and isocyanide 3 was protonated by acid A and intermediates D and E were created. The imidoyl carboxylate compound F was prepared from the attack of carboxylate anion E to the positively charged ion D. In the following, with the Mumm rearrangement and [1+4] cycloaddition reactions of isocyanide 3, iminolactone G was produced. Finally, the product 5 was provided by tautomerizetion of the intermediate G.19
Scheme 4. Proposed mechanism for the formation of fully-substituted furans.
9
Conclusions In conclusions, we have reported a one-pot pseudo-seven component reaction strategy based on the union of MCRs for the synthesis of fully-substituted furan derivatives with high yields production. This synthetic protocol provides very complex and valuable scaffolds with several diversity points and up to ten novel bond formations under mild reaction conditions. These new compounds broaden the scope of MCRs and may be of potential interest in drug discovery. Acknowledgements We gratefully acknowledge the financial support received from the Iran National Science Foundation (INSF) and the Research Council of Shahid Beheshti University.
References 1 2 3 4 5
6
7
8 9
Dömling, A.; Ugi, I. Ange. Chem. In. Ed. En. 1993, 32, 563-564. Zarganes‐ Tzitzikas, T.; Chandgude, A. L.; Dömling, A. Chem. Rec. 2015, 15, 981996. Elders, N.; van der Born, D.; Hendrickx, L. A. Angew. Chem. Int. Ed. 2009, 48, 5856. (a) Doemling, A.; Herdtweck, E.; Ugi, I. Acta Chem. Scand. 1998, 52, 107-113; (b) Mironov, M. A. QSAR. Comb. Sci. 2006, 25, 423-431. (a) Majumdar, K. C.; Chattopadhyay, S. K. Heterocycl. Natur. prod. synth. 2011; (b) Rajesh, M.; Puri, S.; Kant, R.; Sridhar Reddy, M. Org. Lett. 2016, 18, 4332-4335; (c) Kaur, T.; Wadhwa, P.; Bagchi, S.; Sharma, A. Chem. Commun. 2016, 52, 6958-6976. (a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795-819; (b) Zhang, H.; Padwa, A. Org. Lett. 2006, 8, 247-250; (c) Lee, H.-K.; Chan, K.-F.; Hui, C.-W.; Yim, H.-K.; Wu, X.-W.; Wong, H. N. Pure. Appl. Chem. 2005, 77, 139-143. (a) Kirsch, S. F. Org. Biomol. Chem. 2006, 4, 2076-2080; (b) Liu, K. K.-C.; Sakya, S. M.; O’Donnell, C. J.; Flick, A. C.; Li, J. Bioorg. Med. Chem. 2011, 19, 1136-1154; (c) Banerjee, R.; Kumar, H.; Banerjee, M. Int. J. Rev. Life. Sci. 2012, 2, 7-16; (d) Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2001, 44, 3838-3848; (e) Miao, M.; Xu, H.; Jin, M.; Chen, Z.; Xu, J.; Ren, H. Org. Lett. 2018, 20, 3096-3100. (a) Benary, E. Ber. Dtsch. Chem. Ges. 1911, 44, 489-493; (b) Hergué, N.; Mallet, C.; Touvron, J.; Allain, M.; Leriche, P.; Frere, P. Tetrahedron Lett. 2008, 49, 2425-2428. Okitsu, T.; Nakata, K.; Nishigaki, K.; Michioka, N.; Karatani, M.; Wada, A. J. Org. Chem. 2014, 79, 5914-5920.
10
10
11 12 13 14 15
16 17 18 19
(a) Ryu, T.; Eom, D.; Shin, S.; Son, J.-Y.; Lee, P. H. Org. Lett. 2017, 19, 452-455; (b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199-2238; (c) Dong, J.; Bao, L.; Hu, Z.; Ma, S.; Zhou, X.; Hao, M.; Li, N.; Xu, X. Org. Lett. 2018, 20, 1244-1247; (d) Shiroodi, R. K.; Koleda, O.; Gevorgyan, V. J. Am. Chem. Soc. 2014, 136, 13146-13149. Zhao, Y.; Li, S.; Zheng, X.; Tang, J.; She, Z.; Gao, G.; You, J. Angew. Chem. In. Ed. 2017, 56, 4286-4289. Cao, H.; Zhan, H.; Wu, J.; Zhong, H.; Lin, Y.; Zhang, H. Eur. J. Org. Chem. 2012, 2012, 2318-2322. Manna, S.; Antonchick, A. P. Org. Lett. 2015, 17, 4300-4303. Lou, J.; Wang, Q.; Wu, K.; Wu, P.; Yu, Z. Org. Lett. 2017, 19, 3287-3290. (a) Shaabani, A.; Maleki, A.; Hajishaabanha, F.; Mofakham, H.; Seyyedhamzeh, M.; Mahyari, M.; Ng, S. W. J. Comb. Chem. 2009, 12, 186-190; (b) Shaabani, A.; Maleki, A.; Mofakham, H.; Moghimi-Rad, J. J. Orga. Chem. 2008, 73, 3925-3927; (c) Shaabani, A.; Rezayan, A. H.; Ghasemi, S.; Sarvary, A. Tetrahedron Lett. 2009, 50, 1456-1458; (d) Shaabani, A.; Maleki, A.; Mofakham, H.; Khavasi, H. R. J. Comb. Chem. 2008, 10, 323326; (e) Ghandi, M.; Nazeri, M. T.; Kubicki, M. Tetrahedron 2013, 69, 4979-4989; (f) Hooshmand, S. E.; Ghadari. R; Mohammadian. R; Shaabani, A.; Hamid Reza. Kh.; Chem. Select 2019, 4, 11893–11898. Shaabani, A.; Teimouri, M. B. J. Chem. Res. 2002, 2002, 433-435. Alizadeh, A.; Rostamnia, S.; Hu, M.-L. Synlett 2006, 2006, 1592-1594. Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.; Mazzacani, A.; Sartori, G. Tetrahedron Lett. 2001, 42, 5203-5205. Adib, M.; Sheikhi, E.; Kavoosi, A.; Bijanzadeh, H. R. Tetrahedron 2010, 66, 9263-9269.
11
pseudo-seven component reaction base on the union of multicomponent reactions. Synthesis of fully-substituted furan derivatives containing pseudopeptidic groups. The synthetic protocol provides up to ten novel bond formations.
12
S0040-4039(19)31199-2 https://doi.org/10.1016/j.tetlet.2019.151408 TETL 151408
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
1 October 2019 12 November 2019 14 November 2019
Please cite this article as: Nazeri, M.T., Mohammadian, R., Farhid, H., Shaabani, A., Notash, B., An efficient pseudo-seven component reaction for the synthesis of fully-substituted furans containing pseudopeptide base on the union of multicomponent reactions, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151408
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 Ltd.
An efficient pseudo-seven component reaction for the synthesis of fullysubstituted furans containing pseudopeptide base on the union of multicomponent reactions Mohammad Taghi Nazeri,a Reza Mohammadian,a Hassan Farhid,a Ahmad Shaabani,a Behrouz Notasha a
Faculty of Chemistry, Shahid Beheshti University, G.C., P.O. Box 19396-4716, Tehran, Iran
Abstract An atom, step, and energy economic approach based on the union of multicomponent reactions (MCRs) is reported to create higher-order MCRs with unique possibilities for complexity generation of fully-substituted furan derivatives containing pseudopeptidic groups. The unprecedented seven component reaction resulting from implementation of this strategy, provides very complex and valuable scaffolds with several diversity points and up to ten novel bond formations in a one-pot process. This new protocol has proven to be an appropriate green method for the synthesis of biologically relevant furans with extraordinary functional-group from readily available starting materials.
Keywords: Furans; Multicomponent reactions; Pseudopeptide
Corresponding author. Tel.: +982129902800; e-mail: [email protected]
1
Introduction The union of MCRs is a strategy for the rational design and discovering novel MCRs by combining two or more different types of MCRs in a single-pot process, which was firstly introduced by Dömling and Ugi in 1993.1 Significant efforts have been manifested for investigation of various aspects of this novel strategy in drug discovery and pharmaceutical sciences.2 The key point in this strategy is the presence of orthogonal reactivity of functional groups in the product of the primary MCR, which provides the occurrence of the secondary MCR.3 The orthogonal reactivity of functional groups in sequential MCRs avoids the use of protective groups, multiple work-up and increase efficiency in organic synthesis. Over the past 25 years, research in this area has been rising and an incredible range of novel and valuable scaffolds has been produced.4 Nevertheless, the true combination of MCRs in a one-pot manner is generally not possible due to limitations which are arises from experimental procedure, required (de)protection steps and solvent incompatibilities between two MCRs.3 Therefore, with these limitations, designing novel approaches that combine two or more MCRs in one-pot process, which display solvent compatibilities without (de)protection steps would be beneficial. Furans have been known as the important classes of five membered heterocycles, which can be broadly found in many biologically active compounds and natural products.5 Among them, fullysubstituted furans have found widespread application in agrochemicals, chemical industry, functional materials, biological studies, and pharmaceuticals (Figure 1).6 In addition, the peptidesfused heterocyclic skeletons in one structure have been discovered in various biologically occurring compounds.6c, 7
2
Figure 1. Substituted furan derived natural products and drugs
For these reasons, the investigation of novel and more efficient methods for the synthesis of mono, di-, tri-, and fully-substituted furans remain a challenge in combinatorial chemistry.8 Nowadays, several well-established modern methods such as iodocyclization,9 intramolecular cyclization of allenes, propargylic alcohols and alkyne catalyzed by Cu, Ru, Au, Ag, Pd, and Zn,10 transitionmetal-catalyzed vinylic C−H activation/[4 + 2] o-annulation of α-aryl enones,11 and iron-catalyzed oxidative C−H functionalization of internal olefins (Scheme 1) are reported for producing substituted furans.12 However, some of these methods are not economically feasible due to the expensive catalyst and the purification process. In this regard, one of the most attractive traditional methods for the synthesis of furan derivatives is multicomponent reactions. In addition, to the best of our knowledge, in modern methods for the synthesis of biologically active furans containing sequential peptide groups is rarely precedent in the literature.5b Antonchick’s work13
Gao’s work11 3
Yu’s work14
Scheme 1. Transition-metal-catalyzed synthesis of substituted furans
In this aspect and also as a part of our ongoing studies about the synthesis of valuable organic scaffolds using MCRs,15 herein, we wish to report an atom, step, and energy economic approach based on the union of MCRs to achieve higher-order MCRs with unique possibilities for complexity generation of fully-substituted furan derivatives containing pseudopeptidic groups in a one-pot process (Scheme 2). This new protocol which is based on two recently reported MCRs,16 demonstrates extraordinary functional-group and solvent compatibilities.
Scheme 2. Union of MCRs for the synthesis of fully-substituted furans
Results and discussion Initially, we focused on the introduction of a carboxylic acid function on a pseudopeptidic scaffold produced by the primary MCR and using it as one of the starting materials of the secondary MCR. Thus, the reaction of Meldrum's acid 1, 4-nitrobenzaldehyde 2a, and cyclohexyl isocyanide 3a in equal mixture of water and acetonitrile at 70 ˚C led to a clean conversion to form intermediate A.16 Subsequently, a one-pot combination with dimethyl acetylenedicarboxylate (DMAD) 4b, and two 4
equivalents of cyclohexyl isocyanide 3a at the same initial temperature in an Ugi-type 4CR17 afforded 5d after 10 h with overall yield 75% (Scheme 3).
Scheme 3. Pseudo-seven component reaction for synthesis of the fully-substituted furans
For facilitating the procedure, we attempted to use three equivalents of cyclohexyl isocyanide in the initial step for the synthesis of the compound 5d. The results showed that the addition of three equivalents of cyclohexyl isocyanide at the beginning of the reaction did not change the reaction process. Accordingly, two methods have been reported here for the synthesis of fully-substituted furans 5. For the compounds, which have the same isocyanide components in their structures, three equivalents of a one kind isocyanide were used at the first MCR (method A). While, for the synthesis of scaffolds with diverse isocyanide components, isocyanides were added in a sequential fashion (method B). Having found suitable conditions for the synthesis of fully-substituted furan via the pseudo-seven component reaction, we investigated wide range of substrates (Figure 2). Various aldehydes, isocyanides and acetylenic esters were examined, and in all of the cases good yields were obtained. As shown in Figure 2, a broad other reactive reagent could be employed without significantly effect on the yield of the product of fully-substituted furans.
5
6
Figure 2. Substrate scope for synthesis of fully-substituted furans
Structure of compounds 5a-p was confirmed by their analytical and spectral data. For example, the mass spectra of 5a displayed the molecular ion peak at 602 for M+ consistent with the molecular 7
structure. The IR spectrum of 5a displayed characteristic absorption bands at 3320, 1720 and 1600 cm-1 due to NH and C=O stretching vibrations, respectively. The 1H NMR spectrum of 5a (mixture of rotamers) consisted of signals for the tert-butyl groups (δ= 1.23−1.37 ppm, 27H); three signals with multiple splitting for CH2 (δ= 2.33 ppm, dd, J = 16.8, 7.0 Hz, 0.6H; δ= 2.66-2.86 ppm, m, 1H and δ= 3.25 ppm, dd, J = 16.8, 7.0 Hz, 0.4H); OCH3 (δ= 3.69-3.87 ppm, m, 6H) and CH benzylic (δ= 3.98 ppm, dd, J = 9.2, 4.8 Hz, 1H), and; two broad peaks for the NH groups (δ= 5.66-5.71 ppm, bs, 1H and 6.89 ppm, bs, 1H) and two multiplets for aromatic protons (7.45-753 and 8.108.17 ppm, 4H). The 13C NMR spectrum of 5a (mixture of rotamers) also revealed characteristic signals at 172.47, 172.18, 170.35, 165.03, 164.92, 163.26 and 163.09 due to the presence of various amide and ester groups. Unambiguous evidence for the proposed structure of 5f was finally obtained by single-crystal X-ray-diffraction analysis (Figure 3).
Figure 3. X-ray crystal structure of compound 5f.
The proposed mechanism for the formation of fully-substituted furans 5 is shown in Scheme 4. It is well known that the aromatic aldehyde 2 underwent Knoevenagel condensation with Meldrum’s
8
acid 1 furnishing the corresponding intermediate B.17-18 Iminolactone C was resulted from [1+4] cycloaddition reaction of the isocyanide 3 with intermediate B. In the following, removal of acetone and -CO2H group accompanied with the nucleophilic attack of water led to the acid A.17 The
zwitterionic
intermediate
generated
in-situ
from
the
reaction
of
dialkyl
acetylenedicarboxylates 4 and isocyanide 3 was protonated by acid A and intermediates D and E were created. The imidoyl carboxylate compound F was prepared from the attack of carboxylate anion E to the positively charged ion D. In the following, with the Mumm rearrangement and [1+4] cycloaddition reactions of isocyanide 3, iminolactone G was produced. Finally, the product 5 was provided by tautomerizetion of the intermediate G.19
Scheme 4. Proposed mechanism for the formation of fully-substituted furans.
9
Conclusions In conclusions, we have reported a one-pot pseudo-seven component reaction strategy based on the union of MCRs for the synthesis of fully-substituted furan derivatives with high yields production. This synthetic protocol provides very complex and valuable scaffolds with several diversity points and up to ten novel bond formations under mild reaction conditions. These new compounds broaden the scope of MCRs and may be of potential interest in drug discovery. Acknowledgements We gratefully acknowledge the financial support received from the Iran National Science Foundation (INSF) and the Research Council of Shahid Beheshti University.
References 1 2 3 4 5
6
7
8 9
Dömling, A.; Ugi, I. Ange. Chem. In. Ed. En. 1993, 32, 563-564. Zarganes‐ Tzitzikas, T.; Chandgude, A. L.; Dömling, A. Chem. Rec. 2015, 15, 981996. Elders, N.; van der Born, D.; Hendrickx, L. A. Angew. Chem. Int. Ed. 2009, 48, 5856. (a) Doemling, A.; Herdtweck, E.; Ugi, I. Acta Chem. Scand. 1998, 52, 107-113; (b) Mironov, M. A. QSAR. Comb. Sci. 2006, 25, 423-431. (a) Majumdar, K. C.; Chattopadhyay, S. K. Heterocycl. Natur. prod. synth. 2011; (b) Rajesh, M.; Puri, S.; Kant, R.; Sridhar Reddy, M. Org. Lett. 2016, 18, 4332-4335; (c) Kaur, T.; Wadhwa, P.; Bagchi, S.; Sharma, A. Chem. Commun. 2016, 52, 6958-6976. (a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795-819; (b) Zhang, H.; Padwa, A. Org. Lett. 2006, 8, 247-250; (c) Lee, H.-K.; Chan, K.-F.; Hui, C.-W.; Yim, H.-K.; Wu, X.-W.; Wong, H. N. Pure. Appl. Chem. 2005, 77, 139-143. (a) Kirsch, S. F. Org. Biomol. Chem. 2006, 4, 2076-2080; (b) Liu, K. K.-C.; Sakya, S. M.; O’Donnell, C. J.; Flick, A. C.; Li, J. Bioorg. Med. Chem. 2011, 19, 1136-1154; (c) Banerjee, R.; Kumar, H.; Banerjee, M. Int. J. Rev. Life. Sci. 2012, 2, 7-16; (d) Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2001, 44, 3838-3848; (e) Miao, M.; Xu, H.; Jin, M.; Chen, Z.; Xu, J.; Ren, H. Org. Lett. 2018, 20, 3096-3100. (a) Benary, E. Ber. Dtsch. Chem. Ges. 1911, 44, 489-493; (b) Hergué, N.; Mallet, C.; Touvron, J.; Allain, M.; Leriche, P.; Frere, P. Tetrahedron Lett. 2008, 49, 2425-2428. Okitsu, T.; Nakata, K.; Nishigaki, K.; Michioka, N.; Karatani, M.; Wada, A. J. Org. Chem. 2014, 79, 5914-5920.
10
10
11 12 13 14 15
16 17 18 19
(a) Ryu, T.; Eom, D.; Shin, S.; Son, J.-Y.; Lee, P. H. Org. Lett. 2017, 19, 452-455; (b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199-2238; (c) Dong, J.; Bao, L.; Hu, Z.; Ma, S.; Zhou, X.; Hao, M.; Li, N.; Xu, X. Org. Lett. 2018, 20, 1244-1247; (d) Shiroodi, R. K.; Koleda, O.; Gevorgyan, V. J. Am. Chem. Soc. 2014, 136, 13146-13149. Zhao, Y.; Li, S.; Zheng, X.; Tang, J.; She, Z.; Gao, G.; You, J. Angew. Chem. In. Ed. 2017, 56, 4286-4289. Cao, H.; Zhan, H.; Wu, J.; Zhong, H.; Lin, Y.; Zhang, H. Eur. J. Org. Chem. 2012, 2012, 2318-2322. Manna, S.; Antonchick, A. P. Org. Lett. 2015, 17, 4300-4303. Lou, J.; Wang, Q.; Wu, K.; Wu, P.; Yu, Z. Org. Lett. 2017, 19, 3287-3290. (a) Shaabani, A.; Maleki, A.; Hajishaabanha, F.; Mofakham, H.; Seyyedhamzeh, M.; Mahyari, M.; Ng, S. W. J. Comb. Chem. 2009, 12, 186-190; (b) Shaabani, A.; Maleki, A.; Mofakham, H.; Moghimi-Rad, J. J. Orga. Chem. 2008, 73, 3925-3927; (c) Shaabani, A.; Rezayan, A. H.; Ghasemi, S.; Sarvary, A. Tetrahedron Lett. 2009, 50, 1456-1458; (d) Shaabani, A.; Maleki, A.; Mofakham, H.; Khavasi, H. R. J. Comb. Chem. 2008, 10, 323326; (e) Ghandi, M.; Nazeri, M. T.; Kubicki, M. Tetrahedron 2013, 69, 4979-4989; (f) Hooshmand, S. E.; Ghadari. R; Mohammadian. R; Shaabani, A.; Hamid Reza. Kh.; Chem. Select 2019, 4, 11893–11898. Shaabani, A.; Teimouri, M. B. J. Chem. Res. 2002, 2002, 433-435. Alizadeh, A.; Rostamnia, S.; Hu, M.-L. Synlett 2006, 2006, 1592-1594. Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.; Mazzacani, A.; Sartori, G. Tetrahedron Lett. 2001, 42, 5203-5205. Adib, M.; Sheikhi, E.; Kavoosi, A.; Bijanzadeh, H. R. Tetrahedron 2010, 66, 9263-9269.
11
pseudo-seven component reaction base on the union of multicomponent reactions. Synthesis of fully-substituted furan derivatives containing pseudopeptidic groups. The synthetic protocol provides up to ten novel bond formations.
12