Diverging chemoselective reactions of separable amide rotational isomers

Article abstract of DOI:10.1021/ol902808m

[Chemical equation presented] Diverging chemoselective reactions of a pair of amide rotamers have been observed by separating the rotamers and then reacting them individually. Reduction of (Z)-N-allyl-2-(phenylselanyl)-W-(2,4,6- tri-iert-butylphenyl)aceta

Full text of DOI:10.1021/ol902808m

ORGANIC
LETTERS
2010
Vol. 12, No. 3
612-614
Diverging Chemoselective Reactions of
Separable Amide Rotational Isomers
Xiben Li and Dennis P. Curran*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
curran@pitt.edu
Received December 8, 2009
ABSTRACT
Diverging chemoselective reactions of a pair of amide rotamers have been observed by separating the rotamers and then reacting them
individually. Reduction of (Z)-N-allyl-2-(phenylselanyl)-N-(2,4,6-tri-tert-butylphenyl)acetamide with tributyltin hydride at room temperature provides
only the product of 5-exo cyclization, 4-methyl-1-(2,4,6-tri-tert-butylphenyl)pyrrolidin-2-one. In contrast, reduction of the corresponding (E)
amide rotational isomer under identical conditions provides only the reduced product, (E)-N-allyl-N-(2,4,6-tri-tert-butylphenyl)acetamide. Such
diverging reactions of rotamers may be common in transformations involving reactive intermediates (carbenes, radicals, organometallic
intermediates) that have low barriers to onward reactions relative to amide rotation.
Amides with two different substituents on nitrogen gener-
ally exist as pairs of E/Z rotamers,1,2 and selective reactions
of these rotamers are therefore possible.3 For example,
directed metalations of amides typically occur on the
substituent cis to the carbonyl oxygen,4 and rotamer features
of proline-containing amides in peptides and proteins can
dictate their shape and therefore reactions in biological
settings.5 There can also be rotamer preferences when amide-
containing small molecules bind to larger molecules.6
In many amide transformations, a reactive rotamer un-
dergoes a binding or reaction event, while an unreactive
rotamer does not.7 Instead, the unreactive rotamer converts
to the reactive one, then the binding or reaction event shifts
the equilibrium. In other words, both rotamers give the same
product. Figure 1, scenario “a”, illustrates one such pos-
sibility: the selective reaction of RB in one of the rotamers.
This scenario is very common in intramolecular reactions
such as metatheses8 or Diels-Alder reactions9 between an
amide C-N substituent (here RB) and the acyl substituent
R to make a ring.
(1) (a) Stewart, W. E.; Slidell, T. H. Nuclear Magnetic Resonance Studies
of Amides. Chem. ReV. 1970, 70, 517–551. (b) Oki, M. Recent Advances
in Atropisomerism. In Top. Stereochem.; Allinger, N. L., Eliel, E., Wilen,
S. H., Eds.; 1983; Vol. 14, pp 1-81. (c) Oki, M. The Chemistry of Rotational
Isomers; Springer-Verlag: New York, 1993
.
(2) The descriptors E and Z are used here to name amide C(O)-N
rotamers by analogy to the usual E/Z nomenclature for alkenes.
(3) Wolf, C. Dynamic Stereochemistry of Organic Compounds; RSC
Publishing: Cambridge, UK, 2008.
Reactions of amide C(O)-N rotamers with diverging
selectivity have also been postulated.10 That is, under
(4) (a) Seebach, D.; Wykypiel, W.; Lubosch, W.; Kalinowski, H.-O.
HelV. Chim. Acta 1978, 61, 3100–3102. (b) Schlecker, R.; Seebach, D.;
Lubosch, W. HelV. Chim. Acta 1978, 61, 512–526. (c) Hay, D. R.; Song,
Z.; Smith, S. G.; Beak, P. J. Am. Chem. Soc. 1988, 110, 8145–8153.
(5) Etzkorn, F. A.; Travins, J. M.; Hart, S. A. AdVances in Amino Acid
Mimetics and Peptidomimetics; Abell, A., Ed.; Jai Press: Stamford, CT,
1999; Vol. 2, pp 125-163.
(7) Both scenarios in Figure 1 and other variants are described in detail
by Curtin-Hammett Winstein-Holness kinetics: Seeman, J. I. Chem. ReV.
1983, 83, 83–135.
(8) For example: (a) Rodriguez, S.; Castillo, E.; Carda, M.; Marco, J. A.
Tetrahedron 2002, 58, 1185–1192. (b) Colombo, L.; Di Giacomo, M.; Vinci,
V.; Colombo, M.; Manzoni, L.; Scolastico, C. Tetrahedron 2003, 59, 4501–
4513.
(6) Clayden, J.; Moran, W. J.; Edwards, P. J.; LaPlante, S. R. Angew.
Chem., Int. Ed. 2009, 48, 6398–6401.
(9) Roush, W. R. ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, p 513.
10.1021/ol902808m  2010 American Chemical Society
Published on Web 12/28/2009

Kitagawa12 and on the speed and efficiency of tin hydride
mediated cyclizations of R-amidoyl radicals with N-allyl
substituents.10c-e,13
Amide rotational isomers 3Z and 3E were synthesized in
two steps as shown in Scheme 1. Acylation of the sodium
Scheme 1. Stereoselective Syntheses of Amide Rotamers 3Z/3E
Figure 1. Two scenarios for reactions of amide rotamers.
identical reaction conditions, the E-rotamer gives one
product, while the Z-rotamer gives another. Assorted selec-
tivities are possible. Figure 1, scenario “b”, illustrates the
case where one of the rotamers undergoes a reaction on the
amide substituent (here RB f RC), while the other reacts on
the acyl group (R f R′). These reactions typically occur
through reactive intermediates (not shown) whose barriers
for onward reaction must be lower than their barriers for
amide rotation.
salt of 2,4,6-tri-tert-butylaniline 1 with 2-phenylselanyl acetyl
chloride provided 2-(phenylselanyl)-N-(2,4,6-tri-tert-butyl-
phenyl)acetamide 2 in 56% yield. Palladium-catalyzed N-
allylation according to Kitagawa and co-workers12 occurred
under kinetic control to provide a 76/24 mixture of 3Z/3E
in 69% yield. The stereostructures were assigned by char-
1,12
1
acteristic features in the H NMR spectra.
The case for rotational selectivity is generally built on
circumstantial evidence. For example, it is argued that
identical ratios of rotamers in a precursor and a pair of
different products is not likely coincidence but instead
transpires because each rotamer gives one of the products
and not the other.10 Building this kind of circumstantial
case is usually necessary because amide bond rotation of
both the precursors and the products takes place on the
time scale of the experiments and analysis.
Isomers 3Z and 3E could not be separated over standard
silica gel; however, prolonged heating of the 76/24 mixture
in refluxing toluene established equilibrium at a ratio of 9/91.
In a more careful experiment, the ratio of isomers was
followed as a function of time, and the data were processed
in the usual way to provide the rotation barrier. At 70 °C, k
from Z to E is 6.6 × 10-5 s-1, and ∆G‡ ) 26.8 kcal/mol. At
room temperature, the half-life for isomerization from Z to
E is about four months.
Here we catch two amide rotational isomers in the act of
diverging chemoselective reactions. This demonstration
builds on the long-known11 but little recognized4a,b,6 property
that some amide rotamers are stable enough to be separated,
on a recent stereoselective synthesis of such amides by
Figure 2 shows the mechanistic framework for the ensuing
chemoselective radical reductions of 3Z and 3E. Abstraction
of the phenylselanyl group from the precursors 3 by tin
radical provides radicals 4Z and 4E which, like their
precursors, are rotational isomers. Radical 4Z is poised to
undergo 5-exo cyclization followed by hydrogen atom
transfer to give lactam 5.
(10) (a) Cohen, T.; McMullen, C. H.; Smith, K. J. Am. Chem. Soc. 1968,
90, 6866–6867. (b) Snieckus, V.; Cuevas, J. C.; Sloan, C. P.; Liu, H.; Curran,
D. P. J. Am. Chem. Soc. 1990, 112, 896–898. (c) Curran, D. P.; Tamine, J.
J. Org. Chem. 1991, 56, 2746–2750. (d) Esker, J. L.; Newcomb, M. J.
Org. Chem. 1993, 58, 4933–4940. (e) Esker, J. L.; Newcomb, M. J. Org.
Chem. 1994, 59, 2779–2786.
In contrast, 4E is geometrically prohibited from cyclizing
and can only give reduced acetamide 6E.10c-e If all these
(11) (a) Mannschreck, A. Tetrahedron Lett. 1965, 6, 1341–1347. (b)
Staab, H. A.; Lauer, D. Tetrahedron Lett. 1966, 7, 4593–4598. (c) Chupp,
J. P.; Olin, J. F. J. Org. Chem. 1967, 32, 2297–2303. (d) Staab, H. A.;
Lauer, D. Chem. Ber. 1968, 101, 864–878.
(12) (a) Ototake, N.; Taguchi, T.; Kitagawa, O. Tetrahedron Lett. 2008,
49, 5458–5460. (b) Otatake, N.; Nakamura, M.; Dobashi, Y.; Fukaya, H.;
Kitagawa, O. Chem.sEur. J. 2009, 15, 5090–5095
.
(13) Stork, G.; Mah, R. Heterocycles 1989, 28, 723–727
.
Org. Lett., Vol. 12, No. 3, 2010
613

provided products 5 and 6E in ratios that matched the
precursors within experimental error (entries 1 and 2). In an
attempt to erode this selectivity by promoting crossover of
the radicals 4, we also conducted a pair of related experi-
ments at 90 °C in toluene (AIBN initiation). But again, the
product ratios reflected those of the precursors in each
experiment (entries 3 and 4).
These results are already an advance over prior experi-
ments because we could measure product ratio from two
different starting material compositions (kinetic and ther-
modynamic) rather than one. This rules out coincidental
matching of precursor and product ratios. Finally, in survey-
ing various separation options, we discovered that 3Z and
3E could be conveniently separated on a Whelk-O1 col-
umn.14 Though this chiral column is usually used for
enantiomer separation, it served well here for preparative
separation of the diastereomers. Indeed, room temperature
reduction of isomerically pure 3Z provided only lactam 5
with no directly reduced product (entry 5), whereas an
identical reduction of 3E provided only directly reduced
product 6E without detectable amounts of constitutional
isomer 5 (entry 6).
In summary, we have directly observed diverging chemose-
lective reactions of a pair of amide rotamers by separating
them and then reacting them individually under identical
conditions. Different products were formed with no detect-
able crossover. Such reactions are probably rather rare in
direct thermal reactions of amides because the reaction
barriers are higher than those of amide rotation. However,
they are probably rather common in transformations involv-
ing reactive intermediates (carbenes, radicals, organometallic
intermediates) that have low barriers to onward reactions
relative to amide rotation.
Figure 2. Mechanistic framework for diverging reactors of radicals
4Z/4E.
reactions are faster than amide bond rotations, then the ratios
of the products 5 and 6Z should match the ratio of precursors
3Z and 3E. Loss of chemoselectivity could occur by
interconversion of either the precursors 3 or the intermediate
radicals 4. Assuming that the 5-exo cyclization is fast relative
to reduction, the mechanism does not allow for the formation
of the Z-rotamer of the reduced product 6Z (not shown).
However, in principle, this could be formed after the fact
by amide bond rotation. In practice, none of these rotations
was observed.
Data for the reductions of mixtures of 3Z/3E are sum-
marized in Table 1. Reduction of both Z-rich and E-rich
Table 1. Product Yields and Ratios from Tin Hydride
Reductions of Isomers of 3
entry
ratio 3Z/3E
temp
ratio 5/6Ea
Acknowledgment. We thank the National Science Foun-
dation for funding of this work.
1
2
3
4
5
6
76/24
9/91
76/24
9/91
3Z only
3E only
25 °C
25 °C
90 °C
90 °C
25 °C
25 °C
75/25
9/91
75/25
9/91
5 only
6E only
Supporting Information Available: Experimental pro-
cedures and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a Products ratios were determined by 1H NMR analysis of the crude
products; isolated yields of products in entries 1, 5, and 6 were nearly
quantitative.
OL902808M
(14) We tried this column because we had previously observed separa-
tions of amide E/Z rotamers during resolutions of axially chiral anilides.
See: Guthrie, D.; Geib, S. V.; Curran, D. P. J. Am. Chem. Soc. 2009, 131,
15492–15500.
mixtures of 3 with tributyltin hydride at room temperature
under standard conditions (0.05 M, Et3B, air, toluene)
614
Org. Lett., Vol. 12, No. 3, 2010