Regio- and stereoselective isomerizations of allenamides: Synthesis of 2-amido-dienes and their tandem isomerization-electrocyclic ring-closure

Article abstract of DOI:10.1021/ol900647s

A regio- and stereoselective isomerization of allenamides is described, leading to preparations of de novo 2-amido-dienes and a tandem isomerization-6π-electron electrocyclic ring-closure.

Full text of DOI:10.1021/ol900647s

ORGANIC
LETTERS
2009
Vol. 11, No. 10
2125-2128
Regio- and Stereoselective Isomerizations
of Allenamides: Synthesis of
2-Amido-Dienes and Their Tandem
Isomerization-Electrocyclic Ring-Closure
Ryuji Hayashi, Richard P. Hsung,* John B. Feltenberger, and Andrew G. Lohse
DiVision of Pharmaceutical Sciences and Department of Chemistry, UniVersity of
Wisconsin, Madison, Wisconsin 53705
rhsung@wisc.edu
Received March 29, 2009
ABSTRACT
A regio- and stereoselective isomerization of allenamides is described, leading to preparations of de novo 2-amido-dienes and a tandem
isomerization-6π-electron electrocyclic ring-closure.
Synthesis of conjugated dienes via an allene isomerization,
while a thermodynamically favored process, is not trivial
kinetically. The required 1,3-H-shift constitutes a four-
electron [2π + 2σ] process that would call for an antarafacial
approach if proceeding through a concerted and anti-Hu¨ckel
[or Mo¨bius] transition state.1,2 Although impossible in an
allylic system, it is relatively more feasible for an allenic
system because of the presence of orthogonally oriented
p-orbitals of the sp-hybridized central allenic carbon [Scheme
1]. The orthogonal p-orbital at C3 [in blue] introduces a
formal phase change required for an anti-Hu¨ckel transition
state, or formally allows a six-electron [2π + 2σ + 2π]
process when the second set of allenic π-electrons becomes
involved. Nevertheless, the calculated2a ∆Eact value remains
high at 77.7 kcal mol-1 and consequently, concerted or not,
most thermal isomerizations of allenes take place at high
temperatures,3,4 thereby rendering it difficult to control E/Z
ratios of the resulting dienes. There are more practical
approaches would involve stepwise processes promoted by
acid, base, or metal, but their examples are limited and the
level of stereo- and regiochemical control needs to be
improved.3,5
(3) For general reviews on allenes, see: (a) Krause, N.; Hashmi, A. S. K.
Modern Allene Chemistry; Wiley-VCH Verlag GmbH & Co. KGaA:
Weinheim, 2004; Vols. 1 and 2
.
(4) For some examples, see: (a) Meier, H.; Schmitt, M. Tetrahedron
Lett. 1989, 5873. (b) Crandall, J. K.; Paulson, D. R. J. Am. Chem. Soc.
1966, 88, 4302. (c) Bloch, R.; Perchec, P. L.; Conia, J.-M. Angew. Chem.,
Int. Ed. 1970, 9, 798. (d) Jones, M.; Hendrick, M. E.; Hardie, J. A. J. Org.
Chem. 1971, 36, 3061. (e) Patrick, T. B.; Haynie, E. C.; Probat, W. J.
Tetrahedron Lett. 1971, 27, 423. (f) Lehrich, F.; Hopf, H. Tetrahedron Lett.
1987, 28, 2697
.
(5) For some examples, see: (a) Tsuboi, S.; Masuda, T.; Takeda, A. J.
Org. Chem. 1982, 47, 4478. (b) Peng, W.; Zhu, S. Tetrahedron 2003, 59,
4641. (c) Al-Masum, M.; Yamamoto, Y. J. Am. Chem. Soc. 1998, 120,
3809. (d) Bibas, H.; Koch, R.; Wentrup, C. J. Org. Chem. 1998, 63, 2619.
(e) Jacobs, T. L.; Johnson, R. N. J. Am. Chem. Soc. 1960, 82, 6397. (f)
Buzas, A. K.; Istrate, F. M.; Gagosz, F. Org. Lett. 2007, 9, 985. (g) Trost,
B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114, 7933. (h) Guo, C.; Lu,
(1) Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. 1969, 8,
781
.
(2) (a) Jensen, F. J. Am. Chem. Soc. 1995, 117, 7487. (b) Lewis, D. K.;
Cochran, J. C.; Hossenlopp, J.; Miller, D.; Sweeney, T. J. Phys. Chem.
1981, 85, 1787
.
X. J. Chem. Soc., Perkin Trans. 1 1993, 1921.
10.1021/ol900647s CCC: $40.75
Published on Web 04/16/2009
 2009 American Chemical Society

dienes [Scheme 1]. In contrast, substituted allenamides are
quite accessible through R-alkylations of parent allena-
mide15,16 or amidative cross-couplings of allenyl halides.17
Their isomerizations can prove to be an invaluable entry to
amido-dienes. We communicate here a regio- and stereose-
lective isomerization of allenamides in the synthesis of
2-amido-dienes and a tandem isomerization-6π-electron
electrocyclic ring-closure.
Scheme 1. Allene Isomerizations
Screening through various thermal conditions [entries 1-7
in Table 1] including several solvents distinctly revealed that
Table 1. Thermal vs Acidic Conditions
acid
[10 mol %]
temp time
[°C] [h]
25
55
85
115 16
yield
entry
solvent
CH3CN
CH3CN
CH3CN
CH3CN
THF
ClCH2CH2Cl
Tol
CH2Cl2
CH2Cl2
[%]a,b E:Zc
d
1
2
3
4
5
6
7
8
9
-
-
-
-
-
-
-
16
16
16
0
51
88
-
Given that most dienes can be prepared from an array of
stereoselective transformations, synthesizing conjugated dienes
from structurally more challenging allenes through a kineti-
cally demanding and stereochemically undistinguished isomer-
ization does not appear to be a logical first choice. However,
our efforts with the chemistry of allenamides6 allowed us to
envision a much greater potential in constructing amido-
dienes through isomerizing allenamides7-9 because there are
no consistent approaches for synthesizing amido-dienes.10-12
Of the two major methods for preparing amido-dienes,10 the
one involving acid-mediated condensations suffers from
functional group tolerance with the metal-mediated amidative
cross-coupling13,14 suffering from limited access to halo-
g20:1
g20:1
91 [78] 16:1
115
115
150
25
16
51
79
55
0
66
81
9:1
7:1
4:1
16
16
e
HNTf2
PTSA
4-NO2PhCO2H 25
PhCO2H
PPTS
5 min
1
-
25
2:1
10 CH2Cl2
16
15;1
11 CH2Cl2
12 CH2Cl2
13 CH2Cl2
25
25
25
16
85 [55] 18:1
77
16
15:1
CSA
10 min 95 [74] 18:1
a NMR yields. b Isolated yields in the bracket. c Determined by 1H NMR.
d Allenamide 1 was recovered. e Allenamide 1 decomposed.
isomerization of achiral allenamide 1 was the most effective
at 115 °C in CH3CN [sealed tube], leading to 2-amido-diene
218 in 78% isolated yield and 16:1 ratio [entry 4] in favor of
the E-geometry [assigned later]. While there appears to be a
solvent effect on the E/Z ratio [entries 5-7], we found that
with the exception of HNTf2 and PTSA [entries 8-9], a
range of Brønsted acids were equally effective and more
facile at RT in providing 2-amido-diene 2 with excellent E/Z
ratio [entries 10-13].
Generality of this R-isomerization could be established as
shown in Table 2. Key features are: (1) An array of chiral
allenamides 5-7 could be employed to construct de noVo
2-amido-dienes 8-10 with comparable yields and E/Z ratios
under thermal [higher temperature at 135 °C] or acidic
conditions [entries 2-11]; (2) unsubstituted 2-amido-dienes
8d and 9c could also be accessed in good yields [see R ) H
in entries 7 and 9]; (3) allenamide 11 containing an acyclic
(6) For a review on allenamide chemistry, see: Hsung, R. P.; Wei, L.-
L.; Xiong, H. Acc. Chem. Res. 2003, 36, 773.
(7) For an earlier example of allenamide isomerizations, see: Overman,
L. E.; Clizbe, L. A.; Freerks, R. L.; Marlowe, C. K. J. Am. Chem. Soc.
1981, 103, 2807
.
(8) For a study that likely involved an allenamine intermediate, see:
Farmer, M. L.; Billups, W. E.; Greenlee, R. B.; Kurtz, A. N. J. Org. Chem.
1966, 31, 2885
.
(9) For an allenamide isomerization via Grubb’s catalyst, see: (a)
Kinderman, S. S.; van Maarseveen, J. H.; Schoemaker, H. E.; Hiemstra,
H.; Rutjes, F. P. J. T. Org. Lett. 2001, 3, 2045. (b) Also see ref 17a.
(10) For a review on the synthesis of enamides, see: Tracey, M. R.;
Hsung, R. P.; Antoline, J.; Kurtz, K. C. M.; Shen, L.; Slafer, B. W.; Zhang,
Y. In Science of Synthesis, Houben-Weyl Methods of Molecular Transfor-
mations; Weinreb, S. M., Ed.; Georg Thieme: Verlag KG, 2005; Chapter
21.4
.
(11) For reviews on chemistry of dienamides, see: (a) Overman, L. E.
Acc. Chem. Res. 1980, 13, 218. (b) Petrzilka, M. Synthesis 1981, 753. (c)
Campbell, A. L.; Lenz, G. R. Synthesis 1987, 421
.
(12) For reviews on chemistry of 2-amino- or 2-amido-dienes: (a) Krohn,
K. Angew. Chem., Int. Ed. Engl. 1993, 32, 1582. (b) Enders, D.; Meyer, O.
Liebigs Ann. 1996, 1023
.
(13) For reviews on Cu-mediated C-N and C-O bond formations, see:
(a) Lindley, J. Tetrahedron 1984, 40, 1433. (b) Ley, S. V.; Thomas, A. W.
Angew. Chem., Int. Ed. 2003, 42, 5400. (c) Dehli, J. R.; Legros, J.; Bolm,
C. Chem. Commun. 2005, 973. For reviews on Pd-catalyzed N-arylations
of amines and amides, see: (d) Hartwig, J. F. Angew. Chem., Int. Ed. 1998,
37, 2046. (e) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. Acc.
(15) Xiong, H.; Hsung, R. P.; Wei, L.-L.; Berry, C. R.; Mulder, J. A.;
Stockwell, B. Org. Lett. 2000, 2, 2869
.
(16) For synthesis of parent allenamides, see: (a) Wei, L.-L.; Mulder,
Chem. Res. 1998, 31, 805
.
J. A.; Xiong, H.; Zificsak, C. A.; Douglas, C. J.; Hsung, R. P. Tetrahedron
(14) For some examples, see: (a) Klapper, A.; Huang, X.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 7421. (b) Han, C.; Shen, R.; Su, S.;
Porco, J. A., Jr. Org. Lett. 2004, 6, 27. (c) Shen, R.; Lin, C. T.; Bowman,
E. J.; Bowman, B. J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 7889.
Also see ref 26b.
2001, 57, 459.
(17) (a) Trost, B. M.; Stiles, D. T. Org. Lett. 2005, 7, 2117. (b) Shen,
L.; Hsung, R. P.; Zhang, Y.; Antoline, J. E.; Zhang, X. Org. Lett. 2005, 7,
3081.
(18) See Supporting Information.
2126
Org. Lett., Vol. 11, No. 10, 2009

Table 2. Isomerization of Allenamides at the R-Position
Table 3. Isomerization of Allenamides at the γ-Position
a Unless otherwise noted, CH3CN was the solvent for thermal conditions,
and CH2Cl2 was the solvent when using 10 mol % of PTSA or CSA at rt.
In all reactions, concn was 0.10 M. b Isolated yields. c Only E isomers were
observed. d Ninety percent starting allenamide recovered. e Seventy percent
starting allenamide recovered. f Forty-four percent starting allenamide
recovered. g Toluene was the solvent. h MS (4 Å) was used. i Decomposition.
j NMR yields.
a Unless otherwise noted, CH3CN was the solvent for thermal conditions,
and CH2Cl2 was the solvent when using 10 mol % of CSA at rt. For all
reactions, concn ) 0.10 M. b Isolated yields. c Determined by 1H NMR.
d Temp started at -78 °C. e ClCH2CH2Cl was used. f MS (4 Å) was used.
amide is also feasible for the isomerization; and (4) a single-
crystal X-ray structure of 10b was attained to unambiguously
assign the E-configuration [Figure 1].
A keen observation here for the γ-isomerization is that
acidic conditions appear to be more effective in general with
the exception of 17 [entry 15]. In addition, thermal isomer-
izations at the γ-position required higher temperatures and/
or longer reaction times than those of R-isomerizations. This
difference prompted us to explore a possible regioselective
isomerization. As shown in Scheme 2, when heating alle-
Figure 1. X-ray structure of 2-amido-diene 10b.
Scheme 2. Regioselective R-Isomerizations
Although our main interest resides in identifying a useful
protocol for synthesizing 2-amido-dienes given its greater
scarcity,10-12,19,20 we examined isomerizations of allenamides
from the γ-position en route to more well-known 1-amido-
dienes.21 As shown in Table 3, isomerizations of two types
of γ-substituted allenamides, those with a cyclohexylidene
group [see 13-16 in entries 1-13], and those with an
isopropylidene group [see 17-19 in entries 14-19] led to
1-amido-dienes 20-26 exclusively as E-enamides [assigned
based on the trans-olefinic proton coupling constant].
namides 27a and 27b, containing both R- and γ-substituents,
at 135 °C in CH3CN, isomerizations occurred exclusively
at the R-position, leading to 2-amido-dienes 28a and 28b22
in 71 and 94% yields, respectively, all in favor of the
E-enamide [assigned by NOE18]. Isomerization of allenamide
27c took place at RT when in contact with silica gel but
again R-isomerization was favored. This regioselective
isomerization are both mechanistically intriguing23 and
should be great synthetic value in constructing highly
substituted 2-amido-dienes.
(19) For leading examples of 2-amido-dienes, see: (a) Ha, J. D.; Kang,
C. H.; Belmore, K. A.; Cha, J. K. J. Org. Chem. 1998, 63, 3810. (b)
Gonza´lez-Romero, C.; Bernal, P.; Jime´nez, F.; Cruz, M. C.; Fuentes-Benites,
A.; Benavides, A.; Bautista, R.; Tamariz, J. Pure Appl. Chem. 2007, 79,
181, and references cited therein. (c) Movassaghi, M.; Hunt, D. K.; Tjandra,
M. J. Am. Chem. Soc. 2006, 128, 8126
.
(20) For some examples of 2-amino-dienes, see: (a) Enders, D.; Meyer,
O.; Raabe, G. Synthesis 1992, 1242. (b) Barluenga, J.; Canteli, R.-M.; Flrez,
J.; Garca-Granda, S.; Gutirrez-Rodrguez, A.; Mart´ın, E. J. Am. Chem. Soc.
1998, 120, 2514
.
Org. Lett., Vol. 11, No. 10, 2009
2127

The E-selectivity23 attained from R-isomerization provides
an excellent platform for the following important pericyclic
transformation. As shown in Scheme 3, isomerization of
cyclic 2-amido-diene 34a via acid-promoted R-isomerization
followed by ring-closure. Allenamide 32b demonstrated that
the thermal isomerization could be arrested with the gem-
dimethyl group in triene 33b impeding the ring-closure.
Unfortunatedly, attempted ring-closure of 32b at 200 °C led to
an unidentified product instead of 34b.
At last, this process could be rendered in tandem under
thermal conditions to access cyclic 2-amido-dienes 34a, 37, and
38 in good overall yields directly from respective allenamides
32a, 35, and 36 [Scheme 4]. It is noteworthy that these 6π-
Scheme 3. 3-Amido-Trienes and Pericyclic Ring-Closure
Scheme 4. Tandem R-Isomerization-Pericyclic Ring-Closure
R-allylated allenamide 29 under acidic conditions afforded
3-amido-triene 30 in 86% yield. With the E-selectivity, triene
30 is perfectly suited for a thermal 6π-electron electrocyclic
ring-closure24 to give cyclic diene 31. Although only in 35%
yield,25 examples of cyclic 2-amido-dienes such as 31 are more
rare.26 Allenamide 32a provided a good example of synthesizing
electron pericyclic ring-closures mostly took place at 135 °C,
which implies an accelerated process. This feature is consistent
with related ring-closures of 1,3,5-hexatrienes bearing a C3-
donating group.27,28
We have described here a regio- and stereoselective isomer-
ization of allenamides, leading to preparations of de noVo
2-amido-dienes and a tandem isomerization-6π-electron elec-
trocyclic ring-closure. Studies involving applications of these
dienes and this new tandem process as well as mechanistic
understanding of this allene-isomerization are underway.
(21) For examples, see: (a) Terada, A.; Murata, K. Bull. Chem. Soc.
Jpn. 1967, 40, 1644. (b) Overman, L. E.; Clizbe, L. A. J. Am. Chem. Soc.
1976, 98, 2352. (c) Oppolzer, W.; Bieber, L.; Francotte, E. Tetrahedron
Lett. 1979, 4537. (d) Smith, A. B., III.; Wexler, B. A.; Tu, C.-Y.;
Konopelski, J. P. J. Am. Chem. Soc. 1985, 107, 1308. (e) Schlessinger,
R. H.; Pettus, T. R. R.; Springer, J. P.; Hoogsteen, K. J. Org. Chem. 1994,
59, 3246. (f) Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1997, 119,
7165. (g) Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc. 2002,
124, 5950. (h) Robiette, R.; Cheboub-Benchaba, K.; Peeters, D.; Marchand-
Brynaert, J. J. Org. Chem. 2003, 68, 9809.
Acknowledgment. We thank the NIH [GM066055] for
support and Dr. Victor Young [University of Minnesota] for
X-ray structural analysis.
(22) There appears to be ∼5% of 1-amido-diene from γ-isomeriza-
tion.
(23) Without detailed studies, a rationale for lowering of the thermal
activation barrier of 1,3-H-shift is the stabilization of the bi-radical
intermediate provided by the nitrogen atom, assuming a radical intermediate
is considered electron deficient. Based on the this model, this stabilization
is direct when isomerizations take place at the R-position [see i], and
“vinylogous” for isomerizations at the γ-position [see ii]. Thus, thermal
isomerizations at the R-position were faster than at the γ-position.
Supporting Information Available: Experimental proce-
dures as well as NMR spectra, characterizations, and X-ray
structural files are available for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL900647S
(25) When attempting the ring-closure at temperature g180 °C, diene
30 slowly isomerized to the respective 1-amido diene.
(26) For examples, see: (a) Mart´ınez, R.; Jime´nez-Va´zquez, H. A.;
Delgado, F.; Tamariz, J. Tetrahedron 2003, 59, 481. (b) Wallace, D. J.;
Klauber, D. J.; Chen, C. Y.; Volante, R. P. Org. Chem. 2003, 5, 4749. (c)
Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B. Chem.-Eur. J. 2004, 10, 484.
(27) For theoretical studies on substituent effects on electrocyclic ring-
closure of 1,3,5-hexatrienes, see: (a) Spangler, C. W.; Jondahl, T. P.;
Spangler, B. J. Org. Chem. 1973, 38, 2478. (b) Guner, V. A.; Houk, K. N.;
Davies, I. A. J. Org. Chem. 2004, 69, 8024. (c) Yu, T.-Q.; Fu, Y.; Liu, L.;
Guo, G. X. J. Org. Chem. 2006, 71, 6157. (d) Duncan, J. A.; Calkins,
As one reviewer suggested, it is also possible that the nitrogen atom mediates
a polarized transition sate in which an increasing charge density at the
ꢀ-carbon could develop, leading to an N-acyl iminium ion-like character
with the migrating hydrogen behaving more like a proton. This charged
transition state instead of a neutral one should possess a lower thermal
activation barrier for the 1,3-H-shift. Finally, a rationale for the E-selectivity
from the thermal R-isomerization is that the pro-Z-TS experiences a greater
allylic strain than the pro-E-TS during the 1,3-H-shift, although we cannot
rule out equilibration from Z- to E-enamide after the initial isomerization.
(24) For reviews for pericyclic ring-closures, see: (a) Marvell, E. N.
Thermal Electrocyclic Reactions, Academic Press: New York, 1980. (b)
Okamura, W. H.; de Lera, A. R. In ComprehensiVe Organic Synthesis, Trost,
B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon Press: New York, 1991;
Vol. 5, pp 699-750. For reviews on ring-closure in natural product
synthesis, see (c) Pindur, U.; Schneider, G. H. Chem. Soc. ReV. 1994, 409.
(d) Beaudry, C. M.; Malerich, J. P.; Trauner, D. Chem. ReV. 2005, 105,
4757.
D. E. G.; Chavarha, M. J. Am. Chem. Soc. 2008, 130, 6740
.
(28) For examples of accelerated ring-closures of 1,3,5-hexatrienes, see:
(a) Barluenga, J.; Merino, I.; Palacios, F. Tetrahedron Lett. 1990, 31, 6713.
(b) Magomedov, N. A.; Ruggiero, P. L.; Tang, Y. J. Am. Chem. Soc. 2004,
126, 1624. (c) Tessier, P. E.; Nguyen, N.; Clay, M. D.; Fallis, A. G. J. Am.
Chem. Soc. 2006, 128, 4946. (e) Huntley, R. J.; Funk, R. L. Org. Lett.
2006, 8, 3403. (f) Yu, T.-Q.; Fu, Y.; Liu, L.; Guo, Q.-X. J. Org. Chem.
2006, 71, 6157. (g) Su¨nnemann, H. W.; Banwell, M. G.; de Meijere, A.
Eur. J. Org. Chem. 2007, 3879
.
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