Solvent-free Ugi four-component condensation: application to synthesis of philanthotoxins-12 analogues

Article abstract of DOI:10.1016/j.tet.2008.02.051

Philanthotoxins-12 analogues was synthesized by a highly convergent approach, utilizing an efficient, simple, and convenient one-pot Ugi four-component solvent-free method as key step, followed by removal of the protecting groups in the presence of trifluoroacetic acid.

Full text of DOI:10.1016/j.tet.2008.02.051

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3966e3974
www.elsevier.com/locate/tet
Solvent-free Ugi four-component condensation: application
to synthesis of philanthotoxins-12 analogues
*
Nianjin Liu, Song Cao , Jingjing Wu, Jinlong Yu, Li Shen, Xin Feng, Xuhong Qian
*
Shanghai Key Laboratory of Chemical Biology, Center of Fluorine Chemical Technology, School of Pharmacy,
East China University of Science and Technology, Shanghai 200237, China
Received 23 November 2007; received in revised form 1 February 2008; accepted 15 February 2008
Available online 20 February 2008
Abstract
Philanthotoxins-12 analogues was synthesized by a highly convergent approach, utilizing an efficient, simple, and convenient one-pot Ugi
four-component solvent-free method as key step, followed by removal of the protecting groups in the presence of trifluoroacetic acid.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: a-Acylamino amide; Philanthotoxins analogues; Solvent-free; Ugi 4CR
1. Introduction
of N-acylamino acids with appropriately protected poly-
amines.8 Recently, a number of methods for solid-phase syn-
thesis (SPS) of polyamine toxins have been reported. For
example, Olsen described an efficient solid-phase synthesis
of novel hybrid toxins using a backbone amide linker (BAL)
resin.9 However, these methodologies are associated with
several shortcomings such as the limited variation of the
amino acid moiety, the lengthy and repeated protection and
deprotection of amido and carboxyl during the synthesis of
a-acylamino amide backbone, activation of the carboxyl
group, too many steps, and the use of organic solvents.
Among the protocols for the synthesis of peptides or amino
acids, the important method is the Ugi four-component
Polyamine toxins have attracted considerable attention ow-
ing to their diverse biological activities.1 Philanthotoxins-433
(PhTX-433), a low molecular weight natural polyamine toxin
that originally isolated from the venom of wasp,2 showed
potential noncompetitive inhibitory effects on various types
of ionotropic receptors in the central nervous system such as
ionotropic glutamate receptors (iGluRs)3 and nicotinic acetyl-
choline receptors (nAChRs) in mammalians and in insects
(Fig. 1).4 Many new more active and higher selective synthetic
analogues of philanthotoxins-433 have been obtained by mod-
ification of the structure of this natural product.5 For example,
philanthotoxins-12 (PhTX-12), which was obtained via the
change of the polyamine skeleton, has exhibited pronounced
selectivity toward nAChR, whereas is inactive at various
iGluRs.6
HO
Due to their wide applications in medicinal chemistry, the
search for general, efficient syntheses of philanthotoxins ana-
logues under mild conditions is of growing interest for organic
chemists.7 The conventional method has been developed by
Nakanishi et al., involving coupling of p-nitrophenyl esters
amine chain
H
N
HN
X
X
NH2
head group
O
O
PhTX-433 X = NH
PhTX-12 X = CH2
* Corresponding authors. Fax: þ86 21 6425 2603.
E-mail addresses: scao@ecust.edu.cn (S. Cao), xhqian@ecust.edu.cn (X.
Qian).
Figure 1. Structure of PhTX-433 and PhTX-12.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.051

N. Liu et al. / Tetrahedron 64 (2008) 3966e3974
3967
reaction (Ugi 4CR).10 Ugi 4CR offers significant advantages
R3
O
H
N
R4
R1
NH2
over stepwise procedures, especially with respect to diversity,
complexity, green chemistry, and atom economy.11 To date,
many efforts have been made to modify the Ugi 4CR condition
in order to improve the synthetic efficiency.12 Dai reported the
use of microwave-assisted conditions to greatly accelerate the
N
10
O
1
R4= H or 4-methoxyphenyl
Target compounds
Ugi 4CR.13 Fulop focused on the application of a modified Ugi
¨ ¨
reaction in aqueous medium to construct b-lactam libraries.14
Curran developed a new protocol for Ugi multi-component
condensation by using fluorous technology.15 Despite the
latest development, there is still an urgent need for a highly
efficient and mild method for Ugi 4CR.
Ugi 4CR
R3CHO
3
1
+
R COOH
CN
10 NHBoc
2
R2NH2
4
5
In this paper, we report an efficient, simple, and convenient
protocol for the synthesis of a-acylamino amide backbone
under one-pot Ugi four-component solvent-free conditions,
followed by the simple removal of the protecting groups in
the presence of trifluoroacetic acid (TFA) to obtain PhTX-12
derivatives.
Scheme 1. Retrosynthesis of target compounds.
a
H2N
b
NH2
H2N
NHBoc
10
10
6
7
O
c
HCHN
10 NHBoc
CN
NHBoc
10
8
5
2. Results and discussion
Scheme 2. Synthesis of 12-(tert-butoxycarbonylamino)dodecylisocyanide.
(a) (Boc)2O, CH2Cl2/CH3OH (3:2), rt; (b) HCOOH, DCC, CH2Cl2, rt; (c)
PPh3, CCl4, NEt3, ClCH2CH2Cl, 60 ꢀC.
The results of structureeactivity investigations emphasized
the importance of the aromatic headgroup of philanthotoxins.16
For example, PhTX(Cha)-343, an analogue of PhTX-343
(a kind of synthetic analogues of Philanthotoxins-433) in which
the tyrosine moiety has been replaced by cyclohexylalanine
(Cha), showed high selectivity toward human muscle-type
nAChR and exhibited unprecedented activity at nanomolar
concentrations.17 Strømgaard et al. modified the aromatic head-
group of philanthotoxin-56 (another kind of synthetic analogues
of philanthotoxins-433) by changing the butyramide moiety to
adamantylacetamide. They also demonstrated that this modifi-
cation led to a significant improvement in activity at AMPA
receptors.18
However, little has been reported on the structureeactivity
relationships (SAR) of PhTX-12. In 2002, Strømgaard
reported that it would lead to a dramatic decrease in activity
when the number of methylene spacer between the primary
amino group and the aromatic headgroup of PhTX-12 was
less than eleven.19 In addition, he also demonstrated the
S- and R-enantiomers of PhTX-12 had nearly the same activity
on nicotinic acetylcholine receptors.20 Therefore, in this paper
chemical transformations were conducted to modify the aro-
matic headgroup present in PhTX-12 and to synthesize 2 series
of 15 PhTX-12 analogues for further SAR study. The first
series of the target compounds 1aei are a-N-unsubstituted
a-acylamino amides. The second series 1jeo are a-N-
substituted a-acylamino amides.
1,12-diaminododecane 7 was N-formylated with formic acid
in the presence of dicyclohexylcarbodiimide (DCC), and then
tert-butyl 12-formamidododecylcarbamate 8 was dehydrated
by treatment with equimolar amounts of carbon tetrachloride,
triethylamine, and triphenylphosphine (20% excess) to give
the desired product 12-(tert-butoxycarbonylamino)dodecyliso-
cyanide 5.21 This novel isocyanide could be stored for several
months in desiccator at room temperature without obvious
decomposition.
Generally, the Ugi 4CR was performed in organic solvents
such as methanol, tetrahydrofuran at room temperature for 1e2
days.22 According to the classical procedure, methanol is the
best solvent for the Ugi 4CR.23 Therefore, we carried out
this Ugi 4CR with carboxylic acid, aldehyde, amine, and iso-
˚
cyanide in the presence of 4 A molecular sieves in methanol at
room temperature, which afforded the key intermediate in
moderate to good yield. To survey the generality and scope
of this one-pot four-component protocol, and also to enlarge
the SAR studies of parent compound, the methodology was
applied to the synthesis of a variety of a-acylamino amide
derivatives 9aeo. For compounds 9aei, R2 was kept as 2,4-di-
methoxybenzyl (a readily cleavable protecting group) in order
to make its cleavage possible. The reaction times and isolated
yields are summarized in Table 1. In addition, it was reported
that Ugi 4CR could be carried out in boiling methanol
smoothly.24 Hence we also tried to carry out this Ugi reaction
under reflux conditions to synthesize several intermediates 9c,
9j, 9n. Despite the shorter reaction time it needed (9e11 h),
the yields were slightly lower at reflux temperature than those
at room temperature. It seems that refluxing in methanol is
unfavorable to Ugi 4CR.
The retrosynthetic analysis of the target compounds is shown
in Scheme 1. It was indicated that 1 could be resolved into a set
of four easily available building blocks. Therefore, we proposed
that this dipeptide could be made from the Ugi 4CR of carbox-
ylic acid 2, aldehyde 3, amine 4, and mono-N-Boc-protected
12-dodecylisocyanide 5. Firstly, novel isocyanide 5 was syn-
thesized, as illustrated in Scheme 2. Thus, beginning with
1,12-diaminododecane 6, one of the amine was protected by
Boc group using standard method. The mono(Boc)-protected
Although this Ugi 4CR was carried out successfully in
methanol at room temperature to afford the desired

3968
N. Liu et al. / Tetrahedron 64 (2008) 3966e3974
Table 1
Synthesis of compounds 9aeo in methanol or under solvent-free conditions
Compounds
R1
R2
R3
Methanol
Timea (h)
Solvent-free
Timea (h)
Yieldb (%)
Yieldb (%)
9a
9b
9c
9d
9e
9f
6-Chloropyridin-3-yl
6-Chloropyridin-3-yl
2,4-Dimethoxybenzyl
2,4-Dimethoxybenzyl
2,4-Dimethoxybenzyl
2,4-Dimethoxybenzyl
2,4-Dimethoxybenzyl
2,4-Dimethoxybenzyl
2,4-Dimethoxybenzyl
2,4-Dimethoxybenzyl
2,4-Dimethoxybenzyl
4-Methoxyphenyl
6-Chloropyridin-3-yl
Benzo[d][1,3]dioxol-5-yl
6-Chloropyridin-3-yl
43
38
48
39
41
45
42
39
43
42
46
48
37
39
36
71
61
63
63
61
65
68
64
62
57
55
52
64
62
59
0.5
0.6
0.5
0.6
0.5
0.6
0.6
0.6
0.6
0.8
0.7
0.7
0.7
0.6
0.7
83
71
72
70
81
74
75
71
73
60
56
53
68
65
61
4-Trifluoromethylphenyl
4-Trifluoromethylphenyl
2,4,5-Trifluoro-3-methoxyphenyl
2,4,5-Trifluoro-3-methoxyphenyl
4-Trifluoromethylphenyl
4-Fluorophenyl
Benzo[d][1,3]dioxol-5-yl
6-Chloropyridin-3-yl
Benzo[d][1,3]dioxol-5-yl
3-Chloro-2-fluorophenyl
3-Chloro-2-fluorophenyl
3-Chloro-2-fluorophenyl
Benzo[d][1,3]dioxol-5-yl
Benzo[d][1,3]dioxol-5-yl
Benzo[d][1,3]dioxol-5-yl
6-Chloropyridin-3-yl
9g
9h
9i
2-Fluorophenyl
6-Chloropyridin-3-yl
9j
9k
9l
4-Trifluoromethylphenyl
2,4,5-Trifluoro-3-methoxyphenyl
6-Chloropyridin-3-yl
4-Methoxyphenyl
4-Methoxyphenyl
9m
9n
9o
a
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Trifluoromethylphenyl
2,4,5-Trifluoro-3-methoxyphenyl
6-Chloropyridin-3-yl
6-Chloropyridin-3-yl
Time after addition of acid and isocyanide into flask.
Yields of pure isolated compound after silica gel chromatography.
b
compounds, there are some drawbacks in Ugi reaction such as
too long reaction time and using methanol as solvent leading
to side reaction. More recently, Shaabani studied the reaction
of carboxylic acids and isocyanides in methanol at ambient
temperature carefully. Aryl amides were obtained in high yield
after 24 h. He also proved that methanol took part in this reac-
tion and converted to methylformate.25 Furthermore, it was
also reported that methanol took part in the reaction to form
unintended byproducts. For example, de Mello demonstrated
that under the Ugi reaction conditions, the iminium cation
underwent another competing reactions involving reaction sol-
vent (methanol) to give undesired byproduct.26 These studies
have shown that the utility of methanol as solvent led inevita-
bly the formation of some undesired side products.
that 60 ꢀC was the optimum reaction temperature. At low reac-
tion temperature, i.e., 50 ꢀC, the longer reaction time was
needed. When the reaction temperature was higher than 60 ꢀC,
low yield was observed. The optimum conditions were then ap-
plied to the condensation of several different acids, aldehyde,
amine, and isocyanide. The yields and reaction times are listed
in Table 1. As can be seen from Table 1, shorter reaction time
was needed and higher yields have been achieved under
solvent-free conditions compared to conventional method.
Finally, the target compounds 1aeo were obtained via the
deprotection of the Boc group and 2,4-dimethoxybenzyl in
the presence of trifluoroacetic acid in dichloromethane at
room temperature. The crude residue was purified by chroma-
tography to give pure compounds 1aeo.
Organic synthesis involving multi-component reactions
(MCRs) under solvent-free conditions has been receiving
much attention.27 As part of our continuing interest to develop
more efficient and practical methods in organic synthesis, we
explored the possibility of obtaining the key intermediate 9aeo
by the Ugi 4CR under solvent-free conditions (Scheme 3).
To the best of our knowledge, no solvent-free Ugi 4CR has
been documented.
The synthesis of 9c was served as the basic reaction model.
We were delighted to find that the reaction proceeded smoothly
in a much shorter time at elevated temperature and resulted in
the formation of products in higher yield. The reaction was sig-
nificantly affected by the reaction temperature. It was observed
3. Conclusion
In conclusion, we have developed a mild and efficient or-
ganic solvent-free Ugi four-component condensation for the
synthesis of a-acylamino amides 9aeo, the key intermediates
in the synthesis of PhTX-12 derivatives. Reaction times were
dramatically reduced and yields were generally improved by
this new method. Further removal of protective groups, by
treatment with trifluoroacetic acid, gave final products 1aeo.
This new class of compounds may be used as new lead com-
pounds for biological activity evaluation, especially as non-
competitive antagonist of nAChRs.
R3
H
N
NH2
NH2
HN
R1
10
10
R2 = 2, 4-dimethoxybenzyl
R3
O
R3CHO
3
H
N
c
O
a
R2
R1
NHBoc
1a-i
R3
N
R1COOH
10
H
N
+ CN
R2NH2
4
NHBoc
10
R2
R1
c
O
2
5
O
N
b
9a-o
R2 = 4-methoxyphenyl
O
O
1j-o
ꢀ
˚
Scheme 3. Synthesis of PhTX-12 derivatives via Ugi 4CR. (a) No solvent, 60 C; (b) 4 A molecular sieves, CH3OH, rt; (c) TFA, CH2Cl2.

N. Liu et al. / Tetrahedron 64 (2008) 3966e3974
3969
4. Experimental
(d, J¼6.4 Hz, 2H), 1.44 (s, 13H), 1.27 (s, 14H); 13C NMR
(100 MHz, CDCl3): d 155.98, 155.54, 78.99, 41.62, 41.56,
41.50, 40.63, 30.06, 29.50, 29.47, 29.44, 29.33, 29.26, 29.10,
28.68, 28.43, 26.78, 26.30; HRMS (ESI) m/z: 333.2519
[MþNa]þ; calcd for C18H34N2O2þNa: 333.2518.
4.1. General
All reactions were carried out under dry nitrogen except
1
Ugi 4CR and the deprotection reaction. H and 13C nuclear
magnetic resonance (NMR) spectra were recorded on a Bruker
Avance 400 MHz spectrometer (400 and 100 MHz, respec-
tively); chemical shifts (d) are given in parts per million.
High-resolution mass spectra were recorded under electron
impact conditions using a MicroMass GCT CA055 instrument.
4.4. General procedure for the synthesis of compounds 9aeo
in methanol
The appropriate primary amino (1.65 mmol) and aldehyde
(1.5 mmol) were dissolved in 2 mL of anhydrous methanol
and the mixture was stirred at room temperature for 2 h after
Melting points were measured on a Buchi B-540 melting point
¨
˚
apparatus and are uncorrected. All reagents were of analytic
grade and obtained from commercial suppliers and used with-
out further purification with the following exceptions.
Dichloromethane and 1,2-dichloroethane were distilled from
phosphorus pentoxide. Methanol was heated to reflux over
magnesium methoxide for 12 h and then distilled.
adding a small quantity of 4 A molecular sieves. To this solu-
tion the carboxylic acid (1.5 mmol) and isocyanide 5
(1.5 mmol) were added successively. The reaction mixture
was stirred at ambient temperature for 36e48 h. Subsequently,
molecular sieves were removed by filtration and the solid was
washed with adequate methanol. The filtrate was concentrated
under reduced pressure and the resultant crude residue was
purified by chromatography (AcOEt/heptane¼1:5) to give
the corresponding 9aeo in yields of 52e71%.
4.2. Preparation of tert-butyl 12-formamidododecyl-
carbamate 8
To a stirred suspension of mono(Boc)-protected 1,12-diami-
nododecane 7 (24.60 g, 82 mmol) and dried formic acid
(3.2 mL, 82 mmol) in 150 mL CH2Cl2, solution of dicyclohex-
ylcarbodiimide (17.72 g, 86 mmol) in 100 mL CH2Cl2 was
added dropwise for about half an hour at room temperature.
The reaction mixture was stirred for another 5 h (TLC) at
room temperature. A white solid 1,3-dicyclohexylurea (DCU)
was filtered and the filtrate was washed with 8 mL saturated so-
lution of NaHCO3. The organic layer was separated, washed
with water, dried over anhydrous sodium sulfate, and concen-
trated in vacuo, and a white solid mixture was obtained. The re-
sultant crude residue was purified by chromatography (AcOEt/
heptane¼2:1) to obtain the product. Yield: 73%; mp 43e45 ꢀC.
1H NMR (400 MHz, CDCl3): d 8.19 (s, 1H), 5.78 (s, 1H), 3.34e
3.29 (m, 2H), 3.10 (t, J¼7.2 Hz, 2H), 1.54 (t, J¼6.8 Hz, 2H),
1.45 (s, 11H), 1.31e1.27 (m, 16H); 13C NMR (100 MHz,
CDCl3) d 161.38, 156.28, 79.37, 42.05, 41.08, 38.51, 36.80,
34.32, 30.29, 29.66, 29.44, 28.66, 27.01; HRMS (ESI) m/z:
329.2805 [MþH]þ, calcd for C18H36N2O3þH: 329.2804.
4.5. General procedure for the synthesis of compounds 9aei
under solvent-free conditions
To a stirred 2,4-dimethoxybenzyl amine (0.83 mmol), alde-
hyde (0.75 mmol) was added in portions for about 5 min. The
mixture was stirred for 25 min again at room temperature.
Then, the reaction mixture was heated to 60 ꢀC. The isocyanide
5 (0.75 mmol) and carboxylic acid (0.75 mmol) were added in
portions for 10 min. Stirring was continued at 60 ꢀC for
25 min (TLC). The crude residue was purified by chromatogra-
phy (AcOEt/heptane¼1:5) to give the desired products.
4.5.1. tert-Butyl 12-(2-(N-(2,4-dimethoxybenzyl)-2-
chloronicotinamido)-2-(6-chloropyridin-3-yl)acetamido)-
dodecylcarbamate (9a)
White solid, mp 102e104 ꢀC. 1H NMR (400 MHz, CDCl3):
d 8.57 (s, 1H), 8.19 (s, 1H), 7.82e7.78 (m, 2H), 7.37 (d,
J¼8.4 Hz, 1H), 7.22 (d, J¼8.4 Hz, 1H), 7.09 (d, J¼8.4 Hz,
1H), 6.40 (d, J¼8.4 Hz, 1H), 6.25 (d, J¼2.0 Hz, 1H), 5.95
(s, 1H), 5.15 (s, 1H), 4.54 (d, J¼3.6 Hz, 2H), 3.77 (s, 3H),
3.64 (s, 3H), 3.21 (q, J¼6.8 Hz, 2H), 3.09 (t, J¼6.4 Hz, 2H),
1.44 (s, 13H), 1.27e1.23 (m, 16H); 13C NMR (100 MHz,
CDCl3): d 169.44, 167.44, 161.39, 158.08, 155.99, 152.91,
151.29, 150.36, 148.15, 140.04, 137.50, 130.63, 130.38,
130.35, 124.03, 123.96, 115.32, 104.44, 98.51, 79.01, 62.30,
55.45, 55.09, 50.24, 40.06, 30.06, 29.49, 29.34, 29.26, 29.18,
28.43, 26.85, 26.78; HRMS (ESI) m/z: 780.3268 [MþNa]þ;
calcd for C39H53Cl2N5O6þNa: 780.3271.
4.3. 12-(tert-Butoxycarbonylamino)dodecylisocyanide 5
tert-Butyl 12-formamidododecylcarbamate
8 (15.00 g,
46 mmol), carbon tetrachloride (4.50 mL, 46 mmol), triethyl-
amine (6.50 mL, 46 mmol), and triphenylphosphane (14.50 g,
55.2 mmol) were dissolved in 50 mL 1,2-dichloroethane and
the mixture was stirred at 60 ꢀC for about 2.5 h (TLC). Then,
the dark brown reaction mixture was cooled to room tempera-
ture. Subsequently, white triethylamine hydrochloride salt was
removed by filtration and the solid was washed with CH2Cl2.
The filtrate was concentrated under reduced pressure and the re-
sultant crude residue was purified by chromatography (AcOEt/
heptane¼1:8), and white isocyanide 5 was obtained. Yield,
4.5.2. tert-Butyl 12-(2-(N-(2,4-dimethoxybenzyl)-2-
chloronicotinamido)-2-(benzo[d][1,3]dioxol-5-yl)-
acetamido)dodecylcarbamate (9b)
1
Light yellow oil. H NMR (400 MHz, CDCl3): d 8.54 (d,
J¼2.0 Hz, 1H), 7.77 (q, J¼2.0 Hz, 1H), 7.35 (d, J¼8.4 Hz,
1
90%; mp 84e86 ꢀC. H NMR (400 MHz, CDCl3): d 4.51 (s,
1H), 3.40e3.37 (m, 2H), 3.11 (d, J¼6.0 Hz, 2H), 1.67
1H), 7.29 (d, J¼8.4 Hz, 1H), 6.95 (s, 1H), 6.80 (d,

3970
N. Liu et al. / Tetrahedron 64 (2008) 3966e3974
J¼8.0 Hz, 1H), 6.72 (d, J¼8.0 Hz, 1H), 6.44 (dd, J¼2.0,
8.0 Hz, 1H), 6.25 (d, J¼2.0 Hz, 1H), 5.96 (s, 2H), 5.76 (s,
1H), 5.10 (s, 1H), 4.46 (s, 2H), 3.78 (s, 3H), 3.62 (s, 3H),
3.30e3.19 (m, 2H), 3.10 (t, J¼6.8 Hz, 2H), 1.93 (s, 1H),
1.45 (s, 13H), 1.28e1.23 (m, 16H); 13C NMR (100 MHz,
CDCl3): d 169.33, 168.68, 160.66, 157.79, 156.00, 152.48,
148.02, 147.83, 141.24, 137.44, 131.06, 129.28, 128.75,
123.78, 123.54, 116.58, 109.77, 108.32, 104.09, 101.32,
98.24, 79.01, 65.45, 55.38, 54.97, 39.98, 30.06, 29.50,
29.48, 29.32, 29.27, 29.18, 28.43, 26.87, 26.78; HRMS
(ESI) m/z: 767.3790 [MþH]þ; calcd for C41H55ClN4O8þH:
767.3787.
3H), 3.65 (s, 3H), 3.19 (q, J¼6.4 Hz, 2H), 3.08 (d,
J¼5.6 Hz, 2H), 1.43 (s, 13H), 1.24 (s, 16H); 13C NMR
(100 MHz, CDCl3): d 167.28, 165.71, 161.56, 158.33,
155.96, 150.96, 150.14, 139.87, 131.04, 130.33, 123.63,
120.03, 119.99, 119.92, 119.86, 119.79, 119.75, 114.99,
108.81, 108.60, 104.65, 98.57, 78.90, 62.07, 61.82, 55.39,
55.08, 49.59, 39.96, 30.04, 29.46, 29.32, 29.23, 29.18,
28.39, 26.83, 26.74; HRMS (ESI) m/z: 807.3698 [MþH]þ;
calcd for C41H54ClF3N4O7þH: 807.3633.
4.5.6. tert-Butyl 12-(2-(N-(2,4-dimethoxybenzyl)-2,4,5-
trifluoro-3-methoxybenzamido)-2-(benzo[d][1,3]dioxol-
5-yl)acetamido)dodecylcarbamate (9f)
1
4.5.3. tert-Butyl 12-(2-(N-(2,4-dimethoxybenzyl)-4-
(trifluoromethyl)benzamido)-2-(6-chloropyridin-3-
yl)acetamido)dodecylcarbamate (9c)
Light yellow oil. H NMR (400 MHz, CDCl3): d 7.09 (d,
J¼8.4 Hz, 1H), 6.91e6.86 (m, 2H), 6.79 (d, J¼7.2 Hz, 1H),
6.71 (d, J¼8.0 Hz, 1H), 6.38 (dd, J¼2.0, 8.0 Hz, 1H), 6.22
(s, 1H), 5.94 (s, 3H), 5.21 (s, 1H), 4.43 (s, 2H), 4.02 (s,
3H), 3.76 (s, 3H), 3.62 (s, 3H), 3.23 (q, J¼6.8 Hz, 2H), 3.09
(s, 2H), 1.45 (s, 13H), 1.28e1.24 (m, 16H); 13C NMR
(100 MHz, CDCl3): d 168.61, 165.80, 160.80, 158.04,
155.98, 147.82, 147.57, 146.17, 146.07, 143.71, 130.10,
128.78, 123.14, 120.59, 120.35, 116.18, 109.67, 108.79,
108.62, 108.14, 104.10, 101.20, 98.14, 78.98, 64.76, 62.07,
55.34, 54.94, 48.30, 40.70, 39.89, 30.06, 29.49, 29.31,
29.26, 29.19, 28.41, 26.87, 26.77; HRMS (ESI) m/z:
838.3923 [MþNa]þ; calcd for C43H56F3N3O9þNa: 838.3866.
1
Light yellow oil. H NMR (400 MHz, CDCl3): d 8.20 (d,
J¼2.4 Hz, 1H), 7.77 (d, J¼7.2 Hz, 1H), 7.62 (dd, J¼8.0,
19.2 Hz, 4H), 7.17 (d, J¼8.4 Hz, 1H), 7.03 (d, J¼8.4 Hz,
1H), 6.37 (dd, J¼2.0, 8.0 Hz, 1H), 6.22e6.18 (m, 1H), 5.21
(s, 1H), 4.51 (s, 2H), 3.74 (s, 3H), 3.61 (s, 3H), 3.18 (q,
J¼6.8 Hz, 2H), 3.07 (d, J¼6.4 Hz, 2H), 1.42 (s, 13H),
1.25e1.22 (m, 16H); 13C NMR (100 MHz, CDCl3):
d 171.47, 167.79, 161.27, 158.07, 156.02, 150.96, 150.14,
140.19, 139.36, 132.11, 131.79, 131.46, 130.64, 130.47,
127.38, 125.50, 125.46, 124.96, 123.88, 122.28, 115.61,
104.43, 98.44, 79.03, 62.12, 61.56, 55.42, 55.04, 50.14,
40.02, 30.05, 29.50, 29.34, 29.26, 29.20, 28.41, 26.87,
26.77; HRMS (ESI) m/z: 813.3553 [MþNa]þ; calcd for
C41H54ClF3N4O6þNa: 813.3582.
4.5.7. tert-Butyl 12-(2-(N-(2,4-dimethoxybenzyl)-4-
(trifluoromethyl)benzamido)-2-(3-chloro-2-fluorophenyl)-
acetamido)dodecylcarbamate (9g)
1
Colorless oil. H NMR (400 MHz, CDCl3): d 7.64e7.59
4.5.4. tert-Butyl 12-(2-(N-(2,4-dimethoxybenzyl)-4-
(trifluoromethyl)benzamido)-2-(benzo[d][1,3]dioxol-5-
yl)acetamido)dodecylcarbamate (9d)
(m, 4H), 7.50 (s, 1H), 7.22 (t, J¼7.2 Hz, 1H), 7.07 (d,
J¼8.0 Hz, 1H), 6.95 (t, J¼7.6 Hz, 1H), 6.35 (dd, J¼2.0,
8.4 Hz, 2H), 6.14 (d, J¼2.0 Hz, 1H), 5.62 (s, 1H), 4.58 (s,
1H), 4.53 (s, 2H), 3.72 (s, 3H), 3.58 (s, 3H), 3.16 (q,
J¼6.4 Hz, 2H), 3.06 (d, J¼6.0 Hz, 2H), 1.41 (s, 13H),
1.24e1.21 (m, 16H); 13C NMR (100 MHz, CDCl3):
d 171.55, 167.88, 160.71, 157.72, 157.60, 155.98, 155.13,
139.74, 103.82, 98.20, 78.86, 55.26, 54.86, 40.58, 39.85,
30.02, 29.47, 29.28, 29.24, 29.18, 28.37, 26.82, 26.75.
1
Light yellow oil. H NMR (400 MHz, CDCl3): d 7.61 (s,
4H), 7.32 (d, J¼8.0 Hz, 1H), 6.95 (s, 1H), 6.80 (d,
J¼8.0 Hz, 1H), 6.71 (d, J¼8.0 Hz, 1H), 6.43 (dd, J¼2.4,
8.4 Hz, 1H), 6.24 (d, J¼2.0 Hz, 1H), 5.95 (s, 2H), 5.84 (s,
1H), 5.14 (s, 1H), 4.46 (s, 2H), 3.77 (s, 3H), 3.61 (s, 3H),
3.29e3.18 (m, 2H), 3.10 (t, J¼6.8 Hz, 2H), 2.00 (s, 1H),
1.45 (s, 13H), 1.28e1.24 (m, 16H); 13C NMR (100 MHz,
CDCl3): d 171.46, 168.89, 160.51, 157.82, 155.99, 147.92,
147.69, 139.87, 131.70, 131.37, 129.42, 128.97, 127.23,
125.23, 125.11, 123.43, 122.40, 116.90, 109.77, 108.22,
104.03, 101.25, 98.14, 79.00, 65.28, 55.35, 54.90, 39.95,
30.06, 29.49, 29.33, 29.27, 29.19, 28.42, 26.89, 26.78;
HRMS (ESI) m/z: 800.4096 [MþH]þ; calcd for
C43H56F3N3O8þH: 800.4098.
4.5.8. tert-Butyl 12-(2-(N-(2,4-dimethoxybenzyl)-4-
fluorobenzamido)-2-(3-chloro-2-fluorophenyl)acetamido)-
dodecylcarbamate (9h)
1
Colorless oil. H NMR (400 MHz, CDCl3): d 7.52e7.49
(m, 2H), 7.44 (s, 1H), 7.20 (t, J¼6.8 Hz, 1H), 7.09e7.01
(m, 3H), 6.94 (t, J¼8.0 Hz, 1H), 6.46 (t, J¼5.6 Hz, 1H),
6.34 (dd, J¼2.4, 8.4 Hz, 1H), 6.16 (d, J¼2.4 Hz, 1H), 5.53
(s, 1H), 4.60 (s, 2H), 3.71 (s, 3H), 3.58 (s, 3H), 3.15e3.10
(m, 2H), 3.05 (d, J¼6.4 Hz, 2H), 1.40 (s, 13H), 1.24e1.21
(m, 16H); 13C NMR (100 MHz, CDCl3): d 172.00, 168.08,
164.79, 162.30, 160.65, 157.82, 157.63, 155.98, 155.15,
132.21, 132.18, 130.46, 129.99, 129.50, 129.44, 129.36,
124.93, 124.80, 124.16, 124.12, 120.70, 120.52, 116.58,
115.48, 115.27, 103.80, 98.24, 78.82, 55.26, 54.89, 40.58,
39.79, 30.02, 29.48, 29.28, 29.24, 29.19, 28.38, 26.83, 26.75.
4.5.5. tert-Butyl 12-(2-(N-(2,4-dimethoxybenzyl)-2,4,5-
trifluoro-3-methoxybenzamido)-2-(6-chloropyridin-3-yl)-
acetamido)dodecylcarbamate (9e)
1
Light yellow oil. H NMR (400 MHz, CDCl3): d 8.17 (d,
J¼1.6 Hz, 1H), 7.75 (d, J¼6.8 Hz, 1H), 7.19 (d, J¼8.0 Hz,
1H), 6.96 (d, J¼8.0 Hz, 1H), 6.89 (dd, J¼8.4, 6.8 Hz, 1H),
6.38 (dd, J¼2.0, 6.4 Hz, 1H), 6.26 (d, J¼2.0 Hz, 1H), 6.21
(s, 1H), 5.21 (s, 1H), 4.48 (s, 2H), 4.04 (s, 3H), 3.75 (s,

N. Liu et al. / Tetrahedron 64 (2008) 3966e3974
3971
4.5.9. tert-Butyl 12-(2-(N-(2,4-dimethoxybenzyl)-2-
fluorobenzamido)-2-(3-chloro-2-fluorophenyl)-
acetamido)dodecylcarbamate (9i)
122.33, 113.68, 110.68, 108.20, 101.26, 79.00, 65.99, 55.23,
40.64, 39.99, 30.05, 29.67, 29.48, 29.26, 29.19, 28.42,
26.86, 26.77; HRMS (ESI) m/z: 778.3651 [MþNa]þ; calcd
for C41H52F3N3O7þNa: 778.3655.
Colorless oil. 1H NMR (400 MHz, CDCl3): d 7.53 (t,
J¼6.8 Hz, 1H), 7.40e7.32 (m, 2H), 7.22 (t, J¼7.2 Hz, 1H),
7.15 (t, J¼7.6 Hz, 1H), 7.07 (t, J¼8.8 Hz, 1H), 6.99e6.90
(m, 2H), 6.38e6.31 (m, 2H), 6.17 (d, J¼1.6 Hz, 1H), 5.54
(s, 1H), 4.62 (s, 1H), 4.49 (dd, J¼15.2 Hz, 2H), 3.70 (s,
3H), 3.60 (s, 3H), 3.17e3.12 (m, 2H), 3.05 (d, J¼6.4 Hz,
2H), 1.40 (s, 13H), 1.22 (s, 16H); 13C NMR (100 MHz,
CDCl3): d 167.77, 167.58, 161.00, 159.85, 158.17, 157.60,
157.38, 155.99, 155.12, 131.48, 131.40, 130.76, 130.26,
130.08, 128.87, 124.92, 124.78, 124.45, 124.28, 124.07,
124.03, 120.52, 120.34, 116.01, 115.79, 115.72, 103.93,
98.34, 78.82, 60.31, 58.25, 55.26, 54.94, 54.85, 49.50,
40.59, 39.85, 30.02, 29.49, 29.25, 29.21, 29.15, 28.39,
26.80, 26.76.
4.6.3. tert-Butyl 12-(2-(benzo[d][1,3]dioxol-5-yl)-2-(2,4,5-
trifluoro-3-methoxy-N-(4-methoxyphenyl)benzamido)-
acetamido)dodecylcarbamate (9l)
1
Light yellow oil. H NMR (400 MHz, CDCl3): d 6.94 (s,
1H), 6.83e6.77 (m, 1H), 6.67 (d, J¼7.6 Hz, 3H), 6.55 (d,
J¼8.8 Hz, 2H), 6.04 (s, 1H), 5.93 (s, 2H), 5.76 (d,
J¼5.2 Hz, 1H), 4.52 (s, 1H), 3.85 (s, 3H), 3.68 (s, 3H),
3.32e3.29 (m, 2H), 3.09 (t, J¼7.2 Hz, 2H), 1.95 (s, 1H),
1.49e1.45 (m, 13H), 1.28e1.24 (m, 16H); 13C NMR
(100 MHz, CDCl3): d 168.80, 165.43, 158.90, 156.07,
148.16, 147.88, 147.74, 145.74, 131.64, 131.34, 127.62,
124.40, 113.44, 110.57, 109.19, 109.02, 106.20, 101.27,
79.18, 65.45, 61.93, 60.37, 55.22, 40.82, 40.02, 30.04,
29.50, 29.48, 29.43, 29.26, 29.19, 28.42, 26.86, 26.77;
HRMS (ESI) m/z: 772.3798 [MþH]þ; calcd for
C41H52F3N3O8þH: 772.3785.
4.6. General procedure for the synthesis of compounds 9jeo
under solvent-free conditions
At 60 ꢀC, to a stirred 4-methoxybenzenamine (0.83 mmol),
aldehyde (0.75 mmol) was added in portions for about 5 min.
The mixture was stirred for 20 min again. The isocyanide 5
(0.75 mmol) and carboxylic acid (0.75 mmol) were added in
portions for 10 min. Stirring was continued at 60 ꢀC (TLC).
The crude residue was purified by chromatography (AcOEt/
heptane¼1:5) to give the desired products.
4.6.4. tert-Butyl 12-(2-(2-chloro-N-(4-methoxyphenyl)-
nicotinamido)-2-(6-chloropyridin-3-yl)acetamido)-
dodecylcarbamate (9m)
1
Light yellow oil. H NMR (400 MHz, CDCl3): d 8.31 (d,
J¼2.4 Hz, 1H), 8.27 (d, J¼2.0 Hz, 1H), 7.57 (dd, J¼2.4,
8.4 Hz, 1H), 7.49 (dd, J¼2.4, 8.4 Hz, 1H), 7.16 (t,
J¼8.4 Hz, 2H), 6.87 (s, 1H), 6.63 (d, J¼8.0 Hz, 2H), 6.21
(s, 1H), 6.01 (s, 1H), 4.50 (s, 1H), 3.72 (s, 3H), 3.36e3.31
(m, 2H), 3.10 (t, J¼7.2 Hz, 2H), 1.90 (s, 1H), 1.46e1.45
(m, 13H), 1.28e1.25 (m, 16H); 13C NMR (100 MHz,
CDCl3): d 168.02, 167.95, 159.34, 152.35, 151.97, 151.21,
149.50, 140.81, 138.67, 131.68, 131.38, 130.30, 129.09,
126.48, 123.97, 123.47, 121.01, 114.47, 79.09, 62.35, 56.76,
55.32, 40.14, 30.05, 29.44, 29.23, 29.15, 28.43, 26.83,
26.76; HRMS (ESI) m/z: 736.3005 [MþNa]þ; calcd for
C37H49Cl2N5O5þNa: 736.3008.
4.6.1. tert-Butyl 12-(2-(benzo[d][1,3]dioxol-5-yl)-2-
(2-chloro-N-(4-methoxyphenyl)nicotinamido)-
acetamido)dodecylcarbamate (9j)
1
Light yellow oil. H NMR (400 MHz, CDCl3): d 8.28 (d,
J¼2.4 Hz, 1H), 7.59 (dd, J¼2.4, 8.4 Hz, 1H), 7.12
(d, J¼8.4 Hz, 1H), 6.94 (s, 1H), 6.71e6.67 (m, 3H), 6.60 (d,
J¼8.8 Hz, 2H), 6.05 (s, 1H), 5.94 (d, J¼0.8 Hz, 2H), 5.69
(t, J¼5.6 Hz, 1H), 4.51 (s, 1H), 3.71 (s, 3H), 3.36e3.26 (m,
2H), 3.10 (t, J¼6.8 Hz, 2H), 1.95 (s, 1H), 1.45 (s, 13H),
1.28e1.24 (m, 16H); 13C NMR (100 MHz, CDCl3):
d 169.05, 167.69, 158.88, 156.00, 151.81, 149.52, 147.95,
147.81, 138.73, 132.57, 131.64, 131.07, 127.78, 124.47,
123.31, 113.98, 110.59, 108.25, 101.31, 79.00, 66.03, 60.37,
55.26, 40.70, 40.02, 30.06, 29.49, 29.47, 29.44, 29.26,
29.18, 28.43, 26.85, 26.78; HRMS (ESI) m/z: 745.3336
[MþNa]þ; calcd for C39H51ClN4O7þNa: 745.3344.
4.6.5. tert-Butyl 12-(2-(6-chloropyridin-3-yl)-2-
(N-(4-methoxyphenyl)-4-(trifluoromethyl)benzamido)-
acetamido)dodecylcarbamate (9n)
1
Light yellow oil. H NMR (400 MHz, CDCl3): d 8.33 (d,
J¼2.4 Hz, 1H), 7.51 (dd, J¼2.4, 8.4 Hz, 1H), 7.41 (dd,
J¼8.4, 15.2 Hz, 4H), 7.16 (d, J¼8.4 Hz, 1H), 6.86 (s, 1H),
6.59 (d, J¼8.8 Hz, 2H), 6.26 (s, 1H), 6.19 (s, 1H), 4.51 (s,
1H), 3.70 (s, 3H), 3.33 (q, J¼6.4 Hz, 2H), 3.10 (t, J¼7.2 Hz,
2H), 2.21 (s, 1H), 1.55e1.45 (m, 13H), 1.28e1.24 (m,
16H); 13C NMR (100 MHz, CDCl3): d 170.21, 168.20,
159.05, 156.05, 151.65, 151.08, 141.02, 138.99, 131.72,
131.59, 131.22, 129.38, 128.64, 124.84, 124.80, 123.93,
122.19, 114.18, 79.13, 62.17, 60.38, 55.29, 40.77, 40.10,
30.14, 29.47, 29.43, 29.18, 29.05, 28.42, 26.87, 26.76;
HRMS (ESI) m/z: 769.3312 [MþNa]þ; calcd for
C39H50ClN4O7þNa: 769.3320.
4.6.2. tert-Butyl 12-(2-(benzo[d][1,3]dioxol-5-yl)-2-(N-(4-
methoxyphenyl)-4-(trifluoromethyl)benzamido)acetamido)-
dodecylcarbamate (9k)
1
Light yellow oil. H NMR (400 MHz, CDCl3): d 7.41 (s,
4H), 6.93 (s, 2H), 6.73e6.71 (m, 2H), 6.56 (d, J¼9.2 Hz,
1H), 6.07 (s, 1H), 5.94 (d, J¼0.8 Hz, 2H), 5.75 (s, 1H), 4.54
(s, 1H), 3.69 (s, 3H), 3.35e3.29 (m, 2H), 3.10 (t, J¼7.2 Hz,
2H), 1.97 (s, 1H), 1.52e1.45 (m, 13H), 1.26e1.24 (m,
16H); 13C NMR (100 MHz, CDCl3): d 169.96, 169.21,
158.59, 155.98, 147.84, 147.76, 139.84, 133.00, 131.54,
131.06, 130.73, 128.63, 128.07, 124.65, 124.62, 124.36,

3972
N. Liu et al. / Tetrahedron 64 (2008) 3966e3974
4.6.6. tert-Butyl 12-(2-(6-chloropyridin-3-yl)-2-(2,4,5-
trifluoro-3-methoxy-N-(4-methoxyphenyl)benzamido)-
acetamido)dodecylcarbamate (9o)
29.32, 29.28, 29.20, 29.04, 28.89, 26.65; HRMS (ESI) m/z:
517.2581 [MþH]þ; calcd for C27H38ClN4O4þH: 517.2582.
Light yellow oil. 1H NMR (400 MHz, CDCl3): d 8.28
(d, J¼2.0 Hz, 1H), 7.46 (dd, J¼2.4, 8.4 Hz, 1H), 7.14 (d,
J¼8.4 Hz, 1H), 6.86 (s, 1H), 6.79e6.73 (m, 1H), 6.58
(d, J¼8.8 Hz, 2H), 6.25 (s, 1H), 6.21 (s, 1H), 3.86 (s, 3H),
3.69 (s, 3H), 3.36e3.31 (m, 2H), 3.09 (t, J¼7.2 Hz, 2H),
1.53e1.44 (m, 13H), 1.28e1.25 (m, 16H); 13C NMR
(100 MHz, CDCl3): d 171.13, 167.76, 165.79, 159.36,
156.02, 151.78, 151.17, 148.12, 146.01, 145.90, 145.67,
140.92, 131.26, 130.41, 128.96, 123.86, 113.96, 108.93,
108.76, 108.72, 79.07, 61.95, 61.78, 60.38, 55.27, 40.13,
31.57, 30.05, 29.48, 29.40, 29.25, 29.19, 29.04, 28.41,
26.86, 26.76; HRMS (ESI) m/z: 785.3258 [MþNa]þ; calcd
for C39H50F3ClN4O6þNa: 785.3269.
4.7.3. N-(2-(12-Aminododecylamino)-1-(6-chloropyridin-3-
yl)-2-oxoethyl)-4-(trifluoromethyl)benzamide (1c)
White solid, mp 92e94 ꢀC. Yield 87%. 1H NMR
(400 MHz, CDCl3): d 8.53 (s, 1H), 7.89 (d, J¼6.4 Hz, 2H),
7.79 (dd, J¼2.0, 8.0 Hz, 1H), 7.65 (s, 2H), 7.25 (d,
J¼7.6 Hz, 1H), 5.93 (s, 1H), 3.20 (s, 2H), 2.68 (d,
J¼4.8 Hz, 2H), 2.46 (s, 2H), 1.42 (s, 4H), 1.24e1.17 (m,
16H); 13C NMR (100 MHz, CDCl3): d 168.66, 165.92,
151.38, 148.90, 137.40, 136.40, 134.29, 134.00, 133.65,
133.29, 132.95, 129.39, 128.37, 128.12, 127.77, 127.55,
125.62, 124.84, 124.51, 122.13, 119.43, 54.42, 41.92, 40.65,
40.12, 33.08, 29.96, 29.39, 29.32, 29.16, 29.08, 27.56,
27.29, 26.76; HRMS (ESI) m/z: 541.2555 [MþH]þ; calcd
for C27H36ClF3N4O2þH: 541.2557.
4.7. General procedure for the synthesis of compounds 1aeo
4.7.4. N-(2-(12-Aminododecylamino)-1-(benzo[d][1,3]-
dioxol-5-yl)-2-oxoethyl)-4-(trifluoromethyl)-
benzamide (1d)
To a solution of 9aeo (0.50 mmol) in 2 mL CH2Cl2, TFA
(9aei, 30.00 mmol; 9jeo, 15.00 mmol) was added and stirred
for 5 h (TLC, CH2Cl2/CH3OH/28%NH4OH¼100:10:1) at
room temperature. The reaction mixture was basified to pH
14 with 10% aqueous sodium hydroxide solution. The organic
layer was separated, washed with water, dried over anhydrous
sodium sulfate, and concentrated in vacuo. The crude resi-
due was purified by chromatography (CH2Cl2/CH3OH/
28%NH4OH¼500:10:1) to afford the final product.
Colorless oil. Yield 92%. 1H NMR (400 MHz, CDCl3):
d 7.94 (m, 3H), 7.67 (d, J¼8.0 Hz, 2H), 6.99e6.95 (m, 2H),
6.75 (d, J¼7.6 Hz, 1H), 6.43 (s, 1H), 5.92 (s, 2H), 5.64 (d,
J¼6.0 Hz, 1H), 3.23 (q, J¼6.4 Hz, 2H), 2.82 (s, 2H), 2.71 (t,
J¼6.8 Hz, 2H), 1.46 (t, J¼6.8 Hz, 4H), 1.21 (s, 16H); 13C
NMR (100 MHz, CDCl3): d 169.75, 165.37, 148.21, 147.74,
136.97, 133.60, 133.28, 131.88, 127.71, 125.55, 125.52,
124.97, 122.26, 121.08, 108.56, 107.46, 101.28, 57.12,
41.79, 40.02, 32.64, 29.42, 29.39, 29.35, 29.30, 29.24,
29.09, 26.74, 26.69; HRMS (ESI) m/z: 550.2883 [MþH]þ;
calcd for C29H38F3N3O4þH: 550.2893.
4.7.1. N-(2-(12-Aminododecylamino)-1-(6-chloropyridin-3-
yl)-2-oxoethyl)-6-chloronicotinamide (1a)
Colorless oil. Yield 91%. 1H NMR (400 MHz, CDCl3):
d 8.81 (d, J¼2.4 Hz, 1H), 8.49 (d, J¼2.4 Hz, 1H), 8.06 (dd,
J¼2.4, 8.4 Hz, 1H), 7.77 (dd, J¼2.4, 8.0 Hz, 1H), 7.35
(d, J¼8.0 Hz, 1H), 7.25 (s, 1H), 5.86 (s, 1H), 3.20 (d,
J¼6.0 Hz, 2H), 2.68 (t, J¼6.8 Hz, 2H), 2.44 (s, 2H), 1.42
(d, J¼6.0 Hz, 4H), 1.25e1.19 (m, 16H); 13C NMR
(100 MHz, CDCl3): d 168.58, 164.43, 154.78, 151.44,
148.95, 148.83, 137.85, 137.56, 137.44, 132.72, 127.85,
124.56, 124.17, 55.43, 55.06, 54.44, 41.86, 40.17, 40.05,
32.94, 29.58, 29.48, 29.38, 29.36, 29.32, 29.29, 29.15,
29.06, 26.82, 26.74; HRMS (ESI) m/z: 508.2235 [MþH]þ;
calcd for C25H35Cl2N5O2þH: 508.2246.
4.7.5. N-(2-(12-Aminododecylamino)-1-(6-chloropyridin-3-
yl)-2-oxoethyl)-2,4,5-trifluoro-3-methoxybenzamide (1e)
1
Light yellow oil. Yield 89%. H NMR (400 MHz, CDCl3):
d 8.50 (s, 1H), 7.77 (dd, J¼2.4, 8.4 Hz, 1H), 7.42e7.36
(m, 1H), 7.30 (s, 1H), 5.76 (s, 1H), 4.04 (s, 3H), 3.76e3.64
(m, 2H), 3.20 (t, J¼6.4 Hz, 2H), 2.71 (s, 2H), 1.48e1.42 (m,
4H), 1.18 (s, 16H); 13C NMR (100 MHz, CDCl3): d 168.17,
161.02, 151.81, 151.35, 149.34, 149.03, 148.70, 148.60,
137.40, 137.34, 133.09, 124.63, 124.44, 116.47, 111.36,
111.15, 62.28, 54.64, 41.48, 40.11, 40.01, 32.01, 29.51,
29.45, 29.37, 29.34, 29.31, 29.25, 29.16, 29.05, 29.02,
26.72; HRMS (ESI) m/z: 557.2510 [MþH]þ; calcd for
C27H36ClF3N4O3þH: 557.2506.
4.7.2. N-(2-(12-Aminododecylamino)-1-(benzo[d][1,3]-
dioxol-5-yl)-2-oxoethyl)-6-chloronicotin-
amide (1b)
4.7.6. N-(2-(12-Aminododecylamino)-1-(benzo[d][1,3]-
dioxol-5-yl)-2-oxoethyl)-2,4,5-trifluoro-
3-methoxybenzamide (1f)
Colorless oil. Yield 90%. 1H NMR (CDCl3, 400 MHz):
d 8.84 (d, J¼2.0 Hz, 1H), 8.08 (q, J¼2.4 Hz, 1H), 8.03 (s,
1H), 7.36 (d, J¼8.4 Hz, 1H), 6.96 (d, J¼8.0 Hz, 1H), 6.93
(s, 1H), 6.76 (d, J¼8.0 Hz, 1H), 6.28 (s, 1H), 5.94 (s, 2H),
5.59 (d, J¼4.8 Hz, 1H), 3.22 (q, J¼6.8 Hz, 2H), 3.10 (d,
J¼6.0 Hz, 2H), 1.53e1.45 (m, 4H), 1.21 (s, 16H); 13C NMR
(100 MHz, CDCl3): d 169.65, 163.89, 154.47, 148.83,
148.24, 147.82, 137.75, 131.65, 128.27, 124.08, 121.16,
108.59, 107.48, 101.35, 57.15, 41.53, 40.06, 31.86, 30.06,
White solid, mp 86e89 ꢀC. Yield 90%. 1H NMR
(400 MHz, DMSO-d6): d 8.82 (d, J¼7.6 Hz, 1H), 8.26 (d,
J¼4.8 Hz, 1H), 7.76 (s, 2H), 7.42e7.35 (m, 1H), 7.02 (s,
1H), 6.99e6.93 (m, 1H), 6.86 (d, J¼8.0 Hz, 1H), 5.98 (s,
2H), 5.48 (d, J¼7.6 Hz, 1H), 4.00 (s, 3H), 3.07e3.00 (m,
2H), 2.73 (t, J¼7.6 Hz, 2H), 1.52e1.47 (m, 2H), 1.34 (d,
J¼6.0 Hz, 2H), 1.22e1.18 (m 16H); 13C NMR (100 MHz,

N. Liu et al. / Tetrahedron 64 (2008) 3966e3974
3973
DMSO-d6): d 169.85, 169.57, 161.59, 161.41, 151.06, 148.60,
147.98, 147.61, 147.16, 147.07, 137.83, 137.75, 137.66,
133.60, 133.41, 132.77, 129.39, 128.64, 128.55, 121.08,
120.76, 119.96, 111.01, 110.80, 108.43, 107.94, 107.77,
101.47, 62.72, 57.09, 30.76, 29.41, 29.36, 29.26, 29.22,
29.08, 29.01, 27.88, 27.15, 26.60, 26.31; HRMS (ESI) m/z:
566.2832 [MþH]þ; calcd for C29H39F3N3O5þH: 566.2842.
(m, 1H), 7.11 (d, J¼8.4 Hz, 1H), 6.93 (s, 1H), 6.68 (d,
J¼2.0 Hz, 3H), 6.58 (d, J¼8.4 Hz, 2H), 6.05 (s, 1H), 5.93 (t,
J¼1.2 Hz, 2H), 5.81 (d, J¼5.6 Hz, 1H), 3.69 (s, 3H), 3.35e
3.24 (m, 2H), 2.73e2.69 (m, 2H), 2.59e2.40 (m, 2H), 1.48
(s, 4H), 1.23 (s, 16H); 13C NMR (100 MHz, CDCl3):
d 169.08, 167.69, 158.85, 151.80, 149.52, 147.92, 147.78,
138.71, 132.53, 131.66, 131.07, 127.79, 124.46, 123.30,
113.94, 110.60, 108.24, 101.30, 65.96, 55.25, 41.93, 40.01,
32.99, 29.52, 29.50, 29.47, 29.44, 29.39, 29.17, 26.85,
26.81; HRMS (ESI) m/z: 623.3015 [MþH]þ; calcd for
C34H43ClN4O5þH: 623.3000.
4.7.7. N-(2-(12-Aminododecylamino)-1-(3-chloro-2-
fluorophenyl)-2-oxoethyl)-4-(trifluoromethyl)-
benzamide (1g)
White solid, mp 83e85 ꢀC. Yield 85%. 1H NMR
(400 MHz, CDCl3): d 7.97 (d, J¼8.0 Hz, 2H), 7.86 (d,
J¼5.6 Hz, 1H), 7.72 (d, J¼8.0 Hz, 2H), 7.39e7.35 (m, 2H),
7.10 (t, J¼8.0 Hz, 1H), 5.97 (s, 1H), 5.85 (d, J¼6.0 Hz, 1H),
3.27 (q, J¼6.4 Hz, 2H), 2.68 (t, J¼7.2 Hz, 2H), 1.49e1.42
(m, 6H), 1.28e1.23 (m, 16H); 13C NMR (100 MHz,
CDCl3): d 168.16, 165.14, 157.11, 154.65, 136.65, 133.83,
133.51, 130.79, 127.70, 127.06, 126.93, 126.75, 126.72,
125.69, 125.65, 125.27, 125.22, 124.94, 122.23, 121.80,
121.62, 51.76, 51.74, 42.21, 40.17, 33.72, 29.52, 29.48,
29.42, 29.38, 29.21, 29.09, 26.84, 26.61.
4.7.11. N-(2-(12-Aminododecylamino)-1-(benzo[d][1,3]-
dioxol-5-yl)-2-oxoethyl)-N-(4-methoxyphenyl)-
4-(trifluoromethyl)benzamide (1k)
White solid, mp 92e95 ꢀC. Yield 93%. 1H NMR
(400 MHz, CDCl3): d 7.40 (s, 4H), 6.92 (s, 1H), 6.73e6.67
(m, 3H), 6.56 (d, J¼8.8 Hz, 2H), 6.08 (s, 1H), 5.93 (s, 2H),
5.85 (s, 1H), 3.68 (s, 3H), 3.34e3.28 (m, 2H), 2.79 (t,
J¼6.8 Hz, 2H), 1.55e1.48 (m, 4H), 1.24 (s, 16H); 13C NMR
(100 MHz, CDCl3): d 169.98, 169.25, 158.58, 147.82,
147.74, 139.84, 132.95, 131.58, 130.73, 128.63, 128.07,
125.03, 124.67, 124.63, 124.38, 113.67, 110.60, 108.20,
101.26, 65.94, 55.23, 41.62, 39.99, 32.15, 29.47, 29.45,
29.37, 29.31, 29.17, 26.86, 26.74; HRMS (ESI) m/z:
656.3294 [MþH]þ; calcd for C36H44F3N3O5þH: 656.3311.
4.7.8. N-(2-(12-Aminododecylamino)-1-(3-chloro-2-
fluorophenyl)-2-oxoethyl)-4-fluorobenzamide (1h)
White solid, mp 91e93 ꢀC. Yield 88%. 1H NMR (400 MHz,
CDCl3): d 7.89e7.85 (m, 2H), 7.71 (d, J¼6.0 Hz, 1H), 7.38e
7.35 (m, 2H), 7.15e7.08 (m, 3H), 5.98 (s, 1H), 5.84 (d,
J¼6.0 Hz, 1H), 3.26 (q, J¼6.8 Hz, 2H), 2.68 (t, J¼7.2 Hz,
2H), 1.48e1.42 (m, 6H), 1.28e1.23 (m, 16H); 13C NMR
(100 MHz, CDCl3): d 168.35, 166.30, 165.38, 163.79, 157.11,
154.65, 130.66, 129.63, 129.61, 129.56, 129.54, 127.31,
127.18, 126.80, 126.77, 125.22, 125.17, 121.72, 121.54,
115.80, 115.58, 51.75, 51.73, 42.24, 40.13, 33.80, 29.53,
29.49, 29.44, 29.43, 29.39, 29.22, 29.10, 26.85, 26.62.
4.7.12. N-(2-(12-Aminododecylamino)-1-(benzo[d][1,3]-
dioxol-5-yl)-2-oxoethyl)-2,4,5-trifluoro-3-
methoxy-N-(4-methoxyphenyl)benzamide (1l)
White solid, mp 95e97 ꢀC. Yield 90%. 1H NMR
(400 MHz, CDCl3): d 6.95 (s, 1H), 6.79 (d, J¼5.6 Hz, 1H),
6.55 (d, J¼8.4 Hz, 2H), 6.05 (s, 1H), 5.93 (s, 2H), 5.82 (s,
1H), 3.85 (s, 3H), 3.68 (s, 3H), 3.31 (t, J¼5.6 Hz, 4H), 2.77
(s, 2H), 1.52 (d, J¼8.4 Hz, 4H), 1.25 (s, 16H); 13C NMR
(100 MHz, CDCl3): d 168.81, 165.43, 158.92, 147.87,
147.73, 145.75, 131.65, 131.35, 127.66, 124.40, 113.44,
110.57, 109.22, 109.01, 108.19, 101.25, 65.44, 61.91, 55.21,
41.59, 40.02, 32.09, 31.56, 29.45, 29.42, 29.30, 29.17,
29.04, 26.85, 26.74; HRMS (ESI) m/z: 672.3265 [MþH]þ;
calcd for C36H44F3N3O6þH: 672.3260.
4.7.9. N-(2-(12-Aminododecylamino)-1-(3-chloro-2-
fluorophenyl)-2-oxoethyl)-2-fluorobenzamide (1i)
White solid, mp 88e91 ꢀC. Yield 86%. 1H NMR
(400 MHz, CDCl3): d 8.28e8.24 (m, 1H), 8.03 (t, J¼7.6 Hz,
1H), 7.51e7.47 (m, 1H), 7.39e7.35 (m, 2H), 7.24 (d,
J¼7.2 Hz, 1H), 7.18 (dd, J¼8.0, 11.6 Hz, 1H), 7.10 (t,
J¼7.2 Hz, 1H), 5.94e5.89 (m, 2H), 3.30e3.24 (m, 2H),
2.69 (t, J¼6.8 Hz, 2H), 1.55 (s, 2H), 1.49e1.42 (m, 4H),
1.29e1.23 (m, 16H); 13C NMR (100 MHz, CDCl3):
d 168.10, 162.57, 162.54, 162.16, 159.70, 157.07, 154.61,
133.81, 133.71, 131.91, 131.89, 130.77, 130.57, 127.32,
127.18, 126.74, 126.71, 125.26, 125.22, 124.77, 124.74,
121.61, 121.43, 120.43, 120.32, 116.34, 116.10, 51.87,
51.85, 42.25, 40.08, 33.81, 29.54, 29.50, 29.45, 29.44,
29.40, 29.10, 26.86, 26.62, 26.51.
4.7.13. N-(2-(12-Aminododecylamino)-1-(6-chloropyridin-
3-yl)-2-oxoethyl)-6-chloro-N-(4-methoxyphenyl)-
nicotinamide (1m)
White solid, mp 93e96 ꢀC. Yield 95%. 1H NMR
(400 MHz, CDCl3): d 8.40e8.28 (m, 2H), 7.57 (dd, J¼2.0,
8.0 Hz, 1H), 7.48 (dd, J¼2.4, 8.0 Hz, 1H), 7.14 (dd, J¼2.0,
8.0 Hz, 2H), 6.62e6.57 (m, 3H), 6.31 (s, 1H), 3.71 (s, 3H),
3.33e3.28 (m, 2H), 3.01 (s, 2H), 2.42 (s, 2H), 1.78 (t,
J¼7.2 Hz, 2H), 1.51 (t, J¼6.8 Hz, 2H), 1.39e1.23 (m, 16H);
13C NMR (100 MHz, CDCl3): d 168.25, 168.05, 159.28,
152.21, 151.10, 149.45, 138.67, 131.95, 131.68, 131.32,
130.50, 129.64, 124.08, 123.47, 114.47, 114.37, 62.07,
55.31, 40.08, 40.02, 31.27, 29.41, 29.23, 29.05, 28.91,
28.68, 27.51, 26.73, 26.29; HRMS (ESI) m/z: 614.2661
[MþH]þ; calcd for C32H42Cl2N5O3þH: 614.2661.
4.7.10. N-(2-(12-Aminododecylamino)-1-(benzo[d][1,3]-
dioxol-5-yl)-2-oxoethyl)-6-chloro-N-(4-methoxyphenyl)-
nicotinamide (1j)
White solid, mp 112e115 ꢀC. Yield 91%. 1H NMR
(400 MHz, CDCl3): d 8.27 (d, J¼2.4 Hz, 1H), 7.58e7.56

3974
N. Liu et al. / Tetrahedron 64 (2008) 3966e3974
5. Strømgaard, K.; Andersen, K.; Krogsgaard-Larsen, P.; Jaroszewski, J. W.
Mini Rev. Med. Chem. 2001, 1, 317e338.
4.7.14. N-(2-(12-Aminododecylamino)-1-(6-chloropyridin-
3-yl)-2-oxoethyl)-N-(4-methoxyphenyl)-4-(trifluoromethyl)-
benzamide (1n)
6. (a) Strømgaard, K.; Brierley, M. J.; Andersen, K.; Sløk, F. A.; Mellor,
I. R.; Usherwood, P. N. R.; Krogsgaard-Larsen, P.; Jaroszewski, J. W.
J. Med. Chem. 1999, 42, 5224e5234; (b) Brier, T. J.; Mellor, I. R.;
Tikhonov, D. B.; Neagoe, I.; Shao, Z.; Brierley, M. J.; Strømgaard, K.;
Jaroszewski, J. W.; Krogsgaard-Larsen, P.; Usherwood, P. N. R.
Mol. Pharmacol. 2003, 64, 954e964; (c) Tikhonov, D. B.; Mellor, I. R.;
Usherwood, P. N. R. Biophys. J. 2004, 87, 159e170.
White solid, mp 113e115 ꢀC. Yield 92%. 1H NMR
(400 MHz, CDCl3): d 8.34 (s, 1H), 7.47 (dd, J¼2.4, 8.4 Hz,
1H), 7.40 (dd, J¼8.4, 14.4 Hz, 4H), 7.14 (d, J¼8.0 Hz, 1H),
6.88 (s, 1H), 6.57 (d, J¼8.4 Hz, 2H), 6.52 (s, 1H), 6.30 (s,
1H), 3.69 (s, 3H), 3.31 (d, J¼7.2 Hz, 2H), 2.95 (s, 2H), 1.72
(s, 2H), 1.50 (s, 2H), 1.26e1.23 (m, 16H); 13C NMR
(100 MHz, CDCl3): d 170.28, 168.41, 168.33, 158.98, 151.71,
151.34, 151.29, 140.79, 139.06, 131.75, 131.65, 131.48,
131.15, 129.39, 128.61, 124.84, 124.81, 123.86, 122.19,
114.09, 62.11, 55.28, 40.69, 40.08, 36.74, 30.12, 29.32, 29.23,
29.09, 28.80, 27.96, 26.81, 26.50, 26.36; HRMS (ESI) m/z:
647.2956 [MþH]þ; calcd for C34H42ClF3N4O3þH: 647.2976.
7. (a) Wang, F.; Manku, S.; Hall, D. G. Org. Lett. 2000, 2, 1581e1583; (b)
Usherwood, P. N. R.; Jaroszewski, J. W.; Franzyk, H. Eur. J. Org. Chem.
2003, 23, 3288e3299; (c) Olsen, C. A.; Witt, M.; Jaroszewski, J. W.;
Franzyk, H. J. Org. Chem. 2004, 69, 6149e6152; (d) Olsen, C. A.;
Jørgensen, M. R.; Hansen, S. H.; Witt, M.; Jaroszewski, J. W.; Franzyk,
H. Org. Lett. 2005, 7, 1703e1706.
8. (a) Goodnow, R.; Konno, K.; Niwa, M., Jr.; Kallimopoulos, T.; Bukownik,
R.; Lenares, D.; Nakanishi, K. Tetrahedron 1990, 46, 3267e3286; (b)
Nakanishi, K.; Huang, X.; Jiang, H.; Liu, Y.; Fang, K.; Huang, D.; Choi,
S.-K.; Katz, E.; Eldefrawi, M. Bioorg. Med. Chem. 1997, 5, 1969e1988.
9. Olsen, C. A.; Witt, M.; Franzyk, H.; Jaroszewski, J. W. Tetrahedron Lett.
2007, 48, 405e408.
4.7.15. N-(2-(12-Aminododecylamino)-1-(6-chloropyridin-
3-yl)-2-oxoethyl)-2,4,5-trifluoro-3-methoxy-N-
(4-methoxyphenyl)benzamide (1o)
10. (a) Park, W. K. C.; Auer, M.; Jaksche, H.; Wong, C. H. J. Am. Chem. Soc.
1996, 118, 10150e10155; (b) Bauer, S. M.; Armstrong, R. W. J. Am.
Chem. Soc. 1999, 121, 6355e6366; (c) Hebach, C.; Kazmaier, U.
Chem. Commun. 2003, 596e597; (d) Wessjohann, L. A.; Voigt, B.;
Rivera, D. G. Angew. Chem., Int. Ed. 2005, 44, 4785e4790; (e) El
White solid, mp 101e103 ꢀC. Yield 95%. 1H NMR
(400 MHz, CDCl3): d 8.29 (s, 1H), 7.45 (dd, J¼2.4, 8.4 Hz,
1H), 7.14 (d, J¼8.4 Hz, 1H), 6.87 (s, 1H), 6.80e6.75 (m, 1H),
6.58 (d, J¼8.4 Hz, 2H), 6.37 (s, 1H), 6.24 (s, 1H), 3.87 (s, 3H),
3.70 (s, 3H), 3.33 (q, J¼6.4 Hz, 2H), 2.88 (s, 2H), 1.65e1.52
(m, 4H), 1.29e1.25 (m, 16H); 13C NMR (100 MHz, CDCl3):
d 167.81, 165.81, 159.34, 151.85, 151.26, 140.82, 131.28,
130.39, 128.92, 123.83, 113.94, 108.96, 108.92, 108.76,
108.71, 61.97, 61.78, 55.28, 41.78, 40.13, 30.14, 29.46, 29.38,
29.33, 29.17, 29.11, 26.85, 26.76; HRMS (ESI) m/z: 663.2914
[MþH]þ; calcd for C34H42ClF3N4O4þH: 663.2914.
€
Kaım, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005, 44,
7961e7964; (f) Giovenzana, G. B.; Tron, G. C.; Di Paola, S.; Menegotto,
I. G.; Pirali, T. Angew. Chem., Int. Ed. 2006, 45, 1099e1102.
11. Domling, A. Curr. Opin. Chem. Biol. 2002, 6, 306e313.
¨
¨
12. (a) Domling, A. Chem. Rev. 2006, 106, 17e89; (b) Ngouansavanh, T.;
Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 5775e5778.
13. Xing, X.; Wu, J.; Feng, G.; Dai, W. Tetrahedron 2006, 62, 6774e6781.
´
14. Kanizsai, I.; Gyonfalvi, S.; Szakonyi, Z.; Sillanpaa, R.; Fulop, F. Green
¨¨
¨ ¨
Chem. 2007, 9, 357e360.
15. Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P. J. Org. Chem. 1997, 62,
2917e2924.
16. Jørgensen, M. R.; Olsen, C. A.; Mellor, I. R.; Usherwood, P. N. R.; Witt,
M.; Franzyk, H.; Jaroszewski, J. W. J. Med. Chem. 2005, 48, 56e70.
17. Olsen, C. A.; Mellor, I. R.; Wellendorph, P.; Usherwood, P. N. R.; Witt,
M.; Franzyk, H.; Jaroszewski, J. W. ChemMedChem 2006, 1, 303e305.
18. Jensen, L. S.; Bølcho, U.; Egebjerg, J.; Strømgaard, K. ChemMedChem
2006, 1, 419e428.
Acknowledgements
This work was financially supported by National Key Pro-
ject for Basic Research (2003CB114405), the National High
Technology Research and Development Program of China
(863 Program, 2006AA10A201), the Shanghai Foundation of
Science of Technology (073919107), and Shanghai Leading
Academic Discipline Project (B507) for financial support.
19. Strømgaard, K.; Mellor, I. R.; Andersen, K.; Neagoe, I.; Pluteanu, F.;
Usherwood, P. N. R.; Krogsgaard-Larsen, P.; Jaroszewski, J. W. Bioorg.
Med. Chem. Lett. 2002, 12, 1159e1162.
20. Strømgaard, K.; Bjørnsdottir, I.; Andersen, K.; Brierley, M. J.; Rizoli, S.;
Eldursi, N.; Mellor, I. R.; Usherwood, P. N. R.; Hansen, S. H.;
Krogsgaard-Larsen, P.; Jaroszewski, J. W. Chirality 2000, 12, 93e102.
References and notes
21. Appel, R.; Kleistuck, R.; Ziehn, K. D. Angew. Chem., Int. Ed. Engl. 1971,
¨
10, 132.
1. (a) Strømgaard, K.; Mellor, I. Med. Res. Rev. 2004, 24, 589e620; (b)
Mellor, I. R.; Usherwood, P. N. R. Toxicon 2004, 43, 493e508; (c) Nilsen,
A.; England, P. M. J. Am. Chem. Soc. 2007, 129, 4902e4903.
22. (a) Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2, 709e712; (b)
Murphy, P. V.; Bradley, H.; Tosin, M.; Pitt, N.; Fitzpatrick, G. M.; Glass,
W. K. J. Org. Chem. 2003, 68, 5692e5704; (c) Basso, A.; Banfi, L.;
Guanti, G.; Riva, R.; Riu, A. Tetrahedron Lett. 2004, 45, 6109e6111.
23. Xiang, Z.; Luo, T.; Lu, K.; Cui, J.; Shi, X.; Fathi, R.; Chen, J.; Yang, Z.
Org. Lett. 2004, 6, 3155e3158.
2. (a) Eldefrawi, A. T.; Eldefrawi, M. E.; Konno, K.; Mansour, N. A.;
Nakanishi, K.; Oltz, E.; Usherwood, P. N. R. Proc. Natl. Acad. Sci.
U.S.A. 1988, 85, 4910e4913; (b) Andersen, T. F.; Tikhonov, D. B.;
Bølcho, U.; Bolshakov, K.; Nelson, J. K.; Pluteanu, F.; Mellor, I. R.;
Egebjerg, J.; Strømgaard, K. J. Med. Chem. 2006, 49, 5414e5423.
3. (a) Choi, S. K.; Kalivretenos, A. G.; Usherwood, P. N. R.; Nakanishi, K.
Chem. Biol. 1995, 2, 23e32; (b) Bixel, M. G.; Weise, C.; Bolognesi,
M. L.; Rosini, M.; Brierley, M. J.; Mellor, I. R.; Usherwood, P. N. R.;
Melchiorre, C.; Hucho, F. J. Biol. Chem. 2001, 276, 6151e6160.
4. (a) Blagbrough, I. S.; Brackley, P. T. H.; Bruce, M.; Bycroft, B. W.;
Mather, A. J.; Millington, S.; Sudan, H. L.; Usherwood, P. N. R. Toxicon
1992, 30, 303e322; (b) Strømgaard, K.; Jensen, L. S.; Vogensen, S. B.
Toxicon 2005, 45, 249e254.
24. (a) Hanusch-Kompa, C.; Ugi, I. Tetrahedron Lett. 1998, 39, 2725e2728;
(b) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T.
J. Am. Chem. Soc. 2002, 124, 6552e6554.
25. Shaabani, A.; Soleimani, E.; Rezayan, A. H. Tetrahedron Lett. 2007, 48,
6137e6141.
26. Mitchell, M. C.; Spikmans, V.; de Mello, A. J. Analyst 2001, 126, 24e27.
27. (a) Bhagat, S.; Chakraborti, A. K. J. Org. Chem. 2007, 72, 1263e1270;
´
´
(b) Regnier, T.; Berree, F.; Lavastre, O.; Carboni, B. Green Chem.
2007, 9, 125e126.