Synthesis of 5-hydroxy-Δ1-pyrrolines from sec-alkyl aryl ketoximes and acetylene

Article abstract of DOI:10.1016/j.tet.2016.08.088

Synthesis of 5-hydroxy-Δ¹-pyrrolines conjugated with aryl substituents has been effected via the rearrangement of O-vinylketoximes, having only one C–H bond adjacent to the oxime function and readily prepared by addition of sec-alkyl aryl ketox

Full text of DOI:10.1016/j.tet.2016.08.088

Accepted Manuscript
1
Synthesis of 5-hydroxy-Δ -pyrrolines from sec-alkyl aryl ketoximes and acetylene
Dmitrii A. Shabalin, Marina Yu Dvorko, Elena Yu Schmidt, Igor’ A. Ushakov, Boris A.
Trofimov
PII:
S0040-4020(16)30883-3
10.1016/j.tet.2016.08.088
TET 28069
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 June 2016
Revised Date: 19 August 2016
Accepted Date: 30 August 2016
Please cite this article as: Shabalin DA, Dvorko MY, Schmidt EY, Ushakov IA, Trofimov BA, Synthesis of
1
5-hydroxy-Δ -pyrrolines from sec-alkyl aryl ketoximes and acetylene, Tetrahedron (2016), doi: 10.1016/
j.tet.2016.08.088.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of 5-hydroxy-∆1-pyrrolines
Leave this area blank for abstract info.
from sec-alkyl aryl ketoximes and acetylene
Dmitrii A. Shabalin, Marina Yu. Dvorko, Elena Yu. Schmidt, Igor' A. Ushakov, Boris A. Trofimov
R2
R2
R3
R1
R1
R2
R1
R3
R3
KOH/DMSO
HC CH
N
N
OH
80-86%
KOH/DMSO/n-hexane
N
OH
O
52-78%
R1 = Aryl, Hetaryl
R2 = R3 = Me or R2-R3 = (CH2)5
1

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Synthesis of 5-hydroxy-∆1-pyrrolines
from sec-alkyl aryl ketoximes and acetylene
Dmitrii A. Shabalin, Marina Yu. Dvorko, Elena Yu. Schmidt, Igor’ A. Ushakov,
Boris A. Trofimov*
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of
Sciences, 1 Favorsky St., Irkutsk 664033, Russian Federation
Synthesis of 5-hydroxy-ꢀ1-pyrrolines conjugated with aryl substituents has been effected via the
rearrangement of O-vinylketoximes, having only one C-H bond adjacent to the oxime function
and readily prepared by addition of sec-alkyl aryl ketoximes to acetylene. The target compounds
were obtained in 80-86% yields (based on the O-vinylketoximes).
Keywords: hydroxypyrroline, 3,4-dihydro-2H-pyrrol-2-ol, ketoxime, acetylene,
superbase
1. Introduction
The ꢀ1-pyrroline core is widespread in natural products1 and living organisms,2 mainly in
the form of hemes, chlorophylls and alkaloids. It has been shown that ꢀ1-pyrrolines could be
used as templates for new drugs,3 and building blocks for constructing light-driven switches4 and
boranil fluorophores,5 as well as valuable synthons toward biologically active compounds.6 The
syntheses of these important heterocycles include intramolecular cyclizations of bifunctional
compounds and multi-component cyclizations,7 1,3-dipolar cycloadditions,8 and photo- and
thermo-induced reactions.9
In contrast, until now fewer achievements are known in the synthesis of hydroxy-
substituted pyrrolines, especially 5-hydroxy-ꢀ1-pyrrolines (3,4-dihydro-2H-pyrrol-2-ols)
conjugated with aromatic and heteroaromatic moieties, although their reactive hydroxyl function
makes them much more powerful pyrroline synthons. A method for their synthesis from 1,4-
diketones and ammonia was scrupulously studied10 and further employed in a few recent
works.11 Perhaps, the two issues of this synthesis are the limited availability of starting 1,4-
diketones and the reaction selectivity (in some cases, mixtures of isomeric 5-hydroxypyrrolines
were obtained). Condensed 5-hydroxypyrrolines were synthesized from tetramic acids and 2H-
azirines under copper (I)–NHC catalysis.12 Recently, the reaction between phenacylbromide
derivatives, malononitrile and N,N’-bis(arylmethylidene)-arylmethanediamines leading to 5-
* Corresponding author. Tel.: +7 395 242 1411; fax: +7 395 241 9346; e-mail address: boris_trofimov@irioch.irk.ru
2

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hydroxypyrroline-3,3-dicarbonitriles has been reported.13 The other known 5-hydroxypyrrolines
syntheses are occasional and often characterized by narrow substrate scope.14 They include the
brief notes concerning the identification of the 3,3-dimethyl-2-phenyl-5-hydroxypyrroline as the
intermediate in the synthesis of 3H-pyrrole from isopropyl phenyl ketoxime and acetylene.15
Previously, we have developed an expedient method for 3H-pyrroles synthesis from sec-
alkyl aryl(hetaryl) ketoximes and acetylene.16 The key step in this assembly of the 3H-pyrrole
core is the [3,3]-sigmatropic rearrangement of N,O-dialkenylhydroxylamines E (formed by
deprotonation of B with further proton transfer to the nitrogen atom) to iminoaldehydes F, which
further ring close to 5-hydroxypyrrolines G, and undergo base-catalyzed vinylation/elimination
of vinyl alcohol to 3H-pyrroles I (Scheme 1).16,17
R2
R2
R2
O
R1
R1
R1
R3
R3
OH
R3
HC CH
N
N
N
-H2O
OH
O
A
B
C
R2
R2
R2 R3
R1
R1
H2O
OH
R1
R3
R3
[3,3]
HN
N
HN
O
O
O
D
E
F
R3
R3
R3
R2
R1
R2
R1
R2
R1
HC CH
OH
O
N
N
N
-
OH
G
H
I
Scheme 1. Tandem reaction sequence for 3H-pyrrole synthesis from sec-alkyl aryl(hetaryl)
ketoximes and acetylene.
[3,3]-Sigmatropic rearrangements that involve heteroatom-heteroatom bonds in the six-
atom fragment are now becoming more popular in the synthesis of heterocycles.18 Noteworthy,
for ketoximes, having methylene (R2 = H) or methyl substituents (R2 = R3 = H) at the α-position
to the oxime function, the above mentioned reaction sequence can not be stopped at
5-hydroxypyrroline formation due to its easy dehydration and further aromatization to 1H-
pyrrole.17
In the previous works, the 3H-pyrroles synthesis from ketoximes and acetylene via 5-
hydroxy-ꢀ1-pyrrolines was implemented as a one-step procedure both with pressurized
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acetylene16a and under atmospheric pressure.16b Although advantageous as straightforward
transition from ketoximes to the 3H-pyrrole core, this method did not allow understanding the
proper role of the key intermediates, O-vinylketoximes and 5-hydroxy-ꢀ1-pyrrolines, in the
whole process. Therefore, the further study of these syntheses with the emphasis on O-
vinylketoximes as possible starting materials for the preparation of 5-hydroxy-ꢀ1-pyrrolines and
3H-pyrroles was necessary.
Consequently, here we report the first general synthesis of 5-hydroxypyrrolines
conjugated with aromatic systems via rearrangement of O-vinylketoximes (Scheme 2).
R2
R2
R3
R1
R1
R2
R1
R3
R3
KOH/DMSO
HC CH
N
N
OH
N
OH
O
1
2
3
Scheme 2. Synthesis of 5-hydroxy-ꢀ1-pyrrolines from sec-alkyl aryl(hetaryl) ketoximes and
acetylene via O-vinylketoximes.
2. Results and discussion
O-Vinylketoximes 2a-h were synthesized from the corresponding ketoximes 1a-h and
acetylene using a multi-phase superbase system.19 The brief optimization of their synthesis on
the example of the reaction between isopropyl phenyl ketoxime 1a and acetylene has shown that
the appropriate conditions for this process are the following: acetylene under pressure (18-20
atm, an autoclave), KOH/DMSO/n-hexane system (equimolar ratio of ketoxime 1a and KOH),
60 °C, 0.5 h. Under these conditions, the yield of O-vinylketoxime 2a was 28% based on the
ketoxime taken and 72% based on the ketoxime consumed (39% conversion). A significant
experimental benefit of this protocol is the column chromatography-free isolation of the target
compounds: O-vinylketoxime 2a is exhaustively extracted from the reaction mixture with n-
hexane, and ketoxime 1a is recovered after pouring the residual DMSO solution into water with
further extraction with diethyl ether. Table 1 shows that the procedure, carried out at low
conversion of starting ketoxime, allowed us to obtain diversely substituted O-vinylketoximes 2b-
h, including alkyl, aryl and hetaryl substituted ones in 24-39% yields (based on the ketoxime
taken) or 52-78% yields (based on the ketoxime consumed).
Table 1. Synthesis of O-vinylketoximes 2a-h from ketoximes 1a-h and acetylene.a
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R2
R2
O
R1
R1
KOH/DMSO/n-hexane
60 oC, 0.5 h
R3
R3
HC CH
+
N
N
OH
1a-h
2a-h
Ketoxime 1
Conversion of ketoxime 1 (%)
O-Vinylketoxime 2
Yield of 2 (%)b
Me
Me
Me
Me
39
28 (72)
N
N
O
OH
1a
2a
39
52
45
29 (74)
34 (65)
31 (69)
N
N
O
OH
1b
2b
Me
Me
Me
Me
Me
OH
Me
N
N
O
1c
2c
Me
Me
N
N
O
OH
1d
2d
Me
Me
Me
Me
Me
Me
OH
51
50
30 (59)
39 (78)
Me
Me
N
Me
Me
N
O
1e
2e
Me
O
N
Me
O
N
OH
O
1f
2f
Me
Me
OH
Me
Me
34
54
24 (71)
28 (52)
N
N
O
1g
2g
Me Me
Me Me
Me
Me
OH
Me
Me
N
N
O
1h
2h
a
Conditions: ketoxime 1 (12.50 mmol), KOHꢁ0.5H2O (0.813 g, 12.50 mmol), DMSO (25 mL), n-hexane (20 mL),
saturation with acetylene at 18-20 atm, 60 °C, 0.5 h.
b In the brackets yields calculated by the ketoxime consumed are given.
Further, using O-vinylketoxime 2a as an example we have studied the rearrangement of
O-vinylketoximes to 5-hydroxypyrrolines. Despite the fact that methyl and methylene substituted
O-vinylketoximes are transformed to 1H-pyrroles in DMSO (120 °C) without a special
catalyst,19 isopropyl phenyl O-vinylketoxime 2a failed to undergo the analogous rearrangement
(60-120 °C, 1 h) to the expected 5-hydroxypyrroline 3a (in all cases only the starting 2a, tar and
5

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no 3a were observed). The fundamental cause of this is the excessive energy of 3H-pyrroles
compared to their 1H-isomers16a that makes dehydration thermodynamically less favorable than
in the case of O-vinylketoximes with methyl or primary alkyl substituents. Moreover, the
rearrangement of 3H-pyrroles of the synthesized type is impossible without the methyl group
transfer, which is also energy-consuming process. The dehydration can be brought about at a
higher basicity. Our attempts to carry out this reaction were briefly described previously.16a Here,
we have found that addition of equimolar amount of potassium hydroxide to the solution of O-
vinylketoxime 2a in DMSO (room temperature, 4 h) gave 5-hydroxypyrroline 3a in 78% yield.
At a higher temperature (50 °C) and a shorter reaction time (1 h, 2a was consumed entirely
according to TLC), the yield of 3a slightly increased (81%). Cyclization of O-vinylketoximes
2b,d,f with the bulky cyclohexyl substituent was accomplished at 70 °C (Table 2), since at a
lower temperature (50 °C), a considerable amount of tar formation was observed due to a longer
reaction time (ca. 5 h). Diisopropyl O-vinylketoxime 2h, a representative of aliphatic O-
vinylketoximes, turned out to be inactive in this reaction at 50 °C: 55% was recovered, with no
hydroxypyrroline 3h. The traces of the expected 5-hydroxypyrroline 3h were still discernible (1H
NMR spectroscopy) in the crude along with large amounts of unidentifiable products, when the
reaction was carried out at 70 and 90 °C.
Table 2. Cyclization of O-vinylketoximes 2a-h to 5-hydroxypyrrolines 3a-h.a
R2
R3
R2
R1
R1
R3
KOH/DMSO
OH
N
N
O
2a-h
3a-h
O-Vinylketoxime 2
5-Hydroxypyrroline 3
Conditions
Yield of 3 (%)
Me
Me
Me
Me
50 °C,
1 h
OH
N
81
N
O
3a
2a
70 °C,
0.5 h
85
86
82
OH
N
N
O
2b
3b
Me
Me
Me
Me
50 °C,
1 h
Me
OH
N
N
O
Me
3c
2c
Me
70 °C,
0.5 h
OH
N
N
O
Me
2d
3d
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Me
Me
Me
Me
Me
Me
50 °C,
1 h
OH
N
83
80
Me
Me
N
Me
O
3e
2e
Me
70 °C,
0.5 h
OH
N
Me
O
N
Me
O
3f
Me
2f
Me
Me
Me
70 °C,
0.5 h
OH
N
81
N
O
O
2g
3g
Me
Me
Me Me
70 or
90 °C,
1 h
Me
Me
Me
OH
N
traces
N
O
Me
2h
3h
a Conditions: O-vinylketoxime 2 (1.00 mmol), KOHꢁ0.5H2O (0.065 g, 1.00 mmol), DMSO (4 mL).
As previously shown,16 the ketoximes with adjacent C-H moiety are convertible directly
to the corresponding 3H-pyrroles via the subsequent in situ vinylation of the hydroxyl function,
i.e. via the vinyloxy derivatives. This elimination becomes possible due to the absence of
repulsion between ionized hydroxyl group and the attacking hydroxide anion and also because of
easy removal of vinyl alcohol in its stable isomeric form (acetaldehyde).
In fact, as mentioned above, if instead of an aryl substituent was taken sec-alkyl
(compound 2h), only traces of the target product were formed (Table 2) and in the case of
methyl or primary alkyls, the reaction led to NH-pyrroles,17 i.e. the methyl or methylene groups
were preferably involved into the 1H-pyrrole ring formation. Thus, combination of sec-alkyl and
aryl(hetaryl) substitutents in the starting ketoximes appears to be a crucial structural feature for
the transformation of O-vinylketoximes to 5-hydroxy-ꢀ1-pyrrolines. This is in keeping with
destabilization of the initial intermediate carbanion C, generated in the first stage of the
rearrangement under the action of base (Scheme 1), by the second electron-donating isopropyl
substitutent imposing also some steric hindrance for attack of the hydroxide anion (screening of
the CH hydrogen by the methyl group). On the contrary, the aryl and hetaryl substituents
stabilize intermediates E and F due to conjugation with emerging double bonds, both in N-
alkenylhydroxylamine and iminoaldehyde after reprotonation and [3,3]-sigmatropic
rearrangement, thereby facilitating the overall reaction. In fact, this phenomenon is synthetically
advantageous since it allows us to readily conjugate diverse aromatic or heteroaromatic moieties
with the hydroxypyrroline core. As the range of aromatic or heteroaromatic ketoximes with sec-
alkyl groups is essentially unlimited (due to easy straightforward acylation of aromatics and
heteroaromatics) this method may be considered as rather general one.
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3. Conclusions
To summarize, rearrangement of accessible O-vinylketoximes leading to the formation of
5-hydroxy-ꢀ1-pyrrolines in good yields in the presence of a superbase KOH/DMSO system has
been elaborated. The developed methodology provides a short-cut route to valuable unsaturated
azaheterocycles, having a reactive hydroxyl group, which makes them helpful pyrroline synthons
and universal carriers of the ꢀ1-pyrroline core.
4. Experimental section
4.1. General
All chemicals and solvents are commercially available from Sigma Aldrich and were
used without further purification. Starting ketoximes 1a-g were prepared by a literature
method.16a The absolute stereochemistry of O-vinylketoximes 2a-g was determined based on the
13C NMR data.20
IR spectra were recorded on a Bruker Vertex-70 spectrophotometer. NMR spectra were
measured from solutions in CDCl3 on Bruker DPX-400 and AV-400 spectrometers (400.1 MHz
1
13
for H, 100.6 MHz for C, and 40.5 MHz for 15N) using hexamethyldisiloxane (1H, 13C) and
nitromethane (15N) as internal references. Melting points (uncorrected) were measured on a
Kofler micro hot-stage apparatus. The C, H, N microanalyses were performed on a Flash EA
1112 Series elemental analyzer.
4.2. General procedure for the synthesis of O-vinylketoximes 2a-h
A mixture of ketoxime 1a-h (12.50 mmol) and finely powdered KOHꢁ0.5H2O (0.813 g,
12.50 mmol) in DMSO (25 mL) was heated up to 105-110 °C in order to obtain a homogenous
potassium ketoximate solution. The resulting solution and n-hexane (20 mL) were placed into a
0.25-L steel rotating autoclave. Then acetylene gas was transferred to the autoclave to remove air
and the autoclave was charged with acetylene again from a cylinder at room temperature (initial
pressure 18-20 atm). The autoclave was heated (60 °C) upon rotating for 30 min. After cooling
to room temperature and discharging, the n-hexane layer was separated and the DMSO layer was
extracted with n-hexane (4×20 mL). The hexane extracts were combined, washed with water
(3×20 mL) and dried over K2CO3. After evaporation of the n-hexane, O-vinylketoximes 2a-h
were obtained. The DMSO layer was diluted with cold water (10-12 °C, 100 mL), neutralized
with NH4Cl, and extracted with diethyl ether (3×50 mL). The extract was washed with water
(2×50 mL) and dried over K2CO3. After desiccant filtering off and solvent evaporation, starting
ketoximes 1a-h were recovered.
4.2.1. 2-Methyl-1-phenyl-1-propanone O-vinyloxime (2a). Yield: 0.66 g (28%); light yellow
liquid (mixture of isomers, E/Z ≈ 85/15). IR (film): 3060, 3025, 2968, 2935, 2876, 1640, 1605,
1
3
1496, 1444, 1385, 1364, 1335, 1180, 1116, 1009, 981 cm-1. H NMR: δ = 1.16 (d, J = 6.9 Hz,
3
6H, Me, Z-isomer), 1.24 (d, J = 7.2 Hz, 6H, Me, E-isomer), 2.85-2.91 (m, 1H, CH, Z-isomer),
3.51-3.61 (m, 1H, CH, E-isomer), 4.07 (dd, 2J = 1.4 Hz, 3J = 6.6 Hz, 1H, Ha, Z-isomer), 4.16 (dd,
2J = 1.8 Hz, J = 6.6 Hz, 1H, Ha, E-isomer), 4.53 (dd, J = 1.4 Hz, J = 14.3 Hz, 1H, Hb, Z-
3
2
3
isomer), 4.64 (dd, 2J = 1.8 Hz, 3J = 14.3 Hz, 1H, Hb, E-isomer), 6.84 (dd, 3J = 6.6 Hz, 3J = 14.3
Hz, 1H, Hx, Z-isomer), 7.01 (dd, J = 6.6 Hz, J = 14.3 Hz, 1H, Hx, E-isomer), 7.23-7.25, 7.38-
3
3
13
7.45 (m, 10H, Ph, E- and Z-isomers) ppm. С NMR: for E-isomer, δ = 19.6 (2Me), 29.2 (CH),
8

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87.9 (OCH=CH2), 127.9 (Co, Ph), 128.3 (Cm, Ph), 129.0 (Cp, Ph), 135.1 (Ci, Ph), 153.0
(OCH=CH2), 167.1 (C=N) ppm; for Z-isomer, δ = 20.2 (2Me), 34.8 (CH), 87.5 (OCH=CH2),
127.5 (Co, Ph), 128.1 (Cm, Ph), 128.6 (Cp, Ph), 133.8 (Ci, Ph), 152.5 (OCH=CH2), 165.7 (C=N)
ppm. Anal. Calcd. for C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 75.91; H, 7.78; N, 7.65.
4.2.2. Cyclohexyl(phenyl)methanone O-vinyloxime (2b). Yield: 0.83 g (29%); light yellow liquid
(mixture of isomers, E/Z ≈ 70/30). IR (film): 3058, 2930, 2854, 1639, 1616, 1494, 1449, 1382,
1
1325, 1179, 1075, 978 cm-1. H NMR: δ = 1.13-1.56, 1.66-1.90 (m, 20H, CH2, E- and Z-
isomers), 2.50-2.56 (m, 1H, CH, Z-isomer), 3.24-3.30 (m, 1H, CH, E-isomer), 4.06 (dd, 2J = 1.2
3
2
3
Hz, J = 6.9 Hz, 1H, Ha, Z-isomer), 4.16 (dd, J = 1.3 Hz, J = 6.6 Hz, 1H, Ha, E-isomer), 4.52
(dd, 2J = 1.2 Hz, 3J = 14.4 Hz, 1H, Hb, Z-isomer), 4.65 (dd, 2J = 1.3 Hz, 3J = 14.1 Hz, 1H, Hb, E-
isomer), 6.83 (dd, 3J = 6.9 Hz, 3J = 14.4 Hz, 1H, Hx, Z-isomer), 7.01 (dd, 3J = 6.6 Hz, 3J = 14.1
Hz, 1H, Hx, E-isomer), 7.22-7.24, 7.35-7.45 (m, 10H, Ph, E- and Z-isomers) ppm. 13С NMR: for
E-isomer, δ = 26.0 (C-4), 26.3 (C-3, C-5) 29.4 (C-2, C-6), 39.6 (CH), 87.8 (OCH=CH2), 128.1
(Co, Ph), 128.2 (Cm, Ph), 128.8 (Cp, Ph), 135.4 (Ci, Ph), 152.9 (OCH=CH2), 166.5 (C=N) ppm;
for Z-isomer, δ = 26.0 (C-4), 26.2 (C-3, C-5) 30.5 (C-2, C-6), 44.4 (CH), 87.5 (OCH=CH2),
127.3 (Co, Ph), 128.0 (Cm, Ph), 128.5 (Cp, Ph), 134.0 (Ci, Ph), 152.5 (OCH=CH2), 165.2 (C=N)
ppm. Anal. Calcd. for C15H19NO: C, 78.56; H, 8.35; N, 6.11. Found: C, 78.26; H, 8.45; N, 5.84.
4.2.3. 2-Methyl-1-(4-methylphenyl)-1-propanone O-vinyloxime (2c). Yield: 0.86 g (34%); light
yellow liquid (mixture of isomers, E/Z ≈ 85/15). IR (film): 3052, 3030, 2967, 2933, 2876, 1639,
1
3
1615, 1465, 1384, 1365, 1336, 1180, 1116, 980 cm-1. H NMR: for E-isomer, δ = 1.24 (d, J =
2
3
7.2 Hz, 6H, Me), 2.39 (s, 3H, Me), 3.51-3.58 (m, 1H, CH), 4.15 (dd, J = 1.3 Hz, J = 6.9 Hz,
1H, Ha), 4.64 (dd, J = 1.3 Hz, J = 14.4 Hz, 1H, Hb), 7.01 (dd, J = 6.9 Hz, J = 14.4 Hz, 1H,
2
3
3
3
Hx), 7.20 (d, J = 7.9 Hz, 2H, Hm, Ar), 7.35 (d, 3J = 7.9 Hz, 2H, Ho, Ar) ppm; for Z-isomer, δ =
3
1.16 (d, 3J = 6.9 Hz, 6H, Me), 2.40 (s, 3H, Me), 2.86-2.89 (m, 1H, CH), 4.07 (dd, 2J = 1.0 Hz, 3J
= 6.9 Hz, 1H, Ha), 4.55 (dd, 2J = 1.0 Hz, 3J = 14.4 Hz, 1H, Hb), 6.85 (dd, 3J = 6.9 Hz, 3J = 14.4
Hz, 1H, Hx), 7.16 (d, 3J = 7.9 Hz, 2H, Hm, Ar), 7.23 (d, 3J = 7.9 Hz, 2H, Ho, Ar) ppm. 13С NMR:
for E-isomer, δ = 19.6 (2Me), 21.3 (Me, Ar), 29.2 (CH), 87.7 (OCH=CH2), 127.8 (Co, Ar), 128.9
(Cm, Ar), 132.2 (Ci, Ar), 138.9 (Cp, Ar), 153.0 (OCH=CH2), 167.0 (C=N) ppm; for Z-isomer, δ =
20.2 (2Me), 21.4 (Me, Ar) 34.8 (CH), 87.4 (OCH=CH2), 127.5 (Co, Ar), 128.8 (Cm, Ar), 130.8
(Ci, Ar), 138.5 (Cp, Ar), 152.5 (OCH=CH2), 165.7 (C=N) ppm. Anal. Calcd. for C13H17NO: C,
76.81; H, 8.43; N, 6.89. Found: C, 77.09; H, 8.34; N, 6.68.
4.2.4. Cyclohexyl(4-methylphenyl)methanone O-vinyloxime (2d). Yield: 0.95 g (31%); light
yellow liquid (mixture of isomers, E/Z ≈ 70/30). IR (film): 3029, 2929, 2854, 1637, 1615, 1512,
1450, 1382, 1328, 1178, 1082, 978 cm-1. 1H NMR: δ = 1.15-1.42, 1.47-1.57, 1.67-1.89 (m, 20H,
CH2, E- and Z-isomers), 2.38 (s, 3H, Me, E-isomer), 2.39 (s, 3H, Me, Z-isomer), 2.50-2.55 (m,
1H, CH, Z-isomer), 3.23-3.29 (m, 1H, CH, E-isomer), 4.07 (dd, 2J = 1.1 Hz, 3J = 6.9 Hz, 1H, Ha,
Z-isomer), 4.15 (dd, 2J = 1.3 Hz, 3J = 6.7 Hz, 1H, Ha, E-isomer), 4.54 (dd, 2J = 1.1 Hz, 3J = 14.3
Hz, 1H, Hb, Z-isomer), 4.64 (dd, 2J = 1.3 Hz, 3J = 14.4 Hz, 1H, Hb, E-isomer), 6.84 (dd, 3J = 6.9
Hz, 3J = 14.3 Hz, 1H, Hx, Z-isomer), 7.00 (dd, 3J = 6.7 Hz, 3J = 14.4 Hz, 1H, Hx, E-isomer), 7.15
(d, 3J = 8.2 Hz, 2H, Hm, Ar, Z-isomer), 7.19 (d, 3J = 8.0 Hz, 2H, Hm, Ar, E-isomer), 7.22 (d, 3J =
8.2 Hz, 2H, Ho, Ar, Z-isomer), 7.31 (d, 3J = 8.0 Hz, 2H, Ho, Ar, E-isomer) ppm. 13С NMR: for E-
isomer, δ = 21.2 (Me), 26.0 (C-4), 26.1 (C-3, C-5) 29.4 (C-2, C-6), 39.6 (CH), 87.6 (OCH=CH2),
127.9 (Co, Ar), 128.8 (Cm, Ar), 132.5 (Ci, Ar), 138.6 (Cp, Ar), 152.9 (OCH=CH2), 166.3 (C=N)
ppm; for Z-isomer, δ = 21.3 (Me), 25.9 (C-4), 26.3 (C-3, C-5) 30.5 (C-2, C-6), 44.4 (CH), 87.3
(OCH=CH2), 127.3 (Co, Ar), 128.7 (Cm, Ar), 131.0 (Ci, Ar),138.3 (Cp, Ar), 152.5 (OCH=CH2),
165.1 (C=N) ppm. Anal. Calcd. for C16H21NO: C, 78.97; H, 8.70; N, 5.76. Found: C, 78.70; H,
8.61; N, 5.49.
9

ACCEPTED MANUSCRIPT
4.2.5. 1-(2,5-Dimethylphenyl)-2-methyl-1-propanone O-vinyloxime (2e). Yield: 0.81 g (30%);
light yellow liquid (mixture of isomers, E/Z ≈ 25/75). IR (film): 3043, 3019, 2970, 2930, 2874,
1641, 1619, 1501, 1467, 1384, 1364, 1208, 1174, 1040, 977 cm-1. 1H NMR: δ = 1.14 (d, 3J = 6.8
Hz, 3H, Me, Z-isomer), 1.16 (d, 3J = 7.2 Hz, 3H, Me, Z-isomer), 1.23 (d, 3J = 6.8 Hz, 6H, Me, E-
isomer), 2.17 (s, 3H, 2-Me, Ar, Z-isomer), 2.29 (s, 3H, 2-Me, Ar, E-isomer), 2.34 (s, 3H, 5-Me,
Ar, Z-isomer), 2.34 (s, 3H, 5-Me, Ar, E-isomer), 2.75-2.82 (m, 1H, CH, Z-isomer), 3.51-3.54 (m,
1H, CH, E-isomer), 4.06 (dd, 2J = 1.3 Hz, 3J = 6.6 Hz, 1H, Ha, Z-isomer), 4.13 (dd, 2J = 1.5 Hz,
3J = 6.6 Hz, 1H, Ha, E-isomer), 4.55 (dd, 2J = 1.3 Hz, 3J = 14.3 Hz, 1H, Hb, Z-isomer), 4.61 (dd,
3
3
2J = 1.5 Hz, J = 14.3 Hz, 1H, Hb, E-isomer), 6.84 (s, 1H, Ho, Ar, Z-isomer), 6.85 (dd, J = 6.6
Hz, J = 14.3 Hz, 1H, Hx, Z-isomer), 6.96 (s, 1H, Ho, Ar, E-isomer), 7.00 (dd, 3J = 6.6 Hz, J =
14.3 Hz, 1H, Hx, E-isomer), 7.07-7.14 (m, 4H, Ar, E- and Z-isomers) ppm. 13С NMR: for E-
isomer, δ = 19.4 (2Me), 19.7 (2-Me, Ar), 21.0 (5-Me, Ar), 29.7 (CH), 87.5 (OCH=CH2), 129.1
(C-6, Ar), 129.4 (C-4, Ar), 130.5 (C-3, Ar), 133.3 (C-1, Ar), 134.1 (C-5, Ar), 134.9 (C-2, Ar),
153.1 (OCH=CH2), 167.9 (C=N) ppm; for Z-isomer, δ = 19.5 (2Me), 20.2 (2-Me, Ar), 21.1 (5-
Me, Ar), 35.5 (CH), 87.5 (OCH=CH2), 126.7 (C-6, Ar), 129.1 (C-4, Ar), 129.8 (C-3, Ar), 132.3
(C-1, Ar), 134.5 (C-5, Ar), 134.8 (C-2, Ar), 152.6 (OCH=CH2), 165.8 (C=N) ppm. Anal. Calcd.
for C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found: C, 77.11; H, 8.52; N, 6.23.
3
3
4.2.6. Cyclohexyl(2,5-dimethylphenyl)methanone O-vinyloxime (2f). Yield: 1.27 g (39%); light
yellow liquid (mixture of isomers, E/Z ≈ 25/75). IR (film): 3042, 3018, 2930, 2854, 1639, 1618,
1
1500, 1450, 1380, 1204, 1181, 1166, 1151, 1039, 975 cm-1. H NMR: δ = 1.10-1.46, 1.66-1.87,
1.96-2.03 (m, 20H, CH2, E- and Z-isomers), 2.16 (s, 3H, 2-Me, Ar, Z-isomer), 2.27 (s, 3H, 2-Me,
Ar, E-isomer), 2.34 (s, 3H, 5-Me, Ar, Z-isomer), 2.34 (s, 3H, 5-Me, Ar, E-isomer), 2.40-2.45 (m,
1H, CH, Z-isomer), 3.23-3.29 (m, 1H, CH, E-isomer), 4.04 (dd, 2J = 1.2 Hz, 3J = 6.7 Hz, 1H, Ha,
Z-isomer), 4.12 (dd, 2J = 1.3 Hz, 3J = 6.7 Hz, 1H, Ha, E-isomer), 4.53 (dd, 2J = 1.2 Hz, 3J = 14.4
2
3
Hz, 1H, Hb, Z-isomer), 4.61 (dd, J = 1.3 Hz, J = 14.3 Hz, 1H, Hb, E-isomer), 6.81 (s, 1H, Ho,
Ar, Z-isomer), 6.82 (dd, J = 6.7 Hz, J = 14.4 Hz, 1H, Hx, Z-isomer), 6.94 (s, 1H, Ho, Ar, E-
isomer), 6.99 (dd, 3J = 6.7 Hz, 3J = 14.3 Hz, 1H, Hx, E-isomer), 7.06-7.13 (m, 4H, Ar, E- and Z-
isomers) ppm. 13С NMR: δ = 19.4 (2-Me, Ar, Z-isomer), 19.7 (2-Me, Ar, E-isomer), 21.0 (5-Me,
Ar, E-isomer), 21.1 (5-Me, Ar, Z-isomer), 25.9, 26.1, 26.2, 26.4, 29.3, 29.9, 30.5 (cyclohexyl, E-
and Z-isomers), 39.9 (CH, E-isomer), 45.2 (CH, Z-isomer), 87.5 (OCH=CH2, E- and Z-isomers),
126.7 (C-6, Ar, Z-isomer), 129.0 (C-4, Ar, Z-isomer), 129.2 (C-6, C-4, Ar, E-isomer), 129.7 (C-
3, Ar, Z-isomer), 130.4 (C-3, Ar, E-isomer), 132.3 (C-1, Ar, Z-isomer), 133.3 (C-1, Ar, E-
isomer), 134.3 (C-5, Ar, E-isomer), 134.6 (C-5, Ar, Z-isomer), 134.8 (C-2, Ar, Z-isomer), 135.0
(C-2, Ar, E-isomer),152.6 (OCH=CH2, Z-isomer), 153.1 (OCH=CH2, E-isomer), 165.3 (C=N, Z-
isomer), 167.1 (C=N, E-isomer) ppm. Anal. Calcd. for C17H23NO: C, 79.33; H, 9.01; N, 5.44.
Found: C, 79.17; H, 8.73; N, 5.33.
3
3
4.2.7. 1-(2-Furyl)-2-methyl-1-propanone O-vinyloxime (2g). Yield: 0.54 g (24%); light yellow
liquid (mixture of isomers, E/Z ≈ 30/70). IR (film): 3121, 3075, 2972, 2937, 2877, 1639, 1610,
1482, 1468, 1385, 1366, 1307, 1258, 1192, 1181, 1170, 1149, 1117, 1090 cm-1. 1H NMR: for E-
isomer, δ = 1.32 (d, 3J = 7.2 Hz, 6H, Me), 3.47-3.54 (m, 1H, CH), 4.19 (dd, 2J = 1.8 Hz, 3J = 6.7
Hz, 1H, Ha), 4.65 (dd, 2J = 1.8 Hz, 3J = 14.1 Hz, 1H, Hb), 6.45 (dd, 3J = 1.8 Hz, 3J = 3.5 Hz, 1H,
3
4
3
3
H-4, furyl), 6.73 (dd, J = 3.5 Hz, J = 0.6 Hz, 1H, H-3, furyl), 7.01 (dd, J = 6.7 Hz, J = 14.1
Hz, 1H, Hx), 7.50 (dd, 3J = 1.8 Hz, 4J = 0.6 Hz, 1H, H-5, furyl) ppm; for Z-isomer, δ = 1.27 (d, 3J
= 6.6 Hz, 6H, Me), 3.24-3.31 (m, 1H, CH), 4.19 (dd, 2J = 1.6 Hz, 3J = 6.6 Hz, 1H, Ha), 4.71 (dd,
2J = 1.6 Hz, 3J = 14.1 Hz, 1H, Hb), 6.54 (dd, 3J = 1.8 Hz, 3J = 3.6 Hz, 1H, H-4, furyl), 7.00 (dd,
3J = 6.6 Hz, 3J = 14.1 Hz, 1H, Hx), 7.39 (dd, 3J = 3.6 Hz, 4J = 0.8 Hz, 1H, H-3, furyl), 7.48 (dd,
4
13
3J = 1.8 Hz, J = 0.8 Hz, 1H, H-5, furyl) ppm. С NMR: for E-isomer, δ = 19.4 (2Me), 28.3
(CH), 88.4 (OCH=CH2), 111.3 (C-3, C-4, furyl), 143.8 (C-5, furyl), 148.9 (C-2, furyl), 153.2
(OCH=CH2), 157.8 (C=N) ppm; for Z-isomer, δ = 20.8 (2Me), 31.2 (CH), 88.2 (OCH=CH2),
112.1 (C-4, furyl), 119.1 (C-3, furyl), 142.7 (C-5, furyl), 145.0 (C-2, furyl), 153.0 (OCH=CH2),
10

ACCEPTED MANUSCRIPT
153.2 (C=N) ppm. Anal. Calcd. for C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C, 66.83; H,
7.05; N, 7.94.
4.2.8. 2,4-Dimethyl-3-pentanone O-vinyloxime (2h). Yield: 0.55 g (28%); light yellow liquid.
Physical-chemical characteristics were identical to those reported in the literature.19a
4.3. General procedure for the synthesis of 5-hydroxypyrrolines 3a-g
O-Vinylketoxime 2a-g (1.00 mmol) was dissolved in DMSO (4 mL) and finely powdered
KOHꢁ0.5H2O (0.065 g, 1.00 mmol) was added. The suspension obtained was heated for
appropriate time (see Table 2). After cooling to room temperature reaction mixture was poured
into cold water (10-12 °C, 20 mL), neutralized with NH4Cl, and extracted with diethyl ether
(3×15 mL). The extract was washed with water (2×10 mL) and dried over K2CO3. The residue
obtained after filtering off the desiccant and solvent evaporation was mixed with cold n-hexane
(5-7 °C, 2 mL). The powdered 5-hydroxypyrrolines 3a-g were filtered off, their yields as well as
physical-chemical characteristics are given below.
4.3.1. 4,4-Dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-ol (3a). Yield: 0.153 g (81%); beige
powder; mp 104-106 °C (hexane). Physical-chemical characteristics were identical to those
reported in the literature.15a,c
4.3.2. 1-Phenyl-2-azaspiro[4.5]dec-1-en-3-ol (3b). Yield: 0.195 g (85%); beige powder; mp 123-
125 °C (hexane). IR (KBr): 3140, 2993, 2935, 2851, 1602, 1571, 1447, 1334, 1142, 1116, 1042
cm-1. 1H NMR: δ = 1.13-1.23 (m, 1H, cyclohexyl), 1.29-1.39 (m, 1H, cyclohexyl), 1.44-1.50 (m,
2
3
2H, cyclohexyl), 1.60-1.86 (m, 6H, cyclohexyl, 1H, CH2), 2.47 (dd, J = 13.2 Hz, J = 6.5 Hz,
3
1H, CH2), 5.75 (dd, J = 6.5 Hz, 1H, CH), 6.08 (br. s, 1H, OH), 7.40-7.43 (m, 3H, Hm, Hp, Ph),
13
7.61-7.63 (m, 2H, Ho, Ph) ppm. С NMR: δ = 23.2 (C-7), 23.5 (C-9), 25.6 (C-8), 33.2 (C-6),
35.5 (C-10), 42.7 (C-4), 56.2 (C-5), 92.1 (C-3), 128.2 (Co, Ph), 128.3 (Cm, Ph), 129.6 (Cp, Ph),
134.8 (Ci, Ph), 181.9 (C-1) ppm. 15N NMR: δ = −60.5 ppm. Anal. Calcd. for C15H19NO: C,
78.56; H, 8.35; N, 6.11. Found: C, 78.50; H, 8.10; N, 6.26.
4.3.3. 4,4-Dimethyl-5-(4-methylphenyl)-3,4-dihydro-2H-pyrrol-2-ol (3c). Yield: 0.174 g (86%);
beige powder; mp 115-117 °C (hexane). IR (KBr): 3180, 2963, 2927, 2868, 1615, 1566, 1511,
1
1463, 1339, 1314, 1172, 1133, 1110, 1041, 1016 cm-1. H NMR: δ = 1.40 (s, 3H, Me), 1.43 (s,
3H, Me), 1.85 (dd, 2J = 12.8 Hz, 3J = 6.4 Hz, 1H, CH2), 2.27 (dd, 2J = 12.8 Hz, 3J = 5.9 Hz, 1H,
3
3
CH2), 2.39 (s, 3H, Me, Ar), 5.49 (br. s, 1H, OH), 5.75 (dd, J = 5.9 Hz, J = 6.4 Hz, 1H, CH),
3
3
13
7.22 (d, J = 8.2 Hz, 2H, Hm, Ar), 7.68 (d, J = 8.2 Hz, 2H, Ho, Ar) ppm. С NMR: δ = 21.4
(Me, Ar), 27.0 (Me), 27.5 (Me), 49.6 (C-3), 49.9 (C-4), 91.2 (C-2), 128.2 (Co, Ar), 129.2 (Cm,
Ar), 130.8 (Ci, Ar), 140.4 (Cp, Ar), 180.6 (C-5) ppm. 15N NMR: δ = −63.3 ppm. Anal. Calcd. for
C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C, 76.92; H, 8.16; N, 6.78.
4.3.4. 1-(4-Methylphenyl)-2-azaspiro[4.5]dec-1-en-3-ol (3d). Yield: 0.200 g (82%); beige
powder; mp 159-161 °C (hexane). IR (KBr): 3170, 2991, 2933, 2850, 1609, 1564, 1447, 1335,
1
1184, 1112, 1041 cm-1. H NMR: δ = 1.15-1.25 (m, 1H, cyclohexyl), 1.29-1.39 (m, 1H,
2
cyclohexyl), 1.46-1.49 (m, 2H, cyclohexyl), 1.60-1.79 (m, 5H, cyclohexyl), 1.69 (dd, J = 13.3
3
2
Hz, J = 6.2 Hz, 1H, CH2), 1.84-1.91 (m, 1H, cyclohexyl), 2.38 (s, 3H, Me, Ar), 2.47 (dd, J =
3
3
3
13.3 Hz, J = 6.4 Hz, 1H, CH2), 5.63 (br. s, 1H, OH), 5.73 (dd, J = 6.2 Hz, J = 6.4 Hz, 1H,
CH), 7.21 (d, J = 7.9 Hz, 2H, Hm, Ar), 7.57 (d, J = 7.9 Hz, 2H, Ho, Ar) ppm. С NMR: δ =
21.4 (Me, Ar), 23.2 (C-7), 23.5 (C-9), 25.6 (C-8), 33.3 (C-6), 35.5 (C-10), 42.8 (C-4), 56.0 (C-5),
91.9 (C-3), 128.2 (Co, Ar), 129.0 (Cm, Ar), 131.8 (Ci, Ar), 139.8 (Cp, Ar), 181.7 (C-1) ppm. 15N
NMR: δ = −62.0 ppm. Anal. Calcd. for C16H21NO: C, 78.97; H, 8.70; N, 5.76. Found: C, 78.73;
H, 8.44; N, 5.99.
3
3
13
11

ACCEPTED MANUSCRIPT
4.3.5. 5-(2,5-Dimethylphenyl)-4,4-dimethyl-3,4-dihydro-2H-pyrrol-2-ol (3e). Yield: 0.181 g
(83%); beige powder; mp 180-182 °C (hexane). IR (KBr): 3173, 2967, 2925, 2871, 1626, 1609,
1
1500, 1466, 1341, 1311, 1165, 1125, 1114, 1033 cm-1. H NMR: δ = 1.20 (s, 3H, Me), 1.21 (s,
3H, Me), 1.80 (dd, 2J = 13.1 Hz, 3J = 6.1 Hz, 1H, CH2), 2.24 (dd, 2J = 13.1 Hz, 3J = 6.2 Hz, 1H,
CH2), 2.28 (s, 3H, 2-Me, Ar), 2.32 (s, 3H, 5-Me, Ar), 5.53 (br. s, 1H, OH), 5.75 (dd, 3J = 6.1 Hz,
3J = 6.2 Hz, 1H, CH), 6.96 (s, 1H, Ho, Ar), 7.07 (d, 3J = 7.7 Hz, 2H, Hp, Ar), 7.13 (d, 3J = 7.7 Hz,
13
2H, Hm, Ar) ppm. С NMR: δ = 19.5 (2-Me, Ar), 21.1 (5-Me, Ar), 26.3 (Me), 26.8 (Me), 47.3
(C-3), 52.0 (C-4), 92.4 (C-2), 127.7 (C-6, Ar), 129.2 (C-4, Ar), 130.6 (C-3, Ar), 132.9 (C-1, Ar),
15
134.0 (C-5, Ar), 134.3 (C-2, Ar), 182.8 (C-5) ppm. N NMR: δ = −54.2 ppm. Anal. Calcd. for
C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found: C, 77.63; H, 8.52; N, 6.32.
4.3.6. 1-(2,5-Dimethylphenyl)-2-azaspiro[4.5]dec-1-en-3-ol (3f). Yield: 0.205 g (80%); beige
powder; mp 200-202 °C (hexane). IR (KBr): 3158, 2966, 2927, 2852, 1637, 1608, 1441, 1335,
1
1168, 1143, 1097, 1041, 1026 cm-1. H NMR: δ = 0.99-1.09 (m, 1H, cyclohexyl), 1.25-1.47 (m,
2
3
5H, cyclohexyl), 1.61-1.67 (m, 4H, cyclohexyl), 1.72 (dd, J = 13.3 Hz, J = 5.6 Hz, 1H, CH2),
2
3
2.24 (s, 3H, 2-Me, Ar), 2.32 (s, 3H, 5-Me, Ar), 2.37 (dd, J = 13.3 Hz, J = 6.7 Hz, 1H, CH2),
5.73 (dd, 3J = 5.6 Hz, 3J = 6.7 Hz, 1H, CH), 6.24 (br. s, 1H, OH), 6.89 (s, 1H, Ho, Ar), 7.07 (d, 3J
3
13
= 7.8 Hz, 1H, Hp, Ar), 7.12 (d, J = 7.8 Hz, 1H, Hm, Ar) ppm. С NMR: δ = 19.5 (2-Me, Ar),
21.1 (5-Me, Ar), 23.0 (C-7), 23.4 (C-9), 25.3 (C-8), 33.1 (C-6), 35.0 (C-10), 41.4 (C-4), 57.6 (C-
5), 92.9 (C-3), 128.1 (C-6, Ar), 129.1 (C-4, Ar), 130.4 (C-3, Ar), 132.9 (C-1, Ar), 134.1 (C-5,
Ar), 134.5 (C-2, Ar), 183.1 (C-1) ppm. 15N NMR: δ = −55.4 ppm. Anal. Calcd. for C17H23NO: C,
79.33; H, 9.01; N, 5.44. Found: C, 79.57; H, 8.82; N, 5.59.
4.3.7. 5-(2-Furyl)-4,4-dimethyl-3,4-dihydro-2H-pyrrol-2-ol (3g). Yield: 0.145 g (81%); beige
powder; mp 71-73 °C (hexane). IR (KBr): 3185, 2962, 2931, 2872, 1605, 1482, 1461, 1334,
1
2
1153, 1107, 1082, 1044 cm-1. H NMR: δ = 1.37 (s, 3H, Me), 1.50 (s, 3H, Me), 1.86 (dd, J =
13.0 Hz, 3J = 5.9 Hz, 1H, CH2), 2.27 (dd, 2J = 13.0 Hz, 3J = 6.4 Hz, 1H, CH2), 5.82 (dd, 3J = 5.9
3
3
3
Hz, J = 6.4 Hz, 1H, CH), 6.34 (br. s, 1H, OH), 6.49 (dd, J = 1.0 Hz, J = 3.6 Hz, 1H, H-4,
furyl), 7.07 (d, 3J = 3.6 Hz, 1H, H-3, furyl), 7.56 (d, 3J = 1.0 Hz, 1H, H-5, furyl) ppm. 13С NMR:
δ = 26.7 (Me), 27.5 (Me), 48.2 (C-3), 49.6 (C-4), 92.5 (C-2), 111.8 (C-4, furyl), 114.7 (C-3,
furyl), 144.8 (C-5, furyl), 148.8 (C-2, furyl), 171.0 (C-5) ppm. Anal. Calcd. for C10H13NO2: C,
67.02; H, 7.31; N, 7.82. Found: C, 67.25; H, 7.16; N, 7.92.
Acknowledgements
The spectral data were obtained using the equipment of Baikal Analytical Center for
collective use SB RAS.
Supplementary data
1
13
Copies of H and C NMR spectra of all new products. Supplementary data related to
this article can be found at http://dx.doi.org/10.1016/j.tet.XXXX.XX.XXX.
References and notes
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