J. Org. Chem. 1984,49,932-935
932
4 +f>
-
cH3%
CHI 6
I
(3)
NI (acac), ether
-
CHj
84
'c
in the presence of easily prepared dimethylzinc (Li, CHJ, ZnBr2, ether, ultrasonic and a catalytic amount of nickel acetylacetonate also underwent smooth 1,4-conjugate addition (compare with eq 1) to give (*)+ c u p a r e n o n e (1) in a remarkable 84% yield (42-50% overall from 6). Again, no appreciable amount of the 1,2-addition product was formed. These syntheses of P-cuparenone, undoubtedly the simplest and most efficient ones reported to date, indicate clearly that the nickel-catalyzed conjugate addition reaction of organozinc reagents has considerable potential in organic synthesis.
Experimental Section Solvents were generally distilled prior to use. Ether was distilled from sodium hydride-lithium aluminum hydride, and dimethylformamide was distilled under reduced pressure from calcium hydride. Phosphorus oxychloride was distilled from potassium carbonate. Reactions were generally stirred under a nitrogen or argon atmosphere. Thin-layer chromatography was performed on Merck 6OFZM (0.25mm) sheets, which were visualized with molybdophosphoricacid in ethanol. Merck 230 silica gel 60 was employed for column chromatography. A Perkin-Elmer Model 298 or 397 spectrophotometer was used to record the IR spectra (as neat liquid films). A JEOL PMX-60 spectrometer was employed for the 'H NMR spectra (Me4Si as the internal reference in CC4solutions). Microanalyses were performed by the Central Service of the CNRS. 2,2-Dichloro-3,3,4-trimethylcyclobutanone~ To a mixture of 10.0g (ca. 155 mmol) of zinc-copper couple and 5.96 g (85.0 mmol) of 2-methyl-2-butene (4) in 75 mL of dry ether, stirred under argon at room temperature, was added over 45 min a solution of 24.44 g (134.4g mmol) of trichloroacetyl chloride and 20.56 g (134.1mmol) of phosphorus oxychloride in 75 mL of dry ether. The mixture was stirred overnight, after which the ether solution was separated from the excess couple and added to hexane, and the resulting mixture was partiaJly concentratedunder reduced pressure in order to precipitate the zinc chloride. The supernatant was decanted and washed successively with a cold aqueous solution of sodium bicarbonate,water, and brine and then dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure followed by distillation of the residue gave 13.35 g (87%) of knowng 2,2-dichloro-3,3,4-trimethylcyclobutanone: bp 75 "C (2torr); IR 1805,1460,1375,1180,870,805, 745,685 cm-'; 'H NMR 6 1.13 (d, J = 7 Hz, 3 H), 1.18 (s, 3 H), 1.50 (s, 3 H), 3.45 (q,J = 7 Hz, 1 H). 3,4,4-Trimethyl-2-cyclopenten-l-one (5).5 A 2.65-g(14.6 mmol) sample of the above dichlorocyclobutanone was treated with a solution of ca. 1 g of diazomethane in 70 mL of ether and 1.5 mL of methanol at room temperature.6 After 35 min, a small amount of acetic acid was added to consume the excess diazomethane, and the solvents were removed under reduced pressure to give 2.82g of the crude dichlorocyclopentanone(IR 1765 cm-'1. A mixture of 600 mg (ca 3.1 mmol) of this material and 2.60 g (29.9mmol) of lithium bromide in 10 mL of dimethylformamide was heated at 100 "C under argon for 2.5 h. The resultant crude monochloroketone (IR 3070,1715,1615)was isolated with ether in the usual manner and then immediately stirred at 35 "C with 1.00g (15.3mmol) of zinc in 4.0 mL of acetic acid. After 2 h, the crude product was isolated with ether and purified by dry silica gel chromatography with ether in pentane to yield 305 mg (79%) (8) We are most grateful to Dr. L. A. Maldonado (UNAM, Mexico) for the spectra and a sample of enone 3. Three-carbon annelatiod of 2methyl-1-p-tolylpropene also produced 3 but in lower overall yield. For other preparations of 3, see ref 2e-f and 3. (9) Bak, D. A.; Brady, W. T. J. Org. Chem. 1979, 44, 107.
of the known5enone 5: IR 3060,1715-1685,1620,1270,1240,845 cm-'; 'H NMR 6 1.22 (s, 6 H), 2.03 (d, J = 1 Hz, 3 H), 2.16 (s, 2 H), 5.67 (m, 1 H). These values are in good agreement with
those reported in the l i t e r a t ~ r e . ~ ~ , ~ 3,3,4-Trimethyl-4-(4-methylphenyl)cyclopentanone [(&)-@-Cuparenone,1].'t2 From Enone 5. A mixture of 347 mg (2.03 mmol) of p-bromotoluene, 225 mg (1.00mmol) of zinc bromide, and 28 mg (4.0mmol) of lithium7 wire in 6 mL of dry ether under argon at room temperature was sonicated for 15 minS4 A mixture of 62 mg (0.50 mmol) of enone 5 and 3 mg (0.01 mmol) of nickel acetylacetonate in 2 mL of ether was then added and the resulting mixture was magnetically stirred for 20 h at room temperature. The mixture was then added to aqueous ammonium chloride-ether and the crude product was isolated with ether in the usual manner and purified by dry silica gel chromatography with 3% ethyl acetate in hexane to give 72 mg (67%) of pure (*)-@-cuparenone ( 1).lrZ From Enone 3. A mixture of 426 mg (3.00mmol) of methyl iodide, 338 mg (1.50mmol) of zinc bromide, and 42 mg (6.0mmol) of lithium7 wire in 6 mL of dry ether under argon at room temperature was sonicated for 30 min.4 A mixture of 100 mg (0.50 mmol) of enone 32d9sand 3 mg (0.01 mmol) of nickel acetylacetonate in 2 mL of ether was then added dropwise to the mixture at 0 "C and the resulting mixture was magnetically stirred for 20 h at room temperature. The mixture was then added to aqueous ammonium chloride-ether and the crude product was isolated with ether and purified as before to afford 91 mg (84%) of pure (*)-@-cuparenone(l),identical with that prepared above. (f)-@Cuparenone:'z2 IR 1740,1405,1380,1290,1210,1020,820 cm-'; 'H NMR 6 0.70 (s, 3 H), 1.20 (s, 3 H), 1.40 (s, 3 H), 2.16 (s, 2 H), 2.30 (9, 3 H), 2.58 (AB q, J = 18 Hz, A u = ~49 Hz, 2 H), 7.16 (m, 4 H). These values are in excellent agreement with those given in the literature.'sZ Anal. Calcd for C15HzoO:C, 83.28;H, 9.32. Found: C, 83.56;H, 9.37.
Acknowledgment. We thank Prof. Rassat for his interest in this work and the CNRS (LA 332,ATP Chimie Fine) for financial support. Registry No. (&)-l,28152-91-2; 3,58812-72-9; 4,513-35-9; 5, 30434-65-2;(&)-2,2-dichloro-3,3,4-trimethylcyclobutanone, 88303-76-8; Ni(aca&, 3264-82-2; di-p-tolylzinc, 15106-88-4; didichloroketene, 4591-28-0; diazomethane, methylzinc, 544-97-8; 334-88-3, Reactions of Nitroimidazoles with Hydrazine' P. Goldman,*2Socorro M. R a m ~ sand , ~ James D. W ~ e s t * ~
Department of Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, and Departement de Chimie, UniversitC de Montreal, Montrgal, Quebec, H3C 3Vl Canada Received August 10, 1983
Nitroimidazoles have significant biological activity as mutagens, tumorigens, radiosensitizers, and clinically useful antiparasitic and bactericidal agents! For example, metronidazole (1,2-methyl-5-nitro-lH-imidazole-l-ethanol) NO2
I
OzN
'
2
1
is effective against trichomoniasis, various forms of (1) Presented in part at the 65th Conference of the Canadian Institute of Chemists, Toronto, June 2, 1982. (2)Harvard Medical School; present address, Harvard School of Public Health, Boston, MA 02215. (3) Universit6 de Montreal. (4) For a review of the biological activity of nitroheteroaromaticcompounds, see: Grunberg, E.; Titaworth, E. H. Annu. Rev. Microbial. 1973, 27, 317-346.
0022-3263/84/1949-0932$01.50/00 1984 American Chemical Society
J. Org. Chem., Vol. 49, No. 5 , 1984 933
Notes
that could be separated by fractional distillation and amoebiasis, and anaerobic bacterial infection^,^ and misonidazole (2, c~-(methoxymethyl)-2-nitro-1H-imidazole- solubility differences: 3,5-dimethyl-1,2,4-triazol-4-amine (3, 66.4%),13glyoxal dihydrazone (4, 53.8%),14and etha1-ethanol) is a radiosensitizer now undergoing clinical nolammonium nitrite ( 5 , 46.4%). The actual yields of tests.6 Despite the pharmacological importance of nifragments 3-5 are probably substantially higher than these troimidazoles, detailed mechanisms of their biological activities have not yet been established. It is widely beisolated yields, since direct examination of the crude product by NMR showed only minor amounts of other lieved that they are reduced to radical anions, nitrosocompounds. These fragments are complementary, since imidazoles, or (hydroxy1amino)imidazoles and that one of they account for all of the atoms of metronidazole (1) these partially reduced metabolites causes biological acexcept N3, which is presumably lost as ammonia. Thus tivity by reacting with targets like cellular DNA.' This triazole 3 accounts for C2 and the methyl group of mehypothesis is supported by structure-activity investigatronidazole (l),dihydrazone 4 for C4 and C5, and ammotionss and by a kinetic study of the relationship between bactericidal activity and the formation of metabolites nium salt 5 for N 1 and the hydroxyethyl and nitro groups. under reducing condition^.^ The identity of compound 515 was established spectroscopically as well as by tests for nitrite, conversion into a We report here a series of observations that call attention to the susceptibility of 4- and 5-nitroimidazoles to known derivative of ethanolamine, and independent synnucleophilic additions and subsequent fragmentations thesis. Similar reactions occurred with other hydrazines and without reduction of the nitro group.lOJ1 These in vitro with other 4- or 5-nitroimidazoles. For example, treatment observations suggest that related reactions in vivo may be responsible for one or more of the biological activities of of metronidazole (1) with excess phenylhydrazine at 100 "C yielded glyoxal bis(pheny1hydrazone). The hydroxynitroimidazoles. ethyl group of metronidazole (1) plays no special role in In an attempt to prepare partially reduced derivatives these reactions, since hydrazine also converts dimetridazole of nitroimidazoles by catalytic transfer hydrogenation,12 (6,1,2-dimethy1-5-nitro-lH-imidazole) into triazole 3 and we warmed a solution of metronidazole (1) and excess anhydrous hydrazine in a mixture of tetrahydrofuran and ethanol (4 h, 55 OC). A reaction occurred with or without CH3N HOCHzCHzN 5% palladium on charcoal (eq l),giving three products
I3
NHz
HOCHzCHzN
02N
I
CH3
A CH3yN)/cH3 T5HgF(tl;:;ol
yN
I
NH2NH2
OzN'
FN
\=(NO2 7
6
+
N- N
1;
dihydrazone 4 under conditions very similar to those of
3
Scheme I
1 HzNN
H
NNHz
4
R'
R'
H
t HOCH&H~dH3NOp
(1)
5
(5)Goldman, P. N. Engl. J. Med. 1980,303,1212-1218. (6)Fowler, J. F.; Adams, G. E.; Denekamp, J. Cancer Treat. Rev. 1976, 3, 227-256. Dische, S.;Saunders, M. I.; Lee, M. E.; Adams, G. E.; Flockhart, I. R. Br. J.Cancer 1977,35,567-579.Bleehen, N. M.; Wiltshire, C. R.; Plowman, P. N.; Watson, J. V.; Gleave, J. R. W.; Holmes, A. E.; Lewin, W. S.; Treip, C. S.; Hawkins, T. D. Ibid. 1981,43,436-442. Phillips, T. L.; Wasserman, T. H.; Stetz, J.; Brady, L. W. Int. J.Radiat. Oncol., Biol. Phys. 1982,8, 327-334. (7)Ings, R. M. J.; McFadzean, J. A.; Ormerod, W. E. Biochem. Pharmacol. 1974, 23, 1421-1429. Knight, R. C.; Skolimowski, I. M.; Edwards, D. I. Ibid. 1978,27,2089-2093.Koch, R. L.; Chrystal, E. J. T.; Beaulieu, B. B., Jr.; Goldman, P. Ibid. 1979,28,3611-3615. Kennedy, K. A.; Teicher, B. A.; Rockwell, S.; Sartorelli, A. C. Ibid. 1980,29, 1-8. Mason, R. P.; Holtzman, J. L. Biochemistry 1975,14, 1626-1632. LaRusso, N. F.; Tomasz, M.; Miiller, M.; Lipman, R. Mol. Pharmacol. 1977, 13,872-882. Miiller, M. Scand. J. Infect. Dis., Suppl. 1981,26,31-41. Taylor, Y.C.; Rauth, A. M. Cancer Res. 1978,38,2745-2752. Varghese, A. J.; Whitmore, G. F. Ibid. 1980,40,2165-2169. (8) Adams, G. E.; Clarke, E. D.; Jacobs, R. S.; Stratford, I. J.; Wallace, R. G.; Wardman, P.; Watts, M. E. Biochem. Biophys. Res. Commun. 1976, 72,824-829. Chin, J. B.; Sheinin, D. M. K.; Rauth, A. M. Mutation Res. 1978,58,1-10. (9)Chrystal, E.J. T.; Koch, R. L.; McLafferty, M. A.; Goldman, P. Antimicrob. Agents Chemo. 1980, 18, 566-573. Beaulieu, B. B., Jr.; McLafferty, M. A.; Koch, R. L.; Goldman, P. Ibid. 1981,20, 410-414. McLafferty, M. A.;Koch, R. L.; Goldman, P. Ibid. 1982,21, 131-134. (10)For a closely related study of the reactions of nitroimidazoles with thiols, see: Goldman, P.; Wuest, J. D. J. Am. Chem. SOC. 1981, 103, 6224-6226. (11)Other nitroheteroaromatic compounds are also susceptible to nucleophilic additions and subsequent fragmentations or rearrangements. For recent references, see: (a) Barczynski, P.; van der Plas, H. C. J. Org. Chem. 1982,47,1077-1080. (b) Devincenzis, G.;Mencarelli, P.; Stegel, F. Ibid. 1983,48, 162-166. (c) Mugnoli, A.;Dell'Erba, C.; Guanti, G.; Novi, M. J. Chem. SOC.,Perkin Trans. 2 1980,1764-1767. (12)Rondestvedt, C. S., Jr.; Johnson, T. A. Synthesis 1977,850-851. Entwhistle, I. D.;Gilkerson, T.; Johnstone, R. A. W.; Telford, R. P. Tetrahedron 1978,34,213-215.
8 R'
R'
+ 8 R'
9 R'
N-$4
2NH3 t 2RNHz
(5)
12 (13)Herbst, R. M.; Garrison, J. A. J. Org. Chem. 1953,18,872-877. Bowie, R. A.;Gardner, M. D.; Neilson, D. G.; Watson, K. M.; Mahmood, S.; Ridd, V. J. Chem. SOC.,Perkin Trans. 1 1972, 2395-2399. (14)Bayer, E.;Breitmaier, E.; Schurig, W. Chem. Ber. 1968, 101, 1594-1600. (15)For a study of ammonium nitrites, see: Wolfe, J. K.; Temple, K. L. J . Am. Chem. SOC.1948,70,1414-1416.
934 J. Org. Chem., Vol. 49, No. 5, 1984 reaction 1. 4-Nitroimidazoles like 2-methyl-4-nitro-1Himidazole-1-ethanol(7)are generally less biologically active than the isomeric 5-nitroimidaz~les~ and tend to be less susceptible to nucleophilic substitution.1° As expected, compound 7 resisted hydrazinolysis, but it was converted after 6 days in warm hydrazine into fragments 3,4,and 5 in 60.6%, 48.8%, and 60.8% yields, respectively. The related reactions of 4- and 5-nitroimidazoles with hydroxylamine are reported16to lead to nitroimidazolamines. We suggest that hydrazinolyses of 5-nitroimidazoles involve the reactions summarized in Scheme I. The nucleophilic additions and substitutions of eq 2 and 3 are precedented," but the hypothetical intermediates 8 and 9 were not detected. Other plausible intermediates that could be involved in these initial steps include the bicyclic structures and 1l.llb To distinguish these two
10
I NH2 11
possibilities, we treated metronidazole (1) with 1,l-dimethylhydrazine, which is unsymmetrically disubstituted and unlikely to yield a derivative of bicyclic structure 10. Even after exposure to neat 1,l-dimethylhydrazine (28 h, 55 "C), metronidazole (1) could be recovered nearly quantitatively. Furthermore, metronidazole (1) could be recovered in 86% yield after being heated with benzylamine in tetrahydrofuran (17 h, 63 "C). These observations suggest that bicyclic structure 10 may play an important role in the hydrazinolyses. Reaction 4 is reasonable, since imidazolines similar to compound 9 have been formed reversibly by analogous condensation^.'^ Furthermore, reactions similar to eq. 5 are well-known,18and we have independently confirmed that formamidinium acetate is converted into 1,2,4-triazol-4-amine by excess hydrazine in a mixture of tetrahydrofuran and ethanol (3 h, 60 "C). Under our conditions, the nitrous acid liberated in reaction 3 does not appear to oxidize excess hydrazinelg but instead converts amine 12 into the corresponding ammonium nitrite. That addition of thiols to nitroimidazoles leads to nucleophilic substitutionlo while addition of amines leads to fragmentation is probably related to the weakness of carbon-sulfur double bonds. Although treatment of 4- and 5-nitroimidazoles with hydrazine leads to addition and fragmentation, similar reactions of 2-nitroimidazoles lead simply to reduction of the nitro group. For example, treatment of misonidazole (2)with hydrazine and 5 % palladium on charcoal under the normal conditions (eq 6) yielded only the product of transfer hydrogenation, a-(methoxymethy1)-2-amino-lHimidazole-1-ethanol (13,94.5%).20 Partially reduced in(16) SunjiE, V.; Fajdiga, T.; Japelj, M.; Rems, P. J. Heterocycl. Chem. 1969, 6, 53-60.
(17) For a recent reference, see: Malnati, M. L.; Stradi, R.; Rivera, E. J . Heterocycl. Chem. 1981, 18, 921-924. (18) Similar reactions are reviewed by: Migrdichian, V. 'Chemistry of Organic Cyanogen Compounds"; Reinhold: New York, 1947; p 73. Bowie, R. A,; Gardner, M. D.; Neilson, D. G.; Watson, K. M.; Mahmood, S.; Ridd, V. J . Chem. SOC.,Perkin Trans. 1 1972, 2395-2399. Neilson, D. G.; Roger, R.; Heatlie, J. W. M.; Newlands, L. R. Chem. Reu. 1970, 70, 151-170. (19) Perrott, J. R.; Stedman, G.; Uysal, N. J. Chem. SOC.,Dalton Trans. 1976, 2058-2064. (20) (a) Varghese, A. J.; Whitmore, G. F. Chem.-Biol. Interact. 1981, 36, 141-151. (b) Flockhart, I. R.; Large, P.; Troup, D.; Malcolm, S. L.; Marten, T. R. Xenobiotica 1978, 8, 97-105.
Notes
x:
CHxOCHzCHOHCH2N
2
NH2 N HPd,C pNH2
CH~OCHZCHOHCH N'~ N
(6)
\--i
THF/eihanoi 52 * C / 3 5 h
13
termediates could not be detected.21 Misonidazole (2)did not react with hydrazine under these conditions in the absence of palladium, but compound 13 was formed in 72.9% yield under more vigorous conditions (5 days, 55 "C). The product of reduction was assigned the generally favored222-aminoimidazole structure 13 instead of the tautomeric alternative 14 since the chemical shifts of the
1 w
C H ~ O C H ~ C H O H C H Z N NH
14 hydrogens a t C4 and C5 are similar to those of authentic 2-amin0imidazoles.~~Because their one-electronreduction potentials are higher (less negative),@ 2-nitroimidazoles may be more susceptible than 4- or 5-nitroimidazoles to direct reduction by hydrazine and other reagents. The recovery of nitrite 5 indicates that fragmentations of 4- and 5-nitroimidazoles can occur in vitro without reduction of the nitro group. This suggests that the extensive fragmentation known to occur during the bacterial metabolism of n i t r o i m i d a z ~ l e smay ~ ~ ~be ~ due to analogous nonreductive reactions, perhaps initiated by enzyme-catalyzed additions of simple nucleophiles like water. If so, nitrite or nitrous acid may be responsible for the cellular damage that has been linked to fragmentation of the imidazole ring. Nitroimidazoles may simply serve as carriers of nitrite, which is liberated at sensitive sites by reactions with suitable nucleophiles.
Experimental Section All infrared (IR) spectra were recorded on a Perkin-Elmer Model 710B spectrometer. A Bruker WH-90 spectrometer was used to obtain 'H nuclear magnetic resonance (NMR) spectra. Chemical shifts are reported in parts per million downfield from internal tetramethylsilane (6). Mass spectra were recorded at 70 eV on a V.G. Micromass 12-12 quadrupole spectrometer using electron impact (EI) or chemical ionization (CI) mass spectrometry. Galbraith Laboratories, Knoxville, TN, performed all elemental analyses. Melting points were recorded on a ThomasHoover capillary apparatus and are not corrected. Metronidazole (1) was obtained from Searle, misonidazole (2)from HoffmannLaRoche, dimetridazole (6) from May & Baker, and 2-methyl4-nitro-lH-imidazole-l-ethanol(7) from Rhbne-Poulenc. All other reagents used were commercial products of the highest purity available. Hydrazinolysis of 2-Methyl-5-nitro-1H-imidazole-1ethanol (1, Metronidazole). A solution of 2-methyl-5-nitroW-imidazole-1-ethanol(1;278 mg, 1.62 mmol) and hydrazine (400 pL, 95%) in a mixture of tetrahydrofuran (5.0 mL) and absolute ethanol (5.0 mL) was stirred under N2for 4 h at 55 "C. Volatile compounds were then removed by evaporation under reduced pressure, and the residue was distilled at 100 O C (0.60 torr). A. Isolation of 3,5-Dimethyl-l,2,4-triazol-.l-amine (3). The material that did not distill under these conditions was sublimed at 190 "C (0.10 torr). Recrystallization of the sublimate from (21) For an interesting study of partially reduced derivatives of 2nitroimidazoles, see: McClelland, R. A,; Fuller, J. R.; Seaman, N. E.; Rauth, A. M.; Battistella, R. Biochem. Pharmacol., in press. (22) Grimmett, M. R. Adu. Heterocycl. Chem. 1980, 27, 241-326. (23) Maffrand, J.-P.;Pereillo, J.-M.; Eloy, F.; Aubert, D.; Rolland, F.; Barthglemy, G. Eur. J . Med. Chem. 1978, 13, 469-474. (24) Koch, R. L.; Goldman, P. J . Pharmacol. Exp. Ther. 1979, 208, 406-410. Koch, R. L.; Chrystal, E. J. T.; Beaulieu, B. B., Jr.; Goldman, P. Biochem. Pharmacol. 1979,28, 3611-3615. Chrystal, E. J. T.; Koch, R. L.; Goldman, P. Mol. Pharmacol. 1980, 18, 105-111.
J. Org. Chem. 1984,49, 935-939 chloroform yielded pale yellow crystals of 3,5-dimethyl-1,2,4triazol-4-amine (3; 60.3 mg, 0.538 mmol, 66.4%). After a second sublimation and a second recrystallization from chloroform, this material melted at 196.5-198.0 "C (lit.13mp 196.5-197.5 "C) and was identical by NMR with an authentic ~amp1e.l~ B. Isolation of Glyoxal Dihydrazone (4) and Ethanolammonium Nitrite (5). The distillate obtained at 100 "C (0.60 torr) was extracted with dichloromethane (20 mL). Evaporation of solvent from the extract left a colorless, crystalline residue of glyoxal dihydrazone (4; 75.1 mg, 0.872 mmol, 53.8%),which was identical by IR, NMR, and melting point with an authentic ~amp1e.l~ The insoluble fraction, a colorless liquid that could not be crystallized, was ethanolammonium nitrite (5; 81.2 mg, 0.751 mmol, 46.4%): IR (liquid film) 1605,1500,1325,1210,1060,1000 cm-'; 'H NMR (90 MHz, MezSO-d6)6 2.80 (t,2 H, J = 6 Hz), 3.54 (t,2 H, J = 6 Hz); mass spectrum (EI),61,47. This material was identical by IR and NMR with a sample prepared independently from ethanolammonium chloride by ion exchange (Dowex 1-X8, NOz- form), and it gave a positive ferrous sulfate ring test for nitrite.25 Addition of a solution of oxalic acid dihydrate (70.3 mg, 0.558 mmol) in absolute ethanol (2.0 mL) to a solution of in absolute ethanol (3.0 mL) caused nitrite 5 (76.0 mg, 0.703 "01) the precipitation of ethanolammonium oxalate (56.0 mg, 0.264 mmol, 75.1%). Recrystallization from aqueous ethanol provided material melting at 197-198 "C dec (lit.26mp 199-200 "C dec), which was identical by IR and mixture melting point with an authentic sample.26 Hydrazinolysis of 2-Methyl-4-nitro-lH-imidazole-lethanol (7). A solution of 2-methyl-4-nitro-lH-imidazole-lethanol (7; 100 mg, 0.584 mmol) in hydrazine (6.3 mL, 95%) was heated under Ar for 6 days at 60 "C. Volatile compounds were then removed by evaporation under reduced pressure. By the procedure described in the previous experiment, the following three products were isolated from the residue: 3,5-dimethyl1,2,4-triazol-4-amine(3; 19.9 mg, 0.177 mmol, 60.6%);glyoxal dihydrazone (4; 24.5 mg, 0.285 mmol, 48.8%); and ethanolammonium nitrite (5; 38.4 mg, 0.355 mmol, 60.8%). Reduction of a-(Methoxymethyl)-2-nitro-lH-imidazole1-ethanol (2, Misonidazole) by Hydrazine. A solution of (~-(methoxymethyl)-2-nitro-lH-inidazole-l-ethanol (2; 62.1 mg, 0.309 "01) in a mixture of tetrahydrofuran (1.0 mL) and absolute ethanol (1.0 mL) was treated at 30 "C with 5% palladium on charcoal (7.4 mg) and hydrazine (70 pL, 95%). After an initially vigorous evolution of gas had subsided,the mixture was stirred under Nz for 3.5 h at 52 "C. The catalyst was then removed by filtration, and volatile compounds were removed by evaporation under reduced pressure. Molecular distillation of the residue at 125 "C (0.11 torr) yielded a-(methoxymethyl)-2-amino-lHimidazole-1-ethanol (13; 50.0 mg, 0.292 mmol, 94.5%)20as a colorless liquid IR (liquid film) 1615,1535,1490,1260,1185,1100 cm-'; 'H NMR (90 MHz, D20) 6 3.38 (s, 3 H), 3.4 (m, 2 H), 3.8 (m, 2 H), 4.0 (m, 1 H), 6.58 (d, 1 H, J = 2 Hz), 6.70 (d, 1 H, J = 2 Hz); mass spectrum (EI) (relative intensity), 171 (81), 156 (51), 97 (loo), 96 (71), 84 (49), 71 (60), 69 (72), 55 (76). This substance was identical by NMR with material independently prepared by the normal catalytic hydrogenation of misonidazole
935
was financially supported by U.S.Public Health Service Research Grant CA 15260 from the National Cancer Institute, by the Natural Sciences and Engineering Research Council of Canada, and by le Ministere de l'Education du Quebec. Registry No. 1, 443-48-1; 2, 13551-87-6; 3, 3530-15-2; 4, 3327-62-6;5, 31086-83-6;7, 705-19-1;13, 76620-73-0;13*picrate, 88454-11-9;Pd, 7440-05-3; hydrazine, 302-01-2.
Mechanistic Studies of 2-Lithio-1,3-dithiane Reactions with Radical Probes' Sung Kee Chung* and Larson B. Dunn, Jr. Department of Chemistry, Texas A&M University, College Station, Texas 77843 Received July 25, 1983
May & Baker, Dagenham, England, for generous samples of nitroimidazoles. We are also grateful to Dr. A. Martineau, who skillfully recorded our mass spectra. This work
The reaction of a,@-unsaturatedcarbonyls with a variety of organometallic nucleophiles can lead to either [ 1,2] or [1,4] addition products. The regiochemical control of [1,2] vs. [1,4] addition has important consequences in the synthetic design. The ratio of the regioisomers for a given a,@-unsaturatedcarbonyl has been found to be dependent on the nature of the carbon nucleophile (hard or soft), the counterion (ion association vs. carbonyl activation control), and the reaction conditions such as solvent and temperature (kinetic vs. thermodynamic control).2 For example, in reversible reactions, the [1,2] and [1,4] adducts are usually the results of kinetic and thermodynamic control, re~pectively.~Reversible additions are normally observed with carbanions that are well stabilized or highly delocalized (i.e., high level of HOMO),4 and the reversibility is often promoted by high reaction temperature3v5or high solvent p ~ l a r i t y . ~Even , ~ for kinetically controlled reactions, the nature of the solvent, e.g., the addition of HMPA, has been found to have a crucial effect in determining regio~electivity.~ The reasons for the change in regioselectivity caused by the addition of HMPA in these reactions are not clear, although a number of possible explanations may be offered. HMPA perhaps makes the addition process reversible by virtue of its cation-solvating ability.8 It is also possible that the carbonyl activation by the counterion becomes insignificant in the presence of HMPA, thus making [1,4] addition more favorable? Another possibility is that HMPA perturbs the highest occupied molecular orbital (HOMO) of the nucleophile in some manner favoring conjugate addition over [ 1,2] a d d i t i ~ n . Eliel ~ et al. have observed that HMPA causes upfield shifts of the phenyl proton and carbon resonances in their NMR study of 2-lithi0-2-phenyl-1,3-dithiane.'~ They have suggested that the observed shifts are due to the ion-pairing change, namely, a contact ion pair in THF vs. a solvent-separated ion pair in the presence of HMPA. A most significant consequence of this type of perturbation by addition of HMPA is the likelihood of electron transfer between the nucleophile and the electrophile, since the higher level of the nucleophile's HOMO makes an electron donation easier.l' In other words, the nucleophile can act as a reducing agent under the HOMO-raising perturbation, and the electrophiles such as a,&unsaturated carbonyl can behave as electron acceptors.12
(25) Feigl, F. "Spot Tests in Inorganic Analysis"; Elsevier: Amster. dam, 1958; p 332. (26) Keiser, B. Ind. Eng. Chem., Anal. Ed. 1940, 12, 284.
* Address correspondence to SmithKline & French Laboratories, Analytical, Physical, and Structural Chemistry, F-90, 1500 Spring Garden Street, Philadelphia, PA 19101.
(2).20
Treatment of compound 13 with an equimolar amount of picric acid produced a monopicrate, which was purified by crystallization from water: mp 149.0-150.0 "C (lit.20bmp 145-146 "C). Anal. Calcd for C13H18N809:C, 39.01; H, 4.03; N, 20.99. Found: C, 38.93; H, 4.11; N, 20.94.
Acknowledgment. We thank Dr. G. Jolles and Dr. J. C. Blonde1 of RhBne-Poulenc Sant6, Paris, Dr. W. E. Scott of Hoffmann-LaRoche, Nutley, NJ, Dr. E. Kreider of G . D. Searle, Chicago, IL, and Dr. K. R. H. Wooldridge of
0022-3263/84/1949-0935$01.50/0
0 1984 American Chemical Society
