Multicomponent reactions in fungicide research: The discovery of mandipropamid

Article abstract of DOI:10.1016/j.bmc.2007.10.019

Isocyanide-based multicomponent reactions of the Ugi- and Passerini-type have been valuable tools for the rapid exploration of the novel fungicidal compound classes of phenylglycinamides and mandelamides. Mandipropamid (6), which was discovered during this derivatisation, displays excellent activity against the economically important phytopathogens Phytophthora infestans (potato and tomato late blight) and Plasmopara viticola (grape downy mildew).

Full text of DOI:10.1016/j.bmc.2007.10.019

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 1531–1545
Multicomponent reactions in fungicide research:
The discovery of mandipropamid
Clemens Lamberth,a,* Andre Jeanguenat,a Fredrik Cederbaum,a Alain De Mesmaeker,a
Martin Zeller,b Hans-Joachim Kempfc and Ronald Zeunc
aSyngenta Crop Protection AG, Research Chemistry, Schwarzwaldallee 215, CH-4058 Basel, Switzerland
bSyngenta Crop Protection AG, Process Development, Breitenloh 5, CH-4333 Mu¨nchwilen, Switzerland
cSyngenta Crop Protection AG, Research Biology, Schaffhauserstr. 101, CH-4332 Stein, Switzerland
Received 16 May 2007; revised 25 September 2007; accepted 9 October 2007
Available online 12 October 2007
Abstract—Isocyanide-based multicomponent reactions of the Ugi- and Passerini-type have been valuable tools for the rapid explo-
ration of the novel fungicidal compound classes of phenylglycinamides and mandelamides. Mandipropamid (6), which was discov-
ered during this derivatisation, displays excellent activity against the economically important phytopathogens Phytophthora
infestans (potato and tomato late blight) and Plasmopara viticola (grape downy mildew).
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
report how such reactions contributed significantly to
the discovery of the novel oomycetes fungicide mandi-
propamid (6).
In the meantime multicomponent reactions are well-
established as a powerful tool for the rapid construction
of complex and structurally diverse compounds from
relatively simple building blocks.1 High atom-economy,
chemical efficiency and convergence are typical features
of such one-pot condensations of at least three different
starting materials. Because of the remarkable high pur-
ity of libraries, multicomponent reactions are well-suited
for both combinatorial chemistry and high-speed paral-
lel synthesis and therefore possess high exploratory
power.2 Especially isocyanide-based3 and asymmetric4
multicomponent reactions have been emerging fields of
interest in the last decade, but the construction of het-
erocycles via multicomponent reactions was also in the
focus recently.5 However, there are only a few applica-
tions of multicomponent reactions in fungicide research
so far.6,7 In our Laboratorys, isocyanide-based multi-
component reactions of the Ugi- and Passerini-type
have just recently been key instruments for the rapid
exploration of the novel fungicide compound classes of
phenylglycinamides8 and mandelamides.9,10 Herein we
The oomycetes are a family of more than 800 different
species, which are more related to algae than to fungi.11
Some of them live in aquatic, others in terrestrial bio-
topes, some are saprophytes (feeding on dead material),
others are parasites. Despite this ecological diversity, the
oomycetes are a well-defined unit of high physiological
and biochemical uniformity. Their cell walls consist
mainly of cellulose, glucans and hydroxyproline instead
of chitin, which is common in most other phytopatho-
genic fungi, such as the ascomycetes, the basidiomycetes
and the deuteromycetes. In addition, the life cycle of
oomycetes is primarily diploid and not haploid as in
higher fungi. Parasitic members of the oomycetes family
are for instance Peronospara tabacina (tobacco blue
mold) and Pythium ultimum (damping-off), but the eco-
nomically most important diseases are Plasmopara viti-
cola (grape downy mildew) and Phytophthora infestans
(potato and tomato late blight). The latter pathogen
caused the complete devastation of the Irish potato crop
between the years 1845 and 1849. The dependence of the
rural population on the potato harvest and the non-exis-
tence of chemical crop protection resulted in a famine of
unbelievable dimensions, during which one million Irish
people starved to death and two millions emigrated to
North America.12 In the meantime there are several
Keywords: Fungicide; Crop protection; Multicomponent reaction; Ugi
reaction; Passerini reaction; Isocyanide; Oomycetes diseases; Phytoph-
thora infestans; Plasmopara viticola.
*
Corresponding author. Tel.: +41 61 3232373; fax: +41 61 3238529;
e-mail: clemens.lamberth@syngenta.com
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.10.019

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C. Lamberth et al. / Bioorg. Med. Chem. 16 (2008) 1531–1545
well-established oomycetes fungicides on the market.
However, the pressure especially on older products be-
cause of increased resistance, expired patent protection
and public discussions around regular re-registrations
stimulates the search for new agrochemicals with high
activity and a favourable environmental profile.
O
O
NH
H
N
O
O
O
1
In the mid 1990s we were intrigued by the valinamide 1,
which was patented by American Cyanamid (now
BASF) as a compound with anti-oomycetic activity
(Fig. 1).13 Because of in-house experience with sulfony-
lated amino acids, we decided to start a derivatisation of
that lead structure. The replacement of the carbamate
function by a sulfonamide and the elongation of one
of the methoxy groups to a 4-chlorophenylpropargyloxy
substituent finally led to the valinamide 2 with improved
fungicidal activity.8 During the optimisation of 2, we
found out that the isopropyl group of the valinamides
could be replaced by substituted phenyl rings with excel-
lent biological results. Best fungicidal activity of such
novel phenylglycinamides was achieved, when their 4-
chlorophenylpropargyloxy function was shortened to a
simple propargyloxy group, as in 3. Approximately at
the same time we realised that Agrevo (now Bayer)
had found quite similar mandelamides, such as 4, which
were unfortunately only weakly active against oomyce-
tes diseases.7,14 Convinced that the propargyloxy group
in our phenylglycinamide 3 was responsible for at least
part of its excellent fungicidal efficacy, we applied the
propargylation also to the field of mandelamides. Actu-
ally, the resulting compound 5 was clearly more active
than the non-propargylated lead compound 4. The
replacement of methoxy or ethoxy groups by a propar-
gyloxy has also been reported in the pharmaceutical lit-
erature for compounds with antibacterial15 and
leishmanicidal16 activity to lead to increased biological
activity. During the further optimisation of the mandel-
amide 5, the simplest manipulation was the most suc-
cessful. The introduction of a further propargyl group
into the mandelic acid moiety of the molecule resulted
in the discovery of mandipropamid (6), which is highly
active against most foliar oomycete pathogens such as
the economically important diseases P. infestans (potato
and tomato late blight), P. viticola (grape downy mil-
dew) and Pseudoperonospara cubensis (cucumber downy
mildew). Mandipropamid is highly effective in prevent-
ing spore germination, but also inhibits mycelial growth
and sporulation.17 Being rapidly adsorbed to the wax
layer of the plant surface,18 mandipropamid provides a
rainfast and long-lasting barrier to fungal diseases. It
will be launched to the agrochemical market in 2007 un-
der the trade names Revusꢀ and Pergadoꢀ.
O
S
O
NH
H
N
O
O
O
2
Cl
N
S
O
O
NH
H
N
O
O
O
3
OH
H
N
O
O
Cl
Cl
O
4
OH
H
N
O
O
O
Br
5
O
H
N
O
O
O
Cl
6
mandipropamid
Figure 1. Invention pathway from valinamide 1 to mandipropamid (6).
Ugi reaction is a classical multicomponent condensa-
tion, in which an amine, a carbonyl compound, a car-
boxylic acid and an isocyanide are assembled in one
step to an a-acylaminocarboxamide, a new stereogenic
centre is formed at the carbon atom derived from the
prochiral carbonyl group. Therefore, the phenethyl-
amine 7, which is available in two steps from vanilline,8
was converted into the stable and odourless isocyanide
10 by standard N-formylation, O-propargylation and
dehydration. Hereby, the formyl group serves as
2. Chemistry
The phenylglycinamides seemed to be predestined to be
prepared by an Ugi four component condensation,3 be-
cause this reaction offers huge flexibility in the introduc-
tion of substituents into the phenyl ring of the acid
moiety. This was important for the optimisation of this
subclass, because from the first assays it was clear that at
this position we had the broadest chemical scope. The

C. Lamberth et al. / Bioorg. Med. Chem. 16 (2008) 1531–1545
1533
protecting group for the amine function during the
alkylation of the phenol and also as precursor for the
formation of the isocyanide function. The Ugi reaction
of the isocyanide 10 with p-tolualdehyde and ammo-
nium formate, which is both the acid and the amine
component, led to a N-formylphenylglycinamide, which
could be transformed into the phenylglycinamide 11
with a free amino group by acidic hydrolysis. Finally,
N-sulfonylation of 11 yielded the desired N-sulfonylphe-
nylglycinamide 38 (Scheme 1).
nylglycinamide 13 (Scheme 2). In a similar manner, we
have developed a novel asymmetric synthesis of enantio-
pure mandelamide fungicides via a diastereoselective
Passerini reaction with a galacturonic acid derivative
as the acid component20.
The formamide 9, which was already a key intermediate
during the Ugi synthesis of phenylglycinamides, proved
to be also of high value for the preparation of mandela-
mides. Building block 9 could be directly transformed by
Seebach’s variation21 of the Passerini reaction3 into the
mandelamide 14. In the classical Passerini reaction, an
isocyanide is condensed with an aldehyde and a carbox-
ylic acid to afford a-acyloxycarboxamides. During the
reaction, a C–C bond is formed between the carbonyl
carbon atom and the isocyano carbon atom. Using See-
bach’s variation, the application of Lewis acids, like tita-
nium(IV) chloride, instead of carboxylic acids as acid
component delivers not the common a-acyloxycarbox-
amides, but directly a-hydroxycarboxamides.21 Similar
Enantiomerically pure phenylglycinamides could be ob-
tained by carrying out the Ugi reaction with a chiral
amine.19 The condensation of isocyanide 10 with 4-chlo-
robenzaldehyde, formic acid and 2,3,4,6-tetra-O-piv-
aloylgalactosamine resulted in the diastereoselective
formation of the intermediate 12. Removal of the sugar
unit, which served as chiral inducer during the transfor-
mation, as well as of the formyl group and subsequent
sulfonylation delivered the fungicidally active (R)-phe-
HC CCH2Br,
NaOMe
HCO2Et or
HCO2H, Ac2O
H
O
H2N
O
H
N
O
91 %
66 %
OH
OH
7
8
1. 4-MePhCHO,
_
-
+
HCO2 NH4
H
C
N+
O
O
O
H
N
POCl3, NEt3
72 %
2. HCl, EtOH
O
82 %
O
9
10
N
O S
O
NH
NH2
Me2NSO2Cl,
NEt3
H
N
H
N
O
O
O
O
O
56 %
O
3
11
Scheme 1. Synthesis of the phenylglycinamide fungicide 3 via the Ugi product 11.
4-ClPhCHO,
HCO2H, ZnCl2,
O
NH2
PivO
PivO
CHO
Gal
_
N
OPiv
H
C
N+
O
N
O
O
OPiv
56 %
O
O
Cl
12
10
O
S
O
NH
1. HCl, MeOH
H
O
O
N
2. EtSO2Cl, NEt3
O
84 %
Cl
13
Scheme 2. Diastereoselective synthesis of the phenylglycinamide fungicide 13.

1534
C. Lamberth et al. / Bioorg. Med. Chem. 16 (2008) 1531–1545
Passerini-type transformations leading directly to a-
hydroxycarboxamides have also been reported with tri-
fluoroacetic acid,22 boron trifluoride,23,24 mineral
acids24,25 and even water26 as acid component. The
introduction of a second propargyl group into the hy-
droxy group of the mandelic acid moiety of 14 delivers
mandipropamid (6).9 The mandelamide 14 could also
be easily converted into the phenylglyoxylic acid amide
1627 via Swern oxidation. This versatile building block
opened the road to two further fungicide classes, in
which the keto function of 16 is transformed into
either an O-methyloxime, as in 15,27,28 or a methylsulf-
enimine, as in 17.29 The synthesis of the latter subclass
succeeded according to Morimoto’s unique one-step
procedure with N,N-bis(trimethylsilyl)methanesulfena-
mide30 (Scheme 3).
after application, the plants were inoculated by spraying
a sporangial suspension on the upper (tomato) or lower
(grape) side of the leaves. Disease incidence was assessed
after an incubation period of 4 days (tomato) or 6 days
(grape) at 20 ꢁC and 95% relative humidity in a
greenhouse.
Table 1 presents several phenylglycinamides, bearing
different substituents in the phenyl ring of the amino
acid moiety, together with their EC80 values, which
are the concentrations in mg Lꢀ1 (equivalent to ppm)
obtained from greenhouse trials where the tested com-
pound shows 80% activity. Quite soon it became obvi-
ous that small alkyl groups in the para-position, like in
3 and 25, will achieve the best results. Also the para-tri-
fluoromethylated derivative 24 possesses interesting
fungicidal activity. Compound 19, the ortho-substituted
regioisomer of 3, is completely inactive, whereas the
meta-substituted analogue 20 displays only weak effi-
cacy. Halogen or alkoxy substituents in position 4 seem
to be less advantageous. Very interesting is the influ-
ence of the alkyl chain branching factor on the activity
against P. infestans. Linear alkyl groups, like ethyl in
25 and n-propyl in 27, lead to a much better efficacy
than branched alkyl groups, like iso-propyl in 26 and
3. Results and discussion
To determine the efficacy of the new phenylglycinamides
and mandelamides against P. infestans and P. viticola,
three-week-old tomato plants and five-week-old grape
seedlings were treated with the test compounds in a
spray chamber. One day (grape) or two days (tomato)
O
H
O
O
N
O
Cl
Cl
6
HC CCH2Br,
NaOH, TBAB
79 %
OH
Cl3COCO2CCl3, NEt3,
4-Cl-PhCHO, TiCl4
H
N
H
N
O
O
O
O
H
O
O
54 %
9
14
Me2SO,
87 % (COCl)2,
NEt3
O
O
N
H
N
H
N
O
O
O
O
MeONH2.HCl
58 %
O
O
Cl
Cl
16
15
MeS-N(SiMe3)2,
TBAF
35 %
S
N
O
H
N
O
O
Cl
17
Scheme 3. Synthesis of the mandelamide fungicide mandipropamid (6) and the phenylglyoxylic acid amide fungicides 15 and 17 via the Passerini
product 14.

C. Lamberth et al. / Bioorg. Med. Chem. 16 (2008) 1531–1545
1535
Table 1. EC80 values of different phenylglycinamides against Phytoph-
thora infestans and Plasmopara viticola
Table 2. EC80 values of different mandelamides against Phytophthora
infestans and Plasmopara viticola
N
O
S
NH
H
O
O
H
O
O
N
O
O
N
R
O
R
O
Compound
R
H
EC80 (mg Lꢀ1
)
Compound R
EC80 (mg Lꢀ1
)
Phytophthora Plasmopara
infestans (tomato viticola (grape
Phytophthora
Plasmopara
infestans (tomato viticola (grape
late blight)
late blight)
downy mildew)
downy mildew)
18
19
20
21
22
23
3
81.2
>200
149.9
45.7
10.6
7.8
28.5
>200
116.1
78.3
13.8
39.4
3.2
37
38
39
40
41
42
43
44
45
6
H
2-Cl
0.5
81.1
10.2
3.7
4.9
6.4
5.0
46.2
1.8
0.1
3.4
9.7
8.0
2.6
7.5
3.3
4.4
6.1
1.3
>200
1.8
2-CH3
3-CH3
4-F
3-F
3-Cl
2.4
4.9
4-Cl
4-Br
3-Br
3-CH3
3-CF3
3-OCH3
4-F
1.7
3.8
4-CH3
4-CF3
2.5
3.4
24
25
26
27
28
29
30
31
32
33
34
35
36
5.8
5.1
1.7
3.4
4-CH2CH3
4-CH(CH3)2
2.6
26.2
3.1
14.6
16.7
20.2
34.9
46.4
35.0
16.2
51.5
59.8
46.3
28.7
4-Cl
4-Br
1.2
2.6
4-CH2CH2CH3
4-C(CH3)3
4-OCH3
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
142.8
8.0
4-CH3
4-CF3
4-CH2OCH3
4-CH2CH3
4-CH@CH2
5.2
11.6
13.8
3.1
4-OCF3
4-OCH2CH3
4-SCH3
18.8
24.7
34.9
19.2
186.0
109.6
12.2
2.0
1.7
3-Cl–4-Cl
3-Cl–4-F
3-F–4-F
4-CH2CH2CH3
4-CH(CH3)2
2.8
4-CH2CH2CH2CH3 25.9
10.4
1.6
3-CH3–4-CH3
4-OCH3
4-SCH3
2.3
7.6
5.3
2-Cl–3-Cl
3-Cl–4-Cl
168.4
4.8
4.6
25.5
3.4
tert-butyl in 28. A comparison between the 3,4-disubsti-
tuted compounds 33 and 36 and their monosubstituted
counterparts 22 and 3 demonstrates that the introduc-
tion of an additional group into the meta-position is
not advantageous. The influence of different sulfonyl
groups on the fungicidal activity of phenylglycinamides
has already been described.8
2-F–4-F
2-F–4-Br
5.0
1.8
5.3
2.4
3-Cl–4-CH3
3-CH3–4-CH3
3-CH3–5-CH3
3-F–4-F–5-F
2-Cl–3-Cl–5-Cl
1.5
1.6
3.2
41.9
26.2
>200
56.4
19.7
44.2
Mandelamides possess a much higher level of anti-
oomycetic potency than phenylglycinamides, as mani-
fested in Table 2. Regarding structure–activity relation-
ship, both subclasses possess many similarities. As it has
been already the case for phenylglycinamides, the intro-
duction of small lipophilic groups into the para-position
of the phenyl ring of the acid moiety is also for mandel-
amides a requirement for best biological results. In con-
trast to the small alkyl groups, which achieved the
highest activity in the phenylglycinamide family, halo-
gens are the optimum as para-substituents in the man-
delic acid moiety of mandelamides (e.g., 6, 45, 46).
However, surprisingly the unsubstituted mandelamide
37 was the second most active derivative behind the
para-chlorosubstituted mandipropamid (6), which
showed outstanding control of both plant diseases.
Meta-substituted mandelamides, such as 40, 41 and 42,
are still quite active, but clearly weaker than their
para-substituted counterparts. Ortho-substituents other
than hydrogen have a negative effect on the fungicidal
efficacy, as in 38 and 57, with fluorine as the only excep-
tion (59 and 60). If the phenyl ring bears two substitu-
ents, then 3,4-disubstituted mandelamides such as 58
and 62 show much better activity than the correspond-
ing 2,4- or 3,5-disubstituted compounds such as 57
and 63. Also trisubstituted mandelamides such as 64
and 65 have been prepared, but do not belong to the
most active compounds. The influence of other substitu-
ents than propargyl in the mandelic acid moiety as well
as in the phenethylamine part of mandipropamid on the
fungicidal activity of mandelamides has already been
described.9
The huge importance of the Passerini reaction in the
derivatisation of mandipropamid is demonstrated in
Table 3. A broad variety of aliphatic, aromatic and
heterocyclic as well as mono-, bi- and tricyclic aldehydes
could easily be converted to the corresponding a-propa-
rgyloxyacetamides. Especially noteworthy is the

1536
C. Lamberth et al. / Bioorg. Med. Chem. 16 (2008) 1531–1545
Table 3. EC80 values of different a-propargyloxyacetamides against
Phytophthora infestans and Plasmopara viticola
dipropamid, could be obtained by Passerini reaction
from (4-chlorophenoxy)acetaldehyde.31 Interestingly,
stretched mandelamides with one-atom O or CH2 spac-
ers, as in 68, possess a much weaker activity. The 4-chlo-
rophenyl ring of mandipropamid can be replaced by
heterocycles with very good biological results, as dem-
onstrated by the thiophene derivative 74.31 However,
heterocyclic six-membered ring mandipropamid ana-
logs, such as the pyridine 75, did not show sufficient fun-
gicidal activity.
O
H
O
O
N
R
O
Compound R
EC80 (mg Lꢀ1
)
Phytophthora
Plasmopara
4. Conclusion
infestans (tomato viticola (grape
late blight)
downy mildew)
Many phenylglycinamides and mandelamides with a dif-
ferent substitution pattern in the phenyl ring of the acid
moiety possess high fungicidal activity against the
oomycetes diseases P. infestans and P. viticola. The
structure–activity relationship of these chemical classes
could be explored very rapidly by direct conversion of
commercially available benzaldehydes into phenylglyci-
namides and mandelamides under the conditions of
the Ugi and Passerini reactions. Hereby, the lengthy
construction of the corresponding phenylglycines and
mandelic acids and their subsequent transformation into
amides could be avoided. Mandipropamid (6), a novel
fungicide with powerful performance against major
oomycetes diseases, was discovered during this
optimisation.
66
67
47.6
5.3
CH3
51.4
124.0
H3C CH3
Cl
68
69
70
71
72
73
74
75
26.3
0.02
0.1
18.6
0.6
O
Cl
5. Experimental
O
1.8
All new compounds were characterised by standard
spectroscopical and microanalytical methods. 1H and
13C NMR spectra were recorded on a Varian Unity
400 spectrometer at 400 and 100 MHz, using CDCl3
or (CD3)2SO as solvents and tetramethylsilane as inter-
nal standard. Chemical shifts are reported in ppm
downfield from the standard (d = 0.00). Mass spectra
were obtained on Micromass LCT and Finnigan
MAT mass spectrometers. Melting points were deter-
H3C
0.3
20.4
2.2
O
O
O
16.7
4.8
mined on a Buchi 535 melting point apparatus and
¨
are uncorrected. Analytical thin-layer chromatography
(TLC) was performed using silica gel 60 F524 pre-
coated plates. Preparative flash chromatography was
performed using silica gel 60 (40–63 lm, E. Merck).
All reactions were carried out under anhydrous condi-
tions in an inert atmosphere (nitrogen or argon) with
dry solvents.
19.3
1.4
S
N
2.1
5.1. N-[2-(4-Hydroxy-3-methoxyphenyl)-ethyl]-formamide
(8)
186.3
>200
Formic acid (230 g, 5.0 mol) was added dropwise to ace-
tic anhydride (383 g, 3.75 mol) at 0 ꢁC. This mixture was
stirred for 2 h at 55 ꢁC and subsequently cooled again to
0 ꢁC. Five hundred microlitres of tetrahydrofuran was
then added, followed by 4-(2-aminoethyl)-2-methoxy-
phenol hydrochloride (7, 50 g, 0.25 mol).8 The resulting
white suspension was stirred for 16 h at 75 ꢁC while it
changed into a yellow solution. The reaction mixture
was evaporated and the residue was purified by chroma-
‘stretched’ mandelamide 69, whose impressive efficacy
against P. infestans down to 0.02 mg Lꢀ1 was unrivalled
by all other mandelamide derivatives. This compound,
which bears an OCH2 linker between the 4-chlorophenyl
ring and the 2-propargyloxyacetamide function of man-

C. Lamberth et al. / Bioorg. Med. Chem. 16 (2008) 1531–1545
1537
tography on silica gel (ethyl acetate/hexane, 1:3). Yield:
32 g (0.16 mol, 66%). H NMR (CDCl3): d 2.85 (t, 2H,
(3.4 g, 28 mmol) and ammonium formate (2.9 g,
46 mmol) in 30 ml of methanol was heated to reflux
for 6 h. The reaction mixture was cooled to 0 ꢁC
and 10 ml of a 10 M solution of hydrogen chloride
in methanol was added. The reaction mixture was stir-
red at room temperature for 16 h. The mixture was
then poured on ice-water and washed with ethyl ace-
tate. The aqueous phase was made basic by the addi-
tion of 1 N sodium hydroxide and then extracted
twice with ethyl acetate. The combined organic layers
were dried over magnesium sulfate and evaporated,
the remainder was used in the next step without any
further purification. Yield: 6.7 g (19 mol, 82%). 1H
NMR (CDCl3): d 2.38 (s, 3H, CH3), 2.51 (t, 1H,
CꢁCH), 2.76 (t, 2H, CH2CH2), 3.52 (q, 2H,
CH2CH2), 3.83 (s, 3H, OCH3), 4.48 (s, 1H, CHN),
4.73 (d, 2H, CH2CꢁC), 6.62–7.24 (m, 7H, CH arom.).
13C NMR (CDCl3): d 21.1, 34.6, 41.1, 55.7, 56.7, 56.9,
74.3, 75.7, 78.7, 112.5, 114.7, 120.4, 127.7, 129.6,
129.9, 132.5, 139.9, 141.0, 145.4, 149.6, 168.1. HRMS
m/z: Calcd for (C21H24N2O3+H)+: 353.1860. Found:
353.1863.
1
CH2CH2), 3.57 (t, 2H, CH2CH2), 3.82 (s, 3H, OCH3),
5.69 (br s, 1H, NH), 6.67–7.09 (m, 3H, CH arom.),
8.12 (s, 1H, CHO). 13C NMR (CDCl3): d 35.1, 45.9,
55.9, 111.5, 114.7, 121.3, 130.3, 144.4, 146.8, 161.5.
HRMS m/z: Calcd for (C10H13NO3+H)+: 196.0968.
Found: 196.0966.
5.2. N-[2-(3-Methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-
formamide (9)
Sodium methoxide (32 ml of a 5.4 M solution in meth-
anol, 0.17 mol) was added to a solution of N-[2-(4-hy-
droxy-3-methoxyphenyl)-ethyl]-formamide (8, 32 g,
0.16 mol) in 400 ml of methanol. Propargyl bromide
(20 g, 0.17 mol) was added and the mixture was re-
fluxed for 4 h. The reaction mixture was evaporated
and the residue was taken up in ethyl acetate and
washed twice with water. The organic layer was dried
over magnesium sulfate and evaporated. The remainder
was purified by chromatography on silica gel (ethyl
acetate/hexane, 1:4). Yield: 34 g (0.14 mol, 91%). 1H
NMR (CDCl3): d 2.44 (t, 1H, CꢁCH), 2.73 (t, 2H,
CH2CH2), 3.51 (t, 2H, CH2CH2), 3.82 (s, 3H,
OCH3), 4.69 (m, 2H, CH2CꢁC), 5.53 (br s, 1H, NH),
6.62–6.95 (m, 3H, CH arom.), 8.09 (s, 1H, CHO).
13C NMR (CDCl3): d 35.1, 39.2, 55.9, 56.9, 75.8,
78.6, 112.4, 114.7, 120.6, 132.7, 145.5, 149.8, 161.3.
HRMS m/z: Calcd for (C13H15NO3+H)+: 234.1125.
Found: 234.1125.
5.4.1. 2-[(N,N0-Dimethylamino)-sulfonylamino]-N-[2-(3-
methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-p-tolyl-acet-
amide (3). 2-Amino-N-[2-(3-methoxy-4-prop-2-ynyloxy-
phenyl)-ethyl]-2-p-tolylacetamide (11, 2.6 g, 7.5 mmol)
was dissolved in 25 ml of tetrahydrofuran and cooled
to 0 ꢁC. N,N-Dimethylsulfamoyl chloride (1.6 g,
11 mmol) and triethylamine (3.1 g, 31 mmol) were
added and the mixture was stirred for 16 h at room tem-
perature. Subsequently the reaction mixture was taken
up in ethyl acetate and washed with water. The com-
bined organic layer was dried over magnesium sulfate
and evaporated, the residue was purified by silica gel
chromatography (ethyl acetate/hexane, 3:7). Yield:
1.9 g (4.1 mmol, 56%). Mp 96–98 ꢁC. 1H NMR
(CDCl3): d 2.36 (s, 3H, CH3), 2.50–2.56 (m, 7H,
N(CH3)2, CꢁCH), 2.67 (q, 2H, CH2CH2), 3.34–3.57
(m, 2H, CH2CH2), 3.81 (s, 3H, OCH3), 4.72 (d, 2H,
CH2CꢁC), 4.79 (d, 1H, CHN), 5.61 (br s, 1H, NH),
5.80 (d, 1H, NH), 6.44–7.17 (m, 7H, CH arom.). 13C
NMR (CDCl3): d 22.3, 34.7, 39.5, 43.2, 45.9, 55.3,
57.2, 57.4, 74.1, 75.3, 79.8, 112.5, 113.7, 120.6, 126.2,
129.1, 129.8, 133.7, 139.4, 141.6, 144.3, 148.8, 167.0.
HRMS m/z: Calcd for (C23H29N3O5S+H)+: 460.5668.
Found: 460.5671.
5.3. 4-(2-Isocyanoethyl)-2-methoxy-1-prop-2-ynyloxy-
benzene (10)
Triethylamine (20 g, 0.2 mol) was added to a solu-
tion of N-[2-(3-methoxy-4-prop-2-ynyloxyphenyl)-
ethyl]-formamide (9, 8.5 g, 40 mmol) in 65 ml of tetra-
hydrofuran and the mixture was cooled to ꢀ10 ꢁC. A
solution of phosphorus oxychloride (6.6 g, 43 mmol)
in 20 ml of tetrahydrofuran was added dropwise at this
temperature, maintaining the reaction temperature dur-
ing the addition between ꢀ10 and 0 ꢁC. Subsequently
the reaction mixture was stirred at 0 ꢁC for 2 h, cooled
down to ꢀ20 ꢁC and quenched by addition of 80 ml of
water. The mixture was extracted twice with tert-butyl
methyl ether. The combined organic phases were dried
over magnesium sulfate and evaporated. The remain-
der was crystallised from ethyl acetate/hexane 1:1.
Yield: 6.2 g (29 mmol, 72%). 1H NMR (CDCl3): d
2.52 (t, 1H, CꢁCH), 2.94 (t, 2H, CH2CH2), 3.59 (t,
2H, CH2CH2), 3.85 (s, 3H, OCH3), 4.73 (d, 2H,
CH2CꢁC), 6.76–7.01 (m, 3H, CH arom.). 13C NMR
(CDCl3): d 35.2, 43.1, 55.9, 56.8, 75.8, 78.6, 112.5,
114.7, 120.6, 130.8, 146.0, 149.8, 156.7. HRMS m/z:
Calcd for (C13H13NO2+H)+: 216.1019. Found:
216.1022.
5.4.2. 2-[(N,N0-Dimethylamino)-sulfonylamino]-N-[2-(3-
methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-phenyl-acet-
amide (18). Obtained from benzaldehyde (instead of p-
tolualdehyde) according to procedures 5.4. and 5.4.1.
1
Yield: 66%. Mp 81–83 ꢁC. H NMR (CDCl3): d 2.42–
258 (m, 7H, N(CH3)2, CꢁCH), 2.69 (q, 2H, CH2CH2),
3.38–3.60 (m, 2H, CH2CH2), 3.82 (s, 3H, OCH3), 4.77
(d, 2H, CH2CꢁC), 4.82 (d, 1H, CHN), 5.58 (br s, 1H,
NH), 5.83 (d, 1H, NH), 6.44–7.39 (m, 8H, CH arom.).
MS m/z: 446 (C22H27N3O5S+H)+.
5.4. 2-Amino-N-[2-(3-methoxy-4-prop-2-ynyloxyphenyl)-
ethyl]-2-p-tolylacetamide (11)
5.4.3. 2-[(N,N0-Dimethylamino)-sulfonylamino]-N-[2-(3-
methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-o-tolyl-acet-
amide (19). Obtained from o-tolualdehyde (instead of p-
tolualdehyde) according to procedures 5.4. and 5.4.1.
A mixture of 4-(2-isocyanoethyl)-2-methoxy-1-prop-2-
ynyloxybenzene (10, 5.0 g, 23 mmol), p-tolualdehyde

1538
C. Lamberth et al. / Bioorg. Med. Chem. 16 (2008) 1531–1545
1
Yield: 57%. Mp 112–114 ꢁC. H NMR (CDCl3): d 2.28
(s, 3H, CH3), 2.45 (s, 6H, N(CH3)2), 2.53 (t, 1H,
CꢁCH), 2.64 (q, 2H, CH2CH2), 3.37–3.59 (m, 2H,
CH2CH2), 3.80 (s, 3H, OCH3), 4.73 (d, 2H, CH2CꢁC),
5.02 (d, 1H, CHN), 5.38 (br s, 1H, NH), 5.81 (d, 1H,
NH), 6.42–7.29 (m, 7H, CH arom.). MS m/z: 460
(C23H29N3O5S+H)+.
NH), 6.41–7.64 (m, 7H, CH arom.). MS m/z: 514
(C23H26F3N3O5S+H)+.
5.4.9. 2-[(N,N0-Dimethylamino)-sulfonylamino]-2-(4-ethyl-
phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-
acetamide (25). Obtained from 4-ethyl-benzaldehyde (in-
stead of p-tolualdehyde) according to procedures 5.4.
and 5.4.1. Yield: 65%. 1H NMR (CDCl3): d 1.24 (t,
3H, CH2CH3), 2.49–2.57 (m, 7H, N(CH3)2, CꢁCH),
2.62–2.73 (m, 4H, CH2CH2, CH2CH3), 3.35–3.59 (m,
2H, CH2CH2), 3.82 (s, 3H, OCH3), 4.73 (d, 2H,
CH2CꢁC), 4.79 (d, 1H, CHN), 5.64 (br s, 1H, NH),
5.80 (d, 1H, NH), 6.43–7.22 (m, 7H, CH arom.). MS
m/z: 474 (C24H31N3O5S+H)+.
5.4.4. 2-[(N,N0-Dimethylamino)-sulfonylamino]-N-[2-(3-
methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-m-tolyl-acet-
amide (20). Obtained from m-tolualdehyde (instead of p-
tolualdehyde) according to procedures 5.4. and 5.4.1.
1
Yield: 61%. Mp 119–120 ꢁC. H NMR (CDCl3): d 2.36
(s, 3H, CH3), 2.45–2.57 (m, 7H, N(CH3)2, CꢁCH),
2.65 (q, 2H, CH2CH2), 3.38–3.58 (m, 2H, CH2CH2),
3.81 (s, 3H, OCH3), 4.73–4.79 (m, 3H, CH2CꢁC,
CHN), 5.57 (br s, 1H, NH), 5.79 (d, 1H, NH), 6.42–
7.27 (m, 7H, CH arom.). MS m/z: 460
(C23H29N3O5S+H)+.
5.4.10. 2-[(N,N0-Dimethylamino)-sulfonylamino]-2-(4-
isopropyl-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxyphe-
nyl)-ethyl]-acetamide (26). Obtained from 4-isopropyl-
benzaldehyde (instead of p-tolualdehyde) according to
procedures 5.4. and 5.4.1. Yield: 59%. Mp 97–99 ꢁC. 1H
NMR (CDCl3): d 1.24 (d, 6H, CH(CH3)2), 2.46–2.57
(m, 7H, N(CH3)2, CꢁCH), 2.66 (q, 2H, CH2CH2), 2.91
(q, 1H, CH(CH3)2), 3.38–3.58 (m, 2H, CH2CH2), 3.81
(s, 3H, OCH3), 4.72 (d, 2H, CH2CꢁC), 4.78 (d, 1H,
CHN), 5.63 (br s, 1H, NH), 5.74 (d, 1H, NH), 6.42–7.23
(m, 7H, CH arom.). MS m/z: 488 (C25H33N3O5S+H)+.
5.4.5. 2-[(N,N0-Dimethylamino)-sulfonylamino]-2-(4-flu-
oro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxyphenyl)-
ethyl]-acetamide (21). Obtained from 4-fluoro-benzalde-
hyde (instead of p-tolualdehyde) according to proce-
1
dures 5.4. and 5.4.1. Yield: 68%. H NMR (CDCl3): d
2.49–2.56 (m, 7H, N(CH3)2, CꢁCH), 2.68 (q, 2H,
CH2CH2), 3.38–3.61 (m, 2H, CH2CH2), 3.82 (s, 3H,
OCH3), 4.74 (d, 2H, CH2CꢁC), 4.79 (d, 1H, CHN),
5.46 (br s, 1H, NH), 5.78 (d, 1H, NH), 6.44–7.25 (m,
7H, CH arom.). MS m/z: 464 (C22H26FN3O5S+H)+.
5.4.11. 2-[(N,N0-Dimethylamino)-sulfonylamino]-N-[2-
(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-(4-propyl-
phenyl)-acetamide (27). Obtained from 4-propyl-benzal-
dehyde (instead of p-tolualdehyde) according to proce-
1
5.4.6. 2-(4-Chloro-phenyl)-2-[(N,N0-dimethylamino)-sul-
fonylamino]-N-[2-(3-methoxy-4-prop-2-ynyloxyphenyl)-
ethyl]-acetamide (22). Obtained from 4-chloro-benzalde-
hyde (instead of p-tolualdehyde) according to proce-
dures 5.4. and 5.4.1. Yield: 63%. H NMR (CDCl3): d
0.94 (t, 3H, CH2CH2CH3), 1.63 (q, 2H, CH2CH2CH3),
2.49–2.56 (m, 7H, N(CH3)2, CꢁCH), 2.62 (t, 2H,
CH2CH2CH3), 2.70 (q, 2H, CH2CH2), 3.38–3.57 (m,
2H, CH2CH2), 3.82 (s, 3H, OCH3), 4.73 (d, 2H,
CH2CꢁC), 4.78 (d, 1H, CHN), 5.61 (br s, 1H, NH),
5.78 (d, 1H, NH), 6.44–7.17 (m, 7H, CH arom.). MS
m/z: 488 (C25H33N3O5S+H)+.
1
dures 5.4. and 5.4.1. Yield: 65%. H NMR (CDCl3): d
2.48–2.58 (m, 7H, N(CH3)2, CꢁCH), 2.65 (q, 2H,
CH2CH2), 3.37–3.62 (m, 2H, CH2CH2), 3.81 (s, 3H,
OCH3), 4.72–4.79 (m, 3H, CH2CꢁC, CHN), 5.51 (br
s, 1H, NH), 5.80 (d, 1H, NH), 6.41–7.38 (m, 7H, CH
arom.). MS m/z: 481 (C22H26ClN3O5S+H)+.
5.4.12. 2-(4-tert-Butyl-phenyl)-2-[(N,N0-dimethylamino)-
sulfonylamino]-N-[2-(3-methoxy-4-prop-2-ynyloxyphenyl)-
ethyl]-acetamide (28). Obtained from 4-tert-butyl-benz-
aldehyde (instead of p-tolualdehyde) according to proce-
5.4.7. 2-(4-Bromo-phenyl)-2-[(N,N0-dimethylamino)-sul-
fonylamino]-N-[2-(3-methoxy-4-prop-2-ynyloxyphenyl)-
ethyl]-acetamide (23). Obtained from 4-bromo-benzal-
dehyde (instead of p-tolualdehyde) according to proce-
1
dures 5.4. and 5.4.1. Yield: 54%. H NMR (CDCl3): d
1.33 (s, 9H, C(CH3)3), 2.49–2.57 (m, 7H, N(CH3)2,
CꢁCH), 2.70 (q, 2H, CH2CH2), 3.39–3.57 (m, 2H,
CH2CH2), 3.81 (s, 3H, OCH3), 4.74 (d, 2H, CH2CꢁC),
4.79 (d, 1H, CHN), 5.63 (br s, 1H, NH), 5.72 (d, 1H,
NH), 6.44–7.40 (m, 7H, CH arom.). MS m/z: 502
(C26H35N3O5S+H)+.
1
dures 5.4. and 5.4.1. Yield: 66%. Mp 115–117 ꢁC. H
NMR (CDCl3): d 2.52 (t, 1H, CꢁCH), 2.56 (s, 6H,
N(CH3)2), 2.67 (q, 2H, CH2CH2), 3.33–3.60 (m, 2H,
CH2CH2), 3.82 (s, 3H, OCH3), 4.74 (d, 2H, CH2CꢁC),
4.79 (d, 1H, CHN), 5.73 (br s, 1H, NH), 5.89 (d, 1H,
NH), 6.41–7.48 (m, 7H, CH arom.). MS m/z: 525
(C22H26BrN3O5S+H)+.
5.4.13. 2-[(N,N0-Dimethylamino)-sulfonylamino]-2-(4-
methoxy-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxyphe-
nyl)-ethyl]-acetamide (29). Obtained from p-anisalde-
hyde (instead of p-tolualdehyde) according to
procedures 5.4. and 5.4.1. Yield: 69%. 1H NMR
(CDCl3): d 2.50–2.57 (m, 7H, N(CH3)2, CꢁCH), 2.69
(q, 2H, CH2CH2), 3.36–3.58 (m, 2H, CH2CH2), 3.81
(s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.74–4.79 (m, 3H,
CH2CꢁC, CHN), 5.49 (br s, 1H, NH), 5.75 (d, 1H,
NH), 6.46–7.19 (m, 7H, CH arom.). MS m/z: 476
(C22H29N3O6S+H)+.
5.4.8. 2-[(N,N0-Dimethylamino)-sulfonylamino]-N-[2-(3-
methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-(4-trifluoro-
methyl-phenyl)-acetamide (24). Obtained from 4-trifluo-
romethyl-benzaldehyde (instead of p-tolualdehyde)
1
according to procedures 5.4. and 5.4.1. Yield: 62%. H
NMR (CDCl3): d 2.51 (t, 1H, CꢁCH), 2.58 (s, 6H,
N(CH3)2), 2.66 (q, 2H, CH2CH2), 3.37–3.61 (m, 2H,
CH2CH2), 3.81 (s, 3H, OCH3), 4.75 (d, 2H, CH2CꢁC),
4.84 (d, 1H, CHN), 5.55 (br s, 1H, NH), 5.82 (d, 1H,

C. Lamberth et al. / Bioorg. Med. Chem. 16 (2008) 1531–1545
1539
5.4.14. 2-[(N,N0-Dimethylamino)-sulfonylamino]-N-[2-(3-
methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-(4-trifluoro-
methoxy-phenyl)-acetamide (30). Obtained from 4-trifluo-
romethoxy-benzaldehyde (instead of p-tolualdehyde)
procedures 5.4. and 5.4.1. Yield: 68%. Mp 116–118 ꢁC.
1H NMR (CDCl3): d 2.51 (t, 1H, CꢁCH), 2.59 (s, 6H,
N(CH3)2), 2.70 (q, 2H, CH2CH2), 3.37–3.58 (m, 2H,
CH2CH2), 3.82 (s, 3H, OCH3), 4.72 (d, 2H, CH2CꢁC),
4.78 (d, 1H, CHN), 5.79 (br s, 1H, NH), 5.92 (d, 1H,
NH), 6.46–7.18 (m, 6H, CH arom.). MS m/z: 482
(C22H25F2N3O5S+H)+.
1
according to procedures 5.4. and 5.4.1. Yield: 62%. H
NMR (CDCl3): d 2.52 (t, 1H, CꢁCH), 2.57 (s, 6H,
N(CH3)2), 2.70 (q, 2H, CH2CH2), 3.39–3.62 (m, 2H,
CH2CH2), 3.83 (s, 3H, OCH3), 4.73 (d, 2H, CH2CꢁC),
4.82 (d, 1H, CHN), 5.67 (br s, 1H, NH), 5.82 (d, 1H,
NH), 6.47–7.33 (m, 7H, CH arom.). MS m/z: 530
(C23H26F3N3O6S+H)+.
5.4.20. 2-[(N,N0-Dimethylamino)-sulfonylamino]-2-(3,4-
dimethyl-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxyphenyl)-
ethyl]-acetamide (36). Obtained from 3,4-dimethyl-benz-
aldehyde (instead of p-tolualdehyde) according to proce-
1
5.4.15. 2-[(N,N0-Dimethylamino)-sulfonylamino]-2-(4-
ethoxy-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxyphenyl)-
ethyl]-acetamide (31). Obtained from 4-ethoxy-benzalde-
hyde (instead of p-tolualdehyde) according to proce-
dures 5.4. and 5.4.1. Yield: 63%. H NMR (CDCl3): d
2.24 (s, 3H, CH3), 2.27 (s, 3H, CH3), 2.51–2.56 (m,
7H, N(CH3)2, CꢁCH), 2.68 (q, 2H, CH2CH2), 3.38–
3.53 (m, 2H, CH2CH2), 3.83 (s, 3H, OCH3), 4.72–4.76
(m, 3H, CH2CꢁC, CHN), 5.59 (br s, 1H, NH), 5.78
(d, 1H, NH), 6.45–7.14 (m, 6H, CH arom.). MS m/z:
474 (C24H31N3O5S+H)+.
1
dures 5.4. and 5.4.1. Yield: 72%. Mp 114–115 ꢁC. H
NMR (CDCl3): d 1.43 (t, 3H, CH2CH3), 2.51–2.56 (m,
7H, N(CH3)2, CꢁCH), 2.65 (q, 2H, CH2CH2), 3.36–
3.59 (m, 2H, CH2CH2), 3.81 (s, 3H, OCH3), 4.04 (q,
2H, CH2CH3), 4.72–4.78 (m, 4H, CH2CꢁC, CHN),
5.52 (br s, 1H, NH), 5.77 (d, 1H, NH), 6.43–7.09 (m,
7H, CH arom.). MS m/z: 490 (C24H31N3O6S+H)+.
5.5. N-Formyl-2,3,4,6-tetra-O-pivaloyl-b-D-galactopyr-
anosyl-(R)-4-chlorophenylglycine-N0-2-(3-methoxy-4-
prop-2-ynyloxyphenyl)-ethylamide (12)
5.4.16. 2-[(N,N0-Dimethylamino)-sulfonylamino]-N-[2-
(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-(4-methyl-
sulfanyl-phenyl)-acetamide (32). Obtained from 4-meth-
ylthio-benzaldehyde (instead of p-tolualdehyde)
To solution of 2,3,4,6-tetra-O-pivaloyl-b-D-galactopyr-
anosylamine (9.13 g, 17.7 mmol), 4-chloro-benzalde-
hyde (3.18 g, 18.1 mmol), formic acid (0.72 ml,
19.5 mmol), 4-(2-isocyanoethyl)-2-methoxy-1-prop-2-
ynyloxybenzene (10, 4.0 g, 18.6 mmol) in 150 ml of tet-
rahydrofuran was added at 0 ꢁC a 2.23 M solution of
ZnCl2ÆOEt2 in dichloromethane (7.94 ml, 17.7 mmol).
The mixture was stirred for 12 h during which time the
temperature rose to room temperature. After evapora-
tion of the solvents, the residue was taken up in dichlo-
romethane and washed with a solution of sodium
bicarbonate and with brine. The organic layer was dried
over magnesium sulfate and evaporated. The remainder
was purified by crystallisation from ethyl acetate and n-
hexane to give the title compound as a single diastereo-
isomer. Its configuration (2R, b-D) was assigned in anal-
ogy to the literature.19h Yield: 8.95 g (10.0 mmol, 56%).
1H NMR (CDCl3): d 1.16 (s, 24H, piv), 1.26 (s, 12 H,
piv), 2.47 (t, 1H, CꢁCH), 2.65–2.84 (m, 2H, CH2CH2),
3.30–3.72 (m, 2H, CH2CH2), 3.79 (s, 3H, OCH3), 3.84–
4.01 (m, 2H, galactose), 4.11–4.21 (m, 1H, galactose),
4.73 (m, 2H, CH2CꢁC), 5.01 and 5.19 (2· s, 1H, CHa
(2 rotamers)), 5.10–5.30 (m, 1H, galactose), 5.39–5.59
(m, 2H, galactose), 5.96 (d, 1H, CH anomeric), 6.47 (t,
1H, NH), 6.62–6.75 (m, 2H, CH arom.), 6.88–6.95 (m,
1H, CH arom.), 7.18–7.31 (m, 4H, CH arom.), 8.22 (d,
1H, CHO). MS m/z: 943 (C47H63ClN2O13+HCOO)ꢀ.
1
according to procedures 5.4. and 5.4.1. Yield: 63%. H
NMR (CDCl3): d 2.48 (s, 3H, SCH3), 2.51–2.56 (m,
7H, N(CH3)2, CꢁCH), 2.64 (q, 2H, CH2CH2), 3.31–
3.57 (m, 2H, CH2CH2), 3.80 (s, 3H, OCH3), 4.72 (d,
2H, CH2CꢁC), 4.78 (d, 1H, CHN), 5.81 (br s, 1H,
NH), 5.91 (d, 1H, NH), 6.44–7.17 (m, 7H, CH arom.).
MS m/z: 492 (C23H29N3O5S2+H)+.
5.4.17. 2-(3,4-Dichloro-phenyl)-2-[(N,N0-dimethylamino)-
sulfonylamino]-N-[2-(3-methoxy-4-prop-2-ynyloxyphenyl)-
ethyl]-acetamide (33). Obtained from 3,4-dichloro-benz-
aldehyde (instead of p-tolualdehyde) according to proce-
1
dures 5.4. and 5.4.1. Yield: 66%. Mp 131–132 ꢁC. H
NMR (CDCl3): d 2.52 (t, 1H, CꢁCH), 2.59 (s, 6H,
N(CH3)2), 2.70 (q, 2H, CH2CH2), 3.39–3.61 (m, 2H,
CH2CH2), 3.82 (s, 3H, OCH3), 4.73–4.77 (m, 3H,
CH2CꢁC, CHN), 5.56 (br s, 1H, NH), 5.83 (d, 1H,
NH), 6.44–7.45 (m, 6H, CH arom.). MS m/z: 515
(C22H25Cl2N3O5S+H)+.
5.4.18. 2-(3-Chloro-4-fluoro-phenyl)-2-[(N,N0-dimethyl-
amino)-sulfonylamino]-N-[2-(3-methoxy-4-prop-2-ynyloxy-
phenyl)-ethyl]-acetamide (34). Obtained from 3-chloro-4-
fluoro-benzaldehyde (instead of p-tolualdehyde) accord-
1
ing to procedures 5.4. and 5.4.1. Yield: 62%. H NMR
5.6. (2R)-2-(4-Chlorophenyl)-2-ethanesulfonylamino-N-
[2-(3-methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-acetamide
(13)
(CDCl3): d 2.50–2.57 (m, 7H, N(CH3)2, CꢁCH), 2.63
(q, 2H, CH2CH2), 3.36–3.58 (m, 2H, CH2CH2), 3.79
(s, 3H, OCH3), 4.68–4.75 (m, 3H, CH2CꢁC, CHN),
5.54 (br s, 1H, NH), 5.77 (d, 1H, NH), 6.43–7.37 (m,
6H, CH arom.). MS m/z: 499 (C22H25ClFN3O5S+H)+.
Compound 12 (3.0 g, 3.34 mmol) was dissolved in 20 ml
of ethanol and 20 ml of a concentrated solution of HCl
in methanol was added at 0 ꢁC. After 1 h at rt, 10 ml of
the concentrated HCl solution in methanol was added
and the mixture was further stirred for 5 h. After the
addition of 5 ml of water, the solution was stirred for
16 h at room temperature. The ethanol was evaporated
5.4.19. 2-(3,4-Difluoro-phenyl)-2-[(N,N0-dimethylamino)-
sulfonylamino]-N-[2-(3-methoxy-4-prop-2-ynyloxyphenyl)-
ethyl]-acetamide (35). Obtained from 3,4-difluoro-benz-
aldehyde (instead of p-tolualdehyde) according to

1540
C. Lamberth et al. / Bioorg. Med. Chem. 16 (2008) 1531–1545
and the residue was diluted with water, washed with
diethyl ether and the water phase was carefully evapo-
rated to give 1.1 g (2.69 mmol, 81%) of brownish crys-
tals which were directly submitted to the next step.
7.5 mmol) was added slowly at room temperature to a
mixture of 2-(4-chlorophenyl)-2-hydroxy-N-[2-(3-meth-
oxy-4-prop-2-ynyloxyphenyl)-ethyl]-acetamide
(12,
2.6 g, 7.0 mmol), a 30% aqueous sodium hydroxide solu-
tion (3.0 ml, 30 mmol) and catalytic amounts of tetrabu-
tylammonium bromide in 15 ml of dichloromethane.
The reaction mixture was stirred for 16 h at 40 ꢁC. Sub-
sequently the mixture was evaporated and the residue
was diluted with water and dichloromethane. The
phases were separated and the aqueous layer was ex-
tracted twice with dichloromethane. The combined or-
ganic layer was washed with brine and dried over
magnesium sulfate. After evaporation of the solvent,
the residue was purified by silica gel chromatography
(ethyl acetate/hexane, 1:5). Yield: 2.3 g (5.6 mmol,
To a solution of 1.1 g (2.69 mmol) of the material iso-
lated in the previous step in 40 ml THF was added eth-
anesulfonylchloride (0.306 ml, 3.23 mmol) and ethyl-
diisopropylamine (0.970 ml, 5.67 mmol) at 0 ꢁC. The
mixture was stirred for 16 h at room temperature and
then poured over a 2 N HCl solution and extracted with
ethyl acetate. The organic layer was washed again with
2 N HCl, dried over magnesium sulfate and evaporated.
The remainder was purified by chromatography on silica
gel (ethyl acetate/hexane, 6:4). Yield: 1.05 g ( 2.26 mmol,
84%). The compound was analysed on chiral HPLC
(Chiralpack AD, eluent: 50% isopropanol/hexane) and
compared with the racemic analogue: the retention time
of the unique peak was 14.60 min as compared to 11.86
and 14.86 min for the racemate (2 peaks). No trace of
the other enantiomer was found (ee: >98%).1H NMR
(CDCl3): d 1.18 (t, 3H, CH3CH2), 2.45 (t, 1H, CꢁCH),
2.47–2.82 (m, 4H, CH2CH2, CH3CH2), 3.30–3.61 (2m,
2H, CH2CH2), 3.81 (s, 3H, OCH3), 4.77 (m, 2H,
CH2CꢁC), 4.91 (d, 1H, CHa), 5.59 (t, 1H, NH), 5.81
(d, 1H, NH), 6.42 (m, 1H, CH arom.), 6.60 (m, 1H,
CH arom.), 6.84 (d, 1H, CH arom.), 7.20–7.30 (m, 2H,
CH arom.), 7.35–7.41 (m, 2H, CH arom.).
1
79%). Mp 96–97 ꢁC. H NMR (CDCl3): d 2.42 (t, 1H,
CꢁCH), 2.47 (t, 1H, CꢁCH), 2.74 (t, 2H, CH2CH2),
3.46 (q, 2H, CH2CH2), 3.79 (s, 3H, OCH3), 3.91 (dd,
1H, CH2CꢁC), 4.14 (dd, 1H, CH2CꢁC), 4.69 (d, 2H,
CH2CꢁC), 4.91 (s, 1H, CHO), 6.62–7.29 (m, 7H, CH
arom.). 13C NMR (CDCl3): d 22.3, 35.2, 39.5, 55.1,
57.4, 60.7, 72.8, 73.6, 74.7, 76.9, 78.7, 79.0, 111.8,
114.3, 121.4, 128.6, 129.1, 132.1, 133.7, 138.2, 145.5,
149.3,
169.8.
HRMS
m/z:
Calcd
for
(C23H22ClNO4+H)+: 412.8848. Found: 412.8844.
5.7.2. N-[2-(3-Methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-
2-phenyl-2-prop-2-ynyloxyacetamide (37). Obtained
from benzaldehyde (instead of 4-chloro-benzaldehyde)
according to procedures 5.7. and 5.7.1. Yield: 68%.
Mp 73–74 ꢁC. 1H NMR (CDCl3): d 2.44 (t, 1H, CꢁCH),
2.49 (t, 1H, CꢁCH), 2.76 (t, 2H, CH2CH2), 3.51 (q, 2H,
CH2CH2), 3.81 (s, 3H, OCH3), 3.94 (dd, 1H, CH2CꢁC),
4.16 (dd, 1H, CH2CꢁC), 4.73 (d, 2H, CH2CꢁC), 4.97 (s,
1H, CHO), 6.66–7.32 (m, 8H, CH arom.). MS m/z: 378
(C23H23NO4+H)+.
5.7. 2-(4-Chlorophenyl)-2-hydroxy-N-[2-(3-methoxy-4-
prop-2-ynyloxyphenyl)-ethyl]-acetamide (14)
N-[2-(3-Methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-form-
amide (9, 34 g, 0.14 mol) and triethylamine (34 g,
0.34 mol) were dissolved in 120 ml of dichloromethane.
A solution of bis(trichloromethyl)carbonate (triphos-
gene, 16 g, 55 mmol) in 80 ml of dichloromethane was
added at 5 ꢁC. This mixture was stirred for 4 h at 5 ꢁC
and then cooled to ꢀ78 ꢁC. A solution of titanium tetra-
chloride (28 g, 0.15 mol) in 150 ml of dichloromethane
was added and the mixture was stirred for 2 h at
ꢀ40 ꢁC. A solution of 4-chlorobenzaldehyde (20 g,
0.14 mol) in 70 ml of dichloromethane was added drop-
wise and the reaction mixture was stirred for 16 h at
room temperature. Subsequently the mixture was
quenched with 80 ml of 5 N hydrochloric acid, stirred
for 30 min at room temperature and washed with water.
The phases were separated, the organic layer was dried
over magnesium sulfate and evaporated. The residue
was purified by chromatography on silica gel (ethyl ace-
5.7.3. 2-(2-Chlorophenyl)-N-[2-(3-methoxy-4-prop-2-ynylo-
xyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide (38). Ob-
tained from 2-chloro-benzaldehyde (instead of 4-
chloro-benzaldehyde) according to procedures 5.7. and
5.7.1. Yield: 53%. 1H NMR (CDCl3): d 2.42 (t, 1H,
CꢁCH), 2.45 (t, 1H, CꢁCH), 2.77 (t, 2H, CH2CH2),
3.52 (q, 2H, CH2CH2), 3.79 (s, 3H, OCH3), 3.93 (dd,
1H, CH2CꢁC), 4.14 (dd, 1H, CH2CꢁC), 4.69 (d, 2H,
CH2CꢁC), 5.42 (s, 1H, CHO), 6.67–7.35 (m, 7H, CH
arom.). MS m/z: 413 (C23H22ClNO4+H)+.
5.7.4. 2-(3-Fluorophenyl)-N-[2-(3-methoxy-4-prop-2-ynylo-
xyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide (39). Ob-
tained from 3-fluoro-benzaldehyde (instead of 4-
chloro-benzaldehyde) according to procedures 5.7. and
1
tate/hexane, 1:4). Yield: 28 g (75 mmol, 54%). H NMR
(CDCl3): d 2.54 (t, 1H, CꢁCH), 2.72 (t, 2H, CH2CH2),
3.53 (q, 2H, CH2CH2), 3.84 (s, 3H, OCH3), 4.78 (m, 2H,
CH2CꢁC), 4.98 (s, 1H, CHOH), 6.07 (br s, 1H, NH),
6.53–7.38 (m, 7H, CH arom.). 13C NMR (CDCl3): d
21.0, 35.1, 40.5, 55.8, 56.9, 60.5, 73.4, 75.8, 78.7, 112.4,
114.6, 120.5, 128.0, 128.8, 132.4, 134.3, 138.0, 145.5,
1
5.7.1. Yield: 63%. H NMR (CDCl3): d 2.46–2.50 (m,
2H, CꢁCH), 2.78 (t, 2H, CH2CH2), 3.51 (q, 2H,
CH2CH2), 3.83 (s, 3H, OCH3), 3.98 (dd, 1H, CH2CꢁC),
4.19 (dd, 1H, CH2CꢁC), 4.74 (d, 2H, CH2CꢁC), 4.98 (s,
1H, CHO), 6.65–7.32 (m, 7H, CH arom.). MS m/z: 396
(C23H22FNO4+H)+.
149.7,
171.8.
HRMS
m/z:
Calcd
for
(C20H20ClNO4+H)+: 374.1154. Found: 374.1156.
5.7.5. 2-(3-Chlorophenyl)-N-[2-(3-methoxy-4-prop-2-ynylo-
xyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide (40). Ob-
tained from 3-chloro-benzaldehyde (instead of
4-chloro-benzaldehyde) according to procedures 5.7.
5.7.1. 2-(4-Chlorophenyl)-N-[2-(3-methoxy-4-prop-2-ynylo-
xyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide (6). An
80% solution of propargyl bromide in toluene (1.2 g,

C. Lamberth et al. / Bioorg. Med. Chem. 16 (2008) 1531–1545
1541
1
and 5.7.1. Yield: 65%. H NMR (CDCl3): d 2.48–2.53
5.7.11. 2-(4-Bromophenyl)-N-[2-(3-methoxy-4-prop-2-
ynyloxyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide (46).
Obtained from 4-bromo-benzaldehyde (instead of 4-
chloro-benzaldehyde) according to procedures 5.7. and
(m, 2H, CꢁCH), 2.80 (t, 2H, CH2CH2), 3.54 (q, 2H,
CH2CH2), 3.84 (s, 3H, OCH3), 3.98 (dd, 1H, CH2CꢁC),
4.21 (dd, 1H, CH2CꢁC), 4.77 (d, 2H, CH2CꢁC), 4.98 (s,
1H, CHO), 6.68–7.37 (m, 7H, CH arom.). MS m/z: 413
(C23H22ClNO4+H)+.
1
5.7.1. Yield: 62%. Mp 92–93 ꢁC. H NMR (CDCl3): d
2.50 (t, 1H, CꢁCH), 2.54 (t, 1H, CꢁCH), 2.81 (t, 2H,
CH2CH2), 3.54 (q, 2H, CH2CH2), 3.85 (s, 3H, OCH3),
3.99 (dd, 1H, CH2CꢁC), 4.21 (dd, 1H, CH2CꢁC),
4.78 (d, 2H, CH2CꢁC), 4.96 (s, 1H, CHO), 6.70–7.52
(m, 7H, CH arom.). MS m/z: 457 (C23H22BrNO4+H)+.
5.7.6. 2-(3-Bromophenyl)-N-[2-(3-methoxy-4-prop-2-ynylo-
xyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide (41). Ob-
tained from 3-bromo-benzaldehyde (instead of 4-
chloro-benzaldehyde) according to procedures 5.7. and
1
5.7.1. Yield: 61%. H NMR (CDCl3): d 2.42–2.47 (m,
5.7.12. N-[2-(3-Methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-
2-prop-2-ynyloxy-2-p-tolyl-acetamide (47). Obtained
from p-tolualdehyde (instead of 4-chloro-benzaldehyde)
according to procedures 5.7. and 5.7.1. Yield: 71%. Mp
2H, CꢁCH), 2.73 (t, 2H, CH2CH2), 3.46 (q, 2H,
CH2CH2), 3.79 (s, 3H, OCH3), 3.92 (dd, 1H, CH2CꢁC),
4.13 (dd, 1H, CH2CꢁC), 4.69 (d, 2H, CH2CꢁC), 4.90 (s,
1H, CHO), 6.61–7.46 (m, 7H, CH arom.). MS m/z: 457
(C23H22BrNO4+H)+.
1
72–73 ꢁC. H NMR (CDCl3): d 2.37 (s, 3H, CH3), 2.49
(t, 1H, CꢁCH), 2.53 (t, 1H, CꢁCH), 2.82 (t, 2H,
CH2CH2), 3.55 (q, 2H, CH2CH2), 3.86 (s, 3H, OCH3),
3.97 (dd, 1H, CH2CꢁC), 4.19 (dd, 1H, CH2CꢁC),
4.79 (d, 2H, CH2CꢁC), 4.98 (s, 1H, CHO), 6.71–7.25
(m, 7H, CH arom.). MS m/z: 392 (C24H25NO4+H)+.
5.7.7. N-[2-(3-Methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-
2-prop-2-ynyloxy-2-m-tolyl-acetamide (42). Obtained
from m-tolualdehyde (instead of 4-chloro-benzaldehyde)
1
according to procedures 5.7. and 5.7.1. Yield: 64%. H
NMR (CDCl3): d 2.29 (s, 3H, CH3), 2.41 (t, 1H,
CꢁCH), 2.44 (t, 1H, CꢁCH), 2.73 (t, 2H, CH2CH2),
3.47 (q, 2H, CH2CH2), 3.78 (s, 3H, OCH3), 3.90 (dd,
1H, CH2CꢁC), 4.11 (dd, 1H, CH2CꢁC), 4.68 (d, 2H,
CH2CꢁC), 4.89 (s, 1H, CHO), 6.62–7.16 (m, 7H, CH
arom.). MS m/z: 392 (C24H25NO4+H)+.
5.7.13. N-[2-(3-Methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-
2-prop-2-ynyloxy-2-(4-trifluoromethyl-phenyl)-acetamide
(48). Obtained from 4-trifluoromethyl-benzaldehyde (in-
stead of 4-chloro-benzaldehyde) according to proce-
1
dures 5.7. and 5.7.1. Yield: 57%. H NMR (CDCl3): d
2.45–2.49 (m, 2H, CꢁCH), 2.78 (t, 2H, CH2CH2), 3.50
(q, 2H, CH2CH2), 3.81 (s, 3H, OCH3), 3.96 (dd, 1H,
CH2CꢁC), 4.19 (dd, 1H, CH2CꢁC), 4.73 (d, 2H,
CH2CꢁC), 5.02 (s, 1H, CHO), 6.63–7.59 (m, 7H, CH
arom.). MS m/z: 446 (C24H22F3NO4+H)+.
5.7.8. N-[2-(3-Methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-
2-prop-2-ynyloxy-2-(3-trifluoromethyl-phenyl)-acetamide
(43). Obtained from 3-trifluoromethyl-benzaldehyde (in-
stead of 4-chloro-benzaldehyde) according to proce-
dures 5.7. and 5.7.1. Yield: 55%. Mp 89–91 ꢁC. 1H
NMR (CDCl3): d 2.42–2.47 (m, 2H, CꢁCH), 2.73 (t,
2H, CH2CH2), 3.47 (q, 2H, CH2CH2), 3.79 (s, 3H,
OCH3), 3.93 (dd, 1H, CH2CꢁC), 4.16 (dd, 1H,
CH2CꢁC), 4.69 (d, 2H, CH2CꢁC), 5.00 (s, 1H, CHO),
6.61–7.58 (m, 7H, CH arom.). MS m/z: 446
(C24H22F3NO4+H)+.
5.7.14. 2-(4-Methoxymethyl-phenyl)-N-[2-(3-methoxy-4-
prop-2-ynyloxyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide
(49). Obtained from 4-methoxymethyl-benzaldehyde
(instead of 4-chloro-benzaldehyde) according to proce-
1
dures 5.7. and 5.7.1. Yield: 64%. H NMR (CDCl3): d
2.48 (t, 1H, CꢁCH), 2.52 (t, 1H, CꢁCH), 2.80 (t, 2H,
CH2CH2), 3.41 (s, 3H, CH2OCH3), 3.56 (q, 2H,
CH2CH2), 3.85 (s, 3H, OCH3), 3.97 (dd, 1H, CH2CꢁC),
4.18 (dd, 1H, CH2CꢁC), 4.48 (s, 2H, CH2OCH3), 4.77
(d, 2H, CH2CꢁC), 5.02 (s, 1H, CHO), 6.69–7.33 (m,
7H, CH arom.). MS m/z: 422 (C25H27NO5+H)+.
5.7.9. 2-(3-Methoxyphenyl)-N-[2-(3-methoxy-4-prop-2-
ynyloxyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide (44).
Obtained from m-anisaldehyde (instead of 4-chloro-
benzaldehyde) according to procedures 5.7. and 5.7.1.
1
Yield: 61%. H NMR (CDCl3): d 2.44 (t, 1H, CꢁCH),
5.7.15. 2-(4-Ethyl-phenyl)-N-[2-(3-methoxy-4-prop-2-
ynyloxyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide (50).
Obtained from 4-ethyl-benzaldehyde (instead of 4-
chloro-benzaldehyde) according to procedures 5.7. and
5.7.1. Yield: 69%. 1H NMR (CDCl3): d 1.14 (t, 3H,
CH2CH3), 2.41 (t, 1H, CꢁCH), 2.46 (t, 1H, CꢁCH),
2.59 (q, 2H, CH2CH3), 2.74 (t, 2H, CH2CH2), 3.47 (q,
2H, CH2CH2), 3.79 (s, 3H, OCH3), 3.90 (dd, 1H,
CH2CꢁC), 4.11 (dd, 1H, CH2CꢁC), 4.69 (d, 2H,
CH2CꢁC), 4.92 (s, 1H, CHO), 6.63–7.19 (m, 7H, CH
arom.). MS m/z: 406 (C25H27NO4+H)+.
2.48 (t, 1H, CꢁCH), 2.76 (t, 2H, CH2CH2), 3.49 (q,
2H, CH2CH2), 3.78 (s, 3H, OCH3), 3.83 (s, 3H,
OCH3), 3.94 (dd, 1H, CH2CꢁC), 4.15 (dd, 1H,
CH2CꢁC), 4.72 (d, 2H, CH2CꢁC), 4.93 (s, 1H, CHO),
6.65–7.27 (m, 7H, CH arom.). MS m/z: 408
(C24H25NO5+H)+.
5.7.10. 2-(4-Fluorophenyl)-N-[2-(3-methoxy-4-prop-2-ynyl-
oxyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide (45). Ob-
tained from 4-fluoro-benzaldehyde (instead of 4-
chloro-benzaldehyde) according to procedures 5.7. and
1
5.7.1. Yield: 59%. Mp 64–66 ꢁC. H NMR (CDCl3): d
5.7.16. N-[2-(3-Methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-
2-prop-2-ynyloxy-2-(4-vinyl-phenyl)-acetamide (51). Ob-
tained from 4-vinyl-benzaldehyde (instead of 4-chloro-
benzaldehyde) according to procedures 5.7. and 5.7.1.
2.41–2.48 (m, 2H, CꢁCH), 2.74 (t, 2H, CH2CH2), 3.49
(q, 2H, CH2CH2), 3.80 (s, 3H, OCH3), 3.91 (dd, 1H,
CH2CꢁC), 4.13 (dd, 1H, CH2CꢁC), 4.71 (d, 2H,
CH2CꢁC), 4.92 (s, 1H, CHO), 6.63–7.27 (m, 7H, CH
arom.). MS m/z: 396 (C23H22FNO4+H)+.
1
Yield: 50%. H NMR (CDCl3): d 2.49 (t, 1H, CꢁCH),
2.53 (t, 1H, CꢁCH), 2.82 (t, 2H, CH2CH2), 3.54 (q,

1542
C. Lamberth et al. / Bioorg. Med. Chem. 16 (2008) 1531–1545
2H, CH2CH2), 3.85 (s, 3H, OCH3), 4.00 (dd, 1H,
CH2CꢁC), 4.21 (dd, 1H, CH2CꢁC), 4.78 (d, 2H,
CH2CꢁC), 5.01 (s, 1H, CHO), 5.27 (d, 1H, CH@CH2),
5.76 (d, 1H, CH@CH2), 6.68–7.42 (m, 8H, CH arom.,
CH@CH2). MS m/z: 404 (C25H25NO4+H)+.
3H, OCH3), 3.92 (dd, 1H, CH2CꢁC), 4.13 (dd, 1H,
CH2CꢁC), 4.72 (d, 2H, CH2CꢁC), 4.91 (s, 1H, CHO),
6.65–7.19 (m, 7H, CH arom.). MS m/z: 424
(C24H25NO4S+H)+.
5.7.22. 2-(2,3-Dichloro-phenyl)-N-[2-(3-methoxy-4-prop-
2-ynyloxyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide (57).
Obtained from 2,3-dichloro-benzaldehyde (instead of 4-
chloro-benzaldehyde) according to procedures 5.7. and
5.7.17. N-[2-(3-Methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-
2-(4-propyl-phenyl)-2-prop-2-ynyloxyacetamide (52). Ob-
tained from 4-propyl-benzaldehyde (instead of 4-chloro-
benzaldehyde) according to procedures 5.7. and 5.7.1.
Yield: 66%. 1H NMR (CDCl3): d 0.93 (t, 3H,
CH2CH2CH3), 1.55–1.68 (m, 2H, CH2CH2CH3), 2.45
(t, 1H, CꢁCH), 2.49 (t, 1H, CꢁCH), 2.54 (q, 2H,
CH2CH2CH3), 2.80 (t, 2H, CH2CH2), 3.52 (q, 2H,
CH2CH2), 3.80 (s, 3H, OCH3), 3.92 (dd, 1H, CH2CꢁC),
4.13 (dd, 1H, CH2CꢁC), 4.74 (d, 2H, CH2CꢁC), 4.95 (s,
1H, CHO), 6.68–7.24 (m, 7H, CH arom.). MS m/z: 420
(C26H29NO4+H)+.
1
5.7.1. Yield: 52%. H NMR (CDCl3): d 2.49–2.53 (m,
2H, CꢁCH), 2.83 (t, 2H, CH2CH2), 3.59 (q, 2H,
CH2CH2), 3.86 (s, 3H, OCH3), 4.00 (dd, 1H, CH2CꢁC),
4.21 (dd, 1H, CH2CꢁC), 4.77 (d, 2H, CH2CꢁC), 5.53 (s,
1H, CHO), 6.72–7.48 (m, 6H, CH arom.). MS m/z: 447
(C23H21Cl2NO4+H)+.
5.7.23. 2-(3,4-Dichloro-phenyl)-N-[2-(3-methoxy-4-prop-
2-ynyloxyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide (58).
Obtained from 3,4-dichloro-benzaldehyde (instead of 4-
chloro-benzaldehyde) according to procedures 5.7. and
5.7.18. 2-(4-Isopropyl-phenyl)-N-[2-(3-methoxy-4-prop-2-
ynyloxyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide (53).
Obtained from 4-isopropyl-benzaldehyde (instead of 4-
chloro-benzaldehyde) according to procedures 5.7. and
5.7.1. Yield: 60%. 1H NMR (CDCl3): d 1.22 (s, 3H,
CH(CH3)2), 1.25 (s, 3H, CH(CH3)2), 2.46 (t, 1H, CꢁCH),
2.51 (t, 1H, CꢁCH), 2.80 (t, 2H, CH2CH2), 2.89 (q, 1H,
CH(CH3)2), 3.53 (q, 2H, CH2CH2), 3.82 (s, 3H, OCH3),
3.94 (dd, 1H, CH2CꢁC), 4.16 (dd, 1H, CH2CꢁC), 4.75
(d, 2H, CH2CꢁC), 4.96 (s, 1H, CHO), 6.68–7.25 (m,
7H, CH arom.). MS m/z: 420 (C26H29NO4+H)+.
1
5.7.1. Yield: 61%. H NMR (CDCl3): d 2.42–2.47 (m,
2H, CꢁCH), 2.73 (t, 2H, CH2CH2), 3.47 (q, 2H,
CH2CH2), 3.79 (s, 3H, OCH3), 3.93 (dd, 1H, CH2CꢁC),
4.14 (dd, 1H, CH2CꢁC), 4.69 (d, 2H, CH2CꢁC), 4.90 (s,
1H, CHO), 6.61–7.42 (m, 6H, CH arom.). MS m/z: 447
(C23H21Cl2NO4+H)+.
5.7.24. 2-(2,4-Difluoro-phenyl)-N-[2-(3-methoxy-4-prop-
2-ynyloxyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide (59).
Obtained from 2,4-difluoro-benzaldehyde (instead of 4-
chloro-benzaldehyde) according to procedures 5.7. and
1
5.7.19. 2-(4-Butyl-phenyl)-N-[2-(3-methoxy-4-prop-2-
ynyloxyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide (54).
Obtained from 4-butyl-benzaldehyde (instead of 4-
chloro-benzaldehyde) according to procedures 5.7.
and 5.7.1. Yield: 58%. 1H NMR (CDCl3): d 0.95
(t, 3H, CH2CH2CH2CH3), 1.37–1.62 (m, 4H,
CH2CH2CH2CH3), 2.49 (t, 1H, CꢁCH), 2.53 (t, 1H,
CꢁCH), 2.61 (t, 2H, CH2CH2CH2CH3), 2.82 (t, 2H,
CH2CH2), 3.56 (q, 2H, CH2CH2), 3.87 (s, 3H, OCH3),
3.96 (dd, 1H, CH2CꢁC), 4.18 (dd, 1H, CH2CꢁC), 4.77
(d, 2H, CH2CꢁC), 4.98 (s, 1H, CHO), 6.70–7.29 (m,
7H, CH arom.). MS m/z: 434 (C27H31NO4+H)+.
5.7.1. Yield: 56%. H NMR (CDCl3): d 2.49–2.53 (m,
2H, CꢁCH), 2.84 (t, 2H, CH2CH2), 3.58 (q, 2H,
CH2CH2), 3.88 (s, 3H, OCH3), 3.99 (dd, 1H, CH2CꢁC),
4.20 (dd, 1H, CH2CꢁC), 4.78 (d, 2H, CH2CꢁC), 5.25 (s,
1H, CHO), 6.73–7.23 (m, 6H, CH arom.). MS m/z: 414
(C23H21F2NO4+H)+.
5.7.25. 2-(4-Bromo-2-fluoro-phenyl)-N-[2-(3-methoxy-4-
prop-2-ynyloxyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide
(60). Obtained from 4-bromo-2-fluoro-benzaldehyde
(instead of 4-chloro-benzaldehyde) according to proce-
1
dures 5.7. and 5.7.1. Yield: 61%. H NMR (CDCl3): d
2.49–2.55 (m, 2H, CꢁCH), 2.83 (t, 2H, CH2CH2), 3.59
(q, 2H, CH2CH2), 3.87 (s, 3H, OCH3), 3.99 (dd, 1H,
CH2CꢁC), 4.22 (dd, 1H, CH2CꢁC), 4.79 (d, 2H,
CH2CꢁC), 5.23 (s, 1H, CHO), 6.74–7.31 (m, 6H, CH
arom.). MS m/z: 475 (C23H21BrFNO4+H)+.
5.7.20. 2-(4-Methoxyphenyl)-N-[2-(3-methoxy-4-prop-2-
ynyloxyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide (55).
Obtained from p-anisaldehyde (instead of 4-chloro-
benzaldehyde) according to procedures 5.7. and 5.7.1.
1
Yield: 67%. Mp 101–102 ꢁC. H NMR (CDCl3): d 2.43
(t, 1H, CꢁCH), 2.48 (t, 1H, CꢁCH), 2.79 (t, 2H,
CH2CH2), 3.51 (q, 2H, CH2CH2), 3.77 (s, 3H, OCH3),
3.81 (s, 3H, OCH3), 3.91 (dd, 1H, CH2CꢁC), 4.12 (dd,
1H, CH2CꢁC), 4.73 (d, 2H, CH2CꢁC), 4.92 (s, 1H,
CHO), 6.67–7.23 (m, 7H, CH arom.). MS m/z: 408
(C24H25NO5+H)+.
5.7.26. 2-(3-Chloro-4-methyl-phenyl)-N-[2-(3-methoxy-4-
prop-2-ynyloxyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide
(61). Obtained from 3-chloro-p-tolualdehyde (instead of
4-chloro-benzaldehyde) according to procedures 5.7.
and 5.7.1. Yield: 58%. 1H NMR (CDCl3): d 2.41 (s,
3H, CH3), 2.52–2.57 (m, 2H, CꢁCH), 2.84 (t, 2H,
CH2CH2), 3.57 (q, 2H, CH2CH2), 3.88 (s, 3H, OCH3),
4.00 (dd, 1H, CH2CꢁC), 4.23 (dd, 1H, CH2CꢁC),
4.79 (d, 2H, CH2CꢁC), 4.98 (s, 1H, CHO), 6.72–7.39
(m, 6H, CH arom.). MS m/z: 427 (C24H24ClNO4+H)+.
5.7.21. N-[2-(3-Methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-
2-(4-methylsulfanyl-phenyl)-2-prop-2-ynyloxyacetamide
(56). Obtained from 4-methylsulfanyl-benzaldehyde (in-
stead of 4-chloro-benzaldehyde) according to proce-
1
dures 5.7. and 5.7.1. Yield: 59%. H NMR (CDCl3): d
5.7.27. 2-(3,4-Dimethyl-phenyl)-N-[2-(3-methoxy-4-prop-
2-ynyloxyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide (62).
Obtained from 3,4-dimethyl-benzaldehyde (instead of 4-
2.42–2.45 (m, 4H, SCH3, CꢁCH), 2.48 (t, 1H, CꢁCH),
2.76 (t, 2H, CH2CH2), 3.50 (q, 2H, CH2CH2), 3.80 (s,

C. Lamberth et al. / Bioorg. Med. Chem. 16 (2008) 1531–1545
1543
chloro-benzaldehyde) according to procedures 5.7. and
5.7.1. Yield: 66%. 1H NMR (CDCl3): d 2.26 (s, 6H,
CH3), 2.49 (t, 1H, CꢁCH), 2.52 (t, 1H, CꢁCH), 2.83
(t, 2H, CH2CH2), 3.54 (q, 2H, CH2CH2), 3.86 (s, 3H,
OCH3), 3.97 (dd, 1H, CH2CꢁC), 4.18 (dd, 1H,
CH2CꢁC), 4.78 (d, 2H, CH2CꢁC), 4.94 (s, 1H, CHO),
6.72–7.14 (m, 6H, CH arom.). MS m/z: 406
(C25H27NO4+H)+.
cyclohexenyl), 2.29–2.40 (m, 2H, CꢁCH, CH2CHO),
2.52 (t, 1H, CꢁCH), 2.63 (dd, 1H, CH2CHO), 2.82 (t,
2H, CH2CH2), 3.53 (q, 2H, CH2CH2), 3.88 (s, 3H,
OCH3), 4.01–4.09 (m, 3H, CH2CꢁC, CHO), 4.75 (d,
2H, CH2CꢁC), 6.73–7.02 (m, 3H, CH arom.). MS
m/z: 438 (C27H35NO4+H)+.
5.7.33. 3-(4-Chlorophenyl)-N-[2-(3-methoxy-4-prop-2-
ynyloxyphenyl)-ethyl]-2-prop-2-ynyloxypropionamide (68).
Obtained from (4-chlorophenyl)-acetaldehyde (instead
of 4-chloro-benzaldehyde) according to procedures 5.7.
and 5.7.1. Yield: 50%. 1H NMR (CDCl3): d 2.40 (t,
1H, CꢁCH), 2.51 (t, 1H, CꢁCH), 2.70 (q, 2H,
CH2CH2), 2.93 (dd, 1H, CH2CHO), 3.15 (dd, 1H,
CH2CHO), 3.49 (q, 2H, CH2CH2), 3.87 (s, 3H,
OCH3), 4.03 (dd, 2H, CH2CꢁC) 4.14 (dd, 1H, CHO),
4.75 (d, 2H, CH2CꢁC), 6.62–7.29 (m, 7H, CH arom.).
MS m/z: 427 (C24H24ClNO4+H)+.
5.7.28. 2-(3,5-Dimethyl-phenyl)-N-[2-(3-methoxy-4-prop-
2-ynyloxyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide (63).
Obtained from 3,5-dimethyl-benzaldehyde (instead of 4-
chloro-benzaldehyde) according to procedures 5.7. and
5.7.1. Yield: 63%. 1H NMR (CDCl3): d 2.37 (s, 6H,
CH3), 2.53 (t, 1H, CꢁCH), 2.58 (t, 1H, CꢁCH), 2.86
(t, 2H, CH2CH2), 3.59 (q, 2H, CH2CH2), 3.90 (s, 3H,
OCH3), 4.02 (dd, 1H, CH2CꢁC), 4.21 (dd, 1H,
CH2CꢁC), 4.81 (d, 2H, CH2CꢁC), 4.96 (s, 1H, CHO),
6.76–7.05 (m, 6H, CH arom.). MS m/z: 406
(C25H27NO4+H)+.
5.7.34. 3-(4-Chloro-phenoxy)-N-[2-(3-methoxy-4-prop-2-
ynyloxyphenyl)-ethyl]-2-prop-2-ynyloxy-propionamide (69).
Obtained from (4-chlorophenoxy)-acetaldehyde (instead
of 4-chloro-benzaldehyde) according to procedures 5.7.
and 5.7.1. Yield: 59%. Mp 99–100 ꢁC. 1H NMR
(CDCl3): d 2.39 (t, 1H, CꢁCH), 2.43 (t, 1H, CꢁCH),
2.72 (t, 2H, CH2CH2), 3.49 (q, 2H, CH2CH2), 3.80 (s,
3H, OCH3), 4.01–4.33 (m, 5H, OCH2, CH2CꢁC,
CHO), 4.68 (d, 2H, CH2CꢁC), 6.66–7.19 (m, 7H, CH
arom.). MS m/z: 443 (C24H24ClNO5+H)+.
5.7.29. N-[2-(3-Methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-
2-prop-2-ynyloxy-2-(3,4,5-trifluoro-phenyl)-acetamide (64).
Obtained from 3,4,5-trifluoro-benzaldehyde (instead of
4-chloro-benzaldehyde) according to procedures 5.7.
1
and 5.7.1. Yield: 58%. H NMR (CDCl3): d 2.50–2.53
(m, 2H, CꢁCH), 2.81 (t, 2H, CH2CH2), 3.54 (q, 2H,
CH2CH2), 3.87 (s, 3H, OCH3), 4.02 (dd, 1H, CH2CꢁC),
4.24 (dd, 1H, CH2CꢁC), 4.78 (d, 2H, CH2CꢁC), 4.93 (s,
1H, CHO), 6.69–7.06 (m, 5H, CH arom.). MS m/z: 432
(C23H20F3NO4+H)+.
5.7.35. N-[2-(3-Methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-
2-prop-2-ynyloxy-3-p-tolyloxy-propionamide (70). Ob-
tained from p-tolyloxy-acetaldehyde (instead of 4-
chloro-benzaldehyde) according to procedures 5.7. and
5.7.30. N-[2-(3-Methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-
2-prop-2-ynyloxy-2-(2,3,5-trichloro-phenyl)-acetamide (65).
Obtained from 2,3,5-trichloro-benzaldehyde (instead of
4-chloro-benzaldehyde) according to procedures 5.7.
1
5.7.1. Yield: 53%. Mp 82–83 ꢁC. H NMR (CDCl3): d
2.30 (s, 3H, CH3), 2.48 (t, 1H, CꢁCH), 2.53 (t, 1H,
CꢁCH), 2.82 (t, 2H, CH2CH2), 3.58 (q, 2H, CH2CH2),
3.89 (s, 3H, OCH3), 4.13–4.42 (m, 5H, OCH2, CH2CꢁC,
CHO), 4.76 (d, 2H, CH2CꢁC), 6.73–7.10 (m, 7H, CH
arom.). MS m/z: 422 (C25H27NO5+H)+.
1
and 5.7.1. Yield: 56%. H NMR (CDCl3): d 2.50–2.54
(m, 2H, CꢁCH), 2.85 (t, 2H, CH2CH2), 3.58 (q, 2H,
CH2CH2), 3.90 (s, 3H, OCH3), 4.02 (dd, 1H, CH2CꢁC),
4.27 (dd, 1H, OCH2), 4.77 (d, 2H, CH2CꢁC), 5.52 (s,
1H, CHO), 6.72–7.48 (m, 5H, CH arom.). MS m/z:
482 (C23H20Cl3NO4+H)+.
5.7.36. 3-Benzyloxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-
phenyl)-ethyl]-2-prop-2-ynyloxypropionamide (71). Ob-
tained from benzyloxy-acetaldehyde (instead of 4-
chloro-benzaldehyde) according to procedures 5.7. and
5.7.1. Yield: 48%. 1H NMR (CDCl3): d 2.36 (t, 1H,
CꢁCH), 2.42 (t, 1H, CꢁCH), 2.71 (t, 2H, CH2CH2),
3.48 (q, 2H, CH2CH2), 3.69 (dd, 1H, CH2CHO), 3.77–
3.83 (m, 4H, OCH3, CH2CHO), 4.14 (dd, 1H, CHO),
4.20 (dd, 2H, CH2CꢁC), 4.49 (s, 2H, CH2O), 4.67 (d,
2H, CH2CꢁC), 6.63–7.29 (m, 8H, CH arom.). MS m/
z: 422 (C25H27NO5+H)+.
5.7.31. 2-Cyclohexyl-N-[2-(3-methoxy-4-prop-2-ynyloxy-
phenyl)-ethyl]-2-prop-2-ynyloxyacetamide (66). Obtained
from cyclohexanecarbaldehyde (instead of 4-chloro-
benzaldehyde) according to procedures 5.7. and 5.7.1.
Yield: 47%. 1H NMR (CDCl3): d 1.02–1.26 (m, 6H,
cyclohexyl), 1.47–1.75 (m, 5H, cyclohexyl), 2.38 (t, 1H,
CꢁCH), 2.48 (t, 1H, CꢁCH), 2.77 (t, 2H, CH2CH2),
3.52 (q, 2H, CH2CH2), 3.68 (d, 1H, CHOH), 3.83 (s,
3H, OCH3), 4.02 (dd, 2H, CH2CꢁC), 4.71 (d, 2H,
CH2CꢁC), 6.69–6.95 (m, 3H, CH arom.). MS m/z: 384
(C23H29NO4+H)+.
5.7.37. 2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-N-[2-(3-
methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-2-prop-2-ynyloxy-
5.7.32. N-[2-(3-Methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-
2-prop-2-ynyloxy-3-(2,6,6-trimethyl-cyclohex-1-enyl)-pro-
pionamide (67). Obtained from (2,6,6-trimethyl-cyclo-
acetamide
(72).
Obtained
from
2,3-dihydro-
benzo[1,4]dioxine-6-carbaldehyde (instead of 4-chloro-
benzaldehyde) according to procedures 5.7. and 5.7.1.
1
hex-1-enyl)-acetaldehyde
(instead
of
4-chloro-
benzaldehyde) according to procedures 5.7. and 5.7.1.
Yield: 59%. H NMR (CDCl3): d 2.38 (t, 1H, CꢁCH),
2.42 (t, 1H, CꢁCH), 2.71 (t, 2H, CH2CH2), 3.44 (q,
2H, CH2CH2), 3.78 (s, 3H, OCH3), 3.86 (dd, 1H,
CH2CꢁC), 4.06 (dd, 1H, CH2CꢁC), 4.15 (s, 4H, OCH2-
CH2O), 4.66 (d, 2H, CH2CꢁC), 4.80 (s, 1H, CHO),
1
Yield: 60%. H NMR (CDCl3): d 1.04 (s, 3H, CH3),
1.09 (s, 3H, CH3), 1.46 (dd, 2H, cyclohexenyl), 1.61 (t,
2H, cyclohexenyl), 1.70 (s, 3H, CH3), 1.94 (dd, 2H,

1544
C. Lamberth et al. / Bioorg. Med. Chem. 16 (2008) 1531–1545
6.61–6.90 (m, 6H, CH arom.). MS m/z: 436
5.9. 2-(4-Chlorophenyl)-2-methoxyimino-N-[2-(3-meth-
oxy-4-prop-2-ynyloxyphenyl)-ethyl]-acetamide (15)
(C25H25NO6+H)+.
5.7.38. 2-(9H-Fluorene-2-yl)-N-[2-(3-methoxy-4-prop-2-
ynyloxyphenyl)-ethyl]-2-prop-2-ynyloxyacetamide (73).
Obtained from 9H-fluorene-2-carbaldehyde (instead of
4-chloro-benzaldehyde) according to procedures 5.7.
A solution of 2-(4-chlorophenyl)-N-[2-(3-methoxy-4-
(16,
prop-2-ynyloxyphenyl)-ethyl]-2-oxo-acetamide
2.2 g, 5.92 mmol), O-methyl-hydroxylamine hydrochlo-
ride (0.62 g, 7.4 mmol) and pyridine (0.94 ml,
11.6 mmol) in 12 ml of methanol was heated at reflux
for 2 h. After evaporation of the solvent, the remainder
was purified by chromatography on silica gel (ethyl
acetate/hexane, 35:65). Yield: 1.37 g ( 3.4 mmol, 58%).
1H NMR (CDCl3): d 2.44 (t, 1H, CꢁCH), 2.84 (t,
2H, CH2CH2), 3.71 (q, 2H, CH2CH2), 3.81 (s, 3H,
OCH3), 3.91 (s, 3H, OCH3), 4.76 (m, 2H, CH2CꢁC),
6.20 (br s, 1H, NH), 6.72 (m, 2H, CH arom.),
6.97 (m, 1H, CH arom.), 7.32 (m, 2H, CH arom.),
7.50 (m, 2H, CH arom.). MS m/z: 445
(C21H21ClN2O4+HCOO)ꢀ.
1
and 5.7.1. Yield: 63%. H NMR (CDCl3): d 2.50–2.54
(m, 2H, CꢁCH), 2.85 (t, 2H, CH2CH2), 3.59 (q, 2H,
CH2CH2), 3.88 (s, 3H, OCH3), 3.92 (s, 2H, fluorenyl),
4.03 (dd, 1H, OCH2), 4.22 (dd, 1H, OCH2), 4.76 (d,
2H, OCH2), 5.10 (s, 1H, CHO), 6.71–7.82 (m, 10H,
CH arom.). MS m/z: 466 (C30H27NO4+H)+.
5.7.39. N-[2-(3-Methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-
2-prop-2-ynyloxy-2-thiophen-2-yl-acetamide (74). Ob-
tained from thiophene-2-carbaldehyde (instead of 4-
chloro-benzaldehyde) according to procedures 5.7. and
1
5.7.1. Yield: 45%. H NMR (CDCl3): d 2.48–2.53 (m,
2H, CꢁCH), 2.82 (t, 2H, CH2CH2), 3.57 (q, 2H,
CH2CH2), 3.84 (s, 3H, OCH3), 4.06 (dd, 1H, OCH2),
4.23 (dd, 1H, OCH2), 4.77 (d, 2H, OCH2), 5.26 (s, 1H,
CHO), 6.72–7.36 (m, 6H, CH arom.). MS m/z: 384
(C21H21NO4S+H)+.
5.10. 2-(4-Chlorophenyl)-2-methylthioimino-N-[2-(3-
methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-acetamide (17)
A solution of 2-(4-chloro-phenyl)-N-[2-(3-methoxy-4-
prop-2-ynyloxyphenyl)-ethyl]-2-oxo-acetamide
(16,
0.8 g, 2.15 mmol), N,N-bis(trimethylsilyl)methanesulfe-
namide (7.0 g, 33.7 mmol) and tetrabutylammonium
fluoride trihydrate (250 mg, 0.8 mmol) in 18 ml of tetra-
hydrofuran was heated at reflux for 2 h. The solution
was diluted with ethyl acetate and washed with brine.
The organic layer was dried over magnesium sulfate
and evaporated. The remainder was purified by chroma-
tography on silica gel (ethyl acetate/hexane, 3:7). Yield:
5.7.40. N-[2-(3-Methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-
2-prop-2-ynyloxy-2-pyridin-3-yl-acetamide (75). Ob-
tained from pyridine-3-carbaldehyde (instead of 4-
chloro-benzaldehyde) according to procedures 5.7.
and 5.7.1. Yield: 41%. 1H NMR (CDCl3): d 2.49 (t,
1H, CꢁCH), 2.52 (t, 1H, CꢁCH), 2.81 (t, 2H,
CH2CH2), 3.53 (q, 2H, CH2CH2), 3.86 (s, 3H,
OCH3), 3.97 (dd, 1H, CH2CꢁC), 4.18 (dd, 1H,
CH2CꢁC), 4.75 (d, 2H, CH2CꢁC), 4.94 (s, 1H,
CHO), 6.72–7.44 (m, 7H, CH arom.). MS m/z: 379
(C22H22N2O4+H)+.
1
0.31 g ( 0.74 mmol, 35%). H NMR (CDCl3): d 2.51 (t,
1H, CꢁCH), 2.62 (s, 3H, SCH3), 2.84 (t, 2H, CH2CH2),
3.59 (q, 2H, CH2CH2), 3.89 (s, 3H, OCH3), 4.77 (m, 2H,
CH2CꢁC), 6.77 (m, 2H, CH arom.), 6.97 (m, 1H, CH
arom.), 7.17 (br s, 1H, NH), 7.51 (m, 4H, CH arom.).
MS m/z: 417 (C21H21ClN2O3S+H)+.
5.8. 2-(4-Chlorophenyl)-N-[2-(3-methoxy-4-prop-2-ynyl-
oxyphenyl)-ethyl]-2-oxo-acetamide (16)
A solution of dimethyl sulfoxide (0.98 ml, 13.8 mmol)
in 6 ml of dichloromethane was added to a solution
of oxalyl chloride (0.92 ml, 10.9 mmol) in 10 ml of
dichloromethane at ꢀ63 ꢁC in 15 min. A solution of
2-(4-chlorophenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-
Acknowledgments
The authors are very grateful to all colleagues at Syn-
genta who contributed to the discovery and develop-
ment of mandipropamid (6).
2-ynyloxyphenyl)-ethyl]-acetamide
(14,
2.62 g,
7.0 mmol) in 52 ml of dichloromethane was added dur-
ing 10 min at the same temperature. After 15 min stir-
ring, a solution of triethylamine (3.74 ml, 26.8 mmol)
in 8.4 ml of dichloromethane was added during
15 min. After 15 min stirring, the solution was hydroly-
sed with 12 ml water and warmed up to room temper-
ature. The organic layer was separated, washed with a
solution of sodium bisulfite and brine, dried over mag-
nesium sulfate and evaporated. The remainder was
purified by chromatography on silica gel (ethyl ace-
tate/hexane, 1:3). Yield: 2.25 g (6.1 mmol, 87%). 1H
NMR (CDCl3): d 2.51 (t, 1H, CꢁCH), 2.88 (t, 2H,
CH2CH2), 3.63 (t, 2H, CH2CH2), 3.89 (s, 3H,
OCH3), 4.75 (m, 2H, CH2CꢁC), 6.77 (m, 2H, CH
arom.), 6.96 (m, 1H, CH arom.), 7.17 (br s, 1H,
NH), 7.45 (m, 2H, CH arom.), 8.30 (m, 2H, CH
arom.). MS m/z: 370 (C20H18ClNO4ꢀH)ꢀ.
References and notes
1. For recent reviews see: (a) Multicomponent Reactions;
Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim, 2005;
(b) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51; (c)
Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.
Eur. J. 2000, 6, 3321.
2. For recent reviews see: (a) Hulme, C.; Nixey, T. Curr.
Opin. Drug Discov. Devel. 2003, 6, 921; (b) Ugi, I.;
Do¨mling, A. Comb. Chem. 2000, 287; (c) Weber, L.; Illgen,
K.; Almstetter, M. Synlett 1999, 366; (d) Ugi, I. J. Prakt.
Chem. 1997, 339, 499; (e) Armstrong, R. W.; Combs, A.
P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc.
Chem. Res. 1996, 29, 123.
3. For recent reviews see: (a) Do¨mling, A. Chem. Rev. 2006,
106, 17; (b) Banfi, L.; Riva, R. Org. React. 2005, 65, 1; (c)
Do¨mling, A.; Ugi, I. Angew. Chem. 2000, 112, 3300;

C. Lamberth et al. / Bioorg. Med. Chem. 16 (2008) 1531–1545
1545
Angew. Chem. Int. Ed. 2000, 39, 3168; (d) Do¨mling, A.
Curr. Opin. Chem. Biol. 2000, 4, 318.
142763; (b) Do¨ller, U.; Braun, P.; Sachse, B. (Agrevo) WO
94/29267; Chem. Abstr. 1994.
4. For recent reviews see: (a) Dondoni, A.; Massi, A. Acc.
Chem. Res. 2006, 39, 451; (b) Ramon, D. J.; Yus, M.
Angew. Chem. 2005, 117, 1628; Angew. Chem. Int. Ed.
2005, 44, 1602; (c) Banfi, L.; Basso, A.; Guanti, G.; Riva,
R. In Multicomponent Reactions; Zhu, J., Bienayme, H.,
Eds.; Wiley-VCH: Weinheim, 2005; pp 1–30.
5. For recent reviews see: (a) Orru, R. V. A.; de Greef, M.
Synthesis 2003, 1471; (b) Zhu, J. Eur. J. Org. Chem. 2003,
1133; (c) Ugi, I.; Do¨mling, A.; Werner, B. J. Heterocycl.
Chem. 2000, 37, 647; (d) Ugi, I.; Werner, B.; Do¨mling, A.
Targets Heterocycl. Syst. 2000, 4, 1.
6. (a) Haranath, P.; Anasuyamma, U.; Reddy, C. D.; Reddy,
C. S. Heterocycl. Commun. 2005, 11, 335; (b) Dandia, A.;
Singh, R.; Sarawgi, P. J. Fluorine Chem. 2004, 125, 1835;
(c) Altorfer, M.; Ermert, P.; Fa¨ssler, J.; Farooq, S.;
Hillesheim, E.; Jeanguenat, A.; Klumpp, K.; Maienfisch,
P.; Martin, J. A.; Merrett, J. H.; Parkes, K. E. B.; Obrecht,
J.-P.; Pitterna, T.; Obrecht, D. Chimia 2003, 57, 262; (d)
Lu, S.-M.; Chen, R.-Y. Heteroatom Chem. 2000, 11, 317.
7. Ort, O.; Do¨ller, U.; Reissel, W.; Lindell, S. D.; Hough, T.
L.; Simpson, D. J.; Chung, J. P. Pestic. Sci. 1997, 50, 331.
8. Cederbaum, F.; De Mesmaeker, A.; Jeanguenat, A.;
Kempf, H.-J.; Lamberth, C.; Schnyder, A.; Zeller, M.;
Zeun, R. Chimia 2003, 57, 680.
15. Periers, A.-M.; Laurin, P.; Ferroud, D.; Haesslein, J.-L.;
Klich, M.; Dupuis-Hamelin, C.; Mauvais, P.; Lassaigne,
P.; Bonnefoy, A.; Musicki, B. Bioorg. Med. Chem. Lett.
2000, 10, 161.
16. Gomes, D.; De, C. F.; Alegrio, L. V.; Freire De Lima, M.
E.; Leon, L. L.; Araujo, C. A. C. Arzneim.-Forsch./Drug
Res. 2002, 52, 120.
17. Huggenberger, F.; Lamberth, C.; Iwanzik, W.; Knauf-
Beiter, G. In Proc. BCPC Internat. Congress, BCPC:
Alton, 2005, pp 87–92.
18. Hermann, D.; Bartlett, D. W.; Fischer, W.; Kempf, H.-J.
In Proc. BCPC Internat. Congress, BCPC: Alton, 2005, pp
93–98.
19. (a) Ross, G. F.; Herdtweck, E.; Ugi, I. Tetrahedron 2002,
58, 6127; (b) Oertel, K.; Zech, G.; Kunz, H. Angew. Chem.
Int. Ed. 2000, 39, 1431; (c) Linderman, R. J.; Binet, S.;
Petrich, S. R. J. Org. Chem. 1999, 64, 336; (d) Lehnhoff,
S.; Goebel, M.; Karl, R. M.; Klo¨sel, R.; Ugi, I. Angew.
Chem. Int. Ed. 1995, 34, 1104; (e) Kunz, H.; Pfrengle, W.;
Ruck, K.; Sager, W. Synthesis 1991, 1039; (f). Tetrahedron
¨
Lett. 1989, 30, 4109; (g) J. Am. Chem. Soc. 1988, 110, 651;
(h) Kunz, H.; Pfrengle, W. Tetrahedron 1988, 44, 5487.
20. Frey, R.; Galbraith, S. G.; Guelfi, S.; Lamberth, C.; Zeller,
M. Synlett 2003, 1536.
9. Lamberth, C.; Cederbaum, F.; Jeanguenat, A.; Kempf,
H.-J.; Zeller, M.; Zeun, R. Pest Manag. Sci. 2006, 62, 446.
10. Gisi, U.; Lamberth, C.; Mehl, A.; Seitz, T. In Modern
Crop Protection Compounds; Kra¨mer, W., Schirmer, U.,
Eds.; Wiley-VCH: Weinheim, 2007; pp 651–674.
21. (a) Seebach, D.; Adam, G.; Gees, T.; Schiess, M.;
Weigand, W. Chem. Ber. 1988, 121, 507; (b) Schiess, M.;
Seebach, D. Helv. Chim. Acta. 1983, 66, 1618.
22. Semple, J. E.; Owens, T. D.; Nguyen, K.; Levy, O. E. Org.
Lett. 2000, 2, 2769.
11. (a) Gisi, U. In Advances in Downy Mildew Research;
Spencer-Phillips, P. T. N., Gisi, U., Lebeda, A., Eds.;
Kluwer: Dordrecht, 2002; pp 119–159; (b) Schwinn, F.;
Staub, T. In Modern Selective Fungicides; Lyr, H., Ed.;
Fischer: Jena, 1995; pp 323–346; (c) Griffith, J. M.; Davis,
A. J.; Grant, B. R. In Target Sites of Fungicide Action;
Ko¨ller, W., Ed.; CRC Press: Boca Raton, 1992; pp 69–
100.
23. Zeeh, B.; Muller, E. Liebigs Ann. Chem. 1968, 715, 47.
¨
24. Muller, E.; Zeeh, B. Liebigs Ann. Chem. 1966, 696, 72.
¨
25. Hagedorn, I.; Eholzer, U. Chem. Ber. 1965, 98, 936.
26. Passerini, M. Gazz. Chim. Ital. 1926, 56, 826.
27. Zeller, M.; Jeanguenat, A.; Lamberth, C.; Kunz, W.
(Novartis) WO 2000/41998; Chem. Abstr. 2000, 133, 104883.
28. (a) Seitz, T.; Stenzel, K. (Bayer) WO 98/58903; Chem.
Abstr. 1999, 130, 81296; (b) Seitz, T.; Haenssler, G.;
Stenzel, K. (Bayer) WO 96/23763; Chem. Abstr. 1996, 125,
247405.
12. (a) Jordan, T. E. J. R. Soc. Health 1997, 117, 216; (b)
O’Farrel, P. Hist. Stud. 1982, 20, 1.
13. Hunt, D. A.; Lavanish, J. M.; Asselin, M.; Los, M.
(American Cyanamid) EP 493683; Chem. Abstr. 1992, 117,
145306.
14. (a) Do¨ller, U.; Braun, P.; Sachse, B.; Reissel, W.; Ort, O.
P. G.; Hough, T. L.; Simpson, D. J.; Lindner, K.; Lindell,
S. D. (Agrevo) WO 96/17840; Chem. Abstr. 1996, 125,
29. Jeanguenat, A.; Zeller, M.; Ziegler, H. (Novartis) WO
2000/42007; Chem. Abstr. 2000, 133, 120138.
30. Morimoto, T.; Nezu, Y.; Achiwa, K.; Sekiya, M. J. Chem.
Soc., Chem. Commun. 1985, 1584.
31. Lamberth, C.; Kempf, H.-J.; Kriz, M. Pest Manag. Sci.
2007, 63, 57.