Rapid Assembly of Structurally Defined and Highly Functionalized Conjugated Dienes via Tethered Enyne Metathesis

Article abstract of DOI:10.1021/ol016026s

(matrix presented) Conjugated dienes are versatile building blocks in organic synthesis, and the development of new methods for their synthesis remains an important topic in modern synthetic organic chemistry. We describe here an expedient synthesis of hi

Full text of DOI:10.1021/ol016026s

ORGANIC
LETTERS
2001
Vol. 3, No. 13
2069-2072
Rapid Assembly of Structurally Defined
and Highly Functionalized Conjugated
Dienes via Tethered Enyne Metathesis
Qingwei Yao
Department of Chemistry and Biochemistry, The Michael Faraday Laboratories,
Northern Illinois UniVersity, DeKalb, Illinois 60115-2862
qyao@niu.edu
Received April 24, 2001
ABSTRACT
Conjugated dienes are versatile building blocks in organic synthesis, and the development of new methods for their synthesis remains an
important topic in modern synthetic organic chemistry. We describe here an expedient synthesis of highly functionalized conjugated dienes
through sequential silicon-tethered ring-closing enyne metathesis mediated by Grubbs’ Ru carbene catalysts and Tamao oxidation. Notable
attributes of this methodology include short synthetic manipulations and the structural complexity it confers on the resulting diene moiety.
Conjugated dienes are versatile building blocks in organic
synthesis as exemplified by their dominance in the Diels-
Alder reaction and most of its variants.1 There exists a
plethora of synthetic methods for conjugated dienes,2 with
prototypical approaches employing base-induced elimination
from allylic and homoallylic halides or halide equivalents,
double elimination from suitably substituted dihalide sub-
strates, or the Wittig-type olefination of R,â-unsaturated
carbonyl compounds. However, for many practical applica-
tions, the control of both the regio- and the stereochemistry
of the diene moiety has to be rigorously exercised. Cross
coupling of vinylic species utilizing an appropriate organo-
metallic catalyst has proven more effective in controlling
diene stereochemistry and has been extensively used in
organic synthesis.3 However, the preparation of the prereq-
uisite vinyl halides/triflates (Heck),4 vinylstannanes (Stille),5
organoboranes (Suzuki),6 and alkenylzincs (Negishi)7 often
involves tedious multistep manipulation of air-sensitive and,
in the case of organostannanes, toxic compounds.
The rapidly emerging olefin metathesis reaction has found
many spectacular applications in organic synthesis.8 In
particular, diene ring-closing metathesis (RCM) and cross
olefin metathesis mediated by transition metal carbene
complexes have evolved into powerful tools for the formation
(3) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, 1998. (b) Tsuji, J. Transition Metal
Reagents and Catalysts, InnoVation in Organic Synthesis; Wiley: Chich-
ester, 2000.
(4) For recent reviews on the Heck reaction, see: (a) Heck, R. F. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon: New York,
1991; Vol. 4, Chapter 4.3. (b) Bra¨se, S.; de Meijere, A. In Metal-Catalyzed
Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998; Chapter 3. (c) Beletskaya, I. P.; Cheprakov, A. V. Chem.
ReV. 2000, 100, 3009-3066.
(5) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524. (b)
Mitchell, T. N. Synthesis 1992, 803-815. (c) Mitchell, T. N. In Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: Weinheim, 1998; Chapter 4.
(6) For recent reviews, see: (a) Niyaura, N.; Suzuki, A. Chem. ReV. 1995,
95, 2457. (b) Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter
2.
(1) (a) Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction;
Wiley: New York, 1990. (b) Carruthers, W. Cycloaddition Reactions in
Organic Synthesis; Pergamon: Oxford, 1990.
(2) (a) Norman, J. F. In Modern Synthetic Methods; Scheffold, R., Ed.;
Wiley: Chichester, 1983; Vol. 3, pp 139-171. (b) Larock, R. C.
ComprehensiVe Organic Transformations; VCH Publishers: New York,
1989; pp 241-262.
(7) (a) Negishi, E.; Liu, F. in Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter
1. For examples of diene synthesis via coupling of vinyl halides with
organoaluminium and zirconium compounds, see: (b) Baba, S.; Negishi,
E. J. Am. Chem. Soc. 1976, 98, 6729-6731. (c) Negishi, E.; Okukado, N.;
King, A. O.; Van Horn, D. E.; Spiegel, B. I. J. Am. Chem. Soc. 1978, 100,
2254-2256.
10.1021/ol016026s CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/26/2001

of carbon-carbon double bonds over the past 10 years.
Despite its great synthetic utility, the related alkene-alkyne
metathesis has been much less explored.9-11 Whereas enyne
RCM has been shown to be a versatile strategy for the
synthesis of cyclic dienes,9 its intermolecular variant, the
cross alkene-alkyne metathesis, is limited to only a few
cases with less demanding substrates: the cross metatheses
of terminal alkynes and terminal alkenes (eq 1, Scheme 1)10
temporary connection methodology13,14 as a means to facili-
tate the alkene-alkyne metathesis and to provide regio- and
stereochemical control. Specifically, it is expected that
tethering of an alkene and an alkyne with an appropriate
linker followed by enyne RCM9 and tether cleavage would
provide ready access to highly substituted acyclic conjugated
dienes with predetermined regio- and, preferably, stereo-
chemistry (Scheme 2). Even a simplified scenario of Scheme
Scheme 2
Scheme 1
and of internal alkynes and ethylene (eq 2),11 furnishing 1,3-
and 2,3-disubstitued dienes, respectively. To date, the
synthesis of tri- and tetrasubstituted acyclic dienes by
alkene-alkyne metathesis has not been rigorously established
due to the difficulty encountered in the simultaneous control
of their chemo-, regio-, and stereoselectivity.12
2 wherein a terminal alkene (R1 ) R2 ) R3 ) H) is tethered
to an internal alkyne would yield after cleavage of the tether
a trisubstituted diene with complete regio- and stereochem-
ical control.
To overcome the above-mentioned limitations of alkene-
alkyne metathesis, we chose to apply the principle of the
As exemplified in Scheme 3 and summarized in Table 1,
our strategy was successfully implemented with a number
(8) Leading reviews on olefin metathesis: (a) Schuster, M.; Blechert, S.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2036-2056. (b) Fu¨rstner, A. Top.
Organomet. Chem. 1998, 1, 1-231. (c) Armstrong, S. K. J. Chem. Soc.,
Perkin Trans. 1 1998, 371-388. (d) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413-4445. (e) Pandit, U. K.; Overleeft, H. S.; Borer, B. C.;
Biera¨ugel, H. Eur. J. Org. Chem. 1999, 959-968. (f) Phillips, A. J.; Abell,
A. D. Aldrichimica Acta 1999, 32, 75-90.
Scheme 3
(9) For leading references on ring-closing enyne metathesis, see: (a)
Kinoshita, A.; Mori, M. J. Org. Chem. 1996, 61, 8356-8357 (b) Kinoshita,
A.; Mori, M. Synlett 1997, 1020-1022. (c) Mori, M.; Sakakibara, N.;
Kinoshita, A. J. Org. Chem. 1998, 63, 6082-6083. (d) Mori, M.; Kitamura,
T.; Sakakibara, N.; Sato, Y. Org. Lett. 2000, 2, 543-545. (e) Heerding, D.
A.; Takata, D. T.; Kwon, C.; Huffman, W. F. Samanen, J. Tetrahedron
Lett. 1998, 39, 6815-6818. (f) Ackermann, L.; Bruneau, C.; Dixneuf, P.
H. Synlett 2001, 397-399. For examples of tandem dienyne metathesis,
see: (g) Kim, S.-H.; Zuercher, W. J.; Bowden, N. B.; Grubbs, R. H. J.
Org. Chem. 1996, 61, 1073-1081. (h) Renaud, J.; Graf, C.-D.; Oberer, L.
Angew. Chem., Int. Ed. 2000, 39, 3101-3104. (i) Smulik, J. A.; Diver, S.
T. Tetrahedron Lett. 2001, 42, 171-174.
(10) Stragies, R.; Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl.
1997, 36, 2518-2560. (b) Schu¨rer, S. C.; Blechert, S. Comm. Commun.
1999, 1203-1204. (c) Schu¨rer, S. C.; Blechert, S. Tetrahedron Lett. 1999,
40, 1877. (c) Smulik, J. A.; Diver, S. T. Org. Lett. 2000, 2, 2271-2274.
(11) (a) Kinoshita, A.; Mori, M. J. Am. Chem. Soc. 1997, 119, 12388-
12389. (b) Kinoshita, A.; Sakakibara, N.; Mori, M. Tetrahedron 1999, 55,
8155-8167.
(12) For example, the cross coupling shown below gave a complex
mixture of products, see: Stragies, R.; Voigtmann, U.; Blechert, S.
Tetrahedron Lett. 2000, 41, 5465-5468.
of silicon-tethered15 enyne substrates leading to the formation
of a variety of highly functionalized dienes. Thus, treatment
of the tethered enyne 2a, prepared from the commercially
available allylchlorodimethylsilane and propargyl alcohol 1a,
as shown in Scheme 3, with Grubbs catalyst 3a16 (Figure 1)
Figure 1. Grubbs Ru catalysts.
Org. Lett., Vol. 3, No. 13, 2001
2070

Table 1. Synthesis of Functionalized Dienes via Silicon-Tethered Enyne Metathesis
a Unless otherwise noted, RCM was carried out at a concentration of in 0.025 M in CH2Cl2 under an Ar atmosphere. b Isolated yield. c The concentration
of the reaction was 0.05 M. d Ethylene was supplied under balloon pressure. e The concentration of the reaction was 0.005 M.
(3 mol %) in CH2Cl2 (0.025 M) at reflux gave cleanly the
tethered product 4a which, after oxidative cleavage with
H2O2 as described by Tamao et al.,17 afforded diene 5a in
88% overall yield from 2a after purification by flash
chromatography on silica gel.18
Table 1 lists the results with other substrates bearing a
diverse array of substituents on the alkyne. Enyne 2b (entry
2) with an isobutyl group present at the propargylic position
exhibited decreased reactivity relative to that of 2a, and its
RCM required a longer reaction time (12 h) and a higher
concentration in order for the reaction to go to completion.
The ester group in enyne 2c (entry 3) did not cause any
retardation and the RCM of 2c proceeded uneventfully,
furnishing the highly oxygenated diene 5c in high yield after
(13) Stork, G.; Suh, H. S.; Kim, G. J. Am. Chem. Soc. 1991, 113, 7054-
7056.
(14) For recent reviews, see: (a) Bols, M.; Skrydstrup, T. Chem. ReV.
1995, 95, 1253-1277. (b) Templated Organic Synthesis; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 2000.
Org. Lett., Vol. 3, No. 13, 2001
2071

tether cleavage. Substrates derived from a terminal alkyne
(entry 4) or an alkyne containing a hindered phthalimido
group (entry 5) experienced diminished reactivity, and the
use of ethylene gas was found to be crucial to attain complete
conversion.19 RCM of enynes 2f (entry 6) and 2g (entry 7)
leading to the formation of seven-membered tethered dienes
did not go to completion with catalyst 3a, but the use of the
more active catalyst 3b20 resulted in high conversions in both
cases. Finally, a tandem ene-yne-ene metathesis9g-i was
achieved with substrate 2h (entry 8) which provided the
tetrasubstituted diene 5h in high yield after tether cleavage
when the reaction was run under high dilution conditions.
While we have shown that the tethered enyne RCM-
oxidative cleavage methodology can provide an efficient
access to highly functionalized acyclic dienes, preliminary
studies have established that the silicon-tethered diene
intermediates can serve as excellent substrates for highly
stereoselective Diels-Alder reactions.21
(15) For examples of silicon-tethered ring-closing diene metathesis,
see: (a) Chang, S.; Grubbs, R. H. Tetrahedron 1997, 27, 4757-4760. (b)
Meyer, C.; Cossy, J. Tetrahedron Lett. 1997, 38, 7861. (c) Cassidy, J. H.;
Marsden, S. P.; Stemp, G. Synlett 1997, 1411-1413. (d) Taylor, R. E.;
Engelhardt, C.; Schmitt, M. J.; Yuan, H. J. Am. Chem. Soc. 2001, 123,
2964-2969. For related examples, see: (e) Evans, P. A.; Murthy, V. S. J.
Org. Chem. 1998, 63, 6768-6769. (f) Hoye, T. R.; Promo, M. A.
Tetrahedron Lett. 1999, 40, 1429. (g) Briot, A.; Bujard, M.; Gouverneur,
V.; Nolan, S. P.; Mioskowski, C. Org. Lett. 2000, 2, 1517-1519. (h) Yao,
Q. Angew. Chem., Int. Ed. 2000, 39, 3896-3898. (i) Boitea, J. G.; Van de
Weghe, P.; Eustche, J. Tetrahedron Lett. 2001, 42, 239-242.
Acknowledgment. This research was supported by
Northern Illinois University.
Supporting Information Available: NMR (1H and 13C)
and characterization data for compounds 2a-h and 5a-h.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
119, 100-110.
(17) Tamao, K.; Ishida, N.; Kumada, M. Org. Synth. 1990, 69, 96-105.
OL016026S
(19) For a discussion of the effect of ethylene gas in ring-closing enyne
metathesis, see ref 9c.
(20) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(21) For example, treatment of crude 4a with maleiimide in toluene at
reflux led to the formation of the Diels-Alder adduct 6 shown below, which
was isolated in 68-70% yield as a single diastereomer and whose
stereochemistry was established by conformational analysis of its fused
tricyclic structure on the basis of 1H NMR data and NOESY experiments.
(18) Representative experimental procedures for enyne RCM and
Tamao oxidation of tethered diene product (entry 1, Table 1): To a
solution of 2a (136 mg, 0.50 mmol) in CH2Cl2 (0.025 M) was added Grubbs
catalyst 3a (12 mg, 3 mol %), and the reaction mixture was heated to reflux
under Ar. After 3 h, the reaction was cooled to rt and concentrated to dryness
under vacuum. Examination of the crude reaction mixture by 1H NMR
indicated complete consumption of 3a with clean and essentially quantitative
1
formation of the tethered diene 4a. H NMR (CDCl3, 500 MHz) δ: 0.14
(3H, s), 0.29(3H, s), 1.41-1.49 (2H, m), 1.76-1.95 (2H, m), 1.86 (3H, s),
2.71(1H, ddd, J ) 6.8, 10.2, 13.7 Hz), 2.87 (1H, ddd, J ) 4.6, 10.4, 13.7
Hz), 4.70-4.85 (1H, m), 4.73 (1H, s), 4.78 (1H, m), 4.80 (1H, s), 6.05
(1H, dd, J ) 4.6, 7.4 Hz), 7.16-7.30 (5H, m). Crude 4a was then dissolved
in MeOH/THF (5 mL/5 mL) and treated with KF (145 mg, 2.5 mmol) and
KHCO3 (125 mg, 1.25 mmol) followed by H2O2 (30%, 0.56 mL, 5 mmol).
After stirring at rt for 48 h, TLC indicated complete consumption of the
starting material and the reaction mixture was poured into water and
extracted with EtOAc (3% × 20 mL). The combined organic extracts were
washed with 5% Na2S2O4 and brine, dried (Na2SO4), and evaporated. Flash
chromatography on silica gel (EtOAc/hexane 1:1) gave diene 5a (102 mg,
Data for 6. 1H NMR (CDCl3, 500 MHz) δ: 0.14 (3H, s), 0.17 (3H, s), 0.85
(1H, dd, J ) 5.7, 15.2 Hz), 1.52-1.58 (1H, m), 1.66 (3H, d, J ) 1.6 Hz),
1.88-1.99 (2H, m), 2.27 (1H, dd, J ) 6.7, 14.7 Hz), 2.48-2.52 (1H, m),
2.56 (1H, dd, J ) 1.7, 14.7 Hz), 2.60-2.71 (2H, m), 2.97 (1H, dd, J ) 6.1,
8.9 Hz), 3.09 (1H, ddd, J ) 1.7, 6.6, 8.9 Hz), 4.75 (1H, dd, J ) 5.8, 9.0
Hz), 7.16-7.28 (5H, m), 8.11 (1H, s). 13C NMR (CDCl3, 125 MHz) δ:
-0.90, 1.62, 11.55, 19.41, 31.25, 32.32, 33.97, 39.69, 41.53, 47.79, 71.85,
125.79, 128.36, 130.10, 134.47, 141.56, 178.53, 179.36. Anal. Calcd for
C21H27NO23Si: C, 68.26, H, 7.36., N, 7.39. Found: C, 68.10; H, 7.55; N.
3.83.
1
88%) as a thick hygroscopic oil. H NMR (CDCl3, 500 MHz) δ: 1.87-
2.10 (2H, m), 1.90 (3H, s), 2.69 (1H, m), 2.81 (1H, m), 4.29 (1H, dd, J )
6.8, 13.4 Hz), 4.35 (1H, dd, J ) 6.6, 13.4 Hz), 4.63 (1H, dd, J ) 4.5, 8.8
Hz), 4.95 (1H, s), 4.96 (1H, s), 5.78 (1H, t, J ) 6.7 Hz), 7.16-7.34 (5H,
m). 13C NMR (CDCl3, 125 MHz) δ: 22.88, 32.44, 37.85, 58.70, 69.85,
113.82, 125.93, 127.73, 128.41, 128.46, 141.62, 143.22, 145.87. Anal. Calcd
for C15H20O2‚0.2H2O: C, 76.36; H, 8.72. Found: C, 76.67; H, 8.78.
2072
Org. Lett., Vol. 3, No. 13, 2001