A. Rahman, N. Stipani cˇ ev, A.P. Keogh et al.
Tetrahedron Letters xxx (xxxx) xxx
guanidine moiety, but not that of the tert-butyl esters of the Boc-
protected aniline. Thus, compounds 18, 19 and 1 were obtained
in very good yields. On the contrary, exchanging a Cbz by a Fmoc
protecting group (Entry 12, Table 2) was not successful.
1 as starting material. Finally, reactions with aromatic amines such
as aniline gave the worse results and regarding reactivity of the
starting material, the bis-Fmoc-protected compound 2 only pro-
duced decomposition.
All these results indicate that single substitution for the guani-
dine protecting groups is achieved when using amines and double
substitution when using alcohols as reactants. It should be consid-
ered that forming the isocyanate intermediate proposed by Miel
and Rault from carbamate-protected amines requires very high
temperatures (i.e. ~300 °C), which can be lowered by using a base
or a catalyst [2]; however, carbamate-protected guanidines are
much more prone to thermolysis and, hence, isocyanate formation
can be achieved at much lower temperatures and without any aux-
iliaries. Although both substitutions proceed through similar
mechanisms (i.e. thermal decomposition of the carbamate to form
the isocyanate, which then reacts with the alcohol or amine), some
rationale may explain the different outcomes.
In the reactions of the same N,N’,N”-protected 4-(4-guani-
dinophenyloxy)anilines with aliphatic and aromatic alcohols di-
substitution of both of the guanidine N-protecting groups occurred
yielding the corresponding N,N’-bis-substituted guanidino deriva-
tives (16–19). By treatment with the appropriate alcohol it was
possible to exchange both Boc-protecting groups in the guanidine
moiety of compound 1 by Cbz (compound 3, 68% yield) and by
Fmoc (compound 2, 10% yield); it was not possible to exchange
any of the classical N-protecting groups in the reactions with the
bis-Fmoc protected derivative 2; both Cbz-protecting groups in
the guanidine moiety of compound 3 were exchanged by Boc
(compound 1, 51% yield) but not by Fmoc when treated with the
appropriate alcohol.
The most evident reason is the fact that successful reactions
with alcohols were carried out using them as solvents; hence, an
excess of the reactive alcohol was present forcing the exchange
in both guanidine protecting groups. Additionally, assuming that
these reactions proceed through a two-step process and consider-
ing a simplified version of the starting compounds, intermediates
and products, we have calculated at the DFT level (details in the
ESI) all tautomers resulting from the intramolecular hydrogen
bonds (IMHBs) that can be formed between the O atoms (-O-
and C@O) of carbamates or the C@O of thioureas and the NAH of
the guanidine moiety (Fig. 2 and S1-S8), in order to assess their
influence on the products obtained. Thus, these reactions involve
first disrupting one of the NAHꢀ ꢀ ꢀO stabilising IMHB networks
The reactions here studied provide a simple method to prepare
amidinoureas from N,N’-protected guanidines and to interchange
some classical N-protecting groups in the guanidine moieties.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
We thank the Irish Research Council for postgraduate support
for AR (GOIPG/2017/956), NS (GOIPG/2018/2336), and AK
(GOIPG/2014/457). Thanks are given to the Irish Centre for High-
End Computing (ICHEC) for providing computational facilities.
(
e.g. red IMHBs in starting compounds I-II (X = O, and III-a, IV-a,
Fig. 2; average HB distance for I/II = 1.83 Å; Fig. S1-S4) to form
the corresponding isocyanates (Fig. 2). This involves loss of stabil-
ity because this disruption encompasses an energy penalty. Next,
upon attack of the corresponding amine or alcohol, the isocyanates
are transformed into the protected (amidino)ureas or carbamates,
where this IMHB network can only be restored in two of the pos-
sible tautomers for the ureas (I and II, X = NH, average IMHB dis-
tance = 1.745 Å; Fig. S5-S6), or in all tautomers for the carbamate
products (I-II (X = O), III-a and IV-a, average IMHB distance = 1.83 Å;
Fig. S1-S4).
Appendix A. Supplementary data
References
For a second substitution to take place, disruption of both IMHB
networks (e.g. red and blue IMHB in products I-IV; Fig. 2) must
occur for the second isocyanate to be formed; however, this may
not be favoured because the IMHB is slightly shorter/stronger
[
[
15] in the urea versus the ester (Fig. S5 vs. Fig. S1). Hence, it would
[
4] F. Manetti, D. Castagnolo, F. Raffi, A.T. Zizzari, S. Rajamaki, S. D’Arezzo, P. Visca,
be harder to break the networks in the urea than those in the ester
to form the second isocyanate. Supporting this reasoning is the fact
1
that the complex/broad signals observed only in the H NMR spec-
tra of the amidinourea products can be due to the presence of the
proposed tautomers, which in these products do not exchange as
fast as in the ester products indicating a slightly stronger IMHB
network.
[
[
[
Summary
Reactions of N,N’,N”-protected 4-(4-guanidinophenyloxy)anili-
nes with aliphatic and aromatic amines produced only mono-sub-
stitution of one of the guanidine N-protecting groups yielding the
corresponding N-substituted N’-protected amidinoureas (8–14).
The anilino Boc-protecting group was never removed in any of
the reactions carried out. Additionally, the yields obtained for the
mono-substitution of one of the Cbz-protecting groups of the
guanidinium system of compound 3 were lower than those
obtained when using the bis-Boc-protected guanidine compound
[
[
10] D. Seebach, B. Weidmann, L. Widler, in Modern Synthetic Methods 1983; R.
[12] A.L. Schacht, G.F. Smith, M.R. Wiley, US Patent 5914319A.
[
[
[
13] H. Val, M. Calas, R. Escale, V. Vidal, F. Bressolle, M.-L. Ancelin, US Patent 2005/
176819A1.
0
5