Regioselective synthesis of the 5,6-dihydro-4H-furo[2,3-c]pyrrol-4-one skeleton: A new class of compounds

Article abstract of DOI:10.1002/hlca.200900448

We hereby report the first preparation of the 5,6-dihydro-4H-furo[2,3-c] pyrrol-4-one (3) and its derivatives starting from methyl 3-(methoxycarbonyl) furan-2-acetate (8). The ester functionality connected to the methylene group was regiospecifically conv

Full text of DOI:10.1002/hlca.200900448

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Regioselective Synthesis of the 5,6-Dihydro-4H-furo[2,3-c]pyrrol-4-one
Skeleton: A New Class of Compounds
by Gani Kozaa)b), Emrah Karahana), and Metin Balci*a)
a) Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
b) Department of Chemistry, Ahi Evran University, 40100 Kırs¸ehir, Turkey
(fax: þ 90-312-2103200; e-mail: mbalci@metu.edu.tr)
We hereby report the first preparation of the 5,6-dihydro-4H-furo[2,3-c]pyrrol-4-one (3) and its
derivatives starting from methyl 3-(methoxycarbonyl)furan-2-acetate (8). The ester functionality
connected to the methylene group was regiospecifically converted to the desired monohydrazide 9.
Conversion of 9 into the acyl azide 10 followed by Curtius rearrangement gave the corresponding
isocyanate derivative 11 (Scheme 2). Reaction of 11 with different nucleophiles produced urethane and
urea derivatives (Scheme 3). Intramolecular cyclization reactions provided the target compounds
(Scheme 5). Removal of the amine-protecting group formed the title compound 3.
Introduction. – Isoindolinone (¼2,3-dihydro-1H-isoindol-1-one; 1) derivatives
show a wide range of important biological activities. A series of isoindolinone
derivatives have recently been synthesized and screened. Some substituted isoindo-
linone derivatives have quite potent metabotropic glutamate receptor 1 antagonist
activity [1]. Moreover, it has been demonstrated that some derivatives show an
antipsychotic-like effect in an animal model.
Furthermore, it has been shown that the isoindolinone derivative 2 [2], having a 1-
azabicyclo[2.2.2]octane unit, can bind nicotinic acetylcholine receptors in the treatment
of a range of disorders [3], and furopyrrolone derivatives (such as 4) are claimed to be
useful in the treatment of psychotic disorders or intellectual impairment disorders
including Alzheimerꢀs disease [2].
Recently, Zhu et al. [4] developed a four-component synthesis of furopyrrolones on
the basis of the unique reactivity of methyl a-isocyano-4-nitrobenzeneacetate (5)
(Scheme 1). A three-component reaction of 5 with an aldehyde and amine gave the
corresponding methoxyoxazole derivative 6. The reaction of oxazole 6 with prop-2-
ynoyl chloride produced the furopyrrolone 7 [4]. This methodology is useful for the
synthesis of furopyrrolidone derivatives substituted at certain positions. Therefore, an
efficient method for the preparation of the unknown parent compound 3 would be of
ꢁ 2010 Verlag Helvetica Chimica Acta AG, Zꢂrich

Helvetica Chimica Acta – Vol. 93 (2010)
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Scheme 1
interest. In this article, we describe a method for the synthesis of 3, which may also be
applied for the synthesis of specifically substituted derivatives of 3.
Results and Discussion. – Our plan for the construction of the desired heterocyclic
ring system 3 involved an intramolecular cyclization reaction of the isocyanate 11,
which can be generated by Curtius rearrangement [5] of the corresponding acyl azide
10. The most general and versatile synthesis of acyl azides involves the reaction of acyl
chlorides with NaN3 in an aqueous medium. Problems associated with this method and
others turned our attention to the generation of acyl azides via acyl hydrazides. The
starting diester 8 was synthesized by treatment of dimethyl 3-oxopropanedioate with
chloroacetaldehyde in the presence of pyridine as described in [6].
Recently, we have reported that diester 8 was successfully converted to the
corresponding dihydrazide by refluxing in MeOH [7]. However, we noted that the
reactivity of the ester carbonyl groups of 8 is different. The ester functionality
connected to the CH2 group is more reactive than the other. Therefore, for regiospecific
hydrazide formation, the diester 8 was treated with hydrazine at room temperature for
18 h. The desired monohydrazide derivative 9 was formed in 80% yield (Scheme 2).
The hydrazide derivative 9 was treated with NaNO2 and HCl at low temperature to give
monoazide derivative 10 in 82% yield. Finally, 10 was refluxed in benzene for 1 h to
give the corresponding isocyanate derivative 11 in high yield.
Scheme 2. Synthesis of Isocyanate 11
Isocyanate derivative 11 was chosen as a model to explore further reactions, e.g., the
isocyanate can be trapped by a variety of nucleophiles. Treatment of 11 in benzene with
MeOH at 408 for 1 h gave the urethane derivative 12 in 81% yield (Scheme 3). When

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Scheme 3. Reaction of Isocyanate 11 with Various Nucleophiles
t
the reaction was carried out in the presence of BuOH at reflux temperature, Boc-
protected amine derivative 13 was generated, which is a useful intermediate [8] in
organic synthesis. The urea derivative 14 was obtained from 11 in 95% yield after
treatment with aniline in benzene.
At first, the hydrolysis of isocyanate derivative 11 was carried out to synthesize the
amine derivative 15 and to study its cyclization. Treatment of 11 with 8m HCl at room
temperature gave 15 in 73% yield (Scheme 4). However, all efforts to convert 15 into
the target compound 3 failed. Therefore, we turned our attention to the synthesis of the
carboxylic acids 16 – 18.
Scheme 4. Synthesis of Methyl 2-(Aminomethyl)furan-3-carboxylate (15)
To increase the reactivity of the ester C¼O groups in 12 – 14, which is necessary for
the cyclization reaction, the ester functionalities in 12 – 14 should be converted into acyl
chlorides 19 – 21. The ester derivatives 12 – 14 were first hydrolyzed to the correspond-
ing acids 16 – 18 by treatment with 1m NaOH in dioxane/H2O at room temperature for
2 h (Scheme 5). The acids 16 – 18 were then treated with SOCl2 in THF or benzene at
758. The acyl chlorides 19 – 21 were obtained in high yields. For the ring-closing
reaction, acyl chlorides 19 – 21 were refluxed in benzene or THF to give the desired 5,6-
dihydro-4H-furo[2,3-c]pyrrol-4-one derivatives 22 – 24 in high yields.
Finally, hydrolysis of the cyclization product 23 with CF3COOH in CH2Cl2 at 08
gave the target compound 5,6-dihydro-4H-furo[2,3-c]pyrrol-4-one (3) in 66% yield.
The spectral data of 3 were fully in accord with the proposed structure.
Conclusions. – The presented results establish that cyclization of acyl azides is a
valuable method for the synthesis of heterocyclic compounds with new skeletons.
Furthermore, controlling the number of the CH2 groups separating the ester

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Scheme 5. Synthesis of Substituted Furopyrrolone Derivatives 22 – 24 Starting from 12 – 14 and
Hydrolysis to the Target Compound, Dihydrofuropyrrolone 3
functionalities from the furan ring will be a useful approach for the synthesis of six- and
seven-membered heterocycles fused to a furan ring [9].
The authors are indebted to the Scientific and Technological Research Council of Turkey
(TUBITAK, Grant 108-M168), the Department of Chemistry at Middle East Technical University,
and the Turkish Academy of Sciences (TUBA) for their financial support of this work. G. K. thanks
TUBITAK for a postdoctoral fellowship.
Experimental Part
General. TLC: anal. aluminium plates coated with SiO2 60 F254 (0.2 mm, Merck). Column
chromatography (CC): silica gel (SiO2; 60 mesh; Merck). M.p.: Gallenkamp; uncorrected. IR Spectra:
FT-IR Bruker-Vertex-70 instrument; ATR ¼ attenuated total reflectance; soln. in 0.1 mm cells or KBr
1
pellets; ˜n in cmꢀ1. H- and 13C-NMR Spectra: Bruker-BioSpin (DPX-400) instrument; d in ppm rel. to
Me4Si as internal standard, J in Hz; apparent splitting is given in all cases.
Methyl 2-(2-Hydrazinyl-2-oxoethyl)furan-3-carboxylate (9). To a stirred soln. of diester 8 (10.0 g,
50.5 mmol) in MeOH (100 ml) at 08 was added hydrazine monohydrate (7.4 ml, 151.5 mmol) followed by
stirring without removing the ice bath for 18 h. The solvent was evaporated and the crude product
purified by extraction with CHCl3 (200 ml) and H2O (40 ml). The aq. layer was re-extracted with CHCl3
(2 ꢁ 70 ml) and the combined org. extract washed with H2O (40 ml), dried (MgSO4), and concentrated: 9
(8.0 g, 80%). White solid. M.p. 143 – 1448. IR (KBr): 3301, 1712, 1644, 1540, 1439, 1312, 1205, 1068, 755.
1H-NMR (400 MHz, (D)6DMSO): 9.03 (br. s, NH); 7.45 (d, J ¼ 2.0, ¼CH); 6.48 (d, J ¼ 2.0, ¼CH); 4.24
(br. s, NH2); 3.60 (s, CH2); 3.53 (s, MeO). 13C-NMR (100.6 MHz, (D6)DMSO): 166.4; 163.3; 155.9; 142.4;
114.4; 110.3; 51.4; 32.7. Anal. calc. for C8H10N2O4 (198.18): C 48.48, H 5.09, N 14.14; found: C 48.51, H
5.05, N 14.12.
Methyl 2-(2-Azido-2-oxoethyl)furan-3-carboxylate (10). To a stirred soln. of 9 (2.5 g, 12.6 mmol) in
1m aq. HCl (40 ml) at 08 was added dropwise a soln. of NaNO2 (0.91 g, 13.3 mmol) in H2O (10 ml)
followed by stirring at 0 – 58 for 30 min. The mixture was extracted with Et2O (2 ꢁ 60 ml) and the
combined org. phase washed with sat. aq. Na2CO3 soln. (40 ml) and then brine (30 ml), dried (MgSO4),
and concentrated: 10 (2.16 g, 82%). Colorless oil. IR (KBr): 2956, 2143, 1718, 1613, 1443, 1315, 1205,
1
1158, 1034. H-NMR (400 MHz, CDCl3): 7.29 (d, J ¼ 2.0, ¼CH); 6.64 (d, J ¼ 2.0, ¼CH); 4.02 (s, CH2);
3.77 (s, MeO). 13C-NMR (100.6 MHz, CDCl3,): 175.3; 163.7; 153.1; 142.2; 116.1; 110.8; 51.6; 35.7.
Methyl 2-(Isocyanatomethyl)furan-3-carboxylate (11). A soln. of 10 (2.1 g, 10.0 mmol) in dry
benzene (30 ml) was heated under reflux for 1 h. The solvent was evaporated: 11 (1.72 g, 95%). Colorless

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Helvetica Chimica Acta – Vol. 93 (2010)
oil. IR (KBr): 2956, 2258, 1720, 1612, 1515, 1414, 1312, 1081. 1H-NMR (400 MHz, CDCl3): 7.32 (d, J ¼ 2.0,
¼CH); 6.64 (d, J ¼ 2.0, ¼CH); 4.67 (s, CH2); 3.80 (s, MeO). 13C-NMR (100.6 MHz, CDCl3): 163.3; 155.1;
142.3; 125.3; 115.1; 111.0; 51.8; 38.6.
Methyl 2-{[(Methoxycarbonyl)amino]methyl}furan-3-carboxylate (12). To a stirred soln. of 11
(0.42 g, 2.3 mmol) in dry benzene (20 ml) at 408 was added MeOH (0.6 ml, 14.7 mmol) and stirred for 1 h.
The solvent was evaporated to give the crude product which was then purified by CC (SiO2; AcOEt/
hexane 2 :1): 12 (0.4 g, 81%). White solid. M.p. 60 – 628. IR (ATR): 3338, 3150, 2938, 1694, 1601, 1540,
1433, 1353, 1310, 1260, 1199, 1144, 1087. 1H-NMR (400 MHz, CDCl3): 7.33 (d, J ¼ 1.8, ¼CH); 6.69 (d, J ¼
1.8, ¼CH); 5.51 (br. s, NH); 4.68 (d, J ¼ 6.1, CH2); 3.87 (s, MeO); 3.71 (s, MeO). 13C-NMR (100.6 MHz,
CDCl3): 164.0; 158.1; 156.9; 141.5; 114.7; 110.8; 52.3; 51.7; 37.5. Anal. calc. for C9H11NO5 (213.19): C
50.70, H 5.20, N 6.57; found: C 50.75, H 5.13, N 6.59.
Methyl 2-{{[(tert-Butoxycarbonyl]amino}methyl}furan-3-carboxylate (13). To a stirred soln. of 11
(2.81 g, 15.5 mmol) in dry benzene (40 ml) was added excess tBuOH (25 ml), followed by heating under
reflux for 2 d. The solvent and excess tBuOH were evaporated: 13 (3.2 g, 92%). White solid. M.p. 93 –
958. IR (ATR): 3360, 3155, 2996, 1716, 1687, 1604, 1524, 1432, 1405, 1315, 1266, 1251, 1199, 1164, 1126,
1088, 1034. 1H-NMR (400 MHz, CDCl3): 7.23 (d, J ¼ 1.9, ¼CH); 6.59 (d, J ¼ 1.9, ¼CH); 5.19 (br. s, NH);
4.53 (d, J ¼ 5.6, CH2); 3.78 (s, MeO); 1.37 (s, tBu). 13C-NMR (100.6 MHz, CDCl3,): 165.0; 159.3; 156.5;
142.3; 115.4; 111.7; 80.7; 52.6; 38.0; 29.3. Anal. calc. for C12H17NO5 (255.27): C 56.46, H 6.71, N 5.49;
found: C 56.56, H 6.80, N 5.56.
Methyl 2-{{[(Phenylamino)carbonyl]amino}methyl}furan-3-carboxylate (14). To a stirred soln. of 11
(1.7 g, 9.4 mmol) in dry benzene (25 ml) at r.t. was added aniline (1.2 ml, 13.3 mmol), and the resulting
mixture was stirred for 5 min. The precipitate was filtered and washed with a mixture of hexane (30 ml)
and CH2Cl2 (25 ml): 14 (2.45 g, 95%). White solid. M.p. 153 – 1548. IR (ATR): 3305, 3155, 2955, 1709,
1636, 1597, 1568, 1519, 1498, 1313, 1241, 1196, 1130, 1088. 1H-NMR (400 MHz, CDCl3): 7.24 (d, J ¼ 2.0,
¼CH); 7.19 – 7.29 (m, 4 H, ¼CH); 7.00 (tt, J ¼ 7.2, 1.4, ¼CH); 6.72 (br. s, NH); 6.58 (d, J ¼ 2.0, ¼CH);
5.56 (br. t, J ¼ 6.4, NH); 4.64 (d, J ¼ 6.4, CH2); 3.77 (s, MeO). 13C-NMR (100.6 MHz, CDCl3): 164.6;
158.8; 155.7; 141.6; 138.6; 129.1; 123.6; 120.7; 114.5; 110.6; 51.8; 36.7. Anal. calc. for C14H14N2O4 (274.27):
C 61.31, H 5.14, N 10.21; found: C 61.18, H 5.25, N 10.26.
Methyl 2-(Aminomethyl)furan-3-carboxylate (15). A soln. of 11 (4.0 g, 22.1 mmol) in 8m HCl (20 ml)
was stirred for 2 h at r.t. After the completion of the reaction, the mixture was washed with petroleum
ether (80 ml), and the pH value of the aq. phase was adjusted to pH 10 by the addition of 10% NaOH
soln. at 58. The mixture was extracted with Et2O (2 ꢁ 50 ml). The combined org. extract was washed with
brine (50 ml), dried (MgSO4), and concentrated: 15 (2.5 g, 73%). Yellow oil. IR (KBr): 3381, 3154, 2953,
1716, 1597, 1441, 1306, 1201, 1148, 1053. 1H-NMR (400 MHz, CDCl3): 7.22 (d, J ¼ 2.0, ¼CH); 6.59 (d, J ¼
2.0, ¼CH); 4.03 (s, CH2); 3.77 (s, MeO); 1.62 (br. s, NH2). 13C-NMR (CDCl3, 100.6 MHz): 164.1; 162.7;
140.9; 113.1; 110.8; 51.5; 38.6. Anal. calc. for C7H9NO3 (155.15): C 54.19, H 5.85, N 9.03; found: C 54.49, H
6.09, N 9.29.
2-{[(Methoxycarbonyl)amino]methyl}furan-3-carboxylic Acid (16). To a stirred soln. of 12 (0.94 g,
4.4 mmol) in dioxane (45 ml) and H2O (20 ml) was added dropwise 1m aq. NaOH (8.83 ml, 8.83 mmol),
and the resulting mixture was stirred at 308 for 2 h (TLC monitoring). After the completion of the
reaction, the soln. was acidified to pH 2 with 1m HCl and then extracted with AcOEt (3 ꢁ 70 ml). The
combined org. extract was washed with brine (80 ml), dried (MgSO4), and concentrated, and the crude
product purified by crystallization from CH2Cl2/AcOEt 1:1 (80 ml): 16 (0.85 g, 97%). White solid. M.p.
183 – 1858. IR (ATR): 3324, 3154, 2983, 1680, 1594, 1543, 1518, 1429, 1310, 1261, 1221, 1181, 1145, 1122,
1982, 1022. 1H-NMR (400 MHz, (D6)DMSO): 12.76 (br. s, COOH); 7.66 (d, J ¼ 1.9, ¼CH); 7.63 (t, J ¼
5.8, NH); 6.65 (d, J ¼ 1.9, ¼CH); 4.52 (d, J ¼ 5.8, CH2); 3.54 (s, MeO). 13C-NMR ((D6)DMSO,
100.6 MHz): 164.5; 157.7; 157.0; 142.4; 114.8; 111.1; 51.7; 36.8. Anal. calc. for C8H9NO5 (199.16): C 48.25,
H 4.55, N 7.03; found: C 48.03, H 4.44, N 7.05.
2-{[(tert-Butoxycarbonyl)amino]methyl}furan-3-carboxylic Acid (17). As described for 16, with 13
(6.0 g, 23.5 mmol), at 308 for 1.5 h: 17 (5.47 g, 96%). White solid, which was crystallized from hexane/
AcOEt 1:1. M.p. 142 – 1448. IR (ATR): 3379, 3152, 2988, 1680, 1600, 1519, 1464, 1436, 1367, 1321, 1280,
1
1251, 1160, 1125, 1086, 1029. H-NMR (400 MHz, (D6)DMSO): 12.72 (br. s, COOH); 7.65 (d, J ¼ 1.8,
t
¼CH); 7.30 (t, J ¼ 5.7, NH); 6.64 (d, J ¼ 1.8, ¼CH); 4.46 (d, J ¼ 5.7, CH2); 1.38 (s, Bu). 13C-NMR

Helvetica Chimica Acta – Vol. 93 (2010)
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(100.6 MHz, (D6)DMSO): 164.3; 157.8; 155.5; 142.0; 114.3; 110.8; 78.0; 36.3; 28.1. Anal. calc. for
C11H15NO5 (241.24): C 54.77, H 6.27, N 5.81; found: C 54.88, H 6.15, N 5.87.
2-{{[(Phenylamino)carbonyl]amino}methyl}furan-3-carboxylic Acid (18). As described for 16, with
14 (1.1 g, 4.01 mmol), at 358 for 2.5 h: 18 (0.96 g, 92%). White solid, which was crystallized from acetone/
AcOEt 1:1 (150 ml). M.p. 212 – 2138. IR (ATR): 3330, 3146, 2970, 1680, 1637, 1595, 1563, 1513, 1435,
1
1423, 1309, 1220, 1128, 1083, 1021. H-NMR (400 MHz, (D6)DMSO): 12.82 (br. s, COOH); 8.63 (br. s,
NH); 7.66 (d, J ¼ 1.9, ¼CH); 7.38 (br. d, J ¼ 7.6, 2 ¼CH); 7.23 (br. t, J ¼ 7.9, 2 ¼CH); 6.90 (br. t, J ¼ 7.3,
¼CH); 6.68 (d, J ¼ 1.9, ¼CH); 6.59 (t, J ¼ 6.0, NH); 4.60 (d, J ¼ 6.0, CH2). 13C-NMR ((D6)DMSO,
100.6 MHz): 164.7; 158.8; 155.2; 142.3; 140.5; 128.9; 121.5; 118.0; 114.8; 111.2; 35.8. Anal. calc. for
C13H12N2O4 (260.25): C 60.00, H 4.65, N 10.76; found: C 60.21, H 4.78, N 10.81.
Methyl 4,6-Dihydro-4-oxo-5H-furo[2,3-c]pyrrole-5-carboxylate (22). To a stirred soln. of 16 (0.2 g,
1.0 mmol) in dry THF (15 ml) was added SOCl2 (0.15 ml, 2.0 mmol), followed by heating under reflux for
3 h (TLC monitoring). After the completion of the chlorination, the solvent and excess SOCl2 were
evaporated. The residue was dissolved in dry benzene (20 ml) and the soln. heated under reflux for 18 h.
The solvent was evaporated and the crude product purified by CC (SiO2; hexane/AcOEt 1:1): 22 (0.14 g,
78%). White solid. M.p. 173 – 1758. IR (ATR): 3135, 2973, 1764, 1691, 1607, 1437, 1393, 1325, 1255, 1194,
1
1130, 1074. H-NMR (400 MHz, CDCl3): 7.49 (d, J ¼ 2.0, ¼CH); 6.61 (d, J ¼ 2.0, ¼CH); 4.66 (s, CH2);
3.86 (s, MeO). 13C-NMR (100.6 MHz, CDCl3): 167.5; 161.2; 152.5; 149.3; 120.7; 106.3; 53.7; 45.8. Anal.
calc. for C8H7NO4 (181.15): C 53.04, H 3.89, N 7.73; found: C 53.21, H 3.86, N 7.82.
tert-Butyl 4,6-Dihydro-4-oxo-5H-furo[2,3-c]pyrrole-5-carboxylate (23). To a stirred suspension of 17
(2.0 g, 8.29 mmol) in dry benzene (40 ml) was added SOCl2 (1.3 ml, 17.11 mmol), and the resulting
mixture was heated under reflux for 2 h. The solvent and excess SOCl2 were evaporated. The residue was
dissolved in dry benzene (50 ml) and heated under reflux for 48 h. After evaporation of the solvent, the
crude product was separated and purified by CC (SiO2, hexane/AcOEt 3 :1): 23 (1.46 g, 79%). White
solid. M.p. 82 – 838. IR (KBr): 3127, 2980, 1770, 1703, 1616, 1495, 1459, 1369, 1323, 1257, 1152, 1067.
1H-NMR (400 MHz, CDCl3): 7.47 (d, J ¼ 2.0, ¼CH); 6.59 (d, J ¼ 2.0, ¼CH); 4.59 (s, CH2); 1.50 (s, tBu).
13C-NMR (100.6 MHz, CDCl3): 167.3; 161.7; 150.2; 149.0; 121.0; 106.2; 83.0; 45.7; 28.1. Anal. calc. for
C11H13NO4 (223.23): C 59.19, H 5.87, N 6.27; found: C 59.31, H 5.87, N 6.18.
4,6-Dihydro-4-oxo-N-phenyl-5H-furo[2,3-c]pyrrole-5-carboxamide (24). To a stirred soln. of 18
(0.45 g, 1.75 mmol) in dry THF (50 ml) was added SOCl2 (0.25 ml, 3.46 mmol), followed by heating
under reflux for 4 h. The workup of the mixture was done as described above. The crude product was
purified by CC (SiO2; AcOEt/hexane/CH2Cl2 1:1:1): 24 (0.37 g, 89%). White solid. M.p. 172 – 1748. IR
(ATR): 3113, 2971, 1709, 1679, 1596, 1557, 1462, 1438, 1398, 1308, 1275, 1239, 1152, 1126, 1069. 1H-NMR
(400 MHz, CDCl3): 10.4 (br. s, NH); 7.53 (d, J ¼ 2.0, ¼CH); 7.49 (m, 2 ¼CH); 7.28 (m, 2 ¼CH); 7.05 (tt,
J ¼ 7.4, 1.1, 1 H); 6.63 (d, J ¼ 2.0, ¼CH); 4.77 (s, CH2). 13C-NMR (100.6 MHz, CDCl3): 168.2; 165.3;
150.5; 149.5; 137.5; 129.0; 124.1; 120.6; 120.1; 106.0; 45.0. Anal. calc. for C13H10N2O3 (242.23): C 64.46, H
4.16, N 11.56; found: C 64.23, H 4.16, N 11.63.
5,6-Dihydro-4H-furo[2,3-c]pyrrol-4-one (3). To a stirred soln. of Boc-protected 23 (0.30 g,
1.35 mmol) in CH2Cl2 (30 ml) at 08 was added dropwise CF3COOH (1 ml, 13 mmol), and the resulting
mixture was stirred for 1 h at r.t. (TLC monitoring). After the completion of the reaction, 2m aq. NaOH
(6.5 ml) was added to remove excess acid. Then, the mixture was extracted with CH2Cl2 (2 ꢁ 50 ml), the
combined org. extract dried (MgSO4) and concentrated, and the crude product purified by CC (SiO2;
AcOEt): 3 (0.1 g, 66%). White solid. M.p. 141 – 1438. IR (ATR): 3185, 3093, 1726, 1677, 1462, 1443, 1296,
1262, 1173, 1117, 1059, 1037. 1H-NMR (400 MHz, CDCl3): 7.45 (d, J ¼ 2.0, ¼CH); 6.58 (d, J ¼ 2.0, ¼CH);
5.83 (br. s, NH); 4.29 (s, CH2). 13C-NMR (100.6 MHz, CDCl3): 169.0; 167.7; 148.5; 121.1; 105.9; 42.4.
Anal. calc. for C6H5NO2 (123.11): C 58.54, H 4.09, N 11.38; found: C 58.46, H 4.09, N 11.28.
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Received December 15, 2009