Introduction

Organic azides are a class of important compounds that have been used as precursors for nitrenes and in the synthesis of amines, and more popularly in the copper-catalyzed azide-alkyne cycloadditions (known as click chemistry)1,2,3,4,5,6,7,8,9,10. Alkyl azides are typically prepared by nucleophilic substitution (SN2) with an azide ion (N3−), and the diazo-transfer reaction to primary amines using triflyl azide (CF3SO2N3) or fluorosulfuryl azide (FSO2N3) has emerged as a powerful method for the preparation of alkyl azides from primary amines1,11. On the other hand, given the ready availability of structurally diverse alcohols, direct conversion of alcohols to alkyl azides via deoxyazidation would be an attractive synthetic strategy, which avoids the use of genotoxic alkyl halides and sulfonates in azidation reactions12. Unfortunately, the alcoholic hydroxyl group is a poor leaving group, so its direct displacement by azide ion is generally difficult. Previously, Mitsunobu conditions have been investigated by using different azide ion sources such as HN3, TMSN3, (PhO)2P(O)N3, Zn(N3)2•2Py, or n-Bu4NN3, but the Mitsunobu conditions are not amenable to the most readily available and cost-effective azide source—NaN3 (Fig. 1, Eq 1)13,14,15,16,17,18,19,20,21,22,23,24,25,26. Indeed, the currently known NaN3-based deoxyazidation methods are sparse (Fig. 1, Eq 2). Both NaN3/BF3•Et2O27 and NaN3/triphosgene28 systems are only applicable to allylic and benzylic alcohols, and other NaN3-based methods (using NaN3/TsIm29, (2,4-Cl2C6H3O)2P(O)Cl/NaN330, or halocarbon/Ph3P/NaN331,32,33,34) suffer from the high reaction temperatures and/or narrow substrate scope. Therefore, the development of a general method for efficient and direct conversion of alcohols to alkyl azides with NaN3 is highly desirable.

Fig. 1: Deoxyazidation of alcohols.
figure 1

a Illustration of previous work on deoxyazidation of alcohols (Eqs 1–2) and deoxyfluorination of alcohols with SulfoxFluor (Eq 3). b Illustration of this work. Eq 4 refers to the SulfoxFluor-mediated deoxyazidation of alcohols with NaN3. Eqs 1–3 refer to the previously reported deoxyazidation of alcohols (previous work), and eq 4 shows the SulfoxFluor-mediated deoxyazidation of alcohols with NaN3 (this work).

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Sulfonimidoyl compounds possess diverse reactivity (compared with sulfonyl compounds) due to the modulation by the nitrogen substituent35,36,37. During the past decade, our group has been interested in developing fluoroalkyl sulfoximines as versatile fluoroalkylation reagents38,39. Recently, we reported that N-tosyl-4-chlorobenzenesulfonimidoyl fluoride (SulfoxFluor) can serve as a deoxyfluorination reagent for converting alcohols to alkyl fluorides (Fig. 1, Eq 3)40. In this fluorination process, the in situ formed alkyl sulfonimidate (from SulfoxFluor and alcohol) serves as the real electrophilic alkylating agent to react with hydrogen-bonded fluoride ion, affording the desired alkyl fluoride40,41. We envisioned that since fluoride ion is a weak nucleophile42, if there is a strong nucleophile (namely, azide ion) existing in the reaction system, the deoxyazidation of alcohol could become the dominating reaction pathway, giving an alkyl azide as a major product.

Herein, we show a general and practical protocol for deoxyazidation of readily available alcohols with NaN3 using SulfoxFluor as an activator (Fig. 1, Eq 4). A wide range of alkyl azides could be obtained successfully under mild reaction conditions.

Results

Optimization of reaction conditions

At the onset of our investigation, we chose the primary alcohol 2a as a model substrate, NaN3 as an azidation agent, SulfoxFluor as an activator, 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) as a base40,43,44,45,46, and DMF as a solvent; and the reaction was carried out at room temperature. The preliminary result showed that the use of SulfoxFluor (1.0 equiv) afforded azide 3a in 59% yield and a majority of 2a (31%) remained (Table 1, entry 1). Further optimization of the equiv of SulfoxFluor, NaN3, and DBU showed that azide 3a was formed in 84% yield without fluorination and elimination by-products (Table 1, entry 4). Reducing the equiv of NaN3 resulted in the formation of alkyl fluoride 4 (Table 1, entries 5–6). No azide 3a was formed when triethylamine and pyridine were used as bases (Table 1, entries 7–8). For secondary alcohol 2b, it was found that the use of 2.2 equiv of SulfoxFluor was not enough, and the desired alkyl azide 3b was formed in only 38% yield, along with a significant amount of 2b (44%) remained (Table 2, entry 1). Changing the amounts of both SulfoxFluor (2.8 equiv) and DBU (4.0 equiv) resulted in a higher yield (65%) of 3b (Table 2, entries 2–4). Further screening of the reaction conditions showed that an 84% yield of 3b could be obtained in 12 h by performing the reaction with 2b (1.0 equiv), NaN3 (2.0 equiv), SulfoxFluor (2.8 equiv), and DBU (4.0 equiv) at room temperature; and remarkably, alcohol 2b was completely consumed and no fluorination and elimination side products were formed (Table 2, entry 5). Notably, the use of perfluorobutanesulfonyl fluoride (instead of SulfoxFluor) resulted in a decrease of the yield of 3b (68%), with 7% of elimination side product 7 being formed (Table 2, entry 6)45,46,47. Shortening the reaction time to 6 h or using other solvents (such as DMSO, toluene, and CH3CN) did not give better yields of product 3b (Table 2, entries 7–10).

Table 1 Screening of reaction conditions for primary alcohol 2a.
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Table 2 Screening of reaction conditions for secondary alcohol 2b.
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Comparison of various sulfonyl fluorides and sulfonimidoyl fluorides in deoxyazidation of alcohols

To demonstrate the uniqueness of our reagent in the deoxyazidation reaction, several sulfonyl fluorides and sulfonimidoyl fluorides were compared to show their reactivity. 2,2,2-Trifluoroethanol (2c) was chosen as a model substrate to react with these reagents under standard conditions. The results are shown in Table 3. An excellent yield of azide 3c (93%) was formed by using SulfoxFluor as an activator, along with a small amount of 2c (4%) remained (Table 3, entry 1). Changing the S-substituent to an electron-neutral or more electron-deficient 4-nitrophenyl group resulted in a decrease in the yield of 3c (Table 3, entries 2 and 3). Moreover, in the case of 1d with an N-alkyl substituent, no azide 3c was formed and nearly half of 2c was converted to the sulfonimidoyl ester intermediate 8d (Table 3, entry 4). When 2-pyridylsulfonyl fluoride (PyFluor) 1e and tosyl fluoride 1f were used, a full conversion to the corresponding sulfonyl ester intermediates was observed (Table 3, entries 5 and 6). Replacing the N-substituent from tosyl to tertiary butyl led to no azide formation, and a recovery of 2c (82%) was observed (Table 3, entry 7). In the case of perfluorobutanesulfonyl fluoride (PBSF), a lower yield (82%) of 3c was obtained (Table 3, entry 8); however, PBSF was found to give an elimination by-product as mentioned before (Table 2, entry 6). Finally, when SO2F2 was used under similar conditions, a low yield (12%) of azide 3c was formed (Table 3, entry 9). Clearly, SulfoxFluor was superior to other sulfonimidoyl fluorides and sulfonyl fluorides in the present deoxyazidation reaction. It is interesting to note that the use of bis(2,4-dichlorophenyl) chlorophosphate ((2,4-Cl2C6H3O)2P(O)Cl, 1j)/NaN3/DMAP, a state-of-the-art method for deoxyazidation of alcohols at room temperature30, failed to convert 2,2,2-trifluoroethanol (2c) into azide 3c (Table 3, entry 10; for details, see the Supplementary Methods).

Table 3 Azidation of CF3CH2OH with sulfonyl fluorides and sulfonimidoyl fluorides.
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Deoxyazidation of alcohols

With the optimized conditions (Table 1, entry 4 for primary alcohols; Table 2, entry 5 for secondary alcohols) in hand, we investigated the substrate scope of this SulfoxFluor-mediated deoxyazidation reaction using NaN3 as an azide source. The results are shown in Fig. 2. Fifty structurally diverse primary and secondary alcohols were applied in this reaction, nearly half of which are pharmaceutically important molecules. In most cases, the corresponding alkyl azides were obtained in good or excellent yields. The reaction tolerates a variety of functional groups, such as aldehydes, alkenes, alkynes, ketones, esters, amides, halides, nitro, and sulfonyl groups (see Fig. 2). It has been known that aldehydes are not amenable to Mitsunobu reactions owing to the condensation of the aldehyde functionality with Huisgen zwitterions48; however, it is remarkable that under our current azidation reaction conditions, desired product 3w was obtained in 82% yield. Our reaction is also compatible with the majority of heterocycles; heteroaromatic substrates such as indole, benzothiazole, pyridine, thiazole, thiophene, benzothiophene, and pyrimidine are all suitable substrates for this reaction (see 3k–3o, 3x, 3y, and 3ae). The reaction of enantiomerically enriched secondary alcohols 2q and 2v proceeded smoothly to give products 3q and 3v in excellent yields (95% and 96%) and stereospecificity (98.6% and >99.9% e.s.) respectively, which is in accordance with an inversion of configuration resulting from an SN2 mechanism (CCDC 2005774 (3v) contains the supplementary crystallographic data for this paper. These data are provided free of charge by The Cambridge Crystallographic Data Centre.)40,42. Similarly, the stereogenic centers of 3ab, 3af, 3ag, 3av, and 3ba were assigned by analogy. Cyclic alcohols such as four-, five-, and six-membered rings could also undergo efficient deoxyazidation under the standard conditions, giving corresponding products in good to excellent yields (3u–3ae). Notably, the carbamate group in primary alcohol 2g is also compatible without elimination and intramolecular cyclization by-products under the present reaction conditions, giving azide 3g in 60% yield.

Fig. 2: Azidation of alcohols using SulfoxFluora.
figure 2

aIsolated yields. bFor primary alcohols: reactions were conducted on 0.2 mmol scale using 2.2 equiv of SulfoxFluor, 4.0 equiv of NaN3 and 1.8 equiv of DBU. cReaction was conducted on 0.2 mmol scale using 2.5 equiv of SulfoxFluor, 5.0 equiv of NaN3, and 1.8 equiv of DBU. dFor secondary alcohols: reactions were conducted on 0.2 mmol scale using 2.8 equiv of SulfoxFluor, 2.0 equiv of NaN3, and 4.0 equiv of DBU. eThe abbreviation e.s. refers to enantiospecifity, e.s. = (e.e. of 3)/(e.e. of 2) × 100%. fReaction was conducted on a 0.2 mmol scale using 1.05 equiv of 1j, 4.0 equiv of NaN3, and 1.2 equiv of DMAP in DMF (0.2 M) at rt for 12 h. gEpimer ratio >20:1. hReaction was conducted on a 0.4 mmol scale. iReaction was conducted on a 0.16 mmol scale.

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Late-stage modification of structurally complex molecules (such as natural products and drugs) can rapidly generate new pharmaceutical candidates with potentially improved pharmacological profiles49,50,51,52,53,54,55,56,57,58. Late-stage azidation is particularly attractive in this regard because the incorporation of azide functionality (followed by click reaction) can quickly build modular molecular libraries. Inspired by these considerations, we applied our deoxyazidation method in the late-stage functionalization of complex molecules such as isosorbide-2-acetate (2af), TF-HF (2ag) and (-)-Corey lactone benzoate (2ah), and the corresponding azidation products 3af, 3ag, and 3ah were obtained in 92%, 92%, and 81% yields, respectively (Fig. 2). The dansyl chloride derivative 2ai was also efficiently deoxyazidated to give product 3ai in 94% yield, indicating that tertiary amine functionality is compatible with the current azidation conditions. It is interesting to mention that, the current deoxyazidation reaction has good selectivity toward multiple alcohols (such as 2ak-2an), that is, the azidation occurs predominantly on the less hindered hydroxyl group and affords the mono-azidation products in good yields (see 3ak-3an). The drug derivatives estrone (2aq), oxaprozin (2ar), adenosine (2as), indometacin (2at), bendazac (2au), DL-α-tocopherol (2aw), estradiol (2ax), and glucose derivative 2av were all able to undergo deoxyazidation smoothly to afford the corresponding products 3aq-3ax in moderate to good yields. Most remarkably, when antifungal drug posaconazole (2ba), the most complex molecule among the fifty substrates shown in Fig. 2, was subjected to the current deoxyazidation process, product 3ba was isolated in satisfactory yield (47%).

Of note that our synthetic method is also advantageous over the previously reported deoxyazidation system (2,4-Cl2C6H3O)2P(O)Cl/NaN3/DMAP in converting normal secondary alcohols to organoazides. For example, starting from alcohol 2r, the use of SulfoxFluor could afford the corresponding azide 3r in nearly quantitative yield, whereas the use of (2,4-Cl2C6H3O)2P(O)Cl under reported standard conditions30 provided 3r in low yield (21%) even prolonging the reaction time to 12 h. In the latter case, both the bis(2,4-dichlorophenyl) phosphate intermediate and unreacted alcohol 2r were isolated (for detail, see the Supplementary Methods), indicating the low efficiency of (2,4-Cl2C6H3O)2P(O)Cl in the activation of normal secondary alcohols.

Synthetic applications

To further demonstrate the synthetic utility of the current deoxyazidation protocol, we carried out the gram-scale synthesis. As shown in Fig. 3a, the deoxyazidation reaction of dansyl chloride derivative 2ai was carried out under standard conditions. This reaction proceeded well and afforded the desired azide 3ai in 94% yield. Remarkably, the azide product 3ai could be converted to triazole 9 under copper catalysis59 in nearly quantitative yield, which significantly increased the complexity of the molecule and demonstrated the potential application of this azidation protocol in drug discovery. Furthermore, indometacin derivative 2at was subjected to the deoxyazidation reaction and subsequent click reaction in one pot, and triazole 10 was obtained in 83% overall yield (Fig. 3b; for details, see the Supplementary Methods).

Fig. 3: Synthetic applications.
figure 3

a Gram-scale synthesis of alkyl azide 3ai and its further elaboration via Click reaction. b One-pot deoxyazidation and subsequent Click reaction. Conditions A: CuSO4•5H2O (1 mol%), sodium ascorbate (10 mol%), tBuOH/H2O = 1:1, rt, 24 h.

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Experimental investigation of a reaction mechanism

Control experiments were performed to investigate the reaction mechanism (Fig. 4). Alcohol 2a reacted under standard conditions to give azide 3a in 84% yield (determined by 19F NMR; Fig. 4, Eq 1). However, when DBU was not added, the expected product 3a was not detected and the alcohol 2a remained, along with the complete consumption of SulfoxFluor (Fig. 4, Eq 2). This result indicates that SulfoxFluor itself could react with NaN3. Further experiments showed the pre-formed sulfonimidoyl azide intermediate was not able to undergo the desired deoxyazidation reaction (Fig. 4, Eqs 3 and 4). Based on the above-mentioned experiments, a plausible reaction mechanism is proposed for the deoxyazidation of alcohols with SulfoxFluor (Fig. 4, Eq 5). The activated alcohol (by DBU) reacts with SulfoxFluor to form sulfonimidate ester 11, which undergoes a nucleophilic displacement of the sulfonimidate group by azide ion to give the corresponding alkyl azide. The success of the azidation reaction lies in better nucleophilicity of azide ion over that of fluoride ion.

Fig. 4: Mechanistic experiments.
figure 4

a The comparison of the standard experiment and the control experiments. Eq 1 refers to the deoxyazidation reaction conducted under the standard conditions. Eq 2 refers to the control experiment performed in the absence of DBU. Eq 3 refers to the control experiment performed via reverse addition of the reactants. b Proposed mechanism of competitive consumption of SulfoxFluor by NaN3 (Eq 4) and the desired deoxyazidation of alcohols (Eq 5). ND not detected.

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Discussion

We have developed a general protocol for the direct deoxyazidation of alcohols with NaN3, which provides a powerful tool to synthesize structurally diverse alkyl azides from readily available alcohols under mild conditions. Our previously developed SulfoxFluor reagent60,61 plays an important role in this efficient deoxyazidation reaction. To our knowledge, the substrate scope and functional group tolerance of this method are superior to those of other deoxyazidation reactions (starting from alcohols) reported to date. Moreover, we have shown that this method can be applied in the late-stage modification of natural products and pharmaceutically relevant molecules, showcasing that this protocol promises to find practical applications in life sciences and related fields. Further exploration in this direction is underway in our laboratory.

Methods

General

The general procedures for deoxyazidation of primary alcohols 2 with SulfoxFluor 1a are as follows. In a typical experiment, into a 25-mL Schlenk tube (glass) were sequentially added 2-(naphthalen-1-yl)ethan-1-ol 2c (34.4 mg, 0.2 mmol), SulfoxFluor (152.9 mg, 0.44 mmol, 2.2 equiv), NaN3 (52.0 mg, 0.8 mmol), DMF (2.0 mL), and DBU (54 μL, 0.36 mmol, 1.8 equiv) under N2 atmosphere. The mixture was stirred at room temperature for 12 h. Then water (2–5 mL) was added and the mixture was extracted with Et2O (3 × 2 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by chromatography on silica gel to afford alkyl azide 3c (37.7 mg, 96%). The deoxyazidation of secondary alcohols 2 with SulfoxFluor 1a were carried out similarly and the procedures are presented in Supplementary Methods.