Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Stereospecific Synthesis of 1,4,5,6-Tetrahydropyrimidines via Domino Ring-Opening Cyclization of Activated Aziridines with α‑Acidic Isocyanides Aditya Bhattacharyya, Chandan Kumar Shahi, Sajan Pradhan, and Manas K. Ghorai* Indian Institute of Technology Kanpur, 208016, Kanpur, Uttar Pradesh, India S Supporting Information *
ABSTRACT: An expeditious synthetic route to access structurally diverse 1,4,5,6-tetrahydropyrimidines via domino ring-opening cyclization of activated aziridines with α-acidic isocyanides has been established. The transformation proceeds via Lewis acid mediated SN2-type ring opening of activated aziridines with α-carbanion of the isocyanides followed by a concomitant 6-endo-dig cyclization in a domino fashion to furnish the 1,4,5,6-tetrahydropyrimidine derivatives in excellent yields (up to 84%) and also in diastereo- and enantiomerically pure form (dr >99:1, ee >99%).
T
etrahydropyrimidines are one of the privileged classes of heterocyclic motifs occurring in many natural and synthetic products that have intriguing biological properties.1 Structure−activity relationship studies have revealed that the substituents on the tetrahydropyrimidine ring are responsible for their bioactivities (Figure 1).2 Pyrantel (I) and Morantel
Despite their usefulness, only a few reports are available for the efficient and direct synthesis of 1,4,5,6-tetrahydropyrimidines,8 some of which involve condensation of amidines with acrylates,8b Lewis acid catalyzed reaction of diamines and nitriles,8c catalytic hydrogenation of pyrimidines,8d brominecatalyzed tandem ring-opening cyclization (ROC) of bicyclic vinylcyclopropanes,8e etc. In recent years, small ring azaheterocycles have emerged as one of the most useful building blocks in organic synthesis.9 Predicated on our longstanding involvement and synthetic pursuit in the area of Lewis acid assisted SN2-type ring-opening transformations of activated aziridines and azetidines to access a wide array of high-value nitrogenous heterocyclic compounds either by ROC10 or by domino ring-opening cyclization (DROC)11 strategies, we envisaged the synthesis of various racemic and optically pure 1,4,5,6-tetrahydropyrimidines via DROC of activated aziridines with α-acidic isocyanides such as tosylmethyl isocyanide (TosMIC) that still remains the most used reagent due to its versatile reactivity profile.12 Although TosMIC has widely been used in the syntheses of various five-membered heterocyclic compounds such as oxazoles, pyrroles, imidazoles, thiazoles, etc.,12b,13 its use in the synthesis of six-membered heterocycles is very rare.14 We endeavored to engage both the α-acidity and α-addition ability of the isocyanide group of TosMIC in a novel DROC strategy with activated aziridines, and we wish to disclose our preliminary results in this letter. The study commenced with the reaction of activated 2phenyl-N-tosylaziridine (1a) with 1.1 equiv of TosMIC (2a) as the pronucleophile in the presence of 3.0 equiv of sodium hydride and 1.0 equiv of boron trifluoride diethyl etherate (BF3· OEt2) as the Lewis acid in anhydrous tetrahydrofuran at room temperature. To our great pleasure, the designed domino ring-
Figure 1. Representative examples of biologically active tetrahydropyrimidine derivatives.
(II) containing the tetrahydropyrimidine unit are anthelmintic nematicide drugs used for the treatment and prevention of the occurrence of intestinal parasites in small animals.3 CDD-0102 (III), a selective M1 muscarinic cholinergic agonist, is in preclinical development for the treatment of Alzheimer’s disease.4 Trigonoliimines IVa and IVb exhibit anticancer activities against HeLa and U-937 cells.5 The manzacidins (V−VII) show wide-spectrum antiprotozoal activity.1a,6 1,4,5,6Tetrahydropyrimidines have also been utilized as ligands for metal-catalyzed reactions in organic synthesis.7 © XXXX American Chemical Society
Received: March 27, 2018
A
DOI: 10.1021/acs.orglett.8b00986 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters opening cyclization (DROC) reaction instantly ensued and eventually completed in 35 min to furnish the desired product 5-phenyl-1,4-ditosyl-1,4,5,6-tetrahydropyrimidine (3a) as a single diastereomer (dr >99:1) in good yield (62%, Table 1).
Scheme 1. Domino Ring-Opening Cyclization of 2-Aryl-Narylsulfonylaziridines 1a−h with TosMIC (2a) and BetMIC (2b)
Table 1. Optimization Studies for Domino Ring-Opening Cyclization of Aziridine 1a with TosMIC (2a)a
entry
base
Lewis acid
solvent
t (min)
yield (%)
1 2 3b 4 5 6c 7 8b
NaH NaH NaH NaH KOtBu KOtBu DBU KOtBu
BF3·OEt2 Cu(OTf)2 Cu(OTf)2 Sc(OTf)3 BF3·OEt2 BF3·OEt2 BF3·OEt2 BF3·OEt2
THF CH2Cl2 THF THF THF THF THF TBME
35 45 30 60 40 4h 60 40
62 trace trace 51 84 32 15 NR
a
Unless noted otherwise, 1.1 equiv of TosMIC, 3.0 equiv of the base, and 1.0 equiv of Lewis acid were used in all cases. bThe reaction was performed at 60 °C. cThe reaction was performed with 20 mol % Lewis acid.
The structure of 3a was ascertained by spectroscopic analysis, and the relative stereochemistry of the substituents at the 4and 5-positions in 3a was found to be trans as determined by nuclear Overhauser effect (NOE) experiments.15 Next, we proceeded to optimize the reaction conditions for improving the yield of the desired product. Several bases, Lewis acids, and solvents were examined, and the results are summarized in Table 1. The use of a more azaphilic Lewis acid, copper(II) triflate, was found to be severely detrimental to the efficiency of the reaction as 3a was formed in only a trace amount in both 1,2-dichloromethane (entry 2) and THF (entry 3). While the combination of sodium hydride and scandium(III) triflate furnished the corresponding product in moderate yield (51%, entry 4), the best result was obtained with 3.0 equiv of potassium tert-butoxide as the base and 1.0 equiv of BF3· OEt2 as the Lewis acid. The transformation completed in 40 min furnishing the desired 1,4,5,6-tetrahydropyrimidine derivative 3a in 84% yield (entry 5). The reaction was particularly sluggish with 20 mol % BF3·OEt2, and 3a was obtained in 32% yield in 4 h (entry 6). The use of organic bases such as 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) impeded the advancement of the reaction, and 3a was obtained in only 15% yield in 1 h (entry 7). When an acyclic ethereal solvent such as TBME was used, no reaction was observed even at a comparatively higher temperature (entry 8). To generalize the synthetic strategy with a wider substrate scope, various racemic 2-aryl-N-tosylaziridines possessing both electron-donating and -withdrawing groups on the aryl ring were studied under the optimal one-pot DROC conditions. The outcomes of our endeavors are shown in Scheme 1. When a strong electron-rich 2-(4-(tert-butyl)phenyl)-1-tosylaziridine (1b) and 2a were reacted in the presence of 1.0 equiv of BF3· OEt2 and 3.0 equiv of KOtBu in THF at room temperature, the corresponding 1,4,5,6-tetrahydropyrimidine derivative 3b was obtained as a single diastereomer in good yield (78%). Owing to the benefits of the fluorinated compounds in pharmaceutical industries, we synthesized 1,4,5,6-tetrahydropyrimidines with
fluorine substituents by subjecting 2-(4-fluorophenyl)-1-tosylaziridine (1c) and 2a and obtained the corresponding product 3c in an excellent yield (82%). In order to allow further synthetic elaboration of the products, we employed 4-Cl and 4Br variants of 2-aryl-N-tosylaziridines 1d and 1e, respectively, as the substrates, and the corresponding 1,4,5,6-tetrahydropyrimidines 3d and 3e formed in very high yields (entries 3 and 4, Scheme 1). Another fluorinated 1,4,5,6-tetrahydropyrimidine derivative 3f could be synthesized in 84% yield by employing 2-(3-fluorophenyl)-1-tosylaziridine (1f) and 2a in the transformation. The 3-Cl and 2-Cl variants of the 2-aryl-Ntosylaziridines 1g and 1h, respectively, were well-tolerated in the DROC transformation, and the respective 1,4,5,6tetrahydropyrimidines 3g and 3h were obtained in excellent yields (up to 82%). Finally, to investigate the scope of using other α-acidic isocyanides, we employed 1-(isocyanomethyl)1H-benzo-[d][1,2,3]triazole (BetMIC, 2b) as the pronucleophile in the transformation with 1a and 1d, and the corresponding 1,4,5,6-tetrahydropyrimidines 3i and 3j were produced in excellent yields (entries 9 and 10, Scheme 1). Next, to study the electronic effect of the arylsulfonyl groups on the reaction, a variety of N-arylsulfonylaziridines were reacted with TosMIC (2a) in the presence of 1.0 equiv of BF3· OEt2 and 3.0 equiv of KOtBu in THF at room temperature. Gratifyingly, all aziridines 1i−l furnished the corresponding 1,4,5,6-tetrahydropyrimidines 3k−n within 40−60 min as single B
DOI: 10.1021/acs.orglett.8b00986 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters diastereomers in very good yields (up to 82%, entries 11−14, Scheme 1). Reaction of enantiopure (R)-1j (>99% ee) and TosMIC (2a) in the presence of 1.0 equiv of BF3·OEt2 and 3.0 equiv of KOtBu in THF at room temperature afforded the corresponding tetrahydropyrimidine derivative 3l with 75% enantiomeric excess in 78% yield (Scheme 2). The observed loss in
The synthetic versatility of the developed methodology was illustrated by the syntheses of bicyclic 1,4,5,6-tetrahydropyrimidine derivatives by employing cycloalkane-fused aziridines as the substrates in the reaction. Cyclopentyl aziridine 1q and cyclohexyl aziridine 1r were separately subjected to the reaction with TosMIC (2a) under the optimized reaction conditions, and the corresponding cycloalkane-fused 1,4,5,6-tetrahydropyrimidine derivatives 3s and 3t were obtained in 80% and 82% yield, respectively (Scheme 4).
Scheme 2. Synthesis of Enantiopure 1,4,5,6Tetrahydropyrimidine by Enantiospecific DROC of (R)-1j with TosMIC (2a)
Scheme 4. Reaction of Cycloalkane-Fused Aziridines 1q and 1r with TosMIC (2a)
enantiopurity was attributed to the partial racemization of the enantiopure starting material, i.e. activated aziridine (R)-1j in the presence of a Lewis acid (BF3·OEt2).11a,16 With a view to impede the partial racemization process, we subsequently performed the reaction at −30 °C, and to our great satisfaction, the product (4R,5S)-3l was formed without any observable loss of enantiopurity (>99% ee, Scheme 2). To broaden the scope of the methodology, various 2-alkyl-Ntosylaziridines were employed as the substrates. Aziridines having 2-methyl (1m), 2-isopropyl (1n), and 2-benzyl groups (1o) were subjected to a reaction with TosMIC (2a) in the presence of BF3·OEt2 and KOtBu under the optimized conditions. Interestingly, the attack of the in situ generated carbon nucleophile exclusively took place at the sterically less crowded position of the aziridines and the corresponding 1,4,5,6-tetrahydropyrimidines 3o−q were formed as single regioisomers in excellent yields (up to 80%). Similarly, racemic 2-octyl-N-tosylaziridine (1p) furnished the corresponding 1,4,5,6-tetrahydropyrimidine derivative 3r as a single regioand diastereoisomer in very good yield (82%). All the results are summarized in Scheme 3. The relative stereochemistry of the substituents at the 4- and 6-positions was found to be trans as determined by nuclear Overhauser effect (NOE) experiments of 3p as a representative example.15
On the basis of the experimental evidence, a plausible mechanistic pathway is proposed in Scheme 5. Base-mediated Scheme 5. Plausible Mechanism for the Formation of 1,4,5,6-Tetrahydropyrimidines from Activated Aziridines with α-Acidic Isocyanides
generation of the active carbanionic nucleophile and subsequent ring opening of the Lewis acid activated aziridine ring (A) with the carbanion leads to the intermediate B. Further attack on the terminal carbon of the isocyanide group in a 6endo-dig fashion to furnish the desired product 3 as a single diastereomer. To conclude, we have developed a highly desirable and sophisticated synthetic transformation to expeditiously access densely substituted 1,4,5,6-tetrahydropyrimidines via Lewis acid mediated domino ring-opening cyclization (DROC) of activated aziridines with α-acidic isocyanides such as TosMIC and BetMIC. The high-yielding strategy (up to 84%) espouses the step-, pot-, and atom-economic principles of modern organic synthesis and delivers the desired products with excellent diastereoselectivity (dr >99:1) and enantiospecificity (>99% ee). We believe that the developed synthetic approach will be widely utilized in organic and medicinal chemistry.
Scheme 3. Domino Ring-Opening Cyclization of 2-Alkyl-Ntosylaziridines 1m−p with TosMIC (2a)
C
DOI: 10.1021/acs.orglett.8b00986 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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(9) (a) Ghorai, M. K.; Bhattacharyya, A.; Das, S.; Chauhan, N. Top. Heterocycl. Chem. 2015, 41, 49. (b) Dolfen, J.; De Kimpe, N.; D’hooghe, M. Synlett 2016, 27, 1486. (c) Takeda, Y.; Kuroda, A.; Sameera, W. M. C.; Morokuma, K.; Minakata, S. Chem. Sci. 2016, 7, 6141. (d) Takeda, Y.; Ikeda, Y.; Kuroda, A.; Tanaka, S.; Minakata, S. J. Am. Chem. Soc. 2014, 136, 8544. (e) Callebaut, G.; Meiresonne, T.; De Kimpe, N.; Mangelinckx, S. Chem. Rev. 2014, 114, 7954. (f) Schneider, C. Angew. Chem., Int. Ed. 2009, 48, 2082. (g) Nielsen, L. P. C.; Jacobsen, E. N. In Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, 2006; p 229. (h) Stankovic, S.; D’Hooghe, M.; Catak, S.; Eum, H.; Waroquier, M.; Van Speybroeck, V.; De Kimpe, N.; Ha, H.-J. Chem. Soc. Rev. 2012, 41, 643. (i) Dolfen, J.; Vervisch, K.; DeKimpe, N.; D’hooghe, M. Chem. - Eur. J. 2016, 22, 4945. (j) Yin, J.; Hyland, D. C. J. T. Asian J. Org. Chem. 2016, 5, 1368. (k) Chai, Z.; Zhu, Y.-M.; Yang, P.-J.; Wang, S.; Wang, S.; Liu, Z.; Yang, G. J. Am. Chem. Soc. 2015, 137, 10088. (l) Huang, Y.-m.; Zheng, C.-w.; Pan, L.; Jin, Q.-w.; Zhao, G. J. Org. Chem. 2015, 80, 10710. (10) (a) Mal, A.; Goswami, G.; Ahmad Wani, I.; Ghorai, M. K. Chem. Commun. 2017, 53, 10263. (b) Pradhan, S.; Shahi, C. K.; Bhattacharyya, A.; Chauhan, N.; Ghorai, M. K. Org. Lett. 2017, 19, 3438. (c) Shahi, C. K.; Bhattacharyya, A.; Nanaji, Y.; Ghorai, M. K. J. Org. Chem. 2017, 82, 37. (d) Shahi, C. K.; Pradhan, S.; Bhattacharyya, A.; Kumar, R.; Ghorai, M. K. Eur. J. Org. Chem. 2017, 2017, 3487. (11) (a) Bhattacharyya, A.; Kavitha, C. V.; Ghorai, M. K. J. Org. Chem. 2016, 81, 6433. (b) Ghorai, M. K.; Tiwari, D. P. J. Org. Chem. 2013, 78, 2617. (c) Wani, I. A.; Sayyad, M.; Ghorai, M. K. Chem. Commun. 2017, 53, 4386. (d) Mal, A.; Sayyad, M.; Wani, I. A.; Ghorai, M. K. J. Org. Chem. 2017, 82, 4. (e) Lin, T.-Y.; Wu, H.-H.; Feng, J.-J.; Zhang, J. Org. Lett. 2017, 19, 6526. (12) (a) Kaur, T.; Wadhwa, P.; Sharma, A. RSC Adv. 2015, 5, 52769. (b) Van Leusen, A. M.; Hoogenboom, B. E.; Houwing, H. A. J. Org. Chem. 1976, 41, 711. (c) Phanindrudu, M.; Tiwari, D. K.; Sridhar, B.; Likhar, P. R.; Tiwari, D. K. Org. Chem. Front. 2016, 3, 795. (d) Lu, S.; Zhu, X.; Li, K.; Guo, Y.-J.; Wang, M.-D.; Zhao, X.-M.; Hao, X.-Q.; Song, M.-P. J. Org. Chem. 2016, 81, 8370. (e) Kadari, L.; Palakodety, R. K.; Yallapragada, L. P. Org. Lett. 2017, 19, 2580. (13) (a) Mendiola, J.; Minguez, J. M.; Alvarez-Builla, J.; Vaquero, J. J. Org. Lett. 2000, 2, 3253. (b) Coppola, A.; Sucunza, D.; Burgos, C.; Vaquero, J. J. Org. Lett. 2015, 17, 78. (c) Hu, Z.; Li, Y.; Pan, L.; Xu, X. Adv. Synth. Catal. 2014, 356, 2974. (d) Zhang, J.; Gao, Q.; Wu, X.; Geng, X.; Wu, Y.-D.; Wu, A. Org. Lett. 2016, 18, 1686. (e) Wang, J.; Li, J.; Zhu, Q. Org. Lett. 2015, 17, 5336. (f) Zhang, X.; Feng, C.; Jiang, T.; Li, Y.; Pan, L.; Xu, X. Org. Lett. 2015, 17, 3576. (g) Lin, Z.; Hu, Z.; Zhang, X.; Dong, J.; Liu, J.-B.; Chen, D.-Z.; Xu, X. Org. Lett. 2017, 19, 5284. (14) (a) Gutiérrez, S.; Coppola, A.; Sucunza, D.; Burgos, C.; Vaquero, J. J. Org. Lett. 2016, 18, 3378. (b) Du, J.; Xu, X.; Li, Y.; Pan, L.; Liu, Q. Org. Lett. 2014, 16, 4004. (15) See the Supporting Information for details. (16) Ghorai, M. K.; Shukla, D.; Bhattacharyya, A. J. Org. Chem. 2012, 77, 3740.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00986. Experimental procedures, analytical data, NMR spectra, and HPLC chromatograms (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Aditya Bhattacharyya: 0000-0001-7011-2102 Manas K. Ghorai: 0000-0002-0472-4757 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS M.K.G. is grateful to IIT Kanpur, India and CSIR, India for financial support. A.B. thanks CSIR, New Delhi, India for research fellowships. Dedicated to Prof. R. N. Mukherjee on the occasion of his 65th birthday.
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REFERENCES
(1) (a) Shinada, T.; Ikebe, E.; Oe, K.; Namba, K.; Kawasaki, M.; Ohfune, Y. Org. Lett. 2007, 9, 1765. (b) Pastor, J. M.; Salvador, M.; Argandoña, M.; Bernal, V.; Reina-Bueno, M.; Csonka, L. N.; Iborra, J. L.; Vargas, C.; Nieto, J. J.; Cánovas, M. Biotechnol. Adv. 2010, 28, 782. (2) Nair, A. C.; Jayatilleke, P.; Wang, X.; Miertus, S.; Welsh, W. J. J. Med. Chem. 2002, 45, 973. (3) Kopp, S. R.; Kotze, A. C.; McCarthy, J. S.; Traub, R. J.; Coleman, G. T. Vet. J. 2008, 178, 177. (4) (a) Ragozzino, M. E.; Artis, S.; Singh, A.; Twose, T. M.; Beck, J. E.; Messer, W. S. J. Pharmacol. Exp. Ther. 2012, 340, 588. (b) Messer, W. S.; Bachmann, K. A.; Dockery, C.; El-Assadi, A. A.; Hassoun, E.; Haupt, N.; Tang, B.; Li, X. Drug Dev. Res. 2002, 57, 200. (5) Han, S.; Morrison, K. C.; Hergenrother, P. J.; Movassaghi, M. J. Org. Chem. 2014, 79, 473. (6) (a) Scala, F.; Fattorusso, E.; Menna, M.; Taglialatela-Scafati, O.; Tierney, M.; Kaiser, M.; Tasdemir, D. Mar. Drugs 2010, 8, 2162. (b) Namba, K.; Shinada, T.; Teramoto, T.; Ohfune, Y. J. Am. Chem. Soc. 2000, 122, 10708. (7) (a) Ç etinkaya, B.; Alici, B.; Ö zdemir, I.; Bruneau, C.; Dixneuf, P. H. J. Organomet. Chem. 1999, 575, 187. (b) Mao, P.; Yang, L.; Xiao, Y.; Yuan, J.; Liu, X.; Song, M. J. Organomet. Chem. 2012, 705, 39. (8) (a) Zhang, M.; Jiang, H.; Liu, H.; Zhu, Q. Org. Lett. 2007, 9, 4111. (b) Cho, H.; Shima, K.; Hayashimatsu, M.; Ohnaka, Y.; Mizuno, A.; Takeuchi, Y. J. Org. Chem. 1985, 50, 4227. (c) Forsberg, J. H.; Spaziano, V. T.; Balasubramanian, T. M.; Liu, G. K.; Kinsley, S. A.; Duckworth, C. A.; Poteruca, J. J.; Brown, P. S.; Miller, J. L. J. Org. Chem. 1987, 52, 1017. (d) Dunbar, P. G.; Durant, G. J.; Fang, Z.; Abuh, Y. F.; El-Assadi, A. A.; Ngur, D. O.; Periyasamy, S.; Hoss, W. P.; Messer, W. S. J. Med. Chem. 1993, 36, 842. (e) Ganesh, V.; Sureshkumar, D.; Chandrasekaran, S. Angew. Chem., Int. Ed. 2011, 50, 5878. (f) Koteswara Rao, V.; Hari Babu, B.; Raveendra Babu, K.; Srinivasulu, D.; Naga Raju, C. Synth. Commun. 2012, 42, 3368. (g) An, S.; Yin, B.; Liu, P.; Li, X.; Li, C.; Li, J.; Shi, Z. Synthesis 2013, 45, 2525. (h) Zheng, D.; Wu, J. Eur. J. Org. Chem. 2014, 2014, 767. (i) Wang, L.; Yang, D.; Li, D.; Wang, R. Org. Lett. 2015, 17, 3004. (j) Bhanu Prasad, B. A.; Bisai, A.; Singh, V. K. Org. Lett. 2004, 6, 4829. (k) Yadav, V. K.; Sriramurthy, V. J. Am. Chem. Soc. 2005, 127, 16366. (l) Ghorai, M. K.; Das, K.; Kumar, A.; Das, A. Tetrahedron Lett. 2006, 47, 5393. (m) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2009, 50, 1105. D
DOI: 10.1021/acs.orglett.8b00986 Org. Lett. XXXX, XXX, XXX−XXX
