Re Rh(I) 9,206,100 B2 12/2015 Alabugin Et Al

USOO9573871B2

(12) United States Patent (10) Patent No.: US 9,573,871 B2 Vidhani et al. (45) Date of Patent: Feb. 21, 2017

(54) STEREO CONTROLLED SYNTHESIS OF Tetrahedron, 57. (C) 2001 Elsevier Science Ltd., (2001) pp. 3715 (E,Z)-DIENALS VIA TANDEM RHOI) 3724. CATALYZED PROPARGYL CLASEN Wu, Jishan et al., Graphenes as Potential Material for Electronics, REARRANGEMENT Chemical Reviews, vol. 107, No. 3, (C) 2007 American Chemical Society, (2007), pp. 718-747. (71) Applicants: The Florida State University Berresheim, Alexander J. et al., Polyphenylene Nanostructures, Research Foundation, Inc., Chemical Reviews, vol. 99, No. 7, (C) 1999 American Chemical Tallahassee, FL (US); Robert A. Society, (1999), pp. 1747-1785. Holton, Tallahassee, FL (US) Geim, A.K. et al., The Rise of Graphene, Nature Materials, vol. 6, (72) Inventors: Dinesh V. Vidhani, Tallahassee, FL (C) 2007 Nature Publishing Group, (Mar. 2007), pp. 183-191. Kuninobu, Yoichiro et al., Synthesis of Functionalized Pentacenes (US); Marie E. Kraft, Tallahassee, FL from Isobenzofurans Derived from C-H Bond Activation, Organic (US); Igor Alabugin, Tallahassee, FL Letters, vol. 12, No. 22, (C) 2010 American Chemical Society, (Oct. (US) 20, 2010), pp. 5287-5289. (73) Assignee: The Florida State University Scherf, Ullrich, Ladder-type materials, J. Mater. Chem... vol. 9, Research Foundation, Inc., 1999, pp. 1853-1864. Tallahassee, FL (US) Allen, Matthew J. et al., Honeycomb Carbon: A Review of Graphene, Chemical Reviews, vol. 110, No. 1. (C) 2010 American (*) Notice: Subject to any disclaimer, the term of this Chemical Society, (Jul. 17, 2009), pp. 132-145. patent is extended or adjusted under 35 Goldfinger, Marc B. et al., Fused Polycyclic Aromatics via U.S.C. 154(b) by 0 days. Electrophile-Induced Cyclization Reactions: Application to the (21) Appl. No.: 14/724,016 Synthesis of Graphite Ribbons, J. Am. Chem. Soc., vol. 116, No. 17. (C) 1994 American Chemical Society, (1994), pp. 7895-7896. (22) Filed: May 28, 2015 Swartz, Christopher R. et al., Synthesis and Characterization of (65) Prior Publication Data Electron-Deficient Pentacenes, Organic Letters, vol. 7, No. 15, C) 2005 American Chemical Society, (Jun. 30, 2005), pp. 3163-3166. US 2015/0361019 A1 Dec. 17, 2015 Li, Xiaolin et al., Chemically Derived, Ultrasmooth Graphene Nanoribbon Semiconductors, Science, vol. 319, (C) 2008 by the Related U.S. Application Data American Association for the Advancement of Science, (Feb. 29. (60) Provisional application No. 62/011,251, filed on Jun. 2008), pp. 1229-1232. 12, 2014. (Continued) (51) Int. Cl. Primary Examiner — Golam M M Shameem CD7C 4I/08 (2006.01) C07C 45/51 (2006.01) (74) Attorney, Agent, or Firm — Armstrong Teasdale LLP C07C 253/30 (2006.01) (57) ABSTRACT C07D 307/42 (2006.01) CO7D 307/246 (2006.01) A novel Rh(I)-catalyzed approach to synthesizing function (52) U.S. Cl. alized (E,Z) dienal compounds has been developed via CPC ...... C07C 45/513 (2013.01); C07C4I/08 tandem transformation where a stereoselective hydrogen (2013.01); C07C 253/30 (2013.01); C07D transfer follows a propargyl Claisen rearrangement. Z-Ste 307/42 (2013.01); C07D 307/46 (2013.01) reochemistry of the first double bond suggests the involve (58) Field of Classification Search ment of a six-membered cyclic intermediate whereas the CPC ...... C07C 45/513; C07C 41/08 E-stereochemistry of the second double bond stems from the See application file for complete search history. Subsequent protodemetallation step giving an (E,Z)-dienal. (56) References Cited The reaction may be represented by the following sequence. U.S. PATENT DOCUMENTS 8.410.303 B2 4/2013 Alabugin et al. 8,927,728 B2 1/2015 Alabugin et al. 8,927,778 B2 1/2015 Alabugin et al. re Rh(I) 9,206,100 B2 12/2015 Alabugin et al. H Propargyll Claisen 9,273,023 B2 3/2016 Alabugin et al. R Rearrangement 2013,0196985 A1 8/2013 Ding et al. i? \s R

FOREIGN PATENT DOCUMENTS O H N WO 2012O37062 A3 3, 2012 H Hos Stereoselective OTHER PUBLICATIONS R Proton Transfer R R Vidhani et al (2013):STN International, HCAPLUS database (Columbus, Ohio), Accession No. 2013: 1316846.* Mallory, Frank B. et al., Phenacenes: a family of graphite ribbons. Part 3: Iterative strategies for the synthesis of large phenacenes, 6 Claims, 3 Drawing Sheets US 9,573.871 B2 Page 2

(56) References Cited Evans, D.A. et al., 3.3 Sigmatropic Rearrangements of 1.5-Diene Alkoxides. The Powerful Accelerating Effects of the Alkoxide Substituent, Journal of the American Chemical Society, Aug. 6. OTHER PUBLICATIONS 1975, pp. 4765-4766, vol. 97, No. 16, American Chemical Society. Evans, D.A. et al., A General Approach to the Synthesis of 1.6 Paquette, Lee et al., The Square Ester—Polycuinane Connection. Dicarbonyl Substrates. New Applications of Base-Accelerated Oxy An Analysis of the Capacity of Achiral Divinyl Adducts to Rear Cope Rearrangements, Journal of the American Chemical Society, range Spontaneously to Polycyclic Networks Housing Multiple Mar. 29, 1978, pp. 2242-2244, vol. 100, No. 7. American Chemical Sterogenic Centers, J. American Chemical Society, 1997, vol. 119, Society. pp. 1230-1241. Jacobi, Peter A. et al., Bis Heteroannulation. 7. Total Syntheses of Pollart, Daniel J. et al., Generation of (+)-Chididione and (+)-Isognididione, J. Am. Chem. Soc., 1987, pp. (Trimethylsiloxy)(phenylethynyl)ketene and 3041-3043, vol. 106, Amerian Chemical Society. (Trimethylsiloxy)cyanoketene and Their Reactions with Some Paquette, Leo A. Recent Applications of Anionic Oxy-Cope Rear Alkynes, Journal of Org. Chemical, 1989, vol. 54, pp. 5444-5448. rangements, Tetrahedron Report No. 429, 1997, pp. 13971-14020, Arns, Steve et al., Cascading pericyclic reactions: building complex vol. 52, No. 41, Elsevier Science Ltd, Great Britian. carbon frameworks for natural product synthesis, Chem. Commun., Roth, Wolfgang R. et al. A “Frustrated” Cope Rearrangement: 2007, pp. 2211-2221. The Royal Society of Chemistry. Thermal Interconversion of 2,6-Diphenylhepta-1,6-diene and 1.5- Baldwin, Jack E. et al., Rules for Ring Closure: Application to Diphenylbicyclo[3.2.0]heptain, Journal of the American Chemical Intramolecular Aldol Condensations in Polyketonic Substrates, Tet Society, 1990, pp. 1722-1732, vol. 112, American Chemical Soci rahedron, 1982, pp. 2939-2947, vol. 38, No. 19, Great Britain. ety. Butenschon, Holger, Arene chromium complexes with functional Pal, Runa et al., Fast Oxy-Cope Rearrangements of Bis-alkynes: ized anellated rings. Selective formation of highly substituted Competition with Central C-C Bond Fragmentation and Incorpo polycycles, Pure Appl. Chem., 2002, pp. 57-62; vol. 74, No. 1, ration in Tunable Cascades Diverging from a Common Bis-allenic IUPAC. Intermediate, JOC Note, 2010, pp. 3689-8692, vol. 75, J. Org. Carpenter, Barry K., A Simple Model for Predicting the Effect of Chem. Substituents on the Rates of Thermal Pericyclic Reactions, Tetra Zimmerman, Howard E., Kinetic Protonation of Enols, Enolates, hedron, 1978, pp. 1877-1884, vol. 34, Pergamon Press Ltd. and Analogues. The Stereochemistry of Ketonization, Acc. Chem. Dahnke, Karl R. et al., Exploratory Synthetic Studies Involving the Res., 1987, pp. 263-268, vol. 20, American Chemical Society. Tricyclo9.3.0.02,8tetradecane Ring System Peculiar to the Zimmerman. Howard E. et al. The Stereochemistry of Allenic Enol Cyathins, J. Org. Chem., 1994, pp. 885-899, vol. 59, American Tautomerism Independent Generation and Reactivity of he Chemical Society. Enolates, Eur, J. Org. Chem., 2006, pp. 3491-3497, Wiley-VCH Gentric, Lionel et al., Rate Acceleration of Anionic Oxy-Cope Verlag GmbH & Co. Rearrangements Induced by an Additional Unsaturation, Organic Pati, Kamalkishore, et al., Exo-Dig Radical Cascades of Skipped Letters, 2003, pp. 3631-3634, vol. 5, No. 20, American Chemical Enediynes: Building a Naphthalene Moiety within a Polycyclic Society. Framework, Chemistry, A European Journal, 2014, vol. 20, pp. Graulich, Nicole et al., Heuristic thinking makes a chemist Smart, 390-393. Chemical Society Reviews, 2010, pp. 1503-1512, vol. 39. The Vidhani, Dinesh V. et al., “Stereocontrolled Synthesis of (E,Z)- Royal Society of Chemistry. Dienals via Tandem Rh(I)-Catalyzed Rearrangement of Propargyl Huntsman, William D. et al., The Thermal Rearrangement of Vinyl Ethers'. Organic Letters, 2013, pp. 4462-4465, vol. 15, No. 1.5-Hexadiyne and Related Compounds, J. Org. Chem. Jan. 18, 17, American Chemical Society. 1967, pp. 342-347, vol. 89, No. 2, Journal of the American Chemical Society. * cited by examiner U.S. Patent US 9,573,871 B2

U.S. Patent Feb. 21, 2017 Sheet 3 of 3 US 9,573,871 B2

Ou/Teo) "Abueu US 9,573,871 B2 1. 2 STEREO CONTROLLED SYNTHESIS OF -continued (E,Z)-DIENALS VIA TANDEM RHOI) CATALYZED PROPARGYL CLAISEN REARRANGEMENT

CROSS REFERENCE TO RELATED APPLICATION(S) This application claims priority from U.S. provisional Application No. 62/011,251, filed Jun. 12, 2014, the disclo sure of which is hereby incorporated by reference as if set 10 forth in its entirety. STATEMENT REGARDING FEDERALLY CHO SPONSORED RESEARCH OR DEVELOPMENT (2Z.4E)-Dehydrocitral 15 This invention was made with Government support under Grant CHE-1152491 awarded by the National Science Accordingly, polyene motifs with (E. Z) Stereochemistry Foundation. The Government has certain rights in the inven represent synthetically important targets. See (a) Knowles, tion. W. S. Angew. Chem., Int. Ed. 2002, 41, 1998. Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. (b) Sharpless, K. B. FIELD OF THE INVENTION Angew. Chem., Int. Ed. 2002, 41, 2024. (c) Chauvin, Y. The present invention generally relates to a method for Angew. Chem., Int. Ed. 2006, 45, 3740. (d) Schrock, R. R. synthesizing functionalized (E.Z)-dienal compounds. More Angew. Chem., Int. Ed. 2006, 45, 374. (e) Grubbs, R. H. specifically, functionalized (E.Z)-dienal compounds are pre Angew. Chem., Int. Ed. 2006, 45, 3760. Not only are pared by tandem transformation where a stereoselective synthetic routes to Z-alkenes relatively limited but such hydrogen transfer follows a propargyl Claisen rearrange 25 traditional approaches to unsaturated conjugated Z-polyenes ment. as Wittig and Horner-Wadsworth-Emmons reactions, cannot be used to directly deliver unsaturated aldehydes. See (a) BACKGROUND OF THE INVENTION Smith, A. B III, Beauchamp, T. J.; LaMarche, M. J.; Kauf man, M. D.; Qiu, Y.; Arimoto, H.; Jones, D. R.: Kobayashi, Polyene motifs with (E,Z) stereochemistry are ubiquitous 30 in biologically active and naturally occurring systems. See K. J. Am. Chem. Soc. 2000, 122, 8654. (b) Dong, D-J., Li, (a) McGarvey, B. D.; Attygalle, A. B., Starratt, A.N.: Xiang, H-H.; Tian, S-K. J. Am. Chem. Soc. 2010, 132, 5018. (c) B.; Schroeder, F. C.; Brandle, J. E.; Meinwald, J. Nat. Prod. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405. 2003, 66, 1395. (b) Robinson, C. Y.; Waterhous, D. V.: (d) Molander, G. A.; Dehmel, F. J. Am. Chem. Soc. 2004, Muccio, D. D.; Brouillette, W. J. Bioorg. Med. Chem. Lett., 126, 10313. (e) Huang, Z.; Negishi, E-I. J. Am. Chem. Soc. 1995, 5,953. (c) Asfaw, N.; Storesund, H. J.; Skattebol, L.; 35 2007, 129, 14788. (f) Belardi, J. K. Micalizio, G. C.J. Am. Aasen A. J. Phytochemistry 1999, 52, 1491. (d) Hiraoka, H.; Chem. Soc. 2008, 130, 16870. (g) Lindlar, H.; Dubuis, R. Mori, N.; Nishida, R.; Kuwahara, Y. Biosci. Biotechnol. Org Synth. 1966, 46, 89. (h) Randl, S.; Gessler, S.; Waka Biochem., 2001, 65, 2749. (e) Matsumoto, H.; Asato, A. E.; matsu, H.; Blechert, S. Synlett 2001, 430. (i) Kang, B. Kim, Denny, M.: Baretz, B. Yen, Y-P: Tong, D.; Liu, R. S. H. D-H.; Do, Y.; Chang, S. Org. Lett. 2003, 5,3041. () Hansen, Biochemistry, 1980, 19, 4589. Several natural compounds 40 E. C.: Lee, D. Org. Lett. 2004, 6, 2035. (k) Kang, B.: Lee, are shown below: J. M.: Kwak, J.; Lee, Y. S.; Chang, S.J. Org. Chem. 2004, 69, 7661. (1) Sashuk, V.; Samojlowicz, C.; Szadkowska, A.; Grela, K. Chem Commun. 2008, 2468. (m) Crowe, W. E.; Goldberg, D. R. J. Am. Chem. Soc. 1995, 117, 5162. The traditional metal-free approaches to unsaturated con 45 jugated Z-polyenes, which are relatively few such as Wittig and Hornder-Wadsworth-Emmons reactions, cannot be used to directly deliver unsaturated aldehydes. The metal-cata lyzed cross-coupling of two sp-hybridized reactants requires activating functionalities (e.g., organoboranes or 50 organo-stannanes) which may be toxic, expensive and/or deleterious for the overall atom efficiency. Methods for the direct incorporation of the unsaturated C.B-carbonyl com (7E,9Z)-Retinoic Acid pounds with the Z-stereochemistry are limited. See (a) Retinoid X receptor activator Maynard, D. F.; Okamura, W. H. J. Org. Chem. 1995, 60, 55 1763. (b) Duhamel, L. Guillemont, J.; Poirier, J-M. Tetra 21, CHO

hedron Lett. 1991, 32, 4495. (c) Cahard, D.; Duhamel, L.; Lecomte, S.; Poirier, J-M. Synlett 1998, 12, 1399. (d) Amos, R. A.; Katzenellenbogen, J. A.J. Org. Chem. 1978, 43, 555. The metal-catalyzed Claisen rearrangement offers new 60 mechanistic paths to this classic reaction and significantly expands its synthetic utility. See (a) Tejedor, D.; Mendez Abt, G.; Cotos, L., Garcia-Tellado, F. Chem. Soc. Rev., 2013, 42, 458. Aluminium: (b) Bates, D. K. Janes, M. W. J. Org. Chem. 1978, 43.3856. (c) Majumdar, K.C.: Chattopadhyay, 65 B. Synth. Commun. 2006, 36, 3125. (d) Majumdar, K. C.; Sterebin J Islam, R.J. Heterocycl. Chem. 2007, 44, 871. (e)Majumdar, K. C.; Islam, R. Can. J. Chem. 2006, 84, 1632. (f) Majum US 9,573,871 B2 3 4 dar, K. C.; Bhattacharyya, T. Tetrahedron Lett. 2001, 42, nature of this unusual potential energy Surface depends 4231. (g) Majumdar, K. C.; Ghosh, M.; Jana, M.; Saha, D. strongly on Substrate-catalyst coordination and solvent, as Tetrahedron Lett. 2002, 43, 2111. (h) Majumdar, K. C.; illustrated by the successful trapping of the six-membered Bandyopadhyay, A.; Biswas, A. Tetrahedron 2003, 59, 5289. intermediate by nucleophilic attack of water in dioxane Cu(II), Sn(IV), Ti(IV) and La(III): (i)Takanami, T.; Hayashi, reported by the Toste group. See (a) Sherry, B. D.; Maus, L.; M.; Suda, K. Tetrahedron Lett. 2005, 46, 2893. (i) Trost, B. Laforteza, B. N.; Toste, D. J. Am. Chem. Soc. 2006, 128, M.; Schroeder, G. M.J. Am. Chem. Soc. 2000, 122,3785. (k) 8132. Nakamura, S.; Ishihara, K., Yamamoto, H. J. Am. Chem. Soc. 2000, 122,8131. (1) Nasveschuk, C. G.; Rovis, T. Org. SUMMARY OF THE INVENTION Lett. 2005, 7, 2173. (m) Nasveschuk, C. G.; Rovis, T. Angew: 10 Chem., Int. Ed. 2005, 44, 3264. (n) Kaden, S.; Hiersemann, The present invention is directed to the transformation of M. Synlett 2002, 1999. (o) Helmboldt, H.; Hiersemann, M. propargyl vinyl ethers into (E,Z)-dienal compounds using a Tetrahedron 2003, 59, 4031. (p) Abraham, L.: Korner, M.: Rh(I)-catalyzed propargyl Claisen rearrangement and pro Hiersemann, M. Tetrahedron Lett. 2004, 45, 3647. (q) totropic isomerization sequence. Sharghi, H.; Aghapour, G.J. Org. Chem. 2000, 65,2813. (r) 15 Bancel, S.: Cresson, P. C. R. Acad. Sci. Ser: C. 1970, 270, In one preferred embodiment, shown below, the method 2161. (s) Nonoshita, K.; Banno, H.; Maruoka, K. Yama of the present invention provides C. B-unsaturated aldehydes moto, H. J. Am. Chem. Soc. 1990, 112,316. (t) Sugiura, M.: from starting reactants comprising a functionalized aldehyde Nakai, T. Chem. Lett. 1995, 697. (u)Akiyama, K.; Mikami, and a functionalized alkyne in three steps with excellent K. Tetrahedron Lett. 2004, 45, 7217. (v) Itami, K.: stereoselectivity: Yamazaki, D.; Yoshida, J. Org. Lett. 2003, 5, 2161. (w) Jamieson, A. G.; Sutherland, A. Org. Biomol. Chem. 2006, 1.nBuLi, THF, -78° C. 4, 2932. (x)Swift, M.D.; Sutherland, A. Org. Biomol. Chem. 2. HgOAc, Ethyl Vinyl Ether, rt 2006, 4, 3889. (y) Nakamura, I., Bajracharya, G. B. Yama 3. Rh(CO)2Cl2, Toluene, 50° C. moto, Y. Chem. Lett. 2005, 34, 174. (Z) Sattelkau, T.: 25 Eilbracht, P. Tetrahedron Lett. 1998, 39, 1905. (aa) Eil R1so + E R2 bracht, P.; Gersmeier, A.; Lennard, D.; Huber, T. Synthesis H R 1995, 330; (ab) Sattelkau, T.; Hollmann, C.; Eilbracht, P. N H Synlett 1996, 1221.(ac) Sattelkau, T.; Eilbracht, P. Tetrahe R1 S dron Lett. 1998, 39, 9647. 30 When metals coordinate with L-bases, such as alkenes or H CHO alkynes, the first step of the rearrangement can be described as a 6-endo-dig cyclization that leads to a cyclic six In some specific embodiments, the present invention is membered intermediate (See FIG. 1). Thus, this mode of directed to a reaction sequence in which the reactants, rearrangement was termed “cyclization-mediated pathway'. 35 products of each step, and reaction conditions of each step See (a) Henry, P. M. Acc. Chem. Res. 1973, 16. (b) Henry, are as shown below. Starting reactants may include the P. M. Adv. Organomet. Chem. 1975, 13, 363. (c) Overman, following functionalized aldehyde and functionalized L. E. Angew: Chem. Int. Ed. Engl. 1984, 23, 579. On the acetylide: other hand, Lewis acids, such as Cu, Al" and H+ initiate the so-called "cation-accelerated Oxonia Claisen rearrange 40 ment by coordinating with oxygen (See FIG. 1). See (a) Maruoka, K.; Saito, S.; Yamamoto, H. J. Am. Chem. Soc. BrMg R2 1995, 117, 1165. (b) Stevenson, J. W. S.; Bryson. Tetrahe dron Lett. 1982, 23, 3143. (c) Takai, K. Mori, I., Oshima, -- Or K.; Nozaki, H. Bull. Chem. Soc. Jpn. 1984, 57, 446. (d) 45 Li R Takai, K. Mori, I., Oshima, K., Nozaki, H. Tetrahedron R 1984, 40, 4013. (e) Takai, K. Mori, I.; Oshima, K., Nozaki, H. Tetrahedron Lett. 1981, 22, 3985. In some embodiments, the functionalized acetylide may Recently, we reported a mechanistic study of Au(I)- be formed from reaction of a strong base with a function catalyzed propargyl Claisen and allenyl vinyl ether rear 50 alized alkyne. Suitable conditions for the reaction between rangement, where Au(I), commonly considered as an the functionalized aldehyde and the functionalized acetylide alkynophilic Lewis acid, coordinates with the oxygen and include THF as the Solvent at 0° C. or -78° C. for between directs the Claisen rearrangement through an oxonia path. 1 and 2 hrs. See (a) Vidhani, D. V.: Cran, J. W.; Kraft, M. E.; Mano In some embodiments, the product of the first step and the haran, M.; Alabugin, I. V. J. Org. Chem. 2013, 78, 2059. (b) 55 reactant for the second step is a functionalized propargyl. Vidhani, D. V.: Cran, J. W.; Kraft, M. E.; Alabugin, I. V. which may have the following structure: Org. Biomol. Chem., 2013, 11, 1624. The barrier for the alternative cyclization-mediated pathway is 1.5 kcal/mol higher. Two important features of the calculated Au-cata OH lyzed cyclization-mediated pathway includes: 1) lack of 60 substituent effects and 2) selective stabilization of the TS for the Grob fragmentation of the six-membered intermediate Šs by Au(I)-catalysts. R2. The latter effect lowers the barrier to the extent that this intermediate corresponds to a shallow inflection on the 65 Yields of 85-98% potential energy Surface, so the overall process blends the characteristics of a stepwise and a concerted process. The US 9,573,871 B2 5 6 In some embodiments, the product of the second step and group consisting of C-12 alkyl, C2-12 alkenyl, C-12 alkynyl, the reactant for the third step is a functionalized propargyl Cs-12 cycloalkyl, C-12 cycloalkenyl, C-2 aryl, C-1s het vinyl ether, which may have the following structure: eroaryl, amino, and C-2 alkylamino The present invention is further directed to a method to synthesize an (E,Z)-dienal compound having structure (V). 1S The method comprises contacting a compound having struc ture (IV) with a catalyst comprising Rh(I) to thereby prepare the compound having structure (V);

Šs 10 R R O (IV) R I \ In some embodiments, suitable conditions for this reac C and tion include 0.6% Hg(OAc) catalyst in a concentration of 15 0.2 M in a solvent of Ethyl vinyl ether for between 12 and R 16 hrs reflux. (V) In some embodiments, the functionalized propargyl vinyl H R2 ether reactant from above may undergo Rh(I) catalyzed Tandem rearrangement from a functionalized allene-alde R N N H; hyde compound to a functionalized (E,Z)-dienal compound, having the structures as shown below: H CHO

In the above structures, R is selected from the group 'n 25 consisting of C-12 alkyl, C-12 alkenyl, C-12 alkynyl, C-12 cycloalkyl, C-12 cycloalkenyl, C-2 aryl, C-1s heteroaryl, amino, and C-2 alkylamino; and R is selected from the group consisting of C-2 alkyl, C-2 alkenyl, C-2 alkynyl, R R2 30 Cs-12 cycloalkyl, C-12 cycloalkenyl, C-24 aryl, Cs-1s het R2 eroaryl, amino, and C-12 alkylamino. The present invention is still further directed to a method S-1s of preparing a compound having structure (III). The method comprises contacting a compound having structure (I) and a CHO. R compound having structure (II) in the presence of a strong base; wherein the compounds having structures (I), (II), and (III) have the following structures: The above is one non-limiting exemplary embodiment of the method of the present invention. Accordingly, among the provisions of the present inven 40 (I) tion may be noted is a method to synthesize an (E,Z)-dienal compound having structure (V). The method comprises contacting a compound having structure (III) with a catalyst (II) comprising Rh(I) to thereby prepare the compound having (III) structure (V); wherein the compounds having structures (III) 45 H and (V) have the following structures: -N- (III) 50 O1 S-H and R H R In the above structures, R is selected from the group H Šs 55 consisting of C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C-12 R2 cycloalkyl, C-2 cycloalkenyl, C-2 aryl, Cls heteroaryl, (V) amino, and C-2 alkylamino; and R is selected from the H R2 group consisting of C-12 alkyl, C2-12 alkenyl, C-12 alkynyl, H; Cs-12 cycloalkyl, C-12 cycloalkenyl, C-24 aryl, Cs-1s het R S1s 60 eroaryl, amino, and C-12 alkylamino. The present invention is still further directed to a method H CHO to synthesize an allene-aldehyde compound having structure (IV). The method comprises contacting a compound having In the above structures, R is selected from the group structure (III) with a catalyst comprising Rh(I) to thereby consisting of C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C-12 65 prepare the compound having structure (IV); wherein the cycloalkyl, C-12 cycloalkenyl, C-2 aryl, C-1s heteroaryl, compounds having structures (III) and (IV) have the fol amino, and C-2 alkylamino; and R is selected from the lowing structures: US 9,573,871 B2 7

-continued (III) O H H N H Stereoselective O1 S-H and R Proton Transfer H R2 R?. S R The present invention is directed to a novel Rh(I)-cata (IV) 10 lyzed approach to functionalized (E. Z) dienal compounds R O; via tandem transformation where a stereoselective hydrogen N. transfer follows a propargyl Claisen rearrangement. Z-Ste reochemistry of the first double bond suggests the involve ment of a six-membered cyclic intermediate whereas the R2 15 E-stereochemistry of the second double bond stems from the Subsequent protodemetallation step giving an (E,Z)-dienal. In the above structures, R is selected from the group The combination of experiments and computations consisting of C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C-12 reveals unusual features of stereoselective Rh(I)-catalyzed cycloalkyl, C-12 cycloalkenyl, C-2 aryl, C-1s heteroaryl, transformation of propargyl vinyl ethers into (E. Z)-dienals. amino, and C-2 alkylamino; and R is selected from the The first step, the conversion of propargyl vinyl ethers into group consisting of C-12 alkyl, C2-12 alkenyl, C-12 alkynyl, allene aldehydes, proceeds under homogeneous conditions Cs-12 cycloalkyl, C-12 cycloalkenyl, C-24 aryl, Cs-1s het via the “cyclization-mediated mechanism initiated by Rh(I) eroaryl, amino, and C-12 alkylamino. coordination at the alkyne. This path agrees well with the Other objects and features will be in part apparent and in small experimental effects of substituents on the carbinol part pointed out hereinafter. 25 carbon. The key feature revealed by the computational study is the Stereoelectronic effect of the ligandarrangement at the BRIEF DESCRIPTION OF THE DRAWINGS catalytic center. The rearrangement barriers significantly FIG. 1 depicts three mechanistic alternatives for the decrease due to the greater transfer of electron density from metal-catalyzed propargyl Claisen rearrangement. Cycliza 30 the catalytic metal center to the CO ligand oriented trans to tion-mediated pathway depicted on left shows two possi the alkyne. This effect increases electrophilicity of the metal bilities emerging from the six-membered cyclic intermedi and lowers the calculated barriers by 9.0 kcal/mol. Subse ate. quent evolution of the catalyst leads to the in-situ formation FIG. 2 depicts the proposed catalytic cycle. AE values of Rh(I)-nanoclusters which catalyze stereoselective tau correspond to the PCM-SCRF-M05-2X/LANL2DZenergies 35 tomerization. The intermediacy of heterogeneous catalysis of the intermediate species relative to the uncomplexed by nanoclusters was confirmed by mercury poisoning, tem Rh(I)-dimer. perature-dependent sigmoidal kinetic curves, and dynamic FIG. 3 illustrates Curtin-Hammett analysis of the three light scattering. The combination of experiments and com mechanisms. Energies in toluene were calculated at the putations suggest that the initially formed allene-aldehyde PCM-SCRF-M05-2X/LANL2DZ level on the gas phase product assists in the transformation of a homogeneous optimized geometries. 40 catalyst (or “a cocktail of catalysts’) into nanoclusters, which, in turn, catalyze and control the stereochemistry of DETAILED DESCRIPTION OF THE Subsequent transformations. EMBODIMENT(S) OF THE INVENTION In some embodiments, the method of the present inven tion comprises the synthesis of the propargyl vinyl ether The present invention is directed to an efficient process to 45 having structure (III), as depicted below: install synthetically challenging (E,Z) conjugated double bond in three steps starting from a precursor aldehyde and a precursor alkyne with a very high stereoselectivity. The first (III) two steps are high yielding reaction leading to the formation H of a propargyl vinyl ether. The last step is a tandem process 50 which can be interrupted to give an allene-aldehyde com O1 S-H pound or allowed to continue to give a (E,Z)-dienal com H pound. This method is general for aromatic and tertiary R aldehydes. 55 ?t S In some embodiments, the method of the present inven R tion may be represented by the following reaction sequence: In structure (III), R may be selected from the group H consisting of C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C-12 60 cycloalkyl, C-12 cycloalkenyl, C-2 aryl, C-1s heteroaryl, amino, or C. alkylamino. The alkyl, aryl, cycloalkenyl, O1 S-H Rh(I) heteroaryl, amino, and alkylamino groups may be unsubsti H Propargyll Claisen tuted. The alkylamino may be primary, secondary, or ter R Rearrangement tiary. In some embodiments, the alkyl, aryl, cycloalkenyl, ?t N 65 heteroaryl, amino, and alkylamino groups may be substi R tuted. Suitable Substituents include C-2 alkyl, C- alk enyl, C2-12 alkynyl, C-12 cycloalkyl, C-12 cycloalkenyl, US 9,573,871 B2 9 10 C-2 aryl, C-1s heteroaryl, halogen (i.e., fluoro, chloro, carbon atoms. Examples of cycloalkyl include cycobutyl, bromo, iodo), hydroxy, cyano, Calkoxy, nitro, Sulfinyl. cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo Sulfonyl, amino, or C. alkylamino. The alkylamino Sub 2.2.1]heptyl, cyclopentenyl, cyclohexenyl, or adamantly, stituent may be primary, secondary, or tertiary. among others. In some preferred embodiments, R comprises a Caryl In the context of the present specification, cycloalkenyl is or Cls heteroaryl, which may be unsubstituted or may be a non-aromatic ring that can comprise one, two or three further substituted with any of the above described moieties. non-aromatic rings, and is, optionally, fused to a benzene Suitable Substituents include C-2 alkyl, C-2 alkenyl, C-2 ring (for example to form an indanyl, or 1,2,3,4-tetrahy alkynyl, C-2 cycloalkyl, C-2 cycloalkenyl, C-2 aryl, dronaphthyl ring). Cycloalkenyl may comprise from 3 to 12 Cls heteroaryl, halogen (i.e., fluoro, chloro, bromo, iodo), 10 carbon atoms. Examples of cycloalkenyl include cyclopro hydroxy, cyano, C-2 alkoxy, nitro, Sulfinyl, Sulfonyl, penyl, cycobutenyl, cyclopentenyl, cyclohexenyl, cyclohep amino, or C-12 alkylamino. tenyl, cyclooctenyl, etc. In structure (III), R may be selected from the group In the context of the present invention, aryl encompasses consisting of C-12 alkyl, C-12 alkenyl, C-12 alkynyl, C-12 aromatic rings, which may be fused or unfused to other cycloalkyl, C-12 cycloalkenyl, C-2 aryl, C-1s heteroaryl, 15 aromatic or cycloalkyl rings. Aryl may comprise from 6 to amino, or C. alkylamino. The alkyl, aryl, cycloalkenyl, 24 carbon atoms. Examples or aryl include benzene, naph heteroaryl, amino, and alkylamino groups may be unsubsti thalene, acenaphthene, anthracene, benzaanthracene, ben tuted. The alkylamino may be primary, secondary, or ter Zoapyrene, benzoepyrene, chrysene, indeno(1.2.3-cd) tiary. In some embodiments, the alkyl, aryl, cycloalkenyl, pyrene, phenanthrene, pyrene, coronene, fluorene, and the heteroaryl, amino, and alkylamino groups may be substi like. tuted. Suitable substituents include C. alkyl, C- alk In the context of the present specification, heterocyclic enyl, C2-12 alkynyl, C-12 cycloalkyl, C-12 cycloalkenyl, ring is an aromatic or non-aromatic ring having from three C-2 aryl, C.s heteroaryl, halogen (i.e., fluoro, chloro, to eight total atoms forming the ring system. The atoms bromo, iodo), hydroxy, cyano, Calkoxy, nitro, Sulfinyl, within the ring system comprise carbon and at least one of Sulfonyl, amino, or C. alkylamino. The alkylamino Sub 25 nitrogen, Sulfur, and oxygen. A heterocyclic ring may be stituent may be primary, secondary, or tertiary. fused to a homocyclic ring or another heterocyclic ring. The In some preferred embodiments, R comprises a Caryl fused ring system may be aromatic or non-aromatic. Het or Cls heteroaryl, which may be unsubstituted or may be eroaryl may comprise from 3 to 24 carbon atoms. Examples further substituted with any of the above described moieties. include aziridine, azirine, oxirane, oxirene, thirane, thiirene, Suitable substituents include C- alkyl, Calkenyl, C 30 aZetidine, azete, oxetane, oxete, thietane, thiete, diazetidine, alkynyl, C-12 cycloalkyl, C-12 cycloalkenyl, C-2 aryl, dioxetane, dioxete, dithietane, dithiete, pyrrolidine, pyrrole, Cls heteroaryl, halogen (i.e., fluoro, chloro, bromo, iodo), tetrahydrofuran, furan, thiolane, thiophene, imidazolidine, hydroxy, cyano, C. alkoxy, nitro, sulfinyl, sulfonyl, imidazole, pyrazolidine, pyrazole, oxasolidine, oxazole, amino, or C-12 alkylamino. isoxazolidine, isoxazole, piperidine, pyridine, oxane, pyran, In some embodiments, R and R may be the same. In 35 thiane, thiopyran, piperazine, diazines, morpholine, oxazine, Some embodiments, R and R may be different. etc. In the context of the present specification, unless other In some embodiments, the compound having structure wise stated, an alkyl Substituent group or an alkyl moiety in (III) may synthesized by contacting a compound having a Substituent group may be linear or branched. Examples of structure (I) and a compound having structure (II) according C. alkyl groups/moieties include methyl, ethyl, n-propyl. 40 to the following sequence: isopropyl. n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl, isohexyl, neohexyl, n-heptyl, isoheptyl, neoheptyl, n-octyl, isooctyl, neooctyl, n-nonyl, n-decyl H n-undecyl. n-dodecyl, etc. The Substituent group may com 1. Strong prise a double bond, e.g., C-2 alkenyl, a triple bond, e.g., 45 Base O N H C-2 alkynyl, or may comprise more than one double bond. 1N -- R - --> In the context of the present specification, unless other R O 2. Mercuric H wise stated, an alkoxy Substituent group or an alkoxy moiety (I) (II) acetate R H Šs in a substituent group may be linear or branched. Examples of C. alkoxy groups/moieties include methoxy, ethoxy, 50 n-propoxy, isopropoxy, n-butoxy, iso-butoxy, tert-butoxy, (III) n-pentoxy, iso-pentoxy, neopentoxy, n-hexoxy, etc. In the context of the present specification, unless other wherein R and R are as defined above with respect to wise stated, a hydroxyalkyl Substituent group or a hydroxy Structure (III). alkyl moiety in a Substituent group may be linear or 55 The reaction occurs in the presence of a strong base. branched. Examples of C. hydroxyalkyl groups/moieties Suitable strong bases for use in the method of the present include methyl, ethyl, n-propyl, isopropyl. n-butyl, iso invention include organolithium compounds, including butyl, tert-butyl, n-pentyl, n-hexyl, etc, each of which com alkyl lithium compounds, such as n-butyl lithium, sec-butyl prises at least one hydroxyl group Substituent in place of a lithium, isopropyl lithium, etc., or a Grignard reagent, Such hydrogen. 60 as an organomagnesium halide. The n-butyl lithium may be Halogen or halo encompasses fluoro, chloro, bromo, and provided in an alkane (e.g., pentane, hexane, heptane) solu iodo Substituents. tion or in an ether (e.g., diethyl ether, tetrahydrofuran) In the context of the present specification, cycloalkyl is a Solution. non-aromatic ring that can comprise one, two or three In some embodiments, the structure (III) may synthesized non-aromatic rings, and is, optionally, fused to a benzene 65 by contacting a compound having structure (I) and a com ring (for example to form an indanyl, or 1,2,3,4-tetrahy pound having structure (II) according to the following dronaphthyl ring). Cycloalkyl may comprise from 3 to 12 Sequence: US 9,573,871 B2 11 12 clooctadiene)rhodium(I) 99%, (Acetylacetonato) (1,5-cy clooctadiene)rhodium(I) 99%, (Acetylacetonato) (1.5- 1. nBuLi, cyclooctadiene)rhodium(I) 99%, (Acetylacetonato) THF dicarbonylrhodium(I) 98%, (Acetylacetonato) -78°C. dicarbonylrhodium(I) 98%, (Acetylacetonato) 2. HgOAc, H ethyl (norbornadiene)rhodium(I), (Bicyclo[2.2.1]hepta-2,5-diene) vinyl H 1,4-bis(diphenylphosphino)butanerhodium(I) ether, rt tetrafluoroborate, Bicyclo[2.2.1]hepta-2,5-diene-rhodium(I) chloride dimer 96%, Bicyclo[2.2.1]hepta-2,5-diene-rho (III) 10 dium(I) chloride dimer, Bis(acetonitrile) (1,5-cyclooctadi wherein R and R are as defined above with respect to ene)rhodium(I) tetrafluoroborate, (Bisacetonitrile)(norbor Structure (III). nadiene) rhodium(I) hexafluoroantimonate 97%, Bis(1.5- cyclooctadiene)rhodium(I) tetrafluoroborate hydrate 97%, According to some embodiments of the method of the Bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate present invention, a compound having structure (III) is 15 hydrate, Bis(1,5-cyclooctadiene)rhodium(I) hexafluoroanti contacted with a catalyst comprising Rh(I) to thereby pre monate 97%, Bis(1,5-cyclooctadiene)rhodium(I) tetrafluo pare an (E,Z)-dienal compound having structure (V): roborate, Bis(1,5-cyclooctadiene)rhodium(I) tetrakis bis(3, 5-trifluoromethyl)phenylborate, Bis(1,5-cyclooctadiene) rhodium(I) trifluoromethanesulfonate 98%, Bis(1.5- (V) cyclooctadiene)rhodium(I) trifluoromethanesulfonate, 1,1'- Bis(diisopropylphosphino)ferrocene(cod)Rh phosphotungstic acid on silica gel 100-200 mesh, extent of labeling: 0.020 mmol/g Rh loading, Bis(10.11-m)-5-[(11 bS)-dinaphtho2,1-d: 1,2'-f1.3.2dioxaphosphepin-4-yl H CHO 25 KP-5H-dibenzb.flazepinelrhodium(I) tetrafluoroborate wherein R and R are as defined above with respect to salt 97%, 1,4-Bis(diphenylphosphino)butane (1.5-cyclooc Structure (III). tadiene)rhodium(I) tetrafluoroborate 98%, Bis(norborna diene)rhodium(I) tetrafluoroborate, Bis(norbornadiene)rho According to some embodiments of the method of the dium(I) trifluoromethanesulfonate 97%, Bis rhodium.(O.C., present invention, the compound having structure (III) is 30 O'C'-tetramethyl-1,3-benzenedipropionic acid) 96%, Bis contacted with a catalyst comprising Rh(I) in order to (triphenylphosphine)rhodium(I) carbonyl chloride 99.9%, prepare a compound having structure (IV): Chlorobis(cyclooctene)rhodium(I),dimer 98%. Chlorobis (10,11-m)-5H-dibenzoa,dcyclohepten-5-yl)amine-KN rhodium(I) dimer, Chloro(1,5-cyclooctadiene)rhodium(I) (IV) 35 dimer 98%, Chloro(1.5-hexadiene)rhodium(I),dimer 98%, Chlorotris3.3',3'-phosphinidynetris(benzenesulfonato) rhodium(I) nonasodium salt hydrate 99%, (1.5-Cycloocta diene)bis(triphenylphosphine)rhodium(I) hexafluorophos phate dichloromethane complex (1:1), (1.5-Cyclooctadiene) 40 (8-quinolinolato)rhodium(I) 97%, Dicarbonyl (pentamethylcyclopentadienyl)rhodium(I) 99%, Di-u- wherein R and R are as defined above with respect to chloro-tetracarbonyldirhodium(I) 97%, Di-L- Structure (III). In some embodiments of the method of the chlorotetraethylene dirhodium(I), Dirhodium present invention, the compound having structure (IV), i.e., tetracaprolactamate 97%, Hexarhodium(0) hexadecacarbo a compound comprising allene-aldehyde, may be isolated. In 45 nyl Rh 57-60% (approx.), Hydridotetrakis(triphenylphos phine)rhodium(I), Hydroxy(cyclooctadiene)rhodium(I) some embodiments of the method of the present invention, dimer 95%, Methoxy(cyclooctadiene)rhodium(I) dimer, Tri the compound having structure (IV), i.e., a compound com phenylphosphine(2.5-norbornadiene)rhodium(I) tetrafluo prising allene-aldehyde may undergo further rearrangement roborate, polymer-bound Fibre-Cat R, Tris(dimethylphe into the compound having structure (V). 50 nylphosphine)(2.5-norbornadiene)rhodium(I) According to some embodiments of the method of the hexafluorophosphate 97%, Tris(triphenylphosphine)rho present invention, a compound having structure (IV) is dium(I) carbonyl hydride 97%, Tris(triphenylphosphine) contacted with a catalyst comprising Rh(I) to thereby pre rhodium(I) chloride 99.9% trace metals basis, Tris(triph pare an (E,Z)-dienal compound having structure (V): enylphosphine)rhodium(I) chloride, and Tris 55 (triphenylphosphine)rhodium(I) chloride polymer-bound -1% Rh. (V) Suitable Rh(I) catalysts include di-u-chloro-tetracarbo nyldirhodium(I) IRh(CO)Clz, Bis(triphenylphosphine) 60 rhodium(I) carbonyl chloride, tris(triphenylphosphine)rho dium (I) carbonyl hydride, tris(triphenylphosphine)rhodium H CHO (I) carbonyl chloride, among other Rh(I) catalysts. The most unusual feature of this invention is the genera wherein R and R are as defined above with respect to tion of in-situ Rh(I)-nanoclusters which catalyzes the ste Structure (III). 65 reoselective isomerization of allene-aldehyde. The onset of Applicable Rhodium(I) catalysts include Acetylacetona isomerization does not occur until the complete conversion tobis(ethylene)rhodium(I) 95%. (Acetylacetonato) (1,5-cy of Substrate, propargyl vinyl ether, into the allene-aldehyde US 9,573,871 B2 13 intermediate. This is the first example of a shift from homogeneous to heterogeneous catalysis in one pot. Thus, H O the rearrangement can either be stopped at the homogeneous H N step to isolate allene-aldehyde or allowed to continue under O1 S-H Rh(I) H heterogeneous conditions to give (E. Z) dienal with high 5 Propargyll Claisen stereoselectivity. Rearrangement R H To verify the involvement of Rh(I)-nanoclusters in the R i? Šs R2 prototropic rearrangement, we performed dynamic light R2 scattering (DLS) experiments on the allene-aldehyde (IV)

10 (III) derived from the phenyl substituted substrate 2 (See Table O 3). This technique is used to determine the size-distribution H N H of particles in Suspension. Typically, in the DLS experiment, He Stereoselective the solution containing the nanoclusters is irradiated with the R Proton Transfer monochromatic light from the laser and the intensity of the 15 light diffracted by the nanocluster is measured. Since the R scattered light from nanoclusters undergoes constructive and (IV) (V) destructive interference by the Surrounding scatterers, a complex intensity fluctuation pattern containing a detailed information about the time scale of the movement of the The (E,Z)-dienal only starts to form after the complete scatterers emerges. To process this information, a math conversion of propargyl vinyl ether into the allene-aldehyde. ematical tool called autocorrelation, is used to identify a Accordingly, intermediate (IV) can be isolated without pro repeating pattern burried under the complex signal. ceeding to the metal-catalyzed propargyl Claisen rearrange ment into the (E,Z)-dienal having structure (V). The mecha 25 nism of the six-membered intermediate in the metal catalyzed propargyl Claisen rearrangement into (E. Z)-dienals defines stereochemistry in both double bonds of g (q; t): Autocorrelation function the product is thought to proceed as follows: H q: Wave vector 30 t: Delay time N- p, a H O a I: Intensity H - 'll" - - R If \s 1S-1a 2 aM R. R M R Generally, data is interpreted only when the plot of 35 intensity vs. time shows a Smooth and continuous decay of (III) intensity for autocorrelation function. Such plots are classi fied as “proceed-category'. In the present study, the catalyst base (i.e., Cyclic precursor: and the substrate solutions did not show the presence of R-M) Z-enal nanoclusters. Interestingly, the reaction mixture at 50% 40 -H conversion of allene-aldehyde into respective (E,Z)-dienal (Error! Reference source not found.), showed the presence Protodemtallation of 170 nm nanoclusters. Moreover, low observed polydis M---> H persity (5%) Suggested that the Solution consisted of uni 45 Retention: formly sized particles. E-alkene

Accordingly, experimental and computational analysis of the tandem process suggests a cascade transformation that evolves from homogeneous to heterogeneous catalysis. The Rh(I)-catalyzed propargyl Claisen rearrangement involves 50 homogeneous catalysis whereas the Subsequent prototropic rearrangement shows the telltale signs of heterogeneous catalysis. In this work, we disclose a tandem transformation of Au(I)-catalyzed Claisen rearrangements of propargyl and propargyl vinyl ethers into dienals, where stereochemistry at 55 allenyl vinyl ethers were first reported by the groups of Toste both double bonds in the product is defined simultaneously and Kraft, respectively. See Sherry, B. D.; Toste, F. D. J. by the nature of a common cyclic intermediate located at the Am. Chem. Soc. 2004, 126, 15978. (b) Mauleon, P.; Krinsky, Claisen rearrangement hypersurface connecting propargyl J. L.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 4513; and vinyl ethers with allene-aldehyde. Trapping of such cyclic Kraft, M. E.; Hallal, K. M.; Vidhani, D. V.: Cran, J. W. Org. structure via deprotonation coupled with the Grob fragmen 60 Biomol. Chem., 2011, 9, 7535. In a recent mechanistic study tation should lead to the conjugated dienals with E.Z- of these two rearrangements, we found that although the Stereochemistry: the Z-geometry at the C.f3-alkene is defined cyclic intermediate does not correspond to an energy mini by the syn arrangement of the endocyclic O-bonds whereas mum at the DFT potential energy hypersurface in the the E-stereochemistry at Y.8-alkene stems from the syn presence of RPAuShF-catalyst, the details of Au' substrate arrangement of the exocyclic C-R1 and C-M bonds and 65 interactions at this stage suggest that slight modification in proto-demetallation with retention of configuration. See the the nature of the catalyst may be sufficient for creating and following general reaction sequence: trapping such cyclic structure. See (a) Vidhani, D. V., Cran, US 9,573,871 B2 15 16 J. W.; Kraft, M. E.; Manoharan, M.; Alabugin, I. V. J. Org. Remarkably, Rh(CO)Cl] and AuC1 provided cascade Chem. 2013, 78, 2059; (b) Vidhani, D. V.: Cran, J. W.; products in high yields but with the opposite stereochemis Kraft, M. E.; Alabugin, I. V Org. Biomol. Chem., 2013, 11, try. Table 2 summarizes further optimization of the Rh 1624; and (c) Sherry, B. D.; Maus, L.; Laforteza, B. N.; Toste, F. D. J. Am. Chem. Soc. 2006, 128,8132. 5 catalyzed reactions. Coordinating solvents such as acetoni Although trapping via deprotonation has not been trile form a strong complex with Rh(I) and deactivate the reported so far and our initial attempts with weak bases Such catalyst. See (a) Costa, M.; Della Pergola, R.; Fumagalli, A.; as aniline led to deactivation of the Au-catalyst, we were Laschi, F.: Losi, S.; Macchi, P.; Sironi, A.; Zanello, P. Inorg. further encouraged by the results of Toste and coworkers who found that the use of multinuclear Au-catalyst provides 10 Chem., 2007, 46, 552. (b) Fumagalli, A.; Martinengo, S.; access to Such cyclic structure trappable by reaction with Ciani, G.; Moret, M.: Sironi A. Inorg. Chem. 1992, 31, 2900. external nucleophiles. Rearrangement in the mildly coordinating CHCl was slug Because the equilibrium between the metal-alkyne, metal gish (10% dienal 2a and 35% allene-aldehyde 1). The vinyl ether and metal-oxygen complexes should strongly reaction in tetrahydrofuran gave 90% allene-aldehyde 1 at depend on the nature of metal, we Scanned a number of 15 transition metal catalysts. Herein, we report that stereose the room temperature and proceeded slowly towards the 3:1 lective tandem isomerization of propargyl vinyl ethers to mixture of the dienals at 50° C. (E,Z)-dienals can be achieved using Rh(I)-catalysis. Screening of commonly used transition metals showed TABLE 2 that Au-based catalysts promote the Claisen rearrangement step but only AuCl is efficient in moving the cascade further (Table 1). However, the stereoselectivity of the final step Optimization studies was, at best, modest. Pd-based catalysts were only Success ful in promoting the first step. The hard Lewis acids such as entry solvent temp 1 2a 2b Cu(OTf), Zn(OTf) and Sc(OTf) were even less efficient. 25 On the other hand, Rh(CO)Cl] displayed remarkable 1 CDCN 25 N.R. reactivity, effectively promoting both the allene formation and its Subsequent rearrangement into the desired (E,Z)- 2 CDCN 50 N.R. dienal 2a (Table 1, entry 14). Donor phosphine ligands at the 3 CD-NO, 25 Trace Rh center eliminated the catalytic activity (entry 15). 30 4 THF-ds 25 90 5 THF-ds 50 89 8 3 TABLE 1. 6 CD2Cl2 25 35 10 Catalyst screenin 8 Toluene-ds 25 100 7 Toluene-ds 50 b 98 2 35 o11N N. H On 8 C6D6 25 95 Catalyst H 9 C6D6 50 b 95 5 Ph Ph Šs H Standard reaction conditions: All reactions were performed at 0.1M concentration in the Me presence of 10% Rh(CO)2Cl2. Relative ratios were determined by proton NMR. Me 40 Complete conversion of enol ether into 1 was observed that was subsequently fully 1 converted into 2a and 2b. Significant decomposition of substrate was observed. H Me H Me

E. 2 E. CHO On the other hand, conversions in benzene and toluene 45 Ph -- Ph were clean and proceeded in high yield and remarkable E. H CHO H E.Z-selectivity for substrates with the broad range of aro 2a 2b matic substituents at the carbinol carbon. Both donors and acceptors work well. Furthermore, other sp-substituents are entry catalyst 1 2a 2b 50 also compatible with the cascade. For example, a cyclohex 1 AuCl b 28 72 enyl substituted substrate gave dienal product in 62% yield 2 AuCls 72 9 17 3 PhPAuSbF 93 4 3 with excellent (E,Z)-stereoselectivity. Furthermore, the cas 4 AuSbF6 100 cade tolerates steric hindrance—even with the bulky sub 5 IPr-AuSbF 100 55 6 PdCl2 12 stituents such as t-butyl and mesityl, the Claisen products are 7 Pd(PPh3)2Cl2 100 8 Pd(PPh.) 8 3 — quickly formed at 50° C. and smoothly converted to the 9 Pd(PhCN)2Cl2 100 dienals in ~80% yield and excellent stereoselectivity upon 10 PtCl further heating. 11 Cu(OTf), 16 60 12 Zn(OTf), 15 13 Sc(OTf) 10° The following Table 3 provides examples of starting 14 Rh(CO)2Cl2 b 98 2 propargyl vinyl ethers with products that may be obtained 15 (PPh3)RhCl therefrom. The present invention is not limited to this list of Standard reaction conditions; 0.1M Substrate in toluene-d8 at 50° C. in the presence of 10% metal catalyst for 24 hours. Ratios determined by proton NMR. 65 propargyl vinyl ethers and their Subsequent (E,Z)-dienal Complete conversion of substrate into 1 was observed, followed by its full transformation into 2a and 2b, compounds, but rather, the method may be suitable for preparing a broad array of (E,Z)-dienal compounds. US 9,573,871 B2 17 18 TABLE 3 List of Substrates used for the kinetic study. Substrate Product 1s C4H9 S1s Šs CHO Bu MeO MeO (1a) (1)

o1S S1s Šs CHO

(2) (2a)

1s C4H9 S1s Šs B CHO C C

(3a) (3)

1s S1s Šs CHO FC FC (4) (4a)

1s C4H9 S1s Šs B CHO NC NC

(5a) (5)

In some embodiments, the following exemplary com- 65 to this list of compounds, but rather, the method may be pounds provided in Table 4 may be prepared by the method Suitable for preparing a broad array of (E,Z)-dienal com of the present invention. The present invention is not limited pounds. US 9,573,871 B2 19 20 TABLE 4 TABLE 4-continued Products of Rh(I)-catalyzed rearrangements obtained from their Products of Rh(I)-catalyzed rearrangements obtained from their respective propargyl vinyl ethers. respective propargyl vinyl ethers. 9 2a S1s S1s CHO CHO 10 92% 859% (>95) (>95) 10 C4H9 3 15 C4H9 S1s S1s CHO

CHO 50% MeO (>95) 859% (>95) 11

4 25 N CHO S. 80% HO (>95) C Ph 12 91% 30 (>95) S1s

CHO N 1N1 N1 N. 35 62% (>95) CHO NC 13 879% (>95) O S1s 40 N CHO 95% N (>95)

C1N1N1S HO 45 FC Percentages correspond to the isolated yields. In the above 90% list of products, values in parenthesis show percentage of (>95) E.Z isomer determined by proton NMR. "Reaction Condi tions: 0.1 M solution of 0.1 mmol propargyl vinyl ether in 50 toluene in the presence of 10% Rh(CO)Cl] at 50° C.” Rearranges further into a mixture of products. Requires 70° S. C. N The current limitations of this process seem to be asso CHO ciated with the possibility of further prototropic isomeriza 55 tions. For substrates with a n-butyl group at the carbinol 78% carbon, the dienal yields decreases to ~50% due to formation (>95) of several non-identified non-polar by-products. In the pres ence of a secondary (cyclohexyl) substituent, formation of Claisen product proceeded efficiently (>90%) at 50° C. but 60 its Subsequent rearrangement at 70° C. produced only a 1N1 NN1 ns small amount of (E. Z) dienal product together with unknown non-polar products. The cyclopropyl-substituted CHO substrate was unreactive in the presence of Rh(I) at 50° C. and decomposed at higher temperatures. 8.29% 65 DFT calculations at the M05-2X/LANL2DZ level suggest (>95) that the electron rich vinyl ether dissociates 16 electron Rh(I)-dimer to form a 16 electron Rh(I)-VE complex which US 9,573,871 B2 21 22 is expected to be the catalyst resting state. See FIG. 2. The cyclic intermediate in Pd-promoted Cope rearrangement. uncomplexed monomeric 14 electron pre-catalyst, Rh(CO) See Siebert, M. R.; Tantillo, D. J. J. Am. Chem. Soc. 2007, Cl is unlikely to be persistent. See Pitcock, Jr., W. H.; Lord, 129, 8686. R. L.; Baik, M-H. J. Am. Chem. Soc. 2008, 130, 5821. At the M05-2X/LANL2DZ level of theory, we did not Additional information regarding the mechanism of this find an energy minimum corresponding to the six-membered isomerization was provided by DFT calculations. They organorhodium intermediate in the parent system (FIG. 3). revealed that the most stable complex produced via coordi Further mechanistic exploration is needed to fully under nation of Rh(I) with the vinyl ether is catalytically unpro stand the subtleties of this transformation since the (E, ductive due to high barrier (FIG. 2, TS1: 41.2 kcal/mol). Z)-stereochemistry of double bonds in the dienal is fully DFT computations performed at M05-2X level suggests that 10 consistent with the Suggested transformation of the six the less stable complexes formed via coordination of Rh(I) membered intermediate. The stereochemistry of the two double bonds in 2a and 2b was confirmed by selective with the alkyne or the oxygen rearrange via considerably gradient-enhanced 1D NOESY (SELNOGP) and compari lower barriers. See (a) Zhao, Y.; Gonzalez-Garcia, N.; son to the known proton NMRs of the (E,Z) dienals 2a, 7. Truhlar, D. G. J. Phys. Chem. A 2005, 109, 2012. (b) Zhao, 15 8, 10 and 11. See (a) Makin, S. M.; Mikerin, I. E.; Shavry Y.; Truhlar, D. G. Org. Lett. 2007, 9, 1967. (c) Schultz, N.; gina, O.A.: Ermakova, G. A.; Arshava, B.M. Zh. Org. Khim. Zhao, Y.; Truhlar, D. G. J. Phys. Chem. A 2005, 109, 11127. 1984, 20, 2317. (b) Kann, N.; Rein, T.: Akermark, B.: Coordination of Rh(I) to the oxygen initiates the oxonia Helguist, P. J. Org. Chem. 1990, 55, 53.12. (c) Gravel, D.: Claisen rearrangement which proceeds via a dissociative-TS Leboeuf, C. Can. J. Chem. 1982, 60, 574. (d) Taylor, R. J. with 23.4 kcal/mol barrier (See FIG. 2, TS2). Coordination K.; Hemming, K. De Medeiros, E. F. J. Chem. Soc., Perkin of Rh(I) with the alkyne directs rearrangement via a very Trans. 1 1995, 2385. (e) Bellassoued, M.; Malika, S. Bull. low 9.7 kcal barrier (See FIG. 3, TS3). Even after the Soc. Chim. Fr., 1997, 134, 115. Curtin-Hammett correction, the latter route offers the lowest In Summary, Rh-catalyzed Claisen rearrangement fol energy path for the Claisen rearrangement with the barrier of lowed by Stereoselective hydrogen transfer converts prop 17.7 kcal/mol (See FIG. 3). For the stereoelectronic reasons 25 argyl vinyl ethers into the target (E. Z)-dienals in high for the endo-Selectivity in metal-catalyzed reactions yields, excellent stereoselectivity and with minimal waste. (“LUMO umpolung), see: (a) Alabugin, I. Gilmore, K.; The reaction tolerates steric hindrance and is compatible Manoharan, M. J. Am. Chem. Soc. 2011, 133, 12608. with substituents of different electronic demand. This atom Reviews: (b) Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, economical method yields complex and stereochemically 111, 6513. (c) Peterson, P. W.; Mohamed, R. K.; Alabugin, 30 defined dienals in only three steps from commercially avail I. V. Eur. J. Org. Chem., 2013, 2013, 2505. Selected appli able aldehydes. cations: (d) Zhao, J.; Hughes, C.O.; Toste, F. D. J. Am. Chem. Soc. 2006, 128,7436. (e) Byers, P. M.; Rashid, J. I.: EXAMPLES Mohamed, R. K.; Alabugin, I. V. Org. Lett. 2012, 14, 6032. 35 The following non-limiting examples are provided to (f) Hashmi, A. S. K. Braun, I., Rudolph, M.; Rominger, F. further illustrate the present invention. Organometallics 2012, 31, 644. (g) Naoe, S.; Suzuki, Y.: General Consideration. Hirano, K.; Inaba, Y.: Oishi, S.; Fujii, N.; Ohno, H. J. Org. All commercially procured chemicals were used as Chem. 2012, 77, 4907. (i) Hansmann, M. M.; Rudolph, M.: received. Dichloromethane (DCM), tetrahydrofuran (THF), Rominger. F.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2013, 40 triethylamine (Et-N), diethyl ether (EtO) were distilled 52, 2593. from calcium hydride (CaFH). Tetrahydrofuran (THF) was Although the interception of the pericyclic pathway is distilled from lithium aluminum hydride (LAH). Reagent conceptually interesting and increasingly utilized in the grade solvents were used for solvent extraction and organic design of cascade organic transformations, the six-mem extracts were dried over anhydrous sodium sulfate bered intermediate in the “cyclization-mediated pathway' is 45 (NaSO). Silica gel 60 (230-400 mesh ASTM) and neutral often elusive and its presence and lifetime depend on the alumina were used for Flash Chromatography with dry intricate details of transition state complexation with the hexane/ethyl acetate eluent system. "H NMR and "Cspectra catalyst. Selected precedents for the interception of pericy were recorded on 500 MHZ Bruker or 300 MHZ Varian clic pathways: Discovery of aborted pericyclic reactions: (a) spectrometers. The proton chemical shifts (8) are reported as Gilmore, K. Manoharan, M.; Wu, J.; Schleyer, P. V. R: 50 parts per million relative to 2.09 quintet ppm for CDCDs, Alabugin, I. V. J. Amer: Chem. Soc. 2012, 134, 10584. 5.32 for CDC1 and 7.27 for CDC1. The carbon chemical Interrupted pericyclic reactions: (b) Navarro-Vazquez, A.; shifts (ö) were reported as the centerline of triplet at 77.0 Prall, M.; Schreiner, P. R. Org. Lett. 2004, 6, 2981. Recent ppm for CDC1 and quintet at 54.00 ppm for CDC1. reviews: (c) Graulich, N.; Hopf, H.; Schreiner, P. R. Chem. Infrared spectra were recorded on sodium chloride plates Soc. Rev. 2010, 39, 1503. (d) Mohamed, R. K. Peterson, P. 55 using a Perkin-Elmer FT-IR Paragon 1000 spectrometer and W.; Alabugin, I. V. Chem. Rev., 2013, http://dx.doi.org/ frequencies were reported as reciprocal of centimeters 10.1021/cr4000682. For the special properties of alkynes (cm'). Mass spectra were recorded using a Jeol JMS-600 facilitating the design of Such reactions, see: Alabugin, I. V., instrument. The computations were performed using Gauss Gold, B. J. Org. Chem. 2013, 78, http://pubs.acs.org/doi/ ian03 on High Performance Computing facility (HPC) at abs/10.1021/jo401091 w. For example, we had shown in our 60 Florida State University. earlier work on Au-catalyzed rearrangement how coordina Computational Study tion of Au stabilizes TS for the subsequent Grob-type All geometries were optimized at the B3LYP/LANL2DZ fragmentation into the allene-aldehyde product to the extent and M05-2X/LANL2DZ levels which frequently performs that the intermediate corresponds to a shallow inflection at well for the transition metal compounds (e.g. Xia, Y.: the potential energy surface. On the other hand, Siebert and 65 Dudnik, A. S. Gevorgyan, V., Li, Y. JAm ChemSoc. 2008, Tantillo found that a combination of transition-state compl 130, 6940-6941 and Soriano, E.; Marco-Contelles, J. Acc. exation with resonance stabilization converts a TS into a Chem. Res. 2009, 42, 1026-1036) using Gaussian 03 pro US 9,573,871 B2 23 24 gram (see reference). Force Field calculation indicated that H NMR (500 MHz, CDC1,) 8: 746 (m, 2H), 7.37 (m, optimized structures were found to be true minima with no 2H), 6.50 (dd, J=14.2, 6.6 Hz, 1H), 5.49 (t, J=2.0 Hz, 1H), imaginary frequency. 4.46 (dd, J=14.1, 1.9 HZ, 1H), 4.17 (dd, J=6.6, 1.9 HZ, 1H), Gaussian 03, Revision E.01, M. J. Frisch, G. W. Trucks, 2.37 (s, 1H), 2.29 (td, J=7.2, 2.1 Hz, 2H), 1.52 (m, 2H), 1.42 H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheese (m. 2H), 0.91 (t, J=7.3 Hz, 3H). 'C NMR (125 MHz, man, J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C. CDC1) 8: 149.4, 137.1, 1342, 128.7, 128.6, 90.2, 89.9, Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. 76.5, 70.3, 30.53, 21.9, 18.4, 13.3. HRMS (EI+) Calcd. For Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, CHOC1 (Mt): 248,0968, Found: 248.0954. H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Vinyl Ether 16: Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. 10 4-(1-(vinyloxy)hept-2-yn-1-yl)benzonitrile Cross, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Strat mann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salva dor, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. 15 1S Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz., Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, Šs D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Bu Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, NC W. Chen, M. W. Wong, C. Gonzalez, and J. A. Pople, 4-(1-(vinyloxy)hept-2-yn-1-yl)benzonitrile Gaussian, Inc., Wallingford, Conn., 2003. General Procedure for Vinylation of Alcohols: H NMR (500 MHz, CDC1,) 8: 7.72 (m, 2H), 7.67 (m, To a 0.1 M solution of 1-phenylbut-2-yn-1-ol (1 mmol) in 2H), 6.55 (dd, J=14.1, 6.6 Hz, 1H), 5.60 (t, J=1.9 HZ, 1H), ethyl vinyl ether was added 0.6 mmol of mercuric acetate. 25 The reaction mixture was refluxed at 45° C. for 12 hours 4.52 (dd, J=14.1, J=2.0 Hz, 1H), 4.24 (dd, J–6.6, 2.0 Hz, before quenching with a saturated aqueous sodium carbon 1H), 2.33 (td, J=7.2, 2.1 Hz, 2H), 1.56 (m, 2H), 1.45 (m, ate solution. The organic phase was extracted using diethyl 2H), 0.95 (t, J=7.3 Hz, 3H). 'C NMR (125 MHz, CDC1,) ether and dried over anhydrous potassium carbonate. The 8: 149.2, 143.4, 132.3, 127.8, 118.5, 112.3, 90.6, 90.6, 30.4, Solvent was removed under vacuum and the crude vinyl 21.91, 18.3, 13.3. HRMS (EI+) Calcd. For CHON (Mt): ether was purified on alumina gel column using hexane as an 30 239.1310, Found: 239.1299. eluent. Vinyl ether 1 was obtained in 60% yield (0.1 g). Vinyl Ether 17: Vinyl Ether 14: (1-(vinyloxy)but-2-yn-1-yl)benzene (3-(vinyloxy)prop-1-yne-1,3-diyl)dibenzene

35 o1S 1s 40 Šs Ph (1-(vinyloxy)but-2-yn-1-yl)benzene (3-(vinyloxy)prop-1-yne-1,3-diyl)dibenzene

45 "H NMR (500 MHz, CDC1,) 8: 7.55 (m, 2H), 7.43 (m, H NMR (500 MHz, CDC1,) 8: 7.64 (m, 2H), 7.53 (m, 3H), 6.56 (dd, J=14.1, 6.6 Hz, 1H), 5.54 (q, J=2.1 Hz, 1H), 2H), 7.49-7.36 (m, 6H), 6.63 (dd, J=14.2, 6.6 Hz, 1H), 5.80 4.51 (dd, J=14.1, 1.8 Hz, 1H), 4.21 (dd, J=6.6, 1.8 Hz, 1H), (s, 1H), 4.59 (dd, J=14.1, 1.9 HZ, 1H), 4.27 (dd, J=6.6, 2.0 1.97 (d. J=2.2 Hz, 3H). ''C NMR (125 MHz, CDC1,) 8: Hz, 1H). 'C NMR (125 MHz, CDC1,) 8: 149.6, 137.8, 149.6, 138.4, 128.5, 128.5, 127.2, 89.8, 84.9, 76.2, 71.1, 3.4. 131.7, 128.9, 128.8, 128.6, 128.4, 127.4, 122.0, 90.3, 88.1, HRMS (EI+) Calcd. For CHO (M"): 172.0888, Found: 85.9, 71.2. HRMS (EI+) Calcd. For CHO (Mt): 172.0875. 234.1045 Found: 234.1040. Vinyl Ether 15: 1-chloro-4-(1-(vinyloxy)hept-2-yn Vinyl Ether 18: 1,3,5-trimethyl-2-(1-(vinyloxy)but 1-yl)benzene 55 2-yn-1-yl)benzene

1s o1 N. 60 Šs Šs Bu C 1-chloro-4-(1-(vinyloxy)hept-2-yn-1-yl)benzene 65 1,3,5-trimethyl-2-(1-(vinyloxy)but-2-yn-1-yl)benzene

US 9,573,871 B2 33 34 Dienal 13: (2Z.4E)-5-(furan-2-yl)-3-methylpenta-2, As various changes could be made in the above products 4-dienal and methods without departing from the scope of the inven tion, it is intended that all matter contained in the above description and shown in the accompanying drawings shall 5 be interpreted as illustrative and not in a limiting sense.

What is claimed is: 1. A method to synthesize an (E,Z)-dienal compound 10 having structure (V), the method comprising: (2Z.4E)-5-(furan-2-yl)-3-methylpenta-2,4-dienal contacting a compound having structure (III) with a catalyst comprising Rh(I) to thereby prepare the com Using the general procedure described above, 0.1 mmol pound having structure (V); wherein the compounds (16.2 mg) vinyl ether 22 gave 95% (15.5 mg) of dienal 12. 15 having structures (III) and (V) have the following H NMR (500 MHz, CDC1) E, Z8: 10.06 (d. J=7.5 Hz, 1H), Structures: 7.60 (d. J=15.8 Hz, 1H), 6.93 (d. J=1.6 Hz, 1H), 6.23 (d. J=15.8 Hz, 1H), 6.60 (m, 2H), 5.68 (dq, J=7.6, 1.1 Hz, 1H), 1.43 (d. J=1.1 Hz, 3H), 1.77 (m, 2H), 1.69 (m, 2H). 'C (III) NMR (125 MHz, CDC1,) 8: 1883, 1524, 1514, 143.4, H 128.8, 121.9, 111.8, 111.5, 198. O1 S-H and Dienal 8: (2Z.4E)-5-(furan-2-yl)-3-methylpenta-2,4- dienal H 25 R H Šs R2 (V) H R2 30 N R N1s H;

H CHO H CHO (2Z.4E)-5-mesityl-3-methylpenta-2,4-dienal 35 wherein Using the general procedure described above, 0.1 mmol R is selected from the group consisting of C alkyl, (21.4 mg) vinyl ether 18 gave 82% (17.5 mg) of dienal 8. 'H C2-12 alkenyl, C2-12 alkynyl, C-12 cycloalkyl, C-12 NMR (500 MHz, CDC1,) E, Z 8: 10.23 (d. J=7.9 Hz, 1H), cycloalkenyl, C-2 aryl, C-1s heteroaryl, amino, and 7.36 (d. J–16.4 Hz, 1H), 7.10 (d. J=16.4 Hz, 1H), 6.96 (s, 40 C-12 alkylamino; and 2H), 6.00 (dq, J=8.1, 1.2 Hz, 1H), 2.37 (s, 6H), 2.34 (s, 3H), R is selected from the group consisting of C alkyl, 2.28 (d. J=1.2 Hz, 3H). E., E 6: 10.02 (d. J=8.2 Hz, 1H), 7.05 C2-12 alkenyl, C2-12 alkynyl, C-12 cycloalkyl, C-12 (d. J=12.2 Hz, 1H), 6.89 (s. 2H), 6.83 (d. J=12.4 Hz, 1H), cycloalkenyl, C-2 aryl, C-1s heteroaryl, amino, and 5.80 (dq, J=8.3, 1.2 Hz, 1H), 2.31 (s.3H), 2.22 (s, 6H), 1.71 C. alkylamino. (d. J=1.2 Hz, 3H). 45 Mercury Poisoning Experiments. 2. The method of claim 1 wherein the compound having The mercury poisoning experiments were performed to structure (III) is synthesized by contacting a compound determine the role of nanoclusters or colloids in the proton having structure (I) and a compound having structure (II) rearrangement. The 0.1M solution of allene-aldehyde (0.1 according to the following sequence: mmols, 18.6 mg) and 5% Rh(I)-dimer (0.005 mmols, 2 mg) 50 in toluene was monitored until the formation of 20% (E. Z)-dienal at which point the large excess of elemental H mercury (4 gm) was added. The reaction was stirred vigor 1. Stron ously for 2 hours before taking the proton NMR spectrum. Base 9. O N H 55 Apart from reaction inhibition, we observed that the elemen R 1N O + R - 2. Mercuric-> H tal mercury, instead of coalescing, stayed in the dispersed I (II) acetate R phase. ( ) H Šs When introducing elements of the present invention or the preferred embodiments(s) thereof, the articles “a”, “an', “the' and “said are intended to mean that there are one or 60 (III) more of the elements. The terms “comprising”, “including and “having” are intended to be inclusive and mean that there may be additional elements other than the listed wherein R and R2 are as defined in claim 1. elements. 3. The method of claim 1 wherein the compound having In view of the above, it will be seen that the several 65 structure (III) is synthesized by contacting a compound objects of the invention are achieved and other advantageous having structure (I) and a compound having structure (II) results attained. according to the following sequence: US 9,573,871 B2 35 36

1. nBuLi, THF -78°C. o1 N H 1sO -- R -2. HgOAc,-> H (I) (II) ethyl R vinyl H Šs ether, rt R2

(III) 10

wherein R and R2 are as defined in claim 1. 4. The method of claim 1 wherein R comprises a C aryl or Cls heteroaryl. 5. The method of claim 1 wherein R is substituted with 15 a Substituent selected from the group consisting of C-2 alkyl, C-12 alkenyl, C-12 alkynyl, C-12 cycloalkyl, C-12 cycloalkenyl, C-2 aryl, C-1s heteroaryl, halo, hydroxy, cyano, C-12 alkoxy, nitro, Sulfinyl, Sulfonyl, amino, an C-12 alkylamino. 6. The method of claim 1 wherein the compound having structure (III) is contacted with a homogenous catalyst comprising Rh(I), and the preparation of the compound having structure (V) converts the homogenous catalyst com prising Rh(I) into a Rh(I)-nanocluster. 25 k k k k k