Mechanistic studies of a palladium-catalyzed intramolecular hydroamination of unactivated alkenes: Protonolysis of a stable palladium alkyl complex is the turnover-limiting step

Article abstract of DOI:10.1021/ja0734997

Mechanistic studies of the intramolecular hydroamination of unactivated aminoalkenes catalyzed by a dicationic [bis(diphenylphosphinomethyl)pyridine] palladium complex highlight the important role that protonolysis plays in this reaction. Coordination of

Full text of DOI:10.1021/ja0734997

Published on Web 02/07/2008
Mechanistic Studies of a Palladium-Catalyzed Intramolecular
Hydroamination of Unactivated Alkenes: Protonolysis of a
Stable Palladium Alkyl Complex Is the Turnover-Limiting Step
Brian M. Cochran and Forrest E. Michael*
Department of Chemistry, UniVersity of Washington, Box 351700,
Seattle, Washington 98195-1700
Received May 16, 2007; E-mail: michael@chem.washington.edu
Abstract: Mechanistic studies of the intramolecular hydroamination of unactivated aminoalkenes catalyzed
by a dicationic [bis(diphenylphosphinomethyl)pyridine]palladium complex highlight the important role that
protonolysis plays in this reaction. Coordination of the aminoalkene substrate to this complex activates the
alkene toward intramolecular nucleophilic attack to form a dicationic palladium alkyl complex (6). A stable
monocationic palladium alkyl complex (7) was isolated by in situ deprotonation of 6 with mild base, and its
structure was confirmed by X-ray crystallography. Complex 7 reacted rapidly with a variety of strong acids
to undergo protonolysis, resulting in formation of hydroamination product 3 and regenerating the active
catalyst. Evidence that formation of the palladium alkyl complex is reversible under the catalytic conditions
was obtained from observation of the protonolysis at low temperature. During the course of all catalytic
reactions, the resting state of the catalyst was palladium alkyl complex 7, indicating that protonolysis of the
Pd-C bond was the turnover-limiting step. Kinetic studies reveal an unusual inverse dependence of the
reaction rate on the concentration of the aminoalkene substrate. This effect can be accurately explained
by a model in which the carbamate protecting group of the aminoalkene acts as a Brønsted base to remove
free protons from the catalytic cycle and thereby inhibits the turnover-limiting protonolysis step. Formation
of a 2:1 complex (12) between the carbamate and the proton is most consistent with the kinetic data.
Introduction
catalysts tend to be significantly less active, requiring activated
alkenes, either via conjugation or substitution with electron-
The direct addition of a nitrogen-hydrogen bond across an
alkene (hydroamination)1 is an economical way to form
nitrogen-carbon bonds and an effective way to synthesize
biologically active nitrogen-containing heterocycles.2 In spite
of the utility of this reaction, the hydroamination of unactivated
alkenes containing synthetically useful functional groups remains
a challenge. Strong acids3 have been used to promote the
hydroamination of unactivated alkenes; however, forcing condi-
tions are usually required and acid sensitive functional groups
are not tolerated. Lanthanides and Group IV metals4 also
efficiently catalyze the hydroamination of unactivated alkenes,
but these catalysts are extremely air and water sensitive and
are incompatible with many synthetically useful functional
groups.5 On the other hand, late transition metal catalysts6 have
been increasingly employed in hydroamination reactions because
of their greater functional group tolerance. Unfortunately, these
withdrawing groups, and elevated temperatures. Recently, we
reported a new palladium-catalyzed intramolecular hydroami-
nation of unactivated aminoalkenes.7 This transformation takes
place at room temperature and is tolerant of a variety of useful
functional groups. Since this catalyst appears to be significantly
more active than most late transition metal catalysts, under-
standing the mechanistic rationale for its enhanced activity is
especially important.
(4) (a) Watson, D. A.; Chiu, M.; Bergman, R. G. Organometallics 2006, 25,
4731-4733. (b) Meyer, N.; Zulys, A.; Roesky, P. W. Organometallics 2006,
25, 4179-4182. (c) Thomson, R. K.; Bexrud, J. A.; Schafer, L. L.
Organometallics 2006, 25, 4069-4071. (d) Kim, Y. K.; Livinghouse, T.
Angew. Chem., Int. Ed. 2002, 41, 3645-3647. (e) Kim, Y. K.; Livinghouse,
T. Org. Lett. 2005, 7, 4391-4393. (f) Kim, Y. K.; Livinghouse, T. Org.
Lett. 2005, 7, 1737-1739. (g) Young, K. K.; Livinghouse, T.; Horino, Y.
J. Am. Chem. Soc. 2003, 125, 9560-9561. (h) Ryu, J. -S.; Marks, T. J.;
McDonald, F. E. Org. Lett. 2001, 3, 2091-3094. (i) Meyer, N.; Lo¨hnwitz,
K.; Zulys, A.; Roesky, P. W.; Dochnahl, M.; Blechert, S. Organometallics
2006, 25, 3730-3734. (j) Molander, G. A.; Dowdy, E. D. J. Org. Chem.
1998, 63, 8983-8988. (k) Ryu, J. -S.; Marks, T. J.; McDonald, F. E. J.
Org. Chem. 2004, 69, 1038-1052. (l) Ryu, J. -S.; Li, G. Y.; Marks, T. J.
J. Am. Chem. Soc. 2003, 125, 12584-12605. (m) Sukwon, H.; Tian, S.;
Metz, M. V.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 14768-14783.
(5) For example: alcohols, esters, ketones, carbamides, and carbamates.
(6) (a) Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127, 1070-
1071. (b) Brunet, J.-J.; Chu, N. C.; Diallo, O. Organometallics 2005, 24,
3104-3110. (c) Liu, X.-Y.; Li, C.-H.; Che, C.-M. Org. Lett. 2006, 8, 2707-
2710. (d) Han, X.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2006, 45,
1747-1749. (e) Bender, C. F.; Widenhoefer, R. A. Org. Lett. 2006, 8,
5303-5305. (f) Johns, A. M.; Utsunomiya, M.; Incarvito, C. D.; Hartwig,
J. F. J. Am. Chem. Soc. 2006, 128, 1828-1839. (g) Zhang, J. L.; Yang, C.
G.; He, C. J. Am. Chem. Soc. 2006, 128, 1798-1799. (h) Karshtedt, D.;
Bell, A. T.; Tilley, T. D. J. Am. Chem. Soc. 2005, 127, 12640-12646.
(1) For recent reviews, see (a) Mu¨ller, T. E.; Beller, M. Chem. Rev. 1998, 98,
675-704. (b) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem.,
Int. Ed. 2004, 43, 3368-3398. (c) Hartwig, J. F. Pure Appl. Chem. 2004,
76, 507-516.
(2) For examples of nitrogen containing heterocycles, see: (a) O’Hagan, D.
Nat. Prod. Rep. 2000, 17, 435-446. (b) Liddell, J. R. Nat. Prod. Rep.
2002, 19, 773.
(3) (a) Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.; Utsunomiya, M.; Hartwig,
J. F. Org. Lett. 2006, 8, 4179-4182. (b) Schlummer, B.; Hartwig, J. F.
Org. Lett. 2002, 4, 1471-1474. (c) Li, Z. G.; Zhang, J. L.; Brouwer, C.;
Yang, C. G.; Reich, N. W.; He, C. Org. Lett. 2006, 8, 4175-4178. (d)
Anderson, L. L.; Arnold, J.; Bergman, R. G. J. Am. Chem. Soc. 2005, 125,
14542-14543.
9
2786
J. AM. CHEM. SOC. 2008, 130, 2786-2792
10.1021/ja0734997 CCC: $40.75 © 2008 American Chemical Society

Intramolecular Hydroamination of Unactivated Alkenes
A R T I C L E S
Scheme 1. Proposed Catalytic Cycle
The mechanisms of several late transition metal-catalyzed
hydroaminations of activated alkenes have been investigated.8
Milstein has reported an iridium-catalyzed hydroamination of
norbornene that proceeds by initial oxidative addition of the
N-H bond of the amine, followed by alkene insertion into the
Ir-N bond and reductive elimination.9 Hartwig has studied
ruthenium-,10 palladium-,11 and nickel12-catalyzed intermolecular
hydroaminations of conjugated alkenes. The Ru-catalyzed
hydroamination proceeds via initial η6-arene coordination of the
styrene substrate followed by nucleophilic attack by the amine,
forming a Ru η7-benzyl complex that is subsequently protonated
to release the product. In contrast, the palladium- and nickel-
catalyzed versions begin with alkene insertion into a metal
hydride complex, generating an η3-benzyl or allyl intermediate,
respectively. Nucleophilic displacement with the amine com-
pletes the catalytic cycle. The formation of higher hapticity
benzyl complexes in all three of Hartwig’s reactions presumably
prevents â-hydride elimination13 but also inherently limits these
additions to those of vinylarenes and dienes.
In addition to these systems, several hydroaminations of
unactivated alkenes have been reported. Che,6c He,6g and Tilley6h
have reported Au- and Pt-catalyzed intermolecular hydroami-
nations of simple alkenes using sulfonamide nucleophiles, and
the latter two have characterized the active catalyst mixtures
spectroscopically. He also demonstrated with a deuterium
labeling experiment that the addition of N and H groups occurs
with anti relative stereochemistry. However, HOTf is also a
competent catalyst for these reactions under similar conditions,3a-c
and recent reports have cast doubt on whether they actually
proceed via metal catalysis.3a Widenhoefer has reported a Pt-
catalyzed intramolecular hydroamination of secondary alkeny-
lamines and has observed some of the intermediates stoichio-
metrically.6a Widenhoefer has also reported a Au-catalyzed
intramolecular hydroamination of carbamates6e and ureas6d but
to our knowledge has yet to report any mechanistic studies of
this system.
Table 1. Optimized Reaction Conditions without Copper(II) Triflate
[Pd] (x mol %)
Cu(OTf)2 (mol %)
% yield (isolated)
5
0
5
10
10
0
82
0a
94
a Only starting material 2a was isolated.
mechanistic investigation of the palladium-catalyzed intramo-
lecular hydroamination of unactivated alkenes.
In our palladium-catalyzed hydroamination reaction, a tri-
dentate ligand is used to prevent â-hydride elimination. Because
the inhibition of â-hydride elimination is controlled by the
ligand, rather than by the substrate, unconjugated alkenes are
effective substrates for this reaction. Reversible stoichiometric
addition of amines to alkene complexes of this ligand had been
previously observed.14 However, the addition of carbamates and
the protonolysis of the resultant alkyl complexes to complete
the catalytic cycle had not. Herein we present a detailed
Results and Discussion
In the previous report,7 dicationic palladium complex 4 was
found to be an effective catalyst for the hydroamination of
protected aminoalkenes. Based on literature precedent, the
catalytic cycle depicted in Scheme 1 was proposed. Coordination
of the alkene to the electron-deficient dicationic palladium center
activates the substrate toward nucleophilic attack from the
amide, forming protonated alkyl complex 6. Since the tridentate
ligand prevents â-hydride elimination, protonolysis of the Pd-C
bond releases the hydroamination product 3 and regenerates the
active catalyst.
The reaction conditions presented in our original report
included a cocatalytic amount of copper(II) triflate additive
(Table 1, entry 1). Recently, attention has been drawn to the
potential of metal triflates to effect hydroamination reactions
Via acid catalysis.3a To rule out this possibility, substrate 2a
was treated with Cu(OTf)2 in the absence of Pd. No conversion
to product 3a was observed. Additionally, Cu(OTf)2 could be
omitted from the reaction with no loss in yield. These experi-
ments confirmed that the copper salt plays no significant role
in the catalytic hydroamination.15
(7) Michael, F. E.; Cochran, B. M. J. Am. Chem. Soc. 2006, 128, 4246-4247.
(8) For mechanistic studies of hydroaminations using lanthanides, see: (a) Ryu,
J.-S.; Li, G. Y.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 12584-12605.
(b) Arredondo, V. M.; McDonald, F. E.; Marks, T. J. Organometallics 1999,
18, 1049-1960. (c) Li, Y.; Marks, T. J. Organometallics 1996, 15, 3770-
3772.
(9) Casalnuovo, A. L.; Calabrese, J. C.; Milstein, D. J. Am. Chem. Soc. 1988,
110, 6738-6744. A later improvement to this reaction presumably proceeds
via a similar mechanism: Dorta, R.; Egli, P.; Zu¨rcher, F.; Togni, A. J.
Am. Chem. Soc. 1997, 117, 10857-10858.
(10) Takaya, J.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 5756-5757.
(11) Nettekoven, U.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 1166-1167.
(12) Pawlas, J.; Nakao, Y.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc.
2002, 124, 3669-3679.
(13) â-hydride elimination is normally quite facile for late transition metal alkyl
complexes, see (a) Hegedus, L. Angew. Chem., Int. Ed. Engl. 1988, 27,
1113-1116. (b) Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew. Chem., Int.
Ed. 2002, 41, 164-166.
(14) (a) Hahn, C.; Morvillo, P.; Vitagliano, A. Eur. J. Inorg. Chem. 2001, 419-
429. (b) Cucciolito, M. E.; D’Amora, A.; Vitagliano, A. Organometallics,
2005, 24, 3359-3361. (c) Hahn, C.; Morvillo, P.; Herdtweck, E.; Vitagliano,
A. Organometallics 2002, 21, 1807-1818.
(15) The initial beneficial effect of the addition of copper triflate to the reaction
may have been to prevent reduction of the palladium catalyst, ensuring
that the catalytic cycle went to completion.
9
J. AM. CHEM. SOC. VOL. 130, NO. 9, 2008 2787

A R T I C L E S
Cochran and Michael
Scheme 2. Protonolysis of Palladium Complex 7b and Continued
Catalytic Activity
Stoichiometric Studies. According to proposed catalytic
cycle, protonolysis of the palladium-carbon bond of intermedi-
ate 6 is required to release the hydroamination product from
the metal center (Scheme 1); therefore, addition of a base should
inhibit this process and allow isolation of a palladium alkyl
complex (7). Indeed, treatment of aminoalkene 2b with (PNP)-
PdCl2 1 (1 equiv), AgBF4 (2 equiv), and 2,6-lutidine (1 equiv)
in methylene chloride afforded the palladium alkyl complex 7b
as a bench-stable pale yellow solid (eq 2) in 75% yield. Complex
7b was characterized by 1H, 13C, 31P, and COSY NMR
spectroscopy, as well as by X-ray crystallography (Figure 1).
The structure of 7b is similar to that of other palladium and
platinum pincer ligand complexes.16 Interestingly, the palladium
metallacycle adopts a twisted conformation, causing the phenyl
groups to be situated in pseudoequatorial and pseudoaxial
positions.17 The stability of 7b is further confirmation of the
ability of the tridentate ligand to inhibit â-hydride elimination.
After cyclization to form 7, the next step in the catalytic cycle
is the protonolysis of the palladium-carbon bond to form
hydroamination product 3. Treatment of alkyl complex 7b with
acid should result in protonolysis and completes the catalytic
cycle (Scheme 2). Four different acids, TfOH, HBF4‚Et2O, [Ph2-
NH2][BF4], and [Ph2NH2][OTf], were screened. With each acid,
complete consumption of 7b and clean formation of pyrrolidine
3b was observed in less than 15 min at room-temperature.
Additionally, a new palladium complex (8) was formed, as
identified by a single new phosphorus resonance at 30.8 ppm.
This chemical shift is typical of dicationic (PNP)Pd complexes
with a neutral ligand in the fourth coordination site.14 The exact
identity of that ligand (L) has not been determined, but it is
likely to be the carbonyl of product 3b. When excess substrate
2b was added to a solution of 8 and 3b generated in this fashion,
Scheme 3. Possible Protonolysis Mechanisms
complex 8 was completely converted to palladium alkyl complex
7b, and conversion of 2b to 3b was observed over the next
several hours. After 5 days, all of the aminoalkene was
consumed, and complex 8 was the only palladium species
remaining in solution. The fact that palladium alkyl complex
7b was the only palladium complex in the reaction mixture
under catalytic conditions is strong evidence that it is the resting
state of the catalyst and that the turnover-limiting step of the
catalytic cycle is the protonolysis of this complex.
Two potential mechanisms for the protonolysis of metal-
carbon bonds are commonly observed.18 Protonation can occur
at the metal center to form an intermediate palladium(IV)
hydride complex, followed by reductive elimination (Scheme
3, SE(ox) mechanism). Alternatively, direct electrophilic cleav-
age of the palladium-carbon bond with a proton can take place
(SE2 mechanism). The protonolysis of complex 7b was moni-
tored by 1H NMR spectroscopy at low-temperature in an attempt
to distinguish these two possibilities. TfOH was added to a
solution of complex 7b in CD2Cl2 at -78 °C, and the
temperature of the reaction was increased in 5° increments at 5
min intervals. No change was observed until, surprisingly, at
-18 °C substantial amounts of aminoalkene 2b were observed.
Aminoalkene 2b was not observed in the room-temperature
experiment described above. This observation suggests that the
cyclization to form palladium alkyl complex 7b from 2b and 8
is reversible in the presence of added acid. Similar reversible
addition of amines to alkenes under acidic conditions was
observed by Vitagliano in their stoichiometric studies of this
ligand system14,19 and was invoked by Stahl in a related system.
As the mixture was further warmed to room-temperature,
(16) (a) Gorla, F.; Venanzi, L. M.; Albinati, A. Organometallics 1994, 13, 43-
54. (b) Steffey, B. D.; Miedaner, A.; Maciejewski-Farmer, M. L.; Bernatis,
P. R.; Herring, A. M.; Allured, V. S.; Carperos, V.; DuBois, D. L.
Organometallics 1994, 13, 4844-4855. (c) Hahn, C.; Vitagliano, A.;
Giordano, F.; Taube, R. Organometallics 1998, 17, 2060-2066.
(17) Longmire, J. M.; Zhang, X.; Shang, M. Organometallics 1998, 17, 4374-
4379.
Figure 1. X-ray crystal structure of palladium alkyl intermediate 7b (BF4
counterion and a molecule of pentane are omitted for clarity). Selected bond
distances (Å) and angles (deg): Pd1-P1 2.275; Pd1-P2 2.297; Pd1-N1
2.115; Pd1-C32 2.047; P2-Pd1-P1 165.50; C32-Pd1-N1 176.9; C32-
Pd1-P1 94.6; C32-Pd1-P2 99.0; N1-Pd1-P1 82.7; N1-Pd-P2 82.8.
(18) For a recent study of the rate of protonolysis of Pt-C bonds, see: Feducia,
J. A.; Campbell, A. N.; Anthis, J. W.; Gagne´, M. R. Organometallics, 2006,
25, 3114, for a review and discussion of the mechanistic possibilities, see:
Lersch, M.; Tilset, M. Chem. ReV. 2005, 105, 2471-2526.
(19) Timokhin, V. I.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 17888-17893.
9
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Intramolecular Hydroamination of Unactivated Alkenes
A R T I C L E S
aminoalkene 2b and complex 7b disappeared, and hydroami-
nation product 3b and complex 8 were formed. Throughout the
course of the reaction, no signal was seen in the region of the
spectra indicative of a late metal hydride (0 to -60 ppm).18,20
Though the intermediacy of a palladium(IV) hydride in the
protonolysis step cannot be ruled out, it is more likely that direct
protonation of the Pd-C bond is occurring in this case (SE2
mechanism). It is possible that the carbamate and amide-
protected aminoalkenes are uniquely effective in the hydroami-
nation reaction because of their ability to deliver a proton in an
intramolecular fashion to the Pd-C bond, thus promoting the
key protonolysis step.
Kinetic Studies. The stoichiometric studies described above
indicated that the resting state of the catalyst was palladium
alkyl complex 7, and that protonolysis of this intermediate is
the turnover-limiting step. In order to learn more about the rate
of the key protonolysis step, kinetic studies were undertaken.
However, the original (PNP)PdCl2 precatalyst (1) was unsuitable
for monitoring the kinetics of the hydroamination reaction by
1H NMR spectroscopy, because of its poor solubility in
methylene chloride and the need for activation with AgBF4.
A stable palladium catalyst that does not need preactivation
was required. Pentafluorobenzonitrile complex 9 ((PNP)Pd-
NCC6F5) met the necessary requirements (eq 4). The reaction
of (PNP)PdCl2 1, AgBF4, and C6F5CN in CH2Cl2 afforded
complex 9 as a bench-stable light yellow powder. Complex 9
was, by itself, a competent catalyst for the hydroamination of
aminoalkenes 2a and 2b. Furthermore, catalyst 9 displayed
similar behavior to that observed in the protonolysis of complex
7 (Scheme 3); that is, as long as substrate 2a remained in
solution, the resting state of the catalyst was again found to be
palladium-alkyl complex 7 by 31P NMR spectroscopy. After
the aminoalkene was completely consumed, the catalyst reverted
back to the nitrile complex 9.
Figure 2. Initial reaction rates of product formation at different concentra-
tions of aminoalkene 2a. [9] ) 0.001 M. The initial reaction rates were
measured by comparing product concentration vs 1,4-dimethoxybenzene
1
using H NMR spectroscopy.
Table 2. Effect of Carbamate and Amide Protecting Groups on
Reaction Rate
1
entry
PG
[2] M
[10] M
initial rate (s-
)
1
2
3
4
5
6
Cbz
Ac
Cbz
Ac
Cbz
Cbz
2a 0.025
2b 0.025
2a 0.051
2b 0.051
2a 0.202
2a 0.202
0
0
0
0
5.83 × 10-5
5.07 × 10-7
4.73 × 10-5
9.29 × 10-8
8.02 × 10-6
1.46 × 10-6
0
0.202
The reaction rate was measured in the presence of added
carbamate 10 to determine if the observed rate decrease was
due to the carbamate functional group. Carbamate 10 was also
found to have a strong inhibitory effect on the rate of reaction
(Table 2). It is notable that the rate of the reaction in entry 6 is
comparable to the rate of the reaction measured when an initial
2a concentration of 0.404 M was used. In other words, the effect
on the initial rate of adding 0.202 M 10 was comparable to that
of increasing the concentration of 2a by 0.202 M. Despite this
effect, the addition of 10 to the reaction mixture did not change
the resting state of the catalyst, which was still palladium alkyl
complex 7.
With an appropriate catalyst in hand, the kinetics of the
hydroamination reaction were monitored by 1H NMR spectros-
copy. A mixture of substrate 2a (0.253 M), palladium complex
9 (0.001 M), and 1,4-dimethoxybenzene as an internal standard
was prepared, and the rate of pyrrolidine 3a formation was
measured. Unfortunately, both zero-order and first-order kinetic
plots displayed pronounced curvature, indicating that a more
complex analysis of the reaction kinetics was required (Sup-
porting Information).
The observation that palladium alkyl complex 7 is always
the resting state of the catalyst indicates that the inhibitory effect
of added substrate and/or 10 cannot be due to coordination of
the carbamate to palladium, preventing alkene binding. If
carbamate coordination were inhibiting catalytic turnover,
significant amounts of a carbamate complex should be formed
under the reaction conditions. No such carbamate complex was
observed. Furthermore, if competitive carbamate coordination
were occurring, increasing the substrate concentration should
have no effect on the initial rate of the reaction because the
concentration of the carbamate in the reaction mixture cannot
The initial rate of product formation was measured at a
number of different substrate concentrations to avoid the compli-
cations observed in monitoring the entire reaction (Figure 2).
Surprisingly, a strong inverse dependence of the reaction rate
on substrate concentration was observed. This same inverse de-
pendence was also observed with the more basic acetamide 2b.
Furthermore, over a range of concentrations, the acetamide sub-
strate reacts substantially slower than the carbamate (Table 2).
(20) Crabtree, R. H. The Organometallic Chemistry of the Transition Metals,
3rd ed.; John Wiley & Sons, Inc.: New York, 2001; p 68.
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A R T I C L E S
Cochran and Michael
total proton concentration ) [H+] + [11] ) [7] ∼ [Pd]0 (8)
Scheme 4. Proposed Inhibition of Protonolysis by Aminoalkene 2
[H+] + Keq[2][H+] ) [Pd]0
(9)
[Pd]0
[H+] )
(10)
1 + Keq[2]
k1[Pd]0
rate )
(11)
1 + Keq[2]
be increased without also increasing the concentration of the
alkene.21 Overall, this should result in a zero-order dependence
on substrate, not the observed inverse order. Therefore, car-
bamate coordination cannot be competing with alkene coordina-
tion, and the turnover-limiting step of pyrrolidine formation must
be protonolysis of the palladium-carbon bond.
Using eq 11, the unknown parameters k1 and Keq could be
obtained by least-squares fitting to the experimental data (Figure
4). However, the fit obtained using this model was fairly poor,
especially at high substrate concentrations (rms error ) 4.6 ×
10-6).
The stoichiometric experiments described above indicate that
protonolysis of palladium alkyl complex 7 is the turnover-
limiting step of the catalytic cycle, and therefore the added
carbamate must be interfering with this process. It is unlikely
that there is any appreciable interaction between the carbamate
and the coordinatively saturated complex 7.22 However, in order
to form complex 7, a proton must be released into solution. In
the turnover-limiting protonolysis step, complex 7 must react
with this proton. This reveals a potential role of carbamate 2a
in slowing the overall reaction rate; namely, the carbamate of
the aminoalkene could be acting as a Brønsted base, removing
protons from the reaction. If the carbamate-bound protons are
inactive in the protonolysis step, increasing the concentration
of carbamate should inhibit protonolysis and thereby slow the
overall reaction rate. This would also explain the much slower
rates observed with acetamide substrate 2b. Since amides are
more basic than carbamates,23 substrate 2b should be better at
sequestering protons and inhibiting protonolysis.
Examination of the fit obtained using Scheme 4 revealed that
the simulated initial rates did not decrease with increasing
substrate concentration as rapidly as the observed rates did. This
raised the possibility that two aminoalkenes could bind to the
proton, forming a proton-bridged dimer (12) (Figure 3). This
2:1 stoichiometry has been observed for a variety of protonated
amides in nonpolar solutions.24 Replacing compound 11 in the
above rate expression with dimer 12 gives a new equilibrium
constant (eq 12) and rate expression with an inverse second-
order dependence on substrate concentration (eq 13).
[12]
Keq
)
(12)
(13)
[2]2[H+]
2
k1[Pd]0
rate )
1 + Keq[2]2
Based on the observations discussed above, a simplified
model for the kinetic data can be constructed (Scheme 4). First,
since palladium alkyl complex 7 appears to be the only catalyst-
derived species in solution, we assume that intermolecular
protonolysis of palladium alkyl complex 7 is the turnover-
limiting step, and that the overall reaction rate can be described
by a simple second-order rate equation for the reaction of 7
with a proton (eq 6). The proton also undergoes reversible
binding with substrate 2 to generate 11, which does not
participate in protonolysis (eq 7). Note that since we are
attempting to explain initial rates, we do not need to take into
account the fact that the product 3 can also act as a base of
comparable strength. Furthermore, the stoichiometry of the
catalytic cycle requires that for every equivalent of 7 that is
produced, an equivalent of H+ is released (eq 8). Solving eq 7
for [11] and substituting for that quantity in eq 8 gives eq 9.
Solving eq 9 for [H+] results in eq 10. Finally, substitution of
eq 10 and eq 8 into the initial rate equation (eq 6) gives the
reaction rate in terms of the concentrations of substrate (2) and
catalyst ([Pd]0).
A least-squares fit of the experimental rate data gave k1 )
62 M-1 s-1 and Keq ) 127 M-2. The rates obtained from this
simulation are a much better fit for the experimentally deter-
mined rates (rms error ) 1.1 × 10-6, Figure 4). This strongly
suggests that formation of proton-bridged dimer 12 is the cause
for the retardation of the reaction rate at high concentrations of
aminoalkene.
Inspection of eq 13 reveals that the reaction should be second
order in catalyst concentration, despite the fact that none of the
steps involves the interaction of two Pd complexes. This is a
consequence of the fact that the turnover-limiting step requires
the reaction of two species that are directly derived from the
catalyst: the Pd alkyl complex 7, and a proton which can only
have been generated by the formation of 7. A ln/ln plot (Figure
5) of the initial reaction rate versus initial concentrations of Pd
catalyst 9 ranging from 0.001 to 0.005 M has a slope of
approximately 2, indicating a second-order dependence, as
predicted by the model.
(21) Since the rate of the reaction is being determined by initial rates, the
carbamate of the product does not need to be considered.
(22) Pentacoordinate Pd(II) complexes are rare and usually bear tetradentate
ligands. For an example, see Ghilardi, C. A.; Midollini, S.; Moneti, S.;
Orlandini, A.; Ramirez, J. A. J. Chem. Soc., Chem. Commun. 1989, 304-
306.
(23) Carbamates are intermediate in basicity between amides and esters; see
Armstrong, V. C.; Moodie, R. B. J. Chem. Soc. B 1968, 275-277.
(24) For examples of 2:1 complexes of amides with Brønsted acids, see Wilhelm,
M.; Koch, R.; Strasdeit, H. New J. Chem. 2002, 26, 560-566 and references
therein.
rate ) k1[7][H+]
(6)
(7)
[11]
[2][H+]
Keq
)
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Intramolecular Hydroamination of Unactivated Alkenes
A R T I C L E S
Figure 3. Proton-bridged dimer.
Figure 5. ln/ln plot for determination of the catalyst reaction order
indicating second-order dependence.
Scheme 5. Complete Hydroamination Catalytic Cycle
greater rms error of 2.29 × 10-6. Given the small difference in
error, it is difficult to definitively distinguish these conceptually
similar mechanisms. In both models, the substrate acts as a base
in a 2:1 stoichiometry to inhibit the key protonolysis step and
thus inhibits the catalytic reaction.
rate ) k1{2[Pd]0 + Keq[2]2 - (Keq2[2]4 +
4Keq[2]2[Pd]0)1/2}/2 (14)
Figure 4. Simulated initial rates of product formation at different
concentrations of aminoalkene 2a vs experimental reaction rates (a) using
1:1 complex (eq 11); (b) using 2:1 complex (eq 13).
Conclusion
An alternate model involving rate-limiting intramolecular
protonolysis of protonated palladium alkyl complex 6 and direct
abstraction of the proton from 6 by two molecules of carbamate
to form the same proton-bridged dimer 12 was also considered.25
This model avoids invoking the presence of “free” protons in
nonpolar media but leads to a much more complex rate equation
(eq 14). Fitting the experimental data to this equation gave
values of k1 ) 0.08 s-1 and Keq ) 0.129 M-1 and a slightly
In conclusion, an unexpectedly complex mechanism for the
palladium-catalyzed intramolecular hydroamination of unacti-
vated alkenes has been elucidated (Scheme 5). Aminoalkene 2
coordinates to palladium complex 4 to form alkene complex 5,
which rapidly and reversibly cyclizes to give the protonated
palladium alkyl complex 6. Turnover-limiting protonolysis of
the Pd-C bond of 6 results in formation of hydroamination
product 3 and regenerates complex 4. This simple catalytic cycle
is complicated by deprotonation of 6 by mild bases to form
(25) We are grateful to a reviewer who suggested this model. A more detailed
discussion of this model is in the Supporting Information.
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J. AM. CHEM. SOC. VOL. 130, NO. 9, 2008 2791

A R T I C L E S
Cochran and Michael
stable monocationic alkyl complex 7, removing the catalyst from
the catalytic cycle. The amide and carbamate protecting groups
of the substrates are basic enough to deprotonate complex 6
and inhibit the key protonolysis step. This results in an inverse
dependence of the reaction rate on substrate concentration.
Formation of a 2:1 complex (12) between the carbamate and
the proton is most consistent with the kinetic data. In all catalytic
reactions, the resting state of the catalyst was palladium alkyl
complex 7, indicating that protonolysis of the Pd-C bond was
the turnover-limiting step.
Stronger bases, such as tertiary amines and pyridines, form
7 irreversibly, allowing its isolation and characterization by
X-ray crystallography. Isolated palladium alkyl complex 7 could
be returned to the catalytic cycle by treatment with strong acid,
resulting in formation of hydroamination product 3 and regen-
erating complex 4, which readily catalyzes further conversion
of aminoalkene 2 to product 3. Although it cannot be conclu-
sively ruled out, no evidence for a Pd(IV) hydride intermediate
was observed, even at low-temperatures. Protonolysis of 7
appears to be significantly faster than that of the cationic (PPP)-
PtMe complexes investigated by Gagne´.18 The ability of the
carbonyl of the protecting group to deliver a proton intramo-
lecularly may be responsible for this difference in reactivity.
These studies highlight the key role that in situ-generated
Brønsted acid plays in determining the rate of the hydroami-
nation reaction. Since protonolysis of the palladium alkyl
complex is the turnover-limiting step of the catalytic cycle, the
acidity of the reaction medium has a profound effect on the
facility of the hydroamination reaction. The addition of basic
moieties (e.g., protecting groups or solvents) to the mixture
inhibits this reaction by sequestering protons from the catalytic
cycle. On the other hand, the addition of cocatalytic Brønsted
acids, such as TfOH or HBF4, greatly accelerates the desired
process. This concept can be used to further optimize the
hydroamination of specific desired substrates.
Acknowledgment. Werner Kaminsky and Jason Benedict are
acknowledged for X-ray crystallography and the University of
Washington is acknowledged for financial support.
Supporting Information Available: Reaction conditions and
experimental data for synthesis of all new compounds, details
of the X-ray crystal structure of 7b, and detailed kinetic data.
This material is available is available free of charge on the
Internet at http://pubs.acs.org.
JA0734997
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2792 J. AM. CHEM. SOC. VOL. 130, NO. 9, 2008