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DOI: 10.1055/a-2422-1263
Lewis Acid Catalyzed Domino Ring-Opening Cyclization of Azetidines with Alkynes: Synthesis of Tetrahydropyridines
M.K.G. is grateful to the Science and Engineering Research Board (SERB), New Delhi and the Indian Institute of Technology (IIT) Kanpur, India for financial support. D.S., A.B., and R.T. thank the IIT Kanpur. B.S. thanks the Council of Scientific and Industrial Research (CSIR), India; S.S. and A.K.S. thank the University Grants Commission (UGC), India for research fellowships.
Dedicated to Prof. B. C. Ranu on the occasion of his 75th birthday
Abstract
A simple strategy for the synthesis of a variety of tetrahydropyridines in good to excellent yields via a Cu(OTf)2 catalyzed quaternary ammonium salt mediated ring-opening of activated azetidines followed by cyclization with alkynes in a domino ring-opening cyclization (DROC) is described. The formation of the products has been explained by an SN2-type ring-opening of azetidines with alkynes.
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Tetrahydropyridine and derivatives are an important class of compounds used as potential therapeutic and pharmacological agents.[1] [2] [3] Many biologically active natural products and other synthetic compounds have been found to possess a 1,2,3,4-tetrahydropyridine core; for example, alkaloids aminocadambines A (1) and B (2), isolated from Neolamarckia cadamba,[3c] and a new group of potent cardiotonic drugs 3a–f [3d] contain this particular ring system (Figure [1]). A number of methodologies have been reported for the synthesis of tetrahydropyridines.[4] [5] Ring-opening cyclization of azetidines constitutes a powerful atom-economic route for the construction of the heterocyclic product.[6] [7] [8] [9] In 2014, Liu et al. reported a silver-catalyzed [4 + 2] cycloaddition of ynamides with azetidines for the synthesis of 2-amino-1,4,5,6-tetrahydropyridines (Scheme [1a])[6g] and later, in 2018, Tehrani et al. reported a Zn(OTf)2-catalyzed cycloaddition of non-activated azetidine with dimethyl acetylenedicarboxylate to give the corresponding carboxylate derivatives (Scheme [1b]).[6i] Recently, we reported Lewis acid (LA) catalyzed SN2-type domino ring-opening cyclization (DROC) of aziridines with alkynes (Scheme [1c]). In a continuation of that, we anticipated that 1,2,3,4-tetrahydropyridines could be constructed from the SN2-type ring-opening followed by cyclization in domino fashion (DROC) of activated 2-arylazetidines by alkynes under appropriate conditions (Scheme [1d]).
Recently, we reported the LA/persistent salt catalyzed/initiated SN2-type ring-opening of enantiopure 2-aryl-N-tosylaziridines and azetidines by a number of nucleophiles to obtain non-racemic products with high enantiomeric excess.[10] Due to partial racemization of the starting aziridines and azetidines, reduced ee were observed in these cases. By using quaternary ammonium salts the racemization processes could be controlled and such reactions took place more efficiently with enhanced stereoselectivity.[11] Exploring and exploiting our original findings in the area of LA-catalyzed SN2-type ring opening of activated small ring aza-heterocycles, we have developed a strategy for the synthesis of 1,2,3,4-tetrahydropyridines via LA-catalyzed quaternary ammonium salt mediated DROC of azetidines with alkynes in very good to high yields. We provide evidence that supports our mechanistic proposal that the reaction proceeds through an SN2-type pathway, contrary to the earlier reports. Herein, we report our preliminary results as a letter.
With a view to obtaining the tetrahydropyridine ring system, we initially studied the reaction of racemic 2-phenyl-N-tosylazetidine (4a) with phenyl acetylene (5a). When the reaction was attempted in the presence of 20 mol% Cu(OTf)2 in dichloromethane at 0 °C, only a trace amount of the corresponding 1,2,3,4-tetrahydropyridine derivative 6a was obtained, along with allyl amine 7a as the major byproduct (Scheme [2]). With a stoichiometric amount of tetrabutylammonium perchlorate (TBAPC) as an additive, the reaction again yielded the desired product 6a in trace amount (Table [1], entry 2). A similar result was obtained with tetrabutylammonium hydrogen sulfate salt. To our great pleasure, 6a was produced in good yield when the reaction was performed in the presence of 20 mol% Cu(OTf)2 as a Lewis acid and stoichiometric amount of tetrabutylammonium hexafluorophosphate (TBAFP) salt (entry 3), with the allyl amine 7a being formed in a trace amount. Other Lewis acids, such as BF3·OEt2, FeCl3, and AgPF6, did not produce encouraging results.
a LA (0.2 equiv) and R4NX (1.0 equiv) were used, and unless noted otherwise all the reactions were performed in dichloromethane as the solvent at 0 °C.
b Yield of the isolated product 6a after column chromatographic purification.
The reaction was generalized with various alkynes 5a–d (Scheme [3]) and in all the cases the corresponding substituted tetrahydropyridines 6a–d were obtained in moderate to high yields.
Further generalization of the approach was made by studying the reaction of different azetidines 4b–e bearing different 2-aryl and N-sulfonyl groups with the alkyne 5a under the same reaction conditions to produce the corresponding tetrahydropyridines 6e–h in high yields; the results are summarized in Scheme [4]. All the products were characterized by spectroscopic and analytical techniques.
To extend the scope of the reaction for the synthesis of chiral tetrahydropyridine, we carried out the DROC of (S)-2-phenyl-N-tosylazetidine 4a with phenylacetylene 5a serving itself as the solvent. The reaction was completed within 2 min at room temperature and, to our surprise, the corresponding tetrahydropyridine 6a was formed in 62% yield and only 7% ee. When the temperature was reduced to 0 °C the ee increased marginally to 11%.
The DROC of disubstituted azetidine trans-(2S,4R)-8a was then studied. When trans-(2S,4R)-8a was treated with 5a in the presence of 20 mol% Cu(OTf)2 and a stoichiometric amount of TBAFP at 0 °C to room temperature (RT) for 1.5 h, the corresponding tetrahydropyridine derivatives trans-(2R,4R)-10a and cis-(2R,4S)-11a were obtained in 40% yield as a mixture of diastereomers (10a/11a, 5:4; Scheme [5]). Reaction with cis-(2S,4S)-8a was found to be very slow and, after 20 h at room temperature, the corresponding tetrahydropyridines (10a′ and 11a′) were obtained as a 3:2 inseparable mixture of trans-(2S,4S)-10a′ and cis-(2S,4R)-11a′ isomers. On the other hand, when the azetidine trans-(2S,4R)-9a was treated with 5a under the same reaction conditions, the corresponding tetrahydropyridine derivatives cis-(2R,4S)-12a and trans-(2R,4R)-13a were obtained in 40% yield as a mixture of diastereomers (12a/13a, 5:3.5; Scheme [5]) in 1.5 h. Reaction with cis-(2S,4S)-9a was again found to be very slow and, after 15 h at room temperature, the corresponding tetrahydropyridines cis-(2S,4R)-12a′ and trans-(2S,4S)-13a′ were obtained as a 5:4.1 inseparable mixture.
Based on the aforementioned results, we conclude that the reaction proceeds through an SN2-type pathway rather than via a stable 1,4-dipolar intermediate as reported previously. The formation of diastereomers in unequal ratios from trans- and cis-azetidines (Scheme [5]) further supports our mechanistic proposal. If the reaction proceeded via a dipolar intermediate, the diastereomeric ratios in both cases must have been equal. Another observation that the disubstituted cis-isomers react with acetylene at a much slower rate compared to the trans-isomers is reasonable considering the steric factors for an SN2-type attack at the more crowded benzylic position (for the cis-isomer).
A plausible mechanism is illustrated in Scheme [6]. During the reaction, Cu(OTf)2 coordinates with the sulfonamide oxygen of the azetidine (S)-4a, generating a highly reactive intermediate 14 or 14′ (generated by coordination of LA with nitrogen) that is stabilized by the tetraalkylammonium salt, and the racemization of (S)-4a via the 1,4-dipolar intermediate 15 is controlled. Phenyl acetylene 5a then attacks at the benzylic carbon to provide the intermediate 16. The intermediate 16 could either cyclize to afford 1,2,3,4-tetrahydropyridine 6a or undergo another SN2-type attack by phenyl acetylene 5a to form the intermediate 17. Probably, 16 is converted into 17 much faster than its intramolecular cyclization to 6a. Possible cyclization from both 16 and 17 leads to the formation of a mixture of enantiomeric products 6a′ and 6a′′, resulting in very poor ee. Furthermore, 16 and 17 likely revert to the corresponding azetidine (R)-4a and (S)-4a, respectively. As a result, (S)-4a is racemized during the course of the reaction in the presence of phenyl acetylene, furnishing product 6a with very poor ee. This mechanistic proposal is supported by the racemization study of (S)-4a in the presence of 5a under the reaction conditions. The ee values of the recovered azetidine 4a were found to be 66% and 55% after 2 and 5 min, respectively, whereas it was not found to decrease with increasing reaction time in the presence of a catalytic amount of Lewis acid and a stoichiometric amount of tetrabutyl ammonium salt.[11a] [12]
|
Time (min) |
(S)-4a (%) at RT |
Time (min) |
(S)-4a (%) at 0 °C |
|
1.5 |
76 |
5 |
92 |
|
2.5 |
52 |
15 |
80 |
|
3.5 |
25 |
25 |
72 |
|
5 |
5 |
35 |
60 |
|
45 |
50 |
||
|
55 |
44 |
||
|
65 |
40 |
||
|
75 |
26 |
||
|
85 |
16 |
Figure 2 Racemization of (S)-4a at RT in dichloromethane
Figure 3 Racemization of (S)-4a at 0 °C in dichloromethane(c)
In conclusion, a convenient route for the synthesis of a variety of tetrahydropyridine derivatives under mild conditions via Cu(OTf)2-catalyzed, TBAFP-mediated regioselective DROC of N-sulfonylazetidines with alkynes has been developed. It has been demonstrated that the LA-catalyzed reaction of N-activated azetidines proceeds via an SN2-type pathway. Poor stereoselectivity of the product has been rationalized by the rapid racemization of the starting enantiopure azetidine and also the formation of enantiomeric intermediates before the cyclization step under the reaction conditions.
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Conflict of Interest
The authors declare no conflict of interest.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2422-1263.
- Supporting Information
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References and Notes
- 1a Dunbar PG, Durant GJ, Rho T, Ojo B, Huzl JJ. III, Smith DA, El-Assadi AA, Sbeih S, Ngur DO, Periyasamy S, Hoss W, Messer WS. Jr. J. Med. Chem. 1994; 37: 2774
- 1b Morale MC, Serra PA, L’Episcopo F, Tirolo C, Caniglia S, Testa N, Gennuso F, Giaquinta G, Rocchitta G, Desole MS, Miele E, Marchetti B. Neuroscience 2006; 138: 869
- 1c Kadieva MG, Oganesyan ÉT, Mutsueva SK. Pharm. Chem. J. 2005; 39: 453
- 1d Xu K, Xu Y, Brown-Jermyn D, Chen J.-F, Ascherio A, Dluzen DE, Schwarzschild MA. J. Neurosci. 2006; 26: 535
- 1e Cawthon D, Soderblom EJ, Xu ZA, Duhart H, Slikker WJr, Ali SF, Goshe MB. Int. J. Neuroprotec. Neuroregener. 2005; 1: 98
- 1f Picon S, Boulahjar R, Hoguet V, Baron M, Duplan I, Vallez E, Hennuyer N, Dumont J, Touche V, Dorchies E, Lasalle M, Descat A, Piveteau C, Biela A, Chaput L, Villoutreix BO, Lipka E, Sevin E, Culot M, Gosselet F, Lestavel S, Roussel P, Deprez-Poulain R, Leroux F, Staels B, Deprez B, Tailleux A, Charton J. J. Med. Chem. 2023; 66: 11732
- 2a Mitch CH, Bymaster FP, Calligaro DO, Quimby SJ, Schoepp DD, Wong DT, Shannon HE. Bioorg. Med. Chem. Lett. 1994; 4: 1721
- 2b Dunbar PG, Durant GJ, Fang Z, Abuh YF, El-Assadi AA, Ngur DO, Periyasamy S, Hoss WP, Messer WS. Jr. J. Med. Chem. 1993; 36: 842
- 2c Olesen PH, Swedberg MD. B, Rimvall K. Bioorg. Med. Chem. 1998; 6: 1623
- 2d Glase SA, Akunne HC, Heffner TG, Jaen JC, MacKenzie RG, Meltzer LT, Pugsley TA, Smith SJ, Wise LD. J. Med. Chem. 1996; 39: 3179
- 2e León LG, Carballo RM, Vega-Hernández MC, Martín VS, Padrón JI, Padrón JM. Bioorg. Med. Chem. Lett. 2007; 17: 2681
- 2f Makarov MV, Hayat F, Graves B, Sonavane M, Salter EA, Wierzbicki A, Gassman NR, Migaud ME. ACS Chem. Biol. 2021; 16: 604
- 2g Meibom D, Micus S, Andreevski AL, Anlauf S, Bogner P, von Buehler C.-J, Dieskau AP, Dreher J, Eitner F, Fliegner D, Follmann M, Gericke KM, Maassen S, Meyer J, Schlemmer K.-H, Steuber H, Tersteegen A, Wunder F. J. Med. Chem. 2022; 65: 16420
- 2h Lewandowski M, Carmina M, Knümann L, Sai M, Willems S, Kasch T, Pollinger J, Knapp S, Marschner JA, Chaikuad A, Merk D. J. Med. Chem. 2024; 67: 2152
- 3a Ogawa T, Matsumoto K, Yoshimura M, Hatayama K, Kitamura K, Kita Y. Tetrahedron Lett. 1993; 34: 1967
- 3b Taylor MD, Badger EW, Steffen RP, Haleen SJ, Pugsley TA, Shih YH, Weishaar RE. J. Med. Chem. 1988; 31: 1659
- 3c Liu L.-L, Di Y.-T, Zhang Q, Fang X, Zhu F, Chen D.-L, Hao X.-J, He H.-P. Tetrahedron Lett. 2010; 51: 5670
- 3d Krauze A, Vītoliņa R, Garaliene V, Sīle L, Kluša V, Duburs G. Eur. J. Med. Chem. 2005; 40: 1163
- 3e Wang Y, Wang C, Liu J, Sun D, Meng F, Zhang M, Aliper A, Ren F, Zhavoronkov A, Ding X. Bioorg. Med. Chem. 2024; 103: 117662
- 4a Ramachandran PV, Burghardt TE, Bland-Berry L. J. Org. Chem. 2005; 70: 7911
- 4b Han B, Li J.-L, Ma C, Zhang S.-J, Chen Y.-C. Angew. Chem. Int. Ed. 2008; 47: 9971
- 4c Ramachandran R, Jayanthi S, Jeong YT. Tetrahedron 2012; 68: 363
- 4d Maestre L, Fructos MR, Díaz-Requejo MM, Pérez PJ. Organometallics 2012; 31: 7839
- 4e Barber DM, Sanganee HJ, Dixon DJ. Org. Lett. 2012; 14: 5290
- 4f Chen X.-Y, Ye S. Eur. J. Org. Chem. 2012; 5723
- 4g Tong S, Yang X, Wang D.-X, Zhao L, Zhu J, Wang M.-X. Tetrahedron 2012; 68: 6492
- 4h Ramiz MM. M, Abdel Hafiz IS, Elian MA. J. Chin. Chem. Soc. 2012; 59: 758
- 4i Sezer S, Gümrükçü Y, Bakırcı İ, Yağız Ünver M, Tanyeli C. Tetrahedron: Asymmetry 2012; 23: 662
- 4j Pretto LM, Mittersteiner M, Andrade VP, Bonacorso HG, Martins MA. P, Zanatta N. Tetrahedron Lett. 2019; 60: 151336
- 4k He Y, Yang J, Liu Q, Zhang X, Fan X. J. Org. Chem. 2020; 85: 15600
- 5a De Kimpe N, Stevens C. Tetrahedron 1995; 51: 2387
- 5b De Kimpe N, Adams A. Chem. Rev. 2006; 106: 2299
- 5c Verniest G, Surmont R, Hende EV, Deweweire A, Deroose F, Thuring JW, De Kimpe N. J. Org. Chem. 2008; 73: 5458
- 5d Mollet K, D’Hooghe M, De Kimpe N. Mini-Rev. Org. Chem. 2013; 10: 1
- 5e Fujita R, Hanaya K, Sugai T, Higashibayashi S. Sci. Rep. 2021; 11: 24078
- 5f Bastos Braga I, Almir Angnes R, Carlos de Lucca EJr, Carmo Braga AA, Roque Duarte Correia C. Eur. J. Org. Chem. 2022; e202200377
- 5g Xia X.-F, Huang Q, Sun T.-Y, Jiang Y, Ran G. ACS Catal. 2022; 12: 12964
- 5h Terunuma T, Hayashi Y. Nat. Commun. 2022; 13: 7503
- 5i Hu M, Ding H, DeSnoo W, Tantillo DJ, Nairoukh Z. Angew. Chem. Int. Ed. 2023; 62: e202315108
- 5j Muralirajan K, Kancherla R, Maity B, Karuthedath S, Laquai F, Cavallo L, Rueping M. Nat. Commun. 2023; 14: 6622
- 5k Cerveri A, Scarica G, Sparascio S, Hoch M, Chiminelli M, Tegoni M, Protti S, Maestri G. Chem. Eur. J. 2024; 30: e202304010
- 5l Gao P.-S, Pan C.-W, Sui Y, Ye H.-X, Liu C, Liu D.-S, Chen W.-T. Tetrahedron 2024; 155: 133865
- 5m Alizadeh A, Moterassed R. J. Iran. Chem. Soc. 2024; 21: 1635
- 6a Yadav VK, Sriramurthy V. J. Am. Chem. Soc. 2005; 127: 16366
- 6b Van Brabandt W, Van Landeghem R, De Kimpe N. Org. Lett. 2006; 8: 1105
- 6c Mollet K, Catak S, Waroquier M, Speybroeck VV, D’hooghe M, De Kimpe N. J. Org. Chem. 2011; 76: 8364
- 6d Mollet K, Broeckx L, D’hooghe M, De Kimpe N. Heterocycles 2012; 84: 431
- 6e Fang Y, Rogness DC, Larock RC, Shi F. J. Org. Chem. 2012; 77: 6262
- 6f Shimizu T, Koya S, Yamasaki R, Mutoh Y, Azumaya I, Katagiri K, Saito S. J. Org. Chem. 2014; 79: 4367
- 6g Pawar SK, Vasu D, Liu R.-S. Adv. Synth. Catal. 2014; 356: 2411
- 6h Ishida N, Nečas D, Masuda Y, Murakami M. Angew. Chem. Int. Ed. 2015; 54: 7418
- 6i Shehzadi SA, Kushwaha K, Sterckx H, Abbaspour Tehrani K. Adv. Synth. Catal. 2018; 360: 4393
- 6j Hejiang Luo TC. S. Z. Chin. J. Org. Chem. 2021; 41: 3521
- 6k Dolna M, Narodowiec J, Staszewska-Krajewska O, Szcześniak P, Furman B. React. Chem. Eng. 2023; 8: 784
- 7a Ungureanu I, Klotz P, Schoenfelder P, Mann A. Chem. Commun. 2001; 958
- 7b Mehra V, Kumar V. Tetrahedron 2013; 69: 3857
- 7c Alcaide B, Almendros P, Martín-Montero R, Ruiz MP. Adv. Synth. Catal. 2016; 358: 1469
- 7d Luan L.-B, Song Z.-J, Li Z.-M, Wang Q.-R. Beilstein J. Org. Chem. 2018; 14: 1826
- 7e Nastase AF, Griggs NW, Anand JP, Fernandez TJ, Harland AA, Trask TJ, Jutkiewicz EM, Traynor JR, Mosberg HI. ACS Chem. Neurosci. 2018; 9: 1840
- 7f Suto T, Yanagita Y, Nagashima Y, Takikawa S, Kurosu Y, Matsuo N, Miura K, Simizu S, Sato T, Chida N. Bull. Chem. Soc. Jpn. 2019; 92: 545
- 7g Ham JS, Park B, Son M, Roque JB, Jurczyk J, Yeung CS, Baik M.-H, Sarpong R. J. Am. Chem. Soc. 2020; 142: 13041
- 7h Xiao R.-X, Tian T, Yang T.-Y, Lan M.-X, Lv S, Mou X.-Q, Chen Y.-Z, Cui B.-D. Org. Lett. 2024; 26: 3195
- 7i Shukla D, Kashyap S, Singh B, Sharma AK, Bhattacharyya A, Rahman N, Ghorai MK. Synthesis 2024; in press; DOI: 10.1055/a-2415-1629
- 8a Baeg J.-O, Bensimon C, Alper H. J. Org. Chem. 1995; 60: 253
- 8b Alcaide B, Salgado NR, Sierra MA. Tetrahedron Lett. 1998; 39: 467
- 8c Prasad BA. B, Bisai A, Singh VK. Org. Lett. 2004; 6: 4829
- 8d Couty F, Evano G. Synlett 2009; 3053
- 8e Alcaide B, Almendros P, Aragoncillo C. Curr. Opin. Drug Discovery Dev. 2010; 13: 685
- 8f Barbier V, Marrot J, Couty F, David OR. P. Eur. J. Chem. 2016; 549
- 8g Dao Thi H, Decuyper L, Mollet K, Kenis S, De Kimpe N, Van Nguyen T, D’hooghe M. Synlett 2016; 27: 1100
- 8h Dao Thi H, Danneels B, Desmet T, Van Hecke K, Van Nguyen T, D’Hooghe M. Asian J. Org. Chem. 2016; 5: 1480
- 8i Wang X, Liu C, Zeng X, Wang X, Wang X, Hu Y. Org. Lett. 2017; 19: 3378
- 8j Singh A, Sharma B, Sachdeva D, Mehra V, Singh P, Kumar V. ChemistrySelect 2018; 3: 4764
- 8k Dao Thi H, Le Nhat Thuy G, Catak S, Van Speybroeck V, Van Nguyen T, D’hooghe M. Synthesis 2018; 50: 1439
- 8l Boddy AJ, Cordier CJ, Goldberg K, Madin A, Spivey AC, Bull JA. Org. Lett. 2019; 21: 1818
- 8m Yao Z, Feng H, Xi H, Xi C, Liu W. Org. Biomol. Chem. 2021; 19: 4469
- 9a Ghorai MK, Das K, Kumar A, Das A. Tetrahedron Lett. 2006; 47: 5393
- 9b Ghorai MK, Das K, Kumar A. Tetrahedron Lett. 2007; 48: 4373
- 9c Ghorai MK, Das K, Kumar A. Tetrahedron Lett. 2009; 50: 1105
- 10a Kashyap S, Singh B, Ghorai MK. J. Org. Chem. 2024; 89: 11429
- 10b Singh B, Kashyap S, Singh S, Gupta S, Ghorai MK. J. Org. Chem. 2024; 89: 2247
- 10c Singh B, Kumar M, Goswami G, Verma I, Ghorai MK. J. Org. Chem. 2023; 88: 4504
- 10d Wani IA, Sk S, Mal A, Sengupta A, Ghorai MK. Org. Lett. 2022; 24: 7867
- 10e Pradhan S, Chauhan N, Shahi CK, Bhattacharyya A, Ghorai MK. Org. Lett. 2020; 22: 7903
- 10f Bhattacharyya A, Das S, Chauhan N, Biswas PK, Ghorai MK. Synlett 2020; 708 For azetidines, see
- 10g Goswami G, Singh B, Wani IA, Mal A, Ghorai MK. J. Org. Chem. 2024; 89: 11576
- 10h Goswami G, Chauhan N, Mal A, Das S, Das M, Ghorai MK. ACS Omega 2018; 3: 17562
- 10i Ghorai MK, Kumar A, Das K. Org. Lett. 2007; 9: 5441
- 11a Ghorai MK, Shukla D, Bhattacharyya A. J. Org. Chem. 2012; 77: 3740
- 11b Ghorai MK, Kumar A, Tiwari DP. J. Org. Chem. 2010; 75: 137
- 11c Bhattacharyya A. Synlett 2012; 23: 2142
For aziridines see:
(A) General procedure for DROC of azetidine with alkynes in the presence of catalytic Cu(OTf)2 and stoichiometric TBAFP and characterization data of compounds 6a–h and 10a–13a′A solution of azetidine (1.0 equiv), TBAFP (1.0 equiv), and alkyne (3.0 equiv) in dichloromethane was added to anhydrous Cu(OTf)2 (20 mol%) at 0 °C under an argon atmosphere. The reaction mixture was stirred for the appropriate time, then quenched with saturated NaHCO3 at the same temperature. The aqueous layer was extracted with CH2Cl2 (3 × 5.0 mL) and dried over anhydrous Na2SO4. The crude compound was purified by flash column chromatography on neutral alumina (ethyl acetate/petroleum ether) to provide the corresponding cyclized product.During the temperature-dependence studies, the reaction was performed at the appropriate temperature. When the reaction was performed with BF3·OEt2 as the Lewis acid, it was added to the reaction mixture after the addition of all other reagents. These compounds were unstable, and some amount of the product was hydrolyzed during workup or column chromatographic purification or during the preparation of the analytical sample.(B) Racemization studies of (S)-2-phenyl-N-tosylazetidine 4a in the presence of Cu(OTf)2 in dichloromethane (Ref. 11a)We studied the racemization of enantiopure (S)-2-phenyl-N tosylazetidine 4a by performing the reaction with a stoichiometric amount of Cu(OTf)2 in CH2Cl2 at room temperature, as well as at 0 °C without adding nucleophile. The aliquots were taken from the reaction mixture at defined time intervals and analyzed by chiral HPLC (Chiralpak AD-H column, flow rate 1 mL/min; hexane-isopropanol, 95:5). At room temperature, the ee of (S)-4a was found to decrease with increasing time and the compound racemized completely within 5 minutes (Table 2, Figure 2)Table 1 Racemization study of (S)-4a (1.0 equiv) in the Presence of Cu(OTf)2 (1.0 equiv) at RT and 0 °C in CH2Cl2 When the reaction was carried out at 0 °C, the racemization occurred within 1.5 h (Table 2, Figure 3). Racemization of (S)-4a during the course of the reaction is responsible for the reduced ee of the product. When the racemization of (S)-2-phenyl-N-tosylazetidine 4a was studied in the presence of a catalytic amount of Cu(OTf)2 (30 mol%) and stoichiometric TBAHS (1.0 equiv) in CH2Cl2 at 0 °C without adding a nucleophile, the ee of (S)-4a did not decrease with increasing reaction time in dichloromethane.
Corresponding Author
Publication History
Received: 02 August 2024
Accepted after revision: 25 September 2024
Accepted Manuscript online:
25 September 2024
Article published online:
25 October 2024
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References and Notes
- 1a Dunbar PG, Durant GJ, Rho T, Ojo B, Huzl JJ. III, Smith DA, El-Assadi AA, Sbeih S, Ngur DO, Periyasamy S, Hoss W, Messer WS. Jr. J. Med. Chem. 1994; 37: 2774
- 1b Morale MC, Serra PA, L’Episcopo F, Tirolo C, Caniglia S, Testa N, Gennuso F, Giaquinta G, Rocchitta G, Desole MS, Miele E, Marchetti B. Neuroscience 2006; 138: 869
- 1c Kadieva MG, Oganesyan ÉT, Mutsueva SK. Pharm. Chem. J. 2005; 39: 453
- 1d Xu K, Xu Y, Brown-Jermyn D, Chen J.-F, Ascherio A, Dluzen DE, Schwarzschild MA. J. Neurosci. 2006; 26: 535
- 1e Cawthon D, Soderblom EJ, Xu ZA, Duhart H, Slikker WJr, Ali SF, Goshe MB. Int. J. Neuroprotec. Neuroregener. 2005; 1: 98
- 1f Picon S, Boulahjar R, Hoguet V, Baron M, Duplan I, Vallez E, Hennuyer N, Dumont J, Touche V, Dorchies E, Lasalle M, Descat A, Piveteau C, Biela A, Chaput L, Villoutreix BO, Lipka E, Sevin E, Culot M, Gosselet F, Lestavel S, Roussel P, Deprez-Poulain R, Leroux F, Staels B, Deprez B, Tailleux A, Charton J. J. Med. Chem. 2023; 66: 11732
- 2a Mitch CH, Bymaster FP, Calligaro DO, Quimby SJ, Schoepp DD, Wong DT, Shannon HE. Bioorg. Med. Chem. Lett. 1994; 4: 1721
- 2b Dunbar PG, Durant GJ, Fang Z, Abuh YF, El-Assadi AA, Ngur DO, Periyasamy S, Hoss WP, Messer WS. Jr. J. Med. Chem. 1993; 36: 842
- 2c Olesen PH, Swedberg MD. B, Rimvall K. Bioorg. Med. Chem. 1998; 6: 1623
- 2d Glase SA, Akunne HC, Heffner TG, Jaen JC, MacKenzie RG, Meltzer LT, Pugsley TA, Smith SJ, Wise LD. J. Med. Chem. 1996; 39: 3179
- 2e León LG, Carballo RM, Vega-Hernández MC, Martín VS, Padrón JI, Padrón JM. Bioorg. Med. Chem. Lett. 2007; 17: 2681
- 2f Makarov MV, Hayat F, Graves B, Sonavane M, Salter EA, Wierzbicki A, Gassman NR, Migaud ME. ACS Chem. Biol. 2021; 16: 604
- 2g Meibom D, Micus S, Andreevski AL, Anlauf S, Bogner P, von Buehler C.-J, Dieskau AP, Dreher J, Eitner F, Fliegner D, Follmann M, Gericke KM, Maassen S, Meyer J, Schlemmer K.-H, Steuber H, Tersteegen A, Wunder F. J. Med. Chem. 2022; 65: 16420
- 2h Lewandowski M, Carmina M, Knümann L, Sai M, Willems S, Kasch T, Pollinger J, Knapp S, Marschner JA, Chaikuad A, Merk D. J. Med. Chem. 2024; 67: 2152
- 3a Ogawa T, Matsumoto K, Yoshimura M, Hatayama K, Kitamura K, Kita Y. Tetrahedron Lett. 1993; 34: 1967
- 3b Taylor MD, Badger EW, Steffen RP, Haleen SJ, Pugsley TA, Shih YH, Weishaar RE. J. Med. Chem. 1988; 31: 1659
- 3c Liu L.-L, Di Y.-T, Zhang Q, Fang X, Zhu F, Chen D.-L, Hao X.-J, He H.-P. Tetrahedron Lett. 2010; 51: 5670
- 3d Krauze A, Vītoliņa R, Garaliene V, Sīle L, Kluša V, Duburs G. Eur. J. Med. Chem. 2005; 40: 1163
- 3e Wang Y, Wang C, Liu J, Sun D, Meng F, Zhang M, Aliper A, Ren F, Zhavoronkov A, Ding X. Bioorg. Med. Chem. 2024; 103: 117662
- 4a Ramachandran PV, Burghardt TE, Bland-Berry L. J. Org. Chem. 2005; 70: 7911
- 4b Han B, Li J.-L, Ma C, Zhang S.-J, Chen Y.-C. Angew. Chem. Int. Ed. 2008; 47: 9971
- 4c Ramachandran R, Jayanthi S, Jeong YT. Tetrahedron 2012; 68: 363
- 4d Maestre L, Fructos MR, Díaz-Requejo MM, Pérez PJ. Organometallics 2012; 31: 7839
- 4e Barber DM, Sanganee HJ, Dixon DJ. Org. Lett. 2012; 14: 5290
- 4f Chen X.-Y, Ye S. Eur. J. Org. Chem. 2012; 5723
- 4g Tong S, Yang X, Wang D.-X, Zhao L, Zhu J, Wang M.-X. Tetrahedron 2012; 68: 6492
- 4h Ramiz MM. M, Abdel Hafiz IS, Elian MA. J. Chin. Chem. Soc. 2012; 59: 758
- 4i Sezer S, Gümrükçü Y, Bakırcı İ, Yağız Ünver M, Tanyeli C. Tetrahedron: Asymmetry 2012; 23: 662
- 4j Pretto LM, Mittersteiner M, Andrade VP, Bonacorso HG, Martins MA. P, Zanatta N. Tetrahedron Lett. 2019; 60: 151336
- 4k He Y, Yang J, Liu Q, Zhang X, Fan X. J. Org. Chem. 2020; 85: 15600
- 5a De Kimpe N, Stevens C. Tetrahedron 1995; 51: 2387
- 5b De Kimpe N, Adams A. Chem. Rev. 2006; 106: 2299
- 5c Verniest G, Surmont R, Hende EV, Deweweire A, Deroose F, Thuring JW, De Kimpe N. J. Org. Chem. 2008; 73: 5458
- 5d Mollet K, D’Hooghe M, De Kimpe N. Mini-Rev. Org. Chem. 2013; 10: 1
- 5e Fujita R, Hanaya K, Sugai T, Higashibayashi S. Sci. Rep. 2021; 11: 24078
- 5f Bastos Braga I, Almir Angnes R, Carlos de Lucca EJr, Carmo Braga AA, Roque Duarte Correia C. Eur. J. Org. Chem. 2022; e202200377
- 5g Xia X.-F, Huang Q, Sun T.-Y, Jiang Y, Ran G. ACS Catal. 2022; 12: 12964
- 5h Terunuma T, Hayashi Y. Nat. Commun. 2022; 13: 7503
- 5i Hu M, Ding H, DeSnoo W, Tantillo DJ, Nairoukh Z. Angew. Chem. Int. Ed. 2023; 62: e202315108
- 5j Muralirajan K, Kancherla R, Maity B, Karuthedath S, Laquai F, Cavallo L, Rueping M. Nat. Commun. 2023; 14: 6622
- 5k Cerveri A, Scarica G, Sparascio S, Hoch M, Chiminelli M, Tegoni M, Protti S, Maestri G. Chem. Eur. J. 2024; 30: e202304010
- 5l Gao P.-S, Pan C.-W, Sui Y, Ye H.-X, Liu C, Liu D.-S, Chen W.-T. Tetrahedron 2024; 155: 133865
- 5m Alizadeh A, Moterassed R. J. Iran. Chem. Soc. 2024; 21: 1635
- 6a Yadav VK, Sriramurthy V. J. Am. Chem. Soc. 2005; 127: 16366
- 6b Van Brabandt W, Van Landeghem R, De Kimpe N. Org. Lett. 2006; 8: 1105
- 6c Mollet K, Catak S, Waroquier M, Speybroeck VV, D’hooghe M, De Kimpe N. J. Org. Chem. 2011; 76: 8364
- 6d Mollet K, Broeckx L, D’hooghe M, De Kimpe N. Heterocycles 2012; 84: 431
- 6e Fang Y, Rogness DC, Larock RC, Shi F. J. Org. Chem. 2012; 77: 6262
- 6f Shimizu T, Koya S, Yamasaki R, Mutoh Y, Azumaya I, Katagiri K, Saito S. J. Org. Chem. 2014; 79: 4367
- 6g Pawar SK, Vasu D, Liu R.-S. Adv. Synth. Catal. 2014; 356: 2411
- 6h Ishida N, Nečas D, Masuda Y, Murakami M. Angew. Chem. Int. Ed. 2015; 54: 7418
- 6i Shehzadi SA, Kushwaha K, Sterckx H, Abbaspour Tehrani K. Adv. Synth. Catal. 2018; 360: 4393
- 6j Hejiang Luo TC. S. Z. Chin. J. Org. Chem. 2021; 41: 3521
- 6k Dolna M, Narodowiec J, Staszewska-Krajewska O, Szcześniak P, Furman B. React. Chem. Eng. 2023; 8: 784
- 7a Ungureanu I, Klotz P, Schoenfelder P, Mann A. Chem. Commun. 2001; 958
- 7b Mehra V, Kumar V. Tetrahedron 2013; 69: 3857
- 7c Alcaide B, Almendros P, Martín-Montero R, Ruiz MP. Adv. Synth. Catal. 2016; 358: 1469
- 7d Luan L.-B, Song Z.-J, Li Z.-M, Wang Q.-R. Beilstein J. Org. Chem. 2018; 14: 1826
- 7e Nastase AF, Griggs NW, Anand JP, Fernandez TJ, Harland AA, Trask TJ, Jutkiewicz EM, Traynor JR, Mosberg HI. ACS Chem. Neurosci. 2018; 9: 1840
- 7f Suto T, Yanagita Y, Nagashima Y, Takikawa S, Kurosu Y, Matsuo N, Miura K, Simizu S, Sato T, Chida N. Bull. Chem. Soc. Jpn. 2019; 92: 545
- 7g Ham JS, Park B, Son M, Roque JB, Jurczyk J, Yeung CS, Baik M.-H, Sarpong R. J. Am. Chem. Soc. 2020; 142: 13041
- 7h Xiao R.-X, Tian T, Yang T.-Y, Lan M.-X, Lv S, Mou X.-Q, Chen Y.-Z, Cui B.-D. Org. Lett. 2024; 26: 3195
- 7i Shukla D, Kashyap S, Singh B, Sharma AK, Bhattacharyya A, Rahman N, Ghorai MK. Synthesis 2024; in press; DOI: 10.1055/a-2415-1629
- 8a Baeg J.-O, Bensimon C, Alper H. J. Org. Chem. 1995; 60: 253
- 8b Alcaide B, Salgado NR, Sierra MA. Tetrahedron Lett. 1998; 39: 467
- 8c Prasad BA. B, Bisai A, Singh VK. Org. Lett. 2004; 6: 4829
- 8d Couty F, Evano G. Synlett 2009; 3053
- 8e Alcaide B, Almendros P, Aragoncillo C. Curr. Opin. Drug Discovery Dev. 2010; 13: 685
- 8f Barbier V, Marrot J, Couty F, David OR. P. Eur. J. Chem. 2016; 549
- 8g Dao Thi H, Decuyper L, Mollet K, Kenis S, De Kimpe N, Van Nguyen T, D’hooghe M. Synlett 2016; 27: 1100
- 8h Dao Thi H, Danneels B, Desmet T, Van Hecke K, Van Nguyen T, D’Hooghe M. Asian J. Org. Chem. 2016; 5: 1480
- 8i Wang X, Liu C, Zeng X, Wang X, Wang X, Hu Y. Org. Lett. 2017; 19: 3378
- 8j Singh A, Sharma B, Sachdeva D, Mehra V, Singh P, Kumar V. ChemistrySelect 2018; 3: 4764
- 8k Dao Thi H, Le Nhat Thuy G, Catak S, Van Speybroeck V, Van Nguyen T, D’hooghe M. Synthesis 2018; 50: 1439
- 8l Boddy AJ, Cordier CJ, Goldberg K, Madin A, Spivey AC, Bull JA. Org. Lett. 2019; 21: 1818
- 8m Yao Z, Feng H, Xi H, Xi C, Liu W. Org. Biomol. Chem. 2021; 19: 4469
- 9a Ghorai MK, Das K, Kumar A, Das A. Tetrahedron Lett. 2006; 47: 5393
- 9b Ghorai MK, Das K, Kumar A. Tetrahedron Lett. 2007; 48: 4373
- 9c Ghorai MK, Das K, Kumar A. Tetrahedron Lett. 2009; 50: 1105
- 10a Kashyap S, Singh B, Ghorai MK. J. Org. Chem. 2024; 89: 11429
- 10b Singh B, Kashyap S, Singh S, Gupta S, Ghorai MK. J. Org. Chem. 2024; 89: 2247
- 10c Singh B, Kumar M, Goswami G, Verma I, Ghorai MK. J. Org. Chem. 2023; 88: 4504
- 10d Wani IA, Sk S, Mal A, Sengupta A, Ghorai MK. Org. Lett. 2022; 24: 7867
- 10e Pradhan S, Chauhan N, Shahi CK, Bhattacharyya A, Ghorai MK. Org. Lett. 2020; 22: 7903
- 10f Bhattacharyya A, Das S, Chauhan N, Biswas PK, Ghorai MK. Synlett 2020; 708 For azetidines, see
- 10g Goswami G, Singh B, Wani IA, Mal A, Ghorai MK. J. Org. Chem. 2024; 89: 11576
- 10h Goswami G, Chauhan N, Mal A, Das S, Das M, Ghorai MK. ACS Omega 2018; 3: 17562
- 10i Ghorai MK, Kumar A, Das K. Org. Lett. 2007; 9: 5441
- 11a Ghorai MK, Shukla D, Bhattacharyya A. J. Org. Chem. 2012; 77: 3740
- 11b Ghorai MK, Kumar A, Tiwari DP. J. Org. Chem. 2010; 75: 137
- 11c Bhattacharyya A. Synlett 2012; 23: 2142
For aziridines see:
(A) General procedure for DROC of azetidine with alkynes in the presence of catalytic Cu(OTf)2 and stoichiometric TBAFP and characterization data of compounds 6a–h and 10a–13a′A solution of azetidine (1.0 equiv), TBAFP (1.0 equiv), and alkyne (3.0 equiv) in dichloromethane was added to anhydrous Cu(OTf)2 (20 mol%) at 0 °C under an argon atmosphere. The reaction mixture was stirred for the appropriate time, then quenched with saturated NaHCO3 at the same temperature. The aqueous layer was extracted with CH2Cl2 (3 × 5.0 mL) and dried over anhydrous Na2SO4. The crude compound was purified by flash column chromatography on neutral alumina (ethyl acetate/petroleum ether) to provide the corresponding cyclized product.During the temperature-dependence studies, the reaction was performed at the appropriate temperature. When the reaction was performed with BF3·OEt2 as the Lewis acid, it was added to the reaction mixture after the addition of all other reagents. These compounds were unstable, and some amount of the product was hydrolyzed during workup or column chromatographic purification or during the preparation of the analytical sample.(B) Racemization studies of (S)-2-phenyl-N-tosylazetidine 4a in the presence of Cu(OTf)2 in dichloromethane (Ref. 11a)We studied the racemization of enantiopure (S)-2-phenyl-N tosylazetidine 4a by performing the reaction with a stoichiometric amount of Cu(OTf)2 in CH2Cl2 at room temperature, as well as at 0 °C without adding nucleophile. The aliquots were taken from the reaction mixture at defined time intervals and analyzed by chiral HPLC (Chiralpak AD-H column, flow rate 1 mL/min; hexane-isopropanol, 95:5). At room temperature, the ee of (S)-4a was found to decrease with increasing time and the compound racemized completely within 5 minutes (Table 2, Figure 2)Table 1 Racemization study of (S)-4a (1.0 equiv) in the Presence of Cu(OTf)2 (1.0 equiv) at RT and 0 °C in CH2Cl2 When the reaction was carried out at 0 °C, the racemization occurred within 1.5 h (Table 2, Figure 3). Racemization of (S)-4a during the course of the reaction is responsible for the reduced ee of the product. When the racemization of (S)-2-phenyl-N-tosylazetidine 4a was studied in the presence of a catalytic amount of Cu(OTf)2 (30 mol%) and stoichiometric TBAHS (1.0 equiv) in CH2Cl2 at 0 °C without adding a nucleophile, the ee of (S)-4a did not decrease with increasing reaction time in dichloromethane.
