COMMUNICATIONS TO THE EDITOR
1926
VOl. 61
TABLEI Compound
Controls 2,3 - Dimethyl - 1,4 - naphthoquinone Lomatiol H ydroxyhydrolapachol Lapachol Diallyl-l,4-hydroquinone1 Lomatiol methyl ether2 Hydrolapachol Diallyl-1,4-hydroquinonediacetates
No. of birds
Clotting times, min. 5-10 10-20 20-30
5
20
1
10 9 9
10 5 5 1 3 1 2
9 10 9 9 8
..
3
2
.. 2
1 3 2 3 2 3
.. 1
. 1
4 2
..
2
. 1 . .
3
>30
Per cent. 10-min. birds
..
14
20
..
..
100 77 67 45 50 45 45
. .
1
2 .
.
.
3
..
5 3
.
2
..
37
Remarks
Very effective Effective Effective Borderline Borderline Doubtful Borderline Probably not effective Not effective Not effective
9 .. 3 .. 1 6 35 Lapachol methyl ether' 30 Diallyl-l,4-benzoquinone6 10 3 .. .. .. 7 M. p. 130-131', found: C, 75.80; H, 7.40. By rearrangement of hydroquinone diallyl ether (H. B. Dunkle, Dissertation, Harvard University) along with an isomer, m. p. 87-90', found: c, 76.17; H, 7.60 (E. M.F.). * M. p. 61.5-62', found: C, 70.96; H, 6.05; prepared with diazomethane (W. P. (2,). M . p. 111-112", found: C, 70.25; H, 6.70; from the higher melting isomer (E. M. F.). M. p. 51.5-52', found: C, 74.76; H, 6.34 (W. P.C.). M. p. 16", found: C, 76.71; H, 6.75; by oxidation of the 130-131' isomer with silver oxide (E. M. F.).
ring, as postulated for both vitamins. The spectrographic data of Table I1 also indicate a close correspondence between the natural vitamins and model substances of the postulated structure of 2,3-dialkyl-1,4-naphthoquinones. Dr. T. J. Webb of the Merck Research Laboratories independently examined 2,3-dimethyl-1,4-naphthoquinone and pointed out to us definite indications of fine structure in the two intense bands; this was subsequently discerned in a new reading of our plates. The resolution of the most intense band of the 6,7-dimethyl-2,3-diallyl compound CONVERSE MEMORIAL LAB, LOUISF. FIESER is still more distinct, particularly in hexane. We HARVARD UNIVERSITY DOUGLAS M. BOWEN are indebted to Dr. Webb for the other determiCAMBRIDGE, MASS. WILLIAMP. CAMPBELL MARYFIESER nations indicated. EDWARD M. FRY The following examples illustrate methods R. NORMAN JONES developed for the synthesis of quinones of the DEPARTMENT OF CHEMISTRY BYRONRIEGEL type considered favorable for vitamin K activity. NORTHWESTERN UNIVERSITY CARL E. SCHWEITZER EVANSTON,ILLINOIS PERRING. SMITH (1) 2,G-Dimethyl-8-naphthol was allylated, the RECEIVEDJUNE 12, 1939 ether rearranged, and the once distilled allyldimethylnaphthol (b. p. 152-157' a t 2 mm. SYNTHESIS OF ANTIHEMORRHAGIC COMPOUNDS Found: C , 84.20; H, 7.74) converted to the Sir: 5-amine and this oxidized in acetone suspension The further bio-assays by Dr. W. L. Sampson with ferric chloride to give 2,6-dimethyl-3-allylgiven in Table I lend added support to our con- 1,4-naphthoquinone, m. p. 4242.5' (Found: C, ception of the nature of vitamin K1 and Kz. Of 79.82; H, 6.36). (2) The lower melting diallylspecial significance is the contrast between the hydroquinone (87-90") was oxidized with silver highly active 2,3-dimethyl-1,4-naphthoquinoneoxide to the quinone (oil) ; 2,3-dimethylbutadiene and the much less potent 2,6- and 2,7-isomers1 was added to this, the prpduct was isomerized the contrast between quinones of the benzene t o a hydroquinone, and on oxidation with chromic and naphthalene series, and the high potency en- acid this afforded 6,7-dimethyl-2,3-diallyl-1,4countered in a 1,4-naphthoquinone having a 0- naphthoquinone, m. p. 69.5-70.7" (Found: C, unsaturated side-chain (allyl) in the quinonoid 81.46; H, 6.96), 6,7-Dimethyl-1,4-naphthoquiresistant to alkaline hydrolysis (compare Doisy's dihydro vitamin diacetates) ; on cleavage with a Grignard reagent and air oxidation in ether it gave a quinone, m. p. 129-130' (absorption maxima a t 245, 267, and 330 mp in ethanol). 2,3Dimethyl-l,4-naphthoquinoneshows maxima a t 246 and 265 mp (log E between 4.2 and 4.3) and 330 mp (log E = 3.4). The spectra (R. N. J. and D. M. B.) resemble those reported for vitamins K1 and KZ (Doisy, et al., Dam, Karrer, et al.) except for the absence of fine structure in the two intense bands.
July, 1939
C O M M U N I C A T I O N S TO THE
BIO-ASSAYS BY
EDITOR
1927
TABLE I ANSBACHER PROCEDURE
THE
Substance (In, 1 cc. peanut oil)
No. of birds
Controls (1stseries) Peanut oil (1 cc.) Alfalfa (100mg.) Alfalfa (50mg.) Alfalfa (25mg.) Alfalfa (10mg.) 2-a-Heptenyl-3-hydroxy-l,4-naphthoquinone (0.2mg.) 2-n-Hepty1-3-hydroxy-l,4-naphthoquinone (0.2mg.) 2-Allyl-l,4-naphthoquinone (0.2mg.) Controls (2nd series) Alfalfa (150mg.) 2,3-Diallyl-1,4-naphthohydroquinone diacetate (0.2 mi%.) 2,6-Dimethyl-1,4-naphthoquinone (0.2mg.) 2,7-Dimethyl-1,4-naphthoquinone (0.2mg.)
20 10 10 9 10 10 10 10 10 11 10 10 10 10
5
2
..
Clotting times min. 5-10 10-20 ' 20-30
4 3 3
6
..
..
..
5 2 5 1 1 4 1 3 3 4 2 6 10 , .
..
..
..
..
.. .. .. ..
7
3
..
..
1 4 3
..
.. 3
1 1 2 2 2 2
1
2
1 . 1 2
>
30
'
0-min. b h s
30 7 30 .. 80 . 7 7 2 50 2 40 1 70
Remarks
8
Some activity Someactivity Very active
.. ..
80 100
11 ..
0 100
All over 60 min.
.. 5
3
10
6
40
2
60
Inactive Very sl. act. Active
.. ..
TABLE I1 ABSORPTION MAXIMA I n ethanol, except as noted; log e values given in parentheses Maxima (in mp)
Vitamin KI (Doisy, et al.) (Dam, Karrer, et al.) Vitamin Kz (Doisy, et a / . ) 2,3-Dimethyl-1,4-naphthoquinone (T. J. Webb) ( D . M.B., new reading) G,7-Dimethyl-2,3-diaIlyl-1,4-naphthoquinone (In hexane) 2-Allyl-1,4-naphthoquinone ( I n hexane) 2-Methyl-1,4-naphthoquinone(T. J. Webb) 2,6-Dimethyl-1,4-naphthoquinone(T. J. Webb) 2,6-Dimethyl-3-allyl-1,4-naphthoquinone5
243,248 261,270 248 261,270 249 261,269 244,249 (4.29) 264,270 (4.27) 243,249 (4.26) 262,267 (4.24) 253,260 (4.40) 273,278 (4.12) 253,260 (4.41) 271,276 (4.14) 246,251 (4.31) Shoulder 243,251 (4.1) 260 (3.9) 250 (4.29) 263 (4.24) 256 (4.33) 249 (4.30)256 (4.35)266,272 (4.17)
323 328 320 332 (3.39) 330 (3.38) 343 (3.45 338 (3.46) 332 (3.43) Not measured
334 (3.38) 340 (3.47) 335 (3.39)
none, m. p. 118-119' (Found: C, 77.43; H, 5.61), silver oxide oxidation gave 2,3-diallyl-1,4-naphwas similarly prepared from the known diene thoquinone, m. p. 28.5-29.5', identical with the addition product. (3) Monobutadiene-l,4-benzo- above sample. quinone with allyl bromide and potassium carI n the Dam-Karrer color test with sodium ethylate in bonate in acetone gave 5,8-dihydro-l,4-naphtho-ethanol, regarded by some as characteristic of vitamin K1 hydroquinone &allyl ether, m. p. 84-65' (Found: (Almquist and Klose, THISJOURNAL, 61,1610(1939);see, however, Fernholz, et al., ibid., 61, 1613 (1939)), our C779"51 ; H9 7'55), and when heated in kerosene synthetic naphthoquinones having a t least one allyl group this rearranged smoothly to 5,8-dihydro-293- in the quinonoid ring all give intense and transient blue or diallyl-l,4-naphthohydroquinone, m. p. 108-109° purple colors and contrast sharply with the 2,3-dimethyl (Found: C, '79.36; H, 7.78). Chromic acid compound (weak, purplish color)." oxidation in acetic acid gave 2,3-diallyl-1,4a Received June 26, 1939. naphthoquinone, m. p. 29-30' (Found: C, CONVERSEMEMORIALLABORATORY LOUISF.FIESER HARVARD UNIVERSITY DOUGLAS M. BOWEN ; H~ 6.02). The substance (m. P* l3Oo) CAMBRIDGE, MASSACHUSETTS WILLIAMp. CAMPBELL EDWARD M. FRY obtained previously by the action of ethyl or MARSHALL D. GATES,J R . n-butylmagnesium bromide on 2,3-diallyl-1,4RECEIVED JUNE 23,1939 naphthohydroquinone diacetate is a naphthoquinone (spectrum) having two hydrogen atoms THE STEREOCHEMISTRY OF TERVALENT more than the expected diallyl compound (Calcd. NITROGEN for CleHI6O2:C, 79.97; H, 6.71. Found: C, Sir: 80.06, 79.93; Hi 6.78, 6.76). More gentle Jackson and Kenner [ J . Chew. Soc., 573 (1928)] cleavage with methylmagnesium bromide and briefly reviewed the existing evidence bearing
