Reaction of methyl 1-bromocyclopentane- and -cyclohexanecarboxylates with zinc and 2-arylmethylideneindan-1,3-diones

Article abstract of DOI:10.1134/S1070428014060049

Methyl 1-bromocyclopentanecarboxylate and methyl 1- bromocyclohexanecarboxylate reacted with zinc and 2-arylmethylideneindan-1,3- diones to give methyl-1-[(aryl)(1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-methyl] cyclopentane(or cyclohexane)carboxylates and 4-a

Full text of DOI:10.1134/S1070428014060049

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 6, pp. 786–789. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © N.F. Kirillov, E.A. Nikiforova, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 6, pp. 804–807.
Reaction of Methyl 1-Bromocyclopentane- and -cyclohexane-
carboxylates with Zinc and 2-Arylmethylideneindan-1,3-diones
N. F. Kirillov and E. A. Nikiforova
Perm State National Research University, ul. Bukireva 15, Perm, 614990 Russia
e-mail: kirillov@psu.ru
Received November 15, 2013
Abstract—Methyl 1-bromocyclopentanecarboxylate and methyl 1-bromocyclohexanecarboxylate reacted with
zinc and 2-arylmethylideneindan-1,3-diones to give methyl-1-[(aryl)(1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-
methyl]cyclopentane(or cyclohexane)carboxylates and 4′-aryl-2′H-spiro[cyclopentane(or cyclohexane)-1,3′-in-
deno[1,2-b]pyran]-2′,5′(4′H)-diones.
DOI: 10.1134/S1070428014060049
Reformatsky reagents react with α,β-unsaturated
ketones following both 1,2- and 1,4-addition patterns,
and the 1,4-addition products are capable of under-
going cyclization to give unsaturated lactones, deriv-
atives of dihydropyran-2-one [1]. Substituted spirodi-
hydropyran-2-ones were isolated in reactions of ali-
cyclic Reformatsky reagents with unsaturated ketones
[2–8]. In continuation of these studies we examined
reactions of 2-arylmethylideneindan-1,3-diones IIIa–
IIIf with bromozinc derivatives I and II obtained from
methyl 1-bromocyclopentane- and -cyclohexanecar-
boxylates. We found that Reformatsky reagents I and
II add to unsaturated cyclic diketones IIIa–IIIf at the
1,4-positions with formation of intermediates IVa–IVe
and Va–Vf. The final products were either 4′-aryl-
2′H-spiro[cyclopentane-1,3′-indeno[1,2-b]pyran]-
2′,5′(4′H)-diones VIa–VIc and 4′-aryl-2′H-spiro[cyclo-
hexane-1,3′-indeno[1,2-b]pyran]-2′,5′(4′H)-diones
VIIa–VIIc resulting from cyclization of intermediates
IV and V or methyl 1-[(aryl)(1,3-dioxo-2,3-dihydro-
1H-inden-2-yl)methyl]cyclopentanecarboxylates Xd
and Xe and methyl 1-[(aryl)(1,3-dioxo-2,3-dihydro-
1H-inden-2-yl)methyl]cyclohexanecarboxylates XIb–
XIf formed by hydrolysis of IV and V (Scheme 1).
(up to 40–50%) of unreacted compounds III were
isolated. To increase the conversion, the reaction time
was prolonged to 8 h; however, in most cases, the re-
action mixtures contained small amounts of the initial
diketones. Further increase of the reaction time, as well
as replacement of benzene by toluene to raise the reac-
tion temperature, resulted in considerable tarring.
It was found previously that reactions of alicyclic
Reformatsky reagents with 2-arylmethylidene-2,3-di-
hydro-1H-inden-1-ones [7] give only the correspond-
ing lactonization products. The lower yield of the
heterocyclic products in the reactions of 2-arylmethyli-
deneindan-1,3-diones with alicyclic Reformatsky re-
agents as compared to analogous reactions of 2-aryl-
methylidene-2,3-dihydro-1H-inden-1-ones may be
related to reduced nucleophilicity of the enolate
oxygen atom due to conjugation with the carbonyl
group in intermediates IV and V.
The IR spectra of 4′-aryl-2′H-spiro[cycloalkane-
1,3′-indeno[1,2-b]pyran]-2′,5′(4′H)-diones VI and VII
contained absorption bands belonging to stretching
vibrations of the ketone and lactone carbonyl groups in
the regions 1715–1724 and 1775–1789 cm–1, respec-
tively. In the 1H NMR spectra of these compounds, the
most characteristic were singlets from the 4′-H protons
at δ 3.65–3.88 ppm. Methyl 1-[(aryl)(1,3-dioxo-2,3-di-
hydro-1H-inden-2-yl)methyl]cycloalkanecarboxylates
X and XI displayed in the IR spectra absorption bands
due to the ketone and ester carbonyl groups at 1705–
1717 and 1737–1742 cm–1, respectively. The methoxy
It was also found that 2-arylmethylideneindan-1,3-
diones III are considerably less reactive than 2-aryl-
methylidene-1,3-diphenylpropane-1,3-diones [5]
toward Reformatsky reagents. When the reactions of
III with bromozinc derivatives I and II were carried
out under the conditions reported previously (heating
for 4 h in a boiling mixture of benzene, ethyl acetate,
and HMPA at a ratio of 20:5:1), appreciable amounts
1
protons resonated in the H NMR spectra of X and XI
at δ 3.61–3.79 ppm, and the CH signals were observed
786

REACTION OF METHYL 1-BROMOCYCLOPENTANE- ...
787
Scheme 1.
O
Ar
O
O
Ar
Br
ZnBr
Zn
IIIa–IIIf
O
( )n
( )n
COOMe
COOMe
I, II
BrZnO
( )n
OMe
IVa–IVe, Va–Vf
O
O
Ar
–MeOZnBr
( )n
O
VIa–VIc, VIIa–VIIc
O
O
Ar
Ar
H+/H2O
–HOZnBr
O
O
OH
O
( )n
( )n
OMe
OMe
VIIId, VIIIe, IXb–IXf
Xd, Xe, XIb–XIf
I, IV, VI, VIII, X, n = 1; II, V, VII, IX, XI, n = 2; Ar = Ph (a), 4-BrC6H4 (b), 3,4-(MeO)2C6H3 (c), 3-BrC6H4 (d),
4-MeOC6H4 (e), 4-MeC6H4 (f).
at δ 3.55–3.66 and 3.63–4.18 ppm. The latter signals
were mostly doublets with a coupling constant of
lower than 2.4 Hz. However, because of accidental
coincidence of chemical shifts, the CH signals in the
spectra of XIb and XIc appear as two-proton singlets.
Compounds VIc, XId, and XIf were tested for
analgesic activity, and the activity of compounds VIc
and XId was found to be comparable with that of
Metamizole while compound XIf turned out to be even
superior to Metamizole.
prepared as fine turnings, a catalytic amount of
mercury(II) chloride, 5 mmol of 2-arylmethylidene-
indan-1,3-dione, 5.3 mmol of methyl 1-bromocyclo-
alkanecarboxylate, 20 mL of benzene, 5 mL of ethyl
acetate, and 1 mL of HMPA was heated for 8 h under
reflux. The mixture was cooled, the liquid phase was
separated from excess zinc by decanting and treated
with 5% acetic acid, the organic layer was separated,
and the aqueous layer was extracted with two portions
of ethyl acetate. The extracts were combined with the
organic phase and dried over anhydrous sodium sul-
fate, the solvent was distilled off, and ethyl acetate was
added to the residue to isolate compound VIa–VIc or
VIIa–VIIc which was then recrystallized from ethyl
acetate. Ethanol was added to the mother liquor, and
compound Xd, Xe, or XIb–XIf was filtered off and
recrystallized from ethanol.
EXPERIMENTAL
The IR spectra of compounds VIa–VIc, VIIa–
VIIc, Xd, Xe, and XIb–XIf were recorded on a Perkin
Elmer Spectrum Two spectrometer with Fourier trans-
form from samples dispersed in mineral oil. The
1H NMR spectra were measured on a Varian Mercury
Plus-300 spectrometer (300 MHz) using CDCl3 as
solvent and tetramethylsilane as internal reference.
General procedure for the reaction of methyl
1-bromocycloalkanecarboxylates with 2-arylmethy-
lideneindan-1,3-dione. A mixture of 1.5 g of zinc
4′-Phenyl-2′H-spiro[cyclopentane-1,3′-indeno-
[1,2-b]pyran]-2′,5′(4′H)-dione (VIa). Yield 0.69 g
(42%), mp 186–187°C. IR spectrum, ν, cm–1: 1779,
1
1715. H NMR spectrum, δ, ppm: 1.23–2.39 m (8H,
CH2), 3.88 s (1H, CH), 7.06–7.93 m (9H, Harom).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 6 2014

KIRILLOV, NIKIFOROVA
788
C 62.81; H 4.67; Br 18.25. C23H21BrO4. Calculated, %:
C 62.60; H 4.80; Br 18.11.
Found, %: C 79.67; H 5.35. C22H18O3. Calculated, %:
C 79.98; H 5.49.
Methyl 1-[(1,3-dioxo-2,3-dihydro-1H-inden-2-
yl)(4-methoxyphenyl)methyl]cyclopentanecarbox-
ylate (Xe). Yield 1.16 g (59%), mp 114–115°C. IR
4′-(4-Bromophenyl)-2′H-spiro[cyclopentane-
1,3′-indeno[1,2-b]pyran]-2′,5′(4′H)-dione (VIb).
Yield 0.88 g (34%), mp 138–139°C. IR spectrum, ν,
1
spectrum, ν, cm–1: 1737, 1705. H NMR spectrum, δ,
1
cm–1: 1789, 1724. H NMR spectrum, δ, ppm: 1.21–
ppm: 1.22–2.38 m (8H, CH2), 3.55 d (1H, CHAr, J =
2.4 Hz), 3.61 s (3H, MeO), 3.67 s (3H, MeO), 3.95 d
(1H, 2-H, J = 2.4 Hz), 6.63 d and 7.15 d (4H, C6H4, J =
8.7 Hz), 7.70–7.89 m (4H, Harom). Found, %: C 73.63;
H 6.07. C24H24O5. Calculated, %: C 73.45; H 6.16.
Methyl 1-[(4-bromophenyl)(1,3-dioxo-2,3-dihy-
dro-1H-inden-2-yl)methyl]cyclohexanecarboxylate
(XIb). Yield 0.75 g (33%), mp 153–155°C. IR spec-
trum, ν, cm–1: 1741, 1717. 1H NMR spectrum, δ, ppm:
1.08–2.37 m (10H, CH2), 3.66 s (2H, CHAr, 2-H),
3.75 s (3H, MeO), 7.14 d and 7.23 d (4H, C6H4, J =
8.7 Hz), 7.72–7.87 m (4H, Harom). Found, %: C 63.56;
H 5.13; Br 17.32. C24H23BrO4. Calculated, %: C 63.31;
H 5.09; Br 17.55.
2.39 m (8H, CH2), 3.85 s (1H, CH), 6.97 d and 7.29 d
(4H, C6H4, J = 8.7 Hz), 7.81–7.95 m (4H, Harom).
Found, %: C 64.76; H 4.31; Br 19.72. C22H17BrO3.
Calculated, %: C 64.56; H 4.19; Br 19.52.
4′-(3,4-Dimethoxyphenyl)-2′H-spiro[cyclopen-
tane-1,3′-indeno[1,2-b]pyran]-2′,5′(4′H)-dione
(VIc). Yield 0.92 g (47%), mp 156–158°C. IR spec-
trum, ν, cm–1: 1783, 1720. 1H NMR spectrum, δ, ppm:
1.22–2.36 m (8H, CH2), 3.75 s (3H, MeO), 3.77 s (3H,
MeO), 3.84 s (1H, CH), 6.61 s (3H, C6H3), 7.78–
7.93 m (4H, Harom). Found, %: C 73.62; H 5.81.
C24H22O5. Calculated, %: C 73.83; H 5.68.
4′-Phenyl-2′H-spiro[cyclohexane-1,3′-indeno-
[1,2-b]pyran]-2′,5′(4′H)-dione (VIIa). Yield 0.79 g
(46%), mp 223–224°C. IR spectrum, ν, cm–1: 1775,
Methyl 1-[(3,4-dimethoxyphenyl)(1,3-dioxo-2,3-
dihydro-1H-inden-2-yl)methyl]cyclohexanecarbox-
ylate (XIc). Yield 0.68 g (31%), mp 108–109°C. IR
1
1720. H NMR spectrum, δ, ppm: 0.96–2.62 m (10H,
CH2), 3.71 s (1H, CH), 7.04–8.00 m (9H, Harom).
Found, %: C 79.97; H 5.73. C23H20O3. Calculated, %:
C 80.21; H 5.85.
1
spectrum, ν, cm–1: 1740, 1707. H NMR spectrum, δ,
ppm: 1.09–2.39 m (10H, CH2), 3.63 s (2H, CHAr,
2-H), 3.73 s (3H, MeO), 3.76 s (3H, MeO), 3.79 s (3H,
MeO); 6.56 d (1H, J = 8.1 Hz), 6.69 d (1H, J =
8.1 Hz), 6.91 s (1H) (C6H3); 7.68–7.86 m (4H, Harom).
Found, %: C 71.29; H 6.31. C26H28O6. Calculated, %:
C 71.54; H 6.47.
Methyl 1-[(3-bromophenyl)(1,3-dioxo-2,3-dihy-
dro-1H-inden-2-yl)methyl]cyclohexanecarboxylate
(XId). Yield 1.39 g (61%), mp 166–168°C. IR spec-
trum, ν, cm–1: 1741, 1710. 1H NMR spectrum, δ, ppm:
1.07–2.33 m (10H, CH2), 3.65 d (1H, CHAr, J =
1.8 Hz), 3.66 d (1H, 2-H, J = 1.8 Hz), 3.73 s (3H,
MeO); 7.00 t (1H, J = 8.7 Hz), 7.22 d (1H, J = 8.7 Hz),
7.27 d (1H, J = 8.7 Hz), 7.42 s (1H) (C6H4); 7.71–
7.89 m (4H, Harom). Found, %: C 63.61; H 5.04;
Br 17.71. C24H23BrO4. Calculated, %: C 63.31; H 5.09;
Br 17.55.
Methyl 1-[(1,3-dioxo-2,3-dihydro-1H-inden-2-
yl)(4-methoxyphenyl)methyl]cyclohexanecarbox-
ylate (XIe). Yield 1.32 g (65%), mp 117–118°C. IR
spectrum, ν, cm–1: 1739, 1705. 1H NMR spectrum, δ,
ppm: 1.08–2.36 m (10H, CH2), 3.62 d (1H, CHAr, J =
1.8 Hz), 3.65 d (1H, 2-H, J = 1.8 Hz), 3.66 s (3H,
MeO), 3.74 s (3H, MeO), 6.62 d and 7.14 d (2H each,
C6H4, J = 9.3 Hz), 7.68–7.85 m (4H, Harom). Found, %:
C 73.52; H 6.58. C25H26O5. Calculated, %: C 73.87;
H 6.45.
4′-(4-Bromophenyl)-2′H-spiro-[cyclohexane-1,3′-
indeno[1,2-b]pyran]-2′,5′(4′H)-dione (VIIb). Yield
0.59 g (28%), mp 205–206°C. IR spectrum, ν, cm–1:
1
1780, 1715. H NMR spectrum, δ, ppm: 0.92–2.59 m
(10H, CH2), 3.68 s (1H, CH), 6.96 d and 7.28 d (4H,
C6H4, J = 8.7 Hz), 7.79–7.94 m (4H, Harom). Found, %:
C 65.12; H 4.68, Br 18.62. C23H19BrO3. Calculated, %:
C 65.26; H 4.52; Br 18.88.
4′-(3,4-Dimethoxyphenyl)-2′H-spiro[cyclohex-
ane-1,3′-indeno[1,2-b]pyran]-2′,5′(4′H)-dione
(VIIc). Yield 0.49 g (24%), mp 168–170°C. IR spec-
trum, ν, cm–1: 1782, 1721. 1H NMR spectrum, δ, ppm:
0.95–2.59 m (10H, CH2), 3.65 s (1H, CH), 3.75 s (3H,
MeO), 3.77 s (3H, MeO), 6.60 s (3H, C6H3), 7.76–
7.91 m (4H, Harom). Found, %: C 74.41; H 6.03.
C25H24O5. Calculated, %: C 74.24; H 5.98.
Methyl 1-[(3-bromophenyl)(1,3-dioxo-2,3-dihy-
dro-1H-inden-2-yl)methyl]cyclopentanecarboxylate
(Xd). Yield 0.95 g (43%), mp 134–135°C. IR spec-
trum, ν, cm–1: 1742., 1707. 1H NMR spectrum, δ, ppm:
1.22–2.37 m (8H, CH2), 3.58 d (1H, CHAr, J =
2.1 Hz), 3.61 s (3H, MeO), 3.96 d (1H, 2-H, J =
2.1 Hz); 7.02 t (1H, J = 8.7 Hz), 7.23 d (1H, J =
8.7 Hz), 7.26 d (1H, J = 8.7 Hz), 7.42 s (1H)
(3-BrC6H4); 7.72–7.94 m (4H, Harom). Found, %:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 6 2014

REACTION OF METHYL 1-BROMOCYCLOPENTANE- ...
789
Reformatskogo (Reactions and Methods of Investigation
of Organic Reactions. Reformatsky Reaction), Moscow:
Khimiya, 1967, vol. 17.
Methyl 1-[(1,3-dioxo-2,3-dihydro-1H-inden-2-
yl)(4-methylphenyl)methyl]cyclohexanecarboxylate
(XIf). Yield 1.31 g (67%), mp 136–137°C. IR spec-
trum, ν, cm–1: 1740, 1709. 1H NMR spectrum, δ, ppm:
1.07–2.40 m (10H, CH2), 2.33 s (3H, Me), 3.57 d (1H,
CHAr, J = 2.1 Hz), 3.69 s (3H, MeO), 4.18 d (1H, 2-H,
J = 2.1 Hz), 6.91–7.87 m (8H, Harom). Found, %:
C 76.71; H 6.84. C25H26O4. Calculated, %: C 76.90;
H 6.71.
This study was performed under financial support
by the Ministry of Education and Science of the
Russian Federation (project no. 3.3925.2011) and by
the Russian Foundation for Basic Research (project
no. 13-03-96010).
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