The first successful base-promoted isomerization of propargyl amides to chiral ynamides. Applications in ring-closing metathesis of ene-ynamides and tandem RCM of diene-ynamides

Article abstract of DOI:10.1021/ol020097p

(Matrix Presented) A highly useful sequence of reactions is described here. These reactions consist of the first successful base-induced isomerizations of propargyl amides to chiral ynamides, applications of these novel ynamides in ring-closure metathesis

Full text of DOI:10.1021/ol020097p

ORGANIC
LETTERS
2002
Vol. 4, No. 14
2417-2420
The First Successful Base-Promoted
Isomerization of Propargyl Amides to
Chiral Ynamides. Applications in
Ring-Closing Metathesis of
Ene−Ynamides and Tandem RCM of
Diene−Ynamides
,†
Jian Huang, Hui Xiong, Richard P. Hsung,* C. Rameshkumar,
Jason A. Mulder, and Tyler P. Grebe‡
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received May 8, 2002
ABSTRACT
A highly useful sequence of reactions is described here. These reactions consist of the first successful base-induced isomerizations of
propargyl amides to chiral ynamides, applications of these novel ynamides in ring-closure metathesis leading to chiral 2-amidodienes useful
for Diels−Alder cycloadditions, and the first successful tandem RCM of diene−ynamides.
Synthetic utility of ynamides and allenamides, electron-
deficient variants of ynamines and allenamines, respectively,
has recently attracted much attention in the literature.1-6
Ynamides and allenamides offer superior thermal stability7,8
and comparable reactivity relative to ynamines and allena-
mines. The combination of this improved stability and
sufficient reactivity has rendered these two classes of
functionally rich organic building blocks highly useful for
the development of new stereoselective methodologies.3-6
We have been exploring reactivities of novel ynamides5 [2]
and allenamides6 [3] specifically featuring a chiral imida-
† Recipient of 2001 Camille Dreyfus Teacher-Scholar Award.
‡ UMN Undergraduate Research Participant and UROP Fellowship
Awardee.
(1) For a recent review on ynamides and ynamines, see: Zificsak, C.
A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron
2001, 57, 7575.
(2) For a recent review on allenamines and allenamides, see: Saalfrank,
R. W.; Lurz, C. J. In Methoden Der Organischen Chemie (Houben-Weyl);
Kropf, H., Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart, 1993;
p 3093.
(3) For recent synthetic applications of ynamides, see: (a) Rainier, J.
D.; Imbriglio, J. E. J. Org. Chem. 2000, 65, 7272. (b) Rainier, J. D.;
Imbriglio, J. E. Org. Lett. 1999, 1, 2037. (c) Witulski, B.; Go¨ssmann, M.
Synlett 2000, 1793. (d) Witulski, B.; Buschmann, N.; Bergstra¨sser, U.
Tetrahedron 2000, 56, 8473. (e) Witulski, B.; Stengel, T.; Ferna`ndez-
Herna`ndez, J. M. Chem. Commun. 2000, 1965. (f) Witulski, B.; Go¨ssmann,
M. Chem. Commun. 1999, 1879. (g) Witulski, B.; Stengel, T. Angew. Chem.,
Int. Ed. 1998, 37, 489. (h) Witulski, B.; Stengel, T. Angew. Chem., Int. Ed.
1998, 38, 2426. (i) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (j)
Schottelius, M. J.; Chen, P. HelV. Chim. Acta 1998, 81, 2341. (k) Feldman,
K. S.; Bruendl, M. M.; Schildknegt, K.; Bohnstedt, A. C. J. Org. Chem.
1996, 61, 5440. (l) Bru¨ckner, D. Synlett 2000, 1402. (m) Fromont, C.;
Masson, S. Tetrahedron 1999, 55, 5405.
(4) For recent allenamide studies, see: (a) Seebach, D.; Gaul, C. HelV.
Chim. Acta 2002, 85, 772. (b) Gardiner, M.; Grigg, R.; Sridharan, V.;
Vicker, N. Tetrahedron Lett. 1998, 435, and references therein. (c) Kimura,
M.; Horino, Y.; Wakamiya, Y.; Okajima, T.; Tamaru, Y. J. Am. Chem. Soc.
1997, 119, 10869, and references therein. (d) Noguchi, M.; Okada, H.;
Wantanabe, M.; Okuda, K.; Nakamura, O. Tetrahedron 1996, 52, 6581.
(e) Jones, B. C. N. M.; SilVerton, J. V.; Simons, C.; Megati, S.; Nishimura,
H.; Maeda, Y.; Mitsuya, H.; Zemlicka, J. J. Med. Chem. 1995, 38, 1397.
(f) Farina, V.; Kant, J. Tetrahedron Lett. 1992, 3559 and 3563. (g) Ra´dl,
S.; KoVa´roVa´, L. Collect. Czech. Chem. Commun. 1991, 56, 2413.
(5) For our efforts in ynamides, see: (a) Mulder, J. A.; Hsung, R. P.;
Frederick, M. O.; Tracey, M. R.; Zificsak, C. A. Org. Lett. 2002, 4, 1383.
(b) Hsung, R. P.; Zificsak, C. A.; Wei, L.-L.; Douglas, C. J.; Xiong, H.;
Mulder, J. A. Org. Lett. 1999, 1, 1237.
10.1021/ol020097p CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/13/2002

zolidinone or oxazolidinone group [Figure 1]. Our original
plan for accessing ynamides 2 via a facile base-induced
of ynamides 6. Ring-closing metathesis [RCM] is a powerful
tool in organic synthesis,10-16 and the new ynamides 6
represent intriguing substrates for enyne metathesis11,12
leading to useful nitrogen heterocycles.14 The enyne RCM
of C1-heteroatom substituted acetylenes were not known until
the elegant studies reported very recently by Kozmin,13 van
Boom,14 and Mori.15 We report here our first success in the
preparation of ynamides using based-promoted isomeriza-
tions as well as applications of these novel ynamides in the
first tandem diene-ynamide RCM. To examine based-
Scheme 1a
a (a) THF [0.1 M in concentration], 20 mol % of KOt-Bu, rt.
Figure 1.
isomerization of propargyl amides 1 was surprisingly derailed
and inadvertently led us to allenamides 3,9 although this is
a known protocol for synthesis of ynamine.1,7b While this
failure allowed us to study sparsely investigated allenamides
3,6 it also compelled us to access ynamides 2 via an
alternative, but less efficient, route involving dehydrohalo-
genations of Z-â-bromoenamides.9
promoted isomerizations, propargyl urethanes 7a,b and
propargyl amides 8a,b were prepared from 1-amino-2-
propyne via standard conditions consisting of N-alkylations
and N-acylations [Scheme 1].17 The ensuing isomerizations
of 7a,b and 8a,b were carried out using 20 mol % of KOt-
Bu/t-BuOH in THF at rt. Propargyl urethanes 7a,b behaved
exactly the same as propargyl amides 1 [substituted with an
Although other useful methods such as the use of alkynyl
iodonium triflate salts are known for synthesis of 1-sulfonyl
amido alkynes,1,3 a base-induced isomerization protocol
remains the most direct and convenient synthetic entry to
ynamides. The fundamental questions surrounding this
initially failed isomerization, and the need for a practical
entry to ynamides provoked us to investigate other propargyl
amides 4. We subsequently found success in the synthesis
(10) For recent reviews on metathesis, see: (a) Grubbs, R. H.; Miller,
S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446. (b) Shrock, R. R. Tetrahedron
1999, 55, 8141. (c) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012.
(h) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (d) Hoveyda,
A. H.; Schrock, R. R. Chem. Eur. J. 2001, 7, 945.
(11) For reviews on enyne RCM, see: (a) Mori, M. In Topics in
Organometallic Chemistry; Fu¨rstner, A., Ed.; Springer-Verlag: Berlin,
Heidelberg, 1998;Vol. 1, p 133. (b) Mori, M. J. Synth. Org. Chem. Jpn.
1998, 56, 115.
(12) For recent applications of enyne metathesis, see: (a) Clark, J. S.;
Hamelin, O. Angew. Chem., Int. Ed. 2000, 39, 372. (b) Fu¨rstner, A.; Szillat,
H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122, 6785. (c) Stragies, R.;
Voigtmann, U.; Blechert, S. Tetrahedron Lett. 2000, 41, 5465. (d) Fu¨rstner,
A.; Ackermann, L.; Gabor, B.; Goddard, R.; Lehmann, C. W.; Mynott, R.;
Stelzer, F.; Thiel, O. R. Chem. Eur. J. 2001, 7, 3236. (e) Kitamura, T.;
Mori, M. Org. Lett. 2001, 3, 1161. (f) Mori, M.; Kitamura, T.; Sato, Y.
Synthesis 2001, 654.
(13) For silyl ynol ethers, see: (a) Schramm, M. P.; Reddy, D. S.;
Kozmin, S. A. Angew. Chem., Int. Ed. 2001, 40, 4274. For an earlier account
on sugar-substituted alkynol ethers, see: (b) Clark, J. S.; Hamelin, O. Angew.
Chem., Int. Ed. 2000, 39, 372.
(6) For our efforts in allenamides, see: (a) Rameshkumar, C.; Xiong,
H.; Tracey, M. R.; Berry, C. R.; Yao, L. J.; Hsung, R. P. J. Org. Chem.
2002, 67, 1339. (b) Xiong, H.; Hsung. R. P.; Berry, C. R.; Rameshkumar,
C. J. Am. Chem. Soc. 2001, 123, 7174. (c) Xiong, H.; Hsung, R. P.; Wei,
L.-L.; Berry, C. R.; Mulder, J. A.; Stockwell, B. Org. Lett. 2000, 2, 2869.
(d) Wei, L.-L.; Hsung, R. P.; Xiong, H.; Mulder, J. A.; Nkansah, N. T.
Org. Lett. 1999, 1, 2145. (e) Wei, L.-L.; Xiong, H.; Douglas, C. J.; Hsung,
R. P. Tetrahedron Lett. 1999, 40, 6903.
(7) For earlier ynamides, see: (a) Janousek, Z.; Collard, J.; Viehe, H.
G. Angew. Chem., Int. Ed. Engl. 1972, 11, 917. (b) Katritzky, A. R.; Ramer,
W. H. J. Org. Chem. 1985, 50, 852.
(8) For earlier allenamides, see: (a) Dickinson, W. B.; Lang, P. C.
Tetrahedron Lett. 1967, 3035. (b) Overman, L. E.; Marlowe, C. K.; Clizbe,
L. A. Tetrahedron Lett. 1979, 599. (c) Reisch, J.; Salehi-Artimani, R. A. J.
Heterocycl. Chem. 1989, 26, 1803.
(14) For phosphonamides, see: Timmer, M. S. M.; Ovaa, H.; Filippov,
D. V.; Van der Marel, G. A.; Van Boom, J. H. Tetrahedron Lett. 2001, 42,
8231.
(15) During our own studies, Mori communicated their elegant prelimi-
nary studies on enynamide metathesis, see: Saito, N.; Sato, Y.; Mori, M.
Org. Lett. 2002, 4, 803.
(9) Wei, L.-L.; Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas, C.
J.; Hsung, R. P. Tetrahedron 2001, 57, 459.
(16) Hoye, T. R.; Donaldson, S. M.; Vos, T. J. Org. Lett. 1999, 1, 277.
2418
Org. Lett., Vol. 4, No. 14, 2002

imidazolidinone or oxazolidinone group] with the isomer-
ization being arrested exclusively at allenamide intermediates
9a,b. Conversely, propargyl amides 8a,b completely isomer-
ized to the ynamides 12a,b in 83% and 50% yields,
respectively. The length of the reaction time was not a factor
in the observed reactivity difference, but the substitution
pattern on the nitrogen atom appears to be critical since only
the propargyl amide system 8 was successful in the isomer-
ization while propargyl urethanes were not.
Successful isomerization of propargyl amides to ynamides
allowed us to explore the synthetic potential of these novel
ynamides in RCM. The ynamide 15 was readily prepared in
70% overall yield from the propargyl amine 13 via a
sequence consisting of N-acylation and KOt-Bu/t-BuOH-
induced isomerization [Scheme 2]. To examine the ene-
ynamide RCM. In addition, while syringe pump protocol16
appeared not to be necessary under these conditions, tem-
perature was critical in the efficiency of this reaction. Under
the reaction conditions outlined in Scheme 2, the desired
RCM products 16 and 20 were obtained from 15 and 19
[prepared in an analogous manner as 15 from 13 in 50%
overall yield] in 83% and 87% yields, respectively.
An immediate proof-of-concept application for these novel
chiral 2-amidodienes would be their utility in Diels-Alder
cycloaddition reactions. While 1-amino-substituted dienes in
Diels-Alder cycloadditions have been well established since
pioneering work by Overman and Oppolzer,22,23 2-amido-
dienes have remained relatively less known.24,25 The ene-
ynamide ring-closing metathesis of chiral ynamides offers
an excellent entry to highly substituted chiral 2-amido-1,3-
dienes.
As shown in Scheme 3, reactions of 16 with dienophiles
such as maleic anhydride and dimethyl acetylenedicarboxy-
Scheme 2
Scheme 3
late led to the desired cycloadducts 21 and 22 in 62% and
80% yields, respectively. Since diastereoselectivities ob-
served here were only modest, stereochemical assignments
were not vigorously pursued. Cycloadducts such as 21 and
22 can be useful, and the resulting chiral enamide functional-
ity could be further manipulated.26
ynamide ring-closing metathesis closely, the ynamide 15 was
subjected to various RCM conditions using Grubbs’ Ru
catalyst 17 [Scheme 2].10,11,18-21
It was quickly found that the highly reactive second-
generation catalyst 18 developed by Herrmann,19 Nolan,20
and Grubbs21 containing the nucleophilic N,N-dimestylimi-
dazol-2-ylidene ligand was the most effective in the ene-
(20) (a) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am.
Chem. Soc. 1999, 121, 2674, and references therein. (b) Huang, J.; Schanz,
H.-J.; Stevens, E. D.; Nolan, S. P. Organometallics 1999, 18, 2370.
(21) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(22) (a) Overman, L. E.; Freeks, R. L.; Petty, C. B.; Clizbe, L. A.; Ono,
R. K.; Taylor, G. F.; Jessup, P. J. J. Am. Chem. Soc. 1981, 103, 2816. (b)
Oppolzer, W. Angew. chem., Int. Ed. Engl. 1977, 16, 10.
(23) For recent elegant work using 1-amino-siloxy dienes, see: (a) Huang,
Y.; Iwama, T.; Viresh H. Rawal Org. Lett. 2002, 4, 1163. (b) Kozmin, S.
A.; Iwama, T.; Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124,
4628. (c) Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1997, 119, 7165.
(24) For reviews on [4 + 2] cycloaddition using of dienamides, see: (a)
Petrzilka, M.; Grayson, J. I. Synthesis 1981, 753. (b) Campbell, A. L.; Lenz,
G. R. Synthesis 1987, 421.
(17) All new compounds are characterized by 1H NMR, 13C NMR, FTIR,
and mass spectroscopy. See Supporting Information for preparations of
relevant propargyl amides.
(18) For a reference, see: Schwab, P.; France, M. B.; Ziller, J. W.;
Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2039.
(19) For some earlier work, see: (a) Weskamp, T.; Schattenmann, W.
C.; Spiegler, M.; Herrmann, W. A. Angew. Chem., Int. Ed. 1998, 37, 2490.
(b) Herrmann, W. A.; Ko¨cher, C. Angew. Chem., Int. Ed. Engl. 1997, 36,
2162.
Org. Lett., Vol. 4, No. 14, 2002
2419

A distinct advantage of ynamides over other heteroatom
substituted alkynes is that the nitrogen atom can be tethered
with two alkenyl substituents, allowing a tandem RCM.
These results are summarized in Table 1. With two sterically
initiated in an ene-yn-ene manner.10a,11,13a,15,16 However,
the diene ynamide 25 did not lead to the desired 6,8-fused
product 26 [entry 1]. Instead, 27 was isolated in 47% yield
[entry 2] along with 20-30% of ring-closed products 28 and
29, suggesting that the second ring-closing was slower given
the potential ring size. Interestingly, subjecting 27 to the same
conditions provided a mixture of 28 and 29 in 80% overall
yield with a ratio of 2:1 [entry 2]. The use of syringe pump
addition led to 27 in much lower yield and gave 70% yield
of 28 and 29 from 27 with a ratio of 1:1.
Table 1
Compounds 28 and 29 represent the loss of one and two
methylene units, respectively, from the side chain in 27,
suggesting that migration of the olefin had occurred prior to
the RCM and again that the tether may be too long. This
prompted us to examine systems with shorter tethers. The
ynamide 32, prepared in 60% yield from propargyl amide
31 via a successful base-induced isomerization, gave 33 in
40% yield under the same RCM conditions along with an
unidentifiable side product [entry 3]. Isolation of the
compound 33 suggests that migration of the olefins in the
initial tandem ring-closing product 34 had occurred. This
favored migration presumably was driven by aromaticity of
the resulting pyrrole in 33.
Encouraged by this result, a fully successful tandem RCM
was carried out using ynamides 38 and 40 [entries 4 and 5].
Under the same RCM conditions, 38 gave the desired RCM
products 28 and 39 in 77% overall yield with a 1:1 ratio,
suggesting that the Ru catalyst initiated RCM from either
direction [entry 4]. Thus, by using the ynamide 40 with two
sterically differentiated olefinic tethers as we had originally
intended, the direction of the tandem RCM was readily
controlled to favor the product 28 with an overall yield of
70% [entry 5].
We have communicated here the first successful base-
induced isomerization of propargyl amides to chiral ynamides
and the immediate application of these novel ynamides in
ring-closing metathesis leading to dienamides useful for
Diels-Alder cycloadditions. We have also described here
the first tandem RCM of diene-ynamides. The application
of this useful sequence of new reactions toward the synthesis
of natural products is underway.
a For entry 1: propargyl amide 24 was prepared from propargyl amine
23 [HCCCH2NH(CH2)4-trans-CHdCHCH3] using CH2dCH(CH2)2COCl,
Et3N, and DMAP in THF at rt for 8 h. For entry 3: propargyl amide 31
was prepared from propargyl amine 30 [HCCCH2NHCH2CHdCH2] and
CH2dCH(CH2)3COCl. For entry 4: propargyl amide 36 was prepared from
propargyl amine 35a [HCCCH2NH(CH2)3CHdCH2] and CH2dCH(CH2)2-
COCl. For entry 5: propargyl amide 37 was prepared from propargyl amine
35b [HCCCH2NH(CH2)3-trans-CHdCHCH3] and CH2dCH(CH2)2COCl.
b All yields are isolated yields. c Isomerizations were carried out using 20
mol % of KOt-Bu in THF at rt for 8 h. d RCM reactions were carried out
using 5-10 mol % of 18 in toluene [0.1 M] at 75 °C for 12 h. e All ratios
1
were determined using H NMR.
Acknowledgment. The authors thank the NSF [CHE-
0094005], the R. W. Johnson Pharmaceutical Institute, and
the McKnight Foundation for support of this work. H.X. and
J.A.M. thank UMN for Graduate Dissertation Fellowships.
We thank Professor Tom Hoye for invaluable discussions
and Mr. Brian Eklov for supplying ruthenium catalysts.
differentiated alkenes as shown in 25 [entry 1], the direction
of the tandem RCM may be controlled to proceed in the
direction shown by the arrows, assuming the metathesis is
(25) For recent examples of synthesis and cycloadditions of dienamides,
see: (a) Gauvry, N.; Huet, F. J. Org. Chem. 2001, 66, 583. (b) von
Wangelin, A. J.; Neumann, H.; Gordes, D.; Spannenberg, A.; Beller, M.
Org. Lett. 2001, 3, 2895. (c) Ha, J. D.; Kang, C. H.; Belmore, K. A.; Cha,
J. K. J. Org. Chem. 1998, 63, 3810, and refs 1-7 therein.
(26) For our recent study on stereoselective epoxidations of some simple
chiral enamides, see: Xiong, H,; Hsung, R. P.; Shen, L.; Hahn, J. M.
Tetrahedron Lett. 2002, 43, ASAP.
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL020097P
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Org. Lett., Vol. 4, No. 14, 2002