Trapping of N-Acyliminium Ions with Enamides: An Approach to

Letter Cite This: Org. Lett. 2018, 20, 3430−3433

pubs.acs.org/OrgLett

Trapping of N‑Acyliminium Ions with Enamides: An Approach to Medium-Sized Diaza-Heterocycles Lucile Andna and Laurence Miesch* Laboratoire de Chimie Organique Synthétique, Institut de Chimie, CNRS-UdS, UMR 7177, 4, rue Blaise Pascal, CS 90032, 67081 Strasbourg, France S Supporting Information *

ABSTRACT: Enamides equipped with N-acyliminium ion precursors were obtained through reduction of ynamides tethered to N-imides. Intramolecular TMSOTf-mediated trapping of N-acyliminium ions provided a variety of polyfunctionalized medium-sized diaza-heterocycles of putative pharmacological interest.

E

namines as their parent silicon enolates have been extensively used as nucleophiles in aldol-type reactions via aza-ene-type mechanism to form C−C bonds.1 Later, the more stable secondary enamides bearing an electron-withdrawing group on the nitrogen2 emerged as powerful nucleophiles in a large variety of Lewis acid catalyzed reactions, whereas tertiary enamides were initially claimed to be unreactive toward electrophiles.3 However, recent work on tertiary enamides has proven that those substrates display enaminic reactivity toward several classes of electrophiles,4 including epoxides,5 carbonyls,6 imines,7 nitriliums,8 and activated alkynes.9 N-Acyliminium ions (NAIs) are highly reactive electrophiles that have been widely used in intramolecular cyclizations and intermolecular additions for accessing structurally diverse scaffolds of broad biological interest.10 Protonation of the hydroxyl group at the α-position of the N-acyl group is the most common means of producing a leaving group to generate NAIs.11 Tertiary enamides equipped with N-acyliminium ion precursors, e.g., hydroxylated pyrrolidone derivatives, have not been exploited, although they are attractive substrates for the synthesis of heterocycles of putative pharmacological interest (Figure 1).12 Our recent interest in ynamide chemistry13 prompted us to investigate this attractive field. To this end, the required Nimides tethered to ynesulfonamides 4a−n were readily

prepared from anhydrides 1a−j and monoprotected diamines 2a−c in refluxing AcOH, followed by the application of Hsung’s copper-catalyzed N-alkynylation reaction,14 affording the corresponding ynesulfonamides 4a−n (Scheme 1). Among other methods,15 tertiary enamides can be obtained via reduction of ynamides.16 When nonsymmetrical N-imides were used, the reduction step led to mixtures of regioisomers. Whereas ynamides 4a−l bearing an ester group could be reduced in the desired enamides tethered to a NAI precursor through a one-pot procedure, the enamides bearing an aryl group 4m−n were reduced with NiP2,17 followed by NaBH4 reduction. It is worth noting that NiP2 reduction of ynamides provides a new way to provide exclusive access to Z-enamides 5m−n, wherein Lindlar reduction fails,18 and the starting material was fully recovered (Scheme 2). With the enamides 6a−n equipped with an N-acyliminium ion precursor in hand, we began our investigations by examining the treatment of those compounds with BF3·OEt2. Bicyclic diazepine 7a was obtained with good yield through intramolecular trapping of the N-acyliminium ion with tertiary enamide 6a (Scheme 3). Screening of Lewis and Brønsted acids revealed that different acids were able to accomplish this cyclization, although with great yield variations (Table 1). Brønsted acids (Table 1, entries 2 and 3)19 were not as effective in promoting this cyclization reaction. Y(OTf)320 led to the desired diazepine 7a with acceptable yield (Table 1, entry 6), although heating is essential (Table 1, entry 5), and stoichiometric amounts of the Lewis acid led to better yields (Table 1, entry 7). Moderate yields of diazepine 7a were obtained using FeCl3, TiCl4, and InCl3 (Table 1, entries 4, 8, and 9). TMSOTf21 proved to be the most efficient Lewis acid in this cyclization reaction (Table 1, entry 11), although a lower loading of TMSOTf was not beneficial for the cyclization reaction even by increasing the reaction time (Table 1, entry 10). A more

Figure 1. Biologically active benzodiazepines.

Received: May 3, 2018 Published: May 23, 2018

© 2018 American Chemical Society

3430

DOI: 10.1021/acs.orglett.8b01407 Org. Lett. 2018, 20, 3430−3433

Letter

Organic Letters Scheme 1. Synthesis of N-Imide Tethered to Ynesulfonamidea

Scheme 2. Synthesis of Enamides Tethered to NAI Precursors

c

Yield for isolated compounds.

Scheme 3. Intramolecular Trapping of NAI with Tertiary Enamide

a

Yield for isolated compound.

Table 1. Screening of Brønsted and Lewis Acids

entry

acid (equiv)

reaction conditions

yielda (%)

1 2 3 4 5 6 7 8 9 10 11 12

BF3·OEt2 (1.2) p-TsOH (1.2) CSA (1.2) FeCl3 (1.0) Y(OTf)3 (0.9) Y(OTf)3 (0.1) Y(OTf)3 (1.2) TiCl4 (1.2) InCl3 (1.2) TMSOTf (0.1) TMSOTf (1.2) TBSOTf (1.2)

CH2Cl2, rt, 0.5 h CH2Cl2, rt, 3 h CH2Cl2, rt, 3.5 h DCE, rt, 1 h, MS PhCl, rt, 21 h, MS PhCl, 80 °C, 2.5 h, MS PhCl, 80 °C, 1 h, MS DCE, rt, 5 h, reflux, 30 min, MS CH2Cl2, rt, 4.5 h CH2Cl2, rt, 20 h CH2Cl2, rt, 0.75 h CH2Cl2, rt, 0.5 h

78 24 18 42 0 42 64 38 38 traces 83 76

a

Yield of isolated compounds.

The solvent effect was then examined (Figure 2). Whereas CH2Cl2 proved to be the best solvent for this reaction, MeCN, toluene, DCE, and MeNO2 led to diazepine 7a in acceptable yields. A significant drop in yield was observed with Et2O, THF, and acetone. CHCl3 led to total degradation of the starting material, whereas in DMF starting material 6a was fully recovered. Having found that TMSOTf in CH2Cl2 favors best trapping of NAI by tertiary enamides, we evaluated the scope of the reaction by using various NAI precursors, different spacer lengths, as well as different substituents on the enamide moiety (Scheme 4). β-Substituted enamides with aryl or phenyl groups

a Reaction conditions: Unless otherwise specified, the first reaction was carried out with 1a−j (1 equiv), NaOAc (3 equiv), 2a−c (1 equiv), acetic acid, reflux, 24 h. CuII reaction with 3a−l (1 equiv), CuSO4· 5H2O (15 mol %), 1,10-phenanthroline (30 mol %), K2CO3 (2.5 equiv), 1-bromo-1-alkyne (1.15 equiv), toluene, 85 °C, 4 to 24 h. b Yield for isolated compounds.

hindered silyl trifluoromethanesulfonate TBSOTf (Table 1, entry 12) was as efficient as BF3·OEt2 (Table 1, entry 1). 3431

DOI: 10.1021/acs.orglett.8b01407 Org. Lett. 2018, 20, 3430−3433

Letter

Organic Letters Scheme 5. Plausible Mechanism

Figure 2. Solvent screening (isolated yields).

6m−n were tolerated, providing diazepines with good yields (7m, 7n). With bicyclic NAI precursors, the cyclization went smoothly to afford the corresponding diazepines (7c, 7d, 7g). The chemical structure of compound 7d was confirmed by X-ray crystallography (Scheme 4). Unsaturated and spiro NAI precursors were both effective in this cyclization reaction, providing diazepines 7f and 7j in 59 and 63% yields, respectively. Unsymmetrical gem-dimethyl and fluorinated phthalimide NAI precursors 6e and 6h led to mixtures of diazepines 7e (ratio 1:6) and 7h (ratio 1:3). Three methylene units for the spacer length were also allowed (6k, 6n), providing diazocanes (7k, 7n) with tertiary enamides substituted with either an electron-withdrawing group or a phenyl group. Even homologue 6l with four methylene units could undergo this cyclization reaction, providing diazonane 7l, although in a rather moderate yield. The 1,3-diazepine 8 was also observed in this case, obtained by direct trapping of NAI by a nitrogen atom. To explain the formation of diaza-heterocycles 7a−n, we propose the following mechanism. After formation of the Nacyliminium ion B in the presence of Brønsted or Lewis acids, enamidic attack of B to the acyliminium ion provides intermediate C. The bicyclic diazepine evolves upon deprotonation of the β-disubstituted enamide C (Scheme 5). In conclusion, we have shown that enamides equipped with N-acyliminium precursors are accessible through reduction of the corresponding ynamides. These versatile tools lead to functionalized medium-sized diaza-heterocycles prevalent in biologically active molecules. Monocyclic, bicyclic, as well as enamides substituted with ester and aryl groups were tolerated. 1,5-Diazocanes and -diazonanes are accessible through this process, allowing the expansion of synthesis of various diazaheterocycles attractive in the field of drug design.

Scheme 4. Substrate Scope

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01407. Experimental procedures, synthesis of starting materials, and compound characterization data; 1H and 13C NMR spectra (PDF) Accession Codes a

Yield for isolated compound. deposited with the CCDC.

b

CCDC 1831780 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge

Crystallographic data has been

3432

DOI: 10.1021/acs.orglett.8b01407 Org. Lett. 2018, 20, 3430−3433

Letter

Organic Letters

(14) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L. Org. Lett. 2004, 6, 1151. (15) Selected references for the preparation of enamides from ynamides: (a) Evano, G.; Michelet, B.; Zhang, C. C. R. Chim. 2017, 20, 648 and references cited therein. Selected references for preparation of enamides: (b) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667. (c) Gooßen, L. J.; Rauhaus, J. E.; Deng, G. Angew. Chem., Int. Ed. 2005, 44, 4042. (d) Bolshan, Y.; Batey, R. A. Angew. Chem., Int. Ed. 2008, 47, 2109. (e) Yamagishi, M.; Nishigai, K.; Hata, T.; Urabe, H. Org. Lett. 2011, 13, 4873. (f) Panda, N.; Mothkuri, R. J. Org. Chem. 2012, 77, 9407. (g) Kim, S. M.; Lee, D.; Hong, S. H. Org. Lett. 2014, 16, 6168. (h) Li, H.; Ma, T.; Li, X.; Zhao, Z. RSC Adv. 2015, 5, 84044. (i) Panda, N.; Yadav, S. A.; Giri, S. Adv. Synth. Catal. 2017, 359, 654. (16) (a) Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.; Kurtz, K. C. M.; Oppenheimer, J.; Petersen, M. E.; Sagamanova, I. K.; Shen, L.; Tracey, M. R. J. Org. Chem. 2006, 71, 4170. (b) Barbazanges, M.; Meyer, C.; Cossy, J. Org. Lett. 2007, 9, 3245. (c) Siva Reddy, A.; Kumara Swamy, K. C. Angew. Chem., Int. Ed. 2017, 56, 6984. (d) Cook, A. M.; Wolf, C. Angew. Chem., Int. Ed. 2016, 55, 2929. (17) (a) Brown, H. C.; Brown, C. A. J. Am. Chem. Soc. 1963, 85, 1005. (b) Brown, C. A.; Ahuja, V. K. J. Chem. Soc., Chem. Commun. 1973, 553. (c) Brown, C. A.; Ahuja, V. K. J. Org. Chem. 1973, 38, 2226. (18) Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.; Kurtz, K. C. M.; Oppenheimer, J.; Petersen, M. E.; Sagamanova, I. K.; Shen, L.; Tracey, M. R. J. Org. Chem. 2006, 71, 4170. (19) Lecomte, M.; Evano, G. Angew. Chem., Int. Ed. 2016, 55, 4547. (20) Zhou, B.; Li, L.; Zhu, X.-Q.; Yan, J.-Z.; Guo, Y.-L.; Ye, L.-W. Angew. Chem., Int. Ed. 2017, 56, 4015. (21) Yamada, S.; Takahashi, Y. Tetrahedron Lett. 2009, 50, 5395.

Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Laurence Miesch: 0000-0002-0369-9908 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS Support for this work was provided by CNRS and Université de Strasbourg. L.A. thanks M.R.T. for a research fellowship.

■

REFERENCES

(1) (a) Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954, 76, 2029. (b) Stork, G.; Landesman, H. K. J. Am. Chem. Soc. 1956, 78, 5128. (2) (a) Courant, T.; Dagousset, G.; Masson, G. Synthesis 2015, 47, 1799. (b) Carbery, D. R. Org. Biomol. Chem. 2008, 6, 3455. (c) Bernadat, G.; Masson, G. Synlett 2014, 25, 2842. (d) Nugent, C. T.; El- Shazly, M. Adv. Synth. Catal. 2010, 352, 753. (e) Gigant, N.; Chausset-Boissarie, L.; Gillaizeau, I. Chem. - Eur. J. 2014, 20, 7548. (f) Gigant, N.; Chausset-Boissarie, L.; Rey-Rodriguez, R.; Gillaizeau, I. C. R. Chim. 2013, 16, 358. (3) Matsubara, R.; Kobayashi, S. Acc. Chem. Res. 2008, 41, 292. (4) Wang, M.-X. Chem. Commun. 2015, 51, 6039 and references cited therein. (5) (a) Yang, L.; Zheng, Q.-Y.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. Org. Lett. 2008, 10, 2461. (b) Yang, L.; Wang, D.-X.; Pan, J.; Zheng, Q.-Y.; Huang, Z.-T.; Wang, M.-X. Org. Biomol. Chem. 2009, 7, 2628. (c) Cossey, K. N.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 12216. (6) (a) Yang, L.; Wang, D.-X; Huang, Z.-T.; Wang, M.-X. J. Am. Chem. Soc. 2009, 131, 10390. (b) Yang, L.; Lei, C.-H.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. Org. Lett. 2010, 12, 3918. (c) Tong, S.; Wang, D.-X.; Zhao, L.; Zhu, J.; Wang, M.-X. Angew. Chem., Int. Ed. 2012, 51, 4417. (7) (a) Tong, S.; Yang, X.; Wang, D.-X.; Zhao, L.; Zhu, J.; Wang, M.X. Tetrahedron 2012, 68, 6492. (b) Suga, S.; Nishida, T.; Yamada, D.; Nagaki, A.; Yoshida, J.-I. J. Am. Chem. Soc. 2004, 126, 14338. (8) (a) Lei, C.-H.; Wang, D.-X.; Zhao, L.; Zhu, J.; Wang, M.-X. J. Am. Chem. Soc. 2013, 135, 4708. (b) Lei, C.-H.; Wang, D.-X.; Zhao, L.; Zhu, J.; Wang, M.-X. Chem. - Eur. J. 2013, 19, 16981. (c) Lei, C.-H.; Zhao, L.; Wang, D.-X.; Zhu, J.; Wang, M.-X. Org. Chem. Front. 2014, 1, 909. (9) (a) Harrison, T. J.; Patrick, B. O.; Dake, G. R. Org. Lett. 2007, 9, 367. (b) Nayak, S.; Prabagar, B.; Ghosh, N.; Mallick, R. K.; Sahoo, A. K. Synthesis 2017, 49, 4261. (10) (a) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817. (b) Wu, P.; Nielsen, T. E. Chem. Rev. 2017, 117, 7811. (11) (a) Pyne, S. G.; Au, C. W. G.; Davis, A. S.; Morgan, I. R.; Ritthiwigrom, T.; Yazici, A. Pure Appl. Chem. 2008, 80, 751. (b) Morgan, I. R.; Yazici, A.; Pyne, S. G.; Skelton, B. W. J. Org. Chem. 2008, 73, 2943. (c) Morgan, I. R.; Yazici, A.; Pyne, S. G. Tetrahedron 2008, 64, 1409. (12) (a) Siegl, P. K. S; Goldberg, A. I.; Goldberg, M. R.; Chang, P. I. U. S. Patent 5,817,658, 1998. (b) Pardo, L. M.; Tellitu, I.; Dominguez, E. Tetrahedron 2010, 66, 5811. (c) Yaremenko, A. G.; Shelyakin, V. V.; Volochnyuk, D. M.; Rusanov, E. B.; Grygorenko, O. O. Tetrahedron Lett. 2013, 54, 1195. (13) (a) Heinrich, C. F.; Fabre, I.; Miesch, L. Angew. Chem., Int. Ed. 2016, 55, 5170. (b) Beltran, F.; Fabre, I.; Ciofini, I.; Miesch, L. Org. Lett. 2017, 19, 5042. 3433

DOI: 10.1021/acs.orglett.8b01407 Org. Lett. 2018, 20, 3430−3433