Phosphorylated aziridinium salts: Synthesis and ring opening with nucleophiles

Article abstract of DOI:10.1016/j.mencom.2011.07.009

Treatment of 1-tert-butyl-2-dimethoxyphosphoryl-3,3-dimethylaziridine with picric, perchloric or fluoboric acid affords the stable corresponding aziridinium salts, which are prone to undergo ring opening on reaction with alcohols, carboxylate and thiocyan

Full text of DOI:10.1016/j.mencom.2011.07.009

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 198–200
Phosphorylated aziridinium salts:
synthesis and ring opening with nucleophiles
Mukattis B. Gazizov,*a Rafail A. Khairullin,a Alina A. Minnikhanova,a
Anastasiya I. Alekhina,a Rashid Z. Musinb and Oleg G. Sinyashinb
a Kazan State Technological University, 420015 Kazan, Russian Federation.
Fax: +7 843 231 4103; e-mail: mukattisg@mail.ru
b A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of the Russian Academy
of Sciences, 420083 Kazan, Russian Federation. E-mail: oleg@iopc.knc.ru
DOI: 10.1016/j.mencom.2011.07.009
Treatment of 1-tert-butyl-2-dimethoxyphosphoryl-3,3-dimethylaziridine with picric, perchloric or fluoboric acid affords the stable
corresponding aziridinium salts, which are prone to undergo ring opening on reaction with alcohols, carboxylate and thiocyanate ions.
O
O
Phosphorylated aziridines, their salts and ring opening products
contain the corresponding pharmacophoric groups and therefore
they are potential biologically active substanses. 2-Halogenoalkan-
amines in alcohol solution are known to form low-stable aziridi-
nium halides which are susceptible of various transformations.1–3
Aziridinium perchlorates appeared to be stable and can be isolated
in pure form.3,4
(MeO)2PCH CMe2 + HX
NBut
(MeO)2PCH
CMe2
NHBut
X–
1
2a–c
3a–c
a X– = 2,4,6-(O2N)3C6H2O–
b X– = ClO4
c X– = BF4
Previously, C-phosphorylated NH-aziridines5 and their But-N
analogues 1 were documented.6,7 Obtaining of phosphorylated
aziridines 1 by treatment of methanolic solution of 1-tert-butyl-
amino-2-chloroalkylphosphonate with amines or sodium meth-
oxide is the evidence of the formation of intermediate phos-
phorylated aziridinium chloride 3e.6–8 The stable salts of com-
pounds 1 were not described in literature.
Scheme 1
O
1 + 2b,c + 0.5 Dioxane
(MeO)2PCH
CMe2
NHBut · 0.5 Dioxane
X–
Herein, we found that treatment of aziridine 1 with acids 2a–c
led to stable salts 3a–c,† which were isolated as individual
substances (Scheme 1).
4b,c
Room temperature,
+ 0.5 Dioxane
Heat, – 0.5 Dioxane
When the reactions between compounds 1 and 2b,c were
carried out in dioxane, the solvate complexes 4b,c‡ of the salts
3b,c with dioxane were formed in ratio 2:1. The compounds 4b,c
eliminate dioxane on recrystallization from acetone and turn into
salts 3b,c. The loss of dioxane by the solvate complexes 4b,c and
their decomposition into aziridine 1 at 200°C was also shown by
mass spectrometry.‡ Solvates 4b,c were also formed on contact
of salts 3b,c with dioxane (Scheme 2).
3b,c
Scheme 2
Aziridinium salts 3 react with nucleophiles to produce polyfunc-
tional organophosphorus derivatives.§ For example, salt 3a reacts
‡
1-tert-Butyl-2-dimethoxyphosphoryl-3,3-dimethylaziridinium perchlorate
3b and its solvate with dioxane 4b. Under argon atmosphere 0.99 g
(0.098 mol) of 67.5% perchloric acid 2b was added dropwise to 2.3 g
(0.098 mol) of aziridine 1 in 15 ml of dioxane with stirring at 13°C. A slight
warming-up of the reaction mixture was observed. The solvate complex
with dioxane 4b was isolated by precipitation with diethyl ether from
dioxane, yield 3.21 g (86%), mp 119°C. 1H NMR (CD3OD) d: 1.52 (s, 9H,
CMe3), 1.82 and 1.86 (2s, 6H, CMe2), 3.67 (s, 4H, dioxane), 3.78 (d, 1H,
PCH, 2JPH 2.2 Hz), 3.97 and 3.95 (2d, 6H, 2POMe, 3JPH 11.4 Hz), 7.05
(br.s, 1H, +NH). 31P NMR (CD3OD) d: 15.6. MS, m/z (%): 235 (1.5) [M1]+,
220 (5.2) [M – Me]+, 178 (17.0) [M – But]+, 152 (100) [C4H11NO3P]+,
150 (20.4) [C4H9NO3P]+, 125 (10.7) [C8H15N]+, 110 (52.5) [C7H12N]+,
88 (35.4) [M2]+, 79 (36.4) [C2H7P]+, 57 (42.9) [But]+. Found (%): C, 37.94;
H, 7.11; N, 3.69; P, 8.17; Cl, 9.35. Calc. for C12H27NPO5Cl (%): C, 37.51;
H, 7.01; N, 4.10; P, 8.25; Cl, 9.03.
After recrystallization from acetone, the product was proved to be
compound 3b, mp 126°C. 1H NMR (CD3OD) d: 1.52 (s, 9H, CMe3), 1.82
and 1.86 (2s, 6H, CMe2), 3.78 (d, 1H, PCH, 2JPH 3.1 Hz), 3.93 and 3.97
(2d, 6H, 2POMe, 3JPH 11.3 Hz), 7.05 (br.s, 1H, +NH). 31P NMR (MeCN) d:
13.55. MS, m/z (%): 235 (1.3) [M1]+, 220 (5.3) [M – Me]+, 178 (14.3)
[M – But]+, 152 (100) [C4H11NO3P]+, 150 (28.3) [C4H9NO3P]+, 125 (10.8)
[C8H15N]+, 110 (79.7) [C7H12N]+, 79 (15.6) [C2H7P]+, 57 (43.3) [But]+.
†
1H NMR spectra were recorded on a Tesla BS-567A spectrometer (100
MHz, TMS) and 31P NMR spectra – on a CXP-100 spectrometer (36.5
MHz, 85% H3PO4). Mass spectra were measured on a DFS instrument
(Thermo Electron Corporation, USA) with electron ionization (70 eV).
The temperature of the ion source was 280°C, sample inlet system was
used. Processing of the mass spectral data was done using of ‘Xcalibur’
program. Ion peaks with the most abundant isotops were specified.
1-tert-Butyl-2-dimethoxyphosphoryl-3,3-dimethylaziridinium 2,4,6-tri-
nitrophenoxide 3a. A solution of 0.6 g (0.02 mol) of picric acid 2a in 2 ml
of diethyl ether was added dropwise to a stirred solution of 0.47 g (0.02 mol)
of aziridine 1 in 2 ml of diethyl ether under argon atmosphere. A slight
warming-up of the reaction mixture was observed. The mixture was left
at room temperature for 24 h. The crystals precipitated were filtered off,
recrystallized from ethyl acetate and dried in vacuo to afford 0.9 g of
1
aziridinium picrate 3a, yield 97%, mp 120°C. H NMR (acetone-d6) d:
1.68 (s, 9H, CMe3), 1.88 and 2.00 (s and d, 6H, CMe2, 3JPH 0 and 3 Hz),
3.79 (d, 1H, PCH, 2JPH 4 Hz), 3.94 and 3.98 (2d, 6H, 2POMe, 3JPH 12 Hz),
5.15 (br.s, 1H, NH), 8.73 (s, 2H, Ar). 31P NMR (acetone-d6) d: 15.4.
Found (%): C, 41.38; H, 5.39; N, 12.07; P, 6.68. Calc. for C16H25N4PO10
(%): C, 41.17; H, 5.25; N, 12.20; P, 6.84.
© 2011 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2011, 21, 198–200
Cl
O
O
KSCN
withmethanoland3breactswithpotassiumthiocyanateaffording
(EtOH)
the corresponding ring opening products 5a and 6 (Scheme 3).
Compound 6 was also obtained on treatment of dimethyl
(1-tert-butylamino-2-chloro-2-methylpropyl)phosphonate 7 with
potassium thiocyanate in ethanol. The reaction probably pro-
(MeO)2PCH CMe2
(MeO)2PCH CMe2
6
– KCl
ButNH
NHBut
Cl–
7
3e
Scheme 4
O2N
O
ceeds through the intermediate formation of aziridinium salt 3e
(Scheme 4).
3a + MeOH
3b + KSCN
(MeO)2PCH CMe2
O
NO2
ButNH2
OMe
In the case of dichloroacetic acid 2d (Scheme 5) salt 3d was
found to be unstable and it was converted into the salt of (1-tert-
butylamino-2-dichloroacetoxy-2-methylpropyl)phosphonate 8¶
by reacting with the second carboxylate species. Apparently the
dichloroacetate anion in salt 3d acts as a nucleophile attacking
the carbon atom of the aziridinium ring and causing ring opening.
Amine 7 formed is protonated by the second molecule of acid 2d
giving salt 8.
O2N
5a
SCN
O
EtOH
(MeO)2PCH CMe2
– KClO4
ButNH
6
Scheme 3
In conclusion, for the first time the stable phosphorylated
aziridinium salts and their solvates with dioxane were synthesized.
Dioxane (3 ml) was added to 0.5 g (0.0015 mol) of compound 3b with
stirring at room temperature under argon atmosphere. The mixture was
left for 24 h. After removal of the solvent the residue was found to be the
solvate complex 4b, yield 86%.
Cl2CHCOO–
Cl2CHCO2H
2d
(MeO)2PCH CMe2
1
NHBut
O
1-tert-Butyl-2-dimethoxyphosphoryl-3,3-dimethylaziridinium tetrafluoro-
borate 3c and its solvate with dioxane 4c. In a similar manner, 7.2 g
(0.0306 mol) of aziridine 1 in 35 ml of dioxane and 16.73 g (0.0306 mol)
of 40% fluoboric acid 2c gave 10.36 g of the solvate complex with
3d
OCOCHCl2
O
O
1
dioxane 4c, yield 92%, mp 115–117°C. H NMR (CD3OD) d: 1.64 (s,
2d
9H, CMe3), 1.97 and 2.01 (2s, 6H, CMe2), 3.59 (s, 4H, dioxane), 4.01 and
4.05 (2d, 6H, 2POMe, 3J 11.4 Hz), 4.34 (d, 1H, PCH, 2JPH 17.6 Hz), 6.65
(br.s, 1H, +NH). 31P NMR (CD3OD) d: 14.42. MS, m/z (%): 235 (1.4) [M1]+,
220 (5.5) [M – Me]+, 178 (20.2) [M – But]+, 152 (71.5) [C4H11NO3P]+,
150 (15.5) [C4H9NO3P]+, 125 (7.8) [C8H15N]+, 110 (100) [C7H12N]+, 88
(12.2) [M2]+, 79 (29.0) [C2H7P]+, 57 (45.6) [But]+.
(MeO)2PCH CMe2
ButNH OCOCHCl2
(MeO)2PCH CMe2
ButNH2 Cl2CHCOO–
7
8
Scheme 5
After recrystallization from acetone the product was proved to be com-
pound 3c, mp 117°C. 1H NMR (CD3OD) d: 1.64 (s, 9H, CMe3), 1.97 and
1.98 (2s, 6H, CMe2), 3.90 (d, 1H, PCH, 2JPH 16 Hz), 3.96 and 3.94 (2d,
1-tert-Butylamino-1-dimethoxyphosphoryl-2-methylprop-2-yl thiocyanate
6. Method A. Under argon atmosphere 1.93 g (0.0575 mol) of aziridinium
perchlorate 3b was added to a solution of 0.67 g (0.0575 mol) of finely
powdered KSCN in 5 ml of ethanol with stirring at 13°C. A slight warming-
up of the reaction mixture was observed. The mixture was left at room
temperature for 24 h. The precipitated crystals of KClO4 (0.43 g) were
filtered off, the reaction mixture was treated with diethyl ether. The solvent
was evaporated from the ether layer in vacuo. The residue was recrystal-
lized from Et2O–hexane and dried in vacuo, giving 0.6 g of compound 6,
yield 35%, mp 82–83°C. 1H NMR (CDCl3) d: 1.14 (s, 9H, CMe3), 1.62 and
1.84 (2s, 6H, CMe2), 1.71–1.87 (br.s, 1H, NH), 3.18 and 3.20 (2d, 1H,
PCH, 2JPH 16 Hz), 3.78 (d, 6H, 2POMe, 3JPH 11 Hz). 31P NMR (CDCl3) d:
26.5. Found (%): C, 48.80; H, 7.85; N, 9.50; P, 10.49, S, 10.68. Calc. for
C12H23N2PO3S (%): C, 48.60; H, 8.00; N, 9.05; P, 10.66; S, 10.90.
Method B. Dimethyl (1-tert-butylamino-2-chloro-2-methylpropyl)phos-
phonate 7 (5.0 g, 0.184 mol) was added to a solution of finely powdered
KSCN (1.79 g, 0.184 mol) in 20 ml of ethanol with stirring under argon
atmosphere. A slight warming-up of the reaction mixture was observed.
The mixture was left at room temperature for 24 h. The precipitated crystals
of KCl (1.14 g) were filtered off, the reaction mixture was treated with
diethyl ether. The solvent was evaporated from the ether layer in vacuo.
The residue was recrystallized from Et2O–hexane and dried in vacuo to
provide 3.42 g of product 6, yield 63%, which was identical to that obtained
by method A.
3
+
6H, 2POMe, J 11.4 Hz), 7.06 (br.s, 1H, NH). 31P NMR (CD3OD) d:
13.5. MS, m/z (%): 235 (16.0) [M1]+, 220 (66.1) [M – Me]+, 178 (88.6)
[M – But]+, 152 (100) [C4H11NO3P]+, 125 (83.2) [C8H15N]+, 110 (100)
[C7H12N]+, 79 (86.9) [C2H7P]+, 57 (94.8) [But]+.
Dioxane (3 ml) was added to 0.5 g (0.0015 mol) of compound 3c with
stirring at room temperature under argon atmosphere. The mixture was
left for 24 h. After removal of the solvent the residue was found to be the
solvate complex 4c, yield 89%.
§
Interaction of aziridinium salts with nucleophiles.
N-tert-Butyl-N-(1-dimethoxyphosphoryl-2-methoxy-2-methylpropyl)-
ammonium 2,4,6-trinitrophenoxide 5a. Aziridinium picrate 3a (0.9 g,
0.019 mol) was dissolved with stirring in 3 ml of methanol under argon
atmosphere. The mixture was left for 2–3 days. After removal of the
1
solvent product 5a was obtained, yield 95%, mp 115–117°C. H NMR
(CDCl3) d: 1.57 and 1.66 (2s, 9H, CMe3), 1.62 (s, 6H, CMe2), 3.38 (d, 1H,
2
3
PCH, JPH 15.5 Hz), 4.02 (d, 6H, 2POMe, JPH 11 Hz), 8.70 (br.s, 2H,
+NH2), 8.97 (s, 2H, Ar). 31P NMR (CDCl3) d: 20.7. Found (%): C, 41.13;
H, 5.85; N, 11.29; P, 6.25. Calc. for C17H29N4PO11 (%): C, 41.01; H, 5.78;
N, 11.34; P, 6.47.
Reaction between aziridine 1 and 2,4,6-trinitrophenol 2a in methanol.
Method A. A solution of 4.21 g (0.179 mol) of aziridine 1 in 10 ml of
methanol was added dropwise to a stirred solution of 4.10 g (0.179 mol)
of picric acid 2a in 25 ml of methanol under argon atmosphere. A slight
warming-up of the reaction mixture was observed. The mixture was left
at room temperature for 24 h. The precipitated crystals were filtered off
and dried in vacuo to give 10.2 g of the mixture of aziridinium picrate 3a
and the product of its ring opening 5a in 1:1 ratio, yield 60%. 31P NMR
(CD3OD) d: 16.6 and 20.7.
Method B. A solution of 2.00 g (0.085 mol) of aziridine 1 in 2 ml of
methanol was added dropwise to a stirred solution of 1.95 g (0.085 mol)
of picric acid 2a in 2 ml of methanol under argon atmosphere. A slight
warming-up of the reaction mixture was observed. The mixture was left
at room temperature for 2–3 days. The crystals precipitated were filtered
off, recrystallized from ethyl acetate and dried in vacuo to afford 2.84 g
of the product 5a, yield 67%.
¶
N-tert-Butyl-N-(2-dichloroacetoxy-1-dimethoxyphosphoryl-2-methyl-
propyl)ammonium dichloroacetate 8. A solution of 3.29 g (0.256 mol) of
dichloroacetic acid 2d in 2 ml of diethyl ether was added dropwise to a
stirred solution of 3.0 g (0.128 mol) of aziridine 1 in 25 ml of diethyl ether
at 0°C under argon atmosphere. A slight warming-up of the reaction
mixture was observed. The mixture was left at room temperature for 48 h.
After removal of Et2O in vacuo the precipitated crystals were filtered off,
recrystallized from benzene and dried in vacuo to give 5.66 g of product 8,
yield 90%, mp 87–88°C. 1H NMR (CDCl3) d: 1.16 (s, 9H, CMe3), 1.58
and 1.66 (2s, 6H, CMe2), 3.85 (d, 6H, 2POMe, 3JPH 11 Hz), 3.91 (d, 1H,
PCH, 2JPH 18 Hz), 6.41 and 6.47 (2s, 1H, CHCl2), 8.6 (br.s, 2H, +NH2).
31P NMR (CDCl3) d: 27.3. Found (%): N, 2.84; P, 6.29; Cl, 28.80. Calc.
for C14H26NPO7Cl4 (%): N, 2.86; P, 6.33; Cl, 28.99.
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Mendeleev Commun., 2011, 21, 198–200
4 N. J. Leonard and J. V. Paukstelis, J. Org. Chem., 1965, 30, 821.
The salts undergo ring opening on reaction with methanol,
carboxylate and thiocyanate ions. Perchlorate 3b displayed
bactericidal activity with regard to such microorganisms as
Staphylococcus aureus and E. coli.
5 S. Rengazaju and K. Darrel Berlin, J. Org. Chem., 1972, 37, 3304.
6 M. B. Gazizov, R. A. Khairullin, A. I. Alekhina, I. A. Litvinov, D. B.
Krivolapov, Sh. K. Latypov, A. A. Balandina, R. Z. Musin and O. G.
Sinyashin, Mendeleev Commun., 2008, 18, 262.
7 M. B. Gazizov, R. A. Khairullin, A. A. Minnikhanova, A. I. Alekhina, A. A.
Bashkirtsev and O. G. Sinyashin, Zh. Obshch. Khim., 2010, 80, 1963 (Russ.
J. Gen. Chem., 2010, 80, 2425).
8 A. A. Minnikhanova, M. B. Gazizov, R. A. Khairullin, A. I. Alekhina and
K.A. Igoshina, in Sbornik materialovVserossiiskoi konferentsii ‘Aktual’nye
problemy organicheskoi khimii’ (Proceedings of All-russian Conference
‘Actual Problems of Organic Chemistry’), KGTU, Kazan, 2010, p. 5 (in
Russian).
This study was supported by the Federal purpose programme
‘Scientific and pedagogical personnel of innovation Russia for
2009–2013’ (state contract P-1108).
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2 O. C. Dermer and G. E. Ham, Ethyleneimine and OtherAziridines. Chemistry
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3 ComprehensiveOrganicChemistry, eds. D. BartonandW. D. Ollis, Pergamon,
Oxford, 1979, vol. 2.
Received: 26th October 2010; Com. 10/3618
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