Chiral carbanions, part 4: Borylation of (trimethylsilyl)methyl N,N-dialkyl-carbamates - Diastereoselectivity and structural studies

Article abstract of DOI:10.1055/s-2004-831237

(Trimethylsilyl)methyl carbamates were prepared from (trimethylsilyl) methanol and N,N-dialkylcarbamoyl chlorides and were metalated by s-BuLi/TMEDA. The configurationally labile lithiated carbamates were reacted with borates derived from (+)-pinane-2,3-d

Full text of DOI:10.1055/s-2004-831237

2704
PAPER
Chiral Carbanions, Part 4:1 Borylation of (Trimethylsilyl)methyl N,N-Dialkyl-
carbamates – Diastereoselectivity and Structural Studies
Borylation of (T
r
i
imethy
l
lsilyl)m
j
e
thyl
N
a
,
N
-Dialkyl
n
c
arbamates a Peric Simov,a Agnieszka Rohn,a Lothar Brecker,a Gerald Giester,b Friedrich Hammerschmidt*a
a
Institut für Organische Chemie der Universität Wien, Währingerstraße 38, 1090 Wien, Austria
Fax +43(1)42779521; E-mail: friedrich.hammerschmidt@univie.ac.at
b
Institut für Mineralogie und Kristallographie der Universität Wien, Geozentrum, Althanstrasse 14, 1090 Wien, Austria
Received 24 May 2004; revised 17 July 2004
(2) with commercially available carbamoyl chloride 3 in
81% yield.8 The amines (R,R)- and (S,S)-5 were first
transformed into the intermediate carbamoyl chlorides us-
ing trichloromethyl chloroformate, which were converted
Abstract: (Trimethylsilyl)methyl carbamates were prepared from
(trimethylsilyl)methanol and N,N-dialkylcarbamoyl chlorides and
were metalated by s-BuLi/TMEDA. The configurationally labile
lithiated carbamates were reacted with borates derived from (+)-pi-
nane-2,3-diol to give boronates diastereoselectively (yields up to in situ to the (trimethylsilyl)methyl esters (R,R)- and
84%, dr up to 17:1). The absolute configurations at the boron-bear-
ing carbon atoms of three boronates were assigned by single crystal
X-ray structure analyses.
(S,S)-4b in 87% and 82% yield, respectively. The (tri-
methylsilyl)methanol was obtained by a modified
literature procedure7 in two steps from (chloro-
Key words: carbamates, carbanions, lithiation, nucleophilic substi-
tution, diastereoselectivity
methyl)(trimethyl)silane. Nucleophilic substitution of
chloride for acetate in dry DMF with NaOAc and a subs-
toichiometric amount of NaI at 100 °C for 24 hours gave
the (trimethylsilyl)methyl acetate in 76% yield (see exper-
imental part), which was reduced with LiAlH4.
Boronic acids and their esters are versatile compounds in
organic chemistry.2 Their various applications range from
the Suzuki–Miyaura coupling3 and the use of allylbor-
onates for the stereoselective allylation4 of aldehydes to
the asymmetric syntheses based on a-halo boronates5 ele-
gantly developed by Matteson et al. Borylation of lithium
and magnesium organic compounds with trialkyl borates
and hydroboration are very general approaches to their
synthesis. In a project aiming at the direct chemical syn-
thesis of chiral, nonracemic [2H1,3H]methanol we got in-
terested in the preparation of suitable precursors of type 1
(Figure 1). Here we report on their synthesis from meta-
lated (trimethylsilyl)methyl carbamates and borates and
the determination of their structures. Furthermore, we
studied the influence of the solvent and the temperature on
the diastereoselectivity of the reaction, which so far has
not been addressed.
O
O
(i-Pr)2NEt/DMAP
+
OH
Me
Me3Si
toluene/100 °C
N(i-Pr)2
Cl
2
O
N(i-Pr)2
Me3Si
81%
4a
3
O
Me
1) ClC(O)OCCl3/0 °C
(i-Pr)2NEt, toluene
O
N(CHMePh)2
Me3Si
Ph
N
H
Ph
2) DMAP, 2, reflux
(R,R)-4b, 87%
(S,S)-4b, 82%
(R,R)-5, (S,S)-5
Scheme 1
To obtain hydrolytically stable boronates,5 four mixed bo-
ric acid esters containing a 1,2-diol were used for boryla-
tion, isopropanol pinacol boric acid ester9 and three
borates 8 derived from (+)-pinane-2,3-diol (7, 99% ee)
and trialkyl borates 6 by transesterification in high yields
(>90%) (Scheme 2). The methoxyethyl borate 8c was se-
lected because of the additional ether oxygen atom in the
leaving group. Matteson and Man found that boronic acid
esters of pinane-2,3-diol are highly resistant to hydrolysis,
which was desirable for our studies.10
(R3O)2B
R13Si
O
R2
O
N
R2
1
Figure 1
The first experiment was performed with carbamate
(R,R)-4b. It was metalated with two equivalents of s-BuLi
in THF at –78 °C for 15 minutes and then quenched with
isopropanol pinacol boric acid ester (Scheme 3).
Three (trimethylsilyl)methyl carbamates, 4a and (R,R)-
and (S,S)-4b derived from C2 symmetric amines6 (R,R)-
and (S,S)-5 (>99% ee), were prepared to study the diaste-
reoselectivity of borylation (Scheme 1). Carbamate 4a
was formed by esterification of trimethylsilylmethanol7
After allowing the reaction mixture to warm up to room
temperature and work up, a crude product consisting of
starting material and two new compounds of similar po-
larity was obtained. Flash chromatography with hexane–
ethyl acetate furnished a mixture of the two new com-
SYNTHESIS 2004, No. 16, pp 2704–2710
x
x.
x
x
.
2
0
0
4
Advanced online publication: 22.09.2004
DOI: 10.1055/s-2004-831237; Art ID: T05404SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Borylation of (Trimethylsilyl)methyl N,N-Dialkylcarbamates
2705
The ratio of boronates 10:11 in the crude product was
1.7:1. When the metalation was performed in hexane with
two equivalents of s-BuLi/TMEDA for 30 minutes, the
yield of the boronates increased to 77% and the ratio
dropped to 1.5:1. This result demonstrates that the (tri-
methylsilyl)methyl carbamate can be deprotonated and
borylated easily. The diastereomeric ratios of 1.5:1 and
1.7:1 are either the result of a combination of a diastereo-
selective metalation and a configurationally stable organ-
olithium species or of the diastereoselectivity in the
borylation of a configurationally labile organolithium.12
As the stereogenic centers in the carbamoyl group are far
away, their effect on both metalation and borylation are
rather small. Metalated carbamates derived from aliphatic
primary alcohols are configurationally stable as found by
Hoppe and Hense.13
R3
O
OH
OH
toluene/
reflux
B
O
O
(R3O)3B +
6a R3 = i-Pr
R3 = t-Bu
7
8a
b
R
3 = i-Pr, 93%
R3 = t-Bu, 99%
b
(i-PrO)3B/MeOCH2CH2OH
toluene/reflux
7
8c
R
3 = CH2CH2OMe
92%
Scheme 2
O
B
O-i-Pr
O
Li
O
s-BuLi/TMEDA
(R,R)-4b
O
Next, we combined a racemic lithiated carbamate and a
chiral boric acid ester (Scheme 4). Metalation of carbam-
ate 4a in hexane or THF as before with two equivalents of
s-BuLi/TMEDA and borylation with 8a produced mix-
tures of boronates 12a/13a in yields of 86% and 90%, re-
spectively.
NR2
Me3Si
–78 °C
(R,R)-9b
O
O
O
O
O
+
O
O
B
S
B
R
R = (R)-CH(Me)Ph
O
NR2
NR2
Me3Si
Me3Si
10
11
Scheme 3
pounds in 35% yield, which were separated by flash chro-
matography using hexane–ethyl acetate (10:1).
The crystalline compounds turned out to be diastereomer-
ic boronates (for nomenclature see ref.11) on the basis of
their spectroscopic data. A single crystal X-ray structure
analysis of the major diastereomer 10, which is also the
more polar one, revealed that the boron-bearing carbon
atom has (S)-configuration (Figure 2).
Scheme 4
The oily diastereomers could be separated by flash chro-
matography despite the small difference in their polarity
(Rf 0.41 and 0.47 in hexane–ethyl acetate, 10:1). The dia-
stereomeric ratios were 1.25:1 and 4:1, respectively, in
favour of the major diastereomer 12a. The assignment of
the structure to the compounds is postponed and will be
dealt with later. These two experiments prove that the
lithiated carbamate is configurationally labile at the time
scale of borylation. On the contrary, an enantiomerically
enriched 1-lithio-1-(trimethylsilyl)ethyl carbamate was
found to be configurationally stable (Hoppe et al.14).
At last, we combined chiral borates 8a–c with C2 symmet-
ric carbamates (R,R)- and (S,S)-4b to produce mixtures of
boronates 12b/13b and 12c/13c, 12b and 12c being the
major diastereomers (Scheme 5). Lithiations were per-
formed with 1.2 equivalent of s-BuLi/TMEDA, which
evolved as the standard for the metalation of all (trimeth-
ylsilyl)methyl carbamates. n-BuLi was used as base in
one exploratory experiment but was less efficient than s-
BuLi. Single crystal X-ray structure analyses were neces-
sary to determine the (R)-configuration of 13b and the (S)-
configuration of 12c at the boron-bearing carbon atoms
Figure 2 Crystal structure of boronate 10; the hydrogen atoms were
omitted for the sake of clarity
Synthesis 2004, No. 16, 2704–2710 © Thieme Stuttgart · New York

2706
B. P. Simov et al.
PAPER
(Figure 3). Therefore, the major diastereomers obtained in
both cases have (S)-configuration at the newly formed
asymmetric centres irrespective of the configuration of
the 1-phenylethyl groups. The predominating formation
of (S)-configuration is induced by the (+)-pinane-2,3-diol
ligand of the boric acid ester.
O
s-BuLi/
TMEDA
Li
(R,R)-4b
(S,S)-4b
8a–c
O
NR2
Me3Si
–78 °C
(R,R)-9b R = (R)-CH(Me)Phe
(S,S)-9b
R = (S)-CH(Me)Phe
12b/13b: R = (R)-CH(Me)Phe
Figure 4 Crystal structure of boronate 12c; the hydrogen atoms
were omitted for the sake of clarity
12c/13c: R = (S)-CH(Me)Phe
O
O
O
O
O
O
B
R
B
+
The borylations were performed with three borates in ei-
ther diethyl ether or THF at temperatures of –50 °C,
–78 °C or –94 °C. The results are summarised in Table 1.
The diastereoselectivity increased when carbamate (R,R)-
4b and isopropyl borate 8a were used, by lowering the re-
action temperature from –78 °C (12b:13b = 4:1, Entry 1)
to –94 °C (12b:13b = 7:1, Entry 2) in diethyl ether. When
the isopropyl borate 8a was replaced by t-butyl borate 8b
the diastereoselectivity reached was best (12b:13b = 17:1,
Entry 3) but dropped when the reaction temperature was
–94 °C (12b:13b = 9:1, Entry 4) or –50 °C (12b:13b =
6:1, Entry 5). The diastereoselectivity in THF at –78 °C
(12b:13b = 8:1, Entry 6) was about half of that in diethyl
ether under otherwise identical conditions. Surprisingly,
the two diastereomers were formed in equal amounts
when the methoxyethyl borate 8c was used as electrophile
(Entry 7). This may possibly be caused by the additional
oxygen atom in the leaving group. The diastereoselectivi-
ty for carbamate (S,S)-4b was lower than that for carbam-
ate (R,R)-4b under comparable conditions (Entries 8–10).
O
O
NR2
NR2
Me3Si
Me3Si
S
12b
12c
13b
13c
Scheme 5
Figure 3 Crystal structure of boronate 13b; the hydrogen atoms The yields of the boronates were about 70%.
were omitted for the sake of clarity
The diastereoselectivity did not change by going from
N,N-diisopropylcarbamate 4a to (S,S)-N,N-bis(1-phenyl-
Table 1 Preparation of Boronates 12/13b,c
Entry
Carbamate
(R,R)-4b
(R,R)-4b
(R,R)-4b
(R,R)-4b
(R,R)-4b
(R,R)-4b
(R,R)-4b
(S,S)-4b
(S,S)-4b
(S,S)-4b
Borate
8a
Solvent
Et2O
Et2O
Et2O
Et2O
Et2O
THF
Et2O
THF
THF
Et2O
Temperature (°C)
Boronates/Yield (%)/Ratio
12b + 13b/45/4:1
12b + 13b/65/7:1
12b + 13b/78/17:1
12b + 13b/54/9:1
12b + 13b/69/6:1
12b + 13b/80/8:1
12b + 13b/73/1:1
12c + 13c/84/4:1
12c + 13c/66/4:1
12c + 13c/74/6:1
1
2
–78
–94
–78
–94
–50
–78
–78
–78
–78
–94
8a
3
8b
4
8b
5
8b
6
8b
7
8c
8
8a
9
8b
10
8b
Synthesis 2004, No. 16, 2704–2710 © Thieme Stuttgart · New York

PAPER
Borylation of (Trimethylsilyl)methyl N,N-Dialkylcarbamates
2707
ethyl)carbamates 4b, but increased significantly for selectively (dr up to 17:1). The observed stereoselection is
(R,R)-N,N-bis(1-phenylethyl)carbamates 4b in combina- the result of dynamic kinetic resolutions of chiral boron
tion with t-butyl borate 8b. The stereochemistry at the bo- reagents on configurationally labile organolithiums.
ron-bearing carbon atom is borate controlled. Borates
8a,b derived from (+)-pinane-2,3-diol favour the forma-
tion of diastereomers with (S)-configuration at the boron-
bearing carbon atom. The influence of the configuration
of the carbamoyl group on the diastereoselectivity is of
minor importance although (S)-configuration is formed
preferentially from (R,R)-4b and an achiral borate. Com-
bining carbamate (R,R)-4b with 8a,b (matched case) gave
higher diastereoselectivities than combining (S,S)-4b with
8a,8b (mismatched case).15 Consequently, we assume on
the basis of analogy that boronate 12a, the major diaste-
reomer formed from N,N-diisopropylcarbamate 4a, is also
(S)-configured at the boron-bearing carbon atom.
1H NMR spectra were measured in CDCl3 at 300 K on a Bruker
Avance DRX 400 or DRX 600 spectrometer at 400.13 MHz or
600.13 MHz, respectively. COSY, NOESY, HMQC, and HMBC
spectra were recorded on a DRX 600 spectrometer under the same
conditions using 1024 data points and 256 experiments for each
spectrum. 13C Frequency in the heteronuclear correlations was
150.86 MHz. Chemical shifts were referenced to residual CHCl3
(dH = 7.24) and CDCl3 (dC = 77.00). Additional 13C spectra (J mod-
ulated) were measured at 360 K in toluene-d8 on a DRX 400 spec-
trometer at 100.61 MHz and referenced to the CD3 group
(dC = 21.04). All chemical shift (d) are given in ppm and coupling
constants (J) in Hertz. IR spectra were run on a Perkin-Elmer 1600
FT-IR spectrometer; liquid samples were measured as films be-
tween NaCl plates or on a silicon disc.19 Optical rotations were mea-
sured at 20 °C on a Perkin-Elmer 351 polarimeter in a 1 dm cell.
TLC was carried out on 0.25 mm thick Merck plates, silica gel 60
F254. Flash chromatography was performed with Merck silica gel 60
(230–240 mesh). Spots were visualised by UV and/or dipping the
plate into a solution of (NH4)6Mo7O24·4H2O (23.0 g) and of
Ce(SO4)2·4H2O (1.0 g) in 10% aq H2SO4 (500 mL), followed by
heating with a hot gun. Melting points were determined on a
Reichert Thermovar instrument and were uncorrected.
We also tried to deduce the absolute configurations at the
boron-bearing carbon atoms (C-1, which is C-11 in num-
bering used only for X-ray structures) of 12a and 12b by
NMR spectroscopy. First, their proton and carbon signals
(except that of NCH) were assigned. The shifts of respec-
tive atoms in the (+)-pinane-2,3-diol ligand varied insig-
nificantly in CDCl3 at 27 °C (see experimental part).16
Surprisingly, only the chemical shift of H-7a was influ-
enced markedly by the configuration at C-1 (d 1.38 ppm
for 12a and d 1.50 ppm for 13a) which was also noticed
by Matteson et al.17 The same is true for 12b/13b (d 1.48
ppm and d 1.40 ppm) and 12c/13c (d 1.31 ppm and d 1.45
ppm). Unfortunately, the changes for H-7a and other sig-
nals with smaller shift differences are not consistent, so
the configuration at C-1 cannot be deduced from the NMR
spectra. All boronates are conformationally flexible in so-
lution. NOESY spectra of 12a and 13a show NOEs be-
tween H-1 and H-7a indicating a spatial closeness
between these two nuclei. Such vicinity is not present in
any crystal structure [d(C=O···B) = 3.06 Å for 13b and
2.89 Å for 12c]. In solution, however, further conforma-
tions seem to allow a formation of a coordinative bond be-
tween the boron atom and the oxygen or nitrogen of the
carbamoyloxy substituent. The dissociation rate constant
of such coordinative bonds is in the same time scale as
Single crystal X-ray diffraction data of boronates 10, 12c and 13b
were measured at –73 °C on a Nonius KappaCCD diffractometer
(MoKa-radiation, 2qmax = 56.5°) equipped with a 0.3 mm monocap-
illary optics collimator. Several sets of w scans were performed to
complete the sphere. The extraction and correction of the intensity
data, including a pseudoabsorption correction by frame scaling and
the refinement of lattice parameters were performed with the pro-
gram package DENZO-SMN.20 For structure solutions by direct
methods the program SHELXS-9721 was used and the structure re-
finements based on full-matrix least squares techniques of F2 were
done with SHELXL-97.22 The positions of all hydrogen atoms were
located by final difference Fourier maps and refined.
(Trimethylsilyl)methyl Acetate
(Chloromethyl)(trimethyl)silane (24.5 g, 200 mmol), NaOAc (23.0
g, 280.4 mmol) and NaI (8.0 g, 53.4 mmol) in anhyd DMF (150 mL)
were heated at 100 °C (bath temperature) for 24 h. The reaction
mixture was cooled, diluted with H2O (150 mL) and extracted with
Et2O (3 × 100 mL). The combined organic layers were washed with
H2O, 2 M HCl, H2O, a sat. aq solution of NaHCO3 (100 mL each),
chemical shift differences of some respective atoms in the dried (MgSO4) and concentrated under reduced pressure. The resi-
two different conformers. For that reason, 13C atoms di-
due was purified by fractional distillation (70 °C/120 mbar) to give
(trimethylsilyl)methyl acetate7 (22.2 g, 76%) as a colourless liquid.
rectly bound to the nitrogen of the carbamoyl group show
broad signals with low intensity in NMR spectra. Namely
Preparation of Borates 6a–c
A mixture of (+)-pinane-2,3-diol (7.01 g, 41.2 mmol, ee 99%), tri-
isopropyl borate (9.29 g, 11.4 mL, 49.4 mmol, 1.2 equiv) and anhyd
toluene (60 mL) were refluxed for 30 min. After concentration of
the signal of the boron-bearing carbon atom was not di-
rectly detectable in 13C spectra, but indirectly determined
in HMQC and HMBC spectra.18 In toluene-d8 at 87 °C
the reaction mixture under reduced pressure the residue was bulb-
to-bulb distilled (97 °C/0.6 mbar) to give borate 6a (9.85 g, 93%) as
a colourless liquid.
compared to CDCl3 at 27 °C, however, the tendency of the
boron atom to form a coordinative bond is much lower.
For that reason the according dissociation rate constant is
distinctly higher and all 13C atoms (C-1 could not be de-
tected) show sharp signals in the NMR spectra.
Similarly, (+)-pinane-2,3-diol (5.40 g, 31.7 mmol) and tri-t-butyl
borate (8.76 g, 10.8 mL, 38.04 mmol) in anhyd toluene (40 mL)
were transformed into borate 6b (7.94 g, 99%, 100 °C/0.8 mbar) as
a colourless liquid.
In summary, we have shown that (trimethylsilyl)methyl
carbamates are deprotonated easily at –78 °C using s-
BuLi/TMEDA to give configurationally labile organolith-
iums. These are borylated with borates derived from (+)-
pinane-2,3-diol to give boronates in good yields diastereo-
Similarly, (+)-pinane-2,3-diol (3.41 g, 20.0 mmol), triisopropyl bo-
rate (4.51 g, 5.54 mL, 24.0 mmol) and 2-methoxyethanol (1.83 g,
1.89 mL, 24 mmol) in anhyd toluene (25 mL) were transformed into
borate 6c (4.68 g, 92%, 120 °C/0.3 mbar) as a colourless liquid.
Synthesis 2004, No. 16, 2704–2710 © Thieme Stuttgart · New York

2708
B. P. Simov et al.
PAPER
(Trimethylsilyl)methyl N,N-Diisopropylcarbamate (4a)
A mixture of (trimethylsilyl)methanol (2.085 g, 20 mmol), i-
Pr2NC(O)Cl (3.93 g, 24 mmol), i-Pr2NEt (5.23 ml, 3.88 g, 30 mmol)
and DMAP (0.20 g, 1.64 mmol) in anhyd toluene (20 mL) was heat-
ed at 100 °C for 16 h. H2O (1 mL) was added and heating was con-
tinued for another h. After cooling, the mixture was concentrated
and aq HCl (20 ml, 5%) and CH2Cl2 (30 mL) were added. The or-
ganic phase was separated and the aq phase was extracted with
CH2Cl2 (30 mL). The combined organic layers were washed with
H2O, dried (MgSO4) and concentrated. The residue was purified by
flash chromatography (hexane–EtOAc, 2:1; Rf 0.21) and then bulb-
to-bulb distilled (100 °C/16 mbar) to give carbamate 4a (3.75 g,
81%) as a colourless liquid.
washed with HCl (5 mL, 1 M), H2O (5 mL) and a sat. aq solution of
NaHCO3 (5 mL), dried (Na2SO4) and concentrated. The residue was
purified by flash chromatography (hexane–EtOAc, 4:1, (R,R)-4a: Rf
0.59; 11: Rf 0.43, 10: Rf 0.36) to give a mixture of 10 and 11 (0.168
g, 35%, 10/11 1.7:1, by H NMR) which was separated by flash
chromatography (hexane–EtOAc, 15:1).
1
Similarly, a solution of (R,R)-4a (1.067 g, 3 mmol), TMEDA (0.697
g, 0.91 mL, 6 mmol) in anhyd hexane (30 mL) under argon was
cooled at –78 °C. s-BuLi (4.62 mL, 6 mmol, 1.3 M solution in cy-
clohexane) was added dropwise. After stirring for 30 min, isopro-
panol pinacol boric acid ester (1.116 g, 7 mmol) dissolved in anhyd
hexane (5 mL) was added within 10 min. Following the above pro-
cedure with THF, a mixture of 10 and 11 (1.112 g, 77%, 10/11
1.5:1, by 1H NMR) was obtained.
IR (NaCl): 2967, 1694, 1441, 1328, 1310, 1250, 1053 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.00 (br s, 1 H, NCH), 3.75 (br s,
1 H, NCH), 3.70 (s, 2 H, CH2O), 1.11 (d, J = 6.9 Hz, 12 H, Me2CH),
0.06 (s, 9 H, SiMe3).
13C NMR (100.61 MHz, toluene-d8, 360 K): d = 157.4, 59.1, 47.6,
22.4, –1.6.
10
Mp 115–116 °C (EtOH–H2O, 15:1); [a]D20 +81.6 (c 0.25, acetone).
IR (Si): 2976, 1678, 1600, 1330, 1248, 1146 cm–1.
1H NMR (400.13 MHz, CDCl3): d = 7.20–7.00 (m, 10 H, Harom),
5.03 (br s, 2 H, CHN), 3.65 (s, 1 H, BCHSi), 1.66 (d, J = 7.0 Hz, 6
H, NCCH3), 1.220 (s, 6 H, CH3), 1.217 (s, 6 H, CH3), –0.11 (s, 9 H,
SiMe3).
Anal. Calcd for C11H25NO2Si: C, 57.09; H, 10.89; N, 6.05. Found:
C, 57.32; H, 11.24; N, 6.08.
(R,R)-(+)- and (S,S)-(–)-(Trimethylsilyl)methyl N,N-Bis(1-phe-
nylethyl)carbamate [(R,R)- and (S,S)-4b]
13C NMR (100.61 MHz, toluene-d8, 360 K): d = 160.0, 143.6, 129.2,
128.0, 84.2, 56.1, 26.6, 26.2, 20.1, –1.2.
Trichloromethyl chloroformate (1.69 mL, 2.77 g, 14 mmol) was
added dropwise at 0 °C to a stirred solution of (R,R)-N,N-bis(1-phe-
nylethyl)amine (4.51 g, 20 mmol), i-Pr2NEt (10.34 g, 13.94 mL, 80
mmol) in anhyd toluene (50 mL) under argon. After 30 min DMAP
(0.611 g, 5 mmol) and (trimethylsilyl)methanol (3.79 mL, 3.13 g,
30 mmol) were added and the mixture was refluxed for 18 h and
then cooled. Aq HCl (5 mL of concd aq HCl and 50 mL of H2O) was
added. The organic phase was separated and the aq phase was ex-
tracted with toluene (20 mL). The combined organic phases were
washed with H2O (30 mL), a sat. aq solution of NaHCO3, dried
(MgSO4) and concentrated. The residue was purified by flash chro-
matography (hexane–EtOAc, 20:1; Rf 0.37, hexane–EtOAc, 10:1)
to give carbamate (R,R)-4b (6.19 g, 87%) as a colourless oil; last
traces of solvents were removed by heating at 100 °C/0.5 mbar;
Anal. Calcd for C27H40BNO4Si: C, 67.35; H, 8.37; N, 2.91. Found:
C, 67.17; H, 8.29; N, 3.11.
11
Crystalline solid which could not be crystallised from any solvent
as it is too soluble; mp 85–87 °C; [a]D20 +74.6 (c 0.94, acetone).
IR (Si): 2975, 2928, 1681, 1625, 1429, 1354, 1341, 1330, 1250,
1249, 1146 cm–1.
1H NMR (400.13 MHz, CDCl3): d = 7.40–6.90 (m, 10 H, Harom),
5.02 (br s, 2 H, CHN), 3.71 (s, 1 H, BCHSi), 1.68 (d, J = 7.1 Hz, 6
H, NCCH3), 1.24 (s, 6 H, CH3), 1.21 (s, 6 H, CH3), –0.08 (s, 9 H,
SiCH3).
13C NMR (100.61 MHz, toluene-d8, 360 K): d = 159.6, 143.8, 129.2,
129.2, 128.0, 84.4, 56.0, 26.4, 26.2, 19.9, 1.3.
20
[a]D +100.6 (c 2.31, acetone). Bulb-to-bulb distillation (140 °C/
0.005 mbar) gave a product containing a decomposition product (4
mol%).
Anal. Calcd for C27H40BNO4Si: C, 67.35; H, 8.37; N, 2.91. Found:
C, 67.54; H, 8.57; N, 2.95.
Similarly, (S,S)-N,N-bis(1-phenylethyl)amine (6.76 g, 30 mmol)
20
was transformed into carbamate (S,S)-4b (8.74 g, 82%); [a]D
–105.7 (c 7.1, CHCl3).
(S)-Pinanediol {(1S)- and (1R)-[(N,N-Diisopropyl-carbam-
oyl)oxy](trimethylsilyl)methyl}boronate (12a and 13a)
IR (NaCl): 2956, 1686, 1437, 1302, 1249, 1208 cm–1.
Carbamate 4a (0.694 g, 3 mmol) was metalated (30 min) in anhyd
hexane (15 mL) using s-BuLi/TMEDA (6 mmol each), borylated
with 8a (1.67 g, 7 mmol, dissolved in 5 mL of anhyd hexane; 1 h at
–78 °C) and worked up (extraction with Et2O) as described for the
1H NMR (400 MHz, CDCl3): d = 7.04–6.80 (m, 10 H, Harom), 5.06
(br s, 2 H, NCH), 3.64 (AB system, J = 14.3 Hz, OCH2), 1.68 (d,
J = 7.4 Hz, 6 H, CH3), –0.12 (s, 9 H, SiMe3).
13C NMR (100.61 MHz, toluene-d8, 360 K): d = 158.3, 143.9, 129.2,
129.0, 128.1, 59.7, 55.5, 19.9, –1.8.
1
preparation of 10/11. The crude product (12a/13a, 1.25:1 by H
NMR) was flash-chromatographed (hexane–EtOAc, 10:1, 12a: Rf
0.31; 13a: Rf 0.36) to give a mixture of 12a/13a (1.05 g, 86%) which
was separated by flash chromatography (hexane–EtOAc, 20:1).
Anal. Calcd for C21H29NO2Si: C, 70.94; H, 8.22; N, 3.94. Found: C,
71.21; H, 8.41; N, 4.04.
Similarly, carbamate 4a (0.231 g, 1 mmol) gave a mixture of 12a/
13a (0.368 g, 90%; 12a/13a 4:1 in crude product) in anhyd THF (5
mL).
Pinacol {(1S)- and (1R)-[(R,R)-N,N-Bis(1-phenylethyl)carbam-
oyloxy](trimethylsilyl)methyl}boronate (10 and 11)
A solution of (R,R)-4a (0.356 g, 1 mmol) in anhyd THF (10 mL) un-
der argon was cooled at –78 °C. s-BuLi (1.54 mL, 2 mmol, 1.3 M
solution in cyclohexane) was added dropwise. After stirring for 15
min, isopropanol pinacol boric acid ester (0.465 g, 2.5 mmol) dis-
solved in anhyd THF (5 mL) was added within 10 min. The reaction
mixture was allowed to warm up to –40 °C within 3 h and then a sat.
aq solution of NH4Cl (25 mL) and hexane (30 mL) were added. The
organic phase was separated and the aqueous one was extracted
with hexane (2 × 15 mL). The combined organic layers were
12a
Oil; [a]D20 +4.96 (c 2.60, acetone).
IR (Si): 2930, 1684, 1633, 1474, 1368, 1247, 1220, 1156, 1049,
1048 cm–1.
1H NMR (600.13 MHz, CDCl3): d = 4.16 (dd, J = 8.7, 2.2 Hz, 1 H,
3-H), 4.04 (br s, 1 H, CHN), 3.74 (br s, 1 H, CHN), 3.63 (s, 1 H,
BCHSi), 2.29–2.23 (m, 1 H, 4-Hb), 2.09–2.03 (m, 1 H, 7-Hb), 1.93
(t, J = 5.9 Hz, 1 H, 1-H), 1.83–1.79 (m, 1 H, 5-H), 1.80 (td, J = 13.0,
Synthesis 2004, No. 16, 2704–2710 © Thieme Stuttgart · New York

PAPER
Borylation of (Trimethylsilyl)methyl N,N-Dialkylcarbamates
2709
2.6 Hz, 1 H, H-4a), 1.38 (d, J = 10.5 Hz, 1 H, 7-Ha), 1.34 (s, 3 H,
CH3-10), 1.23 (s, 3 H, CH3-8), 1.21 (d, J = 6.8 Hz, 6 H, NCCH3),
1.19 (d, J = 6.8 Hz, 6 H, NCCH3), 0.82 (s, 3 H, CH3-9), 0.09 (s, 9
H, SiMe3).
13C NMR (150.90 MHz, CDCl3): d = 160.8, 83.0, 76.7, 66.9, 52.1,
n.d. (NCH), 40.1, 38.1, 36.4, 29.1, 27.3, 26.4, 24.2, 20.7, –2.4.
13C NMR (100.61 MHz, toluene-d8, 360 K): d = n.d. (CO), 143.6,
129.2, 129.2, 128.0, 86.7, 79.6, 56.1, 53.8, 41.7, 39.6, 37.2, 30.4,
28.6, 28.0, 25.1, 20.1, –1.1.
Anal. Calcd for C31H44BNO4Si: C, 69.78; H, 8.31; N, 2.63. Found:
C, 69.49; H, 8.14; N, 2.61.
13b
13C NMR (100.61 MHz, toluene-d8, 360 K): d = 159.8, 86.2, 79.3,
TLC (hexane–EtOAc, 10:1): Rf 0.38; mp 115–117 °C (ethanol);
53.8, 48.0, 41.8, 39.6, 37.4, 30.4, 28.6, 27.9, 25.1, 22.3, 22.2, –1.1.
[a]D20 +61.20 (c 1.80, acetone).
Anal. Calcd for C21H40BNO4Si: C, 61.60; H, 9.85; N, 3.42. Found:
C, 61.32; H, 10.07; N, 3.28.
IR (Si): 2931, 1680, 1428, 1359, 1315, 1249, 1122, 1078, 1029
cm–1.
13a
1H NMR (400.13 MHz, CDCl3): d = 7.20–7.00 (m, 10 H, Harom),
5.00 (br s, 2 H, NCH), 4.25 (dd, J = 8.8, 2.4 Hz, 1 H, 3-H), 3.81 (s,
1 H, BCHSi), 2.25 (tdd, J = 14.4, 8.8, 2.5 Hz, 1 H, 4-Hb), 2.17 (tdd,
J = 10.9, 5.8, 2.3 Hz, 1 H, 7-Hb), 2.01 (t, J = 5.8 Hz, 1 H, 1-H),
1.88–1.81 (m, 1 H, 5-H), 1.68 (d, J = 7.1 Hz, 6 H, CH3CN), 1.66 (td,
J = 14.4, 2.4 Hz, 1 H, 4-Ha), 1.40 (d, J = 10.9 Hz, 1 H, 7-Ha), 1.27
(s, 3 H, CH3), 1.267 (s, 3 H, CH3), 0.81 (s, 3 H, CH3), –0.09 (s, 9 H,
SiMe3).
Oil, [a]D20 +15.14 (c 2.45, acetone).
IR (Si): 2929, 1684, 1632, 1474, 1439, 1368, 1341, 1312, 1247,
1221, 1156, 1049, 1031 cm–1.
1H NMR (600.13 MHz, CDCl3): d = 4.21 (dd, J = 8.8, 2.4 Hz, 1 H,
3-H), 3.89 (br s, 2 H, NCH), 3.68 (s, 1 H, BCHSi), 2.29 (dddd,
J = 14.3, 8.8, 2.7, 2.4 Hz, 1 H, 4-Hb), 2.14 (ddd, J = 10.7, 6.1, 2.3
Hz, 1 H, 7-Hb), 2.00 (dd, J = 6.1, 5.8 Hz, 1 H, 1-H), 1.84 (tdd,
J = 5.8, 2.4, 2.3 Hz, 1 H, 5-H), 1.77 (ddd, J = 14.3, 2.4, 2.3 Hz, 1 H,
4-Ha), 1.50 (d, J = 10.7 Hz, 1 H, 7-Ha), 1.30 (s, 3 H, CH3-10), 1.25
(s, 3 H, CH3-8), 1.20 (d, J = 6.8 Hz, 6 H, NCCH3), 1.19 (d, J = 6.8
Hz, 6 H, NCCH3), 0.82 (s, 3 H, CH3-9), 0.10 (s, 9 H, SiMe3).
13C NMR (150.90 MHz, CDCl3): d = 158.4, 84.6, 77.1, 62.8, 51.8,
n.d. (NCH), 39.9, 38.3, 36.2, 28.9, 27.3, 26.5, 24.2, 20.6, –2.4.
13C NMR (100.61 MHz, toluene-d8, 360 K): d = 159.5, 86.4, 79.2,
53.8, 48.0, 41.7, 39.6, 37.4, 30.2, 28.6, 28.0, 25.1, 22.3, 22.3, –1.0.
13C NMR (100.61 MHz, toluene-d8, 360 K): d = 159.3, 143.8, 129.2,
129.2, 128.0, 86.9, 79.5, 56.0, 53.7, 41.7, 39.6, 37.1, 30.2, 28.5,
27.9, 25.1, 19.9, –1.2.
Anal. Calcd for C31H44BNO4Si: C, 69.78; H, 8.31; N, 2.63. Found:
C, 70.27; H, 8.07; N, 2.51.
(S)-Pinanediol {(1S)- and (1R)-[(S,S)-N,N-Bis(1-phenyleth-
yl)carbamoyloxy](trimethylsilyl)methyl}boronate(12cand13c)
12c
Mp 87–88 °C (EtOH/10% H2O); TLC (hexane–EtOAc, 10:1): Rf
Anal. Calcd for C21H40BNO4Si: C, 61.60; H, 9.85; N, 3.42. Found:
C, 61.61; H, 10.06; N, 3.38.
0.31; [a]D20 –48.10 (c 1.80, acetone).
IR (Si): 2927, 1679, 1429, 1376, 1358, 1314, 1249, 1208, 1028
cm–1.
Preparation of 12b/13b and 12c/13c; General Procedure
s-BuLi (1.2 mmol, 0.92 mL of a 1.3 M solution in cyclohexane) was
added to a stirred solution of carbamate 4b (0.356 g, 1 mmol) and
TMEDA (0.116 g, 0.15 mL, 1.2 mmol) in anhyd solvent (see
Table 1, 4 mL) under argon at –78 °C. After 30 min, borate 8 (see
Table 1, 1.3 mmol) dissolved in the same solvent (2 mL) was added
dropwise within 10 min (in some experiments a syringe pump was
used) and stirring was continued for 1 h. The reaction mixture was
diluted with a sat. solution of NH4Cl or NaHCO3 (20 mL) and ex-
tracted with Et2O or CH2Cl2 (3 × 20 mL). The combined organic
layers were washed with H2O (20 mL), dried (MgSO4 or Na2SO4)
and concentrated. The residue was flash-chromatographed (hex-
ane–EtOAc, 10:1) to furnish mixtures of 12b/13b or 12c/13c (for
yields and ratios see Table 1), which were separated by flash chro-
matography (hexane–EtOAc, 20:1).
1H NMR (400.13 MHz, CDCl3): d = 7.40–6.80 (m, 10 H, Harom),
5.02 (br s, 2 H, NCH), 4.20 (dd, J = 8.7, 2.0 Hz, 1 H, 3-H), 3.79 (s,
1 H, BCHSi), 2.29 (dddd, J = 15.2, 8.7, 3.2, 2.1 Hz, 1 H, 4-Hb), 2.06
(tdd, J = 10.6, 5.8, 2.0 Hz, 1 H, 7-Hb), 1.96 (t, J = 5.8 Hz, 1 H, 1-H),
1.88–1.81 (m, 2 H, 4-Ha, 5-H), 1.68 (d, J = 7.1 Hz, 6 H, CH3CN),
1.37 (s, 3 H, CH3), 1.31 (d, J = 10.6 Hz, 1 H, 7-Ha), 1.26 (s, 3 H,
CH3), 0.82 (s, 3 H, CH3), –0.07 (s, 9 H, SiMe3).
13C NMR (100.61 MHz, toluene-d8, 360 K): d = 159.5, 143.8, 129.2,
129.1, 128.0, 86.8, 79.6, 56.0, 53.6, 41.6, 39.5, 37.2, 30.3, 28.5,
27.9, 25.0, 20.0, –1.2.
Anal. Calcd for C31H44BNO4Si: C, 69.78; H, 8.31; N, 2.63. Found:
C, 69.86; H, 8.03; N, 2.59.
13c
(S)-Pinanediol {(1S)- and (1R)-[(R,R)-N,N-Bis(1-phenyleth-
Oil, TLC (hexane–EtOAc, 10:1): Rf 0.27; [a]D20 –70.64 (c 2.35, ac-
yl)carbamoyloxy](trimethylsilyl)methyl}boronate (12b and
13b)
etone).
IR (Si): 2930, 1677, 1433, 1376, 1358, 1340, 1314, 1249, 1208,
1029 cm–1.
12b
Oil; TLC (hexane–EtOAc, 10:1): Rf 0.30; [a]D20 +78.39 (c 1.80, ac-
1H NMR (400.13 MHz, CDCl3): d = 7.20–7.10 (m, 10 H, Harom),
5.03 (br s, 2 H, CHN), 4.28 (dd, J = 8.8, 2.5 Hz, 1 H, 3-H), 3.74 (s,
1 H, BCHSi), 2.34 (tdd, J = 14.2, 8.8, 2.3 Hz, 1 H, 4-Hb), 2.18 (tdd,
J = 10.6, 5.8. 2.0 Hz, 1 H, 7-Hb), 2.03 (t, J = 5.8 Hz, 1 H, 1-H),
1.91–1.86 (m, 1 H, 5-H), 1.83 (td, J = 14.2, 2.5 Hz, 1 H, 4-Ha), 1.66
(d, J = 7.1 Hz, 6 H, NCCH3), 1.45 (d, J = 10.6 Hz, 1 H, 7-Ha), 1.37
(s, 3 H, CH3), 1.28 (s, 3 H, CH3), 0.83 (s, 3 H, CH3), –0.08 (s, 9 H,
SiMe3).
etone).
IR (Si): 2931, 1678, 1628, 1433, 1376, 1342, 1313, 1249, 1028
cm–1.
1H NMR (400.13 MHz, CDCl3): d = 7.23–6.98 (m, 10 H, Harom),
5.02 (br s, 2 H, CHN), 4.24 (dd, J = 8.7, 1.9 Hz, 1 H, 3-H), 3.74 (s,
1 H, BCHSi), 2.35–2.26 (m, 1 H, 4-Hb), 2.19–2.12 (m, 1 H, 7-Hb),
2.01 (t, J = 5.6 Hz, 1 H, 1-H), 1.90–1.83 (m, 2 H, 4-Ha, 5-H), 1.67
(d, J = 7.1 Hz, 6 H, CH3CN), 1.48 (d, J = 10.6 Hz, 1 H, 7-Ha), 1.33
(s, 3 H, CH3), 1.28 (s, 3 H, CH3), 0.84 (s, 3 H, CH3), 0.09 (s, 9 H,
SiMe3).
13C NMR (100.61 MHz, toluene-d8, 360 K): d = n.d. (CO), 143.6,
129.2, 129.2, 128.0, 86.7, 79.6, 56.1, 53.8, 41.7, 39.6, 37.2, 30.4,
28.6, 28.0, 25.1, 20.1, –1.1.
Synthesis 2004, No. 16, 2704–2710 © Thieme Stuttgart · New York

2710
B. P. Simov et al.
PAPER
(4) (a) Roush, W. R. In Houben-Weyl Methods of Organic
Anal. Calcd for C31H44BNO4Si: C, 69.78; H, 8.31; N, 2.63. Found:
C, 69.68; H, 8.37; N, 2.56.
Chemistry, 4th ed., Vol. E 21b; Helmchen, G.; Hoffmann, R.
W.; Mulzer, J.; Schaumann, E., Eds.; Thieme: Stuttgart,
1995, 1410. (b) Hoffmann, R. W. Angew. Chem., Int. Ed.
Engl. 1982, 21, 555.
X-ray Crystal Data23 of Boronates 10, 12c and 13b
10
Formula C27H40BNO4Si; space group P21; a = 12.559(2), b =
(5) Matteson, D. S. Tetrahedron 1998, 54, 10555.
(6) Cain, Ch. M.; Cousins, R. P. C.; Coumbarides, G.; Simpkins,
N. S. Tetrahedron 1990, 46, 523.
6.526(3), c = 17.214(3) Å; b = 101.59(1)°; V = 1382.1(4) Å3; Z = 2;
rcalcd
= =
1.16 cm–3; m(MoKa) 1.2 cm–1; crystal size:
0.17 × 0.20 × 0.40 mm3. Single crystal data collection and refine-
ment: Unique data set: 6598; Fo>4s (Fo) = 5845; variables: 468; ex-
tinction coefficient: 0.020(2); flack × parameter: –0.06(10). R1 [for
(7) Ambasht, S.; Chiu, S. K.; Peterson, P. E.; Queen, J. Synthesis
1980, 318.
(8) Carstens, A.; Hoppe, D. Tetrahedron 1994, 50, 6097.
(9) Andersen, M. W.; Hildebrandt, B.; Köster, G.; Hoffmann, R.
W. Chem. Ber. 1989, 122, 1777.
2
Fo>4s(Fo)] [R1 = S||Fo|-|Fc||/S|Fo|] = 0.038; wR2 [for all Fo ] {wR2 =
2
4
[Sw(Fo -Fc2)2/SwFo ]1/2} = 0.098; rmin/max = 0.21/–0.15 eÅ–3.
(10) Matteson, D. S.; Man, H.-W. J. Org. Chem. 1996, 61, 6047.
(11) As the nomenclature of boronates is complex, the practical
system of Matteson et al. is adopted: Matteson, D. S.;
Kandil, A. A.; Soundararajan, R. J. Am. Chem. Soc. 1990,
112, 3964.
(12) Basu, A.; Thayumanavan, S. Angew. Chem. Int. Ed. 2002,
41, 716.
(13) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997, 36,
2282.
12c
Formula C31H44BNO4Si; space group P212121; a = 6.614(1), b =
9.610(1), c = 48.711(10) Å; V = 3096.1(9) Å3, Z = 4; rcalcd = 1.15
cm–3; m(MoKa) = 1.1 cm–1; crystal size: 0.14 × 0.28 × 0.36 mm3.
Single crystal data collection and refinement: Unique data set:
7467; Fo>4s (Fo) = 5225; variables: 520; extinction coefficient:
0.006(1); flack × parameter: –0.12(11). R1 [for Fo>4s(Fo)]
2
2
[R1 = S||Fo|-|Fc||/S|Fo|] = 0.043; wR2 [for all Fo ] {wR2 = [Sw(Fo -
Fc2)2/SwFo ]1/2} = 0.096; rmin/max = 0.18/–0.17eÅ–3.
(14) Hoppe, D.; Paetow, M.; Hintze, F. Angew. Chem., Int. Ed.
Engl. 1993, 32, 394.
4
13b
(15) (a) Horeau, A.; Kagan, H.-B.; Vigneron, J.-P. Bull. Soc.
Chim. Fr. 1968, 3795. (b) Masamune, S.; Choy, W.;
Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985,
24, 1.
(16) Lee, S.-G. Magn. Reson. Chem. 2002, 40, 311.
(17) Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. J. Am. Chem.
Soc. 1986, 108, 810.
(18) Wrackmeyer, B.; Köster, R. In Houben-Weyl Methods of
Organic Chemistry, 4th ed., Vol. 13, 3c; Köster, R., Ed.;
Thieme: Stuttgart, 1984, 377.
Formula C31H44BNO4Si; space group P212121; a = 6.182(1), b =
12.543(2), c = 39.209(6) Å; V = 3040.3(8) Å3; Z = 4; rcalcd = 1.17
cm–3; m(MoKa) = 1.1 cm–1; crystal size: 0.14 × 0.34 × 0.70 mm3.
Single crystal data collection and refinement: Unique data set:
7320; Fo>4s (Fo) = 5992; variables: 520; extinction coefficient:
0.003(1); flack × parameter: –0.01(8). R1 [for Fo>4s(Fo)]
2
2
[R1 = S||Fo|-|Fc||/S|Fo|] = 0.035; wR2 [for all Fo ] {wR2 = [Sw(Fo -
Fc2)2/SwFo ]1/2}: 0.079; rmin/max = 0.15/–0.14 eÅ–3.
4
(19) Mikenda, W. Vib. Spectrosc. 1992, 3, 327.
(20) DENZO-SMN program package, Nonius B. V., The
Netherlands.
(21) Sheldrick, G. M. SHELXS-97, A program for the solution of
crystal structures; Universität Göttingen: Germany, 1997.
(22) Sheldrick, G. M. SHELXS-97, A program for crystal
structure refinement; Universität Göttingen: Germany,
1997.
(23) The structural data of compounds 10, 12c and 13b have been
deposited at the Cambridge Crystallographic Data Centre
under the reference numbers CCDC 239224, 239226,
239225, respectively. Copies of the data can be obtained free
of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [Fax: +44 (1223)336033; e-mail:
deposit@ccdc.cam.ac.uk].
Acknowledgment
We thank the Fonds zur Förderung der wissenschaftlichen For-
schung (Project No. P14985-N03) for financial support and S. Fel-
singer and C. Tyl for recording the NMR spectra.
References
(1) Part 3: Hammerschmidt, F.; Hanninger, A.; Peric Simov, B.;
Völlenkle, H.; Werner, A. Eur. J. Org. Chem. 1999, 3511.
(2) (a) Köster, R. In Houben-Weyl Methods of Organic
Chemistry, 4th ed., Vol. 13, 3a; Köster, R., Ed.; Thieme:
Stuttgart, 1982, 616. (b) Matteson, D. S. Tetrahedron 1989,
45, 1859.
(3) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002,
58, 9633.
Synthesis 2004, No. 16, 2704–2710 © Thieme Stuttgart · New York