J. Org. Chem.
1988,53, 1761-1767
Reaction of 2,B-bis-TST (3b) with 2-Methylpropanal. A mixture of 2,5-bis-TST (3b) (1.15 g, 5 mmol) and the aldehyde (2.27 mL, 25 "01) was stirred at room temperature for 2 h. The crude reaction mixture was diluted with THF (20 mL) and a solution of TBAF in THF (1mL) was added. After additional stirring (30 min), the solvent was removed under vacuum and the residue was dissolved in diethyl ether (30 mL). The solution was washed with saturated NaHC03. Usual workup and chromatography (silica gel, 1:ldiethyl ether-n-hexane) gave 0.81 g (80%) of the alcohol 26b: oil; 'H NMR 6 0.34 (s, 9 H), 0.94 (d, 3 H, J = 4 Hz), 1.01 (d, 3 H, J = 4 Hz), 2.17 (m, 1H), 3.24 (d, 1 H), 4.8 (dd, 1 H), 7.66 ( 8 , 1 H). Anal. Calcd for CloH19NOSSi: C, 52.35; H, 8.35; N, 6.10. Found: C, 52.37; H, 8.32; N, 6.11.
1761
Reaction of the Alcohol 26b with 3-Carbomethoxypropionyl Chloride. A mixture of the alcohol 26b (0.165 g, 0.72 mmol), 3-carbomethoxypropionyl chloride (0.5 mL, 4 mmol), and triethylamine (0.1 mL, 0.72 mmol) was heated at 80 "C for 48 h. The crude mixture was diluted with diethyl ether and washed with saturated NaHC03. Usual workup and chromatography (silica gel, 1:l diethyl etherln-hexane) gave 0.166 g (60%) of compound 29: oil; IR (CHC13)1740,1675 cm-'; 'H NMR 6 0.98 (d, 6 H, J = 7 Hz), 2.34 (m, 1 H), 2.72 (m, 6 H), 3.24 (m, 2 H), 3.69 (s,6 H), 5.9 (d, 1H), 8.3 (e, 1H); mass spectrum, m / e (relative intensity) M+ absent, 271 (38), 245 (19), 229 (27), 213 (32), 115 (100). Anal. Calcd for C1,HBNO,S C, 52.97; H, 6.01; N, 3.63. Found C, 52.95; H, 6.00; N, 3.64.
Synthesis, Molecular Symmetry, and Chemical Reactivity of C-Aryl-Substituted Phosphoraziridines Michael
E. Perlman*' and Thomas J. Bardos
Department of Medicinal Chemistry, School of Pharmacy, S t a t e University of New York a t Buffalo, Buffalo, New York 14260 Received November 5, 1987
PQ-Bis- and P,P,P-tris( 1-aziridiny1)phosphoramidescontaining aryl-substituted aziridine moieties, including para-substituted 2-phenylaziridines, an optically active aziridine, and all the possible C-aryl regioisomers of diphenylaziridine were prepared by condensation of the aziridines with the appropriate phosphoryl chlorides. For the preparation of the sterically hindered diphenylaziridine derivatives, an efficient phosphorylation procedure was developed that involved conversion of the aziridines to their lithium salts. The appearance of the aziridine ring regions of the 'H NMR spectra of these compounds suggested decreased conformational mobility, as well as the presence of an average axis of symmetry in tris(aziridiny1) compounds and a plane of symmetry in certain bis(aziridiny1) systems. The relative reactivities of these new phosphoraziridineswith 4-(p-nitrobenzyl)pyridine indicate the likelihood of significant SN1character in the ring-opening process.
The phosphoraziridines2 AB-163 (la) a n d AB-132 (lb) have been shown i n experimental and clinical studies to be potent antitumor agents as well as radiation sensitizer^.^ Analogues of AB-132 with various alkyl substitution patterns o n t h e aziridine ring have been prepared and considerable variation in b o t h the modes and rates of ring opening by water and 4-(p-nitrobenzyl)pyridine (NBP) was observed for these phosphinyl ~ a r b a m a t e s . ~T h e combination of potent antitumor and radiosensitizing activity, as well as the toxic effect of inhibition of acetyl cholinesterase: is exhibited only by compounds such as la and lb, which possess geminal dimethyl ring substitution. These properties m a y be d u e to a unique mode of hydrolysis involving rapid ring-opening at t h e substituted position a n d subsequent ring expansion? (1) Laboratory of Molecular Biophysics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709. (2) Trivial name for class of compounds comprising N-phosphinyl derivatives of aziridines. (3) Bardos, T. J.; Ambrus, J. L.; Ambrus, C. M. J. Surg. Oncol. 1971, 3,431. Wampler, G. L.; Kupeminc, M.; Regelson, W. Cancer Chemother. Pharmacol. 1980, 4, 49. Belgrad, R.; Wampler, G. L. Int. J. Radiat. Oncol. Biol. Phys. 1982, 8, 1219. (4) Bardos, T. J.; Barua, A. K.; Chmielewicz, Z. F.; Crevar, G. E.; Dailey, J. P.; Divald, S.; Papanastassiou, Z. B. J.Pharm. Sci. 1965,54, 187. Bardos, T. J.; Chmielewicz, Z. F.; Navada, C. K. J.Phurm. Sci. 1965, 54, 399. Bardos, T. J.; Chmielewicz, Z. F.; Ambrus, J. L.; Back, N. Int. Congr. Chemother., Proc., 5th 1967, 181. (5) Bardos, T. J.; Ambrus, J. L. Znt. Congr. Chemother., Proc., 3rd 1964,1036. Lalka, D.; Bardos, T. J. Biochem. Pharmacol. 1975,24,455.
0022-3263/88/1953-1761$01.50/0
l(a) x = OEt l ( b ) x = NHCOOEt
A pronounced tendency toward ring-opening at t h e benzylic carbon i n C-phenyl-substituted aziridines7 suggests t h a t t h e corresponding phosphoraziridines might resemble t h e 2,2-dimethylaziridine series in their chemical reactivity and thereby in their spectrum of biological activity as well. Radiation sensitization b y a free radical process would also be expected to b e favored. I n this report we describe t h e synthesis of C-aryl analogues of t h e bis(1-aziridinyl) compounds 1 as well as those of tris(2,2dimethyl-1-aziridiny1)phosphineoxide (TEPA-132): which has geminal dimethyl substitution b u t lacks t h e ability of (6) Bardos, T. J.; Dunn, J. A.; Perlman, M. E. Int. J. Radiat. Oncol. Biol. Phys., 1979,5, 1653. (7) Hassner, A,; Burke, S. S. Tetrahedron 1974, 30, 2613. (8) Munson, A. E.; Babbitt, H. C.; Segaloff, A.; Chmielewicz, Z. F.; Bardos, T. J.; Ambrus, J. L. Cancer Chemother. Rep. 1967, 51, 253.
0 1988 American Chemical Society
1762
Perlman and Bardos
J. Org. Chem., Vol. 53,No. 8, 1988 Scheme 11
Scheme I CI,(PO)X or POCI, E1,N
Ph
6
3(a) x = O E l 3(b) 3(C)
7 R=NO, R=MeO
io
= NHCOOEt x = YCH,F;HC,H,
X
5(a) x=OEt 5(b) x = NHCOOEI
8
9
Scheme I11
II
H
0
Ph
1
11
i\
MeLi
5(C)
Ph-f-7
1 to potentiate X-irradiation and to undergo the SN1-type ring expansion. Para substituents on 2-phenylaziridme and different isomers of diphenylaziridine were employed in order to probe both electronic and steric effects on ringopening. An efficient procedure for the phosphorylation of hindered aziridines was developed to facilitate the preparation of the diphenylaziridine derivatives.
N Li
/
l2
\
Ph
Results and Discussion 2-Phenylaziridine (2)9 was found to react readily with ethyl phosphorodichloridate, ethyl dichlorophosphinyl carbamate, and phosphorus oxychloride in the presence of triethylamine a t 0 "C by the methods previously described for C-alkylaziridine~~~~J~ to provide the corresponding ester 3a, carbamate 3b, and phosphine oxide 3c, respectively (Scheme I). Compounds 3a-c exhibited complex proton NMR spectra and were isolated as oils or solids having a broad melting range, suggesting that 3a-c were obtained as mixtures of diastereomers. In analogy with the symmetry properties of 2,3,4-trihydroxyglutaric acid (ABA-type) described by Elie1,ll four stereoisomers should be generated by the condensation of two asymmetric aziridines with a molecule of phosphoryl dichloride: a dl pair and two meso forms. Condensation of 3 equiv of an asymmetric aziridine with POC13should also generate four stereoisomers (as pairs of enantiomers). Since individual diastereomers could not readily be isolated from the mixtures obtained from phosphorylation of racemate 2, the syntheses were repeated by utilizing (R)-(-)-a-phenylaziridine (4)12to yield the corresponding single diaste(9)Brois, S.J. J. Org. Chem. 1962, 27, 3532. (10) Chmielewicz,Z.F.; Bardos, T. J.; Munson, A. E.; Babbitt, H. C.; Ambrus, J. L. J. Pharm. Sci. 1967,56, 1179. (11)Eliel, E.L.Stereochemistry of Carbon Compounds, McGraw-Hill: New York, 1962;p 28.
I N P 13 15 16
x=OEI x=CI x=NH,
h
A
P h' 14
reomers (R,R)-5aand -5b and R,R,R isomer 5c (Scheme I). They possessed much simpler 'H NMR spectra than 3a-c, as it was expected, and all had very large optical rotations, e.g., -321' for 5c. 2-(p-Nitrophenyl)aziridine(6) was prepared by epimination of p-nitr~styrenel~ with 3,3-pentamethyleneoxaziridine according to the method of Schmitz,14and then phosphorylated to yield phosphinate 7 as a diastereomeric mixture (Scheme 11). Reduction of p-methoxyacetophenone oxime ( 8 ) with Vitride, based on the general aziridine synthesis of Lqdor,15 and careful workup provided the very labile 2-(p-methoxyphenyl)aziridine (9). (12)Nabeva. A.; Shiaemoto. T.; Iwakura, Y. J . O m . Chem. 1976,40, 3536. (13)Broos, R.;Anteunis,'M. Synth. Commun. 1976, 6, 53. (14)Schmitz, E.; Janisch, IC. Chem. Heterocycl. Compds. (Engl. Transl.) 1974, 1432;Khim. Geterotskl. Soedin. 1974, 1629. (15)Landor, S . R.;Sorola, 0.; Tatchell, H. R. J. Chem. SOC.,Perkin Trans. 1, 1974, 1294.
J. Org. Chem., Vol. 53, No. 8, 1988 1763
C-Aryl-Substituted Phosphoraziridines
Table I. 270-MHz IH N M R Data for N-Phosphorylated Diphenylaziridines (in CDC13)
compd 13 14 15 16 23 26
aziridine isomer gem gem gem gem trans cis
3rd group bound to
coupling constants,b Hz
chemical shifts, ppm
P
H la
OEt aziridine C1 NHZc OEt OEt
2.48 (dd) 2.31 (d) 2.85 (dd) 2.58 (dd) 3.74 (d) 4.10 (d)
HZa OCHp 2.64 (dd) 3.47d (quint)
Ar
CH3 0.88 (t)
7.32 7.21 3.09 (dd) 7.29 2.98 (dd) 7.29 3.83 (d) 2.87 (m), 3.06 (m) (1:l) 0.56d (t) 7.23 4.3Se (quint) 1.32 (t) 7.11
HlHZ PHI PHP
(m) (s) (m), 7.46 (m) (m), 7.41 (m) (m), 7.32 (m), 7.38 (m) (m)
1.5 1.3 1.6
13.8 14.8 13.8 16.2 19.5 13.3 15.8 14.5 15.2 16.5
'Protons on aziridine ring. *Coupling constants are first-order approximations. c6(NH) 1.80 (br d, J = 3.3 Hz). dJ(CH,-CH3) = 6.9 Hz. 'J(CHZ-CH3) 7.2 Hz.
Condensation with ethyl phosphorodichloridate in the presence of a large excess of Et3N, followed by chromatography, yielded the less reactive diastereomeric mixture 10. The analogous condensation reactions of diphenylaziridines with phosphoryl dichlorides proved to be considerably less facile than those of the monophenyl(ary1)aziridines. 2,2-Diphenylaziridine (1 1) was obtained according to Navada16 by treatment of methyl N-(2-iodo1,l-dipheny1ethane)carbamate" with methanolic potassium hydroxide (Scheme 111). Reaction of 11 with ethyl phosphorodichloridate under the conditions employed for the 2-arylaziridines yielded no product, probably due to severe steric hindrance toward condensation. Use of elevated temperatures yielded only polymeric material. Treatment of 11 at 0 "C with MeLi, followed by ethyl phosphorodichloridate, yielded a complex mixture, as did the use of NaH, while n-butyllithium at -78 "C generated the desired product but in variable yields. However, the use of just below 1 equiv of methyllithium per equiv of aziridine at approximately -78 "C in ether solution to generate lithium aziridine 12, followed by addition of phosphorodichloridate and subsequent stirring at 4 "C, resulted in nearly quantitative precipitation of the desired ethyl bis(2,2-diphenyl-l-aziridinyl)phosphinate (13). Tris(aziridiny1)phosphineoxide 14 was obtained in a similar manner by the reaction of phosphorus oxychloride and 4 equiv of aziridine-lithium salt 12. Bis(aziridiny1)phosphinyl carbamate 18 could not be obtained by treatment of the aziridinelithium salt 12 with ethyl dichlorophosphinyl carbamate, presumably due to competing abstraction of the carbamate N H proton. However, bis(2,2-diphenyl-l-aziridinyl)phosphinicchloride (15)could be prepared as a fairly stable, crystalline solid by addition of POCl:, to 2 equiv of 12. The considerable steric bulk of the four benzene rings may be responsible for the much greater stability of 15 than that of the analogous phosphoryl chlorides prepared from ethyleneiminels and 2,2-dimethylaziridine.l9In fact, subsequent reaction of the phosphinic chloride with KOCN in absolute EtOH at 4 "C provided not the phosphinyl carbamate 18 as expected20g21but, based on the infrared spectrum, only a phosphinyl isocyanate was generated that was presumably 17. Heating of 17 in situ yielded a carbamate, but attempts at isolation of either 17 or 18 without ringopening were not successful. However, the phosphinyl (16) Navada, C. K. Ph.D. Dissertation, State University of New York at Buffalo, 1967. (17) Haesner, A.; Lorber, M. E.; Heathcock, C. J. Org. Chem. 1967,32, 540. (18)Friedman, 0. M.; Levi, R. S.; Papanastassiou, Z. B.; Waley, W. M. J. Med. Chem. 1963,6, 449. (19) Perlman, M. E.; Bardos, T. J., unpublished results. (20) Bardos, T. J.; Dillard, R. D.; Papanastassiou, Z. B. Chem. I n d . (London) 1963, 1464. (21) Bardos, T . J.; Papanastassiou, Z. B. U.S. Patent 3 201 313, 1965.
chloride 15 could be converted to amide 16 upon treatment with ammonia.
17 X = NCO 18 X = NHCOOEt
The 'H NMR spectra of bis(2,2-diphenyl-l-aziridinyl)phosphinyl derivatives 13,15,and 16 are all characterized by two apparent doublet-of-doublets for the aziridine ring protons (see Table I for 270-MHz data). The effects of varying field strength and solvent showed that each doublet of doublets is an individual spin system. The spectra of phosphoraziridines of 2,2-dimethylaziridine,such as la,1° normally have a simple doublet for the aziridine = 14 Hz). The methylene protons methylene protons (Jp-H in the corresponding 2,2-diphenylaziridine compounds appear to exhibit geminal coupling, perhaps due to hindrance to aziridine N-inversion or P-N rotation. N-Invertomers were first observed in NMR spectra of secondary amines by Bardos and co-workers in the case of 2,2,3,3tetramethylaziridineZ2 and have also been reported for d i p h e n y l a ~ i r i d i n e s . ~ ~The ? ~ ~aziridine portion of the spectrum of tris(aziridiny1) compound 14 consists only of a doublet, however, as does that reported for the monoaziridinylphosphinate 19.25 The equivalence of the azirR, .
0
OR2
idine rings indicated in the spectrum of 14 may be the result of an average axis of rotational symmetry. The lack of geminal coupling appears to indicate that in addition a plane of symmetry passes through each aziridine ring to yield average C,, symmetry. Thus, in 14 corresponding protons in different rings would be homotopic and those in the same ring enantiotopic, while in 13, 15, and 16 protons in different rings would be enantiotopic (due to a plane of symmetry through P=O) and those in the same ring diastereotopic (see Scheme 111). In the case of the 2-phenylaziridine derivatives, the aziridine proton pattern in the spectrum of 5c is nearly identical with that of the monoaziridinyl analogue 20,26 while 5a and 5b possess much more complex spectra. Thus ~~~~~~~~
~
(22) Bardos, T. J.; Szantay, C.; Navada, C. K. J. Am. Chem. SOC.1966, 87, 5796. (23) Martino, R.; Abeba, J.; Lattes, A. J. Heterocyl. Chem. 1973,10,
91. (24) Martino, R.; Abeba, J.; Lattes, A. J. Tetrahedron Lett. 1973,433. (25) Hassner, A.; Galle, J. E. J . Am. Chem. SOC.1970, 92, 3733. (26) Berlin, K. D.; Rengaraju, S.; Clark, P. E. J. Heterocyl. Chem. 1970, 7, 1095.
Perlman and Bardos
1764 J. Org. Chem., Vol. 53, No. 8, 1988 Scheme IV Ph
-
-N ' +N
