N-Heterocyclic Olefin Catalysis for the Ring Opening of Cyclic Amidine Compounds: A Pathway to the Synthesis of ?-Caprolactam- and γ-Lactam-Derived Amines

Article abstract of DOI:10.1021/acs.joc.8b02823

For the first time, 1,2-dimethyl-3-ethylimidazolium iodide (1a) catalyzes the ring opening of the bicyclic amidine system of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or DBN (1,5-diazabicyclo[4.3.0]non-5-ene) on reaction with aldehydes. The mechanism here

Full text of DOI:10.1021/acs.joc.8b02823

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Article
N-Heterocyclic olefin catalysis for the ring opening
of cyclic amidine compounds: a pathway to the
synthesis of #-caprolactam and #-lactam-derived amines
Daniela Peixoto, Gabriela Malta, Hugo Cruz, Sónia Barroso, Ana
Luisa Carvalho, Luisa Maria Ferreira, and Paula Serio Branco
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02823 • Publication Date (Web): 12 Feb 2019
Downloaded from http://pubs.acs.org on February 13, 2019
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The Journal of Organic Chemistry
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N-Heterocyclic olefin catalysis for the ring opening of cyclic amidine
compounds: a pathway to the synthesis of ε-caprolactam and γ-lac-
tam-derived amines
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Daniela Peixoto,† Gabriela Malta,† Hugo Cruz,† Sónia Barroso,‡‡ Ana Luísa Carvalho,‡‡ Luísa M. Fer-
reira,† and Paula S. Branco*,†.
†LAQV-REQUIMTE, DQ, 2829-516, Caparica, Portugal, Faculdade de Ciꢀncias e Tecnologia, Universidade NOVA de Lis-
boa, 2829-516, Caparica, Portugal.
‡‡UCIBIO-REQUIMTE, DQ, Faculdade de Ciꢀncias e Tecnologia, Universidade NOVA de Lisboa, 2829-516, Caparica, Por-
tugal
Supporting Information
ABSTRACT: For the first time, 1,2-dimethyl-3-ethylimidazolium iodide (1a) catalyzes the ring opening of the bicyclic amidine
system of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or DBN (1,5-diazabicyclo[4.3.0]non-5-ene) on reaction with aldehydes. The
mechanism here proposed involves a N-heterocyclic olefin (NHO) catalytic species that acts as a nucleophile to promote the cyclic
amidine ring opening. The resulting ε-caprolactam and γ-lactam-derived imines were obtained in moderate to excellent yields (28-
99%) and reduced to the corresponding amines by sodium borohydride. Confirmation of the imine product was achieved via single-
crystal X-ray diffraction studies.
INTRODUCTION
cases an oxidative role of 1,2-dimethyl-3-ethylimidazolium io-
dide (1a) was found with the isolation of a transient and unsta-
ble reduced species derived thereof.14 The overlap between
these two important fields, the azolium salts and the NHO spe-
cies to which it can give rise, may provide access to unknown
and unpredictable reactivity with great advance in both parts
and with a new area to which one should be paying attention,
the concept of NHOs from azolium-based salts.16,17
N-heterocyclic olefins (NHO), the alkylidene derivatives of N-
heterocyclic carbenes, emerged in the last years as promising
organocatalysts with enhanced nucleophilicity and Brønsted
basicity in result of its highly polarized C–C bond.1,2 The ex-
ceptional donor capacity of such electron-rich olefin was ex-
plored by some authors in metal complexes1,3-5 as a catalyst in
polymerization of acrylic monomers6,7 or lactone monomers8 in
transesterification reactions9 or as captors and catalyst in reac-
tions with CO2.10,11 As expected, alkylation of this 1,3-dipolar
species is feasible and was used by Beller et al.12 to prepare a
phosphine ligand for a palladium catalyst. Notwithstanding the
extensive work done with the frequently studied class of imid-
azolium-based ionic liquids (IL), very little has been published
concerning the reactivity of these azolium salts when function-
alized at the C2-position from where the NHO emerge on treat-
ment with a base.13 From our recent work we have observed an
unusual reactivity associated to NHO derived from 1,2-dime-
thyl-3-ethylimidazolium iodide (1a), namely the oxidation of
aromatic aldehydes to the corresponding carboxylic acids (2) in
the presence of a mild base14 or the synthesis of a new hetero-
arylidene-9(10H)-anthrone structure (3) (Scheme 1).15 In both
Diamines, specially 1,2-diamines or 1,4-diamines the majority
of which display C2-symmetry have a special role in coordina-
tion chemistry.18-20 The 1,3-diamine family has not been used
so often in coordination chemistry20-22 due to the limited meth-
ods documented for its synthesis. Furthermore, 1,3-diamines
are important structural motifs existing in many natural prod-
ucts with an increasing importance in pharmaceutical chemis-
try.23 They are also an important building block in synthetic or-
ganic chemistry namely as a substrate for the preparation of cy-
clic amidinium salts which are common synthetic precursors for
the preparation of N-heterocyclic carbenes (NHC).24 Even so,
limited efforts have been devoted to the development of effec-
tive synthetic approach to 1,3-diamines.25
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Scheme 1. Reactivity of 2-substituted imidazolium salt with
aldehydes
Table 1. Ring opening of DBU on reaction with benzalde-
hydes to the corresponding ε-caprolactam derived imine by
NHO catalysisa
1
2
3
4
5
6
7
8
9
entry
Time
(h)
4b
5c
1
2
(equiv)
yield
(%)
yield
(%)
yield
(%)
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Rueping et al.26 used enantiopure pyrazolidine and pyrazoline
derivatives as precursors for the preparation of chiral 1,3-dia-
mine derivatives through cleavage of the N-N bond of the py-
razolidine moiety in the presence of SmI2.26 Other methods de-
scribed for the synthesis of 1,3-diamines involved the Michael
addition of nitroalkanes to nitroalkenes 27 or the Mannich-type
reaction between aldimines and nitriles28,29 both requiring fur-
ther hydrogenation. Other methods reported in the literature are
more laborious involving the ring opening of the aziridine by
nucleophiles.30 Although scarcely reported in the literature, a
way of achieving a 1,3-diamine propane chain involves the ring
opening of cyclic amidine compounds such as DBU (1,8-di-
azabicyclo[5.4.0]undec-7-ene) or DBN (1,5-diazabicy-
clo[4.3.0]non-5-ene). The role of DBN or DBU as a sterically
hindered, weakly nucleophilic amidine type strong base and
catalyst is well known,31 especially in dehydrohalogenation re-
actions, but some reports in literature revealed their ability to
act as nucleophiles.32 Its capacity to act as nucleophile led to
some unexpected results revealed by the ring opening of the bi-
cyclic amidine reported the first time by Lambert in 199433 and
followed by a few others involving as ultimate product, ε-ca-
prolactam derivatives.34-37 The nucleophilic character of DBU
and DBN was observed on the reaction with carbonyl electro-
philic species namely, methyl esters,38 p-nitrophenyl car-
bonate,39 imidazolides40) benzoxazinones,37 on the hydrolysis
of amide carbonyls41 or even in palladium-catalyzed carbonyl-
ation reactions42 in all cases towards lactams resulting from the
ring opening of the cyclic amidine. 37,40
1
2
1
1
24
48
72
192
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24
6
6
4
9
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9
85
80
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68
80e
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-
3
1
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1
9
5
0.1
0.25
0.1
0.2
0.2
0
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17
10
0
6
22
20
0
8d
9d
10d
11
6
8
14
>99
11
-
24
aUnless otherwise noted, the reaction was conducted on a scale of
0.2 mmol of 4a, 1.2 equiv of 1a and DBU (1.2 equiv) in 5 mL of
THF at 20-25 °C; brecovered; cyield obtained by NMR integration
of the Et2O layer; dreaction performed with 1 equiv of DBU; eDBU
was identified as 20% in the Et2O layer.
The imidazolium salt remained in the aqueous phase. By thin
layer chromatography it was possible to observe, during the
course of the reaction, the presence of aldehyde which could be
due to unreacted starting material or hydrolysis of the imine
during the elution. Thus, we ran the reaction for several days
(Table 1, entries 1 to 4) without taking particular conditions to
exclude moisture from the reaction mixture. In these cases we
observed an increase on the amount of recovered aldehyde
which could be associated with hydrolysis of compound 5a.
Next, we turned our attention to a possible catalytic role of the
imidazolium 1a. The yields decreased slightly as the amount of
acid increased (Table 1, entry 1 vs entries 5 and 6). Since we
observed that the yield of the aldehyde recovered increased with
time, we reduced the time of reaction (6 h) without the imine
formation yield being affected (Table 1, entries 5 vs 8 and 9 vs
10). A blank assay was performed in the absence of 1a and no
formation of 5a was observed (Table 1, entry 11). A similar
study was performed with DBN which allowed us to achieve
the γ-lactam derived imine (6a) in very good yield 99 %. Using
benzaldehyde as substrate, the best reaction conditions found
comprised the use of 10 mol% of 1a on reaction with DBU and
20 mol% of 1a in reaction with DBN. After optimization of the
reaction conditions for both DBU and DBN, the substrate scope
was explored (Scheme 2). With aliphatic aldehydes we have
observed the GC-MS and on the NMR crude the presence of 5i
in trace amounts. The compound must be instable since the hy-
drolysis compound 8 (Scheme 3) was the major compound
identified by GC-MS together with unreacted DBU. Fortu-
nately, a crystal was obtained for compound 6b which allowed
us to confirm by X-ray crystallography the structure of the γ-
lactam derived imine (SI, Figure S1).
RESULTS AND DISCUSSION
Here we disclose a new role of NHO species as catalysts for the
ring opening of DBU or DBN on reaction with aldehydes to
form the corresponding ε-caprolactam (5) and γ-lactam (6) de-
rived imines. Initial reactions were performed with benzalde-
hyde (4a) and DBU in the presence of a mole equivalent of 1,
and unexpectedly a ring opening of the amidine system was ob-
served with the formation of the ε-caprolactam derived imine
5a in 85% yield (Table 1 entry 1). Opposite to what was previ-
ously observed by us 14 when using other bases on reactions of
4a with 1, the formation of benzoic acid (2a) was here detected
in very small amount (9%). This could correlate with the oxi-
dative ability of the 2-methylimidazolium salts as studied by
cyclic voltammetry and presents a cathodic peak (Ep between -
2.59 and -2.62 V a very small shift) (see supporting infor-
mation). The work up of the reaction involved evaporation to
dryness and wash of the crude residue with Et2O to remove the
product and unreacted aldehyde followed by acidification of the
residue with HCl 1M and extraction with dichloromethane to
remove the corresponding carboxylic acid 2a.
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Scheme 3. Proposed mechanism for the ring opening of cy-
Scheme 2. Scope of substratesa
1
clic amidine by NHO catalysis
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aUnless otherwise noted, the reaction was conducted on a scale of
0.66 mmol DBU and 4 (1 equiv) or 0.8 mmol of DBN and 4 (1
equiv) in 5 mL of THF at 30 °C for 6h. For the ε-caprolactam (5)
20 mol% of 1a were used and for the γ-lactam (6) 10 mol% of 1a
were used.
Table 2. Screening with other imidazolium saltsa
Then, we turned our attention to other imidazolium salts as 1b
and 1c. We have observed that the amount of benzoic acid in-
creased in relation to 1a (Table 2, entries 1 and 7 vs Table 1,
entry 9).
Taking in attention the results, a mechanism proposal is pre-
sented in scheme 3. After the attack of the NHO to the activated
intermediate of DBU-aldehyde (7), a ring opening of the ami-
dine ring occurs in which, after water addition, the ε-caprolac-
tam (5) is obtained and the NHO is recovered. The formation of
the ε-caprolactam ring opening product of DBU (8) was also
identified in mixtures of imine and DBU. Although initially we
though that 8 could have origin on the hydrolysis of 5, the ab-
sence of aldehyde on these samples led us to propose a catalytic
role for DBU on the hydrolysis reaction (Scheme 3) assisted by
the presence of water (no measures for the exclusion of mois-
ture were taken for the samples stored). To exclude the possible
formation of 8 by catalysis of 1a, an assay was performed be-
tween the imidazolium salt 1a and DBU in the absence of alde-
hyde. After 6h and 24h no formation of 8 was observed. Also,
resting samples of mixtures of DBU and 5a shows with time the
formation of compound 8 justifying the mechanism presented.
entry
DBN
4
1
2
5
6
or DBU
yield
(%)
yield
(%)
yield
(%)
1
2
DBUa
DBUa
DBUa
DBNb
DBNb
DBNb
DBUa
DBUa
DBUa
DBNb
DBNb
DBNb
22
22
32
73
4a
4b
4e
4a
4b
4e
4a
4b
4e
4a
4b
4e
1b
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
1c
3
4
72
72
38
5
6
7
13
65
10
29
8
9
To extend the applicability of the methodology, the compounds
were further reduced with NaBH4/PTSA to get the correspond-
ing ε-caprolactam (9) γ-lactam (10) derived amines using a very
simple procedure43 (Scheme 4).
10
11
12
78
59
66
aReaction conducted on a scale of 0.66 mmol of 4 in 5 mL of
THF at 20-25 °C with 20 mol% of 1 for the reaction conducted
with DBU (1 equiv); bReaction conducted on a scale of 0.80
mmol of 4 in 5 mL of THF at 20-25 °C 10 mol% of 1 for the
reaction conducted with DBN (1 equiv). Scheme 4. Reduction
of imines substratesa
3
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Crystallographic details: Crystals of 6b suitable for single-
Page 4 of 9
Scheme 4. Reduction of imines substratesa
1
crystal X-ray analysis grew from the oil obtained from the evap-
oration of a diethyl ether solution of 6b. Selected crystals were
covered with Fomblin (polyfluoroether oil) and mounted on a
nylon loop. The X-ray diffraction data were collected at 296(2)
K on a Bruker D8 Venture diffractometer equipped with a Pho-
ton 100 CMOS detector, using graphite monochromated Mo-
Kα radiation ( = 0.71073 Å). Data were processed using
APEX2 suite software package, which includes integration and
scaling (SAINT), absorption corrections (SADABS) and space
group determination (XPREP). Structure solution and refine-
ment were done using direct methods with the programs
SHELXS-16 inbuilt in APEX and WinGX-Version 2014.144
software packages. All non-hydrogen atoms were refined ani-
sotropically and the hydrogen atoms were inserted in idealized
positions and allowed to refine riding on the parent carbon
atom, except for the hydrogen atoms of the water molecule that
were located in the electron density map and refined isotropi-
cally. The molecular diagrams were drawn with Mercury,45 in-
cluded in the software package. Table S1 contains crystallo-
graphic experimental data and structure refinement parameters.
Selected structural parameters are listed in Table S2. CCDC
1876034 contains the supplementary crystallographic data for
this paper. The data can be obtained free of charge from The
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aUnless otherwise noted, the reaction was conducted on a scale of
0.15 to 0.20 mmol of imines 5 or 6.
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/structures.
General procedure for the synthesis of ε-caprolactam and
γ-lactam derived imines (5 and 6): In a round bottom flask
equipped with a magnetic stirrer, dry THF (C = 0.01M), DBU
or DBN (1 equiv.) and 1,2-dimethyl-3-ethylimidazolium iodide
(1) (20 mol % for DBU or 10 mol % for DBN) were stirred at
rt for 15 min. Then, the aldehyde derivative (4) (1 equiv.) was
added to the reaction mixture. The reaction was stirred at 30ºC
for 6h. The reaction was followed by TLC, eluting with a mix-
ture of CH2Cl2/ MeOH (95/5). The reaction mixture was evap-
orated to dryness and the crude was washed with ethyl ether (20
to 30 mL). The ethyl phase was evaporated under reduced pres-
sure to dryness to give the following products.
CONCLUSIONS
In summary, new families of ε-caprolactam and γ-lactam de-
rived imines were obtained in excellent yields by catalysis with
2-methylimidazolium salt derived NHO. The reactivity of 1,2-
dimethyl-3-alkyl imidazolium iodide (1) highlighted by these
unexpected results as well as by previous work from the group
underlines the broad potential of these compounds, easily pre-
pared and easy to handle, as non-passive species in effecting a
wide range of synthetic applications. The work here presented
is an interesting approach to 1,3-diamines privileged structures.
This is an important motif in natural products, but also an im-
portant building block in synthetic organic chemistry with lim-
ited efforts devoted effectively to its synthetic approach in lit-
erature.
1-(3-(Benzylideneamino)propyl)azepan-2-one (5a): From
DBU (0.05 mL, 0.34 mmol), compound 1 (16.9 mg, 0.07 mmol)
and compound 4a (34 mmL, 0.34 mmol), compound 5a was
1
obtained as a colorless oil (85.7 mg, 0.33 mmol); ƞ = 99% ; H
NMR (CDCl3, 400 MHz) δ: 8.28 (s, 1H, N=CH), 7.72-7.69 (m,
2H, ArH), 7.40-7.38 (m, 3H, ArH), 3.62 (t, J = 7.2 Hz, 2H,
CH2), 3.46 (t, J = 7.2 Hz, 2H, CH2), 3.37-3.34 (m, 2H, CH2),
2.50-2.47 (m, 2H, CH2), 1.92 (t, J = 7.2 Hz, 2H, CH2), 1.70-
1.62 (m, 6H, CH2) ppm. 13C{1H} NMR (CDCl3, 100 MHz) δ:
175.9 (C=O), 161.6 (HC=N), 136.3 (C), 130.7(CH), 128.7
(2xCH), 128.3(2xCH), 59.2 (CH2), 49.5 (CH2), 46.5 (CH2),
37.4 (CH2), 30.1 (CH2), 29.4 (CH2), 28.8 (CH2), 23.6 (CH2)
ppm. HRMS (ESI-TOF) m/z: [M]+ Calcd for C16H22N2O
258.1732; Found 258.1723.
1-(3-((4-Nitrobenzylidene)amino)propyl)azepan-2-one (5b):
From DBU (0.05 mL, 0.34 mmol), compound 1 (16.9 mg, 0.067
mmol) and compound 4b (50.6 mg, 0.34 mmol), compound 5b
was obtained as a yellow oil (100.7 mg, 0.33 mmol); ƞ = 99%;
1H NMR (CDCl3, 400 MHz) δ: 8.38 (s, 1H,N=CH), 8.26 (d, J =
8.4 Hz, 2H, ArH), 7.53 (d, J = 8.4 Hz, 2H, ArH), 3.61 (t, J = 7.2
Hz, 2H, CH2), 3.45 (t, J = 7.2 Hz, 2H, CH2), 3.37-3.35 (m, 2H,
CH2), 2.51-2.48 (m, 2H, CH2) 1.91 (t, J = 7.2 Hz, 2H, CH2),
1.72-1.63 (m, 6H, 3x CH2) ppm. 13C{1H} NMR (CDCl3, 100
MHz) δ: 175.9 (C=O), 159.4 (HC=N), 149.1 (C), 141.8 (C),
128.9 (2xCH), 124.0 (2xCH), 59.4 (CH2), 49.7 (CH2), 46.2
(CH2), 37.4 (CH2), 30.1 (CH2), 29.2 (CH2), 28.9 (CH2), 23.6
EXPERIMENTAL SECTION
General methods and materials. All the reagents and solvents
were obtained commercially and these were used without fur-
ther purification. The solvents used were dried using current la-
boratory techniques. Thin layer chromatography (TLC) was
carried out on aluminium-backed Kieselgel 60 F254 silica gel
plates (Merck). Plates were visualized either by UV light (254
and/or 366nm). Preparative layer chromatography (PLC) was
performed on Merck Kieselgel GF 254 silica gel plates with a
thickness of 0.5 mm or 1 mm. Column chromatography was
carried out using silica gel Kieselgel 60 (Merck), 70 - 230 mesh
particle size as stationary phase, in normal phase chromatog-
raphy. Ultraviolet (UV) spectroscopy spectra were recorded on
a Thermo Corporation spectrophotometer, Helius γ, on quartz
cell support. Absorption spectrum measurements were made in
the range of 220 to 400 nm. 1H and 13C NMR spectra were rec-
orded on a Bruker ARX400 at 400 and 100 MHz, respectively.
Mass spectra (MS) using the ESI-TOF or APCI technique were
obtained from Unidade de Masas e Proteómica, the University
of Santiago de Compostela, Spain.
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1
(CH2) ppm. GC-MS: tr 25.89, m/z 303. HRMS (APCI) m/z: [M
+ H]+ Calcd for C16H22N3O3 304.1656; Found 304.1654.
4-(((3-(2-Oxoazepan-1-yl)propyl)imino)methyl)benzonitrile
(5c): From DBU (0.05 mL, 0.34 mmol), compound 1 (16.9 mg,
0.067 mmol) and compound 4c (43.9 mg, 0.34 mmol), com-
pound 5c was obtained as a yellow oil (94 mg, 0.33 mmol); ƞ =
99%;1H NMR (CDCl3, 400 MHz) δ: 8.32 (s, 1H,N=CH), 7.83
(d, J = 8.0 Hz, 2H, ArH), 7.69 (d, J = 8.0 Hz, 2H, ArH), 3.66 (t,
J = 6.8 Hz, 2H, CH2), 3.46 (t, J = 6.8 Hz, 2H, CH2), 3.37-3.35
(m, 2H, CH2), 2.51-2.48 (m, 2H, CH2) 1.94 (t, J = 6.8 Hz, 2H,
CH2), 1.72-1.64 (m, 6H, 3x CH2) ppm. 13C{1H} NMR (CDCl3,
100 MHz) δ: 175.9 (C=O), 159.8 (HC=N), 140.2 (C), 132.5
(2xCH), 128.6 (2xCH), 118.7 (C), 113.9 (C), 59.3 (CH2), 49.7
(CH2), 46.3 (CH2), 37.4 (CH2), 30.1 (CH2), 29.3 (CH2), 28.9
(CH2), 23.6 (CH2) ppm. GC-MS: tr 24.82, m/z 283. HRMS
(APCI) m/z: [M + H]+ Calcd for C17H22N3O 284.1754 Found
284.1757.
1-(3-((4-Bromobenzylidene)amino)propyl)azepan-2-one (5d):
From DBU (0.05 mL, 0.34 mmol), compound 1 (16.9 mg, 0.067
mmol) and compound 4d (61.9 mg, 0.34 mmol), compound 5d
was obtained as a yellow oil (112 mg, 0.33 mmol); ƞ = 99%; 1H
NMR (CDCl3, 400 MHz) δ: 8.24 (s, 1H,N=CH), 7.59 (d, J = 8.4
Hz, 2H, ArH), 7.53 (d, J = 8.4 Hz, 2H, ArH), 3.68 (t, J = 7.2
Hz, 2H, CH2), 3.47 (t, J = 7.2 Hz, 2H, CH2), 3.38-3.36 (m, 2H,
CH2), 2.51-2.48 (m, 2H, CH2) 1.95 (t, J = 6.8 Hz, 2H, CH2),
1.72-1.64 (m, 6H, 3x CH2) ppm. 13C{1H} NMR (CDCl3, 100
MHz) δ: 175.9 (C=O), 160.4 (HC=N), 135.2 (C), 131.9
(2xCH), 129.6 (2xCH), 125.1 (C), 59.2 (CH2), 49.8 (CH2), 46.4
(CH2), 37.4 (CH2), 30.1 (CH2), 29.4 (CH2), 28.9 (CH2), 23.6
(CH2) ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C16H22BrN2O 337.0911; Found 337.0910.
was obtained as a yellow oil (50 mg, 0.17 mmol); ƞ = 51%; H
NMR (CDCl3, 400 MHz) δ: 8.24 (s, 1H, N=CH), 7.75 (s, 1H,
ArH), 7.56 (d, J = 7.6 Hz, 1H, ArH), 7.37-7.40 (m, 2H, ArH),
3.62 (t, J = 6.8 Hz, 2H, CH2), 3.46 (t, J = 6.4 Hz, 2H, CH2),
3.37-3.35 (m, 2H, CH2), 2.51-2.49 (m, 2H, CH2) 1.92 (t, J = 7.2
Hz, 2H, CH2), 1.73-1.64 (m, 6H, 3x CH2) ppm. 13C{1H} NMR
(CDCl3, 100 MHz) δ: 175.9 (C=O), 160.2 (HC=N), 138.1 (C),
134.9 (C), 130.7 (CH), 130.0 (CH), 127.8 (CH), 126.6 (CH),
59.2 (CH2), 49.8 (CH2), 46.4 (CH2), 37.5 (CH2), 30.1 (CH2),
29.4 (CH2), 28.9 (CH2), 23.6 (CH2) ppm. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C16H22ClN2O 293.1415; Found
293.1415.
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1-(3-((Furan-2-ylmethylene)amino)propyl)azepan-2-one (5h):
From DBU (0.05 mL, 0.34 mmol), compound 1 (16.9 mg, 0.067
mmol) and compound 4h (0.028 mL, 0.34 mmol), compound
5h was obtained as a yellow oil (67 mg, 0.27 mmol); ƞ = 80%;
1H NMR (CDCl3, 400 MHz) δ: 8.10 (s, 1H, N=CH), 7.50 (d, J
= 2.0 Hz, 1H, HetArH), 6.72 (d, J = 3.6 Hz, 1H, HetArH), 6.47
(dd, J = 3.6 and 2.0 Hz, 1H, HetArH), 3.59 (t, J = 6.8 Hz, 2H,
CH2), 3.44 (t, J = 7.2 Hz, 2H, CH2), 3.36-3.34 (m, 2H, CH2),
2.51-2.48 (m, 2H, CH2) 1.94 (t, J = 7.2 Hz, 2H, CH2), 1.71-1.61
(m, 6H, 3x CH2) ppm. 13C{1H} NMR (CDCl3, 100 MHz) δ:
175.9 (C=O), 151.6(C), 150.2 (HC=N), 144.8 (CH), 114.3
(CH), 111.7 (CH), 59.4 (CH2), 49.7 (CH2), 46.3 (CH2), 37.5
(CH2), 30.1 (CH2), 29.4 (CH2), 28.9 (CH2), 23.6 (CH2) ppm.
HRMS (ESI-TOF) m/z: [M
+
H]+ Calcd for
C14H21N2O2 249.1597; Found 249.15981-(3-(Benzylidene-
amino)propyl)pyrrolidin-2-one (6a): From DBN (0.05 mL,
0.40 mmol), compound 1 (16.9 mg, 0.067 mmol) and com-
pound 4a (0.041 mL, 0.40 mmol), compound 6a was obtained
1
as a colourless oil (103.5 mg, 0.40 mmol); ƞ = 99%; H NMR
1-(3-((4-Methoxybenzylidene)amino)propyl)azepan-2-one
(5e):From DBU (0.050 mL, 0.34 mmol), compound 1 (16.9mg,
0.067 mmol) and compound 4e (40.7 mmL, 0.33 mmol), com-
pound 5e was obtained as a yellow oil (75.5 mg, 0.26 mmol); ƞ
= 78%; 1H NMR (CDCl3, 400 MHz) δ: 8.21 (s, 1H,N=CH),
7.66 (d, J = 8.4 Hz, 2H, ArH), 6.91 (d, J = 8.4 Hz, 2H, ArH),
3.84 (s, 3H, OMe), 3.58 (t, J = 7.2 Hz, 2H, CH2), 3.45 (t, J =
7.2 Hz, 2H, CH2), 3.37-3.35 (m, 2H, CH2), 2.51-2.48 (m, 2H,
CH2) 1.91 (t, J = 7.2 Hz, 2H, CH2), 1.71-1.63 (m, 6H, 3x CH2)
ppm. 13C{1H}NMR (CDCl3, 100 MHz) δ: 175.9 (C=O), 161.7
(C), 160.9 (HC=N), 129.7 (2xCH), 129.3 (C), 114.1 (2xCH),
59.2 (CH2), 55.5 (OMe), 49.8 (CH2), 46.5 (CH2), 37.5 (CH2),
30.1 (CH2), 29.5 (CH2), 28.9 (CH2), 23.6 (CH2) ppm. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C17H25N2O2 289.1913;
Found 289.1911.
(CDCl3, 400 MHz) δ: 8.29 (s, 1H, N=CH), 7.72-7.71 (m, 2H,
ArH), 7.41-7.39 (m, 3H, ArH), 3.64-3.61 (m, 2H, CH2), 3.43-
3.37 (m, 4H, 2xCH2), 2.32 (t, J = 8.4 Hz, 2H, CH2), 2.00-1.93
(m, 4H, 2xCH2) ppm. 13C{1H} NMR (CDCl3, 100 MHz) δ:
175.1 (C=O), 161.7 (HC=N), 136.3 (C), 130.7 (CH), 128.7
(2xCH), 128.2 (2xCH), 59.3 (CH2), 47.3 (CH2), 40.9 (CH2),
31.2 (CH2), 28.5 (CH2), 18.0 (CH2) ppm. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C14H19N2O 231.1492; Found
231.1492.
1-(3-((4-Nitrobenzylidene)amino)propyl)pyrrolidin-2-one
(6b): From DBN (0.05 mL, 0.40 mmol), compound 1 (16.9mg,
0.067 mmol) and compound 4b (61 mg, 0.40 mmol), compound
6b was obtained as a yellow solid (66.5 mg, 0.22 mmol); ƞ =
54%; 1H NMR (CDCl3, 400 MHz) δ: 8.37 (s, 1H, N=CH), 8.26
(d, J = 8.4 Hz, 2H, ArH), 7.89 (d, J = 8.4 Hz, 2H, ArH), 3.68 (t,
J = 6.8 Hz, 2H, CH2), 3.44-3.36 (m, 4H, 2x CH2), 2.33 (t, J =
8.0 Hz, 2H, CH2), 2.04- 1.94 (m, 4H, 2x CH2) ppm. 13C{1H}
NMR (CDCl3, 100 MHz) δ: 175.2 (C=O), 159.7 (HC=N), 149.1
(C), 141.8 (C), 128.9 (2xCH), 124.0 (2xCH), 59.3 (CH2), 47.2
(CH2), 40.7 (CH2), 31.2 (CH2), 28.2 (CH2), 18.0 (CH2) ppm.
1-(3-((3-Hydroxybenzylidene)amino)propyl)azepan-2-one
(5f):; From DBU (0.05 mL, 0.34 mmol), compound 1 (16.9 mg,
0.067 mmol) and compound 4f (40.9 mg, 0.34 mmol), com-
pound 5f was obtained as a yellow oil (91 mg, 0.33 mmol); ƞ =
1
99%; H NMR (CDCl3, 400 MHz) δ: 8.19 (s, 1H, N=CH), 7.22
(s, 1H, ArH), 7.17 (t, J = 8.0 Hz, 1H, ArH), 7.08 (d, J = 7.2 Hz,
1H, ArH), 6.90 (d, J = 7.2 Hz, 1H, ArH), 3.60 (t, J = 6.8 Hz,
2H, CH2), 3.47 (t, J = 6.4 Hz, 2H, CH2), 3.37-3.31 (m, 2H, CH2),
2.54-2.49 (m, 2H, CH2) 1.92 (t, J = 7.2 Hz, 2H, CH2), 1.71-1.63
(m, 6H, 3x CH2) ppm. 13C{1H} NMR (CDCl3, 100 MHz) δ:
176.2 (C=O), 162.5 (HC=N), 158.8 (C), 137.2 (C), 129.7 (CH),
119.2 (CH), 118.9 (CH), 115.0 (CH), 58.9 (CH2), 49.8 (CH2),
46.6 (CH2), 37.3 (CH2), 30.0 (CH2), 29.2 (CH2), 28.7 (CH2),
23.4 (CH2) ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C16H23N2O2 275.1756; Found 275.1754.
HRMS (ESI-TOF) m/z: [M
+
H]+ Calcd for
C14H18N3O3 276.1343; Found 276.1346.
4-(((3-(2-Oxopyrrolidin-1-yl)propyl)imino)methyl)benzonitrile
(6c): From DBN (0.05 mL, 0.40 mmol), compound 1 (16.9mg,
67,00µmol) and compound 4c (53 mg, 0.40 mmol), compound
6c was obtained as a yellow solid (73 mg, 0.26 mmol); ƞ = 63%;
1H NMR (CDCl3, 400 MHz) δ: 8.31 (s, 1H, N=CH), 7.83 (d, J
= 8.0 Hz, 2H, ArH), 7.69 (d, J = 8.4 Hz, 2H, ArH), 3.65 (t, J =
6.8 Hz, 2H, CH2), 3.43-3.35 (m, 4H, 2x CH2), 2.33 (t, J = 8.0
Hz, 2H, CH2), 2.03- 1.92 (m, 4H, 2x CH2) ppm. 13C{1H} NMR
(CDCl3, 100 MHz) δ: 175.1 (C=O), 160.0 (HC=N), 140.1 (C),
132.6 (2xCH), 128.6 (2xCH), 118.7 (C), 114.0 (C), 59.2 (CH2),
47.2 (CH2), 40.7 (CH2), 31.2 (CH2), 28.2 (CH2), 18.0 (CH2)
1-(3-((3-Chlorobenzylidene)amino)propyl)azepan-2-one (5g):
From DBU (0.05 mL, 0.34 mmol), compound 1 (16.9mg, 0.067
mmol) and compound 4g (0.039mL, 0.34 mmol), compound 5g
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The Journal of Organic Chemistry
H]+ Calcd for
+ was dried over anhydrous Na2SO4, filtered and concentrated to
Page 6 of 9
ppm. HRMS (ESI-TOF) m/z: [M
C15H18N3O 256.1444; Found 256.1446.
1
give the following products.
1-(3-((4-Bromobenzylidene)amino)propyl)pyrrolidin-2-one
(6d): From DBN (0.05 mL, 0.40 mmol), compound 1 (16.9 mg,
0.067 mmol) and compound 4d (74.9 mg, 0.40 mmol), com-
pound 6d was obtained as a brown oil (121.6 mg, 0.36 mmol);
1-(3-(Benzylamino)propyl)azepan-2-one (9a): From compound
5a (50 mg, 0.19 mmol), sodium borohydride (7.3 mg, 0.19
mmol) and p-toluenesulfonic acid monohydrate (36.8 mg, 0.19
mmol), compound 9a was obtained as a colourless oil (31.4 mg,
0.12 mmol); ƞ = 62%; 1H NMR (CDCl3, 400 MHz) δ: 7.16-
7.28 (m, 5H, ArH), 3.70 (s, 2H, CH2), 3.34 (t, J = 6.8 Hz, 2H,
CH2), 3.23-3.20 (m, 2H, CH2), 2.53 (t, J = 6.8 Hz, 2H, CH2),
2.42-2.39 (m, 2H, CH2), 1.67-1.50 (m, 8H, 4xCH2) ppm.
13C{1H} NMR (CDCl3, 100 MHz) δ: 176.2 (C=O), 139.4 (C),
128.4(2xCH), 128.4 (2xCH), 127.1(CH), 53.8 (CH2), 49.6
(CH2), 45.9 (CH2), 45.7 (CH2), 37.2 (CH2), 30.0 (CH2), 28.5
(CH2), 27.9 (CH2), 23.4 (CH2) ppm. HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C16H25N2O 261.1961; Found 261.1963.
4-(((3-(2-Oxoazepan-1-yl)propyl)amino)methyl)benzonitrile
(9c): From compound 5c (50 mg, 0.18 mmol), sodium bo-
rohydride (6.7 mg, 0.18 mmol) and p-toluenesulfonic acid mo-
nohydrate (33.6 mg, 0.18 mmol), compound 9c was obtained as
2
3
4
5
6
7
8
9
1
ƞ = 89%; H NMR (CDCl3, 400 MHz) δ: 8.23 (s, 1H, N=CH),
7.59 (d, J = 8.4 Hz, 2H, ArH), 7.52 (d, J = 8.4 Hz, 2H, ArH),
3.60 (t, J = 6.8 Hz, 2H, CH2), 3.42-3.35 (m, 4H, 2x CH2), 2.32
(t, J = 8.0 Hz, 2H, CH2), 2.02- 1.90 (m, 4H, 2x CH2) ppm.
13C{1H} NMR (CDCl3, 100 MHz) δ: 175.1 (C=O), 160.6
(HC=N), 153.1 (C), 132.0 (2xCH), 129.6 (2xCH), 125.1 (C),
59.2 (CH2), 47.2 (CH2), 40.8 (CH2), 31.2 (CH2), 28.3 (CH2),
18.0 (CH2) ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C14H18BrN2O 309.0594; Found 309.0597.
1-(3-((4-Methoxybenzylidene)amino)propyl)pyrrolidin-2-one
(6e): From DBN (0.05 mL, 0.40 mmol), compound 1 (16.9mg,
0.067 mmol) and compound 4e (0.049 mL, 0.40 mmol), com-
pound 6e was obtained as a brown oil (115.7 mg, 0.40 mmol);
ƞ = 99%; 1H NMR (CDCl3, 400 MHz) δ: 8.20 (s, 1H, N=CH),
7.64 (d, J = 8.4 Hz, 2H, ArH), 6.90 (d, J = 8.4 Hz, 2H, ArH),
3.83 (s, 3H, OMe), 3.58 (t, J = 6.8 Hz, 2H, CH2), 3.42-3.35 (m,
4H, 2x CH2), 2.31 (t, J = 8.0 Hz, 2H, CH2), 2.01- 1.84 (m, 4H,
2x CH2) ppm. 13C{1H} NMR (CDCl3, 100 MHz) δ: 175.1
(C=O), 161.7 (C-OMe), 161.1 (HC=N), 129.7 (2xCH), 129.2
(C), 114.1 (2xCH), 59.2 (CH2), 55.5 (OMe), 47.2 (CH2), 40.9
(CH2), 31.2 (CH2), 28.5 (CH2), 18.0 (CH2) ppm. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C15H21N2O2 261.1600; Found
261.1598.
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1
a yellow oil (40.3 mg, 0.14 mmol); ƞ = 80%; H NMR (CDCl3,
400 MHz) δ: 7.56 (d, J = 7.6 Hz, 2H, ArH), 7.42 (d, J = 7.6 Hz,
2H, ArH), 3.78 (s, 2H, CH2), 3.41 (br s, 2H, CH2), 3.26 (br s,
2H, CH2), 2.53 (br s, 2H, CH2), 2.45 (br s, 2H, CH2), 1.67 (br s,
4H, 2xCH2), 1.59 (br s, 4H, 2xCH2) ppm. 13C{1H} NMR
(CDCl3, 100 MHz) δ: 176.1 (C=O), 146.1 (C), 132.1 (2xCH),
128.7 (2xCH), 119.0 (CN), 110.5 (C), 53.4 (CH2), 49.4 (CH2),
45.8 (CH2), 45.4 (CH2), 37.1 (CH2), 29.9 (CH2), 28.5 (CH2),
28.0 (CH2), 23.4 (CH2) ppm. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C17H24N3O 286.1916; Found 286.1916.
1-(3-((3-Chlorobenzylidene)amino)propyl)pyrrolidin-2-one
(6g): From DBN (0.05 mL, 0.40 mmol), compound 1 (16.9mg,
0.067 mmol) and compound 4g (0.048 mL, 0.40 mmol), com-
pound 6g was obtained as a colourless oil (116.5 mg, 0.39
1-(3-((4-Bromobenzyl)amino)propyl)azepan-2-one (9d): From
compound 5d (50 mg, 0.15 mmol), sodium borohydride (5.6
mg, 0.048 mmol) and p-toluenesulfonic acid monohydrate
(28.2 mg, 0.15 mol), compound 9d was obtained as a light
1
1
mmol); ƞ = 98%; H NMR (CDCl3, 400 MHz) δ: 8.23 (s, 1H,
brown oil (26.4 mg, 0.078 mmol); ƞ = 52%; H NMR (CDCl3,
N=CH), 7.74 (s, 1H, ArH), 7.56 (d, J = 7.2 Hz, 1H, ArH), 7.38-
7.30 (m, 2H, ArH), 3.62 (t, J = 6.8 Hz, 2H, CH2), 3.43-3.35 (m,
4H, 2x CH2), 2.33 (t, J = 8.0 Hz, 2H, CH2), 2.03-1.90 (m, 4H,
2x CH2) ppm. 13C{1H} NMR (CDCl3, 100 MHz) δ: 175.1
(C=O), 160.3 (HC=N), 138.0 (C), 134.9 (C), 130.7 (CH), 130.0
(CH), 127.8 (CH), 126.6 (CH), 59.2 (CH2), 47.3 (CH2), 40.8
(CH2), 31.2 (CH2), 28.4 (CH2), 18.0 (CH2) ppm. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C14H18ClN2O 265.1102; Found
265.1102.
1-(3-((Furan-2-ylmethylene)amino)propyl)pyrrolidin-2-one
(6h): From DBN (0.05 mL, 0.40 mmol), compound 1 (16.9 mg,
0.067 mmol) and compound 4h (0.034 mL, 0.40 mmol), com-
pound 6h was obtained as a colourless oil (24.6mg, 0.099
mmol); ƞ = 28%; 1H NMR (CDCl3, 400 MHz) δ: 8.09 (s, 1H,
N=CH), 7.49 (br s, 1H, HetArH), 6.72 (br s, 1H, HetArH), 6.46
(br s, 1H, HetArH), 3.58 (t, J = 6.8 Hz, 2H, CH2), 3.42-3.34 (m,
4H, 2x CH2), 2.33 (t, J = 8.0 Hz, 2H, CH2), 2.01-1.94 (m, 4H,
2x CH2) ppm. 13C{1H} NMR (CDCl3, 100 MHz) δ: 175.1
(C=O), 151.5 (C), 150.4 (HC=N), 144.9 (CH), 114.4 (CH),
111.7 (CH), 59.4 (CH2), 47.2 (CH2), 40.8 (CH2), 31.2 (CH2),
28.4 (CH2), 18.0 (CH2) ppm. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C12H17N2O2 221.1282; Found 221.1285.
400 MHz) δ: 7.42 (d, J = 7.6 Hz, 2H, ArH), 7.19 (d, J = 7.6 Hz,
2H, ArH), 3.70 (s, 2H, CH2), 3.41 (br s, 2H, CH2), 3.28-3.26
(m, 2H, CH2), 2.55 (br s, 2H, CH2), 2.49-2.46 (m, 2H, CH2),
1.66-1.67 (m, 4H, 2xCH2), 1.63-1.60 (m, 4H, 4xCH2) ppm.
13C{1H} NMR (CDCl3, 100 MHz) δ: 176.2 (C=O), 139.1 (C),
131.5 (2xCH), 130.1 (2xCH), 120.8 (C), 53.3 (CH2), 49.6
(CH2), 45.9 (CH2), 45.6 (CH2), 37.2 (CH2), 30.0 (CH2), 28.6
(CH2), 28.1 (CH2), 23.5 (CH2) ppm. HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C16H24BrN2O 339.1068; Found 339.1067.
1-(3-((4-Methoxybenzyl)amino)propyl)azepan-2-one
(9e):
From compound 5e (50 mg, 0.17 mmol), sodium borohydride
(6.6mg, 0.17 mmol) and p-toluenesulfonic acid monohydrate
(32.9 mg, 0.17 mmol), compound 9e was obtained as a brown
1
oil (33.8 mg, 0.12 mmol); ƞ = 67%; H NMR (CDCl3, 400
MHz) δ: 7.22 (d, J = 8.4 Hz, 2H, ArH), 6.82 (d, J = 8.4 Hz, 2H,
ArH), 3.76 (s, 3H, OMe), 3.70 (s, 2H, CH2), 3.40 (br s, 2H,
CH2), 3.27 (br s, 2H, CH2), 2.58 (br s, 2H, CH2), 2.46 (br s, 2H,
CH2), 1.70-1.68 (m, 4H, 2xCH2), 1.60 (br s, 4H, 4xCH2) ppm.
13C{1H} NMR (CDCl3, 100 MHz) δ: 176.2 (C=O), 158.7 (C-
OMe), 131.8 (C), 129.6 (2xCH), 113.8 (2xCH), 55.3 (OMe),
53.2 (CH2), 49.6 (CH2), 45.8 (CH2), 45.7 (CH2), 37.2 (CH2),
30.0 (CH2), 28.6 (CH2), 27.9 (CH2), 23.5 (CH2) ppm. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C17H27N2O2 291.2067;
Found 291.2067.
General procedure for the synthesis of ε-caprolactam and
γ-lactam derived amines (9 and 10):43 The sodium borohy-
dride (1 equiv.) and p-toluenesulfonic acid monohydrate (1
equiv.) were added to ε-caprolactam (5) or γ-lactam compound
(6) (1 equiv.) in glass vails for 10–15 min at room temperature
under solvent-free conditions. The reaction mixture was
quenched with saturated aqueous solution of NaHCO3 (10 ml)
and extracted with CH2Cl2 (3x10 mL). The combined extract
1-(3-((3-Hydroxybenzyl)amino)propyl)azepan-2-one
(9f):
From compound 5f (50 mg, 0.18 mol), sodium borohydride (6.9
mg, 0.18 mmol) and p-toluenesulfonic acid monohydrate (34.7
mg, 0.18 mmol), compound 9f was obtained as a colourless oil
(22.3 mg, 0.080 mmol); ƞ = 44%; 1H NMR (CDCl3, 400 MHz)
δ: 7.32 (br s, 1H, ArH), 7.24 – 7.20 (m, 3H, ArH),4.65 (s, 1H,
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The Journal of Organic Chemistry
NH), 3.74 (s, 2H, CH2), 3.42 (t, J = 6.8 Hz, 2H, CH2), 3.30 –
(ESI-TOF) m/z: [M + H]+ Calcd for C14H20BrN2O 311.0752;
1
2
3
4
5
6
7
8
3.27 (m, 2H, CH2), 2.56 (t, J = 6.8 Hz, 2H, CH2), 2.50 – 2.47
(m, 2H, CH2), 1.73-1.67 (m, 4H, 2xCH2), 1.64 – 1.58 (m, 4H,
4xCH2) ppm. 13C{1H} NMR (CDCl3, 100 MHz) δ: 176.9
(C=O), 157.5 (C), 139.8 (C), 129.7 (CH), 119.8 (CH), 115.7
(CH), 115.0 (CH), 53.4 (CH2), 49.6 (CH2), 45.7 (CH2), 45.6
(CH2), 37.1 (CH2), 30.0 (CH2), 28.5 (CH2), 27.4 (CH2), 23.4
(CH2) ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C16H25N2O2 277.1914; Found 277.1911.
Found 311.0754.
1-(3-((4-Methoxybenzyl)amino)propyl)pyrrolidin-2-one (10e):
From compound 6e (50 mg, 0.19 mmol), sodium borohydride
(7.3 mg, 0.19 mmol) and p-toluenesulfonic acid monohydrate
(36.5 mg, 0.19 mmol), compound 10e was obtained as a brown
1
oil (23.3 mg, 0.089 mmol); ƞ = 46%; H NMR (CDCl3, 400
MHz) δ: 7.25 (d, J = 8.4 Hz, 2H, ArH), 6.84 (d, J = 8.4 Hz, 2H,
ArH), 3.78 (s, 3H, OMe), 3.75 (s, 2H, CH2), 3.37 – 3.31 (m, 4H,
2xCH2), 2.64 (t, J = 6.8 Hz, 2H, CH2), 2.36 (t, J = 8.0 Hz, 2H,
CH2), 2.03-1.964 (m, 2H, CH2), 1.81-1.76 (m, 2H, CH2) ppm.
13C{1H} NMR (CDCl3, 100 MHz) δ: 175.7 (C=O), 159.1 (C-
OMe), 131.7 (C), 130.0 (2xCH), 114.0 (2xCH), 55.4 (OMe),
53.0 (CH2), 47.5 (CH2), 45.7 (CH2), 40.2 (CH2), 31.0 (CH2),
26.8 (CH2), 18.0 (CH2) ppm. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C15H23N2O2 263.1758; Found 263.1754.
1-(3-((3-Chlorobenzyl)amino)propyl)pyrrolidin-2-one (10g):
From compound 6g (50 mg, 0.19 mmol), sodium borohydride
(7.1 mg, 0.19 mmol) and p-toluenesulfonic acid monohydrate
(35.9 mg, 0.19mol), compound 10g was obtained as a colour-
less oil (25.8 mg, 0.097 mmol); ƞ = 51%; 1H NMR (CDCl3, 400
MHz) δ: 7.37 – 7.28 (m, 4H, ArH), 3.86 (m, 2H, CH2), 3.37 –
3.31 (m, 4H, 2xCH2), 2.65 (t, J = 6.8 Hz, 2H, CH2), 2.36 (t, J =
8.0 Hz, 2H, CH2), 2.02 - 1.95 (m, 2H, CH2), 1.86 - 1.79 (m, 2H,
CH2) ppm. 13C{1H} NMR (CDCl3, 100 MHz) δ: 175.6 (C=O),
141.0 (C), 134.4 (C), 129.9 (CH), 128.6 (CH), 127.6 (CH),
126.7 (C), 53.1 (CH2), 47.4 (CH2), 45.9 (CH2), 40.1 (CH2), 31.0
(CH2), 27.0 (CH2), 18.0 (CH2) ppm. HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C14H20ClN2O 267.1260; Found 267.1259.
9
1-(3-((3-Chlorobenzyl)amino)propyl)azepan-2-one (9g): From
compound 5g (50 mg, 0.17 mmol), sodium borohydride (6.5
mg, 0.17 mmol) and p-toluenesulfonic acid monohydrate (32.5
mg, 0.17 mmol), compound 9g was obtained as a colourless oil
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(17.8 mg, 0.06 mmol); ƞ = 35%; H NMR (CDCl3, 400 MHz)
δ: 7.10 (t, J = 7.6 Hz, 1H, ArH), 6.88 (br s, 1H, ArH), 6.74 (t, J
=8.4 Hz, 2H, ArH), 3.71 (s, 2H, CH2), 3.44 (t, J = 7.2 Hz, 2H,
CH2), 3.29 – 3.27 (m, 2H, CH2), 2.61 (t, J = 6.4 Hz, 2H, CH2),
2.51 – 2.48 (m, 2H, CH2), 1.69-1.67 (m, 4H, 2xCH2), 1.61 –
1.58 (m, 4H, 4xCH2) ppm. 13C{1H} NMR (CDCl3, 100 MHz)
δ: 176.4 (C=O), 134.3 (C), 128.5 (CH), 127.5 (C), 127.3 (CH),
127.0 (CH), 126.6 (CH), 53.3 (CH2), 49.7 (CH2), 45.8 (CH2),
45.7 (CH2), 37.2 (CH2), 30.1 (CH2), 28.6 (CH2), 27.9 (CH2),
23.5 (CH2) ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C16H24ClN2O 295.1572; Found 295.1570.
1-(3-(Benzylamino)propyl)pyrrolidin-2-one (10a): From com-
pound 6a (50 mg, 0.22 mmol), sodium borohydride (8.2 mg,
0.22 mmol) and p-toluenesulfonic acid monohydrate (41.3 mg,
0.22 mmol), compound 10a was obtained as a colourless oil (38
mg, 0.16 mmol); ƞ = 70%; 1H NMR (CDCl3, 400 MHz) δ: 7.34-
7.29 (m, 5H, ArH), 4.65 (s, 1H, NH), 3.75 (s, 2H, CH2), 3.38 –
3.29 (m, 4H, 2xCH2), 2.58 (t, J = 6.8 Hz, 2H, CH2), 2.33 (t, J =
8.0 Hz, 2H, CH2), 2.00-1.92 (m, 2H, CH2), 1.75-1.68 (m, 2H,
CH2) ppm. 13C{1H} NMR (CDCl3, 100 MHz) δ: 175.3 (C=O),
139.5 (C), 128.5 (2xCH), 128.4 (2xCH), 127.0 (CH), 53.9
(CH2), 47.2 (CH2), 46.0 (CH2), 40.2 (CH2), 31.0 (CH2), 27.2
(CH2), 17.9 (CH2) ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C14H21N2O 233.1648; Found 233.1648.
4-(((3-(2-Oxopyrrolidin-1-yl)propyl)amino)methyl)benzoni-
trile (10c): From compound 6c (50 mg, 0.20 mmol), sodium
borohydride (7.4 mg, 0.20 mmol) and p-toluenesulfonic acid
monohydrate (37.3 mg, 0.20 mmol), compound 10c was obtai-
ned as a colourless oil (25.7 mg, 0.10 mmol); ƞ = 50%; 1H NMR
(CDCl3, 400 MHz) δ: 7.62 (d, J = 8.0 Hz, 2H, ArH), 7.54 (d, J
= 8.0 Hz, 2H, ArH), 4.77 (s, 1H, NH), 3.90 (s, 2H, CH2), 3.40
– 3.25 (m, 4H, 2xCH2), 2.66 (t, J = 6.8 Hz, 2H, CH2), 2.40 (t, J
= 8.0 Hz, 2H, CH2), 2.07-1.99 (m, 2H, CH2), 1.87-1.82 (m, 2H,
CH2) ppm. 13C{1H} NMR (CDCl3, 100 MHz) δ: 176.9 (C=O),
146.4 (C), 132.7 (2xCH), 128.1 (C), 127.2 (2xCH), 118.6 (CN),
52.3 (CH2), 48.0 (CH2), 45.4 (CH2), 39.9 (CH2), 30.9 (CH2),
25.6 (CH2), 18.1 (CH2) ppm. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C15H20N3O 258.1597; Found 258.601.
1-(3-((4-Bromobenzyl)amino)propyl)pyrrolidin-2-one (10d):
From compound 6d (50 mg, 0.16 mmol), sodium borohydride
(6.1 mg, 0.16 mmol) and p-toluenesulfonic acid monohydrate
(30.8 mg, 0.16 mmol), compound 10d was obtained as a light
brown oil (25.7 mg, 0.083 mmol); ƞ = 51%; 1H NMR (CDCl3,
400 MHz) δ: 7.41 (d, J = 8.8 Hz, 2H, ArH), 7.20 (d, J = 8.8 Hz,
2H, ArH), 3.72 (s, 2H, CH2), 3.35 – 3.32 (m, 4H, 2xCH2), 2.57
(t, J = 6.8 Hz, 2H, CH2), 2.35 (t, J = 8.0 Hz, 2H, CH2), 2.02-
1.90 (m, 2H, CH2), 1.98-1.71 (m, 2H, CH2) ppm. 13C{1H}NMR
(CDCl3, 100 MHz) δ: 175.8 (C=O), 131.8 (2xCH), 131.1 (C),
130.5 (2xCH), 128.7 (C), 52.9 (CH2), 47.5 (CH2), 45.7 (CH2),
40.1 (CH2), 31.0 (CH2), 26.7 (CH2), 18.0 (CH2) ppm. HRMS
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Crystallographic data, voltamograms, NMR and mass spectra for
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
* Email: paula.branco@fct.unl.pt
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manu-
script.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the LAQV which is financed by na-
tional funds from FCT/MEC (UID/QUI/50006/2013) and co-
financed by the ERDF under the PT2020 Partnership Agreement
(POCI-01-0145- 710-FEDER-007265), and by UCIBIO which is
financed
by
national
funds
from
FCT/MEC
(UID/Multi/04378/2013) and co-financed by the ERDF under the
PT2020 Partnership Agreement (POCI-01-0145-FEDER-007728).
The National NMR Facility and the SCXRD facility are supported
by Fundação para
BQB/0230/2012 and RECI/BBB-BEP/0124/2012, respectively).
a Ciência e Tecnologia (RECI/BBB-
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Page 8 of 9
We acknowledge the Laboratório de Análises REQUIMTE for the
technical support for the mass spectrometry analyses.
buchwald-hartwig aminations, and sonogashira reactions,
Angew. Chem. Int. Edit. 2010, 49, 8988-8992.
(13) Wang, B.; Qin, L.; Mu, T.; Xue, Z.; Gao, G., Are
ionic liquids chemically stable?, Chem. Rev 2017, 7113–
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