Synthesis of alkyl 4-(1-alkyl-2-aryl-2-oxoethyl)-5,5-dimethyl-2- oxotetrahydrofuran-3-carboxylates and their reactions with amines

Article abstract of DOI:10.1023/B:RUJO.0000045192.57169.4e

Zinc enolates derived from 1-aryl-2-bromoalkanones react with alkyl 5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylates to give alkyl 4-(1-alkyl-2-aryl-2-oxoethyl)-5,5-dimethyl-2-oxotetrahydrofuran-3-carboxylates. Reactions of the latter with amines, such as p-toluidine, cyclohexylamine, and piperidine, lead to the corresponding carboxamides.

Full text of DOI:10.1023/B:RUJO.0000045192.57169.4e

Russian Journal of Organic Chemistry, Vol. 40, No. 7, 2004, pp. 999–1002. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 7, 2004,
pp. 1040–1043.
Original Russian Text Copyright © 2004 by Shchepin, Korzun, Bronnikova.
Synthesis of Alkyl 4-(1-Alkyl-2-aryl-2-oxoethyl)-
5,5-dimethyl-2-oxotetrahydrofuran-3-carboxylates
and Their Reactions with Amines
V. V. Shchepin, A. E. Korzun, and N. V. Bronnikova
Perm State University, ul. Bukireva 15, Perm, 614990 Russia
Received November 18, 2003
Abstract—Zinc enolates derived from 1-aryl-2-bromoalkanones react with alkyl 5,5-dimethyl-2-oxo-2,5-
dihydrofuran-3-carboxylates to give alkyl 4-(1-alkyl-2-aryl-2-oxoethyl)-5,5-dimethyl-2-oxotetrahydrofuran-3-
carboxylates. Reactions of the latter with amines, such as p-toluidine, cyclohexylamine, and piperidine, lead to
the corresponding carboxamides.
One of the main ways of modifying 2,5-dihydro-
furan-2-one derivatives includes their reactions with
nucleophiles [1–3]. With the aim of obtaining func-
tional derivatives of these heterocyclic systems in the
present work we examined reactions of alkyl 5,5-di-
methyl-2-oxo-2,5-dihydrofuran-3-carboxylates IIIa
and IIIb with zinc enolates IIa–IIh generated from
1-aryl-2-bromoalkanones Ia–Ih. Initial compounds
IIIa and IIIb contain three electrophilic centers: the
C4 atom and carbonyl carbon atoms of the lactone and
ester groups. The results showed that zinc enolates as
nucleophiles attack exclusively the soft electrophilic
center in the substrate, the C4 atom with rupture of the
double bond. The products were alkyl 4-(1-alkyl-2-
aryl-2-oxoethyl)-5,5-dimethyl-2-oxotetrahydrofuran-3-
carboxylates Va–Vl.
The structure of compounds Va–Vl was confirmed
1
by the IR and H NMR spectra. The IR spectra con-
tained absorption bands due to stretching vibrations of
the ketone, ester, and lactone carbonyl groups at 1670–
1690, 1725–1745, and 1765–1780 cm–1, respectively.
In the 1H NMR spectra of Va–Vj characteristic signals
at δ 1.39–1.43 (CH3), 1.54–1.56 (CH3), 2.81–2.97
(4-H), 3.80–3.89 (CHR1), and 3.89–3.99 ppm (3-H)
were present. The spectrum of ethyl 5,5-dimethyl-4-[1-
(2,4,6-trimethylbenzoyl)propyl]-2-oxotetrahydrofuran-
3-carboxylate (Vk) considerably differed from those of
compounds Va–Vj. For example, the signal from the
Scheme 1.
R1
H
OZnBr
Ar
Zn
R1CHBrCOAr
Ia–Ih
IIa–IIh
R1
H
R1
COAr
COOR2
COAr
COOR2
H
COOR2
IIa–IIh
H2O
H
ZnBr
O
H
H
Me
Me
Me
Me
–Zn(OH)Br
O
O
O
O
O
Me
Me
IIIa, IIIb
IVa–IVl
Va–Vl
I, II, R1 = Me, Ar = Ph (a), 4-MeC6H4 (b), 4-BrC6H4 (c), 4-MeOC6H4 (d); R1 = Et, Ar = Ph (e), 4-BrC6H4 (f), 2,4,6-Me3C6H2 (g);
R1 = i-Pr, Ar = 4-BrC6H4 (h); III, R2 = Me (a), Et (b); V, R1 = R2 = Me, Ar = Ph (a), 4-MeC6H4 (b), 4-MeOC6H4 (c); R1 = Me,
R2 = Et, Ar = Ph (d), 4-MeC6H4 (e), 4-BrC6H4 (f), 4-MeOC6H4 (g); R1 = Et, R2 = Me, Ar = Ph (h), 4-BrC6H4 (i); R2 = Et, Ar = Ph (j),
2,4,6-Me3C6H2 (k); R1 = i-Pr, R2 = Et, Ar = 4-BrC6H4 (l).
1070-4280/04/4007-0999 © 2004 MAIK “Nauka/Interperiodica”

SHCHEPIN et al.
1000
Scheme 2.
R1
R1
COAr
COAr
O
O
NH
–R2OH
H
H
R3NH2
–R2OH
NHR3
N
Me
Me
Ve, Vi
O
O
O
O
Me
Me
VIa, VIb
VIc
VI, R1 = Me, R3 = 4-MeC6H4, Ar = 4-MeC6H4 (a), R1 = Et, R3 = cyclo-C6H11, Ar = 4-BrC6H4 (b), R1 = Me, Ar = 4-MeC6H4 (c).
4-CH proton of Vk was a doublet displaced by about
1 ppm upfield. Presumably, this is the result of steric
effect of the 2,4,6-trimethylphenyl group which
restricts conformational freedom of the molecule. The
1H NMR spectra of the products also indicated that
the reaction was both regio- and stereoselective. Only
one diastereoisomer (J3,4 = 11 Hz) of the four possible
was obtained. However, its steric structure was not
determined rigorously.
with piperidine (secondary amine) was characterized
by a poor yield (35%), indicating a strong effect of
steric factor on the process.
The structure of compounds VIa–VIc was proved
1
by their elemental compositions and IR and H NMR
spectra. In the IR spectra of VIa–VIc we observed
absorption bands belonging to the amide, lactone, and
ester carbonyl groups at 1630–1640, 1670–1685, and
1755–1765 cm–1, respectively; compound VIb showed
in the spectrum NH absorption band at 3280 cm–1;
NH stretching vibrations of compound VIa gave rise
to a broadened band in the region 3045–3220 cm–1.
With a view to obtain new nitrogen-containing
compounds on the basis of furancarboxylates V we
examined reactions of compounds Ve and Vi with
N-nucleophiles, i.e., amines. The reaction with primary
or secondary amines was charge-controlled: the attack
by amine was directed at the ester carbonyl carbon
atom to afford 4-(1-alkyl-2-aryl-2-oxoethyl)-5,5-di-
methyl-2-oxotetrahydrofuran-3-carboxylates VIa–VIc
(Scheme 2). The yields of products VIa and VIb ob-
tained by reactions with primary amines (both highly
basic cyclohexylamine and weakly basic p-toluidine)
were fairly high (74–85%). The reaction of Ve and Vi
1
The H NMR spectra of amides VIa–VIc are given in
Experimental.
EXPERIMENTAL
The IR spectra were recorded on a UR-20 spec-
trometer from samples dispersed in mineral oil. The 1H
NMR spectra of Va–Vl and VIa–VIc were measured
on a Bruker DRX spectrometer (500 MHz) from
Table 1. Yields, melting points, IR spectra, and elemental analyses of alkyl 4-(1-alkyl-2-aryl-2-oxoethyl)-5,5-dimethyl-2-
oxotetrahydrofuran-3-carboxylates Va–Vl
IR spectrum, νC=O, cm–1
Found, %
Calculated, %
Comp.
no.
Yield, %
mp, °C
Formula
lactone
ester
1735
1730
1725
1725
1735
1735
1735
1735
ketone
C
H
C
H
91
84
81
84
91
72
92
64
148–150
181–183
159–161
136–137
124–125
127–128
115–117
123–124
1775
1775
1770
1770
1770
1765
1775
1775
1675
1680
1680
1680
1670
1675
1675
1675
67.12
67.88
64.57
67.90
68.65
54.42
65.51
67.85
6.59
6.96
6.65
6.99
7.12
5.31
6.90
7.02
C17H20O5
C18H22O5
C18H22O6
C18H22O5
C19H24O5
C18H21BrO5
C19H24O6
C18H22O5
67.09
67.91
64.66
67.91
68.66
54.42
65.50
67.91
6.62
6.97
6.63
6.97
7.28
5.33
6.94
6.97
Va
Vb
Vc
Vd
Ve
Vf
Vg
Vh
71
72
71
57
124–127
109–111
123–124
116–117
1775
1775
1770
1775
1730
1730
1725
1740
1680
1680
1680
1670
54.42
68.60
70.59
56.41
5.32
7.25
8.01
5.99
C18H21BrO5
C19H24O5
54.42
68.66
70.56
56.48
5.33
7.28
8.07
5.92
Vi
Vj
Vk
Vl
C22H30O5
C20H25BrO5
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 7 2004

SYNTHESIS OF ALKYL 4-(1-ALKYL-2-ARYL-2-OXOETHYL)-...
1001
Table 2. 1H NMR spectra of alkyl 4-(1-alkyl-2-aryl-2-oxoethyl)-5,5-dimethyl-2-oxotetrahydrofuran-3-carboxylates Va–Vl
Comp.
no.
Chemical shifts δ, ppm
1.17 d (3H, CHMe), 1.43 s and 1.56 s (6H, Me2C), 2.96 d.d (1H, 4-H), 3.55 s (3H, OMe), 3.89 m (1H, CHMe),
3.95 d (1H, 3-H), 7.56–8.00 m (5H, Ph)
Va
Vb
Vc
Vd
Ve
Vf
1.16 d (3H, CHMe), 1.43 s and 1.55 s (6H, Me2C), 2.38 s (3H, 4-MeC6H4), 2.94 d.d (1H, 4-H), 3.54 s (3H, OMe),
3.85 m (1H, CHMe), 3.92 d (1H, 3-H), 7.36 d and 7.89 d (4H, 4-MeC6H4)
1.16 d (3H, CHMe), 1.42 s and 1.55 s (6H, Me2C), 2.93 d.d (1H, 4-H), 3.53 s (3H, COOMe), 3.83 m (1H, CHMe),
3.87 s (3H, MeOC6H4), 3.91 d (1H, 3-H), 7.06 d and 7.97 d (4H, 4-MeOC6H4)
1.03 d.d (3H, CH2Me), 1.17 d (3H, CHMe), 1.43 s and 1.55 s (6H, Me2C), 2.95 d.d (1H, 4-H), 3.89 m (1H,
CHMe), 3.93 d (1H, 3-H), 3.94 m and 4.03 m (2H, OCH2), 7.56–8.00 m (5H, Ph)
1.03 d.d (3H, CH2Me), 1.16 d (3H, CHMe), 1.43 s and 1.55 s (6H, Me2C), 2.38 s (3H, 4-MeC6H4), 2.83 d.d (1H,
4-H), 3.84 m (1H, CHMe), 3.93 d (1H, 3-H), 3.94 m and 4.03 m (2H, OCH2), 7.36 d and 7.89 d (4H, 4-MeC6H4)
1.05 d.d (3H, CH2Me), 1.21 d (3H, CHMe), 1.43 s and 1.55 s (6H, Me2C), 2.82 d.d (1H, 4-H), 3.80 m (1H,
CHMe), 3.93 d (1H, 3-H), 3.94 m and 4.03 m (2H, OCH2), 7.77 d and 7.95 d (4H, 4-BrC6H4)
1.03 d.d (3H, CH2Me), 1.15 d (3H, CHMe), 1.42 s and 1.55 s (6H, Me2C), 2.81 d.d (1H, 4-H), 3.83 m
(1H, CHMe), 3.86 s (3H, OMe), 3.89 d (1H, 3-H), 3.93 m and 4.02 m (2H, OCH2), 7.06 d and 7.97 d (4H,
4-MeOC6H4)
Vg
0.72 t (3H, CHCH2Me), 1.39 s and 1.55 s (6H, Me2C), 1.66 m (2H, CHCH2Me), 2.95 d.d (1H, 4-H), 3.53 s (3H,
OMe), 3.87 m (1H, CHEt), 3.99 d (1H, 3-H), 7.55–8.03 m (5H, Ph)
Vh
Vi
0.71 t (3H, CH2Me), 1.39 s and 1.55 s (6H, Me2C), 1.62 m (2H, CH2Me), 2.97 d.d (1H, 4-H), 3.54 s (3H, OMe),
3.83 m (1H, CHEt), 3.93 d (1H, 3-H), 7.77 d and 7.96 d (4H, 4-BrC6H4)
0.72 t (3H, CHCH2Me), 1.02 d.d (3H, OCH2Me), 1.40 s and 1.56 s (6H, Me2C), 1.67 m (2H, CHCH2Me), 2.97 d.d
(1H, 4-H), 3.86 m (1H, CHEt), 3.96 d (1H, 3-H), 3.92 m and 4.01 m (2H, OCH2), 7.56–8.04 m (5H, Ph)
Vj
Vk
0.79 t (3H, CHCH2Me), 1.22 s and 1.35 s (6H, Me2C), 1.25 d.d (3H, OCH2Me), 1.62 m and 1.69 m (2H,
CHCH2Me), 2.21 s and 2.24 s (9H, 2,4,6-Me3C6H2), 2.92 d (1H, CHEt), 3.04 d (1H, 4-H), 4.05 d (1H, 3-H),
4.18 m and 4.20 m (2H, OCH2), 6.91 s (2H, 2,4,6-Me3C6H2)
0.81 d and 0.86 d (6H, CHCHMe2), 1.06 d.d (3H, OCH2Me), 1.27 s and 1.54 s (6H, Me2C), 1.96 m (1H,
CHCHMe2), 3.12 d.d (1H, 4-H), 3.81 t (1H, CHCHMe2), 3.98 d (1H, 3-H), 4.01 m and 4.07 m (2H, OCH2),
7.75 d and 8.00 d (4H, 4-BrC6H4)
Vl
solutions in DMSO-d6 using tetramethylsilane as
internal reference.
dried over sodium sulfate, and evaporated. The prod-
ucts were purified by double recrystallization from
methanol (Tables 1, 2).
Alkyl 4-(1-alkyl-2-aryl-2-oxoethyl)-5,5-dimethyl-
2-oxotetrahydrofuran-3-carboxylates Va–Vl (gen-
eral procedure). Alkyl 5,5-dimethyl-2-oxo-2,5-dihy-
drofuran-3-carboxylate IIIa or IIIb, 0.011 mol, and
1-aryl-2-bromoalkanone Ia–Ih, 0.014 mol, were added
to a mixture of 2 g of metallic zinc (prepared as fine
turnings), 7 ml of diethyl ether, and 7 ml of ethyl
acetate. The mixture was heated to initiate the reaction
which then occurred spontaneously. When the reaction
was complete, the mixture was heated for 15 min
under reflux, cooled, treated with 10% hydrochloric
acid, and extracted with diethyl ether. The organic
phase was separated, washed with a 10% solution of
sodium hydrogen carbonate until neutral reaction,
4-(1-Alkyl-2-aryl-2-oxoethyl)-5,5-dimethyl-2-
oxotetrahydrofuran-3-carboxamides VIa–VIc (gen-
eral procedure). p-Toluidine, cyclohexylamine, or
piperidine, 0.0017 mol, was added to a solution of
0.0016 mol of compound Ve or Vi in 6 ml of o-xylene.
The mixture was heated for 6 h, the solvent was
distilled off, and the residue was recrystallized twice
from methanol.
5,5-Dimethyl-4-[1-methyl-2-(4-methylphenyl)-2-
oxoethyl]-2-oxo-N-(p-tolyl)tetrahydrofuran-3-
carboxamide (VIa). Yield 85%, mp 200–202°C. IR
spectrum, ν, cm–1: 1640 (C=O, amide), 1680 (C=O,
ketone), 1765 (C=O, lactone), 3045–3250 (N–H).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 7 2004

SHCHEPIN et al.
1002
1H NMR spectrum (DMSO-d6), δ, ppm: 1.18 d
(CHMe); 1.32 s and 1.56 s (6H, Me2C); 2.27 s and
2.38 s (6H, 4-MeC6H4); 3.07 d.d (1H, 4-H); 3.89 m
(1H, CHMe); 4.02 d (1H, 3-H); 7.09 d, 7.29 d, 7.33 d,
7.86 d (8H, 4-MeC6H4); 9.82 s (1H, NH). Found, %:
C 73.26; H 6.91. C24H27NO4. Calculated, %: C 73.26;
H 6.92.
5,5-Dimethyl-4-[1-(4-methylbenzoyl)ethyl]-N,N-
pentamethylene-2-oxotetrahydrofuran-3-carbox-
amide (VIc). Yield 35%, mp 137–139°C. IR spectrum,
ν, cm–1: 1630 (C=O, amide), 1670 (C=O, ketone),
1
1760 (C=O, lactone). H NMR spectrum (DMSO-d6),
δ, ppm: 1.12 d (3H, CHMe), 1.39 s and 1.50 s (6H,
Me2C), 1.10–1.55 m and 2.95–3.45 m (10H, C5H10N),
2.39 s (3H, 4-MeC6H4), 3.07 d.d (1H, 4-H), 3.80 m
(1H, CHMe), 4.38 d (1H, 3-H), 7.35 d and 7.92 d (4H,
4-MeC6H4). Found, %: C 71.09; H 7.89. C22H29NO4.
Calculated, %: C 71.13; H 7.87.
4-[1-(4-Bromobenzoyl)propyl]-N-cyclohexyl-5,5-
dimethyl-2-oxotetrahydrofuran-3-carboxamide
(VIb). Yield 74%, mp 212–213°C. IR spectrum, ν,
cm–1: 1635 (C=O, amide), 1685 (C=O, ketone), 1755
1
(C=O, lactone), 3280 (N–H). H NMR spectrum
REFERENCES
(DMSO-d6), δ, ppm 0.75 t (3H, CHCH2Me), 0.8–
1.27 m and ~1.50–1.70 m (10H, C6H10), ~1.63 m
(CHCH2Me), 1.22 s and 1.50 s (6H, Me2C), 3.01 d.d
(1H, 4-H), 3.42 m (NHCH), 3.72 m (1H, CHEt),
3.87 d (1H, 3-H), 7.74 d and 7.96 d (4H, 4-BrC6H4),
7.75 d (1H, NH). Found, %: C 59.48; H 6.54.
C23H30BrNO4. Calculated, %: C 59.49; H 6.51.
1. Avetisyan, A.A., Tatevosyan, G.E., and Dangyan, M.T.,
Arm. Khim. Zh., 1971, vol. 24, p. 688.
2. Kristensen, J., Thomsen, I., and Lawesson, S.O., Bull.
Soc. Chim. Belg. 1978, vol. 87, p. 721.
3. Avetisyan, A.A., Galstyan, A.V., and Melikyan, G.S.,
Arm. Khim. Zh., 1984, vol. 37, p. 357.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 7 2004