A convenient dehydration procedure for the synthesis of enantiomerically pure cyanohydrins

Article abstract of DOI:10.1055/s-2000-6403

Starting from protected α-hydroxy amides; cyanohydrins (α-hydroxy nitriles) are obtained through dehydration by cyanuric chloride/DMF in excellent yield. The advantages of the procedure are the extremely mild reaction conditions that prevent racemization.

Full text of DOI:10.1055/s-2000-6403

PAPER
731
A Convenient Dehydration Procedure for the Synthesis of Enantiomerically
Pure Cyanohydrins
Fabrice Aquino,a Horst Pauling,a Willy Walther,b Dietmar A. Plattner,c Werner Bonrath*a
a Vitamins and Fine Chemical Division, Chemical Process Technology, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland
Fax +41(61)6885511; E-mail Werner.Bonrath@Roche.com
b Department of Chemical Technologies (PRPC), F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland
c Laboratorium für Organische Chemie der Eidgenössischen Technischen Hochschule (ETH) Zürich, Universitätstrasse 16, ETH-Zentrum,
CH-8092 Zürich
Fax +41(1)6321280; E-mail: plattner@org.chem.ethz.ch
Received 12 December 1999; revised 21 January 2000
Dedicated to Professor Günther Wilke on the occasion of his 75th birthday
there exists a vast experience with enantiomerically en-
Abstract: Starting from protected a-hydroxy amides, cyanohydrins
riched cyanohydrines concerning synthesis and analytics,
and on the other hand the hydroxy amide precursors are
(a-hydroxy nitriles) are obtained through dehydration by cyanuric
chloride/DMF in excellent yield. The advantages of the procedure
readily available as starting materials. In our model study,
the enantiopure a-hydroxy amide was obtained by ami-
nolysis of D- and L- pantolactone (1), respectively
(Scheme 1). The hydroxy groups were protected with iso-
propenyl methyl ether (IPM).12 Standard procedures for
the introduction of a protecting group for the hydroxy
functionalities did not yield satisfactory results. Protec-
tion with acetone/p-TsOH gave only a yield of 35% of the
dioxane 3, while the alternative acetone/orthoester proce-
dure led to only a slight increase of product yield (55%).
are the extremely mild reaction conditions that prevent racemiza-
tion.
Key words: dehydration, cyanuric chloride/DMF adduct, cyanohy-
drins
Cyanohydrins (a-hydroxy nitriles) are commonly synthe-
sized by the addition of hydrocyanic acid to an aldehyde,
as described in several standard textbooks of organic
chemistry.1 Naturally, this method yields racemic mix-
tures of a-hydroxy nitriles. Starting from an aldehyde,
enantiomerically pure a-hydroxynitriles can be obtained
using an enzyme (oxynitrilase)2,3 or by the chiral Lewis
acid-catalyzed addition of hydrocyanic acid (or cyanotri-
methylsilane) (M = Ti,4 B,5 Sn,6 Re7). Cyanohydrins are
of particular interest as intermediates since they can readi-
ly be converted into a variety of valuable starting materi-
als for synthesis (b-amino alcohols, a-hydroxy ketones, a-
hydroxy carboxylic acids).
NH3
-60 °C, r.t., 6 h
OH
NH2
O
HO
HO
95%
O
O
1
2
IPM
CH2Cl2
p-TsOH, r.t.
97%
An alternative method to prepare a-hydroxy nitriles is the
dehydration of a-hydroxy amides. We became interested
in alternative dehydration methods since all the estab-
lished procedures give rise to insurmountable problems
when conducted on an industrial scale, e.g. expensive re-
agents, large excess of the cyano component, painstaking
workup, toxic solvents, waste problems, etc. The mixture
cyanuric chloride/DMF was introduced by Olah and co-
workers for the dehydration of aliphatic and aromatic
amides to the corresponding nitriles.8 The potential of this
method has so far not been exploited with the notable ex-
ception of the synthesis of heterocyclic carbonitriles.9,10
At around the same time, Rodrigues and Maetz described
the preparation of N-protected chiral a-amino nitriles
from N-protected a-amino acid amides using cyanuric
chloride/DMF.11
MTBE
DMF/CyCl
1 h, r.t.
MeOH
H+
OH
O
O
O
O
O
95%
90-95%
HO
CN
CN
NH2
5
4
3
Scheme 1
The crucial step, the dehydration of the 1,3-dioxane-4-
carboxamide 3 to the nitrile 4, could be conducted in ex-
cellent yields by means of the reaction conditions outlined
in Scheme 1. Standard acid-catalyzed deprotection gives
the desired cyanohydrin 5. The key question was whether
or not the DMF/cyanuric chloride dehydration would give
rise to racemization. In order to determine the enantiomer-
ic ratios it was necessary to separate samples of racemic
3, 4, and 5 which were obtained by conducting the reac-
tion sequence starting from D,L-pantolactone (1). The
Based on our experience with the synthesis of heterocy-
clic amides we decided to extend our methodology to the
dehydration of functionalized amides. We chose cyanohy-
drins as target molecules for two reasons: on the one hand,
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732
F. Aquino et al.
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enantiomeric purity of the intermediates 3 and 4 as well as proved by GC and 1H NMR, this decrease in optical rota-
of the cyanohydrin 5 was determined by gas chromatogra- tion is accompanied by the formation of the ammonium
phy on a chiral column. In all cases, complete base line salt 6, which has the opposite sign of rotation,13 i.e., while
separation was achieved, and the detection limit for one (S )-2 has an [a]D20 of +47.7, the [a]D20 of (S)-6 has a value
enantiomer under these conditions was estimated to be of -10.13. It has been confirmed that under these condi-
< 0.05% (Figure 1).
tions no racemization of (R)-1 or (S)-1 takes place.
Finally, an alternative protection scheme for the dehydra-
tion was worked out. All reactions so far had employed a
protecting group covering both hydroxy functionalities.
We were interested in the influence of the secondary hy-
droxy group on the dehydration reaction. As shown in
Scheme 2, we succeeded in selectively protecting the pri-
mary hydroxy group using a standard Ph3CCl procedure.
As in the case of the dioxane protection scheme, the dehy-
dration is accomplished in excellent yields at ambient
conditions. In contrast to compound 4, however, the
monoprotected cyanohydrin 8 decomposes in the course
of a few days, thus rendering the isolation of the pure
compound very difficult.
Surprisingly, we found that the melting points of (R,S)-2
and (R,S)-3 were considerably higher than those of their
enantionmerically pure counterparts (R)-2, (S)-2 and (R)-
3, (S)-3, respectively. This intriguing behavior prompted
us to have a look at the solid state structures of the chiral
intermediates. We succeeded in growing crystals suitable
for single crystal X-ray diffraction in the case of (R,S)-2,
(R)-3, and (R,S)-3. The conformation of (R)-2 and (R)-3 in
the solid state structures of (R,S)-2 and (R)-3 are shown in
Figures 3 and 4, respectively. All bond lengths and angles
are in the range predicted by crystal chemistry. The amide
moiety in (R)-2 is perfectly planar, with the sum of angles
around the sp2 C-atom exactly 360°. The six-membered
ring in (R)-3 shows an almost ideal chair-like conforma-
tion (Cremer-Pople parameters14 Q = 0.554, q = 5.5°,
Figure 1 Gas chromatogram of (R,S)-5 (chiral stationary phase) af-
ter derivatization to the acetate. The GC conditions are described in
the experimental part.
Under the reaction conditions for the dehydration reaction
of 3, the unprotected hydroxy amide 2 is not dehydrated,
but the starting material is recovered in 94% yield.
The stability of 2 with regard to racemization was tested
in various solvents and at two different temperatures. In
polar organic solvents such as 1,4-dioxane, ethyl acetate,
and ethanol, the optical rotation of (R)- and (S)-2 re-
mained constant over 2 days. In water, however, the opti-
cal rotation decreased continuously (see Figure 2). As
Figure 2 Conversion of (S)-2 to (S)-6 in water at r.t. and 45°C.
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A Convenient Dehydration Procedure for the Synthesis of Enantiomerically Pure Cyanohydrins
733
OH
OH
Ph3CCl
NH2
Ph3C
NH2
HO
O
92%
O
O
2
7
DMF, CyCl
MTBE, r.t.
95%
OH
Ph3C
O
CN
8
Scheme 2
j = 226.5°) with the carboxamide substituent in the equa-
torial position. The sum of angles around the sp2 C-atom
is also 360°. The conformation of (R)-3 is very similar in
both the solid-state structures of (R)-3 and (R,S)-3; the
mean deviation in the six-membered ring is only 0.01 Å,
the maximum deviation between the two amide O-atoms
is 0.37 Å.
Figure 4 Ortep plot of the structure of (R)-3 in the solid state.
enylmethyl ether, DMF, tert-butyl methyl ether, Et3N, triphenyl-
chloromethane (Fluka), ammonia (Carbagas), hexane, and p-TsOH
(Merck) were purchased from the respective companies and used
without further purification.
1H NMR spectra (d, in ppm; J, in Hz; relative to internal TMS in
CDCl3 and DMSO-d6 respectively, at 20 °C) were recorded on a
Bruker AC 250-E spectrometer. The mass spectra were meassured
on a SSQ 7000 mass spectrometer (Finnigan-MAT, Bremen), ion-
ization energy 70 eV, ion source temperature 240 °C, sample intro-
duction directly into the ion source. The mass spectra of compounds
6, 7, and 8 were recorded on a Perkin Elmer Sciex API 300 mass
spectrometer using a pneumatic-assisted electrospray source (flow
injector of 3 mL of an approximately 10 mM/L solution of the sam-
ple, flow rate 20 mL/min). The sample was dissolved in a mixture of
MeCN and H2O (containing 10 mM/L of NH4OAc). Melting points
(mp) were observed under a microscope using a Büchi/Tottoli in-
strument and are not corrected. Boiling points were observed by the
method of Siwoloboff. Capillary gas chromatography was per-
formed with a Hewlett-Packard gas chromatograph HP5890 Series
II equipped with FI-Detector and an Autosampler 7673 A. Peak in-
tegration was done with a Perkin Elmer-Nelson Turbochrom Work-
station, Version 6.0.2. The chiral column used was a 15 m fused
silica column, coated with 25% heptakis(2,3-di-O-methyl-6-O-tert-
butyldimethylsilyl)-b-cyclodextrin in polysiloxanes. Column tem-
perature: 100 °C to 200 °C, programmed at a rate of 2°C/min. Injec-
tor port temperature: 210 °C and detection temperature: 250 °C. The
carrier gas used was H2 at 80 kPa. All samples (3 mg) were reacted
with Ac2O in pyridine to the corresponding acetates and injected at
a split ratio of approximately 1:40. As depicted in Figure 1, baseline
separation was obtained and the detection limit under these condi-
tions for one enantiomer is <0.05%.
Figure 3 Ortep plot of the structure of (R)-2 in the solid phase of
(R,S)-2.
The difference in the melting points of (R)-3 and (R,S)-3
is due to the different intermolecular interactions in their
solid-state structures. In the case of (R)-3, the only signif-
icant interaction between the 1,3-dioxane-4-carboxam-
ides is a rather long hydrogen bond between NH and a
dioxane O-atom (2.16 Å). In the solid state structure of the
racemate, however, the (R)-molecule forms a hydrogen-
bonded dimer with its symmetry-related enantiomer (Fig-
ure 5). The stronger intermolecular interaction is probably
responsible for the significantly higher melting point of
the racemate. In the solid-state structure of (R,S)-2, a quite
elaborate hydrogen-bonded supermolecular network is
formed by intermolecular interactions between the two
hydroxy and the carboxamide moieties (Figure 6).
The purity of the compounds 6 and 7 was confirmed by SFC on an
achiral column (10 m, SB-biphenyl-30, diameter 50 mm, pressure
80-400 atm with a pressure program of 8 atm/min, detector 350 °C,
oven temperature 100 °C).
The enantiomeric separation of 6 and 7 was carried out with a micro
HPLC on a Phoenix 20CU pump, equipped with a chiral 15 cm col-
umn (chiral-OD H, 15 m), mobile phase 95% hexane/5% i-PrOH,
flow 4 mL/min, pressure 1.5 mpa, 30 °C, detector UV 215 nm.
The X-ray crystallographic data of compounds (R,S)-2, (R,S)-3, and
(R )-3 were deposited at the Cambridge Crystallographic Data Cen-
tre (CCDC).
The starting materials (lactones) were Roche material, the solvents
and reagents acetone, cyanuric chloride, CH2Cl2, Et2O, isoprop-
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F. Aquino et al.
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Figure 5 Crystal packing of (R,S)-3, showing the presence of hydrogen-bonded dimers.
Figure 6 Crystal packing of (R,S)-2, showing the presence of a hydrogen bond network.
(R,S)-2,4-Dihydroxy-3,3-dimethylbutyramide [(R,S)-2]; Typi-
cal Procedure
Anal. (C6H13NO3): calcd: C, 48.97; H, 8.90; N, 9.52. Found C,
48.95; H, 8.92; N, 9.50.
D,L-Pantolactone [(R,S)-1; 36.02 g, 277 mmol] was added to liquid
ammonia (350 mL) at -60 °C. After 1 h the suspension turned into
a clear colorless solution and was then warmed up to r.t. The excess
ammonia was evaporated and the resulting colorless solid dried in
vacuo; yield: 40.8 g (~100%); mp 128-129.8 °C.
(R)-2,4-Dihydroxy-3,3-dimethylbutyramide [(R)-2]
D-Pantolactone [(R )-1; 48.00g, 370 mmol] was added to liquid am-
monia (350 mL) at -60 °C and the reaction was carried out as de-
scribed above; yield: 51.44 g (91%); colorless solid; mp 94.4-
95.2 °C; [a]D20 49.07.
IR (nujol): n = 3415, 3309, 2955, 2872, 2854, 1677, 1481, 1458,
Anal. (C6H13NO3): calcd: C, 48.97; H, 8.90; N, 9.52. Found C,
48.84; H, 8.79; N, 9.57.
1297, 1277, 1078, 1055, 987, 911, 767, 704 cm-1.
1H NMR (DMSO-d6): d = 0.81 (s, 3 H, CH3), 0.82 (s, 3 H, CH3),
3.18 (dd, 1 H, JHH = 4.5 Hz, OCH2), 3.31 (dd, 1 H, JHH = 4.7 Hz,
OCH2), 3.66 (d, 1 H, JHH = 5.7 Hz, CHOH), 4.49 (dd, 1 H, J = 4.7
Hz, J = 4.5 Hz, OH), 5.23 (d, 1 H, J = 5.7 Hz, OH), 7.12 (s, 2 H,
CONH2).
(S)-2,4-Dihydroxy-3,3-dimethylbutyramide [(S)-2]
L-pantolactone [(S )-1; 35.96 g, 276 mmol] was added to liquid am-
monia (350 mL) at -60 °C and the reaction was carried out as de-
scribed above; yield: 37.15 g (91%); colorless solid; mp 93.8-
95.0 °C; [a]D20 -47.7.
MS (70 eV): m/z (%) = 148 (4, M - H+) 103 (40), 99 (32), 75 (100).
Synthesis 2000, No. 5, 731–737 ISSN 0039-7881 © Thieme Stuttgart · New York

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A Convenient Dehydration Procedure for the Synthesis of Enantiomerically Pure Cyanohydrins
735
Anal. (C6H13NO3): calcd: C, 48.97; H, 8.90; N, 9.52. Found C,
48.89; H, 9.00; N, 9.35.
(R)-2,2,5,5-Tetramethyl-1,3-dioxane-4-carbonitrile [(R)-4]
A solution of cyanuric chloride (5.57 g, 30.2 mmol) in tert-butyl
methyl ether (110 mL) was added to a solution of (R)-3 (12.6 g,
60.5 mmol) in DMF (25 mL) and the reaction was carried out as de-
scribed above; yield: 10.31 g (91%); colorless liquid; mp -45.7 °C;
bp 148.4 °C/760 Torr; [a]D20 -1.58.
(R,S)-2,2,5,5-Tetramethyl-1,3-dioxane-4-carboxamide [(R,S)-3]
To a suspension of (R,S)-2 (10.00 g, 67.9 mmol) in a mixture of
CH2Cl2 (150 mL) and acetone (150 mL) at 10 °C were added iso-
propenyl methyl ether (13.45 mL, 135.8 mmol) and a solution of
p-TsOH (0.38 g) in acetone (30 mL). The mixture was stirred at r.t.
for 1 h and, after filtration, neutralized with Et3N (~ 1 mL). The
clear yellow solution was dried (Na2SO4), filtered, and the solvent
removed on a rotary evaporator; yield: 12.4 g (98%); colorless sol-
id; mp 122.8-123.4 °C.
Anal. (C9H15NO2): calcd: C, 63.88; H, 8.93; N, 8.28. Found C,
63.96; H, 8.79; N, 8.16.
(S)-2,2,5,5-Tetramethyl-1,3-dioxane-4-carbonitrile [(S)-4]
A solution of cyanuric chloride (7.38 g, 40 mmol) in tert-butyl me-
thyl ether (150 mL) was added to a solution of (S)-3 (15.15 g,
80 mmol) in DMF (50 mL) and the reaction was carried out as de-
scribed above; yield: 12.73 g (94%); colorless liquid; mp -45.8 °C;
bp 148.9 °C/760 Torr; [a]D20 +1.80.
IR (nujol): n = 3483, 3362, 3300, 3246, 3148, 2987, 2961, 2855,
1687, 1649, 1584, 1458, 1382, 1359, 1325, 1292, 1224, 1122, 1041,
972, 867, 771 cm-1.
1H NMR (DMSO-d6): d = 0.92 (s, 3 H, CH3), 0.93 (s, 3 H, CH3),
1.36 (s, 3 H, CH3), 1.38 (s, 3 H, CH3), 3.18 (d, 1 H, JHH = 9.1 Hz,
CH2), 3.63 (d, 1 H, JHH = 9.1 Hz, CH2), 3.97 (s, 1 H, OCH), 6.63 (s,
1 H, CONH2), 7.20 (s, 1 H, CONH2).
Anal. (C9H15NO2): calcd: C, 63.88; H, 8.93; N, 8.28. Found C,
63.94; H, 8.96; N, 8.45.
(R,S)-2,4-Dihydroxy-3,3-dimethylbutyronitrile [(R,S)-5]
Compound (R,S)-4 (1.0 g, 5.9 mmol) was dissolved in MeOH
(20 mL) and hydrolyzed using Amberlite 15 (0.3 g). After 12 h, the
suspension was filtered over speedex, and the bulk of solvent re-
moved at reduced pressure (20 °C/20 mbar, 2 h). After flash-chro-
matography (silica gel 70-230 mesh, EtOAc) (R,S)-5 was obtained
as a colorless liquid; yield: 3.6 g (93%).
MS (70 eV): m/z (%) = 187 (2, M+), 172 (30), 143 (68), 85 (32), 59
(100).
Anal. (C9H17NO3): calcd: C, 57.73; H, 9.15; N, 7.48. Found C,
57.84; H, 8.91; N, 7.46.
(R)-2,2,5,5-Tetramethyl-1,3-dioxane-4-carboxamide [(R)-3]
To a suspension of (R)-2 (17.53 g, 100 mmol) in a mixture of
CH2Cl2 (150 mL) and acetone (150 mL) at 10 °C were added iso-
propenyl methyl ether (14.60 mL, 155.3 mmol) and a solution of
p-TsOH (0.38 g) in acetone (30 mL) and the reaction was carried
out as described above; yield: 18.80 g (96%); colorless solid; mp
92.7-94.1 °C; [a]D20 +56.36.
IR (KBr): n = 3397, 3242, 2965, 2935, 2904, 2879, 2243, 1474,
1466, 1397, 1371, 1331, 1076, 1043, 1025, 978, 967, 957, 946 911,
865 cm-1.
1H NMR (CDCl3): d = 1.08 (s, 3 H, CH3), 1.15 (s, 3 H, CH3), 2.27
(m, 1 H, OH), 3.85 (d, 1 H, JHH = 5.3 Hz, CH2), 3.54 (d, 1 H,
JHH = 5.3 Hz, CH2), 4.09 (n, 1 H, OH), 4.35 (s, 1 H, CNCH).
Anal. (C9H17NO3): calcd: C, 57.73; H, 9.15; N, 7.48. Found C,
57.74; H, 9.15; N, 7.33.
MS (70 eV): m/z (%) = 130 (2, M - H+) 103 (28), 81 (55), 73 (100),
57 (35), 55 (66), 31 (34).
(S)-2,2,5,5-Tetramethyl-1,3-dioxane-4-carboxamide [(S)-3]
To a suspension of (S)-2 (19.48 g, 132 mmol) in a mixture of
CH2Cl2 (150 mL) and acetone (150 mL) at 10°C were added isopro-
penyl methyl ether (18.75 mL; 189.2 mmol) and a solution of p-
TsOH (0.38 g) in acetone (30 mL) and the reaction was carried out
as described above; yield: 24.04 g (97%); colorless solid; mp 92-
95 °C; [a]D20 -55.73.
Anal. (C6H11NO2): calcd: C, 55.80; H, 8.58; N, 10.85. Found C,
53.79; H, 8.47; N, 9.48.
(R)-2,4-Dihydroxy-3,3-dimethylbutyronitrile [(R)-5]
A solution of (R )-4 (8.46 g, 50 mmol) in hexane (80 mL) was hy-
drolyzed by stirring with 37% HCl (0.15 mL). After 2 h distilled wa-
ter (30 mL) was added. The aqueous phase was extracted with Et2O
(60 mL). The bulk of Et2O was removed on a rotary evaporator at
40 °C/50 mbar. (R)-5 remained as colorless liquid in a yield of
6.23 g (97%). No meaningful values for optical rotation and ele-
mental analysis could be obtained due to rapid degradation of the
samples.
Anal. (C9H17NO3): calcd: C, 57.73; H, 9.15; N, 7.48. Found C,
57.12; H, 9.22; N, 7.50.
(R,S)-2,2,5,5-Tetramethyl-1,3-dioxane-4-carbonitrile [(R,S)-4]
A solution of cyanuric chloride (1.3 g, 10.9 mmol) in tert-butyl me-
thyl ether (23 mL) was added to a solution of (R,S)-3 (5.00 g,
27.00 mmol) in DMF (8 mL). The mixture was stirred at r.t. for 1
h, in the course of which the solution turned into a yellow suspen-
sion. The mixture was neutralized with aq 28% NaOH (6 mL). The
aqueous phase was extracted with tert-butyl methyl ether (2 × 20
mL). The combined organic phases were washed with distilled
water (12.5 mL), dried (Na2SO4), and filtered. The solvent was re-
moved on a rotary evaporator to give (R,S)-4 as a colorless liquid;
yield: 3.53 g (95%); mp -42.7 °C; bp 168.1°C/760 Torr.
(S)-2,4-Dihydroxy-3,3-dimethylbutyronitrile [(S)-5]
A solution of (S)-4 (2 g, 11.2 mmol) in hexane (20 mL) was hydro-
lyzed by stirring with 37% HCl (0.03 mL). After 2 h distilled water
(10 mL) was added. The aqueous phase was extracted with Et2O
(50 mL). The bulk of Et2O was removed on a rotary evaporator at
40 °C/50 mbar. (S)-5 remained as colorless liquid in a yield of 1.36
g (95%). No meaningful values for optical rotation and elemental
analysis could be obtained due to rapid degradation of the samples.
IR (KBr): n = 2996, 2967, 2876, 2250, 1736, 1470, 1396, 1380,
(S)-Ammonium Pantoate [(S)-6]
The stability measurements and conversion of 2 were carried out in
the following way:
1262, 1242, 1224, 1197, 1157, 1097, 1048, 934, 857 cm-1.
1H NMR (CDCl3): d = 0.98 (s, 3 H, CH3), 1.28 (s, 3 H, CH3), 1.43
(s, 3 H, CH3), 1.48 (s, 3 H, CH3), 3.48 (d, 1 H, JHH = 9.5 Hz, CH2),
3.63 (d, 1 H, JHH = 9.5 Hz, CH2), 4.47 (s, 1 H, CH).
MS (70 eV): m/z (%) = 170 (8, M-H+), 154 (85), 143 (10), 94 (38),
59 (92), 56 (50), 43 (100).
A solution of 2 (2 g, 13.6 mmol) in H2O (40 mL) was stirred at r.t.
or 45 °C. Samples for GC were taken every 30 min for 4 h, then ev-
ery 60 min for 4 h, and finally every 8 h, dried and silylated (BST-
FA) for GC measurements. After complete conversion the mixture
was concentrated (45 °C/20 mbar). The crude product was stirred
with Et2O (20 mL), filtered and dried (40 °C/10 mbar); yield: 1.8 g
(80%).
Anal. (C9H15NO2): calcd: C, 63.88; H, 8.93; N, 8.28. Found C,
63.60; H, 8.95; N 8.16.
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F. Aquino et al.
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IR (nujol): n = 3359, 3239, 2922, 2854, 2253, 2178, 1932, 1738,
1564, 1462, 1376, 1317, 1287, 1189, 1155, 1069, 1040, 1022, 959,
943, 883, 821, 725, 734 cm-1.
1H NMR (CDCl3): d = 1.04 (s, 3 H, CH3), 1.13 (s, 3 H, CH3), 3.09
(d, 1 H, J = 10.0 Hz, CH2), 3.28 (d, 1 H, J = 9.5 Hz, CH2), 3.55 (d,
1 H, J = 7.5 Hz, CH), 4.32 (d, 1 H, J = 7.75 Hz, OH), 7.19-7.43 (m,
15 Harom).
1H NMR (DMSO-d6): d = 0.71 (s, 3 H, CH3), 0.77 (s, 3 H, CH3),
3.06 (d, 1 H, J = 10.6 Hz, CH2), 3.27 (s, 1 H, OH), 3.35 (d, 1 H, J =
MS (ion spray): m/z = 410.5 (MK+), 394.3 (MNa+) 372.4 (MH+),
+
+
10.9 Hz, CH2), 6.5 (br s, 4 H, NH4 ).
243.3 (CPh3 ).
MS (ion spray): m/z = 147,1 (M-).
Anal. (C25H25NO2): calcd: C, 80.83; H, 6.78; N, 3.77. Found C,
80.60; H, 6.95; N, 3.61.
Anal. (C6H15NO4): calcd: C, 43.63; H, 9.15; N, 8.48. Found C,
43.77; H, 9.22; N, 8.18.
(R)-2-Hydroxy-3,3-dimethyl-4-trityloxybutyronitrile [(R)-8]
The dehydration reaction of (R)-7 with cyanuric chloride was car-
ried out as described above. (R)-8 resulted as a pale yellow solid in
95% yield; [a]D20 -5.06 (c =1.03g/100 mL, EtOH). The compound
still contained 0.1% water and 2.6% hexane, as determined by Karl
Fischer titration and GC integration, respectively.
(R,S)-2-Hydroxy-3,3-dimethyl-4-trityloxybutyramide [(R,S)-7]
To a suspension of (R,S)-2 (3.0 g, 20.4 mmol) in Et3N (6 mL) and
CH2Cl2 (10 mL) was added a solution of triphenylchloromethane
(5.9 g, 20.5 mmol) in CH2Cl2 (50 mL) at 5 °C. The mixture was
heated to r.t. and stirred for 3 h. After hydrolysis with H2O (60 mL),
the phases were separated, the organic layer was dried (Na2SO4), fil-
tered, and concentrated in vacuo. The crude product was purified by
recrystallization from Et2O/hexane; yield: 7.7 g (93%). The purity
according to SFC was 98%; mp 121-122 °C.
Anal. (C25H25NO2): calcd: C, 80.83; H, 6.78; N, 3.77. Found C,
81.19; H, 6.89; N, 3.06.
(S)-2-Hydroxy-3,3-dimethyl-4-trityloxybutyronitrile [(S)-8]
The dehydration reaction of (S)-7 with cyanuric chloride was car-
ried out as described above. (S )-8 resulted as a pale yellow solid in
95% yield; [a]D20 +7.19 (c = 1.069/100 mL, EtOH). The compound
still contained 0.1% water and 2.2% hexane, as determined by Karl
Fischer titration and GC integration, respectively.
IR (nujol): n = 3459, 3449, 3191, 3083, 3002, 2976, 2854, 1968,
1689, 1671, 1665, 1597, 1492, 1463, 1375, 1100, 1080, 1007, 976
958, 899 cm-1.
1H NMR, (CDCl3): d = 0.98 (s, 3 H, CH3), 1.16 (s, 3 H, CH3), 3.02
(d, 1 H, J = 9.0 Hz, OCH2), 3.16 (d, 1 H, J = 9.0 Hz, OCH2), 3.71
(d, 1 H, J = 4.5 Hz, CH), 4.11 (d, 1 H, J = 4.5 Hz, OH), 5.11 (s,
1 H, NH2) 6.15 (s, 1 H, NH2) 7.25-7.45 (m, 15 Harom).
Anal. (C25H25NO2): calcd: C, 80.83; H, 6.78; N, 3.77. Found C,
80.47; H, 6.91; N, 3.04.
Crystal Structure Determinations
+
MS (ion spray): m/z = 428.5 (MK+), 412.3 (MNa+), 243 (CPh3 ).
All measurements were performed on an Enraf Nonius Mach 3
four-circle diffractometer at room temperature using graphite-
monochromatized Mo-Ka radiation (l = 0.7107 Å), and the reflec-
tion intensities were collected using w-scans. The structures were
solved using direct methods (SHELXS8615), all non-hydrogen at-
oms were refined anisotropically, all the hydrogen atoms were lo-
cated from difference Fourier-maps and refined isotropically
without constraints (SHELXL9316).
Anal. (C25H27NO3): calcd: C, 77.09; H, 6.99; N, 3.60. Found C,
77.31; H, 6.97; N, 3.68.
(R)-2-Hydroxy-3,3-dimethyl-4-trityloxybutyramide [(R)-7]
The reaction of (R)-2 with triphenylchloromethane was carried out
as described above. (R)-7 was obrained as a colorless solid in a
yield of 7.6 g (92%). The purity according to SFC was 98.5%; er:
R/S = 99.2:0.8; mp 123-124°C; [a]D20 11.0 (c = 0.95g/100 mL,
EtOH).
Crystal Structure Data of (R,S)-2
Suitable crystals were obtained by recrystallization from EtOH.
Unit cell parameters were obtained by least-squares refinement of
the 2q values of 24 reflections with 10 £ q £ 14°: monoclinic, space
group C2/c (No.15), a = 21.334(2), b = 7.006(1), c = 13.557(1) Å,
b = 129.20(1)°, V = 1570.4(3) Å3, Z = 8, rcalc. = 1.245 gcm-3,
m = 0.10 mm-1, F(000) = 640. Number of unique reflections: 1388
(0 £ q £ 25°), of which 947 [Fo > 4s(Fo)] were used for the determi-
nation and refinement of the structure. The refinement converged at
R1 = 0.038 (R1= 0.73 and R2 = 0.120 for all 1388 reflections)
(wR2 = 0.120, number of variables 143) with the largest difference
peak and hole at 0.15 and -0.19 eÅ-3, respectively.
Anal. (C25H27NO3): calcd: C, 77.09; H, 6.99; N, 3.60. Found C,
76.82; H, 6.88; N, 3.67.
(S)-2-Hydroxy-3,3-dimethyl-4-trityloxybutyramide (S)-7
The reaction of (S)-2 with triphenylchloromethane was carried out
as described above. (S)-7 was obtained as a colorless solid in a yield
of 7.7 g (93%). The purity according to SFC was 99.2%; er: R/
S = 99.2:0; mp 126-127 °C; [a]D20 -11.2 (c = 0.95g/100 mL,
EtOH).
Anal. (C25H27NO3): calcd: C, 77.09; H, 6.99; N, 3.60. Found C,
76.88; H, 7.09; N, 3.64.
(R,S)-2-Hydroxy-3,3-dimethyl-4-trityloxbutyronitrile[(R,S)-8];
Typical Procedure
Crystal Structure Data of (R,S)-3
Suitable crystals were obtained by recrystallization from hexane.
Unit cell parameters were obtained by least-squares refinement of
the 2q values of 21 reflections with 7 £ q £ 14°: triclinic, space
group P-1 (No.2), a = 6.707(1), b = 8.059(1), c = 10.955(2) Å,
a = 99.92(1), b = 98.77(1), g = 111.85(1)°, V = 526.0(1) Å3, Z = 2,
A solution of cyanuric chloride (0.8 g, 4.3 mmol) in tert-butyl
methyl ether (15 mL) was added to a solution of (R,S)-7 (3.4 g,
8.7 mmol) in DMF (4.5 mL). The mixture was stirred at r.t. for 1 h,
in the course of which the solution turned into a yellow suspension.
To the mixture was added H2O (15 mL), and the aqueous phase was
extracted with tert-butyl methyl ether (2 × 30 mL). The combined
organic phases were washed with distilled water (30 mL), dried
(Na2SO4), and filtered. The solvent was removed on a rotary evap-
orator. Crude (R,S)-8 was obtained as pale yellow solid and purified
by recrystallization from acetone/hexane; yield: 3.08 g (95%).
r
calc. = 1.182 gcm-3, m = 0.09 mm-1, F(000) = 204. Number of
unique reflections: 1843 (0 £ q £ 25°), of which 1100 [Fo > 4s(Fo)]
were used for the determination and refinement of the structure. The
refinement converged at R1 = 0.040 (R1 = 0.095 and R2 = 0.184 for
all 1843 reflections)(wR2 = 0.184, number of variables 186) with
the largest difference peak and hole at 0.16 and -0.16 eÅ-3, respec-
tively.
IR (KBr): n = 3459, 3087, 3060, 3038, 2967, 2876, 2245, 1958,
1729, 1672, 1597, 1490, 1447, 1321, 1182, 1077, 1009, 932, 898,
764, 702 cm-1.
Synthesis 2000, No. 5, 731–737 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Convenient Dehydration Procedure for the Synthesis of Enantiomerically Pure Cyanohydrins
737
Crystal Structure Data of (R)-3
Narasaka, K.; Yamada, T.; Minamikawa, H. Chem. Lett. 1987,
Suitable crystals were obtained by recrystallization from hexane.
Unit cell parameters were obtained by least-squares refinement of
the 2q values of 25 reflections with 10 £ q £ 14°: orthorhombic,
space group P212121 (No.19), a = 7.709(2), b = 10.847(2),
c = 12.545(1) Å, V = 1049.0(3) Å3, Z = 4, rcalc. = 1.186 gcm-3,
m = 0.09 mm-1, F(000) = 408. Number of unique reflections: 1211
(0 £ q £ 26°), of which 890 (Fo > 4s(Fo)) were used for the determi-
nation and refinement of the structure. The refinement converged at
R1 = 0.042 (R1 = 0.072 and R2 = 0.127 for all 1211 reflections)
(wR2 = 0.127, number of variables 186) with the largest difference
peak and hole at 0.18 and -0.27 eÅ-3, respectively.
2073.
Minamikawa, H.; Hayakawa, S.; Yamada, T.; Iwasawa, N.;
Narasaka, K. Bull. Chem. Soc. Jpn. 1988, 61, 4379.
Hayashi, M.; Matsuda, T.; Ogui, N. J. Chem. Soc., Chem.
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Hayashi, M.; Miyamoto, Y.; Inoue, T.; Oguni, N. J. Chem.
Soc., Chem. Commun. 1991, 1752.
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1986, 27, 4721.
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Lett. 1989, 30, 3931.
Dalton, D. M.; Garner, C. M.; Fernandez, J. M.; Gladysz, J. A.
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(8) Olah, G. A.; Narang, S. C.; Fung, A. P.; Gupta, B. G. B.
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Eur. Pat. Appl. EP 612 736, 1994; Chem. Abstr. 1994, 121,
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Acknowledgement
The authors thank Dr. W. Arnold (PRPC-S) for the helpful discus-
sions of the NMR experiments, Mr. W. Meister (PRPC-S) for MS
measurement, and Mr. F. Cirillo for his assistance with some of the
experiments.
Bonrath, W.; Karge, R.; Pauling, H.; (F. Hoffmann-La Roche)
U.S. Patent US 5,502,212, 1996.
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1437-210X,E;2000,0,05,0731,0737,ftx,en;Z09199SS.pdf
Synthesis 2000, No. 5, 731–737 ISSN 0039-7881 © Thieme Stuttgart · New York