Mechanistic Study and Development of Catalytic Reactions of Sm(II)

Article abstract of DOI:10.1021/jacs.8b13119

Samarium diiodide (SmI₂) is one of the most widely used single-electron reductants available to organic chemists because it is effective in reducing and coupling a wide range of functional groups. Despite the broad utility and application of SmI₂ in synthesis, the reagent is used in stoichiometric amounts and has a high molecular weight, resulting in a large amount of material being used for reactions requiring one or more equivalents of electrons. Although few approaches to develop catalytic reactions have been designed, they are not widely used or require specialized conditions. As a consequence, general solutions to develop catalytic reactions of Sm(II) remain elusive. Herein, we report mechanistic studies on catalytic reactions of Sm(II) employing a terminal magnesium reductant and trimethylsilyl chloride in concert with a noncoordinating proton donor source. Reactions using this approach permitted reductions with as little as 1 mol % Sm. Mechanistic studies provide strong evidence that during the reaction, SmI₂ transforms into SmCl₂, therefore broadening the scope of accessible reactions. Furthermore, this mechanistic approach enabled catalysis employing HMPA as a ligand, facilitating the development of catalytic Sm(II) 5-exo-trig ketyl olefin cyclization reactions. The initial work described herein will enable further development of both useful and user-friendly catalytic reactions, a long-standing, but elusive goal in Sm(II) chemistry.

Full text of DOI:10.1021/jacs.8b13119

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Article
Mechanistic Study and Development of Catalytic Reactions of Sm(II)
Sandeepan Maity, and Robert A Flowers
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b13119 • Publication Date (Web): 27 Jan 2019
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Mechanistic Study and Development of Catalytic Reactions of Sm(II)
Sandeepan Maity and Robert A. Flowers II*
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Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania 18015, USA.
ABSTRACT: Samarium diiodide (SmI2) is one of the most widely used single electron reductants available to organic chemists
because it is effective in reducing and coupling a wide range of functional groups. Despite the broad utility and application of SmI2
in synthesis, the reagent is used in stoichiometric amounts and has a high molecular weight, resulting in a large amount of material
being used for reactions requiring one or more equivalents of electrons. Although few approaches to develop catalytic reactions
have been designed, they are not widely used or require specialized conditions. As a consequence, general solutions to develop
catalytic reactions of Sm(II) remain elusive. Herein, we report mechanistic studies on catalytic reactions of Sm(II) employing a
terminal magnesium reductant and trimethyl silyl chloride in concert with a non-coordinating proton donor source. Reactions using
this approach permitted reductions with as little as 1 mol% Sm. Mechanistic studies provide strong evidence that during the reac-
tion, SmI2 transforms into SmCl2 therefore broadening the scope of accessible reactions. Furthermore, this mechanistic approach
enabled catalysis employing HMPA as a ligand, facilitating the development of catalytic Sm(II) 5-exo-trig ketyl olefin cyclization
reactions. The initial work described herein will enable further development of both useful and user-friendly catalytic reactions; a
long-standing, but elusive goal in Sm(II) chemistry.
Introduction
lates.39 Endo described the use of SmI2-Mg-trimethylsilyl
chloride in the pinacol coupling of aldehydes and ketones, but
in this system, some reactions took as long as 48 hrs. whereas
stoichiometric reactions are complete in minutes.40 Greeves
and coworkers carried out a more extensive study employing
glymes along with Mg as an additional additive in pinacol
couplings.41 Although excellent diastereoselectivities were
obtained in some of these reactions, reaction time and condi-
tions make scale-up problematic. At the time of the Greeves
report, Orsini was also successful in using SmI2-Mg in Refor-
matsky-type reactions.42 In studies using alternative terminal
reductants, Namy and coworkers have shown that inexpensive
mischmetal (50% Ce, 33% La, 12% Nd, 4% Pr, 1% other lan-
thanides) can reduce substoichiometric amounts of Sm(II) in
some Reformatsky and Barbier reactions.43,44 More recently,
electrochemical methods have been employed to regenerate
Sm(II), but a Sm electrode is required.46,47 In addition to
Sm(II)-based systems, there have been recent studies employ-
ing Eu(II) and Ce(III) as photoredox catalysts for several re-
ductions.48,49
Samarium diiodide (SmI2) and related Sm(II)-based reductants
are important reagents in the arsenal of synthetic chemists.1–9
First introduced by Kagan and coworkers, SmI2 is a versatile
single electron reductant capable of reducing a range of func-
tional groups under mild reaction conditions.10 The majority of
SmI2-based reactions are carried out in THF since the reagent
is stable in this medium and is soluble up to 0.1 M. Initially
considered a “specialized” reagent, a range of studies have
shown that SmI2 is capable of efficiently reducing a wide
range of functional groups.1–9 The rate by which SmI2 reduces
different functional groups varies significantly.11,12 As a re-
sult, SmI2 can be used to selectively reduce a particular func-
tional group in a multifunctional substrate for follow-up bond-
forming reactions and is exceptionally effective in reductive
couplings,13–22 and cascade reactions.23–32 Most importantly, its
use allows for alternative and selective methods for the syn-
thesis of multifunctional targets.4,9 While numerous reactions
have been developed for SmI2, its scope in synthesis certainly
has not been exhausted and new applications for this reagent
are steadily being discovered.36,37 As a consequence, SmI2 has
attained a prominence reserved only for select reagents.3,6,38
While the aforementioned Sm-based catalytic systems are an
excellent initial extension of the utility of this reagent, optimi-
zation of such systems has not occurred and have not been
utilized extensively by synthetic chemists due to their narrow
scope of application.45 Given the overall challenges develop-
ing a catalytic system employing Sm(II), it is our supposition
that if the intent is to develop a catalyst, it is best to start with
a functioning catalytic system and understand the strengths
and limitations of a known process instead of trying to develop
a new system from first principles. Once the mechanistic role
of the various additives and components in a known system
are understood, it enables a rational approach to the design of
a new method or system for regenerating Sm(II) from Sm(III).
During the last several years, we have studied a number of
reported catalytic systems and learned a great deal that is use-
ful in enabling the development of a robust and user-friendly
In spite of the importance and continued use of stoichiometric
Sm(II)-based reactions, economic and environmental concerns
remain an issue with this chemistry, demonstrating the need
for development of practical catalytic approaches as important
tools for synthetic chemists. In nearly all reactions of SmI2, a
stoichiometric amount of the reductant is required. The high
molar mass of SmI2 (molecular weight: 404 g/mol) poses prac-
tical problems for scale up because a great deal of metal and
solvent are required to carry out these reductions. A number of
approaches that employ inexpensive terminal reductants to
regenerate Sm(II) have been developed.39–45 The early work of
Corey on the development of catalytic reactions of SmI2
showed that Zn-Hg in combination with TMSOTf and LiI
gave excellent yields in the coupling of ketones with acry-
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approach to catalytic reactions of Sm(II).50,51 We will focus on
key questions: 1) What are the mechanistic roles of individual
the approaches developed by Endo and Greeves,40,41but note
that all of the systems we have examined to date have similar
challenges. An example of a typical approach is shown in
Scheme 1.
components of the catalytic system? 2) Can turnover be made
more efficient? 3) Can the system be made to be much more
general to accommodate a range of reactions? 4) Can im-
portant bond-forming reactions such as carbonyl-alkene reac-
tions be made catalytic? Herein we present the results of ex-
periments that address these fundamental questions.
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In the systems developed by Endo and Greeves,40,41 substrate
(typically aldehyde) is exposed to a substoichiometric amount
of SmI2 containing superstoichiometric amounts of Mg as the
terminal reductant. During the reaction, reduction of the alde-
hyde by Sm(II), leads to pinacol coupling. Since Sm(III) has a
high affinity for alkoxides, the intermediate coordinates to
Sm(III) preventing regeneration. In addition, the presence of a
silylchloride is necessary to capture the coordinated alkoxide
and cleave the Sm-O bond. During the last step, the sacrificial
reductant converts Sm(III) to Sm(II). The proposed catalytic
cycle for the process is shown in Scheme 1. The only differ-
ence between the two systems is the approach designed by
Greeves uses a glyme which is proposed to enhance the dia-
stereoselectivity of the pinacol coupling.41
Results and Discussion
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Approach in Designing the Catalytic System
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In the pursuit of designing an efficient catalytic system, we
first focused on solubility and reversibility of the
Sm(II)/Sm(III) redox couple. We have investigated several
Sm(III) salts and discovered that SmI3 has highest solubility in
THF. We have also found that it is relatively straightforward
to reduce SmI3 to SmI2 using Mg.52 To further enhance the
solubility of SmI3 in the reaction mixture, we proposed adding
a ligand which is capable of complexing with Sm(III). Glymes
are well known for coordinating with both +3 and +2 oxida-
tion state53,54 of lanthanides and they have been used in the
catalytic Sm(II) mediated reductions studied by Greeves.41 In
Greeves original work, he proposed that the glyme was im-
portant in driving the stereoselectivity of pinacol coupling
reactions. It was our supposition that the role of the glyme
was to facilitate solubility of the Sm(III). To examine the pos-
sibility of SmI3 solubility enhancement tetraglyme was added
to a turbid solution of SmI3. The addition of 10 equivalents of
tetraglyme based on [SmI3] transformed the turbid solution to
a clear, homogeneous solution (Figure 1).
Scheme 1. Proposed Catalytic cycle by Greeves et al.41
Figure 1: Photo of SmI3 and SmI3-tetraglyme in THF. [SmI3] =
0.1 M and [tetraglyme] = 1 M.
Before examining the systems, we saw several challenges.
During the course of reactions with SmI2, iodide ligands are
displaced through exchange with intermediates that have a
higher affinity for Sm than the initial ligand. Additionally,
Sm(III) gains a third contact anion, stemming from its increase
in charge. This ligand exchange likely causes the Sm(III) spe-
cies reduced in the catalytic cycle to gradually produce a re-
ductant other than SmI2. Mechanistic studies on stoichio-
metric systems have shown that even a conservative replace-
ment of iodide by bromide or chloride on Sm(II) has a dra-
matic impact on the reactivity of the reductant.52 In addition,
formation of Sm(III) salts are highly insoluble in THF making
regeneration of Sm(II) more difficult. As a consequence, re-
duction of insoluble Sm(III) by Mg is likely to be slow due to
inefficient electron transfer. Another potential problem is the
lack of a proton donor necessary to protonate substrate after
electron transfer from Sm(II). Finally, many of the catalytic
systems are not general and are only efficient for selective
reactions.40,41,45 To develop an effective and more general
catalytic system, we undertook studies to answer the following
Since the goal of the work is the development of a catalytic
reduction system based on Sm(II)/Sm(III) redox couple, it is
very important to understand the relative affinity of tetraglyme
for both oxidation states of Sm. To examine this the UV-Vis
spectrum of SmI2 (2 mM) and SmI2 with tetraglyme (8 mM)
were obtained. Next, 2 mM of SmI3 was added to
SmI2/tetraglyme. If tetraglyme has an affinity towards SmI3
and SmI2, this will lead to rapid ligand exchange generating
free SmI2 which can easily be detected from its characteristic
UV-Vis. Analysis of Figure 2 suggests that indeed addition of
SmI3 leads to generation of free SmI2 to some extent, however
the affinity of tetraglyme is slightly higher for SmI2. The fact
that tetraglyme has higher affinity towards Sm(II) than Sm(III)
has less importance since solubilization of the relatively insol-
uble Sm(III), facilitates the reduction of Sm(III) to Sm(II) by
the Mg terminal reductant.
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ordinating proton sources are more efficient in proton transfer
than the non-coordinating variants,57 the latter scenario is pre-
ferred since they will not alter the reactivity of Sm. The ra-
tionale behind this supposition comes from the fact that coor-
dinating proton donors generate a very strong Sm(III)-O bond
as result of proton transfer and it is rather difficult to cleave
this bond to liberate Sm(III) for subsequent reduction to re-
generate Sm(II). With this background in mind, trifluoroetha-
nol (TFE) was chosen as a proton source because it does not
coordinate to Sm and is better H-bond donor than non-
fluorinated alcohols typically used in Sm(II)-mediated interac-
tions.59
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Tetraglyme-TFE System
To test the efficiency of the tetraglyme-TFE system, we car-
ried out reduction of a range of substrates displayed in Chart 1.
All reactions employed 10 mol percent Sm using tetraglyme as
a ligand and TFE as the proton donor. Reductions of carbonyl
compounds were completed with 2-3 hrs and reactions with
alkyne 6 and alkene 7 were continued for 15 hrs. Substrates 1-
4 provided the corresponding alcohol as product. Reduction of
amide 5 resulted mixture of alcohol and amine in almost 1:1
mixture.60 Interestingly, the reduced alkyne provided the cis
alkene product exclusively. It is important to note that control
experiments in
Figure 2: UV-Vis of SmI2 (2 mM); SmI2 (2 mM) + tetraglyme (8
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mM) and SmI2 (2 mM) + tetraglyme (8 mM) + SmI3 (2 mM).
With this preliminary study complete, we attempted to reduce
cyclohexylmethyl ketone (1) and 4-phenyl-2-butanone (2)
under the following conditions: SmI2 (0.05 mmol), tetraglyme
(0.8 mmol), substrate (0.5 mmol), TMSCl (2.8 mmol) and Mg
(0.1 g) in 10 mL of THF. Despite several attempts, only start-
ing material was recovered. This could be due to unsuccessful
reduction of substrate, however, in that case the color of SmI2
should have been retained. Decolorization of reaction mixture
was observed in 3-5 min (Figure S1) and color was not regen-
erated even after 24 hrs of stirring. To explore the basis for
the lack of reaction, we examined the reduction of SmI3 in the
absence of substrate. Treatment of SmI3 in the presence of
tetraglyme, TMSCl and Mg led to generation of Sm(II) with 2-
3 min (Figure S2). This observation indicates that unsuccess-
ful reduction was potentially a result of difficulty in cleaving
Sm(III)-oxygen bond to liberate Sm(III).
Chart 1. Substrate used for the reduction by catalytic Sm(II)
system.
the absence of SmI2 do not yield reduction products even for
24 hrs. Reactions performed in the absence of proton donors
or TMSCl also led to recovery of starting material. These find-
ings confirm that all the reaction components present were
necessary for the reaction to proceed. To examine the possibil-
ity of Lewis acid catalyzed substrate reduction by Mg, we
performed the reduction of 1 in the presence of Sm(OTf)3 and
Yb(OTf)3. Analysis of the reaction mixture after 3 hrs showed
neither reduction nor pinacol as product and starting material
was recovered (supporting information, Table S1).
To counter a similar problem, Greeves et al. used Me2SiCl2
instead of TMSCl.41 We have taken an alternate approach to
solve this problem. To enhance the efficiency of cleaving the
intermediate Sm(III)-oxygen bond by TMSCl, we envisioned
that it may be possible to enhance the Lewis acidity of TMSCl
by hydrogen bond (H-bond) donors. This supposition is based
on previous work employing hydrogen bond donors, such as
squaramides to enhance the Lewis acidity of trimethylsilyl
triflate.55 The advantage of H-bond induced Lewis acid en-
hancement is that one can potentially tune this weak interac-
tion to achieve selectivity required for a reaction of interest.
While squaramides have been used previously, employing
them in SmI2 mediated reductions can potentially lead to in-
termediate coordination compounds that can alter the reactivi-
ty of Sm(II). Alcohols which are also known for their H-bond
donor capabilities can be an alternative for the present system.
Apart from H-bonding to TMSCl, the presence of an alcohol
might be advantageous in terms of a) availability of protons
which are necessary for product formation; b) the proton
source can potentially form H-bond with intermediate Sm(III)-
oxygen bonds to weaken the electrostatic interaction and facil-
itate the cleavage of Sm(III)-oxygen bond.56
Mechanistic analysis of the last 30 years has enabled us to
understand the role of proton donors in SmI2 mediated reduc-
tions and classify them under two major categories; a) coordi-
nating proton donors (such as MeOH, water and glycols) and
b) non-coordinating proton donors (ethanol, trifluoroethanol
and t-BuOH).57,58 Although it has been demonstrated that co-
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Table 1: Reduction of substrates with 10 mol % of SmI2 in
the presence of tetraglyme-TFE
is reasonable to assume that it would be rather difficult to use
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HMPA to carry out efficient catalytic turn over since reduction
of Sm(III)-HMPA by a terminal reductant is more difficult
than reduction of Sm(III) alone.64 Nonetheless, given the im-
portance of HMPA in a range of useful bond forming reac-
tions16,22 we thought it was prudent to examine whether a cata-
lytic system could be developed employing the additive.
Substrate
Reaction
time (hrs)
Product
Conversion
(NMR Yield)a,b
1
2
3
4
5
3
3
3
5
5
Alcohol
Alcohol
Alcohol
Alcohol
99 (90)
99 (93)
99 (90)
99 (67)
To our surprise, despite the irreversibility of the SmI2-HMPA
redox couple, catalytic reductions proceeded well using Mg as
a terminal reductant. In initial reactions, 10 mol% Sm was
employed in reactions. One noticeable difference in the reac-
tions with respect to the use of tetraglyme as a ligand is the
ratio of HMPA:Sm was found to be critical. For example, if
0.8 mmol of HMPA was employed in 10 mol percent reactions
(16:1 ratio HMPA:Sm), 0.4 mmol HMPA was required in
reactions using 5 mol percent Sm, otherwise complete conver-
sion of substrate to product was not observed. The results of
initial catalytic reductions using HMPA as ligand are summa-
rized in Table 3. Ketone substrates 1-3 and activated ester 4
provide excellent to very good yields whereas benzamide 5
leads to recovery of starting material. Alkyne 6 provides very
modest yield of the cis-alkene and activated alkene 7 provides
a good yield of reduced product. The lack of reaction of sub-
strate 5 was initially surprising and will be discussed vide in-
fra.
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Alcohol
and 99 (66)
amine (1:1)
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Cis alkene
Alkane
36 (30)
57 (54)
aSmI2: 0.05 mmol; Subs: 0.5 mmol; Tetraglyme: 0.8 mmol; TFE:
2 mmol; TMSCl: 2.8 mmol and Mg: 0.1 g. The amount of
tetraglyme and Mg were chosen based on optimization experi-
b
ments (supporting information, Table S2). Yields were deter-
mined by 1H NMR using naphthalene as an internal standard.
To examine the limit of catalyst loading for the system, we
performed the reduction of cyclohexylmethyl ketone (1) em-
ploying 5, 2 and 1 mol percent of SmI2. These reactions were
performed keeping the substrate amount the same as in the
previous experiment (0.5 mmol) and reducing the amount of
SmI2. All loadings of 5, 2 and 1 mol percent Sm resulted in
99% conversion to corresponding alcohol. Keeping in mind
that conversion of a ketone to an alcohol requires 2 electrons,
up to 200 turnovers were achieved for this system. It is worth
mentioning that in a previous report, the reduction of cyclo-
hexylmethyl ketone to the corresponding pinacol using 20 mol
percent SmI2 required 20 hrs (Table S3).41 In light of the pre-
sent results, the impact of proton donor is remarkable and
clearly facilitates the catalytic turn over. Table 2 represents the
results of reduction of 1 by 5, 2 and 1 mol percent of SmI2.
Reduction of 4-Phenyl-2-butanone (2) and 2-octanone (3) with
1 mol percent of SmI2 resulted 85 and 99 % of corresponding
alcohol respectively under similar condition (see SI, Table
S4).
Table 3: Reduction of substrates with 10 mol %SmI2 in the
presence of HMPA-TFE
Substrate
Reaction
time (hrs)
Product
Conversion
(NMR Yield)a,b
1
2
3
4
5
6
7
4
Alcohol
Alcohol
Alcohol
Alcohol
99 (80)
99 (83)
99 (89)
76 (69)
<5
4
4
4
4
15
15
Cis alkene
Alkane
15 (12)
62 (55)
Table 2: Reduction of cyclohexylmethyl ketone (1) under 5,
2 and 1 mol % of SmI2/tetraglyme-TFE system
aSmI2: 0.05 mmol; Subs: 0.5 mmol; HMPA: 0.8 mmol; TFE: 2
mmol; TMSCl: 2.8 mmol and Mg: 0.1 g. bYields were determined
by 1H NMR using naphthalene as an internal standard.
Catalyst
(SmI2 amount, mmol) (hrs)
loading Reaction time Conversion
(%)a
99
Identity of the active catalyst
5 (0.025)
2 (0.01)
5
It is surprising that although some of the substrates used in this
study fall outside of the range of reduction by
SmI2/tetraglyme/TFE under stoichiometric conditions, suc-
cessful reduction occurred under catalytic conditions. This
finding suggests that the identity of the active Sm(II) reductant
likely changes during catalytic turn over. In nearly all of the
catalytic Sm(II) mediated reductions designed including the
present study, TMSCl or Me2SiCl2 were employed as Lewis
acids to cleave the ion-pair between Sm(III) and negatively
charged products or intermediates.40,41,46,47 The capture of
oxygen by the silyl chloride generates chloride which is
known to have a higher affinity for Sm(II) than iodide.52 As a
consequence, it is likely that SmI2 is converted to SmCl2,
which known to be a more powerful reductant, during the
course of the reaction.46 To examine this supposition, the UV-
Vis spectra for the reduction of 4-phenyl-2-butanone under a
15
24
99
1 (0.005)
99
aSubs: 0.5 mmol; Tetraglyme: 0.8 mmol; TFE: 2 mmol; TMSCl:
2.8 mmol and Mg: 0.1 g
Development of catalytic reactions employing HMPA as a
ligand
The use of HMPA as a ligand for SmI2 has a significant im-
pact on the selectivity, stereoselectivity, and reactivity of the
reagent.11,12,52 While the exact speciation of the intermediate
reductant in solution formed upon addition of HMPA to SmI2
is not known,61,62 HMPA coordinates to Sm(II) displacing
iodide ligands from the inner-sphere of the metal.61,63 Addi-
tionally, HMPA coordination to SmI2 enhances the reducing
power of SmI2 by decreasing its reduction potential and stabi-
lizing the +3 oxidation state.61,64,65 Based on these findings, it
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Figure 4: UV-vis spectra of SmI2-HMPA complex, SmI2-HMPA
series of conditions was measured after completion of the re-
1
2
3
4
5
6
7
8
with 2 eq. of chloride ion, SmI2 with 2 eq. of chloride ion and
SmI2-HMPA mediated reaction mixture. [SmI2] = 6.25 mM.
action.
First, the tetraglyme system was examined by measuring the
UV-Vis spectrum before ([SmI2] = 6.25 mM + 16 eq of
tetraglyme) and after the reaction. UV-Vis spectrum obtained
after the completion of reaction matches very well with previ-
ously reported spectrum of SmCl2 in THF.52,66 To verify that
the change in Sm(II) speciation occurs indeed due to genera-
tion of chloride ion during the course of reaction, 2 eq (with
respect to Sm) of tetrabutylammonium chloride was added to
SmI2-tetraglyme complex. The resultant spectrum matches
very well with spectrum of Sm(II) obtained at the end of the
catalytic reaction. Thus, Figure 3 unequivocally establishes
that SmCl2, a more powerful reductant than SmI2, was gener-
ated during course of catalytic turnover and hence explains the
successful reduction of substrates which are recalcitrant to-
wards electron transfer from SmI2.
While examining the effect of tetraglyme and HMPA on the
SmCl2 (SmI2 + 2 eq of tetrabutylammonium chloride) spec-
trum, we have observed significant differences. Tetraglyme
being a weak ligand, cannot alter the spectrum of SmCl2,
whereas the effect of HMPA coordination is clearly visible in
the spectrum of SmCl2. Addition of 16 eq (with respect to Sm)
of HMPA to SmCl2 solution (SmI2 + 2 eq of tetrabutylammo-
nium chloride) leads to transform a single hump SmCl2 spec-
trum to a double hump (see SI, Figure S3). Addition of excess
of chloride (16 eq with respect to Sm) ion to SmCl2-HMPA
complex was found to have a very modest impact on its UV-
vis spectrum (see SI, Figure S4). Overall, these UV-vis spectra
analyses strongly suggest that the presence of HMPA could
easily be discerned from characteristic double hump spectrum
of Sm(II) absorption irrespective of chloride ion concentration.
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In light of these findings, it is our supposition that SmCl2,
which is formed in HMPA reaction is very weakly bound to
HMPA which is not sufficient to induce the double hump na-
ture in the Sm(II) spectrum, rather it alters the peak maximum.
It is possible that SmCl2 is bound with only 1˗2 molecule of
HMPA and hence electronic structure of Sm(II) is governed
by chloride ion rather than HMPA.
The fact that the spectrum obtained at the end of HMPA medi-
ated reactions is hardly perturbed by HMPA suggests that the
concentration of HMPA decreases as the reaction proceeds
towards completion. A possible mechanistic pathway in which
concentration of HMPA could decrease as reaction proceeds is
catalyst deactivation. In other words, in each catalytic cycle a
fraction of Sm(III)-HMPA was not reduced back to Sm(II)-
HMPA and as a result of that concentration of HMPA de-
creases as reaction proceed. However, since 16 eq of HMPA
per Sm was used in these reactions, even with catalyst deacti-
vation, some amount of HMPA should remain in solution.
Another possible pathway responsible for the apparent disap-
pearance of HMPA from the Sm(II) metal center could be
ligand exchange reaction by of Mg2+ ion as reaction proceeds.
Since it is known that HMPA forms coordination complex
with Mg2+,67,68 and that there is a high concentration of Mg
relative to Sm, we believe this is a likely pathway for the de-
complexation of HMPA from Sm.
Figure 3: UV-vis spectra of SmI2-tetraglyme complex, SmI2-
tetraglyme with 2 eq. of chloride ion and SmI2-tetraglyme mediat-
ed reaction mixture. [SmI2] = 6.25 mM.
Next, a similar analysis of the reaction containing HMPA was
performed (Figure 4). Similar to the tetraglyme reaction, for-
mation of SmCl2 was clearly evident in this case as well. In
this case, addition of 2 eq (with respect to Sm) of tetrabu-
tylammonium chloride to SmI2-HMPA complex changes the
shape of spectrum suggesting that SmI2-HMPA converts to
SmCl2-HMPA complex. Unlike tetraglyme case, the UV-vis
obtained at the end the reaction is very different from the UV-
Vis spectrum of SmCl2-HMPA and is similar to SmCl2 (SmI2
+ 2 eq of tetrabutylammonium chloride). However, it is also
observed that absorption maximum for the spectrum of the
reaction mixture with HMPA is red shifted by 10 nm compare
to SmCl2.
Role of Proton Donors and H-bonding in SmI2 Catalysis
Initial studies foreshadow an important role for proton donors,
but don't provide a great deal of mechanistic insight into their
capacity as H-bond donors to enhance the Lewis acidity of
TMSCl or how mechanistic differences between tetraglyme
and HMPA mediated Sm(II) catalysis can be influenced by
different types of H-bond donors. To elucidate these details,
reduction of cyclohexylmethyl ketone (1) was conducted with
several other H-bond donors (isopropanol, methanol, pinacol
and 1,3-diphenylurea) using tetraglyme and HMPA as ligands
and 10 mol% SmI2. Isopropanol is similar to TFE in terms of
its non-coordinating nature towards SmI2. However, it is less
acidic and more sterically encumbered than TFE and as a con-
sequence is expected to form a weak H-bond with TMSCl.
Methanol and pinacol are known for their ability to coordinate
to SmI2 and hence employing them as H-bond donors may
result in ligand (tetraglyme or HMPA) displacement, that may
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Journal of the American Chemical Society
have a deleterious impact on the Sm(II) catalysis.57,65 1,3-
diphenylurea was employed to provide insight that Sm(II)
catalysis is not only specific with alcohol based H-bond donor,
but rather a more general phenomenon.
Page 6 of 11
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2
3
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8
9
Results of these experiments are summarized in Table 4. There
are several interesting features of these results: 1) With the
exception of TFE, Sm(II) catalysis does not work very well
with other H-bond additives when HMPA was used as ligand.
2) Despite the coordinating nature of MeOH, Sm(II) catalysis
works well when tetraglyme is employed as a ligand. Howev-
er, the reaction yield significantly decreases with pinacol sug-
gesting that MeOH is the limit of employing coordinating
additives. 3) Successful Sm(II) catalysis was observed with
1,3-diphenylurea using tetraglyme as ligand. This supports our
supposition that activation of TMSCl through H-bonding is
critical for Sm(II) catalysis. Surprisingly, this is not the case
with HMPA as ligand.
Table 4: Comparison of TFE, isopropanol, MeOH, Pinacol
and 1,3-diphenylurea
H-bond donors
Tetraglymea
HMPAa
(10 mol% Sm)
(10 mol% Sm)
TFE
99
99
99
33
97
99
50
56
0
10
11
12
13
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Isopropanol
MeOH
Pinacol
1,3-diphenylureab
4
aSmI2: 0.05 mmol, Subs: 0.5 mmol, Ligand: 0.8 mmol, H-bond
donor: 2 mmol, TMSCl: 2.8 mmol and Mg: 0.1 g. Reaction time:
Given the differences among H-bond donors in catalytic reac-
tions using tetraglyme and HMPA, some discussion is war-
ranted. It is our supposition that these differences are a conse-
quence of the fact that HMPA is stripped from Sm metal cen-
ter during the catalytic turnover whereas tetraglyme remains
coordinated. Although MeOH and pinacol are weaker com-
plexing ligands for Sm(II) in comparison to HMPA,63,65 as
HMPA is displaced from the coordination sphere of Sm(II) by
increasing concentrations of Mg as the reactions progresses,
these additives (MeOH and pinacol) are likely to compete with
HMPA. Their coordination to Sm(II) will lead to a very effi-
cient unimolecular proton transfer to organic intermediates
generating a strong Sm(III)-O bond thus prohibiting Sm(II)
regeneration. It is likely that the basis for the failure of the
combination of HMPA and 1,3-diphenyl urea is similar to that
for MeOH and pinacol. We have recently demonstrated that
coordination of amides to SmI2 reduces substrates through a
formal hydrogen atom transfer mechanism generating a strong
Sm(III)-N bond.69 It is likely that the urea is behaving in a
similar fashion. Furthermore, in addition to this potential deac-
tivating pathway, 1,3-diphenylurea is also expected to form an
H-bond with HMPA. To test this supposition, isothermal titra-
tion calorimetry (ITC) of 0.09 M of 1,3-diphenylurea with 1 M
of HMPA in THF shows a strong interaction as shown in Fig-
ure S3 (see SI). This H-bond interaction likely inhibits coordi-
nation of HMPA to Sm(II). With this mechanistic insight one
can rationalize the unsuccessful reduction of 4-
butylbenzamide (5) with Sm(II)-HMPA system (Table 3).
1
4 hrs. Yields were determined by H NMR using naphthalene as
b
an internal standard.. 1 mmol was used due to less solubility in
THF.
Ketyl-Olefin cyclization
With a mechanistic basis for the development of a catalytic
system in hand, we wanted to focus on an important bond-
forming reaction. In this regard, ketyl-olefin cyclization is
arguably one of the most important reactions initiated by SmI2
and is a key step in the synthesis of several natural products.4
Despite significant advances in carrying out ketyl-olefin cycli-
zations with Sm(II), in all cases stoichiometric or super stoi-
chiometric amounts of Sm(II) are required limiting the practi-
cal utility of the reagent.16,24 In light of the importance and
utility of this reaction class, employing catalytic amounts of
Sm(II) to carry out ketyl-olefin cyclization will likely broaden
the practical application of Sm(II) mediated bond-forming
reactions. To explore whether this approach will work, we
examined a range of substrates capable of undergoing 5-exo-
trig cyclization to explore the development of catalytic reac-
tions. Substrates used to study the cyclization reactions are
displayed in Chart 2.
It is interesting that the differences between TFE and isopro-
panol in activating TMSCl through H-bond interactions is
reflected only in the case of HMPA. Although, this observa-
tion is very similar to the outcome when MeOH is used, the
mechanism should be different since isopropanol does not
coordinate to Sm(II). A more likely scenario would be as
HMPA dissociates from the Sm(II) coordination sphere, the
electrostatic interaction between Sm(III) and negatively
charged intermediates is enhanced.56,70 Since TFE is more
acidic and less sterically crowded than isopropanol, it is more
efficient in activating TMSCl and hence Sm(II) catalysis is
more efficient with TFE than isopropanol when HMPA is used
as a ligand. This difference is not reflected in the tetraglyme
reaction, as tetraglyme likely remains coordinated with
Sm(II)/Sm(III) during the course of reaction.
Chart 2: Substrates for cyclization study.
Initial experiments with 8 were designed to examine the use of
tetraglyme and HMPA in the cyclization. Interestingly, it was
found that HMPA was the most useful in obtaining cyclized
product over simple reduction. The results of the study are
summarized in Table 5
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Table 5: Reduction vs cyclization for 8 with tetraglyme served exclusively while performing these reaction in the
presence of stoichiometric amount of SmI2/HMPA complex.16
In addition, the diastereoselectivity observed in the catalytic
reactions are different than that obtained in stoichiometric
reactions.16 It is likely that the difference in the outcome of
catalytic vs. stoichiometric reactions are twofold: a) studies
on the identity of the catalyst described vide infra show that
HMPA is being displaced from Sm during the course of the
reaction and there is a strong evidence that the sterically en-
cumbered Sm-HMPA complex is responsible for high dia-
stereoselectivity observed in stoichiometric reactions.16 b) the
silyl ketyl intermediate which was generated by the cleavage
of Sm(III)-O bond by TMSCl is also likely more prone to-
wards reduction since the sterically demanding trimethyl silyl
inhibits cyclization (Scheme 2).
1
2
3
4
5
6
7
8
and HMPA
Ligand
Proton
donors
8a (%)
8b (%)
Conversion
(%)a
Tetraglyme
HMPA
TFE
TFE
33
54
66
45
99
99
aSmI2: 0.05 mmol; Subs: 0.5 mmol; Ligand: 0.8 mmol; TFE: 2
mmol; TMSCl: 2.8 mmol and Mg: 0.1 g. Reaction time: 4 hrs.
Yields were determined by H NMR using naphthalene as an
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1
internal standard.
It is our supposition that difference between HMPA and
tetraglyme in the yield of cyclization product stems from their
ability to coordinate with Sm(II) vs Sm(III) metal ion. In the
case of HMPA, it has been demonstrated that the ligand forms
a stronger complex with SmI3 compared to SmI2.65 Additional-
ly, previous studies from our lab proposed that HMPA was
required to cleave the Sm(III)-ketyl radical ion pair to facili-
tate 5-exo-trig cyclization.71 Unlike HMPA, tetraglyme shows
higher affinity towards SmI2 rather than SmI3 and hence can-
not efficiently assist the dissociation of ion pair that is critical
for cyclization. Taken together these findings demonstrate the
suitability of HMPA as the best additive to employ in the cy-
clization.
Scheme 2: Proposed mechanism of Si-O intermediate in cy-
clization vs reduction outcome.
To reduce the concentration of the Si-O bond formed as an
intermediate and enhance the cyclization yield, we reasoned
that adding TMSCl slowly over a period of time may lower
the intermediate concentration of II shown above in Scheme 2.
To examine this supposition, reduction of 8 was carried out
using 10 mol% Sm by slowly added TMSCl over a 5 hour
time period. Slow addition of TMSCl increased the yield of
8a from 54 % to 80 %. Similar results were also obtained for 9
and 11. One caveat with this approach is that we discovered
for complete conversion of starting material to products, a
small amount of TMSCl was required to initiate the reaction
reduction of 9 and 11. Results of these reactions and distribu-
tion of TMSCl are summarized in Table 7.
Next, reactions were carried out for all the substrates using
HMPA as the ligand along with 5 or 10 mol percent Sm and
results are summarized in Table 6.
Table 6: Results of cyclization vs reduction for substrate 8-
11.
Substrate 10 mol percent reaction
5 mol percent reaction
Cyclization Total con- Cyclization Total con-
version
99
version
99
8
54 (1:1)
60 (2:1)
95 (12:1)
66 (1:1)
56 (1:1)
63 (2:1)
95 (12:1)
67 (1:1)
Table 7: Results with slow addition for 8, 9 and 11
9
99
99
10
11
99
99
Substrate
TMSCl
(mmol)
reaction
mixture
TMSCl (mmol) Cycliza-
in added slowly
tion/Conversion
99
99
(%)a
Reactions conditions: SmI2: 0.05/0.025 mmol; Subs: 0.5 mmol;
HMPA: 0.8 mmol; TFE: 2 mmol; TMSCl: 2.8 mmol and Mg: 0.1
g. Reaction time: 4 hrs for 10 mol percent and 15 hrs for 5 mol
8
0
2.8
1.4
1.8
80 (2:1)/99
75 (2:1)/99
82 (2:1)/99
9
1.4
1
1
percent. Yields were determined by H NMR using naphthalene
as an internal standard.
11
aSmI2: 0.05 mmol; Subs: 0.5 mmol; HMPA: 0.8 mmol; TFE: 2
mmol; total TMSCl: 2.8 mmol and Mg: 0.1 g. Slow addition time:
5hrs; Reaction time: 15 hrs. Yields were determined by H NMR
Results presented in Table 6 shows that the present system can
be utilized in synthetically relevant bond forming reactions.
To examine the suitability of the present method for larger
scale reactions, we scaled up the catalytic reduction of 10 to 1
g using 10 mol percent Sm. Analysis of the gram scale reac-
tions suggests that amount of cyclized product formed is com-
parable to that with results described in Table 6. The gram
scale reaction proceeds with a high yield of 97% (see SI, Table
S5 for details).
1
using naphthalene as an internal standard.
Although the aforementioned hypotheses are reasonable, we
are currently studying several other substrates to determine the
scope of this approach. Regardless of the mechanistic basis,
the initial data clearly demonstrates that high yields can be
obtained for the catalytic ketyl-olefin cyclization.
While 10 provides cyclized product almost exclusively, a dis-
tribution of cyclized vs reduced products were observed for
substrates 8, 9, and 11 whereas cyclized products were ob-
Conclusion and Future Studies
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Journal of the American Chemical Society
We have demonstrated that it is possible to significantly en-
Page 8 of 11
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hance the catalytic efficiency of Sm(II) in concert with termi-
nal Mg reductant by activating the system with TMSCl in con-
cert with an H-bond donor. This approach has also provided
an opportunity to develop Sm(II) catalysis employing HMPA
as a ligand, which was unsuccessful in previous studies.43,46
Mechanistic studies provided compelling evidence that during
the course of Sm(II) catalysis, SmI2 transforms into the more
reactive SmCl2. The conversion of SmI2 into SmCl2 during the
course of reaction broadens the scope of reactions that can be
carried out via Sm(II) catalysis. Mechanistic studies have also
revealed that HMPA is displaced from Sm by Mg+2 produced
during the course of the reaction. Based on these findings, we
propose the following catalytic cycle (Scheme 3).
Funding Sources
NSF CHE 1565741
ACKNOWLEDGMENT
We thank Caroline Bartulovich and Nicholas Boekell for insight-
ful discussions. We also thank Dr. Matthew McLaughlin for ini-
tial studies. R.A.F. is grateful to the National Science Foundation
(CHE 1565741) for support of this work.
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ASSOCIATED CONTENT
Supporting Information
General experimental methods, spectral data, and isothermal
titration calorimetry data. This material is available free of charge
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*rof2@lehigh.edu
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