Chemo‐ and Regioselective C(sp3)H Arylation of Unactivated Allylarenes by Deprotonative Cross‐Coupling

The combination of aryl bromides, allylbenzene, base and a palladium catalyst usually results in a Heck reaction. Herein we combine these same reagents, but override the Heck pathway by employing a strong base. In the presence of LiN(SiMe₃)₂, allylbenzene derivatives undergo reversible deprotonation. Transmetalation of the resulting allyllithium intermediate to LPdAr(Br) and reductive elimination provide the 1,1‐diarylprop‐2‐enes, which are not accessible by the Heck reaction. The regioselectivity in this deprotonative cross‐coupling process is catalyst‐controlled and very high.     

Chemo‐ and Regioselective C(sp3)?H Arylation of Unactivated Allylarenes by Deprotonative Cross‐Coupling

The combination of aryl bromides, allylbenzene, base and a palladium catalyst usually results in a Heck reaction. Herein we combine these same reagents, but override the Heck pathway by employing a strong base. In the presence of LiN(SiMe₃)₂, allylbenzene derivatives undergo reversible deprotonation. Transmetalation of the resulting allyllithium intermediate to LPdAr(Br) and reductive elimination provide the 1,1‐diarylprop‐2‐enes, which are not accessible by the Heck reaction. The regioselectivity in this deprotonative cross‐coupling process is catalyst‐controlled and very high.     

Direct photo-induced reductive Heck cyclization of indoles for the efficient preparation of polycyclic indolinyl compounds

The photo-induced cleavage of C(sp²)–Cl bonds is an appealing synthetic tool in organic synthesis, but usually requires the use of high UV light, photocatalysts and/or photosensitizers. Herein is described a direct photo-induced chloroarene activation with UVA/blue LEDs that can be used in the reductive Heck cyclization of indoles and without the use of a photocatalyst or photosensitizer. The indole compounds examined display room-temperature phosphorescence. The photochemical reaction tolerates a panel of functional groups including esters, alcohols, amides, cyano and alkenes (27 examples, 50–88% yields), and can be used to prepare polycyclic compounds and perform the functionalization of natural product analogues in moderate to good yields. Mechanistic experiments, including time-resolved absorption spectroscopy, are supportive of photo-induced electron transfer between the indole substrate and DIPEA, with the formation of radical intermediates in the photo-induced dearomatization reaction.

Metal- and photocatalyst-free reductive Heck cyclization of indoles under light irradiation was developed and used to prepare polycyclic compounds and functionalize natural product analogues in moderate to good yields.     

Transmetallation versus β-hydride elimination: the role of 1,4-benzoquinone in chelation-controlled arylation reactions with arylboronic acids

The formation of an atypical, saturated, diarylated, Heck/Suzuki, domino product produced under oxidative Heck reaction conditions, employing arylboronic acids and a chelating vinyl ether, has been investigated by DFT calculations. The calculations highlight the crucial role of 1,4-benzoquinone (BQ) in the reaction. In addition to its role as an oxidant of palladium, which is necessary to complete the catalytic cycle, this electron-deficient alkene opens up a low-energy reaction pathway from the post-insertion σ-alkyl complex. The association of BQ lowers the free-energy barrier for transmetallation of the σ-alkyl complex to create a pathway that is energetically lower than the oxidative Heck reaction pathway. Furthermore, the calculations showed that the reaction is made viable by BQ-mediated reductive elimination and leads to the saturated diarylated product.     

Transmetallation Versus β‐Hydride Elimination: The Role of 1,4‐Benzoquinone in Chelation‐Controlled Arylation Reactions with Arylboronic Acids

The formation of an atypical, saturated, diarylated, Heck/Suzuki, domino product produced under oxidative Heck reaction conditions, employing arylboronic acids and a chelating vinyl ether, has been investigated by DFT calculations. The calculations highlight the crucial role of 1,4‐benzoquinone (BQ) in the reaction. In addition to its role as an oxidant of palladium, which is necessary to complete the catalytic cycle, this electron‐deficient alkene opens up a low‐energy reaction pathway from the post‐insertion σ‐alkyl complex. The association of BQ lowers the free‐energy barrier for transmetallation of the σ‐alkyl complex to create a pathway that is energetically lower than the oxidative Heck reaction pathway. Furthermore, the calculations showed that the reaction is made viable by BQ‐mediated reductive elimination and leads to the saturated diarylated product.     

A model study for constructing the DEF-benzoxocin ring system of menogaril and nogalamycin via a reductive Heck cyclization

A novel reductive Heck cyclization approach was developed in order to construct a model DEF-benzoxocin ring system that is present in nogalamycin, menogaril, and related anthracycline antitumor antibiotics.     

Enantioselective total synthesis of Wieland-Gumlich aldehyde and (-)-strychnine

A total synthesis of (-)-strychnine in 15 steps from 1,3-cyclohexanedione in 0.15% overall yield is described. The sequence followed in the assembling of rings is: E-->AE [2-(2-nitrophenyl)-1,3-cyclohexanedione]-->ACE (3a-aryloctahydroindol-4-one)-->ACDE (arylazatricyclic core)-->ABCDE (strychnan skeleton)-->ABCDEF (Wieland-Gumlich aldehyde)-->ABCDEFG (strychnine). The key steps of the synthesis are the enantioselective construction of the 3a-(2-nitrophenyl)-octahydroindol-4-one ring system and the closure of the piperidine ring by a reductive Heck cyclization to generate the pivotal intermediate (-)-14. In contrast, a Lewis acid promoted a-alkoxypropargylic silane-enone cyclization did not lead to synthetically useful azatricyclic ACDE intermediates. The introduction of C-17 and the closure of the indoline ring by reductive amination of the alpha-(2-nitrophenyl) ketone moiety complete the strychnan skeleton from which, via the Wieland-Gumlich aldehyde, the synthesis of (-)-strychnine is achieved.     

Elucidating reactivity differences in palladium-catalyzed coupling processes: the chemistry of palladium hydrides

This communication describes a series of studies directed at obtaining a better understanding of the Heck reaction. For the first time, the postulated palladium-hydride intermediate (L2PdHX) in the catalytic cycle of the Heck arylation has been identified. In addition, this study establishes that the base-mediated Pd(0)-regeneration step (L2PdHX --> PdL2) of the cycle can be kinetically slow and thermodynamically unfavorable and that the process is remarkably sensitive to the structure of L (PCy3 vs P(t-Bu)3). Finally, this investigation demonstrates that, for certain catalyst systems, slow rates of Heck arylation can be correlated with reluctant reductive elimination of L2PdHX, furnishing a possible rationalization for Br?nsted-base (Cs2CO3 vs Cy2NMe) and ligand (PCy3 vs P(t-Bu)3) effects that have been observed.     

Synthesis of 5-endo-, 5-exo-, 6-endo- and 6-exo-hydroxylated analogues of epibatidine

A convenient, high-yield synthesis of N-Boc-7-azabicyclo[2.2.1]hept-5-en-2-one (7) was developed by SmI₂-mediated desulfonylation of 6. Thus, 5-endo-, 5-exo-, 6-endo-, and 6-exo-hydroxylated epibatidine analogues 2a,b and 3a,b were synthesized from 7 by using a Pd(PPh₃)₄-catalyzed reductive Heck coupling reaction and SmI₂-mediated reduction of the carbonyl group as the key steps. Other reaction conditions for the reductive Heck procedure and the reduction step were also investigated.     

Total Synthesis of (−)‐Strychnine via the Wieland–Gumlich Aldehyde

Fifteen steps suffice for an enantioselective total synthesis of (−)‐strychnine ( 1 ) from 1,3‐cyclohexanedione. The key steps are the easy generation of the enantiopure intermediate 2 , the closure of the piperidine ring by a reductive Heck reaction, and the elaboration of the indoline nucleus in an advanced synthetic stage. TBDMS=tert‐butyldimethylsilyl.     

Revision of the stereochemistry of the reductive Heck cyclisation of 1-(2-iodobenzoyl)-4-substituted-1.4-dihydro-pyridine-3-carbaldehyde aminals

The stereochemistry of reductive and non reductive Heck cyclisations of 4-substituted-1.4-dihydropyridines is reexamined. The both reactions occur mainly via an anti (from the C₄ substituent) 5-exo process without any epimerisation of the C₄-H.     

A short and concise asymmetric synthesis of hamigeran B

The interesting biological properties of the hamigerans wherein hamigeran B is a potent antiviral agent with low cytotoxicity to host cells make these deceptively simple looking structures challenging synthetic targets. A strategy to hamigeran B evolved wherein the three contiguous stereocenters are established ultimately from a Pd catalyzed asymmetric allylic alkylation (AAA). The latter involves an asymmetric allylation of a non-stabilized ketone enolate in 77 % yield and 93 % ee. By using this process, (S)-5-allyl-2-isopropyl-5-methyl-1-trifluoromethanesulfonyloxycyclopentene becomes available in four steps from 2-methylcyclopentanone. Introduction of the aryl unit by cross-coupling proceeded intermolecularly but failed intramolecularly. On the other hand, reductive removal of the triflate permitted a Heck reaction to effect intramolecular introduction of the aryl ring. The unusual conformational properties of this molecular architecture are revealed by the regioselectivity of the beta-hydrogen elimination in the Heck reaction and the diastereoselectivity of the reduction establishing the stereochemistry of the carbon bearing the isopropyl group. The successful route consists of 15 steps from 2-methylcyclopentanone and dimethylorcinol illustrating the efficiency of the route based upon the Pd AAA.     

Synthetic studies towards Chlorahololides A: practical synthesis of a lindenane-type sesquiterpenoid core framework with a 5,6-double bond

Towards Chlorahololides A: a lindenane-type sesquiterpenoid framework that contains a 5,6-double bond was synthesized from simple starting materials. The reductive cyclization of a 1,6-enyne and an unusual endo-type intramolecular Heck reaction was used as key steps for ring closure.     

Enantiocontrolled Total Synthesis of (−)‐Mersicarpine

A racemic synthesis of mersicarpine ( 1 ) was achieved by the Mizoroki–Heck reaction and a DIBALH‐mediated reductive ring‐expansion reaction. Based on a first‐generation synthesis, a second‐generation enantiocontrolled total synthesis of (?)‐mersicarpine ( 1 ) was achieved by an 8‐pot/11‐step sequence in 21 % overall yield from commercially available 2‐ethylcyclohexanone. Subjection of a ketoester, which was prepared by an asymmetric Michael addition (according to the protocol by d’Angelo and Desmaële), and phenylhydrazine to modified Fischer indole conditions provided a six‐membered tricyclic indole. Benzylic oxidation and subsequent oxime formation provided a ketoxime, which was treated with diisobutylaluminum hydride (DIBALH) to construct the characteristic azepinoindole skeleton in good yield. In the DIBALH‐mediated reductive ring‐expansion reaction, gradually increasing the reaction temperature and in situ‐protection of the nitrogen in an oxygen‐sensitive azepinoindole with a benzyloxycarbonyl (Cbz) group were crucial for the high‐yielding process. With these methodologies, the short‐step and efficient synthesis of (?)‐mersicarpine was accomplished. Several synthetic efforts are also described.     

Palladium‐Catalyzed Asymmetric Reductive Heck Reaction of Aryl Halides

Asymmetric reductive Heck reaction of aryl halides is realized in high stereoselectivity. Hydrogen‐bond donors, trialkylammonium salts in a glycol solvent, were used to promote halide dissociation from neutral arylpalladium complexes to access cationic, stereoselective pathways.     

Synthesis of fused indoles by sequential palladium-catalyzed Heck reaction and N-heteroannulation

A route to 3,4-fused indoles via two consecutive palladium-catalyzed reactions; an intramolecular Heck reaction followed by a reductive N-heteroannulation is described. Using this route, a number of indoles have been prepared having a variety of ring sizes anchored to the 3- and 4-position of the indole nucleus. Furthermore, a number of functional groups, both carbon and heteroatom substituents can be introduced in (and on) the additional ring without any detrimental effects on the two reactions.     

Nickel‐Catalyzed Asymmetric Reductive Heck Cyclization of Aryl Halides to Afford Indolines

A nickel‐catalyzed asymmetric reductive Heck reaction of aryl chlorides has been developed that affords substituted indolines with high enantioselectivity. Manganese powder is used as the terminal reductant with water as a proton source. Mechanistically, it is distinct from the palladium‐catalyzed process in that the nickel–carbon bond is converted into a C−H bond to release the product through protonation instead of hydride donation followed by C−H reductive elimination on Pd.     

A straightforward and efficient synthetic access to biologically active marine sesterterpenoids, sesterstatins 4 and 5

A straightforward and efficient synthesis of sesterstatins 4 and 5 is reported, in which the reductive Heck cyclisation was employed as the key step for constructing the D ring.     

Catalytic asymmetric synthesis of quaternary carbons bearing two aryl substituents. Enantioselective synthesis of 3-alkyl-3-aryl oxindoles by catalytic asymmetric intramolecular heck reactions

A practical sequence involving three consecutive palladium(0)-catalyzed reactions has been developed for synthesizing 3-alkyl-3-aryloxindoles in high enantiopurity. The Heck cyclization precursors 10 and 11a-k are generated in one step by chemoselective Stille cross-coupling of 2'-triflato-(Z)-2-stannyl-2-butenanilide 9 with aryl or heteroaryl iodides. The pivotal catalytic asymmetric Heck cyclization step of this sequence takes place in high yield and with high enantioselectivity (71-98% ee) with the Pd-BINAP catalyst derived from Pd(OAc)(2) to construct oxindoles containing a diaryl-substituted all-carbon quaternary carbon center. A wide variety of aryl and heteroaryl substituents, including ones of considerable steric bulk, can be introduced at C3 of oxindoles in this way (Table 4). The only limitations encountered to date are aryl substituents containing ortho nitro or basic amine functionalities and the bulky N-alkyl-7-oxindolyl group. Asymmetric Heck cyclization of butenalide 22 having an o-(N-acetyl-N-benzylamino)phenyl substituent at C2 provided a approximately 1:1 mixture of amide atropisomers 23 and 24 in high yield and high enantioselectivity. These atropisomers are formed directly upon Heck cyclization of 22 at 80 degrees C, as they interconvert thermally to only a small extent at this temperature.     

Efficient synthesis of the 3-benzazepine framework via intramolecular Heck reductive cyclization

A microwave-assisted protocol based on reductive Heck reaction was developed for regio- and stereoselective construction of the 3-benzazepine core.