Novel heterocyclic system - 2,4,1-benzoxazaphosphinine: Convenient substrate for synthesis of derivatives of 2,4-diaminophenylphosphonic acid

Article abstract of DOI:10.1055/s-2001-14584

N-Acylanilides having electron-donating substituents attached at a proper position react with phosphorus (III) bromides forming the new heterocyclic system - 2,4,1-benzoxazaphosphinine. 1-Arylimino-2,4, 1-benzoxazaphosphinines are hydrolyzed with cleavage of an oxazaphosphinine ring affording mixed amides of 2,4-diaminophenylphosphonic acid in high yield.

Full text of DOI:10.1055/s-2001-14584

860
LETTER
Novel Heterocyclic System – 2,4,1-Benzoxazaphosphinine: Convenient
Substrate for Synthesis of Derivatives of 2,4-Diaminophenylphosphonic Acid
Alexei O. Pushechnikov, Dmitrii G. Krotko, Dmitrii M. Volochnyuk, Andrei A. Tolmachev*
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanskaya 5, Kyiv-94, 02094, Ukraine
Fax +380 44 5590480; E-mail: azole@i.com.ua
Received 12 February 2001
The heterocyclization reaction in pyridine is complete at
Abstract: N-Acylanilides having electron-donating substituents at-
room temperature in 10 minutes.9 After the reaction is
tached at a proper position react with phosphorus (III) bromides
complete the NMR 31P spectrum exhibits one resonance
peak. In the case of phosphorus tribromide the signal is at
forming the new heterocyclic system - 2,4,1-benzoxazaphosphin-
ine. 1-Arylimino-2,4,1-benzoxazaphosphinines are hydrolyzed
with cleavage of an oxazaphosphinine ring affording mixed amides 158 ppm. Obtained in this way a solution of the benzox-
of 2,4-diaminophenylphosphonic acid in high yield.
azaphosphinine bromide 2 in pyridine can be utilized as a
starting material to introduce new substituents on phos-
phorous.
Key words: arylamides, phosphorus (III) halides, phosphorylation,
heterocyclization, ring opening
Upon treatment with secondary amines benzoxazaphos-
phinine bromides 2 undergo a halogen substitution yield-
ing amides 4 that can be oxidized e.g. with elemental
sulfur or arylazides affording cyclic amides 510 and 6 re-
spectively. Thioamides 5 are stable to moisture in air,
whereas iminoamides 6 are easily hydrolyzed.11 In the
presence of water the oxazaphosphine ring is opened re-
sulting in high yields of mixed amides of 2,4-diaminophe-
nylphosphonic acid 7.12
Aminophosphinic and aminophosphonic acids and their
derivatives in the past decade are probably the most inves-
tigated class of organophosphorus compounds. Over-
whelming objects of study are the phospha analogues of
natural amino acids, that is aminoalkyl type compounds.
Aminoarylphosphinic and phosphonic acids and their de-
rivatives are illustrated to a lesser degree, however, they
have also found some application in view of their biolog-
ical potency.1-4
Though many methods of synthesis of aminoarylphos-
phonates are known, here we focus on a simple method
that allows a wide range of substituents both in the amide
substituents at the phosphorus, and in the acyl substituents
at the 2-amino group of the benzene ring. The basis for
this method is the non-catalyzed elecrophilic phosphory-
lation of N,N-dimethylaniline with phosphorus (III) ha-
lides.5
m-Acylaminodimethylanilines 16 react with phosphorus
(III) bromides forming the new phosphorus-containing
fused heterocyclic system – 2,4,1-benzoxazaphosphinine
2, 3. The first step, most plausibly, is the attack of the elec-
trophilic reagent at the oxygen atom of the amide group7
followed by heterocyclization at the C-nucleophilic
centre8 giving an energy favorable six-membered ring.
Scheme 2
Scheme 1
Synlett 2001, No. 6, 860–862 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Novel Heterocyclic System – 2,4,1-Benzoxazaphosphinine
861
Table 1 Yields and melting points of the 3-(dimethyamino)anilides
1a-d and 1-amido-3-aryl(hetaryl)-6-(dimethylamino)-2,4,1 5-ben-
zoxazaphosphinine-1-thioxides 5a-e.
Besides the dimethylamino group other electron-donating
groups can be utilized. Thus, as described, derivatives of
6-amino-1,2,3,3-tetramethyl-2,3-dihydro-5-indolylphos-
phonic acid 10 (Scheme 3) were synthesized in high yield.
But activation of the benzene ring with alkoxy groups was
effective only for 3,4,5-trimethoxyanilide 11 (Scheme 4),
as a result compound 13 was obtained in low yield
(16%).13
Table 3 Yields and melting points of the 6-(acylamino)-1,2,3,3-te-
tramethyl-2,3-dihydroindoles 8a-c and 6-(acylamino)-1,2,3,3-tetra-
methyl-2,3-dihydro-5-indolylphosphonic acid amides 10a-d.
a Yields refer to pure isolated products; b melting points are uncorrec-
ted.
Table 2 Yields and melting points of the 2-(acylamino)-4-(dime-
thylamino)phenylphosphonic acid amides 7a-g.
a Yields refer to pure isolated products; b melting points are uncorrec-
ted.
The structure of the new phosphorus (V) substances was
confirmed by 1H, 31P and 13C NMR spectroscopy. The ab-
sence of a signal for an amide proton14 and a signal with a
considerable coupling constant for C(8a) are the most
convincing evidence for the formation of the oxazaphos-
1
phinine ring. For compound 5a JCP = 147 Hz.15 The H
NMR spectra of aminoarylphosphonates 716 and 10 are
characterized by a doublet at = 6.3 6.6 with 2JPNH ~ 8.5
Hz and an amide signal at = 11 12.
a Yields refer to pure isolated products; b melting points are uncorrec-
ted.
Scheme 3
Synlett 2001, No. 6, 860–862 ISSN 0936-5214 © Thieme Stuttgart · New York

862
A. O. Pushechnikov et al.
LETTER
Scheme 4
(10) Typical procedure: To a stirred solution 2 in pyridine9
Acknowledgement
equimolar amounts of amine and elemental sulfur were added.
After full dissolving of the sulfur pyridine was evaporated in
vacuo. The residue was triturated with water and crystallized
from 2-propyl alcohol.
We thank DuPont de Nemours for financial support this work.
References and Notes
(11) a) Kirsanov, A.V.; Shevchenko, V.I. Zh. Obshch. Khim. 1954,
24, 474; Chem. Abstr. 1955, 49, 6164a. b) Kabachnik, M.I.;
Gilyarov, V.A. Izv. Akad. Nauk SSSR 1956, 790; Chem. Abstr.
1957, 51, 1823b.
(1) D.R.P. 397813, Casella&Co.; Zbl. 1924, II, 1271.
(2) Zachariae, G. Dtsch. Med. Wochenschr. 1928, 54, 920; Zbl.
1928, II, 268.
(3) Bhaskaran, R.; Patil, R.V. Indian Vet. J. 1982, 59(7), 518;
Chem. Abstr. 1982, 97, 143460.
(4) a) Kafarski, P.; Lejczak, B. In Aminophosphonic and
Aminophosphinic Acids, Kukhar, V.P.; Hudson, H.R., Eds.;
Wiley: Chichester, 2000; pp 408-411. b) Jane, D.E. In
Aminophosphonic and Aminophosphinic Acids, Kukhar, V.P.;
Hudson, H.R., Eds.; Wiley: Chichester, 2000; pp 505-510.
(5) a) Bourneuf, M. Bull. Soc. Chim. Fr., Memor. 1923, 4, 33,
1808. b) Raudnitz, H. Chem. Ber. 1927, 60, 743.
c) Tolmachev, A.A.; Ivonin, S.P.; Kharchenko, A.V.; Kozlov,
E.S. Zh. Obshch. Khim. 1989, 59, 1193; Chem. Abstr. 1990,
112, 77350.
(6) All starting N-acylanilines are synthesized from the
corresponding anilines and acylchlorides in pyridine medium
- Moeller, F. In Houben-Weyl; 4th ed., Vol. XI/2; Mueller, E.,
Ed.; Thieme: Stuttgart, 1958; p 11.
(7) a) Kawanobe, W.; Yamaguchi, K.; Nakahama, S.; Yamazaki,
N. Makromol. Chem. 1985, 186(9), 1803. b) Sinitsa, A.D.;
Malenko, D.M.; Repina, L.A.; Loktionova, R.A.; Shurubura,
A.K. Zh. Obshch. Khim. 1986, 56, 1262; Chem. Abstr. 1987,
106, 50311.
(8) Malenko, D.M.; Nesterova, L.I.; Luk’yanenko, S.N.; Sinitsa,
A.D. Zh. Obshch. Khim. 1989, 59, 1908; Chem. Abstr. 1990,
112, 77379.
(9) Typical procedure: To a stirred solution 1.5 mmol of anilide 1
in 20 mL of dry pyridine 1.5 mmol phosphorus tribromide was
added. After 10 min reaction mixture can be utilized for
following transformations.
(12) Typical procedure: To a stirred solution 2 in pyridine9 two-
fold excess of amine and equimolar amount of arylazide were
added. The mixture was maintained at 50 °C until the nitrogen
evolution had stopped, and then pyridine was evaporated in
vacuo. The residue was triturated with water and crystallized
from 2-propyl alcohol.
(13) 13: mp 164-166 °C; 1H NMR (300 MHz, DMSO-d6): 2.3 (s,
3H, CH3), 3.58 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.95 (s,
3H, OCH3), 6.42 (m, 1H, CH), 6.95 (d, 1H, 3J = 5.7 Hz, CH),
7.22 (m, 1H, CH), 7.43 (s, 1H, CH), 7.76 (m, 1H, CH), 7.96
(d, 1H, 3J = 3.8 Hz, CH).
(14) 5a: 1H NMR (300 MHz, CDCl3): 3.07 (s, 6H, N(CH3)2), 3.28
(m, 4H, N(CH2)2), 3.58 (t, 4H, O(CH2)2), 6.7 (m, 2H, CH),
7.42 (d, 2H, 3J = 8.5 Hz, CH), 7.6 (dd, 1H, 3JPH = 15.4Hz,
3J = 8.5 Hz, CH), 8.15 (d, 2H, 3J = 8.5 Hz, CH).
(15) 5a: 13C NMR (75 MHz, CDCl3): 40 N(CH3)2, 45.1 NCH2, 67.1
OCH2, 104.1 (1JPC = 147.2 Hz) C(8a), 109.4 (3JPC = 9.1 Hz)
C(7), 112.2 (3JPC = 15.8) C(5), 128.7 °C', 129.6 mC', 130.5
(2JPC = 11.8 Hz) C(8), 130.7 (3JPC = 3.9 Hz) ipso C', 138.2 pC',
147 (4JPC = 4.8 Hz) C(6), 151.8 (2JPC = 12.1 Hz) C(4a), 154.1
(2JPC = 2.8 Hz) C(3).
(16) 7a: 1H NMR (300 MHz, DMSO-d6): 3.01 (s, 6H, N(CH3)2),
3.08 (m, 4H, N(CH2)2), 3.5 (m, 4H, O(CH2)2), 6.54 (d, 1H,
2JPNH = 8.7 Hz, PNH), 7.36 (m, 3H, CH), 7.67 (d, 2H, 3J = 8.4
Hz, CH), 8.06 (d, 2H, 3J = 8.4 Hz, CH), 8.14 (m, 3H, CH),
8.81(d, 1H, 3J = 10.5 Hz, CH), 12.12 (s, 1H, NH).
Article Identifier:
1437-2096,E;2001,0,06,0860,0862,ftx,en;D03601ST.pdf
Synlett 2001, No. 6, 860–862 ISSN 0936-5214 © Thieme Stuttgart · New York