An efficient synthesis of α-aryl β-(N-tosyl)amino phosphonate derivatives from α-diazophosphonate

Article abstract of DOI:10.1016/j.tetlet.2003.08.124

The α-diazophosphonate was added to aryl (N-tosyl)imine to give β-aryl β-(N-tosyl)amino α-diazophosphonates, which were further subjected to TsOH-catalyzed diazo decomposition to yield α-aryl β-(N-tosyl)enaminophosphonates through 1,2 aryl migration. The α-aryl β-(N-tosyl)enamino phosphonates were hydrogenated to give α-aryl β-(N-tosyl)amino phosphonates.

Full text of DOI:10.1016/j.tetlet.2003.08.124

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8339–8342
An efficient synthesis of a-aryl b-(N-tosyl)amino phosphonate
derivatives from a-diazophosphonate
Yonghua Zhao, Nan Jiang and Jianbo Wang*
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology,
College of Chemistry, Peking University, Beijing 100871, China
Received 27 March 2003; revised 10 July 2003; accepted 20 August 2003
Abstract—The a-diazophosphonate was added to aryl (N-tosyl)imine to give b-aryl b-(N-tosyl)amino a-diazophosphonates, which
were further subjected to TsOH-catalyzed diazo decomposition to yield a-aryl b-(N-tosyl)enaminophosphonates through 1,2 aryl
migration. The a-aryl b-(N-tosyl)enamino phosphonates were hydrogenated to give a-aryl b-(N-tosyl)amino phosphonates.
© 2003 Elsevier Ltd. All rights reserved.
a- Or b-amino phosphonic acid derivatives have
attracted considerable attention in recent years because
of their involvement in certain biologically important
processes.1 For example, amino phosphonic acid
derivatives have been served as the transition state
analog in drug design and as haptens in the develop-
ment of catalytic antibody enzymes.2 Consequently, it is
desirable to develop efficient approach to synthesize
racemic or optically active amino phosphonates.1a,3
We have recently reported the based-catalyzed addition
of ethyl diazoacetate to aryl (N-tosyl)imines 1 and the
subsequent 1,2 aryl migration reaction of the resulting
b-(N-tosyl)amino a-diazo carbonyl products under
Rh(II) complex- or TsOH-catalysis condition.4 This
two-step reaction sequence transforms ethyl diazoac-
etate to a-aryl b-(N-tosyl)enamino esters 2, which can
be further hydrogenated to give a-aryl b-(N-
tosyl)amino esters 3 (Scheme 1).5 We conceived that
this highly efficient reaction sequence may be similarly
applied to the corresponding a-diazophosphonate to
give the corresponding b-amino phosphonate deriva-
tives. The results of our investigation are described
herein.
Scheme 1.
The a-diazophosphonate 4 was prepared according to
the literature procedure.6 The DBU-catalyzed addition
of a-diazophosphonate 4 to aryl N-tosylimine 1a–g was
carried out at room temperature and the b-aryl b-(N-
tosyl)amino a-diazophosphonates 5a–g were obtained
in 54–89% isolated yields (Scheme 2).7
* Corresponding author.
Scheme 2.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.124

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Y. Zhao et al. / Tetrahedron Letters 44 (2003) 8339–8342
The similar reaction mechanism for b-phenyl b-(N-
tosyl)amino a-diazoesters4c may be applied to the tran-
sition metal- or acid-catalyzed reaction of 5a (Scheme
4). The diazo compound 5a is first converted to metal
carbene 10 with Rh(II) or Cu(I) catalyst, or was proto-
nated to give 11 in the acid-catalyzed reaction. From 10
or 11, migration of the phenyl group synchronizes with
catalyst dissociation or nitrogen expulsion, respectively,
leading to the formation of 8a or 9a.
The decomposition of the diazo compounds 5a–g was
expected to give 1,2-hydride and 1,2-aryl migration
products. The effect of the catalytic system on the
migratory aptitude was studied in some detail with
transition metal catalysts, Lewis acids and TsOH. The
b-(N-tosyl)amino a-diazo phosphonate 5a was taken as
the substrate and the product distribution are summa-
rized in Scheme 3 and Table 1. In all cases, the diazo
decomposition was highly efficient and 1,2 phenyl
migration predominated. These results are similar to
the corresponding reaction with pheny a-diazo b-(N-
tosyl)amino ester.4,5 However, the E:Z ratio of the 1,2
phenyl migration products varies under different cata-
lytic condition. Most catalysts gave rather low E:Z
ratio, TsOH being the only exception, which gave only
the Z product. It is worthwhile to note that the Z
product is thermodynamically more stable relative to
the E isomer due to the intramolecular hydrogen bond-
ing. It is conceivable that some initially formed E
product isomerizes to the more stable Z isomer under
the TsOH-catalyzed reaction condition.
Since the TsOH-catalyzed reaction gave single product
in excellent yield, this condition was applied to the
other diazo substrates 5b–g.7,8 The results are summa-
rized in Scheme 5 and Table 2. The diazo decomposi-
tion gave the (Z)-a-aryl b-(N-tosyl)enaminophospho-
nates 8a–g in excellent yields. These b-(N-tosyl)-
enamino phosphonates seemed to decompose slowly on
silica gel column; they were rapidly filtrated through
silica gel and were further subjected to hydrogenation
over 10% Pd/C.9 The a-aryl b-(N-tosyl)amino phospho-
nates 12a–f were obtained in high yields, except in one
Scheme 3.
Scheme 4.
Table 1. Product distribution in the decomposition of 5a
using different catalysts
Entry
Catalyst
6a:7a:8a:9aa
Yieldb
1
2
3
4
5
6
7
Rh2(OAc)4
Rh2(O2CCF3)4
Cu(MeCN)4PF6
PhCO2Ag
BF3·Et2O
SnCl2·2H2O
TsOH
12:0:33:55
23:0:34:43
0:0:42:58
3:0:78:19
0:0:63:37
0:0:46:54
0:0:100:0
97
89
88
87
89
89
97
a Product ratio was determined by 1H NMR (300 or 400 MHz).
b Yields after a rapid filtration through silica gel.
Scheme 5.

Y. Zhao et al. / Tetrahedron Letters 44 (2003) 8339–8342
8341
Table 2. Products from TsOH-catalyzed diazo decomposi-
tion of 5a–g and products from hydrogenation of 8a–g
Smith, A. B., III; Taylor, C. M.; Benkovic, P. A.; Taylor,
S. D.; Yager, K. M.; Sprengeler, P. A.; Benkovic, S. J.
Science 1994, 265, 234–237.
Entry
5 (Ar=)
Yield (%), 8a
Yield (%), 12b
3. For recent examples of b-aminophosphonate synthesis,
see: (a) Thomas, A. A.; Sharpless, K. B. J. Org. Chem.
1999, 64, 8379–8385; (b) Pousset, C.; Larcheveque, M.
Tetrahedron Lett. 2002, 43, 5257–5260; (c) Yamagishi, T.;
Suemune, K.; Yokomatsu, T.; Shibuya, S. Tetrahedron
2002, 58, 2577–2583; (d) Wroblewski, A. E.; Piotrowska,
D. G. Tetrahedron: Asymmetry 2002, 13, 2509–2512; (e)
Yamagishi, T.; Kusano, T.; Yokomatsu, T.; Shibuya, S.
Synlett 2002, 1471–1474.
4. (a) Jiang, N.; Qu, Z.; Wang, J. Org. Lett. 2001, 3, 2989–
2992; (b) Jiang, N.; Wang, J. Tetrahedron Lett. 2002, 43,
1285–1287; (c) Jiang, N.; Ma, Z.; Qu, Z.; Xing, X.; Xie, L.;
Wang, J. J. Org. Chem. 2003, 68, 893–900.
1
2
3
4
5
6
7
a, C6H5
b, p-ClC6H4
c, p-FC6H4
d, p-MeOC4H4 82
e, p-PhC6H4 94
f, m-CF3C6H4 96
g, 2-Furyl 80
97
89
89
95
75
94
96
93
81
c
–
a Yields after a rapid filtration through silica gel.
b Yields after silica gel column separation.
c Hydrogenation gave unidentified complex mixture.
5. Jiang, N.; Wang, J. Synlett 2002, 149–151.
6. Seyferth, D.; Marmon, R. S.; Hilbert, P. J. Org. Chem.
1971, 36, 1379–1386.
7. Typical procedure for DBU-catalyzed addition of a-dia-
zophosphonate 4 to aryl N-tosylimine 1a–g. To a solution
of a-diazophosphonate 4 (1.0 mmol) in anhydrous CH3CN
(2 ml), at room temperature under N2, was added succes-
sively a solution of DBU (0.2 mmol) in anhydrous CH3CN
(1 mL) and imine 4 (1.2 mmol) in anhydrous CH3CN (2
mL) via a syringe. After stirring at room temperature for
12 h, the reaction was quenched with saturated aqueous
NaHCO3, and then extracted with CH2Cl2 (15×2 mL). The
solvent was removed by evaporation under reduced pres-
sure, and the crude product was purified by flash chro-
matography to give b-aryl b-(N-tosyl)amino a-diazophos-
phonate 5a–g. The structures of the products were confi-
rmed by IR and 1H NMR (300 or 200 MHz) spectral data.
Dimethyl [1-diazo-2-(N-tosylamino)-2-(p-phenylphenyl)-
ethyl] phosphonate (5e): 1H NMR (300 MHz, CDCl3) l
2.40 (s, 3H), 3.54 (d, 6H, JHP=8.0 Hz, 3H), 3.64 (d,
Scheme 6.
case when the aryl group is 2-furyl, which gave uniden-
tified complex mixture.
Thus, the above three-step reaction sequence can
efficiently transform the a-diazophosphonate to a-aryl
b-(N-tosyl)aminophosphonates. Moreover, the diazo
group in the a-diazo b-(N-tosyl)amino phosphonate
can be subjected to other synthetically useful transfor-
mations. For example, we found that the diazo group
could be oxidized with dimethyl dioxirane to give a-oxo
b-(N-tosyl)amino phosphonate 13, which was
hydrogenolyzed to give a-oxo b-(N-tosyl)amino phos-
phinate 14 in good yield (Scheme 6).
J
HP=7.6 Hz, 3H), 5.23 (dd, J=12.6, 6.9 Hz, 6H), 5.67 (d,
J=6.9 Hz, 1H), 7.25–7.74 (m, 13H). 13C NMR (75 MHz,
CDCl3) l 21.5, 30.9, 53.1, 53.2 (d, JCP=10.4 Hz), 54.7(d,
JCP=5.8 Hz) 126.8, 126.9, 127.2, 127.4, 127.6, 128.8,
129.6, 137.1, 137.2, 140.1, 141.2, 143.6. IR (KBr): w 2098,
1595 cm−1. FAB-MS (m/z, relative intensity) 492 (M+Li)+.
Anal. calcd for C23H24PO5SN3: C, 56.90; H, 4.98; N, 8.66.
Found: C, 56.90; H, 4.90; N, 8.67.
8. General procedure for the TsOH-catalyzed diazo decompo-
sition of 5a–g. To a solution of TsOH (4.6 mg) in anhy-
drous CH2Cl2 (2 mL) at 0°C under N2, was added
dropwise a solution of individual diazo compounds 5a–g
in anhydrous CH2Cl2 (10 mL). The reaction was complete
within 30 min as monitored by TLC. Solvent was removed
by evaporation, and the residue was purified by quick flash
column chromatography over silica gel to give a-aryl
b-enaminophosphonates 8a–g, which were subjected to
subsequent hydrogenation without further purification.
Dimethyl [1-(p-phenylphenyl)-2-(N-tosylamino)ethenyl]-
Acknowledgements
The project is generously supported by Natural Science
Foundation of China (Grant No. 20225205, 20172002),
the Trans-Century Training Programme Foundation
for the Talents by the Ministry of Education of China.
References
1
phosphonate (8e): H NMR (200 MHz, CDCl3) l 2.41 (s,
1. For reviews, see: (a) Kukhar, V. P.; Soloshonok, V. A.;
Solodenko, V. A. Phosphorus, Sulfur and Silicon 1994, 92,
239–264; (b) Collinsova, M.; Jiracek, J. Curr. Med. Chem.
2000, 7, 629–647.
3H), 3.62 (d, JHP=6.2 Hz, 3H), 3.65 (d, J=6.2 Hz, 6H),
7.21–7.80 (m, 14H), 10.51 (d, J=11.6 Hz, 1H). 13C NMR
(75 MHz, CDCl3) l 21.4, 52.3, 52.4, 126.7, 126.9, 127.3,
127.6, 127.8, 128.0, 127.9, 128.7, 129.6, 129.9, 130.0, 137.2,
2. For examples, see: (a) Smith, W. W.; Barlett, P. A. J. Am.
Chem. Soc. 1998, 120, 4622–4628; (b) Hirschmann, R.;
142.0, 142.1, 144.1. IR (film): w 2947, 1611 cm−1
.

8342
Y. Zhao et al. / Tetrahedron Letters 44 (2003) 8339–8342
9. General procedure for the hydrogenation of a-aryl b-enam-
inophosphonates 8a–g. To a solution of a-aryl b-enam-
inophosphonate (0.1 mmol) in absolute MeOH (15 mL)
was added 10% Pd/C catalyst (10 mg). The reaction mix-
ture was stirred for 24 h under 1 atm hydrogen atmo-
sphere. Then catalyst was removed by filtration and
solvent was evaporated to give a residue, which was
purified by flash column chromatography. Dimethyl[1-(p-
phenylphenyl)-2-(N-tosylamino)ethyl]phosphonate (12e):
1H NMR (200 MHz, CDCl3) l 2.34 (s, 3H), 3.43–3.52 (m,
1H), 3.54 (d, JHP=8.4 Hz, 3H), 3.67 (d, JHP=11.4, 1H),
5.28 (t, J=9.0 Hz, 1H), 6.90–7.80 (m, 14H). 13C NMR (50
MHz, CDCl3) l 21.4, 42.8 (d, JCP=45.2 Hz), 45.1, 52.9 (d,
J
CP=7.2 Hz), 53.6 (d, JCP=6.8 Hz), 126.9, 127.5, 127.5,
127.9, 129.4, 129.5, 129.7, 129.9, 136.9, 140.2, 140.7, 143.4;
IR (film): Anal. calcd for
2954, 1607 cm−1
w
.
C23H26NO5PS: C, 60.12; H, 5.70; N, 3.05. Found: C,
60.09; H, 5.62; N, 2.83.