Catalyst-free microwave-assisted synthesis of α-aminophosphonates in a three-component system: R1C(O)R2-(EtO) 2P(O)H-RNH2

Article abstract of DOI:10.1055/s-2005-868519

An effective catalyst-free microwave-assisted synthesis of α-aminophosphonates from ketones in a three-component system was shown. The method affords α-aminophosphonates in high yields from various ketones including natural porphyrine derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-868519

LETTER
1393
Catalyst-Free Microwave-Assisted Synthesis of a-Aminophosphonates in a
Three-Component System: R1C(O)R2–(EtO)2P(O)H–RNH2
C
atalyst-Free Microw
a
a
ve-Assisted
r
S
ynthe
i
sis of
a
a
-Aminophosphon
M
ates . Kabachnik,* Elena V. Zobnina, Irina P. Beletskaya
Department of Chemistry, M. V. Lomonosov Moscow State University, Leninskie Gory, Moscow, 119899, Russian Federation
Fax +7(95)9393618; E-mail: mariamk@mail.ru
Received 17 January 2005
The microwave-assisted reaction of ketones with
(EtO)2P(O)H and primary amines (RNH2, R = Bz, t-Bu, c-
C6H11) has been found not only to produce a-aminophos-
phonates in high yields, but also to decreases the reaction
time greatly. Comparative data on the synthesis of a-ami-
nophosphonates from ketones under microwave irradia-
tion and under conventional heating are presented in
Table 1.
Abstract: An effective catalyst-free microwave-assisted synthesis
of a-aminophosphonates from ketones in a three-component system
was shown. The method affords a-aminophosphonates in high
yields from various ketones including natural porphyrine deriva-
tives.
Key words: a-aminophosphonates, a-aminophosphonic acid, ke-
tones, natural porphyrin, steroid
In the most of the examples the reaction was carried out
under solvent-free conditions in a domestic microwave
oven (102 W). It should be noted that the effective
application of non-expensive domestic microwave ovens
in many organic preparations has been extensively
documented.13 The reaction has been carried out in an
Erlenmeyer flask over 10–28 minutes using the following
ratio of reagents: ketone–(EtO)2P(O)H–RNH2, 1:3:114
(Scheme 1). The necessity to use an excess of dialkyl-
phosphite is accounted for by the partial decomposition of
this reagent under microwave irradiation.
The reaction was monitored by the means of IR and 31P
NMR spectroscopy, and TLC (Silufol, hexane–ethyl ace-
tate, 5:1). a-Amino phosphonates were isolated in 74–
94% yield and the phosphorous atoms were found to have
a chemical shift in the range 19.5–32.5 ppm. It was found,
that the addition of Lewis acids (CdI2, AlCl3) may lead to
further decrease of the reaction time, but did not affect the
yields. Also, it should be noted that ketone structure does
not greatly affect the reaction rate under microwave
irradiation.
The synthesis of a-aminophosphonates exhibiting high
biological activity has recently attracted a lot of atten-
tion.1–3 Due to their structural analogy with a-aminoacids,
this type of organophosphorous compound is widely used
for the development of new inhibitors of enzymes, neuro-
active compounds, antibiotics, and plant-growth regula-
tors.4,5
Among a number of synthetic approaches to a-amino
phosphonates one of the most powerful methods is the
Kabachnik–Fields reaction.6 However this method, usual-
ly applied to aldehydes, has been much less studied with
ketones.7,8
The lower activity of ketones in comparison to aldehydes
necessitates either harsh conditions (heating in an auto-
clave) or the use of various catalysts.2,9
Meanwhile, the application of microwave irradiation has
often been demonstrated to enable facile realization of re-
actions, which otherwise require harsh conditions and are
too slow for practical purposes.10,11 Moreover, the micro-
wave-assisted reactions are believed to satisfy the de-
mands of ‘green chemistry’ allowing for solvent-free
conditions to be employed.
The application of microwave irradiation allows the
preparation of a-aminophosphonates from such ketones
as benzophenone and adamantanone-2,2 which give poor
yields using conventional heating.
Previously we have suggested a method for the synthesis
of a-aminophosphonates, based on the reaction of ald- and
ketimines with dialkylphosphites in the presence of CdI2
under microwave irradiation.12
R1
O
MW
It was first shown that the synthesis of a-aminophospho-
nates and a-aminophosphonic acids from ketones can be
successfully carried out in a three-component system [ke-
tone–(EtO)2P(O)H–RNH2] without catalyst under micro-
wave irradiation. Aliphatic, aromatic, heterocyclic, and
carbocyclic ketones were used in the reaction (see
Table 1).
R1C(O)R2 + (EtO)2P
R3NH2
P(O)(OEt)2
NHR3
IIIa–j
+
R2
H
Ia–j
IIa–j
Scheme 1 I, II, III: a: R1, R2 = c-C6H10, R3 = c-C6H11; b: R1,
R2 = c-C6H10, R3 = CH2Ph; c: R1 = R2 = i-Pr, R3 = CH2Ph; d:
R1 = R2 = Ph, R3 = CH2Ph; e: R1 = Me, R2 = Ph, R3 = t-Bu; f:
R1 = Me, R2 = 5-methyl-2-phuryl, R3 = CH2Ph; g: R1 = Me, R2 = 5-
methyl-2-thienyl, R3 = CH2Ph; h: R1 = Me, R2 = naphthyl,
R3 = CH2Ph; i: R1 = Me, R2 = 7-methoxy-1,2,3,4-tetrahydronaph-
thyl-2, R3 = CH2Ph; j: R1, R2 = 2-adamantyl, R3 = CH2Ph.
SYNLETT 2005, No. 9, pp 1393–1396
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1.
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Advanced online publication: 02.05.2005
DOI: 10.1055/s-2005-868519; Art ID: D01205ST
© Georg Thieme Verlag Stuttgart · New York

1394
M. M. Kabachnik,
LETTER
Table 1 a-Aminophosphonates from the Reaction of Ketones, Primary Amines, and Diethylphosphite
Ketones
Amines
MW
Conventional heating (45 °C)
Time (min)
Yields of a-amino- Time (h)
Yields of a-amino-
phosphonates (%)
phosphonates (%)
IIIa
IIIb
8
86
92
6
9
76
64
NH2
O
PhCH2NH2
10
O
IIIca
IIId
IIIe
(i-Pr)2C=O
PhCH2NH2
PhCH2NH2
t-BuNH2
20
20
18
73
81
79
72
72
72
0
0
2
Ph2C=O
Ph
O
H3C
IIIf
PhCH2NH2
PhCH2NH2
19
9
84
83
24
12
50
57
O
O
IIIg
S
O
IIIh
PhCH2NH2
28
72
72
1.5
O
IIIia
IIIja
PhCH2NH2
PhCH2NH2
19
22
75
74
72
72
1
0
O
O
O
a Carried out in C2H4Cl2.
3-Methoxy-androsta-3,5-diene-17-one and a ketone from was obtained in 82% yield; the 31P NMR spectrum re-
a natural porphyrin derivative were used in the reaction vealed a single product a-aminophosphonate VII, the
for the first time.
only signal appearing at 25.8 ppm.
Analogously, a-aminophosphonate V was obtained, after We have also studied the reaction of ketones with bis(tri-
heating for 24 minutes in C2H4Cl2, in 79% yield (see methylsilylphosphite) and primary amines under micro-
Scheme 2).15 The 31P NMR spectrum revealed two signals wave irradiation. The bis(trimethylsilyl)phosphonate
at 23 ppm and 26 ppm corresponding to two stereoiso- group can be easily transformed into phosphonic acid by
mers.
methanolysis.17 The reaction of cyclohexanone, bis(trim-
ethylsilyl)phosphate, and a-phenylethylamine gave a
phosphonate ester, which was transformed into a-amino-
phosphonic acid VIII in 81% yield.18
The reaction of natural porphyrin derivative VI with t-
BuNH2 and (EtO)2P(O)H was carried out in C2H4Cl2 un-
der microwave irradiation for 4 minutes.16 Porphyrin VII
NHCH2Ph
P(OEt)2
O
O
MW
O
+
PhCH2NH2
+
(EtO)2PH
ClCH2CH2Cl
O
O
IV
V
Scheme 2
Synlett 2005, No. 9, 1393–1396 © Thieme Stuttgart · New York

LETTER
Catalyst-Free Microwave-Assisted Synthesis of a-Aminophosphonates
1395
O
O
NHt-Bu
HN
N
N
HN
N
N
O
O
P(OEt)2
MW
(EtO)2P
+
+
t-BuNH2
ClCH2CH2Cl
H
O
NH
NH
MeOOC
COOMe
MeOOC
COOMe
VI
VII
Scheme 3
O
O
P(OH)2
H3C
H2N
MW
O
+
(Me3SiO)2PH
Ph
+
–Me3SiOSiMe3
NHCH(CH3)Ph
VIII
Scheme 4
(13) (a) Mitra, A. K.; De Karchaudhuri, A. N. Synlett 1998,
1345. (b) Yadav, J. S.; Subba Reddy, B. V.; Madan, Ch.
Synlett 2001, 1131. (c) Kaboudin, B.; Nazari, R.
In summary, a novel catalyst-free version of the Kabach-
nik–Fields reaction under microwave irradiation is pre-
sented in this work, which allows a-aminophosphonates
to be prepared from various ketones, including naturally
occurring ketones.
Tetrahedron Lett. 2001, 42, 8211.
(14) General Procedure: a) Microwave irradiation: Appropriate
ketone (IIIa–j, 0.02 mol), anhydrous amine (0.02 mol) and
freshly distilled (EtO)2P(O)H (0.06 mol) were placed into 25
mL flask and exposed to microwave irradiation at 102 W
using a domestic oven (Daewoo, KOR-4125G) for 10–28
min. The residue was purified by chromatography on silica
(eluent: hexane–EtOAc, 3:2).
Acknowledgment
This work was supported by grant from the Russian Foundation of
Basic Research No 04-03-32710.
All experiments were repeated several times in order to
ensure reproducibility.
b) Conventional method: A mixture of ketone (0.05 mol),
amine (0.05 mol) and diethyl phosphite was refluxed in
benzene (20 mL) for an appropriate time. On completion, the
solvent was evaporated and the residue was purified by
chromatography on silica (eluent: hexane–EtOAc, 3:2).
All new compounds gave satisfactory elemental analyses (C
0.2, H 0.3, N 0.3).
References
(1) Kaboudin, B.; Nazari, R. Tetrahedron Lett. 2001, 42, 8211.
(2) Matveeva, E. D.; Podrugina, T. A.; Tishkovskaya, E. V.;
Tomilova, L. G.; Zefirov, N. S. Synlett 2003, 2321.
(3) Pavlov, V. Ya.; Kabachnik, M. M.; Zobnina, E. V.;
Ponomarev, G. V.; Beletskaya, I. P. Synlett 2003, 2193.
(4) Fields, S. C. Tetrahedron 1999, 55, 12237.
(5) Kleszczynska, H.; Sarapuk, J. Cell. Mol. Biol. Lett. 2001, 6,
83.
(6) Kabachnik, M. I.; Medved, T. Ya. Dokl. Akad. Nauk SSSR
1952, 689; Chem. Abstr. 1953, 47, 2724b.
(7) Gancarz, R. Phosphorus, Sulfur Silicon Relat. Elem. 1993,
83, 59.
1H NMR, 31P NMR and microanalytical data for some newly
obtained a-aminophosphonates are as follows.
Compound IIIc: bp 70–73 °C. 1H NMR (400 MHz, CDCl3):
d = 1.12 (t, 2J = 6.5 Hz, 6 H, CH3CH2O), 1.31 [s, 12 H,
(CH3)2CH], 2.02 (m, 2 H, 2 × (CH3)2CH), 2.91 (br s, 1 H,
NH) 3.82 (q, J = 7.8, 6.3 Hz, 4 H, CH3CH2O), 3.97 (q, J =
7.1, 6.0 Hz, 2 H, CH2-NH), 7.40 (m, 5 H, arom). 31P NMR
(162 MHz, CDCl3): d = 26.1. Anal. Calcd for C18H32NPO3:
C, 63.34; H, 9.38; N, 4.11. Found: C, 63.15; H, 9.40; N, 4.13.
Compound IIId: bp 108–109 °C. 1H NMR (400 MHz,
CDCl3): d = 1.31 (t, 2J = 7.6 Hz, 6 H, OCH2CH3), 3.94 (dd,
J = 7.6, 6.2 Hz, 2 H, NHCH2), 4.08 (q, J = 7.1, 6.2 Hz, 4 H,
2 × OCH2CH3), 4.16 (br s, 1 H, NH), 7.62, 7.49, 7.31 (m, 15
H, arom). 31P NMR (162 MHz, CDCl3): d = 28.0. Anal.
Calcd for C24H28NPO3: C, 70.13; H, 6.67; N, 3.21. Found: C,
70.41; H, 6.85; N, 3.42.
(8) Gancarz, R.; Gancarz, I.; Walkowjak, U. Phosphorus, Sulfur
Silicon Relat. Elem. 1995, 104, 45.
(9) Kabachnik, M. M.; Ternovskaya, T. N.; Zobnina, E. V.;
Beletskaya, I. P. Zh. Org. Khim. 2002, 38, 504.
(10) Saidi, M. R.; Azizi, N. Synlett 2002, 1347.
(11) Lidström, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225.
(12) Kabachnik, M. M.; Zobnina, E. V.; Beletskaya, I. P. Zh. Org.
Khim. 2005, 41, in press.
Compound IIIg: 1H NMR (400 MHz, CDCl3): d = 1.40 (t,
2J = 7.6 Hz, 6 H, OCH2CH3), 1.7 (s, 3 H, CH3), 2.24 (s, 3 H,
Synlett 2005, No. 9, 1393–1396 © Thieme Stuttgart · New York

1396
M. M. Kabachnik,
LETTER
CH3), 3.63 (br s, 1 H, NH), 4.07 (q, J = 7.6, 5.2 Hz, 4 H,
OCH2CH3), 4.09 (dd, J = 7.9, 6.4 Hz, 2 H, NHCH2), 6.47 (d,
J = 2.3 Hz, 1 H, thiophene), 6.56 (d, J = 3.4 Hz, 1 H,
thiophene), 7.36 (m, 5 H, arom). 31P NMR (162 MHz,
CDCl3): d = 24.8 ppm. Anal. Calcd for C17H26NSPO3: C,
57.46; H, 7.32; N, 3.94. Found: C, 57.48; H, 7.53; N, 3.65.
Compound IIIh: 1H NMR (400 MHz, CDCl3): d = 1.33 (t,
J = 7.6 Hz, 6 H, OCH2CH3), 1.65 (d, J = 10.6 Hz, CH3), 3.89
(br s, 1 H, NH), 3.94 (dd, J = 7.6, 5.9 Hz, 2 H, NHCH2), 4.02
(q, J = 7.6, 5.2 Hz, 4 H, OCH2CH3), 7.62, 7.49, 7.31 (m, 12
H, arom). 31P NMR (162 MHz, CDCl3): d = 24.1 ppm. Anal.
Calcd for C23H28NPO3: C, 69.52; H, 7.05; N, 3.53. Found: C,
69.46; H, 7.34; N, 3.81.
a-Aminophosphonate Derived from 3,8-Diacetyl–13,17–
bis(methoxycarbonylethyl)-2,7,12,18-tetramethyl-
porphyrin (VII): 1H NMR (400 MHz, CDCl3): d = 10.24,
9.99, 9.85, 9.84 (s, 4 H, meso-H), 4.34–4.28 (two over-
lapping t, J = 7.4, 7.1 Hz, 4 H, 2 × CH2CH2CO2CH3), 4.22–
4.12 [q, J = 7.1, 6.0 Hz, 8 H, 31-P(O)(OCH2CH3)2], 4.16 (br
s, 1 H, NH), 3.65, 3.65, 3.64, 3.57, 3.55, 3.52 (s, 18 H,
2 × CH2CH2CO2CH3 and 4 × CH3-ring), 3.23–3.19 (two
overlapping t, 4 H, 2 × CH2CH2CO2CH3), 1.68 (m, 2 H,
2 × CH), 1.30–1.26 [t, J = 7.1 Hz, 12 H, 31-P(O)(OCH2CH3)2],
1.24 and 1.23 [s, 9 H, 31-NHC(CH3)3], –4.21 (br s, 2 H,
2 × NH-ring). 31P NMR (162 MHz, CDCl3): d = 19.5 ppm.
MS (ESI+): 624.7 [C52H80N6O10P2 + 2 H – 2 t-Bu –
2 (EtO)2P(O)].
(15) To a solution of the ketone IV (0.001 mol) in ClCH2CH2Cl
(1.5 mL), PhCH2NH2 (0.001 mol) and freshly distilled
(EtO)2P(O)H (0.003 mol) were added. The reaction mixture
was exposed to microwave irradiation at 102 W using a
domestic oven (Daewoo, KOR-4125G) for 24 min. The
residue was purified by chromatography on silica (eluent:
hexane–EtOAc, 3:2).
(17) Bazloo, M.; Jiao, X.-Y.; Wojtowicz, H.; Rajan, P.;
Verbruggen, C.; Augustyns, K.; Haemers, A. Synthesis
1995, 1074.
(18) Cyclohexanone (0.02 mol), PhCH(CH3)NH2 (0.02 mol) and
freshly distilled trimethylsilylphosphite (0.06 mol) were
placed into 50 mL flask and exposed to microwave
irradiation at 102 W using a domestic oven (Daewoo, KOR-
4125G) for 18 min. The residue was purified by
a-Aminophosphonate Derived from 3-Methoxy-
androsta-3,5-diene-17-one (V): mp 143–145 °C. 1H NMR
(400 MHz, CDCl3): d = 0.92 (m, 1 H, 9-CH), 0.94 (s, 3 H,
18-CH3), 1.04 (s, 3 H, 19-CH3), 1.29 (t, J = 7.6 Hz, 6 H,
OCH2CH3), 1.62 (m, 1 H, 8-CH), 1.82 (m, 14 H, all CH2-
ring), 2.25 (dd, J = 7.6, 5.9 Hz, 2 H, NHCH2), 2.57 (br s, 1
H, NH), 3.61 (s, 3 H, CH3O), 3.99 (q, J = 7.9, 5.4 Hz, 4 H,
chromatography on silica (eluent: hexane–EtOAc, 3:2).
a-Aminophosphonic Acid VIII: bp 229 °C. 1H NMR (400
MHz, CDCl3): d = 0.96 (d, J = 7.6 Hz, 3 H, CHCH3), 1.26
(m, 10 H, c-C6H10), 3.58 (s, 2 H, OH), 3.95 (q, J = 7.9, 6.4
Hz, 1 H, NHCH), 7.25 (m, 5 H, arom), 7.51 (br s, 1 H, NH).
31P NMR (162 MHz, CDCl3): d = 19.8 ppm. Anal. Calcd for
C14H22NPO3: C, 59.36; H 7.77; N, 4.95. Found: C, 59.08; H,
7.53; N, 5.02.
OCH2CH3), 5.39 (s, 1 H, 6-CH), 7.37 (m, 5 H, arom). 31
NMR (162 MHz, CDCl3): d = 23.0 and 26.0 ppm. MS
(ESI+): m/z = 391.2 [C31H45NO4P + H(EtO)2P(O)].
P
(16) To solution of ketone VI (0.048 mol) in ClCH2CH2Cl (1.5
mL), PhCH2NH2 (0.048 mol) and freshly distilled
(EtO)2P(O)H (0.144 mol) were added. The reaction mixture
was exposed to microwave irradiation at 102 W using a
domestic oven (Daewoo, KOR-4125G) for 4 min. The
residue was purified by chromatography on silica (eluent:
CH2Cl2–MeOH, 100:1).
Synlett 2005, No. 9, 1393–1396 © Thieme Stuttgart · New York