Multistep solid-phase synthesis of an antibiotic and receptor tyrosine kinase inhibitors using the traceless phenylhydrazide linker

Article abstract of DOI:10.1002/chem.200304821

The hydrazide group is an oxidatively cleavable traceless linker for solid-phase chemistry. This linker technology was used to develop a multistep solid-phase synthesis of an antibiotic that is active against Mycobacterium tuberculosis. Furthermore, we describe an efficient method for the traceless synthesis of 2-aminothiazoles that display dual inhibitory activity against the receptor tyrosine kinases VEGFR-2 and Tie-2. The synthesis method proceeds through 9 steps on the solid phase and should give access to a much larger library of 2-aminothiazoles, from which a new class of anti-angiogenesis drugs may be developed.

Full text of DOI:10.1002/chem.200304821

FULL PAPER
Multistep Solid-Phase Synthesis of an Antibiotic and Receptor Tyrosine
Kinase Inhibitors Using the Traceless Phenylhydrazide Linker
Frank Stieber,[a, b] Uwe Grether,[a, b] Ralph Mazitschek,[c] Natascha Soric,[c]
Athanassios Giannis,*[c] and Herbert Waldmann*[a, b]
Abstract: The hydrazide group is an oxidatively cleavable traceless linker for solid-
phase chemistry. This linker technology was used to develop a multistep solid-phase
synthesis of an antibiotic that is active against Mycobacterium tuberculosis.
Furthermore, we describe an efficient method for the traceless synthesis of
2-aminothiazoles that display dual inhibitory activity against the receptor tyrosine
kinases VEGFR-2 and Tie-2. The synthesis method proceeds through 9 steps on the
solid phase and should give access to a much larger library of 2-aminothiazoles, from
which a new class of anti-angiogenesis drugs may be developed.
Keywords: combinatorial chemistry
¥ inhibitors ¥ phenylhydrazides ¥
solid-phase synthesis
linker
¥
traceless
chemistry. iii) The use of linker groups that guarantee release
of the target compounds from the solid support under the
mildest conditions. Ideally, a linker should release the
products while forming a C H bond in place of the resin
attachment, thus leaving behind no trace of a solid-phase
synthesis (™traceless linker∫).[1] Herein we describe the use of
the traceless hydrazide linker[2, 3] for the multistep synthesis of
potentially biologically active compounds. The linker proves
to be stable in various synthetic transformations and allows
the release of different heterocycles in excellent overall yields
and with high purities (Scheme 1).
Introduction
The combinatorial and parallel synthesis of compound
libraries on polymeric supports is at the heart of research in
modern bioorganic and medicinal chemistry. Paramount to
success in this field is the development of powerful and
efficient solutions to several prevailing problems, in partic-
ular: i) The proper choice of the molecular scaffolds onto
which different functional groups are grafted in the process of
combinatorial synthesis. The generation of large libraries
alone is not sufficient, the underlying basic structure of the
individual library members must be biologically relevant.
ii) The development of reliable multistep sequences on the
polymeric support including widely differing types of trans-
formations. The chemistry must be adapted to the particular
biologically active compound class; the structure of the
targets should not be chosen on the basis of the available
[a] Prof. Dr. H. Waldmann, Dr. F. Stieber, Dr. U. Grether
Max-Planck-Institut f¸r Molekulare Physiologie
Abteilung Chemische Biologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
Scheme 1. Principle of the oxidative cleavage of the hydrazide linker.
[b] Prof. Dr. H. Waldmann, Dr. F. Stieber, Dr. U. Grether
Universit‰t Dortmund, Fachbereich 3, Organische Chemie
44227 Dortmund (Germany)
Results and Discussion
Fax : (‡49)231-133-2499
[c] Prof. Dr. A. Giannis, Dr. R. Mazitschek, Dipl.-Chem. N. Soric
Institut f¸r Organische Chemie, Universit‰t Karlsruhe
Richard-Willst‰tter-Allee 2, 76128 Karlsruhe (Germany)
E-mail: giannis@chemie.uni-leipzig.de
Synthesis of an antibiotic incorporating a biphenyl structure:
For the proper choice of suitable biologically relevant
molecular scaffolds, the principle of identifying ™privileged
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DOI: 10.1002/chem.200304821
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3282 3291
structures∫,[4] that is compound classes that facilitate inter-
actions with various proteins, provides a strong and powerful
guideline. Biphenyls are found in various pharmacologically
active compounds, for example, in vitronectin receptor
antagonists,[5] angiotensin receptor antagonists,[6] inhibitors
of transthyretin-mediated amyloid fibril formation,[7] and
novel antibacterial agents.[8] In addition, the biphenyl unit
has been proposed as a general scaffold for the combinatorial
generation of new drug candidates.[9] In order to prove that
the traceless phenylhydrazide linker can be employed effi-
ciently for the synthesis of biologically and pharmacologically
relevant compounds, biphenyl derivative 18 and its morpho-
line analogue 19 were synthesized (Scheme 2). Compound 18
is a representative member of a recently discovered, new class
of antibiotics that are active against Mycobacterium tuber-
culosis (the bacterium that causes tuberculosis) and against
atypical mycobacteria.[8]
activation with N,N-diisopropylcarbodiimide (DIC) and 1-hy-
droxybenzotriazole (HOBt). The iodophenylhydrazide 11 was
treated with p-formylphenylboronic acid (12) to give rise to
the polymer-bound biphenylaldehyde 13.[3] Initial attempts
with potassium phosphate as the base and [Pd(PPh3)4] as a
palladium source in DMF/water (6:1) yielded only traces of
the product. Subsequent fine tuning of the conditions resulted
in quantitative conversion of the iodophenylhydrazide 11 with
0.2 equiv [Pd(OAc)2], 18 equiv potassium carbonate, 8 equiv
N,N-diisopropyl-N-ethylamine and 8 equiv p-formylphenyl-
boronic acid (12).[11] The resulting biphenyl aldehyde 13 was
then subjected to reductive amination with thiomorpholine
derivative 14[8] and the morpholine derivative 15[12] to yield
polymer-bound secondary amines 16 and 17. Initial attempts
employing sodium cyanoborohydride in methanol at room
temperature[13] yielded the desired product in high yield, but
with poor purities. This problem was solved by utilizing the
conditions developed by Ley et al.[14] The polymer-bound
aldehyde 13 was completely consumed in the presence of
sodium trisacetoxyborohydride in CH2Cl2/HOAc 10:1 and
sodium sulfate to scavenge the released water at room
temperature for 2 h with ultrasound.[4] Finally, the traceless
hydrazide linker was cleaved oxidatively by treatment with
0.5 equiv of [Cu(OAc)2] in methanol and pyridine. The
desired biphenyl antibiotic 18 and its derivative 19 were
obtained in an overall yield of 37 and 31%, respectively after
simple extraction with aqueous NaHCO3 (2%) and subse-
quent evaporation of the organic solvent in >95% purity.
To execute the synthesis, amino-functionalized polystyrene
7 was acylated with adipic acid dichloride (8) to yield the
corresponding carboxy-functionalized resin 9 after hydrolysis.
(Scheme 2).[3, 10] The stable acid-functionalized resin 9 was
used for the attachment of p-iodophenylhydrazine (10) by
Synthesis of a 2-aminothiazole library–Identification of Tie-2
inhibitors: A recently emerging compound class that may
belong to the category of privileged structures are 2-amino-
thiazoles. This structural framework has found application in
drug development for the treatment of allergies,[15] hyper-
tension,[16] inflammation,[17] schizophrenia,[18] bacterial[19] and
HIV infections,[20] and very recently for the treatment of
pain,[21] as fibrinogen receptor antagonists with antithrombot-
ic activity,[22] as new inhibitors of bacterial DNA gyrase B[23]
and in the development of cyclin-dependent kinase inhib-
itors.[24]
In the light of these important and probably even more
widespread applications, the development of efficient meth-
ods for the solid-phase synthesis of 2-aminothiazoles[25] is of
great importance for medicinal, bioorganic and combinatorial
chemistry.
For the solid-phase synthesis of the 2-aminothiazole
nucleus it was planned to employ the Hantzsch synthesis as
the key step, that is, the treatment of polymer-bound N-
monosubstituted and N,N-disubstituted thioureas with a-
bromoketones (Scheme 3). We intended to generate the
intermediary thioureas from polymer-bound anilines by
treatment with an N-protected isothiocyanate. The para-
position to the aniline amino group was chosen as the
attachment point for the traceless hydrazide linker.
Scheme 2. Traceless solid-phase synthesis of antibiotic 18 and its derivative
19 employing a traceless hydrazide linker. a) 20 equiv adipic dichloride (8),
pyridine, CH2Cl2, RT, 18 h, then aqueous work-up; b) 3 equiv p-iodophe-
nylhydrazine (10), 3 equiv DIC, 3 equiv HOBt, 3 equiv NEt3, CH2Cl2, RT,
18 h; c) 8 equiv p-formylphenylboronic acid (12), 18 equiv K2CO3, 10 equiv
N,N-diisopropyl-N-ethylamine, 0.2 equiv [Pd(OAc)2], dioxane/water 6:1,
958C, 24 h; d) 15 equiv aniline 14 or 15, 10 equiv Na2SO4, 10 equiv
NaBH(OAc)3, HOAc, RT, 2 h, ultrasound; e) 0.5 equiv [Cu(OAc)2],
pyridine, methanol, O2, RT, 2 h. DIC ˆ N,N-diisopropylcarbodiimide,
HOBt ˆ 1-hydroxybenzotriazole.
Starting from amino-functionalized polystyrene
7
(1.3 mmolgÀ1) the corresponding carboxy-functionalized res-
in 9 was prepared. An adipic acid monoamide was formed
with adipic methyl ester (20) followed by basic saponification
of the ester group to yield the carboxy-resin with substantially
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3283

A. Giannis, H. Waldmann et al.
FULL PAPER
obtain access to N,N-disubstituted heterocycles as well.
Although this type of transformation is well-established in
solid-phase synthesis, its application to anilines 23 turned out
to be unexpectedly difficult. Thus, treatment of polymer-
bound aniline 23 (R ˆ H) with 10 equiv of 4-bromobenzalde-
hyde, tetramethylorthoformate, and 10 equiv NaBH-
[27a]
(OAc)3
resulted in imine formation, but not reduction to
the N-substituted amine. Employment of DMF/AcOH 100:1
as the solvent[27b] and 2 equiv of the aldehyde gave 60%
reduction product, but 40% of the imine remained. Further
fine tuning of the solvent led to ꢀ70% N-alkylated amine in
THF/AcOH/H2O 100:1:1[27c] and finally to quantitative con-
version if 10 equiv of aldehyde and NaCNBH3 were employed
in THF/AcOH 100:1 as solvent. However, under these
conditions, formation of the tertiary amine as a result of
double reductive alkylation was also observed. This problem
was finally overcome by separating the imine formation from
the reduction step. Firstly, the polymer-bound aniline 23 was
converted into the Schiffs base and the surplus aldehyde 24
was then separated by washing with THF. Then the imine was
reduced by treatment with NaCNBH3 in THF/AcOH 100:1.
These reaction conditions proved to be efficient for a variety
of aromatic and aliphatic aldehydes (see below).
Scheme 3. Plan for the traceless solid-phase synthesis of the 2-amino-
thiazoles 31.
Conversion of anilines 25 to the corresponding thioureas 28
was achieved efficiently by treatment with fluorenylmethox-
ycarbonyl isothiocyanate (Fmoc-NCS, 26)[25b] and subsequent
removal of all three Fmoc groups present in intermediate 27
by treatment with piperidine in DMF. In the acylation step,
the presence of pyridine is probably required to partially
deprotonate the amine. A ninhydrin test indicated that
conversion to the thioureas 28 is quantitative. The removal
of all three Fmoc groups from fully masked resin 27 is not a
problem with regard to the subsequent steps of the synthesis.
On the one hand, model reactions indicated that the polymer-
bound hydrazides do not react with a-bromoketones 29 under
the conditions of the Hantzsch synthesis (see below). On the
other hand, the possible N-alkylation products would no
longer be amenable to the oxidative traceless-cleavage
process.
higher loading levels owing to the prevention of crosslinking
of the resin (Scheme 4).[3, 10] Subsequently, the carboxy-
functionalized resin 9 was treated with 4-nitrophenylhydra-
zines 21 to yield the corresponding polymer-bound nitro-
phenylhydrazides 22.
Prior to the planned reduction of the nitrobenzene groups
to the anilines, the two hydrazide nitrogens of 22 were
acylated with Fmoc-Cl. This precaution was taken since we
intended to generate the required thiourea intermediates
from the corresponding anilines by treatment with Fmoc-
isothiocyanate 26 (see below). Under these conditions, the
unprotected hydrazides are also acylated resulting in the
formation of undesired sideproducts. The acylation with
Fmoc-Cl proceeded only in poor yield with dioxane and
aqueous NaHCO3 or methylene chloride/triethylamine with
10 equiv Fmoc-Cl. The double acylated hydrazide was
smoothly prepared in the solvent system methylene chlor-
ide/pyridine (20:1). A double acylation of the hydrazide was
achieved under these conditions, thus leaving the amide group
of the resin spacer unattached. This was proven by reacting
Fmoc-Cl with a polymer-bound nitrophenylhydrazide em-
ploying an acid-functionalized support with an ether linkage
instead of the amide in resin 9.[3, 10]
After successful introduction of the Fmoc groups, the
reduction of the nitro group to the amino function was
investigated. Initial attempts employing Na2S2O4 in ethanol at
reflux temperature[26a] yielded only traces of product. In the
presence of CrCl2 in DMF at room temperature,[26b] ꢀ80%
conversion could be observed and application of SnCl2 in
NMP[26c] resulted in a conversion of >90% (determined by
GC-MS). Finally, polymer-fixed anilines 23 were formed
quantitatively if DMF was employed as the solvent.[26d,e]
The use of polymer-bound anilines 23 in the subsequent
synthesis sequence leads to the formation of N-monosubsti-
tuted 2-aminothiazoles. N-functionalization of the amines 23
by means of reductive amination was investigated in order to
With the polymer-bound thioureas 28 in hand, the Hantzsch
thiazole synthesis on the polymeric support was investigated.
Gratifyingly, the desired 2-aminothiazoles 30 were formed
smoothly upon two successive treatments with 0.1m solutions
of different a-bromocarbonyl compounds 29 in dioxane
(Scheme 4).
Finally, the target compounds 31 were released from the
solid support by treatment with a catalytic amount of
[Cu(OAc)2] in n-propylamine and purging with O2 to reox-
‡
idize the Cu formed by the oxidation of the linker group.
The copper salt was readily and efficiently separated from
the products by treatment of the reaction mixture with
10 equiv of a copper-chelating polyamine resin (Advanced
Chemtech) or by simple filtration through a silica gel column
for solid-phase extraction.[3] In both cases, examination of the
crude reaction products by means of atomic absorption
spectroscopy indicated that >99.9% of the copper had been
removed.
A total of 23 differently substituted 2-aminothiazoles were
synthesized according to this procedure. The results of the
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Tyrosine Kinase Inhibitors
3282 3291
Table 1. Results of the traceless solid-phase synthesis of 2-aminothiazoles
14.
R1
R2
R3
R4
Overall
Purity[%]
yield[%]
31/1
31/2
31/3
H
H
H
H
H
H
H
69
49
96
99
H
H
34
19
86
99
31/4 m-CN
31/5 m-CN
H
H
H
29
28
89
99
31/6
H
31/7
31/8
31/9
31/10
H
H
H
H
31
38
25
42
92
99
92
99
H
H
H
31/11
31/12
31/13
H
H
H
H
20
30
47
86
87
81
H
H
31/14
31/15
H
H
35
19
84
98
31/16
31/17
H
H
H
24
35
99
86
Scheme 4. Traceless solid-phase synthesis of 2-aminothiazoles 31.
a) 3 equiv adipic monomethyl ester (20V, 3 equiv DIC, 3 equiv HOBt,
3 equiv NEt3, CH2Cl2, RT, 18 h ; b) THF/1% LiOH 1:1, RT, 24 h;
c) 3 equiv nitrophenylhydrazine (21), 3 equiv DIC, 3 equiv HOBt, 3 equiv
NEt3, CH2Cl2, RT, 18 h; d) 10 equiv Fmoc-Cl, pyridine, CH2Cl2, 15 h;
e) 2m SnCl2 Â 2H2O, DMF, RT, 18 h; f) 10 equiv aldehyde 24, THF, HOAc,
RT, 1 h, wash, then 10 equiv NaCNBH3, THF/HOAc, RT, 15 h; g) 3 equiv
Fmoc-NCS 26, CH2Cl2, pyridine, RT, 15 h; h) DMF/piperidine 4:1, RT, 2 Â
5 min; i) 0.1m solution of 29 in dioxane, RT, 2 Â 3 h; k) 0.5 equiv
[Cu(OAc)2], n-propylamine, O2, RT, 2 h, then solid-phase extraction.
31/18
31/19
H
H
H
H
20
33
82
85
31/20
31/21
H
H
35
28
81
93
31/22
31/23
H
H
H
H
42
31
82
84
syntheses are summarized in Table 1. The data demonstrate
that the 2-aminothiazoles are obtained in nine-step syntheses
(N-monosubstituted) and 10-step syntheses (N,N-disubstitut-
ed) in very high overall yields (19 69%, average yield per
step 86 95%). The synthesis is tolerant of substantial
variation in the structure of the substituents, that is, different
aromatic, heteroaromatic, and aliphatic groups can be effi-
ciently introduced. The synthesis sequence proceeds so
cleanly that the compounds are obtained after cleavage of
the traceless linkers in excellent purity (81 99%) without
any further separation and purification steps. In any case, they
are pure enough to be employed directly for further purposes,
for example, biological testing. Of particular interest is the
mildness of the conditions required for the completely
selective cleavage of the traceless hydrazide linker. In the
presence of catalytic amounts of the copper salt employed,
even oxidation-sensitive functional groups, such as furans,
thiophenes, and sulfides, are not attacked at all.
From the different biological and pharmacological activ-
ities of compounds with the 2-aminothiazole scaffold, we were
particularly intrigued by the ability of certain 2-aminothiazole
derivatives to inhibit cyclin-dependent kinases (Cdks, see
above).[24] These serine/threonine kinases drive and control
cell cycle progression and have essential roles in cell
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A. Giannis, H. Waldmann et al.
FULL PAPER
proliferation.[28a, 29a] At least two Cdk inhibitors are under-
going human clinical trials to suppress tumor growth.[28, 29]
Given the relevance of these proteins, we investigated the
2-aminothiazoles as possible inhibitors of Cdk-2 and Cdk-4.
However, none of the compounds showed appreciable
inhibitory activity, which indicates that the individual deco-
ration of the 2-aminothiazole nucleus is paramount to achieve
biological activity in the compound class.
In the light of the high similarity among the structure of the
ATP-binding domains of protein kinases[28, 29] and the notion
that this evolutionary conservatism of Nature can be em-
ployed as guiding principle for the development of compound
libraries,[30] the library was screened for possible inhibitors
against receptor tyrosine kinases, which were selected to
cover a wide spectrum of biological activities.
Table 2. Inhibition of different receptor tyrosine kinases by 2-aminothiazoles.
IC50 for receptor tyrosine kinase[mm][a]
Com-
VEGFR-2 VEGFR-3 Tie-2 IGF1R EGFR ErbB2 FGFR1
pound
31/1
31/2
21
13
31/7
31/8
31/14
31/20
31/23
7.4
31
12
86
63
44
41
9.8
4.8
8.6
28
31
[a] To assay the inhibitory activity, the kinase-catalyzed phosphorylation of
poly(Glu-Tyr) in the presence of varying concentrations of inhibitor was
determined. The kinases were employed as fusion proteins of glutathione-S-
transferase (GST) and the respective kinase domain. The relative amount of
phosphorylated substrate was quantified by means of an anti-phosphotyrosine
enzyme-linked immunosorbent assay (ELISA), which employed an anti-phospho-
tyrosine antibody conjugated to horseradish peroxidase (POD). The bound
antibody was detected by the light emission after addition of a chemiluminescence
substrate for POD.
To this end, epidermal growth factor receptor (EGFR;
ErbB-1), ErbB-2, insulin-like growth factor 1 receptor
(IGF1R), fibroblast growth factor receptor 1 (FGFR1),
vascular endothelial growth factor receptors 2 and
3
clinical trials.[38] The combination of VEGFR-2 inhibitors with
Tie-2 antagonists should potentiate their anti-angiogenic
effects.[36c] Furthermore, inhibitors of VEGFR-3 would sup-
press the metastasis of lymphogenic tumors. To date, however,
only a few cases of small-molecule inhibitors of the Tie-2 and
VEGFR-3 receptors have been reported.[39]
(VEGFR-2 and -3) and Tie-2 were chosen. ErbB-2 (also
named Her-2/Neu) is over-expressed in approximately 30%
of all primary breast, ovary, and stomach cancers. The EGFR,
has been implicated in human tumorigenesis, for example, of
glioblastoma as well as in numerous tumors of epithelial
origin, including breast and oesophageal tumors.[31] The
insulin-like growth factor 1 receptor affects cell mitogenesis,
survival, transformation, and insulin-like activities by the
binding of its ligands, IGF1 and IGF2. This receptor
influences postnatal growth physiology, and its activity has
been associated with malignant disorders, such as breast
cancer.[32]
VEGFR-2 and -3 and Tie-2 are involved in angiogenesis,
the development of new blood vessels from pre-existing ones,
in particular in tumors (see below). Similarly members of the
FGF family, in particular, acidic FGF (FGF1) and basic FGF
(FGF2), are potent inducers of angiogenesis.[33]
The library of the 2-aminothiazoles did not contain any
inhibitor of EGFR, ErbB-2 and IGF1R which warranted
further investigation. Remarkably, however, six compounds
turned out to be inhibitors of Tie-2 and five compounds
inhibited VEGFR-2 (Table 2). In addition, a potent inhibitor
of the FGFR-1 and two inhibitors of VEGFR-3 were
identified. Of particular importance is the finding that the
2-aminothiazoles display dual selectivity for VEGFR-2 and
Tie-2, and in part also for VEGFR-3, namely, three prime
regulators of angiogenesis and lymphoangiogenesis.
Conclusion
We have demonstrated that the traceless phenylhydrazide
linker can be successfully employed in the multistep synthesis
of compound libraries to yield biologically and pharmacolog-
ically relevant compounds. Thus, a representative member of
a recently discovered new class of antibiotics that are active
against Mycobacterium tuberculosis and atypical mycobacte-
ria, and its morpholine-derivative were synthesized. Further-
more, an efficient method for the multistep traceless synthesis
of 2-aminothiazoles that display dual specifity against the
receptor tyrosine kinases VEGFR-2 and Tie-2 was developed.
The synthesis method should rapidly give access to a much
larger library of 2-aminothiazoles from which dual-selective
VEGFR-2 and Tie-2 inhibitors with enhanced biological
potency may be identified that could be developed into a new
class of anti-angiogenesis drugs. These compounds are
obtained readily and efficiently in high overall yields and
with high purity after simple extraction and filtration steps.
Angiogenesis is central to wound repair, inflammation, and
embryonic development. Furthermore, aberrant angiogenesis
is considered to be a key step in tumor growth, spread, and
metastasis.[34] Vascular development depends on the endothe-
lium-specific vascular endothelial growth factor receptors 1
3 (VEGFR1-3) and the Tie-2 receptor.[35] All these receptors
have been implicated in tumor angiogenesis[36] and antago-
nization of Tie-2, VEGFR-2, or VEGF-D (a ligand of
VEGFR-3) inhibits tumor growth and tumor metastasis in
vivo.[36d, 37] The development of low molecular-weight inhib-
itors of these receptor tyrosine kinases is among the most
promising approaches to the development of new, alternative
antitumor drugs, and several inhibitors of VEGFR-2 are in
Experimental Section
General procedures: 1H NMR and 13C NMR spectra were recorded on
Bruker AC250, DRX400 or DRX500 spectrometers. HPLC were meas-
ured on an Agilent1100 Series equipped with
(Macherey & Nagel). GC-MS were measured on a Agilent6890 Series
gas chromatograph connected to a Agilent5973 Series mass spectrometer.
All HPLC was performed with a flow rate of 1 mLminÀ1 and a gradient
which changed from H20/acetonitrile/formic acid 90:10:0.1 (v/v/v) to H20/
acetonitrile/formic acid 10:90:0.1 (v/v/v) within 30 min. High-resolution
mass spectra (HRMS) were measured on a Finnigan MAT8200 spectrom-
eter. IR spectra were measured on Bruker IFS88 or Bruker Vector22
a C18PPN column
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Tyrosine Kinase Inhibitors
3282 3291
spectrometers with a diffuse reflectance headA527 from Spectra Tech. UV
spectra were measured on a Perkin Elmer Cary50 spectrometer.
NH-), 3.42 (s, 2H, Ph-Ph-CH2-NH-Ph-CH2-thiomorpholine), 2.67 (s, 8H,
thiomorpholine-CH2).; GC-MS (70 eV, EI): m/z (%): 374 (44) [M] , 272
‡
(100), 167 (97), 106 (25); HRMS: calcd for: 374.1817; found: 374.1839. The
Materials: TLC was performed on Merck silica gel 60F254 aluminum sheets.
Silica gel (40 60 mm) was used for flash chromatography. The resins were
purchased from Rapp Polymere, Advanced Chemtech and Argonaut
Technologies. All reactions were performed under an argon atmosphere
with freshly distilled, and dried solvents. All solvents were distilled using
standard procedures. Commercial reagents were used without further
purification.
spectroscopic data are in agreement with reported values.[8]
Polystyrene-bound tetracyclic morpholine (17): To
a suspension of
polymer-bound biphenylaldehyde 13 (200 mg, 0.04 mmol) in methylene
chloride (4 mL) and acetic acid (0.4 mL), were added sodium sulfate
(57 mg, 0.4 mmol), sodium triacetoxyborohydride (85 mg, 0.4 mmol), and
4-morpholinomethyl aniline (15,[12] 115 mg, 0.6 mmol). The mixture was
ultrasonicated for 2 h and then filtered. The resin was washed with DMF,
isopropanol, water, DMF, methanol, and methylene chloride (3 Â each),
General procedure for the oxidative cleavage of the phenylhydrazide linker
with [Cu(OAc)2] and n-propylamine (Method A): The resin was suspended
in a solution of 0.5 equiv of [Cu(OAc)2] in n-propylamine (5 mm) and was
shaken at room temperature for 2 h with oxygen bubbling through the
mixture. The solvent was removed under reduced pressure and the work-up
was performed with one of the following procedures: i) diethyl ether and
2% NaHCO3 were added to the residue and, after phase separation, the
organic layer was dried over MgSO4. The solvent was removed and the
residue was dried in vacuo. ii) The residue was suspended in methylene
chloride (50 mLgÀ1 resin) and tris-(2-aminoethyl)amino resin (5 equiv,
Novabiochem, 200 400 mesh) was added. The mixture was shaken for 1 h
at room temperature and then filtered. The filtrate was evaporated and
dried in vacuo. iii) The residue was suspended in cyclohexane/ethyl acetate
(10:1) or methylene chloride/cyclohexane (5:1), filtered through a SPE-
cartridge (SiO2) and washed 3 Â with cyclohexane/ethyl acetate (1:1) or
methylene chloride. The filtrate was evaporated and dried in vacuo.
and dried to constant weight in vacuo to yield the black resin 17 (199 mg).
À1
ˆ
IR (SiO2): nÄ ˆ 3301 (NH), 1667 (C O) cm
.
4'-biphenylmethyl-(4-morpholin-4-ylmethyl-phenyl)-amine 819): Accord-
ing to Method B for the oxidative cleavage of the hydrazide linker 16
(195 mg, 23 mmol) was treated with [Cu(OAc)2] and pyridine in methanol
followed by extractive workup to yield a yellowish oil (2.5 mg, 7 mmol,
31%). Rf ˆ 0.12 (cyclohexane/ethyl acetate 10:1); HPLC: 94% pure
(260 nm); 1H NMR (CDCl3, 250 MHz): d ˆ 7.64 7.55 (m, 4H, arom.
CH), 7.49 7.40 (m, 5H, arom. CH), 7.14 (d, 3J(H,H) ˆ 8.8 Hz, 2H, arom.
CH), 6.65 (d, 3J(H,H) ˆ 8.8 Hz, 2H, arom. CH), 4.40 (s, 2H, Ph-Ph-CH2-
NH-), 3.81 3.58 (m, 6H, Ph-Ph-CH2-NH-Ph-CH2-morpholine, 2 Â CH2-
‡
O), 2.55 (b, 4H, 2 Â CH2-N); GC-MS (70 eV, EI): m/z (%): 358 (15) [M] ,
281 (11), 270 (89), 207 (50), 135 (18), 90 (18), 44 (24), 28 (100); HRMS:
358.2051 (calcd: 358.2045).
General procedure for the oxidative cleavage of the phenylhydrazide linker
with [Cu(OAc)2], methanol and pyridine (Method B): The resin was
suspended in a solution of 0.5 equiv [Cu(OAc)2] (5 mm) and pyridine
(100 mm) in methanol and was shaken at room temperature for 2 h with
oxygen bubbling through the mixture. If polystyrene resins were used, the
same volume of THF was added. The solvent was removed under reduced
pressure and the work-up was performed by means of one of the
procedures described above.
Polystyrene-bound p-nitrophenylhydrazide (22a): N,N-Diisopropylcarbo-
diimide (2.55 mL, 16.5 mmol), 1-hydroxybenzotriazole (2.52 g, 16.5 mmol),
triethylamine (2.31 mL, 16.5 mmol), and p-nitrophenylhydrazine (21a,
2.52 g, 16.5 mmol) were added to a suspension of resin 9[3, 10] (5 g, 5.5 mmol)
in methylene chloride (150 mL). The mixture was shaken at room
temperature for 18 h and then filtered. The resin was washed with
methylene chloride, THF, THF/1n HCl (1:1), THF, methanol, methylene
chloride, and cyclohexane (2 Â each), and dried to constant weight in vacuo
to yield the yellow resin 22a (6.15 g). IR (KBr): nÄ ˆ 3269 (NH), 1677
Polystyrene-bound p-iodophenylhydrazide (11): N,N-Diisopropylcarbodi-
imide (42 mL, 0.27 mmol), 1-hydroxybenzotriazole (41 mg, 0.27 mmol),
triethylamine (38 mL, 0.27 mmol), and p-iodophenylhydrazine (10, 63 mg,
0.27 mmol) were added to a suspension of resin 9[3, 10] (500 mg, 0.09 mmol)
in methylene chloride (10 mL) and the mixture was shaken at room
temperature for 18 h, and then filtered. The resin was washed with
methylene chloride, THF, THF/1n HCl (1:1), THF, methanol, methylene
chloride, and cyclohexane (2 Â each), and dried to constant weight in vacuo
to yield the yellow resin 11 (502 mg). IR (KBr): nÄ ˆ 3290 (NH), 1661
À1
ˆ
(C O), 1351 (NO2) cm
.
Polystyrene-bound 2-cyano-4-nitrophenylhydrazide (22b): N,N-Diisopro-
pylcarbodiimide (2.55 mL, 16.5 mmol), 1-hydroxybenzotriazole (2.52 g,
16.5 mmol), triethylamine (2.31 mL, 16.5 mmol), and 2-cyano-4-nitrophe-
nylhydrazine (21b, 2.93 g, 16.5 mmol) were added to a suspension of resin
9[3, 10] (5 g, 5.5 mmol) in methylene chloride (150 mL). The mixture was
shaken at room temperature for 18 h and then filtered. The resin was
washed with methylene chloride, THF, THF/1n HCl (1:1), THF, methanol,
methylene chloride, and cyclohexane (2 Â each), and dried to constant
weight in vacuo to yield the yellow resin 22b (6.15 g). IR (KBr): nÄ ˆ 3269
À1
ˆ
(C O) cm
.
Polystyrene-bound biphenylaldehyde (13): To a suspension of 11 (400 mg,
0.08 mmol) in dioxane (1.5 mL) and water (0.25 mL), were added p-
formylphenylboronic acid 12 (88 mg, 0.6 mmol), potassium carbonate
(182 mg, 1.3 mmol), and N,N-diisopropyl-N-ethylamine and the mixture
was degassed by ultrasonication. Palladium(ii) acetate (4 mg, 16 mmol) was
added and the mixture was heated to 958C for 24 h, and then filtered. The
resin was washed with DMF, water, ethanol, ethyl acetate and methylene
chloride (3 Â each), and dried to constant weight in vacuo to yield the black
resin 13 (502 mg). IR (SiO2): nÄ ˆ 3307 (NH), 2851 (CHO), 1680
À1
ˆ
(NH), 1677 (C O), 1351 (NO2) cm
.
Polystyrene-bound Fmoc-protected p-aminophenylhydrazide (23a): Fmoc-
Cl (11.55 g, 46 mmol) was added to a suspension of 22a (5 g, 4.6 mmol) in
methylene chloride/pyridine (10:1, 200 mL). The mixture was shaken for
15 h at room temperature and then filtered. The resin was washed with
methylene chloride, THF, methanol, methylene chloride, and cyclohexane
(two  each), and dried to constant weight in vacuo to yield a yellow resin
ˆ
ˆ
(6.85 g). IR (KBr): nÄ ˆ 3308 (NH), 1759 (C O), 1668 (C O), 1350
À1
ˆ
(NO2) cmÀ1 Fmoc-loading: 0.57 mmolgÀ1 (84% starting from amino
.
(C O) cm
.
polystyrene). A suspension of the resin prepared above (6 g, 3.42 mmol)
in 2m SnCl2 Â 2H2O in DMF (130 mL) was shaken for 18 h at room
temperature and then filtered. The resin was washed with DMF, THF,
THF/water (1:1), THF, methanol, methylene chloride, and cyclohexane
Polystyrene-bound tetracyclic thiomorpholine (16): To a suspension of
polymer-bound biphenylaldehyde 13 (300 mg, 0.06 mmol) in methylene
chloride (5 mL) and acetic acid (0.5 mL), were added sodium sulfate
(85 mg, 0.6 mmol), sodium triacetoxyborohydride (127 mg, 0.6 mmol), and
4-thiomorpholinomethyl aniline 14[8] (188 mg, 0.9 mmol). The mixture was
ultrasonicated for 2 h, and then filtered. The resin was washed with DMF,
isopropanol, water, DMF, methanol, and methylene chloride (3 Â each),
(2 Â each), and dried to constant weight in vacuo to yield the off-white
À1
ˆ
ˆ
resin 23a (5.79 g). IR (KBr): nÄ ˆ 3355 (NH), 1752 (C O), 1671 (C O) cm
.
Fmoc-loading: 0.56 mmolgÀ1 (83% starting from amino polystyrene).
and dried to constant weight in vacuo to yield the black resin 16 (303 mg).
Polystyrene-bound Fmoc-protected 2-cyano-4-aminophenylhydrazide
(23b): Fmoc-Cl (11.3 g, 45 mmol) was added to a suspension of 22b (5 g,
4.5 mmol) in methylene chloride/pyridine (10:1, 200 mL). The mixture was
shaken for 15 h at room temperature and then filtered. The resin was
washed with methylene chloride, THF, methanol, methylene chloride, and
cyclohexane (two  each), and dried to constant weight in vacuo to yield
À1
ˆ
IR (SiO2): nÄ ˆ 3255 (NH), 1669 (C O) cm
.
4'-Biphenylmethyl-(4-thiomorpholin-4-ylmethyl-phenyl)amine (18): Ac-
cording to Method B for the oxidative cleavage of the hydrazide linker,
resin 16 (179 mg, 21 mmol) was treated with [Cu(OAc)2] and pyridine in
methanol followed by extractive workup to yield a yellowish oil (2.9 mg,
8 mmol, 37%), HPLC: 97% pure (260 nm). Rf ˆ 0.12 (cyclohexane/ethyl
acetate 10:1); 1H NMR (CDCl3, 250 MHz): d ˆ 7.63 7.54 (m, 4H, arom.
CH), 7.47 7.39 (m, 5H, arom. CH), 7.12 (d, 3J(H,H) ˆ 9.1 Hz, 2H, arom.
CH), 6.63 (d, 3J(H,H) ˆ 9.1 Hz, 2H, arom. CH), 4.38 (s, 2H, Ph-Ph-CH2-
ˆ
the yellow resin 23b (6.80 g). IR (KBr): nÄ ˆ 3314 (NH), 1741 (C O), 1672
(C O), 1351 (NO2) cmÀ1. Fmoc-loading: 0.55 mmolgÀ1 (82% starting from
ˆ
amino polystyrene). A suspension of the resin prepared as described above
(6 g, 3.3 mmol) in a 2m solution of SnCl2 ¥ 2H2O in DMF (130 mL) was
Chem. Eur. J. 2003, 9, 3282 3291
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3287

A. Giannis, H. Waldmann et al.
FULL PAPER
shaken for 18 h at room temperature and then filtered. The resin was
washed with DMF, THF, THF/water (1:1), THF, methanol, methylene
chloride, and cyclohexane (2 Â each), and dried to constant weight in vacuo
to yield the off-white resin 23b (5.68 g). IR (KBr): nÄ ˆ 3303 (NH), 1759
yield the aminothiazole 31/4 (6.2 mg, 17 mmol, 19% overall yield, i.e., 84%
per step); HPLC: 99% pure (260 nm); 1H NMR (CDCl3, 400 MHz): d ˆ
7.92 7.21 (m, 14H, arom. CH); GC-MS (70 eV, EI): m/z (%): 353 (100)
‡
[M] , 276 (3), 250 (2), 210 (10), 178 (26), 165 (25), 121 (6), 104 (7).
(C O), 1670 (C O) cmÀ1. Fmoc-loading: 0.54 mmolgÀ1 (81% starting from
amino polystyrene).
ˆ
ˆ
2-Aminothiazole 31/5: According to Procedure B, 23b (170 mg, 92 mmol)
was treated with Fmoc-NCS (26, 132 mg, 0.47 mmol) in methylene
chloride/pyridine (100:1, 5 mL). The Fmoc groups were removed, and the
resin was treated with 2-bromo-2',5'-dimethoxyacetophenone in dioxane
(0.1m, 2 Â 3 mL) and oxidatively cleaved with [Cu(OAc)2] in n-propyl-
amine to yield the aminothiazole 31/5 (9.0 mg, 27 mmol, 29% overall yield,
i.e., 87% per step); HPLC: 89% pure (260 nm); 1H NMR (CDCl3,
400 MHz): d ˆ 7.82 (d, 4J(H,H) ˆ 3.2 Hz, 1H, arom. CH), 7.76 (dd,
General procedure for the reductive amination of the polymer-bound
amines 23 (Procedure A): To a suspension of the polymer-bound aniline 23
in THF/HOAc (100:1, 5 mL/100 mg resin) was added aldehyde 24
(10 equiv). The mixture was shaken for 6 h and then filtered. The resin
washed with THF (3 Â ), suspended in THF/HOAc (100:1, 5 mL/100 mg
resin) and NaCNBH3 (10 equiv) was added. The mixture was shaken for
12 h at room temperature and then filtered. The resin was washed with
THF, methanol, methylene chloride, and cyclohexane (2 Â each), and dried
to constant weight in vacuo.
3
3J(H,H) ˆ 8.4, J(H,H) ˆ 3.2 Hz, 2H, arom. CH), 7.41 7.23 (m, 2H, arom.
CH), 6.93 6.82 (m, 3H, arom. CH, thiazole-CH), 3.91, 3.89 (2s, 6H,
‡
2OCH3); GC-MS (70 eV, EI): m/z (%): 337 (100) [M] , 304 (16), 290 (9),
194 (17), 179 (29), 161 (53), 151 (9), 102 (7).
General procedure for the preparation 2-aminothiazoles 31 (Procedure B):
Fmoc-NCS 26[25b] (5 equiv) was added to a suspension of the polymer-
bound aniline 23 or 25 in methylene chloride/pyridine (100:1, 3 mL/100 mg
resin). The mixture was shaken for 15 h at room temperature and then
filtered. The resin was washed with methylene chloride, THF, methanol,
methylene chloride, and cyclohexane (2 Â each), and dried to constant
weight in vacuo. The resin was shaken with DMF/piperidine (4:1, 3 mL per
100 mg resin, 2 Â 5 min) at room temperature, and then filtered. It was then
was washed with DMF, THF, methanol, methylene chloride, and cyclo-
hexane (2 Â each), and dried to constant weight in vacuo. This polymer-
bound thiourea was treated twice with a solution of 2-bromocarbonyl
compound in dioxane (0.1m, 3 mL per 100 mg resin) for 3 h at room
temperature, and then filtered. The resin was washed with dioxane, THF,
methanol, methylene chloride, and cyclohexane (2 Â each), and dried to
constant weight in vacuo. The oxidative cleavage of the hydrazide linker
was achieved according to Method A with [Cu(OAc)2] in n-propylamine
followed by work-up with SPE.
2-Aminothiazole 31/6: According to Procedure A, 23a (120 mg, 68 mmol)
was treated with furane-2-carbaldehyde (65 mg, 0.68 mmol) and NaCNBH3
(43 mg, 0.68 mmol). According to Procedure B, this resin was treated with
Fmoc-NCS (26, 96 mg, 0.34 mmol) in methylene chloride/pyridine (100:1,
5 mL). The Fmoc groups were removed, and the resin was treated with
2-bromo-2',5'-dimethoxyacetophenone in dioxane (0.1m, 2 Â 3 mL) and
oxidatively cleaved with [Cu(OAc)2] in n-propylamine to yield the
aminothiazole 31/6 (6.4 mg, 16 mmol, 28% overall yield, i.e., 88% per
step); HPLC: 99% pure (260 nm); 1H NMR (CDCl3, 400 MHz): d ˆ 7.91
(d, 4J(H,H) ˆ 3.2 Hz, 1H, arom. CH), 7.42 7.24 (m, 8H, arom. CH), 7.24 (s,
1H, thiazole-CH), 6.90 (d, 3J(H,H) ˆ 9.0 Hz, 1H, arom. CH), 6.82 (dd,
3J(H,H) ˆ 9.0, 4J(H,H) ˆ 3.2 Hz, 1H, arom. CH), 5.21 (s, 2H, benzyl-CH2),
‡
3.89, 3.86 (2s, 6H, 2OCH3); GC-MS (70 eV, EI): m/z (%): 392 (100) [M] ,
361 (54), 311 (56), 300 (27), 281 (70), 179 (25), 157 (20), 81 (58).
2-Aminothiazole 31/7: According to Procedure A, 23a (120 mg, 68 mmol)
was treated with furane-2-carbaldehyde (65 mg, 0.68 mmol) and NaCNBH3
(43 mg, 0.68 mmol). According to Procedure B, this resin was treated with
Fmoc-NCS (26, 96 mg, 0.34 mmol) in methylene chloride/pyridine (100:1,
5 mL). The Fmoc groups were removed, and the resin was treated with
2-bromo-2-phenyl-acetophenone in dioxane (0.1m, 2 Â 3 mL) and oxida-
tively cleaved with [Cu(OAc)2] in n-propylamine to yield the aminothiazole
31/7 (8.6 mg, 21 mmol, 31% overall yield, i.e., 89% per step); HPLC: 92%
pure (260 nm); 1H NMR (CDCl3, 400 MHz): d ˆ 7.59 7.21 (m, 16H, arom.
CH), 6.40 (d, 3J(H,H) ˆ 3.2 Hz, 1H, arom. CH), 6.32 (dd, 3J(H,H) ˆ 3.3,
4J(H,H) ˆ 1.8 Hz, 1H, arom. CH), 5.29 (s, 2H, benzyl-CH2); GC-MS
2-Aminothiazole 31/1: According to Procedure B, 23a (168 mg, 94 mmol)
was treated with Fmoc-NCS (26, 132 mg, 0.47 mmol) in methylene
chloride/pyridine (100:1, 5 mL). The Fmoc groups were removed, and the
resin was treated with 2-bromo-4'-chloroacetophenone in dioxane (0.1m,
2 Â 3 mL) and oxidatively cleaved with [Cu(OAc)2] in n-propylamine to
yield the aminothiazole 31/1 (18.6 mg, 65 mmol, 69% overall yield, i.e.,
96% per step); HPLC: 96% pure (260 nm); 1H NMR (CDCl3, 400 MHz):
d ˆ 7.79 (d, 3J(H,H) ˆ 8.8 Hz, 2H, arom. CH), 7.44 7.35 (m, 6H, arom.
3
CH), 7.11 (t, J(H,H) ˆ 6.8 Hz, 1H, arom. CH), 6.81 (s, 1H, thiazole-CH);
‡
‡
GC-MS (70 eV, EI): m/z (%): 286 (100) [M] , 168 (19), 150 (16), 133 (14),
(70 eV, EI): m/z (%): 408 (72) [M] , 327 (100), 316 (14), 210 (80), 165 (17),
125 (13), 104 (8), 89 (12), 77 (9).
81 (18).
2-Aminothiazole 31/2: According to Procedure B, 23a (168 mg, 94 mmol)
was treated with Fmoc-NCS (26, 132 mg, 0.47 mmol) in methylene
chloride/pyridine (100:1, 5 mL). The Fmoc-groups were removed, and the
resin was treated with 2-bromo-2',5'-dimethoxyacetophenone in dioxane
(0.1m, 2 Â 3 mL) and oxidatively cleaved with [Cu(OAc)2] in n-propyl-
amine to yield the aminothiazole 31/2 (14.4 mg, 46 mmol, 49% overall yield,
i.e., 92% per step); HPLC: 99% pure (260 nm); 1H NMR (CDCl3,
400 MHz): d ˆ 7.76 (d, 4J(H,H) ˆ 3.1 Hz, 1H, arom. CH), 7.44 7.24 (m, 4H,
arom. CH), 7.08 (t, 3J(H,H) ˆ 7.0 Hz, 1H, arom. CH), 6.93 6.82 (m, 3H,
arom. CH, thiazole-CH), 3.92, 3.85 (2s, 6H, 2OCH3); GC-MS (70 eV, EI):
2-Aminothiazole 31/8: According to Procedure A, 23a (120 mg, 68 mmol)
was treated with 4-bromobenzaldehyde (126 mg, 0.68 mmol) and
NaCNBH3 (43 mg, 0.68 mmol). According to Procedure B, this resin was
treated with Fmoc-NCS (26, 96 mg, 0.34 mmol) in methylene chloride/
pyridine (100:1, 5 mL). The Fmoc groups were removed, and the resin was
treated with 2-bromo-4'-chloroacetophenone in dioxane (0.1m, 2 Â 3 mL)
and oxidatively cleaved with [Cu(OAc)2] in n-propylamine to yield the
aminothiazole 31/8 (11.8 mg, 26 mmol, 38% overall yield, i.e., 91% per
step); HPLC: 99% pure (260 nm); 1H NMR (CDCl3, 400 MHz): d ˆ 7.79
(d, 3J(H,H) ˆ 8.8 Hz, 2H, arom. CH), 7.44 7.24 (m, 11H, arom. CH), 6.68
(s, 1H, thiazole-CH), 5.24 (s, 2H, benzyl-CH2); GC-MS (70 eV, EI): m/z
‡
m/z (%): 312 (100) [M] , 281 (16), 265 (15), 194 (18), 179 (26), 161 (37), 149
(14), 136 (11), 77 (13).
‡
(%): 456 (70) [M] , 364 (11), 285 (100), 245 (45), 168 (63), 90 (23), 77 (18).
2-Aminothiazole 31/3: According to Procedure B, 23a (168 mg, 94 mmol)
was treated with Fmoc-NCS (26, 132 mg, 0.47 mmol) in methylene
chloride/pyridine (100:1, 5 mL). The Fmoc-groups were removed, the
resin was treated with 2-bromo-2'-phenyl-acetophenone in dioxane (0.1m,
2 Â 3 mL) and oxidatively cleaved with [Cu(OAc)2] in n-propylamine to
yield the aminothiazole 31/3 (10.5 mg, 32 mmol, 34% overall yield, i.e.,
89% per step); HPLC: 86% pure (260 nm); 1H NMR (CDCl3, 400 MHz):
d ˆ 7.36 7.25, 7.54 7.51 (2m, 15H, arom. CH); GC-MS (70 eV, EI): m/z
2-Aminothiazole 31/9: According to Procedure A, 23a (120 mg, 68 mmol)
was treated with cyclohexanecarbaldehyde (76 mg, 0.68 mmol) and
NaCNBH3 (43 mg, 0.68 mmol). According to Procedure B, this resin was
treated with Fmoc-NCS (26, 96 mg, 0.34 mmol) in methylene chloride/
pyridine (100:1, 5 mL). The Fmoc groups were removed, and the resin was
treated with 2-bromo-4'-chloroacetophenone in dioxane (0.1m, 2 Â 3 mL)
and oxidatively cleaved with [Cu(OAc)2] in n-propylamine to yield the
aminothiazole 31/9 (7.5 mg, 20 mmol, 29% overall yield, i.e., 92% per step);
HPLC: 92% pure (260 nm); 1H NMR (CDCl3, 400 MHz): d ˆ 7.78 (d,
3J(H,H) ˆ 8.8 Hz, 2H, arom. CH), 7.55 7.22 (m, 7H, arom. CH), 6.69 (s,
1H, thiazole-CH), 3.92 (b, 2H, cyclohexyl-CH2), 1.84 1.12 (m, 11H,
‡
(%): 328 (100) [M] , 251 (6), 210 (10), 178 (17), 165 (4), 150 (17), 121 (6),
104 (8), 77 (8).
2-Aminothiazole 31/4: According to Procedure B, 23b (170 mg, 92 mmol)
was treated with Fmoc-NCS (26, 132 mg, 0.47 mmol) in methylene
chloride/pyridine (100:1, 5 mL). The Fmoc groups were removed, and the
resin was treated with 2-bromo-2'-phenyl-acetophenone in dioxane (0.1m,
2 Â 3 mL) and oxidatively cleaved with [Cu(OAc)2] in n-propylamine to
‡
cyclohexane-CH); GC-MS (70 eV, EI): m/z (%): 384 (15) [M ‡ H] , 382
(35), 285 (21), 250 (10), 168 (25), 97 (100), 77 (9).
2-Aminothiazole 31/10: According to Procedure A, 23a (120 mg, 68 mmol)
was treated with furane-2-carbaldehyde (65 mg, 0.68 mmol) and NaCNBH3
3288
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 3282 3291

Tyrosine Kinase Inhibitors
3282 3291
(43 mg, 0.68 mmol). According to Procedure B, this resin was treated with
Fmoc-NCS (26, 96 mg, 0.34 mmol) in methylene chloride/pyridine (100:1,
5 mL). The Fmoc groups were removed, and the resin was treated with
2-bromo-4'-chloroacetophenone in dioxane (0.1m, 2 Â 3 mL) and oxida-
tively cleaved with [Cu(OAc)2] in n-propylamine to yield the aminothiazole
31/10 (10.5 mg, 29 mmol, 42% overall yield, i.e., 92% per step); HPLC:
99% pure (260 nm); 1H NMR (CDCl3, 400 MHz): d ˆ 7.78 7.12 (m, 10H,
arom. CH), 6.67 (s, 1H, thiazole-CH), 6.32 6.19 (m, 2H, arom. CH), 5.20
pyridine (100:1, 5 mL). The Fmoc groups were removed, and the resin was
treated with 2-bromo-2-phenyl-acetophenone in dioxane (0.1m, 2 Â 3 mL)
and oxidatively cleaved with [Cu(OAc)2] in n-propylamine to yield the
aminothiazole 31/15 (5.5 mg, 13 mmol, 19% overall yield, i.e., 85% per
step); HPLC: 98% pure (260 nm); 1H NMR (CDCl3, 400 MHz): d ˆ 7.58
7.18 (m, 15H, arom. CH), 3.99 (br., 2H, cyclohexyl-CH2), 1.85 1.09 (m,
‡
11H, cyclohexane-CH); GC-MS (70 eV, EI): m/z (%): 424 (35) [M] , 341
(19), 328 (100), 251 (12), 210 (20), 178 (14), 165 (12), 91 (12).
‡
(s, 2H, benzyl-CH2); GC-MS (70 eV, EI): m/z (%): 366 (70) [M] , 337 (9),
2-Aminothiazole 31/16: According to Procedure A, 23a (120 mg, 68 mmol)
was treated with 3,4-dimethoxybenzaldehyde (113 mg, 0.68 mmol) and
NaCNBH3 (43 mg, 0.68 mmol). According to Procedure B, this resin was
treated with Fmoc-NCS (26, 96 mg, 0.34 mmol) in methylene chloride/
pyridine (100:1, 5 mL). The Fmoc groups were removed, and the resin was
treated with 2-bromo-4'-chloroacetophenone in dioxane (0.1m, 2 Â 3 mL)
and oxidatively cleaved with [Cu(OAc)2] in n-propylamine to yield the
aminothiazole 31/16 (7.1 mg, 16 mmol, 24% overall yield, i.e., 87% per
step); HPLC: 99% pure (260 nm); 1H NMR (CDCl3, 400 MHz): d ˆ 7.82
(d, 3J(H,H) ˆ 8.5 Hz, 2H, arom. CH), 7.50 6.76 (m, 10H, arom. CH), 6.68
(s, 1H, thiazole-CH), 5.19 (s, 2H, benzyl-CH2), 3.88, 3.87 (2s, 6H, 2OCH3);
285 (38), 274 (10), 250 (17), 168 (35), 157 (17), 81 (100).
2-Aminothiazole 31/11: According to Procedure A, 23a (120 mg, 68 mmol)
was treated with cyclohexanecarbaldehyde (76 mg, 0.68 mmol) and
NaCNBH3 (43 mg, 0.68 mmol). According to Procedure B, this resin was
treated with Fmoc-NCS (26, 96 mg, 0.34 mmol) in methylene chloride/
pyridine (100:1, 5 mL). The Fmoc groups were removed, and the resin was
treated with 2-bromo-2',5'-dimethoxyacetophenone in dioxane (0.1m, 2 Â
3 mL) and oxidatively cleaved with [Cu(OAc)2] in n-propylamine to yield
the aminothiazole 31/11 (5.6 mg, 14 mmol, 20% overall yield, i.e., 85% per
step); HPLC: 86% pure (260 nm); 1H NMR (CDCl3, 400 MHz): d ˆ 7.85
(d, 4J(H,H) ˆ 3.0 Hz, 1H, arom. CH), 7.49 7.29 (m, 5H, arom. CH), 7.14 (s,
1H, thiazole-CH), 6.90 (d, 3J(H,H) ˆ 8.8 Hz, 1H, arom. CH), 6.82 (dd,
3J(H,H) ˆ 8.8, 4J(H,H) ˆ 3.0 Hz, 1H, arom. CH), 3.97 (b, 2H, C6H11-CH2),
3.89, 3.85 (2s, 6H, 2OCH3), 1.80 1.07 (m, 11H, cyclohexyl-CH); GC-MS
‡
GC-MS (70 eV, EI): m/z (%): 436 (9) [M] , 285 (3), 168 (6), 151 (100), 107
(6).
2-Aminothiazole 31/17: According to Procedure A, 23a (120 mg, 68 mmol)
was treated with 3,4-dimethoxybenzaldehyde (113 mg, 0.68 mmol) and
NaCNBH3 (43 mg, 0.68 mmol). According to Procedure B, this resin was
treated with Fmoc-NCS (26, 96 mg, 0.34 mmol) in methylene chloride/
pyridine (100:1, 5 mL). The Fmoc groups were removed, and the resin was
treated with 2-bromo-2-phenyl-acetophenone in dioxane (0.1m, 2 Â 3 mL)
and oxidatively cleaved with [Cu(OAc)2] in n-propylamine to yield the
aminothiazole 31/17 (11.4 mg, 24 mmol, 35% overall yield, i.e., 90% per
step); HPLC: 86% pure (260 nm); 1H NMR (CDCl3, 400 MHz): d ˆ 7.58
(dd, 3J(H,H) ˆ 7.0, 4J(H,H) ˆ 2.0 Hz, 2H, arom. CH), 7.39 7.20 (m, 11H,
arom. CH), 7.00 (d, 4J(H,H) ˆ 2.0 Hz, 1H, arom. CH), 6.90 (dd, 3J(H,H) ˆ
8.4, 4J(H,H) ˆ 1.9 Hz, 2H, arom. CH), 6.78 (d, 3J(H,H) ˆ 8.0 Hz, 2H, arom.
CH), 5.25 (s, 2H, benzyl-CH2), 3.86, 3.79 (2s, 6H, 2OCH3); GC-MS (70 eV,
‡
(70 eV, EI): m/z (%): 408 (44) [M] , 377 (13), 325 (23), 312 (100), 249 (19),
235 (16), 162 (12), 91 (18).
2-Aminothiazole 31/12: According to Procedure A, 23a (120 mg, 68 mmol)
was treated with thiophene-2-carbaldehyde (76 mg, 0.68 mmol) and
NaCNBH3 (43 mg, 0.68 mmol). According to Procedure B, this resin was
treated with Fmoc-NCS (26, 96 mg, 0.34 mmol) in methylene chloride/
pyridine (100:1, 5 mL). The Fmoc groups were removed, and the resin was
treated with 2-bromo-2-phenyl-acetophenone in dioxane (0.1m, 2 Â 3 mL)
and oxidatively cleaved with [Cu(OAc)2] in n-propylamine to yield the
aminothiazole 31/12 (8.7 mg, 20 mmol, 30% overall yield, i.e., 89% per
step); HPLC: 87% pure (260 nm); 1H NMR (CDCl3, 400 MHz): d ˆ 7.63
(dd, 3J(H,H) ˆ 8.0, 4J(H,H) ˆ 1.8 Hz, 1H, arom. CH), 7.45 7.20 (m, 15H,
arom. CH), 7.03 (d, 3J(H,H) ˆ 3.0 Hz, 1H, arom. CH), 6.93 (dd, 3J(H,H) ˆ
5, 4J(H,H) ˆ 3.5 Hz, 1H, arom. CH), 5.46 (s, 2H, benzyl-CH2); GC-MS
‡
EI): m/z (%): 478 (19) [M] , 368 (11), 327 (9), 227 (9), 210 (18), 151 (100),
107(5).
2-Aminothiazole 31/18: According to Procedure A, 23a (120 mg, 68 mmol)
was treated with 4-bromobenzaldehyde (126 mg, 0.68 mmol) and
NaCNBH3 (43 mg, 0.68 mmol). According to Procedure B, this resin was
treated with Fmoc-NCS (26, 96 mg, 0.34 mmol) in methylene chloride/
pyridine (100:1, 5 mL). The Fmoc groups were removed, and the resin was
treated with 2-bromo-2',5'-dimethoxyacetophenone in dioxane (0.1m, 2 Â
3 mL) and oxidatively cleaved with [Cu(OAc)2] in n-propylamine to yield
the aminothiazole 31/18 (6.5 mg, 13.5 mmol, 20% overall yield, i.e., 85%
per step); HPLC: 82% pure (260 nm); 1H NMR (CDCl3, 400 MHz): d ˆ
‡
(70 eV, EI): m/z (%): 424 (53) [M] , 327 (100), 210 (73), 173 (19), 165 (15),
97 (27).
2-Aminothiazole 31/13: According to Procedure A, 23a (120 mg, 68 mmol)
was treated with thiophene-2-carbaldehyde (76 mg, 0.68 mmol) and
NaCNBH3 (43 mg, 0.68 mmol). According to Procedure B, this resin was
treated with Fmoc-NCS (26, 96 mg, 0.34 mmol) in methylene chloride/
pyridine (100:1, 5 mL). The Fmoc groups were removed, and the resin was
treated with 2-bromo-2',5'-dimethoxyacetophenone in dioxane (0.1m, 2 Â
3 mL) and oxidatively cleaved with [Cu(OAc)2] in n-propylamine to yield
the aminothiazole 31/13 (13.1 mg, 32 mmol, 47% overall yield, i.e., 93% per
4
7.73 (d, J(H,H) ˆ 3.0 Hz, 1H, arom. CH), 7.44 7.24 (m, 9H, arom. CH),
3
7.16 (s, 1H, thiazole-CH), 6.90 (d, J(H,H) ˆ 9.0 Hz, 1H, arom. CH), 6.83
1
3
4
step); HPLC: 81% pure (260 nm); H NMR (CDCl3, 400 MHz): d ˆ 8.02
(dd, J(H,H) ˆ 9.0, J(H,H) ˆ 3.0 Hz, 1H, arom. CH), 5.32 (s, 2H, benzyl-
(d, 3J(H,H) ˆ 3.3 Hz, 1H, arom. CH), 7.43 7.12 (m, 7H, arom. CH), 6.97
6.80 (m, 4H, arom. CH, thiazole-CH), 5.37 (s, 2H, benzyl-CH2), 3.89, 3.86
CH2), 3.89, 3.83 (2s, 6H, 2OCH3); GC-MS (70 eV, EI): m/z (%): 482 (100),
‡
480 (93) [M ‡ H] , 449 (14), 390 (19), 311 (100), 281 (95), 194 (26), 171 (40),
‡
(2s, 6H, 2OCH3); GC-MS (70 eV, EI): m/z (%): 408 (100) [M] , 377 (44),
90 (25), 77 (17).
316 (69), 296 (24), 281 (78), 194 (17), 179 (28), 173 (43), 97 (99), 77 (14).
2-Aminothiazole 31/19: According to Procedure Aπ 23a (120 mg, 68 mmol)
was treated with 4-mercaptobenzaldehyde (103 mg, 0.68 mmol) and
NaCNBH3 (43 mg, 0.68 mmol). According to Procedure B, this resin was
treated with Fmoc-NCS (26, 96 mg, 0.34 mmol) in methylene chloride/
pyridine (100:1, 5 mL). The Fmoc groups were removed, and the resin was
treated with 2-bromo-2',5'-dimethoxyacetophenone in dioxane (0.1m, 2 Â
3 mL) and oxidatively cleaved with [Cu(OAc)2] in n-propylamine to yield
the aminothiazole 31/19 (10.1 mg, 22 mmol, 33% overall yield, i.e., 90% per
step); HPLC: 85% pure (260 nm); 1H NMR (CDCl3, 400 MHz): d ˆ 7.81
2-Aminothiazole 31/14: According to Procedure A, 23a (120 mg, 68 mmol)
was treated with 4-mercaptobenzaldehyde (103 mg, 0.68 mmol) and
NaCNBH3 (43 mg, 0.68 mmol). According to Procedure B, this resin was
treated with Fmoc-NCS (26, 96 mg, 0.34 mmol) in methylene chloride/
pyridine (100:1, 5 mL). The Fmoc groups were removed, and the resin was
treated with 2-bromo-4'-chloroacetophenone in dioxane (0.1m, 2 Â 3 mL)
and oxidatively cleaved with [Cu(OAc)2] in n-propylamine to yield the
aminothiazole 31/14 (10.1 mg, 24 mmol, 35% overall yield, i.e., 90% per
step); HPLC: 84% pure (260 nm); 1H NMR (CDCl3, 400 MHz): d ˆ 7.83
(d, 3J(H,H) ˆ 8.8 Hz, 2H, arom. CH), 7.44 7.24 (m, 9H, arom. CH), 7.18 (d,
3J(H,H) ˆ 8.6 Hz, 2H, arom. CH), 6.61 (s, 1H, thiazole-CH), 5.46 (s, 2H,
benzyl-CH2), 2.46 (s, 3H, SCH3); GC-MS (70 eV, EI): m/z (%): 424 (6)
4
(d, J(H,H) ˆ 3.3 Hz, 1H, arom. CH), 7.35 7.12 (m, 8H, arom. CH), 6.85
(d, 3J(H,H) ˆ 8.8 Hz, 1H, arom. CH), 6.76 (dd, 3J(H,H) ˆ 8.8, 4J(H,H) ˆ
3.3 Hz, 1H, arom. CH), 6.38 (s, 1H, thiazole-CH), 5.19 (s, 2H, benzyl-CH2),
3.85, 3.79 (2s, 6H, 2OCH3), 2.42 (s, 3H, SCH3); GC-MS (70 eV, EI): m/z
‡
‡
‡
[M] , 422 (13) [M ‡ H] , 285 (5), 250 (4), 213 (5), 168 (9), 137 (100), 122
(%): 448 (30) [M] , 417 (11), 356 (10), 309 (13), 281 (15), 213 (15), 137
(13), 77 (5).
(100), 122 (13).
2-Aminothiazole 31/15: According to Procedure A, 23a (120 mg, 68 mmol)
was treated with cyclohexanecarbaldehyde (76 mg, 0.68 mmol) and
NaCNBH3 (43 mg, 0.68 mmol). According to Procedure B, this resin was
treated with Fmoc-NCS (26, 96 mg, 0.34 mmol) in methylene chloride/
2-Aminothiazole 31/20: According to Procedure A, 23a (120 mg, 68 mmol)
was treated with 4-mercaptobenzaldehyde (103 mg, 0.68 mmol) and
NaCNBH3 (43 mg, 0.68 mmol). According to Procedure B, this resin was
treated with Fmoc-NCS (26, 96 mg, 0.34 mmol) in methylene chloride/
Chem. Eur. J. 2003, 9, 3282 3291
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3289

A. Giannis, H. Waldmann et al.
FULL PAPER
pyridine (100:1, 5 mL). The Fmoc groups were removed, and the resin was
treated with 2-bromo-2-phenyl-acetophenone in dioxane (0.1m, 2 Â 3 mL)
and oxidatively cleaved with [Cu(OAc)2] in n-propylamine to yield the
aminothiazole 31/20 (11.0 mg, 24 mmol, 35% overall yield, i.e., 90% per
step); HPLC: 81% pure (260 nm); 1H NMR (CDCl3, 400 MHz): d ˆ 7.60
7.18 (m, 19H, arom. CH), 5.38 (s, 2H, benzyl-CH2), 2.47 (s, 3H, SCH3); GC-
R. S. L. Chang, V. J. Lotti, D. J. Cerino, T. B. Chen, P. J. Kling, K. A.
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2395 2398.
‡
MS (70 eV, EI): m/z (%): 464 (35) [M] , 372 (17), 327 (25), 210 (38), 165
(10), 137 (100), 122 (12).
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2-aminothiazole 31/21: According to Procedure A, 23a (120 mg, 68 mmol)
was treated with 4-bromobenzaldehyde (126 mg, 0.68 mmol) and
NaCNBH3 (43 mg, 0.68 mmol). According to Procedure B, this resin was
treated with Fmoc-NCS (26, 96 mg, 0.34 mmol) in methylene chloride/
pyridine (100:1, 5 mL). The Fmoc groups were removed, and the resin was
treated with 2-bromo-2-phenyl-acetophenone in dioxane (0.1m, 2 Â 3 mL)
and oxidatively cleaved with [Cu(OAc)2] in n-propylamine to yield the
aminothiazole 31/21 (9.5 mg, 19 mmol, 28% overall yield, i.e., 88% per
step); HPLC: 93% pure (260 nm); 1H NMR (CDCl3, 400 MHz): d ˆ 7.47
(dd, 3J(H,H) ˆ 8.2, 4J(H,H) ˆ 1.8 Hz, 2H, arom. CH), 7.36 7.14 (m, 17H,
arom. CH), 5.16 (s, 2H, benzyl-CH2); GC-MS (70 eV, EI): m/z (%): 498
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Pompei, Bioorg. Med. Chem. Lett. 1998, 8, 1493 1498.
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‡
(39) [M] , 496 (38), 404 (24), 327 (97), 210 (100), 178 (15), 165 (21), 90 (11),
77 (10).
2-aminothiazole 31/23: According to Procedure A, 23a (120 mg, 68 mmol)
was treated with 3,4-dimethoxybenzaldehyde (113 mg, 0.68 mmol) and
NaCNBH3 (43 mg, 0.68 mmol). According to Procedure B, this resin was
treated with Fmoc-NCS (26, 96 mg, 0.34 mmol) in methylene chloride/
pyridine (100:1, 5 mL). The Fmoc groups were removed, and the resin was
treated with 2-bromo-2',5'-dimethoxyacetophenone in dioxane (0.1m, 2 Â
3 mL) and oxidatively cleaved with [Cu(OAc)2] in n-propylamine to yield
the aminothiazole 31/22 (13.2 mg, 29 mmol, 42% overall yield, i.e., 92% per
step); HPLC: 82% pure (260 nm); 1H NMR (CDCl3, 400 MHz): d ˆ 7.91
4
(d, J(H,H) ˆ 3.2 Hz, 2H, arom. CH), 7.50 6.76 (m, 9H, arom. CH), 6.68
(s, 1H, thiazole-CH), 5.19 (s, 2H, benzyl-CH2), 3.88, 3.87, 3.85, 3.77 (4s,
‡
12H, 4 OCH3); GC-MS (70 eV, EI): m/z (%): 462 (17) [M] , 370 (16), 281
(7), 227 (9), 151 (100), 107 (6).
2-Aminothiazole 31/23: According to Procedure A, 23a (120 mg, 68 mmol)
was treated with thiophene-2-carbaldehyde (76 mg, 0.68 mmol) and
NaCNBH3 (43 mg, 0.68 mmol). According to Procedure B, this resin was
treated with Fmoc-NCS (26, 96 mg, 0.34 mmol) in methylene chloride/
pyridine (100:1, 5 mL). The Fmoc groups were removed, and the resin was
treated with 2-bromo-4'-chloroacetophenone in dioxane (0.1m, 2 Â 3 mL)
and oxidatively cleaved with [Cu(OAc)2] in n-propylamine to yield the
aminothiazole 31/23 (8.1 mg, 21 mmol, 31% overall yield, 89% per step);
HPLC: 84% pure (260 nm); 1H NMR (CDCl3, 400 MHz): d ˆ 7.87 (d,
3J(H,H) ˆ 8.6 Hz, 2H, arom. CH), 7.45 7.20 (m, 8H, arom. CH), 7.00 (d,
3J(H,H) ˆ 3.1 Hz, 1H, arom. CH), 7.92 (dd, 3J(H,H) ˆ 3.1, 4J(H,H) ˆ
1.8 Hz, 1H, arom. CH), 6.68 (s, 1H, thiazole-CH), 5.44 (s, 2H, benzyl-
¬
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‡
‡
CH2); GC-MS (70 eV, EI): m/z (%): 384 (15) [M] , 382 (35) [M ‡ H] , 285
(21), 250 (10), 168 (25), 97 (100), 77 (9).
¬
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This research was supported by the Bundesministerium f¸r Bildung und
Forschung (BMBF), the BASF AG, and the Fonds der Chemischen
Industrie (Kekule Fellowship for F.S.). R.M. and F.S. are grateful to the
State of Baden-W¸rttemberg for a scholarship from the Landesgraduier-
tenfˆrderung.
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Received: February 5, 2003 [F4821]
Chem. Eur. J. 2003, 9, 3282 3291
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