Enyne cross-metathesis with strained, geminally-substituted alkenes: Direct access to highly substituted 1,3-dienes

Article abstract of DOI:10.1021/ol802007q

(Figure Presented) Ru cat. = variety of second generation Grubbs' catalysts used nine examples, 92-99% isolated yields Angle strain in methylene cyclobutane was used to drive a cross-enyne metathesis with 1-alkynes, giving 1,1,3-trisubstituted 1,3-dienes in good isolated yields. An extensive survey of Grubbs' second-generation catalysts led to an optimized reaction conducted at 0 °C.

Full text of DOI:10.1021/ol802007q

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4927-4929
Enyne Cross-Metathesis with Strained,
Geminally-Substituted Alkenes: Direct
Access to Highly Substituted 1,3-Dienes
Daniel A. Clark, Brenda S. Basile, William S. Karnofel, and Steven T. Diver*
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York,
Amherst, New York 14260
diVer@buffalo.edu
Received August 27, 2008
ABSTRACT
Angle strain in methylene cyclobutane was used to drive a cross-enyne metathesis with 1-alkynes, giving 1,1,3-trisubstituted 1,3-dienes in
good isolated yields. An extensive survey of Grubbs’ second-generation catalysts led to an optimized reaction conducted at 0 °C.
Enyne metathesis has become a useful method for carbon-
carbon bond formation.1 In its most commonly used form, the
Scheme 1. Strained Alkenes Undergo Cross Metathesis
intermolecular (cross) enyne metathesis2 between 1-alkene and
an alkyne generates a 1,3-diene with the 1,3-disubstitution
pattern (R1 ) H, eq 1, Scheme 1). Although enyne metathesis
is often compared to alkene metathesis, there is one notable
difference: in cross alkene metathesis, geminal alkenes can be
crossed with 1-alkenes to give trisubstituted alkene products.3
Knowing this, it seems like trisubstituted dienes of the 1,1,3-
trisubstitution pattern should be accessible from geminally-
substituted alkenes (eq 1, Scheme 1). However, 1,1-disubstituted
alkenes display poor reactivity with the Grubbs catalyst. Because
the enyne metathesis is believed to occur by an “alkylidene-
first” mechanism,4 the alkene is required to react with the
(1) Enyne reviews: (a) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1–
18. (b) Mori, M. Ene-Yne Metathesis. In Handbook of Metathesis; Grubbs,
R. H., Ed.; Wiley-VCH: Weinheim, 2003; Vol. 2, pp 176-204. (c) Diver,
S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317–1382.
catalyst to form the needed alkylidene. In this paper, we show
that angle strain in methylene cyclobutane can effectively drive
the cross enyne metathesis, giving rise to dienes of 1,1,3-
trisubstitution pattern in a single catalytic metathesis step (eq
3, Scheme 1).
There is limited data on geminal alkene reactivity in me-
tathesis. Strain in a geminal alkene can be used to drive the
alkene initiation step. Examination of the literature provides two
examples of geminal alkenes that were shown to form ruthenium
(2) Stragies, R.; Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl.
1997, 36, 2518–2520.
(3) (a) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751–1753.
(b) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360–11370.
(4) (a) Hoye, T. R.; Donaldson, S. M.; Vos, T. J. Org. Lett. 1999, 1,
277–279. (b) Schramm, M. P.; Reddy, D. S.; Kozmin, S. A. Angew. Chem.,
Int. Ed. 2001, 40, 4274–4277. (c) Giessert, A. J.; Diver, S. T. Org. Lett.
2005, 7, 351–354. (d) Galan, B. R.; Giessert, A. J.; Keister, J. B.; Diver,
S. T. J. Am. Chem. Soc. 2005, 127, 5762–5763.
10.1021/ol802007q CCC: $40.75
Published on Web 10/09/2008
2008 American Chemical Society

Figure 1. Grubbs’ catalysts used in this study.
carbenes. In 1995, the Grubbs group showed that the neo-
phylidene complex 1 reacted with both methylene cyclopropane
and methylene cyclobutane (eq 2, Scheme 1).5 The Caltech
group structurally characterized the geminally-substituted metal
carbene 2 derived from methylene cyclobutane. We took this
as a positive indication that the strain release on going to the
spirometallacycle could be used to effect initiation in the second
generation Grubbs carbenes with the (H2IMes)(L)Cl2RudCHPh
ligand environment. Strain release might overcome the other-
wise slow initiation step typical for geminally-substituted
alkenes. Recently, Oishi and co-workers reported a single
example of catalytic cross enyne metathesis using a large excess
of the geminally-substituted alkene 2-methallyl alcohol.6
Reaction of methylene cyclobutane with alkyne 10A was
observed and optimized with respect to the carbene initiator.
The highest reactivity in cross metathesis is typically achieved
with the second generation Grubbs carbene complexes, so we
focused on use of this family of Grubbs carbenes (Figure 1).
The data is summarized in Table 1. In this screen, the number
not initiate at 0 °C, but good reactivity could be obtained by
conducting the reaction at rt or reflux (entries 2 and 3). The
phosphine-free Hoveyda-Blechert7 complex 4 proved to initiate
at low temperature in CH2Cl2 and reacted well in DCE or
benzene at rt. With the more active phosphine-containing
bis(tolyl) complex 58 good reactivity was found, with complete
conversion observed at rt (entry 7, cf. entry 2). The phosphine-
free variant 6 promoted the cross-enyne metathesis at 0 °C. The
Piers catalyst 79 reacted at rt (entry 9), and the newly reported
Grubbs’ complexes10 8 and 9 proved highly active, promoting
the cross metathesis at 0 °C in less than 5 min (entries 10 and
11).
With a good survey of catalyst efficiency, we decided to fine-
tune the conditions with respect to catalyst loading and number
of equivalents alkene.11 At this stage, we settled on a lower
reaction temperature to maintain alkene concentration for
potentially longer reaction times employing fewer equivalents
alkene. The results are summarized in Table 2. First, the excess
Table 2. Refinement of Reaction Parametersa
Table 1. Catalyst Screeninga
carbene
loading
T
%
yield
carbene
complex
T (°C),
time
% yield
(NMR)b
entry complex (mol %) equiv (°C), time
entry
solvent
1
2
3
4
5
6
7
8
9
4
4
6
6
6
8
8
9
9
5
2
0, 2.5 h
0, 4 h
0, 30 h
0, 30 h
0, 30 h
0, 1.5 h
0, 3 h
92
70
99
96
91
40
89
1
3
3
3
4
4
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
0, 5 h
rt, 1 h
NR
93
95
97
86
99
99
97
75
99
99
5
1.25
2
5
2
2
3
reflux, 15 min
0, 15 min
rt, 15 min
rt, 15 min
rt, 20 min
0, 20 min
rt, 20 min
0, <5 min
0, <5 min
2.5
5
4
1.25
3
5
1
6
PhH
5
2
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1
3
0, 3 h
0, 3 h
incomplete
99
8
5
2
9
a Conditions: 0.1 M alkyne, variable methylene cyclobutane in solvent
at temperature indicated. NMR yield vs mesitylene internal standard.
10
11
a Conditions: 0.1 M alkyne, 0.3 M methylene cyclobutane in solvent at
temperature indicated. Reactions went to complete conversion of alkyne
reactant unless otherwise noted. b NMR yield vs mesitylene internal standard.
alkene was decreased to 2 equiv with acceptable yield using
catalyst 4, but further reduction of alkene concentration proved
deleterious to reaction yield and efficiency (entries 1 and 2).
The tolyl complex 6 performed better at both lower alkene
concentration and at 2.5 mol % loading (entry 4). With 5 mol
% of 6, the alkene equivalents could be reduced further (entry
5). Complex 8 did not give complete conversion at very low
loading (1 mol %, entry 6) but performed adequately at 5 mol
of alkene equivalents was kept constant at 3 equiv. With a
volatile, low molecular weight alkene, we sought low temper-
ature conditions. Temperatures lower than room temperature
are not commonly used in the metathesis but are possible when
using more active initiators. The parent Grubbs complex 3 did
4928
Org. Lett., Vol. 10, No. 21, 2008

% over a 3 h reaction time (entry 7). The tolyl complex 9
showed similar performance at 1 mol %, and a higher
conversion was found at 5 mol % loading (entry 9). These data
suggest that the alkene concentration can be dropped to 2 equiv
while maintaining catalyst loading at 2.5-5 mol %. The alkene
concentration and catalyst loading cannot be simultaneously
decreased without diminishing conversion and reaction yield.
From Table 2 we adopted the conditions in entry 4 as our
standard conditions.
The resulting 1,3-dienes are reactive in room-temperature
cycloadditions. The diene products in eq 6 (Table 3) possess
angle strain due to the distortion of the cyclobutane ring from
ideal sp2 bond angles. As a result, dienes 13C and 15readily
undergo Diels-Alder reaction to provide the corresponding
cycloadducts in excellent yield (Scheme 2).
Scheme 2. Room-Temperature Cycloadditions
The standard conditions were applied to a range of terminal
alkynes as shown in Table 3. The propargylic benzoates gave
Table 3. Reaction Scope of the Enyne Metathesis with
Methylenecyclobutanea
In conclusion, we have shown that a strained alkene gives a
highly effective cross metathesis to furnish dienes with geminal
substitution at the terminal position of the diene. A wide variety
of highly active second generation Grubbs carbenes were
screened in the optimization study. The use of angle strain in
the geminal substituents of the alkene offers a means to
overcome poor reactivity of geminal alkenes and elaborates the
accessible substitution patterns by catalytic enyne cross me-
tathesis. Studies using strain as a means of achieving catalytic
efficiency and extending reaction scope further are ongoing and
will be reported in due course.
Acknowledgment. This work was partially supported by
the Petroleum Research Fund (PRF AC-44202) and the NSF
(CHE-601206). We thank Materia (Pasadena, CA) for gener-
ously supplying Grubbs’ catalyst.
Supporting Information Available: Experimental pro-
cedures and full characterization data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
a Standard conditions: 0.2 M alkyne, 0.4 M alkene, 2.5 mol % of 6,
CH2Cl2, 0 °C, 1-3 h; 50 mol % KO2CCH2NC quench. (a) Isolated. (b)
Performed at 0.1 M with 5 mol % 6.
OL802007Q
(5) Wu, Z.; Nguyen, S. T.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem.
Soc. 1995, 117, 5503–5511. For a discussion of the role of strain in
promoting the initiation, see footnote 12 in the above paper by Grubbs et
al.
(6) Watanabe, K.; Minato, H.; Murata, M.; Oishi, T. Heterocycles 2007,
72, 207–212. We thank a reviewer for bringing this to our attention.
(7) (a) Gessler, S.; Randl, S.; Blechert, S. Tetrahedron Lett. 2000, 41,
9973–9976. (b) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168–8179.
excellent results regardless of substitution (entries 1 and 2).
Oxygen functionality at the homopropargylic position was also
tolerated, as in typical12 cross enyne metatheses with 1-alkenes
(entries 3-5). Nitrogen functionality did not prove problematic
(entry 6), and larger substituents in the propargylic position were
acceptable and found to give rapid conversions under the stan-
dard reaction conditions (entries 7 and 8). Last, the homochiral
amino acid derivative 18 underwent an effective cross metath-
esis to give the diene in quantitative chemical yield (entry 9).
In summary, these reactions are very effective13 and high
yielding using a modest amount of methylene cyclobutane, low
reaction temperatures, and low catalyst loading.
(8) (a) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs,
R. H.; Schrodi, Y. Org. Lett. 2007, 9, 1589–1592. (b) Stewart, I. C.; Douglas,
C. J.; Grubbs, R. H. Org. Lett. 2008, 10, 441–444.
(9) Romero, P. E.; Piers, W. E.; McDonald, R. Angew. Chem., Int. Ed.
2004, 43, 6161–6165.
(10) Chung, C. K.; Grubbs, R. H. Org. Lett. 2008, 10, 2693–2696.
(11) Typically 3 equiv (or more) alkene are employed for a successful
cross enyne metathesis.
(12) A notable difference in the present case is the lower reaction
temperature, which is not typical of a cross enyne metathesis.
(13) Internal alkynes were found not to give the cross metathesis under
the standard conditions reported here.
Org. Lett., Vol. 10, No. 21, 2008
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