Cross metathesis of α-methylene lactones II: γ- and δ-lactones

Article abstract of DOI:10.1021/ol070574+

The cross metathesis reactivities of α-methylene-γ- butyrolactone and an α-methylene-δ-lactone have been investigated. α-Methylene-γ-butyrolactone undergoes rapid and efficient olefin isomerization in the presence of second-generation metathesis catalysts. However, cross metathesis can be achieved with the additive 2,6- dichlorobenzoquinone. In contrast, the α-methylene-δ-lactone neither isomerizes nor couples under similar conditions.

Full text of DOI:10.1021/ol070574+

ORGANIC
LETTERS
2007
Vol. 9, No. 9
1699-1701
Cross Metathesis of
Lactones II: - and
r
-Methylene
δ-Lactones
γ
Ravinder Raju, Laura J. Allen, Tri Le, Christopher D. Taylor, and Amy R. Howell*
Department of Chemistry, UniVersity of Connecticut, Storrs, Connecticut 06269-3060
amy.howell@uconn.edu
Received March 7, 2007
ABSTRACT
The cross metathesis reactivities of
r-methylene-γ-butyrolactone and an r-methylene-δ-lactone have been investigated. r-Methylene-γ-
butyrolactone undergoes rapid and efficient olefin isomerization in the presence of second-generation metathesis catalysts. However, cross
metathesis can be achieved with the additive 2,6-dichlorobenzoquinone. In contrast, the
under similar conditions.
r-methylene-δ-lactone neither isomerizes nor couples
We recently reported1 that R-alkylidene-â-lactones could be
prepared by cross metathesis (CM) of R-methylene-â-
lactones and terminal alkenes (Figure 1). The results
and atypical Z-selectivity. The efficiency of the coupling
reactions with these strained enoates spurred us to explore
the scope of CM with other classes of R-methylene lactones.
It was anticipated that larger ring systems would exhibit
metathesis activity similar to that of R-methylene-â-lactones.
We report herein our unexpected results with the simple
substrates R-methylene-γ-butyrolactone (1) and R-methylene-
δ-lactone 2.
Initial investigations began by reacting R-methylene-γ-
butyrolactone with 1-acetoxy-9-decene under the conditions
developed for CM of R-methylene-â-lactones (Table 1, entry
1). Interestingly, isomerization to enone 6 was the sole
reaction pathway observed. Olefin isomerization with ru-
thenium carbene catalysts is well documented.2 Postulating
that the PCy3 ligand might induce isomerization, reaction
using phosphine-free catalyst 4 was attempted (entry 2), and
the outcome was the same. As a control experiment, 1 and
the acetate cross partner were heated to determine if
Figure 1. CM reactions of R-methylene-â-lactones.
represented the first published examples of CM with strained
exocyclic enones and were remarkable for their high yields
(2) (a) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J.
Am. Chem. Soc. 2002, 124, 13390-13391. (b) Alcaide, B.; Almendros, P.
Chem.-Eur. J. 2003, 9, 1258-1262. (c) Finnegan, D.; Seigal, B. A.;
Snapper, M. L. Org. Lett. 2006, 8, 2603-2606.
(1) Raju, R.; Howell, A. R. Org. Lett. 2006, 8, 2139-2141.
10.1021/ol070574+ CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/04/2007

Table 1. Preliminary Investigation of CM of
R-Methylene-γ-butyrolactone (1)a
Table 2. CM Reactions of R-Methylene-γ-butyrolactone (1)
entry
Ra
yield (%)b
E/Z
1
2
3
4
5
6
(CH2)2CH3
CH3
(CH2)8OAc
(CH2)2OAc
(CH2)2Br
CH2Cl
8a, 83
8b, 93
8c, 80
8d, 75
8e, 43
8f, 44
20:1
6:1
15:1
10:1
20:1
20:1
product distributionb
c
entry
catalyst
7 (equiv)
5
6
1
2
3
4
5
6
7
8
3
4
none
3
4
3
4
4
none
none
none
none
none
0.10
0.10
0.10
0
0
-
92
87
0
a
b
-
-
23
67
98d
98c
70c
25
0
For experimental conditions, see footnote 5. All yields are isolated
yields for the combined E/Z isomers. c 2-Methyl-2-butene (10 equiv) is the
cross partner.
0
(83%) using 10 equiv of 2-methyl-2-butene and 5 mol % of
4. In other cases, increasing the equivalents of the cross
partner decreased the rate of formation of 8. For entries 1,
3, and 4, a maximum of 69% conversion was observed
spectroscopically using 5 mol % of 4; to obtain complete
conversion, an additional 5 mol % was required. The low
yields obtained for 8e and f were a consequence of
incomplete conversion, even using 10 mol % of 4. Moreover,
increasing catalyst loading (up to 25 mol %) did not improve
the yields.
On the basis of the CM results with 1, our initial
expectation was that 2 would behave in a similar fashion.
However, 2 failed to undergo either isomerization or
significant CM in the presence of catalysts 3 and 4 (Table
3, entries 1 and 2). Heating for a lengthy period (4 days) or
increasing catalyst loading did not alter the outcome. Running
the reaction at higher temperature (entry 3) gave no cross
product but did result in isomerization. Although the addition
of 7 suppressed isomerization somewhat (from 66% to 26%,
entry 4), it did not promote CM. Puzzled by the lack of
reactivity of 2, we postulated that the catalyst might be
forming a complex with the substrate.6 To address this
possibility, a Lewis acid, Ti(OiPr)4 (11), was added. In
toluene, but not dichloromethane, complete isomerization
occurred within 8 h (entries 5 and 6). No CM was observed,
even in the presence of 7 (entry 7), although this may be a
reflection of incompatability of 11 and 7. These results do
not mean that CM cannot be achieved with R-methylene-
δ-lactones. For example, HOAc4b promoted CM and sup-
a
A preliminary report of this data was disclosed at the ACS meeting in
San Francisco, CA, September 2006. b Determined by 1H NMR. c Absence
d
of a cross partner. 10 mol % of 4, added in two portions.
isomerization was being promoted thermally or even perhaps
by trace acid (entry 3). The result was clear: heat alone did
not promote isomerization.
There have been a variety of explanations for undesirable
olefin isomerization in the presence of ruthenium-based
olefin metathesis catalysts. We reasoned that a ruthenium
hydride complex was fueling the isomerization of 1. To
address the possibility that the cross partner might be
responsible for the formation of a ruthenium hydride
complex, we heated 1 with either 3 or 4 in the absence of a
cross partner (entries 4 and 5). Isomerization was sluggish
using 4 (70% after 24 h) in comparison to 3 (98%, 20 min).
These outcomes suggest that 1 is a viable hydride donor,
and this can be rationalized by a π-allyl or a σ-alkyl/π-allyl
mechanism.3 Although isomerization was interesting, our
goal was to achieve CM.
Electron-deficient benzoquinones have been identified4 as
efficient additives for preventing isomerization in substrates
such as allylic alcohols and amines. Indeed, 2,6-dichloroben-
zoquinone (7) (10 mol %) suppressed the isomerization of
1. Interestingly, isomerization was not completely terminated
with catalyst 3 (Table 1, entry 6) but was with phosphine-
free catalyst 4, although with incomplete conversion (entry
7). Adding 10 mol % of catalyst 4 in two portions over 24
h allowed for complete consumption of 1 (entry 8).
(5) General Cross Metathesis Protocol. The olefin cross partner (1-
1.5 equiv, except for entry 2) was added to a solution of lactone 1 (1 equiv)
in CH2Cl2 (0.3-0.4 M in lactone). Additive 7 (0.10 equiv) was added
followed by the addition of catalyst 4 (0.05 equiv) to the solution, which
was heated under N2 at reflux for 12 h. After 12 h, 0.05 equiv of more
catalyst was added to the reaction mixture. The reaction was monitored by
1H NMR. Upon consumption of 1, the solution was cooled and concentrated
in vacuo, and the brown residue was purified by flash chromatography on
silica gel.
(6) (a) Furstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119, 9130-
9136. (b) Wipf, P.; Weiner, W. S. J. Org. Chem. 1999, 64, 5321-5324.
(c) Bai, C.-X.; Lu, X.-B.; He, R.; Zhang, W.-Z.; Feng, X.-J. Org. Biomol.
Chem. 2005, 3, 4139-4142. (d) Yang, Q.; Xiao, W. J.; Yu, Z. Org. Lett.
2005, 7, 871-874.
Lactone 1 was coupled with a variety of terminal olefins
in the presence of 4 and 7 in refluxing CH2Cl2 (Table 2).5 A
stoichiometric or slight excess of the terminal alkene was
employed for all cases except for the formation of 8b (entry
2). Considerable conversion to 8b was observed after 4 h
(3) Schmidt, B. Eur. J. Org. Chem. 2004, 2004, 1865-1880 and
references therein.
(4) (a) Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2004,
126, 7414-7415. (b) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R.
H. J. Am. Chem. Soc. 2005, 127, 17160-1716.
1700
Org. Lett., Vol. 9, No. 9, 2007

contrast to the ease of CM of â-lactones, the CM of these
larger cyclic enoates is sluggish and hampered by competitive
isomerization. We have circumvented isomerization of 1
using 7 and have effectively promoted CM with reasonable
yields. We are not unmindful of the high catalyst loading
for 1 to undergo CM, but this may also reflect substrate-
catalyst complexation. In sharp contrast, δ-lactone 2 neither
isomerizes nor couples to any significant extent under
conditions used with â-lactones and 1. It is reasonable to
postulate that as the ring size increases a stable chelate may
form, thus sequestering the active catalyst and inhibiting
metathesis. This chelation was reduced at higher tempera-
tures, but then only unwanted isomerization was observed.
Lewis acid 11 efficiently displaced the bound catalyst, but,
once again, isomerization was the only reaction observed.
HOAc suppressed isomerization and modestly promoted CM.
A survey of additives might reveal one compatible with 2.
We feel that the CM reactivity of these four-, five-, and six-
membered R-methylene lactones reveals distinct behaviors
that were not predictable a priori. These results provide a
foundation for further exploration of these systems.
Table 3. Preliminary Investigation of CM of
R-Methylene-δ-lactone (2)
product distributionc
entry catalyst additivea solventb
9
10
1
2
3
4
5
6
7
8d
3
4
3
3
3
3
3
3
none
none
none
7
11
11
CD2Cl2
CD2Cl2
Tol-d8
Tol-d8
CD2Cl2
Tol-d8
Tol-d8
CD2Cl2
19
11
0
0
0
66
26
0
0
0
0
0
100
100
trace
7 and 11
HOAc
54
a
10 mol % of 7, 20 mol % of 11, and/or 150 mol % of HOAc employed
in appropriate entries. b Reactions using CD2Cl2 and Tol-d8 were heated at
reflux. c Determined by 1H NMR. Entries 1-5 reflect conversion after 48 h.
Entries 6 and 7 reflect conversion after 8 h. d 10 mol % of 3 added in two
portions; conversion after 36 h.
Acknowledgment. We are grateful to Boehringer Ingel-
heim for the generous supply of metathesis catalyst 4. We
thank Dr. Martha Morton (University of Connecticut) for
assistance with NMR experiments. This manuscript is based
upon work partially supported by the National Science
Foundation (NSF) under Grant No. CHE-0111522. L.J.A.
(Ohio State University) was supported by NSF-REU Grant
CHE-0354012. We thank Meena Thakur (University of
Connecticut) for assisting L.J.A.
pressed isomerization (entry 8). However, given the catalyst
loading (10 mol %) and inefficient conversion (maximum,
54% at 36 h), HOAc does not appear to be an optimal
additive. From these results, it is apparent that under standard
conditions, even with typical additives, CM does not proceed
efficiently. Nevertheless, it is germane that complete isomer-
ization occurs with 11, and CM proceeds to some extent with
HOAc. This suggests that there may be some combination
of additives or a superior additive that would permit
productive CM.
Supporting Information Available: Experimental pro-
cedures and characterization data, as well as copies of high-
resolution 1H and 13C NMR spectra for those new compounds
for which elemental analyses are not reported. This material
is available free of charge via the Internet at http://pubs.acs.org.
In conclusion, the CM reactivities of R-methylene-γ-
lactone 1 and R-methylene-δ-lactone 2 have been compared
to our previously described results with â-lactones. In
OL070574+
Org. Lett., Vol. 9, No. 9, 2007
1701