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Solid-phase organik syntheses - Burdges K.

Burdges K. Solid-phase organik syntheses - John Wiley & Sons, 2000. - 283 p.
ISBN 0-471-22824-9
Download (direct link): phaseorganicsynthesis2000.pdf
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A comparatively large selection of thioureas can be formed from the reaction of amines with isothiocyanates, hence they are attractive starting materials for formation of guanidines. A common solution-phase approach to this reaction involves abstraction of the sulfur via a thiophillic metal salt, like mercuric chloride.10 For solid-phase syntheses, however, formation of insoluble heavy-metal sulfides can have undesirable effects on resin properties and on biological assays that may be performed on the product. A more relevant strategy, with respect to this chapter, is S-alkylation of thioureas and then reaction of the methyl carbamimidothioates formed (e.g.,
5, Scheme 6) with amines. This type of process has been used extensively in solution-phase syntheses.11-14 Two examples are shown in Scheme 6;11 the second is an intramolecular variant, which involves concomitant detrity-lation.15
N S
4N ISIH2 H
1.2. OUTLINE OF SOME SOLUTION-PHASE APPROACHES TO GUANIDINES 5
Scheme 5.
Methanethiol is a by-product of reactions of the type illustrated in Scheme 6. This is unlikely to be produced in amounts that would cause problems in solid-phase syntheses, but alternatives are available that avoid this noxious by-product. For instance, an S^Ar displacement of fluoride
s Mel, MeOH SMe
,X^ph --------------------> MIA/ph
0
N
H
H2N 'N H2N 'N MeCN, reflux
H
5
.0.

N
.Ph
H2N N
63%
DMF-120 c
MeS
JL
TrHN / N+H IVT^N
H
60%
Scheme 6.
6 SOLID-PHASE SYNTHESES OF GUANIDINES
S
B0C"N^N^0C
I H
Scheme 7.
from 2,4-dinitrofluorobenzene gives the activated system 6.16 The latter can be reacted with amines to give guanidines (Scheme 7), though complications occur for deactivated aromatic amines.
Other electrophiles have been used to activate thioureas in one-pot processes to give guanidines directly. These include water-soluble carbodi-imides17,18 and the Mukaiyama reagent 7, as illustrated in Scheme 8.19 The thioureas shown in Schemes 7 and 8 have two electron-withdrawing substituents. Issues relating to the generality of these reactions are not well documented for thioureas having less electron-withdrawing N-substituents.
S
BOaNAN"BC H H
Shown below are some other electrophiles that have been used to form guanidines from amines. The pyrazole derivatives 820 have been used extensively in peptide> syntheses.21 The aminoiminomethanesulfonic acid derivative 922 might be the intermediate formed when thioureas are oxidized and then reacted with amines to form guanidines; certainly 9 is a useful
1* 7CI HN">h
------------- B0CN'J;N'BC
H2N^Ph , DMF h
Scheme 8.
K2C03) MeCN 1
6
1.2. OUTLINE OF SOME SOLUTION-PHASE APPROACHES TO GUANIDINES 7 X
'( :xn
N S03H NTf
BOCX /W ^BOC A Y\ /Y
N N H2N^NH N N
H H H
8 X = H or N02 9 10 Y = BOC or CBZ
guanylating agent. Triflylguanidines 10 as guanidinylating agents are a relatively new innovation.23 This is a potentially useful discovery because the triflylguanidines can be formed in two steps from guanidine hydrochloride.
Guanidines may also be formed by reaction of amines with carbodi-imides. This reaction is limited by the availability of carbodiimides, which are usually formed by several methods,24 including dehydration of ureas with the Edward Burgess reagent 11 (Scheme 9).25-27
Ph

JJ
H H
Et,N+
Tr

x
V OMe 11
Tr
CH2CI2, 25
N=
Ph
N"'NHNf QJL
DMF NN N
H H
Scheme 9.
NH *02=1\02
.*.. + . = ---------->
N N H H
PPh3, THF 0
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