Dynamic ligand exchange in reactions of samarium diiodide

Article abstract of DOI:10.1021/ol101722c

Mechanistic studies show the importance of iodide displacement by additives that accelerate reactions of samarium diiodide. The key feature important for acceleration of reaction rate is the use of proton donors and other additives that have a high enough affinity for Sm(II) to displace iodide yet do not saturate the coordination sphere inhibiting substrate reduction.

Full text of DOI:10.1021/ol101722c

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4140-4143
Dynamic Ligand Exchange in Reactions
of Samarium Diiodide
Dhandapani V. Sadasivam,† Joseph A. Teprovich, Jr.,† David J. Procter,‡ and
Robert A. Flowers, II*,†
Department of Chemistry, Lehigh UniVersity, Bethlehem, PennsylVania 18015, and
School of Chemistry, UniVersity of Manchester, Manchester M13 9PL, U.K.
rof2@lehigh.edu
Received July 23, 2010
ABSTRACT
Mechanistic studies show the importance of iodide displacement by additives that accelerate reactions of samarium diiodide. The key feature
important for acceleration of reaction rate is the use of proton donors and other additives that have a high enough affinity for Sm(II) to
displace iodide yet do not saturate the coordination sphere inhibiting substrate reduction.
The presence of additives is essential for the success of many
reactions initiated by samarium diiodide (SmI2).1 Lewis
bases, such as HMPA, have a mechanistically complex effect
on reactions. Although HMPA is the additive of choice in
many reactions of SmI2, alcohols and other additives can be
used successfully in some cases to provide high yielding and
selective reaction processes.1c Understanding the mechanistic
details of alternative approaches to enhancing the reactivity
and selectivity of SmI2-based reactions would allow chemists
to design methods for accelerating reductions while avoiding
the use of HMPA. Herein we show that the use of ligands
that displace iodide but do not saturate the coordination
sphere of Sm(II) provides a mechanistic pathway for ac-
celerating the rate of electron transfer from SmI2.
In understanding possible approaches to developing al-
ternative means to facilitate electron transfer from SmI2, it
is useful to consider the mechanism of action of successful
additives. In the case of HMPA, coordination to SmI2
produces a stronger reductant, and simultaneous displacement
of the iodide ligands creates open coordination sites for
substrates while concomitantly producing a sterically en-
cumbered reductant.2 Proton donors including water, alco-
† Lehigh University.
‡ University of Manchester.
(1) (a) Procter, D. J.; Flowers, R. A., II; Skrydstrup, T. Organic Synthesis
Using Samarium Diiodide: A Practical Guide; Royal Society of Chemistry
Publishing: U.K., 2010. (b) Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew.
Chem., Int. Ed. 2009, 48, 7140–7165. (c) Flowers, R. A., II. Synlett 2008,
1427–1439. (d) Flowers, R. A., II; Prasad, E. In Handbook on the Physics
and Chemistry of Rare Earths; Gschneidner, K. A., Jr.; Bunzli, J.-C. G.;
Pecharsky, V. K., Eds.; Elsevier: Amersterdam, 2006; Vol. 36, pp 393-473.
(e) Berndt, M.; Gross, S.; Ho¨lemann, A.; Reissig, H.-U. Synlett 2004, 422–
438. (f) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. ReV. 2004,
104, 3371–3403. (g) Dahle´n, A.; Hilmersson, G. Eur. J. Inorg. Chem. 2004,
3393–3403. (h) Kagan, H. B. Tetrahedron 2003, 59, 10351–10372. (i) Steel,
P. G. J. Chem. Soc., Perkin Trans. 1 2001, 2727–2751. (j) Krief, A.; Laval,
A.-M. Chem. ReV. 1999, 99, 745–777. (k) Molander, G. A.; Harris, C. R.
Chem. ReV. 1996, 96, 307–338. (l) Molander, G. A. Chem. ReV. 1992, 92,
29–68.
(2) (a) Prasad, E.; Flowers, R. A., II. J. Am. Chem. Soc. 2002, 124,
6895–6899. (b) Prasad, E.; Knettle, B. W.; Prasad, E.; Flowers, R. A., II.
J. Am. Chem. Soc. 2004, 126, 6891–6894.
10.1021/ol101722c  2010 American Chemical Society
Published on Web 08/19/2010

hols, and glycols also accelerate reactions. Addition of large
amounts of water to SmI2 in THF creates a thermodynami-
cally stronger reductant, but most alcohols do not.3 Work
by Hilmersson has shown that glycols are more effective
than alcohols because they can chelate SmI2.4 Recent studies
by Hoz show that alcohols accelerate reductions of carbonyls
through coordination to SmI2, which places the proton donor
in close proximity to the developing negative charge on the
substrate being reduced, thus facilitating rapid proton trans-
fer.5
To begin to address the role of water and other additives
in solution, conductance experiments were initiated to assess
the impact of different additives on iodide displacement
(Figure 1). Initially, HMPA was used to benchmark the
Although many alcohols accelerate the reduction of
carbonyls, water is different in that it significantly increases
the rate of reduction of alkyl halides and other substrates.
The unusual mechanistic behavior of water is in part a
consequence of its high affinity for SmI2 and its ability to
increase the ease of oxidation of SmI2.2,6 Other high affinity
proton sources such as diethylene glycol (DG) accelerate
reactions of SmI2 in smaller amounts, but unlike water, larger
amounts create a reductant with a saturated coordination
sphere that retards the rate of substrate reduction.7 In
considering the unusual effect of water, could its mechanism
of action be similar to that of HMPA? While water is capable
of increasing the reducing power of SmI2 (similar to HMPA),
the other key component of HMPA addition to SmI2 is
displacement of iodide to produce coordination sites for
substrates. Does water displace iodide from SmI2 and
accelerate reductions?
One of the difficulties in examining SmI2-additive systems
is the stability of the intermediate formed. Addition of HMPA
and some glycols provides crystals that can be readily
isolated and analyzed. These studies show that HMPA, DG,
glymes, and other additives displace iodide to the outer
sphere.7-10 While attempts to isolate crystals of SmI2-H2O
have been unsuccessful, crytallographic data does not always
mirror solution structures. Solution chemistry is a dynamic
process and insight into the role of additives on the structure
of SmI2 in solution is critical to understanding the impact of
additives on the reactivity of the reagent. To date, only the
solution structures of SmI2-HMPA complexes have been
examined.11 The seminal work of Daasbjerg and Skrydstrup
used conductance measurements as a means to unravel the
role of HMPA on SmI2 in THF.11b Their studies are
consistent with iodide displacement from SmI2 upon the
addition of HMPA.
Figure 1. Plot of the conductivity of 2.5 mM SmI2 with increasing
amounts of DG (b; red), EG (2; green), and H2O (9; black); the
inset shows HMPA (0; blue).
system. The conductivity of SmI2 in THF was zero. Upon
addition of HMPA, the conductance of the solution increased
substantially with the addition of 2 equiv. Further addition
of HMPA increased the conductance of the solution, but to
a lesser extent (inset, Figure 1). Similarly, addition of DG
to SmI2 increased the conductance of the solution substan-
tially up to 6 equiv and then decreased due to precipitation
of the complex. Addition of ethylene glycol (EG) to a
solution of SmI2 showed an increase in conductance up to
20 equiv and then increased more gradually with further
addition up to 100 equiv. Addition of water had no impact
at low concentrations, and the conductance of the solution
began to increase only after the addition of more than 20
equiv of water. The solution conductance increased gradually
with addition of 100 equiv of water. The changes in solution
conductivity are consistent with iodide displacement by each
additive examined.11b
To further characterize the SmI2-additive combinations,
we examined the UV-vis spectra of complexes formed with
additives shown by conductance to displace iodide from the
inner-sphere of SmI2. Figure 2 contains the UV-vis spectra
of SmI2 in THF containing 15 equiv of HMPA, 8 equiv of
DG, 100 equiv of EG, and 500 equiv of water, respectively.
In the first two cases, the displacement of iodide from the
inner sphere of Sm(II) has been confirmed by crystal-
lographic evidence.7,8
(3) (a) Chopade, P.; Prasad, E.; Flowers, R. A., II. J. Am. Chem. Soc.
2004, 126, 44–45. (b) Prasad, E.; Flowers, R. A., II. J. Am. Chem. Soc.
2005, 127, 18093–18099.
(4) Dahle´n, A.; Hilmersson, G. Tetrahedron Lett. 2001, 42, 5565–5569.
(5) (a) Farran, H.; Hoz, S. J. Org. Chem. 2009, 74, 2075–2079. (b)
Amiel-Levy, M.; Hoz, S. J. Am. Chem. Soc. 2009, 131, 8280–8284.
(6) Dahle´n, A.; Hilmersson, G.; Knettle, B. M.; Flowers, R. A. J. Org.
Chem. 2003, 68, 4870–4875
.
(7) Teprovich, J. A., Jr.; Balili, M. N.; Pintauer, T.; Flowers, R. A.
Angew. Chem., Int. Ed. 2007, 46, 8160–8163.
The feature that each of these spectra have in common is
the appearance of an absorption at approximately 480 ( 10
nm. Titrations of SmI2 with each additive showed the
formation of the peak at 480 nm at concentrations shown to
displace iodide in conductance experiments. Addition of
HMPA to SmI2 also shows a shoulder at 480 nm on a broader
absorption at 550 nm that begins to appear with the addition
of 4 equiv of HMPA. While we are not assigning the
(8) Hou, Z.; Zhang, Y.; Wakatsuki, Y. Bull. Chem. Soc. Jpn. 1997, 70,
149–153
.
(9) Teprovich, J. A., Jr.; Prasad, E.; Flowers, R. A., II. Angew. Chem.,
Int. Ed. 2007, 46, 1145–1148
(10) Vestergren, M.; Gustafsson, B.; Johansson, A.; Håkansson, M. J.
Organomet. Chem. 2004, 689, 1723–1733
.
.
(11) (a) Shotwell, J. B.; Sealy, J. M.; Flowers, R. A., II. J. Org. Chem.
1999, 64, 5251–5255. (b) Enemærke, R. J.; Hertz, T.; Skrydstrup, T.;
Daasbjerg, K. Chem.sEur. J. 2000, 6, 3747–3754.
Org. Lett., Vol. 12, No. 18, 2010
4141

Conductance data showed that addition of EG to SmI2
liberates iodide. Since it is bidentate, it should have an
affinity intermediate between water and DG. As a conse-
quence reduced amounts of EG (compared to water) should
be required to induce iodide displacement and enhance
reactivity but not have such a high affinity that it produces
a substitutionally inert complex. Although this additive has
been used in a range of SmI2-based reductions, its mechanism
of action has not been examined.13 To further probe the
system, kinetic experiments were performed to investigate
the role of concentration on the reduction of a model
substrate benzyl bromide.14 The impact of EG and water
concentration on the rate of reduction was monitored and is
shown in Figure 3. Both additives exhibit saturation kinetics
Figure 2. UV-vis spectra of (a) 1 mM SmI2 in THF + 15 equiv
HMPA (blue), (b) 1 mM SmI2 in THF containing 500 equiv of of
water (black), (c) 1 mM SmI2 in THF + 8 equiv of DG (red), and
(d) 1 mM SmI2 in THF + 100 equiv of EG (green).
absorption at 480 as iodide “free” Sm(II), the appearance of
this band is concomitant with concentrations of additives
shown by conductance measurements to displace iodide from
the inner sphere of the metal. As a consequence, the UV-vis
spectra can be used as a guide to examine the impact of
other additives on SmI2 (Vide infra).
Rate data from previous studies on DG and related
additives shows that saturation of Sm leads to a decrease in
reactivity.7 Comparison with data from previous studies on
water indicate that even high concentrations of water do not
lead to complete saturation of Sm(II).3 If this supposition is
correct, it shows that the impact of water is in part a result
of providing open coordination sites without saturating the
metal as exemplified in Scheme 1.
Figure 3. Plot of kobs versus EG (2; green) and H2O (9; black) for
the reduction of benzyl bromide (100 mM) by SmI2 (2 mM).
and substantially increase the rate of reduction, but EG
increases the rate at lower concentrations than water. Unlike
water, which shows complex rate orders for the reaction,3
reductions using EG were first order in additive, SmI2, and
substrate.
Scheme 1
The experiments described above show that addition of
water and EG to SmI2 displace iodide in THF. The affinity
of each additive for SmI2 in THF dictates the amount
necessary to displace bulk solvent and iodide from the inner
sphere of Sm. Kinetic studies show that water and EG
increase the rate of substrate reduction substantially and the
rate of the increase is concomitant with iodide displacement.
In contrast, additives like DG that have a very high affinity
for SmI2 initially enhance the rate of substrate reduction,
but continued addition decreases the rate of reduction through
the saturation of the coordination sphere of the metal thus
inhibiting the ability of substrate to interact with Sm.6 The
The work of Procter has shown that a number of unique
and synthetically important reductions can be initiated by
SmI2 containing high concentrations of water.12 Although
water provides access to exceptional reactivity at high
concentrations, SmI2-water systems oxidize readily, and
working with them can be difficult. The collection of data
above suggests that other additives can be employed in place
of water.
(13) (a) Hanessian, S.; Girard, C. Synlett 1994, 863–864. (b) Linderman,
R. J.; Cusack, K. P.; Kwochka, W. R. Tetrahedron Lett. 1994, 35, 1477–
1480. (c) Tarnopolsky, A.; Hoz, S. J. Am. Chem. Soc. 2007, 129, 3402–
3407.
(12) (a) Duffy, L. A.; Matsubara, H.; Procter, D. J. J. Am. Chem. Soc.
2008, 130, 1136–1137. (b) Guazzelli, G.; De Grazia, S.; Collins, K. D.;
Matsubara, H.; Spain, M.; Procter, D. J. J. Am. Chem. Soc. 2009, 131, 7214–
7215. (c) Parmar, D.; Duffy, L. A.; Sadasivam, D. V.; Matsubara, H.;
Bradley, P. A.; Flowers, R. A., II; Procter, D. J. J. Am. Chem. Soc. 2009,
131, 15467–15473.
(14) Benzyl bromide was chosen as a model substrate to simplify the
kinetic analysis. (a) Andrieux, C. P.; Gallardo, I.; Saveant, J.-M.; Su, K.-
B. J. Am. Chem. Soc. 1986, 108, 638–647. (b) Saveant, J.-M. J. Am. Chem.
Soc. 1987, 109, 6788–6795.
4142
Org. Lett., Vol. 12, No. 18, 2010

collection of these data suggests that water, EG, and other
additives capable of displacing iodide from Sm while leaving
open coordination sites for substrate provide a means to
enhance the reactivity of SmI2 significantly.
Table 2. Reaction of 3 with SmI2 and Additives
The fundamental question remains: is this a viable ap-
proach for determining adequate substitutes for water and,
additionally, for HMPA? First, we examined whether another
additive could be employed to promote transformations that
have only been reported with water.12 To address this issue,
the reduction of lactone 5-decanolide 1 by SmI2 and EG was
examined and compared to the known reduction by SmI2-
water (Table 1). Addition of EG to SmI2 provided reduction
entry additive, equiv time (h) yield 4a (cis:trans) yield 5a
1
2
3
4
5
6b
7
8
none
24
1
1
1
12
2
NR
HMPA, 4
H2O, 20
H2O, 150
EG, 4
EG, 24
ED, 4
98 (1:19)
62 (1:3)
94 (1:3)
78 (1:3)
87 (1:3)
99 (1:3)
99 (1:9)
<2
38
6
22
13
12
3
Table 1. Reduction of 5-Decanolide with Water and EG
DCH, 10
a NMR yields. NR ) no reaction. b [SmI2] ) 3 equiv.
if other additives could be used in the reaction, several
additives were screened using UV-vis as a guide for iodide
displacement. Diamines were shown to displace iodide (as
determined by the presence of an absorbance at 480 nm).
Ethylenediamine (ED) and trans-N,N′-dimethyl-1,2-cyclo-
hexyldiamine (DCH) were chosen for use in the cyclization,
and the data are contained in Table 2. Both additives provided
quantitative yields as determined by 1H NMR. Although ED
provided modest stereoselectivity similar to EG and water,
DCH provided good diastereoselectivity. It is likely that the
increased steric bulk of DCH is in part responsible for the
enhanced diastereoselectivity.
entry
additive, equiv
time (h)
isolated yield 2 (%)
1
2
H2O, 150
EG, 4
7
12
83
80
of 1 similar to water at much lower additive concentrations.
Although higher concentrations of EG accelerated the rate
of reaction, transesterification became the major product.
Since this approach can potentially be used to promote
reactions that only worked with SmI2-water, ketone-alkene
cyclizations were examined to determine if this method could
be applied to more complex bond-forming reactions that
employ HMPA.15,16 2-But-3-enyl-cyclohexan-1-one 3 was
treated with SmI2 in the presence (and absence) of HMPA,
EG, and H2O. The results are shown in Table 2. Addition of
4 equiv of HMPA provided excellent yield of 4 with very
good diastereoselectivity.15,17 The use of 150 equiv of water
and 24 equiv of EG (based on [SmI2]) provided excellent
yields of cyclized product 4 with modest diastereoselectivity.
Although lower concentrations of EG provided good yields
of 4, higher amounts of reduced product 5 were obtained.
Interestingly, the same trend was observed with water
although this additive accelerated the reaction significantly
compared to EG.
Overall, these studies demonstrate that a range of additives
can be used to accelerate reactions of SmI2 through displace-
ment of iodide ligands. The key feature for successful
implementation of this approach is the use of additives that
have a high enough affinity for Sm(II) to displace iodide
yet do not saturate the coordination sphere inhibiting
substrate reduction. We are currently examining this approach
in the development of other Sm(II)-based reactions and these
studies will be reported in due course.
Acknowledgment. R.A.F. thanks the National Science
Foundation (CHE-0844946) for support of this work. We
thank Mr. James Devery (Lehigh University) for his useful
comments on the manuscript.
Although water and EG were effective in the ketone-alkene
cyclization, diastereoselectivities were modest. To determine
(15) Molander, G. A.; McKie, J. A. J. Org. Chem. 1992, 57, 3132–
Supporting Information Available: General methods,
experimental protocols, and spectroscopic data. This material
is available free of charge via the Internet at http://pubs.acs.org.
3139
.
(16) Saadi, J.; Lentz, D.; Reissig, H. U. Org. Lett. 2009, 11, 3334–
3337
.
(17) Sadasivam, D. V.; Antharjanam, P. K. S.; Prasad, E.; Flowers, R. A.,
II. J. Am. Chem. Soc. 2008, 130, 7228–7229
.
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