Manganese-catalyzed ring-opening chlorination of cyclobutanols: regiospecific synthesis of γ-chloroketones

Abstract

We disclose an efficient manganese-catalyzed ring-opening chlorination of cyclobutanols. This reaction has a broad substrate scope, affording a variety of γ-chloro alkyl ketones and medium-sized benzocyclic chlorides in synthetically useful yields and unique regioselectivities. The merits including mild reaction conditions and employment of inexpensive catalysts and reagents make it a practical approach for the production of γ-chlorinated ketones.

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Introduction

Chlorinated alkyl ketones have long been used as versatile key building blocks in organic and medicinal synthesis.¹ Therefore, the convenient acquisition of chlorinated alkyl ketones is of high importance in multidisciplinary fields. Generally, the synthesis of α-chloroketones is achieved by the electrophilic chlorination of a ketone enolate;² the β-chloroketones can be obtained through the Michael addition of chloride to α,β-unsaturated ketones,³ the Baylis–Hillman reaction,⁴ and the direct chlorofunctionalization of carbonyl-activated alkenes.⁵ However, the construction of γ-chloroketones is relatively less investigated. A conventional approach to γ-chloroketones relies on the Friedel–Craft reaction of electron-rich arenes with moisture-sensitive 4-chlorobutyryl chloride in the presence of stoichiometric amounts of strong Lewis acid.⁶ Apparently, the electron-deficient and meta-substituted products cannot be prepared by this method, and many susceptible functional groups are also incompatible with the harsh reaction conditions. Thus, the development of a mild and efficient method to produce a broad diversity of γ-chloroketones is still desirable.

Cyclobutanols have been proven to be privileged precursors for the synthesis of γ-functionalized ketones by breaking the cyclic C–C bond.^7,8 Inspired by the seminar work about the single-electron oxidation of cyclobutanol to enable ring opening by the use of stoichiometric amounts of the high-valent metal oxidants (e.g., CAN and LTA),⁹ we have developed a sequence of catalytic ring-opening functionalization of cyclobutanols to yield γ-fluoro,¹⁰ azido,¹¹ cyano and alkynyl,¹² thio,¹³ and hydrazine-substituted alkyl ketones by means of silver or manganese catalysis.¹⁴

Recently, we firstly disclosed the ring-opening chlorination of cyclobutanols in the presence of a silver catalyst and NCS as the chlorine source (Scheme 1a).¹⁵ Later, Zhang and co-workers revealed the silver-catalyzed chlorination of cyclobutanols by using ^tBuOCl (Scheme 1b).¹⁶ In both cases, the precious metal catalysts and electrophilic chlorinating reagents were harnessed. Herein, we report an utterly different approach of ring-opening chlorination of cyclobutanols in the presence of an inexpensive MnCl₂ catalyst and nucleophilic TMSCl (Scheme 1c). The reaction has a broad substrate scope, affording a variety of synthetically useful γ-chloro alkyl ketones and medium-sized benzocyclic chlorides with exclusive regioselectivities under mild reaction conditions.

Scheme 1 Ring-opening chlorination of cyclobutanols.

Results and discussion

Experimental study

The investigations of ring-opening chlorination of cyclobutanols began with the extensive reaction parameter survey (Table 1). With MnCl₂ as the catalyst and TMSCl as the chlorine source, a set of oxidants were examined. While many oxidants such as H₂O₂, K₂S₂O₈, mCPBA, and DTBP were inefficient (entries 1–4), TBHP delivered a good yield (75%, entry 5). Further examination of oxidants demonstrated that hypervalent iodine reagents were beneficial for this conversion in general (entries 6–9), and among them, IBX improved the isolated yield to 87% (entry 9). Later, many common organic solvents were also examined, implying that acetonitrile was the most suitable solvent for the reaction (entries 10–14). Variation of the MnCl₂ catalyst to Mn(OAc)₃ or Mn(acac)₃ slightly decreased the reaction outcomes (entries 15 and 16). Reducing the amounts of TMSCl (3 equiv.) also compromised the reaction yields (entries 17 and 18). Performing the reaction in air gave lower yield than that under N₂ (entry 19).

Table 1 Reaction parameters survey^a

Entry	Oxidant	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.20 mmol), TMSCl (0.60 mmol, 3.0 equiv.), MnCl2·4H2O (0.02 mmol, 0.1 equiv.), and oxidant (0.40 mmol, 2.0 equiv.) in solvent (1.0 mL, 0.2 M) at 50 °C, N2. b Yields of isolated products. c 25 °C. d Mn(OAc)3·2H2O. e Mn(acac)3. f 2 equiv. TMSCl. g 1.5 equiv. TMSCl. h In air.
1	H2O2	CH3CN	13
2	K2S2O8	CH3CN	<10
3	mCPBA	CH3CN	<10
4	DTBP	CH3CN	21
5	TBHP	CH3CN	75
6^c	PIDA	CH3CN	67
7	PhIO	CH3CN	70
8	BI-OH	CH3CN	76
9	IBX	CH3CN	87
10	IBX	DCE	75
11	IBX	THF	62
12	IBX	Dioxane	65
13	IBX	Toluene	52
14	IBX	DMF	72
15^d	IBX	CH3CN	83
16^e	IBX	CH3CN	81
17^f	IBX	CH3CN	81
18^g	IBX	CH3CN	77
19^h	IBX	CH3CN	67

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With the optimized reaction conditions in hand, we set out to evaluate the generality of this protocol. The reaction demonstrated broad functionality tolerance where both electron-rich and deficient cyclobutanols were compatible with the reaction conditions, affording a diversity of γ-chlorinated ketones in synthetically useful yields (Scheme 2). Generally, phenyl cyclobutanols bearing electron-donating groups led to good reaction outcomes (2a–2d). However, para-methoxy substituted cyclobutanol unexpectedly generated product 2e in moderate yield, which might be attributed to the incompatibility of the 4-methoxybenzene moiety under the highly oxidative conditions. In contrast, meta- and ortho-methoxy substrates generated the corresponding products in good yields (2f and 2g). Naphthyl cyclobutanol was another apt substrate for the reaction (2h and 2i). Electron-deficient cyclobutanols also efficiently provided the γ-chlorinated ketones in good yields (2j–2n). Remarkably, the presence of aryl bromide in 2l could offer a platform for further modification by cross coupling. In addition to aryl cyclobutanols, alkyl and heteroaryl cyclobutanols were also readily converted into the corresponding products in useful yields (2o–2s). According to the Thorpe–Ingold effect,¹⁷ the cyclic skeleton could be significantly stabilized by multiple substitutions on the four-membered ring. Though challenging, the products 2t–2w were still generated in good yields. In the cases of 2v and 2w, most importantly, the chlorine was regioselectively introduced at the methine position, producing secondary alkyl chlorides. The example of 2x is noteworthy, as the chlorination only took place on the ring to give cyclic chloride as the sole product when a bicyclic substrate was employed. With the highly substituted and sterically congested cyclobutanol, tertiary chloride 2y was obtained in acceptable yield.

Scheme 2 Substrate scope. Standard conditions: 1 (0.20 mmol), TMSCl (0.60 mmol, 3.0 equiv.), MnCl₂·4H₂O (0.02 mmol, 0.1 equiv.), and IBX (0.40 mmol, 2.0 equiv.) in CH₃CN (1.0 mL, 0.2 M) at 50 °C. Yields of isolated products. ^a PIDA (0.4 mmol, 2.0 equiv.) was used. ^b BI-OH (0.4 mmol, 2.0 equiv.) was used. ^c 25 °C.

Medium-sized all-carbon rings are widely found in natural products and biologically active compounds, but their synthesis still remains difficult. Under the previous reaction conditions, a portfolio of benzocyclic chlorides ranging from seven- to ten-membered rings were readily obtained in synthetically useful yields (Scheme 3). These transformations could proceed at room temperature in general (3a, 3b, 3f, and 3g), but sometimes a higher temperature (50 °C) was required for the substrates bearing additional substituents on the cyclic framework (3c–3e). It might be anticipated that these products could be conveniently converted into other complex molecules by manipulation of the benzylic chloride.

Scheme 3 Synthesis of medium-sized benzocyclic chlorides. Standard conditions: 3 (0.20 mmol), TMSCl (0.60 mmol, 3.0 equiv.), MnCl₂·4H₂O (0.02 mmol, 0.1 equiv.), and IBX (0.40 mmol, 2.0 equiv.) in CH₃CN (1.0 mL, 0.2 M) at 25 °C. Yields of isolated products. ^a 50 °C. ^b PIDA (0.4 mmol, 2.0 equiv.) was used.

Of note, γ-chloroketones are privileged synthetic intermediates for the production of many drugs and biologically active compounds. For example, compound 2j can be readily converted into antipsychotic medications, e.g. haloperidol, fluanisone, and fupailiduo, by one-step nucleophilic substitution (Fig. 1).¹⁸

Fig. 1 Transformations into drugs and biologically active compounds.

Proposed mechanism

To gain insights into the manganese-catalyzed ring-opening chlorination and elucidate the possible mechanism, some experiments were carried out (Scheme 4). Initially, the reaction of 1a was performed in the absence of MnCl₂ (Scheme 4A, condition a). The obtained low yield clearly implied the critical role of the manganese catalyst in the transformation. The reaction also proceeded by replacing TMSCl with a substoichiometric amount of MnCl₂, which suggested that both TMSCl and MnCl₂ served as the chlorine source (Scheme 4A, condition b). The reaction did not take place without IBX, showing that the oxidant was a requisite for the conversion (Scheme 4A, condition c). Then, we conducted the reaction with cyclobutanol 5 under the standard reaction conditions (Scheme 4B). The formation of 6 explicitly illustrated the in situ generation of electrophilic chlorinating species during the process.

Scheme 4 Mechanistic studies.

Based on the experimental observations and our previous realizations, a radical-mediated reaction mechanism was postulated (Fig. 2). Initially, the interaction between MnCl₂, TMSCl, and the hypervalent iodine reagent led to the high-valent Mn^V–Cl species a,¹⁹ which could single-electron oxidize cyclobutanol to cyclobutoxy radical dvia complex b and concurrently released the Mn^IV–Cl species c. Tautomerization of radical d generated the open-chain alkyl radical e, which was subsequently intercepted by the Mn^IV–Cl species c to eventually furnish the γ-chlorinated ketones.

Fig. 2 Plausible mechanism.

Conclusions

An efficient manganese-catalyzed ring-opening chlorination of cyclobutanols is described. The reaction demonstrated broad functionality tolerance, furnishing a range of γ-chloro alkyl ketones and medium-sized benzocyclic chlorides in synthetically useful yields and exclusive regioselectivities. The advantages of this protocol include mild reaction conditions and employment of inexpensive catalysts and reagents, making it a practical approach for the production of γ-chlorinated ketones.

Experimental section

Cyclobutanol 1 or 3 (0.20 mmol, 1.0 equiv.), MnCl₂·4H₂O (0.02 mmol, 0.1 equiv.), and IBX (0.40 mmol, 2.0 equiv.) were loaded in a flask which was subjected to evacuation/flushing with nitrogen three times. CH₃CN (1.0 mL) followed by TMSCl (0.60 mmol, 3.0 equiv.) was added to the mixture via a syringe and the mixture was then stirred at 50 °C (or 25 °C) until the starting material had been consumed as determined by TLC. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed by using brine, dried over Na₂SO₄, filtered, concentrated, and purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether) to give the product 2 or 4.

Conflict of interest

The authors declare no competing financial interests.

Acknowledgements

C. Z. is grateful for the financial support from Soochow University, the National Natural Science Foundation of China (Grant no. 21402134), the Natural Science Foundation of Jiangsu Province (Grant no. BK20140306), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6qo00443a

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