Novel solution- and solid-phase syntheses of heterocyclic systems

Article abstract of DOI:10.2533/000942903777679280

Heterocyclic compounds are an attractive source of screening library structures because they possess varied structural diversity and can exhibit potent biological activity. In this context, we present some of our new and versatile approaches to rapid and efficient syntheses of pharmacologically relevant core structures. These include: combination of both solution- and solid-phase processes in the synthesis of pyrazolo[1,5-a]-[1,3,5]-triazin-4-ones and pyrazolo[1,5-a]-[1,3,5]-triazines; parallel, multi-generation synthesis of highly functionalized heterocyclic compounds in solution; a multi-step synthesis of 2,5-diketopiperazine on solid support taking advantage of a bicyclic β-lactam scaffold, and a combined solid- and solution-phase synthesis of a new class of 2,4-diaminothiazoles.

Full text of DOI:10.2533/000942903777679280

COMBINATORIAL CHEMISTRY
248
CHIMIA 2003, 57, No. 5
Chimia 57 (2003) 248–254
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
Novel Solution- and Solid-Phase
Syntheses of Heterocyclic Systems
Gaelle Cabon, Berangere Gaucher, Aline Gegout, Sophie Heulle, and Thierry Masquelin*
Abstract: Heterocyclic compounds are an attractive source of screening library structures because they
possess varied structural diversity and can exhibit potent biological activity. In this context, we present
some of our new and versatile approaches to rapid and efficient syntheses of pharmacologically relevant core
structures. These include: combination of both solution- and solid-phase processes in the synthesis of
pyrazolo[1,5-a]-[1,3,5]-triazin-4-ones and pyrazolo[1,5-a]-[1,3,5]-triazines; parallel, multi-generation synthesis
of highly functionalized heterocyclic compounds in solution; a multi-step synthesis of 2,5-diketopiperazine
on solid support taking advantage of a bicyclic β-lactam scaffold, and a combined solid- and solution-phase
synthesis of a new class of 2,4-diaminothiazoles.
Keywords: Bicyclic β-lactam · Combined solution- and solid-phase processes · Heterocycles ·
Parallel multi-generation synthesis
1. Introduction
synthesis; (d) affinity binding selection
approach [1–3]. The original idea of com- approaches to rapid and efficient syntheses
We present below some of our new
The dramatic developments in molecular binatorial chemistry randomly synthesizing of pharmacologically relevant core struc-
biology and high-throughput screening a plethora of compounds, often as mixtures, tures; combination of solution- and solid-
over the past 30 years have intensified with the associated belief that solely high phase processes in the synthesis of pyra-
the demand for highly diverse libraries of numbers could speed up the drug develop- zolo[1,5-a]-[1,3,5]-triazin-4-ones and pyra-
low-molecular weight organic molecules. ment process was a dream-like concept for zolo[1,5-a]-[1,3,5]-triazines; parallel multi-
One way to meet this demand is through many chemists. It took several years before generation synthesis of highly functional-
appropriate application of combinatorial scientists realized that it was not only the ized heterocycles in solution; a multi-step
chemistry. The term combinatorial chem- number of compounds but also their quality synthesis of 2,5-diketopiperazine on a
istry implies: generation of a chemical and diversity that was essential for proper solid support taking advantage of a bicyclic
library, a deconvolution strategy, and a progress in medicinal chemistry. The pre- β-lactam scaffold, and finally a combined
linked high-throughput screening system. vailing approach today is based on both solid-and solution-phase synthesis of a new
Four general approaches have been devel- solution- and solid-phase chemistry directed class of 2,4-diaminothiazoles.
oped for the purpose of synthesis and eval- towards the synthesis of discrete, high-
uation of chemical libraries: (a) libraries purity compounds. Combinatorial chem-
derived from biological sources [1–3]; (b) a istry became a standard tool in medicinal 2. Pyrazolo[1,5-a]-[1,3,5]-triazin-
parallel synthetic approach using solution- chemistry. Nowadays, medicinal chemists 4-ones and Pyrazolo[1,5-a]-[1,3,5]-
phase or solid-phase methodologies or a recognize its power in delivering the target- triazines
combination of the two; (c) ‘split and mix’ ed compounds in a much faster way, and
in acceptable quantities and purities.
Pyrazoles and fused pyrazolo-hetero-
Initial-phase combinatorial chemistry cycles are common components of a large
is applied to discover lead compounds number of natural products and pharma-
rapidly, which are then subjected to lead cologically active molecules. Despite in-
validation, followed by lead optimization tense synthetic interest in these heterocyclic
to produce drug candidates. Since hetero- classes, and a number of unique approaches
cyclic products are pharmacologically rich, to satisfy the ever-growing need for new
possess varied structural diversity, and chemical entities with inherent pharmaco-
exhibit potent biological activity, they are logical activity, there is still a need for new
an attractive source of library structures. In general procedures. Thus, in an extension
this context, one major focus of our activi- of our studies towards the synthesis of
ties is the development of new solution- and versatile heterocycles on solid-supports, we
solid-phase access to a diverse array of low- have established a new general access to
molecular weight heterocyclic compounds. pyrazolo[1,5-a]-[1,3,5]-triazin-4-ones and
*Correspondence: Dr. T. Masquelin
Combinatorial & Parallel Chemistry
Basilea Pharmaceutica Ltd
PO Box 3255
B75/052
Grenzacherstrasse 487
CH–4002 Basel
Tel.: +41 61 606 12 79
E-Mail: thierry.masquelin@basileapharma.com

COMBINATORIAL CHEMISTRY
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CHIMIA 2003, 57, No. 5
pyrazolo[1,5-a]-[1,3,5]-triazines of types
At this stage, we first investigated the re- Finally, oxidation of 10 with 1.3 equiv.
8 and 11 (Scheme 1). The production action of the polymer-bound 3H-pyrazo- of N-(phenylsulfonyl)-3-phenyloxaziridine,
of our libraries starts with key polymer- lo[1,5-a]-[1,3,5]-triazin-4-ones 4 with alkyl- followed by cleavage from the support with
bound 3H-pyrazolo[1,5-a]-[1,3,5]-triazin- halides 5 in DMF at 85 °C, in the presence amines 7, allow us to generate 2,4-diamino-
4-one intermediates 4 synthesized as out- of 1-tert-butyl-4,4,4-tris-(dimethylamino)- pyrazolo[1,5-a]-[1,3,5]-triazines of type 11
lined in Scheme 1. Thus, condensation of 2,2-bis-[tris-(dimethylamino)phosphora- in good yields and high purities (Table 2).
pyrazoles 1 with ethoxycarbonyl isoth- nenylideamino]-2λ5,4λ5-catenadi-(phos- The developed strategy appeared ideally
iocyanate 2 in dry acetone at 65 °C, fol- phazene) (phosphazene; 3.2 equiv.), followed suited for the parallel synthesis of a diverse
lowed by treatment with sodium ethanolate by oxidation with 1.3 equiv. of N-(phenyl- array of low-molecular weight heterocyclic
(1N EtONa/EtOH) in EtOH at 65 ºC gave sulfonyl)-3-phenyloxaziridine [9] and sub- compounds on solid-phase.
3H-pyrazolo[1,5-a]-[1,3,5]-triazin-4-ones sequent cleavage with various amines 7
[4], easily attached onto support, using in dioxane at 65 °C, leading to 2-amino-3-
commercially available Merrifield resin substituted-pyrazolo[1,5-a]-[1,3,5]-triazin- 3. Parallel, Multi-generation
3 (1.8 mmol/g) [5–7], in the presence of 4-ones of type 8 in good yields and high Synthesis of Highly Functionalized
N-ethyldiisopropylamine (DIPEA; 3 equiv.) purities (Table 1).
Heterocycles in Solution
in dry N,N-dimethylformamide (DMF) at
Additionally, treatment of the polymer-
65 ºC (the formation of the resin-bound bound 3H-pyrazolo[1,5-a]-[1,3,5]-triazin-
Among the several possible approaches
compounds of type 4 was followed by 4-ones 4 with phosphorous oxychloride to carry out successfully combinatorial or-
ATR/FT-IR [8]). In this context, the solid- (POCl3) in toluene in the presence of ganic synthesis, we also focused our atten-
phase attachment is used to both purify the DIPEA at 110 °C, afforded the corre- tion on multi-component and multi-gener-
diverse 3H-pyrazolo[1,5-a]-[1,3,5]-triazin- sponding 4-chloro intermediates, which ation solution-phase approaches towards
4-ones using a scavenging process, and underwent nucleophilic substitution with five-membered heterocycles and their con-
introduce new points of diversity taking amines 9 to furnish 4-amino polymer- version into fused heterocycles. The success
advantages of the sulfur-based safety catch bound pyrazolo[1,5-a]-[1,3,5]-triazines 10. of every combinatorial chemistry approach
linkage.
Scheme 1. Reagents and conditions: i) EtO2C-
NCS (2), acetone, rt–65 °C; ii) EtONa, EtOH,
rt–65 °C; iii) Merrifield resin (3), DIPEA, DMF,
rt–65 °C; iv) R3-X (5), phosphazene, DMF, rt–
85 °C; v) CHCl3, oxaziridine, rt; vi) R4R5-NH (7),
diox., rt–65 °C; vii) POCl3, DIPEA, tol., 110 °C;
viii) R6-NH2 (9), diox., rt–65 °C

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CHIMIA 2003, 57, No. 5
Table 1. Preparation of pyrazolo[1,5a]-[1,3,5]-triazin-4-ones 8.
is critically dependent on the availability
of the necessary building blocks. As shown
in Scheme 2, we selected ethyl-2-amino
cyano acetate 13, a multifunctional central
building block, easily accessible by the
reduction of ethyl cyano-(hydroxyimino)
acetate 12 [10–12], to generate a palette of
pharmacologically relevant core structures,
such as thiazoles 15, oxazoles 20 and imi-
dazolones 24, with additional elements of
structural diversity.
Yielda/Purityb
[%]
R1
R2
H
R3
H
Products
R4R5N-
O
8a
45/76
N
NH
NH
N
N
N
H
H
8b
8c
53/95
66/82
N
NH
NH
Thus, we describe in Scheme 2 a rapid
entry into a series of polyfunctionalized
thiazoles 15, easily obtained in pure form
by simple precipitation, in good yields and
purities (Table 3) starting from ethyl-2-
amino cyano acetate 13 and isothiocyanates
14. Subsequent condensation with ethoxy-
carbonyl-isothiocyanate 2 and treatment
with sodium ethanolate in EtOH at 75 °C,
led to the corresponding fused heterocycles
of type 16 in pure form after acidification,
precipitation and filtration of the suspen-
sion (Table 3). S-alkylation of 16 with
MeI performed in acetone with Cs2CO3,
followed by chlorination with POCl3 in
toluene in the presence of DIPEAat 110 °C,
afforded the corresponding 4-chloro inter-
mediates, which underwent nucleophilic
substitution with amines 17 to furnish
compounds of type 18 in pure form (Table 4).
At this stage removal of solution-phase
excess reactants, reagents, and byproducts
is accomplished by incubation with CMR/R
resins (Complementary Molecular Reac-
tivity and Recognition resins: [13]) and fil-
tration of the reaction mixture. The CMR/R
library purification strategy is general and
highly amenable to automation.
H
H
8d
8e
84/96
80/97
OH
NH
N
H
H
N
N
N
H
8f
72/99
N
H
H
Br
Br
H
H
8g
8h
67/99
81/92
N
N
N
O
O
N
N
N
H
CO2Et
H
8i
87/94
aYields in % are based on weight of crude material and are relative to the initial loading. bHPLC
Purity of the purified material (confirmed by 1H-NMR), measured on YMC-Pack Pro C18
column (75ϫ4.6 mm) with a gradient 12% AcCN/H2O → 95% AcCN within 5.4 min; flow rate,
2.64 ml/min; UV detection at 200–300 nm.
In order to explore in depth the potential
of our building block 13 to generate highly
functionalized heterocycles libraries, we
studied the reaction of 13 with acyl chlo-
rides of type 19 under standard conditions
and subjected the corresponding amide
to acid-catalyzed cyclization (Scheme 2),
affording amino-oxazoles 20 in good over-
all yields and purities (Table 5). At this
stage, applying the previously described
process: condensation with ethoxycarbonyl-
isothiocyanate 2, and treatment with sodi-
um ethanolate led to the corresponding
fused heterocycles of type 21 (Table 5).
Finally S-alkylation of 21, followed by
chlorination and nucleophilic substitution
yielded compounds of type 22 in pure
form, using the CMR/R library purification
strategy (Table 4).
Table 2. Preparation of pyrazolo[1,5a]-[1,3,5]-triazines 11.
Yielda/Purityb
R1
R2
H
R4R5N-
R6NH-
NH2
Products
[%]
NH
11a
75/96
O
NH
H
11b
11c
80/99.5
77/95
NH2
O
NH
Me-S
CN
NH2
NH2
F
NH
Me-S
Me
CN
H
11d
11e
83/99
67/92
S
NH
NH
N
NH
N
O
Me
H
11f
67/94
O
Additionally to demonstrate the ver-
satility of our building block 13, we con-
densed 13 with isocyanates 23, and submit-
ted the corresponding intermediates to an
acid-catalyzed cyclization, allowing us to
generate imidazolones of type 24. Fused
aYields in % are based on weight of crude material and are relative to the initial loading. bHPLC
Purity of the purified material (confirmed by 1H-NMR), measured on YMC-Pack Pro C18
column (75ϫ4.6 mm) with a gradient 12% AcCN/H2O → 95% AcCN within 5.4 min; flow rate,
2.64 ml/min; UV detection at 200–300 nm.

COMBINATORIAL CHEMISTRY
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CHIMIA 2003, 57, No. 5
Scheme 2. Reagents and conditions: i) Na2S2O4,
H2O, rt; ii) R1-NCS (14) diox.; iii) EtO2C-NCS
(2), acetone, rt–85 °C; iv) EtONa, EtOH, rt–75 °C;
v) Mel, Cs2CO3, acetone, rt; vi) POCl3, DIPEA,
tol., 110 °C; vii) R2-NH2 (17), diox., rt–95 °C;
viii) R3-COCl (19), TEA, CH2Cl2, rt; ix) HCl g,
diox., rt; x) R4-NCO (23), diox., rt–65 °C
with amino acids 30 in DMF to yield the
polymer-bound di-substituted pyrrolidines
31. At this stage, deprotection of the pyrro-
lidine nitrogen carried out using tetrakis-
(triphenylphosphine) palladium (Pd(PPh3)4)
together with a borane dimethylamine
complex (Me2NH*BH3) [17] furnished the
free amine intermediate, which underwent
a base-catalyzed cyclization using tetra-
methyl guanidine (TMG) in DMF at 60 °C
to afford the corresponding polymer-bound
diketopiperazines of type 32. The com-
pounds could be easily cleaved off the resin
under standard conditions to yield the final
products 33 in good yields and high purities
(Table 7).
Additionally a third vector of diversity
was introduced onto 32, by alkylation with
alkyl halides 34 in the presence of phos-
phazene. The resulting diketopiperazines
of type 35 are easily cleaved off the resin.
This strategy allows for a rapid synthesis
of libraries of diketopiperazines on solid-
support and demonstrates the potential of
heterocycles 25 were generated applying atives. Present in the core of many natural the bicyclic β-lactam building block, which
the previously described modifications to products, diketopiperazine contributes inter- can also be used in many different ways for
24 (Table 6). The described parallel solution esting therapeutic properties [14]. Our sol- the construction of pyrrolidine libraries.
multigeneration strategies combined with id-phase strategy is based on the use of the
the CMR/R library purification method bicyclic β-lactam 27 as starting material,
could be fully automated and performed on which allows the introduction of a large va- 5. Combined Solid- and Solution-
a robotic system.
riety of building blocks, and contains dif- phase Synthesis of a New Class of
ferent potential attachment points for solid- 2,4-Diaminothiazoles and Fused
phase. In our approach the scaffold 27 was Heterocycles
4. A Multistep Synthesis of
2,5-Diketopiperazine on Solid-
Support Taking Advantage of a
Bicyclic β-Lactam Scaffold
attached via the alcohol function to a Wang
resin activated as trichloroacetamidate 26
[15][16] to finally obtain the resin-bound molecules has emerged as an important tool
bicyclic β-lactam 28 (Scheme 3). Therefore, in drug discovery. Another example of a
the β-lactam nitrogen was acylated with successful application of solid-phase chem-
Solid-phase synthesis of small organic
Among the broad range of heterocyclic acid-chlorides 29 in DMF in the presence istry constitutes the highly versatile synthe-
scaffolds representing lead structures for of DIPEA (5 equiv.) and dimethylamino- sis of 2,4-diaminothiazoles, which is an
discovery of potential pharmacophores, we pyridine (DMAP; 2 equiv.) allowing the in- important heterocyclic nucleus in medici-
next focused our attention on a new solid- troduction of the first diversity vector, fol- nal chemistry. Our multigeneration strategy
phase synthesis of diketopiperazine deriv- lowed by the opening of the intermediates combines the cyclocondensation reaction

COMBINATORIAL CHEMISTRY
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CHIMIA 2003, 57, No. 5
Table 3. Preparation of 2,5-diaminothiazole 15 and fused heterocycles 16.
of a polymer-bound thiouronium salt 36
with isothiocyanates 37, α-bromoketones
38 using a polymer-supported auto-scav-
enging (PSAS) purification strategy and a
solution-phase intramolecular cyclization.
Thus, when resin-bound thiouronium salt
36, easily prepared by reaction of thiourea
with commercially available Merrifield
resin, was allowed to react with isothio-
cyanates 37 in DMF in the presence of
DIPEA as well as N,N-diethylaminomethyl
polystyrene resin, and followed by conden-
sation with α-bromoketones 38, the corre-
sponding 2,4-diaminothiazoles 39 were
formed in high yields and purities (Scheme 4;
Table 8). At this stage to be able to perform
the desired intramolecular annelation, de-
protection of the Boc group was carried out
efficiently by the use of Amberlyst A-15
resin. With the free amines 40 in hand, the
intramolecular cyclization was performed
with carbonyl diimidazole (CDI) in DMF
in the presence of triethyl amine (Et3N) to
generate the final products 41 in moderate
yields and high purities (Table 8). The syn-
thesis of a small library of fused heterocy-
cles as outlined in Scheme 4 was carried out
successfully.
Yielda/Purityb
[%]
R1-NCS
Products
Yield/Purity [%]
36/96
Products
O
15a
16a
56/99
NCS
NCS
NCS
O
O
15b
63/92
16b
28/99
O
Cl
15c
15d
99/98
85/97
16c
16d
53/99
62/99
Cl
NC
NCS
NCS
15e
15f
84/97
70/97
16e
16f
55/99
66/99
N
NCS
O
S
N
O
Table 4. Preparation of fused heterocycles 18 and 22.
R1 R3 R2-NH2
Yielda/Purityb
[%]
6. Conclusion
Products
NC
In conclusion, we have demonstrated
the capability of combinatorial chemistry
to produce rapidly and efficiently a diverse
array of low-molecular weight heterocycle
compounds using solution- and solid-phase
strategies. The payoff of combinatorial
chemistry to drug discovery is already be-
coming obvious in terms of significant in-
crease in the number of lead candidates and
time savings from lead candidate identifi-
cation to validation.
NH2
18a
44/98.5
NC
18b
22a
22b
52/99
47/93
58/98
N
N
NH2
NH2
NH2
Table 5. Preparation of 5-amino-oxazoles 20 and fused heterocycles 21.
Yielda/Purityb
[%]
R3-COCl
Products
Yield/Purity [%]
76/99
Products
COCl
20a
21a
22/99
38/99
35/99
COCl
20b
20c
51/98
71/80
21b
21c
F
COCl
Cl
For all Tables:
aYields in % are based on weight of crude
material and are relative to the initial loading.
bHPLC Purity of the purified material (con-
firmed by 1H-NMR), measured on YMC-Pack
Pro C18 column (75ϫ4.6 mm) with a gradient
12% AcCN/H2O → 95% AcCN within 5.4 min;
flow rate, 2.64 ml/min; UV detection at 200–
300 nm.
COCl
20d
20e
74/93
36/96
21d
21e
42/99
27/99
O
COCl

COMBINATORIAL CHEMISTRY
253
CHIMIA 2003, 57, No. 5
Table 6. Preparation of imidazolones 24 and fused heterocycles 25.
Table 7. Preparation of diketopiperazines 33 and 35.
Yielda/Purityb
Yielda/Purityb
[%]
R1
R2
H
R3
Products
R4-NCO
Products
Yield/Purity [%]
Products
[%]
NCO
33a
33/99
24a
24b
97/99
21/92
25a
25b
60/99
48/99
33b
33c
33d
40/99.5
NCO
39/83
39/99
aYields in % are based on weight of crude material and are relative
to the initial loading. bHPLC Purity of the purified material (confirmed
by 1H-NMR), measured on YMC-Pack Pro C18 column (75ϫ4.6 mm)
with a gradient 12% AcCN/H2O → 95% AcCN within 5.4 min; flow rate,
2.64 ml/min; UV detection at 200–300 nm.
O
35a
24/99.5
HO
HO
O
O
O
F
35b
35c
25/99
F
25/99.5
F
35c
25/99.5
HO
aYields in % are based on weight of crude material and are relative
to the initial loading. bHPLC Purity of the purified material (confirmed
by 1H-NMR), measured on YMC-Pack Pro C18 column (75ϫ4.6 mm)
with a gradient 12% AcCN/H2O → 95% AcCN within 5.4 min; flow rate,
2.64 ml/min; UV detection at 200–300 nm.
Scheme 3. Reagents and conditions: i) BF3*Et2O,
THF/CH2Cl2, rt–65 °C; ii) R1-COCl (29), DIPEA,
DMAP, DMF, rt; iii) AAs (30), DIPEA, DMF, rt–
50 °C; iv) Pd(PPh3)4, Me2NH*BH3, DMF, rt;
v) TMG, DMF, rt–60 °C; vi) TFA, CH2Cl2, rt;
vii) R3-X (34), phosphazene, DMF, rt–65 °C

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CHIMIA 2003, 57, No. 5
Acknowledgements
The authors would like to thank L. Bury
and A. Gruschwitz for the purification of the
libraries, Roche colleagues for analytical results,
as well as Prof. M. Page, Dr. G. Schmid, and
Dr. M. Roger-Evans for helpful discussions and
proof-reading.
Received: March 25, 2003
[1] J.K. Scott, G.P. Smith, Science 1990, 249,
386.
[2] S.E. Cwirla, E.A. Peters, R.W. Barrett,
W.J. Dower, Proc. Natl. Acad. Sci. U.S.A.
1990, 87, 6378.
[3] J.J. Devlin, L.C. Panganiban, P.E. Devlin,
Science 1990, 249, 404.
[4] Z. Xin, Z. Pei, T. von Geldem, M. Jirousek,
Tetrahedron Lett. 2000, 41, 1147.
[5] A. Chucholowski, T. Masquelin, D. Ob-
recht, J. Stadlwieser, J.M. Villalgordo,
Chimia 1996, 50, 525.
[6] T. Masquelin, D. Sprenger, R. Baer,
F. Gerber, Y. Mercadal, Helv. Chim. Acta
1998, 81, 646.
[7] D. Obrecht, C. Abrecht, F. Grieder,
J.-M. Villalgordo, Helv. Chim. Acta 1997,
80, 65.
[8] P. Griffiths, ‘Chemical Analysis’, John
Wiley & Sons, New York, 1974, Vol. 43.
[9] F.A. Davis, O.D. Stringer, J. Org. Chem.
1982, 47, 1774.
[10] H.-S. Ahn, A. Bercovici, G. Boykow, A.
Bronnenkant, S. Chackalamannil, J. Chow,
R. Cleven, J. Cook, M. Czarniecki, C. Do-
malski, A. Fawzi, M. Green, A. Gundes,
G. Ho, M. Laudicina, N. Lindo, K. Ma,
M. Manna, B. McKittrick, B. Mirzai,
T. Nechuta, B. Neustadt, C. Puchalski,
K. Pula, L. Silverman, E. Smith, A. Stam-
ford, R.P. Tedesco, H. Tsai, D. Tulshian,
H. Vaccaro, R.W. Watkins, X. Weng,
J.T. Witkowski, Y. Xia, H. Zhang, J. Med.
Chem. 1997, 40, 2196.
Scheme 4. Reagents and conditions: i) a: 37, DIPEA, DEAMP-resin, DMF, rt; b: 38, DMF, rt;
ii) Amberlyst A-15, CH2Cl2, rt; iii) CDI, Et3N, DMF
Table 8. Preparation of 2,4-diaminothiazoles 39 and fused heterocycles 41.
Yielda/Purityb
R1
R2
Products
[%]
[11] J.C. Caille, S. Didierlaurent, D. Lefran-
cois, M.H. Lelievre, C. Sury, J. Aszodi,
Synthesis 1995, 6, 635.
39a
94/96
[12] H.R. Snyder, L. Katz, J. Am. Chem. Soc.
1947, 69, 3140.
[13] D.L. Flynn, J.Z. Crich, R.V. Devraj,
S.L. Hockerman, J.J. Parlow, M.S. South,
S. Woodard, J. Am. Chem. Soc. 1997, 119,
4874.
[14] A. Bianco, J. Furrer, D. Limal, G.
Guichard, K. Elbayed, J. Raya, M. Piotto,
J.-P. Briand, J. Comb. Chem. 2000, 2, 681.
[15] S. Hanessian, F. Xie, Tetrahedron. Lett.
1998, 39, 736; S. Hanessian, F. Xie,
Tetrahedron. Lett. 1998, 39, 737.
[16] M. Steger, C. Hubschwerlen, G. Schmid,
Bioorg. Med. Chem. Lett. 2001, 11, 2537.
[17] P. Gomez-Martinez, M. Dessolin, F. Guibé,
F. Albericio, J. Chem. Soc. Perkin Trans. 1
1999, 2871.
39b
39c
39d
41a
98/93
84/97
87/97
70/93
Me
Cl
Me
41b
41c
58/77
Cl
44/99.5
aYields in % are based on weight of crude material and are relative to
the initial loading. bHPLC Purity of the purified material (confirmed by
1H-NMR), measured on YMC-Pack Pro C18 column (75ϫ4.6 mm) with
a gradient 12% AcCN/H2O → 95% AcCN within 5.4 min; flow rate,
2.64 ml/min; UV detection at 200–300 nm.