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Synlett 2025; 36(11): 1530-1534
DOI: 10.1055/a-2569-9147
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Easily Accessible Halohydrin Esters as Advantageous Hydroxyethylation Reagents

Yuan-Ding Wan
,
Zhi Li 

Financial support for this work was generously provided by the ShanghaiTech University start-up funding.
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Abstract

Halohydrin esters are potentially versatile synthetic reagents, but their conventional synthesis commonly involves hazardous ethylene oxide. An economic, mild, safe, and scalable one-step halohydrin esters synthesis was achieved from easily accessible NaX, concentrated sulfuric acid, and polyol esters. The halohydrin ester products were applied in hydroxyethylation reactions with various nucleophiles in place of highly hazardous and toxic ethylene oxide. Repetition of the protocol allowed unsymmetric difunctionalization of diol esters. The mechanism likely involves an acyloxonium intermediate and proceeds through neighboring group participation.


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Key words

halohydrin esters - hydroxyethylation - sodium bromide - ethylene oxide - acyloxonium.
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Scheme 1 Applications and synthetic strategies of hydroxyethylation

The hydroxyethyl motif is prevalent in many pharmaceutical intermediates, fine chemicals, and natural products (Scheme [1a]).[1] It is commonly introduced to various nucleophiles using electrophilic hydroxyethylation reagents such as ethylene oxide (EO),[2] which is, unfortunately, a highly hazardous and toxic reagent (Scheme [1b]).[3] In addition, EO frequently undergoes oligomerization side reactions due to its high reactivity.[4] Alternatively, bromohydrin and chlorohydrin are also effective hydroxyethylation reagents,[5] [6] [7] [8] [9] [10] but their production both requires hazardous EO, and oligomerization is still a potential problem. Therefore, alternative green hydroxyethylation reagents that can replace EO and halohydrins will be of industrial and environmental significance. Recently, glycolaldehyde,[3] polyols including carbohydrates,[11,12] and ethylene carbonate (EC)[13] have emerged as green hydroxyethylation reagents (Scheme [1b]). We envisioned that polyol esters, in particular esters of ethylene glycol (EG) derived from renewable resources,[14] [15] [16] could be safe and sustainable feedstocks for chemical reactions. Our group developed catalytic reactions of polyol esters as acyloxyethylation reagents for sulfonamides,[17] pyridines,[18] and phenols[19] (Scheme [1c]). The products were hydrolyzed to furnish N- or O-hydroxyethylation products. However, the harsh conditions limited the application of this strategy to a broader scope of substrates. On the other hand, we noted that halohydrin esters have occasionally been used in hydroxyethylation reactions, which would not suffer from oligomerization as occurs with EO or halohydrins.[20] [21] [22] [23]

Table 1 Reaction Conditions Optimizationa

Entry

Deviation from standard conditions

Yield (%)

 1

none

99

 2

0.05 equiv Hf(OTf)4 instead of H2SO4

22

 3

0.1 equiv Hf(OTf)4 instead of H2SO4

36

 4

0.2 equiv Hf(OTf)4 instead of H2SO4

54

 5

0.6 equiv Hf(OTf)4 instead of H2SO4

90

 6

0.1 equiv H2SO4 instead of 1.0 equiv

27

 7

0.2 equiv H2SO4 instead of 1.0 equiv

50

 8

0.6 equiv H2SO4 instead of 1.0 equiv

81

 9

120 °C in PhCl instead of 40 °C (3 h)

99

10

80 °C in PhCl instead of 40 °C (5 h)

99

11

PhCl instead of n-hexane

99

12

DCM instead of n-hexane

75

13

dioxane instead of n-hexane

86

14

THF instead of n-hexane

50

15

neat

90

a Standard conditions: 1a (1 mmol, 1.0 equiv) and NaBr (1 mmol, 1.0 equiv) were added to n-hexane (1 mL), then concentrated sulfuric acid was added and the mixture was stirred at 40 °C for 12 h unless otherwise noted. Yields were determined by 1H NMR analysis of the crude reaction mixtures using 1,1,2,2-tetrachloroethane as the internal standard.

The potential of halohydrin esters as general hydroxyethylation reagents prompted us to establish a direct halogenation route from polyol esters, especially EG esters, to halohydrin esters. Herein, we report an efficient, economic and mild ester halogenation process that can be used to convert polyol esters into halohydrin esters with only 1 equivalent of sodium halide salts and concentrated sulfuric acid each (Scheme [1d]).[24] [25] [26] [27] Synthetic applications of halohydrin esters as hydroxyethylation reagents are also demonstrated.

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Scheme 2 Scope of polyol esters. Standard conditions: Ester 1–3 (10 mmol, 1.0 equiv) and NaY (10 mmol, 1.0 equiv) were added to n-hexane (10 mL), then conc. H2SO4 (1.0 equiv) was added and the mixture was stirred at 40 °C for 12 h, unless otherwise noted. Yields were determined by 1H NMR analysis of the crude reaction mixture using 1,1,2,2-tetrachloroethane as the internal standard. a In PhCl. b NaBr (2 equiv) and conc. H2SO4 (2 equiv). c NaBr (5 equiv) and conc. H2SO4 (5 equiv), in PhCl for 24 h.

The conversion of ethylene glycol diacetate (EGDA) into bromoethyl acetate was the most appealing to us. With 1.0 equivalent of NaBr and 1.0 equivalent of H2SO4 in n-hexane at temperatures as mild as 40 °C, the desired bromohydrin ester 4a-Br was obtained in 99% yield after 12 h reaction time (Table [1], entry 1). Notably, no double bromination product was observed, although there were two identical ester groups in EGDA. The reaction was indeed discovered when Lewis acid Hf(OTf)4 was used as catalyst (Tables S1–S2). Nevertheless, since the product yield seemed to correlate with and was improved by increasing the amount of Hf(OTf)4 (entries 3–5), it was then found to be promoted by stoichiometric Brønsted acid instead of catalytic Lewis acid. Concentrated sulfuric acid was then chosen as the acid due to its high reactivity, low volatility, low content of water, and ready availability. It appeared that 1 equivalent of sulfuric acid was the optimum amount to accomplish the reaction (entries 6–8, and Table S3). Increasing the reaction temperature to 80 °C and 120 °C maintained the high yield and reduced the reaction time (entries 9 and 10, and Table S3). Non-polar solvents were generally preferable to polar solvents (entries 11–14, and Table S4). Under neat conditions, the yield still reached 90% (entry 15).

With the optimized conditions in hand, the scope of polyol esters was investigated (Scheme [2]). The chain length of the glycol is quite influential. The yield of the products gradually decreased for longer 1,n-diol esters (Scheme [2, 4] (a–d)-Br). Diacetates of diols with alkyl or alkenyl substituents conveniently provided the desired products 4(e–i)-Br in high yields. No secondary brominated byproducts were observed for 4(e–g)-Br, indicating excellent regioselectivity favoring primary esters. When both ester groups were attached to secondary carbons, the diastereomer generated by inverting one ester group was the favored product (anti- and syn-4h-Br).[28] Various carboxylates of EG allowed good yields of the corresponding bromohydrin esters under the standard conditions, except bromoethyl pivalate (4m-Br), which gave only 21% yield (4(j–m)-Br). For the less reactive substrates, increasing the reaction temperature allowed higher reactivity (4(m–o)-Br). In contrast to 4h-Br, meso- and dl-cyclohexane-1,2-diyl diacetate (1r) both converged to the same trans-4r-Br product in high stereoselectivity, while the reactivity of dl-1r was much lower than that of meso-1r. Besides polyol esters, imide esters (5(a–c)-Br) and ketone esters (6a-Br) also afforded the corresponding products in good yields. Compound 2a, which is the substrate for 5a-Br, was prepared by catalytic EGDA sulfonamidation with saccharin.[17] Compound 2b, which is the substrate for 5b-Br, was prepared by substitution of the bromide in 4a-Br with potassium phthalimide. For triacylglycerides, the disubstituted products such as 4p-Br were predominately obtained in 99% yield (4p-Br). Pentaerythritol tetraacetate also performed well in the reaction, with three out of the four esters converted into bromide as the product 4q-Br in 80% yield when excess NaBr and H2SO4 were applied. Attempts to obtain mono- or dibromo products only resulted in mixtures of products (Table S5). However, sugar alcohol esters such as erythritol and xylitol acetates were poor substrates even under various temperatures. Finally, the corresponding chloro- and iodohydrin products 4a-Cl and 4a-Iwere obtained using NaCl and NaI as the halogen sources, respectively, albeit in slightly compromised yields.

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Scheme 3 Transformations of halohydrin esters (isolated yields). See the Supporting Information for detailed conditions of each reaction.

The obtained halohydrin esters were suitable hydroxyethylation reagents for further functionalization reactions. A series of transformations were achieved in excellent yields on N-, O-, and S-based nucleophiles (Scheme [3a]). Notably, the reaction between 4a-Br and potassium phthalimide afforded the corresponding product 2b, which itself could undergo another bromination to the difunctionalization platform chemical 5b-Br (Scheme [2]). When 5b-Br was subjected to reactions with various nucleophiles, unsymmetric iterative disubstitution of EDGA to a variety of derivatives was accomplished (Scheme [3a]). Dibromo derivative 4p-Br from triacetin also underwent similar transformations (Scheme [3b]). Secondary halohydrin esters reacted with O- and S-based nucleophiles to allow the construction of C–S and C–O bonds (Scheme [3c]). At a higher temperature, the stereochemistry scrambled in product 7n, which was a much less selective mixture than the starting material. At room temperature, the substitution underwent inversion of stereochemistry (7o). Finally, reacting the bromohydrin esters with a series of sodium carboxylate salts afforded unsymmetric mixed-carboxylates of polyols (Scheme [3a]; 7a and 1s), which could undergo further selective bromination to remove the remaining acetate preferentially (Scheme [3d]). In this way, higher yields of 4m-Br and 4n-Br were achieved than from homo-carboxylates (Scheme [2]).

Based on previous studies on the reactivity of EGDA, the reaction mechanism likely involves a cyclic acyloxonium intermediate that is generated through a neighboring group participation effect.[17] Indeed, the reactions of monoesters under otherwise identical standard conditions were quite poor (Scheme [4a]), suggesting that the neighboring ester group is essential for promoting the reactivity of polyol esters. The decreasing yields observed for diol esters with increasing distance between the esters (Scheme [2, 4] (a–d)-Br) suggested the stability of the cyclic acyloxonium intermediate could be a significant factor determining the progress of the reaction even for the 1,5- and 1,6-diol diesters.[24] Subsequently, a five-membered ring cyclic acyloxonium intermediate was synthesized,[29] [30] which reacted smoothly with NaBr/H2SO4 to give 4a-Br (Scheme [4b]). From these results, we propose the following reaction mechanism: first, NaBr reacts with concentrated sulfuric acid to generate HBr in situ. Activated by HBr, EGDA is protonated and undergoes neighboring group-assisted elimination of carboxylate to give the cyclic acyloxonium intermediate. This is followed by attack of the bromide anion on the acyloxonium to generate the final product (Scheme [4c]). On the other hand, when a secondary ester leaving group is involved, the mechanism seems to be different based on stereoselectivity observations. The meso-1h and dl-1h both favor inversion substitution (Figure S1), which seems more likely to be the result of a direct substitution instead of cyclic acyloxonium intermediate (Scheme [4c], (2)). After activation by HBr, the major product is generated by direct attack of the bromide, leading to the departure of AcOH and stereochemistry inversion. A minor portion might follow the cyclic acyloxonium intermediate pathway to provide the stereoretentive minor products. For cyclic substrate 1r, the cis-isomer might undergo convenient direct substitution to the trans-product by bromide, similar to the open-chain cases. For the trans-isomer, since both ester groups are in the equatorial position in its most stable conformation, the lower reactivity leads to a reduced amount of stereoretention product. The results indicate that the stereochemistry did not allow direct substitution, but rather a cyclic acyloxonium pathway was initiated from the unfavorable diaxial conformation (Scheme [4c], (3)).

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Scheme 4 Mechanistic studies. Yields were determined by 1H NMR analysis of the crude reaction mixtures using 1,1,2,2-tetrachloroethane as the internal standard.

In conclusion, halohydrin esters were demonstrated to be effective alternatives to hazardous hydroxyethylation reagents such as EO and halohydrins. They could be easily obtained using NaX salt as the halide source and conc. H2SO4 as the agonist to generate HX, and polyol esters, many of which could be obtained from renewables, as the feedstock. The reaction conditions are mild and cost-effective. The use of halohydrin esters for hydroxyethylation is also chemically advantageous because, unlike EO or halohydrins, they do not overreact. By halogenation of the remaining ester group of the hydroxyethylated products with the same halogenation protocol, iterative unsymmetric di-substitution of diol esters was achieved.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors acknowledge support from the Analytical Instrumentation Center (Grant No. SPST-AIC10112914), SPST, ShanghaiTech University, for compound characterization.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2569-9147.
  • Supporting Information

Corresponding Author

Zhi Li
School of Physical Science and Technology, ShanghaiTech University
Shanghai 201210
P. R. of China   

Publication History

Received: 24 January 2025

Accepted after revision: 31 March 2025

Accepted Manuscript online:
31 March 2025

Article published online:
12 May 2025

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Zoom Image
Scheme 1 Applications and synthetic strategies of hydroxyethylation
Zoom Image
Scheme 2 Scope of polyol esters. Standard conditions: Ester 1–3 (10 mmol, 1.0 equiv) and NaY (10 mmol, 1.0 equiv) were added to n-hexane (10 mL), then conc. H2SO4 (1.0 equiv) was added and the mixture was stirred at 40 °C for 12 h, unless otherwise noted. Yields were determined by 1H NMR analysis of the crude reaction mixture using 1,1,2,2-tetrachloroethane as the internal standard. a In PhCl. b NaBr (2 equiv) and conc. H2SO4 (2 equiv). c NaBr (5 equiv) and conc. H2SO4 (5 equiv), in PhCl for 24 h.
Zoom Image
Scheme 3 Transformations of halohydrin esters (isolated yields). See the Supporting Information for detailed conditions of each reaction.
Zoom Image
Scheme 4 Mechanistic studies. Yields were determined by 1H NMR analysis of the crude reaction mixtures using 1,1,2,2-tetrachloroethane as the internal standard.