Chemoselective construction of substituted conjugated dienes using an olefin cross-metathesis protocol

Article abstract of DOI:10.1021/ol047929z

(Chemical Equation Presented) Various substituted conjugated dienes have been made by olefin cross-metathesis. Using either electronic or steric "protection," one of the olefins of the conjugated diene was deactivated relative to the other for cross-metathesis. The reactions proceed with very high chemoselectivity and, when steric deactivation is used, very high diastereoselectivity.

Full text of DOI:10.1021/ol047929z

ORGANIC
LETTERS
2005
Vol. 7, No. 2
187-190
Chemoselective Construction of
Substituted Conjugated Dienes Using an
Olefin Cross-Metathesis Protocol
Timothy W. Funk, Jon Efskind, and Robert H. Grubbs*
The Arnold and Mabel Beckman Laboratory of Chemical Synthesis, DiVision of
Chemistry and Chemical Engineering, California Institute of Technology,
Pasadena, California 91125
rhg@its.caltech.edu
Received October 7, 2004
ABSTRACT
Various substituted conjugated dienes have been made by olefin cross-metathesis. Using either electronic or steric “protection,” one of the
olefins of the conjugated diene was deactivated relative to the other for cross-metathesis. The reactions proceed with very high chemoselectivity
and, when steric deactivation is used, very high diastereoselectivity.
The olefin metathesis reaction has recently gained promi-
nence in synthetic organic chemistry.1 The commercial
availability of well-defined catalysts, such as the molybde-
num alkoxyimido alkylidene 1 developed by Schrock et al.2
and ruthenium benzylidene catalysts 23 and 3,4 have made
the olefin metathesis reaction practical for small molecule
synthesis. In particular, ring-closing olefin metathesis (RCM)
reactions5 have been utilized in the construction of a diverse
set of organic molecules. There is strong interest in synthe-
sizing conjugated dienes because they appear in a wide array
of naturally occurring molecules and they also function as
synthetic building blocks.
(1) For recent reviews on olefin metathesis, see: (a) Grubbs, R. H.
Handbook of Metathesis; Wiley-VCH: Weinheim, 2003. (b) Schuster, M.;
Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 20377-2056. (c) Ivin, K.
J. J. Mol. Catal. A: Chem. 1998, 133, 1-16. (d) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413-4450.
(2) (a) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; Dimare,
M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875-3886. (b) Bazan, G.
C.; Khosravi, E.; Schrock, R. R.; Feast, W. J.; Gibson, V. C.; O’Regan, M.
B.; Thomas, J. K.; Davis, W. M. J. Am. Chem. Soc. 1990, 112, 8378-
8387. (c) Bazan, G. C.; Oskam, J. H.; Cho, H. N.; Park, L. Y.; Schrock, R.
R. J. Am. Chem. Soc. 1991, 113, 6899-6907.
(3) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Eng. 1995, 34, 2039-2041. (b) Schwab, P.; Grubbs, R. H.;
Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100-110. (c) Belderrain, T. R.;
Grubbs, R. H. Organometallics 1997, 16, 4001-4003.
(4) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
A wide variety of methods exist for the construction of
conjugated olefins. These include palladium-catalyzed reac-
tions such as the Stille and Suzuki couplings of two olefins
as well as the Sonogashira reaction followed by a Lindlar
reduction to yield an olefin. The advantages of using olefin
(5) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28,
446-452. (b) Nicolaou, K. C.; Posterma, M. H. D.; Yue, E. W.; Nadin, A.
J. Am. Chem. Soc. 1996, 118, 10335-10336. (c) See ref 1b. (d) Kirkland,
T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310-7318. (e) Nicolaou,
K. C.; Winssinger, N.; Pastor, J.; Ninkovic, S.; Sarabia, F.; He, Y.;
Vourloumis, D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel, E. Nature 1997,
387, 268-272.
10.1021/ol047929z CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/22/2004

Table 1. Olefin CM with Electron-Poor Dienesa
Scheme 1
metathesis in the construction of conjugated dienes include
mild reaction conditions, stability of the reagents, and the
wide variety of commercially available olefin partners.
2-Substituted 1,3-butadienes have been synthesized using
enyne metathesis,6 and there are a few examples of macro-
cyclic ring-closing metathesis to form conjugated dienes.7
However, very little work has been focused on synthesizing
conjugated dienes using olefin cross-metathesis due to issues
regarding chemo- and diastereoselectivity.
a Conditions: olefin (1-3 equiv), conjugated diene (1 equiv), and catalyst
3 (5 mol %) for 12 h in refluxing CH2Cl2 (0.2 M). b Isolated yields. c 10
mol % of catalyst 3 was used.
In principle, it should be possible to carry out a cross-
metathesis reaction on only one of the olefins in a diene.
One way to influence the chemoselectivity would be to
sterically or electronically deactivate one of the double bonds
in the conjugated diene. Our strategy is based on shielding
one of the olefins in the conjugated diene by attaching either
electron-withdrawing substituents or steric bulk. Furthermore,
by choosing the appropriate electron-withdrawing substitu-
ents and olefin cross partners, we will be able to further
functionalize the conjugated product. Herein, we report a
chemoselective olefin cross-metathesis reaction with conju-
gated dienes.
Our studies began with the use of ethyl sorbate (4) as the
protected conjugated diene substrate for the olefin cross-
metathesis reaction. When a reaction mixture consisting of
4, 5-hexenyl acetate (5), and catalyst 2 was heated to reflux
in CH2Cl2, only homocoupling of 5 occurred (Scheme 1).
Both of the olefins in 4 are too deactivated to react with 2.
The more active catalyst 3 reacts with both olefins of the
diene to yield 7 and 8 as an 80:20 mixture. The ester
functionality is not sufficiently deactivating when catalyst 3
is used, and both olefins of the diene react.
bromoethyl sorbate, was prepared according to a literature
procedure by Spitzner et al.8 and was used as a 9:1 mixture
of 2Z/2E isomers. This substrate could give synthetically
interesting and useful products because both the vinyl
bromide and the ester group can be further functionalized.
It was not surprising that the cross-metathesis between
allylbenzene (10) and 9 in refluxing CH2Cl2 failed with
catalyst 2. When the more active catalyst 3 was used in the
same system, the R,â-double bond was sufficiently deacti-
vated relative to the γ,δ-double bond to form the desired
product 16 in 68% isolated yield (Table 1, entry 1). The
diastereoselectivity of the reaction was moderately high: a
mixture of E/Z isomers in an 8.5:1 ratio was observed. Other
functionalized olefins also react chemoselectively with 9
(Table 1, entries 1-4). The diastereoselectivity of the
reaction remains moderate in most cases, and is highest when
diene 9 undergoes a homocoupling reaction to yield a
conjugated triene in >20:1 E/Z ratio. When the cross-
metathesis reactions were carried out at 25 °C, the only
product observed was homocoupled olefin and unreacted
diene.
To further reduce the electron density in the R,â-double
bond as well as increase the steric bulk, a vinylic bromide
was introduced at the R-carbon. Compound 9, (2Z,4E)-2-
To determine if the protecting ester functionality could
be replaced with a bromide, 1,1-dibromo-1,3-butadiene was
prepared. Unfortunately, it was found to decompose within
hours after preparation and was therefore not a good
candidate for the cross-metathesis reaction.9 1,1-Dibromo-
1,3-pentadiene (15), however, is much more stable and
(6) Diver, S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317-1382.
(7) (a) Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.; Danishefsky,
S. J. J. Am. Chem. Soc. 2001, 123, 10903-10908. (b) Dvorak, C. A.;
Schmitz, W. D.; Poon, D. J.; Pryde, D. C.; Lawson, J. P.; Amos, R. A.;
Meyers, A. I. Angew. Chem., Int. Ed. 2000, 39, 1664-1666. (c) Wagner,
J.; Cabrejas, L. M. M.; Grossmith, C. E.; Papageorgiou, C.; Senia, F.;
Wagner, D.; France, J.; Nolan, S. P. J. Org. Chem. 2000, 65, 9255-9260.
(8) Braun, N. A.; Burkle, U.; Feth, M. P.; Klein, I.; Spitzner, D. Eur. J.
Org. Chem. 1998, 1569, 9-1576.
(9) Wrobel, J. E.; Ganem, B. J. Org. Chem. 1983, 48, 3761-3764.
188
Org. Lett., Vol. 7, No. 2, 2005

Scheme 2
Scheme 3
product 30 was isolated in 80% yield (Table 2, entry 1).
Table 2 displays the results of cross-metathesis reactions of
1,2-disubstituted 1,3-butadienes with various olefins.10
therefore a more viable cross-partner.9 The results of the
cross-metathesis reactions between 1,1-dibromo-1,3-penta-
diene and various olefins are summarized in Table 1, entries
5s7. Entry 5 shows that the yields are modest when methyl
acrylate (14) is used as the cross-partner, while the use of
styrene (11) or 5 affords cross-metathesis products in good
yields.
The above methodology leads to functionalized butadienes
that contain 1,4-disubstitution. To further extend the chemose-
lective cross-metathesis of conjugated dienes to 2-substituted
butadienes, steric shielding of one of the olefins was
examined. In the initial test reaction, vinyl boronate 23
reacted with isoprene (24) to give the desired diene in 26%
yield (Scheme 2). Although the yield was low, only isomer
25 was isolated. Attempts to improve the conversion led to
a 48% yield under optimized conditions. One potential reason
for the low yield is the low boiling point of isoprene (34
°C) and the higher temperatures needed for the reaction.
Therefore, 3-methyl-1,3-pentadiene (28) (bp ) 76 °C) was
used under the initial reaction conditions, and the desired
Both electron-rich and electron-poor olefins react to give
products in good yields with very high chemoselectivity and
diastereoselectivity. Since the initial study with isoprene
suggested that the substituent in the 2-position caused the
high chemoselectivity, further studies were focused on dienes
containing only 2-substitution (Scheme 3). A temperature
dependence was observed in these reactions; under the
conditions used for 1,2-disubstituted 1,3-butadienes, the
yields of products were moderate. By changing the solvent
from CH2Cl2 to benzene and increasing the temperature from
40 °C to 60 °C, the yield increased from 51% to 72%.
Raising the temperature to 80 °C resulted in a decreased
yield, most likely due to increased catalyst decomposition.
This need for higher temperatures may result from the
formation of a vinylalkylidene catalyst species, which can
be stabilized through vinyl olefin coordination.11
Using the modified conditions, various 2-substituted 1,3-
butadienes reacted with functionalized olefins to form the
desired dienes in good yields with high chemoselectivity and
diastereoselectivity (Table 3). Unreacted diene could be re-
isolated in these reactions. When vinyl boronate 23 was the
olefin, the reactions were stopped after 2 h and clean product
could be isolated. Longer reaction times did not increase the
yield and resulted in an unidentified, inseparable impurity.
Although 2-substituted 1,3-butadienes do not homocouple
and can be considered type III olefins, excess olefin cross
partner is needed.12 The need for excess cross partner may
stem from the importance of not allowing the diene to react
with the catalyst to form a vinylalkylidene species. The
higher concentration of reactive olefin causes less interaction
between the catalyst and the diene.
Table 2. Olefin CM Using 1,2-Disubstituted 1,3-Butadienesa
The vinyl bromide-containing dienes as well as the vinyl
boronate-containing dienes synthesized above are useful
synthetic intermediates and can be further functionalized with
ease. The reaction in Scheme 4 illustrates a palladium-
catalyzed cross-coupling reaction that results in a highly
conjugated system where all of the stereochemistry was set
using cross-metathesis. A one-pot cross-metathesis/Suzuki
a Conditions: olefin (1-4 equiv), diene (1 equiv), and catalyst 3 (5 mol
%) in refluxing CH2Cl2 (0.2 M) for 12 h. b 3-Methyl-1,3-pentadiene (28)
was purchased as a 70:30 mixture of E/Z isomers. c Only the E isomer was
observed in all cases; when 28 was the diene, both E and Z isomers reacted.
d Isolated yields. e Product was not separated from unreacted 5. f Product
was not separated from allyl benzoate formed in the reaction. g None of
the product containing the terminal CdCH2 group was observed (see ref
10).
(10) The reaction between 1,2-disubstituted 1,3-butadienes and most of
the olefins in Table 2 resulted in 7-12% product where the alkyl group in
the 1-position was replaced with a terminal olefin (CH2 group).
(11) This type of vinylalkylidene stabilization has been observed by our
group as well as others: (a) Trnka, T. M.; Day, M. W.; Grubbs, R. H.
Organometallics 2001, 20, 3845-3847. (b) Mori, M.; Sakakibara, N.;
Kinoshita, A. J. Org. Chem. 1998, 63, 6082-6083. (c) See ref 3a.
(12) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360-11370.
Org. Lett., Vol. 7, No. 2, 2005
189

Table 3. Olefin CM with 2-Substituted 1,3-Butadienesa
Scheme 4
In conclusion, the electronic or steric deactivation of one
olefin in a conjugated diene toward olefin metathesis with
catalyst 3 is possible. This “protection” has resulted in highly
chemoselective cross-metathesis reactions of 2-bromoethyl
sorbate and 1,1-dibromo-1,3-pentadiene with a variety of
olefins. It has also led to a highly chemo- and diastereose-
lective cross-metathesis reaction between 1,2-disubstituted
1,3-butadienes and 2-substituted 1,3-butadienes with a
number of olefin partners. The simplicity of use and
functional-group tolerance of catalyst 3, as well as the high
chemo- and diastereoselectivity with which these transforma-
tions occur, makes this an attractive method for synthesizing
functionalized conjugated dienes.
Acknowledgment. This work was supported by a re-
search grant from the National Institutes of Health.
Supporting Information Available: Experimental pro-
cedures and full characterization for dienes 29, 37, and 38
and general procedures and full characterization for com-
pounds 16-22, 30-34, 36, and 39-46. This material is
available free of charge via the Internet at http://pubs.acs.org.
a Conditions: olefin (1-4 equiv), diene (1 equiv), and catalyst 3 (5 mol
%) in benzene (0.2 M) at 60 °C for 12 h. b Only the E isomer was observed.
c Isolated yield. d Yield in parentheses refers to reaction using 10 mol % of
3. e Product was not separated from allyl benzoate formed in the reaction.
f Reaction was stopped after 2 h. g Unidentified impurities were present in
the isolated product sample.
OL047929Z
coupling is shown, which gives a yield comparable to the
analogous two-step sequence.13
(13) An overall yield of 51% was achieved when the two steps of the
reaction were performed independently.
190
Org. Lett., Vol. 7, No. 2, 2005