Efficient synthesis of 4-vinyl α,β-unsaturated γ-lactams by ring-closing enyne metathesis reactions

Article abstract of DOI:10.1016/j.tetlet.2008.10.051

The ring-closing enyne metathesis reaction of alkyl 2-substituted-2-(N-alkynyl acrylamido)esters using the first-generation Grubbs' catalyst afforded five-membered lactams bearing a 1,3-diene moiety in high isolated yields. In the reaction process, the presence of ethylene gas is essential.

Full text of DOI:10.1016/j.tetlet.2008.10.051

Tetrahedron Letters 49 (2008) 7334–7336
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis of 4-vinyl
enyne metathesis reactions
a,b-unsaturated
c-lactams by ring-closing
b,
Qian Yang a,b, Yuan-Yuan Lai a, Wen-Jing Xiao a, , Howard Alper
*
*
a Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, Hubei 430079, PR China
b Center for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
a r t i c l e i n f o
a b s t r a c t
Article history:
The ring-closing enyne metathesis reaction of alkyl 2-substituted-2-(N-alkynyl acrylamido)esters using
the first-generation Grubbs’ catalyst afforded five-membered lactams bearing a 1,3-diene moiety in high
isolated yields. In the reaction process, the presence of ethylene gas is essential.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 4 August 2008
Revised 30 September 2008
Accepted 11 October 2008
Available online 17 October 2008
Unsaturated
cally active materials that are important synthons for the prepara-
tion of
-amino acids,1 various alkaloids,2 and natural products.3
c-lactams and their derivatives are pharmacologi-
Mes
N
N Mes
Ru
PCy3
Ru
Mes
N
N
Mes
Ph
Ph
Cl
Cl
Cl
Cl
c
Cl
Some of these five-membered ring compounds exhibit significant
Ru
PCy3
Cl
antitumor properties,4 as well as inhibition of COX-25 and HIV-1
O
PCy3
protease.6 In this regard, the
c
-lactam framework has been identi-
fied as a ‘privileged’ structure or pharmacaphore. The versatility of
unsaturated -lactams can be extended to their vinyl derivatives.
1
2
3
c
Scheme 1. Widely used Ru-catalysts.
The incorporation of a vinyl group at the C-4 position of pyrro-
linones is useful for further functionalization, including but not
limited to, Diels–Alder reactions, epoxidation, and dihydroxylation,
to afford more complex N-containing compounds for drug discov-
ery.7 Accordingly, the development of synthetic methods to effi-
ciently construct this class of molecules is a desirable goal in
organic chemistry. Few methods are described in the literature to
for their synthesis.10 Indeed, it was found that a dumbbell-type
bicycle vinyl lactam was formed as a by-product in the group
selective reaction of a N-containing enyne in the presence of the
second-generation Grubbs’ catalyst 2.13 We thus envisioned that
the RCEM reaction of simple N-(2-alkynyl) acrylamides should
allow a direct construction of the corresponding vinyl unsaturated
prepare unsaturated
c-lactams containing a conjugated diene
moiety. To our knowledge, only two publication reporting their
preparation have appeared by means of palladium-catalyzed
c
-lactams. We now report the results of our investigation of this
synthetic methodology.
cross-coupling of 4-stannylated
suitable vinyl iodoles.8
a,b-unsaturated c-lactams with
The synthesis of enyne precursors was based on a known proce-
dure14 starting with commercially available racemic
a-amino acids
Recently, diene9 and enyne10 ring-closing metathesis reactions
have emerged as powerful methods for the construction of many
functionalized carbocycles and heterocycles from acyclic diene or
enyne precursors, especially as a result of the development of
well-defined Ru-catalysts 1, 2, and 3 (Scheme 1).
and is shown in Scheme 2. To examine the feasibility of this ap-
proach, the RCEM reaction of enyne 6a was chosen as a model reac-
tion and several Grubbs-type Ru-catalysts (Scheme 1) were tested
under various conditions. First, the reaction of 6a was performed
using 7 mol % of 1 in refluxing CH2Cl2. Surprisingly, the desired
product was not isolated, although the starting material was
totally consumed after 3 h. We then treated 6a with 7 mol % of 2
or 3 in toluene, 1,2-dichloroethane or benzene at higher tempera-
ture, again without success.
Possible reaction pathways for RCEM might include the
so-called ‘yne-then-ene pathway’ or/and ‘ene-then-yne path-
way’.10,15 In both cases, a ruthenium carbene complex, Ru@CH2,
plays an important role in the initiation of the reaction.10 On the
‘ene-then-yne’ mechanism, ruthenium catalysts 1, 2, or 3 could
Along these lines, we reported a method for the preparation of
pyrrolidine derivatives by Lewis acid-assisted direct ring-closing
metathesis (RCM) of diallylamine substrates11 and ring-closing
enyne metathesis (RCEM) of enynes containing a basic N-atom in
the absence of ethylene gas.12 The 1,3-diene structure in vinyl
unsaturated c-lactams suggests that RCEM can be an effective tool
* Corresponding authors. Tel./fax: +86 27 67862041 (W.-J.X.).
E-mail address: wxiao@mail.ccnu.edu.cn (W.-J. Xiao).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.051

Q. Yang et al. / Tetrahedron Letters 49 (2008) 7334–7336
7335
tolerated (Table 2, 69–83% yields). Changing the alkoxyl groups
from MeO to EtO has little impact on the reaction (Table 2, entry 6).
To expand the scope of this RCEM reaction and verify the influ-
ence of ethylene gas, several other substrates 6g–j were prepared.
According to Mori’s results of the RCEM of propargyl tosylamides,
enynes with an internal alkynyl unit smoothly undergoes the
RCEM reaction without the use of ethylene gas.16 Thus, the reaction
of an internal alkynyl substrate 6g was run on a 1 mmol scale,
using 7 mol % of 1 as the catalyst, in 25 mL of toluene at 80 °C
under N2 for 14 h. To our surprise, the reaction only afforded the
expected product 7g in 10% yield (Table 3, entry 1). Using ethylene
instead of N2, the yield of 7g increased appreciably to 54% (Table 3,
entry 2), which demonstrated that the presence of ethylene is cru-
cial for the RCEM reaction for such substrates. When the catalyst
loading was increased to 10 mol %, the reaction of 6g went to com-
pletion in 4 h, and the yield of 7g could be further improved to 75%
Cl
R2
O
O
Br
O
R
R
OR1
OR1
(iPr)2 NEt, CH2Cl2,
o
NH3+Cl-
NH
LiOH H2O, 4AMS
0 oC - rt
DMF, rt
4
5
R2
R
O
OR1
O
R = Bn, Ph, Me etc.
R1 = Me, Et
N
R2 = Me, H
R2
6
Scheme 2. Synthesis of enyne substrates.
(Table 3, entry 3). Other a-substituted 2-[N-(but-2-ynyl)acrylami-
do] acetates were also tested, and the results are presented in Table
first react with the olefinic moiety of the substrate to initiate the
reaction and generate Ru@CH2 for the catalytic cycle.12 On the
other hand, if the RCEM proceeds by an ‘yne-then-ene’ pathway,
the in situ generation of Ru@CH2 will be essential for methylene
transfer with the alkynyl part of the substrate. We envisioned that,
in the case of 6, the electron-withdrawing character of the amide
group might reduce the possibility of the ‘ene-then-yne’ pathway,
and the generation of Ru@CH2 would be key for the efficient RCEM
of substrates such as 6.
Mori et al. demonstrated that ethylene gas is beneficial for the
RCEM of propargyl tosylamides to produce 1-tosyl-5-vinyl-tetra-
hydropyridines.16 Mechanistically, it was proposed that Ru@CH2
first reacted with the alkyne and then ring closed onto the pendant
alkene. Therefore, we ran the reaction of 6a under an ethylene
atmosphere, along with Grubbs’ first- and second-generation cata-
lysts, and the results are summarized in Table 1. Exposure of 6a to
ethylene in the presence of 1 in CH2Cl2 did indeed provide the de-
Table 2
RCEM reaction of
a-substituted alkyl 2-[N-(prop-2-ynyl)acrylamido]acetates under
an atmosphere of ethylenea
Entry Substrate
Time Product
(h)
Yieldb
(%)
O
O
Ph
Ph
OMe
O
OMe
O
1
3
76
83
69
73
76
71
N
N
7a
6a
O
O
Ph
OMe
O
Ph
OMe
O
2
3
4
5
6
3
N
N
sired 4-vinyl
a,b-unsaturated c-lactam 7a in 65% isolated yield
6b
7b
(Table 1, entry 1). Further evaluation of Grubbs’ catalysts revealed
that the second-generation catalyst 2 gave almost the same results
as the first-generation catalyst 1 (Table 1, entries 1 and 2). A survey
of reaction media (Table 1, entries 1 and 2 vs entries 3 and 4) dem-
onstrated that toluene was the optimal solvent (entry 3, 76% yield).
O
O
O
O
MeO
OMe
O
MeO
OMe
O
4.5
N
N
The scope of
amido]acetates for this RCEM reaction was examined under the
optimal reaction conditions. -Substituents of the substrates,
a-substituted alkyl 2-[N-(prop-2-ynyl)acryl-
7c
6c
a
O
O
including phenyl, benzyl, isopropyl, and
x-ester groups, are readily
OMe
O
OMe
O
4
N
N
Table 1
The RCEM reaction of 6a in the presence of ethylene gasa
7d
6d
O
O
O
O
OMe
O
Ru catalyst
OMe
O
OMe
O
OMe
N
N
4
N
N
CH2=CH2
solvent
O
7e
6e
6a
7a
O
O
Entry
Catalyst
Solvent
Temperature (°C)
Yieldb (%)
OEt
O
OEt
O
1
2
3
4
1
2
1
2
CH2Cl2
CH2Cl2
Toluene
Toluene
40
40
80
80
65
63
76
73
3.5
N
N
6f
7f
a
Reaction conditions: 6a (1 mmol), cat. 1 or 2 (0.07 mmol), CH2Cl2 or toluene
(25 mL), 40 or 80 °C, 3 h.
a
Reaction conditions: enynes (1 mmol), 1 (0.07 mmol), toluene (25 mL), 80 °C.
Isolated yield.
b
b
Isolated yield.

7336
Q. Yang et al. / Tetrahedron Letters 49 (2008) 7334–7336
Table 3
Supplementary data
RCEM reaction of a-substituted alkyl 2-[N-(but-2-ynyl)acrylamido]acetates under an
atmosphere of ethylenea
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.10.051.
Entry
Substrate
Time (h)
Product
Yieldb (%)
O
O
References and notes
Ph
Ph
N
OMe
O
OMe
O
1. (a) Ma, D.; Ma, J.; Ding, W.; Dai, L. Tetrahedron: Asymmetry 1996, 7, 2365; (b)
Jouin, P.; Castro, B. J. Chem. Soc., Perkin Trans. 1 1987, 1177.
1c,d
14
10
N
2. (a) Casiraghi, G.; Spanu, P.; Rassu, G.; Pinna, L.; Ulgheri, F. J. Org. Chem. 1994, 59,
2906; (b) Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. J. Am. Chem. Soc. 1989,
111, 2588.
7g
6g
3. (a) Iwasawa, N.; Macyama, K. J. Org. Chem. 1997, 62, 1918; (b) Shiraki, R.;
Sumino, A.; Tadano, K.; Ogawa, S. J. Org. Chem. 1996, 61, 2845; (c) Pettit, G. R.;
Kamano, Y.; Herald, C. L.; Fujii, Y.; Kizu, H.; Boyd, M. R.; Boettner, F. E.; Doubek,
D. L.; Schmidt, J. M.; Chapuis, J.-C.; Michel, C. Tetrahedron 1993, 49, 9151; (d)
Koehn, F. E.; Longley, R. E.; Reed, J. K. J. Nat. Prod. 1992, 55, 613.
4. (a) Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley:
New York, 1997, Vol. 5; (b) Fuji, K.; Yamada, T.; Fujita, E.; Murata, H. Chem.
Pharm. Bull. 1978, 26, 2515; (c) Wiedhopf, R. M.; Trumbull, E. R.; Cole, T. R. J.
Pharm. Sci. 1973, 62, 1206.
2d
3
6g
6g
14
4
7g
7g
54
75
O
O
Ph
N
OMe
O
Ph
OMe
O
5. Bosch, J.; Roca, T.; Catena, J.-L.; Lorens, O.; Perez, J.-J.; Lagunas, C.; Fernandez, A.
G.; Miquel, I.; Fernandez-Serrat, A.; Farrerons, C. Bioorg. Med. Chem. Lett. 2000,
10, 1745.
N
4
9
79
6. (a) Spaltenstein, A.; Almond, M. R.; Bock, W. J.; Cleary, D. G.; Furfine, E. S.;
Hazen, R. J.; Kazmierski, W. M.; Salituro, F. G.; Tung, R. D.; Wright, L. L. Bioorg.
Med. Chem. Lett. 2000, 10, 1159; (b) Smith, A. B.; Hirschmann, R.; Pasternak, A.;
Guzman, M. C.; Yokoyama, A.; Sprengeler, P. A.; Darke, P. L.; Emini, E. A.; Schleif,
W. A. J. Am. Chem. Soc. 1995, 117, 11113.
6h
7h
O
O
7. (a) Saito, N.; Sato, Y.; Mori, M. Org. Lett. 2002, 4, 803; (b) Renaud, J.; Graf, C. D.;
Oberer, L. Angew. Chem., Int. Ed. 2000, 39, 3101; (c) Moreno-Manas, M.; Pleixats,
R.; Santamaria, A. Synlett 2001, 1784; (d) Rosillo, M.; Casarrubios, L.;
Dominguez, G.; Perez-Castells, J. Tetrahedron Lett. 2001, 42, 7029.
8. (a) Reginato, G.; Capperucci, A.; Degl’Innocenti, A.; Mordini, A.; Pecchi, S.
Tetrahedron 1995, 51, 2129; (b) Reginato, G.; Mordini, A.; Degl’Innocenti, A.;
Manganiello, S.; Capperucci, A.; Poli, G. Tetrahedron 1998, 54, 10227.
9. For reviews on diene RCM reaction, see: (a) McReynolds, M. D.; Dougherty, J.
M.; Hanson, P. R. Chem. Rev. 2004, 104, 2239; (b) Stephen, F. M.; Alexander, D.
Chem. Rev. 2004, 104, 2199; (c) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int.
Ed. 2003, 42, 4592; (d) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42,
1900; (e) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim,
2003; Vol. 2, p 1156; (f) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18;
(g) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693; (h) Fürstner, A.
Angew. Chem., Int. Ed. 2000, 39, 3012; (i) Buchmeiser, M. R. Chem. Rev. 2000,
100, 1565; (j) Jørgensen, M.; Hadwiger, P.; Madsen, R.; Stütz, A. E.; Wrodnigg, T.
M. Curr. Org. Chem. 2000, 4, 565; (k) Roy, R.; Das, S. K. Chem. Commun. 2000,
519; (l) Andrew, D. A.; Andrew, J. P. Aldrichim. Acta 1999, 32, 75; (m) Grubbs, R.
H.; Chang, S. Tetrahedron 1998, 54, 4413.
OMe
O
OMe
O
N
5
6
83
N
6i
7i
O
O
OEt
O
OEt
N
N
6
8
74
O
6j
7j
a
Reaction conditions: enynes (1 mmol), 1 (0.1 mmol), toluene (25 mL), 80 °C.
Isolated yield.
The reaction was performed under N2 instead of ethylene.
The catalyst loading was 7 mol %.
b
c
10. For reviews on enyne metathesis, see: (a) Villar, H.; Frings, M.; Bolm, C. Chem.
Soc. Rev. 2007, 36, 55; (b) Diver, S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317;
(c) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1; (d) Mori, M. In Handbook of
Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003; Vol. 2, p
176.
d
11. (a) Yang, Q.; Xiao, W.-J.; Yu, Z. Org. Lett. 2005, 7, 871; (b) Yang, Q.; Li, X.-Y.; Wu,
H.; Xiao, W.-J. Tetrahedron Lett. 2006, 47, 3893; (c) Guo, Y.-C.; Mele, G.; Martina,
F.; Margapoti, E.; Vasapollo, G.; Xiao, W.-J. J. Organomet. Chem. 2006, 691, 5383.
12. Yang, Q.; Alper, H.; Xiao, W.-J. Org. Lett. 2007, 9, 769 and references cited
therein.
3. It can be concluded that this RCEM reaction is quite general with
respect to the enyne architecture and good isolated yields of the
corresponding products were obtained in all cases.
13. Ma, S.; Ni, B.; Liang, Z. J. Org. Chem. 2004, 69, 6305.
14. (a) Cho, J. H.; Kim, B. M. Tetrahedron Lett. 2002, 43, 1273; (b) Wipf, P.; Hopkins,
C. R. J. Org. Chem. 1999, 64, 6881.
15. (a) Kinoshita, A.; Mori, M. Synlett 2004, 1020; (b) Maifeld, S. V.; Miller, R. L.;
Lee, D. J. Am. Chem. Soc. 2004, 126, 12228.
16. Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63, 6082.
In conclusion, we have evaluated the RCEM reaction of various
-substituted alkyl 2-[N-(alk-2-ynyl)acrylamido]acetates by the
a
use of Grubbs’ first-generation catalyst in the presence of ethylene
under mild conditions.17 This new procedure can be used to pre-
pare a diverse series of 4-vinyl a,b-unsaturated c-lactams in good
17.
A general procedure for the ring-closing enyne metathesis is as follows:
yields. We are currently examining further variations of this meth-
odology, and applications to the synthesis of other heterocyclic
compounds.
precursor enyne (1 mmol) was dissolved in freshly distilled and degassed
toluene (15 mL) under nitrogen. After stirring for 10 min at room temperature,
ethylene gas was purged into the flask instead of the nitrogen. After 20 min,
the ruthenium catalyst 1 (41.2 mg, 0.05 mmol) was added quickly. After 3–9 h
of reflux, the reaction was complete as indicated by TLC. The solution was
concentrated via rotavapor under reduced atmosphere, and the residue was
separated by flash column chromatography affording the corresponding five-
membered lactam derivatives 7. (2-Oxo-4-vinyl-2,5-dihydro-pyrrol-1-yl)-
phenyl-acetic acid methyl ester 7a. Product 7a was obtained in 76% yield
from 6a. 1H NMR (400 MHz, CDCl3): d 7.41–7.28 (m, 5H), 6.58 (dd, 1H, J = 17.6
and 10.8 Hz), 6.13 (s, 1H), 6.01 (s, 1H), 5.42 (d, 1H, J = 17.6 Hz), 5.35 (d, 1H,
J = 10.8 Hz), 4.51 (d, 1H, J = 18.4 Hz), 3.78 (s, 3H), 3.65 (d, 1H, J = 18.4 Hz); 13C
NMR (100 MHz, CDCl3): d 171.4, 171.0, 154.5, 134.6, 129.7, 129.1, 128.7, 128.4,
122.6, 119.8, 57.2, 52.4, 48.7; HRMS (EI) m/z calcd for C15H15NO3 (M+)
257.1052, found 257.1032.
Acknowledgments
We are grateful to the Natural Sciences and Engineering Re-
search Council of Canada, the National Natural Science Foundation
of China (20672040 and 20872043), the program for new century
excellent talents in university (NCET-05-0672), and the National
Basic Research Program of China (2004CCA00100) for support of
this research.