Synthesis of α,β-unsaturated 4,5-disubstituted γ-lactones via ring-closing metathesis catalyzed by the first-generation Grubbs' catalyst

Article abstract of DOI:10.1021/ol0504087

(Chemical Equation Presented) 4-Methyl-5-alkyl-2(5H)-furanones have been prepared by ruthenium-catalyzed ring-closing metathesis of the suitable methallyl acrylates, Despite the electron deficiency of the conjugated double bond and of the gem-disubstitution of the allylic alkene moiety in the starting acrylates, the first-generation Grubbs' catalyst I proved to be an effective promoter for the ring closure, affording the expected butenolides in good to high yields.

Full text of DOI:10.1021/ol0504087

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1805-1808
Synthesis of
4,5-Disubstituted
r
,
â
-Unsaturated
-Lactones via
γ
Ring-Closing Metathesis Catalyzed by
the First-Generation Grubbs’ Catalyst
Mauro Bassetti,*,† Andrea D’Annibale,*,‡ Alessia Fanfoni, and Franco Minissi
Istituto CNR di Metodologie Chimiche, Sezione Meccanismi di Reazione,
Dipartimento di Chimica, UniVersita` degli Studi “La Sapienza”, P.le Aldo Moro 5,
00185 Roma, Italy, and Dipartimento di Chimica, and Istituto CNR di Chimica
Biomolecolare, Sezione di Roma, UniVersita` degli Studi “La Sapienza”,
P.le Aldo Moro 5, 00185 Roma, Italy
mauro.bassetti@uniroma1.it; andrea.dannibale@uniroma1.it
Received February 24, 2005
ABSTRACT
4-Methyl-5-alkyl-2(5H)-furanones have been prepared by ruthenium-catalyzed ring-closing metathesis of the suitable methallyl acrylates. Despite
the electron deficiency of the conjugated double bond and of the gem-disubstitution of the allylic alkene moiety in the starting acrylates, the
first-generation Grubbs’ catalyst I proved to be an effective promoter for the ring closure, affording the expected butenolides in good to high
yields.
The olefin metathesis reaction has become a powerful tool
in organic synthesis since the development of well-defined
single-component ruthenium and molybdenum alkylidene
catalysts.1 One of its most successful applications is the ring-
closing metathesis reaction (RCM) which affords cyclic
compounds from diolefinic precursors.1,2
More specifically, the preparation of R,â unsaturated γ-
and δ-lactones through RCM of allyl and homoallyl acrylates
have been reported using either the first-generation (I) or
second-generation (II) Grubbs’ catalysts (Figure 1).7
Among the different classes of cyclic compounds achiev-
able by RCM, unsaturated lactones of various ring sizes were
obtained from R,ω′-diolefinic esters using first- and/or
second-generation Grubbs’ alkylidene catalysts,1c,3 inde-
nylidene4 and cationic allenylidene ruthenium complexes,5
or [RuCl2(p-cymene)]2 under neon light.6
† Istituto CNR di Metodologie Chimiche.
Figure 1.
‡ Dipartimento di Chimica, Universita` “La Sapienza”.
(1) (a) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. 1997, 36, 2036-
2055. (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (c)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3812-3043. (d) Trnka, T.
M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
In the past few years, we have been involved in the metal-
promoted synthesis of five-membered lactones having in-
(2) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371-388.
10.1021/ol0504087 CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/02/2005

teresting odoriferous properties, and we decided to focus our
attention on the preparation of R,â-unsaturated γ-lactones
2, bearing a methyl group at C-4 and alkyl group at C-5.
Indeed, compounds 2 are advanced intermediates on the way
to naturally occurring important γ-lactones with fragrance
properties, like Whisky lactone and Cognac lactone.8 Thus,
we envisaged obtaining compounds 2 through the ring-
closing metathesis of the appropriate methallyl acrylates 1
(Scheme 1), as the key step in the synthesis of γ-lactone
fragrances.
Table 1. Synthesis of Acrylates 1a-e
entry substrate
R1
R2
product (yield, %)a
1
2
3
4
5
3a
3b
3c
3d
3e
n-Bu Me
n-Pn Me
1a (81)
1b (87)
1c (75)
1d (14)
1e (80)
Cy
i-Pr
Me
Me
Scheme 1
n-Bu CH2OSi(i-Pr)3
a Isolated yields.
The acrylate ester 1a was chosen as the model compound
to find the best conditions for the RCM reaction using
complex I as catalyst. The first reactions run on 1a showed
a dependence of the product yield upon the initial concentra-
tion of the substrate. Thus, when a solution 0.25 M of 1a
was refluxed for 24 h in CH2Cl2 in the presence of the
ruthenium complex I (10 mol %) under a standard RCM
procedure,11 the expected 4-methyl-5-butyl-2(5Η)-furanone
2a12 was obtained in 29% yield (entry 1, Table 2). Note-
However, the acrylates 1, characterized by a gem-disub-
stitution of the alkene in the allylic moiety and by an elec-
tron-poor conjugated double bond, were expected to be crit-
ical substrates for a RCM reaction.1c-d,3a,9 According to the
literature, the reaction would have required the use of one
of the catalysts of type II, which were reported as the first
complexes to induce the formation of trisubstituted olefins
in the presence of a deactivating group such as acrylate1c,d,3b
and to exhibit an efficiency comparable to that of the alkoxy-
imido molybdenum complexes developed by Schrock in the
preparation of cyclic sterically hindered olefins.1,10
Table 2. Ring-Closing Metathesis of 1a
In this paper, we show how the RCM reaction of substrates
1 can be performed in the presence of commercially available
complex I, which remains the most attractive catalyst for
synthetic applications due to its lower cost.
The starting methallylacrylate esters have been prepared
by the reaction of the secondary allyl alcohols 3 with acryloyl
chloride, affording the expected products in good yields,
except for the case of the isopropyl derivative 3d (Table 1).
entry
concn of 1a (M)
catalyst (mol %)
yield of 2aa (%)
1
2
3
4
5
6
7
8
0.25
0.11
0.01
0.01
0.04
0.01
0.01
0.01
I (10)
I (10)
I (10)
I (5)
II (5)b
I (5)c
I (10)c
I (10)d
29
48
59
53
55
60
70
85
(3) (a) Fu¨rstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119, 9130-
9136. (b) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan,
S. P. J. Org. Chem. 2000, 65, 2204-2207. (c) Wybrow, R. A. J.; Johnson,
L. A.; Auffray, B.; Moran, W. J.; Adams, H.; Harrity, J. P. A. Tetrahedron
Lett. 2002, 43, 7851-7854. (d) Kangani, C. O.; Brukner, A. M.; Curran,
D. P. Org. Lett. 2005, 7, 379-382.
(4) (a) Fu¨rstner, A.; Schlede, M. AdV. Synth. Catal. 2002, 344, 657-
665. (b) Fu¨rstner, A.; Guth, O.; Du¨ffels, A.; Seidel, G.; Liebl, M.; Gabor,
B.; Mynott, R. Chem. Eur. J. 2001, 7, 4811-4820.
(5) Fu¨rstner, A.; Liebl, M.; Lehmann, C. W.; Picquet, M.; Kunz, R.;
Bruneau, C.; Touchard, D.; Dixneuf, P. H. Chem. Eur. J. 2000, 6, 1847-
1857.
a Isolated yields. b Carried out in toluene, 60 °C. c From a 0.04 M
solution. d From a 0.01 M solution added by a syringe pump.
worthy, however, was the finding that the product yields
could be raised by working with the same mol % of catalyst
but in more dilute solutions of 1a (entries 2 and 3, Table 2).
This positive effect of dilution on the reaction yields was
not surprising. As reported in the literature,9 low substrate
concentration can indeed minimize the formation of dimeric
alkene products, arising from undesired cross-metathesis
processes.
(6) Fu¨rstner, A.; Ackermann, L. Chem. Commun. 1999, 95-96.
(7) (a) Ghosh, A. K.; Cappiello, J.; Shin, D. Tetrahedron Lett. 1998, 39,
4651-4654. (b) Dirat, O.; Kouklovsky, C.; Langlois, Y.; Lesot, P.; Courtieu,
J. Tetrahedron: Asymmetry 1999, 10, 3197-3207. (c) Gosh, A. K.; Liu,
C. Chem. Commun. 1999, 1743-1744. (d) Cossy, J.; Bauer, D.; Bellosta,
V. Tetrahedron Lett. 1999, 40, 4187-4188. (e) Ramachandran, P. V.;
Reddy, M. V. R.; Brown, H. C. Tetrahedron Lett. 2000, 41, 583-586. (f)
Carda, M.; Rodr´ıguez, S.; Gonza´lez, F.; Castillo, E.; Villanueva, A.; Marco,
J. A. Eur. J. Org. Chem. 2002, 2649-2655.
(8) (a) Fra´ter, G.; Bajgrowicz, J. A.; Kraft, P. Tetrahedron 1998, 54,
7633-7703. (b) Otzuka, K.; Zenibayashi, Y.; Itoh, M.; Totsuka, A. Agric.
Biol. Chem. 1974, 38, 485.
(9) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310-7318.
(10) Reaction catalyzed by the molybdenum complex [Mo(CHCMe2-
Ph)(NAr)(OCMe(CF3)2)2] (Ar ) 2,6-(i-Pr)2C6H3): Fu, G. C.; Grubbs, R.
H. J. Am. Chem. Soc. 1992, 114, 7324-7325.
(11) After three vacuum/argon cycles performed on the appropriate
amount of [RuCl2(PCy3)2(dCHPh)] in a Schlenk tube, a solution of the
acrylate ester in anydrous dichloromethane is tranferred via cannula and
the reaction mixture kept under reflux for 20-24 h.
1806
Org. Lett., Vol. 7, No. 9, 2005

An important parameter to be considered is the stability
of the catalyst I in the reaction mixture. Since the alkylidene
ruthenium complexes are known to decompose via second-
order pathways, which are obviously concentration depend-
ent,13 a lower concentration may also imply a longer lifetime
of the catalyst. In fact, when the catalyst load was reduced
to 5% for [1a] ) 0.01 M, there was no significant decrease
in yield (entry 4, Table 2).
triisopropylsilyl ether derivative 5e, a good substrate for an
RCM-based synthetic approach to the 4-hydroxymethyl-5-
alkyl-2(5H)-furanone structures, which are found in many
interesting natural compounds showing bactericide proper-
ties.17
The procedure presented here shows the effectiveness of
the Grubbs’ first-generation complex I in RCM reaction of
diolefins bearing acrylic and gem-disubstituted double bonds
at the R and ω positions.
Importantly, when the reaction was performed using the
second-generation Grubbs’ catalyst II (5 mol %) in dichlo-
romethane under conditions identical to those in entry 4, the
RCM product was isolated only in 15% yield. A further
reaction of 1a (0.04 M) using catalyst II in toluene at 60 °C
(entry 5, Table 2) raised the yield to 55%, a value which is
comparable to those obtained using complex I.14
So far, the formation of cyclic trisubstituted olefins
catalyzed by the first-generation catalyst I or related com-
plexes has been reported to occur in the case of methyl-
substituted dienes derived from malonic esters or from
amides,1,6,18 in which the gem-diester or nitrogen substitution
on the hydrocarbon chain backbone favors a substrate
conformation suitable for cyclization. Moreover, to the best
of our knowledge, the ring-closing metathesis reaction of
diolefins derived from acrylic esters either requires assistance
by the Lewis acid Ti(O-i-Pr)4,7a-d,19 the use of the more active
second-generation Grubbs’ catalyst II,3b or of nitro-substi-
tuted Hoveyda-Grubbs ruthenium carbenes.20 As a matter
of fact, the synthesis of unsaturated five-membered hetero-
cycles with alkyl substituents on the double bond is
considered to be mainly the domain of the N,N′-disubstituted
heterocyclic alkylidene ruthenium catalysts.1c,d,3b,21
In addition to the entropy of reaction, which assists all
RCM processes due to the formation of two molecules from
the diolefin,1c,d,3a it is reasonable to think that the reaction
of the specific substrates 1 is favored by the short length of the
chain connecting the two reactive double bonds and by the
stability of the five-membered lactone products.22 These and
other factors may contribute to overcome the intrinsic low
efficiency of catalyst I with respect to catalysts of type II.
Thus, this work expands the scope of the RCM process
in the synthesis of substituted γ-lactones and reinforces the
Once we verified the unexpected tendency of the diolefinic
acrylic ester 1a to cyclize in the presence of I, we attempted
to further optimize the reaction yields by trying to combine
beneficial effects from dilution and from a continuous supply
of fresh catalyst solution. This has been accomplished by
slow addition from a syringe pump of a solution of complex
I to a refluxing solution of the substrate, both in dichlo-
romethane.15 When a 0.04 M dichloromethane solution of
complex was added to a 0.01 M solution of 1a, over a period
of 6 h, and the reaction mixture kept at reflux for an
additional 12 h, the butenolide 2a was obtained in 60% yield
(I in 5 mol %) or 70% yield (I in 10 mol %), respectively.16
Upon reducing the concentration of I in the syringe to 0.01
M (I in 10 mol %), the yield increased to 85%.
Having found appropriate experimental conditions that
allowed the RCM of the diolefin 1a to be performed with
excellent yields of isolated product, using the first-generation
Grubbs’ catalyst, the same procedure outlined in entry 8 of
Table 2 was extended successfully to the preparation of
butenolides with different alkyl substituents at the 5 position
2b-e (Table 3) in good yields.
(12) (a) Jefford, C. W.; Sledeski, A. W.; Boukouvalas, J. HelV. Chim.
Acta 1989, 72, 1362-1370. (b) Ma, S.; Shi, Z.; Yu, Z. Tetrahedron 1999,
55, 12137-12148.
(13) Ulman, M.; Grubbs, R. H. J. Org. Chem. 1999, 64, 7202-7207.
(14) The higher reactivity of complex II in toluene than in dichlo-
romethane has already been documented; see ref 3b.
Table 3. RCM Reaction of 1a-e Catalyzed by Complex I
(15) Dropwise addition of the title complex has been successfully used
by Brown et al. in the preparation of naturally occurring 6-substituted-5,6-
dihydro-2H-pyran-2-ones via RCM, as reported in ref 7e.
(16) The addition of the catalyst solution can be performed using a
dropping funnel or upon slow continuous addition from an infusion
pump.
(17) (a) Clive, D. L. J.; Huang, X. Tetrahedron 2002, 58, 10243-10250.
(b) Charan, R. D.; McKee, T. C.; Boyd, M. R. J. Nat. Prod. 2002, 65,
492-495. (c) Buchanan, M. S.; Edser, A.; King, G.; Whitmore, J.; Quinn,
R. J. J. Nat. Prod. 2001, 64, 300-303. (d) Hano, Y.; Shi, Y.-Q.; Nomura,
T.; Yang, P.-Q.; Chang, W.-J. Phytochemistry 1997, 46, 1447-1449. (e)
Koenig, G. M.; Wright, A. D.; Sticher, O.; Angerhofer, C. K.; Pezzuto, J.
M. Planta Med. 1994, 60, 532-537. (f) De Silva, E. D.; Scheuer, P. J.
Tetrahedron Lett. 1981, 22, 3147-50.
entry substrate
R1
R2
product (yield, %)a
1
2
3
4
5
1a
1b
1c
1d
1e
n-Bu Me
n-Pn Me
Cy
2a (85)
2b (90)
2c (78)
2d (47)
2e (57)
Me
Me
i-Pr
n-Bu CH2OSi(i-Pr)3
(18) Audic, N.; Clavier, H.; Mauduit, M.; Guillemin, J.-C. J. Am. Chem.
Soc. 2003, 125, 9248-9249.
a Isolated yields.
(19) The catalytic system I/Ti(O-i-Pr)4 proved to be inactive toward the
formation of a trisubstituted six-membered lactone.7d
(20) Michrowska, A.; Bujok, R.; Harutyunyan, S.; Sashuk, V.; Dolgonos,
G.; Grela, C. J. Am. Chem. Soc. 2004, 126, 9318-9325.
(21) (a) Briot, A.; Bujard, M.; Gouverneur, V.; Nolan, S. P.; Mioskowski,
C. Org. Lett. 2000, 2, 1517-1519; (b) Garber, S. B.; Kingsbury, J. S.;
Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168-
8179.
We also ran the cyclization of compound 1e (entry 5). This
was performed in order to test if the RCM conditions were
compatible with a different group on the allylic portion
double bond suitable of further manipulation. We chose the
(22) Galli, C.; Mandolini, L. Eur. J. Org. Chem. 2000, 3117-3125.
Org. Lett., Vol. 7, No. 9, 2005
1807

concept that not one single catalyst is superior to all others
in all possible applications.20
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We acknowledge financial support
from MIUR (COFIN 2002, “Flavors and Fragrances”) and
from University of Rome “La Sapienza” (funds for selected
research topics).
OL0504087
1808
Org. Lett., Vol. 7, No. 9, 2005