Mechanistic study of gold(l)-catalyzed lntermolecular hydroamination of alienes

Article abstract of DOI:10.1021/ja105530q

The intermolecular hydroamination of alienes occurs readily with hydrazlde nucleophlles, In the presence of 3-12% Ph₃PAuNTf₂. Mechanistic studies have been conducted to establish the resting state of the gold catalyst, the kinetic order of the reaction, the effect of ligand electronics on the overall rate, and the reversibility of the last steps in the catalytic cycle. We have found the overall reaction to be first order In gold and aliene and zero order in nucleophile. Our studies suggest that the rate-limiting transition state for the reaction does not involve the nucleophile and that the active catalyst Is monomeric in gold(l). Computational studies support an outersphere mechanism and predict that a two-step, no intermediate mechanism may be operative. In accord with this mechanistic proposal, the reaction can be accelerated with the use of more electron-deficient phosphine ligands on the gold(l) catalyst.

Full text of DOI:10.1021/ja105530q

Published on Web 08/25/2010
Mechanistic Study of Gold(I)-Catalyzed Intermolecular
Hydroamination of Allenes
Z. Jane Wang,† Diego Benitez,‡ Ekaterina Tkatchouk,‡ William A. Goddard III,‡ and
F. Dean Toste*,†
Department of Chemistry, UniVersity of California, Berkeley, California 94720, and Materials
and Process Stimulation Center, California Institute of Technology, Pasadena, California 91125
Received July 5, 2010; E-mail: fdtoste@berkeley.edu
Abstract: The intermolecular hydroamination of allenes occurs readily with hydrazide nucleophiles, in the
presence of 3-12% Ph3PAuNTf2. Mechanistic studies have been conducted to establish the resting state
of the gold catalyst, the kinetic order of the reaction, the effect of ligand electronics on the overall rate, and
the reversibility of the last steps in the catalytic cycle. We have found the overall reaction to be first order
in gold and allene and zero order in nucleophile. Our studies suggest that the rate-limiting transition state
for the reaction does not involve the nucleophile and that the active catalyst is monomeric in gold(I).
Computational studies support an “outersphere” mechanism and predict that a two-step, no intermediate
mechanism may be operative. In accord with this mechanistic proposal, the reaction can be accelerated
with the use of more electron-deficient phosphine ligands on the gold(I) catalyst.
1. Introduction
that an intermolecular variant of this transformation could
provide a valuable platform for a systematic study of the
mechanism of the reaction.
Gold(I)-catalyzed addition of carbon, oxygen, and nitrogen
based nucleophiles to allenes has emerged as a powerful
synthetic transformation in recent years.1 The stability of gold(I)
complexes to air and moisture renders gold catalysis a practical
and mild method for benchtop synthesis.2 However, the mech-
anism of this important class of reactions is only beginning to
be explored. While multiple mechanisms for the hydroamination,
hydroalkoxylation, and hydroarylation of allenes have been
proposed, few studies regarding the nature of the active catalyst,
the rate-limiting step of the reaction, and the role of allene and
nucleophile in the transformation have been performed.3 Part
of the challenge of performing detailed kinetic studies of gold(I)-
catalyzed hydroamination reactions is that many of the most
active catalysts employed are generated in situ from gold(I)
trimers or the gold chloride and the corresponding silver salt.4
This makes it difficult to determine the precise concentration
of catalyst employed.4 In 2009, we reported the intramolecular
hydroamination reaction of allenes with hydrazine nucleophiles
catalyzed by an isolable gold(I) complexes.5 We hypothesized
While experimental observations in gold(III)-catalyzed hy-
droamination and hydroalkoxylation reactions suggest that these
reactions proceed through an innersphere mechanism,6 both
innersphere and outersphere mechanisms for nucleophilic ad-
dition to allenes promoted by gold(I) complexes have been
proposed (Scheme 1).7 In the outersphere mechanism the
cationic gold(I) complex acts as a π-acid to induce addition of
the nucleophile across the C-C π-bond. Protodemetalation of
the vinyl gold intermediate then regenerates the gold(I) catalyst.
In the innersphere mechanism a tricoordinate gold complex is
formed by complexation of both the allene and the nucleophile.
Addition of the nucleophile across the allene then proceeds
directly from this complex. In both mechanisms, a monomeric
cationic gold(I) complex is proposed to be the catalytically
relevant species. However, the “aurophilicity” of gold(I)8 and
the isolation of a vinyl-gold dimer in a gold-catalyzed hydroary-
lation reaction by Gagne´3d suggest that dinuclear gold(I)
(4) For selected examples, see: (a) Hyland, C. T.; Hegedus, L. S. J. Org.
Chem. 2006, 71, 8658. (b) Zhang, Z.; Bender, C. F.; Widenhoefer,
R. A. J. Am. Chem. Soc. 2007, 129, 14148. (c) Liu, C.; Widenhoefer,
R. A. Org. Lett. 2007, 9, 1935. (d) Piera, J.; Krumlinde, P.; Stru¨bing,
D.; Ba¨ckvall, J. E. Org. Lett. 2007, 9, 2235. (e) Hamilton, G. L.; Kang,
E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496. (f) For an example
of a gold(I) trimer precatalyst, see: Sherry, B. D.; Maus, L.; Laforteza,
B. N.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 8132.
† University of California.
‡ California Institute of Technology.
(1) For general reviews, see: (a) Gorin, D. J.; Sherry, B. D.; Toste, F. D.
Chem. ReV. 2008, 108, 3351. (b) Jime´nez-Nu´n˜ez, E.; Echavarren,
A. M. Chem. Commun. 2007, 333. (c) Furstner, A.; Davies, P. W.
Angew. Chem., Int. Ed. 2007, 46, 3410. (d) Hashmi, A. S. K. Chem.
ReV. 2007, 107, 3180. (e) Shen, H. C. Tetrahedron 2008, 64, 3885.
(f) Li, Z.; Brouwer, C.; He, C. Chem. ReV. 2008, 108, 3239.
(2) (a) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395. (b) Shapiro,
N. D.; Toste, F. D. Synlett 2010, 675.
(5) Lalonde, R. L.; Wang, J. Z.; Mba, M.; Lackner, A. D.; Toste, F. D.
Angew. Chem., Int. Ed. 2009, 49, 598.
(6) Nishina, N.; Yamamoto, Y. Angew. Chem., Int. Ed. 2006, 45, 3144.
(7) For proposed outersphere mechanisms, see: (a) Widenhoefer, R. A.;
Han, Q. Eur. J. Org. Chem. 2006, 4555, and ref 3a. For proposed
innersphere mechanisms, see. (b) Zeng, X.; Soleilhavoup, M.; Bertrand,
G. Org. Lett. 2009, 11, 3166, and ref 3bFor evidence of gold-catalyzed
outersphere hydroamination of alkenes, see: (c) LaLonde, R. L.;
Brenzovich, W. E., Jr.; Benitez, D.; Tkatchouk, E.; Kelley, K.;
Goddard, W. A., III; Toste, F. D. Chem. Sci. 2010, 1, 226.
(3) For examples, see: (a) Zhang, Z.; Liu, Cong.; Kinder, R. E.; Han, X.;
Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2006, 128, 9066. (b)
Nishina, N.; Yamamoto, Y. Tetrahedron 2009, 65, 1799. (c) Duncan,
A. N.; Widenhoefer, R. A. Synlett 2010, 419. (d) Weber, D.; Tarselli,
M. A.; Gagne´, M. R. Angew. Chem., Int. Ed. 2009, 48, 5733.
9
13064 J. AM. CHEM. SOC. 2010, 132, 13064–13071
10.1021/ja105530q  2010 American Chemical Society

Au(I)-Catalyzed Hydroamination of Allenes
A R T I C L E S
Scheme 1. Outersphere and Innersphere Mechanisms Proposed
for the Hydroamination of Allenes with Gold(I) Catalysts
Figure 1. Reaction of 1 with methyl carbazate where 0 ) [1], ∆ ) [2],
and O ) [1] + [2].
we found that 1 underwent the desired reaction with 2.5 equiv
of methyl carbazate and 9 mol % Ph3PAuNTf2 in MeNO2 at 45
°C, providing the hydroamination products in a 5:1 trans/cis
ratio with >95% conversion after 12 h (eq 1). Monitoring the
1
first 3.25 h of the reaction by H NMR at 45 °C showed that
the reaction was remarkably clean and that the total concentra-
tion of 1 and 2 during the course of the reaction was consistent
with the concentration of 2 at t ) 0 (Figure 1). In addition, the
hydroamination does not proceed appreciably in the presence
of 20 mol % HNTf2 or 10 mol % AgNTf2. We were encouraged
by these results to further examine the precise role of the
Ph3PAuNTf2 in the catalytic cycle.
2.1. Catalyst Resting State. Phosphorus NMR methods have
been previously used to study gold(I) intermediates, and the
31P signal of the phosphine ligand was found to be very sensitive
to the electronic environment around the gold center.10 Upon
addition of the catalyst to a reaction mixture containing 1 and
methyl carbazate, the signal corresponding to the Ph3PAuNTf2
(30.3 ppm) vanished and a new signal at 45.2 ppm was observed.
As the reaction progressed to higher conversion and the
concentration of 1 remaining in solution was comparable to that
of the catalyst, a second broad peak at 30 ppm also appeared
(Figure 2).
complexes should also be considered as potential intermediates
in gold(I)-mediated processes. Thus, a kinetic study of this class
of reactions is needed to determine the role of each reagent in
the catalytic cycle and the composition of the rate-limiting
transition state.
Toward this goal, we have found an intermolecular gold(I)-
catalyzed hydroamination reaction of allenes by hydrazide
nucleophiles and investigated the mechanism of this transforma-
tion. To distinguish between the inner- and outersphere mech-
anisms, and to discover the stoichiometry of the gold catalyst
in the rate-determining transition state, a detailed study was
performed to determine: (1) the order of the reaction in each
reagent; (2) the resting state of the catalyst and the nature of
other intermediates within the catalytic cycle; (3) the effect of
electronics of the catalyst on the rate of reaction; and (4) the
reversibility of the reaction. These investigations provide
evidence that the rate-limiting transition state involves an
activated allene complex. Trapping of this complex by the
nucleophile and protodemetalation to regenerate the gold catalyst
are rapid and likely irreversible.
Both gold-amine11 and gold-allene12 complexes have been
previously postulated as intermediates in gold-catalyzed reac-
tions. To determine the nature of the compounds comprising
the observed peaks at 30 and 45 ppm, we independently
prepared two samples containing Ph3PAuNTf2 and methyl
carbazate, in a 1:1 ratio, and Ph3PAuNTf2 and 1, in a 1:10 ratio,
in CD3NO2. The sample containing Ph3PAuNTf2 and methyl
carbazate showed a broadened 31P NMR signal at 29.7 ppm
2. Results and Discussion
We began our studies with 1,7-diphenylhepta-3,4-diene (1),
because the symmetry of the substrate greatly simplified the
number of chemically distinct environments in which the gold(I)
catalyst could coordinate. Recently, Ph3PAuNTf2 has been
effectively used in the activation of carbon-carbon multiple
bonds,9 and we hypothesized that this isolable complex would
be a reliable Au+ source for mechanistic analysis. Gratifyingly,
(9) (a) Mezailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133. (b)
Toullec, P. Y.; Blarre, T.; Michelet, V. Org. Lett. 2009, 11, 2888.
(10) (a) Grise´, C. M.; Barriault, L. Org. Lett. 2006, 8, 5905. (b) Grise´,
C. M.; Rodrigue, E. M.; Barriault, L. Tetrahedron 2008, 64, 797. (c)
Seidel, G.; Mynott, R.; Fu¨rstner, A. Angew. Chem., Int. Ed. 2009, 48,
2510.
(11) Mizushima, E.; Hayashi, T.; Tanaka, M. Org. Lett. 2003, 5, 3349.
Also see refs 3b and 7b.
(12) (a) Mauleon, P.; Krinsky, J. L.; Toste, F. D. J. Am. Chem. Soc. 2009,
131, 4513. (b) Benitez, D.; Tkatchouk, E.; Gonzales, A. Z.; Goddard,
W. A., III; Toste, F. D. Org. Lett. 2009, 11, 4798. (c) Deutsch, C.;
Gockel, B.; Hoffman-Roder, A.; Krause, N. Synlett 2007, 11, 1790.
For an example with gold(III), see: Morita, N.; Krause, N. Org. Lett.
2004, 6, 4121.
(8) (a) Schmidbaur, H. Gold Bulletin 2000, 33, 3. (b) Scherbaum, F.;
Grohmann, A.; Huber, B.; Kruger, C.; Schmidbaur, H. Angew. Chem.,
Int. Ed. 1988, 27, 1544. (c) Cheong, P. H.; Morganelli, P.; Luzung,
M. R.; Houk, K. N.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 4517.
9
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A R T I C L E S
Wang et al.
Figure 2. The hydroamination reaction was monitored by 31P NMR spectroscopy.
(eq 2), in the same region that includes the second peak that
appeared as the catalytic reaction progressed. The second sample
containing Ph3AuNTf2 and 1, however, showed the same 31P
NMR signal at 45.2 ppm as was observed in the catalytic
reaction (eq 3).
predicted the barrier for exchange between the two diastereo-
meric faces of a simple disubstituted alkyl allene to be very
low.15 In addition, the energy difference between the two
π-complexes that could form is calculated to be only 1.0 kcal/
mol. Thus, it is likely that under catalytic reaction conditions,
the species observed is a cationic gold-allene complex in which
the gold center is rapidly exchanging between the two faces of
the allene.
2.2. Kinetic Order of the Reaction. 2.2.1. Order in Nucleo-
phile. In order to determine the rate-determining transition state
for the catalytic reaction, we sought to establish the kinetic order
of the reaction in Ph3PAuNTf2, 1, and methyl carbazate. We
began our studies by examining the order of the Ph3PAuNTf2-
catalyzed hydroamination reaction in the nucleophile by the
method of initial rates. The allene (1) (90.9 mM) and
Ph3PAuNTf2 (5.45 mM) were combined with varying concen-
trations of methyl carbazate from 90.0 to 295.5 mM in CD3NO2
The signal at 45.2 ppm is consistent with the 31P NMR shifts
of other alkyl- and vinyl-AuPPh3 species reported in the
literature.13 In addition, the same species can be independently
generated from a solution of Ph3PAuCl and AgBF4 in the
1
at 45 °C. The reactions were monitored by H NMR, and a
16
-
plot of kobs (as determined by (∆[2]/∆t)/[1]0, where [1]0 )
presence of 1 without additional NTf2 . Thus, we hypothesized
that this peak corresponded to a Ph3PAu+-allene complex. In
the catalytic reaction, this complex is in equilibrium with other
cationic gold species, such as Ph3PAu+ and Ph3PAu+-carbazate.
When the concentration of 1 was relatively high at the beginning
of the reaction, the equilibrium favored the gold-allene
complex. As the reaction progressed, the concentration of 1
decreased and the equilibrium shifted such that the other cationic
gold species were also observable by NMR.14
90.91 mM) at each concentration of methyl carbazate provided
a straight line with R2 ) 0.9923 and a slope of -0.0001 h-1
(Figure 3). The order in methyl carbazate was verified by a least-
squares fit to f(x) ) axn, which provided n ) -0.108 (Sup-
porting Information, Figure S3). These results indicate that
methyl carbazate is not involved in the rate-determining
transition state. In contrast, previously proposed mechanisms
Due to the C2 symmetry of the allene, two diastereotopic
π-gold complexes could theoretically be formed; yet we could
not resolve the two complexes by either 31P or 1H NMR at low
temperature (0 to -84 °C). However, computational studies have
(14) The composition of the cationic gold species observed under catalytic
conditions could not be determined as both Ph3PAu+ and 3 show
phosphorous NMR signals around 30 ppm. However, in the absence
of nucleophile, the Keq for the equilibrium between 1, Ph3PAuNTf2,
and 4 was found to be 1.32 at 50 °C using 31P NMR techniques with
PPh3 internal standard. This value is within an order of magnitude to
the Keq reported for structurally similar gold(I) π-alkene complexes.
For example, see: Brown, T. J.; Dickens, M. G.; Widenhoefer, R. A.
J. Am. Chem. Soc. 2009, 131, 6350.
(13) (a) Hashmi, A. S. K.; Ramamurthi, T. D.; Rominger, F. J. Organomet.
Chem. 2009, 694, 592. (b) Shi, Y.; Ramgren, S. D.; Blum, S. A.
Organometallics 2009, 28, 1275. (c) Mohr, F.; Falvello, L. R.; Laguna,
M. Eur. J. Inorg. Chem. 2006, 833. (d) Porter, K. A.; Schier, A.;
Schmidbaur, H. Organometallics 2003, 22, 4922. (e) Herrero-Go´mez,
E.; Nieto-Oberhuber, C.; Lo´pez, J.; Benet-Buchholz, J.; Echavarren,
A. M. Angew. Chem., Int. Ed. 2006, 45, 5455.
(15) Gandon, V.; Lemie´re, G.; Hours, A.; Fensterbank, L.; Malacria, M.
Angew. Chem., Int. Ed. 2008, 47, 7534.
(16) The pseudo-first-order rate constants (kobs) measured reflects the rate
of formation of both trans and cis hydroamination products.
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Au(I)-Catalyzed Hydroamination of Allenes
A R T I C L E S
Figure 5. A plot of kobs versus [Ph3PAuNTf2], using 2.5 equiv of methyl
carbazate.
Figure 3. A plot of kobs versus concentration of methyl carbazate, where
kobs was determined by the method of initial rates.
and methyl carbazate (325 mM) were combined with various
concentrations of Ph3PAuNTf2 (4.5 to 18 mM) in CD3NO2 at
45 °C. Plotting the measured kobs of the reaction at a range of
catalyst loadings provided a straight line with R2 ) 0.9993
(Figure 5). This result suggests that the overall reaction is first-
order in gold and implies that the rate-limiting transition state
contains only one gold center.
2.3. Hammett Analysis. Our group has previously investigated
the ability of ligand electronics to affect the rate of certain
pathways in a gold(I)-catalyzed process.19 Thus, a Hammett
study of the reaction was performed to probe the sensitivity of
the reaction to changes in the electronic properties of the
phosphine ligand in the Ar3PAuNTf2 catalyst. Toward this goal,
phosphine gold catalysts bearing substitution in the para position
were prepared. The reaction of 1 (150 mM) and methyl
carbazate (325 mM) in the presence of 6 mol % (p-X-
C6H4)3PAuNTf2 (X ) CF3, Cl, H, and OMe) in CD3NO2 at 45
1
°C was monitored by H NMR. Plotting log[(kobs,X)/(kobs,H)]
against σ provided a straight line (R2 ) 0.96) with F ) 0.21
(Figure 6). A positive F value is consistent with a decrease in
partial positive charge on the phosphine ligand in the transition
state. The kinetic order and Hammett analysis of the reaction
are consistent with the gold(I) activation of allene as the rate-
limiting transition state in the catalytic cycle.
2.4. Chirality Transfer. We sought to determine whether
chirality transfer was possible from the allene to the hydroami-
nation product to determine whether the reaction went through
chiral or planar gold intermediates. While trisubstituted allenes
are known to racemize rapidly in the presence of gold(I)
catalysts,20 good chirality transfer has been observed with some
unfunctionalized disubstituted allenes.21 In addition, chirality
transfer would exclude a planar allyl cation as part of the
catalytic cycle, as such a species would lead to complete
racemization. Enantioenriched 1 (101 nM, 87% ee) was prepared
by the method described by Myers22 and was combined with
methyl carbazate and Ph3PAuNTf2 at 45 °C. The enantiomeric
Figure 4. A representative plot of -ln[1(t)/10] versus time (h) for the
reaction of 1 and methyl carbazate shows first-order dependence in 1.
have implied nucleophilic addition or protodemetalation to be
the rate-limiting step in gold(I)-catalyzed hydroamination.17
2.2.2. Order in Allene. The order in 1 was next determined
by monitoring the reaction of 1 (150 mM), methyl carbazate
(325 mM), and Ph3PAuNTf2 (13.5 mM) in CD3NO2 at 45 °C
18
1
(Figure 4) by H NMR. The reaction followed pseudo-first-
order kinetics in 1 and provided linear plots of -ln([1]t/[1]0)
vs time with R2 ) 0.9995. The pseudo-first-order rate constants
(kobs) measured reflect the rate of formation of both trans and
cis hydroamination products. The first-order dependence on 1
implies that the allene is involved in the turnover-limiting
transition state.
2.2.3. Order in Gold. The order in Ph3PAuNTf2 was exam-
ined by measuring the pseudo-first-order rate constant, kobs, for
the reaction at various catalyst loadings. Allene 1 (150 mM)
(19) Mauleon, P.; Zeldin, R. M.; Gonzalez, A. Z.; Toste, F. D. J. Am. Chem.
Soc. 2009, 131, 6348.
(17) For examples showing nucleophilic addition as the first irreversible
step in the catalytic cycle, see ref 3b and (a) Kinder, R. E.; Zhang, Z.;
Widenhoefer, R. A. Org. Lett. 2008, 10, 3157. For studies involving
hydroamination of dienes and olefins, see: (b) Kovacs, G.; Ujaque,
G.; Lledos, A. J. Am. Chem. Soc. 2008, 130, 853, and ref 7c.
(18) Also see Supporting Information, Figure S4.
(20) (a) Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978.
(b) Lee, J. H.; Toste, F. D. Angew. Chem., Int. Ed. 2007, 46, 912.
(21) (a) Zhang, Z.; Widenhoefer, R. A. Org. Lett. 2008, 10, 2079. (b) Patil,
N. T.; Lutete, L. M.; Nishina, N.; Yamamoto, Y. Tetrahedron Lett.
2006, 47, 4749.
(22) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492.
9
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A R T I C L E S
Wang et al.
2 (56% ee) was subjected to 2 equiv of methyl carbazate and
10 mol % achiral Ph3PAuNTf2. After 6 h at 45 °C, 2 was
recovered in 56% ee with no apparent erosion of enantiopurity
(eq 9), supporting an irreversible protodemetalation. However,
conservation of the enantiomeric excess could also result from
a reversible reaction that regenerates an enantioenriched
allene-gold intermediate that can then reform 2 with good
chirality transfer.
We hypothesized that a competition experiment with a second
hydrazide nucleophile would be able to distinguish between
these possibilities. If a chiral allene or gold-allene complex
was indeed being reversibly formed, hydroamination products
from trapping with both hydrazide nucleophiles should be
observed. In a competition experiment with 1 equiv of methyl
carbazate and 3 equiv of tert-butyl carbazate, both hydroami-
nation products were observed in a 15:85 ratio in >95%
conversion, indicating that formation of 5 is kinetically competi-
tive with formation of 2. Thus, if the reaction is reversible and
2 is resubjected to catalytic conditions in the presence of 3 equiv
of tert-butyl carbazate, a mixture of 2 and 5 should be expected.
However, heating the reaction to 45 °C for 8 h produced 2 as
the sole product. The lack of detectible amounts of 5 indicated
that chiral allene or gold-allene intermediates could not be
forming reversibly under the reaction conditions.
Figure 6. A Hammett plot of kobs for hydroamination of 1 in the presence
of Ar3PAuNTf2.
Table 1. Chirality Transfer for the Hydroamination of Chiral 1 in
the Presence of Ph3PAuNTf2 Catalyst at Various Equivalents of
Methyl Carbazate
Equiv of Nuc
yield (%)
ee (%)
1.0
2.0
4.0
8.0
81
75
81
79
28
48
56
56
excess of the major hydroamination product 2trans was deter-
mined by chiral HPLC analysis and summarized in Table 1.
Interestingly, though some chirality transfer was observed at
all concentrations of the nucleophile, the highest levels of
transfer were observed for reactions where greater than 4 equiv
of methyl carbazate was used. This indicates that the reaction
cannot be proceeding exclusively through a planar intermediate.
In addition, the ability of nucleophile concentration to affect
chirality transfer suggests that racemization can occur from the
chiral allyl-gold intermediate and this process proceeds at a rate
competitive with trapping of the intermediate by methyl
carbazate. In the absence of any nucleophile, 1 completely
racemizes in the presence of the catalyst after 12 h at 45 °C (eq
4).
2.6. Mechanistic Discussions. To corroborate the kinetic data
observed and to gain insight into the nature of the intermediates
in the catalytic cycle, we investigated the mechanism for
hydroamination of allenes using density functional theory (DFT)
with the B3LYP and M06 functionals. We used the experimental
observations as a guide for exploring the geometry and potential
energy surface for the reaction. We investigated the catalytic
reaction of model (S)-penta-2,3-diene, methyl carbazate, and
Ph3PAu(I)+. We calculated the free energy of coordination of
the allene to Ph3PAu(I)+ to be -9.2 kcal/mol, in favor of the
allene-gold complex A.24 Activation of A proceeds through
transition state TS1, which lies 4.9 kcal/mol higher in energy
than the planar, cationic gold(I) complex 6 (Scheme 2). Though
the methyl carbazate was included in calculations, the nucleo-
phile itself is not associated with TS1 or 6. Malacria and co-
2.5. Reversibility of the Reaction. While protodeauration of
the gold catalyst is conventionally depicted as an irreversible
process in a catalytic reaction, Lee recently reported an example
of reversible hydroalkoxylation23 in the presence of Ph3-
PAuNTf2. Furthermore, an irreversible reaction under catalytic
conditions would allow us to exclude the possibility that the
incomplete chirality transfer we observed previously was due
to racemization of the product. To probe whether the intermo-
lecular hydroamination reaction is reversible, enantioenriched
(24) We calculate isomer A′ to be ∼1 kcal/mol higher in free energy than
A.
(23) Hadfield, M. S.; Lee, A. Org. Lett. 2010, 12, 484.
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Au(I)-Catalyzed Hydroamination of Allenes
A R T I C L E S
Scheme 2. Geometries of (S)-Penta-2,3-diene and [Ph3PAu]+ As Coordination, Transition State, And Allylic Cation Complexes
Scheme 3. Partial Reaction Coordinate Diagram for Au(I) Catalyzed Hydroamination of (S)-Penta-2,3-dienea
a Energy values are free energies (∆G) for the lowest energy isomer at 298 K.
workers reported15 that the steric hindrance at the allylic
positions determines the energies and stabilities of the possible
isomeric forms of the planar, cationic gold(I) complex. In
agreement with their analysis, we found that only intermediate
6 is stable. In comparison, intermediates 7 and 8 are not minima
and relax to A or A′.
As we moved further along the reaction coordinate, a second
transition state (TS2) involving the addition of methyl carbazate
to the allene-gold species was found. We find that transition
state TS1 leads to adjacent transition state TS2 without an
intervening intermediate (Scheme 3). On the basis of our
experimental observations and calculations, we propose a two-
step, no intermediate25 process similar to the one described by
Nevado for a Au(I)-catalyzed cyclization.26 The geometry of
the allene fragment in TS1 and TS2 resembles a bent allene
geometry.15 Intermediate B (∆G ) -14.8 kcal/mol) undergoes
protodeaureation leading to product (∆G ) -24.1 kcal/mol),
in agreement with the irreversibility of the reaction.
mediate 6. At higher nucleophile concentrations, addition of the
nucleophile is fast and the two-step no intermediate pathway is
favored, leading to higher levels of chirality transfer. At lower
concentrations of nucleophile, TS1 leaks to the planar inter-
mediate 6 with loss of chirality. The operating reaction
mechanism is a continuum between a traditional two-step
process with loss of chirality and a two-step no-intermediate
process with retention of the stereochemistry.
We studied the structural and electronic details of the located
transition structures and compared them to Au-allene coordi-
nated complex A. Shown in Figure 7 are key metrical parameters
and natural charges derived from natural population analyses
of the corresponding M06 wave function. We find that, for A,
the charge on C3 is the least negative (vs C1), while the charge
on C1 is the most negative of the allene carbon atoms.
On the basis of the kinetic, ligand effect, reversibility, chirality
transfer, and computational studies performed, we propose a
mechanistic picture for the gold(I)-catalyzed hydroamination of
allenes, as shown in Scheme 4. The resting state of the catalyst
is consistent with a cationic gold-allene complex that is rapidly
exchanging between the two diastereomeric faces of the C2
symmetric allene and is in equilibrium with other cationic gold
species, denoted [Au+]. Our computational studies suggest that
a bent allene-gold complex is the rate-determining transition
state (TS1) in the catalytic cycle, and our kinetic data provide
direct experimental support for these calculations. The overall
The absence or presence of a short-lived intermediate between
transition states TS1 and TS2 is affected by the relative
concentration and reactivity of the nucleophile and, thus, relates
directly to the magnitude of chirality transfer. The reaction
coordinate bifurcates following TS1, leading to TS2 or inter-
(25) Singleton, D. A.; Hang, C.; Szymanski, M. J.; Meyer, M. P.; Leach,
A. G.; Kuwata, K. T.; Chen, J. S.; Greer, A.; Foote, C. S.; Houk,
K. N. J. Am. Chem. Soc. 2003, 125, 1319.
(26) Garayalde, D.; Gomez-Bengoa, E.; Huang, X. G.; Goeke, A.; Nevado,
C. J. Am. Chem. Soc. 2010, 132, 4720.
9
J. AM. CHEM. SOC. VOL. 132, NO. 37, 2010 13069

A R T I C L E S
Wang et al.
Figure 7. Structural and natural atomic charge of selected complexes.
Scheme 4. Proposed Mechanism for Hydroamination of 1 with
Ph3PAuNTf2
Michaelis-Menten equation can be reduced to eq 9, providing
a rate law that is first order in gold and 1.
[ ]
1
]
k Ph PAuNtf
k2 + k-1
[
2
3
2
rate )
rate )
where KM
)
(8)
[ ]
1 + KM
k1
[ ]
k Ph PAuNtf
2
1
]
[
2
3
[ ]
) kobs[Ph3PAuNtf2] 1
(9)
KM
k2k1
k2 + k-1
where kobs
)
A Hammett study of the reaction demonstrates that changing
the electronics of the Ar3P ligand noticeably affected the rate
of reaction and provides quantitative evidence that gold(I)
reactivity can be modulated by ligand electronics. In particular,
phosphines with electron-withdrawing para substituents in-
creased the rate of the reaction while electron-donating sub-
stituents slow the reaction relative to Ph3PAuNTf2. This is
consistent with a rate-determining transition state that exhibits
a reduction in δ+ character on the phosphine relative to the
ground state. Our proposed transition state allows for the
delocalization of positive charge from the Ph3PAu+ onto
the allenic fragment and is hence consistent with the F value
observed. Furthermore, the inability to regenerate the gold-allene
intermediate from the isolated hydroamination products (2)
under catalytic conditions suggests that either the addition or
the protodemetalation step or both are irreversible.
reaction exhibits zeroth-order dependence on the concentration
of the nucleophile, suggesting that nucleophilic addition must
occur after the rate-determining step. This observation is in
agreement with calculated free energy of TS2, which is 3.6 kcal/
mol lower than that of TS1. In addition, the pseudo-first-order
dependence on the concentration of allene and Ph3PAuNTf2
suggests that the catalytic species is monomeric and that the
ratio of allene to catalyst in the transition state is 1:1. Thus, an
innersphere mechanism where the nucleophile coordinates to
the gold center prior to or during allene activation is unlikely,
as such a mechanism would exhibit positive order in the
nucleophile.
3. Conclusions
We have reported the first example of intermolecular hy-
droamination of allenes with a N-N linked nucleophile in the
presence of a gold(I) catalyst, Ph3PAuNTf2. This system has
allowed us to conduct the first detailed kinetic study of the
mechanism of gold(I)-mediated allene activation. Our experi-
ments provide experimental evidence that allene activation is
the rate-limiting step in gold(I)-catalyzed addition of hydrazide
nucleophiles to allenes. Computational studies show that the
reaction examined proceeds via a two-step no-intermediate
mechanism and that the second transition state immediately
following the rate-determining step is not planar, but likely
axially chiral. Importantly, the dependence of the degree of
chirality transfer on the concentration of the nucleophile suggests
that a pathway proceeding through a traditional two-step
pathway involving a planar intermediate is also available. This
mechanistic study has important implications for the future
development of racemic and enantioselective C-X bond form-
ing reactions Via addition of nucleophiles to allenes promoted
We have demonstrated that the nucleophilic addition and
protodemetalation steps are irreversible under catalytic condi-
tions and occur after the rate-limiting transition state. Thus, our
reaction can be simplified and modeled using Michaelis-Menten
kinetics. The general rate law of the reaction follows the
Michaelis-Menten equation (eq 8). The KM for the reaction
can be calculated from a Lineweaver-Burke plot of our kinetic
data and was found to be 3.9(1.5) × 103 mM (Supporting
Information, Figure S8). Thus under the conditions examined,
27
the concentration of 1 is small relative to KM and the
(27) The concentration of substrate examined in our kinetic experiments
ranged from 90.1 to 150 mM.
9
13070 J. AM. CHEM. SOC. VOL. 132, NO. 37, 2010

Au(I)-Catalyzed Hydroamination of Allenes
A R T I C L E S
Computational facilities were funded by grants from ARO-DURIP
and ONR-DURIP.
by gold(I). Using these mechanistic insights, we are currently
working toward developing and investigating the mechanism
of gold(I)-catalyzed additions of various nucleophiles to allenes.
Supporting Information Available: Experimental procedures,
analytic and spectroscopic data for new compounds, spectral
and kinetic data, and computational details are include. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. We thank the NIHGMS (R01 GM073932)
and the Director, Office of Science of the U.S. Department of
Energy under Contract No. DE-AC02-05CH11231 for funding and
Johnson Mathey for a generous donation of AuCl3. Z.J.W. thanks
the Hertz Foundation for a graduate fellowship. We are also grateful
to Dr. Robert Bergman for support during the kinetic studies.
JA105530Q
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