Ynol Ethers: Synthesis and Reactivity

The French connecTion CHIMIA 2016, 70, No. 1/2 93

doi:10.2533/chimia.2016.93 Chimia 70 (2016) 93–96 © Swiss Chemical Society Ynol Ethers: Synthesis and Reactivity

Charlie Verrier, Sébastien Carret, and Jean-François Poisson*

Abstract: Ynol ethers are highly valuable substrates offering a wide range of reactivity. These highly electron- rich heterosubstitued alkynes can be of great synthetic potential. In this mini-review, the different methods for the synthesis of ynol ethers are first presented, divided in three main approaches involving a β-elimination, a carbene rearrangement and a direct oxidation of an alkyne. Their reactivity is then summarized underlying their synthetic utility. This non-exhaustive review aims at presenting the intrinsic reactivity of these compounds, still underexploited in synthesis. Keywords: Alkynes · Enol ethers · Ketenes · Synthesis · Ynol ethers

Introduction dium. Based on a similar strategy, Cramer from tribromoethanol.[6a] The bromo-silyl- reported a more convenient procedure us- enol ethers, obtained by bromine lithium Heterosubstituted alkynes are valuable ing zinc instead of sodium, providing eth- exchange of the silyl ethers of tribromo- synthetic intermediates showing a wide yl- or butylethynyl ethers (Scheme 1a).[2] ethanol followed by a carbenoid rearrange- range of application. Among this class of The bromination of bromoacetaldehyde ment, were converted into the correspond- derivatives, ynol ethers have continuously dialkyl acetals followed by zinc-promot- ing silyloxyacetylides using LDA (Scheme stimulated the creativity of synthetic chem- ed β-elimination afforded 2-bromoenol 1c). The intermediate lithium acetylide ists, leading to reliable synthetic accesses ethers. A second base-promoted elimina- species could be trapped with various elec- and to the emergence of a unique reactivity tion provided the ynol ether. This double trophiles.[6b] pattern. The presence of the oxygen direct- elimination procedure gives moderate Normant, using trichloroethylene, pio- ly connected to the sp-hybridized carbon yields, but is applicable to the preparation neered a complementary strategy, allow- results in a polarized, highly reactive, triple of terminal oxygenated alkynes. A similar ing the stepwise connection of the alkoxy bond. Ynol ethers are known since 1908 method was later published by Newman, moiety first, followed by the substituent when Slimmer reported the isolation and using chloroacetaldehyde diethyl acetal at the second carbon.[7] 1,2-Dichloroenol characterization of phenoxyacetylene.[1] under Birch conditions (Scheme 1b).[3] ethers are initially formed by reaction of Nowadays, functionalized alkyl-, aryl-, The intermediate sodium ethoxyacetylide alkoxides with in situ generated highly and silyl ynol ethers are easily accessible could then react with different alkyl bro- electrophilic dichloroacetylene. Deproton- and are used in a variety of synthetic trans- mides, yielding substituted ynol ethers. A ation at low temperature followed by syn formations. In this short review, which is similar approach has been reported by the β-elimination, and a chlorine/lithium ex- not an exhaustive report, the main synthet- group of Nakaï,[4] using ethers of trifluoro- change leads to the formation of the lithio ic pathways of ynol ethers and a summary ethanol as precursors, and by Pericas using alkoxyacetylide (Scheme 2a).[8] The latter of the reactivity profile are presented. vinyl ethers.[5] can be hydrolyzed or trapped with a variety The enol ether β-substituted with a of electrophiles. This synthesis is certainly leaving group could also be generated the most versatile method in term of scope Synthesis of Acetylenic Ethers

Many strategies have been developed to Br OR Br2 Zn KOH synthesize acetylenic ethers, which can be X=Br H OR (a) Br OR Δ divided into three different approaches: the pyridine Br OR 50-65% OR ynols ethers can be obtained via a carben- 50% 50-55% R=Ph, Et, n-Bu oid rearrangement, by oxidation of alkynes X OR or by β-elimination from enol ethers. NaNH2 RBr X=Cl Na OEt R OEt (b) Ynol Ethers by β-Elimination NH3 liq 65-88% Historically, the elimination reaction R=Me, Et, n-Bu was the first method to access acetylenic ethers, and probably remains the most ef- EtOH ficient and versatile strategy. Slimmer in H OSiR3 1908 reported the synthesis of phenoxy- 88-95% acetylene from dibromoacetals and so- Br 1) n-BuLi MeI Br OSiR 3 Li OSiR3 Me OSiR3 (c) Br 2) LDA 32-69%

*Correspondence: Prof. J.-F. Poisson SiR3 =TIPS, TBDPS, DTBMS TMSCl Université Grenoble Alpes TMS OSiR3 Département de Chimie Moléculaire (SERCO) UMR-5250 CNRS, IMCG FR-2607, 38041 Grenoble, 52% France E-mail: [email protected]. Scheme 1. Formation of ynol ethers through β-elimination. 94 CHIMIA 2016, 70, No. 1/2 The French connecTion

as both alkyl and aryl groups can be in- OR troduced on the oxygen atom, while many Cl n-BuLi Cl OR n-BuLi R'I electrophiles are suitable for trapping the R'/H OR (a) or H2O intermediate lithio acetylide. RO Cl –80to Li Cl Li Starting from ketones, or esters, acet- –40°C 66-88% ylenic ethers can also be obtained. The R=Ar,alkyl R' =Me, Et, Pr,allyl formation of unstable enol triflates from α-alkoxyketones, followed by a treat- ment with potassium tert-butoxide affords O OTf a variety of aryl- and alkyl-substituted LiHMDS t-BuOK R R R OR' (b) ynol ethers (Scheme 2b).[9] Similarly, ace- PhNTf2 OR' tic esters can be converted to ynol ethers OR' 64-90% through enol phosphonate intermediates R=Ar,alkyl, alcynyl [10] (Scheme 2c). R' =Menthyl, t-Bu, Ar A final strategy was recently developed by Evano giving access to aryloxyalkynes LDA in one step from dibromoalkenes (Scheme O OPO(OEt)2 t-BuLi OR (c) 2d).[11] The sequence involves a copper- OR (EtO)2POCl OR pentane catalyzed C–O cross coupling of phenol –100 °C with gem dibromoalkenes to generate a R=primary/secondary alkyl 55-68% bromo-enol ether that is in situ converted into the aryloxyalkyne with a base.

Ynol Ethers via Carbene Br OAr ArOH t-BuOK Rearrangement OAr Br Br (d) The rearrangement of carbenes, or CuI (15 mol%) R carbenoids, constitutes a valuable strat- R 2,2'-bipy R egy to provide acetylenic ethers. Aromatic K3PO4 α-silylated diazoketones undergo thermal R=Ar,Alkyl silyl migration and carbene formation, which evolves through 1,2-migration to si- Scheme 2. Ynol ethers through β-elimination. lyloxyalkynes.[12] A carbenoid can also be formed from esters through the addition of dibromo-methyllithium.[13] The carben- LiTMP/CH2Br2 OLi O n-BuLi TIPSCl oid also evolves through 1,2-migration to Br R OTIPS R R OLi lithio alkoxyacetylene (Scheme 3). 50-74% R OEt –78°C Li Ynol Ethers from Alkynes R=Ar,alkyl, alkenyl Historically, the group of Stang was the Scheme 3. Silyl ynol ethers by α-elimination. first to use terminal alkynes as precursor for silyloxyalkynes.[14] The reported two- step procedure relies on an oxidation of affording the corresponding propargylic on the nature of the metal (Scheme 5b).[22] the alkyne by hypervalent iodine, produc- alcohols.[18] These propargylic alcohols These additions of alkoxyacetylides offer ing an alkynyl tosylate. This intermediate showed an interesting reactivity; under an easy entry to functionalized acetylenic can be detosylated with methyllithium, acid- or metal-catalyzed activation the ethers, complementary to the direct oxi- producing an ynolate that can be trapped motif is converted into an α,β-unsaturated dation of triple bonds in functionalized with bulky silyl chlorides, yielding the cor- ester, through the so-called Meyer-Schus- substrates, which in some cases may not responding silyloxyalkyne in moderated ter rearrangement (Scheme 5a).[19] The be compatible with the oxidation condi- yield (Scheme 4a). Few years later, Julia overall transformation represents an inter- tions. reported a more straightforward route.[15] esting alternative to the classical olefina- The oxidation of a lithium acetylide by tion for hindered ketones.[20] The addition Ynol Ethers as Ketene Precursors lithium tert-butylperoxide, followed by an of metallated ynol ethers to sulfonyl and A first peculiar, and particularly inter- O-silylation, provides a direct transforma- sulfinyl imines provides a modular access esting, reactivity of alkyl-ynol ethers is tion of terminal alkynes to silyloxyalkynes to alkoxypropargyl amines.[21] In the case their propensity to rearrange into ketenes, (Scheme 4b). Finally, alkynyl-sulfon- of chiral sulfinylimines, the relative con- via a retro-ene sigmatropy. This syntheti- amides[16] and alkynyl-sulfones[17] treated figuration of the propargylic center can be cally useful transformation, based on the by potassium tert-butoxide afford the cor- easily controlled and reversed depending thermal instability of acetylenic ethers, responding tert-butoxyacetylenic ethers in good yields. (a) PhI(OTs)(OH) MeLi TBSCl R OTs R OLi R OTBS 52-55% Reactivity of Ynol Ethers R H R=t-Bu, s-Bu

Nucleophilic Addition of Alkoxy i) LiHMDS TIPSCl Acetylide Anions (b) R OLi R OTIPS ii) t-BuOOLi 80-85% The nucleophilic addition of the lithio R=Ph, Alkyl alkoxyacetylides onto aldehydes and ketones was originally reported by Arens, Scheme 4. Oxidation of terminal alkynes. The French connecTion CHIMIA 2016, 70, No. 1/2 95

The intermolecular carbolithiation of OH Meyer- ynol ethers generates an unstable vinyl- Schuster CO2Et (a) lithium intermediate that spontaneously OEt β-eliminates to produce the corresponding internal alkyne (Scheme 8a).[34] Neverthe- O less, via an intramolecular cyclisation, the regioselectivity of the carbometallation PhCHO S HN can be reserved with an anti carbolithia- Me2AlCl (R' =Et) tion process, leading to a more stable or- 0°C R ganolithium species that can be trapped OR' Cl dr =98:2 with various electrophiles (Scheme 8b).[35] n-BuLi (2 equiv.) SOtBu up to 93% Li OR' R N Normant andAlexakis reported the car- –80to–40 °C (b) Cl OR' O bocupration of ynol ethers affording the vi- R=Ar,alkyl S nyl ethers with a lack of selectivity when HN R' =Cy, t-Bu, PMP BF3.Et2O thetriplebondwassubstituted.[36] Recently, -80 to -40 °C R Marek published a solution to circumvent OR' this lack of selectivity, with an effective re- dr =2:98 giodivergent carbocupration process, gov- up to 93% erned by the nature of the substituent on the Scheme 5. Addition of metallated ynol ethers to aldehydes and imines. oxygen of the acetylenic ethers (Scheme 8c).[37] The carbometallation of ynol ethers very much depends on the oxygen sub- Scheme 6. Thermal R3 stituent: primary alkyl ethers being more R2 formation of ketenes R1 Δ O from ynol ethers. stable than secondary, the later being more H H (a) stable than tertiary ether (Scheme 6a).[23] O It has also recently been shown that allylic R3 R2 R R and benzylic acetylenic ethers can rear- R1 range at lower temperatures.[24] OTBDPS This ketene generation is very useful OTBDPS for lactonization or macrolactonization,[25] and has found an interesting application xylene O O OH H in the total synthesis of the complex OH H (b) EtO Bu3N O O OH natural product (+)-Acutiphycin (Scheme OH OH 150 °C Bu [26,27] Bu OH 6b). OH Taking advantage of this in situ ke- 90% tene generation, intramolecular cycload- ditions reactions have been developed. (+)-Acutiphycin For instance, the [2+2] cycloaddition with R an olefin offers fused four/five bicycles (Scheme 6c).[28] t-BuO R toluene X (c) X Recently, Ready reported an elegant 90 °C O H Sonogashira coupling of alkoxyacetylenes Y Y 50-95% followed by a thermal sigmatropic rear- R=Me, OAlkyl X=O,NTs,CH2 rangement offering an in situ generation of Y=Alkyl, OSiR3 a variety of aromatic ketenes.[29] This ketene generation strategy offers an access to 1. [Pd2(dba)3], PR3 CuI, amine, 4Å MS O O a wide range of carbonyl derivatives start- NuH OtBu (d) ing from a single ynol ether intermediate ArI Nu (Scheme 6d). 2. Morpholine,PhMe Ar H Ar 75 °C Ynol Ethers as Precursors of Enol Ethers Ynol ethers also afford a selective en- Scheme 7. Selective H2 enol ether synthesis. try to Z and E enol ethers. Palladium-cat- LAH OR' Pd/BaSO R 4 OR' alyzed hydrogenation selectively affords OR' the Z enol ether,[30] whereas LiAlH reduc- or R R 4 Li/NH tion selectively leads to the E enol ethers 3 (Scheme 7).[31] Ynol ethers are also exclu- sive precursors for a selective synthesis of i) HBpin, THF disubstituted enol ethers. The hydrobora- 55-92% ii) Pd(dba)2 Cs2CO3 tion of ynol ethers produces exclusively an R''X E enol ether by syn addition of pinacolbo- rane.[32] Combined with a subsequent Su- R OR' R=Alkyl, Ar zuki-Miyaura coupling, β,β-disubstituted R' =Et, tBu, Ar vinyl ethers can be efficiently obtained in R'' R'' =Ar, HetAr,Alkenyl a one-pot procedure (Scheme 7).[33] 96 CHIMIA 2016, 70, No. 1/2 The French connecTion

has also recently been extended to car- Scheme 8. Carbo- [38] [39] OEt EtOLi metallation of ynol bonickelation and carbopalladation. OEt R-Li R n-Bu (a) ethers. R n-Bu dioxane n-Bu Cycloisomerization with Ynol Ethers Δ Li Finally, acetylenic ethers can be en- gaged in cycloisomerization processes for OEt Li E OEt OEt the formation of carbocycles. Danheiser n-BuLi E+ (b) reported the [2+2] intermolecular cyclo- 68-90% I addition between ketenes and ynol ethers, n n n providing cyclobutanones that subsequent- n =1,2 E+ =H+,ketone, aldehyde ly rearranges offering an entry to a vari- DMF,ClCO Et ety of phenols.[40] Using either triflic acid 2 OCy or gold complexes Kozmin reported the RCu(CN)ZnR X=CH2 n-Bu transformation of 1-silyloxy-1,5-enynes R 81-87% into cyclohexadienes.[41] This gold-cata- H lyzed ynol activation was then extended O X R=Me, Et, Pr,Bu, Cy to the synthesis of more complex scaffolds n-Bu (c) involving a furan acting stepwise as nu- RMgBr OTHP CuI [21] n-Bu cleophile and electrophile (Scheme 9). E X=O then E+ R 71-85% Conclusion R=Et, Pr,Bu, n-Hex, Bn E+ =H+,EtBr Acetylenic ethers are valuable synthetic intermediates. The variety of reactivity R3 R3 of the polarized triple bond makes it a very R4 R2 AuCl 1mol% R2 R4 useful synthon in organic synthesis: the H R1=H,Me panel of reactivity surely offers opportu- R2=Alkyl, Ph (a) CH2Cl2,rt nities for further exploration, and for the R1 TIPSO R3=H,Me 50-98% R1 R4=Alkyl discovery of novel transformations. OTIPS

O NTs O O Received: July 29, 2015 [Mes3PAu]NTf2 MeO NTs NTs 3mol% (b) O Au R2 PMPO O 74-89% 1 [1] M. Slimmer, Chem. Ber. 1908, 36, 289. R2 R R1 MeO [2] T. L. Jacobs, R. Cramer, J. E. Hanson, J. Am. R1,R2=H,Me, tBu Chem. Soc. 1942, 64, 223. [3] M. S. Newman, J. R. Geib, W. M. Stalick, Org. Scheme 9. Cycloisomerization involving ynol ethers. Prep. Proced. Int. 1972, 4, 89. [4] S. Shuichi, T. Nakai, K. Tanaka, N. Ishikawa, Tetrahedron Lett. 1978, 34, 3103. [20] D.A.Engel,G.B.Dudley, Org.Lett.2006,8,4027. Poisson, Eur. J. Org. Chem. 2009, 4221; e) B. [5] M. A. Pericas, F. Serratosa, E. Valenti, [21] S. K. Hashmi, M. Rudolph, J. Huck, W. Frey, J. Darses, A. E. Greene, J.-F. Poisson, Org. Lett. Tetrahedron 1987, 43, 2316. Bats, M. Hamzic, Angew. Chem. Int. Ed. 2009, 2010, 12, 3994. [6] a) M. Pirrung, J. R. Hwu, Tetrahedron Lett. 48, 5848. [32] R. W. Hoffmann, J. Krüger, D. Brückner, New. 1983, 24, 565; b) R. L. Danheiser, A. Nishida, [22] a) C. Verrier, S. Carret, J.-F. Poisson, Org. Lett. J. Chem. 2001, 25, 102. S. Savariar, M. P. Trova, Tetrahedron Lett. 1988, 2012, 14, 5122; b) C. Verrier, S. Carret, J.-F. [33] W. Cui, M. Mao, G. Zhu, J. Org. Chem. 2013, 29, 4917. Poisson, Monatsh. Chem. 2013, 144, 455; c) C. 78, 9815. [7] J. Normant, Bull. Soc. Chim. Fr. 1963, 1876. Verrier, S. Carret, J.-F. Poisson, Org. Biomol. [34] J. G. A. Kooyan, H. P. G. Hendriks, P. P. [8] B. Darses, A. Milet, C. Philouze, A. E. Greene, Chem. 2014, 12, 1875. Montijn, L. Brandsma, J. F. Arens, Rec. Trav. J.-F. Poisson, Org. Lett. 2008, 10, 4445. [23] J. J. Van Daalen, A. Kraak, J. F. Arens, Rec. Chim. Pays-Bas 1968, 87, 69. [9] J. R. Sosa, A. A. Tudjarian, T. G. Minehan, Org. Trav. Chim. Pays-bas 1961, 80, 810. [35] a) R. L. Funk, G. L. Bolton, K. M. Brummond, Lett. 2008, 10, 5091. [24] a) J. R. Sosa, A. A. Tudjarian, T. G. Minehan, K. E. Ellestad, J. B. Stallman, J. Am. Chem. [10] J. A. Cabezas, A. C. Oehlschlager, J. Org. Org. Lett. 2008, 10, 5091; b) A. A. Tudjarian, T. Soc. 1993, 115, 7023; b) R. Hanna, B. Daoust, Chem. 1994, 59, 7523. G. Minehan, J. Org. Chem. 2011, 76, 3576. Tetrahedron 2011, 67, 92; c) R. Lhermet, [11] K. Jouvin, A. Bayle, F. Legrand, G. Evano, Org. [25] L. Liang, R. Ramaseshan, D. I. MaGee, M. Ahmad, C. Hauduc, C. Fressigne, M. Lett. 2012, 14, 1652. Tetrahedron 1993, 49, 2159. Durandetti, J. Maddaluno, Chem. Eur. J. 2015, [12] G. Maas, R. Brückmann, J. Org. Chem. 1985, [26] R. M. Moslin, T. F. Jamison, J. Am. Chem. Soc. 21, 8105. 50, 2802. 2006, 128, 15106. [36] A. Alexakis, G. Cahiez, J. F. Normant, J. [13] a) C. J. Kowalski, G. S. Lal, M. J. Haque, J. Am. [27] For lactams and imides formation see: a) D. I. Villieras, Bull. Soc. Chim. Fr. 1977, 693. Chem. Soc. 1986, 108, 7127; b) C. J. Kowalski, MaGee, M. Rameseshan, Synlett 1994, 743; b) [37] a) L. Levin, A. Basheer, I. Marek, Synlett 2010, R. E. Reddy, J. Org. Chem. 1992, 57, 7194. D. I. MaGee, M. Rameseshan, J. Leach, Can. J. 329; b) A. Basheer, I. Marek, Beilstein J. Org. [14] P. J. Stang, K. A. Roberts, J. Am. Chem. Soc. Chem. 1995, 73, 2111. Chem. 2010, 6. 1986, 108, 7125. [28] V. Tran,T. G. Minehan, Org. Lett. 2011, 13, 6588. [38] N. Saito, Z. Sun, Y. Sato, Chem. Asian J. 2015, [15] M. Julia, V. Pfeuty Saint-James, J.-N. Verpeaux, [29] W. Zhang, J. M. Ready, Angew. Chem. Int. Ed. 10, 1170. Synlett 1993, 3, 233. 2014, 53, 8980. [39] M. Hari Babu, V. Dwivedi, R. Kant, M. Sridhar [16] V. J. Gray, B. Slater, J. D. Wilden, Chem. Eur. J. [30] A. E. Douglas, S. S. Lopez, G. B. Dudley, Reddy, Angew. Chem. Int. Ed. 2015, 54, 3783. 2012, 18, 15582. Tetrahedron 2008, 64, 6988. [40] R. L. Danheiser, S. K. Gee, J. Org. Chem. 1984, [17] L. Marzo, A. Parra, M. Frias, J. Alemen, J. L. G. [31] a) J. Ceccon, A. E. Greene, J. F. Poisson, Org. 49, 1672. Ruano, Eur. J. Org. Chem. 2013, 4405. Lett. 2006, 8, 4739; b) B. Darses, A. E. Greene, [41] L. Zhang, S. A. Kozmin, J. Am. Chem. Soc. [18] J. C. W. Postma, J. F. Arens, Rec. Trav. Chim. S. C. Coote, J.-F. Poisson, Org. Lett. 2008, 10, 2004, 126, 11806. For a recent review on Pays-Bas 1956, 75, 1408. 821; c) J. Ceccon, G. Danoun, A. E. Greene, J.- silyloxyalkynes in annulation reactions, see: H. [19] A. E. Douglas, S. S. Lopez, G. B. Dudley, F. Poisson, Org. Biomol. Chem. 2009, 7, 2029; Qian, W. Zhao, J. Sun, Chem. Rec. 2014, 14, Tetrahedron 2008, 64, 6988. d) G. Danoun, J. Ceccon, A. E. Greene, J.-F. 1070.