Synthesis of chiral 4-nitrophenyl alkyl methylphosphonothioates: BF3·Et2O-catalyzed alcoholysis of phosphonamidothioates

Article abstract of DOI:10.1016/S0040-4039(02)00735-9

Facile and highly enantioselective synthesis of 4-nitrophenyl alkyl methylphosphonothioates 5a-f was achieved in high yields via BF₃·Et₂O-catalyzed alcoholysis of resolved phosphonamidothioates 4a and 4b.

Full text of DOI:10.1016/S0040-4039(02)00735-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4063–4066
Synthesis of chiral 4-nitrophenyl alkyl methylphosphonothioates:
BF3·Et2O-catalyzed alcoholysis of phosphonamidothioates
Putta Mallikarjuna Reddy† and Ildiko M. Kovach*
Department of Chemistry, The Catholic University of America, Washington, DC 20064, USA
Received 14 June 2001; revised 2 April 2002; accepted 8 April 2002
Abstract—Facile and highly enantioselective synthesis of 4-nitrophenyl alkyl methylphosphonothioates 5a–f was achieved in high
yields via BF3·Et2O-catalyzed alcoholysis of resolved phosphonamidothioates 4a and 4b. © 2002 Elsevier Science Ltd. All rights
reserved.
The stereoselective synthesis of chiral phosphonates has
attracted considerable interest in recent years.1 Chiral
phosphonates demonstrate potential differential inhibi-
tion of cholinesterases, since these enzymes are highly
stereospecific for asymmetric organophosphorus
inhibitors.2–4 They are widely used for the elucidation
of enzymatic reaction mechanisms.3,4 Chiral phospho-
nate ester inhibitors mimic in both their charge distri-
bution and geometry the second transition state
occurring during enzymic carboxyester hydrolysis.3a,b,5,6
Moreover, they are particularly good active-site probes
of serine hydrolase enzymes by providing one more
ligand for interacting with active-site residues than car-
boxyl esters.3,7 Covalent modification of the active sites
is not readily reversible in general. This problem is
compounded in phosphates and phosphonates with an
alkyl side chain that can be dealkylated in an SN1 or
SN2 mechanism commonly known as aging.8 Dealkyla-
tion leads to irreversible inhibition of enzymes and high
toxicity.
forms between the nucleophilic Og of the active serine
of the enzyme and the phosphorus atom.3c,9,10 The
development of different chiral inhibitors of serine
hydrolases for mechanistic studies as well as for appli-
cation prompted us to focus our attention on synthetic
methods towards optically pure 4-nitrophenyl alkyl
methylphosphonothioates.
The standard method for the preparation of optically
active phosphonothioates is conversion of resolved
phosphonothioic acids with chiral amines into their
chlorides and subsequent reaction with alcohols or
phenols.11 This method is tedious and affords poor
yields. However, optically active insecticides were
synthesized12 recently in moderate yields by adopting
stereoselective PꢀO and PꢀN bond cleavage via H2SO4-
catalyzed alcoholysis.13 Herein we wish to report an
efficient stereospecific cleavage of the PꢀN bond via the
BF3·Et2O-catalyzed alcoholysis, and a facile and highly
enantioselective synthetic method for the preparation of
chiral 4-nitrophenyl alkyl methylphosphonothioates in
high yields using (S)-(−)-a-methylbenzylamine (3) as
chiral resolving agent.
Phosphonate esters with 4-nitrophenoxy substitution
are efficient inhibitors of enzymes because the 4-nitro-
phenoxy moiety departs readily, while a covalent bond
Table 1. Physical properties of 4-nitrophenyl N-(a-methylbenzyl) methylphosphoramidothioates 4a–ba
Product no.
Yield (%)
Mp (°C)
[h]2D5 (c=2, CHCl3)
Molecular formula
31P NMR, l (CDCl3)
4a17
4b18
34
28
121–122
80–81
−122.0
+60.5
C15H17N2O3PS
(336.35)
81.55
80.83
a Diastereomeric purity is 100%.
Keywords: asymmetric synthesis; phosphonamidothioates; BF3·Et2O-catalyzed alcoholysis; (S)-(−)-a-methylbenzylamine.
* Corresponding author. Fax: +1-202-319-5381; e-mail: kovach@cua.edu
† Present address: Department of Chemistry, University of California at Santa Barbara, Santa Barbara, CA 93106, USA.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00735-9

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P. M. Reddy, I. M. Ko6ach / Tetrahedron Letters 43 (2002) 4063–4066
S
P
S
P
p-Nitrophenol/TEA
Toluene, 0 oC - reflux
Cl
Cl
Cl
OPNP
H3C
H3C
1
2
CH3
PNP =
NO2
H2N
Ph
[(S)-(-)-3]/DBU
THF, 0 oC - r.t., 1h
S
P
S
CH3
R
OH
/BF3.Et2O
R
P
O
NH
OPNP
Ph
reflux, 10 - 15h
H3C
H3C
OPNP
5a - f
4a, 4b
Scheme 1.
Table 2. Physical properties of optically active 4-nitrophenyl alkyl methylphosphonothioates 5a–f
Precursor
Product no.
5a20
R
Yield (%)
[h]2D5 (c=2, CHCl3)
Molecular formula
31P NMR, l (CDCl3)
4a
4b
4a
4b
4a
4b
4a
4b
4a
4b
CH3
76
79
74
72
69
70
72
70
62
59
(S): −12.5
(R): +11.8
(S): −9.5
(R): +9.2
(S): −8.4
(R): +8.6
(S): −7.8
(R): +7.2
−
C8H10NO4PS
(247.21)
C9H12NO4PS
(261.24)
C10H14NO4PS
(275.26)
C10H14NO4PS
(275.26)
97.22
94.96
93.31
95.20
5b21
C2H5
5c22
CH(CH3)2
(CH2)2CH3
5d23
5e24
5f25
CH(CH3)C2H5
(R)(−)
C11H16NO4PS
(289.29)
82.91a
83.41a
−
a Diastereomeric purity is 99%.
The success of the asymmetric synthesis is prominently
illustrated by the separate 31P NMR signals for the
diastereomers (4a, 4b, 5e and 5f) with above 99%
diastereomeric purity and by the optical rotations for
the enantiomers (5a–d).
4-Nitrophenyl methylphosphonothiochloridate (2) was
conveniently synthesized in fairly good yield from
equimolar quantities of methylphosphonothioic dichlo-
ride (1) and 4-nitrophenol in the presence of triethyl-
amine (TEA).14 The crucial intermediate, a diastereo-
meric mixture of phosphonamidothioate, 4, was pre-
pared in almost quantitative yield by reacting phospho-
nothiochloridate 2 with 3 in the presence of diaza-
bicycloundecane (DBU) in tetrahydrofuran (THF)
under a N2 atmosphere.15 The diastereomers of 4
were easily separated by fractional crystallization from
a benzene–hexane mixture.16 The less soluble diastereo-
mer 4a17 was first recrystallized from a 1:5 mixture
of benzene–hexane and then the more soluble
diastereomer 4b18 was recrystallized from a 1:7 mix-
ture of benzene–hexane. Determination of 1H and
31P NMR chemical shifts using a Jeol 270 MHz
spectrometer revealed 100% purity of both diastereo-
mers P(R+)C(S−) and P(S)C(S). The optical rotations
of the compounds were also determined and are shown
in Table 1.
In conclusion, facile and highly enantioselective prepa-
ration of 4-nitrophenyl methyl alkylphosphonothioates
5a–f was achieved in high yields via BF3·Et2O-catalyzed
alcoholysis of resolved phosphonamidothioates 4.
Acknowledgements
This research was supported in part by the United Sates
Army Medical Research and Material Command con-
tract DAMD17BC-98-8021.
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14. 4-Nitrophenol (4.67 g, 33.6 mmol) and TEA (3.40 g, 33.6
mmol) in 50 mL of dry toluene was added dropwise over
a period of 15 min to methylphosphonothiodichloridate
(1, 5 g, 33.6 mmol) in 50 mL of dry toluene at 0°C. After
stirring for an additional 30 min at 0°C, the temperature
of the reaction mixture was slowly raised and refluxed for
8 h. The precipitated TEA·HCl was filtered off and the
solvent was removed under vacuum. The crude product
was vacuum distilled at 134–138°C/0.05 mmHg to obtain
pure monochloride 2; yield 5.40 g (63%). The distilled
product was solidified at rt and recrystallized from
CHCl3/hexane to obtain crystalline product, mp 71–72°C.
1H NMR (270 MHz, CDCl3): l (ppm) 2.56 (d, J 15 Hz,
1
18. 4b: Mp 80–81°C; H NMR (270 MHz, CDCl3): l (ppm)
1.50 (d, 3H, J 7 Hz), 2.05 (d, 3H, J 16 Hz), 3.53 (bs, 1H),
4.45–4.59 (m, 1H), 7.05 (d, 2H, J 9 Hz), 7.21–7.41 (m,
5H), 8.03 (d, 2H, J 9 Hz); 31P NMR (270 MHz, CDCl3):
l (ppm, phosphoric acid standard) 80.83.
19. Synthesis of phosphonothioates (5): Phosphonamidoth-
ioate 4 (1 mmol) was dissolved in 3 mL anhydrous
alcohol, the solution was cooled to 0°C under a N2
atmosphere and BF3·Et2O (5 mmol) was added dropwise
from a syringe. After 1 h, the solution was allowed to
slowly reach rt and after stirring for an additional hour,
the reaction mixture was slowly heated to reflux tempera-
ture and allowed to continue for 10–15 h. The reaction
mixture was concentrated, the residue was dissolved in 10
mL of CHCl3 and washed successively with 5 mL of 1%
K2CO3, saturated NH4Cl, brine and finally with water.
The CHCl3 layer was dried over anhydrous MgSO4 and
the solvent was removed under reduced pressure. The
resulting product was purified on a short path silica gel
column using a 3:1 mixture of hexane–ethyl acetate as
eluent to afford pure compound 5.
1
20. 5a: H NMR (270 MHz, CDCl3): l (ppm) 2.03 (d, 3H, J
16 Hz), 3.80 (d, 2H, J 14 Hz), 7.29 (dd, 2H, J 11 Hz),
8.24 (d, 2H, J 9 Hz); 31P NMR (270 MHz, CDCl3): l
(ppm, phosphoric acid standard) 97.22.
1
21. 5b: H NMR (270 MHz, CDCl3): l (ppm) 1.32 (t, 3H, J
7 Hz), 2.02 (d, 3H, J 16 Hz), 4.08–4.31 (m, 2H), 7.30 (d,
2H, J 9 Hz), 8.24 (d, 2H, J 9 Hz); 31P NMR (270 MHz,
CDCl3): l (ppm, phosphoric acid standard) 94.96.
1
22. 5c: H NMR (270 MHz, CDCl3): l (ppm) 1.30 (d, 6H, J
6 Hz), 2.01 (d, 3H, J 16 Hz), 4.91 (m, 1H), 7.32 (dd, 2H,

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P. M. Reddy, I. M. Ko6ach / Tetrahedron Letters 43 (2002) 4063–4066
J 9, 2 Hz), 8.23 (d, 2H, J 9 Hz); 31P NMR (270 MHz,
4.29 (m, 1H), 7.02 (dd, 2H, J 9, 2 Hz), 8.01 (d, 2H, J 9
Hz); 31P NMR (270 MHz, CDCl3): l (ppm, phosphoric
CDCl3): l (ppm, phosphoric acid standard) 93.31.
1
acid standard) 82.98.
23. 5d: H NMR (270 MHz, CDCl3): l 0.95 (t, 3H, J 8 Hz),
1.69 (m, 2H), 2.03 (d, 3H, J 15 Hz), 4.01 (m, 2H), 7.29
(dd, 2H, J 9, 2 Hz), 8.23 (d, 2H, J 9 Hz); 31P NMR (270
MHz, CDCl3): l (ppm, phosphoric acid standard) 95.20.
1
25. 5f: H NMR (270 MHz, CDCl3): l 0.90 (t, 3H, J 7 Hz),
1.13 (d, 3H, J 7 Hz), 1.56 (m, 2H), 1.88 (d, 3H, J 15 Hz),
4.28 (m, 2H), 7.18 (dd, 2H, J 9, 2 Hz), 8.14 (d, 2H, J 9
Hz); 31P NMR (270 MHz, CDCl3): l (ppm, phosphoric
acid standard) 83.41.
1
24. 5e: H NMR (270 MHz, CDCl3): l 0.91 (t, 3H, J 7 Hz),
1.16 (d, 3H, J 6 Hz), 1.60 (m, 2H), 1.99 (d, 3H, J 16 Hz),