A Novel Catalytic Three-Component Synthesis (Kabachnick-Fields Reaction) of α-Aminophosphonates from Ketones

Article abstract of DOI:10.1055/s-2003-42118

A novel and highly convenient catalytic variant of the synthesis of α-aminophosphonates on basis of the Kabachnik-Fields reaction [three-component reaction of ketones, diethylphosphite and either benzylamine (series a) of ammonium carbonate (series b)] in the presence of tetra-tert-butylphthalocyanines has been developed. This method affords α-aminophosphonates in acceptable yields for various ketones, including cyclic, sterically hindered and cage ketones. The unsubstituted α-aminophosphonic acids were also obtained from the corresponding esters of series b.

Full text of DOI:10.1055/s-2003-42118

LETTER
2321
A Novel Catalytic Three-Component Synthesis (Kabachnick–Fields Reaction)
of a-Aminophosphonates from Ketones
A
N
ovel Cataly
l
tic Thr
e
ee-Compon
n
ent Synthesi
a
s
of
a
-Aminophos
D
phonates from
K
e
.
tones Matveeva,* Tatyana A. Podrugina, Elena V. Tishkovskaya, Larisa G. Tomilova, Nikolay S. Zefirov*
Department of Chemistry, Moscow Lomonosov University, Moscow, Russia
Fax +7(95)9390290; E-mail: edmatveeva@mail.ru; E-mail: zefirov@org.chem.msu.ru
Received 11 July 2003
lysts. The first three examples were satisfactory mainly
Abstract: A novel and highly convenient catalytic variant of the
synthesis of a-aminophosphonates on basis of the Kabachnik–
Fields reaction [three-component reaction of ketones, diethylphos-
phite and either benzylamine (series a) of ammonium carbonate (se-
for aromatic aldehydes; the last one included aliphatic al-
dehydes and only few ketones. Thus, an efficient proce-
dure for synthesis of a-aminophosphonic acids and a-
ries b)] in the presence of tetra-tert-butylphthalocyanines has been aminophosphonates from ketones, especially hindered
developed. This method affords a-aminophosphonates in accept-
able yields for various ketones, including cyclic, sterically hindered
and cage ketones. The unsubstituted a-aminophosphonic acids were
also obtained from the corresponding esters of series b.
ones, is needed.
In this report, we describe a novel and efficient catalytic
method for the synthesis of a-aminophosphonates and a-
aminophosphonic acids with the involvement of various
ketones. The reactions were performed with diethylphos-
phite and amines in presence of tetra-tert-butyl-substitut-
ed phthalocyanines Pht-1–Pht-322 as catalysts.
Key words: a-aminophosphonates, catalysis, tetra-tert-butyl-
phthalocyanines, ketones, a-aminophosphonic acids
a-Aminophosphonic acids may be considered as phos-
phorous analogues of a-amino acids (‘bioisosterism’),1
and have received considerable attention owing to their
pronounced biological activities. These entities have been
shown to serve as inhibitors of GABA-receptors, inhibi-
tors of various proteolytic enzymes, inhibitors of dialkyl-
glycine decarboxylase, peptide mimetics, antibiotics, and
pharmacological agent, including antitumor, antihyper-
tensive and antibacterial agents.2–15
Various synthetic methods for a-aminophosphonic acids
and a-aminophosphonates have therefore been report-
ed.5,8,9 However, the classical approach to their synthesis
is the Kabachnik–Fields reaction,10–15 which is a one-pot,
three-component operation with carbonyl compound,
amine and dialkyl phosphite. This approach is especially
satisfactory for reactions with aldehydes, and this protocol
was even used for parallel synthesis.16 In contrast, only a
scarce example of the reaction of rather simple ketones
(mainly, acetone, acetophenone and cyclohexanone) has
been documented.2,4,7,9
Figure 1 Pht-1 M = AlCl; Pht-2 M = Co(II); Pht-3 M = Ni(II)
First, the reaction of 3-methylcyclohexanone, 1, with ben-
zylamine and diethylphosphite was tested as a model re-
action. Without any catalysis we obtained product 1a in
20% yield. When tetra-tert-butylphthalocyanine deriva-
tives were used as catalysts, the reaction proceeded
smoothly to produce 1a in better yields (55% for deriva-
tives Pht-2 and 50% for Pht-3), reaching the maximum
98% in the case of Pht-1 (10 mol%). This showed that use
of phthalocyanines, and especially Pht-1, effectively ca-
talyse the reaction indeed.
The mechanism of this reaction is still not clearly under-
stood,12–14 but one of many possible pathways includes
nucleophilic addition of phosphites to the transient imi-
nes. In fact, reaction of phosphites with imines is really
promoted by alkali metal alkoxide or Lewis acids.17,18 In
principle, the Kabachnik–Fields reaction (a three-compo-
nent process) can also be catalyzed by an acid or base. In-
deed, there are also a few examples of catalytic variants of
this reaction, and lanthanide triflate/magnesium sulfate,19
scandium(tris-dodecyl sulfate),20 lanthanide triflates/ionic
liquids21 and indium(III) chloride7 were used as the cata-
Secondly, the reaction of 3-methylcyclohexanone (1), di-
ethylphosphite and ammonia carbonate was tested in the
presence of Pht23 using ethanol as the solvent. When Pht-
1 was used as a catalyst, the reaction proceeds smoothly
to afford the desired product 1b in a good yield (70%).
Thus, the suggested catalyst permits the synthesis of a-
aminophosphonate 1b with unsubstituted primary amino
group.
SYNLETT 2003, No. 15, pp 2321–2324
0
1
.1
2
.2
0
0
3
Advanced online publication: 07.11.2003
DOI: 10.1055/s-2003-42118; Art ID: G16803ST
© Georg Thieme Verlag Stuttgart · New York

2322
E. D. Matveeva et al.
LETTER
12a also show the formation of two diastereomers in ratio
of 3:2. On the other hand, the 1H NMR spectra of a-ben-
zylaminophosphonate (4a) exhibits one signal for tert-bu-
tyl group which indicates the presence of only one of two
possible diastereomers.
1
In the H NMR spectra for symmetric ketones [Table 1:
cyclohexanone (2), 4-tert-butylcyclohexanone (4), diiso-
propylketone (9), adamantanone (10)], the ethoxy groups
are equivalent and their signals are typical for ethoxy
groups.29 If the resulting a-aminophosphonates have the
diastereotopic ethoxy groups [Table 1: 3-methylcyclo-
hexanone (1), acetophenone (3), tetralone (5), indanone
derivatives (6-8)], the situation leads to a duplication of
the corresponding signals.30,31
Scheme 1
This encouraged us to develop the general procedure for
ketones. The reaction of various ketones and diethylphos-
phite with either benzylamine (series a) or ammonia car-
bonate (series b) in the presence of Pht-1 (10 mol%) in
CH2Cl2, C2H5OH or toluene gave the corresponding a-
aminophosphonates as shown in Table 1. Not only cyclo-
hexanones (entries 2, 4) but sterically hindered ketones
(entries 9, 12) worked well to give the corresponding
phosphonates in acceptable yields, although the camphor
(entry 11) afforded the desired product only for case a in
lower yield. It is necessary to stress that many of the ob-
tained a-aminophosphonates are novel compounds and
inaccessible by other methods.25
The pure unsubstituted a-aminophosphonic acids were
obtained from the corresponding esters of series b (1b, 4b,
6b, 8b) using the following steps (Scheme 2): (i) acid hy-
drolysis with 45% HBr, which gives the corresponding
hydrobromides in good yields; (ii) treatment with propy-
lene oxide in methanol at 0 °C. a-Aminophosphonic acids
(1c, 4c, 6c, 8c) were obtained using this protocol in 60–
80% yields.
The composition and structures of synthesized a-benzyl-
aminophosphonates and a-aminophosphonates were es-
1
tablished by elemental analysis,26 IR27 and H NMR, 13C
NMR and 31P NMR spectra.28 In the 31P NMR spectrum
all synthesized a-aminophosphonates have signals at d =
22.00–31.00 ppm which are typical for compounds of this
class.24
1H NMR spectra of a-aminophosphonates can be quite
complicated due either possible existence of diastereo-
mers or diastereotopy of some groups or both. Indeed, in
some cases [Table 1: 3-methylcyclohexanone (1), 4-tert-
butylcyclohexanone (4), camphor (11), norbornanone
(12)] one has to take into account the possible formation
of mixtures of cis- and trans-isomers. The signal of the
Me group of 1a shows the formation of two diastereomers
in 2:1 ratio. Analogously, the 31P NMR spectra of 11a and
Scheme 2
In summary, a novel and highly convenient catalytic
method of the synthesis of a-aminophosphonates in the
presence of tetra-tert-butylphthalocyanines has been per-
formed and the applicability of this method to ketones was
demonstrated. a-Aminophosphonic acid was obtained in
60–80% yields on basis of the synthesized a-aminophos-
phonates.
Table 1 The Ketones Used and the Yields of Corresponding a-Aminophosphonatesa,25
Ketones
Yields of a-aminophosphonates (%)
(Series b)
85 (1b)c
(Series a)
98 (1a)b
1
2
85 (2a)b
70 (2b)c
Synlett 2003, No. 15, 2321–2324 © Thieme Stuttgart · New York

LETTER
A Novel Catalytic Three-Component Synthesis of a-Aminophosphonates from Ketones
2323
Table 1 The Ketones Used and the Yields of Corresponding a-Aminophosphonatesa,25 (continued)
Ketones
Yields of a-aminophosphonates (%)
(Series b)
50 (3b)b
(Series a)
92 (3a)b
3
4
93 (4a)b
52 (4b)c
5
6
74 (5a)c
50 (6a)c
57 (5b)c
35 (6b)c
7
65 (7a)b
–
8
9
98 (8a)b
16 (9a)d
23 (10a)d
15 (8b)c
20 (9b)d
39 (10b)c
10
11
12
18 (11a)c
50 (12a)c
–
20 (12b)c
a Used 0.2 mmol (10 mol%) Ptc-1.
b Carried out in CH2Cl2 at r.t. for 12 h.
c Carried out in EtOH at 78 °C for 24 h.
d Carried out in toluene at 110 °C for 24 h.
Synlett 2003, No. 15, 2321–2324 © Thieme Stuttgart · New York

2324
E. D. Matveeva et al.
LETTER
at 1200 cm–1 (P=O), 3200–3400 cm–1 (N–H and NH2) and
1180 cm–1 (C–O) in the IR spectra of given compounds. IR
spectra of a-benzylaminophosphonates solutions were
measured under the dilution forty times over. At that
intensity and frequency the absorption bands of phosphonic
and NH-associated groups did not change. This fact is
evidence of the presence of intramolecular hydrogen bonds.
(28) Selected NMR data are presented below. Compound 1a. 1H
NMR (400 MHz, CDCl3): d = 0.88 (d, 3 H, CH3-cycl.), 1.34,
1.36 (2 t, 6 H, 2CH3), 1.53, 1.66, 1.87 (3 m, 9 H, cycl., NH),
3.92 (d, 3JPH = 3.2 Hz, 2 H, CH2-Bz), 4.16 (br m, 4 H,
OCH2), 7.31, 7.38 (2 m, 5 H, arom.) ppm. 13C NMR (400
MHz, CDCl3): d = 16.32 (d, 3JCP = 4.6 Hz, CH3), 19.68 (d,
J = 12.2 Hz, CH3, cycl.), 22.15, 25.38, 28.65, 34.09, 37.61
(cycl.), 46.84 (CH2-Bz), 56.30 (d, 1JPC = 141.9 Hz, C-1),
61.83, 61.34 (2JPC = 6.1 Hz, OCH2), 126.39, 127.78, 127.87,
141.09 (C arom.) ppm. 31P NMR (400 MHz, CDCl3): d =
28.52 ppm. IR: 1240 (P=O), 3340, 3470 (NH) cm–1.
Compound 10a. 1H NMR (400 MHz, CDCl3): d = 1.12, 1.27
(2 t, 6 H, 2CH3), 1.34, 1.64, 2.10, 2.24 (4 m, 14 H, cycl.),
2.75 (br s, 1 H, NH), 3.55 (A part AB syst, JAB = 13.2 Hz, 1
H, CH2Bz), 3.83 (B part AB syst, JAB = 13.2 Hz, 1 H,
CH2Bz), 3.80, 3.94, 4.10 (3 m, 4 H, OCH2), 7.27, 7.37 (2 m,
5 H, Ar) ppm. 13C NMR: d = 16.36, 16.58 (2 d, 3JCP = 6.3
Hz, CH3), 24.66, 25.29, 31.31, 34.13, 35.82, 44.18 (cycl.),
51.19 (d, J = 12.6 Hz, CH2-Bz), 60.12 (d, 1JPC = 154.1 Hz,
C-1, cycl.), 62.98, 63.15, (2JPC = 7.8 Hz, OCH2), 127.29,
128.10, 128.52, 128.87 (C Ar). 31P NMR: d = 22.5 ppm. IR:
1235 (P=O), 3260, 3360 (NH) cm–1. Anal. Calcd for
C21H32NPO3(377): C, 66.84; H, 8.49; N, 3.71; P, 8.22.
Found: C, 67.87; H, 7.50; N, 3.57.
Acknowledgment
This work was supported by grants from RFFI No. 01-03-33085,
No. 02-03-32163; UR 05.03.003; Grant of President of Russia for
support of Scientific School -2051.2003.3.
References
(1) Sheridan, R. P. J. Chem. Inf. Comput. Sci. 2002, 42, 103.
(2) Grembecka, J.; Mucha, A.; Cierpicki, T.; Kafarski, P. J.
Med. Chem. 2003, 46, 2641.
(3) Bird, J.; De Mello, R. C.; Harper, G. P.; Hunter, D. J.;
Karran, E. H.; Markwell, R. E.; Miles-Williams, A. J.;
Rahman, S. S.; Ward, R. W. J. Med. Chem. 1994, 37, 158.
(4) McLeod, D. A.; Brinkworth, R. I.; Ashley, J. A.; Janda, K.
D.; Wirsching, P. Bioorg. Med. Chem. Lett. 1991, 653.
(5) Moore, J. D.; Sprott, K. T.; Hanson, P. R. J. Org. Chem.
2002, 67, 8123.
(6) Liu, W.; Rogers, C. J.; Fisher, A. J.; Toney, M. Biochemistry
2002, 41, 12320.
(7) Ranu, B. C.; Hajra, A.; Jana, U. Org. Lett. 1999, 1, 1141.
(8) Kim, K. S.; Hurh, E. Y.; Youn, J. N.; Park, J. I. J. Org. Chem.
1999, 64, 9272.
(9) Osipov, S. N.; Artyushin, O. I.; Kolomiets, A. F.; Bruneau,
C.; Dixneuf, P. H. Synlett 2000, 1031.
(10) Kabachnik, M. I.; Medved’, T. Ya. Dokl. Akad. Nauk SSSR
1952, 689; Chem. Abstr. 1953, 47, 2724b.
(11) Fields, E. K. J. Am. Chem. Soc. 1952, 74, 1528.
(12) Kuchar, V. P.; Solodenko, V. A. Russ. Chem. Rev. 1987, 56,
1504.
(13) Cherkasov, R. A.; Galkin, V. I. Russ. Chem. Rev. 1998, 67,
940.
(14) Kuchar, V. P.; Svistunova, N. Yu.; Solodenko, V. A.;
Soloshonok, V. A. Russ. Chem. Rev. 1993, 62, 284.
(15) Uziel, J.; Genêt, J. P. Zh. Org. Khim. 1997, 33, 1605.
(16) LaPointe, A. M. J. Comb. Chem. 1999, 1, 101.
(17) Pudovik, A. N. Dokl. Akad. Nauk SSSR 1952, 83, 865;
Chem. Abstr. 1953, 47, 4300.
(18) Laschat, S.; Kunz, H. Synthesis 1992, 90.
(19) Quian, C.; Huang, T. J. Org. Chem. 1998, 63, 4125.
(20) Manabe, K.; Kobayashi, S. Chem. Commun. 2000, 669.
(21) Lee, S.-gi.; Park, J. H.; Kang, J.; Lee, J. K. Chem. Commum.
2001, 1698.
Compound 10b. 1H NMR (CDCl3): d = 1.36 (t, 6 H, 2CH3),
1.52, 1.74, 1.85, 2.13, (3 m, 10 H, cycl.), 2.35, 2.42 (2 m, 4
H cycl.), 3.01 (br s, 2 H, NH2), 4.21 (m, 4 H, OCH2), 7.27,
7.37 (2 m, 5 H, Ar) ppm. 13C NMR: d = 16.08 (CH3), 26.13,
26.62, 31.66, 31.77, 33.27, 33.41, 38.77, 46.88 (cycl.), 62.19
(d, 2JPC = 7.8 Hz, OCH2) ppm. 31P NMR: d = 25.39 ppm. IR:
1245 (P=O), 3280 (NH2) cm–1.
Compound 12a. 1H NMR (CDCl3): d = 1.05, 1.15 (2 m, 2 H,
cycl.), 1.34, 1.35 (2 t, 6 H, 2CH3), 1.51, 1.88, 2.12, 2.26, 2.60
(5 m, 10 H, cycl.), 3.69 (A part AB syst., JAB = 13.4 Hz, 1 H,
CH2Bz), 3.85 (B part AB syst, JAB = 13.4 Hz, 1 H, CH2Bz),
3.99–4.23 (m, 4 H, OCH2), 7.21, 7.31, 7.37 (3 m, 5 H, Ar)
ppm. 31P NMR: d = 30.53, 31.44 (2 s, 2:1) ppm.
(22) Tomilova, L. G.; Rodionova, G. N.; Lucyanetz, E. A. Koord.
Chim. 1979, 5, 549; Chem. Abstr. 1979, 91, 221595d.
(23) Kochmann, W.; Gunter, E.; Rothling, T. Z. Chem. 1976, 16,
184.
(29) These signals are at 1.30–1.36 ppm (t, CH3) and at 4.10–4.20
2
ppm (complicated multiplet OCH2 JPH = 3.1 Hz).
(30) In 1H NMR spectra, the protons of CH3 groups were
observed at d = 1.15 and 1.30 ppm (2 t, 1:1). The diastereo-
topic protons of two diastereotopic OCH2 groups appear as
several multiplets at 3.80–4.50 ppm (2JPH = 3.1 Hz): either
four multiplets in ratio 1:1:1:1 or the superposition of three
multiplets in ratio 1:2:1. In 1H NMR spectra of a-benzyl-
aminophosphonates (series a) the signals of diastereotopic
benzyl protons resonate at 3.50–3.70 ppm as two doublets
(JAB = 12.8 Hz).
(24) Fadel, A.; Tesson, N. Eur. J. Org. Chem. 2000, 2153.
(25) General Procedure: To the solution of ketone (2 mmol) in
solvent (3 mL, see Table 1), the benzylamine (2 mmol) or
NH4(CO3)2 (6 mmol), anhyd MgSO4 (2 mmol) and Pht-122
(10 mol%; 0.2 mmol) as a catalyst were added. The reaction
mixture was heated for 3–4 h. Then diethylphosphite (2.4
mmol) was added. The reaction mixture was stirred for 12–
24 h (see Table 1). The desiccant was then filtered and
washed with 2 mL of CH2Cl2. The solvent was evaporated,
and the residue was purified by chromatography on silica gel
(eluent: CH2Cl2/MeOH = 20:1). In the case of steric
hindered and cage ketones (adamantanone-2, camphor and
norbornanone) 50% amine excess is required.
(31) There is the corresponding duplication of signals of the
diastereotopic ethoxy group in 13C NMR spectra. In fact,
CH3 groups resonate as two doublets at d = 16.00 ppm
(3JPC = 6.3–6.5 Hz) and the OCH2 group as two doublets at
62.00–63.00 ppm (2JPC = 8.6 Hz). These values are in
agreement with available literature data.24 The quaternary
carbon atom resonates at d = 50.00-60.00 ppm (1JPC = 140–
150 Hz).27
(26) All obtained compounds gave satisfactory elemental
analyses with the range of C 0.3%, H 0.2%, N 0.3%.
(27) IR spectra registration was carried out in condensed phase
and in the solution in CCl4. There are stretches absorptions
Synlett 2003, No. 15, 2321–2324 © Thieme Stuttgart · New York