Note

Cite This: J. Org. Chem. 2018, 83, 10688−10692 pubs.acs.org/joc

Mechanism of SmI2 Reduction of 5‑Bromo-6-oxo-6-phenylhexyl

Methanesulfonate Studied by Spin Trapping with 2‑Methyl-2-
nitrosopropane
Christopher D. Aretz, Joseph E. McPeak, Gareth R. Eaton, Sandra S. Eaton, and Bryan J. Cowen*
Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208, United States
*
S Supporting Information

ABSTRACT: The radical formed by reduction of 5-bromo-6-oxo-6-

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phenylhexyl methanesulfonate, an α-bromoketone, with SmI2 was spin

trapped with 2-methyl-2-nitrosopropane. Electron paramagnetic resonance
spectra of the spin adduct and the adduct formed in the analogous reaction
with selectively deuterated substrate identify the radical intermediate in this
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SmI2 reduction as a carbon-centered radical. This result supports the proposal that the formation of reactive Sm-enolates arises
from reduction of the carbon−bromine bond rather than a ketyl radical anion.

S amarium(II) iodide (SmI2) is a powerful single electron

reducing agent that can be used under mild conditions to
perform a wide range of synthetically useful reactions.1 Because
its utility in organic synthesis was first shown by Kagan in
1977, particular attention has focused on reductive carbon−
carbon bond forming processes promoted by the reagent.
Samarium enolate generation through reduction of an α-
halogenated or α-oxygenated carbonyl compound has been
shown to be an efficient method for Reformatsky aldol-type
reactions.2 The mechanism of reduction likely depends on
various factors, including the type of carbonyl compound, type
of halogen, nature of samarium reagent, and additives.3
Additionally, chelation of the carbonyl oxygen and α-
heteroatom with the samarium center could influence the
reduction as previously established.4 We recently reported that
enolates generated from action of SmI2 can be exploited in an
intramolecular alkylation reaction of a primary mesylate such
as type 1 and the analogous intramolecular Reformatsky aldol
cyclization of aldehyde type 2 (Scheme 1).5 We now wish to
probe the mechanism of enolate generation from α-bromo aryl
ketones by SmI2, which were utilized for the synthesis of
cyclopentane products of type 3 and 4.
Scheme 1. Reductive Cyclization Reactions Promoted by
SmI2
Based on previous work pioneered by Molander and
coworkers, two scenarios are proposed that could lead to
samarium enolate 5 (Scheme 2).6 In pathway A, donation of a
Scheme 2. Mechanistic Scenarios for Enolate Generation
single electron from Sm(II) to substrate 1 leads to ketyl radical
anion 6. This species can be further reduced by an additional
equivalent of Sm(II) to dianionic intermediate 7 that leads to
elimination of the α-bromo group and formation of the enolate
5. In pathway B, single electron reduction of the α-bromo
group directly would lead to a radical anion that upon
fragmentation of the C−Br bond would give α-centered radical
8. This intermediate would be reduced further to the enolate 5
by Sm(II). Although this question was raised in 1986, it
remains unanswered despite the widespread use of SmI2. We
hypothesized that formation of ketyl radical 6 could be
distinguished from α-centered radical 8 by spin trapping with
MNP (2-methyl-2-nitrosopropane).7 The trapped products
would display distinctive hyperfine coupling patterns in their
EPR spectra, leading to a diagnostic identification of the parent
radical species generated from initial reaction of substrate 1
with SmI2.

Received: June 15, 2018

Published: August 13, 2018

© 2018 American Chemical Society 10688 DOI: 10.1021/acs.joc.8b01517

J. Org. Chem. 2018, 83, 10688−10692
The Journal of Organic Chemistry
We initiated our study by analyzing the reaction between α-
bromoketone substrate 9a and SmI2 in the presence of
trapping agent MNP by EPR spectroscopy (Scheme 3). The
Scheme 3. Intermediate Radical Trapping with MNP
reaction of an unstable radical with a spin trap rapidly forms a
more stable radical that can be studied by EPR.8 In fact, the
bimolecular reaction rate of an alkyl radical with MNP has
been measured to be on the order of 108 M−1 s−1.9 For
comparison, the bimolecular reaction rate of an alkyl radical
with SmI2−hexamethylphosphoramide (HMPA) has been
measured to be ∼106 M−1 s−1 and would be significantly
slower without the HMPA additive.10 The spectrum of the
species that was trapped by MNP during the reaction of 9a
with SmI2 is shown in Figure 1B. The three-line pattern is due
to hyperfine coupling to the nitrogen that is present in all
radicals trapped with MNP.11,12 Although spin trapping
experiments typically are performed in air-saturated solution,
the trapped adduct in this case is sufficiently stable that the
solution could be degassed by freeze−pump−thaw methods.
Figure 1. X-band EPR spectra of spin-trapped adducts in THF after
workup to remove SmI2. Spectra were recorded in air with 0.54 μT B1
and 110 s acquisition time. (A) Adduct 12 from reaction of 11. (B)
Adduct 10a from reaction of 9a. (C) Adduct 10b from reaction of 9b.
To avoid back-exchange, D2O was used in the workup.
10689
Note
The much-better resolved spectrum for the deoxygenated
sample is shown in Figure 2B. The value of the nitrogen
Figure 2. X-band EPR spectra of spin-trapped adducts in
deoxygenated THF after workup to remove SmI2. Spectra were
collected with 0.54 μT B1 and 110 s acquisition time. (A) Adduct 12
from reaction of 11. (B) Adduct 10a from reaction of 9a. (C) Adduct
10b from reaction of 9b. NMR spectra of 9b found a 16:1 ratio of
deuteron to proton at the α-carbon. Simulation of the EPR spectrum
in part C is consistent with this ratio of 10b:10a.
hyperfine splitting, AN (1.39 mT), is consistent with trapping
of a carbon-centered radical by MNP.11,12 The additional
hyperfine splitting, AH, of 0.59 mT indicates that a proton
(nuclear spin I = 1/2) is strongly coupled to the unpaired
electron. For spin adducts of MNP, the α-proton coupling is
strongly dependent on geometry.11 This spectrum is consistent
with structure 10a that is shown in Scheme 3. The structure of
the trapped radical was further substantiated by high resolution
mass spectroscopy of the isolated product.13 Formation of this
product is consistent with pathway B (Scheme 2).
To confirm that the hyperfine coupling of 0.59 mT arises
from the proton at the α-carbon of 10a, the spin trapping
experiment was repeated with selectively deuterated substrate
9b. Spectra of the resulting spin-trapped adduct 10b are shown
in Figure 1C and 2C. Deuterium has I = 1, which splits an EPR
signal into 3 equally spaced lines, with a hyperfine coupling
constant that is a factor of 6.5 smaller than for a proton in the
same chemical environment. The much smaller splitting from
2
H is not resolved in the broad lines of the EPR spectrum for
the air saturated solution (Figure 1C) but is partially resolved
for spectra in deoxygenated solution (Figure 2C). The
hyperfine coupling constants that were obtained by simulation
of the spectra are summarized in Table 1.
DOI: 10.1021/acs.joc.8b01517
J. Org. Chem. 2018, 83, 10688−10692
The Journal of Organic Chemistry
Table 1. Summary of Hyperfine Coupling Constants
entry compound AN (mT) AH (mT) AD (mT)
1 12 1.43 0.56
2 10a 1.39 0.59
3 10b 1.39 0.093
4 13 1.52
5 SmI2 + MNP 1.52
Reaction of SmI2 with MNP in the absence of either 9a or
9b produces the 3-line spectrum shown in Figure 3B and 3C
Figure 3. X-band EPR spectra in THF for (A) 13, after degassing,
recorded with 0.54 μT B1 and 110 s scan time. (B) SmI2 + MNP, after
degassing, recorded with 5.4 μT B1 and 13 min acquisition time. An
off-resonance background spectrum was subtracted, which doubles
data acquisition time to 26 min. (C) SmI2 + MNP, before degassing,
recorded with 8.7 μT B1 and 110 s acquisition time.
for which AN = 1.52 mT. This hyperfine splitting is significantly
larger than that for the spin trapped adducts 10a or 10b. In
spin trapping experiments with MNP that did not produce a
radical that could be trapped, the spectrum of the relatively
stable di-tert-butylnitroxide (DTBN) 13 has been observed.7d
The spectrum of commercially available DTBN in THF is
shown in Figure 3A and has AN = 1.52 mT. This value of AN in
THF is similar to reported values of AN = 1.55 mT in
benzene7d and 1.7114 to 1.72 mT15 in H2O. DTBN has also
been reported as an impurity in MNP15 that can arise from
thermal or photochemical decomposition.14,16
To test the generality of the spin trapping results, the
reaction of SmI2 with 2-bromopropiophenone 11 was studied
(eq 1). The spectrum of the resulting spin-trapped adduct 12 is
shown in Figures 1A and 2A. The spectrum has the
characteristic AN = 1.43 mT of the trapped carbon-centered
10690
Note
radical and AH = 0.56 mT, similar to the spectrum for 10a,
providing additional evidence for pathway B. When the SmI2
reaction was attempted with 2-bromoacetophenone that has
the Br on a primary carbon instead of a secondary carbon, only
DTBN was observed, which indicated that the additional
substituent was needed for stabilization of the resulting carbon-
centered radical. For similar substrates without Br present, only
DTBN was observed.
To rule out the possibility that reduction of the OMs group
could generate a species that impacts the radical reactions, a
spin trapping reaction was performed with SmI2 and Ms-
protected n-octanol (eq 2). Only DTBN (13) was observed.
This result is consistent with the assumption that the OMs
group is not reduced under the reaction conditions17 and acts
only as a leaving group in our previously disclosed intra-
molecular alkylation.5
The following evidence supports the assignment of pathway
B for the reactions shown in Scheme 2. (i) The carbon-
centered radicals 10a, 10b, and 12 were observed. (ii) There is
no obvious pathway by which a ketyl radical formed by
pathway A would rearrange to form the carbon centered
radical formed in pathway B. (iii) The bromine substituent is
required for the chemistry shown in Scheme 2 and for
formation of trapped radicals 10a, 10b, and 12. The only
reports of EPR spectra for spin-trapped ketyl radicals, such as
those that would be formed by pathway A, are for the small
acetone ketyl radical.18 Although the possible formation of
ketyl radicals via pathway A cannot be ruled out, the spin
trapping results support pathway B.19
In summary, radical trapping studies were performed for the
SmI2 reduction of an α-bromoketone utilized previously for
intramolecular enolate alkylation cyclization reactions.5 EPR
analysis of the resulting trapped species support a mechanism
in which direct reduction of the carbon−bromine bond results
in an α-centered radical rather than a ketyl radical
intermediate. While a recent study has shown some
experimental support for the presence of ketyl radical
intermediates in similar reductions, the substrates for that
study contained electronically dissimilar α-bromoamides.20
Further support that SmI2 reduction of α-bromoketones
proceeds through an α-centered radical was established
through spin-trapping studies using deuterium-labeled and
differentially substituted substrates. These studies should
facilitate further development of novel carbon−carbon bond
forming reactions through the generation of samarium
enolates.
■
EXPERIMENTAL SECTION
General Experimental Details. All starting materials were
purchased from commercial sources. Tetrahydrofuran and dichloro-
methane solvents were purified prior to use by an Innovative
Technology Pur Solv system. Reactions were conducted under
DOI: 10.1021/acs.joc.8b01517
J. Org. Chem. 2018, 83, 10688−10692
The Journal of Organic Chemistry
nitrogen atmosphere. NMR spectra were acquired on a Bruker 500
MHz NMR. Proton spectra were acquired at 500 MHz. Carbon
spectra were acquired at 126 MHz. Infrared spectra were measured on
a Thermo Scientific IR. A benzophenone sample gave a carbonyl
stretch at 1655 cm−1. Melting points where acquired on a DigiMelt
MPA160 melting point instrument. Products were purified by column
chromatography on silica gel using a Teledyne Isco CombiFlash Rf
200 or by manual column chromatography. High resolution mass
spectra were obtained on a Waters Synapt G2 HDMS Quadrupole/
ToF mass spectrometer with electrospray ionization (Central
Analytical Laboratory, University of Colorado Boulder). Where two
molecular ion weights are reported, the second is the M+2 molecular
isotope of Br. The spin adducts 10a, 10b, and 12 are sufficiently stable
that an aqueous workup procedure was used to remove the SmI2 and
side products prior to recording the EPR spectra, as described below.
Some samples were also deoxygenated by freeze−pump−thaw on a
vacuum line, which produced narrower lines and improved resolution
of the nuclear hyperfine couplings. EPR spectra were recorded on a
modified Bruker E500T using rapid scan EPR spectroscopy.21
Procedure for Preparation of α-Bromoketone 9a. The
synthesis and characterization of this compound has been described
previously.5
Procedure for Preparation of 6-Oxo-6-phenylhexyl Meth-
anesulfonate (Desbromo 9a). To a flask charged with 6-hydroxy-
1-phenylhexan-1-one (1.025 mmol), synthesized using previously
reported procedure,5 dichloromethane (5.13 mL, [0.2 M]) was added.
The flask was cooled to 0 °C (ice-water bath). After the flask was
cooled, triethylamine (1.538 mmol, 1.5 equiv) and methanesulfonyl
chloride (1.128 mmol, 1.1 equiv) were added. After an hour of stirring
at 0 °C, the reaction was diluted with dichloromethane (50 mL) and
washed with cold H2O (50 mL). The organic layer was collected, and
the aqueous layer was extracted with dichloromethane (50 mL). The
organic layers were combined, dried over anhydrous sodium sulfate,
filtered, and concentrated to dryness. The crude product was purified
by column chromatography. Yield: 212.0 mg (76%). Rf: 0.67 (1:1
ethyl acetate:hexanes). mp (°C): 57.7−58.9. 1H NMR (500 MHz,
Chloroform-d) δ 7.96 (d, J = 7.1 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H),
7.47 (t, J = 7.7 Hz, 2H), 4.25 (t, J = 6.5 Hz, 2H), 3.02 (m, 5H), 1.81
(m, 4H), 1.52 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 199.8, 136.9,
133.1, 128.6, 128.0, 69.8, 38.2, 37.4, 29.1, 25.2, 23.5. IR (cm−1): 3026,
2923, 2853, 1771, 1682, 1597, 1580, 1449, 1412, 1351, 1259, 1216,
1201, 1171, 1067, 1036, 972, 945, 814, 755, 600. HRMS (ESI+) m/z:
[M + H]+ Calcd for C13H19O4S 271.1004; Found 271.1003.
Procedure for Preparation of Octyl Methanesulfonate. 1-
Octanol (5.00 mmol) was mesylated using previously reported
procedure.22
Procedure for Preparation of SmI2. Samarium metal (Sm0)
(2.60 mmol, 1.3 equiv), 1,2-diiodoethane (2.00 mmol, 1 equiv), and
THF (20 mL, [0.1 M]) were added to a flask that had been flame-
dried, evacuated, and backfilled with N2 atmosphere. The reaction was
sonicated under positive N2 atmosphere for 10 min. After which, the
solution of SmI2 was continuous stirred until ready for use.
Procedure for Preparation of NaOD. Sodium hydroxide
(NaOH) (1.00 mmol) was dissolved in 10 mL of D2O. The solution
was boiled until less than 1 mL of solvent remained. After which, the
solution was cooled to 25 °C, and 10 mL of D2O was added and
subjected to boiling until almost dry again. This process was repeated
two additional times. After the final boiling, the volume was brought
to 10 mL with D2O.
Procedure for α-Hydrogen−Deuterium Exchange. To a flask
charged with 6-hydroxy-1-phenylhexan-1-one (369.8 mg, 1.924
mmol) substrate was added 1 mL of the [0.1 M] NaOD in D2O
solution followed by 9 mL of D2O. The reaction was refluxed at 100
°C for 8 h. This was sufficient to undergo hydrogen−deuterium
exchange on the α-carbon of the substrate. The crude product was α-
brominated and then mesylated using previously reported procedure.5
This exchange was confirmed by 1H NMR and HRMS. In the 1H
NMR spectrum the resonances associated with the α-proton were
absent.
10691
Note
6-Hydroxy-1-phenylhexan-1-one-d2. Yield: 285.3 mg (76%). 1H
NMR (500 MHz, Chloroform-d) δ 7.95 (d, J = 7.8 Hz, 2H), 7.55 (s,
1H), 7.46 (t, J = 7.7 Hz, 2H), 3.65 (t, J = 6.5 Hz, 2H), 1.76 (m, 2H),
1.62 (dt, J = 14.4, 6.7 Hz, 2H), 1.45 (p, J = 7.5, 6.9 Hz, 2H). HRMS
(ESI+) m/z: [M + Li]+ Calcd for C12H14D2O2Li 201.1436; Found
201.1445.
2-Bromo-6-hydroxy-1-phenylhexan-1-one-d. Yield: 145.7 mg
(37%). 1H NMR (500 MHz, Chloroform-d) δ 8.02 (d, J = 7.3 Hz,
2H), 7.61 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.8 Hz, 2H), 3.70 (q, J = 6.1
Hz, 3H), 3.46 (t, J = 6.7 Hz, 1H), 2.08 (m, 6H), 1.60 (m, 6H).
HRMS (ESI+) m/z: [M + Li]+ Calcd for C12H14DBrO2Li 278.0478;
Found 278.0482.
9b. Yield: 122.1 mg (65%). 1H NMR (500 MHz, Chloroform-d) δ
8.02 (d, J = 7.3 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz,
2H), 4.27 (m, 3H), 3.46 (t, J = 6.3 Hz, 1H), 3.02 (s, 4H), 2.21 (m,
2H), 1.98 (m, 2H), 1.84 (m, 2H), 1.70 (m, 1H). HRMS (ESI+) m/z:
[M + Na]+ Calcd for C13H16DBrO4SNa 371.9991; Found 371.9986.
Procedure for Spin Trapping. To a flamed dried flask that was
evacuated and backfilled with N2 three times was added a [0.05 M]
solution of the compound of interest (0.025 mmol, 0.5 mL) in THF
and a [0.025 M] solution of MNP (0.0125 mmol, 0.5 mL) in THF,
followed by a [0.1 M] solution of SmI2 (0.05 mmol, 0.5 mL). After
mixing for a few seconds a small portion was removed and added to
an EPR tube. A sample of 10a was analyzed by HRMS.
10a. HRMS (ESI+) m/z: [M+Li]+ Calcd for C17H26NO5SLi
363.1692; Found: 363.1713.
Procedure for Aqueous Workup of Spin Trapping Experi-
ments under Normal Atmosphere. To stirring mixture of spin
trap, SmI2, and compound of interest was added 5 mL of saturated
NaHCO3(aq) solution. This was stirred for 1 h under normal
atmosphere. After an hour, the solution was diluted with ethyl acetate
(25 mL) and the aqueous layer was removed. The organic layer was
washed with saturated brine solution. The organic layer was collected,
dried over anhydrous sodium sulfate, filtered, and concentrated to
dryness. The resulting residue was dissolved in THF (3 mL). A small
portion was withdrawn and added to an EPR tube.
Procedure for Aqueous Workup of Spin Trapping Experi-
ments under Oxygen Free Atmosphere. To stirring mixture of
spin trap, SmI2, and compound of interest was added 5 mL of
saturated NaHCO3(aq) solution. The saturated NaHCO3(aq) had N2
bubbled through the solution for at minimum 15 min prior to
addition. The mixture was stirred for 1 h under N2. After an hour, the
solution was diluted with THF (3 mL) and the aqueous layer was
removed with a syringe. The organic layer was washed with saturated
brine solution. The brine solution had N2 bubbled through the
solution for a minimum of 15 min prior to addition. The aqueous
layer was removed. A small portion of the organic layer was removed
and added to an EPR tube that was evacuated and backfilled with N2
three times.
■
ASSOCIATED CONTENT
*
S Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b01517.
NMR spectra for all new compounds (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: bryan.cowen@du.edu.
ORCID
Christopher D. Aretz: 0000-0002-7125-4388
Joseph E. McPeak: 0000-0001-8677-6405
Gareth R. Eaton: 0000-0001-7429-8469
Sandra S. Eaton: 0000-0002-2731-7986
Bryan J. Cowen: 0000-0001-8543-3195
DOI: 10.1021/acs.joc.8b01517
J. Org. Chem. 2018, 83, 10688−10692
The Journal of Organic Chemistry Note

Author Contributions (14) Spulber, M.; Schlick, S. Fragmentation of Perfluorinated

C.D.A and J.E.M. contributed equally. Membranes Used in Fuel Cells: Detecting Very Early Events by
Selective Encapsulation of Short-Lived Fragments in β-Cyclodextrin.
Notes J. Phys. Chem. B 2011, 115, 12415−12421.
The authors declare no competing financial interest. (15) Alvarez, B.; Demicheli, V.; Duran, R.; Trujillo, M.;

■
ACKNOWLEDGMENTS
Partial support of this work by NSF CHE-1227992 (G.R.E.
and S.S.E.) and NIH CA177744 (G.R.E. and S.S.E.) and by the
University of Denver is gratefully acknowledged. We also thank
Dr. Thomas Lee and Dr. Danijel Djukovic of the University of
Colorado Boulder for the acquisition of HRMS data.
Cevrenansky, C.; Freeman, B. A.; Radi, R. Inactivation of Human
Cu,Zn Superoxide Dismutase by Peroxynitrite and Formation of
Histidinyl Radical. Free Radical Biol. Med. 2004, 37, 813−822.
(16) Perkins, M. J. In Adv. Phys. Org. Chem., Vol. 17; Gold, V.,
Bethell, D., Eds.; Academic Press: 1980; p 1.
(17) Alkyl tosylates were reduced using Sml2 but only in the
presence of Lewis basic additives: (a) Ankner, T.; Hilmersson, G.
Instantaneous Deprotection of Tosylamides and Esters with SmI2/

■
Amine/Water. Org. Lett. 2009, 11, 503−506. (b) Szostak, M.; Spain,
M.; Procter, D. J. Recent advances in the chemoselective reduction of
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(13) See Experimental Section for details.

10692 DOI: 10.1021/acs.joc.8b01517

J. Org. Chem. 2018, 83, 10688−10692