Synthesis of styrenes using ruthenium-catalyzed ring-closing enyne metathesis

Article abstract of DOI:10.1021/ol8009573

(Chemical Equation Presented) The synthesis of substituted styrenes was achieved by ring-closing enyne metathesis (RCEM)/elimination of enyne substrates 12. The synthetic approach was also effective for a different type of enyne substrate 14, yielding corresponding styrene 15.

Full text of DOI:10.1021/ol8009573

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2777-2780
Synthesis of Styrenes Using
Ruthenium-Catalyzed Ring-Closing
Enyne Metathesis
Kazuhiro Yoshida,* Yuka Shishikura, Hidetoshi Takahashi, and Tsuneo Imamoto*
Department of Chemistry, Graduate School of Science, Chiba UniVersity, Yayoi-cho,
Inage-ku, Chiba 263-8522, Japan
kyoshida@faculty.chiba-u.jp; imamoto@faculty.chiba-u.jp
Received April 25, 2008
ABSTRACT
The synthesis of substituted styrenes was achieved by ring-closing enyne metathesis (RCEM)/elimination of enyne substrates 12. The synthetic
approach was also effective for a different type of enyne substrate 14, yielding corresponding styrene 15.
Substituted styrenes are used extensively as key synthetic
intermediates in organic1 and polymer chemistry.2 Functional
group transformations on existing aromatic rings are gener-
ally employed for the synthesis of styrenes. For example,
the Wittig olefination of aryl carbonyl compounds,3 the
transition-metal-catalyzed cross-coupling reaction of aryl
halides,4 the Heck reaction of aryl halides,5 and the elimina-
tion of aryl alcohols to generate a double bond6 have been
widely exploited for the synthesis of styrenes. On the other
hand, there are few reports7 of the construction of benzene
rings of styrenes from acyclic precursors despite the fact that
unique styrenes can be obtained with this entirely different
procedure.
Recently, the formation of carbocyclic and heterocyclic
aromatic compounds with ruthenium-catalyzed ring-closing
olefin metathesis (RCM)8 has attracted much attention.9–11
Since RCM is a very powerful reaction to form carbon-carbon
double bonds of cyclic compounds with its operational
simplicity, high chemoselectivity, and remarkable functional
group tolerance, it is valid to apply this reaction to the
(1) For examples, see: (a) Fassina, V.; Ramminger, C.; Seferin, M.;
Monteiro, A. L. Tetrahedron 2000, 56, 7403–7409. (b) Fu¨rstner, A.;
Thiel, O. R.; Kindler, N.; Bartkowska, B. J. Org. Chem. 2000, 65, 7990–
7995.
(6) For recent examples, see: (a) Antane, S.; Caufield, C. E.; Hu, W.;
Keeney, D.; Labthavikul, P.; Morris, K.; Naughton, S. M.; Petersen, P. J.;
Rasmussen, B. A.; Singh, G.; Yang, Y. Bioorg. Med. Chem. Lett. 2006,
16, 176–180. (b) Nakamura, S.; Sugano, Y.; Kikuchi, F.; Hashimoto, S.
Angew. Chem., Int. Ed. 2006, 45, 6532–6535.
(2) Styrene Polymers. In Encyclopedia of Polymer Science and Engi-
neering, 2nd ed.; Moore, E. R., Ed.; Wiley-Interscience: New York, 1989;
Vol. 16 and references cited therein.
(3) For recent examples, see: (a) Srikrishna, A.; Babu, R. R.; Ravikumar,
P. C. Synlett 2007, 655–657. (b) Tietze, L. F.; Brasche, G.; Grube, A.;
Boehnke, N.; Stadler, C. Chem. Eur. J. 2007, 13, 8543–8563.
(4) For recent examples, see: (a) Zeng, F.; Stehouwer, J. S.; Jarkas, N.;
Voll, R. J.; Williams, L.; Camp, V. M.; Votaw, J. R.; Owens, M. J.; Kilts,
C. D.; Nemeroff, C. B.; Goodman, M. M. Bioorg. Med. Chem. Lett. 2007,
17, 3044–3047. (b) Achmatowicz, M.; Chan, J.; Wheeler, P.; Liu, L.; Faul,
M. M. Tetrahedron Lett. 2007, 48, 4825–4829.
(7) For examples, see: (a) Gevorgyan, V.; Yamamoto, Y. J. Organomet.
Chem. 1999, 576, 232–247. (b) Xi, Z.; Li, Z.; Umeda, C.; Guan, H.; Li, P.;
Kotora, M.; Takahashi, T. Tetrahedron 2002, 58, 1107–1117. (c) Gorin,
D. J.; Watson, I. D. G.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 3736–
3737.
(8) For a comprehensive review, see: (a) Handbook of Metathesis;
Grubbs, R. H., Ed.; Wiley-VCH; Weinheim, Germany, 2003 For reviews,
see: (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–4450. (c)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043. (d) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29. (e) Hoveyda, A. H.;
Zhugralin, A. R. Nature 2007, 450, 243–251.
(5) For recent examples, see: (a) Kotoku, N.; Kato, T.; Narumi, F.;
Ohtani, E.; Kamada, S.; Aoki, S.; Okada, N.; Nakagawa, S.; Kobayashi,
M. Bioorg. Med. Chem. 2006, 14, 7446–7457. (b) Huang, W.-S.; Wang,
Y.; Sundaramoorthi, R.; Thomas, R. M.; Wen, D.; Liu, S.; Lentini, S. P.;
Das, S.; Banda, G.; Sawyer, T. K.; Shakespeare, W. C. Tetrahedron Lett.
2007, 48, 7388–7391.
(9) For a review, see: Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew.
Chem., Int. Ed. 2006, 45, 2664–2670
.
10.1021/ol8009573 CCC: $40.75
Published on Web 06/07/2008
2008 American Chemical Society

synthesis of various aromatic compounds. In our pursuit of
new methods for the synthesis of carbocyclic aromatic
compounds using RCM,12 we found that substituted benzenes
3 can be synthesized in excellent yields by RCM of 1,4,7-
trien-3-ols 1, followed by dehydration of cyclohexa-2,5-
dienols 2 (eq 1).12b In this study, we examined the extension
of acyclic precursors 1 to enyne substrates 4 and the synthesis
of styrenes 6 by ring-closing enyne metathesis (RCEM)13/
elimination of 4 via cyclized product 5 (eq 2).
Scheme 1
of 4 with versatile substitution patterns could be prepared
with these routes.16
We first surveyed the reaction conditions for the synthesis
of styrene 6a from 4a that was chosen as model substrate
(Table 1). When RCEM of 4a with Grubbs second-
Table 1. Survey of Reaction Conditions for Synthesis of
Styrene 6aa
Two synthetic strategies for required 4,7-octadien-1-yn-
3-ols 4 are outlined in Scheme 1. The upper route involves
palladium-catalyzed cis-selective bromoallylation14 of alkynes
with allyl bromides 7 and the coupling of resulting bromo-
dienes 8 with acetylenic aldehydes. The lower route involves
the oxidation of 2,5-hexadienols 9, which can be obtained
by stereoselective carbometalation of propargyl alcohol
followed by allylation,15 and the alkynylation of the resulting
2,5-hexadienals 10 with terminal alkynes. In fact, a series
temp time yield
entry substrate
catalyst
atmosphere (°C) (h) (%)b
1
4a
4a
13 (7.5 mol %) N2
13 (7.5 mol %) C2H4
PtBr2 (2 mol %) N2
13 (7.5 mol %) N2
13 (7.5 mol %) N2
13 (7.5 mol %) N2
13 (7.5 mol %) C2H4
80
80
120
80
80
rt
2
2
9c
3c
4c
9c
2
(10) For reports on the direct synthesis of carbocyclic aromatic
compounds with RCM, see: (a) Iuliano, A.; Piccioli, P.; Fabbri, D. Org.
Lett. 2004, 6, 3711–3714. (b) Walker, E. R.; Leung, S. Y.; Barrett, A. G. M.
Tetrahedron Lett. 2005, 46, 6537–6540. (c) Bonifacio, M. C.; Robertson,
C. R.; Jung, J.-Y.; King, B. T. J. Org. Chem. 2005, 70, 8522–8526. (d)
Pelly, S. C.; Parkinson, C. J.; Van Otterlo, W. A. L.; De Koning, C. B. J.
Org. Chem. 2005, 70, 10474–10481. (e) Collins, S. K.; Grandbois, A.;
Vachon, M. P.; Coˆte´, J. Angew. Chem., Int. Ed. 2006, 45, 2923–2926. For
reports with RCM/elimination protocol, see: (f) Evans, P.; Grigg, R.;
Ramzan, M. I.; Sridharan, V.; York, M. Tetrahedron Lett. 1999, 40, 3021–
3024. (g) Huang, K. S.; Wang, E. C. Tetrahedron Lett. 2001, 42, 6155–
6157. (h) Chen, Y.; Dias, H. V. R.; Lovely, C. J. Tetrahedron Lett. 2003,
44, 1379–1382. (i) Chen, P.-Y.; Chen, H.-M.; Chen, L.-Y.; Tzeng, J.-Y.;
Tsai, J.-C.; Chi, P.-C.; Li, S.-R.; Wang, E.-C. Tetrahedron 2007, 63, 2824–
2828For reports with RCM/oxidation protocol, see: (j) Kotha, S.; Mandal,
K. Tetrahedron Lett. 2004, 45, 2585–2588. (k) Ma, S.; Yu, F.; Zhao, J.
Synlett 2007, 583–586. (l) Kotha, S.; Shah, V. R.; Mandal, K. AdV. Synth.
Catal. 2007, 349, 1159–1172. For a report with RCM/tautomerization
protocol, see: (m) van Otterlo, W. A. L.; Ngidi, E. L.; Coyanis, E. M.; de
Koning, C. B. Tetrahedron Lett. 2003, 44, 311–313.
3d
4
4a
15
2
11a
12a
12a
12a
5
2
92
6
2
23
76
7
80
2
a The reaction was carried out with 4a, 11a, or 12a and ruthenium
catalyst 13 in toluene at 80 °C for 2 h. The reaction mixture was treated
with p-toluenesulfonic acid (15 mol %) at room temperature for 1 h.
b Isolated yield by silica gel chromatography. c NMR yield by 1H NMR
analysis with 1,4-bis(trimethylsilyl)benzene as the internal standard. d The
reaction was carried out with 4a and PtBr2 (2 mol %) in 1,4-dioxane at
120 °C for 15 h.
generation catalyst 1317 at 80 °C followed by dehydration
with a catalytic amount of p-toluenesulfonic acid was carried
out, 6a was obtained in a disappointingly low yield of 9%
(Table 1, entry 1).18 Similar reaction conditions under
ethylene atmosphere (Mori’s conditions)19 fared much worse,
giving 6a in 3% yield (Table 1, entry 2). Furthermore, PtBr2-
catalyzed enyne metathesis conditions20 reported by Yama-
(11) For selected recent reports on the synthesis of heterocyclic
aromatic compounds with RCM, see: (a) Arisawa, M.; Nishida, A.;
Nakagawa, M. J. Organomet. Chem. 2006, 691, 5109–5121. (b) Donohoe,
T. J.; Fishlock, L. P.; Lacy, A. R.; Procopiou, P. A. Org. Lett. 2007, 9,
953–956.
(12) (a) Yoshida, K.; Imamoto, T. J. Am. Chem. Soc. 2005, 127, 10470–
10471. (b) Yoshida, K.; Kawagoe, F.; Iwadate, N.; Takahashi, H.; Imamoto,
T. Chem. Asian J. 2006, 1, 611–613. (c) Yoshida, K.; Horiuchi, S.; Iwadate,
N.; Kawagoe, F.; Imamoto, T. Synlett 2007, 1561–1564. (d) Yoshida, K.;
Toyoshima, T.; Imamoto, T. Chem. Commun. 2007, 3774–3776.
(13) (a) Mori, M. Top. Organomet. Chem. 1998, 1, 133–154. (b) Poulsen,
C. S.; Madsen, R. Synthesis 2003, 1–18. (c) Diver, S. T.; Giessert, A. J.
Chem. ReV. 2004, 104, 1317–1382. (d) Lippstreu, J. J.; Straub, B. F. J. Am.
Chem. Soc. 2005, 127, 7444–7457.
(15) Tessier, P. E.; Penwell, A. J.; Souza, F. E. S.; Fallis, A. G. Org.
Lett. 2003, 5, 2989–2992.
(16) See the Supporting Information for experimental details. The yields
of the products reported in this paper were 100-54% (4 to 12), 70% (4a
to 11a), 39-37% (8 to 4), and 92-31% (10 to 4).
(17) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956. (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, 2546–2558.
(14) (a) Kaneda, K.; Uchiyama, T.; Fujiwara, Y.; Imanaka, T.; Teranishi,
S. J. Org. Chem. 1979, 44, 55–63. (b) Llebaria, A.; Camps, F.; Moreto,
J. M. Tetrahedron 1993, 49, 1283–1296. (c) Ba¨ckvall, J.-E.; Nilsson,
Y. I. M.; Gatti, R. G. P. Organometallics 1995, 14, 4242–4246. (d) Thadani,
A. N.; Rawal, V. H. Org. Lett. 2002, 4, 4317–4320.
(18) The low yield is due to the RCEM step, not the elimination step.
A large amount of decomposed products by reacting 4a with p-toluene-
sulfonic acid was obtained after the reaction.
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Org. Lett., Vol. 10, No. 13, 2008

Table 2. Synthesis of Styrenes 6 by RCEM/Eliminationa
a Enyne metathesis was carried out with 12 and ruthenium catalyst (13, 7.5 mol %) in toluene at 80 °C for 2 h. The reaction mixture was treated with
p-toluenesulfonic acid (15 mol %) at room temperature for 1 h. b Isolated yield by silica gel chromatography. c The reaction was carried out with 2.5 mol
% 13. d When the amount of catalyst 13 was decreased to 0.5 mol %, the isolated yield of 6a was decreased to 15%. e 2,6-Di-tert-butylpyridine (1.2 equiv)
was added as an additive in the RCEM step. f Starting material 12h was recovered in 20% yield. g The reaction was carried out with 10 mol % 13. Stilbene-
type dimer was formed as a byproduct in 18% yield. h When the amount of catalyst 13 was decreased to 2.5 mol %, the isolated yields of 6i and the dimer
were decreased to 9% and 5%, respectively.
moto and co-workers were also not effective (Table 1, entry
3). Since these results could be attributed to the free hydroxyl
group at the propargyl position of 4a,21 we next performed
the reaction with substrates protected at the hydroxyl group.
Although no improvement was observed when methyl-
protected substrate 11a was employed (Table 1, entry 4), a
dramatic improvement was observed when acyl-protected
substrate 12a was employed in RCEM/elimination with
Grubbs second-generation catalyst 13, where 6a was fur-
nished in 92% isolated yield (Table 1, entry 5). Changing
the temperature of the RCEM step from 80 °C to room
temperature resulted in a decrease in reactivity (Table 1, entry
5 vs entry 6) and performing the reaction at 80 °C under
ethylene atmosphere also decreased the yield from 92% to
76% (Table 1, entry 5 vs entry 7).22
After acquiring basic data, we examined the generality of
the synthesis of styrenes 6 from acyl-protected substrates
12 using RCEM/elimination. The results are summarized in
Table 2. All RCEM reactions were conducted with Grubbs
second-generation catalyst 13 in toluene at 80 °C for 2 h.
The formation of styrenes having aryl substituents (Table 2,
(20) In 2005, Yamamoto and co-workers reported an efficient synthesis
of vinylnaphthalenes by PtBr2-catalyzed enyne metathesis/elimination, see:
Bajracharya, G. B.; Nakamura, I.; Yamamoto, Y. J. Org. Chem. 2005, 70,
892–897.
(21) (a) Mori, M.; Tonogaki, K.; Nishiguchi, N. J. Org. Chem. 2002,
67, 224–226. (b) Funel, J.-A.; Prunet, J. J. Org. Chem. 2004, 69, 4555–
4558.
(19) Mori and co-workers reported the beneficial effects of ethylene
atmosphere in RCEM of enyne substrates having terminal alkyne, see: Mori,
M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63, 6082–6083.
(22) Although enyne substrate 12a does not have a terminal alkyne, the
deleterious effect of ethylene was out of our assumption. The reason for
the effect is not known at this stage.
Org. Lett., Vol. 10, No. 13, 2008
2779

entries 1-4) as well as alkyl substituents (Table 2, entries 5
and 6) at the R1 position was accomplished without any
problems. Because of the great functional group tolerance
of the catalyst, introduction of a pyridyl, a haloalkyl, or an
ester group at the R1 position could be successfully achieved
(Table 2, entries 3, 6, and 7). Introduction of substituents at
the R2, R3, or R4 position was also accomplished and did
not give a significant difference on the reactivity of RCEM
(Table 2, entries 1-7). It must be noted that deprotection of
silyl ether occurred when the reaction of 12d was carried
out under the above-mentioned conditions. Since it could
be assumed that the deprotection was caused by acetic acid
that was produced slowly by spontaneous aromatization in
the RCEM step at 80 °C, we examined the effect of adding
a base to trap the acetic acid in this reaction. As a result, the
addition of 2,6-di-tert-butylpyridine (1.2 equiv) successfully
suppressed the deprotection and desired styrene 6d was
obtained in 78% yield (Table 2, entry 4). It is noteworthy
that the addition of pyridine instead of 2,6-di-tert-butylpy-
ridine resulted in decreased activity of the catalyst and the
recovery of a large amount of 12d. In contrast to the results
obtained by introducing a substituent at the R1, R2, R3, or
R4 position, the introduction of a substituent at the R5 position
retarded the reaction. When the reaction of 12h having a
methyl group at the R5 position was performed, desired 6h
was obtained in 53% yield (Table 2, entry 8). Introduction
of a methyl group at the R6 position further decreased the
reactivity. However, a certain extent of reactivity could be
gained by introducing a hydrogen at the R1 position, although
the isolated yield of 6i was still low at 34% (Table 2, entry
9). In this case, a problematic side reaction that involved
dimerization of 6i to give the stilbene-type dimer occurred
even under diluted conditions.
octadien-1-yn-3-ol 4. As a result, the reaction of 14 with
Grubbs second-generation catalyst 13 followed by dehydra-
tion gave corresponding styrene 15 in 74% yield (Scheme
2). It is interesting that RCEM of 14 having no free propargyl
hydroxyl group proceeded well without acyl protection.
Scheme 2
In summary, we have developed an efficient approach for
the synthesis of substituted styrenes, which utilizes RCEM/
elimination. Because of the high reliability of the employed
transformations, this approach can provide a wide variety
of styrenes without the formation of undesirable regioiso-
mers.
Acknowledgment. We appreciate the financial support
from the Sumitomo Foundation, Mitsubishi Chemical Cor-
poration Fund, and Research for Promoting Technological
Seeds from JST, and a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
To extend the scope of RCEM/elimination, we examined
the synthesis of styrene from a different type of enyne
substrate, 1,4-octadien-7-yn-3-ol 14,23 which has terminal
alkene and alkyne at opposite positions relative to 4,7-
OL8009573
(23) 14 was prepared by reacting (E)-2-methyl-3,6-diphenyl-2-hexen-
5-ynal with vinylmagnesium chloride (81% yield).
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Org. Lett., Vol. 10, No. 13, 2008