Base-catalyzed heterocyclization of 2-(R-ethynyl)benzohydroxamic acids

Article abstract of DOI:10.1134/S1070428014040101

Sonogashira alkynylation of methyl 2-iodobenzoate with terminal acetylenes gave a series of methyl 2-(alk-1-yn-1-yl)benzoates which reacted with hydroxylamine in boiling methanol to produce five- or six-membered N-hydroxy lactams, 3-R-methylidene-2-hydroxy-2,3-dihydroisoindol-1-ones or 3-R-isoquinolin-1(2H)-ones, depending on the acetylenic substituent nature.

Full text of DOI:10.1134/S1070428014040101

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 4, pp. 506–509. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © S.F. Vasilevskii, T.F. Mikhailovskaya, A.A. Stepanov, V.I. Mamatyuk, D.S. Fadeev, 2014, published in Zhurnal Organicheskoi
Khimii, 2014, Vol. 50, No. 4, pp. 518–521.
Base-Catalyzed Heterocyclization
of 2-(R-Ethynyl)benzohydroxamic Acids
S. F. Vasilevskiia, b, T. F. Mikhailovskayaa, A. A. Stepanova, b,
V. I. Mamatyukb, c, and D. S. Fadeevc
a Voevodskii Institute of Chemical Kinetics and Combustion, Siberian Branch, Russian Academy of Sciences,
ul. Institutskaya 3, Novosibirsk, 630090 Russia
e-mail: vasilev@kinetics.nsc.ru
b Novosibirsk State University, ul. Pirogova 2, Novosibirsk, 630090 Russia
c Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences,
pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
Received January 24, 2014
Abstract—Sonogashira alkynylation of methyl 2-iodobenzoate with terminal acetylenes gave a series of
methyl 2-(alk-1-yn-1-yl)benzoates which reacted with hydroxylamine in boiling methanol to produce five- or
six-membered N-hydroxy lactams, 3-R-methylidene-2-hydroxy-2,3-dihydroisoindol-1-ones or 3-R-isoquinolin-
1(2H)-ones, depending on the acetylenic substituent nature.
DOI: 10.1134/S1070428014040101
High and unique reactivity of compounds contain-
ing a triple carbon–carbon bond predetermines their
wide application in various fields of organic synthesis,
medicinal chemistry, and materials science [1]. Acety-
lenic compounds possessing a functional group in the
β-position with respect to the triple bond offer addi-
tional synthetic potential. Due to high electrophilicity
of the acetylenic fragment and its spatial proximity to
functional group such compounds are excellent models
for studying factors responsible for regioselectivity of
addition reactions. These structures are prone to self-
assembly, in particular to form heterocyclic com-
pounds that attract interest as potentially biologically
active substances. From the theoretical viewpoint,
studies of their transformations should favor deeper
understanding of the reactivity of acetylenic com-
pounds and accumulation of data relevant to Baldwin’s
rules governing the direction of ring closure reactions
provided that alternative paths are possible. This
problem was reviewed in detail in [2].
atom and two oxygen atoms) implies the possibility
for several concurrent reaction paths. We previously
showed [3] that the cyclization of γ,δ-acetylenic
hydroxamic acids of the pyrazole series yields exclu-
sively 6-endo-dig cyclization products. On the other
hand, analogous benzene derivatives are known to
undergo both 6-endo-dig and 5-exo-dig cyclization [4].
The novelty of the cycloisomerizations discovered
by us and high reactivity of acetylenic derivatives of
benzohydroxamic acid prompted us to examine the
heterocyclization in more detail. For this purpose we
extended the substrate series by including those pos-
sessing both donor and acceptor acetylenic substit-
uents. The required substrates, methyl 2-(alk-1-yn-1-
yl)benzoates Ia–Ic, were synthesized by the Sonoga-
shira cross-coupling of methyl 2-iodobenzoate (II)
with terminal acetylenes IIIa–IIIc in the presence of
Pd(PPh3)2Cl2–CuI–Et3N under argon. The yields of
Ia–Ic were 83–96% (Scheme 1).
The cyclization of Ia–Ic by the action of hydroxyl-
amine could be expected to follow both 6-endo-dig and
5-exo-dig patterns [4]. Despite the presence in mole-
cule Ib of a donor substituent (MeO, +M) which
reduces the electrophilicity of triple-bonded carbon
atoms, we failed to isolate intermediate 2-alkynyl-
benzohydroxamic acid IVb. In all cases, only cyclic
In the present article we report the results of our
study directed toward elucidation of factors affecting
intramolecular cyclization paths of 2-(R-ethynyl)ben-
zohydroxamic acids. The presence in their molecules
of two electrophilic centers (triple-bonded carbon
atoms) and three nucleophilic centers (one nitrogen
506

BASE-CATALYZED HETEROCYCLIZATION OF 2-(R-ETHYNYL)BENZOHYDROXAMIC
507
Scheme 1.
R
Pd(PPh3)2Cl2, CuI
I
Et3N, PhMe, argon
+
HC
R
COOMe
COOMe
Ia–Ic
II
IIIa–IIIc
R
N
OH
R
O
NH2OH, MeOH
Va–Vc
H
N
OH
R
O
IVa–IVc
N
OH
O
V'
R = HOCMe2 (a), 4-MeOC6H4 (b), 4-BrC6H4 (c).
1
products were detected in the reaction mixtures by H
and 13C NMR and high-resolution mass spectrometry.
However, the spectral data did not allow us to distin-
guish between five- and six-membered cyclic struc-
tures V and V′; in particular, the chemical shifts of the
olefinic protons in V (3-CH) and V′ (4-H) are very
similar. Therefore, the product structure was deter-
mined on the basis of the C=O stretching vibration
frequencies in the IR spectra of isomeric five- and six-
membered lactams. It is known [5] that increased steric
strain in going from a six-membered ring to five-
membered leads to increase of νC=O by 30– 35 cm–1. In
the IR spectra of model δ-lactams the C=O stretching
vibration frequency ranges from 1660 to 1680 cm–1,
whereas it amounts to no less than 1695 cm–1 for
γ-lactams. Compounds Va–Vc displayed in the IR
spectra carbonyl absorption bands in the region 1692–
1699 cm–1, which unambiguously indicated 5-exo-dig
cyclization with formation of five-membered ring
(Scheme 1). The use of IR spectroscopy for the
determination of ring size in alternative structures was
reported in other publications [6].
The configuration of the exocyclic C3=C8 double
bond in molecules Vb and Vc was assigned with the
1
aid of two-dimensional H–1H (COSY, NOESY) and
1H–13C (HSQC, HMBC) experiments. According to
1
the H–1H NOESY data, the 4-H and 8-H protons in
both structures appear close to each other, which is
possible only in the Z isomer.
The cyclization of methyl 2-(hex-1-yn-1-yl)ben-
zoate under analogous conditions (NH2OH, boiling
methanol) was reported previously to afford the
6-endo-dig cyclization product, 3-butylisoquinolin-
1(2H)-one [4]. It was interesting to elucidate whether
the same cyclization path will be followed in the reac-
tion with acetylenic derivative already containing hy-
droxycarbamoyl group. For this purpose, 2-iodobenzo-
hydroxamic acid (VI) was brought into Sonogashira
cross coupling with hex-1-yne with a view to obtain
acetylenic derivative VII and accomplish its cycliza-
tion in the presence of a base. However, we failed to
isolate intermediate VII because of its ready cycliza-
tion under the Sohogashira conditions (presumably, by
the action of triethylamine). As a result, six-membered
(rather than five-membered) lactam VIII was formed
in 81% yield. The product was identical to 3-butyl-
2-hydroxyisoquinolin-1(2H)-one described in [4]. It
should be noted that the C=O stretching vibration
frequency of compound VIII was 1666 cm–1, i.e., it is
lower by 30–35 cm–1 than that corresponding to five-
membered lactams V.
11
11
10
10
12
12
OMe
Br
9
9
8
8
4
7
4
7
13
13
14
14
3a
7a
3a
7a
5
6
5
6
3
1
3
1
2N OH
2N OH
O
O
Vb
Vc
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 4 2014

VASILEVSKII et al.
508
Scheme 2.
C4H9
OH
I
C4H9
OH
Pd(PPh3)2Cl2, CuI
Et3N, PhMe, argon
H
H
+
HC
C4H9
N
N
N
OH
O
O
O
VI
VII
VIII
Thus the cyclocondensation of 2-iodobenzohydrox-
amic acid in the Sonogashira reaction with hex-1-yne
follows the same 6-endo-dig pattern as in the cycliza-
tion of methyl (hex-1-yn-1-yl)benzoate with hydroxyl-
amine in boiling methanol.
167°C [9]) were synthesized according to known
methods.
2-Hydroxy-3-R-methylidene-2,3-dihydro-1H-iso-
indol-1-ones Va–Vc (general procedure). Methyl
2-(R-ethylnyl)benzoate Ia–Ic, 2.4 mmol, was added to
a solution of hydroxylamine in methanol, prepared
from 0.84 g (18.6 mmol) of hydroxylamine hydro-
chloride and 1.04 g (12 mmol) of potassium hydroxide,
and the mixture was heated for 3 h under reflux. The
solvent was removed under reduced pressure, the resi-
due was dissolved in water, the solution was acidified
to pH ~5–6 with acetic acid, and the precipitate was
filtered off and recrystallized from ethanol.
To conclude, we have shown that the cyclization of
2-(R-ethynyl)benzohydroxamic acids takes preferen-
tially the 5-exo-dig path leading to (3Z)-2-hydroxy-3-
(R-methylidene)-2,3-dihydro-1H-isoindol-1-ones. On
the other hand, the formation of 6-endo-dig cyclization
product, 3-butyl-2-hydroxyisoquinolin-1(2H)-one
(VIII), in the reaction with 2-(hex-1-yn-1-yl)-substi-
tuted analog requires further studies of the behavior of
aliphatic acetylenic derivatives of benzohydroxamic
acid, including computational methods, to get a deeper
insight into fine details of the effect of the nature of
acetylenic substituent on the cyclization direction.
The results of these studies should be useful for
selective synthesis of fused heterocycles with a desired
structure.
(3Z)-2-Hydroxy-3-(2-hydroxy-2-methylpropyli-
dene)-2,3-dihydro-1H-isoindol-1-one (Va). Yield
68%, mp 134–135°C. IR spectrum: ν 1699 cm–1
1
(C=O). H NMR spectrum, δ, ppm: 1.64 s (6H, CH3),
5.63 s (1H, =CH), 7.15–7.18 m (1H, 4-H), 7.21–
7.28 m (2H, 5-H, 6-H), 7.51–7.53 m (1H, 7-H),
11.82 br.s (1H, NOH). 13C NMR spectrum (CDCl3),
δC, ppm: 31.00, 71.03, 114.83, 118.51, 122.27, 126.36,
128.76, 131.48, 131.91, 132.96, 162.46. Mass spec-
trum: m/z 201.0783 [M – H2O]+. C12H11NO2. Calculat-
ed: 201.0784 [M – H2O].
EXPERIMENTAL
The IR spectra were recorded in KBr on a Bruker
Vector 22 spectrometer. The NMR spectra were
recorded on Bruker AV-400 (400.13 MHz, CDCl3),
Bruker AV-300 (300.13 MHz; CDCl3 or DMSO-d6),
and Bruker AV-600 spectrometers (600.31 MHz,
DMSO-d6). The mass spectra (electron impact, 70 eV)
were obtained on a DFS mass spectrometer (Thermo
Electron Corporation) with direct sample admission
into the ion source (ion source temperature 220–
270°C). Column chromatography was performed using
aluminum oxide (50–150 μm, TU 6-09-3916-75,
Russia) and silica gel Merck 60 (0.063–0.2 mm);
Silufol 60 F254 plates were used for thin-layer chro-
matography.
(3Z)-2-Hydroxy-3-(4-methoxybenzylidene)-
2,3-dihydro-1H-isoindol-1-one (Vb). Yield 64%,
mp 165–166°C. IR spectrum: ν 1692 cm–1 (C=O).
1H NMR spectrum, (acetone-d6), δ, ppm: 3.51 s (3H,
OCH3), 6.51 d.d (2H, 11-H, 13-H, J = 8.8, 2.5 Hz),
6.52 s (1H, 8-H), 7.45 d.d.d (1H, 6-H, J = 7.5, 7.5,
0.7 Hz), 7.56 d.d.d (1H, 5-H, J = 7.7, 7.5, 1.0 Hz),
7.63 d.d.d (1H, 7-H, J = 7.5, 1.0, 0.7 Hz), 7.75 d.d
(2H, 10-H, 14-H, J = 8.8, 2.5 Hz), 7.81 d.d.d (1H, 4-H,
J = 7.7, 0.7, 0.7 Hz). 13C NMR spectrum (DMSO-d6),
δC, ppm: 55.24 (OCH3), 107.77 (C8), 113.52 (C11, C13),
119.65 (C4), 122.24 (C7), 128.23 (C7a), 128.85 (C6),
131.44 (C5), 132.59 (C3), 133.66 (C10, C14), 136.37
(C3a), 159.65 (C12), 164.54 (C1). Mass spectrum: m/z
267.0889 [M]+. C16H13NO3. Calculated: M 267.0890.
Methyl 2-(3-hydroxy-3-methylbut-1-yn-yl)benzoate
(Ia) (nD20 = 1.5512 [7]), methyl 2-(4-methoxyphenyl-
ethynyl)benzoate (Ib) (mp 67–68°C [8]), methyl
2-(4-bromophenylethynyl)benzoate (Ic) (mp 66–68°C
[8]), and 2-iodobenzohydroxamic acid (VI) (165–
(3Z)-3-(4-Bromobenzylidene)-2-hydroxy-2,3-
dihydro-1H-isoindol-1-one (Vc). Yield 57%, mp 186–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 4 2014

BASE-CATALYZED HETEROCYCLIZATION OF 2-(R-ETHYNYL)BENZOHYDROXAMIC
509
187°C. IR spectrum: ν 1693 cm–1 (C=O). H NMR
spectrum (DMSO-d6), δ, ppm: 6.85 s (1H, 8-H),
7.71 m (4H, 10-H, 11-H, 13-H, 14-H), 7.58 d.d.d (1H,
6-H, J = 7.7, 7.5, 0.7 Hz), 7.71 d.d.d (1H, 5-H, J = 7.7,
7.7, 1.0 Hz), 7.75 d.d.d (1H, 7-H, J = 7.5, 1.0, 0.7 Hz),
8.02 d.d.d (1H, 4-H, J = 7.5, 1.0, 0.7 Hz), 10.68 s (1H,
OH). 13C NMR spectrum (DMSO-d6), δC, ppm: 105.40
(C8), 120.1 (C4), 122.46 (C7), 125.40 (C7a), 129.43
(C6), 130.49 (C11, C13), 132.23 (C3), 132.36 (C5),
132.45 (C10, C14), 134.31 (C3a), 163.40 (C1). Mass
spectrum: m/z 314.9883 [M]+. C15H10BrNO2. Calculat-
ed: M 314.9889.
Science Department of the Russian Academy of
1
Sciences (project no. 5.9.3, 2014), by the Ministry of
Education and Science of the Russian Federation, and
by the Chemical Service Center, Siberian Branch,
Russian Academy of Sciences.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 4 2014