Stereochemistry of the reduction of α-chloroketones with sodium borohydride—application to 3-chloroquinoline-2,4-diones: Dedicated to the memory of Professor Dr.?Vojeslav ?těrba who died in September 2015 being nearly 93 years old

Article abstract of DOI:10.1016/j.tet.2016.05.087

3-Chloroquinoline-2,4-diones were reduced with sodium borohydride to give syn- and anti-chlorohydrins, the stereochemistry of which was established by NMR spectroscopy. Both stereoisomeric chlorohydrins were reacted with potassium carbonate in methanol. a

Full text of DOI:10.1016/j.tet.2016.05.087

Tetrahedron 72 (2016) 4490e4497
Contents lists available at ScienceDirect
Tetrahedron
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Stereochemistry of the reduction of
a-chloroketones with sodium
borohydridedapplication to 3-chloroquinoline-2,4-diones
a
,
b
,
c
a
a
*
ꢀ
ꢁ
ꢁ
Antonín Klasek , Antonín Lycka , Filip Kremen , Michal Rouchal
a Department of Chemistry, Faculty of Technology, Tomas Bata University, CZ-762 72 Zlín, Czech Republic
b Research Institute for Organic Syntheses (VUOS), Rybitví 296, CZ-533 54 Pardubice 20, Czech Republic
c
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
University of Hradec Kralove, Faculty of Education, Rokitanskeho 62, CZ 500 03 Hradec Kralove 3, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Chloroquinoline-2,4-diones were reduced with sodium borohydride to give syn- and anti-chlorohy-
drins, the stereochemistry of which was established by NMR spectroscopy. Both stereoisomeric chlo-
rohydrins were reacted with potassium carbonate in methanol. anti-Isomers afforded the corresponding
epoxides or rearranged to 3-hydroxy-4-alkylquinolin-2-ones, whereas syn-isomers did not react. How-
ever, these isomers converted to 4-hydroxyquinolin-2-ones after standing for a long period of time in
DMSO. After reaction with thionyl chloride, the syn-isomers yielded cis- and trans-3,4-dichloroquinolin-
2-ones.
Received 15 March 2016
Received in revised form 13 May 2016
Accepted 31 May 2016
Available online 6 June 2016
Dedicated to the memory of Professor
ꢁ
ꢁ
Dr. Vojeslav Sterba who died in September
2015 being nearly 93 years old
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Chlorohydrins
3,4-Dichloroquinolin-2-ones
NMR
Pinacol rearrangement
Viridicatin alkaloids
1. Introduction
and the reduction of 3-(N-butyl-N-nitrosoamino)quinoline-2,4-
diones with LiAlH4 afforded a mixtures of diastereoisomers
Recently, we published two papers1,2 on the reduction of
quinolinediones substituted with hydroxyl and amino groups at
position 3. The reduction of 3-hydroxyquinolinediones with
NaBH4 proceeds stereospecifically to produce cis-3-alkyl/aryl-
3,4-dihydroxyquinolin-2(1H)-ones.1 These compounds were
subjected to pinacol rearrangement, resulting in 4-alkyl/aryl-3-
hydroxyquinolin-2(1H)-ones. When a benzyl group was present
at position 3 of the starting compound, it was eliminated during
the rearrangement, and the corresponding 3-hydroxyquinolin-
2(1H)-one was obtained.1 3-Aminoquinolinediones were reduced
with NaBH4 also stereospecifically to give syn-3-amino-3,4-
dihydro-4-hydroxyquinolin-2(1H)-ones.2 The deamination of
these compounds using nitrous acid afforded mixtures of several
compounds, from which 3-alkyl/aryl-2,3-dihydro-1H-indol-2-
ones and their 3-hydroxy and 3-nitro derivatives were isolated
as the products of the molecular rearrangement.2 Corresponding
syn-derivatives were also prepared by the reduction of 3-
butylaminoquinoline-2,4-diones and their N-nitrosoderivatives
from which new tricyclic benzooxadiazocines were obtained by
reaction with isocyanic acid.3
The aforesaid data demonstrate that the reduction of 3-
hydroxy- and 3-aminoquinoline-2,4-diones with sodium borohy-
dride provides the corresponding 4-hydroxyderivatives, which are
suitable substrates for molecular rearrangements, in high yields.
In this paper, motivated by the above-mentioned results, we
describe our attempt at the reduction of 3-chloroquinolinediones
with sodium borohydride. According to our experiences, we be-
lieved that the reduction products would also be predisposed to
molecular rearrangements.
2. Results and discussion
3-Chloroquinoline-2,4-diones 1, prepared by the reaction of 4-
hydroxyquinoline-2-ones with sulfuryl chloride,4 were reacted
with NaBH4 in methanol (Scheme 1). Resulting 3-alkyl/aryl-3-
chloro-4-hydroxyquinolin-2(1H)-ones 2, not known in the litera-
ture up to now, were obtained in good yields. Comparised with the
results of the reduction of 3-hydroxy- and 3-aminoqinoline-2,4-
diones,1,2 the reduction of the chloro derivatives is less
* Corresponding author. Fax: þ420 57 72 10 722; e-mail address: klasek@ft.utb.cz
ꢀ
(A. Klasek).
http://dx.doi.org/10.1016/j.tet.2016.05.087
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

ꢀ
A. Klasek et al. / Tetrahedron 72 (2016) 4490e4497
4491
Scheme 1.
stereoselective. We successfully isolated two diastereoisomers us-
ing column chromatography in most cases, but sometimes only one
of diastereoisomer was obtained (Table 1). According to the liter-
compounds were lower than those in 2 by ca. e36, indicating that
the elimination of hydrogen chloride from 2 proceeds during the
formation of epoxides 3. Because of the trans-1,4-elimination of
hydrogen chloride via an intramolecular SN2 reaction, the epoxides
3 can arise only from anti-chlorohydrins.
ature, a-chloroketones, bearing a tertiary chlorine atom, react with
sodium borohydride to only syn-chlorohydrins.5e9 This is caused by
the hydride attack on the face of the carbonyl group that is the least
sterically hindered. Therefore, the chlorine atom exerts efficient
steric control in producing syn-chlorohydrins. However, in other
papers,10e13 the formation of a pair of diastereoisomeric chloro-
hydrins in different proportions has been described.
In addition to compound 3, both diastereoisomers syn-2f and
anti-2f, or syn-2i and anti-2i originate from compounds 2f and 2i
(Table 1). We carried out the reaction of both diastereoisomers of 2i
with potassium carbonate in methanol. The major product of the
reduction of 1i does not react under these reaction conditions,
whereas the minor product provided epoxide 3i. Therefore, the
major product must be the syn-isomer and the minor product the
anti-isomer. The same result was obtained for 3f. Compound 2c
does not react under these reaction conditions, demonstrating that
it must be the syn-2c isomer. In addition, based on the comparison
of the 13C NMR resonances of C(3) and C(4) (Table 2), the major
compounds 2c,f,i have the same syn-configuration. This structure
was again confirmed by results of a NOE experiment proving the
interactions of the hydroxyl group at C(4) with the proton at the
nitrogen atom in position 1. anti-Isomers were isolated in only
small quantities (Table 1) or not at all (2c) because the majority of
these isomers were consumed in their conversion to epoxides 3.
The typical feature of the NMR spectra of compounds 3 (Table 3) is
Table 1
Results of the reduction of 3-chloroquinolin-2-ones 1 with NaBH4 (Method A)
Starting compound
Product(s), (yield, %)
1a
1b
1c
1d
1e
1f
1g
1h
1i
syn-2a (44)
syn-2b (45), anti-2b (22)
syn-2c (27), 3c (29)
syn-2d (38)
anti-2e (27), syn-2e (19)
syn-2f (24), anti-2f (4), 3f (44)
syn-2g (47)
syn-2h (29)
syn-2i (25), anti-2i (3), 3i (33)
the existence of the d(
13C) of carbon C(1a) in a narrow range from
d
¼60.4 to 61.4; logically, no signals of OH were observed in the 1H
From the reduction of compounds 1, bearing a butyl group in
position 3 (1a,d,g), only one of the two possible diastereoisomers
was isolated (Table 1). The NOESY spectra of compounds 2 were
recorded to determine the mutual orientation of the substituents at
the C(3) and C(4) carbons. The results strongly supported through-
space proximity of the C(4) proton with suitable H- atoms of the R2
substituent due to the appearance of appropriate cross-peaks in the
NOESY spectra. However, because the R2 substituents in com-
pounds 2 (especially the butyl group) were not completely rigid,
the dynamic behaviour of the substituents on C(3) and C(4) (certain
rotamers) resulted in some additional cross-peaks. In the NMR
spectra (Table 2) of these compounds, the interaction between H(4)
and the protons of the C(20) atom of the butyl group was observed.
However, due to free rotation of the butyl group, these interactions
can be observed in both the syn or anti configuration. The distance
between H(4) and the C(20) atom is smaller in syn-isomer, and,
therefore, the interaction is stronger. Thus, compounds 2a,d,g can
be syn-isomers.
NMR spectra of compounds 3 dissolved in dimethyl sulfoxide.
3-Benzyl-substituted compounds 1b,e were reduced to two di-
astereoisomers 2, and only one stereoisomer was obtained from
compound 1h (Table 1). The reaction of both products isolated from
the reduction of 1b produced interesting results. The major com-
pound of these two diastereoisomers does not react in alkaline
medium and, demonstrating that it is the syn-isomer. The minor
diastereoisomer (anti) reacts to give compound 4b in lieu of the
expected compound 3b. Its structure, corresponding to that of vir-
idicatin alkaloids,1 was elucidated from elemental analysis and IR,
ESI-MS and NMR spectra. It is obvious that this compound arises
from anti-2b through the corresponding epoxide. However, its
deprotonation at C(4) and the following migration of the benzyl
group, similar to pinacol rearrangement, is unlikely. In the litera-
ture,14,15 pinacol rearrangement in alkaline medium proceeds by
the action of only strong bases and leads to ring contraction. More
likely is assistance of lone pair donation from N resulting in cleav-
age of the C(4)-O bond of the epoxide under formation of oxyanion,
Three isomers of compounds 2 bear a phenyl group at position 3
(2c,f,i), and by-products were also isolated after the reduction of 1
for all of these compounds. The molecular weights of these
which reforms the
p-bond at C(3) with concomitant migration of
the benzyl group and following keto-enol tautomerisation.

ꢀ
A. Klasek et al. / Tetrahedron 72 (2016) 4490e4497
4492
Table 2
1H and 13C chemical shifts of compounds 2 in DMSO-d6
Position
syn-2a
(H)
syn-2b
(H)
anti-2b
(H)
syn-2c
(H)
syn-2d
(H)
syn-2e
(H)
anti-2e
(H)
d
d(C)
d
d(C)
d
d(C)
d
d(C)
d
d(C
d
d
(C
d
d(C
2
3
4
OH
4a
5
6
7
8
d
166.2
73.5
68.9
d
d
165.5
73.2
68.0
d
d
166.5
67.2
70.3
d
d
166.1
76.6
73.1
d
d
165.5
73.5
68.1
d
d
165.0
73.5
67.7
d
d
166.0
67.2
69.9
d
d
d
d
d
d
d
d
4.92
6.18
d
4.55
6.37
d
4.23
6.22
d
5.37
6.14
d
4.95
6.26
d
4.63
6.47
d
4.28
6.35
d
126.9
125.9
122.6
128.1
114.7
135.0
d
126.2
125.9
122.8
128.2
114.8
135.6
d
124.4
126.9
122.5
129.0
115.2
136.4
d
126.3
127.0
122.6
128.6
115.0
137.5
d
128.6
125.4
123.2
128.3
114.5
137.1
30.2
d
127.9
125.8
123.4
128.5
114.6
136.7
30.4
d
125.8
127.0
132.2
129.1
115.2
138.4
30.3
d
7.46
7.10
7.26
6.95
d
7.42
7.06
7.22
6.89
d
7.21
6.96
7.25
6.92
d
7.39
7.03
7.23
6.93
d
7.53
7.20
7.39
7.20
d
7.52
7.21
7.39
7.19
d
7.29
7.10
7.41
7.25
d
8a
10(R1)
20(R1)
30(R1)
40(R1)
10(R2)
10.57
d
10.64
d
10.66
d
10.79
d
3.36
d
3.34
d
3.42
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
2.22
2.08
1.52
1.36
1.36
0.93
d
35.0
3.67
3.33
d
40.2
3.46
3.37
d
37.2
d
135.7
2.25
2.11
1.53
1.36
1.36
0.93
d
35.6
3.72
3.39
d
41.0
3.54
3.45
d
38.2
20(R2)
26.7
134.49
135.0
7.55
127.6
26.7
135.5
134.9
30(R2)
40(R2)
50(R2)
22.6
13.9
d
7.44
7.31
7.26
130.8
128.1
127.1
7.44
7.36
7.31
131.5
128.0
129.1
7.37
7.33
d
128.0
128.2
d
22.6
13.8
d
7.46
7.33
7.28
130.9
128.2
127.2
7.47
7.41
7.36
131.5
128.0
129.3
Position
syn-2f
anti- 2f
(H)
syn-2g
(H)
syn-2h
syn-2i
(H)
anti-2i
d
(H)
d
(C)
d
d
(C)
d
d(C)
d
(H)
d
(C)
d
d
(C)
d
(H)
d(C)
2
3
4
OH
4a
5
6
7
8
d
165.6
77.2
72.7
d
d
165.8
74.0
73.5
d
d
d
165.5
74.2
68.8
d
d
165.1
74.2
68.4
d
d
165.6
77.4
72.9
d
d
165.8
74.1
73.4
d
d
d
d
d
d
5.38
6.23
d
5.08
6.65
d
4.95
6.41
d
4.81
6.53
d
5.61
6.42
d
5.30
6.85
d
127.5
127.3
123.2
128.9
115.0
137.8
30.7
d
127.8
126.3
123.4
128.7
115.0
137.5
30.8
d
128.1
126.1
123.3
128.0
115.7
138.1
138.1
128.9
130.0
128.5
35.5
127.4
126.4
123.5
128.3
115.8
137.8
137.8
128.8
130.0
128.6
40.9
n.o.
127.6
126.5
123.5
128.4
116.0
138.4
138.2
128.9
130.1
128.6
136.1
7.42
7.09
7.30
7.16
d
7.46
7.14
7.36
7.21
d
7.58
7.17
7.17
6.25
d
7.52
7.14
7.42
6.19
d
7.50
7.06
7.12
6.21
d
127.7
123.3
128.7
116.2
139.0
138.4
128.9
130.1
128.6
137.5
7.50
7.07
7.11
6.19
d
8a
10(R1)
20(R1)
30(R1)
40(R1)
10(R2)
3.46
d
3.47
d
d
d
d
d
7.29
7.62
7.54
2.25
2.19
1.60
1.41
1.36
0.93
d
7.20
7.57
7.51
3.65
3.42
d
7.35
7.62
7.55
d
7.34
7.60
7.52
d
d
d
d
d
d
d
d
d
d
137.9
d
136.2
20(R2)
7.46
127.3
7.53
127.4
26.7
135.3
7.56
127.2
7.65
128.8
30(R2)
40(R2)
50(R2)
7.33
7.34
d
128.2
128.4
d
7.29
7.29
d
128.8
128.2
d
22.6
13.8
d
7.40
7.29
7.27
131.0
128.1
127.2
7.40
7.34
d
128.4
128.6
d
7.29
7.29
d
127.7
128.5
d
The comparison of the NMR spectra of both diastereoisomers of
products 2e and 2f reveals that these compounds possess the
configuration presented in Table 2.
Surprising results were obtained by measuring the NMR spectra
of both diastereoisomers of compounds 2b,e,f after standing for
several weeks in a DMSO-d6 solution.
With the intention to establish the stereochemistry of chloro-
hydrins 2, we converted these compounds to hitherto unknown
dichloro derivatives 6. For this purpose we selected thionyl chloride
as the reaction agent. This compound reacts with alcohols via an SNi
mechanism, which should lead to the dichloro derivatives 6 that
possess the same configuration as the starting chlorohydrins 2. The
reaction proceeded smoothly, and compounds 6 were prepared in
good yields (Table 4). However, in four cases (6a,c,f,i), two di-
astereoisomers were obtained from the stereochemically pure ra-
cemate 2, indicating that an isomerization of 2 or 6 takes place
during the reaction with thionyl chloride. In the literature, the re-
action of chlorohydrins with thionyl chloride can provide epimeric
mixtures, which are changed to one of two epimers during their
heating.16 The reaction of 2-chlorocyclohexanols with thionyl
chloride was studied in detail. Using the syn-isomer the reaction
leads to the dichloro derivative without changing of configuration.
However, the syn-isomer provided also the trans-dichloro de-
rivative, which is caused by the transformation of the intermediate
syn-sulfinate to a cyclic chloronium ion, which reacts with a chlo-
ride ion to give the trans-isomer.15 In the presence of pyridine, the
inversion of configuration proceeds naturally.17,18
The NMR spectra of compounds anti-2b,e,f remained un-
changed, whereas drastic changes occurred in syn-2b,e,f. In
their 13C NMR spectra, the signals of aliphatic C(3) and C(4)
are not present and the compounds aromatize to the corre-
sponding 4-hydroxyquinolin-2-ones 5. Their structures were
confirmed by comparison of their NMR spectra with those of
authentic specimens. In a non-basic medium, the elimination of
hydrogen chloride does not proceed from the anti-stereoisomers.
Conversely, at a very long reaction times, syn-stereoisomers
change by virtue of water from wet DMSO to compounds 5
by 1,2-trans elimination, or, more likely, by hydrolysis to 3,4-
dihydroxyderivatives and their subsequent dehydration due
to the catalytic action of the released hydrogen chloride. We
are unable to differentiate between the above-mentioned
possibilities.

ꢀ
A. Klasek et al. / Tetrahedron 72 (2016) 4490e4497
4493
Table 3
1H and 13C chemical shifts of compounds 3 and 5 in DMSO-d6
Position
3c
3e
3i
3f
5b
d
(H)
d
(C)
d(H)
d
(C)
d
(H)
d(C)
d
(H)
d
(C)
d(H)
d(C)
1
1a
2
3
3a
4
4a
5
6
d
d
d
d
d
d
d
d
12.11
d
d
d
d
61.0
166.5
d
d
60.4
166.3
d
d
61.3
166.1
d
d
61.0
166.1
d
d
d
d
d
d
158.1
120.5
d
d
d
d
d
9.47
d
d
137.4
115.4
d
d
138.3
115.1
d
d
139.9
116.0
d
d
138.6
115.2
d
7.11
d
7.18
d
6.27
d
7.33
d
d
143.5
122.2
123.5
122.1
126.0
115.3
d
7.42
7.12
7.69
d
130.4
122.1
130.0
118.7
63.4
d
7.50
7.13
7.65
d
130.5
122.6
130.3
119.7
59.0
d
7.36
7.20
7.63
d
130.2
122.6
130.5
119.6
63.2
d
7.57
7.24
7.78
d
130.6
122.6
130.4
119.8
63.1
d
7.59
7.09
7.14
7.28
d
7
7a
7b
8a
10(R1)
20(R1)
4.50
d
4.45
d
4.70
d
4.59
d
d
139.5
d
10.90
d
d
3.30
d
29.5
d
d
137.7
129.7
128.7
130.2
128.8
134.5
3.44
d
29.8
d
12.11
d
d
7.28
7.45
7.65
7.57
d
d
d
d
d
d
30(R1)
40(R1)
10(R2)
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
135.7
3.72
2.97
d
36.1
d
134.9
4.18
30.0
20(R2)
30(R2)
40(R2)
50(R2)
7.55
7.37
7.33
d
127.6
128.0
128.2
d
135.5
129.9
128.3
126.7
7.61
7.48
7.44
d
127.2
128.0
128.4
d
7.51
7.44
7.46
d
127.1
128.0
128.3
d
d
133.3
128.2
128.4
126.5
7.28
7.28
7.21
7.28
7.23
7.26
Table 4
Results of the reaction of compounds 2 with thionyl chloride (Method C)
From the reaction of the 3-phenyl derivatives syn-2c,f,,i with
Starting compound
Product(s), (yield, %)
thionyl chloride, two isomers of 6 were obtained for compounds
syn-2f and syn-2i. The formation of two stereoisomers confirm, in
accordance with the results of Stevens and Grummitt,17 that the
starting compounds have the syn-configuration. From compound
syn-2c only one isomer cis-6 arises, the configuration of which
resulted from a comparison of the NMR spectra of all compounds 6
(Table 5).
syn-2a
syn-2b
syn-2c
syn-2d
syn-2e
syn-2f
syn-2g
syn-2h
syn-2i
cis-6a (69), trans-6a (17)
cis-6b (48)
trans-6c (15), cis-6c (58)
cis-6d (65)
cis-6e (75)
cis-6f (47), trans-6f (40)
cis-6g (52)
cis-6h (77)
trans-6i (29), cis-6i (50)
From the reaction of 3-butyl derivatives 2a,d,g with thionyl
chloride, two diastereoisomers cis-6a and trans-6a were obtained
Table 5
1H and 13C chemical shifts of compounds 6 in DMSO-d6
Position
cis-6a
(H)
trans-6a
(H)
cis-6b
trans-6c
(H)
cis-6c
(H)
cis-6d
(H)
cis-6e
(H)
d
d
(C)
d
d
(C)
d
(H)
d
(C)
d
d
(C)
d
d(C)
d
d
(C)
d
d(C)
2
3
4
4a
5
6
7
8
d
164.5
74.4
64.2
122.4
127.8
123.1
130.1
115.6
136.0
d
d
164.9
67.5
60.1
122.2
128.8
123.1
130.3
115.8
136.2
d
d
164.6
66.7
60.0
121.9
128.6
123.2
130.4
115.8
136.2
d
d
164.0
75.8
64.7
122.9
127.8
123.1
130.3
115.8
136.2
d
d
163.5
67.7
63.9
122.4
128.5
123.2
130.3
115.7
136.2
d
d
n.o.
n.o.
59.3
n.o.
128.9
123.7
130.6
115.8
n.o.
d
164.1
66.6
59.3
123.2
128.7
123.7
130.6
115.9
138.0
30.5
d
d
d
d
d
d
d
d
5.90
d
5.80
d
5.10
d
6.63
d
6.03
d
5.82
d
5.10
d
7.52
7.13
7.38
7.02
d
7.57
7.11
7.39
7.04
d
7.49
7.00
7.32
7.01
d
7.41
6.95
7.20
6.85
d
7.55
7.11
7.38
7.07
d
7.63
7.22
7.52
7.33
d
7.53
7.11
7.47
7.31
d
8a
10(R1)
20(R1)
30(R1)
40(R1)
10(R2)
10.89
d
10.97
d
11.12
d
11.17
d
11.16
d
3.45
d
30.3
d
3.45
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
2.02
1.89
1.48
1.39
1.26
0.85
d
36.7
2.30
2.22
1.60
33.6
3.59
3.54
d
38.1
d
136.6
d
135.7
2.30
2.26
1.60
34.4
3.63,
3.57
d
39.0
20(R2)
26.3
24.2
133.7
7.50
126.6
128.8
7.82
7.44
129.6
127.4
24.2
133.6
131.3
7.46
30(R2)
40(R2)
50(R2)
22.0
13.7
d
1.47
1.01
d
22.2
14.0
d
7.49
7.41
7.37
131.3
128.3
127.5
7.33
7.29
d
1.47
1.01
d
22,2
14.0
d
129.3
d
7.47
d
128.7
d
7.41
7.37
128.3
127.6

ꢀ
A. Klasek et al. / Tetrahedron 72 (2016) 4490e4497
4494
from 2a. Therefore, 2a must be a syn-isomer. From the reaction of
compounds 2d and 2g, only one isomer 6 was isolated, which
demonstrates that these compounds may have a syn- or anti-con-
figuration. However, the comparison of the NMR spectra of all
the stereogenic centre(s) as a consequence of magnetic non-
equivalence of appropriate protons. Two different proton chem-
ical shifts are given for these methylene groups in Tables 2, 3
and 5.
compounds
configuration.
2
reveals that compounds 2d,g have
a
syn-
The positive-ion EI mass spectra were measured on a Shimadzu
QP-2010 instrument within the mass range m/z¼50e600 using
direct inlet probe (DI). Samples were dissolved in dichloro-
From the reaction of the 3-benzyl derivatives (2b,e,h) with
thionyl chloride only one isomer was isolated, which confirms that
the starting compounds 2b,e,h are syn-stereoisomers and the
products 6b,e,h are cis-stereoisomers. A shift in the
C(4) from
methane (30 m mL of the solution was evaporated in
g mLꢀ1) and 10
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 electrospray mass spectra (ESI-
MS) were recorded using an amaZonꢂion-trap mass spectrometer
(Bruker Daltonics, Bremen, Germany) equipped with an electro-
spray ion source. All experiments were conducted in the positive
polarity mode. Individual samples (with a concentration of
500 ng mLꢀ1) were infused into the ESI source as methanol:water
(1:1, v:v) solutions via a syringe pump with a constant flow rate of
d
(
13C) of carbon
to
d¼67.7e73.5 (eCH(eOH)e) in compounds
2
d
¼59.3e64.7 (eCH(Cl)e) and, logically, the lack of a signal for OH in
the 1H NMR spectra of 6 dissolved in DMSO are typical features of
the NMR spectra of these compounds (Table 5).
We attempted to ascertain the behaviour of compounds 2 in
an acidic environment, where a molecular rearrangement might
be expected. However, after prolonged refluxing of compounds
syn-2e and syn-2i in acetic acid, only starting material was
isolated.
4
m
L minꢀ1.
The other instrumental conditions were as follows: electro-
spray voltage of ꢀ4.2 kV, capillary exit voltage of 140 V, drying
gas temperature of 220 ꢁC, drying gas flow of 6.0 dm3 minꢀ1
nebulizer pressure of 8.0 . Nitrogen was used as the nebulizing
3. Conclusions
,
j
In conclusions, the 3-chloroquinoline-2,4-diones 1 react with
sodium borohydride to give the corresponding chlorohydrins 2. In
most cases, two diastereoisomers of 2 were isolated, whereas the
major product was usually the syn-stereoisomer. When a phenyl
group was present at C(3), epoxides 3 were also obtained. These
epoxides can arise only from anti-chlorohydrins, which contributed
to the clarifying relative stereochemistry of compounds 2. The re-
sults of the reaction of chlorohydrins 2 with thionyl chloride
showed that syn-chlorohydrins provide a cis-dichloro derivatives or
a mixture of two stereoisomeric dichloro derivatives 6, in which cis-
6 is dominant. Compounds 2 do not rearrange upon boiling with
acetic acid.
and drying gases for all experiments. Tandem mass spectra were
collected using collision-induced dissociation (CID) with He as
the collision gas after isolating of the required ions. Column
chromatography was carried out on silica gel (Merck, grade 60,
70e230 mesh) using successive mixtures of chloroform/ethanol
(in ratios from 99:1 to 8:2) (S1) or benzene/ethyl 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), chloro-
form/ethanol (9:1 and 1:1) (S4 and S5), hexane/ethyl acetate
(4:1) (S6), and chloroform/ethyl acetate (7:3) (S7) on AlugramÒ
SIL G/UV254 foils (MachereyeNagel). Elemental analyses (C, H, N)
were performed with a EA Flash EA 1112 Elemental Analyzer
(Thermo Fisher Scientific).
4. Experimental section
4.1. General
4.2. General procedure for the reduction of 3-
chloroquinoline-2,4-diones 1 with NaBH4 (Method A)
Melting points were determined on a Kofler block. IR (KBr)
spectra were recorded on a Smart OMNI-Transmission Nicolet
iS10 spectrophotometer. The 1H and 13C spectra were recorded on
a Bruker Avance 500 spectrometer 500.13 MHz for 1H, 125.76 MHz
for 13C in DMSO-d6. 1H and 13C chemical shifts are given on the
To the stirring solution of compound 1 (2 mmol) in methanol
(10 ml), NaBH4 (85 mg, 2.5 mmol) was added during 5 min at
room temperature. After 20 min, crushed ice (20 g) and conc.
hydrochloric acid (0.17 mL) were added to the reaction mixture.
After 10 min, the mixture was alkalized with 6% NaHCO3
and extracted with chloroform (3ꢂ30 ml). The collected extracts
were dried, evaporated to dryness and crystallized from appro-
priate solvent. The mother liquors were separated on silica gel
column.
d
scale (ppm) and are referenced to internal TMS (
d
¼0.0). All 2D
experiments (gradient-selected (gs)-COSY, gs-NOESY, gs-HMQC,
gs-HMBC) were performed using manufacturer’s software. The
one- and two-dimensional (gradient-selected (gs)-COSY, gs-
TOCSY, gs-NOESY, gs-HMQC, and gs-HMBC) 1H and 13C NMR
spectra of prepared compounds were measured and analysed.
The 1H and 13C chemical shifts are published in Tables 2, 3 and 5.
Protoneproton coupling constants in 1,2-disubstituted benzene
fragments gave a typical ‘doubletetripletetripletedoublet’ split-
ting pattern with 3J(1H, 1H) in the standard range 7.5e8.7 Hz for
all compounds, protons of phenyl groups provided from sepa-
4.2.1. (3R*4R*)-3-Butyl-3-chloro-3,4-dihydro-4-hydroxyquinolin-
2(1H)-one (syn-2a). Compound was prepared from 1a in 44% yield.
White solid, mp 144e147 ꢁC (benzene). IR: 3453, 3200, 3142, 3081,
2950, 2922, 2867, 1692, 1616, 1598, 1487, 1464, 1367, 1251, 1198,
1170, 1155, 1120, 1101, 1071, 950, 845, 827, 752, 710, 661, 625, 602,
533, 503 cmꢀ1. ESI-MS (pos.) m/z (%): 529.1 [(35Cl)2MþNa]þ (48),
292.0 [(35Cl)MþK]þ (26), 276.0 [(35Cl)MþNa]þ (48), 254.0 [(35Cl)
MþH]þ (100). Anal. Calcd (found) for C13H16ClNO2 (253.72): C 61.54
(61.54), H 6.36 (6.47), N 5.52 (5.49).
ꢀ
rated AAMḾX systems to one broadened signal ones corre-
sponding to five protons. Methylene protons from benzyl groups
gave either singlets with relative integral intensity being two or,
in compounds containing the stereogenic centre(s), doublet of
doublets with relative integral intensity 1:1 and 3J(1H, 1H) in the
range 12.6e15.4 Hz. Protoneproton coupling constants in butyl
groups provided a typical ‘tripletemultipletemultipletetriplet’
splitting pattern with 3J(1H, 1H) in the standard range
6.5e7.5 Hz for all compounds. Analogously to methylene protons
from benzyl groups, some methylene protons of butyl fragment
formed complicated splitting patterns in compounds containing
4.2.2. (3R*4R*)-3-Benzyl-3-chloro-3,4-dihydro-4-hydroxyquin-olin-
2(1H)-one (syn-2b). Compound was prepared from 1b in 45% yield.
White solid, mp 219e224 ꢁC (ethyl acetate). IR: 3344, 3061, 3027,
2943, 1677, 1661, 1598, 1489, 1454, 1433, 1386, 1310, 1240, 1130,
1074, 1027, 944, 913, 859, 801, 768, 752, 703, 665, 626, 596, 533,
513 cmꢀ1. ESI-MS (pos.) m/z (%): 597.0 [(35Cl)2MþNa]þ (11), 326.0

ꢀ
A. Klasek et al. / Tetrahedron 72 (2016) 4490e4497
4495
[(35Cl)MþK]þ (61), 310.0 [(35Cl)MþNa]þ (87), 288.0 [(35Cl)MþH]þ
(100). Anal. Calcd (found) for C16H14ClNO2 (287.74): C 66.79 (66.67),
H 4.90 (4.91), N 4.87 (4.82).
for C16H14ClNO2 (287.74): C 66.79 (66.84), H 4.90 (4.86), N 4.87
(4.67).
4.2.9. (3R*4S*)-3-Chloro-3,4-dihydro-4-hydroxy-1-methyl-3-
phenylquinolin-2(1H)-one (anti-2f). Compound was prepared from
1f in 4% yield. White solid, mp 186e189 ꢁC (benzene/cyclohexane).
IR: 3438, 3089, 3026, 1665, 1604, 1495, 1469, 1427, 1368, 1305, 1268,
1247, 1210, 1184, 1135, 1095, 1043, 946, 921, 900, 798, 777, 754, 742,
695, 676, 558, 528 cmꢀ1. ESI-MS (pos.) m/z (%): 597.1 [(35Cl)
2MþNa]þ (22), 326.0 [(35Cl)MþK]þ (46), 310.0 [(35Cl)MþNa]þ
(100), 288.0 [(35Cl)MþH]þ (91), 274.0 [(35Cl)MþNaeHCl]þ (34),
252.0 [(35Cl)MþHeHCl]þ (31), 224.0 [252-CO]þ (16). Anal. Calcd
(found) for C16H14ClNO2 (287.74): C 66.79 (66.91), H 4.90 (4.96), N
4.87 (4.61).
4.2.3. (3R*4S*)-3-Benzyl-3-chloro-3,4-dihydro-4-hydroxyquin-olin-
2(1H)-one (anti-2b). Compound was prepared from 1b in 22%
yield. White solid, mp 204e208 ꢁC (benzene/ethyl acetate). IR:
3244, 3031, 2922, 2803, 2656, 1681, 1615, 1599, 1496, 1455, 1430,
1384, 1319, 1253, 1208, 1129, 1112, 1076, 1044, 1032, 1009, 951, 912,
877, 862, 757, 700, 681, 669, 644, 606, 573, 542, 516 cmꢀ1. ESI-MS
(pos.) m/z (%): 597.0 [(35Cl)2MþNa]þ (8), 326.0 [(35Cl)MþK]þ (29),
310.0 [(35Cl)MþNa]þ (100), 288.0 [(35Cl)MþH]þ (12). Anal. Calcd
(found) for C16H14ClNO2 (287.74): C 66.79 (67.09), H 4.90 (4.93), N
4.87 (4.65).
4.2.4. (3R*4R*)-3-Chloro-3,4-dihydro-4-hydroxy-3-phenylquin-olin-
2(1H)-one (syn-2c). Compound was prepared from 1c in 27% yield.
White solid, mp 132e138 ꢁC (benzene). IR: 3235, 2945, 1688, 1617,
1600, 1491, 1448, 1408, 1373, 1296, 1240, 1201, 1111, 1093, 1069,
4.2.10. (3R*4R*)-3-Butyl-3-chloro-3,4-dihydro-4-hydroxy-1-
phenylquinolin-2(1H)-one (syn-2g). Compound was prepared from
1g in 54% yield. White solid, mp 116e118 ꢁC (cyclohexane). IR: 3413,
3039, 2963, 2935, 2873, 1677, 1604, 1494, 1458, 1356, 1297, 1264,
1122, 1075, 1018, 754, 693, 608, 520 cmꢀ1. ESI-MS (pos.) m/z (%):
681.2 [(35Cl)2MþNa]þ (10), 368.1 [(35Cl)MþK]þ (17), 352.1 [(35Cl)
MþNa]þ (71), 330.1 [(35Cl)MþH]þ (100). Anal. Calcd (found) for
1044, 940, 918, 901, 881, 815, 772, 748, 691, 683, 627, 577, 542 cmꢀ1
.
ESI-MS (pos.) m/z (%): 569.0 [(35Cl)2MþNa]þ (39), 312.0 [(35Cl)
MþK]þ (14), 296.0 [(35Cl)MþNa]þ (100), 274.0 [(35Cl)MþH]þ (59),
260.0 [(35Cl)MþNaeHCl]þ (21), 238.0 [(35Cl)MþHeHCl]þ (25),
210.0 [238-CO]þ (8). Anal. Calcd (found) for C15H12ClNO2 (273.71): C
65.82 (65.78), H 4.42 (4.55), N 5.12 (4.90).
C19H20ClNO2 (329.82): C 69.19 (69.22), H 6.11 (6.25), N 4.25 (4.23).
4.2.11. (3R*4R*)-3-Benzyl-3-chloro-3,4-dihydro-4-hydroxy-1-
phenylquinolin-2(1H)-one (syn-2h). Compound was prepared from
1h in 29% yield. White solid, mp 149e152 ꢁC (benzene). IR: 3406,
3062, 2944, 1682, 1602, 1592, 1493, 1439, 1379, 1347, 1277, 1258,
1203, 1124, 1070, 1027, 964, 921, 883, 757, 700, 692, 670, 656, 633,
624, 565, 522 cmꢀ1. ESI-MS (pos.) m/z (%): 749.2 [(35Cl)2MþNa]þ
(6), 402.0 [(35Cl)MþK]þ (41), 386.1 [(35Cl)MþNa]þ (53), 383.1 [(35Cl)
2MþCa]2þ (19), 364.1 [(35Cl)MþH]þ (100), 350.1 [(35Cl)
MþNaeHCl]þ (8), 328.1 [(35Cl)MþHeHCl]þ (9). Anal. Calcd (found)
for C22H18ClNO2 (363.84): C 72.62 (72.39), H 4.99 (5.01), N 3.85
(3.63).
4.2.5. (3R*4R*)-3-Butyl-3-chloro-3,4-dihydro-4-hydroxy-1-
methylquinolin-2(1H)-one (syn-2d). Compound was prepared from
1d in 47% yield. White solid, mp 116e120 ꢁC (cyclohexane). IR:
3367, 2959, 2927, 2857, 1650, 1603, 1471, 1418, 1369, 1308, 1272,
1243, 1210, 1115, 1076, 1046, 1009, 948, 845, 827, 764, 706, 674, 605,
536. ESI-MS (pos.) m/z (%): 557.1 [(35Cl)2MþNa]þ (10), 306.0 [(35Cl)
MþK]þ (8), 290.0 [(35Cl)MþNa]þ (48), 268.0 [(35Cl)MþH]þ (100).
Anal. Calcd (found) for C14H18ClNO2 (267.75): C 62.80 (62.98), H
6.78 (6.94), N 5.23 (5.47).
4.2.6. (3R*4S*)-3-Benzyl-3-chloro-3,4-dihydro-4-hydroxy-1-
methylquinolin-2(1H)-one (anti-2e). Compound was prepared from
1e in 27% yield. White solid, mp 236e239 ꢁC (benzene). IR: 3363,
3031, 2937, 2910, 1648, 1601, 1496, 1474, 1418, 1383, 1341, 1252,
1210, 1130, 1031, 990, 957, 923, 885, 765, 751, 701, 681, 636, 590,
537 cmꢀ1. ESI-MS (pos.) m/z (%): 625.1 [(35Cl)2MþNa]þ (6), 340.0
[(35Cl)MþK]þ (56), 324.1 [(35Cl)MþNa]þ (100), 302.1 [(35Cl)MþH]þ
(64). Anal. Calcd (found) for C17H16ClNO2 (301.77): C 67.66 (68.14),
H 5.34 (5.44), N 4.64 (4.44).
4.2.12. (3R*4R*)-3-Chloro-3,4-dihydro-4-hydroxy-1,3-
diphenylquinolin-2(1H)-one (syn-2i). Compound was prepared
from 1i in 25% yield. White solid, mp 223e227 ꢁC (benzene). IR:
3496, 3060, 3036, 2860, 1677, 1605, 1591, 1492, 1461, 1405, 1352,
1275, 1259, 1200, 1131, 1089, 1040, 1031, 950, 903, 800, 761, 745,
695, 678, 656, 630, 613, 57, 528 cmꢀ1. ESI-MS (pos.) m/z (%): 721.1
[(35Cl)2MþNa]þ (5), 372.0 [(35Cl)MþNa]þ (100), 350.0 [(35Cl)
MþH]þ (39), 336.1 [(35Cl)MþNaeHCl]þ (35), 314.1 [(35Cl)
MþHeHCl]þ (7), 286.1 [314-CO]þ (7). Anal. Calcd (found) for
C21H16ClNO2(349.81): C 72.10H 4.61 (4.66), N 4.00 (3.82).
4.2.7. (3R*4R*)-3-Benzyl-3-chloro-3,4-dihydro-4-hydroxy-1-
methylquinolin-2(1H)-one (syn-2e). Compound was prepared from
1e in 19% yield. White solid, mp 195e199 ꢁC (benzene). IR: 3447,
3031, 2956, 1664, 1603, 1495, 1474, 1455, 1422, 1366, 1305, 1256,
1205, 1123, 1068, 1049, 1034, 998, 948, 899, 852, 761, 699, 670, 626,
603, 534 cmꢀ1. ESI-MS (pos.) m/z (%): 625.1 [(35Cl)2MþNa]þ (5),
340.0 [(35Cl)MþK]þ (61), 324.1 [(35Cl)MþNa]þ (65), 302.1 [(35Cl)
MþH]þ (100). Anal. Calcd (found) for C17H16ClNO2 (301.77): C 67.66
(67.64), H 5.34 (5.30), N 4.64 (4.42).
4.2.13. (3R*4S*)-3-Chloro-3,4-dihydro-4-hydroxy-1,3-
diphenylquinolin-2(1H)-one (anti-2i). Compound was prepared
from 1i in 3% yield. White solid, mp 200e206 ꢁC (benzene). IR:
3406, 3041, 1672, 1603, 1591, 1491, 1459, 1342, 1266, 1254, 1134,
1085, 1048, 1024, 951, 926, 897, 790, 778, 758, 751, 739, 695, 608,
568, 538 cmꢀ1. ESI-MS (pos.) m/z (%): 721.1 [(35Cl)2MþNa]þ (5),
388.0 [(35Cl)MþK]þ (26), 372.0 [(35Cl)MþNa]þ (28), 350.0 [(35Cl)
MþH]þ (100), 336.1 [(35Cl)MþNaeHCl]þ (11), 314.1 [(35Cl)
MþHeHCl]þ (18), 286.1 [314-CO]þ (19). Anal. Calcd (found) for
4.2.8. (3R*4R*)-3-Chloro-3,4-dihydro-4-hydroxy-1-methyl-3-
phenylquinolin-2(1H)-one (syn-2f). Compound was prepared from
1f in 24% yield. White solid, mp 173e177 ꢁC (benzene). IR: 3422,
3068, 2971, 1673, 1603, 1494, 1472, 1414, 1376, 1334, 1315, 1274,
1241, 1208, 1132, 1099, 1077, 1066, 1037, 937, 907, 872, 861, 811, 759,
747, 698, 626, 598, 557, 516 cmꢀ1. ESI-MS (pos.) m/z (%): 597.1 [(35Cl)
2MþNa]þ (7), 326.0 [(35Cl)MþK]þ (53), 310.0 [(35Cl)MþNa]þ (100),
288.0 [(35Cl)MþH]þ (43), 274.0 [(35Cl)MþNaeHCl]þ (28), 252.1
[(35Cl)MþHeHCl]þ (13), 224.0 [252-CO]þ (7). Anal. Calcd (found)
C
21H16ClNO2 (349.81): cC 72.10 (72.26), H 4.61 (4.70), N 4.00 (3.82).
4.2.14. 1a-Phenyloxireno[2,3-c]quinolin-2(1aH, 3H, 7bH)-one
(3c). Compound was prepared from 1c in 29% yield. White solid,
mp 203e210 ꢁC (benzene). IR: 3212, 3065, 3004, 2941, 1682, 1599,
1497, 1448, 1415, 1366, 1300, 1265, 1225, 1198, 1179, 1106, 1033, 964,
903, 851, 798, 759, 733, 699, 676, 617, 593, 566, 537 cmꢀ1. ESI-MS
(pos.) m/z (%): 497.1 [2MþNa]þ (41), 276.0 [MþK]þ (27), 260.0
[MþNa]þ (100), 238.0 [MþH]þ (65), 210.0 [MþHeCO]þ (7), 194.0

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A. Klasek et al. / Tetrahedron 72 (2016) 4490e4497
4496
[MþHeCO2]þ (18). Anal. Calcd (found) for C15H11NO2 (237.07): C
30.0 (CH2). Anal. Calcd (found) for C16H13NO2 (251.28): C 76.48
(76.44), H 5.21(5.30), N 5.57 (5.47).
75.94 (75.82), H 4.67 (4.70), N 5.90 (5.69).
4.2.15. 1a-Benzyl-3-methyloxireno[2,3-c]quinolin-2(1aH,3H,7bH)-
one (3e). Compound was prepared from anti-2e in 51% yield by
Method B. White solid, mp 85e89 ꢁC (cyclohexane). IR: 3030, 2938,
1660, 1606, 1594, 1498, 1484, 1456, 1430, 1420, 1370, 1330, 1220,
1131, 1101, 1074, 1044, 1016, 937, 881, 844, 820, 752, 732, 695, 678,
637, 584, 561 cmꢀ1. ESI-MS (pos.) m/z (%): 553.1 [2MþNa]þ (18),
417.6 [3MþCa]2þ (48), 304.0 [MþK]þ (41), 288.0 [MþNa]þ (100),
266.0 [MþH]þ (90), 196.9 [MþNaeBn]þ (5), 91.0 [Bn]þ (10). Anal.
Calcd (found) for C17H15NO2 (265.31): C 76.96 (76.75), H 5.70 (5.64),
N 5.28 (4.98).
4.4. General procedure for the reaction of compounds 2 with
thionyl chloride (Method C)
To the solution of compound 2 (1 mmol) in benzene (10 ml),
0.146 ml (2 mmol) of thionylchloride was added. The mixture was
refluxed for 2 h under drying tube filled with anhydrous calcium
chloride, cooled and the solution of NaHCO3 (5%, 10 ml) was added.
The mixture was extracted with benzene (3ꢂ10 ml). Collected ex-
tracts were washed with the solution of NaHCO3 (5%, 10 ml), dried,
evaporated to dryness and the residue was crystallized from ap-
propriate solvent. The mother liquors were separated by column
chromatography on silica gel.
4.2.16. 3-Methyl-1-phenyloxireno[2,3-c]quinolin-2(1aH,3H,7bH)-one
(3f). Compound was prepared from 1f and anti-2f in respective
yields 44 and 45%. White solid, mp 117e125 ꢁC (benzene/hexane).
IR: 3127, 3094, 3053, 2943, 1655, 1603, 1503, 1475, 1446, 1420, 1366,
1314, 1264, 12333, 1143, 1098, 1052, 1028, 943, 909, 853, 756, 727,
699, 662, 615, 596, 550 cmꢀ1. ESI-MS (pos.) m/z (%): 525.1
[2MþNa]þ (9), 290.0 [MþK]þ (16), 274.0 [MþNa]þ (47), 252.0
[MþH]þ (100), 224.0 [MþHeCO]þ (5), 208.0 [MþHeCO2]þ (10).
Anal. Calcd (found) for C16H13NO2 (251.28): C 76.48 (76.42), H 5.21
(5.27), N 5.57 (5.35).
4.4.1. (3R*4R*)-3-Butyl-3,4-dichloro-3,4-dihydroquinolin-2(1H)-one
(cis-6a). Compound was prepared from syn-2a in 69% yield. White
solid, mp 166e169 ꢁC (benzene/hexane). IR: 3203, 3142, 3085,
2953, 2931, 2861, 1684, 1600, 1493, 1467, 1458, 1383, 1365, 1295,
1255, 1209, 1186, 1128, 962, 866, 833, 810, 751, 706, 691, 613, 584,
537 cmꢀ1. ESI-MS (pos.) m/z (%): 565.0 [(35Cl)2MþNa]þ (10), 310.0
[(35Cl)MþK]þ (21), 294.0 [(35Cl)MþNa]þ (17), 272.0 [(35Cl)MþH]þ
(100), 258.0 [(35Cl)MþNaeHCl]þ (9), 236.0 [(35Cl)MþHeHCl]þ (5),
230.2 [258-CO]þ (5). Anal. Calcd (found) for C13H15Cl2NO (272.17): C
57.37 (57.28), H 5.56(5.64), N 5.15 (4.90).
4.2.17. 1a,3-Diphenyloxireno[2,3-c]quinolin-2(1aH,3H,7bH)-one
(3i). Compound was prepared from 1i in 33% yield and from anti-2i
in 51% yield. White solid, mp 140e142 ꢁC (cyclohexane). IR: 3066,
1678, 1606, 1590, 1499, 1490, 1468, 1448, 1404, 1350, 1297, 1225,
1162, 1105, 1071, 1025, 954, 900, 867, 827, 756, 734, 696, 664, 619,
606, 519 cmꢀ1. ESI-MS (pos.) m/z (%): 649.1 [2MþNa]þ (8), 352.0
[MþK]þ (20), 336.0 [MþNa]þ (56), 314.1 [MþH]þ (100), 286.0
[MþHeCO]þ (5), 270.0 [MþHeCO2]þ (16). Anal. Calcd (found) for
4.4.2. (3R*4S*)-3-Butyl-3,4-dichloro-3,4-dihydroquinolin-2(1H)-one
(trans-6a). Compound was prepared from syn-2a in 17% yield.
White solid, mp 164e174 ꢁC (cyclohexane). IR: 3207, 3149, 3089,
2995, 2957, 2927, 2860, 1692, 1599, 1496, 1450, 1389, 1367, 1307,
1262, 1212, 1099, 1033, 949, 919, 885, 867, 854, 835, 817, 756, 694,
681, 629, 585, 541, 527 cmꢀ1. ESI-MS (pos.) m/z (%): 565.0 [(35Cl)
2MþNa]þ (7), 294.0 [(35Cl)MþNa]þ (40), 272.0 [(35Cl)MþH]þ (100),
258.0 [(35Cl)MþNaeHCl]þ (65), 236.0 [(35Cl)MþHeHCl]þ (22),
230.2 [258-CO]þ (53), 200.2 [236-HCl]þ (17). Anal. Calcd (found) for
C
21H15NO2 (313.35): C 80.49 (80.35), H 4.82 (4.88), N 4.47 (4.31).
4.3. Transformation of compounds 2 in alkaline medium
(Method B)
C13H15Cl2NO (272.17): C 57.37 (57.58), H 5.56 (5.56), N 5.15 (4.92).
To the solution of compound 2 (0.1 mmol) in methanol (20 ml),
potassium carbonate (41.5 mg, 0.3 mmol) was added and the
mixture was stirred for 1 h at rt. The course of the reaction was
monitored by TLC. After filtration of the reaction mixture, the fil-
trate was evaporated to dryness. Water (10 ml) was added and the
mixture was extracted with benzene (3ꢂ10 ml). After evaporation
of collected extracts, the residue was crystallized from the appro-
priate solvent.
From the reaction of syn-2c, syn-2e, syn-2f, and syn-2i, only
starting compounds were isolated. From the reaction of anti-2e,
anti-2f and anti-2i, compounds 3e (50%) and compounds 3f and 3i,
identical in all respects to compounds isolated from the reduction
of 1f and 1i, were isolated in respective yields 62 and 51%. While
compound syn-2b does not react under given reaction conditions,
compound anti-2b afford 51% of 3-benzyl-4-hydroxyquinolin-2-
one 4b.
4.4.3. (3R*4R*)-3-Benzyl-3,4-dichloro-3,4-dihydroquinolin-2(1H)-
one (cis-6b). Compound was prepared from syn-2b in 48% yield.
White solid, mp 201e206 ꢁC (benzene/hexane). IR: 3205, 3144,
3086, 2991, 2925, 1686, 1601, 1495, 1389, 1316, 1260, 1205, 1158,
1080, 1030, 951, 835, 753, 700, 688, 667, 647, 588, 520 cmꢀ1. ESI-MS
(pos.) m/z (%): 633.0 [(35Cl)2MþNa]þ (9), 344.0 [(35Cl)MþK]þ (10),
328.0 [(35Cl)MþNa]þ (82), 306.0 [(35Cl)MþH]þ (100). Anal. Calcd
(found) for C16H13Cl2NO (306.19): C 62.76 (63.01), H 4.28 (4.24), N
4.57 (4.36).
4.4.4. (3R*4S*)-3,4-Dichloro-3-phenyl-3,4-dihydroquinolin-2(1H)-
one (trans-6c). Compound was prepared from syn-2c in 15% yield.
White solid, mp 189e193 ꢁC (benzene). IR: 3212, 3095, 2989, 2922,
1690, 1613, 1600, 1492, 1453, 1363, 1296, 1258, 1185, 1160, 1113,
1070, 1037, 1001, 949, 930, 902, 865, 807, 759, 744, 706, 696, 627,
607, 585, 554, 534 cmꢀ1. ESI-MS (pos.) m/z (%): 605.0 [(35Cl)
2MþNa]þ (13), 330.0 [(35Cl)MþK]þ (80), 314.0 [(35Cl)MþNa]þ
(100), 292.0 [(35Cl)MþH]þ (56), 278.0 [(35Cl)MþNaeHCl]þ (51),
256.0 [(35Cl)MþHeHCl]þ (58), 220.2 [256-HCl]þ (24). Anal. Calcd
(found) for C15H11Cl2NO (292.16): C 61.67 (61.79), H 3.79 (3.73), N
4.79 (4.72).
4.3.1. 4-Benzyl-3-hydroxyquinolin-2(1H)-one (4b). Compound was
prepared from anti-2b by Method B in 51% yield. White solid, mp
239e242 ꢁC (benzene/cyclohexane). IR: 3422, 3084, 2995, 2870,
1656, 1634, 1602, 1571, 1507, 1494, 1450, 1406, 1336, 1289, 1258,
1220, 1180, 1076, 1027, 976, 895, 856, 762, 714, 700, 680, 654, 626,
540 cmꢀ1. ESI-MS (pos.) m/z (%): 525.0 [2MþNa]þ (8), 396.5
[3MþCa]2þ (13), 290.0 [MþK]þ (20), 274.0 [MþNa]þ (75), 252.0
[MþH]þ (100). 1H chemical shifts: 12.12 (1H, s, NH), 9.47 (1H, s, OH),
7.57e7.62 (1H, m), 7.21e7.29 (6H, m), 7.08e7.15 (2H, m), 4.18 (2H, s,
CH2), 13C chemical shifts: 158.1, 143.5, 139.5, 133.3, 122.2, 120.6 (all
Cq), 128.4 (2C),128.2 (2C),126.4,126.0,123.5,122.1,115.3 (all¼CHe),
4.4.5. (3R*4R*)-3,4-Dichloro-3-phenyl-3,4-dihydroquinolin-2(1H)-
one (cis-6c). Compound was prepared from syn-2c in 58% yield.
White solid, mp 196e200 ꢁC (benzene/cyclohexane). IR: 3219,
3097, 3000, 2933, 1689, 1619, 1601, 1495, 1446, 1377, 1317, 1304,
1263, 1214, 1199, 1180, 1161, 1072, 1036, 954, 943, 819, 767, 756, 747,
717, 695, 677, 650, 609, 591, 555, 536 cmꢀ1. ESI-MS (pos.) m/z (%):

ꢀ
A. Klasek et al. / Tetrahedron 72 (2016) 4490e4497
4497
605.0 [(35Cl)2MþNa]þ (27), 314.0 [(35Cl)MþNa]þ (37), 292.0 [(35Cl)
MþH]þ (100), 278.0 [(35Cl)MþNaeHCl]þ (44), 256.0 [(35Cl)
MþHeHCl]þ (27), 220.2 [256-HCl]þ (14). Anal. Calcd (found) for
506 cmꢀ1. ESI-MS (pos.) m/z (%): 420.0 [(35Cl)MþK]þ (36), 404.0
[(35Cl)MþNa]þ (61), 382.1 [(35Cl)MþH]þ (100). Anal. Calcd (found)
for C22H17Cl2NO (382.28): C 69.12 (69.46), H 4.48 (4.63), N 3.66
(3.49).
C
15H11Cl2NO (292.16): C 61.67 (61.70), H 3.79 (3.77), N 4.79 (4.77).
4.4.6. (3R*4R*)-3-Butyl-3,4-dichloro-3,4-dihydro-1-methylquin-
olin-2(1H)-one (cis-6d). Compound was prepared from syn-2d in
65% yield. White solid, mp 224e227 ꢁC (benzene/hexane). IR: 3055,
2995, 2963, 2929, 2864, 1673, 1604, 1500, 1475, 1434, 1420, 1376,
1364, 1334, 1279, 1217, 1209, 1167, 1143, 1133, 1097, 1040, 972, 940,
904, 860, 825, 758, 733, 717, 689, 666, 640, 602, 564, 529 cmꢀ1. ESI-
MS (pos.) m/z (%): 593.0 [(35Cl)2MþNa]þ (6), 324.0 [(35Cl)MþK]þ
(16), 308.0 [(35Cl)MþNa]þ (100), 286.0 [(35Cl)MþH]þ (39), 250.0
[(35Cl)MþHeHCl]þ (26), 214.0 [250-HCl]þ (7). Anal. Calcd (found)
for C14H17Cl2NO (286.20): C 58.75 (58.74), H 5.99 (5.97), N 4.89
(4.66).
4.4.12. (3R*4S*)-3,4-Dichloro-1,3-diphenyl-3,4-dihydroquin-olin-
2(1H)-one (trans-6i). Compound was prepared from syn-2i in 29%
yield. White solid, mp 217e220 ꢁC (benzene). IR: 3043, 3009, 1692,
1603, 1590, 1494, 1488, 1463, 1450, 1350, 1314, 1295, 1277, 1227,
1197, 1179, 1160, 1073, 953, 902, 834, 794, 753, 736, 704, 691, 638,
611, 600, 573, 539, 513 cmꢀ1. ESI-MS (pos.) m/z (%): 406.0 [(35Cl)
MþK]þ (28), 390.0 [(35Cl)MþNa]þ (44), 368.1 [(35Cl)MþH]þ (100),
332.1 [(35Cl)MþHeHCl]þ (31), 304.1 [332-CO]þ (19), 296.1 [332-
HCl]þ (7). Anal. Calcd (found) for C21H15Cl2NO (368.26): C 68.49
(68.46), H 4.14 (4.08), N 3.80 (3.73).
4.4.13. (3R*4R*)-3,4-Dichloro-1,3-diphenyl-3,4-dihydroquinolin-
2(1H)-one (cis-6i). Compound was prepared from syn-2i in 50%
yield. White solid, mp 164e168 ꢁC (cyclohexane). IR: 3056, 3004,
1704, 1603, 1592, 1495, 1465, 1446, 1357, 1314, 1303, 1269, 1209,
1186, 1174, 1164, 1114, 1070, 1024, 956, 942, 912, 843, 806, 750, 720,
695, 684, 667, 656, 625, 600, 578, 543, 519 cmꢀ1. ESI-MS (pos.) m/z
(%): 406.0 [(35Cl)MþK]þ (17), 390.0 [(35Cl)MþNa]þ (32), 368.1
[(35Cl)MþH]þ (100), 332.1 [(35Cl)MþHeHCl]þ (25), 304.1 [332-CO]þ
(15), 296.1 [332-HCl]þ (5). Anal. Calcd (found) for C21H15Cl2NO
(368.26): C 68.49 (68.71), H 4.14 (4.15), N 3.80 (3.75).
4.4.7. (3R*4R*)-3-Benzyl-3,4-dichloro-3,4-dihydro-1-methylquin-
olin-2(1H)-one (cis-6e). Compound was prepared from syn-2e in
75% yield. White solid, mp 127e131 ꢁC (cyclohexane). IR: 3071,
3032, 2986, 2945, 1687, 1604, 1498, 1471, 1455, 1434, 1418, 1366,
1333, 1309, 1277, 1212, 1197, 1134, 1078, 1032, 986, 951, 923, 861,
791, 766, 756, 722, 709, 688, 666, 637, 607, 568, 551, 533 cmꢀ1. ESI-
MS (pos.) m/z (%): 660.9 [(35Cl)2MþNa]þ (10), 357.9 [(35Cl)MþK]þ
(27), 342.0 [(35Cl)MþNa]þ (57), 320.0 [(35Cl)MþH]þ (100). Anal.
Calcd (found) for C17H15Cl2NO (320.21): C 63.76 (63.86), H 4.72
(4.73), N 4.37 (4.37).
Acknowledgements
4.4.8. (3R*4R*)-3,4-Dichloro-3,4-dihydro-1-methyl-3-phenyl-quino-
lin-2(1H)-one (cis-6f). Compound was prepared from syn-2f in 47%
yield. White solid, mp 196e200 ꢁC (cyclohexane). IR: 3055, 2981,
1676,1605,1500,1474,1446,1419,1363,1333,1277,1218,1201,1136,
1100, 1052, 1002, 932, 843, 814, 753, 716, 699, 667, 650, 618, 586,
541 cmꢀ1. ESI-MS (pos.) m/z (%): 633.0 [(35Cl)2MþNa]þ (5), 328.0
[(35Cl)MþNa]þ (100), 306.0 [(35Cl)MþH]þ (40), 270.0 [(35Cl)
MþHeHCl]þ (13), 242.0 [270-CO]þ (5), 234.0 [270-HCl]þ (6). Anal.
Calcd (found) for C16H13Cl2NO (306.19): C 62.76 (62.87), H 4.28
(4.31), N 4.57 (4.40).
A.K., F.K., and M.R. thank for the financial support from the in-
ternal grant of TBU in Zlín (No. IGA/FT/2016/004), funded from the
resources of specific university research. The authors thank Mrs. H.
ꢁ
ꢀ
Gerzova (Faculty of Technology, Tomas Bata University in Zlín) for
technical help.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2016.05.087.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
4.4.9. (3R*4S*)-3,4-Dichloro-3,4-dihydro-1-methyl-3-phenyl-quino-
lin-2(1H)-one (trans-6f). Compound was prepared from syn-2f in
40% yield. White solid, mp 173e177 ꢁC (benzene/hexane). IR: 3005,
1675, 1605, 1503, 1475, 1447, 1416, 1365, 1332, 1280, 1237, 1203,
1172, 1130, 1111, 1037, 923, 901, 811, 765, 758, 737, 706, 693, 633,
606, 573, 542 cmꢀ1. ESI-MS (pos.) m/z (%): 633.0 [(35Cl)2MþNa]þ
(5), 334.0 [(35Cl)MþK]þ (35), 328.0 [(35Cl)MþNa]þ (68), 306.0
[(35Cl)MþH]þ (100), 270.0 [(35Cl)MþHeHCl]þ (31), 242.0 [270-
CO]þ (8), 234.0 [270-HCl]þ (12). Anal. Calcd (found) for
References and notes
ꢁ
ꢀ
1. Rudolf, O.; Rouchal, M.; Lycka, A.; Klasek, A. Helv. Chim. Acta 2013, 96,
1905e1917.
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ꢂꢁ ꢁ
2. Klasek, A.; Lycka, A.; Rouchal, M.; Rudolf, O.; Ruzicka, A. Helv. Chim. Acta 2014,
97, 595e612.
3. Klasek, A.; Lycka, A.; Kremen, F.; Ruzicka, A.; Rouchal, M. Helv. Chim. Acta 2015,
98, 318e335.
4. Kafka, S.; Klasek, A.; Polis, J.; Kosmrlj, J. Heterocycles 2002, 57, 1659e1682.
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C
16H13Cl2NO (306.19): C 62.76 (62.77), H 4.28 (4.31), N 4.57 (4.41).
ꢀ
ꢁ
ꢁ
ꢂꢁ ꢁ
ꢀ
ꢁ
4.4.10. (3R*4R*)-3-Butyl-3,4-dichloro-3,4-dihydro-1-phenylquin-
olin-2(1H)-one (cis-6g). Compound was prepared from syn-2g in
52% yield. White solid, mp 130e134 ꢁC (hexane). IR: 3383, 3061,
2955, 2928, 2870, 1700, 1603, 1590, 1493, 1464, 1380, 1355, 1302,
1268, 1215, 1177, 1166, 1125, 1070, 1002, 959, 836, 779, 761, 750, 741,
696, 624, 607, 596, 527, 506 cmꢀ1. ESI-MS (pos.) m/z (%): 386.0
[(35Cl)MþK]þ (17), 370.0 [(35Cl)MþNa]þ (39), 348.1 [(35Cl)MþH]þ
(100), 312.1 [(35Cl)MþHeHCl]þ (39), 276.1 [312-HCl]þ (7), 256.0
[312eC4H8]þ (8). Anal. Calcd (found) for C19H19Cl2NO (348.27): C
65.53 (65.53), H 5.50 (5.63), N 4.02 (3.91).
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phenylquinolin-2(1H)-one (cis-6h). Compound was prepared from
syn-2h in 77% yield. White solid, mp 173e178 ꢁC (benzene). IR:
3032, 2927, 1694, 1603, 1590, 1492, 1460, 1353, 1314, 1295, 1219,
1193, 1178, 1073, 1005, 920, 833, 794, 765, 751, 696, 645, 600, 578,
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