A facile and efficient method for the synthesis of novel pyridone analogues by aminolysis of an ester under solvent-free conditions

Article abstract of DOI:10.1016/j.tet.2007.09.068

A series of 15 pure novel N-alkylated pyridone derivatives have been synthesized in 73-96% yields on treatment of ethyl (2-pyridone)acetates with structurally diverse amines in an efficient aminolysis procedure under 'solvent-free' conditions.

Full text of DOI:10.1016/j.tet.2007.09.068

Tetrahedron 63 (2007) 12303–12309
A facile and efficient method for the synthesis of novel pyridone
analogues by aminolysis of an ester under solvent-free conditions
a
N. David Karis, Wendy A. Loughlin and Ian D. Jenkins
b,*
a
a
Eskitis Institute, Natural Product Discovery, Griffith University, Brisbane, QLD 4111, Australia
Eskitis Institute, School of Biomolecular and Physical Sciences, Griffith University, Brisbane, QLD 4111, Australia
b
Received 24 July 2007; revised 14 September 2007; accepted 27 September 2007
Available online 29 September 2007
Abstract—A series of 15 pure novel N-alkylated pyridone derivatives have been synthesized in 73–96% yields on treatment of ethyl
2-pyridone)acetates with structurally diverse amines in an efficient aminolysis procedure under ‘solvent-free’ conditions.
Ó 2007 Elsevier Ltd. All rights reserved.
(
1
. Introduction
to afford N-alkylated nitropyridone 1. Treatment of 1 with
hydrogen gas in the presence of 10% Pd/C in EtOAc af-
forded amine 2, but required dilute reaction conditions on
a larger scale (8–10 g). More concentrated reaction condi-
tions for the conversion of nitropyridone 1 to amine 2 typi-
cally gave mixtures of starting nitropyridone 1, amine 2,
and side products. Decomposition of amine 2 occurred rap-
idly within 24 h and therefore amine 2 was used directly in
the next step. Acylation of amine 2 with acetyl chloride
gave 3, and with benzoyl chloride gave 4. Next, treatment
of nitropyridone 1 with hydrogen gas, 10% Pd/C, and acetic
anhydride (1 equiv) in EtOAc directly gave acetylpyridone 3
in 99% yield and represents an efficient one-pot synthesis
from pyridone 1. The corresponding reaction with benzoic
acid anhydride was not successful, the product being amine
2 with only minor amounts of benzoyl ester 4. Heating this
reaction did not change the result.
Pyridone based peptidomimetics have found utility as elas-
tase, caspase-1, and non-transition state protease and
1
–6
7,8
9
1
0,11
thrombin
inhibitors. Tethering peptide and non-peptide
functionalities, primarily at the 1, 3, and 4 positions of the
pyridone ring, has provided structural diversity leading to
compounds with high selectivity against key enzymatic
targets. Notably, extension of pyridone scaffolds to create
amide linked moieties in the side chains relies almost exclu-
sively on coupling of activated carboxylic acids (activated in
situ) and amines. Although moderate to good yields can be
obtained, this approach is time consuming, by being
a multi-step process, and not atom-efficient. By comparison,
approaches to simple amides from an amine and ester (with-
1
2–15
out an attached pyridone ring) use either strongly basic
1
6–24
25
or metallic catalysts,
wave ester aminolysis, or alternately, microwave reaction
high pressure reactions or micro-
2
6
2
7–30
of an acid and primary amine.
development of a facile and atom-efficient protocol for the
Here we report on the
a
O
O
N
N
synthesis of N-alkyl amide side chains on a pyridone under
‘
O2N
O
H2N
O
2
1
O
O
O
solvent-free’ conditions.
c
d
b
2
. Results and discussion
O
O
O
O
N
N
N
H
O
The reactants for amide side-chain extension, esters 3 and 4,
were prepared as shown in Scheme 1, commencing with
a modification of a literature preparation for aminopyridone
2 Commercially available 2-hydroxy-3-nitropyridine
was treated with sodium hydride and ethyl bromoacetate
N
H
O
3
O
4
3
1,2
Scheme 1. Reagents and conditions: (a) 10% Pd/C, H
b) 10% Pd/C, H , acetic acid anhydride, EtOAc, rt, 16 h, 99%; (c) acetyl
chloride, triethylamine, dry CH Cl , rt, 4 h, 98%; (d) benzoyl chloride, tri-
ethylamine, dry CH Cl , rt, 4 h, 99%.
2
, EtOAc, 16 h, 100%;
.
(
2
2
2
2
2
Keywords: Aminolysis; Pyridone; Solvent-free.
*
Next, extension of the N-alkyl side chain on the pyridone
ring using an atom-efficient procedure to form amide
Corresponding author. Tel.: +07 3735 7567; fax: +07 3735 7656; e-mail:
w.loughlin@griffith.edu.au
0
040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.068

12304
N. D. Karis et al. / Tetrahedron 63 (2007) 12303–12309
Table 1. Synthesis of pyridones 5–19 from aminolysis of pyridone esters 3 and 4
a
Entry
Amine
Ester
Reaction conditions
Product
Product structure
Isolated yield (%)
84
O
O
ꢀ
N
1
H
H
H
H
H
H
2
2
2
2
2
2
N–CH
N–CH
N–CH
N–CH
2
CH
2
CH
2
CH
2
CH
2
2
2
2
CH
3
3
3
22 C, 15 min
5
N
H
N
H
O
O
O
N
ꢀ
2
3
4
5
6
7
8
9
CH
4
3
4
3
4
3
4
3
4
4
4
3
4
4
22 C, 15 min
6
91
96
87
89
87
81
73
90
95
Ph
N
N
H
H
O
O
O
ꢀ
N
OH
OH
OH
OH
22 C, 15 min
7
N
N
H
H
O
O
O
ꢀ
N
22 C, 15 min
8
Ph
N
N
H
H
O
O
O
ꢀ
N
N–CH(CH
3
)
2
2
22 C, 16 h
9
N
H
N
H
O
O
O
ꢀ
N
N–CH(CH
3
)
22 C, 16 h
10
11
12
13
14
15
16
17
18
19
Ph
O
N
N
H
H
O
O
ꢀ
N
H N
120 C, 2 h
2
N
N
H
H
O
O
O
ꢀ
N
OH
OH
120 C, 16 h
H2N
Ph
N
N
H
H
O
O
O
ꢀ
N
HN
90 C, 4 h
N
N
H
O
O
O
O
O
ꢀ
N
1
1
1
1
1
0
1
2
3
4
5
HN
HN
90 C, 4 h
Ph
Ph
N
N
N
H
O
O
ꢀ
N
N
b
120 C, 2 h
92
N
H
O
O
ꢀ
b
HN
O
120 C, 48 h
86
Ph
N
H
N
O
O
O
O
ꢀ
N
H N
2
Ph
Ph
120 C, 4 h
85
94
N
N
Ph
H
H
O
O
O
ꢀ
N
2
H N
120 C, 2 h
Ph
N
N
Ph
Ph
H
H
O
Ph
OH
O
O
ꢀ
c
1
Melt, 120 C, 1 h
N
OH
82
Ph
N
N
H2N
H
H
O
a
ꢀ
ꢀ
ꢀ
ꢀ
Typically 5 mL of amine was used per mg of ester 3 or 4; amine bp; entries 1 and 2, 48 C; entries 3 and 4, 170 C; entries 5 and 6, 33–34 C; entry 7, 134 C;
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
entry 8, 134–136 C; entries 9 and 10, 87–88 C; entry 11, 106 C; entry 12, 129 C; entries 13 and 14, 184–185 C; entry 15, mp, 91–92 C.
Purified by silica column chromatography.
Mole ratio of amine to ester was 1:1.
b
c
analogues was explored. We initially attempted the amino-
lysis of pyridone ester 4 using a microwave reactor.
Aminolysis of benzoyl ester 4 with benzylamine at 120 C,
200 W for 1 h gave a crude yield of pyridone 18 (99%),
comparable to the crude yield (99%) obtained under thermal
conditions (120 C, 2 h), but with a lower crude purity.
2
7
ꢀ
ꢀ

N. D. Karis et al. / Tetrahedron 63 (2007) 12303–12309
12305
However, with less reactive amines such as morpholine, the
4. Experimental
4.1. General procedures
microwave method required much longer reaction times
and/or higher reaction temperatures. For example, micro-
wave aminolysis of benzoyl ester 4 with morpholine at
ꢀ
2
00 C, 200 W for 80 min still gave incomplete conversion
See Supplementary data.
of the starting ester 4 and an increase in the side products
was observed. This result highlighted the need for a con-
trolled reaction temperature and suggested that direct ami-
nolysis under controlled thermal conditions could provide
a simple and clean reaction. Herein we report that direct
aminolysis of pyridone esters 3 and 4, in the absence of other
solvents, using commercially available amines, gives facile
access to the novel pyridone amides 5–19, in excellent yields
4.2. General method
ꢀ
4.2.1. Method A (aminolysis at 90 or 120 C). Aminolysis
was carried out in a conical micro-scale reaction vessel by
mixing amine (5 mL amine per mg of ester 4 or 5) with ester
(4 or 5) (0.1–1.0 g). The reaction mixture was heated for 2, 4,
ꢀ
or 16 h at 90 or 120 C (see Table 1), then transferred while
(73–96%) (Table 1) and purity (95–99%) without recourse to
a microwave reactor.
still warm to a conical flask, and diluted with diethyl ether.
The diethyl ether mixture was cooled in a freezer overnight
(16 h) and the excess amine was separated from the crude
Thus, pyridone ester (3 or 4, 100 mg) was heated with excess
of the amine (0.5 mL), at a reaction temperature of 22, 90, or
solid product by filtration and washing with additional di-
ethyl ether. The crude solid was recrystallized by dissolving
in hot acetone and then adding small amounts of diethyl
ether, the resulting solution was cooled in a freezer overnight
forming a white solid. The white solid was filtered and
washed with diethyl ether giving the desired amides in
ꢀ
1
20 C, and with a reaction time between 15 min and 48 h
depending on the boiling point and reactivity of the amine
Table 1). Facile isolation of the product was through the re-
(
moval of excess amine under vacuum, or by diluting the
crude reaction mixture with ether, whereupon the product
crashed out as a solid.
1
>70% yields and in 95–99% purity, as determined by H
NMR spectroscopy. Esters 15 and 16 were further purified
by silica column chromatography (EtOAc/CH Cl with
2
2
The aminolysis proceeded readily with primary amines
0.5% Et N).
3
ꢀ
ꢀ
ꢀ
when the amino group was attached to a 1 , 2 , or 3 carbon
atom (entries 1–8 and 13–15, Table 1), and with some com-
mon secondary amines (entries 9–12, Table 1). A melt pro-
4.2.2. Method B (aminolysis at room temperature). Ami-
nolysis was carried out according to method A with the re-
action mixture stirred at room temperature for 15 min or
16 h. The reaction mixture was worked up as for method A.
cedure was required for the reaction of a solid amine (mp
ꢀ
9
1–92 C) (entry 15, Table 1). Other amines such as diethyl-
amine and aniline were unreactive, under the general reac-
tion conditions. Modifying the reaction conditions with
these amines, such as inclusion of a polar solvent (e.g.,
water, ethanol), addition of a Lewis acid (MgCl , ZnCl ,
4.2.3. Method C (aminolysis with solid melt). A 1:1 equi-
molar mixture of ester 4 and solid amine was melted together
and transferred to a conical micro-scale reaction vessel. The
resulting solid mixture was placed in a pre-heated oil bath at
2
2
or CeCl ), or use of microwave conditions, did not produce
3
ꢀ
the desired products. Poor reactivity was attributed to re-
duced nucleophilicity, such as in the aromatic amine aniline,
and a combination of steric factors, and/or a low boiling
point, in the case of diethylamine (the boiling point of dieth-
120 C. Heating was carried out without stirring until a solu-
tion was formed and then with stirring until all eliminated
ethanol was evaporated and a solid formed, or for 4 h if no
solid was formed. The crude reaction mixture was trans-
ferred to a conical flask and re-dissolved in warm acetone.
Small amounts of diethyl ether were added and the resulting
solution cooled in a freezer overnight forming a white solid.
The white solid was filtered and washed with diethyl ether
giving the desired amide in >80% yield and in 99% purity,
ꢀ
ꢀ
ylamine is only 55 C, cf. pyrrolidine, 88 C). By compari-
sion, piperidine (entry 11, Table 1) was relatively reactive
due to the increased nucleophilic nitrogen atom (cf. diethyl-
amine), and in morpholine, the b-oxygen atom either in-
ductively or otherwise reduces the nucleophilicity of the
nitrogen, thus requiring more forcing reaction conditions
1
as determined by H NMR spectroscopy.
(
entry 12, Table 1).
0
4
.2.3.1. 2 -[3-(Acetylamino)-2-oxopyridin-1(2H)-yl]-
N-propylacetamide (5). Ester 3 (0.35 g, 1.47 mmol) and
propylamine (1.8 mL) were treated at room temperature
for 15 min using method B. Compound 5 was obtained as
3
. Conclusions
ꢀ
The direct aminolysis of pyridone esters 3 and 4 with
a range of primary amines and heterocyclic secondary
amines is a very simple procedure that produces the cor-
responding novel pyridone amides in high yield and
purity. Direct aminolysis is an effective process with the
potential for easy scale-up. It avoids multi-step peptide
coupling procedures, chromatography to remove by-prod-
ucts, and the need for technical instrumentation (such as
a microwave reactor). It represents a mild and efficient
process for N-alkyl side-chain extension of pyridones
and should be of interest for other applications in organic
synthesis.
a colorless solid (0.31 g, 84.0%): mp 170–172 C (dec); IR
ꢁ
1 1
(KBr) n 3289, 1663, 1646, 1601, 760, 735 cm ; H NMR
(400 MHz, CDCl ): d 0.84 (t, 3H, J¼7.2 Hz, CH ), 1.46
3
3
(tq, 2H, J¼7.2, 7.2 Hz, CH –CH ), 2.15 (s, 3H, CH –CO),
2
3
3
0
3.14 (dt, 2H, J¼6.8, 6.0 Hz, NH–CH ), 4.56 (s, 2H, H2 ),
2
6.26 (dd, 1H, J¼7.2, 7.2 Hz, H5), 6.83 (br s, 1H,
W w14 Hz, NH–CH ), 7.06 (dd, 1H, J¼7.2, 1.6 Hz, H6),
1
/2
2
1
3
8.35 (m, 2H, H4, NH); C NMR (100 MHz, CDCl ):
3
d 11.5 (CH ), 22.8 (CH –CH ), 24.8 (CH –CO), 41.6
3
2
3
3
0
130.9 (C6), 157.6 (C2), 166.7 (C1 ), 169.4 (CO); LRMS
(NH–CH ), 53.8 (C2 ), 107.6 (C5), 123.2 (C4), 129.5 (C3),
2
0
(ESI) m/z (%): 274.2 ([M+Na] , 100), 258.2 ([M+Li] ,
+
+

12306
N. D. Karis et al. / Tetrahedron 63 (2007) 12303–12309
+
+
+
1
found 274.1162.
00); HRMS: calcd for [M+Na] C H O N $Na 274.1162,
1
([M+H] , 10), 322.3 ([M+Li] , 100). Anal. Calcd for
C H O N : C, 60.94; H, 5.43; N, 13.33%. Found: C,
2 17 3 3
1
6 17 4 3
6
0.66; H, 5.41; N, 13.10%.
0 0
N-{1-[2 -(Propylamino)-2 -oxoethyl]-2-oxo-
,2-dihydropyridin-3-yl}benzamide (6). Ester 4 (0.95 g,
4
.2.3.2.
0
1
4.2.3.5. 2 -[3-(Acetylamino)-2-oxopyridin-1(2H)-yl]-
3
room temperature for 15 min using method B. Compound
.16 mmol) and propylamine (4.8 mL) were treated at
N-isopropylacetamide (9). Ester 3 (0.30 g, 1.26 mmol)
and isopropylamine (1.5 mL) were treated at room tempera-
ture for 16 h using method B. Compound 9 was obtained as
6
2
was obtained as a colorless solid (0.90 g, 91%): mp 214–
ꢀ
ꢁ1
1
ꢀ
15 C; IR (KBr) n 3289, 1654, 1527 cm
;
H NMR
a colorless solid (0.28 g, 89%): mp 119–121 C (dec); IR
;
ꢁ
1
(
1
400 MHz, DMSO-d ): d 0.85 (t, 3H, J¼7.2 Hz, CH ),
(KBr) n 3342, 3265, 1695, 1655, 1597, 1540, 1516 cm
H NMR (400 MHz, DMSO-d ): d 1.06 (d, 6H, J¼6.4 Hz,
6
3
1
.42 (tq, 2H, J¼7.2, 7.0 Hz, CH –CH ), 3.04 (dt, 2H,
2
3
6
0
J¼6.8, 5.6 Hz, NH–CH ), 4.62 (s, 2H, H1 ), 6.33 (dd, 1H,
CH–CH ), 2.09 (s, 3H, CH ), 3.81 (dsept (eight lines), 1H,
3
2
3
0
J¼6.8, 6.8 Hz, H5), 7.40 (dd, 1H, J¼6.8, 1.6 Hz, H6),
J¼7.2, 7.0 Hz, CH), 4.52 (s, 2H, H1 ), 6.20 (dd, 1H,
J¼7.2, 7.2 Hz, H5), 7.28 (dd, 1H, J¼7.2, 1.6 Hz, H6), 8.07
(br d, 1H, J¼7.6 Hz, NH–CH), 8.17 (dd, 1H, J¼7.2,
7
7
8
.52–7.55 (m, 2H, m-Ph), 7.59–7.63 (m, 1H, p-Ph), 7.89–
.92 (m, 2H, o-Ph), 8.19 (br t, 1H, J¼5.6 Hz, NH–CH ),
2
1
3
.28 (dd, 1H, J¼7.2, 1.6 Hz, H4), 9.28 (br s, 1H,
1.6 Hz, H4), 9.20 (br s, 1H, W w8 Hz, NH); C NMR
1/2
13
W w8 Hz, NH); C NMR (100 MHz, DMSO-d ): d 11.4
(
1
(100 MHz, DMSO-d ): d 22.4 (CH–CH ), 24.0 (CH ),
40.7 (CH), 51.6 (C1 ), 104.5 (C5), 122.8 (C4), 128.6 (C3),
1
/2
6
6 3 3
0
133.0 (C6), 156.7 (C2), 165.4 (C2 ), 169.2 (CO); LRMS
0
04.8 (C5), 123.6 (C4), 127.1 (o-Ph), 128.0 (C3), 128.8
CH ), 22.3 (CH –CH ), 40.5 (NH–CH ), 51.6 (C1 ),
3
2
3
2
0
(ESI) m/z (%): 274.2 ([M+Na] , 100), 258.2 ([M+Li] ,
+
+
(
m-Ph), 132.0 (p-Ph), 133.7 (i-Ph), 133.9 (C6), 157.1 (C2),
0
164.8 (CO), 166.2 (C2 ); LRMS (ESI) m/z (%): 336.2
[M+Na] , 100), 314.2 ([M+H] , 40), 320.3 ([M+Li] ,
100). Anal. Calcd for C H O N : C, 57.36; H, 6.82; N,
1
2 17 3 3
+
+
+
(
16.72%. Found: C, 57.21; H, 6.95; N, 16.54%.
1
1
00). Anal. Calcd for C H O N : C, 65.16; H, 6.11; N,
17 19 3 3
3.41%. Found: C, 65.16; H, 5.96; N, 13.28%.
0
0
4.2.3.6. N-{1-[2 -(Isopropylamino)-2 -oxoethyl]-2-oxo-
,2-dihydropyridin-3-yl}benzamide (10). Ester 4 (0.35 g,
1
0
0
0
4
.2.3.3. 2-[3 -(Acetylamino)-2 -oxopyridin-1 (2H)-yl]-
1.17 mmol) and isopropylamine (1.75 mL) were treated at
room temperature for 16 h using method B. Compound 10
was obtained as a colorless solid (0.32 g, 87%): mp 212–
215 C (dec); IR (KBr) n 3375, 3285, 1650, 1520,
760 cm ; H NMR (400 MHz, DMSO-d ): d 1.07 (d, 6H,
0
0
N-(2 -hydroxyethyl)acetamide (7). Ester
.42 mmol) and ethanolamine (0.5 mL) were treated at
room temperature for 15 min using method B. Compound
3
(0.10 g,
0
ꢀ
ꢁ
1 1
7
2
7
was obtained as a colorless solid (0.102 g, 96%): mp
ꢀ
6
12–214 C (dec); IR (KBr) n 3293, 1650, 1609, 1528,
56 cm ; H NMR (400 MHz, DMSO-d ): d 2.09 (s, 3H,
J¼6.8 Hz, CH ), 3.83 (dsept (eight lines), 1H, J¼6.8,
3
ꢁ1
1
0
6.6 Hz, CH), 4.59 (s, 2H, H1 ), 6.32 (dd, 1H, J¼7.2,
6
0
0
CH ), 3.14 (dt, 2H, J¼6.0, 6.0 Hz, H1 ), 3.40 (dt, 2H,
7.2 Hz, H5), 7.39 (dd, 1H, J¼7.2, 1.6 Hz, H6), 7.52–7.55
(m, 2H, m-Ph), 7.59–7.62 (m, 1H, p-Ph), 7.89–7.91 (m, 2H,
o-Ph), 8.11 (br d, 1H, J¼8.0 Hz, NH–CH), 8.27 (dd, 1H,
3
00
J¼6.0, 5.6 Hz, H2 ), 4.57 (s, 2H, H2), 4.67 (t, 1H,
J¼5.6 Hz, OH), 6.21 (dd, 1H, J¼7.2, 7.2 Hz, H5), 7.28
1
3
(
dd, 1H, J¼6.8, 1.6 Hz, H6), 8.16–8.20 (m, 2H, NH–CH ,
J¼7.2, 1.6 Hz, H4), 9.28 (br s, 1H, W w5 Hz, NH);
C
2
1/2
1
3
H4), 9.19 (br s, 1H, W w5 Hz, NH);
C NMR
NMR (100 MHz, DMSO-d ): d 22.4 (CH ), 40.7 (CH),
6 3
1
/2
0
0
0
(
100 MHz, DMSO-d ): d 24.7 (CH ), 42.3 (C1 ), 52.3
0
51.5 (C1 ), 104.7 (C5), 123.7 (C4), 127.1 (o-Ph), 128.0
(m-Ph), 128.8 (C3), 132.0 (p-Ph), 133.8 (C6), 133.9 (i-Ph),
6
3
0
(
C2), 60.4 (C2 ), 105.3 (C5), 123.4 (C4), 129.3 (C3),
33.5 (C6), 157.4 (C2), 167.3 (C1), 169.9 (CO); LRMS
ESI) m/z (%): 276.1 ([M+Na] , 100), 254.1 ([M+H] , 20),
0
336.3 ([M+Na] , 100), 314.3 ([M+H] , 10), 320.3
1
(
157.1 (C2), 164.8 (CO), 165.3 (C2 ); LRMS (ESI) m/z (%):
+
+
+
+
+
+
2
5
1
60.1 ([M+Li] , 100). Anal. Calcd for C H O N : C,
1
([M+Li] , 100). Anal. Calcd for C H O N : C, 65.16; H,
17 19 3 3
6.11; N, 13.41%. Found: C, 65.11; H, 6.03; N, 13.19%.
1
15
4
3
2.17; H, 5.97; N, 16.59%. Found: C, 51.93; H, 5.98; N,
6.36%.
0
N-cyclohexylacetamide (11). Ester 3 (0.10 g, 0.42 mmol)
4
.2.3.7. 2 -[3-(Acetylamino)-2-oxopyridin-1(2H)-yl]-
0
00
0
4.2.3.4.
N-(1-{2 -[(2 -Hydroxyethyl)amino]-2 -oxo-
ꢀ
ethyl}-2-oxo-1,2-dihydropyridin-3-yl)benzamide (8). Es-
ter 4 (0.40 g, 1.33 mmol) and ethanolamine (2.0 mL) were
treated at room temperature for 15 min using method B.
and cyclohexylamine (0.5 mL) were treated at 120 C for
4 h using method A. Compound 11 was obtained as a color-
ꢀ
3500, 3297, 1645 cm ; H NMR (400 MHz, DMSO-d ):
less solid (0.099 g, 81%): mp 229–230 C (dec); IR (KBr) n
ꢁ
1 1
Compound 8 was obtained as a colorless solid (0.37 g,
6
ꢀ
8
1
2
7%): mp 213–216 C (dec); IR (KBr) n 3420, 3301, 1650,
516 cm ; H NMR (400 MHz, DMSO-d ): d 3.15 (dt,
H, J¼6.0, 5.6 Hz, H1 ), 3.42 (dt, 2H, J¼6.0, 5.6 Hz,
d 1.11–1.29 (m, 5H, (CH ) ), 1.57–1.55 (m, 1H, (CH ) ),
2 5
1.65–1.74 (m, 4H, (CH ) ), 2.09 (s, 3H, CH ), 3.46–3.57
2 5 3
2
5
ꢁ1
1
6
00
0
(m, 1H, CH), 4.54 (s, 2H, H1 ), 6.20 (dd, 1H, J¼7.2,
7.2 Hz, H5), 7.28 (dd, 1H, J¼7.2, 1.8 Hz, H6), 8.07 (br d,
1H, J¼8.0 Hz, NH–CH), 8.17 (dd, 1H, J¼7.2, 1.8 Hz,
00
0
H2 ), 4.64 (s, 2H, H1 ), 4.69 (t, 1H, J¼5.6 Hz, OH), 6.33
dd, 1H, J¼7.0, 7.0 Hz, H5), 7.39 (dd, 1H, J¼6.4, 1.6 Hz,
H6), 7.52–7.56 (m, 2H, m-Ph), 7.59–7.63 (m, 1H, p-Ph),
.89–7.91 (m, 2H, o-Ph), 8.24 (br t, 1H, J¼5.4 Hz, NH–
CH ), 8.28 (dd, 1H, J¼8.0, 1.6 Hz, H4), 9.28 (br s, 1H,
(
1
3
H4), 9.20 (br s, 1H, W w5 Hz, NH);
C NMR
1
/2
7
(100 MHz, DMSO-d ): d 23.9 (CH ), 24.4 ((CH ) ), 25.2
((CH ) ), 32.4 ((CH ) ), 47.7 (CH), 51.6 (C1 ), 104.5 (C5),
6 3 2 5
0
122.7 (C4), 128.6 (C3), 132.9 (C6), 156.7 (C2), 165.4
2
2 5
2 5
13
W w5 Hz, NH); C NMR (100 MHz, DMSO-d ): d 41.6
1
/2
6
0
27.1 (o-Ph), 128.0 (C3), 128.8 (m-Ph), 132.0 (p-Ph),
0
0
00
0
100), 292.3 ([M+H] , 15), 298.3 ([M+Li] , 100); HRMS:
+
(
C1 ), 51.5 (C1 ), 59.7 (C2 ), 104.9 (C5), 123.6 (C4),
(C2 ), 169.2 (CO); LRMS (ESI) m/z (%): 314.3 ([M+Na] ,
+
+
1
1
+
33.7 (C6), 133.9 (i-Ph), 157.1 (C2), 164.8 (CO), 166.4
0
calcd for [M+Na] C H O N $Na 314.1475, found
1
5 21 3 3
+
(
C2 ); LRMS (ESI) m/z (%): 338.3 ([M+Na] , 100), 316.3
314.1460.

N. D. Karis et al. / Tetrahedron 63 (2007) 12303–12309
12307
00
0
amino]-2 -oxoethyl}-2-oxo-1,2-dihydropyridin-3-yl)benz-
00
00 00
0
0
4
.2.3.8. N-(1-{2 -[(2 -Hydroxy-1 ,1 -dimethylethyl)-
4.2.3.11.
N-{2-Oxo-1-[2 -oxo-2 -(piperidin-1 -yl)-
0
amide (12). Ester 4 (0.20 g, 0.67 mmol) and 2-amino-2-
ethyl]-1,2-dihydropyridin-3-yl}benzamide (15). Ester 4
(0.150 g, 0.499 mmol) and cyclohexylamine (0.75 mL)
ꢀ
using method A. Compound 12 was obtained as a colorless
ꢀ
15 was obtained as a colorless solid (0.156 g, 92%): mp
methyl-1-propanol (1.0 mL) were treated at 120 C for 4 h
were treated at 120 C for 2 h using method A. Compound
ꢀ
671, 1642, 1597, 1528, 756, 707 cm
ꢀ
1519 cm ; H NMR (400 MHz, DMSO-d ): d 1.40–1.49
(m, 2H, H4 ), 1.52–1.63 (m, 4H, H3 and H5 ), 3.40–3.50
solid (0.17 g, 73%): mp 185–187 C; IR (KBr) n 3457, 3301,
166–167.5 C (dec); IR (KBr) n 3436, 3350, 1646, 1605,
ꢁ1
1
ꢁ1
1
1
(
;
H NMR
400 MHz, DMSO-d ): d 1.19 (s, 6H, CH ), 3.38 (d, 2H,
6
00 00 00
6
3
0
0
0
00
00
0
J¼5.6 Hz, H2 ), 4.60 (s, 2H, H1 ), 4.74 (t, 1H, J¼5.6 Hz,
OH), 6.32 (dd, 1H, J¼7.0, 7.0 Hz, H5), 7.36 (dd, 1H,
(m, 5H, H2 and H6 ), 4.90 (s, 2H, H1 ), 6.33 (dd, 1H,
J¼7.2, 7.2 Hz, H5), 7.36 (dd, 1H, J¼7.2, 1.6 Hz, H6),
7.52–7.56 (m, 2H, m-Ph), 7.59–7.63 (m, 1H, p-Ph), 7.89–
7.91 (m, 2H, o-Ph), 8.28 (dd, 1H, J¼7.2, 1.6 Hz, H4), 9.28
J¼7.0, 1.8 Hz, H6), 7.52–7.56 (m, 2H, m-Ph), 7.59–7.63
0
(
7
m, 1H, p-Ph), 7.72 (br s, 1H, W w6 Hz, 2 -NH), 7.89–
1
/2
1
3
00
.91 (m, 2H, o-Ph), 8.27 (dd, 1H, J¼7.4, 1.8 Hz, H4), 9.28
(s, 1H, NH); C NMR (100 MHz, DMSO-d ): d 23.9 (C3
6
1
3
00 00 00 00 00 00
(
d ): d 23.6 (CH ), 51.7 (C1 ), 54.6 (C1 ), 67.1 (C2 ),
br s, 1H, W w6 Hz, NH); C NMR (100 MHz, DMSO-
or C5 ), 25.2 (C4 ), 25.9 (C3 or C5 ), 42.5 (C2 or C6 ),
1
/2
0
04.7 (C5), 123.7 (C4), 127.1 (o-Ph), 127.9 (C3), 128.8
00
00
00
00
0
127.1 (o-Ph), 128.0 (C3), 128.8 (m-Ph), 132.1 (p-Ph),
45.2 (C2 or C6 ), 50.2 (C1 ), 104.8 (C5), 123.5 (C4),
6
3
1
(
1
(
0
(CO); LRMS (ESI) m/z (%): 362.1 ([M+Na] , 100), 346.2
m-Ph), 132.0 (p-Ph), 133.8 (i-Ph), 133.9 (C6), 157.1 (C2),
0
133.6 (C6), 133.9 (i-Ph), 157.1 (C2), 164.3 (C2 ), 164.8
+
64.8 (CO), 165.8 (C2 ); LRMS (ESI) m/z (%): 366.3
[M+Na] , 100), 344.3 ([M+H] , 10), 350.3 ([M+Li] ,
+
+
+
+
+
([M+Li] , 100); HRMS: calcd for [M+Na] C H O -
19 21 3
1
1
00). Anal. Calcd for C H O N : C, 62.96; H, 6.16; N,
3
2.24%. Found: C, 62.78; H, 6.30; N, 12.13%.
N $Na 362.1475, found 362.1488.
3
1
8
21
4
00 0
N-{1-[2-(Morpholin-4 -yl)-2 -oxoethyl]-2-
oxo-1,2-dihydropyridin-3-yl}benzamide (16). Ester 4
4.2.3.12.
0
ethyl]-1,2-dihydropyridin-3-yl}acetamide (13). Ester 3
(0.82 g, 3.45 mmol) and pyrrolidine (4.1 mL) were treated
ꢀ
at 90 C for 4 h using method A. Compound 13 was obtained
as a colorless solid (0.82 g, 90%): mp 204–205 C (dec); IR
0
00
4
.2.3.9.
N-{2-Oxo-1-[2 -oxo-2 -(pyrrolidin-1 -yl)-
(0.30 g, 1.00 mmol) and morpholine (1.5 mL) were treated
at 120 C for 48 h using method A. Compound 16 was
ꢀ
obtained as a colorless solid (0.29 g, 86%): mp 157–160 C;
ꢀ
1
ꢀ
1
ꢁ1
IR (KBr) n 3359, 3085, 2856, 1646, 1597, 1516 cm ; H
NMR (400 MHz, DMSO-d ): d 3.43–3.45 (m, 2H, H2 or
ꢁ
1
00
H6 ), 3.55–3.59 (m, 4H, H2 or H6 , H3 or H5 ), 3.64–
(
(
KBr) n 3450, 3297, 1667, 1589, 1503 cm ; H NMR
0
6
0
00
00
00
00
0
00
400 MHz, CDCl ): d 1.84 (tt, 2H, J¼6.8, 6.8 Hz, H3 or
3
0
0
00
00
00
00
H4 ), 1.98 (tt, 2H, J¼6.8, 6.8 Hz, H3 or H4 ), 2.12 (s,
3.66 (m, 2H, H3 or H5 ), 4.92 (s, 2H, H1 ), 6.34 (dd, 1H,
J¼6.8, 6.8 Hz, H5), 7.36 (dd, 1H, J¼6.8, 1.6 Hz, H6), 7.52–
7.56 (m, 2H, m-Ph), 7.59–7.64 (m, 1H, p-Ph), 7.89–7.92 (m,
2H, o-Ph), 8.29 (dd, 1H, J¼7.0, 1.6 Hz, H4), 9.28 (br s, 1H,
00
00
3
H, CH ), 3.45 (t, 2H, J¼7.0 Hz, H2 or H5 ), 3.54 (t, 2H,
3
00 00 0
J¼6.8 Hz, H2 or H5 ), 4.64 (s, 2H, H1 ), 6.22 (t, 1H,
J¼7.2, 7.2 Hz, H5), 6.99 (dd, 1H, J¼7.0, 1.8 Hz, H6), 8.33
1
3
13
(
(
m, 2H, H4, NH); C NMR (100 MHz, CDCl ): d 24.2
3
W w5 Hz, NH); C NMR (100 MHz, DMSO-d ): d 41.9
1/2
00
6
0
0
0
00
00
00
00
00
00
00
0
C5 ), 105.0 (C5), 123.6 (C4), 127.1 (o-Ph), 128.0 (C3),
00
C3 or C4 ), 24.7 (CH ), 26.2 (C3 or C4 ), 46.1 (C2 or
3
(C2 or C6 ), 44.8 (C2 or C6 ), 50.1 (C1 ), 66.0 (C3 and
0
C4), 129.2 (C3), 131.2 (C6), 157.4 (C2), 164.4 (C2 ),
00
00
0
00
128.8 (m-Ph), 132.1 (p-Ph), 133.5 (C6), 133.9 (i-Ph), 157.1
(C2), 164.8 (CO), 165.0 (C2 ); LRMS (ESI) m/z (%): 364.3
C5 ), 46.3 (C2 or C5 ), 51.2 (C1 ), 106.7 (C5), 122.7
(
0
69.1 (CO); LRMS (ESI) m/z (%): 286.2 ([M+Na] , 90),
64.2 ([M+H] , 100), 270.2 ([M+Li] , 100). Anal. Calcd
+
0
1
2
+
+
+
+
+
([M+Na] , 100), 342.3 ([M+H] , 10), 348.3 ([M+Li] , 100).
Anal. Calcd for C H O N : C, 63.33; H, 5.61; N, 12.31%.
Found: C, 63.26; H, 5.57; N, 12.15%.
for C H O N : C, 59.30; H, 6.51; N, 15.96%. Found: C,
3
1
3
17
3
18 19 4 3
5
9.26; H, 6.24; N, 15.74%.
0
ethyl]-1,2-dihydropyridin-3-yl}benzamide (14). Ester 4
0
00
0
N-benzylacetamide (17). Ester 3 (0.20 g, 0.84 mmol) and
benzylamine (1.0 mL) were treated at 120 C for 4 h using
4
.2.3.10.
N-{2-Oxo-1-[2 -oxo-2 -(pyrrolidin-1 -yl)-
4.2.3.13. 2 -[3-(Acetylamino)-2-oxopyridin-1(2H)-yl]-
ꢀ
method A. Compound 17 was obtained as a colorless solid
(
at 90 C for 4 h using method A. Compound 14 was obtained
0.87 g, 2.90 mmol) and pyrrolidine (4.4 mL) were treated
ꢀ
as a colorless solid (0.89 g, 94%): mp 169–172 C (dec); IR
ꢀ
ꢀ
(0.21 g, 84%): mp 203–205 C (dec); IR (KBr) n 3318,
3273, 1659, 1600, 1518, 737 cm ; H NMR (400 MHz,
ꢁ
1
1
ꢁ1
1
(
KBr) n 3370, 1659, 1528, 772, 702 cm
;
H NMR
0
0
(
400 MHz, DMSO-d ): d 1.79 (tt, 2H, J¼6.8, 6.8 Hz, H3
CDCl ): d 2.11 (s, 3H, CH ), 4.31 (d, 2H, J¼6.0 Hz, CH ),
6
3
3
2
0
0
00
00
0
or H4 ), 1.93 (tt, 2H, J¼6.8, 6.8 Hz, H3 or H4 ), 3.31 (t,
4.66 (s, 2H, H2 ), 6.23 (t, 1H, J¼7.2, 7.2 Hz, H5), 7.23–
7.35 (m, 6H, Ph, H6), 8.21 (dd, 1H, J¼7.2, 1.6 Hz, H4),
0
0
00
00
2
H, J¼6.8 Hz, H2 or H5 ), 3.52 (t, 2H, J¼7.0 Hz, H2 or
00 0
H5 ), 4.79 (s, 2H, H1 ), 6.34 (dd, 1H, J¼7.2, 7.2 Hz, H5),
8.69 (br t, 1H, J¼6.0 Hz, NH–CH ), 9.24 (br s, 1H,
2
1
3
7
7
.37 (dd, 1H, J¼6.8, 1.6 Hz, H6), 7.52–7.56 (m, 2H, m-Ph),
W w6 Hz, NH); C NMR (100 MHz, CDCl ): d 24.7
1/2 3
0
127.5 (p-Ph), 127.9 (o-Ph), 129.0 (m-Ph), 129.4 (C3),
.59–7.63 (m, 1H, p-Ph), 7.89–7.92 (m, 2H, o-Ph), 8.29
(CH ), 42.9 (CH ), 52.4 (C2 ), 105.4 (C5), 123.5 (C4),
3
2
(
NH); C NMR (100 MHz, DMSO-d ): d 23.7 (C3 or
dd, 1H, J¼6.8, 1.6 Hz, H4), 9.28 (br s, 1H, W w4 Hz,
1
/2
1
3
00
00
0
(CO); LRMS (ESI) m/z (%): 322.1 ([M+Na] , 100), 306.2
133.6 (C6), 139.8 (i-Ph), 157.5 (C2), 167.3 (C1 ), 170.0
6
0
0
0
0
00
00
00
00
+
C4 ), 25.6 (C3 or C4 ), 45.2 (C2 or C5 ), 45.7 (C2 or
C5 ), 50.9 (C1 ), 104.9 (C5), 123.6 (C4), 127.1 (o-Ph),
0
28.0 (C3), 128.8 (m-Ph), 132.1 (p-Ph), 133.5 (C6), 133.9
+
([M+Li] , 100). Anal. Calcd for C H O N : C, 64.20; H,
1
6 17 3 3
1
(
5.72; N, 14.04%. Found: C, 64.23; H, 5.75; N, 13.89%.
0
m/z (%): 348.2 ([M+Na] , 45), 326.2 ([M+H] , 100), 332.2
i-Ph), 157.0 (C2), 164.3 (C2 ), 164.8 (CO); LRMS (ESI)
+
+
0
0
4.2.3.14. N-{1-[2 -(Benzylamino)-2 -oxoethyl]-2-oxo-
1,2-dihydropyridin-3-yl}benzamide (18). Ester 4 (0.73 g,
2.43 mmol) and benzylamine (3.7 mL) were treated at
+
(
[M+Li] , 100). Anal. Calcd for C H O N : C, 66.45; H,
18 19 3 3
5
.89; N, 12.9%. Found: C, 66.46; H, 5.92; N, 12.93%.

1
2308
N. D. Karis et al. / Tetrahedron 63 (2007) 12303–12309
ꢀ
20 C for 4 h using method A. Compound 18 was obtained
R. A.; Feeney, S.; Green, R. C.; Gomes, B.; Kosmider, B. J.;
1
ꢀ
as a colorless solid (0.82 g, 93%): mp 213–215 C (dec); IR
Krell, R. D.; Shaw, A.; Steelman, G. B.; Thomas, R. M.;
Vacek, E. P.; Veale, C. A.; Tuthill, P. A.; Warner, P.; Williams,
J. C.; Wolanin, D. J.; Woolson, S. A. J. Med. Chem. 1994, 37,
1259–1261.
ꢁ
1
1
(
(
(
(
KBr) n 3285, 1650, 1524, 760, 698 cm
;
H NMR
400 MHz, DMSO-d ): d 4.31 (d, 2H, J¼5.6 Hz, CH ), 4.71
6
2
0
s, 2H, H1 ), 6.34 (dd, 1H, J¼7.0, 7.0 Hz, H5), 7.22–7.35
m, 5H, CH Ph), 7.44 (dd, 1H, J¼7.0, 2.0 Hz, H6), 7.52–
2. Warner, P.; Green, R. C.; Gomes, B.; Strimpler, A. M. J. Med.
Chem. 1994, 37, 3090–3099.
2
7
.56 (m, 2H, m-Ph), 7.59–7.63 (m, 1H, p-Ph), 7.89–7.92
(
m, 2H, o-Ph), 8.29 (dd, 1H, J¼7.6, 2.0 Hz, H4), 8.72 (br t,
3. Damewood, J. R., Jr.; Edwards, P. D.; Feeney, S.; Gomes, B. C.;
Steelman, G. B.; Tuthill, P. A.; Williams, J. C.; Warner, P.;
Woolson, S. A.; Wolanin, D. J.; Veale, C. A. J. Med. Chem.
1994, 37, 3303–3312.
1
H, J¼6.0 Hz, NH–CH ), 9.30 (br s, 1H, W w4 Hz, NH);
2
1/2
1
3
C NMR (100 MHz, DMSO-d ): d 42.2 (NH–CH ), 51.7
6
2
0
C1 ), 104.9 (C5), 123.7 (C4), 126.9 (o-Ph), 127.1 (CH Ph),
2
(
1
1
1
3
27.3 (CH Ph), 128.0 (C3), 128.3 (CH Ph), 128.8 (m-Ph),
2
4. Bernstein, P. R.; Andisik, D. W.; Bradley, P. K.; Bryant, C. B.;
Ceccarelli, C.; Damewood, J. R., Jr.; Earley, R. A.; Edwards,
P. D.; Feeney, S.; Gomes, B. C.; Kosmider, B. J.; Steelman,
G. B.; Thomas, R. M.; Vacek, E. P.; Veale, C. A.; Williams,
J. C.; Wolanin, D. J.; Woolson, S. A. J. Med. Chem. 1994, 37,
3313–3326.
2
32.1 (p-Ph), 133.7 (C6), 133.9 (i-Ph), 139.0 (i-CH Ph),
2
0
84.2 ([M+Na] , 40), 362.2 ([M+H] , 100), 368.3
57.2 (C2), 164.9 (NH), 166.5 (C2 ); LRMS (ESI) m/z (%):
+
+
+
(
[M+Li] , 100). Anal. Calcd for C H O N : C, 69.79; H,
21 19 3 3
5
.30; N, 11.63%. Found: C, 69.83; H, 5.26; N, 11.63%.
5
. Bernstein, P. R.; Shaw, A.; Thomas, R. M.; Veale, C. A.;
Warner, P.; Wolanin, E. J. PCT Int. Appl. 1993; WO
9321209, CAN 121:301319.
0 00 00
.2.3.15. N-(1-{2 -[(1 -Benzyl-2 -hydroxyethyl)ami-
no]-2 -oxoethyl}-2-oxo-1,2-dihydropyridin-3-yl)benz-
4
0
amide (19). Ester 4 (0.30 g, 1.00 mmol) and (S)-2-amino-3-
phenyl-1-propanol (0.15 g) were treated at 120 C for 1 h
6. Veale, C. A.; Bernstein, P. R.; Bryant, C.; Ceccarelli, C.;
Damewood, J. R., Jr.; Earley, R.; Feeney, S. W.; Gomes, B.;
Kosmider, B. J.; Steelman, G. B.; Thomas, R. M.; Vacek,
E. P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. J. Med.
Chem. 1995, 38, 98–108.
ꢀ
using method C. Compound 19 was obtained as a colorless
ꢀ
solid (0.33 g, 82%): mp 198–200 C; IR (KBr) n 3383,
;
ꢁ
1
1
3
285, 1679, 1646, 1581, 1524, 702 cm
H NMR
(
400 MHz, DMSO-d ): d 2.66 (dd, 1H, J¼13.6, 7.6 Hz,
7. Semple, G.; Ashworth, D. M.; Baker, G. R.; Batt, A. R.; Baxter,
A. J.; Benzies, D. W. M.; Elliot, L. H.; Evans, D. M.; Franklin,
R. J.; Hudson, P.; Jenkins, P. D.; Pitt, G. R.; Rooker, D. P.;
Sheppard, A.; Szelke, M.; Yamamoto, S.; Isomura, Y. Bioorg.
Med. Chem. Lett. 1997, 7, 1337–1342.
8. Semple, G.; Ashworth, D. M.; Batt, A. R.; Baxter, A. J.;
Benzies, D. W. M.; Elliot, L. H.; Evans, D. M.; Franklin,
R. J.; Hudson, P.; Jenkins, P. D.; Pitt, G. R.; Rooker, D. P.;
Yamamoto, S.; Isomura, Y. Bioorg. Med. Chem. Lett. 1998, 8,
959–964.
9. Sanderson, P. E.; Dyer, D. L.; Naylor-Olsen, A. N.; Vacca, J. P.;
Gardell, S. J.; Lewis, S. D.; Lucas, B. J., Jr.; Lyle, E. A.; Lynch,
J. J., Jr.; Mulichak, A. M. Bioorg. Med. Chem. Lett. 1997, 7,
1497–1500.
10. Sanderson, P. E.; Cutrona, K. J.; Dorsey, B. D.; Dyer, D. L.;
McDonough, C. M.; Naylor-Olsen, A. N.; Chen, I.-W.; Chen,
Z.; Cook, J. J.; Gardell, S. J.; Krueger, J. A.; Lewis, S. D.;
Lin, J. H.; Lucas, B. J., Jr.; Lyle, E. A.; Lynch, J. J., Jr.;
Stranieri, M. T.; Vastag, K.; Shafer, J. A.; Vacca, J. P. Bioorg.
Med. Chem. Lett. 1998, 8, 817–822.
6
CH Ph), 2.84 (dd, 1H, J¼13.6, 7.6 Hz, CH Ph), 3.27–
2
2
00 00
3
.40 (m, 2H, H2 ), 3.84–3.92 (m, 1H, H1 ), 4.61 (ABq, 2H,
0
00
J¼15.6 Hz, H1 ), 4.80 (t, 1H, J¼5.4 Hz, H2 ), 6.31 (dd, 1H,
J¼7.2, 7.2 Hz, H5), 7.15–7.31 (m, 6H, H6, CH Ph), 7.52–
2
7
2
.56 (m, 2H, m-Ph), 7.59–7.63 (m, 1H, p-Ph), 7.89–7.91 (m,
H, o-Ph), 8.17 (d, 1H, J¼8.0 Hz, NH–CH), 8.27 (dd, 1H,
1
3
J¼7.2, 1.6 Hz, H4), 9.28 (s, 1H, NH); C NMR (100 MHz,
0
00
DMSO-d ): d 37.2 (CH Ph), 52.1 (C1 ), 53.6 (C1 ), 62.8
2
6
0
o-Ph), 128.7 (C3), 128.9 (m-CH Ph), 129.5 (m-Ph), 129.9
o-CH Ph), 132.8 (p-Ph), 134.3 (C6), 134.6 (i-Ph), 139.6 (i-
2
0
(
(
(
C2 ), 105.5 (C5), 124.3 (C4), 126.7 (p-CH Ph), 127.8
2
2
0
CH Ph), 157.8 (C2), 165.5 (CO), 166.7 (C2 ); LRMS (ESI)
2
+
+
m/z (%): 428.3 ([M+Na] , 100), 406.3 ([M+H] , 15), 412.3
[M+Li] , 100). Anal. Calcd for C H O N : C, 68.13; H,
+
(
5
2
3 23 4 3
.72; N, 10.36%. Found: C, 68.23; H, 5.71; N, 10.26%.
Acknowledgements
Financial support for this work was provided by (1) Natural
Product Discovery, Griffith University and (2) the Eskitis In-
stitute for Cell and Molecular Therapies, Griffith University.
11. Reiner, J. E.; Lim-Wilby, M. S.; Brunck, T. K.; Ha-Uong, T.;
Goldman, E. A.; Abelman, M. A.; Nutt, R. F.; Semple, J. E.;
Tamura, S. Y. Bioorg. Med. Chem. Lett. 1999, 9, 895–900.
1
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