Synthesis of Ethers via Reaction of Carbanions and Monoperoxyacetals

Article abstract of DOI:10.1021/acs.joc.5b02043

Although transfer of electrophilic alkoxyl ("RO+") from organic peroxides to organometallics offers a complement to traditional methods for etherification, application has been limited by constraints associated with peroxide reactivity and stability. We now demonstrate that readily prepared tetrahydropyranyl monoperoxyacetals react with sp³ and sp² organolithium and organomagnesium reagents to furnish moderate to high yields of ethers. The method is successfully applied to the synthesis of alkyl, alkenyl, aryl, heteroaryl, and cyclopropyl ethers, mixed O,O-acetals, and S,S,O-orthoesters. In contrast to reactions of dialkyl and alkyl/silyl peroxides, the displacements of monoperoxyacetals provide no evidence for alkoxy radical intermediates. At the same time, the high yields observed for transfer of primary, secondary, or tertiary alkoxides, the latter involving attack on neopentyl oxygen, are inconsistent with an S_N2 mechanism. Theoretical studies suggest a mechanism involving Lewis acid promoted insertion of organometallics into the O-O bond.

Full text of DOI:10.1021/acs.joc.5b02043

Article
pubs.acs.org/joc
Synthesis of Ethers via Reaction of Carbanions and
Monoperoxyacetals
ShivaKumar Kyasa,† Rebecca N. Meier,‡ Ruth A. Pardini,‡ Tristan K. Truttmann,‡ Keith T. Kuwata,‡
and Patrick H. Dussault*,†
†Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska 68588-0304, United States
‡Department of Chemistry, Macalester College, Saint Paul, Minnesota 55105, United States
S
* Supporting Information
ABSTRACT: Although transfer of electrophilic alkoxyl (“RO+”)
from organic peroxides to organometallics offers a complement to
traditional methods for etherification, application has been limited
by constraints associated with peroxide reactivity and stability.
We now demonstrate that readily prepared tetrahydropyranyl mono-
peroxyacetals react with sp3 and sp2 organolithium and organo-
magnesium reagents to furnish moderate to high yields of ethers.
The method is successfully applied to the synthesis of alkyl, alkenyl,
aryl, heteroaryl, and cyclopropyl ethers, mixed O,O-acetals, and
S,S,O-orthoesters. In contrast to reactions of dialkyl and alkyl/silyl
peroxides, the displacements of monoperoxyacetals provide no
evidence for alkoxy radical intermediates. At the same time, the high yields observed for transfer of primary, secondary, or
tertiary alkoxides, the latter involving attack on neopentyl oxygen, are inconsistent with an SN2 mechanism. Theoretical studies
suggest a mechanism involving Lewis acid promoted insertion of organometallics into the O−O bond.
rearrangement or fragmentation to carbonyls.18,19 We were
particularly intrigued by reports describing enhanced reactivity of
INTRODUCTION
■
Methods for ether synthesis are overwhelmingly based upon
acyclic peroxyacetals and peroxyaminals with Grignard re-
the attack of nucleophilic oxygen on electrophilic carbon.1−4
agents.20,21 However, the reactions of peroxyaminals displayed
Our lab has been interested in expanding the scope of an
variable regioselectivity,20 while reactions of a mixed ethoxy/
umpoled strategy based upon reaction of carbanions with
electrophilic oxygen.5 The reaction of dialkyl peroxides with
peroxy acetal required a significant excess of the Grignard
reagent.21 In preliminary work, we discovered that tetrahydropyr-
carbanions, while long known,6 has largely remained a curiosity
anyl (THP) monoperoxyacetals selectively transfer the attached
applied mainly to transfer of methoxyl and other unhindered
OR to lithiated 1,3-dithianes.5b We now describe investigations of
alkoxides.7,8 Even a slight increase in steric bulk results in
reduced yields,7 and reactions of di-t-butyl peroxide furnish
reactions between carbanions and several classes of organic
multiple products.9,10 We became interested in a general
peroxides, with an emphasis on monoperoxyacetals. (Figure 1).
method for selective transfer of 1°, 2°, or 3° alkoxides from a
mixed peroxide to a carbanion. In approaching this problem,
we were encouraged by evidence for the strong influence of
substituent groups on peroxide reactivity. Bistrimethylsilyl
peroxide efficiently transfers OSiMe3 to a variety of organo-
metallic reagents;11 curiously, tBuOOSiMe3 transfers neither
OSiMe3 nor tBuO.12 Lithiated peroxides, sometimes described
as “oxenoid” in character, transfer LiO to a variety of car-
banions,13 and similar reactivity patterns have been observed
with other metalloperoxides.14 Bisacyl peroxides even transfer
Figure 1. Substrate classes.
acyloxy groups to enolates and enamines.15 However, transfer
of alkoxide is more challenging. The strain within bicyclic
peroxides has been harnessed to facilitate reaction of more
RESULTS
■
Table 1 illustrates preparation of substrates. Base-promoted
hindered peroxides; unfortunately, the presence of the scaffold
limits the range of potential targets.16 Electronic activation in the
alkylation of hydroperoxides with primary and secondary
form of peresters has been employed to achieve transfer of
tertiary alkoxides to Grignard reagents,17 but broad application is
Received: September 1, 2015
limited by the propensity of peresters to undergo C-to-O
© XXXX American Chemical Society
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Table 1. Substrate Synthesis
triflates22 provided good yields of t-butyl/alkyl peroxides
(8a−11a), monoperoxyacetals (8c,23 8b−10b, 12b, 13b24),
and a 2-methoxyethyl peroxide (9e). Tetrahydropyranyl mono-
peroxyacetals (14b, 15b) were also prepared through
acetalization of hydroperoxides with dihydropyran.25 Ag(I)-
promoted hydroperoxide alkylation was used to prepare allyl
peroxide 16b.26 Alkyl/silyl peroxides 8d and 10d were prepared
through silylation of hydroperoxides.27
Grignard reagents were successful, but somewhat slower.
The corresponding trialkylsilyl peroxide (8d) reacted slowly
with n-BuLi to furnish a large number of products (TLC).
Scheme 1 summarizes reactions of THP monoperoxyacetals
with sp3 organometallics. Reactions with RLi proceeded slowly
a
Scheme 1. Reaction of sp3 RM with Peroxyacetals
Thermal Stability. Thermal analysis was conducted on
one of the dialkyl peroxides (10a) and one of the mono-
peroxyacetals (10b) to provide some baseline stability data for
each class. The results, detailed in Supporting Information,
revealed that 10a and 10b are relatively stable, undergoing
exothermic decomposition only once heated past 170 and
120 °C, respectively.
Table 2 illustrates the reactivity of t-butyl/alkyl and
trialkylsilyl/alkyl peroxides toward sp3 organometallics. t-Butyl
Table 2. Reactions of Dialkyl and Alkyl/Silyl Peroxides
substrate
R1M (equiv)
time (h)
product
yield (%)
8a
8a
8a
8a
8d
n-BuLi (2)
4
17a
70
42
27
70
hexMgBr (3)
allylMgBr (2)
8
17b
0.5
4
17c
a
allylLi (2.5)
17c
n-BuLi (2)
8
multiple
a
a
From allylSnBu3 and n-BuLi.
(a) RLi (1.1 equiv), −78 °C; (b) hexylMgBr (1.1 equiv), 0 °C;
(c) Me3SiCH2MgCl (1.3 equiv), 0 °C.
peroxide 8a reacted with an excess of RLi over a period of
several hours to furnish ethers derived from selective attack
on the less hindered oxygen. The corresponding reactions with
at −78 °C but were complete within minutes at 0 °C.
The monoperoxyacetals failed to react with Grignard reagents
B
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at −78 °C but were consumed rapidly at 0 °C, providing ethers
in yields equal or superior to those obtained with RLi. Transfer
of 1°, 2°, or 3° alkoxides occurred with similar yields; in each
case; we observed only the products of regioselective displace-
ment of OTHP.
Reactions with sp2 Organometallics. Monoperoxyacetal
8b reacted readily with PhLi (−78 °C) and PhMgBr (0 °C) to
furnish good yields of the phenyl ether (18a, Scheme 2).
a
Scheme 2. Reaction of Peroxyacetals with sp2 RM
Lithiated Dithianes. Lithiated 1,3-dithianes have been
widely applied as acyl anion equivalents for reaction with
carbon electrophiles.30 In the only report of their reactivity
toward peroxides, reaction with bistrimethylsilyl peroxide
results in preferential transfer of a silyl group.11a We recently
demonstrated successful reaction of THP monoperoxyacetals
with lithiated dithianes to furnish S,S,O-orthoesters and derived
difluoroalkyl ethers.5b Being curious about the influence of
the peroxide electrophile on the reactivity toward inductively
stabilized anions, we investigated reactions of a monoperoxy-
acetal, a silyl/alkyl peroxide, and a dialkyl peroxide toward a
common lithiated dithiane (Scheme 3). The monoperoxyacetal
Scheme 3. Reactivity towards Lithiated Dithianes
a
THF, −78 to rt (RLi) or 0 °C to rt (RMgX).
Reaction with an alkenyl magnesium bromide or vinyl
lithium, the latter generated in situ, furnished the correspond-
ing enol ethers; the moderate yields may in part reflect
decomposition during purification. Reaction of 2-thienyl
lithium with primary monoperoxyacetals furnished a moderate
yield of 2-alkoxythiophenes 18d and 18e, representatives
of a class of molecules previously explored only to a limited
extent.28
Metalated Alkynes. Alkynyllithium or alkynylmagnesium
reagents failed to react with a dialkyl peroxide (8a) or a
monoperoxyacetal (8b); starting materials could be recovered
even after prolonged reaction periods (eq 1).
10b and alkyl/silyl peroxide 10d gave similar yields of
difluoroether 19, isolated following fluorodesulfurization of
the initial orthoester products. In contrast, the mixed alkyl/
t-butyl peroxide 10a was much less reactive. Reactions were
conducted exclusively in THF; previous investigations of
reactions of lithiated trithianes5b observed no benefit from
the presence of additives (LiCl, MgBr2) or polar cosolvents
(HMPA).
Attempted Synthesis of Trihaloethers. Trifluoromethyl
ethers are of interest as degradation-resistant structural
components in agrochemicals and drug molecules.31 However,
methods for their introduction remain limited.32 We recently
reported an indirect approach to introduction of OCF3 groups
via reaction of a monoperoxyacetal with a lithiated trithiane,
followed by fluorodesulfurization of the resulting S,S,O-
orthocarbonate,5b and we became interested in a more direct
approach based upon reaction of a peroxide with a trifluo-
romethyl anion. This approach requires the targeted C−O
bond formation to occur more rapidly than α-elimination of the
nucleophile.33 We began our investigations with the Ruppert-
Prakash reagent, CF3SiMe3.32,33 The trifluoromethyl ether was
not observed despite application of different activators, solvents
Reaction with Resonance-Stabilized Nucleophiles.
Neither monoperoxyacetals nor a dialkyl peroxide underwent
intermolecular C−O bond formation with enolates (eq 2)
or azaenolates (eq 3); only slow decomposition was ob-
served. The results were not entirely unexpected given our
observations during tandem reactions of enolates with
iodoperoxides.5a In a control experiment, reaction of a THF
solution of 8b with stoichiometric potassium t-butoxide
(eq 4) resulted in slow formation of byproducts indicative
of E1CB fragmentation.19,29 The corresponding t-butyl
peroxide 8a (not shown) decomposed more slowly to furnish
citronellal.
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(DMF, THF), or reaction temperatures (Scheme 4). We also
failed to detect ether formation for base-promoted reaction
of t-butyl perbenzoates with cyclopropyl magnesium bro-
mide.38 We found that the reaction of monoperoxyacetals
with cyclopropyl magnesium bromide furnishes an efficient
approach to primary and secondary cyclopropyl alkyl ethers
(Table 4).
Scheme 4. Attempted Synthesis of Trihalomethyl Ethers
Table 4. Synthesis of Cyclopropyl Ethers
with trifluoroacetaldehyde hydrate,34 or with KCF3 generated
via low temperature deprotonation of fluoroform.35 Formation
of aldehydes derived from Kornblum fragmentation of the
peroxide (see eq 4) was observed in some of these reactions.
Interested in whether the displacements might be more
successful in the presence of a lithium cation, we investigated
reactions with lithiated trihalomethanes but saw no reaction at
temperatures (−110 °C for LiCCl3, −50 °C for LiCBr3) where
the reagents were stable.
Reaction with α-Alkoxylithium Reagents. Lithiated
ethers (α-alkoxylithiums) have been employed as synthons
for acyl anions and hydroxymethyl anions.36 As illustrated
in Table 3, the alkoxylithium reagent generated from a
Mechanistic Investigations. In an effort to gain
information about the possible role of single electron transfer
in the C−O bond-forming step, we investigated reactions of
phenylmethylpropyl peroxides; the derived alkoxy radical
undergoes cleavage to acetone and benzyl radical at ∼108/s
(Scheme 5).39 Dialkyl peroxide 24a was prepared through a
known procedure.40 Silyl peroxide 24d was prepared through
Table 3. Synthesis of O,O-Acetals
peroxide
acetal
yield (%)
Scheme 5. Preparation of Radical Probes
C8H17OOtBu (11a)
Ph(CH2)3OOtBu (9a)
C10H21OOTHP (12b)
21a: R = octyl
57
55
55
21b: R = (CH2)3Ph
21c: R = decyl
tributylstannyl MOM ether (20) reacted with primary alkyl/
t-butyl peroxides or a monoperoxyacetal to give moderate
yields of the mixed O,O-acetals.
The same reaction, when repeated with methoxypropyl
peroxyacetal 8c, did not proceed to completion. The mixed
acetal (21d) was isolated in low yield and accompanied by the
tertiary alcohol (22) derived from trapping of acetone
generated from the cleaved acetal (eq 5).
Co(II)-mediated peroxidation of methallyl benzene with
oxygen and triethylsilane.41 THP acetal 24b was prepared by
deprotection of the silyl peroxide and acetalization of the
intermediate hydroperoxide.25
Monoperoxyacetal 24b underwent rapid reaction with n-BuLi
to furnish mainly the butyl ether (25a), accompanied by
smaller amounts of the tertiary alcohol 26 and recovered
starting material (Table 5). The corresponding reaction with
excess hexylMgBr furnished only the hexyl ether (25b)
resulting from displacement of OTHP. In contrast, reaction
of di-t-alkyl peroxide 24a with n-BuLi generated multiple
products and only trace amounts of the ether. The reaction of
silyl peroxide 24d with n-BuLi provided the most convincing
Application to Cyclopropyl Ethers. We were interested
in application of the reaction of monoperoxyacetals and
organometallics as an approach to cyclopropyl ethers, a
relatively challenging class of targets for which multiple
approaches have been reported.37 In approaching this class
of reactions, we were encouraged by the reported reaction
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a
Table 5. RM Reactions with Radical Probes
subs
R1M
conv. (%)
ether
alcohol
15%
coupling
24b
24b
24a
24d
n-BuLi
hexMgBr
n-BuLi
n-BuLi
93
100
55
R1 = Bu (55%)
R1 = hex (75%)
32%
PhC5H11 (3%)
PhC5H11 (10%)
b
59
11%
a
b
Conditions: n-BuLi (1 equiv), THF, −78 °C, allow to warm to rt; hexylMgBr (2 equiv), 0 °C, allow to warm to rt. Et3SiOH isolated in
24% yield.
a
b
Scheme 6. Predicted Relative Gas-Phase Energies and Solution-Phase Enthalpies of Intermediates and Transition States
a
b
B3LYP/6-31+G(d,p), 0 K; units in kcal/mol. THF at 298 K with the SMD continuum solvent model; units in kcal/mol and enthalpies in
parentheses.
evidence for the intermediacy of radicals in the form of a
significant amount of pentylbenzene product of radical−radical
coupling.
than had been observed even with simple t-butyl peroxides
(eq 8).
Competition between a Dialkyl Peroxide and a
Monoperoxyacetal. A competition between a dialkyl
peroxide and a monoperoxyacetal for capture of a limiting
quantity of n-BuLi generated only the ether (27) derived from
the monoperoxyacetal (eq 6).
Theoretical Investigations. In an effort to gain better
understanding of the reactions described above and the
influence of reaction conditions on product formation, we
conducted B3LYP/6-31+G(d,p) calculations for the simple
model reaction of the transfer of methoxide from a methyl
peroxide or peroxyacetal to a methyl anion (Scheme 6). Our
calculations focused on the impact of changing the metal from
Li to Na and of changing the leaving group from Ot-Bu to
OTHP.
sp3 vs sp2 RLi. A competition between n-BuLi and PhLi for
a limiting quantity of a monoperoxyacetal revealed a strong
preference for reaction with the sp3 reagent (eq 7).
All four sets of conditions appear to favor the same
mechanism: first, formation of a metal-peroxy complex (II),
second, passage through a four-centered transition state (TS
III), third, formation of a complex of the incipient ether with
the metal alkoxide (IV), and, finally, cleavage to final products
(V). (Early calculations found the same mechanism for the
addition of alkyl lithium reagents to carbon−carbon and
carbon−oxygen multiple bonds.)42,43 The calculations predict
that the lithiated system is significantly more reactive than the
sodiated system. This suggests that the metal ion’s interaction
with the peroxy moiety is primarily electrostatic;42 the greater
charge density on the smaller Li+ leads to greater stabilization.
Importance of Chelation vs Acetal Structure. In an
effort to probe the basis for the enhanced reactivity of the
monoperoxyacetals, we investigated C−O bond formation
with 2-methoxyethyl peroxide 9e. This substrate, which
possesses the potential for metal chelation but lacks a
peroxyacetal, provided the corresponding either in lower yields
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The presence of the THP group is found to stabilize the initial
organometallic-peroxide complex (II) and to dramatically lower
the energy for insertion into the peroxide bond. An
approximate treatment of THF solvation using the SMD
continuum model predicts the relative enthalpies of most
intermediates and transition states to be several kcal/mol
higher in energy than the gas-phase calculations. However, the
solvation calculations predict the same trends in reactivity: the
Li+ ion and the THP substituent both significantly stabilize
both the reactive complex and the transition state for insertion.
reaction toward exclusive transfer of the nonanomeric oxygen.
The bidentate coordination available to the organometallic/
Lewis acid is not sufficient to explain the results, as evidenced
by the poor reactivity of the methoxyethyl peroxide. However,
the interaction of Lewis acids with peroxyacetals and ozonides
(1,2,4-trioxolanes) has been previously demonstrated to
activate both C−O and O−O bonds.47
In conclusion, we have shown that monoperoxyacetals,
readily prepared and easily handled derivatives of hydro-
peroxides, enable highly efficient intermolecular transfer of
alkoxide to unstabilized organolithium and organomagnesium
reagents along with some inductively stabilized organolithium
species. The peroxyacetal activating group promotes highly
selective transfer of the nonanomeric OR, regardless of steric
bulk. The bond-forming process, which appears to involve
metal-promoted insertion into the O−O linkage, appears to be
mechanistically distinct from similar reactions of alkyl or alkyl
silyl peroxides. The new methodology offers a new tool with
which to approach ethers, including some poorly accessible
through existing methods.
DISCUSSION
■
Whereas reactions of dialkyl peroxides are largely limited to
transfer of methoxide or primary alkoxide,6−8,10 monoperoxy-
acetals have significantly enhanced reactivity toward unstabi-
lized carbanions, transferring primary, secondary, or tertiary
alkoxides through highly regioselective attack on the nonacetal
oxygen of the peroxide. In contrast to peresters, monoperox-
yacetals appear to promote alkoxide transfer without signifi-
cantly destabilizing the peroxide.44
Reaction is observed between monoperoxyacetals and sp3
and sp2 RLi and RMgX reagents at −78 °C (organolithium
reagents) or 0 °C (Grignard reagents). Both acyclic
(2-methoxyprop-2-yl) and cyclic (THP) peroxyacetals offer
good reactivity; however, the acyclic peoxyacetals sometime
generate side products derived from liberation of a reactive
carbonyl group in the presence of the organometallic. The
monoperoxyacetals do not undergo intermolecular reactions
with enolates or similar stabilized carbanions, paralleling earlier
observations from our lab.5a The monoperoxyacetals also fail to
react with metalated alkynes, an interesting outcome given the
reported reactivity of lithiated hydroperoxides toward carban-
ions,13,45 as well as our observation of successful reaction of
peroxyacetals with inductively stabilized anions such as lithiated
dithianes and lithiated ethers. However, the lack of reactivity
toward sp carbanions is consistent with results observed with
bistrimethylsilyl peroxide, which undergoes mainly silyl
exchange with lithiated alkynes.12
Several mechanisms have been discussed with regard to the
reaction of dialkyl peroxides with unstabilized organometallics.
While early results with unhindered peroxides were consistent
with SN2-type attack on the O−O bond,7 reactions of di-t-alkyl
peroxides have been reported to proceed via intermediate
alkoxy radicals.10,46 Our work found no evidence for radical
intermediates in attack of organolithium reagents on THP
peroxyacetals.
If the reactions involve neither simple displacement nor
cleavage to alkoxy radicals, then what? Lithiated peroxides are
often thought to react with nucleophiles through oxenoid-type
insertion into the C−Li bond; attack on alkenyl lithium and
cyclopropyl lithium appears to occur without loss of stereo-
chemistry.13 However, whereas the transfer of LiO from
lithiated hydroperoxides to organolithium reagents has been
calculated to involve in-line arrangement of the carbanion, the
lithiated oxygen, and the departing oxygen,13b our calculations
suggest side-on insertion of the RLi into the Lewis acid
activated O−O bond. This theoretical result is supported by the
similar yields obtained for transfer of primary, secondary,
and tertiary alkoxides, a result which would seem to rule out an
SN2-type attack on the backside of the breaking O−O bond.
Calculations predict, and experiments confirm, that the pres-
ence of the acetal group significantly lowers the energy for
insertion of unstabilized organometallics and directs the
EXPERIMENTAL PROCEDURES
■
General Experimental. Reagents and solvents were used as
supplied commercially, except for DCM and THF, which were distilled
from CaH2 and Na/Ph2CO, respectively. Reagents supplied as
solutions were dispensed based upon manufacturer-supplied concen-
trations. Reactions were conducted under an atmosphere of N2 except
where noted. Thin-layer chromatography (TLC) was performed on
0.25 mm hard-layer silica G plates visualized with a UV lamp or by
staining: 1% ceric sulfate and 10% ammonium molybdate in 10%
H2SO4 (general stain, after heating); 3% vanillin in 3% H2SO4 in
EtOH (general stain, after heating); or a 1% N,N′-dimethyl-p-
phenylenediamine in 1:20:100 acetic acid/water/methanol (specific
for peroxides).48 Unless otherwise noted, NMR spectra were acquired
in CDCl3; 1H spectra are reported as chemical shift (multiplicity,
J couplings in Hz, number of protons). IR spectra were recorded as
neat films on a ZrSe crystal; selected absorbances are reported in cm−1.
Abbreviations: hexane = Hex; EA = ethyl acetate; THF =
tetrahydrofuran; TBDMS (or TBS) = tert-butyldimethylsilyl; THP =
tetrahydropyranyl.
Calculations. Optimized geometries, harmonic vibrational fre-
quencies, and electronic energies of all structures in Scheme 6 were
obtained with the B3LYP level of density functional theory and the
6-31+G(d,p) basis set.49,50−52 All minima reported (structures I, II, IV,
and V) contain all real frequencies, and all transition states (structures
TS III) contain one imaginary frequency. Intrinsic reaction coordinate
calculations confirmed that each transition state connected a metal-
peroxy complex II and the corresponding metal alkoxide-ether
complex IV. The relative electronic energies were corrected by the
differences in zero-point vibrational energy scaled by 0.9806.53
Solution-phase enthalpies were determined as follows: The thermal
corrections to the electronic energies were calculated based on the
B3LYP/6-31+G(d,p) geometries and harmonic frequencies. Solvation
corrections were based on single-point energy calculations using the
continuum SMD model of Truhlar and co-workers.54
t-Butyl Hydroperoxide (1). [75-91-2], 5.5 M in decane, was used
as purchased.
2-Tetrahydropyranyl (THP) Hydroperoxide (2). [4676-84-0]
was synthesized using a modified version of a known procedure.24
To a 0 °C solution of 50 wt % aq. H2O2 (6.66 mL, ∼118 mmol) was
added 10% aq. H2SO4 (0.1 mL) The mixture was stirred for 10 min,
after which 3,4-dihydro-2H-pyran (4.94 g, 58.8 mmol) was added over
a period of 3 min. The reaction was stirred for 1 h at 0 °C and then
diluted with sat. aq. NH4Cl (15 mL). The solution was extracted with
ether (150 mL), and the organic layer was washed with aq. sat.
(NH4)2SO4 (5 × 10 mL). The resulting solution was dried over
Na2SO4 and concentrated on a rotary evaporator. The residue obtained
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was purified by silica gel flash chromatography using a gradient
of 4−25% EA/Hex to afford the hydroperoxide as a thick and colorless
oil (4.60 g, 66%). Spectral data were identical to those previously
reported.19
2-Methoxyprop-2-yl Hydroperoxide (3). [10027-74-4] was
prepared as a colorless oil (82%, 878 mg) from 2,3-dimethyl-2-butene
(10.0 mmol, 841 mg) using a known procedure.23,55 Rf = 0.3
(15% EA:Hex).
3617−3101 (broad peak), 2915, 1455, 1377, 1053 (mass spec not
attempted due to volatility).
1-Hydroperoxy-1-methylcyclohexane (5). [4952-03-8] was
prepared through a two-step procedure.
Triethyl(1-methylcyclohexylperoxy)silane. (CAS 634600-89-8)
was prepared through a modification of a reported procedure.59
1-Methyl cyclohexene (0.96 g, 10 mmol) and Et3SiH (2.32 g., 20 mmol)
were sequentially added to a solution of Co(acac)2 (1 mmol) in
ethanol (35 mL). The reaction mixture was placed under an
atmosphere of O2 (balloon) until no starting material was observed
(TLC, ∼14 h). The residue obtained upon concentration in vacuo was
purified by silica gel chromatography using 1−8% EA:Hex to furnish
the 1-methyl-1-cyclohexyl triethylsilyl peroxide as a as colorless oil
(0.844 g, 34%): Rf = 0.7 (10% EA/Hex). Spectral data matched those
previously reported.60
8-Hydroperoxy-2,6-dimethyloct-2-ene (4). [123369-58-4] was
prepared by alkylation of a 1,1-dihydroperoxycyclodecane, followed by
hydrolysis of the resulting bisperoxyacetal.22
To a solution of the triethylsilylperoxide (0.78 g, 3.19 mmol) in
THF (10 mL) was added tetra n-butyl ammonium fluoride (1 M
solution in THF, 1.2 equiv).47 The reaction was stirred at room
temperature until no starting material could be observed (TLC,
∼5 min). The residue obtained upon concentration in vacuo was
diluted with hexane (30 mL) and washed with water (10 mL). The
combined organic layers were dried over Na2SO4 and concentrated.
The residue was purified by short-column (3″) flash chromatography
with 5% EA/Hex (two iterations were required to remove silanol/
siloxane byproducts) to furnish the hydroperoxide 5 as a colorless oil
(0.266 g, 64%). Although the hydroperoxide is commercially available,
NMR data are difficult to access and are provided here for con-
A solution of 3,7-dimethyloct-6-en-1-ol (0.936 g, 6 mmol) in dry
DCM (18 mL) was cooled to 0 °C, and triflic anhydride (1.4 equiv)
and 2,6-lutidine (1.5 equiv) were sequentially added via syringe. The
reaction was stirred for 15 min at 0 °C and then diluted with ice-cold
hexane (∼40 mL). The resulting solution was washed with ice cold
0.1 M aq. KHSO4 (40 mL), and the separated aqueous layer was
extracted with another portion of cold Hex (25 mL). The combined
organic layers were dried over Na2SO4 and concentrated on a rotary
evaporator (bath temperature 10 °C). The residue was subjected
to 0.5 mmHg for approximately 5 min to generate nearly pure
3,7-dimethyloct-6-en-1-yl trifluoromethanesulfonate (1.693 g, 98%) as
a light brown oil, which was placed in a −20 °C freezer and used
1
venience: Rf = 0.4 (10% EA:Hex); H NMR: 7.34 (s, 1H), 1.80−1.74
(m, 2H), 1.63−1.53 (m, 2H), 1.51−1.38 (m, 5H), 1.34−1.29 (m, 1H),
1.25 (s, 3H); 13C NMR: 81.7, 34.4, 25.6, 23.8, 22.2, 6.55, 5.76.
3-Phenylpropyl Hydroperoxide (6). [60956-33-4] was prepared
using a route analogous to that employed for hydroperoxide 4.
3-Phenylpropyl trifluoromethanesulfonate [66950-73-0] was pre-
pared (1.34 g, quant.) as a light brown oil from 3-phenylpropanol
(0.681 g, 5 mmol) using the procedure described above: Rf = 0.5
(10% EA/Hex). Other spectral data matched those in a previous
report.5b
within an hour:56 Rf = 0.59 (10% EA/Hex); H NMR: 5.11−5.07 (m,
1
1H), 4.61−4.57 (m, 2H), 2.06−1.96 (m, 2H), 1.93−1.85 (m, 1H),
1.72−1.68 (m, 1H), 1.70 (s, 3H), 1.66−1.64 (m, 1H), 1.62 (s, 3H),
1.42−1.32 (m, 1H), 1.29−1.20 (m, 1H), 0.96 (d, J = 6.3 Hz, 3H); 13C
NMR: 131.8, 123.9, 118.5 (q, J = 323 Hz), 76.2, 36.6, 36.0, 28.6, 25.6,
25.1, 19.0, 17.6.
Using a similar procedure as described earlier, cyclododecanone
1,1-dihydroperoxide (1.05 g, 4.545 mmol) was reacted with the
3-phenylpropyl triflate (2.6 g, 10 mmol) to furnish the bisperoxyacetal
(1.4381 g, 67%) as a colorless oil: Rf = 0.6 (15% EA/Hex); 1H NMR:
7.32−7.29 (m, 4H), 7.23−7.21 (m, 6H), 4.11 (t, J = 6.4, 4H), 2.73 (t,
J = 7.5, 4H), 2.02−1.95 (m, 4H), 1.74−1.70 (m, 4H), 1.56−1.46 (m,
4H), 1.45−1.31 (m, 14H); 13C NMR: 141.7, 128.4, 128.3, 125.8,
113.3, 74.2, 32.3, 29.5, 27.1, 26.1, 22.3, 22.0, 19.4; IR: 2914, 2845,
1462, 1053
Hydrolysis of the bisperoxyacetal (1.35 g, 2.88 mmol) by a similar
procedure as described above furnished hydroperoxide 6 as a colorless
oil (0.725 g, 82%): Rf = 0.57 (20% EA/Hex). Spectral data matched
those previously reported.61
To a 0 °C solution of cyclododecanone-1,1-dihydroperoxide (2.196 g,
9.469 mmol, synthesized as previously described)57 in dry THF (50 mL)
was added KOtBu (2 equiv), followed by the triflate described
above (6.0 g, 20.8 mmol). The reaction mixture was stirred until the
starting material was no longer visible (TLC, ∼20 min). The reaction
mixture was then quenched with water (25 mL) and extracted with EA
(50 mL × 2). The combined organic layers were dried over Na2SO4
and concentrated on a rotary evaporator. The residue was purified by
silica chromatography using 1% EA/hex to furnish 1,1-bis-(3,7
dimethyl-6-octenylperoxy) cyclododecane (2.84 g, 59%) as a colorless
oil: Rf = 0.75 (10% EA:Hex); 1H NMR: 5.10 (m, 2H), 4.17−3.99 (m,
4H), 2.07−1.91 (m, 4H), 1.72−1.64 (m, 9H), 1.69 (s, 3H), 1.61 (s,
3H), 1.58−1.53 (m, 7H), 1.48−1.28 (m, 20H), 1.24−1.15 (m, 2H),
0.92 (d, J = 6.5, 6H); 13C NMR: 131.2, 124.6, 113.1, 73.4, 37.1, 34.6,
29.7, 27.0, 26.1, 25.7, 25.4, 22.3, 21.9, 19.6, 19.4, 17.6; HRMS
(TOFMS-ES): Calcd for C32H60O4Na (M + Na)+ 531.4389 found:
531.4373; IR: 2926, 2850, 1445, 1052.
To a room temperature solution of the bisperoxyacetal (1.01 g,
2 mmol) in THF (20 mL) was added a solution of 50% aq. H2SO4
(1.8 mmol, 6 equiv), and the reaction mixture was stirred at 55 °C
until starting material was nearly consumed (TLC, 1−3 h). The
reaction was then quenched with saturated aq. Na2CO3 (25 mL), and
the resulting mixture was extracted with EA (30 mL × 2). The
combined organic layers were dried over Na2SO4 and concentrated on
a rotary evaporator. The crude product was purified by silica
chromatography using 1−3% EA/Hex to furnish hydroperoxide 4 as
a colorless oil (0.364 mg, 53%). The molecule has previously been
reported without characterization:58 Rf = 0.4 (10% EA/Hex);
1H NMR: 8.53 (s, 1H), 5.09 (m, 1H), 4.10−4.00 (m, 2H), 2.06−
1.93 (m, 2H), 1.73−1.63 (m, 1H), 1.68 (s, 3H), 1.60 (s, 3H), 1.54−
1.35 (m, 2H), 1.33−1.14 (m, 2H), 0.91 (d, J = 6.5, 3H); 13C NMR:
131.3, 124.6, 75.5, 37.1, 34.3, 29.5, 25.7, 25.4, 19.5, 17.6. IR:
10-Phenyldecane Hydroperoxide (7). The title compound was
prepared by an analogous strategy as described for hydroperoxides 4
and 6.
10-phenyldecyl trifluoromethanesulfonate (1.098 g, quant.) was
prepared from 10-phenyldecanol (0.70 g, 3 mmol) as a light brown oil:
1
Rf = 0.65 (10% EA/Hex); H NMR: 7.33−7.28 (m, 2H), 7.22−7.18
(m, 3H), 4.56 (t, J = 6.5 Hz, 2H), 2.63 (t, J = 7.7 Hz, 2H), 1.85 (m,
2H), 1.69−1.59 (m, 2H), 1.46−1.33 (m, 12H); 13C NMR: 142, 128.4,
128.2, 125.5, 118.6 (q, J = 320 Hz), 77.7, 35.9, 31.5, 29.4, 29.37, 29.30,
29.27, 29.22, 28.8, 25.0. HRMS (ESI): Calcd for C17H25F3NaO3 S
(M + Na) 389.1374, found 389.1369.
Using a similar procedure as described above, reaction of
1,1-dihydroperoxycyclododecanone (0.293 g, 1.26 mmol) and the
10-phenyl decyl triflate (1.02 g, 2.787 mmol) was used to prepare
1,1-bis-(10-phenyldecyldioxy)cyclodecanone: (0.834 g, 99%) as a
colorless oil: Rf = 0.74 (15% EA/Hex); 1H NMR: 7.32−7.29 (m, 4H),
7.21−7.19 (m, 6H), 4.09 (t, J = 6.6, 4H), 2.62 (t, J = 7.7, 4H), 1.72−
1.59 (m, 12H), 1.37−1.30 (m, 42H); 13C NMR: 142.9, 128.4, 128.2,
125.5, 113.1, 75.0, 36.0, 31.5, 29.57, 29.53, 29.48, 29.36, 27.8, 27.0,
26.2, 26.1, 22.3, 21.9, 19.4. HRMS (TOF-MS-ES+): Calcd for
G
DOI: 10.1021/acs.joc.5b02043
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
C44H72O4Na (M + Na)+ 687.5328 found 687.5300; IR: 2914, 2845,
1462, 1053.
(m, 1H), 0.92 (d, J = 6.6 Hz, 3H); 13C NMR: δ: 131.2, 124.7, 100.8,
73.7, 62.5, 37.1, 34.6, 29.6, 27.96, 25.7, 25.4, 25.1, 19.7, 19.5, 17.6.
HRMS (ESI+ TOF) calcd for C15H28NaO3 (M + Na): 279.1931;
found: 279.1934; IR: 2923, 2861, 1440, 1040.
Using a procedure similar to that described above, hydrolysis of
the bis-(10-phenyldecyl)peroxyacetal (0.755 g, 1.14 mmol) furnished
10-phenyldecyl hydroperoxide as a colorless oil (0.243 g, 64%): Rf =
8-((2-Methoxypropan-2-yl)peroxy)-2,6-dimethyloct-2-ene
(8c). Using method A, hydroperoxide 3 (0.674 g, 6.35 mmol,
1.5 equiv) was reacted with 3,7-dimethyl-6-octenyl triflate (1.21 g,
4.2 mmol) to furnish 8c as a colorless oil (0.627 g, yield: 61%); Rf =
0.4 (10% EA/Hex); 1H NMR: 5.1 (m, 1H), 4.11−4.01 (m, 2H), 3.33
(s, 3H), 2.06−1.91 (m, 2H), 1.71−1.64 (m, 1H), 1.69 (s, 3H), 1.61 (s,
3H), 1.62−1.54 (m, 1H), 1.47−1.31 (m, 2H), 1.40 (s, 6H), 1.24−1.10
(m, 1H), 0.91 (d, J = 6.5 Hz, 3H); 13C NMR131.2, 124.7, 104.5, 73.4,
49.2, 37.1, 34.6, 29.6, 25.7, 25.4, 22.76, 22.74, 19.5, 17.6; HRMS
(TOF-MS-ES+) calcd for C14H28NaO3 (M + Na): 267.1931; found:
267.1926; IR: 2954, 2874, 1457, 836.
t-Butyldimethylsilyl 3,7-Dimethyl-6-octenyl Peroxide (8d).
Using method D, alkyl hydroperoxide 4 (0.22 g, 1.279 mmol) was
silylated with t-butyldimethylsilyl chloride (TBS-Cl) to furnish 8d as a
colorless oil (0.212 g, 58%): Rf = 0.75 (10% EA/Hex); 1H NMR: 5.12
(m, 1H), 4.06−3.97 (2H), 2.06−1.91 (m, 2H), 1.69 (s, 3H), 1.67−
1.59 (m, 1H), 1.61 (s, 3H), 1.59−1.51 (m, 1H), 1.46−1.30 (m, 2H),
1.22−1.15 (m, 1H), 0.95 (s, 9H), 0.91 (d, J = 6.6), 0.17 (s, 6H);
13C NMR: 131.2, 124.6, 75.3, 37.1, 34.5, 29.6, 26.1, 25.7, 25.4, 19.6,
18.1, 17.6, −5.9; HRMS (TOF-MS-EI+) calcd for C16H34NaO2Si
(M + Na): 309.2220; found: 309.2218; IR: 2928, 2857, 1461, 834.
3-tert-Butylperoxypropyl Benzene (9a). [419568-76-6]: Using
method A, tert-butyl hydroperoxide (1.8 mL, 5.0−6.0 M in decane,
10 mmol) was reacted with 3-phenyl propyl triflate (2.68 g, 10 mmol)
to furnish 9a as a colorless liquid (1.5151 g. 73%). Rf (10% EA/Hex) =
0.65. Spectral data matched those in a literature report.62
2-(3-Phenylpropylperoxy)tetrahydro-2H-pyran (9b).
[1630792-49-2]: Using method A, THP hydroperoxide 1 (1.18 g,
10 mmol) was reacted with 3-phenylpropyl triflate (2.68 g, 10 mmol)
to furnish peroxide 9b as a colorless oil (1.937 g, 82%); Rf = 0.66 (15%
EA/Hex). Spectral properties matched those in a literature report.5b
3-(2-Methoxyethylperoxy)propyl Benzene (9e). The title
compound was prepared in two steps.
2-Methoxyethyl trifluoromethanesulfonate [112981-50-7] was pre-
pared (2.08 g, ∼quant) from 2-methoxyethanol (760 mg, 10.0 mmol)
using the procedure described above and used without purification.
Spectral data matched those reported.63 Rf = 0.5 (30% EA/hex).
Using method A, alkyl hydroperoxide 6 (0.70 g, 4.6 mmol) was
reacted with 2-methoxyethyl trifluoromethanesulfonate (0.956 g,
4.6 mmol) to furnish 9e as a colorless oil (0.723 g, 74%): Rf = 0.62
(20% EA/Hex); 1H NMR: 7.32−7.27 (2H), 7.22−7.18 (3H), 4.15 (m,
2H), 4.05 (t, J = 6.4, 2H), 3.62 (m, 2H), 3.40 (s, 3H), 2.71 (t, J = 7.8,
2H), 2.01−1.93 (2H); 13C NMR: 141.6, 128.46, 128.39, 125.9, 73.59,
73.54, 69.8, 59.1, 32.2, 29.4; HRMS (TOF-MS-CI+) calcd for
C12H18O3Na [M + Na]+: 233.1154; found: 233.1152; IR: 2924,
1496, 1453, 745.
10-(tert-Butylperoxy)decylbenzene (10a). Using method A,
t-butyl hydroperoxide (1.41 mL, 5.0−6.0 M in decane, 7.76 mmol)
was reacted with 10-phenyldecyl triflate (3.125 g, 8.54 mmol) to
furnish 10a as a colorless oil (2.42 g, 92%). Rf = 0.73 (10% EA/Hex);
1H NMR: 7.33−7.20 (m, 2H), 7.22−7.17 (m, 3H), 3.96 (t, J = 6.7 Hz,
2H), 2.62 (t, J = 7.8 Hz, 2H), 1.69−1.56 (m, 4H), 1.32−1.28 (m,
12H), 1.27 (s, 9H); 13C NMR: δ: 142.9, 128.4, 128.2, 125.5, 80.0, 75.1,
36.0, 31.5, 29.5, 29.3, 27.8, 26.3, 26.2. HRMS (ESI+ TOF): Calcd for
C20H34NaO2 (M + Na): 329.2451; found: 329.2470; IR: 2924.8,
2853.72, 1361.5, 697.
2-(10-Phenyldecylperoxy)tetrahydro-2H-pyran (10b).
[1630792-52-7]: Using method A, THP hydroperoxide 2 (0.20 g,
1.77 mmol) was reacted with 10-phenyldecyl triflate (0.65 g, 1.775 mmol)
to furnish 10b as a colorless oil (0.448 g, 75%); Rf = 0.42 (10% EA/Hex).
Spectral properties matched those in a literature report.5b
t-Butyldimethylsilyl 10-Phenyldecyl Peroxide (10d). Using
method D, alkyl hydroperoxide 7 (0.22 g, 0.89 mmol) was converted
into the corresponding silyl peroxide 10d, which was obtained as a
colorless oil (0.267 g, 82%): Rf = 0.8 (10% EA/Hex); 1H NMR:
7.32−7.28 (m, 2H), 7.22−7.19 (m, 3H), 3.99 (t, J = 6.6 Hz, 2H),
1
0.55 (15% EA/Hex); H NMR: 8.04 (t, J = 6.5, 1H), 7.33−7.28 (m,
2H), 7.22−7.20 (m, 3H), 4.04 (t, J = 6.6, 2H), 2.63 (t, J = 7.7, 2H),
1.68−1.61 (m, 4H), 1.32 (m, 12H); 13C NMR: 142.9, 128.4, 128.2,
125.5, 76.6, 36.0, 31.5, 29.5, 29.4, 29.3, 27.5, 25.9; HRMS (TOF-MS-
EI+): Calcd for C16H25O (M − OH)+ 233.1905; found: 233.1920; IR:
3390, 2922, 2852, 1453, 696.
Synthesis of Peroxides via Alkylation of Hydroperoxides
with Triflates (Method A). Synthesis of dialkyl peroxides from alkyl
triflates was based upon reported procedures.22 The hydroperoxide
(10 mmol in a minimum amount of THF) was added under nitrogen
to a 0 °C solution of KOtBu (10 mmol) in dry THF (50 mL). The
reaction mixture was stirred for 3 min, after which was added
preformed alkyl triflate (10 mmol, neat from syringe, remaining triflate
rinsed into the reaction using 1 mL of THF). The reaction was stirred
for 15 min at the same temperature and then quenched with water
(20 mL). The mixture was extracted with 10% EA/Hex (50 mL × 2),
and the organic layer was dried over Na2SO4. The residue obtained
upon concentration was purified by flash silica chromatography using
1% EA/Hex.
Peroxides via Acetalization (Method B). Acetalization of alkyl
hydroperoxides to form tetrahydropyranyl (THP) monoperoxyacetals
employed a modification of a reported procedure.25 A mixture of alkyl
hydroperoxide (1.0 mmol) and 2,3-dihydropyran (1.0 mmol) was
cooled to 0 °C, after which was added 0.05 mL of a solution of 10%
H2SO4 in THF. The stirred reaction mixture was allowed to warm to rt
over a period of 45 min. The reaction was diluted with 10% ether/Hex
(15 mL), and the resulting solution was washed with water (2 mL).
The separated organic layer was dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography using 4% EA/Hex.
Ag-Promoted Alkylation (Method C). Dialkyl peroxide synthesis
using silver oxide was based upon a modification of reported pro-
cedures.26b,c The alkyl hydroperoxide (1.0 mmol) was added to a
suspension (EA, 10 mL) of freshly prepared silver oxide (1.2 mmol).
Alkyl halide (1.0 mmol) was added, and the reaction was stirred at rt
until no starting material could be observed (TLC, approximately
4−10 h). The reaction mixture was filtered through a small pad of
Celite, and the residue was washed with EA (10−20 mL). The
combined filtrates were concentrated, and the residue was purified by
silica gel chromatography using 1−3% EA/Hex.
Trialkylsilylation of Hydroperoxides (Method D). Trialkylsily-
lation was performed based upon a reported procedure, except for a
different order of addition and the use of water rather than aqueous
acid for the wash.27 To a room temperature solution of alkyl hydro-
peroxide (1.0 mmol) in DMF (2 mL) was added tert-butyl dimethylsilyl
chloride (1.2 mmol), followed by imidazole (1.4 mmol). The reaction
was stirred for 1 h and then diluted with water (10 mL). The hexane
extracts (1 × 50, 1 × 10 mL) were dried over Na2SO4 and concen-
trated under reduced pressure. The residue was purified by silica gel
chromatography (4.0 in. tall × 0.5 in. column) using 1% ether/Hex.
8-(tert-Butylperoxy)-2,6-dimethyloct-2-ene (8a). [1592933-
34-0]: Using method A (above), t-butyl hydroperoxide (5.5 M in
decane, 0.588 mL, 3.24 mmol) was reacted with 3,7-dimethyl-6-
octenyl triflate (described above in relation to preparation of peroxide
4, 1.025 g, 3.559 mmol) to furnish 8a as a colorless oil (0.511 g, 69%);
Rf = 0.6 (10% EA/Hex). Spectral data matched those in literature
reports.5a
2-(3,7-Dimethyloct-6-ene-1-yl)peroxy)-tetrahydro-2H-pyran
(8b). Using method A, THP hydroperoxide 1 (0.63 g, 5.34 mmol) was
reacted with 3,7-dimethyl-6-octenyl triflate (1.69 g, 5.87 mmol) to
furnish peroxide 9a as a colorless oil (0.854 g, yield: 62%) Rf = 0.42
1
(10% EA/Hex); H NMR: 5.15 (t, J = 3.5 Hz, 1H), 5.10 (m, 1H),
4.19−4.00 (m, 2H), 4.02 (m, 1H), 3.66−3.61 (m, 1H), 1.98 (m, 2H),
1.78−1.71 (m, 2H), 1.70−1.65 (m, 1H), 1.68 (s, 3H), 1.64−1.53 (m,
5H), 1.60 (s, 3H), 1.49−1.42 (m, 1H), 1.41−1.32 (m, 1H), 1.23−1.1
H
DOI: 10.1021/acs.joc.5b02043
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2.63 (t, J = 7.7 Hz, 2H), 1.66−1.56 (m, 4H), 1.32 (m, 12H), 0.97
(s, 9H), 0.19 (s, 6H); 13C NMR: 142.9, 128.4, 128.2, 125.5, 76.6, 36.0,
31.5, 29.5, 29.3, 27.7, 26.2, 26.1, 18.1, −5.8; HRMS (ESI+ TOF) calcd
for C22H40NaO2Si (M + Na): 387.2690; found: 387.2677; IR: 2925,
2854, 1462, 1248.
tert-Butylperoxy Octane (11a). [38375-34-7]: 1-Octyl tri-
fluoromethanesulfonate [71091-89-9] was prepared (3.08 g, 98%) as
a light brown oil from 1-octanol (1.56 g, 12 mmol) using the general
procedure described above. The 1H NMR spectrum matched data
previously reported:64 Rf = 0.52 (10% EA/Hex); 1H NMR: 4.55 (t, J =
6.54, 2H), 1.84 (m, 2H), 1.46−1.40 (m, 2H), 1.36−1.29 (m, 8H), 0.90
(t, J = 6.9, 3H); 13C NMR: 118.2 (q, J = 320.1 Hz), 76.7, 31.6, 29.2,
28.9, 28.8, 25.0, 22.5, 14.0.
t-Butyl hydroperoxide (1.81 mL, 5.5 M in decane, 10 mmol) was
reacted with octyl triflate (2.88 g, 11 mmol) to furnish 11a as a
colorless oil (1.78 g, 88%): Rf = 0.79 (10% EA/Hex). The molecule
has been previously reported without spectral characterization:65
1H NMR: 3.93 (t, J = 6.7 Hz, 2H), 1.63−1.55 (m, 2H), 1.34−1.26 (m,
10H), 1.25 (s, 9H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR: 79.9, 75.1,
31.8, 29.4, 29.2, 27.8, 26.3, 26.2, 22.6, 14.0; HRMS (ESI-TOF-MS)
Calcd for C12H26NaO2 (M + Na): 225.1825; found: 225.1840; IR:
2924, 2856, 1361, 1197.
1.34−1.28 (m, 10H),5.82− 0.89 (t, J = 6.8 Hz, 3H); 13C NMR: (major
isomer): 136.7, 126.2, 33,6, 32.0, 31.9, 29.4, 29.2, 29.1, 28.8, 22.7, 14.1.
Using method C, hydroperoxide 2 (0.118 mg, 1 mmol) was reacted
with an E/Z-mixture of 2-undecenyl bromide (0.232 g, 1.0 mmol) to
furnish peroxide 16b as a colorless oil (0.197 mg, 73%) consisting
of an inseparable 84:16 E/Z mixture: Rf = 0.42 (10% EA/Hex);
1H NMR: 5.82−5.74 (m, 1H), 5.69−5.55 (m, 1H), 5.16 (m, 1H), 5.64
(d, J = 6.8 Hz, 0.24 H), 4.51 (d, J = 6.8 Hz, 1.76 H), 4.01 (m, 1H),
3.64−3.60 (m, 1H), 2.13−2.02 (m, 2H), 1.73−1.68 (m, 2H), 1.65−
1.53 (m, 4H), 1.38−1.35 (m, 2H), 1.31−1.26 (m, 10H), 0.87 (t, J =
6.8 Hz, 3H); 13C NMR: 137.8, 123.7, 100.8, 76.2, 62.4, 32.3, 31.8, 29.4,
29.2, 29.1, 28.8, 27.8, 25.1, 22.6, 19.6, 14.0. HRMS (TOF-MS-ES+) calcd
for C16H30NaO3 (M + Na): 293.2087; found: 293.2087; IR: 2923, 2851,
1202, 962.
Etherification of Peroxides with sp3 RM. The alkyllithium
(0.55 mmol, 1.1 equiv, typically as a solution in Hex) was added to the
solution of peroxide (0.50 mmol) in dry THF (3 mL) at −78 °C, and
the reaction was stirred for 15 min. For THP monoperoxyacetals, the
reaction was brought to room temperature for 15 min and then
quenched with water (2 mL); for other peroxides, the reaction was
allowed to stir at room temperature for the time indicated. The
mixture was extracted with 20% ether in Hex (1 × 25, 1 × 5 mL), and
the combined organic layers were dried over Na2SO4 and
concentrated. The residue was purified by silica gel chromatography
(0.5 × 4 in. column) using 1% ether in hexane. Note: For volatile
ethers, column fractions were carefully concentrated on a rotary
evaporator at 20 °C bath temperature and then briefly (1 min)
concentrated on high vacuum while held in an ice bath.
For reaction with Grignard reagents, a solution of the alkyl
magnesium bromide (0.55 mmol, 1.1 equiv) in diethyl ether was
added to a 0 °C solution of the THP monoperoxyacetal (0.5 mmol) in
dry THF (3 mL). The reaction was stirred for 15 min and then
brought to room temperature. After 15 min, the reaction was
quenched with water (2 mL) and extracted with 20% ether/Hex (1 ×
25, 1 × 5 mL). The combined organic layers were dried over Na2SO4,
and the concentrated residue was purified by silica gel chromatography
(0.5 × 4 in. column) using 1% ether/Hex. In the case of volatile ethers,
column fractions were concentrated on a rotary evaporator at 20 °C
bath temperature and subsequently subjected to high vacuum
(<1 mm) for 1 min while placed in an ice bath.
2-(Decylperoxy)-tetrahydro-2H-pyran (12b). [1630792-51-6]:
Decyl trifluoromethanesulfonate [53059-89-5] was prepared (3.1 g,
quant = 2.9 g) as a light brown oil from 1-decanol (1.58 g, 10.0 mmol)
using the procedure described above. Spectra closely matched those in
previous reports:66 Rf = 0.52 (10% EA/Hex); H NMR: 4.55 (t, J =
1
6.5 Hz, 2H), 1.84 (m, 2H), 1.43 (m, 2H), 1.36−1.28 (m, 12H), 0.9 (t,
J = 6.8 Hz, 3H); 13C NMR: 118.6 (q, JC−F = 320 Hz), 77.7, 31.8, 29.4,
29.3, 29.2, 28.8, 25.0, 22.6, 14.0.
Using method A, 2-tetrahydropyranyl hydroperoxide 2 (1.18 g,
10 mmol) was reacted with decyl triflate (2.98 g, 10 mmol) to furnish
peroxide 12b as a colorless oil (2.05 g, 79%); Rf = 0.56 (15% EA/
Hex). Spectral properties matched those in a literature report.5b
2-(2-Octylperoxy)-tetrahydro-2H-pyran (13b). [1630792-50-
5]: 2-Octyl trifluoromethanesulfonate [58864-30-5] was prepared
(3.58 g, estimated 91%) as a light brown oil from 2-octanol (2.0 g,
15 mmol) using the procedure described above. Rf = 0.3 (10%
EA/Hex). Spectral properties matched those in a previous report.5b
Using method A, hydroperoxide 2 (0.595 g, 5.01 mmol) was reacted
with 2-octyl triflate (1.47 g, 5.61 mmol) to furnish 13b as a colorless
oil (0.808 g, 70%) Rf = 0.61 (20% EA/Hex). Spectral properties
matched those in a literature report.5b
8-Butoxy-2,6-dimethyloct-2-ene (17a). [71077-30-0]: Using
the general procedure described above, THP monoperoxyacetal 8b
(128 mg, 0.5 mmol) was reacted with n-BuLi (0.34 mL, 1.6 M in Hex,
0.55 mmol) to furnish ether 17a as a colorless oil (86 mg, 81%).
The same procedure, when applied to dialkyl peroxide 8b or
2-methoxypropyl peroxyacetal 8c furnished 17a in 70% and 87%
yields, respectively. Spectral data matched those in previous reports.5a
Rf = 0.6 (5% EA/Hex).
Bis-(tetrahydro-2H-pyranyl) Peroxide (14b). [685877-38-7]:
Using method B, acetalization of 2-tetrahydropyranyl hydroperoxide 2
(0.35 g, 2.97 mmol) with dihydropyran (0.249 g, 2.97 mmol)
furnished peroxide 14b as a colorless oil (0.493 g, 84%). This molecule
has been previously prepared without NMR characterization:67 Rf =
1
0.50 (10% EA/Hex); H NMR: 5.22 (m, 2H), 4.09 (m, 1H), 4.00
8-Hexyloxy-2,6-dimethyl-2-octene (17b). Using the general
procedure for Grignard-promoted etherification described above,
monoperoxacetal 8b (128 mg, 0.5 mmol) was reacted with n-hexyl
magnesium bromide (0.27 mL, 2 M in diethyl ether, 0.55 mmol) to
furnish hexyl ether 17b as a colorless oil (106 mg, 88%). The same
product could be obtained from dialkyl peroxide 8a except in 42%
(m, 1H), 3.63−3.60 (m, 2H), 1.76−1.74 (m, 4H), 1.66−1.53 (m, 8H);
13C NMR: 101.8, 100.2, 62.5, 62,1, 27.9, 27.7, 25.1, 25.0, 19.6, 19.4.
2-(1-Methylcyclohexylperoxy)-tetrahydro-2H-pyran (15b).
Using method B, hydroperoxide 5 (0.266 g, 2.04 mmol) was reacted
with dihydropyran (0.171 g, 2.04 mmol) to furnish 15b as a colorless
1
1
yield: Rf = 0.70 (10% EA/Hex); H NMR: 5.11 (m, 1H), 3.47−3.38
oil (0.326 g, 74%). Rf = 0.50 (10% EA/Hex); H NMR: 5.04 (broad
(m, 4H), 2.08−1.94 (m, 2H), 1.69 (s, 3H), 1.65−1.53 (m, 4H), 1.61
(s, 3H), 1.45−1.31 (m, 8H), 1.23−1.11 (m, 1H), 0.91−0.88 (m, 6H);
13C NMR: 131.1, 124.8, 71.0, 69.1, 37.2, 36.7, 31.7, 29.7, 29.6, 25.9,
25.7, 25.4, 22.6, 19.6, 17.6, and 14.0. HRMS (TOF-MS-EI+) calcd for
C16H32O: 240.2453; found: 240.2453; IR: 2954, 2927, 2858, 1455,
1376, 1112.
triplet, 1H), 4.02 (m, 1H), 3.60 (m, 1H), 1.75 (m, 5H), 1.68−1.53 (m,
6H), 1.47−1.35 (m, 6H), 1.26 (s, 3H); 13C NMR: 101.0, 81.5, 62.7,
35.0, 27.8, 25.7, 25.1, 24.3, 22.5, 22.3, 20.0; HRMS (ESI+ TOF) calcd
for C12H22NaO3 (M + Na): 237.1461; found: 237.1469; IR: 2931,
2852, 1443, 962.
(E,Z)-2-(Undec-2-en-1-yl peroxy)tetrahydro-2H-pyran (16b).
Using a known procedure,68 cross-metathesis of 1-octene (6.72 g,
4.8 mmol) and allyl bromide (1.45 g, 12 mmol) in the presence of the
Grubbs II catalyst furnished 1-bromo-2-undecene (1.109 g, 80%) as a
colorless oil consisting of a 84:16 E/Z mixture using a known
procedure. The portions of the spectra corresponding to the major (E)
isomer closely matched a previous report [67952-61-8]:69 Rf = 0.8
(hexane); 1H NMR: (both isomers, partial integrals given): 5.82−
5.58 (m, 2H), 4.01 (d, J = 8.3 Hz, 0.32 H), 3.96 (d, J = 8.2 Hz,
1.68 H), 2.14 (m, 0.32H), 2.07 (m, 1.68), 1.40−1.35 (m, 2H),
8-Allyloxy-2,6-dimethyloct-2-ene (17c). [139694-24-9]: To a
0.2 M solution of peroxide 8a (229 mg, 1.0 mmol) in THF was
added allyltributyl tin (0.62 mL, 2.0 mmol). The solution was cooled
to −78 °C, and n-BuLi (2.5 mmol, 1.0 mL, 2.5 M in Hex) was added
dropwise. After 30 min, the reaction was quenched with 10 mL of
water and extracted with ether. The combined organic layer was dried
with Na2SO, and concentrated under reduced pressure. The residue
was then purified by column chromatography (2.5% EA/Hex) to
1
yield 137 mg (70%) of 17c as a colorless oil. The H NMR spectrum
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matched the listing in a previous report.70 Rf = 0.25 (5% EA/Hex);
1H NMR: 0.92 (d, 3H, J = 6.7), 1.18 (m, 1H), 1.39 (m, 1H), 1.52−
1.68 (s at 1.62 overlapping unresolved signal, 6H), 1.70 (s, 3H), 2.00
(m, 2H), 3.48 (m, 2H), 3.98 (dt, 2H, J = 5.6, 1.4), 5.14−5.08 (m 1H),
5.19 (app. dq, Hcis, J = 10.6, 1.3, 1H), 5.29 (app. dq, Htrans, J = 17.2,
1.6, 1H), 5.9 (m, 1H); 13C NMR: 17.6, 19.6, 25.5, 25.7, 29.6, 36.7,
37.2, 68.7, 71.8, 116.7, 124.8, 131.2, 135.1.
(t, J = 7.20 Hz, 3H); 13C NMR: 72.8, 59.9, 36.5, 32.8, 25.86, 24.6, 22.2,
19.6, 13.99. HRMS (TOF-MS-EI+) calcd for C11H22O: 170.1671;
found: 170.1671; IR: 2962, 2925, 2862, 1447, 1081.
1-Hexyloxy 1-Methyl Cyclohexane (17k). Using the general
procedure for etherification described above, peroxide 15b (107 mg,
0.50 mmol) was reacted with n-hexyl magnesium bromide (0.27 mL,
2 M in ether, 0.54 mmol) to furnish hexyl ether 17k as a colorless oil
(64 mg, 65%): Rf = 0.65 (5% EA/Hex); 1H NMR: 3.29 (t, J = 6.7 Hz,
2H), 1.71−1.66 (m, 2H), 1.64−1.47 (m, 5H), 1.44−1.27 (m, 11H),
1.11 (s, 3H), 0.90 (t, J = 6.9 Hz, 3H); 13C NMR: 72.9, 60.2, 36.5, 31.8,
30.7, 26.1, 25.8, 24.6, 22.6, 22.2, 14.0; HRMS (TOF-MS-EI+) calcd for
C13H26O: 198.1984; found: 198.1992; IR: 2962, 2925, 2862, 1447,
1081.
8-tert-Butoxy-2,6-dimethyl-2-octene (17d). [436141-44-5]:
Using the general procedure for etherification described above,
peroxyacetal 8b (128 mg, 0.5 mmol) was reacted with t-BuLi
(0.32 mL 1.7 M in pentane, 0.55 mmol) to furnish 17d as a colorless
oil (55 mg, 51%). Spectral data were nearly identical to those
previously described:71 Rf = 0.6 (5% EA/Hex); H NMR: 5.11 (m,
1
1H), 3.42−3.31 (m, 2H), 2.06−1.91 (m, 2H), 1.69 (s, 3H), 1.61 (m,
3H), 1.59−1.51 (m, 2H), 1.39−1.27 (m, 2H), 1.19 (s, 9H), 1.17−1.10
(m, 1H), 0.90 (d, J = 6.5 Hz, 3H); 13C NMR: 131.0, 124.9, 72.3, 59.7,
37.7, 37.2, 29.6, 27.5, 25.7, 25.4, 19.6, 17.6.
3-Phenylpropyl Trimethylsilylmethyl Ether (17e). Using the
general procedure for etherification described above, peroxide 9b
(118 mg, 0.50 mmol) was reacted with 2-trimethylsilyl methyl
magnesium chloride (0.65 mL, 1 M in ether, 0.65 mmol) to furnish
ether 17e as a colorless oil (84 mg, 75%): Rf = 0.8 (10% EA/Hex);
1H NMR: 7.31−7.29 (m, 2H), 7.22−7.19 (m, 3H), 3.42 (t, J = 6.3 Hz,
2H), 3.12 (s, 2H), 2.70 (t, J = 7.7 Hz, 2H), 1.91−1.87 (m, 2H), 0.09
(s, 9H); 13C NMR: 142.3, 128.5, 128.2, 125.6, 74.2, 64.7, 32.3, 31.2,
−2.98; HRMS(TOF-MS-EI+) calcd for C13H22OSi (M)+: 222.1440;
found: 222.1442; IR: 2955, 2845, 1246, 839.
(E/Z)-1-Butoxyundec-2-ene (17l). Using the general procedure
for etherification described above, peroxide 16b (135 mg, 0.50 mmol)
was reacted with n-BuLi (0.34 mL, 1.6 M in Hex, 0.55 mmol) to
furnish ether 17l as a colorless oil (86 mg, 76%): Rf = 0.63 (10%
1
EA/Hex); H NMR: 5.73−5.66 (m, 1H), 5.59−5.52 (m, 1H), 4.01
(m, 0.23 H), 3.91 (dd, J = 0.6, 6.15, 1.76 H), 3.41 (t, J = 6.6 Hz, 2H),
2.05 (m, 2H), 1.61−1.54 (m, 2H), 1.43−1.35 (m, 4H), 1.33−1.27 (m,
10H), 0.93 (t, J = 7.4 Hz, 3H), 0.89 (t, J = 7.1 Hz, 3H); 13C NMR:
134.5, 126.4, 71.6, 69.8, 32.3, 31.88, 31.87, 29.4, 29.27, 29.21, 29.0,
22.7, 19.3, 14.0, 13.9; HRMS (TOF-MS-EI+): Calcd for C15H30O:
226.2297; found: 226.2297; IR: 2954, 2923, 2852, 1465, 1105.
(E/Z)-Hexyl 2-Undecenyl Ether (17m). Using the general
procedure for etherification described above, peroxide 16b (115 mg,
0.50 mmol) was reacted with n-hexyl magnesium bromide (0.27 mL,
2 M in ether, 0.54 mmol) to furnish hexyl ether 17m as a colorless
2-Butoxy Octane (17f). [110458-41-8]: Using the general
procedure for etherification described above, peroxide 13b (115 mg,
0.5 mmol) was reacted with n-BuLi (0.34 mL 1.6 M in Hex,
0.55 mmol) to furnish ether 17f as a colorless oil (73 mg, 78%).
1
oil (104 mg, 81%): Rf = 0.67 (10% EA/Hex); H NMR: 5.73−5.66
(m, 1H), 5.59−5.52 (m, 1H), 4.01 (m, 0.24 H), 3.91 (dd, J = 0.6, 6.2,
1.76 H), 3.40 (t, J = 6.7, 2H), 2.05 (m, 2H), 1.58 (m, 2H), 1.43−1.27
(m, 18H), 0.90−0.87 (6H); 13C NMR: 134.5, 126.4, 71.6, 70.2, 32.3,
31.88, 31.74, 29.76, 29.46, 29.28, 29.22, 29.1, 25.9, 22.67, 22.62, 14.08,
14.03. HRMS (TOF-MS-EI+) calcd for C17H34O: 254.2610; found:
254.2610; IR: 2954, 2923, 2852, 1465, 1105.
72
1
The H NMR data matched those previously reported: Rf = 0.6
(5% EA/Hex); 13C NMR: 75.3, 68.1, 36.7, 32.3, 31.8, 29.4, 25.6, 22.6,
19.7, 19.4, 14.0, 13.9.
2-Hexyloxy Octane (17g). [51182-98-0]: Using the general
procedure for etherification using a Grignard reagent, peroxide 13b
(115 mg, 0.50 mmol) was reacted with n-hexyl magnesium bromide
(0.27 mL, 2 M in diethyl ether, 0.54 mmol) to furnish hexyl ether 17g
as a colorless oil (95 mg, 88%). The product has been partially
characterized:72 Rf = 0.6 (5% EA/Hex); 1H NMR: 3.51−3.29 (m, 1H),
3.40−3.29 (m, 2H), 1.57−1.53 (m, 3H), 1.41−1.29 (m, 15H), 1.12
(d, J = 6.1 Hz, 3H), 0.9 (m, 6H); 13C NMR: 75.3, 68.4, 36.7, 31.8,
31.7, 30.1, 29.4, 25.9, 25.6, 22.63, 22.62, 19.7, 14.05, 14.02.
General Procedure for sp2 C−O Bond Formation. Reactions
involving commercially available reagents were conducted as described
above for sp3 C−O bond formations except that reaction times were
approximately 1 h. Reactions involving in situ formation of vinyl or
heteroaryllithium reagents from the corresponding tributylstannanes
were conducted as described below.
To a −78 °C solution of alkenyl- or aryltributyltin (0.55 mmol) in
dry THF (3 mL) was added n-BuLi (0.55 mmol, 1.6 M in Hex). The
reaction mixture was stirred for 10 min, after which was added a
solution of the monoperoxyacetal (0.50 mmol) in THF (1 mL). The
reaction mixture was stirred until no starting material could be
detected on TLC (approximately 60 min) and then diluted with Hex
(10 mL). The resulting solution was passed though a column of
neutral alumina (1 × 2 in.) and then concentrated (an aqueous
workup could also be conducted employing aq. carbonate to minimize
hydrolysis). The residue was purified by silica flash chromatography
using 1% ether/Hex; chromatography of enol and thienyl ethers
included 0.2% triethylamine.
2-Butoxy-tetrahydro-2H-pyran (17h). [1927-68-0]: Using the
general procedure for etherification described above, peroxide 14b
(101 mg, 0.50 mmol) was reacted with n-BuLi (0.31 mL 1.6 M in
hexane, 0.5 mmol) to furnish ether 17h (12 mg, 15%) accompanied by
16 mg (15%) of recovered 14b. Partial spectral characterization has
been reported.73 Rf = 0.5 (15% EA/Hex); H NMR: 4.59 (m, 1H),
1
3.89 (m, 1H), 3.76 (m, 1H), 3.52 (m, 1H), 3.40 (m, 1H), 1.84 (m,
1H), 1.72 (m, 1H), 1.65−1.49 (m, 6H), 1.45−1.35 (m, 2H), 0.94 (t,
J = 7.3 Hz, 3H); 13C NMR: 98.8, 67.3, 62.3, 31.8, 30.8, 25.5, 19.7, 1.4,
13.9.
2-Hexyloxy-tetrahydro-2H-pyran (17i). [1927-63-5] Using the
general procedure for etherification with alkyl magnesium bromide
described above, peroxide 14b (107 mg, 0.5 mmol) was reacted
with n-hexyl magnesium bromide (0.25 mL, 2 M in diethyl ether,
0.50 mmol) to furnish hexyl ether 17i as a colorless oil (57 mg, 61%).
The 1H NMR data matched those in a previous report.74 Rf = 0.5 (15%
3,7-Dimethyl-6-octen-1-yl Phenyl Ether (18a). [51113-53-2]:
Using the general procedure described above, peroxide 8b (128 mg,
0.5 mmol) was reacted with phenyl lithium (0.30 mL, 1.8 M in dibutyl
ether, 0.54 mmol) to furnish phenyl ether 18a as a colorless oil
(102 mg, 87%).75 The same product was available (78 mg, 67%) by
reaction of peroxide 8b (128 mg, 0.50 mmol) with phenyl magnesium
bromide (0.18 mL, 3.0 M in ether, 0.54 mmol):
1
EA/Hex); H NMR: 4.57 (m, 1H), 3.90−3.84 (m, 1H), 3.76−3.70
(m, 1H), 3.52−3.47 (m, 1H), 3.41−3.35 (m, 1H), 1.87−1.79 (m, 1H),
1.74−1.68 (m, 1H), 1.62−1.50 (m, 6H), 1.42−1.26 (m, 6H), 0.89 (t,
J = 6.8 Hz, 3H); 13C NMR: 98.8, 67.6, 62.3, 31.7, 30.8, 29.7, 25.9, 25.5,
22.6, 19.6, 14.0.
Rf = 0.66 (10% EA/Hex); 1H NMR: 7.32−7.30 (m, 2H), 6.97−6.93
(m, 3H), 5.15 (m, 1H), 4.03 (m, 2H), 2.08 (m, 1H), 2.02 (m, 1H),
1.88 (m, 1H), 1.75−1.71 (m, 1H), 1.73 (s, 3H), 1.65 (s, 3H), 1.64−
1.61 (m, 1H), 1.46−1.41 (m, 1H), 1.30−1.24 (m, 1H), 0.98 (d, J =
6.9 Hz, 3H); 13C NMR: 151.1, 131.3, 129.4, 124.7, 120.5, 114.5, 66.1,
37.2, 36.1, 29.6, 25.8, 25.5, 19.6, 17.7.
1-Butoxy-1-methyl Cyclohexane (17j). Using the general
procedure for etherification described above, peroxide 15b (107 mg,
0.50 mmol) was reacted with n-BuLi (0.34 mL, 1.6 M in Hex,
0.55 mmol) to furnish ether 17j as a colorless oil (61 mg, 71%): Rf =
2-Methylprop-1-en-1-yl 3-Phenylpropyl Ether (18b). Using
the general procedure described above, peroxide 9b (118 mg,
0.5 mmol) was reacted with 2-methyl-1-propenyl magnesium bromide
(1.3 mL, 0.5 M in THF, 0.65 mmol) to furnish ether 18b as a colorless
1
0.70 (10% EA/Hex); H NMR: 3.32 (t, J = 6.4 Hz, 2H), 1.71−1.64
(m, 2H), 1.61−1.45 (m, 5H), 1.43−1.19 (m, 7H), 1.10 (s, 3H), 0.93
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oil (39 mg, 41%), which decomposed during chromatography:
1H NMR: 7.34−7.30 (m, 2H), 7.26−7.21 (m, 3H), 5.83−5.82
(m, 1H), 3.72 (t, J = 6.4 Hz, 2H), 2.75 (t, J = 7.8 Hz, 2H), 2.00−1.93
(m, 2H), 1.68 (s, 3H), 1.59 (s, 3H); 13C NMR: 141.8, 140.0, 128.5,
128.4, 125.8, 110.5, 70.7, 32.0, 31.4, 19.5, 15.0. HRMS (TOF-MS-EI+)
calcd for C13H18O (M)+: 190.1358; found: 190.1363; IR: 2918, 2865,
1689, 1496, 1159.
The residue from the step described above was dissolved in DCM
(12 mL), and the solution cooled to −10 °C. Diisopropyl ethylamine
(0.335 g, 1.3 equiv) was added, followed by chloromethyl methyl ether
(0.177 g, 1.1 equiv). The reaction was stirred for 7 h at rt and then
washed with water (10 mL). The separated organic layer was dried
(Na2SO4) and concentrated on a rotary evaporator. The residue was
chromatographed on silica gel using 1% EA/Hex to afford 20 as a
1
3,7-Dimethyl-6-octen-1-yl Vinyl Ether (18c). Using the
procedure described above for etherifications with in situ generated
sp2 RLi, peroxyacetal 8b (128 mg, 0.5 mmol) was reacted with the
reagent generated from tributyl vinylstannane (237 mg, 0.75 mmol)
and n-BuLi (0.47 mL, 1.6 M in Hex, 0.75 mmol) to furnish ether 18c
as a colorless oil (62 mg, 66%), which partially decomposed upon thin-
colorless liquid (63%, 598 mg): Rf = 0.51 (10% EA/Hex); H NMR:
7.33−7.27 (m, 2H), 7.23−7.19 (m, 3H), 4.65 (d, J = 6.5 Hz, 1H), 4.62
(d, J = 6.5 Hz, 1H), 4.15−4.11 (m, 1H), 3.41 (s, 3H), 2.82−2.66 (m,
2H), 2.22−2.05 (m, 2H), 1.60−1.49 (m, 6H), 1.39−1.29 (m, 6H),
0.96−0.88 (m, 12H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR: 142.4, 128.4,
128.3, 125.7, 96.6, 73.7, 55.5, 37.4, 34.5, 29.2, 27.5, 13.7, 9.2.
1
layer or column chromatography: Rf = 0.7 (10% EA/Hex); H NMR:
Benzene, 3-Methoxymethoxy-3-octyloxypropyl (21a). To a
−78 °C solution of stannane 20 (235 mg, 0.5 mmol) in dry THF
(3 mL) was added a solution of n-BuLi in Hex (1.6 M, 0.5 mmol). After
the reaction had stirred for 3 min, peroxide 11a (100 mg, 0.5 mmol) was
added as a solution in THF (1 mL), and the reaction was stirred for an
additional 30 min at −78 °C. The cold bath was removed, and the reaction
was allowed to warm to rt over 30 min. The reaction was quenched
with water (1 mL) and diluted with hexane (40 mL). The mixture was
washed with water (10 mL), and the separated aqueous layer was
extracted with Hex (10 mL). The combined organic layers were dried
over Na2SO4 and concentrated. The residue was purified by silica gel
chromatography using ether/Hex (1−5%) to furnish recovered
11a (10%) and then the acetal 21a as a colorless oil (88 mg, 57%):
6.48 (dd, J = 6.8, 14.1 Hz, 1H), 5.12 (t, J = 7.0 Hz, 1H), 4.19 (d, J =
14.1 Hz, 1H), 3.99 (d, J = 6.8 Hz, 1H), 3.78−3.68 (m, 2H), 2.08−1.93
(m, 2H), 1.77−1.69 (m, 1H), 1.70 (s, 3H), 1.65−1.58 (m, 1H), 1.62
(s, 3H), 1.54−1.44 (m, 1H), 1.42−1.33 (m, 1H), 1.25−1.16 (m, 1H),
0.93 (d, J = 6.6 Hz, 3H); 13C NMR: 152.0, 131.3, 124.7, 86.2, 66.3,
37.1, 35.9, 29.5, 25.7, 25.4, 19.5, 17.6. HRMS (TOF-MS-EI+ calcd
for C12H22O (M − H)+: 181.1598; found: 181.1602; IR: 2961, 2913,
2871, 1647, 1609, 1200.
2-(3,7-Dimethyloct-6-en-1-oxy)-thiophene (18d). Using the
procedure described above for etherifications with in situ generated
sp2 RLi, peroxyacetal 8b (128 mg, 0.50 mmol) was reacted with
the reagent generated from 2-(tributylstannyl)thiophene (279 mg,
0.75 mmol) and n-BuLi (0.47 mL, 1.6 M in Hex, 0.75 mmol) to
furnish ether 18d as a colorless oil (72 mg, 60%): Rf = 0.75 (10%
EA/Hex); 1H NMR: 6.73 (dd, J = 3.7, 6.0 Hz, 1H), 6.56 (dd, J = 1.2,
6.0 Hz, 1H), 6.22 (dd, J = 1.2, 3.7 Hz, 1H), 5.13 (t, J = 7.1 Hz, 1H),
4.10−4.06 (m, 2H), 2.08−1.98 (m, 2H), 1.89−1.84 (m, 1H), 1.74−
1.67 (m, 1H), 1.72 (s, 3H), 1.64 (s, 3H), 1.62−1.59 (m, 1H), 1.43−
1.38 (m, 1H), 1.27−1.22 (m, 1H), 0.97 (d, J = 6.6 Hz, 3H);
13C NMR: 165.8, 131.4, 124.7, 124.6, 111.7, 104.6, 72.3, 37.0, 36.0, 29.4,
25.7, 25.4, 19.5,17.7; HRMS (TOF-MS-EI+) calcd for C14H22OS (M)+:
238.1391; found: 238.1390; IR: 2963, 2925, 2913, 2871, 1536, 1193.
2-(Decyloxy)-thiophene (18e). Using the procedure described
above, peroxide 12b (129 mg, 0.50 mmol) was reacted with the
reagent generated from 2-(tributylstannyl)thiophene (279 mg,
0.75 mmol) and n-BuLi (0.47 mL, 1.6 M in Hex, 0.75 mmol) to
furnish ether 18e as a colorless oil (65 mg, 54%): Rf = 0.7 (10%
1
Rf = 0.36 (10% EA/hex); H NMR: 7.32−7.27 (m, 2H), 7.24−7.19
(m, 3H), 4.83 (d, J = 6.8 Hz, 1H), 4.70 (d, J = 6.8 Hz, 1H), 4.70−4.66
(m, 1H), 3.68−3.63 (m, 1H), 3.47−3.40 (m, 1H), 3.43 (s, 3H), 2.71−
2.72 (m, 2H), 2.04−1.98 (m, 2H), 1.64−1.57 (m, 2H), 1.40−1.30 (m,
10H), 0.91 (t, J = 6.7 Hz, 3H); 13C NMR: 141.7, 128.4, 125.8, 101.4,
93.3, 66.7, 55.7, 36.4, 31.8, 30.8, 29.8, 29.4, 29.2, 26.2, 22.6, 14.1;
HRMS (ESI+ TOF) calcd for C19H32O3 (M + Na)+: 331.2249; found:
331.2265; IR: 2925, 2855, 1149, 1002.
3-Methoxymethoxy-3-phenylpropoxy Propylbenzene (21b).
The title compound was synthesized as a colorless oil (86 mg, 55%)
from reaction of 9a (104 mg, 0.50 mmol) using the general procedure
described above except that 1.2 equiv each of tributylstannane and
1
n-BuLi was used: Rf = 0.43 (10% EA/Hex); H NMR: 7.35−7.31 (m,
4H), 7.28−7.21 (m, 6H), 4.85 (d,, J = 6.6 Hz, 1H), 4.73 (d, J = 6.6 Hz,
1H), 4.72−4.70 (m, 1H), 3.74−3.69 (m, 1H), 3.51−3.47 (m, 1H),
3.44 (s, 3H), 2.81−2.74 (m, 4H), 2.08−2.02 (m, 2H), 2.00−1.93 (m,
2H); 13C NMR: 141.88, 141.7, 128.5, 128.49, 128.45, 128.42, 128.39,
125.9, 125.8, 101.6, 93.5, 65.8, 55.8, 36.4, 32.4, 31.4, 30.8; HRMS
(TOF MS ES+) calcd for C20H26NaO3 (M + Na)+: 337.1780; found:
337.1775; IR: 2927, 1453, 1122, 1000, 697.
1
EA/Hex); H NMR: 6.74−6.72 (m, 1H), 6.56−6.54 (m, 1H), 6.23−
6.21 (m, 1H), 4.04 (t, J = 6.4 Hz, 2H), 1.83−1.76 (m, 2H), 1.48−1.44
(m, 2H), 1.38−1.30 (m, 12H), 0.91 (t, J = 6.8 Hz, 3H); 13C NMR:
165.9, 124.6, 111.6, 104.5, 74.0, 31.9, 29.5, 29.3, 29.2, 25.8, 22.7, 14.1.
HRMS (TOF-MS-EI+) calcd for C14H24OS (M)+: 240.1548; found:
240.1548; IR: 2920, 2853, 1536, 1456, 1193.
3-Decyloxy-3-methoxymethoxy Propyl Benzene (21c). The
title compound was synthesized as a colorless oil (89 mg, 53%) from
stannane 20 (0.235 g, 0.50 mmol) and peroxyacetal 12b (0.129 g,
0.50 mmol) using the general procedure described above: Rf = 0.40
3,3-Difluoro-3-((10-phenyldecyl)oxy)propyl)benzene (19).
The difluoroether was prepared applying a previously reported two-
step procedure (reaction of lithiated dithiane with the peroxide;
fluorodesulfurization of the poorly stable difluoroether products)5b to
three different precursors: 2-(3-phenylpropyl)-1,3-dithiane and
monoperoxyacetal 10b (100 mg, 51% isolated yield); silyl peroxide
10d (105 mg, 54% isolated yield); t-butyl peroxide 10a (95 mg, 26%,
with 35% recovered starting material). In each case, difluoroether 19
was isolated as a colorless oil with Rf = 0.5 (5% EA/Hex) and with
spectra matching literature values.5b
Tributyl(1-(methoxymethoxy)-3-phenylpropyl)stannane
(20). [123294-00-8] was prepared using a modification of a literature
procedure.76 A solution of diisopropylamine (0.22 g, 1.1 equiv) in
5 mL of THF was cooled to 0 °C, and n-BuLi (1.37 mL, 1.6 M in Hex,
2.2 mmol, 1.1 equiv) was added. The reaction was stirred for 10 min,
after which was added Bu3SnH (0.582 g, 2.0 mmol, 1 equiv). The
reaction was stirred for 15 min at 0 °C and then cooled to −78 °C,
whereupon hydrocinnamaldehyde (268 mg, 2.0 mmol) was added as
a solution in THF (10 mL). After stirring at −78 °C for 5 min, the
reaction was quenched with sat. aq. NH4Cl (10 mL), then allowed
to warm to room temperature. The separated organic layer was dried
over MgSO4 and concentrated (rotary evaporator, followed by high
vacuum).
1
(10% EA/Hex); H NMR: 7.30−7.26 (m, 2H), 7.21−7.17 (m, 3H),
4.82−4.80 (m, 1H), 4.69−4.63 (m, 2H), 3.66−3.60 (m, 1H), 3.40 (s,
3H), 2.74−2.70 (m, 2H), 2.05−1.95 (m, 2H), 1.60−1.54 (m, 2H),
1.38−1.27 (m, 15H), 0.88 (t, J = 6.80 Hz, 3H); 13C NMR: 141.9,
128.4, 125.9, 101.5, 93.4, 66.9, 55.8, 36.4, 32.0, 30.9, 29.9, 29.7,
29.6, 29.5, 29.4, 26.3, 22.7, 14.2. HRMS (TOF MS ES+) calcd for
C21H36NaO3 (M + Na)+: 359.2562; found: 359.2578; IR: 2925, 2856,
1149, 1000.
3-((3,7-Dimethyloct-6-en-1-yl)oxy)-3-(methoxymethoxy)
Propylbenzene (21d). Using the general procedure described above,
peroxide 8c (244 mg, 0.50 mmol) was reacted with alkoxylithium
generated from reaction of stannane 20 (235 mg, 0.5 mmol) and
n-BuLi (0.31 mL, 1.6 M in Hex, 0.5 mmol) to furnish a mixture of
mixed acetal 21d (48 mg, 28%) accompanied by 3-methoxymethyloxy-
2-methyl-5-phenylpentan-2-ol 22 (23 mg, 20%). NMR analysis of the
crude reaction mixture suggested the presence of 40% of mixed acetal
21d; presumably, some was lost during the separation process. The
mixed acetal 16d was contaminated with a small amount of inseparable
byproduct, which could be removed by subjecting a DCM solution
of the crude reaction mixture to brief (∼1 min) room temperature
K
DOI: 10.1021/acs.joc.5b02043
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The Journal of Organic Chemistry
Article
ozonolysis with 2% O3/O2 (1 mmol O3/min) prior to chromatog-
raphy. The separated byproduct was determined to be 3-methox-
ymethoxypropyl benzene (3 mg, ∼3%), the product of protonation of
the functionalized organolithium reagent.
0.47−1.95 (m, 2H); 13C NMR: 70.7, 52.9, 31.9, 29.68, 29.60, 29.57,
29.5, 29.3, 26.2, 22.7, 14.1, 5.4; HRMS: (TOF-MS CI+) calcd for
C13H27O (M + H)+: 199.2062; found: 199.2057; IR: 2922, 2853, 1453,
1343.
1
21d. Rf = 0.5 (5% EA/Hex); H NMR: 7.32−7.27 (m, 2H), 7.23−
Cyclopropyl 2-Octyl Ether (23d). Using the general procedure
described above, THP peroxide 13b (115 mg, 0.50 mmol) was reacted
with cyclopropyl magnesium bromide (1.3 mL, 0.5 M in THF,
0.65 mmol) to furnish cyclopropyl ether 23d as a colorless oil (60 mg,
7.19 (m, 3H), 5.12 (m, 1H), 4.83 (d, J = 6.8 Hz, 1H), 4.70 (d, J =
6.8 Hz, 1H), 4.68−4.66 (m, 1H), 3.73−3.64 (m, 1H), 3.52−3.44 (m,
1H), 3.43 (s, 3H), 2.74 (m, 2H), 2.08−1.91 (m, 4H), 1.70 (s, 3H),
1.68−1.56 (m, 2H), 1.62 (s, 3H), 1.49−1.31 (m, 2H), 1.28−1.14 (m,
1H), 0.93−0.91 (m, 3H); 13C NMR: 141.7, 131.2, 128.4, 128.4,
128.39, 125.8, 124.7, 101.5, 101.4, 93.3, 64.9, 64.8, 55.7, 37.2, 37.1,
36.8, 36.78, 36.39, 30.83, 29.5, 25.7, 25.5, 19.6, 19.5, 17.6; HRMS
(TOF-ESI+) calcd for C21H34O3Na (M + Na)+: 357.2406; found
357.2401; IR: 2927, 1454, 1369, 1002.
1
70%): Rf = 0.6 (10% EA/Hex); H NMR: 3.57−3.49 (m, 1H), 3.33−
3.29 (m, 1H), 1.41−1.23 (m, 10H), 1.18 (d, J = 6.1 Hz, 3H), 0.89
(t, J = 6.8 Hz, 3H), 0.61−0.56 (m, 1H), 0.54−0.51 (m, 1H), 0.49−
0.47 (m, 1H), 0.46−0.40 (m, 1H); 13C NMR: 75.7, 50.7, 36.6, 31.8,
29.4, 25.4, 22.6, 19.9, 14.0, 5.96, 5.42; HRMS (TOF-MS EI+) calcd for
C11H22O (M)+: 170.1671; found: 170.1678; IR: 2927, 2857, 1452,
1373.
3-Methoxymethyloxy-2-methyl-5-phenylpentan-2-ol (22).
1
Rf = 0.3 (15% EA/Hex); H NMR: 7.33−7.27 (m, 2H), 7.22−7.20
t-Butyl 1,1-Dimethyl-2-Phenylethyl Peroxide (24a). [133476-
12-7]: 2-Bromo-2-methylpropyl benzene [23264-13-3] was prepared
(3.79 g, 88%) as a colorless liquid from the corresponding alcohol
(3 g, 20 mmol) using a modification of a reported procedure.40b
Spectral data matched those in a previous report.77 Rf = 0.8 (25%
(m, 3H), 4.84 (d, J = 6.7 Hz, 1H), 4.69 (d, J = 6.7 Hz, 1H), 3.58 (s,
1H), 3.49 (s, 3H), 3.29 (m, 1H), 2.94−2.87 (m, 1H), 2.66−2.58 (m,
1H), 1.88−1.81 (m, 1H), 1.78−1.70 (m, 1H), 1.19 (s, 3H), 1.15 (s,
3H); 13C NMR: 141.9, 128.5, 128.4, 125.9, 99.2, 89.9, 72.0, 56.0,
33.5, 32.7, 26.3, 23.7. HRMS (TOF-ESI+) calcd for C14H22O3Na
(M + Na)+: 261.1467; found: 261.1483; IR: 3461, 2930, 2889, 1028.
3-Methoxymethoxypropylbenzene [91898-11-2] has been reported
on multiple occasions without NMR characterization: Rf = 0.5 (20%
1
EA/Hex); H NMR: 7.35−7.26 (m, 5H), 3.22 (s, 2H), 1.78 (s, 6H);
13C NMR: 137.3, 130.9, 128.0, 127.0, 66.6, 53.4, 33.9.
The t-buyl peroxide was prepared from the bromide (1.89 g
8.9 mmol, 1 equiv) through reaction with t-BuOOH (1.94 mL, 5.5 M
in decane 1.2 equiv, 10.6 mmol), and silver trifluoroacetate (2.34 g,
10.6 mmol 1.2 equiv) using a reported procedure.40a Following a
workup which includes brief exposure to NaBH4 to destroy the
trifluoroacetate ester, peroxide 24a was isolated as a colorless oil
(0.79 g, 40%), which was only modestly responsive to the “peroxide”
TLC stain (see the General Experimental section) even after warming:
Rf = 0.7 (10% EA/Hex). Spectral properties matched those in
literature reports.40a
1
EA/Hex); H NMR: 7.33−7.28 (m, 2H), 7.23−7.18 (m, 3H), 4.66
(s, 3H), 3.57 (t, J = 6.4 Hz, 2H), 3.39 (s, 3H), 2.73 (t, J = 7.8 Hz, 2H),
1.99−1.89 (m, 2H); 13C NMR: 141.9, 128.4, 128.3, 125.8, 96.5, 67.1,
55.2, 32.4, 31.4.
General Procedure for Synthesis of Cyclopropyl Ethers. The
THP monoperoxyacetal (0.50 mmol) was dissolved in dry THF
(5 mL), and the solution cooled to 0 °C. Cyclopropyl magnesium
bromide (1.3 mL, 0.5 M in THF, 0.65 mmol) was then added. The
cooling bath was removed, and the reaction was stirred for 45 min
prior to quenching by sequential dilution with 1 M aq. hydrochloric
acid (∼2 mL) and water (10 mL). The addition of HCl clarified a
previously hazy solution. The combined Hex extracts (20 mL × 2)
were dried over Na2SO4 and concentrated on a rotary evaporator. The
residue was purified by silica gel chromatography (5 in. tall; 0.5 in.
diameter) using 1−2% EA/Hex, with fraction concentrated initially at
80−120 mm. (rotary evaporator, rt) and at 0.5 mm (1 min, 0 °C).
3,7-Dimethyloct-6-en-1-yl Cyclopropyl Ether (23a). Using the
general procedure described above, THP peroxide 8b (128 mg,
0.50 mmol) was reacted with cyclopropyl magnesium bromide
(1.3 mL, 0.5 M in THF, 0.65 mmol) to furnish cyclopropyl ether
23a as a colorless oil (80 mg, 80%): Rf = 0.52 (10% EA/Hex);
1H NMR: 5.13−5.09 (m, 1H), 3.58−3.48 (m, 2H), 3.28−3.24
(m, 1H), 2.05−1.91 (m, 2H), 1.70 (s, 3H), 1.62 (s, 3H), 1.58−1.49
(m, 2H), 1.42−1.31 (m, 2H), 1.23−1.09 (m, 1H), 0.91 (d, J = 6.5 Hz,
3H), 0.58−0.54 (m, 2H), 0.48−0.43 (m, 2H); 13C NMR: 131.1, 124.8,
68.9, 52.9, 37.2, 36.6, 29.5, 25.7, 25.4, 19.5, 17.6, 5.45, 5.41; HRMS
(TOF-MS CI+) calcd for C13H25O (M + H)+: 197.1905; found:
197.1913; IR: 2960, 2916, 1452, 1342.
Cyclopropyl 3-Phenylpropyl Ether (23b). Using the general
procedure described above, THP peroxide 9b (118 mg, 0.50 mmol)
was reacted with cyclopropyl magnesium bromide (1.3 mL, 0.5 M in
THF, 0.65 mmol) to furnish cyclopropyl ether 23b as a colorless oil
(64 mg, 72%): Rf = 0.46 (10% EA/Hex); 1H NMR: 7.32−7.29
(m, 2H), 7.22−7.19 (m, 3H), 3.52 (t, J = 6.4 Hz, 2H), 3.28 (app
septet, likely tt, J = 3.0, 6.0 Hz, 1H), 2.70 (t, J = 7.7 Hz, 2H), 1.94−
1.87 (m, 2H), 0.61−0.57 (m, 2H), 0.49−0.45 (m, 2H); 13C NMR:
141.9, 128.4, 128.3, 125.8, 69.7, 53.0, 32.4, 31.2, 5.5; HRMS:
(TOF-MS EI+) calcd for C12H16O (M+): 176.1201; found:
176.1199; IR: 3031, 2938, 2850, 1452, 1342.
Triethylsilyl (2-Methyl-1-phenylpropan-2-yl) Peroxide (24d).
[830345-47]: 2-Methyl-3-phenyl-1-propene (0.66 g, 5 mmol) and
Et3SiH (1.16 g, 10 mmol) were sequentially added to a solution of
Co(acac)2 (0.50 mmol) in ethanol (15 mL).41 The reaction mixture
was stirred under an atmosphere of O2 (balloon) until no starting
material was observed (TLC, ∼14 h). The residue obtained upon
concentration in vacuo was purified by silica gel chromatography using
1−8% EA/Hex to furnish 24d (0.95 g, 68%) as a colorless oil. The
molecule has previously been reported without NMR character-
ization:41b Rf = 0.7 (10% EA/Hex); H NMR: 7.28−7.18 (m, 5H),
1
2.88 (s, 2H), 1.16 (s, 6H), 1.00 (m, J = 7.9 Hz, 9H), 0.70 (q, J =
7.9 Hz, 6H); 13C NMR: 138.3, 130.8, 127.8, 126.1, 82.6, 44.8, 24.3,
6.9, 4.0.
2-((2-Methyl-3-phenylpropan-1-yl)tetrahydro-2H-pyranyl
Peroxide (24b). To a 0 °C solution of silyl peroxide 24d (0.70 g,
2.5 mmol) in THF (6 mL) was added n-Bu4NF (3 mL, 1 M in THF,
∼3 mmol). After 10 min, the reaction was diluted with 50 mL of Hex
and the resulting solution was washed with water (2 × 5 mL). The
dried (Na2SO4) organic layer was concentrated, and the residue was
purified through a short plug of silica (10% EA/hexane) to furnish
2-hydroperoxy-2-methylpropyl)benzene [1944-83-8] as a colorless
oil (0.41 g, 98%), which displayed spectral data matching literature
reports.78 Rf = 0.35 (10% EA/hex).
The crude hydroperoxide (0.40 g, 2.4 mmol) and dihydropyran
(0.2 g, 2.4 mmol) were reacted using method B to furnish mono-
peroxyacetal 24b as a colorless oil (0.397 g, 66%): Rf = 0.42 (10%
EA/Hex); 1H NMR: 7.29−7.19 (5H), 5.12 (m, 1H), 4.06
(m, 1H), 3.63 (m, 1H), 2.97 (d, J = 13.5 Hz, 1H), 2.86 (d, J = 13.5
Hz, 1H), 1.79−175 (m, 2H), 1.67−1.59 (m, 4H), 1.25 (s, 3H), 1.18
(s, 3H); 13C NMR: 138.0, 130.7, 127.9, 126.2, 101.2, 82.9, 62.8,
45.0, 27.9, 25.3, 24.7, 24.3, 20.1. HRMS (TOF-MS-ES+) calcd for
C15H22NaO3 (M + Na): 273.1461; found: 273.1461; IR: 2928, 2856,
1451.
Cyclopropyl Decyl Ether (23c). Using the general procedure
described above, THP peroxide 12b (129 mg, 0.50 mmol) was reacted
with cyclopropyl magnesium bromide (1.3 mL, 0.5 M in THF,
0.65 mmol) to furnish cyclopropyl ether 23c as a colorless oil (79 mg,
Reaction of Monoperoxyacetal 24b with Organometallic Reagents.
2-Butoxy-2-methylpropylbenzene (25a). Using the procedure
described for reaction of n-BuLi with THP monoperoxyacetals,
reaction of 24b (125 mg, 0.50 mmol) with n-BuLi (0.34 mL, 1.6 M
in Hex, 0.55 mmol) at −78 C for 15 min furnished, after workup and
1
80%): Rf = 0.56 (10% EA/Hex); H NMR: 3.49 (t, J = 6.7 Hz, 2H),
3.26 (app septet, likely tt, J = 3.0, 6.0 Hz, 1H), 1.58−1.54 (m, 2H),
1.34−1.27 (m, 14H), 0.89 (t, J = 7.0 Hz, 3H), 0.57−0.55 (m, 2H),
L
DOI: 10.1021/acs.joc.5b02043
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
chromatography, recovered 24b (9 mg, 7%), alcohol 26 (15 mg, 10%),
and butyl ether 25a (56 mg, 55%).
25a. Colorless oil; Rf = 0.75 (10% EA/Hex); H NMR: 7.29−7.26
(m, 3H); 4.00 (t, J = 6.3 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H), 2.18
(m, 2H); 13C NMR: 159.1, 141.7, 129.5, 128.6, 128.5, 126.0, 120.7,
114.7, 66.9, 32.3, 30.9.
1
Reactivity of Methoxyethoxy Alkyl Peroxide. Using the
general procedure for etherification described above, methoxyethoxy
peroxide 9e (105 mg, 0.5 mmol) was reacted with n-BuLi (0.34 mL,
1.6 M in Hex, 0.55 mmol) to furnish 3-butoxypropyl benzene
(28, 25 mg, 26%) as a colorless oil, accompanied by a small amount
(4 mg, 6%) of 3-phenyl-1-propanol.
Note on Safety. Although no safety issues were encountered in the
course of this work, any preparative work with peroxides should be
conducted with an awareness of the potential for spontaneous and
exothermic decomposition reactions. The reader is directed to a web-
published collection of peroxide-related safety information.80
(m, 2H), 7.23−7.19 (m, 3H), 3.42 (t, J = 6.6 Hz, 2H), 2.79 (s, 2H),
1.59−1.52 (m, 2H), 1.44−1.35 (m, 2H), 1.14 (s, 6H), 0.94 (t, J =
7.3 Hz, 3H); 13C NMR: 138.8, 130.7, 127.8, 126.0, 74.9, 61.2, 47.2,
32.8, 25.3, 19.6, 14.1; HRMS (TOF MS EI+) calcd for C14H22O (M)+:
206.1671; found: 206.1677; IR: 2956, 2927, 1453, 1362, 1080.
(2-Hexyloxy-2-methylpropyl)benzene (25b). By the general
procedure described for reaction of Grignard reagents with mono-
peroxyacetals, a solution of 24c (125 mg, 0.5 mmol) in THF (3 mL)
was reacted with hexylMgBr (0.60 mL, 2 M in ether, 2.4 equiv) to
furnish, after workup and chromatography, hexyl ether 25b as a
colorless oil (88 mg, 75%): Rf = 0.75 (10% EA/Hex); 1H NMR: 7.29−
7.25 (m, 2H), 7.22−7.19 (m, 3H), 3.41 (t, J = 6.7 Hz, 2H), 2.78 (s,
2H), 1.60−1.52 (m, 2H), 1.39−1.30 (m, 6H), 1.14 (s, 6H), 0.91 (t, J =
6.8 Hz, 3H); 13C NMR: 138.8, 130.7, 127.8, 126.0, 74.9, 61.5, 47.1,
31.9, 30.7, 26.1, 25.3, 22.7, 14.2. HRMS Calcd for C16H26ONa
(M + Na)+: 257.1879; found: 257.1881; IR: 2956, 2927, 1453, 1362,
1080.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02043.
Reaction of t-Butyl Peroxide Probe 24a with n-BuLi. Using the
general procedure described for reaction of n-BuLi with THP
peroxides as above, peroxide 24a (222 mg, 1.0 mmol) was reacted
with n-BuLi (0.62 mL, 1.6 M in Hex, 1.1 mmol) at room temperature
for 5 h to furnish, following workup and chromatography, the
following products: unreacted starting material (101 mg, 45%);
alcohol 26 (48 mg, 32%); and pentylbenzene (5 mg, 3%): 2-Methyl-1-
phenylpropan-2-ol (26) [100-86-7]: colorless oil; Rf = 0.35 (10%
Optimized coordinates, electronic energies, and zero-
point vibrational energies of all minima and transition
states considered in Scheme 6; thermal analysis of 10a
1
and 10b; H and 13C spectra of new molecules (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: pdussault1@unl.edu.
■
1
EA/Hex); H NMR: 7.33−7.21 (m, 5H), 2.77 (s, 2H), 1.23 (s, 6H);
13C NMR: 137.9, 130.5, 128.3, 126.6, 70.8, 49.8, 29.2. Pentyl benzene
1
Notes
[538-68-1]: colorless oil; Rf = 0.8 (10% EA/Hex); H NMR: 7.31−
The authors declare no competing financial interest.
7.29 (m, 2H), 7.23−7.19 (m, 3H), 2.63 (t, J = 7.7 Hz, 2H), 1.67−1.62
(m, 2H), 1.40−1.33 (m, 4H), 0.93 (t, J = 7.0 Hz, 3H); 13C NMR:
142.9, 128.4, 128.2, 125.5, 35.9, 31.5, 31.2, 22.5, 14.0.
ACKNOWLEDGMENTS
■
Reaction of Silyl Peroxide Probe 24d with n-BuLi. Peroxide 24d
(280 mg, 1.0 mmol) was reacted with n-BuLi (0.62 mL, 1.6 M in Hex,
1 mmol) at room temperature for 6 h, to furnish a mixture of products
which were separated by chromatography: recovered 24d (115 mg,
41%); Et3SiOH (15 mg, 24%); pentylbenzene (16 mg, 11%) and
alcohol 26 (15 mg, 10%).
We thank the NSF (CHE-1057982 and CHE-1464914) for
support and Profs. James Takacs, Andrzej Rajca, and Stephen
DiMagno for useful discussions. Portions of this research were
conducted in facilities renovated with support from the NIH
(RR0116544-01).
Triethylsilanol [597-52-4]. Colorless oil; Rf = 0.5 (10% EA/Hex);
1H NMR: 1.49−1.44 (bs, 1H), 0.99 (t, J = 8.0 Hz, 9 H), 0.618
(q, J = 8.0 Hz, 6H); 13C NMR: 6.58, 5.79.
REFERENCES
■
(1) (a) Forsyth, C. J., Ed. Science of Synthesis, v. 27: Ethers; George
Thieme Verlag: Stuttgart, 2008; p 992. (b) Shade, R. E.; Hyde, A. M.;
Olsen, J.-C.; Merlic, C. A. J. Am. Chem. Soc. 2010, 132, 1202.
(2) Leading references to metal-catalyzed etherification: (a) Hartwig,
J. F. Acc. Chem. Res. 1998, 31, 852. (b) Gowrisankar, S.; Sergeev, A. G.;
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Int. 2013, 45, 341.
Competition for n-BuLi: Monoperoxyacetal vs Peroxide. To
a −78 °C solution containing peroxyacetal 12b (0.50 mmol, 129 mg)
and peroxide 9a (0.50 mmol, 104 mg) in THF (3 mL) was added
n-BuLi (0.31 mL, 1.6 M in Hex, 0.50 mmol). The reaction was
quenched after 3 min with an excess of water to furnish, as a colorless
oil, n-butyl decyl ether (27, 70 mg, 65%) accompanied by recovered 9a
(90 mg, 86%). Butyl decyl ether (27) [111082-32-7]: Rf = 0.8
1
(10% EA/Hex); H NMR: 3.41−3.37 (m, 4H), 1.61−1.51 (m, 4H),
1.41−1.26 (m, 16H), 0.91 (t, J = 7.4 Hz, 3H); 0.87 (t, J = 6.8 Hz, 3H);
13C NMR: 71.1. 70.7, 32.02. 32.00, 29.9, 29.73, 29.69, 29.62, 29.4, 26.3,
22.8, 19.5, 14.2, 14.0.
(3) Example of electrophile-promoted etherification: Larrosa, I.;
Romea, P.; Urpí, F. Tetrahedron 2008, 64, 2683.
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Competition for Monoperoxyacetal: n-BuLi vs PhLi. Solutions
of n-BuLi (0.47 mL, 0.762 mmol, 1.6 M in Hex) and PhLi (0.42 mL,
0.762 mmol, 1.8 M in dibutyl ether, 0.42 mL) were sequentially drawn
into the same 1 mL syringe, and the contents were rapidly added to a
rapidly stirring −78 °C solution of 9b (0.762 mmol, 180 mg) in dry
THF (5 mL). The reaction was quenched at −78 C after 5 min to
furnish dialkyl ether 28 (78 mg, 53%), phenyl alkyl ether 29 (30 mg,
19%), and biphenyl (5 mg, 4%): 3-Butoxypropyl benzene (28):
Spectral data were nearly identical to those previously reported.79
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1
Rf = 0.7 (10% EA/Hex); H NMR: 7.32−7.28 (m, 2H), 7.23−7.20
(m, 3H), 3.46−3.43 (m, 4H), 2.72 (t, J = 7.6 Hz, 2H), 1.95−1.91 (m,
2H), 1.63−1.57 (m, 2H)1.44−1.40 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H);
13C NMR: 142.1, 128.5, 128.3, 125.7, 70.7, 69.9, 32.4, 31.9, 31.3, 19.4,
14.0. 3-Phenoxy propyl benzene [64806-63-9] (29): Colorless oil;
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1
Rf = 0.6 (10% EA/Hex); H NMR: 7.34−7.21 (m, 7H); 6.99−6.92
M
DOI: 10.1021/acs.joc.5b02043
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