Reaction of Tertiary 2-Chloroketones with Cyanide Ions: Application to 3-Chloroquinolinediones

Article abstract of DOI:10.1002/open.202100024

3-Chloroquinoline-2,4-diones react with cyanide ions in dimethyl formamide to give 3-cyanoquinoline-2,4-diones in small yields due to the strong hindrance of the substituent at the C-3 atom. Good yields can be achieved if the substituent at this position

Full text of DOI:10.1002/open.202100024

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Reaction of Tertiary 2-Chloroketones with Cyanide Ions:
Application to 3-Chloroquinolinediones
Antonín Klásek,*[a] Stanislav Kafka,[a] Ondřej Rudolf,[a] Antonín Lyčka,[b] Michal Rouchal,[a] and
Lukáš Bednář[a]
3-Chloroquinoline-2,4-diones react with cyanide ions in dimeth-
yl formamide to give 3-cyanoquinoline-2,4-diones in small
yields due to the strong hindrance of the substituent at the C-3
atom. Good yields can be achieved if the substituent at this
position is the methyl group. In the methanol solution, the
reaction proceeds by an addition mechanism to form 2-oxo-
1a,2,3,7b-tetrahydrooxireno[2,3-c]quinoline-7b-carbonitriles,
from which 4-hydroxy-3-methoxy-2-oxo-1,2,3,4-tetrahydroqui-
noline-4-carbonitriles are subsequently formed by opening of
the epoxide ring with methanol. Some minor products of these
reactions have also been isolated. The 1H, 13C and 15N NMR
spectra of the prepared compounds were measured, and all
resonances were assigned using appropriate two-dimensional
spectra.
1. Introduction
that was described more frequently. Thus, α-bromoketones
were converted to α-cyanooxiranes with sodium cyanide in
water/dioxane.[8] Using trimethylsilyl cyanide, α-chloroketones
were converted to 3-chloro-2-(trimethylsilyloxy)nitriles[9] in the
presence of zinc(II) iodide. The analogous reaction also
proceeds with α-bromoketones[10] and, especially, α-fluoroke-
tones in the presence of Lewis bases.[11]
α-Haloketones belong to a group of very reactive organic
compounds. In the literature, a good review was found that
summarized the preparation of α-haloketones and their reac-
tions, which are centered to the preparation of different
heterocycles.[1] Several reaction mechanisms were discussed for
the substitution of halogen atom in α-haloketones.[2] The review
described that simple nucleophilic substitution of the bromine
atom in α-bromoketone provides α-cyanoketone in good yields
in a water/ethanol solvent.[3] Similar results were obtained by
executing the reaction in DMSO.[4] However, scarce information
is found in the literature for the reaction of cyanide ions with
tertiary α-haloketones.[5,6] It is known that such compounds
react inconveniently with nucleophiles, but the nucleophility
can be increased, e.g., by creation of a “naked” cyanide anion
using crown ethers.[1] Other problems are linked to some side
reactions, e.g., the attack of the cyanide ion to the carbonyl
group.[1,6a–c]
3-Chloroquinolinediones 1 constitute convenient model
compounds for the study of the reactions of tertiary haloke-
tones with nucleophiles. Due to the presence of two reactive
sites in 3-chloroquinolinediones 1, there are plenty of possible
reactions capable of creating new types of heterocyclic
compounds. Compounds 1 can be smoothly prepared by the
reaction of 4-hydroxyquinolin-2-ones with sulfuryl chloride.[12] It
is known that a considerable amount of quinolinediones are
substituted in position 3 with a functional group containing
heteroatom. 3-Hydroxyquinoline-2,4-diones result from the
oxidation of 4-hydroxyquinolin-2-ones with peroxyacetic acid.[13]
In nature, these compounds were found as metabolites of some
Pseudomonas species.[14] The reaction of 4-hydroxyquinolin-2-
ones with in situ prepared thiocyanogen leads to 3-
thiocyanatoquinolinediones.[15] 3-Fluoroderivatives were pre-
pared from 3-chloro-quinolinediones.[16] 3-Nitroquinolinediones
resulted from the action of nitric acid.[12] 3-Azidoderivatives
were prepared from 3-chloroquinolinediones and sodium
azide.[17] Initial efforts for the conversion of 3-halogenoderiva-
tives to corresponding amines were not very successful. The
substitution of the bromine atom in position 3 of quinoline-2,4-
dione moiety was accomplished by reaction with a tenfold
excess of appropriate secondary amine in diethyl ether,[18] which
was part of larger polycyclic patterns, such as 4H-pyrido[3,2,1-jk]
carbazole-4,6(5H)-dione, 1H-pyrido[3,2,1-kl]phenoxazine-1,3(2H)-
dione and 1H-pyrido[3,2,1-kl]phenothiazine-1,3(2H)-dione with
the dimethylamino or 4-methylpiperazino group. However, the
attempts at ammonolysis of 3-chloroquinolinediones with
aqueous ammonia resulted in the preparation of only one
desired product, namely that product bearing the 3-benzyl
substituent at the C-3 atom.[13] The first 3-aminoquinolinedione
The cyanohydrin reaction is a well-known reaction of
cyanide ions with the carbonyl group. If a halogen is present in
the adjacent position, easy intramolecular dehalogenation
proceeds and α-cyanooxiranes are formed,[7] which is a reaction
[a] Prof. Dr. A. Klásek, Assoc. Prof. Dr. S. Kafka, Dr. O. Rudolf, Dr. M. Rouchal,
L. Bednář
Department of Chemistry
Faculty of Technology, Tomas Bata University
Vavrečkova 275, 760 01 Zlín (Czech Republic)
E-mail: klasek@utb.cz
[b] Prof. Dr. A. Lyčka
Department of Chemistry
Faculty of Science, University of Hradec Králové
Rokitanského 62, 500 03 Hradec Králové 3 (Czech Republic)
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/open.202100024
© 2021 The Authors. Published by Wiley-VCH GmbH. This is an open access
article under the terms of the Creative Commons Attribution Non-Com-
mercial NoDerivs License, which permits use and distribution in any med-
ium, provided the original work is properly cited, the use is non-commercial
and no modifications or adaptations are made.
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was prepared by acid hydrolysis of the corresponding 3-
acetamido derivative, which was obtained by rearrangement of
6-chloro-4-hydroxy-3-imino-1-methyl-4-phenyl-3,4-dihydro-1H-
quinolin-2-one.[17] Only when dimethyl formamide was used as
the reaction medium were the appropriate 3-amino derivatives
prepared in good yields from the corresponding 3-chloro
derivatives and in situ generated ammonia or primary
amines.[20]
To the best of our knowledge, 3-cyanoquinoline-2,4-diones
were not prepared until now. Therefore, we decided to study
their preparation from the reaction of 3-chloroquinolinediones
1 with cyanide ions. Compounds 1 can react with CNÀ ions in
two different ways: first, by simple substitution of the chlorine
compounds 1a–i with cyanide ions was carried out in two
different solvents – DMF and methanol. In DMF, as a polar and
aprotic solvent, the main reaction products were 3-carbonitriles
2 (Table 1, NMR data in Table 2). Compounds 2 gave only one
aliphatic quaternary carbon in the 13C NMR spectra (Table 2). In
the IR spectra of compounds 2, a very weak band correspond-
ing to stretching vibration of CN group appears, as could be
expected, in the region of 2222–2262 cmÀ 1, since a very similar
wavenumber range of CN absorption bands (2220–2273 cmÀ 1)
has been reported earlier for a series of nitriles with two
carbonyl groups in close proximity to the CN group, namely 2-
cyanocycIopent-4-ene-l,3-diones.[21] The reaction is not abso-
lutely regioselective. In two cases (1c and 1f), products 5 were
also isolated (Table 1). Table 1 shows that the yields of 2 were
very poor or even none, whereas unreacted starting materials,
1,3-hydroxyquinolinediones 3 and 4-hydroxy-2-quinolones 4
were isolated or, at least, indicated by TLC in most cases. We
believe that the poor yields of 2 are caused by the steric
hindrance of the substituent R2. This effect is very strong
particularly where R2 is the benzyl or phenyl group. In these
instances, the expected compounds (2b,c,i) were not isolated.
Therefore, we performed experiments with three other com-
atom to form corresponding nitriles and, second, by
a
nucleophilic attack on the carbonyl group. Both possibilities are
studied in this paper.
2. Results and Discussion
In all compounds, H, Me and Ph were chosen as R1, and Bu, Bn
and Ph were chosen as R2 (Scheme 1). The reaction of
Scheme 1. Reaction of 3-chloroquinoline-2,4-diones with cyanide ions in DMF and methanol.
Table 1. The key of substituents and results of the reaction of α-chloroketones 1 with cyanide ions in DMF and in methanol (isolated yields).
a
b
c
d
e
f
g
h
i
j
k
l
R1
R2
H
Bu
H
Bn
H
Ph
Me
Bu
Me
Bn
Me
Ph
Ph
Bu
Ph
Bn
Ph
Ph
H
Me
Me
Me
Ph
Me
In DMF (Method A)
1 [%][a]
2 [%]
27
9
b
40
0
50
8
a
10
5
7
0
7
4
7
4
8
14
10
0
9
20
48
0
12
5
24
58
a
a
55
3 [%][b]
4 [%][b]
5 [%]
b
a
12
7 [%]
6
In methanol (Method B)
1 [%][a]
3 [%][b]
4 [%][b]
5 [%]
6 [%]
7 [%]
8 [%]
3
20
15
24
0
25
0
47
47
30
30
19
a
19
b
0
5
0
2
53
a
0
16
4
5
24
0
0
44
3
40
32
7
[a] Regenerated starting compounds. [b] Compounds 3 and 4 with declared yields were isolated and their structure was confirmed by comparison of their IR
spectra with those of authentic compounds. Non-isolated compounds were indicated by TLC.
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Table 2. 1H, 13C and 15N chemical shifts of compounds 2 in DMSO-d6.
Position
2a
δ[H]
2d
δ[H]
2e
δ[H]
2g
δ[H]
2h
δ[H]
2j
δ[H]
2k
δ[H]
2l
δ[H]
δ[C]
δ[C]
δ[C]
δ[C]
δ[C]
δ[C]
δ[C]
δ[C]
1
2
3
4
4a
5
6
7
8
8a
3-CN
1'(R1)
2'(R1)
–
–
–
–
248.9[a],[b]
165.8
61.0
187.6
117.3
127.2
123.1
136.6
116.7
141.4
116.0
–
–
–
–
–
–
–
–
–
–
–
235.0[a]
165.2
61.9
–
–
–
–
234.2[a]
164.5
62.8
–
–
–
–
–
–
–
–
–
–
–
165.2
61.3
187.1
116.0
127.4
123.4
136.7
116.2
142.5
116.0
30.2
–
164.6
62.3
186.7
119.4
127.2
123.4
136.6
116.0
142.4
115.9
30.0
–
–
–
–
–
7.91
7.23
7.55
6.36
–
166.5
55.0
166.0
55.4
166.0
56.1
187.7
118.0
127.7
123.5
136.4
117.0
143.6
116.9
137.0
129.2
128.8
130.3
129.1
24.9
–
187.1
118.4
127.5
123.5
136.2
116.9
143.5
115.9
137.0
129.3
128.9
130.1
130.4
37.3
186.8
119.1
127.3
123.5
136.2
117.0
143.6
115.9
137.1
129.5
128.4
130.4
130.1
43.9
188.1
116.8
127.4
123.1
136.7
116.7
141.6
117.0
–
187.6
118.3
127.6
123.4
136.8
116.3
142.6
117.0
30.2
–
–
–
–
–
–
7.78
7.16
7.64
7.10
–
7.86
7.27
7.77
7.42
–
–
3.39
–
–
–
–
1.99
1.90
1.35
1.31
1.22
0.79
–
7.83
7.26
7.72
7.31
–
–
3.35
–
–
–
–
3.34
3.31
–
7.87
7.21
7.52
6.29
–
7.81
7.17
7.65
7.11
–
7.89
7.29
7.78
7.43
–
7.94
7.25
7.56
6.37
–
–
–
–
–
–
–
–
3.40
–
–
11.22[b]
–
11.24
–
–
–
–
7.42
7.31
7.42
7.59
2.10
2.19
1.41
–
7.45
7.31
7.62
7.57
3.51
3.54
–
7.45
7.31
7.61
7.57
1.90
–
–
–
–
–
–
–
–
1.99
1.91
1.36
–
1.26
0.80
–
–
–
–
37.6
–
–
–
44.3
–
–
–
–
3'(R1)
4'(R1)
1'(R2)
–
1.73
–
–
–
–
–
–
–
24.7
–
–
–
–
–
–
–
1.72
–
–
–
–
–
–
–
24.9
–
–
–
–
–
–
37.5
2'(R2)
26.6
–
21.3
13.6
–
26.7
–
21.3
13.6
–
132.1
–
128.0
130.1
128.0
26.8
–
21.3
13.6
–
132.2
–
–
–
–
–
–
3'(R2)
4'(R2)
5'(R2)
6.98
7.21
7.11
1.29
0.84
–
7.12
7.28
7.30
130.4
128.1
129.5
–
–
1
[a] δ(15N). [b] J(15N, H)=91.0 Hz.
pounds (1j–1l) bearing the methyl group in position 3. Our
presumption was confirmed and the corresponding compounds
2j,k,l were prepared in good yields of 48–58%.
In methanol, as a polar and protic solvent, compounds 1
reacted differently. As expected, the cyanide ion was added to
the carbonyl group, whereat oxiranes 5 arose due to the
intramolecular nucleophilic substitution of the chlorine atom
(Scheme 1, Table 1). By analogy with compounds 2, in the IR
spectra of compounds 5, a very weak band corresponding to
stretching vibration of CN group appears in the region of 2241–
2260 cmÀ 1. Oxiranes 5 contain the cyano group signal and two
signals of quaternary carbons in the 13C NMR spectra (Table 3),
resonating at 113.7–114.6 ppm (CN), 63.1–66.1 ppm (C-1a) and
56.7–59.1 ppm (C-7b). Compounds 6 gave two aliphatic quater-
nary carbons in 13C NMR spectra (Table 4), and the chemical
shifts were considerably shifted to higher frequencies compared
with those in compounds 5. Compounds 6 resulted from
Table 3. 1H, 13C and 15N chemical shifts of oxiranes 5 in DMSO-d6.
Position
5a
δ[H]
5c
δ[H]
5f
δ[H]
5i
δ[H]
5k
δ[H]
5l
δ[H]
δ[C]
δ[C]
δ[C]
δ[C]
δ[C]
δ[C]
1a
2
3 (N)
3a
4
5
6
7
7a
7b
CN
1'(R1)
2'(R1)
–
–
–
–
7.08
7.51
7.21
7.76
–
65.2
163.5
–
–
–
–
–
7.15
7.55
7.23
7.77
–
66.0
163.5
–
–
–
–
–
7.42
7.69
7.33
7.86
–
–
–
3.41
–
65.8
–
–
–
–
6.32
7.50
7.33
7.92
–
–
–
–
7.42
7.28
7.63
7.55
–
66.1
–
–
–
–
7.23
7.62
7.32
7.82
–
–
–
3.35
–
63.1
–
–
–
–
6.24
7.42
7.28
7.90
–
–
–
–
7.44
7.24
7.60
7.54
1.87
63.4
163.8
–
163.2
À 253.5[a]
138.0
116.2
132.4
123.3
128.8
115.4
59.0
163.2
À 233.1[a]
139.1
116.8
132.0
123.4
128.9
115.2
59.1
113.7
137.0
129.2
128.6
130.4
129.1
130.7
163.9
À 256.0[a]
137.8
115.9
132.0
123.1
128.7
116.6
57.1
136.5
116.1
132.0
122.9
128.4
114.5
56.7
114.2
–
136.8
116.2
132.1
122.9
128.4
114.5
59.1
113.8
–
137.0
116.5
131.7
123.2
128.8
115.4
57.1
114.6
139.1
129.1
128.7
130.3
129.1
15.8
–
–
–
–
113.7
30.3
–
114.6
29.9
–
11.15
–
11.32
–
–
–
3'(R1)
4'(R1)
1'(R2)
–
–
–
–
29.0
–
–
–
–
–
–
–
–
–
–
–
–
1.84
–
–
16.1
2.38
1.83
1.61
1.52
1.37
0.89
–
130.5
131.1
2'(R2)
26.3
7.63
127.9
7.63
127.8
7.73
127.8
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
3'(R2)
4'(R2)
5'(R2)
22.2
13.7
–
7.45
7.45
–
128.1
129.6
–
7.48
7.48
–
128.1
128.7
–
7.47
7.47
–
128.1
129.6
–
[a] δ(15N).
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Table 4. 1H, 13C and 15N chemical shifts of compounds 6 and 7 in DMSO-d6.
Position
6a
δ[H]
6j
δ[H]
7d
δ[H]
7f
δ[H]
7k
δ[H]
δ[C]
δ[C]
δ[C]
δ[C]
δ[C]
1
2
3
4
4a
5
6
7
8
8a
CN
OH
OH
OCH3
1'(R1)
1'(R2)
10.53
–
–
–
–
7.47
7.13
7.44
6.97
–
–
5.94
–
3.07
10.53
1.60
1.38
1.49
1.02
1.13
0.76
–
–
–
–
–
10.53
À 252.6[a],[b]
-
–
–
–
À 242.7[a]
167.0
88.5
189.7
119.2
127.5
123.9
137.6
114.5
142.3
–
–
–
–
29.9
40.5
–
–
–
–
–
À 242.3[a]
168.4
83.9
190.1
119.4
127.7
123.5
137.0
116.2
142.6
–
–
–
–
29.9
21.7
–
–
–
À 242.8[a]
166.4
89.0
187.6
119.0
127.4
123.4
136.4
114.5
141.6
–
169.4
76.8
83.6
118.1
128.5
122.3
131.7
116.3
136.5
115.3
–
–
53.3
–
33.7
–
170.5
–
–
–
–
7.62
7.15
7.66
7.58
–
–
–
–
–
3.25
–
–
b
–
b
b
–
–
–
–
–
7.75
7.22
7.41
7.58
–
3.61
–
–
b
b
b
74,0
83.5
117.8
128.5
122.2
131.7
116.3
136.5
115.2
–
–
53.5
–
22.2
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
7.49
7.13
7.45
6.99
–
–
6.11
–
3.07
10.52
1.22
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
7.88
7.29
7.82
7.50
–
–
–
–
–
3.43
2.20,
–
1.36
–
1.28
0.82
–
–
–
–
–
7.80
7.24
7.58
7.48
–
3.60
2.09
2.02
1.16
0.97
0.64
7.88
7.28
7.78
7.44
–
–
–
–
–
–
–
3.43
1.70
–
29.8
136.2
–
c–
–
c
c
2'(R2)
22.1
24.8
–
3'(R2)
4'(R2)
1'
2'
3'
4'
4a'
5'
6'
7'
22.3
13.9
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
22.0
13.7
–
–
–
–
–
–
–
7.74
7.26
7.59
7.50
–
3.60
1.77
–
–
–
À 252.6[a]
162.4
118.8
155.4
118.5
123.3
121.7
130.2
116.4
137.7
29.6
À 254.5[a]
162.6
117.3
155.2
118.6
123.5
121.6
130.3
114.4
137.6
29.7
11.9
–
À 250.5[a]
162.2
117.6
155.5
118.0
124.4
121.9
130.2
115.8
136.2
29.7
130.8
–
–
–
–
–
–
–
–
–
8'
8a'
1'(R1)'
1'(R2)'
25.6
–
29.5
22.4
2'(R2)'
3'(R2)'
4'(R2)'
–
–
–
–
–
–
–
c
c
b
–
–
–
13.6
[a] δ(15N). [b] 1J(15N, H)=91.3 Hz. [c] δ(1H)=7.30–7.45, 6,70–6,90, broadened overlapped signals. [c] δ(13C)=133.5, 131.1, 129.3, 127.4, 126.7, 126.6.
subsequent nucleophilic attack of methanol on oxiranes 5. The
stretching vibrations of CN groups were not observed in the IR
spectra of some compounds 6 (6a and 6j), which is common
with some cyanohydrines.[20] Table 1 shows that the sum of the
yields of 5 and 6 depends on the nature of the substituent on
C-3. When the starting compounds were 1e and 1h, wherein R2
is a benzyl group, the corresponding compounds 5 and 6 were
not isolated.
The reactions of 1d, 1f and 1k took place in anomalous
way yielding unsymmetrical dimers 7d, 7f and 7k (NMR data in
Table 4). Their origin can be explained by the providing
corresponding 4-hydroxy-2-quinolone 4, which is alkylated by
the molecule of the starting compound 1. The presence of
compounds 4 in the reaction mixture was proved by TLC in
almost all cases. Their formation is caused by the transfer of the
“positive charged” chlorine atom in 1 to a nucleophile (e.g.,
water, CNÀ ).26
boiling. However, the conversions proceeded smoothly in a
short time and compounds 6a,l were obtained in good yields
after addition of NaCN to the reaction mixtures, apparently due
to its basicity by the effect of which methoxide anions were
generated.
Four compounds that do not have the CN group in the
molecule were also isolated. These compounds exhibit signals
of two quaternary carbon atoms and a signal of proton on the
nitrogen atom in the range of 8.66–8.88 ppm in their NMR
spectra (Table 5), which pertains to the imino group. It stands
to reason that the base catalyzed (NaCN) addition of the
molecule of methanol to the nitrile group[24] in compounds 5
proceeded under formation of methyl imidates 8d,g,k,l. (NMR
spectra in Table 5). 15N NMR spectroscopy provided the key
piece of information about the constitution of compounds
1
8d,g,k,l. Gradient selected 1D H-15N-HMQC gave us relatively
1
1
small J(15N, H) coupling constants about 61 Hz while from 2D
1H-15N-HMQC we read 15N chemical shifts of =NÀ H about
À 155 ppm, both typical of methyl imidates. These compounds
were prepared also by the base catalyzed reaction of com-
pounds 5 with methanol.
To support our explanation of the presence of compounds
6 in the reaction mixtures, we investigated the conversion of
compounds 5a and 5l to the corresponding compounds 6a
and 6l. It has been shown that this conversion does not take
place by the action of methanol alone, even with prolonged
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Table 5. 1H, 13C and 15N chemical shifts of imines 8 in DMSO-d6.
Position
8d
δ[H]
8f
δ[H]
8g
δ[H]
8k
δ[H]
8l
δ[H]
δ[C]
δ[C]
δ[C]
δ[C]
δ[C]
1a
2
3 (N)
3a
4
5
6
7
–
–
–
–
7.29
7.52
7.18
7.31
–
64.2
–
–
–
–
7.36
7.58
7.21
7.36
–
65.5
–
–
–
–
6.22
7.30
7.14
7.36
–
64.6
–
–
–
–
7.31
7.51
7.19
7.34
–
61.8
–
–
–
–
6.22
7.29
7.13
7.36
–
62.2
164.1
À 254.0[a]
138.1
115.6
130.8
122.7
129.1
118.2
65.9
164.5
À 253.5[a]
138.5
115.8
131.1
122.7
129.3
118.00
67.8
164.3
À 242.7[a]
139.4
116.3
130.4
122.8
129.3
118.0
66.3
164.8
À 255.2[a]
138.3
115.6
130.8
122.7
129.1
118.2
66.1
164.9
À 240.0[a]
139.6
116.3
130.4
122.8
129.2
118.0
66.3
7a
7b
–
–
–
–
–
C=NH
C=NH
–
8.66
164.0
À 155.0[a]
J=60.1 Hz
53.3
29.7
–
–
8.52
162.5
À 154.1[a]
J=61.1 Hz
52.9
30.0
–
–
8.76
163.9
À 154.2[a]
J=61.2 Hz
53.4
137.2
129.4
128.7
130.3
128.9
27.9
–
8.88
164.1
À 155.4[a]
J=60.1 Hz
53.5
29.8
–
–
8.75
164.1
À 154.8[a]
J=61.0 Hz
53.5
137.3
129.4
128.7
130.2
128.9
13.9
OCH3
1'(R1)
2'(R1)
3.79
3.38
–
3.40
3.42
–
3.84
–
3.79
3.35
–
3.84
–
7.36
7.19
7.58
7.53
1.54
7.37
7.19
7.56
7.52
2.25
1.39
1.39
3'(R1)
4'(R1)
1'(R2)
–
–
–
–
28.2
–
–
–
–
–
–
–
1.50
–
–
14.2
2.28
1.29
1.33
1.26
1.23
0.83
131.8
2'(R2)
26.5
7.36
127.6
26.5
–
–
–
–
3'(R2)
4'(R2)
22.2
13.6
7.36
7.36
127.5
128.5
1.25
0.84
22.3
13.7
–
–
–
–
–
–
–
–
[a] δ(15N).
Experimental Section
3. Conclusion
General Methods
We conclude that the presented reaction of tertiary 2-
chloroketones with cyanide ions is interesting from a theoretical
viewpoint, which is exemplified using 3-chloroquinoline-2,4-
diones 1 as model compounds, and it also leads the way for
preparing new compounds for the study of their biological
activity due to the simple reaction protocol.
Melting points were determined on a Kofler block. IR (KBr) spectra
were recorded on a FT-IR ALPHA-T spectrophotometer (Bruker). The
intensities of the bands are referred to as very strong (vs), strong
(s), medium (m), weak (w), and very weak (vw). NMR spectra were
recorded on a Bruker AVANCE III HD spectrometer (500.13 MHz for
1H, 125.76 MHz for 13C), and on a Bruker AVANCE III HD 400
spectrometer (400.13 MHz for 1H, 100.56 MHz for 13C and 40.55 MHz
Although the yields of products of nucleophilic substitution
of the chlorine atom in aprotic DMF are low owing to a strong
steric hindrance, we demonstrated that they can be substan-
tially enhanced by the suitable selection of the substituent in
the position 3 of the starting compound. We also show that
carrying out the reaction in polar protic solvent (methanol)
leads to the nucleophilic addition of the cyanide ion to the
carbonyl group, which allows preparation of compounds with
oxirane ring 5 as the second row of products that can be
smoothly converted to 4-hydroxy-3-alkoxyquinolinones 6. Oxir-
anes 5 can also act as important synthetic intermediates for the
synthesis of different heterocycles, e.g., indoles by the reaction
with anilines.[25] The reaction of compounds 1d,g,k,l having an
alkyl group in position 3 with cyanide ions in methanol is
interesting, because it does not afford or affords not only
epoxides 5, but also carbamidates 8.
for 15N) in DMSO-d6. H and 13C chemical shifts are given on the δ
1
scale (ppm) and are referenced to internal TMS (δ=0.0). The 15N
chemical shifts were referred to an external 15N enriched nitro-
methane in
a coaxial capillary (δ=0.0). All 2D experiments
(gradient-selected (gs)-COSY, NOESY, gs-HMQC, gs-HMBC) and 1D
1H-15N gs-HMQC were performed using manufacturer’s software.
The positive-ion EI mass spectra (EI-MS) were measured on a
Shimadzu QP-2010 instrument within the mass range m/z=50–600
using direct inlet probe (DI). Samples were dissolved in dichloro-
methane (30 μg/mL) and 10 μL of the solution was evaporated in
°
°
DI cuvette at 50 C. The ion source temperature was 200 C; the
energy of electrons was 70 eV. Only signals exceeding relative
abundance of 5% are listed. The positive as well as negative
electrospray ion mass spectra (ESI-MS) were recorded on an
amaZon X ion-trap mass spectrometer (Bruker Daltonics, Bremen,
Germany) equipped with an ESI source. Individual samples were
infused into the ion source as methanol/water (1/1, v/v) solutions
via a syringe pump at a constant flow rate of 4 μLminÀ 1. The other
instrumental conditions were as follows: m/z range 50–1500,
electrospray voltage �4.2 kV, drying gas temperature 220 C, drying
gas flow 6.0 dm3 minÀ 1, nebulizer pressure 55.16 kPa, capillary exit
�140 V. Nitrogen was used as nebulizing as well as drying gas.
Column chromatography was carried out on silica gel (VWR
CHEMICALS) using chloroform/ethanol (in ratios from 99:1 to 8:2)
(S1), benzene and then successive mixtures of benzene/ethyl
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acetate (in ratios from 99:1 to 8:2) (S2). Reactions as well as the
course of separation and also the purity of substances were
monitored by TLC (elution systems benzene/ethyl acetate (4:1)
(S3), chloroform/ethanol (9:1 and 1:1) (S4 and S5), and chloroform/
ethyl acetate (7:3) (S6) on Alugram® SIL G/UV254 foils (Macherey-
Nagel). Elemental analyses (C, H, N) were performed with an EA
Flash EA 1112 Elemental Analyzer (Thermo Fisher Scientific).Regen-
erated compounds 1 and isolated compounds 3 and 4 were
identified by IR spectra.
H+ +H2O]À (100). For C18H14N2O2 (290.32) calcd C 74.47, H 4.86, N
9.65; found: C 74.24, H 4.82, N 9.43.
2g: Compound was prepared from 1g by Method A in 14% yield.
°
~
Colorless solid, mp 135–139 C (benzene/hexane). IR (KBr): n=2958
(w) ν(CH), 2932 (w) ν(CH), 2258 (w) ν(CN), 1709 (vs) ν(CO), 1682 (vs)
ν(CO), 1601 (s), 1492 (m), 1462 (vs), 1349 (s), 1293 (m), 761 (s), 707
(m) cmÀ 1. ESI-MS (pos.) m/z (%): 659.2 [2·M+Na+]+ (11), 656.2 [4·M
+H+ +K+]2+ (10), 497.2 [3·M+H+ +K+]2+ (100), 357.0 [M+K+]+
(6), 341.1 [M+Na+]+ (37), 319.1 [M+H+]+ (7). ESI-MS (neg.) m/z
(%): 352.9 [M+ClÀ ]À (100). EI-MS: 41 (76), 42 (7), 43 (36), 55 (29), 56
(10), 57 (100), 70 (11), 71 (33), 76 (12),77 (60), 78 (12), 83 (18), 84 (8),
85 (29), 97 (13), 99 (10), 102 (10), 103 (8), 111 (10), 113 (9), 115 (7),
127 (9), 128 (10), 140 (7), 143 (9), 149 (22), 151 (13), 152 (9), 156
(33), 166 (8), 167 (11), 177 (10), 178 (12), 179 (9), 193 (6), 204 (14),
205 (46), 206 (15), 221 (11), 222 (20), 229 (10), 231 (12), 232 (11),
233 (49), 234 (68), 235 (22), 244 (13), 245 (24), 248 (14), 250 (85),
251 (49), 252 (8), 258 (13), 259 (32), 260 (37), 261 (89), 262 (99),
2163 (26), 273 (12), 290 (14), 302 (9), 303 (14), 318 (63), 319 (15). For
C20H18N2O2 (318.37) calcd C 75.45, H 5.70, N 8.80. found C 75.20, H
5.63, N 8.79.
General procedure for the reaction of
3-hloro-quinolinediones 1 with cyanide ions
Method A: NaCN (0.147 g, 3 mmol) was added to the solution of
°
compound 1 (3 mmol) in DMF (12 mL) portionwise at 0 C during
1 h. The orange suspension was stirred for 5 h at room temperature
and then poured onto crushed ice (100 mL). The mixture was
extracted with chloroform (6×25 ml). Collected extracts were dried
with anhydrous sodium sulfate, evaporated to dryness and column
chromatographed.
Method B: The reaction was carried out by the similar procedure as
Method A, with the difference that methanol (12 mL) instead of
DMF was used as solvent. The mixture was stirred for 1 h at room
temperature, subsequently refluxed for 1–3 h and then poured
onto crushed ice. The precipitate solid was filtered off with suction.
The filtrate was extracted with chloroform (6×25 ml). Collected
extracts were dried with anhydrous sodium sulfate, filtered, and
evaporated to dryness. Collected portions were chromatographed
on silica gel column.
2h: Compound was prepared from 1h by Method A in 24% yield,
°
~
Colorless solid, mp 197–200 C (benzene/hexane). IR (KBr): n=3027
(w) ν(CH), 2979 (w) ν(CH), 2258 (w) ν(CN), 1712 (vs) ν(CO), 1681 (vs)
ν(CO), 1599 (s), 1493 (m), 1464 (s), 1352 (s), 765 (s), 708 (m), 683 (m)
cmÀ 1. ESI-MS (pos.) m/z (%): 727.2 [2·M+Na+]+ (39), 705.3 [2·M+
H+]+ (8), 548.1 [3·M+H+ +K+]2+ (9), 391.0 [M+K+]+ (34), 375.1 [M
+Na+]+ (100), 353.1 [M+H+]+ (18). ESI-MS (neg.) m/z (%): 368.9
[M-H+ +H2O]À (100). For C23H16N2O2 (352.39) calcd C 78.39, H 4.58,
N 7.95; found C 78.28, H 4.65, N 7.88.
2a: Compound was prepared from 1a by Method A in 9% yield.
2j: Compound was prepared from 1j by Method A in 58% yield.
°
~
°
Colorless solid, mp 226–229 C (ethyl acetate/hexane). IR (KBr): n=
3218 (w) ν(NH), 3081 (w) ν(CH), 2980 (w) ν(CH), 2259 (w) ν(CN),
1704 (s) ν(CO), 1683 (vs) ν(CO), 1613 (m), 1594 (w), 1484 (m), 1437
(w), 1386 (m), 1249 (w), 787 (w) cmÀ 1. ESI-MS (pos.) m/z (%): 507.1
[2·M+Na+]+ (27), 281.0 [M+Na+]+ (16), 265.0 [M+H+]+ (100). ESI-
MS (neg.) m/z (%): 240.8 [M-H+]À (100). EI-MS: 41 (8), 58 (5), 63 (7),
64 (12), 65 (10), 90 (10), 92 (22), 102 (6), 119 (14), 120 (10), 130 (6),
144 (14), 146 (12), 171 (40), 174 (26), 175 (15), 186 (51), 187 (11),
188 (11), 199 (100), 200 (13), 242 (10). For NMR spectra see Table 1.
For C14H14N2O2 (242.27) calcd. C 69.41, H 5.82, N 11.56; found C
69.29, H 5.87, N 11.29.
~
Colorless solid, mp 239–240 C (ethyl acetate). IR (KBr): n=3220 (w)
ν(NH), 3082 (w) ν(CH), 3001 (w) ν(CH), 2262 (w) ν(CN), 1706 (s)
ν(CO), 1683 (vs) ν(CO), 1614 (m), 1594 (m), 1484 (m), 1395 (m), 1359
(w), 1188 (w), 787 (w) cmÀ 1. ESI-MS (pos.) m/z (%): 439.1 [2·M+K+]+
(4), 423.1 [2·M+Na+]+ (25), 320.2 [3·M+H+ +K+]2+ (12), 239.1 [M
+K+]+ (75), 223.2 [M+Na+]+ (100), 218.2 [M+NH4
] (13), 201.2
+
+
[M+H+]+ (4). ESI-MS (neg.) m/z (%): 199.0 [M-H+]À (100). EI-MS: 50
(10), 51 (8), 52 (16), 63 (24), 64 (32), 65 (12), 76 (9), 77 (6), 90 (16), 91
(14), 92 (56), 119 (100), 120 (10), 146 (14), 149 (12), 171 (14), 172 (9),
199 (6), 200 (41), 201 (5). For C11H8N2O2 (200.19) calcd C 66.00, H
4.03, N 13.99; found: C 66.15, H 3.96, N 13.82.
2d: Compound was prepared from 1d by Method A in 8% yield.
2k: Compound was prepared from 1k by Method A in 48% yield.
°
°
~
Colorless solid, mp 105–108 C (benzene/cyclohexane). IR (KBr): n=
~
Colorless solid, mp 139–141 C (benzene/hexane). IR (KBr): n=2999
2959 (w) ν(CH), 2932 (w) ν(CH), 2261 (w) ν(CN), 1700 (vs) ν(CO),
1675 (vs)), 1661 (vs) ν(CO), 1603 (s), 1475 (vs), 1364 (s), 1297 (m),
1112 (w), 777 (w), 757 (w) cmÀ 1. ESI-MS (pos.) m/z (%): 404.3 [3·M+
H+ +K+]2+ (20), 279.2 [M+Na+]+ (100), 257.3 [M+H+]+ (89), 201.2
[M+H+-C4H8]+ (49). EI-MS: 41 (61), 42 (7), 43 (6), 51 (10), 55 (22), 57
(74), 63 (9), 75 (9), 76 (10), 77 (14), 85 (6), 88 (7), 89 (20), 90 (13), 101
(11), 102 (15), 103 (7), 114 (11), 115 (19), 116 (21), 117 (23), 127 (9),
128 (11), 129 (6), 130 (12), 140 (10), 142 (11), 143 (29), 144 (21), 155
(7), 156 (15), 159 (11), 160 (24), 169 (16), 170 (13), 171 (12), 172 (54),
173 (13), 183 (11), 188 (19), 189 (10), 197 (20), 198 (73), 199 (14),
200 (100), 201 (19), 211 (23), 212 (9), 213 (8), 240 (14), 241 (5), 256
(24). For C15H16N2O2 (256.30) calcd C 70.29, H 6.29, N 10.93; found: C
70.16, H 6.19, N 10.86.
(w) ν(CH), 2942 (w) ν(CH), 2253 (w) ν(CN), 1711 (s) ν(CO), 1673 (vs)
ν(CO), 1602 (s), 1471 (vs), 1380 (m), 1360 (s), 1298 (m), 1105 (s), 759
(s). ESI-MS (pos.) m/z (%): 451.2 [2·M+Na+]+ (32), 341.2 [3·M+H+ +
K+]2+ (69), 253.1 [M+K+]+ (52), 237.2 [M+Na+]+ (100), 232.2 [M+
+
+
NH4
]
(23), 215.2 [M+H+]+ (21). For C12H10N2O2 (214.22) calcd C
67.28, H 4.71, N 13.08); found: C 67.30, H 4.53, N 13.11).
2l: Compound was prepared from 1l by Method A in 55% yield.
°
~
Colorless solid, mp 196–199 C (benzene/hexane). IR (KBr): n=3007
(w) ν(CH), 2948 (w) ν(CH), 2236 (w) ν(CN), 1722 (vs) ν(CO), 1684 (vs)
ν(CO), 1597 (vs), 1492 (m), 1460 (vs), 1336 (vs), 1300 (m), 754 (s),
701 (m) cmÀ 1. ESI-MS (pos.) m/z (%): 591.0 [2·M+K+]+ (32), 575.1
[2·M+Na+]+ (100), 434.1 [3·M+H+ +K+]2+ (19), 315.0 [M+K+]+
(60), 299.0 [M+Na+]+ (97), 277.0 [M+H+]+ (17). EI-MS: 41 (54), 42
(15), 43 (100), 44 (54), 51 (19), 55 (47), 56 (20), 57 (41), 71 (37), 83
(17), 84 (13), 85 (34), 96 (6), 99 (16), 104 (9), 112 (6), 135 (17), 149
(23), 157 (11), 196 (10), 205 (22), 206 (6), 224 (8), 233 (31), 234 (26),
248 (7), 159 (19), 260 (16), 276 (35) For C17H12N2O2 (276.29) calcd C
73.90, H 4.38, N 10.14; found C 73.75, H 4.24, N 10.17.
2e: Compound was prepared from 1e by Method A in 5% yield..
°
~
Colorless solid, mp 151–154 C (benzene/hexane). IR: (KBr): n=3030
(w) ν(CH), 2936 (w) ν(CH), 2257 (w) ν(CN), 1699 (vs) ν(CO), 1664 (vs)
ν(CO), 1601 (vs), 1474 (vs), 1373 (s), 1301 (m), 1247 (w), 761 (s), 700
(m) cmÀ 1. ESI-MS (pos.) m/z (%): 603.2 [2·M+Na+]+ (7), 329.1 [M+
K+]+ (12), 313.1 [M+Na+]+ (100). ESI-MS (neg.) m/z (%): 306.9 [M-
5a: Compound was prepared from 1a by Method B in 4% yield.
°
~
Colorless solid, mp 108–112 C (benzene/hexane).. IR (KBr): n=3207
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(w) ν(NH), 3087 (w) ν(CH), 2934 (w) ν(CH), 2246 (vw) ν(CN), 1691
(vs) ν(CO), 1613 (m), 1599 (m), 1498 (w), 1486 (m), 833 (w), 758 (w),
601 (w) cmÀ 1. ESI-MS (pos.) m/z (%): 265.0 [M+Na+]+ (100), 242.9
[M+H+]+ (29). ESI-MS (neg.) m/z (%): 240.8 [M-H+]À (100). EI-MS: 41
(100), 42 (12), 43 (26), 44 (21), 45 (7), 51 (20), 52 (10), 53 (9), 55 (51),
56 (18), 57 (62), 63 (10), 64 (8), 69 (9), 73 (12), 75 (33), 76 (22), 77
(17), 89 (9), 101 (15), 102 (27), 103 (26), 115 (9), 116 (8), 117 (11),
128 (11), 129 (12), 130 (32), 145 (12), 146 (20), 155 (16), 156 (11),
157 (6), 158 (45), 159 (12), 168 (11), 169 (21), 174 (13), 175 (10), 182
(14), 183 (15), 184 (51), 186 (58), 187 (11), 197 (14), 207 (27), 226 (7),
242 (14). For C14H14N2O2 (242.27) calcd C 69.41, H 5.82, N 11.56;
found C 69.22, H 5.71, N 11.34.
C15H18N2O3 (274.32) calcd C 65.68, H 6.61, N 10.21; found C 65.49, H
6.49, N 9.93.
6j: Compound was prepared from 1j by Method B in 16% yield.
°
~
Colorless solid, mp 189–193 C (benzene). IR (KBr): n=3423 (m)
ν(OH), 3265 (m) ν(NH), 3068 (w) ν(CH), 2984 (w) ν(CH), 2245 (vw)
ν(CN), 1699 (vs) ν(CO), 1671 (m), 1494 (m), 1389 (w), 1356 (m), 1183
(m), 1073 (m), 761 (m) cmÀ 1. ESI-MS (pos.) m/z (%): 503.0 [2·M+K+
+
]
(11), 487.1 [2·M+Na+]+ (100), 270.9 [M+K+]+ (21), 255.0 [M+
Na+]+ (49), 232.9 [M+H+]+ (<1). ESI-MS (neg.) m/z (%): 230.8 [M-
H+]À (100). For C12H12N2O3 (232.24) calcd C 62.06, H 5.21, N 12.06,
found C 61.75, H 5.10, N 12.27.
7d: Compound was prepared from 1d by Method A in 6% yield.
5c: Compound was prepared from 1c by Method A in 12% yield, as
well as by Method B in 24% yield. Colorless solid, mp 214–218 C
°
~
Colorless solid, mp 147–150 C (cyclohexane). IR (KBr): n=2957 (m)
ν(CH), 2871 (w) ν(CH), 1704 (s) ν(CO), 1672 (s) ν(CO), 1629 (vs)
ν(CO), 1598 (s) ν(CO), 1472 (s), 1363 (m), 1300 (w), 1153 (m), 1120
(w), 758 (m) cmÀ 1. ESI-MS (pos.) m/z (%): 499.2 [M+K+]+ (7), 483.2
[M+Na+]+ (100), 461.2 [M+H+]+ (40). For C28H32N2O4 (460.56)
calcd C 73.02, H 7.00, N 6.08; found: C 72.98, H 7.06, N 6.12.
~
(benzene). IR (KBr): n=3214 (w) ν(NH), 3069 (w) ν(CH), 2925 (w)
ν(CH), 2250 (vw) ν(CN), 1699 (vs) ν(CO), 1599 (m), 1495 (m), 1449
(w), 891 (w), 756 (m), 697 (m) cmÀ 1. ESI-MS (pos.) m/z (%): 301.0 [M
+K+]+ (22), 285.0 [M+Na+]+ (100), 263.0 [M+H+]+ (19). ESI-MS
(neg.) m/z (%): 260.8 [M-H+]À (100). For C16H10N2O2 (262.26) calcd C
73.27, H 3.84, N 10.68; found: C 73.22, H 3.67, N 10.42.
7f: Compound was prepared from 1f by Method A in 4% yield..
~
Colorless solid, mp 192–197 C (ethyl acetate). IR (KBr): n=3058 (w)
5f: Compound was prepared from 1f in 7% yield by Method A. as
ν(CH), 2939 (w) ν(CH), 1709 (s) ν(CO), 1676 (s) ν(CO), 1625 (vs)
ν(CO), 1599 (s), 1495 (m), 1473 (s), 1347 (s), 1312 (m), 1114 (m), 700
(m) cmÀ 1. ESI-MS (pos.) m/z (%): 1023.3 [2·M+Na+]+ (16), 539.1 [M
+K+]+ (33), 523.1 [M+Na+]+ (100), 501.2 [M+H+]+ (80). For
C32H24N2O4 calcd. C 76.78, H 4.83, N 5.60; found C 76.70, H 4.63, N
5.65.
°
well as by method B in 53%.yield. Colorless solid, mp 224–228 C
~
(benzene/hexane). IR (KBr): n=3088 (w) ν(CH), 2952 (w) ν(CH), 2250
(vw) ν(CN), 1673 (vs) ν(CO), 1604 (m), 1504 (w), 1471 (m), 1356 (m),
1140 (m), 756 (s), 701 (m), 648 (w) cmÀ 1. ESI-MS (pos.) m/z (%): 575.1
[2·M+Na+]+ (72), 315.0 [M+K+]+ (74), 299.0 [M+Na+]+ (100),
277.0 [M+H+]+ (75). EI-MS: 51 (22), 63 (11), 75 (9), 76 (9), 77 (58),
78 (8), 88 (12), 89 (11), 102 (15), 105 (52), 115 (7), 130 (17), 190 (11),
204 (10), 219 (10), 229 (8), 231 (15), 232 (19), 234 (9), 259 (100), 260
(84), 261 (16), 276 (15). For C17H12N2O2 (276.29) calcd. C 73.90, H
4.38, N 10.14; found C 73.86, H 4.18, N 9.97.
7k: Compound was prepared from 1k by Method B in 3% yield.
Colorless solid, mp 174–178 C (hexane). IR (KBr): n=2986 (w) ν(CH),
°
~
2933 (w) ν(CH), 2887 (w) ν(CH), 1706 (vs) ν(CO), 1675 (vs) ν(CO),
1636 (vs) ν(CO), 1596 (vs), 1475 (s), 1374 (s), 1349 (s), 1094 (s), 734
(m) cmÀ 1. ESI-MS (pos.) m/z (%): 775.3 [2·M+Na+]+ (30), 584.2 [3·M
+H+ +K+]2+ (7), 415.1 [M+K+]+ (26), 399.1 [M+Na+]+ (100),
377.1 [M+H+]+ (43). For C22H20N2O4 (376.41) calcd C 70.20, H 5.36,
N 7.14; found C 70.31, H 5.42, N 6.95.
5i: Compound was prepared from 1i by Method B in 47% yield.
°
~
Colorless solid, mp 179–182 C (benzene/hexane). IR (KBr): n=3071
(w) ν(CH), 2241 (vw) ν(CN), 1678 (vs) ν(CO), 1604 (w), 1499 (w), 1458
(m), 1347 (m), 1295 (w), 755 (m), 695 (m) cmÀ 1. ESI-MS (pos.) m/z
(%): 699.1 [2·M+Na+]+ (50), 377.0 [M+K+]+ (47), 361.1 [M+Na+]+
(100), 339.1 [M+H+]+ (49). For C22H14N2O2 (338.36) calcd C 78.09, H
4.17, N 8.28; found: C 78.24, H 4.11, N 8.15.
8d: Compound was prepared from 1d by Method B in 44% yield.
°
~
Colorless solid, mp 75–78 C (cyclohexane). IR (KBr): n=3319 (w)
ν(NH), 2965 (w) ν(CH), 2942 (w) ν(CH), 2862 (w) ν(CH), 1677 (vs)
ν(CO), 1474 (m), 1443 (m), 1375 (m), 1362 (m), 1349 (m), 1097 (m),
763 (m) cmÀ 1. ESI-MS (pos.) m/z (%): 599.2 [2·M+Na+]+ (77), 327.0
[M+K+]+ (22), 311.0 [M+Na+]+ (98), 289.1 [M+H+]+ (100), 254.0
[M+Na+-C4H9]+ (21), 232.0 [M+H+-C4H9]+ (57). For C16H20N2O3
(288.34) calcd C 66.65, H 6.99, N 9.72; found: C 66.46, H 6.73, N 9.65.
5k: Compound was prepared from 1k in 30% yield by Method B.
°
~
Colorless solid, mp 136–140 C (cyclohexane). IR (KBr): n=2985 (w)
ν(CH), 2945 (w) ν(CH), 2247 (vw) ν(CN), 1677 (vs) ν(CO), 1604 (m),
1506 (w), 1473 (m), 1367 (m), 1110 (m), 777 (w), 761 (m), 739 (w)
cmÀ 1. ESI-MS (pos.) m/z (%): 451.0 [2·M+Na+]+ (41), 236.9 [M+Na+
+
]
(100). EA: C12H10N2O2 (214.22) calc: C 67.28, H 4.71, N 13.08;
8g: Compound was prepared from 1g by Method B in 32% yield
Colorless solid, mp 84–88 C (hexane), IR (KBr): n=3317 (w) ν(NH),
found: C 66.96, H 4.63, N 13.14.
°
~
2958 (w) ν(CH), 2869 (w) ν(CH), 1677 (vs) ν(CO), 1605 (m), 1461 (m),
1439 (m), 1368 (m), 1347 (m), 1094 (m), 1078 (m), 751 (m) cmÀ 1. ESI-
MS (pos.) m/z (%): 723.2 [2·M+Na+]+ (35), 545.2 [3·M+H+ +K+]2+
(20), 389.0 [M+K+]+ (56), 373.1 [M+Na+]+ (75), 351.1 [M+H+]+
(100). For C21H22N2O3 (350.41) calcd C 71.98, H 6.33, N 7.69; found C
71.89, H 6.37, N 7.90.
5l: Compound was prepared from 1l by Method B in 19% yield.
°
~
Colorless solid, mp 135–138 C (hexane). IR (KBr): n=3071 (w) ν(CH),
2249 (vw) ν(CN), 1681 (vs) ν(CO), 1601 (m), 1497 (m), 1460 (m), 1353
(s), 1299 (w), 1214 (w), 1143 (w), 753 (m), 705 (m) cmÀ 1. ESI-MS
(pos.) m/z (%): 575.1 [2·M+Na+]+ (100), 314.9 [M+K+]+ (27), 299.0
[M+Na+]+ (88), 277.0 [M+H+]+ (48), 277.0 [M+H+-CHNO]+ (28).
For C17H12N2O2 (276.28) calcd C 73.90, H 4.38, N 10.14. found: C
73.64, H 4.60, N 9.83.
8k: Compound was prepared from 1k by Method B in 40% yield
and from 5k in 8% yield. Colorless solid, mp 96–102 C
cyclohexane). IR (KBr): n=3303 (m) ν(NH), 2991 (w) ν(CH), 2944 (w)
ν(CH), 1665 (vs) ν(CO), 1606 (m), 1475 (m), 1366 (m), 1113 (m), 1093
(m), 1069 (m), 752 (m) cmÀ 1. ESI-MS (pos.) m/z (%): 285.0 [M+K+]+
(19), 269.0 [M+Na+]+ (100), 247.0 [M+H+]+ (10). ESI-MS (neg.) m/z
(%): 244.8 [M-H+]À (100). For C13H14N2O3 (246.26) calcd C 63.40, H
5.73, N 11.38; found: C 63.66, H 5.66, N 11.35.
°
~
6a: Compound was prepared from 1a by Method B in 5% yield
°
and from 5a in 17% yield. Colorless solid, mp 176–180 C (benzene/
~
hexane). IR (KBr): n=3460 (m) ν(OH), 3268 (m) ν(NH), 2955 (m)
ν(CH), 2932 (w) ν(CH), 2238 (vw) ν(CN), 1706 (vs), 1665 (vs), ν(CO),
1613 (m), 1594 (m), 1481 (m), 1174 (m), 1096 (s), 771 (m) cmÀ 1. ESI-
MS (pos.) m/z (%): 571.2 [2·M+Na+]+ (100), 431.1 [3·M+H+ +K+]2+
(18), 313.0 [M+K+]+ (19), 297.0 [M+Na+]+ (40), 275.0 [M+H+]+
(2). ESI-MS (neg.) m/z (%): 272.9 [M-H+]À (100). EI-MS: 41 (23), 55 (9),
57 (49), 85 (22), 102 (6), 103 (12), 130 (7), 146 (7), 147 (100), 148
(12), 157 (29), 158 (8), 161 (15), 162 (24), 187 (8), 274 (12). For
8l: Compound was prepared from 2l in 7% yield by Method B and
from 5l in 38% yield. Colorless solid, mp 183–189 C (benzene/
hexane). IR (KBr): n=3314 (w) ν(NH), 2979 (w) ν(CH), 2941 (w) ν(CH),
1678 (vs) ν(CO), 1662 (s), 1603 (m), 1439 (m), 1368 (s), 1349 (m),
°
~
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1098 (m), 759 (m), 715 (m) cmÀ 1. ESI-MS (pos.) m/z (%): 639.2 [2·M+
Na+]+ (100), 482.1 [3·M+H+ +K+]2+ (8), 347.0 [M+K+]+ (33), 331.0
[M+Na+]+ (86), 309.0 [M+H+]+ (40). For C18H16N2O3 (308.33) calcd
C 70.12, H 5.23, N 9.09. Found: C 70.12, H 5.34, N 8.81.
Keywords: Cyanides · Cyanohydrin reaction · α-Cyanooxiranes ·
α-Haloketones · Solvent effects
General procedure for the conversion of compounds 5 to 6
and 8
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The solution of 5 (0.3 mmol) in methanol (4 mL) was heated to
reflux for 6 h. According to TLC, the reaction did not proceed. Then
NaCN (0.66 mmol) was added and the mixture was refluxed for
another hour. Methanol was evaporated in vacuo to dryness, water
(6 mL) was added to the residue and the mixture was extracted
with chloroform (4×6 mL). Collected extract was dried, the solvent
was evaporated in vacuo and the residue was column chromato-
graphed.
From 5a, 36% of 6a, from 5k, 8% of 8k, and from 5l, 38% of 8l
was prepared. All these compounds were identical with those
prepared from corresponding compounds 1 (Table 1). From 5f,
compound 8f was prepared:
8f: Compound was prepared from 5f in 56% yield by Method B.
°
~
Colorless solid, mp 202–205 C (benzene/hexane). IR (KBr): n=3313
(w) ν(NH), 3076 (w) ν(CH), 2974 (w) ν(CH), 2939 (w) ν(CH), 1667 (vs)
ν(CO), 1603 (m), 1470 (m), 1444 (m), 1374 (m), 1347 (m), 1105 (m),
768 (m), 758 (m) cmÀ 1. ESI-MS (pos.) m/z (%): 639.2 [2·M+Na+]+
(71), 617.1 [2·M+H+]+ (18), 347.0 [M+K+]+ (35), 331.0 [M+Na+]+
(58), 309.0 [M+H+]+ (100), 252.0 [M+H+-C2H3NO]+ (47). For
C18H16N2O3 (308.33) calcd C 70.12, H 5.23, N 9.09. Found: C 70.13, H
5.10, N 9.09.
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Acknowledgements
This study was supported by Tomas Bata University in Zlin internal
grant No. IGA/FT/2020/007. The authors thank Mrs. H. Geržová
(Faculty of Technology, Tomas Bata University in Zlín) for
technical help.
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Chichester, 2001, 99.
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Conflict of Interest
Manuscript received: February 28, 2021
Revised manuscript received: April 7, 2021
The authors declare no conflict of interest.
ChemistryOpen 2021, 10, 645–652
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© 2021 The Authors. Published by Wiley-VCH GmbH