TiCl4-n-Bu4NI as a reducing reagent: Pinacol coupling and enolate formation from α-haloketones

Full text of DOI:10.1021/jo0004254

5066
J . Org. Chem. 2000, 65, 5066-5068
Sch em e 1
TiCl4-n -Bu 4NI a s a Red u cin g Rea gen t:
P in a col Cou p lin g a n d En ola te F or m a tion
fr om r-Ha lok eton es
Takayuki Tsuritani, Saeko Ito, Hiroshi Shinokubo, and
Koichiro Oshima*
Department of Material Chemistry, Graduate School of
Engineering, Kyoto University, Kyoto 606-8501, J apan
oshima@fm1.kuic.kyoto-u.ac.jp
Received March 21, 2000
ethanediol (1) in good yield with high stereoselectivity
(dl/meso ) 93/7) (Scheme 1).10 In the absence of TBAI,
the reaction did not proceed. The use of tetrabutylam-
monium bromide in place of TBAI also gave no pinacol
product. Further investigation determined that optimal
conditions were 1.5 equivalents of TiCl4 and 2.2 equiva-
lents of TBAI per 1.0 mmol of benzaldehyde (vide infra).
The reaction temperature is crucial for the stereoselec-
tivity. When the reaction was performed at 0 °C, the
stereoselectivity of 1 decreased to 85/15. It was also
essential to add hexane to enhance stereoselectivity.11
Pinacol coupling reactions of various aromatic alde-
hydes under these conditions are summarized in Table
1. Several comments are worth noting. (1) Only aromatic
aldehydes were reactive under these conditions. Aliphatic
aldehydes provided none of the desired diol, and the main
product was an aldol condensation product. (2) Stereo-
selectivity of the product was generally high (>90/10)
except in the cases of 2-bromo- and 2-benzoxybenzalde-
hyde.12 In these cases, meso products were the major
isomers (entries 9 and 10). (3) The reaction conditions
are compatible with aldehydes containing the following
functional groups: halides, ethers, esters, nitriles, or
alcohols. (4) Methyltriphenylphosphonium iodide is as
effective as TBAI (entry 11).13 (5) MePh3PI or MeEt3NI,
which were prepared from Ph3P or Et3N with iodo-
methane in situ, gave similar results (entries 12 and 13).
The pinacol reaction of acetophenone was also inves-
tigated. The desired diol was obtained with extremely
high stereoselectivity, although in modest yield. (Scheme
2). Unfortunately, the reaction of propiophenone under
the same conditions was sluggish and the coupling
product was obtained in only 7% yield. No reaction was
observed in the case of naphthyl methyl ketone.
1
2
Low-valent metallic species such as TiCl3 and CrCl2
have a significant role as reducing reagents for organic
molecules and their applications in organic synthesis
have been extensively explored over the last three
decades. Specifically, TiCl3 is an extremely useful reagent
for pinacol reactions,3 McMurry couplings,4 and Nef
reactions.5 In many cases, Ti(III) species are obtained via
reduction of TiCl4 by another metal or metallic hydride
reagent such as Li, Mg, Zn, or LiAlH4.6 In these cases,
however, concomitant formation of metal salts is inevi-
table. Because of their Lewis acidity, these metal residues
sometimes cause undesirable side reactions, decrease of
selectivities, or decomposition of functionalities. Herein
we wish to report that TiCl4-n-Bu4NI (TBAI) mixed
reagent7 has the same reducing ability as low valent
titanium reagents. These results clearly show that
nonmetallic species such as ammonium iodide can reduce
Ti(IV) species.8
Treatment of TiCl4 with tetrabutylammonium iodide
(TBAI) in dichloromethane at 0 °C provided a dark-red
solution. After stirring for 10 min, benzaldehyde and
hexane were added successively at -78 °C. The resulting
biphasic mixture9 was allowed to warm to ambient
temperature during a period of 12 h. Aqueous workup
provided the pinacol coupling product 1,2-diphenyl-1,2-
(1) (a) McMurry, J . E. Chem. Rev. 1989, 89, 1513. (b) Gundersen,
L.-L. In Encyclopedia of Reagents for Organic Synthesis; Paquette, L.
A., Ed.; Wiley: New York, 1995; p 4911. (c) Pons, J .-M.; Santelli, M.
Tetrahedron 1988, 44, 4295.
(2) (a) Fu¨rstner, A. Chem. Rev. 1999, 99, 991. (b) Saccomano, N. A.
In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: New York, 1991; Vol. 1, Chapter 1.6, p 173. (c) Takai,
K. In Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A.,
Ed.; Wiley: New York, 1995; p 1266.
(3) (a) Grame, M. R. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 3,
Chapter 2.6, p 563. (b) Wirth, T. Angew. Chem., Int. Ed. Engl. 1996,
35. 61.
(4) (a) Lenoir, D. Synthesis 1989, 883. (b) Betschart, C. Seebach, D.
Chimia 1989, 43, 39. (c) Robertson, G. M. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York,
1991; Vol. 3, Chapter 2.7, p 583. (d) Fu¨rstner, A.; Hupperts, A. J . Am.
Chem. Soc. 1995, 117, 4468.
(5) (a) McMurry, J . Acc. Chem. Res. 1974, 7, 281. (b) McMurry, J .
E.; Melton, J . J . Org. Chem. 1973, 38, 4367.
(6) Talukdar, S.; Banerji, S. J . Org. Chem. 1998, 63, 3468 and
references therein.
(7) (a) Taniguchi, M.; Hino, T.; Kishi, Y. Tetrahedron Lett. 1986,
39, 4767. (b) Yachi, K.; Maeda, K.; Shinokubo, H.; Oshima, K.
Tetrahedron Lett. 1997, 38, 5161. (c) Uehira, S.; Han, Z.; Shinokubo,
H.; Oshima, K. Org. Lett. 1999, 1, 1383-1385. (d) Tsuritani, T.;
Shinokubo, H.; Oshima, K. Tetrahedron Lett. 1999, 40, 8121.
(8) Very recently, reduction of TiCl4 to Ti(III) species by triethyl-
amine has been reported, see: Periasamy, M.; Srinivas, G.; Karunakar,
G. V.; Bharathi, P. Tetrahedron Lett. 1999, 40, 7577
(10) For recent examples of titanium mediated pinacol reaction,
see: (a) Li, T.; Cui, W.; Liu, J .; Zhao, J .; Wang, Z. J . Chem. Soc., Chem.
Commun. 2000, 139. (b) Matsubara, S.; Hashimoto, Y.; Okano, T.;
Utimoto, K. Synlett 1999, 1411. (c) Bandini, M.; Cozzi, P. G.; Morganti,
S.; Umani-Ronchi, A. Tetrahedron Lett. 1999, 40, 1997. (d) Yamamoto,
Y,; Hattori, R.; Ito, K. J . Chem. Soc., Chem. Commun. 1999. 825. (e)
Mukaiyama, T.; Kagayama, A.; Shiina, I. Chem. Lett. 1998, 1107. (f)
Hirao, T.; Hatano, B.; Asahara, M.; Muguruma, Y.; Ogawa, A.
Tetrahedron Lett. 1998, 39, 5247. (g) Gansa¨uer, A.; Bauer, D. J . Org.
Chem. 1998, 63, 2070. (h) Hayakawa, R.; Shimizu, M. Chem. Lett. 2000,
724. (i) Mukaiyama, T.; Yoshimura, N.; Igarashi, K. Chem. Lett. 2000,
838.
(11) The role of hexane is not clear at this stage.
(12) Titanium-mediated pinacol reactions of 2-substituted aromatic
aldehydes sometimes affords lower selectivity than reactions of 3- or
4-substituted benzaldehydes. For example, see ref 10b.
(13) The use of sodium iodide as an iodide source provided no pinacol
product.
(14) For reductive coupling of imines, see: Hatano, B.; Ogawa, A.;
Hirao, T. J . Org. Chem. 1998, 63, 9421 and references therein. See
also ref 8.
(9) This mixed reagent is insoluble in hexane because of the low
solubility of TBAI to hexane.
10.1021/jo0004254 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/19/2000

Notes
J . Org. Chem., Vol. 65, No. 16, 2000 5067
Ta ble 1. P in a col Cou p lin g Rea ction of Ar om a tic
Sch em e 4
Ald eh yd esa
Ta ble 2. En ola te F or m a tion fr om r-Ha lok eton es
a
Substrate (1.0 mmol), TiCl4 (1.5 mmol), and TABI (2.2 mmol)
b
were employed unless otherwise noted. Ph3PMeI (2.2 mmol) was
used instead of TBAI. c Et3NMeI prepared in situ from Et3N (2.2
d
mmol) and MeI (2.2 mmol) was used instead of TBAI. Ph3PMeI
prepared in situ from Ph3P (2.2 mmol) and MeI (2.2 mmol) was
used instead of TBAI.
Sch em e 5
Sch em e 2
Sch em e 3
Unfortunately, the reaction of aromatic imines (PhCHd
N-n-Pr and PhCHdNPh) under the same conditions
provided no desired coupling products.14 No reaction took
place and only benzaldehyde was recovered after aqueous
workup.
in the mixture of TiCl4 and TBAI at -78 °C.17 This result
could indicate that practically no reduction of Ti(IV)
occurred in the absence of aromatic aldehyde. Addition-
ally, it has already been reported that this mixed reagent
can induce the nucleophilic attack of iodide to epoxides
or unsaturated carbonyl compounds.7 Based on these
facts, we propose the following mechanism (Scheme 4).
(1) The reaction of TiCl4 with TBAI would form penta-
coordinate titanium ate-complex 2. (2) Coordination of a
carbonyl oxygen to the titanium center of 2 would
facilitate the reduction of 2 to Ti(III) species 3. (3) Finally,
3 could form the corresponding ketyl radical which would
dimerize to afford coupling product 5. Instead of alde-
hyde, the use of epoxide would result in nucleophilic
opening by the iodotitanate compound to form iodoal-
koxytitanium compound 4.
To elucidate the reaction mechanism, further experi-
ments were performed. After quenching the reaction
mixture with water, addition of hexane to the organic
phase provided a black precipitate. This was identified
as n-Bu4NI3 by examination of the NMR spectra and
elemental analysis.15 Thus, the course of this pinacol
reaction is outlined in Scheme 3. Iodide ion can formally
serve as a reducing reagent of Ti(IV) into Ti(III).16
-
However, only a small amount of I3 could be detected
(15) Both 1H and 13C spectra were identical with those of the
authentic sample of n-Bu4NI3 which was prepared by mixing of n-Bu4-
NI and I2. UV absorbance in CH2Cl2 was also identical with that of
the authentic sample. Elemental analysis of this precipitate was also
consistent with n-Bu4NI3. Found: C, 30.81; H, 5.84%. Calcd for
C
16H36I3N: C, 30.84; H, 5.82%.
(16) As shown in Scheme 3, 3 mol of TBAI is needed to reduce 2
(17) After the mixture of TiCl4 (1.2 mmol) and TBAI (1.8 mmol) in
CH2Cl2 was stirred for 30 min at -78 °C, 0.06 mmol of I3- was detected
by titration with aqueous Na2S2O3.
mol of TiCl4. Therefore, the stoichiometry in Scheme 1 can be explained
by Scheme 3.

5068 J . Org. Chem., Vol. 65, No. 16, 2000
Notes
This TiCl4-TBAI mixed system could also reduce
R-iodoketones or R-bromoketones to provide the corre-
sponding titanium enolates 6.18 The resulting enolates
afforded aldol-type adducts 7 in good yields upon treat-
ment with various aldehydes (Table 2). Under these
conditions, 3-chlorobutanone did not react and the chlo-
roketone was recovered quantitatively (entry 5). While
R-iodoesters could be converted into enolates (entry 8 or
9), no reduction proceeded in the case of an R-bromoester.
We examined another quaternary ammonium iodide-
metal halide combination and found that the NbCl5-n-
Bu4NI mixed system could also induce pinacol coupling
reaction of aromatic aldehydes (Scheme 5).19 Interest-
ingly, stereoselectivities were higher than the corre-
sponding reactions run in the presence of TiCl4-n-Bu4NI.
Contrary to the reaction with TiCl4-n-Bu4NI system, the
reaction of 2-substituted benzaldehydes showed high dl-
selectivities.
Exp er im en ta l Section
Gen er a l P r oced u r e for P in a col Rea ction w ith TiCl4-
TBAI System . To a solution of TiCl4 (1.5 mmol) in CH2Cl2 (1.5
mL) was added a solution of tetrabutylammonium iodide (2.2
mmol) in CH2Cl2 (3 mL) at 0 °C. After stirring for 10 min at 0
°C, the resulting dark-red solution was cooled to -78 °C and
benzaldehyde (1.0 mmol) and hexane (3 mL) were added. The
mixture was allowed to warm to ambient temperature during a
period of 12 h. Then the whole mixture was poured into aqueous
NH4Cl and was extracted with ethyl acetate. The organic layer
was washed with aqueous Na2S2O3 and dried over Na2SO4.
Concentration and purification by chromatography afforded 1,2-
diphenyl-1,2-ethanediol (106 mg, 0.49 mmol) in 99% yield.
Gen er a l P r oced u r e for P in a col Rea ction w ith NbCl5-
TBAI System . To a suspension of NbCl5 (1.2 mmol) in CH2Cl2
(2 mL) was added a solution of tetrabutylammonium iodide (1.8
mmol) in CH2Cl2 (2.5 mL) at 0 °C. After stirring for 10 min at 0
°C, to the resulting black solution was added benzaldehyde (1.0
mmol). The mixture was stirred for 3 h at 0 °C. Then, saturated
aqueous NH4Cl (3 mL) was added to the mixture. The whole
mixture was dried over Na2SO4. Ethyl acetate was added and
the solution was washed with aqueous Na2S2O3 and dried over
Na2SO4. Concentration and purification by chromatography
afforded 1,2-diphenyl-1,2-ethanediol (106 mg, 0.49 mmol) in 99%
yield.
In summary, reduction systems based on TiCl4 (or
NbCl5)-quaternary ammonium iodide combinations were
found. Reduction of aromatic aldehydes or R-haloketones
by this mixed reagent can be performed easily without
using another reducing reagent.
Ack n ow led gm en t. This work was supported by a
Grant-in-Aid for Scientific Research on Priority Area (B)
(No. 10208208) from the Ministry of Education, Science,
Sports, and Culture, J apan.
(18) TiCl2-induced enolate formation from R-haloketone has been
reported. Mukaiyama, T.; Kagayama, A.; Igarashi, K.; Shiina, I. Chem.
Lett. 1999, 1157.
(19) Niobium based reduction of carbonyl compounds has been
reported, see: (a) Szymoniak, J .; Besancon, J .; Mo¨ıse, C. Tetrahedron
1992, 48, 3867. (b) Szymoniak, J .; Besancon, J .; Moı¨se, C. Tetrahedron
1994, 50, 2841.
Su p p or tin g In for m a tion Ava ila ble: Spectral data for
new compounds and n-Bu4NI3. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O0004254