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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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B0C'NAN'B0C
H
Scheme 10.
8 SOLID-PHASE SYNTHESES OF GUANIDINES
Finally, alkylation reactions can be used to add substituents to guanidines. These may be performed under quite basic conditions (e.g., NaH/alkyl halide)28,29 or via the Mitsunobu process, as illustrated in Scheme 10.30
1.3. SOLID-PHASE SYNTHESES INVOLVING RESIN-BOUND ELECTROPHILES
1.3.1. Supported Carbodiimides
Supported carbodiimides can be produced via aza-Wittig reactions. The example in Scheme 11 shows the reaction of a benzylic azide with triphenyl-phosphine to give an aminophosphorane.31 This was then coupled with phenylisothiocyanate to give the corresponding carbodiimide.
The sequence shown in Scheme 11 was more effective if the isothiocy-anate was premixed with the azide, rather than added after the phosphine. Aza-Wittig reagents can undergo exchange reactions with carbodiimides;
() HN N-Ph
Q^j, W MS^
H w\,N4 (ii) 95 % TFA
**VR
HpN
Ph
'nYn
NHR
Ph
Me
% purity
96
63
Scheme 11.
1.3. SOLID-PHASE SYNTHESES INVOLVING RESIN-BOUND ELECTROPHILES 9
in the absence of isothiocyanate, this occurs between supported aza-Wittig and supported carbodiimide, giving undesirable symmetric guanidines. This illustrates an important feature in solid-phase syntheses; that is, reactive centers on a support are close enough to perform intermolecular reactions unless the resin loading is kept low. Our group has found that intermolecular reactions are effectively suppressed in one particular reaction when resin loadings of 0.3 mmol/g or less were used. The support used in Scheme 11 was a Rink functionalized pin (Chiron) with an unspecified loading level.
The presence of the aryl spacer groups, derived from the benzylic azide, in Scheme 11 was critical; the reaction failed when short-chain aliphatic linkers were used. We suspect this may be due to unwanted cyclization
PPh*, DEAD
THF, 25
ArNCO
xylene, 23 then 80 X = or S
purity >83% 9 examples
Scheme 12.
10 SOLID-PHASE SYNTHESES OF GUANIDINES
reactions. Moreover, sterically encumbered isothiocyanates and acyl isothiocyanates did not react well in the sequence. Overall, the scope of this process is relatively limited.
Scheme 12 features a similar approach to that shown in Scheme 11, except that the guanidines were designed to undergo Michael addition to give a bicyclic system.32 Mitsunobu reaction of the corresponding nitro cinnamic acid with Wang resin followed by reduction of the N02 functionality (SnCl2) formed the required amino cinnamic acid ester starting material. Formation of the carbodiimide and conversion to the guanidines were monitored by IR (N=C=N, 2135 cm-1). Formation of the guanidines was slower than the Michael addition step, hence the temperature had to be raised in the penultimate step of the sequence.
A carbodiimide-grafted polystyrene resin was reacted with tetramethyl-guanidine to give an interesting biguanide structure (Scheme 13). This was assayed as a catalyst for a transesterification reaction.33 Incidentally, resin-bound guanidines are useful bases for processes involving resin capture.34
NH
Scheme 13.
H
T T
NBu NMe2
1.3.2. Supported Thioureas
Scheme 14 shows a typical example in a series of reactions in which a supported amino acid reacted with fluorenylmethoxycarbonyl isothiocyanate to give a supported (on Rinks amide)35 thiourea.36 Removal of the /'/-protection followed by 5-alkylation gave supported isothioureas. Reaction of these with amines, then cleavage from the resin, afforded substituted guanidines. For 10 examples the purities were between 40 and 92%. An aryl group separates the resin from the guanidine, just as in the sequences shown in Schemes 11 and 12.
1.3. SOLID-PHASE SYNTHESES INVOLVING RESIN-BOUND ELECTROPHILES 11
f^'\r"'N^''NH2 (i) HN DMSO, 70
SMe
H (ii) 95 % TFA(aq)
H2N^Nx 88 % purity

cr
Scheme 14.
Another strategy in which thioureas wereAMinked to a carboxyimidazole resin and then converted to guanidine products is shown in Scheme 15.37 Thus the supported BOC-protected thiourea 12 reacted with aliphatic amines without any activating agent. Aromatic amines, however, required activation, and the Mukaiyama pyridinium 7 was used for this. Conversely, acyl-, aryl-, allyl-, and alkyl-substituted thioureas 13 were linked to the resin as a precursor to other guanidines, many lacking the activating effect of electron-withdrawing groups. The intermediate thioureas were treated with EDC, then with amine, to give the products. The authors of this work state that the method was used extensively to form many different products (>45), but lists of the specific compounds produced were not given.
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