Exploring SmBr2-, SmI2-, and YbI2-mediated reactions assisted by microwave irradiation

Article abstract of DOI:10.1002/chem.200401320

The use of microwave heating in lanthanide(II) halide (LnX₂ = SmBr₂, SmI₂, and YbI₂) mediated reduction and coupling reactions has been investigated for a variety of functional groups including α,β-unsaturated esters, aldehydes, ketones, imines, and alkyl halides. Good to quantitative transformations were obtained within a few minutes without the addition of any co-solvents, such as hexamethyl phosphoramide (HMPA). The redox potential of YbI₂ in tetrahydrofuran (THF) has been determined as -1.02± 0.05 V (versus Ag/AgNO₃) by cyclic voltammetry. A large selectivity difference in various reactions was observed depending on the redox potential of the LnX₂ reagent. The more powerful reductant, SmBr₂, afforded mainly pinacol-coupling products of ketones whereas the weaker reductant YbI₂ afforded mainly reduction products. The results indicate that the reducing power of LnX ₂ has a large impact on not only the pinacol coupling/reduction product ratio of ketones but also on other substrates in which there are competing coupling and reduction reactions. The use of in situ generated LnX₂ has also been explored and proven useful in many of these reactions.

Full text of DOI:10.1002/chem.200401320

FULL PAPER
Exploring SmBr2-, SmI2-, and YbI2-Mediated Reactions Assisted by
Microwave Irradiation
Anders Dahlꢀn,[a] Edamana Prasad,[b] Robert A. Flowers II,[b] and Gçran Hilmersson*[a]
Abstract: The use of microwave heat-
ing in lanthanide(ii) halide (LnX2 =
SmBr2, SmI2, and YbI2) mediated re-
duction and coupling reactions has
been investigated for a variety of func-
tional groups including a,b-unsaturated
esters, aldehydes, ketones, imines, and
alkyl halides. Good to quantitative
transformations were obtained within a
few minutes without the addition of
any co-solvents, such as hexamethyl
phosphoramide (HMPA). The redox
potential of YbI2 in tetrahydrofuran
(THF) has been determined as À1.02Æ
0.05 V (versus Ag/AgNO3) by cyclic
voltammetry. A large selectivity differ-
ence in various reactions was observed
depending on the redox potential of
the LnX2 reagent. The more powerful
reductant, SmBr2, afforded mainly pi-
nacol-coupling products of ketones
whereas the weaker reductant YbI2 af-
forded mainly reduction products. The
results indicate that the reducing
power of LnX2 has a large impact on
not only the pinacol coupling/reduction
product ratio of ketones but also on
other substrates in which there are
competing coupling and reduction re-
actions. The use of in situ generated
LnX2 has also been explored and
proven useful in many of these reac-
tions.
Keywords: cyclic voltammetry
·
lanthanides · microwave irradiation ·
reduction · reductive coupling
Introduction
solvents. This is due to the co-solvent causing a large in-
crease in the oxidation potential.[3] Recently, there have also
been reports on the use of SmBr2, DyI2, NdI2, and TmI2,
which have a higher oxidation potential than SmI2 in tetra-
hydrofuran (THF). With these more potent reducing agents
the use of HMPA is less important.[4] The replacement of
the carcinogenic additive HMPA with amine/water has also
been successful in some SmI2-mediated reactions, particular-
ly in the reduction of alkyl halides and conjugated alkenes,
and pinacol-coupling reactions of aromatic aldehydes, ke-
tones, and imines.[5]
Divalent lanthanides have been widely explored during
recent years and have become much appreciated as single-
electron-transfer reagents in various organic transforma-
tions.[1] The chemistry developed around the divalent lantha-
nides has been focused predominantly on SmI2 as a result of
its ease of preparation, commercial availability, and broad
utility in organic synthesis. The more reactive SmBr2 and
the less reactive YbI2 have so far been considerably less uti-
lized.
The development of rapid and reliable SmI2-mediated
syntheses has been largely dependent on the addition of co-
solvents, for example, hexamethyl phosphoramide
(HMPA).[2] Numerous coupling reactions, as well as the re-
duction of ketones, alkyl halides, and a,b-unsaturated esters,
have been effectively accelerated with the addition of co-
The reagent mixtures of SmI2/H2O/amine often favor re-
duction over intermolecular coupling reactions, such as pina-
col and Barbier-coupling reactions. Due to the importance
of SmI2-mediated intermolecular coupling reactions in or-
ganic synthesis, it is most desirable to find alternative condi-
tions that limit the use of HMPA. Recently, we reported
that microwave heating is a simple and fast method for the
preparation of SmI2, YbI2, SmBr2, and EuI2.[6] Several
single-electron-transfer processes using SmI2 alone are slow
at room temperature. Recently, microwave-accelerated syn-
thesis has proven superior to conventional heating in many
reactions,[7] including homogeneous palladium-catalyzed re-
actions such as Heck,[8] Sonogashira,[9] and cross-coupling re-
actions (Suzuki[10] and Stille[11]), and allylic substitution reac-
tions.[12] As a result of the success of these reactions, it
[a] A. Dahlꢀn, Prof. G. Hilmersson
Department of Chemistry, Gçteborg University
412 96 Gçteborg (Sweden)
Fax : (+46)31-772-3840
E-mail: hilmers@chem.gu.se
[b] Dr. E. Prasad, Dr. R. A. Flowers II
Department of Chemistry, Lehigh University
Bethlehem, PA 18015 (USA)
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seemed reasonable to study some of the fundamental
chemistry mediated by divalent lanthanides under micro-
wave heating for use as a viable alternative to the addition
of co-solvents.
Herein we report the use of microwave irradiation in se-
lected lanthanide(ii) halide (LnX2) mediated reactions, in
which SmBr2, SmI2, and YbI2 have been compared in vari-
ous reductive coupling and reduction reactions. The reduc-
tion potentials of SmBr2 and SmI2 in THF are À2.07 and
À1.55 V (versus Ag/AgNO3), respectively. We have now
also measured the reduction potential of YbI2 in THF. The
reducing power of the divalent lanthanide reagent is found
to have a strong influence on the course of the reaction, for
example, reduction versus coupling.
Scheme 1. Reduction of ketones, imines, a,b-unsaturated esters, and hal-
ides with LnX2 under microwave irradiation.
served either in the presence, or in the absence of methanol.
Another recalcitrant case is the reduction of alkyl halides. 1-
Iododecane was easily reduced within five minutes with
SmI2/MeOH, while 1-chlorodecane, which is hard to reduce
using SmI2/MeOH at room temperature, was difficult to
reduce even under microwave irradiation. Nevertheless,
with the addition of Et3N/H2O instead of methanol the re-
duction was completed within five minutes under microwave
irradiation. On the contrary, chlorobenzene was not under
any circumstances reduced by using microwave irradiation
even though the SmI2/H2O/amine mixture readily reduces
Results and Discussion
Cyclic voltammetry investigation: Cyclic voltammetry was
used to estimate the redox potential of YbI2 in THF for
comparison with the potentials known for SmI2 and SmBr2.
The potential for YbI2 was estimated to be À1.02Æ0.05 V
(versus Ag/AgNO3; Figure 1). Thus, the reducing agent YbI2
has a reducing power approximately 0.5 V smaller than that
of SmI2 (À1.55Æ0.05 V). In addition, SmBr2 (À2.07Æ
0.05 V) is a more powerful reducing agent than SmI2 by
about 0.5 V.
Table 1. Microwave-assisted reduction reactions at 1808C in the presence
of MeOH in THF.[a]
Substrate
Reagent (LnX2)
Reduction [%]
SmBr2
SmI2
YbI2
>99
>99
>99[b]
SmBr2
SmI2
YbI2
>99
>99
>99[b]
SmBr2
SmI2
YbI2
>99
>99
>99[b]
Figure 1. Cyclic voltammogram for YbI2 in THF.
SmBr2
SmI2
YbI2
>99
>99
Microwave-assisted reduction mediated by SmBr2, SmI2, and
YbI2: Reduction of ketones with SmI2 is very slow at
normal pressure and room temperature yielding only 10%
alcohol after several days with methanol as the proton
source.[13] In contrast to this, a quantitative yield was ob-
tained in less than 5 min at 1808C with microwave heating
mediated by either of SmBr2, SmI2, or YbI2 in the presence
of methanol (Scheme 1). This corresponds to a rate en-
hancement of approximately 2000-fold compared with the
rate of reduction at room temperature. This rate enhance-
ment is roughly similar to that expected for the same reac-
tion carried out at a temperature 1608C higher, and it does
not appear to be any microwave effect.[7c] Imines were re-
duced in the same way (Table 1).
>99[b]
SmBr2
SmI2
YbI2
>99
>99
>99[b]
SmBr2
SmI2
YbI2
>99
>99
>99[b]
SmBr2
SmI2
YbI2
>99
>99
>99[b]
[a] LnX2 (2.5 equiv) in THF. The substrate (1 equiv) and methanol
(9 equiv) were added just before the vessel was placed in the microwave
reactor. The reaction mixture was irradiated for 5 min, unless otherwise
stated. All reported conversions are based on GC yield. [b] Reduction re-
actions performed in the presence of YbI2 were irradiated for 10–20 min
to ensure quantitative conversion.
The double bond in a,b-unsaturated esters was easily re-
duced by the LnX2/alcohol mixture. Conversely, reduction
of conjugated carbon–carbon double bonds was not ob-
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Lanthanide(ii) Halide Mediated Reactions
FULL PAPER
chlorobenzene at room temperature. Further studies showed
that the powerful mixture of SmI2/H2O/Et3N could not be
employed, as H2O and Et3N cause deleterious side reactions
with SmI2 at these elevated temperatures and extended re-
action times (i.e., more than 5 min). Methanol was found to
be superior to H2O as a proton donor in the microwave-
heated reduction, because it reacts slowly with LnX2 at any
temperature.
Scheme 2. Coupling of benzyl chloride with LnX2 under microwave irra-
diation. The values represent the yields (%) obtained.
Microwave-assisted coupling reactions mediated by SmBr2,
SmI2, and YbI2: To determine the general utility of micro-
wave-accelerated reactions, the coupling of benzyl chloride
with SmBr2, SmI2, and YbI2 was tested, as this substrate is
easily coupled under ambient conditions. High conversions
were obtained for all mixtures, although SmBr2 appears to
be the superior coupling reagent (Scheme 2). The addition
of methanol to the same mixtures gave almost quantitative
reduction of benzyl chloride to toluene.
Scheme 3. Pinacol-coupling reactions of aliphatic ketones, aldehydes
(top), and imines (bottom) with LnX2. R, R’, R’’, R’’’=alkyl, aryl, or H,
see Table 2.
As previously stated, one of the main objectives of this
study was to find a replacement for HMPA in pinacol-cou-
pling reactions of aliphatic ketones, aldehydes, and imines
(Scheme 3). As reduction is fa-
vored for aliphatic ketones
Table 2. Microwave-assisted pinacol-coupling reactions in THF.[a]
when using the water/amine
method, this approach cannot
be used. Particularly interesting
are pinacol-coupling reactions
mediated by SmBr2, which were
recently reported by Namy
et al.[14] The black suspension of
SmBr2 in THF is obtained by
stirring Sm powder with tetra-
bromoethane in THF for at
least 15 hours at ambient tem-
perature, or alternatively five
minutes at 1808C under micro-
wave irradiation. The ketone or
aldehyde was added to SmBr2,
SmI2, or YbI2 in THF and then
irradiated in the microwave re-
actor. The general trend ob-
served for these coupling reac-
tions was that pinacol coupling
was favored over reduction in
the order SmBr2 >SmI2 >YbI2.
A higher reducing power (as
determined by the redox poten-
tials) correlates well with the
extent of pinacol coupling.
With SmBr2, high isolated
yields for coupling reactions
were obtained (Table 2).
Substrate
Reagent (LnX2)
Reduction [%]
Pinacol [%] (dl/meso)
SmBr2
SmI2
YbI2
3
3
18
97 (73:27)
97 (70:30)
82 (77:23)
SmBr2
SmI2
YbI2
2
4
24
98 (57:43)
96 (32:68)
76 (66:34)
SmBr2
SmI2
YbI2
<1
10
84
>99 (50:50)[b]
90 (50:50)
16 (50:50)[c]
SmBr2
SmI2
YbI2
2
11
83
98 (50:50)[b]
89 (49:51)
17 (55:45)[c]
SmBr2
SmI2
YbI2
<1
5
5
>99 (96:4)[b]
95 (80:20)
95 (91:9)
SmBr2
SmI2
YbI2
14
23
70
86
77
30
SmBr2
SmI2
YbI2
50
50 (100:0)
73 (56:44)
N.R.[d]
27
N.R.[d]
SmBr2
SmI2
YbI2
26
8
12
74
92
88[c]
Surprisingly, the diastereose-
lectivity increased in the oppo-
site order, that is, YbI2 gave the
[a] LnX2 (1.1–2.0 equiv) in THF. The substrate (1 equiv) was added before the vessel was placed in the micro-
wave reactor. The reaction mixture was irradiated for 5 min. [b] Selected pinacol-coupled products were isolat-
ed yielding 85–95% product after flash chromatography. [c] Reactions performed in the presence of YbI2 were
highest
Similar
diastereoselectivity.
diastereoselectivities irradiated for 45–60 min to ensure full conversion. [d] N.R.=no reaction.
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G. Hilmersson et al.
were achieved with SmBr2 at room temperature[14] as with
microwave irradiation at 1808C, but the microwave-assisted
coupling reactions gave a higher conversion in a much short-
er reaction time (5 min compared with 24 h). Moreover, the
possibility of pinacolization with several aliphatic and aro-
matic imines was also explored, and it was found that aro-
matic imines were efficiently coupled, while aliphatic imines
were simply reduced. This was disappointing because we
aimed for a general method for pinacolization. Nevertheless,
it is still useful for the coupling of aromatic imines, as the re-
action time was shortened from 1.5 hours at reflux (658C)[15]
to five minutes in the microwave environment.
Unfortunately, all attempts to initiate intermolecular cou-
pling between a ketone and an alkyl halide, for example, cy-
clohexanone and 1-chlorodecane or 1-iododecane, proved
unsuccessful and led exclusively to reduction of one or both
of the substrates. Ultimately, intramolecular reductive cou-
pling of an aryl iodide to a double bond proved successful
(Scheme 4).
of 2-heptanone and aliphatic imines (entries 9–12, Table 4)
gave complete reduction within 10 minutes in the presence
of methanol using microwave heating. Therefore, we em-
ployed the in situ conditions on various substrates in the ab-
sence of methanol to evaluate the coupling efficiency.
SmBr2 mediates pinacol-coupling reactions of ketones in
situ effectively, however minor amounts (<10%) of uniden-
tified byproducts were also observed occasionally. The same
trend as previously described for prepared SmX2 is also
found for in situ generated SmBr2 and SmI2, that is, an in-
creasing degree of pinacol coupling is obtained with higher
oxidation potential of the lanthanide(ii) reagent. Interesting-
ly, irrespective of the addition of methanol, treatment of
imines with SmI2 or SmBr2 results in reduction only.
Intramolecular coupling between aryl iodides and alkenes
was performed, in which in situ generated SmI2 was proven
to be the superior coupling reagent (Table 5). However, the
formation of phenol and other reduction products was also
observed.
One disadvantage of SmI2-mediated reduction is the low
solubility of SmI2 (0.13m in THF). In addition, one molecule
of SmI2 can only deliver one electron, therefore each sub-
strate requires two equivalents of the single-electron-trans-
fer reagent. Altogether this makes these reactions less at-
tractive with respect to large-scale syntheses. Previously, we
have reported that SmI2 and particularly SmBr2 can be gen-
erated as suspensions in THF,[6] thus requiring a smaller
volume of THF. The use of smaller volumes of solvent in re-
duction reactions is important as it allows reduction reac-
tions to be carried out on a larger scale in smaller reaction
vessels.
We generated SmI2 and SmBr2 from samarium metal and
iodine or tetrabromoethane using only 10% of the required
volume of THF (i.e., 10% of the volume that gives saturat-
ed solutions of SmI2 in THF). These highly “concentrated”
suspensions were then successfully employed in a few of the
above-mentioned reduction and cyclization reactions and it
was concluded that the results were almost identical in
terms of the selectivity using
Scheme 4. Reduction and cyclization with LnX2.
Surprisingly, SmI2 appeared to give the highest degree of
coupling versus reduction in these reactions (Table 3). All
attempts to obtain seven-membered rings were ineffective
and resulted in complete reduction (entries 7–9), which was
also previously observed for the SmI2/H2O/amine method.[16]
In situ generated SmBr2 and SmI2 in single-electron-transfer
reactions: The scope and limits of reduction and coupling of
substrates with in situ generation of SmBr2, SmI2, and YbI2
were also studied. The SmBr2- and SmI2-mediated reduction
Table 3. Microwave-assisted cyclizations in THF.[a,b,c]
either prepared or in situ gener-
Entry
Substrate
Reagent (LnX2)
Reduction [%]
Cyclization [%]
ated suspensions of the SmI2
and SmBr2. Apparently there is
no need to use saturated solu-
tions of LnX2, since the suspen-
sions gave more or less identical
results.
Unfortunately, the use of Yb
and I2 was shown to be less at-
tractive for in situ generation of
YbI2 in the described reactions
(Tables 4 and 5). The generation
of YbI2 was too slow even
under microwave irradiation,
yielding only approximately
43% of the reduced 2-heptanol
from heptanone after 60 min-
utes at 1808C.
1
2
3
SmBr2
SmI2
YbI2
0
2
16
90
95
71
4
5
6
SmBr2
SmI2
YbI2
48
14
70
52
86
30
7
8
9
SmBr2
SmI2
YbI2
>99
>99
>99
0
0
0
10
11
12
SmBr2
SmI2
YbI2
19
12
50
70
71
40
[a] LnX2 (2.5–3.0 equiv) in THF. The substrate (1 equiv) was added just before the vessel was placed in the mi-
crowave reactor. The reaction mixture was irradiated for 10 min. [b] Reactions performed in the presence of
YbI2 were irradiated for 20–30 min. [c] Formation of phenol balances the conversion.
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Lanthanide(ii) Halide Mediated Reactions
FULL PAPER
Table 4. In situ generated SmBr2 and SmI2 reactions in THF.[a]
water/amine reagent does not
appear to be stable under mi-
crowave irradiation.
Entry
Substrate
Reagent (LnX2)
Reduction [%]
Pinacol [%] (dl/meso)
1
2
SmBr2
SmI2
4
5
96 (68:32)
95 (70:30)
Conclusion
3
4
SmBr2
SmI2
11
24
89 (56:44)
76 (66:34)
We have shown that it is effi-
cient to perform rapid coupling
and reduction reactions by
using microwave heating with
lanthanide(ii) reagents. Pinacol-
coupling reactions of ketones
are readily obtained within five
5
6
SmBr2
SmI2
7
38
93 (50:50)
62 (50:50)
minutes using SmBr2 as
a
7
8
SmBr2
SmI2
10
59
90
41
single-electron donor, while the
weaker reducing agent, YbI2,
favors reduction reactions. We
have shown that lanthanide(ii)
reagents generated in situ
under microwave irradiation
can be a viable alternative for
reduction and coupling reac-
tions. Mixing of Sm or Yb
metal and iodine in THF, in a
vessel approved for use in the
microwave reactor, provides an
easy method for the execution
of LnX2-mediated reactions.
9
10
SmBr2
SmI2
100
100
0[b]
0[b]
11
12
SmBr2
SmI2
100
100
0[b]
0[b]
[a] Sm (3.0 equiv) and I2 (2.0 equiv) or tetrabromoethane (1.0 equiv), diluted with THF. The substrate
(1 equiv) was added just before the vessel was placed in the microwave reactor. The reaction mixture was irra-
diated for 10 min. [b] Methanol (9.0 equiv) was added prior to putting the vessel in the microwave chamber to
enhance the rate. No coupling was observed either in the presence or in the absence of MeOH.
Table 5. In situ generated SmBr2 and SmI2 reactions.[a,b]
Experimental Section
Substrate
Reagent (LnX2) Reduction [%] Cyclization [%]
General: THF was dried over sodium and distilled before use. All com-
mercially available chemicals were used without further purification. Syn-
thesized substrates were distilled and stored in a glove box.
SmBr2
SmI2
5
2
84
87
Cyclic voltammetry of YbI2: The redox potential of YbI2 was measured
by using cyclic voltammetry, employing a BAS 100/W MF-9063 Electro-
chemical Workstation. The working electrode was a glassy carbon elec-
trode. The electrode was polished with polishing alumina before use. The
auxiliary electrode was a platinum wire, and the reference electrode was
a saturated Ag/AgNO3 electrode. The scan rate for the experiment was
100 mVsÀ1. The electrolyte used was tetrabutylammonium hexafluoro-
phosphate. The concentrations of YbI2 and the electrolyte were 5mm and
0.1m, respectively. The solution was prepared inside a dry box and trans-
ferred to the electrochemical analyzer for analysis.
SmBr2
SmI2
36
14
64
86
SmBr2
SmI2
19
21
70
61[c]
[a] Sm (3.0 equiv) and I2 (2.0 equiv) or tetrabromoethane (1.0 equiv), di-
luted with THF. The substrate was added just before the vessel was
placed in the microwave reactor. The reaction mixture was irradiated for
10 min. [b] Formation of phenol balances the conversion. [c] Formation
of decomposition products (up to 10%) was observed.
Microwave-assisted synthesis with prepared LnX2: In a typical reduction
of a ketone, imine, or a,b-unsaturated ester, LnX2 (2.5 equiv) in THF
(5 mL) was added to a vessel approved for use in the microwave reactor,
inside a glove box, and sealed with a cap. The substrate (1 equiv) and
methanol (9 equiv) were added through the septum just before placing
the vessel in the microwave reactor. The reactions were performed utiliz-
ing a prototype single-mode applicator equipped with a fluoroptic probe
and irradiated in the microwave reactor for five minutes. All reactions
were performed at a constant temperature of 1808C resulting in a pres-
sure of 11–14 bar. The reactions were quenched by air when the caps
were removed. Hydrochloric acid (20 mL, 0.1m) was added to dissolve in-
organic salts and the products were then extracted into diethyl ether (3ꢂ
40 mL). The organic layer was washed with sodium thiosulfate and satu-
rated brine, and finally dried over sodium sulfate before filtration. Pina-
col-coupling products were separated from the reduced products by flash
We also investigated the possibility of employing micro-
wave heating in deallylation reactions, which was recently
described with the SmI2/H2O/amine method.[17] However, no
reaction occurred with any of the three lanthanide(ii) re-
agents. It appears that the microwave irradiation only en-
hances the reduction rates. However, the powerful SmI2/
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G. Hilmersson et al.
chromatography on silica with ethyl acetate/n-hexanes (1:10). Isolated
products were characterized by 1H and 13C NMR analyses and/or com-
pared to authentic samples by gas chromatography and GC/MS.[18] GC
analyses were used to determine the dl/meso ratio in the pinacol prod-
ucts. The relative amount of pinacol coupling and reduction was estab-
lished from the crude products, that is, before the purification by flash
chromatography.
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Acknowledgements
The authors thank Personal Chemistry AB and Astra-Zeneca R&D in
Mçlndal for supplying us with instruments for this study. Financial sup-
port of this work from the Swedish Natural Research Council (GH) and
from the National Science Foundation (CHE-0413845) (RAF) is grateful-
ly acknowledged.
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Received: December 22, 2004
Published online: March 22, 2005
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