Mechanism of the Platinum(II)-Catalyzed Hydroamination of 4-Pentenylamines

Article abstract of DOI:10.1021/acs.organomet.5b00821

The mechanism of the platinum(II)-catalyzed intramolecular hydroamination of benzyl 4-pentenylamines has been evaluated under stoichiometric and catalytic conditions. Reaction of a benzyl 2,2-disubstituted 4-pentenylamine with [(PPh₃)Pt(μ-Cl)Cl]₂ forms a thermally sensitive platinum amine complex that undergoes irreversible, intramolecular ligand exchange with the pendant C=C bond to form a reactive platinum π-alkene complex. The π-alkene complex undergoes rapid, outer-sphere C-N bond formation, evidenced by the anti addition of Pt and N across the complexed C=C bond, to form a thermally stable zwitterionic platinamethylpyrrolidinium complex. The zwitterionic complex is rapidly and exergonically deprotonated by free amine to form a neutral, bicyclic azaplatinacyclobutane complex that likely exists as a discrete 1:1 adduct with ammonium salt in the nonpolar reaction medium and that represents the resting state of the catalytic cycle. Turnover-limiting intramolecular protodemetalation of the azaplatinacyclobutane-ammonium adduct followed by ligand exchange releases the 2-methylpyrrolidine product.

Full text of DOI:10.1021/acs.organomet.5b00821

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Article
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Mechanism of the Platinum(II)-Catalyzed Hydroamination
of 4‑Pentenylamines
Christopher F. Bender, Timothy J. Brown, and Ross A. Widenhoefer*
Department of Chemistry, French Family Science Center, Duke University, Durham, North Carolina 27708-0346, United States
S
* Supporting Information
ABSTRACT: The mechanism of the platinum(II)-catalyzed
intramolecular hydroamination of benzyl 4-pentenylamines has
been evaluated under stoichiometric and catalytic conditions.
Reaction of a benzyl 2,2-disubstituted 4-pentenylamine with
[(PPh3)Pt(μ-Cl)Cl]2 forms a thermally sensitive platinum amine
complex that undergoes irreversible, intramolecular ligand
exchange with the pendant CC bond to form a reactive
platinum π-alkene complex. The π-alkene complex undergoes
rapid, outer-sphere C−N bond formation, evidenced by the anti
addition of Pt and N across the complexed CC bond, to form
a thermally stable zwitterionic platinamethylpyrrolidinium
complex. The zwitterionic complex is rapidly and exergonically
deprotonated by free amine to form a neutral, bicyclic
azaplatinacyclobutane complex that likely exists as a discrete 1:1 adduct with ammonium salt in the nonpolar reaction medium
and that represents the resting state of the catalytic cycle. Turnover-limiting intramolecular protodemetalation of the
azaplatinacyclobutane−ammonium adduct followed by ligand exchange releases the 2-methylpyrrolidine product.
INTRODUCTION
■
The catalytic addition of the N−H bond of an amine across a
C−C multiple bond has attracted considerable attention as a
potentially expedient and atom-economical route to the
synthesis of acyclic amines and nitrogen heterocycles.1 Of the
myriad permutations of catalytic hydroamination, the addition of
the N−H bond of an unprotected alkylamine across an
Cu(II),17 Zn(II),18,19 Pt-NHC,20 and Pt(II) o-biphenylphos-
unactivated CC bond represents one of the most challenging
phine complexes have been disclosed.21
Experimental investigations of alkene hydroamination cata-
and synthetically desirable variants, and most of the progress in
this area has been realized in the context of the intramolecular
hydroamination of amino alkenes.2 Although the intramolecular
lyzed by late transition metal complexes have established
mechanisms involving either alkene insertion into the M−N
hydroamination of amino alkenes is catalyzed efficiently by rare
bond of a metal amido complex (inner sphere) or addition of the
earth,3 alkaline earth,4 and group 45 metal complexes, the
nucleophile to the coordinated CC bond of a metal alkene
synthetic utility of these methods is compromised by the poor
functional group compatibility and high air and moisture
sensitivity of the catalysts. Brønsted acids also catalyze the
complex (outer sphere).10,11,15,16,19,22−26 However, only a small
subset of these mechanistic investigations involves the hydro-
amination of nonconjugated, electronically unactivated alkenes
with alkylamines and, of these,10,11,15,16,19 most lack the direct
intramolecular hydroamination of amino alkenes, albeit under
forcing conditions.6
observation of catalytically relevant intermediates and/or
information regarding the stereochemistry of C−N bond
Owing to the limitations associated with early transition metal
or Brønsted acid catalyzed hydroamination of amino alkenes,
there has been considerable interest in the development of late
transition metal catalysts for the intramolecular hydroamination
of alkenes with alkylamines.1 The first headway toward this
objective was made by Bender and Widenhoefer, who described
the intramolecular hydroamination of γ- and δ-alkenylamines
catalyzed by a 1:2 mixture of Zeise’s dimer and PPh3 (eq 1).7,8
Since this time, effective methods for the intramolecular hydro-
amination of amino alkenes catalyzed by Rh(I),9−14 Ir(I),14−16
formation. A notable exception is Hartwig’s investigation of
intramolecular hydroamination of primary and secondary
4-pentenyl amines catalyzed by a rhodium mono(phosphine)
complex, which established rhodium π-alkene resting states that
were consumed via rapid and reversible outer-sphere C−N bond
formation followed by turnover-limiting protodemetalation.10,11
Received: September 27, 2015
© XXXX American Chemical Society
A
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Although the reactions of alkylamines with platinum π-alkene
complexes have been investigated,27−40 the systems under
investigation were not competent hydroamination catalysts.
Rather, extant studies of platinum-catalyzed alkene hydro-
amination are restricted to transformations employing less
basic nitrogen nucleophiles. Mayer and Michael have inves-
tigated the mechanism of the platinum-catalyzed intramolecular
hydrohydrazination of alkenes and proposed a pathway involving
inner-sphere C−N bond formation, although there was no direct
experimental information to support this contention.41 Tilley has
studied the mechanism of the intermolecular hydroamination of
norbornene with sulfonamides catalyzed by electron-deficient
platinum bis(triflate) complexes and identified a Brønsted acid
catalyzed pathway involving protonation of norbornene with a
platinum−sulfonamide complex.42 Poli has investigated the
intermolecular hydroamination of ethylene with aniline catalyzed
by PtBr2 both experimentally and computationally and has
proposed mechanisms involving outer-sphere addition of aniline
on a platinum ethylene complex.43
Scheme 1
Herein we report the mechanistic analysis of the platinum-
catalyzed intramolecular hydroamination of the benzyl 2,2-
disubstituted 4-pentenylamines 1 to form pyrrolidines 2 (eq 1).44
This study includes the synthesis and evaluation of potential
intermediates, stereochemical analysis of C−N bond formation,
identification of the catalyst resting state and turnover-limiting
step, and kinetic and spectroscopic analysis of catalytically active
mixtures. These data support a mechanism involving outer-
sphere C−N bond formation and turnover-limiting proto-
demetalation of a bicyclic azaplatinacyclobutane complex.
Scheme 2
RESULTS AND DISCUSSION
■
Synthesis of N-Bound Platinum 4-Pentenylamine
Complexes 4. To gain insight into the mechanism of the
platinum(II)-catalyzed intramolecular hydroamination of
4-pentenylamines 1, we analyzed the stoichiometric reactions
of 1 with the chloride-bridged phosphine dimer [(PPh3)Pt(μ-
Cl)Cl]2 (3). Alkene-free dimer 3,45 which is also an active
hydroamination catalyst, was employed in preference to Zeise’s
dimer to avoid possible complications associated with ethylene
displacement. To this end, treatment of benzyl 2,2-diphenyl-4-
pentenylamine (1a; 15 mM) with 3 (0.5 equiv) in CDCl3
at −20 °C led to immediate (≤5 min) bridge cleavage and
formation of the mononuclear platinum amine complex
(PPh3)Pt{κ1-N-[NH(Bn)CH2C(Ph)2CH2CHCH2]}Cl2
(4a) in 97% yield (1H NMR; Scheme 1). In a similar manner,
reaction of cyclohexyl-substituted 4-pentenylamine 1b (15 mM)
with 3 (0.5 equiv) in CDCl3 at −40 °C for 5 min led to formation
of the platinum amine complex (PPh3)Pt{κ1-N-[NH(Bn)CH2C-
[−(CH2)5−]CH2CHCH2]}Cl2 (4b) in 91% yield (1H NMR;
Scheme 2).
Complexes 4 were thermally unstable and were characterized
without isolation by NMR spectroscopy. For example, complex-
ation of the nitrogen atom of 4a to platinum was established
by the large downfield shift of the amine proton of 4a (δ 3.81)
relative to that of free 1 (δ 0.90), by the presence of
diastereotopic benzylic (δ 4.52, 3.44), C1 (δ 4.13, 3.15), and
C3 (δ 4.57, 3.15) protons of the 4-pentenyl ligand of 4a, and by
the presence of residual 31P−1H coupling observed for one of the
diasterotopic C1 methylene protons (δ 4.57 (JPH = 8.0 Hz)).
Although the 1H NMR resonance of the internal olefinic proton
of 4a (δ 5.94) was shifted downfield relative to that of free 1
(δ 5.33), olefin coordination in 4a was firmly discounted due to
the absence of 195Pt satellites for the olefinic resonances and by
the similar chemical shifts and one-bond CC coupling con-
stant of the olefinic carbon atoms of the 13C-labeled isotopomer
13
(PPh3)Pt{κ1-N-[NH(Bn)CH2C(Ph)213CH213CH CH2]}Cl2
(4a-13C3) (δ 131.5, 120.6, (1JCC = 69 Hz)) relative to those of
1a-3,4,5-13C3 (δ 135.0, 117.7 (1JCC = 69 Hz)). The trans
arrangement of the phosphine and amine ligands of 4a was
unambiguously established by the large 31P−15N coupling con-
stant (JPN = 47 Hz) in the 31P{1H} NMR spectrum of the 15N
isotopomer (PPh3)Pt{κ1-N-[15NH(Bn)CH2C(Ph)2CH2CH
CH2]}Cl2 (4a-15N).46
Synthesis of Zwitterionic Platinamethylpyrrolidinium
Complexes 5. When were warmed to room temperature,
N-bound 4-pentenylamine complexes 4 underwent rearrange-
ment and cyclization to form the thermally stable zwitterionic
platinamethylpyrrolidinium complexes 5 (Schemes 1 and 2). For
example, warming a CDCl3 solution of 4a (29 mM) at 28 °C for
1 h formed (PPh3)Pt[CH2CHNH(Bn)CH2CPh2CH2]Cl2 (5a)
in 94% yield without formation of detectable intermediates
(1H NMR, Scheme 1). Complex 5a was isolated in quantitative
yield from the corresponding preparative-scale reaction
of 1a and 3. In a similar manner, the cyclohexyl-substituted
B
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platinamethylpyrrolidinium complex 5b was isolated in 94%
yield from the reaction of 1b and 3 at 25 °C (Scheme 2).
Complexes 5 were fully characterized by NMR spectroscopy
and mass spectrometry. For example, formal insertion of the
CC bond into the Pt−N bond of 4a was established
1
by the absence of olefinic resonances in the H and 13C NMR
spectra of 5a and its 13C-labeled isotopomer (PPh3)Pt-
[13CH213CHNH(Bn)CH2CPh213CH2]Cl2 (5a-13C3) and by the
presence of diastereotopic protons at δ 1.94 and 1.42 that
displayed partially resolved H−195Pt satellites in the H NMR
spectrum of 5a assigned to the platinum-bound methylene
protons. The presence of a cationic nitrogen atom in 5a was
established by the large downfield shift of the ammonium proton
of 5a (δ 10.1), identified by D2O exchange, relative to the amine
proton of 4a (δ 3.81).
1
1
Figure 1. Partial 1H{31P} NMR spectrum of 6a showing the Pt-bound
methylene proton resonances.
Synthesis of Bicyclic Azaplatinacyclobutane Com-
plexes 6. Zwitterionic complexes 5 reacted rapidly and
exergonically with free amine to form neutral, thermally stable
azaplatinacyclobutane complexes 6 (Schemes 1 and 2). For
example, treatment of 5a (33 mM) with diethylamine (1 equiv)
in CDCl3 at room temperature for 5 min formed (PPh3)Pt{κ2-
C,N-[CH2CHN(Bn)CH2CPh2CH2]Cl (6a) in quantitative yield
by 1H NMR spectroscopy (Scheme 1). In a separate experiment,
when a CD2Cl2 solution of 5a (30 mM) was treated with
diethylamine (1.05 equiv) at −90 °C and monitored periodically
by 1H NMR spectroscopy, conversion of 5a to 6a was complete
within 5 min without detectable formation of any intermediates.
In a preparative-scale experiment, a solution of 1a and 3
(0.5 equiv) was stirred at room temperature overnight and then
treated with diethylamine. Aqueous workup and crystallization
from chloroform/pentane at −10 °C gave 6a in 64% yield as a
white solid. In a similar manner, the cyclohexyl-substituted
azaplatinacyclobutane 6b was isolated in 80% yield as a pale
yellow solid from the reaction of 1b and 3 followed by treatment
with diethylamine (Scheme 2).
Figure 2. ORTEP diagram of 6a·1/2CH2Cl2. Ellipsoids are shown at the
50% probability level with hydrogen atoms and solvent omitted for
clarity. Selected bond lengths (Å) and angles (deg) for 6a: Pt−Cl =
2.4097(13), Pt−P = 2.2049(14), Pt−C1 = 2.039(5), Pt−N = 2.121(4),
C1−C2 = 1.533(4), C2−N = 1.514(4); N−Pt−C(1) = 70.08(15),
C(1)−Pt−P = 100.02(13), N−Pt−P = 168.7(1), C(1)−Pt−Cl =
163.96(13), N−Pt−Cl = 94.44(10), P−Pt−Cl = 95.77(5), C(1)−
C(2)−N = 103.3(4), C(2)−N−Pt(1) = 91.5(3), C(2)−C(1)−Pt =
94.1(3), C(1)−C(2)−C(3) = 114.5(4), C(1)−Pt−N−C(2) = 6.6.
Complexes 6 were fully characterized in solution and, in the
case of 6a, by X-ray crystallography. In particular, formation of
the azaplatinacyclobutane ring was established by the presence
of phosphorus−nitrogen coupling in the 31P{1H} NMR
spectrum (3JNP = 47.4 Hz) of the 15N-labeled isotopomer
complex (PPh3)Pt[κ2-C,N-(CH2CH2NMe2)]Cl (7),48 despite
the presence of the fused pyrrolidine ring in 6a.
Treatment of 6b with a 10-fold excess of HNEt3Cl in dioxane-
d8/diglyme (15/85) or excess HCl in CDCl3 at −50 °C led to no
detectable regeneration of 5b before the onset of protodeme-
talation, pointing to the highly exergonic formation of azaplatina-
cyclobutanes 6 from 5 and free amine (see below).
Reactions of Amines with Platinum Alkene Complexes.
The reactions of amines with platinum π-alkene complexes to
form β-ammonioethanide, and in some cases azaplatinacyclobu-
tane, complexes have been investigated for over 40 years,
although never in the context of an intramolecular C−N bond
forming event.27−40 The reaction of a nitrogen nucleophile
with a platinum(II) π-alkene complex to form a zwitterionic
β-ammonioethanide complex was first reported in 1968 by
Orchin, who demonstrated the reversible formation of PtCl2(Py)
(CH2CH2Py) via reaction of pyridine with platinum ethylene
complex PtCl2(pyridine)(π-H2CCH2).28 Panunzi and co-
workers investigated the stoichiometric reactions of alkylamines
with Pt(II) diene29 and monoolefin complexes30 and established
the anti stereochemistry and outer-sphere nature of C−N bond
formation.31 Green likewise investigated the energetics of the
reversible conversion of the platinum ethylene complexes
(PPh3)Pt{κ2-C,N-[CH2CH15N(Bn)CH2CPh2CH2]Cl (6a-15N),
consistent with a trans arrangement of the amine and phosphine
ligands.46 Worth noting in the 1H NMR spectrum of 6a were the
diastereotopic platinum-bound methylene protons at δ 0.06
(Htrans) and δ −0.34 (Hcis), which displayed well-resolved
1H−195Pt satellites (JPtH ≈ 100 Hz) and which were un-
1
ambiguously assigned by 2D H−1H NOESY/COSY analysis
(Figure 1). These assignments were key to determination of the
stereochemistry of C−N bond formation (see below).
Slow evaporation of a CH2Cl2 solution of 6a gave crystals of
the solvate complex 6a·1/2CH2Cl2 suitable for single-crystal
X-ray diffraction analysis. In the solid state, 6a displayed a
distorted-square-planar arrangement with an acute N−Pt−C(1)
angle (70°) and expanded N−Pt−Cl (∼94°), Cl−Pt−P (96°),
and P−Pt−C(1) (100°) angles (Figure 2). The azaplatinacyclo-
butane moiety deviates slightly from planarity with a C(1)−Pt−
N-C(2) dihedral angle of 6.6° with a narrow C(1)−Pt−N angle
of 70° and a wide C(1)−C(2)−N angle of 103.3°. The Pt−Cl
bond is long (2.41 Å) but is typical for a Pt−Cl bond trans to a
strong σ-donor alkyl ligand.47 The bond lengths and angles of 6a
are similar to those of the related monocyclic azaplatinacyclobutane
C
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PtCl2(amine)(π-H2CCH2) and amine to β-ammonioethanide
complexes PtCl2(amine)(σ-H2CCH2NR3) as a function of
amine and found that Keq increased with decreasing steric bulk
and increasing basicity of the amine. As a benchmark,
thermodynamic parameters of ΔH = −7.4 kcal mol−1 and
ΔS = −20 eu were determined for amine = Et2NH.32 More
recently, Atwood has demonstrated that addition of diethylamine
to (PPh3)PtCl2(π-alkene) (alkene = propene, 1-butene) at
low temperature forms predominantly the anti-Markovnikov
product, which rearranges to the Markovnikov product at room
temperature.33 Similar observations were made by Maresca for
addition of amines to a cationic tetramethylenediamine platinum
alkene complex.34 Panunzi also showed that the Pt−C bond of
the zwitterionic β-ammonioethanide complex undergoes proto-
demetalation with concentrated aqueous HCl to release the
ethylated ammonium salt.30
Scheme 3
Scheme 4
Platinum Azaplatinacyclobutane Complexes. The con-
version of a zwitterionic platinum β-ammonioethanide complex
to an azaplatinacyclobutane complex was first documented by
Green in 1979, who reported that the reaction of (PPh3)PtCl2(π-
H2CCH2) with excess dimethylamine generated the neutral
azaplatinacyclobutane complex (PPh3)PtCl[κ2-C,N-
(CH2CH2NMe2)] (7).35 Since that time, several azaplatinacy-
clobutene complexes, including 7, have been structurally
characterized.34−37,48 Further investigation by Green and
others revealed that conversion of the zwitterionic platinum
β-ammonioethanide complex to the azaplatinacyclobutane
complex is facilitated by alkyl substitution on the amine nitrogen
atom and/or alkene sp2 carbon atoms and by trans-labilizing
ligands such as triphenylphosphine.38−40 Green found that the
equilibrium constants for the formation of azaplatinacyclobu-
tanes from the reaction of (PPh3)PtCl2(π-H2CCH2) with
excess secondary amine were too large to measure accurately and
were on the order of K = 1 × 106 M2.39 Importantly, Green also
found that the ammonium salt generated in the conversion of
(PPh3)PtCl2(π-H2CCH2) to 7 remained intimately associated
with the azaplatinacyclobutane complex in the form of the
isolable 1:1 adduct 7·Me2NH2Cl,39 although the nature of this
interaction was not clarified. Washing the 1:1 adduct with water
and methanol produced the neutral azaplatinacyclobutane 7 that,
aside from the absence of resonances associated with the
ammonium salt, was spectroscopically indistinguishable from 7·
Me2NH2Cl.35,39,40 The formation of 1:1 azaplatinacyclobutane−
ammonium ion adducts in nonpolar solvents has important
implications on the kinetics of Pt(II)-catalyzed hydroamination
(see below).
Stereochemistry of the Conversion of 4 to 5. Owing to
the precedent for outer-sphere intermolecular addition of
nucleophiles to platinum(II) π-alkene complexes,31 we envi-
sioned a mechanism for the conversion of 4 to 5 involving
associative ligand exchange to form the platinum π-alkene
complex 8 followed by intramolecular outer-sphere attack of the
pendant amine on the complexed CC bond. Alternatively,
C−N bond formation could occur through an inner-sphere
pathway involving, for example, chloride displacement to
generate platinum amino alkene complex I followed by
β-migratory insertion and chloride addition (Scheme 3).
Our approach to distinguish between inner- and outer-sphere
pathways for the conversion of 4 to 5 involved the stereochemical
analysis of the stoichiometric reaction of 3 with stereochemically
pure, deuterium-labeled amino alkenes (E)- and (Z)-1a-5-d
(Scheme 4). For example, in the inner-sphere pathway,
β-migratory insertion of the coordinated alkene into the Pt−N
bond of platinum amino alkene complex (E)-Ia-5-d would form
syn-5a-α-d with net syn addition of nitrogen and platinum across
the CC bond of the alkene (Scheme 4, path a). Conversely, in
the outer-sphere pathway, nucleophilic addition of the amine to
the coordinated CC bond of the π-alkene complex (E)-8a-5-d
would yield anti-5a-α-d with net anti addition of the nitrogen and
platinum across the CC bond of the alkene (Scheme 4, path b).
Although there is no obvious way that the diastereomeric,
zwitterionic isotopomers syn-5a-α-d and anti-5a-α-d could be
distinguished spectroscopically, the corresponding azaplatinacy-
clobutane isotopomers cis-6a-α-d and trans-6a-α-d formed via
base-mediated cyclization of syn-5a-α-d and anti-5a-α-d,
respectively, are readily distinguished by 1H NMR spectroscopy
(Figure 1).
In one experiment, treatment of (E)-1a-5-d with 3 (0.6 equiv)
in CDCl3 at room temperature for 2 h followed by addition of
diethylamine (1.0 equiv) formed cis-6a-α-d as the exclusive
1
stereoisomer with ≥95% isotopic purity by H NMR analysis
(eq 2). In a second experiment, treatment of a CDCl3 solution of
(Z)-1a-5-d with 3 led to formation of trans-6-α-d as the exclusive
1
stereoisomer with ≥95% isotopic purity by H NMR analysis
(eq 3). These results establish the net anti addition of N and Pt
across the olefinic CC bond of 1a and provide strong support
D
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Figure 4. Eyring plot for the conversion of 4a (∼30 mM) to 5a in CDCl3
over the temperature range 7−40 °C.
for an outer-sphere pathway for C−N bond formation in the
platinum-catalyzed conversion of 1 to 2 (Scheme 4, path b).
Kinetics of the Conversion of 4 to 5. Although no
intermediates were observed by NMR spectroscopy in the
conversion of 4a to 5a, stereochemical analysis of the cyclization
of isotopically labeled alkenyl amines (E)- and (Z)-1a-5-d
directly implicated the platinum alkene complex 8a in the
conversion of 4a to 5a. To further delineate the mechanism of
the conversion of 4a to 5a, we analyzed the kinetics of this
transformation in CDCl3 at 28 °C employing 1H NMR analysis
(Table S1 in the Supporting Information). A plot of ln[4a]
versus time was linear to >3 half-lives, with a first-order rate
constant of kobs = (1.66 0.02) × 10−3 s−1 (ΔG⧧301 K = 21.45
0.01 kcal mol−1, Figure 3). First-order rate constants for the
Scheme 5
lead to rapid reversion to form platinum amine complex 4a.
Alternatively, if conversion of 4a to 5a were to occur via scenario 2,
in situ generation of 8a would lead to rapid cyclization to form
zwitterion 5a (Scheme 5).
Toward the independent generation of platinum π-alkene
complex 8a, we targeted the platinum π-4-pentenylammonium
precursor 8a·HBF4, which could be deprotonated to reveal 8a
under conditions for which the conversion of 4a to 5a is slow.
Preliminary experiments directed toward the synthesis of
8a·HBF4 revealed both that Zeise’s dimer was an unsuitable
precursor for the synthesis of 8·HBF4 owing to the high binding
affinity of ethylene to Pt(II) and that 1H NMR spectroscopy was
unsuitable for the characterization of 8a·HBF4 owing to excessive
1
broadening of the key vinylic resonances in the H NMR
spectrum, presumably due to fluxional behavior and/or hydro-
gen bonding. To avoid these complications, we targeted the
13C-labeled isotopomer 8a-3,4,5-13C3·HBF4, which was gener-
ated via reaction of the 13C-labeled 4-pentenyl ammonium salt
1a-3,4,5-13C3·HBF4 with the platinum propene precursor cis-
(PPh3)Pt(η2-H2CCHMe)Cl2 (9)49 and which could be
analyzed in situ via 13C NMR spectroscopy. To this end, a
solution of 1a-3,4,5-13C3·HBF4 (44 mM) and 9 (2 equiv) in
CDCl3 was sparged with N2 for 2.5 h to form a ∼4:1 mixture of
8a-3,4,5-13C3·HBF4 and the platinamethylpyrrolidinium iso-
topomer 5a-13C3 as the only 13C-labeled compounds detected
by 13C NMR spectroscopy (Scheme 6). The formation of 8a-
3,4,5-13C3·HBF4 was established by the large upfield shifts and
reduced 1JCC coupling constant for the alkene carbon atoms of
8a-3,4,5-13C3·HBF4 (δ 92.5 (t, J = 42.4 Hz), 73.0 (d, J = 43.2 Hz))
relative to those of 1a-3,4,5-13C3·HBF4 (δ 131.5 (dd, J = 43,
69 Hz), 120.6 (d, J = 69 Hz)). Addition of triethylamine
(4 equiv) to 8a-3,4,5-13C3·HBF4 at 25 °C resulted in immediate
(≤3 min) formation of azaplatinacyclobutane 6a-13C3 with no
detectable formation of 4a-3,4,5-13C3 (Scheme 5).50 This obser-
vation establishes a mechanism for the conversion of 4a to 5a
involving rate-limiting intramolecular ligand exchange to form 8a
followed by rapid outer-sphere attack of amine on the coordi-
nated CC bond of 8a to form 5a. The activation parameters
Figure 3. First-order plot of the conversion of 4a (29 mM) to 5a in
CDCl3 at 28 °C.
conversion of 4a to 5a were likewise obtained as a function of
temperature from 7 to 40 °C. Eyring analysis of this data
provided the activation parameters for the conversion of
4a to 5a: ΔH⧧ = 13.0 0.7 kcal mol−1 and ΔS⧧ = −28 1 eu
(Figure 4).
The first-order rate law and activation parameters for the
conversion of 4a to 5a are consistent with conversion of 4a to 5a
through a highly ordered transition state, and the following two
kinetic scenarios are consistent with these observations: (1)
rapid, endergonic ligand exchange to form 8a followed by rate-
limiting C−N bond formation or (2) rate-limiting, irreversible
ligand exchange to form 8a followed by rapid C−N bond
formation (Scheme 5). Our approach to distinguish these two
possibilities involved independent generation of platinum alkene
complex 8a under conditions for which the conversion of 4a to
5a is slow. Under such conditions, if the conversion of 4a to 5a
were to occur via scenario 1, in situ generation of 8a would
E
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an ammonium salt. Of these two potential pathways, intra-
molecular protodemetalation of a β-ammonioethanide inter-
mediate has been invoked as the product-releasing step in a
number of late-transition-metal-catalyzed alkene hydroamina-
tion processes.10,11,14,15,19,43 Conversely, azametallacyclobutanes
have rarely been invoked as intermediates in late-transition-
metal-catalyzed alkene hydroamination,24,25 and product-releas-
ing protodemetalation of an azametallacyclobutane has not been
documented. Casalnuovo isolated the azairidacyclobutane
hydride complex Ir(PEt3)2(NHPhC7H10)(H)Cl from reaction
of aniline and norbornene with Ir(PEt3)2(C2H4)2Cl that under-
went C−H reductive elimination to form exo-2-(phenylamino)-
norbornane.24 Similarly, Hartwig invoked the intermediacy of an
azarhodiacyclobutane in the anti-Markovnikov hydroamination
of vinylarenes with alkyl amines catalyzed by cationic rhodium
DPEphos complexes (DPEphos = (oxidi-2,1-phenylene)bis-
(diphenylphosphine)) that was presumably consumed via C−H
reductive elimination.25
Scheme 6
Several experiments were performed to evaluate the reactivity
of platinamethylpyrrolidinium complexes 5 with respect to
intramolecular protodemetalation. For example, thermolysis of a
dioxane-d8 solution of platinamethylpyrrolidinium complex 5a
(32 mM) at 80 °C for 18 h led to decomposition without
formation of detectable quantities of 2a (eq 4). In contrast,
determined for the conversion of 4a to 5a therefore correspond
specifically to the irreversible conversion of 4a to 8a.
Nature of the Platinum−Alkene Bond in 8a-3,4,5-13C3·
HBF4. One-bond carbon−carbon coupling constants are roughly
proportional to the sum of the σ character of the two carbon
atoms. For example, 1JCC ≈ 70 Hz for a C(sp2)−C(sp2) bond
while 1JCC ≈ 35 for a C(sp3)−C(sp3) bond.51 For this reason,
the 1JCC coupling constant of an alkene bound to a transition
metal serves as a sensitive measure of d → π* back-bonding,52
which at the extreme leads to complete sp2 → sp3 rehybridization
of the alkene carbon atoms with predominant metallacyclopro-
heating a solution of 5b in CDCl3 at 63 °C for 18 h formed
1
1
pyrrolidine 2b in 80% yield by H NMR analysis (eq 5);
pane character (Figure 5). As points of comparison, the JCC
Figure 5. π-Alkene and metallacyclopropane bonding contributors and
anticipated limiting one-bond carbon−carbon coupling constants.
chloroform was employed in this experiment, owing to the low
solubility of 5b in dioxane/diglyme mixtures. In a separate
experiment, a solution of 5b (50 mM) in CDCl3 at 54 °C was
value of 8a-3,4,5-13C3·HBF4 (42.4 Hz) is significantly larger than
that of the electron-rich platinum(0) π-ethylene complex
(PCy)2Pt(η2-H2CCH2) (1JCC = 31 Hz),53 slightly smaller
than that of the cationic Pd(II) chelate complex {(phen)Pd-
[η1 , η2 -CH(CH2 SiEt3 )CH2 C(CO2 Me)2 CH2 CH
1
monitored periodically by H NMR spectroscopy. Disappear-
ance of 5b obeyed first-order kinetics through ∼1 half-life with an
observed rate constant of kobs = 2.8 × 10−5 s−1 (Figure S1 in the
Supporting Information).
CH2]}+[BAr4]− (Ar = 3,5-C6H3(CF3)2; JCC = 47 Hz),54 and
Several experiments were likewise performed to evaluate the
reactivity of azaplatinacyclobutanes 6 toward protodemetalation
with alkyl ammonium salts. In one experiment, heating an
equimolar mixture of 6a (32 mM) and benzyl-4-pentenylammo-
nium chloride (generated in situ from reaction of 5a and benzyl-
4-pentenylamine) at 120 °C for 16 h formed 2a in quantitative
yield by 1H NMR analysis (eq 6). Similarly, heating a 1:1 solution
of 6b and triethylammonium chloride (50 mM) in diglyme/
dioxane-d8 (85/15 v/v) at 78 °C for 12 h led to proto-
demetalation to form pyrrolidine 2b in 83% yield (1H NMR;
eq 7). In a separate experiment, a solution of 6b (64 mM) and
HNEt3BF4 (0.46 M) in diglyme/dioxane-d8 (85/15 v/v) was
heated at 78 °C and monitored periodically by 31P NMR
spectroscopy.58 A plot of ln[6b] versus time was linear through
1
significantly smaller than that of the cationic gold(I) complex
−
[(IPr)Au(η2-H2CCMe2)]+SbF6 (IPr = 1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidine; JCC = 66 Hz).55 These
1
data suggest that the electrophilicity of cationic Pt(II) complexes
is similar to that of cationic Pd(II) complexes but markedly less
than that of cationic, two-coordinate gold π complexes, consis-
tent with the results of Hammett analysis of vinyl arene binding
affinities for cationic Pd(II), Pt(II), and Au(I) complexes.55−57
Protodemetalation of Complexes 5 and 6. We
envisioned pathways for product formation in the platinum-
catalyzed hydroamination of 1 involving either intramolecular
protonolysis of platinamethylpyrrolidinium complexes 5 or
intermolecular protonolysis of azaplatinacyclobutanes 6 with
F
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Article
As a direct comparison to the intramolecular protodemetalation
of 5b, we determined the rate of protodemetalation of a 1:1
mixture of 6b and EtNHBF4 (50 mM) in CDCl3 at 54 °C.
Disappearance of 6b reactions obeyed first-order kinetics
through 1 half-life with observed rate constants of kobs = 1.7 ×
10−5 s−1 (Figure S1 in the Supporting Information), which is
roughly 60% of that observed for intramolecular protodemeta-
lation of 5b under comparable conditions.
In a final set of experiments, treatment of either 5b or 6b with
anhydrous HCl (1 atm, 0.11 mmol) in CDCl3 at 25 °C for 5 min
led to complete consumption to form the pyrrolidinium chloride
2b·HCl and platinum chloride dimer 3 as the exclusive products.
Basification of the resulting solutions with DBU (1,8-diazabicyclo-
5.4.0 undec-7-ene) produced free pyrrolidine 2b in ≥95% yield
(Scheme 7). In a separate experiment, a CDCl3 solution of 6b
Scheme 7
∼85% conversion with a first-order rate constant of kobs = (9.37
0.07) × 10−5 s−1 (Figure 6). In a similar manner, first-order rate
Figure 6. First-order plot for the protodemetalation of 6b (64 mM) and
HNEt3BF4 (0.64 M) at 78 °C in diglyme/dioxane-d8 (85/15 v/v).
and HCl (1 atm, 0.11 mmol) was generated at −50 °C and
1
analyzed periodically by H and 31P NMR spectroscopy. No
constants were determined as a function of ammonium ion
concentration from 0.10 to 0.64 M. The resulting plot of kobs
versus [HNEt3BF4] was linear with a significant nonzero
intercept (Figure 7), which points to a two-term rate law for
change was observed at −50 °C, but as the solution was warmed
slowly, resonances corresponding to the pyrrolidinium product
2b·HCl began to appear at 0 °C and continued warming to 25 °C
formed 2b·HCl and 3 as the exclusive products (Scheme 7).
Throughout complete conversion of 6b to 2b·HCl, no
resonances were observed that could be attributed to either a
platinum hydride complex or to zwitterionic complex 5b.
Analysis of Catalytic Mixtures of 1 and 3. In an effort to
identify the resting state in the platinum-catalyzed hydro-
amination of 4-pentenylamines, a solution of 1a (0.25 M) and 3
(2.5 mol %) in diglyme-d14 was monitored periodically by
1H NMR spectroscopy at 120 °C. Resonances corresponding to
6a or the corresponding ammonium chloride adduct 6b·R3NHCl
(R3N = 1b or 2b; see below) were observed within the first ∼5%
of conversion, persisted throughout ∼95% conversion of 1a to
2a, and disappeared upon complete consumption of 1a (eq 8).
Similarly, 1H NMR analysis of a solution of 1b and 3 in diglyme-
d14 at 80 °C established azaplatinacyclobutane 6b as the only
organometallic species present during the complete conversion
of 1b to 2b (eq 8).
Figure 7. Ammonium ion concentration dependence of the
protodemetalation of 6b (64 mM) and [HNEt3]BF4 (0.10−0.64 M)
at 78 °C in diglyme/dioxane-d8 (85/15 v/v).
The exclusive accumulation of azaplatinacyclobutane com-
plexes 6a,b during the platinum-catalyzed hydroamination of
1a,b, respectively, established complexes 6 as the catalyst resting
states and protodemetalation of 6 as the turnover-limiting step of
catalysis. An alternative scenario involving reversion of 6 to 5
protodemetalation of 6b: rate = k1[6b] + k2[6b][HNEt3BF4],
where k1 = (6 1) × 10−5 s−1 (ΔG⧧351 K = 27.5 kcal/mol) and
k2 = (1.1 0.2) × 10−4 M−1 s−1 (ΔG⧧
= 27.0 kcal/mol).
351 K
G
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Article
followed by protodemetalation of 5 (in which case 6 would be an
off-cycle catalyst reservoir) can be discounted on the basis of our
stoichiometric experiments involving the protodemetalation of 5
and 6. In the case of the conversion of 1a to 2a, proto-
demetalation of 5a under catalytic conditions is readily
discounted, owing to the failure of 5a to undergo intramolecular
protodemetalation. In the case of the conversion of 1b to 2b,
although our experiments established the viability of the
protodemetalation of 5b, the rate of protodemetalation of 5b
was not sufficient to compete with the extremely facile (∼5 min
at −90 °C) and exergonic conversion of 5b to 6b in the presence
of amine base, such as under catalytic conditions (Scheme 8).
Figure 8. Pseudo-zeroth-order plot for the conversion of 1b (0.42 M) to
2b catalyzed by 3 (16 mM) in diglyme at 120 °C.
To determine the rate dependence on catalyst concentration,
pseudo-zeroth-order rate constants for the platinum-catalyzed
hydroamination of 1b were determined as a function of [3] from
5.5 to 21 mM. A plot of ln[kobs] versus ln[Pt] ([Pt] = 2[3]) was
linear with a slope of 1.14 0.08 (Figure 9), which indicated a
Scheme 8. Comparison of Rates for the Conversion of 5b to
6b and for the Protodemetalation of 5b and 6b in CD2Cl2 or
CDCl3
Figure 9. Plot of ln(kobs) versus ln[Pt] (Pt = 2[3]) for the conversion of
1b (0.42 M) to 2b catalyzed by 3 (5.5−22 mM) in diglyme at 120 °C
(slope 1.14 0.08).
slightly greater than first-order dependence of the rate on catalyst
concentration. To estimate the free energy of activation for the
platinum-catalyzed hydroamination of 1b, a plot of kobs versus
[Pt] provided a first-order rate constant of k1 = (7.5 0.6) ×
10−3 s−1 (Figure S2 in the Supporting Information), which
In particular, the failure to observe detectable quantities of 5b
from the reaction of 6b and HCl suggests that the equilibrium for
the conversion of 5b and amine to form 6b and ammonium
chloride lies far to the right, as was established by Green for the
reactions of (PPh3)PtCl2(π-H2CCH2) with secondary amines
(K ≈ 1 × 106 M2).39 Therefore, for the protodemetalation of 5b
to be catalytically relevant, the rate of protodemetalation of 5b
would need to be orders of magnitude faster than proto-
demetalation of 6b with ammonium salt, and a side by side
comparison of the protodemetalation of 5b and 6b strongly
suggests that this is not the case (Scheme 8).
Kinetics of Catalytic Hydroamination. We sought to
determine the rate behavior of the catalytic hydroamination of 1
under conditions that approximated the relative and absolute
concentrations employed in preparative-scale reactions.7 To this
end, a solution of 1b (0.42 M) and 3 (16 mM; [Pt] = 32 mM) in
diglyme at 120 °C was monitored periodically by GC. A plot of
[1b] versus time was linear through ∼2.5 half-lives and displayed
positive curvature at higher conversion, which established the
zeroth-order dependence of the rate on [1b] over the
concentration range 0.42−0.1 M with a pseudo-zeroth-order
rate constant of kobs = (1.99 0.04) × 10−3 M s−1 (Figure 8).
corresponds to the free energy of activation of ΔG⧧
=
393 K
27 kcal/mol.
Kinetic analysis of the catalytic hydroamination of 1b catalyzed
by 3 pointed to a kinetic scenario that approached the first-order
rate law: rate = k[Pt]. Given the identification of 6b as the catalyst
resting state and protodemetalation of 6b as the turnover-
limiting step of the platinum-catalyzed conversion of 1b to 2b,
the nominal first-order dependence of the rate on platinum
concentration was unanticipated and argues against a bimolec-
ular pathway for protodemetalation. Specifically, because
ammonium salt is formed concomitantly with azaplatinacycle
6b under catalytic conditions and because azaplatinacyclobutane
6b accounted for all of the platinum introduced as 3, [ammonium
ion] ≈ [6b] ≈ [Pt]tot under catalytic conditions. Therefore, a
mechanism involving turnover-limiting, intermolecular proto-
demetalation of 6b with ammonium salt would display second-
order rate dependence on [Pt] (rate = k[Pt]2), which was not
observed (Scheme 9).23 Rather, the approximately first-order
dependence of the rate on platinum concentration (rate ≈ k[Pt])
H
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alkyl ligand trans to the chloride ligand in 6,47 which is reflected
in the long Pt−Cl bond (2.41 Å), may enhance the hydrogen
bond acceptor ability of the chloride ligand to the extent that it
competes effectively with exogenous Cl−. Because of the pre-
ferred 90° angle of the Pt−Cl···H hydrogen bond,59 association
of the ammonium ion via hydrogen bonding would properly
orient the proton for transfer to Pt to generate a reactive Pt(IV)
hydride species which is a potential intermediate in the proto-
demetallation event (see below).63
Scheme 9
Importantly, the free energy of activation for the catalytic
conversion of 1b to 2b (ΔG⧧393 K = 27 kcal/mol) was similar to
that determined for the ammonium ion independent pathway in
the protodemetalation of 6 with triethylammonium salt
(ΔG⧧393 K = 27 kcal/mol). Although stoichiometric protodeme-
talation of 6b pointed to the presence of competing ammonium
ion dependent and independent pathways, the ammonium ion
dependent pathway in these reactions presumably corresponds
to the intermolecular protodemetalation of the azaplatinacyclo-
butane−ammonium ion adduct 6b·Et3NHBF4 and is not likely
relevant to the catalytic hydroamination of 1b. In this regard, it
must be noted that the kinetics of the protodemetalation of 6b
under stoichiometric conditions were determined at ammonium ion
concentrations ([R3NHCl] = 0.10−0.64 M) that far exceed those
realized under catalytic conditions ([R3NHCl] = 11−42 mM).
Rather, extrapolation of the ammonium ion dependent pathway for
the stoichiometric protodemetalation of 6b to catalytically relevant
ammonium ion concentrations predicts no significant (<10%)
contribution of this pathway under catalytic conditions.
Mechanism of Catalytic Hydroamination. All of our
experimental observations, including (1) the irreversible
formation of platinum π-alkene complex 8a, (2) the net anti
addition of platinum and amine across the CC bond of 8a, (3)
the identification of azaplatinacycle 6 as the catalyst resting state,
and (4) the nominal first-order rate law for the catalytic
hydroamination of 1b (rate ≈ k[Pt]), are consistent with the
mechanism for the intramolecular hydroamination of benzyl
4-pentenylamines 1 catalyzed by 3 depicted in Scheme 10.
requires a pathway for consumption of 6 that is largely
independent of ammonium ion concentration.
To account for the near zeroth-order dependence of the rate of
catalytic hydroamination on ammonium ion concentration, we
initially considered a scenario for protodemetalation of 6
involving rate-limiting ligand dissociation to generate a neutral
or cationic three-coordinate species that was trapped by
ammonium ion. However, it appears unlikely that reaction of
the three-coordinate platinum species with ammonium ion
would be fast enough relative to ligand recombination to realize
approximately zeroth-order dependence in ammonium ion
concentration.
An alternative mechanism that accounts for the near-first-
order dependence of the rate of catalytic hydroamination on
catalyst concentration is suggested by Green’s observations
regarding the formation of discrete azaplatinacyclobutane-
ammonium chloride adducts such as 7·Et2NH2Cl. Specifically,
we suggest a mechanism involving turnover-limiting, intra-
molecular protodemetalation of the azaplatinacyclobutane-
ammonium chloride adduct 6b·R3NHCl (R3N = 1b, 2b)
generated from 6b and the ammonium chloride salt under
catalytic conditions (Scheme 9). Provided that the equilibrium
constant K for the formation of 6b·R3NHCl from 6b and
R3NHCl is sufficiently large (i.e., [Pt]tot ≈ [6b·R3NHCl]) as is
suggested by Green’s work,35,39,40 and intramolecular proto-
demetalation represents the lowest energy pathway for
protodemetalation, catalytic hydroamination should display
first-order rate dependence on [Pt] and zeroth-order depend-
ence on [1b], consistent with the experimentally determined rate
law rate ≈ k[Pt]. The slightly greater than first-order rate
dependence on [Pt] points to the contribution of an ammonium
ion dependent pathway for protodemetalation in the catalytic
hydroamination of 1b. Indeed, to the extent that K is not
sufficiently large to achieve the condition [Pt]tot ≈ [6b·
R3NHCl], the rate of catalytic hydroamination displays depend-
ence on ammonium ion concentration, which is manifested as
greater than first-order dependence on [Pt] (Scheme 9).
Although Green did not speculate on the nature of the
azaplatinacyclobutane−ammonium ion adduct, neither he nor
we noted any spectral changes in the presence or absence of
ammonium salt. Given this observation, the most reasonable
structure for an 6b·R3NHCl adduct is that generated via
hydrogen bonding of the ammonium proton to the chloride
ligand of 6. Brammer and others have shown that chloride ligands
of late-transition-metal complexes, platinum in particular, are
good hydrogen bond acceptors and form particularly robust
hydrogen bonds with ammonium salts.59−61 Indeed, hydrogen
bonding to Pt−Cl bonds has been exploited as a construct in
crystal engineering.60 In the case of 6b·R3NHCl, the platinum-
bound chloride would have to compete with exogenous Cl−,
which is typically a stronger hydrogen bond acceptor than is a
M−Cl bond.59,62 However, the presence of a strong σ-donor
Scheme 10
The catalytic cycle is first accessed via the bridge-splitting
reaction of 3 with 1 to form the nitrogen-bound platinum
4-pentenylamine complex 4. Complex 4 undergoes irreversible
I
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intramolecular ligand exchange (ΔG⧧
= 21.45 kcal mol−1
at −78 °C was thawed briefly to form a yellow solution that was placed
into the probe of an NMR spectrometer precooled at −20 °C. 1H NMR
analysis of the resulting solution after 5 min revealed complete
consumption of 1a to form 4a in 97% yield, determined by integrating
the olefinic resonances of 4a at δ 5.90−5.98 (H5), 5.09 (H7), and
4.98 (H6) relative to the methyl resonance of PhSiMe3 at δ 0.02.
301 K
for 4a) to generate the unobserved platinum alkene complex 8,
which undergoes rapid outer-sphere C−N bond formation to
form the zwitterionic platinamethylpyrrolidinium complex 5.
Rapid and exergonic deprotonation of 5 with free amine (R3N =
1, 2) forms the azaplatinacyclobutane complex 6, which
presumably exists as the discrete 1:1 azaplatinacyclobutane−
ammonium chloride adduct 6·R3NHCl in the nonpolar reaction
medium (Scheme 10). The facile and exergonic conversion of
both 8 to 5 and 5 to 6 likely renders C−N bond formation
irreversible under reaction conditions. The azaplatinacyclobu-
tane−ammonium adduct 6·R3NHCl represents the catalyst
resting state and is consumed via turnover-limiting intra-
1
Thermally unstable 4a was characterized without isolation by 1D H,
1H{31P}, and 31P NMR spectroscopy, by 2D 1H−1H COSY and 1H−1H
NOESY spectroscopy (Figures S3−S6 in the Supporting Information),
and through NMR analysis of the isotopomers (PPh3)Pt{κ1-N-
[15NH(Bn)CH2C(Ph)2CH2CHCH2]}Cl2 (4a-15N) and (PPh3)Pt-
{κ1-N-[NH(Bn)CH2C(Ph)213CH213CH CH2]}Cl2 (4a-13C3). The
13
numbering scheme for the aliphatic 1H resonances of 4a is depicted in
Figure 10. 1H{31P} NMR (500 MHz, −20 °C): δ 6.84−7.82 (m, 30 H),
molecular protonolysis (ΔG⧧
= 27 kcal/mol), presumably
393 K
through an unobserved Pt(IV) hydride intermediate followed by
reductive elimination,63 to form the unobserved platinum
pyrrolidine complex II. Associative ligand exchange of 1 with
II would release 2 and regenerate the nitrogen-bound platinum
4-pentenylamine complex 4 (Scheme 10).
CONCLUSIONS
■
1
In summary, we have investigated the mechanism of the
platinum-catalyzed intramolecular hydroamination of 2,2-
disubstituted benzyl 4-pentenylamines to form 2-methylpyrro-
lidines. Our investigation included the independent generation
and evaluation of potential intermediates, stereochemical
analysis of C−N bond formation, identification of the catalyst
resting state and turnover-limiting step, and kinetic analysis of
catalytic hydroamination. Together, these data support the
mechanism depicted in Scheme 10, involving as key steps the
outer-sphere addition of the pendant amine on the coordinated
CC bond of platinum π-alkene complex 8 and turnover-
limiting intramolecular protodemetalation of the 1:1 azaplatina-
cyclobutane−ammonium ion adduct 6·R3NHCl.
Turnover-limiting protodemetalation appears to be a general
feature of late-transition-metal-catalyzed hydroamination of
alkenes with alkylamines, presumably owing to the high
nucleophilicity of the amine, which facilitates C−N bond
formation and weak Brønsted acidity of the resulting ammonium
salt, which retards the rate of protodemetalation. A notable
exception is the intramolecular hydroamination of primary
aminoalkenes catalyzed by a rhodium aminophosphine complex
reported by Hartwig that occurs via turnover-limiting C−N bond
formation.11 Although the platinum-catalyzed intramolecular
hydroamination of 4-pentenylamines follows this general trend,
the turnover-limiting protodemetalation of the azametallacyclo-
butane 6 is perhaps the most distinctive feature of the catalytic
cycle. Indeed, the turnover-limiting protodemetalation of an
azametallacyclobutane intermediate under conditions of catalytic
hydroamination has not previously been documented. A second
notable mechanistic feature of the platinum-catalyzed hydro-
amination of 4-pentenylamines is the facile (ΔG⧧ ≈ 21 kcal
mol−1) irreversible conversion of the N-bound 4-pentenylamine
complex 4 to the π-bound species 8, which avoids amine
inhibition of catalysis despite the greater binding affinity of the
secondary amine to Pt(II) relative to the monosubstituted CC
bond.
Figure 10. Numbering scheme for the H resonances of compounds
4a−6a.
5.90−5.98 (m, 1 H, H5), 5.09 (d, J = 16.9 Hz, 1 H, H7), 4.98 (d, J =
10.3 Hz, 1 H, H6), 4.57 (dd, J = 8.0, 12.5 Hz, 1 H, H3), 4.52 (dd, J = 6.6,
12.7 Hz, 1 H, H1), 4.13 (dd, J = 5.9, 14.1 Hz, 1 H, H4), 3.81 (t, J = 7.1 Hz,
1 H, H2), 3.44 (dd, J = 7.3, 12.8 Hz, 1 H, H1), 3.12−3.19 (m, 2 H,
H3 + H4). 31P{1H} NMR (−20 °C): δ 5.20 (s, JPtP = 3566 Hz).
(PPh3)Pt[CH2CHNH(Bn)CH2CPh2CH2]Cl2 (5a). A solution of 4a
(∼1.7 × 10−2 mmol, ∼29 mM) and phenyltrimethylsilane (0.32 mg,
2.1 × 10−3 mmol) in CDCl3 (580 μL) was warmed to 28 °C for 1 h to
form 5a in 94 5% yield, as determined by integrating the benzylic
resonance of 5a at δ 5.25 relative to the methyl resonance of PhSiMe3 at
δ 0.02. In a separate experiment, a solution of 1a (25 mg, 0.076 mmol)
and 3 (41 mg, 0.039 mmol) in CDCl3 (3 mL) was maintained at room
temperature for 4 h. Solvent was evaporated under vacuum to give pure
5a (66 mg, 100%) as a tan solid. Complex 5a was characterized by 1D
1H{31P}, 13C{1H}, and 31P NMR spectroscopy, by 2D H−1H COSY
NMR spectroscopy (Figures S7 and S8 in the Supporting Informa-
tion), by mass spectrometry, and by NMR analysis of isotopomers
(PPh3)Pt[CH2CH15NH(Bn)CH2CPh2CH2]Cl2 (5a-15N) and (PPh3)-
Pt[13CH213CHNH(Bn)CH2CPh213CH2]Cl2 (5a-13C3). The numbering
1
1
scheme for the aliphatic H resonances of 5a is depicted in Figure 10.
1H NMR (500 MHz): δ 10.11 (br s, 1 H, H2), 7.82 (dd, J = 7.5, 11.3 Hz,
6 H), 7.14−7.48 (m, 20 H), 7.05 (d, J = 7.7 Hz, 2 H), 6.89 (d, J = 7.2 Hz,
2 H), 5.25 (dd, J = 2.8, 12.3 Hz, 1 H, H3), 3.75−3.88 (m, 2 H, H1), 2.72
(dd, J = 5.6, 14.0 Hz, 1 H, H4), 2.62 (dd, J = 10.0, 12.8 Hz, 1 H, H3),
2.39−2.52 (m, 1 H, H5), 2.08 (dd, J = 11.2, 13.6 Hz, 1 H, H4), 1.94
(t, J = 11.1 Hz, 1 H, H6), 1.42 (ddd, J = 3.6, 6.4, 12.0 Hz, 1 H, H6).
13C{1H} NMR: δ 144.3, 142.5, 134.9, 134.8, 130.9, 130.6, 130.6, 130.3,
130.3, 129.9, 129.7, 129.5, 129.4, 128.9, 128.1, 128.0, 128.0, 127.2, 126.7,
125.7, 73.9, 59.5, 57.6, 54.7, 46.0, 8.4. 31P{1H} NMR: δ 14.19 (s, JPtP
=
4844 Hz). ESI-MS calcd (found) for C42H40ClNPPt+ (M+ − Cl): 820.3
(820.2).
Kinetics of the Conversion of 4a to 5a. An NMR tube containing a
solution of 1a (6.0 mg, 1.8 × 10−2 mmol), phenyltrimethylsilane (20 μL
of stock (50 μL in 3 mL of CDCl3), 1.9 × 10−3 mmol) in CDCl3
(580 μL) was placed in the probe of an NMR spectrometer maintained
at 28 °C. After 5 min, the tube was ejected, 3 (17.9 mg, 1.69 × 10−2)
was added, the tube was returned to the spectrometer, and data
acquisition began. Data points were acquired every 109 s. The
concentration of 4a was determined by integrating the allylic resonance
of 4a at δ 4.13 (H4) relative to the methyl resonance of PhSiMe3
at δ 0.02. A plot of ln[4a] versus time was linear to ≥3 half-lives with
EXPERIMENTAL SECTION
■
Synthesis of Platinum Complexes 4a−6a. (PPh3)Pt{κ1-N-
[NH(Bn)CH2C(Ph)2CH2CHCH2]}Cl2 (4a). A frozen suspension of 1a
(5.4 mg, 1.7 × 10−2 mmol), phenyltrimethylsilane (0.32 mg, 2.1 ×
10−3 mmol), and 3 (8.9 mg, 8.4 × 10−3 mmol) in CDCl3 (1.16 mL)
J
DOI: 10.1021/acs.organomet.5b00821
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Organometallics
Article
slope = (1.66
0.02) × 10−3 s−1 (Figure 3). Employing a similar
analysis of the resulting solution revealed formation of 2a in 101 5%
yield by integrating the methyl doublet of 2a at δ 1.21 relative to the
methyl resonance of PhSiMe3 at δ 0.02.
procedure, the first-order rate constants for the conversion of 4a to 5a
were determined in duplicate at 7.3, 11.8, 17.3, 22.9, 33.9, and 39.5 °C
with all rates being determined by linear regression analysis over 2 half-
lives (Table S1 in the Supporting Information). A plot of ln (k/T) versus
1/T was linear with slope = −6550 (Figure 4).
Reaction of 6b with Triethylammonium Tetrafluoroborate. An
NMR tube containing a solution of 6b (20 mg, 2.7 × 10−2 mmol) and
1,3-dimethoxybenzene (1.38 mg, 1.0 × 10−2 mmol) in 15% dioxane/
diglyme (v/v) was placed in the probe of an NMR spectrometer
preheated at 78 °C. An initial 1H NMR spectrum was acquired, the tube
was ejected from the spectrometer, and Et3N·HBF4 (5.7 mg, 3.0 ×
10−2 mmol) was added to the tube. The solution was thoroughly mixed,
(PPh3)Pt{κ2-C,N-[CH2CHN(Bn)CH2CPh2CH2]Cl (6a). Diethylamine
(3.4 μL, 3.3 × 10−2 mmol) was placed in an NMR tube containing a
solution of 5a (3.3 × 10−2 mmol, 33 mM) and PhSiMe3 (1 μL, 6 ×
10−3 mmol) in CDCl3 (1.00 mL), and the tube was shaken briefly.
1H NMR analysis of the resulting solution within 5 min of mixing
revealed formation of 6a in 104 5% yield, as was determined by
integrating the benzylic resonance of 6a at δ 5.04 relative to the methyl
resonance of PhSiMe3 at δ 0.02. In a separate experiment, a solution of
1a (149 mg, 0.455 mmol) and 3 (243 mg, 0.230 mmol) in CHCl3
(12 mL) was stirred overnight at room temperature. Diethylamine
(190 μL, 1.83 mmol) was added, and the resulting mixture was stirred
for 15 min and diluted with CHCl3 (30 mL). The reaction mixture was
washed with water (3 × 25 mL), 0.1 M HCl (3 × 15 mL), and brine
(15 mL), dried (MgSO4), and concentrated to ∼10 mL. Pentane
(200 mL) was added, and the mixture was cooled to −10 °C overnight.
The resultant off-white powder was isolated by vacuum filtration,
washed with pentane (50 mL), and dried under vacuum to yield
1
and the tube was returned to the spectrometer for 12 h. H NMR
analysis of the resulting solution revealed formation of 2b in 83% yield by
integration of the pyrrolidine resonance of 2b at δ 4.01 (d, 1 H) versus the
methoxy resonance of 1,3-dimethoxybenzene at δ 3.81 (s, 6 H).
Kinetics of the Reaction of 6b with Triethylammonium
Tetrafluoroborate. A solution of 6b (36.7 mg, 5.0 × 10−2 mmol,
65 mM) and Et3N·HBF4 (70.9 mg, 0.375 mmol, 0.46 M) in d8-dioxane/
diglyme (1/5 v/v, total volume 0.75 mL at 75 °C) was placed into the
probe of an NMR spectrometer preheated at 75 °C. The sample was
allowed to equilibrate for 5 min and was then monitored periodically by
31P NMR spectroscopy, analyzing the intensity of the phosphorus
resonance of 6b at δ 12.14. Data points (nt = 48) were acquired every
328 s for the first 2.8 h, every 698 s for the next 2.7 h, and every 1058 s
thereafter. A plot of ln[6b] versus time was linear to ∼2.5 half-lives with
a pseudo-first-order rate constant of kobs = (9.37 0.06) × 10−5 s−1
(Figure 6). Using a similar procedure, pseudo-first-order rate constants
for the protodemetalation of 6b with Et3N·HBF4 at 75 °C were
determined at [Et3N·HBF4]0 = 0.10 (kobs = (6.7 0.1) × 10−5 s−1),
0.33 (kobs = (9.4 0.1) × 10−5 s−1), and 0.64 M (kobs = (1.31 0.02) ×
10−4 s−1). A plot of kobs versus [HNEt3BF4] was linear with a significant
nonzero intercept (Figure 7), from which the rate constants k1 = (5.5
0.1) × 10−5 s−1 and k2 = (1.1 0.2) × 10−4 M−1 s−1 were determined.
Reaction of 5b and 6b with HCl. Anhydrous HCl(g) was added to
the headspace of an NMR tube (2.7 mL, 1 atm, 0.11 mmol) containing a
solution of 6b (20 mg, 2.7 × 10−2 mmol) in CDCl3 (0.60 mL), and the
6a (211 mg, 64%). Complex 6a was characterized by 1D H{31P},
1
13C{1H}, and 31P{1H} NMR spectroscopy, by 2D 1H−1H COSY NMR
(Figures S9 and S10 in the Supporting Information) and 1H−1H NOE
spectroscopy (Figure S11 in the Supporting Information), by mass
spectrometry, and by NMR analysis of isotopomers (PPh3)Pt{κ2-C,N-
[CH2CH15N(Bn)CH2CPh2CH2]Cl (6a-15N) and (PPh3)Pt{κ2-C,N-
[13CH213CHN(Bn)CH2CPh213CH2]Cl (6a-13C3). The numbering
1
scheme for the aliphatic H resonances of 6a is depicted in Figure 10.
1H NMR (500 MHz, CDCl3): δ 7.79 (d, J = 7.0 Hz, 2 H), 7.51 (d, J =
7.5 Hz, 2 H), 7.17−7.44 (m, 25 H), 7.06 (t, J = 7.1 Hz, 1 H), 5.26−5.32
(m, 1 H, H3), 5.04 (dd, J = 4.0, 12.5 Hz, 1 H, −CH2Ph), 4.56 (d, J =
11.4 Hz, 1 H, H7), 3.85 (dd, J = 2.9, 12.5 Hz, 1 H, − CH2Ph), 3.35 (dd,
J = 8.3, 11.8 Hz, 1 H, H6), 3.04 (dd, J = 7.8, 13.3 Hz, 1 H, H5), 2.48
(dd, J = 7.5, 13.5 Hz, 1 H, H4), 0.06 (ddd, JPH = 1.8 Hz, J = 3.5, 9.1, 1 H,
H1), −0.34 (ddd, JPH = 4.0 Hz, J = 8.6, 9.1 Hz, 1 H, H2). 13C{1H} NMR:
δ 146.1, 145.8, 135.1, 134.4, 134.3, 133.0, 131.5, 130.9, 130.2, 130.1,
128.9, 128.6, 128.2, 128.1, 127.9, 127.8, 127.1, 126.6, 126.6, 126.3, 76.3,
68.4, 63.1, 55.2, 45.9, −13.0. 31P{1H} NMR: δ 11.09 (s, JPtP = 4402 Hz).
ESI-MS calcd (found) for C42H39NPPt (M+ − Cl): 783.2 (783.3).
1
tube was shaken vigorously. H and 31P NMR spectroscopic analysis
within 5 min of mixing revealed complete consumption of 6b with
formation of 2b·HCl and 3, the latter as the exclusive phosphorus-
containing species. The headspace of the tube was then flushed with N2,
and the solution was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU; 4.1 mg, 2.7 × 10−2 mmol). GC analysis of the resulting solution
revealed formation of pyrrolidine 2b in 101% yield (from 6b). In a
similar procedure, reaction of 5b (10 mg, 0.13 × 10−2 mmol) with HCl
(1 atm, 0.11 mmol) for 5 min formed 2b·HCl and 3 as the exclusive
products. Removal of HCl and treatment with DBU formed 2b in 95%
yield (from 5b) by GC analysis.
(PPh3)Pt[η2-13CH2 CH13CH2C(Ph)2CH2NHBn]Cl2·HBF4 (8a-
13
3,4,5-13C3). A solution of 1a-13C3·HBF4 (11 mg, 2.7 × 10−2 mmol)
and cis-(PPh3)Pt(η2-H2CCHMe)Cl2 (9; 30 mg, 5.3 × 10−2 mmol) in
CDCl3 (0.60 mL) was continually sparged with N2 for 2.5 h to form a 4:1
mixture of 8a-3,4,5-13C3 and 5a-13C3, which were the only isotopically
labeled compounds detected in solution. Complex 8a-3,4,5-13C3 was
analyzed in solution by 13C and 31P NMR spectroscopy without
isolation. 13C{1H} NMR (labeled carbons only): δ 92.5 (t, J = 42.4 Hz),
Data for 2b·HCl: 1H NMR δ 9.58 (br s, 1 H), 7.65−7.80 (m, 5 H),
4.43 (dd, J = 4.6, 13.5 Hz, 1 H), 4.28 (dd, J = 4.6, 13.5 Hz, 1H), 3.71
(dd, J = 6.7, 12.0 Hz, 1H), 3.29−3.37 (m, 1 H), 2.67 (dd, J = 7.7, 12.1 Hz,
1 H), 1.90 (dd, J = 6.0, 13.3 Hz), 1.80 (t, J = 12 Hz, 1 H), 1.5−1.7
(m, 3 H), 1.45 (d, J = 6.4 Hz, 3 H), 1.1−1.4 (m, 7 H). Data for 3:
31P{1H} NMR δ 7.20 (s, JPtP = 5045 Hz).
73.0 (d, J = 43.2 Hz), 41.9 (J = 40.1). 31P{1H} NMR: δ 14.11 (s, JPtP
=
Kinetics of Catalytic Hydroamination. A suspension of 3 (19.7 mg,
1.9 × 10−2 mmol, 16 mM; [Pt] = 32 mM) and n-hexadecane (40 μL,
0.14 mmol) in diglyme (1.0 mL) was heated to 120 °C for 5 min in a
thermostated oil bath and then treated with 1b (120 mg, 0.49 mmol,
0.42 M) to form an amber solution (total volume 1.16 mL). Aliquots
(25 μL) were removed periodically and analyzed by GC to determine
the concentration of 1b as a function of time. The corresponding
plot of [1b] versus time was linear through ∼2.5 half-lives with a
pseudo-zeroth-order rate constant of kobs = (1.99 0.04) × 10−3 M s−1
(Figure 8). Employing a similar procedure, pseudo-zeroth-order rate
constants for the disappearance of 1b were determined at [Pt] = 11
(kobs = (6.6 0.2) × 10−5 M s−1), 21 (kobs = (1.46 0.03) × 10−4 and
(1.29 0.04) × 10−4 M s−1), and 43 mM ((3.3 0.30) × 10−4 M s−1).
A plot of pseudo-zeroth-order rate constants versus platinum
concentration was linear with a slope of k1 = (97.5 0.6) × 10−3 s−1
(Figure S2 in the Supporting Information), and a plot of ln(kobs) versus
ln[Pt] was linear with a slope of 1.14 0.08 (Figure 9).
3324 Hz).
Reaction of 8a-3,4,5-13C3 with Et3N. Triethylamine (15 μL,
0.11 mmol) was placed in an NMR tube containing a 4:1 mixture
of 8a-3,4,5-13C3 and 5a-13C3 in CDCl3 (0.60 mL) at 25 °C, and the
resulting solution was analyzed immediately (∼3 min) by 13C{1H}
NMR spectroscopy, which revealed the presence of 6a-13C3 as the
exclusive 13C-labeled species present in solution.
Protodemetalation Experiments. Reaction of 6a with Benzyl-4-
pentenylammonium Chloride. Benzyl-4-pentenylamine (26.5 mg,
0.151 mmol) was added to a solution of 5a (27 mg, 3.2 ×
10−2 mmol) and PhSiMe3 (1 μL, 6 × 10−3 mmol) in dioxane-d8
1
(1.00 mL). H NMR analysis of the resulting solution 5 min after
mixing revealed complete consumption of 5a to form azaplatinacyclo-
butane complex 6a and benzyl-4-pentenylammonium chloride.
The relative concentration of 6a was determined by integrating the
H7 resonance of 6a at δ 4.56 relative to the methyl resonance of PhSiMe3
at δ 0.02. The solution was then heated to 120 °C for 16 h. 1H NMR
K
DOI: 10.1021/acs.organomet.5b00821
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(8) In 1975, Zambonelli reported that reaction of an aqueous solution
of sodium tetrachloroplatinate with 4-pentenylammonium chloride
forms the zwitterionic π-alkene complex {Cl3Pt[π-H2C
CH(CH2)3NH3]}+, which when heated to 60 °C for 2 weeks formed
2-methylpyrrolidinium chloride as the exclusive organic product.
Addition of 4-pentenylammonium chloride to the resultant solution
initiates subsequent conversion to 2-methylpyrrolidinium chloride, and
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.organomet.5b00821.
■
S
General methods, experimental and spectral data for
isotopically labeled 4-pentenylamines, platinum com-
plexes 4b−6b, and isotopomers of 4a−6a, kinetic plots,
and scans of NMR spectra (PDF)
three such cycles were demonstrated. Ambuhl, J.; Pregosin, P. S.;
̈
Venanzi, L. M.; Ughetto, G.; Zambonelli, L. Angew. Chem., Int. Ed. Engl.
1975, 14, 369.
Crystallographic data for 6a·1/2CH2Cl2 (CIF)
(9) Liu, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 1570.
(10) Liu, Z.; Yamamichi, H.; Madrahimov, S. T.; Hartwig, J. F. J. Am.
Chem. Soc. 2011, 133, 2772.
(11) Julian, L. D.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 13813.
(12) Hesp, K. D.; Stradiotto, M. Org. Lett. 2009, 11, 1449.
(13) Shen, X.; Buchwald, S. L. Angew. Chem., Int. Ed. 2010, 49, 564.
(14) (a) Hesp, K. D.; Stradiotto, M. ChemCatChem 2010, 2, 1192.
(b) Bauer, E. B.; Andavan, G. T. S.; Hollis, T. K.; Rubio, R. J.; Cho, J.;
Kuchenbeiser, G. R.; Helgert, T. R.; Letko, C. S.; Than, F. S. Org. Lett.
2008, 10, 1175.
AUTHOR INFORMATION
Corresponding Author
*E-mail for R.A.W.: rwidenho@chem.duke.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge the NSF (CHE-0555425) for support of this
research.
■
(15) Hesp, K. D.; Tobisch, S.; Stradiotto, M. J. Am. Chem. Soc. 2010,
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DOI: 10.1021/acs.organomet.5b00821
Organometallics XXXX, XXX, XXX−XXX