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Synthesis of Indoles, Benzofurans, and Related Heterocycles Via an Acetylene-Activated Snar/Intramolecular Cyclization Cascade Sequence in Water Or DMSO

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Synthesis of Indoles, Benzofurans, and Related Heterocycles Via an Acetylene-Activated Snar/Intramolecular Cyclization Cascade Sequence in Water Or DMSO Organic & Biomolecular Chemistry Synthesis of indoles, benzofurans, and related heterocycles via an acetylene-activated SNAr/intramolecular cyclization cascade sequence in water or DMSO Journal: Organic & Biomolecular Chemistry Manuscript ID: OB-COM-12-2014-002549.R1 Article Type: Paper Date Submitted by the Author: 08-Jan-2015 Complete List of Authors: Hudson, Reuben; Colby College, Chemistry Bizier, Nicholas; Daemen College, Chemistry Esdale, Kristin; Colby College, Chemistry Katz, Jeffrey; Colby College, Chemistry Page 1 of 12 Organic & Biomolecular Chemistry Journal Name RSCPublishing ARTICLE Synthesis of indoles, benzofurans, and related heterocycles via an acetylene-activated Cite this: DOI: 10.1039/x0xx00000x SNAr/intramolecular cyclization cascade sequence in water or DMSO Received 00th January 2012, Accepted 00th January 2012 R. Hudson,a N. P. Bizier,b K. N. Esdalea and J. L. Katza* DOI: 10.1039/x0xx00000x www.rsc.org/ The synthesis of 2-substituted indoles and benzofurans was achieved by nucleophilic aromatic substitution, followed by subsequent 5-endo-dig cyclization between the nucleophile and an ortho acetylene. The acetylene serves the dual role of the electron withdrawing group to activate the substrate for SNAr, and the C1-C2 carbon scaffold for the newly formed 5-membered heteroaromatic ring. This method allows for the bond forming sequence of Ar-X – N/O – C1 to proceed in a single synthetic step, furnishing indoles and benzofurans in moderate to high yields. Since the method is not transition metal mediated, brominated and chlorinated substrates are tolerated, and benzofuran formation can be conducted using water or water/DMSO mixtures as solvent. Introduction from 2-halo-arylacetylenes and the desired N- coupling partner through Pd,23 Cu,24 or Ni25 mediated processes. Similarly, 26 27 Indoles, benzofurans, and similar motifs are pervasive throughout benzofurans can be produced by Pd or Cu catalyzed nature,1 and represent common building blocks for the synthesis of hydroxylation of aryl halides, followed by subsequent intramolecular 2 cyclization with an ortho acetylene. Even the analogous S- pharmaceuticals or otherwise biologically relevant targets. The 28 29 ubiquity of this type of scaffold and utility of products derived (benzothiophene), and P- (benzophospholes) heterocycles have therefrom for transistors,3 light emitting diodes,4 photovoltaics,5 been synthesized by similar routes. However, the reliance on biosensors6 and other functional organic molecules7 continues to transition metal mediated processes precludes the use of aryl drive the pursuit of new synthetic methodologies, which have been fluorides as the reactive halogen species. The present work instead extensively reviewed for both indole8 and benzofuran9 moieties. utilizes alkyne-activated SNAr for the Ar-X – N/O bond formation, allowing the use of aryl fluorides. Selectivity of N- and O- nucleophiles in an S Ar context for fluorine over alternative Considering routes to indoles that begin with an intact benzene ring, N halogens also means that our method is able to furnish Cl- and Br- the formation of new bonds can occur between C1 - C2,10 Ar-H – substituted indoles and benzofurans, which are difficult to access C2,11 Ar-X – C2,12 Ar-H – N,13 Ar-X – N,14 or N – C115, 16 (scheme using metal-mediated Ar-X – N/O – C1 bond forming schemes. 1). Similarly, the formation of new bonds within a benzofuran motif Since S Ar reactivity benefits from significant polar interactions to can occur between C1 – C2,17 Ar-H – C2,18 Ar-X – C2,19 Ar-H – N stabilize the transition state, water can be used as a sustainable O,20 Ar-X – O21 or O-C1.16, 22 The present work describes a reaction solvent,30 or as a co-solvent along with DMSO, for the procedure for the generation of indoles and benzofurans in which the synthesis of benzofurans by this method. Ar-F – N/O – C1 bonds are formed in a single synthetic step, achieved through the coupling of various N- and O- nucleophiles with 2-fluoro-arylacetylenes. This bond formation sequence is less common, but not without precedent. Indeed, indoles can be formed This journal is © The Royal Society of Chemistry 2013 J. Name., 2013, 00, 1-3 | 1 Organic & Biomolecular Chemistry Page 2 of 12 ARTICLE Journal Name Scheme 1. Strategies for the Synthesis of Indoles and Benzofurans Table 1. Reaction of p-toluidine with various 2-fluoro-arylacetylene electrophiles.a Ar-H - C2 R KOtBu (2.2 equiv) + p-toluidine R Z F DMSO Z N Y (2.2 equiv) Ar-X - C2 p-Tol C1-C2 Z = CH,N X 2 1 Y R Y H3C CH3 C2 R R C1 Y N N N p-Tol p-Tol p-Tol 2a 2b 2c (72%)a (68%)a (72%)a Y X Y CH3 CF3 N N N Ar-X - N/O Y N/O - C1 X p-Tol p-Tol p-Tol Ar-X - N/O - C1 2d 2e 2f a a a X = Halide present work Y = NR, O (69%) (61%) (81%) CN N N N N The use of alkynes as the sole electron-withdrawing group to p-Tol p-Tol p-Tol 2g 2h promote S Ar reactions has been only sparingly covered in the 2i N (79%)a (80%)a (54%)b literature.31 We recently probed the topic in detail,32 determining reaction rates for the substitution of 4-fluorophenylacetylenes wih p- cresol, as well as examining other N- and O- nucleophiles. We found N N N N N N p-Tol p-Tol p-Tol that 2-fluoroarylacetylenes, when reacted with p-toluidine would, 2j 2k 2l after the initial substitution, further cyclize to form the (68%)a (51%)c (78%)a corresponding 2-substituted indole. Aside from examples in our initial report, analogous sequences have been limited to aromatics CF3 with multiple-alkynes for the synthesis of benzotrifurans and N N N N N 33 34, 35 p-Tol p-Tol benzotripyrrols, or the use of highly reactive selenium or 2m 2n 34, 36 sulfur nucleophiles. In the present work, we further develop the (84%)a (88%)a scope of our method for 2-substituted indole formation examining p- toluidine and acetamide nucleophiles with various electrophiles. aConditions: 100 ˚C, 18 h. bConditions: 150 ˚C, 72 h. cConditions: 80˚C, 48 h. 37 Additionally, we expand the substitution/cyclization cascade 1a: Z=CH, R=Ph, 1b: Z=CH, R=o-Tol, 1c: Z=CH, R=m-Tol, 1d: Z=CH, reactivity to hydroxide, which provides the corresponding R=p-Tol, 1e: Z=CH, R=4-tBu-Ph, 1f: Z=CH, R=4-CF3-Ph, 1g: Z=CH, R=3- benzofurans. Py, 1h: Z=CH, R=4-CN-Ph, 1i: Z=CH, R=tBu, 1j: Z=N, R=tBu, 1k: Z=N, R=H, 1l: Z=N, R=Ph, 1m: Z=N, R=4-CF3-Ph, 1g: Z=N, R=3-Py. Results and Discussion The trends for electrophile reactivity observed with p-toluidine also In order to probe the functional group tolerance of the electrophile held true for hydroxide and acetamide. Of the three nucleophiles, and to determine the effects of these groups on SNAr/cyclization, the hydroxide reacted with the highest yield. The superior study compared yields for various 2-fluoro-arylacetylenes 1 in the nucleophilicity of hydroxide was also evident through the formation reaction with p-toluidine under KOtBu conditions (Table 1) a of significant amounts of the corresponding benzofuran products in mechanism for which is included in scheme 2. As expected, the reactions with N- nucleophiles that were not rigorously dried prior to addition of a pyridine nitrogen ortho to the substituting fluorine use. In a competition experiment reacting equimolar amounts of further activated the substrates for SNAr (1j-n), increasing the hydroxide and p-tolylamide with electrophile 1a, hydroxide reacted reaction yields relative to the benzene analogues. The nature of R overwhelmingly to form the corresponding benzofuran product in a pendant to the acetylene also significantly influenced reaction yields, 95:5 ratio over the indole. Acetamide proved an effective generally following the trend for: aryl with EWG (1f-h, 1m-n) > aryl nucleophile as well as ammonia surrogate, by directly providing the (1a, 1l) > aryl with EDG (1b-e) > t-butyl (1i-j) > H (1k). t-Butyl corresponding N-H indole via in situ acetate cleavage, obviating the acetylene electrophile 1i required prolonged reaction times and need for an anhydrous ammonia source to produce this product increased temperatures, although such reduced reactivity could be outcome. mitigated by use of the pyridine analogue 1j. Benzene electrophiles tBu substituted with terminal acetylenes proved problematic due to O H competing alkyne addition side reactions. Selectivity for the desired R R R H SNAr pathway could be restored by use of the pyridine analogue 1k HN p-Tol HN p-Tol 5-endo-dig at longer reaction time and lower temperature, although product R F SNAr NH N N yields remained modest. p-Tol p-Tol p-Tol Scheme 2. Proposed SNAr/intramolecular cyclization cascade mechanism. 2 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 2012 Page 3 of 12 Organic & Biomolecular Chemistry Journal Name ARTICLE Table 2. Reaction of hydroxide, p-toluidine and acetamide with Table 3. Reaction of hydroxide with 2-fluoro-phenylacetylene various 2-fluoro-arylacetylene electrophiles. electrophiles under aqueous conditions R R H2O + NaOH R DMSO + Nu R Z F Z O Z F Y Z Z = CH,N 3 Z = CH,N 2, Y = N(p-Tol) 1 1 3, Y = O 4, Y = NH CF OMe 3 N O N N O N O 3f 3g 3h (96%)a (24%)a (97%)b (trace)a (95%)b Electrophile NaOHa p-toluidineb acetamidec Ph Ph Ph Ph N O N O O N O N N H 3d 3c 3i F p-Tol (0%)a (94%)b (6%)a (95%)b (0%)a (0%)b 1a 3a 2a 4a (92%)d (72%)d (68%)d t-Bu O O t-Bu t-Bu t-Bu 3a 3b O N N H (0%)b (84%)c (0%)b (59%)c F p-Tol 1i 3b 2i 4b (89%)e (54%)e (51%)e a Reaction conditions: 0.5 mmol electrophile, 3 equiv NaOH, H2O (1 Ph mL), 100˚C, 18 h, sealed tube.
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