Simple Synthesis of Aryl p-Nitroarylacetonitriles by Vicarious Nucleophilic Substitution with Carbanions of Protected Cyanohydrins

Article abstract of DOI:10.1002/ejoc.201701507

Acetals of the cyanohydrins of aromatic aldehydes were deprotonated to generate carbanions, which were used in the vicarious nucleophilic substitution of the hydrogen atom of aromatic and heteroaromatic nitro compounds to form p-nitro-substituted diarylac

Full text of DOI:10.1002/ejoc.201701507

A Journal of
Accepted Article
Title: Simple Synthesis of Aryl p-Nitroarylacetonitriles via Vicarious
Nucleophilic Substitution with Carbanions of Protected
Cyanohydrins
Authors: Nazar Rad and Mieczyslaw Makosza
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10.1002/ejoc.201701507
European Journal of Organic Chemistry
FULL PAPER
Simple Synthesis of Aryl p-Nitroarylacetonitriles via Vicarious Nucleophilic
Substitution with Carbanions of Protected Cyanohydrins
Nazar Rad[a] and Mieczysław Mąkosza*[a]
11
proceeds faster than conventional SNAr of halogens. Some α-
halocarbanions are very unstable entities, hence in these cases
RO or ArO substituents can be used as leaving groups instead
of halogens. For instance, VNS cyanomethylation proceeds
Abstract: : Acetals of cyanohydrins of aromatic aldehydes upon
deprotonation enter vicarious nucleophilic substitution of hydrogen
with
a series of carbo- and heteronitroarenes to form para-
nitrosubstituted diarylacetonitriles. The reaction proceeds selectively
in positions para to the nitro group. It was shown that anion of
acetaldehyde hemiacetal is an efficient leaving group in base
induced β-elimination.
more
efficiently
with
aryloxyacetonitriles
than
with
chloroacetonitrile. 10d-f α-Chlorophenyl-acetonitrile does not enter
VNS, because in basic media it undergoes fast conversion into
dicyanostilbene,
whereas
α-phenoxy-
and
α-methoxy
Introduction
phenylacetonitriles afford α-cyanobenzylation of nitroarenes
satisfactorily.10g Due to bulkiness of these carbanions the
substitution proceeds selectively in the para position to the nitro
group to give α-(p-nitrophenyl)phenylacetonitriles in good yields.
These nitriles, valuable intermediates in organic synthesis,
particularly pharmaceuticals,12 can be synthesized also via
conventional SNAr of halogens in p-halonitrobenzenes by
carbanion of phenylacetonitrile,13 oxidative nucleophilic
Introduction of functionalized carbon substituents into
aromatic rings is one on the most important process of organic
synthesis. Amongst a variety of ways for introduction of carbon
substituents into aromatic rings the most frequently used is
electrophilic substitution - many variants of the Friedel-Crafts
1,
2
reaction.
Recently wide application have found numerous
transition metals catalyzed reactions such as Mizoraki-Heck
3
reaction,
substitution of halogens in haloarenes with the
substitution of hydrogen (ONSH) in nitroarenes, with this
5
Grignard reagents and lithium organics,4 Sonogshira reaction,
8
carbanion
or cyanation and rearrangement of some
6
bromoketones.14 Since in the SNAr reactions para-
halonitroarenes are starting materials whereas in ONSH the
substitution can proceed in ortho and para positions and often
overoxidation is observed, VNS is a method of choice for
synthesis of p-nitroaryl arylacetonitriles. Although VNS in
synthesis of diarenes via Suzuki reaction etc. The transition
metals catalyzed processes are of great versatility and
generality, however products of these reactions contain traces of
transition metals hence can be used in pharmacology or
electronics only after laborious purification. 7
Much less recognized is introduction of carbon
substituents into electron-deficient arenes, particularly
nitroarenes via nucleophilic substitution of hydrogen such as
nitroarenes
by
carbanions
of
α-methoxy-
and
α-
phenoxyphenylacetonitriles proceeds satisfactorily,10d,g synthesis
of the starting nitriles does not. There are a few reported
methods of synthesis of such nitriles, rather inconvenient for
multigram preparation.15a-d The simplest method - reaction of
benzaldehyde, sodium cyanide and benzene-sulfonyl chloride to
give benzenesulfonate of the cyanohydride proceeds in good
yield, however further reaction of this benzenesulfonate with
phenols and alcohols is accompanied with side reactions, so
yields of the desired nitriles are usually below 50%. 15e
8,
9
oxidative substitution
and particularly vicarious nucleophilic
substitution of hydrogen, VNS. 10 The VNS reaction proceeds via
addition of α-halocarbanions to nitroarenes at positions occupied
by hydrogen ortho- or para- to the nitro group followed by base
induced β-elimination of HCl from the intermediate σH adducts. A
great variety of α-halocarbanions enter this reaction, so it is a
general process in the sense of introduced substituents. It is
also of general character with respect to nitroarenes. It should
be emphasized that VNS in ortho- and para- halonitrobenzenes
Some years ago we reported that benzaldehyde
cyanohydrins protected as acetals via acid catalyzed reactions
with butyl vinyl ether or dihydropyran, can be deprotonated and
16a
16b
alkylated
and nitroarylated
under PTC conditions. It was
[a]
Institute of Organic Chemistry
Polish Academy of Sciences
Kasprzaka 44/52, 01-224 Warsaw, Poland
E-mail: icho-s@icho.edu.pl
therefore of interest whether carbanion of benzaldehyde
cyanohydrin protected in the form of an acetal could enter VNS
reaction with nitroarene, in other words whether anion of
http://www.icho.edu.pl
1
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10.1002/ejoc.201701507
European Journal of Organic Chemistry
FULL PAPER
acetaldehyde hemiacetal could be eliminated from the σH
adducts in base induced E2 β-elimination.
good yields. Similarly, under the same conditions acetals 1b and
1c reacted with nitroarenes to give expected products 2b-9c.
CH3
X
O
O
CH3
NC
NC
H
Ar
1. t-BuOK
t-BuOK, DMF
Results and Discussion
Y
1a, 1b, 1c
+
Y
2. HCl
+
+
+
N
N
N
O
O
O
O
O
O
Protection of cyanohydrin of benzaldehyde, p-Cl- and p-
MeO benzaldehyde in the acid catalyzed reaction with ethyl vinyl
ether gave expected acetal 1a, 1b and 1c in high yields
(Scheme 1).
2  11
X = H, Cl, OMe
2a 11c
Scheme 2. VNS in monocyclic nitroarenes with carbanions of 1a, 1b and 1c.
CN
OH
CN CH3
Besides of substituted nirobenzenes 2-9 the reaction
proceed with 2-chloro-3-nitro- and 4-methoxy-3-nitropyridine 10,
11 in which para-position to the nitro group is occupied by
hydrogen.
H2C
O
CH3
O
O
O
CH3
+
NaCN
+
H
X
X
X
1a X = H
1b X = Cl
1c X = OMe
Scheme 1. Synthesis of protected cyanohydrins 1a-1c.
Table 1. Results of VNS in monocyclic nitroarenes by carbanions of acetals
1a, 1b and 1c (see scheme 2)
To our satisfaction, the first attempts of the reaction
between 1a and nitrobenzene 2 carried out under conditions
typical for the VNS: excess of t-BuOK in DMF solution at 00 C
gave good result, the mixture turned deep violet and upon
acidification the expected p-nitrophenyl phenyl acetonitrile 2a
was obtained in yield 87%. Thus anion of the hemiacetal of
acetaldehyde was shown to be an active leaving group able to
be eliminated from the σH adduct via base induced E-2 type
process. Effectiveness of the hemiacetals anions as leaving
groups in base induced β-elimination is not surprising, because
one should expect that leaving group RO abilities in the
Educts
№
Products
Yield, %
X
Y
1
2
H
H
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
1a
1c
H
2
3
2a
3a
4a
5a
6a
7a
8a
9a
2b
3b
6b
8b
9b
2c
3c
6c
8c
9c
10a
11с
87
96
83
61
71
66
65
85
89
87
62
76
91
91
86
82
95
87
83
58
2-F
2-Cl
3
H
4
4
H
2-Br
5
5
H
2-OMe
3-Br
6
6
H
7
elimination should correlate with OH acidities of ROH. Some
7
H
3-OMe
3-CN
H
8
17a
data taken from tables of pKa in water are PhOH - 9.9
,
hemicetal – 13.8 17b, MeOH - 15.5 17b, hence hemiacetals should
be less efficient than phenols and more efficient than primary
alcohols. Methoxy group in α-methoxyphenylacetonitrile undergo
fast elimination in the VNS reaction. 10d, g
8
H
9
9
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
2
10
11
12
13
14
15
16
17
18
19
20
2-F
3
2-OMe
3-OMe
3-CN
H
6
VNS reaction as a rule requires at least double excess of
base over carbanion precursors and nitroarenes: one mole is
consumed for deprotonation of the carbanion precursor and
second for β-elimination. Usually anion X‒ produced in β-
elimination is a weak base. In some cases, however, when
eliminated X‒ is a strong base e.g. RO‒, one could expect that it
can also promote β-elimination. This is the case of VNS with
carbanion of 1a, because in the experiment with 1 mole of each:
1a, 2 and t-BuOK, the yield of the product 2a exceeded 75%.
The reaction proceeded selectively at the para position due to
bulkiness of the carbanion of 1a. Under identical conditions a
series of ortho- and meta- substituted nitrobenzenes 3-9 reacted
with 1a to give p-nitroaryl-phenylacetonitriles 3a-9a usually with
8
9
4-Ome
4-Ome
4-Ome
4-OMe
4-OMe
H
2
2-F
3
2-OMe
3-OMe
3-CN
6
8
9
3-Cl-NO2Py
10
11
4-OMe
4-OMe-3-NO2Py
2
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10.1002/ejoc.201701507
European Journal of Organic Chemistry
FULL PAPER
The results presented in Table1 confirm that the reaction
is of general character with respect to monocyclic nitroarenes
provided the positions para to the nitro group is occupied by
hydrogen. Positions ortho- or meta- can be occupied by
electron-donating or electron withdrawing groups.
Mass spectra were recorded with an ESI/MS Mariner
(PerSeptive Biosystem) mass spectrometer.
Cyanohydrins 1a, 1b and 1c were synthesized following the
procedure 16a (78%, 67%, 72%).
Bicyclic nitroarenes are particularly active in VNS
reaction because dearomatisation energy connected with
formation of the σH-adducts is relatively small.18 On the other
hand “para” positions to the nitro group in 1-nitronaphthalene 12
and 8-nitroquinoline 13 are moderately sterically hindered by the
peri- hydrogen. In spite of that VNS in these bicyclic nitroarenes
with carbanion of 1a and 1c proceeds satisfactorily (scheme 3).
General procedure for synthesis of (4-nitroarene)-
arylacetonitriles:
To a stirred solution of t-BuOK (3,5 mmole) in DMF (9 ml) cooled
to 0°C a solution of nitroarene 2-13 (1 mmole) and cyanhydrin
1a-1c (1 mmole) in DMF (1 ml) was added keeping this
temperature under inert atmosphere. The mixture that turned
deep violet was stirred for 15 min and poured into 2% solution of
HCl (20 ml) and extracted with ethyl acetate. The extracts were
concentrated and the products were purified by column
chromatography (hexane : ethyl acetate as the eluent). For
cases, in which the reaction temperature and duration were
different these parameters are specified below.

NO2
NO2
NO2
Z
Z
CN
Ar CH
Z

1.B
tBuOK
+
+
2. H
DMF
Ar
O
O
H
C
H
H
O
O
Ar
CN
CN
Z = CH, 12: N, 13
1a, 1c
12a 91%
13c 78%
Scheme 3. VNS in bicyclic nitroarenes with carbanion of 1a and 1c.
(4-nitrophenyl)(phenyl)acetonitrile (2a): Yield 87%; slight
yellow solid; 1H NMR (400 MHz, CDCl3, 25°C): δ = 8.25 (d, 3JH,H
In all of these cases yields of the products are high. The
reactions were carried out under standard, arbitrary chosen
conditions, hence yields of the individual products can be
improved in course of optimization.
3
= 8.8 Hz, 2H, Ar), 7.57 (d, JH,H = 8.8 Hz, 2H, Ar), 7.48-7.39 (m,
5H, Ph), 5.27 (s, 1H, CH) ppm. 13C NMR (101 MHz, CDCl3,
25°C) : δ = 147.8, 142.8, 134.5, 129.6, 128.9, 128.7, 127.7,
124.4, 118.5, 42.3 ppm. IR (film): 3079 (CHarom), 2248 (CN),
1523 (NO2), 1348 (NO2). HRMS (EI): m/z 238.0741 (238.0742
calc. for C14H10N2O2, M+).
Conclusions
(3-fluoro-4-nitrophenyl)(phenyl)acetonitrile (3a): Yield 96%;
Cyanohydrins of aromatic aldehydes protected in the form of
acetals readily available via acid-catalysed reactions of
cyanohydrins with ethylvinyl ether under treatment with
potassium t-butoxide undergo deprotonation to form reactively
stable carbanions. These carbanions enter vicarious nucleophilic
substitution with nitroarenes via addition and base induced -
elimination of acetaldehyde hemiacetal. Due to bulkiness of
these carbanions the reaction proceeds selectively in position
para to the nitro group. This is a simple and efficient way of
synthesis of p-nitroarylarylacetonitriles.
1
yellow oil; Yield %; yellow oil. H NMR (400 MHz, CDCl3, 25°C):
δ = 8.13-8.08 (m, 1H, Ar), 7.48-7.40 (m, 3H, Ph), 7.38-7.329 (m,
4H, Ph), 5.23 (s, 1H, CH) ppm. 13C NMR (101 MHz, CDCl3,
25°C) : δ = 157.0, 154.3, 144.2 (d), 133.8, 129.8, 129.2, 127.8,
127.0 (d), 123.8 (d), 118.0 (d), 117.8, 42.2 ppm. IR (film): 3053
(CHarom), 2246 (CN), 1529 (NO2), 1351 (NO2). HRMS (EI): m/z
256.0644 (256.0648 calc. for C14H9N2O2F, M+).
(3-chloro-4-nitrophenyl)(phenyl)acetonitrile (4a): Yield 83%;
1
3
yellow oil; H NMR (400 MHz, CDCl3, 25°C): δ = 7.91 (d, JH,H
=
3
8.4 Hz, 1H, Ar), 7.57 (d, JH,H = 0.8 Hz, 1H, Ar), 7.45-7.34 (m,
4H, Ph), 7.37-7.35 (m, 2H, Ph), 5.21 (s, 1H, CH) ppm. 13C NMR
(101 MHz, CDCl3, 25°C) : δ = 147.5, 141.7, 133.9, 131.1, 129.8,
129.2, 128.1, 127.8, 126.9, 126.4, 118.1, 42.0 ppm. IR (film):
3033 (CHarom), 2245 (CN), 1530 (NO2), 1349 (NO2). HRMS (EI):
m/z 272.0351 (272.0353 calc. for C14H9N2O2Cl, M+).
Experimental Section
General information
All reported NMR spectra were recorded with a Brucker
400 MHz spectrometer (at 400 and 100 MHz for 1H and 13C
NMR spectra, respectively); solutions were prepared in CDCl3 or
DMSO with TMS as the internal standard. IR spectra (CH2Cl2,
film) were recorded on a Perkin Elmer FT-IR Spectrum 2000.
(3-bromo-4-nitrophenyl)(phenyl)acetonitrile (5a): Yield 61%;
yellow solid; 1H NMR (400 MHz, CDCl3, 25°C): δ = 7.87 (d, 3JH,H
3
= 8.4 Hz, 1H, Ar), 7.76 (d, JH,H = 2.0 Hz, 1H, Ar), 7.50-7.40 (m,
4H, Ph), 7.37-7.34 (m, 2H, Ph), 5.19 (s, 1H, CH) ppm. 13C NMR
3
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10.1002/ejoc.201701507
European Journal of Organic Chemistry
FULL PAPER
3
(101 MHz, CDCl3, 25°C) : δ = 149.4, 141.6, 134.2, 133.9, 129.8,
129.2, 127.7, 127.5, 126.3, 118.0, 115.5, 41.9 ppm. IR (film):
3031 (CHarom), 2245 (CN), 1531 (NO2), 1348 (NO2). HRMS (EI):
m/z 315.9859 (315.9847 calc. for C14H9N2O2Br, M+).
7.41 (d, JH,H = 8.4 Hz, 2H, ClAr), 5.25 (s, 1H, CH) ppm. 13C
NMR (101 MHz, CDCl3, 25°C) : δ = 148.00, 142.2, 135.2, 132.9,
129.8, 129.1, 128.7, 124.6, 118.1, 41.7 ppm. IR (film): 3081
(CHarom), 2248 (CN), 1523 (NO2), 1348 (NO2). HRMS (EI): m/z
272.0342 (272.0353 calc. for C14H9N2O2Cl, M+).
(3-methoxy-4-nitrophenyl)(phenyl)acetonitrile (6a): Duration
of the reaction 30 min; Yield 71%; orange oil; 1H NMR (400
(4-chlorophenyl)(3-fluoro-4-nitrophenyl)acetonitrile
(3b):
3
MHz, CDCl3, 25°C): δ = 7.86 (d, JH,H = 8.4 Hz, 1H, Ar), 7.45-
Duration of the reaction 20 min; Yield 87%; yellow oil; 1H NMR
(400 MHz, CDCl3, 25°C): δ = 8.15-8.06 (m, 1H, NO2Ar), 7.43 (d,
3JH,H = 8.4 Hz, 2H, ClAr), 7.34-7.28 (m, 4H, ClAr+NO2Ar), ), 5.21
(s, 1H, CH) ppm. 13C NMR (101 MHz, CDCl3, 25°C) : δ = 154.4,
143.6 (d), 135.5, 132.2, 130.0, 129.1, 127.2 (d), 123.7 (d),
118.1, 117.8, 117.5, 41.5 ppm. IR (film): 3052 (CHarom), 2247
(CN), 1529 (NO2), 1350 (NO2). HRMS (EI): m/z 290.0265
(290.0258 calc. for C14H8N2O2ClF, M+).
7.39 (m, 3H, Ph), 7.38-7.34 (m, 2H, Ph), 7.10 (d, 4JH,H = 1.6 Hz,
1H, Ar), 7.01 (dd, 3JH,H = 8.4 Hz, 4JH,H = 1.6 Hz, 1H, Ar), 5.20 (s,
1H, CH), 3.97 (s, 1H, CH) ppm. 13C NMR (101 MHz, CDCl3,
25°C) : δ = 153.4, 142.3, 139.3, 134.4, 129.6, 128.9, 127.7,
126.5, 119.6, 118.5, 112.9, 56.7, 42.54 ppm. IR (film): 2947
(CHarom), 2245 (CN), 1523 (NO2), 1353 (NO2), 1026 (OCH3).
HRMS (ESI): m/z 291.0742 (291.0746 calc. for C15H12N2O3,
(M+Na)+).
(4-chlorophenyl)(3-methoxy-4-nitrophenyl)acetonitrile (6b):
1
(2-bromo-4-nitrophenyl)(phenyl)acetonitrile (7a): Yield 66%;
Duration of the reaction 20 min; Yield 62%; orange oil; H NMR
1
red oil; H NMR (400 MHz, CDCl3, 25°C): δ = 8.50-8.49 (m, 1H,
(400 MHz, CDCl3, 25°C): δ = 7.87 (d, 3JH,H = 8.4 Hz, 1H, NO2Ar),
3
4
Ar), 8.25-8.24 (m, 1H, Ar), 7.72 (d, JH,H = 8.4 Hz, 1H, Ar), 7.44-
7.44-7.40 (m, 2H, ClAr), 7.32-7.28 (m, 2H, ClAr), ), 7.08 (d, JH,H
3
4
7.37 (m, 5H, Ph), 5.73 (s, 1H, CH) ppm. 13C NMR (101 MHz,
CDCl3, 25°C) : δ = 148.0, 142.2, 133.1, 130.8, 129.5, 129.0,
128.6, 127.8, 124.0, 123.2, 118.0, 41.9 ppm. IR (film): 3100
(CHarom), 2250 (CN), 1525 (NO2), 1348 (NO2). HRMS (EI): m/z
315.9861 (315.9847 calc. for C14H9N2O2Br, M+).
= 2.0 Hz, 1H, NO2Ar), 6.98 (dd, JH,H = 8.4 Hz, JH,H = 1.6 Hz,
1H, NO2Ar), 5.18 (s, 1H, CH) ppm. 13C NMR (101 MHz, CDCl3,
25°C) : δ = 153.5, 141.7, 139.5, 135.2, 132.9, 129.8, 129.1,
126.6, 119.6, 118.1, 112.8, 56.7, 41.9 ppm. IR (film): 2944
(CHarom), 2244 (CN), 1523 (NO2), 1352 (NO2), 1282 (OCH3).
HRMS (EI): m/z 302.0464 (302.0458 calc. for C15H11N2O3Cl,
M+).
(2-methoxy-4-nitrophenyl)(phenyl)acetonitrile (8a): Yield
1
65%; red oil; H NMR (400 MHz, CDCl3, 25°C): δ = 7.88 (dd,
3JH,H = 8.4 Hz, 4JH,H = 2.0 Hz, 1H, Ar), 7.78 (d, 4JH,H = 2.0 Hz, 1H,
(4-chlorophenyl)(2-methoxy-4-nitrophenyl)acetonitrile (8b):
3
1
Ar), 7.52 (d, JH,H = 8.4 Hz, 1H, Ar), 7.41-7.34 (m, 5H, Ph), 5.59
Duration of the reaction 20 min; Yield 76%; orange oil; H NMR
(s, 1H, CH), 4.00 (s, 3H, CH) ppm. 13C NMR (101 MHz, CDCl3,
25°C) : δ = 156.5, 149.0, 134.1, 131.6, 129.4, 129.2, 128.5,
127.7, 118.7, 116.2, 106.2, 56.4, 36.4 ppm. IR (film): 2941
(CHarom), 2246 (CN), 1524 (NO2), 1348 (NO2), 1254 (OCH3).
HRMS (EI): m/z 268.0841 (268.0848 calc. for C15H12N2O3, M+).
(400 MHz, CDCl3, 25°C): δ = 7.86 (dd, 3JH,H = 8.4 Hz, 4JH,H = 2.4
4
Hz, 1H, NO2Ar), 7.76 (d, JH,H = 2.0 Hz, 1H, NO2Ar), ), 7.53(d,
3JH,H = 8.4 Hz, 1H, NO2Ar), 7.36-7.29 (m, 4H, ClAr), 5.55 (s, 1H,
CH) ppm. 13C NMR (101 MHz, CDCl3, 25°C) : δ = 156.5, 149.1,
134.6, 132.7, 131.0, 129.4, 129.3, 129.1, 118.4, 116.3, 106.3,
56.5, 36.1. IR (film): 2946 (CHarom), 2248 (CN), 1525 (NO2),
1349 (NO2), 1255 (OCH3). HRMS (EI): m/z 302.0450 (302.0458
calc. for C15H11N2O3Cl, M+).
2-[cyano(phenyl)methyl]-5-nitrobenzonitrile (9a): Yield 85%;
yellow oil; Yield %; yellow oil; 1H NMR (400 MHz, CDCl3, 25°C):
3
δ = 8.57(d, 4JH,H = 2.0 Hz, 1H, Ar), 8.52 (dd, JH,H = 8.8 Hz, 4JH,H
= 2.0 Hz, 1H, Ar), 7.98 (d, 3JH,H = 8.8 Hz, 1H, Ar), 7.47-7.42 (m,
5H, Ph), 5.66 (s, 1H, CH) ppm. 13C NMR (101 MHz, CDCl3,
25°C) : δ = 147.6, 145.7, 132.7, 130.2, 129.9, 129.5, 128.6,
128.4, 127.7, 117.2, 114.9, 113.5, 40.9 ppm. IR (film): 3086
(CHarom), 2234 (CN), 1531 (NO2), 1355 (NO2). HRMS (ESI): m/z
286.0586 (286.0592 calc. for C15H9N3O2, (M+Na)+).
2-[(4-chlorophenyl)(cyano)methyl]-5-nitrobenzonitrile (9b):
1
Duration of the reaction 20 min; Yield 91%; orange oil; H NMR
(400 MHz, CDCl3, 25°C): δ = 8.58 (d, 4JH,H = 2.4 Hz, 1H, NO2Ar),
8.54 (dd, 3JH,H =8.8 Hz, 4JH,H = 2.4 Hz, 1H, NO2Ar), 7.98 (d, 3JH,H
= 8.8 Hz, 1H, NO2Ar), 7.44-7.35 (m, 4H, ClAr), 5.64 (s, 1H, CH)
ppm. 13C NMR (101 MHz, CDCl3, 25°C) : δ = 147.7, 145.1,
135.9, 131.2, 130.2, 130.1, 129.1, 128.7, 128.6, 116.8, 114.8,
113.5, 40.4. IR (film): 3088 (CHarom), 2235 (CN), 1532 (NO2),
1323 (NO2). HRMS (EI): m/z 297.0311 (297.0305 calc. for
C15H8N3O2Cl, M+).
(4-chlorophenyl)(4-nitrophenyl)acetonitrile (2b): Duration of
1
the reaction 20 min; Yield 89%; orange oil; H NMR (400 MHz,
3
CDCl3, 25°C): δ = 8.27 (d, JH,H = 8.8 Hz, 2H, NO2Ar), 7.55 (d,
3
3JH,H = 8.8 Hz, 2H, NO2Ar), 7.41 (d, JH,H = 8.4 Hz, 2H, ClAr), ),
4
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10.1002/ejoc.201701507
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(4-methoxyphenyl)(4-nitrophenyl)acetonitrile (2c): Yield 91%;
red oil; 1H NMR (400 MHz, CDCl3, 25°C): δ = 8.24 (d, 3JH,H = 8.8
(101 MHz, DMSO, 25°C) : δ = 159.9, 147.7, 145.8, 130.8, 130.0,
129.8, 129.4, 125.9, 118.9, 115.5, 115.3, 112.9, 39.8, 55.8. IR
(film): 2936 (CHarom), 2234 (CN), 1511 (NO2), 1352 (NO2), 1252
(OAr). HRMS (ESI): m/z 316.0690 (316.0698 calc. for
C16H11N3O3, (M+Na)+).
3
Hz, 2H, NO2Ar), 7.55 (d, JH,H = 8.8 Hz, 2H, NO2Ar), 7.26 (d,
3JH,H = 8.8 Hz, 2H, MeOAr), 6.94 (d, 3JH,H = 8.8 Hz, 2H, MeOAr),
5.22 (s, 1H, CH), 3.83 (s, 3H, MeO) ppm. 13C NMR (101 MHz,
CDCl3, 25°C) : δ = 160.0, 147.7, 143.2, 129.0, 128.6, 126.4,
124.4, 118.7, 115.0, 55.4, 41.5. IR (film): 2935 (CHarom), 2247
(CN), 1512 (NO2), 1348 (NO2), 1254 (OAr). HRMS (ESI): m/z
291.0735 (291.0746 calc. for C15H12N2O3, (M+Na)+).
(6-chloro-5-nitropyridin-2-yl)(phenyl)acetonitrile
(10a):
Reaction temperature -40°C; Duration of the reaction 15 min;
Yield 83%; red oil; 1H NMR (400 MHz, CDCl3, 25°C): δ = 8.25 (d,
3
3JH,H = 8.4 Hz, 1H, NO2Py), 7.55 (d, JH,H = 8.0 Hz, 1H, NO2Py),
(3-fluoro-4-nitrophenyl)(4-methoxyphenyl)acetonitrile (3c):
Yield 86%; yellow oil; 1H NMR (400 MHz, CDCl3, 25°C): δ =
8.13-8.06 (m, 1H, NO2Ar), 7.36-7.22 (m, 4H, NO2Ar+MeOAr),
7.50-7.39 (d, m, 5H, Ph), 5.39 (s, 1H, CH) ppm. 13C NMR (101
MHz, CDCl3, 25°C): δ = 159.0, 144.0, 143.6, 135.8, 132.7,
129.7, 129.3, 127.8, 121.2, 117.4, 44.9. IR (film): 3078 (CHarom),
2250 (CN), 1532 (NO2), 1348 (NO2). HRMS (EI) 273.0303: m/z
(273.0305 calc. for C13H8N3O2Cl).
3
6.95 (d, JH,H = 8.8 Hz, 2H, MeOAr), 5.17 (s, 1H, CH), 3.84 (s,
3H, MeO) ppm. 13C NMR (101 MHz, CDCl3, 25°C) : δ = 160.2,
157.0, 154.3, 144.7 (d), 129.0, 127.0 (d), 125.6, 123.6 (d),
118.2, 117.8 (d), 115.1, 55.4, 41.4. IR (film): 2935 (CHarom), 2245
(CN), 1512 (NO2), 1349 (NO2), 1254 (OAr). HRMS (ESI): m/z
309.0647 (309.0651 calc. for C15H11N2O3F, (M+Na)+).
(4-methoxy-5-nitropyridin-2-yl)(4-
methoxyphenyl)acetonitrile (11c): Yield 58%; orange oil; 1H
NMR (400 MHz, DCDCl3, 25°C): δ = 8.97 (s, 1H, NO2Py), 7.37
3
(d, JH,H = 8.8 Hz, 2H, MeOAr), 7.12 (s, 1H, NO2Py), 6.94 (d,
(3-methoxy-4-nitrophenyl)(4-methoxyphenyl)acetonitrile
3JH,H = 8.8 Hz, 2H, MeOAr), 5.30 (s, 1H, CH), 4.04 (s, 3H,
OCH3), 3.83 (s, 3H, OCH3) ppm. 13C NMR (101 MHz, DMSO,
25°C): δ = 161.6, 160.1, 160.0, 147.2, 135.8, 128.9, 125.3,
118.3, 114.9, 106.4, 57.0, 55.4, 44.89. IR (film): 2951 (CHarom),
2248 (CN), 1513 (NO2), 1355 (NO2), 1292 (OPy), 1254 (OAr).
HRMS (ESI): m/z 322.0794 (322.0804 calc. for C15H13N3O4,
(M+Na)+).
1
(6c): Yield 82%; red oil; H NMR (400 MHz, CDCl3, 25°C): δ =
3
3
7.85 (d, JH,H = 8.4 Hz, 1H, NO2Ar), 7.26 (d, JH,H = 8.8 Hz, 2H,
MeOAr), 7.09 (d, 4JH,H = 1.6 Hz, 1H, NO2Ar), 6.99 (dd, 3JH,H = 8.4
4
3
Hz, JH,H = 1.6 Hz, 1H, NO2Ar), 6.94 (d, JH,H = 8.8 Hz, 2H,
MeOAr), 5.15 (s, 1H, CH), 3.97 (s, 3H, MeO), 3.83 (s, 3H, MeO)
ppm. 13C NMR (101 MHz, CDCl3, 25°C) : δ = 160.0, 153.4,
142.7, 139.2, 128.9, 126.5, 126.3, 119.5, 118.8, 114.9, 112.8,
56.7, 55.4, 41.8. IR (film): 2939 (CHarom), 2243 (CN), 1512
(NO2), 1351 (NO2), 1253 (OAr). HRMS (ESI): m/z 321.0842
(321.0851 calc. for C16H14N2O4, (M+Na)+).
(4-nitronaphthalen-1-yl)(phenyl)acetonitrile (12a): Yield 91%;
slight yellow solid; 1H NMR (400 MHz, CDCl3, 25°C): δ = 8.54 (d,
3
3JH,H = 8.4 Hz, 1H, NO2Napht), 8.19 (d, JH,H = 8.0 Hz, 1H,
3
NO2Napht), 8.05 (d, JH,H = 7.6 Hz, 1H, NO2Napht), 7.79-7.72
(2-methoxy-4-nitrophenyl)(4-methoxyphenyl)acetonitrile
(m, 2H, NO2Napht), 7.70-7.64 (m, 1H, NO2Napht), 7.42-7.34 (m,
5H, Ph), 5.91 (s, 1H, CH) ppm. 13C NMR (101 MHz, CDCl3,
25°C): δ = 147.7, 137.2, 134.1, 131.2, 129.5, 129.4, 128.9,
128.5, 127.7, 125.7, 125.6, 124.1, 123.7, 122.8, 118.7, 40.1. IR
(film): 3063 (CHarom), 2244 (CN), 1520 (NO2), 1344 (NO2).
HRMS (ESI): m/z 287.0822 (287.0821 calc. for C16H14N2O4, (M-
H)-).
1
(8c): Yield 95%; red oil; H NMR (400 MHz, CDCl3, 25°C): δ =
3
4
7.87 (dd, JH,H = 8.4 Hz, JH,H = 2.0 Hz, 1H, NO2Ar), 7.77 (d,
3
4JH,H = 1.6 Hz, 1H, NO2Ar), 7.52 (d, JH,H = 8.8 Hz, 1H, NO2Ar),
3
3
7.29 (d, JH,H = 8.8 Hz, 2H, MeOAr), 6.91 (d, JH,H = 8.8 Hz, 2H,
MeOAr), 5.25 (s, 1H, CH), 4.00 (s, 3H, MeO), 3.82 (s, 3H, MeO)
ppm. 13C NMR (101 MHz, CDCl3, 25°C) : δ = 159.7, 156.5,
148.9, 132.0, 129.2, 128.9, 125.9, 119.0, 116.2, 114.6, 106.1,
56.4, 55.4, 35.7. IR (film): 2937 (CHarom), 2246 (CN), 1513
(NO2), 1348 (NO2), 1254 (OAr). HRMS (ESI): m/z 321.0843
(321.0851 calc. for C16H14N2O4, (M+Na)+).
(4-methoxyphenyl)(8-nitroquinolin-5-yl)acetonitrile
(13c):
Reaction temperature -40°C; Duration of the reaction 15 min;
1
Yield 78%; white solid; H NMR (400 MHz, DMSO, 25°C): δ =
3
3
9.05 (d, JH,H = 4.0 Hz, 1H, NO2Quin), 8.66 (d, JH,H = 8.8 Hz,
3
2-[cyano(4-methoxyphenyl)methyl]-5-nitrobenzonitrile (9c):
Yield 87%; white solid; 1H NMR (400 MHz, DMSO, 25°C): δ =
8.78 (d, 4JH,H = 2.0 Hz, 1H, NO2Ar), 8.61(dd, 3JH,H = 8.8 Hz, 4JH,H
= 2.4 Hz, 1H, NO2Ar), 8.04 (d, 3JH,H = 8.8 Hz, 1H, NO2Ar), 7.33
1H, NO2Quin), 8.35 (d, JH,H = 8.0 Hz, 1H, NO2Quin), 7.91 (d,
3JH,H = 8.0 Hz, 1H, NO2Quin), 7.81-7.76 (m, 1H, NO2Quin), 7.36
3
3
(d, JH,H = 8.8 Hz, 2H, MeOAr), 6.97 (d, JH,H = 8.8 Hz, 2H,
MeOAr), 6.67 (s, 1H, CH), 3.73 (s, 3H, OCH3) ppm. 13C NMR
(101 MHz, DMSO, 25°C): δ = 159.7, 153.2, 148.7, 139.4, 137.1,
133.1, 129.5, 127.2, 126.2, 126.2, 124.1, 123.2, 120.2, 115.3,
3
3
(d, JH,H = 8.8 Hz, 2H, MeOAr), 7.00 (d, JH,H = 8.8 Hz, 2H,
MeOAr), 6.18 (s, 1H, CH), 3.76 (s, 3H, MeO) ppm. 13C NMR
5
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10.1002/ejoc.201701507
European Journal of Organic Chemistry
FULL PAPER
e) M. Mąkosza, W. Danikiewicz, K. Wojciechowski, Liebigs Ann.
Chem., 1988, 203; f) l. Lerman, M. Weinstock-Rosin, A. Nudelman,
Synthesis, 2004, 3043; g) M. Mąkosza, D. Sulikowski, Eur. J. Org.
Chem., 2011, 6887; h) N.J. Lawrence, C.A. Davies, M. Gray, Org.
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Charushin, Pure Appl. Chem., 2017, 89, 1195.
55.7, 37.6. IR (film): 2956 (CHarom), 2244 (CN), 1531 (NO2),
1360 (NO2), 1254 (OAr). HRMS (ESI): m/z 320.1029 (320.1035
calc. for C18H14N3O3, (M+H)+).
Acknowledgements
This research was supported by National Science Centre
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Keywords: Acetals
•
carbanions
•
diarylacetonitriles
•
nitroarenes
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6
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Cyanohydrins protected with
ethoxyethyl group were successfully
used in vicarious nucleophilic
substitution of hydrogen in the
aromatic nitrocompounds to
Key Topic*
Nazar Rad, Mieczysław Mąkosza*
X
H3
C
O
CH3
CH2
CH
O
NC
Page No. – Page No.
H
NC
1. t-BuOK
2. HCl
+
Y
Y
Simple Synthesis of Aryl p-
synthesized aryl p-nitroacetonitriles.
N+
Nitroarylacetonitriles via Vicarious
Nucleophilic Substitution with
N+
O-
O
O-
O
X
Carbanions of Protected Cyanohydrins
Nucleophilic Substitution with
Carbanions of Protected Cyanohydrins
*one or two words that highlight the emphasis of the paper or the field of the study
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Key Topic*
Author(s), Corresponding Author(s)*
((Insert TOC Graphic here; max. width: 11.5 cm; max. height: 2.5 cm; NOTE: the
final letter height should not be less than 2 mm.))
Page No. – Page No.
Title
Text for Table of Contents
*one or two words that highlight the emphasis of the paper or the field of the study
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