Isolable and Readily Handled Halophosphonium Pre-reagents for

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Isolable and Readily Handled Halophosphonium Pre-reagents for Hydro- and Deuteriohalogenation Florian T. Schevenels,†,‡,§ Minxing Shen,†,‡,§ and Scott A. Snyder*,†,‡ †

Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States

‡

S Supporting Information *

ABSTRACT: Although the addition of acid halides across olefins is well-studied, limitations remain with a number of substrate classes that possess leaving groups, polyunsaturation, and acid-sensitive moieties, particularly polyenes prone to cyclization. The process is also challenging when conducted on a small scale, and moreover, methods for the addition of their deuterated counterparts typically require special techniques, especially when control of stoichiometry is required. Herein is described a readily synthesized and handled reagent class which can accomplish the controlled and selective Markovnikov addition of both HCl and HBr across several alkene classes under mild reaction conditions tolerant of diverse functionality. The process is particularly valuable on a laboratory scale, and direct comparisons to other methods are provided. As a result of indepth mechanistic studies seeking to understand how these novel tools work and the active species behind their efficacy, the means to easily add DCl and DBr using a controlled amount of D2O was discovered along with the critical role of hydrolysis in leading to active hydrohalogenation species.

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surface-supported methods (such as PBr3/SiO2);4d,g,11 antiMarkovnikov side products are possible, though, if the reaction is not under strict protection from air, light, and/or trace peroxides. Overall, this reaction process is much less developed. Additionally, few effective and practical methods exist for either DCl or DBr addition, particularly on a laboratory scale.12 Herein, we describe a new group of stoichiometric prereagents, materials that combine a halophosphonium salt and a Lewis acid, which, once hydrolyzed, can smoothly add HCl, HBr, and their deuterated counterparts to a variety of alkenes. These materials include substrates that have historically proven difficult to hydrohalogenate (or deuteriohalogenate), with the developed technology both complimenting and enhancing existing capabilities, particularly for compounds possessing additional elements of unsaturation in the form of alkenes and alkynes. In several cases, direct comparisons of the efficiency of these pre-reagents versus other available tools are presented. Finally, the structural basis behind their unique properties is also investigated, pointing to a mechanistic picture more complicated than serving simply as progenitors of hydrogen halides.

INTRODUCTION Among all organic reaction transformations, the hydrohalogenation of alkenes is one of the most fundamental; indeed, it has been studied since the dawn of the field and is often among the first reactions taught to students in their introductory organic chemistry courses.1 Moreover, the alkyl halide products of such additions have proven invaluable as synthons for further chemistry, particularly in the form of nucleophilic substitutions and metal-catalyzed cross couplings when the halide is primary or secondary and a range of emerging approaches when the halide is tertiary.2 Conventionally, Markovnikov HCl addition employs dry HCl gas or condensed liquid HCl,3 tools with sufficient operational difficulty that a number of alternatives have been advanced. These include the use of phase-transfer conditions employing lipophilic phosphonium catalysts and aqueous HCl solution, the in situ generation of HCl from highly reactive inorganic/organic chlorides, as well as solid surface-promoted and metal-mediated hydrochlorinations;4 several indirect approaches have been developed as well.5−7 Of significance, Carreira8 recently demonstrated a radical-based process to directly hydrochlorinate terminal alkenes with acid-sensitive moieties that are hard to functionalize through cationic processes.9 Nevertheless, limitations still exist with these methods, largely due to issues with unwanted leaving group displacements, cyclization reactions, and other polymerization events that can occur because of the inherent reaction conditions, especially if conducted on a small scale. Unlike HCl, solutions of HBr can readily add across alkenes10 but typically do so under conditions that are quite harsh, with few alternatives identified for Markovnikov additions outside of © 2017 American Chemical Society

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RESULTS AND DISCUSSION 1. Reagent Discovery and Initial Optimization. Our entry to this field of study occurred during efforts to improve the reactivity profile of CDSC (Et2SCl·SbCl6, 1, Scheme 1),13,14 a highly reactive chloronium source15 we identified that could achieve direct, chloronium-induced polyene cyclizations of Received: December 9, 2016 Published: May 2, 2017 6329

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and 6 as effective reagents in this regard, noting that their structures were, at this point, only proposals due to challenges in characterization beyond melting point analysis due to rapid hydrolysis in standard NMR solvents (see the Supporting Information). However, that structural uncertainty was viewed as initially acceptable (though worth further analysis, vide infra) given their ability to convert 7 predominantly into the dichlorinated product 11 in a deliberate attempt to react both alkenes by using an excess of reagent (5.0 equiv) in CH3NO2. These reagents were themselves prepared in 63%, 97%, and 77% yield, respectively, by combining 1.1 equiv of the phosphine ligand [either 1,2-bis(diethylphosphino)ethane (depe), 1,2-bis(diphenylphosphino)ethane (dppe), or 1,3bis(diphenylphosphino)propane (dppp)] with 1.0 equiv of Cl2 in 1,2-dichloroethane for 5 min at −30 °C, followed by the addition of 1.1 equiv of SbCl5 and stirring for another 1−4 h at ambient temperature; this yield value was based on the assumed stoichiometry of 1:1:1 of the ligand, molecular halogen, and the Lewis acid counterion in the reagent form drawn. Following an extensive screen of additional Lewis acid derived counterions,18,19 we found not only that reagent 12 based on TiCl4 was effective for HCl addition but also that the TiBr4 and HfBr4 salts 13 and 14 (preliminary structural proposals as noted above) could effect HBr addition under the same general design. Thus, with these tools in hand, we sought first to explore their scope with a range of alkene substrates, selecting 5, 6, 13, and 14 for these studies because of their overall ease of synthesis, isolation, and stability as well as their general reactivity profiles based on our initial screens. In section 4, we return to efforts to determine their true structures as part of mechanistic explorations. 2. Exploration of HCl Addition Scope. Starting with HCl addition, a range of alkenes were readily functionalized using either 5 or 6 (2.2 equiv; amount based on the proposed structures in Scheme 1) with stirring in CH3NO2 at 23 °C for 3−16 h. The yields in Figure 1 are indicated specifically for which reagent provided the outcome, noting that because 5 and 6 afforded very similar reactivity profiles, we did not test every substrate with both of these tools. As shown, monoalkene substrates with varying degrees of substitution afforded products (15−26) with tolerance for common protecting groups as well as heteroaromatic substituents with basic atoms, including a phenyl sulfide (16), an unsubstituted indole (17), a benzyl ether (23), and various ester moieties (21, 22, 24− 26).20 Next, in tests of chemoselectivity, the tools readily selected for 1,1-disubstituted and trisubstituted alkenes over terminal/ internal alkynes (27 and 28) as well as monosubstituted terminal alkenes (29) and 1,2-disubstituted alkenes (30 and 31). In fact, in initial tests using simple acyclic substrates possessing only a monosubstituted terminal alkene or a 1,2disubstituted alkene, no reaction was observed with either 5 or 6.21 Importantly, these reagents can differentiate between electronically similar alkenes in distinct steric environments as highlighted by the formation of 32. In addition, 1,1disubstituted and trisubstituted alkenes could be selected over an alkene in an α,β-unsaturated system (33) as well as a tetrasubstituted (and partially deactivated) alkene (34). A highly reactive benzyl bromide (35) was also obtained largely intact, with less than 10% displacement by chloride; neither this material, nor the alkyne-containing products, would likely have survived radical-based hydrochlorination.8,22

Scheme 1. Development of New HCl and HBr Addition Agents Based on Diphosphine Ligands Combined with Molecular Halogen and MXy

substrates such as 7 into 8, albeit in modest yields and diastereoselectivity.13 One design that we explored was exchanging the sulfur-derived Lewis base of 1 for a phosphine.16 Initial experiments revealed that the tri-nbutylphosphine derivative 2 was a reagent that was too unstable to be isolated, while its triphenylphosphine analog (3) was a discrete solid. When this new material (3) was exposed to polyene 7, the major product was not the chlorinated and cyclized adduct 8 but instead the protoncyclized product 9; intriguingly, we also observed small amounts of monohydrochlorinated and noncyclized 10, a material we had not previously obtained to any appreciable extent. As such, we sought to determine if we could select for this product exclusively. Rationalizing that the above result with substrate 7 reflected rapid hydrolysis of 3 in CH3NO2 (vide infra), we attempted next to discover a more stable form of the reagent by screening commercial phosphines including bidentate phosphine ligands. Our thought was that an additional phosphorus atom could potentially complex with the proposed P−Cl+ cation through a Lewis acid/Lewis base interaction (one which might be stabilizing), noting that some complexes made from chlorine and bidentate phosphines had already been reported.17 After exploring several such variants, we identified complexes 4, 5, 6330

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Figure 2. Additional HCl addition products generated with reagents 5 and 6 using polyene substrates. Yields in blue are either literature outcomes or reactions we performed with the alternative reagent indicated.

yields were still acceptable, however. One possible explanation for these differential yields could be that a diminished ability of the ester carbonyl group (comparing a trifluoroacetate to an acetate) to trap an intermediate carbocation affords higher product throughput. Globally, while simple monoalkene substrates can certainly be hydrochlorinated with other tools, we believe that the main advantage of 5 and 6, apart from ease of use and handling, is for polyunsaturated alkenes, where careful control of stoichiometry is required on laboratory scale. We do note that their preparation does require the use of Cl2 gas; however, that use can be on a single occasion to make a large amount of 5 and/or 6 for multiple, future uses. As will be noted in section 4 when we return to the issue of reagent structure, it might be possible to prepare these reagents solely with inorganic sources of chlorine such as PCl3 as well. 3. Exploration of HBr Addition Scope. Figure 3 presents the analogous results for HBr addition with a smaller number of substrates using 13 and 14, separating the two reagents based on some reactivity differences observed with certain substrates. Of note, benzyl ethers and basic nitrogen atoms were tolerated with much of the same chemoselectivity observed in the hydrochlorinations above retained, though in some cases, such as with product 47, yields were reduced. In most cases, however, the throughput was effective, such as the formation of 43 in 91% yield. The main difference between these hydrobrominating tools and their chlorine counterparts, however, was with polyene substrates. Hf-based reagent 14 proved capable of generating monohydrobrominated products such as sulfone 46 in a reasonable yield (61%), while Ti-based 13 instead afforded full alkene consumption of both the distal and internal alkenes, yielding the dihydrobrominated product 48 under the standard reaction conditions.24 The difference in reaction times between the two tools is not responsible for the double addition observed with 13; the longer time was used to drive the process to completion, noting that early stoppage of the reaction gave an inseparable mixture of both mono- and dihydrobrominated material. The key point for this chemistry, however, is that controlled monohydrobromination, particularly for polyunsaturated substrates, is much more challenging to achieve with other

Figure 1. HCl addition products generated with reagents 5 and 6. Yields in blue are either literature outcomes or reactions we performed with the alternative reagent indicated.

Finally, a series of polyenes were monohydrochlorinated at their terminal olefins with good selectivity to deliver 36−40 (Figure 2), even when reactive leaving groups were present such as the trifluoroacetate moiety within 39c. Our reagents worked especially well compared to the known distal alkene hydrochlorination methods,23 such as that promoted by TiCl4 on sulfone-type substrates 36 (97% vs 25%)23b and 37 (95% vs 12%) and geranyl benzoate (40, 82% vs 42%). Intriguingly, for reasons that are not entirely clear, the yields observed with geranyl acetate (39a, 40% vs 97%) and geranyl pivalate (39b, 57% vs 94%) were inferior both to TiCl4 and the outcome obtained with our tools in generating 39c, an arguably more sensitive substrate because of its terminal functional group; the 6331

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Scheme 2. Mechanistic Studies Reveal the Source of the Hydrogen Atom and Allow for Facile Incorporation of Deuterium along with Cl and Br in Various Substrates Using D 2O

incorporation based on available detection methods.25,26 Outside of indicating the key role of water (with quantification experiments described at the end of this section, vide infra), this result formed the basis for a highly efficient means to effect DCl and DBr addition across alkenes using the cheapest and most readily available source of deuteron. As illustrated for the additional substrates in Scheme 2, the method afforded deuteriohalogenated products 52−5527 with equivalent functional group tolerance, as well as in similar yields, as the original reaction processes. Based on this knowledge and other evidence as documented below, we believe we possess a reasonable picture for the overall process behind these reactions, especially for those systems using antimony(V) as source of the Lewis acid counterion. First, we observed that when we exposed the natural product (−)-nootkatone (56, Scheme 3) to 2.2 equiv of 5, unique product formation occurred to deliver 57 in 91% yield wherein both alkene hydrochlorination and conversion of the ketone to a vinyl chloride occurred; this outcome suggested to us that an initial reagent structure with reactivity like POCl3 or PCl5 could be plausible, implicating a P−Cl species.28,29 That supposition was verified when very careful reagent preparation and rapid X-ray crystallographic analysis under strictly anhydrous conditions revealed the true nature of reagents 5 and 6 as drawn in the middle section of Scheme 3, differing only in terms of the counterion where antimonate reduction has occurred in both cases;30 as indicated in the Supporting Information, we also obtained some NMR evidence for 5 and 6 in this form following their exposure to anhydrous CD3CN. What this finding suggests, when 5 is used for purposes of illustration as drawn in the bottom portion of Scheme 3, is that after the generation of the initially proposed reagent structure in terms of its cation component a redox reaction with SbCl5 afforded the dichlorinated ligand along with both [SbCl4]− and Cl−. That new antimonate ion (itself never observed in our crystal structures) either merged with Cl− to generate [SbCl5]2− or with another molecule of itself to make [Sb2Cl8]2−. We believe that both of these ions, as well as potentially Cl−, populate the anionic portion of the reagent, and different crystals might then likely possess different counterions as we observed with 5 and 6.31 As already noted, however, 5 and 6 are best described as prereagents, with rapid hydrolysis affording a new species as observed in those same NMR spectra taken in CD3NO2; it is

Figure 3. HBr addition products generated with reagents 13 and 14. Yields in blue are either literature outcomes or reactions we performed with the alternative reagent indicated.

available approaches. As highlighted by the yields in blue, use of HBr/AcOH in our hands proved challenging with several of the selected substrates, either affording decomposition (as with benzyl ether 41) or full conversion into dihydrobrominated products (as was observed with the substrates leading to alkyne 44 and alkene 47). Of note, we were also able to form 43 in 85% yield with HBr/AcOH, noting that a previous literature report with this same combination documented 53% yield on a larger scale.2c 4. Mechanistic Investigation and DCl/DBr Additions. Given this body of results, we sought to understand both the mechanism for the reaction process as well as establish the structures of our reagents and/or active species, since the structures as drawn within Scheme 1 as noted previously are only proposals based on stoichiometry with no evidence for their connectivities. We began these investigations by attempting to identify the source of the proton in the final products. Critically, we noticed that when our reaction solvent (CH3NO2) was scrupulously dry, the reaction proceeded in far inferior yield, suggesting that adventitious water might be the source of proton as well as a requisite part of the transformation in generating an active reagent (vide infra); indeed, NMR characterization studies (see the SI) showed that all of our reagents produced unique spectra based on 31P, 13C, and 1H NMR following dissolution for varied times in different solvents, suggesting hydrolysis as a critical mechanistic process. In initial support of that idea, we had utilized commercial, nondried CH3NO2 as the solvent in all of the reactions of the preceding sections, a solvent which possessed between 500 and 2000 ppm of H2O as measured by Karl−Fischer titration, and we did not flame-dry our reaction flasks. As shown in Scheme 2, that supposition was further verified with the use of CD3NO2 affording no D incorporation within product 15, while the use of 5 in D2O-saturated CH3NO2 generated 51 in 65% yield with effectively complete (>95%) D 6332

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Journal of the American Chemical Society Scheme 3. Initial Mechanistic Insights Gained by Unique Product Formation and X-ray Data for 5 and 6 Revealing Their True Structuresa

Scheme 4. X-ray Structure of Complex 59 and Proposed Structure for the Active Hydrochlorinating Reagent as Compound 58

other species as part of alkene hydrochlorination mechanistic pictures such as that drawn in the right-hand portion of the inset of Scheme 4.33 Equally critical, we obtained an X-ray structure of a hydrolyzed variant of 5 from wet CH3NO2 in the form of 59, a dimeric protonated bis(phosphine oxide) containing half of an [Sb2Cl8]2− anion and one molecule of CH3NO2 in the unit cell. This compound can be referred to as [dppeO2H]+(1/2)[Sb2Cl8]2− based on the nature of ions or as denoted within the scheme and as will become clear shortly, as dppeO2·SbCl3·HCl based on its overall composition and key atom oxidation states, ignoring the solvent molecule.34 Part of the molecule is shown in Scheme 4, highlighting the placement of the proton attached to one of the phosphine oxides; see the Supporting Information for full drawings of this complex. In an effort to further verify the structure of the active species, we compared the 1H and 31P NMR spectra of various independently prepared phosphine dioxides in CD3CN as well as performed a number of experiments with 59 and other controls.35 For example, we attempted an independent preparation of 59 by combining equimolar amounts of dppeO2, SbCl3, and HCl; as shown in Table 1, that material Table 1. Key 1H and 31P NMR Shifts for Several Phosphine Dioxides and Reagent 5 before and after Hydrolysis

a

A mechanism to account for the formation of these materials is also provided at the bottom of the Scheme.

entry

reagent

1 2 3 4

dppeO2·SbCl3·HCl dppeO2·SbCl3·HCl + HCl (ex) 5 after hydrolysis 5 before hydrolysis

H δ (ppm, m)

1

2.86 (d) 3.05 (d) 3.04 (d) nd

31

P δ (ppm)

43.3 50.7 48.9−50.4 73.9

did not possess 1H and 31P spectra which matched that of the species generated by dissolving 5 in CD3CN, assuming that adventitious water afforded the active reagent in the latter case. However, the observed chemical shifts of dppeO2·SbCl3·HCl + HCl was a near match to 59 (i.e., 5 after hydrolysis), with the exact stoichiometry of HCl possibly accounting for the subtle chemical shift differences. As indicated in Scheme 5, exposure of substrate 50 to 1.0 M HCl in dry CH3NO2 afforded product 15 in only 23% yield with significant starting material remaining after an extended reaction time (40 h). If the oxidized dppe ligand (dppeO2) was added to 1.0 M HCl in dry CH3NO2, the yield increased to 64% within only 16 h of reaction time, suggesting the role of

the resultant material that is expected to be the active hydrochlorinating species. As shown in Scheme 4, we believe that this new species is the protonated bis(phosphine oxide) HCl complex 58, drawn here as only the cationic portion with the assumption being that several antimonate species and/or chloride are also present as already discussed above. As such, HCl coordination to the other components of the reagent is critical for the selectivity and reactivity observed; i.e., it is more than simple in situ generation of HCl, though free HCl could reasonably be expected to convert a portion of the alkene into the hydrochlorinated product as well. In support of this picture, complexes of type 58 are known,32 and modern texts illustrate similar types of HCl coordination to 6333

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activates another molecule of HCl, thus enhancing its reactivity (as shown in 58, Scheme 4). Finally, given the seemingly indispensible role of water in the reaction as noted above, including the observation of some differential yields based on water content as already mentioned in the context of different reagent mixtures within the confines of Scheme 5, we sought to provide a more quantitative assessment of how much water is required/tolerated. In a similar vein, we wanted to see if reagent age (and attendant degree of hydrolysis) could be a relevant factor, aiming to ensure reproducibility of the processes described earlier. Thus, we set up reactions of substrate 50 for a total stir time of 4 h with both freshly prepared 5 and a batch of 5 stored for >1 year, using CH3NO2 with three different levels of water content: 30, 670, and >30000 ppm (i.e., H2O-saturated CH3NO2); the water content was determined by Karl−Fischer titration by measuring a blank flame-dried experiment flask containing solvent as well as all reagents except for 5. As shown in Table 2, we projected yields for both recovered starting material and product based on the idea that 1 equiv of water can maximally generate 2 equiv of HCl in hydrolyzing pre-reagent 5 into 59. As indicated, the year-old reagent worked in all cases, affording product yields which decreased somewhat as water content increased, while reactions with fresh reagent cases closely followed initial projections, though consistently went further to completion than might have been expected. Our analysis of these outcomes is that a certain degree of reagent hydrolysis had also occurred before 5 was added to the solution; for year-old reagent, stored in a bottle opened multiple times for different experimental uses,37 that hydrolysis was likely already complete, while for freshly prepared reagent, it was a level of partial hydrolysis which provided more active reagent than would be expected based on the reaction vessel water-content alone. A key finding, however, is that too much water does not cause problems given the yields observed; sufficient water content and/or reagent hydrolysis is, on the other hand, necessary for complete conversion. As already denoted, commercial CH3NO2 in combination with the use of a nonflame-dried flask (measured water content >500 ppm) was sufficient to effect the reactions without the need for addition of extra water. In addition, we sought to understand the necessity of employing 2.2 equiv of the pre-reagents in order to obtain reasonable yields of product as originally determined in our optimization experiments. As shown in Figure 4, using three

Scheme 5. Further Support for the HX Addition Mechanism

a 2.2 equiv of all reagents used at 23 °C. bStopped after incomplete conversion following 40 h of stirring. cStopped after 16 h of stirring.

complexation of HCl in effecting the process as drawn within 58 (Scheme 4); this result also suggests that the antimonate components of our reagents are spectator ions. To then try and generate 58 “in situ” from 59, we added HCl to 59 in both wet and dry CH3NO2, finding that only in dry solvent did the reaction proceed with similar efficacy (68% yield versus 23% yield). This finding mirrors that of our NMR studies where the addition of HCl to independently prepared dppeO2·SbCl3·HCl was necesssary to generate spectra that matched hydrolyzed 5. In addition, this result indicates that initial reagent hydrolysis is important but that overall water content might matter, a feature we will discuss in more detail shortly. For now, though, it is important to note that despite the ability to seemingly reproduce the active species using 59, from our perspective, both in terms of final yield (79% versus 68% here) as well as operational simplicity, the in situ generation of the active species from 5 is still preferred as it requires simple addition to the alkene of interest in commercial, undried CH3NO2 without any need to measure/handle HCl or rigorously dry the CH3NO2 solvent. As a further observation, 31 P NMR monitoring during the course of the reaction of 50 with 5 showed the reagent 31P peak moving upfield gradually, broadening but getting closer to the value of the protonated dioxide antimony(III) complex 59 (43.3 ppm), suggesting a progressive loss of HCl. Thus, the superior reactivity observed in the in situ protocol could reflect a Brønsted-assisted Brønsted acid as proposed by Yamamoto,36 where in this case the protonated oxygen atom on the phosphine oxide

Table 2. Further Efforts To Determine the Role of Water Content Amount and Reagent Age on the Reproducibility and Facility of the Hydrochlorination of Substrate 50

entrya

reagent age (2.2 equiv)

H2O content (ppm) (1.5 mL of solvent)b

projected starting material recovered (%)

isolated starting material recovered (%)

projected product yield (%)

isolated product yield (%)

1 2 3 4 5 6

1 year 1 year 1 year fresh fresh fresh

30 670 >30000 30 670 >30000

97 41 0 97 41 0

0 0 0 62 29 0

3 59 100 3 59 100

57 45 44 11 46 65

Reactions were all performed on a 0.215 mmol scale using 2.2 equiv of reagent 5 in CH3NO2 at 23 °C, stopping the reaction after 4 h. bH2O content of the CH3NO2 solutions was determined by blank parallel experiments. a

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Detailed experimental procedures, copies of all spectral data, X-ray data, and full characterization (PDF) X-ray data for compound 5 (CIF) X-ray data for compound 6 (CIF) X-ray data for compound 59 (CIF)

AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Scott A. Snyder: 0000-0003-3594-8769 Author Contributions §

F.T.S. and M.S. contributed equally to the science developed in this manuscript.

Figure 4. Rate of starting material disappearance in the reaction converting 50 into 15 using freshly prepared 5 in varying amounts.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Dr. Kevin Gagnon (Lawrence Berkeley) for obtaining an X-ray crystal structure of 59; the Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231. We also thank Dr. Alexander Filatov (University of Chicago) for obtaining X-ray structures of 5 and 6 and Dr. Antoni Jurkiewicz (University of Chicago) and Dr. C. Jin Qin (University of Chicago) for help with NMR spectroscopy and mass spectrometry, respectively. Financial support for this work came from The Scripps Research Institute, the University of Chicago, and the Belgian American Education Foundation (fellowship to F.T.S.).

different amounts of reagent 5 with substrate 50 under the standard reaction conditions and measuring the starting material remaining by NMR analysis, each of the reactions proceeded quickly at the start and then slowed down as time progressed. However, in no case did consumption of the substrate stop; even minor consumption continued after 6 h with 1.1 or 1.65 equiv of 5 used. This outcome might reflect the fact the hydrochlorination relies on a certain concentration of active “HCl” and its consumption obviously lowers its concentration and thus slows down the reaction. Another possibility is that the initially generated active complexes between phosphine oxide and HCl dissociate slowly over time; as such, 2.2 equiv might reflect a necessary stoichiometry to ensure complete conversion on a reasonable time-scale without the formation of excessive amounts of side-products. As a final comment, while we have a strong body of collated evidence for the properties of reagents 5 and 6 at this juncture, the overall process for reagents 12, 13, and 14 may be more complex in terms of the intermediate species produced,38 though all evidence points similarly to the importance of reagent hydrolysis in leading to the active species; further work is needed to clarify the specific details.

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CONCLUSION A new group of pre-reagents is reported that, when hydrolyzed, are efficient in converting a range of alkenes into their hydrohalogenated counterparts, with a simple procedure using D2O-saturated CH3NO2 affording the means to obtain their deuterated congeners with seemingly complete (i.e., >95%) isotopic labeling. Their critical value is their ease of use and effectiveness on polyunsaturated substrates where careful control of stoichiometry is required. Extensive mechanistic studies point to the likely active species, suggesting that there is complexity beyond simple HCl and HBr generation that accounts for the outcomes observed. Further potential applications with other functional groups are the subject of current investigations, as are the development of additional reagents based on related designs.39

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.6b12653. 6335

DOI: 10.1021/jacs.6b12653 J. Am. Chem. Soc. 2017, 139, 6329−6337

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Journal of the American Chemical Society Commun. 2000, 30, 1975. (j) Yadav, V. K.; Babu, K. G. Eur. J. Org. Chem. 2005, 2005, 452. (5) Indirect, but powerful, methods that reduce vinyl chlorides and other rearrangement processes for alkyl bromides have also arisen. For example: (a) Grigg, R. D.; Van Hoveln, R.; Schomaker, J. M. J. Am. Chem. Soc. 2012, 134, 16131. (b) Grigg, R. D.; Rigoli, J. W.; Van Hoveln, R.; Neale, S.; Schomaker, J. M. Chem. - Eur. J. 2012, 18, 9391. (c) Iwasaki, K.; Wan, K. K.; Oppedisano, A.; Crossley, S. W. M.; Shenvi, R. A. J. Am. Chem. Soc. 2014, 136, 1300. (d) King, S. M.; Ma, X.; Herzon, S. B. J. Am. Chem. Soc. 2014, 136, 6884. (e) Van Hoveln, R.; Schmid, S. C.; Tretbar, M.; Buttke, C. T.; Schomaker, J. M. Chem. Sci. 2014, 5, 4763. (f) Van Hoveln, R.; Hudson, B. M.; Wedler, H. B.; Bates, D. M.; Le Gros, G.; Tantillo, D. J.; Schomaker, J. M. J. Am. Chem. Soc. 2015, 137, 5346. (6) Alternatively, it is also possible to indirectly form such products through a hydrometalation/halogen trap sequence with a variety of metals. For example: (a) Brown, H. C.; Rathke, M. W.; Rogić, M. M. J. Am. Chem. Soc. 1968, 90, 5038. (b) Brown, H. C.; Lane, C. F. J. Am. Chem. Soc. 1970, 92, 6660. (c) Brown, H. C.; Lane, C. F. J. Am. Chem. Soc. 1970, 92, 7212. (d) Lane, C. F.; Brown, H. C. J. Organomet. Chem. 1971, 26, C51. (e) Lane, C. F. J. Organomet. Chem. 1971, 31, 421. (f) Sato, F.; Mori, Y.; Sato, M. Chem. Lett. 1978, 7, 833. (g) Makabe, H.; Negishi, E. Eur. J. Org. Chem. 1999, 1999, 969. (h) Gagneur, S.; Makabe, H.; Negishi, E. Tetrahedron Lett. 2001, 42, 785. (i) Podhajsky, S. M.; Sigman, M. S. Organometallics 2007, 26, 5680. (7) For other syntheses of tertiary and secondary halides through C− H functionalization approaches, see the following for chloride additions: (a) Kundu, R.; Ball, Z. T. Org. Lett. 2010, 12, 2460. (b) Liu, W.; Groves, J. T. J. Am. Chem. Soc. 2010, 132, 12847. (c) Qin, Q.; Yu, S. Org. Lett. 2015, 17, 1894. (d) Quinn, R. K.; Könst, Z. A.; Michalak, S. E.; Schmidt, Y.; Szklarski, A. R.; Flores, A. R.; Nam, S.; Horne, D. A.; Vanderwal, C. D.; Alexanian, E. J. J. Am. Chem. Soc. 2016, 138, 696. (f) Wang, Y.; Li, G.-X.; Yang, G.; He, G.; Chen, G. Chem. Sci. 2016, 7, 2679. For bromide additions: (g) Schmidt, V. A.; Quinn, R. K.; Brusoe, A. T.; Alexanian, E. J. J. Am. Chem. Soc. 2014, 136, 14389. See also ref 7b,f. (8) Gaspar, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 5758. (9) For subsequent papers that extend these findings in additional directions, see: (a) Leggans, E. K.; Barker, T. J.; Duncan, K. K.; Boger, D. L. Org. Lett. 2012, 14, 1428. (b) Ma, X.; Herzon, S. B. Chem. Sci. 2015, 6, 6250. (10) Mayo, F. R.; Walling, C. Chem. Rev. 1940, 27, 351. (11) Sanseverino, A. M.; de Mattos, M. C. S. J. Braz. Chem. Soc. 2001, 12, 685. (12) Typically, DCl or DBr is made from the reaction of D2O and a species such as PCl3, TiCl4, PBr3, or BBr3, with distillation, trapping, titration, and/or weighing necessary for controlled use: (a) Brown, H. C.; Groot, C. J. Am. Chem. Soc. 1942, 64, 2223. (b) Skell, P. S.; Allen, R. G. J. Am. Chem. Soc. 1959, 81, 5383. (c) Dewar, J. M. S.; Fahey, R. C. J. Am. Chem. Soc. 1963, 85, 2245. (d) Brown, H. C.; Liu, K.-T. J. Am. Chem. Soc. 1975, 97, 600. (e) Hassner, A.; Fibiger, R. F. Synthesis 1984, 1984, 960. An alternate approach for DBr addition is deuterioboration followed by bromination: (f) Han, B.; Ph.D. Thesis, Rochester Institute of Technology, 1991. (13) Snyder, S. A.; Treitler, D. S.; Brucks, A. P. J. Am. Chem. Soc. 2010, 132, 14303. (14) For the related Br+ and I+ sources, see: (a) Snyder, S. A.; Treitler, D. S. Angew. Chem., Int. Ed. 2009, 48, 7899. (b) Snyder, S. A.; Treitler, D. S.; Brucks, A. P.; Sattler, W. J. Am. Chem. Soc. 2011, 133, 15898. (c) Snyder, S. A.; Brucks, A. P.; Treitler, D. S.; Moga, I. J. Am. Chem. Soc. 2012, 134, 17714. For a recent paper developing active bromonium species with catalytic amounts of sulfur ligands, see: (d) Ke, Z.; Tan, C. K.; Chen, F.; Yeung, Y.-Y. J. Am. Chem. Soc. 2014, 136, 5627. (15) For its relative reactivity, see: Ashtekar, K. D.; Marzijarani, N. S.; Jaganathan, A.; Holmes, D.; Jackson, J. E.; Borhan, B. J. Am. Chem. Soc. 2014, 136, 13355.

(16) Ionic salts of R3P with molecular halogen and SbCl5 are known: (a) Wiley, G. A.; Stine, W. R. Tetrahedron Lett. 1967, 8, 2321. (b) Hartke, J.; Akgün, E. Chem. Ber. 1979, 112, 2436. (17) For such complexes, see: (a) Ellermann, V. J.; Thierling, M. Z. Anorg. Allg. Chem. 1975, 411, 15. For more recent references to the growing body of literature indicating the existence of phosphinephosphenium coordination complexes, see: (b) Burford, N.; Herbert, D. E.; Ragogna, P. J.; McDonald, R.; Ferguson, M. J. J. Am. Chem. Soc. 2004, 126, 17067 and references cited therein. (c) Carpenter, Y.; Burford, N.; Lumsden, M. D.; McDonald, R. Inorg. Chem. 2011, 50, 3342 and references cited therein. In these papers, an arrow would be drawn from the non-charged phosphine to the halophosphonium species to indicate that coordination:

(18) See the Supporting Information section for the full range of counterions attempted. Efforts to make corresponding fluorinated or iodinated counterparts failed in terms of appropriate alkene reactivity. (19) As denoted in the Supporting Information, some Lewis acids screened afforded protocyclization as either the major and/or substantial product. At present, since many of these reactions gave product mixtures, not single adducts, it is challenging to provide a global basis to understand the differential reactivity. One hypothesis, however, is the overall ability of each Lewis acid to dissociate once in solution and afford free halide ions that could readily make HCl or HBr, with greater content of those species facilitating the protocyclization reaction. For a recent paper describing the observation of similar Lewis acid dependence in either protocyclization or hydrochlorination, see: Li, S.; Chiu, P. Tetrahedron Lett. 2008, 49, 1741. (20) The Carreira method (ref 8) worked especially well for several of these same, monoalkene-containing substrates. (21) The one exception to this trend was with a special class of monosubstituted terminal alkenes in the form of styrenes. For example, 4-tert-butylstyrene and 4-chlorostyrene did react with reagents 5 and 6 but typically did so with incomplete conversion as well as concomitant benzyl chloride hydrolysis, rendering these substrates nonviable overall. (22) The main functional groups that were not tolerated with our reagents were free alcohols and silyl protecting groups, presumably due to a pathway similar to alcohol activation by the Hendrickson reagent: Hendrickson, J. B.; Schwartzman, S. M. Tetrahedron Lett. 1975, 16, 277. (23) (a) Julia, M.; Roy, P. Tetrahedron 1986, 42, 4991. (b) Demotie, A.; Fairlamb, I. J. S.; Radford, S. K. Tetrahedron Lett. 2003, 44, 4539. (24) Intriguingly, additional equivalents of reagent 14 or further stirring did not lead to the dihydrobrominated adduct from product 46. We propose that the discrepancy in the reactivity of these two reagents with 46 and 48 might result from the higher Lewis acidity and/or electrophilicity of Ti(IV) versus Hf(IV). This phenomenon, however, is unique to the hydrobromination process as the chlorine counterpart of the Ti(IV) reagent (i.e., 12) did not provide dihydrochlorinated product. (25) D2O-saturated CH3NO2 was prepared by the following procedure: CH3NO2 (10 mL) was added under argon to a flask containing CaH2, and the resultant slurry was heated at 60 °C for 2 min and then was allowed to cool to 23 °C. It was then distilled, with a total of 5−6 mL of CH3NO2 collected. After cooling to 23 °C, the distillate was dried over freshly activated 4 Å molecular sieves (flamedried under high vacuum). It was then transferred into a flame-dried flask under argon, D2O (0.2 mL) was added, and the biphasic mixture was stirred for 5 min at 23 °C. At this time, stirring was stopped, and the CH3NO2 was taken out carefully via syringe so as not to disturb the D2O droplets in the original flask. It was then added into another flame-dried flask, and the same process of D2O addition and syringe removal was repeated twice to obtain D2O-saturated CH3NO2. 6336

DOI: 10.1021/jacs.6b12653 J. Am. Chem. Soc. 2017, 139, 6329−6337

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Journal of the American Chemical Society

(39) For a recent example where we developed competent RS+ sources for polyene cyclizations using related components, see: Schevenels, F. T.; Shen, M.; Snyder, S. A. Org. Lett. 2017, 19, 2.

(26) Preparation of H2O-saturated CH3NO2 in a similar way as described above afforded a water content measurement of >30000 ppm based on Karl−Fischer titration (i.e., out of the limit of detection). (27) Interestingly, compound 53 possesses two chiral centers following deuteriobromination; based on the 1H and 13C NMR obtained, however, only a single diastereomer is formed (noting that that CH2D signal overlaps other protons). This result might suggest a potential directing effect from the OBz group within the initial substrate. (28) Banerjee, A. S.; Engel, R.; Axelrad, G. Phosphorus Sulfur Relat. Elem. 1983, 15, 15. (29) Although we presume that 13 and 14 can form active species similar to those from the corresponding chlorine reagents, we did not note the formation of a similar vinylbromide product using substrate 56; instead, as denoted in Figure 3, we obtained product 45 with reagent 14. (30) The structure of 5 has previously been observed by X-ray: Byers, H. L.; Dillon, K. B.; Goeta, A. E. Inorg. Chim. Acta 2003, 344, 239. This material was prepared differently, using PCl3 instead of Cl2 gas, suggesting it might be possible to avoid gaseous reagents if desired to prepare 5 and 6 (31) From crystal 5, in the [SbCl5]2− portion the Sb atom with five neighboring Cl has bond distances of 2.369, 2.617, 2.623, 2.630, and 2.611 Å along with bond angles that are all around 90 degrees. From crystal 6, in the [Sb2Cl8]2− portion the Sb atom with 5 neighboring Cl has bond distances of 2.368, 2.407, 2.476, 2.813, and 2.954 Å and bond angles close to 90 degrees with some distortions. Similar Sb(III) anions have been observed in many compounds. For selected examples reporting [SbCl5]2−, see ref 30 and: (a) Webster, M.; Keats, S. J. Chem. Soc. A 1971, 298. (b) Bujak, M.; Angel, R. J. J. Phys. Chem. B 2006, 110, 10322. For selected examples reporting [Sb2Cl8]2−, see: (c) Willey, G. R.; Palin, J.; Lakin, M. T.; Alcock, N. W. Transition Met. Chem. 1994, 19, 187. (d) House, D. A.; Browning, J.; Pipal, J. R.; Robinson, W. T. Inorg. Chim. Acta 1999, 292, 73. In addition, polymeric [SbCl4−]n has also been reported: (e) Bujak, M.; Zaleski, J. J. Mol. Struct. 2003, 647, 121. (32) Razak, I. A.; Usman, A.; Fun, H.-K.; Yamin, B. M.; Kasim, N. A. M. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2002, 58, m225. (33) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, 5th ed., Part B: Reactions and Synthesis, Springer, 2007; p 291. (34) Although that designation does not include the solvent, CH3NO2 does play a unique role as other solvents failed. For another case of this phenomenon, see: Dryzhakov, M.; Hellal, M.; Wolf, E.; Falk, F. C.; Moran, J. J. Am. Chem. Soc. 2015, 137, 9555. (35) For the full range of studies of different complexes, conditions, control experiments, and yields, see the Supporting Information. (36) Yamamoto, H.; Futatsugi, K. Angew. Chem., Int. Ed. 2005, 44, 1924. (37) As aptly noted by a reviewer, the suspected hydrolysis of the year-old reagent in the solid phase may not be equivalent to hydrolysis of the reagent in solution. Indeed, different hydrolyzed products may result, and therefore, nonfully equivalent reactivity may result. The fact that long-term stored reagent is effective, however, is an important finding. (38) Attempts to directly crystallize 12, 13, and 14 from the reaction in a fashion similar to that for 5 and 6 led only to amorphous powders with 1,2-dichloroethane or 1,1,2,2-tetrachloroethane as solvents. Recrystallizations of the isolated powders of 12, 13, and 14 in an attempt to obtain their hydrolyzed products failed with all tested solvents (CH3NO2, CH3CN, CHCl3, CCl4, C6H6, C6H5Cl, DMSO, DMF, THF, Et2O, EtOAc, MeOH, EtOH, ethylene glycol, dioxane, and acetone). No signals were observed by IR (ATR and film) for the five synthesized reagents. MS showed the presence of dppeO2 for 5 and 6, while a mixture of dppe, dppeO, and dppeO2 was detected for 12, 13 and 14. NMR studies in CDCl3, CD2Cl2, and CD3NO2 clearly showed the hydrolyzed species for 5 and 6. By contrast, 12, 13, and 14 were insoluble in CDCl3. 6337

DOI: 10.1021/jacs.6b12653 J. Am. Chem. Soc. 2017, 139, 6329−6337