Mechanism of SmI2 Reduction of 5-Bromo-6-oxo-6-phenylhexyl Methanesulfonate Studied by Spin Trapping with 2-Methyl-2-nitrosopropane

Article abstract of DOI:10.1021/acs.joc.8b01517

The radical formed by reduction of 5-bromo-6-oxo-6-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 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.

Full text of DOI:10.1021/acs.joc.8b01517

Note
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
pubs.acs.org/joc
Mechanism of SmI Reduction of 5‑Bromo-6-oxo-6-phenylhexyl
2
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-
phenylhexyl methanesulfonate, an α-bromoketone, with SmI was spin
2
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
SmI reduction as a carbon-centered radical. This result supports the proposal that the formation of reactive Sm-enolates arises
2
from reduction of the carbon−bromine bond rather than a ketyl radical anion.
amarium(II) iodide (SmI ) is a powerful single electron
Based on previous work pioneered by Molander and
coworkers, two scenarios are proposed that could lead to
samarium enolate 5 (Scheme 2). In pathway A, donation of a
2
S
reducing agent that can be used under mild conditions to
1
6
perform a wide range of synthetically useful reactions. Because
its utility in organic synthesis was first shown by Kagan in
977, particular attention has focused on reductive carbon−
Scheme 2. Mechanistic Scenarios for Enolate Generation
1
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
2
reactions. The mechanism of reduction likely depends on
various factors, including the type of carbonyl compound, type
3
of halogen, nature of samarium reagent, and additives.
Additionally, chelation of the carbonyl oxygen and α-
heteroatom with the samarium center could influence the
4
reduction as previously established. We recently reported that
enolates generated from action of SmI can be exploited in an
2
intramolecular alkylation reaction of a primary mesylate such
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
as type 1 and the analogous intramolecular Reformatsky aldol
5
cyclization of aldehyde type 2 (Scheme 1). We now wish to
probe the mechanism of enolate generation from α-bromo aryl
ketones by SmI , which were utilized for the synthesis of
2
cyclopentane products of type 3 and 4.
8
. This intermediate would be reduced further to the enolate 5
Scheme 1. Reductive Cyclization Reactions Promoted by
SmI2
by Sm(II). Although this question was raised in 1986, it
remains unanswered despite the widespread use of SmI . We
2
hypothesized that formation of ketyl radical 6 could be
distinguished from α-centered radical 8 by spin trapping with
7
MNP (2-methyl-2-nitrosopropane). 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
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b01517
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
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
The much-better resolved spectrum for the deoxygenated
sample is shown in Figure 2B. The value of the nitrogen
Scheme 3. Intermediate Radical Trapping with MNP
reaction of an unstable radical with a spin trap rapidly forms a
8
more stable radical that can be studied by EPR. In fact, the
bimolecular reaction rate of an alkyl radical with MNP has
8
−1 −1
9
been measured to be on the order of 10 M s . For
comparison, the bimolecular reaction rate of an alkyl radical
with SmI −hexamethylphosphoramide (HMPA) has been
2
6
−1 −1
measured to be ∼10 M
slower without the HMPA additive. The spectrum of the
s
and would be significantly
10
species that was trapped by MNP during the reaction of 9a
with SmI is shown in Figure 1B. The three-line pattern is due
2
to hyperfine coupling to the nitrogen that is present in all
1
1,12
radicals trapped with MNP.
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 2. X-band EPR spectra of spin-trapped adducts in
deoxygenated THF after workup to remove SmI . Spectra were
2
collected with 0.54 μT B and 110 s acquisition time. (A) Adduct 12
1
from reaction of 11. (B) Adduct 10a from reaction of 9a. (C) Adduct
1
0b 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, A (1.39 mT), is consistent with trapping
N
11,12
of a carbon-centered radical by MNP.
The additional
hyperfine splitting, A , of 0.59 mT indicates that a proton
H
1
(
nuclear spin I = / ) is strongly coupled to the unpaired
2
electron. For spin adducts of MNP, the α-proton coupling is
11
strongly dependent on geometry. 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
13
mass spectroscopy of the isolated product. 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
9
b. 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
Figure 1. X-band EPR spectra of spin-trapped adducts in THF after
workup to remove SmI . Spectra were recorded in air with 0.54 μT B
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.
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.
2
1
To avoid back-exchange, D O was used in the workup.
2
B
DOI: 10.1021/acs.joc.8b01517
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Summary of Hyperfine Coupling Constants
entry
compound
12
10a
10b
13
AN (mT)
AH (mT)
AD (mT)
1
2
3
4
5
1.43
1.39
1.39
1.52
1.52
0.56
0.59
0.093
radical and A = 0.56 mT, similar to the spectrum for 10a,
H
SmI + MNP
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.
2
Reaction of SmI with MNP in the absence of either 9a or
b produces the 3-line spectrum shown in Figure 3B and 3C
2
9
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 SmI and Ms-
2
protected n-octanol (eq 2). Only DTBN (13) was observed.
This result is consistent with the assumption that the OMs
17
group is not reduced under the reaction conditions and acts
only as a leaving group in our previously disclosed intra-
5
molecular alkylation.
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
18
acetone ketyl radical. Although the possible formation of
ketyl radicals via pathway A cannot be ruled out, the spin
19
trapping results support pathway B.
Figure 3. X-band EPR spectra in THF for (A) 13, after degassing,
recorded with 0.54 μT B and 110 s scan time. (B) SmI + MNP, after
In summary, radical trapping studies were performed for the
1
2
SmI reduction of an α-bromoketone utilized previously for
2
degassing, recorded with 5.4 μT B and 13 min acquisition time. An
5
1
intramolecular enolate alkylation cyclization reactions. EPR
off-resonance background spectrum was subtracted, which doubles
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
data acquisition time to 26 min. (C) SmI + MNP, before degassing,
2
recorded with 8.7 μT B and 110 s acquisition time.
1
for which A = 1.52 mT. This hyperfine splitting is significantly
N
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
20
study contained electronically dissimilar α-bromoamides.
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.
7d
stable di-tert-butylnitroxide (DTBN) 13 has been observed.
The spectrum of commercially available DTBN in THF is
shown in Figure 3A and has A = 1.52 mT. This value of A in
N
N
THF is similar to reported values of A = 1.55 mT in
N
7
d
14
15
benzene and 1.71 to 1.72 mT in H O. DTBN has also
been reported as an impurity in MNP 1t4h,1a6t can arise from
2
15
thermal or photochemical decomposition.
To test the generality of the spin trapping results, the
EXPERIMENTAL SECTION
■
reaction of SmI with 2-bromopropiophenone 11 was studied
2
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
(
eq 1). The spectrum of the resulting spin-trapped adduct 12 is
shown in Figures 1A and 2A. The spectrum has the
characteristic A = 1.43 mT of the trapped carbon-centered
N
C
DOI: 10.1021/acs.joc.8b01517
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
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 . 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
6-Hydroxy-1-phenylhexan-1-one-d . Yield: 285.3 mg (76%). H
2
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
−
1
+
(ESI+) m/z: [M + Li] Calcd for C12
H
D
14
O
2
Li 201.1436; Found
2
201.1445.
2-Bromo-6-hydroxy-1-phenylhexan-1-one-d. Yield: 145.7 mg
(37%). H NMR (500 MHz, Chloroform-d) δ 8.02 (d, J = 7.3 Hz,
H), 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 C H DBrO Li 278.0478;
Found 278.0482.
b. Yield: 122.1 mg (65%). H NMR (500 MHz, Chloroform-d) δ
.02 (d, J = 7.3 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz,
H), 4.27 (m, 3H), 3.46 (t, J = 6.3 Hz, 1H), 3.02 (s, 4H), 2.21 (m,
H), 1.98 (m, 2H), 1.84 (m, 2H), 1.70 (m, 1H). HRMS (ESI+) m/z:
M + Na] Calcd for C H DBrO SNa 371.9991; Found 371.9986.
Procedure for Spin Trapping. To a flamed dried flask that was
evacuated and backfilled with N 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 SmI (0.05 mmol, 0.5 mL). After
1
2
00 or by manual column chromatography. High resolution mass
2
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
+
12 14
2
1
9
8
2
2
that an aqueous workup procedure was used to remove the SmI and
2
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
+
[
1
3
16
4
21
2
modified Bruker E500T using rapid scan EPR spectroscopy.
Procedure for Preparation of α-Bromoketone 9a. The
synthesis and characterization of this compound has been described
5
2
previously.
mixing for a few seconds a small portion was removed and added to
Procedure for Preparation of 6-Oxo-6-phenylhexyl Meth-
anesulfonate (Desbromo 9a). To a flask charged with 6-hydroxy-
an EPR tube. A sample of 10a was analyzed by HRMS.
+
1
0a. HRMS (ESI+) m/z: [M+Li] Calcd for C H NO SLi
17
26
5
1
-phenylhexan-1-one (1.025 mmol), synthesized using previously
5
363.1692; Found: 363.1713.
reported procedure, 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
Procedure for Aqueous Workup of Spin Trapping Experi-
ments under Normal Atmosphere. To stirring mixture of spin
trap, SmI , and compound of interest was added 5 mL of saturated
NaHCO (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, SmI , and compound of interest was added 5 mL of
saturated NaHCO (aq) solution. The saturated NaHCO (aq) had N
bubbled through the solution for at minimum 15 min prior to
addition. The mixture was stirred for 1 h under N . 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
2
3
washed with cold H O (50 mL). The organic layer was collected, and
2
(
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%). R : 0.67 (1:1
f
1
ethyl acetate:hexanes). mp (°C): 57.7−58.9. H 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
2
1
3
(
m, 4H), 1.52 (m, 2H). C NMR (126 MHz, CDCl ) δ 199.8, 136.9,
3
3
3
2
−1
1
2
1
33.1, 128.6, 128.0, 69.8, 38.2, 37.4, 29.1, 25.2, 23.5. IR (cm ): 3026,
923, 2853, 1771, 1682, 1597, 1580, 1449, 1412, 1351, 1259, 1216,
2
201, 1171, 1067, 1036, 972, 945, 814, 755, 600. HRMS (ESI+) m/z:
+
[
M + H] Calcd for C H O S 271.1004; Found 271.1003.
1
3
19
4
Procedure for Preparation of Octyl Methanesulfonate. 1-
Octanol (5.00 mmol) was mesylated using previously reported
22
procedure.
0
Procedure for Preparation of SmI . Samarium metal (Sm )
and added to an EPR tube that was evacuated and backfilled with N
2
2
(
2.60 mmol, 1.3 equiv), 1,2-diiodoethane (2.00 mmol, 1 equiv), and
three times.
THF (20 mL, [0.1 M]) were added to a flask that had been flame-
dried, evacuated, and backfilled with N atmosphere. The reaction was
2
ASSOCIATED CONTENT
■
sonicated under positive N atmosphere for 10 min. After which, the
2
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b01517.
solution of SmI was continuous stirred until ready for use.
2
Procedure for Preparation of NaOD. Sodium hydroxide
(
NaOH) (1.00 mmol) was dissolved in 10 mL of D O. The solution
2
was boiled until less than 1 mL of solvent remained. After which, the
NMR spectra for all new compounds (PDF)
solution was cooled to 25 °C, and 10 mL of D O was added and
2
subjected to boiling until almost dry again. This process was repeated
two additional times. After the final boiling, the volume was brought
AUTHOR INFORMATION
to 10 mL with D O.
2
■
*
Procedure for α-Hydrogen−Deuterium Exchange. To a flask
charged with 6-hydroxy-1-phenylhexan-1-one (369.8 mg, 1.924
Corresponding Author
E-mail: bryan.cowen@du.edu.
mmol) substrate was added 1 mL of the [0.1 M] NaOD in D O
2
solution followed by 9 mL of D O. The reaction was refluxed at 100
ORCID
2
°
C for 8 h. This was sufficient to undergo hydrogen−deuterium
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
exchange on the α-carbon of the substrate. The crude product was α-
5
brominated and then mesylated using previously reported procedure.
1
1
This exchange was confirmed by H NMR and HRMS. In the H
NMR spectrum the resonances associated with the α-proton were
absent.
D
DOI: 10.1021/acs.joc.8b01517
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Author Contributions
C.D.A and J.E.M. contributed equally.
(14) Spulber, M.; Schlick, S. Fragmentation of Perfluorinated
Membranes Used in Fuel Cells: Detecting Very Early Events by
Selective Encapsulation of Short-Lived Fragments in β-Cyclodextrin.
J. Phys. Chem. B 2011, 115, 12415−12421.
(15) Alvarez, B.; Demicheli, V.; Duran, R.; Trujillo, M.;
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Notes
The authors declare no competing financial interest.
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.
(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
functional groups mediated by samarium(II) iodide: a single electron
transfer approach. Chem. Soc. Rev. 2013, 42, 9155−9183.
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(
E
DOI: 10.1021/acs.joc.8b01517
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