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DOI: 10.1055/s-0035-1561282
Dehydrogenation Adjacent to Carbonyls Using Palladium–Allyl Intermediates
Publication History
Received: 27 October 2015
Accepted after revision: 16 November 2015
Publication Date:
23 December 2015 (online)
Abstract
Palladium–allyl chemistry has historically been used as a means of allylation of nucleophiles, as developed by Tsuji and Trost in the 1970s. Also during this decade, the Saegusa oxidation, the most prominent palladium-catalyzed dehydrogenation reaction, was developed. This Synpacts article provides a historical overview of dehydrogenation adjacent to carbonyls and our recent contribution to this area: palladium–allyl catalyzed dehydrogenation of nitriles and esters.
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Yifeng Chen (left) was born and grew up in Anhui, China. He received his BA in Chemistry from Soochow University in 2007 and completed his PhD under the supervision of Prof. Yuanhong Liu at Shanghai Institute of Organic Chemistry (SIOC) in 2012, focusing on homogenous gold catalysis. In 2013, he moved to the US as a postdoctoral fellow in the Buchwald group at MIT, working on continuous-flow chemistry. In 2014, he joined the Newhouse group as a postdoctoral fellow.
Timothy R. Newhouse (middle) was born in New Hampshire and grew up in northern New England. He received his BA in chemistry from Colby College (2005) in Waterville, ME, where he was mentored by Prof. Dasan M. Thamattoor. After moving to La Jolla, CA, he completed his PhD at The Scripps Research Institute with Prof. Phil S. Baran (2010). During his time at Scripps, he also worked in the laboratories of Prof. Donna G. Blackmond. He then returned to the east coast for postdoctoral studies with Prof. E. J. Corey at Harvard University. As of 2013, he is an Assistant Professor at Yale University in the Department of Chemistry.
While studies initiated in the mid-19th century used the oxidation of inert C–H bonds as a tool to understand the structure and electronic properties of organic molecules, modern efforts use C–H oxidation to understand reactivity and to access molecules by direct means. These oxidation methodologies often allow for reduction of the number of chemical operations in a synthetic sequence and eliminate the production of waste associated with classical processes. Palladium catalysis has accelerated advancements in the functionalization of C–H bonds with significant contributions coming from the research laboratories of Yu, Sanford, and others to convert C–H σ bonds to C–X σ bonds.[1] A less-studied reaction class is the palladium-catalyzed oxidation of alkanes to alkenes, which converts C–H σ bonds into C–C π bonds. Practical methods using this strategy to transform carbonyls to their α,β-unsaturated counterparts have recently been developed by Stahl and coworkers, as well as by our laboratory.[2]
1Selenium- and Sulfur-Based Dehydrogenations
The direct dehydrogenation adjacent to electron-withdrawing groups dates to studies by Riley and coworkers using selenium dioxide during the interwar period.[3] Since then, several other dehydrogenation methods have been developed.[4] While investigating the introduction of the ketonic function α to esters (1 → 2, Scheme [1, a]), it was serendipitously discovered that the oxidation of ethyl succinate (3) produces the dehydrogenated product, ethyl fumarate (4) instead of the expected keto ester. These oxidation reactions may proceed via β-keto seleninic acid or selenium ester intermediates.[5]
Similar to the earliest studies in carbonyl α,β-dehydrogenation, most methodologies involve initial α-functionalization of a carbonyl compound followed by an elimination reaction (Scheme [1]). Another traditional method, α-halogenation and base-mediated dehydrohalogenation, is still occasionally employed in multistep synthesis.[6] α-Phenyl selenide intermediates are more commonly utilized, owing to the mild conditions under which they can be produced: deprotonation with an amide base followed by treatment with PhSeX at low temperature (Scheme [1, b]).[7] In a separate step, the resulting phenyl selenides can be transformed into the α,β-unsaturated products 6 by oxidation of the selenide to a selenoxide 7, which spontaneously undergoes syn elimination by a [2,3]-sigmatropic rearrangement.[8] Unlike most other dehydrogenation methodologies, this transformation is capable of successfully dehydrogenating most types of carbonyl compounds, including those containing esters and amides. However, it rarely tolerates the presence of other oxidation-prone functionalities such as unprotected alcohols and amines.
In an analogous manner, sulfenylation and sulfoxide elimination also leads to pericyclic dehydrogenation, as shown by Trost in 1973 (8 → 9, Scheme [1, c]).[9] Although it avoids the toxicity of selenium, this technology has been less frequently employed in part due to the higher temperatures under which the elimination occurs (>50 °C). A conceptually similar dehydrogenation was developed by Mukaiyama and coworkers,[10] using N-tert-butyl phenylsulfinimidoyl chloride (12), which can effect an in situ dehydrogenation via the intermediacy of an α-sulfinimidoyl group (13, Scheme [1, d]). A similar cyclic transition state leads to the dehydrogenated compound. While ketone-containing compounds are efficiently dehydrogenated, other carbonyl compounds, such as esters, are more challenging and lead to incomplete conversion of starting materials.[11] Due to their similar polarities, isolating starting materials from products is difficult by chromatographic purification. In addition, the method suffers from limited stability of the reagent, as well as difficulty in removal of the byproducts.
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DDQ and IBX
In the early 20th century, quinones were identified as oxidants capable of dehydrogenating activated carbonyl compounds, and in the mid-20th century 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was identified as the most generally useful quinone oxidant.[12] This reaction represents another class of dehydrogenations, which do not proceed via an α-functionalized intermediate. Historically, DDQ was developed for the dehydrogenation of steroids. While its use for dehydrogenation of unactivated nonsteroidal ketones is limited, studies have attempted to remedy this issue by activation via a silyl enol ether.[13] Despite some advancements, the limited scope of compatible substrates for the DDQ oxidation and the difficulty in removing the stoichiometric byproduct produced has limited its impact on organic synthesis.
Within the area of carbonyl α,β-dehydrogenation, this reagent has been used more modernly for compounds in which aromaticity is a driving force for oxidation,[14] such as chromanones (14 → 15, Scheme [2, a]).[15] α,β-Dehydrogenations of groups less acidic than aldehydes and ketones using DDQ are limited to isolated examples which result in compounds with high degrees of conjugation or aromaticity.[16]
A major advancement was made towards the end of the 20th century by the identification of an alternative stoichiometric oxidant – a hypervalent iodine reagent, 2-iodoxybenzoic acid (IBX) – that effects the conversion of ketones and aldehydes into the corresponding enones and enals (Scheme [2, b]).[17] This dehydrogenation is thought to proceed via a single-electron-transfer mechanism.[18] Taking advantage of this mechanistic insight, ligands such as 4-methylmorpholine-N-oxide (NMO) and 4-methoxypyridine-N-oxide (MPO) have been used to effect mono- or didehydrogenation in a controlled manner.[19] As is the case with other oxidants, IBX has the ability to oxidize alcohols in the presence of carbonyl compounds, as well as to concomitantly perform sequential oxidations (e.g., alcohol to enone). Although limited to ketones and aldehydes, IBX-mediated α,β-dehydrogenation remains one of the premier synthetic methodologies.
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Palladium Catalysis
In the late 20th century, the first examples of palladium-mediated dehydrogenation reactions were discovered. The Saegusa oxidation, now another one of the most widely employed methodologies, proceeds via an alternative mode of carbonyl activation – formation of an enoxysilane (18) – and subsequent dehydrogenation mediated by palladium (Scheme [3, a]).[20] The reaction is believed to proceed via a palladium enolate 19 that undergoes a β-hydride elimination to deliver the α,β-unsaturated product 11, although mechanistic investigations have been limited.[21] Despite the instability of the intermediate enoxysilanes and the cost associated with the high catalyst loadings of palladium required for efficient transformations, it is one of the most frequently employed methods for dehydrogenation adjacent to unactivated ketones.
A mechanistically distinct palladium-catalyzed conversion of ketones and aldehydes into enones and enals was recently reported by Stahl and coworkers (Scheme [3, b]).[22] In these reactions, unsaturated carbonyl compounds are directly accessed by treatment of carbonyl-containing substrates with a palladium(II) source and oxygen as an oxidant under acidic conditions. Choice of ligand allows for the selective formation of the α,β-unsaturated product instead of the higher-oxidation-state phenol product.[23] This process is thought to proceed via palladium-mediated C–H activation (20 → 21), rather than by dehydrosilylation, as in the Saegusa oxidation. Importantly, this methodology allows for the direct conversion to the unsaturated derivatives, avoiding the synthesis of unstable enoxysilane compounds.
Although useful one-step dehydrogenation methodologies have been developed, these techniques have been limited to the oxidation of ketones and aldehydes, while a one-step methodology for α,β-dehydrogenation of less-acidic functionalities, like esters, nitriles, and amides,[24] has remained elusive (Scheme [4, a]). We focused our studies on the synthetic problem of developing a method that would allow for the α,β-dehydrogenation of a wide variety of electron-withdrawing groups that have typically required multiple steps to efficiently dehydrogenate.
We envisioned a dehydrogenation that would initiate with an in situ deprotonation and transmetalation to form a palladium enolate (23, Scheme [4, b]). The reaction pathway would proceed with a β-hydride elimination, in a similar fashion to the Stahl and Saegusa methods, to form the unsaturated product 22. The catalytic cycle would be completed after the resulting allyl–Pd hydride species 24 reductively eliminated to form propene and palladium(0), which would be oxidized by an allyl electrophile to reform the active catalyst 26.[25]
The selection of an allyl electrophile as an oxidant under these reaction conditions meant that the catalytically formed Pd–allyl species could also form the typical allylation product 28 (Scheme [4, c]).[26] Historically, Pd–allyl species have been used primarily for allylation of nucleophiles in the Tsuji–Trost reaction and its variants. This reaction can be traced to 1965, a few years after the discovery of the Wacker process,[27] when Tsuji and coworkers reported the nucleophilic attack of [Pd(allyl)Cl]2 by carbanions to form allylated products, using stoichiometric amounts of palladium. Beginning in the 1970s, Trost and coworkers developed a catalytic and enantioselective variant, culminating in the identification of a ligand that reliably produces allylation products with high enantioselectivity.[28] This reaction proceeds by attack of a nucleophile, such as an enolate, at the carbon of an electrophilic Pd–η3-allyl species to produce a new carbon–allyl bond.[29] Palladium(0) is thus formed, which can undergo oxidative addition to form a new Pd–allyl species.
If the allylation pathway could be avoided, using allyl acetate as a mild oxidant would allow for compatibility with a wide range of functional groups, as allyl acetate is considerably less electrophilic than most typical oxidants. Early investigations of our dehydrogenation reaction were complicated by this well-precedented allylation byproduct 33, as well as condensation byproducts such as 34 that arose from direct attack of the enolate onto the allylic ester oxidant (Scheme [5]). The allylation byproduct may arise via direct attack of the enolate at the carbon of the Pd–allyl species.[30] Alternatively, an inner-sphere mechanism could be envisioned wherein initial attack at palladium of the Pd–allyl complex is followed by C–C bond-forming reductive elimination.[31] We sought to prevent byproduct formation by altering the identity of the enolate.
Transmetalation from a lithium enolate to a less reactive zinc enolate by addition of ZnCl2 eliminated the formation of the condensation byproduct 34. Additionally, this allowed for selectivity for dehydrogenation (32, Scheme [5]), without detection of the allylation byproduct 33. This reversal in selectivity from the usually observed allylation product is likely a function of the ligand environment on palladium and not solely a function of the identity of the enolate,[32] as Negishi has observed that zinc enolates also react at the carbon of a Pd–π-allyl complex with Ph3P as a ligand.[33] The efficiency of this transformation was also a function of the amide base – LiTMP was found to be optimal relative to other readily available amide bases. While allyl pivalate was the most successful oxidant for ester dehydrogenation, allyl acetate was superior in the case of nitriles.
With these optimized reaction conditions in hand, we set out to evaluate the scope of this dehydrogenation reaction. Substrates containing protected alcohols (36a), protected amines (36c,j, 36k), furans (36e), and indoles (36d) all produced high yields of dehydrogenation product (Scheme [6]). It is noteworthy that tertiary amines 36k underwent smooth dehydrogenation, despite their known propensity to undergo oxidation under palladium catalysis.[34] In addition, dehydrogenation adjacent to nitriles and esters both tolerated α-substitution (36a,c,g,h,j,k) as well as β,β-disubstitution (36b,l). Lactones as well as linear and cyclic esters were successfully dehydrogenated. Unlike with other one-step dehydrogenation methods, overoxidation was not observed for any substrate. Dehydrogenation was unsuccessful with some functionalities, including α-amino esters and nitriles, lactones without β-substitution, and α-aryl nitriles.
In order to gain insight into the mechanistic pathway by which this reaction proceeds, we performed kinetic isotope studies. Measurements examining substitution of the β-hydrogen atom with deuterium revealed a parallel KIE value of 2.3 ± 0.1 (Scheme [7, a]), which indicates that C–H bond cleavage or formation is involved in a turnover-limiting step.
To distinguish whether β-hydride elimination or reductive elimination is turnover limiting, the intramolecular KIE value was measured and found to be 1.0 ± 0.1 (Scheme [7, b]). These studies suggested that β-hydride elimination is a reversible process that is followed by a turnover-limiting reductive elimination.
In addition to providing a historical overview of dehydrogenation adjacent to carbonyl compounds, this Synpacts has highlighted the synthetic potential of Pd–allyl intermediates generated from allyl electrophiles. In the area of α,β-dehydrogenation, future work will focus on more challenging substrate classes and on determining by what means site selectivity may be obtained when multiple easily oxidized functionalities are present.
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Acknowledgment
We acknowledge Yale University, the NSF (GRF to A.T., DGE-1122492) and the Anderson Foundation (postdoctoral fellowship to Y.C.) for funding. Mr. Justin P. Romaire is acknowledged for experimental contributions.
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References and Notes
- 1a Chen X, Engle KM, Wang D.-H, Yu J.-Q. Angew. Chem. Int. Ed. 2009; 48: 5094
- 1b Lyons TW, Sanford MS. Chem. Rev. 2010; 110: 1147
- 2 Chen Y, Romaire JP, Newhouse TR. J. Am. Chem. Soc. 2015; 137: 5875
- 3 Astin S, Newman AC. C, Riley HL. J. Chem. Soc., Res. 1933; 391
- 5a Corey EJ, Schaefer JP. J. Am. Chem. Soc. 1960; 82: 917
- 5b Sharpless KB, Gordon KM. J. Am. Chem. Soc. 1976; 98: 300
- 6a Shenvi RA, Guerrero CA, Shi J, Li C.-C, Baran PS. J. Am. Chem. Soc. 2008; 130: 7241
- 6b Trost BM, Bringley DA, Zhang T, Cramer N. J. Am. Chem. Soc. 2013; 135: 16720
- 6c Tartakoff SS, Vanderwal CD. Org. Lett. 2014; 16: 1458
- 6d Kitajima M, Murakami Y, Takahashi N, Wu Y, Kogure N, Zhang R.-P., Takayama H.. Org. Lett. 2014; 16: 5000
- 7a Reich HJ, Reich IL, Renga JM. J. Am. Chem. Soc. 1973; 95: 5813
- 7b Sharpless KB, Lauer RF, Teranishi AY. J. Am. Chem. Soc. 1973; 95: 6137
- 7c Reich HJ, Wollowitz S. Org. React. 1993; 44: 1
- 7d Reich HJ, Wollowitz S. Org. React. 2004; 44: 1
- 8a Jones DN, Mundy D, Whitehouse RD. J. Chem. Soc. D 1970; 2: 86
- 8b Sharpless KB, Young MW, Lauer RF. Tetrahedron Lett. 1973; 14: 1979
- 9a Trost BM, Salzmann TN. J. Am. Chem. Soc. 1973; 95: 6840
- 9b Trost BM, Salzmann TN, Hiroi K. J. Am. Chem. Soc. 1976; 98: 4887
- 10 Mukaiyama T, Matsuo J.-i, Kitagawa H. Chem. Lett. 2000; 29: 1250
- 11 Matsuo J.-i, Aizawa Y. Tetrahedron Lett. 2005; 46: 407
- 12a Braude EA, Brook AG, Linstead RP. J. Chem. Soc., Res. 1954; 3569
- 12b Walker D, Hiebert JD. Chem. Rev. 1967; 67: 153
- 13a Ryu I, Murai S, Hatayama Y, Sonoda N. Tetrahedron Lett. 1978; 19: 3455
- 13b Bhattacharya A, DiMichele LM, Dolling UH, Grabowski EJ. J, Grenda VJ. J. Org. Chem. 1989; 54: 6118
- 14a Linstead RP, Thomas SL. S. J. Chem. Soc., Res. 1940; 1127
- 14b Fu PP, Harvey RG. Chem. Rev. 1978; 78: 317
- 15a Matsuura S, Iinuma M, Ishikawa K, Kagei K. Chem. Pharm. Bull. 1978; 26: 305
- 15b Shanker CG, Mallaiah BV, Srimannarayana G. Synthesis 1983; 310
- 16a Das Gupta AK, Chatterje RM, Paul M. J. Chem. Soc. C 1971; 3367
- 16b Tanaka T, Mashimo K, Wagatsuma M. Tetrahedron Lett. 1971; 12: 2803
- 16c Clarke PD, Fitton AO, Suschitzky H, Wallace TW. Tetrahedron Lett. 1986; 27: 91
- 16d Bhattacharya A, DiMichele LM, Dolling UH, Douglas AW, Grabowski EJ. J. J. Am. Chem. Soc. 1988; 110: 3318
- 17 Nicolaou KC, Zhong YL, Baran PS. J. Am. Chem. Soc. 2000; 122: 7596
- 18 Nicolaou KC, Montagnon T, Baran PS, Zhong YL. J. Am. Chem. Soc. 2002; 124: 2245
- 19 Nicolaou KC, Montagnon T, Baran PS. Angew. Chem. Int. Ed. 2002; 41: 993
- 20a Ito Y, Hirao T, Saegusa T. J. Org. Chem. 1978; 43: 1011
- 20b Larock RC, Hightower TR, Kraus GA, Hahn P, Zheng D. Tetrahedron Lett. 1995; 36: 2423
- 21a Porth S, Bats JW, Trauner D, Giester G, Mulzer J. Angew. Chem. Int. Ed. 1999; 38: 2015
- 21b Cámpora J, Maya CM, Palma P, Carmona E, Gutiérrez E, Ruiz C, Graiff C, Tiripicchio A. Chem. Eur. J. 2005; 11: 6889
- 21c Alexanian EJ, Hartwig JF. J. Am. Chem. Soc. 2008; 130: 15627
- 22a Diao T, Stahl SS. J. Am. Chem. Soc. 2011; 133: 14566
- 22b Diao T, Wadzinski TJ, Stahl SS. Chem. Sci. 2012; 3: 887
- 23a Izawa Y, Pun D, Stahl SS. Science 2011; 333: 209
- 23b Diao T, Pun D, Stahl SS. J. Am. Chem. Soc. 2013; 135: 8205
- 24a Bordwell FG. Acc. Chem. Res. 1988; 21: 456
- 24b Zhang XM, Bordwell FG, Van Der Puy M, Fried HE. J. Org. Chem. 1993; 58: 3060
- 24c Ren J, Cramer CJ, Squires RR. J. Am. Chem. Soc. 1999; 121: 2633
- 25 It is unclear at this time at what point in the catalytic cycle the product alkene dissociates from palladium.
- 27 Michel BW, Steffens LD, Sigman MS. Org. React. 2014; 84: 75
- 28a Trost BM, Strege PE. J. Am. Chem. Soc. 1977; 99: 1649
- 28b Trost BM, Organ MG. J. Am. Chem. Soc. 1994; 116: 10320
- 29a Tsuji J, Takahashi H, Morikawa M. Tetrahedron Lett. 1965; 6: 4387
- 29b Trost BM, Fullerton TJ. J. Am. Chem. Soc. 1973; 95: 292
- 30a Trost BM, Weber L. J. Am. Chem. Soc. 1975; 97: 1611
- 30b Frost CG, Howarth J, Williams JM. J. Tetrahedron: Asymmetry 1992; 3: 1089
- 30c Braun M, Meier T. Angew. Chem. Int. Ed. 2006; 45: 6952
- 31 Unstabilized nucleophiles, such as hydride donors, alkyl zinc halides, and others, undergo attack at palladium of the Pd–allyl unit. For examples, see ref. 26a.
- 32 Tsuji J, Takahashi K, Minami I, Shimizu I. Tetrahedron Lett. 1984; 25: 4783
- 33 John RA, Negishi E. J. Org. Chem. 1983; 48: 4098
For recent examples of halogenation/elimination in total synthesis, see:
Pd/C and a variety of other mild catalysts can also be used to effect dehydrogenation of such activated substrates, see:
-
References and Notes
- 1a Chen X, Engle KM, Wang D.-H, Yu J.-Q. Angew. Chem. Int. Ed. 2009; 48: 5094
- 1b Lyons TW, Sanford MS. Chem. Rev. 2010; 110: 1147
- 2 Chen Y, Romaire JP, Newhouse TR. J. Am. Chem. Soc. 2015; 137: 5875
- 3 Astin S, Newman AC. C, Riley HL. J. Chem. Soc., Res. 1933; 391
- 5a Corey EJ, Schaefer JP. J. Am. Chem. Soc. 1960; 82: 917
- 5b Sharpless KB, Gordon KM. J. Am. Chem. Soc. 1976; 98: 300
- 6a Shenvi RA, Guerrero CA, Shi J, Li C.-C, Baran PS. J. Am. Chem. Soc. 2008; 130: 7241
- 6b Trost BM, Bringley DA, Zhang T, Cramer N. J. Am. Chem. Soc. 2013; 135: 16720
- 6c Tartakoff SS, Vanderwal CD. Org. Lett. 2014; 16: 1458
- 6d Kitajima M, Murakami Y, Takahashi N, Wu Y, Kogure N, Zhang R.-P., Takayama H.. Org. Lett. 2014; 16: 5000
- 7a Reich HJ, Reich IL, Renga JM. J. Am. Chem. Soc. 1973; 95: 5813
- 7b Sharpless KB, Lauer RF, Teranishi AY. J. Am. Chem. Soc. 1973; 95: 6137
- 7c Reich HJ, Wollowitz S. Org. React. 1993; 44: 1
- 7d Reich HJ, Wollowitz S. Org. React. 2004; 44: 1
- 8a Jones DN, Mundy D, Whitehouse RD. J. Chem. Soc. D 1970; 2: 86
- 8b Sharpless KB, Young MW, Lauer RF. Tetrahedron Lett. 1973; 14: 1979
- 9a Trost BM, Salzmann TN. J. Am. Chem. Soc. 1973; 95: 6840
- 9b Trost BM, Salzmann TN, Hiroi K. J. Am. Chem. Soc. 1976; 98: 4887
- 10 Mukaiyama T, Matsuo J.-i, Kitagawa H. Chem. Lett. 2000; 29: 1250
- 11 Matsuo J.-i, Aizawa Y. Tetrahedron Lett. 2005; 46: 407
- 12a Braude EA, Brook AG, Linstead RP. J. Chem. Soc., Res. 1954; 3569
- 12b Walker D, Hiebert JD. Chem. Rev. 1967; 67: 153
- 13a Ryu I, Murai S, Hatayama Y, Sonoda N. Tetrahedron Lett. 1978; 19: 3455
- 13b Bhattacharya A, DiMichele LM, Dolling UH, Grabowski EJ. J, Grenda VJ. J. Org. Chem. 1989; 54: 6118
- 14a Linstead RP, Thomas SL. S. J. Chem. Soc., Res. 1940; 1127
- 14b Fu PP, Harvey RG. Chem. Rev. 1978; 78: 317
- 15a Matsuura S, Iinuma M, Ishikawa K, Kagei K. Chem. Pharm. Bull. 1978; 26: 305
- 15b Shanker CG, Mallaiah BV, Srimannarayana G. Synthesis 1983; 310
- 16a Das Gupta AK, Chatterje RM, Paul M. J. Chem. Soc. C 1971; 3367
- 16b Tanaka T, Mashimo K, Wagatsuma M. Tetrahedron Lett. 1971; 12: 2803
- 16c Clarke PD, Fitton AO, Suschitzky H, Wallace TW. Tetrahedron Lett. 1986; 27: 91
- 16d Bhattacharya A, DiMichele LM, Dolling UH, Douglas AW, Grabowski EJ. J. J. Am. Chem. Soc. 1988; 110: 3318
- 17 Nicolaou KC, Zhong YL, Baran PS. J. Am. Chem. Soc. 2000; 122: 7596
- 18 Nicolaou KC, Montagnon T, Baran PS, Zhong YL. J. Am. Chem. Soc. 2002; 124: 2245
- 19 Nicolaou KC, Montagnon T, Baran PS. Angew. Chem. Int. Ed. 2002; 41: 993
- 20a Ito Y, Hirao T, Saegusa T. J. Org. Chem. 1978; 43: 1011
- 20b Larock RC, Hightower TR, Kraus GA, Hahn P, Zheng D. Tetrahedron Lett. 1995; 36: 2423
- 21a Porth S, Bats JW, Trauner D, Giester G, Mulzer J. Angew. Chem. Int. Ed. 1999; 38: 2015
- 21b Cámpora J, Maya CM, Palma P, Carmona E, Gutiérrez E, Ruiz C, Graiff C, Tiripicchio A. Chem. Eur. J. 2005; 11: 6889
- 21c Alexanian EJ, Hartwig JF. J. Am. Chem. Soc. 2008; 130: 15627
- 22a Diao T, Stahl SS. J. Am. Chem. Soc. 2011; 133: 14566
- 22b Diao T, Wadzinski TJ, Stahl SS. Chem. Sci. 2012; 3: 887
- 23a Izawa Y, Pun D, Stahl SS. Science 2011; 333: 209
- 23b Diao T, Pun D, Stahl SS. J. Am. Chem. Soc. 2013; 135: 8205
- 24a Bordwell FG. Acc. Chem. Res. 1988; 21: 456
- 24b Zhang XM, Bordwell FG, Van Der Puy M, Fried HE. J. Org. Chem. 1993; 58: 3060
- 24c Ren J, Cramer CJ, Squires RR. J. Am. Chem. Soc. 1999; 121: 2633
- 25 It is unclear at this time at what point in the catalytic cycle the product alkene dissociates from palladium.
- 27 Michel BW, Steffens LD, Sigman MS. Org. React. 2014; 84: 75
- 28a Trost BM, Strege PE. J. Am. Chem. Soc. 1977; 99: 1649
- 28b Trost BM, Organ MG. J. Am. Chem. Soc. 1994; 116: 10320
- 29a Tsuji J, Takahashi H, Morikawa M. Tetrahedron Lett. 1965; 6: 4387
- 29b Trost BM, Fullerton TJ. J. Am. Chem. Soc. 1973; 95: 292
- 30a Trost BM, Weber L. J. Am. Chem. Soc. 1975; 97: 1611
- 30b Frost CG, Howarth J, Williams JM. J. Tetrahedron: Asymmetry 1992; 3: 1089
- 30c Braun M, Meier T. Angew. Chem. Int. Ed. 2006; 45: 6952
- 31 Unstabilized nucleophiles, such as hydride donors, alkyl zinc halides, and others, undergo attack at palladium of the Pd–allyl unit. For examples, see ref. 26a.
- 32 Tsuji J, Takahashi K, Minami I, Shimizu I. Tetrahedron Lett. 1984; 25: 4783
- 33 John RA, Negishi E. J. Org. Chem. 1983; 48: 4098
For recent examples of halogenation/elimination in total synthesis, see:
Pd/C and a variety of other mild catalysts can also be used to effect dehydrogenation of such activated substrates, see:
Yifeng Chen (left) was born and grew up in Anhui, China. He received his BA in Chemistry from Soochow University in 2007 and completed his PhD under the supervision of Prof. Yuanhong Liu at Shanghai Institute of Organic Chemistry (SIOC) in 2012, focusing on homogenous gold catalysis. In 2013, he moved to the US as a postdoctoral fellow in the Buchwald group at MIT, working on continuous-flow chemistry. In 2014, he joined the Newhouse group as a postdoctoral fellow.
Timothy R. Newhouse (middle) was born in New Hampshire and grew up in northern New England. He received his BA in chemistry from Colby College (2005) in Waterville, ME, where he was mentored by Prof. Dasan M. Thamattoor. After moving to La Jolla, CA, he completed his PhD at The Scripps Research Institute with Prof. Phil S. Baran (2010). During his time at Scripps, he also worked in the laboratories of Prof. Donna G. Blackmond. He then returned to the east coast for postdoctoral studies with Prof. E. J. Corey at Harvard University. As of 2013, he is an Assistant Professor at Yale University in the Department of Chemistry.