Four Mechanistic Mysteries: The Benefits of Writing a Critical Review

Abstract

While writing a comprehensive review on the reactions of epoxides with titanium(III) reagents, we encountered a series of mechanistic puzzles. Using clues from the literature, many of which were not available at the time that the mysteries emerged, it was possible to demystify a number of these conundrums. We discuss four examples, which we believe will significantly change the way in which titanium(III) chemistry is practiced. Our experience underscores the importance of comprehensive and critical reviews in chemistry and the truism that the authors are prime beneficiaries of the review process.

Graphical Abstract

Introduction

We recently completed a chapter on the ring-opening reactions of epoxides with titanium(III) reagents^[1] for the invaluable Wiley series Organic Reactions. We knew that reading, analyzing, and organizing more than 500 research reports on this versatile reaction would represent a challenge. As the process unfolded, we encountered several remarkable reactions that, at the time of their publication, seemed inexplicable. In some cases, mechanistic proposals were made, but do not hold up to careful scrutiny. Moreover, it became evident that the keys to understanding these mysteries were often available in the years of subsequent published research, provided that we were willing to cast a broad net into related fields of study.

We will begin this essay with a short primer on titanium(III) chemistry for those who are unfamiliar with this useful tool. We will then examine four of the mechanistic mysteries that emerged in our review, along with their often-fascinating explanations. In our concluding remarks, we will focus on how these insights will both change the way that titanium(III) chemistry is practiced and expand the scope of this already broadly useful chemistry.

A Brief Review of Cp₂TiCl Chemistry

When used in organic synthesis, Cp₂TiCl is usually generated in situ by reduction of Cp₂TiCl₂ with zinc or manganese metal powder.^[1–2] A typical epoxide can bind to titanium(III) as shown in structure 1 in Eq. 1. Homolysis of one epoxide C–O bond proceeds by inner sphere electron transfer^[3] and results in formation of a β-titanoxy radical, 2. For a terminal epoxide exemplified by 1, ring-opening at the secondary carbon atom C-2 is favored by both steric and electronic factors.

(1)

The resulting β-titanoxy radicals 2 can undergo a variety of subsequent reactions, depending on what additives are present, as shown in Scheme 1.^[4] In the presence of a hydrogen-atom donor Q–H (for example, 1,4-cyclohexadiene or tert-butyl thiol) these radicals react by hydrogen-atom transfer. The product, after hydrolysis of the resulting titanium alkoxide 3, is the corresponding alcohol. β-Titanoxy radicals can also add to activated alkenes, exemplified by methyl acrylate in Scheme 1. In this case, the final product is hydroxy ester 4. In the absence of additives, the β-titanoxy radical can be trapped by a second equivalent of Cp₂TiCl to afford an organotitanium intermediate 5, which rapidly undergoes deoxygenation to afford the alkene 6.

Scheme 1.

Some available reaction pathways for β-titanoxy radical 2.

In addition, epoxides containing a suitably positioned unsaturation can undergo intramolecular addition reactions as exemplified for the case of 6,7-epoxyhept-1-ene in Scheme 2. The β-titanoxy radical 7 undergoes rapid 5-hexenyl radical cyclization to afford the primary radical 8, which is trapped by a second equivalent of Cp₂TiCl to afford the organotitanium complex 9. Hydrolysis affords the alcohol 10 as a mixture of diastereomers. In the particular case of 6,7-epoxyhept-1-ene, the product 10 is formed as a 2:1 mixture of the cis and trans diastereomers (70% combined yield).^[4–5]

Scheme 2.

Cp₂TiCl-mediated cyclization of 6,7-epoxy-1-heptene.

Many of the reactions of epoxides with Cp₂TiCl can be run using a sub-stoichiometric amount of Cp₂TiCl₂ as a pre-catalyst. It is not possible to directly reduce titanium(IV) alkoxides like 3 and 9 to Cp₂TiCl; they must first be converted back to Cp₂TiCl₂. In one approach, this is accomplished by use of a buffered Brønsted acid, 2,4,6-collidinium hydrochloride (coll•HCl).^[6] Using a stoichiometric amount of coll•HCl and metal reductant and a sub-stoichiometric amount of Cp₂TiCl₂ as pre-catalyst, a catalytic cycle can be achieved as shown in Scheme 3.

Scheme 3.

Protic catalysis of the Cp₂TiCl-mediated reduction of an epoxide.

One additional reaction path for β-titanoxy radicals is especially relevant to Mystery #1 below. When C–O bond homolysis in a trisubsituted epoxide such as 11 results in the formation of tertiary radical 12 (Scheme 4), the radical center is too sterically encumbered to form an organometallic intermediate. Depending on whether a primary or secondary hydrogen is lost, β-scission affords either alkoxide 13a or 13b. This process has been described as a “mixed disproportionation” between a carbon-centered radical 12 and the titanium-centered radical Cp₂TiCl.^[7] Hydrolysis will then afford allylic alcohols 14a and 14b.

Scheme 4.

Reaction of trisubstituted epoxide 11 with Cp₂TiCl.

Mystery 1: The Case of the Vanishing Intermediate

The mixed-disproportionation reaction in Eq. 3 produces both an allylic alkoxide and titanocene hydride chloride. Cp₂Ti(H)Cl has been invoked elsewhere in the literature as an intermediate, notably in ethylene polymerization^[8] and Ti-mediated aminolysis of N-acyl carbamates.^[9] By analogy to zirconocene hydride chloride, Cp₂Zr(H)Cl,^[10] Cp₂Ti(H)Cl was presumed to be a robust organometallic species. Curiously, however, this hydride had never been isolated or even observed in situ. Treatment of Cp₂TiCl₂ with hydride reagents instead consistently affords the titanium(III) complex Cp₂TiCl.^[2,11]

(2)

The perception that Cp₂Ti(H)Cl is a relatively inert molecule led to concerns that it would be difficult to recycle under the conditions of protic catalysis (Scheme 3). It has, for example, been proposed that the use of BEt₃ as an additive will accelerate conversion of Cp₂Ti(H)Cl to Cp₂TiCl₂ under protic conditions, thus promoting catalyst recycle.^[12] Most notably, concerns about Cp₂Ti(H)Cl led to the invention of a valuable alternative to protic catalysis in which collidine hydrochloride is replaced with a combination of Me₃SiCl and collidine.^[13] In this approach, aprotic catalysis, Cp₂Ti(H)Cl was proposed to react with Me₃SiCl affording Cp₂TiCl₂ and Me₃SiH as shown in Eq. 4.^[14]

$${\mathrm{Cp}}_2\mathrm{Ti}(\text{H})\mathrm{Cl}+{\mathrm{Me}}_3\mathrm{SiCl}\to {\mathrm{Cp}}_2\mathrm{Ti}{\mathrm{Cl}}_2+{\mathrm{Me}}_3\mathrm{SiH}$$ (3)

The observation of Me₃SiH as a coproduct is not mentioned in the many publications using aprotic catalysis. And why, if Cp₂Ti(H)Cl is a robust species, had nobody succeeded in its isolation? We clearly needed some thermodynamic insight into aprotic catalysis. Andreas Gansäuer and his student Sven Klare had successfully applied DFT calculations to other Ti(III) reactions.^[15] We requested them to examine the thermal stability of Cp₂Ti(H)Cl and also the thermodynamics of its reaction with Me₃SiCl.

Our collaborators were able to show that reaction of Cp₂Ti(H)CI with Me₃SiCl in Eq. 4 is approximately thermoneutral (ΔG = −0.18 kcal/mol). However, more interesting was the calculation on the thermal stability of Cp₂Ti(H)CI in solvent THF. The decomposition pathway in Eq. 5 was found to be decidedly exothermic (ΔG = −11 kcal/mol). The plot thickens! Details of the calculations have been published elsewhere.^[16]

(4)

At this point, we could not resist going into the lab to have a hands-on look at this chemistry. One of our collaborators, Kendra Dewese prepared the simple model epoxide 11 and added it to a solution of Cp₂TiCl in THF. During the addition she observed vigorous gas evolution! The gas was confirmed to be hydrogen by GC-MS. Even better, using a gas burette it was possible to the measure the amount of hydrogen evolved, which was very close to 0.5 mol per mol of epoxide consumed as predicted in Scheme 4 and Eq. 5. Hydrolysis of the titanium alkoxide product and characterization of the organic product confirmed that allylic alcohols 14a and 14b were formed in a 5:1 ratio.

Thus, it appears that Cp₂Ti(H)Cl is an unstable species, which rapidly decomposes in THF solution at room temperature. A practical consequence of this fact is that it should not be necessary to employ 2 or 3 equivalents of Cp₂TiCl in the conversion of trisubstituted epoxides to allylic alcohols as has been the general practice.^{[7, 17]} The second equivalent of Cp₂TiCl would be unnecessary, since half of the reagent would be converted to Cp₂Ti(H)Cl, which then decomposes, regenerating Cp₂TiCl. We demonstrated this in the laboratory.^[16]

Mystery 2: The Riddle of Reversing Selectivities

The reactions of β,γ-epoxy alcohols with Cp₂TiCl differ from those of unsubstituted epoxides in three ways. First, the site selectivity for epoxide ring-opening is different.^[18] Treatment of trimethysilyl-protected alcohol 15a with Cp₂TiCl in the presence of tert-butyl thiol affords 16, which results from predominant opening at C-3 as shown in Scheme 5. However, when the reaction is repeated with substrate 15b containing an unprotected OH group, C–O bond cleavage occurs at C-2. Trapping with tert-butyl thiol now affords principally the 1,3-diol product 17.^[4]

Scheme 5.

Effect of a hydroxyl protecting group on the regioselectivity of epoxide opening.

A second difference is the course of the reaction in the absence of additives. As shown in Scheme 1, for epoxides lacking an OH group, reaction with a second equivalent of Cp₂TiCl will generally lead to cleavage of the remaining C–O bond from the original epoxide, affording the corresponding alkene. However, in the case of β,γ-epoxy alcohol 18 (Scheme 6), loss of the OH group (“dehydroxylation”) affords 19 in preference to loss of the alkoxide oxygen (“deoxygenation”) to afford 20. ^[19]

Scheme 6.

Exclusive dehydroxylation of epoxy alcohol 18.

The third unusual feature of the reactions of β,γ-epoxy alcohols with Cp₂TiCl is that the intra- and intermolecular addition reactions of the intermediate β-titanoxy radicals proceed with surprisingly high diastereoselectivity. 5-Hexenyl cyclization reactions are generally expected to be unselective as seen in Scheme 2. Yet, when the linalool-derived epoxide 21, which contains a free OH group, is treated with Cp₂TiCl, the resulting cyclization affords (after hydrolytic workup) exclusively 1,2-cis-1,5-trans substituted products 22 (Eq. 6).^[20]

(5)

The high diastereoselectivity in Eq. 6 suggests the intervention of a structurally rigid (presumably cyclic) intermediate. Stepping outside the titanium(III) literature for a moment, it is instructive to illustrate the effects of structural rigidity in free-radical reactions. Radicals 23 and 24 in Scheme 7 were generated by tributyltin hydride reduction. For cyclization of radical 23, which contains only benzyloxy substituents, mainly trans-1,2 selectivity is observed. However, “tying back” two of the oxygen atoms as an acetal in 24 (so that one radical center resides on a six-membered ring) results in exclusive cis-1,2 stereoselectivity.^[21]

Scheme 7.

Effect of structural rigidification on 5-hexenyl radical cyclization.

It has been proposed that the high diastereoselectivity in the reactions of β,γ-epoxy alcohols results from the intermediacy of a radical containing a 1,3-dioxatitanacycle ring.^[22] For example, this mechanism was invoked to explain the stereochemistry of the cyclization of the linalool-derived epoxide 21 as shown in Scheme 8.^[20] Cp₂TiCl initially reacts with the hydroxyl group to afford titanium(III) alkoxide 25. It is then the titanium(III) alkoxide (rather than a second equivalent of Cp₂TiCl) that induces the homolysis of an epoxide C–O bond. This results in a 1,3-dioxatitanacycle ring in 26. Cyclization of the radical center on the rigid, six-membered ring results in a 1,2-cis configuration in the radical 27. The resulting tertiary alkyl radical then reacts with a second equivalent of Cp₂TiCl (or with solvent) to afford the final products.^[20]

Scheme 8.

Application of the 1,3-dioxatitanacycle mechanism to the cyclization of 21.

The 1,3-dioxatitanacycle mechanism explains the stereochemistry of the cyclization of 21 and other epoxy alkenes; however, a problem arises when this mechanism is applied to the dehydroxylation of β,γ-epoxy alcohols. The mechanism requires that both the hydroxyl oxygen atom and the surviving epoxide oxygen atom are converted to chemically similar titanium(IV) alkoxides. How does the epoxy alcohol (for example 18, Scheme 6) “remember” which oxygen atom is derived from the OH in order to favor dehydroxylation over deoxygenation?

As a completely unbiased example, consider the dehydroxylation of the carveol-derived epoxide 28 in Scheme 9.^[23] When epoxide 28 is treated with Cp₂TiCl, trans-carveol is obtained in 79% isolated yield after aqueous workup. Trans-carveol could in principle be obtained by either dehydroxylation or deoxygenation. However, the product isolated from this reaction was (+)-trans-carveol with an optical rotation [α]_D²² = +114.0 (CHCl₃, c 0.4), which may be compared to the literature value ^[24] of [α]_D²⁵ = +210.2 (CHCl₃, c 2.00}. This corresponds to an enantiomer ratio of 77:23. This result indicates that dehydroxylation is the predominant reaction pathway and further implies that the two oxygen atoms do not become equivalent after epoxide ring-opening. This outcome is not predicted by the 1,3-dioxatitanacycle mechanism since such a mechanism would result in formation of a symmetrical intermediate 29, which contains a mirror plane. Subsequent elimination of Cp₂Ti=O from 29 would result in a racemic 1:1 mixture of (+)- and (−)-trans-carveol.

Scheme 9.

Application of 1,3-dioxametallacycle mechanism to epoxy alcohol 28.

Instead of a 1,3-dioxatitanacycle, it seems reasonable to propose that hydrogen bonding plays a key role in the reactions of β,γ-epoxy alcohols with Cp₂TiCl. Although hydrogen bonding has not previously been proposed to play a role in titanium(III) chemistry, examples of stereochemical control of hexenyl radical cyclization through hydrogen bonding are known.^[25]

This modified mechanism is applied to epoxy alcohol 28 in Scheme 10. Reaction of 28 with the first equivalent of Cp₂TiCl results in the unsymmetrical hydrogen-bonded 30 in which the two oxygen atoms do not become equivalent. Abstraction of the hydroxyl group by a second equivalent of Cp₂TiCl may then be considered a group transfer reaction. Structure 30 seems eminently reasonable. The 1,3-diaxial relationship between the two oxygen atoms might in other circumstances be considered destabilizing but is supported by the hydrogen bond between the hydroxyl group and the alkoxide oxygen atom. For similar reasons, the most stable conformation of cis-1,3-cyclohexanediol in dilute solution contains two pseudo-axial hydroxyl groups.^[26] The preference for the relatively bulky isopropenyl group to adopt a pseudo-equatorial conformation will further offset any energetic cost of the 1,3-diaxial interaction between the oxygen atoms.

Scheme 10.

Proposed role of hydrogen bonding in deoxygenation of epoxide 28.

It is noteworthy that the selectivity between apparent dehydroxylation and deoxygenation in Scheme 10 is not 100%. The enantiomer ratio is 77:23. (A note of caution is that this ratio was determined by optical rotation. It would be desirable to repeat this experiment using chiral GLC to refine the result.) The apparent incomplete selectivity for dehydroxylation raises the possibility that the hydroxyl and alkoxide oxygen atoms slowly interconvert in the hydrogen-bonded intermediate 30. This would be consistent with the observation that titanium(IV) alkoxides are substitutionally labile in the presence of excess alcohols.^[27]

In Scheme 11, the effect of hydrogen bonding is considered for the cyclization of the linalool-derived epoxy alcohol 21. As in the 1,3-dioxatitanacycle mechanism, the cis-1,2 stereochemistry is attributed to the fact that the radical center resides on a structurally-rigidified six-membered ring. Moreover, the uncommon 1,5-trans configuration of the product apparently reflects the steric bulk of the alkene acceptor. The “boat-like” transition state 32 is presumably preferred to the “chair-like” 31, which results in the observed 1,5-trans substitution pattern in products 22a and 22b.

Scheme 11.

Proposed role of hydrogen bonding in cyclization of epoxide 21.

In assembling our Orgonic Reactions chapter, we encountered dozens of reactions of β,γ-epoxy alcohols where the stereo-, regio-, and chemoselectivity is consistent with the presence of hydrogen bonding in the intermediate β-titanoxy radical. Recently we collected a number of these examples in a separate publication.^[28]

Mystery 3: Mystery of the Mutating Protecting Group

Chakraborty and coworkers carried out the Cp₂TiCl-mediated reduction of epoxide 33 as part of a formal synthesis of the antifungal antiobiotic (+)-antimycin A_3b (Scheme 12, Ar = 4-methoxyphenyl).^[29] They discovered that the p-methoxybenzyl (PMB) protecting group in 33 was unexpectedly converted into an acetal in the (2S,3S,4S) product 34. Also shown in Scheme 12, the reaction was stereospecific – the diastereomeric epoxide 35 afforded the protected (2S,3R,4R) diol 36. Both the stereospecificity of the transformation and the change in the protecting group are quite remarkable. Given the available literature at the time of this publication, it was not possible to offer a mechanistic rationale for these observations. However, clues from subsequent and concurrent research provide new insight.

Scheme 12.

Stereospecific reduction and protection of epoxy alcohols 33 and 35.

Taking epoxide 35 as our example, treatment with Cp₂TiCl will cause homolysis of the more substituted C–O bond. Keeping in mind the role of hydrogen bonding that we delineated in mystery #2, the resulting β-titanoxy radical will have structure 37 (Scheme 13). The bond dissociation energy for the benzylic C–H bond in 37, ca. 79 kcal/mol,^[30] is significantly lower than that for tertiary alkyl C–H bond, so that hydrogen-atom transfer to afford the benzyl radical 38 is expected. Conversion of 37 to 38 is an example of “radical translocation”.^[31] At the transition state, a linear C–H–C arrangement is expected. It is evident that the absolute configuration at C-4 will be controlled by the configuration at C-3 of starting epoxide 35 and is independent of the configuration at C-2.

Scheme 13.

Radical translocation and S_H2 ring-closure to afford 36.

Conversion of benzyl radical 38 to acetal product 36 requires displacement of Cp₂TiCl from titanium-bound oxygen atom (structure 39). Although breaking a TiߝO bond may at first seem counter-intuitive, Gansäuer and coworkers have provided precedence for such a step.^[32] For example, reaction of epoxide 40 with Cp₂TiCl affords the relatively long-lived, sterically-encumbered tertiary radical 41 (Scheme 14). In the absence of trapping agents, radical 41 undergoes an S_H2 displacement reaction to afford 42 with formation of a tetrahydrofuran ring and release of Cp₂TiCl. Secondary benzylic β-titanoxy radicals also participate in this type of THF ring-closure.^[33]

Scheme 14.

Formation of a tetrahydrofuran ring via S_H2 displacement of Cp₂TiCl.

Thus, it seems entirely reasonable that β-titanoxy radical 39 will cyclize via intramolecular S_H2 substitution to afford protected diol 36. This leads to a fascination possibility. Although Chakraborty and coworkers used excess (5 equiv) of Cp₂TiCl for this reaction, Scheme 12 can potentially be made catalytic.^[34] Cp₂TiCl is required for the initial C–O bond homolysis but is released after the S_H2 reaction. Lest this proposal seem unduly speculative, the S_H2 reaction in Scheme 14 can be run with a sub-stoichiometric amount of titanium(III).^[32b] Recently, the Gansäuer group explored the use of modified cyclopentadienyl ligands in these S_H2 cyclization reactions, which allowed reaction to be run with a catalyst loading of 10 mol % without the need for stoichiometric Mn or collidine hydrochloride.^[35]

Mystery 4: The Case of the Curious Additive

A particularly elegant application of Ti(III)-mediated intermolecular addition was reported by Reisman and coworkers. Reaction of epoxide 43 with Cp₂TiCl (1.6 equiv) in the presence of an acrylate acceptor afforded spirocyclic lactone 44 in good yield as a single diastereomer (Scheme 15). This reaction was used initially for the efficient synthesis of maoecrystal Z^[36] and subsequently in a general synthesis of ent-kauranoid natural products.^[37] The high diastereoselectivity can be rationalized in terms of an approach of the acrylate partner to the intermediate β-titanoxy radical in a way that minimizes non-bonding interaction with adjacent siloxy and axial methyl substituents. But there is nevertheless a surprising element in these results.

Scheme 15.

Intermolecular addition of epoxide 43 to acrylate acceptors.

As noted earlier, collidine hydrochloride is normally employed in titanium(III) chemistry when reactions are run under the conditions of protic catalysis. However, the use of this additive is essential for the success of Scheme 15. In its absence, the principal product of the reaction is not spirolactone 44 but rather the allylic alcohol 45. This alternative product would result from loss of a β-hydrogen atom from the β-titanoxy radical intermediate 46.

This result would have been difficult to rationalize at the time the research was done. However, in subsequent years, the interaction of collidine hydrochloride with Cp₂TiCl has been studied in the context of protic catalysis. DFT calculations indicate that these species form an “ate” complex of structure 47.^[38] Furthermore, cyclic voltammetry studies indicate that 47 will be the predominant species present during catalytic reactions, and thus represents the catalyst resting state.^[39] Complex 47 does not itself react with epoxides, but is in equilibrium with Cp₂TiCl, which rapidly reacts with epoxides.

It appears that the role of 47 in Scheme 15 is to decrease the instantaneous concentration of free Cp₂TiCl. The rate of competing mixed disproportionation to produce 45 is dependent on the concentration of Cp₂TiCl while the rate of addition to acrylate is not. Consequently, use of collidine hydrochloride as an additive will suppress formation of 45 and increase the yield of 44.^[40]

The novel protocol introduced by the Reisman group would seem to have implications well beyond the particular case of Scheme 15. Collidine hydrochloride is likely to be a useful additive in situations where it is desired that a β-titanoxy radical reacts with an added reagent in preference to being trapped by a second equivalent of Cp₂TiCl. Examples of such added reagents would include activated olefins for intermolecular addition and hydrogen atom donors for reduction to the alcohol. Competing pathways promoted by a high concentration of free Cp₂TiCl include epoxide deoxygenation, loss of a β-hydrogen atom, or elimination of a leaving group such as acetate or cyanide.

Concluding Remarks

By now it should be evident that our experience in writing an Organic Reactions chapter profoundly changed how we think about many aspects of titanium(III) chemistry. We believe that those who read the chapter will experience a similar transformation. In addition to the four mysteries described here, others are discussed in the chapter and some remain unsolved as the chapter goes to press.

The practical implications of our analysis are considerable. The excess Cp₂TiCl typically used in reactions with trisubstituted epoxides is not necessary. The effects of the hydroxyl group in β,γ-epoxy alcohols in titanium(III) chemistry are no longer mysterious, and in fact can be used to rationally predict the outcome of reactions. Incorporation of a p-methoxybenzyl protecting group into certain epoxide substrates has the potential to convert previously stoichiometric reactions into catalytic processes. A simple additive, 2,4,6-collidine hydrochloride will likely improve the yield and selectivity for several types of stoichiometric reactions using Cp₂TiCl.

The field of Cp₂TiCl chemistry is fortunate in that reactions can often be carried out in a catalytic fashion using either of two protocols (aprotic catalysis or protic catalysis). It is now possible to rationally predict which protocol will be best for a variety of reaction types, recognizing that the catalyst resting state for aprotic catalysis is Cp₂TiCl whereas that for protic catalysis is complex 47.

We hope that our experience serves as an encouragement to others to write a chapter for Organic Reactions, or any other series that requires a “deep dive” into a particular area of chemistry. A critical and comprehensive review clearly benefits the field but also provides outsized benefits to the authors.