Supporting Information

© Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2008

1

Supplemental Material

"Domino Catalysis in the Direct Conversion of Carboxylic Acids

to Esters"

I. Held, P. von den Hoff, D. S. Stephenson, H. Zipse*

Department Chemie und Biochemie, LMU München, Butenandtstr. 5-

13, D-81377 München, Germany

Fax.: (+49) 089 2180 77738, e-mail: zipse@cup.uni-muenchen.de

O

O

O

O

O

+

O HO

O

O

O

O

O

O

O+

O

O126

4OH

3 5

cat., dioxane

cat.:N

N

8N

N

9N

N

12N

N

10

N

N

N

11

N

23 oC

N7

Scheme S1

2

Ph

O OH

Ph

O O

NO

OH

O O

Ph

1718

15 16

NO

O

O O

Ph

NO

OH

O O

OH

3

1.3 eq. Boc2O0.05 eq. cat.

1 eq. 1,4-dioxane

13 14

NO

O

O O

Scheme S2

20

NO

OH

O O

OH

21

1.3 eq. Boc2O0.05 eq. cat.

1 eq. 1,4-dioxane

13

19

NO

O

O O

FO

HO

23O

HO NO2

22FO

O

24O

O NO2

+

+

+

O

O

O

25

O

O

O

25

O

O

O

25

Scheme S3

3

Experimental Details

All Schlenk flasks used for the esterification reactions were

kept over night in a 125 °C hot oven and were afterwards dried

again under high vacuum with a hot air blower. The flask was

cooled down under nitrogen atmosphere. The ethanol bath for

kinetic measurements was tempered at 23 °C with a JULABO F-25

thermostat. 1H NMR and 13C spectra were recorded on Varian

Mercury 200 MHz, Varian 300 MHz, and Varian INOVA 400 MHz

instruments. All 1H NMR chemical shifts are reported in ppm and

referenced to the respective solvent peak. The abbreviations d

(doublet), t (triplet), q (quartet), sep (septet) and m

(multiplet) denote the corresponding multiplet. IR spectra

were recorded with a PerkinElmer FT-IR system Spectrum BX for

neat measurement of the sample using ATR techniques. Peaks are

characterized as vs = very strong, s = strong, m = medium and

w = weak. Mass spectra were recorded with a Finnigan MAT 95

using either electron impact ionization (EI, 70 eV) or

chemical ionization (CI, isobutane). Electrospray injection

mass spectra were recorded with Thermo Finnigan LTQ FT

instrument. Gas chromatograms were recorded on Varian 3400

using a 25 m CS Supreme-5 capillary column and the Finnigan

MAT 95 mass spectrometer as detector.

Dichloromethane was stirred over conc. H2SO4 for 24 h, then

separated from the inorganic phase, washed twice with

saturated aqueous NaHCO3 solution, and distilled under nitrogen

atmosphere from CaH2. All deuterated solvents, triethylamine,

and pyridine were freshly distilled under nitrogen atmosphere

4

from CaH2. Isobutyric acid was distilled from P2O5 under

nitrogen atmosphere and kept in a Schlenk flask over molecular

sieves (4 Å). All other chemicals were purchased from

commercial suppliers at the highest available grade and used

as such without any further purification.

General procedure for kinetic measurements (a). In a 10 ml

Schlenk flask was added under nitrogen atmosphere 1 eq. (5.0

mmol) acid, 1.1 eq. tert-butanol, 1 eq. dioxane, and 2 eq.

NEt3. The reaction mixture was stirred until homogenous, cooled

to -20 °C and combined with 1.3 eq. of molten Boc2O. The

reaction mixture was stirred for another 2 min. at this

temperature, the cooling bath was removed, the flask was

equipped with a nitrogen-filled balloon and then immersed in a

temperature-controlled ethanol bath held at 23 °C. At this

point the reaction visibly starts as indicated through

evolution of CO2 and the reaction mixture turns yellow after

some minutes (Figure 3).

Figure 3. Reaction of proline derivative 13 in the presence of

1.3 eq. Boc2O, 2 eq NEt3, 1.1 eq. tBuOH and 0.05 eq. 11 (a)

5

after 5 min of reaction time; (b) after 30 min of reaction

time.

The moment when the flask was immersed into the thermostat

held at 23 °C marks the zero point on the reaction time scale.

In defined intervals an aliquot of 0.05 ml was taken out of

the reaction mixture with a syringe and 0.5 ml of dry

deuterated solvent was added. The conversion of the reaction

was monitored by 1H NMR spectroscopy through comparison of the

signal intensities of the tert-butyl group of ester product 4

with that of the internal standard dioxane at 3.67 ppm

according to equation 1. The data points collected in this way

were fitted with either a sigmoidal or mono exponential

function (equation 2 and 3). Half-life times are equal to the

time with respect to 50% conversion. For the fitting of the

mixed and symmetrical anhydride data points a peak function

(equation 4) was used. This function describes the profile of

the data points in a reasonable manner.

( )( )

%100*8

9.

dioxane

Ester

I

IConv = (1)

c

k

tttConv

ca +

−−+

=)(

exp1

1.

0

(2)

6

ckttAConv +−−= ))(exp(. 0 (3)

.)1(1)()(

exp.

1

00 constddk

tt

k

tttConv

d

a +

−

−+

−⋅

−−=

−

(4)

All constants in equations (2) - (4) have no physical meaning

and only serve to determine the half-life times as described

before. Relevant signals of reactants and products have been

collected in Table S1.

Table S1. 1H NMR signals (in ppm) of reactants and products for

the reaction shown in Scheme 2.

compound δ tBu

(9H, s)

δ iPr

(6H, s)

δ iPr

(1H, sep)

other

1 1.49 - - -

2 - 1.14 2.52 -

3 1.22 - - 1.88

(1H, s, OH)

4 1.39 1.06 2.39 -

5 - 1.190 2.62 -

6 1.48 1.195 2.59 -

General procedure for the synthesis of tert-butyl esters (b).

In a 20 ml Schlenk flask was added 1 eq. (5.0 mmol) acid,

0.5 ml (5.5 mmol) tert-butanol, 0.427 ml (5 mmol) 1,4-dioxane,

1.39 ml (10 mmol) NEt3, and 0.05 eq. PPY. The reaction mixture

was stirred until homogenous and cooled to -20 °C. Afterwards

7

1.39 ml (6.5 mmol) of molten Boc2O was added, stirred for

2 min. at this temperature and then allowed to warm to room

temperature. Stirring was continued depending on the substrate

for 4 to 24 h and then worked-up as specified.

tert-Butyl isobutyrate (4). The reaction was carried out as

described in procedure (b) with 10 mmol of isobutyric acid.

After stirring for 6 h the reaction mixture was diluted with

10 ml of DCM and transferred to a separatory funnel, then

washed with 10 ml of 2N HCl, 10 ml sat. aqueous NaHCO3 and

10 ml dem. water. The organic phase was dried over Na2SO4 and

afterwards fractionally distilled (41 °C, 26 mbar). This yields

1.07 g (7.45 mmol, 75%) of 4 as a colorless liquid. 1H NMR

(300 MHz, CDCl3): δ = 1.06 (d, 6H, 3J=6.9 Hz, CH(CH3)2),

1.39 (s, 9H, C(CH3)3), 2.39 (sep., 1H, 3J=6.9 Hz, CH(CH3)2) ppm.

13C NMR (75 MHz, CDCl3): δ = 19.1 (CH(CH3)2), 28.1 (C(CH3)3),

35.0 (CH(CH3)2), 79.7 (C(CH3)3), 176.7 (-COOtBu) ppm. IR (neat):

ν = 2974 (m), 2934 (w), 1729 (C=O, vs), 1469 (m), 1385 (m),

1366 (s), 1216 (m), 1148 (vs), 1097 (w), 1073 (m), 934 (w),

849 (m), 754 (vs), 667 (m), 618 (m) cm-1. The 13C NMR signals

are identical to those reported in the literature.[29]

tert-Butyl-1-phenylcyclohexanecarboxylate (18). The reaction

was carried out as described in general procedure (b) with 5

mmol 1-phenylcyclohexanecarboxylic acid. The reaction mixture

was stirred for 24 h, then diluted with 10 ml DCM and directly

purified by flash chromatography on silica gel (10%

8

EtOAc/isohexane) to afford 1.15 g (4.45 mmol, 89%) of a white

solid. Rf = 0.65 (10% EtOAc/isohexane), 1H NMR (400 MHz, CD2Cl2):

δ = 1.27 - 2.24 (m, 15H), 2.28 (m, 4H), 7.23 (m, 5H) ppm; 13C

NMR (100 MHz, CD2Cl2): δ = 23.6 (C-3, C-5), 25.7 (C-4), 27.9 (-

C(CH3)3), 34.3 (C-2, C-6), 52.4 (Cq, C-1), 81.0 (-C(CH3)3),

126.4, 127.4, 128.9 (Ph-C-H) 142.3 (Cq, Ph), 170.4 (C=O) ppm;

MS(EI) m/z (%): 247 (1), 187 (2), 186 (2), 160 (11),

159 (100), 158 (11), 142 (1), 130 (2), 129 (2), 128 (1),

117 (4), 115 (2), 104 (1), 102 (1), 91 (2), 90 (29), 82 (1),

81 (4), 76 (1), 66 (2), 57 (12); IR (neat): ν = 3057 (w), 2934

(m), 2854 (w), 1796 (s, C=O), 1733 (m), 1599 (w), 1582 (w),

1496 (w), 1452 (m), 1446 (m), 1369 (w), 1294 (m), 1165 (m),

1048 (vs), 1027 (vs), 1012 (vs), 940 (s), 940 (m), 931 (m),

839 (m), 762 (w), 721 (s), 693 (s), 635 (m) cm-1. HR-MS (EI):

calcd for C17H24O2 260.1776 [M+], found 260.1788; HR-LC-ESI-MS:

RT 0.79-1.74, calcd. for C34H48O4 520.3553 [M+M+], found

520.3812, calcd. for C51H74O7 798.5429 [2M+M+], found 798.4731.

(S)-tert-Butyl-benzylpyrrolidine-1,2-dicarboxylate (16). The

reaction was carried out on a 5 mmol scale of 15 according to

procedure (b), except for the additional use of 2 ml dry DCM.

The reaction was stirred for 5 h, diluted with 10 ml DCM,

transferred into a separatory funnel, washed with 10 ml 2N HCl

and 10 ml sat. aqueous NaHCO3 solution. The organic phase was

dried over MgSO4 and the solvent distilled off via rotary

evaporation. The crude product was purified by flash

chromatography on silica gel (3/10, EtOAc/isohexane) to afford

9

1.29 g (4.22 mmol, 85%) of a white solid. Rf = 0.53 (3/10,

EtOAc/isohexane). 23Dα = -52.7° (20 mg/ml, EtOH).

1H NMR (400 MHz, CDCl3): δ = 1.35 - 1.45 (two s, 9H, -C(CH3)3),

1.91-2.24 (m, 4H, CH2-CH2), 3.55 (m, 2H, N-CH2), 4.22 (m, 1H, N-

CH), 5.12 (m, 2H, PhCH2), 7.35 (m, 5H, CH(Ar)) ppm; IR (neat):

ν = 2976 (w), 2877 (w), 1729 (s), 1696 (vs, C=O), 1482 (w),

1456 (w), 1414 (m), 1356 (m), 1343(s), 1310 (m), 1279 (m),

1243 (w), 1223 (m), 1172 (m), 1153 (s), 1117 (s), 1026 (w),

986 (w), 965 (w), 944 (w), 919 (w), 848 (s), 771 (s), 750 (s),

694 (s), 618 (w), 607 (w) cm-1. 1H NMR spectral data[28] and

optical rotation data[25] compare favorably with those reported

earlier.

(S)-Di-tert-butylpyrrolidine-1,2-dicarboxylate (14). The

reaction was carried out as described in general procedure (b)

with 5 mmol (S)-1-((tert-butoxy)carbonyl)pyrrolidine-2-

carboxylic acid (13). The reaction was stirred for 2 h, then

diluted with 10 ml DCM and transferred into a separatory

funnel. The organic layer was washed with 10 ml 2N HCl and 10

ml aqueous NaHCO3 solution. The organic phase was dried over

MgSO4, filtered and the organic solvent distilled off. The

crude product obtained was purified on silica gel (10% EtOAc

in isohexane) to afford 1.18 g (93%) of a clear oil. Rƒ =

0.56 (10% EtOAc in isohexane, staining with Dragendorff-

Munier). 23Dα = -50.8° (10 mg/ml, CHCl3).

10

1H NMR (300 MHz, CDCl3):[31] δ = 1.35, 1.38 (three s, 18H, -

C(CH3)3), 1.81 (m, 4H, CH2-CH2), 3.55 (m, 2H, N-CH2), 4.22 (m,

1H, N-CH). 13C NMR (75 MHz, CDCl3): δ = 23.5, 24.3 (C-4), 28.1,

28.6 (-C(CH3)3), 31.0 (C-3), 46.4, 46.6 (C-5), 59.8 (C-2),

79.5, 79.7, 80.9 (Cq, -C(CH3)), 154.1, 154.5 (Cq, N-COOtBu),

172.4, 172.7 (Cq, -COOtBu). IR (NaCl): ν = 3679 (w), 3370 (w),

2977 (vs), 2881 (vs) 2455 (w), 1742 (vs, C=O), 1702 (vs), 1543

(sh), 1478 (s), 1455 (s), 1394 (s), 1291 (s), 1222 (s), 1152

(s), 1088 (s), 1031 (w), 980 (m), 943 (s), 919 (m), 854 (m),

840 (s), 758 (s), 666 (s) cm-1. GC-MS (EI): RT 7.71-8.68 min,

m/z (%), 272.4 (1), 271.3 (4), 215.2 (2), 171.2 (5),

170.2 (64), 160.2 (2), 143.2 (1), 142.2 (21), 115.1 (10),

114.1 (67), 71.1 (6), 70.1 (87), 58.1 (5), 57.1 (100),

56.1 (9), 55.0 (4), 44.0 (7), 43.0 (5), 42.0 (6), 40.9 (42).

HRMS(EI): calcd. for C14H25NO4 [M+] 271.1784, found 271.1793. The

measured 1H und 13C NMR spectra as well as the optical rotation

are in agreement with published data.[30]

(S)-tert-Butylbenzyl-pyrrolidine-1,2-dicarboxylate (19),

Procedure A: A 25 ml two necked flask with stop cock was

charged with 1.076 g (5 mmol) ( S ) - 1 - ( ( t e r t -

butoxy)carbonyl)pyrrolidine-2-carboxylic acid (13), 1.39 ml

(10 mmol) NEt3, 0.57 ml (5.5 mmol) benzyl alcohol (21), and

0.05 eq. (0.25 mmol, 20 µl) dry pyridine (7). The reaction

solution was cooled to -20 °C and 1.39 ml (6.5 mmol) molten

Boc2O added via syringe. After stirring for 2 min at this

11

temperature the cooling bath was removed and the flask was

allowed to warm to room temperature. Stirring was continued

for 4 h and the reaction solution then diluted with 10 ml DCM

and transferred to a separatory funnel. The organic phase was

washed with 10 ml 2N HCl and 10 ml aqueous NaHCO3 solution. The

organic phase was dried over MgSO4, filtered and the organic

solvent distilled off. The crude product was diluted with a

small amount of eluent (10% isohexane in EtOAc) and filtered

through a frit charged with silica gel. Washing was continued

with 30 ml of eluent. The collected eluate was distilled off

under reduced pressure to obtain 1.07 g (4.19 mmol, 84 %) of

19 as a clear oil.

(S)-tert-Butylbenzyl-pyrrolidine-1,2-dicarboxylate (19),

Procedure B: A 25 ml two necked flask with stop cock was

charged with 1.076 g (5 mmol) ( S ) - 1 - ( ( t e r t -

butoxy)carbonyl)pyrrolidine-2-carboxylic acid (13), 1.39 ml

(10 mmol) NEt3, 0.427 ml (5 mmol) 1,4-dioxane, and 6.10 mg

(0.05 eq.) DMAP. The reaction solution obtained was cooled to

-20 °C and 1.39 ml (6.5 mmol) molten Boc2O added via syringe.

The flask was allowed to warm to room temperature and then

immersed in an ethanol bath held at 23 oC. After 35 min

stirring at this temperature 0.57 ml (5.5 mmol) benzyl alcohol

(21) was added. Stirring was continued for 40 min and the

reaction then worked up as described in procedure A. After

chromatography on silica gel (20 % EtOAc in isohexane) 74 %

12

(1.13 g) of 19 as clear oil was obtained. Rƒ = 0.14 (20 % EtOAc

in isohexane). 23Dα = -44.8° (10 mg/ml, CHCl3).

1H NMR (300 MHz, CDCl3):[31] δ = 1.42-1.32 (three s, 9H, t-Bu),

2.21-1.82 (m, 4H, CH2-CH2), 3.48 (m, 2H, N-CH2-), 4.29 (m, 1H, -

O2C-CH-), 5.43 (m, 2-H, PhCH2-), 7.33 (m, 5H, CHAr). 13C NMR

(75 MHz, CDCl3): δ = 23.0 (m, t-Bu), 46.5 (CH2), 59.4 (CH),

66.2 (CH2) 68.9 (CH2), 82.4 (Cq), 128.5 (m, Ph-C), 136.1 (Cq,

Ph-C), 154.0 (m, Cq, C=O). HRMS(EI): calcd. for C17H23NO4 [M+]

305.1627, found 305.1645. The measured 1H NMR spectra as well

as the optical rotation are in agreement with published

data.[28]

Benzyl 2-fluorobenzoate (22). A 25 ml two necked flask with

stop cock was charged with 1.076 g (5 mmol) 2-flourobenzoic

acid (20), 1.39 ml (10 mmol) NEt3, 0.57 ml (5.5 mmol) benzyl

alcohol (21), and 0.05 eq. (0.25 mmol, 20 µl) dry pyridine (7).

The reaction solution obtained was cooled to -20 °C and 1.39 ml

(6.5 mmol) molten Boc2O added via syringe. After stirring for

2 min at this temperature the cooling bath was removed and the

flask was allowed to warm to room temperature. After stirring

for 3 h at this temperature the reaction mixture was diluted

with 10 ml DCM and worked-up as usual. Column chromatography

on silica gel yields 805 mg (70 %) ester as clear oil. Rƒ =

0.38 (10% EtOAc in Isohexan), 1H NMR (400 MHz, [D6]-Benzene):

δ = 5.11 (s, 2H, PhCH2-), 6.61 (m, 2H, H-3, H-4), 6.81 (m, 1H,

H-5), 6.99-7.20 (m, 5H, CHAr), 7.79 (m, 1H, H-6). 13C NMR

13

(100 MHz, [D6]-Benzene): δ = 66.7 (PhCH2), 116.7 (C-3),

123.8 (C-4), 127.6, 127.7, 127.8, 128.2 (m, Phenyl), 132.3 (C-

6), 134.2 (C-5), 160.8 (Cq, C-F), 163.8 (Cq, -COOCH2Ph). IR

(neat): ν = 3281 (w), 3034 (w), 1713 (s), 1642 (s), 1600 (w),

1520 (m), 1496 (m), 1452 (m), 1412 (w), 1375 (m), 1338 (s),

1294 (m), 1247 (vs), 1189 (m), 1175 (m), 1127 (w), 1072 (m),

1031 (w), 1017 (w), 934 (m), 897 (m), 881 (m), 832 (w),

770 (w), 753 (m), 711 (sh), 697 (vs), 653 (w) cm-1. MS

(DEP/EI): m/z (%) = 231.2 (2), 230.2 (M+,15), 208.2 (8),

153.1 (20), 152.1 (17), 151.1 (14), 146.2 (9), 141.1 (16),

123.1 (38), 108.1 (34), 107.1 (30), 95.1 (9), 92.1 (6),

91.1 (65), 90.1 (11), 79.1 (50), 77.1 (31), 75.0 (8),

65.0 (16), 57 (100), 56 (34), 51 (17), 44.0 (29), 41 (46).

HRMS (EI): calcd. for C14H11FO2 [M+] 230.0743, found 230.0732.

As byproducts a 1:2 mixture of the 2-flourobenzoic acid tert-

butyl ester and tert-butylbenzylcarbonate (25) in a total

amount of 600 mg was isolated, implying an additional yield of

20% of 2-fluorobenzoic acid tert-butylester. Rƒ = 0.63 (10%

EtOAc in isohexane).

Spectroscopic data of 2-fluorbenzoic acid tert-butylester: 1H

NMR (400 MHz, [D6]-Benzene): δ = 1.39 (s, 9H, t-Bu), 6.64 (m,

2H, H-3, H-4), 6.80 (m, 1H, H-5), 7.82 (m, 1H, H-6). 13C NMR

(100 MHz, [D6]-Benzene): δ = 27.9 (-C(CH3)3), 81.1 (Cq, -

C(CH3)3), 116.7 (C-3), 123.6 (C-4), 132.1 (C-6), 133.6 (C-5),

14

160.7 (Cq, C-F), 163.2 (Cq, -COOtBu). HRMS (EI): calcd. for

C11H13FO2 [M+] 196.0900, found 196.0881.

Spectroscopic data for tert-butylbenzylcarbonate (25): 1H NMR

(400 MHz, [D6]-Benzene): δ = 1.26 (s, 9H, -C(CH3)3), 4.90 (s,

2H, PhCH2-), 6.94-7.14 (m, 5H, CHAr). 13C NMR (100 MHz, [D6]-

Benzene): δ = 27.5 (-C(CH3)3), 68.4 (Ph-CH2), 81.9 (Cq, -

C(CH3)3), 127.6, 127.8, 128.2, 128.4 (Ph-C), 153.9 (Cq,

carbonate). HRMS (EI): calcd. for C12H16O3 [M+] 208.1099, found

208.1076.

3-Nitrobenzoic acid benzyl ester (24). A 25 ml two necked

flask with stop cock was charged with 1.076 g (5 mmol) 3-

nitrobenzoic acid (23), 1.39 ml (10 mmol) NEt3, 0.57 ml (5.5

mmol) benzyl alcohol (21) and 0.05 eq. (0.25 mmol, 20 µl) dry

pyridine (7). The reaction solution obtained was cooled to -20

°C and 1.39 ml (6.5 mmol) molten Boc2O added via syringe. After

stirring for 2 min at this temperature the cooling bath was

removed and the flask was allowed to warm to room temperature.

Stirring was continued at this temperature for 4 h and then

10 ml DCM added. After usual work-up the crude material was

purified with chromatography on silica gel (isohexane/EtOAc,

9/1) to afford 1.07 g (84%) of a white solid. Rƒ = 0.32

(isohexane/EtOAc, 9:1) 1H NMR (200 MHz, CDCl3): δ = 5.41 (s,

2H, PhCH2-), 7.35-7.45 (m, 5H, CHAr), 7.63 (t, 3J = 8 Hz, 1H, 5-

H), 8.37 (m, 2H, 4,6-H), 8.87 (s, 1H, 2-H). 13C NMR (75 MHz,

CDCl3): δ = 67.8 (CH2), 124.8 (C-2), 127.7 (C-4), 128.7-

15

128.9 (m, Ph-C), 129.9 (m, Ph-C), 132.1 (Cq), 148.5 (m, Cq),

164.5 (C=O). HRMS (EI): calcd. for C14H11NO4 [M+] 257.0688, found

257.0690.

15

Adamantane carboxylic acid anhydride (27):

O

O

O

The reaction was carried out as described in the general

procedure (b) with 5 mmol adamantane carboxylic acid. After

stirring for 12 h at room temperature the reaction was worked-

up as usual and submitted to coloum chromatography on silica

gel (20% EtOAc/isohexane) to afford 1.28 g (50%) of 27 as a

white powder. In a different fraction di(tert-butyl)carbonate

could be collected.

Spectroscopical data of adamantane carboxylic acid anhydride

(27): 1H NMR (200 MHz, CDCl3): δ = 1.74 (m, 12H), 1.91 (m,

12H), 5.68 (m, 6H). IR (neat): ν = 2904 (m), 2852 (w),

1802 (m), 1734 (s), 1452 (w), 1368 (m), 1289 (m), 1255 (m),

1139 (s), 992 (s), 969 (s), 934 (m), 844 (m), 732 (w).

1H NMR and IR data is consistent with the published data.(1)

Spectroscopical data of di(tert-butyl)carbonat (28)

1H NMR (300 MHz, CDCl3): δ = 1.42 (s, 18H), 13C NMR (75 MHz,

CDCl3): δ = 28.4 (CH3), 86.5 (Cq, C(CH3)), 55.5 (C=O).

(1) D. Plusquellec, F. Roulleau, M. Lefeuvre, E. Brown, Tetrahedron, 1988, 44, 2471.

16

Proton assignment

Assignment of the 1H NMR signals to all appearing compounds of

the esterification of isobutyric acid (2) with tBuOH to the

corresponding tert-butyl ester 4 (compare scheme 2 in the main

manuscript).

The spectrum was recorded after 2 h and 33 min reaction time

on a Varian 400 MHz NMR in CDCl3 at 20 °C. The arrows denoting

the assigned protons to the corresponding NMR signal. Please

note that proton signals can alter with the concentration,

temperature, solvent and pressure. Especially acidic protons

which can exchange with the solvent easly.(2)

(2) a) R. K. Harris, E. D. Becker, S. M. Cabral de Menezes, R. Goodfellow, P. Granger, Pure Appl. Chem. 2001, 73, 1795. b) T. D. Ferris, M. D. Zeidler, T. C. Farrar, Molecular Physics, 2000, 98, 737. c) D. F Ewing, Organic Magnetic Resonance, 1973, 5, 321.

O

O O

O

O O

O

O

O O

O

O

O

O

O

O

O O

OO

OH

OH

O

OO

3 6

1

28

4

3

5 6

4

17

Evidence for the formation of mixed and symmetrical anhydride.

The following figure shows three 1H NMR (400 MHz, CDCl3)

spectra recorded at specified reaction times for the

conversion of isobutyric acid (2) to corresponding tert-butyl

ester 4 in the presents of 1.3 eq. Boc2O (1), 1 eq. 1,4-

dioxane, 1.1 eq. tBuOH (3) and 0.05 eq. DMAP (8). The septet

region in all spectra was expanded. The singulet in the

spectra recorded at 3 min was expanded too.

The singlet in the enlarged spectra at the bottom belongs most

likely to the mixed anhydride 6.

2 5 and 6

5 and 6

6

3 min

15 min

28 min 5 and 6 6

6

1

1

1

18

The appearance of two septet signals (δ = 2.59 ppm) plus the

singlet signal (δ = 1.48 ppm) are a proof for a mixed and

symmetrical anhydride formation as a reaction intermediate.

19

Conversion tables

Table S2. Conversion of isobutyric acid (2), mixed and

symmetrical anhydride (5, 6) and isobutyric acid tert-butyl

ester (4).

time / min conv. / % (2) conv. / % (5, 6) conv. / % (4) 0 100 0 0 3 52 48 0 15 9 88 0 28 0 96 4 41 83 16 54 72 27 69 69 41 84 51 49 98 27 62 115 22 69 129 20 81 141 11 89 154 8 92 159 2 98

Table S3. Conversion of isobutyric acid tert-butyl ester (4)

in the presents of 10 mol% catalyst without triethyl amine.

time / h

conv. / % with

DMAP (8)

conv. / % with

PPY (9) conv. / % with 10

conv. / % with 11

0 0 0 0 0 15 7.6 11.1 30 35 35.7 49.76 81.9 40 99.9 45 91.3 50 100 60 74.7 92.4 98 90 91.8 96.3 120 96.2 96 150 100 180 99.4 100.4

20

Table S4. Conversion of isobutyric tert-butyl ester (4) in the

presence of 0.05 eq. catalyst with triethyl amine.

time / h

conv. / % with

DMAP (8)

conv. / % with

PPY (9) conv. / % with 11

conv. / % with 12

0 0 0 0 1 7 6 21 8 5.7 10 18 13 38 14 20 16 20.8 17 43 18 20 27 23 34.9 24 29.3 58 29 47.6 34 70 35 38.6 36 38 37 65.1 38 43 85 45 77.9 48 50.6 51 93 52 92 56 57 58 99.5 59 96.1 60 58.6 76 72 78 72 92 78.6 95 82 104 84 110 92 122 94.6 128 100.5 134 100

21

X-ray crystal structure of catalyst 11 and its precursor.

During the synthesis of catalysts 11 and its precoursor for

this study we were able to obtain crystals suitable for X-ray

crystallography. The crystals could be obtained from

recrystallization in diethyl ether.

Precursor of 11:

CCDC 636918

Catalysts 11:

CCDC 641485

22

References and Notes

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23

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24

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25

range from RT to 70 oC (sealed NMR tube experiment).