A simple and efficient access to α-amino phosphonates from N-benzyloxycarbonylamino sulfones using indium(III) chloride

Article abstract of DOI:10.1021/jo900558d

(Chemical Equation Presented) Treatment of N-benzyloxycarbonylamino sulfones with triethyl phosphite catalyzed by InCl₃ produces the corresponding protected α-amino phosphonates in high yields (71-92%).

Full text of DOI:10.1021/jo900558d

pubs.acs.org/joc
important compounds such as alafosfalin and (R)-phospho-
A Simple and Efficient Access to r-Amino
Phosphonates from N-Benzyloxycarbonylamino
Sulfones Using Indium(III) Chloride†
tyrosin possess an R-amino phosphonate moiety as their
structural unit.5 In addition, R-amino phosphonates have
been employed as insecticides,6a herbicides,6b,6c and fungi-
cides.6d Due to their interesting biological properties, various
methods have been developed for the synthesis of these
compounds.7 The optically active forms of these molecules
have also been synthesized.3a,5,8 Generally, the carbonyl
compound and amines or directly the imines have been
utilized in these synthetic methods. However, many of these
methods are associated with different drawbacks such as
high temperature, long reaction time, application of costly
reagents, and tedious experimental procedure. Recently,
Biswanath Das,* Kongara Damodar, and Nisith Bhunia
Organic Chemistry Division-I, Indian Institute of Chemical
Technology, Hyderabad 500 007, India
biswanathdas@yahoo.com
Received March 16, 2009
ZrOCl2 8H2O has been introduced as an efficient catalyst
3
for one-pot reaction of amines, aldehydes, and diethyl
phosphite to form R-amino phosphonates in excellent yields
under solvent-free conditions.9 The three-component reac-
tion of aldehydes, 2-aminophenol, and diphenyl phosphite
catalyzed by chiral scandium(III)-N,N0-dioxide complexes
afforded the corresponding R-amino phosphonates with
high diastereoselectivity.10 A four-component reaction for the
preparation of R-amino phosphonates has also been developed
by treatment of methyleneaziridines with Grignard reagents,
alkyl halides, and dialkyl phosphites.11 Herein, we wish to
report the application of N-benyloxycarboxylamino sulfones
for a simple and efficient synthesis of R-amino phosphonates.
Treatment of N-benzyloxycarbonylamino sulfones with
triethyl phosphite catalyzed by InCl3 produces the corre-
sponding protected R-amino phosphonates in high yields
(71-92%).
SCHEME 1. N-Benzyloxycarbonylamino Sulfones as Precursors
of N-Acyliminium Ions
R-Amino phosphonic acids and their derivatives exhibit
various important biological properties1 and can serve as
structural analogues of the corresponding R-amino acids.2
They are used as antibacterial,3a,3b anticancer,3c and anti-
HIV agents.3d These compounds are also utilized as peptide
mimics4a and enzyme inhibitors.4b-4d Several medicinally
† Studies on Novel Synthetic Methodologies. 188.
N-Benyloxycarbonylamino sulfones, generally referred to
as R-amido sulfones, can be conveniently prepared12 from
aldehydes and are generally stable solids which can be stored
for prolonged times. It is known that they can be converted
into the corresponding protected imines (N-acyliminium ions)
on treatment with an appropriate Lewis acid (Scheme 1).13
These imine derivatives contain a positively charged nitrogen
atom and are thus highly suitable for nucleophilic addition.
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DOI: 10.1021/jo900558d
r
Published on Web 07/02/2009
J. Org. Chem. 2009, 74, 5607–5609 5607
2009 American Chemical Society

Das et al.
JOCNote
SCHEME 2. Synthesis of R-Amino Phosphonates from N-Benyl-
oxycarbonylamino Sulfones
TABLE 2. ReactivityofPhosphiteReagentsfortheSynthesisofR-Amino
Phosphonates from N-Benzyloxycarbonylamino Sulfone, 1a, at Room Tem-
peraturea
entry
phosphite reagent
yieldb,c (%)
1
2
3
4
5
6
P(OMe)3
HP(O)(OMe)2
P(OEt)3
HP(O)(OEt)2
P(OPh)3
HP(O)(OPh)2
66
trace
88
trace
59
trace
aReaction conditions: N-benzyloxycarbonylamino sulfone, 1a (1
mmol), phosphite reagent (1.5 mmol), and CH2Cl2 (10 mL); the reaction
was stirred at rt for 10 h. bYields of isolated pure compound after column
chromatography. cThe products were characterized from their IR, 1H and
13C NMR, and MS spectra.
TABLE 1. Synthesis of R-Amino Phosphonates from N-Benzyloxycarbo-
nylamino Sulfone, 1a, Using Different Lewis Acids at Room Temperaturea
TABLE 3. InCl3-Catalyzed Synthesis of R-Amino Phosphonates from
N-Benzyloxycarbonylamino Sulfones and Triethyl Phosphite (Scheme 2)a
entry
Lewis acid
X (mol %)
time (h)
yieldb (%)
1
2
3
4
5
6
7
8
9
CeCl3 7H2O
CeCl3 7H2O
ZrCl4
ZrCl4
VCl3
15
15
15
15
15
15
15
15
10
10
15
15
10
24
10
24
10
24
10
24
10
24
10
24
10
15
25
30
25
35
30
45
50
65
88
90
entry
R
product
time (h)
yieldb (%)
3
3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
C6H5
4-MeC6H4
4-(CH3)2CHC6H4
4-ClC6H4
3-ClC6H4
2,4-(Cl)2C6H3
4-BrC6H4
4-FC6H4
3-Cl,4-FC6H3
2,4,6-(F)3C6H2
4-MeOC6H4
vanilyl
3,4-(-OCH2O-)C6H3
3,4,5-(MeO)3C6H3
4-NO2C6H4
3-NO2C6H4
2-naphthyl
2-furyl
2-thienyl
C6H5CH2
3a
3b
3c
3d
3e
3f
3 g
3 h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
10
9
9
9
10
9
88
90
91
89
88
88
89
86
87
84
92
86
91
89
79
81
87
71c
90
86
83
85
84
VCl3
CuBr2
CuBr2
InCl3
InCl3
InCl3
InCl3
9
12
12
12
8
9
8
10
11
12
aReaction
conditions:
N-benzyloxycarbonylamino
sulfone,
1a (1 mmol), triethyl phosphite (1.5 mmol), and CH2Cl2 (10 mL). bYields
of
graphy.
isolated
pure
compound
after
column
chromato-
9
20
16
13
13
11
11
12
11
11
In continuation of our work14 on the development of useful
synthetic methodologies, we have observed that the treatment
of N-benzyloxycarbonylamino sulfones with triethyl phosphite
in the presence of InCl3 as a catalyst yielded the corresponding
R-amino phosphonates at room temperature (Scheme 2).
Initially, the reaction of N-benzyloxycarbonylamino
sulfone, 1a (R=Ph), with triethyl phosphite was carried
out at room temperature using various Lewis acids
(Table 1). Considering the reaction time and yield, InCl3
(15 mol %) was found to be the most effective. The reaction
of 1a was also studied with different phosphites in the
presence of InCl3 at room temperature (Table 2). Triethyl
phosphite was found to afford the product in highest yield.
However, with diethyl phosphite only a trace amount of the
product was obtained. Thus, the reaction of N-benyloxy-
carbonylamino sulfones with triethyl phosphite using
InCl3 as a catalyst was subsequently employed for the
preparation of a series of protected R-amino phosphonates
(Table 3).
3s
3t
3u
3v
3w
CH3CH2CH2
CH3(CH2)3CH2
(CH3)2CHCH2
aReaction conditions: N-benyloxycarbonylamino sulfone, 1(1 mmol),
triethyl phosphite, 2 (1.5 mmol), InCl3 (15 mmol %), and CH2Cl2 (10 mL);
the reaction was carried out at room temperature. bYields of pure
isolated compounds after column chromatography. cReaction was carried
out with 2.0 mmol of triethyl phosphite.
were used to prepare the sulfones. The reaction was
completed within 8-13 h except for the R-amido sulfones
containing an aromatic ring with an electron-withdrawing
substrate (e.g., Table 3, entries 15 and 16). In the latter
case, the reaction times were somewhat longer (15-20 h).
The reaction conditions were mild, and the products were
formed in high yields (71-92%). Various functionalities
such as ether, hydroxyl, halogen, and nitro groups remained
unchanged. The sulfone derived from an acid-sensitive alde-
hyde such as furfuraldehyde (Table 2, entry 18) and the
sulfone derived from a sterically hindered aldehyde such as
2-naphthaldehyde (Table 2, entry 17) also afforded the corre-
sponding protected R-amino phosphonates in good yields.
The structures of the products were established from their
N-Benzyloxycarbonylamino sulfones derived from var-
ious aldehydes (aromatic and aliphatic) underwent the
present conversion smoothly. Aromatic aldehydes having
electron-donating as well as electron-withdrawing groups
spectroscopic (IR, H and 13C NMR, ESIMS, and HRMS)
data.
Recently, there is only one report of the reaction of N-
benzyloxycarboxylamino sulfones with dialkyl phosphites
1
(14) (a) Das, B.; Damodar, K.; Chowdhury, N.; Saritha, D.; Ravikanth,
B.; Krishnaiah, M. Tetrahedron 2008, 64, 9396–9400. (b) Das, B.; Satya-
lakshmi, G.; Suneel, K.; Shashikanth, B. Tetrahedron Lett. 2008, 49, 7209–
7212. (c) Das, B.; Krishnaiah, M.; Balasubramanyam, P.; Veeranjaneyulu,
B.; Kumar, D. N. Tetrahedron Lett. 2008, 49, 2225–2227.
5608 J. Org. Chem. Vol. 74, No. 15, 2009

Das et al.
JOCNote
using a phase-transfer catalyst to form the protected chiral
R-amino phosphonates.15 The reaction was conducted in the
presence of a base and required a long time (60 h). Moreover,
R-amido sulfones generated from aromatic aldehydes have
not been examined.
In conclusion, we have demonstrated here a simple, mild,
and efficient protocol for the synthesis of protected R-amino
phosphonates at room temperature and in high yields by
applying the reaction of N-benzyloxycarbonylamino sul-
fones (derived from both aromatic and aliphatic aldehydes)
with P(OEt)3 using indium(III) chloride as a catalyst.
(20-35% EtOAc/hexane) to obtain pure protected R-amino phos-
phonate 3.
Benzyl (Diethoxyphosphoryl)(phenyl)methylcarbamate (3a).
Following the general experimental procedure, 1a (395 mg, 1
mmol) produced, after column chromatography (20% EtOAc/
hexane), the R-amino phosphonate 3a (331.8 mg, 88%) as a
white solid: mp = 111-113 °C; IR νmax (KBr)/cm-1 3241, 1716,
1548, 1252, 1030; 1H NMR (200 MHz, CDCl3) δ ppm 7.51-7.23
(10H, m), 6.07(1H, brs), 5.23-5.01(3H, m), 4.28-4.03(2H, m),
3.91(1H, m), 3.66(1H, m), 1.30 (3H, t, J = 7.0 Hz), 1.10 (3H, t,
J = 7.0 Hz); 13C NMR (50 MHz, CDCl3) δ ppm 156.0 (d, J =
10.0 Hz), 137.2, 135.2, 129.1, 128.8, 128.5, 127.8, 67.3, 63.9 (d,
J = 6.5 Hz), 63.3 (d, J = 6.5 Hz), 52.8 (d, J = 156.6 Hz), 16.2 (d,
J = 6.0 Hz), 16.1 (d, J = 6.0 Hz); ESIMS m/z 378 [M þ H]þ, 400
[M þ Na]þ; HRMS (ESI) calcd for C19H25NO5P [M þ H]þ
378.1470, found 378.1478.
Experimental Section
General Experimental Procedure. Triethyl phosphite, 2
(249.2 mg, 1.5 mmol), was added dropwise to a solution of
N-benzyloxycarbonylamino sulfone, 1 (1 mmol), and InCl3
(15 mol %) in CH2Cl2 (10 mL) under nitrogen atmosphere. The
mixture was stirred at room temperature, and the reaction was
monitored by TLC. After completion, distilled water (5 mL)
was added, and the mixture was extracted with EtOAc (3ꢀ10 mL).
The combined organic portions were washed with water (2 ꢀ 10 mL),
dried over anhydrous Na2SO4, and concentrated under vacuum.
The residue was subjected to column chromatography on silica gel
Acknowledgment. We thank CSIR, New Delhi, for finan-
cial assistance. We are also thankful to the NMR, Mass, and
IR divisions of IICT for recording the spectra.
Supporting Information Available: General experimental
information, characterization data of products 3b-w, products
obtained with trimethyl phosphite and triphenyl phosphite
(Table 2, entries 1 and 5), and copies of NMR (1H and 13C)
and HRMS spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) Fini, F.; Micheletti, G.; Bernardi, L.; Pettersen, D.; Fochi, M.; Ricci,
A. Chem. Commun. 2008, 4345–4347.
J. Org. Chem. Vol. 74, No. 15, 2009 5609