LETTER
Synthesis of Two New Azabicyclophosphinic Acids
3009
O
This cyclization was also applied to a more constrained
starting material: N-benzyl-N-allyl-propargyl-amine 5.
Under cyclization conditions applied to 1, only traces of
the expected bicycle were observed by LC/MS even after
refluxing several hours in CH2Cl2 or using a higher
boiling solvent such as DCE. Protection of the acidic
hydrogen of the acetylene by a trimethylsilyl group did
not show any effect. Palladium chemistry on 5 led to the
N-benzyl pyrrolidine 6 bearing two exo-methylenes.9 Ap-
plication of the cyclization conditions led to poly-
merization. A less constrained molecule N-benzyl-N-allyl
butylamine 7 was then used in order to afford a 5,6-bicy-
cle structurally closer to TPMPA. As previously de-
scribed, no cyclization was observed in refluxing DCE
(Scheme 2).
NH
F
F
O
a)
F
F
O
F
+
8
100%
F
NH2
b)
43%
c)
N
N
F
O
F
F
100%
O
10
F
F
9
F
d)
51%
O
P
N
e)
O
S
O
S
N
O
N
O
a)
63%
11
12
N
N
N
N
P
P
N
N
traces
5
6
f)
g)
(30%)
HO
a)
O
P
polymerization
HN
13
Scheme 3 Reagents and conditions: a) TEA, CH2Cl2, 0 °C, 1 h; b)
PPh3, DEAD, 3-buten-1-ol, THF, r.t., 12 h; c) Grubb’s catalyst,
CH2Cl2, r.t., 22 h; d) p-TsCl, K2CO3, MeOH–H2O (7:3), r.t. for 3 h
and then 50 °C for 1 h; e) i. AlCl3, Cl2PNi-Pr2, CH2Cl2, –20 °C and
then r.t. 1 h; ii. 11 at –20 °C and then r.t. 16 h; iii. 0.2 M EDTA–sat.
NaHCO3 (1:1), r.t., 5 h; f) HCl 6 N, reflux, 16 h; g) purification over
DOWEX 50WX4 resin.
a)
N
P
N
N
no reaction
7
Scheme 2 Reagents and conditions: a) i. AlCl3, Cl2PNi-Pr2, DCE,
–20 °C and then r.t. 1 h; ii. 5 or 6 or 7 at –20 °C and then reflux for
16 h.
In conclusion, we have showed the synthesis of two new
azabicyclophosphinic acids using (i-Pr)2NPCl2/AlCl3 as
reagents for the formation of the phosphorus cycle as
constrained analogues of TPMPA.
In order to access a 6,5-bicyclic system, butadiene deriv-
ative 11 was synthesized. Propargyl trifluoroacetamide 8
was obtained quantitatively from the condensation of pro-
pargyl amine and methyl trifluoroacetate. Then, under
Mitsunobu conditions, N-propargyl-N-butene trifluoro-
acetamide 9 was obtained in a 43% yield. Ring-closure
was then carried out with the Grubb’s catalyst in order to
access the corresponding butadiene in a quantitative yield.
Due to its lability in subsequent steps, the trifluoroacet-
amide protecting group was exchanged for p-toluene-
sulfonyl amide by treatment of 10 with p-toluenesulfonyl
chloride in presence of potassium carbonate in methanol–
water. Applying cyclization conditions (no reflux was
needed to ensure complete cyclization) led this time to the
expected bicycle. After oxidative work-up, 12 was ob-
tained in 63% isolated yield. Removal of the protecting
group and hydrolysis of the phosphinic amide was
achieved in one step by refluxing in 6 N HCl. Purification
was realized by filtration of the crude mixture over
DOWEX resin10 to afford the free azabicyclophosphinic
acid 1311 as a single compound. No rearrangement with
migration of the double bond onto the bridge was ob-
served under such harsh conditions (Scheme 3).
Acknowledgment
The authors thank Dr. U. Trendelenburg, M. Bernhard, Dr. J.
Mosbacher, Dr. I. Vranesic and N. Reyman for fruitful discussions,
and R. Denay for the NMR experiments.
References
(1) Most recent reviews on GABAC and references herein:
(a) Johnston, G. A. R.; Chebib, M.; Hanrahan, J. R.; Mewett,
K. N. Curr. Drug Targets: CNS Neurol. Disord. 2003, 2,
260. (b) Johnston, G. A. R. Curr. Top. Med. Chem. 2002, 2,
903.
(2) Hanrahan, J. R.; Mewett, K. N.; Chebib, M.; Burden, P. M.;
Johnston, G. A. R. J. Chem. Soc., Perkin Trans. 1 2001,
2389.
(3) Chebib, M.; Vandenberg, R. J.; Johnston, G. A. R. Br. J.
Pharmacol. 1997, 122, 1551.
(4) Chebib, M. Chem. Aust. 2001, 68, 19.
(5) Quin, L. D.; Middlemas, E.; Rao Nandakumar, S.; Miller, R.
W.; McPhail, A. T. J. Am. Chem. Soc. 1982, 104, 1893.
Synlett 2005, No. 19, 3008–3010 © Thieme Stuttgart · New York