Molecular iodine: An efficient catalyst for the one-pot synthesis of primary 1-aminophosphonates

Article abstract of DOI:10.1007/BF03245883

A new and convenient procedure has been developed for the one-pot synthesis of different types of primary 1-aminophosphonates from aldehydes/ketones, HMDS and diethyl phosphite using I2 as an inexpensive, non-toxic, non-metallic and readily available cata

Full text of DOI:10.1007/BF03245883

J. Iran. Chem. Soc., Vol. 7, No. 1, March 2010, pp. 227-236.
JOURNAL OF THE
Iranian
Chemical Society
Molecular Iodine: An Efficient Catalyst for the One-Pot Synthesis of Primary 1-
Aminophosphonates
S. Sobhani* and A. Vafaee
Department of Chemistry, College of Sciences, Birjand University, Birjand 414, Iran
(Received 31 January 2009, Accepted 4 April 2009)
A new and convenient procedure has been developed for the one-pot synthesis of different types of primary 1-
aminophosphonates from aldehydes/ketones, HMDS and diethyl phosphite using I2 as an inexpensive, non-toxic, non-metallic and
readily available catalyst. These reactions proceeded under solvent-free conditions and produced the desired products in high
yields.
Keywords: 1-Aminophosphonates, Aldehydes, Ketones, Diethyl Phosphite, Iodine
R2
O
INTRODUCTION
R1
P(OR5)2
NR3R4
1-Functionalized phosphonates have found a wide range of
applications in the areas of industrial, agricultural and
medicinal chemistry owing to their biological and physical
properties as well as their utility as synthetic intermediates [1].
Among 1-fuctionalized phosphonates, 1-aminophosphonates
(Scheme 1) has stimulated extensive studies in the past
decades because they serve as important surrogates for the
corresponding 1-amino acids.
primary 1-aminophosphonates: R3=H; R4=H
secondary 1-aminophosphonates: R3=alkyl, aryl; R4=H
tertiary 1-aminophosphonates: R3=alkyl, aryl; R4=alkyl, aryl
Scheme 1
Indeed, a number of potent antibiotics [2], enzyme
iminophosphonates [11].
inhibitors [3] and pharmacological agents [4] are 1-
aminophosphonates or peptide analogues. Moreover,
aminophosphonates are found as constituents of natural
products. There are several multi-step synthetic approaches to
primary 1-aminophosphonates in the literature: a) addition of
the P-H function to imines and nitriles [5,6], b) Hofmann
rearrangement of substituted phosphonoacetic esters [7], c)
alkylation of nucleophilic precursors such as Schiff bases [8],
d) conversion of the corresponding 1-hydroxyphosphonates to
1-aminophosphonates [9,10] and e) reduction of 1-hydroxy-
In contrast to the widespread studies on the one-pot
synthesis of secondary and tertiary 1-aminophosphonates [12-
17], relatively few methods are reported for the one-pot
synthesis of primary 1-aminophosphonates. The most typical
procedure for the one-pot synthesis of primary 1-
aminophosphonates is a Strecker-type reaction [18], which
involves the treatment of an aldehyde with ammonia and
diethyl phosphite. This method, however, is not high yielding
and is unsuitable for large-scale production since the reaction
is performed in a sealed vessel at 100 ºC. Recently, in this
reaction, volatile ammonia has been substituted by ammonium
salts or 1,1,1,3,3,3-hexamethyldisilazane (HMDS). These
*Corresponding author. E-mail: ssobhani@birjand.ac.ir

Sobhani & Vafaee
reactions are conducted by catalysts such as molecular sieve
reduced pressure. The resulting mixture was acidified to pH 1
by addition of HCl (aq) and the solution was washed with
EtOAc (2 × 10 ml) to remove neutral materials. The aqueous
phase was then made alkaline with NaOH (aq). The product
was extracted with EtOAc (2 × 10 ml). The organic phases
were combined, dried over Na2SO4 and filtered. The filtrate
was concentrated under reduced pressure to give diethyl 1-
aminophosphonates (2-29) with high purity.
[19], LiClO4 [20], tetra-tert-butyl-substituted phthalocyanine
[21] and solid supports [22-26]. However, all the existing
methods have drawbacks such as long reaction times [19,21]
amenable only for aldehydes as carbonyl compounds [19,22-
26] using nasty smelling trialkyl phosphite as the phosphorus
nucleophile [20], requiring microwave activation [22-25], low
yields of the products [19,21], formation of 1-
hydroxyphosphonates or 1-trimethylsilyloxyphosphonates as
side products [27] and using large amounts of solid supports or
catalyst which eventually results in the generation of a large
amount of toxic waste [17,22-25].
Spectral
Data
for
Selected
Diethyl
1-
Aminophosphonates
1
2
2. H NMR (CDCl3): ꢀ 1.16 (t, 3 H, JH,H = 7.0 Hz,
2
As part of our ongoing research to develop new synthetic
routes for the preparation of 1-functionalized phosphonates
[28-36], we herein introduce molecular iodine as an efficient
catalyst for the one-pot synthesis of primary 1-
OCH2CH3), 1.26 (t, 3 H, JH,H = 7.0 Hz, OCH2CH3), 2.37 (bs,
NH2), 3.82-4.09 (m, 4 H, OCH2CH3), 4.24 (d, 1 H, 2JP,H = 17.2
Hz, CH), 7.21-7.46 (m, 5 H, C6H5); 13C NMR (CDCl3): ꢀ 16.3
3
3
(d, JC,P = 5.7 Hz, OCH2CH3), 16.4 (d, JC,P = 5.7 Hz,
aminophosphonates
from
coupling
reaction
of
OCH2CH3), 54.0 (d, 1JC,P = 149.5 Hz, CH), 62.7 (d, 2JC,P = 7.7
2
aldehydes/ketones, HMDS and diethyl phosphite under
solvent-free conditions.
Hz, OCH2CH3), 62.8 (d, JC,P = 7.7 Hz, OCH2CH3), 127.5,
127.8, 128.2, 128.5 (C6H5); IR (Neat): 3385, 3298 (NH2) cm-
1; MS (70 eV), m/z (%): 243 (M+), 106 [M-P(O)(OEt)2].
1
2
EXPERIMENTAL
5. H NMR (CDCl3, TMS): ꢁ 1.16 (t, 3 H, JH,H = 7.0 Hz,
2
OCH2CH3), 1.26 (t, 3 H, JH,H = 7.0 Hz, OCH2CH3), 1.88 (bs,
Chemicals and Apparatus
NH2), 3.78 (s, 3H, OCH3), 3.82-4.08 (m, 4H, OCH2CH3), 4.18
Chemicals were purchased from Merck and Fluka Chemical
Companies. All of the products were identified by their
spectral data. IR spectra were run on a Perkin Elmer 780
instrument. NMR spectra were recorded on a Bruker Avance
DPX-250. Mass spectra were recorded on a Shimadzu GCMS-
QP5050A. The purity of the products and the progress of the
reactions were accomplished by TLC on silica-gel polygram
SILG/UV254 plates or by GC on a Shimadazu model GC-14A
instrument.
(d, 1 H, 1JP,H = 16.2 Hz, CH), 6.85-6.88 (m, 2H, C6H4), 7.33-
7.45 (m, 2H, C6H4); 13C NMR (CDCl3, TMS): ꢁ 16.3 (d, 3JC,P
=
3
6.3 Hz, OCH2CH3), 16.4 (d, JC,P = 6.3 Hz, OCH2CH3), 53.4
2
(d, 1JC,P = 150.9 Hz, CH), 55.2 (s, OCH3), 62.6 (d, JC,P = 6.9
2
Hz, OCH2CH3), 62.7 (d, JC,P = 6.9 Hz, OCH2CH3), 128.7,
128.8 (C6H5), 113.8 (d, 3JC,P = 2.5 Hz , C6H5), 159.2 (d, 2JC,P
=
3.1 Hz, C6H5); IR: 3371, 3300 (NH2) cm-1; MS (70 eV), m/e:
273 (M+), 136 [M-P(O)(OEt)2].
10. 1H NMR (CDCl3, TMS): ꢁ 1.15 (t, 3 H, 2JH,H = 7.0 Hz,
2
OCH2CH3), 1.25 (t, 3 H, JH,H = 7.0 Hz, OCH2CH3), 2.19 (bs,
General Procedure for the Preparation of Primary
Diethyl 1-Aminophosphonates (2-29)
NH2), 3.78-4.10 (m, 4H, OCH2CH3), 4.43 (d, 1H, 1JP,H = 17.5
Hz, CH), 7.44-7.48 (m, 2H, C10H7), 7.56-7.60 (m, 1H, C10H7),
7.80-7.90 (m, 4H, C10H7); 13C NMR (CDCl3, TMS): ꢁ 16.3 (d,
3JC,P = 5.7 Hz, OCH2CH3), 16.4 (d, 3JC,P = 5.7 Hz, OCH2CH3),
A mixture of carbonyl compound (2 mmol), HMDS (1
mmol), diethyl phosphite (1 mmol) and I2 (0.01 mmol) was
stirred at room temperature. The reaction was monitored by
TLC or GC. After completion of the reaction, EtOAc (10 ml)
and finely powdered Na2S2O3 (ꢀ0.3 g, in portion) were added
to the reaction mixture. The resulting mixture was stirred for
additional 30 min and filtered. The filtered cake was washed
with EtOAc (10 ml) and the solvent was evaporated under
1
2
54.2 (d, JC,P = 149.7 Hz, CH), 62.8 (d, JC,P = 6.3 Hz,
2
OCH2CH3), 62.9 (d, JC,P = 6.3 Hz, OCH2CH3), 125.7-126.6
(m, C10H7), 127.6-128.1 (m, C10H7), 132.9-133.2 (m, C10H7),
2
135.1 (d, JC,P = 3.8 Hz, C10H7); IR: 3371, 3292 (NH2) cm-1;
MS (70 eV), m/e: 293 (M+), 156 [M-P(O)(OEt)2].
12. 1H NMR (CDCl3, TMS): ꢁ 1.11-1.20 (t, 6H,
228

Molecular Iodine: An Efficient Catalyst
(C6H10) 51.6 (d, 1JC,P = 151 Hz, C6H10), 62.1 (d, 2JC,P = 8.2 Hz,
OCH2CH3), 2.51 (bs, NH2), 3.82-4.03 (m, 4H, OCH2CH3),
OCH2CH3); IR: 3385, 3290 (NH2) cm-1; MS (70 eV), m/e: 235
(M+), 98 [M-P(O)(OEt)2].
4.42 (d, 1H, 1JP,H = 16.7 Hz, CH), 6.87 (t, 2JH,H = 4.0 Hz, 1H,
2
C4H3S), 7.03 (s, 1H, C4H3S), 7.14 (d, JH,H = 5.0 Hz, 1H,
1
2
3
C4H3S); 13C NMR (CDCl3, TMS): ꢁ 16.3 (d, JC,P = 3.8 Hz,
22. H NMR (CDCl3, TMS): ꢀ 1.21 (t, 6H, JH,H = 7 Hz,
OCH2CH3), 1.42-1.52 (m, 12H, C7H12), 1.90 (bs, NH2), 3.96-
4.08 (m, 4H, OCH2CH3); 13C NMR (CDCl3, TMS): ꢀ 16.5 (d,
3JC,P = 5.7 Hz, OCH2CH3), 21.9 (d, 2JC,P = 9.4 Hz, C7H12), 30.3
OCH2CH3), 16.4 (d, 3JC,P = 3.8 Hz, OCH2CH3), 49.9 (d, 1JC,P
=
2
156.2 Hz, CH), 62.9 (d, JC,P = 7.6 Hz, OCH2CH3), 124.9,
125.5, 126.8 (C4H3S), 141 (d, 2JC,P = 3.8 Hz, C4H3S); IR: 3374,
3302 (NH2) cm-1; MS (70 eV), m/e: 249 (M+), 112 [M-
P(O)(OEt)2].
3
1
(s, C7H12), 35.5 (d, JC,P = 3.1 Hz, C7H12) 54.5 (d, JC,P = 144
Hz, C7H12), 62.1 (d, 2JC,P = 7.5 Hz, OCH2CH3); IR: 3369, 3300
(NH2) cm-1; MS (70 eV), m/e: 249 (M+), 112 [M-P(O)(OEt)2].
1
2
13. H NMR (CDCl3, TMS): ꢁ 1.07 (t, 3H, JH,H = 6.5 Hz,
1
2
2
24. H NMR (CDCl3, TMS): ꢁ 0.98 (t, 3H, JH,H = 7.5 Hz,
OCH2CH3), 1.26 (t, 3 H, JH,H = 6.5 Hz, OCH2CH3), 3.03 (bs,
2
2
NH2), 3.85-4.15 (m, 4H, OCH2CH3), 4.63 (d, 1H, 1JP,H = 15.0
CH3), 1.24 (d, 3H, JP,H = 16 Hz, CH3), 1.32 (t, 6H, JH,H = 7
Hz, OCH2CH3), 1.59-1.73 (m, 4H, CH2, NH2); 4.07-4.19 (m,
4H, OCH2CH3); 13C NMR (CDCl3, TMS): ꢁ 7.3 (d, 3JC,P = 7.6
Hz, CH3), 16.6 (d, JC,P = 5.7 Hz, OCH2CH3), 21.7 (d, JC,P
21.7 Hz, CH3), 30.0 (d, JC,P = 3.8 Hz, CH2), 52.0 (d, JC,P
Hz, CH), 6.95-7.70 (m, 4H, C8H6N), 9.33 (bs, NH, C8H6N);
13C NMR (CDCl3, TMS): ꢁ 16.3 (OCH2CH3), 45.9 (d, 1JC,P
=
3
2
=
=
158.7 Hz, CH), 63.1 (OCH2CH3), 110.7, 111.6, 118.8, 119.5,
2
1
2
122, 124.3 (C8H6N), 126.1 (1H, JC,P = 5.7 Hz, C8H6N), 136.1
2
(C8H6N); IR: 3396, 3252 (NH2) cm-1; MS (70 eV), m/e: 282
(M+), 145 [M-P(O)(OEt)2].
147.4 Hz, C), 62.2 (d, JC,P = 7.6 Hz, OCH2CH3); IR: 3378,
3307 (NH2) cm-1; MS (70 eV), m/e: 209 (M+), 72 [M-
P(O)(OEt)2].
1
16. H NMR (CDCl3, TMS): ꢁ 0.80-0.85 (m, 3H, CH3),
1
2
25. H NMR (CDCl3, TMS): ꢁ 0.95 (t, 6H, JH,H = 6.7 Hz,
OCH2CH3), 1.23-1.33 (m, 9H, CH3), 1.46-1.63 (m, 6H, CH2,
NH2), 1.89-1.99 (m, 1H, CH), 4.05-4.17 (m, 4H, OCH2CH3);
1.23-1.75 (m, 14H, OCH2CH3, CH2, NH2), 2.80-2.91 (m, 1H,
CH), 4.04-4.10 (m, 4H, OCH2CH3); 13C NMR (CDCl3, TMS):
ꢁ 18.8 (CH3), 16.5 (d, 3JC,P = 5.5 Hz, OCH2CH3), 22.4, 28.2 (d,
3
13C NMR (CDCl3, TMS): ꢁ 16.6 (d, JC,P = 5 Hz, OCH2CH3),
1
2JC,P = 12.6 Hz, CH2), 30.83 (CH2), 48.6 (d, JC,P = 148.9 Hz,
22.1 (d, JC,P = 1.9 Hz, CH3), 23.2 (d, 2JC,P = 10.1 Hz, CH2),
3
CH), 61.9, 62.0 (OC2H5); MS (70 eV), m/e: 223 (M+), 86 [M-
P(O)(OEt)2].
3
1
25.2 (s, CH3), 45.5 (d, JC,P = 3.1, CH), 52.5 (d, JC,P = 145.3
Hz,), 62.2 (d, 2JC,P = 7.5 Hz, OCH2CH3); IR: 3390, 3302 (NH2)
cm-1; MS (70 eV), m/e: 251 (M+), 114 [M-P(O)(OEt)2].
26. H NMR (CDCl3, TMS): ꢁ 1.33 (t, 6H, JH,H = 7.0 Hz,
OCH2CH3), 1.58 (d, 3H, 3JP,H = 16.2 Hz, CH3), 2.11 (bs, NH2),
3.78 (s, 3H, CO2CH3), 4.06-4.23 (m, 4H, OCH2CH3); 13C
1
19. H NMR (CDCl3, TMS): ꢁ 0.80-0.87 (m, 3H, CH3),
1.25-1.77 (m, 16H, OCH2CH3, CH2), 2.34 (bs, NH2), 2.85-
1
2
2.93 (m, 1H, CH), 4.08-4.13 (m, 4H, OCH2CH3); 13C NMR
3
(CDCl3, TMS): ꢁ 14.0 (CH3), 16.5 (d, JC,P = 5.7 Hz,
OCH2CH3), 22.6, 26.15 (d, 2JC,P = 12.6 Hz, CH2), 29.1, 29.3,
3
1
NMR (CDCl3, TMS): ꢁ 16.5 (d, JC,P = 5.0 Hz, OCH2CH3),
31.1, 31.7 (CH2), 48.5 (d, JC,P = 148.7 Hz, CH), 61.9, 62.0
21.9 (s, CH3), 52.9 (s, CH3), 58.4 (d, 1JC,P = 145.5 Hz, C), 63.4
(OC2H5); MS (70 eV), m/e: 265 (M+), 128 [M-P(O)(OEt)2].
2
2
2
20. 1H NMR (CDCl3, TMS): ꢀ 1.29 (t, 6H, JH,H = 7.2 Hz,
(d, JC,P = 3.2 Hz, OCH2CH3), 63.5 (d, JC,P = 3.2 Hz,
2
OCH2CH3), 172.2 [d, JC,P = 3.8 Hz, C(O)]; IR: 3394, 3316
OCH2CH3), 1.54-1.69 (m, 4H, C5H8), 1.87-2.04 (m, 6H, C5H8,
(NH2) cm-1; MS (70 eV), m/e: 239 (M+), 102 [M-P(O)(OEt)2].
NH2), 4.08-4.20 (m, 4H, OCH2CH3); 13C NMR (CDCl3,
28. 1H NMR (CDCl3, TMS): ꢁ 0.91 (t, 6 H, 2JH,H = 7.5 Hz,
3
2
TMS): ꢀ 16.6 (d, JC,P = 5.7 Hz, OCH2CH3), 24.6 (d, JC,P
=
=
2
3
1
OCH2CH3), 1.28 (d, 3 H, JP,H = 17.1 Hz, CH3), 1.64 (bs,
11.3 Hz, C5H8), 36.3 (d, JC,P = 6.9 Hz, C5H8) 58.7 (d, JC,P
154.7 Hz, C5H8), 62.2 (d, 2JC,P = 6.9 Hz, OCH2CH3); IR: 3368,
3294 (NH2) cm-1; MS (70 eV), m/e: 221 (M+), 84 [M-
P(O)(OEt)2].
NH2), 4.19-4.23 (m, 4H, OCH2CH3), 7.50-7.54 (m, 2H,
C5H4N), 7.68-7.72 (m, 2H, C5H4N); IR: 3377, 3299 (NH2) cm-
1; MS (70 eV), m/e: 258 (M+), 121 [M-P(O)(OEt)2].
1
2
21. H NMR (CDCl3, TMS): ꢀ 1.29 (t, 6H, JH,H = 7.2 Hz,
OCH2CH3), 1.52-1.72 (m, 12H, C6H10, NH2), 4.04-4.15 (m, 4
H, OCH2CH3); 13C NMR (CDCl3, TMS): ꢀ 16.5 (d, 3JC,P = 5.7
RESULTS AND DISSCUSION
3
Recently, we have found iodine as an efficient catalyst for
Hz, OCH2CH3), 19.8 (d, JC,P = 11.3 Hz, C6H10), 25.5, 31.3
229

Sobhani & Vafaee
the preparation
of 1-trimethylsilyloxyphosphonates by
aminophosphonates in good to high yields (Entries 1-8). The
catalyst was compatible with functional groups such as Cl and
O-Me. No competitive nucleophilic methyl ether cleavage was
observed for substrate having an aryl-O-Me group (Entries 2-
4), in spite of good nucleophilic property of phosphites. The
reaction also proceeded well when naphthalene-2-
carbaldehyde was employed as a polynuclear aldehyde (Entry
9). Difunctional aminophosphonate 11 was also prepared in
95% yield from terephthaldehyde by the present method
(Entry 10). Thiophene-2-carbaldehyde and indole-3-
carbaldehyde as heterocyclic aldehydes underwent smooth
reactions under the present reaction conditions and produced
the corresponding diethyl 1-aminophosphonates in excellent
yields (Entries 11 and 12). This catalytic system was also
effective for the preparation of primary 1-aminophosphonates
from aliphatic aldehydes in 80-95% yields (Entries 13-18). In
addition to aldehydes, some ketones were screened to carry
out the coupling reaction by I2 under solvent-free conditions.
The results showed that the reactions involved cyclic ketones
(Entries 19-22), acyclic dialkyl ketones (Entries 23-25) and
alkyl aryl ketones (Entries 26-28) which worked well and the
expected products were easily obtained in 70-96% yields.
In all of the reactions we have studied, primary 1-
aminophosphonates were exclusively formed without any
formation of the side products such as diethyl 1-tri-methyl-
silylation of 1-hydroxyphosphonates with HMDS [28]. This
observation prompted us to examine the efficiency of iodine as
a catalyst in the one-pot three-component reaction of carbonyl
compounds, diethyl phosphite and HMDS for the preparation
of 1-trimethylsilyloxyphosphonates. At first, a reaction of
benzaldehyde, HMDS and diethyl phosphite was chosen as a
model and the feasibility of the reaction was studied in the
presence of I2 (10 mol %) as the catalyst at ambient
temperature under solvent-free conditions. Surprisingly, after
10 min, diethyl N-(phenylmethylene)-1-aminophenylmethyl
phosphonate (1) was obtained in 96% yield without any
formation of 1-trimethylsilyloxyphosphonate (Scheme 2). The
1H NMR spectrum of 1 exhibited a doublet at 8.40 ppm which
is indicative of the coupling of HC-P (1JHP = 5 Hz) moiety in
the molecule. Hydrolysis of 1 with HCl and neutralization of
the
chloride
salt
gave
diethyl
1-
aminophenylmethylphosphonate (2) (Scheme 2).
To show the generality and scope of this method, the
reaction was examined with various structurally diverse
aldehydes and ketones (Scheme 3) at ambient temperature
under solvent-free conditions. The results are compiled in
Table 1.
As shown in Table 1, different substituted benzaldehydes
were successfully converted to their corresponding primary 1-
O
P(OEt)2
O
O
I2 (10 mol%)
+
H
HCl (aq) Ph
Ph
P(OEt)2
C
PhCHO HMDS
HP(OEt)2
solvent-free, rt
N
CH
NH3Cl
Ph
NaOH(aq)
1
O
Ph
P(OEt)2
NH2
2
Scheme 2
O
R1
R1
R2
O
HP(OEt)2
I2 (10 mol%)
solvent-free
O
R2
P(OEt)2
NH2
+
HMDS
R1=alkyl, aryl, heteroaryl
R2=alky, H
2-29
Scheme 3
230

Molecular Iodine: An Efficient Catalyst
Table1. One-Pot Synthesis of Primary 1-Aminophosphonates from Aldehydes/ketones, HMDS and
Diethylphosphite in the Presence of I
2 (10 mol%) at Ambient Temperature under Solvent-Free
Conditions
Entry
1
R1
R2
H
Product
Time
(min)
Yield
(%)a
O
Ph
P(OEt)2
NH2
10
30
93
90
2
O
P(OEt)2
2
3
H
H
H
OMe NH2
OMe
3
O
P(OEt)2
MeO
MeO
30
95
NH2
MeO
MeO
4
5
O
P(OEt)2
4
5
15
15
92
95
NH2
O
P(OEt)2
Me
NH2
H
H
Me
6
Me
O
P(OEt)2
Me
6
7
30
15
90
95
NH2
7
O
P(OEt)2
H
Cl
NH2
Cl
8
O
P(OEt)2
Cl
8
9
H
H
15
15
86
88
NH2
Cl
9
O
P(OEt)2
NH2
10
231

Sobhani & Vafaee
Table 1. Continued
O
O
(EtO)2P
P(OEt)2
OHC
95b
93
H2N
10
H
NH2
3.5 h
2 h
11
O
P(OEt)2
S
NH2
11
12
H
S
12
O
H
N
H
P(OEt)2
HN
30
95
85
NH2
13
O
P(OEt)2
13
H
1 h
NH2
14
O
P(OEt)2
NH2
14
15
H
H
20
30
93
87
15
O
P(OEt)2
NH2
16
O
P(OEt)2
16
17
H
H
25
95
NH2
17
O
P(OEt)2
NH2
1 h
30
90
80
18
O
P(OEt)2
NH2
18
19
H
19
O
P(OEt)2
NH2
5
88
20
232

Molecular Iodine: An Efficient Catalyst
Table 1. Continued
O
P(OEt)2
NH2
5
80
20
21
O
P(OEt)2
21
22
25
30
87
83
NH2
22
O
P(OEt)2
NH2
23
Me
O
Et
P(OEt)2
23
24
Et
Me
Et
35
30
92
96
NH2
24
Me
O
iso-Butyl
P(OEt)2
iso-Butyl
NH2
25
Me
O
MeO2C
P(OEt)2
25
26
Me
CO2Me
Me
15
95
NH2
26
Me
O
P(OEt)2
70c
S
4 h
S
NH2
27
O
Me
N
P(OEt)2
N
27
28
Me
Me
45
83
NH2
28
O
Me
P(OEt)2
82c
NH2
2.5h
29
aIsolated yield. bConditions:diethyl phosphite (4 mmol), HMDS (4 mmol). cReaction temperature = 80 °C.
233

Sobhani & Vafaee
silyloxyphosphonate and diethyl 1-hydroxyphosphonate. These
Table 2. Comparison of Catalytic Efficiency of I2 with the
Reported Promoters for the One-Pot Synthesis of 2
from the Reaction of Benzaldehyde, HMDS and
Diethyl Phosphite
observations indicate excellent selectivity of this method for
the synthesis of a variety of different types of primary diethyl
1-aminophosphonates. Release of ammonia gas was not
detected in any of these transformations. It is worthy of
mention that no evolution of ammonia gas was observed when
a mixture of HMDS and iodine was stirred under similar
reaction conditions. With these results in hand, we suggest a
plausible mechanism for these transformations (Scheme 4). In
this mechanism, I2 polarized Si-N bond in HMDS and
produced a reactive silylating agent (30). The reaction of 30
with carbonyl compound then led to the formation of imine 31
as an intermediate. Imine 31 was converted to 1 after the
reaction with diethyl phosphite and carbonyl compound. I2 is
released during this process and reenters the same catalytic
cycle (Scheme 4). Finally, primary diethyl 1-
aminophosphonate (2-29) is obtained by hydrolysis of 1 under
acidic conditions.
Entry
Catalyst
Time
(min)
10
Yield
(%)a
93
1
2
3
4
I2
Al2O3 (acidic)b
60
15
15
5 [26]
0c [27]
88 [20]
MgO
d
LiClO4
b
aIsolated yield. A mixture of 1 and diethyl-1-hydroxy-1-
phenylmethylphosphonate (1:1 ratio) obtained in the
presence of basic or neutral alumina [26]. cDiethyl-1-
hydroxy-1-phenylmethylphosphonate was obtained as the
major product in 95% yield. d200 mol% of LiClO4 was used.
As the last step in our studies, in Table 2, we have
compared the present method, using I2, with the previously
known procedures for the one-pot synthesis of diethyl 1-
aminophenylmethylphosphonate (2) from benzaldehyde,
HMDS and diethyl phosphite. A comparison of the present
method, with respect to the product yield, with those of the
literature reports in the presence of alumina (acidic, basic and
neutral) and magnesia reveals the high efficiency of this newly
developed method. The desired product (2) was obtained in
R1
I
H
N
I
:O
Me3Si
R2
SiMe3
N
H
Me3Si
SiMe3
30
R1
N
I2
R2
O(SiMe3)2
P(O)(OEt)2
R1
I
R1
I
O
+
SiMe3
+
N:
Me3Si
R2
H
R2
1
R2
R1
R2
TMSOH
O:
R1
R2
R1
P(O)(OEt)2
I
N
SiMe3
I2
+
I
NH
31
SiMe3
HP(O)(OEt)2
Scheme 4
234

Molecular Iodine: An Efficient Catalyst
low yields, when the reaction was carried out on the surface of
[7]
[8]
M. Soroka, P. Mastalerz, Tetrahedron Lett. 14 (1973)
5201.
J.P. Genet, J. Uziel, M. Port, A.M. Touzin, S. Roland,
S. Thorimbert, S. Tanier, Tetrahedron Lett. 33 (1992)
alumina due to the formation of diethyl 1-hydroxyphenyl-
methylphosphonate as a side product (Entry 2) [26]. No
formation of the desired product (2) was observed in the
presence of magnesia and diethyl 1-hydroxyphenyl-
methylphosphonate was isolated as the major product (Entry
3) [27]. Although LiClO4 can catalyze the same reaction to
produce the desired product in high yield, the requirement of
stoichiometric amount of the catalyst (200 mol%) indicates the
lower catalytic activity of LiClO4 in comparison with I2 (Entry
4) [20].
77.
[9]
T. Gajda, M. Matsiak, Synth. Commun. 22 (1992)
2193.
[10] T. Yokomatsu, S. Shibuya, Tetrahedron Asym. 3 (1992)
377.
[11] D. Green, G. Patel, S. Elgendy, J.A. Baban, G. Claeson,
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6917.
CONCLUSIONS
[12] S. Bhagat, A.K. Chakraborti, J. Org. Chem. 72 (2007)
1263.
In summary, the present method provides a new and facile
procedure for the one-pot synthesis of different types of
primary diethyl 1-aminophosphonates from aldehydes/
ketones, HMDS and diethyl phosphite using I2 as an
inexpensive, non-toxic, non-metallic and readily available
catalyst. High yields, solvent-free conditions, using diethyl
phosphite instead of nasty smelling trialkyl phosphite, no by-
product formation, applicability to ketones as well as
aldehydes, using a catalytic amount of I2 without requiring a
promoter, all make this protocol a useful contribution to the
existing methodologies.
[13] M. Zahouily, A. Elmakssoudi, A. Mezdar, A. Rayadh,
S. Sebti, Catal. Commun. 8 (2007) 225.
[14] A. Heydari, H. Hamadi, M. Pourayoubi, Catal.
Commun. 8 (2007) 224.
[15] A.K. Bhattacharya, T. Kaur, Synlett (2007) 745.
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Tetrahedron Lett. 49 (2008) 2208.
[17] T. Ollevier, E. Nadeau, A.A. Guay-Begin, Tetrahedron
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[18] M.E. Chalmers, G.M. Kosolapoff, J. Am. Chem. Soc.
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[19] H. Takahashi, M. Yoshioka, N. Imai, K. Onimura, S.
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ACKNOWLEDGMENTS
We are thankful to Birjand University Research Council
for their support of this work.
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