Dihalohydration of Alkynols: A Versatile Approach to Diverse Halogenated Molecules

Abstract

In this paper we outline how dihalohydration reactions of propargylic alcohols can be used to access a wide variety of useful halogenated building blocks. A novel procedure for dibromohydration of alkynes has been developed, and a selection of dichloro and dibromo diols and cyclic ethers were synthesized. The dihalohydration of homo‐propargylic alcohols provides a useful route to 3‐halofurans, which were shown to readily undergo cycloaddition reactions under mild conditions. Finally, a novel ring expansion of propargylic alcohols containing a cyclopropylalkyne provides access to halogenated alkenylcyclobutanes.

Introduction

Halogenated molecules play an important role in organic chemistry, both as synthetic targets themselves, and as useful reactants for a wide range of metal‐catalysed reactions. For example, chlorinated and brominated functional groups are widely present in agrochemicals1 and in flame retardants, although the latter are causing increasing environmental concerns.2 They are also widely used starting materials for a range of organometallic cross‐coupling methodologies.3 Geminal dihalides have found application as carbene or carbenoid precursors which undergo reaction with metals (e.g. Zn), metal salts (e.g. CrCl₂), or organometallic reagents (e.g. Et₂Zn) to initiate cyclopropanation or olefination reactions.4 Dihaloketones can also serve as useful precursors to enolates under reducing conditions.5 The synthesis of functionalized geminal dihalides is rare, however, as most halogenation processes require harsh conditions. For example, geminal dihalides can be generated from carbonyl groups using deoxohalogenation reagents such as PCl₅, or via halogenation of the hydrazine or oxime derivatives.6 Alternative methods via double carbometallation of alkynes are also incompatible with functionalized substrates.7 We,8 and others,9, 10 have observed that dihalohydration of alkynes offers a mild and preparatively useful approach to α,α‐dihaloketones. These reactions usually proceed with high regioselectivity, and provide functionalized dihaloketones from readily available precursors. To date, however, the potentially interesting chemistry of these functionalized dihalides has not been explored in great detail.

As part of our ongoing interest in the development of novel chemistry employing propargylic alcohols,11 we recently reported two methods for the dihalohydration of these systems 1 (Scheme 1), with a gold‐catalysed iodination reaction providing access to previously unreported α,α‐diiodo‐β‐hydroxyketones 2, and a catalyst‐free procedure using trichloroisocyanuric acid (TCIA) giving α,α‐dichloro‐β‐hydroxyketones 3. The latter procedure could also be extended to alkynols 4 giving access to dichlorolactols of general structure 5a or 5b.

Scheme 1.

Previous work on the diiodohydration and dichlorohydration of alkynols.8

In this article, we describe the extension of this work to the dibromohydration of alkynols, and we also describe preliminary studies on the application of geminal dibromides and dichlorides in further synthetic transformations to access a diverse range of potentially useful halogenated molecules, many of which constitute previously unreported structural frameworks.

Results and Discussion

We set out to develop a method to convert readily accessible propargylic alcohols into the corresponding dibromohydroxyketones, whose properties remain relatively unexplored,10 although they have recently been demonstrated as effective bioisosteres for hydrated ketones in quorum‐sensing inhibitors.12 The required dibromohydration of propargylic alcohols was achieved efficiently using dibromoisocyanuric acid (DBIA)13 under closely related conditions to our previously described dichlorohydration reaction.8 Our initial experiments suggested that the reaction was more efficient with a higher proportion of water in the reaction medium (30 % rather than 10 % H₂O in MeCN).

Pleasingly, the reaction could be applied to primary, secondary and tertiary propargylic alcohols (Scheme 2, e.g. 6a, 6b, 6c). As noted previously, an aryl group on the alkyne was necessary for efficient reaction. However, unsubstituted phenyl rings (6a, 6b, 6e, 6n) and both electron rich (6c, 6d, 6g, 6h, 6j, 6m) and electron deficient (6l, 6m) aryl groups could be used, including examples bearing polyaromatic rings (6i) and a pyridine heterocycle (6k). A very electron‐deficient benzene ring (6l) led to a low yield of the desired dibromide, however. Both aryl and alkyl chains could be incorporated as the R² substituent, including some functional groups (ester 6d, aryl bromide 6e–6f). The novel dichlorides 7n and 7o were also prepared using our previously reported dichlorohydration method. Interestingly, the dibromohydration of an ethoxyacetylene 1p led to the formation of both the desired dibromide 6p and the monobrominated compound 8. The formation of this latter compound as a single diastereoisomer is consistent with our proposed mechanism in which the halogenation reaction proceeds via formation of heterocycle 9 through incorporation of a molecule of acetonitrile (Scheme 3). Heterocycle 9 can then undergo a second bromination to give dibromide 10 which then hydrolyses to yield the dibromoketone product 6. Alternatively, protonation of highly electron rich heterocycle 9 (where R¹ = OEt) may take place selectively on the least hindered side to give 11 which will yield syn‐bromohydrin 8 as the major diastereoisomer after hydrolysis.

Scheme 2.

Dibromohydration of propargylic alcohols. ^[a] 5 equiv. of DBIA were used.

Scheme 3.

Proposed mechanism for dibromohydration.

The bromination reaction could be extended to the synthesis of dibromolactols 12a–12d through reaction of extended alkynol derivatives (Scheme 4), including compounds containing primary (12a, 12c), secondary (12d) and tertiary (12b) alcohols. Dichlorides 13a and 13d were also prepared via dichlorohydration of the alkynes using TCIA.

Scheme 4.

Dibromohydration and dichlorohydration of extended alkynols.

With a selection of dihalohydroxyketones and dihalolactols in hand, we examined their reduction to access halogenated diols and cyclic ethers. Pleasingly, lactols 12a and 13a could be converted into the corresponding dihalo‐1,4‐diols 14/15 or dihalogenated tetrahydrofurans 16/17 through treatment with NaBH₄ or TFA/Et₃SiH respectively. Dichlorohydroxyketones 7n and 7o could readily be converted with high diastereoselectivity into the anti‐dichlorodiols 18 via reduction with Me₄NB(OAc)₃H.14 The same procedure was also used to access anti‐bromodiol 19. We next set out to investigate a complementary method to access the corresponding syn‐dihalodiols. Reduction of 6g with DIBAL‐H in the presence or absence of ZnCl₂ 15 led to the formation of a mixture of products including desired syn‐diol 20, monobrominated anti‐diol 21, and brominated allylic alcohol 22, with the zinc chloride leading to an enhanced selectivity in favour of the desired diol 20. An alternative reduction protocol using catechol borane16 gave a mixture of syn and anti diols in 82 % overall yield (82:18 dr), from which the desired syn diol 20 could be isolated in 64 % yield. The stereochemistry of 20 was confirmed through formation of the acetonide 23 which displayed an nOe between the two axial protons indicated. Using the same method, dichlorohydroxyketone 7n was converted into the corresponding syn‐dichlorodiol 24 in 90 % yield. Interestingly, dibromo‐1,3‐diols such as 19 and 20 have never previously been synthesised (Scheme 5).17

Scheme 5.

Reduction of geminal dihalides to access halogenated diols and cyclic ethers.

We envisaged that lactols such as 12a could readily be converted into synthetically useful 3‐halofurans18 through formal elimination of water and HX. Attempts to convert 12a directly into the 3‐bromofuran were unsuccessful. However, further investigation determined that 3‐halofurans could be successfully obtained through conversion of the lactols 12a, 13a and 13d into the mixed ketal derivatives 25a–25c with AcCl/MeOH, followed by basic elimination of methanol and HX. Using this sequence, we were able to access 3‐bromofuran 26a, 3‐chlorofuran 26b and trisubstituted bromofuran 26c; with complete control over the substitution pattern in the latter compound. This approach is complementary to routes employing ynones,[18a,b,e] providing access to a different regioisomer of the 3‐halofuran (Scheme 6).

Scheme 6.

Synthesis of 3‐halofurans.

We have previously reported that 3‐alkoxyfurans are readily able to undergo Diels–Alder reaction with maleimides to provide endo‐cantharimide derivatives, which are promising lead‐like molecules for medicinal chemistry.19 3‐Halofurans have been reported to show enhanced reactivity in intramolecular Diels–Alder reactions,20, 21 so we were therefore interested in exploring their reactivity with maleimides to access useful halogenated cantharimide derivatives. 3‐Bromofuran 26c gave the endo cantharimide 27 as a single diatereoisomer in excellent yield upon reaction with N‐methylmaleimide. However, 3‐chlorofuran 26b gave a mixture of the separable endo and exo cantharimides 28 in moderate overall yield under similar conditions (Scheme 7).

Scheme 7.

Cycloaddition reactions of 3‐halofurans.

A further interesting transformation was uncovered upon attempted dibromination of cyclopropyl‐containing propargylic alcohol 1q, which yielded the vinylcyclobutane 29a as the major product as a mixture of diastereoisomers. This reaction was extended to the synthesis of 29b.22 Although ring expansion of cyclopropanes to cyclobutanes is precedented,23 the direct ring expansion of cyclopropylacetylenes has rarely been observed (Scheme 8).24

Scheme 8.

Synthesis of cyclobutanes via ring expansion of propargylic alcohols containing cyclopropylacetylenes.

Conclusions

We have reported a new method for the dibromohydration of alkynols to give dibromoketones that is applicable to a wide range of substrates, along with the extension of our previously reported dichlorohydration reaction to new substrates. The dihaloketones obtained from these reactions can be used to prepare structurally diverse halogenated molecules including dihalodiols, dihalogenated tetrahydrofurans, 3‐halofurans, and halogenated cantharimides. We have also discovered a novel halogenation/ring expansion of alkynylcyclopropanes that provides alkenylcyclobutanes. Many of these classes of halogenated compound have never previously been prepared. Further work is underway to optimize these methods, and to explore the interesting properties of these structurally unusual molecules.

Experimental Section

Full experimental procedures for the preparation of all compounds, along with ¹H and ¹³C spectra for all novel compounds can be found in the supporting information.

General Procedure for Dibromohydration Reactions: Dibromoisocyanuric acid (1.1 equiv.) was added to a stirring solution of alkynyl alcohol (1.0 equiv.) in MeCN/H₂O (7:3, 2 mL mmol^–1). The solution was stirred for 10 min after which solvent was removed in vacuo and the resultant residue purified by column chromatography (10 % EtOAc in petrol) to give the dibromohydroxyketone.

General Procedure for Dichlorohydration Reactions: Trichloroisocyanuric acid (1 equiv.) was added to a stirring solution of alkynyl alcohol (1 equiv.) in MeCN/H₂O (10:1, 4 mL mmol^–1). After 30 min the solvent was removed in vacuo and the residue was purified by column chromatography to give the dichlorohydroxyketone.

2,2‐Dibromo‐3‐hydroxy‐1‐phenylpropan‐1‐one (6a): 149 mg, 93 %, yellow oil. ¹H NMR (600 MHz, CDCl₃): δ = 8.40 (dd, J = 8.6, 1.2 Hz, 2 H, 2 × ArH), 7.61 (tt, J = 7.4, 1.2 Hz, 1 H, ArH), 7.49 (dd, J = 8.6, 7.4 Hz, 2 H, 2 × ArH), 4.35 (s, 2 H, CH₂), 3.12 (br. s, 1 H, OH) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 189.5, 134.3, 131.7, 131.4, 128.3, 72.1, 63.4 ppm. HRMS: Found (CI): [M + H]⁺ 306.89622, C₉H₉Br₂O₂: calcd. 306.89693. IR (film): ν̃_max = 3422 (O–H), 2918 (C–H), 1667 (C=O), 1446 (C=C) cm^–1. The synthesis of this compound has been previously reported using a different method.[10b]

2,2‐Dibromo‐3‐hydroxy‐1‐phenylhexan‐1‐one (6b): 818 mg, 74 %, yellow solid, m.p. 54–55 °C. ¹H NMR (CDCl₃, 600 MHz): δ = 8.37 (m, 2 H, ArH), 7.59 (m, 1 H, ArH), 7.48 (m, 2 H, ArH), 4.23 (dd, J = 9.6, 1.4 Hz, 1 H, CH), 3.34 (br. s, 1 H, OH), 2.07 (m, 1 H, 1 × CHCH ₂), 1.80 (m, 1 H, 1 × CHCH₂), 1.74 (m, 1 H, 1 × CH ₂CH₃), 1.52 (m, 1 H, 1 × CH ₂CH₃), 1.02 (t, J = 7.4 Hz, 3 H, CH₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 190.4, 133.9, 132.6, 131.5, 128.1, 77.2, 71.4, 34.9, 19.5, 14.1 ppm. LRMS (NSI): m/z = 375 (49, [M + Na]⁺, 2 × ⁸¹Br), 373 (100, [M + Na]⁺, ⁷⁹Br, ⁸¹Br), 371 (50, [M + Na]⁺, 2 × ⁷⁹Br). HRMS Found 370.9252, C₁₂H₁₄Br₂O₂Na ([M + Na]⁺): calcd. 370.9253. IR (solid): ν̃_max = 3544 (O–H), 2955 (C–H), 2927 (C–H), 2864 (C–H), 1667 (C=O), 1594 (C=C), 1574 (C=C), 1445 cm^–1.

2,2‐Dibromo‐3‐ethyl‐3‐hydroxy‐1‐(p‐tolyl)pentan‐1‐one (6c): 175 mg, 93 %, yellow oil. ¹H NMR (CDCl₃, 600 MHz): δ = 8.21 (d, J = 7.9 Hz, 2 H, ArH), 7.26 (d, J = 7.9 Hz, 2 H, ArH), 4.23 (br. s, 1 H, OH), 2.45 (s, 3 H, ArCH ₃), 2.09 (q, J = 7.4 Hz, 4 H, 2 × CH ₂CH₃), 1.09 (t, J = 7.4 Hz, 6 H, 2 × CH₂ CH ₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 192.9, 144.6, 131.42, 131.38, 128.6, 80.8, 30.7, 21.8, 9.7 ppm. HRMS: Found 398.9553, C₁₄H₁₉Br₂O₂ ([M + H]⁺): calcd. 398.9566. IR (solid): ν̃_max = 3517 (O–H), 2969 (C–H), 2940 (C–H), 2879 (C–H), 1650 (C=O), 1603 (C=C), 1568 (C=C) cm^–1.

Ethyl 4,4‐Dibromo‐3‐hydroxy‐5‐oxo‐5‐(p‐tolyl)pentanoate (6d): 128 mg, 63 %, pale yellow oil. ¹H NMR (600 MHz, CDCl₃): δ = 8.28 (d, J = 8.2 Hz, 2 H, 2 × ArH), 7.27 (d, J = 8.2 Hz, 2 H, 2 × ArH), 4.88 (dd, J = 9.6, 2.2 Hz, 1 H, CHOH), 4.23 (q, J = 7.2 Hz, 2 H, CH₂CH₃), 3.71 (br. s, 1 H, OH), 3.18 (dd, J = 16.0, 2.2 Hz, 1 H, CHOHCHH), 2.88 (dd, J = 16.0, 9.6 Hz, 1 H, CHOHCHH), 2.44 (s, 3 H, ArCH₃), 1.30 (t, J = 7.2 Hz, 3 H, CH₂ CH ₃) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 189.2, 171.1, 145.4, 131.7, 129.4, 128.9, 74.4, 68.5, 61.2, 39.0, 21.9, 14.3 ppm. HRMS: Found (CI): [M + H]⁺ 406.94910, C₁₄H₁₇Br₂O₄: calcd. 406.94936. IR (film): ν̃_max = 3514 (O–H), 2980 (C–H), 1732 (C=O), 1666 (C=O) 1568 (Ar) cm^–1.

2,2‐Dibromo‐3‐(4‐bromophenyl)‐3‐hydroxy‐1‐phenylpropan‐1‐one (6e): 101 mg, 50 %, pale brown solid, m.p. 157–159 °C. ¹H NMR (CDCl₃, 500 MHz): δ = 8.39 (d, J = 8.5 Hz, 2 H, ArH), 7.63–7.59 (m, 1 H, ArH), 7.56 (d, J = 8.6 Hz, 2 H, ArH), 7.53 (d, J = 8.6 Hz, 2 H, ArH), 7.50–7.46 (m, 2 H, ArH), 5.41 (d, J = 3.7 Hz, 1 H, CH), 3.96 (d, J = 3.7 Hz, 1 H, OH) ppm. ¹³C NMR (CDCl₃, 125 MHz): δ = 190.9, 135.5, 134.1, 132.4, 131.9, 131.6, 130.6, 128.1, 123.2, 77.8, 69.1 ppm. LRMS (NSI) 489 (11 %, [M + Na]⁺, 3 × ⁸¹Br), 487 (32 %, [M + Na]⁺, 2 × ⁸¹Br, ⁷⁹Br), 485 (35 %, [M + Na]⁺, 2 × ⁷⁹Br, ⁸¹Br), 483 (10 %, [M + Na]⁺, 3 × ⁷⁹Br), 345 (100 %). HRMS Found 482.8197, C₁₅H₁₁Br₃O₂Na ([M + Na]⁺): calcd. 482.8201. IR (solid): ν̃_max = 3530 (O–H), 2923 (C–H), 2853 (C–H), 1657 (C=O), 1591 (C=C), 1574 (C=C) cm^–1.

2,2‐Dibromo‐3‐(4‐bromophenyl)‐3‐hydroxy‐1‐(p‐tolyl)propan‐1‐one (6f): 190 mg, 95 %, off white solid, m.p. 171–172 °C. ¹H NMR (CDCl₃, 600 MHz): δ = 8.32 (d, J = 8.4 Hz, 2 H, ArH), 7.56 (d, J = 8.5 Hz, 2 H, ArH), 7.53 (d, J = 8.5 Hz, 2 H, ArH), 7.28 (d, J = 8.4 Hz, 2 H, ArH), 5.40 (br. d, J = 2.4 Hz, 1 H, CH), 4.05 (br. d, J = 3.3 Hz, 1 H, OH), 2.45 (s, 3 H, CH₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 190.6, 145.6, 135.6, 132.0, 131.9, 130.6, 129.6, 128.9, 123.3, 77.9, 69.2, 21.9 ppm. LRMS (CI) 480 (3 %, [M]⁺, 3 × ⁸¹Br), 478 (6 %, M⁺, 2 × ⁸¹Br, ⁷⁹Br), 476 (7 %, [M]⁺, ⁸¹Br, 2 × ⁷⁹Br), 474 (3 %, [M]⁺, 3 × ⁷⁹Br), 413 (11 %), 400 (51 %, [M – Br]⁺, 2 × ⁸¹Br) 398 (100 %, [M – Br]⁺, ⁸¹Br, ⁷⁹Br), 396 (54 %, [M – Br]⁺, 2 × ⁷⁹Br), 383 (16 %), 381(31 %), 379 (15 %). HRMS Found 473.8459, C₁₆H₁₃Br₃O₂: calcd. 473.8466. IR (solid): ν̃_max = 3554 (O–H), 1657 (C=O), 1598 (C=C), 1297, 1215 cm^–1.

2,2‐Dibromo‐3‐hydroxy‐1‐(p‐tolyl)hexan‐1‐one (6 g): 111 mg, 87 %, pale yellow solid, m.p. 71–73 °C. ¹H NMR (CDCl₃, 600 MHz): δ = 8.29 (d, J = 8.4 Hz, 2 H, ArH), 7.27 (d, J = 8.4 Hz, 2 H, ArH), 4.22 (dd, J = 9.6, 1.6 Hz, 1 H, CH), 3.46 (br. s, 1 H, OH), 2.44 (s, 3 H, ArCH ₃), 2.12–2.02 (m, 1 H, 1 × CHCH ₂), 1.85–1.76 (m, 1 H, 1 × CHCH ₂), 1.76–1.69 (m, 1 H, 1 × CH ₂CH₃), 1.59–1.47 (m, 1 H, 1 × CH ₂CH₃), 1.02 (t, J = 7.4 Hz, 3 H, CH₂ CH ₃) ppm. ¹³C NMR (CDCl₃, 600 MHz): δ = 190.1, 145.2, 131.7, 129.8, 128.9, 77.2, 71.5, 34.9, 21.9, 19.6, 14.1 ppm. LRMS (ESI⁺) 389 (34 %, [M + Na⁺], 2 × ⁸¹Br), 387 (64 %, [M + Na⁺], ⁷⁹Br, ⁸¹Br), 385 (31 %, [M + Na⁺], 2 × ⁷⁹Br), 367 (34 %, [M + H]⁺, 2 × ⁸¹Br), 365 (100 %, ⁷⁹Br, ⁸¹Br), 363 (48 %, 2 × ⁷⁹Br). HRMS Found 362.9579, C₁₃H₁₇Br₂O₂: calcd. 362.9595. IR (film): ν̃_max = 3502 (O–H), 2958 (C–H), 2865 (C–H), 1658 (C=O), 1600, 1565 cm^–1.

2,2‐Dibromo‐3‐hydroxy‐1‐(o‐tolyl)hexan‐1‐one (6h): 136 mg, 75 %, pale yellow oil, ¹H NMR (CDCl₃, 600 MHz): δ = 8.08–8.01 (m, 1 H, ArH), 7.38 (td, J = 7.6 and 1.2 Hz, 1 H, ArH), 7.29–7.26 (m, 1 H, ArH), 7.25–7.21 (m, 1 H, ArH), 4.36–4.27 (m, 1 H, CHOH), 2.77 (d, J = 6.1 Hz, 1 H, OH), 2.36 (s, 3 H, ArCH ₃), 2.10–2.03 (m, 1 H, 1 × CHCH ₂), 1.79–1.65 (m, 2 H, 1 × CHCH ₂, 1 × CH ₂CH₃), 1.57–1.46 (m, 1 H, 1 × CH ₂CH₃), 1.02 (t, J = 7.3 Hz, 3 H, CH₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 195.9, 137.6, 136.2, 131.3, 131.0, 128.1, 125.0, 76.9, 74.3, 35.4, 20.6, 19.4, 14.0 ppm. HRMS Found 362.9594, C₁₃H₁₇Br₂O₂: calcd. 362.9595. IR (film): ν̃_max = 3479 (O–H), 2958 (C–H), 2929 (C–H), 2871 (C–H), 1694 (C=O), 1600 (C=C), 1456 (C=C) cm^–1.

2,2‐Dibromo‐3‐hydroxy‐1‐(phenanthren‐9‐yl)hexan‐1‐one (6i): 139 mg, 62 %, pale brown solid, m.p. 109–110 °C. ¹H NMR (CDCl₃, 600 MHz): δ = 8.74 (d, J = 8.3 Hz, 1 H, ArH), 8.71 (d, J = 8.3 Hz, 1 H, ArH), 7.99 (dd, J = 9.9, 1.0 Hz, 1 H, ArH), 7.91 (dd, J = 8.2, 1.0 Hz, 1 H, ArH), 7.76 (ddd, J = 8.3, 7.0, 1.4 Hz, 1 H, ArH), 7.71 (ddd, J = 8.3, 7.0, 1.3 Hz, 1 H, ArH), 7.69–7.65 (m, 1 H, ArH), 7.63 (ddd, J = 8.3, 7.0, 1.3 Hz, 1 H, ArH), 4.52–4.46 (m, 1 H, CH), 2.80 (d, J = 7.5 Hz, 1 H, OH), 1.85–1.71 (m, 2 H, CH ₂CH), 1.60–1.50 (m, 2 H, CH ₂CH₃), 1.05 (t, J = 7.4 Hz, 3 H, CH₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 195.9, 133.3, 131.2, 130.5, 130.0, 129.7, 129.3, 128.7, 127.8, 127.41, 127.39, 127.3, 126.4, 123.1, 122.8, 77.1, 75.0, 35.6, 19.4, 14.1 ppm. LRMS (EI) 452 (3 %, [M]⁺, 2 × ⁸¹Br), 450 (7 %, [M]⁺, ⁷⁹Br, ⁸¹Br), 448 (4 %, [M]⁺, 2 × ⁷⁹Br), 205 (100 %, [M – C₅H₉Br₂O]⁺). HRMS Found 447.9647, C₂₀H₁₈Br₂O₂: calcd. 447.9668. IR (film): ν̃_max = 3572 (O–H), 2957 (C–H), 1642 (C=O), 1447 cm^–1.

2,2‐Dibromo‐3‐hydroxy‐1‐(4‐methoxyphenyl)hexan‐1‐one (6j): 138 mg, 73 %, pale yellow solid, m.p. 81–84 °C. ¹H NMR (CDCl₃, 600 MHz): δ = 8.40 (d, J = 9.1 Hz, 2 H, ArH), 6.93 (d, J = 9.1 Hz, 2 H, ArH), 4.19 (ddd, J = 9.6, 4.2, 1.6 Hz, 1 H, CH), 3.90 (s, 3 H, OCH₃), 3.52 (br. d, J = 4.2 Hz, 1 H, OH), 2.11–2.01 (m, 1 H, 1 × CHCH ₂), 1.85–1.77 (m, 1 H, 1 × CHCH ₂), 1.77–1.68 (m, 1 H, 1 × CH ₂CH₃), 1.57–1.45 (m, 1 H, 1 × CH ₂CH₃), 1.01 (t, J = 7.3 Hz, 3 H, CH₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 189.0, 164.1, 134.2, 124.8, 113.3, 77.3, 71.4, 55.6, 34.8, 19.5, 14.0 ppm. LRMS (ES⁺) 405 (12 %, [M + Na]⁺, 2 × ⁸¹Br), 403 (26 %, [M + Na]⁺, ⁷⁹Br, ⁸¹Br), 401 (11 %, [M + Na]⁺, 2 × ⁷⁹Br), 383 (48 %, [M + H]⁺, 2 × ⁸¹Br), 381 (100 %, [M + H]⁺, ⁷⁹Br, ⁸¹Br), 379 (50 %, [M + H]⁺, 2 × ⁷⁹Br). HRMS Found 378.9539, C₁₃H₁₇Br₂O₃: calcd. 378.9544. IR (film): ν̃_max = 3511 (O–H), 2957 (C–H), 1656 (C=O), 1596, 1568 (C=C), 1510 (C=C) cm^–1.

2,2‐Dibromo‐3‐hydroxy‐1‐(pyridin‐3‐yl)hexan‐1‐one (6k): Purified by column chromatography using 1 % MeOH in CH₂Cl₂: 72 mg, 41 %, orange gum (23 % SM recovered). ¹H NMR (CDCl₃, 500 MHz): δ = 9.53 (d, J = 1.4 Hz, 1 H, ArH), 8.78 (d, J = 3.6 Hz, 1 H, ArH), 8.62 (dt, J = 8.1, 2.0 Hz, 1 H, ArH), 7.42 (dd, J = 8.1, 4.8 Hz, 1 H, ArH), 4.23 (br. d, J = 9.4 Hz, 1 H, CHCH₂), 3.29 (br. s, 1 H, OH), 2.11–1.97 (m, 1 H, 1 × CHCH ₂), 1.84–1.74 (m, 1 H, 1 × CHCH ₂), 1.73–1.67 (m, 1 H, 1 × CH ₂CH₃), 1.60–1.44 (m, 1 H, 1 × CH ₂CH₃), 1.02 (t, J = 7.3 Hz, 3 H, CH₃) ppm. ¹³C NMR (CDCl₃, 125 MHz): δ = 189.1, 153.6, 152.1, 138.6, 128.7, 122.9, 76.8, 71.2, 34.8, 19.4, 14.0 ppm. LRMS (ESI) 354 (49 %, [M + H]⁺, 2 × ⁸¹Br), 352 (100 %, [M + H]⁺, ⁷⁹Br, ⁸¹Br), 350 (52 %, [M + H]⁺, 2 × ⁷⁹Br). HRMS Found 349.9383, C₁₁H₁₄Br₂NO₂: calcd. 349.9386. IR (film): ν̃_max = 3113 (O–H), 2962 (C–H), 2927 (C–H), 2872 (C–H), 1681 (C=O), 1585 (C=C), 1417 cm^–1.

2,2‐Dibromo‐3‐hydroxy‐1‐[4‐(trifluoromethyl)phenyl]hexan‐1‐one (6l): 35 mg, 17 %, yellow oil. ¹H NMR (CDCl₃, 500 MHz): δ = 8.44 (d, J = 8.3 Hz, 2 H, ArH), 7.73 (d, J = 8.3 Hz, 2 H, ArH), 4.23 (br. d, J = 9.3 Hz, 1 H, CH), 3.19 (br. s, 1 H, OH), 2.10–2.00 (m, 1 H, 1 × CHCH ₂), 1.82–1.74 (m, 1 H, 1 × CHCH ₂) 1.74–1.67 (m, 1 H, 1 × CH ₂CH₃), 1.59–1.46 (m, 1 H, 1 × CH ₂CH₃), 1.02 (t, J = 7.3 Hz, 3 H, CH₃) ppm. ¹³C NMR (CDCl₃ 125 MHz): δ = 189.4, 135.8, 134.7 (q, J_C,F = 32.9 Hz), 131.6, 125.1 (q, J_C,F = 3.7 Hz), 122.4 (q, J_C,F = 273.0 Hz), 77.0, 71.2, 34.9, 19.4, 14.0 ppm. LRMS (EI) 401 (1 %, [M – H₂O]⁺, 2 × ⁸¹Br), 399 (2 %, [M – H₂O]⁺, ⁷⁹Br, ⁸¹Br), 397 (1 %, [M – H₂O]⁺, 2 × ⁷⁹Br), 348 (11 %, [M – CF₃]⁺, 2 × ⁸¹Br), 346 (24 %, [M – CF₃]⁺, ⁷⁹Br, ⁸¹Br), 344 (13 %, [M – CF₃]⁺, 2 × ⁷⁹Br), 230 (6 %), 228 (14 %), 226 (7 %) 173 (100 %, [M – C₅H₉Br₂O]⁺). HRMS Found 433.9573, C₁₃H₁₇Br₂F₃NO₂ ([M + NH₄]⁺): calcd. 433.9573. IR (film): ν̃_max = 3562 (O–H), 2962 (C–H), 2933 (C–H), 2874 (C–H), 1678 (C=O), 1461 cm^–1.

2,2‐Dibromo‐3‐hydroxy‐1‐(3‐methoxyphenyl)hexan‐1‐one (6m): 618 mg, 31 %, ¹H NMR (CDCl₃, 500 MHz): δ = 7.97 (dd, J = 7.9 Hz, 2.4 1 H, Ar), 7.81 (dd, J = 2.4, 1.7 Hz, 1 H, Ar), 7.34 (t, J = 8.0 Hz, 1 H, Ar), 7.10 (dd, J = 8.2 Hz, 2.5 1 H, Ar), 4.22 (d, J = 9.1 Hz, 1 H, CHOH), 3.84 (s, 3 H, OCH₃), 3.39 (br. s, 1 H, OH), 2.04 (m, 1 H, CH ₂CH),1.73 (m, 2 H, CH ₂CH and CH ₂CH₃), 1.51 (m, 1 H, CH ₂CH₃),1.00 (t, J = 7.4 Hz, 3 H, CH ₃) ppm. ¹³C NMR (CDCl₃ 125 MHz): δ = 190.1, 159.1, 133.8, 129.0, 123.9, 121.0, 116.0, 77.1, 71.7, 55.5, 34.9, 19.5, 14.0 ppm. LRMS (CI) 380.9 ([M + H]⁺, 40), 362.9 ([M – H₂O]⁺, 24), 308.8 (20), 283.0 (100), 221.1 (12), 205.1 (11), 135.0 (30). HRMS Found 378.9540 C₁₃H₁₇Br₂O₃ [M + H]⁺: calcd. 378.9539.

2,2‐Dibromo‐3‐hydroxy‐4‐methyl‐1‐phenylpentan‐1‐one (6n): Yield: 665 mg, 66 %; m.p. 62–65 °C. ¹H NMR (600 MHz, CDCl₃): δ = 8.30 (dd, J = 8.4, 1.1 Hz, 2 H, ArH), 7.58 (t, J = 7.4 Hz, 1 H, ArH), 7.46 (t, J = 7.9 Hz, 2 H, ArH), 4.21 (dd, J = 5.8, 3.5 Hz, 1 H, CHOH), 3.18 (d, J = 6.0 Hz, 1 H, OH), 2.40 [heptd, J = 6.8, 3.5 Hz, 1 H, CH(CH₃)₂], 1.17 [d, J = 6.8 Hz, 3 H, CH(CH ₃)₂], 1.12 [d, J = 7.0 Hz, 3 H, CH(CH ₃)₂] ppm. ¹³C NMR (151 MHz, CDCl₃): δ = 190.7, 133.6, 133.0, 131.2, 128.1, 80.1, 71.8, 31.9, 23.2, 17.9 ppm. LRMS (CI) 366 (51 %, [M + NH₄]⁺, 2 × ⁷⁹Br), 368 (100 %, [M + NH₄]⁺, ⁷⁹Br, ⁸¹Br); 370 (49 %, [M + NH₄]⁺, 2 × ⁸¹Br). HRMS (CI⁺) found 365.96978 C₁₂H₁₄Br₂O₂NH₄: calcd. 265.96988 ([M + NH₄]⁺); ν̃_max = (film) 3539 (O–H), 2964 (C–H), 2932 (C–H), 2874 (C–H), 1671 (C=O), 1235 (C=C), 691 cm^–1 (C–Br).

Ethyl 2,2‐Dibromo‐3‐hydroxy‐5‐phenylpentanoate (6p): Dibromoisocyanuric acid (0.6 equiv.) was added to a stirring solution of propargylic alcohol (1.0 equiv.) in MeCN/H₂O (7:3, 2 mL mmol^–1). The solution was stirred for 10 min after which solvent was removed in vacuo and the resultant residue purified by column chromatography (10 % EtOAc in petrol) to give 6p as a colourless oil (49 mg, 26 %). ¹H NMR (CDCl₃, 600 MHz): δ = 7.35–7.27 (m, 2 H, ArH), 7.26–7.17 (m, 3 H, ArH), 4.34 (q, J = 7.1 Hz, 2 H, CH ₂CH₃), 4.05 (dd, J = 9.9, 3.1 Hz, 1 H, CH), 3.09–2.94 (m, 2 H, OH, 1 × CHCH ₂), 2.77 (ddd, J = 13.8, 9.0, 7.8 Hz, 1 H, 1 × CHCH ₂), 2.35–2.23 (m, 1 H, 1 × CH ₂Ar), 2.08–1.95 (m, 1 H, 1 × CH ₂Ar), 1.34 (t, J = 7.1 Hz, 3 H, CH₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 166.6, 141.3, 128.7, 128.6, 126.3, 7.8, 66.2, 64.2, 34.6, 32.1, 13.8 ppm. LRMS (CI) 400 (51 %, [M + NH₄]⁺, 2 × ⁸¹Br), 398 (100 %, [M + NH₄]⁺, ⁷⁹Br, ⁸¹Br), 396 (50 %, [M + NH₄]⁺, 2 × ⁷⁹Br). HRMS Found 395.9805, C₁₃H₂₀Br₂NO₃ ([M + NH₄]⁺): calcd. 395.9804. IR (film): ν̃_max = 3283 (O–H), 3027 (C–H), 2931 (C–H), 1727 (C=O), 1623, 1536 (C=C), 1496 (C=C), 1453 cm^–1.

2,2‐Dichloro‐3‐hydroxy‐4‐methyl‐1‐phenylpentan‐1‐one (7n): Purified via column chromatography (20 % EtOAc in petrol) to give 7n as a colourless oil which crystallises on standing (6.621 g, 69 %); m.p. 38–44 °C. ¹H NMR (CDCl₃, 400 MHz): δ = 8.24–8.22 (m, 2 H, ArH), 7.61–7.59 (m, 1 H, ArH), 7.48–7.46 (m, 2 H, ArH), 4.32 (dd, J = 5.6, 3.6 Hz, 1 H, CHOH), 3.03 (d, J = 6.0 Hz, 1 H, OH), 2.38 [heptd, J = 6.9, 3.6 Hz, 1 H, CH(CH₃)₂], 1.15 [d, J = 6.8 Hz, 3 H, CH(CH ₃)₂], 1.13 [d, J = 7.0 Hz, 3 H, CH(CH ₃)₂] ppm. ¹³C NMR (CDCl₃, 176 MHz): δ = 190.5, 133.8, 132.3, 131.1, 128.3, 88.9, 79.6, 30.1, 22.8, 17.5 ppm. LRMS (ES⁺) 261 (100 %, [M]⁺, 2 × ³⁵Cl), 263 (60 %, [M]⁺, ³⁵Cl, ³⁷Cl), 265 (10 %, [M]⁺, 2 × ³⁷Cl). HRMS (ES⁺) found 261.0448, C₁₂H₁₅Cl₂O₂ ⁺: calcd. 261.0449 ([M]⁺). IR (film): ν̃_max = 3546 (O–H), 2962 (C–H), 2930 (C–H), 2872 (C–H), 1678 (C=O), 1235, 821, 691 cm^–1.

2,2‐Dichloro‐3‐hydroxy‐1,3‐diphenylpropan‐1‐one (7o): Trichloroisocyanuric acid (1 equiv.) was added to a stirring solution of propargylic alcohol (1 equiv.) in MeCN/H₂O (7:3 4 mL. mmol^–1). The solution was stirred until the reaction was finished (as determined by TLC). the solvent was removed in vacuo and the residue was purified via column chromatography (20 % EtOAc in petrol) which afforded chlorinated hydroxykeytone 7o as a yellow solid (632 mg; 30 %; m.p. 121–128 °C). ¹H NMR (600 MHz, CDCl₃): δ = 8.30 (dd, J = 8.5, 1.1 Hz, 2 H, ArH), 7.63–7.61 (m, 3 H, ArH), 7.49 (t, J = 7.9 Hz, 2 H, ArH), 7.41–7.40 (m, 3 H, ArH), 5.59 (d, J = 4.2 Hz, 1 H, CHOH), 3.75 (d, J = 4.2 Hz, 1 H, OH) ppm. ¹³C NMR (151 MHz, CDCl₃): δ = 190.9, 135.7, 134.2, 132.0, 131.40, 129.90, 129.0, 128.3, 127.7, 86.7, 78.1 ppm. LRMS (NSI) 317 (100 %, [M + Na]⁺, 2 × ³⁵Cl), 319 (60 %, M + Na)⁺, ³⁵Cl, ³⁷Cl, 321 (10 %, [M + Na]⁺, 2 × ³⁷Cl). HRMS Found 317.0107, C₁₅H₁₂Cl₂O₂Na: calcd. 317.0109 ([M + Na]⁺). IR (film): ν̃_max = 3539 (O–H), 3060 (C–H), 3031 (C–H), 2917 (C–H), 1677 (C=O), 1239, 693 cm^–1.

Ethyl 2‐Bromo‐3‐hydroxy‐5‐phenylpentanoate (8): Isolated from the reaction used to synthesise 6p (10 mg, 7 %); colourless oil. ¹H NMR (CDCl₃, 600 MHz): δ = 7.32–7.28 (m, 2 H, ArH), 7.23–7.19 (m, 3 H, ArH), 4.30–4.18 (m, 3 H, CHBr, CH ₂CH₃), 3.90 (dq, J = 7.9, 3.6 Hz, 1 H, CHOH), 2.94 (d, J = 3.6 Hz, 1 H, OH), 2.86 (ddd, J = 14.3, 9.4, 5.3 Hz, 1 H, 1 × CHCH ₂), 2.72 (ddd, J = 13.8, 9.4, 7.8 Hz, 1 H, 1 × CHCH ₂), 2.02–1.92 (m, 1 H, 1 × CH ₂Ar), 1.81–1.76 (m, 1 H, 1 × CH ₂Ar), 1.29 (t, J = 7.1 Hz, 3 H, CH₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 169.5, 141.3, 128.62, 128.61, 126.2, 70.0, 62.6, 52.2, 35.9, 31.7, 14.0 ppm. LRMS (CI) 320 (98 %, [M + H]⁺, ⁸¹Br), 318 (100 %, [M + H]⁺, ⁷⁹Br). HRMS Found 318.0699, C₁₃H₁₈BrO₃: calcd. 318.0699. IR (film): ν̃_max = 3524 (O–H), 3026 (C–H), 2982 (C–H), 2934 (C–H), 1736 (C=O), 1495 (C=C), 1454 (C=C) cm^–1. The anti diastereoisomer of this compound has previously been reported in the literature.25

3,3‐Dibromo‐2‐(p‐tolyl)tetrahydrofuran‐2‐ol (12a): 3.55 g, 84 %, white solid, m.p. 116–117 °C. ¹H NMR (CDCl₃, 500 MHz): δ = 8.27 (d, J = 8.4 Hz, 2 H, minor ArH), 7.71 (d, J = 8.2 Hz, 2 H, major ArH), 7.26 (d, J = 8.4 Hz, 2 H, minor ArH), 7.21 (d, J = 8.1 Hz, 2 H, major ArH), 4.33–4.25 (m, 1 H, major 1 × OCH₂), 4.21–4.14 (m, 1 H, major 1 × OCH₂), 4.01 (t, J = 6.2 Hz, 2 H, minor CH ₂OH), 3.46 (dt, J = 13.5, 9.2 Hz, 1 H, major 1 × CH₂CBr₂), 3.11–3.02 (m, 1 H, major 1 × CH₂CBr₂; m, 2 H, minor CH₂CBr₂), 2.44 (s, 3 H, minor CH₃), 2.39 (s, 3 H, major CH₃) ppm. ¹³C NMR (CDCl₃, 125 MHz): δ = 188.3, 144.8, 139.4, 135.4, 131.5, 129.3, 128.8, 128.4, 127.4, 108.6, 105.9, 68.0, 65.2, 61.6, 49.8, 47.1, 21.8, 21.3 ppm. LRMS (EI) 338 (4 %, [M]⁺, 2 × ⁸¹Br), 336 (9 %, [M]⁺, ⁷⁹Br, ⁸¹Br), 334 (5 %, [M]⁺, 2 × ⁷⁹Br), 136 (82 %), 119 (100 %). HRMS Found 333.9200 C₁₁H₁₂Br₂O₂: calcd. 333.9204. IR (film): ν̃_max = 3409 (O–H), 2971 (C–H), 2908 (C–H), 1401 cm^–1.

3,3‐Dibromo‐5,5‐dimethyl‐2‐(p‐tolyl)tetrahydrofuran‐2‐ol (12b): Yellow solid, 76 %; m.p. 65–67 °C. ¹H NMR (600 MHz, CDCl₃): δ = 7.71 (d, J = 8.2 Hz, 2 H, 2 × ArH), 7.20 (d, J = 8.2 Hz, 2 H, 2 × ArH), 3.41 (d, J = 14.1 Hz, 1 H, CHH), 3.18 (d, J = 14.1 Hz, 1 H, CHH), 2.97 (s, 1 H, OH), 2.38 (s, 3 H, ArCH ₃), 1.62 (s, 3 H, CH₃), 1.52 (s, 3 H, CH₃) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 139.3, 136.3, 128.4, 127.2, 106.8, 81.5, 68.2, 58.8, 32.6, 28.7, 21.4 ppm. HRMS: Found (CI): [M]⁺ 361.95116, C₁₃H₁₆Br₂O₂: calcd. 361.95170. IR (film): ν̃_max = 3519 (O–H), 2970 (C–H) cm^–1.

2‐(Dibromomethyl)tetrahydrofuran‐2‐ol (12c): White crystals, 43 %; m.p. 70–71 °C. ¹H NMR (600 MHz, CDCl₃): δ = 5.72 (s, 1 H, CH), 4.17–4.23 (m, 1 H, OCHH), 4.00–4.07 (m, 1 H, OCHH), 3.05 (br. s, 1 H, OH), 2.19–2.29 (m, 3 H, OCH₂ CH ₂CHH), 2.01–2.10 (m, 1 H, OCH₂CH₂CHH) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 105.6, 70.4, 51.6, 35.2, 25.6 ppm. HRMS: Found (ES): [M – H]⁺ 256.8821, C₅H₇Br₂O₂: calcd. 256.8813. IR (film): ν̃_max = 3354 (O–H), 3014 (C–H) cm^–1.

3,3‐Dibromo‐5‐methyl‐2‐(p‐tolyl)tetrahydrofuran‐2‐ol (12d): Isolated as a mixture of diastereomers (1:2.5); 294 mg, 42 %, white solid, m.p. 98–99 °C. ¹H NMR (CDCl₃, 600 MHz): δ = 7.71 (d, J = 8.2 Hz, 2 H, minor ArH), 7.68 (d, J = 8.2 Hz, 2 H, major ArH), 7.21 (d, J = 8.2 Hz, 2 H, major ArH), 7.19 (d, J = 8.2 Hz, 2 H, minor ArH), 4.65 (dp, J = 9.3, 6.0 Hz, 1 H, major CH), 4.29 (dqd, J = 9.8, 6.5, 3.4 Hz, 1 H, minor CH), 3.74 (s, 1 H, major OH), 3.55 (dd, J = 14.1, 9.8 Hz, 1 H, minor 1 × CH₂), 3.49 (s, 1 H, minor OH), 3.16 (dd, J = 13.3, 6.0 Hz, 1 H, major 1 × CH₂), 3.10 (dd, J = 13.3, 9.3 Hz, 1 H, major 1 × CH₂), 2.93 (dd, J = 14.1, 3.4 Hz, 1 H, minor 1 × CH₂), 2.40 (s, minor ArCH₃), 1.49 (d, J = 6.5 Hz, 3 H, minor CHCH ₃), 1.45 (d, J = 6.0 Hz, 3 H, major CHCH ₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 139.3, 136.0, 135.4, 131.6, 128.4, 128.4, 127.5, 127.5, 106.4, 106.1, 74.7, 72.1, 68.8, 67.3, 54.4, 53.4, 22.4, 21.5, 21.4, 21.1 ppm. LRMS (CI) 370 (8 %, [M + NH₄]⁺, 2 × ⁸¹Br), 368 (20 %, [M + NH₄]⁺, ⁷⁹Br, ⁸¹Br), 366 (10 %, [M + NH₄]⁺, 2 × ⁷⁹Br), 335 (51 %, [M – CH₃]⁺, 2 × ⁸¹Br), 333 (100 %, [M – CH₃]⁺, ⁷⁹Br, ⁸¹Br), 331 (48 %, [M – CH₃]⁺, 2 × ⁷⁹Br). HRMS Found 365.9698, C12H18Br2NO2 ([M + NH₄]⁺): calcd. 365.9699. IR (film): ν̃_max = 3342 (O–H), 2963 (C–H), 1913, 1510 (C=C) cm^–1.

3,3‐Dichloro‐2‐(p‐tolyl)tetrahydrofuran‐2‐ol (13a): Isolated as a mixture of isomers (1:8.3); 1.83 g, 83 %, white solid, m.p. 122–124 °C. ¹H NMR (CDCl₃, 500 MHz): δ = 8.22 (d, J = 8.4 Hz, 2 H, minor ArH), 7.65 (d, J = 8.2 Hz, 2 H, major ArH), 7.30 (d, J = 8.4 Hz, 2 H, minor ArH), 7.22 (d, J = 8.2 Hz, 2 H, major ArH), 4.24 (ddd, J = 9.2, 8.3, 7.1 Hz, 1 H, major 1 × OCH₂), 4.15 (ddd, J = 9.4, 8.3, 2.2 Hz, 1 H, major 1 × OCH₂), 3.99 (t, J = 6.3 Hz, 2 H, minor CH₂OH), 3.50 (br. s, 1 H, major OH), 3.20 (dt, J = 13.1, 9.3 Hz, 1 H, major 1 × CH₂CCl₂), 2.91 (ddd, J = 13.1, 7.1, 2.2 Hz, 1 H, major 1 × CH₂CCl₂), 2.84 (t, J = 6.3 Hz, 2 H, minor CH₂CCl₂), 2.47 (s, 3 H, minor CH₃), 2.41 (s, 3 H, major CH₃) ppm. ¹³C NMR (CDCl₃, 125 MHz): δ = 188.2, 145.0, 139.3, 134.4, 131.4, 129.0, 128.8, 128.5, 127.4, 105.9, 91.1, 85.4, 64.5, 59.3, 47.4, 44.4, 21.8, 21.3 ppm. LRMS (EI) 250 (12 %, M⁺, 2 × ³⁷Cl), 248 (67 %, M⁺, ³⁵Cl, ³⁷Cl), 246 (100 %, M⁺, 2 × ³⁵Cl), 229, 215, 194, 136. HRMS Found 246.02087, C₁₁H₁₂Cl₂O₂: calcd. 246.0209. IR (film): ν̃_max = 3360 (O–H), 3036 (C–H), 2973 (C–H), 2926 (C–H), 2910 (C–H), 1608 (C=O), 1510, 1482 (C=C), 1441, 1400 cm^–1.

3,3‐Dichloro‐5‐methyl‐2‐(p‐tolyl)tetrahydrofuran‐2‐ol (13d): 8 Isolated as a mixture of diastereomers (1:1.8); 463 mg, 89 %, pale yellow oil. ¹H NMR (CDCl₃, 600 MHz): δ = 7.67 (d, J = 8.1 Hz, 2 H, major ArH), 7.63 (d, J = 8.2 Hz, 2 H, minor ArH), 7.23–7.18 (m, 4 H, major ArH, minor ArH), 4.64–4.57 (m, 1 H, minor CH), 4.57–4.49 (m, 1 H, major CH), 3.29 (dd, J = 13.7, 9.2 Hz, 1 H, major 1 × CH₂), 3.16 (br. s, 1 H, major OH), 3.09 (br. s, 1 H, minor OH), 3.01 (dd, J = 13.0, 5.9 Hz, 1 H, minor 1 × CH₂), 2.88 (dd, J = 13.0, 9.5 Hz, 1 H, minor 1 × CH₂), 2.70 (dd, J = 13.7, 3.3 Hz, 1 H, major 1 × CH₂), 2.39 (s, 3 H, major ArCH ₃), 2.38 (s, 3 H, minor ArCH ₃), 1.49 (d, J = 6.4 Hz, 3 H, major CHCH ₃), 1.47 (d, J = 6.3 Hz, 3 H, minor CHCH ₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 139.4, 139.4, 134.9, 134.6, 128.5, 128.5, 127.3, 127.3, 106.5, 106.1, 91.8, 91.2, 74.0, 72.0, 51.8, 51.0, 22.7, 21.4, 21.4, 21.2 ppm. LRMS (CI) 264 (1 %, [M + H]⁺, 2 × ³⁷Cl), 262 (5 %, [M + H]⁺, ³⁵Cl, ³⁷Cl), 260 (6 %, [M + H]⁺, 2 × ³⁵Cl), 247 (14 %, [M – CH₃]⁺), 245 (65 %, [M – CH₃]⁺), 243 (100 %, [M – CH₃]⁺).

Preparation of 1,4 diols: NaBH₄ (23 mg, 0.60 mmol) was added to a stirred solution of lactol 12/13 (0.50 mmol) in MeOH (4 mL) at 0 °C. After 10 min, NH₄Cl (5 mL) was added and the organic phase extracted with EtOAc (2 × 5 mL). The organic layer was washed with brine (2 × 5 mL), dried (MgSO₄), filtered and concentrated in vacuo. The resultant residue was purified by column chromatography (30 % EtOAc in petrol) to give the diol.

2,2‐Dibromo‐1‐(p‐tolyl)butane‐1,4‐diol (14): 198 mg, quantitative, white solid, m.p. 105–107 °C. ¹H NMR (CDCl₃, 600 MHz): δ = 7.47 (d, J = 8.0 Hz, 2 H, ArH), 7.18 (d, J = 8.0 Hz, 2 H, ArH), 5.01 (d, J = 1.9 Hz, 1 H, CH), 4.11–4.00 (m, 2 H, CH ₂OH), 3.84 (d, J = 1.6 Hz, 1 H, CHOH), 2.76 (dt, J = 15.0, 6.4 Hz, 1 H, 1 × CH₂CBr₂), 2.63 (dt, J = 15.0, 5.7 Hz, 1 H, 1 × CH₂CBr₂), 3.04 (s, 3 H, CH₃), 2.26 (s, 1 H, CH₂ OH) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 138.9, 134.1, 129.1, 128.6, 82.3, 79.4, 61.7, 48.1, 21.4 ppm. LRMS (EI) 340 (42 %, M⁺, 2 × ⁸¹Br), 338 (84 %, M⁺, ⁷⁹Br, ⁸¹Br), 336 (41 %, M⁺, 2 × ⁸¹Br), 160 (100 %). HRMS Found 335.9352, C₁₁H₁₄Br₂O₂: calcd. 335.9355. IR (film): ν̃_max = 3338 (O–H), 2902 (C–H), 1515 (C=C) cm^–1.

2,2‐Dichloro‐1‐(p‐tolyl)butane‐1,4‐diol (15): 84 mg, 68 %, white solid, m.p. 92–93 °C. ¹H NMR (CDCl₃, 600 MHz): δ = 7.42 (d, J = 8.0 Hz, 2 H, ArH), 7.18 (d, J = 8.0 Hz, 2 H, ArH), 5.01 (s, 1 H, CH), 4.07–3.95 (m, 2 H, CH₂CCl₂), 2.61 (ddd, J = 15.0, 7.1, 5.6 Hz, 1 H, 1 × CH₂CBr₂), 2.54 (s, 1 H, CH₂ OH), 2.45 (dt, J = 15.0, 5.5 Hz, 1 H, 1 × CH₂CCl₂), 2.37 (s, 3 H, CH₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 138.8, 133.8, 128.9, 128.6, 95.5, 81.2, 59.4, 46.1, 21.4 ppm. LRMS (EI) 252 (1 %, [M]⁺, 2 × 37Cl), 250 (5 %, [M]⁺, ³⁵Cl, ³⁷Cl), 248 (7 %, [M]⁺, 2 × 35Cl), 167 (6 %), 149 (11 %), 121 (100 %). HRMS Found 248.0365, C₁₁H₁₄Cl₂O₂: calcd. 248.0365. IR (film): ν̃_max = 3220 (O–H), 2900 (C–H), 2849 (C–H) cm^–1.

Preparation of Dihalogenated Cyclic Ethers: Using flame dried glassware and under an argon atmosphere, BF₃ ·OEt₂ (213 mg, 1.50 mmol) was added to a solution of lactol 12 (0.50 mmol) and Et₃SiH (116 mg, 1.00 mmol) in CH₂Cl₂ (1 mL) at –78 °C. The reaction was stirred at –78 °C for 5 min and then warmed to room temperature over 30 min. Solvent was removed in vacuo and the resultant residue purified by column chromatography (10 % EtOAc in petrol).

3,3‐Dibromo‐2‐(p‐tolyl)tetrahydrofuran (16): 158 mg, quantitative, colourless oil. ¹H NMR (CDCl₃, 600 MHz): δ = 7.49 (d, J = 8.1 Hz, 2 H, ArH), 7.21 (d, J = 8.1 Hz, 2 H, ArH), 5.02 (s, 1 H, ArCH), 4.29 (td, J = 8.5, 7.4 Hz, 1 H, 1 × CH₂O), 4.16–4.07 (m, 1 H, 1 × CH₂O), 3.23–3.16 (m, 2 H, CH₂CBr₂), 2.39 (s, 3 H, CH₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 138.8, 133.2, 128.6, 127.5, 90.7, 66.8, 65.7, 50.2, 21.5 ppm. LRMS (APCI+) 323 (34 %, [M + H]⁺, 2 × ⁸¹Br), 321 (42 %, [M + H]⁺, ⁷⁹Br, ⁸¹Br), 319 (30 %, [M + H]⁺, 2 × ⁷⁹Br), 305 (34 %, [M + H – H₂O]⁺, 2 × ⁸¹Br), 303 (61 %, [M + H – H₂O]⁺, ⁷⁹Br, ⁸¹Br), 301 (34 %, [M + H – H₂O]⁺, 2 × ⁷⁹Br), 241 (100 %, [M + H – Br]⁺, ⁸¹Br), 239 (96 %, [M + H – Br]⁺, ⁷⁹Br). HRMS Found 300.9225, C₁₁H₁₁Br₂ ([M + H – H₂O]⁺): calcd. 300.9228. IR (film): ν̃_max = 2953 (C–H), 2892 (C–H) cm^–1.

3,3‐Dichloro‐2‐(p‐tolyl)tetrahydrofuran (17): 118 mg, quantitative, colourless oil. ¹H NMR (CDCl₃, 600 MHz): δ = 7.45 (d, J = 8.0 Hz, 2 H, ArH), 7.24 (d, J = 8.0 Hz, 2 H, ArH), 5.10 (s, 1 H, CH), 4.30 (td, J = 8.6, 7.2 Hz, 1 H, 1 × CH₂O), 4.21 (td, J = 8.6, 3.7 Hz, 1 H, 1 × CH₂O), 3.02 (ddd, J = 13.5, 7.2, 3.7 Hz, 1 H, 1 × CH₂CCl₂), 2.96 (dt, J = 13.5, 8.9 Hz, 1 H, 1 × CH₂CCl₂) 2.41 (s, 3 H, CH₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 138.7, 132.1, 128.7, 127.5, 89.7, 89.7, 65.5, 47.7, 21.5 ppm. LRMS (EI) 234 (11 %, [M]⁺, 2 × ³⁷Cl), 232 (58 %, [M]⁺, ³⁵Cl,³⁷Cl), 230 (100 %, [M]⁺, 2 × ³⁵Cl), 215 (34 %), 217 (24 %), 194 (44 %). HRMS Found 230.02585, C₁₁H₁₂Cl₂O: calcd. 230.02597. IR (film): ν̃_max = 2953 (C–H), 2894 (C–H) cm^–1.

2,2‐Dichloro‐4‐methyl‐1‐phenylpentane‐1,3‐diol (18a): Ketone 7n (131 mg, 0.5 mmol) was added to a stirring solution of NMe₄HB(OAc)₃ (8 equiv.) under argon atmosphere in MeCN (0.75 mL) and glacial AcOH (0.75 mL) at –40 °C. After 1 h, the reaction mixture was washed with saturated NaHCO₃ solution (10 mL) and extracted with CH₂Cl₂ (10 mL × 3). The combined organic phases were dried with MgSO₄ and concentrated under reduced pressure which afforded the anti diol as a yellow oil (112.6 mg, 85 %). ¹H NMR (CDCl₃, 400 MHz): δ = 7.56–7.55 (m, 2 H, ArH), 7.39–7.37 (m, 3 H, ArH), 5.29 [s, 1 H, PhCHC(Cl)₂], 4.10 (d, J = 5.3 Hz, 1 H, OH), 3.48 (s, 1 H, OH), 2.79 [d, J = 8.0 Hz, 1 H, CHCH(CH₃)₂], 2.46 [heptd, J = 7.0, 2.8 Hz, 1 H, CH(CH₃)₂], 1.14 [d, J = 3.0 Hz, 3 H, CH(CH ₃)₂], 1.12 [d, J = 3.0 Hz, 3 H, CH(CH ₃)₂] ppm. ¹³C NMR (CDCl₃, 176 MHz): δ = 137.3, 129.3, 128.8, 127.7, 97.2, 80.0, 79.1, 29.8, 23.1, 16.8 ppm. LRMS (ES+) 262.1 (90 %, [M – H]⁺), 263.1 (55 %, [M]⁺). HRMS Found 285.0421, C₁₂H₁₆Cl₂O₂Na: calcd. 285.0420 ([M + Na]⁺). IR (film): ν̃_max = 3405.17 (O–H), 2961.23 (C–H), 2928.81 (C–H), 2871.73 (C–H), 1452.12, 1049.77, 698.36 cm^–1.

2,2‐Dichloro‐1,3‐diphenylpropane‐1,3‐diol (18b): Prepared according to the same procedure as 18a. Purified via column chromatography (30 % EtOAc in Petrol) which afforded diol 18b as a White solid (53 mg, 53 %, m.p. 94–96 °C). ¹H NMR (600 MHz, CDCl₃): δ = 7.57 (br. m, 4 H, ArH), 7.40–7.39 (m, 6 H, ArH), 5.34 (d, J = 4.5 Hz, 2 H, CHOH), 3.48 (d, J = 4.7 Hz, 2 H, OH) ppm. ¹³C NMR (151 MHz, CDCl₃): δ = 137.1, 129.2, 129.1, 127.9, 79.5 ppm. LRMS (NSI) 319 (100 %, [M + Na]⁺, 2 × ³⁵Cl), 321 (60 %, [M + Na]⁺, ³⁵Cl, ³⁷Cl), 323 (10 %, [M + Na]⁺, 2 × ³⁷Cl). HRMS Found 319.0263: calcd. 319.0266 ([M + Na]⁺). IR (film): ν̃_max = 3388 (O–H), 3060 (C–H), 2920 (C–H), 1452, 1026, 907, 698, 670 cm^–1.

anti‐2,2‐Dibromo‐4‐methyl‐1‐phenylpentane‐1,3‐diol (19): Prepared according to the same procedure as 18a: purified via column chromatography (20–70 % EtOAc/Petrol) which afforded 19 as white crystals (31 mg, 0.09 mmol, 29 %); m.p. 79–82 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.63–7.59 (m, 2 H, ArH), 7.39–7.36 (m, 3 H, ArH), 5.19 [d, J = 4.8 Hz, 1 H, PhCHC(Br)₂], 4.03 [dd, J = 7.9, 2.2 Hz, 1 H, CH(OH)CH], 3.61 (d, J = 5.0 Hz, 1 H, OH), 2.86 (d, J = 7.9 Hz, 1 H, OH), 2.54 [heptd, J = 6.9, 2.2 Hz, 1 H, CH(CH₃)₂], 1.15 [d, J = 6.8 Hz, CH(CH ₃)₂], 1.13 [d, J = 7.0 Hz, 3 H, CH(CH ₃)₂] ppm. ¹³C NMR (151 MHz, CDCl₃): δ = 138.0 (C), 129.6 (CH), 128.9 (CH), 127.6 (CH), 85.0 (C), 81.3 (CH), 80.1 (CH), 31.2 (CH), 23.8 (CH₃), 16.9 (CH₃) ppm. LRMS (ES+) 373 (51 %, [M + Na]⁺, 2 × ⁷⁹Br), 375 (100 %, [M + Na]⁺, ⁷⁹Br, ⁸¹Br), 377 (45 %, [M + Na]⁺, 2 × ⁸¹Br). HRMS (ES+) Found 372.9417, C₁₂H₁₆Br₂O₂Na: calcd. 372.9409 ([M + Na]⁺). IR (film): ν̃_max = 3389 (O–H), 2961 (C–H), 2869 (C–H), 1083 (C–O), 733 (C–Br) cm^–1.

(±)‐(1S,3R)‐2,2‐Dibromo‐1‐(p‐tolyl)hexane‐1,3‐diol (20) and 2‐Bromo‐1‐(p‐tolyl)hexane‐1,3‐diol (21): Method A: Using flame dried glassware and under an argon atmosphere, 6g (36 mg, 0.10 mmol) was dissolved in THF (1 mL) and cooled to –78 °C. ZnCl₂‐TMEDA (25 mg, 0.10 mmol) was added, followed by DIBAL‐H (1 m in hexanes, 300 µL, 0.300 mmol). The reaction was stirred at –78 °C for 1 h. The reaction mixture was poured into a mixture of HCl (6 m, 2 mL) and sat. NH₄Cl (2 mL). The organic layer was extracted with Et₂O (3 × 1 mL) and the combined organic layers were dried (Na₂SO₄), filtered and concentrated in vacuo. The resultant residue was purified by column chromatography (10 % EtOAc in petrol).

Method B: Using flame dried glassware and under an argon atmosphere, 6g (36 mg, 0.10 mmol) was dissolved in THF (1 mL) and cooled to –78 °C. DIBAL‐H (1 m in hexanes, 300 µL, 0.300 mmol) was added. The reaction was stirred at –78 °C for 1 h. The reaction mixture was poured into a mixture of HCl (6 m, 2 mL) and sat. NH₄Cl (2 mL). The organic layer was extracted with Et₂O (3 × 1 mL) and the combined organic layers were dried (Na₂SO₄), filtered and concentrated in vacuo. The resultant residue was purified by column chromatography (10 % EtOAc in petrol).

2‐Bromo‐1‐(p‐tolyl)hexane‐1,3‐diol (21): Method A: 7 mg, 24 µmol, 24 %; Method B: 5 mg, 17 µmol, 17 %. ¹H NMR (CDCl₃, 600 MHz): δ = 7.29 (d, J = 8.1 Hz, 2 H, ArH), 7.19 (d, J = 8.1 Hz, 2 H, ArH), 5.01 (d, J = 6.2 Hz, 1 H, ArCH), 4.22 (dd, J = 6.2, 1.7 Hz, 1 H, CHBr), 3.48 (br. t, J = 6.2 Hz, 1 H, CHCH₂), 3.07 (br. s, 1 H, OH), 2.07 (br. s, 1 H, OH), 2.63 (s, 3 H, ArCH ₃), 1.68–1.55 (m, 1 H, 1 × CHCH ₂), 1.55–1.44 (m, 1 H, 1 × CHCH ₂), 1.44–1.23 (m, 2 H, CH ₂CH₃), 0.88 (t, J = 7.4 Hz, 3 H, CH₂ CH ₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 138.3, 137.2, 129.4, 126.5, 76.3, 72.3, 70.6, 39.0, 21.3, 18.7, 14.0 ppm. LRMS (CI) 306 (96 %, [M + NH₄]⁺, ⁸¹Br), 304 (100 %, [M + NH₄]⁺, ⁷⁹Br), 288 (25 %, M⁺, ⁸¹Br), 286 (28 %, M⁺, ⁷⁹Br). HRMS Found 286.0563, C₁₃H₁₉BrO₂: calcd. 286.0563. IR (film): ν̃_max = 3351 (O–H), 2962 (C–H), 2923 (C–H), 1511, 1461 cm^–1.

2,2‐Dibromo‐1‐(p‐tolyl)hexane‐1,3‐diol (20): Using flame dried glassware and under an argon atmosphere, catecholborane (1 m in THF, 10 mL, 10 mmol) was added to a stirring solution of 6g (182 mg, 0.5 mmol) in THF (35 mL) at –10 °C. The reaction was stirred at –10 °C for 6 h. MeOH (10 mL), saturated sodium potassium tartrate (10 mL) and pinacol (750 mg, 6.36 mmol) were added and the reaction was stirred for 18 h at room temperature. The reaction mixture was diluted with EtOAc (30 mL) and washed with NaOH (0.5 m) until the aqueous layer was colourless. The organic layer was washed with brine (2 × 50 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. The resultant residue was purified by column chromatography (20 % EtOAc in petrol) to give 20 as a colourless oil (117 mg, 64 %). ¹H NMR (CDCl₃, 600 MHz): δ = 7.52 (d, J = 8.1 Hz, 2 H, ArH), 7.18 (d, J = 8.1 Hz, 2 H, ArH), 5.21 (s, 1 H, ArCH), 3.42 (br. t, J = 8.0 Hz, 1 H, CHCH₂), 3.31 (br. s, 1 H, OH), 2.36 (s, 3 H, ArCH ₃), 2.23–2.14 (br. d, J = 7.5 Hz, 1 H, OH), 2.19 (m, 1 H, 1 × CHCH ₂), 1.68 (dtd, J = 14.3, 9.7, 4.8 Hz, 1 H, 1 × CHCH ₂), 1.64–1.53 (m, 1 H, 1 × CH ₂CH₃), 1.41–1.33 (m, 1 H, 1 × CH ₂CH₃), 0.93 (t, J = 7.4 Hz, 3 H, CH₂ CH ₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 138.8, 134.6, 128.8, 128.7, 90.8, 80.0, 77.7, 37.3, 21.4, 19.2, 14.0 ppm. LRMS (NSI) 386 (50 %, [M + NH₄]⁺, 2 × ⁸¹Br), 384 (100 %, [M + NH₄]⁺, ⁷⁹Br, ⁸¹Br), 382 (52 %, [M + NH₄]⁺, 2 × ⁷⁹Br) 227 (41 %). HRMS Found 382.0016, [C₁₃H₁₈Br₂O₂ + NH₄]⁺: calcd. 382.0012. IR (film): ν̃_max = 3274 (O–H), 2959 (C–H), 2928 (C–H), 1516 (C=C), 1453 cm^–1.

(±)‐(4R,6S)‐5,5‐Dibromo‐2,2‐dimethyl‐4‐propyl‐6‐(p‐tolyl)‐1,3‐dioxane (23) and (±)‐(4R,6S)‐5‐Bromo‐2,2‐dimethyl‐4‐propyl‐6‐(p‐tolyl)‐1,3‐dioxane (23b): Using flame dried glassware and under an argon atmosphere, 20 (7 mg, 19 µmol) was dissolved in THF (1 mL). p‐Toluenesulfonic acid (4 mg, 21 µmol) was added, followed by 2,2‐dimethoxypropane (20 mg, 19 µmol). The reaction was refluxed for 18 h. The reaction mixture was diluted with sat. sodium hydrogen carbonate (1 mL) and extracted with Et₂O (2 × 1 mL). The combined organic layers were dried (Na₂SO₄), filtered and concentrated in vacuo. The resultant residue was purified by column chromatography (2 % EtOAc in petrol) to give 23 and 23b as a colourless film in a 1:1.3 ratio (4 mg). ¹H NMR (CDCl₃, 600 MHz): δ = 7.53 (d, J = 8.2 Hz, 2 H, 23 ArH), 7.32 (d, J = 8.1 Hz, 2 H, 23b ArH), 7.20–7.15 (m, 4 H, 23 ArH, 23b ArH), 4.94 (s, 1 H, 23 ArCH), 4.82 (d, J = 10.3 Hz, 1 H, 23b ArCH), 4.03 (ddd, J = 10.4, 8.4, 2.3 Hz, 1 H, 23b CHCH₂), 3.89 (dd, J = 9.3, 1.7 Hz, 1 H, 23 CHCH₂), 3.69 (t, J = 10.4 Hz, 1 H, 23b CHBr), 2.37 (s, 3 H, 23 ArCH ₃), 2.35 (s, 3 H, 23b ArCH ₃), 2.11–2.01 (m, 1 H, 23 1 × CHCH ₂), 1.95 (ddd, J = 9.9, 5.8, 5.0, 2.1 Hz, 1 H, 23b 1 × CHCH ₂), 1.78 (dtd, J = 14.1, 9.4, 4.8 Hz, 1 H, 23 1 × CHCH ₂), 1.61 [s, 3 H, 23b 1 × C(CH₃)₂], 1.57 [s, 3 H, 23 1 × C(CH₃)₂], 1.56 [s, 3 H, 23 1 × C(CH₃)₂], 1.55–1.49 (m, 1 H,B 1 × CHCH ₂), 1.46 [s, 3 H, 23b 1 × C(CH₃)₂], 1.45–1.36 (m, 2 H, 23 CH ₂CH₃), 0.99 (t, J = 7.4 Hz, 3 H, 23 CH₂ CH ₃), 0.95 (t, 3 H, 23b CH₂ CH ₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 138.8, 138.6, 136.1 (23b), 132.9 (23), 129.7 (23), 129.1 (23), 128.0 (23b), 127.9 (23b), 100.6 (23), 99.8 (23b), 81.0 (23) 79.4 (23), 77.9 (23), 74.0 (23b), 55.0 (23b), 35.5 (23b), 34.7 (23), 29.9, 29.6, 21.4, 21.4, 19.7, 19.4, 19.1, 18.1, 13.9, 13.9 ppm. LRMS (CI) 426 (49 %, [MA + NH₄]⁺, 2 × ⁸¹Br), 424 (100 %, [MA + NH₄]⁺, ⁷⁹Br, ⁸¹Br), 422 (51 %, [MA + NH₄]⁺, 2 × ⁸¹Br), 368 (23 %), 366 (48 %), 364 (48 %), 346 (11 %, [MB + NH₄]⁺, ⁸¹Br), 344 (11 %, [MB + NH₄]⁺, ⁷⁹Br), 312 (87 %, [MB – CH₃]⁺, ⁸¹Br), 310 (85 %, [MB – CH₃]⁺, ⁷⁹Br), 296 (47 %), 294 (50 %), 279 (54 %), 277 (54 %). HRMS Found 422.0325, [C₁₆H₂₃Br₂O₂ + NH₄]⁺: calcd. 422.0325. IR (film): ν̃_max = 2955 (C–H), 2919 (C–H), 2868 (C–H), 2850 (C–H), 1513, 1455 cm^–1.

An nOe was observed between the methine protons on the six‐membered ring in acetal 23, confirming the syn stereochemistry of the diol.

2,2‐Dichloro‐4‐methyl‐1‐phenylpentane‐1,3‐diol (24): In flame dried glassware and under an argon atmosphere, catecholborane (1 m in THF, 8 mL, 8 mmol) was added to a stirring solution of 7a (261 mg, 1 mmol) in THF (26 mL) at –10 °C. The reaction was stirred at –10 °C for 2 h 30 min. MeOH (8 mL), saturated sodium potassium tartrate (8 mL) and pinacol (568 mg) were added and the reaction was stirred for 20 h at room temp. The reaction mixture was diluted with EtOAc (30 mL) and washed with NaOH (1 m) until the aqueous phase was colourless. The organic phase was washed with brine (3 × 30 mL), dried (MgSO₄), filtered and concentrated in vacuo. The residue was purified by column chromatography (50 % EtOAc in petrol) to give a mixture of diastereomers anti/syn 1:10 as a yellow oil (91 mg, 90 %). ¹H NMR (CDCl₃, 400 MHz): δ = 7.60–7.57 (m, 2 H, ArH), 7.39–7.35 (m, 3 H, ArH), 5.27 [d, J = 3.7 Hz, 1 H, ArCHC(Cl)₂], 3.64 (dd, J = 9.9, 2.5 Hz, 1 H, CHCH), 3.34 (d, J = 3.9 Hz, 1 H, OH), 2.46 [heptd, J = 6.9, 2.6 Hz, 1 H, CH(CH₃)₂], 2.32 (d, J = 10.0 Hz, 1 H, OH), 1.09 [d, J = 6.9 Hz, 3 H, CH(CH ₃)₂], 1.01 [d, J = 7.0 Hz, 3 H, CH(CH ₃)₂] ppm. ¹³C NMR (CDCl₃,176 MHz): δ = 137.1, 129.0, 128.9, 128.0, 100.1, 80.43, 80.37, 30.0, 22.9, 16.4 ppm. LRMS (ES–) 264.0 (30 %, [M + H]⁺), 263. HRMS Found 280.0866, C₁₂H₁₆Cl₂O₂NH₄: calcd. 280.0868 ([M + NH₄]⁺). IR (film): ν̃_max = 3401 (O–H), 2961 (C–H), 2928 (C–H), 2872 (C–H), 1492, 699 cm^–1.

Preparation of 3,3‐Dihalo‐2‐methoxy‐tetrahydrofurans: A solution of acetyl chloride in MeOH (1 m, 2 mL mmol^–1, 2 equiv.) was added to lactol 12/13 (1 equiv.) in MeOH (0.5 mL mmol^–1) and the reaction stirred for 18 h. The reaction mixture was concentrated in vacuo and the product used without further purification.

3,3‐Dibromo‐2‐methoxy‐2‐(p‐tolyl)tetrahydrofuran (25a): 540 mg, 77 %, white solid, m.p. 106–107 °C. ¹H NMR (CDCl₃, 400 MHz): δ = 7.63 (d, J = 8.0 Hz, 2 H, ArH), 7.21 (d, J = 8.0 Hz, ArH), 4.29 (ddd, J = 9.0, 8.3, 7.0 Hz, 1 H, 1 × OCH₂), 4.03 (ddd, J = 10.1, 8.3, 2.0 Hz, 1 H, 2 H, 1 × OCH₂), 3.44 (dt, J = 13.3, 9.5 Hz, 1 H, 1 × CH₂CBr₂) 3.12 (s, 3 H, OCH₃), 3.07 (ddd, J = 13.3, 7.0, 2.0 Hz, 1 H, 1 × CH₂CBr₂), 2.39 (s, 3 H, ArCH ₃) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 139.1, 131.8, 128.4, 127.4, 105.9, 68.3, 64.8, 51.4, 47.2, 21.4 ppm. LRMS (CI) 352 (5 %, [M]⁺, 2 × ⁸¹Br), 350 (11 %, [M]⁺, ⁷⁹Br, ⁸¹Br), 348 (4 %, [M]⁺, 2 × ⁷⁹Br), 321 (50 %, [M – OCH₃]⁺, 2 × ⁸¹Br), 319 (100 %, [M – OCH₃]⁺, ⁷⁹Br, ⁸¹Br), 317 (48 %, [M – OCH₃]⁺, 2 × ⁷⁹Br). HRMS Found 347.9356, C₁₂H₁₄Br₂O₂: calcd. 347.9355. IR (film): ν̃_max = 2958 (C–H), 2932 (C–H) cm^–1.

3,3‐Dichloro‐2‐methoxy‐2‐(p‐tolyl)tetrahydrofuran (25b): 372 mg, quantitative, white solid, m.p. 96–97 °C. ¹H NMR (CDCl₃, 600 MHz): δ = 7.56 (d, J = 8.2 Hz, 2 H, ArH), 7.21 (d, J = 8.2 Hz, 2 H, ArH), 4.26 (ddd, J = 9.0, 8.4, 7.4 Hz, 1 H, 1 × OCH₂), 4.12 (ddd, J = 9.6, 8.4, 2.2 Hz, 1 H, 1 × OCH₂), 3.24–3.16 (m, 1 H, 1 × CH₂CCl₂), 3.13 (s, 3 H, OCH₃), 2.90 (ddd, J = 13.0, 7.3, 2.2 Hz, 1 H, 1 × CH₂CCl₂), 2.39 (s, 3 H, ArCH ₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 139.1, 131.0, 128.6, 128.3, 108.9, 91.4, 64.3, 50.9, 44.6, 21.4 ppm. LRMS (CI) 264 (1 %, [M]⁺, 2 × ³⁷Cl), 262 (8 %, [M]⁺, ³⁷Cl, ³⁵Cl), 260 (13 %, [M]⁺, 2 × ³⁵Cl), 233 (13 %, [M – OCH₃]⁺, 2 × ³⁷Cl), 231 (67 %, [M – OCH₃]⁺, ³⁵Cl, ³⁷Cl) 229 (100 %, [M – OCH₃]⁺, 2 × ³⁵Cl). HRMS Found 260.0366, C₁₂H₁₄Cl₂O₂: calcd. 260.0365. IR (film): ν̃_max = 2966 (C–H), 2936 (C–H), 2349, 1509, 1436 cm^–1.

3,3‐Dibromo‐2‐methoxy‐5‐methyl‐2‐(p‐tolyl)tetrahydrofuran (25c): Isolated as a mixture of diastereomers (1:2.7); 207 mg, quantitative, pale pink gum. ¹H NMR (CDCl₃, 600 MHz): δ = 7.70–7.56 (m, 4 H, major ArH, minor ArH), 7.25–7.18 (m, 4 H, major ArH, minor ArH), 4.72–4.62 (m, 1 H, major CH), 4.46–4.36 (m, 1 H, minor CH), 3.61 (dd, J = 13.9, 9.4 Hz, 1 H, minor 1 × CH₂), 3.17–3.12 (m, 7 H, major OCH₃, minor OCH₃, major 1 × CH₂); 3.09 (dd, J = 13.2, 9.2 Hz, 1 H, major 1 × CH₂), 2.97 (dd, J = 14.0, 3.2 Hz, 1 H, minor 1 × CH₂), 2.40 (s, 3 H, minor ArCH ₃), 2.40 (s, 3 H, major ArCH ₃), 1.56 (d, J = 6.4 Hz, 3 H, minor CHCH ₃), 1.45 (d, J = 6.3 Hz, 3 H, major CHCH ₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 139.1, 139.0, 136.0, 132.6, 131.9, 128.4, 128.4, 127.4, 109.3, 109.1, 74.5, 72.2, 69.3, 67.5, 54.4, 53.8, 51.4, 51.1, 21.9, 21.5, 21.5, 21.2 ppm. LRMS (APCI+) 335 (48 %, [M – OCH₃]⁺, 2 × ⁸¹Br), 333 (100 %, [M – OCH₃]⁺, ⁷⁹Br, ⁸¹Br), 331 (49 %, [M – OCH₃]⁺, 2 × ⁷⁹Br), 179 (12 %). HRMS Found 330.9326, C₁₂H₁₃OBr₂: calcd. 330.9333. IR (film): ν̃_max = 2974 (C–H), 2927 (C–H), 1649 (C=C), 1606, 1512 cm^–1.

Preparation of 3‐Halofurans: DBU (10 equiv.) was added to mixed acetal 24 (1 equiv.) in THF (2 mL mmol^–1) and the mixture heated at reflux until the reaction was complete by TLC. Acetyl chloride in MeOH (1 m) was added to acidify the mixture which was then concentrated in vacuo. The residue was purified by column chromatography (petrol) to give the 3‐halofuran.

3‐Bromo‐2‐(p‐tolyl)furan (26a): 101 mg, 77 %, colourless oil. ¹H NMR (CDCl₃, 600 MHz): δ = 7.85 (d, J = 8.0 Hz, 2 H, ArH), 7.40 (d, 1.4, 1 H, OCH), 7.25 (d, J = 8.0 Hz, 2 H, ArH), 6.52 (d, J = 1.4 Hz, 1 H, CBrCH), 2.38 (s, 3 H, CH₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 149.3, 141.5, 138.1, 129.3, 127.1, 125.6, 116.2, 95.4, 21.5 ppm. LRMS (EI) 238 (100 %, [M]⁺, ⁸¹Br), 236 (98 %, [M]⁺, ⁷⁹Br), 209 (26 %), 207 (24 %), 157 (16 %, [M – Br]⁺), 129 (100 %). IR (film): ν̃_max = 3026 (C–H), 2920 (C–H), 1565, 1519, 1490 cm^–1.

3‐Chloro‐2‐(p‐tolyl)furan (26b): 53 mg, 44 %, colourless oil. ¹H NMR (CDCl₃, 600 MHz): δ = 7.81 (d, J = 8.3 Hz, 2 H, ArH), 7.38 (d, J = 2.0 Hz, 1 H, OCH), 7.24 (d, J = 8.3 Hz, 2 H, ArH), 6.47 (d, J = 2.0 Hz, 1 H, CHCCl), 2.39 (s, 3 H, CH₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 147.7, 140.8, 137.9, 129.4, 126.9, 125.1, 114.1, 110.9, 21.5 ppm. LRMS (APCI+) 194 (34 %, [M]⁺, ³⁷Cl), 192 (100 %, [M]⁺, ³⁵Cl), 179 (87 %), 161 (47 %). HRMS Found: 192.0346, C₁₁H₉ClO: calcd. 192.0342. IR (film): ν̃_max = 3035 (C–H), 2920 (C–H), 1519, 1490 cm^–1.

3‐Bromo‐5‐methyl‐2‐(p‐tolyl)furan (26c): 42 mg, 76 %, orange oil. ¹H NMR (CDCl₃, 600 MHz): δ = 7.82 (d, J = 8.3 Hz, 2 H, ArH), 7.22 (d, J = 8.3 Hz, 2 H, ArH), 6.12 (q, J = 0.9 Hz, 1 H, CH), 3.27 (s, 3 H, ArCH ₃), 2.35 (d, J = 0.9 Hz, 3 H, OCCH₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 151.4, 147.5, 137.5, 129.2, 127.4, 125.2, 112.2, 95.8, 21.5, 13.8 ppm. LRMS (EI) 252 (98 %, [M]⁺, ⁸¹Br), 250 (100 %, [M]⁺, ⁷⁹Br), 209 (22 %), 207 (24 %), 143 (21 %), 128 (36 %). HRMS Found 249.9989, C11H12BrO: calcd. 249.9988. IR (film): ν̃_max = 3022 (C–H), 2915 (C–H), 1599, 1553, 1497 cm^–1.

(±)‐(3aS,4S,7S,7aR)‐5‐Bromo‐2,7‐dimethyl‐4‐(p‐tolyl)‐3a,4,7,7a‐tetrahydro‐1H‐4,7‐epoxyisoindole‐1,3(2H)‐dione (endo‐27): N‐Methylmaleimide (63 mg, 0.57 mmol) was added to a stirring solution of 26c (24 mg, 0.096 mmol) in dimethylcarbonate (1 mL). The reaction was stirred for 3 d at room temp. The reaction mixture was concentrated in vacuo and purified by column chromatography (10 % EtOAc in petrol) to give endo‐27 as a pale orange solid (29 mg, 84 %, m.p. 114–116 °C). ¹H NMR (CDCl₃, 600 MHz): δ = 7.72 (d, J = 8.2 Hz, 2 H, ArH), 7.27 (d, J = 8.2 Hz, 2 H, ArH), 6.42 (s, 1 H, C=CH), 3.84 (d, J = 7.5 Hz, 1 H, CH₃CCH), 3.38 (d, J = 7.5 Hz, 1 H, ArCCH), 2.93 (s, 3 H, NCH₃), 2.40 (s, 2 H, ArCH ₃), 1.88 (s, 3 H, CCH₃) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 174.7, 173.5, 139.1, 136.4, 134.3, 131.8, 129.2, 127.7, 93.8, 88.5, 54.7, 52.6, 25.0, 21.4, 19.0 ppm. LRMS (APCI+) 364 (7 %, [M + H]⁺, ⁸¹Br), 362 (8 %, [M + H]⁺, ⁷⁹Br), 282 (22 %, [M – Br]⁺), 269 (98 %, [M – C₇H₇]⁺, ⁸¹Br), 267 (100 %, [M – C₇H₇]⁺, ⁷⁹Br), 187 (23 %), 172 (43 %). HRMS Found 362.0384, C₁₇H₁₇BrNO₃: calcd. 362.0392. IR (film): ν̃_max = 2918 (C–H), 2851 (C–H), 1689 (C=O), 1584, 1431 cm^–1.

(±)‐(3aS,4S,7S,7aR)‐5‐Chloro‐2‐methyl‐4‐(p‐tolyl)‐3a,4,7,7a‐tetrahydro‐1H‐4,7‐epoxyisoindole‐1,3(2H)‐dione (endo‐28) and (±)‐(3aR,4S,7S,7aS)‐5‐Chloro‐2‐methyl‐4‐(p‐tolyl)‐3a,4,7,7a‐tetrahydro‐1H‐4,7‐epoxyisoindole‐1,3(2H)‐dione (exo‐28): N‐Methylmaleimide (40 mg, 0.36 mmol) was added to a solution of 26b (14 mg, 0.075 mmol) in [D₄]MeOD (0.6 mL) and the reaction mixture placed in an NMR tube. After 7 d the reaction was complete by NMR and the reaction mixture was concentrated in vacuo and purified by column chromatography (10 % EtOAc in petrol) to give endo‐28 (5.8 mg, 25 %). Further elution gave exo‐28 (6.6 mg, 29 %).

endo‐28: 5.8 mg, 25 %, white solid, m.p. 106–109 °C. ¹H NMR ([D₄]MeOD, 600 MHz): δ = 7.70 (d, J = 8.2 Hz, 2 H, ArH), 7.26 (d, J = 8.2 Hz, 2 H, ArH), 6.46 (d, J = 2.0 Hz, 1 H, C=CH), 5.37 (dd, J = 5.5, 2.0 Hz, 1 H, OCH), 3.91 (dd, J = 7.5, 5.5 Hz, 1 H, OCHCH), 3.79 (d, J = 7.5 Hz, 1 H, ArCCH), 2.87 (s, 3 H, NCH₃), 2.38 (s, 3 H, ArCH ₃) ppm. ¹³C NMR ([D₄]MeOD, 150 MHz): δ = 176.4, 175.3, 142.0, 140.1, 132.7, 130.2, 129.9, 128.9, 94.5, 79.7, 51.6, 51.2, 24.9, 21.3 ppm. LRMS (CI) 323 (40 %, [M + NH₄]⁺, ³⁷Cl), 321 (100 %, [M + NH₄]⁺, ³⁵Cl), 193 (17 %). HRMS Found 321.1001, C₁₆H₁₈ClN₂O₃ ⁺ ([M + NH₄]⁺): calcd. 321.1000. IR (film): ν̃_max = 2922 (C–H), 1772, 1689 (C=O), 1589, 1519 cm^–1.

exo‐28: 6.6 mg, 29 %, white solid, m.p. 143–144 °C. ¹H NMR ([D₄]MeOD, 600 MHz): δ = 7.42 (d, J = 8.2 Hz, 2 H, ArH), 7.21 (d, J = 8.2 Hz, 2 H, ArH), 6.57 (d, J = 2.1 Hz, 1 H, C=CH), 5.31 (d, J = 2.1 Hz, 1 H, OCH), 3.53 (d, J = 6.4 Hz, 1 H, OCHCH), 3.37 (d, J = 6.4 Hz, 1 H, ArCCH), 2.79 (s, 3 H, NCH₃), 2.36 (s, 3 H, ArCH ₃) ppm. ¹³C NMR ([D₄]MeOD, 150 MHz): δ = 177.5, 175.2, 144.7, 139.5, 132.0, 130.0, 129.3, 128.3, 95.0, 81.7, 53.6, 50.0, 24.9, 21.3 ppm. LRMS (CI) 323 (40 %, [M + NH₄]⁺, ³⁷Cl), 321 (100 %, [M + NH₄]⁺, ³⁵Cl), 193 (18 %). HRMS Found 321.1001, C₁₆H₁₈ClN₂O₃: calcd. 321.1000. IR (film): ν̃_max = 2920 (C–H), 1764, 1687 (C=O), 1591, 1519 cm^–1.

Preparation of Halogenated Cyclobutanols: Dibromoisocyanuric acid (0.6 equiv.) was added to a stirring solution of propargylic alcohol 1q or 1r (1.0 equiv.) in MeCN/H₂O (7:3, 8.5 mL mmol^–1). The solution was stirred for 1 h. Saturated Na₂S₂O₃ was added and the mixture extracted with EtOAc. The organic layers were dried (MgSO₄), filtered and concentrated in vacuo. The resultant residue was purified by column chromatography (10 % EtOAc in petrol) to give the cyclobutane products.

(E)‐2‐[1‐Bromo‐2‐hydroxy‐2‐(p‐tolyl)ethylidene]cyclobutan‐1‐ol (29a): Isolated as a mixture of diastereomers (1:1.6); 168 mg, 24 %, pale yellow oil. ¹H NMR (CDCl₃, 600 MHz): δ = 7.35 (d, 8.1, 2 H, minor ArH), 7.33 (d, J = 8.1 Hz, 2 H, major ArH), 7.19 (d, J = 8.1 Hz, 4 H, minor ArH, major ArH), 5.54 (br. d, J = 3.6 Hz, 1 H, major ArCH), 5.52 (br. s, 1 H, minor ArCH), 4.97–4.89 (m, 2 H, major CH₂ CH, minor CH₂ CH), 3.58 (br. d, J = 5.7 Hz, 1 H, OH), 3.50 (br. d, J = 3.6 Hz, 1 H, OH), 3.48 (br. s, 1 H, OH), 3.28 (br. s, 1 H, OH), 2.63–2.48 (m, 2 H, major 1 × C=CCH₂, minor 1 × C=CCH₂), 2.42–2.29 (m, 4 H, major 2 × CHCH ₂, minor 2 × CHCH ₂), 2.36 (s, 6 H, major CH₃, minor CH₃) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 144.7 (major), 144.7 (minor), 138.3, 138.2, 138.0, 137.9, 129.4, 127.0 (major), 126.9 (minor), 121.7 (minor), 120.5 (major), 76.3, 75.9, 70.9, 70.5, 27.5, 27.2, 25.8, 25.3, 21.4 ppm. LRMS (CI) 284 (96 %, [M]⁺, ⁸¹Br), 282 (100 %, [M]⁺, ⁷⁹Br), 267 (17 %, [M – OH]⁺, ⁸¹Br), 265 (18 %, [M – OH]⁺, ⁷⁹Br), 185 (19 %). HRMS Found 282.02508, C₁₃H₁₅BrO₂: calcd. 282.02499. IR (film): ν̃_max = 3313 (O–H), 2977 (C–H), 2945 (C–H), 2917 (C–H), 1683, 1510, 1418 cm^–1; Relative geometry assigned by analogy to 29b below.

(E)‐2‐[1‐Bromo‐2‐hydroxy‐2‐(p‐tolyl)ethylidene]cyclobutan‐1‐ol (29b): Isolated as a mixture of diastereomers: (1:1.1); 68 mg, 39 %, pale yellow oil. ¹H NMR (CDCl₃, 600 MHz): δ = 7.51–7.50 (m, 2 H, major ArH), 7.50–7.48 (m, 2 H, minor ArH), 7.36 (d, J = 8.2 Hz, 2 H, minor ArH), 7.31 (d, J = 8.2 Hz, 2 H, major ArH), 5.57 (s, 1 H, minor ArCH), 5.56 (s, 1 H, major ArCH), 4.98–4.90 (m, 2 H, major CH₂ CH, minor CH₂ CH), 2.61–2.49 (m, 2 H, major 1 × C=CCH₂, minor 1 × C=CCH₂), 2.42–2.30 (m, 4 H, major 1 × C=CCH₂, major 1 × CHCH ₂, minor 1 × C=CCH ₂, minor 1 × CHCH ₂), 2.05–1.94 (m, 2 H, major 1 × CHCH ₂, minor 1 × CHCH ₂) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 145.4 (minor), 145.3 (major), 140.0 (minor), 139.9 (major), 131.8 (major), 131.7 (minor), 128.8 (major), 128.7 (minor), 122.3 (major), 122.3 (minor), 121.6 (minor), 120.2 (major), 75.1 (major), 75.1 (minor), 70.9 (major), 70.6 (minor), 27.7 (major), 27.6 (minor), 25.7 (minor), 25.2 (major) ppm. LRMS (NSI) 373 (51 %, [M + Na]⁺, 2 × ⁸¹Br), 371 (100 %, [M + Na]⁺, ⁸¹Br, ⁷⁹Br), 369 (49 %, [M + Na]⁺, 2 × ⁷⁹Br), HRMS Found 370.9076. C₁₂H₁₂Br₂O₂Na requires 370.9076. IR (film): ν̃_max = 3313 (O–H), 2947 (C–H), 1691, 1591 cm^–1. Relative geometry assigned based on NOESY spectra with key correlations indicated (See supporting information, Figure S1).

Supporting information

Supporting Information