Stereoselective synthesis of separable amide rotamers using π-allyl-Pd catalyst and their thermodynamic behavior

Article abstract of DOI:10.1016/j.tetlet.2008.07.017

Separable amide rotamers were prepared with moderate to excellent Z-selectivities by N-allylation of 2,4,6-tri-tert-butyl-NH-anilides using a π-allyl-Pd catalyst. The present allylation proceeded through a unique mechanism involving O-allylation and the subsequent O,N-allylic rearrangement. The prepared amide rotamers of Z-major changed to equilibrium mixtures of E-major when heated in toluene.

Full text of DOI:10.1016/j.tetlet.2008.07.017

Tetrahedron Letters 49 (2008) 5458–5460
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Tetrahedron Letters
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Stereoselective synthesis of separable amide rotamers using
p-allyl-Pd catalyst and their thermodynamic behavior
Nobutaka Ototake a, Takeo Taguchi a, Osamu Kitagawa b,
*
a School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
b Department of Applied Chemistry, Shibaura Institute of Technology, 3-7-5 Toyosu, Kohto-ku, Tokyo, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Separable amide rotamers were prepared with moderate to excellent Z-selectivities by N-allylation of
Received 6 June 2008
Revised 26 June 2008
Accepted 2 July 2008
Available online 4 July 2008
2,4,6-tri-tert-butyl-NH-anilides using a
p-allyl-Pd catalyst. The present allylation proceeded through a
unique mechanism involving O-allylation and the subsequent O,N-allylic rearrangement. The prepared
amide rotamers of Z-major changed to equilibrium mixtures of E-major when heated in toluene.
Ó 2008 Elsevier Ltd. All rights reserved.
O
+
N-Substituted ortho-tert-butylanilide derivatives often show
interesting structural properties. For example, ortho-mono-tert-
butylanilides I are stable atropisomeric compounds due to the
rotational restriction of the N–Ar bond, and have recently received
much attention as a new class of chiral molecules having an N–C
chiral axis (Eq. 1).1
CH2X
N
O
Me
t-Bu
Me
Cl
XH2C
t-Bu
base
O
t-Bu
N
R
XH2C
t-Bu
t-Bu
Δ
NHMe
t-Bu
ð2Þ
R
X=Cl, Br, I
O
Z-II (minor)
O
E-II (major)
"stable"
III
R
R'
"unstable"
Me
"rotational
restriction"
N
R
"rotational
restriction"
-Bu
N
XH2C
-Bu
(R = H, E/Z = 5.6 - 9)
t
t-Bu
t
ð1Þ
In connection with our study on atropisomeric ortho-mono-
tert-butylanilides,4 we felt an interest in 2,6-di-tert-butylanilide
derivatives. In this Letter, we report Z-rotamer-selective synthesis
of various N-allylated 2,4,6-tri-tert-butylanilides through allylation
(large twisting of
aromatic ring)
I
II
"separable amide rotamer"
"axially chiral"
using
a
p-ally-Pd catalyst. Furthermore, unique reaction
On the other hand, in 2,6-di-tert-butylanilide derivatives II
(achiral), the amide rotational isomer can be isolated by rota-
tional restriction around the C(O)–N bond (the rotational barri-
ers = 27–28 kcal/mol) as well as the N–Ar bond (Eq. 1).2
Although such anilides II, which were reported by Chupp et al.
in 1967, should be noted as rare examples of separable amide
rotamers,2,3 systematic investigation using other anilide sub-
mechanism of the present allylation, involving O-allylation and
subsequent O,N-allylic rearrangement, and investigation on
isomerization of these anilide rotamers under thermal conditions
are also described.
2,6-Di- and 2,4,6-tri-tert-butyl-NH-anilides are known to exist
as equilibrium mixture of Z-major (Z/E ’ 8) in solution.5 Accord-
ingly, it was expected that Z-rotamer may be obtained as a
major isomer by N-alkylation of 2,6-di- or 2,4,6-tri-tert-butyl-
NH-anilide. N-Allylation with NH-anilide 1a prepared from
commercially available 2,4,6-tri-tert-butylaniline was initially
examined. However, the reaction of the amide anion from 1a
and NaH with allyl bromide in DMF gave O-allylated imidate
3a in a good yield in place of the desired N-allylated anilide
2a (Eq. 3). This unusual O-allylation should be specific to 2,6-
di-tert-butyl derivatives, because allylation with ortho-mono-
tert-butylanilide under the same conditions gave a quantitatively
N-allylated product.
strates except for
a-haloacetanilides II (X = Cl, Br, I) have not
been performed. Moreover, since their synthesis through the
acylation of N-methyl-2,6-di-tert-butylaniline III requires high
reaction temperature (100–140 °C) because of the low reactivity
of III, the mixtures of E- and Z-rotamers were obtained in a near
equilibrium ratio (E/Z = 5.6–9, Eq. 2). Thus, the stereoselective
synthesis of the thermodynamically unstable Z-rotamer (Z-II)
has not yet been established.
* Corresponding author. Tel.: +81 3 5859 8161; fax: +81 3 5859 8101.
E-mail address: kitagawa@shibaura-it.ac.jp (O. Kitagawa).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.017

N. Ototake et al. / Tetrahedron Letters 49 (2008) 5458–5460
5459
Table 1
O
C2H5
NH
Z-Selective N-allylation of various 2,4,6-tri-tert-butyl anilides
1) 2.3 eq
C2H5
-Bu
NH
O
-Bu
NaH
R
t-Bu
t
t-Bu
t
2) R-X
5.0 mol% dppf
2.2 mol% (allyl-Pd-Cl)2
1.5 eq. CH2=CH-CH2OAc
O
-Bu
NH
DMF, rt
2.3 eq.
NaH
t
-Bu
t
Z-2
+
E-2
(minor)
t
-Bu
t-Bu
DMF, rt, 15 h
(major)
E-1a (minor)
Z-1a (major)
1
t-Bu
R
N
Yielda (%)
Z/Eb
C2H5
O
Entry
1
R
2
ð3Þ
R
C2H5
-Bu
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
Et
Me
Me2CH
Cyclohexyl
MeO2C
2a
2b
2c
2d
2e
2f
99
91
99
81
85
38
70
4.9
3.2
>50
>50
>50
>50
3
O
-Bu
N
t-Bu
t
t
-Bu
t
+
t
-Bu
p-Br–C6H4
MeCH@CH
t
-Bu
(N-alkyl)
2a (trace)
4a (57%, E/Z = 1/2)
1g
2g
R-X
(O-alkyl)
a
Isolated yield.
allyl-Br
Me-I
3a (94%)
5a (39%)
b
The ratio was estimated by 300 MHz 1H NMR.
The formation of such an O-alkylation product was also ob-
served in the reaction of 1a with iodomethane, in this case, a mix-
ture of N- and O-methylation products 4a and 5a was obtained in
57% and 39% yields, respectively (Eq. 3). The steric crowd around
the amide nitrogen atom by two ortho-tert-butyl groups should
cause the unusual O-alkylation of 1a.
The use of dppf as a phosphine ligand led to a further increase in
the chemical yield and Z-rotamer selectivity, in this case, 2a was
obtained with an excellent yield (99%) in a ratio of Z/E = 4.9 (Table
1, entry 1). Under optimized conditions [NaH (2.3 equiv), allyl ace-
tate (1.5 equiv), dppf (5.0 mol %) and (allyl-Pd-Cl)2 (2.2 mol %) in
DMF at rt], N-allylations of various 2,4,6-tri-tert-butyl-NH-anilides
1 were further examined (Table 1).9 In the reaction with acetani-
lide derivative 1b, a slight decrease in Z-rotamer selectivity was
observed (Z-2b/E-2b = 3.2, entry 2). On the other hand, the reaction
After surveying several reactions, we found that the N-allylation
of 1a efficiently proceeds by using
p
-allyl-Pd complex.6 That is,
when amide anion prepared from 1a and NaH (2.3 equiv) was trea-
ted with allyl acetate in the presence of rac-BINAP-(allyl-Pd-Cl)2
catalyst in DMF at rt, anilide 2a was obtained in a good yield
(80%) without the formation of imidate 3a (Scheme 1). Further-
more, in the present reaction, Z-2a was obtained as a major rot-
amer (Z/E = 4).
of anilides 1c and 1d prepared from
a-branched carboxylic acid
proceeded in almost a complete Z-selective manner (entries 3
and 4). The reaction with amidester 1e and benzamide 1f also gave
Z-2e and Z-2f with almost complete selectivity (entries 5 and 6),
while with
a,b-unsaturated amide 1g, product 2g was obtained
with moderate Z-selectivity (Z/E = 3, entry 7). These reactions pro-
ceeded with good to excellent yields (70–99%, entries 1–5 and 7)
except for that of benzamide 1f (entry 6, 38%).10
By careful TLC monitoring, it was found that in the present reac-
tion, imidate 3a is initially formed and then the resulting 3a
changes to anilide 2a via reproduction of
p-allyl-Pd complex and
Z-Selectivity observed in the present reaction may be rational-
ized in accordance with the transition state model shown in Figure
1.11 The transition state (TS-E) for E-2 may be disfavored in com-
parison with TS-Z for Z-2 because of the steric repulsion between
substituent R and the ortho-tert-butyl group in the iminoalcoholate
intermediate. In the reactions of 1c and 1d having bulky substitu-
ent R, such as isopropyl and cyclohexyl groups, excellent Z-selec-
tivity would be observed by further destabilization of TS-E.
Next, the thermodynamic behavior of the obtained various
N-allyl anilides 2a–g was investigated. 2a–g existed without
isomerization between the E- and Z-rotamers for several days at
anilide anion (Scheme 1). Indeed, smooth conversion to N-allylated
amide 2a was observed by treating isolated 3a with BINAP-Pd cat-
alyst and NaH (1 equiv). As far as we know, in allylations of amide
derivatives using a p-allyl-Pd complex, there has been no report on
a reaction which proceeds via such O-allylation and subsequent
O,N-allylic rearrangement.7,8
C2H5
N
O
2.3 eq. NaH
5.0 mol% rac-BINAP
2.2 mol% (allyl-Pd-Cl)2
1.5 eq. CH2=CHCH2OAc
C2H5
-Bu
N
O
-Bu
t
-Bu
t
t-Bu
t
1a
+
DMF, rt
3 (O-allyl)
t
-Bu
t-Bu
E-2a (16%)
Z-2a (64%)
-
O
-
R
"O-allylation"
O
(II)
(II)
"N-allylation"
R
-Bu
N
O
-Bu
N
Pd
Pd
t
-Bu
t
t-Bu
t
X
X
<
C2H5
N
Ph2
(II)
P
t-Bu
C2H5
-Bu
N
t-Bu
O
-Bu
Pd
Ph2
X
Pd(0)
P
t-Bu
t
t
-Bu
t
TS-Z
TS-E
t
-Bu
t-Bu
3a
Z-2 (major)
E-2 (minor)
Scheme 1. N-Allylation of 2,4,6-tri-tert-butyl-NH-anilide using
p
-allyl-Pd catalyst.
Figure 1. Transition state model for Z-selective N-allylation.

5460
N. Ototake et al. / Tetrahedron Letters 49 (2008) 5458–5460
3. Typical examples of separable amide rotamers: (a) Mannschreck, A.
O
R
Tetrahedron Lett. 1965, 1341; (b) Staab, H. A.; Lauer, D. Tetrahedron Lett.
1966, 4593; (c) Schlecker, R.; Seebach, D.; Lubosch, W. Helv. Chim. Acta 1978,
61, 512; (d) Seebach, D.; Wykypiel, W.; Lubosch, W.; Kalinowski, H. O. Helv.
Chim. Acta 1978, 61, 3100.
"steric
repulsion"
R
N
O
-Bu
N
Δ
t-Bu
t
-Bu
t
-Bu
t
(toluene, 100 ºC
10 - 30 h)
4. Our papers on atropisomeric ortho-mono-tert-butylanilides: (a) Kitagawa, O.;
Izawa, H.; Sato, K.; Dobashi, A.; Taguchi, T.; Shiro, M. J. Org. Chem. 1998, 63,
2634; (b) Kitagawa, O.; Takahashi, M.; Yoshikawa, M.; Taguchi, T. J. Am. Chem.
Soc. 2005, 127, 3676; (c) Kitagawa, O.; Yoshikawa, M.; Tanabe, H.; Morita, T.;
Takahashi, M.; Dobashi, Y.; Taguchi, T. J. Am. Chem. Soc. 2006, 128, 12923.
5. Zyryanov, G. V.; Hampe, E. M.; Rudkevich, D. M. Angew. Chem., Int. Ed. 2002, 41,
3854.
"steric
repulsion"
t
-Bu
"n-π repulsion"
Z-2 (minor)
t
-Bu
E-2 (major)
2a (R = Et, E/Z =6), 2b (R = Me, E/Z = 10), 2c (R = Me2CH, E/Z= 1.4),
2d (R = cyclohexyl, E/Z = 1.4), 2e (R = CO2Me, E/Z = 4),
2f (R = p-Br-C6H4, E/Z = 3), 2g (R = MeCH=CH, E/Z = 5)
6. (a) Tsuji, J. J. Syn. Org. Chem. Jpn. 1999, 57, 1036; (b) Trost, B. M. Acc. Chem. Res.
1980, 13, 385.
7. The allylation of ortho-mono-tert-butylanilide using
a p-allyl-Pd catalyst
directly gave N-allylated product without the formation of an O-allylation
product: (a) Kitagawa, O.; Kohriyama, M.; Taguchi, T. J. Org. Chem. 2002,
67, 8682; (b) Terauchi, J.; Curran, D. P. Tetrahedron: Asymmetry 2003, 14,
587.
Figure 2. Thermal isomerization between E-2 and Z-2.
8. It is obvious that the present O,N-allylic rearrangement does not proceed via
rt. Meanwhile, 2a–g of Z-major changed to equilibrium mixture of
E-major when heated for 10–30 h at 100 °C in toluene (Fig. 2). The
equilibrium ratio (E/Z = 1.4–10) considerably depended on substi-
tuent R. The E-rotamer preference of 2 may be explained on the ba-
aza-Claisen reaction, but via reproduction of
p-allyl-Pd complex, because the
reaction through aza-Claisen mechanism should give E-rotamer. Typical papers
on Pd-catalyzed conversions from O-allyl imidates to N-allyl amides: (a)
Overman, L. E. Acc. Chem. Res 1980, 13, 218; (b) Ikariya, T.; Ishikawa, Y.; Hirai,
K.; Yoshikawa, S. Chem. Lett. 1982, 1815; (c) Schenck, T. G.; Bosnich, B. J. Am.
Chem. Soc. 1985, 107, 2058; (d) Calter, M.; Hollis, T. K.; Overman, L. E.; Ziller, J.;
Zipp, C. G. J. Org. Chem. 1997, 62, 1449.
sis of n–p repulsion between the lone pairs on the carbonyl oxygen
and aromatic ring, and steric repulsion between R and allyl group
(Fig. 2).12 Namely, the destabilization of the Z-rotamer due to both
9. General procedure for N-allylation of 2,4,6-tri-tert-butyl-NH-anilide 1. Under an
Ar atmosphere, to 1b (752 mg, 2.48 mmol) in DMF (10 mL) was added NaH
(228 mg, 5.7 mmol, 60% assay). After being stirred for 5 min at rt, the
suspension of (allyl-Pd-Cl)2 (19.8 mg, 0.054 mmol), dppf (68.7 mg,
0.124 mmol), and allyl acetate (0.4 mL, 3.72 mmol) in DMF (3.0 mL) was
added to the mixture, and then the reaction mixture was stirred for 15 h at rt.
The mixture was poured into 2% HCl solution and extracted with AcOEt. The
AcOEt extracts were washed with brine, dried over MgSO4, and evaporated to
dryness. Purification of the residue by column chromatography (hexane/
AcOEt = 12) gave the mixture of Z-2b and E-2b (787 mg, 92%, E/Z = 3.2). Z-2b
(more polar) and E-2b (less polar) were separated by MPLC (hexane/AcOEt = 7).
the n–p repulsion and the steric repulsion may bring about the E-
rotamer preference.4c,12,13 In the cases of 1c and 1d having bulky
substituent R, the decrease in the E/Z ratio of 2 should be observed
because of strong steric repulsion between R and the tert-butyl-
phenyl group in E-2 (E/Z = 1.4).
In conclusion, we succeeded in the development of stereoselec-
tive synthetic method of separable amide rotamer through N-ally-
lation using p-allyl-Pd catalyst. This result should be noted as very
Z-2b: mp 141–143 °C; IR (KBr) 1649 cmꢀ1 1H NMR (CDCl3) d: 7.39 (2H, s), 5.41
;
(1H, tdd, J = 6.7, 10.2, 17.0 Hz), 5.16 (1H, qd, J = 1.3, 17.0 Hz), 5.02 (1H, qd,
J = 1.3, 10.2 Hz), 4.23 (2H, td, J = 1.3, 6.7 Hz), 2.11 (3H, s), 1.37 (18H, s), 1.28 (9H,
s);13C NMR (CDCl3) d: 172.9, 148.3, 146.4, 132.1, 131.7, 125.4, 118.5, 56.2, 37.3,
34.6, 33.1, 31.3, 23.7; MS (m/z) 344 (MH+). Anal. Calcd for C23H37NO: C, 80.41;
H, 10.86; N, 4.08. Found: C, 80.33; H, 10.58; N, 3.96. E-2b: mp 70–73 °C; IR
few examples of kinetically controlled stereoselective synthesis of
separable amide rotamers.3c,d,14 Furthermore, the interesting
mechanism of the present N-allylation, which proceeds via O-ally-
lation and subsequent O,N-allylic rearrangement, and the thermo-
dynamic stabilities of the various prepared amide rotamers were
clarified. Rotamers based on an amide C(O)–N bond play an impor-
tant role in the regulation of the actions in biologically active pep-
tides and functional molecules having amide skeletons.15 Thus, the
present work should provide broad interest from the viewpoint of
structural organic chemistry as well as unique stereoselective reac-
(KBr) 1655 cmꢀ1 1H NMR (CDCl3) d: 7.42 (2H, s), 5.38 (1H, tdd, J = 6.8, 10.2,
;
17.1 Hz), 5.19 (1H, qd, J = 1.5, 17.1 Hz), 5.01 (1H, qd, J = 1.5, 10.2 Hz), 4.27 (2H,
br d, J = 6.8 Hz), 1.85 (3H, s), 1.34 (18H, s), 1.31 (9H, s);13C NMR (CDCl3) d:
171.7, 149.4, 146.7, 132.9, 132.1, 125.9, 118.8, 53.5, 37.6, 34.7, 33.4, 31.3, 24.4;
MS (m/z) 344 (MH+). Anal. Calcd for C23H37NO: C, 80.41; H, 10.86; N, 4.08.
Found: C, 80.34; H, 10.75; N, 3.98.
10. Unfortunately, under the same conditions, the reaction with 2,4,6-tri-tert-
butylchloroacetanilide gave a complex mixture.
11. The stereochemistries of 2a and 2e were determined by NOESY experiment. In
tion (rotamer-selective reaction) and p-allyl-Pd chemistry.
Z-2a and Z-2e, strong NOE between allylic hydrogen and
ester Me group (2e) was observed. Stereochemistries of 2b–d, 2f, and 2g were
determined on the basis of chemical shifts of -hydrogens or ortho-hydrogens
in 1H NMR. That is,
-hydrogens and ortho-hydrogens of E-rotamers appeared
a-hydrogen (2a) or
a
Supplementary data
a
in higher field than those of Z-rotamers because of an anisotropy effect by the
tert-butylphenyl group having large twist angle.3
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.07.017.
12. Typical papers on the E-rotamer preference of N-alkylated anilide derivatives:
(a) Pederson, B. F.; Pederson, B. Tetrahedron Lett. 1956, 2995; (b) Itai, A.;
Toriumi, Y.; Tomioka, N.; Kagechika, H.; Azumaya, I.; Shudo, K. Tetrahedron Lett.
1989, 30, 6177; (c) 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; (d) Azumaya, I.; Yamaguchi, K.; Okamoto, I.; Kagechika, H.; Shudo, K. J.
Am. Chem. Soc. 1995, 117, 9083.
References and notes
1. Typical papers on atropisomeric ortho-mono-tert-butylanilides: (a) Kawamoto,
T.; Tomishima, M.; Yoneda, F.; Hayami, J. Tetrahedron Lett. 1992, 33, 3169; (b)
Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. J. Am. Chem. Soc. 1994, 116, 3131;
(c) Kishikawa, K.; Tsuru, I.; Kohomoto, S.; Yamamoto, M.; Yamada, K. Chem. Lett.
1994, 1605; (d) Clayden, J. Angew. Chem., Int. Ed. 1997, 36, 949; (e) Hughes, A.
D.; Price, D. A.; Simpkins, N. S. J. Chem. Soc., Perkin Trans. 1 1999, 1295; (f) Bach,
T.; Schröder, J.; Harms, K. Tetrahedron Lett. 1999, 40, 9003; (g) Kondo, K.; Iida,
T.; Fujita, H.; Suzuki, T.; Yamaguchi, K.; Murakami, Y. Tetrahedron 2000, 56,
8883; (h) Dantale, S.; Reboul, V.; Metzner, P.; Philouze, C. Chem. Eur. J. 2002, 8,
632; (i) Tetrahedron Symposium-in-print on Atropisomerism, Clayden, J. Ed.,
Tetrahedron 2004, 60, 4325.
13. E-Rotamer preference of N-methylanilides has been rationalized on the basis of
such n–p interaction: Saito, S.; Toriumi, Y.; Tomioka, N.; Itai, A. J. Org. Chem.
1995, 60, 4715. See also Ref. 4c.
14. (a) Beak, P.; Zajdel, W. J. J. Am. Chem. Soc. 1984, 106, 1010; (b) Hay, D. R.; Song,
Z.; Smith, S. G.; Beak, P. J. Am. Chem. Soc. 1988, 110, 8145; (c) Yokokawa, F.;
Sameshima, H.; Shioiri, T. Synlett 2001, 986; (d) Deng, S.; Taunton, J. J. Am.
Chem. Soc. 2002, 124, 916.
15. (a) Tanatani, A.; Azumaya, I.; Kagechika, H. J. Syn. Org. Chem. Jpn. 2000, 58, 556;
(b) Chen, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001, 101, 3219; (c)
Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. Rev. 2001,
101, 3893.
2. (a) Chupp, J. P.; Olin, J. F. J. Org. Chem. 1967, 32, 2297; (b) Molin, W. T.; Porter, C.
A.; Chupp, J. P.; Naylor, K. Pest. Biochem. Phys. 1990, 36, 277.