Kinetics and Mechanism of the Gold-Catalyzed Hydroamination of 1,1-Dimethylallene with N-Methylaniline

Article abstract of DOI:10.1002/chem.202100741

The mechanism of the intermolecular hydroamination of 3-methylbuta-1,2-diene (1) with N-methylaniline (2) catalyzed by (IPr)AuOTf has been studied by employing a combination of kinetic analysis, deuterium labelling studies, and in situ spectral analysis of catalytically active mixtures. The results of these and additional experiments are consistent with a mechanism for hydroamination involving reversible, endergonic displacement of N-methylaniline from [(IPr)Au(NHMePh)]⁺ (4) by allene to form the cationic gold π-C1,C2-allene complex [(IPr)Au(η²-H₂C=C=CMe₂)]⁺ (I), which is in rapid, endergonic equilibrium with the regioisomeric π-C2,C3-allene complex [(IPr)Au(η²-Me₂C=C=CH₂)]⁺ (I′). Rapid and reversible outer-sphere addition of 2 to the terminal allene carbon atom of I′ to form gold vinyl complex (IPr)Au[C(=CH₂)CMe₂NMePh] (II) is superimposed on the slower addition of 2 to the terminal allene carbon atom of I to form gold vinyl complex (IPr)Au[C(=CMe₂)CH₂NMePh] (III). Selective protodeauration of III releases N-methyl-N-(3-methylbut-2-en-1-yl)aniline (3 a) with regeneration of 4. At high conversion, gold vinyl complex II is competitively trapped by an (IPr)Au⁺ fragment to form the cationic bis(gold) vinyl complex {[(IPr)Au]₂[C(=CH₂)CMe₂NMePh]}⁺ (6).

Full text of DOI:10.1002/chem.202100741

Accepted Article
Accepted Article
Title: Kinetics and Mechanism of the Gold-Catalyzed Hydroamination
of 1,1-Dimethylallene with N-Methylaniline
Authors: Ross Widenhoefer, Robert Harris, Kohki Nakafuku, Alethea
Duncan, Robert Carden, and jacob timmerman
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202100741
Link to VoR: https://doi.org/10.1002/chem.202100741
01/2020

10.1002/chem.202100741
Chemistry - A European Journal
FULL PAPER
Kinetics and Mechanism of the Gold-Catalyzed Hydroamination of
1,1-Dimethylallene with N-Methylaniline
Robert J. Harris, Kohki Nakafuku, Alethea N. Duncan, Robert G. Carden, Jacob C. Timmerman, and
Ross A. Widenhoefer*
ABSTRACT. The mechanism of the intermolecular hydroamination
of 3-methyl-1,2-butadiene (1) with N-methylaniline (2) catalyzed by
(IPr)AuOTf has been studied employing a combination of kinetic
analysis, deuterium labelling studies, and in situ spectral analysis of
catalytically active mixtures. The results of these and additional
experiments are consistent with a mechanism for hydroamination
involving reversible, endergonic displacement of N-methylaniline from
[(IPr)Au(NHMePh)]+ (4) by allene to form the cationic gold p-C1,C2-
allene complex [(IPr)Au(h2-H2C=C=CMe2)]+ (I) which is in rapid,
endergonic equilibrium with the regioisomeric p-C2,C3-allene
complex [(IPr)Au(h2-Me2C=C=CH2)]+ (I'). Rapid and reversible outer-
sphere addition of 2 to the terminal allene carbon atom of I' to form
gold vinyl complex (IPr)Au[C(=CH2)CMe2NMePh] (II) is superimposed
on slower addition of 2 to terminal allene carbon atom of I to form gold
The
proliferation
of
gold(I)-catalyzed
allene
hydrofunctionalization processes has likewise spurred interest in
the mechanisms of these processes.[9] Along with insight gained
from computational studies,[10,11] experimental studies have led to
the synthesis of a number of potentially relevant intermediates
including cationic gold p-allene complexes,[12,13] neutral
mono(gold) vinyl complexes[14] and cationic bis(gold) vinyl
complexes.[15,16] Similarly, stereochemical analyses of the gold(I)-
catalyzed hydrofunctionalization of allenes with a diverse range of
nucleophiles have consistently established the net anti-addition of
the H–X bond of the nucleophile across the C=C bond of the
allene, consistent with outer-sphere pathways for C–X bond
formation.[17-21]
Despite the significant progress made in the synthesis and
interrogation of potential intermediates in gold(I)-catalyzed allene
hydrofunctionalization, there remains a dearth of information
regarding the behavior of these potential intermediates under
catalytic conditions, particularly in the context of intermolecular
allene hydrofunctionalization. Mechanistic analysis of the gold(I)-
vinyl complex (IPr)Au[C(=CMe2)CH2NMePh] (III).
Selective
protodeauration of III releases N-methyl-N-(3-methylbut-2-en-1-
yl)aniline (3a) with regeneration of 4. At high conversion, gold vinyl
complex II is competitively trapped by an (IPr)Au+ fragment to form
the
cationic
bis(gold)
vinyl
complex
{[(IPr)Au]2[C(=CH2)CMe2NMePh]}+ (6).
catalyzed
intramolecular
hydroarylation[22]
and
hydroalkoxylation[23-25] of allenes and the related intramolecular
hydroalkoxylation of alkynes[26,27] have established mechanisms
involving turnover-limiting protodeauration with or without the
involvement of off-cycle bis(gold) vinyl complexes. Toste and
Goddard have likewise reported the mechanistic analysis of the
gold(I)-catalyzed intermolecular hydroamination of 1,7-
diphenylhepta-3,4-diene with methyl carbazate and proposed a
mechanism involving turnover-limiting isomerization of a gold h2-
allene complex to a gold h1-allylic cation transition state on the
basis of computational and kinetic data.[28] However, as we have
previously noted,[13,29] ambiguity regarding the nature of the
catalyst resting state(s) in this system precludes the drawing of
firm mechanistic conclusions from these kinetic data.
Introduction
Cationic gold(I) complexes have emerged over the past
decade as highly active catalysts for the p-activation and
subsequent functionalization of C–C multiple bonds,[1] notably for
the
cycloisomerization
of
1,n-enynes[2]
and
the
hydrofunctionalization of C–C multiple bonds.[3] The utility of
cationic gold(I) complexes in these transformations can be traced
to the high electrophilicity and low oxophilicity of the 12-electron
(L)Au+ fragment,[4] which leads to high reactivity coupled with
good functional group compatibility.[1-3] Within this broad family of
gold(I)-catalyzed p-activation processes, the gold(I)-catalyzed
hydrofunctionalization of allenes has received particular attention
owing to the diverse range of nucleophiles that participate in these
transformations[5] and the potential for diastereo-[6] and
enantioselective transformations.[7] Indeed, gold(I)-catalyzed
allene hydrofunctionalization has been applied to good effect in a
number of complex molecule syntheses.[8]
In response to limited experimental information regarding the
mechanisms of gold(I)-catalyzed allene hydrofunctionalization,
we have recently reported the kinetic and mechanistic analysis of
the gold(I)-catalyzed intermolecular hydroalkoxylation of 3-
methyl-1,2-butadiene (1) with 1-phenylpropanol catalyzed by
(IPr)AuOTf.[29] These experiments supported a mechanism
involving endergonic displacement of triflate from (IPr)AuOTf with
1 followed by irreversible, outer-sphere addition of alcohol to the
resulting
gold
p-C1,C2-allene
complex
[(IPr)Au(h2-
H2C=C=CMe2)]+ (I) (Scheme 1, eq 1). The microscopic rate
constants controlling the formation and consumption of I were of
similar magnitude, such that the reaction order varied depending
on the absolute and relative concentrations of 1 and alcohol (eq
1). Under conditions of excess allene 1, the reaction rate
displayed first-order rate dependence on [ROH] and between
zero- and first-order rate dependence on [1], while under
conditions of excess alcohol, the reaction rate displayed first-
[a]
Dr. R. J. Harris, Dr. J C. Timmerman, K. Nakafuku, S. Liu, R. G.
Carden, Dr. A. N. Duncan, Prof. Dr. R. A. Widenhoefer
Department of Chemistry
Duke University
French Family Science Center, Durham, North Carolina, USA
E-mail: rwidenho@chem.duke.edu
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.202100741
Chemistry - A European Journal
FULL PAPER
Me
Me
H
order rate dependence on [1] and zero-order rate dependence on
[ROH].
(IPr)AuOTf (5 mol %)
+
N
Ph
Me
dioxane, 40 °C, 18 h
93 %
OTf–
Me
3a:3b ≥ 97:3
Me
Me
Me
3
ROH
1
2
1
(IPr)Au
Me
Me Me
N
I
Me
Me
OTf–
Me
Me
+
Me
N
H
O
(IPr)AuOTf
Ph
Ph
(IPr)Au
R
3a
3b
Me
Me
OR
Scheme 2. Gold-catalyzed hydroamination of 1 with N-methylaniline.
OTf–
Me
Me
(IPr)Au
OR
Table 1. Pseudo-zero-order rate constants for the hydroamination of 1 with 2
(0.17 M) catalyzed by (IPr)AuOTf in dioxane at 40 °C.
Scheme 1. Mechanism of gold(I)-catalyzed hydroalkoxylation of allene 1.
Entry
[1] (M)
1.7
[(IPr)AuOTf] (mM)
(105)kobs (s–1
1.47 ± 0.05
0.71 ± 0.02
3.2 ± 0.1
)
1
2
3
4
5
6
7a
8.35
4.34
16.0
8.13
8.13
8.13
8.24
ꢄꢅꢄꢆ[ꢇ][ROH][ꢈꢉ]ꢊꢋꢊ
ꢄ–ꢅ + ꢄꢅ[ꢇ] + ꢄꢆ[ROH]
ꢀꢁꢂꢃ =
Eq. (1)
1.7
1.7
We targeted gold(I)-catalyzed allene hydroalkoxylation for
initial kinetic investigation believing this transformation to be
representative of the gold(I)-catalyzed hydrofunctionalization of
allenes with weakly-binding nucleophiles. We sought to gain a
similar understanding of the mechanisms of the gold(I)-catalyzed
intermolecular hydrofunctionalization of allenes with more basic
and potentially strongly binding nucleophiles. To this end, we
have investigated the kinetics and mechanism of the gold(I)-
catalyzed hydroamination of 3-methyl-1,2-butadiene (1) with N-
methylaniline (2; Scheme 2) and herein we provide a full account
of these investigations.
0.83
3.8
0.87 ± 0.04
3.15 ± 0.09
3.9 ± 0.1
4.5
1.7
1.20 ± 0.07
[a] N-methylaniline-N-d (2-N-d, 92% d) was used in this reaction.
0.18
0.16
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
Results and Discussion
Kinetics of the Hydroamination of 1 with 2. Toward the
elucidation of the mechanism of the gold(I)-catalyzed
hydroamination of allenes with aryl amines, we focused our efforts
on the hydroamination of 3-methyl-1,2-butadiene (1) with N-
methylaniline (2) catalyzed by (IPr)AuOTf, which displays both
high efficiency and high regioselectivity for the formation of the
terminally-disubstituted allylic amine 3a (3a:3b ≥97:3; Scheme
2).[30] Similarly, the single component catalyst (IPr)AuOTf was
employed to avoid any potential complications associated with the
presence of silver salts.[31] In an initial experiment, a solution of 1
(1.7 M), 2 (0.17 M), anthracene (70 mM; internal standard), and
a catalytic amount of (IPr)AuOTf (8.35 mM; 5 mol %) in dioxane
at 40 °C was analyzed periodically by HPLC. A plot of [2] versus
time was linear to >3 half-lives with a pseudo-zero-order rate
constant of 1.47 ± 0.05 ´ 10–5 M s–1 (Figure 1, Table 1, entry 1),
which established zero-order dependence of the rate on N-
methylaniline concentration; a plot of [3a] versus time was
0
2
4 6
time (s/1000)
8
10 12
Figure 1. Plot of [2] versus time for the hydroamination of 1 (1.7 M) with 2 (0.17
M) catalyzed by (IPr)AuOTf (8.35 mM) in dioxane at 40 °C.
To determine the dependence of the rate of hydroamination
on catalyst concentration, pseudo-zero-order rate constants were
determined for the gold-catalyzed reaction of 2 (0.17 M) with 1
(1.7 M) as a function of [(IPr)AuOTf] from 0 to 16 mM (Table 1,
entries 1-3). A plot of kobs versus catalyst concentration was linear
(Figure 2), which established the first-order dependence of the
rate on catalyst concentration. To determine the dependence of
the rate of hydroamination on allene concentration, pseudo-zero-
order rate constants were determined for the reaction of 2 (0.17
M) with 1 catalyzed by [(IPr)AuOTf] (~8 mM) as a function of
likewise linear with
a
pseudo-zero-order rate constant
indistinguishable from that determined from a plot of [2] versus
time.[32]
This article is protected by copyright. All rights reserved.

10.1002/chem.202100741
Chemistry - A European Journal
FULL PAPER
Me
allene concentration from 0.83 to 4.5 M (Table 1, entries 1, 4-6).
A plot of the corresponding pseudo-first-order rate constants k (k
= kobs/[cat]) versus [1] was linear (Figure 3), which established the
first-order dependence of the rate on allene concentration and
overall the second-order rate law rate = k'[1][(IPr)AuOTf] where k'
= 1.08 ± 0.05 ´ 10–3 M–1 s–1 (DG‡313K = 22.6 kcal mol–1).
3.5
Me
(IPr)AuOTf
(5 mol %)
Me
D
Me
+
N
Ph
Me
N
Me
dioxane, 40 °C
D
Ph
1
2-N-d, 92% d
3a-d1, 68% d
kH/kD = 1.22 ± 0.08
Scheme 3. Gold-catalyzed deuterioamination of 1 with N-methylaniline-d1.
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Reversibility of Hydroamination. The selective formation of
the terminally disubstituted allylic amine 3a in preference to the
less-stable terminally unsubstituted allylic amine 3b raises the
possibility that 3a is formed under catalytic conditions via the
secondary isomerization of 3b. Indeed, gold(I) complexes are
known to catalyze the 1,3-transposition of allylic ethers in the
presence of alcohols.[33] However, periodic 1H NMR analysis of a
solution of 2 (0.15 M), 1 (1.0 M) and (IPr*)AuOTf (IPr* = IPr-1-
13C1; 7.5 mM) in dioxane-d8 at 60 °C revealed the slow, steady
accumulation of trace amounts of 3b (~3% of the reaction mixture
at 95% conversion), which is not consistent with 3b as an
intermediate in the formation of 3a. Indeed, when a 1:1 mixture
of 3b and 2 and a catalytic amount of (IPr)AuOTf was heated at
40 °C in dioxane, no detectable consumption of 3b or formation
of 3a was observed after 12 h by GC analysis (Scheme 4). Taken
together, these experiments rule out 3b as an intermediate in the
gold(I)-catalyzed hydroamination of 1 with 2 to form of 3a.
0
3
6
9
12 15 18
[(IPr)AuOTf] (mM)
Figure 2. Plot of pseudo-zero-order rate constants versus catalyst
concentration for the hydroamination of 1 (1.7 M) with 2 (0.17 M) catalyzed by
(IPr)AuOTf (0-16 mM) in dioxane at 40 °C.
5
4
3
2
1
0
Me Me
Me
(IPr)AuOTf (10 mol %)
Me
+
N
Ph
N
dioxane, 40 °C
12 h
H
Ph
2
3b
Me
Me
Me
N
0
1
2
3
4
5
Ph
[1] (M)
3a (not observed)
Figure 3. Plot of pseudo-first-order rate constants (k = kobs/[cat]) versus allene
concentration for the hydroamination of 1 (0-5 M) with 2 (0.17 M) catalyzed by
(IPr)AuOTf (8.2 mM) in dioxane at 40 °C.
Scheme 4. Gold-catalyzed reaction of 3b with N-methylaniline rules out 3b as
an intermediate in the formation of 3a.
In situ Spectroscopic Analysis of Hydroamination.
A
To gain insight into the potential involvement of a proton
transfer process in a kinetically relevant step in the gold-catalyzed
hydroamination of 1 with 2, we evaluated the kinetic isotope effect
(KIE) resulting from deuterioamination of 1 with N-deuterio-N-
methylaniline (2-N-d). To this end, reaction of 1 (1.7 M) with 2-N-
d (0.17 M, 92% d) catalyzed by (IPr)AuOTf (8.13 mM) in dioxane
at 40 °C formed 3a-d1 with 68% deuterium incorporation
exclusively at the vinylic position (Scheme 3). The corresponding
plot of [2] versus time was linear with a pseudo-zero-order rate
constant of 1.20 ± 0.07 ´ 10–5 s–1 (Table 1, entry 7). Comparison
of the corresponding pseudo-first-order rate constant with that
determined for the hydroamination of 1 with 2 provides a
deuterium KIE of kH/kD = 1.22 ± 0.08.
series of experiments were performed to gain insight into the
resting state(s) and relevant equilibria in the gold-catalyzed
hydroamination of 1 with 2. In one experiment, a solution of 1 (1.2
M), 2 (0.17 M), and the 13C-labelled gold complex (IPr*)AuOTf
(IPr* = IPr-1-13C1; 18 mM) in dioxane-d8 was monitored
periodically by 13C NMR spectroscopy at 25 °C. The resonance
at d 168.9 corresponding to the carbene carbon atom of N-
methylaniline complex [(IPr*)Au(NHMePh)]+ (4-13C1) was
observed within the first ~5% conversion and was the exclusive
carbene-containing species observed through ~80% conversion
(Figure 4).[34] At higher (~90%) conversion, a new resonance at d
187.8 appeared and accounted for ~20% of the carbene-
containing species. This resonance did not correspond to the
gold triflate complex (IPr)AuOTf (d 162.8), the gold p-C1,C2-
allene complex I (d 184.2),[12,34] or the gold-product complex
[(IPr)Au(h1-NMePhCH2C=CMe2)]+ (5; d 166.4).[34] Rather, the
This article is protected by copyright. All rights reserved.

10.1002/chem.202100741
Chemistry - A European Journal
FULL PAPER
spectroscopy and behaviour of this complex was most consistent
with the terminally-unsubstituted bis(gold) vinyl complex
{[(IPr*)Au]2[C(=CH2)CMe2NMePh]}+ (6-13C2) (see below).
ratio of resonances at d 5.07 (br d, J = 4.4 Hz) and 4.32 (br d, J =
4.5 Hz), assigned to the terminal vinyl protons of 6-13C2, which
grew in concomitantly with the d 187.8 resonance of 6-13C2 in the
13C NMR spectrum, ultimately accounting for ~25% of the reaction
mixture. Upon complete consumption of 4-13C1 (110 min), 1H
NMR analysis revealed the significant broadening of the
resonances corresponding to 3a•H+ and the appearance of
resonances corresponding to allylic amine 3b [d 5.93 (dd, J = 10.4,
17.2 Hz), 5.12 (dd, J = 17.2, 1.6 Hz), 4.87 (dd, J = 10.4, 1.6 Hz)],
which accounted for ~25% of the reaction mixture (Scheme 6).
H
H
Me
Me
Me
Me
N
Me
Me
(IPr)Au NH
(IPr)Au
Me
(IPr)AuOTf
(IPr)Au
N
Ph
(IPr)Au
(IPr)Au
Ph
Ph
Me Me
6 (δ 187.8)
4 (δ 168.9)
I (δ 184.2)
5 (δ 166.4)
δ 162.8
Figure 4. Potential intermediates in the gold-catalyzed hydroamination of 1 with
2 along with the diagnostic 13C NMR chemical shifts of the C1-carbene carbon
atom in dioxane-d8 at 25 °C.[34]
Me
2 (34 mM)
1 (0.51 M)
(IPr*)AuOTf
(34 mM)
(IPr*)Au NH
25 °C
110 min, 25 °C
Ph
4-13C1
A number of additional experiments were conducted to further
clarify the relative binding affinities of 1, 2, and 3a to the twelve-
electron gold fragment (IPr)Au+ and to provide insight into the
structure and reactivity of 6. In one experiment, a large excess of
1 (1.1 M) was added to a solution of (IPr*)AuOTf (33 mM) in
dioxane-d8 (Scheme 5). 13C NMR analysis at 25 °C revealed
quantitative conversion to the gold p-allene complex I-13C (d
184.2).[35] Addition of 2 (1.0 equiv) to this solution led to immediate
(~2 min) and quantitative conversion of I-13C to 4-1-13C1, while 1H
NMR analysis revealed no detectable concentrations of free 2 and
a small amount of 3a, presumably due to employment of a slight
excess of 2.[36-38] From these observations and assuming that
10% of both I-13C and 2 would have been detected in the 13C and
1H NMR spectra, respectively, we can assign a lower limit to the
equilibrium constant for the conversion of I and 2 to 4 and 1 of Keq
= [4][1]/[I][2] ≥ 3 ´ 105. Furthermore, the rapid and quantitative
formation of 4 from the reaction of I with 2 establishes the
reversible formation of I from 4 under catalytic conditions.
H
H
Me
N
Me
Me
N
(IPr*)Au
Ph
+
+
Ph
Ph
N
Me
(IPr*)Au
Me Me
Me
H
Me Me
3b
2 : 1 : 1
3a•H+
6-13C2
Scheme 6. Stoichiometric reaction of 4-13C1 with 1.
In a third experiment, a solution of 6-13C2 in dioxane-d8 was
generated in a manner similar to that described in the preceding
paragraph and the solution was evaporated to dryness,
redissolved in dioxane-d8, and analysed by NMR spectroscopy.
13C NMR analysis revealed
a 1.8:1 ratio of C1-carbene
resonances at d 187.8 corresponding to 6-13C2 and d 166.4
corresponding to the gold-3a adduct 5-13C1, while 1H NMR
analysis revealed a ~2:1:1 mixture of 3a•H+, 5-13C1, and 6-13C2
(Scheme 7). Addition of 2 (~1 equiv) to this solution led to
immediate disappearance of 6-13C2 and 5-13C1 to form 4-13C1 as
the exclusive carbene containing species as determined by 13C
NMR analysis and the formation of a 2.8:1.0:2.4 mixture of 3a, 2,
Me
Me
Me
(IPr*)Au NH
Ph
2 (1 equiv)
Keq ≥ 3 ✕ 105
1 (1.1 M)
(IPr)AuOTf
(33 mM)
dioxane-d8
25 °C
(IPr*)Au
and 4-13C1 and traces of 3b as determined by H NMR analysis
1
4-13C1
(Scheme 7). 1H and 13C NMR analysis of the reaction mixture
also provided a lower limit for the equilibrium constant for the
conversion of 5 and 2 to 4 and 3a (i.e. the relative binding affinity
of 2 relative to 3a) of Keq = [4][3a]/[5][2] ≥ 80, assuming that >5%
of 5 would have been detected in the 13C NMR spectrum. The
failure of the reaction of 6-13C2 with 2 to form significant quantities
of 3b established that 6-13C2 is not predisposed to the formation
of 3b.
I-13C1
Scheme 5. Stoichiometric reaction of I-13C ([Au] = 33 mM) with 2 in dioxane-d8
at 25 °C (IPr* = IPr-1-13C).
In a second experiment, 2 (1 equiv) was added to a solution
of (IPr*)AuOTf (34 mM) in dioxane-d8 at 25 °C. 13C NMR analysis
revealed the immediate and quantitative formation of 4-13C1
(Scheme 6). The resulting solution was treated with excess 1
(0.50 M) and analysed by 13C NMR spectroscopy at 25 °C, which
revealed no detectable formation of I-13C1, consistent with the
much higher binding affinity of 2 to gold relative to 1. However,
periodic 13C NMR analysis of the solution revealed the
quantitative conversion of 4-13C1 to 6-13C2 over the course of 110
min (t1/2 = ~15 min). Periodic 1H NMR analysis of the solution over
this same time period revealed the appearance of resonances
corresponding to protonated product 3a•H+ [d 5.20 (br t, J = 7.0
Hz, 1 H), 4.04 (br d, J = 7.2 Hz, 2 H), 3.06 (br s, 3 H)],[39] which
accounted for ~50% of the reaction mixture after 110 min.
Periodic 1H NMR analysis also revealed the appearance of a 1:1
This article is protected by copyright. All rights reserved.

10.1002/chem.202100741
Chemistry - A European Journal
FULL PAPER
Me
nitrogen atom of 6 relative to 3a owing to the proximal positive
charge present on the bis(gold) fragment of 6.
1) 1 (0.51 M)
(IPr*)Au NH
2) evaporate
Ph
3) dioxane-d8
4-13C1
Proposed Mechanism of Hydroamination. The mechanism
for the hydroamination of 1 with 2 catalyzed by (IPr)AuOTf
depicted in Scheme 8 is consistent with all our experimental
observations. Associative, endergonic displacement of 2 from
gold N-methylaniline complex 4 with allene 1 would form the gold
p-C1,C2-allene complex I, which is in rapid, endergonic
equilibrium (DG‡ » 10 kcal/mol; DG ≥ 2 kcal/mol) with the
regioisomeric gold p-C2,C3-allene complex [(IPr)Au(h2-
Me2C=C=CH2)]+ (I').[12] Rapid and reversible outer-sphere[17-22]
addition of 2 to the terminal allene carbon atom of I' would form
the gold vinyl complex II, whereas slower addition of 2 to the
terminal allene carbon atom of I would form the gold vinyl complex
III. Irreversible protodeauration of II would release allylic amine
3b in the minor reaction pathway while more facile irreversible
protodeauration of III would form 3a via gold p-alkene complex
IV[41] in the major pathway, in both cases with regeneration of 4.
At high conversion where the concentration of 2 is low, gold vinyl
complex II is competitively trapped by a (IPr)Au+ fragment to form
the bis(gold) vinyl complex 6, which accumulates under reaction
conditions and presumably functions as an off-cycle catalyst
reservoir.[24]
6:5:3a = 1:1:2
H
H
Me
Me
Me
N
Me
Ph
(IPr*)Au
(IPr*)Au
+
+
N
Me
(IPr)Au
N
Me
Ph
Me
H
Ph
5-13C1
Me Me
3a•H+
6-13C2
2 (1 equiv)
Me
Me
Ph
Me
(IPr*)Au NH
Me
+
HN
+
N
Me
Ph
Ph
3a
4-13
C
2
2.8 : 1.0 : 2.4
Scheme 7. Reaction of 4-13C1 with excess 1 followed by evaporation and
dissolution in dioxane-d8 to form a mixture of 6-13C2, 5-13C1, and 3a•H+ and
subsequent reaction with 2.
Assignment of 6 as a bis(gold) vinyl complex. All of our
experimental observations are consistent with the assignment of
complex 6 as the terminally unsubstituted bis(gold) vinyl complex
{[(IPr)Au]2[C(=CH2)CMe2NMePh]}+. First, both the chemical shift
and peak separation of the 1H NMR resonances at d 5.07 (br d, J
= 4.4 Hz) and d 4.32 (br d, J = 4.5 Hz) assigned to the vinylic
resonances of 6 and the chemical shift of the 13C carbene
resonance of 6 (d 187.8) are consistent with known bis(gold) vinyl
Me Me
Me Me
Me
N
(IPr)Au
(IPr)Au
k5[H+]
4
(IPr)Au
H
NMePh
+
2
NMePh
Ph
Me Me
3b
H
H
H
II
6
[H+
k–3
]
k3[2]
Me Me
(IPr)Au
I’
complexes
generated
via
gold-mediated
allene
hydrofunctionalization.[15,22,25,40]
Second, the terminally
unsubstituted allylic amine 3b, formed from the reaction of 4 with
1 in the absence of 2 (Scheme 6) is the anticipated product
K
Me
Me
2
2
generated via protodeauration of
6
or, more likely,
(IPr)Au
Me
Me
protodeauration of the corresponding mono(gold) vinyl complex II
(Scheme 8). Third, although neither the spectroscopy of 6 nor its
conversion to 3b distinguish between a terminally unsubstituted
bis(gold)- or mono(gold) vinyl complex, bis(gold) vinyl complexes
are known to be highly resistant toward protodeauration, in sharp
contrast to the facile protodeauration of mono(gold) vinyl
complexes.[15,22,25,40] Therefore, the observed stability of 6 in the
presence of the anilinium salt 3a•H+ (~35 mM) argues strongly
against 6 as a mono(gold) vinyl complex but is fully consistent with
a bis(gold) vinyl complex. Fourth, although (mono)gold vinyl
complexes are known to bind strongly to the twelve-electron
(L)Au+ fragment, under catalytic conditions the mono(gold) vinyl
complex II would complete with the strong binding ligand 2 for
available (IPr)Au+. Therefore, the observed formation of 6 only
under conditions of low [2] under both catalytic and stoichiometric
conditions and the rapid decomposition of mixtures of 6 and 3a•H+
(~35 mM) upon addition of 2 are fully consistent with the
formulation of 6 as a bis(gold) vinyl complex. In addition, the
formation of 3a•H+ concurrently with 6 under stoichiometric
conditions strongly suggests that 6 exists largely in the non-
protonated form, consistent with the diminished basicity of the
k1
k2
k–2
k–1
I
H+
1
Me
Me
Me
(IPr)Au NH
NMePh
Ph
(IPr)Au
4
III
Me
NMePh
k4
H+
Me
Me
Me
3a
(IPr)Au
NMePh
2
IV
Scheme 8. Proposed mechanism for the gold(I)-catalyzed hydroamination of 1
with 2 catalyzed by (IPr)AuOTf.
The rapid formation of gold N-methyl aniline complex 4 upon
treatment of I with 2 under stoichiometric conditions (Scheme 5)
and the much higher binding affinity of 2 for the (IPr)Au+ fragment
relative to 1 (Keq ≥ 3 ´ 105) establishes the reversible, endergonic
(DG298K ≥ 7.5 kcal/mol) formation of I from 4 under catalytic
conditions (Scheme 8). Note also that although the mechanism
depicted in Scheme 8 invokes intermolecular protodeauration, we
This article is protected by copyright. All rights reserved.

10.1002/chem.202100741
Chemistry - A European Journal
FULL PAPER
Ph
have no evidence that would distinguish between inter- and
intramolecular pathways for protodeauration.[42-45]
Ph
O
H
(L)AuOTs/Et3N
toluene, 25 °C
Ph
Ph
The accumulation of 6 under catalytic conditions at high
conversion coupled with the formation of 3b in only trace amounts
(≤3%) under catalytic conditions points to the rapid and reversible
formation of gold vinyl complex II under catalytic conditions.
However, the absence of a large deuterium KIE for the
deuterioamination of 1 with 2-N-d (kH/kD = 1.22 ± 0.08) coupled
with the reversible formation of I from 4 argues against a scenario
involving rapid and reversible formation of both II and III followed
by turnover-limiting protodeauration of III under Curtin-Hammett
conditions, which would be expected to display a large primary
KIE. Rather, these observations are more consistent with a
scenario involving rapid and reversible formation of II
superimposed on much slower formation of III. The small but
H
OH
AuL
8a
R
Ph
Ph
(L)AuOTs/Et3N
toluene, 25 °C
O
Me
R
R = H (7a) or Me (7b)
Me
8b
Scheme 9. Disparate reactivity of terminally substituted and terminally
disubstituted d-allenyl alcohols toward protodeauration.
Kinetic Model for Hydroamination. We sought to derive
differential rate equations for the mechanism depicted in Scheme
significant deuterium KIE points to
a kinetically relevant
8
that would describe the kinetic behaviour of catalytic
protodeauration step, suggesting that the energy barrier for the
protodeauration of III is not significantly higher than is the energy
barrier for formation of III from I and 2 (see below). The failure to
form significant amounts of 3b under catalytic conditions can
therefore be attributed to the less favorable protodeuaration of II
relative to III and not to the preferential attack of aniline on the
terminal allene carbon atom of gold p-C1,C2-allene complex I
relative to attack of aniline on the terminal allene carbon atom of
gold p-C2,C3-allene complex I'.
Both the kinetically preferred addition of 2 to the more
substituted allene terminus of I' relative to the addition of 2 to the
less substituted allene terminus of I and the more facile
protodeauration of III relative to II are consistent with the general
reactivity trends displayed by gold(I) s- and p-complexes. For
example, the kinetically preferred addition of 2 to the more
substituted allene terminus of I' is in accord with the established
polarization of p-bonds upon coordination to (L)Au+[16] and also
with the high Markovnikov selectivity displayed by the gold(I)-
catalyzed hydroamination of alkenes and alkynes.[3] Likewise, the
more facile protodeauration of the terminally disubstituted vinyl
complex III relative to the terminally unsubstituted vinyl complex
II is fully consistent with both experimental and computational
analyses of protodeauration, which have established the
increasing rate of protodeauration with the increasing electron
density of the s-bound ligand.[41,46,47] For example, we have
previously shown that treatment of the terminally unsubstituted d-
allenyl alcohol 7a with a stoichiometric mixture of (P1)AuOTf [P1
hydroamination under conditions where aggregation of
intermediate II to form 6 was negligible (0 - ~90% convn), which
constitutes the concentration regime where the bulk of our kinetic
data was determined. Under these conditions, (1) gold–N-
methylaniline complex 4 is the only gold-containing species that
accumulates under catalytic conditions ([Au]tot = [4]), (2) formation
of allylic amine 3b is negligible (k5 » 0), as is aggregation of II, and
(3) protodeauration (III ® IV), and hence hydroamination, is
irreversible.[42-45] Under these restrictions, application of the
Bodenstein (steady-state) approximation to intermediates I, II,
and III generates the rate expression depicted in eq 2. This rate
equation predicts first-order rate dependence on [catalyst] and [1],
zero-order rate dependence on [2], and the potential for a
deuterium KIE for the deuterioamination of 1, depending on the
magnitude of the microscopic rate constant k4 relative to k–2. For
example, under conditions of turnover-limiting protodeauration
(i.e. k4 << k–2), rate equation 2 simplifies to that depicted in eq 3,
which predicts that the primary deuterium KIE will reach its
maximum. Conversely, under conditions of turnover-limiting C–N
bond formation (i.e. k–2 = 0) rate equation 2 simplifies to rate
equation 4, which predicts that the primary deuterium KIE will fall
to zero.
[ ][
ꢄꢅꢄꢆꢄꢌ ꢇ ꢈꢉ
]
ꢊꢋꢊ
ꢀꢁꢂꢃ =
Eq. (2)
ꢄ–ꢅꢄ–ꢆ + ꢄ–ꢅꢄꢌ + ꢄꢆꢄꢌ
=
P(t-Bu)2o-biphenyl] and Et3N led to isolation of the
ꢀꢁꢂꢃ = ꢍ ꢍꢆꢄꢌ[ꢇ][ꢈꢉ]ꢊꢋꢊ ꢎℎꢃꢏ ꢄꢌ << ꢄ–ꢆ Eq. (3)
ꢅ
corresponding terminally unsubstituted gold vinyl complex 8a
(Scheme 9).[48] In contrast, the analogous reaction of the
terminally disubstituted allenyl alcohol 7b with (P1)AuOTf and
Et3N formed none of the anticipated vinyl gold complex but
instead led to exclusive formation of the vinyl ether 8b, pointing to
the highly facile protodeauration in these latter case (Scheme
9).[48]
[ ][
ꢄꢅꢄꢆ ꢇ ꢈꢉ
]
ꢊꢋꢊ
ꢀꢁꢂꢃ =
ꢎℎꢃꢏ ꢄ–ꢆ = 0 Eq. (4)
ꢄ–ꢅ + ꢄꢆ
The experimental rate law determined for the gold(I)-
catalyzed hydroamination of 1 with 2 (rate = k[1][Au]tot) and the
small
but
significant
deuterium
KIE
observed
for
deuterioamination of 1 with 2-N-d (kH/kD = 1.22 ± 0.08) is
consistent with the kinetic scenario described by rate equation 2
and approaches the limiting scenario described by rate equation
4 involving turnover-limiting C–N bond formation. However, the
small primary KIE observed for deuterioamination indicates that
This article is protected by copyright. All rights reserved.

10.1002/chem.202100741
Chemistry - A European Journal
FULL PAPER
the limiting condition k4 << k–2 associated with rate expression 7
is not fully met, suggesting that the transition state energy for
protodeauration is not significantly lower than is that for C–N bond
formation.
gold h1-allylic cation transition state that is trapped by methyl
carbazate either prior to or after progression to the achiral h1-
allylic cation. Experimentally, this mechanism was supported by
(1) the rate law: rate = k[allene][Au]tot with ~zero-order rate
dependence on methyl carbazate concentration and (2)
assignment of the gold p-allene complex [(Ph3P)Au(h2-
PhCH2CH2C=C=CCH2CH2Ph)]+ (10) as the catalyst resting state
as determined by in situ 31P NMR analysis and independent
syntheses.
The kinetics of the gold-catalyzed hydroamination of 1 with 2
at high conversion (≥90%) become largely intractable owing to (1)
the aggregation of two reactive intermediates (II and 4), (2) the
accumulation of two different catalytic species (4 and 6) under
reaction conditions, and (3) the conversion-dependent change in
catalyst composition. However, consideration of the equilibria
involved in the formation of 6 from 4 suggests that at high
conversion the reaction rate should approach first-order
dependence on [2] and half-order dependence on [cat] while
maintaining first-order dependence on [1]. It is therefore not
surprising that we observed no such deviations from the rate law:
rate = k[1][Au]tot in our kinetic analyses seeing that the onset of
catalyst aggregation to form 6 (>80% convn) was very near the
end range at which kinetic data was collected and because 6
accounted for only ~20% of the catalyst composition at 90%
conversion.
R
NHCO2Me
HN
Ph3PAuNTf2 (cat)
+ H2NNHCO2Me
CD3NO2, 45 °C
R
R
R
9
R = (CH2)2Ph
Scheme 10. Gold-catalyzed hydroamination of 1,7-diphenyl-3,4-heptadiene
with methyl carbazate. [28]
Widenhoefer and Brooner subsequently demonstrated that
the species assigned by Toste and Goddard as p-allene complex
10 is rather the catalyst decomposition product [(PPh3)2Au]+,[13]
and without clear identification of the catalyst resting state(s) in
the gold-catalyzed hydroamination of 1,7-diphenyl-3,4-
heptadiene with methyl carbazate, the zero-order rate
dependence on methyl carbazate concentration need not be
attributed to turnover-limiting allene activation. For example, if the
Relationship
to
Other
Gold(I)-Catalyzed
Hydrofunctionalization Processes. As noted in the Introduction,
we have recently reported the kinetic/mechanistic analysis of the
hydroalkoxylation of 1 with 1-phenylpropanol catalyzed by
(IPr)AuOTf in toluene.[29] Worth noting are two of the key
differences in the catalytic/kinetic behavior of hydroamination of
allene 1 with 2 relative to the hydroalkoxylation of allenes with
aliphatic alcohols that can be traced directly to the greater binding
affinity and basicity of 2 relative to 1-phenylpropanol. Firstly, in
the case of catalytic hydroalkoxylation, complexation of alcohol to
gold was insignificant and the gold triflate complex (IPr)AuOTf and
the gold p-allene complex I both accumulated under reaction
conditions, leading to rate dependence on both [allene] and
[alcohol] that varied between zero- and first-order depending on
reaction conditions. Conversely, in the case of hydroamination,
the binding affinity of 2 so exceeds that of both OTf– and 1 that
the gold aniline complex 4 represented to sole catalyst resting
state prior to the onset of catalyst aggregation, leading to zero-
order rate dependence on [2] and first-order rate dependence on
known
gold
methyl
carbazate
complex
–
[(PPh3)Au(H2NNHCO2Me)]+ NTf2 (11)[28] were the predominant
species that accumulated under catalytic conditions, the
experimentally determined rate law (rate = k[allene][Au]tot) would
be inconsistent with the proposed mechanism involving turnover-
limiting allene activation, but would be consistent with a
mechanism involving reversible formation of 10 followed by either
irreversible, turnover-limiting outer-sphere attack of methyl
carbazate or reversible addition of carbazate to 10 followed by
turnover-limiting intramolecular protodeauration, analogous to the
mechanisms proposed for the gold-catalyzed hydroamination of 1
with 2 depicted in Scheme 8.
[allene].
Secondly, in the case of hydroalkoxylation,
We sought to gain additional information regarding the
distribution of gold-containing species present under reaction
conditions for the gold-catalyzed hydroamination of 1,7-diphenyl-
3,4-heptadiene with methyl carbazate. Unfortunately, as was
reported by Toste and Goddard,[28] 31P NMR analysis of catalytic
mixtures of 1,7-diphenyl-3,4-heptadiene, methyl carbazate, and
Ph3PAuNTf2 at 45 °C showed no discernible peaks in the spectral
range d 25 - 40 that would reveal the accumulation of 10 (d 36)[13]
and/or 11 (d 28),[28] presumably due to rapid intermolecular ligand
exchange, nor would 31P NMR analysis likely distinguish between
methyl carbazate complex 11 and the gold allylic carbazate
complex 12 (d 28) owing to the nominal dispersion of the 31P NMR
resonances of these complexes (Figure 5).[49] However, in the
slow exchange regime (–25 °C) in CD3NO2, the binding affinity of
methyl carbazate exceeds that of 1,7-diphenyl-3,4-heptadienene
by a factor of 70 and of 9 by a factor of 20 (Scheme 11). Because
we do not know the temperature dependence of these equilibria,
no definitive conclusions can be drawn regarding the distribution
protodeauration was fast under all conditions, whereas,
protodeauration was kinetically relevant in the case of the
hydroamination of
1 with 2 (although not rate-limiting),
presumably due to the greater basicity of the aryl amines relative
to alcohols and ethers. In the case of hydroalkoxylation of 1 with
1-phenylpropanol, the significantly more facile protodeauration
relative to C–O bond formation precluded the accumulation of
bis(gold) vinyl complexes.
As was likewise noted in the Introduction, Toste and Goddard
have reported a combined experimental/computational analysis
of the intermolecular hydroamination of 1,7-diphenyl-3,4-
heptadiene with methyl carbazate to form N-allylic carbazate 9
catalyzed by (Ph3P)AuNTf2 in nitromethane at 45 °C (Scheme
10).[28] Some additional comments regarding this mechanism are
warranted in lieu of the results disclosed in this work. The authors
invoked a "two-step, no intermediate" mechanism involving
turnover-limiting isomerization of a gold h2-allene complex to a
This article is protected by copyright. All rights reserved.

10.1002/chem.202100741
Chemistry - A European Journal
FULL PAPER
of catalytic species under reaction conditions (CD3NO2, 45 °C).
Nevertheless, these observations do support a scenario involving
gold methyl carbazate complex 11 as the predominant species
present under catalytic conditions, particularly given the
conditions of excess methyl carbazate employed in the kinetic
analyses,[28] and therefore, support a mechanism analogous to
that depicted in Scheme 8 in favor of the "two-step, no
nucleophile to the less substituted or more substituted allene
terminus, respectively.[3] However, the origins of the nucleophile,
solvent, and ligand-dependent regioselectivity of the gold(I)-
catalyzed hydrofunctionalization of differentially substituted
allenes remain obscure and there has been no unifying
mechanism that might both account for the disparate
regioselectivity of these transformations and be in accord with the
intermediate" mechanism initially proposed for this transformation. established reactivity patterns of gold s- and p-complexes.
Although gold-catalyzed allylic transposition has been invoked to
R
account for selective formation of the linear hydrofunctionalization
NHCOMe
product,[11] our results both herein and in the context of
(Ph3P)Au
R
NHCOMe
N
(Ph3P)Au
N
hydroalkoxylation rule out this possibility.[29]
Rather, the
(Ph3P)Au
H
H
R
H
R
mechanism for regiocontrol proposed herein involving rapid and
reversible attack of nucleophile at the more substituted allene
terminus superimposed on slower addition to the less substituted
allene terminus coupled with more facile protodeauration of the
terminally disubstituted gold vinyl complex might better account
all the observations made in the context of gold-catalyzed allene
hydrofunctionalization. According to such a mechanism, subtle
changes in the relative rates of formation, consumption, and
protodeauration of the gold vinyl intermediates could lead to
complete inversion in regiochemistry of otherwise similar systems.
12 [R = (CH2)2Ph]
10 [R = (CH2)2Ph]
11
Figure 5. Potential intermediates in the gold-catalyzed hydroamination of 1,7-
diphenyl-3,4-heptadiene with methyl carbazate.
R
CD3NO2, –25 °C
10 + H2NNHCO2Me
12 + H2NNHCO2Me
11 +
K = 55
R
Experimental Section
CD3NO2, –25 °C
11 + 9
Experimental details including synthetic preparations, compound
characterization data, kinetic procedures, and kinetic plots can be found in
the Supporting Information.
K = 17
Scheme 11. Key equilibria in the gold-catalyzed hydroamination of 1,7-
diphenyl-3,4-heptadiene with methyl carbazate.
Acknowledgements
Conclusions
We acknowledge the NSF (CHE-1465209) for support of this
research. RGC was supported through a GAANN fellowship
(P200A150114).
In summary, we have investigated the kinetics and
mechanism of the hydroamination of 3-methyl-1,2-butadiene (1)
with N-methylaniline (2) in dioxane. All of our data are consistent
with the mechanism depicted in Scheme 8 involving endergonic
displacement of 2 from the gold N-methyl aniline complex
[(IPr)Au(NHMePh)]+ (4) with 1 to form the cationic gold p-allene
complex I. Rapid and reversible outer-sphere addition of 2 to the
terminal allene carbon atom of I' forms gold vinyl complex II
whereas slower addition of 2 to the terminal carbon atom of I
forms gold vinyl complex III. Selective protodeauration of III
releases the allylic amine product 3a and regenerates 4. The
Conflict of interest
The authors declare no conflict of interest.
Keywords: hydroamination • mechanism • kinetics • gold •
allene
small
but
significant
deuterium
KIE
observed
for
[1]
a) Y. Li, W. Li, J. Zhang, Chem. Eur. J. 2017, 23, 467 – 512; b) A.
Quintavalla, M. Bandini, ChemCatChem 2016, 8, 1437-1453; c) J.
Miróand, C. del Pozo, Chem. Rev. 2016, 116, 11924−11966; d) M. N.
Hopkinson, A. Tlahuext-Aca, F. Glorius, Acc. Chem. Res. 2016, 49,
2261−2272; e) P. H. S. Paioti, A. Aponick, Top. Curr. Chem. 2015, 357,
63–94; f) A. M. Asiri, A. S. K. Hashmi, Chem. Soc. Rev. 2016, 45, 4471-
4503; g) L. Liu, J. Zhang, Chem. Soc. Rev. 2016, 45, 506-516; h) S.
Shin, Top. Curr. Chem. 2015, 357, 25–62; i) V. Michelet, Top. Curr.
Chem. 2015, 357, 95–132.
deuterioamination of 1 with 2-N-d points to a kinetic scenario that
approaches turnover-limiting formation of III with a small but
significant kinetic contribution of protodeauration.
Under
conditions where the concentration of 2 is low, such as at high
conversion, gold vinyl complex II is competitively trapped by
(IPr)Au+ to form the bis(gold) vinyl complex 6, which accumulates
under reaction conditions and accounts for ~20% of the available
catalyst at 90% conversion.
The gold-catalyzed hydrofunctionalization of differentially
substituted allenes has been shown to lead selectively to either
the linear or branched allylic product resulting from addition of the
[2]
a) R. Dorel, A. M. Echavarren, Chem. Rev. 2015, 115, 9028−9072; b)
Y. C. Lee, K. Kumar, Isr. J. Chem. 2018, 58, 531-556; c) E. Jiménez-
Núnêz, A. M. Echavarren, Chem. Rev. 2008, 108, 3326–3350; d) A. S.
This article is protected by copyright. All rights reserved.

10.1002/chem.202100741
Chemistry - A European Journal
FULL PAPER
K. Hashmi, T. M. Frost, J. W. Bats, Highly Selective Gold-Catalyzed
J. Am. Chem. Soc. 2009, 131, 18022-18023; d) L. N. dos Santos
Comprido, J. E. M. N. Klein, G. Knizia, J. Kästner, A. S. K. Hashmi, Chem.
Eur. J. 2017, 23, 10901 – 10905, and references therein.
Arene Synthesis. J. Am. Chem. Soc. 2000, 122, 11553-11554.
[3]
a) R. Blieck, M. Taillefer, F. Monnier, Chem. Rev. 2020, 120,
13545−13598; b) C. Praveen, Coord. Chem. Rev. 2019, 392, 1–34; c)
A. Quintavalla, M. Bandini. ChemCatChem 2016, 8, 1437-1453; d) A.
Arcadi, in Topics in Heterocyclic Chemistry, Bandini, M. Ed. Springer,
2016, pp 53-85; e) J. L. Mascareñas, F. López, in Topics in Heterocyclic
Chemistry, M. Bandini, Ed. Springer, 2016, pp 1-52; f) N. Huguet, A. M.
Echavarren, Top. Organomet. Chem. 2013, 43, 291-324; g) C. Winter,
N. Krause, in Modern Gold Catalyzed Synthesis; A. S.K. Hashmi, F. D.
Toste, Eds.; Wiley-VCH, 2012, pp 363-389; h) A. Corma, A. Leyva-
Pérez, M. J. Sabater, Chem. Rev. 2011, 111, 1657–1712; i) H. C. Shen,
Tetrahedron 2008, 64, 3885-3903; j) X. Han, R. A. Widenhoefer, Eur. J.
Org. Chem. 2006, 4555-4563.
[15] a) D. Weber, M. R. Gagne, Top. Curr. Chem. 2015, 357, 167-211; (b)
A. Gómez-Suárez, S. P. Nolan, Angew. Chem. Int., Ed. 2012, 51, 8156-
8159; Angew. Chem. 2012, 124, 8278– 8281.
[16] For additional reviews on intermediates generated in gold(I) catalysis
with relevance to allene hydrofunctionalization see: a) L.-P. Liu, G. B.
Hammond, Chem. Soc. Rev. 2012, 41, 3129-3139; b) C. Obradors, A.
M. Echavarren, Chem. Commun. 2014, 50, 16-28; c) T. Lauterbach, A.
M. Asiri, A. S. K. Hashmi, Adv. Organomet. Chem. 2014, 62, 261-297;
d) B. Ranieri, I. Escofeta, A. M. Echavarren, Org. Biomol. Chem. 2015,
13, 7103-7118; e) A. C. Jones, Top. Curr. Chem. 2015, 357, 133-165;
f) R. E. M. Brooner, R. A. Widenhoefer, Angew. Chem. Int. Ed. 2013, 52,
11714-11724; Angew. Chem. 2013, 125, 11930-11941; g) H.
Schmidbaur, A. Schier, Organometallics 2010, 29, 2-23; h) M. A. Cinellu,
in Modern Gold Catalyzed Synthesis, ed. A. S. K. Hashmi, D. F. Toste,
Wiley-VCH, 2012, p. 153.
[4]
a) T. J. Brown, M. G. Dickens, R. A. Widenhoefer, J. Am. Chem. Soc.
2009, 131, 6350-6351; b) T. J. Brown, M. G. Dickens, R. A. Widenhoefer,
Chem. Commun. 2009, 6451–6453.
[5]
[6]
a) N. Krause, C. Winter, Chem. Rev. 2011, 111, 1994-2009; b) N.
Nishina, Y. Yamamoto, Tetrahedron 2009, 65, 1799–1808.
[17] a) Z. Zhang, R. A. Widenhoefer, Org. Lett. 2008, 10, 2079-2081; b) Z.
Zhang, C. Liu, R. E. Kinder, X. Han, H. Qian, R. A. Widenhoefer, J. Am.
Chem. Soc. 2006, 128, 9066-9073; c) B. Gockel, N. Krause, Org. Lett.
2006, 8, 4485-4488; d) Z. Zhang, R. A. Widenhoefer, Angew. Chem., Int.
Ed. 2007, 46, 283-285; Angew. Chem. 2007, 119, 287-289; e) C. Winter,
N. Krause, Angew. Chem., Int. Ed. 2009, 48, 6339-6342; Angew. Chem.
2009, 121, 6457–6460; f) N. Morita, N. Krause, Angew. Chem., Int. Ed.
2006, 45, 1897-1899; Angew. Chem. 2006, 118, 1930–1933; g) Z.
Zhang, C. F. Bender, R. A. Widenhoefer, J. Am. Chem. Soc. 2007, 129,
14148-14149.
a) N. T. Patil, Chem. Asian J. 2012, 7, 2186 – 2194; b) D. Campolo, S.
Gastaldi, C. Roussel, M. P. Bertrand, M. Nechab, Chem. Soc. Rev. 2013,
42, 8434—8466.
[7]
[8]
a) W. Zi, F. D. Toste, Chem. Soc. Rev. 2016, 45, 4567-4589; b) A. Pradal,
P. Y. Toullec, V. Michelet, Synthesis 2011, 1501-1514; c) S. Sengupta,
X. Shi, ChemCatChem 2010, 2, 609-619; d) R. A. Widenhoefer, Chem.
Eur. J. 2008, 14, 5382-5391.
a) M. Rudolph, A. S. K. Hashmi, Chem. Soc. Rev. 2012, 41, 2448–2462;
b) D. Pflästerer, A. S. K. Hashmi, Chem. Soc. Rev. 2016, 45, 1331-1367;
c) Z. Liu, A. S. Wasmuth, S. G. Nelson, J. Am. Chem. Soc. 2006, 128,
10352-10353; d) R. M. Zeldin, F. D. Toste, Chem. Sci. 2011, 2, 1706-
1709; e) R. W. Bates, M. R. Dewey, Org. Lett. 2009, 11, 3706-3708; f)
Y. Sawama, Y. Sawama, N. Krause, Org. Biomol. Chem. 2008, 6, 3573-
3579; g) V. M. Schmiedel, S. Stefani, H.-U. Reissig, Beilstein J. Org.
Chem. 2013, 9, 2564-2569; h) O. F. Jeker, E. M. Carreira, Angew.
Chem., Int. Ed. 2012, 51, 3474-3477; Angew. Chem. 2012, 124, 3531–
3534. i) T.Okada, K. Sakaguchi, T. Shinada, Y. Ohfune, Tetrahedron
Lett. 2011, 52, 5744-5746.
[18] Yamamoto established the net anti-addition of the N–H bond of aniline
across the C=C bond of an allene under gold(III) catalysis, but
nevertheless invoked an inner-sphere mechanism for this transformation,
which necessitated the inclusion of the unprecedented
E to Z
isomerization of gold vinyl intermediate to account for preferential
formation of the E allylic amine: N. Nishina, Y. Yamamoto, Angew. Chem.
Int. Ed. 2006, 45, 3314 - 3317; Angew. Chem. 2006, 118, 3392–3395.
[19] Although Stradiotto initially proposed an inner-sphere mechanism to
account for the net syn-addition in the the gold(I)-catalyzed
hydroamination of alkynes with alkyl amines,[20] this proposal was
subsequently repudiated by Zhdanko and Maier who demonstrated that
the syn-addition product in the gold catalyzed hydroaminaton of alkyl
amines with alkynes is generated via stereoisomerization of the gold
iminium intermediate generated via net anti-addition of the N–H bond of
the amine across the CC bond of the alkyne.[21]
[9]
a) W. Yang, A. S. K. Hashmi, Chem. Soc. Rev. 2014, 43, 2941-2955; b)
A. S. K. Hashmi, L. Schwarz, J.-H. Choi, T. M. Frost, Angew. Chem. Int.
Ed. Engl. 2000, 39, 2285-2288; Angew. Chem. 2000, 112, 2382– 2385.
[10] a) O. N. Faza, C. S. López, Top. Curr. Chem. 2015, 357, 213-283; b)
E. Soriano, I. Fernández, Chem. Soc. Rev. 2014, 43, 3041-3105; c) M.;
Malacria, L. Fensterbank, V. Gandon, Top. Curr. Chem. 2011, 302, 157-
182; d) B. Alcaide, P. Almendros, T. M. Campo, E. Soriano, J. Marco-
Contelles, Top. Curr. Chem. 2011 302, 183-224; e) S. Montserrat, G.
Ujaque, F. López, J. L. Mascarenãs, A. Lledós, Top. Curr. Chem. 2011,
302, 225-248; f) V. Gandon, G. Lemiére, A. Hours, L. Fensterbank, M.
Malacria, Angew. Chem. Int. Ed. 2008, ꢀ47, 7534-7538; Angew. Chem.
2008, 120, 7644 –7648; g) S. Montserrat, H. Faustino, A. Lledós, J. L.
Mascareñas, F. López, G. Ujaque, Chem. Eur. J. 2013, 19, 15248-
15260; h) D. Benitez, E. Tkatchouk, A. Z. Gonzalez, W. A. Goddard, F.
D. Toste, Org. Lett. 2009, 11, 4798-4801; i) R.-X. Zhu, D.-J. Zhang, J.-X.
Guo, J.-L. Mu, C.-G. Duan, C.-B. Liu, J. Phys. Chem. A 2010, 114, 4689–
4696.
[20] K. D. Hesp, M. Stradiotto, J. Am. Chem. Soc. 2010, 132, 18026 – 18029.
[21] A. Zhdanko, M. E. Maier, Angew. Chem. Int. Ed. 2014, 53, 7760–7764;
Angew. Chem. 2014, 126, 7894– 7898.
[22] a) D. Weber, M. A. Tarselli, M. R. Gagné, Angew. Chem., Int. Ed. 2009,
48, 5733-5736; Angew. Chem. 2009, 121, 5843 –5846; b) D. Weber, M.
R. Gagné, Org. Lett. 2009, 11, 4962-4965; c) D. Weber, M. R. Gagné,
Chem. Sci. 2013, 4, 335-338.
[23] N. Cox, M. R. Uehling, K. T. Haelsig, G. Lalic, Angew. Chem. Int. Ed.
2013, 52, 4878-4882; Angew. Chem. 2013, 125, 4978-4982.
[24] T. J. Brown, D. Weber, M. R. Gagné, R. A. Widenhoefer, J. Am. Chem.
Soc. 2012, 134, 9134-9137.
[11] a) R. S. Paton, F. Maseras, Org. Lett. 2009, 11, 2237-2240; b) S.
Muñoz-López, A. Couce-Rios, G. Sciortino, A. Lledós, G. Ujaque,
Organometallics 2018, 37, 3543−3551.
[25] T. J. Brown, R. E. M. Brooner, M. A. Chee, R. A. Widenhoefer,
Organometallics 2016, 35, 2014−2021.
[26]
a) A. Zhdanko, M. E. Maier, Chem. Eur. J. 2013, 19, 3932-3942; b) A.
Zhdanko, M. E. Maier, Organometallics 2013, 32, 2000-2006; c) A.
Zhdanko, M. E. Maier, Chem. Eur. J. 2014, 20, 1918-1930.
[12] a) T. J. Brown, A. Sugie, M. G. Dickens, R. A. Widenhoefer, Chem. Eur.
J. 2012, 18, 6959-6971; b) T. J. Brown, A. Sugie, M. G. Dickens, R. A.
Widenhoefer, Organometallics 2010, 29, 4207-4209.
[27] See also: a) W. Wang, M. Kumar, G. B. Hammond, B. Xu, Org. Lett.
2014, 16, 636−639; b) W. Wang, G. B. Hammond, B. Xu, J. Am. Chem.
Soc. 2012, 134, 5697−5705; c) L. Lempke, H. Sak, M. Kubicki, N.
Krause, Org. Chem. Front. 2016, 3, 1514-1519.
[13] R. E. M. Brooner, T. J. Brown, R. A. Widenhoefer, Chem. Eur. J. 2013,
19, 8276-8284.
[14]
a) L.-P. Liu, B. Xu, M. S. Mashuta, G. B. Hammond, J. Am. Chem. Soc.
2008, 130, 17642-17643; b) L.-P. Liu, G. B. Hammond, Chem.–Asian
J. 2009, 4, 1230-1236; c) Y. Shi, K. E. Roth, S. D. Ramgren, S. A. Blum,
[28] Z. J. Wang, D. Benitez, E. Tkatchouk, W. A. Goddard, F. D. Toste, J. ꢀ
Am. Chem. Soc. 2010, 132, 13064-13071.
This article is protected by copyright. All rights reserved.

10.1002/chem.202100741
Chemistry - A European Journal
FULL PAPER
[29] R. J. Harris, R. G. Carden, A. N. Duncan, R. A. Widenhoefer, ASC Catal.
2018, 8, 8941–8952.
[37] T. J. Brown, B. D. Robertson, R. A. Widenhoefer, J. Organomet. Chem.
2014, 758, 25-28.
[30] A. N. Duncan, R. A. Widenhoefer, Synlett 2010, 419-422.
[31] a) A. Zhdanko, M. E. Maier, ACS Catal. 2015, 5, 5994−6004; b) D. Wang,
R. Cai, S. Sharma, J. Jirak, S. K. Thummanapelli, N. G. Akhmedov, H.
Zhang, X. Liu, J. L. Petersen, X. Shi, J. Am. Chem. Soc. 2012, 134,
9012−9019; c) A. Homs, I. Escofet, A. M. Echavarren, Org. Lett. 2013,
15, 5782−5785; d) M. Kumar, G. B. Hammond, B. Xu, Org. Lett. 2014,
16, 3452−3455; e) Y. Zhu, C. S. Day, L. Zhang, K. J. Hauser, A. C. Jones,
Chem. Eur. J. 2013, 19, 12264 – 12271; f) L. Hu, M. C. Dietl, C. Han,
M. Rudolph, F. Rominger, A. S. K. Hashmi, Angew. Chem. Int. Ed. 2021,
60, 10637 –10642; Angew. Chem. 2021, 133, 10731 –10737; g) Y. Yang,
P. Antoni, M. Zimmer, K. Sekine, F. F. Mulks, L. Hu, L. Zhang, M.
Rudolph, F. Rominger, A. S. K. Hashmi, Angew. Chem. Int. Ed. 2019, 58,
5129 –5133; Angew. Chem. 2019, 131, 5183 –5187.
[38] a) X. Cheng, Z. Wang, C. D. Quintanilla, L. Zhang J. Am. Chem. Soc.
2019, 141, 3787−3791; b) X. Li, Z. Wang, X. Ma, P.-n. Liu, L. Zhang,
Org. Lett. 2017, 19, 5744−5747; c) Z. Wang, Y. Wang, L. Zhang, J. Am.
Chem. Soc. 2014, 136, 8887−8890.
[39] A. De Renti, B. Di Blasio, A. Panunzi, C. Pedone, A. Vitagliano J. Chem.
Soc., Dalton Trans. 1978, 1392-1397.
[40] T. J. Brown, D. Weber, M. R, Gagné, R. A. Widenhoefer, J. Am. Chem.
Soc. 2012, 134, 9134–9137.
[41] L. N. dos Santos Comprido, J. E. M. N. Klein, G. Knizia, J. Kästner, A.
S. K. Hashmi, Chem. Eur. J. 2017, 23, 10901 - 10905.
[42] Although H+ is certainly present under catalytic conditions in the form of
the ammonium salt B•H+ [B = 2 or 3], [B] is invariant throughout the
course of the reaction prior to accumulation of 6 (i.e. [B]t = [2]t + [3a]t =
[2]0 = [3a]inf) and the basicity of secondary and tertiary anilines varies by
only a fraction of a pKa unit.[43] For this reason, treating the source of
proton as either H+ or B•H+ leads to indistinguishable rate equations.
Furthermore, because H+ (or B•H+) is a co-reactant in both the forward
and reverse reactions involving III, the reaction rate is invariant of [H+] (or
B•H+). In a similar manner, a mechanism involving N-protonation of III
followed by intramolecular protodeauration likewise produces an
indistinguishable rate equation (See Supporting Information).
[43] The pKa values for aniline, N-methylaniline, and N,N-dimethylaniline in
water (DMSO) are 4.60 (3.72), 4.85 (2.76), and 5.16 (2.51),
respectively.[44,45]
[32] The regioisomeric allylic amines 3a and 3b were not distinguished by
HPLC under these conditions.
[33] a) P. Mukherjee, R. A. Widenhoefer, Chem. Eur. J. 2013, 19, 3437–
3444; b) A. Aponick, B. Biannic, Synthesis 2008, 3356-3359; c) A.
Aponick, C.-Y. Li, J. A. Palmes, Org. Lett. 2009, 11, 121-124; d)
Aponick,; Li, C.-Y.; Biannic, B. Org. Lett. 2008, 10, 669-671; e) A.
Aponick, B. Biannic, M. R. Jong, Chem. Commun. 2010, 46, 6849-6851;
f) M.Bandini, M. Monari, A. Romaniello, M. Tragni, Chem. Eur. J. 2010,
16, 14272-14277; g) B. Biannic, A. Aponick, Bielstein J. Org. Chem.
2011, 7, 802-807; h) A. Aponick, B. Biannic, Org. Lett. 2011, 13, 1330-
1333; i) T.Ghebreghiorgis, B. Biannic, B. H. Kirk, D. H. Ess, A. Aponick,
J. Am. Chem. Soc. 2012, 134, 16307-16318; j) G. Barker, D. G. Johnson,
P. C. Young, S. A. Macgregor, A.-L. Lee, Chem. Eur. J. 2015, 21, 13748
– 13757; k) E. Coutant, P. C. Young, G. Barker, A.-L. Lee, Beilstein J.
Org. Chem. 2013, 9, 1797–1806.
[44] N. F. Hall, M. R. Sprinkle, J. Am. Chem. Soc. 1932, 54, 3469.
[45] R. L. Benoit, M. J. Mackinnon, L. Bergeron, Can. J. Chem. 1981, 59,
1501.
[46] K. E. Roth, S. A. Blum, Organometallics 2010, 29, 1712–1716.
[47] a) R. BabaAhmadi, P. Ghanbari, N. A. Rajabi, A. S. K. Hashmi, B. F.
Yates, A. Ariafard, Organometallics 2015, 34, 3186−3195; b) C. A.
Gaggioli, G. Ciancaleoni, D. Zuccaccia, G. Bistoni, L. Belpassi, F.
Tarantelli, P. Belanzoni, Organometallics 2016, 35, 2275−2285.
[48] T. J. Brown, R. E. M. Brooner, M. A. Chee, R. A. Widenhoefer,
Organometallics 2016, 35, 2014−2021.
[34] Complex I has been previously synthesized.[12] Complexes 4 and 5 were
synthesized independently and fully characterized (See Supporting
Information).
[35] In non-polar solvents such as dioxane, the binding affinity of triflate to the
fragment (IPr)Au+ significantly exceeds that of 1, which necessitates a
large excess of 1 to quantitatively convert (IPr)AuOTf to I.[29]
[36] Isoprene was formed as a byproduct via gold-catalyzed isomerization of
1,[37,38] but was not detected in the presence of 2.
[49] See the Supporting Information for details.
This article is protected by copyright. All rights reserved.

10.1002/chem.202100741
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents
Me
Me
HNMePh
HNMePh
slow
LAu
fast
I
Me Me
Me
Me
LAu
NMePh
NMePh
LAu
III
II
slow
fast H+
H+
Me Me
Me
Me
NMePh
3b
NMePh
3a:3b = 97:3
3a
Kinetic and spectroscopic analysis of the gold-catalyzed hydroamination of 1,1-dimethylallene with N-methylaniline support a
mechanism involving rapid and reversible addition of N-methylaniline to the more substituted terminus of gold p-allene complex I to
form gold vinyl complex II superimposed on slower addition of N-methylaniline to the less substituted terminus of I to form gold vinyl
complex III. Selective formation of the linear allylic amine 3a is attributed to the more facile protodeauration of III relative to II.
This article is protected by copyright. All rights reserved.