A ring-closing yne-carbonyl metathesis of ynamides

Article abstract of DOI:10.1021/ol052487s

An acid-catalyzed ring-closing ynamide-carbonyl metathesis is described here. This hetero RCM methodology is applicable to the construction of carbocycles as well as heterocycles such as chromenes, quinolizidines, indolizidines, and pyrrolizidines.

Full text of DOI:10.1021/ol052487s

ORGANIC
LETTERS
2006
Vol. 8, No. 2
231-234
A Ring-Closing Yne-Carbonyl Metathesis
of Ynamides
Kimberly C. M. Kurtz, Richard P. Hsung,*,† and Yanshi Zhang
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
rphsung@pharmacy.wisc.edu
Received October 13, 2005
ABSTRACT
An acid-catalyzed ring-closing ynamide-carbonyl metathesis is described here. This hetero RCM methodology is applicable to the construction
of carbocycles as well as heterocycles such as chromenes, quinolizidines, indolizidines, and pyrrolizidines.
Ring-closing metathesis (RCM) is widely recognized as one
of the most powerful tools in organic synthesis.1 Considerable
Scheme 1. Formal Hetero Enyne RCM
investigation has taken place in the areas of alkene-alkyne
(or enyne) ring-closing metathesis, and many inventive works
appear in the literature.2-4 However, less common are those
metatheses where one of the reacting partners is a carbonyl-
containing functional group; such transformations are formal
† Current address: Division of Pharmaceutical Sciences and Department
of Chemistry, University of Wisconsin, Madison, WI 53705-2222.
(1) For reviews on RCM, see: (a) Trnka, T. M.; Grubbs, R. H. Acc.
Chem. Res. 2001, 34, 18. (b) Schrock, R. R.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2003, 42, 4592. (c) Walters, M. A. Prog. Heterocycl. Chem. 2003,
15, 1. (c) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127. (d)
Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199. (e) McReynolds,
M. D.; Dougherty, J. M.; Hanson, P. R. Chem. Rev. 2004, 104, 2239. (f)
Wallace, D. J. Angew. Chem., Int. Ed. 2005, 44, 1912.
(2) For reviews on enyne metathesis, see: (a) Diver, S. T.; Giessert, A.
J. Chem. Rev. 2004, 104, 1317. (b) Mori, M. J. Mol. Catal. A 2004, 213,
73. (c) Poulsen, C. S.; Maden, R. Synthesis 2003, 1. (d) Mori, M. In
Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003.
(e) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012.
(3) For some recent examples of enyne metathesis, see: (a) Hansen, E.
Our interest in developing useful synthetic methodologies
C.; Lee, D. J. Am. Chem. Soc. 2004, 126, 15074. (b) Castarlenas, R.; Eckert,
hetero enyne metatheses (Scheme 1).5 Most recently, Krische
reported an elegant account describing a catalytic intramo-
lecular metathesis with acetylenic ketones and aldehydes.6
M.; Dixneuf, P. H. Angew. Chem., Int. Ed. 2005, 44, 2576. (c) Galan, B.
R.; Giessert, A. J.; Keister, J. B.; Diver, S. T. J. Am. Chem. Soc. 2005,
127, 5762. (d) Kim, M.; Lee, D. Org. Lett. 2005, 7, 1865.
(4) For enyne metathesis using heteroatom-substituted alkynes, see: (a)
Saito, N.; Sato, Y.; Mori, M. Org. Lett. 2002, 4, 803. (b) Huang, J.; Xiong,
H.; Hsung, R. P.; Rameshkumar. C.; Mulder, J. A.; Grebe, T. P. Org. Lett.
2002, 4, 2417. (c) Schramm, M. P.; Reddy, D. S.; Kozmin, S. A. Angew.
Chem., Int. Ed. 2001, 40, 4274. (d) Timmer, M. S. M.; Ovaa, H.; Filippov,
D. V.; Van der Marel, G. A.; Van Boom, J. H. Tetrahedron Lett. 2001, 42,
8231. (e) Clark, J. S.; Hamelin, O. Angew Chem., Int. Ed. 2000, 39, 372.
(5) For leading examples, see: (a) Curini, M.; Epifano, F.; Maltese, F.;
Rosati, O. Synlett 2003, 552. (b) Viswanathan, G. S.; Li, C.-J. Tetrahedron
Lett. 2002, 43, 1613. (c) Wempe, M. F.; Grunwell, J. R. Tetrahedron Lett.
2000, 41, 6709. (d) Balog, A.; Geib, S. J.; Curran, D. P. J. Org. Chem.
1995, 60, 345. For some earlier studies, see: (e) Harding, C. E.; Hanack,
M. Tetrahedron Lett. 1971, 12, 1253. (f) Balf, R. J.; Rao, B.; Weiler, L.
Can. J. Chem. 1971, 49, 3135.
(6) For a leading reference, see: Rhee, J. U.; Krische, M. J. Org. Lett.
2005, 7, 2493
10.1021/ol052487s CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/16/2005

using ynamides7-10 led us to explore the possibility of ring-
closing ynamide-carbonyl metathesis possibly promoted by
a Lewis acid (1 f 4), which is not known.11 Mechanistically,
this reaction would proceed through ring opening of an
amide-substituted oxetene intermediate 3 formed through a
stepwise hetero [2 + 2] cycloaddition pathway.12,13 We
communicate here our preliminary success in ring-closing
yne-carbonyl metathesis employing ynamides.
substituted) were also feasible, although yields of the corre-
sponding metathesis products were lower than those of 5.
We attribute these lower yields to the relative stability of
ynamides 7 and 9.
The generality of this hetero RCM is shown in Table 2.
Specifically, six- and seven-membered rings are also acces-
To achieve such a hetero ring-closing metathesis, we
commenced our work by screening a range of Lewis acids
as summarized in Table 1. Specifically, oxazolidinone,
Table 2. Scope of theYne-Carbonyl Ring-Closing Metathesis
Table 1. Screening of Lewis Acids and Catalysts
a All reactions were carried out with BF3-OEt2 in CH2Cl2 at a concentra-
tion of 0.01 M. b Isolated yields. c Entries for substrates 11, 13, 19, and 21
were done at room temperature. d Reaction temperature for 15 and 17 went
from - 78 °C to room temperature. e 1.25 equiv of BF3-OEt2 was used at
room temperature with a concentration of 0.04 M.
a All reactions were carried out in CH2Cl2 at a concentration of 0.01 M.
b Isolated yields. c nd: not determined.
sible via this method (11 f 12 and 13 f 14), though the
seven-membered ring was formed in lower yield. In addition,
ynamides 15 and 17 also underwent the hetero ring-closing
camphor lactam, and sulfonamide based ynamides 5, 7, and
9 were used, as they represent three major classes of
ynamides. Entries 1-6 establish that BF3-OEt2 is an excellent
catalyst with a loading of 25 mol % (entry 3), giving the
highest yield of the oxazolidinone-based metathesis product
6.14 However, other Lewis acids also worked comparably
well at room temperature (entries 8, 9, and 12).
In general, metal triflate catalyzed reactions appear to be
slower than those catalyzed by BF3-OEt2 and required
reaction times of 5 h or greater. The exceptions are InCl3
(entry 7), TiCl4, and Ti(Oi-Pr)3Cl (entries 10 and 11),15 which
failed to give the desired product. Hetero-RCM of less stable
ynamides such as 7 (aza-camphor substituted) and 9 (sulfonyl
(8) For recent reports on ynamides, see: (a) Dunetz, J. R.; Danheiser,
R. L. J. Am. Chem. Soc. 2005, 127, 5776. (b) Riddell, N.; Villeneuve, K.;
Tam, W. Org. Lett. 2005, 7, 3681. (c) Zhang, Y. Tetrahedron Lett. 2005,
46, 6483. (d) Martinez-Esperon, M. F.; Rodriguez, D.; Castedo, L.; Saa´, C.
Org. Lett. 2005, 7, 2213. (e) Bendikov, M.; Duong, H. M.; Bolanos, E.;
Wudl, F. Org. Lett. 2005, 7, 783. (f) Marion, F.; Coulomb, J.; Courillon,
C.; Fensterbank, L.; Malacria, M. Org. Lett. 2004, 6, 1509. (g) Rosillo,
M.; Dom´ınguez, G.; Casarrubios, L.; Amador, U.; Pe´rez-Castells, J. J. Org.
Chem. 2004, 69, 2084. (h) Couty, S.; Lie´gault, B.; Meyer, C.; Cossy, J.
Org. Lett. 2004, 6, 2511. (i) Rodr´ıguez, D.; Castedo, L.; Saa´, C. Synlett
2004, 783. (j) Rodr´ıguez, D.; Castedo, L.; Saa´, C. Synlett 2004, 377. (k)
Hirano, S.; Tanaka, R.; Urabe, H.; Sato, F. Org. Lett. 2004, 6, 727. (l)
Klein, M.; Ko¨nig, B. Tetrahedron 2004, 60, 1087. (m) Marion, F.; Courillon,
C.; Malacria, M. Org. Lett. 2003, 5, 5095. (n) Witulski, B.; Alayrac, C.;
Tevzaadze-Saeftel, L. Angew. Chem., Int. Ed. 2003, 42, 4257. (o) Tanaka,
R.; Hirano, S.; Urabe, H.; Sato, F. Org. Lett. 2003, 5, 67. (p) Witulski, B.;
Lumtscher, J.; Bergstra¨ber, U. Synlett 2003, 708. (q) Naud, S.; Cintrat, J.-
C. Synthesis 2003, 1391. (r) Witulski, B.; Alayrac, C. Angew. Chem., Int.
Ed. 2002, 41, 3281. (s) Timbart, J.-C.; Cintrat. J.-C. Chem. Eur. J. 2002, 8,
1637.
(7) 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.
232
Org. Lett., Vol. 8, No. 2, 2006

metathesis with ketones to give methyl cyclopentenes 16 and
18 in 33% and 89% yields, respectively.
Scheme 3. CuSO4‚5H2O-Catalyzed Metathesis
Intriguingly, ynamides 19 and 21 tethered with imides also
underwent hetero RCM to give indolizidine motifs 20 and
22, respectively, in good yields. In these cases, however,
1.25 equiv of BF3-OEt2 had to be used and triflate salts were
entirely ineffective. These two reactions suggest that the
initial 1,2-addition of ynamides could likely proceed through
either the N-acyl imidinium intermediate A (most likely) or
B (Table 2) obtained via BF3-OEt2 activation of one of the
two imide carbonyl groups.16
Another interesting example of this ynamide-carbonyl
RCM is given in Scheme 2. During the synthesis of ynamide
Scheme 2. Tandem Amidation-Metathesis
To clarify that this is likely a tandem amidation-metathe-
sis and not tandem metathesis-amidation, we carried out
two control studies. As shown in Scheme 3, hetero RCM of
ynamide 5 could be achieved using 25 mol % of CuSO4‚
5H2O, although heating at 65 °C was necessary to drive the
reaction to completion over 32 h, leading to 6 in 56%. On
the other hand, hetero RCM of alkynyl bromide 23 did not
occur while heating with 20 mol % of CuSO4‚5H2O or 40
mol % of 1,10-phenanthroline in addition to CuSO4‚5H2O
at 65 °C.17 This effectively rules out acyl bromide 27 as an
intermediate leading to chromene 25. Because we were
intrigued with potential reactivities of alkynyl halides17 such
as 23, we further attempted the ring-closing metathesis by
employing 10 mol % of AgBF4 at 90 °C in (CH2Cl)2 for 14
h, conditions described in Krische’s report.6 However, we
only observed a trace amount of the potential hetero RCM
product.
26 under our amidation conditions,10b we discovered that the
ynal ring-closing metathesis had occurred concomitantly to
give chromene 25 with an overall yield of 60%, constituting
a tandem amidation-metathesis.
(9) For our recent work on ynamides, see: (a) Zhang, Y.; Hsung, R. P.;
Zhang, X.; Huang, J.; Slafer, B. W.; Davis, A. Org. Lett. 2005, 7, 1047 (b)
Tracey, M. R.; Zhang, Y.; Frederick, M. O.; Mulder, J. A.; Hsung, R. P.
Org. Lett. 2004, 6, 2209. (c) Shen, L.; Hsung, R. P. Tetrahedron Lett. 2003,
44, 9353. (d) Frederick, M. O.; Hsung, R. P.; Lambeth, R. H.; Mulder, J.
A. Tracey, M. R. Org. Lett. 2003, 5, 2663. (e) Mulder, J. A.; Kurtz, K. C.
M.; Hsung, R. P.; Coverdale, H. A.; Frederick, M. O.; Shen, L.; Zificsak,
C. A. Org. Lett. 2003, 5, 1547. (f) Mulder, J. A.; Hsung, R. P.; Frederick,
M. O.; Tracey, M. R.; Zificsak, C. A. Org. Lett. 2002, 4, 1383.
(10) For the synthesis of ynamides, see: (a) Frederick, M. O.; Mulder,
J. A.; Tracey, M. R.; Hsung, R. P.; Huang, J.; Kurtz, K. C. M.; Shen, L.;
Douglas, C. J. J. Am. Chem. Soc. 2003, 125, 2368. (b) Zhang, Y.; Hsung
R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L. Org. Lett. 2004, 6,
1151. Also see: (c) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5,
4011. (d) Couty, S.; Barbazanges, M.; Meyer, C.; Cossy, J. Synlett 2005,
906. (e) Wei, L.-L.; Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas, C.
J.; Hsung, R. P. Tetrahedron 2001, 57, 459.
Having established the feasibility of an ynamide-carbonyl
ring-closing metathesis, we were able to successfully apply
this hetero RCM to the synthesis of an optically enriched
Scheme 4. An Approach to Pyrrolizidine Alkaloids
(11) For a preliminary disclosure of this work, see: Kurtz, K. C. M.;
Hsung, R. P.; Zhang, Y. 229th ACS National Meeting, San Diego, CA,
March, 2005; Abstract ORGN-620.
(12) (a) Fuks, R.; Viehe, H. G. Chem. Ber. 1970, 103, 564. (b) Hsung,
R. P.; Zificsak, C. A.; Wei, L.-L.; Douglas, C. J.; Xiong, H.; Mulder, J. A.
Org. Lett. 1999, 1, 1237.
(13) (a) Mori, S.; Shindo, M. Org. Lett. 2004, 6, 3945. (b) Shindo, M.;
Sato, Y.; Yoshikawa, T.; Koretsune, R.; Shishido, K. J. Org. Chem. 2004,
69, 3912. (c) Shindo, M.; Matsumoto, K.; Mori, S.; Shishido, K. J. Am.
Chem. Soc. 2002, 124, 6840. (d) For a review, see: Shindo, M. Synthesis
2003, 2275.
(14) Procedures and characterizations for all new compounds can be
found in Supporting Information.
(15) In some of these cases, trace amounts of the R-chloroenamide were
observed.
(16) For some examples of related additions to imide carbonyls, see:
(a) Lee, J.; Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1997, 119, 8127. Also
see recently: (b) Dvornikovs, V.; Hoye, T. R. 229th ACS National Meeting,
San Diego, CA, March, 2005; Abstract ORGN-665.
Org. Lett., Vol. 8, No. 2, 2006
233

pyrrolizidine motif. As shown in Scheme 4, starting from
(S)-5-hydroxymethyl-pyrrolidin-2-one 28, TBS protection
and propargylation of the amide nitrogen gave 29 in good
yield over 2 steps. Bromination was carried out with LHMDS
and bromine, and subsequent Cu(II)-catalyzed cross-coupling10b
yielded ynamide 31. Removal of the TBS protecting group
in 31 was followed by oxidation using TEMPO and BAIB
(bisacetoxy-iodobenzene).18 However, under the these oxida-
tive conditions, hetero RCM occurred in situ to give
pyrrolizidinone 34 in 50% yield.
Scheme 6. Comparison with Brønsted Acids
While this success provides a rather facile approach toward
pyrrolizidine alkaloids, we were intrigued by this tandem
oxidation-metathesis, especially after finding that PDC
oxidation of ynamide 35 also led to quinolizidine 37 in 53%
overall yield via the same tandem oxidation-metathesis
process (Scheme 5).
b
a Isolated yields. Entries 2-4 represent the same continuous
c
reaction in which HOAc was added successively. Conversion of
5. Isolated yield at 50% conversion. PNBSA ) p-nitrobenzene-
d
e
sulfonic acid.
Scheme 5. Tandem Oxidation-Metathesis
RCM product 6 was isolated in 64% yield after only 15 min
at room temperature (entry 7). However, overall none of these
reactions was as clean as those promoted by BF3-OEt2.
Nevertheless, the feasibility of using Brønsted acids to
promote this hetero ring-closing metathesis provides another
useful dimension to this methodology, especially when the
RCM occurs in a tandem manner.
In summary, an acid-catalyzed ring-closing ynamide-
carbonyl metathesis has been developed. This method is
applicable to the construction of carbo- as well as oxygen-
and nitrogen-containing heterocycles.
We suspected that HOAc or a related Brønsted acidic
species19 was promoting the hetero RCM during the oxidation
of 32 or 35. As shown in Scheme 6, when in excess, HOAc
could promote the RCM of ynamide 5, although the reaction
is much slower than using BF3-OEt2 (entry 1 versus entries
2-4). A stronger Brønsted acid such as PNBSA9d,f (p-nitro-
benzenesulfonic acid) was an improvement, albeit still
inferior to BF3-OEt2 in terms of the required loading and
reaction time (entries 5 and 6). It turned out that HNTf2 was
again a “magic” Brønsted acid9a,20,21 with an efficiency
comparable to that of BF3-OEt2. By using 25 mol %, the
Acknowledgment.
Authors thank NIH-NIGMS
(GM066055) and NSF (CHE-0094005) for support.
Supporting Information Available: Experimental and
1H NMR spectral and characterizations for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL052487S
(20) For some examples of Brønsted acid catalysis, see: (a) Sun, J.;
Kozmin, S. A.; J. Am. Chem. Soc. 2005, 127, 13512. (b) Williams, A. L.;
Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 1612. (c) Zhang, L.; Kozmin,
S. A. J. Am. Chem. Soc. 2004, 126, 10204. (d) Cossy, J.; Lutz, F.; Alauze,
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H. Synlett 2001, 1851.
(17) For a recent account on methods using alkynyl halides, see: Yoo,
W.-J.; Allen, A.; Villeneuve, K.; Tam, W. Org. Lett. 2005, 7, ASAP.
(18) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J. Org. Chem. 1997, 62, 6974.
(19) Actually, ynamide 5 (neat) slowly underwent hetero RCM upon
standing in the refrigerator, and over a period of 4.5 months, it gave a
mixture of 5 and the metathesis product 6 in 2.7:1 ratio.
(21) For a study on the acidity of HNTf2, see: Thomazeau, C.; Olivier-
Bourbigou, H.; Magna, L.; Luts, S.; Gilbert, B. J. Am. Chem. Soc. 2003,
125, 5264.
234
Org. Lett., Vol. 8, No. 2, 2006