The synthesis of oxazolines and imidazolines was achieved by activation of isocyanides with water. Mechanistic studies show that the organosuperbase proazaphosphatrane is tolerant of water within the reaction medium, with a beneficial and cooperative effect being observed

Honey, Mark A.

Kobayashi, Shū

Yamashita, Yasuhiro

Chemical Communications

Kobayashi, Sh��

Wolverhampton Intellectual Repository and E-theses

ChemComm Cite this: DOI: 10.1039/c0xx00000x www.rsc.org/xxxxxx Dynamic Article Links ►Communication This journal is © The Royal Society of Chemistry [year] [journal], [year], [vol], 00–00  |  1 A Cooperative Water Effect in Proazaphosphatrane-Catalysed Heterocycle Synthesis Mark A. Honey, a Yasuhiro Yamashitaa,b and Shu Kobayashi*b Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x 5 The synthesis of oxazolines and imidazolines was achieved by activation of isocyanides with water. Mechanistic studies show that the organosuperbase proazaphosphatrane is tolerant of water within the reaction medium, with a beneficial and cooperative effect being observed. 10 Catalytic carbon-carbon bond forming reactions are an immensely important set of reactions that help the synthetic organic chemist to construct important natural products and pharmacologically active molecules.1 Among these sets of reactions are those in which base deprotonation of an acidic 15 substrate is a key step in activating a pronucleophile towards nucleophilic addition.2 Such base-initiated reactions are often highly atom economical as no pre-functionalisation of substrates are required. Typically, strong organometallic bases such as metal hydrides,3 metal amides4 and metal alkoxides5 are required to 20 activate the pronucleophile, but as a result of their high basicity and high sensitivity towards moisture, the formation of undesired side-products or reduced activity due to water deprotonation is often observed.  Although the use of organometallic bases have become a staple for the organic chemist, organic bases such as 25 DBU,6 pyridine7 and imidazole8 among many others have also been employed in such systems, often producing a cleaner reaction profile as a result of their lower basicity. However, due to this decrease in basicity, their application is generally limited to relatively activated substrates. Recently, a  stronger class of 30 organic base , the organosuperbase has emerged, having proven to be effective bases for a range of transformations.9 Among this class of organosuperbase, the phosphorus-containing proazaphosphatrane (PAP) has shown relatively broad utility as a result of its high basisity compared to traditionally used organic 35 bases (pKa ~33 in acetonitrile).10 However, as for many organometallic bases, one problem associated with the increased basicisty of PAPs are their generally regarded sensitivity towards water and alcohols, fearing deactivation of the base through deprotonation. In order to truly exploit the benefits of using an 40 organosuperbase such as PAP, a lack of sensitivity to water and tolerance of alcohols within substrates or additives would be truly advantageous.        With this in mind, we herein present a water-activated, PAP-initiated selective synthesis of imidazolines and oxazolines from 45 the weakly acidic benzyl isocyanide with imines and aldehydes respectively. To the best of our knowledge, this is the first example of a PAP containing system which is compatible in the presence of water. We also believe this to be a unique example detailing water activation of isocyanides towards base-50 deprotonation.        The use of PAP with isocyanides has had little documented evidence, with its main use being to deprotonate the relatively activated ethyl 2-isocyanoacetate in the synthesis of oxazolines.11 As only an activated isocyanide in combination with a high 55 loading of PAP was used, we began to explore the ability of iBu-PAP to initiate reactions involving less activated isocyanides.  We chose benzyl isocyanide due to the large pKa difference between itself and the commonly used ethyl 2-isocyanoacetate, and began investigating the synthesis of oxazolines from 60 benzaldehyde. Table 1 Water effect on oxazoline formation PhOPhNCO NPh PhiBu-PAP (5 mol%)Conditions+(1.1 eq)1 2 3 Entry Time (h) Comment  Yield 3 (%) trans/cise 1a,c 18 - 55 87/13 2a,c 18 Repeat of entry 1 82 73/27 3a,c 20 MS 4A 70 80/20 4a,c 20 MS 5A 48 78/22 5a,c 20 H2O (10 mol%) 82 85/15 6b,d 20 H2O (10 mol%) 95 93/7 aDMF/toluene (1/1) was used. bDMF was used. c75οC. d100 οC.                  e determined by 1H NMR analysis of the crude product  After an initial investigation of reaction conditions, the reaction 65 combination in entry 1, Table 1 gave the highest selectivity of the desired oxazoline 3. However, this experiment was not reproducible as every repeat reaction gave conflicting results. Although each reaction was performed under anhydrous conditions, we speculated that the presence of a trace amount of 70 water could rationalise these inconsistent findings. Therefore we added molecular sieves to remove any trace of water, but upon the addition of either MS 4A or MS 5A, a significant decrease in yield was observed along with the formation of uncharacterised side-products. This was perplexing as iBu-PAP is known to be 75 stable in the presence of dehydrating molecular sieves.12 As the removal of water had an apparent negative effect on our reaction system, we next investigated the addition of water. After some optimisation, we found that the presence of 10 mol% water actively stabilised our results, consistently giving our desired 80 oxazoline in the same yield and selectivity. Although the above reaction proceeds smoothly at room temperature, higher temperatures are required in order to increase trans selectivity, presumably as the reaction changes from kinetic to thermodynamic control. 85 Page 1 of 3 ChemCommChemCommAcceptedManuscript 2  |  Journal Name, [year], [vol], 00–00 This journal is © The Royal Society of Chemistry [year]        Encouraged by these initial findings, we next investigated the synthesis of imidazolines from benzyl isocyanide. In the case of imidazolines, the effect of water is rather more striking. Under stricktly anhydrous conditions, our desired reaction competely failed to proceed. Remarkably, the addition of 10 mol% water to 5 the system gave our imidazoline in reasonable yield and good selectivity. Increasing the loading of water to 100 mol% improved selectivity to 98/2 and gave 5 in 80% yield. With the observation that water had a positive effect within our oxazoline and imidazoline syntheses, its role within our reaction system was 10 then examined. Table 2 Water effect on imidazoline formation PhNPhPhNCPhN NPh PhiBu-PAP (5 mol%)24 h, Conditions+(1.1 eq)4 2 5 Entry Solvent Water Loadingc Yield  5 (%) trans/cisd 1a toluene anhydrous NR - 2b toluene anhydrous 26 55/45 3a THF anhydrous NR - 4a THF 10 mol% 47 94/6 5a THF 20 mol% 76 96/4 6c THF 100 mol% 80 98/2 a25 οC. b75 οC. c40 οC. ddetermined by 1H NMR analysis of the crude product  15 Proazaphosphatranes demonstrate an undeniably strongly basic nature,13 with Verkade previously noting that deprotonation of water by PAP is possible.14 Therefore, our first thought was iBu-PAP hydroxide – the result of deprotonation of water by iBu-PAP - was the actual base working within our system. However, after 20 mixing iBu-PAP and water (up to 5 eq) in THF-d8, DMF-d7 or toluene-d8, no deprotonation of water could be observed, even after a period of up to 18 hours. It is worth noting that upon addition of iBu-PAP to pure D2O, deprotonation of D2O can be instantly seen, presumably due to the increased acidity of D2O in 25 its bulk form.15         In light of the fact that our reaction with imines failed to proceed in the absence of water, and with the observation that iBu-PAP does not deprotonate water in our reaction system – and therefore iBu-PAP hydroxide is not the active base - we next 30 investigated the activation of imines by water via hydrogen bonding. Inspired by the report of Gschwind,16 we attempted to observe a change in the chemical shift of water due to hydrogen bonding with  imine 4 by decreasing the sample temperature from 25 οC to -80 οC (see supporting information). Unfortunately only 35 a very slight 1H NMR chemical shift for water was observed, and although hydrogen bond activation of the imine probably does occur, we believe this effect to be slight. We also investigated the extent of hydrogen bonding between iBu-PAP and water, as the lone pair on the phosphorus atom would be easily accessible. 40 However, 1H NMR experiments show little change in the chemical shift of water in the presence of iBu-PAP, as well as little observable shifts in the corresponding 31P NMR spectra, as might be expected if hydrogen bonding to phosphorus occurs. We next turned our attention to benzyl isocyanide, as previous reports 45 have shown that the isocyanide moiety readily complexes with hydrogen bond donors,17 with isocyanide activation via hydrogen bonding having already been utilised in organocatalytic reactions with thioureas.18  Comparison of the 1H NMR spectra of water and benzyl isocyanide and water in THF-d8, shows a significant 50 change in the chemical shift for water upon the addition of benzyl isocyanide. This chemical shift is most probably attributed to the interaction between the terminal isocyanide carbon and one or more molecules of water. Having observed substantial hydrogen bonding between water and isocyanide, we finally investigated 55 the effect of water on the deprotonation of benzyl isocyanide by iBu-PAP, as hydrogen bond activation is known to increase acidity of the isocyanides α-proton.19 When benzyl isocyanide was added to a solution of iBu-PAP in THF-d8, it was clear to see that only free iBu-PAP exists in solution, even after a period of 60 18 hours. However, with the addition of 1-15 equivalents of water, deprotonation of benzyl isocyanide was unmistakeably observed, with an indicative peak for iBu-PAPH+ appearing at approximately -8 ppm in the 31P NMR spectrum. Although this communication mainly concentrates on the effect of water, 65 isopropyl alcohol is also compatible with iBu-PAP, which can act in a similar, albeit reduced manor, in facilitating deprotonation of benzyl isocyanide. As the reaction failed to proceed both in toluene and THF (Table 2) in the absence of water, we presume that both non-polar and polar aprotic solvents have little effect on 70 isocyanide activation. Upon analysis of the combined experimental data just described, we conclude that the involvement of water in isocyanide activation is essential for deprotonation to occur. Although hydrogen bonding undoubtedly exists between each component 75 of our reaction system, and as such could play a pivotal role in stereochemical outcomes of applied reactions, our spectroscopic evidence clearly suggests that significant hydrogen bonding between the isocyanide moiety and water is the biggest contributor, with a possible representation of the mode of 80 activation being shown in Figure 1.  OH OHCHNPhHHHPNRNNNiBuiBu Figure 1 Isocyanide activation by water         With the above in mind, we propose the following mechanism for both the imidazoline and oxazoline syntheses 85 (Scheme 1). Firstly, the water activated isocyanide is deprotonated by iBu-PAP, with iBu-PAP acting as a reaction initiator. The subsequently deprotonated isocyanide 7 – which is possibly stabalised by hydrogen bonding with the phosphours-bound hydrogen - attacks the electrophilic sp2 hybridised carbon 90 of either an imine or aldehyde, giving the addition product 9. Although the main role of water within this system is to activate the isocyanide, subtle electrostatic interactions between water and each reaction component is thought to influence the transition state, and therefore the stereoselective outcome of this step. 95 Subsequent cyclisation of the addition product 9 gives the desired heterocycle 10, which then acts as a product-base to deprotonate the next activated isocyanide. Although it is possible that the protonated iBu-PAPH+ could act as a hydrogen  bond donor to activate the next equivalent of isocyanide, we believe this to be 100 unlikely as the ionic interaction between the iBu-PAPH+ cation and the anionic product to be relatively strong, with the subsequent orientation of iBu-PAPH+ relative to the basic site of the heterocycle, due to steric hindrance associated with the now puckered shape20 of iBu-PAPH+ and the delocalisation of the 105 cationic charge across the structure of iBu-PAP, to disfavour this interaction.        Having elucidated the probable role of water within our reaction mixture, and with some previous optimisation Page 2 of 3ChemCommChemCommAcceptedManuscript This journal is © The Royal Society of Chemistry [year] Journal Name, [year], [vol], 00–00  |  3 experiments having been conducted, the substrate scope for both the reaction with aldehydes and imines was conducted. CN PhXRNXR PhX NCPhRNXR PhiBu-PAPCN Ph+iBu-PAPHiBu-PAPHiBu-PAPHCN PhxH2OxH2OxH2OxH2O678910116 Scheme 1 Proposed mechanism       The entries in Table 3 demonstrate the applicability of 5 numerous aldehydes and imines under our optimum reaction conditions. The reaction is tolerant of both aliphatic and aromatic substituents at R1, allows for variation around the aromatic ring, as well as accepting both electron donating and electron withdrawing groups. Selectivities are excellent for the more 10 sterically demanding substrates, although a more than satisfactory trans/cis ratio of 81/19 (entry 10) can be achieved with the use of the n-alkyl valeraldehyde. Table 3 Oxazoline and imidazoline substrate scope R1XPhNCX NR1Ph+(1.1 eq)12 2 13Conditions Entry R1 X Conditions Yield 13 (%)b trans/cisc 1 Ph O A 95 93/7 2 4-OMeC6H4 O A 84 95/5 3 2-MeC6H4 O A 82 98/2 4 3-MeC6H4 O A 92 97/3 5 4-FC6H4 O A 73 89/11 6a 1-Napthyl O A 86 78/22 7 cyclohexyl O A 80 94/6 8 tButyl O A 88 98/2 9 iButyl O A 82 83/17 10 nButyl O A 79 81/19 11d Ph O A 76 88/12 12 Ph NPh B 80 98/2 13 Ph NPMP B 81 97/3 14 4-FC6H4 NPMP B 86 95/5 15 3-MeC6H4 NPMP B 54 98/2 16 2-BrC6H4 NPMP B 69 89/11 17e,f,g,h cyclohexyl NPMP B 43 91/9 18e,f,g nBu NPMP B 70 77/33 Conditions A: iBu-PAP (5 mol%), H2O (10 mol%), DMF, 100 οC, 20 h. 15 Conditions B: iBu-PAP (5 mol%), H2O (100 mol%), THF, 40 οC, 24 h. aReaction time was 56 h. bIsolated yield. cDetermined by 1H NMR analysis of the crude product. diBu-PAP (3 mol%), H2O (6 mol%) was used. eImine formation with MgSO4 in DMF, filtration and addition of crude product to the reaction mixture. fDMF was used. greaction was 20 conducted at 100 οC. hReaction time was 65 h  In summary, we have described the first known example of a water tolerant iBu-PAP system, with mechanistic evidence eluding to the activation of isocyanide with water. We have 25 utilised this cooperative water effect to increase the acidity of benzylic isocyanides for facile deprotonation by iBu-PAP, for the subsequent synthesis of both oxazolines and imidazolines in good yield and selectivites.       This work was partially supported by a Grant-in-Aid for 30 Science Research from the Japan Society for the Promotion of Science (JSPS), Global COE Program, The University of Tokyo, MEXT, Japan, and NEDO. M.A.H thanks the JSPS for the award of Postdoctoral Research Fellowship for Foreign Researchers and for funding. 35 Notes and references Department of Chemistry, School of Science, The University of      Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp † Electronic Supplementary Information (ESI) available: [details of any 40 supplementary information available should be included here]. See DOI: 10.1039/b000000x/ 1 (a) A. Joshi, J.-B. Veron, J. Unge, A. Rosenquist, H. Wallberg, B. Samuelsson, A. 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Rev., 2010, 110, 5235 20 J. G. Verkade, Coord. Chem. Rev., 1994, 137, 233 85 Page 3 of 3 ChemCommChemCommAcceptedManuscript

A cooperative water effect in proazaphosphatranecatalysed heterocycle synthesis

Water activated isocyanide is deprotonated by the organosuperbase proazaphosphatrane; no deprotonation of water could be observed.</p

Mark A. Honey

Yasuhiro Yamashita

Shū Kobayashi

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A cooperative water effect in proazaphosphatrane-catalysed heterocycle synthesis

https://wlv.openrepository.com/bitstream/2436/622519/1/Honey_et_al_Cooperative_water_effect_2014.pdf

A cooperative water effect in proazaphosphatranecatalysed heterocycle synthesis

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