A base-catalyzed approach for the anti-Markovnikov hydration of styrene derivatives

Abstract

The base-catalyzed addition of 1-cyclopropylethanol to styrene derivatives with an acidic reaction workup enables anti-Markovnikov hydration. The use of either catalytic organic superbase or crown ether-ligated inorganic base permits hydration of a wide variety of styrene derivatives, including electron-deficient, ortho-substituted and heteroaryl variants. This protocol complements alternative routes to terminal alcohols that rely on stoichiometric reduction and oxidation processes. The utility of this method is demonstrated through multigram scale reactions and its use in a two-step hydration/cyclization process of ortho-halogenated styrenes to prepare 2,3-dihydrobenzofuran derivatives.

The base-catalyzed addition of 1-cyclopropylethanol to vinyl (hetero)arenes sequenced with an acidic reaction workup enables anti-Markovnikov hydration in a complementary fashion to traditional hydroboration/oxidation protocols.

Introduction

β-Aryl alcohols are an important alcohol subclass that find wide utility in organic chemistry. This substructure is prominently featured in bioactive compounds (Fig. 1a)¹ and is a common synthetic intermediate for phenethyl-functionalized compounds, including several pharmaceuticals (Fig. 1b).² Medicinal chemistry discovery efforts also frequently employ this building block to perform structure activity relationship (SAR) studies on phenethyl units, with three such examples shown in Fig. 1c.³ Two common approaches to β-aryl alcohols are reduction of arylacetic acids⁴ and hydroboration/oxidation of styrene derivatives.^5,6 While reliable for simple substrates, these methods have limitations that can prevent rapid access to alcohols with diverse aryl groups. For instance, non-commercial arylacetic acids require separate multistep syntheses.⁷ Meanwhile, traditional stoichiometric hydroboration/oxidation protocols⁸ are often unselective and low yielding for electron-deficient or ortho-substituted styrenes and heteroaryl variants, thus requiring alternative hydroboration methods and reagents.⁹ A new approach to β-aryl alcohols from styrene derivatives that does not rely on reduction or oxidation events could therefore improve access to this valuable class of alcohol.¹⁰

Fig. 1. Examples of the importance of β-aryl substituted alcohols.

The catalytic anti-Markovnikov hydration of aryl-substituted alkenes has long been desired as a sustainable and complementary alternative to stoichiometric hydroboration/oxidation processes.¹¹ Several strategies toward this goal have recently been reported for styrenes, including Grubbs' triple relay catalytic process,¹² Arnold's and Li's biocatalytic approaches,¹³ and Lei's photocatalytic alkene oxidation method.¹⁴ While these methods are impressive in their strategy for achieving anti-Markovnikov selectivity, they have yet to be applied toward more complex styrene substrates, including vinyl N-heteroarenes. Thus, there remains a current challenge to develop catalytic hydration methods that can access densely functionalized β-aryl alcohols to better reflect the structural diversity represented in Fig. 1.

We proposed to use base catalysis for the anti-Markovnikov hydration of styrene derivatives as a new approach to β-aryl alcohols. We recently disclosed the use of the phosphazene superbase P₄-t-Bu or 18-crown-6-ligated KO-t-Bu as basic catalysts for the nucleophilic addition of alcohols to aryl-substituted alkenes.^15,16 Water does not participate in this reaction, so we instead sought a nucleophilic “protected water” source that could be used to achieve formal hydration (Fig. 2).¹⁷ Thus, following hydroetherification, facile deprotection could provide straightforward access to β-aryl alcohols with complete regiocontrol. We herein report the discovery of an unconventional nucleophilic water surrogate that enables anti-Markovnikov hydration of styrene derivatives.

Fig. 2. Overview of a base-catalyzed approach to anti-Markovnikov styrene hydration.

Results and discussion

Base-catalyzed alcohol addition reactions to styrene derivatives are reversible such that the substrate identities and reaction conditions contribute to the observed equilibrium yields. These considerations and the identification of effective catalysts are extensively documented in a recent report from our group that served as the basis for this work.^15b,d We began by examining P₄-t-Bu-catalyzed addition reactions using oxygen pronucleophiles that could potentially serve as water surrogates.¹⁸ These reactions were conducted under our previously optimized reaction conditions with 2-chloro-3-vinylpyridine (1) as a model alkene (Scheme 1a).^15d Alcohols comprised of common O-protecting groups, such as trimethylsilanol, phenol, p-methoxybenzyl alcohol and allyl alcohol do not undergo addition. These results are consistent with our previous studies that revealed alcohol addition to styrenes is both kinetically and thermodynamically challenging, indicating a more nucleophilic water surrogate is necessary for addition.^15,19 However, alcohols comprised of common aliphatic protecting groups, such as tert-butanol and 2-trimethylsilylethanol, provide low addition yields. Examination of cyclopropyl-substituted alcohols led to the discovery that 1-cyclopropylethanol undergoes addition in 82% isolated yield. The resulting 1-methyl 1′-cyclopropylmethyl (MCPM) ether is an uncommon protecting group developed for oligosaccharide synthesis.²⁰ For comparison, cyclopropylmethanol, dicyclopropylmethanol and iso-propanol all provide lower addition yields. The isolated MCPM ether 2 undergoes high-yielding deprotection in 3 min using methanesulfonic acid, presumably through a cyclopropyl-stabilized carbocation hydrolysis mechanism (Scheme 1b).²¹

Scheme 1. Optimization studies for (a) superbase-catalyzed alcohol addition and (b) ether hydrolysis. ^a Yields determined by ¹H NMR spectroscopy. ^b Isolated yield of purified product.

We next investigated the substrate scope for anti-Markovnikov hydration using 1-cyclopropylethanol (4) and an in situ acidic workup procedure (Table 1). First, in Table 1a, a comparison of superbase (P₄-t-Bu in PhMe) and inorganic (KO-t-Bu/18-crown-6 in DME) catalysts is shown for two styrene derivatives (5 and 6) and two chlorinated vinyl pyridines (3 and 7). The inorganic conditions were selected based on our prior extensive screening of bases for hydroetherification reactions,^15b with additional information provided in the ESI.† As seen in Table 1a, the inorganic conditions enable synthetically useful alcohol yields (49–61%) while the use of P₄-t-Bu generally provides higher yields (60–83%). The yield differences between the superbase and inorganic conditions are likely a solvent equilibrium effect, as we previously measured alcohol addition to be more favorable in PhMe than in DME.^15b While P₄-t-Bu is an efficient catalyst in both solvents, the KO-t-Bu/18-crown-6 system is most active in DME and typically does not catalyze the reaction in PhMe to its equilibrium position.^15d

Product scope for anti-Markovnikov hydration^a.

^aYields are of purified alcohol product; reactions performed on 0.5 to 1.0 mmol scale.

^b5 equiv. of 4 used.

^c1 h reaction time.

^d4 equiv. of 4 used.

Table 1b shows hydration products of other vinyl arenes using the superbase conditions, while a full comparison to inorganic conditions is provided in the ESI.† Styrenes (5, 6, 8–15) featuring diverse substitution patterns with nitro, fluoro, chloro, bromo, sulfonyl, trifluoromethyl and benzoyl substituents undergo hydration in good yields. A notable feature of this scope is that ortho-substituents are well tolerated. Vinyl heteroarenes are also effective substrates, including those with halogens prone to nucleophilic aromatic substitution. Thus, halogenated 2-, 3-, and 4-vinyl pyridine derivatives (3, 7, 17 and 18) undergo hydration in high yields. Beyond pyridines, quinoline (16) and thiazole (19) derivatives are also hydrated in good yields. Although 1-cyclopropylethanol (4) will add to electron-neutral styrenes and 1,1-disubstituted variants, only low equilibrium yields are observed under these conditions.^15b Representative substrates documenting the electronic limitations of this method are shown in the ESI.†

We next compared the hydration yields of several substrates from Table 1 to traditional hydroboration/oxidation protocols using BH₃·THF and 9-BBN (Scheme 2a). Although use of these boranes results in high yields of β-phenethyl alcohols from electron-neutral styrenes, decreased yields and selectivities are common for electron-deficient and heteroaryl variants.⁸ Hydroboration/oxidation of 2,6-dichlorostyrene (20) leads to mixtures of α- and β-phenethyl alcohols while 2-nitro-4-methylstyrene (21) results in low yields of β-phenethyl alcohol. An even greater limitation is observed for 3-bromo-4-vinylpyridine (22), in which only net hydrogenation occurs with no alcohol formation. In contrast, base-catalyzed hydration gives high yields with exclusive β-regioselectivity for these substrates.

Scheme 2. Comparison of base-catalyzed hydration to hydroboration/oxidation methods. ^a Yields and regioselectivities determined by ¹H NMR spectroscopy of the crude reaction mixture; yields from Table 1 represent isolated yields. ^b Yields are of purified alcohol product. ^c 5 equiv. of 4 used.

Base-catalyzed hydration is also likely to have complementary functional group tolerance to hydroboration/oxidation protocols. This is illustrated in Scheme 2b, where substrates with an aryl thioether (23) and a thiomorpholine (24) that are sensitive to oxidizing conditions undergo P₄-t-Bu-catalyzed hydration in moderate yields.²² Substrate 25, featuring a terminal alkene that is reactive toward traditional hydroboration, illustrates the chemoselectivity of this method for styrene hydration.²³

Scheme 3 demonstrates the scalability of this protocol through three hydration reactions conducted on 10 mmol scale or greater. Hydration of 3-bromo-4-vinylpyridine (22) is best accomplished using P₄-t-Bu and thus 5 mol% catalyst loading provided access to 1.4 grams of alcohol 17.²⁴ The hydration of 2,6-dichlorostyrene (20, 30 mmol) was achieved in 73% yield using catalytic KO-t-Bu, exemplifying the practicality of the inorganic conditions. Although the highest styrene hydration yields are obtained using 3 equiv. of 1-cyclopropylethanol (4), we also identified conditions that allow for only moderately decreased addition yields using 1.2 equiv. of 4. This finding, shown in Table S3† of the ESI,† exploits our previous discovery of a negative alcohol rate order for base-catalyzed hydroetherification reactions.^15b Thus, reactions can be run at lower temperatures when less alcohol is used, thereby decreasing the entropic penalty of addition to counteract Le Chatelier's principle. This effect was extended to a challenging oxa-Michael addition process for acrylamide 26, where just 1.5 equiv. of 4 and 30 min are required for a high-yielding KO-t-Bu-catalyzed hydration process at room temperature.²⁵

Scheme 3. Examples of preparative scale anti-Markovnikov hydration reactions; yields are of isolated alcohol product.

Given that this method is suitable for ortho-halogenated vinyl (hetero)arenes, we reasoned hydration could be sequenced with a cyclization reaction to prepare 2,3-dihydrobenzofuran derivatives.²⁶ Thus, employing substrates from Table 1, base-promoted or metal-catalyzed cyclization reactions produce 28–32 in high yields (Scheme 4). This approach should improve access to this important heterocycle class,²⁷ especially functionalized and aza variants where there is limited availability of the corresponding benzofuran compounds.²⁸

Scheme 4. Utility of Table 1 alcohol products for dihydrobenzofuran derivative synthesis; yields are of isolated product from the cyclization step using given conditions. ^a CuI (10 mol%), 8-quinolinol (15 mol%), Cs₂CO₃ (1.5 equiv.), PhMe, 110 °C, 16 h. ^b NaH (1.5 equiv.), THF, 70 °C, 16 h. ^c Pd(OAc)₂ (3 mol%), JohnPhos (4 mol%), Cs₂CO₃ (1.5 equiv.), PhMe, 80 °C, 22 h.

Conclusions

In conclusion, base-catalyzed addition of 1-cyclopropylethanol to styrene derivatives provides a convenient method for preparing β-aryl substituted alcohols. The use of catalytic P₄-t-Bu superbase allows for superior yields to inorganic bases, although KO-t-Bu/18-crown-6 may be a more practical catalyst system for hydration on larger scale. In the broader context, analogous application of the nucleophilic yet easily deprotected 1-cyclopropylethanol water surrogate can likely enable other challenging hydration processes.

Data availability

Compound characterization data and experimental procedures are openly available in the ESI.†

Author contributions

S. P. P., Z. Q. and S. J. S. performed the experimental work. The mansucript was written by J. S. B. with input from all authors.

Conflicts of interest

There are no conflicts to declare.