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Supporting Information

Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2007

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Supporting Information for Chiral Phosphoric Acid-catalyzed Enantioselective Aza-Friedel-Crafts

Reaction of Indoles

Masahiro Terada,* Shigeko Yokoyama, Keiichi Sorimachi, and Daisuke Uraguchi

Graduate School of Science, Department of Chemistry, Tohoku University, Sendai 980-8578, Japan.

General Information: Infrared spectra were recorded on a Shimazu FTIR-8600PC spectrometer. 1H NMR

spectra were recorded on a JEOL GSX-270 (270 MHz) spectrometer. Chemical shifts are reported in ppm from the

solvent resonance as the internal standard (CDCl3: 7.26 ppm). Data are reported as follows: chemical shift,

integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, br = broad, m = multiplet) and

coupling constants (Hz). 13C NMR spectra were recorded on a JEOL GSX-270 (67.8 MHz) spectrometer with

complete proton decoupling. Chemical shifts are reported in ppm from the solvent resonance as the internal

standard (CDCl3: 77.0 ppm). Analytical thin layer chromatography (TLC) was performed on Merck precoated TLC

plates (silica gel 60 GF254, 0.25 mm). Flash column chromatography was performed on silica gel 60N (spherical,

neutral, 100-210 m; Kanto Chemical Co., Inc.). Optically rotations were measured on a Jasco P-1020 digital

polarimeter with a sodium lamp and reported as follows; [] C D (c = g/100 mL, solvent). Mass spectra analysis

was performed at the Instrumental Analysis Center for Chemistry, Graduate School of Science, Tohoku University.

All reactions were carried out under a nitrogen (N2) atmosphere in dried glassware. All substrate were purified by

column chromatography or distillation prior to use. Dichloromethane, toluene, diethyl ether and tetrahydrofuran

were supplied from Kanto Chemical Co., Inc. as Dehydrated solvent system. Other solvents were dried over

activated MS4A and used under N2 atmosphere. The other simple chemicals were purchased and used as such.

N-TBS protected Indoles (2a-2c), N-Boc protected Imines (3a-3n) were prepared by modified literature procedure.

Experimental Section

1. Preparation of N-TBS Protected Indoles.

2. Preparation of N-Boc Protected Aldimines.

3. Screening of Indole Derivatives

4. Aza-Friedel-Crafts Reaction Catalyzed by Chiral Brnsted Acid.

5. X-Ray Crystallographic Analysis of 4aj.

6. DFT Computational Analysis of BINOL-derived Monophosphoric Acid (R)-1.

7. DFT Computational Analysis of Hydrogen-Bonding Pairs (R)-1/3.

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1. Preparation of N-TBS Protected Indoles.

NH

1) n-BuLi, THF, 0 C

2) TBSCl, rt NTBS

Procedure for Preparation of N-TBS Protected Indole (2a: X = H)[1]: To a stirred solution of indole (2.34 g, 20.0

mmol) in tetrahydrofuran (100 mL) was added n-butyllithium (1.58 mol/L in hexane, 13.9 mL, 22 mmol) over 10 min

at 0 C. After addition completion, resulting clear solution was added t-butyldimethylsilyl chloride (4.52 g, 30

mmol) and stirring was continued for additional 2 h at room temperature. The resulting solution was diluted with

saturated aqueous NH4Cl and extracted with ethyl acetate. Organic extracts were dried over Na2SO4 and filtered.

After concentration, the residue was purified by distillation (150 C, ca. 0.5 mmHg) to give white solid of N-t-

butyldimethylsilyl-indole (2a: X = H, 4.17 g, 90%); 1H NMR (CDCl3, 270 MHz) 0.61 (6H, s), 0.93 (9H, s), 6.22

(1H, d, J = 3.0 Hz), 7.08-7.19 (3H, m), 7.52 (1H, d, J = 7.6 Hz), 7.64 (1H, d, J = 7.6 Hz).

NH

Me1) NaH, THF, 0 C

2) TBSCl, rt NTBS

Me

Procedure for Preparation of N-TBS Protected Indole (2c: X = Me): To a stirred solution of NaH (79 mg, 3.3

mmol) in acetonitrile (3 mL) was added acetonitrile (3 mL) solution of 5-methylindole (394 mg, 3.0 mmol) over 15

min at 0 C. After addition completion, resulting clear solution was added t-butyldimethylsilyl chloride (4.52 g, 30

mmol) and stirring was continued for additional 1 h at room temperature. The resulting solution was diluted with

saturated aqueous NH4Cl and extracted with dichloromethane. Organic extracts were dried over Na2SO4 and filtered.

After concentration, the reaction mixture was purified by silica gel column chromatography (Hexane/EtOAc =

20/1-10/1 as eluent) and distillation (150 C, ca. 0.5 mmHg) to give yellow oil of 5-Methyl

N-t-butyldimethylsilyl-indole (2c: X = Me, 610 mg, 83%); 1H NMR (CDCl3, 270 MHz) 0.64 (6H, s), 0.98 (9H, s),

2.50 (3H, s), 6.59 (1H, d, J = 3.0 Hz), 7.04 (1H, d, J = 8.5 Hz), 7.19 (1H, d, J = 3.0 Hz), 7.46 (1H, t, J = 8.5 Hz), 7.48

(1H, s); 13C NMR (CDCl3, 67.8 MHz) -4.1, 19.5, 21.2, 26.3, 104.3, 113.5, 120.3, 122.9, 128.9, 131.0, 131.6, 139.2;

HRMS (ESI) Calcd for C15H23NaNSi ([M+Na]+) 268.1492. Found 268.1492.

NTBS

Br

2b: X = Br[2]: Reaction performed utilizing the same procedure for preparation of 2c: X = Me; yellow oil (89%);

[1] D. Dhanak, C. B. Resse, J. Chem. Soc. Perkin Trans. I 1989, 2181-2186. [2] Y. L. Song, C. Morin, Synlett 2001, 266-268.

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1H NMR (CDCl3, 270 MHz) 0.620 (3H, s), 0.623 (3H, s), 0.94 (9H, s), 6.58 (1H, d, J = 3.2 Hz), 7.20 (1H, d, J = 3.2

Hz), 7.26 (1H, dd, J = 8.9, 1.8 Hz), 7.40 (1H, d, J = 8.9 Hz), 7.78 (1H, d, J = 1.8 Hz); 13C NMR (CDCl3, 67.8 MHz)

-4.1, 19.4, 26.2, 104.3, 113.1, 115.1, 123.1, 124.1, 132.2, 133.2, 139.6; HRMS (ESI) Calcd for C14H20BrNSi

([M+Na]+) 309.0548. Found 309.0549.

2. Preparation of N-Boc Protected Aldimines.[3]

H

NBoc

F

3e: Ar = 2-FC6H4-: 1H NMR (CDCl3, 270 MHz) 1.59 (9H, s), 7.14 (1H, t, J = 7.6 Hz), 7.22 (1H, t, J = 7.6 Hz),

7.54 (1H, td, J = 7.6, 1.9 Hz), 8.12 (1H, td, J = 7.6, 1.9 Hz), 9.15 (1H, s); 13C NMR (CDCl3, 67.8 MHz) 27.8, 82.4,

116.0 (d, JC-F = 20.6 Hz), 122.0 (d, JC-F = 8.8 Hz), 124.5 (d, JC-F = 3.9 Hz), 128.3, 135.3 (d, JC-F = 9.8 Hz), 162.4,

162.5, 163.8 (d, JC-F = 256.9 Hz); IR (neat): 2982, 1717, 1636, 1229, 1150 cm-1; HRMS (ESI) Calcd for

C12H14FNaNO2 ([M+Na]+) 246.0901. Found 246.0900.

H

NF

Boc

3f: Ar = 3-FC6H4-: 1H NMR (CDCl3, 270 MHz) 1.59 (9H, s), 7.25 (1H, tq, J = 8.1, 1.4 Hz), 7.45 (1H, td, J = 8.1,

5.4 Hz), 7.63-7.68 (2H, m), 8.81 (1H, d, J = 1.1 H ); 13C NMR (CDCl3, 67.8 MHz) 27.9, 82.6, 115.7 (d, JC-F = 25.5

Hz), 120.4 (d, JC-F = 21.6 Hz), 126.5, 130.4 (d, JC-F = 5.9 Hz), 136.3 (d, JC-F = 6.9 Hz), 162.2, 162.9 (d, JC-F = 248.1

Hz), 167.9; IR (KBr): 2982, 1717, 1641, 1246, 1157 cm-1; HRMS (ESI) Calcd for C12H14FNaNO2 ([M+Na]+)

246.0901. Found 246.0901.

H

NBoc

3m: Ar = 4-i-PrC6H4-: 1H NMR (CDCl3, 270 MHz) 1.27 (6H, d, J = 6.8 Hz), 1.59 (9H, s), 2.97 (1H, qui, J = 6.8

Hz), 7.32 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 8.88 (1H, s); 13C NMR (CDCl3, 67.8 MHz) 23.5, 27.8, 34.2,

81.7, 126.9, 130.3, 131.7, 155.1, 162.6, 169.7; IR (KBr): 2964, 2870, 1713, 1626, 1269, 1155 cm-1; HRMS (ESI)

Calcd for C15H21NaNO2 ([M+Na]+) 270.1465. Found 270.1465.

H

NBoc

Ph [3] A. G.. Wenzel, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 12964-12965.

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3m: Ar = 4-PhC6H4-: 1H NMR (CDCl3, 270 MHz) 1.61 (9H, s), 7.40-7.50 (3H, m), 7.64 (2H, dt, J = 8.3, 1.6 Hz),

7.70 (2H, dt, J = 8.3, 1.6 Hz), 8.00 (2H, d, J = 8.3 Hz), 8.94 (1H, s); 13C NMR (CDCl3, 67.8 MHz) 28.2, 82.3, 127.4,

127.6, 128.5, 129.2, 130.9, 133.2, 139.9, 146.3, 162.8, 169.5; IR (KBr): 2980, 1713, 1622, 1256, 1153 cm-1; This

N-Boc protected imine (3m: Ar = 4-PhC6H4-) was not detected with mass spectra analysis.

3. Screening of Indole Derivatives

As shown in Table I, the FriedelCrafts reaction of N-unprotected indole (2d) with N-Boc imine (3a) took

place immediately at room temperature without any catalysts (entry 1). To suppress this uncatalyzed pathway in the

FC reaction, we explored N-protective groups to diminish the reactivity of indoles (2). After several trials,

tert-butyldimethylsilyl group found to be the best. A trace amount of the FC products was obtained without

catalysts even at room temperature for 24 h (entry 2), whereas monophosphoric acid catalyst (5) significantly

accelerated the reaction of 2a with 3a to provide the corresponding product (4aa) quantitatively (entry 3). In

contrast, the FC reaction did not proceed even by using catalyst 5 (entry 4), when N-Ts protected indole (2e) was

employed.

NY

+H Ph

NBoc 5

NY

Ph

HNBoc

2a (Y = TBS)2d (Y = H)2e (Y = Ts)

3a 4

CDCl3, rt*

O

OP

O

OH

5

Table I. Aza-Friedel-Crafts reaction of Indole derivatives (2) with N-Boc imine (3a) catalyzed by 5.

entry 5 [mol%] 2 time yield (%)

1 - 2d < 5 min 98 a

2 - 2a 24 h < 5 a

3 2 mol% 2a < 10 min 98 b

4 2 mol% 2e 48 h no reaction aNMR yield. bIsolated yield.

4. Aza-Friedel-Crafts Reaction Catalyzed by Chiral Brnsted Acid.

NTBS

+H Ph

NBoc 2 mol% (R)-1b

NTBS

Ph

HNBoc

2a 3a 4aa(CH2Cl)2, -40 C, 24 h

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Representativ