One-step synthesis of dicarboxamides through Pd-catalysed aminocarbonylation with diamines as N-nucleophiles

Article abstract of DOI:10.1002/ejoc.201403444

An efficient one-step synthetic strategy was used to prepare a set of dicarboxamides through palladium-catalysed aminocarbonylation of iodoalkenyl and iodoaryl compounds, with use of various alkyl- and aryldiamines as N-nucleophiles. The isolated yields of the dicarboxamides depended significantly on the iodo substrate and diamine structures, as well as on the reaction conditions, the best one (ca. 70%) being achieved with 1-iodocyclohexene as substrate and 1,4-diaminobutane as nucleophile, at 100°C and 30 bar of CO. When iodobenzene was used as model aryl halide, the highest yield of the target dibenzamides (ca. 65%) was obtained with 1,4-diaminobenzene as coupling amine, at 100°C and 10 bar of CO. Preliminary studies on their in vitro cytotoxicity against human lung carcinoma A549 cells showed N,N′(butane-1,4-diyl)dibenzamide and androst-16-ene-based dicarboxamides to be the most efficient cytotoxic agents, with IC₅₀ values of approximately 40 μM.

Full text of DOI:10.1002/ejoc.201403444

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FULL PAPER
DOI: 10.1002/ejoc.201403444
One-Step Synthesis of Dicarboxamides through Pd-Catalysed
Aminocarbonylation with Diamines as N-Nucleophiles
Rui M. B. Carrilho,[a] Ana R. Almeida,[a] Mercédesz Kiss,[b] László Kollár,*[b]
Rita Skoda-Földes,[c] Janusz M. Dabrowski,[d] Maria José S. M. Moreno,[e] and
˛
Mariette M. Pereira*[a]
Keywords: Synthetic methods / Dicarboxamides / Carbonylation / Medicinal chemistry / Antitumor agents
An efficient one-step synthetic strategy was used to prepare
When iodobenzene was used as model aryl halide, the high-
a set of dicarboxamides through palladium-catalysed amino- est yield of the target dibenzamides (ca. 65%) was obtained
carbonylation of iodoalkenyl and iodoaryl compounds, with
use of various alkyl- and aryldiamines as N-nucleophiles.
The isolated yields of the dicarboxamides depended signifi-
cantly on the iodo substrate and diamine structures, as well
as on the reaction conditions, the best one (ca. 70%) being
achieved with 1-iodocyclohexene as substrate and 1,4-di-
aminobutane as nucleophile, at 100 °C and 30 bar of CO.
with 1,4-diaminobenzene as coupling amine, at 100 °C and
10 bar of CO. Preliminary studies on their in vitro cytotoxicity
against human lung carcinoma A549 cells showed N,NЈ-
(butane-1,4-diyl)dibenzamide and androst-16-ene-based di-
carboxamides to be the most efficient cytotoxic agents, with
IC50 values of approximately 40 μM.
be of great importance as molecular umbrellas in drug de-
livery, as antifungal and as cell antiproliferative agents.[20]
Thus, the promising bioactive diversity of this class of com-
pounds serves as a stimulus for the scientific community to
develop efficient and sustainable strategies to synthesize
new dicarboxamide molecules and to perform their bio-
logical evaluation.
Introduction
Recently, dicarboxamides have been receiving significant
attention, due to their numerous applications in several
fields such as synthetic,[1–4] coordination[5,6] and medicinal
chemistry.[7–20] The dicarboxamide functionality is a com-
mon structural motif found in a variety of bioactive com-
pounds exhibiting beneficial properties, including anti-in-
flammatory,[8–10] antifungal[11] and antitumour activi-
ties.[12–14] For instance, diamide-linked γ-cyclodextrin di-
mers,[15] anthranilic diamide derivatives containing aryl-
substituted isoxazoline moieties,[16] 2-(2-aminothiazol-4-yl)-
pyrrolidine-based tartrate diamides[17] and furazan-3,4-di-
amide analogues[18] (Figure 1) have lately been developed
and applied as selective and potent anticancer agents. Bio-
logical tests on imidazole-dicarboxamides have demon-
strated their antiproliferative activity against HL-60 cells.[19]
Furthermore, steroidal dicarboxamides were also found to
[a] Department of Chemistry, CQC, University of Coimbra,
Rua Larga, 3005-535 Coimbra, Portugal
E-mail: mmpereira@qui.uc.pt
http://www.uc.pt/fctuc/dquimica/
[b] Department of Inorganic Chemistry, University of Pécs and
Szentágothai Research Centre, MTA-PTE Research Group for
Selective Chemical Syntheses,
Figure 1. Structures of dicarboxamide-containing molecules with
anticancer activity.
P. O. Box 266, 7624 Pécs, Hungary
http://www.ttk.pte.hu/en
[c] Department of Organic Chemistry, University of Pannonia,
8200 Veszprém, Hungary
The classical methods for the synthesis of amides/di-
amides include the activation of the corresponding acid de-
rivative and its coupling with amines.[21,22] However, this
methodology has several disadvantages, such as limitations
on the availability of the carboxylic acids, as well as con-
[d] Faculty of Chemistry, Jagiellonian University,
Ingardena 3, 30-060 Kraków, Poland
[e] Faculty of Pharmacy, University of Coimbra,
Pólo das Ciências da Saúde, 3000-548 Coimbra, Portugal
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403444.
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tamination and toxicity issues associated with the use of addition of palladium(II) acetate to triphenylphosphine (in
highly pollutant chemicals and chemical processes involving 1:2 molar ratio), together with Et3N as base and DMF as
more than one step. Alternatively, palladium-catalysed solvent. In order to evaluate the effect of the diamide link-
aminocarbonylation of aryl and alkenyl halides in the pres- age, the different linear aliphatic diamines 1,2-diamino-
ence of carbon monoxide (CO), first reported by Heck in ethane (a), 1,3-diaminopropane (b) and 1,4-diaminobutane
1974,[23] is nowadays an attractive synthetic strategy for the (c), the chiral cycloaliphatic diamine (1S,2S)-(+)-1,2-di-
preparation of monocarboxamides.[24–26] The Pd-catalysed aminocyclohexane (d), and the aromatic diamines 1,4-di-
carbonylation of amines for the synthesis of urea-type com- aminobenzene (e) and 2,6-diaminopyridine (f) were used as
pounds has also been reported.[27] However, in spite of its N-nucleophiles (Scheme 1). The isolated yields for the tar-
high efficiency, Pd-catalysed aminocarbonylation has been get diamide products, obtained after workup and purifica-
scarcely used for the synthesis of diamides. Only a few stud- tion, are presented in Table 1 and Table 2.
ies relating to this subject have been reported to date; they
include the synthesis of dicarboxamides through amino-
carbonylation of diiodo substrates,[28] or through the appli-
cation of diamines as N-nucleophiles. Among the latter, the
synthesis of selenophene derivatives[29] and our recent work
on the preparation of 5α-androst-16-ene dimers[30] are the
only examples reported so far.
As part of our continuing research in this field, here we
explore the potential of Pd-catalysed aminocarbonylation
of iodoalkenyl and iodoaryl compounds as an alternative
one-step synthetic route for the preparation of dicarbox-
amide molecules, using various diamines as N-nucleophiles.
Furthermore, the activities of selected examples from these
families of dicarboxamides as cytotoxic agents against
A549 cancer cells have been preliminarily appraised.
Results and Discussion
The diamide motif could be obtained by applying transi-
tion-metal-catalysed carbonylation chemistry. The prepara-
tion of new dicarboxamides with modular structures by
variation either of the iodo compound backbone or of the
diamide linkage was envisioned, in order to modulate their
electronic properties and, consequently, their solubility and
biological properties (Figure 2).
Scheme 1. Pd/PPh3-catalysed aminocarbonylation of 1-iodocyclo-
hexene (1) and iodobenzene (3), with use of diamines as N-nucleo-
philes.
To optimize the aminocarbonylation conditions for the
synthesis of alkyl dicarboxamides, 1-iodocyclohexene (1)
was chosen as the model electrophile and 1,2-diamino-
ethane (a) was selected as its coupling partner. Initially, the
reaction was performed under 1 bar of CO and 50 °C, but
no products were observable after 18 h (Table 1, Entry 1).
This result was surprising because iodoalkenes generally
undergo aminocarbonylation with monoamines under these
conditions.[31] Although an increase in carbon monoxide
pressure to 40 bar resulted in 27% conversion after 18 h
Figure 2. Design of new dicarboxamides based on aminocarb-
onylation.
(Table 1, Entry 2), synthetically viable yields of the target
dicarboxamide 2a could only be obtained at 100 °C
(Table 1, Entries 3 and 4). Because similar results have been
The synthesis of dicarboxamides was accomplished obtained either under 40 bar or 30 bar of carbon monoxide,
through reactions between either 1-iodocyclohexene (1) or the screening of other diamines in aminocarbonylation of 1
iodobenzene (3), CO (1–40 bar) and the desired diamines, was performed at 100 °C and 30 bar of CO (Table 1, En-
in the presence of a palladium catalyst formed in situ by tries 5–9). Under these conditions, the catalytic aminocarb-
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Pd-Catalysed Aminocarbonylation
Table 1. Synthesis of cyclohexenyl dicarboxamides 2 by aminocarb-
onylation of 1-iodocyclohexene (1).[a] Reaction conditions (unless
Table 2. Synthesis of dibenzamides 4 by aminocarbonylation of
iodobenzene (2). Reaction conditions (unless otherwise stated):
otherwise stated): 1 mmol substrate 1, 0.5 mmol diamine, 1 mmol substrate 3, 0.5 mmol diamine, 0.025 mmol Pd(OAc)2,
0.025 mmol Pd(OAc)2, 0.05 mmol PPh3, 0.5 mL triethylamine,
10 mL DMF, time: 3 h, levels of conversion were above 96%.
0.05 mmol PPh3, 0.5 mL triethylamine, 10 mL DMF, T = 100 °C,
time = 3 h, levels of conversion were above 96%.
[a] Isolated yields based on the amount of substrate 1; n.d.: not
determined. [b] 1% conversion in 18 h. [c] 27% conversion in 18 h.
onylation of 1 with diamines a–e proceeded with practically
complete conversions in 3 h, leading to the corresponding
dicarboxamides 2a–2e in isolated yields that varied from
52% (2d) up to 69% (2c), after workup of the crude mixture
and purification.
GC–MS and NMR analysis of crude mixtures and iso-
lated products prior to purification revealed the reactions
to be chemospecific with regard to the transformation of
[a] Isolated yields based on the amount of substrate 3; n.d.: not
determined. [b] T = 50 °C, 4% conversion in 12 h. [c] T = 100 °C,
mixture of carboxamide/ketocarboxamide products (detected by
NMR and GC–MS).
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the iodoalkenyl substrate into bis(carboxamides). This benzamide (4e) was obtained in significantly higher yield
means that no double carbonyl insertion, which would have than all the other dicarboxamides linked by aliphatic
resulted either in carboxamide-ketocarboxamide or bis- chains, due to a lower tendency to formation of ketocarbox-
(ketocarboxamide) derivatives, occurred. This observation amide-type products when aromatic amines are used as nu-
is in agreement with previous findings that showed that cleophiles.[32] A decrease in CO pressure to 1 bar did not
iodoalkene substrates only undergo double carbon mon- substantially affect the reaction chemoselectivity, with iso-
oxide insertion under special conditions, such as higher lated yields similar to those obtained under 10 bar of CO
carbon monoxide pressure (above 100 bar), lower tempera- pressure being achieved (Table 2, Entries 6 and 9 for 4c and
tures (below 50 °C) and/or in the presence of bulky π-acidic 4e, respectively). In most cases, only the bis(carboxamides)
phosphite ligands.[32] However, the presence of amino- 4a and 4c–4f were isolated in appreciable yields. The only
monocarboxamide products was detected by GC–MS and exception was the case of the aminocarbonylation reaction
confirmed by NMR analysis of the reaction mixtures. The with 1,3-diaminopropane (b), in which three products were
use of 2,6-diaminopyridine (f) as N-nucleophile resulted in isolated after purification by chromatography: the bis(carb-
a complex mixture of products, and the target dicarbox- oxamide) 4b (35%), the carboxamide-ketocarboxamide 5b
amide could not be isolated.
(29%) and the bis(ketocarboxamide) 6b (26%) (Scheme 2).
To expand the scope of the method to the synthesis of
Several mechanistic proposals for this reaction have been
aryl dicarboxamides, the aminocarbonylation of iodo- described in the literature.[33,34] With regard to the re-
benzene (3) was also performed, again with diamines a–f as duction of the PdII precursor to Pd0, some authors postu-
N-nucleophiles, and with the same in situ Pd/PPh3 catalyst late that the phosphine ligand in excess acts as reducing
system (Scheme 1). The reaction was initially carried out agent, with O=P(Ph)3 having been identified by NMR spec-
at 50 °C and 30 bar of CO, with 1,2-diaminoethane (a) as troscopy.[34] Other authors propose the involvement of
nucleophile. Under these conditions, only 4% conversion water in Pd-catalysed carbonylation reactions, through for-
was observed after 12 h (Table 2, Entry 1). An increase in mation of I–Pd–CO2H intermediates, which undergo de-
temperature to 100 °C, with the CO pressure kept at 30 bar, carboxylation and successive reductive elimination.[35] Be-
led to a mixture of carboxamide/ketocarboxamide com- cause anhydrous conditions are used in our case, the forma-
pounds (Table 2, Entry 2), a result of the possibility of tion of triphenylphosphine oxide, indicated by GC–MS
double insertion of carbon monoxide. With the goal of im- analysis (m/z [M]+ = 277), suggests that triphenylphosphine
proving the chemoselectivity towards the bis(carboxamide) is probably involved in palladium reduction. The structures
product, the catalytic reaction was then performed at a of 4a–f,[36–39] 5b and 6b were established by NMR spec-
lower CO pressure (10 bar), which allowed the synthesis of troscopy and further confirmed by high-resolution mass
4a in 42% isolated yield (Table 2, Entry 3). Consequently, spectrometry. An attempt to perform the aminocarb-
aminocarbonylation reactions between 3 and other di- onylation of the less reactive bromobenzene under the same
amines were performed at a temperature of 100 °C and a conditions, with use of 1,2-diaminoethane as N-nucleophile,
carbon monoxide pressure of 10 bar. Under these standard was unsuccessful, giving only traces of the desired diamide
conditions, the catalytic aminocarbonylation of 3 with di- observed by NMR spectroscopy.
amines a–f proceeded with complete conversion in 3 h,
Selected dicarboxamide compounds from each family
leading to the corresponding dicarboxamides 4a–4f in mod- (2a, 2c, 2d, 4c and 4f), in addition to the previously devel-
erate isolated yields, ranging from 35% (4b) up to 65% (4e), oped steroid dimers 7c, 7d and 7e[30] (Figure 3), were evalu-
after workup and purification (Table 2, Entries 3–10). The ated as cytotoxic agents against A549 human lung carci-
moderate yields obtained with linear aliphatic and cycloali- noma cells, which have frequently been chosen by our
phatic diamines were the result of the formation of carbox- group[40] and others[41,42] as a suitable cell culture to per-
amide-ketocarboxamide and bis(ketocarboxamide) com- form toxicity tests. Therefore, concentration–response ex-
pounds as side-products, as shown by NMR examination periments were performed to establish the cytotoxic activity
of the crude mixtures. Remarkably, N,NЈ-(1,4-phenylene)di- of each selected compound (Figure 4).
Scheme 2. Isolated products obtained from aminocarbonylation of iodobenzene (3) with 1,3-diaminopropane (b) as N-nucleophile.
4
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Pd-Catalysed Aminocarbonylation
and steroidal skeletons 4c and 7c, respectively, showed
higher cytotoxic activities than the cyclohexenyl-derived di-
mer 2c, over the whole range of concentrations.
The IC50 values expressed in μm, summarised in Table 3,
establish the relative order of effectiveness for the dicarbox-
amides’ cytotoxicities: 4c ≈ 7c ≈ 7e Ͼ 7d ≈ 4f Ͼ 2d Ͼ 2c Ͼ
2a. From these results we can conclude that the bioactivity
of symmetric bis(carboxamides) of this type can be modu-
lated by adjustments both on the diamide linkage and on
the iodo compound backbone. However, the observed slight
differences in cytotoxicity might equally well be due to dif-
ferences in solubility, metabolic stability or permeability of
the compounds themselves. It should be noted that the
cytotoxic activities of the most efficient dicarboxamide
compounds from this series against A549 cancer cells are
comparable with the values for other cytotoxic agents pre-
viously described in the literature.[41,42]
Table 3. IC50 (μm) inhibitory concentrations with A549 human lung
carcinoma cells.
Diamide
2a
2c
2d
4c
4f
7c
7d
7e
IC50 (μm) 65
60
55
40
50
40
50
40
Figure 3. Dicarboxamide steroid dimers[30] also evaluated in this
study as cytotoxic agents against A549 human lung carcinoma cells.
Conclusions
This synthetic methodology constitutes a versatile, one-
step and atom-economical route for the preparation of alk-
enyl and aryl dicarboxamides by catalytic aminocarb-
onylation. The selectivity for dicarboxamides is dependent
on the substrate, reaction conditions and diamine structure,
the highest yield having been obtained with 1-iodocyclohex-
ene (1) as substrate and 1,4-diaminobutane (c) as N-nucleo-
phile, at 100 °C and 30 bar of CO. Preliminary investi-
gations into the cytotoxic effects of the studied dicarbox-
amide compounds against A549 cancer cells suggest that
the cytotoxic activity depends not only on the diamide moi-
ety but also on the iodoalkene/iodoarene skeleton, with the
lowest IC50 values being observed with N,NЈ-(butane-1,4-
diyl)dibenzamide (4c) and the 5α-androst-16-ene-based di-
carboxamides 7c and 7e. These promising results show that
the application of the catalytic diaminocarbonylation reac-
tion as a synthetic tool may open new perspectives for the
preparation of libraries of bioactive dimeric compounds
through fine-tuning both of the dicarboxamide linkage and
of the iodo compound structure.
Figure 4. Cytotoxic activity of dicarboxamide compounds against
A549 carcinoma cells. (The data shown are the means +/– SDs of
at least three independent experiments.).
We observed that N,NЈ-(butane-1,4-diyl)dibenzamide
(4c) was the most efficient cytotoxic agent when a high
agent concentration (50 μm) was used, resulting in the death
of 65% of the A549 cells. However, at lower agent concen-
trations (5–25 μm), the steroidal dimeric compounds 7c and
7e revealed cytotoxic activities similar to or even higher
than that of 4c. With regard to the dicarboxamides based
on bis(cyclohexenyl) skeletons, we could see that the cyto-
toxicities of compounds 2c and 2d were relatively higher
than that of 2a. When the activities of compounds contain-
Experimental Section
General Information: Manipulation of all moisture-sensitive rea-
gents was carried out under argon with use of Schlenk and needle/
syringe techniques. Glassware was dried in an oven at 200 °C and
cooled under argon. NMR spectra were recorded in CDCl3, [D7]-
DMF or [D6]DMSO with Varian Inova 400 and Bruker Avance 400
spectrometers, at 400.13 MHz for 1H NMR and at 100.62 MHz for
ing 1,4-butylenediamide bridges were compared, the phenyl 13C NMR spectroscopy. Chemical shifts (δ) are reported in ppm
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L. Kollár, M. M. Pereira et al.
N], 2.20–2.24 (m, 4 H, CH=CCH2), 2.13–2.17 (m, 4 H,
FULL PAPER
relative to CHCl3 (7.26 and 77.16 ppm for 1H and 13C, respec-
tively), relative to DMF (8.03 and 163.15 ppm for H and 13C) or C=CHCH2), 1.56–1.71 [m, 12 H, C=CHCH2CH2CH2, N-
1
relative to DMSO (2.50 ppm for H and 39.52 ppm for 13C). Sam- CH2(CH2)2CH2-N] ppm. 13C NMR (100.6 MHz, CDCl3): δ =
1
ples of the catalytic reactions were analysed with a Hewlett Packard
5830A gas chromatograph fitted with a capillary column coated
with OV-1 [internal standard: naphthalene; injector temp. 250 °C;
oven: starting temp. 50 °C (hold-time 11 min), heating rate
15 °Cmin–1, final temp. 320 °C; detector temp. 180 °C; carrier gas:
helium (rate: 1 mLmin–1)]. The FT-IR spectra were taken in KBr
pellets with an IMPACT 400 spectrometer (Nicolet) and use of a
DTGS detector in the 400–4000 cm–1 region; the resolution was
4 cm–1. High-resolution mass spectrometry analysis was carried out
with a Bruker Microtof apparatus, equipped with selective ESI de-
tector. The diamines, palladium(II) acetate, triphenylphosphine
and iodobenzene were purchased from Sigma–Aldrich. 1-Iodo-
cyclohexene (1)[31] was prepared from cyclohexanone by a modified
Barton procedure.[43] The steroid dicarboxamides 7c, 7d and 7e
were synthesised by aminocarbonylation of 17-iodo-5α-androst-16-
ene as previously reported.[30]
168.9, 133.6, 133.2, 39.2, 27.2, 25.5, 24.4, 22.3, 21.7 ppm. IR (KBr):
ν = 3344 (v br, NH), 1662 (CO), 1616 (C=C) cm–1. HRMS (ESI):
˜
m/z calcd. for C18H29N2O2 [M + H]+ 305.2224; found 305.2224.
N,NЈ-(trans-Cylohexane-1,2-diyl)bis(cyclohex-1-enecarboxamide)
(2d): Yield 0.086 g (52%), beige solid, m.p. 248–250 °C. Rf = 0.55
(CHCl3/CH3OH 25:1). 1H NMR (400 MHz, CDCl3): δ = 6.58 (s,
2 H, C=CH), 6.20 (br. s, 2 H, NH), 3.74 (br. s, 2 H, N-CH-CH-
N), 2.11–2.17 (m,
8 H, CH=CCH2, C=CHCH2), 1.54–1.78
[m, 12 H, C=CHCH2CH2CH2, N-CHCH2(CH2)2CH2CH-N],
1.24–1.39 [m, 4 H, N-CHCH2(CH2)2CH2CH-N] ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 169.4, 134.1, 133.0, 54.0, 32.5, 25.6, 24.9,
24.3, 22.3, 21.7 ppm. IR (KBr): ν = 3320 (v br, NH), 1660 (CO),
˜
1619 (C=C) cm–1. HRMS (ESI): m/z calcd. for C20H31N2O2 [M +
H]+ 331.2380; found 331.2377.
N,NЈ-(1,4-Phenylene)bis(cyclohex-1-enecarboxamide) (2e): Yield
0.089 g (55%), beige solid, m.p. 240–242 °C (dec.). Rf = 0.20
(CHCl3/CH3OH 10:1). 1H NMR (400 MHz, [D6]DMSO): δ = 9.51
(br. s, 2 H, NH), 7.56 (s, 4 H, Ph-H), 6.62 (br. s, 2 H, C=CH),
Synthesis of Dicarboxamides through Catalytic Aminocarbonylation:
In
a typical reaction, Pd(OAc)2 (5.6 mg, 0.025 mmol), tri-
phenylphosphine (13.2 mg, 0.05 mmol), the iodo substrate
(1 mmol), the diamine nucleophile (0.5 mmol) and triethylamine
(0.5 mL) were dissolved in dried DMF (10 mL) under argon in a
100 mL autoclave. The atmosphere was changed to carbon mon-
oxide and the autoclave was pressurised to the desired pressure
(30 bar CO for cyclohexenedicarboxamides and 1 bar CO for di-
benzamides). The reaction was allowed to proceed for 3 h with stir-
ring at 100 °C, and products were analysed by GC–MS and NMR
spectroscopy. The mixture was then concentrated and the solvents
were evaporated to dryness. The residue was dissolved in chloro-
form (20 mL) and washed with water (3ϫ 20 mL). The organic
phase was dried with Na2SO4, filtered and concentrated to a crys-
talline material or waxy residue. All compounds were subjected to
column chromatography [Silicagel 60 (Merck), 0.063–0.200 mm], or
simply recrystallised from solvents (the exact ratios are specified
below for each compound).
2.16–2.25 (m,
8
H, CH=CCH2), 1.56–1.63 (m,
8
H,
C=CHCH2CH2) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ =
166.7, 134.7, 134.0, 132.6, 120.2, 24.8, 24.0, 21.8, 21.3 ppm. IR
(KBr): ν = 3320 (v br, NH), 1656 (CO), 1623 (C=C) cm–1. HRMS
˜
(ESI): m/z calcd. for C20H25N2O2 [M + H]+ 325.1911; found
325.1917.
N,NЈ-(Ethane-1,2-diyl)dibenzamide (4a):[36] Yield 0.056 g (42%),
white solid (recrystallised from EtOAc/diethyl ether 1:2), m.p. 228–
230 °C. 1H NMR (400 MHz, [D7]DMF): δ = 8.69 (br. s, 2 H, NH),
7.97 (d,
J = 7.2 Hz, 4 H, Ph-ortho), 7.46–7.58 (m, 6 H,
Ph-meta,para), 3.60–3.64 (m, 4 H, N-CH2CH2-N) ppm. 13C NMR
(100.6 MHz, [D7]DMF): δ = 167.9, 136.0, 132.2, 129.4, 128.3,
40.8 ppm. IR (KBr): ν = 3296 (v br, NH), 1633 (CO) cm–1. HRMS
˜
(ESI): m/z calcd. for C16H16N2O2Na [M + Na]+ 291.1104; found
291.1096.
N,NЈ-(Propane-1,3-diyl)dibenzamide (4b):[36] Yield 0.049 g (35%),
beige solid, m.p. 118–120 °C. Rf = 0.15 (CHCl3/EtOAc 2:1). 1H
NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 7.2 Hz, 4 H, Ph-ortho),
7.41–7.54 (m, 6 H, Ph-meta,para), 7.28 (br. s, 2 H, NH), 3.51–3.58
(m, 4 H, N-CH2CH2CH2-N), 1.75–1.85 (m, 2 H, N-CH2CH2CH2-
N) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 168.3, 134.4, 131.7,
128.7, 127.1, 36.4, 30.0 ppm. HRMS (ESI): m/z calcd. for
C17H19N2O2 [M + H]+ 283.1441; found 283.1434.
N,NЈ-(Ethane-1,2-diyl)bis(cyclohex-1-enecarboxamide) (2a): Yield
0.080 g (58%), white solid, m.p. 218–220 °C. Rf = 0.20 (EtOAc/
CHCl3 2:1). 1H NMR (400 MHz, CDCl3): δ = 6.67 (br. s, 2 H,
C=CH), 6.53 (br. s, 2 H, NH), 3.47 (d, J = 2.4 Hz, 4 H, N-
CH2CH2-N), 2.19–2.24 (m, 4 H, CH=CCH2), 2.12–2.18 (m, 4 H,
C=CHCH2), 1.65–1.71 (m, 4 H, CH=CCH2CH2), 1.55–1.61 (m, 4
H, C=CHCH2CH2) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
169.9, 134.5, 132.7, 40.7, 25.6, 24.3, 22.3, 21.7 ppm. IR (KBr): ν =
˜
3298 (v br, NH), 1659 (CO), 1611 (C=C) cm–1. HRMS (ESI): m/z
N-[3-(2-Oxo-2-phenylacetamido)propyl]benzamide
(5b):
Yield
calcd. for C16H25N2O2 [M + H]+ 277.1911; found 277.1908.
0.045 g (29%), beige solid, m.p. 63–65 °C. Rf = 0.25 (CHCl3/EtOAc
1
2:1). H NMR (400 MHz, CDCl3): δ = 8.25 (d, J = 6.0 Hz, 2 H,
N,NЈ-(Propane-1,3-diyl)bis(cyclohex-1-enecarboxamide) (2b): Yield
0.077 g (53%), beige solid, m.p. 110–112 °C. Rf = 0.50 (CHCl3/
Ph-ortho), 7.89 (br. s, 1 H, NH), 7.84 (d, J = 6.0 Hz, 2 H, Ph-
ortho), 7.41–7.48 (m, 5 H, Ph-meta, Ph-para, NH), 7.37 (t, J =
6.0 Hz, 2 H, Ph-meta), 3.44–3.53 (m, 4 H, N-CH2CH2CH2-N),
1
CH3OH 25:1). H NMR (400 MHz, CDCl3): δ = 6.71 (br. s, 2 H,
NH), 6.66 (s, 2 H, C=CH), 3.31 (dd, J = 5.6, 11.2 Hz, 4 H, N-
CH2CH2CH2-N), 2.21–2.28 (m, 4 H, CH=CCH2), 2.10–2.16 (m, 4
1.78–1.84 (m,
2
H, N-CH2CH2CH2-N) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 188.0, 168.0, 163.3, 134.5, 132.1, 132.0,
131.5, 131.0, 128.6, 128.6, 127.1, 36.4, 36.2, 29.5 ppm. HRMS
(ESI): m/z calcd. for C18H18N2O3 [M + H]+ 311.1390; found
311.1395.
H, C=CHCH2); 1.61–1.69 (m,
6 H, CH=CCH2CH2, N-
CH2CH2CH2-N), 1.54–1.60 (m, 4 H, C=CHCH2CH2) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 169.4, 133.9, 133.1, 35.8, 30.0,
25.5, 24.3, 22.3, 21.6 ppm. IR (KBr): ν = 3315 (v br, NH), 1659
˜
(CO), 1617 (C=C) cm–1. HRMS (ESI): m/z calcd. for C17H27N2O2
N,NЈ-(Propane-1,3-diyl)bis(2-oxo-2-phenylacetamide) (6b): Yield
[M + H]+ 291.2067; found 291.2077.
1
0.044 g (26%), yellow oil. Rf = 0.5 (CHCl3/EtOAc 2:1). H NMR
N,NЈ-(Butane-1,4-diyl)bis(cyclohex-1-enecarboxamide) (2c): Yield
0.105 g (69%), white solid, m.p. 202–205 °C. Rf = 0.25 (EtOAc/
(400 MHz, CDCl3): δ = 8.33 (d, J = 7.6 Hz, 4 H, Ph-ortho), 7.60–
7.64 (m, 2 H, Ph-para),7.45–7.50 (m, 4 H, Ph-meta), 7.40 (br. s, 2
CHCl3 2:1). 1H NMR (400 MHz, CDCl3): δ = 6.62 (s, 2 H, C=CH), H, NH), 3.46–3.53 (m, 4 H, N-CH2CH2CH2-N), 1.86–1.92 (m, 2
5.89 (br. s, 2 H, NH), 3.33 [d, J = 6.0 Hz, 4 H, N-CH2(CH2)2CH2-
H, N-CH2CH2CH2-N) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43444
/KAP1
Date: 30-01-15 13:31:04
Pages: 9
Pd-Catalysed Aminocarbonylation
187.7, 162.6, 134.6, 133.4, 131.3, 128.7, 36.4, 29.5 ppm. HRMS
(ESI): m/z calcd. for C19H18N2O4 [M + H]+ 339.1339; found
339.1336.
Acknowledgments
The Coimbra Chemistry Centre is supported by the Portuguese
Agency for Scientific Research, Fundação para a Ciência e a Tec-
nologia (FCT) through the project PEst-OE/QUI/UI0313/2014.
The authors are thankful to FCT, COMPETE (Programa
Operacional Fatores de Competitividade) and QREN/FEDER
for funding through project PTDC/QUI-QUI/112913/2009, and
also to projects SROP-4.2.2.A-11/1/KONV-2012-0065 (Hungary)
and POIG.02.01.00-12-023/08 (Poland). R. M. B. C. thanks Qua-
dro de Referência Estratégica Nacional/Fundo Europeu de Desen-
volvimento Regional (QREN/FEDER) for a LUZACNE project
fellowship. J. M. D. thanks the Polish Ministry of Science and
Higher Education for a Iuventus Plus grant IP2011009471. NMR
data was collected at the UC-NMR facility which is supported in
part by FEDER through the COMPETE Programme, by National
Funds through FCT (REEQ/481/QUI/2006, RECI/QEQ-QFI/
0168/2012, CENTRO-07-CT62-FEDER-002012), and Rede Na-
cional de Ressonância Magnética Nuclear (RNRMN).
N,NЈ-(Butane-1,4-diyl)dibenzamide (4c):[32,33] Yield 0.067 g (45%),
white solid (recrystallised from EtOAc/diethyl ether 1:2), m.p. 172–
174 °C. 1H NMR (400 MHz, [D7]DMF): δ = 8.49 (br. s, 2 H, NH),
7.97 (d, J = 7.2 Hz, 4 H, Ph-ortho), 7.46–7.56 (m, 6 H, Ph-meta,-
para), 3.42–3.45 [m, 4 H, N-CH2(CH2)2CH2-N], 1.69 [br. s, 4 H,
N-CH2(CH2)2CH2-N] ppm. 13C NMR (100.6 MHz, [D7]DMF): δ
= 167.5, 136.2, 132.1, 129.3, 128.3, 40.4, 28.1 ppm. IR (KBr): ν
˜
= 3318 (v br, NH), 1630 (CO) cm–1. HRMS (ESI): m/z calcd. for
C18H20N2O2Na [M + Na]+ 319.1417; found 319.1424.
N,NЈ-[(1S,2S)-Cyclohexane-1,2-diyl]dibenzamide (4d):[36] Yield
0.063 g (39%), beige solid (recrystallised from EtOAc/diethyl ether
1:2), m.p. 230–232 °C. [α]2D0 = +70 (c = 0.5, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.70 (d, J = 7.2 Hz, 4 H, Ph-ortho), 7.38–
7.40 (m, 2 H, Ph-para), 7.28–7.33 (m, 4 H, Ph-meta), 6.96
(br. s, 2 H, NH), 4.04 (br. s, 2 H, N-CH-CH-N), 2.16–2.24 [br. s,
2 H, N-CHCHaHb(CH2)2CHaHbCH-N], 1.85 [br. s, 2 H, N-
CHCHaHb(CH2)2CHaHbCH-N], 1.41–1.51 [m,
4
H, N-
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Date: 30-01-15 13:31:04
Pages: 9
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8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43444
/KAP1
Date: 30-01-15 13:31:04
Pages: 9
Pd-Catalysed Aminocarbonylation
Dicarboxamides and Cytotoxicity
The one-step synthesis of a set of dicarbox-
amides was accomplished through pal-
ladium-catalysed aminocarbonylation of
iodoalkenyl and iodoaryl compounds, with
use of diamines as N-nucleophiles. The
cytotoxic activities of some of the diamides
against human lung carcinoma A549 can-
cer cells have been preliminarily appraised.
R. M. B. Carrilho, A. R. Almeida, M. Kiss,
L. Kollár, R. Skoda-Földes,
J. M. Da˛browski, M. J. S. M. Moreno,
M. M. Pereira ................................... 1–9
One-Step Synthesis of Dicarboxamides
through Pd-Catalysed Aminocarbonylation
with Diamines as N-Nucleophiles
Keywords: Synthetic methods / Dicarbox-
amides / Carbonylation / Medicinal chem-
istry / Antitumor agents
Eur. J. Org. Chem. 0000, 0–0
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