Pinacol coupling reaction of beta-halo-alpha,beta-unsaturated aldehydes promoted by TiI4.

Article abstract of DOI:10.1021/ol026842f

The pinacol reaction of beta-halogenated alpha,beta-unsaturated aldehydes was promoted by titanium tetraiodide to give coupling products in good yields with high dl-selectivity. Subsequent reduction with H(2)/Pd-C gave saturated vic-diols in good yields. Heck coupling reaction enabled the displacement of halogens with vinyl groups without the loss of stereochemical integrities. [reaction: see text]

Full text of DOI:10.1021/ol026842f

ORGANIC
LETTERS
2002
Vol. 4, No. 23
4097-4099
Pinacol Coupling Reaction of
â-Halo-r,â-unsaturated Aldehydes
Promoted by TiI4
Makoto Shimizu,* Hiroshi Goto, and Ryuuichirou Hayakawa
Department of Chemistry for Materials, Mie UniVersity, Tsu, Mie 514-8507, Japan
mshimizu@chem.mie-u.ac.jp
Received September 3, 2002
ABSTRACT
The pinacol reaction of â-halogenated r,â-unsaturated aldehydes was promoted by titanium tetraiodide to give coupling products in good
yields with high dl-selectivity. Subsequent reduction with H /Pd−C gave saturated vic-diols in good yields. Heck coupling reaction enabled the
2
displacement of halogens with vinyl groups without the loss of stereochemical integrities.
A number of 1,2-diols have been utilized as useful synthons
for the synthesis of biologically important compounds such
as HIV protease inhibitors and natural products,1 and several
approaches to their syntheses have been described. Among
them, the pinacol coupling reaction constitutes one of the
most straightforward methods.2 Recently, high diastereo-
selectivity, catalytic use of active species, and cross-coupling
have been attained in such reactions.3 Use of low-valent
metals such as titanium,4 zirconium,5 vanadium,6 samarium,7
and so on is, in principle, needed for promoting the pinacol
coupling, because, for a majority of cases, the reaction
proceeds via a single-electron-transfer mechanism.
We have been interested in the reaction using titanium
tetraiodide, which possesses good reducing ability for various
substrates, including ketones, imines, and sulfoxides,8 and
we have already reported that the pinacol coupling of
aromatic aldehydes is conducted under the influence of
titanium tetraiodide. However, the titanium tetraiodide could
not sufficiently promote the pinacol coupling reaction of
Oshiki, T.; Kiriyama, T.; Tsuchida, K.; Takai, K. Chem. Lett. 2000, 334-
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Takeuchi, H.; Ogawa, A.; Sakurai, H. Synlett 2000, 1658-1660 and
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1998, 54, 12775-12788. Christensen, T. B.; Riber, D.; Daasbjerg, K.;
Skrydstrup, T. Chem. Commun. 1999, 2051-2052. Yanada, R.; Okaniwa,
M.; Kaieda, A.; Ibuka, T.; Takemoto, Y. J. Org. Chem. 2001, 66, 1283-
1286 and references therein.
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M.; Shibuya, K.; Hayakawa, R. Synlett 2000, 1437-1438. Hayakawa, R.;
Sahara, T.; Shimizu, M. Tetrahedron Lett. 2000, 41, 7939-7942. Hayakawa,
R.; Makino, H.; Shimizu, M. Chem. Lett. 2001, 756-757. Shimizu, M.;
Sahara, T.; Hayakawa, R. Chem. Lett. 2001, 792-793. Shimizu, M.;
Takeuchi, Y.; Sahara, T. Chem. Lett. 2001, 1196-1197.
(1) Kammermeier, B.; Beck, G.; Jacobi, D.; Jendralla, H. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 685-687. McMurry, J. E.; Siemers, N. O.
Tetrahedron Lett. 1994, 35, 4505-4508. Kammermeier, B.; Beck, G.; Holla,
W.; Jacobi, D.; Napierski, B.; Jendralla, H. Chem. Eur. J. 1996, 2, 307-
315. Shiina, I.; Iwadare, H.; Sakoh, H.; Hasegawa, M.; Tani, Y.; Mukaiyama,
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(2) For general reviews, see: Robertson, G. M. In ComprehensiVe
Organic Synthesis; Trost B. M., Ed.; Pergamon: New York, 1991; Vol. 3,
pp 563-611. Wirth, T. Angew. Chem., Int. Ed. Engl. 1996, 35, 61-63.
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2000, 100, 2771-2788 and references therein.
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366-367. Reetz, M. T.; Griebenow, N. Liebigs Ann. 1996, 335-348. Kang,
M.; Park, J.; Pederson, S. F. Synlett 1997, 41-43. Gansa¨uer, A. Synlett
1997, 363-364. Hirao, T.; Hatano, B.; Asahara, M.; Muguruma, Y.; Ogawa,
A. Tetrahedron Lett. 1998, 39, 5247-5348. Groth, U.; Jeske, M. Angew.
Chem., Int. Ed. Engl. 2000, 39, 574-576.
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10.1021/ol026842f CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/25/2002

aliphatic aldehydes due to its mild reducing ability.9 Many
useful 1,2-diols are aliphatic; therefore, precursors for
aliphatic derivatives were sought. After screening a series
of substrates, we have found that R,â-unsaturated aldehydes
possessing a halogen serve as excellent substrates for pinacol
coupling, and the subsequent hydrogenation furnished satu-
rated 1,2-diols in good overall yields. Herein we report the
pinacol coupling of â-halo R,â-unsaturated aldehydes pro-
moted by titanium tetraiodide. The results of the pinacol
coupling reaction of R,â-unsaturated aldehydes are sum-
marized in Table 1.10
Scheme 1
Table 1. Pinacol Coupling Reaction of R,â-Unsaturated
Aldehyde
2-hexenal. Whereas the coupling reaction of 2-hexenal in
the presence of titanium tetraiodide gave the desired product
in only 16% yield, â-halo-substituted 2-hexenals afforded
the dl-coupling products in good yields with excellent
selectivity (entries 6-8). In strong contrast to their hydrogen
analogues, the introduction of chlorine enabled the coupling
reaction of the tert-butyl and cyclic enals, although the
product yields were moderate (entries 9-12).
An interesting addition of iodide anion was observed in
the reaction of propynal derivatives. The pinacol coupling
of 3-phenylpropynal in the presence of dry 4 Å molecular
sieves (4 Å MS) gave diol 6 in 63% yield with complete
dl-selectivity, whereas the diiodo derivative 2m was obtained
when the reaction was conducted in the presence of 4 Å MS
containing water.11 The same coupling product was obtained
from the reaction of (E)-3-iodocinnamaldehyde 1m, where
no isomerization of the double bond was observed. These
results indicate that the initial formation of (E)-3-iodocin-
namaldehyde may be involved in the case of 3-phenyl-
propynal in the presence of a limited amount of water.
Scheme 2 may explain the formation of the diiodo diol 4.
temp
(°C)
time yield
(h) (%)a dl:mesob
entry
1: a Ph
2: b Ph
3: c Ph
4: d Ph
5: e Ph
6: f n-Pr
7: g n-Pr
8: h n-Pr
9: i t-Bu
10: j t-Bu
11: k -(CH2)4-
12: l -(CH2)4-
R1
R2 R3
H
H
H
H
Br
H
H
H
H
H
H
from -78 to -20 2.5 83
Cl from -78 to -70 0.5 87
Br from -78 to -50 1.5 85
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
I
H
H
from -78 to -20 4.0 88
from -78 to 0 6.5 68
from -78 to -10 3.5 16
Br from -78 to -20 2.5 82
I
H
from -78 to 0
from -78 to rt
Cl from -78 to rt
from -78 to rt
5.0 72
20
10
24
0
57
0
93:7
97:3
H
Cl from -78 to rt
22.5 32
1
a Isolated yield. b Determined by H NMR. See, refs 4h and 12.
The coupling reaction of cinnamaldehyde gave exclusively
the dl-coupling product in 83% yield (entry 1). The reaction
rate of the present coupling was effectively enhanced by a
halogen substituent at the position â to the carbonyl.
3-Chlorocinnamaldehyde participated in the coupling reaction
to give the diol in good yield in a short reaction time (entry
2). The use of the 3-bromo and iodo counterparts also
provides a clean reaction, giving the products in essentially
the same range of yields (entries 3 and 4). The R-bromo-
substituted analogue, however, gave the coupling product
in decreased yield (entry 5). This particular effect of a
halogen substituent was especially prominent in the case of
Scheme 2
(9) Hayakawa, R.; Shimizu, M. Chem. Lett. 2000, 724-725.
(10) Titanium tetraiodide was purified by sublimation (180 °C/0.8
mmHg). A typical procedure is as follows. Propionitrile (1.0 mL) was added
to TiI4 (1.0 mmol) at ambient temperature under an argon atmosphere. The
solution was stirred for 10 min, and a propionitrile (1.0 mL) solution of
3-iodocinnamaldehyde (0.5 mmol) was added at -78 °C. After being stirred
at from -78 °C to -20 °C, the reaction was quenched with saturated
aqueous NaHCO3, 10% aqueous NaHSO3, and triethylamine. The whole
mixture was filtered through a Celite pad and extracted with ethyl acetate
(3 × 10 mL). The combined organic extracts were dried over anhydrous
Na2SO4 and concentrated in vacuo. Purification on preparative silica gel
TLC (2:1 n-hexane/ethyl acetate as an eluent) gave 1,6-diiodo-1,6-diphenyl-
3,4-dihydroxyhexa-1,5-diene (88%).
An initial 1,4-addition of iodide anion occurred to give the
allenoate 7, which was protonated with water to give (E)-
â-iodoaldehyde 1m. This (E)-iodocinnamaldehyde 1m in turn
(11) Shimizu, M.; Ogawa, T.; Nishi, T. Tetrahedron Lett. 2001, 42,
5463-5466.
4098
Org. Lett., Vol. 4, No. 23, 2002

underwent the pinacol coupling reaction under the influence
of titanium tetraiodide.
the dialkenylated product 9 in good yield without isomer-
ization of the (Z)-geometries of the double bonds.13
Scheme 4 shows a possible reaction pathway of the present
pinacol coupling. An initial iodination of the carbonyl group
The subsequent functional group transformations of the
coupling product demonstrate the utility of the present
reaction. Hydrogenation of the coupling products 2 gave the
saturated 1,2-diols 8 in good yields where no epimerization
of the diol moiety was detected. Table 2 summarizes the
Scheme 4
Table 2. Hydrogenation of Coupling Products
time
(h)
yield
(%)a
entry
R1
Ph
Ph
Ph
I
R2
R3
Cl
Br
I
Ph
H
Br
dl:mesob
1
2
3
4
5
6
H
H
H
H
Br
H
20
18
20
20
18
12
80
83
75
80c
76
72
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
of the aldehyde gives the iodinated intermediate 10, which
is attacked by the iodide anion from titanium tetraiodide to
form an anionic species. It has been reported that a similar
halogenated intermediate was formed in the reaction of BCl3
with aromatic aldehydes.14 The species generated from
reductive dehalogenation in turn undergoes addition to
another aldehyde to form a pinacol product. The formation
of iodinated intermediate 10 appears to be easy in the case
of aldehydes with an electron-withdrawing substituent;
therefore, the present pinacol coupling proceeds readily with
â-halo-substituted R,â-unsaturated aldehydes.
In conclusion, we have shown that a complete dl-selective
pinacol coupling reaction of â-halogenated R,â-unsaturated
aldehyde has been achieved under the influence of titanium
tetraiodide, a readily available and stable solid. The halo-
genovinyl moiety was in turn efficiently utilized for further
functional group transformations, making the present pro-
cedure a good alternative to the stereoselective pinacol
coupling of aliphatic aldehydes previously reported to be
difficult.
Ph
n-Pr
a Isolated yield. b Determined by 1H NMR. See, refs 4f and 12. c 1,6-
Diphenylhexane-3,4-diol was obtained.
results of the hydrogenation. Previously, it was reported that
the pinacol coupling of aliphatic aldehydes with complete
dl-selectivity was not trivial.12 Although an additional step
is needed, the present approach offers a solution to this
problem. Diol 6 arising from phenylpropynal also underwent
a similar hydrogenation reaction to give the saturated diol 8
in good yield without affecting the diol stereochemistry
(Scheme 3). Furthermore, carbon-carbon bond formation
was possible using the Heck coupling reaction. After
acetonide formation, the reaction of the coupling product 2d
with tert-butyl acrylate in the presence of palladium(0) gave
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Science, Sports, Culture, and Technology of the
Japanese Government.
Scheme 3
Supporting Information Available: Experimental pro-
cedures and product characterization for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL026842F
(12) Hirao, T.; Asahara, M.; Muguruma, Y.; Ogawa, A. J. Org. Chem.
1998, 63, 2812-2813. Mukaiyama, T.; Yoshimura, N.; Igarashi, K. Chem.
Lett. 2000, 838-839.
(13) Heck, R. F. Org. React. 1982, 27, 345-390.
(14) Kabalka, G. W.; Wu, Z. Tetrahedron Lett. 2000, 41, 579-581.
Org. Lett., Vol. 4, No. 23, 2002
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