Practical and regioselective halonitrooxylation of olefins to access β-halonitrates

Alkenes, as one of the most abundant and inexpensive chemicals, offer the advantages of wide availability and low cost for organic synthesis¹. For instance, ethylene, a key hydrocarbon, is exceptionally affordable with an annual production exceeding 200 million metric tons². Consequently, the direct difunctionalization of alkenes, which allows for the incorporation of two functional groups into the double bond in a single step, represents an immensely powerful strategy for accessing complex molecules, as evidenced by numerous elegant studies^3,4,5. A central challenge in these transformations is controlling the regioselectivity of olefin addition, which is further complicated by unactivated alkyl-substituted C=C bonds that exhibit poor regioselectivity due to their limited electronic and steric bias. To address this, several primary strategies have been employed to promote regioselective difunctionalizations of aliphatic olefins (Fig. 1a): (1) auxiliary control^6,7,8, using directing groups to coordinate and stabilize the metal center in the presumed organometallic species; (2) reagent control^9,10,11, using specific reagents that dictate the regioselectivity of the reaction; (3) complex catalytic systems^{12,13,14,15,16,17}, employing complex catalysts and/or complex reaction conditions. Therefore, the development of simple and efficient strategies to achieve difunctionalization of alkyl alkenes with high regioselectivity represents a challenging and appealing research goal. Furthermore, although various functional groups such as halogens^18,19,20, hydroxyl²¹, OAc^22,23, azido^24,25, amino²⁶, trifluoromethyl²⁷, cyano²⁸, alkyl²⁹, aryl^30,31, alkynyl^32,33, carboxyl^34,35, etc., have been successfully introduced into double bonds through the difunctionalization of alkenes (Fig. 1a), there is still a significant demand for the introduction of other useful and attractive motifs into alkenes to access their corresponding derivatives.

a Challenges of alkene difunctionalizations. b Previous strategy: anti-Markovnikov hydronitrooxylation of α-olefins via photocatalysis c This work: regioselective halonitrooxylation of olefins. HAT hydrogen atom transfer, TMS trimethylsilyl.

Full size image

Organic nitrates, which serve as potent donors of the signaling molecule nitric oxide (NO), find wide application in pharmaceuticals and bio-active molecules^36,37,38, as exemplified by well-known drugs such as glycerol trinitrate and isosorbide mononitrate. Moreover, hybrid drugs formed by combining the nitrooxy group with drug molecules can exhibit synergistic effects or significantly reduce the side effects of drugs while enhancing their efficacy^39,40,41,42. Despite their importance, there are limited efficient methods for the synthesis of organic nitrates, particularly for the nitrooxylation of alkenes. Previous methods have often relied on metallic or toxic reagents such as mercury nitrate⁴³, chlorine nitrate⁴⁴, thionyl nitrate⁴⁵, pyridinium bromide nitrate⁴⁶, ceric ammonium nitrate^47,48, silver nitrate⁴⁹, or copper nitrate⁵⁰ as the nitrooxy source, resulting in harsh reaction conditions or a limited substrate scope. Recently, Tobias and co-workers achieved the hydronitrooxylation of α-alkenes with aqueous nitric acid via visible-light catalysis to produce the corresponding organic nitrates with moderate to high regioselectivities⁵¹ (Fig. 1b). This elegant work represents a significant advancement in the development of synthetic methods for organic nitrates.

On the other hand, halogens are fundamental elements in pharmaceutical and chemical industries^52,53. For example, over 250 chlorine-containing drugs were approved by the FDA and available on the market in 2019⁵⁴, and halogens (such as chlorine, bromine, and iodine) play a crucial role in numerous important chemical transformations⁵⁵. Given their significance and broad utility, developing an efficient and practical method for simultaneously introducing the nitrooxy group and halogen into alkenes using readily available nitrooxylating reagents to achieve regioselective olefin halonitrooxylation remains highly attractive.

As part of our continuing research in hypervalent iodine chemistry^{56,57,58,59,60}, we have recently introduced a class of highly active noncyclic hypervalent iodine nitrooxylating reagents (1), which were easily prepared from aryliodine diacetates and aqueous nitric acid⁵⁶. Additionally, we discovered that the trimethylsilyl (TMS) group can efficiently convert reagents 1 into the corresponding active intermediates⁵⁶. Motivated by these discoveries, herein we report an efficient and regioselective halonitrooxylation of alkenes using the combination of reagent 1 and TMSX (X = Cl, Br, and I) (Fig. 1c). This protocol exhibits remarkable reactivity, high regioselectivity, and broad substrate generality. Styrene derivatives as substrates exhibit complete regioselectivity under catalyst-free conditions, while the halonitrooxylation of alkyl alkenes in the presence of a catalytic amount of FeCl₃ yield the corresponding products with high regioselectivities. Notably, this method is easily scalable to gram quantities and is suitable for late-stage modification of drug molecules.

Optimization of reaction conditions

We began the investigation by choosing dodec-1-ene as the model substrate. Initially, dodec-1-ene reacted with nitrooxylating reagent 1a/TMSCl directly at 0 °C in dichloromethane, getting the excepted product 2 in 82% yield with poor regioselectivity (3.8:1 rr) (Table 1, entry 1). Subsequently, a series of metal salts were evaluated as catalysts (see the details in SI), and it was found that FeCl₃ could enhance the regioselectivity (>20:1 rr) but decreased the yield to 42% (Table 1, entry 2). Lowering the reaction temperature to −40 °C increased the yield of product 2 to 76% with 16:1 rr (Table 1, entry 3). Due to the high reactivity of reagent 1a, we hypothesized that increasing the stability of the reagents 1 might improve the reaction yield by appropriately reducing the reaction rate. Previous studies indicated that incorporating electron-withdrawing groups into the phenyl group of 1 could enhance the stability of reagents 1⁵⁶. Therefore, we synthesized a series of reagents 1 with electron-withdrawing groups and found that the substituent and its position significantly affected the yield and selectivity of the reaction (Table 1, entries 3–17). Using the 4-CF₃-substituted reagent (1d) as the nitrooxy source improved the yield of product 2 to 83% with >20:1 rr (Table 1, entry 6). Surprisingly, when the catalyst loading was reduced to 0.5 mol %, the target product 2 was still obtained in 82% yield with >20:1 rr (Table 1, entry 18).

Substrate scope

Having established the optimal conditions for chloronitrooxylation, we proceeded to evaluate the scope of unactivated alkenes. Mono-, di-, tri-, and tetra-substituted unactivated alkenes all underwent the chloronitrooxylation reaction smoothly (Fig. 2a). Simple alkyl alkenes (1-dodecene, 1-tridecene, 1-hexene) afforded the corresponding chloronitrooxylation products (2–4) with good yields (74–82%) and excellent regioselectivity (>20:1 rr). The allylbenzene and butenylbenzene also got the corresponding products (5–6) in 64–98% yields with excellent regioselectivity (≥20:1 rr). Substrates bearing numerous substituents such as Br, Cl, OAc, and aldehyde groups were tolerated under the reaction conditions, affording the products (7–13) in 53–99% yields with high regioselectivities (17:1 rr to >20:1 rr). A series of alkenes containing substituted phenyl esters (with F, Ph, CF₃, Ac, Ms(mesyl), NO₂, Br, I, ^tBu, or Me group) obtained the desired products (14–24) with regioselectivity ranging from 13:1 to >20:1. Substrates bearing heterocycles such as thiophene and phthalimide achieved the corresponding products (25–26) in 57–64% yield with 15:1–17:1 regioselectivity. 1,1-Di-, tri-, and tetra-substituted alkenes were compatible, yielding the corresponding products (27–31) with excellent regioselectivities. Deca-1,9-diene reacted with double equivalent amounts of 1d/TMSCl to yield the desired product 32 in 62% yield with high regioselectivity. Additionally, the reaction of cyclic alkenes (cyclopentene, cyclohexene, norbornene) in the absence of FeCl₃ proceeded stereoselectively, affording the respective trans-adducts (33–35) in 55–78% yields. Interestingly, bromonitrooxylation or iodonitrooxylation of alkenes also proceeded effectively using TMSBr or TMSI instead of TMSCl, yielding several representative products (36–44) with comparable yields and relatively lower regioselectivities (for 36–39). Surprisingly, ethylene and 1-butene smoothly underwent halonitrooxylation to get the corresponding vicinal halo-nitrates (45–50) in 63–97% yields.

Reaction conditions: Condition A: substrate (alkene) (0.20 mmol), 1d (0.6 equiv), TMSX (1.2 equiv), FeCl₃ (0.5 mol %), CH₂Cl₂ (2 mL), −40 °C, 2 h; Condition B: substrate (alkene) (0.20 mmol), 1a (0.6 equiv), TMSX (1.2 equiv), CH₂Cl₂ (2 mL), 0 °C, 2–5 min. Yields were for isolated and purified products. Regioisomeric ratios were determined by ¹H NMR spectra of the crude reaction mixtures. ^aSee Supplementary Figs. 1–4 for details. Ac acetyl; Ms methanesulfonyl, ^tBu tert-butyl, Boc tert-butyloxy carbonyl, Bn benzyl, Fmoc fluorenylmethyloxy carbonyl.

Full size image

After investigating the reactions of various alkyl alkenes, we then explored the substrate scope of activated alkenes (Fig. 2b). Aromatic alkenes reacted smoothly with nitrooxylating reagent 1a and TMSCl at 0 °C without any catalyst, affording the desired products with complete regioselectivities. The reactions performed well with a series of styrenes, regardless of electronic nature (e.g. Me, ^tBu, OAc for electron-rich groups; halogens, NO₂, CF₃, CO₂Me, CN for electron-deficient groups; CH₂Cl, Ph for electron-neutral groups) in the para position, affording the corresponding products (51–64) in 62–89% yields. Styrenes bearing substituents in the ortho and meta position were also compatible with the protocol to provide the desired products (65–68) in comparable yields (67–78%). Styrenes containing multiple substituents in the phenyl group reacted well to yield products 69–73 in 50–83% yields, and 2-vinyl naphthalene was converted to the corresponding product 74 in 71% yield. Hetero-aromatic alkenes such as 3-vinylbenzofuran and 2-vinylpyridine were also tolerant of the reaction conditions to get product 75 in 21% yield and product 76 in 26% yield, respectively. 1,1-Disubstituted aromatic alkenes were efficient substrates, furnishing products 77–80 in 39–94% yields. Although acyclic 1,2-disubstituted substrates only yielded products 81–83 with poor diastereoselectivity, cyclic substrates produced trans-adducts (84–87) with excellent regio- and diastereo-selectivity. Moreover, trisubstituted and tetrasubstituted alkenes gave the corresponding products 88–90 in 37–79% yields. In addition, m-divinylbenzene and p-divinylbenzene underwent double reactions by doubling the amount of reagents, affording products 91 and 92 with high regioselectivities and poor diastereoselective ratios, respectively. Fortunately, 1, 3-enynes as the substrates were converted into the corresponding products 93 and 94 in moderate yields. Furthermore, using TMSBr and TMSI instead of TMSCl, the corresponding difunctionalization of styrenes was also conducted well. Several representative substrates underwent the reaction to yield the expected bromonitrooxylation products 95–100 and iodonitrooxylation products 101–105, respectively. The structures of products were further confirmed by single-crystal X-ray structure analysis of 61 and 84.

To highlight the versatility of our protocols, we investigated their applicability to a variety of complex substrates (Fig. 2c). Initially, we synthesized a range of alkenes by introducing styrenyl or aliphatic alkenyl units onto pharmaceuticals or bioactive molecules via a common and efficient condensation reaction (see SI). Encouragingly, these substrates, bearing diverse scaffolds such as pharmaceutical ingredients, sugars, purine nucleosides, amino acids, and peptides, were well-tolerated in the chloronitrooxylation process, yielding the desired products 106–126 in 45–93% yields with at least 13:1 rr. Notably, the bromonitrooxylation and iodonitrooxylation of complex substrates proceeded smoothly, yielding the corresponding products 127 and 128, respectively.

Synthetic utilities

Moreover, the methods can be easily scaled up to gram scale (Fig. 3a). Several reactions were chosen to test the effectiveness, yielding the vicinal chloronitrate 2 (1.65 g, 78% yield, >20:1 rr), 106 (1.72 g, 87% yield), and vicinal bromonitrate 100 (2.45 g, 81% yield). Additionally, 2-iodoethyl nitrates (41, 47) were obtained in 0.97 g (94% yield) and 10.34 g (95% yield), respectively. Compound 106 can be further transformed into a series of derivatives, including vicinal chloroalcohol 129 (83% yield), vicinal chloroether 130 (75% yield), vicinal chlorothiocyanate 121 (90% yield), vicinal chloroazide 132 (33% yield), and vinylazide 133 (83% yield), through smooth reactions (Fig. 3b).

a Scale-up reaction of chloro-, bromo-, and iodo-nitrooxylation. b Synthetic applications of 106. c Synthetic applications of 47. ^aScale-up reaction was carried out based on Condition A depicted in Fig. 2. ^bScale-up reaction was carried out based on Condition B depicted in Fig. 2. THF tetrahydrofuran, DMSO dimethyl sulfoxide, rt room temperature, DMF N,N-dimethylformamide, Cbz benzyloxycarbonyl.

Full size image

Surprisingly, 2-iodoethyl nitrate (47) serves as a powerful synthetic precursor for introducing a nitrooxy group into molecules⁶¹. Various compounds bearing nitrooxy groups 134–147 were easily prepared via nucleophilic substitution of diverse pharmaceuticals/functional groups with 2-iodoethyl nitrate using K₂CO₃ as a base (Fig. 3c). Significantly, nicorandil (143)⁶², a medication used to treat and reduce chest pain caused by angina, was synthesized from nicotinamide in 33% yield⁶³.

Mechanistic studies

To gain a preliminary understanding of the reaction mechanism, several control experiments were conducted. Adding a radical inhibitor such as 1, 4-benzoquinone (BQ) or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to the model reaction using dodec-1-ene or 4-bromostyrene as the substrate resulted in the corresponding product 2 or 56 in comparative yields, respectively (Fig. 4a). Notably, the inhibition of the reaction by TEMPO is likely due to its induction of the decomposition of reagent 1, thereby preventing the reaction (Fig. 4a). In addition, a series of competitive experiments using para-substituted styrenes were performed (Fig. 4b). The Hammett plot (log(k_R/k_H) versus σ) displayed a linear correlation with a ρ value of −2.34 (R² = 0.99)^64,65. The good linearity, along with the results of the radical inhibition experiments mentioned above, implies that the reaction proceeds through an electrophilic route.

a Radical inhibition experiments. b The Hammett equation: y = −2.3421x + 0.1526 (R² = 0.9853). BQ 1,4-benzoquinone, DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, TEMPO 2,2,6,6-tetramethylpiperidoxyl, N.P. no product.

Full size image

We conducted density functional theory (DFT) calculations (The DFT calculation data are provided in the Source Data) to understand the reaction pathway. The computational visualizations, illustrated in Fig. 5a, demonstrate that the formation of the iodonium ion intermediate is less energetically favorable when it arises from the cleavage of the Cl-I bond (Int2’-51 and Int2’-4) compared to the NO₃-I bond breaking (Int2-51 and Int2-4) by 11.83 kcal/mol for styrene (51-S) and by 7.76 kcal/mol for 1-hexene (4-S), suggesting the improbability of the iodonium forming through chlorine displacement. Subsequent reaction steps indicated that the nitrate ion is capable of a direct attack on the iodonium intermediate. With 1-hexene, this leads to computed transition state energy barriers of 13.58 kcal/mol for the primary carbon (TS1’-4) and 7.06 kcal/mol for the secondary carbon (TS1-4). For styrene, the barriers are estimated at 16.27 kcal/mol for the primary carbon (TS1’-51) and 8.57 kcal/mol for the benzyl carbon (TS1-51). Clearly, Markovnikov selectivity is more evident with styrene, partly due to the larger differential in energy between the Markovnikov and anti-Markovnikov processes. Moreover, the low energy barriers for the reactions with 1-hexene signify that they proceed speedily at room temperature, which reduces kinetic selectivity.

All energy units are kcal/mol. a Without FeCl₃ as catalyst. b Using FeCl₃ as catalyst. c Proposed mechanism.

Full size image

The addition of FeCl₃ has shown fascinating effects, as depicted in Fig. 5b. The calculations suggest that FeCl₃ has a stronger binding affinity to the nitrate ion (Int4) by approximately 5 kcal/mol compared to chloride (Int4’), enhancing the stabilization of the resulting iodonium ion. This stabilization leads to a decrease in energy for the iodonium intermediates of styrene (Int5-51) and 1-hexene (Int5-4) by 1.02 kcal/mol and 4.08 kcal/mol respectively. This implies that due to the nitrate being stabilized by FeCl₃, the energy barriers for the subsequent nitrate addition ring-opening reactions increase. For 1-hexene, the barriers for the Markovnikov (TS2-4) and anti-Markovnikov (TS2’-4) ring openings are 14.78 and 24.47 kcal/mol, respectively. For styrene, these barriers sit at 16.98 and 23.45 kcal/mol (TS2-51 and TS2’-51, respectively). It is evident that the substantial energy barriers for the anti-Markovnikov process sufficiently retard the reactions at room temperature, significantly enhancing selectivity.

A plausible reaction mechanism was proposed based on the experimental results and previous related reports^56,66,67 (Fig. 5c). Initially, 1a reacts with TMSCl to form active species PhI(ONO₂)Cl (Int1) and TMSOTMS. FeCl₃ coordinates with the nitrate ion⁶⁸ in Int1 to form Int4. Species Int4 then reacts with alkyl alkene to generate Int5, which subsequently converts to Int6 via a Markovnikov ring opening. Finally, Int6 undergoes reductive elimination to yield the desired product, along with the release of FeCl₃ and the generation of iodobenzene as a byproduct.

In summary, we have demonstrated a highly regioselective and practical halonitrooxylation strategy for a wide range of olefins. This protocol offers high efficiency, mild conditions, simple operation, and good compatibility with various functional groups. Especially, the product of ethylene iodonitrooxylation, 2-iodoethyl nitrate, can be combined with a range of natural products and drugs to obtain corresponding nitrooxylated functional molecules. The gram-scale preparation and late-stage modification of bioactive molecules show the potential utility of the method. Further investigations into expanding the method are currently underway in our laboratory.

General procedure A for the synthesis of β-halonitrates

To a test tube was charged with FeCl₃ (0.001 mmol, 0.5 mol %), olefin (0.20 mmol, 1.0 equiv) and dichloromethane (2 mL), and the mixture was cooled to −40 °C. Then 1d (0.12 mmol, 0.6 equiv) and TMSX (X = Cl, Br, or I; 0.24 mmol, 1.2 equiv) were added and stirred at −40 °C for 2 h. After the reaction was complete, the crude product was purified by column chromatography (petroleum ether /ethyl acetate = 500/1 – 5/1, v/v) via silica gel to afford the desired product.

General procedure B for the synthesis of β-halonitrates

To a test tube was charged with 1a (0.12 mmol, 0.6 equiv) and dichloromethane (2 mL), and the mixture was cooled to 0 °C. Then olefin (0.20 mmol, 1.0 equiv) and TMSX (X = Cl, Br, or I; 0.24 mmol, 1.2 equiv) were added and stirred at 0 °C for 1–5 min. After the reaction was complete, the crude product was purified by column chromatography (petroleum ether/ethyl acetate = 500/1 – 5/1, v/v) via silica gel to afford the desired product.

General procedure for the synthesis of 134–147

In a test tube, the corresponding substrate (0.2 mmol) was placed and DMF (1 mL) was added. Then, K₂CO₃ (2.4 mmol, 1.2 equiv) and 2-iodoethyl nitrate (2.4 mmol, 1.2 equiv) were added and stirred. Upon completion of the reaction, 10 mL of EtOAc were added, followed by 10 mL of H₂O. The reaction mixture was then extracted and washed three times with H₂O (10 mL). The organic layer was washed with brine (20 mL) and was dried with MgSO₄. The filtrate was removed under reduced pressure. The crude mixture was purified by flash column chromatography (petroleum ether /ethyl acetate = 50/1 – 1/1, v/v) to yield the substrates.