Recent Advances in Halogen-Metal Exchange Reactions.

ConspectusThe halogen-metal exchange reaction is a very powerful method for preparing functionalized organometallic reagents in the fields of organic and organometallic chemistry. Since its inception, significant interest has been directed toward the on-demand development of new halogen-metal exchange reactions, primarily through the upgrading of exchange reagents. The enduring quest for optimal reactivity, superior functional group compatibility, and innovative synthetic applications of exchange reagents remains a fundamental objective. In the past several years, the emergence of some significant discoveries in halogen-metal exchange reactions has proclaimed a renaissance to this field. This Account outlines the latest advances within the domain contributed by the Knochel group, including the main points as follows.The stereoretentive I/Li exchange on stereodefined secondary alkyl iodides was developed for the synthesis of nonstabilized chiral secondary alkyllithium reagents. This provided a straightforward method to access chiral organolithium reagents, which can be trapped by various electrophiles or transmetalated with other metals such as copper, zinc, and magnesium, thus enabling the stereoselective synthesis of a series of functionalized compounds and natural products.Faster halogen-magnesium and halogen-zinc exchanges in toluene were realized using a novel kind of exchange reagent complexed with lithium alkoxide. These highly efficient exchange reactions are much faster than traditional ones and performed in an industrially friendly solvent. These advantages are of great value in practical synthesis, paving the way for new developments in this evolving area.Halogen-lanthanide exchanges and their novel applications in organic synthesis were established. These new exchanges introduced the lanthanide metals into halogen-metal exchange reactions for the first time, thereby opening new avenues in synthetic chemistry. Building on these achievements, a comparative analysis of the exchange reaction rates by kinetic study has quantified the relationship between the electronegativity of metals and the rates of halogen-metal exchanges.Br/Na exchange in continuous flow was achieved using a hexane-soluble exchange reagent, 2-ethylhexylsodium. This approach effectively circumvented the poor solubility of the organosodium reagent, which has proven to be of significant practical value and greatly enhanced the synthetic utility of the organosodium reagent in organic synthesis.These remarkable breakthroughs as mentioned above are fueled mainly by upgrading the exchange reagents, resulting in the development of new halogen-metal exchange reactions and innovative applications in organic synthesis. Given the importance of halogen-metal exchanges in synthetic chemistry, the pursuit of other types of exchange reactions, particularly those involving new metals, will be in continuous demand. This Account provides a timely summary of recent progress and will undoubtedly inspire further advances to drive this research field forward.

Selective and Stepwise Functionalization of the Pyridazine Scaffold by Using Thio-Substituted Pyridazine Building Blocks.

We described a regioselective tri- and tetra-functionalization of the pyridazine scaffold using two readily available building blocks: 3-alkylthio-6-chloropyridazine and 3,4-bis(methylthio)-6-chloropyridazine by performing selective metalations with TMPMgCl ⋅ LiCl and catalyst-tuned cross-coupling reactions with arylzinc halides. Several of the resulting pyridazines were converted into more elaborated N-heterocycles such as thieno[2,3-c]pyridazines and 1H-pyrazolo[3,4-c]pyridazines.

Transition-Metal Free Electrophilic Aminations of Polyfunctional O-2,4,6-Trimethylbenzoyl Hydroxylamines with Zinc and Magnesium Organometallics.

We reported a new electrophilic amination of various primary, secondary and tertiary alkyl, benzylic, allylic zinc and magnesium organometallics with O-2,4,6-trimethylbenzoyl hydroxylamines (O-TBHAs) in 52-99 % yield. These O-TBHAs displayed an excellent long-term stability and were readily prepared from various highly functionalized secondary amines via a convenient 3 step procedure. The amination reactions showed remarkable chemoselectivity proceeding without any transition-metal catalyst and were usually complete after 1-3 h reaction time at 25 °C. Furthermore, this electrophilic amination also provided access to enantioenriched tertiary amines (up to 88 % ee) by using optically enriched secondary alkylmagnesium reagents of the type s-AlkylMgCH2 SiMe3 .

In Situ Quench Reactions of Enantioenriched Secondary Alkyllithium Reagents in Batch and Continuous Flow Using an I/Li-Exchange.

We report a practical in situ quench (ISQ) procedure involving the generation of chiral secondary alkyllithiums from secondary alkyl iodides (including functionalized iodides bearing an ester or a nitrile) in the presence of various electrophiles such as aldehydes, ketones, Weinreb amides, isocyanates, sulfides, or boronates. This ISQ-reaction allowed the preparation of a broad range of optically enriched ketones, alcohols, amides, sulfides and boronic acid esters in typically 90-98 % ee. Remarkably, these reactions were performed at -78 °C or -40 °C in batch. A continuous flow set-up permitted reaction temperatures between -20 °C and 0 °C and allowed a scale-up up to a 40-fold without further optimization.

Regioselective Magnesiation and Zincation Reactions of Aromatics and Heterocycles Triggered by Lewis Acids.

Mixed TMP-bases (TMP=2,2,6,6-tetramethylpiperidyl), such as TMPMgCl ⋅ LiCl, TMP2 Mg ⋅ 2LiCl, TMPZnCl ⋅ LiCl and TMP2 Zn ⋅ 2LiCl, are outstanding reagents for the metalation of functionalized aromatics and heterocycles. In the presence of Lewis acids, such as BF3 ⋅ OEt2 or MgCl2 , the metalation scope of such bases was dramatically increased, and regioselectivity switches were achieved in the presence or absence of these Lewis acids. Furthermore, highly reactive lithium bases, such as TMPLi or Cy2 NLi, are also compatible with various Lewis acids, such as MgCl2 ⋅ 2LiCl, ZnCl2 ⋅ 2LiCl or CuCN ⋅ 2LiCl. Performing such metalations in continuous flow using commercial setups permitted practical and convenient reaction conditions.

Reliable Functionalization of 5,6-Fused Bicyclic N-Heterocycles Pyrazolopyrimidines and Imidazopyridazines via Zinc and Magnesium Organometallics.

DFT-calculations allow prediction of the reactivity of uncommon N-heterocyclic scaffolds of pyrazolo[1,5-a]pyrimidines and imidazo[1,2-b]pyridazines and considerably facilitate their functionalization. The derivatization of these N-heterocycles was realized using Grignard reagents for nucleophilic additions to 5-chloropyrazolo[1,5-a]pyrimidines and TMP2 Zn ⋅ 2 MgCl2 ⋅ 2 LiCl allowed regioselective zincations. In the case of 6-chloroimidazo[1,2-b]pyridazine, bases such as TMP2 Zn ⋅ MgCl2 ⋅ 2 LiCl, in the presence or absence of BF3 ⋅ OEt2 , led to regioselective metalations at positions 3 or 8. Subsequent functionalizations were achieved with TMPMgCl ⋅ LiCl, producing various polysubstituted derivatives (up to penta-substitution). X-ray analysis confirmed the regioselectivity for key functional heterocycles.

Preparation of Primary and Secondary Dialkylmagnesiums by a Radical I/Mg-Exchange Reaction Using sBu2 Mg in Toluene.

The treatment of primary or secondary alkyl iodides with sBu2 Mg 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 sBu2 Mg 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.

Regioselective Magnesiations of Fluorinated Arenes and Heteroarenes Using Magnesium-bis-Diisopropylamide (MBDA) in Hydrocarbons.

We report a convenient preparation of a new and storable magnesium amide (iPr2 N)2 Mg (magnesium-bis-diisopropylamide; MBDA) which proved to be especially suitable for the non-cryogenic magnesiation of fluoro-substituted arenes and heteroarenes providing arylmagnesium amides (ArMgDA) or bis-heteroaryl magnesiums (HetAr)2 Mg in hydrocarbons. Further reactions with electrophiles (aldehydes, ketones, allylic bromides, aryl halides (Negishi cross-coupling)) furnished a range of polyfunctional fluoro-substituted unsaturated building blocks. Several postfunctionalizations were described as well as NMR-studies confirming the dimeric structure of the base.

Preparation of Functionalized Amides Using Dicarbamoylzincs.

We report a new convenient preparation of dicarbamoylzincs of type (R1 R2 NCO)2 Zn by the treatment of ZnCl2 and formamides R1 R2 NCHO with LiTMP in THF (15 °C, 15 min) or by the reaction of formamides R1 R2 NCHO with TMP2 Zn (25 °C, 16 h). This second method tolerates sensitive groups such as an ester, ketone or nitro function. Reaction of these dicarbamoylzincs with allylic, benzylic, aryl, alkenyl bromides, acid chlorides, aldehydes or enones provided various polyfunctional amides in 47-97 % yields. 13 C NMR characterization of these new carbamoylzinc derivatives is reported.

Continuous Flow Preparation of Benzylic Sodium Organometallics.

We report a lateral sodiation of alkyl(hetero)arenes using on-demand generated hexane-soluble (2-ethylhexyl)sodium (1) in the presence of TMEDA. (2-Ethylhexyl)sodium (1) is prepared via a sodium packed-bed reactor and used for metalations at ambient temperature in batch as well as in continuous flow. The resulting benzylic sodium species are subsequently trapped with various electrophiles including carbonyl compounds, epoxides, oxetane, allyl/benzyl chlorides, alkyl halides and alkyl tosylates. Wurtz-type couplings with secondary alkyl halides and tosylates proceed under complete inversion of stereochemistry. Furthermore, the utility of this lateral sodiation is demonstrated in the synthesis of pharmaceutical relevant compounds. Thus, fingolimod is prepared from p-xylene applying the lateral sodiation twice. In addition, 7-fold isotopically labeled salmeterol-d7 and fenpiprane as well as precursors to super linear alkylbenzene (SLAB) surfactants are prepared.

Exploiting Coordination Effects for the Regioselective Zincation of Diazines Using TMPZnX⋠LiX (X=Cl, Br).

A new method for regioselective zincations of challenging N-heterocyclic substrates such as pyrimidines and pyridazine was reported using bimetallic bases TMPZnX⋅LiX (TMP=2,2,6,6-tetramethylpiperidyl; X=Cl, Br). Reactions occurred under mild conditions (25-70 °C, using 1.75 equivalents of base without additives), furnishing 2-zincated pyrimidines and 3-zincated pyridazine, which were then trapped with a variety of electrophiles. Contrasting with other s-block metalating systems, which lack selectivity in their reactions even when operating at low temperatures, these mixed Li/Zn bases enabled unprecedented regioselectivities that cannot be replicated by either LiTMP nor Zn(TMP)2 on their own. Spectroscopic and structural interrogations of organometallic intermediates involved in these reactions have shed light on the complex constitution of reaction mixtures and the origins of their special reactivities.

Continuous Flow Acylation of (Hetero)aryllithiums with Polyfunctional N,N-Dimethylamides and Tetramethylurea in Toluene.

The continuous flow reaction of various aryl or heteroaryl bromides in toluene in the presence of THF (1.0 equiv) with sec-BuLi (1.1 equiv) provided at 25 °C within 40 sec the corresponding aryllithiums which were acylated with various functionalized N,N-dimethylamides including easily enolizable amides at -20 °C within 27 sec, producing highly functionalized ketones in 48-90 % yield (36 examples). This method was well suited for the preparation of α-chiral ketones such as naproxene and ibuprofen derived ketones with 99 % ee. A one-pot stepwise bis-addition of two different lithium organometallics to 1,1,3,3-tetramethyurea (TMU) provided unsymmetrical ketones in 69-79 % yield (9 examples).

Transition-Metal-Free Synthesis of Polyfunctional Triarylmethanes and 1,1-Diarylalkanes by Sequential Cross-Coupling of Benzal Diacetates with Organozinc Reagents.

A variety of functionalized triarylmethane and 1,1-diarylalkane derivatives were prepared via a transition-metal-free, one-pot and two-step procedure, involving the reaction of various benzal diacetates with organozinc reagents. A sequential cross-coupling is enabled by changing the solvent from THF to toluene, and a two-step SN 1-type mechanism was proposed and evidenced by experimental studies. The synthetic utility of the method is further demonstrated by the synthesis of several biologically relevant molecules, such as an anti-tuberculosis agent, an anti-breast cancer agent, a precursor of a sphingosine-1-phosphate (S1P) receptor modulator, and a FLAP inhibitor.

Continuous Flow Sodiation of Substituted Acrylonitriles, Alkenyl Sulfides and Acrylates.

The sodiation of substituted acrylonitriles and alkenyl sulfides in a continuous flow set-up using NaDA (sodium diisopropylamide) in EtNMe2 or NaTMP (sodium 2,2,6,6-tetramethylpiperidide)⋅TMEDA in n-hexane provides sodiated acrylonitriles and alkenyl sulfides, which are subsequently trapped in batch with various electrophiles such as aldehydes, ketones, disulfides and allylic bromides affording functionalized acrylonitriles and alkenyl sulfides. This flow-procedure was successfully extended to other acrylates by using Barbier-type conditions.

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

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.

Regioselective Bromine/Magnesium Exchange for the Selective Functionalization of Polyhalogenated Arenes and Heterocycles.

Using the bimetallic combination sBu2 Mg⋅2 LiOR (R=2-ethylhexyl) in toluene enables efficient and regioselective Br/Mg exchanges with various dibromo-arenes and -heteroarenes under mild reaction conditions and provides bromo-substituted magnesium reagents. Assessing the role of Lewis donor additives in these reactions revealed that N,N,N',N'',N''-pentamethyldiethylenetriamine (PMDTA) finely tunes the regioselectivity of the Br/Mg exchange on dibromo-pyridines and quinolines. Combining spectroscopic with X-ray crystallographic studies, light has been shed on the mixed Li/Mg constitution of the organometallic intermediates accomplishing these transformations. These systems reacted effectively with a broad range of electrophiles, including allyl bromides, ketones, aldehydes, and Weinreb amides in good yields.

Recent Advances of the Halogen-Zinc Exchange Reaction.

For the preparation of zinc organometallics bearing highly sensitive functional groups such as ketones, aldehydes or nitro groups, especially mild halogen-zinc exchange reagents have proven to be of great potential. In this Minireview, the latest research in the area of the halogen-zinc exchange reaction is reported, with a special focus lying on novel dialkylzinc reagents complexed with lithium alkoxides. Additionally, the preparation and application of organofluorine zinc reagents and transition-metal-catalyzed halogen-zinc exchange reactions are reviewed.

Diastereo- and Enantioselective Cross-Couplings of Secondary Alkylcopper Reagents with 3-Halogeno-Unsaturated Carbonyl Derivatives.

Chiral secondary alkylcopper reagents were prepared from the corresponding alkyl iodides with retention of configuration by an I/Li-exchange using tBuLi (-100 °C, 1 min) followed by a transmetalation with CuBr⋅P(OEt)3 (-100 °C, 20 s). These stereodefined secondary alkylcoppers underwent stereoretentive cross-couplings with several 3-iodo or 3-bromo unsaturated carbonyl derivatives leading to the corresponding γ-methylated Michael acceptors in good yields and with high diastereoselectivities (dr up to 96:4). The method was extended to enantiomerically enriched alkylcoppers, providing optically enriched advanced natural product intermediates with up to 90 % ee.

Pyrrole-Protected ß-Aminoalkylzinc Reagents for the Enantioselective Synthesis of Amino-Derivatives.

Chiral ß-aminoalkylzinc halides were prepared starting from optically pure commercial ß-amino-alcohols. These amino-alcohols were converted to the corresponding N-pyrrolyl-protected alkyl iodides which undergo a zinc insertion in the presence of LiCl (THF, 25 °C, 10-90 min). Subsequent Negishi cross-coupling or acylation reactions with acid chlorides produced amino-derivatives with retention of chirality. Diastereoselective CBS-reductions of some prepared N-pyrrolyl-ketones provided 1,3-subsituted N-pyrrolyl-alcohols with high diastereoselectivity. Additionally, a deprotection procedure involving an ozonolysis allowed the conversion of the pyrrole-ring into a formamide without loss of optical purity.

Iron-Catalyzed Cross-Coupling of Bis-(aryl)manganese Nucleophiles with Alkenyl Halides: Optimization and Mechanistic Investigations.

Various substituted bis-(aryl)manganese species were prepared from aryl bromides by one-pot insertion of magnesium turnings in the presence of LiCl and in situ trans-metalation with MnCl2 in THF at -5 °C within 2 h. These bis-(aryl)manganese reagents undergo smooth iron-catalyzed cross-couplings using 10 mol% Fe(acac)3 with various functionalized alkenyl iodides and bromides in 1 h at 25 °C. The aryl-alkenyl cross-coupling reaction mechanism was thoroughly investigated through paramagnetic 1H-NMR, which identified the key role of tris-coordinated ate-iron(II) species in the catalytic process.