Letter pubs.acs.org/OrgLett
Direct Spirocyclization from Keto-sulfonamides: An Approach to Azaspiro Compounds Frédéric Beltran,† Indira Fabre,‡,§ Ilaria Ciofini,‡ and Laurence Miesch*,† †
Laboratoire de Chimie Organique Synthétique, Institut de Chimie, CNRS-UdS UMR 7177, 4, rue Blaise Pascal CS 90032, 67081 Strasbourg, France ‡ Chimie ParisTech, PSL Research University, CNRS, Institut de Recherche de Chimie Paris (IRCP), 75005 Paris, France § Département de chimie, École Normale Supérieure, PSL Research University, Sorbonne Universités, UPMC Univ., Paris 06, CNRS, 75005 Paris, France S Supporting Information *
ABSTRACT: Spontaneous spirocyclization of keto-sulfonamides via ynamides through a one-pot process is presented. Push−pull ynamides were obtained through Michael addition/ elimination without Cu. The obtained azaspiro compounds are building blocks for indole alkaloids. Theoretical studies provide insights into the mechanism of the formal Conia-ene reaction.
A
under silver catalysis led to bridged compounds through 7-exo-dig reactions.8 Thus, we focused on the reactivity of substituted ketoynamides fused to aromatic rings. To our surprise, coppercatalyzed N-alkynylation reaction on compound 1a led to azaspiro derivative 2a directly through a one-pot process from sulfonamides. The corresponding ynamide was not observed. Next, sulfonamide 1a was selected as a model for optimization of the reaction conditions (Table 1). The effect of the base was first examined. Whereas K2CO3 was slightly less efficient than Cs2CO3 for spirocyclization (Table 1, entries 1 and 2), 4 equiv of Cs2CO3 at 85 °C provided the most
zaspiro scaffolds are increasingly being used in drug discovery because of their three-dimensionality.1 Introducing a spirocyclic system to rigidify a ligand conformation has a strong impact on the binding of the ligand to a target protein, often providing enhanced benefit over flat rings.2 A large group of bioactive, natural diterpenoids possesses a quaternary carbon incorporated within a spirocyclic system that is part of a more complex ring system. Specifically, spiroindoles such as the aspidosperma alkaloids3 Elacomine4 and Jerantinine E5 are important targets because of their valuable pharmacological profiles, but challenging to prepare owing to the complexity of their tightly fused polycyclic scaffolds (Figure 1).
Table 1. One-Pot Spirocyclization and Optimization
Figure 1. Aspidosperma alkaloids.
Ynamides facilitate the synthesis of significant organic substructures because of the unique polarization of the triple bond.6 In recent decades, transition-metal-catalyzed cycloisomerization reactions of ene-ynamides have emerged as extraordinary tools to create molecular complexity, especially for N-containing heterocycles.7 Yet, spirocyclizations via ketoynamides are lacking, and also, one-pot transformations starting directly from keto-sulfonamides are noticeably absent. Herein we present a direct, new spirocyclization from ketosulfonamides through ynamides. This highly efficient, versatile process generates privileged spirocyclic scaffolds, producing building blocks for indole alkaloids. Previous work on cyclization of silyloxy ene-ynamides demonstrated that cyclization of silyl enol ether-ynesulfonamides © 2017 American Chemical Society
entry
base (equiv)
temp (°C)
% yielda (E/Z ratio)
1 2 3 4 5b 6d
K2CO3 (2.5) K2CO3 (4) Cs2CO3 (2.5) Cs2CO3 (4) Cs2CO3 (4) Cs2CO3 (4)
85 85 85 85 85 90
79 (70/30) 81 (70/30) 81 (70/30) 83 (70/30) −c −e
a
Yield of isolated compound. bCuI (5 mol %)/DMEDA (18 mol %) were used instead of CuSO4·5H2O/1,10-phenanthroline. cStarting material is totally recovered. dFeCl3 (10 mol %)/DMEDA (20 mol %) were used instead of CuSO4·5H2O/1,10-phenanthroline. eDegradation of starting material is observed. DMEDA: N,N′-Dimethylethylenediamine. Received: July 20, 2017 Published: September 20, 2017 5042
DOI: 10.1021/acs.orglett.7b02216 Org. Lett. 2017, 19, 5042−5045
Letter
Organic Letters advantageous yield of spiro compound 2a (Table 1, entry 4). Changing the metal to FeCl39 (Table 1, entry 5) or using CuI10 (Table 1, entry 6) did not improve the yield, and either starting material was recovered or degradation has occurred. Therefore, the reaction conditions listed in entry 4 were selected for further investigations. Next, we focused on various keto-sulfonamides. Monocyclic sulfonamides were converted into the corresponding spiro enamides in rather low yield (Table 2, 2b). Indanone
Table 3. Functionalization of the Ynamide Moiety
Table 2. Substrate Scope
a
Yield of isolated compound.
ynamides bearing an electron-withdrawing group, we wondered whether or not the copper plays a key role in the mechanistic pathway involved. A comparative study was undertaken in this way. Oxidative addition of a Cu(I) species formed in situ20 to the alkynyl bromide generates a Cu(III) alkynylcopper species. The excess base used can lead to double deprotonation of the keto sulfonamide substrate, which complexes the Cu(III) complex, forming copper complex I. As represented on the energy diagram (Figure 2) two geometries for this complex can be considered (IA and I-B), and for this reason, two pathways can be envisaged (Scheme 1). Pathway A would involve reductive elimination to form a C−N bond (II-A), and 1,4-addition of the resulting copper(I) enolate to the alkynoate, leading to alkenylcopper(I) intermediate II. Pathway B would involve reductive elimination to form a C−C bond (II-B), followed by 1,4-addition of an amidocopper(I) species on the alkynoate, providing the same alkenylcopper(II) species (Figure 2). Although both pathways are consistent with the fact that 1,4-addition of a Cu-complexed species is in favor of a one-pot spirocyclization with an electronwithdrawing group, the energetic barrier required to achieve this transformation is 12.8 kcal·mol−1 for pathway A (Figure 2, II-A → II) whereas the corresponding copper-free pathway requires only 5.4 kcal·mol−1 (see SI, Figure A). Pathway B is less favorable: 15.6 kcal·mol−1 are needed to access intermediate II in the Cucatalyzed process (Figure 2, II-B → II), whereas the noncopper pathway requires only 7.7 kcal·mol−1 (see SI, Figure A). A plausible mechanism consistent with this enthalpy profile suggests a 5-endo-dig addition of keto-ynamide enolate in situ, providing the spiro derivative after protonation (Pathway A).
a
Yield of isolated compound. bSee ref 11 for CCDC deposition number.
derivatives (Table 2, 2a, 2d) or tetralone derivatives (Table 2, 2e, 2f) were suitable substrates. Modifying the spacer length (Table 2, 2c) or larger ring sizes (Table 2, 2g) led to the desired spiro derivatives. Even the functionalized indolone building blocks 1h and 1i led to spiro derivatives 2h and 2i in a one-pot process. The scope of the reaction was also investigated with respect to different substituents on the enamide product. The protocol was found to be general for electron-withdrawing groups as substituents (2a, 2l−2s), whereas the phenyl substituent (Table 3, 2j) was not beneficial in this transformation. Yet, an electronwithdrawing group on an aryl ring (Table 3, 2k) was accommodated, affording the desired compound, albeit in lower yield. It is worth mentioning that this reaction was effective for keto derivatives (Table 3, 2a, 2l−2s) as well as amides (Table 3, 2t). To gain insight into the underlying mechanistic pathway, calculations based on Density Functional Theory (DFT) were performed (computational details in the Supporting Information (SI)). DFT calculations have been shown to be efficient in the understanding of the mechanisms of copper-catalyzed crosscoupling reactions.12−19 Sulfonamides derived from indanone 1a and tetralone 1e served as model substrates for all investigated processes. As the one-pot spirocyclization is only compatible for 5043
DOI: 10.1021/acs.orglett.7b02216 Org. Lett. 2017, 19, 5042−5045
Letter
Organic Letters
Figure 2. Comparative study for the mechanistic investigation with copper. Computed reaction pathways A and B (in kcal·mol−1).
Scheme 1. Reaction Pathways A and B Considered for the Mechanistic Investigation with Copper
Table 4. Spirocyclization without Copper
a
Yield of isolated compound. bDegradation of starting material is observed.
Control experiments suggested by a reviewer led to the remarkable observation that the whole process works without copper. Yields of azaspiro derivatives could be improved (Table 4, entries 1−2, 4−7), and the spirocyclization is only suitable for ynamides bearing an electron-withdrawing group (Table 4, entry 3). Transitional push−pull ynamides are probably the result of a Michael addition/elimination process followed by subsequent cyclization in basic medium. A synthesis of ynamides directly from sulfonamides was previously reported, although using a stronger base together with a Lewis acid.21 The mixed azaspiro derivatives 2a and 2e derived from indanones or tetralones, respectively, could be converted to the
sole E compounds quantitatively by treatment with p-TsOH (Scheme 2). Scheme 2. Isomerization of Spiro-enamides
5044
DOI: 10.1021/acs.orglett.7b02216 Org. Lett. 2017, 19, 5042−5045
Letter
Organic Letters
Rev. 2010, 110, 5064. (b) Wang, X.-N.; Yeom, H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.; Kedrowski, B. L.; Hsung, R. P. Acc. Chem. Res. 2014, 47, 560. (c) Evano, G.; Blanchard, N.; Compain, G.; Coste, A.; Demmer, C. S.; Gati, W.; Guissart, C.; Heimburger, J.; Henry, N.; Jouvin, K.; Karthikeyan, G.; Laouiti, A.; Lecomte, M.; Martin-Mingot, A.; Métayer, B.; Michelet, B.; Nitelet, A.; Theunissen, C.; Thibaudeau, S.; Wang, J.; Zarca, M.; Zhang, C. Chem. Lett. 2016, 45, 574. (d) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840. (e) Willumstad, T. P.; Boudreau, P. D.; Danheiser, R. L. J. Org. Chem. 2015, 80, 11794. (f) Gawade, S. A.; Huple, D. B.; Liu, R. S. J. Am. Chem. Soc. 2014, 136, 2978. (g) Theunissen, C.; Métayer, B.; Henry, N.; Compain, G.; Marrot, J.; Martin-Mingot, A.; Thibaudeau, S.; Evano, G. J. Am. Chem. Soc. 2014, 136, 12528. (h) Romain, E.; Fopp, C.; Chemla, F.; Ferreira, F.; Jackowski, O.; Oestreich, M.; Perez-Luna, A. Angew. Chem., Int. Ed. 2014, 53, 11333. (i) Liu, R.; Winston-McPherson, G. N.; Yang, Z. Y.; Zhou, X.; Song, W.; Guzei, I. A.; Tang, W. J. Am. Chem. Soc. 2013, 135, 8201. (j) Frischmuth, A.; Knochel, P. Angew. Chem., Int. Ed. 2013, 52, 10084. (k) Minko, Y.; Pasco, M.; Lercher, L.; Botoshansky, M.; Marek, I. Nature 2012, 490, 522. (l) Valenta, P.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2010, 132, 14179. (7) Selected examples since 2010 and references therein. For publications using Au, see: (a) Li, C. W.; Pati, K.; Lin, G. Y.; Sohel, S. M.; Hung, H. H.; Liu, R. S. Angew. Chem., Int. Ed. 2010, 49, 9891. (b) Ghosh, N.; Nayak, S.; Sahoo, A. K. Chem. - Eur. J. 2013, 19, 9428. (c) Wang, K. B.; Ran, R. Q.; Xiu, S. D.; Li, C. Y. Org. Lett. 2013, 15, 2374. (d) Blanco Jaimes, M. C.; Weingand, V.; Rominger, F.; Hashmi, A. S. K. Chem. - Eur. J. 2013, 19, 12504. (e) Adcock, H. V.; Langer, T.; Davies, P. W. Chem. - Eur. J. 2014, 20, 7262. (f) Wang, T.; Shi, S.; Hansmann, M. M.; Rettenmeier, E.; Rudolph, M.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2014, 53, 3715. (g) Liu, J.; Chen, M.; Zhang, L.; Liu, Y. Chem. - Eur. J. 2015, 21, 1009. (h) Tokimizu, Y.; Wieteck, M.; Rudolph, M.; Oishi, S.; Fujii, N.; Hashmi, A. S. K.; Ohno, H. Org. Lett. 2015, 17, 604. For Pd, see: (i) Greenaway, R. L.; Campbell, C. D.; Holton, O. T.; Russell, C. A.; Anderson, E. A. Chem. - Eur. J. 2011, 17, 14366. (j) Walker, P. R.; Campbell, C. D.; Suleman, A.; Carr, G.; Anderson, E. A. Angew. Chem., Int. Ed. 2013, 52, 9139. Liu, G.; Kong, W.; Che, J.; Zhu, G. Adv. Synth. Catal. 2014, 356, 3314. For Ru, see: (l) Wakamatsu, H.; Sakagami, M.; Hanata, M.; Takeshita, M.; Mori, M. Macromol. Symp. 2010, 293, 5. For Cu, see: (m) Hashmi, A. S. K.; Schuster, A. M.; Zimmer, M.; Rominger, F. Chem. - Eur. J. 2011, 17, 5511. (n) Gati, W.; Couty, F.; Boubaker, T.; Rammah, M. M.; Rammah, M. B.; Evano, G. Org. Lett. 2013, 15, 3122. For Rh, see: (o) Nishimura, T.; Takiguchi, Y.; Maeda, Y. Y.; Hayashi, T. Adv. Synth. Catal. 2013, 355, 1374. (p) See ref 3i. For Ag, see: (q) Garcia, P.; Harrak, Y.; Diab, L.; Cordier, P.; Ollivier, C.; Gandon, V.; Malacria, M.; Fensterbank, L.; Aubert, C. Org. Lett. 2011, 13, 2952. (r) Sueda, T.; Kawada, A.; Urashi, Y.; Teno, N. Org. Lett. 2013, 15, 1560. (8) Heinrich, C. F.; Fabre, I.; Miesch, L. Angew. Chem., Int. Ed. 2016, 55, 5170. (9) Yao, B.; Liang, Z.; Niu, T.; Zhang, Y. J. J. Org. Chem. 2009, 74, 4630. (10) Hirano, S.; Tanaka, R.; Urabe, H.; Sato, F. Org. Lett. 2004, 6, 727. (11) CCDC 1555872 (2h) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre. (12) Yu, H.-Z.; Jiang, Y.-Y.; Fu, Y.; Liu, L. J. Am. Chem. Soc. 2010, 132, 18078. (13) Zhang, S.-L.; Liu, L.; Fu, Y.; Guo, Q.-X. Organometallics 2007, 26, 4546. (14) Jones, G. O.; Liu, P.; Houk, K. N.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 6205. (15) Fabre, I.; Perego, L. A.; Bergès, J.; Ciofini, I.; Grimaud, L.; Taillefer, M. Eur. J. Org. Chem. 2016, 2016, 5887. (16) Lefèvre, G.; Franc, G.; Adamo, C.; Jutand, A.; Ciofini, I. Organometallics 2012, 31, 914. (17) Tsipis, A. C. Coord. Chem. Rev. 2014, 272, 1. (18) Guo, H.; Xue, Y. J. Theor. Comput. Chem. 2012, 11, 1135. (19) Fraile, J. M.; García, J. I.; Martínez-Merino, V.; Mayoral, J. A.; Salvatella, L. J. Am. Chem. Soc. 2001, 123, 7616. (20) Franc, G.; Jutand, A. Dalton Trans. 2010, 39, 7873. (21) Villeneuve, K.; Riddell, N.; Tam, W. Tetrahedron 2006, 62, 3823.
In summary, we have developed a one-pot spirocyclization from sulfonamides to the synthesis of azaspiro derivatives. This chemistry tolerates a variety of alkanones as well as numerous substituents at the alkenyl moiety. Thus, multiple ring sizes for the spiro derivatives are accessible. Furthermore, this strategy enables the efficient construction of azaspirocyclic scaffolds which can be useful building blocks for alkaloid indoles. DFT calculations gave insights into the underlying mechanism and corroborated the results obtained. Further studies expanding the scope and applications of this one-pot process are ongoing in our laboratory.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02216. Experimental procedures, synthesis method of starting materials, and compound characterization data (PDF) 1 H and 13C NMR spectra (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Ilaria Ciofini: 0000-0002-5391-4522 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. F.B. thanks M.R.T. for a research fellowship. We thank a reviewer for a valuable suggestion.
■
REFERENCES
(1) The Practice of Medicinal Chemistry; Wermuth, C. G., Ed.; Elsevier Academic Press: San Diego, 2003. (2) Hung, A. W.; Ramek, A.; Wang, Y.; Kaya, T.; Wilson, J. A.; Clemons, P. A.; Young, D. W. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 6799. (3) Selected examples since 2010: (a) Giampa, G. M.; Fang, J.; Brewer, M. Org. Lett. 2016, 18, 3952. (b) Nibbs, A. E.; Montgomery, T. D.; Zhu, Y.; Rawal, V. H. J. Org. Chem. 2015, 80, 4928. (c) McMurray, L.; Beck, E. M.; Gaunt, M. J. Angew. Chem. 2012, 124, 9422; Angew. Chem., Int. Ed. 2012, 51, 9288. (d) Kawano, M.; Kiuchi, T.; Negishi, S.; Tanaka, H.; Hoshikawa, T.; Matsuo, J.; Ishibashi, H. Angew. Chem. 2013, 125, 940; Angew. Chem., Int. Ed. 2013, 52, 906. (e) Cho, H.-K. T.; Tam, N. T.; Cho, C.-G. Bull. Korean Chem. Soc. 2010, 31, 3382. (f) De Simone, F.; Gertsch, J.; Waser, J. Angew. Chem., Int. Ed. 2010, 49, 5767. (g) Guérard, K. C.; Sabot, C.; Beaulieu, M.-A.; Giroux, M.-A.; Canesi, S. Tetrahedron 2010, 66, 5893. (h) Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature 2011, 475, 183. (i) Jiao, L.; Herdtweck, E.; Bach, T. J. Am. Chem. Soc. 2012, 134, 14563. (j) Lajiness, J. P.; Jiang, W.; Boger, D. L. Org. Lett. 2012, 14, 2078. (k) Huang, J.-Z.; Jie, X.-K.; Wei, K.; Zhang, H.; Wang, M.-C.; Yang, Y.-R. Synlett 2013, 24, 1303. (l) Li, Z.; Zhang, S.; Wu, S.; Shen, X.; Zou, L.; Wang, F.; Li, X.; Peng, F.; Zhang, H.; Shao, Z. Angew. Chem., Int. Ed. 2013, 52, 4117. (m) Nidhiry, J. E.; Prasad, K. R. Tetrahedron 2013, 69, 5525. (n) Zhao, S.; Andrade, R. B. J. Am. Chem. Soc. 2013, 135, 13334. (4) Kamisaki, H.; Nanjo, T.; Tsukano, C.; Takemoto, Y. Chem. - Eur. J. 2011, 17, 626. (5) Frei, R.; Staedler, D.; Raja, A.; Franke, R.; Sasse, F.; Gerber-Lemaire, S.; Waser, J. Angew. Chem., Int. Ed. 2013, 52, 13373. (6) For recent reviews on ynamide chemistry, see: (a) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. 5045
DOI: 10.1021/acs.orglett.7b02216 Org. Lett. 2017, 19, 5042−5045
