(Z)-Selective Takai olefination of salicylaldehydes

(Z)-Selective Takai olefination of salicylaldehydes Stephen M. Geddis‡, Caroline E. Hagerman‡, Warren R. J. D. Galloway, Hannah F. Sore, Jonathan M. Goodman and David R. Spring* Letter Open Access Address: Department of Chemistry, University of Cambridge, Lensfield Rd, Cambridge, CB2 1EW, UK Beilstein J. Org. Chem. 2017, 13, 323–328. doi:10.3762/bjoc.13.35 Email: David R. Spring* - Received: 05 October 2016 Accepted: 09 February 2017 Published: 20 February 2017 * Corresponding author Associate Editor: J. A. Murphy ‡ Equal contributors Keywords: alkenyl iodides; salicylaldehydes; stereoselectivity; Takai olefination; transition state © 2017 Geddis et al.; licensee Beilstein-Institut. License and terms: see end of document. Abstract 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. Introduction The Takai olefination (or Takai reaction) is a method for the conversion of aldehydes 1 into the corresponding alkenyl halides 2 using a haloform–chromium(II) chloride (CHX3–CrCl2) system (Scheme 1A) [1,2]. It is believed that the haloform is first converted to a nucleophilic gem-dichromium species 3 that then attacks the carbonyl group of the aldehyde to generate a β-oxychromium species 4 (Scheme 1B). Subsequent elimination leads to alkene formation. The Takai olefination can also be performed with geminal dihalide reagents rather than haloforms. In addition, the reaction can also be used to generate vinyl stannanes [3], silanes [4] and boronates [5]. One of the most significant features of the Takai olefination is that it is generally highly selective for the formation of (E)- alkenes ((E):(Z)-product ratios are typically around 4:1 or greater). This selectivity has found wide use, particularly in the field of total synthesis where it is often used to install vinyl iodides with high levels of geometric purity which can then be utilised in metal-catalysed cross-coupling reactions [2,6]. Hodgson et al. [7] and later Takai et al. [5] have proposed very similar models to explain the (E)-stereoselectivity observed in the chromium(II)-mediated homologation of aldehydes to alkenes (including vinyl halides). The salient features of both models are the same (Scheme 2). It is presumed that the addition of the gem-dichromium species 3 to the aldehyde 1 proceeds via a six-membered pseudo-chair transition state 5 containing two chromium ions bridged by a halogen. The less 323 Beilstein J. Org. Chem. 2017, 13, 323–328. sition at the analogous position of the ring (Hodgson et al. suggest the X substituent will be axial and the R1 group remains equatorial in this less favourable transition state) [7]. Scheme 1: A) General overview of the Takai olefination for the formation of alkenyl halides 2 from aldehydes 1 and haloforms in the presence of Cr(II)Cl2. B) Proposed course of the Takai olefination. Possible ancillary ligands omitted for clarity. X = Cl, Br or I. sterically hindered equatorial positions are occupied by the aldehyde substituent (R1 in Scheme 2) of 1 and halide group (X) of 3 and the aldehyde oxygen is thought to be coordinated to one of the Cr centres (the “coordinating” Cr centre highlighted in Scheme 2). The resulting β-oxychromium species adduct 4 will exist in a conformation where the two hydrogen atoms across the single bond are anti to each other (referred to as the anti-4 conformation, Scheme 2). Syn-elimination is then thought to take place before rotation of the formed bond to give the (E)-configured olefin, (E)-2 [5]. The minor (Z)-configured product, (Z)-2, presumably results from the reaction through a less favourable transition state which is nearly identical to 5 but differs in that either the R1 substituent originating from the aldehyde or the X substituent originating from the gemdichromium species is in the sterically more hindered axial po- As part of an on-going total synthesis programme, we subjected 6-chlorosalicylaldehyde (6) to standard Takai olefination conditions using iodoform (see Supporting Information File 1 for details) to form alkenyl iodide product 7 (Scheme 3). To our surprise a large excess of the (Z)-isomer of 7 relative to the corresponding (E)-isomer was observed in the crude material (approx. ratio of (E)-7:(Z)-7 of 15:85 according to 1H NMR analysis, see Supporting Information File 1 for more information). There are several other examples of poor (E)-selectivity in the literature [8-10]; however, no detailed investigations as to the origins of this effect have been carried out. We therefore embarked on a study to understand the influence of the substrate structure upon the (E):(Z)-product ratio under Takai olefination conditions. Scheme 3: An unusually high level of (Z)-stereoselectivity was observed in the Takai olefination of 6. (E):(Z)-ratio determined by 1H NMR analysis of crude material obtained after reaction work-up. See Supporting Information File 1 for more information. Results and Discussion In order to understand the influential functional groups responsible for the (Z)-selectivity of 6, a number of ortho-substituted benzaldehydes were subjected to Takai olefination conditions; the results are summarised in Table 1 [11]. Scheme 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. 324 Beilstein J. Org. Chem. 2017, 13, 323–328. Table 1: (E):(Z) product ratios for Takai olefination of ortho-substituted benzaldehydes. Entry R Substrate Product (E):(Z) Ratioa 1 2 3 4 5 6 7 H Me OH OAc NH2 NHAc Cl 8 10 12 14 16 18 20 9 11 13 15 17 19 21 100:0 78:22 44:56 67:33 decomposition 83:17 69:31 acetyl protected analogue gave largely (E)-selective results (Table 1, entry 6). The presence of an ortho-Cl resulted in a moderate amount of (Z)-product (Table 1, entry 7). The above results imply that the presence of an OH group favours the generation of the (Z)-product. The product ratio was then determined for meta-OH benzaldehyde 22; however, this resulted 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 the Takai olefination of 6 with entries 3 and 7 in Table 1, we can conclude that the presence of a C (...truncated)