The first synthesis of β-amino phosphonates using cyclic sulfamidates

Article abstract of DOI:10.1016/j.tetlet.2011.04.115

Cyclic sulfamidates (prepared from α-amino acids and β-amino alcohols) have been used for the first time for the synthesis of novel β-amino phosphonates (chiral and achiral) by treatment with dialkyl phosphites using sodium hydride. 2-Substituted and 1,2-disubtituted β-amino phosphonates have efficiently been prepared following this method. The products are formed in high yield (79-84%) within 8-12 h.

Full text of DOI:10.1016/j.tetlet.2011.04.115

Tetrahedron Letters 52 (2011) 3496–3498
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The first synthesis of b-amino phosphonates using cyclic sulfamidates q
⇑
Biswanath Das , Cheruku Ravindra Reddy, Siddavatam Nagendra, Maram Lingaiah
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclic sulfamidates (prepared from a-amino acids and b-amino alcohols) have been used for the first time
Received 3 February 2011
Revised 28 April 2011
Accepted 29 April 2011
Available online 6 May 2011
for the synthesis of novel b-amino phosphonates (chiral and achiral) by treatment with dialkyl phos-
phites using sodium hydride. 2-Substituted and 1,2-disubtituted b-amino phosphonates have efficiently
been prepared following this method. The products are formed in high yield (79–84%) within 8–12 h.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
b-Amino phophonate
Cyclic sulfamidate
Dialkyl phosphite
Chiral and achiral products
b-Amino phosphonic acid and its derivatives possess various
important medicinal properties including anti-bacterial, enzyme
inhibition, and anti-HIV activities.1 Some of these compounds have
been identified as natural products.2 The parent acid was first iso-
lated from Celiata protozoa3 and subsequently the compound along
with its different derivatives was obtained from various other
organisms.4 These compounds have opened a new area of bio-
chemistry.5 The other important use of these compounds is as pes-
ticides.6 They have also been applied in the preparation of valuable
metal complexes.7 Thus the synthesis of b-amino phosphonic acid
derivatives is an attractive target to the organic chemists and some
methods have been developed for the preparation of these com-
pounds.8 However, to our knowledge, b-amino phosphonates have
not yet been prepared using cyclic sulfamidates.
RuCl3ꢀ3H2O to form the corresponding sulfamidates (5).12 The sul-
famidates (5) were prepared from the
a-amino acids, glycine
(Table 1, entries a and b), alanine (entry c), 2-phenyl glycine
(entries d and e), leucine (entries f and g), and phenyl alanine (en-
tries h and i). Two b-amino alcohols, (R)-2-amino-3, 3-dimethyl
butane-1-ol, and (2R, 3R)-methyl-2-amino-3-hydroxybanoate
were also used to prepare the sulfamidates (5) (entry j for the first
and entries k and l for the second) following the similar sequence
of reactions as described above (Scheme 1).
The prepared cyclic sulfamidates (5) were treated with dialkyl
phosphites using NaH in THF under reflux to furnish b-amino phos-
phonates (6) (Scheme 2).
In recent years, cyclic sulfamidates have been used as an impor-
tant precursor for the synthesis of a wide range of bioactive com-
pounds.9 These compounds can easily be prepared in chiral and
achiral forms and can conveniently be cleaved with nucleophiles.
In continuation of our work10 on the construction of phosphonate
derivatives having an amine moiety we have now prepared several
cyclic sulfamidates and utilized them for the synthesis of b-amino
phosphonates. The cyclic sulfamidates were prepared from differ-
H2N
R
OH
R'
H2N
R
OH
O
Boc NH
R
b
d
a
OH
R'
c
3
1
2
O
S
ent
a-amino acids (1) (Scheme 1). The latter were reduced with
11
O
O
NaBH4–I2 to afford the amino alcohol 2 which were converted
into the corresponding Boc-derivatives 3 by treatment with Boc2O
in Et3N. Compounds 3 were subsequently treated with SOCl2 in
Et3N in the presence of imidazole to form the cyclic sulfamidites
(4).12 These sulfamidites (4) were then oxidized with NaIO4 and
S
Boc
Boc
N
N
O
O
R
R
R'
R'
5
4
Scheme 1. Synthesis of cyclic sulfamidates (5) from
a-amino acids (1). Reagents
q
Part 221 in the series ‘Studies on novel synthetic methodologies’.
Corresponding author. Tel./fax: +91 40 27160512.
E-mail address: biswanathdas@yahoo.com (B. Das).
and conditions: (a) NaBH4, I2, THF, 70 °C, 18–22 h 93–97%; (b) (Boc)2O, Et3N, DCM,
2 h, rt; 95–98%; (c) SOCl2, Et3N, Imidazole, DCM, 2 h, 0 °C, rt, 63–69%; (d)
RuCl3ꢀ3H2O, NaIO4, CH3CN, 0 °C, 6 h, 91–96%.
⇑
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.115

B. Das et al. / Tetrahedron Letters 52 (2011) 3496–3498
3497
Table 1
Synthesis of b-amino phosphonates 6a
Entry
a
Sulfamidate (5)
Productb (6)
Time (h)
11
Yieldc (%)
O
O
O
OMe
S
Boc
P
Boc
Boc
Boc
79
80
NH
N
O
OMe
O
O
O
P
OEt
S
Boc
NH
b
c
9.5
9.5
N
O
OEt
O
O
O
OMe
S
Boc NH
P
N
O
82
81
OMe
O
O
P
O
O
OMe
OMe
Boc
NH
S
S
Boc
N
O
O
d
e
9
8
Ph
Ph
O
O
P
OEt
OEt
Boc
NH
Boc
N
84
81
83
Ph
Ph
O
O
O
O
P
OMe
OMe
S
S
Boc
Boc
Boc
Boc NH
N
N
O
f
12
10
O
O
P
OEt
OEt
Boc NH
Boc NH
O
g
O
O
O
OMe
OMe
S
P
N
O
h
11.5
79
Ph
O
N
Ph
O
O
OEt
OEt
S
Boc
Boc
Boc NH
P
O
i
j
8.5
9.0
82
81
Ph
O
N
Ph
O
O
OMe
OMe
S
Boc
NH
P
O
O
O
P
O
OMe
Boc
S
Boc
NH
NH
N
O
k
l
11
80
82
OMe
MeOOC
Boc
MeOOC
Boc
O
O
P
O
OEt
OEt
S
N
O
9.5
MeOOC
MeOOC
a
b
c
Reaction conditions: cyclic sulfamidate (1 mmol), dialkyl phosphites (1.2 mmol), NaH (1.3 mmol), 65 °C.
The structures of the products were established from their spectral (IR, 1H and 13C NMR, ESI–MS) data.
Isolated yields after purification.
Various b-amino phosphonates were prepared from 5 following
aryl, as well as benzyl group at the b- position. The structures of
the products were established from their spectral (IR, 1H, and 13C
NMR and MS) and analytical data.13
In conclusion, we have developed an efficient method for the
synthesis of novel b-amino phosphonates using cyclic sulfamidates
for the first time. The method is suitable to generate the products
the above method (Table 1). The reaction was complete within 8–
12 h and the products were formed in high yield (79–84%). Both
chiral and achiral b-amino phosphonates were efficiently prepared.
The conversion afforded the products equally with dimethyl and
diethyl phosphites. The prepared phosphonates contained alkyl,

3498
B. Das et al. / Tetrahedron Letters 52 (2011) 3496–3498
mixture of EtOAc and water (1:1, 10 mL) was added. The organic layer was
separated and concentrated. The residue was subjected to column
O
O
HP(O)(OR'')3
NaH
THF, 650C
8-12 h
OR''
S
Boc
O
Boc
chromatography (silica gel, hexane–EtOAc) to obtain
phosphonate.
a pure b-amino
N
NH
R
O
P
OR''
The spectral and analytical data of some representative products are given
below:
R
R'
R'
tert-Butyl 2-(methoxyphophono)-ethylcarbamate (6a): IR: 3429, 1689, 1518,
1457, 1369, 1252 cmꢁ1 1H NMR (200 MHz, CDCl3): d 5.05 (1H, br s), 3.74 (6H,
;
79-84 %
d, J = 10.0 Hz), 3.43–3.33 (2H, m), 2.08–1.98 (2H, m), 1.43 (9H, s); 13C NMR
(50 MHz, CDCl3): d 155.2, 79.1, 51.0, (d, J = 6.5 Hz), 45.1, 31.1 (d, J = 140.0 Hz),
28.3; ESI–MS: m/z 254 [M+H]+. Anal. Calcd for C9H20NO5P: C, 42. 69; H, 7.91; N,
5.53%. Found: C, 42.75; H, 7. 87; N, 5.57%.
5
6
Scheme 2. Synthesis of b-amino phosphonates (6) from cyclic sulfamidates(5).
tert-Butyl-(S)-1-(methoxyphosphono)-propan-2-carbamate (6c): ½a D22
ꢂ
= +7.87
(c = 0.5, CHCl3); IR: 3445, 1692, 1512, 1457, 1320, 1261 cmꢁ1
;
1H NMR
in both chiral and achiral forms. The Boc group of the products can
be deprotected and the resulting amino compounds can be utilized
for the preparation of their derivatives.
(200 MHz, CDCl3): d 4.84 (1H, br s), 4.02 (1H, m), 3.79 (6H, d, J = 10.0 Hz), 2.29
(1H, m), 2.02 (1H, m), 1.43 (9H, s), 1.33 (3H, d, J = 7.0 Hz); 13C NMR (50 MHz,
CDCl3): d 154.8, 79.4, 52.1, (d, J = 6.5 Hz), 48.2, 31.0 (d, J = 140 Hz), 28.2, 21.1;
ESI–MS: m/z 268 [M+H]+. Anal. Calcd for C10H22NO5P: C, 44. 94; H, 8.24; N,
5.24%. Found: C, 44.82; H, 8.30; N, 5.29%.
Acknowledgments
tert-Butyl-(R)-1-(ethoxyphosphono)-4-methylpentan-2-ylcarbamate
(6g):
½ ꢂ ;
a 2D2 = -20.3 (c = 0.8, CHCl3); IR: 3422, 1691, 1522, 1466, 1367, 1248 cmꢁ1
1H NMR (200 MHz, CDCl3): d 5.14 (1H, br s), 4.20–3.91 (5H, m), 2.25 (1H, m), 2.
02 (1H, m), 1.75–1.61 (3H, m), 1.42 (9H, s), 1.32 (6H, t, J = 7.0 Hz), 0.92 (6H, d,
J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 155.2, 79.0, 68.0 (d, J = 6.5 Hz), 48.6,
40.5, 30.9 (d, J = 140.0 Hz), 28.3, 24.8, 23.1, 16.2; ESI–MS: m/z 338 [M+H]+. Anal.
Calcd for C15H32NO5P: C, 53.41; H, 9.50; N, 4.15%. Found: C, 53.49; H, 9.58; N,
4.12%.
The authors thank the UGC and CSIR, New Delhi for financial
assistance.
References and notes
tert-Butyl-(R)-1-(methoxyphosphono)-3-phenylpropan-2-ylcarbamate (6h):
1. (a) Allen, J. G.; Arthenton, F. R.; Hall, M. J.; Hassall, C. H.; Holmes, S. W.;
Lambert, R. W.; Nisbet, L. J.; Ringrose, R. S. Nature 1978, 272, 56; (b) Smith, W.
W.; Bartlett, P. A. J. Am. Chem. Soc. 1998, 120, 4622; (c) Alonso, E.; Alenso, E.;
Solis, A.; Del Pozo, C. Synlett 2000, 698.
2. Fields, S. C. Tetrahedron 1999, 55, 12237.
3. Horiguchi, M.; Kandatsu, M. Nature 1959, 184, 901.
a 2D5 = -9.54 (c = 0.5, CHCl3); IR: 3422, 1688, 1505, 1455, 1367, 1249 cmꢁ1
½ ꢂ
;
1H NMR (200 MHz, CDCl3): d 7.33–7.15 (5H, m), 5.12 (1H, br s), 3.99 (1H, m),
3.72 (6H, d, J = 10.0 Hz), 3.00 (1H, m), 2.88 (1H, m), 2.28 (1H, m), 1.97 (1H, m),
1.48 (9H, s); 13C NMR (50 MHz, CDCl3): d 151.9, 137.9, 129.6, 128.5, 126.3, 79.6,
52.2 (d, J = 6.5 Hz), 48.9, 41.3, 30.9 (d, J = 140.0 Hz), 28.4; ESI–MS: m/z 344
[M+H]+. Anal. Calcd for C16H26NO5P: C, 55.98; H, 7.58; N, 4.08%. Found: C,
55.83; H, 7. 52; N, 4.12%.
4. (a) Hammerschmidt, F. Liebigs Ann. Chem. 1988, 531; (b) Hammerschmidt, F.;
Vollenkle, H. Liebigs Ann. Chem. 1989, 577.
5. (a) Kittredge, J. S.; Isbell, A. F.; Huges, R. R. Biochemistry 1967, 6, 289; (b) Korn,
E. D.; Dearborn, D. G.; Fales, H. M.; Sokoloski, E. D. J. Biol. Chem. 1973, 248, 2257.
6. Eto, M. Organophophopates Pesticide: Organic and Biological Chemistry; CRC
Press: Cleveland, OH, 1977.
7. Caseiola, M.; Castantino, W.; Peraio, A.; Rega, T. Solid State Ionics 1995, 77, 229.
8. (a) Yuan, C.; Li, S.; Li, C.; Chen, S.; Huang, W.; Wang, G.; Pan, C.; Zhang, Y. Pure
Appl. Chem. 1996, 68, 907; (b) Palacios, F.; Alonso, C.; de los Santos, J. M. Chem.
Rev. 2005, 105, 899; (c) Grishkun, E. V.; Kolodyazhnyi, O. I. Russ. J. Gen. Chem.
2009, 79, 2705.
9. (a) Melendez, R. E.; Lubell, W. D. Tetrahedron 2003, 59, 2581; (b) Bower, J. F.;
Rujirawanich, J.; Gallagher, T. T. Org. Biomol. Chem. 2010, 8, 1505.
10. (a) Das, B.; Balasubramanyam, P.; Krishnaiah, M.; Veeranjaneyulu, B.; Reddy, G.
C. J. Org. Chem. 2009, 74, 4393; (b) Das, B.; Damodar, K.; Bhunia, N. J. Org. Chem.
2009, 74, 5607; (c) Das, B.; Satyalakshmi, G.; Suneel, K.; Damodar, K. J. Org.
Chem. 2009, 74, 8400.
tert-Butyl-(R)-1-(methoxyphophono)-3-phenylpropan-2-ylcarbamate
(6i):
½
a 2D2
ꢂ
= -8.45 (c = 0.5, CHCl3); IR: 3444, 1688, 1637, 1501, 1454, 1248 cmꢁ1
;
1H NMR (200 MHz, CDCl3): d 7.29–7.05 (5H, m), 5.21 (1H, br s), 4.30–3.98 (5H,
m), 2.99 (1H, m), 2.85 (1H, m), 2.23 (1H, m), 2.01 (1H, m 1.40 (9H, s), 1.24 (6H,
t, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 152.8, 139.0, 129.0, 128.3, 127.1,
78.7, 68.0 (d, J = 6.5 Hz), 46.8, 41.2, 31.9 (d, J = 140.0 Hz), 28.8, 14.5; ESI–MS: m/
z 372 [M+H]+. Anal. Calcd for C18H30NO5P: C, 58.22; H, 8.09; N, 3.77%. Found: C,
58.29; H, 8.12; N, 3.73%.
tert-Butyl-(R)-1-(methoxyphosphono)-3,3-dimethylbutane-2-ylcarbamate (6j):
½ ꢂ ;
a 2D2 = -6.76 (c = 0.5, CHCl3); IR: 3427, 1689, 1520, 1468, 1252 cmꢁ1 1H NMR
(200 MHz, CDCl3): d 4.87 (1H, br s),3.82 (6H, d, J = 10.0 Hz), 4.03 (1H, m), 2.27
(1H, m), 2.02 (1H, m), 1.45 (9H, s), 1.11 (9H, s); 13C NMR (50 MHz, CDCl3): d
154.2, 79.3, 52.2 (d, J = 6.5 Hz), 48.0, 34.1, 30.8 (d, J = 140.0 Hz), 28.4, 24.5; ESI–
MS: m/z 310 [M+H]+. Anal. Calcd for C13H28NO5P: C, 50.49; H, 7.06; N, 4.53%.
Found: C, 50.58; H, 7.11; N, 4.49%.
(2R,3S)-Methyl-2-(tert-butoxycarbonylamino)-3-(ethoxyphosphono)-butanoate
11. Mckennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M. J. Org. Chem. 1993, 58,
3568.
(6l):
½
a 2D5
ꢂ
= +5.67 (c = 0.5, CHCl3); IR: 3452, 1736, 1623, 1483, 1363,
;
1247 cmꢁ1
1H NMR (200 MHz, CDCl3): d 9.74 (1H, br s), 4.32 (1H, m), 3.85
12. Baldwin, J. E.; Spivey, A. C.; Schofield, C. J. Tetrahedron: Asymmetry 1990, 1, 881.
13. General experimental procedure for the preparation of b-amino phosphonates: To a
solution of NaH (1.3 mmol) in THF (5 mL) dialkyl phosphite (1.2 mmol) was
added and the mixture was stirred at 0 °C for 10 min. Sulfamidate (1.0 mmol)
was added to the mixture which was again stirred at 65 °C. The reaction was
monitored by TLC. After completion, the reaction was quenched with ice and a
(3H, s), 4.15–3.99 (4H, m), 2.01 (1H, m), 1.68 (3H, d, J = 7.0 Hz), 1.44 (9H, s),
1.35 (6H, t, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 164.2, 151.2, 80.9, 68.6 (d,
J = 6.5 Hz), 52.1, 45.8, 31.0 (d, J = 140.0 Hz), 28.6, 14.2, 12.3; ESI–MS: m/z 354
[M+H]+. Anal. Calcd for C14H28NO7P: C, 47.59; H, 7.93; N, 3.97%. Found: C,
47.48; H, 7.97; N, 3.92%.