Isomerization of hetaryl analogues of α-benzoins in basic media

Article abstract of DOI:10.1081/SCC-200032447

The α → β isomerization of hetaryl analogues of benzoins occurring in basic media on heating is a convenient preparative way to obtain hydroxy-methylcarbonyl-substituted derivatives of π-excessive heterocycles. The reaction is favored by increased catalyst basicity, solvent polarity, and the electron-donor ability of a hetaryl residue. At room temperature, oxidation to hetaryl analogues of benzil becomes dominating.

Full text of DOI:10.1081/SCC-200032447

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Isomerization of Hetaryl
Analogues of α‐Benzoins in
Basic Media
Sergey P. Ivonin a & Andrey V. Lapandin a
a Department of Organic Chemistry ,
Dnepropetrovsk National University , Nauchnaya
Street, 13, Dnepropetrovsk, 49050, Ukraine
Published online: 19 Apr 2010.
To cite this article: Sergey P. Ivonin & Andrey V. Lapandin (2004) Isomerization of
Hetaryl Analogues of α‐Benzoins in Basic Media, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry,
34:20, 3727-3735, DOI: 10.1081/SCC-200032447
To link to this article: http://dx.doi.org/10.1081/SCC-200032447
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 20, pp. 3727–3735, 2004
Isomerization of Hetaryl Analogues of
a-Benzoins in Basic Media
*
Sergey P. Ivonin and Andrey V. Lapandin
Department of Organic Chemistry, Dnepropetrovsk National University,
Nauchnaya Street, 13, Dnepropetrovsk, 49050, Ukraine
ABSTRACT
The a ! b isomerization of hetaryl analogues of benzoins occurring in
basic media on heating is a convenient preparative way to obtain hydroxy-
methylcarbonyl-substituted derivatives of p-excessive heterocycles.
The reaction is favored by increased catalyst basicity, solvent polarity,
and the electron-donor ability of a hetaryl residue. At room temperature,
oxidation to hetaryl analogues of benzil becomes dominating.
Key Words: Basic catalyst; Benzoins; p-Excessive heterocycles;
Isomerization; Solvent polarity.
*
Correspondence: Sergey P. Ivonin, Department of Organic Chemistry, Dnepro-
petrovsk National University, Nauchnaya Street, 13, Dnepropetrovsk, 49050,
Ukraine; Tel.: þ380 562 463143; E-mail: ivonin@dp.ukrtel.net.
3727
DOI: 10.1081/SCC-200032447
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3728
Ivonin and Lapandin
INTRODUCTION
Benzoin condensation represents a facile synthetic route to both sym-
metric and unsymmetric benzoins.[1] Using thiazolium salts as catalysts
enabled not only an increase in the total yield and optical purity of benzoins
but also an application of the reaction concerned in modeling the enzyme-
assisted C22C bond formation in biological systems (where the catalysis is
exerted by thiamine diphosphate).[2–11] The research on the benzoin conden-
sation mechanism and the establishment of the fact that the acyl carbanion
intermediate is involved in the reaction made it possible to obtain, as a
result of a two-step process,[12–17] a-benzoins (less stable than b-isomers),
which could not be produced by the classical procedure of the benzoin con-
densation.[1] However, the yields of the a-benzoins thus prepared are not
high, and their hetaryl analogues obtained in this manner include only furan
and pyridine derivatives.[17] Aldehydes derived from p-excessive hetero-
cycles are inert under the conditions of the benzoin condensation;[18] that is
why the synthesis of pharmacologically active hydroxymethylcarbonyl-
substitutedindoles required electrophilic acylation, which subsequently
resulted in several auxiliary steps requisite to obtain benzoins.[19,20]
40-Dimethylaminobenzoin (a-isomer) can be isomerized in conforming
b-isomer in the basic media.[1] It was interesting to use a ! b-isomerization
for obtaining more stable b-benzoins.
RESULT AND DISCUSSION
Starting compounds served hetaryl analogues of a-benzoins, which can
easily be obtained by hydroxymethylation with arylglyoxals of conforming
p-excessive heterocycles.[21]
Isomerization of a-benzoins 1–8 has been found to proceed at the pre-
sence of triethylamine as the base in boiling ethanol and to result in conform-
ing hetaryl analogues of benzoins 9–16 with high yields (Sch. 1, Table 1).
a ! b Isomerization is also possible in the presence of potassium hydroxide.
A higher thermodynamic stability of the b-isomer resulting from the
electron-donor nature of a p-excessive hetaryl residue is a driving force of
the isomerization. Thus, the reaction time increases with the decreasing
electron-donor ability of a hetaryl group in the series (Sch. 2).
As a consequence of the much lower electron-donor ability of furan
compared to pyrrole, a-benzoin 8 is considerably less reactive than 1 and 4.
By varying substituents at the pyrrole ring and its binding position, we
have shown that the isomerization time increases as the electron-donor
ability of hetaryl residues reduces in the order shown in Sch. 3.

Isomerization of Hetaryl Analogues of a-Benzoins in Basic Media
3729
Scheme 1. Izomerization of hetaryl analogues of a-benzoins in basic media.
The highest reactivity is exhibited by a-benzoin 4 in which the reaction
center is bound to the most active electron-donor residue. Substituting an
alkyl group at the nitrogen atom by a less active electron-donor aryl group
results in an increased isomerization time. Because the reaction center is
sensitive to the electronic effects of substituents in the aryl ring, the pyrrole
derivative 2 is somewhat more reactive than 3. For a-benzoins 5–7, the
a-hydroxyketone moiety is bound to the less active electron-donor 3-pyrrolyl
Table 1. Times and yields of isomerization of a-benzoins 1–8.
Starting
compound
Product
Time (h)a
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1.5
3.5
4
50
80
70
85
64
92
85
90
3
11.5
12
12
6.5
aThe reaction time was determined by monitoring the vanishing
spot of a starting compound on the thin-layer chromatography
(TLC) (each 30 min).

3730
Ivonin and Lapandin
Scheme 2.
residue. Therefore, the isomerization proceeds slower, because a substituent at
the nitrogen atom has a secondary and, hence, veiled effect.
1
For the b-benzoins obtained, H-NMR doublet signals arising from the
o-protons of the unsubstituted phenyl ring are shifted 0.5–0.6 ppm upfield
from those for initial a-benzoins. Moreover, a- and b-benzoins differ from
each other by the characteristic shape of the doublet concerned.[21] These regu-
larities were employed in structural determination of isomeric benzoins.[22]
A behavior of a-benzoin 17 in the presence of triethylamine proved to be inter-
esting. Boiling 17 with triethylamine in ethanol finally resulted in product 18
Scheme 3.

Isomerization of Hetaryl Analogues of a-Benzoins in Basic Media
3731
(Sch. 4). A switch from ethanol to aprotic THF or pyridine exerted no effect on
the course of the reaction.
Interestingly, the b-benzoin 19 is stable in boiling pyridine.
In conclusion, we have shown that the reaction studied represents a
convenient preparative way to obtain hydroxymethylcarbonyl-substituted
derivatives of p-excessive heterocycles.
EXPERIMENTAL
Hydrogen nuclear magnetic resonance (1H-NMR) spectra were recorded
in DMSO-D6 on a Varian VXR-300 instrument with tetramethylsilane
(TMS) as the internal standard. To monitor the course of the reactions and
to control the product purities, TLC on Silufol-UV-254 plates was performed,
using benzene:acetone (5 : 1) for elution and iodine vapor for visualization.
a-Benzoins 1–8, 17 were prepared by the procedure in the literature.[21]
The physical and spectroscopic data of compounds 18 are in agreement
with published data.[21]
General Procedure of Isomerization of Benzoins 1–8 (Table 1)
A solution of benzoin (1.50 mmoles) and base (1.80 mmoles) in ethanol
(6 ml) was boiled. The solution obtained was evaporated under vacuum, and
the residue was recrystallized. The following b-benzoins were thus obtained:
2-Hydroxy-1-(1-methyl-1H-pyrrol-2-yl)-2-phenyl-ethanone (9). Color-
1
less prisms (hexane). M.p. 107–1088C. H-NMR: d ¼ 3.84 (s, 3H),
5.58 (d, J ¼ 5.7, 1H), 5.70 (d, J ¼ 5.7, 1H), 6.05 (dd, J ¼ 3.9,
J ¼ 2.4, 1H), 7.05 (d, J ¼ 2.4, 1H), 7.20 (d, J ¼ 6.9, 1H), 7.21
(d, J ¼ 3.9, 1H), 7.27 (t, J ¼ 6.9, 2H), 7.42 (d, J ¼ 6.9, 2H). Anal.
Calcd. for C13H13NO2: C, 72.54; H, 6.09. Found: C, 72.53; H, 6.10.
Scheme 4.

3732
Ivonin and Lapandin
1-[1-(4-Ethoxy-phenyl)-1H-pyrrol-2-yl]-2-hydroxy-2-phenyl-ethanone
1
(10). Straw-colored powder (80% ethanol). M.p. 78–798C. H-NMR:
d ¼ 1.40 (t, J ¼ 7.0, 3H), 4.10 (q, J ¼ 7.0, 2H), 5.60 (d, J ¼ 5.6,
1H), 5.64 (d, J ¼ 5.6, 1H), 5.88 (dd, J ¼ 3.9, J ¼ 2.4, 1H), 6.04
(d, J ¼ 2.4, 1H), 6.87 (d, J ¼ 3.9, 1H), 7.04 (d, J ¼ 8.7, 2H),
7.36 (d, J ¼ 7.8, 1H), 7.45 (d, J ¼ 8.7, 2H), 7.47 (t, J ¼ 7.8, 2H),
7.58 (d, J ¼ 7.8, 2H). Anal. Calcd. for C20H19NO3: C, 74.75; H,
5.96. Found: C, 74.79; H, 5.99.
2-Hydroxy-2-phenyl-1-(1-p-tolyl-1H-pyrrol-2-yl)-ethanone (11). Color-
1
less oil (hexane). H-NMR: d ¼ 2.38 (s, 3H), 5.71 (d, J ¼ 6.3, 1H),
5.82 (d, J ¼ 6.3, 1H), 6.30 (dd, J ¼ 3.9, J ¼ 3.9, 1H), 6.93
(d, J ¼ 9.0, 2H), 7.17 (d, J ¼ 9.0, 2H), 7.25 (d, J ¼ 3.9, 1H),
7.29 (d, J ¼ 3.9, 1H), 7.31 (d, J ¼ 8.1, 1H), 7.34 (t, J ¼ 8.1, 2H),
7.44 (d, J ¼ 8.1, 2H). Anal. Calcd. for C19H17NO2: C, 78.33; H,
5.88. Found: C, 78.27; H, 5.59.
2-Hydroxy-1-(1H-indol-3-yl)-2-phenyl-ethanone (12). Colorless prisms
(toluene). M.p. 194–1968C. 1H-NMR: d ¼ 5.70 (d, J ¼ 4.2, 1H),
5.77 (d, J ¼ 4.2, 1H), 7.12 (t, J ¼ 8.1, 1H), 7.15 (t, J ¼ 8.1, 1H),
7.20 (d, J ¼ 7.3, 1H), 7.28 (t, J ¼ 7.3, 2H), 7.40 (d, J ¼ 8.1,
1H), 7.51 (d, J ¼ 7.3, 2H), 8.18 (d, J ¼ 8.1, 1H), 8.43 (d, J ¼ 3.0,
1H), 11.88 (d, J ¼ 3.0, 1H). Anal. Calcd. for C16H13NO2: C, 76.48;
H, 5.21. Found: C, 76.47; H, 5.21.
2-Hydroxy-2-phenyl-1-(1,2,5-trimethyl-1H-pyrrol-3-yl)-ethanone (13).
Colorless plates (benzene). M.p. 135–1368C. 1H-NMR: d ¼ 2.08
(s, 3H), 2.45 (s, 3H), 3.31 (s, 3H), 5.26 (d, J ¼ 5.7, 1H), 5.53
(d, J ¼ 5.7, 1H), 6.29 (s, 1H), 7.18 (d, J ¼ 6.9, 1H), 7.27 (t, J ¼ 6.9,
2H), 7.36 (d, J ¼ 6.9, 2H). Anal. Calcd. for C15H17NO2: C, 74.05;
H, 7.04. Found: C, 74.01; H, 7.04.
1-[1-(4-Bromo-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-2-hydroxy-2-phenyl-
ethanone (14). Straw-colored powder (80% ethanol). M.p. 160–1618C.
1H-NMR: d ¼ 1.91 (s, 3H), 2.25 (s, 3H), 5.39 (d, J ¼ 5.7, 1H), 5.55
(d, J ¼ 5.7, 1H), 6.44 (s, 1H), 7.22 (d, J ¼ 7.5, 1H), 7.23 (d, J ¼ 8.4,
2H), 7.31 (t, J ¼ 7.5, 2H), 7.42 (d, J ¼ 7.5, 2H), 7.68 (d, J ¼ 8.4,
2H). Anal. Calcd. for C20H18BrNO2: C, 62.51; H, 4.72. Found: C,
62.53; H, 4.71.
1-(2,5-Dimethyl-1-p-tolyl-1H-pyrrol-3-yl)-2-hydroxy-2-phenyl-ethanone
(15). Straw-colored powder (80% ethanol). M.p. 126–1278C.
1H-NMR: d ¼ 1.89 (s, 3H), 2.24 (s, 3H), 2.40 (s, 3H), 5.29
(d, J ¼ 6.3, 1H), 5.52 (d, J ¼ 6.3, 1H), 6.37 (s, 1H), 7.09 (d, J ¼ 8.1,

Isomerization of Hetaryl Analogues of a-Benzoins in Basic Media
3733
2H), 7.21 (d, J ¼ 6.9, 1H), 7.28 (d, J ¼ 8.1, 2H), 7.30 (t, J ¼ 6.9, 2H),
7.41 (d, J ¼ 6.9, 2H). Anal Calcd. for C21H21NO2: C, 78.97; H, 6.63.
Found: C, 78.98; H, 6.65.
2-Hydroxy-1-(5-methyl-furan-2-yl)-2-phenyl-ethanone (16). Colorless
1
needless (ethanol). M.p. 150–1518C. H-NMR: d ¼ 2.33 (s, 3 H),
5.63 (d, J ¼ 3.9, 1H), 5.94 (d, J ¼ 3.9, 1H), 6.24 (d, J ¼ 3.0, 1H),
7.21 (d, J ¼ 7.5, 1H), 7.29 (t, J ¼ 7.5, 2H), 7.43 (d, J ¼ 7.5,
2H), 7.46 (d, J ¼ 3.0, 1H). Anal. Calcd. for C13H12O3: C, 72.21; H,
5.59. Found: C, 72.19; H, 5.62.
2,2-Bis-(4-dimethylamino-phenyl)-1-phenyl-ethanone (18). A solution of
a-benzoin 1 (250 mg, 1.00 mmol) with or without triethylamine
(0.17 mL, 1.20 mmol) in corresponding (Scheme 4) solvent (4 mL)
was boiled for 2 h. The precipitating product 18 on cooling was recrys-
tallized from ethanol. Yield 96%. Yellow needless. M.p. 167–1688C.
ACKNOWLEDGMENTS
We are pleased to acknowledge the financial support provided by the
Ministry of Education and Science of Ukraine (Grant No. 0101U001529).
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Received in the UK January 19, 2004