An efficient one-pot synthesis of novel polysubstituted 4-amino-2,3-dihydropyridines

Article abstract of DOI:10.1016/j.tetlet.2011.01.017

A convenient and efficient one-pot multi-component synthesis of novel polysubstituted 4-amino-2,3-dihydropyridines from carbonyl compounds, malononitrile and acetonitrile, using indium triflate is reported. Acetonitrile acts both as a solvent as well as a

Full text of DOI:10.1016/j.tetlet.2011.01.017

Tetrahedron Letters 52 (2011) 1265–1268
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient one-pot synthesis of novel polysubstituted
4-amino-2,3-dihydropyridines
Nitu Mahajan a, Ambika Sambyal a, Ajay P. S. Pannu b, T. K. Razdan a,
⇑
a Department of Chemistry, University of Jammu, Ambedkar Road, Jammu 180 006, India
b Department of Chemistry, G.N.D. University, Amritsar, Punjab 154 003, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and efficient one-pot multi-component synthesis of novel polysubstituted 4-amino-2,3-
dihydropyridines from carbonyl compounds, malononitrile and acetonitrile, using indium triflate is
reported. Acetonitrile acts both as a solvent as well as a substrate.
Received 19 November 2010
Revised 23 December 2010
Accepted 7 January 2011
Available online 20 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aldehydes
2,3-Dihydropyridines
Indium triflate
Ketones
Malononitrile
Multi-component reaction
Dihydropyridines constitute an important class of bioactive het-
erocycles.1–5 Among these, 4-substituted 1,4-dihydropyridines are
established calcium channel regulators and their synthesis has
been the subject of extensive study.6–12 On the other hand, the syn-
thesis of 2,3-dihydropyridines,which are useful intermediates in
the formation of biologically active substances, has not received
adequate attention. This may be due to their tendency to undergo
facile disproportionation to pyridine derivatives.13 The known
methods for the synthesis of 2,3-dihydropyridines include the
oxidative dehydrogenation of tetrahydropyridine,14 thermal cycli-
zation of allene amidines,15 acid catalyzed cyclization of some
2,4-dinitrophenyl hydrazones,16 Ritter reaction of saturated and
unsaturated diols17 and the reduction of pyridinium salts.18 Trial-
kyl 2,3-dihydropyridinium salts have been prepared by the Lewis
acid catalyzed condensation–cyclization of acyclic aldehydes and
benzyl ammonium chloride.19 These reactions also afforded the
corresponding pyridinium salts in the ratio of 3:1. Despite their
attractiveness, most of the known methodologies are associated
with the limitations of stringent reaction conditions, formation of
multitude of products, and poor yield. Therefore, a simple and
efficient synthetic methodology for the preparation of usefully
functionalized 2,3-dihydropyridines is still desirable.
organic chemistry.20–22 Our aim to establish a synthetic methodol-
ogy for the one-pot preparation of stable polysubstituted 2,3-dihy-
dropyridines, from the readily accessible substrates, led us to
explore the reaction of alkyl and aryl ketones with malononitrile
and acetonitrile in the presence of Lewis acids. Herein, we wish
to report a simple and efficient one-pot synthesis of novel polysub-
stituted 2,3-dihydropyridines, under ambient reaction conditions,
and their subsequent semi-synthetic transformation to carboxylic
acid and amino derivatives.
Acetonitrile has been used as a solvent in many Lewis acid cat-
alyzed reactions. We assumed that in the presence of Lewis acids,
acetonitrile, by virtue of the presence of a triple bond, may partic-
ipate actively in chemical reactions and behave as a substrate as
well. Initially, we studied the reaction of acetone, malononitrile,
and acetonitrile, in the presence of Lewis acids, at room tempera-
ture, as a model for our methodology. After trying several Lewis
acids viz ZnCl2, BiCl3, TiCl4 and their triflates it was observed that
indium triflate and triethylamine catalyzed the multi-component
reaction, at room temperature, to afford the 2,3-dihydropyridine
(3a), albeit in low yield (40%).
In order to improve the yield, we set out to modify the catalyst
system and found that the addition of a catalytic amount of triflic
acid to the catalyst mixture of In(OTf)3 and triethylamine enhanced
the catalytic activity of the mixture and carried forward the reac-
tion efficiently, at room temperature.
Since, multi-component reactions are flexible, atom-economic,
and eco-friendly they have gained great importance in synthetic
Optimization of the reaction conditions revealed that for the
best performance the concentration of In(OTf)3, Et3N, and triflic
⇑
Corresponding author.
E-mail address: tk_razdan@rediffmail.com (T.K. Razdan).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.017

1266
N. Mahajan et al. / Tetrahedron Letters 52 (2011) 1265–1268
NC
NC
R1
R2
R1
R2
acid in the catalyst mixture was 20 mol %, 1 mol equivalent of ace-
tone, and 0.1 mol %, respectively. Moreover, acetonitrile was
needed in slight excess. With optimized conditions in hand, a mix-
ture of acetone, acetonitrile, and malononitrile (1:5:2 mol) were
stirred, at room temperature, in the presence of the catalyst
mixture.23 The reaction was complete within 8 h and the product
3a separated out as a colorless crystalline solid in 89% yield
(Table 1). Its IR spectrum displayed characteristic absorption bands
at mmax 3333 (NH2), 2210, 2215 (C„N), 1645 (C@N), 1580 (C@N).
The 1H NMR spectrum24 was quite simple and displayed resonance
signals at d 1.35, 1.39, 1.93 (s, 3H each), and 7.04 (s br, exch. D2O,
2H, and NH2). 13C NMR spectrum confirmed the presence of three
nitrile groups, dC 112.0, 113.4, and 114.4. The structure of com-
pound 3a was finally confirmed by XRD (CCDC No. 66716).25
In order to determine the scope and limitations of the indium tri-
flate promoted multicomponent reaction, the reaction was ex-
tended to higher homologs of acetone and various methyl aryl
ketones (Scheme 1). Under optimized reaction conditions, these
reactions afforded the corresponding 4-amino-2,3-dihydropyri-
dine-3,3,5-tricarbonitrile derivatives 3b–3j, as the major products
and in high yield (Table 1). The reaction was also carried out with
different aldehydes. Acetaldehyde did not afford the required 2,3-
dihydropyridine derivative. This may be due to its tendency to poly-
merize. However, the reaction of aromatic aldehydes afforded com-
plex mixtures of compounds, which were not further investigated.
Mechanistically, the reaction leading to the formation of 4-ami-
no-2,3-dihydropyridine-3,3,5-tricarbonitriles seems to proceed by
a condensation-addition reaction (Scheme 2). Acetonitrile func-
tions both as a substrate as well as a solvent. It may be pertinent
to mention here that with the current methodology, we were able
to prepare multigram quantities of the compounds 3a–3j.
NC
NC
In(OTf)3 / Et3N
-H2O
H
N
+
O
+
R1
R2
NC
NC
CN
H2C
H3C
C
N
H3C
NC
C
NH
CN
H
N
CN
N
-H
R1
R2
NC
NC
R1
R2
NC
NC
N
N
CN
H
CN
NH
NH2
Scheme 2. Rationalization of the formation of polysubstituted 2,3-
dihydropyridines.
BF3–Et2O. These results substantiate that for the stability of these
products the presence of a quaternary carbon at position 2 of
2,3-dihydropyridines is essential.
Next, compounds 3a–3j were subjected to metal hydride reduc-
tion. The reduction of 3a–3j with sodium borohydride did not give
satisfactory results. However, reduction with lithium aluminum
hydride proceeded smoothly, at room temperature,28 and afforded
the corresponding compounds 6a–6j in 80–96% yield (Table 3 and
Scheme 5). On spectral analysis,29 the products 6a–6j were found
to result from the regiospecific decyanation and reduction of 3a–
3j. These products were characterized as 4-amino-2,3-dihydropyr-
idine-3,3-dimethyl amine derivatives. While the present study
substantiates that in the presence of metal hydrides
iles undergo decyanation30 it also suggests that in the compounds
possessing several nitrile groups at the -position the group, which
a-aminonitr-
a
is conjugated to an amino group via a double bond is decyanated
The structural features of compounds 3a–3j prompted us to
study their chemical behavior. The compounds did not respond
to hydrolysis with methanolic HCl and NaOH, at room tempera-
ture. However, on heating the compounds with 1 M HCl in 90%
MeOH on a water bath (temp. 99.5 °C) for 36–48 h,25 compounds
3a–3h afforded the corresponding 3,5-dicarboxylic acids
4a–4h26,27 in 60–65% yield (Scheme 3 and Table 2). The reaction
of compounds 3i and 3j afforded a mixture of products, which were
separated by column chromatography on silica gel and were char-
acterized as pyridine derivatives, 4i, 4j and 5i, 5j (Scheme 4). Sim-
ilar results, with improved yield (70–75%) (Table 2), were obtained
by refluxing the methanolic solutions of 3a–3j in the presence of
preferentially than the non-conjugated nitrile groups.
In summary, we have developed a convenient and efficient
three component synthesis of novel polysubstituted 4-amino-2,3-
dihydropyridines, which may be further elaborated to useful prod-
ucts by simple chemical manipulation. The advantages of the
aforementioned methodologies are that the reactions are opera-
tionally simple, efficient, cost-effective, and eco-friendly. The mul-
R1
R1
R2
R2
HO
N
N
(i) HCl - MeOH
(ii) NH4 OH, pH 7.1
NC
OH
or
CN
NC
BF3.Et2O
NH2
O
NH2
O
Table 1
Yield of Products 3a–3j
3a-3h
4a-4h
Compd Reaction time (h) % Yield Compd Reaction time (h) % Yield
3a/4a: R1 = R2 = CH3
3e/4e: R1 = CH3; R2 = C6H5
3b/4b: R1 = CH3; R2 = C2H5
3c/4c: R1 = CH3; R2 = C3H7
3d/4d: R1 = CH3; R2 = C3H7
3f/4f: R1 = CH3; R2 = 4-CH3OC6H5
3g/4g: R1 = CH3; R2 = 4-NO2C6H5
3h/4h: R1 = CH3; R2 = 2-ClC6H5
3a
3b
3c
3d
3e
8
10
10
12
12
89
84
86
88
84
3f
3g
3h
3i
10
12
9
8
8
90
80
81
80
82
Scheme 3. Hydrolysis of 4-amino-2,3-dihydropyridine-3,3,5-tricarbonitrile
derivatives.
3j
R1
Table 2
R1
R2
+
In(OTf) (20 mol %),
3
R2
N
Yield of hydrolyzed products 4a–4j and 5i, 5j
TfOH (0.1 mol %),
+
CN
NC
H3C
C
N
NC
O
Et3N (1 mol eq. of ketone),
room.temp. 8 - 12 h
CN
Compd Reaction % Yield % Yield
Compd Reaction % Yield % Yield
NC
1a-1j
2
NH2
time (h) (HCl–
MeOH)
(BF3ÁEt2O)
time (h) (HCl–
MeOH)
(BF3ÁEt2O)
3a-3j
1a/3a: R1 = R2 = CH3
1f/3f: R1 = CH3; R2 = 4-CH3OC6H5
4a
4b
4c
4d
4e
4f
48
36
36
24
28
26
60
62
64
62
60
65
75
71
74
73
71
72
4g
4h
4i
4j
5i
36
34
24
24
24
24
60
61
32
31
28
27
73
70
24
25
75
73
1b/3b: R1 = CH3; R2 = C2H5
1c/3c: R1 = CH3; R2 = C3H7
1d/3d: R1 = CH3; R2 = C3H7
1e/3e: R1 = CH3; R2 =C6H5
1g/3g: R1 = CH3; R2 = 4-NO2C6H5
1h/3h: R1 = CH3; R2 = 2-ClC6H5
1i/3i: R1 = H; R2 = C2H5
1j/3j: R1 = H; R2 = C3H7
5j
Scheme 1. Preparation of polysubstituted 2,3-dihydropyridines.

N. Mahajan et al. / Tetrahedron Letters 52 (2011) 1265–1268
1267
R2
9. Goldman, S.; Stoltefuss, J. Angew. Chem., Int. Ed. 1991, 30, 1559.
R2
O
R2
NC
N
N
N
(i) HCl - MeOH
10. Jiang, J. L.; Li, A. H.; Jang, S. Y.; Chang, L.; Melman, N.; Moro, S.; Ji, X. D.;
Lobkowsky, E.; Clardy, J.; Jacobson, K. J. Med. Chem. 1999, 42, 3055.
11. Love, B.; Goodman, M.; Snader, K.; Tedeschi, R.; Macko, E. J. Med. Chem. 1974,
17, 956–965.
(ii) NH4 OH, pH 7.1
+
HO
OH
OH
BF .Et O/ MeOH
CN
or
3
2
NC
NH2
NH2
O
NH2
O
12. Bossert, F.; Meyer, H.; Wehinger, E. Angew. Chem., Int. Ed. 1981, 20, 762–769.
13. Charman, H. B.; Rowe, J. M. Chem. Commun. 1971, 476–477.
3i-3j
4i-4j
5i-5j
14. Scriba, G. K. E.; Borchardt, R. T. Brain Res. 1989, 501, 175–178.
15. Fuks, R.; Merenyi, R.; Viehe, H. Bull. Soc. Chim. Belg. 1976, 85, 147.
16. (a) Cavill, G. W. K.; Ford, D. L.; Solomon, D. H. Aust. J. Chem. 1960, 13, 469; (b)
Sakurai, A.; Midorikevich, E. I. Zh. Obshch. Biol. 1960, 30, 3287.
17. (a) Meyers, A. I.; Ritter, J. J. J. Org. Chem. 1958, 23, 1918; (b) Meyers, A. I.;
Schneller, J.; Ralhan, N. K. J. Org. Chem. 1963, 28, 2944; (c) Meyers, A. I.; Betrus,
B. J.; Ralhan, N. K. J. Heterocycl. Chem. 1964, 1, 13.
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Wiley and Sons: New York, 1974.
19. Yu, L. B.; Chen, D.; Li, J.; Ramirez, J.; Wang, P. G. J. Org. Chem. 1997, 62,
208–211.
Scheme 4. Hydrolysis of 3i and 3j.
Table 3
Yield of reduced products 6a–6j
Compd Reaction time (h) % Yield Compd Reaction time (h) % Yield
6a
6b
6c
6d
6e
24
36
36
48
40
94
91
92
90
93
6f
6g
6h
6i
36
48
36
24
38
90
80
94
96
94
20. (a) Ramon, D. J.; Miguel, Y. Angew. Chem., Int. Ed. 2005, 44, 1602–1634; (b) Orru,
R. V. A.; de Greef, M. Synthesis 2003, 1471–1499; (c) Ugi, I.; Heck, S. Comb.
Chem. High Throughput Screening 2001, 4, 1–34; (d) Weber, L.; Illgen, K.;
Almstetter, M. Synlett 1999, 366–374.
6j
21. (a) Tu, S.; Jiang, B.; Zhang, Y.; Jia, R.; Zhang, J.; Yao, C.; Feng, S. Org. Biomol.
Chem. 2007, 5, 355–359; (b) Tejedor, D.; Garcia-Tellado, F. Chem. Soc. Rev. 2007,
36, 484–491; (c) Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley-VCH,
Weinheim: Germany, 2005; (d) Domling, A. Chem. Rev. 2006, 106, 17–89.
22. Wan, J. P.; Gan, S. F.; Sun, G. L.; Pan, Y. J. J. Org. Chem. 2009, 74, 2862–2865.
23. General experimental procedure for the preparation of polysubstituted
dihydropyridines: see Supplementary data.
24. Spectral data of selected polysubstituted dihydropyridines (3a): colorless crystals,
mp 137 °C. IR: mmax cmÀ1 3321, 2986, 2218, 2210, 2209, 1654, 1578, 1400,
1380, 1257, 1156, 994, 874. 1H NMR (CD3)2CO: d 1.35 (s, 3H), 1.39 (s, 3H), 1.93
(s, 3H), 7.04 (s br, exch. D2O, 2H). 13C NMR (CD3)2CO: dC 19.2, 22.3 (2C), 40.8,
49.1, 69.5, 112.0, 113.4, 114.4, 161.4, 166.9. HRMS: m/z (rel. int.) 213.1020
(100) (M+), (calcd for C11H11N5, 213.1014), 187 (58), 172 (72), 107 (34), 106
(28), 66 (35), 41 (42). Anal. Calad for CHN: C, 61.96; H, 5.20; N, 32.84. Found: C,
61.99; H, 5.25; N, 32.86. Compound 3f: colorless crystals, mp 144 °C. IR: mmax
cmÀ1 3325, 2984, 2210, 2209, 1648, 1562, 1465, 1450, 1375, 1350, 1270, 1145,
986, 876. 1H NMR (CD3)2CO: d 1.20 (s, 3H), 1.89 (s, 3H), 2.62 (s br, exch. D2O,
2H), 3.76 (s, 3H), 7.02 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H). 13C NMR
(CD3)2CO: dC 19.6, 26.1, 48.1, 51.3, 57.1, 69.5, 112.2, 114.6, 114.8, 125.4 (2C),
128.6 (2C), 151.2, 158.0, 161.2, 166.7. HRMS: m/z (rel. int.) 305.1282 (100)
(M+), (calcd for C17H15N5O, 305.1277), 279 (59), 264 (73), 198 (26), 107 (38), 66
(33), 41 (45). Anal. Calad for CHN: C, 66.87; H, 4.95; N, 22.94. Found: C, 66.86;
H, 4.99; N, 22.91.
R1
R1
R2
H2N
R2
N
N
NC
LAH, THF, 24 - 48 h
room temp.
CN
NC
H2N
NH2
NH2
3a - 3j
6a - 6j
3a/6a: R1 = R2 = CH3
3f/6f: R1 = CH3; R2 = 4-CH3OC6H5
3g/6g: R1 = CH3; R2 = 4-NO2C6H5
3h/6h: R1 = CH3; R2 =2-ClC6H5
3i/6i: R1 = H; R2 = C2H5
3b/6b: R1 = CH3; R2 = C2H5
3c/6c: R1 = CH3; R2 = C3H7
3d/6d: R1 =CH3; R2 = C3H7
3e/6e: R1 = CH3; R2 = C6H5
3j/6j: R1 = H; R2 = C3H7
Scheme 5. Lithium aluminum hydride reduction of 4-amino-2,3-dihydropyridine-
3,3,5-tricarbonitrile derivatives.
ticomponent reaction of ketones, malononitrile, and acetonitrile
can be scaled up easily. Moreover, the synthesized compounds
may also find significant use for the preparation of complex nitro-
gen heterocycles, with useful pharmacological properties. The
scope of the reaction and further synthetic applications of these
products are currently under investigation in our laboratory.
25. For XRD studies, single crystals were obtained by slow evaporation of the
acetone–chloroform solution of the compound. The compound crystallized in
triclinic form (Table 1 of Supplementary data). The ORTEP diagram of the
compound 3a is given in the Supplementary data for this Letter.
26. General procedure for hydrolysis of 3a–3j: see Supplementary data.
27. Spectral data of selected hydrolysis products (4a): colorless crystals, mp 171 °C.
IR: mmax cmÀ1 3448, 3116, 2925, 2851, 2670, 1691 (COOH), 1607, 1542, 1430,
1351, 1200, 1110, 1014, 932. 1H NMR (CD3OD): d 1.20 (s, 6H), 1.86 (s, 3H), 2.60
(s br, exch. D2O, 2H), 3.10 (s, 1H), 11.46 (s br, exch. D2O, 1H), 12.51 (s br, exch.
D2O, 1H). 13C NMR (CD3OD): dC 22.7, 27.5, 28.3, 43.3, 69.5, 113.9, 167.3, 168.2,
170.0, 178.1. HRMS: m/z (rel. int.) 226.0959 (100) (M+), (calcd for C10H14N2O4,
226.0954), 182 (45), 166 (60), 138 (65), 122 (72), 85 (77). Anal. Calad for CHN:
C, 53.09; H, 6.24; N, 12.38. Found: C, 53.12; H, 6.26; N, 12.32. Compound 4i:
colorless crystals, mp 210 °C. IR: mmax cmÀ1 3452, 3224, 3181, 2673, 1692,
1605, 1572, 1547, 1530, 1410, 1350, 1210, 985. 1H NMR (CD3OD): d 1.24 (t,
J = 6.9 Hz, 3H), 2.56 (s, 3H), 2.36 (q, J = 6.9 Hz, 2H), 4.56 (s br, exch. D2O, 2H),
11.45 (s br, exch. D2O, 2H). 13C NMR (CD3OD): dC 16.8, 22.4, 30.5, 109.5, 109.7,
110.4, 158.1, 166.1, 169.4, 169.6. HRMS: m/z (rel. int.) 224.0790 (100) (M+),
(calcd for C10H12N2O4, 224.0797), 183 (42), 180 (45), 139 (43), 136 (72), 107
(50), 85 (31). Anal. Calad for CHN: C, 53.57; H, 5.39; N, 12.49. Found: C, 53.59;
H, 5.36; N, 12.48. Compound 5i: colorless crystals, mp 187 °C. IR: mmax cmÀ1
3455, 3220, 3184, 2675, 1692, 1606, 1576, 1544, 1533, 1410, 1352, 1210, 986.
1H NMR (CD3OD): d 1.27 (t, J = 6.7 Hz, 3H), 2.48 (q, J = 6.7 Hz, 2H), 2.55 (s, 3H),
3.85 (s br, exch. D2O, 2H), 6.73 (s, 1H), 11.20 (s br, exch. D2O, 1H). 13C NMR
(CD3OD): dC 16.0, 22.5, 31.2, 107.3, 108.8, 160.0, 163.6, 164.1, 169.8. HRMS: m/
z (rel. int.) 180.0895 (100) (M+), (calcd for C9H12N2O2, 180.0899), 139 (42), 136
(72b), 107 (49), 85 (31). Anal. Calad for CHN: C, 59.99; H, 6.71; N, 15.55. Found:
C, 59.96; H, 6.78; N, 15.56.
Acknowledgments
The authors are thankful to Dr. S.K. Koul (Indian Institute of
Integrative Medicine; formerly Regional Research Laboratory, Jam-
mu), Prof. T.S. Banipal and Prof. M.P.S. Isher of Guru Nanak Dev
University, Amritsar (India), for providing spectral facilities. We
are also grateful to Prof. M.S. Hundal, Department of Chemistry,
Guru Nanak Dev University, Amritsar (India), for XRD.
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data of compounds, crystallographic data, and ORTEP diagram
for compound 3a) associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2011.01.017.
References and notes
28. General procedure for lithium–aluminum hydride reduction of 3a–3j: see
Supplementary data.
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Rev. 1982, 82, 223; (c) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 291; (d)
Comins, D.; O’Connor, S. Adv. Heterocycl. Chem. 1988, 44, 199.
2. Singer, T. P.; Kearney, E. B. Adv. Enzymol. 1954, 15, 79.
3. Kaplan, N. O. Rec. Chem. Prog. 1955, 16, 177.
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6. Schleifer, K.-J. J. Med. Chem. 1999, 42, 2204.
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29. Spectral data of selected reduced products (6a): colorless crystals, mp 192 °C. IR:
m
max cmÀ1 3240, 3231, 2977, 1640, 1469, 1373, 1350, 1238, 1145, 927. 1H NMR
(CDCl3): d 1.14 (s, 3H), 1.27 (s, 6H), 1.78 (s br, exch. D2O, 4H), 2.0 (s br, exch.
D2O, 2H), 3.62 (t, J = 3.2 Hz, 4H), 4.77 (s, 1H). 13C NMR (CDCl3): dC 16.9, 22.1
(2C), 38.5 (2C, 2x CH2), 45.2, 60.9, 79.5, 162.6, 168.3. HRMS: m/z (rel. int.)
196.1694 (100) (M+), (calcd for C10H20N4, 196.1688), 151 (44), 122 (78), 114
(39), 85 (45), 84 (50), 56 (64), 43 (36). Anal. Calad for CHN: C, 61.19; H, 10.27;
N, 28.54. Found: C, 61.16; H, 10.25; N, 28.50. Compound 6f: colorless crystals,
mp 167 °C. IR: mmax cmÀ1 3230, 2980, 1650, 1641, 1560, 1465, 1456, 1450,
1380, 1350, 1275, 1240, 1210, 1180, 1040, 860, 970. 1H NMR (CDCl3): d 1.13 (s,
3H), 1.25 (s, 3H), 1.80 (s br, exch. D2O, 4H), 2.10 (s br, exch. D2O, 2H), 3.61 (t,
8. Triggle, D. J.; Lang, D. A. Med. Res. Rev. 1989, 9, 123.

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J = 3.2 Hz, 4H), 3.73 (s, 3H), 4.70 (s, 1H), 6.69 (d, J = 8.3 Hz, 2H), 7.12 (d,
(40), 177 (45), 148 (65), 84 (51), 43 (33). Anal. Calad for CHN: C, 66.64; H, 8.39;
N, 19.43. Found: C, 66.68; H, 8.36; N, 19.48.
30. (a) Husson, H.-P.; Royer, J. Chem. Soc. Rev. 1999, 28, 383; (b) Bonin, M.; Romero,
J. R.; Grierson, D. S. Tetrahedron Lett. 1982, 23, 3369.
J = 8.3 Hz, 2H). 13C NMR (CDCl3): dC 16.5, 23.2, 36.1 (2C), 55.7, 57.4, 61.3, 84.9,
114.6 (2C), 129.9 (2C), 134.6, 157.8, 162.3, 168.5. HRMS: m/z (rel. int.)
288.1956 (100) (M+), (calcd for C16H24N4O, 288.1950), 243 (40), 214 (78), 182