Retropinacol/cross-pinacol coupling reactions - A catalytic access to 1,2-unsymmetrical diols

Article abstract of DOI:10.1002/adsc.201200358

A new concept to access unsymmetrical 1,2-diols with high yields is reported. This new methodology is based on a retropinacol/cross-pinacol coupling process. This transformation is characterized by its operational simplicity and very mild reaction condi tions.

Full text of DOI:10.1002/adsc.201200358

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DOI: 10.1002/adsc.201200358
Retropinacol/Cross-Pinacol Coupling Reactions – A Catalytic
Access to 1,2-Unsymmetrical Diols
Ulf Scheffler,a Reinhard Stçßer,a and Rainer Mahrwalda,*
a
Department of Chemistry, Humboldt-University, Brook-Taylor Str. 2, 12 489 Berlin, Germany
E-mail: rainer.mahrwald@rz.hu-berlin.de
Received: May 7, 2012; Revised: June 26, 2012; Published online: September 28, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200358.
Abstract: A new concept to access unsymmetrical
1,2-diols with high yields is reported. This new
methodology is based on a retropinacol/cross-pina-
col coupling process. This transformation is charac-
terized by its operational simplicity and very mild
reaction conditions.
pounds. In such an event a catalyst has to recognize
and discriminate between these two carbonyl com-
pounds. This so far unsolved problem can be over-
come by several experimental manipulations: precom-
plexation of one reactant by equimolar amounts of
a reagent, excess of one reactant or retarded addition
of one reactant. Competitively formed symmetrical
1,2-diols have to be laboriously separated.[3] A direct
access to cross-pinacol products can be achieved by in
situ generation of one coupling-reactant and simulta-
neous generation of the low-valent metalcatalyst. This
concept was realized under conditions of retropinacol
coupling. Although several examples of a reversible
Keywords: catalysis; cross-pinacol coupling reac-
tion; mechanism; unsymmetrical 1,2-diols
Traditionally, vicinal diols can be prepared by reduc- pinacol coupling reaction were reported,[4] this
tive coupling of ketones or aldehydes in the presence method has never been used for a cross-pinacol cou-
of active metals. Especially symmetrical 1,2-diols are pling reaction.[5]
generated in an extensive manner by this methodolo-
We have observed the formation of 1.1-diphenyl-
gy.[1] In contrast to that only a few publications have 1,2-diol 4a in reactions of benzopinacol 1 and acetone
described a successful execution of cross-pincol cou- in the presence of catalytic amounts of titanium(IV)
pling reactions.[2] The intermolecular cross-pinacol alkoxides (Scheme 1). At the same time equimolar
coupling reaction remains a challenge for chemists, amounts of benzophenone 3 were formed. Symmetri-
especially due to the non-existence of a real catalytic cal 1,2-diols could not be detected. Titanium(IV) alk-
execution of this transformation.
oxides are not sufficient for a real catalytic perfor-
High chemoselectivity is the base for a successful mance – long reaction times were observed. A dra-
cross-pinacol coupling of two different carbonyl com- matic enhancement of both reaction rates and yields
Scheme 1. Cross-pinacol coupling reactions with acetone.
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Retropinacol/Cross-Pinacol Coupling Reactions – A Catalytic Access to 1,2-Unsymmetrical Diols
Table 2. Retropinacol/cross-pinacol coupling reactions of ke-
tones.
is accomplished by addition of trialkylchlorosilanes.
This increase is controlled by the bulkiness of the
alkyl substituents. When used with triethylchlorosi-
lane, the amounts of essential titanium(IV) alkoxides
can be reduced to 5–10 mol%. Trialkylchlorosilanes
and titanium(IV) alkoxides were deployed in equimo-
lar amounts. Titanium(IV) tert-butoxide and triethyl-
chlorosilane were used to avoid undesirable side reac-
tions (Meerwein–Ponndorf–Verley reactions, forma-
tion of silyl ethers or pincol rearrangement).
Reactions were performed at room temperature in
dichloromethane, but toluene or acetonitrile can also
be used. An inert atmosphere is not necessary. Also,
a defined sequence of reactant addition is not re-
quired; the reaction starts in any reactant order. The
1,2-diols 2a–s of functionalized and even enolizable
aldehydes were generated in good to quantitative
yields under these reaction conditions. When used
with a-unbranched aldehydes substantial amounts of
the corresponding acetals were detected (2a, 2b and
2p, Table 1).
Entry
Product
R1
R2
Yield [%][a]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
Me
Me
Me
Me
Me
Et
Me
Et
n-Pr
i-Bu
Bn
99
99
99
99
98
92
98
99
94[b]
99
97
38
90
87
93
97
78
67
71
Et
-(CH2)4-
-(CH2)5-
9
-CHMeACHTNUGETRNNU(G CH2)4-
Ph
Ph
Ph
10
11
12
13
14
15
16
17
18
Me
Et
i-Pr
CH2OMe
3-pyridyl
CH=CH2
CH2Cl
CO2Et
Ph
Me
Me
Me
Me
Me
Me
The scope of this retropinacol/cross-pinacol cou-
pling process was substantially expanded by the de-
ployment of ketones (Table 2). The 1,2-diols 4a–
s were formed in good to quantitative yields in the
CH
CH2OMe
ACHTUNGERTN(NUNG OMe)2
presence of catalytic amonts of Ti
(O-t-Bu)4 and 19
4s
[a]
Isolated yield.
[b]
dr syn/anti: 4/1; reaction conditions: 10 mol% TiACHTUNGTRENNUNG(O-t-
Table 1. Retropinacol/cross-pinacol coupling reactions of al-
dehydes.
Bu)4/Et3SiCl; CH2Cl2; room temperature; 4 equiv.
ketone.
Et3SiCl at room temperature. Symmetrical 1,2-diols
were not detected under these reaction conditions.
In general, electron-rich aldehydes or ketones ex-
hibited higher yields than electron-poor carbonyl
compounds (compare entry 3 with 17, Table 1 or 19
with 13, Table 2). By deployment of ketones with
bulky substituents a decrease of yields is observed
(compare entry 12 with 11, Table 2).
Equimolar amounts of benzophenone 3 are detect-
ed during this transformation as mentioned above.
Symmetrical 1,2-diols were not detected. These obser-
vations support the following conclusion. Benzopina-
col 1 is homolytically cleaved by the titanium com-
plex. The generated radical immediately reacts with
the carbonyl compound to form an unsymmetrical
1,2-diol. Simultaneously oxidation to benzophenone 3
proceeds. The exact role of triethylchlorosilane is not
fully clarified until now. An acceleration of ligand re-
placement of intermediate titanium complexes is as-
sumed (D!A, Scheme 2).[6] A proposed reaction
mechanism is depicted in Scheme 2.
Entry
Product
R1
Yield [%][a]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
Me
n-Pr
i-Pr
t-Bu
60 (99)
85(99)
99
92
98
99
99
98
98
98
89
78
99
80
97
62(99)
71
56
i-Bu
(Et)2CH
cyclohexyl
Ph
4-Me-C6H4
4-t-Bu-C6H4
4-Br-C6H4
4-NO2-C6H4
2,4,6(Me)3-C6H2
2-MeO-C6H4
9
10
11
12
13
14
15
16
17
18
19
ꢀ
Ph CH=CH
ꢀ
Me CH=CH
EtO2C
N
2s
76
ESR experiments were performed in acetonitrile to
verify the proposed reaction pathway. These investi-
gations were focused on the initial retropinacol reac-
tion step. An ESR spectrum of a freshly prepared
[a]
Isolated yield (conversion: product+formed acetal); re-
action conditions: 5 mol% Ti(O-t-Bu)4/Et3SiCl; CH2Cl2;
AHCTUNGTRENNUNG
room temperature; 3 equiv. aldehyde.
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Ulf Scheffler et al.
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Scheme 2. Proposed reaction mechanism for the retropinacol/cross-pinacol coupling reactions.
benzophenone-titanium complex A in the presence of in detail.[7] A broad signal (g’=1.908) appears after
an excess of dichlorodimethylsilane is depicted in a longer reaction time in concentrated solutions, indi-
Figure 1. Under these conditions benzopinacol 1 is cating the existence of a trichlorotitaniumACTHUNRTGNE(GNU III) aceto-
oxidized quantitatively to benzophenone 3. Simulta- nitrile complex. Integration of the signals reveals
neously a diamagnetic titanium(II) species must be a continuous decrease of the paramagnetic com-
generated due to the stoichiometric ratio. However pounds.[8] A typical signal shape of benzophenone
a signal appears, clearly indicating the existence of radical anions was not detected during the measure-
a titanium
(III) complex F (Scheme 3). This signal disappears these species or the intermediate formation of an h2-
within a couple or several hours. ESR experiments of titanium(IV)-benzophenone complex E.[9]
ACHTUNGTRENNUNG(III) species (g’=1.944), propably titanium- ments. This result suggests a very short life-time of
ACHTUNGTRENNUNG
titanium
G
An intensive blue-coloured precipitate is observed
in highly concentrated reaction solutions. The molecu-
lar structure of this compound was unambiguously
elucidated by single-crystal X-ray structure analysis as
the titaniumACHTUNTRGNEUNG(III) chloride acetonitrile complex 5
(Figure 2).[10] A complete oxidation of benzopinacol
1 does not occur under these reaction conditions.
These investigations confirm the generation of
titaniumACTHNUTRGNEUG(N III)species during the retropinacol step of
diol 1 and thus support the reaction mechanism
(Scheme 3).
To sum up, we have developed a new and catalytic
methodology for rapid access to cross-pinacol-cross
coupling. The unsymmetrical 1,2-diols were mostly
obtained in excellent yields. Corresponding symmetri-
cal pinacol products were not detected. In addition,
important details were attained to propose a catalytic
cycle. So far, this new concept has been discussed on
the base of deployment of benzopinacol 1. An exten-
sion of this transformation is possible by deployment
of other 1,2-diols that involves further modification of
Figure 1. ESR-spectra of the retropinacol reaction of benzo-
phenone A with dichlorodimethylsilane in acetonitrile; stan-
dard gref =1.9796; at the top: after 1 h reaction time g’=
1.944; at the bottom: after 6 h reaction time g’=1.908
(broad signal); g’=1.944.
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Retropinacol/Cross-Pinacol Coupling Reactions – A Catalytic Access to 1,2-Unsymmetrical Diols
Scheme 3. Proposed reaction mechanism for the oxidation of the benzopinacolato-ligand.
Experimental Section
General Procedure for Retropinacol/Cross-Pinacol
Coupling Reactions
Aldehydes: In a typical experiment 366 mg benzopinacol
1 (1.0 mmol) and 3 equiv. of the corresponding aldehyde
were dissolved in 3 mL dry DCM. 1.0 mL of a separately
prepared solution containing 0.05 mol/L TiACTHNURTGNENG(U O-t-Bu)4 and
Et3SiCl was added. The resulting solution was stirred at am-
bient temperature in a sealed reaction tube. The reaction
was continuously monitored by thin layer chromatography
(hexane/acetone: 9/1). When no more benzopinacol 1 was
detectable (1 h–3 d) the resulting mixture was extracted
with DCM and successively washed by saturated aqueous
NH4Cl and NaHCO3 solutions. The organic layers were sep-
arated, dried (MgSO4) and the solvent was removed under
vacuum. The residue was purified by flash column chroma-
tography.
Figure 2. Molecular structure of the titaniumACTHNURTGNEU(GN III) chloride
acetonitrile complex 5.
Ketones: In a typical experiment 366 mg benzopinacol
1 (1.0 mmol) and 4 equiv. of the corresponding ketone were
dissolved in 3 mL dry DCM. 1.0 mL of a separately pre-
catalysts and reaction conditions. This could be dem-
onstrated by the employment of 2.3-diphenyltartrate
6. 1,2-diol 6 was successfully reacted with even enoliz-
able aldehydes by slight changes of catalyst composi-
tion (Scheme 4).
This new retropinacol/cross-pinacol coupling pro-
cess can be established by further generalization as an
important tool for the synthesis of unsymmetrical 1,2-
diols. Investigations on the enantioselective execution
of this reaction are under way.
pared solution containing 1 mol/L TiACTHNUTRGNE(UNG O-t-Bu)4 and Et3SiCl
was added. The resulting solution was stirred at ambient
temperature in a sealed reaction tube. The reaction was con-
tinuously monitored by thin layer chromatography (hexane/
acetone: 9/1). When no more benzopinacol 1 was detectable
(12 h–5 d) the resulting mixture was extracted with DCM
and successively washed by saturated aqueous NH4Cl and
NaHCO3 solutions. The organic layers were separated, dried
(MgSO4) and the solvent was removed under vacuum. The
residue was purified by flash column chromatography.
Supporting Information
Experimental details and characterization data of new com-
pounds are given in the Supporting Information.
Acknowledgements
Scheme 4. Retropinacol/cross-pinacol coupling of 2,3-diphe-
nyltartrates.
The authors thank Deutsche Forschungsgemeinschaft, Bayer
Pharma AG, Chemtura Organometallics GmbH Bergkamen,
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Ulf Scheffler et al.
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Bayer Services GmbH, BASF AG, and Sasol GmbH for fi-
nancial support.
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