Highly substituted 2-amido-furans from rh(ll)-catalyzed cyclopropenations of ynamides

Article abstract of DOI:10.1021/ol901860b

Rh(II)-catalyzed cyclopropenations of ynamides are described. Although an actual amido-cyclopropene intermediate may not be involved, these reactions provide a facile entry to highly substituted 2-amido-furans, thereby formerly constituting a [3 + 2] cycloaddition. An application of these de novo 2-amido-furans In N-tethered intramolecular [4 + 2] cycloadditions is also illustrated, leading to dihydroindoles and tetrahydroqulnolines

Full text of DOI:10.1021/ol901860b

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4462-4465
Highly Substituted 2-Amido-furans From
Rh(II)-Catalyzed Cyclopropenations of
Ynamides
Hongyan Li and Richard P. Hsung*
DiVision of Pharmaceutical Sciences and Department of Chemistry, UniVersity of
Wisconsin, Madison, Wisconsin 53705
rhsung@wisc.edu
Received August 10, 2009
ABSTRACT
Rh(II)-catalyzed cyclopropenations of ynamides are described. Although an actual amido-cyclopropene intermediate may not be involved,
these reactions provide a facile entry to highly substituted 2-amido-furans, thereby formerly constituting a [3 + 2] cycloaddition. An application
of these de novo 2-amido-furans in N-tethered intramolecular [4 + 2] cycloadditions is also illustrated, leading to dihydroindoles and
tetrahydroquinolines.
Our involvement with the chemistry of ynamides1,2 and
recent interest in cyclopropanation reactions3,4 of various
enamides5-7 converged and provoked us to investigate a
possible ynamide-cyclopropenation manifold8 that could be
useful in synthesis. As shown in Scheme 1, cyclopropenations
of ynamides 1 could take place via metal decomposition of
R-diazoacetates4,9,10 to provide cyclopropenes 2 [pathway a]
or metal-bound zwitterionic intermediates or 1,3-dipoles 3a
and 3b [pathway b]. The former can ring-open to give
zwitterion 4 [or leading to 3b with the metal assistance],
(1) For reviews on ynamides, see: (a) Zificsak, C. A.; Mulder, J. A.;
Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575.
(b) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett 2003, 1379. (c)
Katritzky, A. R.; Jiang, R.; Singh, S. K. Heterocycles 2004, 63, 1455
.
(3) For a leading review on cyclopropanations, see: Lebel, H.; Marcoux,
J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV. 2003, 103, 977.
(4) For other recent reviews on cyclopropanations, see: (a) Brackmann,
F.; de Meijere, A. Chem. ReV. 2007, 107, 4493. (b) Pellissier, H. Tetrahedron
2008, 64, 7041. (c) Gnad, F.; Reiser, O. Chem. ReV. 2003, 103, 1603. (d)
Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. ReV. 2003, 103,
1213. (e) de Meijere, A.; Kozhushkov, S. I. Chem. ReV. 2000, 100, 93.
(5) Song, Z.; Lu, T.; Hsung, R. P.; Al-Rashid, Z. F.; Ko, C.; Tang, Y.
Angew. Chem., Int. Ed. 2007, 46, 4069.
(2) For chemistry of ynamides just in the past 8 months from the literature,
see: (a) Cockburn, N.; Karimi, E.; Tam, W. J. Org. Chem. 2009, 74, 5762.
(b) Yao, B.; Liang, Z.; Niu, T.; Zhang, Y. J. Org. Chem. 2009, 74, 4630.
(c) Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G. Angew. Chem., Int.
Ed. 2009, 48, 4381. (d) Gourdet, B.; Lam, H. W. J. Am. Chem. Soc. 2009,
131, 3802. (e) Couty, S.; Liegault, B.; Meyer, C.; Cossy, J. Tetrahedron
2009, 65, 3882. (f) Deweerdt, K.; Birkedal, H.; Ruhland, T.; Skrydstrup,
T. Org. Lett. 2009, 11, 221. (g) Alayrac, C.; Schollmeyer, D.; Witulski, B.
Chem. Commun. 2009, 1464. (h) Garcia, P.; Moulin, S.; Miclo, Y.; Leboeuf,
D.; Gandon, V.; Aubert, C.; Malacria, M. Chem.sEur. J. 2009, 15, 2129.
(i) Sato, A.; Yorimitsu, H.; Oshima, K. Synlett 2009, 28. (j) Oppenheimer,
J.; Johnson, W. L.; Figueroa, R.; Hayashi, R.; Hsung, R. P. Tetrahedron
2009, 64, 5001. (k) Zhang, Y.; DeKorver, K. A.; Lohse, A. G.; Zhang,
(6) Lu, T.; Song, Z.; Hsung, R. P. Org. Lett. 2008, 10, 541.
(7) Lu, T.; Hayashi, R.; Hsung, R. P.; DeKorver, K. A.; Lohse, A. G.;
Song, Z.; Tang, Y. Org. Biomol. Chem. 2009, 9, 3331.
(8) For reviews on cyclopropenations of alkynes: (a) Padwa, A.
Molecules 2000, 6, 1. (b) Padwa, A. J. Organomet. Chem. 2001, 617-618,
3. (c) Doyle, M. P.; Hu, W. Synlett 2001, 1364.
Y.-S.; Hsung, R. P. Org. Lett. 2009, 11, 899
.
10.1021/ol901860b CCC: $40.75
Published on Web 09/09/2009
 2009 American Chemical Society

reductive elimination [via 5],14,15 thereby formerly constitut-
ing a [3 + 2] cycloaddition. Given that there have been no
studies on cyclopropenations of ynamides,1,16 we explored
this process and report here our success in the synthesis of
highly substituted 2-amido-furans via a Rh(II)-catalyzed
cyclopropenation of ynamides.
Scheme 1. Possible Cyclopropenations of Ynamides
Initial cyclopropenation attempts were carried out employ-
ing ethyl R-diazoacetate with either well-known metal
catalysts8-13 such as Rh2(OAc)4 and Cu(OTf)2 or newer
Rh(II) catalysts such as Rh2(capy)417 and Dubois’ catalyst18
(Scheme 2). These attempts led to a range of low-yielding
Scheme 2. Initial Attempts with Ethyl R-Diazoacetate
while the latter can in fact serve as intermediates en route
to cyclopropenes 2 or provide metallo-oxocyclohexadiene 5
without actually proceeding through a cyclopropenation
process.
While it is difficult to precisely distinguish the two
pathways, we were interested in the possibility of observing
the actual cyclopropenes 2, which can be synthetically useful
as demonstrated by an array of elegant work that has
appeared in the recent literature.8,11-13 Although cyclopro-
penations of alkynes have already been beautifully demon-
strated as a practical entry to cyclopropenes,8,11-13 accessing
2 could be challenging because with the amide substitution
the ring-opening pathway leading to 1,3-dipoles 4 would be
expedited even without the metal assistance.
products, which included 2-amido-furan 8, cyclopentadiene
9, and diene 10.19 However, amido-cyclopropene 11 was not
one of them.20 The formation of cyclopentadiene 9 could
be readily rationalized through a [3 + 2] cycloaddition of
zwitterion 12 along with an ensuing 1,5-H-shift to rearrange
the conjugation (Scheme 3).21 On the other hand, diene 10
could be derived from 2-amido-furan 8 through a second
On the other hand, we were equally intrigued by either
metal bound zwitterionic intermediates 3a and 3b or
nonmetal bound 4, as both could afford synthetically useful
2-amido-furans 6, respectively, via 5-dig-cyclization and
(9) For reviews on cyclopropanations via metal-catalyzed decompositions
of diazo-esters, see: (a) Doyle, M. P. Chem. ReV. 1986, 86, 919. (b) Padwa,
A.; Krumpe, K. E. Tetrahedron 1992, 48, 5385. (c) Calter, M. A. Curr.
Org. Chem. 1997, 1, 37. (d) Doyle, M. P.; Forbe, D. C. Chem. ReV. 1998,
98, 911. (e) Davies, H. M. L.; Autoulinakis, E. Org. React. 2003, 57, 1. (f)
Maas, G. Chem. Soc. ReV. 2004, 33, 183. (g) Doyle, M. P. J. Org. Chem.
(14) For earlier documentations of furan formation from cyclopropena-
tion processes, see: (a) Cho, S. K.; Liebeskind, L. S. J. Org. Chem. 1987,
52, 2631. (b) Davies, H. M. L.; Romines, K. R. Tetrahedron 1988, 44,
3343. (c) Mu¨ller, P.; Pautx, N.; Doyle, M. P.; Baheri, V. HelV. Chim. Acta
1990, 73, 1233. (d) Hoye, T. R.; Dinsmore, C. J.; Johnson, D. S.; Korkowski,
P. F. J. Org. Chem. 1990, 55, 4518. (e) Padwa, A.; Kassir, J. M.; Xu, S. L.
J. Org. Chem. 1991, 56, 6971. (f) Fairfax, D. J.; Austin, D. J.; Xu, S. L.;
2006, 71, 9253
.
(10) Also see: Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis With Diazo Compounds; John Wiley and
Sons, Inc., 1998; Chapter 4 and references therein.
(11) For recent informative reviews on cyclopropene synthesis and its
chemistry: (a) Marek, I.; Simaan, S.; Masarwa, A. Angew. Chem., Int. Ed.
2007, 46, 7364. (b) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. ReV.
2007, 107, 3117. (c) Rubin, M.; Rubina, M.; Gevorgyan, V. Synthesis 2006,
1221. (d) Fox, J. M.; Yan, N. Curr. Org. Chem. 2005, 9, 719. (e) Baird,
M. S. Chem. ReV. 2003, 103, 1271. (f) Walsh, R. Chem. Soc. ReV. 2005,
34, 714. (g) Dolbier, W. R., Jr.; Battiste, M. A. Chem. ReV. 2003, 103,
Padwa, A. J. Chem. Soc., Perkin Trans. 1 1992, 2837.
(15) For recent examples of synthesizing furans from cyclopropenations,
see: (a) Zhao, L.-B.; Guan, Z.-H.; Han, Y.; Xie, Y.-X.; He, S.; Liang, Y.-
M. J. Org. Chem. 2007, 72, 10276. (b) Ma, S.; Lu, L.; Lu, P. J. Org. Chem.
2005, 70, 1063. (c) Rubin, M.; Gevorgyan, V. Synthesis 2004, 796. (d)
Padwa, A.; Straub, C. S. J. Org. Chem. 2003, 68, 227. (e) For an example
of using iodonium ylide C see: Lee, Y. R.; Yoon, S. H. Synth. Commun.
1071
.
2006, 36, 1941.
(12) For earlier reviews, see: (a) Deem, M. L. Synthesis 1972, 675. (b)
Billups, W. E.; Haley, M. M.; Lee, G.-A. Chem. ReV. 1989, 89, 1147. (c)
(16) For alone example of pyrrole-substituted ynamine-cyclopropenation,
see: Pirrung, M. C.; Zhang, J.; Morehead, A. T., Jr. Tetrahedron Lett. 1994,
35, 6229.
Padwa, A.; Fryxell, G. E. AdV. Strain Org. Chem. 1991, 1, 117
.
(13) For leading examples on cyclopropenations of alkynes and recent
chemistry of cyclopropenes, see: (a) Panne, P.; Fox, J. M. J. Am. Chem.
Soc. 2007, 129, 22. (b) Chuprakov, S.; Gevorgyan, V. Org. Lett. 2007, 9,
4463. (c) Chuprakov, S.; Hwang, F. W.; Gevorgyan, V. Angew Chem., Int.
Ed. 2007, 46, 4757. Yang, Z.; Xie, X.; Fox, J. M. Angew. Chem., Int. Ed.
2006, 45, 3960. (d) Rubin, M.; Gevorgyan, V. Synthesis 2004, 796. (e)
Davis, H. M.; Lee, G. H. Org. Lett. 2004, 6, 1233. (f) Doyle, M. P.; Hu,
W. Tetrahedron Lett. 2000, 41, 6265. (g) Doyle, M. P.; Ene, D. G.; Forbes,
D. C.; Pillow, T. H. Chem. Commun. 1999, 1691. (h) Mu¨ller, P.; Imogai,
H. Tetrahedron: Asymmetry 1998, 9, 4419. (i) Padwa, A.; Kassir, J. M.;
(17) Rh2(capy)4: dirhodium(II) tetrakis(caprolactam). For leading refer-
ences, see: (a) Doyle, M. P.; Peterson, C. S.; Protopopova, M. N.; Marnett,
A. B.; Parker, D. L., Jr.; Ene, D. G.; Lynch, V. J. Am. Chem. Soc. 1997,
119, 8826. (b) Padwa, A.; Austin, D. J.; Hornbuckle, S. F.; Semones, M. A.;
Doyle, M. P.; Protopopova, M. N. J. Am. Chem. Soc. 1992, 114, 1874.
(18) Dubois’ catalyst: Bis[rhodium(RR, R′,R′-tetramethyl-1,3-benzene-
dipropionic acid)]. For a leading reference, see: Espino, C. G.; Fiori, K. W.;
Kim, M.; Du Bois, J. J. Am. Chem. Soc. 2004, 126, 15378.
(19) See Supporting Information.
(20) As suggested by a referee, we are currently attempting to detect
possible formation of cyclopropenes at low temp using NMR.
Xu, S. L. J. Org. Chem. 1997, 62, 1642
.
Org. Lett., Vol. 11, No. 19, 2009
4463

A and B. It is noteworthy that the optimized conditions
involved delivering diazo malonate A as a toluene solution
via syringe pump over 1-2 h and addition of ylide B as
solids in four separate portions over 1 h.
Scheme 3. Pathways to Cyclopentadiene 10 and Diene 11
These protocols turned out to be general for constructing
a diverse array of de novo 2-amido-furans as summarized
Table 1. General Synthesis of 2-Amido-furans
cyclopropanation process followed by cyclopropyl ring-
opening [see 13a22]. The stereochemistry of the vinylogous
carbonate double bond in 10 was unassigned.
While cyclopentadiene 9 and diene 10 can be useful
synthetically, 2-amido-furan 8 represents the most attractive
building block in addition to being an emerging pharma-
cophore with a range of important biological activities.23
Consequently, we focused on identifying an effective cata-
lytic protocol for the furan formation, which constitutes a
[3 + 2] cycloaddition. As shown in Scheme 4, we elected
Scheme 4. Success with Diazo Malonate A and Ylide B
a Isolated yields. b When using A, all reactions were run in toluene at
80 °C with 2 mol % Rh2(OAc)4, and ynamide concn ) 0.15 M. Reagent A
[3.0 equiv] was delivered over 1-2 h as a solution in toluene [concn )
0.30 M] via a syringe pump. c When using B, all reactions were run in
CH2Cl2 at rt for 1.5 h with 5 mol % Rh2(OAc)4 and 4 Å MS, and ynamide
concn ) 0.15 M. Reagent B [2.0 equiv] was delivered as solid in 0.5 equiv
portions over 1 h. d 4.0 equiv of A and 5 mol % Rh2(OAc)4 were used, and
the temp was 110 °C. e Reactions were carried out in ClCH2CH2Cl [concn
) 0.15 M] at 50 °C, and a total of 4.0 equiv of reagent B was used.
to use diazo dimethyl malonate A as well as phenyl iodonium
ylide B15e,24 as the cyclopropenating agent. While the
corresponding cyclopropene product remained elusive, after
optimizations, we were able to isolate the desired 2-amido-
furan 14 in 70% and 48% yield, respectively, from employing
in Table 1 and Table 2. In Table 1, a clear trend is that
diazo malonate A is a better cyclopropenating agent than
phenyl iodonium ylide B, consistently providing higher
yields in all entries. In addition, sulfonyl-substituted
ynamides 21-24 were quite feasible [entries 4-9] and
so were terminally substituted ynamides 29a and 29b to
give tetra-substituted furans 30a and 30b, albeit reactions
(21) For a beautiful precedent, see: Hoye, T. R.; Dinsmore, C. J.
Tetrahedron Lett. 1991, 32, 3755.
(22) For reports on isolable products related to intermediate 13a, see:
(a) Bo¨hm, C.; Schinnerl, M.; Bubert, C.; Zabel, M.; Labahn, T.; Parisini,
E.; Reiser, O. Eur. J. Org. Chem. 2000, 2955. (b) Schinnerl, M.; Bo¨hm,
C.; Seitz, M.; Reiser, O. Tetrahedron: Asymmetry 2003, 14, 765.
(23) For recent references on biological activities of amino-furans, see:
(a) Patch, R. J.; Brandt, B. M.; Asgari, D.; Baindur, N.; Chadha, N. K.;
Georgiadis, T.; Cheung, W. S.; Petrounia, I. P.; Donatelli, R. R.; Chaikin,
M. A.; Player, M. R. Bioorg. Med. Chem. Lett. 2007, 17, 6070. (b) Hall,
A.; Billinton, A.; Brown, S. H.; Chowdhury, A.; Giblin, G. M. P.; Goldsmith,
P.; Hurst, D. N.; Naylor, A.; Patel, S.; Scoccitti, T.; Theobald, P. J. Bioorg.
Med. Chem. Lett. 2008, 18, 2684. (c) Isabel, L. C.; Garcia-Mera, X.;
Stefanachi, A.; Nicolotti, O.; Isabel Loza, M.; Brea, J.; Esteve, C.; Segarra,
(24) For some examples of using iodonium ylides, see: (a) Batsila, C.;
Kostakis, G.; Hadjiarapoglou, L. P. Tetrahedron Lett. 2002, 43, 5997. (b)
Muller, P.; Allenbach, Y. F.; Bernardinelli, G. HelV. Chim. Acta 2003, 86,
3164. (c) Huang, X.-C.; Liu, Y.-L.; Liang, Y.; Pi, S.-F.; Wang, F.; Li, J.-
H. Org. Lett. 2008, 10, 1525. (d) Also see ref 15e.
V.; Vidal, B.; Carotti, A. Bioorg. Med. Chem. 2009, 17, 3618
.
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Org. Lett., Vol. 11, No. 19, 2009

Table 2. Other Diazo Compounds and Iodonium Ylides
Figure 1. X-ray structure of 2-amido-furan 34.
isolated in high yields. These final products are a result of
loss of MeOH from the initial cycloadducts. It is noteworthy
that the ability to carry out these N-tethered intramolecular
Diels-Alder cycloadditions demonstrates a distinct advan-
tage of furan synthesis from ynamides through the cyclo-
propenation process.
Scheme 5. Application of 2-Amido-furans in Diels-Alder
a Isolated yields. For reaction conditions, see footnotes b and c in Table
1. b 4 Å MS was not used, and 3.0 equiv of the ylide was added over 8 h
with the reaction mixture being stirred at rt for 20 h after addition.
were slower and yields are lower as a consequence [entries
10 and 11].
We have described here a process of Rh2(OAc)4-catalyzed
cyclopropenations of ynamides. Although an actual amido-
cyclopropene intermediate may not be involved, these
reactions provide a facile entry to highly substituted de novo
2-amido-furans, which formerly constitute a [3 + 2] cy-
cloaddition. Development of useful applications of this furan
formation is underway.
In Table 2, we were able to examine other diazo
compounds as well as iodonium ylides. While yields are
again better with diazo compounds in comparison to the
respective ylides, when using either diazo compound E
or ylide F, the furan formation was highly regioselective
[entries 2-5 and 7]. The regiochemistry was unambigu-
ously assigned via X-ray single-crystal structure of
2-amido-furan 34 (Figure 1).
Lastly, we engaged in an immediate application of these
2-amido-furans given their power in serving as a platform
for intramolecular Diels-Alder cycloadditions.25 As shown
in Scheme 5, after heating 2-amido-furans 27b and 27c at
160 °C in toluene in a sealed tube for 20 h, respective
products dihydroindole 38 and tetrahydroquinoline 39 were
Acknowledgment. Authors thank NIH [GM066055] for
financial support. We thank Dr. Victor G. Young, Jr. of the
University of Minnesota for solving X-ray structure. We also
thank Professor Huw Davies for invaluable discussions and
suggestions.
Supporting Information Available: Experimental pro-
cedures as well as characterizations, X-ray structural data,
and NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(25) For leading examples of intramolecular Diels-Alder reactions of
1-amido-furans, see: (a) Boonsombat, J.; Zhang, H.; Chughtai, M. J.;
Hartung, J.; Padwa, A. J. Org. Chem. 2008, 73, 3539. (b) Zhang, H.; Padwa,
A. Org. Lett. 2006, 8, 247. (c) Padwa, A.; Brodney, M. A.; Dimitroff, M.
J. Org. Chem. 1998, 63, 5304.
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