3304 J . Org. Chem., Vol. 40, No. 22, 1975 Grunwald-Winstein correlations. Both p and m are widely considered to indicate the extent of charge separation in the transition state, but both substituents and solvent must also modify the charge. We anticipate that p 2 would be smaller (less negative) than p 1 but the m values show that there is a continuous variation in the extent of charge separation. The value of p must be taken, therefore, as an averaged measure of the charge separation. The assumption that the charge separation is invariant within a reaction serieslg only leads to confnsion. The trend in the rn-log k relationship observed here is in accord with the Hammond postulate2” but not with Thornton’s “push-pull” model of the S N 1 mechanism.21 This model, however, requires weak nucleophilic solvent participation which is scarcely conceivable, owing to the congestion of the reaction center, and which, moreover, is absent even in tert-butyl chloride solvolysis.22 The values of ( ~ , , E ~ O H / ~ H O A ~ determined )Y~~ a t 50.5O for 2 (0.28-0.32) are similar to those of 1- and 2-adamantyl tosylates in which solvent is sterically excluded from the backside of the reaction Values below unity are commonly encountered where hydrogen bonding to the leaving group O C C U ~ S or ~ ~where , ~ electrophilic catalysis by acetic acid is possible,24 as in the present case. We have no direct evidence regarding the extent of ion-pair return in these systems. Nevertheless, it can be deduced from the low values of m and of (kaqEtOH/kHOAc)Y that this is not an important process; the high values of A S (1.8, 2.1, and 2.4 eu for 2b, 2c, and 2d, respectively) tend to confirm this conclusion.22~24 R e g i s t r y No.-la, 40601-70-5; lb, 40544-04-5; IC, 56437-67-3; Id, 40544-05-6; le, 40544-06-7; If, 56437-66-2; lg, 56437-65-1; 2b, 56437-64-0; 2c, 56437-63-9; 2d, 56437-62-8.

References and Notes (1) E. Grunwald and S. Winstein, J. Am. Chem. SOG.,70, 846 (1948): A. H. Fainberg and S. Winstein, bid., 78, 2770 (1956). (2) (a) H. Tanida and H. Matsumura, J. Am. Chem. SOC., 95, 1586 (1973); (b) W. Duismann and C. Ruchardt, Chem. Ber., 108, 1083 (1973). (3) Reviewed by A. Streitwieser, Chem. Rev., 58, 571 (1956). (4) (a) S. G. Smith, A. H. Fainberg. and S.Winstein, J. Am. Chem. SOC., 83, 618 (1961): (b) A. H. Fainberg and S. Winstein, ibid., 79, 1608 (1957); (c) S.Winstein, A. H. Fainberg, and E. Grunwald, ibid., 79, 4146 (1957). (5) There is no evidence for neighboring methyl group assistance in Id, which is, surprisingly, less reactive than tert-cumyl pnitrobenzoate, probably owing to steric inhibition of resonance between the aryl group and the incipient carbonium Ion.’ (6) P. D.Bartlett and T. T. Tidwell, J. Am. Chem. SOC., 90, 4421 (1968). (7) S. Winstein and A. H. Fainberg, J. Am. Chem. SOC.,79, 5937 (1957): ml/m2 = (T2/Tl)’ where a is 1.58 for tert-butyl chloride in 80-100% acetic acid. (8) J. L. Fry, C. J. Lancelot, L. K. M. Lam, J. M. Harris, R. C. Bingham, D. J. Raber, R. E. Hall and P. v. R. Schleyer, J. Am. Chem. SOC., 92, 2538 (1970), and references cited therein. (9) R. L. Buckson and S.G. Smith, J. Org. Chem., 32,634 (1967). (IO) Conversely, the m values for some bridgehead bromides differing in reactivity by are uniformly high (1.03-1.20) and indicate no trend in charge separation relative to reactivity: R. C. Bingham and P. v. R. Schleyer, J. Am. Chem. SOC.,93, 3189 (1971). (11) (a) For the para-substituted derivatives la, Ib, Id, and le there is a !inear correlation of slope 1.19 between our values and Tanida’s? whence our p j would be -2.13, but when calculated from reliable meta I d and If, p , = -2.48. From the deviations of para substituents, IC, substituents, the Yukawa-Tsuno r value‘lb is 0.41. The previous authors*’ calculated p , and r (0.49) simultaneously from five para-substituted compounds only, a less reliable procedure. (b) Y. Yukawa and Y. Tsuno, J. Chem. SOC.Jpn., Pure Chem. Sect., 88, 873 (1965): Y. Yukawa. Y. Tsuno, and M. Sawada, Bull. Chem. SOC.Jpn., 39,2274 (1966). (12) Z. Rappoport and J. Kaspi, J Am. Chem. SOC., 92, 3220 (1970): z. Rappoport and Y. Apeloig, Tetrahedron Lett., 1817 (1970); H. P. Fischer. ibld., 285 (1968). (13) If m depends on substituents, p of course depends on the solvent,14 becoming smaller with increase in solvent polarity, as ls observed in the dissociation equilibria of carboxylic acids15 and anillnium ions’’ and elsewhere,” but not in tertcumyl chloride solvolysis.’8 (14) J. E. Leffler and E. Grunwald, “Rates and Equilibria of Organic Reactions”, Wiley. New York, N.Y.. 1963, p 312. (15) (a) I A. Koppel and V. A. Palm in “Advances in Linear Free Energy Relationships”, N. E. Chapman and J. Shorter, Ed., Plenum Press. New York, N.Y. 1972, Chapter 5; (b)0. Exner, ibid., Chapter 1: (c) E. Grunwald and €3. J. Berkowitz, J. Am. Chem. Soc., 73, 4939 (1951).

Notes B. Gutzberzahl and E. Grunwald, J. Am. Chem. SOC., 75, 559 (1953). For leading references see ref 15a,b. See also J. Vencl, J. Hetflejs, J. Cermak. and V. Chvalovsky. Collect. Czech. Chem. Commun., 38, 1256 (1973). Y. Okamoto and H. C. Brown, J. Am. Chem. SOC.,80,4972 (1958). C. D.Johnson and K. Schofield. J. Am. Chem. Soc., 95,270 (1973). (a) For valuable comment on the Hammond postulate,20bsee D. Farcasiu, J. Chem. €doc.. 52, 76 (1975): (b) G. S. Hammond, J. Am. Chem. SOC.,77, 334 (1955). G. J. Frisone and E. R. Thornton, J. Am. Chem. SOC., 90, 1211 (1968). D.J. Raber. R. C. Bingham, J. M. Harris, J. L. Fry, and P. v. R. Schleyer, J. Am. Chem. SOC., 92, 5977 (1970). 97.7% aqueous ethanol has the same Y value (-1.64) as anhydrous acetic acid: see ref 3. D. N. Kevill, K. C. Kolwyck, and F. L. Weitl, J. Am. Chem. SOC.,92, 7300 (1970).

A New Approach to Triaminopyrimidine N-Oxides J. M. McCall,* R.E.TenBrink, and J. J. Ursprung

Research Laboratories, The Upjohn Company, Kalamazoo, Michigan 49001 Received June 25,1975

2,4-Diamino-6-(substitutedamino)pyrimidine 3-oxides have useful hypotensive activity in man.l A general route to these compounds is reported below. Generally, pyrimidine N-oxides are prepared (a) by modification of a preexisting pyrimidine N-oxide, (b) by direct N-oxidation, or (c) by cyclization reactions.2 In the past, 6-aminopyrimidine N-oxides have been prepared in this laboratory by reaction of various amines with 2,4-diamino-6-chloropyrimidine 3-0xide.~The literature contains very few examples of the second general route, direct Noxidation of triaminopyrimidines.4 This paper describes a cyclization approach which uses hydroxylamine as a condensation agent in the synthesis of triaminopyrimidine Noxides. H y d r ~ x y l a m i n e ~and - ~ its derivatives, benzyloxya m i r ~ e ,hydroxyurea,lOJ1 ~,~ b e n z y l o ~ y u r e a , ~and ~ J ami~~~~ dooxime ethers14have been used to introduce the requisite N-0 bond of pyrimidine N-oxides. However, the preparation of a triaminopyrimidine N-oxide by cyclization with hydroxylamine or its derivatives has not yet been reported. Results and Discussion Formally, triaminopyrimidine N-oxide 6 is an adduct of hydroxyguanidine and cyanoacetamide 2 or a suitable derivative such as 3. In our hands, neither compounds 2 nor 3 gave pyrimidine 6 when reacted with hydroxyguanidine. Therefore, compound 5 was constructed from smaller molecular fragments (see Chart I). Reactions of ethyl cyanoacetate with a variety of amines efficiently produced the corresponding cyanoacetamides 2 (see Chart I). Amide 2 was 0-methylated with either methyl fluorosulfonate or trimethyloxonium fluoroborate (see Chart I). The resultant salt was treated with either potassium carbonate or sodium methoxide to give enol ether 3. Compound 3 reacted with cyanamide in alcoholic solvent to give cyanoiminopropionitrile 4. When NR1R2 was piperidine, the tautomeric structure 4 (3-cyanoimino-3-piperidinopropionitrile) was suggested by NMR (CH2 singlet at 6 3.93) and by ir (lack of N-H stretch). In the normal application of this synthesis, compound 4 was not isolated, but was treated with hydroxylamine to form triaminopyrimidine N-oxide 6, presumably via postulated intermediate 5. Yields for the three-step process from amide 2 to crystalline pyrimidine N-oxide 6 range in most cases from 40 to

J . Org. Chem., Vol. 40, No. 22, 1975 3305

Notes

Table I Preparation of Triaminopyrimidine N-Oxides (6) by Method A Reaction time, hr Step 2

Compd 6

a"

bb CC

E thy lamino n -Butylamine n -Decylamino

16 4 28 3.3 7.5 24 24 24 16

Step

3

6 1.6 9 2.5 16 40 6 19

% yield of

Step

16 17 16

4

6 from 2

49 45 46 43 23 33 43 46 73

Mp of 6,h

O c

275 d e c 22 1-22 1.5 118 218-220 186.5-1 88 246 d e c 260 d e c 278 dec 188 d e c

15 C yclohexylamino 48 Di -n -butylamine 68 Dicyclohexylamino 1.6 g" Piperidino 30 hf Pyr rolidino 80 10 ig Methylamino =From N-ethyl-2-cyanoacetamide: K. G. Naik and Y. N. Bhat, Q J. Indian Chem. Soc., 4, 547 (1927). From N-(n-butyl)-Z-cyanoacetamide (mp 72-73" from EtzO). From N-(n-decyl)-2-cyanoacetamide (mp 78-79" from EtaO-hexane). From N-cyclohexy1-2-cyanoacetamide.l? e From N-(2-cyanoacetyl)piperidine.l7Method B for the preparation of 6g is described in the Experimental Section. From N-(2-~yanoacetyl)pyrrolidine: T. S. Osdene and A. A. Santilli, U.S. Patent 3,138,592 (1964). g From N-methyl-2-cyanoacetamide: E. C. Kornfeld and E. G. Fornefeld, C.S. Patent 2,749,353 (1956). /I Compounds recrystallized from MeOH-CHSCN. dd

e f

'

50% (see Table I). Compound 6g prepared by the method of Chart I was identical with a sample which was prepared

Experimental Section

Melting points were determined in capillary tubes with a Thomas-Hoover apparatus and are uncorrected. Infrared spectra were obtained with a Perkin-Elmer Model 421 infrared spectrophotometer as Nujol mulls. NMR spectra were recorded on a VarChart I ian A-60 spectrophotometer. NMR peaks are recorded in parts per Synthesis of 2,4-Diamino-6-(substituted million downfield from tetramethylsilane. Samples for NMR were amino)pyrimidine 3-Oxides generally dissolved in MezSO-dC. The diagnostic singlet for the C-5 hydrogen of compound 6 occurs between 5.15 and 5.38 ppm in 0 0 all the cases of Table I. Mass spectra were run at 70 eV on an Atlas Model CH-4 spectrometer. Reactions were monitored by an HPLC (high-pressure liquid chromatography) unit consisting of a Miltonfmethod .4) 1 2 Roy minipump, Chromatronix injector, and glass columns (0.125 2 FS0,CH , SaOMe in. X 150 cm), and an LDC LUV monitor. Columns were packed (method B) with floated TLC grade silica gel. Satisfactory analytical data NR'R? NR'R2 (f0.496 for C, H, N) were obtained for all the new compounds of / / Table I and compound 4g unless otherwise stated.l' / step 3 / step 4 NCCH=C The amides of cyanoacetic acid were prepared by the method of NCCH,-C \ \\ Whitehead and Traverso.ls Elemental analyses were not obtained NCN OCHJ for these amides. The melting points and crystallization solvents for new compounds of this class are cited in Table I. 3 4 6-Piperidino-2,4-diaminopyrimidine3-Oxide (6g). Method OH 1 0 A. A solution of 11.44 g (0.0753 mol) of N-(2-cyanoacetyl)piperidine (mp 87-89', from EtOAc) and 10.95 g (0.0739 mol) of trimethyloxonium fluoroboratelg was stirred in 120 ml of dry CH&1Zz0 for 24 hr under Nz. The reaction mixture was poured with vigorous stirring into 10.95 g of K&03 and 11 ml of HzO. After stirring for 30 min, the organic phase was decanted from the coagulated potassium fluoroborate. The residue was washed several times with methylene chloride. The combined organics were washed quickly with >O% aqueous KzC03, dried by passage 5 6a-i through KzC03, and concentrated in vacuo. The NMR indicates that cis-trans isomers are present. The concentrate was dissolved by reaction of piperidine and 2,4-diamino-6-chloropyrimi- in 180 ml of absolute EtOH and 3.22 g (0.0753 mol) of cyanamide was added. The reaction mixture was stirred at 25' for 6 hr under dine 3-0xide.~ N2. Then 21.9 g (0.158 mol) of KzC03, 8.27 g (0,119 mol) of hyIn step 4 we assume that hydroxylamine attacks the droxylamine hydrochloride, and 90 ml of absolute EtOH were more electron-deficient N-cyano group rather than the reladded and the mixture was stirred at 25' for 16 hr. The reaction atively electron-rich aliphatic cyano to give 5 which has mixture was filtered and the residue washed with MeOH. The filnever been observed. In the cyclization of 5, both the amino trate was concentrated and chromatographed on silica gel (15% and the hydroxyamino groups can react with the nitrile MeOH-1% NH40H-CHzC12) to give 6.77 g (43%) of crystalline product. This was recrystallized from MeOH-CH&N to give 5.48 function. Preferential attack by the hydroxyamino group is g (35%), mp ca. 260' dec. the only observed reaction. Such preferential closures to The spectral properties and decomposition points of this comform heterocyclic N-oxides rather than hydroxylamine pound are identical with those of 6-piperidino-2,4-diaminopyrimidsubstituted heterocyclic derivatives have been reine 3-oxide prepared by reaction of piperidine and 6-chloro-2,4ported.581%15,16 diaminopyrimidine 3-0xide.~ Compounds of type 6 can be prepared from 2,4-diamino6-Piperidino-2,4-diaminopyrimidine3-Oxide (6g). Method B. A solution of 50.0 g (0.329 mol) of N-(2-~yanoacetyl)piperidine 6-chloropyrimidine by m-chloroperbenzoic acid oxidation and 41.25 g (0.362 mol) of methyl fluorosulfonate (Aldrich, magic to the 3-oxide and subsequent reaction with aliphatic methyl) in 250 ml of CHzC1Zz0was stirred for 72 hr. The reaction In genamines to give 2,4-diamino-6-(amino)pyrimidines. mixture was cooled to 0' and 78 g (0.362 mol) of 25% NaOMe in eral, the method of Chart I gives higher yields, requires less MeOH was added. The cooling bath was removed and the reaction chromatography, and is substantially more economical mixture was stirred for 20 min. The reaction mixture was filtered than the route via the chloro N-oxide. through Celite to remove sodium fluorosulfonate. The residues

a

r

3306

J. Org. Chem., Vol. 40, No. 22, 1975

were washed with CHzC12, and the combined organic phases were concentrated in vacuo. The residue was stirred with 13.82 g (0.329 mol) of cyanamide in 200 ml of MeOH for 6 hr. A mixture of 27.44 g (0.395 mol) of hydroxylamine hydrochloride, 54.48 g (0.395 mol) of KzC03, and 500 ml of MeOH was added. After stirring for 15 hr a t 50' the reaction mixture was cooled to room temperature and filtered through Celite. The residues were washed with MeOH. The combined organics were concentrated, diluted with 500 ml of HlO, and continuously extracted with CHzCll to give the product, which was triturated with CH3CN and then crystallized from MeOH-H2O to give 27.9 g of product. Silica gel chromatography of the residues from trituration and recrystallization gave an additional 6.1 g of recrystallized product. Total yield was 34.0 g (49%), mp ca. 265' dec. The product obtained by method B was identical with that obtained by method A. 3-Cyanoimiso-3-piperidinopropionitrile (4g). The portion of method A applicable to preparation of this compound was followed. A mixture of 5.00 g (0.0329 mol) of N-(2-cyanoacetyl)piperidine and 5.00 g (0.0338 mol) of trimethyloxonium fl~oroborate'~ was first stirred in 50 ml of CH2C1220 for 23 hr. The product was isolated and stirred with 1.38 g (0.0329 mol) of cyanamide in 25 ml of absolute EtOH for 5 hr and the mixture was concentrated in vacuo. The product mixture was chromatographed by HPLC on 30-50 silica gel in MeOH-CHC13 to afford 2.12 g of pure 3-cyanoimino-3-piperidinopropionitrile: mp 73-74.5'; NMR (CDC13) 6 1.75 [br, s, 6, -CH3-)3], 3.48-3.91 [m, 4, N(CH&], 3.93 (s, 2, CH2); uv (EtOH) end absorption, A,, 252 nm ( t 19000); mass spectrum m / e (re1 intensity) 176 (749), 122 (698), 109 (999), 96 (334), 83 (556); ir (Nujol) 2260 (C=N), 2180 (NCEN), 1595 cm-l (C=N), no N-H.

Acknowledgment. The authors are indebted to E. C. Olson and his associates for physical and analytical data. In particular, the authors are grateful to L. Baczynskyj for helpful discussion with regard to mass spectra and to Paul Meulman for informative discussions about infrared spectra. Registry No.-2 (R1 = H; R2 = Et), 15029-36-4; 2 (R1 = H; R2 = Bu), 39581-21-0; 2 (R1 = H; R2 = decyl), 52493-40-0; 2 (R' = H; R2 = cyclohexyl), 15029-38-6; 2 (R' = R2 = Bu), 53807-36-6; 2 (R1 = R2 = cyclohexyl), 56487-99-1; 2 (R1, R2 = piperidino), 1502930-8; 2 (R', R2 = pyrrolidino), 14227-95-3; 2 (R1 = H; R2 = Me), 6330-25-2; 4g, 56488-00-7; 6a, 55921-54-5; 6b, 55921-55-6; 612, 55921-56-7; 6d, 55921-57-8; 6e, 55921-62-5; Sf, 55921-63-6; 6g, 38304-91-5; 6h, 55921-65-8; 6i,55973-02-9.

References and Motes

Notes

A Convenient Synthesis of the Sesquiterpene (f)-a-Curcumene.VI. Application of Alkylation-Reduction to the Total Synthesis of Terpenes Stan S. Hall,* Frank J. McEnroe, and Ho-Jane Shue

Carl A. Olson Memorial Laboratories, Department of Chemistry, Rutgers University, Newark, New Jersey 07102 Received J u n e 18,1975

This laboratory has been developing the concept of tandem alkylation-reduction of aromatic carbonyl systems as a convenient method of preparing aromatic hydrocarbons by the lithium-ammonia-ammonium chloride reduction of benzyl alkoxides generated in situ by a1kylation.l Recently we extended this convenient procedure to the selective synthesis of rather complex aromatic hydrocarbons in excellent isolated yields by the phenylation-reduction of appropriate aldehydes and ketones.2 One of the purposes of that study, which demonstrated that challenging organic structures could be rapidly assembled by the proper selection of the requisite carbonyl system, was to explore the potential applicability of this simple procedure to the total synthesis of aromatic terpenes. Herein we wish to report an example of the use of the procedure, which is performed in the same reaction vessel without the isolation or purification of intermediates, for the total synthesis of (&)-a-curcumene(3). The entire synthesis consumed only ca. 8 hr and the overall isolated yield of the pure aromatic sesquiterpene 3 was in the range of 90-92% in repeated runs. * Addition of 6-methyl-5-hepten-2-one (1) to a T H F solution of p-tolylmagnesium bromide, generated in situ from p-bromotoluene and a dark gray suspension of highly reactive magnesium metal3 in T H F in a metal-ammonia reaction vessel, produces the intermediate benzyl alkoxide 2. Subsequently ammonia is distilled into the vessel, excess lithium foil is quickly added, and the resultant dark blue mixture is quenched with ammonium chloride. The latter are conditions that protonate the benzyl alkoxide 2 and then rapidly reduce the resultant benzyl alcohol to the sesquiterpene (f)-a-curcumene (3) before all the excess lithium is destroyed, thereby completing the synthesis.

(a) E. Gilmore, J. Weil, and C. Chidsey 111, N. Engl. J. Med., 282, 521 (1970); (b) T. B. Gottlleb, F. H. Katz. and C. Chidsey 111, Circulation, 45, 571 (1972); (c) C. J. Limas and E. D. Freis, Am. J. Cardiol., 31, 355 (1973); (d) W. A. Pettinger and H. C. Mltchell, N. Engl. J. Med., 289, 167 (1973): (e) W. A. Pettlnger and H. C. Mitchell, Clin. fharmacol. Ther., 14, 143 (1973).

For a review, see A. R. Katritsky and J. M. Lagowskl, "Chemistry of the Heterocyclic N-Oxides". Academic Press, New York, N.Y., 1971, pp 22-140.

W. C. Anthony, U.S. Patent 3,644,364 (1962). T. J. Delia, D. E. Portlock, and D. L. Venton, J. Heterocycl. Chem., 5, 449 (1968).

R. M. Cresswell, H. K. Maurer, T. Strauss, and G. B. Brown. J. Org. Chem., 30, 4086 (1965). J. Romo, L. Rodriguez-Hahn, and M. Jimenez, Can. J. Chem., 46, 2807 (1968). J. Streith, C. Leibovici. and P. Martz, Bull, SOC.Chim. f r . , 4152 (1971). W. Kbtzer and M. Herberz, Monatsh. Chem., 96, 1721 (1965). W. Klotzer, Monatsh. Chem., 95, 1729 (1964). W. Klotzer, Monatsh. Chem., 95, 265 (1964). A. L. Cossey and J. N. Phillips, Chem. lnd. (London),58 (1970). W. Kltitzer. Monatsh. Chem., 96, 169 (1965). W. Klotzer and M. Herberz. Monatsh. Chem., 99, 847 (1968). E. Ziegler, A. Argyaides, and W. Steiger, Z.Naturforsch., B, 27, 1169 (1972). N. A. Stevens, H. W. Smith, and G. 8. Brown, J. Am. Chem. Soc., 62, 3189 (1962). R. M. Cresswell and G. 8 . Brown. J. Org. Chem., 28, 2560 (1963). Compound 6a, C t0.42; 61, H -0.43; 4g, N -0.42. C. W. Whitehead and J. J. Traverso, J. Am. Chem. Soc., 77, 5867 (1955). Trimethyloxonium fluoroborate was obtained by direct reaction of methyl ether, epichlorohydrin, and boron trifluorlde etherate rather than by (20)

exchange with triethyloxonium fluoroborate. Dried by passage through Woelm basic alumina, activity grade I.

1

2

3

Although there have been numerous methods reported for the total synthesis of this racemic sesquiterpene: the best overall yield starting from commercially available material seems to be ca. 3 5 % ~ ~ ~ Since a-curcumene has previously been reduced to 0curcumene in sodium-ammonia-ethanol (92% yield)4d and cyclized in phosphoric acid to calamenene (80%yield): this tolylation-reduction procedure constitutes a convenient method for the preparation of these sesquiterpenes as well.

Experimental Section6 General Comments. The entire reaction sequence was performed under a static argon (prepurified) atmosphere, which is connected by a T tube to the assembly and to a soda lime drying trap that is connected in series to an oil bubbler, and is operated at a moderate flow rate throughout the synthesis. All glassware was to temperature in a large box Oven dried and tor, and then quickly assembled. Anhydrous magnesium chloride was weighed in a nitrogen atmosphere. Potassium metal was wiped