Atropisomeric amides as chiral, ligands: Using (-)-sparteine-directed enantioselective silylation to control the conformation of a stereogenic axis

Article abstract of DOI:10.1021/jo0007074

An enantiomerically pure (1-trimethylsilyl)ethyl group, constructed by a (-)-sparteine-directed enantioselective quench of a laterally lithiated tertiary aromatic amide, exerts powerful thermo-dynamic control over the conformation of the adjacent tertiary amide substituent. Ortholithiation and functionalization of the amide in the 6-position allows the single amide conformer to be trapped as an enantiomerically and diastereoisomerically pure amide atropisomer. Protodesilylation of the amide gives functionalized atropisomeric amides with a stereogenic axis of single absolute configuration, whose barriers to racemization have been determined by polarimetry. Enantiomerically pure amides bearing phosphine substituents are effective ligands in a Pal-catalyzed allylic substitution reaction - the first use of a nonbiaryl atropisomer as a chiral ligand - and give products with 90% ee. The rate of racemization of the phosphine-substituted amide is powerfully influenced by the presence of palladium.

Full text of DOI:10.1021/jo0007074

J . Org. Chem. 2000, 65, 7033-7040
7033
Atr op isom er ic Am id es a s Ch ir a l Liga n d s: Usin g
(-)-Sp a r tein e-Dir ected En a n tioselective Silyla tion to Con tr ol th e
Con for m a tion of a Ster eogen ic Axis
J onathan Clayden,* Paul J ohnson, J ennifer H. Pink, and Madeleine Helliwell
Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.
j.p.clayden@man.ac.uk
Received May 8, 2000
An enantiomerically pure (1-trimethylsilyl)ethyl group, constructed by a (-)-sparteine-directed
enantioselective quench of a laterally lithiated tertiary aromatic amide, exerts powerful thermo-
dynamic control over the conformation of the adjacent tertiary amide substituent. Ortholithiation
and functionalization of the amide in the 6-position allows the single amide conformer to be trapped
as an enantiomerically and diastereoisomerically pure amide atropisomer. Protodesilylation of the
amide gives functionalized atropisomeric amides with a stereogenic axis of single absolute
configuration, whose barriers to racemization have been determined by polarimetry. Enantiomeri-
cally pure amides bearing phosphine substituents are effective ligands in a Pd-catalyzed allylic
substitution reactionsthe first use of a nonbiaryl atropisomer as a chiral ligandsand give products
with 90% ee. The rate of racemization of the phosphine-substituted amide is powerfully influenced
by the presence of palladium.
In tr od u ction
auxiliaries.9,10 Single enantiomers of compounds related
to 1 have been made by kinetic resolution using (-)-
sparteine,11 by atroposelective transformation of an
enantiomerically pure arene-chromium tricarbonyl com-
plex,12 and by a dynamic resolution under thermody-
namic control using a proline-derived diamine as the
source of asymmetry.13 Conformational stability sufficient
for the existence of atropisomers requires severe steric
hindrance, and this leads to the unreactivity that pre-
vents the successful recycling of chiral auxiliaries derived
from 1 and 2. Our aim more recently has therefore been
to synthesize single enantiomers of amides 1 for use, not
as auxiliaries, but as chiral ligands for metal-catalyzed
asymmetric reactions. We set out to make bidentate
target ligands containing a second point of coordination
(in addition to the amide O or N) which we would
introduce using the amides’ versatile ortholithiation
chemistry.14
Atropisomeric biaryls are well established as one of the
most important classes of ligands for asymmetric metal-
catalyzed reactions.1 The angled aromatic rings serve as
a useful scaffold for the attachment of metal-coordinating
heteroatoms, and biaryl-complexed transition metals
provide modern chemistry with some of its most powerful
asymmetric catalysts.2
Nonbiaryl atropisomers, on the other hand, have never
been used as chiral ligands.3 A number of types of
nonbiaryl atropisomers are known,4 and most prominent
among them recently have been the chiral tertiary
amides 15 and the chiral anilides 2.6 Both types have a
powerful ability to control relative stereochemistry in the
racemic series,7,8 and both have been used as chiral
(8) For reactions of atropisomeric benzamides and naphthamides
in the racemic series, see refs 15-17: Bowles, P.; Clayden, J .;
Tomkinson, M. Tetrahedron Lett. 1995, 36, 9219. Clayden, J.; Westlund,
N.; Wilson, F. X. Tetrahedron Lett. 1996, 37, 5577. Clayden, J .; Pink,
J . H. Tetrahedron Lett. 1997, 38, 2561. Clayden, J .; Darbyshire, M.;
Pink, J . H.; Westlund, N.; Wilson, F. X. Tetrahedron Lett. 1997, 38,
8587. Clayden, J .; Westlund, N.; Wilson, F. X. Tetrahedron Lett. 1999,
40, 3329. Clayden, J .; Westlund, N.; Wilson, F. X. Tetrahedron Lett.
1999, 40, 7883.
(9) Atropisomeric anilides as chiral auxiliaries: Hughes, A. D.; Price,
D. A.; Shishkin, O.; Simpkins, N. S. Tetrahedron Lett. 1996, 37, 7607.
Hughes, A. D.; Simpkins, N. S. Synlett 1998, 967. Hughes, A. D.; Price,
D. A.; Simpkins, N. S. J . Chem. Soc., Perkin Trans. 1 1999, 1295.
Kitagawa, O.; Izawa, H.; Taguchi, T.; Shiro, M. Tetrahedron Lett. 1997,
38, 4447. Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi, A.; Taguchi, T.
J . Org. Chem. 1998, 63, 2634. Kitagawa, O.; Momose, S.-i.; Fushimi,
Y.; Taguchi, T. Tetrahedron Lett. 1999, 40, 8827.
* To whom correspondence should be addressed. Fax: 0161 275
4939.
(1) Rosini, C.; Franzini, L.; Raffaelli, A.; Salvadori, P. Synthesis
1992, 503.
(2) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994.
(3) Clayden, J . Angew. Chem., Int. Ed. Engl. 1997, 36, 949.
(4) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley: New York, 1994.
(5) Clayden, J . Synlett 1998, 810.
(10) Atropisomeric naphthamides as chiral auxiliaries: Clayden, J .;
McCarthy, C.; Cumming, J . G. Tetrahedron Lett. 2000, 41, 3279.
(11) Thayumanavan, S.; Beak, P.; Curran, D. P. Tetrahedron Lett.
1996, 37, 2899.
(6) Curran, D. P.; Hale, G. R.; Geib, S. J .; Balog, A.; Cass, Q. B.;
Degani, A. L. G.; Hernandes, M. Z.; Freitas, L. C. G. Tetrahedron:
Asymmetry 1997, 8, 3955.
(7) For reactions of atropisomeric anilides in the racemic series, see
ref 6: Curran, D. P.; Qi, H.; Geib, S. J .; DeMello, N. C. J . Am. Chem.
Soc. 1994, 116, 3131; Bach, T.; Schro¨der, J .; Harms, K. Tetrahedron
Lett. 1999, 40, 9003.
(12) Koide, H.; Uemura, M. J . Chem. Soc., Chem. Commun. 1998,
2483.
(13) Clayden, J .; Lai, L. W. Angew. Chem., Int. Ed. Engl. 1999, 38,
2556.
10.1021/jo0007074 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/19/2000

7034 J . Org. Chem., Vol. 65, No. 21, 2000
Clayden et al.
Sch em e 1. Rela yin g Ster eoch em istr y th r ou gh a n
Am id e Axisa
The potential thermal lability of a chiral axis makes
thermodynamically controlled equilibration an attractive
method for the synthesis of single atropisomeric dia-
stereoisomers. The proline-derived diamine mentioned
above13 exerts its effect by favoring one diastereoisomeric
conformer over the other at equilibrium. In general, a
stereogenic center bearing sterically well differentiated
groups S, M, and L becomes conformationally interlocked
with an adjacent tertiary amide, resulting in a strong
preference for a single axial conformation.5 For example,
with R1 ) H, conformer 3a is significantly favored over
conformer 3b when S ) H, M ) Me, L ) R3Si,15 or S )
H, M ) NHMe, L ) secondary alkyl.16 For such 2-sub-
stituted benzamides, the diastereoisomeric conformers
about the Ar-CO bond interconvert rapidly (on the
laboratory, though not the NMR, time scale), with a half-
life of <1 s.17,18 For a 2,6-disubstituted benzamides, on
the other hand, with R1 * H, the diastereoisomeric
conformers interconvert much more slowly:19 they become
diastereoisomeric atropisomers20 and heat may be re-
quired to convert 3b to 3a .
a
Key: (i) s-BuLi, -78 °C, THF; (ii) Me3SiCl; (iii) EtI.
Sch em e 2. Asym m etr ic Silyla tion of a
2-Eth ylben za m id ea
a
Key: (i) s-BuLi, (-)-sparteine, t-BuOMe, pentane, -78 °C; (ii)
Me3SiCl; (iii) recrystallize × 2 (petroleum ether).
phine derivatives of 1 function as ligands for asymmetric
palladium-catalyzed allylic substitution reactions.
Resu lts
We have exploited the preferences of amides bearing
chiral 2-substituents by using rotationally restricted
amides to relay stereochemistry from one stereogenic
center to another, for example, by the route shown in
Scheme 1.15 Lateral lithiation and silylation gives racemic
amide 5, which adopts predominantly the conformation
shown. Ortholithiation and introduction of a 6-substitu-
ent then lock this conformation into the structure of a
single atropisomeric diastereoisomer (()-6. Finally, dia-
stereoselective lateral lithiation, controlled by the Ar-
CO axis, and stereospecific quench with Me3SiCl, gives
meso-7.
In this paper, we describe the application of (-)-
sparteine-mediated silylation of 421,22 to the asymmetric
synthesis of 1 via enantiomerically enriched 5. We also
describe the first use of nonbiaryl atropisomers as chiral
ligands for metal-catalyzed reactions, showing that phos-
Asym m etr ic Syn th esis of Atr op isom er ic Am id es.
Amide 4 was laterally lithiated and silylated in the
presence of freshly distilled and rigorously degassed (-)-
sparteine, using the method of Beak and co-workers
(Scheme 2).21 We obtained the product silane (S)-5 in 93%
yield and 69% ee. Two recrystallizations from petroleum
ether returned material of >97% ee, and this material
was used for all subsequent reactions. From the X-ray
crystal structure (Figure 1) of (S)-5, we were able to
confirm its absolute stereochemistry, which in earlier
work had been deduced by conversion to a compound of
known optical rotation.21
Figure 1b shows the X-ray crystal structure of 5 viewed
along the Ar-CH(Me)SiMe3 bond. It indicates that the
conformation of 5 in the crystalline state is in accord with
our proposal that compounds of the general structure 3
adopt a conformation 3a , though it does not prove that
this conformation is preferred in solution. We were,
(14) Snieckus, V. Chem. Rev. 1990, 90, 879.
(15) Clayden, J .; Pink, J . H.; Yasin, S. A. Tetrahedron Lett. 1998,
39, 105.
(16) Clayden, J .; Westlund, N.; Wilson, F. X. Tetrahedron Lett. 1999,
40, 3331.
(17) Bowles, P.; Clayden, J .; Helliwell, M.; McCarthy, C.; Tomkinson,
M.; Westlund, N. J . Chem. Soc., Perkin Trans. 1 1997, 2607.
(18) Ahmed, A.; Bragg, R. A.; Clayden, J .; Lai, L. W.; McCarthy, C.;
Pink, J . H.; Westlund, N.; Yasin, S. A. Tetrahedron 1998, 54, 13277.
(19) Cuyegkeng, M. A.; Mannschreck, A. Chem. Ber. 1987, 120, 803.
(20) Oki, M. Top. Stereochem. 1983, 14, 1.
(21) Thayumanavan, S.; Lee, S.; Liu, C.; Beak, P. J . Am. Chem. Soc.
1994, 116, 9755; Thayumanavan, S.; Basu, A.; Beak, P. J . Am. Chem.
Soc. 1997, 119, 8209.
1
however, able to use H NMR to deduce that (S)-5 exists
in predominantly one conformer about its Ar-CO axis
in CDCl3. The Ar-CO rotation of 2-substituted tertiary
benzamides, while not leading to separable atropisomers,
is typically slow on the NMR time scale.18 When the
interconverting conformers are enantiomeric, this slow
rotation manifests itself in the appearance of two pairs
of diastereotopic doublets corresponding to the diaste-
reotopic N-i-Pr2 methyl groups. For (-)-5, Ar-CO rota-
tion leads to diastereoisomeric conformers, which we
would expect to see as two complete sets of signals in
(22) Pirkle, W. H. Top. Stereochem. 1982, 13, 263.

Atropisomeric Amides as Chiral Ligands
J . Org. Chem., Vol. 65, No. 21, 2000 7035
F igu r e 2. X-ray crystal structure of 8d .
Sch em e 3. En a n tioselective Syn th esis of
Atr op isom er ic Am id esa
single diastereoisomeric atropisomers (by 1H NMR) after
purification by chromatography. Oxidation of 8d to 8c
was minimized by using a nonaqueous workup procedure.
The final step in the asymmetric synthesis required
removal of the silyl group to leave single enantiomeric
atropisomers. Protodesilylation was easily achieved for
all five compounds 8a -e by treatment with TBAF at 20
°C for 5 min, giving 9a -e (Scheme 3 and Table 1).
The stereochemistry of 8d was proved by X-ray crystal
structure determination (Figure 2), which, although it
could not re-confirm the absolute stereochemistry of the
compound, did confirm the relative stereochemistry
between the stereogenic center and the amide axis, which
remains as shown for 5. Presumably, therefore, the major
conformer of 5 in solution, whose lithiation leads to 8,
has the same Ar-CO conformation as that shown by 5
in the crystalline state. Figure 2 also clearly indicates
the perpendicular arrangement of the ring and the amide
group, and the continued conformational preference of
the (trimethylsilyl)ethyl substituent.
F igu r e 1. X-ray crystal structure of (S)-5: (a) viewed from
front; (b) viewed along Ar-CH(Me)SiMe3 bond.
Ta ble 1. En a n tioselective Syn th esis of Atr op isom er ic
Am id es
8, yield 9, yield
electrophile
R
(%)
(%)
8, [R]23 9, [R]23
D D
acetone
MeI
Ph2P(O)Cl
Ph2PCl
PhSSPh
Me2C(OH)- 8a , 50 9a , 99
+42.5
+18.9
+40.3
-44.0
+32.0
+3.2
Me-
8b, 98 9b, 99
8c, 81 9c, 99
8d , 79 9d , 86
8e, 87
Ph2P(O)-
Ph2P-
PhS-
+18.0
-4.0
The enantiomeric purity of 9b was confirmed to be
>98% ee by 1H NMR in the presence of the chiral
solvating agent (+)-TFAE,22 which clearly split the Ar-
Me singlet of racemic 9b into two enantiomeric signals.
Ba r r ier s to Ra cem iza tion of th e Atr op isom er s.
Although compounds 9 are still 2,6-disubstituted benz-
amides, and are therefore expected to be kinetically
stable to racemization,18 their silylated precursors 8 had,
additionally, thermodynamic stability relative to their
atropisomeric diastereoisomers (see discussion below and
Scheme 5). With this thermodynamic resistance to Ar-
CO rotation removed, there was a danger that slow
racemization of 9 might take place even at room tem-
perature. We assessed the ease of racemization of each
of the final products by following the first-order decay in
optical rotation with time at a suitable temperature. The
9e, 100 -28.9
-29.2
1
1
the H NMR spectrum at ambient temperature. The H
NMR spectrum of (-)-5 shows these two sets of signals
in a ratio of 10:1, indicating that (-)-5 is 90% one
conformer about the Ar-CO axis at ambient tempera-
ture.
Trapping the major conformer of (-)-5 as a major
atropisomer allowed us to cash in the absolute stereo-
chemistry of the silicon-bearing center. To do this,
rotation of the amide group was blocked with a second
ortho substituent on the benzamide ring. The amide (-)-5
was treated with s-BuLi to ortholithiate it,14 and the
organolithium was quenched with the range of electro-
philes shown in Table 1 to give 8a -e (Scheme 3). The
NMR spectra of the crude reactions mixtures indicated
>10:1 atroposelectivity (in some cases much higher36) in
these reactions, and all of the products were obtained as
Eyring equation23 was used to derive a value for ∆Gq
rac
from the rate constant k. For 9d we repeated the

7036 J . Org. Chem., Vol. 65, No. 21, 2000
Ta ble 2. Ra te of Ra cem iza tion of Atr op isom er ic Am id es
Clayden et al.
25
entry
amide
R
additivea
T/°Cb
k/10-5 s-1
∆Gqrac/kJ mol-1
t1/2
rac
1
2
3
4
5
6
7
8
9
9a
9b
9c
9d
9d
9d
9e
9b
9d
9d
9d
Me2C(OH)-
Me
Ph2P(O)-
Ph2P
Ph2P
Ph2P
PhS
Me
93c
50
50
55
45
35
40
50
45
45
45
1.04 ( 0.03
2.76 ( 0.01
7.65 ( 0.07
18.7 ( 0.1
125.2 ( 0.3
107.5 ( 0.3
104.8 ( 0.3
104.0 ( 0.3
104.2 ( 0.3
104.0 ( 0.3
98.8 ( 0.3
108.1 ( 0.5
87.9 ( 0.3
104.1 ( 0.3
104.4 ( 0.5
30 years
10 days
3 days
2 days
2 days
2 days
6 hours
10 days
5 min
5.17 ( 0.005
1.49 ( 0.01
21.40 ( 0.07
2.27 ( 0.15
2400 ( 50
[PdCl(π-allyl)]2
[PdCl(π-allyl)]2
Ti(OEt)2
Ph2P
Ph2P
Ph2P
10
11
5.30 ( 0.04
4.83 ( 0.14
2 days
2 days
AlMe3
a
b
1 equiv in metal. (0.5 °C. c Dioxane as solvent.
Sch em e 4. Asym m etr ic Allylic Su bstitu tion Usin g
8d a s a Ch ir a l Liga n d
experiment at three temperatures and determined that
|∆Sqrac| < 30 J mol-1 K-1 24
.
On the basis of this assump-
tion, we estimated half-lives for racemization of 9a -e at
25 °C. All of these values are presented in Table 2 (entries
1-7).
Racemization was slowest with R ) alkyl, and 9a (with
a tertiary alkyl substituent) had almost complete con-
formational stability (entry 1). Even 9b, with R ) Me
(entry 2), racemised more slowly than the phosphorus
compounds 9c and 9d (entries 3 and 4). We have already
noted that a trialkylsilyl group provides a poor block to
bond rotation,18 and this feature appears to be general
for the second row elements, with sulfide 9e racemizing
still more rapidly (entry 7). Phosphine 9d was nonethe-
less conformationally stable enough for us to hope for its
successful application as a chiral ligand at room temper-
ature or below and on time-scales shorter than 24 h.
There was little difference between the rate of racem-
ization of the phosphine 9d and the phosphine oxide 9c.
Th e F ir st Use of Non bia r yl Atr op isom er s a s
Ch ir a l Liga n d s. A wide range of heterosubstituted
arylphosphines have been used as ligands in palladium-
catalyzed asymmetric allylic substitution reactions.25
Among the most successful of these are Trost’s amido-
phosphines, and many others are P,N or P,O-bidentate
ligands. The stereoelectronics of such “soft-hard” ligand-
metal complexes has been proposed as a key factor in
the stereocontrol exerted by some of these ligands.26,27
Our first trial allylic substitutions were carried out
with 8d , whose silyl group eliminates the danger of slow
atropisomerization during the reaction by making it
thermodynamically stable to epimerization. 1,3-Diphe-
nylpropenyl acetate 10 and dimethyl malonate 11 were
treated with 1 mol % Pd (as [PdCl(π-allyl)]2) in the
presence of 0.5 mol % 8d as a chiral ligand (Scheme 4).
The reaction took 3 days at 25 °C to give 60% yield of
product (-)-12, which was formed with 90% ee (by chiral
GC).
ligand 9d . However, when the reaction of 10 and 11 was
repeated using this ligand, although the rate was similar
(36% yield after 48 h) the product 12 was racemic.
Moreover, the ligand 9d recovered from the reaction
turned out to be optically inactive, rather than having
the ca. 35-40% ee we would expect after 3 days at 25 °C
(see Table 2, entry 4).
To find out why 9d had racemized so quickly, its rate
of racemization was re-determined in the presence of
palladium (Table 2, entry 9). Remarkably, palladium
caused the barrier to racemization to drop by 16 kJ mol-1
,
and the rate of racemization to increase 500-fold, giving
an estimated half-life for the racemization of 9d at 25
°C in the presence of palladium of only 5 min. The lack
of enantiomeric enrichment in the allylic substitution
product is simply explained by the fact that racemization
of the ligand occurs much faster than the substitution
reaction.
The increase in rate of racemization appears to be due
both to the phosphine substituent and to the presence of
palladium, since adding palladium to the methyl-
substituted 9b (entry 8) had almost no effect on the rate
of racemization. The hard, oxophilic Lewis acids Ti(OEt)4
and AlMe3 similarly had essentially no effect on the rate
of racemization of the phosphine 9d (entries 10, 11).
We presume the asymmetric induction in this reaction
arises from the chirality of the stereogenic axis of 8d ,
and that the silicon-bearing stereogenic center has little
direct influence on the reaction center. We therefore
expected a similar result with the silyl-“deprotected”
Discu ssion
The novel strategy employed in the asymmetric syn-
thesis of 9 is outlined in Scheme 5. The starting amide 4
is a pair of rapidly interconverting (small ∆Gqrac) enan-
tiomeric (aR and aS) conformers about the Ar-CO bond.
Asymmetric construction of the stereogenic center in 5
perturbs the populations of the conformers, favoring aR
over aS. This thermodynamic perturbation of populations
is then fixed kinetically, by introduction of the substitu-
ent R into 8. Now the thermodynamic perturbationsthe
(23) Eyring, H. Chem. Rev. 1935, 17, 65.
(24) Activation entropies for bond rotations are frequently (Stewart,
W. H.; Siddall, T. H. Chem. Rev. 1970, 70, 517) though not always
(Spivey, A. C.; Fekner, T.; Spey, S. E.; Adams, H. J . Org. Chem. 1999,
64, 9430) close to zero, and the assumption that ∆Sq ) 0 and that ∆Gq
is invariant with temperature allows convenient estimates of racem-
ization half-lives to be made.
(25) Trost, B. M.; van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(26) Frost, C. G.; Williams, J . M. J . Tetrahedron Lett. 1993, 34, 2015.
(27) Reiser, O. Angew. Chem., Int. Ed. Engl. 1993, 32, 547.

Atropisomeric Amides as Chiral Ligands
J . Org. Chem., Vol. 65, No. 21, 2000 7037
Sch em e 5. Str a tegy in th e Asym m etr ic Syn th esis of 9
stereogenic centerscan be removed, and the kinetic
barrier to reestablishment of equilibrium (large ∆Gq
allows enantiomeric excess to be retained in the products
9.
CO rotation in this case had been a consequence simply
of an increased rate of C-N rotation due to N-Pd
coordination, a similar effect would be expected for
methyl-substituted 9b. Addition of the same palladium
complex to 9b to resulted in no increase in rotation rate.
Similarly, Ti and Al Lewis acids, which would be expected
to slow C-N rotation, had no significant effect on Ar-
CO rotation in 9d .
While the racemization of 9d precludes the use of this,
and similar, atropisomeric compounds as ligands for
palladium, the use of conformational interlocking (such
as that in 8d ) to control the conformation around a
ligand’s binding site is an important and more generally
exploitable concept. The 90% ee obtained in the reaction
of 8d is remarkble because presumably the palladium
also lowers the barrier to atropisomerization of 8d .
However, the silyl group makes 8d thermodynamically
stable relative to its diastereoisomer and prevents it
epimerising. We now aim to use the versatile lithiation
chemistry of tertiary amides to develop a novel range of
conformationally constrained ligands for use in this, and
other, metal catalyzed reactions.
)
rac
The Pd-catalyzed substitution reactions presumably
involve phosphines 8d and 9d as bidentate ligands for
Pd. Trost’s secondary amido-phosphine ligands28 are
superficially similar in structure, and they too perform
better when some degree of conformational restriction is
introduced into the amide and C-P bonds, allowing
chirality to be transferred from the ligand backbone to
the metal. Our ligand has a soft (P) and a hard (probably
N, but possibly O) coordination site, each surrounded by
considerable steric encumbrance, and with few bonds able
to rotate freely. Further investigation will be required
before we can propose a detailed transition state for the
reaction.
As for the accelerated racemization of 9d in the
presence of palladium - presumably, a P-Pd-N (or
maybe a P-Pd-O) chelate stabilizes the transition state
for Ar-CO rotation. Metal complexation is known to
affect rates of C-N rotation in amides, with hard,
oxophilic Lewis acids lowering the rate,29 and soft,
azaphilic metals raising it.30 We have found, in a similar
amide, that C-N rotation and Ar-CO rotation are
interlocked, with the two occurring simultaneously
through a gearing effect.31 In other cases, rates of C-N
and Ar-CO rotation are closely matched, again pointing
to interlocked rotation.18 Yet if the increased rate of Ar-
Exp er im en ta l Section
Gen er a l Meth od s. Pentane was distilled under nitrogen
from calcium hydride. tert-Butyl methyl ether, diethyl ether
(referred to as “ether”) and tetrahydrofuran (THF) were
distilled under nitrogen from sodium benzophenone ketyl. Dry
solvents were transferred to reaction vessels by syringe.
“Petrol” refers to redistilled bp 40-60 °C petroleum ether. (-)-
Sparteine was distilled at reduced pressure from calcium
hydride directly before use. Commercial sec-butyllithium (as
a solution in hexanes) was titrated using diphenylacetone
tosylhydrazone prior to use. Melting points are uncorrected.
Column chromatography was performed using the method of
Still, Kahn and Mitra32 with Merck silica gel 60H (230-300
(28) Trost, B. M.; Bunt, R. C. Angew. Chem., Int. Ed. Engl. 1996,
35, 99.
(29) Fussenegger, R.; Rode, B. M. Chem Phys Lett 1976, 44, 95.
(30) Cox, C.; Ferraris, D.; Murthy, N. M.; Lectka, T. J . Am. Chem.
Soc. 1996, 118, 5332.
(31) Clayden, J .; Pink, J . H. Angew. Chem., Int. Ed. Engl. 1998, 37,
1937.

7038 J . Org. Chem., Vol. 65, No. 21, 2000
Clayden et al.
mesh) as the stationary phase. Thin-layer chromatography was
performed using Merck silica 60 F254 aluminum-backed plates.
purified by column chromatography (eluting with petrol/EtOAc
9:1) to yield the title compound 8a (91 mg, 50%) as a white
solid: mp 83-84 °C; Rf(petrol/EtOAc 4:1) 0.37; IR (film/CHCl3)
3540 (br), 2958, 1602 cm-1;1H NMR (CDCl3, 300 MHz) δ 7.21
(1H, t, J ) 8 Hz), 6.99 (2H, dq, J ) 1.5, 8 Hz), 3.66 (1H, sept,
J ) 6.5 Hz), 3.51 (1H, sept, J ) 7 Hz), 3.11 (1H, br s), 2.34
(1H, q, J ) 7.5 Hz), 1.58 (6H, s), 1.57 (3H, d, J ) 7 Hz), 1.55
(3H, d, J ) 7 Hz), 1.37 (3H, d, J ) 7.5 Hz), 1.14 (3H, d, J )
6.5 Hz), 1.13 (3H, d, J ) 6.5 Hz), -0.05 (9 H, s); 13C NMR
(CDCl3, 75 MHz) δ 173.1, 145.8, 143.2, 132.0, 127.2, 124.0,
123.2, 74.4, 50.5, 45.8, 34.9, 31.2, 24.2, 20.6, 20.3, 19.6, 19.5,
16.5, -2.8; MS (EI) m/z (rel intensity) 363 (M+, 30), 304 (53),
263 (100); HRMS (EI) calcd for C21H37NO2Si (M+) 363.2593,
N,N-Diisop r op yl-2-eth ylben za m id e 4.21 sec-Butyllithium
(9.48 mL, 1.3 M solution in cyclohexane, 12.32 mmol) was
added dropwise to a solution of N,N-diisopropylbenzamide
(2.30 g, 11.20 mmol) in THF (120 mL), cooled to -78 °C under
an atmosphere of nitrogen. After 1 h at - 78 °C, ethyl iodide
(1.79 mL, 22.40 mmol) was added. The solution was allowed
to warm to room temperature, water (50 mL) was added, and
the THF was removed under reduced pressure. The aqueous
phase was extracted with dichloromethane (3 × 30 mL), and
the combined extracts were washed with water (30 mL), dried
over magnesium sulfate, and filtered. The solvent was evapo-
rated, and the crude product was purified by column chroma-
tography (eluting with 5% ethyl acetate in light petroleum) to
give the amide 4 as a white crystalline solid (2.61 g, 100%):
mp 90-92 °C (lit.21 mp 91-93 °C); Rf(petrol/EtOAc 9:1) 0.47;
1H NMR (CDCl3, 300 MHz) δ 7.34-7.17 (3H, m), 7.11 (1H, d,
J ) 7.3 Hz), 3.71 (1H, sept, J ) 7 Hz), 3.54 (1H, sept, J ) 7
Hz), 2.79-2.58 (2H, m), 1.61 (6H, d, J ) 7 Hz), 1.29 (3H, t, J
) 7.5 Hz), 1.14 (3H, d, J ) 7 Hz), 1.11 (3H, d, J ) 7 Hz); 13C
NMR (CDCl3, 75 MHz) δ 170.5, 139.8, 138.0, 128.5, 128.1,
125.6, 124.6, 50.6, 45.6, 25.6, 20.6, 20.6, 20.5, 20.4, 15.1.
found 363.2587 (1.7 ppm); [R]23 +42.5 (CHCl3, c ) 1).
D
(S ,R a )-N ,N -Diisop r op yl-2-(1-t r im e t h ylsilyle t h yl)-6-
m eth ylben za m id e 8b. In the same way, benzamide 5 (153
mg) and methyl iodide gave an oil that was purified by column
chromatography (eluting with petrol/EtOAc 19:1) to yield the
title compound 8b (156 mg, 98%) as a white solid: mp 84-85
°C; Rf(petrol/EtOAc 19:1) 0.17; IR (film/CHCl3) 2960, 1628,
1
cm-1; H NMR (CDCl3, 300 MHz) δ 7.16 (1H, t, J ) 7.5 Hz),
6.96 (1H, d, J ) 7.5 Hz), 6.94 (1H, d, J ) 7.5 Hz), 3.69 (1H,
sept, J ) 6.5 Hz), 3.52 (1H, sept, J ) 6.5 Hz), 2.30 (3H, s),
2.15 (1H, q, J ) 7.5 Hz), 1.62 (3H, d, J ) 6.5 Hz), 1.61 (3H, d,
J ) 6.5 Hz), 1.35 (3H, d, J ) 7.5 Hz), 1.14 (3H, d, J ) 6.5 Hz),
1.10 (3H, d, J ) 6.5 Hz), 0.00 (9H, s); 13C NMR (CDCl3, 75
MHz) δ 170.0, 142.4, 136.6, 133.4, 127.3, 126.1, 123.4, 50.1,
45.6, 25.3, 21.0, 20.9, 20.3 (×2), 19.3, 16.4, -2.9; MS (CI) m/z
(S )-N ,N -Diisop r op yl-2-(1-t r im e t h ylsilyle t h yl)b e n z-
a m id e 5.21 Freshly distilled (-)-sparteine (644 mg, 3 mmol,
1.2 equiv) was added to 2-ethylbenzamide 4 (582 mg, 2.5 mmol,
1 equiv) in a predried, nitrogen filled flask. Pentane (75 mL)
and tert-butyl methyl ether (75 mL) were added, and the
resulting solution degassed using three freeze-pump-thaw
cycles. The solution was cooled to -78 °C, and sec-butyllithium
(2 mL of a 1.4 M solution, 1.1 equiv) was added, turning the
(rel intensity) 320 (MH+, 100); HRMS (CI) calcd for C19H33
-
NOSi (MH+) 319.2331, found 319.2325 (2.0 ppm); [R]23D +18.9
(CHCl3, c ) 3). Anal. Calcd for C19H33NOSi: C, 71.41; H, 10.41;
N, 4.38. Found: C, 71.73; H, 10.04; N, 4.42.
solution deep purple. After
a further 1.5 h at -78 °C,
(S,Sa )-N,N-Diisop r op yl-2-(1-t r im et h ylsilylet h yl)-6-d i-
p h en ylp h osp h on ylben za m id e 8c. In the same way, benz-
amide 5 (153 mg) and diphenylphosphinic chloride gave an
oil which was purified by column chromatography (eluting with
petrol/EtOAc 1:1) to yield the title compound 8 (204 mg, 81%)
as a white solid: mp 165-167 °C, Rf(petrol/EtOAc 1:1) 0.23;
IR (film/CHCl3) 2956, 2928, 1631, 1204 cm-1;1H NMR (CDCl3,
300 MHz) δ 7.29-7.61, (11H, m), 7.18 (1H, dt, J ) 3, 7.5 Hz),
6.84 (1H, ddd, J ) 1, 7.5, 13.5 Hz), 3.66 (1H, sept, J ) 7 Hz),
3.51 (1H, sept, J ) 6.5 Hz), 2.44 (1H, q, J ) 7.5 Hz), 1.59 (3H,
d, J ) 7 Hz), 1.49 (3H, d, J ) 7 Hz), 1.40 (3H, d, J ) 6.5 Hz),
1.39 (3H, d, J ) 7.5 Hz), 1.13 (3H, d, J ) 6.5 Hz), -0.07 (9H,
s); 13C NMR (CDCl3, 75 MHz) δ 167.6 (d, J ) 3.5 Hz), 144.8
(d, J ) 10.0 Hz), 140.5 (d, J ) 8.0 Hz), 134.4 (d, J ) 103.0
Hz), 133.4 (d, J ) 105.5 Hz), 132.3 (d, J ) 9.0 Hz), 131.8 (d, J
) 10.5 Hz), 131.4 (d, J ) 3.5 Hz), 131.4 (d, J ) 3.0 Hz), 129.6
(d, J ) 13.0 Hz), 129.5 (d, J ) 3.0 Hz), 128.4 (d, J ) 100.5
Hz), 128.2 (d, J ) 12.0 Hz), 128.0 (d, J ) 5.5 Hz), 126.6 (d, J
) 13.5 Hz), 50.4, 45.8, 24.5, 21.2, 20.4, 19.7, 19.5, 16.1, -2.9;
MS (CI) m/z (rel intensity) 506 (MH+, 100); HRMS (EI) calcd
for C30H40NO2PSi (M+) 505.2566, found 505.2754 (1.6 ppm);
[R]23D +40.3 (CHCl3, c ) 4). Anal. Calcd for C30H40NO2PSi: C,
71.25; H, 7.97; N, 2.77; P, 6.12. Found: C, 71.33; H, 8.09; N,
2.77; P, 6.27.
(S,Sa )-N,N-Diisop r op yl-2-(1-t r im et h ylsilylet h yl)-6-d i-
p h en ylp h osp h in ylben za m id e 8d . In the same way, benza-
mide 5 (153 mg) was lithiated and treated with chlorodiphe-
nylphosphine. In place of the usual aqueous workup, the
reaction was allowed to warm to room temperature and was
then poured quickly through a pad of Celite. The flask and
the Celite were washed with ether, and the filtrate was
concentrated under reduced pressure. The resulting sticky oil
was purified by column chromatography (eluting with petrol)
to give the title compound 8d (193 mg, 79%) as a white foam,
which crystallized from petrol as colorless needles: mp 140-
142 °C; Rf(petrol/EtOAc 9:1) 0.54; IR (film/CHCl3) 3053, 2956,
2871, 1629 cm-1;1H NMR (CDCl3, 300 MHz) δ 7.19-7.36 (12H,
m), 6.83-6.87 (1H, m), 3.84 (1H, sept, J ) 6.5 Hz), 3.57 (1H,
sept, J ) 7 Hz), 2.32, (1H, q, J ) 7.5 Hz), 1.67 (3H, d, J ) 7
Hz), 1.59 (3H, d, J ) 7 Hz), 1.42 (3H, d, J ) 7.5 Hz), 1.31 (3H,
d, J ) 6.5 Hz), 1.19 (3H, d, J ) 6.5 Hz), 0.00 (9H, s); 13C NMR
(CDCl3, 75 MHz) δ 169.0 (d, J ) 5.0 Hz), 143.0 (d, J ) 35.5
Hz), 143.0 (d, J ) 8.0 Hz), 138.4 (d, J ) 12.0 Hz), 137.0 (d, J
trimethylsilyl chloride (0.5 mL, 1.5 equiv) was added. Stirring
at -78 °C was continued for a further 7 h, after which the
solution was pale red in color. Methanol (1 mL) was added,
and the solution was allowed to warm to room temperature.
Phosphoric acid (0.5 M aq) was added, and the mixture was
extracted into ether. The organic layer was separated and
washed again with phosphoric acid (0.5 M aq) and then with
water, before being dried (magnesium sulfate) and concen-
trated under reduced pressure to give the crude product as a
viscous clear oil. The crude product was purified by column
chromatography (eluting with petrol/EtOAc 19:1), to give the
title compound 5 (708 mg, 93%), as a colorless, crystalline solid
with an enantiomeric excess of 69% (by GC on chiral stationary
phase). Successive recrystallization of this compound from
petrol afforded material of 98% ee [by chiral GC: 25m × 0.32
mm 0.25u CP-Chirasil-DEX CB, retention times 77:08.1
(99.133%), 77:43.3 (0.867%)]. mp 71-72 °C (Lit.21 68-70 °C),
Rf(petrol/EtOAc 19:1) 0.15; IR (film/CHCl3) 2962, 1632 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 7.05-7.29 (5H, m), 3.67 (1H,
sept, J ) 6.5 Hz), 3.49 (1H, sept, J ) 6.5 Hz), 2.17 (1H, q, J )
7.5 Hz), 1.57 (6H, t, J ) 6.5 Hz), 1.34 (3H, d, J ) 7.5 Hz), 1.13
(3H, d, J ) 6.5 Hz), 1.04 (3H, d, J ) 6.5 Hz), 0.00 (9H, s) -
about 10% of less stable conformer visible at 3.81 (sept, J )
6.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 170.6, 142.5, 137.4, 127.9,
126.4, 125.0, 124.4, 50.3, 45.5, 25.4, 20.6, 20.3, 16.3, -2.9; MS
(CI) m/z (rel intensity) 306 (MH+, 100); HRMS (EI) calcd for
C
18H31NOSi (M+) 305.2175, found 305.2172 (0.9 ppm).
Or th olith ia tion of Silyla ted Ben za m id e 5. sec-Butyl-
lithium (1.1 equiv) was added to a solution of benzamide 5 (1
equiv) in THF (0.03M) at -78 °C. The resulting orange solution
was then stirred at this temperature for 30 min, followed by
addition of the electrophile (1.5 equiv). The reaction was
allowed to warm to room temperature, poured into water, and
extracted into EtOAc. The combined extracts were dried
(magnesium sulfate) and concentrated under reduced pressure
to give the crude product, which was purified by column
chromatography to give 8a -e.
(S,Ra )-N,N-Diisop r op yl-2-(1-t r im et h ylsilylet h yl)-6-(1-
h yd r oxy-1-m eth yl)eth ylben za m id e 8a . By this method,
benzamide 5 (153 mg) and acetone gave an oil which was
(32) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

Atropisomeric Amides as Chiral Ligands
J . Org. Chem., Vol. 65, No. 21, 2000 7039
) 11.0 Hz), 133.8 (d, J ) 15.5 Hz), 133.3 (d, J ) 19.0 Hz),
133.2 (d, J ) 19.5 Hz), 130.6 (d, J ) 2.0 Hz), 128.3 (d, J ) 6.0
Hz), 128.1 (d, J ) 4.0 Hz), 128.0 (d, J ) 6.5 Hz), 127.7, 126.8,
50.3, 45.8, 25.3, 21.1, 20.8 (d, J ) 6.0 Hz), 20.4, 20.0 (d, J )
2.0 Hz), 16.1, -2.8; MS (CI) m/z (rel intensity) 490 (MH+, 100),
306 (35) 187 (70); HRMS (EI) calcd for C30H40NOPSi (M+)
1). Anal. Calcd for C16H25NO: C, 77.68; H, 10.19; N, 5.66.
Found: C, 77.76; H, 10.47; N, 5.72.
The 1H NMR spectrum of this material in the presence of
(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol (TFAE)22 showed an
Ar-Me signal originating from the minor enantiomer of
comparable size to the 13C-coupled side-peaks of the Ar-Me
signal of the major enantiomer, from which we deduce an ee
of >98%. Addition of (()-9b to the sample of (+)-9b proved
the identity of this minor peak.
489.2617, found 489.2622 (1.1 ppm); [R]23 -44.0 (CHCl3, c )
D
2.68). Anal. Calcd for C30H40NOPSi: C, 73.58; H, 8.23; N, 2.86;
P, 6.32. Found: C, 73.46; H, 8.29; N, 2.70; P, 6.32.
(Sa )-N,N-Diisop r op yl-2-et h yl-6-d ip h en ylp h osp h on yl-
ben za m id e 9c. Silylated benzamide 8c (170 mg) was treated
with TBAF according to the general procedure. Purification
of the crude product by column chromatography (eluting with
petrol/EtOAc 3:1 at ca. 0-5 °C) gave the title compound 9c
(144 mg, 99%), as a white foam: Rf(petrol/EtOAc) 0.40; IR
(S ,S a )-N ,N -Diisop r op yl-2-(1-t r im e t h ylsilyle t h yl)-6-
p h en ylsu lfa n ylben za m id e 8e. In the same way, benzamide
5 (76 mg) and diphenyl disulfide (55 mg, 1.5 equiv, as a
solution in 2 mL of THF) gave a waxy crude product that was
purified by column chromatography (eluting with petrol/EtOAc
19:1) to give the title compound 8e (90 mg, 87%) as a white
solid: mp 140-142 °C; Rf(petrol/EtOAc 19:1) 0.27; IR (film/
CHCl3) 2960, 1631, cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.10-
7.36 (6H, m), 7.00 (1H, dd, J ) 1, 8 Hz), 6.95 (1H, dd, J ) 1,
8 Hz), 3.72 (1H, sept, J ) 6.5 Hz), 3.51 (1H, sept, J ) 6.5 Hz),
2.21 (1H, q, J ) 7.5 Hz), 1.60 (3H, d, J ) 6.5 Hz), 1.57 (3H, d,
J ) 6.5 Hz), 1.35 (3H, d, J ) 7.5 Hz), 1.19 (3H, d, J ) 6.5 Hz),
1.13 (3H, d, J ) 6.5 Hz), 0.00 (9H, s); 1H NMR (CDCl3, 75 MHz)
δ 168.0, 143.9, 138.4, 136.1, 132.3, 131.0, 128.9, 128.2, 128.1,
126.8, 124.9, 50.4, 45.8, 25.6, 21.0, 20.8, 20.3, 20.1, 16.3, -2.8;
MS (CI) m/z 414 (MH+, 100); HRMS (EI) calcd for C24H35NOSSi
(M+) 413.2209, found 413.2223 (3.5 ppm); [R]23D -28.4 (CHCl3,
c ) 1). Anal. Calcd for C24H35NOSSi: C, 69.68; H, 8.53; N,
3.39; S, 7.75. Found: C, 69.65; H, 8.84; N, 3.43; S, 7.92.
Desilyla tion of Ben za m id es 8. TBAF (1 M solution in
THF, 10 equiv) was added to a solution of the silylated amide
8 in THF (0.02M) at room temperature. The resulting solution
was stirred for 5 min, then poured into cold water and
extracted into ether. The combined extracts were dried (Mg-
SO4) and concentrated under reduced pressure at <20 °C to
give the crude products, which were purified by column
chromatography (fractions kept at ca. 0-5 °C), to give the
desilylated products 9.
(film/CHCl3) 2975, 2929, 1630 cm-1 1H NMR (CDCl3, 300
;
MHz) δ 7.59-7.67 (4H, m), 7.38-7.55 (7H, m), 7.23 (1H, dt, J
) 3.0, 8.0 Hz), 7.00 (1H, ddd, J ) 1.0, 7.5, 13.5 Hz), 3.68 (1H,
sept, J ) 7.0 Hz), 3.50 (1H, sept, J ) 7.0 Hz), 2.80 (1H, dq, J
) 15, 7.5 Hz), 2.65 (1H, dq, J ) 15, 7.5 Hz), 1.55, (3H, d, J )
7.0 Hz), 1.51 (3H, d, J ) 7.0 Hz), 1.36 (3H, d, J ) 6.5 Hz),
1.25 (3H, t, J ) 7.5 Hz), 1.10 (3H, d, J ) 6.5 Hz); 13C NMR
(CDCl3, 75 MHz) δ 167.6 (d, J ) 3.5 Hz), 142.1 (d, J ) 8.0
Hz), 141.4 (d, J ) 10.0 Hz), 134.1 (d, J ) 103.0 Hz), 132.9 (d,
J ) 108.0 Hz), 132.2 (d, J ) 9.0 Hz), 131.9 (d, J ) 9.0 Hz),
131.8 (d, J ) 5.5 Hz), 131.5 (d, J ) 3.0 Hz), 131.5 (d, J ) 2.0
Hz), 131.0 (d, J ) 13.0 Hz), 128.3 (d, J ) 12.0 Hz), 128.1 (d, J
) 101.5 Hz), 128.1 (d, J ) 13.0 Hz), 126.9 (d, J ) 13.5 Hz),
51.0, 45.9, 25.1, 20.9, 20.3, 19.9, 19.7, 14.9; MS (EI) m/z (rel
intensity) 434 (MH+, 100), 333 (20) 100 (42); HRMS (EI) calcd
for C27H32NO2P (M+) 433.2171, found 433.2175 (1.0 ppm);
23
[R]D +18.0 (CHCl3, c ) 1.6). Anal. Calcd for C27H32NO2P: C,
74.80; H, 7.44; N, 3.23; P, 7.14. Found: C, 74.56; H, 7.61; N,
3.05; P, 6.83.
(Sa )-N,N-Diisop r op yl-2-et h yl-6-d ip h en ylp h osp h in yl-
ben za m id e 9d . Silylated benzamide 8d (112 mg) was treated
with TBAF according to the general procedure. Purification
of the crude product by column chromatography (eluting with
petrol/EtOAc 9:1 at ca. 0-5 °C) gave the title compound 9d
(82 mg, 86%) as white solid: mp 129-130 °C; Rf(petrol/EtOAc
(Sa )-N,N-Diisop r op yl-2-et h yl-6-(1-h yd r oxy-1-m et h yl)-
eth ylben za m id e 9a . Silylated benzamide 8a (35 mg) was
treated with TBAF according to the general procedure. Puri-
fication of the crude product by column chromatography
(eluting with petrol/EtOAc 9:1 at ca. 0-5 °C) gave the title
compound 9a (28 mg, 99%) as a white solid: mp 96-98 °C;
Rf(petrol/EtOAc 4:1) 0.17; IR (film/CHCl3) 3415, 2975, 2932,
1
4:1) 0.46; IR (film/CHCl3) 2969, 1628 cm-1; H NMR (CDCl3,
300 MHz) δ 7.22-7.38 (12H, m), 7.05 (1 H, ddd, J ) 1, 3.5,
7.5 Hz), 3.80 (1H, sept, J ) 6.5 Hz), 3.59 (1H, sept, J ) 6.5
Hz), 2.81 (1H, dq, J ) 15, 7.5 Hz), 2.67 (1H, dq, J ) 15, 7.5
Hz), 1.70 (3H, d, J ) 6.5 Hz), 1.63 (3H, d, J ) 6.5 Hz), 1.32
(3H, d, J ) 7.5 Hz), 1.24 (3H, d, J ) 6.5 Hz), 1.18 (3H, d, J )
6.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 168.9 (d, J ) 5.0 Hz),
144.5 (d, J ) 36.5 Hz), 139.6 (d, J ) 8.5 Hz), 138.1 (d, J )
11.5 Hz), 137.0 (d, J ) 11.5 Hz), 133.6 (d, J ) 15.5 Hz), 133.4
(d, J ) 19.5 Hz), 133.1 (d, J ) 19.0 Hz), 132.1 (d, J ) 2.5 Hz),
129.0, 128.3, 128.3 (d, J ) 5.5 Hz), 128.2 (d, J ) 7.5 Hz), 128.0,
127.8, 21.0, 20.8 (d, J ) 6.0 Hz), 20.5, 20.1 (d, J ) 2.0 Hz),
14.7; MS (EI) m/z (rel intensity) 418 (MH+, 10 - self-CI), 417
(M+, 8), 374 (50), 332 (100); HRMS (EI) calcd for C27H32NOP
1
2874, 1609 cm-1; H NMR (CDCl3, 300 MHz) δ 7.22 (1H, t, J
) 8 Hz), 7.12 (1H, d, J ) 7 Hz), 7.07 (1H, d, J ) 8 Hz), 3.61
(1H, sept, J ) 7.5 Hz), 3.50 (1H, sept, J ) 6.5 Hz), 2.85 (1H,
br s), 2.75 (1H, dq, J ) 15, 7.5 Hz), 2.58 (1H, dq, J ) 15, 7.5
Hz), 1.60 (3H, s), 1.57 (3H, s), 1.57 (3H, d, J ) 6.5 Hz), 1.56
(3H, d, J ) 6.5 Hz), 1.22 (3H, t, J ) 7.5 Hz), 1.16 (3H, d, J )
6.5 Hz), 1.09 (3H, d, J ) 6.5 Hz); 13C NMR (CDCl3, 75 MHz)
δ 173.0, 145.4, 140.1, 133.5, 127.6, 126.4, 124.7, 74.5, 50.9, 45.7,
34.7, 31.2, 25.3, 20.2, 20.1, 19.5, 15.3; MS (CI) m/z (rel
intensity) 292 (MH+, 100), 274 (20); HRMS (CI) calcd for
(M+) 417.2221, found 417.2218 (0.7 ppm); [R]D -4.0 (CHCl3,
23
C18H30NO2 (MH+) 292.2276, found 292.2274 (0.6 ppm); [R]D
23
c ) 1). Anal. Calcd for C27H32NOP: C, 77.67; H, 7.72; N, 3.35;
P, 7.42. Found: C, 77.38; H, 8.05; N, 3.31; P, 7.35.
+32.0 (CHCl3, c ) 1). Anal. Calcd for C18H30NO2: C, 74.18; H,
10.03; N, 4.81. Found: C, 73.83; H, 10.24; N, 4.72.
(Sa )-N,N-Diisop r op yl-2-et h yl-6-p h en ylsu lfa n ylb en za -
m id e 9e. Silylated benzamide 8e (47 mg) was treated with
TBAF according to the general procedure. Purification of the
crude product by column chromatography (eluting with petrol/
EtOAc 9:1 at ca. 0-5 °C) gave the title compound 9e (42 mg,
quantitative) as a white solid: mp 94-95 °C; Rf(petrol/EtOAc
(Ra )-N,N-Diisop r op yl-2-eth yl-6-m eth ylben za m id e 9b.
Silylated benzamide 8b (150 mg) was treated with TBAF
according to the general procedure. Purification of the crude
product by column chromatography (eluting with petrol/EtOAc
9:1 at ca. 0-5 °C) gave the title compound 9b (115 mg, 99%)
as white solid: mp 102-103 °C; Rf(petrol/EtOAc 9:1) 0.49; IR
1
4:1) 0.45; IR (film/CHCl3) 2971, 1630 cm-1; H NMR (CDCl3,
(film/CHCl3) 2629, 2933, 2876, 1621 cm-1 1H NMR (CDCl3,
;
300 MHz) δ 7.51-7.54 (2H, m), 7.37-7.46 (3H, m), 7.27-7.29
(2H, m), 7.14-7.17 (1H, m), 3.83 (1H, sept, J ) 6.5 Hz), 3.67
(1H, sept, J ) 7 Hz), 2.87 (1H, dq, J ) 15, 7.5 Hz), 2.71 (1H,
dq, J ) 15, 7.5 Hz), 1.75 (6H, t, J ) 7 Hz), 1.41 (3H, t, J ) 7.5
Hz), 1.36 (3H, d, J ) 6.5 Hz), 1.25 (3H, d, J ) 6.5 Hz); 13C
NMR (CDCl3, 75 MHz) δ 168.0 (DEPT: quat), 140.6 (quat),
139.3 (quat), 135.5 (quat), 132.3 (quat), 131.5 (CH), 129.2 (CH),
129.0 (CH), 128.3 (CH), 127.0 (CH), 126.7 (CH), 50.9 (CH), 45.9
(CH), 25.6 (CH2), 21.0 (CH3), 20.9 (CH3), 20.5 (CH3), 20.1 (CH3),
14.8 (CH3); MS (CI) m/z (rel intensity) 342 (MH+, 100); HRMS
(EI) calcd for C21H27NOS (M+) 341.1813, found 341.1816 (0.8
300 MHz) δ 7.08 (1H, t, J ) 7.5 Hz), 6.99 (1H, d, J ) 7.5 Hz),
6.93 (1H, d, J ) 7.5 Hz), 3.52 (1H, sept, J ) 6.5 Hz), 3.43 (1H,
sept, J ) 6.5 Hz), 2.57 (1H, dq, J ) 15, 7.5 Hz), 2.46 (1H, dq,
J ) 15, 7.5 Hz), 2.21 (3H, s), 1.52 (3H, d, J ) 6.5 Hz), 1.16
(3H, t, J ) 7.5 Hz), 1.03 (3H, d, J ) 6.5 Hz), 1.01 (3H, d, J )
6.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 170.0, 139.4, 137.5, 133.1,
127.6, 127.5, 125.3, 50.6, 45.7, 25.7, 21.0, 20.4, 20.4, 19.0, 15.1;
MS (EI) m/z (rel intensity) 247 (M+, 10), 232 (15), 218 (15),
204 (10), 147 (100); HRMS (EI) calcd for C16H25NO (M+)
247.1936, found 247.1929 (2.8 ppm); [R]23 +3.2 (CHCl3, c )
D

7040 J . Org. Chem., Vol. 65, No. 21, 2000
Clayden et al.
ppm); [R]D23 -29.2 (CHCl3, c ) 1). Anal. Calcd for C21H27NOS:
C, 73.86; H, 7.97; N, 4.10. Found: C, 73.66; H, 8.11; N, 4.14.
Ra tes of Ra cem iza tion of 9. The barriers to rotation of
the amide axis in compounds 9a -e were established by
racemization studies at constant temperature. These studies
were carried out by monitoring the optical rotations of solu-
tions of the amides (in chloroform or dioxane, using a mercury
source at 578 nm) in a jacketed cell. The cell was kept at
constant temperature by pumping water from a thermostati-
cally controlled heating bath through the cell jacket. Observa-
tion of the optical rotation (R) over regular time intervals gave
a smooth first-order decay curve from which the rate constant
for racemization (k) was calculated using the curve-fitting
application “Ultrafit” for the Macintosh.
solid, with data matching that described in the literature35 and
enantiomeric excess of 90% (by HPLC on chiral stationary
phase: Regis Whelk-O1 column 4.6 × 250 mm, eluting with
20% IPA in hexane, flow rate 1 mL/min, retention times 10.1
and 11.06 min): mp 95-96 °C; IR (CHCl3)/cm-1 3028, 2952,
1757, 1738;1H NMR (CDCl3, 300 MHz) δ 7.14-7.31 (10H, m),
6.45 (1H, d, 15.5 Hz), 6.29 (1H, dd, 8.5, 15.5 Hz), 4.23 (1H, dd,
J ) 8.5, 11.0 Hz), 3.92 (1H, d, J ) 11.0 Hz), 3.67 (3H, s), 3.48
(3H, s); 13C NMR (CDCl3, 75 MHz) δ 168.1, 167.7, 140.1, 136.8,
131.8, 129.1, 128.7, 128.4, 127.8, 127.5, 127.1, 126.4, 57.6, 52.5,
52.4, 49.1; [R]23 -16.9 (CHCl3, c ) 1).
D
Ack n ow led gm en t. We are grateful for grants from
the EPSRC and from the Leverhulme Trust.
Asym m etr ic Allylic Su bstitu tion Rea ction s.33,34 Potas-
sium acetate (1 mg), N,O-bistrimethylsilyl acetamide (BSA,
609 mg, 3 equiv), dimethyl malonate (396 mg, 3 equiv), and
acetate 10 (252 mg, 1 equiv) were added to a solution of
allylpalladium dichloride dimer (1.8 mg, 1 mol % Pd) and
phosphine 8d (2.5 mg, 0.5 mol %) in dichloromethane (2 mL)
under nitrogen. The mixture was stirred at room temperature
for 36 h, poured into water, extracted into dichloromethane,
dried over magnesium sulfate, and concentrated under reduced
pressure to give the crude product oil. The crude product was
purified by column chromatography (eluting with petrol/EtOAc
9:1) to give the substitution product (-)-12 as a crystalline
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 8a -e and 9a -e. X-ray crystal data for
1
(-)-5 and 8d . H NMR spectrum of (+)-9b in the presence of
(+)-TFAE. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0007074
(35) Breeden, S.; Wills, M. J . Org. Chem. 1999, 64, 9735.
(36) Higher selectivity may be obtained because the 10:1 ratio of
conformers may improve at -78 °C or in THF (though NMR experi-
ments at -30 °C showed conformational ratios similar to those at +25
°C) or because of epimerization of the thermodynamically less stable
isomer during the reaction workup. The yield of diastereoisomerically
pure 8b suggests that at least in this case this second mechanism is
operating.
(33) von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32,
566.
(34) Leutenegger, U.; Umbricht, G.; Fahrni, C.; von Matt, P.; Pfaltz,
A. Tetrahedron 1992, 48, 2143.