Queffelec et al.
FIGURE 1. Some examples of known 1,3-azaphospho-heterocycles.
SCHEME 1. Synthesis of 2-Aminoethyl-H-phosphinic Acid 9
FIGURE 2. The three precursors used in this study.
tions of protected versions of 8 have appeared,8 because of the
utility of the synthons for phosphinopeptide synthesis.9
A
synthesis of aminomethyl-H-phosphinic acid 8 and some
derivatives is described in Supporting Information.
2-Aminoethyl-H-phosphinic Acid. 2-Aminoethyl-H-phos-
phinic acid 9 was synthesized using our hydrophosphinylation
of N-vinylphthalimide with hypophosphorous acid H3PO2
(Scheme 1).10
Phthalimide reacted with vinyl acetate according to the
literature procedure.11 Palladium-catalyzed hydrophosphinyla-
tion with H3PO2 using our reusable polymer-supported catalyst10
gave phosphinic acid 11 in 60-70% yield. When the homo-
geneous catalyst (0.25 mol % Pd/xantphos) was used, 11 was
obtained in 72-87% yield. Simple acid hydrolysis of phthal-
imide 11 gave hydrochloride 9 as a white solid. Other syntheses
of 2-aminoethyl-H-phosphinic acid 9 and some derivatives have
been reported previously.12 Kafarski reported8c a nice prepara-
tion of 9 via Hoffman degradation (NaOH, Br2, -15 °C, 77%
yield after propylene oxide treatment) of H2PO2CH2CH2-
C(O)NH2 itself prepared by thermal conjugate addition of H3PO2
with acrylamide.13
(7) For example, see: (a) Kukhar, V. P.; Hudson, H. R. Aminophosphonic
and Aminophosphinic Acids; John Wiley & Sons, Inc.: New York, 2000. (b)
Quin, L. D. A Guide to Organophosphorus Chemistry; Wiley: New York, 2000.
(c) Palacios, F.; Alonso, C.; de los Santos, J. M. Chem. ReV. 2005, 105, 899. (d)
Collinsova, M.; Jiracek, J. Curr. Med. Chem. 2000, 7, 629. (e) Fields, S. C.
Tetrahedron 1999, 55, 12237.
3-Aminopropyl-H-phosphinic Acid. We14 and others15 have
reported previously the preparation of the biologically active
GABA analog 3-aminopropyl-H-phosphinic acid and related
compounds. For the present study, we opted for a simple
synthesis using our Pd-catalyzed hydrophosphinylation on ethyl
N-allylcarbamate 12 in place of the more expensive benzyl and
tert-butyl carbamates, since acid hydrolysis would ultimately
be employed to form compound 10. Scheme 2 shows the
preparation of 10 from allylamine. As with N-vinylphthalimide,
this reusable polymer catalyst10 was employed to directly deliver
H-phosphinic acid 13. Hydrolysis then provided hydrochloride
10. If the synthesis of 10 is desired, alternate routes via other
intermediates14 are more expensive, atom-wasteful, and lower-
yielding in the case of 14.14a
(8) (a) Li, S.; Whitehead, J. K.; Hammer, R. P. J. Org. Chem. 2007, 72,
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Overall, compounds 8-10 were synthesized in reasonable
yields and on a multigram scale, using some methodologies we
had developed previously. The syntheses are generally simpler
than comparable literature approaches, and ion-exchange chro-
matography is avoided in all cases. With the compounds in hand,
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