Oxidative diamination of alkenes with ureas as nitrogen sources: Mechanistic pathways in the presence of a high oxidation state palladium catalyst

Article abstract of DOI:10.1021/ja075041a

A first palladium-catalyzed intramolecular diamination of unfunctionalized terminal alkenes has recently been reported. This study investigates the details of its mechanistic course based on NMR titration, kinetic measurements competition experiments, and deuterium labeling. It concludes a two-step procedure consisting of syn-aminopalladation with an unligated palladium(II) catalyst state followed by oxidation to palladium(IV) and subsequent C-N bond formation to give the final products as cyclic diamines. Related reactions employing sulfamides give rise to aminoalkoxy-functionalization of alkenes. This process was investigated employing deuterated alkenes and found to follow an identical mechanism where stereochemistry is concerned. It exemplifies the importance of cationic palladium(IV) intermediates prior to the final reductive elimination from palladium and proves that the nucelophile for this step stems from the immediate coordination sphere of the palladium(IV) precursor. These results have important implications for the general development of alkene 1,2-difunctionalization and for the individual processes of aminopalladation and palladium-catalyzed C_alkyl-N bond formation.

Full text of DOI:10.1021/ja075041a

Published on Web 12/15/2007
Oxidative Diamination of Alkenes with Ureas as Nitrogen
Sources: Mechanistic Pathways in the Presence of a High
Oxidation State Palladium Catalyst
Kilian Mun˜iz,* Claas H. Ho¨velmann, and Jan Streuff
Contribution from the Institut de Chimie, UMR 7177, UniVersite´ Louis Pasteur, 4 rue Blaise
Pascal, F-67000 Strasbourg Cedex, France
Received July 24, 2007; E-mail: muniz@chimie.u-strasbg.fr
Abstract: A first palladium-catalyzed intramolecular diamination of unfunctionalized terminal alkenes has
recently been reported. This study investigates the details of its mechanistic course based on NMR titration,
kinetic measurements competition experiments, and deuterium labeling. It concludes a two-step procedure
consisting of syn-aminopalladation with an unligated palladium(II) catalyst state followed by oxidation to
palladium(IV) and subsequent C-N bond formation to give the final products as cyclic diamines. Related
reactions employing sulfamides give rise to aminoalkoxy-functionalization of alkenes. This process was
investigated employing deuterated alkenes and found to follow an identical mechanism where stereo-
chemistry is concerned. It exemplifies the importance of cationic palladium(IV) intermediates prior to the
final reductive elimination from palladium and proves that the nucelophile for this step stems from the
immediate coordination sphere of the palladium(IV) precursor. These results have important implications
for the general development of alkene 1,2-difunctionalization and for the individual processes of
aminopalladation and palladium-catalyzed Calkyl-N bond formation.
Introduction
of natural products, molecules of general pharmaceutical and
biological interest, and functional metal complexes and cata-
The direct oxidative conversion of alkenes into vicinal
diamines represents a challenging transformation. Over the past
three decades, several protocols for transition metal mediated
direct diamination of alkenes have been developed,1 which rely
on the use of thallium,2 mercury,3 palladium,4 osmium,5
selenium,6 and copper,7 and have even been extended to the
development of stereoselective synthesis of chiral diamines8 and
chiral-at-osmium complexes.9 This extensive investigation
underlines the importance of oxidative alkene diamination as a
direct approach to vicinal diamines. 1,2-Diamines constitute
important functional groups that are present in a large variety
lysts.10
The development of a transition metal catalyzed alkene
diamination is therefore of particular interest, but an efficient
solution remained elusive. Problems in its realization departing
from established stoichiometric metal reactivity originate from
exceedingly high reoxidation potentials (thallium), the potential
involvement of exceedingly toxic intermediates (mercury), and
issues of catalyst regeneration due to diamine chelation (osmium,
palladium).
In view of the broad versatility of palladium in homogeneous
catalysis, this metal appears to be a particularly promising
candidate. Development of a catalytic diamination process would
emerge from the earlier seminal stoichiometric chemistry from
Ba¨ckvall.4 In seminal studies on diamination and aminoalkoxy-
lation of alkenes, a complex multistep scenario was elucidated.11
As to its underlying key steps, the stoichiometric diamination
reaction consists, hence, of alkene coordination to palladium
(A) followed by amine coordination to palladium and clean
trans-aminopalladation.12 Intermediate B undergoes oxidation
to palladium(IV) derivative C, which is attacked from an
(1) Mun˜iz, K. New J. Chem. 2005, 29, 1371.
(2) Go´mez Aranda, V.; Barluenga J.; Aznar, F. Synthesis 1974, 504.
(3) (a) Barluenga, J.; Alonso-Cires, L.; Asensio, G. Synthesis 1979, 962. (b)
Barluenga, J.; Aznar, F.; de Mattos, M. C. S.; Kover, W. B.; Garc´ıa-Granda,
S.; Pe´rez-Carren˜o, E. J. Org. Chem. 1991, 56, 2930.
(4) (a) Ba¨ckvall, J.-E. Tetrahedron Lett. 1978, 19, 163. (b) Earlier report on
diamination as a side reaction in oxyamination: Ba¨ckvall, J.-E. Tetrahedron
Lett. 1975, 16, 2225.
(5) (a) Mun˜iz, K. Chem. Soc. ReV. 2004, 33, 166. (b) Chong, A. O.; Oshima,
K.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 3420. (c) Anhaus, J. T.;
Kee, T. P.; Schofield, M. H.; Schrock, R. R. J. Am. Chem. Soc. 1990, 112,
1642. (d) Schofield, M. H.; Kee, T. P.; Anhaus, J. T.; Schrock, R. R.;
Johnson, K. H.; Davis, W. M. Inorg. Chem. 1991, 30, 3595. (e) Mun˜iz,
K.; Iesato, A.; Nieger, M. Chem.sEur. J. 2003, 9, 5581. (f) Deubel, D.
V.; Mun˜iz, K. Chem.sEur. J. 2004, 10, 2475. (g) Mun˜iz, K. Eur. J. Org.
Chem. 2004, 2243.
(6) (a) Sharpless, K. B.; Singer, S. P. J. Org. Chem. 1976, 41, 2504. (b)
Bruncko, M.; Khuong, T.-A. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1996, 35, 454.
(7) (a) Zabawa, T. P.; Kasi, D.; Chemler, S. R. J. Am. Chem. Soc. 2005, 127,
11250. (b) Zabawa, T. P.; Chemler, S. R. Org. Lett. 2007, 9, 2035.
(8) (a) Mun˜iz, K.; Nieger, M. Synlett 2003, 211. (b) Mun˜iz, K.; Nieger, M.
Chem. Commun. 2005, 2729.
(9) Mun˜iz, K.; Nieger, M.; Mansikkama¨ki, H. Angew. Chem., Int. Ed. 2003,
42, 5958.
(10) (a) For a general review on chiral diamines, see: Lucet, D.; Le Gall, T.;
Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580. (b) For a review
on trans-1,2-diamino cyclohexane and chiral derivatives thereof, see:
Bennani, Y. L.; Hanessian, S. Chem. ReV. 1997, 97, 3161.
(11) (a) Ba¨ckvall, J.-E. Acc. Chem. Res. 1983, 16, 335. (b) Åkermark, B.;
Ba¨ckvall, J.-E.; Zetterberg, K. Acta Chem. Scand. 1982, B36, 577. (c)
Hegedus, L. S. Tetrahedron 1984, 40, 2415.
(12) (a) Åkermark, B.; Zetterberg, K. J. Am. Chem. Soc. 1984, 106, 5560. (b)
Åkermark, B.; Ba¨ckvall, J. E.; Siirala-Hanse´n, K.; Sjo¨berg, K.; Zetterberg,
K. Tetrahedron Lett. 1974, 15, 1363. (c) Åkermark, B.; Ba¨ckvall, J. E.
Tetrahedron Lett. 1975, 16, 819.
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J. AM. CHEM. SOC. 2008, 130, 763-773
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A R T I C L E S
Mun˜iz et al.
changes allow for the use of catalytic amounts of palladium-
(II), which does not require ligand stabilization. At the same
time, approaches toward oxidative palladium catalyzed diami-
nation reactions of 1,3-butadienes furnishing vinylic cyclic ureas
were reported.14
These examples of diamination add to the growing number
of palladium-catalyzed oxidative alkene aminations and alkene
1,2-difunctionalizations, respectively. As a common feature,
these reactions initiate by nitrogen transfer to the alkene.15
Oxidative product diversification is then accomplished under
specific reaction conditions. For example, recent research has
seen the development of aminobromination16 and aminochlo-
rination, aminoalkoxylation,17 aerobic aminocarbonylation,18
aza-Wacker-type reactions,19 and pyrrolidine formation.20,21
Despite this growing number of impressive reactions, precise
mechanistic knowledge on these transformations remains lim-
ited.
Figure 1. Key steps in the stoichiometric diamination of alkenes developed
by Ba¨ckvall. Oxidant ) Pb(OAc)4, Br2, mCPBA.
Scheme 1
Herein, detailed investigation on the course of intramolecular
diamination of alkenes with palladium catalysts is presented,
which clarifies the role of the urea in the aminopalladation step
and the stereochemical course of the second palladium-catalyzed
C-N-bond formation via a Pd(II/IV) catalysis.
Results and Discussion
Reaction Conditions. Typical reaction conditions and ex-
amples for the palladium-catalyzed intramolecular diamination
of terminal alkenes are given in Table 1 and Scheme 1. The
reaction allows for a number of ureas ranging from alkylamine
components to aniline derivatives and includes substrates with
2,2-disubstitution that give rise to quaternary stereogenic
products 2a-2h. This chemistry can also be extended to related
guanidines such as 1i. Tricyclic compounds of the type 2j can
be accessed through oxidative conversion of aniline 1j.
The optimized reaction conditions call for 5 mol % palladium
and do not require the stabilization by addition of conventional
phosphine or carbene ligands, and common commercially
(14) (a) Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem.
Soc. 2005, 127, 7308. (b) Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc.
2007, 129, 762. (c) Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc.
2007, 129, 7496. (d) Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem.
Soc. 2007, 129, 11688. (e) For a copper catalyzed variant: Yuan, W.; Du,
H.; Zhao, B.; Shi, Y. Org. Lett. 2007, 9, 2689.
(15) Minatti, A.; Mun˜iz, K. Chem. Soc. ReV. 2007, 36, 1142.
(16) (a) Lei, A.; Lu, X.; Liu, G. Tetrahedron Lett. 2004, 45, 1785-1788. (b)
Manzoni, M. R.; Zabawa, T. P.; Kasi, D.; Chemler, S. R. Organometallics
2004, 23, 5618-5621. (c) Li, G.; Kotti, S. R. S. S.; Timmons, C. Eur. J.
Org. Chem. 2007, 2745.
a General reaction conditions: 5 mol % Pd(OAc)2, PhI(OAc)2 (2 equiv),
NMe4Cl/ NaOAc (1 equiv), CH2Cl2, RT, 12 h.
(17) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005, 127,
7690.
(18) Yip, K.-T.; Yang, M.; Law, K.-L.; Zhu, N.-Y.; Yang, D. J. Am. Chem.
Soc. 2006, 128, 3130.
(19) (a) Review: Kotov, V.; Scarborough, C. C.; Stahl, S. S. Inorg. Chem. 2007,
46, 1910. (b) Selected recent work: Timokhin, V. I.; Anastasi, N. R.; Stahl,
S. S. J. Am. Chem. Soc. 2003, 125, 12996. (c) Rogers, M. M.; Wendlandt,
J. E.; Guzei, I. A.; Stahl, S. S. Org. Lett. 2006, 8, 2257.
external amine to furnish the final diamine upon palladium
reductive displacement (Figure 1). As a result of these steps,
the reaction is highly stereospecific and generates syn-diamines
from (E)-alkenes. Although the palladium is finally released in
its original +II oxidation state, a catalytic transformation based
on this chemistry was never reported.
Work from our laboratory recently described a first palladium-
catalysis for alkene diamination, which relies on intramolecular
reaction control (Scheme 1).13 It employs iodosobenzene diac-
etate as stoichiometric oxidant and uses urea groups as sources
for the two transferable nitrogen atoms to furnish cyclic urea
products in order to prevent catalyst poisoning. These two
(20) Scarborough, C. C.; Stahl, S. S. Org. Lett. 2006, 8, 3251.
(21) For additional recent oxidative alkene transformations under palladium
catalysis that do not include an aminopalladation step, see: (a) For a
review: Stahl, S. S. Angew. Chem., Int. Ed 2004, 43, 3400. For
dialkoxylation, see: (b) Schultz, M. J.; Sigman, M. S. J. Am. Chem. Soc.
2006, 128, 1460. (c) Zhang, Y.; Sigman, M. S. J. Am. Chem. Soc. 2007,
129, 3076. For hydroalkoxylation, see: (d) Gligorich, K. M.; Schultz, M.
J.; Sigman, M. S. J. Am. Chem. Soc. 2006, 128, 2794. (e) Zhang, Y.;
Sigman, M. S. Org. Lett. 2006, 8, 5557. (f) For acetal formation, see: Balija,
A. M.; Stowers, K. J.; Schultz, M. J.; Sigman, M. S. Org. Lett. 2006, 8,
1121. For dibromination, see: (g) El-Qisairi, A. K.; Qaseer, H. A.;
Katsigras, G.; Lorenzi, P.; Trivedi, U.; Tracz, S.; Hartman, A.; Miller, J.
A.; Henry, P. M. Org. Lett. 2003, 5, 439. For Wacker-type cyclizations,
see: (h) For a review, see: Cornell, C. N.; Sigman, M. S. Inorg. Chem.
2007, 46, 1903. (i) Cornell, C. N.; Sigman, M. S. J. Am. Chem. Soc. 2005,
127, 2796. (j) Cornell, C. N.; Sigman, M. S. Org. Lett. 2006, 8, 4117. (k)
Mun˜iz, K. AdV. Synth. Catal. 2004, 364, 1425.
(13) Streuff, J.; Ho¨velmann, C. H.; Nieger, M.; Mun˜iz, K. J. Am. Chem. Soc.
2005, 127, 14586.
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Oxidative Diamination of Alkenes
A R T I C L E S
Scheme 2. Diamination of Selectively Deuterated Alkenes 1b
a General reaction conditions same as from Scheme 1.
of the diamination. As a direct conclusion, a process based on
Pd(II)/Pd(0) catalysis must appear improbable.
Figure 2. Initial reaction profiles for oxidative conversion of 1b to 2b
under standard conditions in dichloromethane (gray 9) and acetonitrile ([).
Overall Reaction. In initial experiments, a combination of
tetramethylammonium chloride and sodium acetate was em-
ployed for a convenient in situ generation of tetramethylam-
monium acetate base. Although this formally adds a stoichio-
metric amount of chloride ions to the reaction mixture, these
were found to have no effect on both reaction rate and product
as reactions in the presence of Me4NCl/NaOAc and Me4NOAc
were found to proceed identically (Table 1, entries 1,2). Hence,
a potential involvement of chlorinated intermediates can be
excluded.
The overall reaction of urea transformation is carried out in
the presence of acetate, which originates from the base and the
oxidant. This acetate concentration is significantly enhanced
during the course of the reaction with the formation of acetic
acid. In order to exclude the involvement of intermediary species
from acetate incorporation, and hence a diamine formation
through nucleophilic substitution processes, compound 3 was
synthesized independently from proline. When submitted to the
conditions of the oxidation catalysis, no conversion to the
respective diamination product 2a was observed (eq 2):
Table 1. Scope of Reaction Conditions
entry
palladium source
solvent
oxidant
base
yield [%]
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(O2CCF3)2
PdCl2
CH2Cl2 PhI(OAc)2
CH2Cl2 PhI(OAc)2
Me4NCl/NaOAc
Me4NOAc
92
91
84
92
70
90
89
90
89
88
88
DMF
PhI(OAc)2
Me4NCl/NaOAc
Me4NCl/NaOAc
Me4NCl/NaOAc
Me4NCl/NaOAc
Me4NCl/NaOAc
Me4NCl/NaOAc
Me4NCl/NaOAc
CH3CN PhI(OAc)2
tBuOH PhI(OAc)2
CH2Cl2 PhI(OAc)2
CH2Cl2 PhI(OAc)2
Pd(NCCH3)2Cl2 CH2Cl2 PhI(OAc)2
Pd2(dba)3 CH2Cl2 PhI(OAc)2
10 Pd(OAc)2
11 Pd(OAc)2
CH2Cl2 PhI(O2CtBu)2 Me4NCl/NaOAc
CH2Cl2 PhI(OH)OTos Me4NCl/NaOAc
available palladium compounds such as Pd(OAc)2, PdCl2,
(MeCN)2PdCl2, Pd(O2CCF3)2, Pd2(dba)3 serve as catalyst source
(Table 1, entries 1, 6-9). The presence of base is a major
requirement and no diamination takes place in its absence. The
oxidative diamination is a completely chemoselective process,
proceeds under ambient air without the requirement of absolute
conditions and uses hypervalent iodines as terminal oxidant.
Commercial iodosobenzene diacetate is usually employed for
convenience, while related iodosobenzene dipivalate and Koser’s
reagent work equally well (entries 10 and 11). The reaction is
remarkably robust and does not show significant solvent
dependences. For example, the diamination of 1b proceeds well
with over 90% isolated yield in CH2Cl2, DMF, CH3CN and
even reasonably well in t-BuOH (entries 2-5).
Monitoring of the reaction progress for reactions of 1b in
dichloromethane and acetonitrile over the initial period of 5 h
revealed comparable reaction profiles (Figure 2). This is a
surprising observation in view of the mostly required solvent
optimization or even solvent dependence in palladium-catalyzed
alkene functionalization and underlines the robustness of the
present process.
As a result the intramolecular diamination of alkenes in the
presence of palladium catalysts is understood to represent a two-
step nitrogen transfer reaction, which consists of an aminomet-
allation followed by an oxidative C-N-bond forming process.
This sequence raises the question on the stereochemical course
of each of these two steps. A deuterium-labeling showed that
(E)-1b-d1 is cleanly transformed into syn-2b-d1 under the
diamination conditions, whereas the corresponding (Z)-1b-d1
yields diastereomerically pure anti-2b-d1.
It is to be noted within this context that the relative
stereochemistry of 2b-d1 was inadvertently misassigned in our
earlier communication.22 The corrected analysis is depicted in
Scheme 2 and additional details on the NMR analyses are
included in the Supporting Information.
Importantly, a stoichiometric reaction with palladium(II)-
acetate did not promote any diamination of 1b or 1e. This
indicates that the role of PhI(OAc)2 consists not of a mere
reoxidant to palladium, but must be involved during the course
(22) This incorrect assumption of a trans-aminopalladation was recently cited
in related work on aminopalladation24,25 and diamination.7b,14b The authors
apologize for the resulting confusion.
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A R T I C L E S
Mun˜iz et al.
In view of the stereochemical outcome of the two-step
process, the overall sequence must contain one step with
inversion of configuration, hence it must proceed either as a
syn-aminopalladation/anti-C-N-bond forming process or, al-
ternatively, as an anti-aminopalladation/syn-C-N-bond forming
process.
spectrum with two new sets of signals which correspond to the
two new compounds 4 and 5.
The decisive experiment consisted of an NMR tritration
experiment of 1b and Pd(OAc)2 with the base NMe4OAc.28 This
experiment led to the gradual formation of the same two new
compounds already observed in the earlier experiment. The
spectral progress is depicted in the Supporting Information,
whereas Figure 3 reproduces the initial, the intermediate, and
the final spectra.
The titration experiments suggest that the coordination of the
urea to palladium is followed by the alkene entering the
coordination sphere of the palladium in a second step. Upon
addition of a second equivalent of base, the reaction proceeds
to exclusive formation of 5 in a highly selective manner.
Intermediate 5 shows clearly distinguished signals from the final
product 2b.
First Step: Aminopalladation. The stereochemical course
of intramolecular aminopalladation23 and subsequent â-hydride
elimination to form allylamines was recently the focus of elegant
work from Stahl.24 In this investigation, ω-alkenyl-tosylamides
were employed and a syn-aminopalladation was revealed on the
basis of detailed deuterium labeling experiments. Earlier work
on intermolecular aminoalkoxylation had already suggested the
involvement of syn-aminopalladation.25,26
The relative solvent independence of the overall diamination
as observed from the initial kinetics suggests that solvent
coordination to palladium does not play a decisive role and that
the initial step is presumably a syn-aminopalladation with
transfer of amine occurring from within the coordination sphere
of a precomplexed palladium. Attempts to isolate defined
palladium(II) complexes from these experiments remained
unsuccessful.
Formation of 5 from 4 is a temperature-dependent reaction.
The reaction progress was monitored at different temperatures,
and the aminopalladation was found to be irreversible.29,30 For
the overall transformation from 4 to 5, different relative reaction
rates in the range between k1 ) 6.7 × 10-5 s-1 and k1 ) 9.0 ×
10-4 s-1 were determined in the temperature range from 273
to 308 K. The data for monitoring this reaction progress allow
for an estimation of the activation energy, which was determined
to EA ) 52 kJ/mol. Describing the process of activation by
thermodynamic function leads to an activation enthalpy ∆Hq
) 49.2 kJ/mol, an activation entropy ∆Sq ) -144 J/mol and
an overall reaction enthalpy of ∆G(298 K)q ) 92.1 kJ/mol. The
negative value for ∆Sq reflects the enhancement in order for
the transition state of aminopalladation including potential η2-
alkene coordination. It confirms that the process from 4 to 5 is
indeed a slow reaction. The exact course from 4 to 5 might
include additional events of ligand dissociation/association
within the Pd coordination sphere. However, solvent coordina-
tion appears negligible on the basis of the observed rate simi-
larity for coordinating and noncoordinating solvents (Figure 2).
All this data is consistent with the postulation of a syn-
aminopalladation as the initial step. The spectrum of 5 represents
a rare direct observation of an intermediate from alkene
aminopalladation. In solution, 5 is stable for about 2 h before
inconsistent decomposition and palladium black precipitation
take place. With regard to the isolation of structural evidence
in aminopalladation, we notice the report on the N-acetyl
derivative 6 from 1k by Hegedus.31 However, this compound,
which was found to be of low reactivity, has eluded attempts
at complete characterization. We synthesized the corresponding
urea derivative 1l, which did not yield a stable aminopalladation
product, but under our standard conditions, reacted with
complete diastereoselectivity to the new tricyclic compound 2l.
This high diastereoselectivity should encourage application of
the diamination in the synthesis of higher elaborate molecules.
In order to understand the initial reaction step, the coordina-
tion behavior of ureas to palladium is decisive. A first indica-
tion for metal-urea precomplexation prior to alkene
functionalization arose from the observation that use of chiral
bidentate ligands such as (-)-sparteine, BINAP, and TolBINAP
only yielded racemic diamination products. 31P NMR studies
on the addition of equimolar amounts as well as 2-, 5-, and
20-fold excesses of 1e and acetate base to BINAP-Pd(OAc)2,
DPPF-Pd(OAc)2, or (PPh3)2Pd(OAc)2 lead to rapid formation
of complex mixtures that contained free phosphines as major
components. For a mixture of (PPh3)2Pd(OAc)2 and 1e, free
PPh3 accounts for more than 80% of the 31P signals after 30
min. These results suggest rapid and irreversible displacement
of the phosphines from the Pd coordination sphere in favor of
the urea and/or alkene favoring subsequent syn-aminopalladation
events.
In order to further investigate the behavior of urea coordina-
tion to palladium, titration experiments were undertaken for the
dimethyl derivative 1b. It was again observed that a simple
titration of a CD2Cl2 solution of 1b with palladium acetate did
not result in any change of the signals for urea 1b and that the
final 1:1-mixture of 1b and Pd(OAc)2 is that of two independent
compounds. However, administering an equimolar amount of
NMe4OAc and treatment of a 1:1 mixture of 1b and NMe4-
OAc gives conclusive information about the initial steps of the
diamination reaction. First, complete and irreversible deproto-
nation of the tosylamide N-H group takes place, which is in
accordance with an estimated pKa of 4.0-5.0 for this group.27
Addition of Pd(OAc)2 to deprotonated 1b gave rise to a final
(27) The pKa value for 1b was estimated to be in this range taking into account
pKa values of related compounds (in water): 5.16 for N-butyl, N′-tosyl
urea [http://www.syrres.com/esc/physdemo.htm] and 3.70 for ethyl N-tosyl
carbamate [Taylor, L. D.; Pluhar, M.; Rubin, L. E. J. Polym. Sci., B: Polym.
Phys. 1967, 5, 77].
(28) For an NMR titration experiment on (C2H4)PdCl2 with Et2NH: Hegedus,
L. S.; Åkermark, B.; Zetterberg, K.; Olsson, L. F. J. Am. Chem. Soc. 1984,
106, 7122.
(23) In a stricter sense, the nitrogen sources in this and related work are amides
and, in a more correct manner, one should refer to these reactions as
amidopalladation. See reference 15 for a general discussion. For conven-
ience, we continue to use the term aminopalladation throughout this text.
(24) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328.
(25) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179.
(26) For related work that implies syn-aminopalladation, see: (a) Ney, J. E.;
Wolfe, J. P Angew. Chem., Int. Ed. 2004, 43, 3605. (b) Ney, J. E.; Wolfe,
J. P J. Am. Chem. Soc. 2005, 127, 8644. (c) Nakhla, J. S.; Kampf, J. W.;
Wolfe, J. P J. Am. Chem. Soc. 2006, 128, 2893. (d) Isomura, K.; Okada,
N.; Saruwatari, M.; Yamasaki, H.; Taniguchi, H. Chem. Lett. 1985, 385.
(29) For an example of reversibility in intermolecular aminopalladation:
Timokhin, V. I.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 17888.
(30) For stoichiometric reactions in the presence of only equimolar or lower
amounts of base, formation of 5 is slow.
(31) Hegedus, L. S.; McKearin, J. M. J. Am. Chem. Soc. 1982, 104, 2444.
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Oxidative Diamination of Alkenes
A R T I C L E S
Figure 3. Aminopalladation scenario for compound 1b: NMR spectroscopic monitoring (0.1M solution, CD2Cl2) and kinetic process regarding 1b-H+ ([)
4 (4) and 5 (9) at 308 K.
It furthermore exemplifies the reaction control that is exercized
by the urea moiety on the initial course of aminopalladation as
related aminoalkoxylation with 1m under comparable conditions
leads to mixtures of pyrrolidines and piperazines with different
levels of diastereomeric induction.17 The stereochemistry of the
new stereogenic center in 2l was deduced from 2D-NMR
9
J. AM. CHEM. SOC. VOL. 130, NO. 2, 2008 767

A R T I C L E S
Mun˜iz et al.
Scheme 3. Diastereoselective Diamination with 1l
a General reaction conditions same as from Scheme 1.
Scheme 4. Diamination of 2-Deuterated Compound 1b
butadienes and hexatrienes. The expected active catalyst state
H is the direct consequence of oxidative homolytic cleavage of
a N-N bond in a diaziridinone by palladium(0).14b After
insertion of the butadiene, the reaction yields an allyl palladium
complex I/I′, which represents the η3-analogue33 of intermediate
5.
Aniline derivative 1j was found to undergo slower diamina-
tion than related alkyl substrates 1a-1h and 1i. This behavior
can be attributed to a less pronounced nucleophilic character
of the aniline nitrogen in the aminopalladation step. A series of
derivatives was employed for a Hammett correlation regarding
the influence of aniline basicity on the reaction rate. A clear
correlation was determined, and the negative slope of the
Hammett plot (F ) -0.45) suggests the importance of electron
density at the aniline nitrogen as the decisive factor for rate
enhancement in the aminopalladation step. The observation of
such a correlation for the irreversible initial aminopalladation
concludes that this first step must be rate-determining. This
observation matches with the earlier outcome of the kinetic
studies, where the negative value for ∆Sq characterized the
aminopalladation as a slow reaction step.
a General reaction conditions same as from Scheme 1.
Second Step: Csp3-N-Bond Formation. This second step
of the overall diamination is of particular importance because
it represents the rare event of a catalyzed Csp3-N-bond
formation.
Figure 4. Different modes of syn-aminopalladation.
In particular, the ease of this step and the absence of any
side-reaction are remarkable. Catalytic Csp3-N-bond forming
reactions are still not available by reductive elimination from
the coordination sphere of a palladium(II) complex.34,35 The only
precedence of general C-N bond formation in palladium
catalysis belongs to related Csp2-N-bond formations as pio-
neered by Buchwald and Hartwig,36 and allylations within the
Tsuji-Trost reaction.37,38
experiments. It matches a transition state of syn-aminopallada-
tion preventing unfavorable pseudo-1,3-diaxial hydrogen inter-
actions.
No secondary kinetic isotope effect was observed in the
diamination of selectively 2-deuterated 1b (Scheme 4). This
result does not provide differentiation between syn- and anti-
aminopalladation, but supports the former as it involves
simultaneous transfer of nitrogen and palladium to the
alkene.
In general, syn-aminopalladation reactions proceed through
precoordination of the amine/amide to palladium prior to
insertion of an alkene into the N-Pd bond.15 For intramolecular
reactions, such a process is equivalent to a step D to E, as
recently discussed by Stahl24 (Figure 4). A major feature of the
NMR titration experiments reveals that for the present system,
the syn-aminopalladation consists of a reaction of the remaining
noncoordinated amine from the urea with the alkene. Therefore,
the syn-addition results from geometric requirements of the urea
tethering rather than from amine-palladium coordination. In
general, symmetrical urea coordination to palladium has been
known before.32 A related syn-addition of urea-palladium(II)
complexes is also involved in the catalytic diamination of
(33) (a) Butler, D. C. D.; Inman, G. A.; Alper, H. J. Org. Chem. 2000, 65,
5887. (b) Zhou, H.-B.; Alper, H. J. Org. Chem. 2003, 68, 3439. (c) Inman,
G. A.; Butler, D. C. D.; Alper, H. Synlett 2001, 914. (d) Trost, B. M.;
Fandrick, D. R. J. Am. Chem. Soc. 2003, 125, 11836.
(34) For recent attempts on reductive elimination of alkylamines from alkyl-
amido-palladium complexes, see: (a) Ney, J. E.; Wolfe, J. P. J. Am. Chem.
Soc. 2006, 128, 15415. (b) Esposito, O.; Lewis, A. K. de K.; Hitchcock, P.
B.; Caddick, S.; Cloke, F. G. N. Chem. Commun. 2007, 1157.
(35) For a Calkyl-N bond formation from palladium under oxidative conditions,
see: Brice, J. L.; Harang, J. E.; Timokhin, V. I.; Anastasi, N. R.; Stahl, S.
S. J. Am. Chem. Soc. 2005, 127, 2868.
(36) (a) Murci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131. (b)
Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046. (c) Hartwig, J. F.
Inorg. Chem. 2007, 46, 1936. (d) Hartwig, J. F. Acc. Chem. Res. 1998, 31,
852. (e) Schlummer, B.; Scholz, U. AdV. Synth. Catal. 2004, 346, 1599.
(f) Hartwig, J. F. Synlett 2006, 1283. (g) Buchwald, S. L.; Mauger, C.;
Mignani, G.; Scholz, U. AdV. Synth. Catal. 2006, 348, 23. (h) Wolfe, J. P.;
Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31,
805. (i) For a mechanistic investigation, see: Shekhar, S.; Ryberg, P.;
Hartwig, J. F.; Mathew, J. S.; Blackmond, D. G.; Strieter, E. R.; Buchwald,
S. L. J. Am. Chem. Soc. 2006, 128, 3584.
(37) (a) Amatore, C.; Genin, E.; Jutand, A.; Mensah, L. Organometallics 2007,
26, 1875 and cited lit. (b) Mora, G.; Deschamps, B.; van Zutphen, S.; Le
Goff, X. F.; Ricard, L.; Le Floch, P. Organometallics 2007, 26, 1846. (c)
For a different approach, see: Devine, S. K. J.; Van Vranken, D. L. Org.
Lett. 2007, 9, 2047.
(32) For isolated Pd-urea complexes: (a) Paul, F.; Fischer, J.; Ochsenbein, P.;
Osborn, J. A. C. R. Chimie 2002, 5, 267. (b) Paul, F.; Moulin, S.;
Piechaczyk, O.; Le Floch, P.; Osborn, J. A. J. Am. Chem. Soc. 2007, 129,
7294.
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Oxidative Diamination of Alkenes
A R T I C L E S
complexes.40 The latter undergo rapid irreversible oxidation in
the presence of hypervalent iodine reagents.43 This difference
in oxidation potential could be illustrated by a diamination
reaction of 1b with stoichiometric amounts of palladium acetate.
Stirring equimolar amounts of 1b, Pd(OAc)2 and base for 45
min at room-temperature prior to addition of hexachloropalladate
gave rise to the expected formation of diamine 2b which was
isolated in 71% yield:
This oxidation of alkylpalladium(II) to alkylpalladium(IV)
under conditions that do not oxidize palladium(II) salts is key
for the overall transformation. In this context, the nature of the
metal and its oxidation potential are decisive to the course of
the catalytic reaction. In contrast to palladium, platinum(II)
catalysis does not promote the reaction efficiently since oxida-
tion of 1b in the presence of 2 equiv of PhI(OAc)2 and 10 mol
% PtCl2 gave only less than 5% product even after prolonged
reaction time of 72 h. No other product was formed and
unreacted 1b was reisolated. In contrast, when 1b was treated
with a stoichiometric amount of PtCl2 for several hours prior
to oxidation with PhI(OAc)2 a yield of 49% of 2b was isolated.44
This difference is due to the presence of PhI(OAc)2 already at
the outset of the catalysis. Due to the lower oxidation potential
for Pt(II)/Pt(IV),45 all platinum(II) is readily oxidized and
removed from a potential catalytic cycle.46
The observation of rapid oxidation of the alkyl-palladium
intermediate confirms the rate-limiting nature of the aminopal-
ladation step. As a consequence, the second C-N bond will be
formed rapidly via reductive elimination of palladium(II). This
fast process must hence prevent any detectable observation on
a potential electronic influence regarding the nitrogen source.
Indeed, use of electronically different arylsulfonyl substituents
for the second nitrogen atom did not lead to a measurable
difference in relative rate (Scheme 5).
Figure 5. Hammett correlation for competitive diamination of aniline
derivatives (R2 ) 0.9925). Yields from eq 4 refer to those from independent
a
diamination reactions. General reaction conditions same as from Scheme
c
1. bNonoptimized yield. Together with 30% recovered starting material.
It is important to note that the present C-sp3-N bond
formation proceeds readily at room temperature while related
C-sp2-N bond forming reactions with urea do require high
temperatures and show pronounced ligand dependence.39 For
the present reaction, this significant difference in reactivity is
best understood by the involvement of a palladium(IV) inter-
mediate40 in the C-N reductive elimination. Such an oxidation
state had been postulated by Ba¨ckvall for stoichiometric
oxidation of alkyl palladium compounds4a,11 with bromine, lead
tetraacetate, or mCPBA and was recently confirmed by Sanford
in a study on stoichiometric benzyl-N and aryl-N-bond formation
from Pd(IV).41,42
For the present diamination, the isolated intermediate 5 does
not give rise to diamine formation under the NMR conditions
and no product formation is observed in the absence of the
hypervalent iodine under the catalytic conditions. The involve-
ment of a palladium(IV) by oxidation of the alkyl-palladium-
(II) intermediate after aminopalladation is the consequence of
a suitable difference in oxidation potential between simple
palladium(II) chloride and acetate salts and alkyl palladium
This second step of diamination is strongly dependent on the
electronic nature of the second nitrogen. Substituents other than
sulfonyl such as phenyl, benzyl, or trichloromethylcarbonyl do
not react or do not undergo diamination. This underlines that
partial sp3 character at nitrogen due to the sulfonyl substituent
is important as it induces the required nucleophilicity for the
second amination.
The stereochemical course of this second step of amination
must proceed with inversion of configuration in order to be in
agreement with the observed overall stereochemistry from the
(38) For a recent palladium-catalyzed allylic C-H to C-N conversion, see:
Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129, 7274.
(39) (a) Artamkina, G. A.; Sergeev, A. G.; Beletskaya, I. P. Tetrahedron Lett.
2001, 42, 4381. (b) Sergeev, A. G.; Artamkina, G. A.; Beletskaya, I. P.
Tetrahedron Lett. 2003, 44, 4719. (c) Sergeev, A. G.; Artamkina, G. A.;
Beletskaya, I. P. Russ. J. Org. Chem. 2003, 39, 1741. (d) Artamkina, G.
A.; Sergeev, A. G.; Beletskaya, I. P. Russ. J. Org. Chem. 2003, 38, 538.
(e) Popkin, M. E.; Bellingham, R. K.; Hayes, J. F. Synlett 2006, 2716.
(40) Canty, A. J. Acc. Chem. Res. 1992, 25, 83.
(43) A redox potential of -1.53 eV was recently reported for the PhI(OAc)2 +
2e-/PhI+2OAc- system: Baran, P. S.; DeMartino, M. P. Angew. Chem.,
Int. Ed. 2006, 45, 7083.
(44) Amino-platination as the initial step in this sequence is a well-established
process, for leading references, see: (a) Bender, C. F.; Widenhoefer, R.
A. J. Am. Chem. Soc. 2005, 127, 1070. (b) Karshtedt, D.; Bell, A. T.; Tilley,
T. D. J. Am. Chem. Soc. 2005, 127, 12640. (c) Qian, H.; Widenhoefer, R.
A. Org. Lett. 2005, 7, 2635. (d) Krogstad, D. A.; Cho, J.; DeBoer, A. J.;
Klitzke, J. A.; Sanow, W. R.; Williams, H. A.; Halfen, J. A. Inorg. Chim.
Acta 2006, 359, 136.
(41) Dick, A. R.; Remy, M. S.; Kampf, J. W.; Sanford, M. S. Organometallics
2007, 26, 1365.
(42) For selected examples of Caryl-O and C-X bond forming processes from
Pd(IV), see: (a) Dick, A. R.; Kampf, J. W.; Sanford, M. S. J. Am. Chem.
Soc. 2005, 127, 12790. (b) Canty, A. J.; Denney, M. C.; Skelton, B. W.;
White, A. H. Organometallics 2004, 23, 1122. (c) Canty, A. J.; Denney,
M. C.; van Koten, G.; Skelton, B. W.; White, A. H. Organometallics 2004,
23, 5432. (d) Canty, A. J.; Jin, H.; Skelton, B. W.; White, A. H. Inorg.
Chem. 1998, 37, 3975. (e) Dick, A. R.; Kampf, J. W.; Sanford, M. S.
Organometallics 2005, 24, 482. (f) Dick, A. R.; Sanford, M. S. Tetrahedron
2006, 62, 2439.
(45) The oxidation potential for PdCl62- + 2e-/ PdCl42- + 2Cl- is 1.29 V and
0.74V for PtCl6 + 2e-/PtCl4 + 2Cl-. Values from Weast, R. C.
Handbook of Chemistry and Physics, 50th ed.; The Chemical Rubber Co.:
Cleveland, 1969; D-110.
2-
2-
(46) Stahl, S.S.; Labinger, J. A.; Bercaw, J. E. Angew. Chem., Int. Ed. 1998,
37, 2180 and refs therein.
9
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A R T I C L E S
Mun˜iz et al.
Scheme 5. Investigation on Potential Acidity Influence in Second Step C-N Bond Formation
a General reaction conditions same as from Scheme 1. Yields from eq 6 refer to those from independent diamination reactions.
deuteration experiments (Scheme 2). This stereochemical pro-
cess had previously been confirmed for related C-O bond
forming processes in platinum(IV) chemistry.46,47 The stereo-
chemical course of C-N bond formation in reactions of
palladium(IV) was first investigated by Ba¨ckvall,4,11a,b who
concluded clean inversion for his intermolecular palladium-
mediated amination reactions. Here, this step is understood to
proceed through a state J (Figure 6), for which stereoelectronic
reasons require weakening the bonding extent for the palladium-
alkyl bond upon formation of the new alkyl-N bond.
For the present diamination, the prerequisite of backsite attack
in the second C-N bond formation requires displacement of
the tosylamide from the palladium coordination sphere prior to
this final step.48 This generates a cationic octahedral palladium-
(IV) state within an ion pair, enhances the electrophilicity of
the palladated methylene group, and thereby induces the
propensity for Pd reductive elimination.49-51 Prior to this, the
reaction requires rotation of the Pd-C bond with respect to the
amide. An alternative pathway of reductive elimination from a
state K as encountered in related reductive elimination reactions
from Pd(II) centers in aryl36 and vinyl52 aminations would not
agree with the observed overall stereochemistry of the deutera-
tion experiments (Scheme 2). In addition, such reductive
eliminations are particularly rare for electron-demanding amides
and usually require high temperatures.53,54
for the final alkyl-X-bond formation from the palladium(IV)
coordination sphere was obtained from an investigation with
sulfamides. Related to ureas, sulfamides represent a potential
coordination group for palladium and a potential nitrogen source
for alkene diamination. These precursors are conveniently
accessed by treatment of primary amine precursors with Burgess
reagents.55,56 Attempts to employ these compounds as substrates
in palladium-catalyzed diamination met with little success.57
Instead, standard reaction conditions of the urea-based diami-
nation reaction gave a mixture of aminochlorination and
diamination products 8 and 9. In this case, however, the diamine
product 9 is not formed directly, as a control experiment revealed
that it is generated under the basic reaction conditions from the
aminochlorination product 8 over time.
When the reaction was shifted to tetramethylammonium
acetate or simply sodium acetate as base, i.e., processing at a
lower base concentration, competing aminoacetoxylation instead
of diamination dominated. Importantly, selectively deuterated
precursor 10-d1 gave a diastereomerically enriched product 11-
d1. The major isomer was selectively transformed into the free
cyclic sulfamide 12 via a sequence of acetate cleavage and
Mitsunobu cyclization. Comparison of the NMR coupling
constants allowed for the unambiguous deduction of a relative
anti-position of the two hydrogen atoms of the former alkene
and hence for a formal syn-/anti-sequence to 11-d1. This
outcome is reminiscent of the overall process of our diamination
with ureas and the corresponding aminoacetoxylations from
Sorensen17 and Stahl.25 In particular, Stahl recently presented
an investigation on related intermolecular aminoacetoxylation
reactions25 and concluded a sequence of syn-aminopalladation-
followed by SN2-type acetoxylation at the palladated carbon.58
When changing the oxidant further, we were able to observe
selective amino-X-functionalization processes for use of PhI-
Sulfamides. Additional conclusive evidence for the involve-
ment of syn-aminopalladation and release of the nucleophile
(47) (a) Williams, B. S.; Holland, A. W.; Goldberg, K. I. J. Am. Chem. Soc.
1999, 121, 252. (b) Williams, B. S.; Goldberg, K. I. J. Am. Chem. Soc.
2001, 123, 2576.
(48) Through oxidation of the intermediate 5, formation of a palladium(IV)
intermediate of octahedral geometry is assumed. Figure 6 describes this
compound as a syn-diacetate, based on a recent X-ray structure of a related
palladium(IV) compound.42b The remaining coordination sites should be
filled by additional donor groups L, which are unknown to date and might
include solvent molecules, additional urea groups, acetic acid, acetate or
halides (where present). The latter two would result in formation of formally
anionic intermediates, which cannot be discarded completely at present.
(49) The importance of cationic metal states in related Pt(IV) chemistry was
established both for alkyl-X and aryl-X bond formation. See ref 44 and (a)
Goldberg, K. I.; Yan, J. Y.; Winter, E. L. J. Am. Chem. Soc. 1994, 116,
1573. (b) Goldberg, K. I.; Yan, J. Y.; Breitung, E. M. J. Am. Chem. Soc.
1995, 117, 6889. (c) Yahav-Levi, A.; Goldberg, I.; Vigalok, A. J. Am. Chem.
Soc. 2006, 128, 8710. (d) Periana, R. A.; Taube, D. J.; Gamble, S.; Taube,
H.; Satoh, T.; Fujii, H. Science 1998, 280, 560.
(53) (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043. (b) Yin,
J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101. (c) Sergeev, A. G.; Artamkina,
G. A.; Khrustalev, V. N.; Antipin, M. Y.; Beletskaya, I. P. MendeleeV
Commun. 2007, 17, 142. (d) Fujita, K.-i.;Yamashita, M.; Puschmann, F.;
Alvarez-Falcon, M. M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 9044. (e) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2007,
129, 7734.
(54) For an exception, see: Mun˜iz, K.; Iglesias, A. Angew. Chem., Int. Ed. 2007,
46, 6350.
(55) Winum, J.-Y.; Toupet, L.; Barragan, V.; Dewynter, G.; Montero, J.-L. Org.
Lett. 2001, 3, 2241.
(50) For methanol elimination from neutral Pt(IV) complexes under basic
conditions, see: (a) Vedernikov, A. N.; Binfield, S. A.; Zavalij, P. Y.;
Khusnutdinova, J. R. J. Am. Chem. Soc. 2006, 128, 82. (b) Khusnutdinova,
J. R.; Zavalij, P. Y.; Vedernikov, A. N. Organometallics 2007, 26, 3466.
(51) While this manuscript was in the refereeing process, Goldberg described
an identical mechanistic scenario for formation of achiral C-N bonds via
reductive elimination from a methyl, tosylamido-Pt(IV) complex: Paw-
likowski, A. V.; Getty, A. D.; Goldberg, K. I. J. Am. Chem. Soc. 2007,
129, 10382.
(56) Nicolaou introduced Burgess reagents for stoichiometric transformation of
vicinal amino alcohols into cyclic sulfamides: (a) Nicolaou, K. C.;
Longbottom, D. A.; Snyder, S. A.; Nalbanadian, A. Z.; Huang, X. Angew.
Chem., Int. Ed. 2002, 41, 3866. (b) Nicolaou, K. C.; Snyder, S. A.;
Longbottom, D. A.; Nalbanadian, A. Z.; Huang, X. Chem.sEur. J. 2004,
10, 5581.
(57) Mun˜iz, K.; Streuff, J.; Ho¨velmann, C. H.; Nu´n˜ez, A. Angew. Chem., Int.
Ed. 2007, 46, 7125.
(52) Barluenga, J.; Valde´s, C. Chem. Commun. 2005, 4891.
9
770 J. AM. CHEM. SOC. VOL. 130, NO. 2, 2008

Oxidative Diamination of Alkenes
A R T I C L E S
Scheme 6. Aminoacetoxylation Reactions of Sulfamides. DIAD ) Diisopropyl Azodicarboxylate
Table 2. Pd-Catalyzed Vicinal Amino-X-Functionalization
a Isolated yield after column chromatography.
(O2CtBu)2, PhI(O2CCD3)2, and under conditions of Me4NCl
addition. Control experiments confirmed that these reactions are
indeed metal-catalyzed and that there is no uncatalyzed back-
ground reaction involved.59
Interestingly, all of these vicinal functionalization reactions
occur with complete selectivity regarding the transfer of the
second nucleophile. For all of these reactions, the nucleophile
originates from the oxidant, and in no case from the anionic
base. This selectivity depends on the crucial absence of acids
because protons are known to promote exchange of the anions
in hypervalent iodine reagents of type ArIX2.60 Indeed, formation
of chlorinated products must stem from partial or complete
exchange of acetate for chloride where tetramethylammonium
is involved.
This observation was further corroborated from experiments
with deuterated material and acetate/pivalate bases (Table 2,
entries 2-4). Again, in all of these cases, only the anion that is
transferred to palladium within the oxidation step finally finds
(58) For a recent cascade reaction with open relative stereochemistry in C-OAc
bond formation from Pd(IV), see: Welbes, L. L.; Lyons, T. W.; Cychosz,
K. A.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 5836.
(59) For a direct aminoalkoxylation with PhI(O2CCF3)2, see: Correa, A.; Tellitu,
I.; Dom´ınguez, E.; SanMartin, R. J. Org. Chem. 2006, 71, 8316.
(60) Stang, P. J.; Boehshar, M.; Wingert, H.; Kitamura, T. J. Am. Chem. Soc.
1988, 110, 3272.
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A R T I C L E S
Mun˜iz et al.
Figure 6. Mechanistic pathway for C-N bond formation from Pd(IV).
Figure 7. Overall sequence for amino-X functionalization of alkenes employing sulfamides.
Figure 8. Overall catalytic cycle for palladium-catalyzed intramolecular diamination.
incorporation into the product. This observation is equivalent
to the conclusion that the anion X in eq 7 proceeds from the
immediate coordination sphere of the palladium(IV) oxidation
state where it is introduced within the oxidation step of Pd(II)
to Pd(IV) and hence plays a role reminiscent of the dissociating
tosylamide in the diamination (Figure 6). Such a course has
precedence for oxygenation reactions in platinum(IV) chemis-
try,47,49 but to the best of our knowledge, has never been proven
in conclusive detail for palladium(IV) chemistry.51
The importance of the transfer of the anion from palladium
to carbon within a sequence of dissociation and SN2-type
nucleophilic substitution is of particular importance to the related
course of the diamination reactions. It exemplifies that the NMR
observation of a coordination of the tosylamide group to
tetrahedral palladium(II) is obviously reversed after oxidation
to octahedral palladium(IV), enabling a subsequent nucelophilic
substitution/reductive depalladation with clean inversion of
configuration. Palladium catalysis for oxidative alkene 1,2-
difunctionalization with sulfamides yields different products
depending on the reaction conditions, but proceeds throughout
identical stereochemical pathways (Figure 7). The difference
in product formation is contributed to the different leaving group
character of the involved groups. Although the amide in tosyl
ureas represents a leaving group character comparable to acetate,
the related sulfamide cannot compete with the latter with respect
to dissociation from the palladium center. Since the mechanistic
pathway for final C-X bond formation proceeds via nucleo-
philic attack and not through direct reductive elimination,
intramolecular diamination does not represent a feasible pathway
for sulfamides.57
Conclusion
On the basis of the presented data, it is reasonable to conclude
a two-step mechanism for the palladium-catalyzed oxidative
diamination of alkenes employing urea groups as nitrogen
sources. The resulting catalytic cycle is given in Figure 8. The
reaction is initiated upon base-mediated coordination of pal-
ladium to the urea moiety. Coordination of the alkene to
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772 J. AM. CHEM. SOC. VOL. 130, NO. 2, 2008

Oxidative Diamination of Alkenes
A R T I C L E S
palladium gives rise to aminopalladation. This occurs with the
urea and the alkene being subsequently placed within the
coordination sphere of palladium and hence constitutes a process
with syn-stereochemistry. The step from 4 to 5 is slow and for
the first time could be studied as a stoichiometric process under
NMR conditions. The product from aminopalladation is a
square-planar alkyl-palladium(II) complex that was detected by
NMR spectroscopy. It undergoes rapid oxidation to octahedral
palladium(IV). Its high oxidation state is a prerequisite for the
formation of the diamination product since at oxidation state
+IV, palladium enhances the electrophilicty of the neighboring
carbon of its alkyl ligand. This electrophilic character is
pronounced further upon dissociation of the urea ligand from
the coordination sphere of palladium. Diamine formation is
accomplished via nucleophilic nitrogen-carbon bond formation
under clean SN2-type conditions with clean anti-stereochemistry.
This latter step leads to concomitant depalladation and regener-
ates the palladium catalyst in its original oxidation state.
All of these steps are in excellent agreement with the
investigation on individual reaction steps including deuterium
labeling, kinetics, solvent influence, electronic substitution
effects, in situ NMR investigation and comparison with related
aminoalkoxylation processes of sulfamides. It is interesting to
compare the two stereochemistry-defining steps to the earlier
stoichiometric protocol from Ba¨ckvall.4 Here, the nature of
simple aliphatic amines precludes clean anti-aminopalladation
of precoordinated alkenes and hence marks the stereochemical
difference with respect to the catalytic intramolecular transfor-
mation employing ureas. The second C-N bond formation
requires previous dissociation of the amide from the palladium
coordination sphere. Hence, both the catalytic and the stoichio-
metric variant proceed with clean inversion of stereochemistry
at this stage.
Our work has thus detailed the mechanistic basis of the first
catalytic diamination of alkenes with a palladium-catalyst. It
has further led to the discussion of the first general palladium-
catalyzed Csp3-N bond forming processes, the importance of
nitrogen-tethered groups on a stereospecific reaction course in
related amino-X-functionalizations. In addition, the reaction is
catalyzed by simple ligand-free palladium salts and does not
require ligand fine-tuning. All of these points should set the
basis for additional development in the area of palladium-
catalyzed alkene oxidation reactions.
Acknowledgment. We thank Dr. A. Nu´n˜ez for experimental
contributions, and Prof. Dr. Jose´ Gonza´lez and Esther Campos-
Go´mez for a generous gift of compound 1i. K.M. acknowledges
the German Fonds der Chemischen Industrie, the Deutsche
Forschungsgemeinschaft, the German-Israeli Science Founda-
tion, the Otto-Ro¨hm-Geda¨chtsnisstiftung, and the French Agence
Nationale de la Recherche for financial support over the course
of this project. We thank Prof. Dr. J. M. Lehn and Prof. Dr. N.
Winssinger at ISIS, Prof. Dr. K. H. Do¨tz for his support at Bonn
University during the early stages of this project, and U.
Weynandt (Bonn) and J.-L. Schmitt (Strasbourg) for assistance
with several NMR experiments.
Supporting Information Available: Experimental details, full
characterization of new compounds, spectral reproduction for
NMR experiments, and additional graphical material. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA075041A
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J. AM. CHEM. SOC. VOL. 130, NO. 2, 2008 773