A novel titanium tetrahalide-mediated carbon-carbon bond-forming reaction: Regioselective synthesis of substituted (E,Z)-1,5-dihalo-1,4-dienes

Article abstract of DOI:10.1021/ol026507r

(matrix presented) Reactions of aldehydes with 2 equiv of alkyne in the presence of TiX₄ (X = Cl, Br) regioselectively generated 1,5-dihalo-1,4-dienes in moderate to good yields with high (E,Z)-stereoselectivity.

Full text of DOI:10.1021/ol026507r

ORGANIC
LETTERS
2002
Vol. 4, No. 20
3415-3417
A Novel Titanium Tetrahalide-Mediated
Carbon−Carbon Bond-Forming
Reaction: Regioselective Synthesis of
Substituted (E,Z)-1,5-Dihalo-1,4-dienes
George W. Kabalka,* Zhongzhi Wu, and Yuhong Ju
Departments of Chemistry and Radiology, The UniVersity of Tennessee,
KnoxVille, Tennessee 37996-1600
kabalka@utk.edu
Received July 12, 2002
ABSTRACT
Reactions of aldehydes with 2 equiv of alkyne in the presence of TiX (X ) Cl, Br) regioselectively generated 1,5-dihalo-1,4-dienes in moderate
4
to good yields with high (E,Z)-stereoselectivity.
Titanium(IV) halides are very versatile reagents in organic
synthesis.1 TiCl4 is widely used in many carbon-carbon
bond-forming reactions, including the coupling of carbonyl
and aldimine compounds,2 aldol condensations,3 alkynyla-
tions of carbonyl compounds,4 and ene reactions.5 Other
syntheses involve the additions of allylsilane,6 allyltin,7
propargylsilane,8 and 2,4-pentadienylsilane9 reagents to al-
dehydes, ketones, R-keto esters, and ketals. Titanium(IV)
chloride is also used in the carbocyclization of active methane
compounds with alkyne groups,10 Claisen rearrangements,11
as well as Baylis-Hillman12 and Friedel-Crafts reactions.13
In addition, numerous organic functional group transforma-
tions have been achieved using TiCl4. Examples include
conversion of propargylic alcohols to R,â-acetylenic alde-
hydes,14 alkyl azides and ketones to amides,15 R-nitro ketones
(8) (a) Pornet, J.; Miginiac, L.; Jaworski, K.; Randrianoelina, B.
Organometallics 1985, 4, 333. (b) Pornet, J.; Randrianoelina, B.; Miginiac,
L. Tetrahedron Lett. 1984, 25, 651. (c) Pornet, J.; Mesnard, D.; Miniac, L.
Tetrahedron Lett. 1982, 23, 4083. (d) Pornet, J.; Kolani, N. Tetrahedron
Lett. 1981, 22, 3609. (e) Pornet, J.; Randrianoelina, B. Tetrahedron Lett.
1981, 22, 1327. (f) Pornet, J. Tetrahedron Lett. 1981, 22, 453.
(9) (a) Seyferth, D.; Pornet, J. J. Org. Chem. 1980, 45, 1721. (b) Pornet,
J. Tetrahedron Lett. 1980, 21, 2049. (c) Seyferth, D.; Pornet, J.; Weinstein,
R. M. Organometallics 1982, 1, 1651.
(10) Kitagawa, O.; Suzuki, T.; Inoue, T.; Watanabe, Y.; Taguchi, T. J.
Org. Chem. 1998, 63, 9470.
(11) Yoon, T. P.; Dong, V. M.; MacMillan, D. W. C. J. Am. Chem. Soc.
1999, 121, 9726.
(12) (a) Shi, M.; Feng, Y. S. J. Org. Chem. 2001, 66, 406. (b) Shi, M.;
Jiang, J. K.; Cui, S. C.; Feng, Y. S. J. Chem. Soc., Perkin Trans. 1 2001,
390. (c) Shi, M.; Jiang, J. K.; Feng, Y. S. Org. Lett. 2000, 2, 2397. (d)
Kataoka, T.; Kinoshita, H.; Kinoshita, S.; Iwamura, T.; Watanabe, S. Angew.
Chem., Int. Ed. Engl. 2000, 39, 2358. (e) Wei, H.-X.; Kim, S. H.; Caputo,
T. D.; Purkiss, D. W.; Li, G. Tetrahedron 2000, 56, 2397. (f) Li, G.; Wei,
H.; Gao, J.; Caputo, D. Tetrahedron Lett. 2000, 41, 1.
* To whom correspondence should be addressed.
(1) Reetz, M. T. Organotitanium Reagents in Organic Synthesis;
Springer: Berlin, 1986.
(2) (a) Tsuritani, T.; Ito, S.; Shinokubo, H.; Oshima, K. J. Org. Chem.
2000, 65, 5066. (b) Periasamy, M.; Srinivas, G.; Karunaker, G. V.; Bharathi,
P. Tetrahedron Lett. 1999, 40, 7577. (c) Lalic, G.; Petrovski, Z.; Galonic,
D.; Matovic, R.; Saicic, R. N. Tetrahedron 2001, 57, 583. (d) Li, T.; Cui,
W.; Liu, J.; Zhao, J.; Wang, Z. Chem. Commun. 2000, 139.
(3) (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc.
1997, 119, 7883. (b) Han, Z.; Uehiya, S.; Tsuritani, T.; Shinokubo, H.;
Oshima, K. Tetrahedron 2001, 57, 987. (c) Crimmins, M. T.; Chaudhary,
K. Org. Lett. 2000, 2, 775. (d) Harrison, C. R. Tetrahedron Lett. 1987, 28,
4135. (e) Aldrian, J. C. Jr.; Barkin, J. L.; Fox, R. J.; Chick, J. E.; Hunter,
A. D.; Nicklow, R. A. J. Org. Chem. 2000, 65, 6264.
(4) Yamamoto, Y.; Nishi, S.; Maruyama, K. Chem. Commun. 1986, 102.
(5) (a) Vidari, G.; Bonicelli, M. P.; Anastasia, L.; Zanoni, G. Tetrahedron
Lett. 2000, 41, 3471. (b) Miura, K.; Takasami, M.; Hondo, T.; Saito, H.;
Hosomi, A. Tetrahedron Lett. 1997, 38, 4587.
(6) Sakurai, H. Pure Appl. Chem. 1982, 54, 1.
(7) (a) Basavaiah, D.; Sreenivasulu, B. Tetrahedron Lett. 2002, 43, 2987.
(b) Haruta, J.; Nishi, K.; Matsuda, S.; Tamura, Y.; Kita, Y. Chem. Commun.
1989, 1065. (c) Boaretta, A.; Marton, D.; Tagliavini, G.; Ganis, P. J.
Organomet. Chem. 1987, 321, 199.
(13) (a) Ishibashi, H.; Mino, M.; Sakata, M.; Inada, A.; Ikeda, M. Chem.
Pharm. Bull. 1991, 39, 1148. (b) Liguori, L.; Bjorsvik, H. R.; Fontana, F.;
Bosco, D.; Galimberti, L.; Minisci, F. J. Org. Chem. 1999, 64, 8812.
(14) Han, Z.; Shinokubo, H.; Oshima, K. Synlett 2001, 1421.
10.1021/ol026507r CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/31/2002

to anti-â-nitro alcohols,16 ketamines to pyrroles,17 carbonyl
compounds to acetals,18 acetals and ketals to carbonyl
compounds,19 ethers to alcohols,20 and enamines to anilines.21
TiCl4 and TiBr4 are reported to react with alkynes to
produce (E)-2-halo-1-alkenes after hydrolysis.22 However,
the vinyl-titanium intermediates have not been utilized in
carbon-carbon bond-forming reactions other than the reac-
tion of 3,3,3-trifluoro-1-propynylamines with carbonyl com-
pounds to generate the corresponding R-(trifluoromethyl)-
R,â-unsaturated amides23 and addition of alkynes to
expoxides.24 We felt that titanium(IV) might be useful for
reactions involving the addition of alkynes to carbonyl
compounds to generate new carbon-carbon bonds, a reaction
we previously reported for borane reagents.25 We investigated
the reaction of aldehydes with alkynes in the presence of
titanium(IV) halides and discovered that (E,Z)-1,5-dihalo-
1,4-dienes were generated (Scheme 1). These dihalodiene
Table 1. Synthesis of (E,Z)-1,5-Dihalo-1,4-dienes via
Reactions of Aldehydes with Alkynes in the Presence of TiX4
(X ) Cl, Br)
R
R′
X
time (h)
% yielda,b
Ph
p-Cl-Ph
o-F-Ph
Ph
Ph
Ph
Ph
Ph
p-F-Ph
p-Me-Ph
Ph
n-butyl
p-F-Ph
Ph
Ph
Ph
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
10
16
24
24
8
20
14
20
24
26
24
14
8
56 (3a )
55 (3b)
54 (3c)
50 (3d )
56 (3e)
52 (3f)
45 (3g)
51 (3h )
68 (3i)
63 (3j)
40 (3k )
45 (3l)
40 (3m )
44 (3n )
52 (3o)
50 (3p )c
59 (3q)c
p-NC-Ph
p-Me-Ph
p-Cl-Ph
p-Cl-Ph
n-hexyl
n-hexyl
n-hexyl
p-F-Ph
p-Cl-Ph
p-Me-Ph
p-Cl-Ph
p-Me-Ph
n-hexyl
n-hexyl
p-Me-Ph
p-Cl-Ph
p-Me-Ph
Ph
12
14
12
10
Scheme 1
a Isolated yields. b All products were characterized by elemental analyses
and NMR spectroscopy. c (Z,E):(Z,Z) ratio ) 1:1.
responding 1,5-dihalodiene derivatives in moderate to good
yields (Table 1). All compounds were characterized by
compounds are potentially useful intermediates in organic
synthesis due to the number of functional groups present in
the molecules, which can subsequently be transformed
through coupling, substitution, and cyclization reactions.26
In this paper, we report the preliminary results of our study.
The reaction was first carried out by introducing 1 equiv
of TiCl4 to a mixture of phenylacetylene and 4-chlorobenz-
aldehyde (1:1 ratio) in CH2Cl2. (E,Z)-1,5-Dichloro-3-(4-
chlorophenyl)-1,5-diphenyl-1,4-pentadiene was formed in
modest yield. When 2 equiv of phenylacetylene and 1 equiv
of 4-chlorobenzaldehyde were allowed to react with 1 equiv
of TiCl4, (E,Z)-1,5-dichloro-3-(4-chlorophenyl)-1,5-diphenyl-
1,4-pentadiene was formed along with a trace amount of the
(Z,Z)-isomer. Reactions carried out using TiBr4 also gener-
ated the corresponding (E,Z)-1,5-dibromodiene compounds.
A series of aldehydes and alkynes were subjected to the
new reaction. All reactions successfully produced the cor-
elemental analyses and NMR spectroscopy. The 1H and 13
C
NMR spectra of the products indicate that they are (E,Z)-
dienes except for compounds 3p and 3q. A single crystal of
compound 3b was analyzed by X-ray crystallography.27 The
X-ray data for 3b confirmed the NMR assignment. As can
be seen from the data contained in Table 1, the reactions of
substrates bearing electron-withdrawing groups tend to
proceed more slowly. The low yields of bromo products,
when compared to the chloro analogues, may be due to the
low solubility of TiBr4. Solvents such as diethyl ether,
tetrahydrofuran, methylene chloride, hexane, and toluene
were also examined. Methylene chloride produced the highest
yields. Reactions in diethyl ether and THF gave poor yields
with low stereoselectivity. A series of internal alkynes were
also examined. However, only monoaddition of the alkyne
to the aldehyde occurred, producing the allylic alcohol
product. In addition, ketones did not give desired products.
SnCl4, AlCl3, and FeCl3 were also examined, but none
produced the desired dienes.
(15) Desai, P.; Schildknegt, K.; Agries, K. A.; Mossman, C.; Milligan,
G. L.; Aube, J. J. Am. Chem. Soc. 2000, 122, 7226.
(16) Ballini, R.; Bosica, G.; Marcantoni, E.; Vita, P. J. Org. Chem. 2000,
65, 5854.
(17) Periasamy, M.; Srinivas, G.; Bharathi, P. J. Org. Chem. 1999, 64,
4204.
(18) Clerici, A.; Pastori, N.; Porta, O. Tetrahedron 2001, 57, 217.
(19) Balme, G.; Gore, J. J. Org. Chem. 1983, 48, 336.
(20) Tsuritani, T.; Shinikubo, H.; Oshima, K. Tetrahedron Lett. 1999,
40, 8121.
(21) Srinivas, G.; Periasamy, M. Tetrahedron Lett. 2002, 43, 2785.
(22) Lemarchand, D.; M’Baye, N.; Braun, J. J. Organomet. Chem. 1972,
39, C69.
Reactions were monitored by NMR spectroscopy. In one
experiment, TiCl4 and 2 equiv of phenylacetylene were
dissolved in CDCl3 in a NMR tube. The reaction solution
1
immediately turned dark. However, the H and 13C NMR
spectra of the reaction mixture revealed only resonances
corresponding to the alkyne moiety at 3.04 ppm (1H) as well
as 83.7 and 77.2 ppm (13C). The NMR data revealed that no
vinyl intermediate formed even after a week at room
temperature. However, the hydrolysis of the reaction mixture
resulted in formation of R-chlorostyrene. In a separate
(23) Mantani, T.; Shiomi, K.; Konno, T.; Ishihara, T.; Yamanaka, H. J.
Org. Chem. 2001, 66, 3442.
(24) Marson, C. M.; Khan, A.; McGregor, J.; Grinter, T. Tetrahedron
Lett. 1995, 36, 7145.
(25) Kabalka, G. W.; Wu, Z.; Ju, Y. Org. Lett. 2002, 4, 1491.
(26) (a) Suzuki, A. Pure Appl. Chem. 1986, 58, 829. (b) Suzuki, A. ReV.
Heteroat. Chem. 1997, 17, 271.
(27) For details of the X-ray crystal structure and data for 3b, see
Supporting Information.
3416
Org. Lett., Vol. 4, No. 20, 2002

intermediate 4, which could then react with a second
molecule of alkyne to generate 5, followed by migration of
vinyl group to afford final product 3. Alternatively, inter-
mediate 4 might generate an allylic cation that could add to
alkyne 2 in an anti fashion to form 3. In a control experiment,
TiCl4 was added to a mixture of 4-chlorobenzaldehyde and
phenylacetylene (1:1 ratio), and (Z)-3-chloro-3-phenyl-1-(4-
chlorophenyl)propenol was isolated upon hydrolysis. This
result suggests the presence of intermediate 4 in the reaction.
In conclusion, we have developed a novel carbon-carbon
bond-forming reaction involving titanium(IV) tetrahalides.
The reaction is applicable to both aromatic and aliphatic
substrates and produces (E,Z)-1,5-dihalo-1,4-dienes. Efforts
to elucidate the reaction mechanism and to utilize titanium
halides to synthesize a variety of monohalogenated and
nonhalogenated 1,4-dienes are currently underway.
Scheme 2
experiment, 2 equiv of phenylacetylene were added to a
mixture of TiCl4 and 4-chlorobenzaldehyde in CDCl3.28 The
NMR spectra of the reaction mixture revealed the disap-
pearance of the aldehyde and displayed new resonances
corresponding to the (E,Z)-1,5-dichloro-3-(4-chlorophenyl)-
1,5-diphenyl-1,4-pentadiene. On the basis of these experi-
ments, we postulate the mechanism presented in Scheme 2.
The reaction presumably undergoes a concerted six-
membered ring transition state to form haloallyloxide
Acknowledgment. We thank the U.S. Department of
Energy and the Robert H. Cole Foundation for support of
this research.
Supporting Information Available: General experimen-
tal procedures and characterization data for all compounds
prepared and details of the X-ray diffraction data and
structure of compound 3b. This material is available free of
charge via the Internet at http://pubs.acs.org.
(28) For the structures of complexes of TiCl4 with carbonyl compounds,
see: Cozzi, P. G.; Solari, E.; Floriani, C.; Chiesi-Villa, A.: Rizzoli, C.
Chem. Ber. 1996, 129, 1361.
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