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Defined Palladium Phthalimidato Catalysts for Improved Oxidative Amination
Claudio Martínez[a] and Kilian Muñiz*[a,b]

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

Defined amination reactions at carbon centers constitute the most versatile approach towards the important class of nitrogenated
organic molecules.[1] Within this context, phthalimide 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 applicability employing the
concept of nucleophilic displacement.[2] In addition to such nucleophilic substitution, the enhanced stability of phthalimide under
oxidative conditions has enabled additional seminal transformation of hydrocarbons within this particular area.[3,4]
AcO

Pd(NCMe)2Cl2 (10 mol%)
PhI(OAc)2 (2 equiv),
(CH2Cl)2, 70 oC
(Z)-1

O

Aminohydroxylation Reaction

N

O

N

O

3a

+
O
NH
2a

O

Pd(NCMe)2Cl2 (10 mol%)

(R'SO2)2N

(R'SO2)2NH (1.2 equiv)
PhI(O2CtBu)2 (2 equiv),
(CH2Cl)2, 70 oC

O

Diamination Reaction

4a

Scheme 1. Palladium-catalyzed aminoacetoxylation and diamination reactions using phthalimdie as nitrogen source.

Some time ago, the combination of palladium and phthalimide 2a was found to permit unique intermolecular aminoacetoxylation[5]
and diamination reactions,[6] all of which proceed under the conditions of PdII/PdIV redox catalysis.[7] This work has generated a
synthetic methodology that converts internal alkenes such as 1 into the corresponding difunctionalized products 3a and 4a with
complete regio-, chemo- and diastereoselectivity (Scheme 1),[6,8] although the structural basis for the involved palladium catalysts has
so far remained undetermined. In general, while homogeneous palladium catalysis has reached paramount synthetic applicability
over past decades,[9] definite knowledge on the catalyst states involved in individual reactions has often remained missing, in
particular when oxidation reactions are concerned.[7,10] Here, we report the isolation of defined bisphthalimidato palladium(II)
complexes and present their behavior as tailor-made catalysts in advanced oxidative alkene diamination with phthalimide within
significantly simplified experimental protocols.
Our investigation started with the assumption that a transformation of the palladium dichloride source prior to the catalysis should
be involved in reactions from Scheme 1. We had identified a preheating period between palladium complexes (RCN)2PdCl2 and
phthalimide as the crucial point in the generation of the active Pd
catalyst.[6] For clarification, we studied the reaction between the
palladium precursor and phthalimide. First, palladium diacetate
[a]
Dr. C. Martínez, Prof. Dr. K. Muñiz
reacts readily with phthalimide 2a or tetrafluorophthalimide 2b at
Institute of Chemical Research of Catalonia (ICIQ),
room temperature in the presence of a nitrile to provide the new
The Barcelona Institute of Science and Technology
Av. Països Catalans 16, 43007 Tarragona, Spain
complexes 5a-d as air-stable crystalline solids (Scheme 2).[11]
E-mail: kmuniz@iciq.es
The underlying high stability of the Pd-amide bond is reminiscent
[b]
Prof. Dr. K. Muñiz
to those of peptidic palladium complexes.[12] Complexes 5a-d
Catalan Institution for Research and Advanced Studies (ICREA),
form irreversibly and do not revert back to Pd acetate complexes
Pg. Lluís Companys 23, 08010 Barcelona, Spain
even in the presence of large excesses of the free carboxylic
Supporting information for this article is given via a link at the end of
acid.[13] They are equally stable in the presence of hypervalent
the document.

iodine reagents involved in the difunctionalization reactions.[13]
R
O

X

X
X

2 HN

Pd(OAc)2
MeCN, RT

X
O

X

2a: X = H,
2b: X = F

99%
[- 2 HOAc]

O

X

N

X

O

X

N Pd N
X
X

O

N

X
O

X

R
5a: R = Me, X = H, 5b: R = Me, X = F

5c: R = Ph, X = H, 5d: R = Ph, X = F

PhCN,
RT,
99%

Scheme 2. Synthesis of new palladium-phthalimidato complexes 5a-d.

Complexes 5a-d engaged in rapid dissociation of neutral nitrile ligands in solution. Attempts to grow crystals were unsuccessful
except for one case, where the structure of the new bis(aqua) complex 6 formed from a toluene solution of 5a (Figure 1).[14] In a
similar manner, alkenes may replace the nitrile ligands in 5a-d, however, the resulting alkene coordination is again of labile nature
and could not be confirmed either by NMR or by X-ray crystallography. Instead, heating of 5a,c or prolonged standing in solution
results in the formation of the unprecedented trimeric complex 7. The same complex 7 is obtained from (MeCN)2PdCl2 and free
phthalimide under more forcing conditions that resemble the preheating period under the conditions of catalysis.[6]
Me
O

N

O

O

N Pd N
O

N

O

N Pd N
[H2O]

OH2

O

R
N

O

O
O

N

N Pd N
O

N

O

6

5a Me

O

O

OH2

toluene, RT

O O

OO
O

O

O

R
5a,c

N

Pd
Pd

N
N

N
N

Pd
O

O
O

O

7
(CH2Cl)2, 70ºC
99%

[- 6 HCl, - 6 MeCN]
O

3 (MeCN)2PdCl2

+ 6 HN
O 2a

Scheme 3. Synthesis of advanced palladium-phthalimidato complexes 6 and 7 arising from labile nitrile coordination in complexes 5a-d.

Figure 1. X-ray structures of complexes 6 (top) and 7 (bottom). Selected bond lengths (A) and angles (°): Pd1-O3 2.018(3), Pd1-N1 2.046(4), O3-Pd1-O3 180.0,
O3 Pd1 N1 90.25(15), O3-Pd1-N1 89.75(15) (complex 6) and Pd1-N1 1.992(4), Pd1-N2 1.975(5), Pd1-O2 2.017(4), Pd1-O4 2.026(4), N2-Pd1-N1 91.67(19), N2Pd1-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) (complex 7).

Pd catalyst,
PhthNH (1 equiv),

NTs2

PhI(O2CtBu)2, Ts2NH,
NPhth

DCE, 70 ºC, 20 h
(Z)-1

4a

Pd catalyst:
Pd(NPhth)2(PhCN)2 5c (10 mol%): 90%
Pd(NPhth)2(OH2)2 6 (10 mol%):
80%
Pd3(NPhth)6 7 (3.3 mol%):
90%
Pd(NPhth4F)2(PhCN)2 5d
(10 mol%)
HNPhth4F (1 equiv),

NTs2

PhI(O2CtBu)2, Ts2NH,
NPhth4F

DCE, 70 ºC, 20 h

4b (80%)

(Z)-1
Pd(NPhth)2(PhCN)2 5c
(10 mol%)
PhthNH, PhI(O2CR)2,

O2CR

DCE, 70 ºC, 20 h
(Z)-1

NPhth

3a: R = Me (54%)
with additive HN(COCF3)2 3b: R = CF3 (74%)

Scheme 4. Reactivity of palladium-phthalimidato complexes. HNPhth = phthalimide, HNPhth

4F

3b (X-ray)

= tetrafluorophthalphthalimide.

The isolated phthalimidato complexes of palladium 5a-d and 7 are versatile catalysts for the diamination and aminooxygenation
of alkenes using phthalimides as nitrogen sources, as exemplified with the internal alkene (Z)-β-methylstyrene as substrate (Scheme
4). For the corresponding diamination reaction to 4a, all three new catalysts 5c, 6 and 7 provide complete selectivity and high isolated
yields of 80-90%. The same observation is made for a diamination with tetrafluorophthalimide in the presence of catalyst 5d. Finally,
aminoxygenation to 3a proceeds with yields comparable to previous in situ protocols, while addition of bistrifluoroacetamide provides
a new aminooxygenation variant to 3b in 74% yield.
The formation of 5a-d and 7 upon its concomitant complete loss of the chloride atoms also lends an explanation to the absence of
any alkene isomerization pathway over the course of the difunctionalization reactions from Schemes 1 and 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
demonstrates equal product formation for both phthalimide and tetrafluorophthalimide from (Z)-1; kinetic control experiments confirm
equal rates for the two individual reactions.

Further kinetic control experiments suggest 7 to be a precatalyst, particularly in the absence of loosely coordinating ligands such
as nitriles.[17] For the transformation of (Z)-1 to 4a, a first order dependence on catalyst was observed confirming a monomeric
catalyst state.[13] In line with these observations, 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 palladium than nitriles, where the alkene
oxidation proceeds exclusively throughout the iodine(III)-mediated channel.[18] The mechanistic conclusion is that a free coordination
site at palladium is required for alkene coordination within the initial aminopalladation.[8b,c]
Pd(NCMe)2Cl2 (10 mol%)
HNPhth/HNPhth4F
(1/1)

+

Ts2NH (1.2 equiv)
(Z)-1

PhI(O2CtBu)2 (2 equiv),
(CH2Cl)2, 70 oC

Ts2N

Ts2N

NPhth4F

NPhth
4a

4b
4a:4b = 1:1

4F

Scheme 5. Role of the phthalimide source in diamination of (Z)-1 (above) and individual rates for diamination of (Z)-1 with 5a and HNPhth and HNPhth ,
respectively.

In addition to the identification of complexes 5 and 7 as the catalysts providing the observed chemoselectivity, these complexes
also improve existing diamination reactions. For example, the isolated palladium phthalimidato complexes catalyze the diamination of
allylic ethers (Scheme 6). In comparison to earlier work,[20] which employed phthalimide as limiting agent with an excess of two
oxidants (NFSI and hypervalent iodine), under the optimized protocol the reaction only requires 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 demonstrated for substrate 8d, the reaction can be up-scaled
conveniently. Besides common allylic substrates 8a-g, the scope could be enhanced to selective monodiamination of dienes (9h-j) or
to the corresponding tetraamination reaction (9k). The reaction can be conducted with complete diastereoselectivity (9l). Higherfunctionalized allylic ethers including epoxides 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 diamination with more readily removable[13] phthalimide (Scheme 7).
Examples include representative aliphatic alkenes 10a,b for phthalimide and 10j,k for tetrafluorophthalimide, respectively.

O

R'
R

+

O

NPhth
NTs2

RO

9a (R = Me): 82% (67%)[a]
9b (R = Et): 87% (68%)
9c (R = n-Pr): 74%
9d (R = n-Bu): 88% (71%), 82%[b]
9e (R = n-Oct): 75% (65%)

NPhth
NTs2

O

O

NPhth
O

NPhth
NTs2

O

9f (R = Bn): 90%
9g (R = Bz): 58%
O

NPhth
NTs2

O

9l: 51%

NPhth
NTs2

O
O

9m: 50%

NPhth
NTs2

9j: 57%

Ph

NPhth
NTs2

NTs2
NPhth

NPhth
NTs2

RO

9i: 60%

9k: 51%

O

O

9a-p

NPhth
NTs2 Ph

O
O

9h: 55%

Ts2N

R

Ts2NH (1.2 equiv)
PhI(O2CtBu)2 (1.1 equiv)
(CH2Cl)2, 70 oC, 16 h

O
2a (1 equiv)

8a-p (1 equiv)

R'

Pd(NPhth)2(PhCN)2 5c
(10 mol%)

NH

9l (X-ray)

9n: 78%
O

NPhth
NTs2

O

NPhth
NTs2

O

O

N

O 9p: 52%

9o: 50%

Scheme 6. Palladium catalyzed diamination of allylic ethers employing preformed phthalimidato complexes.
b
situ conditions. Yield from a 4 mmol scale reaction.

R

+

HNPhth (2a)
or
HNPhth4F (2b)

10 a-l (1 equiv)

1 equiv

[Pd] 5a or 5d (10 mol%)

NPhth
n

11a (n = 0): 50%
11b (n = 1): 53%
3

NRTs
NPhth

11e (R = Ts): 61%
11f (R = Ms): 50%
R

NTs2
NPhth

Ph

NTs2
NPhth
11g: 63%

Ph

11j (R = C6H13): 55%
11k (R = C10H21): 50%

O

Ph
11j (X-ray)

11d: 60%

NRTs
NPhth

11h (R = Ts): 70%
11i (R = Ms): 63%

NTs2
NPhth4F

NTs2
NPhth

NPhth
NTs2

N

11c: 35%

Yields in brackets refer to the outcome from the in

11 a-l
O

NC

NTs2

Br

R

Ts2NH (1.2 equiv)
PhI(O2CtBu)2 (1.1 equiv)
(CH2Cl)2, 70 oC, 16 h

a

11h (X-ray)
NTs2
NPhth4F
11l: 90%

Scheme 7. Palladium catalyzed diamination of terminal alkenes employing preformed phthalimidato complexes.

Functionalized alkenes are equally tolerated (11d-g), including the nitrile 10c. The latter is entirely non-reactive without 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 present 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 examples 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 C-H 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 C-H amination product in 70% yield. This compares

favorably to a related transformation with a combination of palladium acetate and tris(tert-butyl)phosphine as catalyst, which provides
12 in only 30% yield (Scheme 8).[21]
O
catalyst, PhthNH (1 eq),
N
PhI(OAc)2 (2 eq), C6H6, 100 ºC
O
catalyst:

14

Pd(OAc)2(10 mol%)/PtBu3 (10 mol%), 24h
Pd(NPhth)2(PhCN)2 5a (10 mol%), 12h

70%

30%

Scheme 8. Palladium catalyzed C-H amination of benzene.

In summary, we have succeeded in the isolation and structural characterization of new palladium phthalimidato complexes and
have demonstrated that these complexes greatly improve the scope of palladium catalyzed oxidative amination reactions.

Acknowledgements
Financial support for this project was provided from the Spanish Ministerio de Economía y Competitividad and FEDER (CTQ201456474R 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. Escudero-Adán for the X-ray structural analyses.
Keywords: alkenes • diamination • palladium • phthalimide • oxidation
[1]

[2]
[3]
[4]
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[10]

[11]
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[14]
[15]
[16]
[17]

[18]
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Layout 2:

COMMUNICATION
Text for Table of Contents

Claudio Martínez and Kilian Muñiz*

Page No. – Page No.

Defined Palladium Phthalimidato Catalysts
for Improved Oxidative Amination

Coordination mission completed: free phthalimide forms stable monomeric or trimeric coordination compounds with palladium. These
complexes serve as defined palladium catalysts for oxidative amination reactions with phthalimide as nitrogen source. Examples include the
diamination and aminooxygenation of alkenes and the C-H amination of benzene.