Dynamic resolution of atropisomeric amides using proline-derived imidazolines and ephedrine-derived oxazolidines

Article abstract of DOI:10.1016/j.tet.2004.01.101

Condensation of atropisomeric tertiary 2-formyl naphthamides or 2-formyl benzamides with some chiral diamines and amino alcohols leads, via a dynamic resolution process, to single atropisomers of tertiary amides bearing chiral imidazolidines or oxazolidin

Full text of DOI:10.1016/j.tet.2004.01.101

Tetrahedron 60 (2004) 4399–4412
Dynamic resolution of atropisomeric amides using proline-derived
imidazolines and ephedrine-derived oxazolidines
*
Jonathan Clayden, Lai Wah Lai and Madeleine Helliwell
Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Received 15 December 2003; revised 19 January 2004; accepted 21 January 2004
Abstract—Condensation of atropisomeric tertiary 2-formyl naphthamides or 2-formyl benzamides with some chiral diamines and amino
alcohols leads, via a dynamic resolution process, to single atropisomers of tertiary amides bearing chiral imidazolidines or oxazolidines.
Hydrolysis of the new heterocycle competes a dynamic thermodynamic resolution of the starting aldehyde, and rapid reduction allows the
isolation of atropisomeric amides bearing 2-hydroxymethyl substituents in enantiomerically enriched form. Evidence that the reactions are
under thermodynamic control is presented.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
member of the relatively small class of dynamic thermo-
dynamic resolutions.29
Tertiary aromatic amides are now well known to have the
potential for atropisomerism: We,1 and others,2–4 have
demonstrated that they are resolvable5 by chromatography
on a chiral stationary phase. Given the wide utility of other
more well known classes of atropisomers such as the
biphenyls and binaphthyls in asymmetric catalysis6,7
(principally because of the flexibility inherent in a
stereogenic axis as opposed to a stereogenic centre8), we
set out to develop a method for the resolution of tertiary
aromatic amides on a practical scale which would open up
the opportunity for their development as a new family of
chiral ligands based on the aromatic amide structure. A
small number of enantiomerically pure atropisomeric
amides have already been used as effective chiral ligands,
being made in enantiomerically pure form either by
classical resolution9 or by asymmetric synthesis.10,11
Dynamic kinetic resolution12,13 and enantioselective lithia-
tion14–17 have also been used to synthesise atropisomeric
amides in enantiomerically form, and some of these
compounds have also been used as chiral reagents4 and
auxiliaries18 or are of biological interest.19–25 Our studies
into the resolution of aromatic amides via the condensation
of amidoaldehydes with 1,2-diamines and 1,2-amino-
alcohols to form imidazolidines and oxazolidines are
described in full in this paper.26–28 During the course of
this work, we discovered a remarkable propensity of the
atropisomers being resolved to equilibrate and thus facilitate
a dynamic resolution, a reaction which appears to be a
2. Results and discussion
2.1. Starting materials
The known30,31 2-formyl naphthamides 1 were made in
good yield from the parent amides by a modification of the
ortholithiation conditions described by Beak and Brown,32,33
quenching with DMF as electrophile (Scheme 1). The
benzamides 2a-d were also made by ortholithiation, though
the ethyl group of 2c was protected as its 1-silyl derivative
to prevent competing lateral lithiation.34 Ortholithiation and
formylation of 335 gave 4 which was desilylated to yield 2c.
2d was made from benzamide 5 by two successive
ortholithiation reactions. 2e was made from the mesitamide
717 by lateral lithiation and hydroxylation to yield 8 which
was oxidised with the Dess Martin periodinane36,37 to the
aldehyde.
2.2. Condensation with a proline-derived diamine
The documented easy formation and cleavage of aminals
derived from 1,2-diamines38 prompted us to try, initially,
the proline-derived diamine 939 as a resolving agent for
these aldehydes. We heated 9, which is available in two40 or
four39 steps from pyroglutamate or proline respectively,
with aldehydes 1a and 1b in toluene at reflux for 24 h. The
NMR spectrum of the crude reaction mixture showed,
surprisingly, only a single diastereoisomer (.90:10 dia-
stereoselectivity) of the imidazolines 10a and 10b, and
purification by chromatography on neutral alumina (the
Keywords: Atropisomeric amides; Imidazolines; Oxazolidines; Ephedrine.
*
Corresponding author. Tel.: þ44-161-275-4612; fax: þ44-161-275-4939;
e-mail address: j.p.clayden@man.ac.uk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.101

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J. Clayden et al. / Tetrahedron 60 (2004) 4399–4412
Scheme 1. The starting 2-formylnaphthamides.
imidazolines are somewhat sensitive to chromatography on
silica) allowed us to isolate these compounds in 88–89%
yield (Scheme 2). X-ray crystallography (Fig. 1) proved the
stereochemistry of M-10a.
The formation of the imidazolines creates a new stereogenic
centre at the aminal carbon, but based on previous results
published by Mukaiyama41 we expected this aspect of the
reaction to be highly stereoselective: aldehydes RCHO tend
to form imidazolidines exo-11 rather than endo-11, which
places R on the endo face of the bicyclic system (Scheme 3).
However, the aldehydes 2 are chiral racemic compounds, so
our initial expectation was that we would see the formation
of M- and P-10 in approximately equal quantities. The
formation of a single isomer of 10a and 10b must indicate
that rotation about the Ar–CO axis takes place under the
conditions of the reaction, either before the formation of the
imidazolidines, or both before and after their formation. In
common with other atropisomers in which bond rotation is
blocked by a trigonal carbon substituent,42–44 the barrier to
racemisation of aldehydes 1 and 2 is expected to be low
relative to those bearing, say, a methyl group in the place of
the formyl substituent: 1a has a half-life of racemisation of
only ca. 12 min at 20 8C,43 which extrapolates to ca. 0.1 s at
110 8C, the temperature of the condensation. Naphthamides
bearing branched substituents with a steric demand similar
to the imidazolines of 10 have barriers to Ar–CO rotation
Scheme 2. Synthesis of naphthamide-derived imidazolidines.
of the order of 110 kJ mol21 43
which would suggest
,
Scheme 3. Typical stereoselectivity in the formation of proline-derived
imidazolidines.
Figure 1. X-ray crystal structure of M-10a.

J. Clayden et al. / Tetrahedron 60 (2004) 4399–4412
4401
epimerisation of 10 should take place over a period of only
minutes at 110 8C, easily within the timescale of the
reaction. We shall return to the likely mechanism of the
stereoselectivity later.
stereocontrol at the new stereogenic centre (Scheme 6).48–51
Condensation of 1a with ephedrine and with pseudo-
ephedrine, and 1b with ephedrine, gave essentially single
diastereoisomers of the product imidazolines 16 and 17,
which were isolated after chromatography on silica (the
oxazolidines are more stable to silica than the imidazolines)
in good yield (Scheme 7). The stereochemistry of 16a was
proved by an X-ray crystal structure (Fig. 2), and is
consistent with the expected ‘all-syn’ stereochemistry51,50
which allows the four oxazolidine substituents in 16 to lie
pseudoequatorial on the new five-membered ring.
The same diamine 9 was condensed with 2-formyl
benzamides 2b-e and the reactions were similarly diaster-
eoselective: 1H NMR analysis of the crude reaction mixture
indicated that the products were formed with at least .95%
stereochemical purity (Scheme 4). Chromatography on
alumina yielded pure imidazolines 12b-e in good yield.
Scheme 4. Synthesis of benzamide-derived imidazolidines.
However, as previously reported,18,45 diastereoselectivity in
the condensation of the peri-substituted naphthamides 1c
and 1d was rather poorer, with 20–25% of a minor epimer
being evident in the 1H NMR spectrum of the crude reaction
mixture (Scheme 5).
Figure 2. X-ray crystal structure of M-16a.
1
The H NMR spectra of the crude products 16 showed
consistently 5–10% of a minor diastereoisomer, unlike
those of the crude products 10 which were essentially free of
diastereoisomeric impurities. Although we were unable to
isolate and fully characterise this diastereoisomer, it had a
distinctive pattern of signals in the region of 5–6 ppm
Scheme 5. Lower selectivity in more hindered peri-substituted
naphthamides.
Scheme 6. Oxazolidines from ephedrine.
2.3. Condensation with chiral amino alcohols
Although condensation with the diamine 9 is a simple and
versatile way of introducing chirality into the atropisomeric
amides, 9 is rather expensive commercially and its
synthesis, though not difficult, poses some practical
problems on scale-up.46 Moreover, we found that the
imidazolidines were unstable to further lithiation reactions:
attempted ortholithiation33 of 12b or lateral lithiation47 of
12c gave complex mixtures of products. We, therefore,
sought a more readily available ‘resolving agent’, especially
one which would be stable to lithiation conditions.
We chose readily available aminoalcohols (1R,2S)-(2)-
ephedrine and (1S,2S)-(þ)-pseudoephedrine as likely can-
didates. Both are known to condense with aldehydes to yield
stable imidazolidines 15 with good, though not perfect,
Scheme 7. Synthesis of naphthamide-derived oxazolidines.

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J. Clayden et al. / Tetrahedron 60 (2004) 4399–4412
Scheme 8. Oxazolidines from benzamides and a peri-substituted naphthamide.
which we have found in other work52 to be characteristic of
ephedrine-derived oxazolidines with endo relative stereo-
chemistry (Scheme 6). Indeed, condensations of aldehydes
with ephedrine typically give varying amounts of the endo
product, according to solvent and conditions,51,50 and
for this reason we assume this minor diastereoisomer is
P-endo-16 rather than the alternative P-16, of which we saw
no sign (,5% by NMR). Nonetheless, it was a straight-
forward matter to remove this minor impurity during
purification.
2.4. Completion of the resolution: hydrolysis of the
imidazolidines and oxazolidines
Hydrolysis of the imidazolidines and oxazolidines back to
the aldehydes 1 and 2 should complete a method for the
dynamic resolution of 1 and 2. However, as noted before,
atropisomeric 2-formyl amides have low barriers to
racemisation relative to structurally similar amides bearing
tetrahedral 2-substituents.43,53 The products of hydrolysis
are, therefore, likely to racemise too fast for it to be possible
to isolate them in enantiomerically enriched form. We,
therefore, sought conditions which would allow us to
remove the resolving agent (the diamine or aminoalcohol),
preferably by hydrolysis at low temperature, and then
rapidly reduce the formyl group to a methyl or hydroxy-
methyl substituent.
Condensation of the aldehydes 2a-2c with (2)-ephedrine
was similarly diastereoselective, with the oxazolidines
18a-18c being formed with high diastereoselectivity, even
if instability towards hydrolysis led to a low yield after
purification in one case (Scheme 8). As with the diamine 9,
condensation of a hindered peri-substituted naphthamide
with (2)-ephedrine gave much poorer selectivities, and 1c
gave a 1:1 mixture of the two diastereoisomers of 16c in
90% yield.45
After a series of trial hydrolyses, we found that the
imidazolidine 10a was completely hydrolysed by 1 M
aqueous HCl in THF at 0 8C over a period of 30 min.
Scheme 9. Deprotection and recovery of enantiomerically enriched amides.
Table 1. Completion of the resolution
Entry
S.M.
Conditions
Product
Yield
ee
Overall yield from 1 or 2a
1
2
3
4
5
6
10a
10b
12d
12e
16a
16b
1 M HCl
1 M HCl
1 M HCl
1 M HCl
CF3CO2H
CF3CO2H
(2)-19a
(2)-19b
(2)-20d
(2)-20ev(2)-8
(2)-19a
(2)-19b
94
84
90
93
85
85
89
97
77
53
74
74
83
75
77
58
73
74
a
Representing the efficiency of the resolution.

J. Clayden et al. / Tetrahedron 60 (2004) 4399–4412
4403
Hydrolysis of the ephedrine-derived oxazolidines was much
slower, and remaining starting material was evident even
after treatment with 6 M HCl in THF at 0 8C for 30 min.
However, stirring with a excess of trifluoroacetic acid in wet
THF at 0 8C for 30 min promoted complete hydrolysis of the
oxazolidine to the aldehyde.
products, and overall yields for the condensation–hydroly-
sis–reduction sequence which results in resolution of
racemic aldehyde to enantiomerically pure alcohol were in
most cases well over 50% (final column), demonstrating the
very practical nature of this dynamic resolution process. In
general, the ees obtained from the oxazolidines were lower,
reflecting the harsher conditions necessary to force the
hydrolysis to completion, and the imidazolidine method is
to be preferred as a method for dynamic resolution.
Reduction of the aldehyde to the alcohol was achieved by
adding a large excess of sodium borohydride to the acidic
solution containing the crude aldehydes. Because of the low
pH, the borohydride rapidly decomposed somewhat
exothermically under these conditions, and for reduction
of the imidazolidine-derived aldehydes we added the
sodium borohydride as a cold slurry in a solution of sodium
methoxide in ethanol. A later improvement, which was used
for reduction of the oxazolidine-derived aldehydes, was to
add first an excess of methoxide to neutralise the
trifluoroacetic acid and then to add the borohydride. Scheme
9 and Table 1 detail the application of these conditions for
hydrolysis and reduction to the imidazolidines 10 and 12
and oxazolidines 16. For determination of ee, where
necessary, racemic alcohols 19 and 20 were also made by
sodium borohydride reduction of the racemic aldehydes 1
and 2.
2.5. Mechanism of the resolution and origin of the
stereoselectivity
When we set out to resolve racemic, atropisomeric
aldehydes 1 and 2c-e, we expected to obtain a 1:1
diastereoisomeric mixture of the imidazolidines 10 and 12
and the oxazolidines 16-18. Formation of anything other
than a 1:1 mixture of atropisomers of 10 and 12 can be
explained only by dynamic resolution, involving Ar–CO
bond rotation. As explained earlier, the conditions of the
condensation reaction are such that for most of the aldehyde
starting materials Ar–CO rotation is likely to be rapid prior
to condensation and still possible over a period of minutes
even after condensation.
In many cases, excellent enantiomeric excesses were
observed in the atropisomeric hydroxymethyl amide
Two distinct dynamic resolution mechanisms are possible,
both of which may be operative at least to some extent. One
Scheme 10. Dynamic kinetic resolution of 2.
Scheme 11. Dynamic Thermodynamic resolution of 2.

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J. Clayden et al. / Tetrahedron 60 (2004) 4399–4412
amounts to a dynamic resolution under kinetic control;54–57
the other a dynamic resolution under thermodynamic
control.29 In the first, equilibration between stereoisomers
by rotation about the Ar–CO bond occurs before formation
of the imidazoline or oxazolidine; one enantiomer of the
aldehyde reacts with the aldehyde faster than the other, and
an excess of one product stereoisomer is formed (Scheme
10). In the second, stereochemistry is defined by equili-
bration after the formation of the imidazolines: whatever
the initial ratio of products, the final product ratio is defined
by their relative stability and not by their relative rate
of formation (Scheme 11). We were unable to prove
conclusively which mechanism operates, but we have strong
evidence that the stereoselectivity of the reactions both with
the diamine 9 and with ephedrine 13 is under thermo-
dynamic control, that is, Scheme 11 best represents the
mechanism of the resolution.
condensation of 1c or 1d with 9 or 13 (Schemes 5 and 8)
to yield 10c, 10d and 16c, a dynamic thermodynamic
resolution is prevented by very high barriers to Ar–CO
rotation in the peri-substituted products, though dynamic
kinetic resolution should still be possible because of the
lower barriers to Ar–CO rotation in the aldehydes 10c and
10d.43,58 Yet selectivity is poor, suggesting that intercon-
version of the imidazolidine or oxazolidine products is
necessary for good stereoselectivity.
Second, the imidazolidine 12a, and the oxazolidines 18a
and 18b, in which the Ar–CO bond is free to rotate (a typical
tertiary amide bearing a single branched 2-substituent
shows a half-life for Ar–CO rotation of the order of
0.01 s at 20 8C43,35) all exist as single conformers (.95:5 by
NMR: Ar–CO rotation in such amides is slow on the NMR
timescale). Evidently structures 12 and 18 display a
thermodynamic preference for the stereochemistry of
M-18 (Scheme 11) when equilibration of the products is
possible, a preference which is likely to persist in related
structures 10, 12, 16 and 18.
First, we repeated the condensation of 1a with 9, but
allowed it to take place in an NMR tube in C6D6. NMR
showed that as starting material disappeared at 20 8C, two
products in a proportion of 3:1 were seen to increase in
concentration. The minor product was the imidazolidine
M-10a which we had previously isolated; the major product,
however, appeared to be an epimer of 10a, probably P-10a,
although a structure related to endo-11 cannot be ruled out.
Attempts to characterise this epimer fully failed, though
HPLC allowed us to obtain a small quantity which
converted to M-10a on standing at ambient temperature
for 20 min. Since M-10a is clearly not the kinetic product of
the condensation, the stereoselectivity of the reaction must
be due to control by an alternative, presumably thermo-
dynamically controlled, mechanism. If the major epimer
formed under kinetic control is indeed P-10a then interest-
ingly a dynamic kinetic resolution appears to be operating
inconsequentially in the opposite direction from the overall
dynamic resolution.
We therefore propose that the selectivity of all the
condensation reactions arises because whatever the initial
ratio of atropisomers formed in the condensation, inter-
conversion of the products in refluxing toluene allows them
to equilibrate to a ratio which is almost entirely the
stereoisomer shown as, or analogous to, M-18 in Scheme
11. Our proposed rationale for the favourability of this
isomer, both for the imidazolidines and the oxazolidines, is
illustrated in Scheme 12. In both series, we presume the
benzylic stereogenic centre must arrange itself such that its
smallest substituent, the C–H bond, more or less eclipses
the amide group. For the imidazolidines, the favoured
isomer allows the bulky N,N-dialkyl group of the amide to
lie anti to the N-phenyl substituent. For the oxazolidines, the
N,N-dialkyl group must choose between lying syn to N–Me
or to smaller O, and presumably favours the latter,
Moreover, an electronic factor presumably also favours
the alignment of the amide CvO dipole and the oxazolidine
C–O dipole anti to one another.
Supporting evidence that a dynamic kinetic resolution is not
the origin of the stereoselective formation of 10, 12, 16 or 18
is provided by two further observations. First, in the
Scheme 12. Conformational preference in amidoimidazolidines and amidooxazolidines.

J. Clayden et al. / Tetrahedron 60 (2004) 4399–4412
4405
3. Conclusion
Varian Unity 500 (500 MHz); 13C NMR spectra were
recorded on a Bruker XC300 (75 MHz) or a Varian Unity
500 (125 MHz). Chemical shifts are quoted in part per
million downfield from tetramethylsilane. Coupling con-
stants J are given in Hertz (Hz).
Condensation of 2-formyl benzamides and naphthamides
with the proline-derived diamine 9 or with (2)-ephedrine 13
yields single atropisomers of imidazolidine or oxazolidine
products by a process of dynamic thermodynamic resolu-
tion. Enantiomerically enriched products may be obtained
by subsequent deprotection of these compounds by
hydrolysis in aqueous acid, though for isolation of products
in good ee it is necessary to ‘fix’ the stereochemistry of the
aldehydes by immediate reduction to the corresponding
alcohols.
Infrared spectra were recorded on an ATI Genesis Series
FTIR and only structurally significant peaks are listed. Mass
spectra were recorded on a Fisons VG Trio 2000 (EI/CI and
FAB) or a Concept IS (HRMS) Spectrometer.
Micronanalyses were performed using a Carlo-Erba com-
bustion analyzer on C, H or N. Melting points are
uncorrected and were carried out on a Gallenkamp melting
point apparatus. Optical rotations were performed using an
AA-100 polarimeter and are quoted in units of
Dynamic thermodynamic resolution protocols seem par-
ticularly well-suited for the synthesis of enantiomerically
enriched atropisomers, in which epimerisation may be the
result merely of thermally induced bond rotation. More
recent developments of this work,59 to be reported shortly
in full, have employed sulfinyl substituents as versatile
alternatives to the imidazolidinyl or oxazolidinyl groups
described here.
8 g21 mol dm21
.
4.1.1. N,N-Diethyl-2-formyl-6-(1-trimethylsilylethyl)-
benzamide 4. N,N-Diethyl-2-(1-trimethylsilyl)ethylbenz-
amide 335 (831 mg, 3.0 mmol) in THF (10 mL) was added
dropwise to a stirred solution of sec-butyllithium (6 mL of a
1.5 M solution in cyclohexane, 3.0 equiv.) and TMEDA
(1.35 mL, 9.0 mmol, 3.0 equiv.) in dry THF (40 mL) at
278 8C under an atmosphere of nitrogen. After 60 min,
DMF (0.93 mL, 12.0 mmol, 4.0 equiv.) was added. The
mixture was warmed to ambient temperature (colour change
from dark yellow/orange to colourless) and stirred over-
night. Water was added and the organic layer was separated.
The aqueous layer was extracted with diethyl ether
(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 aldehyde 4 (871 mg, 95%) as a rapidly interconverting
mixture of diastereoisomeric atropisomers/conformers,
which were used without further purification. dH
(300 MHz; CDCl3) (Peaks for major atropisomer/confor-
mer) 9.99 (1H, s, CHO), 7.70 (1H, dd, J¼6, 3 Hz, ArH),
7.48–7.41 (3H, m, ArH), 3.71 (1H, dq, J¼14, 7 Hz, NCH2),
3.54 (1H, dq, J¼14, 7 Hz, NCH2), 3.08 (2H, m, NCH2), 2.15
(1H, m, CHSiMe3), 1.38 (3H, t, J¼8 Hz, NCH2CH3), 1.31
(3H, t, J¼7 Hz, NCH2CH3), 0.99 (3H, t, J¼7 Hz, CH2CH3),
0.0 [12H, s, Si(CH3)3]; dC (75 MHz, CDCl3) (Peaks for
major atropisomer/conformer) 191.0 (CvO), 167.7 (CvO),
144.1, 137.6, 132.3, 128.4, 126.5, 125.5 (aromatics), 42.5
(NCH2), 38.7 (NCH2), 25.2 (CH2CH3), 16.2, 13.7
(NCH2CH3), 12.4 (CH2CH3), 3.0 (SiMe3).
4. Experimental
4.1. General
Aldehydes 1a,43 1b,30 2a60 and 2b61 were made by
published methods.
X-ray crystal structures of M-10a and M-16a have been
deposited with the Cambridge Crystallographic Database,
Deposition numbers: M-10a: 228413; M-16a: 166016.
All commercially available solvents are distilled before use.
Tetrahydrofuran (THF) was dried over sodium and distilled
under dry nitrogen using benzophenone as an indicator.
Dichloromethane was distilled from calcium hydride under
an atmosphere of nitrogen. Toluene was distilled using
a Dean–Stark apparatus and stored over 4 A molecular
sieves. ‘Petrol’ refers to petroleum ether (bp 40–60 8C);
‘ether’ refers to diethyl ether.
˚
Thin layer chromatography (TLC) was performed using
commercially available Macherey-Nagel 0.25 mm silica gel
pre-coated aluminum sheets with fluorescent indicator
UV254. In the cases of the imidazolidines, TLC was
performed on Merck neutral aluminum oxide pre-coated
aluminum sheets. Flash chromatography refers to chroma-
tography carried out on Merck silica gel 60H (40–63 m,
230–300 mesh) stationary phase by the method of Still,
Kahn and Mitra.62
4.1.2. N,N-2-Triethyl-6-formylbenzamide 2c. tetra-n-
Butylammonium fluoride (4.0 equiv. of a 1 M solution in
THF) was added to a stirred solution of benzamide 4
(871.8 mg, 2.85 mmol) in THF (20 mL). The crude mixture
was filtered though a pad of Celitew which was washed with
THF (20 mL). The solvent was evaporated to give a crude
product which was purified by chromatography eluting with
petrol/EtOAc (5:1) to afford benzamide 2c (168.2 mg, 24%)
as an oil. dH (300 MHz; CDCl3) 10.05 (1H, s, CHO), 7.82
(1H, dd, J¼7, 1 Hz, ArH), 7.59 (1H, dd, J¼7, 1 Hz, ArH),
7.52 (1H, t, J¼8 Hz, ArH), 3.76 (1H, dq, J¼14, 7 Hz,
NCH2), 3.64 (1H, dq, J¼14, 7 Hz, NCH2), 3.12 (2H, t, J¼
7 Hz, NCH2), 2.68 (2H, m, CH2CH3), 1.37 (3H, t, J¼7 Hz,
NCH2CH3), 1.31 (3H, t, J¼8 Hz, CH2CH3), 1.04 (3H, t,
J¼7 Hz, NCH2CH3); dC (75 MHz, CDCl3) 190.09 (CvO),
Analytical HPLC was carried out on a Chiralpak AD,
25 cm£4.6 mm ID or (R,R) Whelk-01, 25 cm£4.6 mm ID
column at room temperature using a Merck Hitachi L-6200
Intelligent pump, typically eluting with 10% ethanol in
hexane, flow rate 1 mL/min, 10 mL injection. Detection was
carried out using a Merck L-300 Photo Diode Array System
at UV absorbance at 280 nm.
1H NMR spectra were recorded on a Varian XL 300
spectrometer at 300 MHz, a Bruker XC300 (300 MHz) or a

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J. Clayden et al. / Tetrahedron 60 (2004) 4399–4412
167.9 (CvO), 141.0, 138.4, 132.2, 134.3, 128.8, 127.4
(aromatics), 42.7 (NCH2), 38.6 (NCH2), 25.2 (CH2CH3),
14.8, 13.5 (NCH2CH3), 12.4 (CH2CH3); nmax(thin film)/
cm21 1690 (aldehyde CvO), 1628 (amide CvO); m/z (CI)
234 (100%, MþHþ); m/z (EI) 234 (10.3%, MþHþ), 204
(100%, M2CH2CH3), 161 (73%, MþHþ–CHO and
NCH2CH3). (Found: MþHþ 234.1487; C14H19NO2 requires
MþHþ 234.1495).
20.3, 20.3, 20.1, 19.7 (NCHCH3CH3); nmax(thin film)/cm21
2970, 2929, 1631 (CvO); m/z (CI) 278 (100%, MþHþ),
246 (55%, M2OCH3); m/z (EI) 278 (4%, MþHþ), 145
(100% M2OCH3, NCH(CH3)2CH(CH3)2). Found: M
277.2044; C17H27NO2 requires M 277.2042.
4.1.4. N,N-Diisopropyl-2-formyl-6-(1-methoxy-1-methyl-
ethyl)benzamide 2d. By the method for the lithiation of 3
in the preparation of 4, amide 6 (500 mg, 1.80 mmol) was
treated with sec-BuLi and quenched with DMF (2 equiv.).
The crude product was purified by flash chromatography,
eluting with petrol/EtOAc (85:15, Rf¼0.17) to yield
aldehyde 2d (165 mg, 30%) as a white crystalline solid,
mp 88.3–91.7 8C. dH (300 MHz; CDCl3) 10.1 (1H, s, CHO),
7.8 (1H, d, J¼8 Hz, ArH), 7.59 (1H, d, J¼8 Hz, ArH), 7.34
(1H, t, J¼8 Hz, ArH), 3.56–3.3 (2H, m, NCH), 3.18 (3H, s,
OCH3), 1.55–1.48 (12H, m, NCHCH3CH3 and COCH3
(CH3)2), 1.07 (3H, d, J¼7 Hz, NCHCH3CH3), 0.88 (3H, d,
J¼7 Hz, NCHCH3CH3); dC (75 MHz, CDCl3), 191.7
(CvO), 145.0, 138.9, 132.9, 132.8, 128.0, 126.1 (aro-
matics), 78.0 (COCH3), 51.0 (NCH), 49.3 (OCH3), 46.2
(NCH), 27.3, 26.3 (CCH3), 20.4, 20.1, 20.0, 19.5
(NCHMe2); nmax(thin film)/cm21 1690 (aldehyde CvO),
1628 (amide CvO);; m/z (CI) 306 (100%, MþHþ); m/z (EI)
306 (100%, MþHþ). Found: MþHþ 306.2065; C18H27NO3
requires MþHþ 306.2071. Anal. Calcd for C18H27NO3: C,
70.79; H, 8.91; N, 4.59. Found: C, 70.61, H, 9.03, N, 4.16.
4.1.3. N,N-Diisopropyl-2-(1-methoxy-1-methylethyl)-
benzamide 6. sec-Butyllithium (13.6 mL of a 1.4 M
solution in cyclohexane, 19 mmol, 1.3 equiv.) was added
dropwise to a stirred solution of N,N-diisopropylbenzamide
532 (3.0 mg, 14.6 mmol) in dry THF (40 mL) at 278 8C
under an atmosphere of nitrogen. After 60 min at 278 8C,
dry, distilled acetone (1.88 mL, 30 mmol, 2.0 equiv.) in
THF (10 mL) was added dropwise to the reaction mixture.
The mixture was warmed to ambient temperature (colour
change from dark cloudy brown to clear) and water was
added. Most of the THF was removed by evaporation under
reduced pressure and the aqueous residue was extracted
with diethyl ether (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 an oil, which was purified by flash chromatography,
eluting with petrol/EtOAc (85:15, Rf 0.17) to yield the
adduct (1.56 g, 40.6%) as a white crystalline solid, mp
82.3–83.1 8C; dH (300 MHz; CDCl3), 7.40–7.29 (2H, m,
ArH), 7.25 (1H, td, J¼7, 2 Hz, ArH), 7.15 (1H, d, J¼7 Hz,
ArH), 3.87–3.84 (1H, broad s, OH), 3.76 (1H, septet,
J¼7 Hz, NCH), 3.53 (1H, septet, J¼7 Hz, NCH), 1.69 (3H,
s, C(OH)CH3CH3), 1.6 (3H, d, J¼7 Hz, NCHCH3), 1.59
(3H, s, C(OH)CH3CH3), 1.57 (3H, d, J¼7 Hz, NCHCH), 1.2
(6H, d, J¼7 Hz, NCHCH3CH3); dC (75 MHz, CDCl3),
174.2 (CvO), 145.9, 135.1, 128.3, 126.9, 126.2 (aro-
matics), 73.3 (COH), 32.5, 31.0 (CCH3), 20.3, 20.1, 19.7
(NCHCH3CH3); nmax(thin film)/cm21 2886, 1609 (CvO);
m/z (CI) 264 (100%, MþHþ), 246 (53.8%, MþHþ–OH);
m/z (EI) 264 (100%, MþHþ), 246 (16.6%, MþHþ–OH).
Found: M 263.1888; C16H25NO2 requires M 263.1885.
Anal. Calcd for C16H25NO2: C, 72.97; H, 9.57; N, 5.32.
Found C, 73.07, H, 9.38, N, 5.22.
4.1.5. N,N-Dicyclohexyl-2-hydroxymethyl-4,6-dimethyl-
benzamide 8. sec-Butylithium (1.4 mL of a 1.4 M solution
in cyclohexane, 2 mmol) was added to a stirred solution of
N,N-dicyclohexyl-2,4,6-trimethylbenzamide 717 (500 mg,
1.53 mmol) in THF under argon at 278 8C. The resulting
orange solution was stirred for 60 min. Oxygen was bubbled
though the reaction solution for 20 min, when the mix-
ture became colourless. (TLC, 1:1 petrol/EtOAc: starting
material Rf 0.58, product alcohol Rf 0.39; traces of aldehyde
also present at Rf 0.52). Water was added and the mixture
was extracted with ether (3£30 mL). The combined organic
extracts were washed with brine (3£30 mL), dried (MgSO4)
and concentrated to an oil which was purified by flash
chromatography, eluting with petrol/EtOAc (4:1) to yield
the alcohol 8 (330.1 mg, 63%) as a white crystalline solid,
mp 142.7–144.6 8C. dH (300 MHz; CDCl3) 7.06 (1H, s),
6.90 (1H, s), 4.54 (1H, d, J¼13 Hz, CHAHBOH), 4.29 (1H,
d, J¼13 Hz, CHAHBOH). 3.97–3.71 (1H, broad s, OH),
3.21–2.99 (2H, m, NCH), 2.98–2.56 (2H, m, cyclohexyl-
H), 2.95 (3H, s, CCH3), 2.22 (3H, s, CCH3), 1.96–0.72
(20H, m, cyclohexyl-H); dC (75 MHz, CDCl3) 170.9
(CvO), 137.6, 136.9, 134.0, 132.6, 129.7, 126.8 (aro-
matics), 62.8 (CN), 60.0 (CH2OH), 56.1 (CN), 31.3, 31.2,
29.7, 29.7, 26.5, 25.5, 25.5, 25.2, 25.0 (cyclohexyl carbons),
21.0, 18.7 (CCH3); nmax(thin film)/cm21 3339 (OH), 1609
(CO).
This alcohol (500 mg, 1.9 mmol) was dissolved in dimethyl-
formamide (15 mL). Sodium hydride (0.17 g of a 60%
suspension in mineral oil) was added at 0 8C. After 95 min,
methyl iodide was added (0.5 mL, excess). The mixture was
allowed to room temperature and stirred overnight. Water
was added, and the mixture was extracted with ether
(2£30 mL). The organic extracts were washed with brine
(3£50 mL), dried (MgSO4), filtered and concentrated to
yield an oil which was purified by flash chromatography,
eluting with 7:1 petrol/EtOAc) to afford the amide 6
(357.5 mg, 68%) as a white crystalline solid, mp 84.7–
85.9 8C. dH (300 MHz; CDCl3) 7.48 (1H, d, J¼8 Hz, ArH),
7.31 (1H, t, J¼7 Hz, ArH), 7.23 (1H, t, J¼7 Hz, ArH), 7.06
(1H, d, J¼7 Hz, ArH), 3.69 (1H, septet, J¼7 Hz, NCH),
3.47 (1H, septet, J¼7 Hz, NCH), 3.23 (3H, s, OCH3), 1.55–
1.42 (12H, m, NCHCH3CH3 and COCH3(CH3)2), 1.14
(3H, d, J¼7 Hz, NCHCH3CH3), 1.09 (3H, d, J¼7 Hz,
NCHCH3CH3); dC (75 MHz, CDCl3), 171.9 (CvO), 143.8,
136.7, 127.8, 126.6, 126.4 (aromatics), 77.6 (COCH3), 51.0
(NCH), 49.6 (OCH3), 45.2 (NCH), 27.4, 26.4 (CCH3CH3),
4.1.6. N,N-Dicyclohexyl-2-formyl-4,6-dimethylbenz-
amide 2e. A solution of N,N-dicyclohexyl-2-hydroxy-
methyl-4,6-dimethylbenzamide 8 (476.7 mg) in CH2Cl2
(20 mL) was added to a stirred solution of the Dess Martin
reagent36,37 (707.9 mg, 1.2 equiv.) in CH2Cl2 (20 mL).
After 30 min, the mixture was diluted with ether (50 mL),
and 1.3 M NaOH (100 mL) was added. After stirring for
20 min, the aqueous mixture was extracted with ether

J. Clayden et al. / Tetrahedron 60 (2004) 4399–4412
4407
(2£20 mL), and the extracts washed with 1.3 M HCl
(2£20 mL), brine (2£30 mL) and dried (MgSO4). Concen-
tration under reduced pressure gave an oil which was
purified by flash chromatography, eluting with petrol/
EtOAc (9:1) to yield the aldehyde 2e (291.9 mg, 62%) as
a white crystalline solid, mp 149.9–151.2 8C; Rf¼0.52 (1:1
petrol/EtOAc); dH (300 MHz; CDCl3) 9.95 (1H, s, CHO),
7.48 (1H, s, CHCCH3), 7.19 (1H, s, CHCCH3), 3.08–2.88
(2H, m, NCH), 2.31 (3H, s, CH3), 2.24 (3H, s, CH3), 1.83–
1.74 (2H, m, CH2), 1.68–1.53 (8H, m, CH2), 1.50–1.07
(10H, m, CH2); dC (75 MHz, CDCl3) 191.0 (CHO), 168.1
(CvO), 138.4, 137.9, 136.9, 134.4, 131.9, 126.5 (aro-
matics), 60.1 and 56.4 (NCH), 31.4, 30.9, 29.8, 29.6, 26.5,
25.6, 25.5, 25.2, 24.9 (cyclohexyl), 20.9 and 19.3 (CH3);
m, ArH), 5.7 (1H, s, CHNN), 3.9 (1H, q, J¼8 Hz,
NCHCH2CH2), 3.71 (3H, m, NCH2CH3 and NCHHCHN),
3.27–3.09 (3H, m, NCH2CH3 and NCHHCHN), 2.98
(1H, dq, J¼14, 7 Hz, NCHHCH2), 2.72–2.61 (1H, m,
NCHHCH2), 2.02–1.7 (4H, m, PhNCH2CHCH2CH2),
1.37 (3H, t, J¼7 Hz, NCH2CH3), 0.89 (3H, t, J¼7 Hz,
NCH2CH3); dC (75 MHz, CDCl3) 169.5 (CO), 145.8, 138.0,
134.5, 134.5, 132.6, 129.7, 129.1, 127.9, 127.9, 126.0,
125.9, 125.2, 124.0 115.9, 112.0 (aromatics), 80.6 (CNN),
61.0 (PhNCH2CH), 53.8 (PhNCH2), 52.9 (NCH2CH2), 43.5
(NCH2CH3), 38.9 (NCH2CH3), 29.6 (NCHCH2), 28.3
(NCH2CH2CH2), 24.0 (NCH2CH2CH2), 13.4 (CH3) and
13.3 (CH3); nmax (thin film)/cm21 2907, 1632 (CvO); m/z
(CI)) 414 (100%, MþHþ), 226 (3.8%, M2C6H10N2Ph); m/z
(EI) 84 (100%, MþHþ–C6H10N2Ph and C10H6). Found: M
413.2460. C27H31N3O requires M, 413.2467. Anal. Calcd
for C27H31N3O; C, 78.42, H, 7.56, N, 10.16: Found C,
78.64, H, 7.70, N, 9.90.
n
max(thin film)/cm21 1696 (CHO), 1625 (CO); m/z (CI) 342
(100%, MþHþ); m/z (EI) 342 (3%, MþHþ2CH(CH3)2
CH(CH3)2). Found: M 341.2359; C22H31NO2 requires M
341.2355. Anal. Calcd for C22H31NO2: C, 77.38; H, 9.15, N,
4.10. Found C, 77.78, H, 9.15, N, 4.08.
4.1.9. (M,20R,40S)-N,N-Diethyl-2-(2-phenylperhydropyr-
rolo-[1,2c]-imidazol-3-yl)benzamide 12b. In the same
way, 2-formyl-N,N-diethyl-1-benzamide 2b gave, after
purification by flash chromatography on alumina eluting
with petrol/EtOAc (8:1)þ0.1% Et3N, the imidazolidine 12b
(294.2 mg, 81%) as an oil; Rf¼0.76 (petrol/EtOAc 8:1);
[a]2D1¼20.11 (c¼25., ethanol); dH (300 MHz, CDCl3)
7.28–7.16 (6H, m, ArH), 6.70 (1H, t, J¼7 Hz, ArH), 6.60
(2H, d, J¼8 Hz, ArH), 6.00 (1H, s, CHN), 3.90 (1H, quintet,
J¼7 Hz, PhNCH2CHN), 3.70 (1H, q, J¼8 Hz, PhNCH2),
3.65 (1H, t, J¼8 Hz, NCH), 3.6–3.49 (1H, quintet, J¼7 Hz,
NCH), 3.35–3.22 (2H, m, PhNCH2 and NCHHCH2), 2.75–
2.63 (2H, m, NCH2CH2), 2.09–1.81 (4H, m, PhNCH2
CHCH2CH2), 2.58 (1H, dq, J¼14, 7 Hz, CH2CH3), 2.51
(1H, dq, J¼14, 7 Hz, CH2CH3), 1.89–1.66 (4H, m,
NCH2CH2CH2CH), 1.24 (3H, t, J¼7 Hz, NCH2CH3), 1.09
(3H, t, J¼8 Hz, CH2CH3), 1.02 (3H, t, J¼7 Hz, NCH2CH3);
dC (75 MHz, CDCl3) 171.2 (CO), 146.5, 139.0, 137.9,
129.1, 127.9, 126.7, 126.54, 125.55, 115.8, 111.9 (aro-
matics), 79.3 (CHN), 60.7 (PhNCH2CH), 52.7 (PhNCH2),
52.4 (NCH2CH2), 51.0 (NCH), 45.5 (NCHCH2), 25.4
(CH2CH3), 23.9 (NCH2CH2CH2), 14.7 (NCH2CH3), 13.1
(NCH2CH3), 13.0 (CH2CH3); nmax (thin film)/cm21 1625
(CvO); m/z (CI)) 364 (100%, MþHþ), 363 (1.3%, M); m/z
(EI) 363 (3.8%, M). Found: M 363.2620. C23H29N3O
requires M, 363.2624.
4.1.7. (M,20R,40S)-N,N-Diisopropyl-2-[-2-phenylperhydro-
pyrrolo-(1,2c)-imidazol-3-yl]-1-naphthamide 10a. Alde-
hyde 1a (250 mg, 0.882 mmol) and (S)-2-(anilinomethyl)-
pyrrolidine 9 (155.1 mg, 0.885 mmol) were heated at reflux
in dry toluene (25 mL) for 16 h. The solvent was removed
under reduced pressure and the residue purified by flash
chromatography on alumina eluting with petrol/EtOAc
(10:1) to afford the imidazolidine 10a (282.4 mg 88%) as
a pale yellow solid, mp 210.6–212.1 8C; [a]2D2¼þ0.84
(c¼0.100, ethanol); Rf¼0.75 (petrol/EtOAc 10:1); dH
(300 MHz, CDCl3) 7.85 (1H, dd, J¼8, 1 Hz, ArH), 7.69
(1H, dd, J¼7, 3 Hz, ArH), 7.59 (1H, d, J¼9 Hz, ArH),
7.43–7.33 (2H, m, ArH), 7.18 (2H, d, J¼9 Hz, ArH), 7.05
(2H, t, J¼7 Hz, ArH), 6.56–5.45 (3H, m, ArH), 5.88 (1H,
s, CHN), 3.92 (1H, q, J¼7 Hz, NCHCH2), 3.70 (1H, t,
J¼8 Hz, PhNCH), 3.57 (1H, septet, J¼7 Hz, NCHCH3),
3.45 (1H, septet, J¼7 Hz, NCHCH3), 3.27–3.19 (2H,
m, NCHHCH2CH2 and PhNCHHCHN), 2.65 (1H, m,
NCHHCH2CH2), 2.02–1.81 (4H, m, PhNCH2CHCH2CH2),
1.76 (3H, d, J¼7 Hz, NCHCH3), 1.65 (3H, d, J¼7 Hz,
NCHCH3), 1.09 (3H, d, J¼7 Hz, NCHCH3), 0.91 (3H, d,
J¼7 Hz, NCHCH3); dC (75 MHz, CDCl3) 169.5 (CO),
145.8, 138.0, 134.5, 134.5, 132.6, 129.7, 129.1, 127.9,
127.9, 126.0, 125.9, 125.2, 124.0 115.9, 112.0 (aromatics),
79.6 (CHN), 60.9 (PhNCH2CH), 53.4 (PhNCH2), 52.5
(NCH2CH2), 51.3 (NCH), 46.2 (NCH), 27.9 (CH2), 23.5
(CH2), 21.1 (CH3), 20.5 (CH3), 20.3 (CH3), 19.98 (CH3);
nmax (thin film)/cm21 2940, 1623 (CvO); m/z (CI) 442
(100%, MþHþ); m/z (EI) 442 (12.2%, MþHþ); 441 (9%,
M), 356 (100%, MþHþ–C6H14). Found: M 441.2771.
C29H35N3O requires M, 441.2781. Anal. Calcd for
C29H35N3O, C, 78.88, H, 7.59, N, 9.52. Found: C, 78.86,
H, 7.86, N, 9.59.
4.1.10. (M,20R,40S)-N,N,2-Triethyl-6-(2-phenylperhydro-
pyrrolo[1,2-c]imidazol-3-yl)benzamide 12c. In the same
way, N,N-2-triethyl-6-formylbenzamide 2c (132.6 mg)
gave, after purification by flash chromatography on
alumina, eluting with petrol/EtOAc (11:1), the imidazoli-
dine 12c (130.9 mg, 59%) as an oil, [a]2D4¼211.7 (c¼0.463,
CHCl3); dH (300 MHz; CDCl3) 7.12–7.05 (.4H, m, ArH),
6.91 (1H, t, J¼5 Hz, ArH), 6.56 (1H, t, J¼7 Hz, ArH), 6.44
(2H, d, J¼8 Hz, ArH), 5.55 (1H, s, CHNN), 3.81–3.69 (2H,
m, NCH2CH3 and NCHCH2CH2), 3.59 (1H, t, J¼8 Hz,
PhNCHH), 3.39 (1H, dq, J¼14, 7 Hz, NCH2CH3), 3.20 (1H,
dq, J¼14, 7 Hz, NCH2CH3), 3.11 (1H, dq, J¼15, 7 Hz,
NCH2CH3), 3.06–2.98 (2H, m, NCH2CH2 and PhNCH2
CH2), 2.58 (1H, dq, J¼14, 7 Hz, CH2CH3), 2.51 (1H, dq,
J¼14, 7 Hz, CH2CH3), 1.89–1.66 (4H, m, NCH2CH2CH2
CH), 1.24 (3H, t, J¼7 Hz, NCH2CH3), 1.09 (3H, t, J¼8 Hz,
CH2CH3), 1.02 (3H, t, J¼7 Hz, NCH2CH3); dC (75 MHz,
4.1.8. (M,20R,40S,)-N,N-Diethyl-2-(2-phenylperhydropyr-
rolo-[1,2c]imidazol-3-yl)-1-naphthamide 10b. In the same
way, aldehyde 1b (987.1 mg) gave, after purification by
flash chromatography on alumina eluting with petrol/EtOAc
(11:1, Rf¼0.77), the imidazolidine 10b (1.42 g, 89%) as a
yellow solid, mp 97.2–198.7 8C; [a]2D2¼þ107.2 (c¼0.218,
CHCl3); dH (300 MHz, CDCl3), 7.76–7.68 (2H, m, ArH),
7.64 (1H, d, J¼9 Hz, ArH). 7.39 (2H, m, ArH), 7.26 (1H, d,
J¼8 Hz, ArH), 7.07 (2H, t, J¼7 Hz, ArH), 6.60–6.48 (3H,

4408
J. Clayden et al. / Tetrahedron 60 (2004) 4399–4412
CDCl3) 164.9 (CvO), 146.0 (NCC5H5), 104.0, 143.8,
136.0, 129.0, 128.0, 126.9, 123.4, 115.9, 112.1, 80.1
(CHNN), 60.6 (NCHCH2), 53.2 (NCH2CH2), 52.5
(PhNCH2), 43.2 (NCH2CH3), 38.4 (NCH2CH3), 28.0
(NCH2CH2), 25.4 (CH2CH3), 23.9 (NCH2CH2CH2), 14.7
(NCH2CH3), 13.1 (NCH2CH3), 13.0 (CH2CH3); nmax(thin
film)/cm21 2963–2931 (CH3), 1627 (CvO); m/z (CI)
392 (100%, MþHþ); m/z (EI) 394 (8.9%, MþHþ).
Found: MþHþ 392.5641; C25H33N3O requires MþHþ
392.5692.
4.1.13. (M,20S,40S,50R)-N,N-Diisopropyl-2-[3,4-dimethyl-
5-phenyl-1,3-oxazolan-2-yl]-1-naphthamide 16a. 2-For-
myl-N,N-diisopropyl-1-naphthamide 1a (251 mg, 0.89 mmol)
and (1R,2S)-ephedrine 13 (165 mg, 1.0 mmol, 1.1 equiv.)
were heated to reflux in toluene (25 mL) for 16 h. The
mixture was concentrated under reduced pressure and
purified by flash chromatography on silica, eluting with
petrol/EtOAc (11:1) to afford the oxazolidine 16a
(328.1 mg, 86%) as a white crystalline solid, mp 214.0–
217.1 8C; [a]2D0¼2157.1 (c¼0.252, CHCl3); dH (300 MHz;
CDCl3) 8.08 (1H, d, J¼9 Hz, ArH), 7.95 (1H, d, J¼9 Hz,
ArH), 7.94–7.86 (2H, m, ArH), 7.57–7.52 (4H, m, ArH),
7.42 (2H, t, J¼7 Hz, ArH), 7.35 (1H, d, J¼7 Hz, ArH), 5.18
(1H, d, J¼8 Hz, OCHPh), 4.99 (1H, s, CHOCHPh), 3.68
(2H, septet, 2£NCH), 3.01 (1H, d quintet, J¼2, 9 Hz,
CHPhCHCH3), 2.23 (3H, s, NCH3), 1.82 (3H, d, J¼7 Hz,
NCHCH3), 1.75 (3H, d, J¼7 Hz, NCHCH3), 1.15 (3H, d,
J¼7 Hz, NCHCH3), 0.99 (3H, d, J¼7 Hz, NCHCH3), 0.86
(3H, d, J¼7 Hz, CHCH3); dC (75 MHz, CDCl3) 168.4
(CvO), 139.6, 137.3, 133.9, 130.8, 129.2, 128.4, 128.1,
127.9, 127.9, 127.6, 126.6, 126.5, 125.3, 125.0 (aromatics),
94.8 (CHNCH3), 82.4 (OCHPh), 64.1 (CHPhCHCH3), 51.3
(NCH), 46.2 (NCH), 35.8 (NCH3), 20.9, 20.5, 20.3, 20.3
(CNHCH3CH3), 15.3 (CHCH3); nmax(thin film)/cm21
3062–2756 (CH3), 1626 (CvO); m/z (CI) 431 (100%,
MþHþ), 313 (7.7%, MþHþ–C6H14ON); m/z (EI) 431
(28%, MþHþ), 313 (7.7%, MþHþ–C6H14ON), 212
(100%, MþHþ–C11H14NO and C3H7), 155 (9%, MþHþ–
C15H14NO and C6H14N), 127 (10.2%, C15H14NO and
C6H14NOC). Found: MþHþ 431.2700; C28H34N2O2
requires MþHþ 431.2699. Anal. Calcd for C28H34N2O2:
C, 78.1; H, 7.96; N, 6.51. Found C, 77.73, H, 7.72, N, 6.31.
4.1.11. (P,20R,40S)-N,N-Diisopropyl-2-(1-methoxy-1-
methylethyl)-6-(2-phenylperhydropyrrolo[1,2-c]imida-
zol-3-yl)benzamide 12d. In the same way, aldehyde 2d
gave the imidazolidine 12d (96 mg, 85%) as an amorphous
solid, [a]2D5¼þ34.8 (c¼0.145, CHCl3); dH (300 MHz;
CDCl3) 7.24–7.15 (3H, m, ArH), 7.09 (2H, d, J¼8 Hz,
ArH), 6.74 (2H, d, J¼8 Hz, ArH), 6.62 (1H, t, J¼7 Hz,
ArH), 5.68 (1H, s, CHN), 4.32–4.22 (1H, m, PhNCH2
CHCH2), 3.84–3.76 (1H, m, PhNCH2), 3.74–3.69 (1H, m,
PhNCH2), 3.66–3.54 (2H, m, NCH), 3.37–3.26 (5H, m,
NCH2, NCH2CH2 and NCH2CH2CH2), 2.74–2.62 (1H, m,
NCH2CH2CH2), 3.26 (3H, s, OCH3), 1.70 (3H, d, J¼7 Hz,
NCHCH3), 1.66 (3H, d, J¼7 Hz, NCHCH3), 1.64 (3H, s,
CH3), 1.55 (3H, s, CH3), 0.99 (3H, d, J¼7 Hz, NCHCH3),
0.95 (3H, d, J¼7 Hz, NCHCH3); dC (75 MHz, CDCl3) 170.6
(CvO), 144.4 [NC(C5H5)], 142.8, 140.0, 135.6, 129.0,
127.7, 126.4, 125.4 (aromatics), 120.8, 115.6, 112.2
(aromatics), 79.4 (CHN), 60.4 (NCHCH2), 53.7 (NCH),
52.6 (OCH3), 50.8 (NCH), 49.2 (PhNCH2), 45.9 (NCH2),
29.0 (NCH2CH2), 27.9 (NCH2CH2CH2), 25.7 (CCH3), 23.3
(CH3), 20.9, 20.6, 20.3, 19.6 (NCHCH3); m/z (CI) 464
(100%, MþHþ), 388 (6.4%, MþHþ–C4H9O and CH3); m/z
(EI) 464 (23%, MþHþ), 463 (2%, M), 388 (100%, MþHþ–
C4H9O and CH3). Found: MþHþ 464.3284; C29H41N3O2
requires MþHþ 464.3278.
4.1.14. (M,20S,40S,50R)-N,N-Diethyl-2-[3,4-dimethyl-5-
phenyl-1,3-oxazolan-2-yl]-1-naphthamide 16b. In the
same way, 2-formyl-N,N-diethyl-1-naphthamide 1b gave
the oxazolidine 16b (196.2 mg, 87%) as white needles,
mp 139.1–141.8 8C; [a]2D4¼293.6 (c¼0.588, CHCl3); dH
(300 MHz; CDCl3) 8.12 (1H, d, J¼9 Hz, ArH), 7.95 (1H, d,
J¼9 Hz, ArH), 7.96–7.88 (1H, m, ArH), 7.86–7.79 (1H, m,
ArH), 7.60–7.49 (5H, m, ArH), 7.41 (1H, dt, J¼7, 1 Hz,
ArH), 7.35 (1H, dd, J¼7, 1 Hz, ArH), 5.2 (1H, d, J¼9 Hz,
OCHPh), 4.98 (1H, s, CHOCHPh), 3.79 (2H, m, NCH2),
3.16 (2H, m, NCH2CH3), 3.08 (1H, d quintet, J¼2, 8 Hz,
CHPhCHCH3), 2.25 (3H, s, NCH3), 1.46 (3H, t, J¼7 Hz,
NCH2CH3), 0.97 (3H, t, J¼7 Hz, NCH2CH3), 0.86 (3H, d,
J¼7 Hz, CHCH3); dC (75 MHz, CDCl3) 168.7 (CvO),
139.7, 136.2, 133.8, 131.4, 129.2, 128.9, 128.1, 127.9,
127.9, 127.6, 126.7, 126.7, 125.1, 124.9 (aromatics), 94.9
(CHNCH3), 82.5 (OCHPh), 63.8 (CHPhCHCH3), 43.3
(NCH2), 38.8 (NCH2), 35.6 (NCH3), 15.2, 13.8 (CNCH2-
CH3), 12.8 (CHCH3); nmax(thin film)/cm21 1629 (CvO);
m/z (CI) 403 (100%, MþHþ), 212 (23%, MþHþ–
C11H14NO and CH3); m/z (EI) 403 (19.2%, MþHþ), 254
(7.7%, M2C2H10N),212 (100%, MþHþ–C11H14NO and
CH3), 127 (10.2%, MþHþ–C11H14NO and C2H10NO).
Found: MþHþ 403.2388; C26H30N2O2 requires MþHþ
403.2386.
4.1.12. (M,20R,40S)-N,N-Dicylohexyl-2,4-dimethyl-6-(2-
phenylperhydropyrrolo[1,2-c]imidazol-3-yl)benzamide
12e. In the same way, benzamide 2e (88 mg) gave, after
flash chromatography eluting with petrol/EtOAc (8:1;
Rf¼0.42), the imidazolidine 12e (80.1 mg, 62%) as a
white solid, mp 154.5–157.2 8C; [a]2D1¼þ42.1 (c¼0.28,
CHCl3); dH (300 MHz; CDCl3) 7.06 (2H, t, J¼8 Hz, ArH),
6.78 (1H, s, ArH), 6.64 (1H, s, ArH), 6.53 (1H, t, J¼7 Hz,
ArH), 6.40 (2H, d, J¼9 Hz, ArH), 5.60 (1H, s, CHN), 3.82–
3.73 (1H, m, PhNCH2CHCH2), 3.56 (1H, t, J¼8 Hz,
PhNCH2), 3.17–2.84 (5H, m, NCH, NCH, PhNCH2 and
NCH2CH2), 2.78–2.62 (3H, m, NCH2CH2 and NCH2CH2),
2.52–2.43 (2H, m, NCH2CH2CH2), 2.24 (3H, s, ArCH3),
2.11 (3H, s, ArCH3), 2.06–0.65 (20H, m, cyclohexyl-H); dC
(75 MHz, CDCl3) 170.7 (CvO), 146.2, 136.7, 134.8, 133.2,
129.8, 129.0, 128.8, 124.3, 119.2, 115.6, 111.8 (aromatics),
79.6 (CHNN), 60.6 (NCHCH2), 60.1 (NCH), 56.0 (NCH),
52.7 (PhNCH2), 52.0 (NCH2), 30.9 (NCH2CH2), 30.8
(NCH2CH2CH2), 30.7, 29.3, 27.6, 26.7, 26.7, 25.8, 25.8,
25.4, 25.3, 23.4 (cyclohexyl), 21.4 (CH3), 19.3 (CH3);
n
max(thin film)/cm21 3005 (Ar–CH), 1609 (CO); m/z (CI)
500 (100%, MþHþ); m/z (EI) 499 (100%, M), 456 (34.6%,
M2CH3), 319 (28.2%, M2C12H22N), 303 (9%, M2ON
(C6H11)2, 289 (52.6%, MþHþ–ON(C6H11)2 and CH3), 187
(47.4%, M2C6H2ON(C6H11)2 and [CH3]2). Found: M
499.3560; C22H31NO2 requires M 499.3562.
4.1.15. (M,20S,40S,50S)-N,N-Diisopropyl-2-[3,4-dimethyl-
5-phenyl-1,3-oxazolan-2-yl]-1-naphthamide 17. Simi-
larly, 2-formyl-N,N-diisopropyl-1-naphthamide 1a (124 mg,
0.44 mmol) and (1S,2S)-(2)-pseudoephedrine 14 (80 mg,

J. Clayden et al. / Tetrahedron 60 (2004) 4399–4412
4409
0.48 mmol, 1.1 equiv.) gave, after purification by flash
chromatography eluting with petrol/EtOAc (11:1), the
oxazolidine 17 (165.9 mg, 88%) as a white crystalline
solid, mp 114.8–116.4 8C; [a]1D9¼2135.2 (c¼0.5, CHCl3);
dH (300 MHz; CDCl3) 7.92–7.85 (4H, m, ArH), 7.58–7.52
(2H, m, ArH), 7.46–7.34 (5H, m, ArH), 5.23 (1H, s,
CHOCHPh), 4.87 (1H, d, J¼9 Hz, OCHPh), 3.65 (2H,
septet, J¼7 Hz, 2£NCH), 2.62–2.53 (1H, m,
CHPhCHCH3), 2.27 (3H, s, NCH3), 1.84 (3H, d, J¼7 Hz,
NCHCH3), 1.81 (3H, d, J¼7 Hz, NCHCH3), 1.28 (3H, d,
J¼7 Hz, NCHCH3), 1.18 (3H, d, J¼7 Hz, NCHCH3), 0.99
(3H, d, J¼7 Hz, CHCH3); dC (75 MHz, CDCl3) 168.5
(CvO), 140.3, 136.5, 133.7, 132.4, 128.4, 128.2, 128.1,
127.9, 126.7, 126.6, 126.5, 125.2 (aromatics), 85.7
(CHNCH3), 87.4 (OCHPh), 68.9 (CHPhCHCH3), 51.3
(NCH), 46.2 (NCH), 35.2 (NCH3), 20.9, 20.5, 20.4, 20.2
(CNHCH3CH3), 14.2 (CHCH3); nmax(thin film)/cm21 1620
(CvO); m/z (CI) 431 (100%, MþHþ), 313 (7.7%, MþHþ–
C6H14ON); m/z (EI) 431 (28%, MþHþ),313 (7.7%,
MþHþ–C6H14ON), 212 (100%, MþHþ–C11H14NO and
C3H7). Found: MþHþ 431.2700; C28H34N2O2 requires
MþHþ 431.2699.
4.1.16. M,20S,40S,50R)-N,N-Diisopropyl-2-(3,4-dimethyl-
5-phenyl-1,3-oxazolan-2-yl)benzamide 18a. In a similar
way, aldehyde 2a (2.0 g) and (1R,2S)-ephedrine 13 (1.42 g)
gave, after purification by flash chromatography on silica,
eluting with 11:1 petrol/EtOAc, the oxazolidine 18b
(2.89 g, 89%) as an oil which crystallised to a yellow wax
upon standing, [a]2D0¼239.4 (c¼0.28, CHCl3). dH
(300 MHz; CDCl3) 8.01 (1H, d, J¼8 Hz, CHCCHNO),
7.54–7.28 (8H, m, ArH), 7.15 (1H, d, J¼8 Hz, ArH), 5.13
(1H, d, J¼8 Hz, COCHPh), 4.89 (1H, s, CHOCHPh), 3.76
(1H, septet, J¼6 Hz, NCHCH3), 3.56 (1H, septet, J¼6 Hz,
NCHCH3), 2.93 (1H, m, CHCH3), 2.2 (3H, s, CHNCH3),
1.58 (6H, d, J¼6 Hz, NCHCH3CH3), 1.08 (3H, t, J¼6 Hz,
NCHCH3), 1.01 (3H, t, J¼6 Hz, NCHCH3), 0.77 (3H, d,
J¼6 Hz, NCHCH3); dC (400 MHz, CDCl3) 169.5 (CvO),
140.1–124.5 (aromatics), 94.3 (CHNO), 82.3 (OCHPh),
63.9 (NCCH3), 51 (NCH3), 45.7 (NCH3CHCH3), 35.8
(CHCH3), 20.5–15.1 (COCNCH3CH3); nmax(thin film)/
cm21 1621 (CvO); m/z (CI) 381 (100%, MþHþ), 162
(11.3%, MþHþ–C11H14NO and C3H7); m/z (EI) 381 (10%,
MþHþ), 162 (100%, MþHþ–C11H14NO and C3H7).
Found: MþHþ 381.2549; C24H32N2O2 requires MþHþ
381.2543.
(CHCH3); nmax(thin film)/cm21 1627 (CvO); m/z (CI) 352
(100%, MþHþ), 175 (6.7%, M2C11H14NO); m/z (EI) 367
(100%, MþHþ), 175 (4.7%, M2C11H14NO). Found:
MþHþ 352.4817; C23H30N2O2 requires MþHþ 352.4807.
4.1.18. (P,20S,40S,50R)-N,N-Diisopropyl-2-(3,4-dimethyl-
5-phenyl-1,3-oxazolan-2-yl)-6-ethylbenzamide 18c. In
the same way aldehyde 2c (100.1 mg) and (1R,2S)-
ephedrine 13 gave, after flash chromatography on alumina,
eluting with petrol/EtOAc (11:1), the oxazolidine 13c
(136.8 mg, 87%) as an oil which formed a yellow wax on
standing, [a]2D4¼211.7 (c¼0.463, CHCl3). dH (300 MHz;
CDCl3) 7.56 (1H, d, J¼8 Hz, ArH), 7.14 (2H, d, J¼8 Hz,
ArH), 7.1–6.98 (5H, m, Ar), 4.79 (1H, d, J¼8 Hz, OCHPh),
4.23 (1H, s, CHOCHPh), 3.35 (1H, m, NCH2CH3), 2.63
(1H, d quintet, J¼2, 7 Hz, CHPhCHCH3), 2.43–2.23 (1H,
m, NCH2CH3), 1.88 (3H, s, NCH3), 0.99 (6H, t, J¼7 Hz,
NCH2CH3 and CH2CH3), 0.72 (3H, t, J¼7 Hz, NCH2CH3),
0.49 (3H, t, J¼7 Hz, CHCH3); dC (75 MHz, CDCl3), 169.1
(CvO), 139.8, 139.0, 137.9, 133.9, 128.7–125.1 (aro-
matics), 94.8 (CHOCHPh), 82.3 (OCHPh), 63.7
(CHPHhCCH3), 43.0 (NCH2), 38.1 (CH2), 35.7 (NCH3),
25.6 (CH2CH3), 14.7, 13.4 (NCH2CH3£2), 12.6 (CHCH3),
7.8 (CH2CH3); nmax(thin film)/cm21 1627 (CvO); m/z (CI)
367 (100%, MþHþ), 190 (6.7%, M2C11H14NO); m/z (EI)
367 (100%, MþHþ), 190 (2.7%, M2C11H14NO). Found:
MþHþ 367.2380; C23H30N2O2 requires MþHþ 367.2386.
4.1.19. (M)-(2)-2-Hydroxymethyl-N,N-diisopropyl-1-
naphthamide 19a. (a) By hydrolysis-reduction of imida-
zolidine 10a. A solution of 1 M HCl (2 mL, 2.5 equiv.) was
added to a stirred solution of imidazolidine 10a (331.6 mg,
0.79 mmol) in THF (20 mL) at 0 8C. After 35 min, a
solution of sodium borohydride (2.7 equiv.) and sodium
methoxide (1.0 equiv.) in methanol (20 mL) (a few droplets
of ethanol was added to improved solubility) was added
dropwise to the reaction mixture while keeping the
temperature around 0 8C. The mixture was allowed to
warm to room temperature over a period of 35 min. The
mixture was concentrated under reduced pressure, without
heating, to half of its original volume. It was extracted with
diethyl ether (3£30 mL), and the combined extracts were
washed with brine (2£30 mL), dried (MgSO4) and evapor-
ated under reduced pressure without heating. Purification by
flash chromatography, eluting with petrol/EtOAc (5:1) gave
enantiomerically enriched alcohol (2)-19a (202 mg, 94%
yield) as a white solid, [a]2D0¼2105.7 (c¼0.5, CHCl3);
Rf¼0.55 (petrol/EtOAc 7:1). Analytical HPLC on a chiral
stationary phase (see below), eluting with 8% ethanol in
hexane at 1 mL/min, indicated an ee of 89%.
4.1.17. (M,20S,40S,50R)-N,N-2-Diethyl-2-[3,4-dimethyl-5-
phenyl-1,3-oxazolan-2-yl]benzamide 18b. In the same
way, N,N-diethyl-2-formylbenzamide 2b (125 mg) gave,
after purification by flash chromatography eluting with
petrol/EtOAc (11:1), the oxazolidine 18a (80 mg, 34%) as
an oil, [a]2D4¼225.8 (c¼0.115, CHCl3); dH (300 MHz;
CDCl3) 7.56 (1H, d, J¼8 Hz, ArH), 7.14 (2H, d, J¼8 Hz,
ArH), 7.1–6.98 (5H, m, ArH and ArH), 4.79 (1H, d,
J¼8 Hz, OCHPh), 4.23 (1H, s, CHOCHPh), 3.35 (1H, m,
NCH2CH3), 2.63 (1H, d quintet, J¼2, 7 Hz, CHPhCHCH3),
2.43–2.23 (1H, m, NCH2CH3), 1.88 (3H, s, NCH3), 0.99
(6H, d, J¼7 Hz, NCH2CH3), 0.72 (3H, t, J¼7 Hz,
NCH2CH3); dC (75 MHz, CDCl3), 169.1 (CvO), 139.8,
139.0, 137.9, 133.9, 128.7–125.1 (aromatics), 94.8
(CHOCHPh), 82.3 (OCHPh), 63.7 (CHPHhCCH3), 43.0
(NCH2), 35.7 (NCH2), 14.7, 13.4 (NCH2CH3£2), 12.6
(b) By hydrolysis-reduction of oxazolidine 16a. A mixture
of trifluroacetic acid (2.3 mL, 30 mmol, 20.0 equiv.) and
water (0.5 mL, 3 mmol, 2.0 equiv.) was added dropwise to a
solution of oxazolidine 16a (346 mg, 1.51 mmol) in THF
(30 mL) at 0 8C. After 60 min sodium methoxide (2.5 g,
33 equiv.) was added in small batches. The acidity of the
solution reached pH 6. A slurry of sodium borohydride
(10 equiv.) in ethanol (20 mL) was added at 0 8C. After
30 min, the mixture was allowed to warm to room
temperature and evaporated under reduced pressure without
applying heat until reduced to half its original volume. Cold
water was added, and the mixture was extracted with diethyl

4410
J. Clayden et al. / Tetrahedron 60 (2004) 4399–4412
ether (3£30 mL). The combined organic extracts were
washed with brine (2£30 mL), dried (MgSO4), filtered and
concentrated under reduced pressure without applying any
external heating. Purification by flash chromatography, as
before, gave enantiomerically enriched alcohol (2)-19a
(183 mg, 85%). HPLC on a chiral stationary phase (see
below) indicated an enantiomeric excess of 74%.
4.1.22. (6)-2-Hydroxymethyl-N,N-diethyl-1-naphtha-
mide 19b. By the method used for (^)-19a, 2-formyl-
N,N-diethyl-1-naphthamide 1b (250 mg) was reduced with
sodium borohydride to give a crude product which was
purified by flash chromatography, eluting with petrol/
EtOAc (5:1), to give the corresponding alcohol (^)-19b
as a oil (219.2 mg, 87% yield). dH (300 MHz; CDCl3), 7.75
(1H, dd, J¼2, 5 Hz, ArH), 7.72 (1H, d, J¼8.9 Hz, ArH),
7.62 (1H, m, ArH), 7.43 (3H, m, ArH), 4.65 (1H, d, J¼
13 Hz, CHAHBOH), 4.48 (1H, d, J¼13 Hz, CHAHBOH),
3.74–3.52 (2H, m, NCH2CH3), 3.42 (1H, broad m, OH),
2.96 (2H, q, J¼7 Hz, NCH2CH3), 1.30 (3H, t, J¼7 Hz,
NCH2CH3), 0.83 (3H, t, J¼7 Hz, NCH2CH3); dC (75 MHz,
CDCl3) 169.7 (CvO), 135.0, 132.7, 132.6, 129.2, 129.0,
128.2, 126.9, 126.4, 126.2, 124.5 (aromatics), 63.1
(CH2OH), 43.2, 39.0 (NCH2), 26.6, 13.8, 12.8
(NCH2CH3); nmax(thin film)/cm21 3386 (broad s), 2974–
2849, 1611 (CvO); m/z (CI) 258 (100%, MþHþ), 227
(1.7%, MþHþ–CH2OH); m/z (EI) 258 (3.6%, MþHþ), 257
(100% M), 227 (3.8%, MþHþ–CH2OH). Found: MþHþ
258.3387; C16H19NO2 requires MþHþ 258.3432.
4.1.20. (6)-2-Hydroxymethyl-N,N-diisopropyl-1-
naphthamide (6)-19a. Sodium borohydride (80 mg,
2 equiv.) was added to a stirred solution of 2-formyl-N,N-
diisopropyl-1-naphthamide 1a (300 mg, 1.0 mmol) in
ethanol (15 mL) at 0 8C. After 100 min, water (30 mL)
was added. The mixture was extracted with ether
(2£20 mL), and the combined extracts washed with brine
(2£20 mL), dried (MgSO4), evaporated under reduced
pressure, and purified by flash column chromatography
eluting with petrol/EtOAc (1:1) to afford alcohol (^)-19a
(281.6 mg, 93%) as a white solid, mp 105–106.8 8C; Rf
0.25, petrol/EtOAc, 1:1); dH (300 MHz, CDCl3) 7.80–7.70
(3H, m, ArH), 7.50–7.40 (3H, m, ArH), 4.77 (1H, dd, J¼12,
3 Hz, CHAHBOH), 4.52 (1H, dd, J¼12, 2 Hz, CHAHBOH),
3.56 (1H, septet, J¼7 Hz, NCH), 3.51 (1H, septet, J¼7 Hz,
NCH), 3.10 (1H, br m, CH2OH), 1.64 (3H, d, J¼7 Hz,
NCHCH3), 1.62 (3H, d, J¼7 Hz, NCHCH3) 1.24 (3H, d,
J¼7 Hz, NCHCH3) and 0.98 (3H, J¼7 Hz, NCHCH3); dC
(75 MHz, CDCl3) 170 (CHO), 134.3, 132.7, 129.2, 128.6,
128.2, 126.8, 126.3, 124.6 (aromatics), 63.4 (CH2OH), 51.4
(NCH), 46.3 (NCH), 20.8 (CH3), 20.5 (CH3), 20.5 (CH3);
4.1.23. (P)-(2)-N,N-Diisopropyl-2-(hydroxymethyl)-6-
(1-methoxy-1-methylethyl)benzamide (2)-20d. By the
method used for the hydrolysis and reduction of imidazo-
lidine 10a, imidazolidine 12d was reduced to give a crude
residue which was purified by flash chromatography, eluting
with petrol/EtOAc (11:1), to give the enantiomerically
enriched alcohol (2)-20d (56 mg, 90%), [a]2D0¼214.1
(c¼0.5, CHCl3). Formation of the Mosher’s ester63 of this
compound and integration of the resulting 1H NMR
spectrum (in comparison with the ester of racemic material)
indicated an enantiomeric excess of 77%.
n
max(thin film)/cm21 2941 (OH), 1610 (CvO); m/z CI 286
(100%, MþHþ), 254 (1.3%, MþHþ–CH2OH); m/z (EI) 286
(100%, MþHþ), 285 (11.5% M), 254 (3.8%, MþHþ–
CH2OH), 168 (MþHþ–ONC6H14). Found: MþHþ
286.1729; C18H23NO2 requires MþHþ 286.1708. Anal.
Calcd for C18H23NO2 C, 75.76; H, 8.12; N, 4.91%. Found C,
75.96; H, 8.05, N, 4.91%.
4.1.24. (6)-N,N-Diisopropyl-2-(hydroxymethyl)-6-(1-
methoxy-1-methylethyl)benzamide (6)-20d. By the
method used to make (^)-19a, aldehyde 2d (250 mg) was
reduced by sodium borohydride to yield a crude product
which was purified by flash chromatography, eluting with
petrol/EtOAc (5:1), to give the corresponding racemic
alcohol (^)-20d (218.9 mg, 87%) as a white solid, mp
94.2–95.8 8C. dH (300 MHz; CDCl3) 7.35–7.29 (3H, Benz-
H), 4.79 (1H, d, J¼13 Hz, CHAHBOH), 4.37 (1H, d, J¼
13 Hz, CHAHBOH), 3.53 (1H, septet, J¼7 Hz, NCH), 3.41
(1H, septet, J¼7 Hz, NCH), 3.25 (3H, s, OCH3), 1.63 (3H,
d, J¼7 Hz, NCHCH3), 1.59 (3H, d, J¼7 Hz, NCHCH3),
1.58 (3H, s, COHCH3CH3CH3), 1.52 (3H, s, COHCH3CH3
CH3), 1.16 (3H, d, J¼7 Hz, NCHCH3), 0.97 (3H, d, J¼
7 Hz, NCHCH3); dC (75 MHz, CDCl3) 171.6 (CvO),
143.8, 138.0, 134.4, 128.1, 128.0, 126.2 (aromatics), 77.9
(COHCH3), 63.4 (CH2OH), 50.7 and 45.8 (NCH), 28.0 and
26.1 (CCH3), 20.4, 20.2, 20.0, 19.6 (4£NCHCH3CH3);
Analytical HPLC on a Chiralpak AD (250£4.6 mm)
column, eluting with 10% EtOH in hexane at 1 mL/min,
resolved two enantiomers at 6.49–6.59 min and 8.14–
8.19 min.
4.1.21. (M)-(2)-2-Hydroxymethyl-N,N-diethyl-1-
naphthamide (2)-19b. (a) By hydrolysis–reduction of
imidazolidine 10b. By the method used for hydrolysis-
reduction of 10a, imidazolidine 10b (331.6 mg, 0.79 mmol)
gave a product which was purified by flash column
chromatography, eluting with petrol/EtOAc (3:1) to afford
enantiomerically enriched alcohol (2)-19b (180.5 mg,
84%) as an oil, [a]1D8¼238.2 (c¼0.5, CHCl3). Analytical
HPLC on a chiral stationary phase (see below), eluting with
16% ethanol in hexane at 1 mL/min, indicated an enantio-
meric excess of 97%.
n
max(thin film)/cm21 3367 (OH), 1607 (amide CvO); m/z
(CI) 308 (20%, MþHþ), 276 (100%, M2OCH3); m/z (EI)
308 (2%, MþHþ), 86 (100%, M2CH2OH, C4H9O, C6H3,
NO). Found: MþHþ 308.2225; C18H29NO3 requires MþHþ
308.2226. Anal. Calcd for C18H29NO3: C, 70.32; H, 9.51; N,
4.56. Found C, 70.94, H, 9.60, N, 4.43.
(b) By hydrolysis–reduction of oxazolidine 16b. By the
method used for oxazolidine 16a, oxazolidine 16b (331 mg)
was reduced to give a crude alcohol which was purified by
flash column chromatography, eluting with petrol/EtOAc
(3:1), to afforded enantiomerically enriched alcohol (2)-
19b (182.6 mg, 85%) as an oil. Analytical HPLC on a chiral
stationary phase (see below) eluting with 6% ethanol in
hexane at 1 mL/min indicated an enantiomeric excess of
74%.
4.1.25. (M)-(2)-N,N-Dicyclohexyl-2-hydroxymethyl-4,6-
dimethylbenzamide (2)-8. By the method used for the
hydrolysis–reduction of imidazolidine 10a, but at a
temperature of 215 8C, imidazolidine 12e (250 mg) gave

J. Clayden et al. / Tetrahedron 60 (2004) 4399–4412
4411
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a crude residue which was purified by flash chromatography
eluting with petrol/EtOAc (5:1), to afford the enantio-
merically enriched alcohol (2)-8 (158 mg, 93%) as a white
solid [a]1D8¼272.1 (c¼0.5, CHCl3); Rf 5:1 (petrol/EtOAc,
in the presence of Pirkle’s chiral shift reagent (R)-TFAE,64
in comparison with the racemic alcohol 8, indicated an
enantiomeric excess of 53%.
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1
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Acknowledgements
30. Clayden, J.; McCarthy, C.; Westlund, N.; Frampton, C. S.
J. Chem. Soc., Perkin Trans. 1 2000, 1363.
We are grateful to GlaxoSmithKline for support of this
work, and to Dr. Andrew Craven for valuable discussions.
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