Synthesis and reactions of 4-oxiranylmethylfuro-[3,2-b]pyrroles and their benzo derivatives

Article abstract of DOI:10.1023/A:1014557226260

Methyl 4-oxiranylmethyl-4H-furo[3,2-b]pyrrole-5-carboxylates 2a-c and methyl 1-oxiranylmethyl-1H-benzo[4,5]furo[3,2-b]pyrrole-2-carboxylate (2d) were prepared by reaction of the appropriate starting compounds 1a-d with excess chloromethyloxirane. The compounds 2a-d undergo oxirane ring opening by heterocyclic amines (morpholine, pyrrolidine, piperidine or 4-methylpiperazine) giving N-2-hydroxy-3-heteroaminopropyl-substituted compounds 3a-f or substituted 4,5-dihydrofuro[2′,3′:4,5]pyrrolo-[2,1-c][1,4]oxazin-8-ones 4a-e.

Full text of DOI:10.1023/A:1014557226260

Chemistry of Heterocyclic Compounds, Vol. 37, No. 12, 2001
SYNTHESIS AND REACTIONS
OF 4-OXIRANYLMETHYLFURO-
b
[3,2- ]PYRROLES AND THEIR
BENZO DERIVATIVES*
A. Krutosikova, L. Krystofova-Labudova, and M. Dandarova
2a c
Methyl 4-oxiranylmethyl-4H-furo[3,2-b]pyrrole-5-carboxylates - and methyl 1-oxiranylmethyl-1H-
2d
benzo[4,5]furo[3,2-b]pyrrole-2-carboxylate ( ) were prepared by reaction of the appropriate starting
1a d
2a d
compounds - with excess chloromethyloxirane. The compounds - undergo oxirane ring opening
by heterocyclic amines (morpholine, pyrrolidine, piperidine or 4-methylpiperazine) giving N-2-hydroxy-
3a f
or substituted 4,5-dihydrofuro[2',3':4,5]pyrrolo-
3-heteroaminopropyl-substituted compounds
4a e
-
[2,1-c][1,4]oxazin-8-ones - .
Keywords: benzo[4,5]furo[3,2-b]pyrroles, furo[3,2-b]pyrroles, furo[2',3':4,5]pyrrolo[2,1-c][1,4]-
oxazines, oxirane ring opening.
Investigations of indole isosters (furopyrroles, thienopyrroles), in which the benzene ring is replaced by
the furan or thiophene ring, resulted in the discovery of many biologically active compounds [1]. Therefore,
efficient synthetic routes to these types of heterocycles are of great interest [1]. In continuation of our program
aimed at developing efficient syntheses of fused oxygen-nitrogen containing heterocycles we have reported the
use of substituted furo[3,2-b] and furo[2,3-b]pyrroles in organic synthesis [2-9]. In our previous studies [7],
comparing the course of Diels–Alder reactions of furo[3,2-b]pyrroles with their [2,3-b] isomers, we concluded
that the [2,3-b] system is a more reactive diene than its [3,2-b] isomer. This observation is supported by high-
level ab initio calculations [9]. We have also reported [8] the results of the use of substituted furo[3,2-b]pyrrole
and furo[2,3-b]pyrrole-type aldehydes in the synthesis [8]. Both systems with a formyl substituent at C(2) are
comparable in their reactivity. The aim of this study was to synthesize some new 4-(2-oxiranylmethyl)furo-
[3,2-b]pyrroles 2a-c and their benzo derivatives 2d and to follow up their reactions with heterocyclic amines.
An excess of chloromethyloxirane gave with 1a-d [2, 3], under catalysis by trimethylbenzylammonium
hydroxide, the compounds 2a-d. We have used the procedure which was described in detail by Rybar and his
co-workers [10-13]. Transformation of 2a-d into the final 3 or 4 was effected by opening of the oxirane ring
with the appropriate heterocyclic amines – morpholine, pyrrolidine, piperidine, or 4-methylpiperazine
(Scheme 1).
_______
* Dedicated to Prof. Dr. Edmunds Lukevics in honor of his 65th birthday.
__________________________________________________________________________________________
Department of Chemistry, Faculty of Natural Sciences, University of St. Cyril and Methodius,
SK-917 01 Trnava, Slovak Republic, e-mail: krutosik@ucm.sk. Department of Organic Chemistry, Slovak
University of Technology, Radlinskeho-9, SK-81237 Bratislava, Slovak Republic. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 12, pp. 1664-1669, December, 2001. Original article submitted October 4,
2001.
0009-3122/01/3712-1511$25.00©2001 Plenum Publishing Corporation
1511

Scheme 1
O
9
7
8
H
N
1
1
O
R
R
4
N
CH Cl
CO CH
CO CH
2
2
3
2
3
3
5
R
R
6
O
2 O
1
2
1
HNu
Nu
Nu
10
9
8
6
7
5
4 N
7
O
OH
CO CH
1
1
R
R
4 N
2
3
3
3
8
O
5
9
R
R
6
2
2
O
O
3
4
1, 2 a R = R1 = H; b R = R1 = Me; c R = Ph, R1 = H; d R+R1 = –CH=CH–CH=CH–.
3 a R = R1 = H, Nu = morpholin-1-yl; b R = R1 = Me, Nu = morpholin-1-yl;
c R = Ph, R1 = H, Nu = piperidin-1-yl; d R = R1 = H, Nu = piperidin-1-yl; e R = R1 = H, Nu = pyrrolidin-1-yl;
f R = R1 = H, Nu = 4-methylpiperazin-1-yl. 4 a R = R1 = H, Nu = pyrrolidin-1-yl; b R = R1 = H, Nu = 4-methylpiperazin-1-yl;
c R = Ph, R1 = H, Nu = morpholin-1-yl; d R = R1 = H, Nu = pyrrolidin-1-yl; e R = Ph, R1 = H, Nu = 4-methylpiperazin-1-yl
The formation of the compounds 4 is a result of intramolecular reaction of the OH group formed with
the CO2CH3 group present at C(5) of furo[3,2-b]pyrrolo unit under MeOH elimination. It is interesting that the
structure of the starting compound influences the product formation. The compound 2a, which possess free
C(2), gave both types of structures 3a or 4a and 4b depending on the amine. The compound 2c behaves
exceptionally with phenyl substituent at C(2). In this case mainly the compounds 4c-e with the oxazine ring
fused to furo[3,2-b]pyrrolo moiety were obtained. Finally if the positions C(2) and C(3) were occupied, e.g. in
compounds 2b or 2d, only the acyclic products 3b, 3d-f were formed.
Nu
11
O
10
OH
9
8
8
7
7
N
N
CO CH
CO CH
2
3
2
3
6
2
2
6
3
3
5
O
5
O
4
4
3d–f
2d
All the synthesized compounds are stable solids. Their structure has been confirmed by FT IR, UV, and
1H and 13C NMR (using APT and spectroscopic data of 13C, 1H-COSY techniques).
The formation of cyclic products 4a-e was confirmed by the absence of signals of CO2CH3 groups in
their 1H and 13C NMR spectra, which on the other hand were identified in all acyclic compounds 3a-f. In the IR
spectra of acyclic compounds the OH group exhibited characteristic broad bands at 3130-3425 cm-1.
1512

EXPERIMENTAL
Melting points were determined on a Kofler hot plate apparatus and are uncorrected. Samples for
analysis were dried over P4O10 at 60°C and 30 Pa for 8-10 h. UV spectra of dioxane solutions (λmax (log );
ε λmax
in nm, in m2·mol-1) were taken on a Specord UV-vis M-40 (Zeiss, Jena) instrument. Infrared spectra were
ε
recorded on a Philips FTIR PU 9802/25 spectrophotometer with only major absorbances being quoted. Unless
1
otherwise stated, IR spectra were measured using KBr pellets (0.5 mg/300 mg KBr). NMR H (300 MHz) and
13C (75.43 MHz) spectra were recorded at ambient temperatures using a Varian VXR-300 spectrometer with
TMS as an internal reference in CDCl3. Chemical shifts are given in ppm ( -scale), coupling constants (J) in Hz.
δ
The reported data [3, 14-6] were used for the signal assignment. Elemental analyses were determined using a
Carlo Erba CHNS-OEA 1108-Elemental Analyser. The reaction progress and purity of all prepared compounds
was followed by TLC (Silufol UV254, Kavalier, Votice, Czech Republic) in the system chloroform–methanol 9:1
and spots were visualized using UV lamp or iodine vapor. Solvents were purified according to published
methods. The starting compounds methyl 4H-furo[3,2-b]pyrrole-5-carboxylate (1a) and 2-phenyl-4H-furo-
[3,2-b]pyrrole-5-carboxylate (1c) were prepared according to ref. [3], and methyl 2,3-dimethyl-4H-furo[3,2-b]-
pyrrole-5-carboxylate (1b) and methyl 1H-benzo[4,5]furo[3,2-b]pyrrole-2-carboxylate (1d) according to ref. [2].
b
A suspension of
Methyl 4-Oxiranylmethyl-4H-furo[3,2- ]pyrrole-5-carboxylate (2a).
1a
(4 g,
24 mmol) in freshly distilled 2-chloromethyloxirane (100 ml) and trimethylbenzylammonium hydroxide
(0.15 ml, 40% ethanolic solution) was mixed and refluxed (6 h), cooled, filtered, and evaporated in vacuo, and
the dark residue was crystallized from methanol. Yield 5.2 g (52%); mp 76-77°C (methanol). Found, %:
C 59.62; H 5.21; N 6.28. C11H11NO4 (221.21). Calculated, %: C 59.73; H 5.01; N 6.33. UV (dioxane), λmax, nm
1
(log ): 297 (3.48), 356 (2.39). NMR H (CDCl3), , ppm, J (Hz): 7.50 (1H, d, J2,3 = 2.2, H-2); 6.51 (1H, dd,
ε
δ
J
2,3 = 2.2, J3,6 = 0.7, H-3); 6.48 (1H, d, J3,6 = 0.7, H-6); 5.00 (1H, dd, J7d,7e = 14.7, J7d,8c = 2.9, H-7d); 4.29 (1H,
dd, J7d,7e = 14.7, J7e,8c = 5.6, H-7e); 3.83 (3H, s, COOCH3); 3.35 (1H, m, H-8c); 2.80 (1H, t, J9a,9b = 4.7,
13
J
9b,8c = 4.7, H-9b); 2.51 (1H, dd, J9a,9b = 4.7, J9a,8c = 2.5, H-9a). NMR C (CDCl3), , ppm: 162.45 (COOCH3);
δ
148.66 (C(2)); 145.76 (C(6a)); 133.72 (C(3a)); 122.96 (C(5)); 98.99 (C(3)); 98.87 (C(6)); 51.34 (COOCH3); 51.12
(C(8)); 48.99 (C(7)); 45.14 (C(9)).
The compounds 2b-d were prepared similarly starting from 1b-d.
b
Yield 69%;
Methyl 2,3-Dimethyl-4-oxiranylmethyl-4H-furo[3,2- ]pyrrole-5-carboxylate (2b).
mp 95°C (methanol). Found, %: C 62.75, H 6.23, N 5.58. C13H15NO4 (249.26). Calculated, %: C 62.64, H 6.07,
1
N 5.62. UV (dioxane), λmax, nm (log ): 312 (3.54), 356 (2.35). NMR H (CDCl3), , ppm, J (Hz): 6.73 (1H, s,
ε
δ
H-6); 4.90 (1H, dd, J7d,7e = 14.8, J7e,8c = 2.7, H-7d); 4.43 (1H, dd, J7d,7e = 14.8, J7e,8c = 5.2, H-7e); 3.80 (3H, s,
COOCH3); 3.33 (1H, m, H-8c); 2.77 (1H, t, J9a,9b = 4.7, J9b,8c = 4.5, H-9b); 2.42 (1H, dd, J9a,9b = 4.7, J9a,8c = 2.6,
13
H-9a); 2.30 (3H, s, C(2)–CH3); 2.14 (3H, s, C(3)–CH3). NMR C (CDCl3), , ppm: 162.51 (COOCH3); 155.26
δ
(C(2)); 143.58 (C(6a)); 135.32 (C(3a)); 120.85 (C(5)); 103.89 (C(3)); 98.66 (C(6)); 51.69 (COOCH3); 50.87 (C(8));
47.47 (C(7)); 45.10 (C(9)); 12.45 (C(2)–CH3); 8.33 (C(3)–CH3).
b
Yield 79%;
Methyl 4-Oxiranylmethyl-2-phenyl-4H-furo[3,2- ]pyrrole-5-carboxylate (2c).
mp 103-104°C (methanol). Found, %: C 68.78, H 5.22, N 4.81. C17H15NO4 (297.31). Calculated, %: C 68.68;
1
H 5.09; N 4.71. UV (dioxane), λmax, nm (log ): 336 (3.69). NMR H (CDCl3), , ppm, J (Hz): 7.70 (2H, m,
ε
δ
o-Ph); 7.37 (2H, m, m-Ph); 7.26 (1H, m, p-Ph); 6.85 (1H, d, J3,6 = 0.9, H-6); 6.77 (1H, d, J3,6 = 0.9, H-3); 4.97
(1H, dd, J7d,7e = 14.7, J7d,8c = 2.7, H-7d); 4.26 (1H, dd, J7d,7e = 14.7, J7e,8c = 5.8, H-7e); 3.82 (3H, s, COOCH3);
3.35 (1H, m, H-8c); 2.81 (1H, t, J9a,9b = 4.7, J9b,8c = 4.7, H-9b); 2.53 (1H, dd, J9a,9b = 4.7, J9a,8c = 2.6, H-9a); NMR
13C (CDCl3), , ppm: 162.26 (COOCH3); 159.94 (C(2)); 145.51 (C(6a)); 135.31 (C(3a)); 130.94 (i-Ph); 128.63
δ
(o-Ph); 127.97 (p-Ph); 124.00 (m-Ph); 122.69 (C(5)); 98.88 (C(6)); 93.56 (C(3)); 51.35 (COOCH3); 51.08 (C(8));
48.97 (C(7)); 45.11 (C(9)).
b
Yield 50%;
Methyl 1-Oxiranylmethyl-1H-benzo[4,5]furo[3,2- ]pyrrole-2-carboxylate (2d).
mp 119-121°C. Found, %: C 66.38, H 4.88, N 5.19. C15H13NO4 (271.27). Calculated, %: C 66.41, H 4.83,
1
N 5.16. UV (dioxane), λmax, nm (log ): 326 (3.54), 361 (2.32). NMR H (CDCl3), , ppm, J (Hz): 7.71-7.27
ε
δ
1513

(4H, m, H-5, H-6, H-7, H-8); 6.89 (1H, s, H-3); 5.09 (1H, dd, J9d,9e = 14.7, J9d,10c = 3.1, H-9d); 4.63 (1H, dd,
J
J
9d,9e = 14.7, J9e,10c = 5.4, H-9e); 3.86 (3H, s, COOCH3); 3.45 (1H, m, H-10c); 2.81 (1H, t, J11a,11b = 4.6,
11b,10c = 4.6, H-11b); 2.57 (1H, dd, J11a,11b = 4.6, J11a,10c = 2.6, H-11a). NMR 13C (CDCl3), , ppm: 162.07
δ
(COOCH3); 160.61 (C(4a)); 147.18 (C(3a)); 128.74 (C(2)); 125.00 (C(6)); 123.48 (C(8b)); 122.76 (C(7)); 118.37 (C(8));
118.14 (C(8a)); 112.58 (C(5)); 99.06 (C(3)); 51.57 (COOCH3); 51.34 (C(10)); 49.17 (C(9)); 45.16 (C(11)).
Reactions of Compounds 2a-d with Heterocyclic Amines (General Procedure). A solution of the
selected amine (morpholine, piperidine, pyrrolidine or 4-methylpiperazine) (30 mmol) and one of the
compounds 2a-d (5 mmol) in methanol (7 ml) was refluxed until the reaction was ceased (TLC-checked). After
evaporation of the amine excess and methanol in vacuum the crude product was purified by column
chromatography (silica gel and CHCl3 as eluent) and crystallized.
H
b
Methyl 4-(2-Hydroxy-3-morpholin-4-yl-propyl)-4 -furo[3,2- ]pyrrole-5-carboxylate (3a).
Yield 79%; mp 132-134°C (methanol). Found, %: C 58.63; H 6.68; N 9.01. C15H20N2O5 (308.33).
Calculated, %: C 58.43%; H 6.54; N 9.09. UV (dioxane), λmax, nm (log ): 298 (3.44); 269 (3.03). IR (KBr),
ε
, cm-1: 1686 (CO); 3130 (OH). NMR H (CDCl3), , ppm, J (Hz): 7.50 (1H, d, J2,3 = 2.3, H-2); 6.83 (1H, d,
1
ν
J
δ
3,6 = 0.9, H-6); 6.53 (1H, dd, J2,3 = 2.2, J3,6 = 0.9, H-3); 4.63 (1H, dd, J7d,7e = 14.1, J7d,8c = 3.4, H-7d); 4.34 (1H,
dd, J7d,7e = 14.1, J7e,8c = 6.6, H-7e); 4.10 (1H, m, H-8c); 3.82 (3H, s, COOCH3); 2.48 (1H, dd, J9a,9b = 12.4,
J
9a,8c = 3.9, H-9a); 2.32 (1H, dd, J9a,9b = 12.4, J9b,8c = 9.9, H-9b); morpholin-4-yl: 3.62 (4H, m, O(CH2)2); 2.50
13
(4H, m, N(CH2)2). NMR C (CDCl3), , ppm: 162.81 (COOCH3); 148.55 (C(2)); 145.65 (C(6a)); 134.37 (C(3a));
δ
122.99 (C(5)); 99.34 (C(3)); 98.96 (C(6)); 67.21 (C(8)); 53.65 (C(7)); 51.18 (COOCH3); 50.93 (C(9)); morpholin-4-yl:
66.93 (O(CH2)2); 61.39 (N(CH2)2).
b
Methyl 4-(2-Hydroxy-3-morpholin-4-yl-propyl)-2,3-dimethyl-4H-furo[3,2- ]pyrrole-5-carboxylate
(3b). Yield 60%; mp 94-95°C (methanol). Found, %: C 60.92; H 7.09; N 8.45. C17H24N2O5 (336.38).
Calculated, %: C 60.70; H 7.19; N 8.33. UV (dioxane), λmax, nm (log ): 312 (3.48); 307 (3.46); 270 (2.87).
ε
IR (KBr), , cm-1: 1688 (CO); 3425 (OH). NMR H (CDCl3), , ppm, J (Hz): 6.70 (1H, s, H-6); 4.61 (1H, dd,
1
ν
δ
J7d,7e = 14.0, J7d,8c = 3.2, H-7d); 4.24 (1H, dd, J7d,7e = 14.0, J7e,8c = 7.5, H-7e); 4.03 (1H, m, H-8c); 3.76 (3H, s,
COOCH3); 2.46 (1H, dd, J9a,9b = 12.4, J9a,8c = 4.2, H-9a); morpholin-4-yl: 3.63 (4H, m, O(CH2)2); 2.59-2.40 (5H,
m, N(CH2)2, H-9b); 2.28 (3H, s, C(2)–CH3); 2.17 (3H, s, C(3)–CH3). NMR 13C (CDCl3), , ppm: 162.73
δ
(COOCH3); 155.08 (C(2)); 143.46 (C(6a)); 135.43 (C(3a)); 120.62 (C(5)); 103.98 (C(3)); 98.55 (C(6)); 67.46 (C(8));
53.61 (C(7)); 50.81 (COOCH3); 50.32 (C(9)); 12.41 (C(2)–CH3); 8.55 (C(3)–CH3); morpholin-4-yl: 66.80
(O(CH2)2); 61.67 (N(CH2)2).
b
Methyl 4-(2-Hydroxy-3-piperidin-1-yl-propyl)-2-phenyl-4H-furo[3,2- ]pyrrole-5-carboxylate (3c).
Yield 58%; mp 117°C (methanol). Found, %: C 69.39; H 6.77; N 7.43. C22H26N2O4 (382.45). Calculated, %:
C 69.09; H 6.85; N 7.32. UV (dioxane), λmax, nm (log ): 354 (3.37); 338 (3.42); 282 (2.51). IR (KBr), , cm-1:
ε
ν
1697 (CO); 3208 (OH). NMR 1H (CDCl3), , ppm, J (Hz): 7.71 (2H, m, o-Ph); 7.37 (2H, m, m-Ph); 7.25 (1H, m,
δ
p-Ph); 6.82 (1H, s, H-6); 6.80 (1H, s, H-3); 4.62 (1H, dd, J7d,7e = 14.1, J7d,8c = 3.3, H-7d); 4.30 (1H, dd,
J
J
7d,7e = 14.1, J7e,8c = 6.6, H-7e); 4.08 (1H, m, H-8c); 3.81 (3H, s, COOCH3); 2.41 (1H, dd, J9a,9b = 12.4,
9a,8c = 3.9, H-9a); 2.25 (1H, dd, J9a,9b = 12.4, J9b,8c = 10.1, H-9b); piperidin-1-yl: 2.53-2.30 (4H, m, N(CH2)2);
1.51-1.40 (6H, m, 3 × CH2). NMR 13C (CDCl3), , ppm: 162.55 (COOCH3); 159.71 (C(2)); 145.42 (C(6a)); 136.02
δ
(C(3a)); 131.16 (i-Ph); 128.63 (o-Ph); 127.85 (p-Ph); 124.00 (m-Ph); 122.70 (C(5)); 98.69 (C(6)); 94.27 (C(3));
67.19 (C(8)); 54.59 (C(7)); 51.10 (C(9)); 51.07 (COOCH3); piperidin-1-yl: 61.52 (N(CH2)2); 26.03 (2 × CH2);
24.17 (CH2).
b
Methyl 1-(2-Hydroxy-3-piperidin-1-yl-propyl)-1H-benzo[4,5]furo[3,2- ]pyrrole-2-carboxylate (3d).
Yield 50%; mp 126-128°C (methanol). Found, %: C 67.55; H 6.64; N 7.88. C20H24N2O4 (356.42).
Calculated, %: C 67.40; H 6.79; N 7.86. UV (dioxane), λmax, nm (log ): 324 (3.53); 318 (3.51); 263 (3.04); 253
ε
δ
(2.78). IR (KBr), , cm-1: 1695 (CO); 3230 (OH). NMR H (CDCl3), , ppm, J (Hz): 7.85; 7.46; 7.25 (1H, 1H,
1
ν
2H, m, H-5, H-6, H-7, H-8); 6.87 (1H, s, H-3); 4.80 (1H, dd, J9d,9e = 14.0, J9d,10c = 3.5, H-9d); 4.54 (1H, dd,
J
J
9d,9e = 14.0, J9e,10c = 7.0, H-9e); 4.13 (1H, m, H-10c); 3.82 (3H, s, COOCH3); 2.47 (1H, dd, J11a,11b = 12.0,
11a,10c = 4.2, H-11a); 2.34 (1H, dd, J11a,11b = 12.0, J11b,10c = 9.3, H-11b); piperidin-1-yl: 2.60-2.23 (4H, m,
1514

N(CH2)2); 1.37 (6H, m, 3 × CH2). NMR 13C (CDCl3), , ppm: 162.34 (COOCH3); 160.64 (C(4a)); 147.04 (C(3a));
δ
129.13 (C(8b)); 124.76 (C(6)); 123.38 (C(2)); 122.49 (C(7)); 119.11 (C(8)); 118.58 (C(8a)); 112.38 (C(5)); 98.76 (C(3));
67.67 (C(10)); 54.67 (C(11)); 51.79 (C(9)); 51.26 (COOCH3); piperidin-1-yl: 61.80 (N(CH2)2); 26.04 (2 × CH2);
24.18 (CH2).
b
Methyl 1-(2-Hydroxy-3-pyrrolidin-1-yl-propyl)-1H-benzo[4,5]furo[3,2- ]pyrrole-2-carboxylate (3e).
Yield 34%; mp 99-104°C (methanol). Found, %: C 66.74; H 6.33; N 8.24. C19H22N2O4 (342.39). Calculated, %:
C 66.65; H 6.48; N 8.18. UV (dioxane), λmax, nm (log ): 325 (3.56); 318 (3.55); 263 (3.07); 253 (3.05).
ε
IR (KBr), , cm-1: 1697 (CO); 3220 (OH). NMR H (CDCl3), , ppm, J (Hz): 7.84; 7.46; 7.25 (1H, 1H, 2H, m,
1
ν
δ
H-5, H-6, H-7, H-8); 6.87 (1H, s, H-3); 4.82 (1H, dd, J9d,9e = 14.0, J9d,10c = 3.5, H-9d); 4.56 (1H, dd, J9d,9e = 14.0,
J9e,10c = 7.0, H-9e); 4.12 (1H, m, H-10c); 3.83 (3H, s, COOCH3); 2.67 (1H, dd, J11a,11b = 12.3, J11a,10c = 4.1,
H-11a); 2.50 (1H, dd, J11a,11b = 12.3, J11b,10c = 9.8, H-11b); pyrrolidin-1-yl: 2.43-2.65 (4H, m, N(CH2)2); 1.70
13
(4H, m, 2 × CH2). NMR C (CDCl3), , ppm: 162.44 (COOCH3); 160.65 (C(4a)); 147.04 (C(3a)); 129.15 (C(8b));
δ
124.79 (C(6)); 123.44 (C(2)); 122.50 (C(7)); 119.13 (C(8)); 118.56 (C(8a)); 112.39 (C(5)); 98.80 (C(3)); 69.68 (C(10));
59.22 (C(11)); 51.89 (C(9)); 51.33 (COOCH3); pyrrolidin-1-yl: 54.12 (N(CH2)2); 23.60 (–CH2–CH2–).
b
Methyl 1-[2-Hydroxy-3-(4-methylpiperazin-1-yl)-propyl)-1H-benzo[4,5]furo[3,2- ]pyrrole-2-
carboxylate (3f). Yield 63%; mp 69-72°C (methanol). Found, %: C 64.49; H 6.71; N 11.17. C20H25N3O4
(371.43). Calculated, %: C 64.67; H 6.78; N 11.31. UV (dioxane), λmax, nm (log ): 325 (3.54); 318 (3.53); 263
ε
(3.05); 253 (3.02). IR (KBr), , cm-1: 1696 (CO); 3240 (OH). NMR 1H (CDCl3), , ppm, J (Hz): 7.85; 7.47; 7.26
ν
δ
(1H, 1H, 2H, m, H-5, H-6, H-7, H-8); 6.89 (1H, s, H-3); 4.82 (1H, dd, J9d,9e = 14.0, J9d,10c = 3.4, H-9d); 4.56 (1H,
dd, J9d,9e = 14.0, J9e,10c = 7.1, H-9e); 4.14 (1H, m, H-10c); 3.83 (3H, s, COOCH3); 2.52 (1H, dd, J11a,11b = 12.4,
J11a,10c = 4.3, H-11a); 2.43 (1H, dd, J11a,11b = 12.4, J11b,10c = 9.4, H-11b); 4-methylpiperazin-1-yl: 2.60 (4H, m,
N(CH2)2), 2.45 (4H, m, N(CH2)2); 2.28 (3H, s, N–CH3). NMR 13C (CDCl3), , ppm: 162.38 (COOCH3); 160.64
δ
(C(4a)); 147.04 (C(3a)); 129.13 (C(8b)); 124.83 (C(6)); 123.40 (C(2)); 122.54 (C(7)); 119.05 (C(8)); 118.54 (C(8a));
112.46 (C(5)); 98.87 (C(3)); 67.79 (C(10)); 53.13 (C(11)); 51.74 (C(9)); 51.33 (COOCH3); 4-methylpiperazin-1-yl:
61.09 (N(CH2)2); 55.07 (N(CH2)2); 45.90 (N–CH3).
c
. Yield 45%;
6-Pyrrolidin-1-ylmethyl-4,5-dihydrofuro[2',3':4,5]pyrrolo[2,1- ][1,4]oxazin-8-one (4a)
mp 128-130°C (methanol). Found, %: C 64.72; H 6.11; N 10.68. C14H16N2O3 (260.29). Calculated, %: C 64.60;
H 6.20; N 10.76. UV (dioxane), λmax, nm (log ): 305 (3.44); 298 (3.42); 270 (3.05). IR (KBr), , cm-1: 1695
ε
ν
(CO); NMR 1H (CDCl3), , ppm, J (Hz): 7.56 (1H, d, J2,3 = 2.2, H-2); 6.92 (1H, d, J3,9 = 0.7, H-9); 6.46 (1H, dd,
δ
J2,3 = 2.2, J3,9 = 0.7, H-3); 4.82 (1H, m, H-6c); 4.32 (1H, dd, J5d,5e = 12.8, J5d,6c = 3.4, H-5d); 4.07 (1H, dd,
J
J
5d,5e = 12.8, J5e,6c = 10.1, H-5e); 2.97 (1H, dd, J10a,10b = 12.8, J10a,6c = 7.6, H-10a); 2.85 (1H, dd, J10a,10b = 12.8,
10b,6c = 5.1, H-10b); pyrrolidin-1-yl: 2.62 (4H, m, N(CH2)2); 1.79 (4H, m, 2 × CH2). NMR 13C (CDCl3), , ppm:
δ
159.21 (C(8)); 149.59 (C(2)); 147.46 (C(9a)); 130.49 (C(3a)); 120.35 (C(8a)); 97.85 (C(3)); 97.45 (C(9)); 76.17 (C(6));
57.11 (C(5)); 45.06 (C10)); pyrrolidin-1-yl: 54.84 (N(CH2)2); 23.58 (–CH2–CH2–).
c
6-(4-Methylpiperazin-1-yl)methyl-5,6-dihydrofuro[2',3':4,5]pyrrolo[2,1- ][1,4]oxazin-8-one (4b).
Yield 62%; mp 163-164°C (methanol). Found, %: C 62.46; H 6.59; N 14.66. C15H19N3O3 (289.33).
Calculated, %: C 62.27; H 6.62; N 14.52. UV (dioxane), λmax, nm (log ): 305 (3.46); 298 (3.45); 270 (3.05).
ε
IR (KBr), , cm-1: 1698 (CO). NMR H (CDCl3), , ppm, J (Hz): 7.54 (1H, d, J2,3 = 2.3, H-2); 6.90 (1H, d,
1
ν
δ
J
J
3,9 = 0.7, H-9); 6.45 (1H, dd, J2,3 = 2.3, J3,9 = 0.7, H-3); 4.81 (1H, m, H-6c); 4.25 (1H, dd, J5d,5e = 12.8,
5d,6c = 3.4, H-5d); 4.04 (1H, dd, J5d,5e = 12.8, J5e,6c = 10.0, H-5e); 2.80 (1H, dd, J10a,10b = 13.2, J10a,6c = 7.1,
H-10a); 2.72 (1H, dd, J10a,10b = 13.2, J10b,6c = 5.1, H-10b); 4-methylpiperazin-1-yl: 2.58 (4H, m, N(CH2)2); 2.42
13
(4H, m, N(CH2)2); 2.28 (3H, s, N–CH3). NMR C (CDCl3), , ppm:159.30 (C(8)); 149.71 (C(2)); 147.51 (C(9a));
δ
130.55 (C(3a)); 120.36 (C(8a)); 97.86 (C(3)); 97.60 (C(9)); 75.45 (C(6)); 59.10 (C(5)); 45.04 (C(10));
4-methylpiperazin-1-yl: 55.01 (N(CH2)2); 54.01 (N(CH2)2); 45.97 (N–CH3).
c
.
6-Morpholin-4-ylmethyl-2-phenyl-5,6-dihydrofuro[2',3':4,5]pyrrolo[2,1- ][1,4]oxazin-8-one (4c)
Yield 64%; mp 169-170°C (methanol). Found, %: C 68.32; H 5.62; N 7.79. C20H20N2O4 (352.38).
Calculated, %: C 68.17; H 5.72; N 7.95. UV (dioxane), λmax, nm (log ): 354 (3.36); 338 (3.40); 280 (2.48).
ε
IR (KBr), , cm-1: 1692 (CO). NMR 1H (CDCl3), , ppm, J (Hz): 7.70 (2H, m, o-Ph); 7.39 (2H, m, m-Ph); 7.30
ν
δ
1515

(1H, m, p-Ph); 6.91 (1H, s, H-9); 6.67 (1H, s, H-3); 4.81 (1H, m, H-6c); 4.29 (1H, dd, J5d,5e = 12.9, J5d,6c = 3.4,
H-5d); 4.04 (1H, dd, J5d,5e = 12.9, J5e,6c = 10.0, H-5e); 2.80 (1H, dd, J10a,10b = 13.4, J10a,6c = 5.1, H-10a); 2.70 (1H,
dd, J10a,10b = 13.4, J10b,6c = 7.0, H-10b); morpholin-4-yl: 3.69 (4H, m, O(CH2)2); 2.55 (4H, m, N(CH2)2). NMR
13C (CDCl3), , ppm: 161.12 (C(8)); 159.06 (C(2)); 147.18 (C(9a)); 132.19 (C(3a)); 130.54 (i-Ph); 128.81 (o-Ph);
δ
128.53 (p-Ph); 124.10 (m-Ph); 119.93 (C(8a)); 97.58 (C(9)); 92.21 (C(3)); 75.08 (C(6)); 59.58 (C(5)); 44.92 (C(10));
morpholin-4-yl: 66.83 (O(CH2)2); 54.41 (N(CH2)2).
c
2-Phenyl-6-pyrrolidin-1-ylmethyl-5,6-dihydrofuro[2',3':4,5]pyrrolo[2,1- ][1,4]oxazin-8-one (4d).
Yield 54%; mp 156-157°C (methanol). Found, %: C 71.55; H 5.83; N 8.39. C20H20N2O3 (336.38).
Calculated, %: C 71.41; H 5.99; N 8.33. UV (dioxane), λmax, nm (log ): 354 (3.37); 338 (3.42); 280 (2.48).
ε
IR (KBr), , cm-1: 1705 (CO). NMR 1H (CDCl3), , ppm, J (Hz): 7.72 (2H, m, o-Ph); 7.40 (2H, m, m-Ph); 7.31
ν
δ
(1H, m, p-Ph); 6.94 (1H, s, H-9); 6.69 (1H, s, H-3); 4.82 (1H, m, H-6c); 4.33 (1H, dd, J5d,5e = 13.0, J5d,6c = 3.3,
H-5d); 4.07 (1H, dd, J5d,5e = 13.0, J5e,6c = 10.3, H-5e); 2.98 (1H, dd, J10a,10b = 12.8, J10a,6c = 5.0, H-10a); 2.86 (1H,
dd, J10a,10b = 12.8, J10b,6c = 7.7, H-10b); pyrrolidin-1-yl: 2.63 (4H, m, N(CH2)2); 1.80 (4H, m, 2 × CH2). NMR 13C
(CDCl3), , ppm: 160.95 (C(8)); 159.14 (C(2)); 147.15 (C(9a)); 132.08 (C(3a)); 130.55 (i-Ph); 128.72 (o-Ph); 128.40
δ
(p-Ph); 124.12 (m-Ph); 120.00 (C(8a)); 97.42 (C(9)); 92.21 (C(3)); 76.04 (C(6)); 57.09 (C(5)); 45.00 (C(10));
pyrrolidin-1-yl: 54.84 (N(CH2)2); 23.58 (–CH2–CH2–).
c
6-(4-Methylpiperazin-1-yl)methyl-2-phenyl-5,6-dihydrofuro[2',3':4,5]pyrrolo[2,1- ][1,4]oxazin-8-one
(4e). Yield 42%; mp 189-190°C (methanol). Found, %: C 69.18; H 6.31; N 11.57. C21H23N3O3 (365.43).
Calculated, %: C 69.02; H 6.34; N 11.50. UV (dioxane), λmax, nm (log ): 354 (3.36); 338 (3.40); 280 (2.45).
ε
IR (KBr), , cm-1: 1705 (CO). NMR 1H (CDCl3), , ppm, J (Hz): 7.71 (2H, m, o-Ph); 7.40 (2H, m, m-Ph); 7.30
ν
δ
(1H, m, p-Ph); 6.92 (1H, s, H-9); 6.67 (1H, s, H-3); 4.81 (1H, m, H-6c); 4.27 (1H, dd, J5d,5e = 12.9, J5d,6c = 3.4,
H-5d); 4.02 (1H, dd, J5d,5e = 12.9, J5e,6c = 10.1, H-5e); 2.82 (1H, dd, J10a,10b = 13.3, J10a,6c = 5.0, H-10a); 2.72 (1H,
dd, J10a,10b = 13.3, J10b,6c = 7.1, H-10b); 4-methylpiperazin-1-yl: 2.60 (4H, m, N(CH2)2), 2.45 (4H, m, N(CH2)2),
2.28 (3H, s, N–CH3). NMR 13C (CDCl3), , ppm: 160.97 (C(8)); 159.11 (C(2)); 147.11 (C(9a)); 132.10 (C(3a));
δ
130.50 (i-Ph); 128.75 (o-Ph); 128.44 (p-Ph); 124.11 (m-Ph); 119.93 (C(8)); 97.40 (C(9)); 92.22 (C(3)); 75.27 (C(6));
59.03 (C(5)); 44.91 (C(10)); 4-methylpiperazin-1-syl: 55.02 (N(CH2)2); 54.01 (N(CH2)2); 45.97 (N–CH3).
Acknowledgments: The Grant Agency of the Slovak Ministry of Education (Bratislava) supported this
study (project No. 1/6249/99), which is gratefully acknowledged.
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