Enamide-Olefin Ring-Closing Metathesis

Article abstract of DOI:10.1021/ol016013e

(matrix presented) The first examples of ring-closing metathesis reactions of olefin-containing enamides using ruthenium-based catalysts have been demonstrated. A preliminary investigation into the scope and limitations, leading to protected five- and six-membered cyclic enamides, will be presented.

Full text of DOI:10.1021/ol016013e

ORGANIC
LETTERS
2001
Vol. 3, No. 13
2045-2048
Enamide−Olefin Ring-Closing Metathesis
Sape S. Kinderman,† Jan H. van Maarseveen,† Hans E. Schoemaker,†,‡
,†,§
Henk Hiemstra,† and Floris P. J. T. Rutjes*
Institute of Molecular Chemistry, UniVersity of Amsterdam,
Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands, DSM Research,
Life Science Products, P.O. Box 18, 6160 MD Geleen, The Netherlands, and
Department of Organic Chemistry, UniVersity of Nijmegen, ToernooiVeld 1,
6525 ED Nijmegen, The Netherlands
rutjes@sci.kun.nl
Received April 20, 2001
ABSTRACT
The first examples of ring-closing metathesis reactions of olefin-containing enamides using ruthenium-based catalysts have been demonstrated.
A preliminary investigation into the scope and limitations, leading to protected five- and six-membered cyclic enamides, will be presented.
The use of ring-closing olefin metathesis in organic synthesis
has seen explosive growth over the past decade.1 This is not
only expressed by the large number of articles appearing on
this subject but also by the rapid emergence of new improved
catalysts with a higher stability under more forcing conditions
and a wider functional group tolerance.2
olefin metathesis catalysts 1, 2 and 3, 4, respectively (Figure
1), have been employed to give high yields of the metathesis
The importance of ring-closing and related ring-opening
metathesis strategies is further underlined by an impressive
number of total syntheses of natural products.1a In the
majority of these syntheses, the first- and second-generation
† University of Amsterdam.
‡ DSM Research.
§ University of Nijmegen.
Figure 1. First- and second-generation olefin metathesis catalysts.
(1) For review articles, see: (a) Fu¨rstner, A. Angew. Chem., Int. Ed.
2000, 39, 3012. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18. (c) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (d) Phillips,
A. J.; Abell, A. D. Aldrichimica Acta 1999, 32, 75. (e) Wright, D. L. Curr.
Org. Chem. 1999, 3, 211. (f) Alkene Metathesis in Organic Synthesis;
Fu¨rstner, A., Ed.; Springer: Berlin, 1998.
(2) (a) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am.
Chem. Soc. 1999, 121, 2674. (b) Scholl, M.; Trnka, T. M.; Morgan, J. P.;
Grubbs, R. H. Tetrahedron Lett. 1999, 40, 2247. (c) Scholl, M.; Ding, S.;
Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953. (d) Zhu, S. S.; Cefalo,
D. R.; La, D. S.; Jamieson, J. Y.; Davis, W. M.; Hoveyda, A. H.; Schrock,
R. R. J. Am. Chem. Soc. 1999, 121, 8251. (e) Wheaterhead, G. S.; Ford, J.
G.; Alexanian, E. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2000, 122, 1828.
products. Ring-closing metathesis is routinely applied to
construct cyclic olefins of virtually all ring sizes containing
ether, ester, amide, and/or amine functionalities.1
The synthesis of sulfur-3 and phosphorus-containing
heterocycles4 via ring-closing metathesis has also been
reported.
Considering the numerous examples, it becomes apparent
that ring-closing metathesis of olefins connected directly to
10.1021/ol016013e CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/02/2001

a heteroatom are significantly less abundant. For example,
ring-closing metathesis of enol ethers is more difficult to
achieve than that of regular olefinic ethers.5 In addition,
successful metathesis cyclizations of olefins substituted with
a phosphorus atom (viz. vinylphosphonates and vinylphos-
phonamides) have recently been carried out.6 In contrast, to
the best of our knowledge, ring-closing metathesis of
enamines or enamides so far has not been reported in the
literature.7
In this paper, we wish to present the first examples of
ring-closing metathesis of olefinic enamides, to obtain the
corresponding cyclic enamides. These enamides are versatile
structural moieties, which are amenable to further function-
alization.8 Most of the enamide RCM precursors were
synthesized using the procedure of Breederveld, see Table
1.9 The yields of the precursors 10 and 14 (entries 1 and 5)
In addition to the unsubstituted and 1-substituted enamides
shown in Table 1, we prepared similar 2-substituted en-
amides. This proceeded via a reaction that was accidentally
encountered during the palladium-catalyzed N,O-acetal for-
mation of tosylamide 22.10 Reaction of tosylamide 22 with
phenyl propadienyl ether (21) in the presence of Pd(OAc)2
led to the initial formation of the N,O-acetal 23. This acetal
spontaneously isomerized during the aqueous workup, lead-
ing to the thermodynamically more stable enamide 24 in 41%
yield after column chromatography (Scheme 1).
Scheme 1. Synthesis of Enamide 24 via the
Palladium-Catalyzed N,O-Acetal Formation with Phenyl
Propadienyl Ethera
Table 1. Synthesis of the RCM Precursors
a Conditions: (a) Pd(OAc)2, dppp, Et3N, MeCN, room temper-
ature, 16 h; (b) aqueous workup.
entry imine
n
R
electrophile product (PG) yield (%)a
With these precursors in hand, we commenced the ring-
closing metathesis experiments (Table 2). We were very
pleased to find that the five-membered ring precursors
(entries 1-6) readily underwent ring closure at temperatures
between 20 and 40 °C using Grubbs catalyst 2 (the reaction
1
2
3
4
5
6
7
8
9
5
6
6
6
7
8
8
8
9
9
9
1
1
1
1
2
2
2
2
3
3
3
H
Ts2O
10 (Ts)
11 (Ts)
12 (Bz)
13 (CO2Et)
14 (Ts)
15 (Ts)
16 (Bz)
17 (CO2Et)
18 (Ts)
19 (Bz)
14
37
40
30
5
52
44
41
48
63
68
Me Ts2O
Me BzCl
Me (EtO2C)2O
H
Me Ts2O
Me BzCl
Me (EtO2C)2O
Me Ts2O
Me BzCl
Ts2O
1
was monitored by TLC and H NMR). Silica gel column
chromatography was used to remove the catalyst, yielding
the pure cyclic enamides 25-28 in isolated yields around
60% and higher.
10
11
With a methyl substituent on the 1-position of the
precursor (entry 2), the yield dropped slightly when the same
catalyst was used. Gratifyingly, the yield increased again to
86% by subjecting the tosyl-protected precursor 26 to the
more stable catalyst 3 at 84 °C (entry 3). Experiments with
a benzoyl or ethoxycarbonyl protecting group partly led to
degradation of starting materials and products at elevated
temperatures. Therefore, the yield of 27 could not be
Me (EtO2C)2O
20 (CO2Et)
a Isolated yield after column chromatography.
were low, probably due to the instability of both the starting
aldimines and the products. The yields of the other precursors
11-13 and 15-20 were comparable to the yields reported
in the literature for Breederveld conditions on similar
compounds.
(5) (a) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J.
Am. Chem. Soc. 2000, 122, 3783. (b) Postema, M. H. D.; Calimente, D.;
Liu, L.; Behrmann, T. L. J. Org. Chem. 2000, 65, 6061. (c) Clark, J. S.;
Kettle, J. G. Tetrahedron Lett. 1997, 38, 123, 127. (d) Sturino, C. F.; Wong,
J. C. Y. Tetrahedron Lett. 1998, 39, 9623. An efficient approach was
recently published: Rainier, J. D.; Cox, J. M.; Allwein, S. P. Tetrahedron
Lett. 2001, 42, 179.
(6) (a) Timmer, M. S. M.; Ovaa, H.; Filippov, D. V.; van der Marel, G.;
van Boom, J. H. Tetrahedron Lett. 2000, 41, 8635. (b) Hanson, P. R.;
Stoianova, D. S. Tetrahedron Lett. 1999, 40, 3297. (c) Stoianova, D. S.;
Hanson, P. R. Org. Lett. 2000, 2, 1769.
(3) For RCM examples to sulfur-containing heterocycles, see: (a) Shon,
Y.; Lee, T. R. Tetrahedron Lett. 1997, 38, 1283. (b) Armstrong, S. K.;
Christie, B. A. Tetrahedron Lett. 1996, 37, 9373. (c) Hanson, P. R.; Probst,
D. A.; Robinson, R. E.; Yau, M. Tetrahedron Lett. 1999, 40, 4761. (d)
Paquette, L. A.; Leit, S. M. J. Am. Chem. Soc. 1999, 121, 8126. (e) Long,
D. D.; Termin, A. P. Tetrahedron Lett. 2000, 41, 6743. (f) Dougherty, J.
M.; Hanson, P. R.; Klein, T. A.; Moore, J. D.; Probst, D. A. Robinson, R.
E.; Snelgrove, K. A. Tetrahedron 2000, 56, 9781. (h) Lane, C.; Snieckus,
V. Synlett 2000, 1294.
(4) For RCM examples to phosphorus-containing heterocycles, see: (a)
Hetherington, L.; Greedy, B.; Gouverneur, V. Tetrahedron 2000, 56, 2053.
(b) Leconte, M.; Jourdan, I.; Pagano, S.; Lefebvre, F.; Basset, J.-M. J. Chem.
Soc., Chem. Commun. 1995, 857. (c) Hanson, P. R.; Stoianova, D. S.
Tetrahedron Lett. 1998, 39, 3939. (d) Bujard, M.; Gouverneur, V.;
Mioskowski, C. J. Org. Chem. 1999, 64, 2119. (e) Trevitt, M.; Gouverneur,
V. Tetrahedron Lett. 1999, 40, 7333. (f) Schuman, M.; Trevitt, M.; Redd,
A.; Gouverneur, V. Angew. Chem., Int. Ed. 2000, 39, 2491. (g) Sørensen,
A. M.; Nielsen, P. Org. Lett. 2000, 2, 4217. (h) Osipov, S. N.; Artyushin,
O. I.; Kolomiets, A. F.; Bruneau, C.; Dixneuf, P. H. Synlett 2000, 1031. (i)
Sprott, K. T.; McReynolds, M. D.; Hanson, P. R. Synthesis 2001, 612.
(7) For an attempt, see: Agami, C.; Couty, R.; Rabasso, N. Tetrahedron
Lett. 2000, 41, 4113.
(8) (a) For N-acyliminium ion chemistry on enamides, see: Hiemstra,
H.; Speckamp, W. N. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2, p 1047. (b) For a recent
example of an asymmetric Heck reaction on cyclic enamides, see: Tietze,
L. F.; Thede, K. Synlett 2000, 1470.
(9) (a) Breederveld, H. Recl. TraV. Chim. Pays-Bas 1960, 79, 401. (b)
Bach, T.; Schro¨der, J. J. Org. Chem. 1999, 64, 1205.
(10) Tjen, K. C. M. F.; Kinderman, S. S.; Schoemaker, H. E.; Hiemstra,
H.; Rutjes, F. P. J. T. Chem. Commun. 2000, 699.
2046
Org. Lett., Vol. 3, No. 13, 2001

(EDC) as the solvent (entry 10). The isolated yield of the
carbamate-protected precursor 17 dropped to 57% under the
same conditions (entry 11). Precursor 24, bearing a substitu-
ent on the 2-position of the enamide part, gave the ring-
closed product 25 in only a moderate yield using catalyst 2.
However, with catalyst 3 at higher temperature this precursor
showed full conversion on both TLC and 1H NMR, leading
to an isolated yield of 75% of 25 after column chromatog-
raphy (entries 12 and 13).
Table 2. Ring-Closing Metathesis of the Olefinic Enamides
Inspired by the successful enamide ring-closures and the
recently reported examples of allene cross-metathesis,11 we
set out to explore ring-closing metathesis of olefin-containing
allenamides.
We anticipated that due to the impossibility of forming
cyclic six-membered allenes, the corresponding cyclic en-
amides would be formed. The advantage of this approach is
the better accessibility of the precursors. Therefore, precur-
sors 35 and 36 were synthesized using a base-induced
isomerization of the corresponding alkynyl precursors 33 and
34 (Scheme 2),12 which were obtained in good yields (86
Scheme 2. Synthesis and Attempted RCM of the Olefinic
Allenamides 35 and 36a
a Conditions: (a) t-BuOK, THF, room temperature; (b) 2,
CH2Cl2, 40 °C or 3, EDC, 84 °C, no reaction; (c) 3, EDC, 84 °C.
and 60%, respectively) from the tosylamides. Allenamide
35 was subjected to ruthenium catalyst 2 at 40 °C and to
catalyst 3 at 84 °C, but in both cases no cyclic products were
observed and only starting material was recovered. We
reasoned that this might be due to the fact that the ruthenium
catalyst has a greater affinity for the allene fragment of the
molecule. Once the initial metathesis takes place at this end,
it will not react further with the double bond, since further
reaction would require incorporation of the allene fragment
in the ring.
Next, a comparison was made with precursor 36 containing
a methyl substituent on the allene side, thus preventing initial
metathesis at that side. Instead of cyclization, an interesting
and unprecedented ruthenium-catalyzed isomerization to
dienamide 37 was observed.
a 17.5 µM substrate concentration; 1-5 mol % of catalyst. Catalyst 2
was used in dichloromethane; catalyst 3 was used in ethylene dichloride
unless otherwise stated. b Isolated yield after column chromatography. c In
toluene.
increased (entry 5). To obtain the five-membered cyclic
enamide 28, the use of catalyst 2 at 40 °C (entry 6) gave an
optimal result. In the case of the six-membered rings, the
same trend was observed. The 2-unsubstituted enamide 14
closed in a good yield of 80% at 40 °C in 2 h (entry 7). In
contrast, with the same catalyst it took 24 h to ring-close
the methyl-substituted analogue in the somewhat disappoint-
ing yield of 26% (entry 8). Use of the Ru-imidazoline
catalyst 3 also led to an improved yield of 75% for 30 at 80
°C in toluene at a reasonable rate (entry 9). With the benzoyl
protecting group, the isolated yield exceeded 90% when the
same catalyst was used at 84 °C with 1,2-dichloroethane
A remarkable phenomenon was encountered in attempts
to create seven-membered cyclic enamides through ring-
(11) Ahmend, M.; Arnauld, T.; Barrett, A. G. M.; Braddock, D. C.; Flack,
K.; Procopiou, P. A. Org. Lett. 2000, 2, 551.
(12) For a recent example, see: Wei, L.; Hsung, R. P.; Xiong, H.; Mulder,
J. A.; Nkansah, N. T. Org. Lett. 1999, 1, 2145.
Org. Lett., Vol. 3, No. 13, 2001
2047

closing metathesis. Subjection of precursors 18-20 to the
metathesis conditions (Ru catalyst 3, 84 °C, EDC, entries
1-3, Table 3) surprisingly led to six- rather than seven-
membered rings. Probably, ruthenium-catalyzed isomeriza-
tion to the more stable olefins 38-40 took place, followed
by ring closure of the isomerized intermediates to the six-
membered enamides 30-32.
In conclusion, the first successful examples of ring-closing
metathesis of olefin-containing enamides are described. We
demonstrated the possibility of constructing five- and six-
membered cyclic enamides in good yields using this pathway.
Because of a remarkable isomerization of the seven-
membered ring precursors, a challenge lies ahead for the
construction of medium-sized enamide rings. An interesting
problem was encountered in the case of the allenamides,
where the catalyst has to discriminate between the allene
moiety and the olefin part. Thus far, there are no such
examples, but investigations to successfully carry out these
types of olefin-allenamide metathesis reactions are currently
underway.
Table 3. Seven-Membered Ring Precursors 18-20 Leading to
Six-Membered Ring Products 30-32
Acknowledgment. This research has been financially
supported by the Council for Chemical Sciences of The
Netherlands Organization for Scientific Research (CW-
NWO).
Supporting Information Available: Representative ex-
perimental procedures and spectroscopic data of the com-
pounds 10-20, 24-32, and 35. This material is available
free of charge via the Internet at http://pubs.acs.org.
a 17.5 µM substrate concentration; 1-5 mol % of catalyst. Catalyst 3
was used in ethylene dichloride unless otherwise stated. b Isolated yield after
column chromatography. c In toluene. d Determined by 1H NMR. An
inseparable mixture of isomerized and ring-closed products was formed.
OL016013E
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Org. Lett., Vol. 3, No. 13, 2001