Enantioselective Synthesis of 3-Substituted Indolines by Asymmetric Intramolecular Carbolithiation in the Presence of (-)-Sparteine

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Enantioselective Synthesis of 3-Substituted Indolines by Asymmetric Intramolecular Carbolithiation in the Presence of(-)-Sparteine

Gema Sanz Gil and Ulrich Groth*

Fakultiitfiir Chemie, Universitiit Konstanz, M-720, Universitiitsstr.10, D-78457 Konstanz, Germany

Experimental 'procedure

Typical procedure for the enantioselective carbolithiation. Synthesis of (3R)-1-Benzyl-3- methyl-2,3-dihydro-lH-indol¹3a

A solution of N-Allyl-N-benzyl-2-bromoaniline (302 mg, I mmol) indrytoluene (hnl) was added dropwise at -90°C to a solution oftBuLi / hexane (1.3 ml, 2.2 mmol) in presence of (_)_

sparteine (235 Ill, 1.5 mmol) in drytoluene (8 ml). After 18h at -90°C MeOH (1 ml) was added and the reaction mixture was poured into NHtCI sat. The organic phase was dried over MgS0⁴ and after evaporation of the solvent the residue was chromatographed on silical gel . (eluent: petrolether / toluene: 4/1 containing a few drops of32% NH_3).Yield 85% (190 mg);

(a102o

= -49.7° (c = 1, CH2Ch); IR (neat): v = 2958, 1605, 1448, 1451 cm-I; IH-MNR (250 MHz, CDCh): 0 = 1.30 (d, J= 6.8 Hz, 3H), 2.83 (t, J=8.4 Hz, IH), 3.30 (sext.,J= 8.2 Hz, IH), 3.51 (t,j= 8.5 Hz, IH), 4.11 and 4.36 (AB-Signal,JAiF 14.8 Hz, 2H), 6.50 (dd,J= 1.0, 7.4 Hz, IH), 6.70 (dt,J= 1.0, 7.3 Hz, IH), 7.00-7.15 (m, 2H, C4-H), 7.20-7.40 (m, 5H);· 13C_

NMR (100 MHz, CDCh): 0= 18.6,35.2,53.4,61.6, 107.0, 117.7,123.1, 127.0, 127.4, 127.9, . 128.4, 135.0, 138.5, 152.1; MS, mI e (reI. intensity) 223 (95) (M+l, 208 (45) (M+-CH₃

1,

'91

.

,

(base) (C6H⁵

WJ.

"Anal. Ca1cd. for C I6H17BrN: C, 86.05; H, 7.67; N, 6.27. Found: C, 86.20;

iI,

7.70; N, 6.40.

Synthesis of(3R)-1-Benzyl-6-benzyloxy-3-methyl-2,3-dihydro-lH-indol 3c

Yield 86% (283 mg);(000²⁰ = -39.0° (c= 0.65,CH2Ch); IR (CH₂Ch): v = 2926,2870,2826, 1620 (C=C), 1495 cm-I; IH_MNR (400 MHz, CDCh): 8 = 1.26 (d,J=6.6 Hz, 3H), 2.85 (t,J=

8.6 Hz, IH), 3.24 (sext.,J=7.0 Hz, lE), 3.51 (t, 8.6 Hz, IH), 4.10 and 4.31 (AB-Signal,JAB = 14.8Hz, 2H), 4.98 (s, 2H), 6.18 (d,J=2.2 Hz, IH), 6.29 (dd,J=2.2,8.2 Hz, IH), 6.93 (dd,J=

ISole, 0; Cancho, Y; L1ebaria, A; Moreto, I.M; Oelgado, A.J.Org. Chem. 1996,61,5895-5904.

Konstanzer Online-Publikations-System (KOPS) URL: http://www.ub.uni-konstanz.de/kops/volltexte/2008/4668/

URN: http://nbn-resolving.de/urn:nbn:de:bsz:352-opus-46688

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2000'American _Ch~mical Society, J. Am. Chem. Soc., Gil ja0012164 Supporting Info Page 2

0.9, 8.2 Hz, lH), 7.22-7.46 (m, 10H); 13C_NMR (lOO MHz, CDCi)): 8= 19.0, 34.5, 53.0, 61.9, 70.1, 95.4, 10~.4, 123.3, 127.1, 127.5, 127.77, 127.83, 127.87, 128.4, 128.5, 137.4, 138.2, 153.3, 159.4; MS m / e (reI. intensity) 329 (5) lM+l, 238 (41) lM+-CH2Phl, 91 (base) lCJIsWl.Anal. Calcd. for C23H23NO: C, 83.85; H, 7.04; N 4.25. Found: C, 83.65; H, 7.05; N, 4.36.

Procedure for NMR-determination of enantiomeric purity of (3R)-1-Benzyl-6-benzyloxy- 3-methyl-2,3-dihydro-lH-indoI3c

Into a dried NMR tube were introduced the chiral indoline (5-10 mg), binaphthylphosphonic acid (1.0 equiv) and CDCh (700I!I). The tube was shaking until completed dissolution and the^IH spectrum :was~ecorded; ^{ee= 88%.}

Typical procedure for the deprotection of N-bezylindolines. Synthesis of (3R)-3-Methyl- 2,3-dihydro-l-H-indoI²

To a flask were added 3a (223 mg, 1.0 mmol), NaI (300 mg, 2.0 mmol), 1-cWoroethyl cWoroformate (0.2 ml, 1.8 mmol), and acetone (3 cm1). The resulting mixture was stirred at room temperature for 3h, after which time the solvent was removed, dissolved in a minimum amount of ether and was eluted down a flash column using 9: 1 petroletherlether as eluent. The carbamat was collected and dissolved in methanol (3ml). The solution was heated to reflux, for 90 min, cooled to room temperature and poured into a separatory funnel containing ether and NaHC03 solution. The organic layer was collected, washed with water and brine, dried over MgS04 and the solvent were removed by rotary evaporation. The product was isolated by.

flash chromatography to give 114 mg(86%) of a colorless oil. IR (neat): v: 3383 (NH), 2960,

. -I I · .

2925,2874, 1608, 1488, 1462, 1240 cm . H-MNR (400 MHz, CDCi): 0= 1.30 (d,J=7.0, lH), 3.09 (t,J= 8.6 Hz, Hz, 1H), 3.57 (br s, lH), 3.67 (t,J= 8.6 Hz, lH), 6.62 (d,J=7.4 Hz, lH), 6.73 (t,J=7.4 Hz, lH), 7.02 (t,J=7.8 Hz, lH), 7.08 (d,J=7.4 Hz, lH). 13C-NMR (62.5 MHz, CDCi): 0= 18.5, 36.5, 55.3, 109.4, 118.6, 123.3,127.2, 134.3, 151.1; MS m / e(reI.

intensity) 133 (12), 118 (base) lM+-CH3l, 91 (47) rCJIsNl. GC analysis was performed using CYCLOSIL-B chiral column. flow rate 30 mUmin, method 50°C fo 2 min, ramp @ lO°C/min to 220 for 15 min, Tr : 14.83 (38) and 15.01 (3R)provided the ee= 87%..

2Buchwald, S.L.; Tidwell, J.H.J.Am. Chem. Soc.1994,JJ6, 11797-11810.

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American Chemical Society, J. Am. Chem. Soc., Gil ja0012164 Supporting Info Page 3

(3S)-I -Benzyl-3-bromomethyl-2,3-dihydro-I -H-indol Sa

A solution of N-Allyl-N-benzyl-2-bromoaniline (302 mg, 1 mmol) in drytoluene (lml) was added dropwise at -90°C to a solution oftBuLi / hexane (1.3 ml, 2.2 mmol) in presence of (-)- sparteine (235

Jll,

1.5 mmol) indrytoluene (8 ml). After l8h at -90°C dibromoethan (l72)..ll, 2 mmol) in lml toluene was added and the reaction mixture was poured into Nl4Cl sat. The organic phase was dried over MgS04 and after evaporation of the solvent the residue was chromatographed on silical gel (eluent: cydohexane / toluene : 4 / 1 containing a few drops of 32% NH_3). Yield 70% (210 mg) ; (alDzo

= -50.8° (c = 1, CHzClz); IH_MNR (400 MHz, CDCh): 0= 3.28 (dd,J= 5.3, 9.8 Hz, 1H), 3.43 (t,J= 11.0 Hz, 1H), 3.53 (t,J= 8.95 Hz, 1H), 3.60-3.70 (m, 2H, C3-H), 4.27 (s, 1H), 6.51 (d,J= 8.2 Hz, 1H), 6.69 (t,J= 7.4 Hz, 1H), 7.09-

13 .

7.13 (m, 2H), 7.27-7.35 (m, 5H); C-NMR (lOO MHz, CDCh): 0 = 35.6, 43.5, 52.8, 58.5, 107.4, 117.6, 124.3, 127.2, 127.7, 128.5, 128.8, 129.8, 137.9, 152.3; MSm Ie (reI. intensity) 301 /303 (35) (M+l, 222 (40) (M+-CHzBrl, 91 (base) (C6HsW1; Anal. Calcd. forCI~I~rN:C, 63.59; H, 5.34; N 4.63. Found: C, 63.80; H, 5.10; N, 4.23.

I,3-Dil,lenzyl-2,3-dihydro-IH-indoe 7

A solution of6E or 6Z (287 mg, 1 mmol) indry toluene (lml) was added dropwise at -78°C to a solution oftBuLi / hexane (1.3 ml, 2.2 mmol) ~presence of (-)-sparteine (235 )..ll, 1.5 mmol) in dry toluene (8 ml). After 18h at -50°C MeOH(1 ml) was added and the reaction mixture was poured into NH₄Cl sat. The organic phase Was dried over MgS0₄ and after evaporation of the solvent the residue was chromatographed on silical gel (eluent: petrolether / toluene: 10 /1 containing a few drops of32% NH_3).Yield 90% (270 mg) ; (alDzo= -34.6° (c

=

1, CH2Clz); IR (neat): V

=

3064, 3025, 2920, 2851, 1603, 1495, 1452 cm-I; IH_MNR (400 MHz, CDCh): 0=_.2.78 (dd,J= 9.1, 13.7 Hz, IH), 3.04 (dd,J= 6.5,8.7 Hz, lH), 3.09 (dd,, J=

5.7, 13.7 Hz, IH), 3.31 (t,J= 8.8, IH), 3.52 (qn,J=8.3 Hz, lH), 4.17 and 4.24 (AB- Signal, JAr 15.3 Hz, 2H), 6.48 (d,J=8.1 Hz, IH), 6.65 (t,J=7.3 Hz, lH), 6.95 (d,J= 7.2 Hz, lH), 7.06 (t, J= 7.6 Hz, 1H), 7.12-7.34 (m, 10H); 13C-NMR (lOO MHz, CDCh): 0 = 40.4,42.1, 53.1,59.0, 107.0, 117.5, 123.9, 126.1, 127.0, _127~6, 127.7, 128.3, 128.4, 129.0, 132.9, 138.4, 140.0, 152.2; MS m I e (reI. intensity) 299 (19) [Ml, 208 (62), [~-CH2Ph+], 91 (100) [C~sW];Anal. Calcd. for C22H21N: C, 88.25; H, 7.07; N, 4.68. Found: C, 87.90; H, 7.28; N, 4.47.

, 1. Inanaga, 1.; Ujikawa,0;Yamaguchi, M. Tetrahedron Left. 1991,32, 1737-1740.

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2000'American Chemical Society, J. Am. Chem. Soc., Gilja0012164 Supporting Info Page 4

.r

I-Benzyl-3-vinyl-2,3-dihydro-IH-indol9

A solution of SE or SZ (346 mg, 1 mmol)

In

^drytoluene (lml) was added dropwise at -78°C·

to a solution of tBuLi / hexane (1.3 ml, 2.2 mmol) in presence of (-)-sparteine (235111, 1.5 mmol) in drytoluene (8 m!). After 18h at -90°C MeOH (1 ml) was added and the reaction mixture~was poured into NH4CI sat. The organic .phase was dried over MgS0₄ and after evaporation of the solvent the residue was chromatographed on silical gel (eluent: petrolether / toluene : 4 / 1 containing a few drops of 32% NH_3). Yield 95% (223 mg) ; ee = 0%; IR (CH2Clz): v = 3064, 3033, 2989, 2926, 2820, 1589, 1493, 1474 cm-I; IH-MNR (400 MHz, CDCb): 0= 3.02 (t, J= 9.0 Hz, 1H), 3.53 (t,J= 8.6 Hz, 1H), 3.87 (q, J= 8.6 Hz, 1H), 4.11 and 4.39 (AB- Signal, JAB=14.4 Hz, 2H), 5.09-5.20 (m, 2H), 5.84-5.93 (m, 1H), 6.53 (d, J= 7.8.

Hz, 1H), 6.71 (t, J= 7.4 Hz, 1H), 7.03 (d,J= 7:4 Hz, 1H), 7.09 (t, J= 7.4 Hz, 1H), 7.11-7.37 (m, 5H); 13C-NMR (62.5 MHz, CDCb): 0 = 45.5, 53.3, 59.4, 107.2, 115.8, 117.9, 124.4, 127.0,127.8, 128.4, 129.1, 131.8, 138.1, 138.5,and 152.0; MSm le(reI. intensity) 235 (base) [Ml, 144 (43) [M+-C6HSN], 91 (65) [C6HsNl; Anal. Calcd. for C17H17N: C, 86.77; H, 7.28;

"

N, 5.95. Found: C, 87.10; H, 7.40; N, 6.10.

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2000 American Chemical Society, J. Am. Chem. Soc., Gil ja0012164 Supporting Info Page 10

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Area Percent Report

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Sorted By Multiplier Dilution Sample Amount

Retention Time 1.0000

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1 1.894 1 PB 12.16715 1.72107 14.67353 2 19.939 1· BP 14.53669 1.70853 17.53118 3 20.375 1 BB 56.21522 6.25381 67.79529

Totals B2.91906 9.68341

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2000 American Chemical Society, J. Am. Chem. Soc., Gil ja0012164 Supporting Info Page 19

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