An expeditious one-pot synthesis of diethyl N-Boc-1-aminoalkylphosphonates

Article abstract of DOI:10.1016/S0040-4039(01)02289-4

A general one-pot, purification-free synthesis of diethyl N-Boc-1-aminoalkylphosphonates has been developed. The procedure involves base-catalyzed Michael-type addition of sodium diethyl phosphite to N-Boc imines generated in situ by the action of sodium

Full text of DOI:10.1016/S0040-4039(01)02289-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1079–1080
An expeditious one-pot synthesis of diethyl
N-Boc-1-aminoalkylphosphonates
Anna Klepacz and Andrzej Zwierzak*
:
Institute of Organic Chemistry, Technical University (Politechnika), Zeromskiego 116, 90-924 Lodz, Poland
Received 25 October 2001; revised 21 November 2001; accepted 30 November 2001
Abstract—A general one-pot, purification-free synthesis of diethyl N-Boc-1-aminoalkylphosphonates has been developed. The
procedure involves base-catalyzed Michael-type addition of sodium diethyl phosphite to N-Boc imines generated in situ by the
action of sodium hydride on a-amidoalkyl-p-tolyl sulfones in tetrahydrofuran. © 2002 Elsevier Science Ltd. All rights reserved.
1-Aminoalkylphosphonic and phosphinic acids and the
corresponding phosphono- and phosphinopeptides can
interfere in biological mechanisms inducing enzyme
inhibitor properties.1 Consequently, their synthesis has
recently received an increasing amount of attention.2–5
Phosphonamidate peptides are most often prepared
from monoalkyl or monoaryl N-protected amino-
alkylphosphonochloridates by coupling them with an
appropriate amino acid ester or suitably protected pep-
tide.6 N-Protected diethyl 1-aminoalkylphosphonates
can also be considered as possible alternative substrates
for the synthesis of phosphonamidate peptides.
In the course of our studies on potential applications of
a-amidoalkyl-p-tolyl sulfones 2 as N-Boc imine 3
equivalents, we found that sodium hydride can be
employed for base-induced elimination of p-toluene-
sulfinic acid from 2. Trapping of N-Boc imines 3 thus
formed by Michael-type addition of sodium diethyl
phosphite affords diethyl N-Boc-1-aminoalkylphospho-
nates 4 in high yields and excellent purity (Scheme 1).
Two possible alternative mechanisms to account for the
formation of 4 are: (a) an elimination of p-toluenesulfi-
nic acid giving N-Boc imine 3, which is then trapped by
Ts
Boc-NH2, TsNa, MeOH / H2O
R CHO
HCO2H, 48h, R.T.
R
NH Boc
1
2
NaH, (EtO)2P(O)H, R.T., 2h
Boc
−
(EtO)
P ONa
+
2
R
N
68-93%
[
]
3
=
(EtO) P O
2
NH4Claq., 100C
R = H, alkyl, aryl
NH
R
Boc
4
Scheme 1.
Keywords: a-amidoalkyl-p-tolyl sulfones; N-Boc imines; diethyl phosphite.
* Corresponding author. Fax: (48-42)636-55-30.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02289-4

1080
A. Klepacz, A. Zwierzak / Tetrahedron Letters 43 (2002) 1079–1080
Table 1. a-Amidoalkyl-p-tolyl sulfones 2 and diethyl N-Boc 1-aminoalkylphosphonates 4a
Entry
R
2 Yield (%)b
2 Mp (°C)
4 Yield (%)b
4 Mp (°C)c
a
b
c
d
e
f
g
h
i
H
Me
Et
Pr
i-Pr
Bu
i-Bu
Ph
55d
76
74
74
76
82
82.5
65
116–118
104–106
114–116
120–122
127–129
110–111
122–124
182–184 (dec.)
174–176 (dec.)
68
90
83
82
78
77
82
87
93
Oil
54–56 (55)
39–41
55–57
52–55 (52–54)
36–38
58–60 (60)
116–118 (116–118)
78–80
p-MeO-C6H4
68
a All compounds were fully characterized by MS, IR and 1H NMR spectroscopy.
b Yields of crude, analytically pure products.
c Mps of crude, analytically pure products. Mps of the same compounds obtained by an independent procedure10 are given in parentheses.
d 30% aqueous solution of formaldehyde (formalin) was used for the preparation of 2a.
sodium diethyl phosphite to form the final product 4;
(b) a direct SN2 sulfinate displacement leading directly
to 4. We have not investigated which of these two
mechanisms is operating. However, the following obser-
vation is relevant. When sulfone 2 was treated with 1
equiv. of sodium diethyl phosphite, the desired product
4 was formed in 25% yield only; the remainder con-
tained 55% of unreacted 2 together with some diethyl
phosphite. This result shows that direct nucleophilic
displacement of a sulfinate anion by means of sodium
diethyl phosphite is highly improbable and, in contrast
to literature suggestions,7 supports the alternative elimi-
nation–addition route via N-Boc imine 3.
Aminophosphinic Acids Chemistry and Biological Activ-
ity; Kukhar, V. P.; Hudson, H. R., Eds. The biological
activity of phosphono- and phosphinopeptides. John
Wiley: Chichester, 2000; pp. 407–443.
2. Sikora, D.; Nonas, T.; Gajda, T. Tetrahedron 2001, 57,
1619–1625.
3. Cristau, H.-J.; Coulombeau, A.; Genevois-Borella, A.;
Pirat, J.-L. Tetrahedron Lett. 2001, 42, 4491–4494.
4. Xu, J.; Fu, N. J. Chem. Soc., Perkin Trans. 1 2001,
1223–1226.
5. Xu, J.; Wei, M. Synth. Commun. 2001, 31, 1489–1497.
6. Kafarski, P.; Lejczak, B. In Aminophosphonic and
Aminophosphinic Acid Chemistry and Biological Activity;
Kukhar, V. P.; Hudson, H. R., Eds. Synthesis of phos-
phono- and phosphinopeptides. John Wiley: Chichester,
2000; pp. 173–205.
The following typical experimental conditions were
used. Sodium hydride (0.24 g, 10 mmol) was suspended
in THF (25 ml). Crude, finely powdered a-amidoalkyl-
p-tolyl sulfone 28 (5 mmol) was added portionwise with
stirring at room temperature over ca. 5 min. A solution
of diethyl phosphite (0.69 g, 5 mmol) in THF (5 ml)
was then added dropwise over ca. 10 min. The reaction
was slightly exothermic. The resulting mixture was
stirred at room temperature for 2 h, cooled to 10°C and
quenched with satd aq. NH4Cl (15 ml). Water (10 ml)
was added, the organic layer was separated and the
aqueous phase extracted with CH2Cl2 (2×20 ml). All
impurities were water soluble and remained in the
aqueous phase. The combined extracts and organic
phase were dried over MgSO4 and evaporated to give
analytically pure 4 (1H NMR, MS). Yields and mps of
2 and 4 are compiled in Table 1.
7. Morton, J.; Rahim, A.; Walker, E. R. H. Tetrahedron
Lett. 1982, 23, 4123–4126.
8. Bernacka, E.; Klepacz, A.; Zwierzak, A. Tetrahedron
Lett. 2001, 42, 5093–5094. Slightly modified experimen-
tal procedure for the preparation of 2: A mixture of
aldehyde 1 (20 mmol), crude t-butyl carbamate9 (2.34
g, 20 mmol), anhydrous sodium p-toluenesulfinate (3.57
g, 20 mmol), water (40 ml), methanol (20 ml) and for-
mic acid (5 ml) was stirred for ca. 15 min until it
became homogeneous and then left for 48 h at room
temperature. The crystalline sulfone 2 was filtered off
with suction, washed with water (30 ml) and dried in
an oven at ca. 70°C. Sulfones 2h and 2i were washed
successively with water (30 ml) and ether (15 ml) and
dried over P2O5. Crude 2 were analytically pure and
their mps were virtually unchanged after crystallization.
All other components of the reaction mixture were
water soluble and could be removed during washing of
crude 2.
The outlined method for the synthesis of diethyl N-Boc
1-aminoalkylphosphonates 4 represents a versatile and
economic approach to these compounds from easily
available starting materials.
9. Loev, B.; Kormendy, M. F. J. Org. Chem. 1963, 28,
3421–3426. Crude carbamate prepared in CH2Cl2 was
ca. 90% pure (1H NMR) and had mp 90–93°C.
10. Gajda, T.; Nonas, T. J. Chem. Soc., Perkin Trans. 1, to
be published shortly.
References
1. Kafarski, P.; Lejczak, B. In Aminophosphonic and