Simple asymmetric synthesis of 2H-azirines derived from phosphine oxides

Full text of DOI:10.1021/jo9915426

J . Org. Chem. 2000, 65, 3213-3217
3213
Sim p le Asym m etr ic Syn th esis of
2H-Azir in es Der ived fr om P h osp h in e
Oxid es†
Francisco Palacios,*,‡ Ana Maria Ochoa de Retana,‡
J ose Ignacio Gil,‡ and J ose Maria Ezpeleta§
Departamento de Quı´mica Orga´nica and Departamento de
Fı´sica Aplicada, Facultad de Farmacia, Universidad del
Paı´s Vasco, Apartado 450, 01080 Vitoria, Spain
F igu r e 1. Biologically active 2H-azirines.
Received October 5, 1999
cytotoxic and inhibits the growth of Gram-negative
bacteria,5b (+)-(S)-disydazirine enantiomer or (+)-(S)-
antazirine are inactive against a standard panel of
microorganisms.5c For this reason the development of new
asymmetric syntheses of substituted 2-azirines is an
important synthetic goal.
Substituted and functionalized azirines are excellent
precursors to potential medicinal targets. In particular,
2H-azirines containing a carboxylic ester group1 are
excellent reagents for preparing functionalized aziri-
dines1,6 and R-6b,7a-d and â-amino acid derivatives.6b,7e-g
Furthermore, phosphorus substituents regulate many
important biological functions with molecular modifica-
tions influencing the biological activity.8 For these rea-
sons, functionalized azirines containing a phosphorus
substituent in the 2-position (II, Figure 1) are potential
isosteric analogues of I in the enantioselective synthesis
of R- and â-aminophosphorus derivatives.
Many procedures for the synthesis of 2H-azirines
involve the thermolysis or photolysis of vinyl azides,1a,b,9a-c
the thermolysis of isoxazoles9d or oxazaphospholines,9e or
the ring closure of nitrile ylides9f or employ the Neber
reaction.9g-i However, 2H-azirines directly substituted
with a phosphorus-containing functional group have
received scarce attention. To the best of our knowledge,
only the 2-phosphino-, 2-phosphonio-, and 2-thioxo-phos-
The highly strained 2H-azirine ring systems, the
smallest of the nitrogen-unsaturated heterocycles, rep-
resent a very important class of compounds because of
not only their theoretical interest but also the high
reactivity of this ring system toward nucleophilic and
electrophilic reagents,1 as well as their versatile thermal
and photochemical behavior.2,3 Each of the three bonds
of the azirine ring can be cleaved, depending on the
experimental conditions, and they can be used as key
intermediates in the preparation of functionalized amino
derivatives such as nonproteinogenic amino acids1a,4a,b
and peptolides,4c as well as for the synthesis of substi-
tuted aziridines,4d indoles,4e bis-steroidal pyrazines,4f or
bicyclic compounds.4g Optically active 2H-azirines with
an asymmetric center in the azirine cycle, namely,
azirinomycin5a (Ia , R ) Me, R′ ) H, Figure 1), isolated
from Streptomyces aureus, and both (-)-(R)-5b and (+)-
(S)-disydazirine,5c (Ib, R ) (E)-C13H27CHdCH, R ′) Me,
Figure 1) and (+)-(S)-antazirine5c (Ic, R ) (E)-Br2CdCH-
(CH2)9CHdCH, R′ ) Me, Figure 1), isolated from the
marine sponge Dysidea fragilis, are naturally occurring
antibiotics. The configuration of the asymmetric center
seems to play an important role in the biological activity
of these compounds; whereas (-)-(R)-disydazirine is
† Dedicated to Professor Dr. J ose´ Elguero on the occasion of his 65th
birthday.
* Telephone: (+34) 945-013103. Fax: (+34) 945-130756. E-mail:
qoppagaf@vc.ehu.es.
(6) (a) Osborn, H. M. I.; Sweeney, J . Tetrahedron: Asymmetry 1997,
8, 1693-1715. (b) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33,
599-619.
‡ Departamento de Qu´ımica Orga´nica.
§ Departamento de F´ısica Aplicada.
(1) For reviews on azirines see: (a) Backes, J . In Methoden der
Organische Chemie (Houben-Weyl); Klamann, D., Ed.; G. Thieme:
Stuttgart, 1992; Vol. E16c, pp 317-369. (b) Heimgartner, H. Angew.
Chem., Int. Ed. Engl. 1991, 30, 238-264. (c) Padwa, A.; Woolhouse,
A. D. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees,
C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 4, pp 47-95. (d)
Fowler, F. W. Adv. Heterocycl. Chem. 1971, 13, 45-76.
(2) For reviews see: (a) Hansen, H. J .; Heimgartner, H. In 1,3
Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York,
1984; Vol. 1, Chapter 2, pp 177-290. (b) Padwa, A. In Comprehensive
Organic Synthesis; Trost, B., Fleming, I., Semmelhack, M. F., Eds.;
Pergamon Press: Oxford, 1991; Vol. 7, pp 1069-1109. (c) Weinreb, S.
M. In Comprehensive Organic Synthesis; Trost, B., Fleming, I.,
Paquette, L. A., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, pp 402-
449.
(7) (a) Filigheddu, S. N.; Taddei, M. Tetrahedron Lett. 1998, 39,
3857-3860. (b) Zwanengburg, B.; Thijs, L. Pure Appl. Chem. 1996,
68, 735-738. (c) Davis, F. A.; Liu, H.; Reddy, C. V. Tetrahedron Lett.
1996, 37, 5473-5476. (d) Ploux, O.; Caruso, M.; Chassaing, G.;
Marquet, A. J . Org. Chem. 1988, 53, 3154-3158. (e) Righi, G.;
D′Achielle, R.; Bonini, C. Tetrahedron Lett. 1996, 37, 6893-6896. (f)
Lim, Y.; Lee, W. K. Tetrahedron Lett. 1995, 36, 8431-8434. (g) Tanner,
D.; Birgersson, C.; Dhaliwal, H. K. Tetrahedron Lett. 1990, 31, 1903-
1906.
(8) For reviews see: (a) Engel, R. In Handbook of Organophosphorus
Chemistry; M. Dekker, Inc.: New York, 1992. (b) Kafarski, P.; Lejezak,
B. Phosphorus Sulfur Relat. Elem, 1991, 63, 193-215. (c) Hoagland
R. E. In Biologically Active Natural Products; Culter, H. G., Ed.; ACS
Symposium Series 380. American Chemical Society: Washington, DC,
1988; p 182. (d) Toy, A. D. F.; Walsh, E. N. In Phosphorus Chemistry
in Everyday Living; American Chemical Society: Washington, DC,
1987; p 333.
(3) For
a recent contribution see: (a) Albrecht, E.; Mattay, J .;
Steenken, S. J . Am. Chem. Soc. 1997, 119, 11605-11610.
(4) (a) Haddach, M.; Pastor, R.; Riess, J . G. Tetrahedron Lett. 1990,
31, 1989-1990. (b) Bucher, C. B.; Heimgartner, H. Helv. Chim. Acta
1996, 79, 1903-1915. (c) Lehmann, J .; Linden, A.; Heimgartner, H.
Tetrahedron 1999, 55, 5359-5376. (d) Davis, F. A.; Liang, C.-H.; Liu,
H. J . Org. Chem. 1997, 62, 3796-3797. (e) Russell, G. A.; Yao, C. F. J .
Org. Chem. 1992, 57, 6508-6513. (f) Dro¨gemu¨ller, M.; J autelat, R.;
Winterfeldt, E. Angew. Chem. Int. Ed. Engl. 1996, 35, 1572-1574. (g)
Bhullar, P.; Gilchrist, T. L.; Maddocks, P. Synthesis 1997, 271-272.
(5) (a) Miller, T. M.; Tristram, E. W.; Wolf, F. J . J . Antibiot. 1971,
24, 48-50. (b) Molinski, T. F.; Ireland, C. M. J . Org. Chem. 1988, 53,
2103-2105. (c) Salomon, C. E.; William, D. H.; Faulkner, D. J . J . Nat.
Prod. 1995, 58, 1463-1466.
(9) (a) Hassner, A. In Azides and Nitrenes: Reactivity and Utility;
Scriven, E. F. V., Ed.; Academic Press: Orlando, 1984; pp 25-94. (b)
Hassner, A.; Wiegand, N. H.; Gottlieb, H. E. J . Org. Chem. 1986, 51,
3176-3180. (c) Melo, T. M. V. D. P. E.; Gonsalves, A. M. D. R.; Lopes,
C. S. J .; Gilchrist, T. L Tetrahedron Lett. 1999, 40, 789-792. (d) Padwa,
A.; Chen, E.; Ku, A. J . Am. Chem. Soc. 1975, 97, 6484-6491. (e)
Hassner, A.; Alexanian, V. J . Org. Chem. 1979, 44, 3861-3864. (f)
Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263-309. (g) Neber,
P. W.; Burghard, A. J ustus Liebigs Ann. Chem. 1932, 493, 281-294.
(h) McCarthy, C. G. In The Chemistry of the Carbon-Nitrogen Bond;
Patai, S., Ed.; Interscience: New York, 1973; pp 447-452. (i) Mu¨ller,
F.; Karwe, A.; Mattay, J . J . Org. Chem. 1992, 57, 6080-6082.
10.1021/jo9915426 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/14/2000

3214 J . Org. Chem., Vol. 65, No. 10, 2000
Notes
Sch em e 2. 2H-Azir in e F or m a tion th r ou gh
Sch em e 1. Gen er a l Str a tegy for th e P r ep a r a tion
of 2H-Azir in es
Rea ction of Vin yl Azid e 1
Sch em e 3. 2H-Azir in e F or m a tion th r ou gh
Mod ified Neber Rea ction of Tosyl Ketoxim es 5
phoranyl-2-silyl-2H-azirines10a,b and 2-(diethoxyphospho-
ryl)-2H-azirines10c with a phenyl group in the 2-position
have been described.
We are interested in the design of new 2H-azirine
derivatives bearing a phosphorus-containing group in the
2-position of the heterocyclic system. In this context, we
have used functionalized vinyl azides in the synthesis of
azadienes11a,b and â-functionalized phosphorus deriva-
tives in the preparation of phosphorylated nitrogen
heterocycles11c,d and unsaturated oximes.11e Continuing
with our interest in the synthesis of new phosphorus-
substituted heterocycles, we here report an easy and high
yielding synthesis of 2-phosphinoyl-2H-azirines 2 from
1-phosphinoylvinyl azides 1 (Scheme 1, route a) and the
synthesis of 2H-azirines 2 from easily available tosyl-
oximes containing a phosphine oxide 5 (R ) Ts, Scheme
1, route b). The required oximes 4 (R ) H, Scheme 1)
can be prepared by addition of hydroxylamine11e to
allenes 3. Subsequent tosylation gives â-phosphorylated
tosyloximes 5. Enantiomerically enriched 2-alkoxycar-
bonyl-2H-azirines were previously prepared from chiral
N-substituted aziridine 2-carboxylic esters,12a,b by using
the Neber reaction.12c,d Nevertheless, the asymmetric
preparation and synthetic use of 2H-azirines with a
phosphine oxide group have not, to the best of our
knowledge, been studied.
Ta ble 1. Non r a cem ic Azir in es 2
yield
(%)
[R]22
D
entry compound
base
ee (%)a
(deg)b
1
2
3
2a
2a
2b
quinidine
hydroquinidine
quinidine
96
94
95
82 (R) -17.41
24 (R)
30 (R)
-4.98
-4.98
Determined by 31P NMR using Yb(tfc)3 as chiral shift reagent.
Determined using concentration c ) 0.75 in CH2Cl2.
a
b
The thermolysis of vinyl azides is not suited for the
preparation of single enantiomers of azirines. For this
reason, the modified Neber reaction of the tosyl ke-
toximes 5a was investigalted. The C-1 methylene protons
in these substrates are doubly activated, and therefore
the use of a mild base could be sufficient for the formation
of the azirine. The preparation of â-tosyloximes 5 by the
addition of tosyl hydroxylamine to allenes 3 (R1 ) H, CH3)
was not successful, but the desired â-tosyloximes 5 were
conveniently obtained by the addition of hydroxylamine
to allenyl-phosphine oxides 3.11e Subsequent reaction of
functionalized â-oximes 4 with tosyl chloride in pyridine
led to the formation of â-tosyloximes 5 (Scheme 3).
Compounds 5 were isolated as a mixture of the (Z)- and
(E)-oximes 5.
2-Phosphinoyl-2H-azirine 2a (R1 ) H) was generated
in good yield by refluxing a toluene solution of function-
alized vinyl azide 1a (R1 ) H).11b This process involved
nitrogen loss from the vinyl azide 1a followed by ring
closure to give exclusively 3-phosphorylated 2H-azirines
derived from phosphine oxide 2a (R1 ) H) in good yields
in a regioselective fashion (Scheme 2). Spectroscopic data
were in agreement with the assigned structure of com-
pound 2.
2H-Azirines 2 were prepared from â-ketoximes 5 by
treatment with triethylamine at room temperature for 1
h in benzene (Scheme 3). This process can be used for
the asymmetric synthesis of 2H-azirine 2 by employing
hydroquinidine or quinidine bases,12d with the best
results being obtained with quinidine in benzene (Scheme
3, Table 1, entries 1-3). The enantiopurity13 of azirines
derived from phosphine oxide 2 (ee 24-82%) was deter-
mined by 31P NMR measurements in CDCl3 using a chiral
shift reagent (Yb(tfc)3). The absolute configuration of the
azirines 2 was established by reduction to aziridines and
(10) (a) Alcaraz, G.; Wecker, U.; Baceiredo, A.; Dahan, F.; Bertrand,
G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1246-1248. (b) Piquet, V.;
Baceiredo, A.; Gornitzka, H.; Dahan, F.; Bertrand, G. Chem. Eur. J .
1997, 3, 1757-1264. (c) Davis, F. A.; McCoull, W. Tetrahedron Lett.
1999, 40, 249-252.
(11) (a) Palacios, F.; Herran, E.; Rubiales, G. J . Org. Chem. 1999,
64, 6239-6246. (b) Palacios, F.; Aparicio, D.; de los Santos, J . M.
Tetrahedron 1996, 52, 4857-4866. (c) Palacios, F.; Ochoa de Retana,
A.; Oyarzabal, J . Tetrahedron 1999, 55, 5947-5964. (d) Palacios, F.;
Ochoa de Retana, A.; Oyarzabal, J .; Ezpeleta, J . M. Tetrahedron 1998,
54, 2281-2288. (e) Palacios, F.; Aparicio, D.; de los Santos, J . M.;
Rodr´ıguez, E. Tetrahedron 1998, 54, 599-614.
(12) (a) Davis, F. A.; Reddy, G. V.; Liu, H. J . Am. Chem. Soc. 1995,
117, 3651-3652. (b) Gentillucci, L.; Grijzen, Y.; Thijs, L.; Zwanenburg,
B. Tetrahedron Lett. 1995, 36, 4665-4668. (c) Piskunova, I. P.;
Eremeev, A. V.; Mishnev, A. F.; Vosekalna, I. A. Tetrahedron 1993,
49, 4671-4676. (d) M. H. Verstappen, M.; Ariaans, G. J . A.; Zwanen-
burg, B. J . Am. Chem. Soc. 1996, 118, 8491-8492.
(13) Further studies using other chiral bases and varying the
experimental conditions are now in progress in our laboratories to
improve the enantiopurity of azirines.

Notes
J . Org. Chem., Vol. 65, No. 10, 2000 3215
Sch em e 4. F or m a tion of En a n tiop u r e Azir id in es 6, 8, a n d 9
formation of the enantiopure cis-N-(p-toluenesulfinyl)-
aziridine-2-phosphine oxides 8 and 9 and N-unsubsti-
tuted aziridines 6.
9 substituted with a phosphine oxide group in the
2-position, from available starting materials. These
heterocycles may be very useful intermediates in organic
synthesis1,4 and for the preparation of a large variety of
molecules that could be useful in the synthesis of biologi-
cally active compounds.1,4-7
Reduction of azirines 2 with sodium borohydride in
ethanol led exclusively to the formation of the previously
unknown cis-aziridines 6. The stereochemical assignment
was based on the large ring proton coupling constant
observed for 6a (3J HH ) 6.9 Hz), while in the case of trans
isomers a lower coupling constant has been reported
(3J HH ) 2.3-4.0 Hz).7d,14 Furthermore, no trace of the
trans-aziridine could be observed by 31P NMR,4a,12d and
no loss of chirality was observed.
Exp er im en ta l Section
See reference 11e for general experimental methods. Vinyl
azide 1a ,11b allenes 3,17 oximes 4,11e and (-)-(S)-menthyl-p-
toluenesulfinate 715 were synthesized according to literature
procedures.
Enantiopure (+)-(Ss,2S,3R)- and (+)-(Ss,2R,3S)-cis-N-
sulfinyl aziridines 8a and 9a , respectively, were prepared
by treatment of (-)-(S)-menthyl p-toluenesulfinate 715
with aziridine 6 in THF at 0 °C in the presence of sodium
hydride (Scheme 4). The products were isolated by flash
chromatography, and new aziridines (+)-(Ss,2S,3R)-8a
and (+)-(Ss,2R,3S)-9a were obtained. Similarly, aziri-
dines (-)-(Ss,2S,3R)-8b and (-)-(Ss,2R,3S)-9b were pre-
pared (Scheme 4). N-Sulfinyl aziridines 8 and 9 were
treated separately with trifluoroacetic acid at 0 °C for 2
h to afford (+)- and (-)-aziridines 6, respectively, (Scheme
4) with retention of the configuration.16 The chirality at
the 2-position in (+)-8a was established as (S) by single-
crystal X-ray analysis. The corresponding ORTEP draw-
ing with the appropriate atom numbering is available in
Supporting Information. In the conversion of (+)-2a to
(+)-6a and (+)-8a the bonds around the chiral carbon are
not broken, so it is possible to assign the (S) configuration
to the minor enantiomer (+)-2a and the (R) configuration
to the major enantiomer (-)-2a , as well as the (2R,3S)
configuration for the aziridine (-)-6a .
P r ep a r a tion of 2-Dip h en ylp h osp h or yl-3-m eth yl-1-a zir -
in e (2a ) fr om Vin yl Azid e (1a ). Rou te a : A solution of (2-
azido-1-propenyl)diphenylphosphine oxide 1a (5 mmol) in tolu-
ene (10 mL) was stirred at reflux for 1 h. When the nitrogen
loss stopped the solvent was evaporated under reduced pressure.
The residue was precipitated with diethyl ether and crystallized
from hexane/AcOEt to yield 1.15 g (90%) of 2a as a white solid:
mp 97-98 °C; 1H NMR (300 MHz, CDCl3) δ 7.88-7.36 (m, 10H),
2
2.38 (s, 3H), 2.18 (d, J PH ) 36.5 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 163.1 (d, 3J PC ) 3.5 Hz), 133.1-128.3 (m), 27.2 (d, 1J PC
) 111.8 Hz), 13.9 (d, 3J PC ) 1.5 Hz); 31P NMR (120 MHz, CDCl3)
δ 29.8; IR (KBr) 3062, 1442, 1192; MS (EI) m/z 255 (M+, 63),
201 (POPh2+, 36). Anal. Calcd for C15H14NOP: C, 70.58; H, 5.53;
N, 5.49. Found: C, 70.35; H, 5.51; N, 5.51.
Gen er a l P r oced u r e for th e P r ep a r a tion of (Z)- a n d (E)-
2-(N -p -T o lu e n e s u lfo n y lo x im in o )a lk y ld ip h e n y lp h o s -
p h in e Oxid e (5). To a 0 °C solution of (Z)- and (E)-2-(N-
hydroximino)alkyldiphenylphosphine oxide 4 (5 mmol) in pyri-
dine (2.4 mL) was added tosyl chloride (1.05 g, 5.5 mmol, freshly
recrystallized from hexane) in portions. Then, the mixture was
allowed to warm to room temperature, and the reaction mixture
was stirred for 3 h. A portion of ice water was added with
continued stirring, and a white precipitate was formed rapidly.
This was collected by suction filtration, washed with cold water
and ethyl ether, and dried under reduced pressure. The products
were crystallized from hexane/AcOEt to yield 5.
In conclusion, we have devised a simple, mild, and
convenient strategy for the asymmetric synthesis of 2H-
azirines 2, as well as of enantiopure aziridines 6, 8, and
(Z)- a n d (E)-2-(N-p -Tolu en esu lfon yloxim in o)p r op yl-
d ip h en ylp h osp h in e Oxid e (5a ). As described in the general
procedure, 1.30 g (61%) of 5a was obtained as a white solid from
(Z)- and (E)-2-(N-hydroximino)propyldiphenylphosphine oxide 4a
(1.37 g, 5 mmol): 1H NMR (300 MHz, CDCl3) δ 7.78-7.21 (m,
(14) (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J . Am. Chem.
Soc. 1994, 116, 2742-2753. (b) Evans, D. A.; Faul, M. M.; Bilodeau,
M. T.; Anderson, B. A.; Barnes, D. M. J . Am. Chem. Soc. 1993, 115,
5328-5329.
(15) Hulce, M.; Mallomo, J . P.; Frye, L. L.; Kogan, T. P.; Posner, G.
H. In Organic Syntheses. Coll. Vol. VII; Freeman, J . P., Ed.; J . Wiley,
New York, 1990; pp 495-500.
(16) Davis, F. A.; Zhou, P.; Reddy, G. V. J . Org. Chem. 1994, 59,
3243-3245.
2
28H) for Z and E isomers, 3.53 (d, J PH ) 15.0 Hz, 2H) for Z
2
isomer, 3.29 (d, J PH ) 14.1 Hz, 2H) for E isomer, 2.44 (s, 3H)
(17) Brandsma, L.; Verkruijsse, H. D.Synthesis of Acetylenes, Allenes
and Cumulenes. A Laboratory Manual; Elsevier: Amsterdam, 1981;
p 199.

3216 J . Org. Chem., Vol. 65, No. 10, 2000
Notes
4
for E isomer, 2.40 (s, 3H) for Z isomer, 2.11 (d, J PH ) 1.8 Hz,
h. The solution was cooled to 0 °C and, then (-)-(S)-menthyl-
p-toluenesulfinate 7 (0.21 g, 7.5 mmol) was added in portions.
The mixture was allowed to warm to room temperature, the
reaction mixture was stirred for 22 h, methanol was added, and
the solvents were evaporated. The residue was diluted with CH2-
Cl2 and washed with water. The organic layer was dried with
anhydrous magnesium sulfate and filtered, and the solvent was
evaporated under reduced pressure, affording a mixture of
diastereoisomers 8 and 9 (3:2 ratio). The mixture was separated
and purified by flash chromatography eluting with 1:2 AcOEt/
hexane and crystallized from hexane/CH2Cl2.
3H) for Z isomer, 2.08 (d, J PH ) 1.8 Hz, 3H) for E isomer; 13C
4
2
NMR (75 MHz, CDCl3) δ 161.8 (d, J PC ) 6.3 Hz) for E isomer,
2
159.3 (d, J PC ) 6.3 Hz) for Z isomer, 144.8 for Z isomer, 144.7
for E isomer, 132.3-128.5 (m) for Z and E isomers, 37.8 (d, 1J PC
1
) 63.3 Hz) for E isomer, 33.7 (d, J PC ) 64.7 Hz) for Z isomer,
21.6 for Z and E isomer, 17.2 for Z and E isomers; 31P NMR
(120 MHz, CDCl3) δ 27.6 and 26.7 for E and Z isomers; IR (KBr)
3040, 1593, 1434, 1363, 1190; MS (APCI) m/z 428 (M+ + 1, 46),
256 (M+ - TsO, 100), 201 (POPh2+, 19). Anal. Calcd for C22H22
-
NO4PS: C, 61.82; H, 5.19; N, 3.28; S, 7.50. Found: C, 61.95; H,
5.17; N, 3.29; S, 7.45.
(+)-(Ss,2S,3R)-cis-2-Dip h en ylp h osp h or yl-3-m eth yl-N-p-
t olu en esu lfin yla zir id in e (8a ) a n d (+)-(Ss,2R,3S)-cis-2-
Dip h e n ylp h osp h or yl-3-m e t h yl-N -p -t olu e n su lfin yla zir i-
d in e (9a ). As described in the general procedure, 8a and 9a
were obtained from (()-cis-2-diphenylphosphoryl-3-methylaziri-
dine 6a (1.29 g, 5 mmol). Data for 8a : 0.57 g (29%) as a white
Gen er a l P r oced u r e for t h e P r ep a r a t ion of 2-Dip h en -
ylp h osp h or yl-3-a lk yl-1-a zir in e (2). Rou te b: To a 0-5 °C
solution of (E)- and (Z)-2-(N-p-toluenesulfonyloximino)alkyl-
diphenylphosphine oxide 5 (5 mmol) in benzene was added the
corresponding base (5.5 mmol) slowly. Then, the mixture was
allowed to warm to room temperature, and the reaction mixture
was stirred for 1-2 h. The solution was diluted with CH2Cl2
and washed with 2 N hydrochloric acid and water. The organic
layer was dried with anhydrous magnesium sulfate and filtered,
and the solvent was evaporated under reduced pressure. The
oil was precipitated with diethyl ether and crystallized from
hexane/AcOEt to yield 2. The base was recovered with 2 N
sodium hydroxide solution.
solid; mp 129-130 °C; [R]22 +1.45 (c 0.55, CH2Cl2); 1H NMR
D
2
(300 MHz, CDCl3) δ 7.65-6.87 (m, 14H), 3.05 (dd, J PH ) 23.2
Hz, 3J HH ) 7.2 Hz, 1H), 2.84 (ddd, 3J PH ) 6.0 Hz, 3J HH ) 5.8 Hz,
3J HH ) 7.2 Hz, 1H), 2.23 (s, 3H), 1.57 (d, 3J HH ) 5.8 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) δ 141.5, 140.7, 132.0-124.8 (m), 35.9 (d,
2J PC ) 4.0 Hz), 29.1 (d, J PC ) 102.7 Hz), 21.4, 13.4; 31P NMR
1
(120 MHz, CDCl3) δ 24.0; IR (KBr) 3051, 1440, 1208; MS (APCI)
+
m/z 396 (M+ + 1, 18), 256 (M+ - CH3PhSO, 60), 201 (POPh2
,
2-Dip h en ylp h osp h or yl-3-m eth yl-1-a zir in e (2a ). As de-
scribed in the general procedure 1.13 g (89%) of 2a was obtained
as a white solid from (E)- and (Z)-2-(N-p-toluenesulfonyloximi-
no)propyldiphenylphosphine oxide 5a (2.14 g, 5 mmol), using
triethylamine as a base. For spectroscopic data see above.
Asym m etr ic Syn th esis of (-)-(R)-2-Dip h en ylp h osp h or yl-
3-m eth yl-1-a zir in e (2a ). (A) As described in the general
procedure, 1.22 g (96%) was obtained as a white solid from (E)-
and (Z)-2-(N-p-toluenesulfonyloximino) propyldiphenylphosphine
oxide 5a (2.14 g, 5 mmol) and using quinidine as a base: ee 82%;
36). Anal. Calcd for C22H22NO2PS: C, 66.82; H, 5.61; N, 3.54; S,
8.11. Found: C, 66.97; H, 5.62; N, 3.55; S, 8.01. Data for 9a :
0.45 g (23%) as a white solid; mp 112-113 °C; [R]22 +1.59 (c
D
0.50, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 7.75-7.23 (m, 14H),
2.75 (m, 2 H), 2.34 (s, 3H), 1.20 (d, 3J HH ) 5.8 Hz, 3H); 13C NMR
1
(75 MHz, CDCl3) δ 142.1, 141.1, 133.5-124.9 (m), 35.2 (d, J PC
2
) 103.8 Hz), 30.8 (d, J PC ) 4.5 Hz), 21.4, 12.9; 31P NMR (120
MHz, CDCl3) δ 24.7; IR (KBr) 3051, 1433, 1202; MS (APCI) m/z
396 (M+ + 1, 81), 256 (M+ - CH3PhSO, 68), 201 (POPh2+, 29).
Anal. Calcd for C22H22NO2PS: C, 66.82; H, 5.61; N, 3.54; S, 8.11.
Found: C, 66.91; H, 5.60; N, 3.54; S, 7.99.
[R]22 -17.41 (c 0.75, CH2Cl2). For spectroscopical data see
D
compound (()-2a . (B) As described in the general procedure, 1.20
g (94%) was obtained as a white solid from (E)- and (Z)-2-(N-p-
toluenesulfonyloximino)propyldiphenylphosphine oxide 5a (2.14
g, 5 mmol), using hydroquinidine as a base: ee 24%; [R]22D -4.98
(c 0.75, CH2Cl2). For spectroscopical data see compound (()-2a .
Gen er a l P r oced u r e for th e P r ep a r a tion of (()-cis-3-
Alk yl-2-d ip h en ylp h osp h or yla zir id in e (6). To a 0 °C solution
of the corresponding 3-alkyl-2-diphenylphosphoryl-1-azirine 2
(5 mmol) in ethanol (15 mL) was added sodium borohydride (0.57
g, 15 mmol) in portions. Then, the mixture was allowed to warm
to room temperature, and the reaction mixture was stirred for
2 h. The solution was diluted with CH2Cl2 and washed with
water. The organic layer was dried with anhydrous magnesium
sulfate and filtered, and the solvents were evaporated under
reduced pressure. The solid residue was washed with ethyl ether
and crystallized from hexane/CH2Cl2 to yield 6 as a white solid.
(()-cis-2-Dip h en ylp h osp h or yl-3-m eth yla zir id in e (6a ). As
described in the general procedure, 1.09 g (85%) was obtained
as a white solid from 2-diphenylphosphoryl-3-methyl-1-azirine
2a (1.28 g, 5 mmol): mp 161-162 °C; 1H NMR (300 MHz, CDCl3)
Gen er a l P r oced u r e for th e Syn th esis of (+)-(2S,3R)- a n d
(-)-(2R,3S)-cis-3-Alkyl-2-diph en ylph osph or ylazir idin es (6).
To N-sulfinylaziridines 8 or 9 (5 mmol) at 0 °C was added
trifluoroacetic acid (3.9 mL, 50 mmol), and the mixture was
stirred for 2 h at this temperature. The residue was dissolved
in CH2Cl2 and washed with six portions of a saturated solution
of sodium carbonate. The organic layer was dried with anhy-
drous magnesium sulfate and filtered, and the solvent was
evaporated under reduced pressure. The solid residue was
washed with diethyl ether and crystallized in hexane/CH2Cl2,
affording 6 as a white solid.
(+)-(2S, 3R)-cis-2-Dip h en ylp h osp h or yl-3-m et h yla zir i-
d in e (6a ). As described in the general procedure, 1.04 g (81%)
was obtained as a white solid from (+)-(Ss,2S,3R)-cis-2-diphen-
ylphosphoryl-3-methyl-N-p-toluenesulfinylaziridine 8a (1.98 g,
5 mmol): [R]22D +1.40 (c 0.50, CH2Cl2). For spectroscopical data
see compound (()-6a .
X-r a y Cr ysta llogr a p h y. Single-crystal X-ray diffraction
experiments were carried out on a STOE IPDS diffractometer
using graphite-monochromated Mo Ka radiation (λ ) 0.7173 Å).
A prismatic crystal of dimensions 0.31 mm × 0.20 mm × 0.15
mm was used for data collection. Crystal data: monoclinic, space
group P21/n, a ) 14.263(5), b ) 8.366(2), c ) 17.032(3) Å, â )
95.19(3)°, V ) 2024.0(9) Å3, Dcalcd ) 1.298 g cm-3. Data collection
was performed at 293 K, with 2θmax ) 52°. Intensities were
measured on a image plate with oscillating crystal geometry.
The total number of measured reflections was 13 913, of which
3921 were independent. The criterion for observed reflections
was I > 2σ(I). Lorentzian polarization correction was applied
using STOE software18 but no absorption correction (µ ) 0.256
mm-1). The structure was solved by direct methods, using SIR97
program.19 It was refined by full-matrix least-squares against
2
δ 7.77-7.37 (m, 10H), 2.32 (m, 1H), 2.19 (ddd, J PH ) 23.1 Hz,
3
3
3J
) 6.6 Hz, J
) 6.9 Hz, 1H), 1.95 (s, 1H), 1.41 (d, J HH
HH
HH
) 5.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 132.1-128.5 (m),
32.8 (d, 1J PC ) 102.7 Hz), 30.8, 14.5; 31P NMR (120 MHz, CDCl3)
δ 28.4; IR (KBr) 3204, 3065, 1443, 1188; MS (EI) m/z 257 (M+,
9), 242 (M+ - CH3, 18), 201 (POPh2+, 100). Anal. Calcd for
C15H16NOP: C, 70.03; H, 6.27; N, 5.44. Found: C, 69.92; H, 6.25;
N, 5.43.
(-)-(2R ,3S )-cis-2-Dip h e n ylp h osp h or yl-3-m e t h yla zir i-
d in e (6a ). As described in the general procedure, 1.08 g (84%)
was obtained as a white solid from (-)-(R)-2-diphenylphosphoryl-
3-methyl-1-azirine 2a (1.28 g, 5 mmol, ee 82%): ee 82%; [R]22
D
|F| , and all reflections were considered (SHELXL-97 software).20
-1.14 (c 0.61, CH2Cl2). For spectroscopical data see compound
(()-6a .
2
The total number of parameters was 245, and all H atoms were
Gen er a l P r oced u r e for th e P r ep a r a tion of (Ss,2S,3R)-
a n d (Ss,2R,3S)-cis-3-Alk yl-2-d ip h en ylp h osp h or yl-N-p-tolu -
en esu lfin yla zir id in e (8) a n d (9). To a 0 °C suspension of
sodium hydride (0.14 g, 6 mmol) in THF (25 mL) was added the
corresponding (()-cis-3-alkyl-2-diphenylphosphorylaziridine 6 (5
mmol) in portions. Then, the mixture was allowed to warm to
room temperature, and the reaction mixture was stirred for 1
(18) STOE IPDS Software; STOE: Darmstadt, Germany, 1998.
(19) Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.;
Molitemi, A. G. G.; Burla, M. C.; Polidori, G.; Camalli, M.; Spagna, R.
SIR97; Universities of Bari, Perugia and Roma: Italy, 1997.
(20) Sheldrick, G. M. SHELXL-97; University of Go¨ttingen, Ger-
many, 1997.

Notes
J . Org. Chem., Vol. 65, No. 10, 2000 3217
generated using geometrical criteria and refined isotropically.
Final values for R-indices: Rw(all) ) 0.1252, Rw(obs) ) 0.0921,
R(all) ) 0.1093 and R(obs) ) 0.0395. Residual electron density:
min ) -0.192 and max ) 0.182. Crystallographic data (exclud-
ing structure factors) for the structure reported in this paper
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC-132458. Copies
of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. (fax: (+44)
1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
PB96-0252) and by the Gobierno Vasco (Departamento
de Educacio´n, Universidades
e Investigacio´n del
Gobierno Vasco, Vitoria, PI 1998-53). J .I.G. thanks the
Universidad del Pa´ıs Vasco for a predoctoral fellowship.
Su p p or tin g In for m a tion Ava ila ble: Preparation, analy-
sis, and spectral data (1H, 13C, and 31P NMR, IR, and MS) for
compounds 5b, 2b, (-)-2b, (-)-6a , (()-6b, (-)-6b, (+)-6b, (-)-
8b, and (-)-9b, suplementary tables, and ORTEP drawing and
X-ray crystallography data for 8a . This material is available
free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. The present work has been
supported by the Direccio´n General de Ensen˜anza
Superior e Investigacio´n Cient´ıfica (Madrid DGESIC,
J O9915426