Biomedical Engineering Reference
In-Depth Information
10.3. FLUOROUS DISPLACEABLE LINKERS FOR THE
SYNTHESIS OF HETEROCYCLIC COMPOUNDS
Perfluoroctanesulfonyl benzaldehyde is a convertible linker that has been used in
many multicomponent reaction-based syntheses of heterocyclic scaffolds [27]. Per-
fluoroctanesulfonate is a longer version of triflate and has multiple roles in fluorous
synthesis such as (1) a phenol protecting group, (2) a fluorous tag for F-SPE, and (3) an
activation group for Pd-catalyzed linker cleavage reactions [28-30].
Imidazo[1,2- a ]pyridines and imidazo[1,2- a ]pyrazines are biologically inter-
esting compounds that possess antifungal, antibacterial, cytoprotective, cardiac
stimulating, and benzodiazepine receptor antagonistic properties [31]. The
Groebke-Blackburn-Bienaym ´ (GBB) reaction is a three-component reaction that
is able to efficiently assemble those two heterocyclic systems in one pot [32]. Zhang
and Lu employed fluorous benzaldehyde in the GBB reaction for the synthesis of
3-aminoimidazo[1,2- a ]pyridine and pyrazine libraries (Scheme 10.6) [33].
Four fluorous benzaldehydes 25 , three isonitriles, and five 2-aminopyridines and
2-aminopyrazines were used for an array of 60 reactions to form imidazo[1,2- a ]pyridines
and -pyrazines 26 . The condensation products were purified by F-SPE and some selected
compounds were used for Pd-catalyzed reactions with two boronic acids and two thiols to
form 16 biaryl-substituted products 27 and 16 thio-substituted products 28 .
As a privileged ring system, benzodiazepine and related ring skeletons can be
found in many commercial drugs and drug candidates. Yan and coworkers employed
fluorous benzaldehydes 25 as a key component in the Ugi four-component reaction
(U-4CR) for the synthesis of two 1,4-benzodiazepine-1,5-dione libraries ( 32 and 35 )
(Scheme 10.7).
In the first case, U-4CRs of 25 , amino esters 29 , Boc-anthranilic acids, and
cyclohexyl isonitrile afforded the condensed products 30 [34]. After F-SPEpurification,
Ugi products 30 were used for the acetyl chloride-promoted de-Boc/cyclizations to
form1,4-benzodiazepine-2,5-diones 31 . The cyclization of the amino group selectively
attacked the ester group to form the seven-membered ring. The last step featuring a
Suzuki coupling was conducted under microwave heating to cleave the fluorous linker,
introduce the biaryl functional group, and thus produce the desired compound 32 .Inthe
second case, regular amineswere used to replace amino ester 29 in the U-4CRs to afford
condensed compounds of type 33 [35]. The outcome of the de-Boc/cyclization
X
R 1
R 3
R 2
Sc(OTf) 3
R 1
HN
R 2
N
NH 2
CHO
μ
W (150°C, 10 min)
N
C 8 F 17 O 2 SO
F-SPE
X
N
25
C 8 F 17 O 2 SO
R 3 NC
22-100%
26
R 3
R 3
R 1
HN
R 2
R 1
HN
R 2
R 4 C 6 H 4 B(OH) 2 or R 5 SH
Pd(dppf)Cl 2, K 2 CO 3
N
N
R 4
X
or
R 5
X
N
S
N
μ
W (150-180°C, 5-10 min)
F-SPE
27 (8-91%)
28 (42-93%)
(X = NH or C)
SCHEME 10.6 Synthesis of imidazo[1,2- a ]pyridines and -pyrazines.
 
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