Titanium(IV) halide mediated coupling of alkoxides and alkynes: An efficient and stereoselective route to trisubstituted (E)-alkenyl halides

Article abstract of DOI:10.1021/ol900669t

Alkoxide C - 0 bond cleavage occurs readily at room temperature in the presence of titanium(IV) halide. Capture of the resultant carbocation by alkynes provides an efficient route to trisubstituted (E)-alkenyl halides with high stereoselectivity.

Full text of DOI:10.1021/ol900669t

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2647-2649
Titanium(IV) Halide Mediated Coupling
of Alkoxides and Alkynes: An Efficient
and Stereoselective Route to
Trisubstituted (E)-Alkenyl Halides
Min-Liang Yao, Travis R. Quick, Zhongzhi Wu, Michael P. Quinn, and George
W. Kabalka*
Departments of Chemistry and Radiology, The UniVersity of Tennessee,
KnoxVille, Tennessee 37996-1600
kabalka@utk.edu
Received March 31, 2009
ABSTRACT
Alkoxide C-O bond cleavage occurs readily at room temperature in the presence of titanium(IV) halide. Capture of the resultant carbocation
by alkynes provides an efficient route to trisubstituted (E)-alkenyl halides with high stereoselectivity.
In 2005, we reported the first transition-metal-free nucleophilic
substitution of hydroxyl groups, through the corresponding
Scheme 1
.
Swift Stereochemistry via Changing Reactant Adding
Sequence
alkoxides, by stereodefined haloalkenyl moieties (Scheme 1).1,2
The reaction involves the unprecedented C-O bond cleavage
of an alkoxide in the presence of halovinylboron dihalide
and provides a practical route to trisubstituted (Z)-alkenyl
halides. The reaction proceeds quite well with alkoxides
generated in situ from reactions of aldehydes and alkyllithium
reagents which further adds versatility to the method.1b,3
During ongoing mechanistic studies of the aldehyde-alkyne
coupling reaction,4 we discovered that changing the mode of
reagent addition greatly affects the stereochemistry of the
product formed. Thus, coupling alkoxides with terminal alkynes
in the presence of boron trihalide yields trisubstituted (E)-alkenyl
halides as the major products with moderate stereoselectivities5
(Scheme 1). In these cases, we believe that carbocations are
generated from alkoxides in the presence of boron trihalide and
subsequently captured by the terminal alkynes.
(1) (a) Kabalka, G. W.; Yao, M.-L.; Borella, S.; Wu, Z.-Z. Chem.
Commun. 2005, 2865. (b) Kabalka, G. W.; Yao, M.-L.; Borella, S.; Wu,
Z.-Z. Org. Lett. 2005, 7, 2865
.
(2) Recent reports related to transition-metal-free nucleophilic substitu-
tion of hydroxyl groups with alkenyl moieties. See: (a) Morgan, I. R.; Yazici,
A.; Pyne, S. G. Tetrahedron 2008, 64, 1409. (c) Nishimoto, Y.; Kajioka,
Our recent study of boron tribromide-mediated aryl propargyl
ether cleavage6 suggests that the addition of boron trihalide to
terminal alkynes is a very fast process. Methoxy groups (known
to react with BBr3) were found to survive the reaction conditions
M.; Saito, T.; Yasuda, M.; Baba, A. Chem. Commun. 2008, 6396
.
(3) Kabalka, G. W.; Yao, M.-L.; Borella, S. Org. Lett. 2006, 8, 879
.
(4) Kabalka, G. W.; Yao, M.-L.; Borella, S.; Wu, Z.-Z.; Ju, Y.-H.; Quick,
T. J. Org. Chem. 2008, 73, 2663.
10.1021/ol900669t CCC: $40.75
Published on Web 05/15/2009
 2009 American Chemical Society

because of the high reactivity of BBr3 toward the terminal alkynes.
This observation led us to propose that the moderate stereoselec-
tivity for the reaction shown in Sequence 2 (Scheme 1) resulted
from a competitive reaction involving the facile formation of (Z)-
vinylboron dihalide (giving the Z-isomer after coupling with the
alkoxide). To minimize this undesired competitive reaction, we
felt that replacement of boron trihalide with Lewis acids that do
not undergo facile addition to alkynes might enhance the stereo-
selectivity of the overall coupling reaction. Previous studies from
our group,7 as well as other groups,8 have demonstrated that C-O
bond cleavage in alkoxide-type RC-OMXn (M ) Ti, Fe)
intermediates can occur smoothly at room temperature. In 2008,
Fuchter and Levy reported a one-pot method for the conversion
of carbonyl electrophiles to allylic chlorides by activating the in
to screen other metal halides. Fortunately, the desired reaction
occurred smoothly at room temperature using TiCl4; product
1a was isolated in 78% yield and with excellent stereose-
lectivity (E/Z ) 96:4).13 ZnCl2 and NiCl2 proved to be
ineffective. The product’s E stereochemistry was confirmed
by X-ray analysis of compound 1d.14
To evaluate the scope and limitations of the reaction, a
variety of benzylic, allylic, and propargylic alcohols were
prepared and subjected to the new reaction conditions (Table
1). Several examples illustrate that ether moieties, double
Table 1. Titanium(IV) Chloride Mediated Coupling of
Alkoxides with Alkynesa
9
situ generated magnesium alkoxides using TiCl4. Related work
by Murai and co-workers documented successful C-S bond
cleavage.10 Herein we report our preliminary results focused on
the stereoselective synthesis of trisubstituted (E)-alkenyl halides.
The reaction of lithium diphenylmethanoxide with phe-
nylacetylene was chosen as the model system (Scheme 2).
Scheme 2. Lewis Acid Induced Coupling Reaction
Due to its low cost, FeCl3 was initially used to test the
feasibility of the coupling reaction.
Several solvents were surveyed but the poor solubility of
FeCl3 led to modest yield even after 24 h at room temper-
ature. Elevating the reaction temperature did increase the
yield but led to decreased stereoselectivity. These results are
consistent with a recent publication concerning the FeCl3
mediated coupling of benzyl alcohols and aryl alkynes in
refluxing CH2Cl2 which reports the formation of trisubstituted
(E)-alkenyl halides as the major products but with only
moderate stereoselectivities (E/Z ) ∼8:1).11 Notably, in 2008
Jana et al. reported that the FeCl3 mediated reaction in
nitromethane at 80 °C gives aryl ketones, rather than
trisubstituted (E)-alkenyl halides.12 Due to the poor solubility
of FeCl3 in organic solvents at room temperature, we decided
a Reaction was carried out at 0 °C for 10 min, then maintained at room
temperature (see experimental section for details). b E:Z ratio determined
by NMR. c Isolated yield based on alcohol. d E:Z stereoselectivity and yield
using BCl3 instead of TiCl4.
bonds, and triple bonds all tolerate the reaction conditions.
The E products are produced in excellent stereochemical
yields.15 Even lithium di(4-fluorobenzyl)methanoxide gives
excellent stereoselectivity (entry 5) using TiCl4. In our
previous work, this reaction afforded very poor stereoselec-
tivity (E/Z ) 60:40) when BCl3 was used.5 Successful
coupling using an aliphatic alkyne is notable, though the
stereoselectivity is rather poor (E/Z ) 70:30, entry 7). In
recent reports,11,12 it was noted that the FeCl3 mediated
coupling reaction of benzylic alcohols with alkynes is only
successful for aryl alkynes. The lower stereoselectivity
(E/Z) for aliphatic alkynes is most likely due to the lack of
steric bulk of the n-butyl group.
(5) Kabalka, G. W.; Yao, M.-L.; Borella, S. J. Am. Chem. Soc. 2006,
128, 11320.
(6) Yao, M.-L.; Reddy, M. S.; Zeng, W.-b.; Hall, K.; Walfish, I.;
Kabalka, G. W. J. Org. Chem. 2009, 74, 1385.
(7) (a) Kabalka, G. W.; Yao, M.-L.; Borella, S.; Goins, L. K. Organo-
metallics 2007, 26, 4112. (b) Kabalka, G. W.; Ju, Y.; Wu, Z. J. Org. Chem.
2003, 68, 7915. (c) Kabalka, G. W.; Wu, Z.; Ju, Y. Org. Lett. 2002, 4,
3415.
(8) (a) Karunakar, G. V.; Periasamy, M. J. Org. Chem. 2006, 71, 7463.
(b) Falck, J. R.; Bejot, R.; Barma, D. K.; Bandyopadhyay, A.; Joseph, S.;
Mioskowski, C. J. Org. Chem. 2006, 71, 8178. (c) Miranda, P. O.; Diaz,
D. D.; Padron, J. I.; Ramirez, M. A.; Martin, V. S. J. Org. Chem. 2005, 70,
57.
(9) Fuchter, M. J.; Levy, J.-N. Org. Lett. 2008, 10, 4919.
(10) (a) Murai, T.; Asai, F. J. Org. Chem. 2008, 73 (2), 9518. (b) Murai,
T.; Asai, F. J. Am. Chem. Soc. 2007, 129, 780.
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Org. Lett., Vol. 11, No. 12, 2009

Because of the synthetic potential of alkenyl bromides in
transition metal catalyzed coupling reactions, we examined
the use of TiBr4 (Table 2). Again, the reaction proceeds
3). The reaction of the lithium alkoxide with TiX4 first forms
intermediate 3 [R1R2CHO-TiCl3]. Carbocation 4 is then
generated from either intermediate [R1R2CHO-TiCl3] or an
oxonium ion intermediate [R1R2CHO-(TiCl4)TiCl3].16 At
present, there is insufficient data available to distinguish
between these two pathways. Capture of carbocation 4 by
the alkyne affords final product 1 or 2. The carbocation nature
of the reaction is supported by compounds 1 and 2 possessing
the same stereochemistry with compounds that were obtained
in a previously reported reaction of benzylic carbocations
with alkynes.17
Table 2. Titanium(IV) Bromide Mediated Coupling of
Alkoxides with Alkynesa
Scheme 3. Proposed Reaction Mechanism
In summary, a method for preparing trisubstituted (E)-
alkenyl halide derivatives with high stereoselectivity is
described. Both trisubstituted (E)-alkenyl halide and (Z)-
alkenyl halide derivatives can now be prepared from readily
available alkoxides and acetylenes. The feasibility of gen-
erating carbocations from alkoxides under Brønsted acid-
free reaction conditions was further confirmed. Application
of this new synthetic method is currently underway.
a Reaction was carried out at 0 °C for 10 min, then maintained at room
temperature (see experimental for details). b E:Z ratio determined by NMR.
c Isolated yield based on alcohol used. d Lithium alkoxide was generated
in situ from the reaction of benzaldehyde and lithium acetylide.
readily at room temperature and good yields are obtained.
We then examined the reactions of in situ generated lithium
propargyloxides (from aryl aldehydes and lithium acetylide)
with phenylacetylene (entries 4 and 5). High stereoselectivity
and good yields were obtained in both cases.
Acknowledgment. Acknowledgement is made to the
Donors of the American Chemical Society Petroleum
Research Fund for partial support of this research. We also
wish to thank the U.S. Department of Energy, and the Robert
H. Cole Foundation.
In view of the previously reported results4,5 along with the
dark purple color of reaction mixture, we postulate that the
reactions proceed through a carbocation mechanism (Scheme
1
Supporting Information Available: H and 13C NMR
(11) During the preparation of this manuscript, the FeCl3 mediated
coupling reaction of alcohols with alkynes in refluxing CH2Cl2 was reported.
The low stereoselectivity, we believe, is due to the enhanced reaction
temperature. Liu, Z.-Q.; Wang, J.; Han, J.; Zhou, B. Tetrahedron Lett. 2009,
50, 1240.
data for all new compounds reported, X-ray data for
compound 1d. This material is available free of charge via
the Internet at http://pubs.acs.org.
(12) Jana, U.; Biswas, S.; Maiti, S. Eur. J. Org. Chem. 2008, 5798.
(13) Typical reaction procedure: Diphenylmethanol (276 mg, 1.5 mmol)
and dichloromethane (15 mL) were placed in a dry, argon-flushed, 100 mL
round-bottomed flask equipped with a magnetic stirring bar. The solution
was cooled to 0 °C in an ice bath and n-butyllithium (1.6 mmol, 1.6 mL of
a 1.0 M hexanes solution) was added via syringe. The solution was allowed
to stir for 10 minutes at 0 °C and then for 30 minutes at room temperature.
Phenylacetylene (0.16 mL, 1.5 mmol) was added via syringe, followed by
titanium(IV) chloride (1.65 mmol, 1.65 mL of a 1.0 M dichloromethane
solution). The reaction solution gradually turned dark purple and was
allowed to react overnight. The resulting mixture was hydrolyzed with water
(15 mL) and extracted into dichloromethane (3 × 15 mL). The organic
layer was separated and dried over anhydrous MgSO4. Product 1a (356
mg, E/Z ) 96:4, 78% yield) was isolated by flash column chromatography,
using hexanes as eluent.
OL900669T
(15) The stereoselectivity can be readily determined using 1H NMR
since the resonances for vinyl protons and allylic protons in the E-isomer
and Z-isomer are quite different. Generally, the allylic proton in the E-isomer
appears near 4.80 ppm, whch is upfield compared to the corresponding
proton in the Z-isomer (generally found near 5.40 ppm).
(16) Forming carbocations from an oxonium ion intermediate [R1R2CHO-
(MCln)MCln-1], see: (a) Kabalka, G. W.; Yao, M.-L.; Borella, S.; Quick,
T. J. Chem. Soc.: Dalton Trans. 2008, 776. (b) Kim, S. H.; Shin, C.; Pae,
A. N.; Koh, H. Y.; Chang, M. H.; Chung, B. Y.; Cho, Y. S. Synthesis 2004,
1581. (c) Yokozawa, T.; Furuhashi, K.; Natsume, H. Tetrahedron Lett. 1995,
36, 5243. (d) Braun, M.; Kotter, W. Angew. Chem., Int. Ed. 2004, 45, 1514.
(17) Marcuzzi, F.; Melloni, G.; Modena, G. J. Org. Chem. 1979, 44,
3022.
(14) For details of the crystallographic data of compound 1d, see
Supporting Information.
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