1070 CHINESE JOURNAL OF CHEMISTRY 2002, 20, 1070-1072

A Practical Synthesis of 1-0x0-1 2 3 4-tetrahydroisoquinoline- 3-carboxylic Acid Esters

TANG, Lei($S) YANG, Yu-Sheo(&3ie) JI, h-Yd%tikS) S w Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, shanghai IIlJtitlues for Biologic$ &ienceJ, Chinese Academy ofsciacRp, shanghai 2 W 3 1 , China

A practical synthetic method for methyi l-ox+l,2,3,4-tel1ahy- ddsaquholine3-carboxylak wsp developed by means d trpdmsgene. Seve.tal aualoguea were prepared by this new method.

Introduction

l-Oxc~1,2,3,4-tetrahydmisoquinoline is a basic structure of some compounds with central nervous system activity' or with q-adrenoceptor inhibiting a~t iv i ty .~ Such a compound has been syntheaized mostly by Bischler- Napieralski reaction. ?he p d m involved some dras- tic reaction conditions and some moisture sensitive cata-

lysts such as SnCb, Tf20 were often In our work, we designed to synthesize some substituted methyl 1 -0x0- 1 ,2,3,4- tetrahydmieoquinoline-3-cahoxylatea. Al- though methyl l-0x0-l, 2,3,4-tet1ahyd~)i~oq~inohe-3- cadmylate was ever manufactured by means of phos- gene,4 this method has been little applied due to its low yield and the toxicity of phosgene. In our attempt to syn-

carboxylate by Bider-Napieralski reaction following lit- erature ' s method, no product was detected by TLC .

Bis ( trichlommethyl) carbonate ( triphosgene, Bn:) is a safe alternative of dangerous phoggene, and it has .been widely used in organic synthesis in recent years.5 Bn: reacts with primary amine to yield i~ocyanate.~'

thesize methyl 1 -OX* 1 ,2 ,3 ,4- te trahyd1~i i0he-3-

When we treated the isocyanate derived fmm phenylala- nine with AlCl3 in CH2Cl2, D ( - )-1-oxo-l ,2,3,4-te- trahydxoiioline3-c&xylic acid methyl ester (2a) was doded with a good yield. Furthemre, al l reactions could be carried out in one-pot , thus avoiding the appear- ance of sticky reaction mixture when CS, was used as the solvent .4 l h i s will make it suitable for be-sca le pmpa- ration.

Several substituted methyl 1-oxo-l,2,3, Ctetmhy- d m ~ o h e 3 - c a r b o x y ~ t e s ( 2b- 2d) and methyl ( R) -I-ox0-~-carboI.ine-3-&xy~te (3) have been syn- thesized by our improved method (Scheme 1) . But for the reason of the inactivation of nib p u p , the correspond- ing isocyanate derived from p-nitmphenylalanine ( R = N 4 ) did not react with AlCl3. 7-Methoxy-subetituted derivative (R = OCH3) was obtained in low yield, which might be due to the demethylation by AlCl3 in CH2Cl2. 'Ihis might ale0 explain why 7-benzy10xy-substituted derivative (R = OCHZPh) can not be produced h m p - benzyloxyphenylalanine .

Secondary amine reacts with Bn= to give N-chlom- formyl derivatives ." However, the reaction of N-chlom- formyl derivativea attaching to an aromatic compound was d y reported before. So 1-benzyl-phenyhhine was al-

so tried in our new method, and N-benzyl-l-oxc~l,2,3, 4-tetrahyhisquinoline-3-~lic acid methyl ester ( 4 ) was syntheaized successfully in a moderate yield (Scheme 1 ) .

Ed: ysyang@d.ehcnc.ac.cn; Tel. : 021-64311833-346 Received March%, 2332; revised May21, 2002; accepted June6, 2002.

Vol. 20 No. 10 2002 Chinese Joumal of Chemistry 107 1

l a 2a

l b , l ~ , (do-ld Zb, 2c, (d4-2d

0

Experimental

'H NMR spectra were recorded on a Varian Mercury 400 NMR instrument. Mass spectra were determined with a Finnigan MAT-95 spectrometer. Elemental analyses were carried out on a Vario EL element analyzer. Optical mtations were recorded on a Perkin-Elmer 241 p o k e - ter. Inframd spectra were recorded on a Nicolet Msgna FT-IR-750 spectrometer. All melting point3 were uncor- rected. CH2Cl2 was dried over CaH2 and distilled out be- fore used.

&nerd p m h f o r the prepamhn of wmpoundc 2a - 2d and 3

Triphosgene (210 mg, 0.7 mmol) was dissolved in CHZC12 ( 4 mL) . A mixture of 2 m l of the starting material and 1.04 mL of diisopmpylethylamine in CHzC12 (6 mL) was added slowly to the stined solution of

4

triphosgene over a period of 30 min using a syringe pump. '' After stirring for another 30 min at mom temper- ature, AC13 (0.6 g) was added to the solution at 0 T . 'Ihe mixture was d u x e d for 1 h, then cooled to 0 '32 and treated with 5 mL of water; the addition of water was dropwise first, more rapid later. After stirring for 30 min, the CHzC12 layer was separated, and dried over Mg- SO,. CH2Cl2 was distilled off and the residue was pudied by column chroaatography on silica gel to give 2a -2d and 3.

3-cmbyhe (2a) Yield, 73.1%, m.p. 8 8 - 9 0 T, [a]g-!39.4 ( C 0.90, CH3OH), Lit.3[a]z-83 ( c 2, CH30H); 'H NMR (DMSO-d6, 300 MHz) 6: 3.15(dd, J = 1 6 . 1 H z , 3 . 3 & , l H ) , 3 . 3 8 ( d d , J = 16.1 Hz, 7.0 Hz, l H ) , 3.59 (s, 3H), 4.16-4.21 (m, lH) , 7.29 (d , J = 7 . 7 Hz, l H ) , 7.35 ( t , J = 7.7 Hz, lH) , 7.47 ( t , J = 7 . 4 Hz, lH) , 7.83 ( d , J =7.7 Hz, l H ) , 8.18 (br, l H , &O exchangeable); MS (70 eV) m / z (%) : 205 (M' , 22). Anal. calcd

M&9 ( 3 R ) - 1 - 1 ~ 0 - 1 , 2 , 3 , 4 - ~ ~ ~ 1 k -

1072 Methyl 1 -oxo- 1 ,2,3,4-tetrahydroi~ohe-3-c&xylate TANG, YANG & JI

for C I I H I I N 4 : C 64.39, H 5.36, N 6.83; found C 64.39, H 5.19, N 6.82.

Methyl (3S)-7-methoxy-1-oxo-l, 2,3,4-tetrahy- droisoquinoline- 3 -carboxylute (2b) Yield, 36.2% , m.p. 85-87 T, [a]f+49.5 ( c 0.49, CH30H); 'H NMR (CDCl3, 300 M H z ) 6: 3.16 (dd, J = 15.4 Hz, 9.9 Hz, lH), 3.25 (dd, J=5.7, 5.1 Hz, lH), 3.78 (s , 3H), 3.81 ( 9 , 3H), 4.34-4.40 (m, lH), 6.61 (br, IH), 7.00 (dd, J = 8 . 4 , 2.6 Hz, lH) , 7.16 (d, J=8.4Hz, lH), 7.58(d, J=3.0Hz, 1H); MS (70 eV) m / z (%I: 235 ( M ' , 18). Anal. calcd for C12H13N04: C 61.27, H 5.53, N 5.%; found C 61.41, H5.70, N6.15.

Me&$ 7-[2-(5-+-2-&4--CazCurdyl) -1- 1-OAD lV2 ,3 ,4 - t e tmhydro i soquino l ine -3 -~ (2)

Yield, 65.9%, m. p. 88-90 "c, [ a ] g + 20.6 ( C 0.48, CH30H); 'H NMR (CDCl3, 300 M H z ) 6 : 2.39 (9, 3H), 2.98 ( t , 5=6.6Hz, 2H), 3.11 (dd, J=15.4, 9.9Hz, lH), 3.23 (dd, J=15.7, 5.1 Hz, lH), 3.78 ( 9 , 3H), 4.30 ( t , J = 6.6 Hz, 2H), 4 .334 .40 (m, lH), 6.40 (br, lH), 7.00 (dd, J =8.4, 2.5 Hz, lH), 7.11 (d, J = 8 . 4 Hz, lH), 7.37-7.43 ( m , 3H), 7.59 (d, J = 2 . 9 Hz, lH) , 7.94-8.00 ( m , 2H); MS (70 eV) m / z (a): 406 ( M + , 56). Anal. calcd for h H z N 2 4 : C 67.98, H 5.42, N6.89; foundC68.11, H5.46, N6.72.

Me&$ 7 - w - 1 - m 1,2,3,4-- 3-c1dm$& [ ( d ) - M I Yield, 85.0%, m . p . 90- 91 T; 'H NMR (CDCl3, 300 M H z ) 6: 0.98 ( t , J = 7.3 Hz, 3H), 1.42- 1.50 ( m , 2H), 1.70-1.80 (m, 2H), 3.11 (dd, J=15.5, 10.1 Hz, lH) , 3.25 (dd, J= l5 .4 , 5.1 Hz, lH), 3.78 ( 8 , 3H), 3.99 ( t , J = 6.6 Hz, 2H), 4 .334 .40 ( m , lH), 6.42 (br, lH), 6.99 (dd, 5 ~ 8 . 2 , 2.7 Hz, lH), 7.12 (d, J = 8 . 4 Hz, lH) , 7.58 (d, J = 2.7 Hz, 1H); MS (70 eV) m/z (%) : 277 (M', 22); Anal. calcd for CuH19- N04: C 64.98, H 6.86, N 5.05; found C 65.06, H 7.32, N 5.06 (HRMS calcd for C ~ S H ~ ~ N O ~ 277.1314, found 277.1327).

Methyl ( 3 R ) - 9 -methyl- 1 -oxo-~cat6oltne- 3 -car- boxyEate (3) Yield, 82.1%, m.p . 136-138 t, [ a ] g - 2 3 . 5 ( c 1.22, CH3OH); 'HNMR (CDC13, 300 MHz) 6 : 3.25 (dd, J = 16.1, 9.9 Hz, lH) , 3.45 (dd, J = 15.8, 5.9 Hz, lH), 3.80 ( s , 3H), 4.12 (s, 3H), 4.48-4.54 (m, lH) , 6.04 (br , l H ) ,

. . .

7.13-7.18 ( m , lH) , 7.35-7.39 ( m , 2H), 7.60 (d, J = 8.0 Hz, 1H); MS (70 eV) m/z ( % ) : 258 ( M ' , 51). Anal. calcd for C14H14N24: C 65.12, H 5.43, N10.85; foundC64.80, H5.75, N 10.59.

Triphosgene ( 102 mg , 0.34 mad) was dissolved in CH2Cl2(2 d). A mivture of 0.269 g of N-benzyl- phenylalanine methyl ester (2 mmol) and 80 rJ. of dry pyridine in CH2Cl2 (3 mL) was added slowly to the stir- ring solution of triphosgene. 'Ihe resultant solution was stirred for 48 h at mom temperatwe and AIC13 (0.4 g)

was added at 0 "c . Stirring was continued for 4 h at room temperature, and the left procedure was similar to that for compound 2.

3- (4) Yield, 47.4%, m . p . 112-114 T; 'H NMR (CDC13, 300 M H z ) 6: 3.10 (dd, J = 16.2, 2.2 Hz, lH) , 3.30 (dd, J = 16.0, 6.3 Hz, lH), 3.59 (9 , 3H), 3.99 (AB system, d , J = 15.1 Hz, lH), 4.20 (dd, J = 6 . 6 , 2.2 Hz, lH) , 5.70 (ABsystem, d, J=15.1Hz, lH) ,7 .12 (d , J = 7 . 4 Hz, lH), 7.25-7.45 (m, 7H), 8.13 (dd, J = 7 . 7 , 1.6 Hz, 1H); MS (70 eV) m/z ( % I : 295 (M', 27). Anal. calcd for ClaH17N$: C 73.22, H 5.76, N 4.74; foundC73.36, H5.84, N4.78.

. . mhyi 2-bemyG1-m1,2,3,4-- liae-

References

1

2

Maeda, H.; Suzuki, M.; -0, H.; Yamarmw. M.; Ishida, R. Chem. Phann. Bull. 1988, 36, 190. Gary, L. G.; T i , M. C. ; Qifang, L.; V h , H. D. ;Brynn ,M. ;KRr in .R . C. J . M d . Gem. 1999, 42, 4351. (a) Tsuda, Y.; h b e , K.; Taga, J. H m 1976, 5, 157. (b) James, M.; J h , M.; Ramelo, G.;'Ruowei, M.; Sonja, W . ; Gange, R. P.; JMbext, L. H.; Michael, R. B. Bioorg. Med. &m. Lctt. 2001, 11, 169.

4 C o b S. G.; Schultz, R. M. J . B i d . Chen. 1968, 243, 2607.

5 (a ) Cotama, L.; Mop, P . ; Nadell, A . ; h j i p , V.

(b) Cortez, R. ; Rivem, I. A. ; Somanathem, R. ; Aguirre, G . ; RamLez, F. Synth. Commun. 1991, 21, 285. (c) Majer, P.; Randad, R. S. J . Org. Chtm. 1994, 59, 1937.

3

sryhecis 1996, 553.

(ED203264 PAN, B. F.; LING, J . )