Simple one-pot synthesis of 5-(chloromethyl)isoxazoles from aldoximes and 2,3-dichloro-1-propene

Article abstract of DOI:10.1007/s10593-019-02606-2

[Figure not available: see fulltext.] A one-pot synthesis of 3-substituted 5-chloromethylisoxazoles from available starting aldoximes and 2,3-dichloro-1-propene, serving both as a solvent and reagent, is proposed. Excess 2,3-dichloro-1-propene is recovered after the reaction. The synthesis is effective for oximes of both aromatic and aliphatic aldehydes.

Full text of DOI:10.1007/s10593-019-02606-2

DOI 10.1007/s10593-019-02606-2
Chemistry of Heterocyclic Compounds 2019, 55(12), 1228–1232
Simple one-pot synthesis of
5-(chloromethyl)isoxazoles from
aldoximes and 2,3-dichloro-1-propene
Evgeniy V. Kondrashov1*, Nina S. Shatokhina1
1 A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences,
1 Favorsky St., Irkutsk 664033, Russia; е-mail: ekondrs@gmail.com
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(12), 1228–1232
Submitted July 31, 2019
Accepted August 27, 2019
A one-pot synthesis of 3-substituted 5-chloromethylisoxazoles from available starting aldoximes and 2,3-dichloro-1-propene, serving
both as a solvent and reagent, is proposed. Excess 2,3-dichloro-1-propene is recovered after the reaction. The synthesis is effective for
oximes of both aromatic and aliphatic aldehydes.
Keywords: 2,3-dichloro-1-propene, isoxazoles, nitrile oxides, oximes, aromatization, 1,3-dipolar cycloaddition, one-pot synthesis.
Scheme 1
The isoxazole ring is a constituent of the structures of
many medications and is a well-known carrier of
pharmacophore properties.1 In this regard, new methods for
the preparation and functionalization of isoxazoles are
currently being actively developed.2 One of the convenient
ways of introducing an isoxazole fragment into organic
molecules is the reaction of halomethylisoxazoles with O-,3
N-,4 S-nucleophiles,5 including peptides.5d Thus, halo-
methylisoxazoles are in demand as building blocks for the
synthesis of isoxazole derivatives, and the development of
new methods for their preparation is still relevant.6
The existing methods for obtaining 5-(chloromethyl)-
isoxazoles are based on the reaction of hydroxylamine with
α,β-unsaturated γ-chloro ketones containing a chlorine
atom7 or isothiocyanate fragment8 at the double bond as a
leaving group (Scheme 1, a). The method is effective in the
synthesis of 3-alkyl-5-(chloromethyl)isoxazoles (75–85%
yields) and somewhat less effective in the case of 3-aryl-
substituted derivatives (60–73% yields). The starting
γ-chloro ketones are obtained from acid chlorides and
2,3-dichloro-1-propene9 or propargyl chloride.10
Another approach to the synthesis of 5-(halomethyl)-
isoxazoles involves the cycloaddition of nitrile oxides to
propargyl halides or propargyl alcohol11,5a (Scheme 1, b, c).
In this case, the reactions are accompanied by the
formation of furoxans as byproducts and resinification,
prevention of which mandates careful selection of the
conditions or the use of catalysts based on Cu(II)12a or
Ce(III)12b salts.
Alternatively, 5-(chloromethyl)isoxazoles can be
prepared by cycloaddition of nitrile oxides to 2,3-dichloro-
1-propene (DCP), which can be considered the synthetic
equivalent of propargyl chloride, followed by dehydro-
chlorination of the intermediate isoxazoline. The
implementation of this approach would avoid the
0009-3122/19/55(12)-1228©2019 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2019, 55(12), 1228–1232
Scheme 2
Method I
Et3N, 1 h
R
R
Py, NCS
Cl
23–87%
DCP
OH
Cl
R
N
O
R
N
OH
Cl
DCP, rt, 30 min
then 40°C 3–24 h
N
N
Method II
BnN+Et3Cl–, NaOH
H2O, rt, 2 h
R
N
Cl
O
O
1a–l
3a l
–
2a–l
4a–l
5a–l
8–77%
DCP= 2,3-dichloro-1-propene
a R = Me, b R = n-C7H15, c R = Cy, d R = Ph, e R = 4-MeOC6H4, f R = 4-FC6H4, g R = 4-ClC6H4,
h R = 2-ClC6H4, i R = 4-O2NC6H4, j R = 2-O2NC6H4, k R = 2-HOC6H4, l R = PhCH=CH
Table 1. Yields of isoxazoles 5a,b,d,l
disadvantages inherent in the reactions of nitrile oxides
with acetylenes. On the other hand, DCP is a cheap
depending on the nature of the base, %
commercially
available
reagent
obtained
from
Compound
5b 5d
organochlorine chemicals production waste streams.13
However, to date, only two examples of the use of DCP in
the synthesis of 5-(chloromethyl)isoxazoles are presented
in the literature. Thus, its reaction with bromonitrile oxide14
obtained in situ and stable 2,6-dichlorophenyl nitrile
oxide15 with the yields of the desired 5-(chloromethyl)-
isoxazoles of 81 and 65%, respectively, is described.
Thus, the aim of this work was to develop a simple
convenient method for the synthesis of 5-(chloromethyl)-
isoxazoles from DCP and aldoximes, to determine the
scope and limitations of the method and the characteristics
of the process.
Base
5a
62
8
5l
Et3N (method I)
86
52
87
77
57
64
NaOH (method II)
isoxazoles 5d,l slightly depend on the nature of the base
(Table 1). At the same time, the replacement of the organic
base with an alkali leads to a significant decrease in the
yields of 3-alkylisoxazoles 5a,b, probably due to side
reactions involving the active methylene group of nitrile
oxide or hydrolysis of chloro oxime 2.
Isolation of individual nitrile oxides or their precursors,
N-hydroxyimidoyl chlorides, presents a certain problem
due to the chemical instability of these compounds. For
instance, the time for complete dimerization of lower alkyl
nitrile oxides into furoxans at 18°С is less than 1 min.16 To
optimize the process of obtaining the desired isoxazoles,
we synthesized N-hydroxyimidoyl chlorides and then
nitrile oxides from them sequentially in one pot without
isolation of intermediates.
To carry out the transformations, we proposed the use of
DCP as the solvent in the chlorination of oximes 1a–l with
N-chlorosuccinimide (NCS) and as a reactant in the
subsequent 1,3-dipolar cycloaddition reaction (Scheme 2).
The synthesis of N-hydroxyimidoyl chlorides 2a–l in a
DCP solution was carried out similarly to the known
methods for the chlorination of aldoximes in CH2Cl2 or
CHCl3 in the presence of catalytic amounts of pyridine.17
Under the selected conditions, we did not observe any
adverse reactions of chlorination of DCP or the addition of
NCS at the C=C double bond of DCP. Chlorination of
aliphatic aldoximes was, as a rule, faster than aromatic
aldoximes and complete in 3–4 h. The progress of the
reaction was monitored by TLC.
Upon subsequent addition of 2 equiv of the base, a
cascade of transformations took place, as shown in Scheme 2.
In the first step, chloro oximes 2a–l are dehydrochlorinated
to nitrile oxides 3a–l, which react with DCP to form
isoxazolines 4a–l. The action of the second equivalent of
the base brings about aromatization of isoxazolines 4a–l to
isoxazoles 5a–l. After the reactions, the excess DCP is
distilled off under reduced pressure and can be reused.
We used Et3N (method I) or an aqueous solution of
NaOH (method II) as the base. The yields of the target
In a dedicated experiment, we determined that DCP is
not subjected to dehydrochlorination to propargyl chloride
by the action of Et3N or an aqueous solution of NaOH
under the reaction conditions. Consequently, nitrile oxides
formed in situ enter the cycloaddition reaction precisely
with DCP.
Considering the high propensity of nitrile oxides to
dimerize into furoxans, the generation of nitrile oxides 3a–l
in a DCP solution, that is, under conditions of multiple
molar excess of the reactant, favorably affects the
conversion of nitrile oxides 3 to isoxazoles 5. Thus, under
optimal conditions, we did not observe the formation of
furoxans, unlike existing literature methods for the
synthesis of nitrile oxides in organic solvents.
It should be noted that the cycloaddition of nitrile oxides
to DCP occurs regioselectively with the formation of only
one regioisomer, in this case, 5-(chloromethyl)isoxazoles.
The observed fact is consistent with the general reactivity
of nitrile oxides with terminal alkenes.18
Using the example of isoxazoles 5g,k, we compared the
efficacy of methods for the synthesis of heterocycles 5a–l
from various precursors: oximes 1 (method I) and chloro
oximes 2 (method III). In the synthesis of 3-(4-chloro-
phenyl)isoxazole 5g, both methods gave similar results (81
and 84% yields when using methods
I and III,
respectively). However, the yield of isoxazole 5k from the
preliminarily obtained chloro oxime 2k (method III) was
significantly higher compared to the yield obtained with
method I (45% versus 23%). This is obviously due to the
low efficiency of obtaining chloro oxime 2k in DCP
solution as compared with CHCl3.
Unfortunately, we were not able to extend this synthesis
method to the oximes of furfural and thiophene-2-carbox-
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Chemistry of Heterocyclic Compounds 2019, 55(12), 1228–1232
aldehyde. The chlorination of furan-2-carboxaldehyde
NaOH (200 mg) in H2O (3 ml) was added with vigorous
stirring. The reaction mixture was stirred for 2 h, H2O
(20 ml) and CH2Cl2 (25 ml) were added, the organic phase
was separated, dried over MgSO4, and the solvents were
distilled off under reduced pressure. In order to recover
DCP, the distilled solvent mixture was fractionated. An
analytically pure sample was obtained by flash
chromatography (the same as in method I).
oxime by NCS in a DCP medium occurs mainly at position
5 of the ring accompanied by extensive resinification and
then extremely slowly at the aldoxime group. A similar
problem was observed during a reaction in a CH2Cl2
solution.19 Similar chlorination of thiophene-2-carbox-
aldehyde oxime in DCP by 2 equiv of NCS, after addition
of the base, results in a difficult to separate mixture of
3-(thiophen-2-yl)- and 3-(5-chlorothiophen-2-yl)-5-(chloro-
methyl)isoxazoles and unidentified impurities.
Method III. Chloro oxime 2 (2 mmol) prepared by a
published procedure was dissolved in DCP (5 ml). A
solution of Et3N (455 mg, 4.5 mmol) in DCP (1 ml) was
added with vigorous stirring to the mixture at room tempe-
rature. Heating of the mixture and precipitation occurred. The
reaction mixture was stirred for 1 h, DCP was distilled off
under reduced pressure, and the target compound was
isolated by flash chromatography (the same as in method I).
5-(Chloromethyl)-3-methylisoxazole (5а). A drop of
pyridine was added and then a solution of acetaldoxime
(237 mg, 4 mmol) in DCP (2 ml) was added dropwise to a
suspension of NCS (560 mg, 4.2 mmol) in DCP (5 ml). A
slight heating, dissolution, and precipitation were observed.
After 3 h, a solution of Et3N (910 mg, 9 mmol) in DCP
(2 ml) was added with vigorous stirring, resulting in
heating and formation of a large volume of precipitate.
Stirring was continued at room temperature for 1 h, the
reaction mixture was diluted with pentane (20 ml), the
precipitate was filtered off, and the filtrate was evaporated.
The residue was purified by flash chromatography on silica
gel, eluent CH2Cl2. Yield 327 mg (62%, method I), 42 mg
The structure of the obtained compounds 5a–l was
proved by NMR spectroscopy and GCMS, while the
composition was confirmed by elemental analysis. The
1H NMR spectra contain the characteristic singlet signals of
the CH2Cl group protons at 4.56–4.70 ppm and of the 4-CH
proton of the isoxazole ring at 6.14–6.16 ppm (for
3-alkylisoxazoles 5a–c) and 6.45–6.78 ppm (for 3-aryl-
isoxazoles). In the 13C NMR spectra, the signals of C-4
carbon atoms of the isoxazole ring of compounds 5b,h–l
are observed at 101–105 ppm, while the signals of C-3,5
1
atoms are evident in the 160–168 ppm region. H NMR
spectra of the known isoxazoles 5a,c–g correspond to the
published data.5d,6
To conclude, we developed in this work a one-pot
method for the synthesis of 3-substituted 5-(chloromethyl)-
isoxazoles from the simple and available starting
compounds, aldoximes and 2,3-dichloro-1-propene.
Experimental
1
IR spectra were registered on a Varian 3100 FT-IR
spectrometer with the sample in thin film. 1H and 13C NMR
spectra were acquired on a Bruker DPX-400 (400 and
100 MHz, respectively) in CDCl3, with TMS as internal
standard. Mass spectra were recorded on a Shimadzu
GCMS-QP5050A mass spectrometer (EI ionization, 70 eV).
Elemental analysis was performed on a Thermo Finnigan
Flash series 1112 Elemental analyzer. Silica gel (215–
400 mesh) was used for column chromatography.
(8%, method II), colorless oil. H NMR spectrum, δ, ppm:
2.27 (3Н, s, CH3); 4.55 (2Н, s, СН2Cl); 6.14 (1Н, s, Н-4).
13C NMR spectrum, δ, ppm: 11.4; 34.5; 104.4; 160.1;
167.2. Analytical data match those published previously.5d
5-(Chloromethyl)-3-heptylisoxazole (5b). Yield 370 mg
(86%, method I), 228 mg (52%, method II), colorless oil.
IR spectrum, ν, cm–1: 734 (C–Cl), 1005, 1139, 1271, 1427,
1460, 1608 (C=C, C=N), 2858 (CH Alk), 2927 (CH Alk),
1
3131 (CH Het). H NMR spectrum, δ, ppm (J, Hz): 0.86–
Et3N and 2,3-dichloro-1-propene were dried before use.
Oxime 1a was commercially available, oximes 1b–l,20
chloro oximes 2g20 and 2k17d were synthesized according to
literature methods.
0.89 (3Н, m, СН3); 1.28–1.33 (8Н, m, 4СН2); 1.62–1.69
(2Н, m, СН2); 2.65 (2Н, t, J = 7.7, СН2); 4.58 (2Н, s, СН2Cl);
6.16 (1Н, s, H-4). 13C NMR spectrum, δ, ppm: 14.1; 22.6;
26.0; 28.2; 29.0; 29.2; 31.7; 34.6; 103.4; 164.4; 167.1. Mass
spectrum, m/z (Irel, %): 215 [M]+ (1), 186 [M–C2H5]+ (6),
172 [M–C3H7]+ (9), 166 [M–СН2Cl]+ (28), 144 [M–C5H11]+
(35), 131 [M–C6H12]+ (100), 96 (19), 41 (56). Found: %:
С 61.17; Н 8.71; N 6.72. C11H18ClNO. Calculated, %:
С 61.25; Н 8.41; N 6.49.
Synthesis of compounds 5a–l (General procedure).
Method I. A drop of pyridine and then NCS (294 mg,
2.2 mmol) with stirring were added to a suspension of
oxime 1 (2 mmol) in DCP (5 ml). Dissolution of the NCS
took place, followed by precipitation of succinimide. The
mixture was stirred at room temperature for 30 min, then
heated to 40°С for 3–24 h (TLC control). A solution of
Et3N (455 mg, 4.5 mmol) in DCP (1 ml) was added with
vigorous stirring to the mixture at room temperature.
Heating of the mixture and precipitation occurred. The
reaction mixture was stirred for 1 h, DCP was distilled off
under reduced pressure, and the target compound was
isolated by flash chromatography on silica gel, eluent
CH2Cl2 or CHCl3, Rf 0.6–0.8.
5-Chloromethyl-3-(cyclohexyl)isoxazole (5c).6 Yield
343 mg (86%, method I), colorless oil. 1H NMR spectrum,
δ, ppm: 1.25–1.46 (5Н, m, CH2); 1.72–1.98 (5Н, m, CH2);
2.69–2.75 (1Н, m, СН); 4.56 (2Н, s, CН2Cl); 6.14 (1Н, s,
Н-4).
5-(Chloromethyl)-3-phenylisoxazole (5d). Yield 337 mg
(87%, method I), 298 mg (77%, method II), white powder,
1
mp 68–69 °С (mp 69–70 °С11c, 63–65 °С6). H NMR
spectrum, δ, ppm: 4.67 (2Н, s, СН2Сl); 6.65 (1Н, s, Н-4);
7.47–7.49 (3Н, m, H Ph); 7.80–7.83 (2Н, m, H Ph).
Method II. Benzyltriethylammonium chloride (22 mg,
0.1 mmol) was added to a solution of in situ prepared
chloro oxime 2 in DCP (method I), then a solution of
5-(Chloromethyl)-3-(4-methoxyphenyl)isoxazole (5e).
Yield 349 mg (78%, method I), white powder, mp 78–79°С
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Chemistry of Heterocyclic Compounds 2019, 55(12), 1228–1232
1
(mp 75–77°С6). H NMR spectrum, δ, ppm (J, Hz): 3.87
(3Н, s, OСН3); 4.65 (2Н, s, СН2Cl); 6.59 (1Н, s, Н-4); 6.97–
7.00 (2Н, d, J = 8.0, H Ar); 7.75 (2Н, d, J = 8.0, H Ar).
H Ar); 7.34 (1Н, t, J = 8.0, H Ar); 7.43–7.45 (1Н, m,
H Ar); 9.22 (1Н, s, ОН). 13C NMR spectrum, δ, ppm: 34.2
(СН2Cl); 101.5; 112.8; 117.6; 119.9; 128.0; 132.0; 156.6;
162.7; 167.2. Mass spectrum, m/z (Irel, %): 211 [M]+ (18),
209 [M]+ (55), 174 [M–Cl]+ (18), 160 [M–СН2Cl]+ (100),
132 (45), 104 (26), 91 (21), 77 (32). Found, %: С 57.16;
Н 3.87; N 6.40. C10H8ClNO2. Calculated, %: С 57.30;
Н 3.85; N 6.68.
5-(Chloromethyl)-3-(4-fluorophenyl)isoxazole (5f). Yield
322 mg (76%, method I), white powder, mp 63–64°С
1
(mp 62–63°С6). H NMR spectrum, δ, ppm: 4.66 (2Н, s,
СН2Сl); 6.61 (1Н, s, H-4); 7.13–7.18 (2Н, m, H Ar); 7.77–
7.81 (2Н, m, H Ar).
5-(Chloromethyl)-3-(4-chlorophenyl)isoxazole (5g). Yield
370 mg (81%, method I), 383 mg (84%, method III), white
5-(Chloromethyl)-3-((E)-2-phenylethenyl)isoxazole (5l).
Yield 245 mg (57%, method I), 279 mg (64%, method II),
white powder, mp 77–78°C. IR spectrum, ν, cm–1: 696,
731, 809, 967, 1288, 1438, 1605 (C=C, C=N), 1644, 3037
powder, mp 104°С (mp 105°С12a, 96–98°С6). H NMR
1
spectrum, δ, ppm (J, Hz): 4.67 (2Н, s, СН2Сl); 6.62 (1Н, s,
H-4); 7.45 (2Н, d, J = 8.0, H Ar); 7.74 (2Н, d, J = 8.0,
H Ar).
1
(CH Ph), 3123 (CH Het). H NMR spectrum, δ, ppm
(J, Hz): 4.63 (2Н, s, СН2Cl); 6.57 (1Н, s, Н-4); 7.12 (1Н, d,
J = 16.5, СН); 7.19 (Н, d, J = 16.5, СН); 7.34–7.43 (3Н, m,
H Ph); 7.52–7.55 (2Н, m, H Ph). 13C NMR spectrum,
δ, ppm: 34.5 (СН2Cl); 100.9; 115.6; 127.1 (2С); 128.9
(2С); 129.1; 135.6; 136.5; 162.0; 167.4. Mass spectrum,
m/z (Irel, %): 221 [M]+ (10), 220 [M–H]+ (27), 219 [M]+
(30), 218 [M–H]+ (65), 190 (59), 170 [M–CH2Cl] (41), 142
(76), 128 (25), 115 (71), 103 (55), 77 (100). Found, %:
С 65.40; Н 4.43; N 6.29. C12H10ClNO. Calculated, %:
С 65.61; Н 4.59; N 6.38.
5-(Chloromethyl)-3-(2-chlorophenyl)isoxazole (5h).
Eluent Et2O–hexane, 1:5. Yield 339 mg (74%, method I),
colorless oil. IR spectrum, ν, cm–1: 737 (C–Cl), 945, 1048,
1265, 1401, 1447, 1605 (C=C, C=N), 2966–3063 (CH Ar),
1
3141 (CH Het). H NMR spectrum, δ, ppm: 4.69 (2Н, s,
СН2Cl); 6.81 (1Н, s, Н-4); 7.34–7.42 (2Н, m, H Ar); 7.48–
7.51 (1Н, m, H Ar); 7.73–7.75 (1Н, m, H Ar). 13C NMR
spectrum, δ, ppm: 34.5 (СН2Cl); 105.2; 127.3; 128.0;
130.6; 131.1; 131.2; 133.0; 161.4; 167.3. Mass spectrum,
m/z (Irel, %): 229 [M]+ (14), 227 [M]+ (21), 192 [M–Cl]+
(6), 178 [M–CH2Cl]+ (100), 150 (30), 75 (29). Found, %:
С 52.78; Н 3.07; N 5.99. C10H7Cl2NO. Calculated, %:
С 52.66; Н 3.09; N 6.14.
1
Supplementary information file containing IR, H and
13C NMR spectra of the synthesized compounds is
available at the journal website at http://link.springer.com/
journal/10593.
5-(Chloromethyl)-3-(4-nitrophenyl)isoxazole (5i). Before
the addition of NCS, DMF (0.3 ml) was added to the
reaction mixture for homogenization. Eluent EtOAc–
hexane, 1:3. Yield 248 mg (52%, method I), white powder,
mp 120–122 °С (mp 204–206 °С12b). IR spectrum, ν, cm–1:
698, 731 (C–Cl), 855, 945, 1344 (NO2), 1432, 1512 (NO2),
1600 (C=C, C=N), 3034 (CH Ar), 3082 (CH Ar), 3124
Spectral and analytical data were obtained using the
equipment of the Baikal Analytical Center for Collective
Use of Irkutsk Institute of Chemistry of the Siberian Branch
of the Russian Academy of Sciences.
1
References
(CH Het). H NMR spectrum, δ, ppm (J, Hz): 4.70 (2Н, s,
СН2Сl); 6.73 (1Н, s, Н-4); 7.99 (2H, d, J = 8.0, H Ar); 8.33
(2H, d, J = 8.0, H Ar). 13C NMR spectrum, δ, ppm: 34.4
(CH2Cl); 102.0; 124.3 (2C); 127.8 (2C); 134.7; 148.9;
161.0; 169.3. Found, %: С 50.38; Н 2.92; N 11.64.
C10H7ClN2O3. Calculated, %: С 50.33; Н 2.96; N 11.74.
5-(Chloromethyl)-3-(2-nitrophenyl)isoxazole (5j).
Yield 320 mg (73%, method I), yellow oil. IR spectrum,
ν, cm–1: 743 (C–Cl), 948, 1354 (NO2), 1405, 1531 (NO2),
1606 (C=C, C=N), 2924, 3136 (CH Het). 1H NMR
spectrum, δ, ppm (J, Hz): 4.66 (2Н, s, CН2Cl); 6.45 (1H, s,
H-4); 7.61–7.72 (3Н, m, H Ar); 7.99 (1Н, d, J = 8.0, H Ar).
13C NMR spectrum, δ, ppm: 34.4 (СН2Cl); 104.2; 124.0;
124.8; 131.0; 131.8; 133.2; 148.6; 160.3; 168.0. Mass
spectrum, m/z (Irel, %): 238 [M]+ (1), 203 [M–Cl]+ (2), 159
(4), 132 (100), 121 (13), 102 (25), 76 (35), 69 (50). Found,
%: С 50.32; Н 3.27; N 11.92. C10H7ClN2O3. Calculated, %:
С 50.33; Н 2.96; N 11.74.
2-[5-(Chloromethyl)isoxazol-3-yl]phenol (5k). Yield
96 mg (23%, method I), 190 mg (45%, method III), light-
yellow powder, mp 59–60°С. IR spectrum, ν, cm–1: 736
(C–Cl), 827, 961, 1166, 1243, 1286, 1405, 1462, 1582,
1616, 3032 (CH Ar), 3130 (CH Het), 3216 (ОН). 1H NMR
spectrum, δ, ppm (J, Hz): 4.67 (2Н, s, СН2Cl); 6.72 (1Н, s,
Н-4); 6.94 (1Н, t, J = 8.0, H Ar); 7.06 (1Н, d, J = 8.0,
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