Unique structural properties of 2,4,6-tri-tert-butylanilide: Isomerization and switching between separable amide rotamers through the reaction of anilide enolates

Article abstract of DOI:10.1002/chem.201300201

Herein, we report a unique structural property of 2,4,6-tri-tert- butylanilide, which can be separated into its amide rotamers at room temperature. Interconversion between the rotamers of anilide enolates occurs readily at room temperature and their react

Full text of DOI:10.1002/chem.201300201

FULL PAPER
DOI: 10.1002/chem.201300201
Unique Structural Properties of 2,4,6-Tri-tert-butylanilide: Isomerization and
Switching between Separable Amide Rotamers through the Reaction of
Anilide Enolates
Shiori Tsukagoshi, Nobutaka Ototake, Yusuke Ohnishi, Mayu Shimizu, and
Osamu Kitagawa*[a]
Abstract: Herein, we report a unique
structural property of 2,4,6-tri-tert-
butylACHTUNGTRENNUNGanilide, which can be separated
tion of the 2,4,6-tri-tert-butylacetanilide
enolate with reactive electrophiles,
such as allyl bromide or protic acids,
gives mixtures of the anilide rotamers
in which the E rotamer is the major
component, whereas less-reactive elec-
trophiles, such as 1-bromopropane and
2-iodopropane, yield mixtures of the
rotamers in which the Z rotamer is the
major component. The rotameric ratio
of the product is also strongly depend-
ent on the reactivity of the anilide eno-
late. Switching between the anilide ro-
tamers can be achieved through proto-
nation of a less-reactive enolate by a
less-reactive protic acid and thermal
isomerization of the anilide.
into its amide rotamers at room tem-
perature. Interconversion between the
rotamers of anilide enolates occurs
readily at room temperature and their
reaction with electrophiles gives mix-
tures of the rotamers in a ratio that de-
pends on the reactivity of the corre-
sponding electrophile. That is, the reac-
Keywords: amides
· electrophilic
addition · enolates · isomerization ·
rotamers
Introduction
Rotational isomers, owing to the double-bond character of
À
the amide C(O) N bond, play a key role in regulating the
activity of biologically active peptides and functional mole-
cules that contain amide skeletons.[1] Moreover, these iso-
mers are known to significantly influence the chemical reac-
tivity of substrates that contain an amide tether.[2] Although
the existence of such amide rotamers is often confirmed by
means of NMR spectroscopy, they generally cannot be iso-
lated because interconversion between the two rotamers
occurs easily at room temperature.
In 1967, Chupp and Olin reported that the amide bond in
2,6-di-tert-butylanilides had a high rotational barrier (27–
28 kcalmolÀ1) and that the individual rotamers could be iso-
lated at room temperature (Figure 1).[3] This report is note-
worthy as a rare example of a separable amide rotamer,[4]
but no systematic study with anilide substrates, other than
a-haloacetanilides (R1 =XCH2; X=Cl, Br, I), or the stereo-
selective syntheses of anilide rotamers have been reported.
In addition, the structural properties of these anilides have
not been investigated in detail.
Figure 1. Separable rotamers of 2,6-di-tert-butylanilides.
Recently, we reported the highly selective stereodivergent
synthesis of the E and Z rotamers of various N-allylated
2,4,6-tri-tert-butylanilide derivatives through Pd-catalyzed
N-allylation and aza-Claisen-rearrangement reactions.[5]
Moreover, the relative thermodynamic stabilities of the ob-
tained anilide rotamers was also clarified.[5]
Herein, we report a unique structural property of 2,4,6-
tri-tert-butylanilide derivatives.[6] Interconversion between
the rotamers of anilide enolates proceeds readily at room
temperature and their reaction with some electrophiles
gives mixtures of rotamers in a ratio that depends on the re-
activities of both the enolate and the electrophile
(Scheme 1). Switching between anilide rotamers through
protonation of the anilide enolates and thermal isomeriza-
tion is also described.
[a] S. Tsukagoshi, N. Ototake, Y. Ohnishi, M. Shimizu,
Prof. Dr. O. Kitagawa
Department of Applied Chemistry
Shibaura Institute of Technology
3-7-5 Toyosu, Koto-ku, Tokyo 135-8548 (Japan)
Fax : (+81)3-5859-8161
Results and Discussion
E-mail: kitagawa@shibaura-it.ac.jp
Isomerization through the formation of acetanilide enolates:
During the course of our investigation of the reactivity of a
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6845

À
Rotation around the N C bond of enolate 1A should
occur more easily in comparison with that of anilide 1a be-
cause of the decrease in double-bond character. In asym-
metric a-alkylation reactions with chiral amide enolates, it
À
has been pointed out that such a N C bond rotation may
bring about a decrease in stereoselectivity.[8] However, be-
cause ordinary amide rotamers cannot be isolated at RT,
À
N C bond rotation in the amide enolate has so far been dif-
ficult to confirm. Scheme 2 should provide the first evidence
À
for N C bond rotation in an amide enolate.
The reactions of acetanilide enolate 1A with various alkyl
halides were further examined under the conditions given in
Scheme 2 (Table 1). In these alkylation reactions, an inter-
esting tendency of the isomerization step was observed.
The reaction of enolate 1A with allyl bromide gave a sim-
ilar result to the protonation shown in Scheme 2. That is, the
allylation of enolate 1A, which was prepared from rotamers
(E)-1a and (Z)-1a, proceeded smoothly to afford rotamer
mixtures of allylation product 2b in ratios of (E)-2b/(Z)-
2b=2.4:1 and 2.5:1, respectively (Table 1, entries 1 and 2).
In the reaction with benzyl bromide, preferential formation
of E rotamer (E)-2c was also observed, although the E/Z
ratios decreased slightly ((E)-2c/(Z)-2c=1.8:1 and 1.7:1;
Table 1, entries 3 and 4). In contrast to Table 1, entries 1–4,
with 3-bromocyclohexene, Z rotamer (Z)-2d was obtained
as the major isomer ((E)-2d/(Z)-2d=1:2.6 and 1:2.3;
Table 1, entries 5 and 6). The preference for the Z rotamer
increased with decreasing reactivity of the alkyl halide. The
reaction with 1-bromopropane gave the product (2e) in the
ratio (E)-2e/(Z)-2e=1:6.2 (Table 1, entries 7 and 8). In the
reaction with less-reactive 2-iodopropane, a further increase
in the preference for the Z rotamer was observed ((E)-2 f/
(Z)-2 f=1:15.4 and 1:18.9; Table 1, entries 9 and 10). Thus,
the rotamer ratios of the alkylated products (2) were found
Scheme 1. Isomerization and switching between 2,4,6-tri-tert-butylanilide
rotamers through the formation of anilide enolates.
lithium enolate that was prepared from N-(n-propyl)-2,4,6-
tri-tert-butylacetanilide (1a), we unexpectedly found that
the reaction of an anilide enolate with an electrophile gave
mixtures of anilide rotamers. That is, when Z rotamer (Z)-
1a was treated with nBuLi (1.3 equiv) for 10 min at RT, fol-
lowed by HCl (aq), rotamer mixtures in which the E rotam-
er was the major component were obtained in the ratio of
(E)-1a/(Z)-1a=3.0:1 (Scheme 2). Under the same condi-
tions, the reaction of E rotamer (E)-1a also gave rotamer
mixtures with the same E/Z ratio (3.0:1, Scheme 2).
These results indicate that the interconversion between
the rotamers of anilide enolate 1A occurs quickly at RT to
afford equilibrium mixtures of (E)-1A and (Z)-1A within
10 min (Figure 2). Enolate (E)-1A may be somewhat more
stable than (Z)-1A and exist as the predominant rotamer.[5,7]
The preferential formation of anilide (E)-1a in the protona-
tion of enolate 1A may be due to the equilibrium ratio of
1A.
Table 1. Reaction of 2,4,6-tri-tert-butylacetanilide enolates with various
alkyl halides.
Scheme 2. Protonation with the lithium enolate that was prepared from
rotamers (E)-1a and (Z)-1a.
1a
2
Yield [%][a]
E/Z[b]
À
R X
À
1
2
3
4
5
6
7
8
9
(E)-1a
(Z)-1a
(E)-1a
(Z)-1a
(E)-1a
(Z)-1a
(E)-1a
(Z)-1a
(E)-1a
(Z)-1a
allyl Br
2b
2b
2c
2c
2d
2d
2e
2e
2 f
2 f
99
98
70
74
57
53
84
80
71
62
1
2.4:1
2.5:1
1.8:1
1.7:1
1:2.6
1:2.3
1:6.2
1:6.2
1:15.4
1:18.9
À
allyl Br
À
PhCH2 Br
À
PhCH2 Br
3-bromocyclohexene
3-bromocyclohexene
À
nC3H7 Br
À
nC3H7 Br
À
iC3H7
I
I
À
iC3H7
10
[a] Yield of isolated product. [b] Ratio estimated by H NMR (400 MHz)
Figure 2. Interconversion between lithium enolates (E)-1A and (Z)-1A.
spectroscopy.
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Unique Structural Properties of 2,4,6-Tri-tert-butylanilide
FULL PAPER
Scheme 3. Reaction of compound (Z)-1a with electrophiles at À208C.
Isomerization through the formation of propionanilide eno-
late: Next, the reaction of propionanilide enolate with vari-
ous electrophiles was examined further (Table 2). After
treating compound (E)-2a or (Z)-2a with nBuLi (2 equiv)
for 30 min at RT in THF,[10] the resulting anilide enolate was
reacted with various electrophiles. Protonation of the anilide
enolate that was prepared from compounds (E)-2a and (Z)-
2a afforded (E)-2a as the major rotamer in the ratio E/Z=
2.1:1 (Table 2, entries 1 and 2). Although the E-selectivity
was lower, these results were similar to those with acetani-
lide 1a (Scheme 2). Moreover, the reaction with allyl bro-
mide preferentially gave Z rotamer (Z)-3b in E/Z ratios=
1:6.8 and 1:7.3 (Table 2, entries 3 and 4). With benzyl bro-
mide, similar preference for the Z rotamer was also ob-
served ((E)-3c/(Z)-3c=1:8.6 and 1:9.1; Table 2, entries 5
and 6).
Figure 3. Origin of the selectivity for the E or Z rotamers in the reaction
of acetanilide enolate 1A with different electrophiles.
to significantly depend on the reactivity of the alkylated re-
agents.
These results may be rationalized as follows (Figure 3): In
the reaction with a reactive alkyl halide, such as allyl bro-
mide, the a-alkylation might proceed at a faster rate than in-
terconversion between enolates (E)-1A and (Z)-1A. Hence,
similar to the protonation shown in Scheme 2, the rotameric
ratio of allylation product 2b is mainly determined by the
equilibrium ratio of enolate 1A to give compound (E)-1a as
the major product. On the other hand, with a less-reactive
alkyl halide, because alkylation occurs slowly in comparison
with the interconversion of the enolate, the rotameric ratio
is influenced by the relative reactivity of enolate rotamers
(E)-1A and (Z)-1A rather than by the thermodynamic sta-
bility of enolate 1A. Rotamer (E)-1A should be less reac-
tive than (Z)-1A, because the a-carbon atom of rotamer
(E)-1A is shielded by two ortho-tert-butyl groups. Accord-
ingly, compound (Z)-2 is preferentially obtained through the
selective alkylation of reactive enolate (Z)-1A. The contri-
bution of the reactivity of the enolate to controlling the out-
come should increase with decreasing the reactivity of the
alkyl halides, thereby leading to an increase in the prefer-
ence for the Z rotamer (Figure 4).
These Z-selectivities are notably in contrast with the ob-
served E-selectivity in the allylation and benzylation of ac
ACHTUNGTRENNUNGet-
A
ACTHUNGTRENNUNiG ACHTUNGTRENNNUG
of the enolate. Because the reactivity of propionanilide eno-
late 2A is lower than that of acetanilide enolate 1A, the re-
action with reactive allyl bromide and benzyl bromide may
proceed at a slower rate than the interconversion between
Table 2. Reaction of 2,4,6-tri-tert-butylpropionanilide enolates with vari-
ous alkyl halides.
The isomerization shown in Scheme 2 and Table 1 was
barely noticeable at À208C. When rotamer (Z)-1a was
treated with nBuLi for 10 min at À208C and subsequently
reacted with HCl (aq) or allyl bromide, only a small amount
of the E rotamer was formed (Scheme 3). These results indi-
À
cate that rotation around the N C bond of enolate 1A
occurs very slowly at À208C.
À
2a
E X
2a or 3
Yield [%][a]
E/Z[b]
À
1
2
3
4
5
6
7
8
(E)-2a
(Z)-2a
(E)-2a
(Z)-2a
(E)-2a
(Z)-2a
(E)-2a
(Z)-2a
H Cl (aq)
H Cl (aq)
2a
2a
3b
3b
3c
3c
3e
3e
95
93
98
95
93
86
73
75
2.1:1
2.1:1
1:6.8
1:7.3
1:8.6
1:9.1
1:46
À
À
allyl Br
À
allyl Br
À
PhCH2 Br
À
PhCH2 Br
nC3H7 Br
nC3H7 Br
À
À
1:46
Figure 4. Relationship between the selectivity for the Z rotamer and the
[a] Yield of the isolated product. [b] Ratio estimated by 1H NMR
reactivity of the electrophile.
(400 MHz) spectroscopy.
Chem. Eur. J. 2013, 19, 6845 – 6850
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6847

O. Kitagawa et al.
Table 3. Protonation of 2,4,6-tri-tert-butylpropionanilide enolates.
Additive
H+
E/Z[a]
Figure 5. Origin of the selectivity for the E or Z rotamers in the reaction
of propionanilide enolate 2A with different electrophiles.
1
2
3
4
5
6
7
8
none
none
CuI
HCl (aq)
2.1:1
2.2:1
1:1.2
1:4.6
1:2.7
1.5:1
3.5:1
5.4:1
DTB-phenol[b]
HCl (aq)
CuI
DTB-phenol[b]
DTB-phenol[b]
DTB-phenol[b]
DTB-phenol[b]
DTB-phenol[b]
enolates (E)-2A and (Z)-2A (Figure 5). Accordingly, the ro-
tameric ratios are controlled by the relative reactivity of
enolate 2A, rather than by the stability of compound 2A,
which preferentially generates alklylation product (Z)-3
from reactive enolate (Z)-2A. Thus, rotamer selectivity was
found to be influenced not only by the reactivity of the elec-
trophile but also by the reactivity of the enolate.
CuI[c]
ZnCl2
NiBr2
Cp2ZrCl2
[a] Ratio estimated by 1H NMR (400 MHz) spectroscopy. [b] DTB-
phenol=2,6-di-tert-butylphenol. [c] CuI (2 equiv).
The reaction with less-reactive 1-bromopropane proceed-
ed in an almost-completely Z-selective manner to give pro-
pylated product (Z)-3e (E/Z=1:46; Table 2, entries 7 and
8). It should be noted that the propylation of (E)-2a occur-
red with almost-complete inversion of the rotational isomer-
ism (Table 2, entry 7).
In these reactions, a solution of the alkyl bromide in THF
was slowly added to the enolate in THF (about 5 min),
whereas quick addition of alkyl bromide resulted in a con-
siderable decrease in the Z-selectivity.
of CuI, protonation by 2,6-di-tert-butylphenol led to an in-
crease in Z-selectivity and, in this case, compound (Z)-2a
was preferentially obtained in the ratio E/Z=1:4.6 (Table 3,
entry 4). The additive effect of CuI is specific; such Z-selec-
tivity was not observed with other metal salts (Table 3, en-
tries 6–8).
This Z-selective protonation with copper enolate can be
applied to various anilides (2c–2g, Table 4). Under the same
conditions, the E rotamers of anilides 2c–2g were converted
into rotameric mixtures with E/Z ratios of 1:2.2 to 1:6.1
(Table 4, entries 2–6). In these reactions, the slow addition
(about 15 min) of 2,6-di-tert-butylphenol (in THF) to the
copper enolate was required. Quick addition of 2,6-di-tert-
butylphenol resulted in lower Z-selectivity.
Although the protonation of acetanilide enolate was also
investigated under the same conditions, in this case, com-
pound (E)-1a was obtained as the major rotamer ((E)-1a/
(Z)-1a=2.5:1). This result indicates that the reaction of ace-
tanilide copper enolate with 2,6-di-tert-butylphenol still
occurs at a faster rate than the interconversion between eno-
late rotamers.
Switching between the anilide rotamers: Next, as an applica-
tion of isomerization through the formation of the enolate,
reversible interconversion between the anilide rotamers was
investigated.[9] We previously reported that, in N-allylated
2,4,6-tri-tert-butyl anilides, the E rotamers were thermody-
namically more stable than the Z rotamers and that thermal
isomerization of the anilides gave rotameric mixtures in
which the E rotamer was the major component.[5] Accord-
ingly, if the Z rotamers could be preferentially formed
through the protonation of the anilide enolate, switching be-
tween the anilide rotamers should be achievable. However,
the protonation of enolates 1A and 2A with HCl (aq), by
exerting control that was based on the thermodynamic sta-
bility of the enolates, gave rotameric mixtures in which the
E rotamer was the major component (Scheme 2, Table 2, en-
tries 1 and 2; Table 3, entry 1). Moreover, we expected that
the reaction of a less-reactive anilide enolate with a less-re-
active proton source might lead to control based on the re-
activity of the enolate to preferentially form the Z rotamer.
Although lithium enolate 2A, which was prepared from
propionanilide (E)-2a, was protonated by using the bulky
2,6-di-tert-butylphenol (DTB-phenol), no change in selectivi-
ty was observed ((E)-2a/(Z)-2a=2.2:1; Table 3, entries 1
and 2). To decrease the reactivity of the enolate, the addi-
tion of several metal salts was examined. When a solution of
enolate 2A was treated with CuI (1 equiv), followed by HCl
(aq), compound 2a was obtained with slight Z-selectivity
((E)-2a/(Z)-2a=1:1.2; Table 3, entry 3). After the addition
Table 4. Protonation of various 2,4,6-tri-tert-butylanilide enolates.
(E)-2
R
Yield [%][a]
E/Z[b]
1
2
3
4
5
6
(E)-2a
(E)-2c
(E)-2d
(E)-2e
(E)-2 f
(E)-2g
CH3
PhCH2
cyclohexene-3-yl
nC3H7
81
88
84
88
93
78
1:4.6
1:4.1
1:2.2
1:4.6
1:3.7
1:6.1
iC3H7
cyclohexyl
[a] Yield of the isolated product. [b] Ratio estimated by 1H NMR
(400 MHz) spectroscopy.
6848
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Chem. Eur. J. 2013, 19, 6845 – 6850

Unique Structural Properties of 2,4,6-Tri-tert-butylanilide
FULL PAPER
Table 5. Thermal isomerization between the anilide rotamers.
gen atoms was observed, whereas, in the E rotamers, no
NOE between these hydrogen atoms was detected.
Conclusion
We have reported a unique isomerization between the sepa-
rable rotamers of 2,4,6-tri-tert-butylanilide derivatives
through the formation of the anilide enolate; that is, in ani-
lide enolates, interconversion between the rotamers readily
occurs at room temperature and their reaction with electro-
philes gives rotameric mixtures of the products in a ratio
that depends on the reactivity of the electrophiles. The reac-
tion of the 2,4,6-tri-tert-butylacetanilide enolate with reac-
2
R
E/Z[a,b]
E/Z[b,c]
1
2
3
4
5
6
2a
2c
2d
2e
2 f
2g
CH3
PhCH2
cyclohexene-3-yl
nC3H7
Z only
1:3.5
Z only
1:4.7
1:3.8
Z only
10:1
8.4:1
6.2:1
8.3:1
5.7:1
6.2:1
iC3H7
cyclohexyl
[a] Ratio before heating. [b] Ratio estimated by 1H NMR (400 MHz)
tive electrophiles predominantly gives the
E rotamer,
whereas, in the reaction with less-reactive electrophiles, the
Z-rotamer products predominate. The rotamer ratio in the
products is also strongly dependent on the reactivity of the
anilide enolate. Furthermore, as an application of this iso-
merization reaction, switching between the anilide rotamers
was achieved. These results show a new structural property
of 2,4,6-tri-tert-butylanilide derivatives.
spectroscopy. [c] Ratio after heating (equilibrium ratio).
The results of the thermal isomerization of anilides 2a–2g
are shown in Table 5. When anilides 2a–2g, in which the
Z rotamers were the major components, were heated for
20 h at 1008C in toluene, in all cases, equilibrium mixtures
were obtained in which the E rotamers were the major com-
ponents, with (E)-2/(Z)-2 ratios of 5.7:1 to 10:1. The E/Z
ratios of hindered anilides 2d, 2 f, and 2g (E/Z=5.7:1 to
6.2:1; Table 5, entries 3, 5, and 6) were slightly lower than
those of less-hindered anilides 2a, 2c, and 2e (E/Z=8.3:1 to
10:1; Table 5, entries 1,2,4). As mentioned in our previous
paper, these E-selectivities can be explained by the destabi-
Experimental Section
Melting points are uncorrected. 1H and 13C NMR spectra were recorded
at 400 and 100 MHz, respectively. Chemical shifts are expressed in d
(ppm) downfield of CHCl3 (d=7.26 ppm) and CDCl3 (d=77.0 ppm), re-
spectively. Mass spectra were recorded by using electron impact or chem-
ical ionization. Column chromatography was performed on silica gel (75–
150 mm). Medium-pressure liquid chromatography (MPLC) was per-
formed on a pre-packed silica-gel column (10 mm, 25ꢁ4 cm i.d.) with a
UV detector.
À
lization of the Z rotamer, owing to 1) the n p repulsion be-
tween the lone pair on the carbonyl oxygen atom and the p-
electron on the tert-butylphenyl group and 2) steric repul-
sion between the n-propyl group and the acyl substituent.[5.7]
Thus, reversible interconversion (switching) between ani-
lide rotamers was achieved through the protonation of ani-
lide enolates and the thermal isomerization of anilides
(Scheme 4).
General procedure for the a-alkylation of acetanilide 1a: Under a N2 at-
mosphere, nBuLi (0.24 mL, 1.6m in n-hexane) was added to a solution of
compound (E)-1a (104 mg, 0.3 mmol) in THF (4.0 mL). After stirring for
10 min at RT, a solution of 1-bromopropane (55 mg, 0.45 mmol) in THF
(1.0 mL) was slowly added (over 5 min) and the reaction mixture was
stirred for a further 30 min at RT. Then, the mixture was poured into a
2% HCl solution and extracted with EtOAc. The EtOAc extracts were
washed with brine, dried over MgSO4, and evaporated to dryness. Purifi-
cation of the residue by column chromatography on silica gel (n-hexane/
EtOAc, 20:1) gave a mixture of compounds (Z)-2e and (E)-2e (98 mg,
84% yield) in a 6.2:1 ratio. Compounds (Z)-2e (less polar) and (E)-2e
(more polar) were separated by MPLC (n-hexane/EtOAc, 20:1).
The stereochemistry of the anilide rotamers was deter-
1
mined based on the chemical shifts in their H NMR spec-
tra. In general, the a-hydrogen atoms in compounds (E)-2
and (E)-3 appeared at higher field (d=0.2–0.4 ppm) than
those of compounds (Z)-2 and (Z)-3, owing to the anisotro-
py that was caused by the large twist angle in the tert-butyl-
phenyl group. These stereochemical assignments were also
confirmed by NOESY experiments. For examples, in the
Z rotamers of compounds 2 f and 3e, a strong NOE correla-
tion between the N-CH2 hydrogen atoms and the a-hydro-
(Z)- and (E)-N-
2e and (E)-2e)
ACHTUNGTREN(NUNG n-Propyl)-N-(2,4,6-tri-tert-butylphenyl)pentamide ((Z)-
(Z)-2e: M.p. 97–988C; 1H NMR (CDCl3): d=7.36 (s, 2H), 3.37–3.42 (m,
2H), 2.24 (t, J=7.3 Hz, 2H), 1.65 (quint, J=7.5 Hz, 2H), 1.39 (sext, J=
7.5 Hz, 2H), 1.33 (s, 18H), 1.28 (s, 9H), 1.02–1.14 (m, 2H), 0.94 (t, J=
7.3 Hz, 3H), 0.85 ppm (t, J=7.3 Hz, 3H); 13C NMR (CDCl3): d=174.7,
148.0, 146.7, 132.0, 125.0, 53.2, 37.3, 34.8, 34.6, 33.1, 31.3, 26.3, 22.7, 20.3,
14.0, 11.6 ppm; IR (KBr): n˜ =1645 cmÀ1; MS: m/z: 388 [M+H]+; HRMS:
m/z calcd for C26H46NO: 388.3579 [M+H]+; found: 388.3582.
(E)-2e: M.p. 98–998C; 1H NMR (CDCl3): d=7.39 (s, 2H), 3.40–3.47 (m,
2H), 1.96 (t, J=7.3 Hz, 2H), 1.59 (quint, J=7.8 Hz, 2H), 1.32 (s, 18H),
1.31 (s, 9H), 1.24 (sext, J=7.8 Hz, 2H), 0.97–1.10 (m, 2H), 0.86 (t, J=
7.3 Hz, 3H), 0.83 ppm (t, J=7.3 Hz, 3H); 13C NMR (CDCl3): d=174.0,
149.0, 146.8, 131.8, 125.9, 51.8, 37.6, 35.9, 34.7, 33.5, 31.3, 26.6, 22.6, 19.5,
14.0, 11.6 ppm; IR (KBr): n˜ =1647 cmÀ1; MS: m/z: 388 [M+H]+; HRMS:
m/z calcd for C26H46NO: 388.3579 [M+H]+; found: 388.3584.
Scheme 4. Switching between anilide rotamers (E)-2 and (Z)-2.
Chem. Eur. J. 2013, 19, 6845 – 6850
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www.chemeurj.org
6849

O. Kitagawa et al.
General procedure for the a-alkylation of propionanilide 2a: Under a N2
atmosphere, nBuLi (0.37 mL, 1.6m in n-hexane) was added to a solution
of compound (E)-2a (107 mg, 0.3 mmol) in THF (4.0 mL). After stirring
for 30 min at RT, a solution of allyl bromide (73 mg, 0.6 mmol) in THF
(1.0 mL) was slowly added (over 5 min) and the reaction mixture was
stirred for a further 30 min at RT. Then, the mixture was poured into a
2% HCl solution and extracted with EtOAc. The EtOAc extracts were
washed with brine, dried over MgSO4, and evaporated to dryness. Purifi-
cation of the residue by column chromatography on silica gel (n-hexane/
EtOAc, 25:1) gave a mixture of compounds (Z)-3b and (E)-3b (118 mg,
98% yield) in a 6.8 ratio. Compounds (Z)-3b (less polar) and (E)-3b
(more polar) were separated by MPLC (n-hexane/EtOAc, 20:1).
Curran, J. Am. Chem. Soc. 1990, 112, 896–898; c) T. Ishikawa, M.
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Org. Lett. 2010, 12, 612–614.
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[4] For examples of separable amide rotamers, see: a) A. Mannschreck,
Tetrahedron Lett. 1965, 6, 1341–1347; b) L. Toldy, L. Radics, Tetra-
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1968, 101, 864–878; e) R. Schlecker, D. Seebach, W. Lubosch, Helv.
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Chem. 2000, 65, 419–425.
(Z)- and (E)-N-ACHTUNGTRENNUNG(n-Propyl)-N-(2,4,6-tri-tert-butylphenyl)-2-methyl-4-pen-
tenamide ((Z)-3b and (E)-3b)
(Z)-3b: M.p. 101–1038C; 1H NMR (CDCl3): d=7.38 (s, 2H), 5.83 (dddd,
J=6.4, 8.2, 10.1, 16.9 Hz, 1H), 5.09 (d, J=16.9 Hz, 1H), 5.06 (d, J=
10.1 Hz, 1H), 3.46–3.57 (m, 2H), 2.68 (m, 1H), 2.48 (m, 1H), 2.21 (td,
J=8.7, 14.2 Hz, 1H), 1.36 (s, 9H), 1.35 (s, 9H), 1.29 (s, 9H), 1.16 (d, J=
6.9 Hz, 3H), 1.03–1.14 (m, 2H), 0.84 ppm (t, J=7.3 Hz, 3H); 13C NMR
(CDCl3): d=176.9, 147.9, 146.8, 146.7, 136.5, 132.7, 125.2, 125.0, 116.9,
53.1, 37.6, 37.5, 37.1, 36.9, 34.6, 33.4, 31.3, 20.4, 15.5, 11.6 ppm; IR (KBr):
n˜ =1639 cmÀ1 MS: m/z: 400 [M+H]+; elemental analysis calcd (%)
;
C27H45NO: C 81.14, H 11.35, N 3.50; found: C 80.68, H 11.22, N 3.50.
[5] a) N. Ototake, T. Taguchi, O. Kitagawa, Tetrahedron Lett. 2008, 49,
5458–5460; b) N. Ototake, M. Nakamura, Y. Dobashi, H. Fukaya,
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Takahashi, S. Yamada, Y. Dobashi, O. Kitagawa, Tetrahedron Lett.
2011, 52, 53–55.
(E)-3b: M.p. 92–948C; 1H NMR (CDCl3): d=7.41 (s, 2H), 5.54 (dddd,
J=6.4, 8.2, 10.5, 17.0 Hz, 1H), 4.92 (d, J=10.5 Hz, 1H), 4.89 (d, J=
17.0 Hz, 1H), 3.42–3.48 (m, 2H), 2.37 (m, 1H), 2.08–2.25 (m, 2H), 1.36
(s, 9H), 1.35 (s, 9H), 1.31 (s, 9H), 1.04–1.17 (m, 2H), 1.02 (d, J=6.4 Hz,
3H), 0.90 ppm (t, J=7.3 Hz, 3H); 13C NMR (CDCl3): d=176.8, 148.9,
147.3, 147.1, 136.0, 130.7, 126.4, 116.8, 52.8, 37.72, 37.70, 37.6, 36.6, 34.6,
33.8, 33.7, 31.2, 19.5, 16.5, 11.6 ppm; IR (KBr): n˜ =1641 cmÀ1; MS: m/z:
400 [M+H]+; elemental analysis calcd (%) for C27H45NO: C 81.14,
H 11.35, N 3.50; found: C 80.76, H 11.34, N 3.54.
[6] For a preliminary communication of this work, see: Y. Ohnishi, M.
Sakai, S. Nakao, O. Kitagawa, Org. Lett. 2011, 13, 2840–2843.
[7] In N-substituted anilide derivatives, it is well-known that E rotamers
are generally more stable than their corresponding Z rotamers. The
thermal isomerization of 2,4,6-tri-tert-butylanilides also gives an
equilibrium mixture in which the E rotamer is the major component
(see reference [5] and Table 5). For anilide enolates 1A and 2A, the
E rotamers may also be thermodynamically more favored than the
Z rotamers. For a typical report on the preference of N-alkylated
anilide derivatives for the E rotamer, see: a) B. F. Pedersen, B. Ped-
ersen, Tetrahedron Lett. 1965, 6, 2995–3001; b) A. Itai, Y. Toriumi,
N. Tomioka, H. Kagechika, I. Azumaya, K. Shudo, Tetrahedron Lett.
1989, 30, 6177–6180; c) I. Azumaya, K. Yamaguchi, I. Okamoto, H.
Kagechika, K. Shudo, J. Am. Chem. Soc. 1995, 117, 9083–9084; d) S.
Saito, Y. Toriumi, N. Tomioka, A. Itai, J. Org. Chem. 1995, 60,
4715–4720.
[8] a) D. A. Evans, in Asymmetric Synthesis Vol. 3 (Ed.: J. D. Morrison),
Academic Press, New York, 1984, p. 84; b) Y. Kawanami, Y. Ito, T.
Kitagawa, Y. Taniguchi, T. Katsuki, M. Yamaguchi, Tetrahedron
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Kagaku Kyokaishi 1986, 44, 532–544; d) A. D. Hughes, D. A. Price,
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e) K. J. Kolonko, I. A. Guzei, H. J. Reich, J. Org. Chem. 2010, 75,
6163–6172.
General procedure for protonation of the copper enolate: Under a N2 at-
mosphere, nBuLi (0.30 mL, 1.6m in n-hexane) was added to a solution of
compound (E)-2e (97 mg, 0.25 mmol) in THF (3.0 mL). After stirring for
30 min at RT, CuI (48 mg, 0.25 mmol) was added and the reaction mix-
ture was stirred for a further 20 min at RT. Then, a solution of 2,6-di-tert-
butylphenol (119 mg, 0.58 mmol) in THF (4.0 mL) was slowly added to
the mixture (over 15 min) and the mixture was stirred for a further
30 min at RT. The mixture was poured into an aqueous solution of
NH4Cl and extracted with EtOAc. The EtOAc extracts were washed with
brine, dried over MgSO4, and evaporated to dryness. Purification of the
residue by column chromatography on silica gel (n-hexane/EtOAc, 20:1)
gave a mixture of compounds (E)-2e and (Z)-2e (85 mg, 88% yield) in a
4.6:1 ratio.
Acknowledgements
[9] For reports on switching between inseparable amide rotamers, see:
a) R. Yamasaki, A. Tanatani, I. Azumaya, S. Saito, K. Yamaguchi,
H. Kagechika, Org. Lett. 2003, 5, 1265–1267; b) I. Okamoto, R. Ya-
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Azumaya, H. Kagechika, A. Tanatani, Tetrahedron 2012, 68, 2778–
2783.
This work was party supported by a Grant-in-Aid for Scientific Research
and by the Ministry of Education, Science, Sports and Culture of Japan.
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[10] The use of nBuLi (1 equiv) resulted in a decrease in the chemical
yield, owing to the incomplete formation of the enolate.
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Received: January 19, 2013
Published online: March 27, 2013
6850
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Chem. Eur. J. 2013, 19, 6845 – 6850