Full Paper
was stirred for an additional 3 h, and then the volatiles were re-
moved under reduced pressure. Analysis of the crude mixture by
31P NMR analysis was used to determine the conversion into the
product. The crude mixture was diluted with CH2Cl2 (30 mL), and
the resulting solution was washed with water (5 × 10 mL), dried
with anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude residue was purified by column chromatogra-
phy [2.5 cm (diameter) × 10 cm (height of silica); CH2Cl2/MeOH/
Et3N, 100:0:0 to CH2Cl2/MeOH/Et3N, 100:1:0.5; see Supporting Infor-
mation for additional details]. The product fraction overlapped with
that of N,N-dimethylmorpholino-urea, which was later removed by
kugelrohr distillation (125 °C, 6–9 Torr, 2 h, product stays, urea is
removed).
ings of carbodiimide-mediated phosphonamidation reactions
that show the order of addition of reagents is crucial to obtain
significant conversion into product. As mentioned above, this
had already been established in 1957 by Burger and Ander-
son[5] and implemented, but not specifically discussed, by Ishi-
bashi and Kitamura in 2009.[11]
Conclusions
Herein, we have presented a comprehensive study of the coup-
ling agent-mediated phosphonamidation reaction by primarily
using the non-hydroxybenzotriazole-based coupling agents
COMU and PyOxim to mediate the coupling of monoesters of
phosphonic acids and amines. The realization that the reaction
required a preactivation period without the amine coupling
partner was of crucial importance, as the amine irreversibly con-
sumes the coupling agent in an unproductive pathway. The
implementation of this preactivation step allowed for successful
phosphonamidate reactions that used other well-established
coupling agents such as DIC, DCC, and HBTU. All major reactive
intermediates that were observed during the preactivation pe-
riod of the COMU-mediated phosphonamidation were synthe-
sized separately to confirm their identity and evaluate their re-
activity. Furthermore, by limiting the formation of pyrophos-
phonates in the preactivation step and assuring a low concen-
tration of the phosphonic acid derivative relative to that of the
coupling agent and Oxyma, we have shown that a higher con-
version into the desired phosphonamides can be achieved. Em-
ploying this strategy, we were able to obtain comparable results
to those obtained by the hydroxybenzatriazole-based coupling
agent PyBOP in the reaction of the phosphonic acid derivative
and several primary amines. A decrease in the conversion into
the phosphonamides was observed with secondary amines,
which was traced back to the aminolysis of the Oxyma-phos-
phonate. No byproducts could be isolated to account for the
low conversion into the product. When the monomethyl ester
of benzylphosphonic acid was used, a similar reduction in the
yield was observed. Analysis of the crude reaction mixture from
the preactivation step showed that the reduced conversion
could be traced back to byproducts that originated from the
preactivation step rather than the aminolysis of the activated
phosphonate, as was observed in the case of secondary amines.
Supporting Information (see footnote on the first page of this
article): Syntheses of relevant compounds and experimental setup.
Acknowledgments
This work was supported by the Research Council of Norway
(KOSK II program, grant number 206970) and the University of
Oslo.
Keywords: Synthetic methods · Phosphonamidation ·
Reaction mechanisms · Reactive intermediates · Phosphorus ·
Amines
[1] a) A. P. Kaplan, P. A. Bartlett, Biochemistry 1991, 30, 8165–8170; b) P. A.
Bartlett, C. K. Marlowe, Biochemistry 1983, 22, 4618–4624; c) N. E. Jacob-
sen, P. A. Bartlett, J. Am. Chem. Soc. 1981, 103, 654–657; d) N. P. Camp,
P. C. D. Hawkins, P. B. Hitchcock, D. Gani, Bioorg. Med. Chem. Lett. 1992,
2, 1047–1052; e) D. A. McLeod, R. I. Brinkworth, J. A. Ashley, K. D. Janda,
P. Wirsching, Bioorg. Med. Chem. Lett. 1991, 1, 653–658; f) B. Lejczak, P.
Kafarski, Top. Heterocycl. Chem. 2009, 20, 31–63; g) V. P. Kukhar, H. R.
Hudson, Aminophosphonic and Aminophosphinic Acids, John Wiley, Chi-
chester, UK, 2000.
[2] From monoalkyl esters of phosphonic acids, see: a) W. P. Malachowski,
J. K. Coward, J. Org. Chem. 1994, 59, 7625–7634; b) R. Hirschmann, K. M.
Yager, C. M. Taylor, J. Witherington, P. A. Sprengeler, B. W. Phillips, W.
Moore, A. B. Smith III, J. Am. Chem. Soc. 1997, 119, 8177–8190; c) B. P.
Morgan, J. M. Scholtz, M. D. Ballinger, I. D. Zipkin, P. A. Bartlett, J. Am.
Chem. Soc. 1991, 113, 297–307; from phosphite, see: d) G. Wang, R. Shen,
Q. Xu, M. Goto, Y. Zhao, L.-B. Han, J. Org. Chem. 2010, 75, 3890–3892; e)
N. M. Neisus, M. Lutz, D. Rentsch, P. Hemberger, S. Gaan, Ind. Eng. Chem.
Res. 2014, 53, 2889–2896; from phosphonic dichloride, see: f) L. Maier,
Phosphorus Sulfur Silicon Relat. Elem. 1990, 47, 465–470; g) M. P. J. Harger,
A. Williams, J. Chem. Soc. Perkin Trans. 1 1986, 9, 1681–1686; h) K. L.
Mlodnosky, H. M. Holmes, V. Q. Lam, C. E. Berkmann, Tetrahedron Lett.
1997, 38, 8803–8806; from dialkyl phosphonate, see: i) P. Fourgeaud, C.
Midrier, J.-P. Vors, J.-N. Volle, J.-L. Pirat, D. Virieux, Tetrahedron 2010, 66,
758–764; j) G. Németh, Z. Greff, A. Sipos, Z. Varga, R. Székely, M. Sebes-
tyén, Z. Jászay, S. Béni, Z. Nemes, J.-L. Pirat, J.-N. Volle, D. Virieux, Á.
Gyuris, K. Kelemenics, É. Áy, J. Minarovits, S. Szathmary, G. Kéri, L. Őrfi, J.
Med. Chem. 2014, 57, 3939–3965.
Experimental Section
COMU-Mediated Phosphonamidation Procedure for Com-
pounds 2, 8, and 12–22: COMU (650 mg, 1.5 mmol) and Oxyma
(72 mg, 0.5 mmol) were placed in a reaction vial with a magnetic
stir bar, and CH2Cl2 (dried, 1 mL) was added. The heterogeneous
mixture was then added dropwise (0.9 mL h–1 by using an auto-
mated syringe pump) to a solution of the monoalkyl ester of benz-
ylphosphonic acid (1 mmol) and Et3N (0.3 mL, 2.15 mmol) in CH2Cl2
(2 mL) with vigorous stirring. The resulting mixture was aged for
an additional 2 h to primarily afford the corresponding Oxyma-
phosphonate with trace amounts of the pyrophosphonates and the
anion of the phosphonic acid derivative. The solution of the amine
(2 mmol) dissolved in CH2Cl2 (0.5 mL) was then added dropwise (by
using an automated syringe pump) over 1 h. The reaction mixture
[3] N. Aurbek, N. M. Herkert, M. Koller, H. Thiermann, F. Worek, Chemico-
Biological Interactions 2010, 187, 215–219.
[4] S. D. Rushing, R. P. Hammer, J. Am. Chem. Soc. 2001, 123, 4861–4862.
[5] A. Burger, J. J. Anderson, J. Am. Chem. Soc. 1957, 79, 3575–3579.
[6] To achieve a successful coupling reaction, the coupling agent and the
acid had to be preactivated before the addition of the amine. Otherwise,
an unreactive guanidinium-type structure would form.
[7] K. Yamauchi, M. Kinoshita, M. Imoto, Bull. Chem. Soc. Jpn. 1972, 45, 2528–
2531.
[8] M. Hariharan, R. J. Motekaitis, A. E. Martell, J. Org. Chem. 1975, 40, 470–
473.
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