A Mechanochemical-Assisted Oxidation of Amines to Carbonyl Compounds and Nitriles

Article abstract of DOI:10.1002/ejoc.201700689

A mild, efficient, metal- and solvent-free oxidation of primary amines to aldehydes, ketones, and nitriles under ball-milling conditions is presented. This method has proved to be compatible with various functional groups and only requires easily accessible starting materials. Simple purification of the reaction mixtures by short-column chromatography afforded pure aldehydes, ketones, and nitriles as products.

Full text of DOI:10.1002/ejoc.201700689

DOI: 10.1002/ejoc.201700689
Full Paper
Mechanochemical Oxidation
A Mechanochemical-Assisted Oxidation of Amines to Carbonyl
Compounds and Nitriles
Silvia Gaspa,[a] Andrea Porcheddu,[b] Antonio Valentoni,[a] Sebastiano Garroni,[c,d]
Stefano Enzo,[a] and Lidia De Luca*[a]
Abstract: A mild, efficient, metal- and solvent-free oxidation of easily accessible starting materials. Simple purification of the
primary amines to aldehydes, ketones, and nitriles under ball-
milling conditions is presented. This method has proved to be
compatible with various functional groups and only requires
reaction mixtures by short-column chromatography afforded
pure aldehydes, ketones, and nitriles as products.
Introduction
from readily available and abundant precursors like amines. The
existing methodologies, despite their efficiency, suffer from the
required use of stoichiometric amounts of toxic metal-contain-
ing reagents, such as KMnO4,[3] argentic picolinate,[4] ZnCr2O7
trihydrate,[5] and nicotinium dichromate,[6] or palladium-,[7] cop-
per-,[8] and ruthenium-based[9] catalysts, and toxic solvents.
In addition, these methodologies are sometimes affected by
poor yields, overoxidation of the carbonyl products to carb-
oxylic acids, or the formation of imines as side-products. For
the above-mentioned reasons, new procedures, run under neat
and metal-free conditions, would be particularly desirable and
attractive, especially to avoid toxic metal contamination of the
final products and the use of toxic and volatile organic solvents.
Nitriles are used as versatile intermediates in organic synthe-
sis, as they can be readily converted into carboxylic acids, es-
ters, and amides. Different methodologies have been devel-
oped for their synthesis,[10] and, of these, the preparation of
nitriles from amines appears to be the most direct and suitable.
However, the selective oxidation of primary amines to nitriles
presents many difficulties due to the fact that amines are sub-
ject to a variety of oxidative processes that yield an array of
products.[11] Ruthenium-[12] and copper-catalyzed[13] oxidations
of amines to nitriles have recently been reported, but, despite
their large substrate scope, they suffer from low selectivity, the
use of toxic solvents, and drastic reaction conditions. Other in-
teresting metal-free procedures have been reported, but, even
if they have a large substrate scope and are high-yielding, they
demand the use of large excesses of oxidants and bases, which
makes them impractical for large-scale synthesis.[14]
The oxidation of amines is a potent tool for the production of
a broad range of available synthetic intermediates, such as
imines, amides, oximes, nitro compounds, nitriles, aldehydes,
and ketones (Scheme 1).[1]
Scheme 1. Oxidation of amines.
The conventional route to aldehydes and ketones involves
the oxidation of primary and secondary alcohols,[2] but a chal-
lenging alternative is the synthesis of carbonyl compounds
[a] Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari,
via Vienna 2, 07100 Sassari, Italy
E-mail: ldeluca@uniss.it
https://www.dcf.uniss.it/it
[b] Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di
Cagliari, Cittadella Universitaria,
09042 Monserrato, Italy
[c] International Research Centre in Critical Raw Materials-ICCRAM,
University of Burgos,
Plaza Misael Banuelos s/n, 09001 Burgos, Spain
[d] Advanced Materials, Nuclear Technology and Applied Bio/Nanotechnology,
Consolidated Research Unit UIC-154, University of Burgos,
Hospital del Rey s/n, 09001 Burgos, Spain
In this context, ball-milling synthesis has attracted significant
interest in the scientific community due to its advantages over
traditional solution-based methods.[15] The major benefit of this
technology is that it is solvent-free and minimizes traditional
workup procedures.[16] Higher yields and selectivity, fewer by-
products, and minimum purification requirements are addi-
tional benefits of this procedure.[17] For these reasons we have
decided to investigate a new approach to the oxidation of
amines under ball-milling conditions.[18]
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201700689.
Eur. J. Org. Chem. 2017, 5519–5526
5519
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Results and Discussion
was performed with benzylamine (1a, 1.5 mmol; Scheme 2) in
the presence of N-chlorosuccinimide (2, 3 mmol; Scheme 2)
under solvent-free (neat) conditions at room temperature for
15 min. Then triethylamine (2.25 mmol) was added, and the
reaction mixture was stirred under solvent-free (neat) condi-
tions at room temperature for 20 min. Benzaldehyde (5a) was
obtained in 9 % yield after acid hydrolysis.
Oxidation of Primary Benzylamine to Carbonyl
Compounds
As part of our on-going efforts to design new synthetic meth-
odologies for the preparation of aldehydes and ketones,[19] we
have developed a highly useful procedure for converting
primary amines into aldehydes and ketones under ball-milling
and solvent-free conditions at room temperature. To the best
of our knowledge, this is the first example of an oxidative trans-
formation of amines to carbonyl compounds by a mechano-
chemical-assisted procedure.
Scheme 2. Oxidation of benzylamine to benzaldehyde under neat conditions.
We started our investigation by mixing benzylamine (1a,
1.5 mmol) with N-chlorosuccinimide[20] [NCS (2), 3 mmol] at
room temperature for 10 min (Table 1), sealing the two rea-
gents in a zirconia jar (50 mL) containing two balls (d =
11.2 mm) of the same material. The corresponding dichloro-
amine 3a was quantitatively formed. Then triethylamine
(4.5 mmol) was added, and the mixture was subjected to me-
chanical treatment at room temperature for a further 10 min.
Upon completion of the ball-milling process and subsequent
hydrolysis carried out with 5 % HCl(aq), benzaldehyde (5a) was
obtained in 66 % yield (Table 1, Entry 1). To find the optimum
reaction conditions, the quantity of triethylamine was de-
creased to 3.0 mmol (Table 1, Entry 2) and 2.25 mmol (Table 1,
Entry 3), and the desired aldehyde 5a was obtained in yields of
70 and 82 %, respectively. Different bases were also screened:
Pyridine (3.0 mmol; Table 1, Entry 4) gave the product 5a in
Having optimized the reaction conditions (Table 1, Entry 3),
the scope of the reaction was investigated (Scheme 3). In gen-
eral, all the reactions proceeded without any significant side-
40 % yield, whereas NaOHaq (2 mL, 1.5
M, 3 mmol; Table 1,
Entry 5), K2CO3 (4.5 mmol; Table 1, Entry 6), and MgO (4.5 mmol;
Table 1, Entry 7) did not furnish benzaldehyde (5a), but the
dichloroamine 3a was recovered.
Table 1. Screening of reaction conditions.
Entry
Base
Amount of base [mmol]
Yield[a] [%]
1
2
3
4
5
6
7
NEt3
NEt3
NEt3
pyridine
NaOHaq
K2CO3
MgO
4.5
3.0
2.25
3.0
3.0
4.5
4.5
66
70
82
40
–
–
–
[a] Yield refers to the isolated product.
Experiments to compare the reaction under neat conditions
and ball milling were carried out, which revealed the ball-mill-
ing process to give a better performance. Thus, the reaction
Scheme 3. Oxidation of amines to aldehydes: Scope of the reaction with
respect to benzylamines.
Eur. J. Org. Chem. 2017, 5519–5526
www.eurjoc.org
5520
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
products, no overoxidation of the aldehydes to carboxylic acids
Finally, the gram-scale synthesis of product 5a was per-
was observed, and the corresponding carbonyl compounds 5a– formed. Under the optimized conditions, benzylamine (1a,
m were obtained in satisfactory yields.
1.0 g, 7.1 mmol) was mixed with N-chlorosuccinimide [NCS (2),
1.89 g, 14.1 mmol] and then milled in a zirconia jar (50 mL) for
10 min. The corresponding dichloroamine 3a was quantitatively
formed. Then triethylamine (1.48 mL, 10.6 mmol) was added,
and the mixture was subjected to mechanical treatment at
room temperature for a further 10 min. Upon completion of the
ball-milling process and subsequent hydrolysis carried out with
5 % HCl(aq), benzaldehyde (5a) was obtained in 83 % yield. The
yield and purity were analogous to those of the small-scale
reaction, which indicates the flexibility and scalability of the
methodology.
The reactions of benzylamines with electron-donating sub-
stituents on the aromatic ring (Scheme 3, products 5b–5d, 5j,
and 5k) gave better results than amines bearing electron-with-
drawing substituents (Scheme 3, products 5e–5i). Benzylamines
bearing a substituent at the ortho position are also suitable
substrates for this process (Scheme 3, product 5k).
The reactions carried out with benzylamines bearing a halide
substituent on the aromatic ring (Scheme 3, products 5e, 5f,
and 5l) gave the corresponding aldehydes, which could be fur-
ther transformed by traditional cross-coupling reactions. The
oxidation of 1,2,3,4-tetrahydroisoquinoline, a cyclic amine,
notably gave selectively only 3,4-dihydroisoquinoline, the corre-
sponding conjugated cyclic imine (Scheme 3, product 5m). The
procedure was applied to aliphatic amines, but at the end of
the entire procedure the corresponding N,N-dichloroamines
were recovered and not the corresponding aldehydes.
α-Substituted benzylamines were also successfully trans-
formed into the corresponding ketones by this oxidative proce-
dure. Both symmetrical and unsymmetrical α-substituted
benzylamines were easily oxidized to the corresponding ket-
ones (Scheme 4, products 5n–5u). α-Substituted benzylamines
bearing both electron-donating and -withdrawing substituents
on the aromatic ring worked well in this procedure.
Oxidation of Primary Benzylic Amines to Nitriles
After the successful oxidation of primary benzylic amines to
aldehydes and ketones, we investigated the possibility of trans-
forming amines into nitriles under ball-milling and solvent-free
conditions at room temperature. The same methodology used
to oxidize the amines to carbonyl compounds was employed
to allow a one-pot oxidation of amines to nitriles but with an
increase in the amount of triethylamine and ball-milling time.
We started our investigation by treating benzylamine (1a,
1.5 mmol) with N-chlorosuccinimide (2, 3 mmol) in a shaker mill
consisting of a ZrO2 milling jar (50 mL) containing two balls
(d = 11.2 mm) of the same material at room temperature for
10 min (Scheme 5). The corresponding dichloroamine 3a was
quantitatively formed. Then triethylamine (4.5 mmol) was
added, and the mixture was subjected to ball milling at room
temperature for 20 min. Upon completion of the ball-milling
process, benzonitrile (6a) was obtained in 95 % yield
(Scheme 5).
Scheme 5. Oxidation of amines to nitriles.
Then the scope of the methodology was tested. Generally,
all the reactions proceeded to give the corresponding nitriles
6a–k in satisfactory yields without any significant side-products.
The reactions of benzylamines with electron-donating substitu-
ents on the aromatic ring (Scheme 6, products 6b–6d) gave
yields comparable to those of amines bearing electron-with-
drawing substituents (Scheme 6, products 6e–6i and 6k).
Benzylamines with a substituent at the ortho position are also
suitable substrates for this process (Scheme 6, product 6j). The
reactions carried out with benzylamines bearing a halide sub-
stituent on the aromatic ring (Scheme 6, products 6e, 6f, and
Scheme 4. Oxidation of amines to ketones: Scope of the reaction with respect
to α-substituted benzylamines.
Eur. J. Org. Chem. 2017, 5519–5526
www.eurjoc.org
5521
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
6k) gave the corresponding benzonitriles, which could be fur-
ther transformed by traditional cross-coupling reactions.
Scheme 7. Proposed mechanism for the formation of the carbonyl com-
pounds and nitriles.
Conclusions
Scheme 6. Oxidation of amines to nitriles: Scope of the reaction with respect
to benzylamines.
We have developed a mild, efficient, and metal-free method for
the synthesis of aldehydes, ketones, and nitriles from primary
amines under ball-milling conditions, which may constitute a
significant addition to the field of mechanochemical synthesis.
The method has proved to be compatible with various func-
tional groups and only requires easily accessible starting materi-
als.
The gram-scale synthesis of product 6a was also investi-
gated. Under the optimized conditions for the preparation of
nitriles, benzylamine (1a, 1.0 g, 7.1 mmol) was mixed with N-
chlorosuccinimide (2, 1.89 g, 14.1 mmol) and then milled in a
zirconia jar (50 mL) for 10 min. Then triethylamine (2.95 mL,
21.2 mmol) was added, and the mixture was subjected to me-
chanical treatment at room temperature for a further 20 min.
Upon completion of the ball-milling process benzonitrile (6a)
was obtained in 94 % yield. Also, the yield and purity were
analogous to those of the small-scale reaction.
Experimental Section
General: All reagents and solvents were used as obtained from
commercial sources. All solvents were dried by the usual methods
and distilled under argon. Short-column chromatography was gen-
A plausible reaction mechanism is shown in Scheme 7 in
which we propose that benzylamine (A) reacted with N-chloro- erally performed with a column of 4 cm diameter charged with
24 g of silica gel (pore size 60 Å, 32–63 nm particle size), and the
reactions were monitored by TLC on Merck Kieselgel 60 F254 plates
and visualized by using UV light at 254 nm with KMnO4 and 2,4-
DNP staining. An 8000M Mixer/Mill® ball-milling apparatus was used
for all reactions with a rotation frequency of 875 rpm. 1H and 13C
NMR spectra were recorded with a Bruker Avance III 400 spectrome-
ter (400 or 100 MHz, respectively) using CDCl3 solutions. Chemical
shifts are reported in parts per million (ppm) relative to internal
tetramethylsilane standard (TMS: δ = 0.00 ppm). The peak patterns
are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; dd, doublet of doublets; br., broad. The coupling con-
succinimide (NCS) in the ball-milling process (10 min), probably
by a radical pathway, to yield N,N-dichlorobenzylamine (B),
which was isolated and characterized. Then B reacted with NEt3
(1.5 equiv.) in the ball-milling process (10 min; Scheme 7,
path a)[21] to form N-chlorobenzylimine (C), which was also iso-
lated and characterized.[22] N-Chlorobenzylimine (C) was then
converted into the corresponding benzaldehyde (D) by aque-
ous hydrolysis. Alternatively, B reacted with NEt3 (3 equiv.) in
the ball-milling process (20 min; Scheme 7, path b) to yield
benzonitrile (E).
Eur. J. Org. Chem. 2017, 5519–5526
www.eurjoc.org
5522
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1
stants (J) are reported in Hertz (Hz). Melting points were deter- chromatography (Rf = 0.433, hexane/ethyl acetate, 4.5:0.5). H NMR
mined in open capillary tubes.
(400 MHz, CDCl3): δ = 10.10 (s, 1 H), 8.01 (d, J = 8.0 Hz, 2 H), 7.81
(d, J = 8.0 Hz, 2 H) ppm.[28] 13C NMR (100 MHz, CDCl3): δ = 191.1,
138.7, 135.6 (q, J = 37.5 Hz), 129.9, 126.1 (q, J = 7.5 Hz), 123.5 (q,
J = 270 Hz) ppm.[29]
4-Nitrobenzaldehyde (5h):[25] Yellow solid; yield: 0.093 g, 41 %;
m.p. 106–107 °C. The desired pure product was obtained after
short-column chromatography (Rf = 0.385, hexane/ethyl acetate,
4.5:0.5). 1H NMR (400 MHz, CDCl3): δ = 10.16 (s, 1 H), 8.39 (d, J =
8.6 Hz, 2 H), 8.07 (d, J = 8.6 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 190.2, 151.1, 140.0, 130.5, 124.3 ppm.
General Procedure for the Oxidation of Primary Benzylamines
to Carbonyl Compounds: The respective benzylamine 1a–1u
(1.5 mmol) and N-chlorosuccinimide (2, 0.400 g, 3 mmol) were
milled in a zirconia vial (50 mL) containing two balls (d = 11.2 mm)
of the same material. The reagents were then subjected to ball-
milling in a shaker milling device at room temperature for 10 min
(the disappearance of benzylamine was monitored by TLC). Then
NEt3 (0.227 g, 2.25 mmol) was added, and the mixture was sub-
jected to ball-milling at room temperature for a further 10 min.
Upon completion of the ball-milling process, the jar was opened,
and THF (10 mL) was added and the mixture transferred to a round-
bottomed flask for the hydrolysis. A 5 % HCl(aq) solution (15 mL)
was added and the mixture stirred at room temperature for 2 h and
then extracted with CH2Cl2 (3 × 10 mL). The combined organic pha-
ses were dried with anhydrous Na2SO4, and the solvent was evapo-
rated under reduced pressure. The crude products 5a–5u were puri-
fied by short-column chromatography (hexane/ethyl acetate).
4-Formylbenzonitrile (5i):[30] White solid; yield: 0.053 g, 27 %; m.p.
102–103 °C. The desired pure product was obtained after short-
1
column chromatography (Rf = 0.333, hexane/ethyl acetate, 4:1). H
NMR (400 MHz, CDCl3): δ = 10.07 (s, 1 H), 7.97 (d, J = 8.1 Hz, 2 H),
7.82 (d, J = 8.1 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 190.6,
138.6, 132.8, 129.7, 117.6, 117.4 ppm.
3,4-Dimethoxybenzaldehyde (5j):[31] White solid; yield: 0.204 g,
82 %; m.p. 42–43 °C. The desired pure product was obtained after
short-column chromatography (Rf = 0.379, hexane/ethyl acetate,
3.5:1.5). 1H NMR (400 MHz, CDCl3): δ = 9.84 (s, 1 H), 7.45 (dd, J =
8.2, 1.9 Hz, 1 H), 7.40 (d, J = 1.8 Hz, 1 H), 6.97 (d, J = 8.2 Hz, 1 H),
3.96 (s, 3 H), 3.93 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 190.8,
154.4, 149.6, 130.1, 126.8, 110.4, 108.9, 56.1, 56.0 ppm.
2-Methoxybenzaldehyde (5k):[27] Yellow oil; yield: 0.126 g, 62 %.
The desired pure product was obtained after short-column chroma-
tography (Rf = 0.333, hexane/ethyl acetate, 4.8:0.2). 1H NMR
(400 MHz, CDCl3): δ = 10.47 (s, 1 H), 7.82 (dd, J = 7.7, 1.8 Hz, 1 H),
7.56–7.52 (m, 1 H), 7.03–6.97 (m, 2 H), 3.92 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 189.7, 161.8, 135.9, 128.5, 124.8, 120.6, 111.6,
55.6 ppm.
3-Chlorobenzaldehyde (5l):[32] Colorless oil; yield: 0.148 g, 70 %.
The desired pure product was obtained after short-column chroma-
tography (Rf = 0.548, hexane/ethyl acetate, 4.5:0.5). 1H NMR
(400 MHz, CDCl3): δ = 9.88 (s, 1 H), 7.75–7.70 (m, 1 H), 7.67 (d, J =
7.7 Hz, 1 H), 7.51–7.46 (m, 1 H), 7.39 (t, J = 7.8 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 190.5, 137.6, 135.1, 134.0, 130.1, 128.8,
127.7 ppm.
Compound Characterizations for 5a–5u
Benzaldehyde (5a):[23] Colorless oil; yield: 0.130 g, 82 %. The de-
sired pure product was obtained after short-column chromatogra-
phy (Rf = 0.314, hexane/ethyl acetate, 4.5:0.5). 1H NMR (400 MHz,
CDCl3): δ = 10.00 (s, 1 H), 7.86 (d, J = 7.5 Hz, 2 H), 7.61 (t, J = 7.1 Hz,
1 H), 7.52 (d, J = 7.7 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
192.2, 136.3, 134.3, 129.6, 128.9 ppm.
4-Methoxybenzaldehyde (5b):[23] Colorless oil; yield: 0.180 g,
88 %. The desired pure product was obtained after short-column
chromatography (Rf = 0.344, hexane/ethyl acetate, 4:1). 1H NMR
(400 MHz, CDCl3): δ = 9.83 (s, 1 H), 7.78 (d, J = 8.5 Hz, 2 H), 6.95 (d,
J = 8.6 Hz, 2 H), 3.83 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
190.6, 164.4, 131.8, 129.8, 114.1, 55.4 ppm.
1,1′-Biphenyl-4-carbaldehyde (5c):[24] White solid; yield: 0.189 g,
69 % yield; m.p. 56–58 °C. The desired pure product was obtained
after short-column chromatography (Rf = 0.4, hexane/ethyl acetate,
4.5:0.5). 1H NMR (400 MHz, CDCl3): δ = 10.07 (s, 1 H), 7.96 (d, J =
8.1 Hz, 2 H), 7.76 (d, J = 8.0 Hz, 2 H), 7.64 (d, J = 7.6 Hz, 2 H), 7.49
(t, J = 7.5 Hz, 2 H), 7.42 (t, J = 7.4 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 191.9, 147.2, 139.7, 135.2, 130.2, 129.0, 128.5, 127.7,
127.3 ppm.
4-Methylbenzaldehyde (5d):[25] Colorless oil; yield: 0.122 g, 68 %.
The desired pure product was obtained after short-column chroma-
tography (Rf = 0.613, hexane/ethyl acetate, 4.5:0.5). 1H NMR
(400 MHz, CDCl3): δ = 9.96 (s, 1 H), 7.77 (d, J = 8.0 Hz, 2 H), 7.33 (d,
J = 7.8 Hz, 2 H), 2.44 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
192.0, 145.5, 134.2, 129.8, 129.7, 21.9 ppm.
3,4-Dihydroisoquinoline (5m):[33] Colorless oil; yield: 0.147 g,
75 %. The desired pure product was obtained after short-column
chromatography (Rf = 0.125, hexane/ethyl acetate, 1:1). 1H NMR
(400 MHz, CDCl3): δ = 8.35 (s, 1 H), 7.37 (t, J = 6.8 Hz, 1 H), 7.33–
7.27 (m, 2 H), 7.17 (d, J = 7.3 Hz, 1 H), 3.79 (t, J = 7.2 Hz, 2 H), 2.76
(t, J = 7.8 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.3, 136.2,
131.0, 128.4, 127.3, 127.2, 127.0, 47.2, 24.9 ppm.
Benzophenone (5n):[34] White solid; yield: 0.199 g, 73 %; m.p. 47–
4-Fluorobenzaldehyde (5e):[26] Colorless oil; yield: 0.132 g, 71 %.
49 °C. The desired pure product was obtained after short-column
The desired pure product was obtained after short-column chroma-
1
=
0.59, hexane/ethyl acetate, 4.5:0.5). 1H NMR
chromatography (Rf = 0.285, hexane/ethyl acetate, 4.5:0.5). H NMR
tography (Rf
(400 MHz, CDCl3): δ = 7.81 (d, J = 7.5 Hz, 4 H), 7.59 (t, J = 7.4 Hz, 2
H), 7.48 (t, J = 7.5 Hz, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
196.7, 137.6, 132.4, 130.0, 128.2 ppm.
Acetophenone (5o):[35] Colorless oil; yield: 0.106 g, 59 %. The de-
sired pure product was obtained after short-column chromatogra-
phy (Rf = 0.333, hexane/ethyl acetate, 4.7:0.3). 1H NMR (400 MHz,
CDCl3): δ = 7.93 (d, J = 7.3 Hz, 2 H), 7.56–7.50 (m, 1 H), 7.43 (t, J =
7.6 Hz, 2 H), 2.57 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.9,
137.0, 132.9, 128.4, 128.2, 26.4 ppm.
(400 MHz, CDCl3): δ = 9.91 (s, 1 H), 7.85 (dd, J = 8.6, 5.6 Hz, 2 H),
7.15 (t, J = 8.5 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 190.3,
166.3 (d, J = 255 Hz), 132.8 (d, J = 2.4 Hz), 132.5 (d, J = 9.6 Hz),
116.2 (d, J = 22.2 Hz) ppm.
4-Chlorobenzaldehyde (5f):[27] White solid; yield: 0.116 g, 55 %;
m.p. 46–47.5 °C. The desired pure product was obtained after short-
column chromatography (Rf = 0.451, hexane/ethyl acetate, 4.5:0.5).
1H NMR (400 MHz, CDCl3): δ = 9.97 (s, 1 H), 7.81 (d, J = 8.4 Hz, 2 H),
7.50 (d, J = 8.3 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 190.8,
140.9, 134.7, 130.8, 129.4 ppm.
Propiophenone (5p):[36] Colorless oil; yield: 0.149 g, 74 %. The de-
sired pure product was obtained after short-column chromatogra-
phy (Rf = 0.354, hexane/ethyl acetate, 4.7:0.3). 1H NMR (400 MHz,
4-(Trifluoromethyl)benzaldehyde (5g): Colorless oil; yield: 0.102 g,
39 %. The desired pure product was obtained after short-column
Eur. J. Org. Chem. 2017, 5519–5526
www.eurjoc.org
5523
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
CDCl3): δ = 7.95 (d, J = 7.8 Hz, 2 H), 7.53 (t, J = 7.4 Hz, 1 H), 7.43 (t,
J = 7.6 Hz, 2 H), 2.98 (q, J = 7.2 Hz, 2 H), 1.21 (t, J = 7.3 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 199.8, 135.9, 131.8, 127.5,
126.9, 30.7, 7.2 ppm.
2 H), 3.85 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.8, 133.9,
119.2, 114.7, 103.9, 55.5 ppm.
1,1′-Biphenyl-4-carbonitrile (6c):[41] Yellow solid; yield: 0.191 g,
71 %; m.p. 88–89 °C. The desired pure product was obtained after
short-column chromatography (Rf = 0.4, hexane/ethyl acetate,
1-(p-Tolyl)ethan-1-one (5q):[37] Colorless oil; yield: 0.133 g, 66 %.
The desired pure product was obtained after short-column chroma-
tography (Rf = 0.286, hexane/ethyl acetate, 4.5:0.5). 1H NMR
(400 MHz, CDCl3): δ = 7.87 (d, J = 8.1 Hz, 2 H), 7.27 (d, J = 8.0 Hz,
2 H), 2.59 (s, 3 H), 2.42 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
197.8, 143.8, 134.6, 129.2, 128.4, 26.4, 21.5 ppm.
1
4.5:0.5). H NMR (400 MHz, CDCl3): δ = 7.74–7.67 (m, 4 H), 7.59 (d,
J = 7.4 Hz, 2 H), 7.51–7.41 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 145.6, 139.1, 132.5, 129.1, 128.6, 127.7, 127.2, 118.9, 110.8 ppm.
4-Methylbenzonitrile (6d):[42] Colorless oil; yield: 0.124 g, 71 %.
The desired pure product was obtained after short-column chroma-
tography (Rf = 0.385, hexane/ethyl acetate, 4.5:0.5). 1H NMR
(400 MHz, CDCl3): δ = 7.50 (d, J = 8.0 Hz, 2 H), 7.23 (d, J = 7.5 Hz,
2 H), 2.38 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 143.6, 132.0,
129.8, 119.1, 109.3, 21.8 ppm.
1-(4-Methoxyphenyl)ethan-1-one (5r):[35] Colorless oil; yield:
0.169 g, 75 %. The desired pure product was obtained after short-
1
column chromatography (Rf = 0.345, hexane/ethyl acetate, 4:1). H
NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 8.7 Hz, 2 H), 6.92 (d, J =
8.8 Hz, 2 H), 3.85 (s, 3 H), 2.54 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 196.6, 163.4, 130.5, 130.3, 113.6, 55.4, 26.3 ppm.
4-Fluorobenzonitrile (6e):[43] Colorless oil; yield: 0.174 g, 96 %. The
desired pure product was obtained after short-column chromatog-
raphy (Rf = 0.59, hexane/ethyl acetate, 4.5:0.5). 1H NMR (400 MHz,
CDCl3): δ = 7.65 (dd, J = 8.7, 5.2 Hz, 2 H), 7.15 (t, J = 8.5 Hz, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 164.9 (d, J = 254 Hz), 134.5
(d, J = 9 Hz), 117.85, 116.7 (d, J = 13 Hz), 108.42 (d, J = 22 Hz) ppm.
1-[4-(Dimethylamino)phenyl]ethan-1-one (5s):[38] White solid:
yield: 0.171 g, 70 %; m.p. 103–104 °C. The desired pure product was
obtained after short-column chromatography (Rf = 0.345, hexane/
ethyl acetate, 4:1). 1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.9 Hz,
2 H), 6.65 (d, J = 8.9 Hz, 2 H), 3.05 (s, 6 H), 2.50 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 196.3, 153.3, 130.5, 125.4, 110.6, 40.0,
25.9 ppm.
4-Chlorobenzonitrile (6f):[41] White solid; yield: 0.161 g, 78 %; m.p.
91–93 °C. The desired pure product was obtained after short-col-
1
umn chromatography (Rf = 0.344, hexane/ethyl acetate, 4.8:0.2). H
1-(4-Nitrophenyl)ethan-1-one (5t):[39] White solid; yield: 0.124 g,
50 %; m.p. 76–77 °C. The desired pure product was obtained after
short-column chromatography (Rf = 0.7, hexane/ethyl acetate, 4:1).
1H NMR (400 MHz, CDCl3): δ = 8.31 (d, J = 8.3 Hz, 2 H), 8.11 (d, J =
8.7 Hz, 2 H), 2.68 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 196.2,
150.4, 141.4, 129.3, 123.8, 27.0 ppm.
NMR (400 MHz, CDCl3): δ = 7.60 (d, J = 8.5 Hz, 2 H), 7.47 (d, J =
8.5 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 139.5, 133.3, 129.7,
117.9, 110.8 ppm.
4-(Trifluoromethyl)benzonitrile (6g):[42] Colorless oil; yield:
0.177 g, 69 %. The desired pure product was obtained after short-
column chromatography (Rf = 0.613, hexane/ethyl acetate, 4.5:0.5).
1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.3 Hz, 2 H), 7.76 (d, J =
8.3 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 134.6 (q, J =
33.6 Hz), 132.7, 126.2 (q, J = 3.7 Hz), 123.1 (q, J = 273.5 Hz), 117.4,
116.1 ppm.
Ethyl 2-Oxo-2-phenylacetate (5u):[40] Yellow oil; yield: 0.198 g,
74 %. The desired pure product was obtained after short-column
chromatography (Rf = 0.3, hexane/ethyl acetate, 4.2:0.8). 1H NMR
(400 MHz, CDCl3): δ = 8.00 (d, J = 7.6 Hz, 2 H), 7.65 (t, J = 7.4 Hz, 1
H), 7.50 (t, J = 7.7 Hz, 2 H), 4.45 (q, J = 7.1 Hz, 2 H), 1.42 (t, J =
7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 186.4, 163.8, 134.8,
132.4, 130.0, 128.8, 62.3, 14.1 ppm.
4-Nitrobenzonitrile (6h):[44] White solid; yield: 0.157 g, 71 %; m.p.
88–89 °C. The desired pure product was obtained after short-
column chromatography (Rf = 0.385, hexane/ethyl acetate, 4.5:0.5).
1H NMR (400 MHz, CDCl3): δ = 8.36 (d, J = 8.7 Hz, 2 H), 7.89 (d, J =
8.7 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.0, 133.4, 124.3,
118.4, 116.8 ppm.
General Procedure for the Oxidation of Primary Benzylic
Amines to Nitriles 6a–6k: The respective benzylamine 1a–1k
(1.5 mmol) and N-chlorosuccinimide (2, 0.400 g, 3 mmol) were
milled in a zirconia vial (50 mL) containing two balls (d = 11.2 mm)
of the same material. The reagents were then subjected to ball-
milling in a shaker milling device at room temperature for 10 min
(the disappearance of benzylamine was monitored by TLC). Then
NEt3 (0.455 g, 4.5 mmol) was added, and the mixture was subjected
to further milling at room temperature for 20 min. Upon completion
of the ball-milling process, the crude product was purified by short-
column chromatography (hexane/ethyl acetate) to provide benzoni-
triles 6a–6k.
Terephthalonitrile (6i):[44] White solid; yield: 0.169 g, 88 %; m.p.
222–223 °C. The desired pure product was obtained after short-
1
column chromatography (Rf = 0.333, hexane/ethyl acetate, 4:1). H
NMR (400 MHz, CDCl3): δ = 7.79 (s, 4 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 132.8, 117.0, 116.7 ppm.
2-Methoxybenzonitrile (6j):[42] Colorless oil; yield: 0.150 g, 75 %.
The desired pure product was obtained after short-column chroma-
tography (Rf = 0.333, hexane/ethyl acetate, 4.8:0.2) 1H NMR
(400 MHz, CDCl3): δ = 7.56–7.46 (m, 2 H), 7.00–6.92 (m, 2 H), 3.88
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.0, 134.3, 133.5,
120.6, 116.3, 111.2, 101.4, 55.8 ppm.
Compound Characterizations for 6a–6k
Benzonitrile (6a):[41] Colorless oil; yield: 0.147 g, 95 %. The desired
pure product was obtained after short-column chromatography
(Rf = 0.314, hexane/ethyl acetate, 4.5:0.5). 1H NMR (400 MHz, CDCl3):
δ = 7.66 (d, J = 7.5 Hz, 2 H), 7.61 (t, J = 7.6 Hz, 1 H), 7.47 (t, J =
7.7 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 132.7, 132.1, 129.1,
118.8, 112.4 ppm.
3-Chlorobenzonitrile (6k):[43] Colorless oil; yield: 0.148 g, 72 %. The
desired pure product was obtained after short-column chromatog-
1
raphy (Rf = 0.548, hexane/ethyl acetate, 4.5:0.5). H NMR (400 MHz,
CDCl3): δ = 7.67–7.63 (m, 1 H), 7.61–7.54 (m, 2 H), 7.43 (t, J = 7.9 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 135.3, 133.2, 131.9, 130.5,
130.3, 117.4, 114.0 ppm.
4-Methoxybenzonitrile (6b):[41] Colorless oil; yield: 0.184 g, 92 %.
The desired pure product was obtained after short-column chroma-
General Procedure for the Synthesis of N,N-Dichloro-1-phenyl-
tography (Rf = 0.406, hexane/ethyl acetate, 4.3:0.7). 1H NMR methanamine (3a):[45] Benzylamine (1a, 0.212 g, 1.5 mmol) and N-
(400 MHz, CDCl3): δ = 7.58 (d, J = 7.2 Hz, 2 H), 6.94 (d, J = 8.4 Hz,
chlorosuccinimide (2, 0.400 g, 3 mmol) were milled in a zirconia vial
Eur. J. Org. Chem. 2017, 5519–5526
www.eurjoc.org
5524
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(50 mL) containing two balls (d = 11.2 mm) of the same material.
The reagents were then subjected to ball-milling in a shaker milling
device at room temperature for 10 min (the disappearance of benz-
ylamine was monitored by TLC). Upon completion of the ball-mill-
ing process, the crude product 3a was purified by short-column
chromatography (hexane/ethyl acetate). White solid; yield: 0.174 g,
66 %. The desired pure product was obtained after short-column
patto ambientale”(CRP 72-Bando “Capitale Umano ad Alta Qual-
ificazione, Annualità 2015_L.R. 7 agosto 2007, no. 7”). S. G.
gratefully acknowledges the Sardinia Regional Government for
the financial support of her Ph. D. scholarship (P.O.R. Sardegna
F.S.E. Operational Programme of the Autonomous Region of
Sardinia, European Social Fund 2007–2013-Axis IV Human Re-
sources, Objective l.3, Line of Activity l.3.1).
1
chromatography (Rf = 0.518, hexane/ethyl acetate, 4.8:0.2). H NMR
(400 MHz, CDCl3): δ = 7.41 (s, 5 H), 4.70 (s, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 134.9, 130.0, 129.2, 128.5, 78.9 ppm.
Keywords: Ball milling · Oxidation · Aldehydes · Ketones ·
General Procedure for the Synthesis of (E)-N-Chloro-1-phenyl- Nitriles · Mechanochemistry
methanimine (4a):[46] Benzylamine (1a, 0.212 g, 1.5 mmol) and N-
chlorosuccinimide (2, 0.400 g, 3 mmol) were milled in a zirconia vial
[1] a) K. C. Nicolaou, C. J. N. Mathison, T. Montagnon, J. Am. Chem. Soc.
(50 mL) containing two balls (d = 11.2 mm) of the same material.
The reagents were then subjected to ball-milling in a shaker milling
device at room temperature for 10 min(the disappearance of benz-
ylamine was monitored by TLC). Then NEt3 (0.227 g, 2.25 mmol)
was added, and the mixture was subjected to milling at room tem-
perature for a further 10 min. Upon completion of the ball-milling
process, the crude product was purified by short-column chroma-
tography (hexane/ethyl acetate). White solid; yield: 0.113 g, 54 %.
The desired pure product was obtained after short-column chroma-
tography (Rf = 0.392, hexane/ethyl acetate, 4.5:0.5). 1H NMR
(400 MHz, CDCl3): δ = 8.81 (s, 1 H), 7.68 (d, J = 7.5 Hz, 2 H), 7.52–
7.42 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.6, 133.2,
132.1, 129.0, 128.0 ppm.
2004, 126, 5192–5201; b) G. Chu, C. Li, Org. Biomol. Chem. 2010, 8, 4716–
4719; c) P. Galletti, F. Funiciello, R. Soldati, D. Giacomini, Adv. Synth. Catal.
2015, 357, 1840–1848; d) V. V. Patil, E. M. Gayakwad, G. S. Shankarling, J.
Org. Chem. 2016, 81, 781–786; e) V. V. Patil, G. S. Shankarling, J. Org.
Chem. 2015, 80, 7876–7883; f) X. Wu, C. B. Bheeter, H. Neumann, P. H.
Dixneuf, M. Beller, Chem. Commun. 2012, 48, 12237–12239; g) J. W. Kim,
K. Yamaguchi, N. Mizuno, Angew. Chem. Int. Ed. 2008, 47, 9249–9251;
Angew. Chem. 2008, 120, 9389–9391; h) Y. Wang, H. Kaboyashi, K. Yama-
guchi, N. Mizuno, Chem. Commun. 2012, 48, 2642–2644.
[2] a) G. Tojo, M. Fernandez, Oxidation of Alcohols to Aldehydes and Ketones,
1st ed., Springer, New York, 2006.
[3] S. S. Rawalay, H. Shechter, J. Org. Chem. 1967, 32, 3129–3131.
[4] R. G. R. Bacon, W. J. W. Hanna, J. Chem. Soc. 1965, 4962–4968.
[5] S. Sabhani, M. F. Maleki, Synlett 2010, 383–386.
[6] S. Sobhani, S. Aryanejad, M. F. Maleki, Helv. Chim. Acta 2012, 95, 613–
617.
[7] S. Chandrasekhar, G. P. K. Reddy, C. Nagesh, C. R. Reddy, Tetrahedron Lett.
2007, 48, 1269–1271.
[8] a) J. Srogl, S. Voltrova, Org. Lett. 2009, 11, 843–845; b) S.-i. Naya, T. Niwa,
R. Negishi, H. Kobayashi, H. Tada, Angew. Chem. Int. Ed. 2014, 53, 13894–
13897; Angew. Chem. 2014, 126, 14114–14117.
[9] N. Iqbal, E. J. Cho, Adv. Synth. Catal. 2015, 357, 2187–2192.
[10] R. C. Larock (Ed.), Comprehensive Organic Transformations, Wiley-VCH,
Weinheim, 1999, pp. 819–939.
General Procedure for the Synthesis of (E)-N-Chloro-1-phenyl-
methanimine (4a) from N,N-Dichloro-1-phenylmethanamine
(3a): N,N-Dichloro-1-phenylmethanamine (0.264 g, 1.5 mmol) and
NEt3 (0.227 g, 2.25 mmol) were milled in a zirconia vial (50 mL),
containing two balls (d = 11.2 mm) of the same material at room
temperature for 10 min (the disappearance of N,N-dichloro-1-
phenylmethanamine was monitored by TLC). Upon completion of
the ball-milling process, the crude product was purified by short-
column chromatography (hexane/ethyl acetate) providing (E)-N-
chloro-1-phenylmethanimine (0.123 g, 59 %).
[11] a) For a review of the oxidation of amines, see: D. H. Rosenblatt, E. Bur-
rows in The Chemistry of Amino, Nitroso, and Nitro Compounds and Their
Derivatives, Supplement F, vol. 1, part 2 (Ed.: S. Patai), Wiley, Chichester,
1982, pp. 1085–1149; b) C. R. Noller, Textbook of Organic Chemistry, vol.
3, W. B. Saunders Company, Philadelphia, PA, 1966, p. 229.
[12] a) K. Yamaguchi, N. Mizuno, Angew. Chem. Int. Ed. 2003, 42, 1480–1483;
Angew. Chem. 2003, 115, 1518–1521; b) Y. Zhang, K. Xu, X. Chen, T. Hu,
Y. Yu, J. Zhang, J. Huang, Catal. Commun. 2010, 11, 951–954; c) S. Ven-
katesan, A. S. Kumar, J.-F. Lee, T.-S. Chan, J.-M. Zen, Chem. Eur. J. 2012,
18, 6147–6151; d) M. T. Schümperli, C. Hammond, I. Hermans, ACS Catal.
2012, 2, 1108–1117; e) E. C. Corker, J. Ruiz-Martinez, A. Riisager, R. Fehr-
mann, Catal. Sci. Technol. 2015, 5, 5008–5015.
[13] a) J. Kim, S. S. Stahl, ACS Catal. 2013, 3, 1652–1656; b) D. Damodara, R.
Arundhathi, P. R. Likhar, Adv. Synth. Catal. 2014, 356, 189–198.
[14] a) K. C. Nicolaou, C. J. N. Mathison, Angew. Chem. Int. Ed. 2005, 44, 5992–
5997; Angew. Chem. 2005, 117, 6146–6151; b) J. Zhang, Z. Wang, Y. Wang,
C. Wan, C. Wan, X. Zheng, Z. Wang, Green Chem. 2009, 11, 1973–1978;
c) K. M. Lambert, J. M. Bobbitt, S. A. Eldirany, K. B. Wiberg, W. F. Bailey,
Org. Lett. 2014, 16, 6484–6487; d) K. M. Lambert, J. M. Bobbitt, S. A.
Eldirany, L. E. Kissane, R. K. Sheridan, Z. D. Stempel, F. H. Sternberg, W. F.
Bailey, Chem. Eur. J. 2016, 22, 5156–5159.
[15] a) G.-W. Wang, Chem. Soc. Rev. 2013, 42, 7668–7700; b) R. S. Varma, Green
Chem. 2014, 16, 2027–2041; c) T. K. Achar, S. Maiti, P. Mal, RSC Adv. 2014,
4, 12834–12839; I. Dokli, M. Gredicak, Eur. J. Org. Chem. 2015, 2727–
2732; d) S. L. James, C. J. Adams, C. Bolm, D. Braga, P. Collier, T. Friščić, F.
Grepioni, K. D. M. Harris, G. Hyett, W. Jones, A. Krebs, J. Mack, L. Maini,
A. G. Orpen, I. P. Parkin, W. C. Shearouse, J. W. Steed, D. C. Waddell, Chem.
Soc. Rev. 2012, 41, 413–447; e) J. G. Hernández, C. Bolm, J. Org. Chem.
2017, 82, 4007–4019; f) J.-L. Do, T. Friščić, ACS Cent. Sci. 2017, 3, 13–19.
[16] R. Mocci, L. De Luca, F. Delogu, A. Porcheddu, Adv. Synth. Catal. 2016,
358, 3135–3144.
General Procedure for the Synthesis of Carbonyl Compounds
5 from (E)-N-Chloro-1-phenylmethanimine (4a): (E)-N-Chloro-1-
phenylmethanimine (4a, 0.209 g, 1.5 mmol) was dissolved in THF
(10 mL) and the mixture transferred to a round-bottomed flask for
the hydrolysis. A 5 % HCl(aq) solution (15 mL) was added to the
mixture, which was stirred at room temperature for 2 h and then
extracted with CH2Cl2 (3 × 10 mL). The combined organic phases
were dried with anhydrous Na2SO4 and the solvent was evaporated
under reduced pressure. The crude product was purified by short-
column chromatography (hexane/ethyl acetate) to provide benz-
aldehyde 5a (0.134 g, 84 %).
General Procedure for the Synthesis of Nitriles 6 from N,N-
Dichloro-1-phenylmethanamine (3a): N,N-Dichloro-1-phenyl-
methanamine (3a, 0.264 g, 1.5 mmol) and NEt3 (0.455 g, 4.5 mmol)
were milled in a zirconia vial (50 mL) containing two balls (d =
11.2 mm) of the same material at room temperature for 20 min (the
disappearance of N,N-dichloro-1-phenylmethanaminewas moni-
tored by TLC). Upon completion of the ball-milling process, the
crude product was purified by short-column chromatography (hex-
ane/ethyl acetate) to provide benzonitrile (6a, 0.148 g, 96 %).
Acknowledgments
This work was financially supported by the Regione Autonoma
della Sardegna within the project “Valorizzazione di biomasse
d'interesse regionale attraverso processi chimici a basso im-
Eur. J. Org. Chem. 2017, 5519–5526
www.eurjoc.org
5525
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[17] a) M. K. Beyer, H. Clausen-Schaumann, Chem. Rev. 2005, 105, 2921–2941;
b) P. J. Walsh, H. Li, C. A. de Parrodi, Chem. Rev. 2007, 107, 2503–2545;
c) T. K. Achar, P. Mal, J. Org. Chem. 2015, 80, 666–672; d) L. Li, J.-J. Wang,
G.-W. Wang, J. Org. Chem. 2016, 81, 5433–5439; e) L. Konnert, F. Lamaty,
J. Martinez, E. Colacino, J. Org. Chem. 2014, 79, 4008–4017; f) Z.-J. Jiang,
Z.-H. Li, J.-B. Yu, W.-K. Su, J. Org. Chem. 2016, 81, 10049–10055; g) V.
Porte, M. Thioloy, T. Pigoux, T.-X. Metrò, J. Martinez, F. Lamaty, Eur. J. Org.
Chem. 2016, 3505–3508; h) T.-X. Métro, J. Bonnamour, T. Reidon, A. Du-
prez, J. Sarpoulet, J. Martinez, F. Lamaty, Chem. Eur. J. 2015, 21, 12787–
12796; i) A. Beillard, X. Bantreil, T.-X. Mètro, J. Martinez, F. Lamaty, New J.
Chem. 2017, 41, 1057–1063; j) J. G. Hernández, E. Juaristi, J. Org. Chem.
2010, 75, 7107–7111; k) J. G. Hernández, E. Juaristi, J. Org. Chem. 2011,
76, 1464–1467; l) J. M. Landeros, E. Juaristi, Eur. J. Org. Chem. 2017, 41,
687–694.
[18] a) R. Thorwirth, F. Bernhardt, A. Stolle, B. Ondruschka, J. Asghari, Chem.
Eur. J. 2010, 16, 13236–13242; b) I. Huskić, I. Halasz, T. Friščić, H. Vančik,
Green Chem. 2012, 14, 1597–1600; c) G. Cravotto, E. C. Gaudino in Ball
Milling Towards Green Synthesis: Applications, Projects, Challenges (Eds.: A.
Stolle, B. Ranu), RSC Green Chemistry Series, RSC, Cambridge, 2014, pp.
58–80; d) R. Ghorbani-Vagheri, H. Veisi, Synthesis 2009, 6, 945–950.
[19] a) L. De Luca, G. Giacomelli, A. Porcheddu, Org. Lett. 2001, 3, 3041–3043;
b) L. De Luca, G. Giacomelli, A. Porcheddu, Org. Lett. 2001, 3, 1519–1521;
c) L. De Luca, G. Giacomelli, A. Porcheddu, J. Org. Chem. 2001, 66, 7907–
7909; d) M. G. Mura, L. De Luca, M. Taddei, J. M. J. Williams, A. Porcheddu,
Org. Lett. 2014, 16, 2586–2589.
[25]
[26]
[27]
W. Han, B. Liu, J. Chen, Q. Zhou, Synlett 2017, 28, 835–840.
L. Gu, C. Jin, Chem. Commun. 2015, 51, 6572–6575.
C. M. Nicklaus, P. H. Phua, T. Buntara, S. Noel, H. J. Heeres, J. G. de Vries,
Adv. Synth. Catal. 2013, 355, 2839–2844.
C.-P. Zhang, J. Cai, C.-B. Zhou, X.-P. Wang, X. Zheng, Y.-C. Gu, J.-C. Xiao,
Chem. Commun. 2011, 47, 9516–9518.
H. Huang, X. Li, C. Yu, Y. Zhang, P. S. Mariano, W. Wang, Angew. Chem.
Int. Ed. 2017, 56, 1500–1505; Angew. Chem. 2017, 129, 1522–1527.
E. Barragan, A. Bugarin, J. Org. Chem. 2017, 82, 1499–1506.
S. H. Christensen, E. P. K. Olsen, J. Rosenbaum, R. Madsen, Org. Biomol.
Chem. 2015, 13, 938–945.
Q. Feng, Q. Song, J. Org. Chem. 2014, 79, 1867–1871.
D. Leow, Org. Lett. 2014, 16, 5812–5815.
S. Kamijo, K. Tao, G. Takao, H. Tonoda, T. Murafuji, Org. Lett. 2015, 17,
3326–3329.
H. Jiang, J. R. Bak, F. J. Lopez-Delgado, K. A. Jorgensen, Green Chem.
2013, 15, 3355–3359.
M. Iinuma, K. Moriyama, H. Togo, Eur. J. Org. Chem. 2014, 772–780.
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37] B. Skillinghaug, C. Sköld, J. Rydfjord, F. Svensson, M. Behrends, J. Säv-
marker, P. J. R. Sjöberg, M. Larhed, J. Org. Chem. 2014, 79, 12018–12032.
[38] H. Niu, L. Lu, R. Shi, C. W. Chaing, A. Lei, Chem. Commun. 2017, 53, 1148–
1151.
[39] G. Olivo, S. Giosia, A. Barbieri, O. Lanzalunga, S. Di Stefano, Org. Biomol.
Chem. 2016, 14, 10630–10635.
[40] Y. Kumar, Y. Jaiswal, A. Kumar, J. Org. Chem. 2016, 81, 12247–12257.
[41] B. V. Rokade, S. K. Malekar, K. R. Prabhu, Chem. Commun. 2012, 48, 5506–
5508.
[42] C. Tao, B. Wang, L. Sun, Z. Liu, Y. Zhai, X. Zhang, J. Wang, Org. Biomol.
Chem. 2017, 15, 328–332.
[20] The principal advantages of using NCS include the ease in handling, the
mild conditions under which chlorination proceeds, and the simplicity
of removal of the innocuous byproduct succinimide.
[21] a) J. M. Antelo, F. Arce, J. Crugeiras, C. Pastoriza, A. Rios, J. Chem. Res.
Synop. 2001, 20–21; b) J. M. Antelo, F. Arce, J. Crugeiras, M. Parajò, J.
Phys. Org. Chem. 1997, 10, 631–636; c) S. R. Rajamäki, L. De Luca, F.
Capitta, A. Porcheddu, RSC Adv. 2016, 6, 38553–38557.
[22] N,N-Dichlorobenzylamine (B) and N-chlorobenzylimine (C) were used in
separate reactions as starting materials to prove the pathways leading
to compounds D and E.
[43] Q. Feng, Q. Song, Adv. Synth. Catal. 2014, 356, 1697–1702.
[44] Y.-J. Zhuang, J. Liu, Y.-B. Kang, Tetrahedron Lett. 2016, 57, 5700–5702.
[45] L. Jia, X. Junchao, R. Jiangmeng, Z. Bu-Bing, Chem. Lett. 2014, 43, 190–
192.
[46] R. Kupfer, U. H. Brinker, J. Org. Chem. 1996, 61, 4185–4186.
[23] A. Wang, H. Jiang, J. Org. Chem. 2010, 75, 2321–2326.
[24] P. Li, L. Wang, L. Zhang, G.-W. Wang, Adv. Synth. Catal. 2012, 354, 1307–
1318.
Received: May 18, 2017
Eur. J. Org. Chem. 2017, 5519–5526
www.eurjoc.org
5526
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim