2-Arylacetamides as Versatile Precursors for 3-Aminoisocoumarin and Homophthalimide Derivatives: Palladium-Catalyzed Cascade Double Carbonylation Reactions

Article abstract of DOI:10.1002/adsc.201600224

The synthesis of biologically relevant homophthalimide and 3-aminoisocoumarin nuclei via palladium-catalyzed carbonylation of 2-(2-iodoaryl)acetamides has been developed. The degree of N-substitution on the starting amide substrate dictates whether C?N or

Full text of DOI:10.1002/adsc.201600224

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DOI: 10.1002/adsc.201600224
2-Arylacetamides as Versatile Precursors for 3-Aminoisocoumarin
and Homophthalimide Derivatives: Palladium-Catalyzed Cascade
Double Carbonylation Reactions
Roberto Frutos-PedreÇoa and Josꢀ-Antonio Garcꢁa-Lꢂpeza,*
a
Grupo de Quꢁmica Organometꢃlica. Dpto. Quꢁmica Inorgꢃnica, Universidad de Murcia, Campus de Espinardo, 30100,
Murcia, Spain
E-mail: joangalo@um.es
Received: February 24, 2016; Revised: May 5, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600224.
Abstract: The synthesis of biologically relevant ho-
mophthalimide and 3-aminoisocoumarin nuclei via
palladium-catalyzed carbonylation of 2-(2-iodoar-
give rise to 3,4-alkyl-, aryl-, alkoxy-, acyl- and ester-
substituted isocoumarins.
The presence of heteroatomic substituents in bio-
logically relevant scaffolds might confer new proper-
ties or applications to these compounds. Therefore
new synthetic methodologies with the aim of intro-
ducing O,[16] S,[17] I,[18–20] Br, Cl,[19] Se,[18] or Si[11] sub-
stituents in the isocoumarin core are being developed.
Only a few papers on the introduction of N-substitu-
ents in the 3 or 4 positions of the isocoumarin scaffold
have been published.[7,21] Among them, there is a mul-
ticomponent Ugi reaction involving the coupling of 2-
formylbenzoic acid, an amine and an isocyanide
ACHTUNGTRENNUNG
À
À
tates whether C N or C O coupling takes place in
the final step of the catalytic cycle giving rise to
each type of heterocycle. The introduction of
À
a second C halogen bond in the starting acetamides
allows a catalytic cascade double carbonylation in-
volving a C H activation step to give fused hetero-
cyclic structures.
À
À
Keywords: carbonylation; cascade reactions; C H
functionalization; heterocycles; palladium
Isocoumarin and homophthalimide nuclei are privi-
leged six-membered O- and N-heterocycles, respec-
tively, with a widespread presence in biologically
active compounds exhibiting antifungal,[1] anti-inflam-
matory,[2,3] and cytotoxic activities,[4,5] among many
others.[6,7] They are also present in the core of natural
products such as sescandelin B or phelligridin D
(Scheme 1).
In the last decades there has been a considerable
effort to develop new and efficient synthetic routes to
obtain these types of scaffolds with different substitu-
tion patterns. The main methods to synthesize isocou-
marins involve the cyclization of 1,2-difunctionalized
arenes (including ortho-alkynylbenzoic,[8] 2-haloben-
zoate[9,10] or phthalic anhydride derivatives[11]) with
coupling partners such as alkynes or CO
(Scheme 2).[12,13] Lately, transition metal-catalyzed car-
À
boxylate-directed ortho C H activation of benzoic
acid derivatives has emerged as an interesting ap-
Scheme 1. Examples of biologically active or natural com-
pounds containing the isocoumarin or homophthalimide
proach to isocoumarins.[14,15] All these methodologies structural motif.
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Catalytic cascade reactions have gained attention in
recent years since they allow the construction of com-
plex molecular structures from simple substrates in
a straightforward and efficient manner.[33] In these
processes the initial transformation of a conveniently
designed substrate affords a new structural motif
which is, in turn, susceptible to undergo a further
functionalization carried out by the same catalytic
system. Cascade reactions become especially relevant
À
when they involve C H activation processes in some
or all of their steps because they improve the overall
atom-economy of the synthesis.[34] We envisioned that
the introduction of a pendant reactive site in the ni-
trogen atom of the starting 2-arylacetamide could
give rise to structures primed for cascade Pd-cata-
lyzed carbonylation processes (such as those depicted
in the Scheme 3) based on the initial production of
either homophthalimide or isocoumarin cores.
Scheme 2. Main routes for the synthesis of isocoumarins.
Hence, in this contribution we report the synthesis
of both homophthalimides and 3-aminoisocoumarins
giving rise to 3,4-diamino-substituted isocoumarins as from 2-(2-haloaryl)acetamides in a catalytic fashion,
the primary adduct.[21]
as well as the development of catalytic cascade
In contrast to isoquinolones, the synthesis of the double carbonylation reactions from the appropriate
structurally related homophthalimides (1,3-isoquino- 2-arylacetamide derivatives achieving interesting
ACHTUNGTRENNUNG
compounds. Homophthalimides are mainly obtained tion reaction of 2-(2-iodophenyl)-N,N-dimethylacet-
by reaction of an amine with homophthalic acid[22] or
ACHTUNGTRENNUNG
anhydride derivatives.[2,23,24]
The functionalization of 2-arylacetic acids or ditions did provide the expected isocoumarin 2a,
À
amides through transition metal-catalyzed C H acti- albeit in a low yield. After a short optimization pro-
vation is an attractive route that has been successfully cess, the yield was improved to nearly full conversion
applied to their arylation,[25,26] alkenylation,[26] acetox- of the starting material by generating Pd(0) in situ
ylation,[27] and halogenation.[28] Nevertheless only from simple Pd(OAc)2 (5 mol%) and PPh3 (20 mol%)
a few examples of transition metal-catalyzed carbony- in either dry toluene or 1,4-dioxane at 1008C (en-
À
lation reactions of these substrates via C H activation tries 3 and 7, Table 1). Lower temperatures or catalyst
have been reported, requiring harsh conditions (both loadings decreased the performance of the catalytic
high temperature and catalyst loading)[29] or the use carbonylation (entries 4, 5 and 6, Table 1). Although
À
of a bidentate directing group to facilitate the C H the NMR yield for the 3-dimethylaminoisocoumarin
activation step.[30] Hence, 2-haloarylacetamides might 2a was good, it proved to be sensitive to purification
be worthy complementary substrates in these carbon- by flash column chromatography on silica gel, proba-
ylation reactions.
bly due to hydrolysis processes leading to the opening
Our research group has been interested in the of the heterocyclic structure. The use of neutral alu-
study of the reactivity of cyclopalladated complexes mina improved the efficiency of the chromatographic
toward CO.[31] Thus, we reported recently the carbon- purification, furnishing a 51% isolated yield of isocou-
ylation reaction of cyclopalladated arylacetamide marin 2a.
complexes.[32] In the stoichiometric model, the nature
A range of 2-(2-iodophenyl)-N,N-disubstituted acet-
of the starting amide dictated the outcome of this re- amides 1a–g were submitted to the carbonylation con-
action. When the substrate contained an NH2 or ditions, giving rise to the 3-substituted isocoumarins
NHR group, the intermediate acyl-palladium complex 2a–g (including cyclic amines as substituents such as
underwent a reductive elimination with subsequent piperidine and morpholine) in moderate isolated
À
C N bond formation to give the corresponding homo- yields (Scheme 4). The extension of the reaction
phthalimide derivative. Remarkably, when tertiary scope to other heteroatom-containing substrates was
À
amides were employed instead, the C O bond forma- performed by using the ester 1h and the thioester 1i
tion took place preferentially upon enolization of the as starting materials, which provided the correspond-
acidic alpha CH2 group, affording 3-aminoisocoumar- ing 3-O- and 3-S-substituted isocoumarins 2h and 2i
ins.
in moderate yield. The attempts to replace the iodi-
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Scheme 3. Proposed catalytic cascade double carbonylation reactions from 2-arylacetamides.
Table 1. Screening of the reaction conditions for the Pd-catalyzed synthesis of isocoumarin 2a.[a]
Entry
Pd source (mol%)
Ligand (mol%)
Base (equiv.)
Yield [%][b]
1
2
3
4
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (1)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
–
TMEDA (1.2)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
10
80
95
90
TMEDA (10)
PPh3 (20)
PPh3 (10)
PPh3 (4)
PPh3 (20)
PPh3 (20)
5
78
6[c]
7[d]
12
96 (51)[e]
[a]
Reactions carried out using substrate 1a (0.6 mmol), dry toluene (3 mL) and CO (1.2 atm.) in a Carius tube at 1008C.
NMR yields.
Reaction carried out at 508C.
Dry 1,4-dioxane (3 mL) was used as the solvent.
Isolated yield after column chromatography.
TMEDA=N,N,N’,N’-tetramethylethylenediamine.
[b]
[c]
[d]
[e]
[f]
nated substrates 1 for the cheaper but more challeng- alkyl, allyl and aryl substituents on the nitrogen atom,
ing chlorinated analogues proved unfruitful even on as well as the presence of electron-donating or elec-
heating up to 1408C or using the Buchwaldꢅs precata- tron-withdrawing groups in the aromatic ring. The
lyst as the palladium source.[36]
presence of a bromine atom in the N-aryl substrate 3g
We then turned our attention to unsubstituted or was tolerated under the reaction conditions, obtaining
N-monosubstituted 2-arylacetamide substrates 3a–3g. a 59% yield of the homophthalimide 4g. The method
As stated in our previous stoichiometric study,[32] the could be extended to the synthesis of the 7-membered
palladium-catalyzed carbonylation of these substrates benzazepin-1,3-dione 4h in good yield by using N-
led to the formation of homophthalimides 4a–4g in methyl-3-(2-iodophenyl)propanamide as starting ma-
good yields (Scheme 5). The reaction tolerates well terial.[35]
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chain on the nitrogen atom fulfilled two conditions:
first, it should contain a reactive site which should not
À
hamper the initial oxidative addition of the C I bond
to Pd(0) (in order to render the desired homophthal-
AHCTUNGTREGiNNUN mide/isocoumarin intermediate); and second, the
length of the tethering chain should be appropriate to
place the Pd atom in close proximity to the homo-
phthalimide or isocoumarin core, allowing the cycliza-
tion step to occur. We chose the 2-bromoaryl moiety
as a suitable substituent on the nitrogen atom of the
À
amide. The C I bond present in the aryl substrates
undergoes a faster oxidative addition to Pd(0) com-
À
pared to the C Br bond, hence the later would not
represent a significant competitor in the first step of
the reaction, minoring the generation of by-products.
Moreover, the oxidative addition of palladium to the
À
C Br bond of the resulting N-aryl-substituted isocou-
marins 2 or homophthalimides 4 (Scheme 3), would
lead to suitable six-membered palladacycles where
CO insertion and oxidative cyclization are possible, as
demonstrated in stoichiometric models of similar
size.[31a,d,32].
We had observed that the N-aryl-substituted acet-
amide 3g (bearing the bromine atom) afforded the
homophthalimide 4g in good yield. Hence we at-
tempted harsher conditions in order to make it fur-
ther react. The desired fused heterocycle 5g was
indeed formed when the reaction was performed in
dry toluene at 1408C, albeit in a low 20% yield
(Scheme 6). Unfortunately, the change of other reac-
tion parameters such as the base (t-BuOK), catalyst
loading (increased to 10%), reaction times (up to
24 h) or the palladium(0) source (Buchwaldꢅs precata-
Scheme 4. Scope on 3-N-, O- and S-substituted isocoumar-
ins.
Scheme 5. Scope of the synthesis of homophthalimides.
With these reaction conditions in hand, we decided
to explore the use of 2-(2-iodoaryl)acetamides for the
development of catalytic cascade carbonylation pro-
cesses. We reasoned that the cascade cyclization lead-
ing to the fused heterocyclic systems 5 and 6
Scheme 6. Attempted catalytic double carbonylation of ho-
(Scheme 3) could be successful when the tethering mophthalimide derivatives.
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Next, we focused on the cascade reaction based on
the initial formation of the isocoumarin core. When
the N-arylated acetamide 1j was submitted to the
standard catalytic carbonylation conditions (1,4-diox-
ane at 1008C) a small amount of the expected fused
heterocycle 6j was formed, along with a substantial
amount of the isocoumarin derivative 2j (Scheme 7).
We were pleased to observe an increase in the yield
of the doubly carbonylated product 6j to 60% when
the reaction was performed in toluene at 1408C
(Scheme 8). The replacement of PPh3 for other biden-
tate phosphine ligands such as dppe or dppf gave di-
vergent results. While dppe hampered the second car-
bonylation, affording only traces of 6j and a 12% of
the indole derivative 7j, dppf gave nearly the same re-
sults as those obtained with PPh3, 62% of the doubly
carbonylated product 6j and a small amount of 7j.
The cascade carbonylation could be extended to the
substrates 1j–n, which afforded the corresponding
heterocycles 6j–6n in moderate isolated yields, show-
ing the tolerance of the reaction to both electron-do-
nating and electron-withdrawing groups in the starting
materials (Scheme 8). The required tertiary nature of
the amides 1j–n (for the reaction to proceed through
the isocoumarin formation) could be accomplished
Scheme 7. Synthesis of the fused heterocycle 6j from 1j and
2j.
lyst)[36] did not improve the formation of 5g. The with groups such as Me or Bn on the nitrogen atom.
double carbonylation was also unsuccessful with the Along with the formation of compounds 6, the reac-
substrate 3i bearing a 2-bromobenzyl substituent on tion produced concomitantly a small amount of the
the nitrogen atom (Scheme 6).
indole derivatives 7, which could be isolated and char-
Scheme 8. Catalytic cascade carbonylation of subtrates 1j–n.
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3 (primary/secondary amides) in the carbonylation
process share some common intermediates, which are
depicted in Scheme 10. The oxidative addition to in
À
situ generated Pd(0) species of the C I bond present
in the starting material would generate a six-mem-
bered intermediate palladacycle A, which could un-
À
dergo the insertion of CO into the Pd C bond leading
to a Pd-acyl intermediate B. The participation of in-
termediates A and B in the reaction was confirmed
by previous stoichiometric studies, where such com-
pounds were isolated.[32] The decomposition pathway
of the intermediate B depends on the degree of sub-
stitution on the nitrogen atom. When the starting
À
amide is tertiary, the formation of the C N bond is
disfavoured. Instead, the presence of acidic protons in
the alpha position to the amide moiety enables the
formation of an enolate intermediate which evolves
À
through an oxidative C O bond formation, leading to
3-aminoisocoumarins 2 (path a, Scheme 10). In the
Scheme 9. Carbonylation reaction of substrates leading to
seven-membered rings.
case of primary and secondary 2-arylacetamides, the
C N bond formation is preferred, giving rise to ho-
mophthalimide derivatives 4 (path b, Scheme 10). The
À
acterized in the cases of the substrates 2l–n. Notewor- substrates 1j–n (bearing the 2-bromoaryl substituent
thy, the overall cascade double carbonylation reaction on the nitrogen atom) could undergo a further oxida-
À
represents the breakage of two C halogen and two tive addition to Pd(0), placing the resulting Pd(II)
À
C H bonds in the substrates 1 giving rise to the for- atom in a privileged position to activate the alkenyl
À
À
À
mation of one C O and three new C C bonds pres- C H bond of the isocoumarin core (path c,
ent in the scaffolds 6.
Scheme 10) to afford the six-membered C,C-pallada-
We also explored more challenging substrates cycle C. This intermediate could undergo the reduc-
which could potentially lead to seven-membered rings tive elimination of Pd(0) with subsequent formation
when submitted to the cascade carbonylation reac- of the indole derivatives 7. Nevertheless, CO insertion
À
tion. While the substrate 1o afforded the expected into any of the C Pd bonds of palladacycle C may
polycyclic product 6o in low yield (14%) along with happen preferentially prior to the reductive elimina-
the intermediate 3-aminoisocoumarin 2o, the sub- tion step, producing the fused heterocycles 6. Alterna-
strate 1p, bearing a benzylic bromide moiety, gave tively, the CO insertion step could also take place
À
a complex mixture of products (Scheme 9).
before the C H activation event (path d, Scheme 10).
In order to confirm that isocoumarine 2 are the in- The formation of the indole derivatives 7 might possi-
termediates in the synthesis of the doubly carbonylat- bly be minored in favour of the heterocycles 6 under
ed products 6, the isocoumarin 2j was submitted to high CO pressure conditions. An additional reaction
the standard cascade carbonylation conditions with pathway involving a Heck-type palladation of the al-
Pd(OAc)2/PPh3 in toluene at 1408C for 12 h, affording kenyl moiety of the N-2-bromoarylisocoumarins 2 by
a 45% yield of 6j (Scheme 7). These results, along Pd(II) species cannot completely be ruled out, howev-
with the isolation of the indole derivatives 7j–n in the er it seems less probable since it would imply the fur-
À
reactions with substrates 2j–n, strongly point toward ther oxidative addition of the C Br bond to give
a C H activation step involving the alkenyl group a Pd(IV) intermediate, which could later undergo the
À
present in the isocoumarine 2.
CO insertion.
Palladium-mediated or -catalyzed carbonylation re-
In summary, we have developed the palladium-cat-
actions have become a powerful and versatile tool to alyzed carbonylation reaction of 2-(2-iodoaryl)aceta-
introduce one carbonyl group in organic substrates.[37] mides, extendable to esters and thioesters. This syn-
Nevertheless, double carbonylation processes remain thetic methodology enables the use of CO as a cheap
underexplored and are mainly restricted to a reduced C1 feedstock in the synthesis of homophthalimides
number of transformations, the synthesis of a-diketo and 3-aminoisocoumarins, depending on whether the
derivatives being the most developed.[38] Remarkably, starting material is a primary/secondary or tertiary ar-
À
double carbonylation reactions involving C H activa- ylacetamide. These carbonylation reactions constitute
tion steps are exceptionally rare.[39]
a new way to introduce N-, O- and S-substituents in
Most likely, the reaction pathways followed by the the isocoumarin scaffold. Moreover, conveniently de-
two types of 2-arylacetamides 1 (tertiary amides) and signed arylacetamides allow the performance of cas-
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Scheme 10. Possible reaction pathway for the synthesis of 3-aminoisocoumarins 2, homophthalimides 4 and the doubly car-
bonylated products 6.
Representative Procedure for the Synthesis of
Derivatives 6
cade double carbonylations involving the activation of
the alkenyl C H moiety present in the 3-substituted
isocoumarin core, affording interesting fused hetero-
cycles.
À
A Carius tube was charged with N-arylacetamide (1)
(0.5 mmol, 1 equiv.), K2CO3 (140 mg, 1 mmol, 2 equiv.),
Pd(OAc)2 (6 mg, 0.026 mmol, 5 mol%), PPh3 (26 mg,
0.099 mmol, 20 mol%) and a teflon-coated stirrer bar. Three
vacuum-nitrogen cycles were applied to the tube and dry
toluene (3 mL) was added. The tube was evacuated, refilled
with CO (1.5 atm.) and sealed. The reaction mixture was
heated in an oil bath at 1408C for 16 h. After cooling the
Carius tube to room temperature, the reaction mixture was
diluted with CH2Cl2 (150 mL) and filtered through a Celite
pad. The filtrate was concentrated to ca. 2 mL and the crude
material was purified either by column chromatography or
fractional crystallization.
Experimental Section
Representative Procedure for the Synthesis of Iso-
coumarin and Homophthalimide Derivatives 2 and 4
A Carius tube was charged with the starting acetamide (1 or
3) (0.6 mmol, 1 equiv.), K2CO3 (83 mg, 0.6 mmol, 1 equiv.),
Pd(OAc)2 (7 mg, 0.03 mmol, 5 mol%), PPh3 (32 mg,
0.122 mmol, 20 mol%) and a teflon-coated stirrer bar. Three
vacuum-nitrogen cycles were applied to the tube and dry
1,4-dioxane (3 mL) was added. The tube was evacuated, re-
filled with CO (1.2 atm.) and sealed. The reaction mixture
was heated in an oil bath at 1008C for 16 h. After cooling
the Carius tube to room temperature, the reaction mixture
was diluted with EtOAc (30 mL) and filtered through
a Celite pad. The filtrate was concentrated and the crude
product was purified by column chromatography.
Acknowledgements
We thank the Spanish Ministerio de Economꢀa y Competitivi-
dad (grant CTQ2015-69568-P) and Fundaciꢁn Sꢂneca (grant
19890/GERM/15) for financial support. Professors J. Vicente
and I. Saura-Llamas are acknowledged for useful comments
and discussion.
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These are not the final page numbers!

UPDATES
10 2-Arylacetamides as Versatile Precursors for 3-
Aminoisocoumarin and Homophthalimide Derivatives:
Palladium-Catalyzed Cascade Double Carbonylation
Reactions
Adv. Synth. Catal. 2016, 358, 1 – 10
Roberto Frutos-PedreÇo, Josꢀ-Antonio Garcꢁa-Lꢂpez*
Adv. Synth. Catal. 0000, 000, 0 – 0
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ꢄ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!