A highly diastereoselective pinacol coupling reaction of aldehydes and ketones using low-valence niobium generated from Nb(V)

Article abstract of DOI:10.1248/cpb.52.287

A simple method for the diastereoselective synthesis of racemic 1,2-diol mediated by low-valence niobium generated in situ is described. A 1,4-dioxane-toluene solvent system was found to be essential to achieve higher selectivities and to prevent other reactions of pinacols, such as deoxygenation and acetal formation. Aromatic aldehydes and ketones were converted to the corresponding pinacols with up to 97 and 85% de, respectively.

Full text of DOI:10.1248/cpb.52.287

February 2004
Notes
Chem. Pharm. Bull. 52(2) 287—288 (2004)
287
A Highly Diastereoselective Pinacol Coupling Reaction of Aldehydes and
Ketones Using Low-Valence Niobium Generated from Nb(V)
*
Shigeru ARAI, Yukinori SUDO, and Atsushi NISHIDA
Graduate School of Pharmaceutical Sciences, Chiba University; Yayoi-cho, Inage-ku, Chiba 263–8522, Japan.
Received November 10, 2003; accepted December 3, 2003
A simple method for the diastereoselective synthesis of racemic 1,2-diol mediated by low-valence niobium
generated in situ is described. A 1,4-dioxane-toluene solvent system was found to be essential to achieve higher
selectivities and to prevent other reactions of pinacols, such as deoxygenation and acetal formation. Aromatic
aldehydes and ketones were converted to the corresponding pinacols with up to 97 and 85% de, respectively.
Key words carbonyl compound; niobium; pinacol coupling; vicinal diol; zinc
Pinacol coupling is recognized as a powerful method for ology was suitable for a variety of substrates with excellent
the synthesis of symmetric 1,2-diols and can be promoted or de values under the optimized conditions. For example, 2-, 3-
catalyzed by various metals. In this article, we report an im- and 4-chlorobenzaldehydes 1b—d were smoothly trans-
proved methodology for a Nb-mediated highly diastereo- formed to the corresponding pinacols 2b—d in 77, 87 and
selective pinacol coupling reaction.1—3) A NbCl3 DME com- 79% yields and with good diastereoselectivities, respectively
plex, which is both commercially available and the most (entries 1—3). Electron-donating groups such as 3-Me and
common reductant among niobium agents, has been reported 3-MeO substituents, as shown in entries 4 and 5, were also
to generate 1,2-dianions from alkynes and imines that react successfully converted into the corresponding diols 2e and 2f
with multiple bonds, and its utility in organic synthesis is in 67 and 54% yields with higher selectivity. Surprisingly,
well established.4,5) On the other hand, few examples using electron-donating substituents at the 2- and 4-positions
low-valence Nb prepared from Nb(V) in situ have been ap- strongly affected the chemical yields. For example, 2-Me, 2-
plied to pinacol coupling.1,2)
We were interested in the reactivity of low-valence Nb and low yields of 2 (less than 28% yield) because these function-
sought to establish a simple and inexpensive protocol. alities promote the further deoxygenation of pinacols to give
MeO, 4-Me and 4-MeO groups gave complex mixtures and
First, a suitable solvent for the pinacol coupling of 1a was A due to the stabilizing effect of benzylic carbocation. On
surveyed with low-valence Nb, which was generated in situ the other hand, the reaction with an electron-withdrawing
by treatment with zinc powder. In general, DME is known to group such as a 4-CF3 group, which is thought to prevent fur-
be a useful solvent in Nb(III)-mediated reactions and a Nb ther reactions, proceeded smoothly to give 2g in 66% yield
complex with DME and an alkyne has been characterized.6) with 24 of diastereo ratio (entry 6). These results are summa-
Although the reaction proceeded smoothly to give the desired rized in Table 2.
pinacol 2a in 61% yield, its diastereoselectivity was low, as
Having succeeded with aromatic aldehydes, we next
shown in entry 1. A non-coordinative solvent such as toluene sought to confirm the generality of this reaction system using
was ineffective and gave 2a in only 9% yield (entry 2). More- a variety of ketones 3, and found significantly different re-
over, THF, gave 2a in reasonable yield but with unsatisfac- sults than with aldehydes. For example, treatment of ace-
tory diastereoselectivity (entry 3). The most critical problem tophenone 3a under similar conditions gave the desired pina-
was the rapid polymerization of THF due to the strong Lewis col 4a in 40% yield together with 5a (46%) (entry 1). The
acidity of Nb. 1,4-Dioxane at room temperature (rt) surpris- latter rearrangement product seems to be produced from 4a
ingly increased the ratio to 69 : 1 (entry 4). This system by the Lewis acidity of Nb(V). To limit further reaction, the
shows great advantages in that minimize other subsequent re- addition of excess Zn powder, which rapidly produces low-
actions of the initially formed pinacols, such as acetal forma-
Table 1. Diastereoselective Pinacol Coupling Using 1a
tion and deoxygenation, as observed in Szymoniak’s results.1)
To examine this system at a lower temperature, a mixed
solvent system was investigated. After optimization,
dioxane : toluene (1 : 4) was revealed to be the best solvent
and gave 2a with a ratio of 79 : 1 (entry 5). Moreover, 1.1 eq
of zinc powder was sufficient for the reaction to proceed with
similar results, however a stoichiometric amount of NbCl5
was essential (entry 6 vs. 7). We assume that 1,4-dioxane
plays important roles in both promoting the smooth reduction
of Nb(V) by Zn powder and reducing the Lewis acidity of
Nb(V) by coordination to prevent the side reaction such as
acetal formation of 2a. These results are summarized in
Table 1.
Yield of dl/meso
2a (%) of 2aa)
Entry
Solvent
Zn (eq) Conditions
1
2
3
4
5
6
7
DME
Toluene
THF
2
2
2
2
0 °C, 3 h
0 °C, 3 h
0 °C, 3 h
rt, 3 h
61
9
2.5
1.0
2.2
67
53
75
78
53
1,4-Dioxane
69
1,4-Dioxane/PhMe (1/4)
1,4-Dioxane/PhMe (1/4)
1,4-Dioxane/PhMe (1/4)b)
2
1.1
1.1
0 °C, 3 h
0 °C, 3 h
0 °C, 3 h
79
71
11
By examining the scope and limitations of this reaction
using various aromatic aldehydes, we found that this method-
a) Determined by 1H-NMR. b) NbCl5 (0.5 eq) was used.
To whom correspondence should be addressed. e-mail: arai@p.chiba-u.ac.jp
© 2004 Pharmaceutical Society of Japan

288
Vol. 52, No. 2
Table 2. Diastereoselective Pinacol Coupling Using Aromatic Aldehydes
Table 3. Diastereoselective Pinacol Coupling Using 3
Entry
1
Time (h)
Yield (%)
dl/meso
Yield of
4 (%)
Entry
2
Zn (eq) Time (h)
dl/mesoa)
1
2
3
4
5
6
1b: Arϭ2-Cl-Ph
1c: Arϭ3-Cl-Ph
1d: Arϭ4-Cl-Ph
1e: Arϭ3-Me-Ph
1f: Arϭ3-MeO-Ph
1g: Arϭ4-CF3-Ph
1.5
1.5
2
2.5
2
2b: 77
2c: 87
2d: 79
2e: 67
2f: 74
2g: 66
12
29
43
54
77
24
1
2
3
4
5
3a: RϭPh
3a: RϭPh
3b: Rϭ4-Me-Ph
3c: Rϭ4-CF3-Ph
3d: RϭPh(CH2)2
1.1
2
2
2
2
3
4a: 40 (5a: 46%) 29
4a: 70 (5a: 8%)
4b: 35
12
46
2.5
2
2.5 4c: 88
4d: 60
2
2
2
1
a) Determined by 1H-NMR.
valence Nb species, was examined. As expected, the re-
arrangement is sufficiently prevented and the reaction pre- (40499-44-5).
Representative experimental procedure for pinacol coupling of 1a (Table
1, entry 5); A suspension of activated Zn powder (77 mg, 1.2 mmol) and
NbCl5 (159 mg, 0.59 mmol) in 1,4-dioxane–toluene (1 : 4, 3.0 ml) was stirred
for 1 h at rt under an argon atmosphere. Benzaldehyde 1a was then added at
0 °C. After the mixture was stirred for an additional 3 h, the reaction was
quenched with aqueous 10% aq. K2CO3 (2.0 ml) and subjected to ultrasoni-
cation for 1 h. The resulting slurry was filtered off by celite and the layers
were extracted with AcOEt (5.0 mlϫ3), washed with brine and dried over
Na2SO4. After the solvents were removed in vacuo, the crude product was
purified by flash column chromatography (hexane : AcOEtϭ5 : 2) to give the
desired product 2a as a white solid (47 mg, 0.22 mmol, 75%, dl/mesoϭ
dominantly gave dl-4a in 70% yield in a reasonable ratio
(12 : 1) together with 5a (8%) (entry 2). While the reason for
the significant decrease in de is still unclear, we assume that
these results are dependent on the kinetic difference between
dl- and meso-4a in being transformed into the subsequent re-
arrangement products. With regard to substituents effect, a
methyl group at the 4-position gave 4b in 35% yield (entry 3)
and, as expected, an electron-withdrawing group such as 4-
CF3, prevented such additional reaction to give 4c in good
yield (entry 4). Furthermore, the reaction of aliphatic ketone
3d proceeded without selectivity in moderate yield (entry 5).
These results are summarized in Table 3.
1
79 : 1). The diastereoselectivity was determined by H-NMR analysis with
comparison to the literature.2)
References
In conclusion, we found that the low-valence Nb which is
generated in situ promoted the pinacol coupling of aromatic
aldehydes and ketones with good to excellent de. The stere-
oselectivities are significantly controlled by a coordinative
co-solvent and/or by the substituents on the substrates. How-
ever, the generality of the substrate is not still satisfactory,
and further studies are needed.
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The desired compounds are identified by reg. #; 2b (24133-53-7), 2c
(209900-08-3), 2d (38152-44-2), 2e (24133-60-6), 2f (156091-01-9), 2g
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