Defined Palladium-Phthalimidato Catalysts for Improved Oxidative Amination

Article abstract of DOI:10.1002/chem.201601128

New palladium(II)-phthalimidato complexes have been synthesized, isolated, and structurally characterized. As demonstrated from over 30 examples, they constitute superior catalysts for oxidative amination reactions of alkenes with phthalimide as the nitrogen source. This work streamlines vicinal difunctionalization of alkenes and provides access to significantly improved and experimentally simplified synthetic protocols.

Full text of DOI:10.1002/chem.201601128

DOI: 10.1002/chem.201601128
Communication
&
Amination
Defined Palladium–Phthalimidato Catalysts for Improved
Oxidative Amination
Claudio Martínez[a] and Kilian MuÇiz*[a, b]
Dedicated to Professor Naoto Chatani on the occasion of his 60th birthday
Abstract: New palladium(II)–phthalimidato complexes
have been synthesized, isolated, and structurally charac-
terized. As demonstrated from over 30 examples, they
constitute superior catalysts for oxidative amination reac-
tions of alkenes with phthalimide as the nitrogen source.
This work streamlines vicinal difunctionalization of alkenes
and provides access to significantly improved and experi-
mentally simplified synthetic protocols.
Defined amination reactions at carbon centers constitute the
most versatile approach towards the important class of nitro-
gen-containing organic molecules.[1] Within this context, phthal-
imide has been identified as a particularly versatile ammonia
surrogate in organic synthesis. Its potassium salt was originally
introduced by Gabriel for amination reactions with broad ap-
plicability employing the concept of nucleophilic displace-
ment.[2] In addition to such nucleophilic substitution, the en-
hanced stability of phthalimide under oxidative conditions has
enabled an additional seminal transformation of hydrocarbons
within this particular area.[3,4]
Scheme 1. Palladium-catalyzed aminoacetoxylation and diamination reac-
tions using phthalimide as the nitrogen source.
reactions has often remained elusive, in particular when oxida-
tion reactions are concerned.[7,10] Herein, we report the isola-
tion of defined palladium(II)–phthalimidato complexes and
present their behavior as tailor-made catalysts in advanced oxi-
dative alkene diamination with phthalimide within significantly
simplified experimental protocols.
Earlier, the combination of palladium and phthalimide 2a
was found to permit unique intermolecular aminoacetoxyla-
tion[5] and diamination reactions,[6] all of which proceed under
the conditions of PdII/PdIV redox catalysis.[7] This work has gen-
erated a synthetic methodology, which converts internal al-
kenes, such as 1, into the corresponding difunctionalized prod-
ucts 3a and 4a with complete regio-, chemo-, and diastereose-
lectivity (Scheme 1),[6,8] though the structural basis for the in-
volved palladium catalysts has so far remained undetermined.
In general, although homogeneous palladium catalysis has
reached paramount synthetic applicability over past decades,[9]
definite knowledge on the catalyst states involved in individual
Our investigation started with the assumption that a transfor-
mation of the palladium dichloride source prior to the catalysis
should be involved in reactions from Scheme 1. We had identi-
fied
a preheating period between palladium complexes
[(RCN)2PdCl2] and phthalimide as the crucial point in the gener-
ation of the active Pd catalyst.[6] For clarification, we studied
the reaction between the palladium precursor and phthal-
imide. First, palladium diacetate reacts readily with phthalimide
2a or tetrafluorophthalimide 2b at room temperature in the
presence of a nitrile to provide the new complexes 5a–d as
air-stable crystalline solids (Scheme 2).[11] The underlying high
[a] Dr. C. Martínez, Prof. Dr. K. MuÇiz
Institute of Chemical Research of Catalonia (ICIQ)
The Barcelona Institute of Science and Technology
Av. Pa¨ısos Catalans 16, 43007 Tarragona (Spain)
E-mail: kmuniz@iciq.es
[b] Prof. Dr. K. MuÇiz
Catalan Institution for Research and Advanced Studies (ICREA)
Pg. Lluís Companys 23, 08010 Barcelona (Spain)
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under http://dx.doi.org/10.1002/
chem.201601128.
Scheme 2. Synthesis of new palladium–phthalimidato complexes 5a–d.
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stability of the Pd–amide bond is reminiscent to those of pep-
tide–palladium complexes.[12] Complexes 5a–d form irreversi-
bly and do not revert back to Pd–acetate complexes even in
the presence of large excesses of the free carboxylic acid.[13]
They are equally stable in the presence of hypervalent iodine
reagents involved in the difunctionalization reactions.[13]
Complexes 5a–d engaged in rapid dissociation of neutral ni-
trile ligands in solution. Attempts to grow crystals were unsuc-
cessful except for one case, in which the structure of the new
bis(aqua) complex 6 (Scheme 3) formed from a toluene solu-
Figure 1. X-ray structures of complexes 6 (top) and 7 (bottom). Selected
bond lengths (Š) and angles (8); complex 6: Pd1ÀO3 2.018(3), Pd1ÀN1
2.046(4), O3-Pd1-O3 180.0, O3-Pd1-N1 90.25(15), O3-Pd1-N1 89.75(15) and
complex 7: Pd1ÀN1 1.992(4), Pd1ÀN2 1.975(5), Pd1ÀO2 2.017(4), Pd1ÀO4
2.026(4), N2-Pd1-N1 91.67(19), N2-Pd1-O2 170.44(17), N1-Pd1-O2 87.6(2), N2-
Pd1-O4 88.6(2), N1-Pd1-O4 169.32(17), O2-Pd1-O4 90.3(2).
the absence of any alkene isomerization pathway over the
course of the difunctionalization reactions from Scheme 1 and
Scheme 4. Alkene isomerization is known to be rapid with
[(RCN)2PdCl2][15] and completely suppressed upon formation of
the phthalimidato complexes of type 5.[13] Moreover, the
nature of the phthalimide[16] does not alter the course of the
reaction (Scheme 5). An internal competition experiment dem-
onstrates equal product formation for both phthalimide and
tetrafluorophthalimide from (Z)-1; kinetic control experiments
confirm equal rates for the two individual reactions.
Scheme 3. Synthesis of advanced palladium–phthalimidato complexes 6 and
7 arising from labile nitrile coordination in complexes 5a–d.
tion of 5a (Figure 1).[14] In a similar manner, alkenes may re-
place the nitrile ligands in 5a–d; however, the resulting alkene
coordination is again of labile nature and could not be con-
firmed either by NMR or X-ray crystallography. Instead, heating
of 5a,c or prolonged standing in solution resulted in the for-
mation of the unprecedented trimeric complex 7. The same
complex 7 is obtained from [(MeCN)2PdCl2] and free phthal-
imide under more forcing conditions that resemble the pre-
heating period under the conditions of catalysis.[6]
Further kinetic control experiments suggest 7 to be a preca-
talyst, particularly in the absence of loosely coordinating li-
gands, such as nitriles.[17] For the transformation of (Z)-1 to 4a,
a first-order dependence on the catalyst was observed, con-
firming a monomeric catalyst state.[13] In line with these obser-
vations, participation of phthalimidato complexes of palladium
sets the basis for the chemoselectivity in catalytic diamination
reactions, which kinetically override the potentially competing
stoichiometric background reaction based on PhI(NTs2)2. This
particular reaction had previously been investigated by us.[18]
Indeed, this background reaction does become dominant in
the presence of ligands that exercise stronger coordination to
the palladium than nitriles, in which the alkene oxidation pro-
ceeds exclusively throughout the iodine(III)-mediated chan-
nel.[18] The mechanistic conclusion is that a free coordination
site at palladium is required for the alkene coordination within
the initial aminopalladation.[8b,c]
The isolated phthalimidato complexes of palladium, 5a–d
and 7, are versatile catalysts for the diamination and amino-
oxygenation of alkenes using phthalimides as nitrogen sources,
as exemplified with the internal alkene (Z)-b-methylstyrene as
substrate (Scheme 4). For the corresponding diamination reac-
tion to 4a, all three new catalysts 5c, 6, and 7 provide com-
plete selectivity and high isolated yields of 80–90%. The same
observation is made for a diamination with tetrafluorophthal-
imide in the presence of catalyst 5d. Finally, aminoxygenation
to 3a proceeds with yields comparable to the previous in situ
protocols, whereas addition of bistrifluoroacetamide provides
a new aminooxygenation variant to 3b in 74% yield.
The formation of 5a–d and 7 upon its concomitant com-
plete loss of the chloride atoms also lends an explanation to
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Scheme 4. Reactivity of palladium–phthalimidato complexes.
HNPhth=phthalimide, HNPhth4F =tetrafluorophthalphthalimide.
Scheme 6. Palladium-catalyzed diamination of allylic ethers employing pre-
formed phthalimidato complexes. [a] Yields in brackets refer to the outcome
from the in situ conditions. [b] Yield from a 4 mmol scale reaction.
could be enhanced to selective monodiamination of dienes
(9h–j) or to the corresponding tetraamination reaction (9k).
The reaction can be conducted with complete diastereoselec-
tivity (9l). Higher functionalized allylic ethers, including epox-
ides and acetal substituents, are also tolerated (9m–p).
More importantly, terminal alkenes, which according to our
previous protocols required the use of saccharine as a nitrogen
source,[20] can now be employed in the palladium-catalyzed di-
amination with more readily removable[13] phthalimide
(Scheme 7). Examples include representative aliphatic alkenes
10a,b for phthalimide and 10j,k for tetrafluorophthalimide.
Functionalized alkenes are equally tolerated (11 d–g), includ-
ing the nitrile 10c. The latter is entirely nonreactive without
the preformed catalyst, resulting in an alkene consumption by
the iodine(III)-mediated background reaction.[18] Although still
low in rate, the present reaction with 5a occurs selectively
within the Pd oxidation manifold. Finally, allyl benzene was
employed as a substrate to demonstrate again that the pres-
ent reaction conditions proceed without any detectable alkene
isomerization. As a result, the present protocol substitutes the
former saccharine variant, with the particular advantage of
milder deprotection conditions for phthalimide.[13] All these ex-
amples demonstrate the advantage of preformed palladium–
phthalimidato catalysts in the difunctionalization of alkenes,
where they currently provide the best protocols. Moreover, the
new complexes should also be of value in additional catalytic
transformations. The direct CÀH amination of benzene was
chosen to explore this assumption, and treatment of benzene
with preformed complex 5a led to clean formation of N-
phenyl phthalimide 12 as the CÀH amination product in 70%
yield. This compares favorably to a related transformation with
Scheme 5. Role of the phthalimide source in diamination of (Z)-1 (above)
and individual rates for diamination of (Z)-1 with 5a, HNPhth, and HNPhth4F.
In addition to the identification of complexes 5 and 7 as cat-
alysts providing the observed chemoselectivity, these com-
plexes also improve existing diamination reactions. For exam-
ple, the isolated palladium–phthalimidato complexes catalyze
the diamination of allylic ethers (Scheme 6). In comparison to
earlier work,[20] which employed phthalimide as a limiting
agent with an excess of two oxidants (NFSI and hypervalent
iodine), under the optimized protocol the reaction only re-
quires phthalimide and a hypervalent iodine. In addition, the
reaction can now be conducted with a limiting amount of
alkene, which significantly improves the reaction attractiveness
from an economic point of view. For all reactions, yields under
the present conditions are superior to previous ones,[19] and
even surpass those from an in situ catalyst formation. As dem-
onstrated for substrate 8d, the reaction can be scaled-up con-
veniently. Besides common allylic substrates 8a–g, the scope
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Scheme 7. Palladium-catalyzed diamination of terminal alkenes employing
preformed phthalimidato complexes.
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(Scheme 8).[21]
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[13] See the Supporting Information for details.
Scheme 8. Palladium-catalyzed CÀH amination of benzene.
[14] CCDC 885869 (9l),
885868 (11 h),
885870 (11 j),
1447007 (3b),
In summary, we have succeeded in the isolation and struc-
tural characterization of new palladium–phthalimidato com-
plexes and have demonstrated that these complexes greatly
improve the scope of palladium-catalyzed oxidative amination
reactions.
1447008 (6), and 1447009 (7) contain the supplementary crystallograph-
ic data for this paper. These data are provided free of charge by The
Cambridge Crystallographic Data Centre.
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[16] pKa (phthalimide)=8.3 (H2O, taken from the pKa table at www.chem.
wisc.edu/areas/reich/pkatable); pKa (tetrafluorophthalimide)=5.3 (calcu-
lated value at scifinder.com).
[17] To the best of our knowledge a trimeric palladium catalyst precursor,
such as 7, has no precedence in nucleopalladation. For a discussion on
related bimetallic systems: a) R. S. Paton, J. M. Brown, Angew. Chem. Int.
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[19] K. MuÇiz, J. Kirsch, P. Chµvez, Adv. Synth. Catal. 2011, 353, 689.
[20] . Iglesias, E. G. PØrez, K. MuÇiz, Angew. Chem. Int. Ed. 2010, 49, 8109;
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Acknowledgements
Financial support for this project was provided from the Span-
ish Ministerio de Economía y Competitividad and FEDER
(CTQ2014-56474R grant to K.M., and Severo Ochoa Excellence
Accreditation 2014–2018 to ICIQ, SEV-2013-0319), and from
Cellex Foundation (fellowship to C.M.). The authors thank E. Es-
cudero-Adµn for X-ray structural analyses.
Keywords: alkenes · oxidation · palladium · phthalimides ·
synthetic methods
[21] R. Shrestha, P. Mukherjee, Y. Tan, Z. C. Litman, J. F. Hartwig, J. Am. Chem.
Soc. 2013, 135, 8480.
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Received: March 10, 2016
Published online on April 25, 2016
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