Notable structural property of 2,4,6-Tri- tert -butylanilide enolates: Interconversion between the rotamers and their reactivity

Article abstract of DOI:10.1021/ol200814m

Interconversion between the separable 2,4,6-tri-tert-butylanilide rotamers was found to easily occur through formation of the lithium enolate. Protonation of the anilide enolate gave the anilide rotamer mixture of E-major. On the other hand, reactions of

Full text of DOI:10.1021/ol200814m

ORGANIC
LETTERS
2011
Vol. 13, No. 11
2840–2843
Notable Structural Property of
2,4,6-Tri-tert-butylanilide Enolates:
Interconversion between the Rotamers
and Their Reactivity
Yusuke Ohnishi, Masahi Sakai, Shouta Nakao, and Osamu Kitagawa*
Department of Applied Chemistry, Shibaura Institute of Technology, 3-7-5 Toyosu,
Koto-ku, Tokyo 135-8548, Japan
kitagawa@shibaura-it.ac.jp
Received March 29, 2011
ABSTRACT
Interconversion between the separable 2,4,6-tri-tert-butylanilide rotamers was found to easily occur through formation of the lithium enolate.
Protonation of the anilide enolate gave the anilide rotamer mixture of E-major. On the other hand, reactions of lithium enolate prepared from 2,4,6-
tri-tert-butylpropionanilide with alkyl bromides preferentially afforded a Z-rotamer of alkylated products.
Amide C(O)ÀN bonds have a higher rotational barrier
than a CÀN bond of simple amines because of the double
bond character. Rotational isomerism based on such
amide bonds plays an important role in the chemical
reactivity of substrates having an amide tether1 and the
regulation of actions of biologically active peptides.2 On
the other hand, amide rotamers are generally difficult to
isolate because their interconversion occurs easily at rt.
2,6-Di-tert-butyl anilide derivatives, which were reported
by Chupp et al. in 1967, are a rare example of separable
amide rotamers (Figure 1).3,4 However, a systematic study
using anilide substrates other than R-haloacetanilides and
stereoselective synthesis of anilide rotamers has not been
described. In addition, the structural properties between the
rotamers have not been investigated in detail.
(1) (a) Gshwend, H. W.; Lee, A. O. J. Org. Chem. 1978, 38, 2169–
2175. (b) Sniekus, V.; Cueva, J. C.; Solan, C. P.; Liu, H.; Curran, D. P.
J. Am. Chem. Soc. 1990, 112, 896–898. (c) Ishikawa, T.; Senzaki, M.;
Kadoya, R.; Miyake, N.; Izawa, M.; Saito, S. J. Am. Chem. Soc. 2001,
123, 4607–4608. (d) Bragg, R. A.; Clayden, J.; Morris, G. A.; Pink, J. H.
Chem.;Eur. J. 2002, 8, 1279–1289. (e) Li, X.; Curran, D. P. Org. Lett.
2010, 12, 612–614.
(2) (a) Tanatani, A.; Azumaya, I.; Kagechika, H. Yuki Gosei Kagaku
Kyokaishi 2000, 58, 556–567. (b) Cheng, R. P.; Gellman, S. H.; DeGra-
do, W. F. Chem. Rev. 2001, 101, 3219–3232. (c) Hill, D. J.; Mio, M. J.;
Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. Rev. 2001, 101, 3893–
4011. (d) Clayden, J.; Moran, W. J.; Edwards, P. J.; LaPlante, S. R.
Angew. Chem., Int. Ed. 2009, 48, 6398–6401.
(3) (a) Chupp, J. P.; Olin, J. F. J. Org. Chem. 1967, 32, 2297–2303. (b)
Molin, W. T.; Porter, C. A.; Chupp, J. P.; Naylor, K. Pest. Biochem.
Phys. 1990, 36, 277–280.
(4) Examples of separable amide rotamers: (a) Mannschreck, A.
Tetrahedron Lett. 1965, 1341–1347. (b) Toldy, L.; Radics, L. Tetrahe-
dron Lett. 1966, 4753–4757. (c) Staab, H. A.; Lauer, D. Tetrahedron Lett.
1966, 4593–4598. (d) Staab, H. A.; Lauer, D. Chem. Ber. 1968, 101, 864–
878. (e) Schlecker, R.; Seebach, D.; Lubosch, W. Helv. Chim. Acta 1978,
61, 512–516. (f) Seebach, D.; Wykypiel, W.; Lubosch, W.; Kalinowski,
H. O. Helv. Chim. Acta 1978, 61, 3100–3102. (g) Rice, K. C.; Brossi, A.
J. Org. Chem. 1980, 45, 592–601. (h) Hay, D. R.; Song, Z.; Smith, S. G.;
Beak, P. J. Am. Chem. Soc. 1988, 110, 8145–8153. (i) Tan, L. T.;
Williamson, R. T.; Gerwick, W. H. J. Org. Chem. 2000, 65, 419–425.
Figure 1. Separable 2,6-di-tert-butylanilide rotamers.
r
10.1021/ol200814m
Published on Web 05/06/2011
2011 American Chemical Society

Recently, we succeeded in the highly selective stereo-
divergent synthesis of E- and Z-rotamers of various N-al-
lylated 2,4,6-tri-tert-butylanilide derivatives using Pd
chemistry.5 Furthermore, the thermodynamic stabilities
of anilide rotamers were also clarified. In this paper, we
report on the novel structural property of 2,4,6-tritert-
butylanilide derivatives, namely, interconversion between
the anilide rotamers through the formation of the lithium
enolate and notable reactivity of the anilide enolate toward
several electrophiles(Scheme 1). Insomecases, thisprocess
occurs with almost complete inversion of the rotational
isomerism. The detailed mechanisms on the interconver-
sion and the reaction are also described.
E-2a = 1/2.4. This Z/E ratio (1/2.4) is very similar to that
(1/2.5) in the allylation of Z-1a at rt.
Scheme 2. Allylation with Lithium Enolate Prepared from Z-1a
and E-1a
Scheme 1. Interconversion between Anilide Rotamers through
the Formation of Lithium Enolates and the Reaction with an
Electrophile
A similar isomerization was also observed in the proto-
nation of the anilide enolate. The treatment of Z-1a with
n-BuLi for 10min atrtand subsequent protonationbyHCl
aq gave a rotamer mixture of E-major in a ratio of Z-1a/E-
1a = 1/3.0 (Scheme 3). Under the same conditions, the
reaction with E-1a also gave a rotamer mixture in the same
Z/E ratio (Z-1a/E-1a = 1/3.0). Such isomerization was
hardly observed through the treatment with n-BuLi for 10
min at À20 °C and subsequent protonation.
In the course of our investigation of the allylation with
lithium enolate prepared from N-propyl 2,4,6-tri-tert-bu-
tylacetanilide 1a, we unexpectedly found that the rota-
tional isomerism of the allylated product was remarkably
changed by the reaction temperature. That is, when the
Z-rotamer Z-1a was treated with n-BuLi for 10 min at
rt and subsequently reacted with an allyl bromide, the
E-rotamer of allylated product 2a was obtained as a major
isomer (Z-2a/E-2a = 1/2.5, Scheme 2). In contrast, the
enolateformation from Z-1aatÀ20°C and the subsequent
allylation gave Z-2a as a major rotamer (Z-2a/E-2a =
11.8/1, Scheme 2). In both reactions, allylated product 2a
was obtained in an excellent yield (98% and 90%).
Scheme 3. Protonation with Lithium Enolate Prepared from Z-
1a and E-1a
The allylation with E-rotamer E-1a was also examined.
Allylation of E-1a at À20 °C proceeded with almost
complete retention of the rotational isomerism to give E-
2a with a high rotamer ratio (Z-2a/E-2a = 1/28.6,
Scheme 2). On the other hand, in the allylation of E-1a
at rt, the rotamer mixture was obtained in a ratio of Z-2a/
These results indicate that the interconversion of the
anilide enolate 1A occurs quickly at rt (but slowly
at À20 °C) to afford the equilibrium mixture of E-1A and
Z-1A within 10 min (Figure 2). E-1A may be somewhat
(5) (a) Ototake, N.; Nakamura, M.; Dobashi, Y.; Fukaya, H.;
Kitagawa, O. Chem.;Eur. J. 2009, 15, 5090–5095. (b) Nakamura, M.;
Takahashi, I.; Yamada, S.; Dobashi, Y.; Kitagawa, O. Tetrahedron Lett.
2011, 52, 53–55.
Org. Lett., Vol. 13, No. 11, 2011
2841

more stable than Z-1A and exist as a major isomer.6 The
preferential generation of the E-rotamer observed in the
protonation and allylation of 1A at rt may be due to this
equilibrium ratio.
(30 min at rt), gave the mixture of the anilide rotamer in the
same ratio (Z-3a/E-3a = 1/2.1), respectively (entries 1,2).
These slight E-rotamer selectivities are similar to those of
protonation and allylation using acetanilide enolate 1A.
Table 1. Reaction of Propionanilide 3a with Several Electro-
philes
Figure 2. Interconversion between lithium enolates E-1A and
Z-1A.
The rotation around a NÀC bond of the enolate 1A
should easily occur in comparison with that of anilide 1a
because of the decrease in the double bond character. In
asymmetric R-alkylation using chiral amide enolates, it has
been pointed out that such a NÀC bond rotation brings
about a decrease in stereoselectivity.7 However, since the
amide rotamers of the R-alkylated products cannot be
isolated at rt, the NÀC bond rotation in the amide enolate
has so far been difficult to confirm. Scheme 2 should
provide the first direct evidence for NÀC bond rotation
in an amide enolate.
entry
3
EÀX
3 or 4
yield (%)a
Z/Eb
1
2
3
4
5
6
7
8
Z-3a
E-3a
Z-3a
E-3a
Z-3a
E-3a
Z-3a
E-3a
HÀCl aq
3a
3a
4a
4a
4b
4b
4c
4c
93
95
95
98
86
93
75
73
1/2.1
1/2.1
7.3/1
6.8/1
9.1/1
8.6/1
46/1
HÀCl aq
allylÀBr
allylÀBr
PhCH2ÀBr
PhCH2ÀBr
n-C3H7ÀBr
n-C3H7ÀBr
The reaction with the lithium enolate from N-propyl
2,4,6-tritert-butylpropionanilide 3a was further investi-
gated (Table 1).8 The protonation of enolate 3A, which
was prepared from Z-3a and E-3a by treating with n-BuLi
46/1
a Isolated yield. b The ratio was determined by 400 MHz 1H NMR.
(6) In N-substituted anilide derivatives, it is well-known that E-
rotamers are generally more stable than Z-rotamers. We also previously
reported that the isomerization of N-allyl 2,4,6-tri-tert-butyl-acetanilide
and -propionanilide under thermal conditions gives the equilibrium
mixture of E-major in E/Z ratios of 10.1 and 6.0, respectively (see ref
5a). The thermal instabilities of Z-rotamers have been rationalized on
the basis of n-π repulsion between the lone pairs on the carbonyl oxygen
and aromatic ring and steric repulsion with the substituent on nitrogen
atom. In anilide enolates 1A and 3A, E-rotamers may be also thermo-
dynamically favored more than Z-rotamers. Typical papers on the E-
rotamer preference of N-alkylated anilide derivatives: (a) Pederson,
B. F.; Pederson, B. Tetrahedron Lett. 1956, 2995–3001. (b) Itai, A.;
Toriumi, Y.; Tomioka, N.; Kagechika, H.; Azumaya, I.; Shudo, K.
Tetrahedron Lett. 1989, 30, 6177–6180. (c) Azumaya, I.; Yamaguchi, K.;
Okamoto, I.; Kagechika, H.; Shudo, K. J. Am. Chem. Soc. 1995, 117,
9083–9084. (d) Saito, S.; Toriumi, Y.; Tomioka, N.; Itai, A. J. Org.
Chem. 1995, 60, 4715–4720.
(7) (a) Evans, D. A. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1984; Vol. 3, p 84. (b) Kawanami, Y.; Ito, Y.;
Kitagawa, T.; Taniguchi, Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron
Lett. 1984, 25, 857–860. (c) Katsuki, T.; Yamaguchi, M. Yuki Gosei
Kagaku Kyokaishi 1986, 44, 532–544. (d) Hughes, A. D.; Price, D. A.;
Simpkins, N. S. J. Chem. Soc., Perkin Trans. 1 1999, 1295–1304. (e)
Kolonk, K. J.; Guzei, I. A.; Reich, H. J. J. Org. Chem. 2010, 75, 6163–
6172.
Contrarily, the reaction of enolate 3A from Z-3a and
E-3a with allyl bromide led to the preferential formation of
Z-rotamer Z-4a (entries 3, 4). In these cases, the mixture of
the allylated products Z-4aand E-4awas obtainedinratios
of Z/E = 7.3/1 and 6.8/1, respectively. In these reactions,
the THF solution of the allyl bromide was slowly added to
enolate 3A in THF (2À3 min), while the quick addition
of allyl bromide resulted in a considerable decrease in
Z-selectivity (Z/E = 1.1À3.1/1).9 The reaction with benzyl
bromide also proceeded with similar Z-selectivity to give
benzylated product4b in ratios of Z/E = 9.1/1 (from Z-3a)
and 8.6/1 (from E-3a), respectively (entries 5, 6). With
n-propyl bromide, the Z-isomer of propylated product Z-4c
was obtained in almost complete selectivity (Z/E = 46/1,
entries 7, 8). In particular, it should be noteworthy that
propylation of E-3a occurred with almost complete inver-
sion of the rotational isomerism to selectively afford the
Z-rotamer of the propylated product Z-4c (entry 8 and
Scheme 4).
(8) The stereochemistries of the alkylated products 2 and 4 were
determined based on chemical shifts in NMR spectra. R-Hydrogen
atoms of the E-rotamer appeared at higher fields than those of the Z-
rotamer because of the anisotropy effect caused by the tert-butylphenyl
group having a large twist angle (see ref 5a). These stereochemical
assignments were also confirmed by an NOE experiment. For example,
in the Z-isomer of propylation product 4c, the strong NOE between the
R-hydrogen atom and hydrogen atoms of N-CH2 was observed, while, in
the E-isomer, no NOE between these hydrogen atoms was detected.
The considerable changeof selectivity bythe electrophile
may be rationalized as follows (Figure 3). The protonation
(9) In the allylation with the enolate from acetanilide E-1a, the Z/E
ratio of the allylated product 2a was hardly changed by the addition rate
of the allyl bromide.
2842
Org. Lett., Vol. 13, No. 11, 2011

Scheme 4. Propylation with Lithium Enolate from E-3a
of enolate 3A proceeds at a faster rate than the intercon-
version between Z-3A and E-3A to give the rotamer
mixture 3a of E-major in a near-equilibrium ratio of
enolate 3A (similar to acetanilide enolate 1A, E-3A may
be slightly more stable than Z-3A6). On the other hand,
since the reaction of 3A with an alkyl bromide occurs at a
slow rate in comparison with the equilibrium rate between
Z-3A and E-3A, the rotamer ratio of the alkylated product
may depend on the relative reactivity of Z-3A and E-3A
rather than the equilibrium ratio. E-3A should be less
reactive than Z-3A, because the R-carbon of E-3A is
shielded by two ortho-tert-butyl groups. Accordingly, the
Z-products Z-4aÀc should be preferentially obtained
through the selective alkylation of reactive enolate Z-3A.
In particular, with less reactive n-propyl bromide, alkyla-
tion from the reactive Z-3A should occur with almost
complete selectivity.
Figure 3. Interconversion and reactivity of lithium enolate from
anilide 3a.
these anilide derivatives. Furthermore, the reaction me-
chanism on the basis of equilibrium and reactivity between
the rotamers of the anilide enolate intermediate was also
clarified.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds,
In conclusion, we found interconversion between 2,4,6-
tri-tert-butylanilide rotamers through the formation of an
anilide enolate and notable reactivity of the enolate toward
several electrophiles. This is a novel structural property of
1
and H and 13C NMR spectra of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 11, 2011
2843