Allylation and heterocycloaddition reactions of aldimines: Furan- and quinolinecarboxaldehydes

Article abstract of DOI:10.1007/PL00013465

New derivatives of α-substituted furans were prepared in high yields from easily available α-furfurylidenbenzilamines via nucleophilic C-allylation. The homoallylamines obtained this way were used for the synthesis of some polyfunctional aminobutene derivatives. In addition, 4-thiazolidinones some of which are hetaryl substituted at the 2-position were prepared by the reaction of mercapto acids with quinoline carboxaldehydes and p-phenetidine. All new products were fully characterized.

Full text of DOI:10.1007/PL00013465

Monatshefte f uÈ r Chemie 129, 671±677 (1998)
Allylation and Heterocycloaddition
Reactions of Aldimines: Furan-
and Quinolinecarboxaldehydes
Vladimir Kouznetsov2 , N uÈ ket Ocal , Zuhal Turgut , Fedor Zubkov ,
;Ã
È
1;Ã
1
3
1
3
S; eniz Kaban , and Alexei V. Varlamov
1
_
Yõldõz Technical University, Department of Chemistry, 80270 S; i s; li, Istanbul, Turkey
School of Chemistry, Industrial University of Santander, Bucaramanga, Colombia
Department of Organic Chemistry, Russian Peoples Friendship University, Moscow 117923,
Russia
2
3
Summary. New derivatives of ꢀ-substituted furans were prepared in high yields from easily
available ꢀ-furfurylidenbenzilamines via nucleophilic C-allylation. The homoallylamines obtained
this way were used for the synthesis of some polyfunctional aminobutene derivatives. In addition, 4-
thiazolidinones some of which are hetaryl substituted at the 2-position were prepared by the reaction
of mercapto acids with quinoline carboxaldehydes and p-phenetidine. All new products were fully
characterized.
Keywords. Diels-Alder adduct; ꢀ-Furfurylidenbenzilamine; Nitrone; ꢀ-Substituted furan; 4-Thia-
zolidinone.
Allylierungs- und Heterocycloadditionsreaktionen von Aldiminen: Furan- und
Chinolincarboxaldehyde
Zusammenfassung. Aus den leicht zug aÈ nglichen ꢀ-Furfurylidenbenzilaminen wurden durch
nucleophile C-Allylierung neue Derivative ꢀ-substituierter Furane mit hohen Ausbeuten dargestellt.
Die dabei gewonnenen Homoallylamine wurden f uÈ r die Synthese von polyfunktionalen
Aminobutenderivaten eingesetzt. Dar uÈ ber hinaus wurden durch Reaktion von Merkaptos aÈ uren mit
Chinolincarboxaldehyden und p-Phenetidin an der 2-Stelle heterosubstituierte 4-Thiazolidinone
gebildet. Alle Produkte wurden entsprechend charakterisiert.
Introduction
Furans have been proven to be useful precursors for a wide variety of carbo- and
heterocycles which are present in numerous natural products [1]. The preparation
of 1,4-dicarbonyl compounds and cyclopentanones from furans is a well
documented process [2]. Aldimines derived from furfural or furfurylamine have
à Corresponding author

672
V. Kouznetsov et al.
been successfully used in the synthesis of different ꢁ-lactams [3, 4]. Recently,
such imines have been involved in Pd-catalyzed sequential and cascade[3‡2]-
cycloadditions to produce bicyclic ꢁ-lactams [5]. The ready availability of the
starting materials and the simplicity of the procedures make N-allyl-ꢀ-
furfurylamines attractive candidates for intramolecular Diels-Alder reactions [6,
7
]. Furthermore, in the organometallic domain, the nucleophilic addition of allyl
carbanions to aldimines to give homoallylamines [8, 9] is of particular interest
owing to the many possible transformations of the double bond of the allyl group.
However, these reactions have not been studied in the ꢀ-furfurylidenamine series
so far. On the other hand, most of the 4-thiazolidinones display a large variety of
activities such as antibiotic, diuretic, organoleptic, tuberculostatic, antileukemic,
antibacterial, and antiparasitical [10, 11]. The biological signi®cance of these
compounds prompted us to study the synthesis of some 3-(4-ethoxyphenyl)-2-
hetaryl-4-thiazolidinones.
Results and Discussion
As part of an ongoing project aiming at the use of homoallylamines in the synthesis
of various nitrogen heterocycles of biological interest, we required ꢀ-substituted
furans comprising an N-benzylaminobutenyl radical. For this purpose, we
performed some Grignard allylation reactions on aldimines derived from
substituted furfurals and benzylamines using allyl bromide and magnesium.
Addition of allyl magnesium bromide to aldimines 1±4 gave homoallylamines
5
±8 as shown in Scheme 1. In each case, the reaction was conducted in diethyl
ꢀ
ether with initial addition of aldimines to the Grignard reagent at 0 C. After
stirring at the same temperature for 0.5 hours, the reaction mixture was allowed to
warm to room temperature, and stirring was continued for 1 hour before standard
work-up. The homoallylamines 5±8 were isolated as stable yellow oils in 65±86%
yield after distillation under reduced pressure. Their structure was established
using IR, NMR, and mass spectroscopy. The IR spectra showed the bands of the
Scheme 1

Reactions of Aldimines
673
�
1
1
amine group in the region of 3325±3340 cm ; the molecular ions in the mass
spectra corresponded to their formulas. In the H NMR spectra, the protons of the
allyl residue gave rise to three groups of signals: the triplet of the CH -group was
2
observed in the region of 2.49±2.57 ppm, and the multiplet signals of the =CH2
and CH= groups, respectively, appeared at low ®eld, i.e. between 4.98±5.14 and
5.57±5.70 ppm. Compound 6 is formed as a mixture of two pairs of diastereo-
1
isomers which was con®rmed by its H NMR spectrum.
Reaction of compound 5 with dimethyl acetylenedicarboxylate (DMAD)
ꢀ
carried out in diethyl ether at 0 C afforded a polyfunctional Diels-Alder adduct (9)
as colorless crystals in high yields. Under these conditions, we did not observe the
formation of any products resulting from nucleophilic NH-addition to the triple
1
bond. The H NMR spectrum of this adduct shows doublet and triplet signals at
6.27 and 7.34 ppm corresponding to 6-H and 5-H. The protons of the allyl group
resonate between 5.08 and 5.74 ppm as two characteristic multiplets.
It is well known that nitrones [12, 13] are useful synthons in natural products
synthesis and are effective spin traps (for example, phenyl tert-butyl nitrone (10)
[14]). To our knowledge there are no reports on the synthesis of such compounds
bearing an ꢀ-furfuryl moiety. Thus, the ®rst nitrone of this series (11) was
conveniently prepared by oxidation with 30% H O in the presence of a catalytic
2
2
amount of Na WO in acetone at room temperature. It was isolated as a stable,
4
2
Scheme 2

674
V. Kouznetsov et al.
colorless solid which could be puri®ed on a chromatographic column and was
recrystallized from hexane. The presence of four multiplet signals, i.e. HC=C
(
ꢂ ˆ 5.8 ppm), CH =CH (ꢂ ˆ 5.1 ppm), CH =CH
(ꢂ ˆ 5.2 ppm), and -CH -
2
cis
2
trans
2
1
(
ꢂ ˆ 3.25 ppm) in its H spectra proves that the allyl fragment is not oxidized under
these reaction conditions. The signal of the aldiminic proton (HC=N) appears at
.41 ppm.
In conclusion, allylation of easily available ꢀ-furfurylidenbenzylamines
7
constitutes a convenient procedure for the preparation of the corresponding
homoallylamines. It should be noted that the new compounds 9 and 11 obtained
from these amines still contain the allylic fragment which might be used in
intramolecular cyclization reactions.
On the other hand, 4-thiazolidinones have been prepared by the reaction of
thioglycolic acid or thiolactic acid with Schiff bases derived from quinoline-2-, 6-
methylquinoline-2-, quinoline-4-, and quinoline-8-carboxaldehydes with p-phene-
tidine [15]. The biological activities of these compounds are under investigation at
the Karl Franzens University in Graz, Austria.
The structures of the new compounds were ®rmly established on the basis of
their IR, NMR, and mass spectra. In general, the strong sharp band at 1610±
�
1
1
thiazolidinones, and a characteristic ꢃ(C=O) appeared in the region of 1710±
620 cm in the IR spectra of the Schiff bases was absent in the spectra of the
�
1
1
680 cm .
Experimental
Melting points are uncorrected and were measured in open capillaries with an Electrothermal IA
9
100 melting point apparatus. IR spectra were recorded on Perkin Elmer 599B-FT and Philips PU
714 spectrometers in KBr pellets unless otherwise indicated. The NMR spectra were determined on
9
Bruker WP-200 (compounds 5±8), Bruker WH-400 (compounds 9, 11), and Varian Gemini 200
(
compounds 12±19) spectrometers in CDCl3 with tetramethylsilan (TMS, ꢂ ˆ 0 ppm) as internal
standard. Mass spectra were obtained from an LKB-9000 spectrometer with 70 eV electron impact
ionization. Elemental analyses were performed on a Leco CHN-600 analyzer. The purities of the
obtained substances and the compositions of the reaction mixtures were monitored by TLC on Alufol
60, and Silufol UV254 plates and Eastman Kodak Chromatogram 13181 silica gel sheets with
¯uorescent indicator. Elemental analyses were in satisfying agreement with the calculated data.
Allylation of aldimines 1±4; general procedure
A solution of 1±4 (0.1 mol) dissolved in dry ether (30 ml) was added dropwise to a stirred suspension
of allyl magnesium bromide prepared from allyl bromide (0.3 mol) and magnesium (0.6 mol) in dry
ꢀ
ꢀ
ether (100 ml) at 0 C. After stirring at 0 C for a 0.5 h, the reaction mixture was allowed to warm to
room temperature and stirred for 1 h. Work-up with a cold saturated solution of NH4Cl, extraction
with ether (3Â50 ml), and vacuum distillation of the dried extracts (Na2SO4) afforded the
homoallylfurfurylamines 5±8 as yellow oils.
4-N-Benzylamino-4-(2-furyl)-1-butene (5; C15H17NO)
Yield: 82%; b.p.: 115±118 C/2 mm Hg; IR (KBr): ꢃ ˆ 3330, 1645 cm ; 1H NMR (CDCl3, ꢂ,
ꢀ
� 1
0
2
00 MHz): 7.35 (1H, d, ꢀ-Fu), 7.30±7.05 (5H, m, Ph), 6.27 (1H, d, ꢁ-Fu), 6.13 (1H, t, ꢁ -Fu), 5.69

Reactions of Aldimines
675
(
1H, ddt, =CH±), 5.05±4.99 (2H, m, ˆ CH2), 3.74 (1H, t, CH±Fu), 3.72 and 3.56 (2H, dd, CH2±N),
‡
2
.49 (2H, t, CH2±CH=), 1.70 (1H, br s, NH) ppm; MS: m/z ˆ 227 (M ).
4-N-Benzylamino-4-(5-methyl-2-furyl)-1-butene (6; C16H19NO)
ꢀ
� 1
1
Yield: 70%; b.p.: 140±142 C/10 mm Hg; IR (KBr): ꢃ ˆ 3325, 1641 cm ; H NMR (CDCl3, ꢂ,
0
2
5
2
00 MHz): 7.36 (1H, d, ꢀ-Fu), 7.35±7.15 (5H, m, Ph), 6.27 (1H, d, ꢁ-Fu), 6.13 (1H, t, ꢁ -Fu), 5.70±
.60 (1H, m, =CH±), 5.10±4.98 (2H, m, =CH2), 3.75 and 3.65 (1H, q, CH±N), 3.45 (1H, t, CH±Fu),
.55 and 2.49 (2H, t, CH2±CH=), 1.68 (1H, br s, NH), 1.42 and 1.35 (1H, d, Me) ppm; MS:
m/z ˆ 241 (M‡).
4-N-Benzylamino-4-(5-bromo-2-furyl)-1-butene (7; C16H19NO)
Yield: 86%; b.p.: 124±126 C/2 mm Hg; IR (KBr): ꢃ ˆ 3340, 1648 cm ; 1H NMR (CDCl3, ꢂ,
ꢀ
� 1
0
2
00 MHz): 7.35±7.25 (5H, m, Ph), 6.09 (1H, d, ꢁ-Fu), 5.93 (1H, d, ꢁ -Fu), 5.57 (1H, ddt, =CH±),
5
.14±5.09 (2H, m, =CH2), 3.74 (1H, t, CH±Fu), 3.82 and 3.65 (2H, dd, CH2±N), 2.57 (2H, m, CH2±
C=), 2.32 (3H, s, Me), 1.75 (1H, br s, NH) ppm; MS: m/z ˆ 241 (M‡).
4-N-(ꢀ-Methylbenzyl)amino-4-(2-furyl)-1-butene (8; C15H16BrNO)
Yield: 64%; viscous oil; IR (KBr): ꢃ ˆ 3326, 1640 cm 1; 1H NMR (CDCl3, ꢂ, 200 MHz): 7.35±7.30
�
0
(
5H, m, Ph), 6.26 (1H, d, ꢁ-Fu), 6.09 (1H, d, ꢁ -Fu), 5.74 (1H, ddt, =CH±), 5.11±5.09 (2H, m,
=CH2), 3.80 and 3.63 (2H, dd, CH2±N), 3.74 (2H, t, CH±Fu), 2.54 (2H, m, CH2±C=) ppm; MS:
m/z ˆ 306 (M‡).
0
0
0
1
-(4 -N-Benzylamino-1 -butenyl-4 )-2,3-dimethoxycarbonyl-7-oxabicyclo[2.2.1]hepta-2,3-diene
(
9; C21H23NO5)
A solution of 5 (0.026 mol) and dimethyl acetylenedicarboxylate (DMAD, 0.029 mol) in Et2O
40 ml) was allowed to stand in a loosely stoppered ¯ask for 12 h. The resulting solid was ®ltered and
recrystallized from hexane with a small amount of ethyl acetate to give 9 as colorless crystals.
(
Yield: 85%; m.p.: 67±69 C; IR (KBr): ꢃ ˆ 3375, 1736, 1697 cm ; 1H NMR (CDCl3, ꢂ,
ꢀ
� 1
2
00 MHz): 7.34 (1H, t, 5-H; J4;5 ˆ J6;5 ˆ 1.3 Hz), 7.28±7.18 (3H, m, Ph), 7.07±7.03 (2H, m, Ph), 6.27
(
2H, d, 4-H, 6-H; J4;5 ˆ J6;5 ˆ 1.3 Hz), 5.74 (1H, ddt, =CH±), 5.12±5.08 (1H, m, =CH2), 4.65 (1H, t,
CH±N; J4;3 ˆ 7.8 Hz), 4.59 (1H, br s, NH), 4.36 and 4.19 (2H, AB, CH2±N; JA;B ˆ 16.8 Hz), 3.96 and
‡
3
.55 (3H, s, COOMe), 2.70 (2H, m, CH2±C=) ppm; MS: m/z ˆ 369 (M ).
0
0
0
Phenyl-(4 -ꢀ-furyl-1 -butenyl-4 )nitrone (11; C15H15NO2)
To a suspension of 1 (5 mol) and Na2WO4 Á 2H2O (0.25 mol) in acetone (50 ml), 30% H2O2 (20 mol)
was added dropwise. The mixture was stirred at room temperature for 5 h (TLC control) and then
diluted with H2O (100 ml). The organic products were extracted with Et2O (4Â50 ml) and puri®ed
on a chromatographic column (Al2O3, hexane/ethyl acetate, 10:1). The residue was crystallized from
hexane and afforded 11 as colorless crystals.
Yield: 43%; m.p.: 91±92 C; IR (KBr): ꢃ ˆ 1644, 1579, 1565, 1155, 930 cm ; 1H NMR (CDCl3,
ꢀ
� 1
ꢂ, 200 MHz): 8.22 (2H, m, o-Ph), 7.43±7.35 (3H, m, Ph), 7.43 (2H, d, ꢀ-Fu), 7.41 (1H, s, HC=N),
0
6
.41 (4H, d, ꢁ,ꢁ -Fu), 5.79 (1H, ddt, =CH±), 5.23±5.11 (2H, m, =CH2), 5.05 (1H, t, CH±Fu), 3.25
‡
(
2H, ddd, CH2±C=) ppm; MS: m/z ˆ 241 (M ).

676
V. Kouznetsov et al.
Preparation of 3-(4-ethoxyphenyl)-2-hetaryl-4-thiazolidinones 12±19
To a solution of the Schiff bases derived from quinolinecarboxaldehydes (0.01 mol) in 15 ml dry
benzene, thioglicolic acid or thiolactic acid (0.01 mol) was added. The mixture was re¯uxed on a
water bath for 8 h, then cooled and poured into water. The upper organic layer was washed with
NaHCO3 solution (15 ml, 10%) and then with H2O, dried (Na2SO4), and the benzene was distilled
ꢀ
off. Upon crystallization of the residue from petroleum ether (40±60 C)/ethanol (1:1), the
thiazolidinones were obtained as yellow crystals (exceptions: 18 and 19).
3-(4-Ethoxyphenyl)-2-(2-quinolinyl)-4-thiazolidinone (12; C20H18N2O2S)
ꢀ
� 1
1
Yield: 89%; m.p.: 114 C; IR (KBr): ꢃ ˆ 1660 cm ; H NMR (CDCl3, ꢂ, 200 MHz): 6.70±8.20
(
10H, m, ArH), 6.20 (1H, s, CH), 4.10 (2H, d, CH2), 3.80 (2H, q, OCH2CH3), 1.30 (3H, q,
‡
OCH2CH3) ppm; MS: m/z ˆ 350 (M ).
3-(4-Ethoxyphenyl)-5-methyl-2-(2-quinolinyl)-4-thiazolidinone (13; C21H20N2O2S)
ꢀ
� 1
1
Yield: 78%; m.p.: 126 C; IR (KBr): ꢃ ˆ 1660 cm ; H NMR (CDCl3, ꢂ, 200 MHz): 6.70±8.20
(
10H, m, ArH), 6.20 (1H, s, CH), 4.20 (2H, q, OCH2CH3), 3.80 (1H, q, CHCH3), 1.60 (3H, d,
‡
CHCH3), 1.30 (3H, q, OCH2CH3) ppm; MS: m/z ˆ 364 (M ).
3-(4-Ethoxyphenyl)-2-(6-methyl-2-quinolinyl)-4-thiazolidinone (14; C21H20N2O2S)
Yield: 72%; m.p.: 117 C; IR (KBr): ꢃ ˆ 1665 cm ; 1H NMR (CDCl3, ꢂ, 200 MHz): 6.69±8.07 (9H,
ꢀ
� 1
m, ArH), 6.23 (1H, s, CH), 4.06 (2H, d, CH2), 3.70 (2H, q, OCH2CH3), 2.50 (3H, s, CH3), 1.33 (3H,
‡
q, OCH2CH3) ppm; MS: m/z ˆ 364 (M ).
3-(4-Ethoxyphenyl)-5-methyl-2-(6-methyl-2-quinolinyl)-4-thiazolidinone (15; C22H22N2O2S)
Yield: 68%; m.p.: 93 C; IR (KBr): ꢃ ˆ 1660 cm ; 1H NMR (CDCl3, ꢂ, 200 MHz): 6.70±7.60 (9H,
ꢀ
� 1
m, ArH), 6.15 (1H, s, CH), 4.20 (2H, q, OCH2CH3), 3.80 (1H, q, CHCH3), 2.50 (3H, s, CH3), 1.60
‡
(
3H, d, CHCH3), 1.30 (3H, q, OCH2CH3) ppm; MS: m/z ˆ 378 (M ).
3-(4-Ethoxyphenyl)-2-(4-quinolinyl)-4-thiazolidinone (16; C20H18N2O2S)
ꢀ
� 1
1
Yield: 92%; m.p.: 118 C; IR (KBr): ꢃ ˆ 1665 cm ; H NMR (CDCl3, ꢂ, 200 MHz): 6.72±8.87
(
11H, m, ArH and CH), 4.01 (2H, d, CH2), 3.80 (2H, q, OCH2CH3), 1.25 (3H, q, OCH2CH3) ppm;
MS: m/z ˆ 350 (M‡).
3-(4-Ethoxyphenyl)-5-methyl-2-(4-quinolinyl)-4-thiazolidinone (17; C21H20N2O2S)
ꢀ
� 1
1
Yield: 84%; m.p.: 142 C; IR (KBr): ꢃ ˆ 1660 cm ; H NMR (CDCl3, ꢂ, 200 MHz): 6.60±8.80
(
11H, m, ArH and CH), 4.20 (2H, q, OCH2CH3), 3.92 (1H, q, CHCH3), 1.70 (3H, d, CHCH3), 1.30
‡
(
3H, q, OCH2CH3) ppm; MS: m/z ˆ 364 (M ).
3-(4-Ethoxyphenyl)-2-(8-quinolinyl)-4-thiazolidinone (18; C20H18N2O2S)
ꢀ
� 1
1
Yield: 92%; m.p.: 127 C; IR (KBr): ꢃ ˆ 1660 cm ; H NMR (CDCl3, ꢂ, 200 MHz): 6.72±8.96
(
11H, m, ArH and CH), 4.02 (2H, d, CH2), 3.77 (2H, q, OCH2CH3), 1.20 (3H, q, OCH2CH3) ppm;
MS: m/z ˆ 350 (M‡).

Reactions of Aldimines
-(4-Ethoxyphenyl)-5-methyl-2-(8-quinolinyl)-4-thiazolidinone (19; C21H20N2O2S)
677
3
ꢀ
� 1
1
Yield: 85%; m.p.: 134 C; IR (KBr): ꢃ ˆ 1660 cm ; H NMR (CDCl3, ꢂ, 200 MHz): 6.60±8.90
(
11H, m, ArH and CH), 4.20 (2H, q, OCH2CH3), 3.85 (1H, q CHCH3), 1.70 (3H, d, CHCH3), 1.30
‡
(
3H, q, OCH2CH3) ppm; MS: m/z ˆ 364 (M ).
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Received January 12, 1998. Accepted (revised) February 28, 1998