The Takai olefination (or Takai reaction) is a method for the conversion of aldehydes to vinyl iodides, and has seen widespread implementation in organic synthesis. The reaction is usually noted for its high (E)-selectivity; however, herein we report the highly (Z)-selective Takai olefination of salicylaldehyde derivatives. Systematic screening of related substrates led to the identification of key factors responsible for this surprising inversion of selectivity, and enabled the development of a modified mechanistic model to rationalise these observations.The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no [279337/DOS]. In addition, the group research was supported by grants from the Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Medical Research Council and Wellcome Trust

Galloway, WRJD

Geddis, SM

Goodman, JM

Hagerman, CE

Sore, HF

Spring, DR

Beilstein Journal of Organic Chemistry

Apollo (Cambridge)

323(Z)-Selective Takai olefination of salicylaldehydesStephen M. Geddis‡, Caroline E. Hagerman‡, Warren R. J. D. Galloway, Hannah F. Sore,Jonathan M. Goodman and David R. Spring*Letter Open AccessAddress:Department of Chemistry, University of Cambridge, Lensfield Rd,Cambridge, CB2 1EW, UKEmail:David R. Spring* - spring@ch.cam.ac.uk* Corresponding author    ‡ Equal contributorsKeywords:alkenyl iodides; salicylaldehydes; stereoselectivity; Takai olefination;transition stateBeilstein J. Org. Chem. 2017, 13, 323–328.doi:10.3762/bjoc.13.35Received: 05 October 2016Accepted: 09 February 2017Published: 20 February 2017Associate Editor: J. A. Murphy© 2017 Geddis et al.; licensee Beilstein-Institut.License and terms: see end of document.AbstractThe Takai olefination (or Takai reaction) is a method for the conversion of aldehydes to vinyl iodides, and has seen widespreadimplementation in organic synthesis. The reaction is usually noted for its high (E)-selectivity; however, herein we report the highly(Z)-selective Takai olefination of salicylaldehyde derivatives. Systematic screening of related substrates led to the identification ofkey factors responsible for this surprising inversion of selectivity, and enabled the development of a modified mechanistic model torationalise these observations.IntroductionThe Takai olefination (or Takai reaction) is a method for theconversion of aldehydes 1 into the corresponding alkenylhal ides 2  using a haloform–chromium(II)  chloride(CHX3–CrCl2) system (Scheme 1A) [1,2]. It is believed that thehaloform is first converted to a nucleophilic gem-dichromiumspecies 3 that then attacks the carbonyl group of the aldehyde togenerate a β-oxychromium species 4 (Scheme 1B). Subsequentelimination leads to alkene formation. The Takai olefination canalso be performed with geminal dihalide reagents rather thanhaloforms. In addition, the reaction can also be used to generatevinyl stannanes [3], silanes [4] and boronates [5].One of the most significant features of the Takai olefination isthat it is generally highly selective for the formation of (E)-alkenes ((E):(Z)-product ratios are typically around 4:1 orgreater). This selectivity has found wide use, particularly in thefield of total synthesis where it is often used to install vinyliodides with high levels of geometric purity which can then beutilised in metal-catalysed cross-coupling reactions [2,6].Hodgson et al. [7] and later Takai et al. [5] have proposed verysimilar models to explain the (E)-stereoselectivity observed inthe chromium(II)-mediated homologation of aldehydes toalkenes (including vinyl halides). The salient features of bothmodels are the same (Scheme 2). It is presumed that the addi-tion of the gem-dichromium species 3 to the aldehyde 1proceeds via a six-membered pseudo-chair transition state 5containing two chromium ions bridged by a halogen. The lessBeilstein J. Org. Chem. 2017, 13, 323–328.324Scheme 2: Proposed model for the chromium(II)-mediated homologation of aldehydes to form (E)-alkenes. Hodsgon et al. [7] and Takai et al. [5]have hypothesised that the addition of the gem-dichromium species 3 to aldehyde 1 proceeds via a six-membered pseudo-chair transition state 5.X = Cl, Br or I. Other ligands on chromium omitted for clarity.Scheme 1: A) General overview of the Takai olefination for the forma-tion of alkenyl halides 2 from aldehydes 1 and haloforms in the pres-ence of Cr(II)Cl2. B) Proposed course of the Takai olefination. Possibleancillary ligands omitted for clarity. X = Cl, Br or I.sterically hindered equatorial positions are occupied by thealdehyde substituent (R1 in Scheme 2) of 1 and halide group(X) of 3 and the aldehyde oxygen is thought to be coordinatedto one of the Cr centres (the “coordinating” Cr centre high-lighted in Scheme 2). The resulting β-oxychromium speciesadduct 4 will exist in a conformation where the two hydrogenatoms across the single bond are anti to each other (referred toas the anti-4 conformation, Scheme 2). Syn-elimination is thenthought to take place before rotation of the formed bond to givethe (E)-configured olefin, (E)-2 [5]. The minor (Z)-configuredproduct, (Z)-2, presumably results from the reaction through aless favourable transition state which is nearly identical to 5 butdiffers in that either the R1 substituent originating from thealdehyde or the X substituent originating from the gem-dichromium species is in the sterically more hindered axial po-sition at the analogous position of the ring (Hodgson et al.suggest the X substituent will be axial and the R1 group remainsequatorial in this less favourable transition state) [7].As part of an on-going total synthesis programme, we subject-ed 6-chlorosalicylaldehyde (6) to standard Takai olefinationconditions using iodoform (see Supporting Information File 1for details) to form alkenyl iodide product 7 (Scheme 3). To oursurprise a large excess of the (Z)-isomer of 7 relative to the cor-responding (E)-isomer was observed in the crude material(approx. ratio of (E)-7:(Z)-7 of 15:85 according to 1H NMRanalysis, see Supporting Information File 1 for more informa-tion). There are several other examples of poor (E)-selectivity inthe literature [8-10]; however, no detailed investigations as tothe origins of this effect have been carried out. We thereforeembarked on a study to understand the influence of the sub-strate structure upon the (E):(Z)-product ratio under Takai olefi-nation conditions.Scheme 3: An unusually high level of (Z)-stereoselectivity was ob-served in the Takai olefination of 6. (E):(Z)-ratio determined by1H NMR analysis of crude material obtained after reaction work-up.See Supporting Information File 1 for more information.Results and DiscussionIn order to understand the influential functional groups respon-sible for the (Z)-selectivity of 6, a number of ortho-substitutedbenzaldehydes were subjected to Takai olefination conditions;the results are summarised in Table 1 [11].Beilstein J. Org. Chem. 2017, 13, 323–328.325Table 2: (E):(Z)-product ratios for Takai olefination of substituted salicylaldehydes. Ortho- and meta-nomenclature refers to the substituents’ relation-ship to the aldehyde moiety.Entry R 2-Substituted (ortho) 3-Substituted (meta)Substrate Product (E):(Z) Ratioa Substrate Product (E):(Z) Ratioa1 F 24 25 26:74 30 31 36:642 Cl 6 7 15:85 32 33 25:753 Br 26 27 13:87 34 35 23:774 I 28 29 26:74 36 37 32:685 OMe – – – 38 39 72:286 CO2Me – – – 40 41 36:64aDetermined by analysis of 1H NMR spectra of crude materials obtained after reaction work-up. See Supporting Information File 1 for more informa-tion.Table 1: (E):(Z) product ratios for Takai olefination of ortho-substitutedbenzaldehydes.Entry R Substrate Product (E):(Z) Ratioa1 H 8 9 100:02 Me 10 11 78:223 OH 12 13 44:564 OAc 14 15 67:335 NH2 16 17 decomposition6 NHAc 18 19 83:177 Cl 20 21 69:31aDetermined by analysis of 1H NMR spectra of crude materials ob-tained after reaction work-up. See Supporting Information File 1 formore information.Unsubstituted benzaldehyde (Table 1, entry 1) gave the usualhigh (E)-selectivity expected of the Takai olefination (Takai etal. reported an (E):(Z)-ratio of 94:6 under identical conditions).The introduction of an ortho-methyl group (Table 1, entry 2)resulted in a slight increase in the amount of (Z)-product; how-ever, this effect was dwarfed by the introduction of an ortho-OH group (Table 1, entry 3), where the (Z)-alkene was pro-duced in a higher ratio. This effect was attenuated upon acetylprotection of the OH group (Table 1, entry 4). Attempted Takaiolefination of the ortho-NH2 substrate resulted only in decom-position of the starting materials (Table 1, entry 5), whereas theacetyl protected analogue gave largely (E)-selective results(Table 1, entry 6). The presence of an ortho-Cl resulted in amoderate amount of (Z)-product (Table 1, entry 7).The above results imply that the presence of an OH groupfavours the generation of the (Z)-product. The product ratio wasthen determined for meta-OH benzaldehyde 22; however, thisresulted in a much lower amount of (Z)-product (Scheme 4),implying that an ortho-relationship is optimum for the (Z)-selectivity. Interestingly, comparison of our initial results of theTakai olefination of 6 with entries 3 and 7 in Table 1, we canconclude that the presence of a Cl substituent in addition to theortho-OH results in a higher (Z)-selectivity than for either sub-stituent in isolation.Scheme 4: Takai olefination of meta-hydroxybenzaldehyde.In order to further investigate this cooperative effect, the(E):(Z)-product ratios were determined for various substitutedsalicylaldehydes (with ortho-OH substitution already demon-strated as optimum for favouring the (Z)-product); the resultsare shown in Table 2 along with the previously obtained resultfor 6.Beilstein J. Org. Chem. 2017, 13, 323–328.326In order to determine whether the (E):(Z)-ratios presented abovereflect those which might be obtained during the course of asynthetic scheme, the crude yield was determined (using aninternal NMR standard) for a larger scale reaction. Unsubsti-tuted salicylaldehyde (12) was chosen for this experiment, as itcontains the core structure present in all the examples above,and gives approximately equal amounts of the (E)- and (Z)-products (Scheme 5). Initially, low recovery of material was ob-served, which we postulate was due to coordination (vide supra)of both starting material and product to the superstoichiometricamount of chromium present. However, work-up conditionswere found (see Supporting Information File 1 for details)which facilitated the recovery of material accounting for 44% ofthe material submitted to the reaction conditions. Volatility ofthe starting material may also account for the moderate totalyield. Critically, the ratio of (E):(Z)-products did not show sig-nificant deviation from that determined during the smaller scaletests, and sufficient material was recovered to give confidencethat these ratios reflect the dominant behaviour of the reaction.Scheme 5: Yield for both products and residual starting materialfollowing a scaled up Takai olefination of salicylaldehyde (12) usingoptimised work-up conditions. (Yields determined from crude NMRusing 1,3,5-trimethoxybenzene as an internal standard. See Support-ing Information File 1 for details).Using the appropriate Hammett substituent constant (σm) [12]as a measure of the net electron-withdrawing effect of a givensubstituent, for the meta-halogenated series, a positive correla-tion with the relative amount of (Z)-product was observed(Figure 1). Whilst Hammett parameters are not tabulated forortho-substitution, precluding an analogous quantitative analy-sis, the trend for ortho-halogenated substrates is qualitativelysimilar, although with even higher amounts of (Z)-product. Thisimplies that electron-withdrawing groups favour the productionof the (Z)-product upon Takai olefination, with the effect drop-ping off with increasing distance of the electron-withdrawinggroup from the aldehyde and hydroxy moieties. To further testthis theory, meta-OMe and CO2Me substrates were subjected tothe reaction conditions (Table 2, entries 5 and 6). As expected,the electron-donating methoxy group caused a drop in theFigure 1: Positive correlation between the amount (Z)-product and σmfor the series of meta-halogenated salicylaldehydes.amount of (Z)-product, and conversely for the electron-with-drawing CO2Me group.Our results highlight two key points: a) generation of the (Z)-product during Takai olefination of benzaldehydes is favouredby the presence of an ortho-OH group; b) this effect is magni-fied if the substrate also possesses electron-withdrawing groups.These observations should prove useful during the planning ofsynthetic schemes by providing warning that a planned Takaiolefination may not proceed with the expected (E)-selectivity.Additionally, with careful design of substrates, synthetic routesutilising (Z)-selective Takai olefinations can now be considered,a strategy which has been hitherto unprecedented.A control experiment showed that, in the presence of 0.5 equiv-alents of salicylaldehyde, benzaldehyde was converted to theexpected (E)-product (See Supporting Information File 1). Thisprecludes the possibility that the salicylaldehydes are func-tioning as ligands for chromium. In light of this and the aboveobservations, we propose an alternative pathway by which thereaction may proceed in order to favour the (Z)-product(Scheme 6). Our proposed mechanism commences with nucleo-philic addition of gem-dichromium species to the aldehydemoiety via a six membered pseudo-chair transition state, as isgenerally accepted [5,7]. However, rather than proceeding viathe transition state which places most groups in a pseudo-equa-torial position (pathway 1), we propose that for the substratesunder discussion, the ortho-OH group is able to coordinate tothe neighbouring Cr centre if the aldehyde aromatic substituentoccupies a pseudo-axial conformation, thus favouring pathway2. Following syn-elimination, this then leads to the observed(Z)-olefin products, (Z)-47. Whilst further experimental data isrequired in order to bolster this hypothesis, our proposed mech-anism should act as a starting point for future detailed mecha-nistic investigations.Beilstein J. Org. Chem. 2017, 13, 323–328.327Scheme 6: Proposed mechanism for (Z)-selective Takai olefination, whereby coordination of the ortho-OH to the neighbouring Cr centre causes thealdehyde substituent to adopt a pseudo-axial orientation.Our observation that this alternative pathway is favoured byelectron-withdrawing substituents initially seems counter-intu-itive, as it might be predicted that these could attenuate theortho-hydroxy’s ability to coordinate to the Cr centre. Al-though the effect appears to correlate with lowered pKa of thishydroxy group, moderate amounts of (Z)-product are generatedwhen this group is acetylated (14) and the relevant proton istherefore absent. This implies that increased acidity is not theprimary factor at play. Instead, based on the higher (Z)-selec-tivity observed whenever the electron-withdrawing group wascloser to the aldehyde moiety (Table 2), we propose that it iswithdrawal of electron density from this group which is the key.An electron-deficient aldehyde is less able to supply electrondensity to the Cr centre in transition state 44. In order to coun-teract this deficit in electron donation, the ortho-OH chelatesthe Cr, thus favouring the pseudo-axial conformation, as dis-cussed above.ConclusionFollowing our observation of unusually high levels of (Z)-olefinproduct following Takai olefination of a particular aromaticsubstrate, systematic screening of related substrates revealed thecharacteristics a substrate should possess in order to lead to (Z)-selective Takai olefination. The substrate should possess anortho-OH group, and the effect will be larger if the substratealso possesses electron-withdrawing substituents. These obser-vations will allow synthetic chemists to predict a priori whethera planned Takai olefination will proceed with lower (E)-selec-tivity than predicted, and could also lead to synthetic routesbased upon the (Z)-selective Takai olefination of suitably de-signed substrates. In addition, a modified mechanistic modelwas proposed accounting for these observations.Supporting InformationSupporting Information File 1Experimental procedures and analytical data.[http://www.beilstein-journals.org/bjoc/content/supplementary/1860-5397-13-35-S1.pdf]AcknowledgementsThe research leading to these results has received funding fromthe European Research Council under the European Union’sSeventh Framework Programme (FP7/2007-2013)/ERC grantagreement no [279337/DOS]. In addition, the group researchwas supported by grants from the Engineering and PhysicalSciences Research Council, Biotechnology and BiologicalSciences Research Council, Medical Research Council andWellcome Trust. Data accessibility: all data supporting thisstudy are provided as Supporting Information accompanyingthis paper.References1. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,7408–7410. doi:10.1021/ja00283a0462. Kürti, L.; Czakó, B. Strategic Applications of Named Reactions inOrganic Synthesis Background and Detailed Mechanisms; ElsevierScience: Oxford, U.K., 2005.3. Hodgson, D. M. Tetrahedron Lett. 1992, 33, 5603–5604.doi:10.1016/S0040-4039(00)61158-94. Takai, K.; Kataoka, Y.; Okazoe, T.; Utimoto, K. Tetrahedron Lett. 1987,28, 1443–1446. doi:10.1016/S0040-4039(00)95949-55. Takai, K.; Shinomiya, N.; Kaihara, H.; Yoshida, N.; Moriwake, T.;Utimoto, K. Synlett 1995, 963–964. doi:10.1055/s-1995-5141Beilstein J. Org. Chem. 2017, 13, 323–328.3286. Nicolaou, K. C.; Snyder, S. A. Classics in total synthesis II: moretargets, strategies, methods; Wiley-VCH: Weinheim, Germany, 2003.7. Hodgson, D. M.; Boulton, L. T.; Maw, G. N. Tetrahedron Lett. 1994, 35,2231–2234. doi:10.1016/S0040-4039(00)76805-58. Lim, D. S. W.; Anderson, E. A. Org. Lett. 2011, 13, 4806–4809.doi:10.1021/ol201833u9. Tortosa, M.; Yakelis, N. A.; Roush, W. R. J. Org. Chem. 2008, 73,9657–9667. doi:10.1021/jo801794s10. Chen, M.; Roush, W. R. Org. Lett. 2012, 14, 1556–1559.doi:10.1021/ol300282e11. In each case, the (E)- and (Z)-olefin peaks were clearly visible in the1H NMR of the crude reaction mixture, allowing the relative amountpresent to be determined. See Supporting Information File 1 for moredetails.12. Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165–195.doi:10.1021/cr00002a004License and TermsThis is an Open Access article under the terms of theCreative Commons Attribution License(http://creativecommons.org/licenses/by/4.0), whichpermits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.The license is subject to the Beilstein Journal of OrganicChemistry terms and conditions:(http://www.beilstein-journals.org/bjoc)The definitive version of this article is the electronic onewhich can be found at:doi:10.3762/bjoc.13.35

(Z)-selective Takai olefination of salicylaldehydes

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(Z)-selective Takai olefination of salicylaldehydes

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