Heteroatom Nucleophile Induced CÂŒC Fragmentations to Access

Laureates: awards and Honors, sCs FaLL Meeting 2011 CHIMIA 2012, 66, No. 4 205

doi:10.2533/chimia.2012.205 Chimia 66 (2012) 205–207 © Schweizerische Chemische Gesellschaft Heteroatom Nucleophile Induced C–C Fragmentations to Access Functionalized Allenes

Tanguy Saget§ and Nicolai Cramer*

§SCS-Metrohm Foundation Award for best oral presentation

Abstract: The rich structural and reactivity profile of allenes render them versatile synthetic intermediates. However, application of allenes in organic chemistry is often attenuated by inconvenient methods of preparation. Herein we present an operationally simple route to functionalized allenes from vinyl triflate precursors through a Grob-type fragmentation induced by heteroatom nucleophiles such as water, alcohols, thiols or amines. The fragmentation occurs under mild conditions and is well suited for one-pot or domino processes allowing access to a range of synthetically useful intermediates. Keywords: Allenes · Cyclization · Domino reactions · Fragmentation · Radicals

The allene moiety is a versatile and 1).[6] However, their method is limited by was not required for this transformation. uniquely reactive functional group which the use of hard carbon-nucleophiles such After careful examination of the reaction has become popular in modern organic as organolithium or organocerium re- parameters, we found that 1a is quanti- chemistry, especially in transition-metal agents. Moreover, only products with the tatively transformed into enone 6 when catalysis.[1] Although several methods for carbonyl moiety at the ketone oxidation heated in DMF at 100 °C in the presence their preparation are established, addi- level or tertiary alcohols resulting from a of potassium carbonate.[8] One can ratio- tional and complementary methods to ac- second addition of the nucleophile are ac- nalize the formation of 6 by a mechanism cess them are of synthetic significance.[2] cessible. Reactions induced by heteroatom which starts by a nucleophile-induced Additionally, the use of mild reaction con- nucleophiles that would provide versatile Grob-fragmentation in which DMF acts ditions is highly desirable since the reactive carbonyl bearing products at the carboxyl- as the attacking nucleophile. The resulting profile of the allene would be well suited ic acid oxidation level are not possible with intermediate 4a or its acyl triflate equiva- for one pot or domino processes. Such an the reported set of reaction conditions. lent 4b can subsequently undergo an intra- approach would lead to a rapid increase in Our group has a long-standing inter- molecular Friedel-Crafts acylation leading molecular complexity from rather simple est in the development of metal-catalyzed to allylic carbenium 5 which gives 6 after precursors. C–H bond activations.[7] In this context, we proton elimination (Scheme 2). After this The carbonyl-generating Grob frag- have prepared compounds such as vinyl initial discovery, we decided to follow up mentation is a well-established cleaving triflate 1 as substrates to develop enanti- this reactivity and to explore the potential process which has found widespread ap- oselective palladium-catalyzed C(sp3)-H of this transformation. First we reasoned plication in synthesis.[3] Since the seminal functionalizations. Unexpectedly, 1a was that if DMF can promote the fragmenta- work of Eschenmoser,[4] numerous related converted to product 6 under several reaction of 1, then other nucleophiles such as reactions have been reported in the litera- tion conditions we tested. To our surprise, alcohols and amines might be competent ture. Dudley and coworkers studied nucleo- we discovered that a palladium catalyst as well. phile-induced Grob-type fragmentation reactions of vinylogous acyl triflates leading Scheme 1. Nucleo- 2 [5] R2 R1 R R1 phile induced Grob- to ω-substituted alkynes. Furthermore, O 1 O OTf Nu OTf TfO R 3 3 O type fragmentations Williams and coworkers recently extended Nu R R R2 • to access allenes. this strategy to access allenes (Scheme Nu R3 R3 R3 R3 3 1 2

Scheme 2. Lead dis- Pr TfO O covery of a domino Pr Pr Pr • reaction consisting O O O OTf NMe2 Pr DMF,K CO 4a of a fragmentation O 2 3 Pr and a Friedel-Crafts 4AMS, 100°C Pr Me N H *Correspondence: Prof. Dr. N. Cramer 2 O 5 reaction. 1a Pr • DMF Ecole Polytechnique Fédérale de Lausanne OTf 4b Et EPFL SB ISIC LCSA O BCH 4305 CH-1015 Lausanne Pr Tel.: +41 21 693 9839 6 Fax: +41 21 693 9700 99% 4,4:1 Z/E E-mail: [email protected] 206 CHIMIA 2012, 66, No. 4 Laureates: awards and Honors, sCs FaLL Meeting 2011

In this respect, the fragmentation was ing carboxylic acids 7e,f were obtained by standard cross-coupling reactions. initially examined with substrate 1a and in high yields. Finally, thiophenol is also Alternatively, such tetrasubstituted ole- benzyl alcohol as the promoter in the pres- competent to promote the reaction giving fins are directly obtained from allenes 7 ence of a base. We found that the reaction access to valuable thioester 7h, available through a one-pot fragmentation-arylative proceeds equally well in polar aprotic sol- for further derivatization reactions, e.g. cyclization sequence.[11] The addition of a vents such as DMF, DMA or DMSO while Liebeskind-couplings. catalytic amount of [Pd(dba) ] and tricy- 2 nonpolar solvents like toluene or DCE are To showcase the utility of this reac- clohexyl phosphine with phenyl iodide to not competent. The influence of the base tion, we studied the lactonization of the allenes 7 induces lactonization to products was also investigated. Cesium carbonate carboxylic acid products as the resulting 8e,f. From a mechanistic point of view, gave the best results, allowing fast con- γ-butyrolactones represent an abundant oxidative addition of Pd0 to the aryl iodide versions at room temperature. Potassium motif in natural products (Scheme 4).[9] generates an [Ar-PdII-X] species which can carbonate displayed somewhat lower re- For instance, cyclization to the desired act as a π-Lewis acid to activate the allene activity whereas poor conversions were five-membered allylic lactones 8a,b oc- moiety of 5, thus promoting a Wacker-type observed with sodium bicarbonate, tri- curs in good yields in the presence of tri- cyclization followed by a reductive elimi- ethylamine or in the absence of any base. fluoroacetic acid. The reaction proceeds nation. A second possible mechanism is Under the optimized reaction conditions, presumably via protonation of the allene. a carbo-palladation of the allene to form the desired allene 7a was obtained in 70% The resulting allylic carbocation is in turn a π-allyl palladium intermediate which is yield (Scheme 3). Different allenes such as intramolecularly trapped by the carboxylic trapped by an intramolecular nucleophilic 7b could be synthesized with similar effi- acid moiety to give 8a,b. We found that attack of the carboxylic acid.[11] ciency. The more acidic phenol works even acids 7 also undergo iodolactonizations in We then evaluated nitrogen-contain- better as shown for 7c,d. Remarkably, the a one-pot process from 1 by simply add- ing nucleophiles as a second major class ambident nucleophile 4-aminophenol re- ing iodine to the reaction mixture after of heteroatom nucleophiles for the frag- acts selectively with the hydroxyl group to completion of the fragmentation step.[10] mentation. We were pleased that they ef- give 7g in good yield. Moreover, water is a The resulting vinyl iodides 8c,d are valu- ficiently promote the reaction with only powerful promoter and by simply running able intermediates which can be further minor changes to the prior established the reaction in wet solvent, the correspond- transformed into tetrasubstituted olefins reaction conditions. Both primary and secondary amines lead to allenes 9a,b in excellent yields (Scheme 5). Aniline and Scheme 3. Oxygen R2 R1 even free ammonia are also competent nu- O OTf R1 and sulfur nucleo- cleophiles (9c,d). Moreover, significantly NuH R3 R3 O philes induce the R2 • less nucleophilic sulfonamides can pro- Cs2CO3,DMA, 23°C Nu fragmentation. R3 R3 7 mote the fragmentation provided that ce- 1 sium carbonate is used as base instead of Pr Bn Pr potassium carbonate. Interestingly, when O O O Pr • Me • Pr • the fragmentation was conducted with the OBn OBn OPh ambident N-phenyl hydroxylamine, the 70 %67a 5% 7b 92 % 7c nitrogen atom selectively reacts to afford

Allyl Ph Pr hydroxamic acid derivative 9f. O O O Inspired by a recent report on oxida- Allyl • Allyl • Pr • OPh OH OH tive cyclization of unsaturated hydroxamic 88 % 7d 86 % 7e 99 % 7f acids,[12] 9f seemed to be an ideal precur- sor for a further cyclization. Heating 9f Pr NH Allyl O 2 O in acetic acid in the presence of oxygen Pr • Allyl • O SPh and lauroyl peroxide at 60 °C resulted in 70 %67g 6% 7h the formation of 1,2-oxazinone 13 in fair yield. From a mechanistic point of view, Scheme 4. Lactoni- we presume that the initially formed oxy- O O zation reactions of gen centered radical 10 cyclizes to gener- O O carboxylic acid inter- ate a highly reactive vinyl radical species Pr Me mediates. 11, which in turn is trapped by molecular H Pr H Bn oxygen. The resulting hydroperoxide 12 99 %68a 9% 8b O 1:2.3 Z/E rearranges into hydroxyketone product 13 O (Scheme 6). This radical cyclization rep- TFA Pr resents a convenient approach to densely 2 1 R R I Pr functionalized 1,2-oxazinones which are O OTf R1 I2 78 % H2O,K2CO3 R3 R3 O 8c an important class of heterocycles encoun- R2 • O OH tered in several biologically active com- R3 R3 7 O pounds. 1 Me Finally, we turned our attention to so- cat. Pd0 PhI I Bn dium azide as another nitrogen-contain- 83 % 8d ing promoter for the fragmentation of 1 1:1.3 Z/E O O (Scheme 7). With the azide anion as nu- O O cleophile, this would lead to the formation Pr Me of an acyl azide intermediates 14. These

H Pr H Bn derivatives are known to undergo Curtius- 62 % 8e 60 % 8f rearrangements generating isocyanates 15. 2.1:1 Z/E Indeed, heating 1a in the presence of NaN 3 Laureates: awards and Honors, sCs FaLL Meeting 2011 CHIMIA 2012, 66, No. 4 207

Scheme 5. Frag- Allene Chemistry’, Eds. N. Krause, A. S. K. R2 R1 1 mentation induced by Hashmi, Wiley-VCH, Weinheim, 2004. O OTf NuH R R3 R3 O nitrogen containing [2] a) K. M. Brummond, J. E. Deforrest, Synthesis R2 • K2CO3,DMA, 50°C Nu nucleophiles. 2007, 795; b) S. Yu, S. Ma Chem. Commun. R3 R3 2011, 47, 5384. 9 1 [3] K. Pranz, J. Mulzer, Chem. Rev. 2010, 110, 3741. Allyl Me Allyl O O O [4] A. Eschenmoser, A. Frey, Helv. Chim. Acta Allyl • Bn • Allyl • NHBn N NHPh 1952, 35, 1660. 96 %89a 99 % 9b O 4% 9c [5] a) S. Kamijo, G. B. Dudley, J. Am. Chem. Soc. 2005, 127, 5028; b) S. Kamijo, G. B. Dudley, Org. Lett. 2006, 8, 175; c) D. M. Jones, S, Allyl Pr Pr O O O Kamijo, G. B. Dudley, Synlett 2006, 936; Allyl • Pr • Pr • Ph d) S. Kamijo, G. B. Dudley, J. Am. Chem. NH NHTs N 2 Soc. 2006, 128, 6499; e) S. Kamijo, G. B. 94 % 9d 91 %79e 5% 9f OH Dudley, Tetrahedron Lett. 2006, 47, 5629; f) J. Tummatorn, G. B. Dudley, J. Am. Chem. Soc. Scheme 6. Oxidative 2008, 130, 5050; g) D. M. Jones, M. P. Lisboa, Ph Pr radical cyclization of S. Kamijo, G. B. Dudley, J. Org. Chem. 2010, O O N lauroylperoxide, O (1 atm) O Pr allenic hydroxamic 75, 3260. Pr • Ph 2 Pr N acid 9f. [6] R. V. Kolakowski, M. Manpadi, Y. Zhang, T. J. AcOH, 60°C OH 9f OH Emge, L. J. Williams, J. Am. Chem. Soc. 2009, O 13 131, 12910. 52 % R [7] a) T. Seiser, O. A. Roth, N. Cramer, Angew. Chem. Int. Ed. 2009, 48, 6320; M. Albicker, N. Ph Ph Cramer, Angew. Chem. Int. Ed. 2009, 48, 9139; Pr O O N O N D. N. Tran, N. Cramer, Angew. Chem. Int. Ed. O Pr O O Pr Pr • Ph 2 2010, 49, 8181; D. N. Tran, N. Cramer, Angew. N Pr Pr Chem. Int. Ed. 2011, 50, 11098; T. Saget, S. J. 10 O O Lemouzy, N. Cramer, Angew. Chem. Int. Ed. 11 12 OH 2012, 51, 2238. [8] T. Saget, N. Cramer, Angew. Chem. Int. Ed. 2010, 49, 8962. Scheme 7. Domino Pr [9] a) M. S. Maier, D. I. G. Marimon, C. A. Stortz, Pr reaction consisting of R1 M. T. Adler, J. Nat. Prod. 1999, 62, 1565; b) • the fragmentation and R3 R3 O S.-C. Lee, G. D. Brown, J. Nat. Prod. 1998, 61, R2 • a Curtius rearrange- 29; c) R. R. A. Kitson, A. Millemaggi, R. J. K. R2 R1 N 14 3 ment. Taylor, Angew. Chem. Int. Ed. 2009, 48, 9426. O OTf NaN H2O NH 3 -N [10] X. Jiang, C. Fu, S. Ma, Chem. Eur. J. 2008, 14, 2 O DMA, 100°C R1 NH 9656. R3 R3 R3 R3 [11] R. D. Walkup, L. Guan, M. D. Mosher, S. W. 1 R2 • N 99 % • Kim, Y. S. Kim, Synlett 1993, 88. 15 O • 16 [12] V. A. Schmidt, E. J. Alexanian, Angew. Chem. Pr Int. Ed. 2010, 49, 4491. Pr ROH, RR1NH or RSH

O O O

HN OBn HN OEt HN OBn

Pr • Pr • Me •

Pr 17a 77 % Pr 17b 80 % Bn 17c 68 % O O O

HN NHBn HN NMe2 HN SPh

Pr • Pr • Pr •

Pr 17d 67 %6Pr 17e 9% Pr 17f 38 % at 100 °C in DMF resulted in full conver- and well suited to be coupled to one-pot sion to isocyanate 15a which was isolated or domino processes. In this case, one as the symmetrical urea 16 upon aqueous can benefit from the inherent reactivity of work-up. When alcohols are added to the allenes which allow transformations of reaction mixture from the beginning, iso- these intermediates into a wide range of cyanates 15 are directly trapped to the cor- synthetically useful compounds. responding carbamates 17a,c. A similar strategy can be used with amines or thiols leading to ureas 17d,e and thiocarbamate Acknowledgments 17f. In these cases, the nucleophile has to T. S. would like to cordially thank Metrohm be added after completion of the fragmen- and the Swiss Chemical Society for the SCS- tation step. Metrohm award. We thank the ETH Zurich In conclusion, we have reported a (ETH-16 09-3) and EPF Lausanne for funding. practical and operationally simple syn- Received: January 13, 2012 thesis of functionalized allenes from read- ily available vinyl triflate precursors. The [1] a) ‘The Chemisty of Allenes’, Ed. S. R. Landor, employed reaction conditions are mild Academic Press, London, 1982; b) ‘Modern