J.Org. Chem., Vol. 41, No. 5, 1976
Cyclization of Unsaturated Hydroxylamine Derivatives
J. M. Bobbitt, I. Noguchi, H. Yagi, and K. H. Weisgraber, J. Org. Chem., preceding paper in this issue. J. M. Bobbitt, I. Noguchi, H. Yagi and K. H. Weisgraber, J. Am. Chem. SOC.,93, 3551 (1971). J. M. Bobbitt, K. H. Weisgraber, A. S. Steinfeid, and S. G. Weiss, J. Org. Chem., 35, 2884 (1970). (a) G. Krow, Top. Stereochem., 5, 31-68 (1970). (b) Recently, G. Helmchen and V. Prelog [Helv. Chim. Acta, 55, 2599 (1972)] prepared biaryl atropisomers having pseudodissymmetry owing to the presence of enantiomeric chirai centers at the ortho,ortho' positions of one ring. (c) J. J. Dannenberg and A. L. Blackwood, J. Am. Chem. SOC.,97, 4753 (1975).
would give t h e S configuration at C-6 and (2-12 of 3 and would retain the P twist of t h e biphenyl.
Acknowledgment. T h e author is grateful for t h e technical assistance of Mr. Ingo Hartmann in this study. Appreciation is due Professor James M. Bobbitt for supplying t h e compounds and for enlightening discussion. She is most appreciative for t h e suggestions of the referees a n d discussion with Dr. A. Moscowitz, but she alone is responsible for t h e conclusions described herein. T h e author is grateful t o t h e University of Virginia Chemistry Department for their courtesy during t h e preparation of this manuscript. Registry No.-(-)-l, 36-3; 3b, 57550-05-7.
35053-29-3; 2a, 35053-14-6; 2b,
CH, CONHCHMePh(S1
35048-
References and Notes (1) (a) Part VI1 of Rotatory Dispersion Studies Series. Part Vi: 0. 0. Lyle and M. J. Piazza, J. Org. Chem., 33, 2478 (1968). (b) Presented in part before the 9th International Symposium on the Chemistry of Natural Products, IUPAC, Ottawa, Canada, June 1974, Abstracts, 308. (2) (a) K. Mislow, Ann. N.Y. Acad. Sci., 93, 457 (1962); (b) K. Mislow in "Optical Rotatory Dispersion and Circular Dichroism In Organic Chemistry", G. Snatzke, Ed., Heyden and Son, London, 1967, pp 153-172. (3) D. Muriel Hail, Prog. Stereochem. 4, 1-42 (1969). (4) (a) K. Mislow, M. A. W. Glass, R. E. O'Brien, P. Rutkin, D. H. Steinberg, J. Weiss, and C. Djerassi, J. Am. Chem. SOC., 84, 1455 (1962); (b) K. Mislow, E. Bunnenberg, R. Records, K. Wellman, and C. Djerassi, ibid., 85, 1342 (1963). (5) (a) P. Crabbe, "Optical Rotatory Dispersion and Circular Dichroism in Organic Chemistry", Holden-Day, San Francisco, Callf., 1965, pp 244256, 291; (b) S. F. Mason, R. H. Seal, and D. R. Roberts, Tetrahedron, 30, 1671 (1974); (c) S. F. Mason in ref 2b, pp 71-81. (6) W. Hug and G. Wagniere, Tetrahedron, 28, 1241 (1972).
855
' '
, I
I
(18) (19) (20) (21) (22) (23) (24)
I
*
'NO?
COh'HCHMePh ( R )
/
(a) R. S.Cahn, C. K. ingold, and V. Preiog, Angew. Chem., h t . Ed. Eng/., 5,385 (1966); (b) IUPAC Rules, J. Org. Chem., 35, 2849 (1970). (a) M. Shamma and W. A. Slusarchyk, Chem. Rev.. 64. 59 (1964). (b) M. Shamma, Experientia, 16, 484 (1960). J. H. Brewster, ?op. Stereochem., 2, 63-66 (1967). R. Grinter and S.F. Mason, Trans. faraday SOC., 60, 274 (1964). H. Suzuki, Bull. Chem. SOC.Jpn., 32, 1340 (1959). J. R. PIatt, J. Chem. Phys., 17, 484 (1949); 19, 263 (1951). A. L. Sklar, J. Chem. Phys., 7, 984 (1939); L. Goodman, i. G. Ross, and E. Shull, ibid., 28, 474 (1957). W. H. Jaffe and M. Orchin, "Theory and Applications of Ultraviolet Spectroscopy", Wiiey, New York, N.Y., 1962, pp 397-407. G. Snatzke and P. C. Ho, Tetrahedron, 27, 3645 (1971). W. Kuhn and R. Rometsch, Helv. Chim. Acta, 27, 1080, 1346 (1944). L. Verbit and H. C. Price, J. Am. Chem. SOC., 94, 5143 (1972). J. P. Ferris, C. 8. Boyce, R. C. Briner, U. Weiss, I. H. Qureshi, and N. E. Sharpless, J. Am. Chem. SOC.,93, 2963 (1971). J. C. Craig and S.K. Roy, Tetrahedron, 21, 395 (1965). S. F. Mason in "Some Newer Physical Methods in Structural Chemistry", R. Bonnett and J. G. Davis, Ed., United Trade Press, London, 1967, pp 149-158.
Cyclization of Unsaturated Hydroxylamine Derivatives' Herbert 0. House,*2aDavid T.
David G . Melillo,2aLen F. Lee,2a0. R. HaynesFb and Bruce E. WilkesZb
School of Chemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, and Research and Development Department, Union Carbide Corporation, South Charleston, West Virginia 25303 Received April 29, 1975 Reaction of t h e a - a l l y l P-diketones 5 w i t h excess HONH2 yielded t h e bicyclic p y r r o l i d i n e derivatives 7 in w h i c h a new N-C b o n d h a d been f o r m e d by cyclization o f a n intermediate N-(4-pentenyl)hydroxylamine14. Study of conversion o f t h e N - a l k e n y l h y d r o x y l a m i n e 20 t o f o r m t h e cyclic hydroxylamine 24a a n d t h e electrochemical o x i 15 occur by a radical chain prod a t i o n of hydroxylamines 20,24a, a n d 31 suggested t h a t these ring closures 14 cess i n v o l v i n g a n intermediate n i t r o x i d e radical 37.
-
An earlier investigation3 of t h e reaction of 3,3-disubstituted 2,4-pentanediones (1, Scheme I) with excess hydroxylamine had provided the curious observation t h a t although the dimethyl derivative la could be converted either to t h e isoxazoline 2 or the dioxime 3, the dipropargyl derivative l b was remarkably resistant t o conversion beyond the isoxazoline stage 2. In seeking further information relating t o these observations, reaction of the diallyl derivative IC with excess hydroxylamine was also examined. Again, formation of an isolable dioxime 3 was unfavorable; treatment of t h e isoxazoline 2 (R = allyl) with hydroxylamine under vigorous conditions led to t h e formation of a n unexpected isomeric substance subsequently shown t o have t h e structure 4. In this paper we describe the evidence on which t h e assignment of structure 4 is based and also described are our observations pertaining t o the mode of formation of this substance. Two 1,a-diketone substrates, 5a and 5 b (Scheme 11),
Scheme I
-
",OH
R2C(COCH,),
la R = CH, b. R = CH,C=CH c.
-
C=N
I
R,C/
\
CH/
R = CH,CH=CH,
".,OH
I
e-0
'OH 2
CHJ
I
R,C
CH,CH=CH,
or \
C'NOH
I
CHJ 3
C H ,-C-
II
N,
I I ,e,
C-CH,
,&H-cH, O I N CH,( OH 4
856
J.Org. Chem., Vol. 41, No. 5, 1976
House, Manning, Melillo, Lee, Haynes, and Wilkes
Scheme I1
R I
CH3CO- C
I
sumably in equilibrium with the dioxime 12) followed by closure t o cyclic product 7. T h e unusual reaction in this sequence is the final cyclization 13 7 (or more generally, 14 15) t h a t results in t h e formation of a new C-N bond a t an unactivated olefinic carbon under mild conditions. I n considering the nature of this reaction, we were attracted by the apparently analogous oxidative cyclizations5 of the unsaturated hydroxylamine 16 t o the nitroxide 175a and t h e N-chloroamine 18 t o the bicyclic amine 19.5b T o examine this cyclization further, the unsaturated hydroxylamine 20 was synthesized by the route indicated in Scheme IV. The synthesis of hydroxylamine 20 was initially complicated by t h e fact t h a t the nitro olefin 22 was not reduced by a mixture of aluminum amalgam and HzO in Et20 or T H F , conditions which reduce the seemingly analogous 3nitro-3-methylpropane t o 31 in high yield.6 Consequently, t h e more vigorous reducing system, Zn and aqueous NHdC1, was employed7 resulting in partial overreduction of t h e nitro olefin 22 t o form a mixture of the hydroxylamine 20 and t h e amine 23. T h e synthesis was further complicated by t h e instability of 20; when mixtures 3ontaining this hydroxylamine 20 were either heated or allowed t o stand, conversion t o the cyclic hydroxylamine 24a occurred and exposure of mixtures containing 20 t o air resulted in rapid oxidation either t o the cyclized products 24a or 27 or t o a
1 equiv
-CHzCH= CHZ
hOCHJ 5a, R = CH,CH=CH, b, R = CH,
R
6a, R = CH2CH=CHz
b, R = CH,
R
R
I
OH 7a, R = CH,CH=CH, b, R = CH,j n-C,H,
I
-
-
",OH
bCOPh 8a, R = CH,CH=CH,
b, R = CH, 0
Scheme I11
C-CH,
CH~C-C-
R
II CH,NOH I II
HON
10
9
HON 6
R
R
were selected for further study. Reaction of either of these products with 1 molar equiv of NHzOH (from HONHSCl NaOAc) in aqueous dioxane or aqueous E t O H afforded the corresponding isoxazoline 6 t h a t was isolated and fully characterized. Reaction of either the diketone 5 or the corresponding isoxazoline 6 with excess NHzOH in refluxing aqueous E t O H or refluxing aqueous dioxane for a period of 6-24 h produced the bicyclic products 7. In each case, the predominant product was one stereoisomer of structure 7; from the reaction with the diallyl ketone 5a, a second unidentified minor product, isomeric with 7a, was isolated t h a t appears t o be a structural rather than a stereoisomer of 7a. From reaction with the diketone 5b, two stereoisomers of structure 7b and a third minor component identified as the dioxime 9 were also isolated. This saturated dioxime 9 is not further altered by the conditions of the reaction and, consequently, is not an intermediate in the formation of the bicyclic hydroxylamine 7b. When these same reaction conditions were applied t o t h e a-allyl ketone 10, only the expected oxime 11 was isolated indicating that the ring-closure reactions t o form products 7 were not characteristic of prolonged reaction of simple a-allyl ketones with NHzOH.~ The spectroscopic properties (see Experimental Section) of the cyclic hydroxylamine derivatives 7 and the corresponding 0-benzoates 8 taken with the structures of the starting materials 5 and the intermediates 6 served to define completely the structures 7. I t was therefore probable t h a t the reaction pathway involved in these transformations was the transformation of the isoxazoline 6 (Scheme 111) to the unsaturated hydroxylamine 13 (which is pre-
CH,C
+
(HO!!),
I
I ICCH,CH=CH, =CH$-C-CHzCH=CHz II N, /c\ 0 I NHOH
*
I
CH,
12
13
R
OH 7
R&-CHzCHzCH=CH,
1
-+
H2C-CHz &C; N-CH-
I
I OH
NHOH 14
15
I
~HOH
n. v
16
17
I
19
c1 18
CH,
J.Org. Chem., Vol. 41, No. 5, 1976 857
Cyclization of Unsaturated Hydroxylamine Derivatives
-
Scheme IV
CH2-CHCHO
(CHj)$HNO2
P h jP=CH2
7
(CHJ,CCH&H&HO
PhCH,N'Me,OH-
I
NO2
21 Zn,NH4C1
(CHJ,CCH&HXCH=CH,
I
H 2 0 ,Et,O
I
I
NHOH 20
NHz
23
NH-CO-R
OR 24a,I i = H b, R = COPh (CH&CCHpCH2CH=CH2
25a,R = CH, b,R=Ph
(CH3h m N+C H 3
I
Scheme V
027
26
(CH3),CCH2CH2CH=CH,
28
-
-
I
HN-OCOCH3
I N--COPh I 0--COPh
electrochemically, we studied the behavior of hydroxylamine derivatives 20, 24a, 26, and also, as model compounds, hydroxylamine derivatives 31 and 33 (Scheme VI). It should be noted in passing t h a t 0-acylated N-alkyl hydroxylamines such as 26 and 33, whose regioselective preparation has sometimes presented difficulty? were readily prepared by reaction of the N-alkyl hydroxylamines 20 and 31 with AczO in the absence of pyridine. By contrast, reaction of these hydroxylamines with either PhCOCl or CHBCOCl in t h e presence of pyridine yielded t h e N,O-diacylated derivatives 28, 34, and 35. Neither the 0-acetates 26 and 33 in MeOH solution nor the hydroxylamine 31 in DMF or in neutral (pH 7) aqueous solution exhibited a polarographic oxidation wave a t a potential less positive than +0.2 V vs. SCE. As aqueous or methanolic solutions of 31 were made more basic, the oxidative wave shifted to progressively more negative potentials (corresponding t o increasing ease of oxidation) with Eli2 values of -0.20 V vs. S C E and -0.51 V vs. SCE being obtained for aqueous solutions of 31 a t p H 10.0 and ca. 13, respectively.1° This observation, taken with the estimatedgb pK, values 6 and 12-13 for the transformations RN+HZOH - H+ RNHOH H+ RNHO-, suggest t h a t t h e hydroxylamine anion, RNHO-, is probably the species responsible for the very
I NO2 (CHJ$CH2CH?CH=CH?
I NO
21
"1
1. Zn, NH4CI. H,O
36
volatile blue material believed t o be the nitroso compound 36. These experimental difficulties were circumvented by acylating the mixture of the hydroxylamine 20 and the amine 23 t o form mixtures of either t h e acetyl derivatives 25a and 26 or the benzamide 25b and the dibenzoyl derivative 28. Each of these mixtures was separable by chromatography and the N,O-dibenzoyl derivative 28 was sufficiently stable to permit purification and complete characterization. Although the thermal instability of the liquid 0-acetate 26 prevented us from obtaining it in analytically pure form, i t was obtained in sufficient purity by chromatography t o permit its use in a base-catalyzed methanolysis t o generate solutions of the hydroxylamine 20 uncontaminated with t h e amine 23. Solutions of this hydroxylamine 20, obtained either from the nitro compound 22 or from t h e 0-acetate 26, underwent cyclization t o the cyclic hydroxylamine 24a (characterized as the benzoate 24b) when either heated on a !ateam bath or allowed t o stand overnight. Exposure of this cyclic hydroxylamine 24a t o 0 2 (air), especially in the presence of a catalytic amount of a Cu(I1) salt, resulted in oxidation t o form the nitrone 27. Authentic samples of the cyclic hydroxylamine 24a, the benzoate 24b, and the nitrone 27 were obtained from the nitrone 30 as indicated in Scheme V. Deliberate exposure of solution of the hydroxylamine 20 t o 0 2 resulted in the generation of a volatile, blue-colored material (presumable t h e nitroso compound 36) and resulted in diminished yields of the cyclized products 24 and 27. The best yield of benzoylated cyclized product 24b (20% based on the 0-acetate 2618 was obtained when the most precautions were taken t o minimize t h e concentration of 0 2 present during the cyclization. T o examine the oxidation of N-alkyl hydroxylamines
-n+
(CHJZCCHlCHlCH I \n
2. H,,
"
NO, 29
030
OH
6COPh
24a
24b
I
027
-
Scheme VI
t-BuNHOH
31
Ac,O
t-BuNHOCOCH,
t-BuIUO
33
32
25'
pyridine
t-Bu-N-
OCOCH, COCH,
PhCOCl pyridine
34 t-Bu-N-
I
OCOPh
CO-Ph 35
858
House, Manning, Melillo, Lee, Haynes, and Wilkes
J.Org. Chem., Vol. 41, No. 5,1976
ready air oxidation of RNHOH compounds in neutral and alkaline solution. In alkaline MeOH solution t h e hydroxylamines 31 (E112 = -0.39V vs. SCE), 20 (Ell2 = -0.42 V vs. SCE, prepared from 26), and 24a (E1/2= -0.47 V vs. SCE) are all oxidized with about equal ease. Consequently, our data suggest that t h e ring closure reaction being studied proceeds from t h e acyclic hydroxylamine 14 (or 20) to t h e cyclic hydroxylamine 15 (or 24a) and t h a t subsequent formation of a nitrone such as 27 (or a nitroxide such as 176awhere nitrone formation is not possible) is t h e result of oxidation of the intermediate cyclic hydroxylamine (e.g., 15). Since the transformation 14 --c 15 involves no net change in oxidation level and yet appears t o be promoted by traces of oxidizing agents, we believe that the most reasonable interpretation involves a radical chain mechanism such as t h a t illustrated in Scheme VII.llc In Scheme VI1
,CH2-CH,
H 38
I
OH 15
RNHOH -I-RN=O 40 41
=F= SRNHO. 42
this scheme only a catalytic amount of t h e intermediate nitroxide 37 is required t o propagate the reaction chain and t h e subsequently formed carbon radical 38 (whose formation is analogous t o t h e cyclization of a 5-hexenyl radical and to cyclization of t h e N radical derived from 18) should be readily reduced by t h e hydroxylamine 15 present. Although t h e generation of the nitroxide 37 is formulated as a direct oxidation, i t is also possible that the nitroxide arises by initial oxidation of a small amount of the starting hydroxylamine 40 t o a nitroso compound 41 followed by t h e knownl1asb interaction of 40 a n d 41 t o produce a nitroxide 42. This latter equilibration involving a nitroso compound is consistent with our observations that a faint blue color (attributable to 36) was always observed when we generated a solution of the hydroxylamine 20 in t h e absence of a reducing agent. We hope t o define t h e scope and limitations of this cyclization reaction in synthesis from experiments now in progress. One preliminary experiment (see Experimental Section) with a solution of t h e hydroxylamine 31 in cyclohexene suggested that intermolecular analogues of t h e reaction 14 ---, 15 are not favorable.
Experimental Sectioni2 Reaction of the Diketone 5a with HONH2. The diallyl diketone 5a, obtained by the alkylation of 2,4-~entanedione,'~ exhib-
ited the following NMR peaks (CCI4):6 4.8-5.9 (6 H, m, vinyl CHI, 2.62 (4 H, d, J = 6 Hz, allylic CHz), and 2.03 (6 H, s, CHsCO). A solution of 60.0 g (0.33 mol) of the diketone 5a, 23.2 g (0.33 mol) of HONHZ-HCl,and 27.9 g (0.33 mol) of NaOAc in 175 g of H2O and 205 g of dioxane was refluxed for 6.5 h and then concentrated under reduced pressure. The residue was extracted with Et20 and the Et20 solution was dried and concentrated to leave 67.1 g of residual yellow liquid containing (GLC, silicone SE-30 on Haloport F) the diketone 5a (retention time 3.4 min, ca. 2%), an unknown component (4.9 min, ea. 12%), and the isoxazoline 6a (7.3 min, ca. 86%).A 34-g fraction of the crude product was distilled to separate 11.8 g of forerun [bp 84 "C (1.5 rnm)-100 OC (0.5 mm)], and 17.2 g of the pure (GLC) isoxazoline 6a: bp 100 O C (0.5 mm); ir (CCL) 3590,3420 (broad, free and associated OH), and 1640 cm-' (C-C); NMR (CCld) 6 4.8-6.2 (6 H, m, vinyl CH), 4.22 (1 H, s, OH), 1.9-2.9 (4 H, m, allylic CH2), 1.83 (3 H, s, CH3), and 1.47 (3 H, s, CH3). Anal. Calcd for CllH17N02: C, 67.66; H, 8.78; N, 7.17. Found: C, 67.37; H, 8.66; N, 7.15. After a solution of 485 mg (2.69 mmol) of the diketone Sa, 1 . 8 7 g (26.9 mmol) of HONHpHCl, and 220 mg (26.9 mmol) of NaOAc in 15 ml of H2O and 15 ml of dioxane had been refluxed for 6 h, the reaction solution was partitioned between H2O and CHzC12. The CH2CIz solution was washed with HzO, dried, and concentrated to leave 539 mg of colorless liquid that was chromatographed on silica gel with EtzO-hexane mixtures as eluents. After separation of 8 mg of an early fraction containing an uncharacterized solid (mp 192-198 "C), the subsequent fractions contained 441 mg (84%) of the liquid isoxazoline 6a followed by 43 mg of the bicyclic hydroxylamine 7a. The latter fraction was crystallized from hexane-Et20 to separate 40 mg (7.1%) of one isomer of the bicyclic hydroxylamine 7a as white prisms, mp 82-84 O C . When an analogous oxperiment was performed using 507 mg (2.59 mmol) of the isoxazoline with 1.80 g (25.9 mmol) of HONH2sHCl and 2.13 g (25.9 mmol) of NaOAc, the bicyclic material 7a isolated after chromatography and crystallization amounted to 40 mg (7.4%), mp 81.5-83.5 O C . Recrystallization raised the melting point of the bicyclic hydroxylamine 7a to 88-89 OC: ir (CCW 3580, 3420 (free and associated OH), and 1640 cm-' (C=C); NMR (CCla) 6 4.9-6.0 (3 H, m, vinyl CH), 2.5-3.0 (1H, m, NCC=N+-0-); uv rnax (95%EtOH) 229 nm (e 7300) [lit.20c231 nm (e 8400)l; NMR (CDC13) 6 2.4-2.9 (2 H, m, CHzC=N), 1.8-2.2 (5 H, m, CHz and a broad CH3 singlet at 2.02), and 1.40 (6 H, s, CH3); mass spectrum m/e (re1 intensity) 127 (M+, 77), 112 (36), 95 (24), 69 (23), 58 (37), 55 (46), 43 (85), 42 (39), 41 (loo),and 39 (26). Preparation of Acyl Derivatives of t-BuNHOH (31). Samples of t-BuNHOH (31) and the dimer of t-BuNO (32) were prepared by previously described procedures! A solution of 1.00 g (11 mmol) of t-BuNHOH in 3.0 ml of AczO was allowed to stand at 25O for 20 min and then the mixture was partitioned between Et20 and aqueous NaHC03. After the Et20 layer had been dried and concentrated, distillation of residual yellow oil (200 mg) under reduced pressure in a short-path still separated 157 mg (11%)of the acetate 33 as a colorless liquid: nZ5D1.4100; ir (Cc4) 3210 (NH) and 1735 cm-I (ester C=O); NMR (Cc4) 6 7.37 (1 H, broad, NH, exchanged with DzO), 2.05 (3 H, s, CHaCO), and 1.08 (9 H, s, t Bu); mass spectrum m/e (re1 intensity) 118 (11, 115 (41, 72 (15), 70 (16), 60 (25), 58 (1001, 57 (73), 56 (42), 55 (31), 44 (38), 43 (62), 42 (45), 41 (60), and 39 (42). Anal. Calcd for CeH13N02: C, 54.94; H, 9.99; N, 10.68. Found: C, 54.89; H, 10.01; N, 10.70. A solution of 0.50 g (5.6 mmol) of t-BuNHOH in 6.0 ml of pyridine was treated with 3.0 ml of CH3COCl and the resulting semisolid mixture was allowed to stand at 25 "C for 20 min. The reaction mixture was partitioned between Et20 and aqueous NaHC03 and the Et20 layer was dried and concentrated. The residual liquid (310 mg) was chromatographed on silica gel. After separation of early unidentified fractions (8 mg), the crude ester amide 34 was eluted with hexane-Et20 (9:l v/v) as 220 mg of pale yellow liquid. Distillation under reduced pressure in a short-path still separated 200 mg (21%)of the pure ester amide 34 as a colorless liquid n25D 1.4350 [litz1bp 102 "C (19 mm)]; ir (Cc4) 1795 (ester C=O) and 1688 cm-' (amide C=O); NMR (CC4) 6 2.15 (3 H, s, CH3COO), 1.85 (3 H, s, CHsCON), and 1.37 (9 H, s, t-Bu); mass spectrum m/e (re1 intensity) 173 (M+, l),131 (24),57 (57), 56 (28), and 43 (100). A cold (5 "C) solution of 300 mg (3.4 mmol) of t-BuNHOH in 6.0 ml of pyridine was treated with 3.0 ml of PhCOCl and the resulting mixture was allowed to stand at 25 "C for 1 h. After the reaction mixture had been partitioned between Et20 and aqueous NaHC03, the Et20 layer was dried and concentrated to leave 1.8 g of liquid. Chromatography on silica gel with a PhH-hexane eluent (1:1 v/v) separated (PhC0)ZO in early fractions followed by 1.07 g of liquid containing the ester amide 35. Crystallization from pentane afforded 200 mg (20%)of the pure ester amide 35 as colorless
862 J . Org. Chem., Vol. 41, No. 5,1976 needles: mp 97-99 "C (lit.21 mp 98-99 "C); ir (cc14)1768 (ester C=O) and 1678 cm-' (amide C=O); uv max (95% EtOH) 233 nm (c 17000); NMR (cc14) 8 7.1-7.9 (10 H, m, aryl CH) and 1.58 (9 H, 8, t-Bu); mass spectrum m/e (re1 intensity) 105 (loo), 77 (31), 51 (111, and 41 (5). To examine the possibility of an intermolecular addition of t BuNHOH to an olefin, a solution of 1.0 g (11.2 mmol) of t-BUNHOH and 1 mg of the dimer of t-BuNO in 10 g (122 mmol) of freshly purified cyclohexene was heated to 60" under an Nz atmosphere with stirring for 16 h and then concentrated under reduced pressure. The NMR spectrum (Cc4) of the residual solid (0.50 g) exhibited only NMR peaks attributable to t-BuNHOH with no indication that N-tert-butyl-N-cyclohexylhydroxylaminehad been formed. Methanolysis of the 0-Acetates 26 and 33 and Cyclization of the Hydroxylamine 23. A solution of 30 mg (0.22 mmol) of the 0-acetate 33 in 150 pl of MeOH exhibited NMR singlets at 6 2.08 (COCH3) and 1.19 (t-Bu). Upon dropwise addition of methanolic 1 M NaOH, 10 pl (0.01 mmol) was required to catalyze the complete conversion of the 0-acetate 33 to MeOCOCH3 (NMR singlet a t 8 2.02) and the hydroxylamine 31 (NMR singlet at 6 1.10) at 25 OC. Similarly, when a solution of 30 mg (0.18 mmol) of the 0-acetate 26 in 200 pl of MeOH at 25" (NMR singlets at 6 2.09 and 1.01) was treated with 30 p1 (0.03 mmol) of methanolic 1 M NaOH, the solution contained CH3OCOCH3 (NMR singlet at 8 2.02) and the hydroxylamine 26 (NMR singlet at 6 1.05). When this solution of the hydroxylamine 26 was refluxed for 5 min, the NMR spectra of the solution exhibited a multiplet in the region B 1.0-1.2 characteristic of the cyclic hydroxylamine 24a. This conversion was repeated on a larger scale by treating a solution of 445 mg (2.6 mmol) of the 0-acetate 26 in 5 ml of MeOH with 200 mg (5.0 mmol) of NaOH. The solution, which immediately turned pale blue in color, was stirred under Nz for 2 min, neutralized with C02, and filtered to remove the NaHC03 precipitate. The residue was washed with Et20 and the combined organic solutions were concentrated under reduced pressure to leave 220 mg of the crude liquid hydroxylamine 20. This crude product was heated on a steam bath for 2 min and then cooled and treated with 1.0 ml of PhCOCl and 2.0 ml of pyridine. The resulting mixture was stirred for 10 min at 25O and then partitioned between Et20 and aqueous 3 M HC1. After the ethereal layer had been washed with aqueous NaHC03, dried, and concentrated, the residual crude product (912 mg) was chromatographed on silica gel with EtzOpentane mixtures as eluents. After separation of the early fractions [mixtures of (PhC0)ZO and PhCOzH], the fractions (350 mg of yellow liquid) eluted with 1:l (v/v) EtzO-pentane mixtures were partitioned between Et20 and aqueous NaHC03. The Et20 layer was dried and concentrated and the residue (308 mg) was rechromatographed on silica gel to separate 180 mg (20% yield based on the acetate 26) of the liquid benzoate 24b, n25D 1.5130, that was identified with the previously described authentic sample by comparison of ir and NMR spectra. Electrochemical Measurements. The polarographic and cyclic voltammetry measurements employed a custom-made polarographic module, utilizing solid-state amplifiers, that followed the typical three-electrode design. Descriptions of the cells, working electrodes (Pt sphere electrode for cyclic voltammetry and dropping Hg electrode for polarography), reference electrodes, reagent purification procedures, and procedures used to calculate E112 values have been published previously.22The polarographic reduction of solutions of the nitroso compound 32 (6.7-8.9 X M) in anhydrous DMF containing 0.5 M n-B4NBF4 gave E112 -1.48 V vs. SCE ( n = 0.8, id = 39-44 Reduction of the same solution by cyclic voltammetry (scan rate 500 mV/s) gave a cathodic peak at -1.86 V vs. SCE but no anodic peak was observed. When sufficient H2O was added to make the solution 1.0 M in H20, the cathodic peak was shifted to -1.75 V vs. SCE and an anodic peak, attributable to an unidentified reaction product, was observed at -0.87 V vs. SCE. Attempts to examine the oxidation of t-BUNHOH by cyclic voltammetry in a 0.5 M solution of n-BwNBFr in either anhydrous DMF or in DMF containing 1M HzO gave no OXidation peak within the range -1.3 to +0.5 V. Similarly, a solution of t-BuNHOH in an aqueous buffer (pH 7.0) exhibited no polarographic oxidation wave in the range -0.5 to +0.2 V VS. SCE. In more basic solution, the oxidation wave was shifted to more negative values.24In aqueous pH 10.0 buffer, the t-BuNHOH (8.3-8.5 X low3M) solution exhibited an oxidation wave with Eilz -0.20 V vs. SCE (n = 0.9, id = 48-52 pA) and in a more alkaline aqueous solution (pH 13, 1.5 M NaZS03 and 0.14 M KOH),25t-Bu"OH (6.7-7.6 X M) exhibited an Ell2 value of -0.51 V VI. SCE ( n
-
House, Manning, Melillo, Lee, Haynes, and Wilkes = 1.5, i d = 46-47 MA).A solution of the 0-acetate 33 (0.009 M) in aqueous MeOH (15:85 v/v) containing 0.5 M n-BwNBF4 exhibited no polarographic oxidation wave in the range -0.5 to 0.0 V; when sufficient methanolic NaOH solution was added to saponify the 0-acetate 33 and make the solution 0.05 M in NaOH, a polarographic oxidation wave attributable to 31 was observed with Ell2 = -0.39 V vs. SCE ( n = 1.0, id = 24 PA). Comparable behavior was observed for the 0-acetate 26 (2.7-12 X lob3 M) whose solution in aqueous MeOH containing 0.5 M n-Bu4NBF4 exhibited no polarographic oxidation wave in the range -0.5 to 0.0 V. After addition of methanolic NaOH to saponify the acetate 26 and make the solution 0.05 M in NaOH, this solution of the hydroxylamine 20 exhibited a polarographic oxidation wave at Ell2 = -0.42 V vs. SCE ( n = 1.1, i d = 5-27 PA). The polarographic oxidation of this solution was reexamined at intervals after the solution had been stirred under N2 and after the solution had been exposed to 0 2 of the air. The i d value decreased regularly as the solution was stirred but no new oxidation peak was observed. After exposure to 0 2 of the air for 10 min, the oxidation wave attributable to hydroxylamines 20 and/or 24a was no longer observed indicating that oxidation of 20 to the corresponding nitroso compound or 24a to the nitrone 27 was complete. Polarographic oxidation of a solution of the cyclic M) in aqueous MeOH (15:85 hydroxylamine 24a (1.4-2.0 X v/v) containing 0.5 M n-BuNBF4 and 0.05 M NaOH gave Ell2 = -0.47 V vs. SCE ( n = 0.8, id = 19-24 PA). Since the Ell2 values for oxidation of the hydroxylamine 20 before (-0.42 V) and after cyclization (to form 24a, Ell2 = -0.47 V) are very similar, our failure to observe two resolved oxidation waves during the change 20 24a 27 is understandable.
-
4
Registry No.-5a, 3508-79-0; 5b, 53315-95-0; 6a, 57620-40-3; 6b, 57620-41-4; 7a, 57620-42-5; 7b, 57620-43-6;8a, 57620-44-7; 8b, 57620-45-8; 9, 57620-46-9; 10, 16178-87-3; 11, 57620-47-0; 20, 57620-48-1; 21, 57620-49-2; 22, 57620-50-5; 23, 819-45-4; 24a, 57620-51-6; 24b, 57620-52-7; 25a, 57620-53-8; 25b, 835-85-8; 26, 57620-54-9; 27, 4567-18-4; 28, 57620-55-0; 29, 57620-56-1; 30, 3317-61-1; 31, 16649-50-6; 33, 51338-99-9; 34, 53242-00-5; 35, 51339-08-3; HONHZ-HCl, 5470-11-1; PhCOCl, 98-88-4; 3-methyl2,4-pentanedione, 815-57-6; allyl bromide, 106-95-6; 3-methyl-3propyl-2,4-pentanedione, 57620-57-2; methyllithium, 917-54-4; 1acetoxy-2-methylcyclohexene,1196-73-2; 2-nitropropane, 79-46-9; acrolein, 107-02-8; methylenetriphenylphosphorane, 3487-44-3; acetic anhydride, 108-24-7;acetyl chloride, 75-36-5.
References and Notes (1) This research has been supported in part by Public Health Service Grant 9-R01-GM-20197 from the National institute of General Medical Sciences. The execution of this research was also assisted by Institutlon Research Grants from the National Science Foundation for the purchase of a mass spectrometer and a Fourier transform NMR spectrometer. (2) (a)Georgia institute of Technology; (b) Union Carbide Corp. (3) D. T. Manning and H. A. Coleman, J. Org. Chem., 34, 3248 (1969). (4) This experiment was performed in our laboratories by Dr. R. A. Auerbach. (5) (a) W. E. Motherwell and J. S. Roberts, Chem. Commun., No. 6 , 328. 329 (1972). We are Indebted to Dr. James S. Roberts, who supplied additional experimental details concerning the preparation and cycllzatlon of hydroxylamine 18. (b) J. M. Surzur and L. Stella, Tetrahedron Left., 2191 (1974). (c) For other examples of additions of N-centered radicals (derived from Kchioro amines) to olefins, see F. Minisci. Acc. Chem. Res., 8, 165 (1975); R. Furstoss, 0 . Esposito, P. Telssier, and E. Waegeil, Bull. Soc. Chim..Fr., 2485 (1974). (6) A Caider, A. R. Forrester, and S . P. Hepburn, Org. Synth., 52. 77 (1972). (7) This same reducing system was also employed to prepare the hydroxylamine 18. See ref 5a. (8) This relatively low isolated yield is attributable to the difficulties in isolating the hydrolytically and thermally unstable liquid benzoate 24b. NMR anaiysls of the reaction mixture indicated that hydroxylamine 24a is the major product formed from 20. (9) For examples, see (a) T. R. Juneja and H. Dannenberg, TetraMmn, S I , 695, 701 (1975); (b) P. A. S. Smith, "The Chemistry of OpenGhain Organic Nitrogen Compounds", Voi. 2, W. A. Benjamin, New Yo&. N.Y., 1968, pp 2-3 and 10-11. (IO) The shift of El,* values for the oxidation of PhNHOH to increasingly negative values with increasing pH has been noted previously by J. W. Smith and J. G. Wailer, Trans. Faraday Soc., 48, 290 (1950). (11) (a) T. A. J. W. Wajer. A. Mackor, and T. J. deBoer, Tetrahedron, 25, 175 (1969). (b) D. F. Bowman, J. L. Brokenshire, T. Giiian, and K. U. ingold, J. Am. Chem. Soc., g3, 6551 (1971). (c) A referee has suggestacl that the ring-closure step, rather than Involving the radical addition to an olefin indicated In structure 37, involves an initial H atom transfer i to yield an intermedlate nitroso radical ii that cycilzes to Ill. Although the second step, /I ill, in this sequence would clearly be favorable. we
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J. Org. Chem., Vol. 41, No. 5, 1976 863
Synthesis of 2-Alkylpyrrolidines and 2-Alkylpiperidines
-
are unaware of precedent for the first step, I ii, the transfer of an H. atom from a radical to a double bond. Consequently, we presently prefer the radical addltlon mechanism (37 in Scheme VII) for which some precedent exists (ref 5b,c) but have no experimental basis for excluding ii iii. the alternative radical chain process involving i %CCH1CH2-CH=~~,
I
1
i
&CCH2CH,CHCHJ
I
,
--
H.
trader
cychaatmon
‘C-CH2CH2
I
-
I
RNHOH
0-N-CHCH, iii
product
+ R’NHO,
ii
(12) Ail melting points are corrected and all boiling points are uncorrected. Unless otherwise stated MgSO4 was employed as a drying sgent. The ir spectra were determlned with a Perkin-Elmer Model 237 or Model 257 infrared recording spectrophotometer fitted with a gratlng. The uv spectra were determined with a Cary Model 14 or a Perkin-Elmer Model 202 recording spectrophotometer. The proton NMR spectra were determined at 60 MHz wlth a Varian Model A-60 or Model T-60 NMR spectrometer and the 13C NMR spectra were obtalned with a JEOL Fourier transform spectrometer, Model PFT-100. The chemical shift values are expressed in 6 values (parts per mlllion) relative to a Me4SI Internal standard. The mass spectra were obtained wlth an Hltachi Perkin-Elmer Model RMU-7 or a Varlan Model M-66 mass spectrometer. All reactions involving strong bases or reactive organometallic Intermediates were performed under a nitrogen atmosphere. (13) R. 8. Davis and P. Hurd, J. Am. Chem. SOC.,77, 3284 (1955).
I. I. Grandberg, S.V. Tabak, G. K. Faizova, and A. N. Kost, Zh. Obshch. Khim., 33, 2585 (1963); Chem. Abstr., SO, 515 (1964). M. Gall and H. 0. House, Org. Synth., 52,39 (1972). J. M. Conia and F. Leyendecker, Bull. SOC.Chim. Fr., 830 (1967). Initial studies of this reaction were carrled out in our laboratory by Drs. We1 C. Llang and James J. Good. H. Shechter, D. E. Ley, and L. Zeldin. J. Am. Chem. SOC.,74, 3664 (1952). When the benzoate 24b was heated, it slowly decomposed to form PhCOZH, presumably accompanled by an imine. (a) R. Bonnett. V. M. Clark, A. Glddey, and A. Todd, J. Chem. SOC., 2087 (1959); (b) R. Bonnett, R. F. C. Brown, V. M. Clark, I. 0. Sutherland, and A. Todd, bid., 2094 (1959); (c) L. S.Kamlnsky and M. Lamchen, J. Chern. SOC.6, 1085 (1968). F. Klaaes, R. Heinle, H. Sltz, and E. SDeCht. Chem. Ber.. 96. 2387 (1963): I (a) H. 0. House and E. F. Kinloch, J. Org. Chem., 39, 1173 (1974); (b) H. 0. House, D. Koepseii, and W. Jaeger, ibid., 38, 1167 (1973); (c) K. W. Bowers, R. W. Giese, J. Grlmshaw, H. 0. House, N. H. Kolodny, K. Kronberger, and D. K. Roe, J. Am. Chem. SOC.,92, 2783 (1970); (d) R. N. Adams, “Electrochemistry at Solid Electrodes”, Marcel Dekker, New York, N.Y., 1969, pp 143-158. (23) (a) An €112 value of -1.36 V vs. SCE has been reported for t-BuNO in acetonitrile solution: H. Sayo, Y. Tsukltanl, and M. Masui, Tetrahedron, 24, 1717 (1988). (b) The reduction of PhNO in aqueous solutions of varying pH has been studied polarographically (ref 10) and the reduction of PhNO in aprotic solvents has been studied by cyclic voltammetry [M. R. Asirvatham and M. D. Hawley, Electroanal. Chem., lnrerfacial € k c trochem., 57, 179 (1974)]. (24) The shift of €112 to more negative potentials with Increasing pH has also been observed in the polarographic oxidation of PhNHOH. See ref
IO. (25) These conditions for the polarographic determlnation of Kalkylhydroxyiamlnes were described by P. E. lverson and H. Lund, Anal. Chem., 41, 1322 (1969). These authors report an €1,2 value of -0.47 V vs. SCE for f-BuNHOH.
A New Synthesis of 2-Alkylpyrrolidines and 2-Alkylpiperidinesl Herbert 0. House* and Len F. Lee School of Chemistry, Georgia Institute of Technology, Atlanta, Georgia 30332
Received September 5,1975 E a c h o f t h e N-(4-pentenyl)hydroxylaminederivatives 7 a n d 17 underwent facile cyclization t o t h e 2-methylp y r r o l i d i n e derivatives 10 a n d 18 when t h e starting materials were warmed b r i e f l y t o 50-60 “C. Subsequently red u c t i o n a n d acetylation w i t h Zn, H O A c , a n d AczO afforded t h e corresponding amides 12 a n d 19. Cyclization o f t h e homologous N-(5-hexenyl)hydroxylamines27 a n d 34 t o t h e 2-methylpiperidine derivatives 28 a n d 35 (isolate d after conversion t o t h e amides 29 a n d 22) r e q u i r e d higher temperatures (130-140 “C) a n d longer reaction times (1-2 h). A t t e m p t s to cyclize t h e unsaturated hydroxylamines 38 a n d 39 were unsuccessful. T h e ease a n d direction o f these various cyclizations, believed t o b e radical chain reactions, parallels t h e behavior o f related alkenyl carb o n radicals 5.
In an accompanying paper2 we have described a study of the cyclization of certain unsaturated hydroxylamines 1 (Seheme I) t o the corresponding N-hydroxypyrrolidines 2. We believe this cyclization t o be a radical chain process involving the intermediate radicals 3 and 4 in which the step 3 --* 4 is analogous t o the cyclization 5 -* 6 of certain carbon radicals 5.3-6 In the previous study2 the synthetic attractiveness of the cyclization 1 2 was mitigated by the facts t h a t synthesis of the starting hydroxylamines 1 by selective reduction of the corresponding nitro olefins was tedious and isolation of the thermally unstable, easily oxidized cyclic hydroxylamines 2 was difficult. In this paper we describe alternative procedures t h a t overcome these problems. An especially simple and efficient synthesis of unsaturated hydroxylamine derivatives, e.g., 7 (Scheme 11),from the corresponding unsaturated carbonyl compounds 8 utilized the selective reduction of the oxime 9 with NaB(CN)H3 in acidic MeOH.6 Although the original procedure recommended6a performing the reaction a t p H 4 (bromocresol blue indicator), we found the reduction of ketox-
-
dcheme I oxidation
R,CCRZCH,CH=CHz
F&CCR&H&H=CH,
I
I
~HOH
H-N. “0
1
-.
3
CRZ---CH,
I
I
F&C\ /CH-CH,. H
2’ I
CRz--CH,
H+ transfer
R,&dCHCH,
1
I
I
0-
OH
4
.CH,CH,(CH,),CH=CHZ
-
H. transfer from 1
2 3
5
6b
