Intramolecular hydroamination of aminoalkenes by calcium and magnesium complexes: A synthetic and mechanistic study

Published on Web 06/24/2009

Intramolecular Hydroamination of Aminoalkenes by Calcium

and Magnesium Complexes: A Synthetic and

Mechanistic Study

Mark R. Crimmin,^‡Merle Arrowsmith,^†Anthony G. M. Barrett,*^,‡Ian J. Casely,^‡

Michael S. Hill,*^,†and Panayiotis A. Procopiou^§

Department of Chemistry, UniVersity of Bath, ClaVerton Down, Bath BA2 7AY, U.K.,

Department of Chemistry, Imperial College London, Exhibition Road, South Kensington,

London SW7 2AZ, U.K., and GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road,

SteVenage, Hertfordshire SG1 2NY, U.K.

Received January 20, 2009; E-mail: msh27@bath.ac.uk

Abstract: The ꢀ-diketiminate-stabilized calcium amide complex [{ArNC(Me)CHC(Me)NAr}Ca{N(SiMe₃)₂}-

(THF)] (Ar ) 2,6-diisopropylphenyl) and magnesium methyl complex [{ArNC(Me)CHC(Me)NAr}Mg(Me)(THF)]

are reported as efﬁcient precatalysts for hydroamination/cyclization of aminoalkenes. The reactions

proceeded under mild conditions, allowing the synthesis of ﬁve-, six-, and seven-membered heterocyclic

compounds. Qualitative assessment of these reactions revealed that the ease of catalytic turnover increases

(i) for smaller ring sizes (5 > 6 > 7), (ii) substrates that beneﬁt from favorable Thorpe-Ingold effects, and

(iii) substrates that do not possess additional substitution on the alkene entity. Prochiral substrates may

undergo diastereoselective hydroamination/cyclization depending upon the position of the existing

stereocenter. Furthermore, a number of minor byproducts of these reactions, arising from competitive alkene

isomerization reactions, were identiﬁed. A series of stoichiometric reactions between the precatalysts and

primary amines provided an important model for catalyst initiation and suggested that these reactions are

facile at room temperature, with the reaction of the calcium precatalyst with benzylamine proceeding with

∆G°(298 K) ) -2.7 kcal mol^-1. Both external amine/amide exchange and coordinated amine/amide

exchange were observed in model complexes, and the data suggest that these processes occur via low-

activation-energy pathways. As a result of the formation of potentially reactive byproducts such as

hexamethyldisilazane, calcium-catalyst initiation is reversible, whereas for the magnesium precatalyst, this

process is nonreversible. Further stoichiometric reactions of the two precatalysts with 1-amino-2,2-diphenyl-

4-pentene demonstrated that the alkene insertion step proceeds via a highly reactive transient alkylmetal

intermediate that readily reacts with N-H σ bonds under catalytically relevant conditions. The results of

deuterium-labeling studies are consistent with the formation of a single transient alkyl complex for both the

magnesium and calcium precatalysts. Kinetic analysis of the nonreversible magnesium system revealed

that the reaction rate depends directly upon catalyst concentration and inversely upon substrate

concentration, suggesting that substrate-inhibited alkene insertion is rate-determining.

Introduction

parallels between the chemistry of the heavier alkaline-earth

metals and that of the trivalent lanthanides have often been

Although the past two decades have overseen some dramatic

advances in our appreciation of heavier alkaline-earth (Ca, Sr,

and Ba) complex structures and coordination behavior,¹a well-

deﬁned or applied reaction chemistry of these elements is now

only beginning to emerge. This is in stark contrast to the

widespread use of magnesium-based compounds (Grignard

reagents, Hauser bases), which have been employed as sto-

ichiometric reagents in organic synthesis since the beginning

of the 20th century.²

The exclusively divalent compounds of the alkaline earths

are redox-inactive³and unambiguously d⁰complexes, so the

bonding is dictated only by ionic and nondirectional interactions

between the metal and the auxiliary ligands. In this respect,

drawn. This latter series of elements has a well-deﬁned and

versatile reaction chemistry, and the pioneering research of

Marks and subsequent researchers has demonstrated that triva-

lent organolanthanide compounds of the form L₂LnX, where L

is a monoanionic (typically cyclopentadienyl) spectator ligand

and X is a monoanionic σ-bonded (e.g., hydrido, alkyl, amido,

phosphido) substituent, are applicable to a wide range of

catalytic transformations.^4-6This catalytic behavior is ef-

fectively founded upon two fundamental types of reactivity: (i)

σ-bond metathesis and (ii) insertion of unsaturated carbon-carbon

or carbon-heteroatom bonds into Ln-X σ bonds (Figure 1).

Incorporation of these two reaction steps into catalytic cycles

has enabled the development of a vast number of lanthanide-

mediated synthetic reactions, including intra- and intermolecular

heterofunctionalization of carbon-carbon bonds,⁴polymeriza-

tion of low-molecular-weight alkenes,^5,6and C-H activation

^†University of Bath.

^‡Imperial College London.

^§GlaxoSmithKline Medicines Research Centre.

9

9670 J. AM. CHEM. SOC. 2009, 131, 9670–9685

10.1021/ja9003377 CCC: $40.75  2009 American Chemical Society

Intramolecular Hydroamination of Aminoalkenes

A R T I C L E S

observed the insertion of both 1,4-diphenylbutadiyne and

benzonitrile into the metal-phosphorus bond of a series

of homoleptic heavier alkaline-earth phosphides, [M{P-

(SiMe₃)₂}₂(THF)₄] (M ) Ca, Sr, Ba).⁸In a related study, it

has been demonstrated that the analogous amide complexes

[M{N(SiMe₃)₂}₂(THF)₂] also undergo insertion reactions with

benzonitrile.⁹Although in all cases the initial reaction

products underwent decomposition with silyl-group migra-

tion, the isolated products can be rationalized in terms of

the insertion step. This work parallels early studies by Gilman

and Coles, which showed that ill-deﬁned heavier alkaline-

earth complexes containing metal-carbon σ bonds react with

unsaturated substrates such as CO₂, benzonitrile, and

1,1-diphenylethene.^10,11Mingos has demonstrated the inser-

tion of carbonyl sulﬁde, carbon disulﬁde, and sulfur dioxide

into group-2 metal-alkoxide bonds.¹²Perhaps more impor-

tantly, the work of Harder has shown that the highly reactive

heavier group-2 benzyl complexes [Ba{C(Ph)₂(CH₂CH₂Ph)}₂-

(THF)₂] and [M(DMAT)₂(THF)₂] (M ) Ca, Sr; DMAT )

2-dimethylamino-R-trimethylsilylbenzyl) are suitable initia-

tors for the polymerization of styrene via reactions that occur

through multiple insertions of the alkene into the metal-carbon

σ bond of an intermediate organometallic species.¹³Harder

has also reported that ligand control may be exerted to an

extent in this reaction, and heteroleptic complexes of the form

[LMX(THF)], where X is DMAT and L is a bulky silyl-

substituted ﬂuorenyl ligand, have been shown to initiate

styrene polymerization with a degree of control over polymer

tacticity.^13j

Figure 1. Fundamental reactions of trivalent lanthanide organometal-

lics.

within even nonreactive hydrocarbons such as methane.^6a

Research in our laboratories and elsewhere has set out to

investigate the potential for related reaction chemistries within

the heavier alkaline-earth series. Although the intrinsic basicity

of derivatives of these elements signiﬁes that tolerance toward

more delicate functional groups will be an issue for longer-

term applicability,⁷these studies have sought to establish

whether well-deﬁned group-2 complexes may be employed as

catalytic reagents using similar σ-bond metathesis and insertion

reaction chemistries and to understand the potential relationship

between any reactivity and the nature (radius, ionic character)

of the metal dication involved.

In this regard, it is noteworthy that several precedents exist

in stoichiometric heavier group-2 chemistry that are consistent

with the fundamental reaction types observed for trivalent

organolanthanide complexes. Westerhausen, for example, has

In addition to these observations, σ-bond metathesis (or

protonolysis) has frequently been employed in stoichiometric

heavier group-2 chemistry to synthesize new organometallic

species. Examples include the reaction of the heavier group-2

metal amides [M{N(SiMe₃)₂}₂(THF)_n] (M ) Ca, Sr, Ba; n )

0, 2) with alcohols, thiols, selenols and tellurols, pyrroles and

pyrazoles, terminal alkynes, cyclopentadiene and derivatives,

phosphines, or arsines to yield the corresponding metal alkox-

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J. AM. CHEM. SOC. VOL. 131, NO. 28, 2009 9671

A R T I C L E S

Crimmin et al.

of rac-lactide,²²is a highly effective catalyst for the intramo-

lecular hydroamination of aminoalkenes and aminoalkynes.²³

The reaction was postulated to occur by the generalized catalytic

cycle outlined in Figure 2, which was assumed, by direct

analogy to the experimentally validated cycle in lanthanide-

mediated hydroamination reactions, to proceed via both σ-bond

metathesis (protonolysis) and intramolecular CdC insertion for

catalyst activation, thereby continuing the catalytic turnover.

In subsequent and related work, Harder has described the

application of the heavier alkaline-earth complexes [(DMAT)₂-

M(THF)₂] (M ) Ca, Sr) to intermolecular hydrosilylation of

styrenes and dienes with phenylsilane and phenyl(methyl)silane

and the use of [{ArNC(Me)CHC(Me)NAr}CaH(THF)]₂as a

precatalyst for hydrogenation of activated alkenes and hydrosi-

lylation of ketones.²⁴While Roesky has reported aminotropi-

noate-supported calcium and strontium amides for intramolec-

ular hydroamination catalysis,²⁵further work in our laboratory

has demonstrated both the application of 1a to intermolecular

hydrophosphination of alkenes, alkynes, and carbodiimides²⁶

and the use of the simple heavier group-2 amides [M{N-

(SiMe₃)₂}₂(THF)₂] (M ) Ca, Sr, Ba) as precatalysts for

hydroamination of carbodiimides and isocyanates.²⁷

Figure 2. Generalized postulated catalytic cycle for calcium-mediated

intramolecular hydroamination.

ide,¹⁴thiolate,¹⁵selenolate and tellurate,¹⁶pyrrolide and pyra-

zolide,¹⁷acetylide,¹⁸cyclopentadienide,¹⁹phosphide,²⁰or ars-

enide²¹MX₂species along with the reaction byproduct

HN(SiMe₃)₂. The former homoleptic organometallic species

commonly demonstrate low solubility in hydrocarbon solvents

and are often isolated upon addition of a charge-neutral chelating

ligand.

In this submission, we provide a complete account of our

experimental studies of the atom-efﬁcient intramolecular hy-

droamination of aminoalkenes catalyzed by calcium and mag-

nesium complexes. We also provide a mechanistic appraisal

based upon stoichiometric reactivity and preliminary kinetic

experiments.

On the basis of these precedents, we previously reported in

preliminary form that the ꢀ-diketiminate-stabilized calcium

amide 1a (Figure 2), a compound originally reported by

Chisholm and co-workers as a catalyst for the polymerization

Results and Discussion

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Precatalyst Synthesis. An underlying challenge in the devel-

opment of catalytic reagents based upon the heavier alkaline

earths is the propensity of heteroleptic compounds of the form

LMX to undergo Schlenk-like and/or irreversible solution

redistribution reactions to the homoleptic compounds L₂M and

MX₂. When X is sterically undemanding, the MX₂species are

often polymeric and/or have low solubility in noncoordinating

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complexes are unreactive. In effect, solution redistribution may

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9672 J. AM. CHEM. SOC. VOL. 131, NO. 28, 2009

Intramolecular Hydroamination of Aminoalkenes

A R T I C L E S

Scheme 1. Synthesis of ꢀ-Diketiminate-Stabilized Alkaline-Earth Amides 1a-c

complexes, including a number of group-2 organometallics.^28,29

Scheme 2. Modiﬁed Synthesis of ꢀ-Diketiminate-Stabilized

Magnesium Alkyl Complex 2

Following the conditions reported by Chisholm,²²we reported

previously that the reaction of the ꢀ-iminoenamine [ArNHC-

(Me)CHC(Me)NAr] (Ar ) 2,6-diisopropylphenyl) with 2 equiv

of potassium bis(trimethylsilyl)amide and 1 equiv of MI₂in THF

resulted in the formation of the series of heteroleptic complexes

[{ArNC(Me)CHC(Me)NAr}M{N(SiMe₃)₂}(THF)] [M ) Ca

(1a), Sr (1b), Ba (1c)] (Scheme 1).³⁰For the larger alkaline

earths strontium and barium, formation of the desired hetero-

leptic products was accompanied by production of the known

homoleptic compounds [{ArNC(Me)CHC(Me)NAr}₂M], which

are subject to further dynamic equilibria. These initial observa-

tions suggested that the bulky ꢀ-diketiminate ligand [ArNC-

(Me)CHC(Me)NAr]^-provided sufﬁcient kinetic stabilization to

heteroleptic calcium complexes but was of limited use for

strontium and barium derivatives.

These studies suggested that 1a may be a useful compound

with which to investigate hydroamination catalysis with het-

eroleptic calcium organometallics. Although the strontium and

barium analogues of 1a were deemed unsuitable for this purpose,

for comparison we also synthesized the magnesium complex

[{ArNC(Me)CHC(Me)NAr}Mg(Me)(THF)] (2) by modiﬁcation

of the literature procedure (Scheme 2).^28bThis compound proved

to be stable under a number of reaction conditions and, although

highly moisture-sensitive, provided no evidence of Schlenk-

like redistribution in solution.

(28) For Mg diketiminate complexes, see: (a) Gibson, V. C.; Segal, J. A.;

White, A. J. P.; Williams, D. J. J. Am. Chem. Soc. 2000, 122, 7120.

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9

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A R T I C L E S

Crimmin et al.

barrier to the reaction resulting from the repulsion of the lone

pair of the nitrogen and the carbon-carbon π bond. The

widespread search for homogeneous reagents capable of cata-

lyzing this intramolecular process has given rise to a burgeoning

and mechanistically diverse area of research³⁰that has utilized

alkali metal,^31c,32,33Sc,^34,35Ti and Zr,^36,37Re,³⁸Fe,³⁹Ru,^40,41

Rh and Ir,^40,42Pd,^40,43,44fPt,⁴⁴Ag,⁴⁵Au,⁴⁶Zn,⁴⁷Hg(II),^33band

4f-^48-58and 5f-element⁵⁹complexes. In addition, Brønstead

acids have been reported to catalyze intramolecular hydroami-

nation reactions.^36s,60

Catalytic systems based upon trivalent organolanthanides of

the form L_nLnX¹devised and pioneered by Marks and co-

workers,⁴⁸are especially notable for being highly efﬁcient in

catalyzing the intramolecular hydroamination of aminoalkenes,

aminoalkynes, aminoallenes, and aminodienes. The availability

of a single common oxidation state (+3) precludes an oxidative

addition/reductive elimination pathway as a viable mechanism

for organolanthanide catalysts. Rather, the reactivity patterns

are deﬁned by alkene insertion into polar, largely ionic Ln-X²

bonds and σ-bond metathesis, both of which may be modulated

by judicious selection of the Ln³⁺cationic radius and the

supporting ligands. Both computational^58aand experimental^48a,d

data are consistent with the intramolecular hydroamination of

alkenes occurring via (i) σ-bond metathesis of the precatalyst

Cp*₂LnX¹[X¹) H, CH(SiMe₃)₂] with the aminoalkene to form

a heteroleptic lanthanide amide intermediate, (ii) rate-limiting

intramolecular insertion of the alkene into the Ln-N bond of

the amide, and (iii) σ-bond metathesis of the resulting lanthanide

alkyl species with a further equivalent of aminoalkene.^48dWhile

Marks has suggested that the observed rate law, V ∝

[catalyst]¹[substrate]⁰, and the moderate ∆H^qand large negative

∆S^qvalues of these reactions are consistent with a highly ordered

polar transition state for carbon-nitrogen bond formation via

a rate-determining insertion step, Hultzsch and co-workers have

derived an alternative rate law and suggested that the reaction

rate depends upon the substrate concentration at t ) 0 because

the substrate and product effectively inhibit the alkene insertion

step to similar extents.^50e

In subsequent studies, numerous 4f-element-based catalysts

have been developed, and while initial studies centered upon

the application of cyclopentadienyl and ansa-bridged cyclo-

pentadienyl ligand sets, more recent investigations have included

noncyclopentadienyl-based ligands with an emphasis on the

design of nonracemic catalysts to effect stereocontrolled in-

tramolecular hydroamination reactions.^49-57Density functional

theory computational studies of the intramolecular hydroami-

nation of alkenes,^48adienes,^48b,eallenes,^48cand alkynes^48dhave

been undertaken and recently reviewed.^48f

(37) For synthetic applications of Ti- and Zr-mediated intramolecular

hydroamination, see: (a) McGrane, P. L.; Livinghouse, T. J. Org.

Chem. 1992, 57, 1323. (b) McGrane, P. L.; Livinghouse, T. J. Am.

Chem. Soc. 1993, 115, 11485.

Calcium compound 1a and magnesium compound 2 were

examined as catalysts for hydroamination of a variety of

aminoalkenes. Reactions were conducted in NMR tubes using

C₆D₆as the solvent with tetrakis(trimethylsilyl)silane (TMSS)

as an internal standard, and the yields were measured by

(38) Ouh, L. L.; Mu¨ller, T. E.; Yan, Y. K. J. Organomet. Chem. 2005,

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Organometallics 2000, 19, 170.

1

integration of the H NMR peaks. Subsequent repetition on a

preparative scale allowed isolation of the heterocyclic products,

which were puriﬁed by short-path (ku¨gelrohr) distillation. The

results of these experiments are provided in Table 1.

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Reaction Scope. This group-2-catalyzed hydroamination/

cyclization reaction allows access to derivatives of pyrrolidines,

piperidines, and hexahydroazepines in near-quantitative yields

under mild (25-80 °C) conditions using 2-20 mol % precata-

lyst. Structures of the reaction products were assigned using

NMR spectroscopy by comparison to literature data where

applicable and, in the case of Table 1, entries 16-18, using

single-crystal X-ray diffraction of the hydrochloride salt of the

isolated pyrrolidine (see the Supporting Information).

Examination of the data in Table 1 reveals that in all but one

case (see below), the calcium precatalyst 1a catalyzes the

reaction with a shorter reaction time than the corresponding

magnesium complex 2. Although kinetically favorable (Thorpe-

Ingold effect)⁶¹cyclizations could be achieved, more demanding

substrates, such as those possessing substitution at the alkene

terminus (either 1,1- or 1-substitution; Table 1, entries 12-15),

were recovered unchanged. A limitation of the more active

calcium system became apparent when reactions were conducted

at higher temperatures and over extended times. In many of

these cases, catalysis was accompanied by Schlenk-like, and

effectively irreversible, redistribution of 1a to the homoleptic

calcium compound [{ArNC(Me)CHC(Me)NAr}₂Ca] (Ar ) 2,6-

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29a

1

diisopropylphenyl), as observed by H NMR spectroscopy.

In contrast, no such solution redistribution equilibria were

apparent during catalysis with compound 2 containing the

smaller Mg²⁺cation.

9

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Intramolecular Hydroamination of Aminoalkenes

A R T I C L E S

Table 1. Scope of Calcium- and Magnesium-Mediated Intramolecular Hydroamination Reactions

^aNMR yields were measured against TMSS as an internal standard; reactions were conducted in C₆D₆or toluene-d₈. ^bProducts were accompanied by

alkene isomerization byproduct (see text for details).

9

J. AM. CHEM. SOC. VOL. 131, NO. 28, 2009 9675

A R T I C L E S

Crimmin et al.

Figure 3. Stack plot of NMR spectra for the reaction of (1-allylcyclohexyl)methylamine with 2 mol % 1a taken at 10 min intervals.

The empirical experimental observations listed in Table 1 are

consistent with the calcium amide catalyst 1a effecting the

cyclization of aminoalkenes at a higher rate than the magnesium

species 2. In moving from Mg²⁺to Ca²⁺, there is an increase

in the ionic radius of the dication [from 0.72 to 1.00 Å for Mg²⁺

and Ca²⁺in six-coordinate complexes].⁶¹Although not isoleptic,

both species would be expected to form similar group-2 primary

amide intermediates following the initial protonolysis reaction

with the aminoalkene substrate (see below). The trend within

the lanthanide series is a marked increase in turnover frequency

(TOF) with increasing coordinative unsaturation at the metal

center.^48a,dHence, for a given ligand set, the activity decreases

across the lanthanide series with increasing atomic number

because of contracting Ln³⁺radii. In order to further quantify

this observation, the kinetics of the cyclizations of (1-allylcy-

clohexyl)methylamine in C₆D₆mediated by 1a and 2 were

hydroamination product (Figure 3), and the kinetic data were

taken from the integration of the substrate and product peaks

relative to the TMSS peak. The reactions were conducted with

identical initial concentrations of 0.44 M in aminoalkene and

∼0.01 M in catalyst (2-3 mol %) in the two experiments and

monitored by consumption of the aminoalkene over 3 half-lives.

TOFs were calculated using linear-ﬁt data derived from the plot

of log[aminoalkene] versus time (Figure 4). Although only a

preliminary analysis, this kinetic data revealed a marked increase

in TOF with increasing ionic radius of the metal: 1a and 2

effected the cyclization of 1-aminomethyl-1-allylcyclohexane

with TOFs of 54.5 and 17.0 h^-1, respectively. Indeed, attempts

to monitor the cyclization reaction at higher concentrations of

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1

followed by H NMR spectroscopy. The in situ NMR studies

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9

9676 J. AM. CHEM. SOC. VOL. 131, NO. 28, 2009

Intramolecular Hydroamination of Aminoalkenes

A R T I C L E S

Figure 4. Plots of log[aminoalkene] vs time for the cyclization of (1-allylcyclohexyl)methylamine with 1a (blue b) and 2 (dark-blue [).

Figure 5. Thorpe-Ingold effect in intramolecular hydroamination catalyzed by 1a at room temperature.

the calcium compound 1a proved unsuccessful because of the

high rate of the reaction.

The intramolecular hydroamination reaction was inﬂuenced

greatly by the substitution pattern on the aminoalkene.

Typically, geminally disubstituted alkenes gave the shortest

reaction times and could be cyclized using just 2 mol % 1a

or 2-5 mol % 2. These substrates beneﬁted from a favorable

Figure 6. Effect of alkene substitution upon intramolecular hydroamination

catalysis.

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Gagne, M. R.; Marks, T. J. J. Am. Chem. Soc. 1994, 116, 10241. (g)

Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1996, 118, 707. (h) Li, Y.;

Marks, T. J. J. Am. Chem. Soc. 1996, 118, 9295. (i) Li, Y.; Marks,

T. J. Organometallics 1996, 15, 3770. (j) Roesky, P. W.; Stern, C. L.;

Marks, T. J. Organometallics 1997, 16, 4705. (k) Li, Y.; Marks, T. J.

J. Am. Chem. Soc. 1998, 120, 1757. (l) Arredondo, V. M.; McDonald,

F. E.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 4871. (m) Arredondo,

V. M.; Tian, S.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc.

1999, 121, 3633. (n) Tian, S.; Arrendondo, V. M.; Stern, C. L.; Marks,

T. J. Organometallics 1999, 18, 2568. (o) Arredondo, V. M.;

McDonald, F. E.; Marks, T. J. Organometallics 1999, 18, 1949. (p)

Ryu, J.-S.; Marks, T. J.; McDonald, F. E. Org. Lett. 2001, 3, 3091.

(q) Hong, S.; Marks, T. J. J. Am. Chem. Soc. 2002, 124, 7886. (r)

Douglass, M. R.; Ogasawara, M.; Hong, S.; Metz, M. V.; Marks, T. J.

Organometallics 2002, 21, 283. (s) Ryu, J.-S.; Li, G. Y.; Marks, T. J.

J. Am. Chem. Soc. 2003, 125, 12584. (t) Hong, S.; Kawaoka, A. M.;

Marks, T. J. J. Am. Chem. Soc. 2003, 125, 15878. (u) Ryu, J.-S.;

Marks, T. J.; McDonald, F. E. J. Org. Chem. 2004, 69, 1038.

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the conformational freedom of the aminoalkene, favoring

reactive conformations. Although rigorous quantitative kinetic

experiments were not performed, it can be seen from the data

in Figure 5 that for a given catalyst, both the loading and

reaction time decreased with increasing steric demand of the

geminal substituents.

Substitution about the CdC bond lengthened the reaction time

(Figure 6). Mono- and disubstitution at the terminal carbon

caused the hydroamination reaction to shut down completely

under the conditions utilized (Table 1, entries 12-15). It is likely

that increasing the substitution on the alkene raises the energy

of the transition state for M-C and C-N bond formation, not

only because of steric factors but also the formation of

energetically unfavorable transition-state structures with partial

2° and 3° group-2 alkyl character in the insertion step (see

(50) (a) Gribkov, D. V.; Hultzsch, K. C.; Hampel, F. Chem.sEur. J. 2003,

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J. Inorg. Chem. 2004, 4091. (e) Gribkov, D. V.; Hultzsch, K. C.;

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Chem. Soc. 2003, 125, 9560.

9

J. AM. CHEM. SOC. VOL. 131, NO. 28, 2009 9677

A R T I C L E S

Crimmin et al.

Figure 7. Effect of ring size on intramolecular hydroamination catalysis.

below). Similar observations have been made in organolan-

thanide chemistry, and a number of coordinatively unsaturated

half-sandwich organolanthanide catalysts have been designed

to effect the hydroamination/cyclization of highly substituted

aminoalkenes.^48n,p,u

membered-ring product in 88% yield, albeit in an exceedingly

slow reaction (5.5 days at 80 °C). While alternative scenarios

may be envisaged, this observation is likely an effect of the

relative stability of the two precatalysts 1a and 2, with the

magnesium species being more robust at higher temperatures.

Consistent with Baldwin’s guidelines for ring formation, the

ease of the catalytic reactions increases with decreasing ring

size (5 > 6 > 7).⁶³In all cases, more forcing reaction conditions

(higher reaction temperatures, higher catalyst loadings) were

required for the hydroamination/cyclization of aminoalkenes to

produce piperidines and hexahydroazepines (Figure 7). The last

case provided a notable exception to the trends in these catalytic

reactions. While calcium amide 1a proved ineffective in the

intramolecular hydroamination of 1-amino-2,2-diphenyl-6-hep-

tene, the magnesium catalyst 2 gave the corresponding seven-

Cyclization of aminoalkenes possessing two prochiral centers

potentially results in the formation of a mixture of diastereoi-

someric products. Although substitution at the ꢀ position of the

aminoalkene had little effect upon the diastereoselectivity of

the reaction (entry 9 in Table 1 gave a 1:1 mixture of

diastereoisomers), R-substituted aminoalkenes underwent dias-

tereoselective intramolecular hydroamination cyclization reac-

tions. Thus, the catalytic reactions of 1-amino-1-phenyl-4-

pentene and 2-amino-5-hexene with 1a or 2 yielded the

corresponding trans-pyrrolidines with diastereoisomeric excesses

of 90 or 98% (Table 1, entries 16-18) and 78 or 84% (Table

1, entries 19 and 20), respectively. The reaction of 1-amino-1-

phenyl-4-pentene with the magnesium-based catalyst 2 was

considerably slower, requiring 96 h to reach 72% conversion

at room temperature. Under the same reaction conditions,

calcium amide 1a effected the cyclization of this substrate in

under 2 h and in effectively quantitative yield, albeit with lower

diastereoisomeric excess. The relative stereochemistry of the

product was assigned by single-crystal X-ray diffraction of the

hydrochloride salt isolated by treatment of the product with HCl

in diethyl ether (see the Supporting Information). Similar trends

in the intramolecular hydroamination of R-substituted aminoalk-

enes have been observed for the organolanthanide series, and

the reaction of 2-amino-5-hexene with [{(C₅Me₄)₂SiMe₂}-

La{CH(SiMe₃)₂}] has been reported to yield an 8:1 trans/cis

mixture of heterocyclic products at 0 °C.^48dThe magnesium-

centered catalyst also provided the greater degree of diastereo-

differentiation in the cyclization of 2-amino-5-hexene, and it is

notable that for a given ligand set, the diastereoselectivity of

this reaction has also been shown to increase for the later,

smaller lanthanides.⁴⁸ⁿ

(52) (a) Burgstein, M. R.; Berberich, H.; Roesky, P. W. Organometallics

1998, 17, 1452. (b) Burgstein, M. R.; Berberich, H.; Roesky, P. W.

Chem.sEur. J. 2001, 7, 3078. (c) Roesky, P. W. Z. Anorg. Allg. Chem.

2003, 629, 1881. (d) Panda, T. K.; Zulys, A.; Gamer, M. T.; Roesky,

P. W. Organometallics 2005, 24, 2197. (e) Panda, T. K.; Zulys, A.;

Gamer, M. T.; Roesky, P. W. J. Organomet. Chem. 2005, 690, 5078.

(f) Meyer, N.; Zulys, A.; Roesky, P. W. Organometallics 2006, 25,

4179. (g) Rasta¨tter, M.; Zulys, A.; Roesky, P. W. Chem.sEur. J. 2007,

13, 3606. (h) Panda, T. K.; Hrib, C. G.; Jones, P. G.; Jenter, J.; Roesky,

P. W.; Tamm, M. Eur. J. Inorg. Chem. 2008, 4270.

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Scott, P. Chem. Commun. 2003, 1770. (b) O’Shaughnessy, P. N.; Scott,

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Gillespie, K. M.; Knight, P. D.; Munslow, I. J.; Scott, P. Dalton Trans.

2004, 2251.

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2003, 3048. (b) Collin, J.; Daran, J.-C.; Jacquet, O.; Schulz, E.;

Trifonov, A. Chem.sEur. J. 2005, 11, 3455. (c) Riegert, D.; Collin,

J.; Meddour, A.; Schulz, E.; Trifonov, A. J. Org. Chem. 2006, 71,

2514. (d) Riegert, D.; Collin, J.; Daran, J.-C.; Fillebeen, T.; Schulz,

E.; Lyubov, D.; Fukin, G.; Trifonov, A. Eur. J. Inorg. Chem. 2007,

1159. (e) Aillaud, I.; Collin, J.; Duhayon, C.; Guillot, R.; Lyubov,

D.; Schulz, E.; Trifonov, A. Chem.sEur. J. 2008, 14, 2189. (f)

Hannedouche, J.; Aillaud, I.; Collin, J.; Schulz, E.; Trifonov, A. Chem.

Commun. 2008, 3552.

(55) Gilbert, A. T.; Davies, B. L.; Emge, T. J.; Broene, R. D. Organome-

tallics 1999, 18, 2125.

The stereochemistry of reaction is most readily explained by

consideration of the energetically dissimilar transition states for

carbon-nitrogen bond formation in the insertion step. Of the

four seven-membered-ring transition states that can be envisaged

for the carbon-nitrogen bond-forming step (Figure 8), the

enantiomeric transition conformers A and D leading to the cis-

pyrrolidine possess a potentially destabilizing 1,3-diaxial steric

interaction. This latter conformation may raise the activation

energy for carbon-nitrogen bond formation and hence favor

the trans diastereoisomer via transition states B and C.^48dThe

higher degree of diastereodifferentiation observed for the

cyclization of 1-amino-1-phenyl-4-pentene for either 1a or 2

may be related to the greater steric demands of the 1-phenyl

substituent versus the 1-methyl one. In this regard, it appears

that substitution at the ꢀ position does not result in differentiation

of the transition states for carbon-nitrogen bond formation, as

such unfavorable diaxial interactions are not present. The

(56) (a) Xiang, L.; Wang, Q.; Song, H.; Zi, G. Organometallic 2007, 26,

5323. (b) Zi, G.; Xiang, L.; Song, H. Organometallics 2008, 27, 1242.

(c) Wang, Q.; Xiang, L.; Song, H.; Zi, G. Inorg. Chem. 2008, 47,

4319.

(57) (a) Hong, S.; Tian, S.; Metz, M. V.; Marks, T. J. J. Am. Chem. Soc.

2003, 125, 14768. (b) Yu, X.; Marks, T. J. Organometallics 2007,

26, 365. (c) Yuen, H. F.; Marks, T. J. Organometallics 2008, 27, 154.

(58) (a) Motta, A.; Lanza, G.; Fragala`, I. L.; Marks, T. J. Organometallics

2004, 23, 4097. (b) Tobisch, S. J. Am. Chem. Soc. 2005, 127, 11979.

(c) Tobisch, S. Chem.sEur. J. 2006, 12, 2520. (d) Motta, A.; Fragala`,

I. L.; Marks, T. J. Organometallics 2006, 25, 5533. (e) Tobisch, S.

Chem.sEur. J. 2007, 13, 9127. (f) Hunt, P. Dalton Trans. 2007, 1743.

(59) (a) Stubbert, B. D.; Stern, C. L.; Marks, T. J. Organometallics 2003,

22, 4836. (b) Stubbert, B. D.; Marks, T. J. J. Am. Chem. Soc. 2007,

129, 4253. (c) Stubbert, B. D.; Marks, T. J. J. Am. Chem. Soc. 2007,

129, 6149. (d) Andrea, T.; Eisen, M. S. Chem. Soc. ReV. 2008, 37,

550.

(60) Ackermann, L.; Althammer, A. Synlett 2008, 995.

(61) Jung, M. E.; Piizii, G. Chem. ReV. 2005, 105, 1735.

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9

9678 J. AM. CHEM. SOC. VOL. 131, NO. 28, 2009

Intramolecular Hydroamination of Aminoalkenes

A R T I C L E S

Figure 8. Four possible transition states A-D for the hydroamination/cyclization of 1-amino-1-phenyl-2-pentene and 2-amino-5-hexene.

Scheme 3. Reaction Products from the Hydroamination/Cyclization of 1-Amino-5-hexenes with 1a

improved diastereoselectivity in the case of the magnesium

catalyst can be similarly attributed to the shorter M-N and

M-C bond lengths in magnesium-containing complexes than

in calcium-containing ones, tightening the transition state of the

insertion reaction in the former and therefore increasing any

effects exerted by nonbonding interactions.

lecular proton transfer (Scheme 3). Subsequent σ-bond metath-

esis (protonolysis) of this latter species with a further equivalent

of amine may regenerate the starting materials or yield the

alkene isomerization product.

It is noteworthy that under these catalytic conditions, the

isomerization products do not undergo subsequent catalyzed

intramolecular hydroamination. Furthermore, no such byproducts

were observed when catalytic reactions were conducted with

the magnesium complex 2. The isomerization products were

observed as single geometric isomers that were assigned as trans

These data suggest that the scope of group-2-mediated

intramolecular hydroamination catalysis is dictated by stereo-

electronic effects. While the nature of the metal dication and

auxiliary coordination at the metal is undoubtedly important,

the facility of substrate cyclization appears to depend upon the

ease with which a reactive conformation can be obtained as the

alkene approaches the metal center. In the case of the cycliza-

tions of 1-amino-2,2-dimethyl-5-hexene and 1-amino-2,2-di-

phenyl-5-hexene catalyzed by 10 mol % 1 in C₆D₆at room

temperature, in addition to the expected intramolecular hy-

droamination products (Table 1, entries 17 and 20), the

corresponding alkene isomerization byproducts trans-1-amino-

2,2-dimethyl-4-hexene (14% yield) and trans-1-amino-2,2-

3

on the basis of J_1H-1Hvalues, with 1-amino-2,2-diphenyl-2-

hexene and 1-amino-2,2-dimethyl-2-hexene both possessing 13.5

Hz coupling constants for the proton resonances of the 1,2-

disubstituted alkene. This stereochemistry was unambiguously

deﬁned by an independent synthesis of 1-amino-2,2-diphenyl-

2-hexene and may be rationalized in terms of either a reversible

reaction (forming the most thermodynamically stable alkene)

or protonolysis of the pro-trans intermediate allyl complex

represented in Scheme 3.

1

diphenyl-4-hexene (12% yield) were identiﬁed by H NMR

Alkene isomerization byproducts were also observed during

the cyclization of N-allyl-1-amino-4-pentene catalyzed by 10

mol % 1a in C₆D₆. In this instance, both cis- and trans-3 were

apparent on the basis of ¹H NMR spectroscopy (13% yield, 1:4.5

cis/trans), as characterized by a series of high-ﬁeld enamide

resonances [trans-3, 4.22 (dq, 1H, J ) 6.4, 12.4 Hz); cis-3,

4.42 (dq, 1H, J ) 7.0, 8.9 Hz). NMR monitoring of the reaction

revealed that the concentration of these species began to increase

only at longer reaction times. As with the byproducts observed

from the hydroamination of 1-amino-5-hexenes, isomerization

may occur via an intramolecular proton transfer, albeit in this

case from the transient metal alkyl intermediate, followed by

protonolysis with a further equivalent of aminoalkene (Scheme

4). In this regard, it is possible that as the substrate is depleted,

the rate of isomerization increases relative to the rate of σ-bond

metathesis of the intermediate alkyl complex with a further

equivalent of aminoalkene. Thus, isomerization products are

only observed at higher substrate conversion, and their formation

is likely to be highly dependent upon the initial substrate and

catalyst concentrations. Marks and co-workers have reported

that N-allyl-1-amino-4-pentene undergoes an organolanthani-

spectroscopy (Scheme 3). Monitoring of the reaction of 1-amino-

2,2-diphenyl-5-hexene with 1a by ¹H NMR spectroscopy

revealed that the isomerization occurred in tandem with the

hydroamination, suggesting that both products are derived from

the aminoalkene rather than further reaction of the hydroami-

nation products (see Figure S5 in the Supporting Information).

Although unprecedented in organolanthanide(III) chemistry and

not reported by Roesky and co-workers during the application

of aminotropinoate calcium and strontium complexes to hy-

droamination catalysis, alkene isomerization products have been

observed during Na/K alloy- and n-BuLi-catalyzed intramo-

lecular hydroaminations of 1-amino-4-pentenes.³²For the reac-

tions presented herein, the byproduct may be rationalized in

terms of stereoelectonic effects: following precatalyst initiation

to form a ꢀ-diketiminate calcium amide intermediate (see

below), these reactions may proceed via either (i) an eight-

membered-ring transition state yielding the hydroamination

cyclization product via insertion of the alkene into the

metal-nitrogen bond or (ii) a boatlike six-membered-ring

transition state leading to a group-2 allyl species via intramo-

9

J. AM. CHEM. SOC. VOL. 131, NO. 28, 2009 9679

A R T I C L E S

Crimmin et al.

Scheme 4. Reaction Products from the Hydroamination/Cyclization of N-Allyl-1-amino-4-pentene with 1a

Scheme 5. Reaction of 1a with Primary Amines

Scheme 6. Reactions of 2 with Primary and Secondary Amines

de(III)-mediated tandem hydroamination/cyclization reaction to

form the bicyclic product 4.^48gThe catalytic reaction of N-allyl-

1-amino-4-pentene with 1a has not been studied at higher

temperatures or low substrate concentrations, and it remains

possible that the bicyclic product 4 may be formed under

different reaction conditions.

The σ-Bond Metathesis (Protonolysis) Step. By analogy to

the mechanism for organolanthanides, the ﬁrst step of the

proposed mechanism of the alkaline-earth-mediated intramo-

lecular hydroamination involves the reaction of the precatalyst,

1a or 2, with the aminoalkene to form a group-2 primary amide

species (Figure 2). Our understanding of the catalytic hydroami-

nation reaction was enhanced through further consideration of

our previously reported studies of the stoichiometric reaction

of 1a with a range of primary amines and anilines.^30,64

We reported previously that the reaction of 1a with benzyl-

amine is reversible and forms a quantiﬁable dynamic equilib-

rium, as depicted in Scheme 5. Through pulsed-gradient spin-

echo (PGSE) NMR experiments, it was shown that the isolated

reaction product 5 [i.e., in the absence of HN(SiMe₃)₂], which

was characterized by X-ray crystallography, retains a dimeric

constitution in solution. A van’t Hoff analysis of the equilibrium

mixture was conducted, and the concentrations of 1a, 5, and

1

benzylamine were measured by H NMR using TMSS as an

internal standard, allowing ∆H° and ∆S° for the forward process

depicted in Scheme 5 to be calculated as -12.2 kcal mol^-1and

-32 cal K^-1mol^-1, respectively, thereby leading to the

64b

derivation of ∆G°(298 K) as -2.7 kcal mol^-1

.

A further reaction of 1a with the potentially bidentate species

2-methoxyethylamine resulted in quantitative formation of the

corresponding calcium primary amide 6 (Scheme 5),^64adem-

onstrating that under certain conditions the position of the amine/

amide equilibrium may be perturbed signiﬁcantly to one side.

Again through detailed studies of its solution dynamics and

X-ray crystallography, we showed that compound 6 maintains

its dimeric constitution in solution and in the solid state. In C₆D₆

solution, 6 was characterized by a distinctive resonance for the

calcium amide proton, which occurred as a heavily shielded

triplet at -1.63 ppm and in the current context provided a useful

model for the initial primary amide σ-bond metathesis product

(64) (a) Avent, A. G.; Crimmin, M. R.; Hill, M. S.; Hitchcock, P. B. Dalton

Trans. 2004, 3166. (b) Barrett, A. G. M.; Crimmin, M. R.; Hill, M. S.;

Kociok-Ko¨hn, G.; Lachs, J. R.; Procopiou, P. A. Dalton Trans. 2008,

1292. (c) Barrett, A. G. M.; Casely, I. J.; Crimmin, M. R.; Hill, M. S.;

Lachs, J. R.; Mahon, M. F.; Procopiou, P. A. Inorg. Chem. 2009, 48,

4445.

9

9680 J. AM. CHEM. SOC. VOL. 131, NO. 28, 2009

Intramolecular Hydroamination of Aminoalkenes

A R T I C L E S

Scheme 7. Stoichiometric Reaction of 1a and 2 with 1-Amino-2,2-diphenyl-4-pentene

from the reaction of 1a with primary aminoalkenes (see below).

A similar stoichiometric reaction of 1a with 2,6-diisopropyla-

niline cleanly gave the corresponding calcium primary anilide

[{ArNC(Me)CHC(Me)NAr}Ca(NHAr){THF}] (7 in Scheme

5).³⁰This latter compound illustrated the potential for solution

redistribution observed in catalytic hydroamination reactions

conducted with 1a and proved to be unstable toward a

(nonreversible) equilibration in solution to give [{ArNC(Me)-

CHC(Me)NAr}₂Ca] (∼30% conversion after 20 days at room

temperature) and the precipatation of an insoluble material

assumed to be polymeric/oligomeric calcium anilide or imide

species. In related studies, Harder and co-workers demonstrated

that 1a reacts with ammonia to form the corresponding metal

amide/amine complex [{ArNC(Me)CHC(Me)NAr}Ca(NH₂)-

(NH₃)₂]₂, which exhibits facile intramolecular interconversion

elevated temperatures and/or over long reaction times, the

heteroleptic calcium primary amide compounds show a pro-

pensity to undergo deleterious Schlenk-like equilibria. No such

equilibria are observed for magnesium complexes.

When this study began, previous examples of heavier alkaline-

earth primary amides reported in the literature remained conﬁned

to polymeric species that are soluble only in liquid ammonia.⁶⁵

Although several reports have since documented the synthesis

and characterization of heavier group-2 primary amide com-

plexes,⁶⁶the examples discussed herein are well-deﬁned hy-

drocarbon-soluble compounds that provide useful models for

the intermediacy of heteroleptic calcium amide species in the

intramolecular hydroamination of aminoalkenes with 1a.

The Insertion Step. Because of the instability of the proposed

group-2 alkyl intermediate under catalytic reaction conditions,

speciﬁcally in the presence of N-H bonds, the nature of the

insertion step is more challenging to investigate through

stoichiometric reaction studies. Nevertheless, a series of reac-

tions of the catalysts 1a and 2 with 1-amino-2,2-diphenyl-4-

pentene and (1-allylcyclohexyl)methylamine-d₂were conducted.

The stoichiometric reaction of 1a with 1-amino-2,2-diphenyl-

4-pentene in C₆D₆yielded a mixture apparently containing the

catalyst starting material and 2-methyl-4,4-diphenylpyrrolidine,

which arose from the intramolecular hydroamination reaction,

as monitored by ¹H NMR (Scheme 7). This experimental

observation can be explained by considering that the reversible

σ-bond metathesis step occurs with the liberation of HN(SiMe₃)₂.

Following the cyclization, the alkylmetal intermediate may react

with HN(SiMe₃)₂to reform the catalyst 1a and liberate the

hydroamination/cyclization product.

In order to isolate the metal-bound insertion product, the initial

σ-bond metathesis step must be nonreversible. Such conditions are

met with the heteroleptic magnesium alkyl complex 2. The methane

byproduct from the initiation step is a volatile gas that is

insufﬁciently acidic to undergo proton transfer under these reaction

conditions and, once produced, plays no further part in the reaction.

A stoichiometric reaction between 2 and 1-amino-2,2-diphenyl-

4-pentene in C₆D₆, therefore, gave the corresponding cyclic

magnesium amide 11 in near-quantitative yield (Scheme 7).

Complex 11 was characterized by ¹H and ¹³C NMR, including

COSY, NOESY, and PGSE NMR experiments. The PGSE

experiments conﬁrmed that 11 is a single compound in solution,

not a mixture of pyrrolidine and catalyst, and gave a single value

for the diffusion coefﬁcient in C₆D₆. Importantly, the multi-

nuclear NMR data are consistent with those acquired for not

only the recently reported solvent-free complex formed upon

reaction of [{ArNC(Me)CHC(Me)NAr}Mg(^n/sBu)] with 2-meth-

yl-4,4-diphenylpyrrolidine in C₆D₆solution^64cbut also the

isoelectronic cationic scandium complex [{ArNC(Me)CHC(Me)-

NAr}Sc{N(CH(Me)CH₂CPh₂CH₂)}]⁺[MeB(C₆F₅)₃]^-reported

by Piers, Schafer, and co-workers in the context of intramo-

lecular hydroamination catalysis.³⁴The connectivity of the

amide moiety was conﬁrmed by the COSY experiments. The

¹H resonances of the magnesium-bound heterocycle were shifted

1

of the amine and amide ligand sets as evidenced by H NMR

spectroscopy.^29f

Similarly, an easily prepared analogue of 2, [{ArNC(Me)-

CHC(Me)NAr}MgBu^n/s], reacts with 2-methoxyethylamine and

benzylamine at room temperature to yield the corresponding

magnesium amide complexes (8 and 9 in Scheme 6). In this

1

instance, although monitoring of the reactions by H NMR

spectroscopy revealed complete conversion to the products by

the ﬁrst point of analysis (20 min) at room temperature, these

σ-bond metathesis reactions were found to be nonreversible,

proceeding with liberation of alkane byproducts, which played

no further part in the reactivity. A further reaction of

[{ArNC(Me)CHC(Me)NAr}MgBu^n/s] with the isolated hy-

droamination product 2-methyl-4,4-diphenylpyrrolidine provided

the model complex 10, which in turn was used in the

investigation of the insertion step (see below). These studies

suggest that while 8 and 9 are dimeric in solution and the solid

state, complex 10 retains a monomeric constitution at room

temperature in hydrocarbon solutions.^64c

This series of experiments demonstrated several important

features of the group-2-mediated hydroamination catalysis: (i)

σ-Bond metathesis reactions of amines with 1a or 2 are facile,

with the reaction of 1a with benzylamine occurring with

negative Gibbs’ free energy of ∆G° ) -2.7 kcal mol^-1at room

temperature. (ii) This reaction may be reversible, and the

potential exists to form equilibrium mixtures of the form LMX¹

+ HX²a LMX²+ HX¹when the species HX¹has a pK_avalue

similar to that of HX². (iii) Compound 5 was shown to undergo

fast external amine/amide exchange in the presence of an excess

of benzylamine. (iV) Intramolecular site exchange between

amine and amide ligands was observed by Harder and co-

workers in [{ArNC(Me)CHC(Me)NAr}Ca(NH₂)(NH₃)₂]₂(Ar )

2,6-diisopropylphenyl), and NMR studies yielded an activation

29f

Gibbs free energy of ∆G^q) 11.3 ( 0.1 kcal mol^-1

,

which

compares favorably to the value of 12.0 ( 0.1 kcal mol^-1

reported by Marks and co-workers for [(Cp*)La(NHMe)-

(NH₂Me)].^48d(V) For reactions with simple unbranched primary

amines, dimeric products are observed in solution and the solid

state for both magnesium and calcium analogues. (Vi) At

9

J. AM. CHEM. SOC. VOL. 131, NO. 28, 2009 9681

A R T I C L E S

Crimmin et al.

Scheme 8. Catalytic Reaction of 1a or 2 with (1-Allylcyclohexylmethyl)amine-d₂

noticeably upﬁeld from those in the free pyrrolidine, with those

adjacent to the amide nitrogen exhibiting the strongest effect.

This experiment suggests that the alkyl intermediate is not

long-lived in the catalytic cycle and readily forms the more

stable alkaline-earth amide by either an intra- or intermolecular

σ-bond metathesis (or protonolysis) reaction. In order to infer

the formation of the alkyl complex, deuterium-labeling experi-

ments were conducted. Thus, catalytic reactions of (1-allylcy-

clohexyl)methylamine-d₂(>95% deuteration) with 1a and 2 in

C₆D₆solutions not only provided evidence for the formation of

the alkyl intermediate but also demonstrated that no further

proton migration steps or ligand activation reactions occurred

under the catalytic conditions. In both cases, exclusive deutera-

tion of the exocyclic methyl group, characterized by a 1:1:1

that alkene coordination (and polarization) is required to effect

the insertion, and this requires a vacant “coordination site” at

the metal.

With the use of steady-state theory and neglecting the effect

of THF, the rate law presented in Figure 11 can be derived. In

this simpliﬁed model, the reaction rate is dictated by catalytic

turnover governed by a rate-determining intramolecular insertion

reaction of intermediate B. The substrate and product both

effectively inhibit catalytic turnover by formation of A and A′,

and on the basis of the acquired linear plots of log[aminoalkene]

versus time (Figures 9 and 10), the effect of the product can be

assumed to be approximately equal to the effect of the substrate.

Thus, it may be concluded that the rate of the reaction should

increase with increasing initial catalyst concentration and

increasing amine dissociation rate constant k_dand decrease with

increasing initial substrate concentration and increasing amine

association rate constant k_a.

triplet resonance at 21.3 ppm in the ¹³C NMR spectrum (¹J

¹³C-D

) 19.3 Hz), was observed, consistent with deuteronolysis of

an intermediate group-2 alkyl complex (Scheme 8). Reactions

conducted at high catalyst loadings (25 mol %) also revealed

that no deuteration of the ꢀ-diketiminate ligand occurred during

catalytic turnover, consistent with the latter species acting solely

as a spectator during hydroamination catalysis.⁶⁷

Kinetic Studies. Once it had been established that intramo-

lecular hydroamination reactions catalyzed by the magnesium

alkyl complex 2 proceed via fast, nonreversible catalyst initia-

tion, further kinetic studies were undertaken to determine the

effect of the catalyst and substrate concentrations upon the

reaction rate. Reactions of (1-allylcyclohexyl)methylamine with

2 with either variable catalyst concentration at constant substrate

concentration or variable substrate concentration at constant

catalyst concentration were monitored by ¹H NMR spectroscopy.

NMR-scale reaction mixtures were prepared in C₆D₆solution

in a glovebox, instantly frozen to 193 K, and then thawed and

transferred directly to the NMR spectrometer. The results of

these experiments are presented in Figures 9 and 10.

The reaction rate increased linearly with increasing catalyst

concentration, indicating that the reaction is ﬁrst-order in 2

(Figure 9). The data acquired at 283 K provided a good ﬁt over

the 10-50 mM catalyst concentration range relevant to the

experiments presented in Table 1. While similar ﬁrst-order data

were observed at 298 K, at higher temperatures (313 and 328

K) the reactions became too rapid to monitor effectively over

the same concentration range using ¹H NMR spectroscopy. This

difﬁculty prevented further data analysis and left the authors

reluctant to quantify these data.

Although Marks also proposed a similar model as a candidate

to explain the reactivity, it was argued that the observed kinetic

isotope effects, k_H2/k_D2[2.7(4) for 1-amino-4-pentene at 60 °C;

5.2(8) for 1-amino-1-methyl-4-pentene at 25 °C; 4.1(8) for

1-amino-2,2-dimethyl-4-pentene at 25 °C], militate against rate-

determining alkene insertion occurring from a coordinatively

unsaturated lanthanide amide species.^48dFor group-2 catalysis

occurring with nonreversible catalyst initation, the studies

detailed herein provide a weight of evidence for rate-determining

alkene insertion with similar rates of reaction inhibition by

substrate and product. It may be envisioned that catalytic

turnover is occurring from a coordinatively unsaturated com-

pound, i.e., through dissociation from [L_nM(NHR)S_n] to form

[L_nM(NHR)S_n-1] (S ) Lewis base).

Proposed Mechanism. On the basis of these data, it is now

possible to present a clearer picture of hydroamination catalysis

mediated by group-2 diketiminate complexes. It is proposed that

the two catalyst systems described herein give rise to two

independent catalytic cycles occurring with (a) nonreversible

and (b) reversible catalyst initiation for 2 and 1a, respectively

(Figures 12 and 13).

For nonreversible initiation, the kinetic analysis suggests rate-

limiting alkene insertion, and while the complexity of the system

proceeding with reversible catalyst initiation precluded such

studies for that case, similar rate-determining insertion is

expected by analogy. Further anecdotal evidence for this model

is provided by the observed Thorpe-Ingold effect on cycliza-

tion, the fact that the ease of cyclization followed Baldwin’s

guidelines (5 > 6 > 7), and the dramatic effect of alkene

substitution upon the reaction, all of which are more easily

explained by rate-determining alkene insertion than rate-limiting

protonolysis. Rate-limiting protonolysis also seems unlikely in

light of the fast and potentially reversible σ-bond metathesis

reactions of group-2 alkyls and amides with amines documented

herein.

In line with the ﬁndings of Hultzsch and co-workers,^50ethe

reaction of (1-allylcyclohexyl)methylamine catalyzed by 2 at

constant catalyst concentration at 298 K in C₆D₆showed a

dependence upon the initial substrate concentration, with the

reaction rate increasing with decreasing initial concentration of

the substrate (Figure 10). This behavior is not consistent with

a rate-determining σ-bond metathesis reaction step but rather

indicates substrate/product inhibition of catalysis of the rate-

determining alkene insertion step. Thus, it may be considered

9

9682 J. AM. CHEM. SOC. VOL. 131, NO. 28, 2009

Intramolecular Hydroamination of Aminoalkenes

A R T I C L E S

Figure 9. Plots of (a) log[aminoalkene] vs time for a series of different concentrations of 2 and (b) k_obsvs [2]. Data were collected with [aminoalkene]₀)

0.6 M at 283 K in C₆D₆.

1a and monomeric and/or dimeric calcium amide species

(exempliﬁed by the model complexes 5-7). Indeed, for many

reactions, primary amide complexes were observed, as

evidenced by the presence of a highly shielded NH resonance

occurring at high ﬁeld in the ¹H NMR spectra (-0.5 to -1.7

ppm). Speciﬁcally, in the attempted intramolecular hydroami-

nation of 1-amino-2,2-diphenyl-6-heptene with 1a, for which

no conversion to the reaction product was recorded, high

catalyst loadings led to the observation of a broad resonance

at -1.72 ppm, which compares well to the value of -1.63

ppm reported for 6. For nonreversible catalyst initiation

(Figure 12), the catalyst resting state may lie with either

monomeric or dimeric primary amide complexes. Despite the

formation of dimeric complexes as catalyst resting states,

Figure 10. Inhibition kinetics: Plot of log[aminoalkene] vs time for different

substrate concentrations at a constant [2] of 25 mM at 298 K.

on the basis of the coordination chemistry of 10 along with

For reversible catalyst initiation (Figure 13), the stoichio-

metric studies suggest that the catalyst resting state is

characterized by an equilibrium mixture partitioned between

(65) (a) Juza, R. Angew. Chem. 1964, 76, 290. (b) Juza, R.; Schumacher,

H. Z. Anorg. Allg. Chem. 1963, 324, 278. (c) Kaupp, M.; Schleyer, P.

v. R. J. Am. Chem. Soc. 1992, 114, 491.

9

J. AM. CHEM. SOC. VOL. 131, NO. 28, 2009 9683

A R T I C L E S

Crimmin et al.

Figure 11. Proposed model for hydroamination catalysis mediated by 2.

Figure 12. Proposed mechanism of group-2-mediated intramolecular hydroamination catalysis for nonreversible catalyst initiation.

the ﬁrst-order behavior with respect to catalyst, we propose

that catalytic turnover occurs from discrete monomeric

species and that the formation of dimeric group-2 amide

complexes is simply a nonreactive pathway in the catalytic

cycle.

and M(X¹)₂, and (iii) coordinative saturation of intermediate

species by auxiliary Lewis bases such as THF, substrate, or

product.

Summary and Conclusions

The ꢀ-diketiminate-stabilized calcium amide 1a and its

magnesium analogue 2 are reported to be efﬁcient precatalysts

for hydroamination/cyclization of aminoalkenes. The reactions

proceed under mild conditions, allowing the synthesis of ﬁve-,

six-, and seven-membered heterocyclic products. Qualitative

assessment of these reactions has revealed that the ease of

catalytic turnover increases (i) for smaller ring sizes (5 > 6 >

7), (ii) substrates that beneﬁt from favorable Thorpe-Ingold

effects, and (iii) substrates that do not possess additional

substitution on the alkene component. Extension of this

chemistry to the known strontium and barium analogues 1b and

1c was not undertaken because of the propensity of these species

to undergo deleterious Schlenk-like solution equilibria to form

ill-deﬁned mixtures under catalytically relevant conditions. In

this regard, it is apparent that the kinetic stabilization provided

Hence, it becomes apparent that there are several mech-

anisms for inhibiting catalytic turnover, involving either

formation of organometallic intermediates that are no longer

able to re-enter the catalytic cycle or inhibition of the rate-

limiting step. Important reactions include (i) dimerization of

intermediate metal amide species, (ii) deleterious Schlenk-

like equilibria that form homoleptic species of the form L₂M

(66) (a) Ga¨rtner, M.; Go¨rls, H.; Westerhausen, M. Inorg. Chem. 2007, 46,

7678. (b) Ga¨rtner, M.; Go¨rls, H.; Westerhausen, M. Dalton Trans.

2008, 1574.

(67) It has previously been reported that the exocyclic methyl groups of

the ꢀ-diketiminate ligand may undergo C-H activation in the presence

of a calcium-benzyl σ bond. See: Harder, S. Angew. Chem., Int. Ed

2003, 42, 3430.

9

9684 J. AM. CHEM. SOC. VOL. 131, NO. 28, 2009

Intramolecular Hydroamination of Aminoalkenes

A R T I C L E S

Figure 13. Proposed mechanism of group-2-mediated intramolecular hydroamination catalysis for reversible catalyst initiation.

by the diketiminate ligand to the calcium and magnesium species

is of vital importance.

the heavier alkaline earths of the form LMX (M ) Mg, Ca, Sr,

Ba) in solution, have dramatic effects on reactivity. In contrast

to the situation for the trivalent organolanthanides, the reaction

rates and selectivity cannot be considered simply in terms of

increasing ionic radius that decreases the coordinative saturation

at the metal center. We are continuing to study the reaction

chemistry of organometallic compounds of the heavier alkaline

earths and will report our ﬁndings in subsequent publications.

In organolanthanide(III)-mediated hydroamination catalysis,

the effect of ionic radius on reaction kinetics is well-documented.

For a given substrate, intramolecular hydroamination with a

given precatalyst proceeds at lower rates with decreasing size

of the metal ionic radius as a result of the greater degree of

coordinative saturation at the electrophilic metal center, which

increases the energy of the transition state for the rate-

determining insertion step. As such, the choice of metal, with

consideration of the lanthanide contraction, may be used as

means of tuning the reactivity/selectivity of the catalyst. In

contrast to the relatively small change in ionic radius of M³⁺in

crossing the period from lanthanum to lutetium (19.9%),⁶²there

is a drastically large change in the M²⁺ionic radius (87.5%) in

descending group-2 from magnesium to barium.⁶²The effect

of metal radius upon reaction rate in the group-2 system is

evidently more complex. Although the results presented herein

suggest that the calcium complex 1a is superior to the

magnesium analogue 2 as a catalyst, further studies in our group

and that of Roesky have demonstrated that this trend does not

extend neatly to strontium.^23,25It is clear that large variations

in the size and resultant charge density of M²⁺, as well as

Schlenk-like redistribution and/or aggregation of complexes of

Acknowledgment. We thank GlaxoSmithKline for the generous

endowment (to A.G.M.B.), the Royal Society for a University

Research Fellowship (to M.S.H.) and the Royal Society Wolfson

Research Merit Award (to A.G.M.B.), and the Engineering and

Physical Sciences Research Council and GlaxoSmithKline for

generous support of our studies. We also thank the referees for

their insightful comments, which have signiﬁcantly enhanced the

quality of our manuscript.

Supporting Information Available: Full experimental details

and details of the X-ray analysis of the (()-trans-1-phenyl-4-

methylpyrrolidine ·HCl cyclization product (CIF). This material

is available free of charge via the Internet at http://pubs.acs.org.

JA9003377

9

J. AM. CHEM. SOC. VOL. 131, NO. 28, 2009 9685

Article Doi

Intramolecular hydroamination of aminoalkenes by calcium and magnesium complexes: A synthetic and mechanistic study

DOI: 10.1021/ja9003377

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Article abstract of DOI:10.1021/ja9003377

Full text of DOI:10.1021/ja9003377

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