J. Org. Chem.

1981,46,3953-3955 3953
dissolved in ethanolic sodium ethoxide [prepared by dissolving mL of benzene with separation of water as a benzene azeotrope
Na (0.06 g) in 30 mL of absolute EtOH]. The mixture was heated for 2 h. The reaction mixture was evaporated to dryness. The
at reflux for 3 h. The solvent was removed by evaporation in residue was triturated with ether, and the resulting precipitate
vacuo, and the residue was dissolved in cold water. The reaulting was collected by fitration to give 2.19 g (94%) of 9, mp 244-246
precipitate was collected by filtration to give 0.115 g of 6:7 mp "C. Recrystallization from water gave analytically pure 9: 1.26
68-60 "C. Recrystallization from petroleum ether gave pure 7 g (54%);mp 256257 "C; NMR (MeaO-dd 3.23 (3 H, 8, CH,),
mp 65-67 "C; maw spectrum, m / e 209 (M+);W A,- 322,256, 3.44 (3 H, 8, CHJ, 8.05 (1 H, 8, CH=C), 8.63 (1 H, 8, C&);
234 (e 3000,11300,34900). spectrum, m / e 234 (M'); UV X, 344,265,234 (e 16 700,7500,
Ethyl 5-Cyano-6-hydroxynicotinate (8). (a) A mixture of 5800). Anal. Calcd for C&loO,N1: C, 51.28; H, 4.30; N, 23.92.
1 (0.504 g, 0.003 mol) and cyanoacetamide (0.84 g, 0.01 mol) in Found C, 50.98; H, 4.18; N, 23.71.
ethanolic sodium ethoxide [prepared by dissolving Na (0.23 g, 6-Acetyl-l,3,7-trimethylquinamline-2,4( lH$a)-dione (12).
0.01 mol) in 40 mL of absolute EtOH] was heated at reflux for A mixture of 10 (0.546 g, 0.003 mol), acetylacetone (0.360g, 0.0036
1 h. The solvent was removed in vacuo, and the residue was mol), piperidine (1 drop), and acetic acid (1 drop) in 80 mL of
dissolved in cold water (20 mL). Upon acidification with con- benzene was refluxed with separatingwater aa a benzene azeotrope
centrated HCl, the crystalline product precipitated and was for 12 h. The reaction mixture waa evaporated to dryness. The
collected by fitration: 0.233 g (46%);16 mp 218-221 "C. Re- residue was triturated with ether, and the resulting precipitate
crystallization f "water gave analytically pure 8: mp 223-225 was collected by fiitration and recrystaked from ethanol to give
OC; NMR (MeaO-da) 6 1.30 (3 H, t, J = 7, CH,), 4.24 (2 H, q, 0.340 g (46%) of 1 2 mp 210-211 "C; NMR (CDClB) 6 2.67 (3 H,
J = 7, CH.J,8.29 (1 H, d, J 2, C&), 8.42 (1 H, d, J = 2, C4 H), 8, COCHB), 2.70 (3 H, 8, CTCH,), 3.49 (3 H, 8, NCH,), 3.62 (3 H,
13.08 (1 H, br, OH); maas spectrum, m / e 192 (M'); W A- 332, 8, NCHB), 7.04 (1 H, s, C&), 8.62 (1 H, 8, C&); W X, 284,241
261,218 (sh),(e 7200,15 100,14000). Anal. Calcd for C&0$J2: (e 15 200,42 300);mass spectrum, m / e 246 (M+),231 (M+- 15).
C, 56.26; H, 4.20; N, 14.58. Found: C, 56.26; H, 4.16; N, 14.79. Anal. Calcd for Cl9HI4O3N2:C, 63.40; H, 5.73; N, 11.38. Found
(b) A solution of 9 (0.702 g, 0.003 mol) in ethanolic sodium C, 63.28; H, 5.80, N, 11.13.
ethoxide [prepared by dissolving Na (0.138 g, 0.006 mol) in 40
mL of absolute W H ] was heated at reflux for 3.5 h The reaction Registry No. 1, 4869-46-9; 4a, 57009-53-7; ab, 57009-12-8; 4c,
solution was evaporated to dryness, and the residue was dissolved 74442-95-8;4d,5985-25-1;b,74442-97-0;4f, 36727-23-8; 4g, 74442-
in cold water (20 mL). The solution was acidified with concen- 96-9; Sa, 74442-98-1;Sb, 78515-04-5;6,78515-05-6;7,78515-06-7;8,
trated HC1 to give 8: 0.445 g (77%); mp 220-222 "C. The IR 74443-00-8; 9, 74442-99-2; 10, 23941-84-6; 12, 78515-07-8; acetyl-
spectrumwas identical with that of the compound prepared above. acetone, 123-54-6;1,3-dimethylurea,96-31-1; acetoacetamide,5977-
5-(2-Carbamoyl-2-cyanovinyl)-1,3-dimethyluracil(9). A 14-0; ethyl acetoacetate, 141-97-9; dimethyl acetonedicarboxylata,
mixture of 1 (1.68 g, 0.01 mol), cyanoacetamide(1.01 g, 0.012 mol), 1830-54-2;phenylacetone, 103-79-7;malononitrile, 109-77-3;1,3-di-
piperidine (1 drop), and acetic acid (1 drop) was refluxed in 80 methyluracil, 874-14-6; cyanoacetamide, 107-91-6.

Neber Rearrangement of Amidoximesulfonates. Synthesis of

2-Amino-l-azirines
John A. Hyatt
Research Laboratories, Tennessee Eastman Company, Eastman Chemicals Division, Eastman Kodak Company,
Kingsport, Tennessee 37662
Received December 24, 1980

Amidoxime8 prepared from a-cyanoacetanilides and (phenylsulfony1)acetnitrilewere converted to the cor-

responding 0-tceyl derivatiwa. Upon treatment with base, theae amidoximeOsulfonateaaf€orded 2-amino-l-azirines
instead of the expected 3-amino-2-pyrazolin-5-ones. This transformation can be viewed as a new variant of the
Neber rearrangement. Azirinea bearing unaubstituted amino groups have not been reported previously; structure
proof and reactions of these compounds are discussed.

Introduction to l-azirines are a~ailable,~

however, and in recent years
syntheses of 2-(N,N-dialkylamino)-l-azirines have been
The Neber re"gement Of ketoxime-Odfonates to
repo&d.4,6 A considerable body of work,
amino ketones, shown in clmic form in eq 1,proceeds by
via l-azirine intermediates but has not been a generally Ghosez6 and by Heimgbner7 and their co-workers, has
useful preparation method for l-azirines.l3 Other routes demonstrated that compounds of the type are remark-
ably useful for the synthesis of a large
- array
NOS02C7H7 of heterocyclic compounds.
NO, II

1, R, = H or alkyl or aryl; R, = alkyl or aryl; R, = alkyl

(2) Haeener, A.; Fowler, F. J. Am. Chem. SOC.1968,90, 2869.

(3) F. Fowler In "Advances in Heterocyclic Chemistry";Academic
(1) Press: New York, 1971; Vol. 13, p 45.
(4) Rem, M.; Ghosez, L. Tetrahedron Lett. 1970, 3765.
(5) de Voghel, G.; Eggerichs,T.; Clamot, B.; Viehe, H. Chimia 1976,
30, 191.
(6) Demoulii, A.; Goriasen, H.; Heabain-Frieque,A. M.; Ghosez, L. J.
Am. Chem. SOC.1975,97,4409.
(1) O'Brien, C. Chem. Rev. 1964,64,81. (7) For leading references,see Heimgartner, H. ChimM 1979,33,111.

0022-3263/81/1946-3953$01.25/0 0 1981 American Chemical Society

3954 J. Org. Chem., Vol. 46, No. 20,1981 Hyatt
We have recently examined the reaction of certain am- (6 2.73) attributable to the azirine CS-H. ‘9c NMR analysis
idoxime 0-tosylates 2 with base. The reaction shown in also supports structure 6a. In addition to aryl and amide
eq 2 gives high yields of azirines la which bear a free amino carbons,azirine Cz is at 148.9 ppm; azirine C3bears a single
group at position 2. This reaction is a new application of proton (J13C-H = 200 H Z ) . ~These physical data are con-
the Neber rearrangement and provides access to 2- sistent with the existence of either tautomer, a or b, in 6a
amino-1-azirines which have not been obtained via the or with an equilibrium mixture of both; form a is drawn
previously reported routes. merely as a con~ention.~
H
NOSO2ClH7

la
a b
R = ArNHCO or &SO,
Compound 6a upon treatment with acetic acid afforded
Results and Discussion tris(amidel9 in good yield. This type of ring opening has
been seen before in 2-(N~-diallrylamino)-l-a~irines’~and
Equation 3 shows the conversion of 2-cyano-2’,4’,6’- serves as good chemical evidence for structure 6a. Upon
trichloroacetanilide3a to amidoxime 4a. Tosylation of 4a 0
gave amidoxime 0-tosylate 5a, which upon reaction with
C H $0 2H
sodium methoxide in methanol gave 2-amino-1-azirine 6a RCHCNH2
as the sole product. The formation of 6a was somewhat I
N-OH
\ NH2 AHCOCH;,
RCHzCN
HONHZ II
E~OH-RCHzCNHz -
T r C I , Py 6a,b

3a,b 4a, 66%

b, 88%
11, R = C,H,SO,-
treatment with excess sodium methoxide in methanol, 6a
underwent a novel rearrangement to give a single product
s a , 69% for which we propose the 2-amino-5imidazolonestructure
b, 82% 6a, 88% 10. The structure 10 is assigned from the physical data
b, 74% [see the Experimental Section; in particular, the presence
of ArNC(NH&=N (IR, NMR) and CH2groups (‘H and
13C NMR)] and chemical evidence (base hydrolysis to
2,4,6-trichloroaniline1’).Several mechanisms can be drawn
to account for this transformation. The bicyclo[2.1.0]
surprising in view of the possibilities offered by 5a for other intermediate (eq 5 ) appears reasonable, since other
reactions. Thus no traces of pyrazolone 7 or cyanamide 8 H
8 were detected in the reaction mixture (eq 4).

10
mechanisms (for instance, “vinylcyclopropane-like”ring
tl expansion, or opening of the Cz-C3 bond to give a 1,3-
dipolar intermediate followed by closure to 10) do not a
priori require the presence of base. Compound 6a did not
rearrange or react with l,&dipolarophilesupon heating in
neutral solution. Nevertheless,the mechanism in eq 5 has
not yet been rigorously proven.
C I *Cl To demonstrate that this Neber route to 2-amino-l-
8 azirines is not limited to amides of the type 6a, the se-
The structure assigned to 6a is supported by both (8) For ’% N M R spectra of other 1-arizinee, see Isomura, K.; Tani-
physical and chemical evidence. Compound 6a has mo- guchi, H Mishima, M.; Fujio, M.; Tsuno, Y.Org. Magn. Reson. 1977,9,
lecular weight 277 (mass spectrum) and displays C=N 559.
stretch in the infrared as a split band at 5.45 and 5.50 (9) For characterization of an N,”-dialkylaziridine imine, see Quast,
H.; Schmitt, E. Angew. Chem., Int. Ed. EngZ. 1970,9,381.
pm.2” In addition to the expected aryl and NH2 signals, (IO) Vittorelli, P.; Heimgartner, H.; Schmid, H.; Hmt, P.; Ghoeez, L.
the ‘H NMR spectrum of 6a displays a one-proton slnglet Tetrahedron 1974,30, 3131.
Neber Rearrangement of Amidoximesulfonates J. Org. Chem., Vol. 46, No. 20, 1981 3955
quence 3b through 6b (eq 3) was carried out. Aminoazirine @-AT), 132.6 (Cl-Ar), 134.5 (o-Ar), 148.9 (azirine CJ, 170.3 (amide
6b,like 6a,was a stable solid with physical and chemical carbonyl); mass spectrum (FD), m / e 277 (M'), 195 (5%).
properties in accord with the proposed structure (see the Anal. Calcd for C&C13N30: C, 38.80, H, 2.17; N, 15.08.
Experimental Section for spectral data; conversion of 6b Found C, 38.56; H, 2.29; N, 15.28.
Base-Catalyzed Rearrangement of Azirine 6a to 10. A
to 11 for chemical evidence). Unlike 6a, azirine 6b did not stirred mixture of 1.5 g (0.0054 mol) of aminoazirine 6a, 30 mL
give rise to a rearrangement product upon base treatment; of MeOH, and 0.5 g (0.0092 mol) of sodium methoxide was re-
decomposition to afford a mixture of unidentified, fluxed for 10 min. TLC analysis (silica gel, 10% MeOH in CHClJ
water-soluble degradation products occurred instead. showed loss of 6a and formation of a single, more polar product.
T h i s route to l-azirines appears limited to acetamid- The reaction mixture was stripped in vacuo, and the resultant
oximes bearing strongly electronegative a-substituents orange solid residue was dissolved in 10 mL of water and neu-
(COR, S0,R); an attempted synthesis of 6 from 3 (R = tralized with acetic acid. The precipitated product was filtered
C,H,) failed to produce azirine in the final step. to give 1.07 g (71%) of 10 as a white solid: mp (MeOH) 242-244
OC, IR (mull) 3.1-3.9,5.92,6.15,8.21,9.60,11.4,12.14 pm; 'H NMR
Conclusion (MeaO-ds) 6 7.33 (a, 2 H), 5.0 (bra, 2 H), 3.89 (a, 2 H); '% NMR
(Me2SO-de)47.8 (C4of imidazole), 125.9 (p A),127.7 (m-Ar),
In summary, the chemistry presented here describes a 127.6 (Cl-Ar), 129.0 (a-Ar),152.1 (C2of imidazole), 173.5 (C5 of
new variant of the Neber rearrangement which affords, in imidazole); mass spectrum, m / e 277 (M'), 220 (100%).
straightforward operations and in preparatively useful Anal. Calcd for C&&l3N30: C, 38.80; H, 2.17; N, 15.08.
yields, certain 2-(unsubstituted amino)-l-azirines which Found C, 38.78; H, 2.37; N, 15.29.
were heretofore inaccessible,and which may have consid- Malondiamide 9 from Aminoazirine 6a. A mixture of 1.0
erable value in heterocyclic synthesis. g (0.0036 mol) of azirine 6a and 40 mL of glacial HOAc was
warmed at about 50 "C for 1 h and cooled to 25 "C, and the
Experimental Section resulting crystalswere fiitered, washed with ethanol, and air-dried
to give 0.80 g (66%)of amide 9: mp 262-263 "C (EtOH); IR (KBr)
Melting points are uncorrected. Infrared spedra were recorded 3.0,5.93,6.09,6.62,7.31,8.75,11.61,12.4pm; 'H NMR (CFsCO&I)
on a Perkin-Elmer Model 137 instrument; 'H NMR spectra were 6 9.0 (br a, 1 H, exchangeable with D2O), 8.20 (d, J = 6 , l H, D2O
obtained with Varian EM-360and JEOLCO MH-100 spectrom- exchangeable), 7.60 (br a, 2 H, exchangeable with DZO), 7.57 (a,
eters; chemical shifts are reported relative to internal Me,Si. '% 2 H), 5.52 (d, J = 6 , l H; collapses to s on D20 addition), 2.43
NMR spectra were obtained on a Bruker 90 instrument; mass (a, 3 H); mass spectrum, m / e 337 (M9.
spectra were taken with Consolidated Electrodynamics Corpo- Anal. Calcd for Cl1HloClSN3O3:C, 39.01; H, 3.19; N, 12.41.
ration Model 21-llOB (electron impact) or Varian MAT 731 Found: C, 39.18; H, 3.07; N, 12.37.
systems (field desorption). (Phenylsulfony1)acetamidoxime (4b). (Phenylsulfonyl)-
Amidoxime 4a from Nitrile 3a. Hydroxylamine hydro- acetamidoxime (4b) was prepared from (phenylsulfony1)aceto-
chloride (1.7 g, 0.025 mol) was added to a stirred mixture of 2.7 nitrile in 88% yield, according to the published procedure.lS
g (0.025 mol) of sodium carbonate and 10 mL of 50% aqueous Amidoxime Torrylate 5b. Amidoxime 4b was tosylated by the
EtOH. This mixture was diluted with 100 mL of EtOH, and 5.28 same procedure used for compound Sa (82% yield). The product
g (0.020 mol) of nitrile 3a12was added. The mixture was stirred had a melting point at 177-179 "C;IR (KBr) 2.95,3.02,6.10,7.52,
at reflux for 1 h, cooled, and poured into 1 L of ice water. Fil- 8.60,11.60,12.10, and 12.29 pm; 'H NMR (MeaO-ds) 6 8-7.3 (m,
tration gave 3.9 g (66%)of 4a as a tan powder. An analytical 9 H), 6.70 (br a, 2 H, D20 exchangeable), 4.00 (a, 2 H), 2.40 (a,
sample was recrys- from EtOH mp 200 "C; IR (KBr) 2.85, 3 HI.
2.94,6.00,6.60,8.48,10.28, and 11.62 pm; 'H NMR (MezSO-d6) Anal. Calcd for C1&16Nz0&i&: C, 48.89; H, 4.37; N, 7.60.
6 9.2 (br a, 1 H), 7.41 (a, 2 H), 5.28 (br a, 2 H), 3.20 (a, 2 H). Found: C, 48.97; H, 4.48; N, 7.70.
Anal. Calcd for CJ-I8Cl3N3Oz: C, 36.40; H, 2.71; N, 14.17. 2-Amino-3-(phenylsulfonyl)-l-azirine (6b). A mixture of
Found C, 36.29; H, 2.84; N, 13.86. 30 g (0.082 mol) of tosylate 5b and 250 mL of MeOH was stirred
Tosylate 5a from Amidoxime 4a. A solution of 7.2 g (0.024 at 25 "C during addition (30 min) of 4.54 g (0.082 mol) of sodium
mol) of amidoxime 4a in 35 mL of pyridine was cooled to 0 "C methoxide in 50 mL of MeOH. The mixture was stripped of
and treated with 5.0 g (0.026 mol) of tosyl chloride. After 1 h MeOH and partitioned between water and EtOAc. The organic
at ( k 5 "C, the mixture was added to ice water and fiitered to give phase was dried and stripped in vacuo to give an orange syrup
7.5 g (69%) of tQSylate5a as a white solid. An analytical sample which crystallized when scratched. The resulting solid was
from EtOH had a melting point at 151-152 " C IR (KBr) 2.93, triturated with toluene, fitered, and air-dried to give 12.0 g (74%)
3.10, 6.00, 6.09, 7.51,8.57, and 12.2 pm; 'H NMR (Me2SO-ds)6 of azirine 6b as a tan solid mp 106-107 "C (toluene-CHC13);IR
9.62 (br a, 1 H), 7.90 (d, J = 9, 2 H), 7.49 (8, 2 H), 7.33 (d, J = (KBr) 2.91,3.02,5.47,5.51,6.96,7.6-7.8,8.7-8.8,9.27, 10.50,13.17,
9, 2 H), 6.31 (bra, 2 H), 3.28 (a, 2 HI, 2.36 (8, 3 HI. 14.08, and 14.60 pm; 'H NMR (CDC13)6 8.2-7.5 (m, 5 H), 6.70
Anal. Calcd for Cl6Hl4Cl3N3O,S: C, 42.63; H, 3.13; N, 9.32. (br a, 2 H), 3.68 (a, 1 H); 13C NMR (CDC13)50.2 (C3 of azirine),
Found C, 42.96; H, 3.29; N, 9.51. 127.6 (a-Ar), 129.2 (m-Ar),133.5 (p-Ar), 139.0 (C, of Ar), 149.0
Aminoazirine 6a from Toeylate Sa. A slurry of 35.0 g (0.078 (C2of azirine); mass spectrum (FD), m / e 196 (M'), 141 (100%).
mol) of h y l a t e 5a in 350 mL of MeOH was treated dropwise at Anal. Calcd for C&,N2O& C, 48.W; H, 4.10; N, 14.28. Found
25 "C with a solution of 4.2 g (0.078 mol) of sodium methoxide C, 48.82; H, 4.14; N, 14.33.
in 25 mL of MeOH. TLC analysis (silicagel, 5% MeOH in CHCls) Amide 11 from Azirine 6b. A mixture of 1.0 g (0.0051 mol)
indicated complete reaction in 20 min. The initially white slurry of 6b and 10 mL of HOAc was warmed at 50-70 "C for 0.5 h and
gave a clear yellow solution midway through the addition; tan solid cooled to 25 "C. The crystalline product was filtered, washed with
reappeared at the end of the reaction. The mixture was cooled EtOH, and air-dried to give 0.94 g (72%)of amide 11: mp 162-163
to 0 "C and fitered, and the solid product was washed thoroughly "C (EtOH); IR (KBr) 2.9-3.1,5.9,6.0,7.7,8.78,9.3,13.7, and 14.55
with water and air-dried. The yield of 6a was 18.9 g (88%).An pm. 'H NMR (MezSO-d6)6 8.90 (d, J = 9 , 1 H, DzOexchange-
analytical sample was recrystallized from MeOH: mp 148-150 able), 8.1-7.6 (m, 5 H), 7.50 (br s, 2 H, D20 exchangeable), 6.08
"C; IR (KBr) 3.0-3.4, 5.45, 5.50, 6.10, 6.45, 6.67, 6.69, 7.37, 7.51, (d, J = 9, 1 H, collapses to s on D20 addition), 1.74 (a, 3 H).
7.95, 8.35, 10.15, 10.54, 11.71, 12.14, and 14.3 pm; 'H NMR Anal. Calcd for Cl,,HI2N2O4S:C, 46.87; H, 4.68. Found C,
(MeaO-ds) 6 9.43 (br a, 1 H), 7.59 (a, 2 H), 7.47 (br a, 2 H),2.73 46.71; H, 5.02.
(a, 1 H);'9c NMR ( M 4 O - G 32.9 (azirine Cs), 128.4 (m-Ar),132.0
Acknowledgment. The author is grateful to A. T.
Spaugh for collection and analysis of the '3c NMR spectra.
(11) When 10 was refluxed in 20% aqueous NaOH, 2,4,6-trichloro-
aniline waa the sole organic-soluble product formed (78%yield). Registry No. 3a, 24522-44-9;4a, 78515-46-5;4b, 17665-60-0;Sa,
(12) Seidel, M.; Viste, K.; Yih,R. Ger. Offen.1900947,1969,to Rohm 78515-47-6; Sb, 78515-48-7; 6a, 78515-49-8; 6b, 78515-50-1; 9,
and Haas Co.; Chem. Abstr. 1970, 72,21616g. 78515-51-2; 10, 78515-52-3; 11, 78515-53-4; hydroxylamineeHC1,
(13) Santilli, A.; Morris, R. J. Heterocycl. Chem. 1979, 16, 1197. 5470-11-1;tosyl chloride, 98-59-9.