Comments on a novel synthesis of diethyl 1-aminoarylmethylphosphonates on the surface of alumina

Article abstract of DOI:10.1016/S0040-4039(03)00112-6

Contrary to the literature statement we found that aromatic aldehydes react with diethyl phosphite and hexamethyldisilazane to give 1-(trimethylsilyloxy)-1-arylmethylphosphonates and not 1-amino-1-arylmethylphosphonate derivatives. Therefore, for preparat

Full text of DOI:10.1016/S0040-4039(03)00112-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1863–1865
Comments on a novel synthesis of diethyl
1-aminoarylmethylphosphonates on the surface of alumina
Mirosław Soroka* and Krzysztof Kołodziejczyk
Politechnika Wrocławska, Instytut Chemii Organicznej, Biochemii i Biotechnologii, Wybrzez; e Wyspian´skiego 27,
PL-50370 Wrocław, Poland
Received 14 June 2002; revised 6 December 2002; accepted 10 January 2003
Abstract—Contrary to the literature statement we found that aromatic aldehydes react with diethyl phosphite and hexamethyl-
disilazane to give 1-(trimethylsilyloxy)-1-arylmethylphosphonates and not 1-amino-1-arylmethylphosphonate derivatives. There-
fore, for preparation of diethyl N-arylidene-1-amino-1-arylmethylphosphonate, we recommend the direct reaction of hydrobenza-
mides with diethyl phosphite, instead of aromatic aldehydes, hexamethyldisilazane and alumina as catalyst on solid phase, as has
been described previously (Sardarian, A. R.; Kaboudin, B. Tetrahedron Lett. 1997, 38, 2543–2546). © 2003 Elsevier Science Ltd.
All rights reserved.
In 1997 Sardarian and Kaboudin1 published unex-
pected results—they claimed a novel synthesis of
diethyl 1-amino-1-arylmethylphosphonates2 in the reac-
tion of aromatic aldehydes, hexamethyldisilazane and
diethyl phosphite, via diethyl N-arylidene-1-amino-1-
arylmethylphosphonate,3 on the surface of alumina.
They suggested that the use of ‘the technique of sur-
face-mediated solid phase reaction’, alumina in this
case, played an essential role in their experiments. Since
hexamethyldisilazane does not react with carbonyl
compounds4 and moreover, reacts with aldehydes (or
ketones) and dialkyl phosphites to give 1-hydroxy-
alkylphosphonic acid derivatives—but not 1-
aminoalkylphosphonates5—there is no reason to believe
that addition of ‘acidic alumina’ would change dramat-
ically the route of this reaction (Scheme 1).
have also found enough evidence for the rest of their
compounds. So, there is no reason to question their
results. Nevertheless, the question remains how it is
possible to obtain diethyl N-arylidene-1-amino-1-aryl-
methylphosphonates in the reaction of hexamethyldisi-
lazane with aromatic aldehydes and diethyl phosphite?
Therefore, we decided to analyze and reinvestigate this
reaction. The results of our investigation can be sum-
marized as follows:
1. We found that the only effect of the application of
acidic alumina in this protocol was decomposition of
hexamethyldisilazane with evolution of ammonia.6 The
reaction of hexamethyldisilazane with alumina (even
However, the authors described the preparation of nine
diethyl 1-amino-1-arylmethylphosphonates with reason-
ably good yields and for one representative compound
they confirmed the structure of the 1-aminophospho-
nate by NMR and IR. We expect they undoubtedly
Scheme 2.
Scheme 1.
Keywords: hydrobenzamide; aminoalkylation; aminophosphonate; addition reaction; imine.
* Corresponding author. Tel.: +48-71-3202404; fax: +48-71-3284064; e-mail: soroka@kchf.ch.pwr.wroc.pl
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00112-6

1864
M. Soroka, K. Kołodziejczyk / Tetrahedron Letters 44 (2003) 1863–1865
Scheme 3.
dried in an oven) gives ammonia. So, the mixture of
hexamethyldisilazane and alumina is just a source of
ammonia in this reaction.
Chem. 1988, 66, 310; (b) Dehnel, A.; Finet, J. P.; Lavielle,
G. Synthesis 1977, 474; (c) Heymes, A.; Chekroun, I.
Synthesis 1987, 245; (d) Malenko, D. M.; Nesterova, L.
I.; Luk’yanenko, S. N.; Sinitsa, A. D. Zh. Obshch. Khim.
1990, 60, 1186; (e) Onis’ko, P. P.; Kim, T. V.; Kiseleva,
E. I.; Sinitsa, A. D. Zh. Obshch. Khim. 1996, 66, 1283; (f)
Onys’ko, P. P.; Kim, T. V.; Kiseleva, E. I.; Prokopenko,
V. P.; Sinitsa, A. D. Zh. Obshch. Khim. 1990, 60, 523; (g)
Onys’ko, P. P.; Kim, T. V.; Kiseleva, E. I.; Sinitsa, A. D.
Zh. Obshch. Khim. 1987, 57, 1233; (h) Onys’ko, P. P.;
Kim, T. V.; Kiseleva, E. I.; Sinitsa, A. D. Zh. Obshch.
Khim. 1993, 63, 1906; (i) Onys’ko, P. P.; Kim, T. V.;
Kiseleva, E. I.; Sinitsa, A. D. Zh. Obshch. Khim. 1997, 67,
1642; (j) Onys’ko, P. P.; Kim, T. V.; Kiseleva, E. I.;
Turov, A. V. Zh. Obshch. Khim. 1990, 60, 1425; (k)
Russell, G. A.; Yao, C.-F. J. Org. Chem. 1992, 57, 6508;
(l) Tupchienko, S. K.; Dudchenko, T. N.; Sinitsa, A. D.
Zh. Obshch. Khim. 1985, 55, 776.
7
2. Ammonia reacts ‘in situ’ with aromatic aldehydes to
give
hydrobenzamides
(1-aryl-N,N%-bis(arylidene)-
methanediamine) as sole products (Scheme 2).8
3. Then, the hydrobenzamide reacts with diethyl
phosphite9 to give a diethyl N-arylidene-1-amino-1-
arylmethylphosphonate (Scheme 3), which can be easily
hydrolyzed to a diethyl 1-amino-1-arylmethylphospho-
nate and isolated as its sulphonate or hydrochloride.
In conclusion, for the preparation of diethyl 1-amino-1-
arylmethylphosphonates via diethyl N-arylidene-1-
amino-1-arylmethylphosphonates we recommend the
direct reaction of hydrobenzamide with diethyl phos-
phite,10 instead of aromatic aldehydes with hexamethyl-
disilazane and alumina as the catalyst and solid phase,
as has been described previously.1
4. Since the hexamethyldisilazane does not react with a
freshly distilled dry aldehyde, a simple preparation of
trimethylsilylimines in the reaction of an aldehyde with
hexamethyldisilazane is possible only under harsh condi-
tions for nonenolizable aldehydes. For a recent review
see: (a) Panunzio, M.; Zarantonello, P. Org. Process Res.
Develop. 1998, 2, 49–59. For examples of the preparation
and use of N-trimethylsilylimines see: (b) Cainelli, G.;
Giacomini, D.; Panunzio, M.; Martelli, G.; Spunta, G.
Tetrahedron Lett. 1987, 28, 5369; (c) Cainelli, G.; Panun-
zio, M.; Giacomini, D. Tetrahedron Lett. 1991, 32, 121;
(d) Chan, L.-H.; Rochow, E. G. J. Organomet. Chem.
1967, 9, 231; (e) Georg, G. I.; Harriman, G. C. B.;
Hepperle, M.; Clowers, J. S.; Vandervelde, D. G.; Himes,
R. H. J. Org. Chem. 1996, 61, 2664–2676; (f) Georg, G.
I.; Harriman, G. C. B.; Peterson, S. A. J. Org. Chem.
1995, 60, 7366; (g) Guillemin, J.-C.; Ammi, L.; Denis,
J.-M. Tetrahedron Lett. 1988, 29, 1287; (h) Ha, D.-C.;
Hart, D. J.; Yang, T.-K. J. Am. Chem. Soc. 1984, 106,
4819; (i) Hart, D. J.; Kanai, K.-I.; Thomas, D. G.; Yang,
T.-K. J. Org. Chem. 1983, 48, 289; (j) Kruger, C.;
Rochow, E. G.; Wannagat, U. Chem. Ber. 1963, 96, 2132.
5. 1-Amino-1-arylmethylphosphonates were prepared for
the first time by Kabachnik and Medved2d in a reaction
of ammonia, diethyl phosphite and an aldehyde (or
ketones), the so called Kabachnik–Medved reaction—for
a recent review see: (a) Cherkasov, R. A.; Galkin, V. I.
Uspekhi Khim. 1998, 67, 940–968. However, the use of
ammonia in this, Mannich type, reaction gave a rather
low yield of the desired product. Imines are not the
primary products of the reactions of ammonia with alde-
hydes or ketones. Ammonia reacts with formaldehyde to
give hexamethylenetetramine, with aliphatic aldehydes to
give 2,4,6-trialkyl-1,3,5-hexahydrotriazines and with aro-
matic aldehydes to give hydrobenzamides. For a disscus-
sion see: (b) Nielsen, A. T.; Atkins, R. L.; Moore, D. W.;
Scott, R.; Mallory, D.; LaBerge, J. M. J. Org. Chem.
1973, 38, 3288. Moreover, an equilibrium between hex-
References
1. Sardarian, A. R.; Kaboudin, B. Tetrahedron Lett. 1997,
38, 2543–2546.
2. The 1-amino-1-arylmethylphosphonates are very well
known compounds. For examples of their previous
preparation, see: (a) Chalmers, M. E.; Kosolapoff, G. M.
J. Am. Chem. Soc. 1953, 75, 5278; (b) Gross, H.; Beisert,
S.; Costisella, B. J. Prakt. Chem. 1981, 323, 877; (c)
Issleib, K.; Doepfer, K.-P.; Balszuweit, A. Z. Natur-
forsch. B Anorg. Chem. Org. Chem. 1981, 36, 1392; (d)
Kabachnik, M. I.; Medwed’, T. Ya. Izv. Akad. Nauk
SSSR Ser. Khim. 1953, 868; Kabachnik, M. I.; Medwed’,
T. Ya. Dokl. AN SSSR 1952, 83, 689; (e) Kreutzkamp,
N.; Cordes, G. Justus Liebigs Ann. Chem. 1959, 623, 103;
(f) Krzyzanowska, B.; Stec, W. J. Synthesis 1978, 521; (g)
Kudzin, Z. H.; Kotynski, A. Synthesis 1980, 1028; (h)
Kudzin, Z. H.; Majchrzak, M. W. J. Organomet. Chem.
1989, 376, 245; (i) Lukszo, J.; Tyka, R. Pol. J. Chem.
1978, 52, 959; (j) Lukszo, J.; Tyka, R. Synthesis 1977,
239; (k) Rachon, J.; Wasielewski, C. Rocz. Chem. 1975,
49, 397; (l) Takahashi, H.; Yoshioka, M.; Imai, N.;
Onimura, K.; Kobayashi, S. Synthesis 1994, 763; (m)
Topolski, M.; Rachon, J. Phosphorus, Sulfur Silicon
Relat. Elem. 1991, 55, 97; (n) Yamauchi, K.; Kinoshita,
M.; Imoto, M. Bull. Chem. Soc. Jpn. 1972, 45, 2528; (o)
Yuan, C.; Wang, G.; Chen, S. Synthesis 1990, 522.
3. The N-arylidene-1-amino-1-arylmethylphosphonates were
also described previously. See for examples: (a) Dehnel,
A.; Kanabus-Kaminska, J. M.; Lavielle, G. Can. J.

M. Soroka, K. Kołodziejczyk / Tetrahedron Letters 44 (2003) 1863–1865
1865
ahydrotriazines and imines has never been proved. Since
the hexahydrotriazines react with diethyl phosphites to
give complex mixtures of products with low yields of
aminophosphonates, several groups have tried to improve
the yield of aminoalkylation of tervalent phosphorus
compound, essentially by introducing ammonia equiva-
lents such as benzylamine: (c) Tyka R. Tetrahedron Lett.
1970, 9, 677; 1-phenylcyclopentylamine (see Refs 2i,j);
benzhydrylamine (see Ref. 2c); and tritylamine: (d)
Soroka, M.; Zygmunt, J. Synthesis 1988, 370. We have
also tried hexamethyldisilazane as an ammonia equiva-
lent. However, in the reaction of dry acetaldehyde with
hexamethyldisilazane and diethyl phosphite we isolated
only diethyl 1-trimethylsilyloxyethylphosphonate in
almost quantitative yield without any trace of
aminophosphonate. Similar results were obtained with
benzaldehyde—also the trimethylsilylated 1-hydrox-
yphosphonate was the sole product of this reaction. In
the cases of acetone or cyclohexanone the corresponding
diethyl 1-hydroxyalkylphosphonates were isolated in
crystalline states. According to our observation hexam-
ethyldisilazane is an excellent base in the Abramov reac-
tion: (d) Abramov, V. S. Zh. Obshch. Khim. 1952, 22,
647; and when 1-hydroxyalkylphosphonates are not steri-
cally hindered, it is also a silylating agent which converts
hydroxyphosphonic acids into their O-trimethylsilyl
derivatives. O-trimethylsilyl-1-hydroxyalkylphosphonates
are well known compounds. For examples see: (e)
Nesterov, L. V.; Krepysheva, N. J.; Sabirova, R. A.;
Romanova, G. N. Zh. Obshch. Khim. 1971, 41, 2449;
(f) Novikova, Z. S.; Mashoshina, S. N.; Sapozhnikova,
T. A.; Lutsenko, I. F. Zh. Obshch. Khim. 1970, 41, 2622;
(g) Evans, D. A.; Hurst, K. M.; Takacs, J. M. J. Am.
Chem. Soc. 1978, 100, 3467 and references cited therein.
6. When we mixed hexamethyldisilazane with any of the
alumina samples we had in our stock, we have always
observed ammonia evolution (by smell and by pH indica-
tor paper). Mixing alumina with benzaldehyde and hex-
amethyldisilazane gave hydrobenzamide as the sole
product after extraction and evaporation of the solvent.
Addition of a few drops of a saturated ethereal solution
of water into the mixture of acetaldehyde and hexa-
methyldisilazane in ether, resulted in precipitation of
white crystals identified as 2,4,6-trimethyl-1,3,5-hexahy-
drotriazine-‘acetaldehyde-ammonia trimer’ (see Aldrich
Catalogue, nr. 10.820-0). The same procedure in the case
of benzaldehyde resulted in practically quantitative isola-
tion of hydrobenzamide.
preparation of benzylidenaminophenylacetonitrile (sic!) in
the reaction of hydrobenzamide with hydrogen cyanide:
(b) Reinecke, A.; Beilstein, F. Ann. Chem. 1865, 136, 173.
In the Beilstein data base (Beilstein Informationssysteme
GmbH; BS9804PR) 88 substances related to hydrobenza-
mide and 318 of their reactions were recorded. For recent
examples see: (c) Karupaiyan, K.; Srirajan, V.; Desh-
mukh, A. R. A. S.; Bhawal, B. M. Tetrahedron Lett.
1997, 38, 4281–4284; (d) Larter, M. L.; Phillips, M.;
Ortega, F.; Aguirre, G.; Somanathan, R.; Walsh, P. J.
Tetrahedron Lett. 1998, 39, 4785–4788; (e) Kupfer, R.;
Brinker, U. H. J. Org. Chem. 1996, 61, 4185–4186; (f)
Kayukov, Ya. S.; Nasakin, O. E.; Urman, Ya. G.;
Khrustalev, N. V.; Nesterov, V. N.; Antipin, M. Y.;
Lyshchikov, A. N.; Lukin, P. M. Khim. Geterotsikl.
Soedin. 1996, 32, 1395; (g) Nasakin, O. E.; Lyshchikov,
A. N.; Lukin, P. M.; Bulaj, A. Kh. Khim. Geterotsikl.
Soedin. 1994, 30, 353; (h) Rey, A. W.; Droghini, R.;
Douglas, J. L.; Vemishetti, P.; Boettger, S. D.; Racha, S.;
Dillon, J. L. Can. J. Chem. 1994, 72, 2131; (i) Levai, L.;
Bozsing, D.; Benko, P.; Lax, G.; Mikite, G. Synth. Com-
mun. 1992, 22, 47; (j) Goerlitzer, K.; Schmidt, E. Arch.
Pharm. (Weinheim) 1991, 324, 785. The preparation of
hydrobenzamide is also described in (k) Vogel, A. I. A
Text-book of Practical Organic Chemistry, 3rd ed.; Long-
mans, Green & Co. Ltd: London, 1961; pp. 735 (Polish
Edition 1964, WNT Warszawa).
9. In fact, the reaction of hydrobenzamides and diethyl
phosphite was also reported in the literature: (a)
Kreutzkamp, N.; Cordes, G. Liebigs Ann. Chem. 1959,
623, 103; (b) Rogozhin, S. V.; Davankov, V. A.; Belov,
Yu. P. Izv. Akad. Nauk SSSR, Ser. Khim. 1973, 955; (c)
Belov, Yu. P.; Rakhnovich, G. B.; Davankov, V. A.;
Godovikov, N. N.; Aleksandrov, G. G.; Struchkov, Ju.
T. Izv. Akad. Nauk SSSR, Ser. Khim. 1980, 1125; (d)
Pudovik, A. N.; Shagidullin, R. R.; Khairullin, V. K.;
Vandyukova, I. I.; Chernova, A. V.; Gainullin, R. M.;
Pudovik, M. A. Izv. Akad. Nauk SSSR, Ser. Khim. 1996,
1303; (e) Gross, H.; Beisert, S.; Costisella, B. J. Prakt.
Chem. 1981, 323, 877.
10. The following synthesis of diethyl N-arylidene-1-amino-
1-arylmethylphosphonate is representative: diethyl phos-
phite (0.30 mole, Aldrich D9,923-4) was added to
hydrobenzamide8k (0.20 mole, Aldrich 16,764-9). The
mixture was heated (80-90oC for about 2 h, until evolu-
tion of ammonia ceased). The yield of diethyl N-benzyli-
dene-1-amino-1-phenylmethylphosphonate
was
ascertained by 31P NMR and isolation was accomplished
by evaporation to give the crude product in nearly quan-
titative yield (31P{1H} NMR (CDCl3): 21.2; 1H NMR
(CDCl3): 1.2 (dt, 6H, CH3, J=7.4), 4.0 (dq, 4H, CH2,
J=7.4), 4.9 (d, 1H, CH-P, J=18.5), 7.4–7.8 (m, 10H,
ArH), 8.4 (d, 1H, CH=N, J=4.8) which could be used
directly in the next reaction (for the preparation of
diethyl 1-amino-1-phenylmethylphosphonate hydrochlo-
ride, for example) or purified by vacuum distillation
(bp0.1 160–162°C3b).
7. Hexamethyldisilazane is a very well known mild ‘silaniz-
ing’ agent. See Fluka’s Silylating Agents; Fluka Chemie
AG 1995 (ISBN 3-905617-13-7), p. 21 and 120.
8. Hydrobenzamide was described for the first time in 1836
by Laurent in the reaction of benzaldehyde (‘Bitterman-
del o¨l’) with gaseous ammonia: (a) Laurent, M. A. Ann.
Pharm. 1837, 21, 130–134; ‘Ueber das Hydrobenzamid’;
Ann. Chim. Phys. 1836, 62, 23. It is noteworthy that as
early as in 1865 Reinecke and Beilstein reported the