Received 6th June 2013,Accepted 10th September 2013
DOI: 10.1039/c3ob41172a
www.rsc.org/obc
Recent developments in Cope-type hydroaminationreactions of hydroxylamine and hydrazine derivatives
André M. Beauchemin
Cope-type hydroaminations are versatile for the direct amination of alkenes, alkynes and allenes using
hydroxylamines and hydrazine derivatives. These reactions occur via a concerted, 5-membered cyclic tran-
sition state that is the microscopic reverse of the Cope elimination. This article focuses on recent develop-
ments, including intermolecular variants, directed reactions, and asymmetric variants using aldehydes as
tethering catalysts, and their applications in target-oriented synthesis.
Introduction
The large structural diversity and interesting properties associ-ated with nitrogen-containing molecules are intimately tied totheir importance, which ranges from their roles in livingsystems to applications in pharmaceuticals, agrochemicals,organic materials and catalysis (e.g. ligands, organocatalysts).Consequently, synthetic chemists continue to devise new and
more efficient approaches to nitrogen-based functional groupsand complex structures from simple starting materials. Someclasses of reactions are inherently difficult and remain under-developed. In this category, reactions allowing the direct con-version of cheap and readily available alkenes into variousnitrogen-containing motifs – for example by performing hydro-amination, diamination, aziridination or oxidative aminationreactions – are the focus of intense research efforts. Effectivestrategies to overcome the high activation energy associatedwith reactions involving electron-rich π-bonds and nitrogen-based reagents are critically needed.
Catalysis is by far the most common strategy used todevelop π-bond amination reactions.1 The important syntheticadvances and the development of asymmetric variants for thesynthesis of enantioenriched amines and derivatives havebeen discussed in many review articles. However there can beinherent limitations associated with catalysis: limited reactionscope, catalyst inhibition, harsh reaction conditions fordifficult transformations, catalyst selectivity when multiplereaction pathways are possible, limited functional group com-patibility, catalyst sensitivity, and purification issues associ-ated with toxic metal byproducts. Despite progress in thesynthetic reach of catalytic aminations, the importance ofnitrogen-containing molecules has led to the emergence ofcomplementary approaches to achieve the formation of C–Nbonds under metal-free conditions.
More specifically, research efforts directed at hydroamina-tion reactivity converting alkenes, alkynes and allenes directlyinto more complex nitrogen-containing molecules have beenintense, with over 1300 publications, including over 100 eachyear since 2009!2 The majority of recent work focuses onmetal-catalysed hydroaminations and this subject has beenreviewed extensively.3 However, further developments arerequired to increase the applicability of hydroaminationapproaches in heterocyclic synthesis, and improve intermole-cular reactions. This is especially needed for intermolecular
André M. Beauchemin
Born in Québec city, André Beau-chemin obtained his B.Sc. atUniversité Laval (1996), and hisPh.D. under the guidance ofAndré B. Charette (Université deMontréal, 2001). As a NSERCpost-doctoral fellow at HarvardUniversity (David A. Evans), heworked toward the total syn-thesis of azaspiracid-1. Since2004, André is at the Universityof Ottawa and his researchprogram focuses on metal-freeπ-bond amination reactivity
(hydroamination and aminocarbonylation) and catalysis usingcarbonyl compounds. His group has developed approachesto various types of nitrogen-containing molecules, includinghydroxylamines, hydrazines, oximes, several saturated nitrogenheterocycles, pyridines, pyrazines, β-aminocarbonyl motifs andenantioenriched diamines.
Centre for Catalysis Research and Innovation, Department of Chemistry, University of
Ottawa, 10 Marie-Curie, Ottawa, ON K1N 6N5, Canada.
reactions of alkenes and broadly applicable asymmetric vari-ants. In this emerging area article, we will describe our worktoward these objectives using a metal-free approach. Ourresults with hydroxylamines and hydrazines highlight thepotential of using bifunctional reagents to perform aminationreactions. Over the past seven years, we have observed thatsuch reagents are reliable to achieve intra and intermolecularreactivity with a variety of alkenes, alkynes and allenes. Wehave also used these derivatives to achieve excellent stereo-control in intermolecular reactions of allylic amines.
Cope-type hydroamination: hydroxylaminesand hydrazines as bifunctional reagents
The Cope elimination, the thermolysis (ca. 100–150 °C) ofamine-oxides leading to alkenes and hydroxylamines,4 is areversible transformation.5 Consequently, one of the mostreliable experimental procedures to achieve high yieldsinvolves thermolysis under vacuum (and condensation of theproducts on a cold surface), which de facto prevents any rever-sibility or decomposition that could occur upon heating of thealkene and hydroxylamine products. Since it is known that theCope elimination occurs through a concerted, 5-memberedtransition state, the microscopic reverse inherently offerspotential as a concerted, thermal hydroamination approach(eqn (1)).5
ð1Þ
Hydroamination using hydroxylamines
First reported by Laughlin (1973, intermolecular, unactivatedalkenes) and House (1976, intramolecular),6 several contri-butions have established that this concerted, thermal “hydro-amination” reactivity is broadly applicable in intramolecularsystems.7 Over the years, reports showed that alkenyl-, alkynyl-,and allenyl-hydroxylamines can cyclize readily, with reactivityat or below room temperature occurring when the tether8 lengthis optimal. Given that this “reverse-Cope cyclization” reactivityhas been the focus of an excellent review by Knight,5 only thereactivity trends are illustrated in Fig. 1.
We initiated efforts toward related intermolecular variantsin 2006, as a strategy to overcome ionic side-reactions that we
encountered in work toward strain-release intermolecularhydroaminations of cyclic alkenes.9 At the time, reports ofintermolecular Cope-type hydroaminations with electron-richπ-bonds were rare and had narrow synthetic applicability.6a,7f
After considerable efforts toward analogous intermolecularhydroamination reactivity of hydrazine derivatives, we turnedour attention to the use of aqueous hydroxylamine and rapidlyunveiled encouraging reactivity using phenylacetylene. Weoptimized this into a reliable reaction allowing the conversionof a variety of alkynes into oximes, and noted high selectivityfor the formation of Markovnikov products (eqn (2) andFig. 2). Representative examples are provided in Fig. 2, whichshows the structure of the major products; yields of the minoranti-Markovnikov products are also indicated in parentheses.10
ð2Þ
Our preferred conditions involve heating solutions ofaqueous NH2OH in alcoholic solvents such as i-PrOH at temp-eratures ranging from 90 to 160 °C, using microwave heatingfor convenience and to allow for shorter reaction times (ca.5–10 times faster than conventional heating). The products inFig. 2 illustrate the functional group compatibility associatedwith this transformation, which has routinely been carried outon gram-scale as part of a collaboration centred on oxime-based bidentate ligands.10c,11
A discussion on the name of this transformation is war-ranted at this point. A summary of the debate raging in the1990s can be found in Knight’s review5 and two names havebeen favoured in the literature: reverse-Cope elimination orreverse-Cope cyclization. The discovery of intermolecular reac-tivity and, in our opinion, the need to align the nomenclaturewith the larger body of work published in the hydroaminationarea (a field that emerged after the previous debate) ledus to suggest the name Cope-type hydroamination.10a Other
advantages of this nomenclature are that it implies the con-certed nature of the transition state, that it can simply bedescribed as either intra- or intermolecular, and that it is moreillustrative!
Intermolecular Cope-type hydroamination: remarkablesolvent effects and increased reactivity via hydrogenbonding
In parallel to optimization work for the reaction of alkynesshown in eqn (2), we embarked on efforts to achieve intermo-lecular reactions using alkenes. Much to our surprise, initialinvestigations using norbornene and styrene provided, atbest, only minimal amounts of hydroamination products(ca. 3–20% yield).10a Fortunately, a thorough solventscan unveiled a remarkable solvent effect. As illustrated ineqn (3), the reaction between norbornene and aqueousNH2OH improved significantly in the presence of alcoholicsolvents.
ð3Þ
Following this key observation, continued optimizationeventually led to broadly applicable intermolecular reactivity ofalkenes. Initial development using NH2OH with strainedalkenes afforded mixtures of mono- and bis-hydroaminationproducts, with ratios dependent on the presence of excessalkene under the reaction conditions (eqn (4)).10c At first, reac-tions using N-alkyl-hydroxylamines proved highly dependenton the structure of the reagent, with most hydroxylaminesbeing thermally labile under the reaction conditions. Hydroxy-lamine decomposition pathways such as disproportionationare solvent dependent, and N-alkyl-hydroxylamines areespecially labile upon heating in polar solvents.12 Fortunately,exploration of intermolecular reactivity using the more robustN-cyclohexylhydroxylamine provided encouraging results.10a
This prompted a search for additives that could minimizedecomposition of both the hydroxylamine reagents and pro-ducts under the reaction conditions. NaCNBH3 proved anexcellent additive, which allowed the development of a moregeneral Cope-type intermolecular alkene hydroamination pro-cedure using strained alkenes (eqn (5)) and vinylarenes (eqn(6)).10b NaCNBH3 appears to inhibit the decomposition of boththe hydroxylamine starting materials and the products at highreaction temperatures,10b which have been postulated to occurthrough bimolecular reaction pathways.5
ð4Þ
ð5Þ
ð6Þ
As shown above, the hydroamination of vinylarenesrequired heating at 140 °C (eqn (6)). Unfortunately, the yieldsproved quite variable and ranged from modest to good. Giventhat Hartwig had observed that the catalytic intermolecularhydroamination of vinylarenes is essentially thermoneutralat 80 °C,13 the variability in yields suggested that our systemhad also reached a thermodynamic equilibrium. This wasunambiguously proven in a crossover experiment (eqn (7)).10b
ð7Þ
Following the development of the “NaCNBH3 in n-PrOH”
conditions, we explored the reactivity of allenes with hydroxyl-amines.14 During reaction optimization, we discovered thatt-BuOH proved a uniquely effective solvent for the thermolysis ofN-alkylhydroxylamines. Using these conditions, various keto-nitrones were accessed from monosubstituted allenes (eqn (8)).Using t-BuOH in challenging intramolecular reactions22 hasalso proven more effective than the conditions reported byOppolzer et al. to achieve difficult cyclizations.7e To emphasizethis key experimental finding, we reported on the use ofrelated conditions to form ketonitrones simply upon heatingketones and N-alkylhydroxylamines in t-BuOH (eqn (9)).15
The observed solvent effects suggested that hydrogenbonding was important to favour Cope-type hydroaminations.As reported in 2008, hydrogen bonding is likely important tostabilize the N-oxide intermediate and thus helps minimizethe unproductive Cope elimination that would regenerate thereactants (eqn (10)).10b In addition, we proposed that alcoholscould help facilitate the proton transfer step, which is necess-ary to afford more stable products. We provided computationalsupport for a remarkably facile alcohol-mediated proton trans-fer step occurring through a five-membered transition state(see eqn (10)). However, experimentally it remained unclear ifthis proton transfer could be rate determining in intermolecu-lar Cope-type hydroaminations of alkenes. Indeed, this wasstudied experimentally under improved reaction conditionswith norbornene and N-cyclohexyl-hydroxylamine and the reac-tion rate proved independent of the concentration of alcoholpresent in the media.16
ð10Þ
The solvent effects observed also suggested that hydrogenbonding could be used to achieve either catalysis or increasedCope-type hydroamination reactivity. Indeed, the highly polar-ized nature of the hydroamination transition state suggestedthat additives could preferentially stabilize this transition state(vs. the reactants) and consequently lead to rate accelerations.In 2012 we used this approach to achieve mild intermolecularreactions of allylic amines (eqn (11)), and provided experi-mental support that this reactivity is directed by hydrogenbonding.17 In 2013, Jacobsen et al. reported that chiral thio-ureas are effective asymmetric catalysts for intramolecular Cope-type hydroaminations (eqn (12)).18 This is in line with ourresults that several hydrogen bonding catalysts (thioureas,polyols…) accelerate intermolecular variants.16
ð11Þ
ð12Þ
Our optimization efforts on hydrogen-bonding reactivity(eqn (11)) also provided an unexpected result; we noted thatthis reaction works best in the presence of excess of the allylicamine, and that addition of more N-alkylhydroxylamine resultsin diminished reactivity. This observation is consistent withthe presence of unreactive hydroxylamine dimers under thereaction conditions (eqn (13)).17
ð13ÞThis experimental evidence for dimer formation thus pro-
vides a possible rationale for the reactivity trend related to thepresence of nitrogen substituents (N-alkyl ≫ N–H in cycliza-tions, see Fig. 1). Indeed, formation of dimers is likely morefavourable for N–H hydroxylamines. The impact of nitrogensubstitution was also addressed computationally, and this willbe discussed below.
Studies targeting the “thermoneutrality problem” for alkenehydroamination
We had targeted asymmetric alkene hydroaminations from thebeginning of our hydroamination efforts. Being aware of thereversibility of the reaction (eqn (7)),10b,13 we became inter-ested in developing reaction sequences that could alter thepotential energy surface of the hydroamination reaction andmake the reaction more thermodynamically favourable. Thisway, a fast and irreversible reaction following the hydro-amination event would ensure the kinetic control required forhigh stereocontrol. An early proof of concept was achieved withthe Cope-type hydroamination/[2,3]-Meisenheimer rearrange-ment sequence (eqn (14)).19 This sequence was developed withN-methallyl-hydroxylamines in intermolecular systems and withN-allyl-hydroxylamines to achieve difficult cyclizations.
Besides providing a proof of concept, this novel sequenceprovides the opportunity to form more stable N-alkyl-N-allyl-hydroxylamines starting from disubstituted hydroxylamines(rather than less stable N-oxides). Several reports of intramole-cular reactions had noted that N-alkyl reagents are signifi-cantly more reactive than N–H hydroxylamines (see Fig. 1).Consequently, this methodology was used in syntheses of(±)-coniine and (±)-norreticuline featuring challenging intra-molecular Cope-type hydroaminations (eqn (15) and (16)).
ð15Þ
ð16ÞIn our experience, such cyclizations still suffered from the
relatively difficult nature of the [2,3]-Meisenheimer rearrange-ment. Indeed, the cyclization of the coniine precursor requiredthe use of the less bulky (but more labile) N-allyl reagents. Inthe norreticuline system, a competing Cope elimination of theN-oxide intermediate to afford the E isomer of the startingmaterial was also observed (eqn (16)). Interestingly, these reac-tions were more efficient in benzene, but the addition of H2O(10 equiv.) proved beneficial, likely due to stabilization of theN-oxide intermediate.
In parallel to experimental efforts, density functional theory(DFT) calculations were performed to obtain insight onvarious aspects of this intermolecular hydroamination reacti-vity. Related calculations on the Cope elimination had beenreported, but these only provided information regarding themicroscopic reverse of the intermolecular hydroaminationreactivity of alkenes.20 In 2008, in collaboration with Dr SergeGorelsky, we reported a thorough computational analysis ofintermolecular Cope-type hydroaminations of alkenes andalkynes.10b In 2009, we also reported DFT results withallenes.14 In 2012, Krenske, Houk and Holmes reported a com-putational study on intramolecular Cope-type hydroamina-tions.8 Overall, these results have yielded in a wealth ofcomputational information on this reactivity, and only selecteditems will be discussed herein.
Most importantly, our calculations gave insight into thenature of the Cope-type hydroamination transition state. The
calculated activation energies for the hydroamination ofalkenes, alkynes and allenes were studied for various hydroxy-lamines and substrate substitution patterns. Overall, the mostfavourable Gibbs activation energies were ca. 30–33 kcal mol−1,an observation that is consistent with the typical experimentalconditions (∼100 °C) required for intermolecular hydroamina-tion to occur. Several important reactivity trends can beexplained by looking at the molecular orbitals involved:HOMONH2OH → LUMOCC and HOMOCC → LUMONH2OH
(Fig. 3). The strength of these stabilizing interactions will varydepending on the substrate, but significant stabilization canbe achieved with both electron-poor and electron-rich alkenes(via HOMONH2OH → LUMOCC and HOMOCC → LUMONH2OH,respectively). The high selectivity observed for the formation ofthe Markovnikov products is also in agreement with the mole-cular orbitals involved (e.g. HOMOCC → LUMONH2OH implies abuildup of a partial positive charge on the more substitutedcarbon). Overall, these results are in line with the bifunctionalnature of hydroxylamines (i.e. nucleophilic nitrogen atom andacidic hydrogen atom), and account for the broad substraterange observed for Cope-type hydroamination.
In addition, calculations highlighted differences betweenthe potential energy surfaces of the reactions of alkenes andalkynes. The increased stability of the C–C π bond in alkenesleads to a near thermoneutral reaction profile (from a thermo-dynamic perspective) and to a higher energy N-oxideintermediate. With alkenes, this N-oxide intermediate issignificantly less stable than the reactants and Cope elimi-nation is thus possible. Stabilizing this intermediate can helpminimize reversibility and can result in a more facile protontransfer step (leading to the products). These DFT results areconsistent with the important solvent effects observed withalkenes.
Fig. 3 (Top) The transition states for hydroamination of C2H4 (A) and C2H2
(B) showing the internuclear distances and bond orders (italics) and NPA charges(blue). (Bottom) Most important donor–acceptor interactions that favour bondformation between NH2OH, C2H4 and C2H2.
The effects of substitution on the reactants were alsoexplored to study the variability of Cope-type hydroaminationreactivity and probe the reactivity trends observed in intra-molecular reactions. Interestingly, DFT results suggest thatN-alkylhydroxylamines are only slightly more reactive thanNH2OH and N,N-dialkylhydroxylamines. This suggests that thesuperior reactivity of N,N-dialkylhydroxylamines in intramole-cular systems (see Fig. 1) is likely due to conformational effectsand to the presence of more stable hydroxylamine dimers withRNHOH vs. R2NOH (see eqn (13)).
Hydroamination using hydrazine derivatives
In contrast to hydroxylamines, there were no reports of hydro-amination reactivity of hydrazine derivatives in the literatureprior to our work. We were drawn to hydrazines due to theirhigh thermal stability, tunability, synthetic utility, and esta-blished track record in asymmetric synthesis.21 Initial efforts toachieve hydroamination of alkenes and alkynes met with verylimited success. However, exploration proved more fruitfulonce we realized that hydrazines required heating at highertemperatures than hydroxylamines, and that the presence ofalcohols as solvent also allowed for increased reactivity. Ingeneral, our efforts suggest that both alkyl hydrazines andhydrazides react via a concerted (Cope-type) hydroaminationpathway (eqn (17)).22 While not discussed herein, these reac-tions have also been studied computationally.22
ð17Þ
Initial efforts with aqueous hydrazine to achieve hydroami-nation of arylacetylenes afforded a mixture of Markovnikovand anti-Markovnikov products. We speculated that monosub-stituted reagents could destabilize preferentially the Markovni-kov pathway due to steric hindrance in the concertedhydroamination transition state. Gratifyingly, and in contrastto reactions with NH2OH (see eqn (2)), preferential formationof the anti-Markovnikov, linear hydrazones was achieved usingmethylhydrazine (eqn (18)).22a From a molecular orbital per-spective, this regioselectivity is in agreement with strongerHOMONH2NHR → LUMOCC and weaker HOMOCC →LUMONH2NHR interactions.
ð18Þ
We then became interested in the reactivity of hydrazides,which are easily handled, bench stable crystalline solids. Weexpected that the increased N–H acidity would lead toimproved reactivity compared to hydrazines and this proved to
be the case in intramolecular alkene hydroaminations. Indeed,a variety of such cyclizations were achieved upon heating(eqn (19)), with reactivity trends mirroring those observed forCope-type hydroaminations.22b
ð19Þ
The scope of this reaction was initially surveyed withbenzoic hydrazides, and this reaction proved reliable to accessa variety of heterocyclic ring systems: pyrrolidines, piperidines,morpholines and piperazines were formed. Substitution onthe alkene was tolerated, and this also led to the cyclizationof a coniine precursor under forcing conditions (235 °C).To put things in perspective, cyclization to form coniineproved low yielding with N–H hydroxylamines, and couldonly be achieved through the development of the Cope-typehydroamination/Meisenheimer rearrangement sequence (seeeqn (15)).19,23
The forcing conditions required to achieve cyclization ofchallenging substrates led us to perform a systematic study onthe impact of the electron-withdrawing group present in thereagent.22c This study revealed that cyclizations of bis-tri-fluoromethyl benzhydrazides could be performed at tempera-tures 25–50 °C lower than benzhydrazides, presumably viaimproved stabilization of the negative charge being developedat the hydroamination transition state (and present inthe azomethine ylide intermediate). These derivatives inturn enabled the development of an alkyne hydroaminationreaction providing access to azomethine imines (eqn (20)),24
and facilitated development of intermolecular reactivity(eqn (21)).22c
In parallel to this work, we also performed DFT studies togain insight on the nature of the hydroamination and protontransfer steps (eqn (22), Fig. 4).22a,b
ð22Þ
Interestingly, computational results supported both a 5-membered, concerted (Cope-type) hydroamination transitionstate via the Z hydrazide conformer, and also suggested thatthe hydrazide group facilitates proton transfer of theammonium ylide intermediate. We also gained experimentalevidence for a concerted hydroamination event in the courseof mechanistic studies.16 Experimentally, we had suspectedparticipation of the hydrazide group in the proton transferstep since (in contrast to hydroxylamines) this reaction isefficient in a variety of solvents.
Hydrazides: discovery of alkene aminocarbonylation reactivity
Initially, the lack of reactivity observed with hydrazine deriva-tives led to the use of forcing conditions to allow the desiredhydroamination reactivity. Surprisingly, initial trials with car-bazate derivatives led to the formation of an unknown alkeneamination product. Analysis by 1H NMR showed that thealkene had reacted, but had not formed a hydroaminationproduct. Eventually, we assigned the structure as the amino-carbonylation product depicted in eqn (23).22b
ð23ÞThis transformation likely involves an amino-isocyanate
intermediate, and the bifunctional nature of this intermediateallows for a concerted, 5-membered aminocarbonylation event.
Proton transfer is then required to form the neutral product,and thus this reactivity bears resemblance to the Cope-typehydroamination approach. Related alkyne aminocarbonylationreactivity had been reported by Lwowski in 1974.25 Overall,this unexpected reactivity caused an expansion of our researchefforts to include nitrogen-substituted isocyanates, due tonovelty of this transformation and to the importance of β-amino-carbonyl motifs. Recently, we reported on a related, milderintermolecular variant, which allows the synthesis of azo-methine imines from a variety of alkenes and hydrazone pre-cursors (eqn (24)).26 Of note, the dipoles formed using afluorenone-derived hydrazone were derivatized into β-amino-carbonyl compounds via reductive ring cleavage of the dipolarproducts.26a
ð24Þ
Given that this article is focused on hydroamination reacti-vity, the reactivity of nitrogen-substituted isocyanates will notbe discussed further. However, reactions of both amino- andimino-isocyanates are currently under development in ourgroup.
Other developments in heterocyclic synthesis
As part of the systematic investigation of bifunctional hydro-amination reagents possessing the N–X–H motif, we decidedto evaluate the hydroamination reactivity of oximes with unac-tivated C–C π bonds. Our objective was to build on the pioneer-ing work of Grigg, who studied the aza-protio transfer(hydroamination) reactivity of oximes.27
We were especially drawn toward applications in the syn-thesis of aromatic nitrogen heterocycles, since the high oxi-dation state associated with the oxime functionality is wellaligned with the oxidation state levels present in aromaticnitrogen heterocycles. We selected pyridines and other related6-membered, π-deficient heterocycles as targets due to theirimportance in medicinal chemistry. In addition, we felt thatthis reactivity could provide a rare example of a hydroamina-tion (hydro-iminiumation28) approach to the synthesis of6-membered aromatic heterocycles. Our attempts to perform ahydroamination/isomerization/aromatization sequence underthermal conditions met with limited success, notably due to acompeting oxidation process of the pyridine produced underthe forcing conditions (180 °C) required for this reaction tooccur (eqn (25)).29 Eventually, acid-catalysis allowed for thesynthesis of pyridines and pyrazines to occur under somewhatmilder conditions (eqn (26)).29
ð25Þ
Fig. 4 Transition state structures for the intramolecular hydrohydrazidation (A)and subsequent proton transfer step (B) (eqn (22) is provided for reference).
ð26ÞRecently Yu, Bao and co-workers have reported two
advances in the synthesis of aromatic heterocycles using Cope-type hydroaminations. They have shown that both hydroxyl-amine and hydrazine react with a variety of diynes substrates,providing isoxazoles (eqn (27))30 and pyrazoles (eqn (28)).31
Interestingly, these reactions were performed in DMSO, andthe latter reaction proceeded at 60 °C. These mild reactionconditions, in contrast to 113–140 °C for related reactions (eqn(18)),22a show that conjugated diynes are excellent activatedsubstrates for Cope-type hydroaminations.
In contrast to the aminocarbonylation reaction described pre-viously, our efforts to achieve intermolecular alkene hydroami-nation routinely led to unsatisfying results. Indeed, onlybiased alkenes such as strained alkenes and styrenes led tosuccessful intermolecular alkene hydroaminations. Even then,forcing conditions were required and equilibrium was reachedwith styrenes (at 140 °C!) due to the entropic penalty associ-ated with this transformation (and due to the increased stabi-lity of styrenes). Even if this issue of thermoneutrality hadbeen addressed in our earlier efforts toward hydroaminationsequences, we felt that for the more stable and less reactivedisubstituted alkenes a different solution had to be conceived.
We thus became interested in using temporary intramolecu-larity as an approach to inherently address the entropicpenalty associated with intermolecular hydroaminations.Hydroamination reactions benefiting from temporary tethershad not been reported when we initiated this project.However, the benefits of using temporary intramolecularity,32
in particular in the form of stoichiometric temporary tethers,33
were well recognized. Indeed for dozens of synthetic
transformations this approach has been used to achieveincreased reactivity and control (chemo-, stereo-, and/or regio-selectivity). From a hydroamination perspective, we felt thatthis strategy could facilitate the development of stereoselectivehydroamination reactions. A priori this approach appearedonly applicable to allylic alcohols and amines (Fig. 5). Never-theless, we felt that such directed34 hydroaminations wouldadd a valuable synthetic tool, potentially allowing the conver-sion of allylic amines into vicinal diamines, and of allylic alco-hols into vicinal aminoalcohols.
Since Cope-type hydroaminations forming five membered-rings can cyclize at or below room temperature (see Fig. 1), wewere optimistic about this approach provided that a suitabletethering could be assembled. At the design stage we alsonoticed that tethering strategies are usually stepwise and stoi-chiometric, and typically require three or four steps to performtether assembly, the desired step, and removal of the tether.33
We thus decided to develop a catalytic tethering strategy, oper-ating via the prototypical catalytic cycle shown below (Fig. 6).
This catalytic tethering strategy, which relies on temporaryintramolecularity, is based on the possibility that intramolecu-lar reactions can be up to 108 times faster compared to inter-molecular reactions performed at a 1 M concentration.32b
While there has been a recent resurgence of interest in cataly-tic systems operating via temporary intramolecularity,35 thelack of tethering catalysts (i.e. of catalysts operating only byperforming preassociation of the reagents without activation)is worth highlighting. While looking at potential tetheringatoms (e.g. boron, silicon, etc.), we were drawn to the pioneer-ing work of Knight on an unusual, hydroamination-basedvicinal diamine synthesis involving the addition of allylaminesto nitrones (eqn (29)).36
ð29Þ
This stoichiometric precedent addressed a key concern: theneed to selectively form a tether via the nitrogen atom ofthe hydroxylamine. Indeed, this selectivity was needed toretain the ability to perform a Cope-type hydroamination, as
substitution on the oxygen atom would remove the requiredhydrogen atom required for hydroamination. In addition,selecting a carbon atom as a linker minimized the possibilitythat tether distortion8 could lead to reduced reactivity (forexample the incorporation of larger silicon atom could havesignificantly changed the reactivity). However, it was unclear ifthis system could become catalytic in aldehyde, especially con-sidering the formation of the cyclic products observed byKnight (see eqn (25)) which could result in catalyst inhibition.Reasoning that a difficult preassociation event (i.e. difficult for-mation of aminal I) was preventing ideal reactivity in Knight’ssystem,36b we screened a variety of aldehydes for catalyticactivity with emphasis on destabilized aldehydes (which tendto hydrate readily). Gratifyingly, we observed that α-benzyloxy-acetaldehyde showed both the desired propensity to performreagent preassociation and encouraging catalytic activity(eqn (30)).37
ð30Þ
An encouraging proof of concept was thus obtained usingα-benzyloxyacetaldehyde as catalyst (20 mol%) operating atroom temperature. While several carbonyl-catalysed reactionshave been reported,38 this work provides the most complexaldehyde-catalysed reaction operating via temporary intramole-cularity. Establishing that enantiopure α-chiral aldehydescould operate as asymmetric catalysts became a natural exten-sion of this work. While encouraging enantioselectivities wereinitially obtained with ketals of (R)-glyceraldehyde (up to 87%ee), optimized conditions had to be developed to minimize acompeting catalyst racemization pathway. Eventually, wereported on both an improved procedure with the diphenyl-ketone-derived ketal of (R)-glyceraldehyde (up to 97% ee,eqn (31)), and on the development of a more robust bicyclicaldehyde that can be used as a pseudo-enantiomer (up to−94% ee, eqn (32)).39
ð31Þ
ð32Þ
In parallel to this work, mechanistic studies were per-formed to gain more insight on this transformation.40 Mostimportantly, kinetic studies determined that the reaction wasindeed first order in catalyst. The reaction was also first orderin allylic amine but proved inverse order in the hydroxylamine,which is consistent with the formation of an unreactive sym-metrical hydroxylamine dimer. A primary kinetic isotope effect(kH/kD = 2.8 ± 0.9) was also observed. Overall, these obser-vations are consistent with a rate-determining Cope-typehydroamination event, and the catalytic cycle and inhibitionpathways are presented in Fig. 7. The rate law was alsodetermined.40
As expected, we determined during these studies that thepreassociation step is inherently part of the rate law of thereaction. Unfortunately, the catalysts and reaction conditionsshown in eqn (26)–(28) were only efficient with terminal allylicamines and were sensitive to the steric hindrance present on
Fig. 6 Design of a catalytic tethering strategy: achieving rate acceleration viatemporary intramolecularity (T = tethering catalyst).
Fig. 7 Catalytic cycle for aldehyde-catalysed Cope-type hydroaminations ofallylic amines.
the reactants. We were thus pleased that these mechanisticstudies led to the identification of a more reactive catalyticsystem. Indeed, the use of both paraformaldehyde andaqueous formaldehyde under modified reaction conditions ledto improved catalytic activity, with loadings of 5–10 mol%being possible with terminal allylamines (eqn (33)).40 Evalu-ation of the scope of this remarkably simple catalyst is cur-rently under investigation using more challenging substrates.
ð33Þ
Our results show that aldehydes can be powerful tetheringcatalysts and excellent asymmetric catalysts. This catalytictethering strategy also led to the highest enantioselectivityreported for an enantioselective intermolecular alkene hydro-amination. More broadly, these reactions illustrate the syntheticefficiency that can be achieved by catalysts operating via tem-porary intramolecularity. The simplicity of the tetheringapproach and the presence of similar simple aldehydes inNature also suggest that their role as catalysts in chemical evolu-tion and in biological systems should be investigated. Expan-sion of the scope of this carbonyl-directed hydroaminationmethodology to other substrates and applications of aldehydecatalysis to other transformations are ongoing and will bereported in due course.
Conclusions and outlook
Cope-type hydroaminations are versatile for the direct ami-nation of alkenes, alkynes and allenes using hydroxylaminesand hydrazine derivatives. Important solvent effects were dis-covered and this finding enabled the generalization of thisreactivity by extending its applicability to intermolecularsystems using alcohols as solvents. This concerted reactionwas studied both experimentally and computationally; thesesolvent effects are consistent with the importance of stabiliz-ing the developing charges present in the dipolar intermedi-ates, thus achieving both faster reactions and stabilization ofthe key reaction intermediate (preventing a Cope eliminationevent). Hydrazines and hydrazides were also developed asorthogonal reagents for Cope-type hydroaminations, and theirscope was explored in target-oriented synthesis. In addition,directed reactions of hydroxylamines were developed toachieve asymmetric hydroaminations, using both hydrogenbonding and a covalent linker approaches to induce temporaryintramolecularity. The latter strategy was especially efficient,and used aldehydes as tethering catalysts to form vicinal di-amines from allylic amines. Formaldehyde proved to be aremarkably efficient achiral catalyst, allowing increased reacti-vity with reduced catalyst loadings (5–10 mol%). Excellentenantioselectivities (up to 97% ee) were also achieved using
chiral aldehydes, thus validating the use of aldehydes as chiraltethering organocatalysts. Overall, Cope-type hydroaminationshave recently emerged as remarkably versatile tool that is bydesign complementary to the use of transition metal catalysts.Indeed, this strategy illustrates that bifunctional reagents areefficient for the amination of C–C π bonds under metal-freeconditions.
However, further developments in hydroamination methodo-logies remain critically needed. Intramolecular approacheswith broad applicability, allowing the formation of variousring systems (and not only pyrrolidines) – from both terminaland internal alkenes, under mild conditions – have yet toemerge. Improved intermolecular reactivity also remains a keyobjective, as intermolecular reactions of unactivated alkenestypically require forcing conditions. Potentially useful trans-formations, such as the direct hydroamination of allylic alco-hols, have not been reported. Besides for allylic amines,39
highly enantioselective reactions have only been reported forthree alkenes: norbornene, styrene and 1,3-cyclohexadiene.Procedures that allow high diastereoselectivities in both intra-molecular and intermolecular systems still need to be develo-ped. Finally, uses of hydroamination reactions in the contextof complex reaction sequences also holds excellent potentialfor further development.
It is likely that Cope-type hydroaminations can help withfuture development work. The recent reports of H-bonding cata-lysis17,18 suggest that milder conditions will be possible inboth intramolecular and intermolecular systems. Lewis-acidcatalyzed variants, which have yet to be developed, will alsolikely emerge. Laughlin’s seminal report on the hydroamina-tion of 1-hexene suggests that reactions of unactivated alkenesare feasible.6a Strategically, the concerted nature of the Cope-type hydroamination process distinguishes it from otherapproaches. By design, this ensures broad functional groupcompatibility, absence of catalyst inhibition, and avoids theformation of unstable reaction intermediates. It is likely inreactions of alkenes, where the reaction intermediates are typi-cally least stable, that this advantage will be most useful andwhere reaction intermediates could lead to divergent reactivity(e.g. 2° carbocations, metal–alkyl intermediates, etc.). Never-theless, synthetic chemists need a variety of approaches thatmatches the large diversity present in the nitrogen-containingstructures present in natural products, pharmaceuticals andagrochemicals. Hydroamination practitioners will thus beactive for years to come…
Acknowledgements
Contributions from the students and postdocs involved in thiswork and collaborations with Dr Serge Gorelsky and Prof.Muralee Murugesu are gratefully acknowledged. Financialsupport from the University of Ottawa, the Canadian Foun-dation for Innovation, the Ontario Ministry of Research andInnovation (Ontario Research Fund and Early ResearcherAward to A.M.B.), NSERC (Discovery Grant, Discovery
Accelerator Supplement and CREATE grants to A.M.B.), andAstraZeneca is also gratefully acknowledged. The impact of theearly support of this work via a 2005 Enantioselective SynthesisGrant (sponsored by the Canadian Society for Chemistry,AstraZeneca Canada, Boehringer Ingelheim (Canada) Ltd. andMerck Frosst Canada), and the NSERC Collaborative R&DProgram should also be emphasized. Acknowledgment is alsomade to the donors of The American Chemical Society Pet-roleum Research Fund for support of related research efforts(aldehydes as tethering organocatalysts).
Notes and references
1 (a) Catalyzed Carbon-Heteroatom Bond Formation, ed.A. K. Yudin, Wiley-VCH, 2011; (b) J. F. Hartwig, Nature,2008, 455, 314; (c) T. E. Muller, in Encyclopedia of CatalysisVol. 3, ed. I. T. Horváth, Wiley-Interscience, 2003,pp. 518–541.
2 SciFinder search performed August 9, 2013 for the termhydroamination (“as entered”) and including only books,journal articles and reviews, and patents. Duplicates wereremoved. References related to reactions with carbonylcompounds or alcohols were removed (these were commonbetween 1980 and 2000, as the term hydroaminationbecame broadly accepted). No attempts were made toperform a more inclusive or refined search, covering forexample early work in the area and reactions such as theRitter amination and Cope-type hydroaminations.
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