Tcuahlron Lcttcrs. Vol.32, No.37. pp 49654968. 1991

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SYNTHESIS OF 4-AZAHOMOADAMANT-4-ENE N-OXIDES AND THEIR

1,3-DIPOLAR CYCLOADDITION REACTIVITY’

Yang Yu, Masatomi Ohno, Shoji Eguchi*

Institute of Applied Organic Chemistry, Faculty of Engineering,

Nagoya University, Chikusa-ku, Nagoya 464, Japan

Summary: Nitrones incorporated in a homoadamantane ring system, which were obtained by SeO,-

H,O, oxidation of 4+tzahomoadamantane, underwent 1,3-dipolar cycloaddition reaction with electron-

deficient alkynes (not with alkenes) to give 4-substituted isoxazoline specifically by steric reasons.

Adamantane-heterocycles have drawn much attention for their potential pharmacological activities.’

Numerous adamantane-substituted and -fused heterocycles are developed and subjected to screening tests.

Along this line, the bridging nitrone incorporated in a homoadamantane ring system is one of the attractive

functional groups to access this class of compound. Nitrones are occasionally documented to be useful for

preparing a variety of heterocycles? We now wish to report here the first synthesis of 4-azahomoadamant-4-

ene N-oxides 3,4 and their 1,3-dipolar cycloaddition reactions, in which remarkable steric effect was observed.

These nitrones are also of interest from the mechanistic viewpoint, associated with the reaction of the related

oxaziridine 12 with acetylenic compounds to afford a pyrrole derivative4; previously, we postulated this ring

transformation occurred through either direct route via a zwitterionic intermediate or indirect route via nitrone

4 which might be reorganized from 12. Thus the reaction of 4 gives some mechanistic aspects for this

problem.

The 4-azahomoadamant-4-enes 1 are reasonable precursors of choice for 3 and 4, since they are easily

obtained by our established ring-expansion method starting from 2-adamantanols and sodium azide’. Attempted

oxidation6 of 1 with KMnO, under phase-transfer catalyzed conditions, however, gave none of nitrones 3 and

4. Conversion of oxaziridine7 12 under catalyzed conditions also failed. Successful oxidation was achieved by

applying the Murahashi’s procedure (SeO,-H,O, toward cyclic amine)? Required amines, 4-

azahomoadamantanes 2 were obtained by reduction of 1; in this case, LiAlH, was not an efficient reagent (less

than 50% reduction after refluxing for 24 h in THF) and, actually, a high yield (90-98%) was realized with

NaBH,CN.9 The smaller size of reductant could avoid steric hindrance due to environmental homoadamantane

ring protons. According to the similar procedure as reported, nitrones 3 (R=H) and 4 (R=Me) were obtained

in 65% and 84% yields, respectively (Scheme l).” The recorded reaction time (3 h) caused serious

decomposition, and 0.5 h for 3 and 2 h for 4 allowed acceptable yields as above. These nitrones were colorless

crystallines after purification (sublimation or trap-to-trap distillation and chromatography), and stored at room

4965

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temperature under dried conditions (very hygroscopic). The structures were characterized by spectral and

elemental analyses; in addition to molecular ion peaks at m/e 165 for 3 and 179 for 4 (MS), an imine absorption

appeared at 1610 cm -1 (1R) and an imine proton of 3 was indicated at 6 7.35 (~H-NMR).

NaBH3CN ~ 30% H202, Se02 , ~ N ~ NH = N-~

R R R 1 2 3, 4

O

Schemel 3: R = H , 4: R = C H 3

The 1,3-Dipolar cycloaddition reaction of 3 and 4 was carried out in toluene with electron-deficient

alkenes and alkynes. The reaction proceeded very smoothly at room temperature with acetylenic compounds

such as methyl propiolate, dimethyl acetylenedicarboxylate and cyanoacetylene to give the corresponding

products, which were purified by preparative TLC (Table).

Table. 1,3-Dipolar Cycloaddition Reaction of Nitrones 3 and 4 with Acetylenes

Nitrone Acetylene Reaction Conditions Product Y ie ld Melting Point

No. R 1 R 2 Temp.(°C) Time(h) (%) (°C)

3 C02Me H 0 2 5a 78 42.5-45.5

3 C02Me C02Me 20-25 1 5b 70 83.5-86.5

3 CN H 20-25 0.2 5¢ 79 oil

4 C02Me H 20-25 2 6a 73 oil

4 C02Me C02Me 20-25 2 6b 63 89.0-91.0

4 CN H 20-25 0.5 6c 93 98.5-100.5

These products were composed of a single regioisomer and the structures were determined as a 1:1

cycloadduct, isoxazoline 5, 6.1~ Furthermore, 1H-NMR spectral inspections confirmed the regiochemistry;

relative chemical shifts of C4-H and Cs-H clearly indicated an electron-withdrawing group to be located at C a

position. I: This regiochemical outcome (4-substituted isoxazoline) is consistent with the orbital correlation

HOMO(nitrone)-LUMO(dipolarophile). Nevertheless, this is not the case when steric effect is minimized, for

example, as seen in N-(t-butyl)nitrone in which rather 5-substituted isoxazoline predominates as the result of

mixing with HOMO(dipolarophile)-LUMO(nitrone). 3" 12 In this case, nitrone-oxygen seems to be free from

4967

steric hindrance whereas bridging imine moiety is highly surrounded by ring protons. Therefore, whole effects

forced unilateral interaction between nitrone-oxygen and 13-carbon of acetylene (i.e., nonsynchronous pathway).

Notably, the reaction with alkenes (methyl acrylate, acrylonitrile, N-phenylmaleimide etc.) afforded none of

isolable cycloadducts, suggesting that it was severely restricted because of nonlinear molecular geometry. In

contrast to the electron-deficient alkyne, phenylacetylene reacted with 4, but homoadamantane-fused pyrrole

8 (Yield 72%) was obtained directly at elevated temperature (150°C, 24h).

The 3-methyl-substituted isoxazoline is known to rearrange to pyrrole via acylaziridine and/or enamine 13.

This rearrangement aptitude was also observed in 6a and 6b, although considerably higher temperature (170°C)

was required than the reported one (130°C). TM The product obtained from 6a was assigned to 2-

methoxycarbonyl-substituted pyrrole 9 by comparison with authentic samples, in The attained substitution

pattern indicated that the present isoxazoline---*pyrrole rearrangement proceeded via acylaziridine 7.13

These results are compared with the reaction of oxaziridine 12 with acetylenes to give the similar pyrrole

derivative. 4 Firstly, while the pyrrole 11 was formed, 12 did react at 85°C but 6b did not react at all under the

same conditions. Secondly, the reaction of 12 with methyl propiolate in methanol was found to give the

isomeric 3-substituted pyrrole 10.15 These facts indicate that the nitrone 4 is not involved in the case of

oxaziridine ---* pyrrole.

~ N.-~ O

R

3, 4

R t C = C R 2

N R 1

CH3

12 8-11

i1.- R

R 2

5, 6

A (R=CH3)

C R

7

Scheme 2 8: RI=H, R2=Ph

9: R1=COOMe, R2=H,

10: RI=H, R2=COOMe

11: R1=R2=COOMe

5: R=H

6: R=CH 3

a, RI=COOMe, R2=H

b, RI=R2=COOMe

c, R1=CN, R2=H

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REFERENCES AND NOTES

1. Synthesis of Novel Carbo- and Heteropolycycles. 19. For Part 18, see Takeuchi, H.; Matsushita,Y.;

Eguchi, S. J. Org. Chem. 1991, 56, 1535. 2. For examples, see: a) Fort, R. C., Jr. In Adamantane-The Chemistry of Diamond Molecules; Marcel

Dekker; New York, 1976, Chapter 7. b) Cody, V.; Suttan, P. A.; Welsh, W. J. J. Am. Chem. Soc., 1987, 109, 4053.

3. For recent reviews, see: a) Tufariello, J.J. In 1,3- Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;

John Wiley & Sons; New York, 1984; Vol. 2, Chapter 9. b) Confalone, P. N.; Huie, E. M. In Organic

Reactions; Kende, A. S., Ed.; John Wiley & Sons; New York, 1988; Vol. 36, Chapter 1. c) Breuer, E. In Nitrones, Nitronates and Nitroxides; Patai, S.; Rappoport, Z., Eds.; John Wiley & Sons; New York, 1989, Chapter 2.

4. Eguchi, S.; Asai, K.; Sasaki, T. Heterocycles, 1989, 287, 125. 5. a) Sasaki, T.; Eguchi, S.; Toi, N. Heterocycles, 1977, 7, 315. b) Sasaki, T.; Eguchi, S.; Toi, N. J. Org.

Chem. 1978, 43,~1~0. c) Sasaki, T.; Eguchi, S.; Toi, N. J. Org. Chem. 1979, 44, 3711. Christensen, D.i" J~rg~ensen, K. A. J. Org. Chem. 1989, 54, 126. 6.

7. Lee, T. D.; Keana, J. F. W. J. Org. Chem. 1976, 41, 3237. 8. Murahashi, S-I.; Shiota, T. Tetrahedron Letters', 1987, 28, 2383. 9. a) Botch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897. b) Borch, R. F.; Durst,

H. D. J. Am. Chem. Soc. 1969, 91, 3996. 10. The nitrones gave following spectral data. 3: m. p. 250-253°C(sub); IR(KBr): 1610 cm-1; 1H-NMR(6,

CDCI3): 7.35(dd, J=8.0 Hz, J=2.0 Hz, 1H), 4.16(m, 1H), 2.53(m, 1H); MS m/e (%): 165(M +, 16), 149(4), 135(22), 79(96), 67(100). 4: m. p. 98.5-102.5°C; IR(KBr): 1615 cm-1; ~H-NMR(6, CDCI3): 4.29(m, 1H), 2.64(m, 1H), 2.16(s, 3H); MS m/e (%): 179(M ÷, 27), 163(14), 149(10), 79(100), 67(70).

11. All new compounds satisfied microanalytical data. Spectral data are as follows: 5a: IR(KBr): 1695, 1610 cm-1; ~H-NMR(6, CDC13): 7.39(d, J=l.6 Hz, 1H), 4.93(m, 1H), 3.70(s, 3H), 2.56(m, 1H); MS m/e(%): 249(M +, 8), 84(100). 5b: IR(KBr): 1760, 1705, 1655 cm-1; 1H-NMR(6, CDC13): 5.07(d, J=2.6 Hz, 1H),

3.89(s, 3H), 3.72(s, 3H), 2.50(m, 1H); MS nge (%): 307(M ÷, 18), 248(100). 5c: IR(neat): 2215, 1630 cm-1; 1H-NMR(6, CDCl3): 7.21(d, J=l.8 Hz, 1H), 4.92(m, 1H), 3.80(m, 1H); MS m/e(%): 216(M ÷, 74), 78(100). 6a: IR(neat): 1710, 1625 cm-1; 1H-NMR(6, CDCI3): 7.42(s, 1H), 3.70(s, 3H), 2.64(m, 1H), 1.55(s, 3H);

MS m/e(%): 263(M +, 3), 79(100). 6b: IR(KBr): 1755, 1710, 1650 cm-~; 'H-NMR(6, CDCI3): 3.89(s, 3H), 3.72(s, 3H), 2.56(m, 1H), 1.60(s, 3H); MS m/e(%): 321(M +, 6), 306(100), 262(90). 6c: IR(KBr): 2210, 1625 cm-~; 1H-NMR(~, CDCL3): 7.21(s, 1H), 3.70(m, 1H), 1.55(s, 3H); MS m/e(%): 230(M +, 10), 215(58), 79(100).

12. Sims, J.; Houk, K. N.. / . Am. Chem. Soc. 1973, 95, 5798.

13. a) Grigg, R. Chem. Commun. 1966, 607. b) Schmidt, G.; Stracke, H-U; Winterfeldt, E. Chem. Ber.

1970, 103, 3196. c) Freeman, J. P. Chem. Rev. 1983, 241. 14. Eguchi, S.; Wakata, Y.; Sasaki, T. J. Chem. Research(S), 1985, 1737.

15. The formation of pyrroles from 12 might depend on the solvent employed; in benzene, 9 was produced (ref. 4). In the present study we could establish the structure of homoadamantane-fused isoxazoline 5 and 6 discretely, which, unexpectedly, were not consistent with the compounds derived from 12 and acetylenes (ref. 4). Therefore, these structures remain uncharacterized.

(Received in Japan 10 April 1991)