Novel synthesis of 3-carboxamidolactam derivatives via palladium-catalysed aminocarbonylation

Article abstract of DOI:10.1016/j.tet.2018.08.046

Aminocarbonylation of alkenyl and (hetero)aryl iodides using medium-sized 3-aminolactams as N-nucleophiles was carried out in the presence of in situ palladium(0) catalysts. While the iodoalkenes were converted to the corresponding carboxamide under mild

Full text of DOI:10.1016/j.tet.2018.08.046

Accepted Manuscript
Novel synthesis of 3-carboxamidolactam derivatives via palladium-catalysed
aminocarbonylation
László Kollár, Attila Takács
PII:
S0040-4020(18)31028-7
10.1016/j.tet.2018.08.046
TET 29766
DOI:
Reference:
To appear in: Tetrahedron
Please cite this article as: Kollár Láó, Takács A, Novel synthesis of 3-carboxamidolactam derivatives via
palladium-catalysed aminocarbonylation, Tetrahedron (2018), doi: 10.1016/j.tet.2018.08.046.
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Novel synthesis of 3-carboxamidolactam derivatives via palladium-catalysed
ACCEPTED MANUSCRIPT
aminocarbonylation.
László Kollár, Attila Takács*
Graphical abstract
1

Novel synthesis of 3-carboxamidolactam derivatives via palladium-
ACCEPTED MANUSCRIPT
catalysed aminocarbonylation.
László Kollára,b), Attila Takácsb) *
a) Department of Inorganic Chemistry, University of Pécs and Szentágothai Research Centre, H-7624
Pécs, P.O. Box 266, Hungary; e-mail: kollar@gamma.ttk.pte.hu
b) MTA-PTE Research Group for Selective Chemical Syntheses, H-7624 Pécs, Ifjúság u. 6., Hungary;
takacsattila@gamma.ttk.pte.hu
Abstract: Aminocarbonylation of alkenyl and (hetero)aryl iodides using medium-
sized 3-aminolactams as N-nucleophiles was carried out in the presence of in situ
palladium(0) catalysts. While the iodoalkenes were converted to the corresponding
carboxamide under mild reaction condition (1 bar of CO, 50 °C) by using Pd(OAc)2 /
PPh3 catalysts, the iodobenzene shown decreased reactivity (39% conversion after 2
days) under the similar reaction conditions in the presence of 3-aminoazepan-2-one.
The reactivity of iodobenzene and other iodo(hetero)aromatic substrates was
increased with 3-aminoazepan-2-one under high (40 bar) carbon monoxide pressure,
but the chemoselectivity was shifted towards the 2-ketocarboxamides formed via
double carbon monoxide insertion (except 2-iodopyridine). Changing
triphenylphosphine to Xantphos, the expected carboxamides were chemoselectively
formed in all cases when iodo(hetero)aryl substrates were used in the presence of all
of the three 3-aminolactams under mild reaction conditions. The products synthesized
in the reactions mentioned above were isolated in moderate to high yields.
Key-words: palladium, 3-aminolactam, carbonylation, carbon monoxide, carboxamide
2

1. Introduction
Aminocarbonylation, i.e. the palladium-catalysed carbonylation of alkenyl or aryl halides (preferentially
ACCEPTED MANUSCRIPT
iodides) or their synthetic surrogates, sulfonates (preferentially triflates) in the presence of N-nucleophiles
was discovered by Heck et al ('Heck carbonylation')1 and widely applied in synthesis.2 This homogeneous
catalytic procedure proved to be highly efficient for the synthesis of carboxamides possessing even more
complicated skeletons of biological importance.3 The double insertion of CO leading to 2-ketocarboxamides
was also investigated.4
The mechanistic details of the reaction were also investigated but most studies are focused on the oxidative
addition step only.5 To the best of our knowledge, sporadic results are published on a reaction mechanism
6
involving carbon monoxide activation and insertion. Recently, computational chemistry studies were also
started to shed some light onto mechanistic details. 7
Concerning N-nucleophiles, a wide variety of primary and secondary amines, among them functionalised
ones such as amino acid esters, N-heterocycles, etc. have already been used. Aminolactams are challenging
nucleophiles for aminocarbonylation since the series of N-acylated aminolactams with biological importance
could be available in this way.8
Fig. 1. 3-(Acylamino)lactam-based compounds of biological importance
In this paper, the use of aminolactams as building block in aminocarbonylation reaction will be described. In
other words, the highly efficient acylation of the amino functionality of a lactam ring via palladium-catalysed
reaction can be carried out.
3

2. Results and discussion
2.1. Aminocarbonylation of iodoalkenes (1-5) in the presence of 3-aIPmino lactam (a-c) N-nucleophiles
ACCEPTED MANUSCR T
1-Iodocyclohexene (1), 4-tert-butyl-1-iodocyclohexene (2), 17-iodoandrost-16-ene (3), 2-iodobornene
(4), and trans-1-iodo-1-octene (5) were aminocarbonylated using 3-aminoazepan-2-one (a, n=3), 3-
aminopiperidin-2-one (b, n=2) and 3-aminopyrrolidin-2-one (c, n=1) under carbon monoxide atmosphere
(Scheme 1). A coordinatively unsaturated, low-ligated palladium(0) catalyst, prepared in situ from
palladium(II) acetate and two molar equivalents of triphenylphosphine, was used.9 According to the generally
accepted mechanism10, the palladium(0) catalyst is indispensable to oxidatively add the starting iodoalkene
substrate.
Scheme 1. Aminocarbonylation of iodoalkenes (1-5) in the presence of 3-aminolactams (a-c)
The substrates have shown excellent reactivity leading to practically complete conversion within less
o
than 2 hours (Table 1, entries 1, 2; 12, 13) under standard conditions (1 bar CO, 50 C). The reaction was
completely chemoselective, i.e., carboxamides were formed exclusively due to single CO insertion. All three
aminolactams (a-c) proved to be excellent N-nucleophile.
A slight decrease of the reaction temperature (to 40 oC) resulted in longer reaction times needed to get
full conversion (entry 3 and 6). Increasing CO pressure did not affect the chemoselectivity, and no double
CO insertion was observed (entry 5). The high conversion and selectivity enabled facile isolation of the target
compounds in good to excellent yields.
It is worth noting that the widely used solvent DMF can be substituted for green solvents such as GVL
(γ-valerolactone) (entry 7) and methyl 4-methoxybutyrate11 (entry 8) without substantial loss of activity.
4

Table 1. Aminocarbonylation of 1-5 in the presence of 3-aminolactams a)
ACCEPTED MANUSCRIPT
Entry
Substrate
Amine R. time Conv. b) Isolated yield c)
[h]
[%]
[%]
1
2
3 d)
1
2
5
1
2
5
1
4
1
1
1
1
2
1
2
3
1
1
1
4
1
90
n. i. h)
87 (1a)
79 (1a)
74 (2a)
n. i. h)
1
1
1
2
2
2
2
2
3
4
5
1
1
2
2
3
4
5
1
3
5
a
a
a
a
a
a
a
a
a
a
a
b
b
b
b
b
b
b
c
>98
>98
>98
88
4
5 e)
6 d)
7 f)
8 g)
9
>98
>98
>98
>98
>98
>98
90
72 (2a)
70 (2a)
61 (2a)
81 (3a)
87 (4a)
76 (5a)
n. i. h)
10
11
12
13
14
15
16
17
18
19
20
21
>98
40
75 (1b)
n. i. h)
>98
>98
>98
>98
>98
>98
>98
73 (2b)
67 (3b)
75 (4b)
72 (5b)
51 (1c)
54 (3c)
52 (5c)
c
c
a) Reaction conditions: 0.5 mmol of substrate (1-5), 0.55 mmol of 3-aminolactams (a-c), 0.0125 mmol of
Pd(OAc)2, 0.025 mmol of PPh3, 0.25 mL (1.625 mmol) of Et3N, 5 mL of DMF, 1 bar of CO, 50 oC.
b) Determined by GC-MS.
c) Yields of the isolated target compound (based on the substrates (1-5))
d) The reaction was carried out in THF at 40 oC.
e) The reaction was carried out at 40 bar of CO.
f) The reaction was carried out in GVL.
g) The reaction was carried out in methyl 4-methoxybutyrate.
h) Not isolated.
5

2.2. Aminocarbonylation of iodoarenes (6-9) using 3-amino-ε-caprolactam (a) in the presence of Pd(OAc)2 /
2 PPh3 catalysts
ACCEPTED MANUSCRIPT
The parent 'in situ' catalytic system formed from Pd(OAc)2 and 2 PPh3 was tested in the aminocarbonylation
of various iodoarenes (6-9) with 3-amino-ε-caprolactam (a) as N-nucleophile. The aminocarbonylation of
iodoaromatics needed longer reaction times than the iodalkenes (2.1.). Furthermore, in contrast to the
iodoalkene substrates, a mixture of two products were obtained in all cases (Scheme 2). The single and
double CO insertion led to the formation of carboxamides (6a-9a) and 2-ketocarboxamides (6a'-9a'),
respectively.
In general, the formation of carboxamides is favored at atmospheric pressure using substrate 6 (entries 1-3.).
Due to the low conversion (42%) after 48 hours the reaction had to be carried out under high carbon
monoxide pressure (40 bar) to reach complete conversion (entry 6., Fig. 2.). Using iodobenzene (6) and other
iodoheteroaromatic substrates (8-9), the 2-ketocarboxamides (6a’, 8a’, 9a’) were preferentially formed at
elevated carbon monoxide pressure (entries 6., 10., 12.). 2-Iodopyridine (7) as model compound has shown a
completely different behavior regarding chemoselectivity: the corresponding 2-ketocarboxamide (7a') was
formed as minor product even at high pressure (entry 8.). This observation is in accordance with the results
obtained in our previous systematic investigations with nitrogen-containing iodoheteroaromatics.12
Comparing the reactivity of the heteroaryl iodides, the 2-iodopyridine (7) showed much more reactivity (75%
conversion after 6 hours) than the 3-iodopyridine (8) and the 2-iodothiophene (9) substrates in the presence
of 3-amino-ε-caprolactam at 40 bar of carbon monoxide pressure (Fig. 3.).
H
N
O
NH
HN
O
Pd(OAc)2 / 2 PPh3
R
I
H2N
O
NH
O
+
+
O
1 or 40 bar of CO
DMF, Et3N, 50 °C
NH
O
R
R
6-9
a
6a-9a
6a'-9a'
R=
N
N
S
6
7
8
9
Scheme 2. Aminocarbonylation of iodoarenes (6-9) with 3-amino-ε-caprolactam (a) in the presence of
Pd(OAc)2 / 2 PPh3 catalysts
6

Table 2. Aminocarbonylation of iodoarenes (6-9) with 3-amino-ε-caprolactam (a) in the presence of
Pd(OAc)2 / 2 PPh3 catalysts a)
ACCEPTED MANUSCRIPT
Entry Substrate
R. time
p(CO) Conv. b) Ratio of the carbonylated products b)
[h]
[bar]
[%]
carboxamide
2-ketocarboxamide
(6a-9a)
(6a’-9a’)
1
2
2
1
<1
10
66 (6a)
78 (6a)
73 (6a)
23 (6a)
27 (6a)
24 (6a)
95 (7a)
93 (7a), 81 c)
25 (8a)
22 (8a)
12 (9a)
12 (9a)
34 (6a’)
22 (6a’)
6
6
6
6
6
6
7
7
8
8
20
48
2
1
3
4
5
6
1
42
27 (6a’)
40
40
40
40
40
40
40
40
40
4
77 (6a’)
20
48
6
43
73 (6a’)
76 (6a’), 47 c)
95
7
8
75
5 (7a’)
24
48
96
48
96
>98
84
7 (7a’)
75 (8a’), 38 c)
9
10
11
>98
73
78 (8a’)
88 (9a’)
88 (9a’), 44 c)
9
9
12
>98
a) Reaction conditions: 0.5 mmol of substrate (6-9), 0.55 mmol of 3-amino- ε-caprolactam (a), 0.0125 mmol
of Pd(OAc)2, 0.025 mmol of PPh3, 0.25 mL (1.625 mmol) of Et3N, 5 mL of DMF, 1 or 40 bar of CO, 50
°C.
b) Determined by GC-MS.
c) Yields of the isolated target compounds (%), (based on the substrates (6-9)).
Conv. [%]
100
90
80
70
60
50
40
30
20
10
0
2
20
48
Time [h]
Substrate 6, Amine a, DMF, Temp. 50 oC PCO
:
1 bar CO
40 bar CO
Fig. 2. Conversion as a function of time of the aminocarbonylation of 6 in the presence of amine a.
7

Conv. [%]
ACCEPTED MANUSCRIPT
100
90
80
70
60
50
40
30
20
10
0
2
6
24
48
96
8
Time [h]
7
9
Fig. 3. Conversion as a function of time of the aminocarbonylation of 7, 8 and 9 in the presence of amine a
8

2.3 Aminocarbonylation of iodoarenes (6-11) in the presence of 3-aminolactam (a-c) N-nucleophiles using
Xantphos
ACCEPTED MANUSCRIPT
Using the observations above obtained with the parent Pd-PPh3 catalytic system, a large bite-angle ligand,
Xantphos was selected to achieve higher yields and selectivities in the aminocarbonylation of iodoarenes
(Scheme 3). In fact, an active catalyst even at atmospheric pressure both in DMF (Table 3, entries 1-3) and
THF (entries 7-10) was obtained for the aminocarbonylation of 6 with a (n=3) as nucleophile. The Xantphos-
containing system provided not only higher activity but also prefect selectivity toward carboxamide at low
pressure. As expected, a carboxamide / 2-ketocarboxamide mixture was obtained at 40 bar CO pressure
(entries 4-6). Under standard mild conditions (1 bar CO, 50 oC) high selectivity toward carboxamide products
was observed with the other iodoarenes (7-11) as well (entries 11-15).
The other two nucleophiles (b (n=2) and c (n=1)) has shown similar activities with the series of substrates
(entries 16-25).
H
O
H2N
O
N
n
Pd(OAc)2 / Xantphos
R
I
+
NH
1 bar of CO
DMF, Et3N, 50 °C
R
O
n=1-3
N
H
n
6-11
a-c
6a-c - 11a-c
R=
N
N
H
H
N
N
S
6
7
8
9
10
11
Scheme 3. Aminocarbonylation of iodoarenes (6-11) in the presence of 3-aminolactam (a-c) N-nucleophiles
using Xantphos
9

Table 3. Aminocarbonylation of iodoarenes (6-11) in the presence of 3-aminolactams (a-c) N-
nucleophiles using Xantphos
ACCEPTED MANUSCRIPT
Entry
Substrate
Amine R. time Conv. b) % of Carboxamide b)
[h]
[%]
1
2
1
63
88
100 (6a)
100 (6a)
100 (6a), 77 c)
20 e) (6a)
6
6
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
b
b
b
b
b
b
b
b
b
c
4
3
24
6
>98
13
6
4 d)
5 d)
6 d)
7 f)
8 f)
9 g)
10 g)
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
6
24
48
24
48
24
48
1
30
40 e) (6a)
36 e) (6a)
6
88
6
52
100 (6a)
6
95
100 (6a)
6
71
100 (6a)
6
>98
>98
>98
>98
>98
>98
95
100 (6a)
6
100 (7a), 88 c)
100 (8a), 54 c)
100 (9a), 68 c)
100 (10a), 69 c)
100 (11a), 74 c)
100 (6b)
7
22
22
22
22
6
8
9
10
11
6
8
>98
94
100 (6b), 56 c)
6
1
100 (7b)
7
2
>98
84
100 (7b), 76 c)
100 (8b)
100 (8b), 36 c)
7
12
24
12
24
24
2
8
>98
81
8
100 (9b)
9
>98
>98
>98
100 (9b), 45 c)
100 (10b), 71 c)
100 (6c), 47 c)
9
10
6
a) Reaction conditions: 0.5 mmol of substrate (6-11), 0.55 mmol of 3-aminolactams (a-c), 0.0125 mmol of
Pd(OAc)2, 0.0125 mmol of Xantphos, 0.25 mL (1.625 mmol) of Et3N, 5 mL of DMF, 1 bar of CO, 50 oC.
b) Determined by GC-MS.
c) Yields of the isolated target compounds (%), (based on the substrates (6-11)).
d) The reaction was carried out at 40 bar of CO.
e) The corresponding 2-ketocarboxamide (6a’) was also formed in the reaction. The ratio of the products was
determined by GC-MS.
f) The reaction was carried out in THF at 40 oC.
g) The reaction was carried out in THF at 50 oC.
10

Comparing the Pd-PPh3 and Pd-Xantphos systems, the higher activity of the latter is obvious (Fig. 4). In case
of the Xantphos system, the higher COACpres ur resulte in lo r aIPctivity (Fig. 5). That is, carbon monoxide
has an inhibition effect on catalytic activity.
s e d we
CEPTED MANUSCR T
The DMF proved to be more suitable solvent than THF (Fig 6). In general, approximately one day is needed
to accomplish aminocarbonylation with nucleophile a under given conditions. However, 2-iodopyridine (7),
the substrate providing carboxamide only, can be fully converted within 1 h (Fig. 7). A similar phenomenon,
i.e. the high reactivity of 7 was observed using nucleophile b (Fig. 8).
Conv. [%]
100
90
80
70
60
50
40
30
20
10
0
2
4
20
Time [h]
Substrate 6, Amine a, DMF, 50 oC, PCO 1 bar, Ligands: PPh3 XantPhos
Fig. 4. Conversion as a function of time of the aminocarbonylation of 6 in the presence of amine a.
Conv. [%]
100
90
80
70
60
50
40
30
20
10
0
Time [h]
2
4
24
48
Substrate 6, Amine a, DMF, 50 oC, Xanthphos, PCO:
1 bar CO
40 bar CO
Fig. 5. Conversion as a function of time of the aminocarbonylation of 6 in the presence of amine a.
11

Conv. [%]
ACCEPTED MANUSCRIPT
100
90
80
70
60
50
40
30
20
10
0
2
4
24
48
DMF THF
Time [h]
Fig. 6. Conversion as a function of time of the aminocarbonylation of 6 in the presence of amine a.
Conv. [%]
100
90
80
70
60
50
40
30
20
10
0
1
2
4
22
Time [h]
9 11
Amine a, Temp. 50 oC, DMF, Xanthphos, PCO 1 bar, Substrate:
7
8
Fig. 7. Conversion as a function of time of the aminocarbonylation of 7, 8, 9 and 11 in the presence of amine
a.
12

Conv. [%]
100
90
80
70
60
50
40
30
20
10
0
ACCEPTED MANUSCRIPT
1
4
6
12
7
Time [h]
Amine b, Temp. 50 oC, DMF, Xanthphos, PCO 1 bar, Substrate:
6
8
9
Fig. 8. Conversion in a function of time of the aminocarbonylation of 6, 7, 8, and 9 in the presence of amine
b.
13

2.4. Conclusions
In summary, medium-sized 3-aminolactamEDderivativesSC(3-am
ACCEPT MANU RIPTino-azepan-2-one, 3-amino-piperidin-2-
one, 3-amino-pyrrolidin-2-one) can be used as N-nuclophiles in palladium-catalysed aminocarbonylation.
Compounds with iodoalkene functionalities, among them compounds possessing biologically important
skeletons, undergo facile aminocarbonylation toward carboxamides as exclusive products in the presence of
Pd(OAc)2 / PPh3 catalysts at atmospheric carbon monoxide pressure. In contrast, the iodo(hetero)arenes have
shown much lower reactivity than the above mentioned iodoalkenes using the similar catalysts and reaction
conditions. Increasing the carbon monoxide pressure (40 bar) the chemoselectivity was shifted towards the
corresponding 2-ketocarboxamides (except 2-iodopyridine) due to double CO insertion. However, the
aminocarbonylation of the iodo(hetero)aryl substrates with 3-aminolactam nucleophiles was carried out under
atmospheric carbon monoxide pressure by using Xantphos instead of the monodentate PPh3 providing
selectively the expected carboxamide derivatives.
As described above, the yields of the target compounds are of synthetic importance especially in case
of 7- and 6-membered lactams (Fig. 9a and Fig. 9b, respectively). The yields are acceptable even with 5-
membered lactam (c) (Fig. 9c). It has to be added that the isolation procedures were not optimized, i.e. the
yields depicted in Fig. 9a-c were obtained under these conditions.
In this way, a new synthetic method for the synthesis of various 3-(acylamino)-lactams has been
described. The mild reaction conditions, the high selectivity and the moderate to high isolated yields, as well
as the presence of the medium-sized lactam rings make this reaction of both synthetic and pharmacological
importance.
14

ACCEPTED MANUSCRIPT
Fig. 9a. Products formed in the aminocarbonylation of 1-11 using a as nucleophile (isolated yields in
brackets).
15

O
H
O
N
ACCEPTED MANUSCRIPT
NH
O
O
H
N
H
N
NH
NH
O
O
1b (75%)
2b (73%)
3b (67%)
O
H
NH
N
O
O
NH
O
NH
4b (75%)
5b (72%)
O
O
H
N
O
H
N
H
N
NH
N
N
NH
NH
O
O
O
6b (56%)
7b (76%)
8b (36%)
HN
O
O
H
N
H
N
S
NH
NH
O
O
9b
10b
(71%)
(45%)
Fig. 9b. Products formed in the aminocarbonylation of 1-10 using b as nucleophile (isolated yields in
brackets).
Fig. 9c. Products formed in the aminocarbonylation of 1, 3, 5 and 6 using c as nucleophile (isolated
yields in brackets).
16

3. Experimental
3.1. General procedures
ACCEPTED MANUSCRIPT
1H and 13C NMR spectra were recorded in CDCl3 on a Bruker Avance III 500 spectrometer at 500 and
125.7 MHz, respectively. Chemical shifts δ are reported in ppm relative to CHCl3 (7.26 and 77.00 ppm for 1H
and 13C, respectively). Elemental analyses were measured on a 1108 Carlo Erba apparatus. The FT-IR spectra
were taken in KBr pellets using an IMPACT 400 spectrometer (Nicolet) applying a DTGS detector in the
region of 400-4000 cm-1, the resolution was 4 cm-1. The amount of the samples was ca. 0.5 mg. Mass
spectrometry data have been obtained using a GC-MS system consisting of a Perkin Elmer AutoSystem XL
gas-chromatograph. Melting points are uncorrected and were measured with a Büchi apparatus. TLC plates
(silica gel or aluminium oxide on TLC Al foils with fluorescence indicator 254 nm) were purchased from
Sigma-Aldrich. The eluents used in thin-layer chromatography are specified below.
trans-1-Iodo-1-octene (5), iodo(hetero)aromatic substrates (6-11) and 3-aminolactams (a-c) were
purchased from Sigma-Aldrich and were used without further purification. 1-Iodocyclohexene13 (1), 4-tert-
butyl-1-iodocyclohexene13 (2), 17-androst-16-ene14 (3), 2-iodobornene15 (4) were synthesized by the
modified Barton-procedure16.
The characterization of the carboxamides 1a8c, 6a17, 7a18, 8a17, 9a19 6b17, 8b17, which were synthesized
by the conventional (acylation) reactions was already published. The compounds isolated in this work gave
practically identical spectra. However, due to some further analytical details (for instance detailed description
of NMR spectra) the full characterization is given below for all compounds.
3.2. Aminocarbonylation of iodoalkenes (1-5) and iodo(hetero)arenes (6-11) in the presence of nucleophiles
a-c under atmospheric pressure of carbon monoxide.
In a typical experiment Pd(OAc)2 (2.81 mg, 0.0125 mmol), triphenylphosphine (6.55 mg, 0.025 mmol)
or Xantphos (7.23 mg, 0.0125 mmol), iodoalkene (1-5) or iodo(hetero)arene (6-11) substrates (0.5 mmol),
and 3-aminolactams (3-amino-azepan-2-one (a), 3-amino-piperidin-2-one (b), 3-amino-pyrrolidin-2-one (c))
(0.55 mmol) and triethylamine (0.25 mL) were dissolved in DMF (5 mL) under argon in a 100 mL three-
necked flask equipped with reflux condenser connected to a balloon filled with argon. The atmosphere was
°
changed to carbon monoxide. The reaction was conducted for the given reaction time upon stirring at 50 C
and analyzed by Gc and GC-MS. The cooled reaction mixture was then distilled to dryness under reduced
pressure. The residue was dissolved in chloroform (15 mL) and washed twice with water (15 mL). The
organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure to a solid material. All
compounds (except 10a, 10b) were subjected to column chromatography (Silicagel 60 (Sigma), 0.063-0.200
mm) or Aluminum oxide (Sigma), activated, neutral, Brockmann activity I), CHCl3/MeOH or CHCl3/EtOH
eluent mixtures (the exact ratios are specified in Characterization (3.4) for each compound). In the case of
10a and 10b chloroform (10 mL) was added to the residue and the insoluble material (product) was filtered
and dried.
17

3.3. Aminocarbonylation of iodoalkenes (1-5) and iodo(hetero)arenes (6-11) in the presence of nucleophiles
ACCEPTED MANUSCRIPT
a-c under atmospheric pressure of carbon monoxide.
In a typical experiment Pd(OAc)2, triphenylphosphine or Xantphos, iodoalkene (1-5) or
iodo(hetero)arene (6-11) and 3-aminolactam nucleophile (a-c) and triethylamine were used in the same
amount as above and were dissolved in 5 mL of DMF under argon in a 100 mL autoclave. The atmosphere
was changed to carbon dioxide and the autoclave was pressurized to the given pressure with carbon
monoxide. (Caution: High pressure carbon monoxide should only be used with adequate ventilation (hood)
°
using CO sensors as well.) The reaction was conducted for the given reaction time upon stirring at 50 C.
After the given reaction time the reaction mixture was cooled to room temperature and the autoclave was
carefully depressurized in a well-ventilated hood. The product mixture was analyzed by GC and GC-MS. The
work-up of the reaction mixture was identical to that discussed for the atmospheric experiments.
3.4. Characterization of the products
3.4.1. N-(2’-Oxoazepan-3’-yl)cyclohex-1-enecarboxamide (1a)
Yield: 103 mg (87%), White powder, m.p. 177-178 °C; [Anal. Calcd. for C13H20N2O2: C, 66.07; H,
8.53; N, 11.85. Found: C, 66.00; H, 8.42; N, 11.75.]; Rf (2% MeOH/CHCl3) 0.35. δH (500 MHz, CDCl3) 7.17
(1H, d, J 4.2 Hz, CONH), 6.74-6.69 (1H, m, CH=C), 6.16 (1H, br s, CONH-CH2), 4.59 (1H, ddd, J 11.3 Hz,
5.4 Hz, 1.4 Hz, CHNH), 3.39-3.23 (2H, m, CH2NH), 2.26 (1H, br d, 13.0 Hz, lactam CH2), 2.36-2.23 (2H, m,
CH2CH=C), 2.22-2-17 (2H, m, CH2CH=C), 2.26 (1H, br d, J 14.4 Hz, lactam CH), 2.08-1.98 (1H, m, lactam
CH), 1.95-1.82 (2H, m, lactam CH x2), 1.74-1.68 (2H, m, cyhex CH x2), 1.66-1.58 (2H, m, cyhex CH x2),
1.56-1.37 (2H, br m, lactam CH x2). δC NMR (125.7 MHz) 175.9, 1.67.5, 134.0, 132.9, 52.2, 42.2, 31.7,
29.0, 27.0, 25.4, 24.1, 22.1, 21.6. IR (KBr, ν (cm-1)): 3403, 3212 (NH), 1676 (lactam CON), 1656 (CON),
1626 (C=C), 1504 (NH); MS m/z (rel. int.): 236 (66, M+), 191 (5), 164 (6), 137 (4), 127 (89), 109 (100), 81
(76), 53 (28).
3.4.2. 4-(tert-Butyl)-N-(2’-oxoazepan-3’-yl)cyclohex-1-enecarboxamide (2a)
Yield: 108 mg (74%), White solid material, m.p. 216-217 °C; [Anal. Calcd. for C17H28N2O2: C, 69.83;
H, 9.65; N, 9.58. Found: C, 69.81; H, 9.80; N, 9.43.]; Rf (2% MeOH/CHCl3) 0.47. δH (500 MHz, CDCl3)
7.16 (1H, br s, CONH), 6.76-6.72 (1H, m, CH=C), 6.60 (1H, br s, CONH-CH2), 4.58 (1H, ddd, J 11.3 Hz, 5.4
Hz, 1.4 Hz, CHNH), 3.37-3.22 (2H, m, CH2NH), 2.28-1.80 (8H, br m, overlapping of 4 x lactam CH and 4 x
cyhex CH), 1.54-1.36 (2H, br m, lactam CH x2), 1.33-1.23 (1H, m, cyhex CH), 1.22-1.12 (1H, m, cyhex
CH). δC NMR (125.7 MHz) 176.0, 167.2, 134.5, 132.7, 52.1, 43.4, 42.2, 32.1, 31.7, 31.6, 28.9, 28.0, 27.1,
25.6, 23.6. IR (KBr, ν (cm-1)): 3378, 3246 (NH), 1680 (lactam CON), 1658 (CON), 1631 (C=C), 1510 (NH);
18

MS m/z (rel. int.): 292 (68, M+), 277 (9), 264 (3), 235 (15), 207 (5), 182 (10), 165 (56), 127 (100), 107 (41),
ACCEPTED MANUSCRIPT
84 (29), 57 (44), 51 (20).
3.4.3. N-(2’-Oxoazepan-3’-yl)androst-16-ene-17-carboxamide (3a), (ca. 1/1 mixture of two epimers)
Yield: 167 mg (81%), White solid material, m.p. 203-204 °C; [Anal. Calcd. for C26H40N2O2: C, 75.68;
H, 9.77; N, 6.79. Found: C, 75.74; H, 9.64; N, 6.55.]; Rf (3% MeOH/CHCl3) 0.59. δH (500 MHz, CDCl3)
7.15/7.13 (1H, d, J 6.1 Hz, CONH), 6.47/6.43 (1H, dd, J 3.0 Hz, 1.6 Hz, 16 CH=C), 6.23 (1H, br s, CONH-
CH2), 4.59 (1H, ddd, J 11.3 Hz, 5.4 Hz, 1.4 Hz, CHNH), 3.43-3.19 (2H, m, CH2NH), 2.30-2.11 (3H, m,
overlapping of lactam CH and 2 x skeleton CH), 2.09-0-73 (25H, br m, 20 x skeleton protons and 5 x lactam
protons), 1.01/0.98 (3H, s, 18-CH3), 0.84 (3H, s, 19-CH3). δC NMR (125.7 MHz) 175.8, 165.1/164.9,
150.4/150.2, 136.8/136.6, 56.9/56.8, 55.2, 52.1/52.0, 47.3, 46.5/46.4, 42.2, 38.5, 36.5, 35.1/34.9, 33.8, 32.0,
31.8/31.7, 31.6/31.5, 29.1, 29.0, 28.9, 28.0, 26.8, 22.2, 20.7, 16.6/16.5, 12.2. IR (KBr, ν (cm-1)): 3301, 3208
(NH), 1677 (lactam CON), 1650 (CON), 1630 (C=C), 1525 (NH); MS m/z (rel. int.): 412 (81, M+), 397
(100), 342 (2), 302 (7), 284 (37), 267 (45), 255 (43), 207 (3), 161 (12), 127 (60), 91 (28), 68 (25), 55 (25).
3.4.4. 1,7,7-Trimethyl-N-(2’-oxoazepan-3’-yl)bicyclo[2.2.1]hept-2-ene-2-carboxamide (4a), (ca. 1/1
mixture of two epimers)
Yield: 126 mg (87%), White solid material, m.p. 154-155 °C; [Anal. Calcd. for C17H26N2O2: C, 70.31;
H, 9.02; N, 9.65. Found: C, 70.20; H, 9.21; N, 9.57.]; Rf (3% MeOH/CHCl3) 0.47. δH (500 MHz, CDCl3)
7.10 (1H, br s, CONH), 6.54/6.51 (1H, d, J 3.3 Hz, 3-CH=C), 6.29 (1H, br s, CONH-CH2), 4.59 (1H, ddd, J
11.3 Hz, 5.4 Hz, 1.4 Hz, CHNH), 3.39-3.21 (2H, m, CH2NH), 2.42 (1H, dd, J 4.1 Hz, 3.2 Hz, 4-CH),
2.17/2.14 (br d, J 13.8 Hz, lactam CH), 2.07-1.98 (1H, m, lactam CH), 1.96-1.80 (3H, br m, overlapping of 2
x lactam CH and 5-CHaHb), 1.63 (1H, ddd, J 12.1 Hz, 9.1 Hz, 3.5 Hz, 6-CHaHb), 1.58-1.36 (2H, br m, lactam
CH x2), 1.31-1.21 (4H, s and m, overlapping of 8-CH3 and 6-CHaHb), 1.07-0.98 (1H m, 5-CHaHb), 0.83/0.82
(3H, s, 9-CH3), 0.80 (3H, s, 10-CH3). δC NMR (125.7 MHz) 175.9/175.8, 166.1/165.8, 145.0/144.7,
139.4/139.3, 56.8/56.6, 54.4/54.3, 52.0/51.9, 51.9/51.8, 42.2, 31.9/31.8, 31.4/31.3, 29.0, 28.0/27.9, 24.9/24.8,
19.4, 19.2/19.1, 11.9/11.7. IR (KBr, ν (cm-1)): 3300, 3212 (NH), 1670 (lactam CON), 1644 (CON), 1630
(C=C), 1525 (NH); MS m/z (rel. int.): 290 (28, M+), 262 (7), 235 (2), 199 (1), 162 (100), 147 (49), 135 (37),
129 (22), 119 (42), 101 (18), 91 (35), 84 (15), 77 (16), 55 (25).
3.4.5. (E)-N-(2-Oxoazepan-3-yl)non-2-enamide (5a)
Yield: 101 mg (76%), White powder, m.p. 165-166 °C; [Anal. Calcd. for C15H26N2O2: C, 67.63; H,
9.84; N, 10.52. Found: C, 67.76; H, 9.89; N, 10.38.]; Rf (3% MeOH/CHCl3) 0.75. δH (500 MHz, CDCl3) 6.92
(1H, d, J 5.6 Hz, CONH), 6.85 (1H, dt, J 15.2 Hz, 7.1 Hz, =CH), 6.74 (1H, br s, CONH-CH2), 5.87 (1H, dt, J
19

15.3 Hz, 1.3 Hz, =CH), 4.62 (1H, ddd, 11.3, 5.4, 1.4 Hz, CHNH), 3.39-3.22 (2H, m, CH2NH), 2.25-2.11 (3H,
ACCEPTED MANUSCRIPT
br m, overlapping of lactam CH and chain CH2), 2.07-1.98 (1H, m, lactam CH), 1.95-1.82 (2H, m, lactam CH
x2), 1.57-1.37 (4H, br m, overlapping of 2 x lactam CH and chain CH2), 1.36-1.23 (6H, m, 3 x chain CH2),
0.91 (3H, t, J 6.9 Hz, CH3). δC NMR (125.7 MHz)175.8, 165.1, 145.0, 123.5, 52.1, 42.2, 32.0, 31.7, 31.6,
28.9, 28.8, 28.2, 27.9, 22.6, 14.1. IR (KBr, ν (cm-1)): 3316, 3218 (NH), 1671 (lactam CON), 1663 (CON),
1624 (C=C), 1529 (NH); MS m/z (rel. int.): 266 (27, M+), 238 (2), 209 (9), 181 (39), 156 (16), 139 (38), 127
(100), 110 (26), 99 (22), 83 (38), 69 (42), 55 (92).
3.4.6. N-(2’-Oxoazepan-3’-yl)benzamide (6a)
Yield: 90 mg (77%), White powder, m.p. 208-209 °C; [Anal. Calcd. for C13H16N2O2: C, 67.22; H, 6.94;
N, 12.06. Found: C, 67.34; H, 6.90; N, 11.83.]; Rf (3% MeOH/CHCl3) 0.43. δH (500 MHz, CDCl3) 7.87 (2H,
d, J 7.1 Hz, CHortho(Ph)), 7.70 (1H, d, J 4.9 Hz, CONH), 7.52 (1H, t, J 7.4Hz, CHpara(Ph)), 7.46 (2H, t, J 7.4
Hz, CHmeta(Ph)), 6.74 (1H, br s, CONH-CH2), 4.75 (1H, ddd, J 11.3 Hz, 5.4 Hz, 1.4 Hz, CHNH), 3.42-3.26
(2H, m, CH2NH), 2.26 (1H, br d, J 12.7 Hz, lactam CH), 2.11-2.00 (1H, m, lactam CH), 1.98-1.87 (2H, m,
lactam CH x2), 1.66-1.53 (1H, m, lactam CH), 1.51-1.40 (1H, m, lactam CH). δC NMR (125.7 MHz) 175.9,
166.3, 134.2, 131.6, 128.5, 127.1, 52.6, 42.2, 31.6, 28.9, 28.0. IR (KBr, ν (cm-1)): 3254, 3204 (NH), 1661
(lactam CON), 1649 (CON), 1540 (NH); MS m/z (rel. int.): 232 (18, M+), 204 (1), 175 (8), 135 (3), 127 (28),
105 (100), 77 (68), 51 (17).
3.4.7. 2-Oxo-N-(2’-oxoazepan-3’-yl)-2-phenylacetamide (6a’)
Yield: 61 mg (47%), White solid material, m.p. 199-200 °C; [Anal. Calcd. for C14H16N2O3: C, 64.60;
H, 6.20; N, 10.76. Found: C, 64.52; H, 6.05; N, 10.64.]; Rf (3% MeOH/CHCl3) 0.60. δH (500 MHz, CDCl3)
8.32 (2H, d, J 7.4 Hz, CHortho(Ph)), 8.28 (1H, d, J 5.8 Hz, CONH), 7.64 (1H, t, J 7.4Hz, CHpara(Ph)), 7.50
(2H, t, J 7.4 Hz, CHmeta(Ph)), 7.22 (1H, br s, CONH-CH2), 4.68 (1H, ddd, J 11.3 Hz, 5.4 Hz, 1.4 Hz, CHNH),
3.39-3.33 (2H, m, CH2NH), 2.22 (1H, br d, 12.9 Hz, lactam CH), 2.15-2.06 (1H, m, lactam CH), 1.98-1.88
(2H, m, lactam CH x2), 1.72-1.61 (1H, m, lactam CH), 1.54-1.30 (1H, m, lactam CH). δC NMR (125.7 MHz)
187.5, 174.8, 161.4, 134.3, 133.4, 131.0, 128.5, 52.4, 42.2, 31.1, 28.8, 28.0. IR (KBr, ν (cm-1)): 3368, 3212
(NH), 1690 (lactam CON), 1656 (CON), 1503 (NH); MS m/z (rel. int.): 217 (3, M+-43), 189 (1), 155 (100),
127 (4), 105 (35), 77 (40), 51 (13).
3.4.8. N-(2’-Oxoazepan-3’-yl)picolinamide (7a)
Yield: 103 mg (88%), White powder, m.p. 187-188 °C; [Anal. Calcd. for C12H15N3O2: C, 61.79; H,
6.48; N, 18.01. Found: C, 61.60; H, 6.52; N, 18.11.]; Rf (1% MeOH/CHCl3; aluminium oxide) 0.56. δH (500
MHz, CDCl3) 9.18 (1H, d, J 4.7 Hz, CONH),8.64 (1H, d, J 4.6 Hz, Py CH), 8.18 (1H, d, J 7.7 Hz, Py CH),
20

7.86 (1H, dt, J 7.6, 1.2 Hz, Py CH), 7.44 (1H, dd, J 7.8 Hz, 4.9 Hz, Py CH), 6.40 (1H, br s, CONH-CH2),
ACCEPTED MANUSCRIPT
4.76 (1H, ddd, J 11.3 Hz, 5.4 Hz, 1.4 Hz, CHNH), 3.46-3.26 (2H, m, CH2NH), 2.23 (1H, br d, J 13.8 Hz,
lactam CH), 2.14-2.02 (1H, m, lactam CH), 1.99-1.87 (2H, m, lactam CH x2), 1.73-1.60 (1H, m, lactam CH),
1.55-1.41 (1H, m, lactam CH). δC NMR (125.7 MHz) 175.4, 163.7, 150.0, 148.5, 137.1, 126.1, 122.0, 52.3,
42.2, 31.7, 29.0, 28.1. IR (KBr, ν (cm-1)): 3341, 3251 (NH), 1670 (lactam CON), 1658 (CON), 1513 (NH);
MS m/z (rel. int.): 233 (28, M+), 205 (10), 188 (13), 161 (4), 147 (31), 127 (38), 106 (32), 99 (38), 78 (100),
51 (24).
3.4.9. N-(2’-Oxoazepan-3’-yl)nicotinamide (8a)
Yield: 63 mg (54%), White powder, m.p. 225-226 °C; [Anal. Calcd. for C12H15N3O2: C, 61.79; H, 6.48;
N, 18.01. Found: C, 61.59; H, 6.40; N, 17.79.]; Rf (3% EtOH/CHCl3; aluminium oxide) 0.64. δH (500 MHz,
CDCl3) 9.11 (1H, d, J 1.7 Hz, Py CH), 8.77 (1H, dd, J 4.8 Hz, 1.6 Hz, Py CH), 8.17 (1H, dt, J 7.9 Hz, 2.0 Hz,
Py CH), 7.74 (1H, d, J 4.7 Hz, CONH), 7.41 (1H, ddd, J 8.0 Hz, 3.8 Hz, 0.7 Hz, Py CH), 6.22 (1H, br s,
CONH-CH2), 4.76 (1H, ddd, J 11.3 Hz, 5.4 Hz, 1.4 Hz, CHNH), 3.45-3.28 (2H, m, CH2NH), 2.28 (1H, br d,
J 13.3 Hz, lactam CH), 2.15-2.06 (1H, m, lactam CH), 1.97-1.88 (2H, m, lactam CH x2), 1.68-1.57 (1H, m,
lactam CH), 1.54-1.43 (1H, m, lactam CH). δC NMR (125.7 MHz) 175.3, 164.4, 152.4, 148.4, 134.8, 129.8,
123.4, 52.7, 42.3, 31.5, 28.9, 28.0. IR (KBr, ν (cm-1)): 3339, 3225 (NH), 1676 (lactam CON), 1644 (CON),
1529 (NH); MS m/z (rel. int.): 233 (23, M+), 205 (9), 188 (13), 161 (5), 147 (24), 127 (33), 106 (29), 99 (35),
78 (100), 51 (23).
3.4.10. 2-Oxo-N-(2’-oxoazepan-3’-yl)-2-(pyridin-3-yl)acetamide (8a’), (ca. 2/3 mixture of two C(O)N
rotamers)
Yield: 49 mg (38%), Yellow solid material, m.p. 111-112 °C; [Anal. Calcd. for C13H15N3O3: C, 59.76;
H, 5.79; N, 16.08. Found: C, 59.87; H, 5.89; N, 16.01.]; Rf (3% EtOH/CHCl3; aluminium oxide) 0.39. δH (500
MHz, CDCl3) 9.52 (1H, s, Py CH), 8.85 (1H, d, J 3.6 Hz, Py CH), 8.17 (1H, dt, J 8.0 Hz, 1.8 Hz, Py CH),
8.39 (1H, d, J 5.4 Hz, CONH), 7.41 (1H, dd, J 8.0 Hz, 3.8 Hz, Py CH), 6.74/6.44 (minor/major, 1H, br s,
CONH-CH2), 4.63/4.48 (major/minor, 1H, ddd, J 11.3 Hz, 5.4 Hz, 1.4 Hz, CHNH), 3.41-3.32/3.31-3.22
(major/minor, 2H, m, CH2NH), 2.24-2.16 (1H, m, lactam CH), 2.15-2.07 (1H, m, lactam CH), 1.96-1.87 (2H,
m, lactam CH x2), 1.70-1.59 (1H, m, lactam CH), 1.55-1.44 (1H, m, lactam CH). δC NMR (125.7 MHz)
186.1, 177.1/174.4 (minor/major), 160.2, 154.2, 152.2, 138.3, 129.3, 123.4, 53.3/52.4 (minor/major),
42.3/42.2 (minor/major), 32.0/31.0 (minor/major), 29.0/28.9 (minor/major), 28.1/28.0. IR (KBr, ν (cm-1)):
3355, 3217 (NH), 1667 (br, lactam CON, CO and CON), 1539 (NH); MS m/z (rel. int.): 233 (2, M+-28), 191
(1), 155 (100), 127 (3), 106 (12), 84 (8), 79 (24), 69 (16), 51 (13).
21

3.4.11. N-(2’-Oxoazepan-3’-yl)thiophene-2-carboxamide (9a)
ACCEPTED MANUSCRIPT
Yield: 81 mg (68%), White powder, m.p. 201-202 °C; [Anal. Calcd. for C11H14N2O2S: C, 55.44; H,
5.92; N, 11.76. Found: C, 55.52; H, 5.80; N, 11.59.]; Rf 2% MeOH/CHCl3;) 0.50. δH (500 MHz, CDCl3) 7.59
(1H, dd, J 3.8 Hz, 1.1 Hz, Tioph CH), 7.53 (1H, d, J 5.1 Hz, CONH), 7.49 (1H, dd, J 5.1 Hz, 1.1 Hz, Tioph
CH), 7.09 (1H, dd, J 5.2 Hz, 3.8 Hz, Tioph CH), 6.57 (1H, br s, CONH-CH2), 4.71 (1H, ddd, J 11.3 Hz, 5.4
Hz, 1.4 Hz, CHNH), 3.40-3.25 (2H, m, CH2NH), 2.25 (1H, br d, J 13.7 Hz, lactam CH), 2.11-2.01 (1H, m,
lactam CH), 1.97-1.84 (2H, m, lactam CH x2), 1.64-1.53 (1H, m, lactam CH), 1.51-1.39 (1H, m, lactam CH).
δC NMR (125.7 MHz) 175.5, 160.9, 139.0, 130.1, 128.2, 127.6, 52.6, 42.2, 31.7, 28.9, 28.0. IR (KBr, ν (cm-
1)): 3254, 3204 (NH), 1670 (lactam CON), 1643(CON), 1546 (NH); MS m/z (rel. int.): 238 (17, M+), 205 (3),
181 (4), 141 (3), 127 (16), 111 (100), 83 (17), 51 (5).
3.4.12. 2-Oxo-N-(2-oxoazepan-3-yl)-2-(thiophen-2-yl)acetamide (9a’)
Yield: 58 mg (44%), Yellow solid material, m.p. 187-188 °C; Rf 2% MeOH/CHCl3;) 0.64. δH (500
MHz, CDCl3) 8.54 (1H, d, J 5.1 Hz, CONH), 8.38 (1H, dd, J 3.8 Hz, 1.1 Hz, Tioph CH), , 7.84 (1H, dd, J 5.1
Hz, 1.1 Hz, Tioph CH), 7.21 (1H, dd, J 5.2 Hz, 3.8 Hz, Tioph CH), 6.74 (1H, br s, CONH-CH2), 4.60 (1H,
ddd, J 11.3 Hz, 5.4 Hz, 1.4 Hz, CHNH), 3.38-3.28 (2H, m, CH2NH), 2.17 (1H, br d, J 13.7 Hz, lactam CH),
2.13-2.05 (1H, m, lactam CH), 1.95-1.82 (2H, m, lactam CH x2), 1.69-1.57 (1H, m, lactam CH), 1.54-1.41
(1H, m, lactam CH). δC NMR (125.7 MHz) 177.9, 174.6, 160.1, 138.4, 137.7, 128.2, 52.5, 42.1, 31.0, 28.9,
28.1. IR (KBr, ν (cm-1)): 3333, 3203 (NH), 1687 (CO), 1669(lactam CON), 1653 (CON), 1495 (NH); MS
m/z (rel. int.): 195 (1, M+-71), 155 (100), 127 (3), 111 (36), 83 (10), 69 (15), 55 (4).
3.4.13. N-(2’-Oxoazepan-3’-yl)-1H-indole-5-carboxamide (10a)
Yield: 93 mg (69%), Beige solid material, m.p. 260-261 °C; [Anal. Calcd. for C15H17N3O2: C, 66.40; H,
6.32; N, 15.49. Found: C, 66.47; H, 6.44; N, 15.37.]; Rf 5% MeOH/CHCl3) 0.44. δH (500 MHz, DMSO-d6)
11.34 (1H, br s, indole-NH), 8.14 (1H, br s, Ar-H), 8.03 (1H, d, J 5.6 Hz, CONH), 7.91 (1H, br s, CONH-
CH), 7.61 (1H, d, J 7.8 Hz, Ar-H), 7.45 (1H, d, J 7.8 Hz, Ar-H), 7.42 (1 H, s, Ar-H), 6.57 (1 H, br s, CONH-
CH2), 4.72-4.57 (1H, m, CHNH), 3.19-3.01 (2H, br m, CH2NH), 2.01-1.91 (2H, m, lactam CH x 2), , 1.88-
1.67 (2H, br m, lactam CH x2), 1.63-1.49 (1H, br m, lactam CH), 1.36-1.24 (1H, m, lactam CH). δC NMR
(125.7 MHz) 175.1, 166.6, 137.9, 127.6, 127.2, 125.7, 120.7, 120.2, 111.5, 102.7, 52.3, 41.2, 31.5, 29.4,
28.2. IR (KBr, ν (cm-1)): 3377 (indole-NH), 3292, 3230 (NH), 1665 (lactam CON), 1634(CON), 1529 (NH);
MS m/z (rel. int.): 271 (24, M+), 207 (1), 160 (7), 144 (100), 127 (14), 116 (32), 89 (10), 56 (1).
3.4.14. N-(2’-Oxoazepan-3’-yl)-1H-indole-7-carboxamide (11a)
22

Yield: 100 mg (74%), Pale brown solid material, m.p. 186-187 °C; [Anal. Calcd. for C15H17N3O2: C,
ACCEPTED MANUSCRIPT
66.40; H, 6.32; N, 15.49. Found: C, 66.52; H, 6.38; N, 15.43.]; Rf 3% MeOH/CHCl3;) 0.46. δH (500 MHz,
CDCl3) 10.39 (1 H, brs, indole-NH), 7.92 (1 H, d, J 4.7 Hz, CONH), 7.83 (1H, d, J 7.8 Hz, Ar-H), 7.59 (1 H,
d, J 7.7 Hz, Ar-H), 6.58 (1 H, dd, J 3.0 Hz, 2.3 Hz, indole-H), 7.35 (1H, dd, J 3.3 Hz, 2.8 Hz, indole-H), 6.81
(1H, br s, CONH-CH2), 6.61 (1H, dd, J 3.3 Hz, 2.8 Hz, indole-H), 4.81 (1H, ddd, J 11.3 Hz, 5.4 Hz, 1.4 Hz,
CHNH), 3.45-3.25 (2H, br m, CH2NH), 2.31 (1H, br d, J 13.0 Hz, lactam CH), 2.17-2.06 (1H, m, lactam
CH), 2.01-1.87 (2H, m, lactam CH x2), 1.72-1.59 (1H, m, lactam CH), 1.55-1.41 (1H, m, lactam CH). δC
NMR (125.7 MHz) 176.1, 167.0 135.4, 129.5, 125.5, 124.9, 119.7, 118.8, 115.7, 102.0, 52.4, 42.3, 31.7,
28.9, 28.1. IR (KBr, ν (cm-1)): 3410 (indole-NH), 3381, 3212 (NH), 1672 (lactam CON), 1637(CON), 1527
(NH); MS m/z (rel. int.): 271 (67, M+), 225 (2), 198 (2), 171 (6), 160 (15), 143 (100), 127 (32), 116 (68), 89
(26), 56 (5).
3.4.15. N-(2’-Oxopiperidin-3’-yl)cyclohex-1-enecarboxamide (1b)
Yield: 83 mg (75%), White powder, m.p. 161-162 °C; [Anal. Calcd. for C12H18N2O2: C, 64.84; H, 8.16;
N, 12.60. Found: C, 64.80; H, 8.32; N, 12.52.]; Rf (5% MeOH/CHCl3) 0.38. δH (500 MHz, CDCl3) 6.74-6.69
(1H, m, CH=C), 6.68 (1H, d, J 4.8 Hz, CONH), 6.19 (1H, br s, CONH-CH2), 4.31 (1H, dt, 11.5 Hz, 5.4 Hz,
CHNH), 3.41-3.34 (2H, m, CH2NH), 2.63 (1H, dq, 12.8 Hz, 4.6 Hz, NHCH-CH2), 2.37-2.27 (1H, m, cyhex
CH), 2.26-2.12 (3H, br m, cyhex CH x 3), 2.01-1.89 (2H, m, lactam CH2), 1.67 (1H, tt, 12.4 Hz, 7.8 Hz,
NHCH-CH2), 1.74-1.68 (1H, m, cyhex CH), 1.74-1.65 (2H, m, cyhex CH x2), 1.64-1.49 (3H, br m,
overlapping of cyhex CH x 2 and lactam CH). δC NMR (125.7 MHz) 172.1, 168.7, 134.2, 132.9, 50.7, 41.7,
27.2, 25.4, 24.2, 22.1, 21.5, 21.0. IR (KBr, ν (cm-1)): 3319, 3212 (NH), 1654 (lactam CON), 1632 (CON),
1614 (C=C), 1533 (NH); MS m/z (rel. int.): 222 (61, M+), 204 (14), 177 (4), 150 (3), 126 (7), 113 (89), 109
(100), 98 (18), 81 (84), 71 (30), 53 (30.
3.4.16. 4-(tert-Butyl)-N-(2’-oxopiperidin-3’-yl)cyclohex-1-enecarboxamide (2b), (ca. 1/1 mixture of
two epimers)
Yield: 101 mg (73%), White solid material, m.p. 216-217 °C; [Anal. Calcd. for C16H26N2O2: C, 69.03;
H, 9.41; N, 10.06. Found: C, 69.10; H, 9.52; N, 9.89.]; Rf (5% MeOH/CHCl3) 0.43. δH (500 MHz, CDCl3)
6.72 (2H, br s, overlapping of CONH and CH=C), 6.39 (1H, brs, CONH-CH2), 4.31 (1H, dt, J 11.5 Hz, 5.4
Hz, CHNH), 3.42-3.31 (2H, m, CH2NH), 2.62 (1H, dq, J 12.8 Hz, 4.6 Hz, NHCH-CH2), 2.56-2.36 (1H, m,
cyhex CH), 2.33-2.09 (2H, m, 2 x cyhex CH), 2.04-1.85 (4H, m, overlapping of 2 x lactam CH and 2 x cyhex
CH), 1.56 (1H, tt, J 12.4 Hz, 7.8 Hz, NHCH-CH2), 1.33-1.23 (1H, m, cyhex CH), 1.17 (1H, qd, J 12.1 Hz,
4.6 Hz, cyhex CH). δC NMR (125.7 MHz) 172.1, 168.5/168.4, 134.7, 132.7/132.6, 50.7/50.6, 43.4, 41.7,
23

32.1, 27.2, 27.1, 25.7, 25.6, 23.6, 21.0. IR (KBr, ν (cm-1)): 3280, 3256 (NH), 1675 (lactam CON), 1659
ACCEPTED MANUSCRIPT
(CON), 1621 (C=C), 1547 (NH); MS m/z (rel. int.): 278 (79, M+), 263 (10), 221 (25), 202 (8), 193 (3), 182
(6), 165 (58), 137 (6), 113 (92), 107 (100), 79 (44), 57 (60).
3.4.17. N-(2’-Oxopiperidin-3’-yl)androst-16-ene-17-carboxamide (3b), (ca. 1/1 mixture of two
epimers)
Yield: 133 mg (67%), White powder, m.p. 209-210 °C; [Anal. Calcd. for C25H38N2O2: C, 75.33; H,
9.61; N, 7.03. Found: C, 75.22; H, 9.70; N, 6.91.]; Rf (5% MeOH/CHCl3) 0.50. δH (500 MHz, CDCl3)
6.73/6.71 (1H, d, J 5.1 Hz, CONH), 6.47/6.40 (1H, dd, J 3.4 Hz, 1.7 Hz, 16 CH=C), 6.42 (1H, br s, CONH-
CH2), 4.30 (1H, dt, J 11.5 Hz, 5.4 Hz, CHNH), 3.40-3.29 (2H, m, CH2NH), 2.64 (1H, dq, J 12.8 Hz, 4.6 Hz,
NHCH-CH2), 2.25-2.12 (2H, m, 2 x skeleton CH), 2.05-1.88 (3H, m, overlapping of lactam CH2 and skeleton
CH), 1.73-0-73 (20H, br m, 19 x skeleton protons and lactam CH), 1.00/0.97 (3H, s, 18-CH3), 0.83 (3H, s,
19-CH3). δC NMR (125.7 MHz) 172.1, 166.3/166.0, 150.3/150.0, 137.1/136.8, 56.9/56.7, 55.1, 50.5, 47.2,
46.6/46.4, 41.7, 38.5, 36.5, 35.1/34.9, 33.8, 31.9, 31.7/31.6, 29.0, 28.9, 27.3/27.2, 26.8, 22.1, 21.0/20.9, 20.7,
16.6/16.5, 12.2. IR (KBr, ν (cm-1)): 3292, 3252 (NH), 1677 (lactam CON), 1653 (CON), 1521 (NH); MS m/z
(rel. int.): 398 (100, M+), 383 (85), 365 (8), 302 (4), 285 (47), 269 (95), 257 (56), 207 (9), 161 (19), 115 (42),
91 (35), 68 (30), 55 (37).
3.4.18. 1,7,7-Trimethyl-N-(2’-oxopiperidin-3’-yl)bicyclo[2.2.1]hept-2-ene-2-carboxamide (4b), (ca. 1/1
mixture of two epimers)
Yield: 103 mg (75%), White solid material, m.p. 153-154 °C; [Anal. Calcd. for C16H24N2O2: C, 69.53;
H, 8.75; N, 10.14. Found: C, 69.59; H, 8.66; N, 10.01.]; Rf (5% MeOH/CHCl3) 0.43. δH (500 MHz, CDCl3)
6.67 (1H, d, J 4.3 Hz, CONH), 6.54/6.47 (1H, d, J 3.3 Hz, 3-CH=C), 6.44 (1H, br s, CONH-CH2), 4.26 (1H,
dt, J 11.5 Hz, 5.4 Hz, CHNH), 3.36-3.28 (2H, m, CH2NH), 2.58 (1H, dq, J 12.8 Hz, 4.6 Hz, NHCH-CH2),
2.42 (1H, dd, J 4.1 Hz, 3.2 Hz, 4-CH), 1.96-1.82 (3H, br m, overlapping of 2 x lactam CH and 5-CHaHb),
1.67-1.47 (2H, br m, overlapping of lactam NHCH-CH2 and 6-CHaHb), 1.31-1.21 (4H, s and m, overlapping
of 8-CH3 and 6-CHaHb), 0.99 (1H, ddd, J 12.1 Hz, 9.1 Hz, 3.5 Hz, 5-CHaHb), 0.79/0.78 (3H, s, 9-CH3), 0.77
(3H, s, 10-CH3). δC NMR (125.7 MHz) 177.2, 167.2/167.9, 144.9/144.6, 139.4/139.3, 56.8/56.5, 54.3,
51.9/51.8, 50.4/50.3, 41.6/41.5, 31.4/31.3, 27.4/27.2, 24.9/24.8, 21.0/20.9, 19.4, 19.1, 11.8/11.7. IR (KBr, ν
(cm-1)): 3259, 3226 (NH), 1671 (lactam CON), 1629 (CON), 1539 (NH); MS m/z (rel. int.): 276 (21, M+),
262 (7), 248 (7), 221 (2), 190 (1), 162 (100), 147 (60), 135 (44), 119 (56), 113 (23), 91 (36), 77 (10), 55 (11).
3.4.19. (E)-N-(2-Oxopiperidin-3-yl)non-2-enamide (5b)
24

Yield: 91 mg (72%), White powder, m.p. 218-219 °C; [Anal. Calcd. for C14H24N2O2: C, 66.63; H, 9.59;
ACCEPTED MANUSCRIPT
N, 11.10. Found: C, 66.52; H, 9.70; N, 11.03.]; Rf (5% MeOH/CHCl3) 0.34. δH (500 MHz, CDCl3) 6.85 (1H,
dt, J 15.2 Hz, 7.1 Hz, =CH), 6.53 (1H, br s, CONH), 6.16 (1H, br s, CH2NH), 5.84 (1H, dt, J 15.3 Hz, 1.3 Hz,
=CH), 4.35 (1H, dt, J 11.5 Hz, 5.4 Hz, CHNH), 3.41-3.32 (2H, m, CH2NH), 2.64 (1H, dq, J 12.8 Hz, 4.6 Hz,
NHCH-CH2), 2.19 (2H, q, J 7.1 Hz, CH2CH3), 2.02-1.85 (3H, br m, overlapping of lactam CH and chain
CH2), 1.57 (1H, tt, J 12.4 Hz, 7.8 Hz, NHCH-CH2), 1.50-1.40 (2H, m, chain CH2), 1.37-1.22 (6H, br m, 3 x
chain CH2), 0.90 (3H, t, J 7.1 Hz, CH2CH3). δC NMR (125.7 MHz) 172.0, 166.3, 145.3, 123.3, 50.6, 41.7,
32.1, 31.6, 28.9, 28.2, 27.2, 22.6, 21.0, 14.1. IR (KBr, ν (cm-1)): 3306, 3203 (NH), 1690 (lactam CON), 1668
(CON), 1625 (C=C), 1541 (NH); MS m/z (rel. int.): 252 (35, M+), 223 (1), 195 (12), 167 (22), 156 (15), 140
(48), 113 (100), 98 (19), 85 (24), 69 (59), 55 (87).
3.4.20. N-(2’-Oxopiperidin-3’-yl)benzamide (6b)
Yield: 64 mg (56%), White powder, m.p. 189-190 °C; [Anal. Calcd. for C12H14N2O2: C, 66.04; H, 6.47;
N, 12.84. Found: C, 66.15; H, 6.54; N, 12.70.]; Rf (5% MeOH/CHCl3) 0.38. δH (500 MHz, CDCl3) 7.85 (2H,
d, J 7.4 Hz, CHortho(Ph)), 7.52 (1H, t, J 7.4Hz, CHpara(Ph)), 7.45 (2H, t, J 7.4 Hz, CHmeta(Ph)), 7.28 (1H, d, J
5.5 Hz, CONH), 6.34 (1H, br s, CONH-CH2), 4.46 (1H, dt, J 11.5 Hz, 5.4 Hz, CHNH), 3.44-3.37 (2H, m,
CH2NH), 2.73 (1H, dq, J 12.8 Hz, 4.6 Hz, NHCH-CH2), 2.04-1.95 (2H, m, lactam CH2), 1.67 (1H, tt, J 12.4
Hz, 7.8 Hz, NHCH-CH2). δC NMR (125.7 MHz) 171.9, 167.6, 134.2, 131.6, 128.5, 127.1, 51.0, 41.7, 27.1,
21.0. IR (KBr, ν (cm-1)): 3310, 3206 (NH), 1687 (lactam CON), 1632 (CON), 1532 (NH); MS m/z (rel. int.):
218 (18, M+), 196 (1), 173 (3), 161 (3), 133 (3), 113 (41), 105 (100), 77 (60), 51 (17).
3.4.21. N-(2’-Oxopiperidin-3’-yl)picolinamide (7b)
Yield: 84 mg (76%), Off white solid material, m.p. 141-142 °C; [Anal. Calcd. for C11H13N3O2: C,
60.26; H, 5.98; N, 19.17. Found: C, 60.18; H, 5.90; N, 19.03.]; Rf (6% EtOH/CHCl3; aluminium oxide) 0.66.
δH (500 MHz, CDCl3) 8.71 (1H, d, J 6.5 Hz, CONH), 8.56 (1H, d, J 4.6 Hz, Py CH), 8.17 (1H, d, J 7.8 Hz,
Py CH), 7.83 (1H, dt, J 7.7, 1.6 Hz, Py CH), 7.44 (1H, dd, J 7.7 Hz, 4.8 Hz, 1.0 Hz, Py CH), 6.94 (1H, br s,
CONH-CH2), 4.52 (1H, dt, J 11.5 Hz, 5.4 Hz, CHNH), 3.39-3.23 (2H, m, CH2NH), 2.57 (1H, dq, J 12.8 Hz,
4.6 Hz, NHCH-CH2), 2.00-1.91 (2H, m, lactam CH2), 1.74 (1H, tt, J 12.4 Hz, 7.8 Hz, NHCH-CH2). δC NMR
(125.7 MHz) 171.6, 164.5, 149.7, 148.2, 137.2, 126.2, 122.1, 50.4, 41.8, 27.5, 21.2. IR (KBr, ν (cm-1)): 3336,
3199 (NH), 1687 (lactam CON), 1648 (CON), 1521 (NH); MS m/z (rel. int.): 219 (29, M+), 191 (4), 174
(11), 161 (13), 147 (11), 139 (5), 134 (19), 113 (60), 106 (30), 85 (41), 78 (100), 70 (29), 51 (29).
3.4.22. N-(2’-Oxopiperidin-3’-yl)nicotinamide (8b)
25

Yield: 39 mg (36%), Pale yellow solid material, m.p. 164-165 °C; [Anal. Calcd. for C11H13N3O2: C,
ACCEPTED MANUSCRIPT
60.26; H, 5.98; N, 19.17. Found: C, 60.10; H, 6.01; N, 19.04.]; Rf (5% MeOH/CHCl3; aluminium oxide) 0.30.
δH (500 MHz, CDCl3) 9.08 (1H, d, J 1.7 Hz, Py CH), 8.74 (1H, dd, J 4.8 Hz, 1.5 Hz, Py CH), 8.18 (1H, dt, J
7.9 Hz, 2.0 Hz, Py CH), 7.54 (1H, br s, CONH), 7.40 (1H, ddd, J 8.0 Hz, 4.0 Hz, 0.8 Hz, Py CH), 6.36 (1H,
br s, CONH-CH2), 4.48 (1H, dt, J 11.5 Hz, 5.4 Hz, CHNH), 3.46-3.34 (2H, m, CH2NH), 2.67 (1H, dq, J 12.8
Hz, 4.6 Hz, NHCH-CH2), 2.05-1.97 (2H, m, lactam CH2), 1.70 (1H, tt, J 12.4 Hz, 7.8 Hz, NHCH-CH2). δC
NMR (125.7 MHz) 171.6, 165.8, 152.3, 148.4, 135.1, 129.8, 123.4, 51.0, 41.8, 27.1, 21.1. IR (KBr, ν (cm-1)):
3321, 3264 (NH), 1669 (lactam CON), 1647 (CON), 1556 (NH); MS m/z (rel. int.): 219 (20, M+), 191 (3),
174 (5), 161 (7), 149 (11), 123 (22), 113 (60), 106 (100), 78 (69), 70 (23), 51 (33).
3.4.23. N-(2’-Oxopiperidin-3’-yl)thiophene-2-carboxamide (9b)
Yield: 52 mg (46%), Beige solid material, m.p. 195-196 °C; [Anal. Calcd. for C10H12N2O2S: C, 53.55;
H, 5.39; N, 12.49. Found: C, 53.40; H, 5.47; N, 12.33.]; Rf 6% EtOH/CHCl3, aluminium oxide) 0.45. δH (500
MHz, CDCl3) 7.58 (1H, dd, J 3.8 Hz, 1.1 Hz, Tioph CH), 7.49 (1H, dd, J 5.1 Hz, 1.1 Hz, Tioph CH), 7.19
(1H, d, J 3.8 Hz, CONH), 7.08 (1H, dd, J 5.2 Hz, 3.8 Hz, Tioph CH), 6.19 (1H, br s, CONH-CH2), 4.43 (1H,
dt, J 11.5 Hz, 5.4 Hz, CHNH), 3.44-3.38 (2H, m, CH2NH), 2.67 (1H, dq, J 12.8 Hz, 4.6 Hz, NHCH-CH2),
2.05-1.97 (2H, m, lactam CH2), 1.71 (1H, tt, J 12.4 Hz, 7.8 Hz, NHCH-CH2). δC NMR (125.7 MHz) 171.7,
162.2, 138.7, 130.2, 128.4, 127.6, 51.1, 41.8, 27.2, 21.1. IR (KBr, ν (cm-1)): 3288, 3194 (NH), 1682 (br,
CON), 1540 (NH); MS m/z (rel. int.): 224 (20, M+), 206 (2), 179 (3), 154 (2), 128 (3), 113 (33), 111 (100),
87 (10), 70 (14), 53 (3).
3.4.24. N-(2’-Oxopiperidin-3’-yl)-1H-indole-5-carboxamide (10b)
Yield: 91 mg (71%), Pale brown solid material, m.p. 220-221 °C; [Anal. Calcd. for C14H15N3O2: C,
65.35; H, 5.88; N, 16.33. Found: C, 65.19; H, 5.98; N, 16.18.]; Rf 5% MeOH/CHCl3) 0.24. δH (500 MHz,
DMSO-d6) 11.33 (1H, br s, indole-NH), 8.41 (1H, d, J 7.8 Hz, Ar-H), 8.15 (1H, s, Ar-H), 7.64 (1H, d, J 8.2
Hz, Ar-H), 7.62 (1H, br s, CONH), 7.74-7.40 (2H, br s, overlapping of CONH-CH2 and Ar-H), 6.54 (1H, s,
Ar-H), 4.47-4.34 (1H, m, CHNH), 3.19 (2H, br s, CH2NH), 2.08-1.97 (1H, m, NHCH-CH2), 1.89-1.69 (3H,
br m, 3 x lactam CH). δC NMR (125.7 MHz) 170.7, 167.3, 137.9, 127.4, 127.1, 125.8, 121.0, 120.4, 111.3,
102.6, 49.9, 41.7, 28.3, 21.9. IR (KBr, ν (cm-1)): 3377 (indole-NH), 3324, 3212 (NH), 1674 (lactam CON),
1631 (CON), 1525 (NH); MS m/z (rel. int.): 257 (23, M+), 207 (6), 160 (8), 144 (100), 116 (31), 89 (12), 51
(1).
3.4.25. N-(2’-Oxopyrrolidin-3’-yl)cyclohex-1-enecarboxamide (1c)
26

Yield: 53 mg (51%), White powder, m.p. 198-199 °C; [Anal. Calcd. for C11H16N2O2: C, 63.44; H, 7.74;
ACCEPTED MANUSCRIPT
N, 13.45. Found: C, 63.30; H, 7.91; N, 13.28.]; Rf (3% MeOH/CHCl3) 0.28. δH (500 MHz, CDCl3) 6.75-6.70
(1H, m, CH=C), 6.66 (1H, br s, CONH-CH2), 6.41 (1H, d, J 4.5 Hz, CONH 1H, br s, CONH-CH2), 4.42 (1H,
ddd, J 10.7 Hz, 8.2 Hz, 5.2 Hz, CHNH), 3.47-3.36 (2H, m, CH2NH), 2.86-2.77 (1H, m, NHCH-CH2), 2.36-
2.21 (2H, br m, cyhex CH2), 2.20-2.14 (2H,m, cyhex CH2), 2.02-1.90 (1H, m, NHCH-CH2), 1.74-1.65 (2H,
m, cyhex CH2), 1.64-1.57 (2H, m, cyhex CH2). δC NMR (125.7 MHz) 176.1, 169.0, 134.7, 132.5, 50.9, 39.4,
30.2, 25.4, 24.2, 22.1, 21.5. IR (KBr, ν (cm-1)): 3248 (br, NH), 1701 (lactam CON), 1669 (CON), 1617
(C=C), 1558 (NH); MS m/z (rel. int.): 208 (57, M+), 190 (39), 165 (5), 136 (1), 126 (19), 109 (100), 99 (25),
81 (79), 53 (25).
3.4.26. N-(2’-Oxopyrrolidin-3’-yl)androst-16-ene-17-carboxamide (3c), (ca. 1/1 mixture of two
epimers)
Yield: 104 mg (54%), Beige solid material, m.p. 130-131 °C; [Anal. Calcd. for C24H36N2O2: C, 74.96;
H, 9.44; N, 7.28. Found: C, 74.90; H, 9.53; N, 7.16.]; Rf (2% EtOH/CHCl3, aluminium oxide) 0.40. δH (500
MHz, CDCl3) 6.86/6.84 (1H, br s, CONH), 6.46/6.40 (1H, dd, J 3.4 Hz, 1.7 Hz, 16 CH=C), 6.42 (1H, br s,
CONH-CH2), 4.39 (1H, ddd, J 10.7 Hz, 8.2 Hz, 5.2 Hz, CHNH), 3.47-3.33 (2H, m, CH2NH), 2.80 (1H, m,
NHCH-CH2), 2.27-2.15 (2H, m, 2 x skeleton CH), 2.01-1.89 (2H, m, overlapping of lactam CH and skeleton
CH), 1.73-0-76 (19H, br m, skeleton protons), 0.99/0.96 (3H, s, 18-CH3), 0.82 (3H, s, 19-CH3). δC NMR
(125.7 MHz) 176.2, 168.6/168.4, 149.9/149.7, 137.2137.0, 56.8/56.7, 55.1, 50.7, 47.2, 46.7/46.6, 39.5, 28.5,
36.5, 35.1/34.9, 33.8, 32.0, 31.8/31.7, 30.3/30.2, 29.0, 28.9, 26.8, 22.1, 20.7/20.6, 16.6/16.5, 12.2. IR (KBr, ν
(cm-1)): 3326 (br, NH), 1703 (lactam CON), 1655 (CON), 1530 (NH); MS m/z (rel. int.): 384 (62, M+), 369
(52), 351 (6), 302 (6), 285 (37), 269 (100), 257 (59), 207 (4), 161 (14), 147 (18), 105 (20), 91 (24), 68 (20),
55 (20).
3.4.27. (E)-N-(2-Oxopyrrolidin-3-yl)non-2-enamide (5c)
Yield: 91 mg (72%), White powder, m.p. 209-210 °C; [Anal. Calcd. for C13H22N2O2: C, 65.51; H, 9.30;
N, 11.75. Found: C, 65.40; H, 9.44; N, 11.63.]; Rf (4% MeOH/CHCl3, aluminium oxide) 0.59. δH (500 MHz,
CDCl3) 6.89 (1H, dt, J 15.2 Hz, 7.1 Hz, =CH), 6.38 (1H, br s, CONH), 6.31 (1H, br s, CONH-CH2), 5.84
(1H, dt, J 15.3 Hz, 1.3 Hz, =CH), 4.45 (1H, ddd, J 10.7 Hz, 8.2 Hz, 5.4 Hz, CHNH), 3.47-3.37 (2H, m,
CH2NH), 2.90-2.79 (1H, m, NHCH-CH2), 2.19 (2H, q, J 7.1 Hz, CH2CH3), 2.04-1.93 (1H, m, NHCH-CH2),
1.52-1.40 (2H, m, chain CH2), 1.38-1.22 (6H, br m, 3 x chain CH2), 0.90 (3H, t, J 7.1 Hz, CH2CH3). δC NMR
(125.7 MHz) 175.8, 166.7, 145.9, 122.9, 50.9, 39.3, 32.1, 31.6, 30.3, 28.8, 28.2, 22.6, 14.1. IR (KBr, ν (cm-
1)): 3276, 3199 (NH), 1695 (lactam CON), 1669 (CON), 1630 (C=C), 1560 (NH); MS m/z (rel. int.): 238 (14,
M+), 220 (3), 199 (7), 181 (9), 156 (59), 138 (47), 99 (54), 81 (27), 69 (45), 55 (100).
3.4.28. N-(2’-Oxopyrrolidin-3’-yl)benzamide (6c)
Yield: 48 mg (47%), White powder, m.p. 220-221 °C; [Anal. Calcd. for C11H12N2O2: C, 64.69; H, 5.92;
N, 13.72. Found: C, 64.61; H, 5.97; N, 13.55.]; Rf (5% MeOH/CHCl3) 0.28. δH (500 MHz, CDCl3) 7.84 (2H,
27

d, J 7.4 Hz, CHortho(Ph)), 7.52 (1H, t, J 7.4Hz, CHpara(Ph)), 7.46 (2H, t, J 7.4 Hz, CHmeta(Ph)), 6.90 (1H, d, J
3.4 Hz, CONH), 6.22 (1H, br s, CON -CHE2P), .56 (1H dd , J Hz, 8.2 Hz, 5.2 Hz, CHNH), 3.53-3.44
A
H
C
C
4 , d 10.7
TED MANUSCRIPT
(2H, m, CH2NH), 3.01-289 (1H, m, NHCH-CH2), 2.14-2.02 (1H, m, NHCH-CH2). δC NMR (125.7 MHz)
175.6, 168.0, 133.7, 131.8, 128.6, 127.1, 51.2, 39.4, 30.3. IR (KBr, ν (cm-1)): 3252 (br, NH), 1695 (lactam
CON), 1670 (CON), 1561 (NH); MS m/z (rel. int.): 204 (21, M+), 186 (4), 161 (4), 143 (2), 122 (28), 106
(100), 99 (10), 77 (55), 51 (18).
Acknowledgement: The authors thank the Hungarian Scientific Research Fund (K113177) and
GINOP-2.3.2-15-2016-00049 grant for the financial support. Johnson Matthey for the generous gift of
palladium(II) acetate and Gábor Mikle for the iodoalkene substrates. This work was supported by the ÚNKP-
17-4-II. New National Excellence Program of the Ministry of Human Capacities. The project has been
supported by the European Union, co-financed by the European Social Fund Grant no.: EFOP-3.6.1.-16-
2016-00004 entitled by Comprehensive Development for Implementing Smart Specialization Strategies at the
University of Pécs. The present scientific contribution is dedicated to the 650th anniversary of the foundation
of the University of Pécs, Hungary.
28

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