Ruthenium(II)-Catalyzed C-H Activation with Isocyanates: A Versatile Route to Phthalimides

Article abstract of DOI:10.1002/chem.201404261

A cationic ruthenium(II)-complex was utilized in the efficient synthesis of phthalimide derivatives by C- H activation with synthetically useful amides. The reaction proceeded through a mechanistically unique insertion of a cycloruthenated species into a C- Het multiple bond of isocyanate. The novel method also proved applicable for the synthesis of heteroaromatic unsymmetric diamides as well as a potent COX-2 enzyme inhibitor. A convenient route to phthalimide: A convergent method for the ruthenium(II)-catalyzed imidation of easily accessible benzamides by C- H functionalization was developed (see scheme). The methodology was successfully applied to the preparation of synthetically challenging unsymmetrical heteroaromatic diamides and proved amenable to a step-economic synthesis of a potent COX-2 enzyme inhibitor.

Full text of DOI:10.1002/chem.201404261

DOI: 10.1002/chem.201404261
Communication
&
Synthetic Methods
Ruthenium(II)-Catalyzed CÀH Activation with Isocyanates:
A Versatile Route to Phthalimides
Suman De Sarkar and Lutz Ackermann*[a]
tionalization.[6] Very recently, rhodium(III)-catalyzed imidation of
Abstract: A cationic ruthenium(II)-complex was utilized in
the efficient synthesis of phthalimide derivatives by CÀH
activation with synthetically useful amides. The reaction
proceeded through a mechanistically unique insertion of
a cycloruthenated species into a CÀHet multiple bond of
isocyanate. The novel method also proved applicable for
the synthesis of heteroaromatic unsymmetric diamides as
well as a potent COX-2 enzyme inhibitor.
benzoic acid derivatives with isocyanates was reported.[7] This
CÀH activation-based[8] approach ceased the necessity of pre-
functionalized ortho-halo benzoic acid derivatives,[9] but was
limited to electron-rich substrates.
In recent years, ruthenium complexes have emerged as a ver-
satile, less-expensive alternative to commonly used transition
metals in CÀH activation chemistry.[10] Along this line, rutheni-
um(II)-catalyzed cyclometalation followed by migratory inser-
tion of CÀC multiple bonds is well-documented in the litera-
ture.[10] However, in striking contrast to rhodium or rhenium
catalysis,[11] the addition to polar CÀHet multiple bonds is ex-
tremely rare in ruthenium-catalyzed transformations and was
hitherto only accomplished with strongly coordinating arylpyri-
dines, which are unfortunately extremely difficult to remove or
modify.[12] In consideration of the practical importance of CÀH
activations with synthetically useful auxiliaries,[8a] we explored
readily available amides for CÀH functionalization with isocya-
nates (Scheme 1). Within our program on sustainable CÀH
functionalization,[8j] we herein disclose a convergent method
for the imidation of easily accessible benzamides by CÀH func-
tionalization. Thereby, a novel route to synthetically challeng-
Phthalimide derivatives have been largely utilized in medicinal
chemistry due to their broad range of applications as anti-in-
flammatory, anticonvulsant, analgesic, immunomodulatory, and
hypolipidimic activities (Figure 1).[1] In addition, phthalimide an-
alogues have found extensive use as agrochemicals, polymers,
and in different branches of material sciences.[2]
Figure 1. Selected bioactive phthalimide derivatives.
The most commonly used strategy for the synthesis of
phthalimide involves reactions between the corresponding
phthalic acids or anhydrides and amines.[3] However, the limit-
ed availability of differently substituted phthalic acids, mostly
due to the harsh reaction conditions in their preparation, calls
for alternative protocols. Carbonylative cyclizations of prefunc-
tionalized ortho-halo benzoic acid derivatives[4a–c] or ortho-
dihalo arenes[4d,e] in the presence of amines are thus attractive
routes. Formamides were also utilized to construct the phthali-
mide scaffold by the action of a palladium catalyst.[5] In select-
ed cases, other transition metal catalysts were employed in the
carbonylation of secondary benzamides by CÀH bond func-
[a] Dr. S. De Sarkar, Prof. Dr. L. Ackermann
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
Fax: (+49)551-39-6777
E-mail: lutz.ackermann@chemie.uni-goettingen.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404261.
Scheme 1. Strategies for phthalimide synthesis. FG=functional group.
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Table 1. Optimization studies.[a]
Entry
LG
Additive
2a [equiv]
T [8C]
Yield [%][b]
1
2
3
4
5
6
7
8
NMe2
NMe2
NMe2
NMe2
NMe2
OH
OMe
NHMe
AgSbF6
AgPF6
KPF6
2
2
2
2
3
3
3
3
3
3
3
3
3
3
120
120
120
100
100
100
100
100
100
100
100
100
100
100
32
26
0
34
37
12
0
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
0
9
N(iPr)2
trace
54
71
8
trace
74
10
11
12
13
14[c]
N(OMe)Me
pyrrolidinyl
piperidinyl
morpholinyl
pyrrolidinyl
Scheme 2. Ruthenium(II)-catalyzed imidation with substituted amides 1.
[a] Corresponding regioisomers were also obtained: 3k’: 9%; 3m’: 11%.
[a] Reaction conditions:
1 (0.5 mmol), 2a (1.0–1.5 mmol), [RuCl2(p-
cymene)]2 (5.0 mol%), additive (20 mol%), solvent (2.0 mL), 22 h, under
N2, LG=leaving group. [b] Isolated yield. [c] 24 h.
aryl amides underwent imidation efficiently, and good yields
were obtained with both 3,4- and 3,5-dimethoxy amide deriva-
tives 1l and 1m, respectively. Gratifyingly, the new method
was not limited to arenes. Indeed, alkenylic CÀH activation was
found to be suitable for acrylamide 1n, thereby furnishing
product 3n.
ing unsymmetrical heteroaromatic diamides was established as
well.
We began our optimization studies (Table 1 and Table S1 in
the Supporting Information) by exploring the effect of different
co-catalytic additives in the annulation reaction by using dime-
thylbenzamide as the model substrate (entries 1–3). A cationic
ruthenium(II) complex, generated by the addition of co-catalyt-
ic amounts of AgSbF6, was found to be more effective than
catalysts derived from either AgPF6 or KPF6. The effect exerted
by the leaving group on the catalytic efficiency was studied
next (entries 6–14). The free carboxylic acid delivered unsatis-
factory results, whereas the ester, the secondary amide, and
the bulky tertiary amide were completely inert in the annula-
tion (entries 6–9). The Weinreb amide improved the yield
(entry 10), but the most astonishing result was obtained with
pyrrolidinyl as the leaving group, and the desired imide was
isolated in 71% yield (entry 11). Surprisingly, six-membered
heterocyclic amides were ineffective in the imidation process
(entries 12 and 13).
A wide substrate scope was observed when employing dif-
ferently decorated isocyanates 2 (Scheme 3). Both electron-rich
as well as electron-poor aryl isocyanates gave high yields of
the desired imides 4b and 4c. Halogen substituents (4d), as
well as alkyl groups, were well-tolerated (4e). Highly electron-
deficient and electron-rich multiply functionalized aromatic iso-
cyanates delivered the desired products 4 f and 4g. Benzyl
amine derivative 1h and sterically challenging a-naphthyla-
mine-derived isocyanate 1i underwent clean imidation. Finally,
Having the optimized reaction conditions in hand, we ex-
plored the substrate scope using differently substituted benz-
amide derivatives 1 (Scheme 2). Good to excellent yields were
obtained with 4-alkyl substituted amides 1b and 1c, as well as
conjugated biphenyl derivative 1d. Electron-rich amide 1e was
found to be most reactive and amino derivative 3 f was also ef-
ficiently produced. Fortunately, electron-poor substituted arene
1g was a viable substrate, likewise other halogen substituents
were also found to be tolerated by the catalytic system (1h
and 1i), which should prove useful for further functionaliza-
tions by cross-coupling chemistry. 3-Methyl substituted arene
1j exclusively underwent the CÀH functionalization at the less-
hindered position, whereas the opposite regioselectivity was
observed with a fluoro-substituted arene 1k.[13] Di-substituted
Scheme 3. Ruthenium(II)-catalyzed imidation with substituted isocyanates 2.
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alkyl-substituted isocyanates 1j and 1k were tested, delivering
the desired products 4j and 4k, respectively, in good yields.
Cyclooxygenase (COX) enzyme is responsible for the forma-
tion of different biological mediators and pharmacological in-
hibition of COX can provide relief from the symptoms of in-
flammation and pain.[14] We were pleased to find that our
newly developed method proved applicable to the effective
and step-economic synthesis of COX-2 enzyme inhibitor 5 pos-
sessing IC50 =0.4 mm (Scheme 4).[14c]
Scheme 4. Synthesis of COX-2 enzyme inhibitor 5.
Scheme 6. Chemoselective reduction of the diamide 6a.
Ruthenium(II)-catalyzed amidation was also successfully ap-
plied to different heteroaromatic substrates (Scheme 5). Inter-
Scheme 7. Intermolecular competition experiments with amides 1.
Scheme 5. CÀH amidation with heteroaromatic amides.
Scheme 8. H/D exchange reaction with 1e.
estingly, with the five-membered heterocycles 1o and 1p, un-
symmetrically substituted diamides were obtained, which are
challenging to produce using other methods. Notably, the un-
symmetrical diamide 6a can be chemoselectively reduced to
the corresponding amines (Scheme 6), giving step-economical
access to the products 7a, 7b, and 7c.
To understand the catalysts mode of action, we performed
an intermolecular competition experiment between amides 1e
and 1g (Scheme 7). Hence, electron-rich arene 1e emerged as
the more reactive substrate, which could be rationalized in
terms of a base-assisted IES-type[15] CÀH activation mode. The
imidation was also performed in the presence of D2O (1 equiv),
which affirmed a reversible H/D-exchange, as was observed for
both the product [Dn]-3e and the reisolated starting material
[Dn]-1e (Scheme 8).
Based on these mechanistic studies, a plausible catalytic
cycle is depicted in Scheme 9. Initial reversible CÀH ruthena-
tion on amide 1 delivers cationic complex 9. Coordination of
the isocyanate 2, followed by migratory insertion, forms the
CÀC bond and produces key intermediate 11. It is noteworthy
that such additions to CÀHet multiple bonds are scarce in ruth-
Scheme 9. Proposed catalytic cycle.
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enium(II)-catalyzed CÀH activation. Proto-demetalation of inter-
mediate 11 gives rise to diamide 6, or direct imidation yields
product 3 and regenerates the cationic ruthenium species 8.
In summary, we have developed the first ruthenium(II)-cata-
lyzed direct imide synthesis by CÀH bond functionalization.
This versatile method proved applicable to a wide variety of
easily accessible aromatic amides as well as acrylamide.[16] Im-
portantly, heteroarenes delivered unsymmetrical diamides,
which were chemoselectively reduced to a variety of mono-
and diamines. The novel strategy provided step-economical
access to a potent COX-2 enzyme inhibitor. Mechanistic studies
revealed an initial reversible CÀH bond metalation by a cationic
ruthenium(II)-complex in the amidation process.
Experimental Section
A suspension of amide 1 (0.50 mmol), isocyanate 2 (1.50 mmol),
[RuCl2(p-cymene)]2 (15.3 mg, 5.0 mol%), and AgSbF6 (34.3 mg,
20 mol%) in dichloroethane (DCE, 2.0 mL) was stirred at 1008C for
24 h under N2. At RT, the reaction mixture was filtered through
a short pad of Celite and eluted with EtOAc (20 mL). The combined
solution was concentrated under reduced pressure. The crude
products were purified by column chromatography (n-hexane/
EtOAc) on silica gel to yield the desired products 3–6.
Acknowledgements
Generous support by the Alexander von Humboldt Foundation
(fellowship to SDS) and the European Research Council under
the European Community’s Seventh Framework Program (FP7
20072013)/ERC Grant Agreement No. 307535 is gratefully ac-
knowledged. We also thank Alejandra Requena (Gçttingen Uni-
versity) for the synthesis of substrates.
Keywords: amides · CÀH activation · imidation · isocyanate ·
ruthenium
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Received: July 5, 2014
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Published online on && &&, 0000
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COMMUNICATION
&
Synthetic Methods
S. De Sarkar, L. Ackermann*
&& – &&
Ruthenium(II)-Catalyzed CÀH
Activation with Isocyanates:
A Versatile Route to Phthalimides
A convenient route to phthalimide: A
convergent method for the rutheni-
um(II)-catalyzed imidation of easily ac-
cessible benzamides by CÀH functionali-
zation was developed (see scheme). The
methodology was successfully applied
to the preparation of synthetically chal-
lenging unsymmetrical heteroaromatic
diamides and proved amenable to
a step-economic synthesis of a potent
COX-2 enzyme inhibitor.
&
&
Chem. Eur. J. 2014, 20, 1 – 6
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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