Preparation of Primary and Secondary Dialkylmagnesiums by a Radical I/Mg‐Exchange Reaction Using sBu₂Mg in Toluene

Abstract

The treatment of primary or secondary alkyl iodides with sBu₂Mg in toluene (25–40 °C, 2–4 h) provided dialkylmagnesiums that underwent various reactions with aldehydes, ketones, acid chlorides or allylic bromides. 3‐Substituted secondary cyclohexyl iodides led to all‐cis‐3‐cyclohexylmagnesium reagents under these exchange conditions in a highly stereoconvergent manner. Enantiomerically enriched 3‐silyloxy‐substituted secondary alkyl iodides gave after an exchange reaction with sBu₂Mg stereodefined dialkylmagnesiums that after quenching with various electrophiles furnished various 1,3‐stereodefined products including homo‐aldol products (99 % dr and 98 % ee). Mechanistic studies confirmed a radical pathway for these new iodine/magnesium‐exchange reactions.

Primary and secondary dialkylmagnesium reagents were prepared in toluene by the reaction of sBu₂Mg with alkyl iodides (25–40 °C, 1–4 h). Stereoconvergent I/Mg‐exchanges were observed for secondary cyclohexyl iodides leading after quenching reactions to products with high enantio‐ and diastereoselectivity, including homo‐aldol products. Mechanistic studies confirmed radical pathways for these exchanges.

Organomagnesium reagents are indispensable organometallic reagents with numerous synthetic applications. ^[1] They combine the inherent high reactivity of the carbon‐magnesium bond with a good functional group tolerance ^[2] and an excellent compatibility with Lewis acid catalysts. ^[3] Magnesium organometallics are prepared by a direct insertion of magnesium turnings into organic halides ^[1] or by a directed magnesiation of aromatic and heterocyclic derivatives ^[4] triggered by magnesium bases such as TMPMgCl ⋅ LiCl ^[5] or TMP₂Mg ⋅ 2 LiCl ^[6] (TMP=2,2,6,6‐tetramethylpiperidyl). Recently, sBu₂Mg in toluene was used for directed magnesiations ^[7] allowing the preparation of various diaryl‐ and diheteroaryl‐magnesium reagents in toluene, an industrially friendly solvent. ^[8] A further preparation of organomagnesium reagents involves a halogen/magnesium exchange of aryl iodides or bromides. ^[9] In contrast to the insertion of magnesium turnings, this reaction is of high industrial relevance and more practical for many synthetic applications due to its homogeneous nature. iPrMgCl ⋅ LiCl ^[10] or sBu₂Mg ⋅ 2 LiOR ^[11] are highly efficient exchange reagents broadly used for the preparation of unsaturated aryl‐, heteroaryl‐ and alkenylmagnesium reagents. However, the preparation of alkylmagnesium derivatives using an I/Mg‐exchange is scarcely described in literature and suffers from a highly narrow substrate scope limited to primary alkyl iodides bearing a remote oxygen‐coordinating group on the alkyl iodide (Scheme 1a). ^[12] A more general protocol for preparing alkylmagnesium reagents was therefore highly desirable. Herein, we wish to report a sBu₂Mg mediated I/Mg‐exchange reaction of various primary or secondary alkyl iodides of type 1 in toluene providing dialkylmagnesiums of type 2 under mild reaction conditions. Trapping with various electrophiles (E⁺) provided a range of polyfunctional products of type 3 (Scheme 1). Furthermore, we have found that this new exchange reaction proceeded via a radical mechanism. ^[13] Applied to secondary alkyl iodides, the new method allowed the stereoconvergent preparation of diastereomerically and enantiomerically enriched secondary dialkylmagnesiums.

Scheme 1.

Preparation of dialkylmagnesium reagents 2 from primary or secondary alkyl iodides 1 via an I/Mg‐exchange in toluene using sBu₂Mg leading after quenching reactions with electrophiles to products of type 3.

Thus, in preliminary experiments, we have examined the reaction of octyl iodide (1 a) with iPrMgCl ⋅ LiCl in THF and have obtained mostly the corresponding substitution product (2‐methyldecane in 71 % yield) with little amount of desired Oct₂Mg 2 a (<5 %). ^[14] Quenching 2 a with allyl bromide in the presence of 5 mol % CuCN ⋅ 2 LiCl ^[15] furnished 1‐undecene (3 a) which yield was easily determined by GC‐analysis. Furthermore, switching from THF to toluene as solvent provided 2 a in 21 % GC‐yield. ^[14] These results led us to look for alternative exchange reagents and we found that sBu₂Mg gave the best results. ^[14] sBu₂Mg was conveniently prepared by treating sBuMgCl with sBuLi in a cyclohexane:ether mixture. Evaporation of the solvent and replacement with toluene produced 0.43–0.48 M homogeneous solutions of sBu₂Mg. ^[7a] Furthermore, variation of the solvent at 25 °C showed that running the reaction in pure toluene without any coordinating co‐solvent led to superior yields of 3 a (entries 1–3 of Table 1). ^[16] Performing the reaction at 40 °C further increased the yield of 3 a to 65 % (entry 4). By using 0.7 equiv. of the exchange reagent sBu₂Mg, 3 a was formed in 81 % yield (entry 5).

Table 1.

Optimization of the reaction of octyl iodide (1 a) with sBu₂Mg leading after allylation to undecene (3 a).

Entry	Equiv of sBu2Mg	Solvent	T [°C]	Yield of 3 a [%][a]
1	0.6	THF	25	3
2	0.6	Bu2O	25	traces
3	0.6	toluene	25	55
4	0.6	toluene	40	65
5	0.7	toluene	40	81

[a] All reactions were performed on a 0.5 mmol scale. Yields were determined by GC‐analysis using undecane as internal standard.

With these optimized results in hand, we treated magnesium reagent 2 a with various electrophiles and investigated the reaction scope (Scheme 2). Thus, acylation of the copper derivative of 2 a obtained by adding CuCN ⋅ 2 LiCl (as 1 M solution in THF; 1 equiv) ^[15] and further reaction with benzoyl chloride or cyclopropanecarbonyl chloride (0.6 equiv, −40 °C, 3 h) furnished the corresponding ketones 3 b–c in 70–86 % isolated yield. Addition of 2 a to 3‐iodo‐2‐cyclohexanone (0.6 equiv, 0 °C, 1 h) provided the tertiary alcohol 3 d in 50 % yield. Fe‐catalyzed cross‐coupling (5 % Fe(acac)₃, 20 % TMEDA) ^[17] with (E)‐3‐styryl bromide (0.6 equiv, 0 °C, 0.5 h) gave (E)‐1‐phenyl‐1‐undecene (3 e) in 71 % yield (E : Z=99 : 1). Unsaturated 1‐iodo‐4‐pentene (1 b) gave after I/Mg‐exchange di(4‐pentenyl)magnesium (2 b). After transmetalation with CuCN ⋅ 2 LiCl and reaction with benzoyl chloride, ketone 3 f was obtained in 75 % yield. (Z)‐4‐Phenyl‐4‐hexenyl iodide (1 c) ^[18] reacted similarly and the corresponding dialkylmagnesium 2 c was benzoylated with 3,4,5‐trimethoxybenzoyl chloride (−40 °C, 3 h) giving the ketone 3 g (Z : E=99 : 1) in 79 % yield. A diastereoselective addition of 2 c to (S)‐carvone in toluene gave the tertiary alcohol 3 h in 54 % yield (Z : E=99 : 1; dr=95 : 5). ^[19] The terpenic iodide derived from (R)‐nopol (1 d) gave the expected diorganomagnesium species 2 d which after a Cu‐transmetalation underwent a smooth acylation with benzoyl chloride as well as an addition‐elimination with 3‐iodo‐2‐cyclohexen‐1‐one ^[20] leading to the corresponding ketones 3 i–j in 82–84 % yield. Homopropargylic iodide 1 e ^[14] and the chloro‐substituted iodide 1 f were selectively converted with sBu₂Mg under the standard conditions to the dialkylmagnesiums 2 e and 2 f which afforded after addition of furfural the corresponding alcohols 3 k and 3 l in 80–86 % yield. 2‐(4‐Fluorophenyl)ethyl iodide (1 g) ^[14] furnished after I/Mg‐exchange, transmetalation with CuCN ⋅ 2 LiCl and acylation with 3‐(chloromethyl)benzoyl chloride ketone 3 m in 72 % yield. Silyl‐substituted iodides such as 6‐tert‐butyldimethylsilyloxychlorohexane (1 h) ^[14] gave after I/Mg‐exchange the corresponding dialkylmagnesium 2 h which was added to a functionalized benzaldehyde leading to alcohol 3 n in 77 % yield. Heterocyclic iodides such as 3‐(2‐iodoethyl)thiophene (1 i) ^[14] underwent cleanly the I/Mg‐exchange with sBu₂Mg and after transmetalation and acylation with 4‐chlorobutyroyl chloride or 3‐fluorobenzoyl chloride gave the ketones 3 o–p in 81–85 % yield.

Scheme 2.

Preparation of various primary dialkylmagnesiums (2 a–2 i) from the corresponding iodides (1 a–1 i) ^[14] using sBu₂Mg in toluene and quenching with various electrophiles leading to products 3 b–3 p.

Then we turned our attention to secondary alkyl iodides and chose cyclohexyl iodide (4 a) as a model substrate. ^[14] We have found again that the best exchange was obtained at 25 °C in toluene using sBu₂Mg (0.6 equiv) affording dicyclohexylmagnesium (5 a) after only 2 h reaction time in 42 % GC‐yield. In contrast to primary alkyl iodides, no heating was required. Quenching with allyl bromide gave 2‐propenyl cyclohexane 6 a in 48 % isolated yield. ^[14] Although a higher conversion could not be reached, these promising results led us to examine some substituted iodocyclohexane derivatives such as 4 b–4 e. Although, we realize that this radical reaction may result in an absolute stereochemistry loss of the carbon‐iodine bond, a good relative stereoselectivity may still be reached in favourable equilibration processes. Therefore, we have chosen the secondary alkyl iodides 4 b–4 e bearing a bulky substituent in position 3. ^[21] These cyclohexyl iodides used as cis‐trans mixtures reacted with sBu₂Mg (0.6 equiv) at 25 °C within 2 h and provided the corresponding dicyclohexylmagnesium species 5 b–5 e (optimum conversion of 75 %) tentatively written as cis‐isomers. Accordingly, quenching reactions of 5 b–5 e with dicyclopropyl ketone provided only the diastereomerically pure cis‐tertiary alcohols 6 b–6 e in 52–56 % yield showing that the exchange reaction proceeded in a stereoconvergent way (Scheme 3). In the case of the TIPSO‐substituted dicyclohexylmagnesium 5 e, quenching with benzaldehyde followed by PCC‐oxidation (PCC=pyridinium chlorochromate) ^[22] led to an epimerization and provided the diastereomerically pure trans‐ketone 6 f in 51 % yield (dr=1 : 99).

Scheme 3.

Stereoconvergent I/Mg‐exchange on cyclohexyl iodides 4 b–4 e leading to dialkylmagnesium reagents 5 b–5 e and subsequent addition to dicyclopropyl ketone providing the diastereomerically pure cis‐alcohols 6 b–6 e and the trans‐ketone 6 f.

With these results in hand, we turned our attention to silylated oxygenated derivatives of commercially available optically enriched (R,R)‐pentanediol (98 % ee). ^[23] We anticipated that the presence of a closely located silyl‐ether function would improve the conversion of these I/Mg‐exchanges. Thus, epimeric mixtures of iodides 7 a or 7 b were submitted to the usual I/Mg‐exchange protocol using sBu₂Mg (0.6 equiv) in toluene (25 °C, 2 h). As expected a stereoconvergent I/Mg‐exchange ^[23] provided diastereomerically enriched Grignard reagents 8 a and 8 b as shown by subsequent quenching reactions with dicyclopropyl ketone affording the tertiary alcohol 9 a (dr=99 : 1) and 9 b (dr=88 : 12). These results indicated that the stereoconvergence of the formation of Grignard reagent 8 is highest with the TIPS‐protected substrate (7 a). Thus, we have treated 8 a with various electrophiles such as ethyl cyanoformate, S‐methyl benzenethiosulfonate, phenyl isocyanate and methyl pinacolyl borate leading to the corresponding products 10 a–10 d with high enantiomeric and diastereomeric purity (98 % ee and dr up to 99 : 1; Scheme 4).

Scheme 4.

Preparation of enantiomerically and diastereomerically enriched dialkylmagnesium reagents 8 a and 8 b followed by trapping with various electrophiles.

The relative stereochemistry of products of type 10 was confirmed by treating 10 a with CF₃SO₃H in dichloromethane, 25 °C, 2 h affording the corresponding trans‐2,4‐dimethylbutyrolactone in 79 % yield.[ ¹⁴ , ²³ ] Additionally, we have reacted 8 a with 3,4‐dimethoxybenzaldehyde or furfural (−20 °C, 2 h) producing intermediate alcohols which were oxidized using the Dess‐Martin periodinane ^[24] affording the valuable homo‐aldol products 11 a and 11 b in 56–57 % overall yields (dr=99 : 1; 98 % ee).

Preliminary mechanistic studies were undertaken to demonstrate the radical nature of this I/Mg‐exchange. Thus, the treatment of radical clock probes ^[25] such as alkyl iodides 1 j, 1 k and 1 l provided evidence of a radical pathway, since cyclopropylmethyl iodide 1 j gave, after quenching with PhCOCl, mostly the open‐chain product 3 q with less than 10 % of the non‐rearranged ketone 3 r. On another hand, treatment of 5‐hexenyl iodide (1 k) under the I/Mg‐exchange conditions afforded after benzoylation a significant amount of ring closure product cyclopentylmethyl phenyl ketone (3 s) as well as open‐chain product 3 t. As expected 3‐butenyl iodide (1 l) furnished under the same conditions only the open‐chain ketone 3 q in 79 % yield (Scheme 5).

Scheme 5.

Radical clock experiments using alkyl iodides 1 j, 1 k and 1 l for I/Mg‐exchanges and subsequent benzoylations.

The cyclic iodo‐acetal 12 ^[26] was subjected to the I/Mg‐exchange under various conditions. We have observed the formation of products 13, 14 and 15 in various proportions, ^[14] but could optimize the reaction to produce the cyclic iodide 13 in 67 % yield (dr=95 : 5) by using commercial nBu₂Mg or sBu₂Mg in THF in the presence of sBuI (3 equiv). Interestingly, the addition of styrene inhibited the reaction completely showing the radical character of this reaction. ^[14] This cyclization may be rationalized by an atom‐transfer mechanism ^[27] (Scheme 6). Thus, we assumed that the initiation step was a homolytic cleavage of sBu₂Mg, ^[1b] followed by a radical chain reaction induced by a s‐butyl radical producing the radical 16 from the iodide 12. After cyclization, the new radical 17 was produced and trapped by sBuI affording the major product 13 in 67 % yield. Reaction of 17 with THF gave the bicyclic acetal 14. Recombination of 17 with the sBuMg radical will provide 15, which was detected in 2 % yield. These observations supported an atom‐transfer mechanism for the I/Mg‐exchange.

Scheme 6.

Atom‐transfer cyclization of 12 triggered by sBu₂Mg providing selectively the bicyclic iodide 13.

In conclusion, we have reported a new preparation of various primary dialkylmagnesiums in toluene using sBu₂Mg as an exchange reagent. This exchange reaction allowed the preparation of various primary dialkylmagnesiums in toluene and was extended to several secondary cyclohexyl iodides providing the thermodynamically most favored Grignard reagents. The diastereomeric ratio of these I/Mg‐exchanges on secondary iodides could be further improved by using secondary alkyl iodides bearing a TIPSO‐group at the 3‐position. Thus, chiral secondary dialkylmagnesiums were prepared from 3‐substituted silyl enol ethers and gave after various quenching reactions with electrophiles, highly enantiomerically and diastereomerically enriched products (up to dr=99 : 1 and 98 % ee). Mechanistic investigations supported an atom‐transfer mechanism.

Conflict of interest

The authors declare no conflict of interest.

Supporting information

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Supporting Information

A. S. Sunagatullina, F. H. Lutter, P. Knochel, Angew. Chem. Int. Ed. 2022, 61, e202116625; Angew. Chem. 2022, 134, e202116625.

Data Availability Statement

The data that support the findings of this study are available in the Supporting Information of this article.