A stereoselective enyne cross metathesis

Article abstract of DOI:10.1021/ol034408n

(Matrix presented) Intermolecular enyne metathesis reaction of alkynes with olefins catalyzed by second-generation Grubbs catalyst (1) proceeded stereoselectively under ethylene atmosphere to produce 1,3-disubstituted butadienes with E stereochemistry.

Full text of DOI:10.1021/ol034408n

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1855-1858
A Stereoselective Enyne Cross
Metathesis
,†
,‡
Hee-Yoon Lee,* Byung Gyu Kim,†,‡ and Marc L. Snapper*
Center for Molecular Design & Synthesis, Department of Chemistry and School of
Molecular Science (BK21), Korea AdVanced Institute of Science & Technology,
Daejon 305-701, Korea, and Department of Chemistry, Merkert Chemistry Center,
Boston College, 2609 Beacon Street, Chestnut Hill, Massachusetts 02467-3860
leehy@kaist.ac.kr
Received March 7, 2003
ABSTRACT
Intermolecular enyne metathesis reaction of alkynes with olefins catalyzed by second-generation Grubbs catalyst (1) proceeded stereoselectively
under ethylene atmosphere to produce 1,3-disubstituted butadienes with E stereochemistry.
With the development of new metathesis catalysts by Schrock
and Grubbs,1 olefin metathesis has attracted much attention
from the synthetic organic chemistry community and numer-
ous synthetic strategies based on metathesis have been
developed. On the other hand, enyne metathesis,2 which is
catalyzed by the same catalysts, has not been developed as
much, although the reaction produces 1,3-diene, a useful
synthon for various cycloadditions.3,4 Since the first reported
enyne metathesis,5 most research efforts have focused on the
ring-closing enyne metathesis, which not only provides
cycloalkenes with a conjugated terminal olefin for further
manipulation6 but also allows tandem metathesis processes
for the formation of polycyclic compounds.2a The major
shortcoming of the metathesis reaction has been that
intermolecular metathesis reaction has rarely been used in
the enyne metathesis reaction mainly due to the formation
of a mixture of olefin isomers.7 This lack of stereoselectivity
(3) (a) Banti, D.; North, M. Tetrahedron Lett. 2002, 43, 1561. (b)
Moreno-Manas, M.; Pleixats, R.; Santamaria, A. Synlett 2001, 1784. (c)
Zheng, G.; Dougherty, T. J.; Pandey, R. K.; Pandey, R. K. Chem. Commun.
1999, 2469. (d) Schurer, S. C.; Blechert, S. Chem. Commun. 1999, 1203.
(e) Fringluelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction; John
Wiley & Sons Inc.: New York, 1990.
† Korea Advanced Institute of Science & Technology (KAIST).
‡ Boston College.
(1) For recent reviews on olefin metathesis, see: (a) Grubbs, R. H.;
Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446. (b) Schuster, M.;
Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (c) Schmalz,
H.-G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1833. (d) Furstner, A. Topics
in Organometallics Chemistry; Springer-Verlag: Berlin, Germany, 1998;
Vol. 1. (e) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (f)
Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371. (g) Philips, A.
J.; Abell, A. D. Aldrichim. Acta 1999, 32, 75. (h) Furstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3013. (i) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Soc.
2001, 34, 18.
(4) (a) Wender, P. A.; Nuss, J. M.; Smith, D. B.; Suarez-Sobrino, A.;
Vagberg, J.; Decosta, D.; Bordner, J. J. Org. Chem. 1997, 62, 4908 and
references therein. (b) Harmata, M. Acc. Chem. Res. 2001, 34, 595.
(5) Katz, T. J.; Sivavec, T. M. J. Am. Chem. Soc. 1985, 107, 737.
(6) (a) Schramm, M. P.; Reddy, D. S.; Kozmin, S. A. Angew. Chem.,
Int. Ed. 2001, 40, 4274. (b) Furstner, A.; Ackermann, L.; Gabor, B.;
Goddard, R.; Lehmann, C. W.; Mynott, R.; Stelzer, F.; Thiel, O. R. Chem.-
Eur. J. 2001, 7, 3236. (c) Kitamura, T.; Sato, Y.; Mori, M. AdV. Synth.
Catal. 2002, 344, 678. (d) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org.
Chem. 1998, 63, 6082. (e) Renaud, J.; Graf, C.-D.; Oberer, L. Angew. Chem.,
Int. Ed. 2000, 39, 3101. (f) Clark, J. S.; Elustondo, F.; Trevitt, G. P.; Boyall,
D.; Robertson, J.; Blake, A. J.; Wilson, C.; Stammen, B. Tetrahedron 2002,
58, 1973.
(2) For recent reviews on enyne metathesis, see: (a) Poulsen, C. S.;
Madsen, R. Synthesis 2003, 1. (b) Mori, M. Top. Organomet. Chem. 1998,
1 133.
10.1021/ol034408n CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/01/2003

diminishes the value of this facile methodology for the
preparation of substituted dienes, otherwise useful in organic
synthesis.
metathesis product 4a with only E stereochemistry in 82%
yield (Scheme 2). The H NMR spectrum of the reaction
1
Herein, we would like to report the development of a
stereoselective enyne cross metathesis using second-genera-
tion Grubbs catalyst (1).8 Our strategy for stereoselective
enyne cross metathesis is based on Mori’s pioneering work
on the role of ethylene gas in the enyne metathesis reaction,9
where ethylene served not only as a substrate for the reaction,
but also to maintain the reactivity of the catalyst. We
envisioned that if we added ethylene to the enyne cross-
metathesis reaction, ethylene will react first with the alkyne
to form the monosubstituted diene and the diene will
subsequently react with the terminal olefin to form the
disubstituted diene (Scheme 1). Even though diene-ene cross
Scheme 2. Enyne Cross Metathesis under Ethylene
Atmosphere
mixture before purification showed no indication of the Z
isomer.
We then expanded the enyne cross-metathesis reaction to
other alkynes and alkenes. The results are summarized in
Table 1.12 Alkynes 2a-d were reacted with alkenes 3a-d
to give cross-metathesis products 4a-n in good yields, all
Scheme 1. Strategy for Stereoselective Enyne Cross
Metathesis
1
with E stereochemistry as determined by H NMR.
Table 1. Enyne Cross-Metathesis Reaction
yielda
entry
1
alkyne
alkene
diene (E/Z)b,c
metathesis has not been reported, this idea was deemed
plausible since the intramolecular diene-ene metathesis
reaction has been used in organic synthesis.10 The mono-
substituted diene intermediate was expected to provide
enough bias to form the E stereoisomer selectively during
the metathesis reaction.
We tested the idea with an initial experiment using benzyl
butynyl ether (2a) and 1-octene (3a). A mixture of 2a, and
3a (10 equiv) with 1 (10 mol %)11 in dichloromethane was
stirred for 24 h under ethylene atmosphere to afford cross-
2a
3a
4a
4b
4c
4d
4e
4f
82%
(100/0)
88%
(100/0)
74%
(>20/1)
57%
(>20/1)
71%
(100/0)
83%
R ) BnO(CH2)2
R′ ) (CH2)5Me
2
3
2a
3b
R′ ) nPr
2a
2a
3c
R′ ) C2H4Br
4
3d
R′ ) C2H4O2CEt
5
2b
3a
R ) TsO(CH2)2
6
2b
3b
3c
3d
3a
3c
3d
3a
3b
3c
(100/0)
64%
(>20/1)
59%
(>20/1)
68%
(100/0)
60%
(>20/1)
62%
(>20/1)
82%
(100/0)
55%
(100/0)
67%
(7) (a) Stragies, R.; Schuster, M.; Blechert, S. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2518. (b) Kinoshita, A.; Sakakibara, N.; Mori, M. J. Am.
Chem. Soc. 1997, 119, 12388. (c) Schurer, S. C.; Blechert, S. Synlett 1998,
166. (d) Schuster, M.; Blechert, S. Tetrahedron Lett. 1998, 39, 2295. (e)
Stragies, R.; Schuster, M.; Blechert, S. Chem. Commun. 1999, 237. (f)
Smulik, J. A.; Diver, S. T. J. Org. Chem. 2000, 65, 1788. (g) Kotha, S.;
Halder, S.; Brahmachary, E.; Ganesh, T. Synlett 2000, 853. (h) Stragies,
R.; Voigtmann, U.; Blechert, S. Tetrahedron Lett. 2000, 41, 5465. (i) Smulik,
J. A.; Diver, S. T. Org. Lett. 2000, 2, 2271. (j) Smulik, J. A.; Diver, S. T.
Tetrahedron Lett. 2001, 42, 171. (k) Rodriguez-Conesa, S.; Candal, P.;
Jimenez, C.; Rodriguez, J. Tetrahedron Lett. 2001, 42, 6699. (l) Smulik, J.
A.; Giessert, A. J.; Diver, S. T. Tetrahedron Lett. 2002, 43, 209. (m)
Tonogaki, K.; Mori, M. Tetrahedron Lett. 2002, 43, 2235. Also refs 3a,
6b, and 6c.
7
2b
2b
4g
4h
4i
8
9
2c
R ) TBDPSOCH2
2c
10
11
12
13
14
4j
2c
4k
4l
2d
(8) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
RdAcO(CH2)3
2d
4m
4n
(9) Tonagaki, K.; Mori, M. Tetrahedron Lett. 2002, 43, 2235.
(10) (a) 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. (b) Smulik, J. A.; Diver, S. T. Tetrahedron Lett. 2001, 42, 171.
(c) Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.; Danishefsky, S. J. J.
Am. Chem. Soc. 2001, 123, 10903. (d) Bach, T.; Lemarchand, A. Synlett,
2002, 1302. (e) 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.
2d
(>20/1)
a Isolate yield after 24 h. b E/Z ratio was determined by H NMR. c In
all cases, ∼30% of the remaining olefin was converted into the correspond-
ing dimer.
1
1856
Org. Lett., Vol. 5, No. 11, 2003

Scheme 3. Plausible Reaction Mechanism for E
Scheme 4
Stereoselectivity
tively, or sterically biased by the allylic substitution13 (Table
2). 3f and 3g produced enyne cross-metathesis products with
A plausible reaction mechanism is shown in Scheme 3.
The metathesis catalyst 1 was converted to the active
ruthenium carbene complex (I), which in turn could react
either with alkyne to give 1,3-diene (II) or with alkene to
give another ruthenium complex (III). The 1,3-diene could
then react with ruthenium complex (III) to afford enyne
cross-metathesis product exclusively with E stereochemistry
as we have anticipated. However, we could not rule out
another pathway, where ruthenium complex (III) reacted
with alkyne to give enyne cross-metathesis product as a
mixture of E and Z isomers, and the Z isomer could have
been equilibrated to the thermodynamically more stable E
isomer via 1,3-diene (II) through reversible diene-ene cross-
metathesis reaction in the presence of ethylene.
To possibly distinguish between the two pathways, we
prepared monosubstituted diene 5 and an E/Z mixture of 4a.
The metathesis reaction between 5 and 1-octene produced
4i exclusively with the E stereoisomer in 88% yield.
Treatment of the E/Z mixture of 4a with catalyst 1 under
ethylene atmosphere isomerized effectively the mixture to
the E isomer exclusively along with the formation of II (R
) BnOC2H4) (Scheme 4). While either pathway could not
be ruled out, these results support a thermodynamically
driven isomerization to provide a stereoselective synthesis
of 1,3-dienes where the formation of intermediate II was
the key to the stereoselectivity.
Table 2. Enyne Cross-Metathesis Reaction
yielda
(E/Z)b
entry
1
alkyne
2c
alkene
diene
3e
4o
79%
(1.3/1)
44%
(3/1)
49%
(6.5/1)
84%
(1.4/1)
42%
(3/1)
48%
(9/1)
79%
(1.3/1)
86%
(1.6/1)
89%
(100:0)c
R′ ) CH2SiMe3
2
3
4
5
6
7
8
9
2c
2c
2b
2b
2b
2a
2d
3f
4p
4q
4r
R′ ) CH2OnBu
3g
R′ ) CH2OAc
3e
3f
4s
4t
3g
3e
3e
3e
4u
4v
4w
2e
R ) Ph3Si
a Isolate yield after 24 h. b E/Z ratio was determined by 1H NMR. c Only
the E isomer was obtained even without ethylene in 75% yield.
The stereoselectivity of diene formation eroded in cases
of olefins with heteroatom substitution at the allylic position
as the reaction pathway could be electronically, coordina-
moderate selectivity for E isomers in 40-50% yields and
3e produced dienes in good yield but with no selectivity
except for a silylacetylene (entry 9). Complete selectivity
for the E stereoisomer of diene from triphenylsilylacetylene
was observed even in the absence of ethylene. Blechert
(11) The amount of olefins and the catalyst had to be maintained to that
level to drive the cross-metathesis reaction to completion and to minimize
the formation of II.
(12) General Procedure. Alkyne (0.1 mmol) and olefin (1.0 mmol, 10
equivalent) were dissolved in CH2Cl2 (0.2 mL). Second-generation Grubbs
catalyst was added to the reaction mixture at room temperature and the
resulting reaction mixture was stirred for 24 h at room temperature under
ethylene atmosphere (through balloon attachment) and concentrated under
reduced pressure. Then the residue was purified by flash column chroma-
tography on silica gel to afford the desired product.
(13) (a) Liu, B.; Das, S. K.; Roy, R. Org. Lett. 2002, 4, 2723. (b)
Engelhardt, F. C.; Schmitt, M. J.; Taylor, R. E. Org. Lett. 2001, 3, 2209.
(c) Maishal, T. K.; Shina-Mahapatra, D. K.; Paranjape, K.; Sarkar, A.
Tetrahedron Lett. 2002, 43, 2263 and references therein. (d) Crowe, W.
E.; Goldberg, D. R.; Zhang, Z. J. Tetrahedron Lett. 1996, 37, 2117.
Org. Lett., Vol. 5, No. 11, 2003
1857

reported a similar observation with trimethylsilylacetylene
where the cross-metathesis reaction of 3e with TMS-
acetylene produced the diene selectively (E/Z ) 6/1).8i The
complete stereoselectivity (entry 9) appeared to be due to
unfavorable steric interaction of the triphenylsilyl group in
the Z stereoisomer of diene product.
Allylic alcohol derivatives and allylsilanes seemed to be
much less reactive than aliphatic olefins toward dienes as
evidenced by the fact that allylsilane 3e did not react at all
with diene 5.14 This result reiterated the importance of the
diene intermediate II in the stereoselectivity of the cross-
metathesis reaction.
In summary, we have developed a stereoselective enyne
cross-metathesis reaction by including ethylene in the reac-
tion. This protocol generates 1,3-disubstituted butadienes with
E stereochemistry for the newly generated 1,2-disubstituted
olefins in good yields.
Acknowledgment. H.Y.L acknowledges CMDS-KOSEF
at KAIST, and M.L.S. acknowledges the National Science
Foundation (CHE-013221) for financial support.
Supporting Information Available: Experimental pro-
cedure for the metathesis reaction and spectral data of cross-
metathesis products 4a-w. This material is available free
of charge via the Internet at http://pubs.acs.org.
(14) Treatment of 1,3-diene 5 with allyl trimethylsilane 3e in CH2Cl2
under ethylene atmosphere for 24 h resulted in only the unreacted starting
materials. Allyl butyl ether gave a similar result.
OL034408N
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Org. Lett., Vol. 5, No. 11, 2003