(2‐Ethylhexyl)sodium: A Hexane‐Soluble Reagent for Br/Na‐Exchanges and Directed Metalations in Continuous Flow

Abstract We report the on‐demand generation of hexane‐soluble (2‐ethylhexyl)sodium (1) from 3‐(chloromethyl)heptane (2) using a sodium‐packed‐bed reactor under continuous flow conditions. Thus, the resulting solution of 1 is free of elemental sodium and therefore suited for a range of synthetic applications. This new procedure avoids the storage of an alkylsodium and limits the handling of metallic sodium to a minimum. (2‐Ethylhexyl)sodium (1) proved to be a very useful reagent and undergoes in‐line Br/Na‐exchanges as well as directed sodiations. The resulting arylsodium intermediates are subsequently trapped in batch with various electrophiles such as ketones, aldehydes, Weinreb‐amides, imines, allyl bromides, disulfides and alkyl iodides. A reaction scale‐up of the Br/Na‐exchange using an in‐line electrophile quench was also reported.

Organosodiumreagentsarehighlyreactiveorganometallics towards various electrophiles due to the very ionic character of the CÀNa bond. [1] Despite the appealing chemical properties and the low price, high abundancy and low toxicity of sodium, these compounds have seldomly found applications in organic syntheses. [2] Dimethylethylamine soluble NaDA (sodium diisopropylamide) was prepared by Collum and coworkers as an alternative to the frequently used LDA (lithium diisopropylamide). [3] Recently, Asako and Takai have reported a new method for the preparation of arylsodiums via a Br/Na-exchange using neopentylsodium, which was prepared by the reaction of neopentyl chloride with sodium dispersion (Scheme 1 a). This procedure seems to limit the trapping of the resulting arylsodium to R 3 SiCl, D 2 O and transmetalation reactions. [4] The presence of residual sodium dispersion may hamper the use of more complex electrophiles. In contrast to well established lithium chemistry, [5] the use of organosodium reagents remains underexploited in continuous flow due to their poor solubility. [6] We have reported the generation of organosodium and -potassium derivatives in continuous flow using Na-and K-amide bases. [7] In the course of this work, we envisioned a new procedure for generating soluble alkylsodiums in continuous flow expanding pioneering work of Alcµzar, [8] Ley, [9] McQuade [8a] and others, [10] which established the use of metal-packed-bed reactors for the direct preparation of Mg or Zn organometallics in continuous flow. Herein, we report a new sodiumpacked-bed reactor for on-demand generation of the hexanesoluble sodium reagent (2-ethylhexyl)sodium (1) [11] from readily available 3-(chloromethyl)heptane (2), which was used for performing in-line Br/Na-exchanges as well as directed metalations (Scheme 1 b) in continuous flow.
To prepare the packed-bed reactor, we charged a glass column (7.5 mL) with sodium particles (3.4 mL, Ø ca. 1 mm). [12,13] The resulting mixed-bed reactor [14] was flushed with dry hexane and was activated using a 0.1 m solution of i-PrOH in hexane. Pumping alkyl chloride 2 (0.2 m in hexane, 2.0 mL min À1 , 258C) through the reactor afforded a slightly yellow solution of 1 in hexane (ca. 0.15 m). [15] This soluble alkylsodium species [16] was free of metallic sodium and was directly used for in-line Br/Na-exchanges as well as directed sodiations. Collected aliquots of 1 prepared in continuous flow showed moderate stability (Figure 1), demonstrating the importance of the direct use of the sodium species. This ondemand procedure avoids storage problems of instable 1 and considerably limits hazards of working with metallic sodium. Whereas preparation of 1 in batch led to a dark solution over metallic sodium, the flow procedure resulted in a slightly yellow solution of 1 free of elemental sodium ( Figure 1). Scheme 1. a) Generation of neopentylsodium in batch and its use in halogen/sodium-exchange reactions. b) On-demand continuous flow generation of (2-ethylhexyl)sodium (1) and subsequent in-line Br/Naexchange and directed metalation.
Abstract: We report the on-demand generation of hexanesoluble (2-ethylhexyl)sodium (1) from 3-(chloromethyl)heptane (2) using a sodium-packed-bed reactor under continuous flow conditions. Thus, the resulting solution of 1 is free of elemental sodium and therefore suited for a range of synthetic applications. This new procedure avoids the storage of an alkylsodium and limits the handling of metallic sodium to a minimum. (2-Ethylhexyl)sodium (1) proved to be a very useful reagent and undergoes in-line Br/Na-exchanges as well as directed sodiations. The resulting arylsodium intermediates are subsequently trapped in batch with various electrophiles such as ketones, aldehydes, Weinreb-amides, imines, allyl bromides, disulfides and alkyl iodides. A reaction scale-up of the Br/Na-exchange using an in-line electrophile quench was also reported.  (1) in hexane prepared via a sodium-packed-bed reactor, 5 min after collecting. (2-Ethylhexyl)sodium (1) in hexane prepared via a packed-bed sodium reactor, 18 h after collecting.
Nitrogen containing heterocycles are important building blocks in pharmaceutical and agricultural chemistry. [18] Therefore, the functionalization of those scaffolds is an ongoing task in synthetic chemistry. [19] The exchange procedure was extended towards heterocyclic bromides using the optimized reaction conditions. Br/Na-exchange on 2-bromopyridine (7 a) at À40 8C using a combined flow rate of 3.0 mL min À1 led to the desired aryl-sodium 8 a, which was subsequently quenched in batch with ketones 5 a and 5 m affording the tertiary alcohols 9 aa and 9 am in 81-86 % yield (Table 2). Similarly, 5-methyl-2-bromopyridine (7 b) and highly substituted bromopyrimidine 7 c underwent Br/Na-exchanges. Batch quenching using various electrophiles of type 5 led to the functionalized N-heterocycles 9 bc, 9 cg, 9 cn, 9 cc and 9 cl in 78-96 % yield. Furthermore, 2-bromothiazole (7 d) was converted into the corresponding sodium species 8 d, which was quenched with ketone 5 j resulting in 9 dj (66 % yield). Trapping 8 d with a racemic mixture of a-ionone (5 o) gave the 1,2-addition product 9 do (50 % yield, dr 1:1). Table 1: On-demand preparation of alkylsodium reagent 1 from alkyl chloride 2 followed by Br/Na-exchange on aryl bromides of type 3 leading to arylsodiums of type 4 and subsequent batch quench with electrophiles of type 5 leading to products of type 6.
Yields of analytically pure products.
[d] From the disulfide. Table 2: On-demand preparation of alkylsodium reagent 1 from alkyl chloride 2 followed by Br/Na-exchange on heteroaryl bromides of type 7 leading to heteroarylsodiums of type 8 and subsequent batch quench with electrophiles of type 5 leading to products of type 9.
Yields of analytically pure products.
To demonstrate the scalability [20] of the Br/Na-exchange reaction, an in-line electrophile quench was set up. Thus, pumping a solution of 2 (0.2 m, 2.0 mL min À1 ) through the sodium-packed reactor resulted in the sodium exchange reagent 1. 2-Bromopyridine (7 a, 0.2 m, 1.0 mL min À1 ) was mixed with the solution of 1 in a T-shaped mixer. After passing through a micro-reactor (0.6 s, À40 8C, combined flow rate: 3.0 mL min À1 ), the pyridylsodium 8 a was trapped in-line with a solution of benzophenone (5 a, 0.1 m, 3.0 mL min À1 ). Increasing the runtime 10-or 17.5-fold (2.0 or 3.5 mmol) led to the functionalized pyridine 9 aa in 64-65 % isolated yield (Scheme 2).
Apart from halogen/lithium-exchanges, alkyllithiums are frequently used in directed metalations converting readily available arene starting materials into highly reactive aryllithiums, therefore allowing the functionalization of previously unreactive aromatic CÀH bonds. [21] We expected 1 to behave similarly, and indeed without changing the set-up of the continuous flow procedure, (2-ethylhexyl)sodium (1) was able to metalate benzothiophene (10 a) resulting in the corresponding sodium species 11 a. [22] Quenching with carbonyl electrophiles 5 m, 5 c, and 5 g gave the expected products 12 am, 12 ac and 12 ag in 73-87 % yield (Table 3). Imidazole 10 b was metalated similarly and subsequent batch quench gave the products 12 bl, 12 bd and 12 bf in 55-79 % isolated yield. The electron rich 1,3-dimethoxybenzene (10 c) was converted to the arylsodium 11 c. Trapping with ketone 5 m or disulfide 5 p gave the desired products 12 cm and 12 cp in 86-88 % yield. Additionally, transition metal free Wurtztype coupling, [23] with iodooctane (5 q) gave the alkylated product 12 cq in 46 % yield.
In summary, we have reported the on-demand generation of sodium metal free, hexane-soluble (2-ethylhexyl)sodium from 3-(chloromethyl)heptane using a sodium-packed-bed reactor in a commercially available continuous flow set-up. The procedure avoids storage of alkylsodium species and limits the handling of metallic sodium to a minimum. (2-Ethylhexyl)sodium was used for in-line sodiations and Br/Naexchange reactions. The resulting arylsodiums were subsequently trapped with various electrophiles such as ketones, aldehydes, Weinreb-amides, imines, allyl bromides, disulfides and alkyl iodides. A reaction scale-up of the Br/Na-exchange using an in-line electrophile quench was reported. Further investigations on the use of alkylsodium reagents are currently under way in our laboratories.
Scheme 2. Scale-up of the Br/Na-exchange reaction using 2-bromopyridine (7 a), (2-ethylhexyl)sodium (1) as exchange reagent and benzophenone (5 a) as electrophile, applying in-line quenching conditions. Table 3: On-demand preparation of alkylsodium reagent 1 from alkyl chloride 2 followed by directed metalation of (hetero)arenes of type 10 leading to (hetero)arylsodiums of type 11 and subsequent batch quench with electrophiles of type 5 leading to products of type 12.
Yields of analytically pure products.
[a] From the Weinreb-amide. [b] 2.0 equiv E-X were used [c] From the disulfide.
[d] From the alkyl iodide.