Ding & Yan
NOTE
slowly. The solution was stirred at -78 ℃ for 3 h then poured in-
to cold saturated NH4Cl solution. The mixture was extracted with
ether, dried over anhydrous Na2SO4 and concentrated in vaccum.
Purification of this residue by column chromatography (DCM/
MeOH, 50∶1, V/V) allowed the isolation of viscous liquid 6 (0.71 g,
57% yields over two steps). 1H NMR (500 MHz, CDCl3) δ: 8.01 (d,
J=7.5 Hz, 2H), 7.36 (dd, J1=2.5 Hz, J2=8.5 Hz, 2H), 4.38 (q, J=
7.0 Hz, 2H), 4.01—4.06 (m, 2H), 3.22 (d, J=17.5 Hz, 2H), 1.37—
1.41 (m, 6H), 1.29 (t, J=7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ: 166.3, 137.4 (d, J=7.50 Hz), 129.9 (d, J=2.50 Hz), 129.6 (d, J=
6.25 Hz), 129.2 (d, J=3.75 Hz), 61.0, 60.7 (d, J=6.25 Hz), 38.2 (d,
quently, alcohol 7 was transformed via the Mitsunobu
reaction[12] at 0 ℃ to room temperature into phthali-
mide derivative 8. Finally, removal of the phthalimide
protecting group was achieved via treatment with 40%
aqueous methylamine to afford the desired compound 1
with good yield.
Conclusions
In conclusion, this is the first time that the synthetic
sequence to new aminomethylmonoalkylphosphinate
analogs with the total yield 31.3% has been reported,
which was developed from a simple starting material.
At the same time, the key factor concerning the problem
of possible competitive side reactions was discussed.
The reported synthetic strategy in this communication is
explored for a general access to those analogs.
J=86.25 Hz), 16.6 (d, J=6.25 Hz), 14.3, 13.5 (d, J=93.75 Hz); 31
P
NMR (CDCl3) δ: 49.68. HRMS (EI) calcd for C13H19O4P 270.1021,
found 270.1025. (2) Synthesis of compound 7: 100 mL round-bot-
tom flask was charged with 50 mL anhydrous CH2Cl2 and compound
6 (1.0 g, 3.704 mmol) at -78 ℃, Dibal-H (11.1 mL, 11.10 mmol)
was added drop-wise to the above mixture. After stirred for 3 h at
the same temperature, the mixture was quenched by saturated NH4Cl.
The aqueous phase was extracted with ether for 3 h and the organic
layers were combined. Then the organic phase was dried over anhy-
drous Na2SO4 and concentrated. The residue was purified by column
chromatography (DCM/MeOH, 40∶1, V/V) and gave the alcohol 7
in 100% yield (0.84 g); 1H NMR (500 MHz, CDCl3) δ: 7.32 (d, J=
8.0 Hz, 2H), 7.24 (dd, J1=2.0 Hz, J2=8.0 Hz, 2H), 4.66 (s, 2H),
3.99—4.05 (m, 2H), 3.13 (dd, J1=3.0 Hz, J2=18.0 Hz, 2H), 2.77
(br, 1H), 1.35 (d, J=14.0 Hz, 3H), 1.30 (t, J=7.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ: 140.1 (d, J=3.8 Hz), 131.0 (d, J=7.5
Hz), 129.7 (d, J=5.0 Hz), 127.4 (d, J=2.5 Hz), 64.6, 60.6 (d, J=
6.25 Hz), 37.5 (d, J=87.5 Hz), 16.6 (d, J=6.25 Hz), 13.2 (d, J=
93.75 Hz); 31P NMR (CDCl3) δ: 51.29. HRMS (EI) calcd for
C11H17O3P 228.0915, found 228.0910. (3) Synthesis of compound 8:
DEAD (1.95 g, 11.2 mmol) was added drop-wise via syringe to a
solution of alcohol 7 (0.84 g, 3.68 mmol), phthalimide (1.65 g, 11.2
mmol), and PPh3 (2.93 g, 11.2 mmol) in THF at 0 ℃. The mixture
was allowed to room temperature and stirred for 40 min. Then the
solvent was evaporated and the crude material was purified by col-
umn chromatography (DCM/MeOH, 60∶1, V/V) and afforded the
phthalimide 8 as a viscous liquid (1.20 g, 91%). 1H NMR (500 MHz,
CDCl3) δ: 7.83—7.85 (m, 2H), 7.70—7.72 (m, 2H), 7.38 (d, J=8.0
Hz, 2H), 7.21 (dd, J1=2.0 Hz, J2=8.0 Hz, 2H), 4.82 (s, 2H), 3.98—
4.06 (m, 2H), 3.10 (d, J=17.5 Hz, 2H), 1.34 (d, J=13.5 Hz, 3H),
1.28 (t, J=7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ: 168.0,
135.1 (d, J=3.75 Hz), 134.0, 132.1, 131.7 (d, J=7.5 Hz), 129.9 (d,
J=5.0 Hz), 129.0 (d, J=3.75 Hz), 123.4, 60.5 (d, J=7.5 Hz), 41.2,
37.6 (d, J=87.5 Hz), 16.6 (d, J=6.25 Hz), 13.3 (d, J=93.75 Hz);
31P NMR (CDCl3) δ: 50.70. HRMS (EI) calcd for C19H20NO4P
357.1130, found 357.1138. (4) Synthesis of compound 1:
Phthalimide derivative 8 (0.60 g, 1.68 mmol) was dissolved in 20
mL THF. 5 mL 40% aqueous methylamine was added to the reac-
tion mixture. The solution was heated at 70 ℃ for 2 h and then di-
luted with ethyl acetate. The organic layer was washed with satu-
rated NH4Cl. Then, The organic layer was dried over Na2SO4, fil-
tered and concentrated. The residue was purified by column chro-
matography (DCM/MeOH, 35∶1, V/V) and compound 1 was ob-
References and Notes
[1] (a) Soulier, E.; Clement, J.-C.; Yaouanc, J.-J.; des Abbayes, H. Tet-
rahedron Lett. 1998, 39, 4291; (b) Alexandre, F.-R.; Amador, A.;
Bot, S.; Caillet, C.; Convard, T.; Jakubik, J.; Musiu, C.; Poddesu, B.;
Vargiu, L.; Liuzzi, M.; Roland, A.; Seifer, M.; Standring, D.; Storer,
R.; Dousson, C. B. J. Med. Chem. 2011, 54, 392.
[2] (a) Jackson, P. F.; Tays, K. L.; Maclin, K. M.; Ko, Y.-S.; Li, W.;
Vitharana, D.; Tsukamoto, T.; Stoermer, D.; Lu, X.-C. M.; Wozniak,
K.; Slusher, B. S. J. Med. Chem. 2001, 44, 4170; (b) Karanewsky, D.
S.; Badia, M. C.; Cushman, D. W.; DeForrest, J. M.; Dejneka, T.;
Loots, M. J.; Perri, M. G.; Petrillo, E. W., Jr.; Powell, J. R. J. Med.
Chem. 1988, 31, 204; (c) Vayron, P.; Renard, P.-Y.; Valleix, A.;
Mioskowski, C. Chem.-Eur. J. 2000, 6, 1050.
[3] For some examples: (a) Cui, J.; Marankan, F.; Fu, W.-T.; Crich, D.;
Mesecar, A.; Johnson, M. E. Bioorg. Med. Chem. 2002, 10, 41; (b)
Grembecka, J.; Mucha, A.; Cierpicki, T.; Kafarski, P. J. Med. Chem.
2003, 46, 2641; (c) Baudy, R. B.; Fletcher III, H.; Yardley, J. P.;
Zaleska, M. M.; Bramlett, D. R.; Tasse, R. P.; Kowal, D. M.; Katz,
A. H.; Moyer, J. A.; Abou-Gharbia, M. J. Med. Chem. 2001, 44,
1516; (d) Kinney, W. A.; Lee, N. E.; Garrison, D. T.; Podlesny Jr., E.
J.; Simmonds, J. T.; Bramlett, D.; Notvest, R. R.; Kowal, D. M.;
Tasse, R. P. J. Med. Chem. 1992, 35, 4720; (e) Verbruggen, C.;
Craecker, S. D.; Rajan, P.; Jiao, X.-Y.; Borloo, M.; Smith, K.; Fair-
lamb, A. H.; Haemers, A. Bioorg. Med. Chem. Lett. 1996, 6, 253,
[4] Fields, S. C. Tetrahedron 1999, 55, 12237
[5] Markoulides, M. S.; Regan, A. C. Tetrahedron Lett. 2011, 52, 2954
[6] Simov, B. P.; Wuggenig, F.; Lammerhofer, M.; Lindner, W.; Zarbl,
E.; Hammerschmidt, F. Eur. J. Org. Chem. 2002, 1139
[7] Cristau, H. J.; Herve, A.; Virieux, D. Tetrahedron 2004, 60, 877
[8] Snyder, H. R.; Merica, E. P.; Force, C. G.; White, E. G. J. Am. Chem.
Soc. 1958, 80, 4622
[9] Westland, R. D.; McEwen, W. E. J. Am. Chem. Soc. 1952, 74, 6141.
[10] Beard, R. L.; Chandraratna, R. A. US 5556996, 1996 [Chem. Abstr.
1996, 125, 275649].
[11] The procedure for the preparation of compounds 6, 7, 8 and 1.
(1) Synthesis of compound 6: Compound 4 (1.50 g, 5 mmol) and
POCl3 (0.80 g, 5.125 mmol) were heated at 60 ℃ for 3 h, then the
mixture was connected with a receiver flask which was cooled with
dry ice and excess POCl3 was vacuum transferred at r.t. After 40 min,
the receive flask was disconnected and the crude ethyl 4-((chloro-
(ethoxy)phosphoryl)methyl)benzoate (5) was used in the next step
immediately without purification. A solution of the above compound
5 in anhydrous THF was cooled to -78 ℃ and CH3MgBr (1.5
mol/L in THF, freshly made, 3.33 mL, 5 mmol) was then added
1
tained as an oil (278.4 mg, 73%). H NMR (400 MHz, CDCl3) δ:
7.24—7.27 (m, 2H), 7.18—7.20 (m, 2H), 3.95—4.04 (m, 2H), 3.82
(s, 2H), 3.10 (d, J=17.6 Hz, 2H), 2.03 (br, 2H), 1.32 (d, J=13.6 Hz,
3H), 1.26 (t, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 141.5
(d, J=4.0 Hz), 130.6 (d, J=7.0 Hz), 129.8 (d, J=5.0 Hz), 127.7 (d,
J=3.0 Hz), 60.5 (d, J=6.0 Hz), 46.0, 37.6 (d, J=88.0 Hz), 16.7 (d,
J=6.0 Hz), 13.4 (d, J=94.0 Hz); 31P NMR (CDCl3) δ: 53.09.
HRMS (EI) calcd for C11H18NO2P 227.1075, found 227.1069.
[12] Mitsunobu, O.; Wada, M.; Sano, T. J. Am. Chem. Soc. 1972, 94,
679.
(Zhao, X.)
1908
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Chin. J. Chem. 2012, 30, 1906—1908