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An atom-economical purification protocol, using solution phase processing via ring-opening metathesis polymerization (ROMP) has been developed for the synthesis of tricyclic sultams. This chromatography-free method allows for convenient isolation of reductive-Heck products and reclamation of excess starting material via sequestration involving metathesis catalysts and a catalyst-armed Si-surface., (This journal is © The Royal Society of Chemistry 2011)

The development of new methods to skeletally diverse sultams based on a central α-halo benzene sulfonamide building block is reported. Several salient features of this building block are utilized in multiple reaction pathways, including the Heck reaction, C- and O-arylation, Sonogashira-Pauson-Khand, Sonogashira-intramolecular hydroamination, lithiative cyclization and domino aza-Michael Heck for the generation of 5-, 6- and 7-membered benzofused bicyclic and tricyclic sultams.

The parallel synthesis of gamma-turn-inspired peptidomimetic libraries has been demonstrated through two approaches toward the preparation of 1,4-diazepin-5-ones. In the first approach, 1,4-diazepin-5-ones scaffolds were prepared on gram scale and subsequently diversified to produce libraries. In a second approach, libraries of 1,4-diazepin-5-ones were produced directly through a three-component strategy that maximizes the diversity obtained in a single step.

Bicyclic alkenes, including oxa- and azabenzonorbornadienes and their derivatives, can be readily activated by transition metal complexes face-selectively due to their unsymmetrical bicyclic structure and the intrinsic angle strain on the carbon-carbon double bond. We have developed several stereo-, regio-, and chemoselective reactions catalyzed by nickel and palladium complexes using these bicyclic alkenes as substrates, providing a unique means of constructing a variety of synthetically useful carbocycles and heterocycles with high efficiency not generally accessible by traditional methods. This Account outlines these new metal-catalyzed reactions that include couplings, cycloadditions, and cyclization reactions.

A palladium-catalyzed 1,4-enyne synthesis was developed based the decarboxylative coupling of acetylides with allyl electrophiles. Stereochemical studies have implicated palladium-allyl-acetylides as intermediates. Thus, decarboxylative metalation was established as an environmentally benign alternative to transmetalation from alkynyl tin reagents.

A highly regio- and stereoselective method for the synthesis of various 2-silylallylboronates 7 from allenes 1 and 2-(dimethylphenylsilanyl)-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (5) catalyzed by palladium complexes and initiated by organic iodides is described. Treatment of monosubstituted aryl and alkylallenes RCH=C=CH(2) (1a-m) and 1,1-dimethylallene (1n) with borylsilane 5 in the presence of Pd(dba)(2) (5 mol %) and organic iodide 3a (10 mol %) afforded the corresponding silaboration products 7a-n in moderate to excellent yields. This catalytic silaboration is totally regioselective with the silyl group of 5adding to the central carbon and the boryl group to the unsubstituted terminal carbon of allene. Furthermore, the reactions show very high E stereoselectivity with the Z/E ratios lying in the range from 1/99 to 7/93. In the absence of an organic iodide, silaboration of 1 with 5 still proceeds, but gives products having completely different regiochemistry as that of 7. The silaboration chemistry can be applied to the synthesis of homoallylic alcohols. Treatment of allenes (1) with borylsilane 5 and aldehydes 14 in the presence of Pd(dba)(2) (5 mol %) and 3a (10 mol %) at 80 degrees C in ethyl acetate for 5 h afforded homoallylic alcohols 15a-p in one pot in good to excellent yields, with exceedingly high syn selectivity (>93%). Mechanistic pathways involving an unusual palladium-catalyzed three-component assembling reaction of dimethylphenylsilyl iodide, allene 1, and borylsilane 5 were proposed to account for these catalytic reactions.

A highly regio- and stereoselective ring-opening addition of alkenylzirconium reagents to bicyclic olefins catalyzed by nickel complexes was described. Treatment of 7-oxa- and 7-azabenzonorbornadienes (1a-e) with various terminal alkenylzirconium reagents 2a-f (Cp(2)ZrClCH=CHR; R = t-Bu, n-Pr, n-Oct, 1-cyclohexenyl, SiMe(3), and Ph) in the presence of Ni(PPh(3))(2)Cl(2) and Zn powder (or a combination of ZnCl(2) and NEt(3)) in dry THF at 50 degrees C afforded the corresponding cis-2-alkenyl-1,2-dihydronaphthalene derivatives 3a-l in moderate to excellent yields. Under similar reaction conditions, internal alkenylzirconium reagents 2g,h (Cp(2)ZrClCR=CHR: R = Et and n-Pr) also undergo ring-opening addition to oxanorbornadienes 1a and 1d to give cis-2-alkenyl-1,2-dihydronaphthalene derivatives 4a-c in good yields. Possible pathways involving the transfer of alkenyl group in the alkenylzirconium reagent to the Ni(II) center followed by migration of the alkenyl group from the Ni(II) center to the carbon-carbon double bond of 7-oxanorbornadiene or the reaction of 7-oxanorbornadiene with Ni(0) to form a Ni(II)-pi-allyl prior to the transfer of the alkenyl group as key steps for the catalytic reaction were proposed and discussed.

An efficient cobalt-catalyzed carbocylization for the synthesis of indenols and indenes and a new method for reductive decyanation are described. 2-Iodophenyl ketones and aldehydes 1a-g undergo carbocyclization with various disubstituted alkynes 2a-k in the presence of Co(dppe)I(2) and zinc powder in acetonitrile at 80 degrees C for 3 h to afford the corresponding indenol derivatives 3a-s and4a-m in good to excellent yields. For some unsymmetrical alkynes, the carbocyclization was remarkably regioselective, affording a single regioisomer. The cobalt-catalyzed carbocyclization reaction was successfully extended to the synthesis of indene derivatives. Thus, the reaction of 2-iodophenyl ketones and aldehydes (1) with acrylates H(2)C=CHCO(2)R (7a-d) and acrylonitrile H(2)C=CHCN (7e) proceeds smoothly in the presence of Co(dppe)Cl(2)/dppe and zinc powder in acetonitrile at 80 degrees C for 24 h to afford the corresponding indenes 8a-k and 9a-c in moderate to good yields. Interestingly, when 7e was employed for the carbocylization, reductive decyanation also occurred to give an indene derivative without the cyano functionality. A possible mechanism for this cobalt-catalyzed carbocyclization reaction is also proposed.

The reaction of o-bromobenzoate (1 b) with benzaldehyde (2 a) in the presence of [NiBr(2)(dppe)] (dppe=1,2-bis(diphenylphosphino)ethane) and zinc powder in THF (24 hours, reflux temperature), afforded 3-phenyl-3H-isobenzofuran-1-one (3 a) in an 86 % yield. Similarly, o-iodobenzoate reacts with 2 a to give 3 a, but in a lower yield (50 %). A series of substituted aromatic and aliphatic aldehydes (2 b, 4-MeC(6)H(4)CHO; 2 c, 4-MeOC(6)H(4)CHO; 2 d, 3-MeOC(6)H(4)CHO; 2 e, 2-MeOC(6)H(4)CHO; 2 f, 4-CNC(6)H(4)CHO; 2 g, 4-(Me)(3)CC(6)H(4)CHO; 2 h, 4-C(6)H(5)C(6)H(4)CHO; 2 i, 4-ClC(6)H(4)CHO; 2 j, 4-CF(3)C(6)H(4)CHO; 2 k, CH(3)(CH(2))(5)CHO; 2 l, CH(3)(CH(2))(2)CHO) also underwent cyclization with o-bromobenzoate (1 b) producing the corresponding phthalide derivatives in moderate to excellent yields and with high chemoselectivity. Like 1 b, methyl 2-bromo-4,5-dimethoxybenzoate (1 c) reacts with tolualdehyde (2 b) to give the corresponding substituted phthalide 3 m in a 71 % yield. The methodology can be further applied to the synthesis of six-membered lactones. The reaction of methyl 2-(2-bromophenyl)acetate (1 d) with benzaldehyde under similar reaction conditions afforded six-membered lactone 3 o in a 68 % yield. A possible catalytic mechanism for this cyclization is also proposed.

The NiBr(2)(dppe)-Zn system effectively catalyzes the [2+2+2] cocyclotrimerization of arynes with allenes, leading to 10-methylene-9,10-dihydrophenanthrenes in moderate to good yields. The cocyclotrimerization is highly selective with only the internal double bond of the allenes being involved in the reaction.

In the presence of Ni(dppe)Br(2) and Zn powder in acetonitrile at 80 degrees C, oxa-bicyclic olefins undergo cyclization with o-iodobenzoate and with beta-iodo-(Z)-propenoates to give the benzocoumarin derivatives in moderate to good yields. This methodology offers a simple efficient way for the synthesis of structurally complicate coumarins in one pot. [reaction: see text]

[reaction: see text] Treatment of various o-iodobenzaldehydes and o-iodophenyl ketones with alkynes in the presence of Co(dppe)I(2) and Zn powder in acetonitrile at 80 degrees C afforded the corresponding indenols in moderate to excellent yields with exceedingly high regioselectivity. For most unsymmetrical alkynes tested, the carbocyclization gave a single regioisomer.

Cyclohexylallene (1a) and alkenylzirconium reagent (n-PrCH=CHZr(Cp)2Cl) undergo three-component assembly with a variety of aromatic iodides (R1-I: R1 = 4-PhOMe, 4-PhCOMe, 4-PhMe, 2-thiophene, 2-PhOMe, 3-PhOMe, and 4-PhCO2Et) in the presence of NiCl2(PPh3)2 and zinc powder in THF at 50 degrees C to afford corresponding three-component assembly products in moderate to good yields with very high regio- and stereoselectivity. In addition to cyclohexylallene, also phenylallene, n-butylallene, cyclopentylallene, and cycloheptylallene underwent the three-component assembling reaction to furnish the corresponding 1,4-diene derivatives in good yields. Several alkenylzirconium reagents (R2CH=CHZr(Cp)2Cl: R2 = Ph (3b), t-Bu, TMS) were also employed for this three-component assembly. The nickel-catalyzed three-component assembly was further extended to vinyl iodides. Thus, 1a reacts with 3b and ethyl (Z)-3-iodoacrylate to produce a highly substituted triene in excellent yield. In all of these three-component assembly reactions, the E isomers were formed predominantly with E/Z ratios between 94/6 and 99/1. A possible mechanism for this highly regio- and stereoselective three-component assembly is proposed.

2-Halophenyl ketones 1a-e (1a, o-IC(6)H(4)COCH(3)) undergo carbocyclization with alkyl propiolates (2a, CH(3)(CH(2))(4)C[triple bond]CCO(2)CH(3); 2b, TMSC[triple bond]CCO(2)Et 2c, CH(3)C[triple bond]CCO(2)CH(3); 2d, CH(3)OCH(2)C[triple bond]CCO(2)CH(3); 2e, CH(3)(CH(2))(3)C[triple bond]CCO(2)CH(3); 2f, PhC[triple bond]CCO(2)CH(3); and 2g, (CH(3))(3)C[triple bond]CCO(2)CH(3)) in the presence of Ni(dppe)Br(2) and zinc powder in acetonitrile at 80 degrees C to afford the corresponding indenol derivatives 3a-m with remarkable regioselectivity in good to excellent yields. The nickel-catalyzed carbocyclization reaction was successfully extended to other simple disubstituted alkynes. Thus, the reaction of 2-halophenyl ketones 1a-e with disubstituted alkynes (2h, PhC[triple bond]CPh; 2i, CH(3)C(6)H(4)C[triple bond]CC(6)H(4)CH(3); 2j, CH(3)CH(2)C[triple bond]CCH(2)CH(3); 2k, PhC[triple bond]CCH(3); 2l, TMSC[triple bond]CCH(3); and 2m, PhC[triple bond]C(CH(2))(3)CH(3)) proceeded smoothly to afford the corresponding indenols 4a-t in good to excellent yields. For unsymmetrical alkynes 2k-m, the carbocyclization gave two regioisomers with regioselectivities ranging from 1:2 to 1:12 depending on the substituents on the alkyne and on the aromatic ring of halophenyl ketone. A possible mechanism for this nickel-catalyzed carbocyclization reaction is also proposed.

[reaction: see text] Asymmetric reductive ring opening of oxa- and azabenzonorbornadienes with organic acids and zinc powder under mild conditions catalyzed by Ni(binap)Cl(2) or Pd(binap)I(2) produces the corresponding 1,2-dihydronaphth-1-ols in good to excellent yields with high enantioselectivity.

A new class of substituted seven-membered lactones 3 were conveniently synthesized via cyclization of o-iodobenzyl alcohol 1 (o-IC(6)H(4)CH(2)OH) with various propiolates 2 (RC triple bond CCOOMe) in the presence of Ni(dppe)Br(2) and Zn powder in acetonitrile at 80 degrees C. The catalytic reaction is highly regio- and stereoselective affording seven-membered lactones in moderate to good yields. This methodology can be successfully extended to various substituted o-iodobenzyl alcohols. An intermediate 7 was obtained from the reaction of 1a with methyl 2-octynoate (2a) in the presence of Ni(dppe)Br(2) and Zn at room temperature. A mechanism involving an unusual E/Z isomerization of the carbon-carbon double bond of 7 prior to lactone formation is proposed to account for the catalytic reaction.

[reaction: see text] Treatment of 7-oxa- and 7-azabenzonorbornadienes with terminal acetylenes in the presence of Ni(dppe)Cl2, ZnCl2, and Zn powder in toluene at 90 degrees C afforded the corresponding cis-2-alkynyl-1,2-dihydronaphthalene derivatives in moderate to excellent yields with remarkably high stereoselectivity.

Carbocylization of o-halophenyl ketones with propiolates in the presence of Ni(dppe)Br2 and Zn powder in acetonitrile at 80 degrees C afforded the corresponding 2,3-disubstituted indenols.

Bicyclic alkenes 1a-e and 5 undergo [2 + 2] cycloaddition with a variety of alkynes PhC(triple bond)CPh, (TMS)C(triple bond)CH, HC(triple bond)C(CH(3))(2)OH, (TMS)C(triple bond)CCO(2)Et, PhC(triple bond)CCH(3), C(2)H(5)C(triple bond)CC(2)H(5), CH(3)C(triple bond)CC(3)H(7), and CH(3)C(triple bond)CC(2)H(5) in the presence of Co(PPh(3))(2)I(2), PPh(3), and Zn powder in toluene to afford the corresponding exo-cyclobutene derivatives 3a-m, 6, and 8a-g in fair to excellent yields. The yield of this cycloaddition is highly sensitive to the cobalt catalyst, solvent, ligand, and temperature used. A mechanism involving a metallacyclopentene intermediate is proposed to account for this cobalt-catalyzed cyclization.

Oxabenzonorbornadienes 1 and 2 and azabenzonorbornadiene 3 undergo [2+2] cycloaddition with alkynes (PhC triple bond Ph, PhC triple bond CMe, PhC triple bond CCO2Et, PhC triple bond CCH(OEt)2, and HC triple bond C(CH2)4Me) in the presence of [Ni(PPh3)2Cl2], PPh3, and Zn powder in toluene to afford the corresponding exo-cyclobutene derivatives 4a-e, 5a-e, and 6 in fair to excellent yields. Under similar conditions. EtCO2C triple bond CCO2Et does not react with 1 in toluene to give the [2+2] cycloaddition product, but in acetonitrile, the catalytic [2+2] cycloaddition proceeds and cycloadduct 4 f is isolated in 83% yield. At high temperature, these cyclobutene derivatives readily undergo ring expansion to yield the corresponding 8-membered carbocyclic dienes. Thus, flash vacuum pyrolysis of 4a, 4d, 4f, 6, and 14 at 500 degrees C affords dienes 13a-d and 15 in 70-96% yields. This interesting ring expansion may be viewed as the insertion of an alkyne moiety into the carbon-carbon double bond of a cyclic olefin resulting in the enlargement of the ring by two carbons. Compound 13a is readily deoxygenated by TiCl4 and Zn in THF to give a cyclooctatetraene derivative 16 in 89% yield.

Cyclic enones 2-cyclohexen-1-one (1a), 4,4-dimethyl-2-cyclohexen-1-one (1b), 2-cyclopenten-1-one (1c), and 2-cyclohepten-1-one (1d) react with octa-1,7-diyne (2) in THF in the presence of Ni(PPh(3))(2)I(2), ZnI(2), and Zn powder at 62 degrees C to give [2 + 2 + 2] cycloaddition-dehydrogenation products 3a-d in 32-80% yields. alpha,beta-Unsaturated lactone 5a (5,6-dihydro-2H-pyran-2-one) undergoes [2 + 2 + 2] cycloaddition with 2 to give both the corresponding cyclohexadiene product 6 (29%) and dehydrogenation product 7 (39%). Under similar reaction conditions, 3-buten-2-one reacts with 2 and various substituted hepta-1,6-diynes 9a-c to give [2 + 2 + 2] cycloaddition-dehydrogenation products 11a-d in 68-80% yields. Diphenylacetylene also reacts with 1a-d, 5a, and 2(5H)-furanone (5b) to afford the corresponding [2 + 2 + 2] cocyclotrimerization products 13a-d and 14a-b. No dehydrogenation of products 13 and 14 was observed under the reaction and workup conditions. The reactions of acrylates with alkynes catalyzed by nickel complexes give products that depend greatly on the reaction conditions. Treating ethyl acrylate (15a) with 1-phenyl-1-propyne (16) in the presence of Ni(PPh(3))(2)Cl(2) and Zn at 90 degrees C in toluene affords cocyclotrimerization product 19aas the major product (54% yield). However, treatment of CH(2)CHCOOR (R = Et and t-Bu) with mono alkynes 16 and 12 in the presence of Ni(PPh(3))(2)X(2) (X = Cl and I) and Zn powder in toluene at 60 degrees C affords the corresponding conjugated trienes 17a-c in 82-92% yields. The MS data of 17firmly support an adduct of two molecules of alkyne and a molecule of acrylate. Similarly, the reaction of 15a with octa-1,7-diyne in the presence of Ni(PPh(3))(2)I(2), ZnI(2), and zinc gives triene derivative 21 in 68% yield. NOE and X-ray results indicate that in these trienes the substituents from each alkyne and alkene moiety are cis to each other. The unique stereoselectivity can be attributed to the exclusive formation of seven-membered nickelacycloheptadiene intermediate 25during the catalytic reaction.