Synthesis of (2S)-2-(benzoylamino)-3-(heteroaryl)propyl benzoates

Article abstract of DOI:10.1002/(SICI)1522-2675(20000412)83:4<760::AID-HLCA760>3.0.CO;2-R

(3E,5S)-1-Benzoyl-5-[(benzoyloxy)methyl]-3- [(dimethylamino)methylidene]pyrrolidin-2-one (9) was prepared in two steps from commercially available (S)-5-(hydroxymethyl)pyrrolidin-2-one (7) (Scheme 1). Compound 9 gave, in one step, upon treatment with vari

Full text of DOI:10.1002/(SICI)1522-2675(20000412)83:4<760::AID-HLCA760>3.0.CO;2-R

760
Helvetica Chimica Acta ± Vol. 83 (2000)
Synthesis of (2S)-2-(Benzoylamino)-3-(heteroaryl)propyl Benzoates
a
a
a
b
Ï
by Marko Skof ), Jurij Svete )*, Branko Stanovnik )*, and Simona GolicÏ-Grdadolnik )
a) Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia
b) National Institute of Chemistry, Ljubljana, Slovenia
(3E,5S)-1-Benzoyl-5-[(benzoyloxy)methyl]-3-[(dimethylamino)methylidene]pyrrolidin-2-one (9) was
prepared in two steps from commercially available (S)-5-(hydroxymethyl)pyrrolidin-2-one (7) (Scheme 1).
Compound 9 gave, in one step, upon treatment with various C,N- and C,O-1,3-dinucleophiles 10 ± 18, the
corresponding 3-(quinolizin-3-yl)- and 3-(2-oxo-2H-pyran-3-yl)-substituted (2S)-2-(benzoylamino)propyl ben-
zoates 19 ± 27 (Schemes 1 and 2).
Introduction. ± Chiral b-amino alcohols and their derivatives found a wide
application in the synthesis of optically active compounds, especially as chiral building
blocks, chiral auxiliaries, and resolving agents (for an illustration, see [1]; for the
synthesis of some b-amino alcohols, see [2]). As a consequence, numerous chiral
synthons of this type, e.g., (2S)-3-aminopropane-1,2-diol (1), (2S)-2-phenylglycinol (2),
(1R,2S)-ephedrine (3), (1R,2S)-norephedrine (4), (3S)-pyrrolidin-3-ol (5), (4S)-4-
hydroxypyrrolidin-2-one (6), and (5S)-5-(hydroxymethyl)pyrrolidin-2-one (7), are
commercially available, usually in both enantiomeric forms. Previously, we have shown
that 3-(dimethylamino)prop-2-enoates can serve as useful and versatile synthetic tools
for the preparation of a variety of heterocyclic systems; for short reviews, see [3]; for
recent publications, see [4]. In this connection, we have recently used chiral 3-
(dimethylamino)prop-2-enoate analogs derived from l-glutamic and l-pyroglutamic
acid for the preparation of (S)-3-(heteroaryl)alanine and (S)-3-(heteroaryl)lactic acid
derivatives, as well as for the preparation of heterocyclic systems with an a-amino acid
structural element partially incorporated into the cyclic system [5 ± 11]. In continuation
of our work in this field, we now report a novel, one-step synthesis of 3-(heteroaryl)-
substituted (2S)-2-(benzoylamino)propyl benzoates 19 ± 27 from easily available
(3E,5S)-1-benzoyl-5-[(benzoyloxy)methyl]-3-[(dimethylamino)methylidene]pyrrolidin-
2-one (9).
Results and Discussion. ± The starting pyrrolidinone 9 was prepared in two steps
from commercially available (S)-5-(hydroxymethyl)pyrrolidin-2-one (7) (Scheme 1).
This was first fully protected by benzoylation of the OH and NH groups to give (S)-1-
benzoyl-5-[(benzoyloxy)methyl]pyrrolidin-2-one (8), which, upon treatment with tert-
butyl bis(dimethylamino)methyl ether (Bredereckꢀs reagent) and according to the
procedure described previously for the preparation of analogous 5-substituted (3E,5S)-
3-(dimethylamino)methylidene]pyrrolidin-2-ones and (3E,5S)-3-(dimethylamino)me-
thylidene]tetrahydrofuran-2-ones [5][6], afforded the desired pyrrolidinone 9. The
orientation around the exocyclic CˆC bond of 9 was determined by NMR.

Helvetica Chimica Acta ± Vol. 83 (2000)
761
No NOE effect was observed between Me2N CHˆC and H C(4) of 9, thus indicating the (E)-
configuration. Additionally, the chemical shift d for Me2N CHˆC of 9 (7.08 ppm) is in agreement with that for
Me2N CHˆC in structurally closely related methyl (2S,4E)-1-benzoyl-4-[(dimethylamino)methylidene]-5-
oxopyrrolidine-2-carboxylate (28) (7.02 ppm) [5]. The (E)-configuration in 9 is also in agreement with the
configuration of acyclic alkyl 3-(dimethylamino)prop-2-enoates, where the dimethylamino group is always
trans-oriented with respect to the ester group [3][4].
Pyrrolidinone 9 was then treated in refluxing AcOH with two types of 1,3-
dinucleophiles: pyridine-2-acetic acid and quinoline-2-acetic acid derivatives 10 ± 12
and carbocyclic and heterocyclic 1,3-dicarbonyl compounds and their analogs 13 ± 18
(Schemes 1 and 2). Treatment of 9 with C,N-dinucleophiles 10 ± 12 afforded substituted
(2S)-2-(benzoylamino)-3-(quinolizin-3-yl)propyl benzoates 19 ± 21, while, with C,O-
dinucleophiles 13 ± 18, (2S)-2-(benzoylamino)-3-(2-oxo-2H-pyran-3-yl)propyl ben-
zoates 22 ± 27 were formed. Presumably, the transformation of 9 with 1,3-dinucleo-
philes 10 ± 18 into 3-(heteroaryl)alaninol derivatives 19 ± 27 proceeds via the ꢁring
switchingꢀ mechanism (Scheme 1). Thus, first the substitution of the dimethylamino
group takes place, followed by the second attack of a dinucleophile at the ring carbonyl
group, which results in simultaneous cleavage of the pyrrolidinone ring and formation
of the 3-(heteroaryl)-substituted (2S)-2-(benzoylamino)-3-(heteroaryl)propyl ben-
zoate. The proposed mechanism is supported by our previous results from the cyclic
and acyclic 3-(dimethylamino)prop-2-enoate series [3][4][7 ± 11], and by the results of
Young and co-workers on the transformations of closely related (S)-3-(formyl)pyro-
glutamic-acid derivatives [12].
The structures of compounds 19 ± 27 were confirmed by 1H- and 13C-NMR
spectroscopy and by elemental analysis for C, H, and N. 1H- and 13C-NMR Spectra of
compounds 19 ± 27 are in agreement with NMR spectra of closely related 3-
(heteroaryl)alanine and 3-(heteroaryl)lactic acid derivatives [7 ± 10]. So far, the
optical purity of the isolated products was not studied in detail; however, it might be
presumed that, under the reaction conditions employed, a pronounced racemization of
the b-amino alcohol structural element would be unlikely. The yields were not
optimized and were generally relatively poor, especially when compared with the yields
of related 3-(heteroaryl)alanine derivatives [7]. Nevertheless, since the precursor 9 is
easily available and only one step is required for further transformation into amino

762
Helvetica Chimica Acta ± Vol. 83 (2000)
Scheme 1
i) PhCOCl, pyridine, r.t. ii) (Me2N)2CHOtBu, toluene, 1008.
alcohols 19 ± 27, this method could be conveniently employed for a simple preparation
of 3-(heteroaryl)alaninols.

Helvetica Chimica Acta ± Vol. 83 (2000)
763
Scheme 2
Experimental Part
General. All starting materials were commercially available (in most cases from Fluka) and purified by
standard techniques. TLC: Merck, Al foils, silica gel 60 F 254, 0.2 mm. M.p.: Kofler micro hot stage. Optical
rotations: Perkin-Elmer-241-MC polarimeter. 1H- and 13C-NMR: Bruker-Advance-DPX-300 spectrometer.
Elemental analyses: Perkin-Elmer CHN analyser 2400.
(5S)-1-Benzoyl-5-[(benzoyloxy)methyl]pyrrolidin-2-one (8). Benzoyl chloride (12.8 ml, 110 mmol) was
added to a soln. of (5S)-5-(hydroxymethyl)pyrrolidin-2-one (7; 5.750 g, 50 mmol) in pyridine (50 ml), and the
mixture was stirred at r.t. for 2 h. Volatile components were evaporated; CHCl3 (150 ml) was added to the
residue, the resulting soln. washed with 4% HCl soln. (100 ml) and aq. NaHCO3 soln. (50 ml), dried (Na2SO4),
and evaporated. The residue was triturated with Et2O/petroleum ether 1:1 (60 ml), cooled (08), and filtered off:
8 (13.25 g, 82%). M.p. 69 ± 728 (Et2O/petroleum ether). [a]D23
ˆ
153.2 (c ˆ 0.85, CH2Cl2). 1H-NMR (300 MHz,
CDCl3): 2.10 ± 2.20 (m, H C(4)); 2.29 ± 2.43 (m, H C(4)); 2.56 (ddd, J ˆ 4.2, 9.8, 18.1, H C(3)); 2.79
(ddd, J ˆ 9.0, 9.8, 17.7, H C(3)); 4.57 (dd, J ˆ 3.0, 11.7, 1 H, PhCOOCH2); 4.78 (dd, J ˆ 4.1, 11.7, 1 H,
PhCOOCH2); 4.87 ± 4.93 (m, H C(5)); 7.35 ± 7.61 (m, 8 arom. H); 7.97 ± 8.01 (m, 2 arom. H). 13C-NMR
(75.5 MHz, CDCl3): 20.4; 31.4; 55.5; 64.7; 127.6; 128.5; 128.7; 129.1; 129.9; 131.6; 133.4; 134.8; 165.5; 170.1;
174.8. Anal. calc. for C19H17NO4 (323.35): C 70.85, H 5.30, N 4.33; found: C 71.05, H 5.36, N 4.30.
(3E,5S)-1-Benzoyl-5-[(benzoyloxy)methyl]-3-[(dimethylamino)methylidene]pyrrolidin-2-one (9). A mix-
ture of 8 (3.231 g, 10 mmol), toluene (20 ml), and tert-butyl bis(dimethylamino)methyl ether (2.610 g,
15 mmol) was heated at 90 ± 1008 for 2 h. The volatile components were evaporated and the solid residue
crystallized from Et2O: 9 (2.690 g, 71%). M.p. 116 ± 1188 (AcOEt/hexane). [a]D23
ˆ
29.9 (c ˆ 0.95, CH2Cl2).
1H-NMR (300 MHz, CDCl3): 2.98 (ddd, J ˆ 1.5, 3.4, 14.3, H C(4)); 2.98 (s, Me2N); 3.20 (ddd, J ˆ 1.5, 9.4, 14.3,
H
C(4)); 4.63 (dd, J ˆ 3.8, 11.3, 1 H, PhCOOCH2); 4.68 (dd, J ˆ 3.8, 11.3, 1 H, PhCOOCH2); 4.70 ± 4.77
(m, H C(5)); 7.08 (br. t, J ˆ 1.5, Me2N CHˆC); 7.33 ± 7.47 (m, 5 arom. H); 7.52 ± 7.58 (m, 3 arom. H); 8.00 ±
8.03 (m, 2 arom. H). 13C-NMR (75.5 MHz, (D6)DMSO): 26.4; 42.4; 53.6; 65.3; 92.6; 127.9; 128.8; 128.9; 130.1;
130.3; 131.3; 133.5; 136.4; 147.5; 166.9; 170.7; 171.4. Anal. calc. for C22H22N2O4(378.43): C 69.83, H 5.86, N 7.40;
found: C 69.98, H 5.90, N 7.52.

764
Helvetica Chimica Acta ± Vol. 83 (2000)
(2S)-2-(Benzoylamino)-3-(heteroaryl)propyl Benzoates 19 ± 27: General Procedure. A mixture of
9
(0.379 g, 1 mmol), 1,3-dinucleophile 10 ± 18 (1 mmol), and glacial AcOH (4 ml) was heated under reflux for
2 ± 3 h. Volatile components were evaporated, and the solid residue was crystallized from the appropriate
solvent: (2S)-2-(benzoylamino)-3-(heteroaryl)propyl benzoates 19 ± 27.
(2S)-2-(Benzoylamino)-3-[1-(ethoxycarbonyl)-4-oxo-4H-quinolizin-3-yl]propyl Benzoate (19). From ethyl
pyridine-2-acetate (10) (3 h): 0.122 g (24%) of 19. M.p. 205 ± 2078 (AcOEt). [a]D23
ˆ
75.1 (c ˆ 0.57, DMF).
1H-NMR (300 MHz, (D6)DMSO): 1.22 (t, J ˆ 7.2, COOCH2Me); 2.95 (dd, J ˆ 9.0, 13.6, H C(3)); 3.18 (dd, J ˆ
5.1, 13.4, H C(3)); 4.22 (q, J ˆ 7.2, COOCH2Me); 4.37 (dd, J ˆ 6.6, 11.1, H C(1)); 4.57 (dd, J ˆ 5.3, 10.9,
H
C(1)); 4.64 ± 4.75 (m, H C(2)); 7.37 ± 7.52 (m, 5 arom. H, H C(7')); 7.61 ± 7.66 (m, 1 H of Ph); 7.72 ± 7.75
(m, 2 H of Ph); 7.82 ± 7.87 (m, H C(8')); 7.94 ± 7.96 (m, 2 H of Ph); 8.37 (s, H C(2')); 8.52 (d, J ˆ 8.3, NH); 9.05
(d, J ˆ 9.0, H C(9)); 9.20 (d, J ˆ 7.2, H C(6')). 13C-NMR (75.5 MHz, (D6)DMSO): 15.0; 33.2; 48.7; 61.1; 66.9;
101.3; 116.3; 117.7; 123.9; 128.0; 128.9; 129.0, 129.5; 130.0; 130.5; 132.0; 134.2; 134.8; 135.6; 140.5; 144.1; 158.8;
165.4; 166.4; 167.4. Anal. calc. for C29H26N2O6 (498.54): C 69.87, H 5.26, N 5.62; found: C 69.69, H 5.07, N 5.70.
(2S)-2-(Benzoylamino)-3-(1-cyano-4-oxo-4H-quinolizin-3-yl)propyl Benzoate (20). From pyridine-2-ace-
tonitrile (11) (3 h): 0.135 g (30%) of 20. M.p. 194 ± 1968 (AcOEt). [a]D23
ˆ
92.3 (c ˆ 0.62, MeCOOH).
1H-NMR (300 MHz, (D6)DMSO): 2.94 (dd, J ˆ 8.7, 13.6, H C(3)); 3.13 (dd, J ˆ 5.7, 13.6, H C(3)); 4.38
(dd, J ˆ 6.8, 10.9, H C(1)); 4.47 (dd, J ˆ 5.3, 10.9, H C(1)); 4.69 ± 4.81 (m, H C(2)); 7.40 ± 7.54 (m, 5 H of Ph,
H
C(7)); 7.60 ± 7.66 (m, 1 H of Ph); 7.72 ± 7.75 (m, 2 H of Ph); 7.83 ± 7.94 (m, H C(8'), H C(9'), 2 H of Ph);
8.06 (s, H C(2')); 8.46 (d, J ˆ 8.7, NH)); 9.12 ± 9.15 (m, H C(6')). 13C-NMR (75.5 MHz, (D6)DMSO): 32.5;
47.5; 66.0; 82.7; 114.0; 117.2; 117.3; 117.4; 122.5; 127.0; 128.1; 128.5; 128.9; 129.0; 131.1; 133.2; 134.5; 134.9; 139.3;
144.3; 157.2; 165.4; 166.5. Anal. calc. for C27H21N3O4 (451.48): C 71.83, H 4.69, N 9.31; found: C 71.55, H 4.68,
N 9.54.
(2S)-2-(Benzoylamino)-3-[4-(methoxycarbonyl)-1-oxo-1H-benzo[c]quinolizin-2-yl]propyl Benzoate (21).
From methyl quinoline-2-acetate (12) (3 h): 0.162 g (30%) of 21. M.p. 217 ± 2198 (AcOEt). [a]D23
ˆ
8.4 (c ˆ
0.56, CH2Cl2). 1H-NMR (300 MHz, (D6)DMSO): 2.92 (dd, J ˆ 9.9, 14.1, H C(3)); 3.17 (dd, J ˆ 4.5, 13.2,
H
C(3)); 3.76 (s, MeO); 4.41 (dd, J ˆ 6.8, 10.9, H C(1)); 4.51 (dd, J ˆ 5.1, 11.1, H C(1)); 4.75 ± 4.83
(m, H C(2)); 7.39 ± 7.52 (m, 5 H of Ph); 7.57 ± 7.65 (m, 1 H of Ph, 2 H of Het); 7.71 ± 7.74 (m, 2 H of Ph); 7.82 ±
7.86 (m, 1 H of Het); 7.88 (d, J ˆ 9.4, H C(6')); 7.94 ± 7.97 (m, 2 H of Ph); 8.14 (s, H C(3')); 8.49 (d, J ˆ 8.7,
NH); 8.62 (d, J ˆ 9.4, H C(5')); 9.33 ± 9.36 (m, 1 H of Het). 13C-NMR (75.5 MHz, (D6)DMSO): 33.8; 48.4;
52.9; 67.1; 104.3; 120.9; 122.7; 124.8; 126.4; 127.9; 128.0; 128.8; 129.0; 129.3; 129.5; 130.0; 130.5; 132.0; 133.8;
134.2; 135.3; 135.6; 138.4; 144.5; 164.3; 166.2; 166.5; 167.5. Anal. calc. for C32H26N2O6 (534.57): C 71.90, H 4.90,
N 5.24, found: C 71.74, H 4.54, N 4.95.
(2S)-2-(Benzoylamino)-3-(5,6,7,8-tetrahydro-7,7-dimethyl-2,5-dioxo-2H-[1]benzopyran-3-yl)propyl Ben-
zoate (22). From 5,5-dimethylcyclohexane-1,3-dione (13) (3 h): 0.126 g (27%) of 22. M.p. 140 ± 1428 (AcOEt).
[a]2D3
ˆ
72.1 (c ˆ 0.68, CH2Cl2). 1H-NMR (300 MHz, (D6)DMSO): 0.97 (s, Me); 1.02 (s, Me); 2.33 (s, CH2(8'));
2.70 (dd, J ˆ 9.4, 13.6, H C(3)); 2.73 (s, CH2(6')); 2.89 (dd, J ˆ 4.3, 13.4, H C(3)); 4.35 (dd, J ˆ 5.8, 11.1,
H
C(1)); 4.46 (dd, J ˆ 5.3, 10.9, H C(1)); 4.60 ± 4.68 (m, H C(2)); 7.39 ± 7.55 (m, 5 H of Ph); 7.63 ± 7.70
(m, 3 H of Ph, H C(4')); 7.96 ± 7.99 (m, 2 H of Ph); 8.40 (d, J ˆ 8.7, NH). 13C-NMR (75.5 MHz, (D6)DMSO):
28.2; 28.5; 33.2; 33.0; 47.7; 50.5; 66.9; 113.7; 123.4; 127.9; 129.1; 129.6; 130.1; 130.4; 132.1; 134.3; 135.4; 137.2;
162.0; 166.4; 167.6; 172.7; 194.8. Anal. calc. for C28H27NO6(473.54): C 71.02, H 5.75, N 2.96; found: C 70.86,
H 5.66, N 3.26.
(2S)-2-(Benzoylamino)-3-(5,6-dihydro-2,5-dioxo-2H-pyrano[3,2-c]pyridin-3-yl)propyl Benzoate (23).
From pyridine-2,4-diol (14) (2 h): 0.166 g (37%) of 23. M.p. 229 ± 2328 (AcOEt). [a]D23
ˆ
153.6 (c ˆ 0.50,
1
DMF). H-NMR (300 MHz, (D6)DMSO): 2.77 (dd, J ˆ 9.6, 13.8, H C(3)); 2.94 (dd, J ˆ 4.5, 13.6, H C(3));
4.37 (dd, J ˆ 6.8, 10.9, H C(1)); 4.46 (dd, J ˆ 5.3, 10.9, H C(1)); 4.61 ± 4.73 (m, H C(2)); 6.31 (d, J ˆ 6.8,
H
C(8')); 7.39-7.56 (m, 5 H of Ph, H C(7')); 7.62 ± 7.72 (m, 3 H of Ph); 7.78 (s, H C(4')); 7.96 ± 7.98 (m, 2 H of
Ph); 8.44 (d, J ˆ 8.7, NHBz); 11.90 (s, H N(6')). 13C-NMR (75.5 MHz, (D6)DMSO): 33.2; 48.0; 66.9; 98.3;
109.0; 123.1; 128.0; 129.1; 129.5; 130.1; 130.5; 132.0; 134.2; 135.5; 138.4; 138.8; 159.8; 161.4; 163.3; 166.4; 167.6.
Anal. calc. for C25H20N2O6 (444.44): C 67.65, H 4.54, N 6.30; found: C 67.79, H 4.40, N 6.49.
(2S)-2-(Benzoylamino)-3-(2,5-dioxo-2H,5H-pyrano[3,2-c][1]benzopyran-3-yl)propyl Benzoate (24). From
4-hydroxy-2H-1-benzopyran-2-one (15) (2 h): 0.256 g (52%) of 24. M.p. 231 ± 2338 (AcOEt). [a]D23
ˆ
311.1
(c ˆ 0.44, DMF). 1H-NMR (300 MHz, (D6)DMSO): 2.87 (dd, J ˆ 9.4, 13.9, H C(3)); 3.02 (dd, J ˆ 4.7, 13.8,
H
C(3)); 4.40 (dd, J ˆ 6.4, 10.9, H C(1)); 4.51 (dd, J ˆ 5.3, 10.9, H C(1)); 4.70 ± 4.79 (m, H C(2)); 7.39 ± 7.52
(m, 5 H of Ph, 2 H of Het); 7.58 ± 7.63 (m, 1 H of Ph); 7.70 ± 7.80 (m, 2 H of Ph, 1 H of Het); 7.90 (s, H C(4'));
7.96 ± 8.00 (m, 2 H of Ph, 1 H of Het); 8.49 (d, J ˆ 8.7, NH). 13C-NMR (75.5 MHz, (D6)DMSO): 33.3; 47.8; 66.8;
104.3; 113.7; 117.9; 123.7; 126.2; 126.3; 128.0; 129.1; 129.5; 130.1; 130.4; 132.1; 134.2; 135.1; 135.4; 138.3; 153.5;

Helvetica Chimica Acta ± Vol. 83 (2000)
765
159.3; 160.2; 160.5; 166.4; 167.7. Anal. calc. for C29H21NO7(495.49): C 70.30, H 4.27, N 2.83; found: C 70.15,
H 4.37, N 2.93.
(2S)-2-(Benzoylamino)-3-(1,6-dihydro-6-oxo-1,3-diphenylpyrano[2,3-c]pyrazol-3-yl)propyl Benzoate (25).
From 2,5-diphenyl-3H-pyrazol-3-one (16) (3 h): 0.128 g (22%) of 25. M.p. 209 ± 2128 (AcOEt). [a]D23
ˆ
43.7
1
(c ˆ 0.81, CH2Cl2). H-NMR (300 MHz, (D6)DMSO): 2.84 (dd, J ˆ 9.2, 13.8, H C(3)); 3.00 (dd, J ˆ 4.5, 13.9,
H
C(3)); 4.43 (dd, J ˆ 6.7, 10.9, H C(1)); 4.52 (dd, J ˆ 4.9, 10.9, H C(1)); 4.67 ± 4.77 (m, H C(2)); 7.36 ± 7.41
(m, 2 H of Ph); 7.43 ± 7.52 (m, 7 H of Ph); 7.59 ± 7.65 (m, 3 H of Ph); 7.73 ± 7.81 (m, 4 H of Ph); 7.86 ± 7.88 (m, 2 H
of Ph); 7.96 ± 7.98 (m, 2 H of Ph); 8.22 (s, H C(4')); 8.50 (d, J ˆ 8.7, NH). 13C-NMR (75.5 MHz, (D6)DMSO):
33.5; 48.1; 66.9; 100.5; 117.9; 121.8; 127.6; 128.0; 128.5; 128.9; 129.1; 129.5; 129.9; 130.0; 130.4; 130.5; 132.1;
132.2; 134.2; 135.3; 137.3; 138.0; 145.8; 150.8; 160.3; 166.4; 167.6. Anal. calc. for C35H27N3O5 (495.49): C 73.78,
H 4.78, N 7.38; found: C 73.87, H 4.65, N 7.45.
(2S)-2-(Benzoylamino)-3-(1,6-dihydro-3-methyl-6-oxo-1-phenylpyrano[2,3-c]pyrazol-3-yl)propyl
Ben-
zoate (26). From 5-methyl-2-phenyl-3 H-pyrazol-3-one (17) (3 h): 0.120 g (24%) of 26. M.p. 160 ± 1628
(AcOEt). [a]2D3
ˆ
26.3 (c ˆ 0.65, CH2Cl2). 1H-NMR (300 MHz, (D6)DMSO): 2.29 (s, Me); 2.77 (dd, J ˆ 8.5,
13.8, H C(3)); 2.94 (dd, J ˆ 5.7, 13.9, H C(3)); 4.39 (dd, J ˆ 7.0, 11.1, H C(1)); 4.49 (dd, J ˆ 5.1, 11.1,
H
H
C(1)); 4.63 ± 4.75 (m, H C(2)); 7.37-7.64 (m, 9 H of Ph); 7.72 ± 7.78 (m, 4 H of Ph); 7.96 ± 7.98 (m, 2 H of Ph,
C(4')); 8.45 (d, J ˆ 8.7, NH). 13C-NMR (75.5 MHz, (D6)DMSO): 12.8; 33.8; 48.2; 66.7; 102.1; 116.4; 121.1;
127.9; 128.0; 128.0; 129.1; 129.5; 130.0; 130.4; 132.0; 134.2; 135.5; 137.4; 137.9; 144.8; 150.2; 160.7; 166.4; 167.6.
Anal. calc. for C30H25N3O5 (507.55): C 70.99, H4.96, N 8.28; found: C 71.24, H 4.83, N 8.18.
(2S)-2-(Benzoylamino)-3-(2,3,4,7-tetrahydro-1,3-dimethyl-2,4,7-trioxo-2H-pyrano[2,3-d]pyrimidin-6-yl)-
propyl Benzoate (27). From 1,3-dimethylbarbituric acid (18) (3 h): 0.155 g (32%) of 27. M.p. 189 ± 1918
(AcOEt). [a]2D3
ˆ
148.2 (c ˆ 0.51, MeCOOH). 1H-NMR (300 MHz, (D6)DMSO): 2.79 (dd, J ˆ 9.4, 14.3,
H
C(3)); 2.89 (dd, J ˆ 4.7, 13.8, H C(3)); 3.20 (s, Me); 3.35 (s, Me); 4.34 (dd, J ˆ 6.4, 10.9, H C(1)); 4.47
(dd, J ˆ 5.1, 11.1, H C(1)); 4.59 ± 4.70 (m, H C(2)); 7.40 ± 7.54 (m, 5 H of Ph); 7.61 ± 7.68 (m, 1 H of Ph); 7.73 ±
7.76 (m, 2 H of Ph); 7.91 (s, H C(4')); 7.96 ± 7.99 (m, 2 H of Ph); 8.43 (d, J ˆ 8.7, NH). 13C-NMR (75.5 MHz,
(D6)DMSO): 28.8; 29.6; 32.3; 47.9; 66.9; 92.9; 116.0; 128.0; 129.1; 129.5; 130.1; 130.4; 132.1; 134.2; 135.4; 140.6;
150.2; 158.2; 159.5; 159.6; 166.4; 167.5. Anal. calc. for C26H23N3O7 (489.48): C 63.80, H 4.74, N 8.58; found:
C 63.55, H 4.59, N 8.58.
The financial support of the Minestry of Science and Technology of Slovenia is gratefully acknowledged.
REFERENCES
[1] J. Mulzer, ꢁBasic Principles of EPC Synthesisꢀ, in ꢁStereoselective Synthesis, Methods of Organic Chemistry
(Houben-Weyl)ꢀ, 4th edn, Vol. 1, Ed. G. Helmchen, 1996, p. 75.
[2] H. Hahn, H. Heitsch, R. Rathmann, G. Zimmermann, C. Bormann, H. Zähner, W. A. König, Liebigs Ann.
Chem. 1987, 803; J. Jurczak, A. Golebiowski, Chem. Rev. 1989, 89, 149; N. G. Park, S. Lee, H. Maeda, H.
Aoyagi, T. Kato, Bull. Chem. Soc. Jpn. 1989, 62, 2315; B. J. Williams, P. D. Leeson, G. Hannah, R. Baker,
Chem. Commun. 1989, 1740; J. Ariza, J. Font, R. M. OrtunÄo, Tetrahedron 1990, 46, 1931; A. G. M. Barrett,
D. Dhanak, S. A. Lebold, M. A. Russell, J. Org. Chem. 1991, 56, 1894; R. F. W. Jackson, A. B. Rettie,
Tetrahedron Lett. 1993, 34, 2985; C. Schmeck, L. Hegedus, J. Am. Chem. Soc. 1994, 116, 9927. V. Jäger, R.
Müller, T. Leibold, M. Hein, M. Schwarz, M. Fengler, L. Jaroskova, M. Pätzel, P.-V. LeRoy, Bull. Soc. Chim.
Belg. 1994, 103, 491; G. Casiraghi, F. Zanardi, Chem. Rev. 1995, 95, 1677.
[3] B. Stanovnik, Molecules 1996, 1, 123; B. Stanovnik, ꢁMethyl 2-(Benzoylamino)-3-(dimethylamino)prope-
noate in the Synthesis of Heterocyclic Systemsꢀ, in ꢁProgress in Heterocyclic Chemistryꢀ, Eds. H. Suschitzky,
E. F. V. Scriven, Pergamon Press, Oxford, 1993, Vol. 5, p. 34.
Ï
Ï
Ï
[4] L. Selic, S. Golic-Grdadolnik, B. Stanovnik, Helv. Chim. Acta 1997, 80, 2418; J. Smodis, B. Stanovnik,
Ï
Ï
Tetrahedron 1998, 54, 9799; L. Selic and B. Stanovnik, Helv. Chim. Acta 1998, 81, 1634; L. Selic, S. Strah, R.
Toplak, B. Stanovnik, Heterocycles 1998, 47, 1017; L. Pizzioli, B. Ornik, J. Svete, B. Stanovnik, Helv. Chim.
Ï
Ï
Acta 1998, 81, 231; U. Bratusek, A. Hvala, B. Stanovnik, J. Heterocycl. Chem. 1998, 35, 1281; G. Sorsak, S.
Ï
Ï
Golic-Grdadolnik, B. Stanovnik, J. Heterocycl. Chem. 1998, 35, 1275; L. Selic, B. Stanovnik, J. Heterocycl.
Ï
Ï
Chem. 1998, 35, 1527; L. Selic, B. Stanovnik, Synthesis 1999, 479; R. Toplak, J. Svete, B. Stanovnik, S. Golic-
Ï
Grdadolnik, J. Heterocycl. Chem. 1999, 35, 225; R. Toplak, J. Svete, S. Golic-Grdadolnik, B. Stanovnik,
Coll. Czech. Chem. Commun. 1999, 64, 177.
Ï
Ï
Ï
Ï
[5] M. Skof, J. Svete, B. Stanovnik, L. Golic, S. Golic-Grdadolnik, L. Selic, Helv. Chim. Acta 1998, 81, 2332.

766
Helvetica Chimica Acta ± Vol. 83 (2000)
Ï
Ï
Ï
Ï
Ï
Ï
Ï
Ï
[6] M. Skof, J. Svete, M. Kmetic, B. Stanovnik, S. Golic-Grdadolnik, Eur. J. Org. Chem. 1999, 1581.
[7] M. Skof, J. Svete, B. Stanovnik, Heterocycles 1999, 51, 1051.
[8] M. Skof, J. Svete, B. Stanovnik, Heterocycles 2000, 52, 845.
[9] M. Skof, J. Svete, B. Stanovnik, Heterocycles 2000, 52, 339.
[10] M. Skof, J. Svete, B. Stanovnik, J. Heterocycl. Chem., in press.
[11] M. Skof, J. Svete, B. Stanovnik, Acta Chim. Slov. 1999, 46, 567 (see also http//acta.chem-soc.si).
[12] A. N. Bowler, P. M. Doyle, D. W. Young, Chem. Commun. 1991, 314; A. Dinsmore, P. M. Doyle, D. W.
Young, Tetrahedron Lett. 1995, 36, 7503; A. N. Bowler, A. Dinsmore, P. M. Doyle, D. W. Young, J. Chem.
Soc., Perkin Trans. 1 1997, 1297.
Received December 27, 1999