A new Yb3+-catalyzed pinacol and imine-coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2010.01.057

Ytterbium triflate, Yb(OTf)₃, catalyzes the intermolecular reductive homocouplings of imines, aldehydes, and ketones at loadings of 5 mol % in the presence of Mg and Me₃SiCl to give isolated yields of up to 95%. Diastereoselectivity of up to 4/96 (dl/meso) is achieved for aromatic aldehydes, up to 100% dl for aliphatic aldehydes, and 100% dl for an intramolecular imine coupling.

Full text of DOI:10.1016/j.tetlet.2010.01.057

Tetrahedron Letters 51 (2010) 1558–1561
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Tetrahedron Letters
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A new Yb3+-catalyzed pinacol and imine-coupling reaction
*
*
Helen C. Aspinall , Nicholas Greeves , Shane Lo Fan Hin
Department of Chemistry, University of Liverpool, Crown Street, Liverpool L69 7ZD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Ytterbium triflate, Yb(OTf)3, catalyzes the intermolecular reductive homocouplings of imines, aldehydes,
and ketones at loadings of 5 mol % in the presence of Mg and Me3SiCl to give isolated yields of up to 95%.
Diastereoselectivity of up to 4/96 (dl/meso) is achieved for aromatic aldehydes, up to 100% dl for aliphatic
aldehydes, and 100% dl for an intramolecular imine coupling.
Received 18 November 2009
Revised 11 January 2010
Accepted 15 January 2010
Available online 22 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Samarium iodide (SmI2) combines mild Lewis acidity with a
useful reduction potential, and has proved to be a valuable and
effective reagent for the reductive homocoupling of carbonyl1
and imine2 substrates to give the corresponding 1,2-diols or dia-
mines. While it is a unique and extremely versatile reagent,3
SmI2 is rather expensive to buy and quite demanding to work with,
making its use in stoichiometric quantities unattractive for large
scale syntheses. In order to address these problems we have devel-
oped a SmI2-catalyzed pinacol-coupling reaction that delivers high
diastereoselectivity with a catalytic loading of 10 mol % using Mg
as reductant.4
Annunziata et al. have reported the influence of various Lewis
acids [including Yb(OTf)3] used in conjunction with stoichiometric
SmI2 on the outcomes of pinacol5 and imine-coupling reactions,6,7
and have noted some enhancement of diastereoselectivity. This
prompted us to investigate the use of catalytic SmI2 with added Le-
wis acid and Mg as reductant.
Annunziata et al. reported one instance of catalytic SmI2
(0.2 equiv) used in conjunction with Mg (8 equiv) and stoichiome-
tric Yb(OTf)3 for imine coupling, which gave an isolated yield of
62% and diastereoselectivity of 56/44 (dl/meso) for N-phenylbenz-
aldimine.6 We started our work by re-examining this method ap-
plied to 4-chlorobenzaldehyde phenyl imine. We noted that the
deep blue solution of SmI2 was decolorized when it was added to
anhydrous Yb(OTf)3 and reasoned that SmI2 was reducing Yb3+ to
Yb2+. This suggested to us that SmI2 was not the active reducing
agent and so we carried out a series of reactions in the absence
of SmI2 (Table 1). We also tested the activity of Yb(OTf)2 (generated
in situ by addition of EtMgBr to Yb(OTf)38) and found that it was
completely inactive in the imine-coupling reaction. Mg in the
absence of the rare earth Lewis acid was also inactive (Table 1,
entry 1).
The use of stoichiometric Yb(OTf)3 with Mg (entries 2 and 3)
gave good isolated yields of coupled products, and we found that
hydrated Yb(OTf)3 was somewhat more active and gave slightly
better diastereoselectivity. After this promising start we looked
at sub-stoichiometric amounts of Lewis acid, and found that in
the absence of Me3SiX (X = Cl or OTf), the reaction was extremely
sluggish. Anhydrous YbCl3 (entry 9) is difficult to dissolve and
was significantly less active than Yb(OTf)3. The use of Me3SiCl in
the catalytic cycle will result in chloride-triflate exchange and
the likely formation of YbCl3, which might be detrimental to the
reaction. In order to prevent this, we investigated the use of Me3-
SiOTf with Yb(OTf)3. However, this resulted in reduced catalytic
activity (entry 8). We therefore conclude that the low activity of
anhydrous YbCl3 is due only to the difficulty of dissolving solid
YbCl3 in the solvents we used. We found that Y(OTf)3 was also an
effective catalyst for the imine-coupling reaction (Table 1, entry
9), though less active than Yb(OTf)3, consistent with its lower Le-
wis acidity due to the larger ionic radius of Y3+ compared with
Yb3+. The activity of Y(OTf)3, which does not have an accessible
+2 oxidation state in solution, supports our view that the role of
Yb(OTf)3 is as a Lewis acid, and Yb is not involved as a reducing
agent.
The scope of the imine-coupling reaction is shown in Table 2
where we explored substrates with a range of substituents and
substitution patterns. Although the strongly electron-donating
OMe substituent resulted in reduced activity, it was tolerated
when it was present on just one of the aryl rings (entries 3, 4, 7
and 8), but not when it was present on both (entry 9). We had
hoped to improve the diastereoselectivity by introducing an OMe
substituent in a position where it could chelate to the Lewis acid
catalyst (entries 3 and 4). In one case (entry 3 vs entry 1) there
was a reversal in diastereoselectivity, but in the other case (entry
4 vs entry 2) the effect was negligible. It is noteworthy that halo-
gen substituents were well tolerated (entries 2, 4, 5, and 6), and
we observed no side reactions such as Grignard formation.
Both cyclic and acyclic polyether ligands are known to influence
the redox chemistry of Sm and Yb by stabilizing the +2 oxidation
* Corresponding authors. Fax: +44 (0) 151 794 3588 (H.C.A.); +44 (0) 151 794
3588 (N.G.).
E-mail addresses: hca@liv.ac.uk (H.C. Aspinall), ngreeves@liv.ac.uk (N. Greeves).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.057

H. C. Aspinall et al. / Tetrahedron Letters 51 (2010) 1558–1561
1559
Table 1
Table 3
Optimization of the conditions for imine coupling
Yb(OTf)3-catalyzed pinacol coupling of aldehydes and ketones
O
Yb(OTf)3 (5 mol%)
catalyst
NPh
Cl
2
R1 R2
10Mg, Me3SiX,
THF, reflux
10 Mg, 2 Me3SiCl
solvent, reflux
Cl
HO
R2
R1
R1
R2
OH
R1
HO
Cl
Cl
Cl
R2
R2
+
R1
OH
+
meso
dl
Entry
Substrate
Solventa
THF
Time
Yieldb (%), dl:mesoc
PhHN
NHPh
PhHN
NHPh
dl
meso
1a
1b
1c
90 min
3 h
4 h
91 (80:20)
71 (4:96)
74 (27:63)
95 (40:60)
O
CH2Cl2/THF
CH2Cl2/THFd
MeCN
Entry
Catalyst/mol
equiv
Mol equiv
Me3SiX
Time
Yielda (%), dl:mesob
1d
45 min
1
2
3
4
5
6
7
8
9
10
None
1e
0
0
0
0
1.5 h
1 h
7 h
40 min
3 d
2 h
45 min
3 h
4 h
No reaction
81 (47:53)
No reaction
81 (65:35)
69 (64:36)
64 (63:37)
77 (59:41)
55 (48:52)
61 (64:36)
70 (65:35)
2a
2b
2c
THF
20 h
24 h
30 h
23 h
64 (75:25)
65 (93:7)
60 (60:40)
69 (60:40)
O
Yb(OTf)3c/1
Yb(OTf)3c/1
Yb(OTf)3e/1
CH2Cl2/THF
d
CH2Cl2/THFd
MeCN
2d
Yb(OTf)3e/0.5
Yb(OTf)3e/0.5
Yb(OTf)3e/0.05
Yb(OTf)3e/0.05
YbCl3c/0.05
1f
1f
1g
1f
1f
3a
3b
O
THF
CH2Cl2/THF
15 h
15 h
61 (69:31)
60 (60:40)
n-C7H15
4a
4b
THF
CH2Cl2/THF
3.5 h
3.5 h
55 (56:44)
53 (79:21)
Y(OTf)3e/0.05
1.25 h
Ph
O
O
a
b
c
d
e
f
5a
5b
THF
CH2Cl2/THF
18 h
18 h
95 (dl only)
89 (dl only)
Isolated yield.
Determined by 1H NMR spectroscopy.
Anhydrous.
Reaction run at 40 °C.
Hydrated.
Me3SiCl.
6a
6b
THF
CH2Cl2/THF
90 min
3 h
85 (67:33)
75 (55:45)
O
g
Me3SiOTf.
a
b
c
CH2Cl2/THF = 4:1.
Isolated yield.
Determined by GC and confirmed by GCMS.
Reaction run at room temperature.
state.9,10 We4 and Skrydstrup and co-workers11 have shown that
the addition of tetraglyme enhances the diastereoselectivity of
SmI2-catalyzed pinacol coupling, and so we investigated the effect
of added ligand (1:1 ligand:catalyst) on the outcome of the imine-
coupling reactions reported here. We found that added ligand (2,2-
bipyridyl, triethyleneglycol, triglyme, tetraglyme, 18-crown-6 or
15-crown-5) had no significant effect on either the yield or
diastereoselectivity.
d
Intramolecular imine coupling is a useful route to 2,3-disubsti-
tuted piperazines, and this reaction has been reported using Mn as
reductant with a Brønsted acid catalyst,12 and using Zn as reduc-
tant catalyzed by a stoichiometric amount of the Lewis acid [Ti-
Cl2(OPri)2].13 When we applied our imine-coupling protocol to
this reaction we achieved a yield of 85% after recrystallization
and 100% diastereoselectivity for the dl product, making this an
attractive alternative to the published methods.
Table 2
Yb(OTf)3-catalyzed imine coupling
Z
5 mol% Yb(OTf)3
10 Mg
H
N
Yb(OTf)3 (5 mol%)
Ph
Ph
N
N
Ph
Ph
85% yield
100% dl
N
10Mg, 2Me3SiCl
THF, reflux
2TMSCl
THF reflux
18 h
N
H
Y
X
Ar1
Ar2HN
NHAr2
Ar1
Ar1
Ar1
After these promising results with imine coupling, we next investi-
gated Yb(OTf)3 catalysis of the pinacol-coupling reaction (Table 3).
Isolated yields were good to excellent and significantly, we ob-
served no reduction product in any of these reactions.
+
Ar2HN
NHAr2
dl
meso
In our previous work with SmI2/tetraglyme-catalyzed pinacol
coupling we found a clear selectivity for the meso product with
aromatic substrates and the dl product with aliphatic substrates.4
The stereochemical outcome of the present method is much less
clear-cut, and in the three solvent systems that we investigated,
we observed some dramatic effects on the diastereoselectivity.
In THF the dl product was favored in all cases (aromatic and
aliphatic) that we examined. THF is likely to compete with the sub-
strate for binding to the Lewis acid center, possibly reducing cata-
lytic activity. We therefore examined the 4:1 CH2Cl2/THF solvent
system and found that although it resulted in slightly decreased
rather than enhanced activity, in some cases it had a dramatic
Entry
X
Y
Z
Time
2 h
45 min
4 h
3.5 h
2.5 h
2 h
5 h
5 h
Yielda (%), dl:mesob
1
2
3
4
5
6
7
8
9
H
Cl
H
Cl
H
Cl
OMe
H
OMe
H
H
OMe
OMe
H
H
H
H
H
H
H
H
H
Br
Br
H
77 (62:38)
77 (59:41)
63 (31:69)
50 (65:35)
69 (40:60)
79 (50:50)
63 (67:33)
56 (56:44)
No product isolated
OMe
OMe
18 h
a
Isolated yield.
Determined by 1H NMR spectroscopy.
b

1560
H. C. Aspinall et al. / Tetrahedron Letters 51 (2010) 1558–1561
effect on the diastereoselectivity of the reaction. For benzaldehyde
(Table 3, entries 1a and b) the diastereoselectivity was reversed on
changing solvent, and in CH2Cl2/THF the meso product was heavily
favored. For cyclohexanecarboxaldehyde, (Table 3, entries 2a and
b) the use of CH2Cl2/THF dramatically enhanced the selectivity to-
ward the dl isomer. An enhancement of diastereoselectivity in
CH2Cl2/THF was also observed for the unsaturated substrate cinna-
maldehyde (Table 3 entries 4a and b). We observed slightly en-
hanced activity in MeCN cf. THF for the coupling of benzaldehyde
(Table 3, entry 1c) and cyclohexanecarboxaldehyde (entry 2c),
but poorer diastereoselectivity. As our reactions were carried out
in refluxing solvents, variation of the solvent resulted not only in
different donor properties and dielectric constants, but also in a
change in reaction temperature. The highest diastereoselectivity
was achieved in the lowest boiling solvent, CH2Cl2/THF (entries
1b and 2b), and so we repeated these reactions at room tempera-
ture (entries 1c and 2c), and found that the reduced reaction tem-
perature gave significantly poorer diastereoselectivity. This proves
that the high diastereoselectivity achieved in CH2Cl2/THF is due to
the properties of the solvent system and is not simply due to reac-
tion temperature.
We found that tetraglyme was highly effective in enhancing the
diastereoselectivity of SmI2-catalyzed pinacol-coupling reactions4
and so we examined the effect of this pentadentate ligand on the
pinacol coupling of benzaldehyde; the results are summarized in
Table 4. In the three solvent systems that we examined there
was a slight decrease in activity in the presence of tetraglyme,
but there was a dramatic effect on diastereoselectivity, in all cases
resulting in selectivity for the meso diastereomer. In THF (entries
1a and b) addition of tetraglyme caused reversal of diastereoselec-
tivity; in MeCN, an increase in selectivity was observed, and in
CH2Cl2/THF there was a slight decrease in selectivity.
Two paths for the pinacol-coupling reaction can be envisaged,
as summarized in Scheme 1. Path I, an intermolecular coupling, re-
sults in meso product and is favored when there is a high concen-
tration of ketyl radical. This situation is most likely with an easily
reduced substrate, a more powerful Lewis acid or a higher reaction
temperature. Path II is an intramolecular coupling, and two factors
are required for this path to predominate: there must be a low con-
centration of ketyl radical and sufficient coordinative unsaturation
at the Lewis acid to allow coordination of a second substrate mol-
ecule. Solvent effects in this reaction are complex; the relevant fac-
tors are: dielectric constant (which will influence Lewis acid
strength), boiling point (which determines the reaction tempera-
ture), and donor number (which will determine the competition
between solvent and substrate for coordination to the Lewis acid).
Given the complexity of the reaction variables it is not surprising
that the diastereoselectivity appears unpredictable.
Yb3+
O
R1
R2
OH
HO
R2
R1
R1
R2
R2
R1
O
meso
Yb3+
R2 R1
PATH I
O
Yb3+
Yb3+
Mg
O
O
R1 R2
R1 R2
O
R2 R1
PATH II
Mg
Yb3+
HO
R2
R1
R2
OH
Yb3+
O
O
O
O
R1
R1
R2
R1
R2
R1 R2
R2 R1
dl
Scheme 1. Diastereoselectivity in the Yb(OTf)3-catalyzed pinacol-coupling
reaction.
a slight selectivity for the meso diastereomer, consistent with
predominance of Path I. Addition of tetraglyme would limit the
available binding sites at the Lewis acid, effectively blocking Path
II, and so addition of tetraglyme resulted in excellent meso selectiv-
ity (entry 2b). In THF (bp 66 °C; dielectric constant 7.5), the Lewis
acidity of Yb(OTf)3 is reduced compared with that in MeCN and
this, combined with the somewhat reduced reaction temperature,
is expected to give a lower concentration of coordinated ketyl
radicals and hence lead to predominance of Path II and dl selectiv-
ity (entry 1a). Added tetraglyme would occupy five coordination
sites at Yb3+ 14
blocking Path II and resulting in meso selectivity
,
(entry 1b). The situation was much more finely balanced in CH2Cl2,
where the reaction was significantly slower and addition of
tetraglyme resulted in some reduction in meso selectivity (entries
3a and 3b).
In conclusion, we have developed an extremely straightforward
method for the intermolecular homocoupling of aryl imines and
aromatic and aliphatic carbonyl compounds, using Mg as the
reducing agent and Yb(OTf)3 as a Lewis acid catalyst.15 Products
are isolated in good to excellent yields and diastereoselectivity of
up to 100% has been achieved.
The coupling of benzaldehyde (Table 4) is the simplest case to
consider. The most rapid reaction was achieved in acetonitrile (en-
try 2a), which has the highest boiling point (82 °C) and the highest
dielectric constant (37), and in the absence of tetraglyme there was
Supplementary data
Table 4
Effect of solvent and added ligand on the pinacol coupling of benzaldehydea
Characterization data for key compounds. Supplementary data
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.01.057.
Entry
Solvent
THF
Ligand
Time
Yieldb (%), dl:mesoc
1a
1b
2a
2b
3a
3b
None
Tetraglyme
None
Tetraglyme
None
Tetraglyme
1.5 h
1.5 h
45 min
45 min
3 h
91 (80:20)
80 (6:94)
95 (40:60)
62 (5:95)
71 (4:96)
69 (13:87)
MeCN
References and notes
CH2Cl2/THFd
1. Souppe, J. L.; Namy, J.; Kagan, H. B. Tetrahedron Lett. 1983, 24, 765–766.
2. Machrouhi, F.; Namy, J. L. Tetrahedron Lett. 1999, 40, 1315–1318.
3. Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem., Int. Ed. 2009, 48, 7140–
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5. Annunziata, R.; Benaglia, M.; Cinquini, M.; Raimondi, L. Eur. J. Org. Chem. 1999,
3369–3374.
4 h
a
b
c
Conditions: 0.05 equiv hydrated Yb(OTf)3, 1 equiv Me3SiCl, 10 equiv Mg, reflux.
Isolated yield.
Determined by GC and confirmed by GC–MS.
CH2Cl2/THF = 4:1.
d

H. C. Aspinall et al. / Tetrahedron Letters 51 (2010) 1558–1561
1561
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atmosphere of Ar or N2. The reaction was monitored by TLC and was quenched
with brine (20 cm3). The crude product was extracted with EtOAc (3 Â 20 cm3)
and the combined extracts were dried (MgSO4). The crude product was purified
by flash chromatography using hexane/Et2O on silica.
8. Hanamoto, T.; Sugimoto, Y.; Sugino, A.; Inaga, J. Synlett 1994, 377–378.
9. Bünzli, J.-C. G.; Pilloud, F. Inorg. Chem. 1989, 28, 2638–2642.
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15. Experimental procedures. General procedure for Yb(OTf)3-catalyzed imine
coupling: Yb(OTf)3 (0.05 mmol), imine (1 mmol) and activated Mg turnings
(10 mmol) were placed in Schlenk flask and freshly distilled THF (8 cm3) was
added. The mixture was stirred for 10 min and then Me3SiCl (0.2 cm3, 1 mmol)
was added and the mixture was heated to reflux with stirring under an
General procedure for Yb(OTf)3-catalyzed pinacol-coupling reaction: Yb(OTf)3
(0.05 mmol) and activated Mg powder (10 mmol) were placed in a Schlenk
flask and freshly distilled THF (8 cm3) was added. Aldehyde or ketone (1 mmol)
was added and the mixture was stirred for 10 min. Me3SiCl (0.2 cm3, 1 mmol)
was then added and the mixture was heated to reflux with stirring under an
atmosphere of Ar or N2. The reaction was monitored by TLC and was quenched
with saturated brine (20 cm3). The crude product was extracted with EtOAc
(3 Â 20 cm3) and the combined extracts were dried (MgSO4). The crude
product was purified by flash chromatography using hexane/Et2O on silica.
General procedure for imine synthesis: The aldehyde (10 mmol), aniline
(10 mmol) and 4 Å molecular sieves (1.66 mm pellets, 10 g) were mixed in
dry CH2Cl2 (30 cm3). The mixture was allowed to stir at rt and reaction was
monitored by TLC. When the reaction was complete, the mixture was filtered
through a pad of Celite and the residue was washed with dry CH2Cl2. The
filtrate was collected and evaporated in vacuo and the imine was then dried
under high vacuum and stored in a sealed container at rt.