Asymmetric synthesis of enantiomerically enriched atropisomeric amides by desymmetrisation of N,N-dialkylmesitamides

Article abstract of DOI:10.1039/b008678i

Asymmetric synthesis of enantiomerically enriched atropisomeric amides was carried out by desymmetrisation of N,N-dialkylmesitamides. Lithiation and silylation of the latter using chiral lithium amide bases was performed. The technique of including an ele

Full text of DOI:10.1039/b008678i

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Asymmetric synthesis of enantiomerically enriched atropisomeric
amides by desymmetrisation of N,N-dialkylmesitamides†
Jonathan Clayden,* Paul Johnson and Jennifer H. Pink
1
Department of Chemistry, University of Manchester, Oxford Road, Manchester, UK M13 9PL
Received 27th October 2000, Accepted 3rd January 2001
First published as an Advance Article on the web 29th January 2001
Lithiation and silylation of N,N-dialkylmesitamides using chiral lithium amide bases leads to enantiomerically
enriched atropisomeric amides (up to 89% ee) by desymmetrisation of the enantiotopic methyl groups.
Desymmetrisation of an achiral precursor is a powerful way
of producing chiral molecules as single enantiomers, often
with the creation of several stereogenic centres in one step.1
However, desymmetrisation as a method for the asymmetric
synthesis of atropisomers (for example, biaryls) as single
enantiomers has been explored only in a very limited way. An
early result in this area was Raston’s synthesis2 of the biaryl 3.
Desymmetrisation of 1 by benzylic lithiation with n-BuLi in the
presence of (Ϫ)-sparteine, gave 2 in 40% ee (Scheme 1). More
Scheme 2 Desymmetrisation of a biphenyl by enantioselective Pd-
catalysed coupling.
element in a ligand-controlled metal-catalysed reaction, making
7 the first example of a new class of chiral ligands for palladium
chemistry.15 We made the ligand 7 as a single enantiomer by
a method whose success derives from the powerful thermo-
dynamic influence that the configuration of a stereogenic centre
may have over the conformation of an adjacent axis.16 We have
also published a method for the synthesis of enantiomerically
pure atropisomeric amides based on a dynamic thermodynamic
resolution,17 at the heart of which is the same concept.
Given the tendency for 2-alkyl substituted tertiary benz-
amides to undergo lateral lithiation with great ease,18,19 we
realised that the desymmetrisation of a 2,6-dialkylbenzamide
ought to be possible by employing a chiral base to distinguish
between two enantiotopic alkyl groups.20 In this paper we
describe a method for achieving this desymmetrisation, and
demonstrate the means by which the products may be converted
to functionalised atropisomeric amides.
We made some N,N-dialkylmesitamides 9a–c by treating
mesitoyl chloride 8 with diethylamine, diisopropylamine or
dicyclohexylamine. These three achiral amides were treated
with a range of chiral bases and the resulting organolithiums
were quenched with electrophiles to give the chiral atropisomers
10 (Scheme 3). The yields and enantiomeric excesses of the
products 10 are shown in Table 1.
Entries 1–3 indicate that the mesitamides 9 are deprotonated
by either s-BuLi 11 or LDA 12, and may be quenched with
electrophiles (Me3SiCl or acetone) to give racemic 10 in good
yield. In the light of this, we tried two types of chiral base:
firstly, s-BuLi complexed with the chiral diamine (Ϫ)-sparteine
(13)21 and, secondly, a range of chiral lithium amide bases
Scheme
1
Desymmetrisation of a biphenyl by enantioselective
lithiation.
recently, Hayashi and co-workers3–5 have succeeded in carrying
out the desymmetrising couplings of achiral aryl bis-triflates
such as 4 with aryl and alkynyl Grignards to yield products
such as 5 with near complete atroposelectivity (Scheme 2).
A desymmetrising acetal-forming reaction between 2,2Ј,6,6Ј-
tetrahydroxybiphenyl and menthone has been used to syn-
thesise atropisomeric biphenol derivatives.6
For some years, we have been investigating the stereoselective
reactions of the hindered tertiary aromatic amides 6,7,8 which
can exhibit atropisomerism about the Ar–CO bond.9,10 Most
of our work has been carried out in the racemic series, where
we have shown that the chiral Ar–CO axis of 6 is a powerful
agent for stereocontrol over long distances.11–14 We recently
found that a chiral Ar–CO axis can be the stereocontrolling
† The IUPAC name for mesitamide is 2,4,6-trimethylbenzamide.
DOI: 10.1039/b008678i
J. Chem. Soc., Perkin Trans. 1, 2001, 371–375
371
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Table 1 Desymmetrisation of 9
Entry
Base
Starting material
R =
Eϩ
=
Methoda
Yield (%)
Ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
11
11
12
13
14
14
14
14
15
16
16
17
18
19
9b
9c
9b
9a
9b
9c
9b
9b
9b
9b
9b
9b
9b
9b
i-Pr
c-Hx
i-Pr
Et
i-Pr
c-Hx
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Me3SiCl
Me3SiCl
A
A
A
A
A
A
B
C
B
A
B
100
95
74
61
54
57
55
33
64
25
45
0
—
—
—
4
78
85
89
75
62
59
79
—
—
—
Me2C᎐O
᎐
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
A
A
A
0
0
a Method A: electrophile added after deprotonation is complete (external quench). Method B: electrophile present during deprotonation (in situ
quench). Method C: external quench with LiCl added before deprotonation.
also an improvement in yield in one case. The addition of LiCl
(which is present during the deprotonation when an in situ
quench is used24) simply lowered the yield of product. The best
base of those tried was 14, which gave yields above 50% and
enantiomeric excesses in the range 75–90%. Base 15 gave better
yields, but poorer enantiomeric excesses, while 16 gave good
enantiomeric excesses but poorer yields.‡
The use of the product 10 (E = SiMe3) in the synthesis of
enantiomerically enriched atropisomers depends on its thermal
stability to racemisation.9,25 We determined the barrier to
Scheme 3 Desymmetrisation of a mesitamide by enantioselective
deprotonation.
racemisation9 ∆G‡ of 10b (E = SiMe3) to be 101.9 0.3 kJ
rac
molϪ1 at 50 ЊC (giving a half-life to racemisation of approxi-
mately 24 h at 25 ЊC) by following the decay in optical rotation
with time, and the barrier to racemisation ∆G‡ of 10c
rac
(E = SiMe3) to be 99.5 0.3 kJ molϪ1 at 35 ЊC (giving a half-life
to racemisation of approximately 9 h at 25 ЊC) by following the
decay in ee with time by HPLC.§ Both barriers are too low for
this method to be a truly practical route to enantiomerically
pure ligands related to 7 since some racemisation must be
expected during subsequent transformations of 10.
Nonetheless, we found that it was possible to use a regio-
selective lithiation of 10b (E = SiMe3) to introduce further
functionality.¶ Lithiation of 10b (E = SiMe3) with s-BuLi is
irreversible, and gave a mixture of organolithiums, leading to
a 2:1 mixture of methylated products 20 and 21 on treatment
with MeI (Scheme 4). However, by using LDA to carry out a
reversible lithiation, leading to the most thermodynamically
stable organolithium, we were able to obtain a single regio-
isomer of the product 20. Further functionalisation of
the remaining methyl group and removal of the silyl group
opens up many possibilities for using the desymmetrisation
as the starting point for a range of enantiomerically enriched
atropisomeric amides. Alternatively, alkenes can be made from
10 by Peterson olefination: lithiation of 10b (E = SiMe3) with
LDA followed by a cyclobutanone quench gave the unsaturated
amide 22 in 92% yield.
14–19 which have performed well in a number of other classes
of desymmetrisation reactions.22,23
The complex 13 rarely performs well in THF,21 and we found
that the product of lithiation and silylation of 9a with this base
was essentially racemic (entry 4). In fact, unless the (Ϫ)-
sparteine was carefully degassed prior to use, the major product
from these lithiations was that of oxidation, 10a (E = OH),
in unknown ee.
Experimental
General
1H and 13C NMR spectra were recorded on either Varian
XL300 (300 and 75 MHz) or Bruker XC300 (300 and 75 MHz)
Experiments with lithium amide bases were much more
successful. The amides 9b and 9c were deprotonated by all
of 14–16 (but not 17–19, which failed to lithiate 9c) and gave
10 (E = SiMe3) in good to excellent enantiomeric excess after
quenching with Me3SiCl. The technique of including the
electrophile (Me3SiCl) in situ in the reaction mixture appeared
to lead to a slight improvement in enantiomeric excess, and
‡ The absolute stereochemistry of the products 10 is unknown.
§ Values for rates of racemisation at 25 ЊC are estimated assuming
∆G‡ to be constant (i.e. ∆S‡ Ӎ0). Entropies of activation for
rac
rac
bond rotations are frequently,26 though not always,27 small, and in a
similar compound to 10 (E = SiMe3) we determined a value of
15
|∆S‡rac| < 30 J molϪ1 KϪ1
.
¶ The reactions in Scheme 4 were carried out using racemic 10b.
372
J. Chem. Soc., Perkin Trans. 1, 2001, 371–375

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m/z (CI) 248 (MHϩ, 100%), 147 (15%), [Found Mϩ 247.1939,
C16H25NO requires M 247.1936].
N,N-Dicyclohexyl-2,4,6-trimethylbenzamide 9c
2,4,6-Trimethylbenzoyl chloride (2 g) was added to dicyclo-
hexylamine (10 ml). The reaction mixture was stirred at
room temperature for 4 days, dissolved in CH2Cl2, washed
with saturated aqueous ammonium chloride and dried over
magnesium sulfate. The solvent was removed under reduced
pressure. Purification of the crude product by flash chroma-
tography28 (petrol–EtOAc 9:1) gave the title compound (1.51 g,
42%) as a white foam which slowly solidified, mp 114–115 ЊC;
δH (300 MHz, CDCl3) 6.79 (2 H, s), 3.15 (2 H, tt, J 3.5, 11.5),
3.04, (2 H, tt, J 3.5, 11.5), 2.77 (2 H, br dq, J 3.5, 12.5), 2.26
(3 H, s), 2.22 (6 H, s), 1.82–1.84 (2 H, m), 1.61–1.70 (6 H, m),
1.39–1.50 (4 H, m), 1.26–1.30 (4 H, m), 1.00 (2 H, br s); δC (75
MHz, CDCl3) 170.6, 136.7, 135.5, 132.9, 128.0, 59.8, 55.9, 31.6,
29.9, 26.6, 25.7, 25.3, 25.1, 21.0, 18.9; m/z (CI) 328 (MHϩ,
100%), 147 (15%). Found Mϩ, 327.2563; C22H33NO requires M
327.2562.
Scheme 4 Transformations of 10b. a Yield from 1H NMR spectrum of
crude reaction product on using s-BuLi as the base. b Isolated yield on
using LDA as the base (100% 20).
( )-N,N-Diisopropyl-2,4-dimethyl-6-trimethylsilylmethyl-
benzamide ( )-10b (E ؍ SiMe3)
spectrometers. Mass spectra were recorded using Chemical
Ionisation (CI) on a Fisons VG Trio 2000 or a Concept IS
(HRMS) spectrometer. Infra-red spectra were recorded on an
ATi Genesis Series FTIR spectrometer. All samples were run
as an evaporated film on a sodium chloride plate. Petrol refers
to petroleum ether, bp 40–60 ЊC.
sec-Butyllithium (0.4 ml, 1.4 M) was added to a solution of
N,N-diisopropyl-2,4,6-trimethylbenzamide 9b (124 mg) in THF
(10 ml) under an atmosphere of nitrogen at Ϫ78 ЊC. The orange
reaction mixture was stirred at this temperature for 30 min,
chlorotrimethylsilane (0.5 ml) was added, and the mixture was
allowed to warm to room temperature. Saturated aqueous
ammonium chloride was added and the mixture was extracted
with ether. The combined extracts were washed with water,
dried over magnesium sulfate, and concentrated under reduced
pressure to give the crude product. Purification of the crude
product by flash chromatography28 (petrol–EtOAc 9:1) gave
the title compound (318 mg, quantitative) as a colourless oil,
Rf 0.19 (petrol–EtOAc 9:1), νmax (film)/cmϪ1 2962, 2900, 1631,
853; δH (300 MHz, CDCl3) 6.72 (1 H, s), 6.66 (1 H, s), 3.62 (1 H,
sept, J 6.5), 3.47 (1 H, sept, J 7.0), 2.25 (3 H, s), 2.22 (3 H, s),
2.00 (1 H, d, J 13.5), 1.93 (1 H, d, J 13.5), 1.58 (6 H, d, J 7.0),
1.10 (3 H, d, J 6.5), 1.07 (3 H, d, J 6.5), 0.02 (9 H, s); δC (75
MHz, CDCl3) 170.38, 136.4, 136.3, 134.1, 133.3, 126.6, 126.5,
50.5, 45.5, 23.5, 21.1, 21.1, 20.9, 20.4, 20.4, 19.0, Ϫ1.2; m/z (CI)
320 (MHϩ, 100%), 304 (35%), 147 (55%). Found: Mϩ 319.2327;
C19H33NOSi requires M, 319.2331.
N,N-Diethyl-2,4,6-trimethylbenzamide 9a
2,4,6-Trimethylbenzoyl chloride (0.80 ml, 4.82 mmol) was
added dropwise to a rapidly stirred diethylamine (10 ml) cooled
in an ice-bath. The reaction mixture was allowed to stir under a
nitrogen atmosphere at room temperature for 16 h. Dichloro-
methane (20 ml) and water (20 ml) were added and the aqueous
phase was extracted with dichloromethane (2 × 20 ml). The
combined organic extracts were washed with water (20 ml),
dilute HCl (2 M, 20 ml), saturated aqueous sodium hydrogen
carbonate solution (20 ml) and brine (20 ml), dried over
magnesium sulfate and filtered. The solvent was removed under
reduced pressure and the residue was purified by flash chroma-
tography28 [4:1 light petroleum–ethyl acetate (Rf 0.36, 7:3 light
petroleum–ethyl acetate)] to afford the amide as a white crystal-
line solid (0.92 g, 87%), mp 35 ЊC; νmax (Nujol mull)/cmϪ1 1643;
δH (300 MHz, CDCl3) 6.86 (2H, s, ArH), 3.63 (2H, q, J 7,
NCH2CH3), 3.14 (2H, q, J 7, NCH2CH3), 2.29 (3H, s,
p-ArCH3), 2.23 (6H, s, 2 × o-ArCH3), 1.29 (3H, t, J 7,
NCH2CH3), 1.15 (3H, t, J 7, NCH2CH3); δC (75 MHz, CDCl3)
170.5 (s, CO), 137.5 (s, p-CCH3), 134.0 (s, CCO), 133.3 (s, 2 ×
o-CCH3), 128.1 (d, 2 × ArH), 42.2 (t, NCH2), 38.2 (t, NCH2),
21.0 (q, p-ArCH3), 18.8 (q, 2 × o-CCH3), 13.8 (q, NCH2CH3),
12.6 (q, NCH2CH3); m/z (CI) 221 (22%), 220 (100%), 147
(39%). Found: Mϩ 219.1625; C14H21NO requires M 219.1623.
The enantiomers of ( )-10b (E = SiMe3) could be resolved
analytically by HPLC using a Chiralpak AD 250 × 4.6 mm
chiral stationary phase, Merck–Hitachi system, eluant 2%
EtOH in hexane, flow rate 1 ml minϪ1, UV detection at 255 nm,
retention times 7.08 and 8.71 min.
( )-N,N-Diisopropyl-2,4-dimethyl-6-(2-hydroxy-2-methyl-
propyl)benzamide ( )-10b (E ؍ Me2COH)
sec-Butyllithium (0.37 ml, 1.3 M solution in cyclohexane,
0.481 mmol) was added dropwise to a solution of the N,N-
diisopropyl-2,4,6-trimethylbenzamide 9b (108 mg, 0.437 mmol)
in THF (30 ml) at Ϫ78 ЊC under an atmosphere of nitrogen.
The resultant orange solution was stirred at Ϫ78 ЊC for 1.25 h.
Acetone (48 µl, 0.656 mmol) was added, the mixture
was warmed to 0 ЊC, water (30 ml) was added, and the THF was
removed under reduced pressure. The aqueous phase was
extracted with dichloromethane (3 × 25 ml) and the combined
organic extracts were washed with water (30 ml), brine (30 ml),
dried over magnesium sulfate and filtered. The solvent was
evaporated and the crude product purified by flash chrom-
atography28 [5:1 light petroleum–ethyl acetate, Rf 0.13] to give
the title compound as a white crystalline solid (98 mg, 74%),
mp 106 ЊC; νmax (Nujol mull)/cmϪ1 1598; δH (300 MHz, CDCl3)
6.92 (2H, s, ArH), 4.59 (1H, s, OH), 3.59 (1H, sept, J = 6.7,
N,N-Diisopropyl-2,4,6-trimethylbenzamide 9b
2,4,6-Trimethylbenzoyl chloride (3 g) was added to diisoprop-
ylamine (10 ml). The reaction mixture was heated to reflux for
6 h, cooled to room temperature, dissolved in CH2Cl2, washed
with saturated aqueous ammonium chloride and dried over
magnesium sulfate. The solvent was removed under reduced
pressure. Recrystallisation of the crude product (petrol–EtOAc)
gave the pure title compound (3.21 g, 79%) as a white crystalline
solid, mp 106–107 ЊC, Rf 0.50 (petrol–EtOAc 2:1), νmax (film)/
cmϪ1 2963, 2929, 1621; δH (300 MHz, CDCl3) 6.82 (2 H, s), 3.65
(1 H, sept, J 6.5), 3.51 (1 H, sept, J 7.0), 2.27 (3 H, s), 2.25 (6 H,
s), 1.60 (6 H, d, J 7.0), 1.11 (6 H, d, J 6.5); δC (75 MHz, CDCl3)
170.5, 137.0, 135.4, 133.2, 128.1, 50.7, 45.8, 21.1, 20.6, 18.9;
J. Chem. Soc., Perkin Trans. 1, 2001, 371–375
373

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NCH), 3.57 (1H, sept, J = 6.7, NCH), 2.71 (2H, AB q, J = 13.6,
ArCHAHBCOH), 2.35 (3H, s, ArCH3), 2.29 (3H, s, ArCH3),
1.68 (3H, d, J = 6.9, NCHCH3), 1.61 (3H, d, J = 6.7, NCH-
CH3), 1.34 (3H, s, COHCH3), 1.23 (3H, s, COHCH3), 1.19 (3H,
d, J = 6.7, NCHCH3), 1.07 (3H, d, J = 6.6, NCHCH3); δC (75
MHz, CDCl3) 172.5 (s, CO), 137.0 (s, Ar), 135.3 (s, Ar), 134.1
(s, Ar), 132.8 (s, Ar), 129.0 (d, Ar), 129.0 (d, Ar), 69.2 (s, COH),
50.9 (d, NCH), 46.0 (d, NCH), 46.0 (t, ArCH2), 32.6 (q,
CH3COH), 28.1 (q, CH3COH), 21.1 (q, ArCH3), 21.1 (q,
NCHCH3), 20.5 (q, NCHCH3), 20.5 (q, NCHCH3), 20.3 (q,
NCHCH3), 18.9 (q, ArCH3); m/z (CI) 306 (100%), 288 (10), 247
(9), 232 (8), 147 (9). Found: (M ϩ H)ϩ 306.2436; C19H32NO2
requires M 306.2433.
CH2CH3), 0.00 (9H, s, Si(CH3)3); δC (75 MHz, CDCl3) 170.4
(s, CO), 136.9 (s, Ar), 136.4 (s, Ar), 133.6 (s, Ar), 132.8 (s, Ar),
126.7 (d, Ar), 126.6 (d, Ar), 42.3 (t, NCH3), 38.5 (t, NCH3), 23.4
(t, CH2Si), 21.1 (q, ArCH3), 19.2 (q, ArCH3), 13.8 (q, CH2CH3),
12.6 (q, CH2CH3), 1.1 (q, Si(CH3)3); m/z (EI) 294 (12%), 293
(44%), 292 (100%), 276 (21%), 219 (11%). Found: M 291.2023;
C17H29NOSi requires M 291.2018.
HPLC analysis was performed on a Chiralpak stationary
phase (250 × 10 mm), eluant 1% ethanol in hexane, flow rate
2.4 ml minϪ1, UV detection at 255 nm, retention times 9.00
(47.3%) and 9.81 min (50.87%), ee = 3.6%.
General method for desymmetrisation of 9 with chiral lithium
amide bases
( )-N,N-Dicyclohexyl-2,4-dimethyl-6-trimethylsilylmethyl-
benzamide ( )-10c (E ؍ SiMe3)
(؉)-N,N-Diisopropyl-2,4-dimethyl-6-trimethylsilylmethyl-
benzamide (؉)-10b (E ؍ SiMe3). sec-Butyllithium (1.2 eq.) was
added to a solution of chiral amine (1.3 eq.) in THF (ca. 0.1 M)
at Ϫ78 ЊC. The solution was allowed to warm to 0 ЊC for 15 min
and cooled to Ϫ78 ЊC. For the internal quench experiments,
chlorotrimethylsilane (5 eq.) was added, followed by the amide
9 (1 eq.) in THF. For the external quench experiments, amide 9
(1 eq.) in THF was added, the reaction mixture was stirred at
Ϫ78 ЊC for 30 min, and chlorotrimethylsilane (2 eq.) was added.
The product was poured into ice-cold saturated aqueous
ammonium chloride and quickly extracted into ether, dried
over magnesium sulfate and concentrated to give a crude
product which was purified by flash chromatography28 (eluting
with chilled petrol–EtOAc 4:1, and cooling collected fractions
in ice) to give the silylated amide with spectroscopic data
identical with that of the racemic material. Enantiomeric
sec-Butyllithium (0.21 ml, 1.3 M solution in hexanes, 0.336
mmol) was added dropwise to a solution of N,N-dicyclo-
hexyl-2,4,6-trimethylbenzamide 9c (100 mg, 0.305 mmol) in
THF (20 ml) at Ϫ78 ЊC under an atmosphere of nitrogen.
The resultant orange solution was stirred for 1 h at Ϫ78 ЊC.
Chlorotrimethylsilane (58 µl, 0.458 mmol) was added. The
colourless solution was allowed to warm to 0 ЊC, water (20 ml)
was added and the THF was removed under reduced pressure.
The aqueous phase was extracted with dichloromethane (3 ×
20 ml). The combined organic extracts were washed with water
(20 ml), dried over magnesium sulfate, filtered and con-
centrated. Flash chromatography28 (7% ethyl acetate in light
petroleum) gave the silane ( )-10c (E = SiMe3) as a colourless
oil (105 mg, 95%), νmax (film)/cmϪ1 1626; δH (300 MHz, CDCl3)
6.69 (1H, s, ArH), 6.63 (1H, s, ArH), 3.20–2.92 (2H, br m,
2 × NCH), 2.86–2.66 (2H, br m, CH2’s), 2.24 (3H, s, ArCH3),
2.19 (3H, s, ArCH3), 2.40–1.87 (2H, AB q, J 13.5, ArCHAHB),
1.90–0.80 (18H, br m, CH2’s), 0.00 (9H, s, Si(CH3)3); δC (75
MHz, CDCl3) 170.6 (s, CO), 136.2 (s Ar), 135.9 (s, Ar), 134.2
(s, Ar), 133.1 (s, Ar), 126.5 (d, Ar), 126.4 (d, Ar), 59.6 (d, NCH),
55.8 (d, NCH), 31.5, 31.5, 29.8, 29.8, 29.6, 26.7, 26.6, 25.6, 25.3,
25.1 and 23.4 (d, CH2’s), 21.1 (q, ArCH3), 19.1 (q, ArCH3),
Ϫ1.2 (q, Si(CH3)3); m/z (EI) 399 (8%), 384 (27), 316 (28), 302
(100), 220 (30), 147 (45), 73 (46). Found: Mϩ 399.2953;
C19H41NOSi requires M 399.2957.
1
excesses were calculated by H NMR in the presence of 4 eq.
of the shift reagent 2,2,2-trifluoro-1-(9-anthryl)ethanol,29,30
examining splitting of the signals of the 4- and 6-methyl
singlets. The optical rotation of a sample of 10b (E = SiMe3) of
39% ee was found to be: [α]D24 = ϩ15.0 [c = 1.0, CHCl3].
The barrier to racemisation of 10b (E = SiMe3) was estab-
lished by monitoring the optical rotation of a solution of
the amide (in chloroform, using a mercury source at 578 nm)
in a jacketed cell at a constant temperature of 50 ЊC. A smooth
first-order decay curve was obtained from which the rate
constant for racemisation (k) was calculated using the curve-
fitting application “Ultrafit” for the Macintosh.9
The barrier to racemisation of 10c (E = SiMe3) was estab-
lished by resolving a small sample of racemic material using
an analytical Chiralpak-AD HPLC column and monitoring by
HPLC its racemisation on heating in hexane at 35 ЊC.9
The enantiomers of ( )-10c (E = SiMe3) could be resolved
analytically by HPLC using a Chiralpak AD 250 × 10 mm
chiral stationary phase, Merck–Hitachi system, flow rate 2.4 ml
minϪ1, eluant 1% ethanol in hexane, UV at 255 nm, retention
times 7.62 and 8.70 min.
Desymmetrisation of N,N-diethyl-2,4,6-trimethylbenzamide 9a
with s-BuLi-(؊)-sparteine
N,N-Diisopropyl-2-(1-trimethylsilyl)ethyl-4,6-dimethyl-
benzamide 20. sec-Butyllithium (0.8 ml, 1.4 M solution in
hexanes, 1.1 eq.) was added to a solution of diisopropylamine
(0.16 ml, 1.2 eq.) in THF (20 ml) at Ϫ78 ЊC under nitrogen.
The solution was allowed to warm to 0 ЊC for 15 min, cooled
to Ϫ78 ЊC, and N,N-diisopropyl-2,4-dimethyl-6-trimethylsilyl-
methylbenzamide 10b (E = SiMe3) (260 mg, 1 eq.) was added.
The dark brown solution was stirred for 30 min at Ϫ78 ЊC,
methyl iodide (0.15 ml) was added, and the mixture was allowed
to warm to room temperature. Phosphoric acid (aqueous,
0.5 M) was added, and the mixture was extracted into EtOAc,
dried over magnesium sulfate and concentrated. The crude
product was purified by flash chromatography28 to give the
title compound (196 mg, 71%) as a waxy solid; νmax (film)/cmϪ1
2975, 2949, 2924, 2904, 2872, 1618, 1332; δH (300 MHz, CDCl3)
6.78 (2 H, s), 3.73 (1 H, sept, J 6.5), 3.50 (1 H, sept, J 6.5), 2.27
(3 H, s), 2.24 (3 H, s), 2.01 (1 H, q, J 7.5), 1.59 (3 H, d, J 6.5),
1.57 (3 H, d, J 6.5), 1.29 (3 H, d, J 7.5), 1.12 (3 H, d, J 6.5), 1.11
(3 H, d, J 6.5), 0.09 (9 H, s); δC (75 MHz, CDCl3) 170.3, 142.9,
137.0, 135.8, 133.4, 127.7, 126.3, 50.3, 45.7, 26.1, 21.9, 21.3,
20.9, 20.5, 20.3, 19.5, 19.3, Ϫ1.7; m/z (CI) 334 (MHϩ, 100%).
Found (M ϩ H)ϩ 334.2571. C20H36NOSi requires M 334.2566.
sec-Butyllithium (0.386 ml, 1.3 M solution in hexanes, 0.502
mmol) was added to a solution of freshly distilled and degassed
sparteine (0.115 ml, 0.502 mmol) in THF (10 ml) at Ϫ78 ЊC and
under an atmosphere of nitrogen. After stirring for 15 min the
solution was transferred via a cannula to a solution of N,N-
diethyl-2,4,6-trimethylbenzamide 9a (100 mg, 0.456 mmol) in
THF (20 ml) at Ϫ78 ЊC. The resultant orange–red solution was
stirred for 5 min, and chlorotrimethylsilane (87 µl, 0.684 mmol)
was added. The colourless solution was allowed to warm
to 0 ЊC. Water (20 ml) was added and the THF was removed
under reduced pressure. The aqueous phase was extracted
with dichloromethane (3 × 15 ml) and the combined organic
extracts were washed with water (20 ml), dried over magnesium
sulfate, filtered and concentrated. Purification by flash chrom-
atography28 (10% ethyl acetate in light petroleum, Rf 0.19)
afforded the silane as a colourless oil (81 mg, 61%); δH (300
MHz, CDCl3) 6.70 (1H, s, ArH), 6.66 (1H, s, ArH), 3.66–3.42
(2H, m, CH2CH3), 3.16–2.96 (2H, m, CH2CH3), 2.24 (3H,
s, ArCH3), 2.16 (3H, s, ArCH3), 1.96–1.82 (2H, AB q, J 13.7,
CHAHBTMS), 1.23 (3H, t, J 7.1, CH2CH3), 0.98 (3H, t, J 7.1,
374
J. Chem. Soc., Perkin Trans. 1, 2001, 371–375

View Article Online
9 A. Ahmed, R. A. Bragg, J. Clayden, L. W. Lai, C. McCarthy,
J. H. Pink, N. Westlund and S. A. Yasin, Tetrahedron, 1998, 54,
13277.
N,N-Diisopropyl-2-cyclobutylidenemethyl-4,6-dimethyl-
benzamide 22. In a similar way, sec-butyllithium (0.24 ml, 1.4 M
solution in hexanes), diisopropylamine (0.06 ml), N,N-diiso-
propyl-2,4-dimethyl-6-trimethylsilylmethylbenzamide 10b (E =
SiMe3) (79 mg) and cyclobutanone (0.04 ml, 2 eq.) gave a crude
product which was purified by flash chromatography28 to give
the title compound (68 mg, 92%) as an oil; νmax (film)/cmϪ1 2976,
2946, 2899, 2862, 1616, 1330; δH (300 MHz, CDCl3) 6.93 (1 H,
s), 6.84 (1 H, s), 6.10 (1 H, quintet, J 2.2), 3.62 (1 H, sept, J 6.5),
3.51 (1 H, sept, J 6.5), 3.1 (1 H, m), 2.9 (2 H, m), 2.8 (1 H, m),
2.31 (3 H, s), 2.26 (3 H, s), 2.1 (2 H, m), 1.63 (3 H, d, J 6.5), 1.61
(3 H, d, J 6.5), 1.51 (3 H, d, J 7.5); δC (75 MHz, CDCl3) 170.3,
145.3, 136.7, 134.2, 133.5, 133.3, 128.4, 124.5, 118.2, 50.8, 45.8,
32.6, 32.6, 21.3, 21.0, 20.55, 20.5, 20.4, 18.8, 18.1.
10 P. Bowles, J. Clayden, M. Helliwell, C. McCarthy, M. Tomkinson
and N. Westlund, J. Chem. Soc., Perkin Trans. 1, 1997, 2607.
11 J. Clayden, M. N. Kenworthy and L. H. Youssef, Tetrahedron Lett.,
2000, 41, 5171.
12 J. Clayden, N. Westlund and F. X. Wilson, Tetrahedron Lett., 1999,
40, 3331.
13 A. Ahmed, J. Clayden and M. Rowley, Tetrahedron Lett., 1998, 39,
6103.
14 J. Clayden and J. H. Pink, Tetrahedron Lett., 1997, 38, 2561.
15 J. Clayden, P. Johnson, J. H. Pink and M. Helliwell, J. Org. Chem.,
2000, 65, 7033.
16 J. Clayden, J. H. Pink and S. A. Yasin, Tetrahedron Lett., 1998, 39,
105.
17 J. Clayden and L. W. Lai, Angew. Chem., Int. Ed. Engl., 1999, 38,
2556.
18 R. D. Clark and A. Jahangir, Org. React., 1995, 47, 1.
19 J. J. Court and D. J. Hlasta, Tetrahedron Lett., 1996, 37, 1335.
20 T. Hata, H. Koide and M. Uemura, Synlett, 2000, 1145. For the use
of a chiral base to distinguish between enantiomeric molecules
of a rotationally restricted amide (and hence give rise to a kinetic
resolution), see S. Thayumanavan, P. Beak and D. P. Curran,
Tetrahedron Lett., 1996, 37, 2899.
Acknowledgements
We are grateful to the EPSRC and the Leverhulme Trust for
grants, and to Dr Peter O’Brien (University of York) for kind
donations of the diamine precursors to 18 and 19.
21 D. Hoppe and T. Hense, Angew. Chem., Int. Ed. Engl., 1997, 36,
2282.
22 K. Bambridge, B. P. Clark and N. S. Simpkins, J. Chem. Soc., Perkin
Trans. 1, 1995, 2535.
23 P. O’Brien, J. Chem. Soc., Perkin Trans. 1, 1998, 1439.
24 B. J. Bunn, N. S. Simpkins, Z. Spavold and M. J. Crimmins, J. Chem.
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