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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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24
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25
range from RT to 70 oC (sealed NMR tube experiment).
Recommended