A Career in Catalysis: Howard Alper

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A Career in Catalysis: Howard Alper Dong-Mei Yan, Cathleen M. Crudden, Jia-Rong Chen, and Wen-Jing Xiao ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b01789 • Publication Date (Web): 11 Jun 2019 Downloaded from http://pubs.acs.org on June 11, 2019

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ACS Catalysis

A Career in Catalysis: Howard Alper Dong-Mei Yan,† Cathleen M. Crudden,*,‡ Jia-Rong Chen,*,† and Wen-Jing Xiao*,† †Key

Laboratory of Pesticides and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, China ‡Department

of Chemistry, Queen’s University, Chernoff Hall, Kingston, Ontario, K7L 3N6, Canada

ABSTRACT: Still going strong in his seventies, Professor Howard Alper continues to make an impact on chemistry internationally. This account highlights some of his key scientific achievements in catalysis. What began as a fundamental interest in the chemistry of metal carbonyls and their activity modes, evolved into a versatile program addressing some of the most significant and challenging issues in catalysis. Using well-defined metal carbonyl complexes, he and his lab were able to make fundamental insights into diverse transformations involving the catalytic properties of metal carbonyls, including carbonylative ring expansions. His creative and truly interdisciplinary research in catalysis has also resulted in notable contributions to carbonylation, hydrofunctionalization, and cycloaddition chemistry.

KEYWORDS: metal carbonyls, carbonylation, carbonylative ring expansion, hydrofunctionalization, cycloaddition 1. INTRODUCTION

The remarkable career of Dr. Howard Alper exemplifies the profound synergy between organometallic chemistry and catalytic chemistry. On the occasion of Howard Alper’s fiftieth year in catalysis, we are honored to reflect and highlight a few aspects of his distinguished career in the chemistry of organometallic complexes, homogeneous catalysis, phase transfer catalysis, including carbonylation, hydrofunctionalization, and cycloaddition reactions. With around 550 papers to his name, and having mentored 114 students and postdoctoral fellows, his creative and truly interdisciplinary research is so broad that it would require a huge monograph to include all of his work. Thus, we do not presume to strive for a comprehensive overview of Dr. Alper’s contributions of

50 years. Instead, we aim to highlight some of his key contributions that we hope illustrate his enduring influence on organometallic chemistry, carbonylation and catalysis. Born in Montreal, Canada, in 1941, Howard Alper completed his Ph.D. with Jack Edward at McGill University in 1967. After spending one year as a NATO postdoctoral fellow with Paul Schleyer at Princeton University, he began his career at the State University of New York at Binghamton in 1968. In 1975, he moved to the University of Ottawa in 1975 as associate professor, where he was appointed as full professor in 1978. He held various roles at the University of Ottawa including Professor, Department Head, Associate Vice President Research and Vice President Research until his retirement from a formal university professorship. He still remains highly active in the scientific community, working for the Governor General of Canada to facilitate scientific excellence in Canada and travelling internationally to advise governments on scientific investment. 2. METAL CARBONYLS Metal carbonyls are among the most fundamental organometallic reagents for organic synthesis. Inspired by a seminar on the chemistry of iron carbonyls, Alper saw the potentially remarkable power of these unique organometallic reagents and began what would become a life-long interest in the chemistry and catalysis of transition metals and carbon monoxide.

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Alper’s earliest professional contributions involved the use of metal carbonyls as stoichiometric reagents, intermediates, or catalysts in synthetic organic chemistry.1 Among these, the most useful processes include metal carbonyl-mediated or -catalyzed reduction, coupling, and carbonylation of various organic substrates. Some representative works in this area will be highlighted in this section. In 1967, Alper and Edward found that the reaction of oximes and iron pentacarbonyl [Fe(CO)5] in the presence of a catalytic amount of boron trifluoride in boiling butyl ether led to conversion of the oximes into their parent carbonyl compounds.2 Though the precise reaction mechanism was not clear at that stage, this work opened a new avenue for the exploration of the use of iron pentacarbonyl in organic chemistry. Drawing inspiration from this enigmatic reaction, Alper and co-workers began an extensive exploration of the chemical activities, and reaction modes of Fe(CO)5 as well as other metal carbonyls with organic compounds. Among these discoveries, the most useful and representative processes included reduction (e.g., deoxygenation, desulfurization, dehalogenation.), coupling reactions, and carbonylation reactions. 2.1. Reduction. Alper’s investigations during the 1970's demonstrated that iron carbonyls such as Fe(CO)5, Fe2(CO)9 and Fe3(CO)12, were a versatile class of reagents for many synthetic transformations. For instance, Alper and Edward disclosed that Fe(CO)5 can convert primary amides, thionamides, and benzamides to nitriles with moderate to good yields.3 On the basis of this preliminary investigation, Alper and co-workers then extensively studied the substrate scope of Fe(CO)5-mediated deoxygenation reactions. It was found that a range of compounds containing an N-O linkage, such as amine oxides, azoxybenzenes, nitrones, and nitrobenzenes can be deoxygenated with generally good yields, when using Fe(CO)5 in hot nBu2O.4 Through this process, a range of amine oxides and nitrobenzenes were converted to amines 2, (Scheme 1a), azobenzenes 4 and/or arylamines 5 in good yields depending on the property and location of the substituents (Scheme 1b). As shown in the case of amine oxides 1, it was postulated that the first step should involve nucleophilic attack of the oxygen on the carbonyl carbon of Fe(CO)5 (Scheme 1a). Treatment of nitroxyl radicals with Fe(CO)5 in benzene with small amount of MeOH also allowed their efficient conversion to amines 2.5 Alper and co-worker further found that absorption of Mo(CO)6 or Fe3(CO)12 on Al2O3 led to heterogenenous reagents that enabled the deoxygenation of azoxybenzenes and N-oxides to azobenzenes and amines with similar yields under milder conditions compared to the Fe(CO)5/nBu2O system.6 Remarkably, they demonstrated for the first time that combination of phase transfer catalyst PhCH2NEt3+Cl- and stoichiometric Fe3(CO)12 enabled the efficient deoxygenation of nitrobenzenes 3 to anilines 5 with high yields and selectivity at room temperature in an aqueous NaOH/benzene mixture (Scheme 1c).7 It is likely that a

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nucleophilic iron carbonyl hydride such as [HFe3(CO)11-] might be involved in this process. Shortly thereafter, Alper and Damude reported a facile method for the generation of HFe3(CO)11- by treatment of Fe3(CO)12 with KF or nBu4NF, thus enabling efficient reduction of nitro compounds to amines.8 Interestingly, Alper and co-worker later disclosed that nitroarenes can be catalytically transformed into formamides or carbamate esters, when using Fe3(CO)12 or Ru3(CO)12 as the catalyst respectively, in the presence of CO/H2 (1:1) and NaOMe.9 Subsequently, it was found that a dual catalytic system comprising Pd-clay and Ru3(CO)12 enabled a highly selective reductive carbonylation of mono- and dinitro aromatic compounds, providing a useful approach to various valuable mono- and diurethanes in high yields.10 It was proposed that the Pd-clay catalyst was responsible for reduction of the nitro group to the amine, while Ru3(CO)12 catalyzed the subsequent carbonylation of the in situ formed amine. Scheme 1. Iron Carbonyl-Mediated Deoxygenation R3

O C Fe(CO)4

O

N

R3

O

N

1 NO2

n

+ Fe(CO)5

R

R

+ Fe3(CO)12

3 O S

R

6

R

+

Fe(CO)5

Fe(CO)4

R 3N (a) 2, 46-79% yield CO2 + Fe(CO)4 ArN NAr and/or ArNH2

Bu2O (reflux)

11-76% yield

3 NO2

C O

aq. NaOH benzene

Ar

8

+ Fe2(CO)9 Ar

O R

R

NH2

PhCH2NEt3+Cl0.75-2.0 h, rt 5, 60-92% yield

diglyme or (C4H9)2O 130-135 oC, 3 h

rt, 36 h

(c)

S (d) R R 7, 12-96% yield S

dry benzene Ar

Ar

(e)

9, 24-54% yield

+

Fe(CO)5

TMU 145 oC, 2.0-2.5 h

R

(f)

11, 22-95% yield

10 OH

(b) 5

R

O S

4

+

12

Fe(CO)5

K/PhCH3 reflux, 12 h

H (g) R 13, 43-90% yield

The strategy of Fe(CO)5-mediated deoxygenation was successfully expanded to sulfoxides (Scheme 1d),11 diarylsulfines (Scheme 1e),12 epoxides (Scheme 1f),13 and even more challenging alcohols (Scheme 1g),14 giving the corresponding sulfides 7, thiobenzophenones 9, alkenes 11, and hydrocarbons 13 with moderate to good yields. The reactions of these substrates likely also occur through a pathway analogous to that proposed for the deoxygenation of amine oxides involving initial nucleophilic addition of oxygen to the CO group of Fe(CO)5.

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ACS Catalysis

Alper and Paik also revealed that Co2(CO)8 in refluxing benzene can reductively deoxygenate substituted nitroarenes to azo compounds with moderate yields.15 In sharp contrast to the homogeneous version, nitroarenes were directly reduced to amines probably via different intermediates, when using the related heterogeneous Co2(CO)8/Al2O3 catalyst.16 2.2. Desulfurization. The extrusion of sulfur from organosulfur compounds is relevant to the problem of the desulfurization of fuel oil and flue gasses. In the 1970's, Alper and co-workers initiated a series of studies directed toward the development of new and efficient desulfurization reagents that might be potentially applicable to the desulfurization of crude oil and Athabasca bitumen. For instance, in 1975, Alper reported that HFe(CO)4-, generated in situ from Fe(CO)5 and KOH in H2O/1,4-dioxane, can serve as desulfurization reagent (Scheme 2a).17 Treatment of a series of aliphatic or aromatic thioketones 14 or thioamides 15 with this reagent gave the corresponding desulfurized hydrocarbons 16 and amines 17 in good yields. Deuteration experiments suggested that the mechanism involved initial thiophilic attack of HFe(CO)4on the thioketones 14 to give intermediate 14-A. Then, 14A can be converted to hydrocarbon 16 by attack of another molecule of HFe(CO)4-. Dicarbonylcyclopentadienyliron anion [Bu4N]+[C5H5Fe(CO)2]- was also identified as an efficient desulfurization reagent, allowing the conversion of thiobenzophenones to fulvenes.18 Interestingly, treatment of thiobenzophenones with (Ph3P)2N+Co(CO)4- resulted in their conversion to tetraarylethylenes in good yields.19 Scheme 2. Metal Carbonyl-Induced Desulfurization Organic Sulfur Compounds S

Fe(CO)5 KOH/H2O

S

H H H H or 1,4-dioxane R R R NHR1 R R R NHR reflux, 10 h 14 15 16 17 38-81% yield KOH/H2O HFe(CO)4Fe(CO)5 1,4-dioxane SFe(CO)4HFe(CO)4R C SFe(CO)4R H 14-A or

1

i) HOAC, 115-120 oC 3-3.5 h

R-SH + Mo(CO)6 or ii) SiO2, THF 18 rt-45 oC R-SH + Co2(CO)8 18

Co(CO)4-

CO (900 psi) bezene/H2O 185-190 oC

(a)

R-H + R-SCOMe (b) 19, 48-90% 20

R-H + COS (c) 19, 44-91%

Thiols are another class of organic sulfur compounds that are susceptible to desulfurization. By appropriate modification of Mo(CO)6, Alper and co-worker documented that the use of Mo(CO)6 in HOAc for the desulfurization of thiols 18 to hydrocarbons 19 efficiently, together with some thioesters 20 as by-product in some

cases (Scheme 2b).20 Alper and co-workers also developed a range of heterogeneous reagents by deposition of Mo(CO)6 onto silica,21 or capitalizing Mo(CO)6 on florisil,22 or adsorption of FeCl2 and NaEt3BH onto Al2O3,23 which also proved to be active as desulfurization agent for thiols and even crude oil. Notably, Alper and co-workers further disclosed that the use of a catalytic amount of Co2(CO)8 under atmosphere of CO resulted in the development of a catalytic version of desulfurization of a wide variety of benzylic thiols and thiophenols 18 (Scheme 2c).24 The corresponding hydrocarbons 19 were obtained in reasonable yields. It was proposed that Co(CO)4- should be the key catalyst that was formed in situ by waterinduced disproportionation of Co2(CO)8. Obviously, this catalytic reaction is superior to the other stoichiometric metal carbonyl-mediated processes. This catalytic system could be extended to conversion of disulfides to thioesters,25 as well as desulfurization/carbonylation of thiols to carboxylic esters.26 On the basis of the versatile reactivity modes of Fe(CO)5, Alper and co-worker also investigated the reaction of α-halo ketones with Fe(CO)5. It was found that treatment of a range of primary, secondary, and tertiary aromatic and aliphatic α-halo ketones 21 with Fe(CO)5 in refluxing 1,2-dimethoxyethane (DME), and work-up with water resulted their conversion to 1,4diketones 22 as major products (Scheme 3a).27 Small amounts of monoketones 23 and β–epoxy ketones 24 were formed as by products in some instances. Mechanistic studies implied that the reaction should proceed through an initial addition of the trigonal bipyramidal Fe(CO)5 to the α-halo ketone, giving octahedral intermediate 21-A. Loss of CO from 21-A affords 21-B, that is then converted to product 22 by reaction with another equivalent of 21 in the presence of Fe(CO)5. Alternatively, 21-A can react directly with another molecule of 21 to give the coupled product 22. Inspired by this reaction pathway, Alper also achieved the facile conversion of sulfonyl chlorides to thiosulfonate esters employing Fe(CO)5 alone or as a 1:1 mixture of Fe(CO)5 and boron trifluoride etherate.28 Interestingly, when the reaction of α-halo ketones with group 6 metal carbonyls such as Mo(CO)6 was investigated, the reaction was found to proceed in a different manner as compared to Fe(CO)6, giving the methyl ketones by direct dehalogenation as major products in moderate to good yields.29 Using Mo(CO)6 supported on Al2O3, the dehalogenation reaction proceeded even faster than the homogeneous variant under very mild conditions, and gave the monoketones in good yields.30 Combination of Co2(CO)8 and phase transfer catalyst BnNEt3+Cl- or Co2(CO)8/Al2O3 was also an efficient system for dehalogenation of α-bromo ketones31 and α-bromo sulfoxides,32 likely via a radical process. Scheme 3. Metal Carbonyl-Promoted Dehalogenation and Coupling

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O X

R

+ Fe(CO)5

O

DME then H2O

O 22 4.6-63% yield

21

R

CO

Fe

25

21, Fe(CO)5 R

X

CO 21-A CO

NOH Cl

RCOMe (a) 23 + R RCOCH2 24

O

-4CO

CO

R

21

Fe(CO)5 -CO O

R

R

FeX

2

21-B NOH

+ Fe(CO)5

THF reflux

R CN 26 33-76%

R

Fe(CO)3 Cl 25-A

(b)

On the basis of the mechanistic insights into the Fe(CO)5-mediated dehalogenation/coupling of α-halo ketones, Alper and co-workers proposed that benzohydroxamoyl chlorides 25 might also undergo oxidative addition with Fe(CO)5 to give 25-A, which would then trigger new transformations (Scheme 3b).33 Building on this idea, they disclosed that treatment of benzohydroxamoyl chlorides 25 with Fe(CO)5 in refluxing THF indeed enabled their efficient conversion to nitriles 26 in good yields. Intermediate-trapping experiments also suggested the intermediacy of nitrile oxides. 3. TRANSITION CARBONYLATION

METAL-CATALYZED

Carbonylation reactions are considered to be one of the most important classes of transition metal complexcatalyzed processes for the catalytic synthesis of carbonyl-containing compounds, such as carboxylic acids, esters, and amides. As hallmark of his research program, Alper and co-workers provided significant insight into this field, developing various transition metal complex-catalyzed processes.34,35,36 3.1. Carbonylation of Halides. The transition metal complex-catalyzed carbonylation of halides is a useful and atom-efficient method for the synthesis of carboxylic acids and their derivatives. The Alper group is recognized pioneer in the development of transition metal complexcatalyzed carbonylation using a wide variety of readily accessible catalysts and substrates. In 1984, Alper and coworkers documented the first example of carbonylation of benzyl bromides 27 with trialkylborates and carbon monoxide using 1,5-hexadienerhodium(I) chloride dimer ([1,5-HDRhCl]2) as catalyst, producing carboxylic esters 29 in high yields (Scheme 4a).37 The borate esters (28) served as the alkoxy transfer agents. As for the less reactive benzylic chlorides or symmetric ethers,38 it was found that the addition of iodide ion such as KI, could efficiently promote their carbonylation respectively in the presence of carbon monoxide. Remarkably, the use of a bimetallic catalyst system consisting of [1,5-HDRhCl]2 and Pd(PPh3)4 significantly expanded the substrate scope, permitting a range of unactivated bromides, such as alkyl, vinyl, and aromatic bromides to react smoothly with organoborates and

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carbon monoxide, giving the corresponding carboxylic esters in good yield.39 Moreover, this type of bimetallic catalyst system was highly versatile, and could employ aluminum,40 titanium, and zirconium alkoxides as formal alkoxy transfer agents.41 In addition to metal alkoxides, formate esters can also be employed as alkoxy transfer agents.42 By using zwitterionic rhodium complex, (COD)Rh(η6-C6H5BPh3) ([Rh]-1) and phase transfer catalyst, tetra-n-hexylammonium hydrogen sulfate ((H13C6)4N+HSO4), Alper and Amaratunga also developed the first alkoxycarbonylation of benzylic and allylic bromides under phase transfer conditions.43 The carbonylation of halides can also be affected with a range of phosphine-modified palladium complexes. For example, the combination of Pd(OAc)2 with DPPP or DIBPP in the presence of different bases enabled selective carbonylation of iodoarenes with 3- and 4-aminophenols producing diaryl esters.44 Alper and co-workers also showed that Pd complexes of PAMAM (polyaminoamido) dendrimers supported on SiO2 were valuable heterogeneous catalysts for the carbonylation of iodoarenes.45 Remarkably, thiocarbonylation could also be affected with unprotected thiols (18) and a relatively simple catalyst system (Pd(OAc)2/PPh3) (Scheme 4b).46 Employing Et3N as the base in phosphonium salt ionic liquid (PSIL) as solvent gave thioesters 31 in good yields. Considering the impressive compatibility of thiols with simple palladium catalysts, the Alper group went on to develop Pd-catalyzed sequential intramolecular C-S coupling/intermolecular carbonylations of 2-gemdihalovinylthiophenols with alcohols, phenols, and amines.47 This procedure proceeds through the formation of 2-halobenzo[b]thiophenes as key intermediates. Scheme 4. Carbonylation of Halides ArCH2Br + CO + B(OR)3 27 28

O

[1,5-HDRhCl]2 o

75 C, 1 atm

Ar

OR

+ BBr3

(a)

29 46-100% yield BPh3 Rh (COD)

PTC [Rh]-1 I

R

+ + (C6H13)4N HSO4

+ CO + R1SH

30

18

O

Pd(OAc)2/PPh3/Et3N 100 oC, 18 h, 200 psi Phosphonium salt ionic liquids (1.5 g)

R

SR1 (b) 31 43-95% yield

The transition metal complex-catalyzed hydroxycarboxylation of organic halides is also a powerful method for the synthesis of carboxylic acids. The Alper group has developed many phase transfer catalysts and transition metal complex-based catalytic systems for the hydroxycarboxylation of halides leading to carboxylic acids. For example, in 1982, Alper and co-workers revealed that a combination of Pd(PPh3)4 and tetrahexylammonium hydrogen sulfate ((H13C6)4N+HSO4-) as phase transfer catalyst can catalyze the selective

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hydroxycarbonylation of benzylic halides 27 to give the corresponding carboxylic acids 32 in good yields under mild conditions (5N NaOH and CH2Cl2 under 1 atm of CO at room temperature, Scheme 5a).48 This biphasic and phase transfer catalytic method is widely applicable, including to the carbonylation of vinylic bromides,49 chloroarenes50 and iodoxyarenes.51 The products of this reaction are carboxylic acids, which are generated with retention of E/Z configuration of alkene.49 Notably, Alper, Yu and Zhao reported that vinyl bromides 33 could also undergo stereoselective hydroxycarbonylation efficiently in ionic liquid [BMIM]PF6, giving the corresponding α,βunsaturated carboxylic acids 34 in generally good yields with excellent E/Z selectivity (Scheme 5b).52 This method also features simple purification procedure without any column chromatography or recrystallization, and recyclability of the ionic liquid. Scheme 5. Hydroxycarboxylation of Halides for Synthesis of Carboxylic Acids O Pd(PPh3)4 ArCH2X + CO + OH (1 atm) (C6H13)4N HSO4 , 5 N NaOH ArCH2 32 27 CH2Cl2 or benzene, rt 57-84% yield

R1 R2 33

ArI 30

Br +

+

(a)

Pd(PPh3)2Cl2 (5 mol%) CO2H (b) CO R1 H2O (5 equiv), Et3N (2 equiv) 2 (20 bar) R o [BMIM]PF6, 100 C 34, 48-99% yield E/Z = 88:12 to E only Ni(CN)2 4H2O CO + (C H 16 33)N(CH3)3 Br (CTAB) (1 atm) 5 N NaOH, toluene, rt

O Ar

OH 35 40-80% yield

(c)

Detailed mechanistic studies carried out by Grushin and Alper suggested the involvement of alkali-induced disproportionation of the starting Pd(II) complex to the requisite Pd(0) species, and concomitant phosphine oxidation (Scheme 6).53,54 The use of enantiomerically enriched phosphines enabled detailed analysis of the mechanism of reduction of the Pd(II) precatalyst, specifically that R3PO is formed by attack of hydroxide on Pd followed by inner sphere reductive elimination rather than attack at phosphine. These results likely have wideranging impact since any cross-coupling reaction employing wet amine bases or hydrated inorganic bases will be able to proceed by this manifold. Sheme 6. Proposed Mechanism of Alkali-Induced Disproportionation of the Pd(II) Complex to the Pd(0) Species

LCl2Pd

PPh3

OH-

Ph LCl2Pd P- OH Ph Ph

Path A

OH Cl Pd PPh3 L

Path B

Cl-

- OPPh3 [LCl2PdH]

- OPPh3

-

- Cl-, - HCl

[LPd]

- HCl

[LClPdH]

PhI L = PPh3

[I-LPd-Ph]

OH[I-LPd-Ph]2

[Ph-LPd-OH]2

Pd-catalyzed carbonylations of aromatic, vinylic, and benzylic halides can also be carried out with CO formed in situ from CHCl3 and aqueous alkali.55 This was one of the early examples of the use of CO surrogates in place of CO itself, a field that has continued to attract interest to this day. The use of aryl or alkyl metal carboxylates (RCO2M, where M = Na, K or Ca) as nucleophiles in the carbonylation reaction results in the formation of anhydrides.56 The combination of nickel cyanide and quaternary ammonium salt, C16H33N(CH3)3+Br-, is also effective for the smooth carbonylation of aryl iodides 30 (Scheme 5c),57 benzyl chlorides,58 as well as vinyl bromides and chlorides59 with or without lanthanide salts (CeCl3, LaCl3). Cobalt complexes (e.g., CoCl2·6H2O, Co(OAc)2·4H2O, or Co2(CO)8) can also catalyze the smooth carbonylation of iodoarenes, iodoalkanes,59 and benzyl chlorides61 in the presence of PEG-400 as the phase transfer agent along with Lewis acid activators. 3.2. Carbonylation of Unsaturated Carbon-Carbon Bonds. The transition metal complex-catalyzed hydroesterification of unsaturated carbon-carbon bonds such as alkenes, alkynes and allenes, by carbon monoxide and alcohols is an industrially important and highly atom economical reaction for the synthesis of esters. In 1984, Alper and co-workers reported an interesting alkoxyalkoxycarbonylation of allenes 36 under mild conditions consisting of CO/O2/PdCl2/CuCl2/MeOH at 0°C, giving branched chain unsaturated esters 37 as the principal products in moderate to good yields (Scheme 7a).62 Despite the limited substrate scope, this pioneering work provided a new method for the hydroesterification of unsaturated carbon-carbon bonds. This system also catalyzed the regioselective carbonylation of simple alkenes with various formate esters in dioxane to give branched chain carboxylic esters.63 In further work, it was found that the palladium complexes played an important role in the regiochemical control in carbonylation of alkenes. In the case of carbonylation of alkenes with formate ester, Pd(0) complexes such as Pd(PPh3)4, and Pd(dba)2, together with dppb can efficiently catalyze the reaction to produce linear carboxylic esters 39 as the major products in reasonable yields (Scheme 7b).64 The combination of Pd(OAc)2 or PdCl2 with sterically hindered monodentate phosphine ligands such as P(p-anisyl)3 and 1,3,5,7tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (CYTOP 292) in the presence of salicylicborate65 or Lewis acids (SnCl2 or Ti(OiPr)4),66 also affected highly anti-

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Markovnikov alkoxycarbonylation of 1-alkenes and alcohols, giving linear esters in good yields. The regioselective alkoxycarbonylation of allyl aryl ethers could also be carried out yielding linear phenoxy esters by employment of Pd2(dba)3/dppb and syngas (CO/H2) in CHCl3/alcohol.67 Scheme 7. Carbonylation of Unsaturated CarbonCarbon Bonds O

R

PdCl2, CuCl2, HCl

+ CO + MeOH

C

36 R = H, Me or R, R = (CH2)5

O

OMe OMe 85%

(a)

R R

O2, 0-25 oC, 1 atm

R

OMe

OMe 37 R = Me, or R, R = (CH2)5 19-46% yield O

Pd(PPh3)4 or Pd(dba)2 + CO + HCO2R1 dppb, toluene, 150 oC R (82 atm)

R 38

OR1 39 (major) 27-67% yield

R1 = nPr, nBu, sBu

(b)

Although sulfur-containing compounds are often considered to be challenging substrates for metal catalyzed reactions, Alper and co-workers were able to affect the highly regioselective thiocarbonylation of a wide range of mono- and di-substituted allenes 36 with free thiols 18 (Scheme 8).68 The thiocarbonylation occurred regioselectively at the less-substituted double bond, with the corresponding linear chain β,γunsaturated thioesters 40 being isolated in 73-94% yields. After generation of Pd(0) from Pd(OAc)2 by a number of possible routes including phosphine, thiol or CO reduction, the resulting Pd(0) species underwent oxidative addition with RSH to form a Pd(II)thiolate, followed by insertion of the less hindered double bond of the allene, generating allylpalladium intermediate 36-B. Subsequent CO insertion and reductive elimination then generated the desired thioesters (Scheme 8). Scheme 8. Thiocarbonylation Carbon-Carbon Bonds R C R

36

of

Pd(OAc)2 (3 mol%)

+ CO + R3SH (400 psi) 18

Unsaturated O R

PPh3 (12 mol%) THF, 100 oC

40 73-94% yield

C H Pd SR L L 36-A

L

L R

Scheme 9. Aminocarbonylation of Unsaturated Carbon-Carbon Bonds

R3SH

RS Pd H L L

R

also developed the first enantioselective thiocarbonylation of 1,3-conjugated dienes to give the branched chain β,γ-unsaturated thioesters with up to 89% ee.72 The reaction of 1,3-conjugated enynes with a terminal triple bond showed the same regioselectivity, with the thiocarbonyl group found exclusively at carbon-2 of the 1,3-conjugated enynes.73 Transition metal complexes, such as [Rh(CO)2Cl]2,74 and Ru3(CO)1275 are also able to catalyze the regiospecific direct insertion of CO into various C-S bonds, providing complementary approaches to the synthesis of various functionalized thioesters. Extending this concept, aminocarbonylation of alkenes can give rise to branched and linear chain amides. Recently, Alper and co-workers developed a highly ligand-tuned chemoand regioselective aminocarbonylation of styrene derivatives 38 with 4-, 3and 2-aminophenols 41 by the combination of Pd(II) complexes with phosphine ligands (Scheme 9).76 In the presence of B(OH)3 and 5-chlorosalicylic acid as an additive, the catalyst system consisting of Pd(CH3CN)4(BF4)2 and P(p-MeOC6H4)3 (L1) in CH3CN enabled the high-yielding formation of linear amides 42A, while the use of PdCl2 and the bulky, rigid ligand 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6phosphaadamantane (L2) led to branched amides 42-B as principal products in butanone as reaction medium. In all of these reactions, no alkoxycarbonylation products, namely esters, were detected. In the case of simple terminal alkynes, the use of Pd(OAc)2/dppb in ionic liquid [bmim]Tf2N also resulted in the regiospecific formation of branched aminocarbonylation products, namely acrylamides.77 Recently, Alper and co-worker successfully extended this strategy of ligand- and additive-controlled Pd-catalyzed aminocarbonylation to the reaction of alkynes and aminophenols.78 It was found that a system involving boronic acid and 5-chlorosalicylic acid as additive along with 1,2-bis(di-tert-butylphosphinomethyl)benzene (DTBPMB) as the ligand enabled the formation of linear α,β-unsaturated amides with high selectivity and yields; while a combination of DPPP and p-TsOH led to branched α,β-unsaturated amides with comparable results.

R

Pd(0)L4

R

SR3

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Pd

SR3

Pd(CH3CN)4(BF4)2 (5 mol%) L1 (10 mol%), B(OH)3 (10 mol%)

O +CO

R

Pd L

R

R 36-B

SR3

R 38

L

36-C

+

CO (20 bar) NH2

HO R1 41

This Pd-catalyzed thiocarbonylation method could be extended to allylic alcohols,69 conjugated dienes,70 and vinylcyclopropanes71 for the synthesis of a variety of β,γunsaturated thioesters. Using a catalyst system comprising Pd(OAc)2 and (R,R)-DIOP, the Alper group

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H N

5-ClSA (20 mol%) CH3CN, 120 oC

O

R1 42-A

PdCl2 (5 mol%) L2 (10 mol%), B(OH)3 (10 mol%) 5-ClSA (20 mol%) butanone, 120 oC

Ar

HO

HO

CH3 Ph

O P H 3C CH3 O O CH3 L2

Ar

H N R1

O 42-B

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ACS Catalysis

The hydrocarboxylation of alkenes and alkynes is another useful variant of this reaction that generates carboxylic acids directly. The Alper group disclosed that catalytic amounts of hydrated nickel cyanide in the presence of phase transfer agent cetyltrimethylammonium bromide, C16H33N(CH3)3+Br-, efficiently catalyzed the mild and regiospecific hydrocarboxylation of terminal alkynes 43 to the corresponding branched methylene acids 44 in moderate to good yields (Scheme 10).79 It was postulated that the reaction involved the initial generation of cyanotricarbonylnickelate anion followed by its conversion to the key nickel hydride species that then hydrometalates the alkyne. When this catalytic system was applied to the hydrocarboxylation of alkynols, it was found that unsaturated diacids were obtained as mixtures of Z/E products under homogeneous80 or phase transfer conditions.81 These were likely formed from sequential hydrocarboxylation of the alkyne moiety and carbonylation of the initially formed allylic alcohols. Interestingly, the use of cationic palladium(II) aquo hydride, trans-(Cy3P)2Pd(H)(H2O)+BF4-, and dppb as catalyst in the presence of p-TsOH, resulted in hydrocarboxylation of propargylic alcohols to linear cross-conjugated dienoic acids with good yields.82 Under this catalytic system, however, the reaction of α-allenic alcohols gave rise to branched products, α-vinylacrylic acids instead.83 Scheme 10. Hydroxycarboxylation of Alkynes R

+

43 R = Ph, alkyl

CO (1 atm)

Ni(CN)2 4H2O

Ni(CN)2 4H2O

R

(C16H33)N(CH3)3+Br- (CTAB) aq. NaOH, toluene, 90 oC

CO, NaOH, toluene CTAB

Ni(CO)3CN-

-OH-

Scheme 11. Cyclocarbonylation of Allylic Alcohols and 2-Allylphenols R

OH

OH

O 44 30-68% yield

H 2O

to γ-butyrolactones 46 using the catalytic system of PdCl2/CuCl2 under 1 atm of CO and O2 in acidic THF at ambient temperature (Scheme 11a). The reaction can be applied to a range of primary, secondary, and tertiary allylic alcohols, giving the corresponding products in moderate to good yields.85 When achiral allylic alcohols were employed, the use of chiral ligands such as diethyl tartrate or poly-L-leucine enabled a catalytic asymmetric version, giving optically active γ-butyrolactones in good yields. For the carbonylation of but-2-en-1-ol to -methyl-butyrolactone using poly-L-leucine, an enantiomeric excess of 61% was obtained.86 Notably, it was found that the combination of Pd(OAc)2 with dppb allowed stereoselective cyclocarbonylation of β,γ-substituted allylic alcohols with a 1/1 mixture of CO/H2. In this case, (E)-allylic alcohols were exclusively transformed into the trans-α,βsubstituted lactones.87 Alper and co-workers further developed a highly enantioselective catalytic cyclocarbonylation of a series of prochiral allylic alcohols 47 using a chiral palladium complex formed from [Pd2(dba)3]·CHCl3 and (-)-BPPM (Scheme 11b).88 The Pdcatalyzed cyclocarbonylation could also be applied to propargylic alcohols for the synthesis of 2(5H)furanones.89,90

3.3. Cyclocarbonylation. The transition metal complex-catalyzed carbonylation and cyclization, also known as cyclocarbonylation, of unsaturated carboncarbon bonds containing a nucleophilic moiety represents a powerful and versatile synthetic approach to heterocycles. As part of their continuing study on the chemistry of carbonylation, Alper and co-workers have created an extensive repertoire of Pd-catalyzed regioselective cyclocarbonylation reactions of readily available starting materials, such as unsaturated alcohols, 2-allylphenols, and o-iodoanilines. In 1985, Alper and co-worker described a mild method for regiospecific cyclocarbonylation of allylic alcohols 45

CO (1 atm)

R

O2, PdCl2, CuCl2

(a)

THF, HCl, rt

O

O OH

R

Pd2(dba)3 CHCl3

Ph2P O

(-)-bppm, CH2Cl2 100 oC, 48 h

+

47

O

46, 35-70% yield

45

HNi(CO)3CN

The carbonylation of alkynes could also be achieved by with indoles as carbon nucleophiles, when using Pd(CH3CN)4(BF4)2/Xantphos as catalyst under CO pressure (300 psi).84 This protocol tolerated a wide range of N-protected or NH indoles, and electron-deficient terminal alkynes, providing access to selective synthesis of linear α, β-unsaturated ketones.

+

R 48 56-96% yield 25-84% ee

CO/H2 (400/400 psi) R1 2

OH

R1

49 + CO/H2 (300 or 500 psi)

R1 [Pd], dppb o

solvent, 120 C 48-100% yield

R

O

(b)

(-)-bppm

R2 R

R

PPh2 N Boc

R2 (c)

+ R

O 50

Pd(PCy3)2(H)(H2O)+BF4CH2Cl2, major

O

O

51 Pd(OAc)2 toluene, major

Alper and co-workers reported that Pd-catalyzed cyclocarbonylation could be successfully extended to 2allylphenols 49 by reaction with CO/H2 (Scheme 11c).91 The regioselectivity could be fine-tuned by the application of different palladium complexes The corresponding five- or seven-membered ring lactones, 50 and 51 were obtained as the major products by combination of [(PCy3)2Pd(H)(H2O)]+BF4- or Pd(OAc)2 and dppb in CH2Cl2 or toluene, respectively. The reactions of 2-aminostyrene also proceeded regioselectively to give five-, six-, or seven-membered ring lactams depending on the combination of Pd(OAc)2 with different ligands. The cyclocarbonylation of 2allylphenols with Pd•clay–based catalysts, prepared from

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Pd(COD)Cl2 and Na+-exchanged montmorillonite, afforded seven-membered ring lactones as the major products.92 Ionic liquids, such as BMIMPF6 or BMIMNTf2 can also be used as recyclable media to effect the Pdcatalyzed regioselective cyclocarbonylation of 2vinylphenols and anilines.93 Moreover, the combination of PdI2 and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6phosphaadamantane (CYTOP 292) led to the conversion of 2-allylphenols to 3-methyl-3,4-dihydrocoumarins.94 The combination of Pd(OAc)2 and (+)-DIOP is also an effective asymmetric cyclocarbonylation system, and can convert o-isopropenylphenols 52, in the presence of CO/H2, into 3,4-dihydro-4-methylcoumarins 53 with good yields and enantioselectivities (Scheme 12a).95 In the case of cyclocarbonylation of 2-vinylanilines 54, Pd(OAc)2/(S,S)-DDPP gave 3,4-dihydroquinolin-2-ones 55 with good yields and enantioselectivities (Scheme 12b).96,97 In contrast, when replacing of H2 with oxidants such as air or 1,4-benzoquinone, the Pd-catalyzed cyclocarbonylations of 2-vinylphenols,98 2-vinylanilines,99 and propargylic pyridines,100 gave rise to coumarins, 2(1H)-quinolinones, and indolizines respectively. Alper and co-worker also successfully applied their previously developed Pd-complexed dendrimers on silica to the intramolecular cyclocarbonylation of substituted 2-(2ethynylphenoxy)anilines toward synthesis of medium ring tricyclic lactams.101 Scheme 12. Cyclocarbonylation of 2-Vinylphenols and 2-Vinylanilines

+

R OH 52

CO (500 psi) H2 (100 psi) O

R1 R2 + R

54

H PPh2

PPh2 H (+)-DIOP

O

NH2

Pd(OAc)2/(+)-DIOP CH2Cl2, 100 oC, 48 h Ph2P PPh2 N H (S,S)-DDPP

Pd(OAc)2/(S,S)-DDPP

CO (500 psi) H2 (100 psi) CH2Cl2, 110-135 oC, 48 h

(a)

R O O 53 65-85% yield 15-90% ee

R1 R2 (b) N O H R 55 40-98% yield 16-84% ee

Alper and co-workers have also carried out extensive research into palladium complex-catalyzed multicomponent cyclocarbonylations of aryl halides containing nucleophilic group and a point of unsaturation. These types of reactions usually proceeded through a sequential hydrofunctionalization or coupling, followed by intramolecular cyclocarbonylation, thus providing powerful access to various diversely functionalized carbocycles and heterocycles. Alternatively, the processes might also involve initial oxidative addition of Pd(0) to a carbon-halogen bond and CO insertion, followed by cyclocarbonylation. For instance, Alper and Xiao disclosed that 2-iodothiophenol 56 could undergo carbonylative heteroannulation efficiently with allenes 57 and carbon monoxide, when using Pd(OAc)2/dppf in benzene at 100 oC, furnishing thiochroman-4-ones in good yield (Scheme 13a).102 It was postulated that

Page 8 of 21

iodothioether 56-A might be the key intermediate that underwent intramolecular cyclocarbonylation to give the final products 58. Scheme 13. Multi-component Cyclocarbonylation of Substituted 2-Iodothiophenols, 2-Iodophenols and 2Iodoanilines I +

R SH

R1 CO + (400 psi)

56

C

R2

57

I

Pd(OAc)2 dppf, iPr2NEt benzene 100 oC, 36 h

O R

R

R1 S R2 56-A key intermediate

I R NH2

CO + + (5 atm)

R3 Pd2(dba)3CHCl3 dppb, iPr2NEt

C R1

59

R2 60

(a)

O R N H

61 21-85% yield

R3 R2 R1

(b)

O

I +

R OH

CO + (1 atm)

R1

62

R

BMIMPF6 90 oC, 20 h

R1 S R2 58 68-92% yield

63

I

+ CO + C (300 psi) X OH 65

R

I O

PdCl2, Et3N C14H29(C6H13)3P+Br- R 110 oC, 24 h

Pd(OAc)2, iPr2NEt, or NR1 Pd2(dba)3CHCl3, K2CO3 R dppb, benzene or THF 100 oC, 24-48 h

66 NR

1

X

(c) O R1 64 64-96% yield O NR1 (d) O X 67 1 X = O, NR 45-96% yield

key intermediate

Based on this concept, Alper and co-workers developed similar multi-component cyclocarbonylations of oiodoanilines 59 with allenes 60 (Scheme 13b),103 as well as o-iodophenols 62 with terminal alkynes 63 (Scheme 13c).104 They also significantly expanded the substrate scope of the cyclocarbonylation to a range of other aniline derivatives formed in situ from the reactions of oiodoanilines with acid chlorides,105 imidoyl chlorides,106 diethyl ethoxycarbonylbutendienoate,107 Ntoluenesulfonyl aldimines,108 as well as other in situgenerated aryl halide derivatives.109-113 It was found that o-iodophenols 55 underwent smooth Pd-catalyzed multi-component cyclocarbonylation with heterocumulenes 66, such as carbodiimides and isocyanates under CO pressure (Scheme 13d).114 The reaction provided efficient access to various biologically relevant benzo[e]-1,3-oxazin-4-ones 67 and derivatives in good yields. This protocol could also be expanded to include o-iodoanilines and heterocumulenes for the synthesis of 4(3H)-quinazolinone derivatives.115 Intramolecular cyclocarbonylations of 2-(2iodophenoxy)aniline derivatives could be catalyzed by recyclable Pd-complexed dendrimers supported on silica gel, providing general and mild methods for synthesis of O-, N-, and S-containing medium-sized heterocycles.116-118 4. CATALYTIC CARBONYLATIVE RING EXPANSION REACTION

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ACS Catalysis

Transition metal-catalyzed carbonylative ring expansion of heterocyclic compounds is another interesting and synthetically useful transformation. This reaction class allows both ring expansion and functionalization of a large of variety of parent N-, O, and S-containing heterocycles by the insertion of CO into their carbonheteroatom or heteroatom-heteroatom bond.119 In this context, Alper and co-workers have made significant contributions to the transition metal complex-catalyzed carbonylative ring expansion of heterocycles using carbon monoxide gas. Some representative results of these studies from the Alper group are discussed in this section. The presence of strain in three-membered ring heterocycle, such as aziridines, oxiranes, and thiranes makes them attractive substrates for carbonylative ring expansion. In 1981, Alper and co-workers reported an elegant approach to the synthesis of β-bicyclic-lactams 69 from azirines 68 using CO in the presence of Pd(PPh3)4 as catalyst (Scheme 14a).120 It was postulated that the reaction proceeded through a sequential Pd-catalyzed formation of bicyclic system 68-A and insertion of CO into one of the strained C-N bonds. Drawing inspiration from this work, Alper developed a series of carbonylative ring expansion reactions of simple aziridines towards the construction of biologically important monocyclic βlactams. The regioselectivity of the insertion into one of the two C-N bonds was dependent on the nature of substituents on the aziridine ring. For instance, Rhcatalyzed carbonylation of 2-arylaziridines 70 occurred regiospecifically at the aryl-substituted C-N bond, giving β-lactams 71 in quantitative yields (Scheme 14b).121 They proposed that aryl group might direct the metal insertion via the formation of a π-benzyl intermediate. Notably, this catalytic system enabled carbonylation of cis-1isopropyl-3-methyl-2-phenylaziridine to give the cis-3,4disubstituted β-lactam 72 with retention of configuration at both stereocenters.122 When the reaction was carried out in the presence of d or l-menthol, a kinetic resolution of the starting aziridine (70, R = tBu, Ar = Ph) could be accomplished. Moreover, rhodium-complexed dendrimers supported on a resin were found to be efficient catalysts for the carbonylative ring expansion reactions of aziridines, showing comparable activity.123 Scheme 14. Carbonylative Ring Expansion of ThreeMembered Heterocycles

R H

Ar

N 68

R1

70

CO (1 atm)

benzene, 40 oC

H

R

O

Ar

N Ar

N H R

69 25-63% yield Ar

N R

+

Pd(PPh3)4

+

[Rh(CO)2Cl]2 CO benzene, 90 oC (20 atm)

R = tBu, 1-adamantyl

Ar N R O 71 (R1 = H) quantitative

R H

Ar N N

Ar

68-A H R intermediate Me i

Ar (b)

N

Pr O 72 (R1 = Me) 81% yield

R1

Co2(CO)8 (8 mol%) R1 or NaCo(CO)4 + CO N N DME, 100 oC (33 atm) R R O 73 74 R = PhCH2CH2, Bn, iPr, MeOC6H4 64-94% yield R1 = Et, nBu, tBu

(a)

O N

(c) R

75

When the reaction is performed with Co2(CO)8 as catalyst under ~33 atm of CO, the insertion reaction is also highly specific, but occurs into the less substituted of the two ring C-N bonds, giving the corresponding βlactams 74 with good to excellent yields (Scheme 14c).124 It was postulated that the reaction begins by SN2-type ring opening of the aziridine by the in situ-formed tetracarbonylcobaltate anion (Co(CO)4-), which occurs at the less substituted carbon of aziridine. In support of this mechanism, clean inversion of the configuration is always observed at the reacting carbon. Remarkably, even when the reacting aziridine is annelated onto a cyclohexyl ring in cis-configuration, it can be converted into trans-βlactam as the only product. This result was unexpected due to the considerable strain induced in the fused 6/4 trans ring junction. Alper and co-workers also identified Pd(PPh3)4 as an efficient catalyst for carbonylative ring expansion of methyleneaziridines for the synthesis of α-methylene-βlactams.125 Interestingly, styrene oxides underwent double carbonylation to give 4,5-dihydro-4-phenylfuran-2,3diones in the presence of Co2(CO)8 as catalyst.126 Though carbonylative ring expansion of oxetanes typically required high pressure of CO and harsh conditions, in 1989, Alper and co-workers found that this reaction could be achieved under somewhat lower pressures (60 atm) using 1:1 mixture of Co2(CO)8/Ru3(CO)12, although high temperatures (165-240 oC) are still required.127 Under these conditions, a range of substituted oxetanes 76 underwent CO insertion at the less substituted C-O bond to give the corresponding lactones 77 in good yields (Scheme 15a). Interestingly, carbonylation of multi-substituted oxetanes also worked well with retention of configuration at all of the carbon centers on the ring (e.g., 78). This mixed catalytic system of Co2(CO)8/Ru3(CO)12 (1:1) could also be applied to structurally analogous thietanes, which underwent CO insertion into the less substituted C-S bond to furnish γthiolactones. Scheme 15. Carbonylative Ring Expansion of FourMembered Heterocycles

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R2 R3

R1 +

CO (60 atm)

Co2(CO)8/Ru3(CO)12 (1:1)

O 76 1 R = H, Hex; R2 = H, Me R3 = H, Me, CH2OCOMe

79

+ R1

R2

CO (3.4 atm)

R1 = Me, tBu R2 = Me, tBu, Ph

Ph

R1 O

Me

R2

N R

O (a)

Me

R1

78 O

77 O

3

+

S

RhZW, P(OPh)3

CO/H2 (21 atm)

R1

82

Co2(CO)8 benzene

N R1

R

2

O

or

O 80, R2 = Me, tBu, CH2OMe, 83-91%

R2

N R1

(b)

81, R2 = Ph 90% yield

R2 R

1

R3 N

H

S

RhL* 82-A

R

R2

L* Rh

Scheme 16. Carbonylative Ring Expansion of FiveMembered Heterocycles

O

S

H

CO

H

S

RhL*

82-B S N R 84

R3

H-RhL* H2 O

R3 N

+

O

CO/H2 (300 psi)

H2

(a) R3

S

83 61-90% yield

N

82-C

R1

In contrast to oxetanes, the carbonylative ring expansion of azetidines can be achieved under relatively mild conditions, and the regioselectivity is dependent on the substituents at the 2-position of the ring.128 For example, for 2-alkylazetines, carbonylation occurred at the less substituted C-N bond to give 5-alkylpyrrolidinone 80, while 2-arylazetidines 79 gave rise to 3arylpyrrolidinones 81 (Scheme 15b). Alper and co-workers also applied this dual catalytic system, Co2(CO)8/Ru3(CO)12 (1/1), to 2-substituted pyrrolidines.129 In analogy to azetidines, these 2substituted pyrrolidines also showed same modes of CO insertion, leading to the regioselective synthesis of piperidinones. However more drastic conditions were required (54 atm CO, 200–220 °C), presumably because of the lack of ring strain in the five membered ring starting materials. Under these more drastic conditions, several interesting metal–catalyzed rearrangements were also observed. Interestingly, during the study of carbonylative ring expansion of acetylenic thiazoles, Alper and co-worker found that treatment of acetylenic thiazoles 82 with catalytic amounts of zwitterionic rhodium complex (η6C6H5BPh3)-Rh+(1,5-COD) and triphenyl phosphite, in the presence of CO/H2 led to cyclohydrocarbonylative ring expansion, affording 7-membered thiazepiones 83 with 61-90% yield (Scheme 16a).130 This novel transformation proved to be quite general and tolerated a variety of functional groups at the thiazole and alkyne components. A possible mechanism was proposed, in which hydrometallation of the alkyne generates intermediate 82-A, which undergoes carbonylation to give 82-B. Then, intermediate 82-B reacts with the heterocyclic nitrogen to initiate a subsequent cyclization/hydrogen addition/hydrogen–transfer/ring-opening cascade to give 82-E. Addition of hydrogen to 82-E gives the final product, with re-generation of the active rhodium complex H-RhL*.

1

O

H N H

R2

CH2Cl2, 110 oC, 18-36 h

H-RhL*

R2

R2 N

DME, 165-240 oC (45-89% yield)

R3

Page 10 of 21

R2

*LRh R2

N 3 RhL* R

R1 S H 82-D

Pd(PPh)4 (5 %mol) pyridine, 80 oC

O

R1

N H S

R3

82-E O

S N

(b)

R 85, 56-95% yield

In sharp contrast to the carbonylation of carbonheteroatom bonds of cyclic compounds, little attention has been devoted to carbonylative insertion into heteroatom-heteroatom bonds. In this regard, Alper and co-workers have also reported several examples. For example, a series of 2-substituted-2,3-dihydro-1,2benzisothiazoles 84 underwent a highly regioselective carbonylation at the N-S bond, giving 3-substituted-3,4dihydro-2H-1,3-benzothiazin-2-ones 85 with good to excellent yields (Scheme 16b).131 Six-membered heterocycles, 3,6-dihydro-2H-1,2-oxazines could also undergo carbonylative ring expansion to afford 4,7dihydro-1,3-oxazepin-2(3H)-ones in moderate yields using Co2(CO)8 as catalyst.132 5. HYDROFUNCTIONALIZATION OF UNSATURATED CARBON-CARBON BONDS The transition metal complex-catalyzed hydrocarboxylation, hydroesterification and related hydroformylation reactions of unsaturated carbon-carbon systems, such as alkenes and alkynes, are among the most extensively investigated transformations in homogeneous catalysis. The starting materials of these reactions are derived from simple chemical feedstocks, and the products are usually of considerable industrial value. The Alper group has made a number of important contributions to this field and developed many efficient and highly selective homogeneous as well as heterogeneous catalytic systems to affect these transformations. 5.1. Hydrocarboxylation. In 1983, Alper and coworkers made a pioneering contribution to alkene hydrocarboxylation chemistry describing a remarkably mild and completely regiospecific hydrocarboxylation of alkenes (86) producing branched chain acids 87 under acidic conditions (Scheme 17a).133 In the presence of (S)(+)-1,1'-binaphthyl-2,2 ′ -diyl hydrogenphosphate, the enantioselective hydrocarboxylation of styrene derivatives could be accomplished, producing a substructure common to important commercially important drugs, including ibuprofen and naproxen.134 A complementary method was found employing Pd(OAc)2/dppb (250:1:2 ratio of alkene:Pd(II):dppb), which was catalytically active in the presence of formic

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ACS Catalysis

acid as promoter at low pressure of CO (6.8 atm) (Scheme 17b).135,136 This catalytic system proved to be highly effective and regioselective for the hydrocarboxylation of simple and functionalized alkenes 88 as well as methylenecycloalkanes. In most cases, the method was selective for straight-chain acids 89.137 Mechanistic studies implied that HCO2H played an important role in the key steps of the reaction mechanism as a source of “H” and “OH” in the product carboxylic acid. Notably, Alper et al. disclosed that the heterogeneous catalyst Pd/C displayed similar catalytic activity. Scheme 17. Hydrocarboxylation of Simple and Functionalized Alkenes

+

R

CO (1 atm)

CO2H

PdCl2, CuCl2, HCl

86

THF/H2O, rt, O2

O P

R

O

87 30-100% yield

O OH

(a)

(S)-BNPPA O

R or R1 R 88

+

CO (6.8 atm)

Pd(OAc)2, dppb, HCO2H

R

DME, 150 oC, 3-16 h 74-100% yield

R R

1

OH

or

89

(b)

O

confirmed that both oxygen and hydrochloric acid are essential for the reaction. The high selectivity led the authors to also postulate the intermediacy of carbocations considering the high acidity of the medium. Notably, the combined catalyst system of PdCl2 and CuCl2 with THF as solvent also enabled selective monohydroesterification of diols, providing a regioselective access to branched chain monohydroxy esters.141 This method could also be applied to the selective hydroesterification of alkynes.142 In these reactions, terminal alkynes gave rise to unsaturated cis-diesters, while internal alkynes resulted in cis-monoesters. In contrast, the catalytic system Pd(OAc)2/dppb/PPh3/pTsOH affected the hydroesterification of alkynes and alkynols 92 for synthesis of trans-unsaturated esters 94 and 95, (Scheme 18b).143 The immobilization of Pd(II) complexes onto montmorillonite also gave efficient catalysts for the hydroesterification of alkenes in the presence of PPh3 and acid promoters (e.g., HCl, p-TsOH). These heterogeneous catalysts demonstrated similar regiochemistry to their homogenous analogs.144,145 Scheme 18. Hydroesterification of Alkenes

OH

Interestingly, the catalytic system comprised of both mono and bidentate ligands (Pd/PPh3/dppb, 1/4/2 ratio) also enabled the highly regioselective hydrocarboxylation of alkynes into branched chain, α,β-unsaturated acids as the major products. A series of deuterium labeling studies, along with other control experimental results further suggested that the reaction might involve the addition of the O-H bond of formic acid or oxalic acid to the Pd center to form a cationic hydrido(alkyne)palladium intermediate.138 The Alper group further extended the Pd(OAc)2-dppbHCO2H system to the hydrocarboxylation of 1,2polybutadiene, affording the corresponding hydrocarboxylated polymer with carboxylic acid groups at the terminal carbon atom of the pendant double bonds.139 A milder and regiospecific hydrocarboxylation of alkynes could be achieved using nickel cyanide as the transition metal catalyst and cetyltrimethylammonium bromide (CTAB) as the phase transfer catalyst.79 5.2. Hydroesterification. Hydroesterification of alkenes is another important process involving transition metal hydrides as intermediates. In these reactions, linear and branched chain esters can typically be produced. In this regard, the Alper group has developed many efficient Pd-based catalytic systems that effect the regiospecific hydroesterification of alkenes under remarkably mild reaction conditions. For instance, it was found that their previously developed catalytic system involving combination of PdCl2 and CuCl2 (5-10/1 ratio of CuCl2/PdCl2) was effective for the hydroesterification of a large variety of terminal and cyclic alkenes 86 with several alcohols 90, giving the branched chain esters 91 in high yields (Scheme 18a).140 Control experiments

+

R

CO (1 atm) +

PdCl2, CuCl2, HCl

OR1

O

(a)

benzene or toluene R rt, O2 91 90, R = alkyl 30-100% yield 1

86

R

R1OH

1

CO R + (20 atm) HCO2R3 93

Pd(OAc)2 dppb, PPh3

2

92

R 86

p-TsOH, THF 100 oC, 48 h

+ CO + MeOH (20.4 atm)

R1 R 3O

R2

R1

R2

+ (b) H H OR3 O 94 O 95 (94+95), 50-76% yield

(Cy3P)2Pd(H)(H2O)+BF4p-TsOH, dppb, THF 100 oC, 2 days

O R

OMe 96 45-100% yield

(c)

In sharp contrast to the activity of PdCl2, Alper et al. disclosed that the cationic palladium complex, (Cy3P)2Pd(H)(H2O) +BF4-, combined with dppb and pTsOH was an efficient system for the hydroesterification of a wide variety of acyclic and cyclic alkenes 86 (Scheme 18c). The corresponding straight chain esters 96 could therefore be obtained with good yields and regioselectivity.146 5.3. Hydroformylation. The transition metalcatalyzed hydroformylation of alkenes and alkynes is an industrially important reaction that allows transformation of various alkenes into linear or branched chain aldehydes by reaction with carbon monoxide and hydrogen. The development of mild, regiospecific methods and catalytic systems for hydroformylation continues to attract great interest. In 1990, Alper described the first example of the use zwitterionic rhodium complexes to catalyze the hydroformylation of alkenes 86 (Scheme 19a).147 The key zwitterionic complex (η6-C6H4-BPh3)-Rh+(1,5-COD) ([Rh]-1) can be readily prepared from rhodium

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trichloride, sodium tetraphenylborate, and 1,5cyclooctadiene in aqueous MeOH. This complex catalyzes the hydroformylation of a series of alkenes using a 1/2 mixture of CO/H2 under exceptionally mild reaction conditions. The hydroformylation of vinylarenes and vinyl ethers gives rise to branched chain aldehydes 97 with high regioselectivity, while aliphatic and 1,1disubstituted alkenes yield linear aldehydes 98 in a regiospecific manner. The combination of analogous zwitterionic rhodium complex (NBD)Rh+(C6H5-BPh3) ([Rh]-2) with (S,S)-BDPP or (R)-BINAP enabled the highly asymmetric hydroformylation of 4-vinyl β-lactam, providing the regio- and stereoselective synthesis of important 1-methyl carbapenem intermediates.148 Vinyl silanes were also suitable substrates for hydroformylation with [Rh-1], giving the corresponding α- or β-silyl aldehydes depending on reaction conditions.149 Notably, homogeneous Rh-catalyzed hydroformylation can also be carried out on styrene-butadiene copolymers (e.g., Duradene 707 and Duradene 709), when using [Rh(COD)2]BF4 and [Rh(COD)Cl]2 as catalysts.150 Scheme 19. Hydroformylation of Alkenes +

R 86

BPh3

BPh3 Rh (COD)

[Rh]-1

R1 99

+

+

N Rh

Rh

CO2R2

R

O

H [Rh]-1, CHCl3 O and/or CO/H2 o R 47-80 C, 3-43 h R (1/2, 200 psi) 46-100% conv. 97

N [Rh]-2

CO/H2

(1/1, 600 psi)

[Rh]-1, dppb, CH2Cl2 80-130 oC, 12-24 h

H

(a)

98 -

Cl Rh Cl

[Rh]-3 O R H R 2O 2C R 1 100 20-79% yield

(b)

However, poor regioselectivity was observed in the hydroformylation of α,β-unsaturated esters 99 when using complex [Rh]-1 alone as catalyst. Alper et al. found that the addition of dppb as ligand not only significantly enhanced the reaction efficiency, but also the selectivity for the branched products 100, which was always great than 95:5 (Scheme 19b).151 Replacement of dppb with (R)-BINAP as chiral ligand led to a system that affected the asymmetric hydroformylation of α-methylene-γ-butyrolactone with 37% ee.152 In addition, the complex [Rh]-1 was suitable for vinyl sulfones and sulfoxides,153 as well as unsaturated amines.154 In 2005, Alper et al. developed a novel ionic diamine-rhodium complex [Rh]-3, comprising an anionic rhodium center having chlorides and a cationic rhodium center coordinated with a diamine, which displayed high catalytic activity and regioselectivity in the hydroformylation of alkenes without the addition of any phosphorus ligand.155 Clay minerals have been established as high valuable solid supports, and among the smectite clays, montmorillonite was investigated extensively because of its natural abundance, easy availability and good swelling

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capability. Alper et al. also attempted to synthesize and explore the activity of clay-intercalated rhodium catalysts in hydroformylation. Thus, they found that Rh-clay, readily prepared by reaction of [Rh(COD)Cl]2 with the silicate layers of Na+-exchanged montmorillonite, was an active catalyst for regioselective hydroformylation of trialkylvinylsilanes and allylacetates, with the advantage of facile product separation and catalyst recovery.156,157 A novel water-soluble polymer, poly(enolate-co-vinyl alcohol-co-vinyl acetate) (PEVV) ， was identified as an efficient ligand for the Rh-catalyzed biphasic hydroformylation of alkenes. (Scheme 20).158 This catalyst displayed high regioselectivity for the formation of branched chain aldehyds from aliphatic alkenes, which is a highly challenging transformation. Although low conversion was observed with styrenes as the substrates, this limitation could be overcome by use of a related water-soluble complex Rh/PPA(Na+)DPPEA, which was readily synthesized from poly(4-pentenoic acid) (PPA) and bis[2-(diphenylphosphino)ethyl]amine (DPPEA).159 The highly branched property of dendrimers and multiple coordination sites has made them an interesting class of supports for transition metal catalysts. Alper and co-workers developed a novel class of heterogeneous polyaminoamido diphosphonated dendrimers built on a silica gel core support (PPh2-PAMAM-SiO2).160,161 This type of dendrimer, when complexed with Rh(I), proved to be a highly recyclable catalyst for the hydroformylation of a wide range of aryl alkenes and vinyl esters. Notably, in hydroformylation reactions,161 the dendrimer catalyst PPh2-PAMAM-SiO2 can be easily recovered by microporous filtration upon completion of the reaction, washed by CH2Cl2, and reused in the next catalytic cycle, without no obvious effect on conversion after several cycles. On the basis of these studies, Alper and coworkers further developed a series of dendritic phosphine ligands supported on resin by a divergent, solid-phase approach,162-164 in addition to catalysts supported on silica-coated magnetic nanoparticles,165 and large pore Davisil silica.166 The rhodium complexes of these dendritic ligands were found to be highly active and recyclable catalysts for alkene hydroformylation. Scheme 20. Polymer-and Dendrimer-Supported Rhodium Catalysts for Alkene Hydroformylation

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Ph2 P

O

N

NaO2C

[Rh]

( OH O

O

OH O

Rh

O O

) ( 0.8n

O Rh

)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

Rh/PPA(Na+)/DPPEA Ph2 P

Rh-PEVV O N H H N

N O

SiO2

O O Si O

NH

PPh2

O

PPh2 Rh(CO)2Cl PPh2

O NH

N H H N

N

Rh-PPh2-PAMAM-SiO2

Rh(CO)2Cl

PPh2

N

N

O

P Ph2 O 0.1n O

Rh(CO)2Cl

N

PPh2

N

PPh2

O

PPh2

6. TRANSITION METAL CYCLOADDITION

Rh(CO)2Cl

In 1999, based on the successful use of zwitterionic complex (η6-C6H5BPh3)-Rh+(1,5-COD) ([Rh]-1) in the hydroformylaton of alkenes, Alper et al. explored this catalyst, along with (PhO)3P, in the hydroformylation of both simple and functionalized aliphatic 1-en-3-ynes 101. Under mild conditions, [Rh]-1/(PhO)3P afforded the branched formyl dienes 102 with good regioselectivity and yields (Scheme 21).167 In all cases, nonconjugated unsaturated aldehydes 103 were also formed as byproducts. It was proposed that the reaction begins with the coordination of the unsaturated rhodium catalyst to both the double and triple bonds (101-A) to direct the intramolecular addition of Rh-H to the triple bond yielding (E)-isomer 101-B. Carbonyl insertion (102-C) followed by hydrogenation and reductive elimination gives rise to the final product 102 with release of the catalytically active Rh-H species. Scheme 21. Hydroformylation of Alkynes

+

CO/H2

R (1/1, 12 atm) 101

[Rh]-1 (4 mol%) (PhO)3P (16 mol%) 47-80 oC, 3-43 h 46-100% conv. BPh3

H-RhLx

Rh (COD) [Rh]-1

R

O H O H 102, major 103, minor 50-70% yield

H RhLx 101-B

CO O

COMPLEX-CATALYZED

In connection with their investigation into transition metal complex-catalyzed carbonylative ring expansions of heterocycles, Alper and co-workers have also carried out extensive studies on the cycloaddition of three-, four-, and five-membered ring heterocycles with various heterocumulenes. The resulting heterocycles are typically of potential biological activity and are usually not easily accessible by other means. 6.1. Cycloaddition of Simple Aziridines and Azetidines. In 1992, Alper and Baeg disclosed that the use of bis(benzonitrile)palladium dichloride (PdCl2(PhCN)2) as a catalyst enabled an efficient formal [3+2] cycloaddition of aziridines 104 with carbodimides 105 in toluene at 100 oC (Scheme 22a).173 The reaction proceeded in a regioselective fashion, with the aziridine reacting by cleavage of the more substituted C-N bond, producing imidazolidenimines 106 in 40-95% yield. This catalytic system was also successfully applied to the reaction of 1,2,3-trisubstituted aziridines 107 with aryl isocyanates 108 and isothiocyanates 109; however, the presence of one electron-withdrawing substituent at an aziridine carbon atom is required to weaken the C-N bond and improve reactivity (Scheme 22b).174 Notably, these reactions occurred in a regio- and stereospecific manner to give imidazolidinones 110 and thiazolidinimines 111 in good yields. In analogy to carbodimides, sulfur diimides,175 and ketenimines176 were also found to be suitable partners for this formal [3+2] cycloaddition with aziridines.

H-RhLx R

R R Rh Lx H 101-A

R +

H2

hydroformylation of acetylenic thiophenes, and α,β– unsaturated aldehydes with the aldehyde and thiophene attached to the same alkene carbon atom.168 The ability of the Rh-H to bind to the thiophene sulfur atom was exploited to govern the regioselectivity. This strategy also proved applicable to the hydroformylation of a variety of substituted propargylic alcohols.169 Alper and co-workers have also developed several tandem processes involving hydroformylation as the initial steps. Representative examples include the rhodium-catalyzed hydroaminomethylation of 2isopropenylanilines,170 the hydroformylation/SiO2promoted deformylation of N-allyl oxazolidines,171 and the hydroformylation/reduction sequence of styrene derivatives.172

Scheme 22. Azetidines

RhLx 101-C

Interestingly, in the case of enynes containing ether substituents, the addition of an extra coordination site has a significant effect on the regisoselectivity of hydroformylation. Inspired by this finding, Alper and coworker explored this catalytic system in the regioselective

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Cycloaddition

of

Aziridines

and

ACS Catalysis R H

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

R N R1 104

PdCl2(PhCN)2

+ ArN C NAr

Me

toluene, 100 oC 24 h, N2 (5 psi)

105

ArN C O 108 + or ArN C S 109

CO2R n

N Bu

107

CO2R N

ArN C NAr

+

R1 112

Ar N

105

PdCl2(PhCN)2 toluene, 120 oC 20 h, N2 (5 psi)

(a)

N Ar N R1 106 40-95% yield Ar N

RO2C H H Me

H

CO2R

S (b) Ar N N n Bu 111 70-75% yield

H O or Me

N n Bu 110 72-86% yield H CO2R Ar N

PdCl2(PhCN)2 toluene, 130 oC 48 h, N2 (5 psi)

N R1

N Ar

(c) 113 64-97% yield

When using PdCl2(PhCN)2) as the catalyst, substituted azetidines 112 with lower ring strain could also undergo formal [4+2] cycloaddition with heterocumulenes, such as carbodimides 105 (Scheme 22c),177 and aryl 178 isothiocyanates, in a regio- and stereospecific manner. The corresponding six-membered ring tetrahydropyrimidin-2-imines 113 and tetrahydrothiazin2-imines were obtained in good to excellent yields. 6.2. Cycloaddition of 2-Vinyloxiranes, 2vinylaziridines, and 2-vinyloxetanes. As shown in the cycloaddition of the simple three- and four-membered Nheterocycles with heterocumulenes, reaction temperatures above 100 oC are usually required to affect this transformation. However, if vinyloxiranes and 2vinylaziridines are employed as substrates, the Pd(0)catalyzed formal [3+2] cycloaddition proceeded under milder conditions. For instance, the combination of Pd2(dba)3·CHCl3 and chiral ligand (S)- or (R)-TolBINAP could catalyze the formal [4+2] cycloaddition of vinyloxiranes 114 with heterocumulenes, carbodimides 105 and aryl isocyanates 108, in THF at ambient temperature (Scheme 23a).179 High yields and moderate to high enantioselectivities were obtained. Scheme 23. Cycloaddition of 2-Vinyloxiranes and 2Vinylpyrrolidines ArN C O Pd2(dba)3CHCl3 (3 mol%) 108 R + or TolBINAP O ArN C NAr (6 mol%) 114 THF, N2, rt R = H, Me 105 O L

N R R1 117

Pd R L

+

R2 NCO 108

R

Ar

O O

N Ar

or

dppp (10 mol%) THF, N2 (5 psi) 40-60 oC

N O

115 up to 99% yield 49% ee

Pd2(dba)3CHCl3 (5 mol%)

R

(a) N Ar

116 up to 98% yield 94% ee

R N

R2 (b) O N 118 R1 11-82% yield

It was postulated that zwitterionic (π-allyl) palladium complexes generated by oxidative addition of vinyloxirane to the Pd(0) species were involved as the key intermediates in the process. In the case of

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unsymmetrical carbodiimides, two regioisomers were obtained, in varying ratios from 2:1 to 9:1 depending on the relative steric effects and the ligands involved.180 This catalytic strategy was also extended to the challenging reaction of 2-vinylthiiranes with heterocumulenes (e.g., carbodiimides, isocyanates, and ketenimines.).181 The formal [3+2] cycloaddition of 2-vinylaziridines with isocyanates, isothiocyanates, and carbodiimides could also be catalyzed by Pd(OAc)2/PPh3 or Pd2(dba)3·CHCl3/(S)-BINAP/CeCl3 at room temperature and ambient pressure.182,183 The use of CeCl3 in the latter case was found to improve enantioselectivity. 2-Vinyloxetanes also underwent a formal [4+2] cycloaddition with carbodiimides and isocyanates respectively, when using Pd2(dba)3·CHCl3 and bidentate phosphine (dppe or dppp) as catalyst in THF at ambient temperature, providing efficient and practical access to 1,3-oxazine derivatives184 Similar reaction modes between N-alkyl-2-vinylazetidines with heterocumulenes, including aryl- and alkylisocyanates, diarylcarbodiimides, arylisothiocyanates, ketenimines, and ketenes were also achieved in the presence of Pd(OAc)2 and PPh3 as precatalysts.185,186 Alper and Zhou also successfully expanded the Pdcatalyzed ring cycloaddition strategy to more challenging substrates, five-membered ring 2-vinylpyrrolidines 117 (Scheme 23b).187 It was revealed that the highly regioselective formal [5+2] cycloaddition between 2vinylpyrrolidines 117 and aryl isocyanates 108 can be achieved by using Pd2(dba)3·CHCl3 and dppp at 40-60 oC, giving seven-membered ring diazepin-2-ones 118 in reasonable yields. In contrast, the use of Pd(OAc)2 and PPh3 as catalyst typically led to the formation conjugated dienes by intramolecular hydrogen migration.  SUMMARY Professor Howard Alper has had a long and distinguished career in organomeatallic chemistry and catalysis, with landmark contributions to metal carbonyl chemistry, carbonylation, carbonylative ring expansion, hydrofunctionalization, and cycloaddition reactions. In addition to surveying some of the highlights of his contributions to chemistry in this article, we hope that we have been able to illustrate some of the logical progressions of chemistry in his lab, from early interest in metal carbonyls as stoichiometric species, to reagents and eventually to highly effective catalysts or catalytic intermediates. Indeed, by understanding the way in which metal complexes react with carbon monoxide and complex organic structures, Alper has made groundbreaking contributions to the field of catalysis.

 AUTHOR INFORMATION  Corresponding Author *E-mail: [email protected] *E-mail: [email protected] *E-mail: [email protected]

 ORCID

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Cathleen M. Crudden: 0000-0003-2154-8107 Jia-Rong Chen: 0000-0001-6054-2547 Wen-Jing Xiao: 0000-0002-9318-6021

Notes

The authors declare no competing financial interest.

 ACKNOWLEDGMENT The authors are grateful for the opportunity to illustrate the work of Professor Howard Alper.

 REFERENCES (1) Alper, H. New Applications of Metal Carbonyls as Reagents and Catalysts in Synthesis. Pure Appl. Chem. 1980, 52, 607-614. (2) Alper, H.; Edward, J. T. Regeneration of Carbonyl Compounds from Oximes using Iron Pentacarbonyl and Boron Trifluoride. J. Org. Chem. 1967, 32, 2938-2938. (3) Alper, H.; Edward, J. T. Reaction of Iron Carbonyls with Amides and Thionamides. Can. J. Chem. 1968, 46, 3112-3115. (4) Alper, H.; Edward, J. T. Reactions of Iron Pentacarbonyl with Compounds Containing the N—O Linkage. Can. J. Chem. 1970, 48, 1543-1549. (5) Alper, H. Reaction of Nitroxyl Radicals with Metal Carbonyls. J. Org. Chem. 1973, 38, 1417-1418. (6) Alper, H.; Gopal, M. Preparation of Azo Compounds and Amines by Triiron Dodecacarbonyl or Molybdenum Hexacarbonyl on Alumina. J. Org. Chem. 1981, 46, 2593-2594. (7) Des Abbayes, H.; Alper, H. Phase-Transfer Catalyzed and Two-Phase Reactions of Aromatic Nitro Compounds with Iron Carbonyls. J. Am. Chem. Soc. 1977, 99, 98-101. (8) Alper, H.; Damude, L. C. Metal Carbonyl Anion Generation Using Potassium Fluoride or Tetrabutylammonium Fluoride. Organometallics 1982, 1, 579-581. (9) Alper, H.; Hashem, K. E. Iron and Ruthenium Carbonyl Catalyzed Reductive Carbonylation of Nitro Compounds by Sodium Methoxide. A Significant Effect of the Metal on the Reaction Course. J. Am. Chem. Soc. 1981, 103, 6514-6515. (10) Valli, V. L. K.; Alper, H. Reductive Carbonylation of Monoand Dinitroarenes Catalyzed by Montmorillonitebipyridinylpalladium(II) Acetate and Ruthenium Carbonyl. J. Am. Chem. Soc. 1993, 115, 3778-3779. (11) Alper, H.; C.H. Keung, E. Deoxygenation of Sulfoxides by Iron Pentacarbonyl. Tetrahedron Lett. 1970, 11, 53-56. (12) Alper, H. Reactions of Sulfines with Iron and Manganese Carbonyls; Dexoygenation vs. ortho-Metalation. J. Organomet. Chem. 1975, 84, 347-350. (13) Alper, H.; Des Roches, D. Deoxygenation of Epoxides by Iron Pentacarbonyl. Tetrahedron Lett. 1977, 18, 4155-4158. (14) Alper, H.; Sališová, M. The Iron Carbonyl Induced Deoxygenation of Alcohols. Tetrahedron Lett. 1980, 21, 801-804. (15) Alper, H.; Paik, H.-N. A Convenient Synthesis of Azobenzenes. Interesting Solvent Effects. J. Organomet. Chem. 1978, 144, C18-C20. (16) Alper, H.; Gopal, M. Heterogeneous Cobalt CarbonylNitroarene Reactions: A Significant Difference From the homogeneous Process. J. Organomet. Chem. 1981, 219, 125-127. (17) Alper, H. Hydridotetracarbonylferrate Anion. Convenient Desulfurization Reagent. J. Org. Chem. 1975, 40, 2694. (18) Alper, H.; Paik, H.-N. Reaction of Thiobenzophenones with the Dicarbonylcyclopentadienyliron Anion: A Novel Fulvene Synthesis via Desulphurization. J. Chem. Soc., Chem. Commun. 1977, 126-127. (19) Alper, H.; Paik, H.-N. New Effective Desulfurization Reagents. J. Org. Chem. 1977, 42, 3522-3524.

(20) Alper, H.; Blais, C. Modified Molybdenum Carbonyl Species; Excellent Reagents for the Desulphurization of Thiols. J. Chem. Soc., Chem. Commun. 1980, 169-170. (21) Alper, H.; Blais, C. Removal of Sulphur from Fuels by Molybdenum Hexacarbonyl on Silica. Fuel 1980, 59, 670. (22) Alper, H.; Gopal, M.; Heveling, J. Use of Molybdenum Carbonyl on Florisil for the Desulphurization of Crude Oil. Fuel 1982, 61, 1164. (23) Alper, H.; Ripley, S.; Prince, T. L. Desulfurization of Thiols and Thioketones by Sodium Triethylborohydride and Iron(II) Chloride on Alumina. J. Org. Chem. 1983, 48, 250-252. (24) Shim, S. C.; Antebi, S.; Alper, H. Desulfurization of Mercaptans to Hydrocarbons by Carbon Monoxide and Water in the Presence of Cobalt Carbonyl. Tetrahedron Lett. 1985, 26, 1935-1938. (25) Antebi, S.; Alper, H. Cobalt Carbonyl Catalyzed Reactions of Disulfides: Carbonylation to Thioesters and Desulfurization to Sulfides. Tetrahedron Lett. 1985, 26, 2609-2612. (26) Shim, S. C.; Alper, H. Desulfurization and Carbonylation of Mercaptans. J. Org. Chem. 1985, 50, 147-149. (27) Alper, H.; Keung, E. C. H. Formation of 1,4-Diketones, Monoketones, and β-Epoxy Ketones by Reaction of Iron Pentacarbonyl with α-Halo Ketones. Possible Mechanism for Iron Pentacarbonyl-Halide Reactions. J. Org. Chem. 1972, 37, 2566-2572. (28) Alper, H. Reaction of Iron Pentacarbonyl with Sulfonyl Chlorides. Tetrahedron Lett. 1969, 10, 1239-1242. (29) Alper, H.; Des Roches, D. Dehalogenation and Condensation Reactions of Molybdenum Carbonyls with Activated Halides. J. Org. Chem. 1976, 41, 806-808. (30) Alper, H.; Pattee, L. Simple and Mild Dehalogenation Reactions Effected by Molybdenum Hexacarbonyl on Alumina. J. Org. Chem. 1979, 44, 2568-2569. (31) Alper, H.; Logbo, K. D.; des Abbayes, H. Cobalt Carbonyl Catalyzed Dehalogenation and Coupling Reactions by Phase Transfer Catalysis. Tetrahedron Lett. 1977, 18, 2861-2864. (32) Alper, H.; Gopal, M. Selective Dehalogenation of α-Bromo Sulfoxides by Dicobalt Octacarbonyl on Alumina. J. Org. Chem. 1983, 48, 4390-4391. (33) Genco, N. A.; Partis, R. A.; Alper, H. Iron Pentacarbonyl and the Hydridoundecacarbonyltriferrate Anion as Reagents for Converting Benzohydroxamoyl Chlorides to Nitriles. Deoxygenation of Nitrile Oxides. J. Org. Chem. 1973, 38, 43654367. (34) Alper, H. Homogeneous and Phase Transfer Catalyzed Carbonylation Reactions. J. Organomet. Chem. 1986, 300, 1-6. (35) Alper, H. Metal Catalyzed Carbonylation and OxidationReduction Reactions. Pure Appl. Chem. 1988, 60, 35-38. (36) El Ali, B.; Alper, H. The Application of Transition Metal Catalysis for Selective Cyclocarbonylation Reactions. Synthesis of Lactones and Lactams. Synlett 2000, 161-171. (37) Woell, J. B.; Alper, H. Synthesis of Esters by Rhodium(I) Catalyzed Borate Ester-Benzylic Bromide Carbonylation Reactions. Tetrahedron Lett. 1984, 25, 3791-3794. (38) Alper, H.; Hamel, N.; Woell, J. B.; Smith, D. J. H. Iodide Ion Promotion of Benzyl Chloride-Borate Ester Carbonylation Reactions. Tetrahedron Lett. 1985, 26, 2273-2274. (39) Hashem, K. E.; Woell, J. B.; Alper, H. Palladium(O) and Rhodium(I) Catalysis of the Carbonylation of Unactivated Bromides. Tetrahedron Lett. 1984, 25, 4879-4880. (40) Alper, H.; Antebi, S.; Woell, J. B. Metal-Catalyzed Carbonylations of Benzyl and Aryl Bromides in the Presence of Aluminum Alkoxides; A Straightforward Ester Synthesis. Angew. Chem. Int. Ed. 1984, 23, 732-733. (41) Woell, J. B.; Fergusson, S. B.; Alper, H. Rhodium-Catalyzed and Palladium-Catalyzed Carbonylation Reactions with

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Titanium and Zirconium Alkoxides. J. Org. Chem. 1985, 50, 21342136. (42) Buchan, C.; Hamel, N.; Woell, J. B.; Alper, H. Mono- and Bimetallic Catalysed Formate–Halide Carbonylation Reactions. J. Chem. Soc., Chem. Commun. 1986, 167-168. (43) Amaratunga, S.; Alper, H. Catalytic Carbonylation of Benzylic and Allylic Bromides by a Rhodium Zwitterionic Complex under Phase Transfer Catalysis Conditions. J. Organomet. Chem. 1995, 488, 25-28. (44) Xu, T.; Alper, H. Pd-Catalyzed Chemoselective Carbonylation of Aminophenols with Iodoarenes: Alkoxycarbonylation vs Aminocarbonylation. J. Am. Chem. Soc. 2014, 136, 16970-16973. (45) Antebi, S.; Arya, P.; Manzer, L. E.; Alper, H. Carbonylation Reactions of Iodoarenes with PAMAM Dendrimer-Palladium Catalysts Immobilized on Silica. J. Org. Chem. 2002, 67, 66236631. (46) Cao, H.; McNamee, L.; Alper, H. Palladium-Catalyzed Thiocarbonylation of Iodoarenes with Thiols in Phosphonium Salt Ionic Liquids. J. Org. Chem. 2008, 73, 3530-3534. (47) Zeng, F.; Alper, H. Palladium-Catalyzed Domino C-S Coupling/Carbonylation Reactions: An Efficient Synthesis of 2Carbonylbenzo[b]thiophene Derivatives. Org. Lett. 2011, 13, 2868-2871. (48) Alper, H.; Hashem, K.; Heveling, J. Selective Phase Transfer and Palladium(0)-Catalyzed Carbonylation, Carbalkoxylation, and Reduction Reactions. Organometallics 1982, 1, 775-778. (49) Galamb, V.; Alper, H. Biphasic and Phase Transfer Catalyzed Carbonylation of Vinylic Bromides. Transition Met. Chem. 1983, 8, 271-273. (50) Grushin, V. V.; Alper, H. An Exceptionally Simple Biphasic Method for the Metal Catalysed Carbonylation of Chloroarenes. J. Chem. Soc., Chem. Commun. 1992, 611-612. (51) Grushin, V. V.; Alper, H. Simple and Efficient PalladiumCatalyzed Carbonylation of Iodoxyarenes in Water under Mild Conditions. J. Org. Chem. 1993, 58, 4794-4795. (52) Zhao, X.; Alper, H.; Yu, Z. Stereoselective Hydroxycarbonylation of Vinyl Bromides to α,β-Unsaturated Carboxylic Acids in the Ionic Liquid [BMIM]PF6. J. Org. Chem. 2006, 71, 3988-3990. (53) Grushin, V. V.; Alper, H. Alkali-Induced Disproportionation of Palladium(II) Tertiary Phosphine Complexes, [L2PdCl2], to LO and Palladium(O). Key Intermediates in the Biphasic Carbonylation of ArX Catalyzed by [L2PdCl2]. Organometallics 1993, 12, 1890-1901. (54) Grushin, V. V.; Alper, H. Indirect Formation of Carboxylic Acids via Anhydrides in the Palladium-Catalyzed Hydroxycarbonylation of Aromatic Halides. J. Am. Chem. Soc. 1995, 117, 4305-4315. (55) Grushin, V. V.; Alper, H. Novel Palladium-Catalyzed Carbonylation of Organic Halides by Chloroform and Alkali. Organometallics 1993, 12, 3846-3850. (56) Pri-Bar, I.; Alper, H. Formation of Anhydrides by Homogeneous Palladium(II)-Catalyzed Carbonylation of Aryl Halides and Metal Carboxylates. J. Org. Chem. 1989, 54, 36-38. (57) Amer, I.; Alper, H. Nickel Cyanide and Phase-TransferCatalyzed Carbonylation of Aryl Iodides in the Absence of Light. J. Org. Chem. 1988, 53, 5147-5148. (58) Amer, I.; Alper, H. Lanthanide-Promoted and Nickel Cyanide-Catalyzed Carbonylation Reactions under PhaseTransfer Conditions. J. Am. Chem. Soc. 1989, 111, 927-930. (59) Alper, H.; Amer, I.; Vasapollo, G. Stereospecific Nickel and Phase Transfer Catalyzed Carbonylation of Vinyl Bromides and Chlorides. Tetrahedron Lett. 1989, 30, 2615-2616. (60) Lee, J. T.; Alper, H. Lewis Acid Promoted, Cobalt-Catalyzed, and Phase-Transfer-Catalyzed Carbonylation of Iodo Arenes and Iodo Alkanes. Organometallics 1990, 9, 3064-3066.

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(61) Zucchi, C.; Pályi, G.; Galamb, V.; Sámpár-Szerencsés, E.; Markó, L.; Li, P.; Alper, H. Cobalt-Catalyzed Carbonylation of Benzyl Halides Using Polyethylene Glycols as Phase-Transfer Catalysts. Organometallics 1996, 15, 3222-3231. (62) Alper, H.; Hartstock, F. W.; Despeyroux, B. The Alkoxy– Alkoxycarbonylation of Allenes. J. Chem. Soc., Chem. Commun. 1984, 905-906. (63) Mlekuz, M.; Joo, F.; Alper, H. Palladium Chloride-Catalyzed Olefin-Formate Ester Carbonylation Reactions. A Simple, Exceptionally Mild, and Regioselective Route to Branched Chain Carboxylic Esters. Organometallics 1987, 6, 1591-1593. (64) Lin, I. J. B.; Alper, H. Regiochemical Control in Palladium(0) and Palladium(II) Catalysed Alkene–Formate Ester Carbonylation Reactions. J. Chem. Soc., Chem. Commun. 1989, 248-249. (65) Vieira, T. O.; Green, M. J.; Alper, H. Highly Regioselective anti-Markovnikov Palladium-Borate-Catalyzed Methoxycarbonylation Reactions: Unprecedented Results for Aryl Olefins. Org. Lett. 2006, 8, 6143-6145. (66) Amezquita-Valencia, M.; Achonduh, G.; Alper, H. PdCatalyzed Regioselective Alkoxycarbonylation of 1-Alkenes Using a Lewis Acid [SnCl2 or Ti(OiPr)4] and a Phosphine. J. Org. Chem. 2015, 80, 6419-6424. (67) Amezquita-Valencia, M.; Alper, H. Regioselective Alkoxycarbonylation of Allyl Phenyl Ethers Catalyzed by Pd/dppb Under Syngas Conditions. J. Org. Chem. 2016, 81, 38603867. (68) Xiao, W.-J.; Vasapollo, G.; Alper, H. Highly Regioselective Palladium-Catalyzed Thiocarbonylation of Allenes with Thiols and Carbon Monoxide. J. Org. Chem. 1998, 63, 2609-2612. (69) Xiao, W.-J.; Alper, H. Highly Regioselective Thiocarbonylation of Allylic Alcohols with Thiols and Carbon Monoxide Catalyzed by Palladium Complexes: A New and Efficient Route to β,γ-Unsaturated Thioesters. J. Org. Chem. 1998, 63, 7939-7944. (70) Xiao, W.-J.; Vasapollo, G.; Alper, H. Palladium-Catalyzed Ring-Opening Thiocarbonylation of Vinylcyclopropanes with Thiols and Carbon Monoxide. J. Org. Chem. 2000, 65, 4138-4144. (71) Li, C.-F.; Xiao, W.-J.; Alper, H. Palladium-Catalyzed RingOpening Thiocarbonylation of Vinylcyclopropanes with Thiols and Carbon Monoxide. J. Org. Chem. 2009, 74, 888-890. (72) Xiao, W.-J.; Alper, H. First Examples of Enantioselective Palladium-Catalyzed Thiocarbonylation of Prochiral 1,3Conjugated Dienes with Thiols and Carbon Monoxide: Efficient Synthesis of Optically Active β,γ-Unsaturated Thiol Esters. J. Org. Chem. 2001, 66, 6229-6233. (73) Xiao, W.-J.; Vasapollo, G.; Alper, H. Highly Chemo- and Regioselective Thiocarbonylation of Conjugated Enynes with Thiols and Carbon Monoxide Catalyzed by Palladium Complexes: An Efficient and Atom-Economical Access to 2(Phenylthiocarbonyl)-1,3-dienes. J. Org. Chem. 1999, 64, 20802084. (74) Khumtaveeporn, K.; Alper, H. Novel, Metal-Catalyzed Carbonylation of Acyclic Organic Compounds. The Regiospecific Carbonylation of N,S-Acetals. J. Org. Chem. 1994, 59, 1414-1417. (75) Crudden, C. M.; Alper, H. Insertion of Carbon Monoxide into Allylic Carbon-Sulfur Bonds Catalyzed by Palladium and Ruthenium Complexes. J. Org. Chem. 1995, 60, 5579-5587. (76) Xu, T.; Sha, F.; Alper, H. Highly Ligand-Controlled Regioselective Pd-Catalyzed Aminocarbonylation of Styrenes with Aminophenols. J. Am. Chem. Soc. 2016, 138, 6629-6635. (77) Li, Y.; Alper, H.; Yu, Z. Palladium-Catalyzed Regiospecific Aminocarbonylation of Alkynes in the Ionic Liquid [bmim][Tf2N]. Org. Lett. 2006, 8, 5199-5201. (78) Sha, F.; Alper, H. Ligand- and Additive-Controlled PdCatalyzed Aminocarbonylation of Alkynes with Aminophenols:

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Highly Chemo- and Regioselective Synthesis of α,β-Unsaturated Amides. ACS Catal. 2017, 7, 2220-2229. (79) Amer, I.; Alper, H. Mild, Regiospecific Hydrocarboxylation of Alkynes Catalyzed by Nickel Cyanide under Phase Transfer Conditions. J. Organomet. Chem. 1990, 383, 573-577. (80) Satyanarayana, N.; Alper, H. Stereoselective Synthesis of Diacids by the Nickel Cyanide and Phase-Transfer-Catalyzed Carbonylation of Alkynols. Novel Dependency of Product Stereochemistry and Optimum Stirring Speed on the Nature of the Phase-Transfer Agent. Organometallics 1991, 10, 804-807. (81) Zhou, Z.; Alper, H. Lewis Acid Promoted, Nickel Cyanide Catalyzed Double Insertion of Carbon Monoxide in Reaction with Alkynols Using PEG-400 as a Phase-Transfer Agent. Role of Phase-Transfer Catalysts in Determining the Stereochemistry of the Reaction. Organometallics 1996, 15, 3282-3288. (82) Huh, K. T.; Orita, A.; Alper, H. Synthesis of Dienoic Acids and Esters by Cationic Palladium Complex Catalyzed Carbonylation of Alkynols and Alkynediols. J. Org. Chem. 1993, 58, 6956-6957. (83) Piotti, M. E.; Alper, H. Regioselective and in Some Cases Stereoselective Carbonylation of α-Allenic Alcohols to αVinylacrylic Acids Catalyzed by a Cationic Palladium Complex. J. Org. Chem. 1994, 59, 1956-1957. (84) Zeng, F.; Alper, H. Pd-Catalyzed Direct Coupling of Indoles with Carbon Monoxide and Alkynes: Selective Synthesis of Linear α,β-Unsaturated Ketones. Org. Lett. 2013, 15, 2034-2037. (85) Alper, H.; Leonard, D. Facile Oxidative Cyclization and Carbonylation of Allylicalcohols. Tetrahedron Lett. 1985, 26, 5639-5642. (86) Alper, H.; Hamel, N. Poly-L-leucine as an Added Chiral Ligand for the Palladium Catalysed Carbonylation of Allylic Alcohols. J. Chem. Soc., Chem. Commun. 1990, 135-136. (87) Brunner, M.; Alper, H. The First Stereoselective PalladiumCatalyzed Cyclocarbonylation of β,γ-Substituted Allylic Alcohols. J. Org. Chem. 1997, 62, 7565-7568. (88) Yu, W.-Y.; Bensimon, C.; Alper, H. A Novel PalladiumCatalyzed Asymmetric Cyclocarbonylation of Allylic Alcohols to γ-Butyrolactones. Chem. Eur. J. 1997, 3, 417-423. (89) Yu, W.-Y.; Alper, H. Palladium-Catalyzed Cyclocarbonylation of Terminal and Internal Alkynols to 2(5H)Furanones. J. Org. Chem. 1997, 62, 5684-5687. (90) Xiao, W.-J.; Alper, H. The First Examples of the PalladiumCatalyzed Thiocarbonylation of Propargylic Alcohols with Thiols and Carbon Monoxide. J. Org. Chem. 1997, 62, 3422-3423. (91) El Ali, B.; Okuro, K.; Vasapollo, G.; Alper, H. Regioselective Palladium(II)-Catalyzed Synthesis of Five- or Seven-Membered Ring Lactones and Five-, Six- or Seven-Membered Ring Lactams by Cyclocarbonylation Methodology. J. Am. Chem. Soc. 1996, 118, 4264-4270. (92) Orejon, A.; Alper, H. Cyclocarbonylation of 2-Allylphenols Catalyzed by Palladium-Montmorillonite. J. Mol. Catal. A: Chem. 1999, 143, 137-142. (93) Ye, F.; Alper, H. Recyclable Selective Palladium-Catalyzed Synthesis of Five-, Six- or Seven-Membered Ring Lactones and Lactams by Cyclocarbonylation in Ionic Liquids. Adv. Synth. Catal. 2006, 348, 1855-1861. (94) Amezquita-Valencia, M.; Alper, H. PdI2-Catalyzed Regioselective Cyclocarbonylation of 2-Allyl Phenols to Dihydrocoumarins. Org. Lett. 2014, 16, 5827-5829. (95) Dong, C.; Alper, H. Catalytic Asymmetric Cyclocarbonylation of o-Isopropenylphenols: Enantioselective Synthesis of Six-Membered Ring Lactones. J. Org. Chem. 2004, 69, 5011-5014. (96) Dong, C.; Alper, H. Enantioselective Cyclocarbonylation of 2-Vinylanilines to Six-Membered Ring Lactams. Tetrahedron: Asymmetry 2004, 15, 35-40.

(97) Okuro, K.; Kai, H.; Alper, H. Palladium-Catalyzed Asymmetric Cyclocarbonylation of 2-(1-Methylvinyl)anilines. Tetrahedron: Asymmetry 1997, 8, 2307-2309. (98) Ferguson, J.; Zeng, F.; Alper, H. Synthesis of Coumarins via Pd-Catalyzed Oxidative Cyclocarbonylation of 2-Vinylphenols. Org. Lett. 2012, 14, 5602-5605. (99) Ferguson, J.; Zeng, F.; Alwis, N.; Alper, H. Synthesis of 2(1H)-Quinolinones via Pd-Catalyzed Oxidative Cyclocarbonylation of 2-Vinylanilines. Org. Lett. 2013, 15, 19982001. (100) Xu, T.; Alper, H. Synthesis of Indolizine Derivatives by PdCatalyzed Oxidative Carbonylation. Org. Lett. 2015, 17, 45264529. (101) Lu, S.-M.; Alper, H. Sequence of Intramolecular Carbonylation and Asymmetric Hydrogenation Reactions: Highly Regio- and Enantioselective Synthesis of Medium Ring Tricyclic Lactams. J. Am. Chem. Soc. 2008, 130, 6451-6455. (102) Xiao, W.-J.; Alper, H. Regioselective Carbonylative Heteroannulation ofo-Iodothiophenols with Allenes and Carbon Monoxide Catalyzed by a Palladium Complex: A Novel and Efficient Access to Thiochroman-4-one Derivatives. J. Org. Chem. 1999, 64, 9646-9652. (103) Ye, F.; Alper, H. Ionic-Liquid-Promoted PalladiumCatalyzed Multicomponent Cyclocarbonylation of oIodoanilines and Allenes to form Methylene-2,3-dihydro-1Hquinolin-4-ones. J. Org. Chem. 2007, 72, 3218-3222. (104) Yang, Q.; Alper, H. Synthesis of Chromones via PalladiumCatalyzed Ligand-Free Cyclocarbonylation of o-Iodophenols with Terminal Acetylenes in Phosphonium Salt Ionic Liquids. J. Org. Chem. 2010, 75, 948-950. (105) Larksarp, C.; Alper, H. A Simple Synthesis of 2-Substituted4H-3,1-benzoxazin-4-ones by Palladium-Catalyzed Cyclocarbonylation ofo-Iodoanilines with Acid Chlorides. Org. Lett. 1999, 1, 1619-1622. (106) Zheng, Z.; Alper, H. Palladium-Catalyzed Cyclocarbonylation of o-Iodoanilines with Imidoyl Chlorides to Produce Quinazolin-4(3H)-ones. Org. Lett. 2008, 10, 829-832. (107) Okuro, K.; Alper, H. Palladium-Catalyzed Intermolecular Cyclocarbonylation of 2-Iodoanilines with the Michael Acceptor, Diethyl Ethoxycarbonylbutendienoate. J. Org. Chem. 2012, 77, 4420-4424. (108) Okuro, K.; Alper, H. Palladium-Catalyzed Intermolecular Cyclocarbonylation of 2-Iodoanilines with N-Toluenesulfonyl Aldimines. Tetrahedron Lett. 2012, 53, 2540-2542. (109) Zheng, Z.; Alper, H. Palladium-Catalyzed Carbonylation−Decarboxylation of Diethyl(2-iodoaryl)malonates with Imidoyl Chlorides: An Efficient Route to Substituted Isoquinolin-1(2H)-ones. Org. Lett. 2008, 10, 4903-4906. (110) Zeng, F.; Alper, H. Tandem Palladium-Catalyzed Addition/Cyclocarbonylation: An Efficient Synthesis of 2Heteroquinazolin-4(3H)-ones. Org. Lett. 2010, 12, 1188-1191. (111) Cao, H.; Vieira, T. O.; Alper, H. Synthesis of Unsaturated Seven-Membered ring Lactams through Palladium-Catalyzed Amination and Intramolecular Cyclocarbonylation Reactions of Amines and Baylis-Hillman Acetates. Org. Lett. 2011, 13, 11-13. (112) Okuro, K.; Alper, H. Palladium-Catalyzed Synthesis of 4Alkoxycarbonyl-3,4-dihydroisoquinolin-1(2H)-ones. Tetrahedron Lett. 2012, 53, 4816-4818. (113) Xu, T.; Alper, H. Synthesis of Pyrido[2,1-b]quinazolin-11ones and Dipyrido[1,2-a:2',3'-d]pyrimidin-5-ones by Pd/DIBPPCatalyzed Dearomatizing Carbonylation. Org. Lett. 2015, 17, 1569-1572. (114) Larksarp, C.; Alper, H. Palladium-Catalyzed Cyclocarbonylation ofo-Iodophenols and 2-Hydroxy-3iodopyridine with Heterocumulenes: Regioselective Synthesis of Benzo[e]-1,3-oxazin-4-one and Pyrido[3,2-e]-1,3-oxazin-4-one Derivatives. J. Org. Chem. 1999, 64, 9194-9200.

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(115) Larksarp, C.; Alper, H. Palladium-Catalyzed Cyclocarbonylation ofo-Iodoanilines with Heterocumulenes: Regioselective Preparation of 4(3H)-Quinazolinone Derivatives. J. Org. Chem. 2000, 65, 2773-2777. (116) Lu, S.-M.; Alper, H. Intramolecular Carbonylation Reactions with Recyclable Palladium-Complexed Dendrimers on Silica: Synthesis of Oxygen, Nitrogen, or Sulfur-Containing Medium Ring Fused Heterocycles. J. Am. Chem. Soc. 2005, 127, 14776-14784. (117) Lu, S.-M.; Alper, H. Synthesis of Large Ring Macrocycles (12-18) by Recyclable Palladium-Complexed Dendrimers on Silica Gel Catalyzed Intramolecular Cyclocarbonylation Reactions. Chem. Eur. J. 2007, 13, 5908-5916. (118) Yang, Q.; Cao, H.; Robertson, A.; Alper, H. Synthesis of Dibenzo[b,f][1,4]oxazepin-11(10H)-ones via Intramolecular Cyclocarbonylation Reactions Using PdI(2)/Cytop 292 as the Catalytic System. J. Org. Chem. 2010, 75, 6297-6299. (119) Khumtaveeporn, K.; Alper, H. Transition Metal Mediated Carbonylative Ring Expansion of Heterocyclic Compounds. Acc. Chem. Res. 1995, 28, 414-422. (120) Alper, H.; Perera, C. P.; Ahmed, F. R. A Novel Synthesis of β-Lactams. J. Am. Chem. Soc. 1981, 103, 1289-1291. (121) Alper, H.; Urso, F.; Smith, D. J. H. Regiospecific MetalCatalyzed Ring Expansion of Aziridines to β-Lactams. J. Am. Chem. Soc. 1983, 105, 6737-6738. (122) Calet, S.; Urso, F.; Alper, H. Enantiospecific and Stereospecific Rhodium(I)-Catalyzed Carbonylation and Ring Expansion of Aziridines. Asymmetric Synthesis of β-Lactams and the Kinetic Resolution of Aziridines. J. Am. Chem. Soc. 1989, 111, 931-934. (123) Lu, S.-M.; Alper, H. Carbonylative Ring Expansion of Aziridines to β-Lactams with Rhodium-Complexed Dendrimers on a Resin. J. Org. Chem. 2004, 69, 3558-3561. (124) Piotti, M. E.; Alper, H. Inversion of Stereochemistry in the Co2(CO)8-Catalyzed Carbonylation of Aziridines to β-Lactams. The First Synthesis of Highly Strainedtrans-Bicyclic β-Lactams. J. Am. Chem. Soc. 1996, 118, 111-116. (125) Alper, H.; Hamel, N. Regiospecific Synthesis of αMethylene-β-lactams by a Homogeneous Palladium Catalyzed Ring Expansion-Carbonylation Reaction. Tetrahedron Lett. 1987, 28, 3237-3240. (126) Alper, H.; Arzoumanian, H.; Petrignani, J.-F.; SaldanaMaldonado, M. Phase Transfer Catalysed Double Carbonylation of Styrene Oxides. J. Chem. Soc., Chem. Commun. 1985, 340-341. (127) Wang, M. D.; Calet, S.; Alper, H. Regiospecific Carbonylation and Ring Expansion of Thietanes and Oxetanes Catalyzed by Cobalt and/or Ruthenium Carbonyls. J. Org. Chem. 1989, 54, 20-21. (128) Roberto, D.; Alper, H. Novel Synthesis of Pyrrolidinones by Cobalt Carbonyl Catalyzed Carbonylation of Azetidines. A New Ring-Expansion-Carbonylation Reaction of 2-Vinylazetidines to Tetrahydroazepinones. J. Am. Chem. Soc. 1989, 111, 7539-7543. (129) Wang, M. D.; Alper, H. Regioselective Synthesis of Piperidinones by Metal-Catalyzed Ring ExpansionCarbonylation Reactions. Remarkable Cobalt and/or Ruthenium Carbonyl Catalyzed Rearrangement and Cyclization Reactions. J. Am. Chem. Soc. 1992, 114, 7018-7024. (130) Van den Hoven, B. G.; Alper, H. Remarkable Synthesis of 2(Z)-6-(E)-4H-[1,4]-Thiazepin-5-ones by Zwitterionic RhodiumCatalyzed Chemo- and Regioselective Cyclohydrocarbonylative Ring Expansion of Acetylenic Thiazoles. J. Am. Chem. Soc. 2001, 123, 1017-1022. (131) Rescourio, G.; Alper, H. Synthesis of 3-Substituted-3,4dihydro-2H-1,3-benzothiazin- 2-ones via a Highly Regioselective Palladium-Catalyzed Carbonylation of 2-Substituted-2,3dihydro-1,2-benzisothiazoles. J. Org. Chem. 2008, 73, 1612-1615.

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(132) Okuro, K.; Tuan, D.; Khumtaveeporn, K.; Alper, H. Cobalt Carbonyl Mediated Carbonylative Ring Expansion Reactions of 3,6-Dihydro-2H-1,2-oxazines. Tetrahedron Lett. 1996, 37, 27132716. (133) Alper, H.; Woell, J. B.; Despeyroux, B.; Smith, D. J. H. The Regiospecific Palladium Catalysed Hydrocarboxylation of Alkenes under Mild Conditions. J. Chem. Soc., Chem. Commun. 1983, 1270-1271. (134) Alper, H.; Hamel, N. Asymmetric Synthesis of Acids by the Palladium-Catalyzed Hydrocarboxylation of Olefins in the Presence of (R)-(-)- or (S)-(+)-1,1'-Binaphthyl-2,2'-diyl hydrogen Phosphate. J. Am. Chem. Soc. 1990, 112, 2803-2804. (135) El Ali, B.; Alper, H. Formic Acid—Palladium Acetate—1,4Bis(diphenylphosphino)butane: An Effective Catalytic System for Regioselective Hydrocarboxylation of Simple and Functionalized Olefins. J. Mol. Catal. 1992, 77, 7-13. (136) El Ali, B.; Alper, H. Palladium Acetate Catalyzed Synthesis of Cycloalkylacetic Acids by Regioselective Hydrocarboxylation of Methylenecycloalkanes with Formic Acid and 1,4Bis(diphenylphosphino)butane. J. Org. Chem. 1993, 58, 35953596. (137) El Ali, B.; Vasapollo, G.; Alper, H. Use of Formic or Oxalic Acid for the Regioselective Hydrocarboxylation of Alkenes and Alkynes Catalyzed by Palladium/Carbon and 1,4Bis(diphenylphosphino)butane. J. Org. Chem. 1993, 58, 47394741. (138) Zargarian, D.; Alper, H. Palladium-Catalyzed Hydrocarboxylation of Alkynes with Formic Acid. Organometallics 1993, 12, 712-724. (139) Ajjou, A. N.; Alper, H. Catalytic Hydrocarboxylation and Hydroesterification Reactions of 1,2-Polybutadiene. Macromolecules 1996, 29, 1784-1788. (140) Despeyroux, B.; Alper, H. The Remarkably Mild, Regiospecific, and Catalytic Homogeneous Hydroesterification of Olefins. Ann. N.Y. Acad. Sci. 1983, 415, 148-151. (141) Fergusson, S. B.; Alper, H. Selective Palladium Catalysed Monohydroesterification of Diols. J. Chem. Soc., Chem. Commun. 1984, 1349. (142) Alper, H.; Despeyroux, B.; Woell, J. B. Selective Hydroesterification of Alkynes to Mono- or Diesters. Tetrahedron Lett. 1983, 24, 5691-5694. (143) Ali, B. E.; Alper, H. Regioselective Palladium (II) Catalyzed Hydroesterification of Alkynes and Alkynols using Formate Esters. J. Mol. Catal. A: Chem. 1995, 96, 197-201. (144) Lee, C. W.; Alper, H. Hydroesterification of Olefins Catalyzed by Pd(OAc)2 Immobilized on Montmorillonite. J. Org. Chem. 1995, 60, 250-252. (145) Lee, B.; Alper, H. Regiospecific Hydroesterification of Vinylsilanes Catalyzed by Palladium-Montmorillonite. J. Mol. Catal. A: Chem. 1996, 111, L3-L6. (146) Huh, K.-T.; Alper, H. Use of a Cationic Hydridoaquopalladium(II) Complex As a Catalyst for Olefin Hydroesterification. Bull. Korean Chem. Soc. 1994, 15, 304-306. (147) Amer, I.; Alper, H. Zwitterionic Rhodium Complexes as Catalysts for the Hydroformylation of Olefins. J. Am. Chem. Soc. 1990, 112, 3674-3676. (148) Park, H. S.; Alberico, E.; Alper, H. Regio- and Stereoselective Synthesis of Key 1-Methyl Carbapenem Intermediates via Hydroformylation Using a Zwitterionic Rhodium Catalyst. J. Am. Chem. Soc. 1999, 121, 11697-11703. (149) Crudden, C. M.; Alper, H. The Regioselective Hydroformylation of Vinylsilanes. A Remarkable Difference in the Selectivity and Reactivity of Cobalt, Rhodium, and Iridium Catalysts. J. Org. Chem. 1994, 59, 3091-3097. (150) Chen, J.; Ajjou, A. N.; Chanthateyanonth, R.; Alper, H. Catalytic Hydroformylation of Styrene−Butadiene Copolymers. Macromolecules 1997, 30, 2897-2901.

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(151) Alper, H.; Zhou, J. Q. Excellent Regiochemical Control in the Hydroformylation of alpha,beta-Unsaturated Esters Catalyzed by Zwitterionic Rhodium Complexes and 1,4Bis(diphenylphosphino)butane. J. Org. Chem. 1992, 57, 37293731. (152) Lee, C. W.; Alper, H. Influence of 1,4Bis(diphenylphosphino)butane on the Hydroformylation of alpha,beta-Unsaturated Esters Catalyzed by Zwitterionic, Cationic, and Neutral Rhodium(I) Complexes. The Asymmetric Hydroformylation of alpha-Methylene-gamma-Butyrolactone. J. Org. Chem. 1995, 60, 499-503. (153) Totland, K.; Alper, H. Hydroformylation of Vinyl Sulfones and Sulfoxides Catalyzed by a Zwitterionic Rhodium Complex. A Diastereoselective Process. J. Org. Chem. 1993, 58, 3326-3329. (154) Zhou, J. Q.; Alper, H. Synthesis of Pyrrolidines and Pyrrolidinones by the Rhodium Complex Catalyzed Cyclization of Unsaturated Amines. J. Org. Chem. 1992, 57, 3328-3331. (155) Kim, J. J.; Alper, H. Ionic Diamine Rhodium(I) Complexes-Highly Active Catalysts for the Hydroformylation of Olefins. Chem. Commun. 2005, 3059-3061. (156) Valli, V. L. K.; Alper, H. Organorhodium Complex on Smectite Clay: Preparation, Characterization, and Catalytic Activity for the Hydroformylation of Vinylsilanes. Chem. Mater. 1995, 7, 359-362. (157) Lee, B.; Alper, H. Regioselective Hydroformylation of Allyl Acetates Catalyzed by Rhodium-Montmorillonite. J. Mol. Catal. A: Chem. 1996, 111, 17-23. (158) Chen, J.; Alper, H. A Novel Water-Soluble Rhodium−Poly(enolate-co-vinyl alcohol-co-vinyl acetate) Catalyst for the Hydroformylation of Olefins. J. Am. Chem. Soc. 1997, 119, 893-895. (159) Ajjou, A. N.; Alper, H. A New, Efficient, and in Some Cases Highly Regioselective Water-Soluble Polymer Rhodium Catalyst for Olefin Hydroformylation. J. Am. Chem. Soc. 1998, 120, 14661468. (160) Bourque, S. C.; Maltais, F.; Xiao, W.-J.; Tardif, O.; Alper, H.; Arya, P.; Manzer, L. E. Hydroformylation Reactions with Rhodium-Complexed Dendrimers on Silica. J. Am. Chem. Soc. 1999, 121, 3035-3038. (161) Bourque, S. C.; Alper, H. Manzer, L. E.; Arya, P. Hydroformylation Reactions Using Recyclable RhodiumComplexed Dendrimers on Silica. J. Am. Chem. Soc. 2000, 122, 956-957. (162) Arya, P.; Rao, N. V.; Singkhonrat, J.; Alper, H.; Bourque, S. C.; Manzer, L. E. A Divergent, Solid-Phase Approach to Dendritic Ligands on Beads. Heterogeneous Catalysis for Hydroformylation Reactions. J. Org. Chem. 2000, 65, 1881-1885. (163) Arya, P.; Panda, G.; Rao, N. V.; Alper, H.; Bourque, S. C.; Manzer, L. E. Hydroformylation Reactions with Recyclable Rhodium-Complexed Dendrimers on a Resin. J. Am. Chem. Soc. 2001, 123, 2889-2890. (164) Lu, S. M.; Alper, H. Hydroformylation Reactions with Recyclable Rhodium-Complexed Dendrimers on a Resin. J. Am. Chem. Soc. 2003, 125, 13126-13131. (165) Abu-Reziq, R.; Alper, H.; Wang, D.; Post, M. L. Metal Supported on Dendronized Magnetic Nanoparticles: Highly Selective Hydroformylation Catalysts. J. Am. Chem. Soc. 2006, 128, 5279-5282. (166) Reynhardt, J. P. K.; Yang, Y.; Sayari, A.; Alper, H. Rhodium Complexed C2-PAMAM Dendrimers Supported on Large Pore Davisil Silica as Catalysts for the Hydroformylation of Olefins. Adv. Synth. Catal. 2005, 347, 1379-1388. (167) Van den Hoven, B. G.; Alper, H. Regioselective Hydroformylation of Enynes Catalyzed by a Zwitterionic Rhodium Complex and Triphenyl Phosphite. J. Org. Chem. 1999, 64, 3964-3968.

(168) Van den Hoven, B. G.; Alper, H. The First Regioselective Hydroformylation of Acetylenic Thiophenes Catalyzed by a Zwitterionic Rhodium Complex and Triphenyl Phosphite. J. Org. Chem. 1999, 64, 9640-9645. (169) Nanayakkara, P.; Alper, H. Synthesis of 3-Substituted Furans by Hydroformylation. Adv. Synth. Catal. 2006, 348, 545550. (170) Vieira, T. O.; Alper, H. Rhodium(I)-Catalyzed Hydroaminomethylation of 2-Isopropenylanilines as a Novel Route to 1,2,3,4-Tetrahydroquinolines, Chem. Commun. 2007, 2710-2711. (171) Vasylyev, M.; Alper, H. Diastereoselective Synthesis of Hexahydropyrrolo[2,1-b]oxazoles by a Rhodium-Catalyzed Hydroformylation/Silica-Promoted Deformylation Sequence. Angew. Chem. Int. Ed. 2009, 48, 1287-1290. (172) Vasylyev, M.; Alper, H. Conventional and Tandem Hydroformylation. Synthesis 2010, 2893-2900. (173) Baeg, J. O.; Alper, H. Regiospecific Palladium-Catalyzed Cycloaddition of Aziridines and Carbodiimides. J. Org. Chem. 1992, 57, 157-162. (174) Baeg, J.-O.; Bensimon, C.; Alper, H. The First Enantiospecific Palladium-Catalyzed Cycloaddition of Aziridines and Heterocumulenes. Novel Synthesis of Chiral Five-Membered Ring Heterocycles. J. Am. Chem. Soc. 1995, 117, 4700-4701. (175) Baeg, J.-O.; Alper, H. Novel Palladium(II)-Catalyzed Cyclization of Aziridines and Sulfur Diimides. J. Am. Chem. Soc. 1994, 116, 1220-1224. (176) Maas, H.; Bensimon, C.; Alper, H. Ring-Opening Cycloaddition of Aziridines to Ketenimines. J. Org. Chem. 1998, 63, 17-20. (177) Baeg, J.-O.; Bensimon, C.; Alper, H. Regiospecific and Stereospecific Palladium-Catalyzed Cycloaddition of Azetidines and Carbodiimides. J. Org. Chem. 1995, 60, 253-256. (178) Baeg, J.-O.; Alper, H. Synthesis of Tetrahydrothiazin-2imines by the Regiospecific Palladium(II)-Catalyzed Cycloaddition of Azetidines and Isothiocyanates. Isolation of Bis(azetidine)palladium Dichloride, a Key Catalytic Intermediate. J. Org. Chem. 1995, 60, 3092-3095. (179) Larksarp, C.; Alper, H. Palladium(0)-Catalyzed Asymmetric Cycloaddition of Vinyloxiranes with Heterocumulenes Using Chiral Phosphine Ligands: An Effective Route to Highly Enantioselective Vinyloxazolidine Derivatives. J. Am. Chem. Soc. 1997, 119, 3709-3715. (180) Larksarp, C.; Alper, H. Highly Enantioselective Synthesis of 1,3-Oxazolidin-2-imine Derivatives by Asymmetric Cycloaddition Reactions of Vinyloxiranes with Unsymmetrical Carbodiimides Catalyzed by Palladium(0) Complexes. J. Org. Chem. 1998, 63, 6229-6233. (181) Larksarp, C.; Sellier, O.; Alper, H. Palladium-Catalyzed Cyclization Reactions of 2-Vinylthiiranes with Heterocumulenes. Regioselective and Enantioselective Formation of Thiazolidine, Oxathiolane, and Dithiolane Derivatives. J. Org. Chem. 2001, 66, 3502-3506. (182) Butler, D. C. D.; Inman, G. A.; Alper, H. Room Temperature Ring-Opening Cyclization Reactions of 2-Vinylaziridines with Isocyanates, Carbodiimides, and Isothiocyanates Catalyzed by [Pd(OAc)2]/PPh3. J. Org. Chem. 2000, 65, 5887-5890. (183) Dong, C.; Alper, H. CeCl3 Promoted Asymmetric Cycloaddition of Isocyanates with 2-Vinylaziridines. Tetrahedron: Asymmetry 2004, 15, 1537-1540. (184) Larksarp, C.; Alper, H. Synthesis of 1,3-Oxazine Derivatives by Palladium-Catalyzed Cycloaddition of Vinyloxetanes with Heterocumulenes. Completely Stereoselective Synthesis of Bicyclic 1,3-Oxazines. J. Org. Chem. 1999, 64, 4152-4158. (185) Inman, G. A.; Butler, D. C. D.; Alper, H. Mild Pd(OAc)2/PPh3 Catalyzed Cyclization Reactions of 2Vinylazetidines with Heterocumulenes: An Atom-Economy

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Synthesis of Tetrahydro-pyrimidinone, Tetrahydropyrimidinimine, and Thiazinanimine Analogs. Synlett 2001, SI, 914-919. (186) Martorell, A.; Inman, G. A.; Alper, H. Regioselective Palladium-Catalysed Cycloaddition Reactions of 1-Alkyl-2vinylazetidines with Ketenimines and Ketenes. J. Mol. Catal. A: Chem. 2003, 204-205, 91-96. (187) Zhou, H. B.; Alper, H. Synthesis of Seven-Membered Ring Diazepin-2-ones via Palladium-Catalyzed Highly Regioselective Cyclization of 2-Vinylpyrrolidines with Aryl Isocyanates. J. Org. Chem. 2003, 68, 3439-3445.

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