Advancing palladium-catalyzed C-N bond formation: Bisindoline construction from successive amide transfer to internal alkenes

Article abstract of DOI:10.1021/ja075655f

The sequential transfer of two sulfonamides to internal alkenes affords the construction of vicinal diamines. In the presence of a palladium catalyst, the reaction proceeds through two mechanistically different C-N bond formation reactions. It is initiate

Full text of DOI:10.1021/ja075655f

Published on Web 11/07/2007
Advancing Palladium-Catalyzed C-N Bond Formation: Bisindoline
Construction from Successive Amide Transfer to Internal Alkenes
Kilian Mun˜iz
Institut de Chimie, UMR 7177, UniVersite´ Louis Pasteur, 4 rue Blaise Pascal, F-67000 Strasbourg Cedex, France
Received July 29, 2007; E-mail: muniz@chimie.u-strasbg.fr
Aminopalladation of alkenes1 has emerged as a versatile method
Table 1. Optimization of Reaction Conditions
for the synthesis of alkyl nitrogen bonds. In contrast, alternative
palladium catalysis for the direct installment of C-N bonds from
alkyl-palladium η1-amido complexes remains a challenging task.2
The sequential combination of both approaches enables stepwise
oxidative diamination of alkenes and offers new synthetic meth-
odology toward the important class of vicinal diamines.3 Such a
sequence was recently realized for palladium(II) catalysis using
ureas as tethered nitrogen sources under intramolecular reaction
control.4,5 This chemistry relies on the use of iodosobenzene
diacetate as oxidant and may be understood on the basis of a high
oxidation state metal intermediate.4b,6,7 This work now presents the
first examples for catalytic diamination of internal alkenes employ-
ing Pd catalysis. Its approach relies on simple amido groups as
nitrogen source and, within an operationally convenient oxidation
reaction, allows for the construction of bisindoline, bipyrrolidine,
and annelated indoline heterocycles containing vicinal diamine
moieties.
base
time
(h)
yielda
(%)
entry
catalyst
solvent
(1.1 equiv)
1
2
3
4
5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
CH2Cl2
CH2Cl2/DMF
DMF
DMF
DMF
NaOAc/Me4NCl
NaOAc/Me4NCl
Me4NOAc
NaOAc/Me4NCl
NaOAc/Me4NCl
36
36
14
14
24
79
88
88
89
74
b
Pd(OAc)2
a Isolated product after reductive workup and column chromatography.
b 5 mol % catalyst loading.
Table 2. Pd-Catalyzed Bisindoline and Bipyrrolidine Synthesisa
After an extensive screening of candidates for catalytic diami-
nation with simple amides,8 it was discovered that a precursor 1a
undergoes a highly selective diamination to form protected bisin-
doline 2a (Table 1). Optimized reaction conditions for the oxidative
diamination employ PhI(OAc)2 as oxidant. Acetate base is required
for high rate, and the combination of NMe4Cl and NaOAc was
found to be most convenient. DMF represents the optimum solvent
for complete solubility of the starting material. Less polar solvents
such as dichloromethane require longer reaction times due to low
solubility. A quantity of 10 mol % of catalyst allowed for complete
conversion during 14 h reaction time, although the reaction proceeds
at lower catalyst loading as well.
It is noteworthy that the reaction is not influenced by steric or
electronic factors (Table 2, eq 1). For example, sterically congested
di(2,4,6-tri-iso-propylphenyl) derivative 1e underwent clean diami-
nation to yield a single isomer 2e in 93% isolated yield, and the
nosyl substitution in 1d was similarly tolerated. The reaction is
highly stereospecific and furnishes chiral C2-symmetric products
from E-configured alkene precursors. This stereochemistry was
unambiguously confirmed by X-ray analysis of product 2a.
The high efficiency of precursors that require formal endo-
amination can be understood on the basis of the ligand-free,
coordinatively unsaturated palladium catalyst. Palladium-tosyla-
mide precoordination as initial step was recently established for
catalytic diamination with ureas.4b In the present case, similar
nitrogen-palladium interaction9 is assumed to pose the path for
selective anti-aminopalladation by the second amido group. At this
state, syn-aminopalladation1,5b,9,10 cannot proceed for geometrical
reasons. anti-Aminopalladation leads to a chelation-controlled state
B, which inhibits potential â-hydride elimination pathways in
aliphatic substrates (eq 3). This complex B then undergoes oxidation
to palladium(IV),7 amide dissociation, and selective anti-amination/
depalladation.4b,11 This final step is in complete agreement with
a Yields refer to isolated material after column chromatography or
crystallization and are average from at least two independent reactions (0.5
mmol scale). b Reaction on 5 mmol scale. Yield refers to crystallized
product.
recent detailed work on a related platinum(IV) complex12 and again
proceeds with complete stereochemical selectivity. Furthermore, it
constitutes the first general examples of secondary Csp3-N bond
formation in palladium catalysis.10,13
These reactions are noteworthy for the fact that the palladium
catalyst exercises a remarkable flexibility throughout the course of
9
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J. AM. CHEM. SOC. 2007, 129, 14542-14543
10.1021/ja075655f CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Catalytic Oxidation of Unsymmetrical Internal Alkenes
1h-l and Alkyne 3a
the synthetic potential of the stepwise diamination of unsaturated
C-C bonds to generate annelated indole 4.17 Although overall
related in mechanism to the alkene diamination, the reaction
required significantly higher temperature. For the second C-N bond
formation, this observation can be rationalized on the basis of a
thermal reductive elimination from within the Pd coordination
sphere18 instead of the SN2-type mechanism in the final step of
alkene diamination (state C, Figure 1).
In summary, the sequential catalytic transfer of two sulfonamides
to internal alkenes was shown to afford the construction of vicinal
diamines. The reaction consists of two different palladium-catalyzed
C-N bond formation reactions and provides convenient access to
heterocyclic structures such as bisindolines, annelated indolines,
and bipyrrolidines.
Acknowledgment. The author thanks the Agence Nationale de
la Recherche and the Fonds der Chemischen Industrie for generous
financial support, and Dr. Lydia Brelot for the X-ray structure
determination.
Supporting Information Available: Discussion on the reaction
scope, detailed experimental procedures, data for new products, and
spectral characterization. This material is available free of charge via
the Internet at http://pubs.acs.org.
a Yields refer to isolated material after column chromatography and are
average from two independent reactions.
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Figure 1. Proposed catalytic cycle for Pd-catalyzed diamination of 1.
the reaction. It first catalyzes a regioselective amination of an sp2-
carbon within the initial alkene aminopalladation. Next, it installs
the second Csp3-N bond within a completely stereospecific
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