\?' A REMERS,R H ROTH,A N D XI J
4GlB
described above 1 was dried over magnesium sulfate for 16 hr. a t room temperature, the solution turned black. I t was: filtered and conceritrated under reduced pressure and the dark residue was purified by chronirrtography on Florid" with benzene as eluent. Concentration o f the golden eluate afforded 236 ing. of golden yellow plates,. liecrystallizdtioii from methanol gave 195 mg. (5('; ) of methyl 7-benzyloxy-1-chloropyrrolo [ 1,2-a]indole-3niethyleiiecarboxylate (111) as golden needles, m . p . 146'; A,,,,3, 5.9, 0.2 p ; 261 ( e 12,000), 280 ( e ll,O00), 407 ( e 23,000) nip; n.1n.r.: 6.23 (three protons, methyl ester), 4.93 (two protons, benzylic), 4.12 (proton on exocyclic double bond), 3.65 (C-9 proton), 2.63 (C-2 proton), 3.05 (doubled doublet, Jj,s= 9 c.P.s., J6.$ = 2 c . p . s . , C-6 proton), 2.88 (doublet, J 6 . x = 2 c.p.s., C-8 proton), 2.75 (doublet, jj.6 = 9 c.p.s., C-5 proton), 2.80 (five protons, phenyl) T . A n a l . Calcd. for C.lH1&lSO,j (365.80): C , 68.93; H , 4.41; Cl, 9.69; S ,3.83. Found: C, 69.15; H , 4.68; C1, 10.17; S ,
3.38. Methyl 7-Benzyloxy-9H-pyrrolo[1,Z-alindole-3-oxalate (VIII). -An ice-cooled solution of 520 mg. ( 2 mmoles) of i-benzyloxy9H-pyrrolo[l,2-nlindole [ \ . I ) j in 10 ml. of methylene chloride was treated with 254 mg. ( 2 mmoles) of oxalyl chloride. After 2 hr. the mixture was concentrated under reduced pressure and the residue was treated with methanol and solid sodium bicarbonate. This mixture was boiled and filtered, then cooled. Tan prisms, m . p . 83-85", crystallized from the filtrate. Recrystallization from methanol afforded 283 mg. (41' i ) of methyl 7-berizyloxy9H-pyrrolo[l,2-n]indole-3-o.ualate (1.111 J as yellow needles, 111.p. 83--85"; A,,,,,, 5.75 (ester carbonyl), 6.05 (oxalyl keto group); ultraviolet spectrum it1 Fig. 1; 1I.m.r.: 6.18 (two protons, C-9 methylene), 6.03 (three protons, niethosylj, 4.95 (two protons, benzylic niethylene'l, 3.78 (doublet, Jl,?= 4 c.p.s., C-1 proton), 3.08 (doubled doublet, J5,b= 9 c.p.s., .j6.3 = 2 c.p.s., c - 6 prot o n ) , 3.03 (doublet, = 2 c.p.s., C-8 proton), 2.60 (five protons, p h e n y l ) , 2.53 (doublet, J = 4 c.p.s., C-2 proton), 1.40 (doublet, .7 = 9 c.P.s., C-5 proton) T . A n a ) . Calcd. for CllH1;SOJ (347.35): C , 72.61; II, 4.93; S ,4.03. Fuuiid: C , 72.56; H , 5.04;S,3.72. l-Chloro-3-chlorooxalyl-7-methoxy-6-methyl-9H-pyrrol0 [l,Z-a] indole (IX).-To an ice-cooled solution of 1.08 g. ( 5 mrnoles) of 2 , 3 - d i h y t l r o - 7 - m e t l i o x y - ~ ~ - 1 ~ ~ e ~ ~ i y l --lpyrrolo[ - o ~ o - l H1,2 - alindole (T.II)l" in 75 ml. of methylene chloride was added a solution of 1.27 g . I 10 mmoles) of oialyl chloride in 10 nil. of methylene ~
(171 I'lonsil is t h e ti-ademark u i t h e F l u r i d i n C o . for a magnesia-silica gel adsorhent
[COYTRIIIL-TION FROM
TIIE
1-01 S(i
\\-EISS
chloride. .lfter 20 min. the orange needles that separated bvcrc collected, washed with cold methylene cliloride, anti dried. T l i i i procedure gave 0.45 g. of l-chloro-3-cliloroohalJ.l-7-illethos)~iiiethyl-9H-pyrrolci[l,~-u!indole ( I S ) , 1n.p. 154-l(iOo. LVork-up of the mother liquor and wash gave 0.58 g. of orange nectllcs, n1.p. 142-145'. After two recrystallizations from iiietliylciic chloride, orange needles, n1.p. 164-167', were obtained; A,,,,,, 5.65 (acid chloride carbonyl), 6.03 (oxalyl keto group) p , I I O 1keto group; 247 ( e 13,000), 305 ( E 10,000), 330 ! e l 0 , 0 0 0 ~ nip; positive test with alcoholic silver nitrate; i t . n i . r . : 7.72 (three protons, &methyl), 6.36 (two protons, C-9 rnethylene 1, 6.15 (three protons, 0-methyl), 3.07 t C-8 proton), 2.70 (C-2 proton), 1.60 (C-5 proton) T . A n d . Calcd. for C15H1,ClrSOa(324.15): C , 55.58; 14, 3.42; CI, 21.88; S ,4.32. Found: C , 55.85; H , 3.57; CI, 22.01; S , 4.48. When a mixture of 86 mg. (0.4 mmole) of 2,3-dihydro-7niethoxy-6-methyl-1-oxo-1H-pyrrolo [ 1,2--a]itidole (1-1 I ) a n d 51 mg. (0.4 mmole) of oxalyl chloride in 5 nil. of ether \ v x . kept a t 25' for 20 hr., then conceritrated under reduced pressure, the tali solid residue (80 nig.) had an infrared absorption spectruin ideiitical u i t h that of starting inaterial. Methyl l-Chloro-7-methoxy-6-methyl-9H-pyrrolo [ 1,Z-tr 1 indole3-oxalate (XI.--A sample of l-chloro-3-cliloroosalyl-7-iiietli~i~y-~~inethyl-QH-pyrrolo[1,%-a]indoIe ( I Sj was dissolved in warn1 methanol. The yellow solid that crystallized from the solutiori was methyl l-cliloro-~-methoxy-6-metliyl-9H-p~-rrolo[ 1,2-i1]itidole-3-oxalate (S), 1ii.p. 148"; A,, 5.77 (ester curbonyl I , ii.05 (oxaly1ketogroup)p; 247(e 13,000),305(c 10,000),: 3 3 0 ( e 10,000,) nip; n.m.r.: 7.77 (three protons, 6-tnethyl), 6.24 ( t w o protons, C-9 methylene), 6.18 (three protons, C-7 methc protons, methyl ester), 3.13 (C-8 proton), 2. 1.57 (C-5 proton) T . Anal. Calcd. for C16HlaC1SOI: C, 60.09; H , 4,41; CI, 11.09; N, 4.38; mol. wt., 319.74. Found: C , 60.18; H , 4.61; C1, 11.07; S, 4.88; mol. wt., 329.
Acknowledgment.-The author is indebted to l I r . G. Morton and Xlr. it-.Fulmor for spectral d;tta and assistance in interpretation; t o l l r . L. I3ranconc anti staff for microanalyses; to Dr. G . R . A i l l e ~Jr., ~ , for a generous supply of certain compounds; to Tlr, A. S. Kende for molecular orbital calculations; and to Dr. 51.J . m'eiss and Dr. J . S. ivebb for helpful discussions and encouragement.
O R G A ~ CHEMICAL IC RESEARCH SECTION, LEDERLE LABORATORIES DIVISION,.\MERICAN C Y A Y A M CO ID , P E A R L RIVER, NEIV \-ORK]
The Mitomycin Antibiotics. Synthetic Studies. IV.' Introduction of the 9-Hydroxymethyl Group into the 1-Ketopyrrolo [ 1,Z-a ]indole System BE'~ V I L L I A M X KEMERS,RETAH ROTH,A N D MARTISJ WEISS RECEIVED J C L V1, 1964 T h e development of a method for preparing 9-hydroxytnethylpyrrolo [1,2-a]indoles(e.g., I1 ) bearing a group such a s a carbonyl in ring X was important to the synthesis of mitomycin analogs. It was not possible to prepare such compounds b y Diecktnann cyclizations with 1-cyanoethyl-2-carbethosyindoles having potential hydroxymethyl groups a t the 3-position However, by formylation a t C-9 (directl5- in poor yield or in higher yield m a ketone reduction, acetylation, %formylation, deacetylation, and oxidation) of a precyclized 1-ketopyrrolo[ 1,2-aj indole ( I ) , follouzed by preferential reduction of the 9-formyl group with diborane, a useful method for preparing compounds such as I1 was obtained T h e 1-keto group of I1 effectively stabilized the potentially labile 9hydro )i y meth yl group
-4spart of a coniprehensive program for the synthesis of analogs of the mitomycin antibiotics' i t was necessary to develop a useful method for the introduction of the 9-hvdroxvmethvl substituent into a pvrrolo._ 11) Pirceriinp papers in t h i s series: G I< ;Illen, J r . , J. I;. Polelto. and X I . J \Yeis\, .i. A r i l C h c m S i r c . , (a1 86, :38i7 (1'1641, ( b ) 86, 3878 (1964) ( 2 ) ( a i J S 1Vebh. 11. 11. C
