Supporting Information

Home , Isobutyric acid

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: [email protected]

O O O H O O O O O O O O 6 O 2 1 + O + O O cat., dioxane 4 OH O 23 oC 3 5

N N N N N N N cat.: N N N N N N 7 8 9 10 11 12

Scheme S1 2

OH O N N O O O O O O

13 14

OH OH O N 3 N O O O O O O 1.3 eq. Boc2O Ph 0.05 eq. cat. Ph 15 1 eq. 1,4-dioxane 16

O OH O O Ph 17 Ph 18

Scheme S2

O OH O N N O O O O + O O O O 25 19

13 OH O 21 + O O HO O 1.3 eq. Boc2O 25 O F 0.05 eq. cat. O F 22 20 1 eq. 1,4-dioxane

O O + HO O NO2 NO2 25 O O 23 24

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.

(I Ester 9) Conv. = *100% (1) (I dioxane 8)

      1 Conv. = t   + c (2) a  c     (−t − t0 )  1+ exp        k   6

Conv. = Aexp(−(t − t0 )k) + c (3)

d −1   (t t )   (t t )      − 0   − 0    Conv. = ta exp − ⋅ + d −1 (d −1) + const. (4)          k   k   

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 δ iPr δ iPr other (9H, s) (6H, s) (1H, sep) 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

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

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

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

t 35.0 (CH(CH3)2), 79.7 (C(CH3)3), 176.7 (-COO Bu) 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

1 solid. Rf = 0.65 (10% EtOAc/isohexane), H 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,

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

1 H 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-

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

1 [31] H NMR (300 MHz, CDCl3): 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,

13 1H, N-CH). C 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),

t 79.5, 79.7, 80.9 (Cq, -C(CH3)), 154.1, 154.5 (Cq, N-COO Bu),

t 172.4, 172.7 (Cq, -COO Bu). 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-((tert- 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-((tert- 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

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

1 [31] H NMR (300 MHz, CDCl3): 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, -

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

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

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

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

(100 MHz, [D6]-Benzene): δ = 66.7 (PhCH 2), 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

t 160.7 (Cq, C-F), 163.2 (Cq, -COO Bu). 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,

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

Benzene): δ = 27.5 (-C(CH 3)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. R ƒ = 0.32

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

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

1 (27): H 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)

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

O 4 O OH

3 O O O O O O O 5 6 O O O O O O O 4 1 O

O O O O OH O O 28 3 6

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. 17

Evidence for the formation of mixed and symmetrical anhydride.

1 The following figure shows three H 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.

28 min 5 and 6 1 6

5 and 6 1 15 min

1 5 and 6 2 3 min

The singlet in the enlarged spectra at the bottom belongs most likely to the mixed anhydride 6. 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.

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.

conv. / % conv. / % with with conv. / % conv. / % time / h DMAP (8) PPY (9) with 10 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

Table S4. Conversion of isobutyric tert-butyl ester (4) in the presence of 0.05 eq. catalyst with triethyl amine.

conv. / % conv. / % with with conv. / % conv. / % time / h DMAP (8) PPY (9) with 11 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

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

References and Notes

[1] J. Otera, Esterification: Methods, Reactions and

Applications, Wiley-VCH, Weinheim, 2003.

[2] K. Takeda, A. Akiyama, H. Nakamura, S. Takizawa, Y.

Mizuno, H. Takayanagi, Y. Harigaya, Synthesis 1994, 1063.

[3] L. J. Gooßen, A. Döhring, Adv. Synth. Catal. 2003, 345,

943.

[4] L. J. Gooßen, A. Döhring, Synlett 2004, 2, 263.

[5] D. K. Mohaptra, A. Datta, J. Org. Chem. 1999, 64, 6879-

6880.

[6] a) V. F. Podnez, Tetrahedron Lett. 1995, 36, 7115-7118. b)

V. F. Podnez, Int. J. Peptide Protein Res. 1992, 40, 407-414. c) V. F. Podnez, Int. J. Peptide Protein Res. 1994, 44, 36-48.

[7] M. R. Heinrich, H. S. Klisa, H. Mayr, W. Steglich, H.

Zipse, Angew. Chem. 2003, 115, 4975; Angew. Chem. Int. Ed.

2003, 42, 4826.

[8] I. Held, A. Villinger, H. Zipse, Synthesis 2005, 1425.

[9] I.Held, S. Xu, H. Zipse, Synthesis 2007, 1185.

[10] (a) S. Singh, G. Das, O. V. Singh, H. Han, Org. Lett.

2007, 9, 401. (b) Tetrahedron Lett. 2007, 48, 1983.

[11] S. Xu, I. Held, B. Kempf, H. Mayr, W. Steglich, H. Zipse,

Chem. Eur. J. 2005, 11, 4751.

[12] C. B. Fischer, S. Xu, H. Zipse, Chem. Eur. J. 2006, 12,

5779.

[13] F. M. F. Chen, N. L. Benoiton, Can. J. Chem. 1987, 65,

619-625.

[14] (a) S. A. Sikchi, P. G. Hultin, J. Org. Chem. 2006, 71, 23

5888. (b) R. Varala, S. Nuvala, S. R. Adapa, J. Org. Chem.

2006, 71, 8283. (c) X. Jia, Q. Huang, J. Li, S. Li, Q. Yang,

Synlett 2007, 806.

[15] L. F. Tietze, U. Beifuss, Angew. Chem. Int. Ed. 1993, 32,

131; Angew. Chem. 1993, 105, 137.

[16] L. F. Tietze, Chem. Rev. 1996, 96, 115.

[17] A. Bruggink, R. Schoevaart, T. Kieboom, Org. Proc. Res.

Dev. 2003, 7, 622.

[18] D. E. Fogg, E. N. dos Santos, Coord. Chem. Rev. 2004,

248, 2365.

[19] J.-C. Wasilke, S. J. Obrey, R. T. Baker, G. C. Bazan,

Chem. Rev. 2005, 105, 1001.

[20] C. J. Chapman, C. G. Frost, Synthesis 2007, 1.

[21] A. G. Baboul, L. A. Curtiss, P. C. Redfern, K.

Raghavachari, J. Chem. Phys. 1999, 110, 7650.

[22] Gaussian 03, Revision C.02, M. J. Frisch, G. W. Trucks,

H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman,

J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C. Burant,

J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B.

Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H.

Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J.

Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H.

Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B.

Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.

Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J.

W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P.

Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. 24

D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D.

Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui,

A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G.

Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D.

J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara,

M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W.

Wong, C. Gonzalez, and J. A. Pople, Gaussian, Inc.,

Wallingford CT, 2004.

[23] F. Brotzel, B. Kempf, T. Singer, H. Zipse, H. Mayr, Chem.

Eur. J. 2007, 13, 336 - 345.

[24] P. Chevallet, P. Garrouste, B. Malawska and J. Martinez,

Tet. Lett. 1993, 34, 7409.

[25] G. W. Anderson, F. M. Callahan, J. Am. Chem. Soc. 1960,

82, 3359.

[26] B. Neises, W. Steglich, Angew. Chem. Int. Ed. Engl. 1978,

17, 522; Angew. Chem. 1978, 90, 556.

[27] G. Höfle, W. Steglich, H. Vorbrüggen, Angew. Chem. 1978,

90, 602; Angew. Chem. Int. Ed. Engl. 1978, 17, 569.

[28] A. M. M. Marquet, M. A. Gaudry, S. Boru, FR 2585354 A1,

1987.

[29] F. Orsini, F. Pelizzoni, G. Ricca, Tetrahedron, 1984, 40,

2781.

[30] P. Barraclough, P. Dietrich, C. A. Spray, D. W. Young,

Org. Biomol. Chem. 2006, 4, 1483.

[31] Proline esters exist in several slowly interconverting, but distinc conformers at room temperature. This was verified

1 by taking a series of H NMR spectra in C6D6 in a temperature 25 range from RT to 70 oC (sealed NMR tube experiment).