Z. Al-Shuhaib et al. / Tetrahedron Letters 54 (2013) 6716–6718
6717
O
HN
OH
(a)
(b),(c)
OH
HO
OH
HN
N
O
BocN
3
1
2
NHBoc
N
HN
OAc
(d)
(e)
N
6a
;
BocN
BocN
N
4
NHBoc
5
BocN
NHBoc
Boc
Scheme 1. Reagents and conditions: (a) PPh3, phthalimide, THF, DEAD, 82%; (b) NH2NH2ÁH2O, EtOH, reflux, (c) Et3N, 6a rt, 24 h, 56%; (d) Ac2O, py, DMAP, CH2Cl2, 0 °C, 30 min,
72% (e) Pd(OAc)2/PPh3, THF, reflux 3 h, 90%.
the lack of cyclisation might be based on the presence of the bulky
Boc-protecting groups and we thus turned our attention to the Z-
protected analogue 14b (Scheme 2).
guanidine carbon at dC 158.2 and the signals at dH 3.15 (2H, t,
J = 5.8 Hz, CH2N) and 3.94–3.98 (1H, m, CHN) were also observed.
In conclusion we have demonstrated that the Pd-mediated p-al-
Reaction of 14b with Pd(PPh)4 in acetonitrile at reflux led to a
rapid consumption of the starting material as evidenced by TLC,
and the appearance of a new product at a similar Rf to the previ-
ously prepared 5. A small sample was removed from the reaction
mixture and 1H NMR spectroscopy demonstrated the presence of
the bis-protected guanidine 16 as evidenced by an ABX signal at
dH 5.85 (1H, ddd, J = 4.4, 10.4, 17.4 Hz) for the vinylic CH and a
complex multiplet at dH 5.22–5.00 (6H, m) for the benzyl and
vinylic methylene protons. Attempted purification of the reaction
product after work-up failed to yield any material at this Rf and in-
stead a lower running fraction was obtained which was identified
as the mono-Cbz-protected guanidine 17, and which unfortunately
co-eluted with Ph3PO formed as a by-product in the reaction. In or-
der to circumvent this problem we reacted 14b with Pd(OAc)2 and
LiBr in THF in the presence of Et3N under phosphine-free condi-
tions and obtained 17 in 39% yield after chromatography. In an at-
tempt to improve this yield we reacted 14b with a catalytic
amount of Pd(dppe)2 in THF in the presence of Et3N under reflux
for 24 h which gave 17 in 84% yield. (Scheme 2) Diagnostic signals
in the 1H NMR spectrum were at dH 5.70 (1H, ddd, J = 5.4, 10.3,
17.2 Hz) for the vinylic methine proton and at dH 5.19 (1H, d,
J = 10.3 Hz, CH) and 5.21 (1H, d, J = 17.2 Hz, CH) for the vinylic
methylene protons. Long range HMBC correlations between the
lyl cyclisation of bis-Cbz- and bis-Boc-protected guanidines is a
feasible and high yielding process, particularly in the case of five-
membered ring systems. However, problems exist in the labile nat-
ure of the protecting groups and this might be a limiting factor in
their use. Despite this, the reaction has potential applications in syn-
thesis6 and similar reactions of carbamates and ureas7–10 have been
reported with considerable success. We are currently applying our
findings to the synthesis of the novel guanidine-containing natural
product, nitensidine E,11 and will report our findings in due course.
Acknowledgements
Thanks are given to the ESF (I.V.J.), the ERASMUS/SOCRATES
Program (H.B and E.D) and to the Iraqi government (Z.A.S.) for
funding, and also to the EPSRC Mass Spectrometry service at Swan-
sea for analytical data.
A. Supplementary data
Supplementary data associated with this article can be found, in
09.093. These data include MOL files and InChiKeys of the most
important compounds described in this article.
TBSO
(a)
(c)
(b)
HO
TBSO
9
7
8
OH
OAc
OH
OAc
(d)
(e)
(f)
TBSO
TBSO
HO
HN
10
11
12
OAc
OAc
O
OAc
13
(g)
(h)
N
HN
NHR
NR
14a; R = Boc
R = Boc
NHBoc
15
O
NH
R = Cbz
14b; R = Cbz
(i)
H
H
N
N
N
6b
N
CbzN
16
N
Cbz
CbzN
N
CbzN
NHCbz
H
17
Scheme 2. Reagents and conditions: (a) DMF, tBDMSCl/imid., 0 °C to rt, 16–24 h, 100%; (b) THF, n-BuLi, paraformaldehyde, À78 °C to rt, 1 h, 64%; (c) Ni(OAc)2Á4H2O, EtOH, H2,
NaBH4, ethylenediamine, 88%; (d) Ac2O, py, DMAP, CH2Cl2, 0 °C, 30 min, 95%; (e) THF, TBAF, 0 °C to rt 4 h, 84%; (f) PPh3, phthalimide, THF, DIAD; (g) (i) NH2NH2.H2O, EtOH,
reflux, (ii) Et3N, 6a or 6b, rt, 16–24 h, 14a: 90% (from 12); 14b: 47% (from 12); (h) Pd(OAc)2/PPh3, THF, reflux; (i) see text.