Polar reactive organometallic species have been key reagents in synthesis for more than a century. Stereodefined 1,2-dimetallated alkenes offer promising synthetic utility; however, few methods are available for their preparation due to their relatively low stability. Here we report the reductive anti-1,2-dimetallation of alkynes to stereoselectively generate trans-1,2-dimagnesio- and 1,2-dialuminoalkenes, which are stable and have been demonstrated in organic synthesis. These stereodefined 1,2-dimetallated alkenes are prepared through the use of a sodium dispersion as a reducing agent, and organomagnesium and organoaluminium halides as reduction-resistant electrophiles. Highly nucleophilic 1,2-dimagnesioalkenes serve as dual Grignard reagents and have been demonstrated to react with various electrophiles to afford anti-difunctionalized alkenes. The 1,2-dialuminoalkenes react with paraformaldehyde with dearomatization of the aryl moieties to form the corresponding dearomatized 1,4-diols, with the overall reaction being regarded as alkynyl-directed dearomatization of arenes. X-ray crystallographic analysis further supports the formation of trans-1,2-dimagnesio- and 1,2-dialuminoalkenes, with computational studies providing insight into the mechanism of dearomative difunctionalization.
Organometallic species bearing a polar carbon–metal bond occupy an indispensable position in organic chemistry due to their high reactivity1. As a representative organomagnesium species, Grignard reagents have been widely used for the synthesis of useful molecules ranging from bioactive compounds to organic semiconductors since their discovery in 19002,3. Nowadays, a variety of polar organometallic species, such as organolithium, organozinc and organoaluminium compounds, are readily available and have significantly contributed to the development of organic chemistry.
The preparation of such polar organometallics is often dependent on deprotonation at acidic C–H bonds or on metallation of organic halides via a reductive process or halogen–metal exchange (Fig. 1a)4,5,6. Although these methods are reliable, special classes of precursors, acidic hydrocarbons and halogenated compounds are necessary. Unsaturated hydrocarbons such as alkenes and alkynes represent another important class of precursor (Fig. 1b). Hydrometallation and carbometallation across unsaturated bonds provide highly useful reactive organometallic species such as alkyl and alkenyl metals7,8,9,10,11,12. A key advantage of metallating unsaturated bonds is the increase in molecular complexity and values by starting from simple unsaturated compounds such as alkynes, which are among the most prevalent and primitive structures in organic molecules. The subsequent conversion of the resulting carbon–metal bond then offers straightforward routes to target molecules.
Given the unparalleled importance of monometallation such as hydrometallation and carbometallation, 1,2-dimetallation of unsaturated bonds would be a fascinating transformation. For example, two-electron reduction of alkynes should ideally lead to 1,2-dimetallation (Fig. 1c). The resulting 1,2-dimetalloalkenes should engage in further bond formations at the two reactive carbon–metal bonds to provide a wide variety of multisubstituted alkenes that are otherwise difficult to synthesize. Despite this promising utility, few methods for generating polar reactive 1,2-dimetalloalkenes have been reported13,14,15,16,17,18. The limited research is considered to be due to the following reactivity–stability trade-off issues. (1) Electron injection into alkynes requires strong reductants such as alkali metals and solvated electrons. (2) After electron injection from alkali metal occurs, the resulting radical anion intermediates and the 1,2-dimetalloalkene products are too unstable for use in organic synthesis. When the electron injection to alkynes is too slow, as in the reduction of diphenylacetylene with lithium in Et2O, the generated radical anion intermediates readily dimerize to form 1,4-dimetallo-1,3-butadienes19,20. While 1,2-dilithio- and 1,2-disodioalkenes can be generated from diphenylacetylene and alkali metal in THF13, they decompose via protonation by the THF solvent even at −78 °C and cannot be used for organic synthesis (Fig. 1d). Another notable example is that the dissolving metal reduction of alkynes always ends up with the formation of trans-alkenes via smooth protonations of anionic intermediates by a protic solvent (liquid ammonia) with isolation of any vinylic metal intermediates being elusive. (3) As examples of very limited successful cases, engineered bulky dinuclear Mg(I) and Al(II) complexes14,15,16 are known to undergo anti-dimetallation and yield stable trans-1,2-dimetalloalkenes (Fig. 1e). Bulky diiminatoaluminium chloride complexes are also known to undergo anti-dialumination in the presence of potassium metal via the addition of an aluminium-centred radical to alkynes17,18. However, these complexes are ingeniously designed and decorated with special ligands, and are thus not readily accessible. Furthermore, the generated 1,2-dimetalloalkenes were not used for organic synthesis but were examined to undergo simple protonolysis, iodonolysis and transmetallation to zinc. (4) While a different approach to 1,2-dimetalloalkenes could be dimetallation of 1,2-dihaloalkenes, β-elimination from the 1-metallo-2-haloalkene intermediates takes place more rapidly than the second metallation21,22,23. Therefore, there remains ample room to develop facile synthesis and applications of potentially useful 1,2-dimetalloalkenes.
We have been interested in the development of alkali-metal-promoted reductive transformation of unsaturated compounds24,25,26,27,28 using reduction-resistant electrophiles as key reagents29,30,31. On one hand, this class of electrophiles, which includes trialkoxyboranes, are resistant to single-electron reduction and hence can coexist in the same pot where the reduction of unsaturated substrates takes place. On the other hand, they are sufficiently electrophilic to immediately trap the unstable anions thus formed. We have developed sodium-mediated 1,2-syn-diboration of alkynes with trimethoxyborane30. This success encouraged us to develop a new method to generate more reactive and polar 1,2-dimetalloalkenes that are much more difficult to prepare and use. Here we report that the sodium-mediated reductive dimetallation of alkynes proceeds in the presence of magnesium- and aluminium-based reduction-resistant electrophiles (Fig. 1f). The reaction efficiently affords the corresponding reactive but stable 1,2-dimetalloalkenes with, more importantly, high anti-selectivity that is hard to achieve. The resulting trans-1,2-dimagnesioalkenes react with various electrophiles to afford the corresponding trans-difunctionalized alkenes. Their aluminium equivalents were found to induce an unexpected dearomatization32,33,34,35,36,37,38 at the terminal arene upon treatment with an aldehyde. Crystallographic analysis of the intermediates and density functional theory (DFT) calculations of the dearomatization are also described herein.
Results and discussion
Optimization and reaction scope of dimagnesiation
We started our investigation by optimizing the reaction conditions for 1,2-dimagnesiation of diphenylacetylene (1a) (Table 1). The corresponding organomagnesium species 2a should be sensitive to air and moisture, and burdensome to isolate; therefore, the reaction efficiency was evaluated by the yield of stable diborylated product 3a after treatment of 2a with a boron electrophile. Following the conditions of the diboration of alkynes30, we initially employed magnesium alkoxides and halides as reduction-resistant magnesium electrophiles. However, magnesium ethoxide and related alkoxides were not readily soluble in THF, so that 3a was not obtained at all. Magnesium dichloride was not resistant to reduction and underwent preferential reduction to Rieke-type magnesium39 without forming 3a. After further trials, it was discovered that the Grignard reagents are suitable reduction-resistant magnesium electrophiles in the presence of alkynes although they are always considered as nucleophiles in organic synthesis.
In the presence of 2 equiv. of isopropylmagnesium bromide, 1a was reduced by 2 equiv. of a sodium dispersion (in mineral oil) in THF at 0 °C before treatment with methoxypinacolborane (MeOBpin) at 60 °C for 1 h (entry 1). The expected dimagnesiation and diborylation proceeded to afford 3a in 90% yield, although without stereoselectivity. Other boron electrophiles such as ethoxypinacolborane (EtOBpin) and isopropoxypinacolborane (iPrOBpin) were screened, which identified iPrOBpin as the best for stereoretentive diboration (entries 2 and 3). The effect of the substituent on the organomagnesium species was investigated next. When methylmagnesium bromide (MeMgBr) was used, the conversion of 1a was relatively low, possibly because the reduction of MeMgBr competed with that of 1a (entry 4). The use of tert-butylmagnesium bromide or phenylmagnesium bromide afforded 3a with low stereoselectivities, although with good yields (entries 5 and 6). Finally, cyclopentylmagnesium bromide (cPentMgBr) was found to be optimal in terms of both yield and selectivity (entry 7). When sodium lumps (diameter, ∼2 mm) or lithium granules (diameter, ∼2 mm) were used as the reductant, the efficiency of the electron transfer was so low because of their small surface area that the conversion of 1a was insufficient (entries 8 and 9). The use of lithium powder (diameter, ∼0.12–0.25 mm) improved the yield of 3a to 59%, although a lower yield than that in entry 7 (entry 10). Employing sodium naphthalenide resulted in the formation of 3a in 74% yield with good stereoselectivity (entry 11).
Having optimized reaction conditions (Table 1, entry 7), we investigated the scope of this dimagnesiation–diborylation sequence with respect to diarylacetylenes (Fig. 2a). It is worth noting that yields of the pure E isomers of 3 are shown here since the major isomers (E)-3 could be easily separated from the minor isomers (Z)-3 (E:Z = 77:23–91:9) by means of routine silica-gel chromatography (see Supplementary Information for the yields and isomeric ratios of the products in crude reaction mixtures). A variety of diarylacetylenes underwent the reduction to yield the corresponding (E)-diborylalkenes 3a–j in high yields, which represents a rare example of formal anti-diboration of alkynes40,41,42,43,44. In spite of the strongly reducing and basic conditions, ether (3c and 3f), thioether (3d), fluoro (3f) and silyl (3g) moieties were well tolerated during the reaction. Moreover, sterically demanding ortho-substituents in diarylacetylenes 1i and 1j did not hamper the reaction. In addition, the present anti-diboration also accommodates arylacetylene with a π-extended naphthyl group (1h). Instead of boron electrophiles, carbonyl compounds such as paraformaldehyde reacted with 2 to yield 1,4-diols 4aa and 4fa in high yields (Fig. 2b).
To our delight, 1,2-dimagnesioalkenes 2 reacted with other electrophiles with the aid of a copper catalyst (Fig. 2c). CuCN·2LiCl (ref. 45) catalysed the reaction of 2 with isobutylene oxide to provide the corresponding 1,6-diols 4ab, 4eb and 4kb with complete E-selectivity, where none of the Z isomers were detected in crude reaction mixtures. Copper-catalysed reactions with methoxymethyl chloride and with allyl chloride similarly gave (E)-1,4-diether 4ac and 4lc and (E)-1,4,7-octatrienes 4ad and 4fd with exclusive stereoselectivity. Not only diarylacetylenes but alkylarylacetylene 1l was also applicable to the present reaction. Moreover, the sequential addition of two different electrophiles to 1,2-dimagnesioalkenes 2 catalysed by copper accomplished unsymmetric 1,2-difunctionalizations. The desired unsymmetrically difunctionalized product 4ae was obtained from symmetric diphenylacetylene (1a), and a differently tetrasubstituted alkene 4ie was obtained via the regio- and stereoselective unsymmetric 1,2-difunctionalization of unsymmetric alkyne 1i.
Dialumination and subsequent dearomatization reaction
Encouraged by the success of the dimagnesiation, dialumination was attempted using an aluminium-based electrophile. When dimethylaluminium chloride was used as the electrophile, similar anti-dimetallation took place (Fig. 3a). Surprisingly, the subsequent reaction of the dialuminoalkene 5a with paraformaldehyde resulted in the formation of not 4aa but an unexpected product, dearomatized diol 6a, with regeneration of the alkyne unit and with exclusive anti-selectivity. Further optimization (Supplementary Table 2) of the conditions for the dialumination (in 4-methyltetrahydropyran (4-MeTHP) at −78 °C), as shown in Fig. 3b, afforded 6a in 86% yield without the formation of 4aa and its stereoisomer 4aa′.
With the optimal conditions established, the scope with respect to arylacetylenes was explored (Fig. 3b). Diarylacetylenes 1a, 1b, 1h and 1m underwent the dearomatization to afford the corresponding 1,4-diols 6 in good yields. The naphthyl moiety of 1h was selectively dearomatized, probably due to its lower aromaticity than that of the phenyl moiety. It is noteworthy that sterically demanding 1m participated in the reaction to give a mixture of two regioisomers 6m and 6m′, regardless of the ortho-methyl substituent. The reaction also accommodates alkylarylacetylenes 1l and 1n–p. Biphenyl substrate 1o reacted selectively on the phenyl ring with an alkynyl substituent to yield 6o. Arylsilylacetylenes 1q and 1r were converted while the frangible silyl groups were untouched. These transformations are regarded as a novel class of dearomatization reaction of arylacetylenes directed by a carbon–carbon triple bond. As an additional note, these are rare examples of alkyne-directed reactions with the alkyne unit left in the products, while reported transformations directed by a carbon–carbon triple bond have always accompanied irreversible conversions of the reactive triple bond into a double bond46,47.
The obtained dearomatized 1,4-diol 6a could be further transformed into complex molecules that would otherwise be difficult to synthesize (Fig. 3c). The Diels–Alder reaction with N-methylmaleimide or 4-phenyl-1,2,4-triazoline-3,5-dione gave the corresponding bicyclo[2.2.2]octene 7 or 8 in excellent yield as a single isomer. Gold-catalysed cycloisomerization of 6a proceeded efficiently to form a tricyclic acetal 9 (ref. 48). Oxidation of the diene moiety by photosensitized singlet oxygen followed by treatment with thiourea and acetylation gave densely oxygenated tetraacetate 10 (ref. 49). Moreover, formal cleavage of two carbon–carbon bonds in a benzene ring by means of the aluminium-mediated dearomatization of 1a and the subsequent Diels–Alder reaction–retro-Diels–Alder reaction sequence provided trans-2-butene-1,4-diol 11, along with 12, in 90% yield from 6a and in 77% overall yield50.
X-ray crystallography of trans-1,2-dimetalloalkenes
The structures of key dimetalloalkene intermediates 2 and 5 were unambiguously determined by X-ray crystallography (Fig. 4). A dimagnesioalkene for X-ray diffraction analysis was synthesized by a reaction of 1a with mineral-oil-free sodium lumps in the presence of isopropylmagnesium chloride for a long reaction time of 16 h. After removal of NaCl, recrystallization from toluene provided the corresponding trans-1,2-dimagnesioethene 2aiPr(THF)4 as yellowish orange crystals in 47% yield. Following a similar procedure, trans-1,2-dialuminoethene 5aEt(THF)2 was prepared from diethylaluminium chloride as pale yellow crystals in 12% yield. The verification of the trans stereochemistry of 5 is important to eliminate the possibility of the preferential formation of its cis isomer51. X-ray diffraction analysis of single crystals of both 2aiPr(THF)4 and 5aEt(THF)2 displayed dimetallic structures where the two metals occupy the trans-positions to each other in the central ethene skeletons. The C1–C1′ bonds in the [PhCCPh] unit delivered from diphenylacetylene are elongated to typical C=C double bonds (1.328(6) Å for 2aiPr(THF)4 and 1.355(2) Å for 5aEt(THF)2) along with formation of comparable C(sp2)–metal bonds (C1–Mg1 in 2aiPr, 2.195(4) Å; C1–Al1 in 5aEt, 2.005(2) Å) to those in the reported 1,2-dimagnesioethene14 and 1,2-dialuminoethenes15,16,17. Akin to the Ci symmetric system in the crystal structures, NMR spectral analysis of 2aiPr(THF)4 and 5aEt(THF)2 also revealed symmetric features in solution. Notably, the 13C NMR spectra of 2aiPr(THF)4 and 5aEt(THF)2 showed highly downfield-shifted 13C NMR resonances at 195.9 ppm and 175.9 ppm, respectively, compared with that of free diphenylacetylene, while the phenyl rings of 2aiPr(THF)4 and 5aEt(THF)2 were observed in the typical aromatic region.
Having the isolated 1,2-dimetalloethenes 2aiPr(THF)4 and 5aEt(THF)2 in hand, we resorted to demonstrating reactivity similar to that shown in Figs. 2c and 3b. 1,2-Dimagnesioethene 2aiPr(THF)4 underwent the copper-catalysed hydroxyalkylation using isobutylene oxide to afford 4ab in 80% yield (Supplementary Fig. 4a). 1,2-Dialuminoethene 5aEt(THF)2 reacted with paraformaldehyde to provide 6a in 80% yield (Supplementary Fig. 4b).
Computational investigation of dearomatization
To investigate the mechanism of the unique dearomatization of arylacetylenes (Fig. 3a,b), DFT calculations were performed using the reaction of 1,2-dialumino-1,2-diphenylethene 5aMe with monomeric formaldehyde in THF solvent as a model reaction (Fig. 5).
In the case of dearomatization (Fig. 5a), the reaction begins with the coordination of a formaldehyde molecule to one of the aluminium atoms of 5aMe to form metastable intermediate INT-d1tAl. The subsequent C–C bond formation with dearomatization of the neighbouring phenyl ring occurs via a six-membered cyclic transition state TS-d1tAl to provide a transient allenyl intermediate INT-d2tAl. Barrierless recoordination of a THF molecule to the tricoordinated aluminium atom gives a stable intermediate INT-d3tAl. The subsequent ligand exchange of THF with formaldehyde at the other aluminium atom affords INT-d4tAl before the second C–C bond formation proceeds again through a six-membered cyclic transition state TS-d2tAl. Favourable recoordination of a THF solvent molecule to the aluminium atom yields a dearomatized 1,4-diolate INT-d5tAl as the final product. The first C–C bond-forming step via TS-d1tAl with dearomatization is rate-determining (ΔG‡ = 18.8 kcal mol−1) while the second C–C bond-forming step proceeds more smoothly (ΔG‡ = 8.3 kcal mol−1), which is consistent with the experimental result that the allenylic by-products derived from INT-d3tAl were not observed at all. Benzylic metal species, especially benzylmagnesiums, are known to undergo nucleophilic addition to aldehyde with dearomatization despite low efficiency and regioselectivity52,53. Our reaction is much more efficient and regioselective, probably because the second nucleophilic attack drives the reaction forward and suppresses the collapse back to the original dialuminoalkene 5aMe and formaldehyde. The low activation energy for each step allows the entire process to proceed smoothly even at room temperature. Although the reaction between 5 and paraformaldehyde was performed at 60 °C, high temperature is necessary for the decomposition of paraformaldehyde to the monomeric species H2C=O (Fig. 3b).
In the case of the conceivable twofold ipso-alkylation (Fig. 5b), the first and second C–C bond formations occur via four-membered cyclic transition states TS-i1tAl and TS-i2tAl, respectively. Unlike the dearomatization in Fig. 5a, the rate-determining step is the second C–C bond-forming step (INT-i3tAl → TS-i2tAl; ΔG‡ = 22.0 kcal mol−1 versus 21.3 kcal mol−1 for the first step), which is in good agreement with the experimental fact that a trace amount of monohydroxymethylated alkene derived from INT-i3tAl was observed as a side product. The difference between the activation energies for the first steps in Fig. 5a,b was calculated to be 2.6 kcal mol−1 (18.8 kcal mol versus 21.3 kcal mol−1) in favour of the dearomatization process.
Similar calculations for the reaction of the magnesium counterpart 2aMe with two molecules of formaldehyde were next conducted to identify similar pathways for the dearomatization and the twofold ipso-hydroxymethylations (Supplementary Figs. 7 and 8). In contrast to the aluminium case, the activation barrier of the first C–C bond formation step for the ipso-hydroxymethylation is much lower than that for the dearomatization (ΔΔG‡ = 7.6 kcal mol−1), which coincides with the exclusive ipso-hydroxymethylation without the dearomatization as shown in Fig. 2b. Based on distortion/interaction analyses54,55 (Supplementary Figs. 15−17), we assume that the shorter C–Al bond (2.08 Å) in TS-i1tAl would induce a larger ring strain in the four-membered transition state TS-i1tAl than the C–Mg bond (2.22 Å) in TS-i1tMg, and consequently render the activation energy at TS-i1tAl higher.
We have uncovered reductive anti-1,2-dimetallation of arylacetylenes using sodium dispersion as a reducing agent and cyclopentylmagnesium bromide and dimethylaluminium chloride as reduction-resistant electrophiles. The intermediates, trans-1,2-dimagnesio- and dialuminoalkenes, represent rare examples of trans-1,2-dimetalloalkenes that are difficult to prepare, reasonably stable and useful for organic synthesis. Highly nucleophilic 1,2-dimagnesioalkenes reacted with a wide variety of electrophiles to afford anti-difunctionalized alkenes in a stereoselective manner. Interestingly, the reaction of the 1,2-dialuminoalkenes with paraformaldehyde induced dearomatization of the aryl moieties to form the corresponding dearomatized 1,4-diols with recovery of the alkyne unit, which is regarded as alkynyl-directed dearomatization of arenes. These represent the synthetic versatility of the dimagnesioalkenes and the unique reactivity of the dialuminoalkenes. The structures of 1,2- dimagnesio- and aluminoalkenes were unambiguously determined by X-ray crystallography to confirm their intermediacy. The mechanism of the dearomative difunctionalization was investigated using DFT calculations to clarify the unusual behaviour of unique organoaluminium species. Further exploration of the synthesis and utility of 1,2-dimetalloalkenes is ongoing in our laboratory.
General procedure for synthesis of 1,2-diborylalkenes 3
See Fig. 2a. An oven-dried 20 ml Schlenk tube was charged with alkyne 1 (1.0 mmol), cPentMgBr (1.0 M in THF, 2.0 ml, 2.0 mmol) and THF (2.0 ml). After cooling the mixture to 0 °C, sodium dispersion (10 M, 0.20 ml, 2.0 mmol) was added dropwise over 30 s to the tube, and the resulting suspension was stirred at 0 °C for 30 min. After the addition of iPrOBpin (1.2 ml, 6.0 mmol) to the tube, the reaction mixture was warmed to 60 °C and stirred at the same temperature for an additional 2 h. After cooling the mixture to room temperature, aqueous HCl (2 M, 2 ml) and H2O (2 ml) were added to the tube, and the resulting biphasic solution was extracted with Et2O (4 ml × 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (eluent: hexane/EtOAc) provided 3.
General procedure for copper-catalysed trans-difunctionalization of alkynes 1
See Fig. 2c. An oven-dried 20 ml Schlenk tube was charged with alkyne 1 (1.0 mmol), cPentMgBr (1.0 M in THF, 2.0 ml, 2.0 mmol) and THF (2.0 ml). After cooling the mixture to 0 °C, sodium dispersion (10 M, 0.20 ml, 2.0 mmol) was added dropwise over 30 s to the tube, and the resulting suspension was stirred at 0 °C for 30 min. After the addition of CuCN·2LiCl (1.0 M in THF, 0.10 ml, 0.10 mmol) and an electrophile (4.0 mmol) to the tube, the reaction mixture was allowed to warm to room temperature and stirred for an additional 1 h. The reaction was then quenched by the addition of aqueous HCl (2 M, 2 ml) and H2O (2 ml), and the resulting biphasic solution was extracted with Et2O (4 ml × 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (eluent: hexane/EtOAc) provided 4. If necessary, further purification was done by gel permeation chromatography.
General procedure for synthesis of dearomatized diols 6
See Fig. 3b. An oven-dried 20 ml Schlenk tube was charged with alkyne 1 (1.0 mmol), Me2AlCl (1.0 M in hexane, 2.0 ml, 2.0 mmol) and 4-MeTHP (6.0 ml). After cooling the mixture to −78 °C, sodium dispersion (10 M, 0.22 ml, 2.2 mmol) was added dropwise over 30 s to the tube, and the resulting suspension was stirred at −78 °C for 30 min. After the addition of paraformaldehyde (4.0 mmol) to the tube, the reaction mixture was allowed to warm to room temperature over 10 min and then stirred at 60 °C for an additional 1 h. After cooling the mixture to room temperature, the reaction was quenched by the addition of aqueous HCl (2 M, 3.5 ml), and the resulting biphasic solution was extracted with Et2O (4 ml × 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (eluent: hexane/EtOAc) provided 6.
Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2167281 (2aiPr(THF)4), CCDC 2167282 (5aEt(THF)2), CCDC 2167622 (5aEt-Cl(THF)2) and CCDC 2167689 (8). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. The data supporting the findings of this study are available within the Article and its Supplementary Information.
Schlosser, M. (ed.) Organometallics in Synthesis: A Manual (Wiley, 2002).
Harutyunyan, S. R., den Hartog, T., Geurts, K., Minnaard, A. J. & Feringa, B. L. Catalytic asymmetric conjugate addition and allylic alkylation with Grignard reagents. Chem. Rev. 108, 2824–2852 (2008).
Knappke, C. E. I. & von Wangelin, A. J. 35 years of palladium-catalyzed cross-coupling with Grignard reagents: how far have we come? Chem. Soc. Rev. 40, 4948–4962 (2011).
Knochel, P. et al. Highly functionalized organomagnesium reagents prepared through halogen–metal exchange. Angew. Chem. Int. Ed. 42, 4302–4320 (2003).
Boudier, A., Bromm, L. O., Lotz, M. & Knochel, P. New applications of polyfunctional organometallic compounds in organic synthesis. Angew. Chem. Int. Ed. 39, 4414–4435 (2000).
Hevia, E. Towards a paradigm shift in polar organometallic chemistry. Chimia 74, 681–688 (2020).
Marek, I. Enantioselective carbometallation of unactivated olefins. J. Chem. Soc. Perkin 1 1999, 535–544 (1999).
Flynn, A. B. & Ogilvie, W. W. Stereocontrolled synthesis of tetrasubstituted olefins. Chem. Rev. 107, 4698–4745 (2007).
Müller, D. S. & Marek, I. Copper mediated carbometalation reactions. Chem. Soc. Rev. 45, 4552–4566 (2016).
Murakami, K. & Yorimitsu, H. Recent advances in transition-metal-catalyzed intermolecular carbomagnesiation and carbozincation. Beilstein J. Org. Chem. 9, 278–302 (2013).
Wei, D. & Darcel, C. Iron catalysis in reduction and hydrometalation reactions. Chem. Rev. 119, 2550–2610 (2019).
Fürstner, A. trans-Hydrogenation, gem-hydrogenation, and trans-hydrometalation of alkynes: an interim report on an unorthodox reactivity paradigm. J. Am. Chem. Soc. 141, 11–24 (2019).
Levin, G., Jagur-Grodzinski, J. & Szwarc, M. Chemistry of radical anions and dianions of diphenylacetylene. J. Am. Chem. Soc. 92, 2268–2275 (1970).
Dange, D. et al. Acyclic 1,2-dimagnesioethanes/-ethene derived from magnesium(I) compounds: multipurpose reagents for organometallic synthesis. Chem. Sci. 10, 3208–3216 (2019).
Zhao, Y., Liu, Y., Lei, Y., Wu, B. & Yang, X.-J. Activation of alkynes by an α-diimine-stabilized Al–Al-bonded compound: insertion into the Al–Al bond or cycloaddition to AlN2C2 rings. Chem. Commun. 49, 4546–4548 (2013).
Hofmann, A. et al. Dialumination of unsaturated species with a reactive bis(cyclopentadienyl)dialane. Chem. Commun. 54, 1639–1642 (2018).
Chlupatý, T., Turek, J., De Proft, F., Růžičková, Z. & Růžička, A. Addition of in situ reduced amidinatomethylaluminium chloride to acetylenes. Dalton Trans. 44, 17462–17466 (2015).
Cui, C. et al. Facile synthesis of cyclopropene analogues of aluminum and an aluminum pinacolate, and the reactivity of LAl[η2-C2(SiMe3)2] toward unsaturated molecules (L = HC[(CMe)(NAr)]2, Ar = 2,6-i-Pr2C6H3. J. Am. Chem. Soc. 123, 9091–9098 (2001).
Schlenk, W. & Bergmann, E. Forschungen auf dem gebiete der alkaliorganischen verbindungen. I. Über produkte der addition von alkalimetal an mehrfache kohlenstoff-kohlenstoff-bindungen. Justus Liebigs Ann. Chem 463, 1–97 (1928).
Smith, L. I. & Hoehn, H. H. The reaction between lithium and diphenylacetylene. J. Am. Chem. Soc. 63, 1184–1187 (1941).
Engler, T. A., Combrink, K. D. & Ray, J. E. An efficient method for the synthesis of 1-arylalkynes. Synth. Commun. 19, 1735–1744 (1989).
Spencer, J. T. & Grimes, R. N. Organotransition-metal metallacarboranes. 9. nido-2,3-Dibenzyl-2,3-dicarbahexaborane(8) [(PhCH2)2C2B4H6], a versatile multifunctional nido-carborane: iron–polyarene sandwich compounds and chromium tricarbonyl π-complexes. Organometallics 6, 328–335 (1987).
Al-jumaili, M. A. & Woodward, S. Syntheses of 7-substituted anthra[2,3-b]thiophene derivatives and naphtho[2,3-b:6,7-b′]dithiophene. J. Org. Chem. 83, 11437–11445 (2018).
De, P. B., Asako, S. & Ilies, L. Recent advances in the use of sodium dispersion for organic synthesis. Synthesis 53, 3180–3192 (2021).
An, J., Work, D. N., Kenyon, C. & Procter, D. J. Evaluating a sodium dispersion reagent for the Bouveault–Blanc reduction of esters. J. Org. Chem. 79, 6743–6747 (2014).
Asako, S., Nakajima, H. & Takai, K. Organosodium compounds for catalytic cross-coupling. Nat. Catal. 2, 297–303 (2019).
Peters, B. K. et al. Scalable and safe synthetic organic electroreduction inspired by Li-ion battery chemistry. Science 363, 838–845 (2019).
Burrows, J., Kamo, S. & Koide, K. Scalable Birch reduction with lithium and ethylenediamine in tetrahydrofuran. Science 374, 741–746 (2021).
Takahashi, F., Nogi, K., Sasamori, T. & Yorimitsu, H. Diborative reduction of alkynes to 1,2-diboryl-1,2-dimetalloalkanes: its application for the synthesis of diverse 1,2-bis(boronate)s. Org. Lett. 21, 4739–4744 (2019).
Ito, S., Fukazawa, M., Takahashi, F., Nogi, K. & Yorimitsu, H. Sodium-metal-promoted reductive 1,2-syn-diboration of alkynes with reduction-resistant trimethoxyborane. Bull. Chem. Soc. Jpn. 93, 1171–1179 (2020).
Fukazawa, M., Takahashi, F., Nogi, K., Sasamori, K. & Yorimitsu, H. Reductive difunctionalization of aryl alkenes with sodium metal and reduction-resistant alkoxy-substituted electrophiles. Org. Lett. 22, 2303–2307 (2020).
Cheng, Y.-Z., Feng, Z., Zhang, X. & You, S.-L. Visible-light induced dearomatization reactions. Chem. Soc. Rev. 51, 2145–2170 (2022).
Sharma, U. K., Ranjan, P., Van der Eyken, E. V. & You, S.-L. Sequential and direct multicomponent reaction (MCR)-based dearomatization strategies. Chem. Soc. Rev. 49, 8721–8748 (2020).
Huck, C. J. & Sarlah, D. Shaping molecular landscapes: recent advances, opportunities, and challenges in dearomatization. Chem 6, 1589–1603 (2020).
Wertjes, W. C., Southgate, E. H. & Sarlah, D. Recent advances in chemical dearomatization of nonactivated arenes. Chem. Soc. Rev. 47, 7996–8017 (2018).
Zheng, C. & You, S.-L. Catalytic asymmetric dearomatization by transition-metal catalysis: a method for transformations of aromatic compounds. Chem 1, 830–857 (2016).
Zhuo, C.-X., Zhang, W. & You, S.-L. Catalytic asymmetric dearomatization reaction. Angew. Chem. Int. Ed. 51, 12662–12686 (2012).
Roche, S. P. & Porco, J. A. Jr. Dearomatization strategies in the synthesis of complex natural products. Angew. Chem. Int. Ed. 50, 4068–4093 (2011).
Rieke, R. D. Preparation of highly reactive metal powders and their use in organic and organometallic synthesis. Acc. Chem. Res. 10, 301–306 (1977).
Kojima, C., Lee, K.-H., Lin, Z. & Yamashita, M. Direct and base-catalyzed diboration of alkynes using the unsymmetrical diborane(4), pinB-BMes2. J. Am. Chem. Soc. 138, 6662–6669 (2016).
Yoshimura, A. et al. Photoinduced metal-free diboration of alkynes in the presence of organophosphine catalysts. Tetrahedron 72, 7832–7838 (2016).
Nagashima, Y., Hirano, K., Takita, R. & Uchiyama, M. Trans-diborylation of alkynes: pseudo-intramolecular strategy utilizing a propargylic alcohol unit. J. Am. Chem. Soc. 136, 8532–8535 (2014).
Nagao, K., Ohmiya, H. & Sawamura, M. Anti-selective vicinal silaboration and diboration of alkynoates through phosphine organocatalysis. Org. Lett. 17, 1304–1307 (2015).
Ohmura, T., Morimasa, Y. & Suginome, M. 4,4′-Bipyridine-catalyzed stereoselective trans-diboration of acetylenedicarboxylates to 2,3-diborylfumarates. Chem. Lett. 46, 1793–1796 (2017).
Knochel, P., Yeh, M. C. P., Berk, S. C. & Talbert, J. Synthesis and reactivity toward acyl chlorides and enones of the new highly functionalized copper reagents RCu(CN)ZnI. J. Org. Chem. 53, 2390–2392 (1988).
Minami, Y., Shiraishi, Y., Yamada, K. & Hiyama, T. Palladium-catalyzed cycloaddition of alkynyl aryl ethers with internal alkynes via selective ortho C–H activation. J. Am. Chem. Soc. 134, 6124–6127 (2012).
Chernyak, N. & Gevorgyan, V. Exclusive 5-exo-dig hydroarylation of o-alkynyl biaryls proceeding via C–H activation pathway. J. Am. Chem. Soc. 130, 5636–5637 (2008).
Alcaide, B., Almendros, P. & Carrascosa, R. Gold-catalyzed direct cycloketalization of acetonide-tethered alkynes in the presence of water. Tetrahedron 68, 9391–9396 (2012).
Baran, A. & Balci, M. Stereoselective synthesis of bishomo-inositols as glycosidase inhibitors. J. Org. Chem. 74, 88–95 (2009).
Ohno, T., Ozaki, M., Inagaki, A., Hirashima, T. & Nishiguchi, I. Synthesis of 1,2-disubstituted benzenes and biphenyls from phthalic acids through electroreduction followed by electrocyclic reaction with alkynes. Tetrahedron Lett. 34, 2629–2632 (1993).
Lehmkuhl, H., Čuljković, J. & Nehl, H. Reaktionen von Trialkylaluminium mit Alkalimetallen oder Magnesium und elektronenaffinen Olefinen. Liebigs Ann. Chem. 1973, 666–691 (1973).
Benkeser, R. A. & Snyder, D. C. Mechanism of the reaction between benzylmagnesium chloride and carbonyl compounds. A detailed study with formaldehyde. J. Org. Chem. 47, 1243–1249 (1982).
Eisch, J. J. & Fichter, K. C. Kinetic control and locoselectivity in the electrophilic cleavage of allylic aluminum compounds: reactions of acenaphthenylaluminum reagents with carbonyl substrates. J. Org. Chem. 49, 4631–4639 (1984).
Fernández, I. & Bickelhaupt, F. M. The activation strain model and molecular orbital theory: understanding and designing chemical reactions. Chem. Soc. Rev. 43, 4953–4967 (2014).
Bickelhaupt, F. M. & Houk, K. N. Analyzing reaction rates with the distortion/interaction-activation strain model. Angew. Chem. Int. Ed. 56, 10070–10086 (2017).
This work was supported by JST CREST grant number JPMJCR19R4 and by JSPS KAKENHI grant number JP19H00895 to H.Y. F.T. acknowledges a JSPS Predoctoral Fellowship (JSPS KAKENHI grant number JP20J22814). H.Y. thanks The Asahi Glass Foundation for financial support. We thank Kobelco Eco-Solutions for providing the sodium dispersion. F.T. thanks H. Saito for insightful discissions on the computational chemistry. We also thank H. Kawaguchi and Y. Ishida for conducting elemental analyses of 2aiPr(THF)4 and 5aEt(THF)2 at the Tokyo Institute of Technology.
The authors declare no competing interests.
Peer review information
Nature Synthesis thanks the anonymous reviewers for their contribution to the peer review of this work. Primary handling editor: Thomas West, in collaboration with the Nature Synthesis team.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figs. 1−143, Tables 1−5 and Discussion.
Supplementary Data 1
Crystallographic data for 2aiPr(THF)4 CCDC 2167281.
Supplementary Data 2
Structure factors for 2aiPr(THF)4 CCDC 2167281.
Supplementary Data 3
Crystallographic data for 5aEt(THF)2 CCDC 2167282.
Supplementary Data 4
Structure factors for 5aEt(THF)2 CCDC 2167282.
Supplementary Data 5
Crystallographic data for 5aEt-Cl(THF)2 CCDC 2167622.
Supplementary Data 6
Structure factors for 5aEt-Cl(THF)2 CCDC 2167622.
Supplementary Data 7
Crystallographic data for 8 CCDC 2167689.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Takahashi, F., Kurogi, T. & Yorimitsu, H. Synthesis of trans-1,2-dimetalloalkenes through reductive anti-dimagnesiation and dialumination of alkynes. Nat. Synth 2, 162–171 (2023). https://doi.org/10.1038/s44160-022-00189-z