Conformational preference in aromatic amides bearing chiral ortho substituents: Its origin and application to relayed stereocontrol

Article abstract of DOI:10.1039/b514557k

Tertiary aromatic amides bearing stereogenic centres ortho to the amide group may adopt two diastereoisomeric conformations which interconvert slowly on the NMR timescale at ambient temperature, and are therefore detectable by NMR. Certain classes of ster

Full text of DOI:10.1039/b514557k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Conformational preference in aromatic amides bearing chiral ortho
substituents: its origin and application to relayed stereocontrol
Mark S. Betson, Jonathan Clayden,* Madeleine Helliwell, Paul Johnson, Lai Wah Lai, Jennifer H. Pink,
Christopher C. Stimson, Neoclis Vassiliou, Neil Westlund, Samreen A. Yasin and Latifa H. Youssef
Received 13th October 2005, Accepted 23rd November 2005
First published as an Advance Article on the web 22nd December 2005
DOI: 10.1039/b514557k
Tertiary aromatic amides bearing stereogenic centres ortho to the amide group may adopt two
diastereoisomeric conformations which interconvert slowly on the NMR timescale at ambient
temperature, and are therefore detectable by NMR. Certain classes of stereogenic centre—particularly
sulfoxides, ephedrine-derived oxazolidines, and proline-derived imidazolidines—strongly bias the
population of the two conformers. We propose a model, supported by molecular mechanics
calculations, which rationalises the sense and magnitude of the conformational selectivity attained in
terms of the steric and electronic properties of the controlling centre. The control over conformation
may be exploited either by trapping the favoured conformer as an atropisomer, or by using it to relay
information about the stereochemistry of the controlling centre.
to surprisingly high levels of conformational control, mainly
in 1-naphthamides.17 These observations have covered such chi-
Introduction
ral groups as 1-silylethyl18,19 and 1-stannylethyl20,21 groups, 1-
hydroxyalkyl3,6 and 1-aminoalkyl22,23 groups, sulfinyl groups9,15,24
and oxazolidinyl14,25,26 and imidazolidinyl14,27 groups derived by
condensation of aldehydes with (−)-ephedrine or with a diamine
derived from (−)-proline. In this paper, we now report in full
our studies of the ability of these and other chiral groups to
control the orientation of tertiary aromatic amides in general,
and offer a qualitative and quantitative rationalisation for some
of the observations by molecular modelling, and we show how
the conformational control achieved can be applied to the use of
amides to relay stereochemical control.
Tertiary aromatic amides bearing at least one ortho substituent,
such as 1, adopt conformations in which the ring and the amide
group lie more or less perpendicular.1,2 Given an unsymmetrically
substituted aromatic ring, this feature gives rise to enantiomeric
conformers P-1 and M-1 (Scheme 1) and we3–9 and others10,11 have
studied the rate at which these conformers interconvert. In many
2,6-disubstituted amides,1,3 the rate of conformer interconversion
is, in principle12 (and in many cases, in practice3,5,7,9,10,13–16), slow
enough for them to become atropisomers, separable into axially
chiral stereoisomers. 2-Substituted benzamides 1 with only one
ortho substituent are typically not atropisomeric (Scheme 1),3,†
but Ar–CO rotation in such compounds is nonetheless slow on
the NMR timescale (a half-life for Ar–CO rotation of the order of
0.01 s), a feature which allows dynamic NMR methods to be used
as a means of determining rotational barriers.3,4
Earlier observations
We have previously shown, in a series of publications,1,6,19,21,22,28,29
that the perpendicular architecture of an aromatic amide is able
to exert kinetic stereochemical control over the formation of
new stereogenic centres, leading to the synthesis of atropisomeric
diastereoisomers with high levels of stereoselectivity. Among the
best of these stereoselective reactions is the lateral lithiation–
electrophilic substitution of 2-ethyl naphthamide 2,19,21 which on
stannylation gives the anti product anti-3 (Scheme 2).21 The first
indication that the newly formed stereogenic centre was able to
reverse the sense of stereocontrol in the reaction which formed
it came when we were isolating the stannane anti-3:20,21 even
gentle heating was enough to promote its equilibration, by Ar–
CO rotation, to the apparently more stable syn isomer. After 48 h
at 65 ◦C in toluene, a 97 : 3 ratio of atropisomers in favour of the
syn isomer was observed by integration of the NMR spectrum of
the equilibrated mixture.21
Scheme 1 Conformers of tertiary benzamides.
Given an unsymmetrically and chirally substituted ring, the
two conformers of 1 about the Ar–CO bond become di-
astereoisomeric, with their relative stability and therefore the
ratio in the equilibrating mixture determined by the relative
importance of the diastereoisomeric interactions between the
chiral axis and chiral substituent X. In previous publications
we have reported scattered observations that this effect can lead
2-Substituted tertiary naphthamides such as 2 typically exhibit
barriers to Ar–CO rotation of >100 kJ mol−1:3,9 their Ar–CO
conformers are atropisomeric (with a half-life for diastereoiso-
meric interconversion at room temperature typically of the order
School of Chemistry, University of Manchester, Oxford Road, Manchester,
UK M13 9PL. E-mail: clayden@man.ac.uk; Fax: +44 161 275 4939
† The principal exceptions are peri-substituted naphthamides. See ref. 5.
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Scheme 2 Equilibration between diastereoisomeric atropisomers.
of hours or more) and equilibrate only on heating. 2-Substituted,
6-unsubstituted tertiary benzamides 1 by contrast have barriers to
Ar–CO rotation typically of only around 70 kJ mol−1: their Ar–
CO conformers interconvert rapidly at room temperature (t1/2 ca.
0.01 s).3 This rate is however still slow on the NMR timescale,30
and NMR analysis of the benzamides 47,31 bearing a chiral 2-
substituent confirmed that indeed two conformers (Scheme 3) were
clearly discernible in the NMR spectrum at, or for 4b just below,
room temperature. The ratio of conformers was easily established
by integration of the spectra: 4a shows two conformers in the ratio
88 : 12 at 23 ◦C, 4b two conformers in the ratio 78 : 22 at −20 ◦C.
Fig. 1 shows a portion of the NMR spectrum (the upfield CHMe2
signal) of 4a.
Fig. 2
2-substituted naphthamides of the general structure 5 (Fig. 2a–c).
In this model, S, M and L are the smallest, medium-sized and
largest groups at the stereogenic centre, respectively. We propose
that the favoured conformation, shown in Fig. 2 as A, is one in
which the smallest group S more or less eclipses the amide Ar–CO
bondwhilethe largest group L occupies a positionas far as possible
from the amide’s bulky N-substituents. Similar conformations are
well established for chiral centres next to alkene p systems.32 Fig. 2a
illustrates the way we shall usually draw this conformer of 5 and 6;
Fig. 2b represents a perspective view of the same conformer; Fig. 2c
represents this conformer in the form of a Newman projection
along what we will term the “Ar–X* bond”; Fig. 2d shows the
same conformation as a Newman projection along the Ar–CO
bond. The angle h may lie anywhere in the region of 90–120◦ and
φ anywhere in the region of 90◦: the difference in h between Fig. 2b
and 2c is due to the need for representational clarity and is not
intended to carry any significance (i.e., while the two show slightly
different conformations they are intended to represent the same
conformer33).
Scheme 3 Conformers of 2-(1-silyl)ethyl benzamide 4.
Fig. 1 A portion of the 1H NMR spectrum of 4, illustrating the presence
of two diastereoisomeric conformers.
Results and analysis
Conformational control in aromatic amides bearing chiral
2-substituents
The X-ray crystal structure of 4a led us to put forward a model to
account for the conformational preference of 4a7,17 which we now
propose to refine and use to rationalise conformational preferences
in both 2-substituted benzamides of the general structure 6 and in
Several naphthamides 5 bearing chiral 2-substituents were avail-
able from diverse research projects, and Table 1 summarises
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Table 1 Conformational preferences in naphthamides 5 bearing chiral 2-substituents
Entry
1
Compound
R
Ratio of diastereoisomers A : B
Solvent
Toluene
T/◦C
65
Reference
5a
—
60 : 40
21
2
3
5b
5c
—
94 : 6
Toluene
Toluene
65
60
20
21
Me
88 : 12
4
5
5d
5e
Bu
Me
97 : 3
62 : 38
Toluene
Dioxane
65
62
21
3
6
7
8
56 : 44a
58 : 42
51 : 49
64 : 36
63 : 37a
65 : 35
64 : 36
59 : 41a
11 : 89
82 : 18
Dioxane
Dioxane
Toluene
Dioxane
Dioxane
EtOH
Dioxane
Dioxane
Toluene
CDCl3
60
55
60
61.5
61.5
60
60
62
3
3
3
3
3
3
3
3
5f
Et
Bu
5g
9
10
11
12
13
14
15
5h
Ph
5i
5j
t-Bu
Me
110
60
34
22
16
17
5k
5l
Bu
Me
80 : 20
62 : 38
CDCl3
CDCl3
60
60
22
22
18
19
5m
5n
Bu
—
47 : 53
>90 : 10
CDCl3
Toluene
60
110
22
14
20
21
—
—
>90 : 10
>95 : 5
Toluene
Toluene
110
110
14
14
5o
5p
22
23
—
Me
>95 : 5a
99.5 : 0.5
Toluene
CDCl3
110
25
14
24
24
25
26
5q
5r
5s
t-Bu
Ph
p-Tol
>98 : 2
>98 : 2
>99 : 1
CDCl3
CDCl3
CDCl3
25
25
25
24
24
24
a N,N-Diethylamide.
the ratios obtained when the atropisomeric diastereoisomers of
these naphthamides were thermally equilibrated by heating in
solution.
of compounds bearing electronically similar S, M and L groups.
For example, while 5b–d, with L = SiR3 or SnR3 and M = Me
show high selectivity, in 5a, with L = Et and M = Me, selectivity
is poor. We made 8, the benzamide analogue of 5a, by lateral
lith◦iation and ethylation of 7 (Scheme 4); its NMR spectrum at
23 C in C6D6 showed two sets of peaks in a predictably almost
unbiased ratio of 55 : 45. We confirmed that these represented
diastereoisomeric conformers by variable temperature NMR (VT
1. 2-Alkyl, 2-(1ꢀ-trialkylsilyl)ethyl and 2-(1ꢀ-trialkylstannyl)-
ethyl substituents. The equilibrated ratios of atropisomers of the
naphthamides in Table 1, entries 1–4, suggest that steric contrast
between M and L is essential for good selectivity in these groups
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conformations both with L more or less perpendicular to the plane
of the ring. Of these, the favoured conformation approximates to
that shown in Fig. 2, with 100◦ < h < 130◦ in both cases, in
other words, H almost but not quite eclipsing the Ar–CO bond.
Secondly, it confirms that in 4a with L = SiR3, the most stable
conformations of the two Ar–CO conformers differ in energy ◦by
4.05 kJ mol−1, corresponding to a conformational ratio at 25 C
of 80 : 20. The same is not true for 8 with L = Et, in which the
most stable conformations of the two Ar–CO conformers differ
by only 1.51 kJ mol−1, corresponding to a ratio of 55 : 45 at
25 ◦C. The absolute values of these figures are remarkably close to
the experimentally determined ratios of 88 : 12 for 4a and 55 : 45
for 8.
In further support of the model in Fig. 2, though only insofar
as the crystalline state gives an impression of conformation
in solution, analysis of the X-ray crystal structures of some
benzamides 4a (shown in Fig. 4),7 6-diphenylphosphanyl-4a7 and
the related naphthamides 5a21 and 5c21 showed that the values of h
and φ (Figs. 2c, 2d) favoured by these compounds in the crystalline
state (Table 2, entries 1–4) were more or less in agreement with
our modelling. We are confident therefore that the model shown
in Fig. 2 is fundamentally sound.
Scheme 4 Conformers of a 2-sec-alkyl benzamide 8.
NMR): coalescence between the pairs of peaks was observed at
temperatures approaching 70 ◦C.
In order to investigate the validity of the conformational model
shown in Fig. 2 when applied to compounds 4a and 8 (and hence,
by extension, 5a–d) we modelled the two Ar–CO conformers A
and B of 4a and 8 using Macromodel (MM2*).35 Fig. 3a shows
a dihedral drive plot of energy against h for the two Ar–CO
conformers of 8 (A and B) and Fig. 3b the two Ar–CO conformers
of 4a (A and B)
Fig. 4 View of X-ray crystal structure of 4a7 along the Ar–X* bond.
2. 2-(1ꢀ-Hydroxy)alkyl substituents. In the naphthamide
series, thermal equilibration of the atropisomeric alcohols 5e–5h
(Table 1, entries 5–14) indicated a weak thermodynamic preference
=
for atropisomer A, with the amide C O and OH group syn when
drawn as the conformer shown in Fig. 2.3 The ratios showed a
weak solvent dependence. Only in 5i, in which R is a t-butyl group
(Table 1, entry 14) was the “anti” atropisomer B favoured.
To establish the effect of a chiral 2-substituent on the conforma-
tion of benzamides or the analogous nicotinamides, we made the
Table 2 Dihedral angles in selected X-ray crystal structures (see Fig. 2c,
2d)
Entry
Compound
h (deg)
φ (deg)
Reference
1
2
3
4
5
6
7
8
4a
107.4
101.3
106.2
99.5
134.3
132.8
133.2
127.9
78.3
88.3
88.7
89.7
89.4
86.9
80.8
86.4
7
7
21
21
6-PPh2–4a
Fig. 3 (a) Plot of E vs. h (see Fig. 2c) for 8A (solid circles) and 8B (open
circles); (b) plot of E vs. h (see Fig. 2c) for 4aA (solid circles) and 4aB (open
circles).
5a
5c
5o
14
33b
33f
33g
This work
This work
This work
The calculations confirm two features of our model. Firstly, for
both Ar–CO conformers of both compounds, there are two stable
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Table 3 Conformational preferences in benzamides and nicotinamides with hydroxyl-bearing 2-substituents
Entry
Compound
R1
R2
Yield (%)
Ratio of diastereoisomers A : B
Solvent
1
2
3
4
5
6
7
8
9
12a
10b
12b
10c
12c
Ph
Et
Et
Ph
Ph
H
67
59
83
60
61
50 : 50
50 : 50
50 : 50
90 : 10
90 : 10
85 : 15
80 : 20
70 : 30
60 : 40
50 : 50
50 : 50
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
80 : 20 CDCl3–CD3OD
60 : 40 CDCl3–CD3OD
CD3OD
Me
Me
Me
Me
d6-DMSO
D2O
CDCl3
10
11
10d
10e
59
59
12
50 : 50
CDCl3
13
14
15
13
14
Ph
Me
H
85
40
30 : 70
30 : 70
34 : 66
CDCl3
CD3OD
CDCl3
CH2OR
alcohols 10 and 12 by ortholithiation of 936–38 or 1139 and addition
to benzaldehyde, 2-butanone, acetophenone, norbornanone or
fenchone (Scheme 5). Alcohol 12c was methylated to give 13.
We also investigated the ether 14, made from 9 by sequential
double lithiation and quench with SEMCl.40 Interconversion of
the diastereoisomeric conformers is slow on the NMR timescale
and integration of the NMR spectra of the products in a variety
of solvents gave the conformational ratios shown in Table 3.
We were unable to identify unambiguously the structure of the
major conformer: assignments are made by analogy with the
atropisomeric diastereoisomers in entries 5–14 of Table 1 and by
assuming that the X-ray crystal structure of 10c (Fig. 5) represents
its favoured conformation in solution.
Fig. 5 X-Ray crystal structure of 10c.
In cases where analogous pairs were made, the nicotinamides
and benzamides had essentially identical conformational prefer-
ences, and comparing the nicotinamide 10a with the naphthamide
5h in Table 1, entry 12, showed a comparable lack of conforma-
tional bias. Neither was any significant conformational preference
evident in the alcohols 10b, 10d, 10e or 12b, obtained by addition
to ketones 2-butanone, norbornanone or menthone. However,
addition of 9 or 11 to acetophenone gave alcohols 10c and 12c
which showed a relatively strong bias towards one conformer in
CDCl3. Moving successively to more polar solvents (entries 5–
10) gradually decreased the bias to, in water, just 1 : 1. This
bias seems to be due principally to hydrogen bonding, rather
than solely dipole effects, because alkylation to give 13 reduced
(and possibly—we cannot be sure of the assignment—inverted)
the preference from 90 : 10 to 30 : 70.‡ Furthermore, the X-ray
crystal structure (Fig. 5) of 10c shows the molecule adopting a
conformation in the solid state approximating to 10cA with an
‡ Hydrogen-bonding seems to have a powerful role to play in the
conformational preferences of analogous compounds with the chiral
hydroxyalkyl substituent in the 8-position. See ref. 6.
Scheme 5
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intramolecular hydrogen bond evident between the hydroxyl group
and the amide carbonyl oxygen atom.
The surprisingly weak conformational preference in most of
these compounds is presumably due to a balance between the
conflicting demands of steric encumbrance, hydrogen bonding
and dipole repulsion. We propose the model shown in Fig. 6 as
a means of accounting for these effects, though the orientation
of the groups R1, R2 and OH, particularly for conformer B,
remains very much open to question. Two main features are clear.
Firstly, intramolecular hydrogen bonding favours conformation
A, and for 12c the more hydrogen-bonding the solvent the less
populated is conformer A (entries 5–10). Similarly, methylation
of 12c to yield 13 reduces the population of A (Table 3, entries
5 and 13) and removes this solvent dependence (Table 3, entries
8 and 14). Secondly, steric contrast seems relatively unimportant
in this series, except when R1 is t-Bu, when conformer B becomes
favoured (Table 1, entry 14), presumably because of its more severe
interaction with NR2 in conformer A. Finally, in compounds
13 and 14, where two of the substituents differ principally in
electronegativity only, rather than size, the conformer with the
Fig. 8 View of X-ray crystal structure of 5j22 along the Ar–CH(Me)-
NHMe bond.
hydrogen bond is evident in the X-ray crystal structure of 5j:22
Fig. 8 shows the X-ray crystal structure of 5j viewed along the
Ar–CH(Me)NHMe bond). Removing the potential for hydrogen
bonding decreases the conformational preference, and indicates
that the NMeBn group behaves as though it were relatively small.§
=
C O and C–O dipoles opposed appears to be weakly favoured
(Table 3, entries 13–15). In general, stereogenic centres of these
types offered relatively weak conformational preferences, and we
did not pursue further the use of chiral alcohols or their derivatives
as a means of attaining conformational control.
4. Proline-derived imidazolidines. Mukaiyama has demon-
strated the use in asymmetric synthesis of imidazolidines formed
by condensation of aldehydes with the proline-derived diamine
16.42,43 The R group of the aldehyde RCHO invariably lies exo on
the bicylic imidazolidine.43 In the naphthamide series, imidazoli-
dine 5n, derived by condensation of a 2-formylnaphthamide with
diamine 16, displays a strong (>90 : 10) conformational preference
(Table 1, entry 19, 20) and is isolated as a single diastereoisomer
at both the aminal centre and at the Ar–CO axis. Similarly,
the room temperature NMR spectrum of the imidazolidine 17
contains a single set of sharp peaks strongly suggesting not only
that the amide is a single diastereoisomer at the aminal centre,
but also that it essentially adopts one Ar–CO conformation in
solution, presumably (by analogy with the related naphthamide)
17A (Scheme 6). Fig. 9 illustrates our rationalisation for this
preference in both naphthamide 5n and benzamides 17 and for
comparison Fig. 10 shows the X-ray crystal structure of 5n14
viewed along the Ar–X* bond.
Fig. 6 Conformational preferences in 2-hydroxyalkyl benzamides and
their derivatives.
3. 2-(1ꢀ-Amino)alkyl substituents. Comparing the conforma-
tional preference of the naphthamides 5j and 5k in entries 15 and
16 of Table 1 with those in entries 5 and 8, which differ only in the
substitution of an NHMe for an OH substituent, shows that the
preference for conformer A is stronger in the amine than in the
alcohol. Increasing the bulk of the amino group by benzylation
to yield 5l and 5m (entries 17, 18) has an effect contrary to
what would be expected on steric grounds. It seems reasonable
to propose therefore that the conformational preference of 5j and
=
5k is dictated by the potential for hydrogen bonding between C O
and N–H (Fig. 7) (though it is worth noting that no intramolecular
Scheme 6 Conformational control with a proline-derived diamine (R =
Et).
The imidazolidine 17 (R = i-Pr) was modelled using the
Macromodel35 implementation of the MM2*, MM3 and MMFF
forcefield. Two 5000-step Monte-Carlo conformational searches
were carried out for each forcefield, the first search starting from
17A, the second from 17B. In each case the Ar–CO dihedral
§ In an accompanying paper (ref. 41) we show how the apparent small
size of the NMeR group can be exploited to relay conformational control
between remote atropisomeric axes.
Fig. 7 Conformational preferences in 2-aminoalkyl benzamides and their
derivatives.
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We condensed the aldehydes 15, 21 and 26 with (−)-ephedrine
18 or (+)-pseudoephedrine 19 by refluxing in toluene for 24 h
(Scheme 8). The oxazolidines 22, 23 and 24 were formed from
15 and 21 as single diastereoisomers by NMR: there was no
evidence for the presence of endo diastereoisomers (the distinctive
NMR spectra of which47 are discussed below). Moreover, the
NMR spectra of the products showed single sharp sets of
signals, indicating that the Ar–CO bond adopts essentially a
single conformation, as is known to be the case when the Ar–
CO atropisomers of the naphthamide analogues 5o are allowed
to equilibrate (Table 1, entries 21, 22). By analogy with the
naphthamides 5o, we assume the major Ar–CO conformers of
22 and 23 are as shown, and this conformation is evident in the
X-ray crystal structure of derivatives of 22 (Table 2, entries 5–
8). The conformation of the pseudoephedrine-derived product 23
was not assigned unambiguously, though the configuration of the
new stereogenic centre at C2 of the oxazolidine ring is presumably
controlled by the stereochemistry at the CHMe group, as is known
for related compounds.46
Fig. 9 Conformational preference in a proline-derived aminal.
Fig. 10 View of the X-ray crystal structure of 5n14 along the Ar–X* bond
(h = 142.0; φ = 76.7◦).
was constrained to 90◦. In this way two sets of conformers
were generated, one set with Ar–CO orientation approximating to
conformer A and one set with Ar–CO orientation corresponding
conformer B. While all three force fields predict 17A to be the
lower energy conformer by at least 3.5 kJ mol−1, only in MMFF is
the energy difference (16.5 kJ mol−1) sufficient to account for the
observed thermodynamic selectivity (>95 : 5).
Scheme 8 Condensation of an amidoaldehyde with ephedrine and
pseudoephedrine.
5. (−)-Pseudoephedrine- and (−)-ephedrine-derived oxazoli-
dines. Condensation of (−)-ephedrine 18 or (+)-pseudoe-
phedrine 19 with aldehydes is typically diastereoselective,44–47 and
with aromatic aldehydes the reaction creates a new stereogenic
centre adjacent to the aromatic ring. Scheme 7 shows the reported
products from condensation of ArCHO with (−)-ephedrine 18:
the major product (>90%) from benzaldehyde is exo-20, in
which all of the substituents around the oxazolidine ring may
lie pseudoequatorial. The minor product (<10%) is endo-20.
Selectivity for the exo isomer is thermodynamic in nature,45,47 and
endo-20 has been observed as the kinetic product of reactions with
electron-deficient ArCHO, especially in alcoholic solvents.47
The condensation of the diamide 26, made via lithiation
of 25, with (−)-ephedrine was less straightforward. When the
condensation was carried out simply by refluxing in toluene for
24 h, a single diastereosiomer of the product was formed which
X-ray crystallography confirmed was the exo oxazolidine exo-27
(Fig. 11a). The NMR spectrum of this compound was sharp
and clean (see Fig. 12a) and it appears to exist in solution as
a single conformer (>95 : 5), much like 23. However, if the
condensation was carried out using a Dean–Stark apparatus to
remove water from the mixture, the crude product contained
two diastereoisomers of the product in a 3 : 1 ratio, which were
separable by flash chromatography. The major diastereoisomer
was exo-27, but the minor diastereoisomer was shown by X-
ray crystallography to be endo-27. The NMR spectra of the
two oxazolidines 27 are shown in Fig. 12. The most distinctive
differences (shown boxed in Fig. 12) between the two are the
signals for H2 and H5 of the oxazolidine rings (Scheme 9). This
spectroscopic feature has been noted previously,47 and we now
routinely make use of it to identify endo and exo oxazolidines.48,49
The differing stereoselectivities of the two condensations of
26 are presumably the result of kinetic vs. thermodynamic
control. Agami47 showed that condensation of aldehydes with (−)-
ephedrine gives exo oxazolidines as the thermodynamic products
Scheme
7
Diastereoselective condensation of (−)-ephedrine with
aldehydes.
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Scheme 9 Condensation of a diamidoaldehyde with ephedrine: kinetic
and thermodynamic control.
Fig. 12 (a) NMR spectrum of exo-27; (b) NMR spectrum of endo-27.
In order to clarify the reason for the preferred orientation of
the amide bond in the amidooxazolidines 5o, 5p, 22–24 and exo-
27, we used Macromodel35 to carry out a Monte Carlo search
of the conformations of 5o with 3000 steps, finding 63 unique
conformations, of which 26 minimised with good convergence.
The global minimum of 34.1 kJ mol−1 was found 8 times, and
corresponded to the conformation shown in Fig. 13a. The lowest
energy conformation of opposite relative stereochemistry at the
Ar–CO axis was 10.1 kJ mol−1 higher in energy, an energy
difference corresponding to a conformational selectivity at 25 ◦C
◦
of >98 : 2 or at 110 C of >96 : 4. Interestingly, the 10 kJ mol−1
difference in energy was made up almost entirely of a contribution
from the electrostatic term. We therefore propose Fig. 1314 as our
rationalisation of the preferred Ar–CO conformation in 5o, 5p,
21–23 and exo-27, in which dipole repulsion between the amide
Fig. 11 (a) X-Ray crystal structure of exo-27; (b) X-ray crystal structure
of endo-27.
but that reactions in polar solvents or with electron-deficient
aldehydes yield initially endo oxazolidines, which only slowly
epimerise to exo. The additional electron-withdrawing amide
group of 26, coupled with the rapid removal of water by the
Dean–Stark apparatus, which would otherwise perhaps increase
the rate of general acid catalysed epimerisation of the oxazolidine,
must both contribute to the formation of the unexpected endo
diastereoisomer. Resubjecting the endo oxazolidine endo-27 to 1 h
in refluxing toluene led to incomplete epimerisation to a 1 : 1
mixture of endo and exo-27.
Fig. 13 Conformational preference in an ephedrine-derived oxazolidine.
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=
C O and the oxazolidine C–O is the principal factor governing
the conformation. For comparison, Fig. 14 shows a corresponding
this conformation minimises interactions between the S–O and
9
=
C O dipoles (Fig. 16). The X-ray crystal structure of 28 (Fig. 15)
view of the X-ray crystal structure of 5o. We assume that a strong
shows that this conformer is the one populated in the solid state.
=
preference to place C O anti to C–O is also at the root of the
single conformation exhibited by endo-27.
Fig. 14 View of X-ray crystal structure of 5o14 along Ar–X* bond (h =
134.3; φ = 89.4◦).
6. 2-Sulfinyl substituents. Naphthamides bearing 2-sulfinyl
substituents are not atropisomeric because of the poor barrier
to rotation offered by second row substituents,7 but they exhibit
extremely high levels of conformational control: for 5p we found
that one Ar–CO conformer is populated to a degree of >99.5% at
ambient temperature.24
Fig. 15 (a) X-Ray crystal structure of 28;9 (b) view of the X-ray crystal
structure of 28 along the Ar–S bond [reflected image shown for consistency
with Fig. 16] (h = 93.0; φ = 87.7◦).
We made enantiomerically enriched sulfoxide 28 by or-
tholithiation of N,N-diisopropylnaphthamide
9 and reac-
tion with (1R,2S,5R,SS)-(−)-menthyl p-toluenesulfinate 29
(Scheme 10).9,50,51¶ The variable temperature NMR spectrum of 28
showed a single clean set of peaks at temperatures down to −50 ◦C
in CDCl3, and from this we deduce that 28, like 5p, exhibits a
strong preference for the same single Ar–CO conformer, which we
rationalise by proposing (on the basis of modelling studies24) that
Fig. 16 Conformational preference in a 2-sulfinyl benzamide (for con-
sistency, with other conformational diagrams in the paper, compounds
shown are enantiomeric with 24).
7. Oxathiolanes, oxathianes and oxathiolane S,S-dioxides.
The outstanding levels of conformational control achieved with
sulfoxides prompted us to investigate whether the electonegativity
difference between S and O would similarly be able to control the
orientation of an amide, opening up the possibility of using chiral
hydroxythiols53 to control amide stereochemistry in a manner
analogous to our use of (−)-ephedrine. Aldehydes 21 and 3054
were condensed with 2-mercaptoethanol or 3-mercaptopropanol
in the presence of NBS or indium triflate to yield the oxathianes
and oxathiolanes 31a–c (Scheme 11). The NMR spectrum of all
three compounds showed two sets of peaks in a 1 : 1 ratio. For
Scheme 10 Synthesis of 2-sulfinyl benzamide 28.
¶ Sulfoxide 25 has an optical rotation but we have not established beyond
doubt that it is enantiomerically pure. Sulfoxide synthesis from 29 is not
always reliably stereospecific: see ref. 52.
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Scheme 11 Formation of S,O-heterocycles.
31a, these must correspond to diastereoisomeric conformers (and
indeed coalescence of the peaks at high temperature indicated
that this was the case), indicating a total lack of conformational
control. In 31b and 31c additional steric hindrance offers the
possibility that the two sets of peaks are diastereoisomers,3,54 and
indeed two spots were visible in both cases by TLC. Separation by
flash chromatography however did not give pure samples of each
diastereoisomer, and within a few hours in chloroform, the ratio
in each case returned to 1 : 1.
Oxathiolane 31a was oxidised to the S,S-dioxide 32 with
m-CPBA. The NMR spectrum of 32 in CDCl3 showed two
conformers in a ratio of 89 : 11 which coalesced on running the
spectrum at higher temperatures. The ratio was lower in more polar
solvents—76 : 24 in DMSO and 74 : 26 in methanol—suggesting
that the conformational selectivity originates in dipole repulsion
rather than steric hindrance, and we tentatively suggest that 32A
is favoured over 32B (Fig. 17).
Fig. 18 (a) X-Ray crystal structure of 33b; (b) X-ray crystal structure of
33f; (c) X-ray crystal structure of 33g.
Trapping conformational preference as atroposelectivityꢁ
While the two orientations of the amide group in a 2-substituted
benzamide merely define two conformers of a single compound,
in a 2,6-disubstituted benzamide the two orientations define two
diastereoisomeric atropisomers. We therefore set out to convert
the conformational selectivity exhibited by 17, 22, 23 and 28 into
atroposelectivity by using ortholithiation38,55,56 to introduce a 6-
substituent ortho to the amide, trapping the preferred conformer
as an atropisomer. A similar strategy has proved successful with
enantiomerically pure amide 4b,7 and has been used to study the
conformation of intermediates in atroposelective reactions.19
Of 17, 22, 23 and 28, only the oxazolidines 22 and 23 could be
successfully ortholithiated. Treatment of 17 or 28 with s-BuLi and
a variety of electrophiles gave only complex mixtures of products.
Fig. 17 Conformational preference in
S,S-dioxide 32.
a 2-oxathiolanylbenzamide
Summary: achieving conformational control in benzamides
High levels of conformational control in benzamides 6 were
achieved with (a) 2-(1-trialkylsilyl)ethyl groups (4); (b) 2-
imidazolidinyl groups (17); (c) 2-oxazolidinyl groups (22–24, 27)
and (d) 2-sulfinyl groups 28. In all cases, the chiral substituent is, or
can easily be made, enantiomerically enriched or enantiomerically
pure. The remainder of the paper describes “proof-of-concept”
studies of some ways in which the controlled conformational
preference of such amides may be exploited.
ꢁPreliminary report: see ref. 26.
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Table 4 Trapping conformers as atropisomers
Entry
R
E+
E
Yield 33 (%)
Yield 34 (%)
Ee 34 (%)
1
2
3
4
5
6
7
Et
MeI
MeI
EtI
Me2NCHO
Me2C
Me2S2
Ph2S2
Me
Me
Et
CHO
Me2COH
SMe
SPh
33a 58
33b 55
33c 69
33d 8940
33e 89
33f 39
33g 53
—
—
8
28
—
—
0
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
34b 82
34c 87
—
—
34f 20
—
=
O
—
Sulfoxide 28 is presumably susceptible to nucleophilic attack at
sulfur,57 and was insufficiently acidic to be deprotonated by LiTMP
or LDA.55 Amides bearing additional organolithium-coordinating
sites are known to behave problematically in ortholithiation
reactions, often requiring large excesses of lithiating agent.58
Treatment of 22 or 23 with s-BuLi followed by the electrophiles
listed in Table 4 however generally gave good yields of the 2,6-
disubstituted benzamides 33a–g which were isolated as single
atropisomers with no traces of other diastereoisomers in the NMR
spectra of the crude reaction mixtures (Scheme 12). The X-ray
crystal structures of three of these products confirmed the expected
orientation of the amide group, and are shown in Figs. 18a–c (see
also Table 2, entries 5–8).
its influence over the formation of a new stereogenic centre. It
is well known that the orientation of an atropisomeric amide
can exert powerful kinetic control over nucleophilic6,13,22,29 and
electrophilic1,19,21 addition reactions. It seemed reasonable to
suppose therefore that the conformation of an amide which,
though lacking a kinetic barrier to Ar–CO rotation sufficiently
high to be atropisomeric itself, is held in a preferred orientation,
might allow the stereochemistry of the controlling centre to be
relayed via the amide to control a new stereogenic centre relatively
remote from the source of stereochemical information. We first
reported on such a concept early in 1998,61 and Davies,62 Renaud63
and Sibi63 have since published conceptually related stereoselective
reactions involving what they have termed “chiral relay”. The
strategy is illustrated schematically in Scheme 13.
Scheme 12 Atroposelective synthesis via ephedrine-derived oxazolidines.
We hoped that hydrolysis under mild conditions would allow us
to remove the ephedrine “auxiliary” and permit isolation of the
2,6-disubstituted amides in enantiomerically enriched form.14,25
The sequence of reactions starting with 22 or 23 and culminating in
such a deprotection would amount to a dynamic thermodynamic
resolution.59 The problem with the strategy is that, as noted
previously,14 while ephedrine-derived oxazolidines are rather stable
to hydrolysis, the aldehyde products are relatively configurationally
unstable at the Ar–CO bond. We therefore tried hydrolysing
the oxazolidines 33b, 33c and 33f with trifluoroacetic acid at
Scheme 13 Stereochemical relay.
We decided to make use of two reactions known to be diastereos-
elective in the naphthamide series, namely (a) the diastereoselective
lateral lithiation–electrophilic quench of 2-ethyl amides,19,20 and
(b) the chelation-controlled nucleophilic addition of aryl Grignard
reagents to 2-formyl amides.22,64 We employed derivatives of the
conformationally uniform amides 4a and 23 to probe this idea.
The racemic silane 4a was treated with s-BuLi and the or-
tholithiated product quenched with ethyl iodide to yield 35 as
a single diastereoisomer (Scheme 14). Diastereoselective lithiation
with s-BuLi and electrophilic quench with Me3SiCl gave a product
36, again as a single diastereoisomer by NMR and with >10 : 1
selectivity by HPLC. The simplicity of the NMR spectrum of 36
(only two 6H doublets for the Ni–Pr2 group) indicated the presence
of a plane of symmetry, and from the known conformational
preference of 4a7 it is evident that 36 has the structure shown,
in which information about the stereochemistry of the first
0
◦C for as brief a time as possible, before neutralising and
reducing the product aldehyde, still at 0 ◦C, and isolating the
alcohols 34 (atropisomers carrying ortho-hydroxymethyl groups
are typically more configurationally stable about their stereogenic
axis than their aldehyde congeners3,14,60). Unfortunately, the best
result which could be obtained was 28% ee for 34c. Racemisation
of the aldehyde intermediate is evidently still fast and further
extension of this work was abandoned.
Using conformational preference to relay stereochemistry from
centre to centre via an axis∗∗
While it generally proved difficult to trap a conformational
preference as a single atropisomer, we proposed that the induced
conformational preference could still make its presence felt by
∗∗Preliminary reports: see refs. 26 and 61.
Scheme 14 Remote stereoselective silylation.
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Z = 2; m = 0.076 mm−1; 5134 reflections; Rint = 0.0348; R(F) =
0.0405. CCDC reference number 286005
endo-27. Crystal data C31H45N3O3; M = 507.70; monoclinic P21;
◦
˚
˚
˚
a = 10.547(8) A; b = 12.605(5) A; c = 12.023(4) A; b = 96.44(4) ;
3
−1
˚
V = 1588.3(15) A ; T = 296.2 K; Z = 2; m = 0.535 mm ; 3456
reflections; Rint = 0.0540; R(F) = 0.0500. CCDC reference number
286006
Scheme 15 Remote stereoselective ethylation.
Experimental
General methods have been published previously.14 Flash chro-
matography was performed by the method of Still, Kahn and
Mitra.66
Published elsewhere
Scheme 16 Remote stereoselective addition to a carbonyl group.
The synthesis of the naphthamides detailed in Table 1, along with
benzamides 4a,7 4b31 17,14 22,14 and 2314 have been published
previously. Benzamide 14 is published in the following paper,49 and
diamide 2567 will be published in the context of related research
shortly.
silyl-bearing centre has been relayed through the amide axis to
the second.
The same sequence of reactions starting from the conforma-
tionally uniform amide 23 gave, via 33b, the oxazolidine 37,
again as a single diastereoisomer (Scheme 15). The sense of the
stereoselective silylation was assumed to be the same as in the
formation of 36.19,20 In both of these reactions, it is probable that
the laterally lithiated derivative of 35 or 33b has very low kinetic
configurational stability about the Ar–CO bond on the timescale
of the silylation,65 and that the overall stereoselectivity is in fact
the result of the continued thermodynamic influence of the fixed
stereogenic centre over the amide axis in the lateral lithiation step.
Chelation-controlled nucleophilic addition of phenylmagne-
sium bromide22 to the conformationally uniform aldehyde 33e gave
38 (Scheme 16), again as a single diastereoisomer by NMR, with
stereochemistry deduced from precedent.22
In all three of these reactions, 1,5-stereocontrol is delivered by
relaying stereochemical information from a starting centre via
the amide axis to a new centre in the final product 1,5-related
to the source of stereochemical information. The operation of a
stereochemical relay (also termed “chiral relay”) effect has been
deduced in other contexts, for example the alkylation of amino-
acid derived diazines,62 and in asymmetric Diels Alder reactions.63
Uniquely in the reactions of these amides, however, is it possible
to be certain, by NMR, of the conformational preference at the
root of the relay effect. In future papers we shall show how amides
can relay stereochemistry not only to new centres but also to
further amide axes, leading to much more remote transmission of
stereochemical information.
2-(1-Methylpropyl)-N,N-diisopropylbenzenecarboxamide
(8).
sec-Butyllithium (1.1 equiv., 1.3 solution in hexane)
M
was added dropwise to a stirred solution of 2-ethyl-N,N-
diisopropylbenzenecarboxamide 77 (0.2 g, 0.857 mmol) in THF
under nitrogen at −78 ◦C. The burgundy solution was allowed
to stir at this temperature for an hour and ethyl iodide (0.1 ml,
1.286 mmol) was added. The solution became colourless. The
reaction mixture was allowed to warm to ambient temperature.
Saturated aqueous ammonium chloride solution was added,
the precipitate dissolved with a small amount of water, and
the majority of the THF removed under reduced pressure. The
aqueous suspension was extracted into dichloromethane (×3),
and the combined organic extracts were washed with distilled
water, dried (MgSO4), and evaporated under reduced pressure
to yield the pale yellow crude product. Purification by flash
chromatography (7.5% ethyl acetate in light petroleum) afforded
the pure amide 8 as white solid. (0.0202 g, 9%), Rf (10% ethyl
acetate–light petroleum) 0.36, (plus a mixture of 7 and 8); dH
(300 MHz; CDCl3) Signals for major conformer: 6.98–7.27 (4H,
m, Ar–H), 3.65 (1H, sept, J 6.5, NCH(Me)2), 3.40 (1H, m,
NCH(Me)2), 2.65 (1H, m, CHCH2), 1.65 (2H, m, CH2), 1.56
(3H, d, J 7.0, NCHMeAMeB), 1.55 (3H, d, J 7.0, NCHMeAMeB),
1.19 (3H, d, J 7.0, MeCH), 1.05 (6H, m, NCHMe2), 0.8 (3H, m,
MeCH2); dC (75 MHz; CDCl3) 175.0, 128.5, 128.1, 125.6, 124.7
(Ar–C); 50.6 (–NC(Me)2), 45.6 (NC(Me)2), 25.6 (CH2CH3),
20.7, 20.6, 20.5, 20.4 (2xNC(Me)2), 15.0 (–CH2CH3); m/z CI
262 (6%, M + H+), 234 (100%, C15H23NO + H+), EI 234 (2%).
Found M+ 261.2101. C17H27NO requires M 261.20925.
X-Ray crystallography
X-ray crystal structures described in this paper have been
deposited with the Cambridge Crystallographic Database
(ccdc@cam.ac.uk).‡‡ Details are as follows:
4a,7 5j,22 5n,14 5o,14 33b,26 33f,26 33g,26 exo-2726 and 289 were
published previously.
2-(1-Hydroxy-1-methylethyl)-N,N-diisopropylbenzamide (10b).
sec-Butyllithium (1.41 ml, 1.3 mol dm−3 solution in hex-
ane) was added dropwise to a stirred solution of N,N-
diisopropylbenzamide 937 (0.25 g, 1.22 mmol) in dry THF (5 ml)
under nitrogen at −78 ◦C. After 20 min at −78 ◦C, butanone
(0.218 ml, 2.44 mmol) was added and the mixture was allowed
to reach room temperature, quenched with saturated ammonium
chloride solution, and extracted with ether (10 ml). The combined
ether extracts were washed with aqueous ammonium chloride
10c. Crystal data C21H27NO2; M = 325.44; triclinic P-1; a =
◦
˚
˚
˚
˚
7.3320(14) A; b = 8.9703(18) A; c = 14.588(3) A; a = 73.464(4) ;
◦
◦
3
b = 84.682(3) ; g = 77.268(3) ; V = 896.7(3) A ; T = 100(2) K;
‡‡ CCDC reference numbers 286005–286006. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/b514557k
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(3 × 25 ml), dried (MgSO4) and evaporated under reduced
pressure. The compound was purified by flash chromatography
(petroleum ether–ethyl acetate, 90 : 10) to give the alcohol 10b
(0.200 g, 59%) as a yellow oil; Rf (ether–ethyl acetate, 90 : 10) 0.26;
2-(1-Hydroxy-2-isopropyl-5-methylcyclohexyl)-N,N-diisopropyl-
benzamide (10e). sec-Butyllithium (1.5 equiv., 1.4 mL,
1.83 mmol, 1.3 M solution in cyclohexane), was added to
a stirred solution of N,N-diisopropylbenzamide 937 (0.25 g,
1.22 mmol) in THF (20 ml) under a nitrogen atmosphere at
−78 ◦C. The resultant orange solution was left to stir for 90 min
at −78 ◦C. Menthone (1.6 equiv., 0.34 mL, 1.952 mmol) was
added at −78 ◦C and stirred for 10 min. The mixture was then
allowed to warm to room temperature and the solution became
colourless. Water was added and the mixture was extracted
with dichloromethane. The organic fractions were washed with
brine, dried over magnesium sulfate and concentrated under
reduced pressure to afford a white crude solid. Purification by
flash chromatography using 3 : 1 petrol (bp 40–60 ◦C)–EtOAc
as eluent afforded a single diastereoisomer of the product 10e
as a colourless oil (0.26 g, 59%) (1 : 1 mixture of conformers),
mmax (film)/cm−1 2952, 2927, 1765, 1612, 1447, 1342, 1033, 757;
dH (300 MHz; CDCl3) 7.38–7.18 (6H, m, ArH), 7.12–7.02 (2H,
m, ArH), 3.88 (1H, sept, J 6.7, NCHMe2), 3.73 (1H, sept,
J 6.7, NCHMe2), 3.51 (2H, sept, J 6.7, NCHMe2), 2.88 (1H, d,
J 2.8, COH), 2.70 (1H, s, COH), 2.41–2.30 (2H, m, CHCHMe2),
1.88–1.82 (2H, m, CHCHMe2), 1.78–1.70 (4H, m, CCH2),
1.61–1.52 (8H, m, CCH2), 1.38–1.32 (2H, m, CHMe), 1.29
(6H, s, CHCH3), 1.02 (6H, d, J 6.7, NCHMe2), 0.90–0.86 (12H,
m, menthone CHCHMe2), 0.96 (6H, d, J 6.7, NCHMe2), 0.82
(6H, d, J 6.9, NCHMe2), 0.76 (6H, d, J 6.9, NCHMe2); m/z
CI 360 (100%, M + H+) (Found (EI) M+, 359.2831. C23H36NO2
requires M, 359.2824).
mmax (film)/cm−l 1633 (C O), 2970 (CH), 3420 (OH); dH (300 MHz;
=
CDCl3), 7.6–7.2 (4H, m), 3.72 (1H, sept, J 7), 3.40 (1H, sept, J 7),
1.80 (3H, s, Me), 1.5–1.3 (2H, m, CH2), 1.2–0.9 (15 H, 5 × d, J 7,
Me × 5) and 0.70 (3 H, t, J 7); m/z CI 276 (10%, M+), 147 (98%),
105 (85%).
2-(1-Hydroxy-1-methylbenzyl)-N,N-diisopropylbenzamide (10c).
In a similar way, N,N-diisopropylbenzamide 937 and acetophe-
none gave the alcohol 10c (0.240 g. 60%) as a yellow oil; Rf (ether–
ethyl acetate, 90 : 10) 0.39; mmax (film)/cm−l 1604 (C O), 2977
=
(C–H), 3270 (O–H); dH (300 MHz; CDCl3) 7.8–6.9 (9H, m, Ar),
3.9 (1H minor, sept, J 7), 3.5 (1H minor, sept, J 7), 3.3 (1H major,
sept, J 7) 3.15 (1H major, sept, J 7), 2.03 (3H minor, s), 1.79 (3H
major, s), 1.6–1.4 (12H minor, 4 × d, J 7), 1.39, 1.10, 1.02, 0.30
(4 × 3H major, 4 × 4, J 7); m/z 325 (10%, M+), 105 (50%), 77
(45%).
2-(2-Hydroxy-bicyclo[2.2.1]hept-2-yl)-N,N-diisopropyl-benza-
mide (10d). sec-Butyllithium (1.5 equiv., 2.9 mL, 3.73 mmol,
1.3 M solution in cyclohexane), was added to a stirred solution of
N,N-diisopropylbenzamide 937 (0.51 g, 2.49 mmol) in THF (40 ml)
under a nitrogen atmosphere at −78 ◦C. The resultant orange
solution was left to stir for 1.5 h at −78 ◦C. 2-Norbornanone (1.6
◦
equiv., 0.44 g, 3.98 mmol) in THF (10 ml) was added at −78 C
N,N-Diisopropylnicotinamide (11)68. Nicotinic acid (1.0 g,
8.1 mmol) was heated to reflux in thionyl chloride (5 ml) for 30 min
until all of the solid had dissolved. The mixture was cooled to room
temperature and excess thionyl chloride removed under vacuum.
The resulting yellow solid was dissolved in dichloromethane
(25 ml) and diisopropylamine (1.4 ml, 10.0 mmol) added. After
stirring for 3 h the mixture was diluted with dichloromethane
(25 ml), washed with saturated ammonium chloride solution (3 ×
20 ml) and solvent removed under reduced pressure. The residue
was purified by flash chromatography (SiO2; EtOAc) to give the
amide (1.44 g, 90%) as a orange crystals; Rf (70 : 30 petrol–EtOAc)
0.09; dH (300 MHz; CDCl3) 1.44 (6H, m (broad), CH3), 1.33 (6H,
m (broad), CH3), 3.60 (2H, m (broad), CH3), 7.17 (1H, m, ArH),
7.55 (1H, m, ArH), 8.42–8.54 (2H, m, ArH). Spectroscopic data
were in agreement with the literature.68
and stirred for 10 min. The mixture was allowed to warm to
room temperature and the solution became colourless. Water was
added and the mixture was extracted with dichloromethane. The
organic fractions were washed with brine, dried over magnesium
sulfate, filtered and concentrated under reduced pressure to
afford the crude product as a white solid. Purification by flash
chromatography eluting with [4 : 1 petrol (bp 40–60 ◦C)–EtOAc]
afforded a single diastereoisomer of the product 12d as a white
solid (0.46 g, 59%), mp 110.3–111.9 ◦C; Rf [4 : 1 petrol (bp
40–60 ◦C)–EtOAc] 0.46; mmax (film)/cm−1 3341, 2964, 1606, 1442,
1341, 1031, 762; dH (300 MHz; CDCl3) (mixture of major and
minor conformers) 7.66–7.60 (1H, d, J 7.8, major & minor
ArH), 7.42–7.19 (3H, m, major & minor ArH), 6.09 (1H, s,
major CHOH), 5.01 (1H, s, minor CHOH), 4.06–3.85 (1H, m,
major & minor NCHMe2), 3.58 (1H, sept, J 6.7, major & minor
NCHMe2), 2.04–1.96 (1H, m, major & minor COHCH), 1.71(1H,
d, J 3.0, major & minor COHCH2), 1.67 (1H, d, J 3.0, major &
minor COHCH2), 1.63 (3H, d, J 6.7, major & minor NCHMe2),
1.59 (3H, d, J 6.7, minor NCHMe2), 1.57 (3H, d, J 6.7, major
NCHMe2), 1.54–1.50 (1H, m, major & minor COHCH2CH),
1.50–1.43 (4H, m, major & minor COHCHCH2), 1.42–1.34 (2H,
m, major & minor COHCHCH2), 1.28 (3H, d, J 6.6, major &
minor NCHMe2), 1.19 (3H, d, J 6.6, major NCHMe2), 1.18 (3H,
4-(1-Hydroxybenzyl)-N,N -diisopropylnicotinamide
(12a).
N,N-Diisopropylnicotinamide 11 (312 mg, 1.0 mmol) was
dissolved in dry THF (3 ml) and added dropwise to a solution of
LiTMP (3.0 mmol in 3 ml THF) at −78 ◦C under nitrogen giving
a bright red solution. After stirring for 3 h, distilled benzaldehyde
(3.5 mmol, 0.36 ml) was added dropwise at −78 ◦C and the
mixture was left to warm to room temperature and quenched
with saturated ammonium chloride solution (1 ml). The THF
was removed under reduced pressure and the mixture dissolved in
dichloromethane (30 ml) and washed with saturated ammonium
chloride solution (3 × 15 ml), dried (MgSO4) and solvents
evaporated under reduced pressure. The residue was purified
by flash chromatography (SiO2; EtOAc) to◦give the alcohol 12a
(325 mg, 67%) as yellow prisms, mp 38–40 C; Rf (EtOAc) 0.33;
=
d, J 6.7, minor NCHMe2); dC (75 MHz; CDCl3) 173.9 (C O),
147.7, 136.1, 128.8, 127.1, 125.9, 124.8 (aromatic) 79.4 (COH),
51.1, COHCH), 48.2 (COHCH2), 46.1, 43.9 (NCH(CH3)2), 38.2
(COHCHCH2), 29.0 (COHCHCH2), 27.1 (COHCH2CH), 21.71
(COHCHCH2), 20.57, 20.312, 20.16, 20.05 (NCHMe2); m/z (CI)
316 (100%, M + H+) (Found (EI): M+, 315.2200. C20H29NO2
requires M, 315.2198).
mmax/cm−1 3307 (O–H), 2972 and 2933 (C–H), 1627 (C O); dH
=
436 | Org. Biomol. Chem., 2006, 4, 424–443
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(300 MHz; CDCl3) (1 : 1 mixture of conformers), 0.51 (3H, d,
J 7, CH3), 0.66 (3H, d, J 7, CH3), 1.16 (3H, d, J 7, CH3), 1.18
(3H, d, J 7, CH3), 1.33 (3H, d, J 7, CH3), 1.46 (3H, d, J 7, CH3),
1.53 (3H, d, J 7, CH3), 1.55 (3H, d, J 7, CH3), 3.34 (1H, sept, J 7,
CH), 3.45–3.60 (3H, m, CH), 5.76 (1H, s, CH), 6.10 (1H, s, CH),
7.25–7.38 (10H, m, ArH), 7.46 (2H, d, J 5, ArH), 8.39 (1H, s,
ArH), 8.45 (1H, s, ArH), 8.59 (1H, d, J 5, ArH), 8.64 (1H, d, J 5,
ArH); dC (75 MHz; CDCl3) 20.4, 20.4, 20.6, 20.6, 20.8, 20.9, 21.0,
46.7, 46.8, 51.7, 51.7, 72.1, 76.1, 76.9, 122.4, 125.4, 126.3, 127.5,
128.0, 128.5, 128.7, 129.0, 132.3, 132.5, 141.0, 142.7, 145.8, 147.7,
150.2, 150.9, 151.1, 151.4, 168.5, 169.6; m/z (CI) 313 (100%,
MH+); Found (M+) 312.1832. C19H24N2O2 requires (M) 312.1832.
(100%, MH+); Found (M+) 341.2222 (C21H18N2O2 requires (M)
341.2224).
(Ra,2ꢀS,4ꢀS,5ꢀS)-N,N-Diisopropyl-2-[3,4-dimethyl-5-phenyl-1,3-
oxazolan-2-yl]benzamide
(24). (1S,2S)-(+)-Pseudoephedrine
(1.75 equiv., 1.24 g, 7.51 mmol) in toluene (80 ml) was added
to aldehyde 2169 (1.0 g, 4.29 mmol) and heated at reflux using a
Dean–Stark apparatus. The solution was then allowed to cool to
room temperature. Toluene was removed under reduced pressure.
The reaction mixture was extracted with dichloromethane,
organic fractions washed with water, dried over MgSO4, filtered
and concentrated under reduced pressure to afford the crude
product as a white solid. Purification by flash chromatography
eluted with [3 : 1 petrol (bp 40–60 ◦C)–EtOAc] afforded the
product 24 as a yellow oil (1.21 g, 75%), [a]1D9 = + 14.4 (c =
1.37, CH2Cl2); Rf [3 : 1 petrol (bp 40–60 ◦C)–EtOAc] 0.31;
mmax (film)/cm−1 2968, 1632, 1440, 1374, 1338, 1036, 755; dH
(300 MHz; CDCl3) 7.78 (1H, dd, J 7.7 and 1.1, Ar–H), 7.38–7.12
(7H, m, Ar–H (2H), Ph (5H)), 7.05 (1H, dd, J 7.6 and 1.2, Ar–H),
5.10 (1H, s, CHPh), 4.63 (1H, d, J 8.7, OCH), 3.61 (1H, sept,
J 6.7, NCHMe2), 3.45 (1H, sept, J 6.7, NCHMe2), 2.43 (1H,
dq, J 8.7 and 5.9, NCHMe) 2.17 (3H, s, NMe), 1.58 (3H, d,
J 6.7, NCHMe2), 1.52 (3H, d, J 6.7, NCHMe2), 1.14 (3H, d,
J 6.0, NCHMe), 1.00 (3H, d, J 6.9, NCHMe2), 0.97 (3H, d, J
4-(2-Hydroxybut-2-yl)-N,N-diisopropylnicotinamide (12b). In
the same way, N,N-diisopropylnicotinamide 11 (312 mg,
1.0 mmol) and butan-2-one (3.5 mmol, 0.31 ml) gave the alcohol
12b (349 mg, 83%) as a colourless oil, Rf (6 : 4 EtOAc–petrol) 0.15;
mmax/cm−1 3367 (O–H), 2971, 2934 and 2878 (C–H), 1620 (C O);
=
dH (300 MHz; CDCl3) (1 : 1 mixture of conformers), 0.80 (3H,
t, J 7, CH3), 0.89 (3H, t, J 7, CH3), 1.17–1.22 (12H, m, CH3),
1.50 (3H, s, CH3), 1.56–1.60 (15H, m, CH3), 1.82–2.02 (4H, m,
CH2), 3.19 (1H, s (broad), OH), 3.42 (1H, s (broad), OH), 3.54
(1H, sept, J 7,CH), 3.54 (1H, sept, J 7, CH), 3.71 (1H, sept, J 7,
CH), 3.77 (1H, sept, J 7, CH), 7.14 (1H, d, J 5, ArH), 7.18 (1H, d,
J 7, ArH), 8.33 (1H, s, ArH), 8.36 (1H, s, ArH), 8.51 (1H, d, J 6,
ArH), 8.52 (1H, d, J 6, ArH); m/z (CI) 278 (100%, MH+); Found
(M+) 277.1905. C16H26N2O2 requires (M) 277.1911.
=
6.7, NCHMe2); dC (75 MHz; CDCl3), 169.6 (C O), 140.4, 139.5,
135.5, 128.8, 128.5, 128.2, 128.1, 127.7, 126.6, 124.2 (aromatics),
95.1 (NCO), 86.8 (NMe), 68.9 (OCHPh), 51.0, 45.7 (NCHMe2),
35.3 (NCHMe), 20.5, 20.4, 20.1 (NCHMe2), 14.2 (NCHMe);
m/z (CI) 381 (100%, M + H+) (Found (EI) M + H+, 381.2543.
C24H32N2O2 requires M + H, 381.2542).
4-(1-Hydroxy-1-methylbenzyl)-N,N -diisopropylnicotinamide
(12c). In the same way, N,N-diisoproylnicotinamide 11 (312 mg,
1.0 mmol) and distilled acetophenone (3.5 mmol, 0.41 ml) gave
the alcohol 12c (301 mg, 61%) as a colourless oil, Rf (6 : 4
EtOAc–petrol) 0.30; mmax/cm−1 3261 (O–H), 2978 (C–H), 1604
N,N,Nꢀ,Nꢀ-Tetraisopropyl-4-formylisophthalamide (26). sec-
Butyllithium (2 equiv., 43.0 mL, 60.2 mmol, 1.4 M solution in
cyclohexane) was added to a solution of 2569 (10.0 g, 30.1 mmol)
in THF (100 ml) at −78 ◦C under a nitrogen atmosphere. The re-
sultant yellow solution was stirred at −78 ◦C for 1 h and quenched
with N,N-dimethylformamide (4 equiv., 9.3 mL, 120.4 mmol) and
allowed to warm to room temperature. Water (50 ml) was added
and the mixture was extracted with dichloromethane, organic
fractions washed with brine, dried over MgSO4, filtered and
concentrated under reducedpressure toaffordthe crudeproductas
a white solid. Purification by flash chromatography eluted with [1 :
1 petroleum ether (bp 40–60 ◦C)–EtOAc] gave the aldehyde 26 as
a white solid (8.45 g, 78%), mp 137.1–139.3 ◦C; Rf [3 : 1 petrol (bp
40–60 ◦C)–EtOAc] 0.31; mmax (film)/cm−1 2969, 2934, 1701, 1627,
1440, 1340, 1211, 1034, 778; dH (300 MHz; CDCl3), 10.17 (1H, s,
CHO), 7.97 (1H, dd, J 7.7 and 1.4, ArH) 7.55 (1H, t, J 7.7, ArH),
7.45 (1H, dd, J 7.6 and 1.4, ArH), 3.72 (2H, sept, J 6.7, NCHMe2),
3.56 (2H, sept, J 6.7, NCHMe2), 1.63 (3H, d, J 6.9, NCHMe2),
1.55–1.60 (9H, m, NCHMe2), 1.31 (3H, d, J 6.6, NCHMe2), 1.26
(3H, d, J 6.6, NCHMe2), 1.10 (3H, d, J 6.7, NCHMe2), 1.04 (3H,
d, J 6.6, NCHMe2); dC (75 MHz; CDCl3), 190.1 (CHO), 167.8,
=
(C O); dH (300 MHz; CDCl3) (9 : 1 mixture of conformers :
signals for major conformer), 0.44 (3H, d, J 7, CH3), 1.15 (3H, d,
J 7, CH3), 1.19 (3H, d, J 7, CH3), 1.42 (3H, d, J 7, CH3), 1.84
(3H, s, CH3), 3.26 (1H, sept, J 7, CH), 3.38 (1H, sept, J 7, CH),
6.76 (1H, s (broad), OH), 7.20–7.41 (5H, m, ArH), 7.66 (1H, d,
J 5, ArH), 8.43 (1H, s, ArH), 8.69 (1H, d, J 5, ArH); dC (75 MHz;
CDCl3) 20.2, 20.5, 20.6, 20.9, 31.6, 46,8, 51.5 122.0, 126.0, 127.0,
128.6, 148.0, 151.0, 154.9, 170.7; m/z (CI) 327 (100%, MH+);
Found (M+) 326.1986: C20H26N2O2 requires (M) 326.1989.
4-(1-Methoxy-1-methylbenzyl)-N,N -diisopropylnicotinamide
(13). Alcohol 12c (105 mg, 0.32 mmol) in THF (1 ml) was added
to a solution of 60% NaH (26 mg, 0.64 mmol) in THF (3 ml) at
0
◦C. After 5 min, the solution was raised to 45 ◦C, stirred for
10 h and quenched with saturated ammonium chloride (1 ml).
The THF was removed under reduced pressure and the mixture
dissolved in ether (30 ml) and washed with saturated ammonium
chloride solution (3 × 15 ml), dried (MgSO4) and solvents
evaporated under reduced pressure. The residue was purified by
flash chromatography (SiO2; EtOAc) to give the methyl ether 13
(93 mg, 85%) as a clear oil, Rf (EtOAc) 0.54; mmax/cm−1 2976,
=
166.0 (C O), 137.5, 136.8, 131.8, 130.7, 128.4, 127.9 (aromatics)
51.5, 51.2, 46.3, 45.8 (4 × NCHMe2), 20.4, 20.4, 20.3, 20.3, 20.1,
20.0, 19.9, 19.7 (4 × NCHMe2); m/z (CI) 361 (100%, M + H+)
(Found (EI): M + H+, 361.2486. C21H32N2O3 requires M + sH,
361.2491).
=
2933 (C–H), 1632 (C O); dH (300 MHz; CDCl3) 3 : 1 mixture of
conformers, 1.16 (3H, d, J 7, CH3), 1.25 (3H, d, J 7, CH3), 1.60
(3H, d, J 7, CH3), 1.62 (3H, d, J 7, CH3), 1.98 (3H, s, CH3), 3.09
(3H, s, CH), 3.54 (1H, sept, J 7, CH), 3.81 (1H, sept, J 7, CH),
6.47 (1H, d, J 5, ArH), 7.29–7.41 (5H, m, ArH), 8.26 (1H, d, J 5,
ArH), 8.35 (1H, s, ArH), 8.41 (1H, d, J 5, ArH); m/z (CI) 341
(Ra,Sa,2ꢀS,4ꢀS,5ꢀR)-N,N,Nꢀ,Nꢀ-Tetraiisopropyl-3-[3,4-dimethyl-
5-phenyl-1,3-oxazolan-2-yl]phthalamide (exo-27) and (Ra,Sa,2ꢀR,
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4ꢀS,5ꢀR)-N,N,Nꢀ,Nꢀ-Tetraisopropyl-3-[3,4-dimethyl-5-phenyl-1,3-
oxazolan-2-yl]phthalamide (endo-27). (1R,2S)-(−)-Ephedrine
(1.5 equiv., 2.35 g, 14.4 mmol) in toluene (100 ml) was added to
26 (3.45 g, 9.6 mmol) and heated at reflux using a Dean–Stark
apparatus for 2 d under nitrogen (until no starting material
was present on TLC). The solution was then allowed to cool
to room temperature. Toluene removed under reduced pressure.
The reaction mixture was extracted with dichloromethane,
organic fractions washed with water, dried over MgSO4, filtered
and concentrated under reduced pressure to afford the crude
product as a white solid. NMR of the crude product showed
that the 2 diastereoisomers were present. Purification by flash
chromatography eluting with [4 : 1 petrol (bp 40–60 ◦C)–EtOAc]
afforded the oxazolidine exo-27 as a white powder (2.53 g, 64%),
EtOAc gave the sulfoxide 28 as colourless crystals (2.57 g, 81%),
mp 89.3–92.5 ◦C; Rf [2 : 1 petrol (bp 40–60 ◦C)–EtOAc] 0.12;
[a]D20 = − 85.2 (c = 1.00, CH2Cl2); mmax (film)/cm−1 2962, 2361, 1628,
1440, 1340, 1042; dH (300 MHz; CDCl3) 7.86 (1H, d, J 7.6, ArH),
7.72 (2H, d, J 8.0, sulfoxide ArH), 7.52–7.42 (2H, m, sulfoxide
ArH), 7.30–7.22 (3H, m, ArH), 3.86–3.72 (1H, m, NCHMe2),
3.66–3.52 (1H, m, NCHMe2), 2.37 (3H, s, ArCH3), 1.63 (3H, d,
J 6.9, NCHMe2), 1.59 (3H, d, J 6.7, NCHMe2), 1.30 (3H, d,
J 6.3, NCHMe2), 1.10 (3H, broad s, NCHMe2); dC (75 MHz;
=
CDCl3) 167.4 (C O), 143.4, 141.0, 140.9, 131.1, 129.8, 129.7,
125.4, 125.1, 124.8 (Ar) 51.3, 46.2 (NCHMe2), 30.8 (ArMe), 21.2,
20.7, 20.5, 20.1 (NCHMe2); m/z (CI) 344 (100%, M + H+); m/z
(EI) 343 (41%, M+) and 227 (100%) (Found (EI): M+, 343.1611.
C20H25NO2S requires M, 343.1606).
◦
[a]2D4 = − 74.5 (c = 1.02, CH2Cl2); mp 147.6–149.2 C; Rf [4 : 1
N,N-Diisopropyl-2-(1,3-oxathiolan-2-yl)benzamide (31a). By
the method of Kamal, 2-mercaptoethanol (0.26 cm3, 3.86 mmol,
1.00 equiv.) was added dropwise to a stirred solution of N-
bromosuccinimide (0.14 g, 0.77 mmol, 0.30 equiv.) and 2-formyl-
N,N-diisopropylbenzamide 21 (0.60 g, 2.58 mmol, 1.50 equiv.) in
dry CH2Cl2 (20 cm3) at room temperature. The mixture was stirred
at this temperature for 8 h. An aqueous solution of 2.0 mol dm−3
NaOH (10 cm3) was added and the resulting mixture extracted
with CH2Cl2 (2 × 15 cm3). The combined organic phases were
washed with brine (30 cm3), dried (Na2SO4) and concentrated
under reduced pressure. The crude product was purified by
flash chromatography (SiO2, petrol–EtOAc, 8 : 1) to give the
oxathioacetal 31a (0.61 g, 81%) as a white solid, mp 93–96 ◦C. Rf
petrol (bp 40–60 ◦C)–EtOAc] 0.58; mmax (film)/cm−1 2965, 2931,
1618, 626, 1440, 1341, 1049; dH (300 MHz; CDCl3) 8.00 (1H, dd,
J 7.8 and 1.0, Ar–H), 7.54–7.28 (7H, m, Ar–H (2H), Ph (5H)),
7.22 (1H, dd, J 7.4 and 1.1, Ar–H), 5.14 (1H, d, J 8.4, CHPh),
4.83 (1H, s, OCH), 3.82–3.65 (2H, m, NCHMe2), 3.61–3.44
(2H, m, NCHMe2), 2.94 (1H, dq, J 8.4 and 6.5, NCHCH3) 2.21
(3H, s, NMe), 1.63 (3H, d, J 6.7, NCHMe2), 1.50–1.58 (9H, m,
NCHMe2), 1.28 (3H, d, J 6.6, NCHMe2), 1.24 (3H, d, J 6.6,
NCHMe2), 1.16 (3H, d, J 6.6, NCHMe2), 1.08 (3H, d, J 6.7,
NCHMe2), 0.83 (3H, d, J 6.5, NCHMe); dC (75 MHz; CDCl3),
=
168.9, 167.2 (C O), 139.3, 135.8, 135.3, 134.5, 128.2, 128.0,
127.9, 127.9, 127.7, 125.7 (Ar) 94.1 (NCO), 82.2 (NMe) 64.2
(OCHPh) 51.3, 50.9, 45.8, 45.5 (NCHMe2), 36.2 (NCHMe) 20.5,
20.4, 20.3, 20.3, 20.2, 20.1, 20.2 (NCHMe2), 15.4 (NCHMe);
m/z (CI) 508 (100%, M + H+) (Found (EI): M + H+, 508.3538.
C31H45N3O3 requires M + H, 508.3539).
(4 : 1 petrol–EtOAc) 0.22 & 0.10; mmax(film)/cm−1: 2969, 2934, 2872
1
=
(C–H), 1629 (C O), 1438, 1338. H-NMR (300 MHz, CD3OD):
d = 1 : 1 mixture of conformers, 7.78 (1H, dd, J = 7.5 and 1.5 Hz,
ArH), 7.69 (1H, dd, J = 7.8 and 1.5 Hz, ArH), 7.48–7.36 (4H, m,
ArH), 7.19 (2H, m, ArH), 6.21 (1H, s, SCHO), 6.04 (1H, s, SCHO),
4.63–4.54 (2H, m, OCH2), 3.95–3.81 (2H, m, OCH2), 3.74–3.61
(4H, m, NCH(CH3)2), 3.31–3.18 (4H, m, CH2S), 1.58 (3H, d,
J = 6.9 Hz, NCH(CH3)2), 1.57 (6H, d, J = 6.9 Hz, NCH(CH3)2),
1.56 (3H, d, J = 6.6 Hz, NCH(CH3)2), 1.26 (3H, d, J = 6.6 Hz,
NCH(CH3)2), 1.18 (3H, d, J = 7.2 Hz, NCH(CH3)2), 1.15 (6H, d,
J = 6.9 Hz, NCH(CH3)2); 13C-NMR (75 MHz, CD3OD): d =
170.8, 170.7, 137.3, 136.8, 136.3, 135.6, 128.9, 128.9,128.8, 128.3,
127.4, 124.9, 124.5, 83.8, 83.3, 72.3, 72.1, 51.8, 51.6, 46.2, 46.1,
33.6, 33.5, 19.6, 19.5, 19.4, 19.4, 19.3; m/z CI: 294 (100%, M+ +
H) m/z EI: 294 (18%, M + H). (Found: M + H, 294.1522.
C16H24O2NS, requires M + H 294.1522).
The aminal endo-27 was also isolated as a white solid (1.22 g,
◦
25%), [a]2D4 = − 39.6 (c = 1.02, CH2Cl2); mp 159.9–161.3 C; Rf
◦
[4 : 1 petrol (bp 40–60 C)–EtOAc] 0.47; dH (300 MHz; CDCl3)
7.81 (1H, dd, J 7.8 and 1.1, Ar–H), 7.47–7.28 (7H, m, Ar–H
(2H), Ph (5H)), 7.18 (1H, dd, J 7.6 and 1.2, Ar–H), 5.73 (1H, d,
J 4.8, CHPh), 5.39 (1H, s, OCH), 3.90–3.42 (5H, m, NCHMe2
and NCHMe), 2.28 (3H, s, NMe), 1.63 (3H, d, J 6.7, NCHMe2),
1.57 (3H, d, J 6.9, NCHMe2), 1.53 (6H, d, J 6.7, NCHMe2),
1.33 (3H, d, J 6.5, NCHMe2), 1.35 (3H, d, J 6.5, NCHMe2), 1.24
(3H, d, J 6.6, NCHMe2), 1.09 (3H, d, J 6.6, NCHMe2), 0.68 (3H,
=
d, J 6.7, NCHMe); dC (75 MHz; CDCl3), 168.9, 167.3 (C O),
138.8, 136.7, 135.2, 134.9, 128.0, 128.0, 127.9, 127.7, 125.9, 125.3
(aromatics) 90.4 (NCO), 83.0 (NMe) 61.6 (OCHPh) 51.2, 50.8,
45.8, 45.5 (NCHMe2), 32.8 (NCHMe) 20.4, 20.4, 20.2, 20.2, 20.1,
20.0, (NCHMe2), 7.3 (oxazolidine NCHMe).
N,N-Diisopropyl-2-methoxy-6-[1,3]oxathiolan-2-yl-benzamide
(31b). 2-Mercapoethanol (0.20 ml, 2.85 mmol, 1.5 equiv.) was
added to a stirred solution of indium triflate (0.053 g, 5 mol%)
and 2-formyl-5-methoxy-N,N-diisopropylbenzamide 3070 (0.50 g,
1.90 mmol) in toluene (40 ml). The mixture was heated under
a Dean–Stark condenser for 1 h. The mixture was allowed to
cool to room temperature and the solvent was evaporated under
reduced pressure. Flash chromatography yielded a mixture of
two diastereoisomers of the oxathiolane 31b (0.55 g, 90%),
mp168–172 ◦C; Rf (petrol–EtOAc 5 : 3) 0.55 and 0.45; mmax
N,N-Diisopropyl-2-(toluene-4-sulfinyl)benzamide (28). Amide
9 (2.00 g, 9.25 mmol) in THF (50 ml) at −78 ◦C was treated
with sec-butyllithium (1.5 equiv., 10.67 mL, 13.8 mmol, 1.3 M
solution in cyclohexane). After 30 min, (1R,2S,5R)-(−)-menthyl
p-toluenesulfinate 2951 (2 equiv., 5.74 g, 18.5 mmol) in THF
(10 ml) was added. The solution was stirred for a further
30 min, warmed to room temperature and quenched with saturated
aqueous ammonium chloride. The aqueous phase was extracted
with dichloromethane (×3) and the combined organic extracts
were dried using magnesium sulfate, filtered and concentrated
under reduced pressure to afford the crude product. Purification
by recrystallisation from petrol (bp 40–60 ◦C) and a few drops of
(NaCl)/cm−1 2963, 2929, 1627 (s, C O); dH (500 MHz; CDCl3),
=
7.34–7.27 (4H, m), 6.82 (lH, dd, J 7.5, 2.0), 6.80 (lH, dd, J 8.0,
1.5), 6.10 (lH, s), 6.00 (lH, s), 4.60–4.52 (2H, m), 3.84 (2H, sept,
J 6.0), 3.80 (3H, s), 3.79 (3H, s), 3.64 (lH, sept, J 6.5), 3.59 (lH,
sept, J 6.5), 3.51 (2H, dt, J 6.5, 3.0), 3.48 (2H, dt, J 6.5, 3.0), 1.58
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(3H, d, J 6.5), 1.56 (6H, d, J 6.5), 1.55 (3H, d, J 6.5), 1.17 (3H, d,
J 6.5), 1.13 (3H, d, J 6.5), 1.12 (3H, d, J 6.5), 1.05 (3H, d, J 6.5);
The mixture was warmed to ambient temperature (colour change
from dark yellow/orange to colourless solution) and was stirred
overnight. Water was added and the organic layer was separated.
The reaction mixture was reduced pressure at room temperature
to half of its origin volume. It was extracted with diethylether
(3 × 30 ml). The organic fractions were combined and washed
with brine (50 ml), water (50 ml), dried (MgSO4) and evaporated
under reduced pressure to afford the crude product. Purification
by flash chromatography, eluting with petroleum ether bp (40–
60◦)–EtOAc (11 : 1) to afford amide 33a as an oil (60 mg,
57.7%). dH (400 MHz; CDCl3) 7.81 (1H, d, J 8, ArH), 7.49
(2H, d, J 8, ArH), 7.35–7.21 5H, m, ArH), 5.07 (1H, d,
CHOCHPh), 4.75 (1H, s, CHO), 3.68 (2H, m, NCH2CH3), 2.91–
2.84 (1H, dqn, J 2 and 7, CHPhCHCH3), 2.43–2.23 (2H, m,
NCH2CH3), 2.33 (3H, s, NCH3), 2.15 (3H, s, ArCH3), 1.62 (3H,
dt, J 2 and 7, NCH2CH3), 0.72 (3H, t, J 7, NCH2CH3), 0.71
=
dC (500 MHz; CDCl3) 166.9 (C O), 137.9 (C), 136.9 (C), 129.8
(C), 120.3 (C), 111.3 (C), 110.8 (C), 56.0 (*CH), 51.5 (OCH3),
46.5 (OCH2), 46.3 (OCH2), 34.7 (CH), 34.3 (CH), 22.3 (CH3),
21.0 (CH3), 20.8 (CH3), 20.4 (CH3); m/z 324 (MH+); (found:
MH+, 324.1629, C17H25NO3S. MH+ requires 324.1629).
N,N-Diisopropyl-2-methoxy-6-[1,3]-oxathian-2-yl benzamide
(31c). Similarly, aldehyde 30, indium triflate, and 3-mercapto-1-
propanol (0.16 ml, 2.85 mmol, 1 equiv.) gave two diastereoisomers
of the amide 31c (0.57 g, 90%). Mp168–172 ◦C; Rf (petrol–EtOAc
5 : 3) 0.67 and 0.55; mmax (NaCl)/cm−l 2964, 2360, 1628 (s, C O);
=
dH (500 MHz; CDCl3), 7.32–7.30 (4H, m), 6.89–6.80 (2H, m),
5.82 (lH, s), 5.77 (lH, s), 4.29–4.23 (2H, m), 3.79 (6H, s), 3.79–
3.66 (2H, m), 3.64–3.55 (2H, m), 3.54–3.49 (2H, m), 3.15 (lH, dt,
J 13.0, 2.5), 3.10 (lH, dt, J 13.0, 3.0),2.84–2.78 (2H, m), 2.12–
2.04 (2H, m), 1.75–1.70 (2H, m), 1.61 (3H, d, J 6.5), 1.60 (6H, d,
J 6.5),1.59 (3H, d, J 6.5), 1.16 (3H, d, J 6.5), 1.14 (3H, d, J 6.5),
1.11 (3H, d, J 6.5), 1.03 (3H, d, J 6.5); dC (500 MHz; CDCl3),
=
(3H, d, J 7, CHPhCHCH3); dC (75MHz, CDCl3) 169.1 (C O),
139.8, 139.0, 137.9, 133.9 (Cq), 128.7–125.1 (aromatics), 94.8
(CHOCHPh), 82.3 (OCHPh), 63.7 (CHPhCCH3), 51.0 (Benz–
CH3), 43.0 (NCH2), 35.7 (NCH2), 14.7, 13.4 (2 × NCH2CH3), 12.6
=
166.9 (C O), 137.7 (C), 129.8 (C), 120.3 (C), 120.3 (C), 111.3 (C),
(CHCH3). mmax(thin film)/cm−1 1620 (C O); (found; M 366.5124;
=
110.8 (C), 55.9 (*CH), 51.5 (OCH3), 46.4 (OCH2), 46.2 (OCH2),
29.9 (CH), 29.5 (CH), 26.3 (CH3), 26.1 (CH3), 21.2 (CH3), 20.8
(CH3); m/z 338 (MH+); (found: MH, 338.1783, C18H27NO3S + H+
requires M 338.1783).
C25H34N2O2 requires M 366.5078); m/z (CI) 367 (100%, M + H+);
m/z (EI) 367 (15.4%, M + H+), 366 (100%, M); [a]2D5 − 14.9 (c =
0.99, CHCl3).
General method for the preparation of oxazolidines 33b–g from 23
N,N-Diisopropyl-2-(1,3-oxathiolan-2-yl)benzamide-S,S-dioxide
(32). The oxathioacetal 31a (0.25 g, 0.85 mmol, 1.00 equiv.)
in dry CH2Cl2 (3.0 cm3) was added dropwise to a solution
of 3-chloroperoxybenzoic acid (ca. 50%, 0.74 g, 2.13 mmol,
2.50 equiv.) in dry CH2Cl2 (15 cm3) at 0 ◦C and the reaction was
stirred at this temperature for 1 h. 10% Aqueous sodium sulfite
(10 cm3) was added and the mixture was extracted with CH2Cl2
(2 × 20 cm3). The combined organic phases were washed with
saturated NaHCO3 (30 cm3), brine (30 cm3), dried (MgSO4) and
concentrated under reduced pressure. The residue was purified
by flash chromatography (petrol–EtOAc, 6 : 1) to yield the
sulfone 32 (0.21 g, 74%) as a white solid, mp 134–137 ◦C. Rf
(4 : 1 petrol–EtOAc) 0.34maj & 0.21min; mmax(film)/cm−1: 2968,
sec-Butyllithium (1.3 equiv.) was added dropwise to a stirred
solution of amide 23 (1.0 equiv.; 3.92 mmol) in dry THF (40 ml)
at −78 ◦C under an atmosphere of nitrogen. After 60 min at
◦
−78 C, the electrophile (2.0 equiv.) in THF (10 ml) was added
dropwise to the reaction mixture. The mixture was warmed to
ambient temperature and water was added. Most of the THF
was removed under reduced pressure at room temperature and
the mixture extracted with diethyl ether (3 × 30 ml). The organic
fractions were combined and washed with brine (50 ml) and water
(50 ml), dried (MgSO4) and evaporated under reduced pressure to
afford the crude product.
(2ꢀS,4ꢀS,5ꢀR)-N,N-Diisopropyl-2-[3,4-dimethyl-5-phenyl-1,3-
oxazolan-2-yl]-6-methylbenzamide (33b). In this way, benzamide
23 (250 mg) and methyl iodide (2.0 equiv.) gave a crude oil.
Purification by flash chromatography, eluting with petroleum
ether (40–60◦)–EtOAc (11 : 1) gave a single diastereoisomer 33b
as crystalline white solid (142.5 mg, 55%), mp 153.4–155.3 ◦C.
dH (400 MHz; CDCl3) 7.81 (1H, d, J 7, ArH), 7.49 (2H, d, J 7,
PhH), 7.35 (3H, m, ArH and PhH), 7.30–7.24 (1H, m, PhH),
7.21 (1H, d, J 7, benz-H), 5.07 (1H, d, J 8, OCHPh), 4.72 (1H, s,
CHOCHPh), 3.68 (1H, septet, J 7, NCHCH3CH3), 3.54 (1H,
septet, J 7, NCHCH3CH3), 2.91–2.84 (1H, m, CHPhCHCH3),
2.33 (3H, s, NCH3), 2.15 (3H, s, ArCH3), 1.62 (6H, d, J 7,
NCHCH3CH3), 1.11 (3H, d, J 7, NCHCH3CH3), 1.07 (3H,
d, J 7, NCHCH3CH3), 0.78 (3H, d, J 7, CHPhCHCH3); dC
=
=
=
2930, 2880, 1624 (C O), 1340, 1320 (S O), 1158, 1130 (S O);
1H-NMR (300 MHz, CDCl3) (7.9 : 1 mixture of conformers):
d = 7.68 (1Hmaj + min, m, ArH), 7.53–7.43 (2Hmaj + min, m, ArH),
7.27 (1Hmaj + min, m, ArH), 5.73 (1Hmaj, s, SCHO), 5.26 (1Hmin, s,
SCHO), 4.70 (1Hmaj + min, dd, J = 10.2 and 10.2, OCH2), 4.45–
4.35 (1Hmaj + min, m, OCH2), 3.83 (1Hmaj + min, sept, J = 6.3 Hz,
NCH(CH3)2), 3.57 (1Hmaj + min, sept, J = 6.6 Hz, NCH(CH3)2),
3.48–3.28 (2Hmaj + min, m, CH2SO2), 1.64 (6Hmaj + min, d, J = 6.9 Hz,
NCH(CH3)2), 1.59 (6Hmaj + min, d, J = 6.6 Hz, NCH(CH3)2), 1.23
(6Hmaj + min, d, J = 6.0 Hz, NCH(CH3)2), 1.21 (6Hmaj + min, d, J =
6.0 Hz, NCH(CH3)2); 13C-NMR (75 MHz, CDCl3): d = 169.2,
138.4, 129.7, 129.2, 128.3, 127.2, 125.8, 90.7, 64.7, 51.7, 49.1, 46.5,
21.2, 20.7, 20.6, 20.4; m/z CI: 326 (20%, M+ + H). (Found: M +
H+, 326.1420. C16H24O4NS, M + H+ requires 326.1420).
=
(100 MHz, CDCl3), 169.3 (C O), 140.0, 139.3, 133.9, 134.3, 133.9,
(2ꢀS, 4ꢀS, 5ꢀR)-N,N-Diethyl-2-[3,4-dimethyl-5-phenyl-1,3-oxa-
zolan-2-yl]-6-methylbenzamide (33a). A solution of oxazolidine
22 (99.7 mg) in THF (10 ml) was added dropwise to a stirred
solution of sec-butyllithium (3.0 equiv.) and TMEDA (3.0 equiv.)
in dry THF (40 ml) at −78 ◦C under an atmosphere of nitrogen.
130.9, 128.3, 128.0, 127.7, 125.7 (Ar), 94.8 (CHOCHPh), 82.3
(OCHPh), 64.1 (CHPhCCH3), 51.0 (ArCH3), 46.0 (NCHMe2),
35.8 (CHNCH3), 20.9, 20.6, 20.4, 18.9 (4 × NCHCH3CH3), 15.2
+
(CHCH3); mmax(thin film)/cm−1 1626 (C O); Found: M + H
=
395.2714; C25H34N2O2 requires M + H+ 395.2699); m/z (CI) 395
(100%, M + H+), 176 (11%); m/z (EI) 395 (15%, M + H+), 176
◦
After 60 min at −78 C, methyl iodide (12.0 equiv.) was added.
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(55%); C35H34N2O2 requires C, 76.2; H, 8.78; N, 6.86. Found: C,
d, J 7.0, NCHCH3), 0.77 (3H, J 7, CHCH3); dC (100 MHz,
76.10, H, 8.69, N, 7.10; [a]2D5 − 47.9 (c = 0.31, chloroform).
CDCl3), 167.3 (C O), 140.0, 139.7, 135.3, 134.3, 128.8, 128.5,
=
128.0, 127.7, 125.9 (aromatics), 94.4 (CHOCHPh), 82.4 (OCHPh),
64.1 (CHPhCCH3), 51.4, 46.2 (NCH), 35.9 (NCH3), 20.8, 20.6,
(2ꢀS, 4ꢀS, 5ꢀR)-N,N-Diisopropyl-2-[3,4-dimethyl-5-phenyl-1,3-
oxazolan-2-yl]-6-ethylbenzamide (33c). In the same way, amide
23 (250 mg) and ethyl iodide (2.0 equiv.) gave a crude oil. Purified
by flash chromatography on silica, eluting with petroleum ether
(40–60◦)–EtOAc (11 : 1) gave the corresponding oxazolidine 33c
as a waxy oil (251.2 mg, 69%). dH (300 MHz; CDCl3) 7.82 (1H, d,
J 7, ArH), 7.47 (2H, d, J 7, PhH), 7.40 (1H, t, J 7, ArH), 7.37–7.33
(2H, m, ArH and PhH), 7.30–7.26 (2H, m, ArH and PhH), 5.70
(1H, d, J 8, OCHPh), 4.72 (1H, s, CHOCHPh), 3.67 (1H, septet,
J 7, NCHMe2), 3.54 (1H, septet, J 7, NCHMe2), 2.91–2.84 (1H,
m, CHPhCHCH3), 2.70 (1H, dq, J 14 and 7, CH2CH3), 2.58 (1H,
dq, J 14 and 7, CH2CH3), 2.15 (3H, s, NCH3), 1.62 (3H, d, J 7,
NCHMe), 1.61 (3H, d, J 7, NCHMe), 1.26 (3H, t, J 7, CH2Me),
1.11 (3H, d, J 7, NCHCH3CH3), 1.05 (3H, d, J 7, NCHCH3CH3),
20.4, 20.1 (NCHCH3), 17.1 (SCH3), 15.2 (CHCH3); mmax(thin
+
film)/cm−1 1627 (C O). (Found; M + H 427.2412; C27H38N2O3
=
requires M + H+ 427.2387) m/z (CI) 427 (100%, M + H+); m/z
(EI) 427 (100%, M + sH+); C25H34N2O2S requires C, 70.10; H,
8.11; N, 6.41; S, 6.41. Found: C, 70.38; H, 8.03; N, 6.41; S, 6.57.
[a]2D4 − 104.4 (c = 0.228, chloroform).
(2ꢀS, 4ꢀS, 5ꢀR)-N,N-Diisopropyl-2-[3,4-dimethyl-5-phenyl-1,3-
oxazolan-2-yl]-6-(phenylsulfanyl)benzamide (33g). In the same
way, benzamide 23 (250 mg) and phenyl disulfide (2.0 equiv.) gave a
yellow oil. Purification by flash chromatography on silica, eluting
with petroleum ether (40–60◦)–EtOAc (9 : 1), gave oxazolidine
33g as a crystalline pale yellow solid (170.2 mg, 53%) mp 147–
◦
=
149.1 C. dH (400 MHz; CDCl3) 7.88 (1H, dd, J 8 and 1, ArH),
0.77 (3H, d, J 7, CHCH3). dC (100 MHz, CDCl3), 168.9 (C O),
7.73–7.42 (2H, m, ArH), 7.2–7.4 (10H, m, Ph × 2), 5.09 (1H, d,
J 8, OCHPh), 4.78 (1H, s, CHOCHPh), 3.76 (1H, septet, J 7,
NCHCH3CH3), 3.56 (1H, septet, J 7, NCHCH3CH3), 2.95–2.87
(1H, m, CHPhCHCH3), 2.19 (3H, s, NCH3), 1.63 (3H, d, J 7,
NCHCH3CH3), 1.18 (3H, d, J 7, NCHCH3CH3), 1.13 (3H, d, J 7,
NCHCHCH3), 0.78 (3H, J 7, CHCH3); dC (100 MHz, CDCl3),
139.8, 139.1, 139.0, 133.9, 128.9, 128.5, 128.0, 127.7, 125.8 (Ar),
94.8 (CHOCHPh), 82.3 (OCHPh), 64.1 (CHPhCCH3), 50.9 and
46.0 (NCH), 35.9 (NCH3), 25.5 (CH2CH3), 20.9–20.3 (NCHCH3),
15.2 (CHCH3), 15.0 (CH2CH3). mmax(thin film)/cm−1 1627 (C O);
=
(found; M + H+ 409.5901; C26H36N2O2 requires M + H+ 409.5969);
m/z (CI) 409 (100%, M + H+), 190 (11%); m/z (EI) 409 (12%, M +
H+), 190 (100%); [a]2D5 − 56.7 (c = 0.04, chloroform).
=
167.0 (C O), 141.3, 139.3, 135.4, 127.9, 132.7, 131.5, 129.2,
129.0, 128.0, 127.7, 127.3, 127.2 (aromatics), 94.4 (CHOCHPh),
82.4 (OCHPh), 64.0 (CHPHhCCH3), 51.4 and 46.2 (NCH),
(2ꢀS, 4ꢀS, 5ꢀR)-N,N-Diisopropyl-2-[3,4-dimethyl-5-phenyl-1,3-
oxazolan-2-yl]-6-(1-hydroxyl-1-methylethyl)benzamide (33e). In
the same way, benzamide 23 (250 mg) and dry acetone (2.0 equiv.)
gave a crude oil. Purification by flash chromatography on silica,
eluting with petroleum ether (40–60◦)–EtOAc (11 : 1), gave the
oxazolidine 33e as a waxy oil (197.9 mg, 69%). dH (300 MHz;
CDCl3) 7.94 (1H, d, J 8, ArH), 7.55–7.28 (7H, m, ArH and
PhH), 5.13 (1H, d, J 9, OCHPh), 4.87 (1H, s, CHOCHPh), 3.74
(1H, septet, J 7, NCHCH3), 3.59 (1H, septet, J 7, NCHCH3),
2.29–2.86 (2H, m, CHPhCHCH3 and OH), 2.15 (3H, s, NCH3),
1.64 (12H, m, CCH(CH3)2 and NCHCH3CH3), 1.09 (3H, d, J 7,
NCHCH3), 1.08 (3H, d, J 7, NCHCH3), 0.80 (3H, d, J 7, CHCH3);
35.9 (NCH3), 20.8, 20.6, 20.4, 20.1 (NCHCH3), 15.2 (CHCH3).
+
mmax(thin film)/cm−1 1620 (C O); (found; M + H 489.6987;
=
C30H36N2O2S requires M + H+ 489.7055) m/z (CI) 489(100%, M +
H+); m/z (EI) 489 (20%, M + H+), 488 (100%, M); [a]2D1 − 123.4
(c = 0.421, chloroform).
General procedure for the deprotection-reduction of oxazolidines 33
A solution of trifluoroacetic acid (20.0 equiv.) and water
(2.0 equiv.) was added dropwise to a solution of oxazolidine
(1.51 mmol) dissolved in THF (30 ml) at 0 ◦C (ice-bath). After
60 min, small batches of sodium methoxide (33 equiv.) were added
slowly until pH 6 was attained, followed by a slurry of sodium
borohydride (10 equiv.) in ethanol (20 ml) at 0 ◦C. The mxture
was allowed to warm to room temperature. Evaporation under
reduced pressure without external heating reduced the solution
to half its original volume. It was extracted with diethyl ether
(3 × 30 ml), washed with brine (2 × 30 ml), dried (MgSO4)
and filtered. Evaporation under reduced pressure without external
heating afforded the crude alcohol 34.
=
dC (75 MHz, CDCl3), 171.9 (C O), 145.0, 139.5, 135.1, 134.6,
128.1, 128.0, 127.9, 127.9, 127.6, 127.0 (Ar), 93.5 (CHOCHPh),
82.1 (OCHPh), 74.5 [COH(CH3)2], 64.1 (CHPHhCCH3), 51.3 and
46.0 (NCH), 35.8 (NCH3), 34.6 and 31.298 [COHC(CH3)2], 20.1
[COH(CH3)2], 19.8 and 19.3 (NCHMe2), 15.3 (CHCH3); mmax(thin
+
film)/cm−1 3421 (OH), 1621 (C O); (found; M + H 439.2963;
=
C27H38N2O3 requires M + H+ 439.2961,) m/z (CI) 439 (100%, M +
H+); m/z (EI) 439 (45%, M + H+), 381 (100%), 263 (57%); [a]2D1
−
21.3 (c = 0.14, chloroform).
(2ꢀS, 4ꢀS, 5ꢀR)-N,N-Diisopropyl-2-[3,4-dimethyl-5-phenyl-1,3-
oxazolan-2-yl]-6-(methylsulfanyl)benzamide (33f). In the same
way, benzamide 23 (250 mg) and methyl disulfide (2.0 equiv.)
gave a yellow oil. Flash chromatography on silica, eluting with
petroleum ether (40–60◦)–EtOAc (12 : 1), gave the oxazolidine 33f
as a white crystalline solid (109.3 mg, 69%) mp 135.1–136.6 ◦C. dH
(400 MHz; CDCl3) 7.81 (1H, dd, J 8 and 1, ArH), 7.47–7.25 (7H,
m, ArH), 5.07 (1H, d, J 8, OCHPh), 4.74 (1H, s, CHOCHPh),
3.63 (1H, septet, J 7, NCHCH3CH3), 3.55 (1H, septet, J 7,
NCHCH3CH3), 2.93–2.85 (1H, m, CHPhCHCH3), 2.47 (3H, s,
SCH3), 2.17 (3H, s, NCH3), 1.63 (3H, d, J 8, NCHCH3), 1.62
(3H, d, J 8, NCHCH3), 1.19 (3H, d, J 7, NCHCH3), 1.09 (3H,
(Ra )-N,N -Diisopropyl-2-methyl-6-(hydroxymethyl)benzamide
(34b). In this way oxazolidine 33b (157 mg) was reduced to give
the crude alcohol. Purification by flash column chromatography
eluting with petroleum ether–EtOAc (5 : 1) gave enantiomerically
enriched alcohol 34b as an oil (81.2 mg, 82%). Integration of the
1H NMR spectrum of this material in the presence of Pirkle’s
chiral shift reagent71 indicated an enantiomeric excess of 8%.
dH (300 MHz; CDCl3), 7.41–7.08 (2H, m, Ar–H), 7.04 (1H, d,
J 7, Ar–H), 4.55 (1H, d, J 13, CHAHBOH), 4.30 (1H, d, J 13,
CHAHBOH), 3.54 (1H, sept, J 7, NCH), 3.47 (1H, sept, J 7,
NCH), 2.22 (3H, s, ArCH3), 1.54 (3H, d, J 7, NCHCH3), 1.50
(3H, d, J 7, NCHCH3), 1.09 (3H, d, J 7, NCHCH3), 0.87 (3H, d,
440 | Org. Biomol. Chem., 2006, 4, 424–443
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=
J 7, NCHCH3); dC (75 MHz, CDCl3) 170.3 (C O), 139.3, 137.0,
136.6, 128.5, 127.4, 126.6 (Ar), 63.5 (CH2OH), 50.9 (NCH2),
46.2 (ArCH3), 46.0 (NCH2), 20.9, 20.6, 20.4, 20.3 (NCHCH3);
petroleum, Rf 0.31) to give the silane 35 as a colourless oil which
crystallised on standing in the freezer (171 mg, 52%). M+ 333.2488
(C20H35NOSi requires 333.2488); mmax (thin film) 1632 cm−1; dH
(300 MHz; CDCl3), 7.23 (1H, t, J 7.7, p-ArH), 7.02 (1H, d, J 7.7,
m-ArH), 6.97 (1H, d, J 7.7, m-ArH), 3.67 (1H, sept, J 6.7, NCH),
3.52 (1H, sept, J 6.7, NCH), 2.77–2.45 (2H, m, ArCH2CH3), 2.16
(1H, q, J 7.4, ArCH), 1.63 (3H, d, J 6.7, NCHMe), 1.61 (3H, d,
J = 6.7 Hz, NCHMe), 1.36 (3H, d, J 7.4, ArCHMe), 1.26 (3H,
t, J 7.6, ArCH2Me), 1.14 (3H, d, J 6.7, NCHMe), 1.08 (3H, d, J
6.7, NCHMe), 0.00 (9H, s, Si(CH3)3); dC (75 MHz; CDCl3), 169.8
(s, CO), 142.3 (s, Ar), 139.6 (s, Ar), 135.9 (s, Ar), 127.4 (d, Ar),
123.9 (d, Ar), 123.3 (d, Ar), 50.0 (d, NCH), 45.6 (d, NCH), 25.8
(d, ArCH), 25.3 (t, ArCH2), 20.9 (q, NCHMe), 20.8 (q, NCHMe),
20.3 (q, NCHMe), 20.2 (q, NCHMe), 16.3 (q, CH3), 15.0 (q, CH3),
−2.9 (q, Si(CH3)3); m/z CI + 336 (6%), 335 (23%), 334 (100%),
304 (8%), 290 (4%), 233 (4%), 161 (10%), 90 (5%), 73 (4%).
mmax(thin film)/cm−1 3510 (br, OH), 1617 (C O). (Found: M +
=
H+ 250.3567; C15H23NO2 requires M + H+ 250.3601); m/z (CI)
250 (100%, M + H+), 235 (11%); m/z (EI) 250 (22%, M + H+),
235 (100%), 104 (15%).
(Ra )-N,N -Diisopropyl-2-ethyl-6-(hydroxymethyl)benzamide
(34c). In the same way, oxazolidine 33c (259 mg) was reduced
to give a crude alcohol. This was purified by flash column
chromatography eluting with petroleum ether (40–60◦)–EtOAc
(5 : 1) to afford enantiomerically enriched alcohol 34c as white
1
powder (145.2 mg, 87%). Integration of the H NMR spectrum
of this material in the presence of Pirkle’s chiral shift reagent71
indicated an enantiomeric excess of 28%. dH (300 MHz; CDCl3),
7.39–7.26 (2H, m, ArH), 7.23 (1H, d, J 7, ArH), 4.69 (1H, d,
J 13 and 3, CHAHBOH), 4.42 (1H, d, J 13 and 2, CHAHBOH),
3.65 (1H, sept, J 7, NCH),3.22 (1H, sept, J 7, NCH), 2.70
(1H, dq, J 14 and 7, CHAHBCH3), 2.60 (3H, dq, J 14 and
7, CHAHBCH3), 1.66 (3H, d, J 7, NCHCH3), 1.62 (3H, d,
J 7, NCHCH3), 1.28 (3H, t, J 8, CH2CH3), 1.19 (3H, d, J 7,
NCHCH3), 0.08 (3H, d, J 7, NCHCH3); dC (75MHz, CDCl3)
(1RS,1ꢀSR)-N,N-Diisopropyl-2,6-bis-{(1-trimethylsilyl)ethyl}-
benzamide (36). sec-Butyllithium (0.25 ml, 1.3M solution in
cyclohexane, 0.323 mmol) was added dropwise to a solution of
benzamide 35 (92 mg, 0.276 mmol) in dry THF (30 ml) at −78 ◦C,
under an atmosphere of nitrogen. The resultant orange solution
was stirred at −78 ◦C for 1.5 h and trimethylsilyl chloride (56 ll,
0.441 mmol) was added. The solution was then allowed to warm
to 0 ◦C, water (30 ml) was added and the THF was removed
under reduced pressure. The aqueous phase was extracted with
dichloromethane (3 × 30 ml), the combined extracts were washed
with water (40 ml), dried over magnesium sulfate, filtered and
the solvent was evaporated. The symmetrical amide was obtained
pure following column chromatography (2% ethyl acetate in
light petroleum, Rf 0.48) as a white crystalline solid (67 mg,
60%) in addition to starting material, Rf 0.24 (25 mg, 27%). Mp
113.5–114 ◦C; M 405.2889 (C23H43NOSi2 requires 405.2883); mmax
1619 cm−1; dH (300 MHz; CDCl3), 7.20 (1H, t, J 7.7, p-ArH),
6.89 (2H, d, J 7.7, 2 × m-ArH), 3.73 (1H, sept, J 6.7, NCH), 3.52
(1H, sept, J 6.7, NCH), 2.15 (2H, q, J 7.4, 2 × CHSi), 1.61 (6H,
d, J 6.7, NCHMe2), 1.36 (6H, d, J 7.4, 2 × ArCHMe), 1.11 (6H,
d, J 6.7, NCHMe2), 0.00 (18H, s, 2 × Si(CH3)3); dC (75 MHz;
CDCl3), 170.1 (s, CO), 142.8 (s, 2 × o-Ar), 134.7 (s, CCON, 127.3
(d, p-ArH), 122.1 (d, 2 × m-ArH), 49.5 (d, NCH), 45.5 (d, NCH),
25.5 (d, 2 × ArCH), 20.9 (q, NCHMe2), 20.2 (q, NCHMe2), 16.4
(q, 2 × ArCHMe), 2.8 (q, 2 × Si(CH3)3); m/z CI+ 407 (33%), 406
=
170.3 (C O), 139.3, 137.0, 136.6, 128.5, 127.4, 126.6 (aromatics),
63.5 (CH2OH), 50.9, 46.0 (NCH2), 25.5 (CH2CH3), 20.9, 20.6,
20.4, 20.3 (NCHCH3), 14.9 (CH2CH3); mmax(thin film)/cm−1 3488
+
=
(br, OH), 1613 (C O); (found; M + H 264.1967; C16H25NO2
requires M + H+ 264.1964); m/z (CI) 264 (100%, M + H+), 234
(5%); m/z (EI) 264 (100%, M + H+), 234 (31%), 133 (13%).
(Sa )-N,N -Diisopropyl-2-hydroxymethyl-6-(methylsulfanyl)-
benzamide (34f). In the same way, oxazolidine 33f (78 mg) was
reduced to give a crude alcohol. This was purified by flash column
chromatography eluting with petroleum ether (40–60◦)–EtOAc
(5 : 1) as to afford enantiomerically enriched alcohol 34f as
an oil (10.9 mg, 20%). Integration of the 1H NMR spectrum
of this material in the presence of Pirkle’s chiral shift reagent71
indicated an enantiomeric excess of <1%. dH (300 MHz; CDCl3),
7.43 (2H, m, ArH), 7.26 (1H, dd, J 7 and 3, ArH), 5.8 (1H, d,
J 13, CHAHBOH), 5.06 (1H, d, J 13, CHAHBOH), 3.54 (2H,
septet, J 7, NCH), 2.49 (3H, s, S–CH3), 1.65 (3H, d, J 7,
NCHCH3), 1.61 (3H, d, J 7, NCHCH3), 1.29 (3H, d, J 7,
NCHCH3), 1.13 (3H, d, J 7, NCHCH3); dC (75 MHz, CDCl3)
˚
(100%). HPLC analysis of the crude product (Phenosphere 80 A
=
170.0 (C O), 139.0, 137.1, 136.6, 129.0, 128.3, 127.1 (aromatics),
64.1 (CH2OH), 50.7 (NCH2), 47.1 (SCH3), 46.0 (NCH2), 20.9,
20.6, 20.4, 20.3 (NCH2CH3).
100 × 8.00 mm 5 lm silica column, Merck–Hitachi system, eluent
1% ethanol in hexane, flow rate 2 ml min−1, showed 36 room
temperature 1.65 min (64.5%), 35 2.13 min plus further peaks of
6 and 4% intensity.
N,N-Diisoproyl-2-ethyl-6-(1-trimethylsilyl)ethylbenzamide (35).
sec-Butyllithium (0.83 ml, 1.3 M solution in cyclohexane,
1.08 mmol) was added dropwise to a solution of N,N-diisopropyl-
2-(1-trimethylsilyl)ethylbenzamide (300 mg, 0.982 mmol) in THF
(2ꢀS, 4ꢀS, 5ꢀR)-N,N-Diisopropyl-2-[3,4-dimethyl-5-phenyl-1,3-
oxazolan-2-yl]-6-(1-trimethylsilylethyl)benzamide (37). In a simi-
lar way, amide 33b (150 mg, 0.37 mmol) was lithiated with sec-BuLi
and quenched with ethyl iodide. Chromatography (SiO2; EtOAc)
gave the alcohol 37 (77 mg, 50%) as a yellow oil, Rf (9 : 1 : 0.1
petrol–EtOAc–NEt3) 0.30; [a]D = − 132.0◦ (c = 2.0, acetone);
◦
(80 ml) cooled to −78 C under an atmosphere of nitrogen. The
resultant orange-pink solution was stirred for 1 h at −78 ◦C before
the addition of ethyl iodide (0.16 ml, 1.96 mmol). The solution was
allowed to warm to 0 ◦C, water (40 ml) was added and the THF was
removed under reduced pressure. The aqueous phase was extracted
with dichloromethane (3 × 40 ml) and the combined organic
extracts were washed with water (40 ml), dried over magnesium
sulfate and filtered. The solvent evaporated and the residue was
purified by column chromatography (3% ethyl acetate in light
mmax/cm−1 2963, 2930 and 2873 (CH), 1628 (C O); dH (300 MHz;
=
CDCl3, 0.81 (3H, d, J 7, CH3), 0.90 (3H, t, J 7, CH3), 1.12 (3H, d,
J 7, CH3), 1.17 (3H, d, J 7, CH3), 1.29 (3H, d, J 7, CH3), 1.65 (3H,
d, J 7, CH3), 1.69 (3H, d, J 7, CH3), 2.21 (3H, s, NMe), 2.72 (2H,
m, CH), 2.92 (1H, m, CH), 3.56 (1H, sept, J 7, CH), 3.76 (1H,
sept, J 7, CH), 4.78 (1H, s, CH), 5.11 (1H, d, J 8, CH), 7.30–7.53
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(7H, m, ArH), 7.87 (1H, dd, J 7 and 1, ArH); dC (75MHz; CDCl3)
12.5, 15.6, 20.5, 20.6, 20.7, 21.1, 32.9, 36.3, 37.5, 46.3, 51.0, 64.4,
82.5, 95.1, 126.3, 126.8, 127.9, 128.2, 128.3, 128.8, 134.1, 138.9,
140.1, 143.6, 169.1; m/z (CI) 437 (20%, MH+); 218 (60%); Found
(M+) 436.2988; C28H40N2O2 requires (M) 436.3090.
21 J. Clayden, M. Helliwell, J. H. Pink and N. Westlund, J. Am. Chem.
Soc., 2001, 123, 12449.
22 J. Clayden, C. McCarthy, N. Westlund and C. S. Frampton, J. Chem.
Soc., Perkin Trans. 1, 2000, 1363.
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28 J. Clayden, SYNLETT, 1998, 810.
29 J. Clayden, N. Westlund, R. L. Beddoes and M. Helliwell, J. Chem.
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Acknowledgements
We are grateful to the EPSRC, Leverhulme Trust, GlaxoSmithK-
line, Eli Lilly & Co., AstraZeneca and Roche for supporting this
work and to Ms Thelma Koullourou and Ms Shengning Bi for
synthetic assistance.
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