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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 very similar method has been used by Lin and Ganesan to produce yV-acyl-yV'-carbamoylguanidines.38 The activating agent used by them was mercuric chloride, and the waste heavy metal was removed by filtration at the end of the synthesis. Scheme 16 shows two compounds prepared by this method.
12
SOLID-PHASE SYNTHESES OF GUANIDINES
^ N Ph
N M CO H2N Ph NEt3 II
OcAnAn'boc ---------^h2n nh2
H H
12 (i)PhNH2 if] NEt3
NaNHCSNHg f N+ Cl
(ii) TFA^-\'
N"Ph
Q- HjN^NHj
S
X V
H NHR 1
THF
NaNH"~ '
S (i)R,R'NH NH
/-% A X EDCNMP X
(VxD N NHR -----------------------------R'R'N NHR
H
13 (ii) TFA/CH2CI2
'Pr3SiH
Scheme 15.
o H H H
A .N./N. .N^ u K1
h2n ^ H?N
/N
Scheme 16.
Work by Dodd and Wallace on solid-phase guanidine syntheses is unique insofar as an 5-linked thiourea 14 was used.39 Their approach exploits the previous findings of one of these researchers regarding the efficacy of Ws-BOC-protected guanidines in Mitsunobu reactions (Scheme 10).30 They treated Merrifield resin with excess thiourea to give a supported thiouronium salt, as illustrated in Scheme 17. Both nitrogen atoms of this material were masked, on the solid phase by reactions with (B0C)20 and Hunigs base. Mitsunobu reactions of the supported Ws-BOC-protected isothiourea gave a monoalkylated product. This was then reacted with
1.3. SOLID-PHASE SYNTHESES INVOLVING RESIN-BOUND ELECTROPHILES 13
(j) S
NBOC
H2N NH2 JL
O^CI ---------------> fV^S^NHBOC
' /- ~7f\ on
DMF, 70 ^ 'Pr02CN=NC02'Pr
() (boc)2o PPh3 THF
NBOC |\ . NBOC

Ph ---------------> N N Ph
DMF, 50 c H .QC
Scheme 17.
ammonia or primary alkylamines to give guanidines with concomitant cleavage from the resin. This paper featured 13 examples and a typical experimental procedure was given; it describes what appears to be an excellent solid-phase synthesis of many guanidines.
(i) (COCI)2, DMF /=\ 1,2-dichloroethane /-x /
co2H - CK_>4cs
(ii) Bu4NNCS
NH3, EDC, Et'Pr2N
CHCI3
Scheme 18.
14 SOLID-PHASE SYNTHESES OF GUANIDINES
Wilson and Li have recently used supported acylisothiocyanates to capture amines as thioureas.40 The latter were then activated using a carbodiimide reagent, then reacted with a second amine to form guanidine products. An appealing feature of this approach is that hindered and relatively unreactive anilines can be used in the first step due to the electro-philicity of the acylisothiocyanates (Scheme 18).
1.4. SOLID-PHASE SYNTHESES INVOLVING ELECTROPHILES IN SOLUTION
In general, solid-phase syntheses tend to work better when an excess of a reactive intermediate in solution is allowed to react with a less reactive entity on a solid phase. This approach is not always used, often due to the cost and/or availability of one of the reagents; indeed, all the reactions highlighted in the previous section adopted the opposite strategy. Consequently, it is interesting to compare those reports with one described in this section wherein the reactive reagent was used in solution.
Four supported amines, one primary, one secondary, and two arylamines, were reacted with guanylating agents in solution and on a solid phase in a set of comparative experiments (Scheme 19).41 The supported primary and secondary amines 15 and 16 gave high yields of product (>85%) when
Q-x

0)
NH?
15
S
x
BOCNH NHBOC
DIC, 25 (ii) TFA, CH2CI2
H02C
Y
NH
87 % yield
(1)

N
N'
(i) \
I? BOCN^NHBOC H2C\r ^
OW4! -------------------8-----------------^ I .Ljnh (2)
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