Thermal intramolecular [4 + 2] cycloadditions of allenamides: A stereoselective tandem propargyl amide isomerization-cycloaddition

Article abstract of DOI:10.1021/ol901283m

A stereoselective intramolecular normal demand [4 + 2] cycloaddition of allenamides under thermal conditions without metal assistance is described. This work led to the development of a stereoselective tandem propargyl amide-isomerization-[4 + 2] cycloadd

Full text of DOI:10.1021/ol901283m

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3430-3433
Thermal Intramolecular [4 + 2]
Cycloadditions of Allenamides: A
Stereoselective Tandem Propargyl
Amide Isomerization-Cycloaddition
Andrew G. Lohse and Richard P. Hsung*
DiVision of Pharmaceutical Sciences and Department of Chemistry, UniVersity of
Wisconsin, Madison, Wisconsin 53705
rhsung@wisc.edu
Received June 9, 2009
ABSTRACT
A stereoselective intramolecular normal demand [4 + 2] cycloaddition of allenamides under thermal conditions without metal assistance is
described. This work led to the development of a stereoselective tandem propargyl amide-isomerization-[4 + 2] cycloaddition sequence
amenable for rapid assembly of complex nitrogen heterocycles.
We have been embarking on the chemistry of allenamides
over the past 10 years.1,2 In particular, allenamides have
proven to be an excellent source of nitrogen-stabilized
oxyallyl cations3,4 through DMDO-epoxidation, thereby
allowing us to develop highly stereoselective [4 + 3]
cycloaddition manifolds5-7 including intramolecular8,9 cy-
cloadditions such as using N-tethered allenamide 19 en route
(4) For leading examples of nitrogen-stabilized oxyallyl cations in [4
+ 3] cycloadditions, see: (a) MaGee, D. I.; Godineau, E.; Thornton, P. D.;
Walters, M. A.; Sponholtz, D. J. Eur. J. Org. Chem. 2006, 3667. (b) Myers,
A. G.; Barbay, J. K. Org. Lett. 2001, 3, 425. (c) Sung, M. J.; Lee, H. I.;
Chong, Y.; Cha, J. K. Org. Lett. 1999, 1, 2017. (d) Dennis, N.; Ibrahim,
B.; Katritzky, A. R. J. Chem. Soc., Perkin Trans. 1976, 1, 2307
.
(1) For a review on the chemistry of allenamides, see: Hsung, R. P.;
(5) For our nitrogen-stabilized oxyallyl cations in intermolecular [4 +
3] cycloadditions with furans and pyrroles, see: (a) Xiong, H.; Hsung, R. P.;
Berry, C. R.; Rameshkumar, C. J. Am. Chem. Soc. 2001, 123, 7174. (b)
Antoline, J. E.; Hsung, R. P.; Huang, J.; Song, Z.; Li, G. Org. Lett. 2007,
Wei, L.-L.; Xiong, H. Acc. Chem. Res. 2003, 36, 773
.
(2) For recent reports on allenamide chemistry, see: (a) Hayashi, R.;
Hsung, R. P.; Feltenberger, J. B.; Lohse, A. G. Org. Lett. 2009, 11, 2125.
(b) Skucas, E.; Zbieg, J. R.; Krische, M. J. J. Am. Chem. Soc. 2009, 131,
5054. (c) Armstrong, A.; Emmerson, D. P. G. Org. Lett. 2009, 11, 1547.
(d) Beccalli, E. M.; Broggini, G.; Clerici, F.; Galli, S.; Kammerer, C.;
Rigamonti, M.; Sottocornola, S. Org. Lett. 2009, 11, 1563. (e) Broggini,
G.; Galli, S.; Rigamonti, M.; Sottocornola, S.; Zecchi, G. Tetrahedron Lett.
2009, 50, 1447. (f) Brummond, K. M.; Yan, B. Synlett 2008, 2303. (g)
Fuwa, H.; Tako, T.; Ebine, M.; Sasaki, M. Chem. Lett. 2008, 37, 904. (h)
9, 1275. (c) Antoline, J. E.; Hsung, R. P. Synlett 2008, 739
(6) For our asymmetric [4 + 3] cycloadditions, see Huang, J.; Hsung,
R. P. J. Am. Chem. Soc. 2005, 127, 50
.
.
(7) Also see :(a) Harmata, M.; Ghosh, S. K.; Hong, X.; Wacharasindu,
S.; Kirchhoefer, P. J. Am. Chem. Soc. 2003, 125, 2058. (b) For an
enantioselective formal [4 + 3] cycloaddition, see: Dai, X.; Davies, H. M. L.
AdV. Synth. Catal. 2006, 348, 2449
.
´
Gonza´lez-Go´mez, A.; An˜orbe, L.; Poblador, A.; Dom´ınguez, G.; Pe´rez-
(8) For intramolecular [4 + 3] cycloadditions of C-tethered allenamides,
see: Rameshkumar, C.; Hsung, R. P. Angew. Chem., Int. Ed. 2004, 43, 615
Castells, J. Eur. J. Org. Chem. 2008, 1370
.
.
(3) For excellent reviews on heteroatom-substituted oxyallyl cations in
(9) For intramolecular [4 + 3] cycloadditions of N-tethered allenamides,
[4 + 3] cycloadditions, see:(a) Harmata, M. AdV. Synth. Catal. 2006, 348,
see: Xiong, H.; Huang, J.; Ghosh, S.; Hsung, R. P. J. Am. Chem. Soc. 2003,
2297. (b) Harmata, M. Rec. Res. DeV. Org. Chem. 1997, 1, 523
.
125, 12694.
10.1021/ol901283m CCC: $40.75
Published on Web 07/10/2009
 2009 American Chemical Society

to synthetically useful nitrogen heterocycle 3 (Scheme 1).
isomerization-intramolecular [4 + 2] cycloaddition se-
However, the dependence on DMDO as the key oxidant for
quence.
To commence our studies, we initially examined an
N-Boc-substituted allenamide, but it was not useful for
platinum and gold protocols (see ref 18 for results).
Consequently, N-sulfonyl-allenamide 919 was prepared from
propargyl amide 8 via our base-promoted isomerization
protocol using catalytic t-BuOK.20 We quickly found that
with the exception of AuCl (entries 5-7 in Table 1),
Scheme 1. Cycloadditions of N-Tethered Allenamides
Table 1. Exploring Conditions for the Cycloaddition
4 Å
MS
temp
(°C)
yield
(%)a
entry
catalysts
solvents
time
1
PtCl2
PtCl4
PtCl4
PtCl4
AuCl
AuCl
AuCl
yes
yes
yes
yes
yes
yes
yes
DCE
DCE
65
65
65
23
23
65
65
23
65
65
65
65
65
65
65
65
110
<12 h
3 h
0
the transformation can pose a challenge in terms of scale
and operational convenience. Mascaren˜as’s report10 intrigued
us because of their usage of PtCl2/CO in catalyzing a [4 +
3] cycloaddition of allenes. More significantly, they also
documented that a different catalyst [AuCl] could effectively
direct the reactivity toward the competing [4 + 2] cycload-
dition instead of the [4 + 3] cycloaddition. Recently, Toste11
revealed a similar divergence in [4 + 2] versus [4 + 3]
cycloaddition when using different ligands along with a Au(I)
catalyst. Our own efforts in exploring Mascaren˜as’s PtCl2
versus AuCl protocol10,12,13 while adopting allenamides led
us to an interesting and different direction than the initially
anticipated issues regarding competing [4 + 3] and [4 + 2]
2
13c
15c
11c
66
3
THF
6 h
4
toluene
DCEb
THF
1 h
10 min
6 h
<30 min
1 h
10 min
6 h
6 h
6 h
<12 h
<12 h
8 h
30 h
20 h
5
6
35c
42c
16c
0
7
toluene
DCE
8
AuCl/AgSbF6 yes
9
AuCl3
AgSbF6
AgBF4
AgBF4
AgBF4
CSAd
PPTSd
no
yes
yes
yes
yes
yes
yes
yes
yes
no
DCE
10
11
12
13
14
15
16
17
DCE
85c
94
DCE
toluene
THF
80c
57c
92c
94c
91c
93
DCE
DCE
THF
no
d8-toluene
a Isolated yields unless otherwise indicated. b DCE: 1,2-dichloroethane.
c NMR yields determined with phenanthrene as the internal standard. d 10
mol % was used.
+
3
+ 2
cycloadditions (see 4-TS4
f 6 vs 4-TS4
f 7,
respectively, in Scheme 1). We report here a rare normal
electron-demand1,14-17 [4 + 2] cycloaddition involving
electron-rich heteroatom-substituted allenes under thermal
conditions and a stereoselective tandem propargyl amide
platinum catalysts (entries 1-4), and Au(III) catalyst (entry
9) were not useful in generating any cycloaddition types of
products. Concentrations did not appear to have any impact,
as reactions run at 0.04 M led to the same outcome.
(10) For a recent account on intramolecular [4 + 3] cycloadditions of
allenes using PtCl2, see: Trillo, B.; Lo´pez, F.; Gul´ıas, M.; Castedo, L.;
Mascaren˜as, J. L. Angew. Chem., Int. Ed. 2007, 47, 951. (b) Trillo, B.;
Lo´pez, F.; Montserrat, S.; Ujaque, G.; Castedo, L.; Lledo´s, A.; Mascaren˜as,
J. L. Chem.sEur. J. 2009, 15, 3336.
Most intriguingly, the illustration of the corresponding [4
+ 2] cycloadduct 10 shown in Table 1 has the benefit of
hindsight after a series of subsequent studies. As shown in
Figure 1, although 10 and its regioisomer 11 are readily
distinguishable, it is not obvious how to unambiguously
(11) Mauleo´n, P.; Zeldin, R. M.; Gonza´lez, A. Z.; Toste, F. D. J. Am.
Chem. Soc. 2009, 131, 6348.
(12) For a leading review on this chemistry, see: Nevado, C.; Echavarren,
A. M. Synthesis 2005, 167
.
(13) For reviews on platinum and gold chemistry, see: (a) Fu¨rstner, A.;
Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410. (b) Arcadi, A. Chem.
ReV. 2008, 108, 3266. (c) Shen, H. C. Tetrahedron 2008, 64, 3885. (d)
(18) When utilizing a Boc-substituted allenamide (see i), reactions
promoted by PtCl2, PtCl4, AuCl, or AuCl3 (in 10-100 mol % at rt to 65
°C) led to very low yields of possible cycloadduct (ii) with mostly hydrolysis
of the starting allenamide and decomposition. Only when using AgSbF6
was a modest yield attained for cycloadduct ii.
Shen, H. C. Tetrahedron 2008, 64, 7847
.
(14) For a compendium on chemistry of allenes, see: Krause, N.; Hashmi,
A. S. K. Modern Allene Chemistry; Wiley-VCH Verlag GmbH & Co.
KGaA: Weinheim, 2004; Vols. 1 and 2
(15) For a leading reference on normal electron-demand Diels-Alder
cycloadditions of allenamides generated in situ, see: Lee, M.; Morimoto,
.
H.; Kanematsu, K. Tetrahedron 1996, 52, 8169
(16) For an example using N-allenylsulfenimide, see: Bacci, J. P.;
Greenman, K. L.; van Vranken, D. L. J. Org. Chem. 2003, 68, 4955
.
.
(17) For some examples of normal electron-demand Diels-Alder cy-
cloadditions of allenoethers, see: (a) Hayakawa, K.; Aso, K.; Shiro, M.;
Kanematsu, K. J. Am. Chem. Soc. 1989, 111, 5312. (b) Wu, H.-J.; Liu,
C.-F.; Fang, Z.; Lin, H.-C. Tetrahedron Lett. 2007, 48, 6192, and references
cited therein. (c) For an example of allenyl sulfides, see Yeo, S.-K.; Shiro,
(19) See Supporting Information.
(20) (a) Wei, L.-L.; Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas,
C. J.; Hsung, R. P. Tetrahedron 2001, 57, 459. (b) Xiong, H.; Hsung, R. P.;
Wei, L.-L.; Berry, C. R.; Mulder, J. A.; Stockwell, B. Org. Lett. 2000, 2,
2869.
M.; Kanematsu, K. J. Org. Chem. 1994, 59, 1621
.
Org. Lett., Vol. 11, No. 15, 2009
3431

shown in Table 2, this thermally driven allenic-[4 + 2]
cycloaddition manifold possesses a much broader synthetic
potential than previous work.10,11
The substrate scope is composed of (1) different N-
substituents (entries 1-3) including carbamates; (2) substitu-
tions at the allenic γ-position ((()-15a and (()-15b in entries
4 and 5, respectively) that gave the respective cycloadducts
16a and 16b with the major isomers shown as assigned via
NOE experiments (Figure 2); (3) various furan substitutions
Figure 1. [4 + 2] versus [4 + 3] cycloadducts.
distinguish 10 from potential [4 + 3] cycloadduct 12 solely
1
based on the key H NMR resonances. However, as we
continued our explorations and began to achieve high-
yielding reactions with silver salts (entries 10-13), Brønsted
acids (entries 14 and 15), and then ultimately simple thermal
conditions with (entry 16) or without 4 Å MS (entry 17),
we recognized that this did not appear to be a simple [4 +
3] cycloaddition process. Instead, it turned out to be
exclusively a [4 + 2] cycloaddition pathway under all
conditions after attaining an X-ray crystal structure (vide
infra).
Figure 2. NOE experiments and X-ray structure of 14a.
Table 2. Thermal [4 + 2] Cycloadditions of of Allenamides
(entries 6 and 7); (4) a longer tethering that led to the
regiochemical outcome in favor of the internal olefin of the
allenic motif (22 in entry 8), which is found as a single
diastereomer,21 and also notably in this case, when using 10
mol % of AgBF4 and 4 Å MS, 22 was isolated in 58% yield
as the only regioisomer after heating in toluene at 110 °C
for 36 h;21 and last, (5) a simple butadiene (entry 9).
Scheme 2
.
Tandem Propargyl Amide-Isomerization-[4 + 2]
Cycloaddition
a Unless otherwise noted, all reactions were carried out in THF at 85
°C at concn ) 0.10 M. Reactions in entries 3 and 8 were run in toluene.
Entries 4 and 8 were run at 45 and 110 °C, respectively. b Isolated yields.
c Only one isomer by 1H NMR but absolute configuration unassigned. d 16a
and 16b were found as a ∼3:1 inseparable isomeric mixture. e Regioisomeric
ratio of regioisomers 22 and 23 is ∼4:1.
The ability to pursue this cycloaddition thermally repre-
sents a unique opportunity for two major reasons. First, as
The X-ray structure of cycloadduct 14a unambiguously
confirms the [4 + 2] cycloaddition pathway (Figure 2) and
3432
Org. Lett., Vol. 11, No. 15, 2009

provides a general mechanistic picture for this allenic
cycloaddition. Based on the NOE assignments of the
respective major isomers for 16a and 16b (dr 3:1), the current
mechanistic picture also implies that the furan approaches
from the more hindered side with R * H. We are not certain
of reasons behind this contra-steric approach.
Table 3. Tandem Isomerization-[4 + 2] Cycloadditions
Second and more importantly, we recognized the pos-
sibility of developing a tandem sequence consisting of
propargyl amide isomerization followed by cycloaddition.
As shown in Scheme 2, in the presence of 20 mol % t-BuOK
at 65 °C, isomerization of propargyl amide 8 and the ensuing
cycloaddition led to 10 in 86% yield over three steps from
furan (or two steps from commercially available 2-(furan-
2-yl)ethanol 26). Likewise, cycloadduct 29 could be obtained
in 68% yield in two steps from furfuryl alcohol. We note
here that without t-BuOK, this tandem process does not take
place even after heating in toluene at 110 °C for 24 h, thereby
suggesting that the tandem sequence proceeds through
exclusively the respective allenamide intermediate.
a Unless otherwise noted, all reactions were carried out in THF at concn
) 0.10 M with 20 mol % of t-BuOK. For entries 1 and 5, reaction temp )
65 °C; for entries 3 and 4, temp ) 85 °C; and for entry 2, temp ) 25 °C.
b Isolated yields. c dr ) ∼3:1. d dr ) ∼2:1. e The reaction was slower, and
also observed was hydrolysis of the starting allenamide.
In addition, with platinum or gold catalysts, the reaction
proceeded through a very different pathway.22,23 Moreover,
in a related example from Kanemastu’s account,15 5.0 equiv
of t-BuOK was used and the reaction afforded ring-opened
and aromatized products instead of furan-cycloadduct 29.
The use of catalytic amount of t-BuOK proves to be the key
in accessing these structurally more useful cycloadducts.
Finally, this tandem process is general for a range of
propargyl amides (Table 3) including those that are terminally
substituted (entries 2-4), thereby also representing first
examples of successful base-promoted isomerizations of
terminally substituted propargyl amides to allenamides.20,24
It is noteworthy that all propargyl amides employed here
were prepared from respective furyl alcohols featuring a
Mitsunobu reaction using N-sulfonylated propargyl amine
(see 27 in Scheme 2), making this tandem process amenable
for facile constructions of complex nitrogen heterocycles
from very simple commercially available material.
We have described here a rare normal electron-demand
[4 + 2] cycloaddition of N-tethered allenamides under
thermal conditions without assistance of any metals. Our
efforts also led to the development of an efficient and highly
stereoselective tandem propargyl amide-isomerization-[4 +
2] cycloaddition sequence amenable for rapid assembly of
highly functionalized nitrogen heterocycles from very simple
commercial furyl alcohols. Applications of this method
toward constructing isoquinoline-, quinoline-, or isoindole-
containing natural products are underway.
(21) NOE experiments of cycloadduct 22 and its possible cycloaddition
transition state.
Acknowledgment. The authors are grateful for NIH-
NIGMS funding (GM066055) and thank Dr. Vic Young,
University of Minnesota for providing X-ray structural
analysis.
In addition, the regioisomeric cycloadduct 23 was found to equilibrate to
22 via retro-[4 + 2] and [4 + 2] after heating at 110 °C in toluene for 22 h.
(22) When using PtCl4, we were able to isolate some products (iii and
iv) that are related to those reported by Hashmi amd Echavarren (see ref
23).
Supporting Information Available: Experimental and 1H
NMR spectral and characterizations for all new compounds
and X-ray structural data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL901283M
(23) For leading references, see: (a) Hashmi, A. S. K.; Salathe´, R.; Frey,
W. Chem.sEur. J. 2006, 12, 6991. (b) Hashmi, A. S. K.; Frost, T. M.;
Bats, J. W. J. Am. Chem. Soc. 2000, 122, 11553. (c) Mart´ın-Matute, B.;
Ca´rdenas, D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2001, 40, 4754.
(24) For a review, 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 Transformations; Weinreb, S. M., Ed.;
Georg Thieme Verlag KG: Stuttgart, 2005; Chapter 21.4.
Org. Lett., Vol. 11, No. 15, 2009
3433