The Redox-Neutral Approach to C�H Functionalization
Bo Peng and Nuno Maulide*[a]
� 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2013, 19, 13274 – 1328713274
DOI: 10.1002/chem.201301522
Introduction
The C�H bond is a quasi-ubiquitous feature in organic com-pounds. Direct C�H functionalization strategies have re-cently received considerable attention due to the intrinsicatom economy and step efficiency associated with such ap-proaches.[1] Nevertheless, the C�H bond (and particularlythe sp3 C�H linkage) is traditionally considered to be chemi-cally inert, although notable progress has been attained inthis area. The major topical challenges of this “hot” researchfield can be condensed in two key questions: 1) how to en-hance the intrinsically “costly” thermodynamics of splittingthe inert sp3 C�H bond, and 2) how to improve the selectivi-ty of sp3 C�H activation. The strategic employment of di-recting groups to guide an oxidant (e.g., a high-valent transi-tion metal) for (de facto intramolecular) C�H activation hasbeen extensively studied (Scheme 1, type I).[2] The tetheringof the oxidant and the C�H bond allows both reactivity andselectivity to be considerably improved.
On the other hand, the introduction of an internal oxida-tive functional group to enable the selective activation ofC�H bonds has emerged (Scheme 1, type II) as an alterna-
tive to the use of an external oxidant. For example, an N-haloamine is used in the Hofmann–Lçffler–Freytag reactionas an internal oxidant for a remote intramolecular free-radi-cal C�H bond activation.[3] Benzophenone and hydroperox-ide derivatives can also be thought of as internal oxidativefunctional groups for C�H activation through single-elec-tron-transfer processes.[4]
In addition to these developments, a novel approach toC�H activation through internal hydride transfer was re-vived in 2005 by Sames (Scheme 2).[5a] Early examples[6] of
this type of transformation involved thermal activation,wherein an electron-deficient alkene formally accepts aACHTUNGTRENNUNGhydride by means of a 1,5-hydride-transfer process(Scheme 3). Subsequent cyclization of the thus generated
zwitterionic intermediate furnished the C�H functionaliza-tion product. This Minireview focuses on the developmentof this approach to C�H functionalization in recent years.[7]
Electron-Deficient Olefins as Hydride Acceptors
In 2005 Sames and co-workers proposed a 1,5-hydride-shift/cyclization strategy for the intramolecular cross coupling ofsterically hindered sp3 C�H bonds and isolated alkenes.[5a]
As shown in Scheme 4, alkene activation by an electrophilicmetal (M) may induce an internal hydride shift leading to azwitterionic intermediate. This intermediate ultimately col-lapses forming the product of ring-closure.
This approach was successfully extended to the synthesisof various spiro- and bicyclic compounds, and selected ex-amples are shown in Table 1. Tetrahydropyran substratescarrying an a,b-unsaturated aldehyde (1 a) or ketone (1 b
Abstract: The direct functionalization of C�H bonds isan attractive strategy in organic synthesis. Although sev-eral advances have been made in this area, the selectiveactivation of inert sp3 C�H bonds remains a dauntingchallenge. Recently, a new type of sp3 C�H activationmode through internal hydride transfer has demonstrat-ed the potential to activate remote sp3 C�H linkages inan atom-economic manner. This Minireview attempts toclassify recent advances in this area including the transi-tion to non-activated sp3 C�H bonds and asymmetrichydride transfers.
Keywords: atom economy · C�H activation · C�H func-tionalization · hydride transfer · redox chemistry
[a] Dr. B. Peng, Dr. N. MaulideMax-Planck-Institut f�r KohlenforschungKaiser-Wilhelm-Platz 145470 M�lheim an der Ruhr (Germany)Fax: (+49) 2083062974E-mail : [email protected]
Scheme 1. Conformationally enhanced sp3 C�H activation modes.
Scheme 2. Internal hydride-transfer-induced sp3 C�H activation.
Scheme 3. Early example of a 1,5-hydride-transfer/cyclization reactionunder thermal conditions.
Scheme 4. Sames� 1,5-hydride-shift/cyclization strategy.
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MINIREVIEW
and 1 c) as the hydride acceptor efficiently underwent thetransformation to give products 2 a–c in excellent yields.However, an a,b-unsaturated ester moiety (1 d) was not re-active under the same conditions.
The use of Sc ACHTUNGTRENNUNG(OTf)3 instead of BF3·Et2O proved benefi-cial on alkylidene malonate derivatives (1 e and 1 f). Nota-bly, geminal substitution along the olefin tether is not re-quired for a successful reaction (entry 3; Table 1). In addi-tion to tertiary C�H bonds, secondary positions could alsobe functionalized affording fused bicyclic products (entry 4,Table 1). Remarkably, the reaction of an acyclic ether alsoproceeded smoothly by exposure to substoichiometricamounts of BF3·Et2O at elevated temperature (entry 5,Table 1).
It was found that the a,b-unsaturated aldehyde 3 under-goes very slow cyclization, affording a low yield of product 4even after four days at room temperature (Scheme 5).[5b] Incontrast, the dioxolane 5 underwent redox-neutral isomeri-zation much more efficiently, affording a good yield of thecyclic product 6 after only one hour. This reactivity en-hancement can be explained by the transient generation ofan oxocarbenium intermediate (5 A), which further lowersthe LUMO of the acceptor system.
The hydride-shift/cyclization strategy was subsequentlyapplied to benzylidene malonates (7) (Schemes 6 and 7).[8–10]
An efficient access to polycyclic tetrahydroquinolines 8 wasenabled by gadolinium (III) triflate catalysis. It is worth
Nuno Maulide was born in Lisbon (Portu-gal). After graduating in chemistry fromthe Instituto Superior T�cnico in 2003, hecompleted an M.Sc. at the Ecole Polytech-nique in 2004 and received his Ph.D. fromthe Universit� catholique de Louvain(Istv�n E. Mark�) in 2007. He subsequent-ly moved to Stanford University (Barry M.Trost) for postdoctoral studies before re-turning to Europe to take an endowed po-sition as Max-Planck Research GroupLeader at the Max-Planck-Institut f�rKohlenforschung in early 2009, where healso currently holds a European ResearchCouncil (ERC) Starting Grant (2011). His research interests span diverseareas within organic chemistry, including original pericyclic rearrange-ments, catalytic asymmetric synthesis of small rings, new concepts in thechemistry of hypervalent sulfur and the development of redox-neutralprocesses. This work has been rewarded, among others, by the ADUCPrize for Habilitands of the German Chemical Society (2011–12), theBayer Early Excellence Award (2012) and the Heinz Maier-Leibnitz Prizeof the German Science Foundation (2013).
Bo Peng was born in Jingde Zhen(China). He graduated from Nanjing Uni-versity of Science and Technology with hisB.Sc. degree (2004), and then obtained hisPh.D. from Dalian University of Technol-ogy (2010) with Prof. M. Bao. Since 2011,he began Postdoctoral work in the groupof Prof. Nuno Maulide in Max-Planck-In-stitut f�r Kohlenforschung (Germany). Hisinterests focus on the understanding ofnew reactivity, design of new reactionmodels and creation of new concepts.
Table 1. Lewis acid catalyzed 1,5-hydride shift using electron-deficientolefins as hydride acceptors.
Substrate[a] CatalystACHTUNGTRENNUNG(amountACHTUNGTRENNUNG[mol %])
t[h]
Product Yield[%](d.r.)
1BF3·Et2O(30)
12 (1 a)10 (1 b)36 (1 c)
– (1 d)
91(3.7:1)94 (2:1)98 (3:1)no reac-tion
2Sc ACHTUNGTRENNUNG(OTf)3
(5)2 94
3Sc ACHTUNGTRENNUNG(OTf)3
(5)12 99
4 PtCl4 (30) 3877(<15:1)
5BF3·Et2O(75)
4590(<15:1)
[a] E=-COOEt, E’=-COOMe; for 1 a R=CHO, for 1b R= COMe, for1c R=COPh; for 1d R =CO2Me.
Scheme 5. 1,5-Hydride-shift acceleration through the generation of a re-active alkenyl oxocarbenium.
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N. Maulide and B. Peng
noting that both cyclic and linear amines could be used asthe hydride donors. The less reactive aryl ethers 9 alsoproved to be competent reducing agents, but successful ex-amples were limited to secondary alkyl ethers or moreactive benzylic and allylic ethers.
Interestingly, an “ortho-substituent effect” was observed;the introduction of substituents ortho to the alkoxy groupsignificantly enhanced the rate of benzylic C�H activation(“buttressing effect”). This led to the desired benzopyransin excellent yields and short reaction times (Scheme 8).[11]
The hydride acceptor could also be generated in situthrough condensation between an aldehyde and indole(Scheme 9). Seidel and co-workers designed an acid-cata-lyzed redox-neutral annulation by means of a condensation/1,5-hydride-shift/ring-closure domino sequence, forming pol-ycyclic azepinoindoles 14 in a single step with good to excel-lent yields.[12]
Although the reactions discussed thus far proceed by aformal 1,5-hydride shift—an intriguing 1,4-hydride shift ontobenzylidene malonates was developed by Vidal and co-workers (Scheme 10). In the event, an acetalic hydrogen(15) was used as hydride donor. Due to the hydrolysis of theacetal moiety in the strongly Lewis acidic medium, this reac-
tion does not provide high chemical yields of product. Thisproblem was solved by introduction of a 1,3-dithiolane 17,alleviating the issue of ketal hydrolysis.[13]
C=O and C=N Bonds as Hydride Acceptors
Sames and co-workers also demonstrated the possibility ofdirectly using aldehydes as hydride acceptors. In this reac-tion, the direct transformation of tertiary and sterically hin-dered secondary sp3 C�H bonds into C�O bonds was realiz-ed and afforded spiroketals (20 a–c and 20 f), bicyclic ketalsand aminals (20 d and 20 e). Selected examples are depictedin Table 2.[14]
Scheme 6. Tetrahydroquinoline synthesis through a 1,5-hydride-shift/cycli-zation reaction.
Scheme 7. Dihydrobenzopyran synthesis through a 1,5-hydride-shift/cycli-zation reaction.
Scheme 8. “Buttressing effect” in 1,5-hydride-shift processes.
Scheme 9. Cascade reaction involving a 1,5-hydride-transfer step.
Scheme 10. 1,4-Hydride shift with an acetal C�H bond as the hydridedonor.
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MINIREVIEWC�H Functionalization
In contrast to the analogous transformation relying onelectron-deficient olefins as hydride acceptors (Table 1), ex-cellent diastereoselectivity was observed in this reaction(Table 2). The authors rationalized this by invoking a rever-sible character for this transformation, as elegantly demon-strated through the ring opening of cyclic ether (21) into itsacyclic aldehyde isomer (22) in presence of BF3·Et2O(Scheme 11) and supported by DFT studies.[14] Importantly,
these observations further established the latent reversibilityof internal redox reactions. A similar phenomenon had beenobserved decades earlier by Woodward et al., who proposeda reversible internal redox mechanism for the acid-catalyzedepimerization of the “normal” and “iso” sapogenins at C-25(Scheme 12).[15]
When imines are employed in the role of hydride accept-ors, two reaction modes become accessible, namely the exo-
1,5-hydride-shift/cyclization (Scheme 13 a, b) and endo-1,6-hydride-shift/cyclization processes (Scheme 13 c).[16–18] Thefirst of these reaction classes affords six-membered aminals
as products (24 and 26). In an early example, this reactionwas performed under harsh conditions (high temperaturesand prolonged reaction times, Scheme 13 a).[16] Recently,Seidel and co-workers introduced the use of catalyticamounts of acid to promote both imine formation and hy-dride-shift/cyclization reactions in a one-pot fashion (Sche-me 13 b).[17] The other (abnormal) subset of these reactionsinvolves an unusual endo-1,6-hydride shift to provide five-membered aminal products (Scheme 13 c).[18]
Alkynes and Allenes as Hydride Acceptors
In 2009, the Sames group expanded the scope of hydride ac-ceptors to terminal unactivated alkynes (Scheme 14),[19] a
Table 2. Aldehyde as hydride acceptor[a]
Substrate CatalystACHTUNGTRENNUNG(amount ACHTUNGTRENNUNG[mol %])t[h]
Product Yield[%] (d.r.)
1 BF3·Et2O (30) 3 91
2 BF3·Et2O (30) <8 93 (>15:1)
3 BF3·Et2O (5) 3 96
4 TiF4 (20) 24 90 (>50:1)
5 TiF4 (1.3 equiv) 48 68 (>50:1)[b]
6 TiF4 (1.0 equiv) 3 30 (<50:1)
[a] All reactions were performed on a 0.5 or 0.25 mmol scale in DCM(0.025 m substrate) at room temperature. [b] The reaction was carried outunder 50 8C.
Scheme 11. Mechanistic study on the reversibility of 1,5-hydride-shiftprocess.
Scheme 12. Woodward�s classical interconversion of “normal” and “iso”sapogenins.
Scheme 13. Imines as hydride acceptors in exo- and endo-cyclizationmodes.
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N. Maulide and B. Peng
pioneering advance in the field. This reaction allowed thegeneration of complex heterobicyclic compounds from read-ily available cycloalkylethers and -amines (29).
Two plausible mechanisms can be envisaged, as shown inScheme 13. In pathway A, PtI4 coordinates to the alkyneand induces the hydride transfer leading to the formation ofthe zwitterionic alkenyl metal intermediate 29 B. Then, nu-cleophilic attack of the alkenyl platinum to the oxocarbeni-um ion furnishes a platinum carbene intermediate 29 C,bearing a new C�C bond. Finally, this intermediate under-goes a 1,2-hydrogen shift accounting for the observed prod-uct (30) and thus liberating the catalyst. The alternativemechanistic rationale is expressed through pathway B, inwhich a platinum vinylidene 29 D is formed first. A 1,6-hy-dride transfer to the formally sp-hybridized center thenleads to the intermediate 29 B, from which a sequence ofevents similar to path A takes place.
Gagosz and co-workers simultaneously developed a goldvariant of the reaction (Schemes 15 and 16) leading to 5-exoalkenylation products (32).[20] Remarkably, using alkynylether 33 as substrate led to 6-endo alkenylation product 34,
a result rationalized by invok-ing a 1,2-alkyl shift instead of a1,2-hydride shift as the finalstep (Scheme 16).
The gold-mediated activa-tion of allenes being generallyas effective as that of al-kynes,[21] the Gagosz group fur-ther explored the use of acti-vated allenes as hydride ac-ceptors.[22] A variety of fused-or spirocyclic tetrahydrofuransand -pyrans were accessed em-ploying not only gold, but alsoBrønsted acid catalysis (a se-lected example shown inScheme 17).[23] The acid orgold activation of the allenemoiety promoted a 1,5-hydrideshift to produce a common in-termediate oxocarbenium 35 A.
In presence of HNTf2, this intermediate might be capturedby the pendant alkene to afford carbocation 35 B. A subse-
Scheme 14. Platinum-activated teminal alkynes as hydride acceptors.
Scheme 15. Bicyclic ether synthesis by means of a gold-catalyzed hy-dride-shift/cyclization reaction.
Scheme 16. Spiroether synthesis through a formal 6-endo, gold-catalyzedhydride-shift/cyclization reaction.
Scheme 17. Gold or Brønsted acid activated allenes as hydride acceptors.
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MINIREVIEWC�H Functionalization
quent proton results in the formation of the fused tetrahy-dropyran 36.
In the gold-catalyzed variant, reaction of the pendantvinyl gold moiety produces intermediate 35 C, which subse-quently undergoes allylic isomerization to product 37.
Urabe and co-workers found that sulfonylacetylenes canbe used as hydride acceptors through activation with rhodi-ACHTUNGTRENNUNGum(II).[24] In the event, two types of hydride shift were ob-served (Scheme 18). The first process (Scheme 18 a) is analo-gous to those described previously took place affording di-hydropyran products 39. Interestingly, when modified reac-tion conditions with H2O as co-solvent were applied to al-kynyl ethers 40, the reaction proceeded through a putativeintramolecular hydride-shift/intermolecular nucleophilic ad-dition of water sequence, generating ketoolefins as products(41; Scheme 18 b). The intermolecular capture of formal“hydride-shift” products is a rather unusual observation.
Most recently Gong and co-workers found that terminalalkynes activated by stoichiometric amounts of a strongBrønsted acid transiently generate vinyl cations such as(42 A),[25] which play a pivotal role in a new cyclization proc-ess (Scheme 19). In this reaction, pyridine-N-oxide functionsas an external oxidant allowing an overall oxidative transfor-mation to the cycloalkylketone product. Two mechanisms(depicted as paths a and b, Scheme 19) were proposed. Oneof the crucial differences between these two pathways relieson the nature of the hydride-transfer step. In path a, theelectron poor enolate 42 C serves as hydride acceptor. As analternative, hydride transfer could also occur on the alleneiminium intermediate 42 B, in which case it becomes mecha-nistically akin to a [1,5]-sigmatropic shift of hydrogen.It is worth noting that the [1,5]-sigmatropic hydrogenshift has been previously in-voked to explain other formal[1,5]-hydride shift processestaking place in aromatic sub-strates.[26] However, the dis-tinction between “1,5-hydrideshift” and “1,5-sigmatropichydrogen shift” remainssomewhat blurred in most sys-tems.
Hydride Transfer andCyclization of
Unactivated C�H Bonds
The prototypical hydridedonor in all hydride-shift/cy-ACHTUNGTRENNUNGclization transformations pre-sented thus far is a a-hetero-ACHTUNGTRENNUNGatom C�H bond. This is read-ily justified by the enhancedstabilization (imparted by thathetero ACHTUNGTRENNUNGatom) of the carbo ACHTUNGTRENNUNGcat-ACHTUNGTRENNUNGion generated upon hydride
shift. In search for ways to overcome this apparent limita-tion, Sames (Scheme 20 a, b) and Fillion (Scheme 20 c) foundthat benzylic methylene groups can also function as hydridedonors (Scheme 19).[5,27] However, an electron-rich aromaticring (44, 46 and 48) was required to accelerate the hydride-transfer process.
Scheme 18. Rh-activated internal triple bond as the hydride acceptor.
Scheme 19. Alkynes activated by Brønsted acids as the hydride acceptors.
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N. Maulide and B. Peng
In 2011 Akiyama and co-workers remarkably expandedthe scope of hydride donors to aliphatic, nonbenzylic C�Hbonds (Schemes 21 and 22).[28] It is worth noting that the pe-
culiar nature of the benzylidene barbiturate C=C bond usedas acceptor might be a key issue for the hydride transferfrom a relative inert C�H bond. Nonetheless, hydrogenatoms located either on a benzylic or an aliphatic tertiarycarbon could smoothly be delivered, with the subsequentcyclization ultimately leading to excellent yields of tetralineproducts 51. However, secondary C�H bonds proved to beunreactive (cf. 51 e), even under more forcing conditions.This result suggests that the generation of a somewhat
stable carbocation intermediate could be an importantfactor in facilitating hydride shift processes in general.
When the authors switched to the substrates 52, bearing agem-dimethyl group at the g-position, the indane derivatives53 were surprisingly obtained. This result, indicative of a1,6-shift process, can be rationalized by a Friedel–Crafts cyc-lization (Scheme 22), which kinetically supersedes the alter-native formation of a seven-membered ring.
Enantioselective 1,5-Hydride-Shift Processes
Seidel and co-workers developed the first asymmetric ver-sion of a redox cyclization reaction (Scheme 23).[29] Employ-ing a box-type ligand/magnesium salt as catalytic system,benzylidene–oxazolidinones 54 were successfully convertedto tetrahydroquinolines 55 in good yields and promisingenantioselectivity. Nevertheless, the improvement of diaster-
Scheme 20. Hydride transfer from a non-activated benzylic position.
Scheme 21. 1,5-Hydride shift/cyclization of non-activated tertiary C�Hbonds. [a] 5mol % catalyst. [b] 30mol % catalyst.
Scheme 22. 1,5-Hydride shift/Friedel–Crafts cyclization of a non-reactivetertiary C�H bond.
Scheme 23. Lewis acid catalyzed enantioselective 1,5-hydride-shift/cycli-zation reaction.
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MINIREVIEWC�H Functionalization
eoselectivity for this exciting transformation remains an ex-citing challenge.
Feng and co-workers also developed a chiral N,N’-diox-ide-CoII complex catalyst for the catalytic enantioselective1,5-hydride-shift/cyclization reaction of o-dialkylamino-sub-stituted alkylidene malonates 56 (Scheme 24).[30] This cata-lytic system allows the use of remarkably mild conditions.
It is by now apparent to the reader that “hydride-shift”-initiated redox cyclizations can generally be triggered by avariety of LUMO-lowering strategies. In that context, it isperhaps surprising that it would take until 2010 for organo-catalysis to enter the fray, with the work of Kim et al.(Scheme 25).[31] In this iminium-promoted redox-neutral iso-merization, the chiral secondary amine (60) previously de-veloped by MacMillan[32] was found to be the most efficientcatalyst. Remarkably, the hydride-transfer/cyclization pro-ACHTUNGTRENNUNGcess takes place at room temperature. Chiral tetrahydroqui-noline derivatives (59) were obtained in moderate yieldsand diastereoselectivities, but very high levels of enantiose-
lectivity. Particularly interesting is the requirement for longreaction times (4–10 days), a characteristic feature of severalearly aminocatalytic processes.[33]
More recently, Tu and co-workers successfully achievedthe enantioselective 1,5-hydride-shift/cyclization reaction ofracemic cyclic ethers 61 (Scheme 26).[34] Impressive levels of
diastereoselectivity were attained in this transformation. Inparticular, a variety of optically active spiroethers were ac-cessed in a practical manner, with good yields and highenantioselectivities under mild conditions in a relativelyshort reaction time.
The Akiyama group demonstrated the power of chiralBrønsted acid catalysis for redox-neutral C�H functionaliza-tion (Scheme 27).[35a] In the event, phosphoric acid activa-tion of an alkylidene malonate moiety allowed various N,N-dibenzyl (63 a–c) and even N-alkylaniline substrates (63 dand 63 e) to smoothly undergo rearrangement to the corre-sponding tetrahydroquinolines (64), in good to excellentenantioselectivities. Interestingly, a further manifestation ofthe “buttressing effect” on the reaction rate was observed(compare 64 a to 64 b/c), consistent with Akiyama�s ownprior observations (Scheme 8).
For further understanding of this transformation, the au-thors independently submitted chiral, enantiomeric amines(S)-67 d and (R)-67 d to the reaction conditions (Scheme 28).It was found that these antipodes exhibited totally differentreactivities towards catalyst (S)-65 a, characteristic of a“match/mismatch” pair, with substrate (S)-67 d appearing tocorrespond to the “matched” situation.
Furthermore, in the reaction of (S)-67 d with an achiralLewis acid (Yb ACHTUNGTRENNUNG(OTf)3) as catalyst, the chiral information ofthe substrate was preserved through the hydride shift/cycli-zation events. Such effects had been previously observedupon thermal activation of enantiomerically pure substratesby Reinhoudt.[6b]
These two results indicate that, at least in this process, theobservation of high enantioselectivity mainly stems from the
Scheme 24. Cobalt-catalyzed enantioselective 1,5-hydride-shift/cyclizationprocess.
Scheme 25. Organocatalytic enantioselective 1,5-hydride-shift/cyclizationreaction.
Scheme 26. Chiral-amine-catalyzed enantioselective 1,5-hydride-shift/cy-ACHTUNGTRENNUNGclization reactions of cyclic ethers. [a] Reactions were performed at 0 8C.
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hydride-transfer process through a selective activation ofenantiotopic hydrogen (Scheme 29). The thus generatedheli ACHTUNGTRENNUNGcally chiral zwitterionic intermediate (63 A) might under-go the final ring closure to achieve the desired product. Thisis somewhat surprising, especially taking into account thatall enantioselective approaches reported thus far were basedon enantioselective LUMO-lowering at the acceptor frag-
ment and may thus have been predicated (by their authors)on the assumption that enantioselective C�C bond forma-tion after the hydride-shift event would be decisive for theattainment of high stereoselectivities. The realization thatthe Akiyama process is indeed an enantioselective C�H ac-tivation is one that should bear important consequences forthe further development of this field.
Also employing chiral Brønsted acid catalysis, Gong andco-workers developed a redox-neutral C�H functionaliza-tion reaction.[35b] In contrast to the aforementioned Akiyamareport,[35a] the hydride-transfer substrate was preformed bytreatment of o-aminobenzoketones with anilines and thesubsequent hydride-transfer/ring-closing reaction providedcyclic aminals in good diastereo- and enantioselectivities.
Most recently, Luo and co-workers introduced a binaryacid catalyst consist of MgX2 and a chiral phosphoric acidfor enantioselective redox cyclization (Scheme 30).[36] In thiscase, chiral phosphoric acid 71 is used as a ligand which en-hances the electrophilicity of the magnesium center. A relat-ed theoretical study[37] suggested that the stereoselectivityobserved stems from the hydride transfer step, consistentlywith the proposals of Akiyama and Reinhoudt.[35a,6b]
A gold(I)-catalyzed enantioselective domino reaction wasdeveloped by Zhang and co-workers (Scheme 31).[38] In thisinstance, a gold-catalyzed furan formation takes place alongthe hydride-shift/cyclization process.
�endo’-Type 1,5-Hydride Shift
In contrast to the 1,5-hydride shifts described above, an al-ternative endo-1,5-hydride shift might result in a 1,4-dipolarzwitterionic intermediate (e.g., 74 B, Scheme 32).[39] Such an
Scheme 27. Chiral Brønsted acid catalyzed enantioselective 1,5-hydride-shift/cyclization reaction. [a] (S)-65a used as catalyst. [b] (R)-66 b used ascatalyst. [c] (S)-65 b used as catalyst.
Scheme 28. Mechanistic study of the Chiral Brønsted acid catalyzedredox-neutral isomerization: chirality transfer.
Scheme 29. Plausible reaction pathway for the chiral Brønsted acid cata-lyzed redox-neutral isomerization through enantioselective C�H activa-tion.
Scheme 30. Asymmetric binary-acid-catalyzed 1,5-hydride-shift/cycliza-tion reaction.
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MINIREVIEWC�H Functionalization
intermediate cannot easily access a ring-closure reactionmanifold, as a four-membered cyclization product wouldresult. As a result, this type of species offers intriguing op-portunities for further reactivity.
Che and co-workers developed a transformation of chiralpropargylamines 74 to axially chiral allenes 75 throughsilver catalysis (Scheme 32).[39] In this reaction, coordinationof the silver catalyst to the alkyne triggers an endo-1,5-hy-dride-transfer process resulting in a 1,4-dipolar zwitterionicspecies (74 B). Subsequent elimination of silver provides di-substituted allenes (75) in high yields and excellent enantio-selectivities.
Ma reported a ZnI2-mediated access to 1,3-disubstitutedallenes from 1-alkynes, aldehydes, and morpholine (a select-ed example shown in Scheme 33).[40] An alkynyl zinc species,transiently generated by reaction of ZnI2 and the terminalalkyne partner, reacts with the iminium ion formed in situfrom an aldehyde and morpholine, to produce the propar-gylamine. An endo-hydride shift akin to that displayed inScheme 28 furnishes 1,3-disubstituted allene (77).
The group of Nakamura established a zinc(II)-catalyzedcross-dehydrogenative coupling reaction between propargyl-amines 78 and terminal alkynes 79 (Scheme 34).[41] In thisreaction, propargylamines (78) presumably undergo a endo-1,5-hydride shift leading to a 1,4-dipolar species 78 B(Scheme 35). The iminium ion portion of this dipolar speciescan be captured by the 1-alkynyl zinc species 79 A generatedthrough reaction of ZnBr2 and terminal alkynes, while the
vinyl zinc portion can be quenched by a proton to deliverN-tethered 1,6-enyne products (80). Importantly, the authorsdemonstrated the possibility of nucleophilic trapping of the1,4-dipolar species generated by 1,5-hydride transfer, an ob-
Scheme 31. Gold-catalyzed enantioselective redox-neutral domino reac-tion.
Scheme 32. Formation of chiral allenes by means of 1,5-hydride transfer.
Scheme 33. One pot synthesis of di-sustituted allenes through 1,5-hydridetransfer.
Scheme 34. Nucleophilic trap of 1,4-dipolar species formed through 1,5-hydride transfer. [a] Determined by 1H NMR spectroscopy of the E/Zmixture. [b] N,N-Diisobutyl propargyl amine (0.45 mmol), alkyne (0.3mmol) were used.
Scheme 35. Proposed mechanism for the transformation depicted inScheme 30.
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N. Maulide and B. Peng
servation that might open further avenues for hydride trans-fer reactions.
In their work on the synthesis of allenes by hydride trans-fer, Gagosz and co-workers (Scheme 36) showed that benzylpropargyl ethers 81 can undergo a endo-1,5-hydride shift toafford dipolar intermediates 81 B.[42] Elimination providesthe substituted allene products 82, accompanied by oneequivalent of benzaldehyde.
Complementing the progress reported by Nakamura onintermolecular reactions of 1,4-dipolar intermediates gener-ated via endo-1,5-hydride shift (Schemes 34 and 35), Harma-ta and co-workers discovered a related transformation on al-kenyl sulfoximines 83 (Scheme 37).[43] It was found that thesulfoximine 83 a can be readily converted to four-memberedcyclic derivative 84 a under thermal conditions. Unfortunate-ly, this transformation cannot be readily extended to other
substrates. When an alcohol co-solvent was employed, a re-duced N�H sulfoximine 85 was obtained through protona-tion and hydrolytic cleavage of the zwitterionic intermediate83 A.
Applications of 1,5-Hydride-Shift/CyclizationReactions
Hurd and co-workers successfully applied the hydride-shift/cyclization protocol to the synthesis of (�)-PNU-286607,a member of a novel class of antibacterial agents(Scheme 38).[44] Enantiomerically pure (�)-PNU-286607 was
synthesized in a practical two-step sequence. Interestingly,the chiral trans-dimethylmorpholine of starting material (89)was efficiently transformed into the cis-dimethylmorpholineembedded in the product (90). This result might be ex-plained by the reversible formation of enamine 89 B, whichenabled epimerization into the cis-dimethylmorpholinemoiety of the product (90).
Maulide and co-workers developed a one-pot C�H func-tionalization method (Scheme 39).[45] In this process, C�Hbonds a to nitrogen can be formally oxidized through a hy-dride-shift reaction, enabling a subsequent nucleophilic ad-dition to provide a C�H functionalization product. Usingthis protocol, a concise and direct total synthesis of (�)-in-dolizidine 167B was achieved in five steps with 25 % overallyield (Scheme 40).
Scheme 36. Synthesis of polysubstituted allenes by means of a gold-cata-lyzed 1,5-hydride shift.
Scheme 37. Reactivity of 1,4-dipolar species generated through endo-1,5-hydride shift.
Scheme 38. Synthesis of (�)-PNU-286 607.
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MINIREVIEWC�H Functionalization
Summary and Outlook
Through this article, recent developments on a unique sp3
C�H activation mode induced by internal hydride transferare reviewed. This strategy allows a range of syntheticallyuseful compounds to be prepared in an atom-economicalmanner. The usual acceptors for hydride transfer encoun-tered in the work reviewed herein are electron-poor alkenes,aldehydes, ketones, but also transition-metal-activated al-kynes and allenes. C�H bonds adjacent to oxygen or nitro-gen, the more “classical” hydride donors, are now joined bythe relatively inert C�H bonds of unactivated secondary ortertiary alkanes as successful partners for the hydride-shift/cyclization of some special substrates. More importantly, al-though the classical 1,5-spatial relationship between hydrideacceptor and hydride donor remains a key point for sub-strate design, 1,4- and 1,6-hydride shifts have also been real-ized in several cases. It would appear that more than a spa-tial relationship, it is a conformational requirement that iscrucial for the hydride transfer event to take place. Doubt-less, the exploration of more fundamental diverse substratestructures and in-depth mechanistic studies shall clarify thecore factors at play in the hydride transfer phenomenon.
In contrast to the now well-established hydride-shift/cycli-zation sequences, the endo-mode of hydride transfer giving1,4-dipolar species, which avoids the cyclization step, enablesopportunities for the overall reduction of alkynes and al-kenes through the oxidation of C�H bonds of amines. Webelieve that this reactivity mode will open up avenues forfurther future developments due to the intriguing reactivityof the in situ generated dipolar intermediates.
Although great progress has been made in this field, sub-strates still need to be carefully designed and no general
platform has been provided to direct the development ofnew substrates so far. We anticipate that more convenientelectrophilic fragments will be developed as hydride-accept-or templates that can be readily connected to complextarget compounds. A further exciting path for redox-neutral,hydride-transfer reactions is the development of catalyticasymmetric transformations. Though several successful ex-amples have been reported in recent years, there is certainlyroom for more general and efficient catalytic asymmetrichydride transfer reactions.
Hydride transfer as an intriguing approach to sp3 C�H ac-tivation manifolds has now been recognized by the syntheticcommunity. If compared to traditional C�H activation ap-proaches that mandate the use of external oxidants, thesereactions benefit from significant atom-economy. Addition-ally, the nature of the redox process can provide polyfunc-tionalized products in a single step. We believe that this C�H activation mode has all the inklings of ultimately becom-ing a powerful protocol for target-oriented synthetic chemis-try.
Acknowledgements
We are highly indebted to the Max-Planck Society and the Max-Planck-Institut f�r Kohlenforschung for generous support of our research pro-grams.
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Scheme 40. Application of internal redox-triggered C�H functionaliza-tion strategy to the total synthesis of indolizidine 167B.
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Published online: September 11, 2013
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MINIREVIEWC�H Functionalization
