NOTES stir for 2.0 hr at 0" after which t,ime it was quenched by cautiously pouring it into 100 ml of saturated aqueous sodium bicarbonate. The entire mixture was vacuum filtered to remove all solids, the ether layer was separated, and the aqueous portion was extracted with two additional 20-ml portions of ether. The combined ethereal solutions were washed with 50 ml of brine, dried (anhydrous potassium carbonate), and concentrated in vacuo to afford 654 mg of a yellow oil. Preparative tlc on pH 7 buffered silica plates21 eluted with 9 : 1 carbon tetrachloride: ethyl acetate gave three distinct bands. The fastest' migrating band (Rr = 0.5) was collected to afford 307 mg (48y0) of ket,one 1 as a pale yellow oil. This material was not further purified for use in subsequent, reactions: nmr (CDCl,) 6 0.80 (s, 3 H ) , 1.20-2.80 (m, 11 H ) , 3.45 (s, 3 H ) , 4.52 (unresolved m, 1 H); ir (CHClI) 1715 cm-' ((2-0). lO-Methyldecal-l,6-dione (3).-Preparative tlc of ketone 1 o n a nonbuffered silica plate yielded white crystalline material of mp 74-77'. Three recrystallizations from hexane containing a trace of ether afforded an analytical sample of dione 3 as white needles: mp 84-83'; ir (CHCl,) 1710 (C=O), 1378 (CHI bend) cni-1; nmr (CDCl,) 6 0.78 (s, 3 €I),1.50-2.82 (m, 13 H); mass ;spectrum (70 eV) m/e 180 (>I+), 165 (AI+ - CHI), 137 (165 CO), 124, 111,96,93,35. A n a l . Calcd for CllHI6O2: C, 73.30; H, 8.95. Found: C, 73.32; 13, 8.98. Preparation of Ketone 4.-In a 10-ml three-neck flask 555 mg (1.55 mmol) of triphenylmethylphosphonium bromide and 150 mg (1.34 mmol) of freshly sublimed potassium tert-butoxide were intimately mixed under a nitrogen atmosphere. Anhydrous ether (6.0 ml) mas introduced and the mixture turned bright yellow. T o thid solution of methylene triphenylphosphorane was added 60 mg (0.31 mmol) of ketone 1 in 3.0 nil of anhydrous ether and the reaction was allowed to stir at room temperature for 10 hr. The reaction was quenched by the addit,iori of 5 ml of 1 X hydrochloric acid followed by 3 ml of water. The ether layer was separated and the aqueous port,ion was washed with two addilional portions of ether. The combined ethereal extracts were washed with saturated aqueous bicarbonate and brine, dried (magnesium sulfate), and concentrated in vacuo to afford 293 mg of an oil with traces of solid.22 The yield of ketone 4 as determined by glpc23 using hexadecane as an added calibrat'ed internal standard was 487,. A pure sample (24 mg, 4373 yield) was obtained by preparative silica gel tlc which was eluted with 9 : l hexane:ether (Rf = 0.30): ir (thin film) 3090, 1713, 1645, 893, 887 cni-I; nnir (CC1,) 6 4.48 (s, 1 H ) , 4.78 (s, 1 H), 0.72 (s, 3 H), 2.3-0.90 (m, all other protons); mass spectrum (70 eV) m/r: 178 (AI+, base), 163 (M+ - CHI), 150 ( A I + CO), 133, 79. Preparation of Ketone 5.-Into a 10-ml three-neck flask in which a nitrogen atmosphere mas maintained was introduced 60 mg (0.31 mniol) of ketone 1 in 2.0 ml of anhydrous ether. The solution was cooled to 0" and 0.5 ml of 2.0 M (1.0 mmol) methyllithium was added. After ing for 20 min at O", the reaction was allowed to warm t o room temperature, and 5.0 ml of saturated aqueous sodium bicarbonate was cautiously added. An additional 10 ml of ether was added and the organic layer was separated. The aqueous phase was extracted with two additional 10-ml portions of ether. The combined extracts were washed with 10 ml of brine, dried (anhydrous potassium carbonate), and concentrated in vacuo to afford 64 nig of an oil. This crude met~hyllithiumadduct was dissolved in 2.0 ml of freshly dried pyridine and to this solution was added 2.0 nil of a solution made from 0.4 ml of thionyl chloride in 20 nil of pyridine. The reaction mixture was allowed to stir at room temperature for 15 min after which time it was poured into 15 g of ice and acidified with 1 hydrochloric acid to pH 2. The mixture was extracted with two 13-ml portions of ether. The combined ether extracts were washed with water, saturat,ed aqueous sodium bicarbonate, and brine, dried (magnesium sulfate), and concentrated in vacuo to afford 35 nig (70%) of ketone 5 as an oil. A pure sample of 5 was obtained via preparative gas-liquid chromatography:24 nmr (21) Plates x e r e prepared in the standard manner except t h a t a n aqueous solution containing 1% of a standard p H 7 buffer solution was used in place of pure water. These plates were dried a t room temperature for a t least 24 hr prior t o use. (22) Most of this crude material consists of phosphine oxides. (23) I n a 7 Et X ' 1 s in. SE-30 column a t 160° with a helium flow rate of 45 mlimin. (24) I n a 20 X 2 / 8 in. QF-1 column a t 175' x i t h a helium flow rate of 100 ml/min. A smaller peak (< 10%) was also detected but was not isolated.
J. Org. Chem., Vol. 38, No. 26, 1973 4461 (CCl,) 6 1.70 (s, CHI), 1.00 (8, CHS); ir (thin film) 1712, 1455, 1265; mass spectrum (70 eV) m/e 178 (&I+),163 (AT+ - CHI), 150 (&I+- CO), 135, 121, 107, 105,93,79.
Acknowledgment. -This work was supported by Public Health Service Research Grant S o . 1 R01 CA12658 from the National Cancer Institute. Registry No.-1, 42246-15-1; 2 , 2844-80-6; 3, 42246-17-3; 4, 3241-65-4; 5 , 2658-95-9.
C h e m i s t r y of Heterocyclic Compounds. 12. P r e p a r a t i o n a n d Reactions of
2-Pyridylacet ylenes l GI':ORGI.: R.NE;WKOXJC* A N D 1).L. KOPPKRSMITH Department of Chemistry, Louisiana State University, Batorb Rouge, Louisiana 70803 Received M a y 31, 1973
The preparation of 2-pyridylacetylenes has becn besieged by sporadic results; for example, dehydrobromination of stilbazole dibromide (2a) has been shown to give stilbazole, bromostilbazole, and/or 2phenylethynylpyridinc, depending upon reaction conditions. Scheuing and Winterhalder* were the first to isolate 2-phenylethynylpyridine (3a) by treatment of the dibromide 2a with refluxing ethanolic potassium hydroxide. Attempted repetition of this reaction afforded, in one caseJ3only stilbazole (la) and an unstipulated bromostilbazole, whereas others4 obtained 3a, bromostilbazole, and a-(2-pyridyl)ac~tophenone.~ Recently, Acheson and Bridson,? utilizing these reaction conditions,2 obtained 2-phenylethynylpyridine (3a) containing a t best approximately 30% of bromostilbazole, which was identified as 2-(l-bromo-cis-2phenylviny1)pyridine. The purc acetylene 3a was prepared' (83y0)by using potassium tert-butoxide, as the dehydrobromination reagent, in refluxing tertbutyl alcohol. During the course of our studies, we needed the previously prepared di(2-pyridy1)acetylme (7a)*and di(6methyl-2-pyridy1)acetylene (7b). We herein describe the preparation of pure 7, as well as the structural determination of the major side products, which arise when more rigorous conditions2 are utilized. (1) This research has been supported by Public Health Service Grant No. 5-R01-hf S-09930 from the National Institute of Neurological Diseases a n d Stroke, t h e donors of the Petroleum Research Fund, administered by t h e American Chemical Society, and the Research Corp. ( 2 ) G. Scheuing and L. Winterhalder, Justus Liebigs Ann. Chem., 473, 126 (1929). (3) J. W. Blood and B. D. Shaw, J . Chem. Soc., 504 (1930). ( 4 ) T. Katsumoto and A. Honda, J . Chem. SOC. J a p . , 84, 527 (1963). (5) Preparations of other phenylethynyl heterocycles8 have utiliized the original, or slightly modified, procedure of Scheuing and Winterhalder.2 Analyses of t h e acetylenic products are generally outside t h e acceptable analytical limits, which are indicative of halogenated contaminants. ( 6 ) (a) J. M. Smith, J r . , H. W. Stewart, B. Roth, and E. H. Northey, J. Amer. Chem. Soc., 70, 3997 (1948); (b) K. Schofield and T. Swain, J . Chem. Sac., 2393 (1949); (0) H. C. Beyerman, W. Eveleens, and Y . M. F. Muller, Reel. Trau. Chim. Pays-Bas, 75, 63 (1956); (d) T. Nakashima, Yakugaku Zasshi, 77, 1298 (1957); (e) A. I. Kiprianov a n d G. G. Dyadyusha, Zh. Obshch. Khim., 30, 3647 (1960); (f) I. Ernest, Collect. Czech. Chem. Commun., 26, 748 (1960). (7) R. M. Acheson and J. N. Bridson, J . Chem. Soc. C, 1143 (1969). (8) D . Jerchel and W. Melloh, Justus Liebigs Ann. Chem., 622, 53 (1959).
4462
R
J . Org. Chem., Vol. 38, No. 26, 19?3
J&O-R%0
6b
Br
la, R = H b, R = CH=CHC,H,
Za,
-
NOTES 7b
--+
H
R=H
A 3a, R = H
P 4a, R = H
Preparation of the di(2-pyridrrl)acet~lenesbasically follows the procedure shown in Scheme I. Condensallb
SCHEME I
,WCH0
5a. R = H b, R = C H ,
R R 6a, R = H
b; R = CHJ
R 7a, R = H b, R=CH3
tion of picoline with pyridinecarboxaldehyde gave 5a, and lutidine with 6-methyl-2-pyridinecarboxaldehyde affordcd 5b along with a 2 : 1 product 8 whose trans, trans configuration can now be assigned on the basis of the 16.5-Ha coupling constant (220 illHz nmr). Bromination of 5a and 5b in chloroform or acetic acid gave (79%) the dibroniides 6a9and 6b,Iorcspectivcly. Owing t o the insolubility of 6 , deuterated dimethyl sulfoxide was used in an attempt t o obtain thcir nmr spectra; ho\vever, upon warming t o lOO", facile debromination occurred, affording the starting olefin 5 with only traces of the dibromide. Dehydrobroniination of 6 is extremely sensitive to the reaction conditions, with the best conditions being the rapid additzon of small quantities of the dibromide to refluxing rnethanolic potassium hydroxide, followed by a brzef 20-30-min reflux period. After the standard work-up procedure, yield data in the range of 90-960/16 can be realized. Monobromide products, such as experienced in the dehydrobromination of 2, were not detected under these reaction conditions. Deviation, e.g., a single addition of 6b, from this procedure resulted in increased quantities of starting olefin, whereas, under prolonged reflux periods, acetylene 7b underwent addition of solvent (methanol) forming isomeric enol ethers 9 and 10. With calcium carbonate in dimethylacetamide, 6b was recovered unchanged after 12 hr a t BO", but at 90-100° debromination occurred exclusively. The configurations of the enol ethers were assigned on the basis of their nmr spectra. In 9, the trans aryl groups approach coplanarity with the double bond; thus the 6-methyl substituents (8 2.56 and 2.58) are (9) G Harris and G. H. LBnBrt, Justus Laebags Ann, Chem., 410, 95 (1915). (10) W.Baker, K M. Ruggle, J F. W. McOmie, and D. A. M. Watkins, J . Chem. Soc., 3594 (1958).
lla
subjected to approximately the same environment. Coplanarity of the cis aryl groups in 10 is not possible owing to steric interactions; therefore, one of the 6methyl groups ( 6 2.42 and 2.53) is shifted owing to the anisotropy of the neighboring pyridyl ring. The chemical shifts of thc vinyl proton [9 (in aromatic region), 10 (8 6.08)] and the methoxyl group [9 (6 3.73), 10 (6 3.58) ] further substantiate the structural assignments. Hydrolysis of 9 and 10 with dilute acid gave the expected enol, l l b , which was synthesized according to the method of Goldberg, et al.," from methyl 6-methylpicolinate and 6-methyl-2-picolyllithium. Hydrolysis of 10 was essentially complete after 8 hr, whereas 9 was only partially (33%) hydrolyzed under identical conditions. These chemical data are consistent with the assigned configuration of the enol ethers. l 2 Experimental Section13 (E)-1,Z-Di(6-methyl-Z-pyridyl)ethene (5b).-A mixture of 6niethylpyridinecarboxaldehyde (50 g, 0.413 mol, Aldrich Chemical Co.), redistilled lutidine (150 ml), and acet'ic anhydride (60 ml) was refluxed for 4 hr. The volatile unreacted starting materials were removed in vacuo and the residue was vacuum distilled, affording the crnde olefin 5b, bp 136-140" (0.5 mm). Recrystallization from benzene-cyclohexane gave 44 g (48%) of the colorless, crystalline olefin: mp 110-112" (lit.10 mp 111113"); nmr (CDC13)6 7.7 (HC=CH, s), 2.38 (6-pyr-Me, s). The residue from the above vacuum distillation afforded, upon cryst,allization from benzene, 1.5 g (2%) of (E,E)-2,6-di[2(6-methyl-2-pyridy1)vinyllpyridine:mp 132-135' (lit.lo mp 129-133'); nmr (CDC13, 220 MHz) 6 2.57 (6-pyr-Me, s, 6 €I), 7.03 (HE,d, J = 7.8 H a , 2 H), 7.30 and 7.305 (Ha, Hat, Hb', d , J = 7.8 Hz, 4 H ) , 7.35 and 7.59 (H4 and Ha', t , J = 7.8 Hz, 3 H), 7.59 and7.78 (transHC,=CH,d, J = 16.311z,4H). (11) N. N. Goldberg, L. R . Barkley, and R. Levine, J . Amer. Chem. SOC., 7a,43oi (1951). (12) Hydrolysis of a mixture of enol ethers 9 and 10 and olefin Sb gave a condensation product (i), based on its spectral and analytical data. Attempted repetition of the hydrolysis conditions failed to afford additional quantities of i.
Wi C H , (13) Infrared spectra were recorded with a Perkin-Elmer 237B grating spectrometer. N m r spectra were obtained with a Varian A-60A or HR-220 (220-MHz) spectrometer and are reported in 6 units (parts per million) relative t o tetramethylsilane as the internal standard. Elemental analyses mere performed by M r . Seab in our laboratories. Melting points and boiling points are uncorrected.
J. Org. Chem., Vol. 58, N o . 26, 1915 4463
NOTES
Anal. Calcd for ClEH1QL\TZO(ethers): C, 74.97; H, 6.71; N, 11.66. Found: C,74.86; H,6.80; N , 11.58. Hydrolysis of (E)-l-Methoxy-1,2-di(6-methyl-2-pyridyl)ethene (lo).-A solution of the E vinyl ether (55 mg, 0.23 mmol) in methanol (10 ml) and 5 N HC1 (. ml) i was refluxed for 8 hr. I
H4 8
(E)-1,2-Di(2-pyridyl)ethene(5a) was prepared in an identical manner, bp 160-180" (1-2 mm), mp 117-119" (lit.8 mp 1181190). Bromination of ( E ) -1,2-Di(6-methyl-2-pyridy1)ethene. Method A.-To a stirred suspension of 1 g (4.8 mmol) of ( E ) 1,2-di(6-methyl-2-pgridyl)ethene in 10 ml of chloroform, a solution of bromine (770 mg, 4.8 mmol) in 10 ml of chloroform was added dropwise over 1 hr. During the addition, the crude dibromide slowly crystallized, yield 1.4 g (79%), mp 193-195" dec. Recrystallization of 6b from ethanol increased the melting point to208-209" dec (lit.l~mp194-196'). Method B .--Bromination was identical except that, acetic acid was used as solvent, yield 1.4 g (797,), mp 184-185" dec. Recrystallization of 6b from ethanol increased the melting point to 202-203" dec. 1,Z-Di(2-pyridyl)1,2-dibromoethane (6a) was prepared (927,) by method -4, nip 149-150' (lit.8mp153-154'). Di(6-methyl-2-pyridyl)acetylene (7b).-To a refluxing solution of potassium hydroxide (3 g) in absolute methanol (20 nil), the above solid dibroniide 6b (1.0 g ) was rapidly added in 50mg (or less) quantities. Potassium bromide instantaneously precipitated. The suspension was refluxed for 30 min after completion of addition. The solvent was removed i n vacuo. The residue was dissolved in ice-water and the organic material was extracted with et,her, washed with a saturated salt solution, dried, and concentrated, affording the crude acetylene. Recrystallization from cyclohexane affoided 550 mg (95%) of the white, crystalline acetylene: mp 138-139"; nmr (CDC13) 6 2.56 (6pyr-Me, s, 3 H ) , 7.1-7.9 (pyr H, m, 4 H ) ; Raman (solid) 2215 em-' (sym-acetylene). A d . Calcd for C1J112h-2: C, 80.74; H, 6.81; N, 13.4.5. Found: C,80.45; H,5.78; N, 13.35. Di(2-pyridy1)acetylene (7a) was prepared in an identical niannerin93% yield,mpA9-7l0 (lit.*mp69-70°). Di(6-methyl-2-pyridyl)acetylene. Rapid Addition and Extended Reflux Times.-The solid dibromide 6b (4.5 g, 12.2 mmol) was added rapidly to a refluxing methanolic potassium hydroxide solut,ion (6 g/20 ml). The reaction mixture was refluxed for 6 hr and cooled, and the potassium bromide precipitate [2.8 g (2.0 g theoretical weight)] was removed by filtration. The solvent was removed in vacuo and ice-water was added; the residue was extracted with ether, washed with a saturated salt solution, dried, and concentrated, affording a yellow oil, 2.9 g. Upon standing, the starting olefin 5b crystallized as white needles, yield 350 mg, mp 110-113' (recrystallized from low-boilingpetroleuni ether, mp 112-113'). The crude oil (2.35 g) was distilled, affording three major fractions, bp 134-148" (0.6 mm), all of which possess different percentages, a8 quantitatively determined by vpc (10% OV 101 on Gas-Chrorn Q 100-120 mesh, 6 ft X 0.125 in.), of four major components, which were isolated by thick layer chroniatography (Brinkmann silica gel PF, 50% ethyl acetate-50% cyclohexane, 500 mg). The fastest moving component was the starting olefin 5b: RE0.50; yield 165 mg (33%), 35y0 via vpc; mp 111-113"; nmr (CI)C13) 6 2.68 (6-pyr-Me, s ) and 7.7 (trans HC=CH, s). The second component was (%)-l-methoxy-1,2-di(6-methyl-2pyridy1)ethene (9): RC 0.42; yield 200 mg (407,), 457, via vpc; nmr (CIlC13) 6 2.66 and 2.58 (6-pyr-Me, 2 s, 6 H), 3.73 (-OMe, s, 3 H), 6.82-8.02 (pyr H and >C=CH, m, 7 H ) ; ir (neat) 1640, 1580,1460,1330,1310,1080,1020 em-'. The third component was di(6-niethyl-2-pyridyl)acetylene (7b): IZr0.25; yield5mg(1yG),17,~6avpc:mp 133-137'. The fourth component was (E)-l-methoxy-l,2-di(6-methyl2-pyridy1)ethene (10): Xi 0.06; yield 65 mg (13%), 14% via vpc; nmr (cI>C13) 6 2.42 (6-pyr-Me, s, 3 H), 2.53 (6-pyr-Me, s, 3 I l ) , 3.88 (-Ohre, 3 H), 6.08 (>C=CH, s, 1 H), 6.44-7.6 (pyr H, 111,6 fl); ir (neat) 1640, 1580,1450, 1210,1140 em-'.
The solution was cooled, basified with a saturated sodium carbonate solution, and extracted with ether. The extract was washed with a saturated salt solution, dried over anhydrous magnesium sulfate, and concentrated i n uacuo, giving (100C/C) the yellow crystalline ketone (as enol): mp 122-123"; nmr (CDC13) 6 2.50 and 2.56 (6-pyr-Me, 2 s, 6 H ) , 6.7-7.8 (pyr H , m, 7 H ) ; ir (KBr) 2500-3500 (-OH, broad), 1645, 1600, 1560, 1455,1305,830,805,765cm-l. Anal. Calcd for C14H1dN20: C, 74.31; H , 6.24; X, 12.38. Found: C, 74.33; H, 6.21; N , 12.40. Hydrolysis of (Z)-l-methoxy-1,2-di(6-methyl-Z-pyridyl)ethene (9) under identical conditions as above afforded the ketone, mp 122-123', in 33% (nmr and isolated) yield and the unreacted 2 enol ether. Hydrolysis of the enol ethers 9 and 10 in the presence of olefin 5b under identical conditions as above initially afforded a viscous oil, which gave colorless crystals upon standing overnight. The crystals were recrystallized from ether-petroleum ether (bp 30--6O"), affording an analytical sample of the tctrapyridyl ketone:lt nip 178-179"; R, 0.1 (50% ethyl acetate-50% cyclohexane); nnir ( C l l C l ~ 6) 2.22, 2.41, 251, 2.59 (6-pyr-Me, 4 b , 3Heach),2.9-3.1.5(-CH2-,J = 7 , 1 1 H z , 2 H ) , 4 . 3 - 4 . 8 (>CH2-, J = 7, 7 H z , 1 H ) , 6.4 (>CHlCO-, J = 7 Hz, d, 1 H , exchanged slowly with I l 2 0 ) , and 6.6-7.7 (pyr H , m, 12 H ) ; ir (KBr) 1706 (>C=O), 1592, 1575, 1457, 1378, 1328, 1292, 1263, 1152, 1093,992 cm-'. Anal. Calcd for CmH,, NAO: C. 77.04:, H ., 6.47:, N .. 12.83. Found: C,76.83; H,-6.?2; N, 12.75. 1,2-Di(6-methyl-2-pyridyl)ethanone (11)was prepared (20.6%) according t o the method of Goldberg, et al.," from methyl 6methylpicolinate14 and 6-methyl-2-picolyllithium, mp 122-123" (cyclohexane). The mother liquor afforded, after chromatography with cyclohexane-ethyl acetate (3: l ) , 1,2,3-t~i(B-methyl2-pyridyl)propan-l-o1:1~ bp 167-169" (1.2 mm); nmr (CIICI,) 6 2.40 [1,3-(2-pgr-Me), s, 6 HI,2.45 [2-(2-pyr-Me), s, 3 HI, 3.25 (-CH2-, d, J = 11 Hz), 3.56 (-CHI-, d, J = 11 Hz), and 6.7-7.5 ( p y r H , m , 9 H ) . Registry No.-Sa, 13341-40-7; Sb, 16552-23-1; 6a, 42296-31-1; 6b, 42296-32-2; 7a, 28790-65-0; 7b, 42296-34-4; 8, 39689-97-9; 9, 42296-37-7; 10, 42296-38-8; l l b , 42296-39-9; i, 42296-36-6; G-methylpyridine-2-carboxaldehyde, 1122-72-1; 2,6-butadicne, 108-48-5; 2-picoline, 109-06-8; 2-pyridenecarboxaldehyde, 112142447-96-1. 60-4; 1,2,3-tri(6-rnethyl-2-pyridyl)propan-l-ol, (14) R. Mathes, W. Sauermilch, and T. Klein, Chem. Ber., 86, 584 (1953). (15) Attempted further purification was thwarted by decomposition t o lutidine and l,Z-di(6-rnethyl-2-pyridyl)ethanone.Additional evidence on this point mill be presented in R subsequent communication.
Preparation of Cis and Trans Isomers of 4-Phenylcyclohexyl and 4-Cyclohexylcyclohexyl Bromides W. NOVISSMITH] Department of Chemistry, University of California, Berkeley, California Received July 6, 1973
Substituted cyclohexane compounds have been extensively used in the investigation of steric and conformational properties of functional groups, and for the elucidation of certain mechanistic aspects of ckemical reactions. For a number of these investigations, bulky, inert functional groups having a strong prefer(1) Address correspondence t o Foote Mineral Co., Exton, Pa.
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