The effect of proton donors on the facial stereoselectivity in SmI 2 reduction of norcamphor

Article abstract of DOI:10.1021/jo1023206

The endo/exo product ratio in the reactions of SmI₂ with norcamphor in the presence of various proton donors was determined. The effect of MeOH, EtOH, trifluoroethanol (TFE), ethylene glycol (EG), and water was investigated at various concentrations of these proton donors. At low concentrations of EtOH, TFE, and EG, an endo/exo ratio near unit was found. This ratio increased as the concentration of the proton donor increased. However, MeOH and water gave a U-type curve, in a plot of the endo/exo ratio vs proton donor concentration. The difference between the two groups of proton donors was shown not to result from differences in their acidities or polarity effects. It is suggested that at low MeOH and water concentrations, the second electron transfer takes place from the dimer of SmI₂ rather than from the monomer. This bulky electron donor approaches the radical anion preferentially from the exo direction giving rise to the high endo/exo ratio at the left arm of the U-shaped curve. Comparison of kinetic and product H/D isotope effects shows that protonation on carbon, the step that locks the stereochemistry, is a post rate determining step.(Figure Presented)

Full text of DOI:10.1021/jo1023206

pubs.acs.org/joc
The Effect of Proton Donors on the Facial Stereoselectivity in SmI2
Reduction of Norcamphor
Sarasij Kumar Upadhyay and Shmaryahu Hoz*
Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel
shoz@mail.biu.ac.il
Received November 22, 2010
The endo/exo product ratio in the reactions of SmI2 with norcamphor in the presence of various
proton donors was determined. The effect of MeOH, EtOH, trifluoroethanol (TFE), ethylene glycol
(EG), and water was investigated at various concentrations of these proton donors. At low con-
centrations of EtOH, TFE, and EG, an endo/exo ratio near unit was found. This ratio increased as
the concentration of the proton donor increased. However, MeOH and water gave a U-type curve, in
a plot of the endo/exo ratio vs proton donor concentration. The difference between the two groups of
proton donors was shown not to result from differences in their acidities or polarity effects. It is
suggested that at low MeOH and water concentrations, the second electron transfer takes place from
the dimer of SmI2 rather than from the monomer. This bulky electron donor approaches the radical
anion preferentially from the exo direction giving rise to the high endo/exo ratio at the left arm of the
U-shaped curve. Comparison of kinetic and product H/D isotope effects shows that protonation on
carbon, the step that locks the stereochemistry, is a post rate determining step.
Introduction
various additives in the chemistry of samarium iodide is far
from complete. HMPA, one of the most commonly used
additives, coordinates effectively with SmI2 and increases its
reduction potential from -1.3 to -2.05 V, rendering the
reduction reaction more facile.9 On the other hand, alcohols
Since its discovery, samarium iodide has proven itself as a
useful reagent in organic synthesis.1 It has been widely
applied in the synthesis of important building blocks and
natural products.2 Its ability to form complexes with various
reagents3 such as HMPA,4 methanol,5 glycols,6 water,5a,7
etc. has added to its versatility in terms of reactivity and
stereoselectivity.8 A judicious choice of these additives and
their fine-tuning may turn out to be extremely helpful in
synthetic processes. Still, our understanding of the role of the
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T.; Mataka, S. Tetrahedron. Lett. 2005, 46, 5277–5279. (b) Pospisil, J.; Pospisil,
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Skrydstrup, T.; Daasbjerg, K. Chem.;Eur. J. 2000, 6, 3747–3754. (e) Shotwell,
J. B.; Sealy, J. M.; Flowers, R. A. J. Org. Chem. 1999, 64, 5251–5255. (f) Hou,
Z.; Zhang, Y.; Wakatsuki, Y. Bull. Chem. Soc. Jpn. 1997, 70, 149–153.
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Lett. 2004, 6, 2685–2688. (c) Hutton, T. K.; Muir, K. W.; Procter, D. J. Org.
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DOI: 10.1021/jo1023206
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Upadhyay and Hoz
JOCArticle
such as glyme coordinate to SmI2 but do not change its
reduction potential.10 Coordination by methanol greatly
enhances various reactions. The rate enhancement, which
in this case is not due to a higher reduction potential, must be
realized by a different mechanism. We have shown11 that
when the electron transfer is highly endothermic, the lifetime
of the radical anion formed is too short to enable an en-
counter with a proton donor from the bulk solution before
back transfer of the electron to the Sm3þ. However, if a
methanol molecule is coordinated to the samarium cation in
the ion pair, it can rapidly transfer its proton to the radical
anion, capturing it in a unimolecular reaction. This is demon-
strated by the reduction of R-cyanostilbenes as shown in eq 1,
where no reaction was observed in the presence of trifluor-
oethanol (TFE) as the proton donor, yet a facile reaction
took place in the presence of MeOH.
incipient alkoxide is stabilized by a neighboring Sm3þ cation.
It is clear that the size of the coordination shell of the SmI2
increases with the concentration of the ligand in the reaction
mixture (up to a saturation level). Thus, whenever there are
two possible approach directions to the substrate differing in
their steric accessibility, the stereoselection will vary with the
size of the protonating complex, and hence, with the con-
centration of the ligand.
We have chosen to use norcamphor, one of the classical
substrates for such studies,15 for our investigation. Its re-
duction yields two isomers, endo and exo (eq 2).
In this substrate the exo approach of the proton donor
(leading to an endo product) is sterically less hindered than
the endo one. We may therefore expect an effect of the
concentration of proton donor on the facial stereoselectivity.
When the proton donating system (coordinated SmI2) is
large, the exo approach will be preferred and hence, the
production of the endo alcohol will be favored. However, as
In this case, MeOH efficiency is due to its coordination to
the SmI2. Therefore, once the SmI2 transfers its electron to
the substrate, the MeOH being in the close vicinity of the
radical anion can protonate it before back electron transfer
takes place. The same concept of capturing an unstable radi-
cal anion before it donates its electron back to the samarium
cation was employed also in photochemical reactions achiev-
ing some previously unattainable reactions.12 Thus, through
various mechanisms, additives can significantly shorten
reaction times and in some cases convert a “no go” reaction
into a “go” reaction. However, there may also be a down side
to this coordination. It was shown in several instances that
coordination by HMPA, for example, hampers inner-sphere
electron transfer reactions.4d,6b,13
will be shown later on, this naıve hypothesis does not
¨
describe the reality in full.
Results and Discussion
All the reactions were conducted in THF at room tem-
perature under nitrogen. The standard concentration of the
norcamphor was 0.023 M and that of SmI2 0.048 M. Unless
otherwise indicated, the reactions were conducted until
discoloration of the SmI2 was observed.
In the present paper we report the effect of the coordina-
tion of SmI2 on the stereochemical outcome of a carbonyl
reduction reaction. It should be pointed out that coordina-
tion to lanthanides has been shown to increase the acidities of
alcohols by ca. 15 orders of magnitude.14 Thus, in most of
these cases, the protonation that locks the stereochemistry
takes place either from a proton donor which is precoordi-
nated to the samarium or in a transition state in which the
In general, the mechanism for reduction of carbonyl com-
pounds by SmI2 consists in most cases of the following
sequence: electron, proton, electron, proton transfer steps.16
The step that locks the stereochemistry is the protonation on
the carbon atom. Since the reactions are conducted in a sol-
vent of low polarity, the incipient alkoxide in the transition
state of the proton transfer step is most likely stabilized by a
samarium cation.17 Theeffect found upon variation of MeOH
concentration on the stereochemistry is given in Table 1 and
Figure 1.
(7) (a) Bradley, P. A.; Flowers, R. A.; Procter, D. J. J. Am. Chem. Soc.
2009, 131, 15467–15473. (b) Dahlen, A.; Nilsson, A.; Hilmersson, G. J. Org.
Chem. 2006, 71, 1576–1580.(c) Dahlen, A.; Hilmersson, G. J. Am. Chem. Soc.
2005, 127, 8340–8347. (d) Jensen, C. M.; Lindsay, K. B.; Taaning, R. H.;
Karaffa, J.; Hansen, A. M.; Skrydstrup, T. J. Am. Chem. Soc. 2005, 127, 6544–
TABLE 1. Yield and Endo/Exo Percentage in the Reduction of Nor-
camphor with SmI2 in the Presence of Various Concentrations of MeOH
ꢀ
6545. (e) Dahlen, A.; Hilmersson, G. Chem.;Eur. J. 2003, 9, 1123–1128. (f)
[MeOH], M
time, h
yield, %
endo, %
exo, %
Kamochi, Y.; Kudo, T. Chem. Lett. 1993, 1495–1498. (g) Hasegawal, E.;
Curran, D. P. J. Org. Chem. 1993, 58, 5008–5010. (h) Kamochi, Y.; Kudo, T.
Chem. Lett. 1991, 893–896.
(8) (a) Edmonds, D. J.; Muir, K. W.; Procter, D. J. J. Org. Chem. 2003, 68,
3190–3198. (b) Keck, G. E.; Wager, C. A.; Sell, T.; Wager, T. T. J. Org. Chem.
1999, 64, 2172–2173.
(9) Shabangi, M.; Flowers, R. A. Tetrahedron Lett. 1997, 38, 1137.
(10) Pedersen, H. L.; Christensen, T. B.; Enemaerke, R. J.; Daasbjerg, K.;
Skrydstrup, T. Eur. J. Org. Chem. 1999, 565–572.
0.1
0.3
0.5
1
2
4
96
96
48
20
15
10
87
80
80
76
62
42
81
77
62
55
65
83
19
23
38
45
35
17
(11) Amiel-Levy, M.; Hoz, S. J. Am. Chem. Soc. 2009, 131, 8280–8284.
(12) Amiel-Levy, M.; Hoz, S. Chem.;Eur. J. 2010, 16, 805–809.
(13) (a) Farran, H.; Hoz, S. Org. Lett. 2008, 10, 4875–4877. (b) Prasad, E.;
Flowers, R. A. J. Am. Chem. Soc. 2002, 124, 6895–6899. (c) Miller, R. S.;
Sealy, J. M.; Shabangi, M.; Kuhlman, M. L.; Fuchs, J. R.; Flowers, R. A.
J. Am. Chem. Soc. 2000, 122, 7718–7722. (d) Shabangi, M.; Kuhlman, M. L.;
Flowers, R. A. Org. Lett. 1999, 1, 2133–2135.
Surprisingly, the data show that as the MeOH concentration
increases, the endo/exo ratio first decreases to a minimum
(15) Ashby, E. C.; Laemmle, J. T. Chem. Rev. 1975, 75, 521–546.
(16) House, H. O. Modern Synthetic Reactions, 2nd ed.; W. A. Benjamin:
Menlo Park, CA, 1972.
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228–234.
(17) Tarnopolsky, A.; Hoz, S. J. Am. Chem. Soc. 2007, 129, 3402–3407.
1356 J. Org. Chem. Vol. 76, No. 5, 2011

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TABLE 5. Yield and Endo/Exo Percentage in the Reduction of Nor-
camphor with SmI2 in the Presence of Various Concentrations of H2O
[H2O], M
time, h
yield, %
endo, %
exo, %
0.05
0.1
0.3
0.5
0.8
1
96
72
10
86
79
85
92
96
87
79
82
80
63
57
58
63
75
18
20
37
43
42
37
25
0.1
0.05
0.03
0.008
4
FIGURE 1. The effect of MeOH concentration on the endo/exo
ratio in the reduction of norcamphor with SmI2.
TABLE 2. Yield and Endo/Exo Percentage in the Reduction of Nor-
camphor with SmI2 in the Presence of Various Concentrations of EtOH
[EtOH], M
time, h
yield, %
endo, %
exo, %
0.5
1
2
144
96
60
83
85
86
67
75
80
33
25
20
TABLE 3. Yield and Endo/Exo Percentage in the Reduction of Nor-
camphor with SmI2 in the Presence of Various Concentrations of TFE
FIGURE 2. The effect of EtOH, TFE, and EG concentration on
the endo/exo ratio.
[TFE], M
time, h
yield, %
endo, %
exo, %
0.1
0.3
0.5
1
240
240
192
120
31
65
70
86
53
65
79
84
47
35
21
16
TABLE 4. Yield and Endo/Exo Percentage in the Reduction of Nor-
camphor with SmI2 in the Presence of Various Concentrations of EG
[EG], M
time, h
yield, %
endo, %
exo, %
0.05
0.1
0.3
0.5
1
96
48
10
0.25
0.1
84
100
89
91
91
64
67
75
89
92
36
33
25
11
8
around 1 M and then increases again to close to the initial
value. Because of this unexpected result, the effect of four addi-
tional proton donors;EtOH, trifluoroethanol (TFE), ethy-
lene glycol (EG), and water;was examined.18 The results are
shown in Tables 2-3,4,5 and in Figures 2 and 3.
FIGURE 3. The effect of H2O concentration on the endo/exo ratio.
will stabilize the alkoxide when formed. This also is a large
group of a size similar to that of the ketyl oxygen with its
Sm3þ. The near similar size of the two groups leads to a lack
of steric preference and the endo/exo ratio is indeed close to
unity. As the concentration of the proton donor increases,
the equilibrium depicted in eq 3 will be shifted to the right
and a larger proportion of the ketyl oxygen will be proto-
nated.
As can be seen, there is no uniform behavior among the
various proton donors. MeOH and H2O show a minimum,
whereas the three other alcohols display a continuous in-
crease in the endo/exo ratio as the proton donor concentra-
tion increases. The behavior of these three alcohols can be
explained as follows. In the absence of a proton donor, or at
low concentration thereof, the oxygen atom of the radical
anion generated upon the first electron transfer is coordi-
nated to the Sm3þ (1). This would constitute a bulky group
that would prefer to occupy the exo position. On the other
hand, regardless of the intimate details of the mechanism,
protonation of the carbanion at a later stage must involve a
party of two, the proton donor and a samarium cation, which
(18) Side products were observed in some cases, at higher concentrations
of the proton donors. Reaction with ethylene glycol (2 M) as a proton donor
resulted in poor yield (∼20%) because of the loss of material during aqueous
workup.
Since the OH group in 2 is smaller than the bulky pro-
tonation complex, it will preferentially assume an endo posi-
tion allowing the ROH SmI2 to approach 2 from the exo
3
J. Org. Chem. Vol. 76, No. 5, 2011 1357

Upadhyay and Hoz
JOCArticle
direction. Thus, as the concentration of the proton donor
increases the endo/exo ratio increases as well. The limited data
at hand are insufficient for a suggestion of a detailed unequi-
vocal mechanism for these reactions. This could involve a
protonation of the oxygen of 1 by the protonating complex
TABLE 6. Acidities in DMSO and the Gas Phase (Calculated) of the
Proton Donors
proton donor
pKa in DMSO
calcd, kcal/mol
TFE
23.45
29.0
29.6a
31.2
n/a
311.6
325.7
325.5
324.6
315.9b
MeOH
EtOH
H2O
ROH SmI2 forming 2, followed by an electron transfer to
3
generate the corresponding carbanion to produce 3, which
subsequently undergoes protonation with retention of config-
uration to produce preferentially the endo product (eq 4).
EG
aInterpolated. bIn the cis conformation.
Alternatively, an electron could be transferred to the
radical anion 1, generating the dianion 4, now stabilized by
two Sm3þ ions, followed by protonation with retention of
configuration to generate preferentially the endo product
(eq 5).
FIGURE 4. The effect of proton donors at 0.1, 0.5, and 1M
concentration on the ET30 values of their solutions in THF.
tions were performed with Gaussian 09 at the B3LYP/6-
31þG* level with the PCM solvation model.21
For the polarity effect of these proton donors on the THF
solutions we used the ET30 scale.22 The results are presented
graphically in Figure 4 and in Table S1 in the SI.
Interestingly, the polarity (ET30) of the pure additives
decreases in the following order: water (63.1) > TFE (59.5)
> EG (56.3) > MeOH (55.5) > EtOH (51.9).23 Yet, exa-
mination of the data shows that water, when mixed with THF,
affects the polarity much like the least polar proton donor
used;EtOH. It should be noted that the high polarity of water
is a colligative property. Namely, the dipole moment of water is
1.87 D, similar to that of MeOH (1.7 D).24 The high polarity of
water as a solvent is due to its highly ordered structure.23 How-
ever, in its THF solution at low concentration, water molecules
exist, most likely as monomer, dimer, or low molecular weight
aggregates which are bound to THF molecules (the concentra-
tion of THF in THF is 12.3 M). Under these circumstances, the
highly ordered lattice of water and hence the high polarity effect
cannot be manifested and the water effect is similar to that of
the low molecular weight alcohols.
In both parameters, acidity and polarity, two distinct
groups are formed. One consists of TFE and EG and the
other of EtOH, MeOH, and water. Thus, none of these
properties make methanol and water a group distinguished
from the rest of the proton donors. Another parameter one
should consider is the ability to form a complex with SmI2.
Methanol and water are known to complex efficiently to
The quandary is: What is the common denominator of the
two proton donors, MeOH and water, that distinguishes
them from the other proton donors? We have examined the
acidity of these proton donors and their effect on the polarity
of the THF solution. In the absence of data in THF we used
the Bordwell scale in DMSO.19 The data are given in Table 6.
(The value for EtOH is interpolated between that of MeOH
and i-PrOH.20) In the third column of the table, the calcu-
lated proton affinities in THF are displayed. The calcula-
(19) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463.
(20) The interpolation is based on the number of Me groups: zero for
MeOH and two for i-PrOH (pKa 30.25)
(21) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.: Strain,
M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski,
J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen,
W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision B.04;
Gaussian, Pittsburgh, PA, 2003.
(22) Reichardt, C. Angew. Chem. 1965, 4, 29–40.
(23) Reichardt, C. Solvent Effects in Organic Chemistry; Verlag Chemie:
New York, 1979.
(24) Weast, C. W., Ed. CRC Handbook of Chemistry and Physics, 67th
ed.; CRC Press: Cleveland, OH, 1986-7.
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SmI2. However, EG is also an efficient complexant to SmI2;
yet, it does not exhibit the U-shaped graph of Figures 1 and 3.
We suggest that the governing factor is a combination of
complexation ability and size. At very low proton donor
concentrations, the radical anion has the structure of 1. To
obtain a large endo/exo ratio, the protonating group must
approach the radical anion preferentially from the exo
direction. For this it must be significantly larger than the
O-Sm3þ unit of 1. An aggregate of SmI2 with coordinated
MeOH or H2O molecule(s) satisfies this demand and seems
to be the only conceivable protonating species that is con-
siderably larger than the O-Smþ3 unit of 1. Recently
Flowers et al. reported the existence of a SmI2 dimer in the
presence of water.25 The concentration of the dimer increases
with the concentration of water in the solution and the
reduction potential of the dimer is much higher than that
of the monomer. Thus, one can assume that such a dimer
could be formed also with MeOH but not with the larger
proton donor EG. We also assume that minute amounts of
the dimer are present in the reaction mixture also at low
concentrations of these proton donors.
FIGURE 5. The effect of SmI2 concentration (solid line 0.084 M,
dashed line 0.048 M) on the endo/exo ratio in the presence of various
MeOH concentrations.
As the concentration of MeOH or water increases, more
of the complex SmI2 (MeOH or H2O)n, which is of size
3
similar to that of the O-Sm3þ unit, is formed. This
complex competes with the dimer and therefore the
endo/exo ratio decreases as the proton donor concentra-
tion increases. At a certain point, the mechanism shifts to
that of the other proton donors. Namely, 1 is converted to
2 and the relative amount of the endo isomer starts to
increase.
At low concentrations of MeOH or water the reaction is
indeed very slow. It is thus possible that the dimer, in spite of its
low concentration, by virtue of its high activity, takes part in the
second electron transfer. Due to its large size, it approaches the
radical anion 1 from the exo direction as depicted in 5 (R = H
or Me). This dimer can transfer an electron to the ion-paired
radical anion 1 to generate 4 with the C-Sm unit at the exo
position, followed by protonation on the carbanion (eq 6).
Consistent with the dimer assumption is the result of the
experiment in which we increased the SmI2 concentration
from 0.048 to 0.084 M while maintaining the concentra-
tion of substrate at 0.023 M. This increase in the SmI2
concentration should, in principle, increase the concen-
tration of the dimer in the solution. In this case the
intervention of the monomeric SmI2 in the reduction
should be attenuated. Indeed, the decrease in the endo/
exo ratio became more moderate and the minimum was
obtained at a higher endo/exo ratio (Figure 5, also Table S2
in the SI).
Finally, we wanted to know whether protonation on the
carbon is the rate determining step of the reaction. For this
purpose we quenched two reactions, one with MeOH and
one with MeOD (1M) after 5 and 10 h. The NMR yields were
33((2)% after 5 h and 40((1)% after 10 h for both alcohols.
Thus, it seems that there is no kinetic isotope effect on the
reaction rate. In the second experiment;incorporation iso-
tope effect (6);we ran a reaction with a mixture of MeOH
and MeOD in a ratio of 1:3, respectively. The total concen-
tration of MeOH(D) was 1 M. The ratio of H/D incorpora-
tion into the carbinol carbon was 42/58. Thus, the product
distribution isotope effect is 2.2. This clearly shows that
protonation of the carbon, the step that locks the stereo-
chemistry, is a postrate determining step. It should be noted
that the incorporation ratios for the endo and exo isomers
were the same within experimental error. Thus, the product
Alternatively it could, as suggested above for the mono-
mer, transfer a proton to the oxygen and concomitantly an
electron to the carbon-centered radical to generate 3 (eq 7).
(26) In another product distribution isotope effect experiment carried out
under irradiation we obtained an isotope effect of 2.1, similar to that of the
thermal reaction. (A solution of norcamphor (23 mM) in a 50 mL volumetric
flask was allowed to react with SmI2 (48 mM) in the presence of proton donor
[1 M]. The solution was irradiated with a 400 W sun lamp until the blue color
of SmI2 disappeared.) This implies that within the resolution of this techni-
que, the carbanions in the thermal and the photochemical reactions are of
identical structure, although in the latter, the endo/exo ratio was different
from the thermal: 2.4 and 3.2 for 0.1 and 1 M MeOH, respectively.
(25) Prasad, E.; Flowers, R. A. J. Am. Chem. Soc. 2005, 127, 18093–18099.
J. Org. Chem. Vol. 76, No. 5, 2011 1359

Upadhyay and Hoz
JOCArticle
isotope effect is not sensitive enough to distinguish between
these two environments.26
over Na wire þ benzophenone under argon atmosphere. TFE,
EtOH, and MeOH were dried according to known proce-
dures.27 Water content was determined and found to be lower
than 20 ppm. SmI2 was diluted as needed from a 0.1 M freshly
prepared28 THF solution. The concentration of the SmI2
solution was spectroscopically determined (λ = 615 nm;
ε = 635). The reactions were performed in a glovebox under
nitrogen atmosphere at room temperature. The reduced pro-
ducts (norborneols) of norcamphor are known in literature.29
The product ratios and percentage conversion were deter-
mined by high-resolution NMR (600 or 300 MHz) analyses
of the crude reaction mixture after extraction, drying, and
solvent evaporation.
Summary and Conclusions
Reduction with Samarium Iodide: General Procedure. A solu-
tion of norcamphor (23 mM) in THF was allowed to react with
SmI2 (48 mM) in the presence of the desired concentration of the
proton donor. The reaction was carried out in the glovebox until
the deep blue solution became colorless. Phosphate buffer (5%;
15 mL) was added, and the solution was extracted with dichlor-
omethane (3 ꢀ 25 mL). The combined organic layer was washed
with water (2 ꢀ 15 mL) followed by brine (2 ꢀ 20 mL), dried over
anhydrous Na2SO4, and evaporated under reduced pressure to
give crude reaction mixture. The percentage conversion and
ratio of product distribution were calculated by using NMR
In this paper we explored the effect of the size of the
coordination shell around the SmI2 on the stereochemical
outcome in the reduction of norcamphor. We find two
groups of proton donors. The first consists of water and
methanol which at low concentrations yield a high endo/exo
ratio. This ratio decreases to a minimum as the proton donor
concentration is raised and then rises again yielding a U-type
profile. EtOH, TFE, and EG start at an endo/exo ratio
around one showing no facial preference. This ratio increases
with the concentration of the proton donor. The increasing
endo/exo ratio with the concentration of the proton donor
could be easily understood. On the other hand, the counter-
intuitive observation that MeOH and water at low concen-
trations display a high endo/exo ratio that then decreases is
less understood. It implies that the second electron transfer
followed by protonation on the carbon takes place prefer-
entially from the exo position. Namely, the species which
approaches the radical anion must be larger than the O-SmI2
unit, so as to force the later into the more hindered endo
position. Such a species could be the dimer of SmI2, which
was first discovered by Flowers25 using water as an additive.
We suggest that such a dimer is generated also with the other
small proton donor;MeOH. This dimer, being the most
reactive electron donor and the bulkiest species in the system,
approaches the radical anion from the less hindered exo
direction leading to the formation of the endo product.
Consistent with this mechanism is the observed dependence
of the endo/exo ratio on the SmI2 concentration.
1
signals of the crude reaction mixture (see SI). H NMR (600
MHz) endo alcohol (carbinol proton; δ 4.23-4.2, m, 1H); exo
alcohol (carbinol proton; δ 3.76-3.74, m, 1H); ketone (bridge-
head protons; δ 2.66-2.59, m, 2H). 13C NMR (150 MHz) of the
crude; ketone (218.2, 49.8, 45.2, 37.6, 35.4, 27.1, 24.1); endo
alcohol (73.0, 42.5, 39.5, 37.5, 37.1, 29.8, 19.8); exo alcohol
(74.9, 44.3, 42.3, 35.3, 34.3, 28.1, 24.4).
Incorporation Isotope Effect. The incorporation ratio was
determined in an internal competition experiment in which the
reaction medium contained both MeOH and MeOD. A solu-
tion of norcamphor (23 mM) was allowed to react with SmI2
(48 mM) in the presence of 1 M proton donor with the composi-
tion ratio 3:1 (MeOD, 0.75 M; MeOH, 0.25 M). After 24 h,
phosphate buffer (5%; 15 mL) was added, and the solution was
extracted with dichloromethane (3 ꢀ 25 mL). The combined
organic layer was washed with water (2 ꢀ 15 mL) followed by
brine (2 ꢀ 20 mL), dried over anhydrous Na2SO4, and evapo-
rated under reduced pressure to give crude reaction product.
The ratio of product distribution was obtained by integrating
NMR (13C; 75 MHz) signals of the crude reaction mixture (see
the SI). C signals for major product (endo alcohol) were segre-
gated at C-1 (δ 42.39 for H; 42.27 for D isomers) and C-3 (δ 39.30
for H; 39.17 for D isomers), similarly C signals for minor product
(exo alcohol) were segregated at C-1 (δ 44.10 for H; 44.39 for D
isomers) and C-3 (δ 42.11 for H; 42.01 for D isomers). The NMR
spectra are presented in the Supporting Information.
These results justify the statement we posited in the
introduction saying that it is not enough to select the type
of additive for the SmI2 reductions. Fine tuning of their
concentrations may be of no lesser importance.
Experimental Section
Supporting Information Available: Tables S1 and S2,
Gaussian archives for the acidities of the proton donors, and
H and C13 NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
General. NMR spectra were recorded at 600 and 300 MHz on
a FT-NMR spectrometer. THF was dried and freshly distilled
(27) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: New York, 1989.
(28) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102,
2693.
(29) The Aldrich Library of 13C and 1H FT NMR Spectra, 1st ed.; Aldrich
Chemical Co.: Milwaukee , WI, 1992; Vol. 1, p 249.
1360 J. Org. Chem. Vol. 76, No. 5, 2011