Sequential catalytic carbonylation reactions for sustainable synthesis of biologically relevant entities

Article abstract of DOI:10.1016/j.jorganchem.2020.121417

The sustainable synthesis of highly functionalised formylcarboxamide compounds with biological relevance is reported through a sequential aminocarbonylation/hydroformylation approach. The optimisation of palladium-catalysed aminocarbonylation of iodoaromatic substrates, using allylamine as nucleophile was first performed, with molybdenum hexacarbonyl as alternative CO source versus gaseous carbon monoxide. The combination of microwave irradiation with molybdenum hexacarbonyl allowed to selectively prepare a set of N-heterocyclic-based allylcarboxamides. Subsequent rhodium-catalysed hydroformylation of the allylcarboxamide intermediates led to the preparation of new pyridine, pyrazoline and chalcone derivatives containing both carboxamide and formyl moieties.

Full text of DOI:10.1016/j.jorganchem.2020.121417

Journal Pre-proof
Sequential catalytic carbonylation reactions for sustainable synthesis of biologically
relevant entities
Liliana Damas, Fábio M.S. Rodrigues, Andreia C.S. Gonzalez, Rui M.B. Carrilho,
Marta Pineiro, Mariette M. Pereira
PII:
S0022-328X(20)30319-3
DOI:
https://doi.org/10.1016/j.jorganchem.2020.121417
JOM 121417
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 1 June 2020
Accepted Date: 23 June 2020
Please cite this article as: L. Damas, Fá.M.S. Rodrigues, A.C.S. Gonzalez, R.M.B. Carrilho, M.
Pineiro, M.M. Pereira, Sequential catalytic carbonylation reactions for sustainable synthesis of
biologically relevant entities, Journal of Organometallic Chemistry (2020), doi: https://doi.org/10.1016/
j.jorganchem.2020.121417.
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Sequential Catalytic Carbonylation Reactions for Sustainable Synthesis of
Biologically Relevant Entities
Liliana Damas, Fábio M.S. Rodrigues, Andreia C.S. Gonzalez, Rui M.B. Carrilho*, Marta
Pineiro and Mariette M. Pereira*,¥
University of Coimbra, Coimbra Chemistry Centre, Department of Chemistry
Rua Larga, 3004-535 Coimbra, Portugal
Abstract
The sustainable synthesis of highly functionalised formylcarboxamide compounds with
biological relevance is reported through a sequential aminocarbonylation/hydroformylation
approach. The optimisation of palladium-catalysed aminocarbonylation of iodoaromatic
substrates, using allylamine as nucleophile was first performed, with molybdenum hexacarbonyl
as alternative CO source versus gaseous carbon monoxide. The combination of microwave
irradiation with molybdenum hexacarbonyl allowed to selectively prepare a set of N-heterocyclic-
based allylcarboxamides. Subsequent rhodium-catalysed hydroformylation of the
allylcarboxamide intermediates led to the preparation of new pyridine, pyrazoline and chalcone
derivatives containing both carboxamide and formyl moieties.
Keywords: sequential reactions; aminocarbonylation; hydroformylation; microwave synthesis; N-
heterocycles; chalcones.
* corresponding authors: mmpereira@qui.uc.pt (M. M. Pereira), rui.carrilho@uc.pt (R. M. B.
Carrrilho) Address: University of Coimbra, Department of Chemistry, Rua Larga, 3004-535
Coimbra, Portugal, Telephone: +351 239 854 474.
¥Dedicated to Professor Laszló Kollár, on the occasion of his 65th birthday.
1

1. Introduction
Carbonyl compounds, such as carboxamides and aldehydes, are among the most relevant
synthons for preparation of highly functionalised molecules with potential applications in
medicinal chemistry [1-6]. Particularly, those containing N-heterocycles [7-14] and chalcone [15-
17] cores are frequently present in important pharmacological entities, such as antibiotics,
antibacterial, anti-hypertensive, anti-inflammatory and anticancer drugs (Figure 1).
Figure 1. Examples of N-heterocyclic and chalcone-based carbonyl compounds with
pharmacological activity.
Therefore, there has been an increasing interest in the search for efficient and sustainable
chemical processes for preparing such molecules. Among them, transition metal catalysed
hydroformylation [18-25] and aminocarbonylation [26-34] reactions are two paradigmatic
examples of efficient one-pot and versatile synthetic approaches to get access to carbonyl
compounds, such as aldehydes and carboxylic acid derivatives. Regarding these topics, it should
be highlighted the relevant contribution of L. Kollár, with more than 300 published papers [35].
Furthermore, the development of sequential carbonylation reactions have led to significant
reduction in costs, purification steps and waste formation. Such sequential reactions present
higher atom economy, allowing to improve the general processes efficiency and sustainability
[36-44]. It should be also noted that the global demands for implementation of more sustainable
synthetic processes have boosted the search for alternative CO sources [45-49], including metal-
carbonyl compounds [50-53] and the development of energetically favourable processes, such as
microwave-assisted carbonylation reactions [54-58].
Along the last years, we have been focused on the development of efficient transition-metal
catalysed carbonylation-based sequential processes applied to biologically relevant substrates for
the preparation value-added products with biological activity and/or industrial interest, including
hydroformylation/arylation
[59],
hydroformylation/isomerisation
[60],
2

hydroformylation/reductive
amination
[61,62],
hydroformylation/Strecker
[62],
hydroformylation/hydrogenation [63] and aminocarbonylation/cyclisation [64].
As part of our continuing research in this field, herein we report an original sequential
process for preparation of biologically relevant formylcarboxamide compounds comprising N-
heterocycle and chalcone scaffolds, through microwave-assisted palladium-catalysed
aminocarbonylation of iodoaromatic substrates with allylamine, followed by rhodium-catalysed
hydroformylation of the allylcarboxamide intermediates, to obtain carbonylated products
containing both formyl and carboxamide motifs (Scheme 1).
Scheme 1
3

2. Results and discussion
The palladium-catalysed aminocarbonylation step was first optimised, using iodobenzene
(1) as a model substrate, allylamine as nucleophile, palladium (II) acetate as catalytic precursor,
DBU as base and dioxane as solvent. The reactions were carried out in the presence of carbon
monoxide or molybdenum hexacarbonyl as alternative CO carbonyl source, at 125 °C, using
either conventional heating or microwave irradiation. Conversion and selectivity were determined
by GC-MS analysis of the crude mixtures and the results are presented in Table 1.
Table 1. Aminocarbonylation of iodobenzene (1) using allylamine as nucleophile.a
Carbonyl
source
Time
(min)
Conversion Selectivity
TOF
(h-1)
Entry
Heating
(%)
(%)
CO
(3 bar)
CO
Conv.
60
5
79
69
32
365
40
1
2
3
4
MW
(150W)
76
62
(3 bar)
Mo(CO)6
Conv.
60
5
99
82
MW
(150 W)
Mo(CO)6
99
76
475
a) Reaction conditions: iodobenzene (0.4 mmol), allylamine (0.6 mmol), Pd(OAc)2 (0.01 mmol),
Mo(CO)6 (0.4 mmol), DBU (0.2 mL), dioxane (3 mL), 125 °C.
Using a CO pressure of 3 bar and conventional heating, a conversion of 79% was obtained
in 60 min (TOF = 32 h-1), with 69% selectivity for the carboxamide product (2) (Table 1, entry
1). Under microwave irradiation (150 W), a similar conversion was obtained in just 5 min,
leading to a substantial increase in TOF (365 h-1), although a slightly slower selectivity (62%)
was observed (Table 1, entry 2). Alternatively, the use of Mo(CO)6 complex as alternative
carbonyl source, under conventional heating, provided full conversion in 60 min (TOF = 40 h-1),
with 82% selectivity for the carboxamide (2) (Table 1, entry 3). In addition, under microwave
irradiation, the reaction proceeded with full conversion in 5 min (TOF = 475 h-1) and with 76%
selectivity for the carboxamide product (2) (Table 1, entry 4). In sum, microwave irradiation
allowed to significantly reduce the required reaction time from 60 min to 5 min with
enhancement of the activity (TOF = 40 and 475 h-1 respectively), maintaining the reaction
selectivity.
4

With optimised conditions, microwave-assisted Pd-catalysed aminocarbonylation reactions,
using Mo(CO)6 as carbonyl source, were applied to different iodoaromatic substrates with
biologically relevant scaffolds, including 1-bromo-4-iodo benzene (3), 4-iodoanisole (4),
iodopyridine (5), 7-iodoindole (6), 5-iodoindole (7) and iodopyrazoline (8) and iodochalcone (9)
[68]. Conversion and yields were determined by GC-MS analysis of the crude mixtures and the
results are presented in Table 2.
Table 2. Microwave-assisted Pd-catalysed aminocarbonylation using allylamine as nucleophile.a
Product (yield, %)b
Entry
1
Substrate
O
N
H
2
(76)
2
3
4
5
6
7d
5

8
a) Reaction conditions: substrate (0.4 mmol), allylamine (0.6 mmol), Pd(OAc)2 (0.01 mmol),
Mo(CO)6 (0.4 mmol), DBU (0.2 mL), dioxane (3 mL), 125 °C, 5 min, 150 W.
b) Yield determined by GC-MS analysis of crude mixtures.
c) 1 h.
The microwave-assisted aminocarbonylation reactions proceeded with ca. 99% conversion
in 5 min and allylcarboxamide derivatives were obtained as major products in all cases, in yields
ranging from 65% (for product 11) to 87% (for product 13). In addition, the aminocarbonylation
of substrates 3 and 5 led to predominant formation mono-carbonylated products 10 and 12,
respectively (Table 2, entries 2 and 4), which indicate that oxidative addition to the palladium
complex occurs mainly through the most reactive C–I bond, while C–Br and C–Cl bonds remain
unchanged under these conditions. Moreover, in the case of iodopyrazoline (8), the reaction
required 1 h, under microwave irradiation, to obtain the corresponding allylcarboxamide product
(15), obtained in 70% yield. In all cases, GC-MS indicated the formation of ketocarboxamides as
13
minor products (up to ca. 10 %), corroborated by the C NMR spectra which presented typical
signals around 190 ppm. After work up and purification by column chromatography in silica gel,
using EtOAc/n-hexane or EtOAc/CH2Cl2 mixtures as eluents, the carboxamide products 2 and
10-16 have been isolated and fully characterised. In sum, microwave-assisted palladium-
catalysed aminocarbonylation of iodoaromatic substrates, using allylamine as a nucleophile,
allowed optimising the first step of the sequential process and provided the access to a set of
allylcarboxamide products.
In order to minimise product losses by work-up and purification procedures, a sequential
catalytic aminocarbonylation/hydroformylation methodology was then carried out, without work-
up or purification of the allylcarboxamide intermediates. Thus, using iodobenzene (1) as a model
substrate, the crude mixture obtained in the microwave-assisted aminocarbonylation step was
directly subjected to hydroformylation conditions (8 bar H2/CO) with
a
rhodium/triphenylphosphine catalyst, at 50 °C. However, in a first attempt, no conversion was
observed after 6 h. This was attributed to the formation of a sterically hindered rhodium/DBU
complex of type 17 [65,66], which leads to formation of catalytically inactive species.
6

To overcome this issue, the crude mixture, resulting from the aminocarbonylation step, was
passed through a silica-pad previous to hydroformylation. Following this procedure, full substrate
conversion was obtained in 5 h, with 72% chemoselectivity for oxo-products and 44%
regioselectivity for the branched aldehyde (18) (Table 3, entry 1). Then, aiming the preparation of
biologically relevant formylcarboxamide molecules, the scope of this sequential
aminocarbonylation/hydroformylation methodology was expanded to iodopyridine (5),
iodopyrazoline (8) and iodochalcone (9) substrates.
Table 3. Synthesis of formylcarboxamides by sequential aminocarbonylation/hydroformylation
methodology.a
Product
(isolated yield, %)
Entry
1
Substrate
Chemo (%)b iso-Regio (%)c
72
73
44
51
2
3d
56
64
46
36
4d
7

a) Reactions conditions: aminocarbonylation step substrate (0.4 mmol), allylamine (0.6 mmol),
Pd(OAc)2 (0.01 mmol), Mo(CO)6 (0.4 mmol), DBU (0.2 mL), dioxane (3 mL), 125 °C, 150 W, 5
min,; hydroformylation step: Rh(acac)(CO)2/PPh3 = 1:5; Rh/substrate = 1:100; P = 8 bar H2/CO;
50 °C, 5 h. Conversion was ca 99% in all cases.
b) Chemoselectivity for oxo-products (determined by 1H NMR).
c) Regioselectivity for the branched aldehyde (iso) (determined by 1H NMR).
d) 12 h
In a typical sequential aminocarbonylation/hydroformylation experiment, the iodo-
substrate, allylamine, Pd(OAc)2, Mo(CO)6 and DBU were dissolved in dioxane and placed inside
a microwave vial. The mixture was then subjected to microwave irradiation (P = 150 W), the
reaction proceeding at 125 °C for 5 min. After cooling down to room temperature, the obtained
mixture was filtered through a silica pad and the residue was introduced via cannula into an
autoclave containing the precursor, Rh(CO)2acac and triphenylphosphine (PPh3). The autoclave
was then pressurised with 8 bar H2/CO and kept at 50 °C for 5 h (or 12 h). At the end, the solvent
was evaporated and the crude mixture was analysed by 1H and 13C NMR spectroscopy.
The sequential aminocarbonylation/hydroformylation processes proceeded with complete
conversions and the chemoselectivity for oxo-products was in the range 56-73%. The
regioselectivity for the branched aldehydes varied from 36 to 51% (Table 3, entries 2-4). Upon
purification by column chromatography in silica gel, the branched formylcarboxamide products
18-21 were isolated in yields ranging from 19 to 22%. These low yields can be explained by the
significant formation of linear aldehydes and the respective cyclisation products (not isolated),
resultant from intramolecular condensation between the carboxamide and formyl moiety of the
linear aldehydes, which leads to the formation of a stable 5 membered ring (Scheme 2) [67],
evidenced by 1H NMR and GC-MS.
Scheme 2
It is worth mentioning that, in the case of chalcone-derived substrate (9), the
hydroformylation of the allyl moiety occurred concomitantly with reduction of the conjugated
internal C=C double bond, which resulted in the formation of formylcarboxamide 21, obtained as
major product (Table 3, entry 4).
8

4. Conclusions
We have developed an innovative catalytic aminocarbonylation/hydroformylation sequential
approach to prepare new formylcarboxamide molecules. The optimisation of the first step of the
catalytic sequence was achieved through microwave-assisted palladium-catalysed
aminocarbonylation of iodoaromatic substrates, using allylamine as nucleophile and Mo(CO)6 as
alternative carbonyl source, which provided an efficient strategy for the synthesis of
allylcarboxamide derivatives. The subsequent Rh/triphenylphosphine-catalysed hydroformylation
of the allylcarboxamide intermediates allowed the synthesis of a set of new N-heterocyclic and
chalcone-based formylcarboxamides, including 6-chloro-N-(2-methyl-3-oxopropyl)nicotinamide,
4-(1,3-diphenyl-4,5-dihydro-1H-pyrazol-5-yl)-N-(2-methyl-3-oxopropyl)benzamide and (E)-N-
(2-methyl-3-oxopropyl)-4-(3-oxo-3-phenylprop-1-en-1-yl)benzamide. In sum, this transition-
metal catalysed aminocarbonylation/hydroformylation sequential process opens new perspectives
regarding the preparation of biologically relevant molecules containing both carboxamide and
formyl motifs.
5. Experimental section
5.1. General
Manipulation of all moisture sensitive reagents was carried out under nitrogen atmosphere by
using Schlenk techniques. Glassware was dried in an oven at 200 °C and cooled under a nitrogen
atmosphere. Palladium (II) acetate, triphenylphosphine, Mo(CO)6, iodobenzeno, 1-bromo-4-
iodobenzene, 4-methoxyiodobenzene, 2-chloro-5-iodopyridine, 7-iodoindole, 5-iodoindole, DBU
and dioxane were purchased from Merck and used without further purification. The
iodopyrazoline 8 and iodochalcone 9 substrates were synthesised through a mechanochemical
synthetic methodology, recently developed by some of us [68].
Microwave-assisted experiments were performed in thick-walled glass vials under closed-
vessel conditions, using a CEM Discover® SP Focused MicrowaveTM Synthesis System. NMR
1
spectra were recorded on a Bruker Avance 400 spectrometer, operating at 400.13 MHz for H
NMR and 100.62 MHz for 13C NMR. Chemical shifts (δ) are reported in ppm relatively to CDCl3
1
13
(7.260 and 77.16 ppm for H and C, respectively) or tetramethylsilane (TMS). High-resolution
mass spectrometry analysis was carried out on a Bruker Microtof apparatus, equipped with
selective ESI detector. Samples of the reactions were analysed by: a) gas chromatography carried
out on Agilent-7820A GC System equipped with a non-polar capillary HP-5 column (5%
diphenyl and 95% dimethylpolysiloxane), with 30 m length and 0.32 mm inside diameter and
using nitrogen as carrier gas, and equipped with an FID detector; or b) gas chromatography
9

coupled with mass spectrometry (GC-MS) using an Agilent 7820A GC System, equipped with a
HP-5 MS column, coupled to an Agilent 5975 MSD System Technologies spectrometer, using EI
(70 eV) and helium as carrier gas. Carboxamide derivatives were analysed by gas
chromatography using the following methods: a) GC-FID method: injector temp 250 °C, oven:
starting temp 50 °C (hold-time 2 min), heating rate 30 °C min-1, final temp 280 °C (hold-time 9
min); detector temp 280 °C, carrier gas: nitrogen (rate: 1.6 mL min-1); b) GC-MS method:
injector temp 250 °C, oven: starting temperature 50 °C (hold-time 1 min), heating rate 15 °C min-
1, final temp 280 °C (hold-time 15 min); detector temp 280 °C, carrier gas: helium (rate: 1 mL
min-1).
5.2. Microwave-assisted palladium-catalysed aminocarbonylation
The iodoaryl substrate (0.4 mmol), allylamine (45 µL, 0.6 mmol), Pd(OAc)2 (2.2 mg, 0.01
mmol), Mo(CO)6 (105.6 mg, 0.4 mmol), DBU (180 µL, 1.2 mmol) were dissolved in dioxane (3
mL) and placed into a microwave vial. The mixture was subjected to microwave irradiation
(Initial Power = 150 W) and the reaction was conducted at 125 °C for 5 min. The mixture was
then cooled to room temperature, filtered through a small plug of celite and evaporated to dryness
with the crude being analysed by GC-MS and/or GC-FID (methods described in section 5.1). The
residue obtained was dissolved in dichloromethane (20 mL) and washed with water (3×20 mL).
The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to a solid material
or to a waxy residue. The reaction products were isolated and purified by column
chromatography (Silicagel 60 (Merck), 0.063-0.200 mm), using EtOAc/n-hexane or
EtOAc/CH2Cl2 mixtures as the eluents (specified below for each compound).
5.3. General procedure of sequential aminocarbonylation/hydroformylation
For the sequential aminocarbonylation/hydroformylation process the iodoaromatic substrate
(0.4 mmol), allylamine (45 µL, 0.6 mmol, 1.5 equiv.), Pd(OAc)2 (2.2 mg, 0.01 mmol), Mo(CO)6
(105.6 mg, 0.4 mmol), DBU (180 µL, 1.2 mmol) and dioxane (3 mL) were placed into a
microwave vial. The mixture was subjected to microwave irradiation (Initial Power = 150 W) and
the reaction was conducted at 125 °C for 5 min. After cooled down to room temperature, the
aminocarbonylation crude mixture was filtered through a small plug of silica gel and introduced
via cannula into the autoclave. The rhodium precursor Rh(acac)(CO)2 (4×10-3 mmol, 1.03 mg)
and triphenylphosphine (0.02 mmol, 5.24 mg) were dissolved in dioxane (3 mL), under argon
atmosphere, and introduced via cannula into the autoclave. After purging the system with three
cycles of vacuum/syngas the reactor was pressurised with 8 bar of H2/CO (1:1) and kept at 50 °C.
10

After 5 h, the reactor was cooled to room temperature and slowly depressurised. The reaction
1
mixture was evaporated to dryness analysed by H NMR spectroscopy. The reaction products
were isolated and purified by column chromatography (Silicagel 60 (Merck), 0.063-0.200 mm),
using EtOAc/n-hexane or EtOAc/CH2Cl2 mixtures as the eluents (specified below for each
compound).
5.4.1 Characterisation of products
The spectroscopic data of 2, 10 and 11 are in agreement with that previously reported [69,70,71].
N-allyl-6-chloronicotinamide (12)
Rf (CH2Cl2/EtOAc 1:1) = 0.74. Beige solid, Yield 23%, 18 mg (0.09 mmol). 1H RMN (400 MHz,
CDCl3, ppm): δ 8.75 (d, J = 7.6 Hz, 1H), 8.10 (dd, J = 8.3, 2.5 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H),
6.18 (s, 1H), 5.97 – 5.90 (m, 1H), 5.28 (dd, J = 17.1, 1.2 Hz, 1H), 5.23 (dd, J = 10.2, 0.9 Hz, 1H),
13
4.12 – 4.08 (m, 2H). C RMN (100 MHz, CDCl3, ppm): δ 164.5; 154.5; 148.0; 138.1; 133.6;
129.2; 124.6; 117.6; 42.8. HRMS (ESI) (m/z): found 197.0477 [M+H]+ (calcd. 197.0476).
N-allyl-1H-indole-7-carboxamide (13)
Rf (EtOAc/n-hex 1:4) = 0.37. White solid. Yield 20%, 16 mg (0.08 mmol). 1H RMN (400 MHz,
CDCl3, ppm): δ 10.32 (br s, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 7.4 Hz, 1H), 7.33 – 7.32
(m, 1H), 7.12 (t, J = 7.7 Hz, 1H), 6.58 – 6.57 (m, 1H), 6.47 (s, 1H), 6.01 – 5.94 (m, 1H), 5.30 (dd,
J = 17.2, 1.4 Hz, 1H), 5.21 (dd, J = 10.2, 1.3 Hz, 1H), 4.16 – 4.13 (m, 2H). 13C RMN (100 MHz,
CDCl3, ppm): δ 167.8; 135.6; 134.4; 129.7; 125.8; 125.0; 118.9; 118.8; 116.8; 115.9; 102.1; 42.2.
HRMS (ESI) (m/z): found 201.1023 [M+H]+ (calcd. 201.1022).
N-allyl-1H-indole-5-carboxamide (14)
1
Rf (CH2Cl2/EtOAc 2:1) = 0.51. White solid. Yield 23%, 18 mg (0.09 mmol). H RMN (400
MHz, CDCl3, ppm): δ 8.53 (br s, 1H), 8.11 (s, 1H), 7.66 (dd, J = 8.5, 1.5 Hz, 1H), 7.42 (d, J = 8.5
Hz, 1H), 7.28 – 7.26 (m, 1H), 6.62 (s, 1H), 6.23 (br s, 1H), 6.01 – 5.94 (m, 1H), 5.29 (dd, J =
13
17.1, 1.5 Hz, 1H), 5.19 (dd, J = 10.2, 1.3 Hz, 1H), 4.14 – 4.12 (m, 2H). C RMN (100 MHz,
CDCl3, ppm): δ 168.6; 137.7; 134.7; 127.7; 126.6; 125.7; 121.2; 120.3; 116.6; 111.2; 103.8; 42.6.
HRMS (ESI) (m/z): found 201.1024 [M+H]+ (calcd. 201.1022).
N-allyl-4-(1,3-diphenyl-4,5-dihydro-1H-pyrazol-5-yl)benzamide (15)
Rf (EtOAc/n-hex 1:1) = 0.66. Yellow solid. Yield 21%, 32 mg (0.08 mmol). 1H RMN (400 MHz,
CDCl3, ppm): δ 7.73 (t, J = 7.3 Hz, 4H), 7.31 – 7.25 (m, 4H), 7.34 (d, J = 7.2 Hz, 2H), 7.20 –
11

7.16 (m, 3H), 7.04 (d, J = 7.8 Hz, 2H), 6.80 (t, J = 7.3 Hz, 1H), 6.19 (br s, 1H), 5.95 – 5.88 (m,
1H), 5.30 (dd, J = 12.4, 7.2 Hz, 1H), 5.24 (dd, J = 17.2, 1.4 Hz, 1H), 5.17 (dd, J = 10.2, 1.2 Hz,
13
1H), 4.07 – 4.04 (m, 2H), 3.86 (dd, J = 17.0, 12.4 Hz, 1H), 3.11 (dd, J = 17.1, 7.2 Hz, 1H). C
RMN (100 MHz, CDCl3, ppm): δ 167.0; 146.9; 146.3; 144.7; 134.2; 134.0; 132.6; 129.1; 128.9;
128.7; 128.0; 126.3; 125.9; 119.5; 116.9; 113.5; 64.3; 43.5; 42.5. HRMS (ESI) (m/z): found
381.1835 [M+] (calcd. 381.1841).
(E)-N-allyl-4-(3-oxo-3-phenylprop-1-en-1-yl)benzamide (16)
Rf (EtOAc/n-hex 1:1) = 0.56. Yellow solid. Yield 25%, 29 mg (0.1 mmol). 1H RMN (400 MHz,
CDCl3, ppm): δ 8.04 – 8.02 (m, 2H), 7.85 – 7.79 (m, 3H), 7.70 (d, J = 8.2 Hz, 2H), 7.63 – 7.59
(m, 2H), 7.55 (d, J = 10.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 6.26 (s, 1H), 5.99 – 5.92 (m, 1H),
13
5.28 (dd, J = 17.1, 1.4 Hz, 1H), 5.21 (dd, J = 10.2, 1.2 Hz, 1H), 4.13 – 4.10 (m, 2H). C RMN
(100 MHz, CDCl3, ppm): δ 190.4; 166.6; 143.4; 138.0; 137.9; 136.0; 134.1; 133.2; 128.8; 128.7;
128.6; 127.7; 123.8; 117.0; 42.7. HRMS (ESI) (m/z): found 292.13302 [M+H]+ (calcd.
292.1332).
N-(2-methyl-3-oxopropyl)benzamide (18)
Rf (CH2Cl2/EtOAc 7:3) = 0.54. Yellow oil. Yield 21%, 16 mg (0.08 mmol). 1H RMN (400 MHz,
CDCl3, ppm): δ 9.71 (s, 1H), 7.74 – 7.72 (m, 2H), 7.50 – 7.46 (m, 1H), 7.40 (dd, J = 10.2, 4.6 Hz,
2H), 6.73 (br s, 1H), 3.75 – 3.69 (m, 1H), 3.57 – 3.50 (m, 1H), 2.82 – 2.74 (m, 1H), 1.21 (d, J =
7.5 Hz, 3H). 13C RMN (100 MHz, CDCl3, ppm): δ 204.5; 167.7; 134.3; 131.7; 128.7; 127.0; 46.9;
39.9; 11.6. HRMS (ESI) (m/z): found 214.08399 [M+Na]+ (calcd. 214.0839).
6-chloro-N-(2-methyl-3-oxopropyl)nicotinamide (19)
Rf (CH2Cl2/EtOAc 1:2) = 0.27. Beige solid. Yield 20%, 18 mg (0.08 mmol). 1H RMN (400 MHz,
CDCl3, ppm): δ 9.70 (s, 1H), 8.73 (d, J = 2.2 Hz, 1H), 8.04 (dd, J = 8.3, 2.5 Hz, 1H), 7.39 (d, J =
8.3 Hz, 1H), 6.92 (s, 1H), 3.78 – 3.70 (m, 1H), 3.56 – 3.48 (m, 1H), 2.86 – 2.78 (m, 1H), 1.23 (d,
J = 7.5 Hz, 3H). 13C RMN (100 MHz, CDCl3, ppm): δ 204.6; 164.8; 154.4; 148.2; 139.2; 129.3;
124.8; 46.7; 39.0; 11.7. HRMS (ESI) (m/z): found 227.0581 [M+H]+ (calcd. 227.0582).
4-(1,3-diphenyl-4,5-dihydro-1H-pyrazol-5-yl)-N-(2-methyl-3-oxopropyl)benzamide (20)
Rf (EtOAc/n-hex 2:1) = 0.44. Yellow solid. Yield 19%, 31 mg (0.08 mmol). 1H RMN (400 MHz,
CDCl3, ppm): δ 9.69 (s, 1H), 7.73 – 7.66 (m, 4H), 7.39 – 7.34 (m, 5H), 7.19 – 7.15 (m, 2H), 7.03
(d, J = 7.8 Hz, 2H), 6.79 (t, J = 7.3 Hz, 1H), 6.60 (t, J = 5.9 Hz, 1H), 5.30 (dd, J = 12.5, 7.0 Hz,
1H), 3.86 (dd, J = 17.1, 12.4 Hz, 1H), 3.74 – 3.67 (m, 1H), 3.53 – 3.50 (m, 1H), 3.10 (dd, J =
12

13
17.1, 7.3 Hz, 1H), 2.80 – 2.74 (m, 1H), 1.21 (d, J = 7.5 Hz, 3H). C RMN (100 MHz, CDCl3,
ppm): δ 204.5; 167.3; 152.3; 146.9; 146.4; 133.8; 133.8; 129.1; 128.9; 128.7; 128.0; 126.4;
125.9; 119.5; 113.5; 64.3; 46.9; 43.5; 39.9; 11.6. HRMS (ESI) (m/z): found 412.2020 [M+H]+
(calcd. 412.2020).
(E)-N-(2-methyl-3-oxopropyl)-4-(3-oxo-3-phenylprop-1-en-1-yl)benzamide (21)
1
Rf (CH2Cl2/EtOAc 1:1) = 0.6. Yellow solid. Yield 22%, 28 mg (0.09 mmol). H RMN (400
MHz, CDCl3, ppm): δ 9.71 (s, 1H), 7.95 – 7.93 (m, 2H), 7.67 (d, J = 8.2 Hz, 2H), 7.56 (t, J = 7.4
Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 6.63 (s, 1H), 3.73 (ddd, J = 13.7, 6.7,
4.3 Hz, 1H), 3.53 (ddd, J = 13.8, 8.0, 5.8 Hz, 1H), 3.30 (t, J = 7.5 Hz, 2H), 3.11 (t, J = 7.5 Hz,
2H), 2.81 – 2.76 (m, 1H), 1.22 (d, J = 7.5 Hz, 3H). 13C RMN (100 MHz, CDCl3, ppm): δ 204.5;
198.9; 167.5; 145.5; 136.8; 133.3; 132.2; 128.8; 128.8; 128.1; 127.3; 46.9; 40.0; 39.9; 30.0; 11.6.
HRMS (ESI) (m/z): found: 324.1591 [M+H]+ (calcd. 324.1594).
Acknowledgements
This work was supported by national funds from FCT – Fundação para a Ciência e a
Tecnologia, I.P., through projects UID/QUI/00313/2019 to the Coimbra Chemistry Centre
(CQC), PTDC/QUI-OUT/27996/2017 (DUALPI) and POCI-01–0145-FEDER-016387
(SunStorage). LD thanks MATIS - Materiais e Tecnologias Industriais Sustentáveis (CENTRO-
010145-FEDER- 00014) and FMSR thanks FCT PhD CATSUS program (PD/BD/114340/2016)
for funding.
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20

Highlights
• Pd-catalysed aminocarbonylation of iodoaromatics using MW irradiation and
Mo(CO)6 as CO source
• Synthesis of N-heterocyclic and chalcone-derived allylcarboxamides
• Catalytic aminocarbonylation/hydroformylation sequential process
• Synthesis of biologically relevant N-heterocyclic and chalcone derived
formylcarboxamides

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: