Mg-promoted mixed pinacol coupling

Article abstract of DOI:10.1016/j.tetlet.2004.03.109

Mg-promoted reduction of a mixture of aromatic ketones (or imines) and aliphatic carbonyl compounds in N,N-dimethylformamide (DMF) brought about unique mixed pinacol type of cross coupling to give unsymmetrical vicinal diols (or amino alcohols) or α-hydroxyketones in good to moderate yields. The reaction may be initiated by electron transfer from magnesium metal to an aromatic carbonyl compound possessing a less negative reduction potential. The difference of reduction potential between aromatic ketones (or imines) and aliphatic carbonyl compounds was found to be one of the important key factors in this selective cross coupling.

Full text of DOI:10.1016/j.tetlet.2004.03.109

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3869–3872
Mg-promoted mixed pinacol couplingq
Hirofumi Maekawa, Yoshimasa Yamamoto, Hisashi Shimada, Kazuaki Yonemura
and Ikuzo Nishiguchi*
Department of Chemistry, Nagaoka University of Technology, 1603-1, Kamitomiokacho, Nagaoka, Niigata 940-2188, Japan
Received 14 February 2004; revised 19 March 2004; accepted 22 March 2004
Abstract—Mg-promoted reduction of a mixture of aromatic ketones (or imines) and aliphatic carbonyl compounds in N,N-di-
methylformamide (DMF) brought about unique mixed pinacol type of cross coupling to give unsymmetrical vicinal diols (or amino
alcohols) or a-hydroxyketones in good to moderate yields. The reaction may be initiated by electron transfer from magnesium metal
to an aromatic carbonyl compound possessing a less negative reduction potential. The difference of reduction potential between
aromatic ketones (or imines) and aliphatic carbonyl compounds was found to be one of the important key factors in this selective
cross coupling.
Ó 2004 Elsevier Ltd. All rights reserved.
Coupling between carbonyl groups such as pinacol
coupling, McMurry coupling, and acyloin condensation
is one of the most important reactions in organic
chemistry, and has been extensively studied from syn-
thetic and mechanistic aspects.1–5
turnings through electron transfer process to give the
corresponding C-acylation products in good yields.
In this study, we wish to report unique and convenient
Mg-promoted mixed pinacol coupling of aromatic
ketones (or imines) and aliphatic carbonyl compounds
to give unsymmetrical vicinal diols (or amino alcohols)
in good to moderate yields.
Especially, reductive dimerization of aldehydes and ke-
tones by electron transfer process has been well-known
as ‘pinacol coupling’ on which much attention has been
focused as useful and important methods for construc-
tion of vicinally heteroatom-functionalized compounds
such as 1,2- diols.6–19 Numerous and extensive studies
have been accomplished for the homo-coupling of same
carbonyl compounds including asymmetric induction.
Only a little, however, have been reported for mixed
pinacol coupling of different carbonyl compounds as
yet7;8 although their synthetic utility may be relatively
limited owing to small applicable range for reduction
potential such as Zn, less generality and/or troublesome
procedure.
Typical procedure is as follows: To a 100 mL three-
necked round flask equipped with a thermometer and a
dropping funnel was placed magnesium turnings for
Grignard reagent (25 mmol) in dry DMF(25 mL). After
cooling the flask in an ice–salt bath, a mixture of aro-
matic ketone (1) (5 mmol), aliphatic carbonyl compound
(2) (50 mmol), and trimethylchlorosilane (TMSCl:
25 mmol) in DMF(20 mL) was added under magnetic
stirring over 30 min. The reaction mixture was allowed
to stir at room temperature overnight and was extracted
with ether. After evaporation of the solvent under re-
duced pressure, the crude material was dissolved into
50 mL of methanol with stirring. Aqueous 5% sulfuric
acid was carefully added into the methanol solution and
the reaction mixture was stirred for 6 h at room tem-
perature. After neutralization, the reaction mixture was
treated through usual work-up and the product 3 was
purified through column chromatography.
On the other hand, we have found that reductive cross-
coupling of aromatic carbonyl compounds with acid
chlorides20 was efficiently promoted by magnesium
Keywords: Carbonyl compounds; Electron transfer; Magnesium and
compounds; Coupling reaction.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.03.109
Thus, treatment of a mixture of acetophenone (1a) and a
large excess of acetone with magnesium turnings in
DMFat room temperature followed by acid-cata-
lyzed hydrolysis afforded the cross-coupling product,
* Corresponding author. Tel.: +81-258-47-9307; fax: +81-258-47-9300;
e-mail: nishiiku@vos.nagaokaut.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.109

3870
H. Maekawa et al. / Tetrahedron Letters 45 (2004) 3869–3872
2-phenyl-3-methyl-butan-2,3-diol (3a), in 70% yield as
the main product. The symmetrical pinacol-coupling
product of acetone and aldol condensation product were
not observed in this coupling although simply reduced
product and pinacol coupling product of acetophenone
were detected in gas chromatographic analysis in 1–2%
yield, respectively. Stereochemistry of 3i,j, and 3m were
determined through comparison of 1H NMR spectra
of the products with those of authentic samples in the
literature.21
Furthermore, aromatic and heteroaromatic imino
compounds (4) were also found to be usable for the
present cross-coupling with acetone followed by
hydrolysis to give the corresponding 1,2-amino alcohols
(5) in moderate to good yields (Table 2).
Similar treatment of diketones (6) bearing both of aro-
matic and aliphatic carbonyl groups in the same mole-
cule, with Mg metal in the presence of TMSCl brought
about facile and selective intramolecular reductive cyc-
lization to give the corresponding bis(trimethylsilyl)
ethers of 1,2-cycloalkanediols (7) in good yields, as
shown in Table 3. It is noteworthy that even the 4-
membered product (7a,c) with some ring strain was
Though commercially easily available magnesium turn-
ing for Grignard reaction could be employed without
any pre-treatment, some addition of TMSCl was nee-
ded for smooth proceedings of the reaction, possibly
through continuous activation of magnesium surface.
Under the similar conditions, Mg-promoted cross-cou-
pling reactions of various kind of aromatic carbonyl
ketones (1) with aliphatic ketones and aldehydes (2)
gave the corresponding vicinal diols (3) in moderate to
good yields, as shown in Table 1.
Table 2. Mg-promoted unsymmetrical pinacol coupling between aro-
matic imine and aliphatic carbonyl compounds
Ph
PhNH
N
O
1) Mg / TMSCl/DMF
2) H3O+
Ar
R
+
R
Ar
5
2
4
OH
In this reaction, steric bulkiness of alkyl groups of the
substrates (1), (2) was found to give a noteworthy effect
on product yield. Thus, increase in bulkiness of alkyl
groups of aromatic ketones (1) and those of aliphatic
ketones (2) brought about some decrease in the yields of
3 (Table 1, 3a–c, 3n), and similar tendency was also
observed in the case of alicyclic ketones (Table 1, 3p,q)
while those of aliphatic aldehydes gave less effects on
product yield (Table 1, 3i–m), possibly owing to suitable
balance between less reactivity toward reduction by Mg
and steric hindrance. Presence of an electron-donating
group in aromatic ring of acetophenone showed some
decrease in the product yield (Table 1, 3d,e,g).
Entry
Ar
R
Yield (%) RP (4)
1
2
3
4
5
Ph
Ph
CH3
CH3CH2
5a
5b
5c
5d
5e
85
41a
57
64
58
ꢀ2.23
––
2-Pyridyl CH3
2-Thienyl CH3
2-Furanyl CH3
ꢀ2.04
ꢀ2.18
ꢀ2.24
Reaction conditions: 1%Bu4NC1O4/DMF, rt, sweep rate 200 mV/s,
working electrode: Pt, counter electrode: Pt, reference electrode: Ag/
AgCl.
a Diastereoisomer ratio (50:50).
bReduction potential (V vs Ag/AgCl).
Table 1. Mg-promoted unsymmetrical pinacol coupling
OH
R
R
OH
1) Mg / TMSCl
1
3
O
O
Ar
R
+
3
1
2
2
Ar
R
R
R
2) 5% H SO aq.
2
4
3
2
1
Ar
R1
R2
R3
Yield (%)/3
C6H5
C6H5
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
3a
3b
3c
3d
3e
3f
70
43
CH3CH2
CH3CH2CH2
CH3
46
53
m-CH3C6H4
p-CH3C6H4
m-CH3OC6H4
p-ClC6H4
m-FC6H4
C6H5
CH3
CH3
36
60
CH3
CH3
3g
3h
3i
40
53
CH3
CH3
44a
55a
66a
56a
64a;b
32a
44
C6H5
C6H5
CH3CH2
H
3j
CH3
CH3
CH3CH2CH2
(CH3)2CH
(CH3)3C
H
3k
3l
C6H5
C6H5
C6H5
H
CH3
CH3
H
CH3
3m
3n
3p
3q
CH3CH2
ꢀ
ꢀ
C6H5
C6H5
CH3
CH3
–(CH2)4
–(CH2)5
49
a Diastereoisomers ratio (55:45–80:20). The structures of major isomers are not clear.
b erythro:threo¼8:2.

H. Maekawa et al. / Tetrahedron Letters 45 (2004) 3869–3872
3871
Table 3. Intramolecular cyclization of dicarbonyl compounds
OH
R
R
90% HCOOH
15min, reflux
O
Me SiO
3
O
Mg / TMSCl
DMF
n
OH
R
Ph
n
3
Ph
R
10
R = CH , 10a, Yield = 94%
O
3
6
OSiMe
7
3
R = H, 10i, Yield = 75%
O
HO
OH
conc. H SO
2
4
Entry
R
n
Yield (%)/3
a
b
c
CH3
CH3
H
1
2
1
2
3
7a
7b
7c
7d
7e
73 (60:40)a
88 (60:40)a
69 (80:20)a
78 (55:45)a;b
76 (60:40)a;c
n
11
3
n
11p Yield : 82% (n=1)
(Ring Enlargement)
83% (n=2)
11q
HO
d
e
H
n
conc. H SO
2
4
n = 1
O
H
a Diastereoisomers ratio.
b trans:cis¼8:2.
OH
12a
Yield : 91%
7'
c Product is glycol.
(Ring Contraction)
n = 2
obtained in good yield. The structure of the major iso-
1
mer of 7c was determined through H NMR spectra
since a signal of methin proton of the trans isomer in 4-
membered ring showed a high field-shift attributed to
ring current of the aromatic ring.
O
13b
Yield : 64%
(Alkyl Shift)
Scheme 2.
On the other hand, intramolecular cyclization of keto-
esters (8) could be accomplished to form 5- and 6-
membered ring, a-hydroxy-a-phenylcycloalkanones (9),
as shown in Scheme 1. However, construction of a 4-
membered ring product failed to give simply reduced
product as a main product in this case.
From measurement of cyclic voltammetry of some
substrates as shown in Tables 2 and 4, the following
scheme shown in Scheme 3 may be postulated as one of
the most plausible reaction mechanism for the present
unsymmetrical pinacol coupling.
Less negative reduction potentials of aromatic carbonyl
compounds (Ep ¼ ꢀ2:05 to ꢀ 2:23 V vs Ag/AgCl) in
comparison with those of aliphatic carbonyl compounds
and TMSCl (Ep ¼more negative than 3.00 V) indicates
that the reaction may be initiated by electron transfer
from Mg metal to the carbonyl group of acetophenones
(1) or the imino group of acetophenone imines (4). The
generated corresponding anion radicals (14) may be
subjected to electrophilic attack of TMSCl to the oxygen
atom of the carbonyl groups followed by the fast elec-
tron transfer, giving a-siloxybenzylic anions (15), which
may react with aliphatic carbonyl compounds followed
by O-silylation to form the mixed coupling products
(17).
Acid-catalyzed treatment of the unsymmetrical 1,2-diol
derivatives (3), (7) obtained from the present unique
cross coupling provided a various types of rearrange-
ment, such as homologated alkyl shift, ring enlargement,
and ring contraction. Thus, pinacol rearrangement of 2-
phenyl-2,3-butanediols (3a,i) obtained by the coupling
between acetophenone and acetone led to selective alkyl
or hydride-shift, respectively, giving 2-butanones (10) in
excellent to good yields. Furthermore, ring enlargement
was observed on treatment of 1-(1-hydroxy-1-phenyl-
ethyl)-cycloalkanols (3p,q) with concd sulfuric acid at
ꢀ5–0 °C to afford the corresponding 1-phenyl-1-methyl-
cyclohexanone (11p) and cycloheptanone (11q) in 82–
83% yields, respectively.
Since it is suggested that standard reduction potential of
magnesium metal in aqueous solvent system will be
It may be quite interesting that the similar acid-cata-
lyzed reaction of 1-phenyl-2-methyl-1,2-cyclobutanol
(7a0) unexpectedly brought about ring contraction to
give 1-phenyl-1-acetylcyclopropane (12a) in 91% yield,
possibly because of fast rearrangement of a cyclobutyl
to a cyclopropylcarbinyl cation stabilized by nonclassi-
cal conjugation1 (Scheme 2).
Table 4. Cyclic voltammetry of aromatic and aliphatic carbonyl
compounds and aromatic imine
Reduction potential (V)
C6H5–CO–CH3
C6H5–CO–CH2–CH2–CO–CH3
ꢀ2.10
ꢀ2.05
C H
6
5
N
)2.23
O
HO
Ph
C H -C CH
3
6
5
1) Mg / TMSCl
2) 5% H2SO4 aq.
n
CO2Me
Ph
CH3–CO–CH3
CH3CH2CH2–CHO
ꢀ2.96
ꢀ2.93
n
O
8
9a, n = 1, GC Yield = 78 %
9b, n = 2, GC Yield = 43 %
Reaction conditions: 1%Bu4NC1O4/DMF, rt, sweep rate 200 mV/s,
working electrode: Pt, counter electrode: Pt, reference electrode: Ag/
AgCl.
Scheme 1.

3872
H. Maekawa et al. / Tetrahedron Letters 45 (2004) 3869–3872
Acknowledgements
This research was supported by a Grant-in-Aid for
Scientific Research on Priority Areas (No. 14350467)
from Ministry of Education, Science, Sports and Cul-
ture, Japan.
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ketones and imines in the presence of excess amount of
aliphatic ketones or aldehydes gave mixed pinacol
products, 1,2-diols or 1,2-aminoethanols in good to
moderate yield. The reaction is characterized by unique
reaction pattern, simple procedure, mild reaction con-
ditions, use of biologically friendly Mg metal, reason-
able yield, and much usefulness of the products.
€
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Supplementary Material. Experimental procedures and
characterization for structure of the compounds 3, 5,7,9,
10, 11, and 13 are available.