Experimental and Theoretical Study on the Olefin Metathesis of Alkenyl Baylis-Hillman Adducts Using Second-Generation Grubbs Catalyst

Article abstract of DOI:10.1021/ol048776i

We have investigated the olefin metathesis from alkenyl Baylis-Hillman adducts using second-generation Grubbs catalyst. In the experiment, the ring-closing metathesis (RCM) product could be found, while the cross-metathesis (CM) products were f

Full text of DOI:10.1021/ol048776i

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3313-3316
Experimental and Theoretical Study on
the Olefin Metathesis of Alkenyl
Baylis−Hillman Adducts Using
Second-Generation Grubbs Catalyst
,‡
,†
Mi Jung Lee,† Ka Young Lee,† Jin Yong Lee,* and Jae Nyoung Kim*
Department of Chemistry and Institute of Basic Science, Chonnam National UniVersity,
300 Yongbong-Dong, Bugku, Gwangju 500-757, Korea, and Institute for Condensed
Matter Theory and Department of Chemistry, Chonnam National UniVersity,
300 Yongbong-Dong, Bugku, Gwangju 500-757, Korea
jinyong@chonnam.ac.kr; kimjn@chonnam.ac.kr
Received June 28, 2004
ABSTRACT
We have investigated the olefin metathesis from alkenyl Baylis−Hillman adducts using second-generation Grubbs catalyst. In the experiment,
the ring-closing metathesis (RCM) product could not be found, while the cross-metathesis (CM) products were found. The computational
studies provided consistent explanations for the experimental result. The most limiting factor for the RCM process using second-generation
Grubbs catalyst is caused by the high strain and steric effect in the metallacyclobutane intermediates.
Olefin metathesis, termed in 1967 by Calderon and co-
workers for the first time,1 is a powerful method for the
formation of carbon-carbon double bonds.2 In particular,
ring-closing metathesis (RCM) has been used for the
synthesis of a variety of cyclic compounds that include
carbocyclic, heterocyclic, and fused ring frameworks.3,4
However, until several years ago, such reactions were limited
because of insufficient catalytic performance. The desire to
apply olefin metathesis to new synthetic challenges has
motivated many chemists to improve catalytic performance.
The ruthenium complexes have been used as catalysts for a
variety of reactions.5 The first members of a family of L2X2-
RudCHR (Grubbs catalysts) complexes opened new vistas
in olefin metathesis.6 Among them, (PCy3)2Cl2RudCH2 has
attracted a lot of theoretical interest.7 A second-generation
Grubbs catalyst where one of the PCy3 ligands is replaced
by an N-heterocyclic carbene (NHC) ligand with a mesityl
† Department of Chemistry and Institute of Basic Science.
‡ Institute for Condensed Matter Theory and Department of Chemistry.
(1) (a) Calderon, N. Acc. Chem. Res. 1972, 5, 127. (b) Calderon, N.;
Chen, H. Y.; Scott, K. W. Tetrahedron Lett. 1967, 34, 3327.
(2) (a) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. (b) Smith,
A. B., III; Adams, C. M.; Kozmin, S. A. J. Am. Chem. Soc. 2001, 123,
990. (c) Wang, X.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 6040. (d)
Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(3) (a) Adlhart, C.; Chen, P. J. Am. Chem. Soc. 2004, 126, 3496. (b)
Huang, J.; Stevens, E. D.; Nolan, S. P.; Peterson, J. L. J. Am. Chem. Soc.
1999, 121, 2674.
(4) (a) Lee, C. W.; Grubbs, R. H. J. Org. Chem. 2001, 66, 7155. (b)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (c) Lee, C. W.;
Grubbs, R. H. Org. Lett. 2000, 2, 2145. (d) Bielawski, C. W.; Grubbs, R.
H. Angew. Chem., Int. Ed. 2000, 39, 2903. (e) Blackwell, H. E.; Sadowsky,
J. D.; Howard, R. J.; Sampson, J. N.; Chao, J. A.; Steinmetz, W. E.; O’Leary,
D. J.; Grubbs, R. H. J. Org. Chem. 2001, 66, 5291. (f) Schuster, M.;
Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (g) Blackwell,
H. E.; O’Leary, D. J.; Chatterjee, A. K.; Washenfelder, R. A.; Bussmann,
D. A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58.
10.1021/ol048776i CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/18/2004

group has been shown to have significantly higher activity
than that of the parent Grubbs catalyst.3b,8
Scheme 1. Synthesis of Baylis-Hillman Adducts
Recently, we synthesized 2,5-dihydrofuran and 2,5-dihy-
dropyrrole skeleta from the Baylis-Hillman adducts of 5,6-
dihydro-2H-pyran-2-one via the RCM reaction using the
Grubbs second-generation catalyst.9 The latter catalyst has
also been successfully used to synthesize di-, tri-, and
tetrasubstituted R,â-unsaturated lactones or lactams of ring
size 5-7.10 There have been several theoretical3,7,11 and
experimental11-13 attempts to explain the mechanism and
activity of olefin metathesis with the Grubbs catalyst and
its derivatives. Most of the theoretical studies have been
carried out on simplified model systems. However, the size
of the ligands, their electronic properties, and conformational
flexibility are reported to greatly influence the catalytic
reactivity.13a,14 In this letter, we report a synthetic and
theoretical study of the olefin metathesis of two Baylis-
Hillman adducts 3a and 3b using the second-generation
Grubbs catalyst.
in acetonitrile, we were able to synthesize the starting
materials 3a and 3b in moderate yield (Scheme 1). (For the
detailed synthesis and spectroscopic data of prepared com-
pounds, see Supporting Information.)
Scheme 2. Possible Products of Olefin Metathesis
We prepared the required starting materials 3a and 3b as
shown in Scheme 1. The Baylis-Hillman adduct 1 was
converted into the acid 2 according to the reported method,15
and following esterification with 12a and 12b using DBU
(5) (a) Choi, J. H.; Kim, N.; Shin, Y. J.; Park, J. H.; Park, J. Tetrahedron
Lett. 2004, 45, 4607. (b) Choi, J. H.; Choi, Y. K.; Kim, Y. H.; Park, E. S.;
Kim, E. J.; Kim, M.-J.; Park, J. J. Org. Chem. 2004, 69, 1972. (c) Kim,
M.-J.; Chung, Y. I.; Choi, Y. K.; Lee, H. K.; Kim, D.; Park, J. J. Am.
Chem. Soc. 2003, 125, 11494. (d) Hinderling, C.; Adlhart, C.; Chen, P.
Angew. Chem., Int. Ed. 1998, 37, 2685. (e) Huang, X.; Lin, Z. Organo-
metallics 2003, 22, 5478. (f) Yin, C.; Xu, Z.; Yang, S.-Y.; Ng, S. M.; Wong,
K. Y.; Lin, Z.; Lau, C. P. Organometallics 2001, 20, 1216. (g) Wong, W.-
Y.; Ting, F.-L.; Lin, Z. Organometallics 2003, 22, 5100. (h) Fung, W. K.;
Huang, X.; Man, M. L.; Ng, S. M.; Hung, M. Y.; Lin, Z.; Lau, C. P. J. Am.
Chem. Soc. 2003, 125, 11539.
(6) (a) Nguyen, S. T.; Johnson, L. K.; Grubbs, R. H.; Ziller, J. W. J.
Am. Chem. Soc. 1992, 114, 3974. (b) Nguyen, S. T.; Grubbs, R. H.; Ziller,
J. W. J. Am. Chem. Soc. 1993, 115, 9858. (c) Schwab, P.; France, M. B.;
Ziller, J. W.; Grubbs, R. H. Angew. Chem. 1995, 107, 2179; Angew. Chem.,
Int. Ed. Engl. 1995, 34, 2039. (d) Wu, Z.; Nguyen, S. T.; Grubbs, R. H.;
Ziller, J. W. J. Am. Chem. Soc. 1995, 117, 5503. (e) Schwab, P.; Grubbs,
R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100.
With compounds 3a and 3b in hand, we examined their
RCM reactions with 4 under high-dilution conditions in order
to minimize the intermolecular reactions. Initially, we carried
out the reaction of 3a in toluene with 14 mol % catalyst 4 at
70-80 °C for 40 h. Unfortunately, however, we could never
detect or isolate the desired RCM product. Instead, the cross-
metathesis products 10a (8%) and 11a (46%) were isolated
along with recovered starting material 3a (27%).
When we performed the same reaction with 3b, similar
results were obtained. The starting material 3b was recovered
in 45% yield, benzaldehyde in about 40% yield, and the CM
product 11b in 11% yield. Although similar approaches have
been successful for the synthesis of five- or six-membered
lactones using the RCM reaction has been reported using
(PCy3)2Cl2RudCHPh10b or (IMes)(PCy3)Cl2RudCHPh,10a
our experiments failed to produce the desired RCM products.
During the reaction, we monitored the reaction frequently
using TLC to detect the formation of any trace of the RCM
product 9a. The reference sample of 9a was prepared by
the Baylis-Hillman reaction of benzaldehyde and lactone
(5,6-dihydro-2H-pyran-2-one) derivative according to the
(7) Aagaard, O. M.; Meier, R. J.; Buda, F. J. Am. Chem. Soc. 1998,
120, 7174.
(8) (a) Huang, J.; Schanz, H.-J.; Stevens, E. D.; Nolan, S. P. Organo-
metallics 1999, 18, 5375. (b) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R.
H. Org. Lett. 1999, 1, 953. (c) Chatterjee, A. K.; Grubbs, R. H. Org. Lett.
1999, 1, 1751. (d) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R.
H. J. Am. Chem. Soc. 2000, 122, 3783. (e) Ackermann, L.; Furstner, A.;
Weskamp, T.; Kohl, F. J.; Herrmann, W. A. Tetrahedron Lett. 1999, 40,
4787. (f) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron
Lett. 1999, 40, 2247.
(9) Kim, J. M.; Lee, K. Y.; Lee, S.; Kim, J. N. Tetrahedron Lett. 2004,
45, 2805.
(10) (a) Furstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan,
S. P. J. Org. Chem. 2000, 65, 2204. (b) Anand, R. V.; Baktharaman, S.;
Singh, V. K. Tetrahedron Lett. 2002, 43, 5393. (c) Gruttadauria, M.; Meo,
P. L.; Noto, R. Tetrahedron Lett. 2004, 45, 83.
(11) Adlhart, C.; Hinderling, C.; Baumann, H.; Chen, P. J. Am. Chem.
Soc. 2000, 122, 8204.
(12) Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1997,
119, 3887.
(13) (a) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 6543. (b) Trnka, T. M.; Morgan, J. P.; Sanford, M. S.; Wilhelm,
T. E.; Scholl, M.; Choi, T.-L.; Ding, S.; Day, M. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 2546. (c) Sanford, M. S.; Ulman, M.; Grubbs, R. H.
J. Am. Chem. Soc. 2001, 123, 749. (d) Hong, S. H.; Day, M. W.; Grubbs,
R. H. J. Am. Chem. Soc. 2004, 126, 7414. (e) Ulman, M.; Grubbs, R. H.
Organometallics 1998, 17, 2484. (f) Ulman, M.; Grubbs, R. H. J. Org.
Chem. 1999, 64, 7202.
(15) (a) Martinez, I.; Andrews, A. E.; Emch, J. D.; Ndakala, A. J.; Wang,
J.; Howell, A. R. Org. Lett. 2003, 5, 399. (b) Krishna, P. R.; Kannan, V.;
Ilangovan, A.; Sharma, G. V. M. Tetrahedron: Asymmetry 2001, 12, 829.
(14) Love, J. A.; Sanford, M. S.; Day, M. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 10103.
3314
Org. Lett., Vol. 6, No. 19, 2004

formation of a π-complex and cyclic four-membered ring
intermediates as suggested for the most favored reaction
mechanism3a,7 (Figure 1). For the olefin metathesis of 3a
with 4, the catalyst is considered to react first with the
monosubstituted terminal double bond of 3a because it is
least electronically deactivated and sterically least hindered.19
There are three possible products: 9a, 10a, and 11a. Lactone
9a is the product of ring-closing metathesis (RCM), while
10a and 11a are the products of the cross-metathesis (CM)
of 5a with styrene (CM1) and 3a (CM2), respectively. The
relative energies of the three different reaction pathways are
shown in Figure 2.
Figure 1. Postulated mechanisms for olefin metathesis.
literature method.16 Thus, we can exclude the possibility for
the formation of the RCM product followed by the conver-
sion to more thermodynamically favorable products over time
at high temperature. To find out the effect of hydroxyl group
of 3a on the RCM reaction, we synthesized the MEM-
protected 3a and tried the RCM reaction. Again, we could
not obtain the RCM product as before.17
This may arise from the fact that under the high-dilution
conditions for the reaction (favorable for the RCM reaction),
the activation energy for forming the desired RCM product
is much higher than those for the CM products (10a and
11a). To shed light on these RCM and CM processes, we
investigated the conversion of 3a into 9a, 10a, and 11a by
theoretical calculation. Most of the computational studies to
date have considered truncated model systems such as PH3
instead of PCy3.3,7,11 However, we have included the actual
molecular systems in our computations. We compared the
relative reaction barriers for the RCM and CM processes
using ab initio calculations. All the structures were fully
optimized at the Hartree-Fock level of theory with 3-21G
basis sets using the Gaussian 98 suite of programs.18
It has been assumed that the olefin metatheses take place
through the dissociation of the PCy3 ligand followed by the
Figure 2. Relative energies (in kcal/mol) along the pathways from
4a to 6a (RCM), 7a (CM1), and 8a (CM2).
For the RCM pathway, the relative energies of the
intermediates, 4a, 5a + PCy3, and 6a + PCy3, are 0, 26.5,
and 82.4 kcal/mol, respectively. For the CM1 pathway, the
(18) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.
W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.6; Gaussian,
Inc.: Pittsburgh, PA, 1998.
(16) Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. Org. Chem. 2003, 68,
692.
(17) In the reaction, we could isolate the homodimerized product in low
yield (9-12%), with abundant starting material being recovered. At the
early stage of this project, we examined the reaction of 3a in CH2Cl2 (8%
catalyst, reflux, 100 h). We obtained a low yield (7-8%) of 10a, starting
material 3a (35%), and appreciable amounts of benzaldehyde. Thus, we
changed the solvent to toluene as described in this paper. In another
substrate, deoxy-3a, in toluene, the RCM product was not found either.
The benzaldehyde appears to be generated by the retro-Baylis-Hillman
(BH) reaction of 3a and 3b. The BH reaction, which can be catalyzed by
tertiary amines or phosphines, is a reversible process. (Cipanek, E. Organic
Reactions; John Wiley & Sons: New York, 1997; Vol. 51, pp 201-350).
(19) Rodriguez, S.; Castillo, E.; Carda, M.; Marco, J. A. Tetrahedron
2002, 58, 1185.
Org. Lett., Vol. 6, No. 19, 2004
3315

relative energies of the intermediates, 4a + styrene, 5a +
styrene + PCy3, and 7a + PCy3, are 0, 26.5, and 59.7 kcal/
mol, respectively. For the CM2 pathway, the relative energies
of the intermediates, 4a + 3a, 5a + 3a + PCy3, and 8a +
PCy3, are 0, 26.5, and 63.0 kcal/mol, respectively. Thus, the
reaction barriers for RCM, CM1, and CM2 pathways are
82.4, 59.7, and 63.0 kcal/mol, respectively. These reaction
barriers are consistent with the experimental observation that
the yields of 10a and 11a are 8 and 46%, respectively, while
the RCM product 9a was not obtained. The low yield (8%)
of 10a, despite this reaction pathway being lower in energy
than that for 11a, is presumably due to using a small amount
(14%) of ruthenium catalyst, which is the only source of
styrene.
The barrier difference for CM1 and CM2 is only 3.3 kcal/
mol, but that for CM1 and RCM is 22.7 kcal/mol, which
implies that the steric hindrance contributes slightly. Thus,
the most dominant factor for the difference in reaction barrier
may be the ring strain. The ring strain for 6a seems to be
much higher than that for 7a and 8a, where the electronic
effect is operating almost equivalently. The electronic effect
was previously discussed in detail for various ligands.13a
The RCM of isopentenyl methacrylate gives the corre-
sponding six-membered lactone when it is mediated by 4.10a
The barrier for this reaction has been compared with the
barrier for the CM of 3a and styrene. The barrier difference
between the RCM and CM processes is calculated to be about
16.5 kcal/mol, which is much reduced compared with that
(22.7 kcal/mol) in our substrates having a ring substituent.
Nevertheless, the difference is still very high, which would
make it difficult to realize the RCM reactions. The second-
generation Grubbs catalyst seems to be inefficient for our
RCM reactions, while it seems to be much more efficient
for the CM reactions. The main reason for the inefficiency
for the RCM reaction may result from the inherent strain
and steric effect in the cyclic four-membered ring intermedi-
ates. This conclusion applies to the substrates investigated
and needs to be further studied for other RCM/CM reactions.
The four membered-ring intermediates 6a, 7a, and 8a may
have several different conformers according to the cis or trans
conformation for the two chlorines, as well as two substit-
uents constituting the four-membered rings. The X-ray
structures of 45e and its derivative8a are known. In our
calculations, we chose the halide and other ligand orientations
assuming that their orientation did not change after phosphine
dissociation despite their exact positions being unknown. For
the cyclic intermediate 7a, we tried to compare the energies
of the four different conformers, trans-trans, trans-cis, cis-
trans, and cis-cis. We name cis-trans in cases where the
two chlorines have a cis conformation and the two substit-
uents (phenyl and ester moieties) have a trans conformation,
respectively. The trans-trans conformer is slightly more
stable than the trans-cis conformer by 1.45 kcal/mol. In the
case of cis conformation for chlorines, we found an interest-
ing behavior. The cis-cis conformer changed into the
dissociated complex 5a and styrene during the geometry
optimization. The cis-trans conformer proceeded to the
product-like complex. Thus, the metathesis reaction seems
to proceed via the configurational exchange from trans to
cis for the halides, where the Cl-Ru-Cl is in the trans
configuration in the crystal structures. This observation is
closely related to the explanation of the catalytic activity by
the trans influence of halides, phosphines, and olefins.12,13a
Significantly, this configurational exchange is found to be
facile even at room temperature from the quantum molecular
dynamics study.7 The structural details are presented in
Supporting Information.
In conclusion, we have investigated the RCM and CM
reactions of 3a with the second-generation Grubbs catalyst
4 both experimentally and theoretically. In the former case,
we obtained only CM products and no RCM product even
at high-dilution conditions. The experimental results are
clearly explained by reaction barrier differences for the RCM
and CM reactions based on ab initio calculations for the full
molecular systems.
Acknowledgment. This work was supported by Korea
Research Foundation Grant (KRF-2002-015-CP0215).
Supporting Information Available: Synthetic details and
characterization data and calculated conformations for com-
pounds styrene, PCy3, 3a, 4a, 5a, 6a, 7a, 8a, four configura-
tions (trans-trans, trans-cis, cis-trans, cis-cis) of 7a, and
metallacyclobutane intermediates for RCM and CM pro-
cesses of isopentenyl methacrylate. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL048776I
3316
Org. Lett., Vol. 6, No. 19, 2004