A chiral axis due to an acyclic imide-Ar bond: A study of steric effects of acyl groups on racemization

Article abstract of DOI:10.1016/S0040-4020(00)00852-8

Studies on the racemization in a series of optically active compounds 3a-e, including the steric effect of their acyl groups, are described. The first example of optically active compounds 3c and 3d, which possess axial chirality based on an acyclic imide-Ar bond, has been reported. A quite interesting result has been revealed, namely, that 3a bearing a bulky acyl group rather than a relatively small one racemized more easily. To explain this observed phenomenon, ¹³C NMR experiments and the reaction with benzylamine of 3a-e were undertaken. These results suggested that the t-BuCO-N bond in 3a which racemized easily, is more twisted, compared with the RCO-N bonds in 3b-e which are relatively stable to racemization. Furthermore, the absolute configuration of 3b and 3c has been determined to be R by the CD spectrum and the X-ray crystallographic analysis of racemic 3f has been accomplished. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00852-8

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8883±8891
A Chiral Axis due to an Acyclic Imide±Ar Bond: a Study of Steric
Effects of Acyl Groups on Racemization
Kazuhiro Kondo,a Takeko Iida,a Hiroko Fujita,a Tomoko Suzuki,a Kentaro Yamaguchib
and Yasuoki Murakamia,
*
aSchool of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
bChemical Analysis Center, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 14 August 2000; accepted 20 September 2000
AbstractÐStudies on the racemization in a series of optically active compounds 3a±e, including the steric effect of their acyl groups, are
described. The ®rst example of optically active compounds 3c and 3d, which possess axial chirality based on an acyclic imide±Ar bond, has
been reported. A quite interesting result has been revealed, namely, that 3a bearing a bulky acyl group rather than a relatively small one
racemized more easily. To explain this observed phenomenon, 13C NMR experiments and the reaction with benzylamine of 3a±e were
undertaken. These results suggested that the t-BuCO±N bond in 3a which racemized easily, is more twisted, compared with the RCO±N
bonds in 3b±e which are relatively stable to racemization. Furthermore, the absolute con®guration of 3b and 3c has been determined to be R
by the CD spectrum and the X-ray crystallographic analysis of racemic 3f has been accomplished. q 2000 Published by Elsevier Science
Ltd.
Introduction
Results and Discussion
Optically active biaryl compounds such as binaphthyl and
biphenyl derivatives, due to the rotational barrier about the
Caryl±Caryl bond, have been well known,1 but optically active
compounds which possess axial chirality based on the N±C
bond, have received little attention.2 After a pioneering
report by Curran in 1994,3 several examples of optically
active N±Ar axially chiral cyclic imides and amides, have
been reported.4,5 However, to the best of our knowledge, no
optically active compound has been reported that possesses
axial chirality based on an acyclic imide N±Ar bond. In the
course of our study on the reactivity6 of the imide in N-acyl-
N-arylacetamides, we became very interested in the imide
N±Ar axial chirality of these compounds.7,8 In this paper,
we would like to report the ®rst example of optically active
compounds 3c and 3d which possess axial chirality based on
the acyclic imide N±Ar bond.7 A quite interesting result is
also described, namely, that 3a bearing a bulky acyl group
rather than a relatively small one racemized more easily.
Furthermore, the absolute con®guration of optically active
compounds 3b and 3c has been determined by the CD spec-
trum, and the X-ray crystallographic analysis of racemic 3f,
whose conformation should be similar to that of 3e, has been
accomplished.
The imide group and the phenyl ring in 1 are not coplanar in
the ground state, but instead twist in order to relieve
unfavorable steric interactions between the ortho-hydrogen
on the phenyl ring and the imide group.9 Replacing one
ortho-hydrogen with a bulky group (from 1 to 2) increases
both the imide N±Ar torsion angle and the barrier to rotation
through planarity. On the basis of the foregoing concept, we
planned to search for an optically active N±Ar axially chiral
compound. We chose compound 3 bearing one large
(t-butyl) and one small (H) ortho substituents on the phenyl
ring as the candidates, which might retain suf®cient
rotational barriers to be stable to racemization at room
temperature.
Optically active compounds 3a±e were given through the
optical resolution of racemic 3a±e, which were prepared by
acylation of N-(2-tert-butylphenyl)acetamide, by HPLC
using chiral phase column (DAICEL CHIRALCEL OD,
eluent: hexane/isopropanol). At ®rst, the stability to racemi-
zation in benzene was investigated with optically active
compounds 3a, 3b and 3d.10,11 The results are shown in
Keywords: N±C axial chirality; atropisomer; acyclic imide; twist; steric
effect.
* Corresponding author. Tel.: 181-47-472-1585; fax: 181-47-472-1595;
e-mail: murakami@phar.toho-u.ac.jp
0040±4020/00/$ - see front matter q 2000 Published by Elsevier Science Ltd.
PII: S0040-4020(00)00852-8

8884
K. Kondo et al. / Tetrahedron 56 (2000) 8883±8891
Table 1. Initial study of the stability to racemization with optically active
3a, 3b, and 3d (all reactions were carried out in benzene at 258C)
Entry
Compound
Results
1
2
3
3a
3b
3d
0 h, 64% ee; within 30 min, 0% ee
0 h, 91% ee; after 3 days, 89% ee
0 h, .99% ee; after 3 days, .99% ee
Figure 1.
Table 1. Surprisingly, optically active compound 3a bearing
a bulky t-BuCO group racemized rapidly at 258C within
30 min, affording the racemate (entry 1). Slight racemi-
zation of 3b bearing a sterically medium-sized i-PrCO
group was observed at 258C (entry 2). On the other hand,
no loss of the optical purity of 3d bearing a sterically small
EtCO group, was observed at 258C, even after 3 days (entry
3). As an initial result, it was found that 3 bearing a smaller
acyl group was more stable to racemization.
us to investigate the relationship between the imide struc-
ture in the ground state and the stability to racemization of
3a±e.
The assignments of absolute con®gurations of optically
active compounds 3b and 3c were achieved by comparison
with the CD spectrum of 4 of known con®guration,4c though
the absolute con®guration of 3d and 3e could not be deter-
mined by the CD spectrum. The representative CD spectra
of the enantiomers, 3c and 4, are shown in Fig. 2. As a result,
the absolute con®gurations of (2)-3b and (2)-3c with nega-
tive values of the speci®c rotation were determined to be R
as shown in Fig. 3.
With the intention of gaining further insight into the steric
effects of acyl groups on racemization, we planned to obtain
the kinetic parameters of racemization for 3c and 3e bearing
i-BuCO and PhCO groups, in addition to 3a, 3b and 3d
bearing t-BuCO, i-PrCO and EtCO groups as shown in
Table 2. Heating optically active compounds 3b±e in ben-
zene at four different temperatures and measurement of the
rate constants for their racemization at each temperature,
gave transition-state functions,12 though, unfortunately, the
racemization of 3a was too rapid at 258C for the exact rate
constant to be determined. The free energies of activation
³
In order to obtain structural information on the imide
moieties of 3a±e in the ground state, we undertook a series
of 13C NMR experiments as shown in Table 3.13 The data of
the acyl carbonyl signals14 of 3a±e were corrected by
subtracting those of the corresponding planar N,N-dimethyl
carboxyamides 5a±f, to cancel out the substituent effect on
the carbonyl group, and the differences were indicated as
Dd13C. From these results, it is clear that the Dd13C value of
t-butylcarbonyl carbon of 3a is much larger than those of the
acetyl carbonyl carbon in 3a and the other acyl carbonyl
ones of 3b±e. The large difference can be explained as
due to the reduction of amide resonance throughout the
RCO±N bond rotation. Accordingly, the t-BuCO±N bond
in 3a is more twisted than the MeCO±N bond in 3a and the
other RCO±N bonds in 3b±e.
(DG ) at 278C for racemization of 3b, 3c, 3d and 3e were
27.0, 30.5, 28.6 and 26.3 kcal/mol, respectively. These
³
values in the DG were found to be affected by the steric
effect of their acyl groups. Accordingly, 3b (Rˆi-Pr) and 3e
(RˆPh) bearing relatively large acyl groups rather than a
small one (Rˆi-Bu or Et), racemized more easily. To the
best of our knowledge, the relatively stable compounds 3c
and 3d are the ®rst example of optically active compounds
which possess axial chirality based on the acyclic imide
³
N±Ar bond. The enthalpies of activation (DH ) for racemi-
zation of 3b, 3c, 3d and 3e were 22.7^1.4, 27.8^0.6,
28.1^0.4 and 25.1^0.2 kcal/mol, respectively. These
differences in the DH would be mainly due to the destabi-
³
lization in the ground state. Accordingly, a repulsion
between the acetyl CvO and the acyl R group in 3 (Fig.
1), might cause their destabilization. The entropies of acti-
³
vation (DS ) for racemization of 3b, 3c, 3d and 3e were
213.3^4.5, 28.98^1.92, 21.44^1.27 and 24.05^0.71,
respectively. The nearly zero value in the entropy of acti-
vation for 3d is interesting. The DS of 3d would suggest
³
that its racemization occurs with retention of the imide
geometry in the ground state. These steric effects prompted
Table 2. Transition-state functions of 3b±e (all reactions were carried out in benzene)
³
DG at 278C (kcal/mol)
Entry
Compound
DH³a (kcal/mol)
DS³a (cal/K´mol)
b
b
b
1
2
3
4
5
3a
3b
3c
3d
3e
±
±
±
22.7^1.4
27.8^0.6
28.1^0.4
25.1^0.2
213.3^4.5
28.94^1.92
21.44^1.27
24.05^0.71
27.0
30.5
28.6
26.3
a The transition-state functions were calculated according to Eyring's equation.
b The racemization of 3a was too rapid at 258C for the exact rate constant to be determined.

K. Kondo et al. / Tetrahedron 56 (2000) 8883±8891
8885
Figure 2. The representative CD spectra of 3c and 4 in CH3CN.
ones.15 The twisted t-BuCO±N bond in 3a is expected to be
readily attacked by 6, whereas the MeCO±N bond in 3a and
the other RCO±N bonds in 3b±e are not. The results are
shown in Table 4. As can be seen, only the t-BuCO±N bond
in 3a was readily reacted with 6 to give 7 chemoselectively
(entry 1). On the contrary, the reactivity of the RCO±N
bonds in 3b±d was quite low (entries 2±4), and acetamide
8 was formed selectively. The reaction of 3e required a
prolonged period (10 h, entry 5): the reactivity of this aryl
group might be somewhat different from those of the alkyl
acyl groups. Again, these results support that the t-BuCO±N
bond in 3a is relatively more twisted than the MeCO±N
bond in 3a and the other RCO±N bonds in 3b±e. It is
noteworthy that the t-BuCO±N bond in 3a, which
racemized easily, is more twisted, compared with the
RCO±N bonds in 3b±e which were relatively stable to
racemization.
Figure 3.
In order to verify the large twist of the t-BuCO±N bond in
3a, we chose to investigate the reactivity of 3a±e with
benzylamine (6). It has been known that twisted amide
groups are more reactive to a nucleophile than the planar
Table 3. 13C NMR chemical shifts (d, ppm) of acyl carbonyl in 3a±e
(recorded at 100 MHz in C6D6)
Entry Compound
d
13C
Dd 13C
The X-ray crystallographic analysis of racemic 3f was
accomplished, though our attempt for 3a±e proved to be
unsuccessful. The ORTEP drawing of racemic 3f is shown
in Fig. 4.16 The 2-tert-butylphenyl group and the imide
plane were approximately orthogonal. The imide geometry
was the exo±endo arrangement17 with acetyl carbonyl trans
and benzoyl carbonyl cis to the 2-t-butylphenyl group. The
nature of imide nitrogen can be represented in terms of two
angle parameters, the summation of the three valence angles
around the nitrogen u, and the twist angle18 t of the amide
bond calculated by the average of v1 (C3C2NC5) and v2
(O2C2NC1), its range19 being between 0 and 908 (the highest
RCO
CH3CO
RCO CH3CO
1
2
3
4
5
3a
3b
3c
3d
3e
184.6 (176.4)a 173.2 (169.2)f
180.2 (175.9)b 173.2 (169.2)f
174.6 (170.7)c 172.4 (169.2)f
176.4 (172.4)d 172.8 (169.2)f
173.1 (170.8)e 173.3 (169.2)f
8.2
4.3
3.9
4.0
2.3
4.0
4.0
3.2
3.6
4.1
a The data of 5a.
b The data of 5b.
c The data of 5c.
d The data of 5d.
e The data of 5e.
f The data of 5f.
Table 4. Reaction of 3a±e with benzylamine (6)
Entry
Compound
Time (h)
Yield (%) of 7
Yield (%) of 8
1
2
3
4
5
3a
3b
3c
3d
3e
3.5
7.5a
7.5a
7.5a
10
72
0
0
3
80
0
8
5
8
0
a The quite slow reaction was observed.

8886
K. Kondo et al. / Tetrahedron 56 (2000) 8883±8891
compounds 3c and 3d, which possess axial chirality based
on an acyclic imide N±Ar bond.21 Furthermore, a quite
interesting result has also been found, namely, that 3a
bearing a bulky acyl group rather than a small one race-
mized more easily. Since the large rotation barrier around
the N±Ar bond of imide compounds has been utilized for
stereoselective synthesis3,4 and molecular recognition,22 our
novel ®ndings would be utilized for their further develop-
ment.
Experimental
All melting points (mp) were determined on a Yanagimoto
melting point apparatus and are uncorrected. IR spectra
were measured on a JASCO FT/IR-230 diffraction grating
IR spectrophotometer. 1H and 13C NMR spectra were
measured on a JEOL AL-400 or JEOL EX-400 NMR spec-
trometer, operating at 400 MHz for 1H NMR and at
100 MHz at 13C NMR. H and 13C NMR spectra were
1
Figure 4. The ORTEP drawing of (^)-3f.
reported in d units, parts per million (ppm) down®eld
from tetramethylsilane (dˆ0). Electron impact (EI) MS
spectra were measured on a JEOL JMS-DX-303 instrument.
Speci®c rotations (in deg cm3 g21 L21) were determined on
a JASCO DIP-1000 digital polarimeter. UV spectra were
measured on a Shimadzu UV-265 instrument. Circular
dichroisms (CD) were measured on a JASCO J-720W spec-
tropolarimeter. The enantiomeric excess was determined by
HPLC analysis.
t value2c reported for imide is 83.28). The parameter of
racemic 3f is shown in Table 5. The essentially sp2 nature
of the imide nitrogen was con®rmed: uˆ359.88 (the angle u
of the ideal sp2 planar nitrogen atom is 3608). The twist
angle t of 3f was 18.58, which was a small value compared
with the highest t value 83.28 reported for imide.2c
The racemization of 3 should occur when this N±Ar bond
rotates across the ortho substituent (3-A or 3-B, Fig. 5).
Taking all the experimental results into consideration, one
possible reason for the facile racemization of 3a bearing a
t-BuCO group would be as follows. Due to the largely
twisted t-BuCO±N bond in 3a, 3a is strongly destabilized
in the ground state, compared with 3b±e which were
slightly twisted.20 Therefore, the activation energy of 3a
for racemization is smaller than those of 3b±e, facilitating
the racemization of 3a.
2-tert-Butylaniline, and authentic samples of N,N-Dimethyl-
isobutyramide (5b), N,N-dimethylpropionamide (5d) and
N,N-dimethylacetamide (5f) were commercially available.
All reagents were available from commercial sources and
used without further puri®cation unless otherwise stated. In
general, all reactions were carried out in dry solvents under
an argon atmosphere. All racemization experiments were
performed on Taitec Thermo Minder SM-05 or Toyo Lab
Thermo LH-1000. Pyridine was distilled under an argon
atmosphere from CaH2. Benzene was distilled under an
argon atmosphere from Na. Benzylamine (6) was distilled
under an argon atmosphere from Zn powder. Silica gel
column chromatography was performed on Kanto Chemical
Silica gel 60 (spherical, 100±210 mm).
Conclusion
We have demonstrated the ®rst example of optically active
Table 5. Angle around N, twist angle of aryl bond and selected bond lengths of 3f
1
C ±N (A)
1
C vO (A)
1
2
C ±N (A)
2
2
C ±O (A)
Twist anglea t of aryl bond (8)
Ê
Ê
Ê
Ê
Angle around N u (8)
359.8
18.5
1.432 (10)b
1.199 (9)b
1.374 (10)b
1.213 (9)b
a The twist angle t was calculated by the average of v1 (C3C2NC5) and v2 (O2C2NC1).
b Standard deviations are shown in parentheses.
Figure 5.

K. Kondo et al. / Tetrahedron 56 (2000) 8883±8891
8887
Syntheses of (^)-3a±f
(ddd, Jˆ7.7, 7.7, 1.5 Hz, 1H), 7.04 (ddd, Jˆ7.7, 7.7, 1.5 Hz,
1H), 7.29 (dd, Jˆ7.7, 1.5 Hz, 1H). 13C NMR (C6D6):
dˆ19.29, 19.84, 27.54, 31.93, 35.46, 36.14, 127.1, 128.9,
129.7, 132.1, 138.0, 147.1, 173.2 (CvO of acetyl group),
180.2 (CvO of isobutyryl group). EI-MS: m/zˆ261 (M1),
191, 176, 158, 134, 106, 83, 57, 43 (bp). Anal. Calcd for
C16H23NO2: C, 73.53; H, 8.87; N, 5.36. Found: C, 73.57; H,
9.06; N, 5.43.
N-(2-tert-Butylphenyl)acetamide. To a stirred solution of
2-tert-butylaniline (3.10 mL, 19.9 mmol) in pyridine
(58.0 mL) was gradually added acetic anhydride (3.80 mL,
40.0 mmol) at 08C. The reaction mixture was stirred at 258C
for 15 h, cooled to 08C, quenched by the addition of 10%
aqueous HCl at the same temperature, and extracted with
EtOAc. The combined organic extracts were washed with
saturated aqueous NaHCO3 and brine, dried over Na2SO4
and concentrated using a rotary evaporator to afford the
crude product. Puri®cation by recrystallization (benzene±
hexane) afforded the analytically pure N-(2-tert-butyl-
phenyl)acetamide (3.66 g, 96%) as colorless needles of
mp 158±158.58C. Rf valueˆ0.51 (hexane±EtOAcˆ2:1).
IR (KBr): nˆ3240, 1642 cm21. UV (CH3CN): lmax 225.7
(RS)-N-(2-tert-Butylphenyl)-N-isovalerylacetamide [(^)-
3c]. To a stirred solution of isovaleric acid (0.64 mL,
5.87 mmol) in CH2Cl2 (3.70 mL) were added CCl4
(5.80 mL, 60.1 mmol) and PPh3 (4.62 g, 17.6 mmol) at
08C. The reaction mixture was stirred at 258C for 2.5 h,
cooled to 08C and then, to this mixture were added pyridine
(19.6 mL) and N-(2-tert-butylphenyl)acetamide (1.12 g,
5.86 mmol) at the same temperature. The whole mixture
was stirred at 258C for 1 h, cooled to 08C, quenched by
the addition of H2O at the same temperature and extracted
with EtOAc. The combined organic extracts were washed
with brine, dried over Na2SO4 and concentrated using a
rotary evaporator to afford the crude product. Puri®cation
by chromatography on silica gel (hexane±EtOAcˆ5:1, the
silica gel was pretreated with 1% Et3N in hexane) afforded
the analytically pure (^)-3c (364 mg, 23%) as a clear color-
less oil accompanied with N-(2-tert-butylphenyl)acetamide
(168 mg, 15%). Rf valueˆ0.40 (hexane±EtOAcˆ3:1). IR
(nujol): nˆ1710 cm21. UV (CH3CN): lmax 270.1 (803.0),
1
(4170) nm. H NMR (CDCl3): dˆ1.41 (s, 9H), 1.89 (s,
3H£1/3), 2.21 (s, 3H£2/3), 7.00±7.29 (m, 3H), 7.36±7.56
(m, 2H), 7.66 (br s, 1H). EI-MS: m/zˆ191 (M1), 176, 149,
134 (bp). Anal. Calcd for C12H17NO: C, 75.35; H, 8.96; N,
7.32. Found: C, 75.55; H, 8.74; N, 7.21.
(RS)-N-(2-tert-Butylphenyl)-N-pivaloylacetamide [(^)-
3a]. To a stirred solution of N-(2-tert-butylphenyl)aceta-
mide (100 mg, 0.523 mmol) in pyridine (1.10 mL) was
gradually added pivaloyl chloride (0.06 mL, 0.487 mmol)
at 08C. The mixture was stirred at 258C for 3 h, cooled to
08C, quenched by the addition of H2O and extracted with
EtOAc. The combined organic extracts were washed with
brine, dried over Na2SO4 and concentrated using a rotary
evaporator to afford the crude product. Puri®cation by
chromatography on silica gel (hexane±EtOAcˆ45:1, the
silica gel was pretreated with 2% Et3N in hexane) afforded
the analytically pure (^)-3a (105 mg, 73%) as a clear color-
less oil. Rf valueˆ0.58 (hexane:EtOAcˆ4:1). IR (KBr):
1
257.6 (1226) nm. H NMR (C6D6): dˆ0.85 (d, Jˆ6.6 Hz,
3H), 0.90 (d, Jˆ6.6 Hz, 3H), 1.23 (s, 9H), 2.16 (s, 3H),
2.30±2.49 (m, 3H), 6.58 (dd, Jˆ7.8, 1.5 Hz, 1H), 6.91
(ddd, Jˆ7.8, 7.8, 1.5 Hz, 1H), 7.03 (ddd, Jˆ7.8, 7.8,
1.5 Hz, 1H), 7.29 (dd, Jˆ7.8,1.5 Hz, 1H). 13C NMR
(C6D6): dˆ22.59, 22.65, 25.02, 27.51, 31.83, 36.02,
47.84, 126.9, 128.5, 129.5, 131.9, 137.4, 146.5, 172.4
(CvO of acetyl group), 174.6 (CvO of isovaleryl group).
EI-MS: m/zˆ275 (M1), 218, 191, 173, 158, 132, 106 (bp).
Anal. Calcd for C17H25NO2: C, 74.14; H, 9.15; N, 5.09.
Found: C, 74.16; H, 9.28; N, 5.06.
1
nˆ1708, 1696 cm21. H NMR (C6D6): dˆ1.28 (s, 9H),
1.41 (s, 9H), 1.71 (s, 3H), 6.68 (dd, Jˆ8.7, 1.7 Hz, 1H),
6.86 (ddd, Jˆ8.7, 8.7, 1.7 Hz, 1H), 7.00 (ddd, Jˆ8.7, 8.7,
1.7 Hz, 1H), 7.27 (dd, Jˆ8.7, 1.7 Hz, 1H). 13C NMR (C6D6):
dˆ26.06, 28.29, 31.91, 36.28, 43.95, 126.4, 128.6, 129.9,
132.1, 138.9, 147.6, 173.2 (CvO of acetyl group), 184.6
(CvO of pivaloyl group). EI-MS: m/zˆ275 (M1), 191, 176,
158, 134, 106, 83, 57 (bp). Anal. Calcd for C17H25NO2: C,
74.14; H, 9.15; N, 5.09. Found: C, 74.19; H, 8.96; N, 5.03.
(RS)-N-(2-tert-Butylphenyl)-N-propionylacetamide
[(^)-3d]. To a stirred solution of N-(2-tert-butylphenyl)-
acetamide (413 mg, 2.16 mmol) in THF (3.0 mL) was
gradually added BuLi (1.53 M in hexane, 2.10 mL,
3.21 mmol) at 08C. The mixture was stirred at 258C for
1.5 h, cooled to 08C, and then to this mixture was added
(EtCO)2O (1.10 mL, 8.58 mmol) at the same temperature.
The whole mixture was stirred at 258C for 26 h, cooled to
08C, quenched by the addition of H2O at the same tempera-
ture and extracted with EtOAc. The combined organic
extracts were washed with saturated aqueous NaHCO3 and
brine, dried over Na2SO4 and concentrated using a rotary
evaporator to afford the crude product. Puri®cation by
chromatography on silica gel (hexane±EtOAcˆ20:1, the
silica gel was pretreated with 3% Et3N in hexane) afforded
the analytically pure (^)-3d (315 mg, 59%) as a clear pale
yellow oil. Rf valueˆ0.43 (hexane±EtOAcˆ4:1). IR (KBr):
nˆ1709 cm21. 1H NMR (C6D6): dˆ1.02 (t, Jˆ7.3 Hz, 3H),
1.19 (s, 9H), 2.20 (s, 3H), 2.34 (q, Jˆ7.3 Hz, 2H), 6.53 (dd,
Jˆ8.0, 1.5 Hz, 1H), 6.91 (ddd, Jˆ8.0, 8.0, 1.5 Hz, 1H), 7.04
(ddd, Jˆ8.0, 8.0, 1.5 Hz, 1H), 7.28 (dd, Jˆ8.0, 1.5 Hz, 1H).
13C NMR (C6D6): dˆ8.94, 27.54, 31.77, 32.72, 36.03,
127.2, 128.9, 129.7, 132.2, 137.8, 146.7, 172.8 (CvO of
(RS)-N-(2-tert-Butylphenyl)-N-isobutyrylacetamide
[(^)-3b]. To a stirred solution of N-(2-tert-butylphenyl)-
acetamide (608 mg, 3.18 mmol) in pyridine (9.50 mL) was
gradually added isobutyryl chloride (0.68 mL, 6.49 mmol)
at 08C. The reaction mixture was stirred at 258C for 1 h,
cooled to 08C, quenched by the addition of H2O at the
same temperature and extracted with EtOAc. The combined
organic extracts were washed with brine, dried over Na2SO4
and concentrated using a rotary evaporator to afford the
crude product. Puri®cation by chromatography on silica
gel (hexane±EtOAcˆ10:1, the silica gel was pretreated
with 3% Et3N in hexane) afforded the analytically pure
(^)-3b (756 mg, 91%) as a clear colorless viscous oil. Rf
valueˆ0.52 (hexane±EtOAcˆ4:1). IR (KBr): nˆ
1707 cm21. UV (CH3CN): lmax 270.2 (486.7), 250.4
1
(806.5) nm. H NMR (C6D6): dˆ1.05 (d, Jˆ6.7 Hz, 3H),
1.11 (d, Jˆ6.7 Hz, 3H), 1.22 (s, 9H), 2.15 (s, 3H), 3.01
(septet, Jˆ6.7 Hz, 1H), 6.64 (dd, Jˆ7.7, 1.5 Hz, 1H), 6.91

8888
K. Kondo et al. / Tetrahedron 56 (2000) 8883±8891
acetyl group), 176.4 (CvO of propionyl group). EI-MS:
m/zˆ247 (M1), 214, 191, 177, 173, 134 (bp). Anal. Calcd
for C15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found: C, 72.76;
H, 8.71; N, 5.64.
(S)-N-(2-tert-Butylphenyl)-N-isobutyrylacetamide [(1)-
3b]. Retention Timeˆ22 min (eluent: hexane±isopropa-
nolˆ450:1). [a]2D7ˆ1238 (c 0.57, benzene, .99% ee). CD
(CH3CN): lext 247.0 (21.32) nm. Other spectral data of
(1)-3b were identical with those of (^)-3b.
(RS)-N-(2-tert-Butylphenyl)-N-benzoylacetamide [(^)-
3e]. To a stirred solution of N-(2-tert-butylphenyl)aceta-
mide (100 mg, 0.523 mmol) in pyridine (1.70 mL) was
gradually added benzoyl chloride (0.13 mL, 1.12 mmol) at
08C. The reaction mixture was stirred at 258C for 11 h,
cooled to 08C, quenched by the addition of H2O at the
same temperature and extracted with EtOAc. The combined
organic extracts were washed with brine, dried over Na2SO4
and concentrated using a rotary evaporator to afford the
crude product. Puri®cation by chromatography on silica
gel (hexane±EtOAcˆ5:1, the silica gel was pretreated
with 1% Et3N in hexane) afforded the analytically pure
(^)-3e (145 mg, 94%) as a colorless solid. Recrystallization
(benzene±hexane) afforded colorless prisms of mp 83±
848C. Rf valueˆ0.35 (hexane±EtOAcˆ4:1). IR (KBr): nˆ
1687 cm21. 1H NMR (C6D6): dˆ1.30 (s, 9H), 1.86 (s, 3H),
6.79 (dd, Jˆ7.3, 1.5 Hz, 1H), 6.90 (ddd, Jˆ7.3, 7.3, 1.5 Hz,
1H), 7.00±7.05 (m, 4H), 7.28 (dd, Jˆ7.3, 1.5 Hz, 1H),
7.71±7.74 (m, 2H). 13C NMR (C6D6): dˆ26.15, 31.77,
36.06, 127.2, 128.1, 129.0, 129.2, 129.6, 131.3, 132.8,
136.9, 137.9, 147.3, 173.1 (CvO of benzoyl group),
173.3 (CvO of acetyl group). EI-MS: m/zˆ295 (M1),
253, 239, 197, 149, 135, 93, 77 (bp). Anal. Calcd for
C19H21NO2: C, 77.26; H, 7.17; N, 4.74. Found: C, 77.25;
H, 7.19; N, 4.73.
(R)-N-(2-tert-Butylphenyl)-N-isobutyrylacetamide [(2)-
3b]. Retention Timeˆ29 min (eluent: hexane±isopropa-
nolˆ450:1). [a]2D7ˆ2238 (c 0.87, benzene, .99% ee). CD
(CH3CN): lext 246.0 (11.23) nm. Other spectral data of
(2)-3b were identical with those of (^)-3b.
(S)-N-(2-tert-Butylphenyl)-N-isovalerylacetamide [(1)-
3c]. Retention Timeˆ24 min (eluent: hexane±isopropa-
nolˆ450:1). [a]2D7ˆ1168 (c 1.05, benzene, .99% ee). CD
(CH3CN): lext 244.0 (20.36) nm. Other spectral data of
(1)-3c were identical with those of (^)-3c.
(R)-N-(2-tert-Butylphenyl)-N-isovalerylacetamide [(2)-
3c]. Retention Timeˆ31 min (eluent: hexane±isopropa-
nolˆ450:1). [a]2D7ˆ2198 (c 1.06, benzene, .99% ee). CD
(CH3CN): lext 246.5 (10.42) nm. Other spectral data of
(2)-3c were identical with those of (^)-3c.
(1)-N-(2-tert-Butylphenyl)-N-propionylacetamide [(1)-
3d]. Retention Timeˆ39 min (eluent: hexane±isopropa-
nolˆ450:1). [a]2D7ˆ1148 (c 0.57, benzene, .99% ee).
Other spectral data of (1)-3d were identical with those of
(^)-3d.
(2)-N-(2-tert-Butylphenyl)-N-propionylacetamide [(2)-
3d]. Retention Timeˆ42 min (eluent: hexane±isopropa-
nolˆ450:1). [a]2D7ˆ2158 (c 1.10, benzene, .99% ee).
Other spectral data of (2)-3d were identical with those of
(^)-3d.
(RS)-N-(2-tert-Butylphenyl)-N-(4-tri¯uorometylbenzoyl)-
acetamide [(^)-3f]. To a stirred solution of N-(2-tert-butyl-
phenyl)acetamide (1.07 g, 5.59 mmol) in pyridine (16.0
mL) was added 4-tri¯uorometylbenzoyl chloride (1.60
mL, 10.8 mmol) at 08C. The reaction mixture was stirred
at 258C for 5 h, cooled to 08C, quenched by the addition of
H2O at the same temperature and extracted with EtOAc. The
combined organic extracts were washed with saturated
aqueous NaHCO3 and brine, dried over Na2SO4 and concen-
trated using a rotary evaporator to afford the crude product.
Puri®cation by chromatography on silica gel (hexane±
EtOAcˆ7:1, the silica gel was pretreated with 3% Et3N in
hexane) afforded the analytically pure (^)-3f (1.82 g, 90%)
as a colorless solid. Recrystallization (benzene±hexane)
afforded colorless plates of mp 125±1268C. Rf valueˆ0.67
(hexane±EtOAcˆ2:1). IR (nujol): nˆ1678, 1722 cm21. 1H
NMR (C6D6): dˆ1.26 (s, 9H), 1.73 (s, 3H), 6.70 (dd, Jˆ7.7,
1.5 Hz, 1H), 6.91 (ddd, Jˆ7.7, 7.7, 1.5 Hz, 1H), 7.03 (ddd,
Jˆ7.7, 7.7, 1.5 Hz, 1H), 7.25±7.29 (m, 3H), 7.53 (d,
Jˆ8.1 Hz, 2H). 13C NMR (C6D6): dˆ25.76, 31.65, 35.97,
124.1 (q, Jˆ272 Hz), 124.9 (q, Jˆ3.3 Hz), 127.1, 128.6,
129.0, 129.4, 132.1, 132.1 (q, Jˆ32.5 Hz), 136.9, 140.0,
146.8, 171.4 (CvO of 4-tri¯uoromethylbenzoyl group),
172.6 (CvO of acetyl group). EI-MS: m/zˆ363 (M1),
265, 149, 83 (bp). Anal. Calcd for C20H20O2NF3: C, 66.11;
H, 5.55; N, 3.85. Found: C, 66.14; H, 5.58; N, 3.93.
(2)-N-(2-tert-Butylphenyl)-N-benzoylacetamide [(2)-
3e]. Retention Timeˆ32 min (eluent: hexane±isopropa-
nolˆ150:1). [a]2D7ˆ2288 (c 0.45, benzene, .99% ee). CD
(CH3CN): lext 240.0 (12.33), 223.0 (22.48) nm. Other
spectral data of (2)-3d were identical with those of (^)-3e.
(1)-N-(2-tert-Butylphenyl)-N-benzoylacetamide [(1)-
3e]. Retention Timeˆ40 min (eluent: hexane±isopropa-
nolˆ150:1). [a]2D7ˆ1298 (c 1.38, benzene, .99% ee). CD
(CH3CN): lext 240.0 (22.12), 220.0 (12.97) nm. Other
spectral data of (1)-3e were identical with those of (^)-3e.
General procedure for racemization experiment of 3b±e
A solution of optically active 3b±e (8.89£1023 mmol) in
benzene (3.0 mL) was stirred at four different temperatures
(sealed-tube experiments). The rate constants for their
racemization were measured in the 15±70% range of reac-
tion conversion.
The rate constants of 3b±e are shown below.
Optical resolution of (^)-3a±e
3b. k (408C)ˆ1.22^0.09£1026 s21, k (478C)ˆ2.44^0.06£
1026 s21, k (548C)ˆ5.54^0.36£1026 s21, k (618C)ˆ12.8^
Optical resolutions of (^)-3a±e were performed by HPLC
using a chiral phase column (DAICEL CHIRALCEL OD:
25 cm£1 cm i.d.).
1.0£1026 s21
.
3c. k (408C)ˆ1.50^0.02£1027 s21, k (508C)ˆ6.35^0.14£

K. Kondo et al. / Tetrahedron 56 (2000) 8883±8891
8889
1027 s21, k (578C)ˆ14.9^0.1£1027 s21, k (648C)ˆ40.4^
3H£2). 13C NMR (C6D6): dˆ28.33, 37.80, 38.54, 176.4
(CvO). EI-MS: m/zˆ129 (M1), 114, 87, 74, 47 (bp).
Anal. Calcd for C7H15NO: C, 65.07; H, 11.70; N, 10.84.
Found: C, 64.86; H, 11.86; N, 10.37.
0.1£1027 s21
.
3d. k (498C)ˆ3.08^0.10£1027 s21, k (568C)ˆ8.36^0.22£
1027 s21, k (638C)ˆ20.9^0.1£1027 s21, k (708C)ˆ48.5^
0.1£1027 s21
.
N,N-Dimethylisovaleramide (5c). Yield 35%. A colorless
oil. Rf valueˆ0.36 (EtOAc-hexaneˆ3:1). IR (nujol): nˆ
3e. k (338C)ˆ1.02^0.02£1026 s21, k (408C)ˆ2.73^0.09£
1026 s21, k (518C)ˆ10.9^0.2£1026 s21, k (588C)ˆ25.0^
1644 cm21
.
1H NMR (C6D6): dˆ0.95 (d, Jˆ6.6 Hz,
3H£2), 1.87 (d, J ˆ 6.6 Hz, 2H), 2.21 (s, 3H), 2.29 (tq,
Jˆ6.6, 6.6 Hz, 1H), 2.67 (s, 3H). 13C NMR (C6D6):
dˆ22.92, 25.54, 34.78, 36.29, 42.05, 170.7 (CvO).
EI-MS m/z: 129 (M1), 84, 72, 58 (bp). Anal. Calcd for
C7H15NO: C, 65.07; H, 11.70; N, 10.84. Found: C, 64.68;
H, 12.09; N, 10.46.
0.4£1026 s21
.
(Ra, 2S)-N-Allyl-N-(2-tert-butylphenyl)-2-acetoxypropiona-
mide [(1)-4] and (Sa, 2S)-N-allyl-N-(2-tert-butylphenyl)-
2-acetoxypropionamide [(2)-4]. (1)-4 and (2)-4 were
prepared according to the published procedure.4c
N,N-Dimethylbenzamide (5e). Yield 75%. A colorless oil.
Rf valueˆ0.49 (EtOAc-hexaneˆ2:1). IR (KBr): nˆ
3H), 7.05±7.07 (m, 3H), 7.30±7.33 (m, 2H). 13C NMR
(C6D6): dˆ34.97, 38.72, 127.7, 128.5, 129.3, 137.4, 170.8
(CvO). EI-MS: m/zˆ149 (M1), 135, 105, 83 (bp). Anal.
Calcd for C9H11NO: C, 72.46; H, 7.43; N, 9.39. Found: C,
72.17; H, 7.57; N, 9.68.
(1)-4. The physical data shown below were comparable to
those reported.4c A colorless solid of mp 40±438C. Reported
mp 448C. [a]2D5ˆ151.08 (c 1.0, CHCl3). Reported [a]2D5ˆ
1632 cm21
.
1H NMR (C6D6): dˆ2.32 (s, 3H), 2.75 (s,
1
155.08 (c 1.0, CHCl3). IR (KBr): nˆ1742, 1663 cm21. H
NMR (CDCl3): dˆ1.29 (d, Jˆ6.4 Hz, 3H), 1.38 (s, 9H),
1.98 (s, 3H), 3.36 (dd, Jˆ14.1, 8.1 Hz, 1H), 4.95 (tdd,
Jˆ14.1, 4.9, 1.5 Hz, 1H), 5.02 (q, Jˆ6.4 Hz, 1H), 5.11
(md, Jˆ17.0 Hz, 1H), 5.18 (dd, Jˆ10.2, 0.8 Hz, 1H), 5.99
(dddd, Jˆ17.0, 10.2, 8.1, 4.9 Hz, 1H), 7.06 (dd, Jˆ7.8,
1.6 Hz, 1H), 7.15 (dt, Jˆ7.8, 1.5 Hz, 1H), 7.32 (ddd,
Jˆ7.8, 7.2, 1.5 Hz, 1H), 7.56 (dd, Jˆ7.2, 1.6 Hz, 1H). 13C
NMR (CDCl3): dˆ15.79, 20.82, 32.27, 36.11, 54.65, 67.55,
118.6, 126.1, 128.6, 129.9, 131.7, 137.7, 145.8, 168.9,
169.1. EI-MS: m/zˆ304 (M111), 303 (M1), 245 (bp).
Representative procedure for reaction of 3a±e with
benzylamine (6) corresponding to entry 1 in Table 4
To a stirred solution of 3a (151 mg, 0.549 mmol) in benzene
(0.55 mL) was added benzylamine (6) (3.66 M in benzene,
75.0 mL, 0.275 mmol) at 08C. The reaction mixture was
stirred at 258C for 3.5 h, cooled to 08C, quenched by the
addition of 10% aqueous HCl at the same temperature and
extracted with EtOAc. The combined organic extracts were
washed with saturated aqueous NaHCO3 and brine, and
dried over Na2SO4. Evaporation of the solvent yielded the
colorless residue (143 mg). Puri®cation by chromatography
on silica gel (benzene-EtOAcˆ8:1) and subsequent PTLC
(hexane: EtOAcˆ10:1) afforded N-benzylpivalamide
(37.8 mg, 72%) as a colorless solid and N-(2-tert-butyl-
phenyl)acetamide (99.9 mg, 95%) as a colorless solid. No
[(2)-4]. The physical data shown below were comparable to
those reported.4cA colorless solid of mp 92±958C. Reported
mp 94±958C. [a]2D5ˆ292.08 (c 1.0, CHCl3). Reported
[a]2D5ˆ299. 08 (c 1.0, CHCl3). IR (KBr): nˆ1736,
1
1670 cm21. H NMR (CDCl3): dˆ1.30 (d, Jˆ6.5 Hz, 3H),
1.35 (s, 9H), 2.02 (s, 3H), 3.34 (dd, Jˆ14.1, 8.2 Hz, 1H),
4.95 (tdd, Jˆ14.1, 5.0, 1.3 Hz, 1H), 5.08 (q, Jˆ6.5 Hz, 1H),
5.09 (md, Jˆ17.1 Hz, 1H), 5.18 (d, Jˆ10.4 Hz, 1H), 5.98
(m, 1H), 6.92 (dd, Jˆ7.8, 1.5 Hz, 1H), 7.19 (dt, Jˆ7.4,
1.4 Hz, 1H), 7.34 (ddd, Jˆ7.4, 1.5 Hz, 1H), 7.58 (dd,
Jˆ8.2, 1.5 Hz, 1H). 13C NMR (CDCl3): dˆ17.19, 20.99,
31.64, 36.17, 54.47, 67.77, 119.0, 126.4, 128.8, 130.2,
131.4, 131.8, 137.7, 146.2, 169.5, 169.6. EI-MS: m/zˆ304
(M111), 303 (M1), 247, 204 (bp).
1
N-benzylacetamide (8) was detected by TLC and H NMR
of the crude product.
N-Benzylpivalamide. The physical data shown below were
comparable to those reported.23 A colorless solid of mp 82±
82.58C. Reported mp 82±838C. Rf valueˆ0.35 (hexane±
1
General procedure for preparation of 5a, 5c and 5e
EtOAcˆ4:1). IR (nujol): nˆ3297, 1633 cm21. H NMR
(CDCl3): dˆ1.23 (s, 9H), 4.43 (d, Jˆ5.7 Hz, 2H), 5.93 (br
s, 1H), 7.24±7.35 (m, 5H). 13C NMR (CDCl3): dˆ27.56,
38.62, 43.48, 127.1, 127.3, 128.4, 138.3, 177.8. EI-MS: m/
zˆ191 (M1), 149, 106, 91 (bp).
To a stirred solution of N,N-dimethylamine hydrochloride
(4.65 g, 57.0 mmol) in benzene (6.20 mL) were added Et3N
(8.30 mL, 59.5 mol) and acyl chloride (2.85 mmol) at 08C.
The reaction mixture was stirred at 258C for 4 h, cooled to
08C, quenched by the addition of 10% aqueous HCl at the
same temperature and extracted with EtOAc. The combined
organic extracts were washed with saturated aqueous
NaHCO3 and brine, dried over Na2SO4, and concentrated
using a rotary evaporator to afford the crude product.
Puri®cation by chromatography on silica gel afforded the
desired compound.
The physical data of other amides in entries 2±5, Table 4,
are shown below.
Entries 2±4. N-Benzylacetamide (8). The physical data
shown below were comparable to those reported.23 A color-
less solid of mp 58±598C. Reported mp 61±628C. Rf
valueˆ0.25 (hexane±EtOAcˆ1:1). IR (nujol): nˆ3289,
1
1633 cm21. H NMR (CDCl3): dˆ2.01 (s, 3H), 4.41 (d,
N,N-Dimethylpivalamide (5a). Yield 44%. A colorless oil.
Rf valueˆ0.26 (EtOAc-hexaneˆ3:1). IR (KBr): nˆ
Jˆ5.7 Hz, 2H), 5.90 (br s, 1H), 7.26±7.35 (m, 5H). 13C
NMR (CDCl3): dˆ23.09, 43.58, 127.1, 127.5, 128.3,
137.9, 169.6. EI-MS: m/zˆ149 (M1), 148, 108, 106 (bp).
1627 cm21
.
1H NMR (C6D6): dˆ1.15 (s, 9H), 2.57 (s,

8890
K. Kondo et al. / Tetrahedron 56 (2000) 8883±8891
Entry 4. N-Benzylpropionamide. The physical data shown
below were comparable to those reported.23 A colorless
solid of mp 51±51.58C. Reported mp 48±49.58C. Rf
valueˆ0.42 (hexane±EtOAcˆ1:1). IR (nujol): nˆ3292,
CCD diffractometer, graphite monochromated MoKa
Ê
(lˆ0.71069 A) radiation, 11603 re¯ections measured,
giving 877 with I.3.00s (I).
1
1637 cm21. H NMR (CDCl3): dˆ1.18 (t, Jˆ7.5 Hz, 3H),
Structure analysis and re®nement
2.24 (q, Jˆ7.5 Hz, 2H), 4.43 (d, Jˆ5.7 Hz, 2H), 5.81 (br s,
1H), 7.25±7.36 (m, 5H). 13C NMR (CDCl3): dˆ9.85, 29.58,
43.43, 127.1, 127.4, 128.3, 138.1, 173.2. EI-MS: m/zˆ163
(M1), 107, 106, 91 (bp).
The structure was solved by direct methods using DIFABS24
and was re®ned by full-matrix least-squares techniques
using DIRDIF94.25 The non-hydrogen atoms were re®ned
anisotropically. The ®nal residuals for re¯ections with
I.3.00s (I) were Rˆ0.061, Rwˆ0.062.
Entry 5. N-Benzylbenzamide. The physical data shown
below were comparable to those reported.6b A colorless
solid of mp 108±1098C. Reported mp 107±1098C. Rf
valueˆ0.28 (hexane±EtOAcˆ4:1). IR (nujol): nˆ3290,
Acknowledgements
1638 cm21
.
1H NMR (CDCl3): dˆ4.65 (dd, Jˆ5.7,
1.8 Hz, 2H), 6.49 (br s, 1H), 7.27±7.50 (m, 8H), 7.78±
7.81 (m, 2H). 13C NMR (CDCl3): dˆ43.96, 126.7, 127.2,
127.5, 128.2, 128.4, 131.5, 134.0, 137.9, 167.0. EI-MS:
m/zˆ211 (M1), 105, 91, 77 (bp).
This study was ®nancially supported by a Grant-in-Aid for
Scienti®c Research from the Ministry of Education, Science
and Culture, Japan, a Sasakawa Scienti®c Research Grant
from The Japan Science Society, and the Mitsubishi
Chemical Corporation Fund.
The physical data of other resulting anilides in entries 2±4,
Table 4, are shown below.
References
Entry 2. N-(2-tert-butylphenyl)isobutyramide. A color-
less solid of mp 140±141.58C. Rf valueˆ0.55 (hexane±
1. (a) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; Wiley: New York, 1994. (b) Pu, L. H. Chem. Rev.
1998, 98, 2405±2494.
1
EtOAcˆ2:1). IR (nujol): nˆ3259, 1651 cm21. H NMR
(CDCl3): dˆ1.31 (d, Jˆ6.8 Hz, 3H£2), 1.42 (s, 9H), 2.57
(septet, Jˆ6.8 Hz, 1H), 7.13±7.26 (m, 3H), 7.38 (d,
Jˆ7.7 Hz, 1H), 7.62 (d, Jˆ7.7 Hz, 1H). 13C NMR
(CDCl3): dˆ19.51, 30.63, 34.49, 36.63, 125.6, 126.1,
126.4, 127.5, 135.0, 141.9, 174.4. EI-MS: m/zˆ219 (M1),
162, 149, 134 (bp). Anal. Calcd for C14H21NO: C, 76.67; H,
9.65; N, 6.39. Found: C, 76.55; H, 9.78; N, 6.48.
2. For recent reports in relation to non-biaryl axial chirality except
an imide N±Ar axis, see: (a) Kawabata, T.; Yahiro, K.; Fuji, K.
J. Am. Chem. Soc. 1991, 113, 9694±9696. (b) Dogan, I.; Pustet, N.;
Mannschreck, A. J. Chem. Soc., Perkin Trans. 2 1993, 1557±1560.
(c) Azumaya, I.; Yamaguchi, K.; Okamoto, I.; Kagechika, H.;
Shudo, K. J. Am. Chem. Soc. 1995, 117, 9083±9084. (d) Ohno,
A.; Kunitomo, J.; Kawai, Y.; Kawamoto, T.; Tomishima, M.;
Yoneda, F. J. Org. Chem. 1996, 61, 9344±9355. (e) Ikeura, Y.;
Ishichi, Y.; Tanaka, T.; Fujishima, A.; Murabayashi, M.; Kawada,
M.; Ishimaru, T.; Kamo, I.; Doi, T.; Natsugari, H. J. Med. Chem.
1998, 41, 4232±4239. (f) Clayden, J. Synlett 1998, 810±816. (g)
Koide, H.; Uemura, M. Chirality 2000, 12, 352±359, and
references cited therein.
Entry 3. N-(2-tert-Butylphenyl)isovaleramide. A color-
less solid of mp 118±1198C. Rf valueˆ0.55 (hexane±
1
EtOAcˆ2:1). IR (nujol): nˆ3213, 1650 cm21. H NMR
(CDCl3): dˆ1.04 (d, Jˆ5.1 Hz, 3H£2), 1.41 (s, 9H),
2.26±2.34 (m, 3H), 7.14±7.26 (m, 3H), 7.38 (d, Jˆ
7.7 Hz, 1H), 7.60 (d, Jˆ7.7 Hz, 1H). 13C NMR (CDCl3):
dˆ22.56, 26.14, 30.68, 34.48, 47.11, 125.7, 126.2, 126.5,
127.5, 134.9, 141.9, 170.3. EI-MS: m/zˆ233 (M1), 176,
149, 134 (bp). Anal. Calcd for C15H23NO: C, 77.21; H,
9.93; N, 6.00. Found: C, 77.02; H, 9.93; N, 6.03.
3. (a) Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. J. Am.
Chem. Soc. 1994, 116, 3131±3132. (b) Curran, D. P.; Hale, G. R.;
Geib, S. J.; Balog, A.; Cass, Q. B.; Degani, A. L. G.; Hernandes, M.
Z.; Freita, L. C. G. Tetrahedron: Asymmetry 1997, 8, 3955±3975.
4. (a) Hughes, A. D.; Price, D. A.; Shishkin, O.; Simpkins, N. S.
Tetrahedron Lett. 1996, 37, 7607±7610. (b) Kitagawa, O.; Izawa,
H.; Taguchi, T.; Shiro, M. Tetrahedron Lett. 1997, 38, 4447±4450.
(c) Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi, A.; Taguchi, T.;
Shiro, M. J. Org. Chem. 1998, 63, 2634±2640. (d) Hughes, A. D.;
Simpkins, N. S. Synlett 1998, 967±968. (e) Fujita, M.; Kitagawa,
O.; Izawa, H.; Dobashi, A.; Fukaya, H.; Taguchi, T. Tetrahedron
Lett. 1999, 40, 1949±1952. (f) Hughes, A. D.; Price, D. A.;
Simpkins, N. S. J. Chem. Soc., Perkin Trans 1 1999, 1295±1304.
(g) Kitagawa, O.; Momose, S.; Fushimi, Y.; Taguchi, T.
Tetrahedron Lett. 1999, 40, 8827±8831. (h) Godfrey, C. R. A.;
Simpkins, N. S.; Walker, M. D. Synlett 2000, 388±390. (i) Fujita,
M.; Kitagawa, O.; Yamada, Y.; Izawa, H.; Hasegawa, H.; Taguchi,
T. J. Org. Chem. 2000, 65, 1108±1114. (j) Shimizu, K. D.;
Heather, O. F.; Richard, D. A. Tetrahedron Lett. 2000, 41,
5431±5434.
Entry 4. N-(2-tert-Butylphenyl)propionamide. A color-
less solid of mp 102±1038C. Rf valueˆ0.32 (hexane±
1
EtOAcˆ2:1). IR (nujol): nˆ3244, 1645 cm21. H NMR
(CDCl3): dˆ1.23 (t, Jˆ7.3 Hz, 3H), 1.40 (s, 9H), 2.43 (q,
Jˆ7.3 Hz, 3H), 7.15±7.26 (m, 3H), 7.38 (d, Jˆ7.6 Hz, 1H),
7.55 (d, Jˆ7.6 Hz, 1H). 13C NMR (CDCl3): dˆ9.73, 30.66,
35.51, 125.8, 126.2, 126.5, 127.8, 134.9, 142.2, 171.5. EI-
MS: m/zˆ205 (M1), 148, 84, 57 (bp). Anal. Calcd for
C13H19NO: C, 76.06; H, 9.33; N, 6.82. Found: C, 75.77;
H, 9.42; N, 6.75.
Crystal data for 3f
Ê
C20H20O2NF3, Mˆ363.38, monoclinic, aˆ8.815(2) A, bˆ
Ê
9.900(2) A,
Ê
cˆ21.953(5) A,
bˆ97.671(4)8,
Vˆ
Ê 3
1898.5(6) A , space group P21/n (#14), Zˆ4, Dcalc
ˆ
5. For recent studies in relation to the rotational barrier around a
cyclic imide N±Ar bond, see: (a) Kishikawa, K.; Tsuru, I.;
Kohmoto, S.; Yamamoto, M.; Yamada, K. Chem. Lett. 1994,
1.271 g cm23. Crystal dimensions 0.42£0.33£0.22 mm,
m(MoKa)ˆ1.01 cm21. Data collection and processing:

K. Kondo et al. / Tetrahedron 56 (2000) 8883±8891
8891
Table 6. 13C NMR chemical shift (d, ppm) of acyl carbonyl (recorded at
100 MHz in C6D6)
1605±1606. (b) Kishikawa, K.; Yoshizaki, K.; Kohmoto, S.;
Yamamoto, M.; Yamaguchi, K.; Yamada, K. J. Chem. Soc., Perkin
Trans. 1 1997, 1233±1239.
Compound
d13
C
Dd13
C
6. (a) Murakami, Y.; Kondo, K.; Miki, K.; Akiyama, Y.;
Watanabe, T.; Yokoyama, Y. Tetrahedron Lett. 1997, 38, 3751±
3754. (b) Kondo, K.; Murakami, Y. Chem. Pharm. Bull. 1998, 46,
1217±1219. (c) Kondo, K.; Kurosaki, T.; Murakami, Y. Synlett
1998, 725±726. (d) Kondo, K.; Sekimoto, E.; Miki, K.; Murakami,
Y. J. Chem. Soc., Perkin Trans. 1 1998, 2973±2974. (e) Kondo, K.;
Sekimoto, E.; Nakao, J.; Murakami, Y. Tetrahedron 2000, 56,
5843±5856.
RCO
CH3CO
RCO
0.7
CH3CO
3.4
3f
169.9 (169.2)a
172.6 (169.2)b
a The data of 5g.
b The data of 5f.
7. For our preliminary communication for the steric effects of acyl
groups, see: Kondo, K.; Fujita, H.; Suzuki, T.; Murakami, Y.
Tetrahedron Lett. 1999, 40, 5577±5580.
conformation, see: Noe, E. A.; Raban, M. J. Am. Chem. Soc. 1975,
97, 5811±5820.
8. For our preliminary communication for the electronic effects of
acyl groups, see: Kondo, K.; Fujita, H.; Suzuki, T.; Murakami, Y.
Enantiomer 2000, 5, 115±118.
18. (a) Winkler, F. K.; Dunitz, J. D. J. Mol. Biol. 1971, 59, 169±
182; (b) Dunitz, J. D.; Winkler, F. K. Acta. Cryst. 1975, B31, 251±
263.
9. For leading references: (a) Jones, K.; Storey, J. M. D. J. Chem.
Soc., Chem. Commun. 1992, 1766±1767. (b) Curran, D. P.;
DeMello, N. C. J. Chem. Soc., Chem. Commun. 1993, 1314±1317.
10. The use of other solvents such as DMF and CH3CN instead of
benzene, led to the decomposition of 3.
19. Twist angle t is de®ned as follows: t ˆ 1=2 ꢀv1 1 v2†:
According to the de®nition, the t value lies in the range between
2180 and 1808. However, the larger the distortion, the nearer the
value lies to 90 or 2908; on the other hand, the smaller the dis-
tortion, the nearer the value lies to 0, 1808, or 21808. Therefore, in
order to avoid confusion regarding the magnitude of t, we repre-
sented the twist angle as utu (for 08#utu#908) or 1802utu (for
908#utu).
11. The optical resolution of racemic 3g bearing a cyclohexane-
carbonyl group could not be achieved by using HPLC on a chiral
stationary phase. This disappointing result could be due to decom-
position of 3g by a chiral column.
20. Facile racemization of 8-diphenylphosphinoyl-80-methoxy-
1,10-binaphthyl due to its large strain energy, has been reported,
see: Fuji, K.; Sakurai, M.; Tohkai, N.; Kuroda, A.; Kawabata, T.;
Fukuzawa, Y.; Kinoshita, T.; Tada, T. Chem. Commun. 1996,
1609±1610.
21. Instead of the optical resolution of racemic 3d, optically active
3d could be obtained by asymmetric synthesis as shown in. Quite
recently, the similar asymmetric synthesis of anilides has been
reported by Simpkins et al., see: Ref. [4f] Scheme 1.
³
³
12. According to Eyring's equation, DH and DS of 3b±e were
calculated. For Eyring's equation, see: Cagle, Jr., F. W.; Eyring, H.
J. Am. Chem. Soc. 1951, 73, 5628±5630.
13. For the relationship between the twisted CO±N angle and 13
C
NMR spectral data: (a) Fong, C. W.; Grant, H. G. Aust. J. Chem.
1981, 34, 957±967. (b) Yamada, S. Angew. Chem., Int. Ed. Engl.
1993, 32, 1083±1085. (c) Yamada, S. J. Org. Chem. 1996, 61,
941±946. (d) Yamada, S.; Nunami, N.; Hori, K. Chem. Lett.
1998, 451±452.
14. The assignment of the acyl carbonyl signals of 3a±e was
determined by CNOE and LSPD experiments.
15. (a) Blackburn, G. M.; Plackett, J. D. J. Chem. Soc., Perkin
Trans. 2 1972, 1366±1371. (b) Bennet, A. J.; Wang, Q.-P.;
Slebocka-Tilk, H.; Somayaji, V.; Brown, R. S.; Santarsiero, B. D.
J. Am. Chem. Soc. 1990, 112, 6383±6385. (c) Yamada, S. J. Org.
Chem. 1992, 57, 1591±1592. (d) Yamada, S. Tetrahedron Lett.
1992, 33, 2171±2174. (e) Yamada, S. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1113±1115. (f) Yamada, S.; Ohe, T. Tetrahedron
Lett. 1996, 37, 6777±6780. (g) Yamada, S.; Sugaki, T.; Matsuzaki,
K. J. Org. Chem. 1996, 61, 5932±5938.
Scheme 1. Asymmetric synthesis of 3d.
22. (a) Rebeck, Jr., J. Angew. Chem., Int. Ed. Engl. 1990, 29, 245±
255. (b) Shimizu, K. D.; Dewey, T. M.; Rebek, Jr., J. J. Am. Chem.
Soc. 1994, 116, 5145±5149.
23. Kita, Y.; Akai, S.; Ajimura, N.; Yoshigi, M.; Tsugoshi, T.;
Yasuda, H.; Tamura, Y. J. Org. Chem. 1986, 51, 4150±4158.
24. Walker, N. S. Acta Cryst. 1983, A39, 158±166.
16. The Dd13C values (Table 6) of arylcarbonyl and acetyl-
carbonyl carbon of 3f were 0.7 and 3.4.
25. Beurskens, P. T.; Admiraal, G.; Beurskens, G.; Bosman, W.
P.; de Gelder, R.; Israel, R.; Smits, J. M. M., the DIRDIF-94
program system, Technical Report of the Crystallography Labora-
tory, University of Nijmegen, The Netherlands, 1994.
17. In the case of a simple acyclic imide, the endo±exo arrange-
ment of imide carbonyl groups would be the generally preferred