Improved facile synthesis of α-amino phosphonates by the reaction of α-amido sulfones with dialkyl trimethyl silyl phosphites catalyzed by Fe(III) chloride

Article abstract of DOI:10.1080/00397911.2016.1270323

An improved efficient synthesis of α-amino phosphonates has been discovered by the reaction of N-benzyloxycarbonylamino sulfones with dialkyl trimethyl silyl phosphites in the presence of FeCl₃as a catalyst. The products were formed in high yie

Full text of DOI:10.1080/00397911.2016.1270323

An improved facile synthesis of α-amino phosphonates by the reaction of α-amido
sulfones with dialkyl trimethyl silyl phosphites catalyzed by Fe (III) chloride
Veeranjaneyulu Boyapati1, Biswanath Das1
1Department of Chemistry, D.C.R.M Degree College & P.G Courses, Inkollu
Address correspondence to Veeranjaneyulu Boyapati. E-mail: anjuiict@gmail.com
Abstract
An improved efficient synthesis of α-amino phosphonates has been discovered by the
reaction of N-benzyloxycarbonylamino sulfones with dialkyl trimethyl silyl phosphites in
the presence of FeCl3 as a catalyst. The products were formed in high yields (86-94%)
within 2-4 h. The catalyst is inexpensive, easily available and highly active. The
unreacted dialkyl trimetyl silyl phosphites can easily be removed from the products due
to their low boiling points. The sulfones can conveniently be prepared and are generally
stable.
Graphical Abstract
KEYWORDS: α-amino phosphonates; N-benzyloxycarbonylamino sulfones; stable
solids; Dialkyl trimetyl silyl phosphites; FeCl3 catalyst
INTRODUCTION
1

α-Amino phosphonic acids and their esters are considered [1] structural analogues of α-
amino acids. They possess several attractive biological activities including insecticidal,
herbicidal and fungicidal properties[2]. They have also been employed as enzyme
inhibitors, peptide mimetics, catalytic antibodies and antibiotics [3]. Some of these
compounds are used as antirhematic, antioxidant and anti-HIV agents [4]. Thus a number
of methods have been developed for the synthesis of α-amino phosphonates, both in
racemic and chiral forms [5]. Generally these synthetic methods have been applied to
carbonyl compounds and amines or directly to the corresponding imines for
hydrophosphonylation. However, several Lewis acids used for catalyze these reactions
deactivate or decompose in the presence of amine and water produced during imine
formation and many of the imines are unstable. Though methods involving catalyst and
solvent free conditions for the synthesis of α-amino phosphonates were developed [6], the
serious draw back in such methods is the difficulty in the deprotection of N-phenyl group
in the products to the corresponding amine under mild conditions. On the other hand, α-
amido sulfones, a valuable source of imines, can easily be prepared and generally they
are stable solids and can be stored for a long time. Further, unlike in many of the
reported methods, the N-benzyloxycarbonyl group in the products obtained can easily be
demasked to the corresponding primary amine which allows structural modifications.
Here we would like to describe the synthesis of α-amino phosphonates using α-amido
sulfones in the presence of a catalytic amount of Fe (III) chloride.
In connection with our work [7] on the development of useful synthetic methodologies we
have discovered that N-benzoyloxycarbonylamino sulfones, when allowed to react with
2

dialkyl trimethyl silyl phosphite using Fe (III) chloride as a catalyst, afforded the
protected α-amino phosphonates in high yields (Scheme 1).
RESULTS AND DISCUSSION
The above conversion of N-benzoyloxycarbonylamino sulfones into α-amino
phosphonates was initially standardized using diethyl trimethyl silyl phosphite and
various metal salts. In absence of a catalyst the present conversion did not proceed (Table
1). The transformation was found to be most effective when FeCl3 (10 mol %) and
diethyl trimethyl silyl phosphite (1.1 mmol) were allowed to react with sulfone (1.0
mmol) in CH2Cl2 at 20 oC under N2 atmosphere (Table 1). The reaction was completed in
2h with 91% yield (Table 1, entry 1). The conversion was less efficient with other
catalysts (e.g., ZnCl2, ZrCl2, CuCl and NiCl2.6H2O) when compared to FeCl3. The
catalytic activity of FeCl3 was also better than that of the non-transition metal salt InCl3,
as conversions required a longer time with the latter (Table 1). Considering reaction times
and yields, FeCl3 was found to be the catalyst of choice. This compound is comparatively
inexpensive and easily available.
Then the reaction was optimised further by the reaction of sulfones with different
phosphites (e.g., Me3SiOP(OEt)2, H(O)P(OEt)2 and P(OEt)3) using FeCl3 as catalyst
(Table 2). It has also been observed that the reaction times were shorter and the yields
were higher when the conversions were conducted using FeCl3 and dialkyl trimethyl silyl
phosphites instead of other phosphonating agents (Table 2) as had been done earlier when
InCl3 was used as the catalyst [8]. The reaction of α-amido sulfones with dialkyl trimethyl
3

silyl phosphites in the presence of InCl3 also took longer reaction times to afford the
products in lower yields (Table 1).
The experimental procedure of the present conversion is also convenient as a dialkyl
trimethyl phosphite (having lower b.p.) can easily be removed from the reaction mixture
by simple evaporation under vacuum. On the other hand, a trialkyl phosphite (having
higher b.p.) is difficult to remove from the reaction mixture. Thus the treatment of N-
benzoyloxycarbonylamino sulfones with dialkyl trimethyl silyl phosphite catalyzed by
FeCl3 constitutes an improved method for the synthesis of α-amino phosphonates
(Scheme 1). Recently another method involving the reaction of N-
benzoyloxycarbonylamino sulfones and dialkyl phosphites in the presence of a phase
transfer catalyst and a base has been reported [9]. However, the reaction time was long (60
h) and the sulfones derived from aromatic aldehydes were not utilized.
A series of α-amino phosphonates have successfully been prepared from N-
benzoyloxycarbonylamino sulfones generated[10] from different aldehydes (aromatic,
hetero-aromatic and aliphatic). Sulfones containing electron-donating as well as electron-
withdrawing groups in the aromatic ring underwent the conversion smoothly. Both
dimethyl trimethyl silyl phosphite and diethyl trimethyl silyl phosphite were used to
prepare the α-amino phosphonates (Table 3). The N-Cbz group of the products can easily
be deprotected and the free amine group may be utilized to prepare their different
analogues [11]
.
4

The reaction was conducted at 200C because at higher temperatures the silyl reagent
decomposed to some extent. The conversion was completed within 2-4 h and the yields
were impressive (86-94%). Different functional groups such as hydroxyl, ether, halogen
and nitro remained intact. The structures of the products were confirmed from their
spectral (IR, 1H, 13C NMR, ESIMS and HRMS) properties. The products 2a-2f are new
compounds. The spectral data of the products 2g-2r are fully in agreement with the
reported data [7].
It is known that α-amido sulfones on treatment with a suitable Lewis acid can be
converted into the corresponding protected imines containing a positively charged
nitrogen [11]. Here N-benzoyloxycarbonylamino sulfones 1 are converted first in the
presence of FeCl3 into the imines A which then undergo phosphonylation with dialkyl
trimethyl silyl phosphite to form the corresponding protected α-amino phosphonates 2
(Scheme 2).
CONCLUSION
In conclusion, we have developed an improved efficient and general method for the
synthesis of protected α-amino phosphonates by treatment of N-
benzoyloxycarbonylamino sulfones with dialkyl trimethyl silyl phosphites in the presence
of FeCl3 as a catalyst. The application of an easily available, inexpensive and highly
active catalyst has made the process simple, improved and practical. The N-Cbz group of
the products can easily be deprotected and the free amine group can be utilized to prepare
their different analogues.
5

EXPERIMENTAL
All commercially available reagents were used directly without further purification unless
otherwise stated. The solvents used were all of AR grade and were distilled under a dry
N2 atmosphere where necessary. All reactions were performed in pre-dried apparatus
unless otherwise stated. The progress of the reactions was monitored by analytical thin-
layer chromatography (TLC) performed on Merck Silica Gel 60 F254 plates. Column
chromatography (CC) was carried out using silica gel 60 – 120 mesh (Qingdao Marine
Chemical, China). Melting points of the final compounds were recorded on a Buchi-510
instrument. IR spectra were recorded on a Perkin-Elmer IR-683 spectrophotometer with
KBr optics (values were reported in cm-1). 1H & 13C-NMR spectra were recorded on a
Gemini 200 MHz, Bruker 300 MHz and Inova 500 MHz spectrometers with TMS as
internal standard in CDCl3. The chemical shifts are expressed as values in ppm and the
coupling constants (J) are given in Hz. ESI-MS were recorded with VG-Autospec
micromass and HRMS with QSTAR XL, Hybrid MS system (Applied Biosystems). Yields
were of purified compounds unless otherwise stated.
General Experimental Procedure For The Synthesis Of Α-Amino Phosphonates (2a-
2o)
To a stirred mixture of α-amido sulfone, 1 (1 mmol) and FeCl3 (10 mol %) in dry CH2Cl2
(5 ml) dialkyl trimethyl silyl phosphate (1.2 mmol) was added under N2 at 20 0C. The
reaction was monitored by TLC. After completion, the reaction mixture was diluted with
CH2Cl2 (10 ml) and washed with water (2x10 ml). The organic portion was separated,
dried over anhydrous Na2SO4 and concentrated. The residue was subjected to column
6

chromatography (silica gel, hexane-EtOAc) to obtain pure protected α-amino
phosphonate 2. The spectral data of some of the representative products are given below.
Spectral Data For The Selected Compounds benzyl
(dimethoxyphosphoryl)(phenyl)methylcarbamate (2a)
White solid. m.p. 118-119 0C; IR: 3325, 1714, 1551, 1458, 1255. 1H NMR (300 MHz,
CDCl3): δ 7.50-7.41 (m, 2 H); 7.38-7.21 (m, 8 H); 6.40 (dd, J = 10.0, 4.0, 1 H); 5.21-4.99
(m, 3 H); 3.70 (d, J = 10.0, 3 H); 3.41 (d, J = 10.0, 3 H). 13C-NMR (75 MHz, CDCl3):
156.0 (d, J = 9.0); 136.2; 135.1; 128.9; 128.3; 128.0; 67.2; 53.9 (d, J = 6.5); 53.5 (d, J =
6.0); 52.2 (d, J = 154.4). ESI-MS: [M + H]+ = 350, [M + Na]+ = 372; HRMS (ESI) Calcd
for [C17H20NO5P+Na]+ = 372.0976, found = 372.0995.
Benzyl (Dimethoxyphosphoryl)(Furan-2-Yl)Methylcarbamate (2e)
White solid; m.p. 69-72 0C; IR: 3243, 1718, 1533, 1458, 1262; 1H NMR (200MHz,
CDCl3): 7.40 (brs, 1 H), 7.30 (brs, 5 H), 6.41 (brs, 1 H), 6.33 (m, 1 H), 5.59 (brd, J =
10.0, 1 H), 5.29 (dd, J = 24.0, 10.0, 1 H), 5.14 (d, J = 12.0, 1 H), 5.07 (d, J = 12.0, 1 H),
3.72 (d, J = 10.0, 3 H), 3.63 (d, J = 10.0, 3 H); 13C NMR (50 MHz, CDCl3):155.7 (d, J =
9.0), 148.0, 143.0, 136.2, 128.6, 128.2, 111.1, 109.1, 67.3, 53.8 (d, J = 6.0), 53.2 (d, J =
6.2), 46.1 (d, J = 155.0); ESIMS: [M + H]+ = 340, [M + Na]+= 362; HRMS (ESI): Calcd
for [C15H18NO6P+H]+ =340.0950, found = 340.0955.
Benzyl 3-(Diethoxyphosphoryl)(3,4,5-Trimethoxyphenyl)Methylcarbamate (2g)
7

White solid; m.p. 109-1110C; IR: 3238, 1712, 1594, 1234; 1H NMR (200 MHz, CDCl3)
7.36-7.22 (m, 5 H), 6.63 (s, 2 H), 5.84 (brs, 1 H), 5.12 (d, J = 12.0, 1 H), 5.07 (d, J =
12.0, 1 H), 5.01 (d, J = 24.0, 10.0, 1 H), 4.14-4.01 (m, 2 H), 3.95 (m, 1 H), 3.85 (s, 6H),
3.81 (s, 3 H), 3.70 (m, 1 H), 1.28 (t, J = 7.0, 3 H), 1.12 (t, J = 7.0, 3 H); 13C NMR (50
MHz, CDCl3):155.7, 153.3, 136.1, 130.8, 128.5, 128.3, 117.1, 116.1, 105.1, 105.0, 67.4,
63.4 (d, J = 6.2), 63.1 (d, J = 6.2),60.8, 56.1, 52.1 (d, J = 155.5), 16.4 (d, J = 6.0), 16.3
(d, J = 6.0); ESIMS: [M + H]+ = 468; HRMS (ESI): Calcd for [C22H30NO8P+H]+ =
468.1782, found = 468.1784.
FUNDING
The authors thank CSIR, New Delhi for financial assistance.
SUPPORTING INFORMATION
The scanned copies of 1H-NMR, 13C-NMR and HRMS spectra for new compounds 2a-2f
and for known compounds 2g-2h are provided. This material can be found via the
“Supplementary Content” section of this article’s webpage.
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10

Table 1. Studies on activity of different catalysts for the synthesis of α-amino
phosphonates by reaction of α-amido sulfones with diethyl trimethyl silyl phosphate.a
Entry
1
Sulfone
Catalyst
t (h)
Yield (%) b
NHCbZ
SO2Tol
FeCl3
2
91
InCl3
9
74
ZnCl2
16
16
16
16
24
65
ZrCl4
69
CuCl
59 c
62 c
NR d
NiCl2.6H2O
No Catalyst
NHCbZ
SO2Tol
2
FeCl3
2
94
InCl3
9
76
MeO
ZnCl2
16
16
16
16
24
68
ZrCl4
71
CuCl
62 c
66 c
NR d
NiCl2.6H2O
No Catalyst
NHCbz
SO2Tol
3
FeCl3
4
86
InCl3
12
16
16
20
20
24
64
O2N
ZnCl2
51
ZrCl4
54
CuCl
48 c
53 c
NR d
NiCl2.6H2O
No Catalyst
11

aReaction conditions: Sulfone (1 mmol), phosphite (1.2 mmol) and FeCl3 (10 mol %)
were used. bYields of isolated, pure compounds after column chromatography. cCatalyst
(20 mol %) was used. dNo Reaction.
12

Table 2. Reactivity of various phosphites on treatment with α-amido sulfones in the
presence of FeCl3 catalyst at 20oC.a
Entry
1
Sulfone
Phosphite
t (h)
Yield (%) b
Me3SiOP(OEt)2
H(O)P(OEt)2
P(OEt)3
2
91c)
15
NHCbz
SO2Tol
12
10
74
NHCbZ
SO2Tol
2
3
Me3SiOP(OEt)2
H(O)P(OEt)2
P(OEt)3
2
94c
20
12
10
4
MeO
76
NHCbZ
Me3SiOP(OEt)2
H(O)P(OEt)2
P(OEt)3
86c
Trace
42
SO2 Tol
12
10
O2N
aReaction conditions: Sulfone (1 mmol), phosphite (1.2 mmol) and FeCl3 (10 mol %)
were used. b Yields of isolated, pure compounds after column chromatography. c Reaction
conducted at 20oC.
13

Table 3. FeCl3-catalyzed synthesis of α-amino phosphonates by the reaction of α-amido
sulfones with dialkyl trimethyl silyl phosphites (Scheme 1)a
Entry R
1
R1 Productb 2
Time (h) Yield (%)c
Me
Me
2
90
87
2a
2b
2
2.5
Cl
3
Me
Me
2.5
2
86
91
2c
F
O
O
4
2d
5
6
Me
Me
Et
3
2.5
2
87
90
94
2e
2f
O
S
MeO
7
8
9
2g
MeO
OMe
Et
Et
2
2
92
91
2h
2i
EtO
OMe
14

10
11
12
13
14
Et
Et
Et
Et
Et
2.5
2.5
4
90
89
86
89
92
2j
2k
2l
Cl
F
O2N
2.5
2
2m
2n
Br
HO
OMe
15
16
Et
Et
2
2
94
88
2o
2p
MeO
S
17
18
n Butyl
n Hexyl
Et
Et
3
86
87
2q
2r
3.5
aReaction conditions: Sulfone (1 mmol), phosphite (1.2 mmol) and FeCl3 (10 mol %)
were used. bAll the products were fully characterized by usual spectroscopic techniques. c
Yields of isolated, pure compounds after column chromatography.
15

Scheme 1. Conversion of α-amido sulfones into α-amino phosphonates.
16

Scheme 2. Proposed mechanism for the synthesis of α-amino phosphonates from α-
amido sulfones.
17