Synthesis of novel asymmetrical 1,4-dihydropyridine derivatives

Article abstract of DOI:10.1080/00397910500297305

Asymmetrical 1,4-dihydropyridine esters 3a and 3i-k were synthesized from the symmetrical precursor 1 through the intermediate 2-bromomethyl derivative 2. Then, compound 3a was subjected to a different transformation for preparation of 1,4-dihydropyridine

Full text of DOI:10.1080/00397910500297305

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Synthesis of Novel
Asymmetrical
1,4‐Dihydropyridine
Derivatives
Adeleh Moshtaghi Zenouz a , Mina Raisossadat Oskuie
a & Shirin Mollazadeh a
a Chemistry Department, Faculty of Science,
Azarbaijan University of Tarbiat Moallem, Tabriz,
Iran
Available online: 22 Aug 2006
To cite this article: Adeleh Moshtaghi Zenouz, Mina Raisossadat Oskuie & Shirin
Mollazadeh (2005): Synthesis of Novel Asymmetrical 1,4‐Dihydropyridine Derivatives,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:22, 2895-2903
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Synthetic Communicationsw, 35: 2895–2903, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500297305
Synthesis of Novel Asymmetrical
1,4-Dihydropyridine Derivatives
Adeleh Moshtaghi Zenouz, Mina Raisossadat Oskuie,
and Shirin Mollazadeh
Chemistry Department, Faculty of Science, Azarbaijan University
of Tarbiat Moallem, Tabriz, Iran
Abstract: Asymmetrical 1,4-dihydropyridine esters 3a and 3i–k were synthesized
from the symmetrical precursor 1 through the intermediate 2-bromomethyl derivative
2. Then, compound 3a was subjected to a different transformation for preparation of
1,4-dihydropyridine derivatives 3b–h.
Keywords: Calcium channel blockers, 1,4-dihydropyridines, Hantzsch esters,
Hantzsch synthesis
INTRODUCTION
The 1,4-dihydropyridine Ca2þ channel blockers are clinically significant anti-
hypertensive drugs[1–3]and have been immensely valuable as molecular tools
with which to probe structural and functional aspects of Ca2þ channel
function.[4,5]
Most of the 1,4-dihydropyridines were prepared via the Hantzsch
procedure,[6] employing all the components in different combinations
(Scheme 1). This procedure is simple, and isolation of the product is
generally straightforward. It works moderately well for symmetrical dihydro-
pyridines, but the yield of the desired products decreases very rapidly for
asymmetrically substituted dihydropyridines.[7] In this work we synthesized
some new derivatives of asymmetrically substituted 1,4-dihydropyridine
Received in the UK January 16, 2005
Address correspondence to Adeleh Moshtaghi Zenouz, Chemistry Department,
Faculty of Science, Azarbaijan University of Tarbiat Moallem, Tabriz, Iran. E-mail:
adelehmz@yahoo.com
2895

2896
A. M. Zenouz, M. R. Oskuie, and S. Mollazadeh
Scheme 1. Hantzsch synthesis of 1,4-DHPs.
rings. The compounds 3a and 3i–k were synthesized by using nucleophilic
attack of thiourea, 2-mercapto-4,6-dimethyl pyrimidine, 6-methyl-2-thioura-
cil, and sodium azide on the 2-bromomethyl-l,4-dihydropyridine 2. The
others were obtained by different transformation of isothiouronium salt 3a.
RESULTS AND DISCUSSION
Synthesis was started by Hantzsch reaction of ethyl acetoacetate with
3-nitrobenzaldehyde and ammonia in refluxing ethanol, which afforded the
1,4-dihydropyridine 1 in 58% yield. Reaction of 1 with l. l equivalents of pyri-
dinium bromide perbromide in dichloromethane/pyridine at 2208C for
45 min afforded the crude product 2 as a yellow gum. We have already
published the synthesis of 2 in high yield[8] by modifying the literature
methods.[7,9,10] Without further purification this brominated adduct was
coupled with a range of nucleophiles at different conditions to give 2-substi-
tuted 1,4-dihydropyridines 3a and 3i–k (see Table 1).
In spite of the low stability of 2, which undergoes decomposition upon
heating to yield the expected lactone. It reacts with thiourea, 2-mercapto-
4,6-dimethyl pyrimidine, and sodium azide in refluxing ethanol in high to
moderate yields. In the reaction of 2 with thiourea in refluxing ethanol for
5 h, evaporation of solvent, and recrystallization from EtOAc/Hex, isothio-
uronium salt 3a is formed (entry 1). Transformation of isothiouronium salt
3a into its isothiourea 3b, as free base,was carried out by treatment of 3a in
CH2C12/H2O with Na2CO3 with vigorous stirring at room temperature
(entry 2). Because the isothioureido group may easily be introduced and
isothiourea is easily transformed, the process is particularly flexible and

Asymmetrical 1,4-Dihydropyridine Derivatives
2897
Table 1. Compounds of 3
Entry
Product
R
Yield (%)
Mp (8C)
199.5a
1
2
3a
3b
80
60
126–127
3
4
5
6
7
3c
3d
3f
-SSDHP
-SH
-S CH3
30
45
47
55
49
184–185
143a
119–120
Oil
3g
3h
-S (CH2)5 CH3
-S CH2CH ¼ CH2
125–126.5
8
3i
80
177–178
9
3j
31
60
204–206
122–123
10
3k
-N3
aIt decomposes at the melting point.
adaptable to different synthetic procedures. During purification of 3b by
recrystallization from protic solvents such as ethanol, it decomposes to a
thiol derivative that it is oxidized and converted to disulfide derivative 3c
(entry 3). Hydrolysis of ethanolic solution of 3b into thiol derivative 3d was
performed under an inert gas atmosphere in the presence of aqueous sodium
hydroxide solution at room temperature for 30 min (entry 4). By increasing
the reaction time (1.5 h), the only product of this reaction was thiolactone
derivative 3e, which resulted from the nucleophilic attack of intermediate thio-
late anion on adjacent ester group (Scheme 2). Additionally, to prepare the
diasteromeric salts of 3b, the mixture of 3b and (1S)-(þ)-camphor-10-
sulfonic acid in CH3CN was refluxed for 4 h but the product obtained was
the thiol derivative 3d. Conversely, reaction of isothiouronium salt 3a with
electrophilic species RX (methyl iodide, 1-bromo hexane, and allyl
bromide) in the presence of base produces S-alkylated derivatives 3f, 3g,
and 3h respectively (Scheme 2). 2-Mercapto-4,6-dimethyl pyrimidine was

2898
A. M. Zenouz, M. R. Oskuie, and S. Mollazadeh
Scheme 2.
reacted easily with 2 in refluxing ethanol to give 3i in high yield without any
base (entry 8). However, reaction of 6-methyl-2-thiouracil with 2 needs basic
conditions (entry 9).
The reaction of 2 with sodium azide in refluxing ethanol for 24 h gave 3 k
(entry 10). The reduction of 3 k with NaBH4 in refluxing ethanol for 1 h
afforded the lactam derivative 31, which resulted from the nucleophilic
attack of in situ–obtained amin derivative on an adjacent ester group
(Scheme 3).
EXPERIMENTAL
S-[(6-Methyl-3,5-dicarboethoxy-4-(3-nitrophenyl)1,4-
dihydropyridin-2-yl)-methyl]-isothiouronium bromide 3a
A mixture of 2-bromomethyl-3,5-dicarboethoxy-4-(3-nitrophenyl)-6-methyl-
l,4-dihydropyridine[8] (obtained from 1.34 mmol of 1), thiourea (0.11 g,
Scheme 3.

Asymmetrical 1,4-Dihydropyridine Derivatives
2899
1.47 mmol), and ethanol (40 ml) was heated to reflux for 5 h and then evapo-
rated. Recrystallization of crude product from EtOAc/Hex furnished 3a
(0.56 g, 80%) as yellow crystals.
IR (KBr) n ¼ 3500–2600 (broad s), 1700 (s), 1662 (s), 1653 (s), 1528 (s),
¯
1
1349 (s) cm21; H NMR (400 MHz, DMSO-d6): d ¼ 1.13 (m, 6H, 2 ꢀ CH3
ester), 2.50 (s, 3H, CH3-6), 4.02 (m, 4H, 2 ꢀ CH2 ester), 4.54 (s, 2H, CH2-2),
4.98 (s, 1H, CH-4), 7.60–8.04 (m, 4H, ArH), 9.35 (br s, 4H, NH), 10.04
(br s, 1 H, NH) ppm.
S-[(6-Methyl-3,5-dicarboethoxy-4-(3-nitrophenyl)1,4-
dihydropyridin-2-yl)-methyl]-isothiourea 3b
Sodium bicarbonate (0.08 g, 0.94 mmol) was added to the miture of 3a (0.5 g,
0.94 mmol) in CH2Cl2/H2O (2 : 1, 15 ml) at room temperature and under
vigorous stirring. After 30 min stirring at room temperature, the organic
phase was separated, washed with water, dried over Na2SO4, and evaporated.
Recrystallization of crude product from Et2O furnished 3b (0.25 g, 60%) as
yellow crystals.
IR (KBr) n ¼ 3416 (s), 3319 (s), 3205 (m), 3066 (w), 2978 (w), 1696 (s),
¯
1679 (s), 1637 (s), 1518 (s), 1348 (s) cm21
,
1H NMR (400 MHz, CDCl3):
d ¼ 1.22 (t, J ¼ 8 Hz, 6H, 2 ꢀ CH3 ester), 2.30 (s, 3H, CH3-6), 4.01–4.14
(m, 4H, 2 ꢀ CH2 ester), 4.40 (AB quartet, J ¼ 14 Hz, 2H, CH2-2), 5.09
(s, 1H, CH-4), 7.37 (t, J ¼ 8 Hz, 1H, ArH), 7.65 (d, J ¼ 8 Hz, 1H, ArH), 8.00
(m, 1H, ArH), 8.15 (m, 1H, ArH), 10.04 (br s, 1H, NH); anal, calcd. for
C20H24N4O6S: C, 53.57; H, 5.35; N, 12.50. Found: C, 53.44; H, 5.60; N, 12.64.
Bis-[(6-Methyl)-3,5-dicarboethoxy-4-(3-nitrophenyl)1,4-
dihydropyridin-2-yl)-methyl]-disulfide 3c
After preparation of 3b recrystallization was performed in EtOH and 3c was
obtained in 30% yield.
IR (KBr) n ¼ 3320 (s), 3100 (m), 2985 (m), 1700 (s), 1355 (s) cm21; 1H
¯
NMR (400 MHz, CDC13): d ¼ 1.17 (t, J ¼ 8 Hz, 12H, 4 ꢀ CH3 ester), 2.22
(s, 6H, CH3-6, CH3-60), 3.99–4.06 (m, 12H, 4 ꢀ CH2 ester, CH2-2, CH2-20),
5.06 (s, 2H, H-4, H-40), 6.77 (br s, 2H, NH), 7.29–8.10 (m 8H, ArH ppm;
anal. calcd. for C38H42N4O12S2: C, 56.29; H, 5.22; N, 6.91. Found: C, 56.0;
H, 5.30; N, 6.82.
2-Mercaptomethyl-3,5-dicarboethoxy-6-methyl-4-(3-nitrophenyl)-
1,4-dihydropyridine 3d
An aqueous solution of NaOH (32%, 0.5 ml) was added to a stirred solution
of 3a (0.5 g, 0.94 mmol) in ethanol/water (1 : 1, 25 ml) under an argon

2900
A. M. Zenouz, M. R. Oskuie, and S. Mollazadeh
atmosphere. After 30 min stirring, at rt and evaporating the solvent, the residue
was partitioned between CH2C12 and 2 M HCI, and the organic layer washed
with water, dried over Na2SO4, and evaporated. The crude product was
purified by column chromatography on silica gel using EtOAc/Hex 3 : 2 as
eluent. An appropriate fraction (Rf ¼ 0.75) was obtained (0.17 g, 45%) as a
yellow solid.
IR (KBr) n ¼ 3340 (s), 3050 (w), 2963–2850 (m), 2510 (w), 1700 (s),
¯
1650 (s), 1529 (s), 1497 (s), 1373 (s), 1261 (s), 1214 (s), 1095 (s), 801 (s)
1
cm21; H NMR (400 MHz, CDC13): d ¼ 1.22 (t, J ¼ 8 Hz, 6H, 2 ꢀ CH3
ester), 2.02 (m, 1H, SH), 2.39 (s, 3H, CH3-6), 3.80 (m, 1H, H-2), 3.95
(m, 1H, H-2), 4.08 (m, 4H, 2 ꢀ CH2 ester), 5.09 (s, 1H, CH-4), 6.56 (s, 1H,
NH), 7.38 (t, J ¼ 8 Hz, 1H, ArH), 7.63 (d, J ¼ 8 Hz, 1H, ArH), 8.00
(d, J ¼ 8 Hz, 1H, ArH), 8.12 (s, 1 H, ArH) ppm.
Thiolactone Derivative 3e
The experimental procedure is the same as for 3d, only the reaction time was
increased to 90 min. The compound 3e (Rf ¼ 0.15 in EtOAc/Hex 3 : 2) was
obtained in 57% yield.
Mp171–1728C;IR(KBr) n ¼ 3320(s), 3080(w), 2963–2850(m), 1700 (s),
¯
1645 (s), 1520 (m), 1490 (s), 1350 (s) 1261 (s), 1100 (s), 800 (s) cm21; 1H NMR
(400 MHz, CDCl3): d ¼ 1.13 (t, J ¼ 7.2 Hz, 3H, CH3 ester), 2.43 (s, 3H, CH3-6),
3.87 (AB quartet, J ¼ 20Hz, 2H, CH2-2), 4.03 (q, J ¼ 7.2 Hz, 2H, CH2 ester),
5.09 (s, 1H, CH-4), 7.38 (s, 1H, NH), 7.43 (t, J ¼ 8 Hz, 1H, ArH) 7.68
(d, J ¼ 8 Hz, 1H, ArH), 8.04 (m, 1H, ArH) ppm; anal. calcd. for
C17H16N2O5S: C, 60.00; H, 4.70; N, 8.23. Found: C, 60.40; H, 4.86; N, 8.63.
2-(Methyl thio)-methyl-3,5-dicarboethoxy-6-methyl-4-(3-
nitrophenyl)-1,4-dihydropyridine 3f
An aqueous solution of NaOH (32%, 1 ml) was added to a stirred solution of
3a (1 g, 1.89 mmol) and methyl iodide (1.22 g, 4.54 mmol) in ethanol/water
(1 : 1, 40 ml) under an argon atmosphere. After 3 h stirring at room tempera-
ture, the mixture was filtered. Recrystallization of the crude product from
ethanol furnished compound 3f in 47% yield.
IR (KBr) n ¼ 3320 (s), 3094 (w), 2980–2850 (m), 1676 (s), 1644 (m),
¯
1620 (m), 1527 (s), 1494 (s), 1351 (s), 1289 (s), 1212 (s), 1101 (s) cm21
;
1H NMR (400 MHz, CDC13): d ¼ 1.16 (t, J ¼ 7.2 Hz, 6H, 2 ꢀ CH3 ester),
1.99 (s, 3H, S-CH3), 2.34 (s, 3H, CH3-6), 3.86–4.07 (m, 6H, 2 ꢀ CH2 ester,
CH2-2), 5.06 (s, 1H, H-4), 6.92 (s, lH, NH), 7.31 (t, J ¼ 7.6 Hz, 1H, ArH)
7.57 (d, J ¼ 7.6 Hz, IH, ArH), 7.94 (d, J ¼ 7.6 Hz, 1H, ArH), 8.07 (s, 1H,
ArH) ppm; anal. calcd. for C20H24N2O6S: C, 57.14; H, 5.71; N, 6.66.
Found: C, 57.51; H, 5.83; N, 7.05.

Asymmetrical 1,4-Dihydropyridine Derivatives
2901
2-(n-Hexyl thio)-methyl-3,5-dicarboethoxy-6-methyl-4-(3-
nitrophenyl)-1,4-dihydropyridine 3g
An aqueous solution of NaOH (32%, 1 ml) was added to a stirred solution of
3a (1 g, 1.89 mmol) and 1-bromo hexane (0.74 g, 4.54 mmol) in ethanol/water
(l : l, 40 ml) under an argon atmosphere. After 20 h stirring at room tempera-
ture, the mixture was diluted with water (10 ml) and extracted with CH2C12
(20 ml). The organic phase was washed with 2 M HCl and water, dried over
Na2SO4, and evaporated. The crude product was purified by preparative
chromatography on silica gel using EtOAc/hexane 2 : 3 as eluent. An appro-
priate fraction (Rf ¼ 0.65) was obtained as a yellow oil in 55% yield.
IR (neat) n ¼ 3350 (m), 3020 (w), 2962 (m), 1688 (s), 1529 (s), 1474 (s),
¯
1
1351 (s), 1216 (s), 1100 (s) cm21; H NMR (400 MHz, CDCl3): d ¼ 0.77
(t, J ¼ 7.2 Hz, 3H, CH3), 1.09–1.27 (m, 12H, 2 ꢀ CH3 ester, 3 ꢀ CH2),
1.42–1.49 (m, 2H, CH2), 2.33 (s, 3H, CH3-6), 2.39 (t, J ¼ 7.2 Hz, 2H
S-CH2), 3.88–4.08 (m, 6H, 2 ꢀ CH2 ester, CH2-2), 5.06 (s, 1H, CH-4),
7.08 (s, lH, CH-4), 7.31 (t, J ¼ 8 Hz, 1H, ArH), 7.56 (m, 1H, ArH), 7.93
(m, lH, ArH), 8.06 (m, lH, ArH) ppm; anal. calcd. for C25H32N2O6S: C,
61.22; H, 6.94; N, 5.71. Found: C, 60.96; H, 6.91; N, 6.03.
2-(Allyl thio)-methyl-3,5-dicarboethoxy-6-methyl-4-(3-
nitrophenyl)-1,4-dihydropyridine 3h
An aqueous solution of NaOH (32%, 1 ml) was added to a stirred solution of
3a (1 g, 1.89 mmol) and allyl bromide (0.55 g, 4.54 mmol) in ethanol/water
(1 : 1, 40 ml) under an argon atmosphere. After 1 h stirring at room tempera-
ture, the mixture was filtered. Recrystallization of the crude product from
ethanol furnished compound 3h as yellow needle crystals in 49% yield.
IR (KBr) n ¼ 3319 (s), 3091 (w), 2978–2850 (m), 1675 (s), 1639 (m),
¯
1
1619 (m), 1527 (s), 1350 (s), 1288 (s), 1211 (s), 1101 (s) cm21; H NMR
(500 MHz, CDC13): d ¼ 1.16 (t, J ¼ 6.8 Hz, 6H, 2 ꢀ CH3 ester), 2.35
(s, 3H, CH3-6), 3.05 (d, J ¼ 7.2 Hz, 2H, S-CH2), 3.88–4.10 (m, 6H,
2 ꢀ CH2 ester, CH2-2), 4.93–5.02 (m, 2H,55CH2), 5.06 (s, 1H, CH-4),
5.66–5.76 (m, 1H,55CH), 6.93 (s, lH, NH), 7.31 (t, J ¼ 6.8 Hz, 1H, ArH),
7.57 (d, J ¼ 7.6 Hz, 1H, ArH), 7.96 (m, 1H, ArH), 8.06 (m, lH, ArH) ppm;
anal. calcd. for C22H26N2O6S: C, 59.19; H, 5.83; N, 6.27. Found: C, 58.83;
H, 5.89; N, 6.42.
2-[(4,6-Dimethyl Pyrimidin-2-yl)thio-]-methyl-3,5-dicarboethoxy-6-
methyl-4-(3-nitrophenyl)-1,4-dihydropyridine 3i
A mixture of 2-bromomethyl-3,5-dicarboethoxy-6-methyl-4-(3-nitrophenyl)-
1,4-dihydropyridine (obtained from 2.3 mmol of 1), 2-mercapto-4,6-

2902
A. M. Zenouz, M. R. Oskuie, and S. Mollazadeh
dimethyl pyrimidine (0.35 g, 2.5 mmol), and ethanol (20 ml) was heated to
reflux for 0.5 h and then evaporated. The residue was partitioned between
CH2Cl2 (30 ml) and saturated Na2CO3 solution, and the organic layer, was
washed with water, dried over Na2SO4, and evaporated. Recrystallization of
crude product from 2-propanol furnished 3i 0.942 g, 80%) as yellow crystals.
IR (KBr) n ¼ 3350 (s), 3050 (m), 2982 (m), 1689 (s), 1647 (s), 1532 (s),
¯
1
1348 (s) cm21; H NMR (400 MHz, CDCl3): d ¼ 1.23 (m, 6H, 2 ꢀ CH3
ester), 2.29 (s, CH3-6), 2.50 (s, 6H, 2 ꢀ CH3), 4.00–4.20 (m, 4H, 2 ꢀ CH2
ester), 4.52 (AB quartet, J ¼ 18 Hz, 2H, CH2-2), 5.10 (s, 1H, CH-4), 6.83
(s, 1H, H-5 pyrimidine), 7.35–8.15 (m, 4H, ArH), 8.75 (br s,1H, NH) ppm;
anal. calcd. for C25H28N4O6S: C, 58.58; H, 5.51; N, 10.93. Found: C,
58.60; H, 5.35; N, 11.00.
2-(6-Methyl-2-thiouracil-2-yl)-methyl-3,5-dicarboethoxy-6-methyl-
4-(3-nitrophenyl)-1,4-dihydropyridine 3j
A mixture of 6-methyl-2-thiouracil (0.04 g, 0.3 mmol), aq. NaOH (3 ml,
0.3 mmol), and MeOH (20 ml) was stirred at rt for 1 h. Then 2-bromo-
methyl-3,5-dicarboethoxy-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine
(obtained from 0.8 mmol of 1) was added and the mixture stirred at room
temperature for 2 h. After evaporating the solvent, the residue was partitioned
between CH2C12 and 2M HCI, the organic layer was washed with water, dried
over Na2SO4, and evaporated. Recrystallization of crude product from
2-propanol furnished 3j (0.27 g, 31%) as yellow crystals.
IR (KBr) n ¼ 3208, 3082, 1676, 1585, 1525, 1348 cm21
;
1H NMR
¯
(500 MHz, CDC13): d ¼ 1.23 (m, 6H, 2 ꢀ CH3 ester), 2.34 (s, 3H, CH3-6),
2.41 (s, 3H, CH3), 4.02–4.17 (m, 4H, 2 ꢀ CH2 ester), 4.55 (d, J ¼ 14.5 Hz,
1H, CH2-2), 4.63 (d, J ¼ 14.5 Hz, 1H, CH2-2), 5.01 (s, 1H, CH-4), 6.16
(s, 1H, H-5 uracil), 7.39–8.15 (m, 4H, ArH), 8.53 (br s, 1H, NH), 13.01 (br
s, IH, NH) ppm; anal. calcd. for C24H26N4O7S: C, 56.03; H, 5.05; N, 10.89.
Found: C, 56.23; H, 5.01; N, 11.03.
2-Azidomethyl-6-methyl-3,5-dicarboethoxy-4-(3-nitrophenyl)-1,4-
dihydropyridine 3k
A mixture of 2-bromomethyl-3,5-dicarboethoxy-6-methyl-4-(3-nitrophenyl)-
1,4-dihydropyridine (obtained from 2.67 mmol of 1), sodium azide (0.18 g,
2.84 mmol) and ethanol (40 ml) was heated to reflux for 24 h and then evapo-
rated. The residue was partitioned between CH2C12 (20 ml) and 2 M HCl
solution, and the organic layer was washed with water, dried over Na2SO4,
and evaporated. Recrystallization of crude product from Et2O furnished 3k
in 60% yield.

Asymmetrical 1,4-Dihydropyridine Derivatives
2903
IR (KBr) n ¼ 3354 (s), 3050 (w), 2978–2850 (m), 2107 (s), 1693 (s),
¯
1653 (m), 1625 (m), 1527 (s), 1487 (s), 1351 (s), 1273 (s), 1200 (s), 1099
1
(s) cm21; H NMR (400 MHz, CDCl3): d ¼ 1.22 (m, 6H, 2 ꢀ CH3 ester),
2.41 (s, 3H, CH3-6), 4.09 (m, 4H, 2 ꢀ CH2 ester), 4.82 (AB quartet, J ¼ Hz,
2H, CH2-2), 5.10 (s, 1H, CH-4), 6.69 (s, 1H, NH), 7.39 (t, J ¼ 6.8 Hz, lH,
ArH), 7.62 (m, 1H, ArH), 8.03 (m, 1H, ArH), 8.12, (m, 1H, ArH) ppm;
anal. calcd. for C19H21N5O6: C, 54.94; H, 5.06; N, 16.86. Found: C, 55.06;
H, 5.10; N, 16.54.
Lactam Derivative 3l
A mixture of 3k (0.1 g, 0.24 mmol), sodium borohydride (0.03 g, 0.96 mmol),
and ethanol (20 ml) was heated to reflux for 1 h and then evaporated. The
residue was partitioned between CH2Cl2 (20 m1) and 10% HCl solution,
and the organic layer was washed with water, dried over Na2SO4, and
evaporated. Recrystallization of crude product from CH2C12/Hex furnished
31 in 54% yield.
Mp 225–2278C; IR (KBr) n ¼ 3354 (s), 3250 (m), 3060 (w), 2978–2850
¯
(w), 1671 (s), 1524 (s), 1346 (s), 1203 (s), 1088 (s) cm21; 1H NMR (400 MHz,
CDCl3): d ¼ 1.11 (t, J ¼ 8 Hz, 3H, CH3 ester), 2.41 (s, 3H, CH3-6), 3.83–4.14
(m, 4H, CH2 ester and CH2-2): 5.05 (s, lH, CH-4), 6.08 (s, lH, NH), 6.94 (s, lH,
NH), 7.39 (t, J ¼ 8 Hz, lH, ArH) 7.69 (d, J ¼ 8 Hz, lH, ArH), 7.99
(d, J ¼ 8 Hz, 1H, ArH), 8.10 (s, 1H, ArH) ppm.
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