Titanium alkoxide-based method for stereoselective synthesis of functionalized conjugated dienes

Article abstract of DOI:10.1021/ja9905694

Treatment of an internal acetylene such as 1-silyl-1-octyne (3) with a low-valent titanium reagent, (η²-propene)Ti(O-i-Pr)₂ (1) readily prepared from Ti(O-i-Pr)₄ and i-PrMgCl in situ, generates an acetylene -titanium compl

Full text of DOI:10.1021/ja9905694

7342
J. Am. Chem. Soc. 1999, 121, 7342-7344
Titanium Alkoxide-Based Method for Stereoselective Synthesis of
Functionalized Conjugated Dienes
Takashi Hamada, Daisuke Suzuki, Hirokazu Urabe, and Fumie Sato*
Contribution from the Department of Biomolecular Engineering, Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
ReceiVed February 23, 1999
Abstract: Treatment of an internal acetylene such as 1-silyl-1-octyne (3) with a low-valent titanium reagent,
(η2-propene)Ti(O-i-Pr)2 (1) readily prepared from Ti(O-i-Pr)4 and i-PrMgCl in situ, generates an acetylene-
titanium complex. This complex was allowed to react with a terminal acetylene, 4-(benzyloxy)-1-butyne (5),
to give the intermediate titanacyclopentadiene (6) which, upon hydrolysis, deuteriolysis, or iodinolysis, gave
diene 8, or its bis-deuterated (>99% d2) and bis-iodinated counterparts (9 and 10), in good yields and with
high selectivities. This reaction is applicable to the cross-coupling reaction of functionalized acetylenes such
as 2-alkynoates and 2-alkynamides 12-18 and a variety of terminal acetylenes 24-28 to give dienes 36-50
in good yields. A terminal acetylene 28 carrying an olefinic bond at the other terminus reacted with a
silylpropiolate to afford the expected diene 42 without any complication.
Introduction
Chart 1
Stereoselective preparation of functionalized, conjugated
dienes is an important synthetic transformation, because such
dienes are frequently found as a partial structure of naturally
occurring products1 and are also useful intermediates in organic
synthesis,2 as has been amply demonstrated in the Diels-Alder
and related reactions.3 When regio- and stereoselective align-
ment of the substituent(s) and functional group(s) on the diene
skeleton is considered, their synthesis is not necessarily a facile
process and, rather, often requires a multistep procedure.4 In
this respect, group 4 metal (Ti or Zr) complex-assisted assembly
of acetylenes to furnish conjugated dienes as formulated in eq
1 (M ) metal, L ) ligand) is an attractive method.5,6 However,
the synthesis of functionalized dienes such as those in Chart 1
(R ) alkyl groups, X ) OR or NR2) by this method via a cross-
coupling of different types of acetylenes inVolVing an R,â-
acetylenic ester or amide has remained undeveloped.7 We report
herein that a low-valent titanium reagent, (η2-propene)Ti(O-i-
Pr)2 (1) readily prepared from Ti(O-i-Pr)4 and i-PrMgCl in
situ,8-11 could realize the above process to give dienes of the
general structures shown in Chart 1 in addition to other relevant
1,3-dienes.
(1) Glasby, J. S. Encyclopaedia of the Terpenoids; Wiley: Chichester,
1982. Devon, T. K.; Scott, A. I. Handbook of Naturally Occurring
Compounds; Academic Press: New York, 1972; Vol. II.
(2) Luh, T.-Y.; Wong, K.-T. Synthesis 1993, 349.
(3) Desimoni, G.; Tacconi, G.; Barco, A.; Pollini, G. P. Natural Products
Synthesis through Pericyclic Reactions; American Chemical Society:
Washington, DC, 1983. Fringuelli, F.; Taticchi, A. Dienes in the Diels-
Alder Reaction; Wiley: New York, 1990. Carruthers, W. Cycloaddition
Reactions in Organic Synthesis; Pergamon Press: Oxford, 1990. Oppolzer,
W. In ComprehensiVe Organic Synthesis; Trost, B. M.; Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 5, p 315. Weinreb, S. M. In
ComprehensiVe Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 5, p 401. Roush, W. R. In ComprehensiVe
Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 5, p 513.
(4) Smith, M. B. Compendium of Organic Synthetic Methods; Wiley:
New York, 1988; Vol. 6, p 484; 1992, Vol. 7, p 462; 1995, Vol. 8, p 531.
More examples can be found in the earlier volumes of this series. For the
coupling of alkenylmetals and alkenyl halides, see: Knight, D. W. In
ComprehensiVe Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 3, p 481. Zweifel, G.; Miller, J. A. In Organic
Reactions; Dauben, W. G., Ed.; Wiley: New York, 1984; Vol. 32, Chapter
2. For more recent reports on the synthesis of electron-deficient dienes,
see: Jeges, G.; Skoda-Fo¨ldes, R.; Kolla´r, L.; Horva´th, J.; Tuba, Z.
Tetrahedron 1998, 54, 6767. Kim, H.-O.; Ogbu, C. O.; Nelson, S.; Kahn,
M. Synlett 1998, 1059. Bodwell, G. J.; Pi, Z.; Pottie, I. R. Synlett 1999,
477 and references therein.
(5) For reviews, see: Buchwald, S. L.; Nielsen, R. B. Chem. ReV. 1988,
88, 1047. Negishi, E. In ComprehensiVe Organic Synthesis; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, p 1163. Broene,
R. D.; Buchwald, S. L. Science 1993, 261, 1696. Negishi, E.; Takahashi,
T. Acc. Chem. Res. 1994, 27, 124. Maier, M. In Organic Synthesis Highlights
II; Waldmann H., Ed.; VCH: Weinheim, 1995; p 99. Ohff, A.; Pulst, S.;
Lefeber, C.; Peulecke, N.; Arndt, P.; Burkalov, V. V.; Rosenthal, U. Synlett
1996, 111. Negishi, E.; Takahashi, T. Bull. Chem. Soc. Jpn. 1998, 71, 755.
(6) For the preparation of 1,3-dienes via a group 4 metal complex-
mediated intermolecular coupling of acetylenes, see: (a) Buchwald, S. L.;
Watson, B. T.; Huffman, J. C. J. Am. Chem. Soc. 1987, 109, 2544. (b)
Buchwald, S. L.; Nielsen, R. B. J. Am. Chem. Soc. 1989, 111, 2870. (c)
Hill, J. E.; Balaich, G.; Fanwick, P. E.; Rothwell, I. P. Organometallics
1993, 12, 2911. (d) Takahashi, T.; Kageyama, M.; Denisov, V.; Hara, R.;
Negishi, E. Tetrahedron Lett. 1993, 34, 687. (e) Xi, Z.; Hara, R.; Takahashi,
T. J. Org. Chem. 1995, 60, 4444.
(7) As functionalized acetylenes, alkynyl ether and sulfide have been
reported to give the corresponding diene. Nugent, W. A.; Thorn D. L.;
Harlow, R. L. J. Am. Chem. Soc. 1987, 109, 2788. Van Wagenen, B. C.;
Livinghouse, T. Tetrahedron Lett. 1889, 30, 3495. Homo-coupling of
dimethyl acetylenedicarboxylate with Cp2Ti(CO)2 was documented. Dem-
erseman, B.; Dixneuf, P. H. J. Chem. Soc., Chem. Commun. 1981, 665.
(8) For a review, see: Sato. F.; Urabe, H.; Okamoto, S. J. Synth. Org.
Chem., Jpn. 1998, 56, 424.
10.1021/ja9905694 CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/03/1999

StereoselectiVe Synthesis of Conjugated Dienes
J. Am. Chem. Soc., Vol. 121, No. 32, 1999 7343
Table 1. Preparation of Functionalized Dienes via Cross-Coupling
Results and Discussion
Reactiona
Treatment of an internal acetylene such as 5-decyne (2) or
1-silyl-1-octyne (3) with the above titanium complex 1 generates
the acetylene-titanium complex (4),12 which was allowed to
react with a terminal acetylene, 4-(benzyloxy)-1-butyne (5), as
the second component as shown in eq 2. The intermediate
titanacyclopentadiene (6) was hydrolyzed, or intercepted with
D+ or I2, to give the diene 7 or 8, or its bis-deuterated (9) or
bis-iodinated counterpart (10) in good yields. If an excess
amount of 5 is used, the yield of 8 (based on 3) decreases. The
carbon-carbon bond formation occurred exclusively at the
carbon â to the silyl group of 3 and at the terminal carbon of
5. Other regio- and stereoisomers were not identified. In
addition, under these reaction conditions, the amount of homo-
coupling products resulting from 3 or 5 was kept to less than a
trace amount. The present cross-coupling method between
internal and terminal acetylenes appears to be operationally
simple as compared to other methods using a group 4 metal
complex.13
a See eq 2 and Experimental Section. b Isolated yields. c Yield
1
determined by H NMR is shown, because the separation of diene 36
from 53 was unsuccessful at our hands.
Chart 2
The preparation of other conjugated dienes according to eq
2 is shown in Table 1. An acetal moiety at the propargylic
position of internal acetylene 11 does not hamper the reaction
(entry 6). A few functional groups in the side chain of terminal
acetylenes 19, 20, and 23, which include carbonic and carboxylic
esters or silyl ether at a remote position from the reacting center,
can tolerate the reaction to give the corresponding dienes 29,
30, and 35 (entries 2, 3, and 6). The silylated propargyl alcohol
derivatives 21 and 22 similarly participated in the reaction
(entries 4-5), but these substrates led to the formation of a
mixture of regioisomers 31 + 32 or 33 + 34.
above. The results are summarized in entries 7-19 in Table 1.
It should be emphasized that the successful preparation of
functionalized dienes 36-50 is, at the outset, dependent on the
clean generation of a functionalized alkyne-titanium complex
from acetylenes 12-18. For representative cases, the presence
of the complexes 51 and 52 (Chart 2), which have not yet been
reported elsewhere, has been separately verified by the isolation
of (Z)-olefins 53 and 54 upon hydrolytic workup (77 and 89%
yields, respectively) and by the exclusive deuterium uptake after
deuteriolysis (Chart 2). The coupling reaction of internal
acetylenes 12-18 with terminal acetylenes 24-28 proceeded
again in a highly regio- and stereoselective manner. The new
carbon-carbon bond formation took place selectively at the
carbon â to the ester group in the case of (nonsilylated)
2-alkynoate 12 (entries 7-8), but the silylpropiolates 13-16
reversed this preference (entries 9-15) where the reaction took
place exclusively at the â position to the silyl group consistent
with the observation for other silylalkynes 3 and 11 shown in
entries 1-6. The intermediate titanacycle such as 55 in Chart 2
(to give 39 upon hydrolysis) has been confirmed by deuteration
to give bis-deuterated 56 (in place of 39). These functionalized
titanacycles would be useful intermediates for further carbon-
carbon bond formation and functionalization,9 which will be
More importantly, we were pleased to find that the present
method is nicely applicable to the cross-coupling reaction of
functionalized acetylenes such as 2-alkynoates and 2-alkyn-
amides, which is otherwise difficult to achieve as described
(9) For intramolecular coupling of (nonfunctionalized) diynes with 1,
see: Urabe, H.; Hata, T.; Sato, F. Tetrahedron Lett. 1995, 36, 4261. Urabe,
H.; Sato, F. J. Org. Chem. 1996, 61, 6756. Urabe, H.; Sato, F. J. Am. Chem.
Soc. 1999, 121, 1245.
(10) For homo-coupling of (nonfunctionalized) acetylenes with 1, see:
Yamaguchi, S.; Jin, R.-Z.; Tamao, K.; Sato, F. J. Org. Chem. 1998, 63,
10060. Launay, V.; Beaudet, I.; Quintard, J.-P. Synlett 1997, 821.
(11) For intramolecular cyclization of functionalized enynes with 1,
see: Suzuki, K.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 1996, 118, 8729.
Urabe, H.; Suzuki, K.; Sato, F. J. Am. Chem. Soc. 1997, 119, 10014.
(12) Harada, K.; Urabe, H.; Sato, F. Tetrahedron Lett. 1995, 36, 3203.
Takayanagi, Y.; Yamashita, K.; Yoshida, Y.; Sato, F. Chem. Commun. 1996,
1725.
(13) The cross-coupling of terminal and internal acetylenes with the
zirconocene-based reagent requires the hydrozirconation of the former (with
Schwartz’s reagent, Cp2ZrCl(H)) prior to the coupling reaction (refs 6a and
b). More recently, a terminal acetylene such as PhCtCH was reported to
give cross-coupling products with internal acetylenes via the ligand exchange
reaction of zirconacyclopentene (ref 6e).

7344 J. Am. Chem. Soc., Vol. 121, No. 32, 1999
Hamada et al.
reported in due course. The 2-alkynamide 17 showed the same
tendency as the corresponding ester 12 (entries 16-17), but the
silylpropynamide 18 afforded a mixture of regioisomers with a
varying ratio dependent on the coupling partners (entries 18-
19). This phenomenon could show that the amide group is a
more potent regiocontrolling element than the aforementioned
ester group and is parallel to or exceeds the effect of the silyl
group. Another interesting point is that a terminal acetylene 28
carrying an olefinic bond at the other terminus did not
complicate the reaction (i.e., via the coupling reaction at its
olefinic position or its own cyclization) as shown in eq 3 and
in entry 13, Table 1. Thus, the preparation of substrates ready
for an intramolecular Diels-Alder reaction like 42 is also
encouraged by this method.
locene-mediated reactions, the metal portion used herein goes
to an aqueous solution upon workup, thus avoiding contamina-
tion of the organic products) are advantageous features of the
present method. A study on the asymmetric Diels-Alder
reaction taking advantage of the optically active dienes prepared
herein14 is now in progress.
Experimental Section
General. See Supporting Information.
Representative Procedure for the Preparation of Functionalized
Dienes. (1RS,2SR)-2-Phenyl-1-cyclohexyl (3E)-2-[(Z)-(Trimethylsi-
lyl)methylene]-3-decenoate (39). To a stirred solution of (1RS,2SR)-
2-phenyl-1-cyclohexyl 3-(trimethylsilyl)propiolate (14) (500 mg, 1.66
mmol) and Ti(O-i-Pr)4 (0.614 mL, 2.08 mmol) in 25 mL of Et2O was
added a 1.43 M solution of i-PrMgCl in ether (2.91 mL, 4.16 mmol)
at -78 °C under argon to give a yellow homogeneous solution. The
solution was warmed to -50 °C over 30 min, during which period its
color turned red. After the solution was stirred at -50 °C for an
additional 5 h, 1-octyne (24) (0.196 mL, 1.33 mmol) was introduced
to the reaction mixture at -50 °C, and the solution was stirred at -50
°C for 3 h. The reaction was terminated by the addition of 1 N HCl,
and the organic products were extracted with ether. The combined
organic layers were washed with an aqueous solution of NaHCO3, dried
over Na2SO4, and concentrated in vacuo to give a crude oil, which
was chromatographed on silica gel (hexanes-ether) to afford the title
compound (429 mg, 78%). Even after careful 1H NMR analysis, other
isomers of this compound could not be identified.1H NMR (300 MHz,
CDCl3) δ 0.04 (s, 9 H), 0.88 (t, J ) 7.1 Hz, 3 H), 1.16-1.44 (m, 8 H),
1.44-1.62 (m, 4 H), 1.72-2.00 (m, 5 H), 2.28 (symmetric m, 1 H),
2.76 (d/t, J ) 4.5, 10.8 Hz, 1 H), 5.09 (d/t, J ) 15.6, 6.9 Hz, 1 H),
5.18 (d/t, J ) 4.5, 10.8 Hz, 1 H), 5.76 (d, J ) 15.6 Hz, 1 H), 5.84 (s,
1 H), 7.13-7.32 (m, 5 H). Irradiation of the proton at δ 0.04 ppm
(Me3Si) showed 6% nOe enhancement to the peak at δ 5.84 ppm (Me3-
SiCHdC). Irradiation of the proton at δ 5.84 ppm (Me3SiCHdC)
showed 5% nOe enhancement to the peak at δ 5.09 ppm (CHdCHCH2).
Thus, the regiochemistry as well as the olefinic stereochemistry has
been fully confirmed. 13C NMR (75 MHz, CDCl3) δ -0.70, 14.00,
22.51, 24.71, 25.68, 28.65, 28.85, 31.63, 32.34, 32.87, 34.56, 49.69,
76.87, 126.58, 127.68, 128.52, 129.41, 134.26, 136.89, 143.40, 146.80,
168.23; IR (neat) 3075, 3035, 2930, 2860, 1720 (CdO), 1465, 1450,
1250, 1205, 1140, 1120, 1015, 960, 860, 845, 755, 700 cm-1. Anal.
Calcd for C26H40O2Si: C, 75.67; H, 9.77. Found: C, 75.38; H, 10.15.
Conclusion
Preparation of certain kinds of functionalized dienes is readily
achieved by the low-valent titanium alkoxide-mediated cross-
coupling of alkynes. The functionalized titanacyclopentadienes
as well as the intermediate alkyne-titanium complexes would
be also a useful species for further synthetic transformation. In
practice, the use of very inexpensive reagents such as Ti(O-i-
Pr)4 and a Grignard reagent, the simple operation, and the easy
isolation of the products (in contrast to other group 4 metal-
(14) To the best of our knowledge, the utility of 1,3-dienes like 39-44
having an optically active ester at its 2-position has not been examined in
asymmetric Diels-Alder reaction, see: Whitesell, J. K. Chem. ReV. 1992,
92, 953. Waldmann, H. Synthesis 1994, 535. Jones, G. B.; Chapman, B. J.
Synthesis 1995, 475. Seyden-Penne, J. Chiral Auxiliaries and Ligands in
Asymmetric Synthesis; Wiley: New York, 1995; p 513. As a preliminary
result, we found that the following Diels-Alder reaction of 44 proceeds in
a highly diastereoselective manner.
Acknowledgment. We thank the Ministry of Education,
Science, Sports and Culture (Japan) for financial support.
Supporting Information Available: Procedures for the
preparation of key starting materials 14-16 and dienes 8, 35,
and 44, and characterization data for the starting materials and
products (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
JA9905694