Chemiluminescence-promoted oxidation of alkyl enol ethers by NHPI under mild conditions and in the dark

Article abstract of DOI:10.1016/j.tet.2020.131874

The hydroperoxidation of alkyl enol ethers using N-hydroxyphthalimide and molecular oxygen occurred in the absence of catalyst, initiator, or light. The reaction proceeds through a radical mechanism that is initiated by N-hydroxyphthalimide-promoted autoxidation of the enol ether substrate. The resulting dioxetane products decompose in a chemiluminescent reaction that allows for photochemical activation of N-hydroxyphthalimide in the absence of other light sources.

Full text of DOI:10.1016/j.tet.2020.131874

Tetrahedron 82 (2021) 131874
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chemiluminescence-promoted oxidation of alkyl enol ethers by NHPI
under mild conditions and in the dark
T.E. Anderson, Alexander A. Andia, K.A. Woerpel*
Department of Chemistry, New York University, 100 Washington Square East, New York, NY, 10003, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The hydroperoxidation of alkyl enol ethers using N-hydroxyphthalimide and molecular oxygen occurred
in the absence of catalyst, initiator, or light. The reaction proceeds through a radical mechanism that is
initiated by N-hydroxyphthalimide-promoted autoxidation of the enol ether substrate. The resulting
dioxetane products decompose in a chemiluminescent reaction that allows for photochemical activation
of N-hydroxyphthalimide in the absence of other light sources.
Received 9 October 2020
Received in revised form
7 December 2020
Accepted 9 December 2020
Available online 24 December 2020
© 2020 Elsevier Ltd. All rights reserved.
Keywords:
Enol ether
Oxidation
Radical
NHPI
Dark
Autoxidation
Chemiluminescence
1. Introduction
with aryl- and alkyl-substituted enol ethers to generate b-hydro-
peroxy-N-alkoxyamine acetal products, and it exhibits chemo-
selectivity in the presence of other alkenes or alkynes. The
oxidation reaction occurs through a radical mechanism that does
not require heat or light, and is instead initiated by NHPI-promoted
autoxidation of the enol ether. The resulting chemiluminescent
autoxidation pathway provides both chemical and photochemical
means by which the radical addition reaction can be initiated.
Enol ethers are versatile building blocks in organic synthesis
that have been utilized in oxidation reactions [1,2], cyclizations [3],
carbonecarbon bond forming reactions [4e6], and protection of
hydroxyl groups [7], among other transformations. While the
reactivity of silyl enol ethers, as well as more highly reactive boron
enolates and metal enolates, have been extensively researched over
the past several decades [8,9], transformations involving less
reactive alkyl enol ethers have remained relatively underdeveloped
[10]. Oxidation reactions involving alkyl enol ethers, which are far
less prevalent than those involving silyl enol ethers [11e17], pre-
dominantly rely on the use of metal catalysts [18e20]. While less
reactive than their silyl counterparts, alkyl enol ethers may be ex-
pected to undergo similar transformations, that, when paired with
their relative stability, make them uniquely useful [21e23]. The
identification of reactions unique to alkyl enol ethers, that proceed
under mild conditions, is thus desirable.
2. Results/discussion
We recently reported a strain-promoted oxidation of alkylide-
necyclopropanes with NHPI under mild conditions (Scheme 1) [24].
The reaction proceeds through a radical pathway that does not
require stabilized intermediates such as those involved in oxida-
tions of styrene and enyne derivatives [25e31], but is rather driven
by strain-induced destabilization of the starting alkene. We hy-
pothesized that unstrained alkenes with suitable electronic acti-
vation could undergo oxidation in the presence of NHPI, whether
through destabilization of the starting material or stabilization of
the radical intermediate.
Herein, we report the oxidation of enol ethers with molecular
oxygen and N-hydroxyphthalimide (NHPI) under mild conditions
and in the absence of catalyst (Scheme 1). The reaction proceeds
Enol ethers were promising candidates for reaction with the
electrophilic phthalimide-N-oxyl (PINO) radical due to their
electron-rich character and the potentially stabilizing effect of the
* Corresponding author.
E-mail address: kwoerpel@nyu.edu (K.A. Woerpel).
https://doi.org/10.1016/j.tet.2020.131874
0040-4020/© 2020 Elsevier Ltd. All rights reserved.

T.E. Anderson, A.A. Andia and K.A. Woerpel
Tetrahedron 82 (2021) 131874
Scheme 1. NHPI-mediated oxidation of alkenes.
oxygen atom on
(methoxymethylene)cyclohexane (4a) with NHPI (2) in an oxygen
atmosphere resulted in the formation -hydroperoxy-N-alkoxy-
a radical intermediate [32]. Treatment of
b
amine acetal 5a (Table 1). The yield of 5a was substantially reduced
at a higher reaction concentration (Table 1, entry 3), while smaller
changes to yield were observed when more dilute concentrations
were employed (Table 1, entries 4,5). This sensitivity to concen-
tration is indicative of a radical pathway that can undergo self-
termination through dimerization or other undesired side re-
actions [33]. The reaction yield was also highly dependent upon the
use of an oxygen atmosphere (Table 1, entry 6), and it proceeded
most efficiently in solvents that could dissolve oxygen best, such as
acetonitrile and acetone (Table 1, entries 8,9) [34]. The reaction
proceeded largely independently of any light source, and the
absence of any light resulted in the highest yield (Table 1, entries
4,7,8).
The oxidation reaction was general for a number of different
enol ethers (Scheme 2). Trisubstituted enol ethers 4ae4h all reac-
ted under the present conditions to give their respective
b-
Table 1
Optimization of reaction conditions in the oxidation of (methoxymethylene)cyclo-
hexane (4a) with NHPI.
Scheme 2. Scope of NHPI-mediated oxidation of enol ethersa.
hydroperoxy-N-alkoxyamine
acetals.
Carbonyl
groups,
Entry
Conc. (M)
Solvent
Light
Oxidant
Yielda
carbonecarbon double bonds, and carbonecarbon triple bonds
were all tolerated. Ketone 5g′, observed in addition to peroxide 5g
following treatment of enol ether 4g under the present conditions,
likely arises through a Criegee rearrangement of 5g [35]. The
involvement of an aryl-stabilized radical intermediate was not
necessary in the case of trisubstituted enol ethers, as was evidenced
by the comparable yields of alkyl- and aryl-substituted substrates
4aed and 4eeh, respectively. Stabilization with an aryl group was
necessary for reaction with disubstituted enol ether 3i, however, as
treatment of non-stabilized disubstituted enol ether 4n with NHPI
and oxygen resulted in formation of both regioisomers 5n and 5n’
in similar amounts (Scheme 3). Regioselectively was restored in the
1
2
3
4
5
6
7
8
0.1
0.1
0.3
MeCN
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Ambient
Dark
O2
O2
O2
O2
O2
Air
O2
O2
O2
O2
O2
50%
55%
16%
58%
52%
31%
59%
69%
53%
41%
20%
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
MeCN
0.05
0.01
0.05
0.05
0.05
0.05
0.05
0.05
9
10
11
Dark
Dark
Dark
1,4-Dioxetane
DCE
a
Yields determined by 1H NMR spectroscopy of the unpurified reaction mixture
using mesitylene as an internal standard.
2

T.E. Anderson, A.A. Andia and K.A. Woerpel
Tetrahedron 82 (2021) 131874
NMR spectroscopy. The addition of NHPI to 4e resulted in the rapid
and concurrent formation of acetophenone and peroxide product,
as detected by TLC.
Autoxidation of alkenes with triplet oxygen likely involves the
direct addition of triplet oxygen to the alkene, rather than forma-
tion of an initial charge-transfer complex [60]. Direct addition
would form the triplet diradical 3A (Scheme 5) [53,60]. Formation
of dioxetane 4 through radical recombination of 3A is a spin-
forbidden process that can only occur following intersystem
crossing (ISC) to form the singlet diradical 1A [61]. The slow rate of
autoxidation in the absence of NHPI suggests that intersystem
crossing is largely outcompeted by the dissociation of dioxygen to
reform enol ether 4a and triplet oxygen.
NHPI may promote autoxidation through stabilization of triplet
diradical 3A, thereby allowing time for the formation of the singlet
species 1A through ISC. In the absence of hydrogen bonding, the
difference in energy between the transition state of addition and
the resulting triplet diradical should be small (0.3 kcal/mol) [53].
NHPI, however, may provide stabilization through hydrogen
bonding, both within the transition state TS1 of the addition of
triplet oxygen to 3a, as well as in the resulting triplet diradical
through complex 3A’ (Scheme 5). Such hydrogen bonding between
the methoxy group of the enol ether and the peroxyl radical should
result in a larger energy difference between the transition state and
the diradical intermediate (0.7 kcal/mol) [53], thereby allowing
more time for the conversion of 3Ae1A.
Autoxidation of enol ethers is also promoted in the presence of
other highly polarized hydrogen bond donors. Treatment of enol
ether 4e with N-hydroxysuccinimide (NHS) or acetic acid under an
oxygen atmosphere both resulted in the formation of acetophe-
none 7e (Scheme 6). The higher yields of 7e observed in these re-
actions compared to that of treatment with NHPI is likely due to the
absence of any competing radical addition pathway, as no addition
products were observed in either reaction. The absence of any
subsequent addition reaction in these hydrogen bond-promoted
autoxidation reactions of 4e suggests that these two processes
occur discretely in the case of the NHPI-promoted oxidations of
enol ethers.
The decomposition of dioxetane 6 to form cyclohexanone 7a
and methylformate is a chemiluminescent reaction that is accom-
panied by the emission of blue light (lmax ¼ 420 nm) [62e65].
Given the use of blue light to induce formation of the PINO radical
in previous reports [27,66,67], we explored the possibility that this
chemiluminescence could drive formation of the PINO radical in
the absence of other light sources.
Scheme 3. Oxidation of disubstituted enol ether 4n.
case of monosubstituted enol ether 4j to give peroxyacetal 5j in
moderate yields, although exposure to blue LED light was necessary
for the reaction to proceed. Exposure to blue light was also
necessary for the oxidation of silyl enol ether 4k. The a,b-unsatu-
rated enol ether 4l did not react to give peroxide 5l, nor was
enamine 4m reactive under the present conditions.
NHPI-mediated oxidations generally proceed through radical
pathways that require conversion of NHPI to the PINO radical
through homolytic cleavage of the hydrogeneoxygen bond [32].
The present reaction also appears to proceed through a radical
pathway, as is evidenced by the complete inhibition of the reaction
in the presence of the radical traps (2,2,6,6-tetramethylpiperidin-1-
yl)oxyl (TEMPO) and butylated hydroxytoluene (BHT, Scheme 4A).
While initiation to form the PINO radical generally depends upon
light [27,36e38], heat [39e42], or catalyst [25,26,28,29,32,43e45]
as an external source of activation, we recently reported formation
of the PINO radical through interaction with a minor autoxidation
side reaction in the oxidation of alkylidenecyclopropanes [24]. The
presence of cyclohexanone 7a in the unpurified reaction mixture
following treatment of 4a with NHPI suggests that a similar
autoxidation reaction is occurring in the case of oxidations of enol
ethers, and that the formation and decomposition of a dioxetane
intermediate is likely (Scheme 4B).
The generation of cyclohexanone 7a appears to involve a radical
mechanism characteristic of triplet oxygen, as evidenced by the
susceptibility of the reaction to radical trapping and the ability of
the reaction to proceed in the dark. Although the addition of mo-
lecular oxygen to alkenes more commonly involves the excited
singlet state of oxygen [46], triplet oxygen can add to alkynes [47],
alkenes [48e51], and enols [52e59].
The rate of autoxidation of the alkyl enol ethers was enhanced in
the presence of NHPI. While cyclohexanone and acetophenone
were observed in samples of 4a and 4e, respectively, following one
week of storage at 4 ꢀC, exposure of either of these enol ethers to an
oxygen atmosphere in acetone for 16 h did not result in the for-
mation of autoxidation products at a level detectable by TLC or
Inhibition of the oxidation reaction of enol ethers by lumines-
cence quenching indicates that light plays a role in the reaction
Scheme 4. Mechanistic experiments.
Scheme 5. NHPI-promoted autoxidation of 4a.
3

T.E. Anderson, A.A. Andia and K.A. Woerpel
Tetrahedron 82 (2021) 131874
Scheme 6. Hydrogen bond-promoted autoxidation of 4e. aYields determined by 1H
NMR spectroscopy of the unpurified reaction mixture using mesitylene as an internal
standard.
even in the dark. Treatment of enol ether 4a with NHPI in the
presence of methyl orange 8, a dye with a peak absorption at
460 nm [68], in the dark resulted in a concentration-dependent
inhibition of the oxidation reaction (Table 2, entries 2,3). Reac-
tivity in the presence of methyl orange was restored with exposure
to blue light, suggesting that the inhibitory effect is light-
dependent (Table 2, entries 4,5).
Photometric analysis of the oxidation reaction of 4a over time
revealed a small but detectable emission of light from the reaction
mixture (Fig. 1). By the second hour of the reaction, chem-
iluminescence was detected in the reaction mixture, and this
chemiluminescence persisted over the next several hours.
Based on the above experiments, a reaction mechanism is pro-
posed in Scheme 7. NHPI-promoted autoxidation of enol ether 4a
results in formation of dioxetane 6. Decomposition of 6 yields
cyclohexanone (7a) and methyl formate (9) in a chemiluminescent
reaction that induces homolytic cleavage of the hydrogeneoxygen
bond in NHPI to form the PINO radical. While the PINO radical may
also form through the interaction of NHPI with the diradical
Fig. 1. Chemiluminescence during reaction of 4a with NHPIa. Error bars represent
standard deviation (n ¼ 10). asterisks represent statistically significant differences in
the number of counts compared to measurements of MeCN (p < 0.01).
intermediates 3A or 1A (Scheme 5), the susceptibility of the reaction
to inhibition through luminescence quenching suggests a light-
based pathway for PINO radical initiation (Table 2). Once the
PINO radical is formed, the reaction likely proceeds through a
mechanism similar to those previously reported for oxidations of
alkenes with NHPI [25,27e29,69]. The PINO radical adds across the
alkene to generate alkyl radical B [70], and subsequent addition of
molecular oxygen yields peroxyl radical C. Abstraction of hydrogen
from another molecule of NHPI yields
b-hydroperoxy-N-alkoxy-
amine acetal 5a and regenerates the PINO radical.
The regioselectivity observed in the products of the oxidation
reaction indicates that, for trisubstituted alkenes, steric interactions
are a greater determinant of regiochemistry than the stability of the
resulting radical intermediates. Although an alkyl radical
a to the
methoxy group should be favored over the tertiary alkyl radical
b
Table 2
Inhibition of the peroxidation of (methoxymethylene)cyclohexane (4a) with methyl
orange.
(by 1.9 kcal/mol) [71], no products resulting from this intermediate
were observed from reaction with trisubstituted enol ethers. The
expected HOMO-SOMO interaction between the electron-rich enol
ether and the electrophilic PINO radical should also favor addition
to the
b carbon, where the molecular orbital coefficient is greater
[70,72,73]. Steric effects are nevertheless a strong determinant of
regioselectivity in the addition of even relatively small radicals to
alkenes [70,74,75], and preferential addition to the
a position has
been observed in radical additions to enol ethers [76]. The large
PINO radical may be expected to be highly sensitive to steric effects
within the enol ether substrate.
Generation of the less stable radical intermediate following
addition of the PINO radical may also be rationalized through
consideration of the possible configurations of the three valence
electrons directly involved in the transition state of the reaction
[77,78]. A polarized electron configuration, in which electron den-
sity is localized onto the oxygen atom of the PINO radical, is likely to
be a significant contributor to the transition state due to the
Entry
Light Source
Methyl Orange
Yield of 5a
1
2
3
4
5
Dark
Dark
Dark
Blue LED
Blue LED
None
69%
33%
4%
66%
26%
0.3 equiv
3.0 equiv
0.3 equiv
3.0 equiv
4

T.E. Anderson, A.A. Andia and K.A. Woerpel
Tetrahedron 82 (2021) 131874
Table 3
Alkyl enol ether-activated oxidation of silyl enol ether 4k.
Entry
Equiv 4a
Equiv NHPI
Yield 5ka
Yield 5aa
1
2
3
0
0.1
1
1.2
1.2
2.4
0%
34%
50%
e
49%
45%
a
Yields determined by 1H NMR spectroscopy of the unpurified reaction mixture
using mesitylene as an internal standard.
undergo reaction with triplet oxygen may reflect this decreased
reactivity. The relatively electron-deficient monosubstituted alkyl
enol ether 4j also appears to lack a sufficient degree of electron
density to undergo reaction with triplet oxygen, requiring blue light
for addition to NHPI. The carbonyl group in enol ether 4l renders
the alkene too electron-deficient to react with either triplet oxygen
or the PINO radical, so no reaction was observed. The observed
trends in reactivity cannot be entirely be explained by consider-
ation of nucleophilicity, however, because the highly nucleophilic
enamine 4m failed to react under the present conditions [81]. The
presence of an oxygen atom may be necessary for the formation of
the hydrogen bonds between the enol ether, NHPI, and molecular
oxygen that allow autoxidation to occur (Scheme 6). Even the bulky
trimethylsilyl group may interfere with these interactions, as sug-
gested by the failure of silyl enol ether 4k to undergo autoxidation.
Scheme 7. Proposed reaction mechanism.
electrophilic nature of the PINO radical (Scheme 8). In the case of a-
addition, the resulting carbocation is stabilized through resonance
with the methoxy group (Scheme 8, TS5a). No such resonance
stabilization is possible within the transition state of b-addition,
making this electron configuration relatively unfavorable (Scheme
8, TS5a’).
The enol ether substrates that required blue light in order to
undergo reaction with NHPI are capable of reacting with the PINO
radical, but incapable of inducing its formation through reaction
with triplet oxygen (Scheme 7). Consequently, when silyl enol ether
4k was treated with NHPI in the dark in the presence of alkyl enol
ether 4a, which can induce formation of the PINO radical through
autooxidation, peroxide product 5k was formed in yields compa-
rable to those observed with the use of blue light (Table 3).
The degree of electron density in the alkene is expected to be an
important determinant of success, both for the addition of the enol
ether to the PINO radical as well as for the autoxidation reaction, as
both of these events involve reaction with an electrophilic radical
[32,79]. Silyl enol ethers are less nucleophilic than their alkyl enol
ether counterparts [80], and the inability of silyl enol ether 4k to
It is less clear, however, why an a-oxygen substituent, as opposed to
a nitrogen atom, is necessary for the reaction of the alkene with the
PINO radical.
3. Conclusion
The NHPI-mediated oxidation of enol ethers with molecular
oxygen expands the scope of alkene oxidations and suggests a
novel means by which NHPI can be converted into the reactive
PINO radical. As previously demonstrated with the use of ring strain
[24], the identification of substrates with suitable electronic acti-
vation allows for oxidation of alkenes in the absence of catalyst,
initiator, heat, or light. The utilization of chemiluminescence for
photochemical activation in the dark has been implicated in a
number of biological processes [82], and this work suggests that
there is potential use within synthetic chemistry as well.
4. Experimental section
4.1. General experimental
1H and 13C NMR spectra were obtained at room temperature
using Bruker AV-400 and 100 MHz, Bruker AV-500 and 125 MHz,
and Bruker AVIII-600 and 150 MHz spectrometers, respectively, as
indicated. The data are reported as follows: chemical shift in ppm
referenced to residual solvent (1H NMR: CDCl3
CDCl3
d
7.26; 13C NMR:
77.2, multiplicity (br ¼ broad, s ¼ singlet, d ¼ doublet,
Scheme 8. Transition states in the addition of NHPI to 4a.
d
5

T.E. Anderson, A.A. Andia and K.A. Woerpel
Tetrahedron 82 (2021) 131874
t ¼ triplet, q ¼ quartet, quint ¼ quintet, sept ¼ septet, dd ¼ doublet
of doublets, dt ¼ doublet of triplets, dq ¼ doublet of quartets,
m ¼ multiplet), coupling constants (Hz), and integration. Structures
were determined using COSY, HSQC, and HMBC experiments.
Overlapping carbon peaks were determined using HSQC experi-
ments. High resolution mass spectra (HRMS) were acquired on an
Agilent 6224 Accurate-Mass time-of-flight LC/MS spectrometer
with atmospheric pressure chemical ionization (APCI) or electro-
spray ionization (ESI) sources and were obtained by peak matching.
Infrared (IR) spectra were obtained on a Nicolet 6700 FT-IR spec-
trometer using attenuated total reflectance (ATR). Melting points
are reported uncorrected. Analytical thin layer chromatography
was performed on silica get 60 Å F254 plates. Liquid chromatog-
raphy was performed using forced flow (flash chromatography) of
the indicated solvent system on Silicycle silica gel (SiO2) 60
(230e400 mesh). All reactions were performed under an atmo-
sphere of nitrogen in glassware that had been flame-dried under
vacuum unless otherwise stated. Non-deuterated solvents were
purified via the Pure Solv-MD Standard Design Solvent Purification
System before use. Aqueous solutions were prepared from nano-
for C9H16Na (M þ Na e H2O)þ 147.1144, found 147.1142.
4.2.1.2. 4-(Methoxymethylene)cyclohexan-1-one (4c). To a solution
of 8-(methoxymethylene)-1,4-dioxaspiro [4.5]decane (S1, 0.737 g,
4.00 mmol) in acetone/H2O (132 mL/28 mL, 5:1) was added pyr-
idinium p-toluenesulfonate (0.202 g, 0.800 mmol). The reaction
mixture was heated to 70 ꢀC for 18 h, then poured into saturated
aqueous sodium bicarbonate (150 mL). The solution was extracted
with diethyl ether (3 ꢂ 50 mL), dried over MgSO4, and concentrated
in vacuo. The resulting oil was purified by flash column chroma-
tography (20:80 EtOAc:hexanes) to yield 4-(methoxymethylene)
cyclohexan-1-one (4c) as a colorless oil (0.306 g, 55%): 1H NMR
(400 MHz, CDCl3)
d
5.94 (s, 1H), 3.60 (s, 3H), 2.57e2.51 (m, 2H),
212.1 (C), 141.6
2.41e2.30 (m, 6H); 13C NMR (100 MHz, CDCl3)
d
(CH), 112.6 (C), 59.7 (CH3), 42.3 (CH2), 40.9 (CH2), 28.9 (CH2), 23.9
(CH2); IR (ATR) 2936, 2842, 1709, 1685, 1224, 1122 cmꢁ1; HRMS
(ESI) m/z calcd for C8H13O2 (M þ H)þ 141.0910, found 141.0908.
4.2.1.3. 1-Methoxy-2-methylhepta-1,6-diene (4d). Following the
representative procedure for the synthesis of enol ethers,
pure water with a resistivity over 18 M
U
-cm. For reactions con-
(methoxymethyl)triphenylphosphonium
chloride
(2.06
g,
ducted under blue light, a Feit Electric 7 W blue LED lamp (SKU:
PAR38/B/10KLED/BX) was positioned approximately 10 cm away
from the reaction vessel. All experiments were conducted in bo-
rosilicate glass vessels, which filters frequencies of light below
approximately 280 nm [83]. Chemiluminescence studies were
conducted using a Tecan Spark microplate reader. Unless otherwise
stated, all reagents and substrates were commercially available.
6.00 mmol), potassium tert-butoxide (0.673 g, 6.00 mmol), and
hept-6-en-2-one (S3, 0.561 g, 5.00 mmol) were combined in THF
(25 mL) to give 1-methoxy-2-methylhepta-1,6-diene (4d) as a
mixture of diastereomers in a 1.00:0.85 ratio as a colorless oil
(0.253 g, 36%): 1H NMR (400 MHz, CDCl3)
d 5.90e5.73 (m, 3.7H),
5.05e4.90 (m, 3.7H), 3.57e3.48 (m, 5.55H), 2.10e1.98 (m, 5.55H),
1.88 (t, J ¼ 7.5 Hz, 2H), 1.59e1.56 (m, 3H), 1.53e1.51 (m, 2.55H),
1.50e1.42 (m, 3.55H); 13C NMR (100 MHz, CDCl3)
d 142.1 (CH,
4.2. Reaction procedures and characterization data
major),141.9 (CH, minor),139.3 (CH, minor),139.1 (CH, major),114.5
(CH2, major),114.32 (CH2, minor),114.31 (C, minor),113.9 (C, major),
59.4 (CH3, major), 59.3 (CH3, minor), 33.7 (CH2, minor), 33.5 (CH2,
major), 33.4 (CH2, major), 28.5 (CH2, minor), 27.4 (CH2, major), 26.9
(CH2, minor), 17.3 (CH3, minor), 12.8 (CH3, major); IR (ATR) 2927,
2856, 1684, 1456, 1205, 1134, 909 cmꢁ1; HRMS (ESI) m/z calcd for
C9H20NO (M þ NH4)þ 158.1539, found 158.1547.
4.2.1. Representative procedure for the synthesis of enol ethers
((methoxymethylene)cyclohexane (4a)
According to the procedure of Chepiga et al. [84], to a suspension
of (methoxymethyl)triphenylphosphonium chloride (8.23 g,
24.0 mmol) in dry THF (100 mL) stirring at ꢁ78 ꢀC was added po-
tassium tert-butoxide (2.69 g, 24.0 mmol) in portions. The reaction
mixture was allowed to warm to 0 ꢀC over 20 min, then cooled
to ꢁ78 ꢀC, after which cyclohexanone (2.08 mL, 20.0 mmol) was
added. The reaction mixture was allowed to warm to room tem-
perature and stirred overnight. The reaction mixture was then
washed with saturated aqueous ammonium chloride (2 ꢂ 40 mL)
and brine (2 ꢂ 40 mL), dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The resulting oil was purified by flash col-
umn chromatography (5:95 CH2Cl2:pentane) followed by distilla-
tion at reduced pressure to give (methoxymethylene)cyclohexane
(4a) as a colorless oil (1.75 g, 70%). The NMR spectroscopic data are
in agreement with those previously reported:84 1H NMR (400 MHz,
4.2.1.4. (1-Methoxyprop-1-en-2-yl)benzene (4e). Following the
representative procedure for the synthesis of enol ethers,
(methoxymethyl)triphenylphosphonium
chloride
(4.11
g,
12.0 mmol), potassium tert-butoxide (0.673 g, 12.0 mmol), and
acetophenone (1.17 mL, 10.0 mmol) were combined in THF (50 mL)
to give (1-methoxyprop-1-en-2-yl)benzene (4e) as a mixture of
diastereomers in a 1.00:0.58 ratio as a colorless oil (1.14 g, 77%): 1H
NMR (400 MHz, CDCl3) d 7.63e7.58 (m,1.16H), 7.36e7.26 (m, 5.16H),
7.22e7.14 (m, 1.58H), 6.42 (s, 1H), 6.13 (s, 0.58H), 3.72 (s, 3H), 3.68
(s, 1.74H), 2.00 (s, 3H), 1.93 (1.74H); 13C NMR (100 MHz, CDCl3)
d
145.3 (CH, major), 144.7 (CH, minor), 140.8 (C, major), 138.5 (C,
CDCl3)
d
5.74 (s, 1H), 3.52 (s, 3H), 2.17 (t, J ¼ 5.5 Hz, 2H), 1.93 (t,
minor), 128.5 (CH, major), 128.1 (CH, minor), 127.6 (CH, major),
126.2 (CH, minor), 126.0 (CH, minor), 125.1 (CH, major), 114.6 (C,
major), 111.0 (C, minor), 60.3 (CH3, minor), 60.0 (CH3, major), 18.4
(CH3, minor), 12.7 (CH3, major); IR (ATR) 2932, 2835, 1652, 1442,
1222, 1131, 1075 cmꢁ1; HRMS (ESI) m/z calcd for C10H11 (M þ H e
H2O)þ 131.0855, found 131.0852.
J ¼ 5.5 Hz, 2H), 1.55e1.44 (m, 6H); 13C NMR (100 MHz, CDCl3)
d
138.9 (CH), 118.6 (C), 59.4 (CH3), 30.7 (CH2), 28.5 (CH2), 27.2 (CH2),
27.0 (CH2), 25.6 (CH2); HRMS (ESI) m/z calcd for C8H15O (M þ H)þ
127.1117, found 127.1116.
4.2.1.1. (Methoxymethylene)heptane (4b). Following the represen-
tative procedure for the synthesis of enol ethers, (methoxymethyl)
triphenylphosphonium chloride (8.23 g, 24.0 mmol), potassium
tert-butoxide (2.69 g, 24.0 mmol), and 4-heptanone (2.79 mL,
20.0 mmol) were combined in THF (100 mL) to give (methoxy-
methylene)heptane (4b) as a colorless oil (1.82 g, 64%): 1H NMR
4.2.1.5. (1-Methoxyhepta-1,6-dien-2-yl)benzene (4f). Following the
representative procedure for the synthesis of enol ethers,
(methoxymethyl)triphenylphosphonium
chloride
(2.06
g,
6.00 mmol), potassium tert-butoxide (0.673 g, 6.00 mmol), and 1-
phenylhex-5-en-1-one (S4, 0.871 g, 5.00 mmol) were combined
in THF (25 mL) to give (1-methoxyhepta-1,6-dien-2-yl)benzene (4f)
as a mixture of diastereomers in a 1.00:0.77 ratio as a colorless oil
(400 MHz, CDCl3)
d
5.76 (s, 1H), 3.52 (s, 3H), 2.01 (t, J ¼ 7.6 Hz, 2H),
1.83 (t, J ¼ 7.6 Hz, 2H), 1.43e1.32 (m, 4H), 0.92e0.84 (m, 6H); 13C
NMR (100 MHz, CDCl3)
d
142.3 (CH),118.6 (C), 59.4 (CH3) 33.8 (CH2),
(0.643 g, 64%): 1H NMR (400 MHz, CDCl3)
d 7.50e7.44 (m, 1.54H),
29.0 (CH2), 21.4 (CH2), 21.1 (CH2), 14.2 (CH3), 13.9 (CH3); IR (ATR)
7.35e7.26 (m, 5.54H), 7.22e7.15 (m, 1.77 H), 6.30 (s, 1H), 6.07 (s,
0.77H), 5.92e5.67 (m, 1.77H), 5.03e4.88 (m, 3.54H), 3.69 (s, 3H),
2957, 1740, 1676, 1453, 1137, 1096, 841 cmꢁ1; HRMS (ESI) m/z calcd
6

T.E. Anderson, A.A. Andia and K.A. Woerpel
Tetrahedron 82 (2021) 131874
3.63 (s, 2.31H), 2.55e2.50 (m, 2H), 2.33e2.28 (m, 1.54H), 2.10e2.01
(CH, minor),128.3 (CH, minor),125.9 (CH, minor),125.8 (CH, major),
125.2 (CH, major), 105.8 (CH, minor), 105.2 (CH, major), 60.8 (CH3,
minor), 56.6 (CH3, major); IR (ATR) 2933, 1639, 1455, 1235, 1150,
1095, 934 cmꢁ1; HRMS (ESI) m/z calcd for C9H14NO (M þ NH4)þ
152.107, found 152.1065.
(m, 3.54H),1.52e1.40 (m, 3.54H); 13C NMR (100 MHz, CDCl3)
d 145.5
(CH, major), 144.4 (CH, minor), 139.9 (C, major), 139.1 (CH, major),
138.9 (CH, minor), 137.5 (C, minor), 128.5 (CH, major), 128.3 (CH,
minor), 128.1 (CH, minor), 126.2 (CH, minor), 126.1 (CH, major),
126.0 (CH, major), 119.9 (C, major), 116.5 (C, minor), 114.7 (CH2,
minor), 114.4 (CH2, major), 60.2 (CH3, minor), 60.0 (CH3, major),
33.8 (CH2, major), 33.4 (CH2, minor), 32.1 (CH2, minor), 28.2 (CH2,
minor), 27.6 (CH2, major), 26.6 (CH2, major); IR (ATR) 2929, 1642,
4.2.1.9. (Cyclohexylidenemethoxy)trimethylsilane (4k). To a solution
of cyclohexanecarboxaldehyde (0.489 mL, 4.04 mmol) in acetoni-
trile (6 mL) was added sodium iodide (0.719 g, 4.80 mmol). After
1440, 1221, 1131, 908, 760 cmꢁ1; HRMS (ESI) m/z calcd for C14H19
(M þ H)þ 203.1430, found 203.1429.
O
5 m, triethylamine (0.836 mL, 6.00 mmol) and chloro-
trimethylsilane (0.609 mL, 4.80 mmol) were added and the solution
was stirred overnight. The reaction mixture was then cooled to 0 ꢀC
and hexanes (10 mL) and saturated aqueous ammonium chloride
(10 mL) were added. The organic layer was separated, and the
aqueous layer was extracted with hexanes (2 ꢂ 10 mL). The com-
bined organic layers were washed with ice water (20 mL) and
saturated aqueous ammonium chloride (20 mL), dried over MgSO4,
filtered, and concentrated in vacuo. Purification by flash column
chromatography (pentane) yielded (cyclohexylidenemethoxy)tri-
methylsilane (4k) as a colorless oil (0.625 g, 85%). The NMR spec-
troscopic data are in agreement with those previously reported:
4.2.1.6. (1-Methoxy-3-methylbut-1-en-2-yl)benzene
(4g).
Following the representative procedure for the synthesis of enol
ethers, (methoxymethyl)triphenylphosphonium chloride (2.06 g,
6.00 mmol), potassium tert-butoxide (0.673 g, 6.00 mmol), and
isobutyrophenone (0.750 mL, 5.00 mmol) were combined in THF
(25 mL) to give (1-methoxy-3-methylbut-1-en-2-yl)benzene (4g)
as a mixture of diastereomers in a 1.00:0.40 ratio as a colorless oil
(0.290 g, 33%): 1H NMR (400 MHz, CDCl3)
d 7.35e7.17 (m, 7H), 5.97
(s, 0.4H), 5.93 (s, 1H), 3.64 (s, 3H), 3.56 (s, 1.2H), 3.04 (sept, J ¼ 7.1,
1H), 2.70e2.56 (m, 0.4H), 1.12 (d, J ¼ 7.1, 6H), 1.03 (d, J ¼ 6.8, 2.4H);
[85] 1H NMR (400 MHz, CDCl3)
d
5.99 (s, 1H), 2.17 (t, J ¼ 5.5 Hz), 1.93
13C NMR (100 MHz, CDCl3)
d
145.1 (CH, major), 142.7 (CH, minor),
(t, J ¼ 5.5 Hz), 5.55e5.42 (m, 6H), 0.16 (s, 9H); 13C NMR (100 MHz,
140.1 (C, major), 138.4 (C, minor), 129.1 (CH, minor), 128.6 (CH,
major), 127.99 (CH, minor), 127.95 (CH, major), 126.4 (C, major),
126.3 (CH, minor), 126.2 (CH, major), 124.7 (C, minor), 60.0 (CH3,
minor), 59.9 (CH3, major), 31.5 (CH, minor), 28.6 (CH, major), 22.4
(CH3, minor), 21.5 (CH3, major); IR (ATR) 2958, 2929, 1646, 1220,
1129, 1103, 766 cmꢁ1; HRMS (ESI) m/z calcd for C12H17O (M þ H)þ
177.1274, found 177.1274.
CDCl3) d 130.2 (CH),122.7 (C), 30.7 (CH2), 28.6 (CH2), 27.2 (CH2), 27.1
(CH2), 25.5 (CH2), 0.41 (CH3); HRMS (ESI) m/z calcd for C10H20KOSi
(M þ K)þ 223.0915, found 223.0917.
4.2.1.10. 1-Methoxyhept-1-ene (4n). Following the representative
procedure for the synthesis of enol ethers, (methoxymethyl)tri-
phenylphosphonium chloride (2.06 g, 6.00 mmol), potassium tert-
butoxide (0.673 g, 6.00 mmol), and hexanal (0.614 mL, 5.00 mmol)
were combined in THF (25 mL) to give 1-methoxyhept-1-ene (4n)
as a mixture of diastereomers in a 1.00:0.53 ratio as a colorless oil
4.2.1.7. (1-Methoxyhept-1-en-6-yn-2-yl)benzene
(4h).
Following the representative procedure for the synthesis of enol
ethers, (methoxymethyl)triphenylphosphonium chloride (1.25 g,
3.65 mmol), potassium tert-butoxide (0.410 g, 3.65 mmol), and 1-
phenylhex-5-yn-1-one (S6, 0.524 g, 3.04 mmol) were combined
in THF (15 mL) to give (1-methoxyhept-1-en-6-yn-2-yl)benzene
(4h) as a mixture of diastereomers in 1.00:0.83 ratio as a colorless
(0.457 g, 71%): 1H NMR (400 MHz, CDCl3)
d
6.26 (d, J ¼ 12.6 Hz, 1H),
5.86 (d, J ¼ 6.2 Hz, 0.53 H), 4.73 (dt, J ¼ 7.3, 12.6 Hz, 1H), 4.37e4.30
(m, 0.53H), 3.57 (s, 1.59H), 3.50 (s, 3H), 2.09e2.01 (m, 1.06 H),
1.95e1.87 (m, 2H), 1.37e1.23 (m, 10.71H), 0.91e0.86 (m, 4.59H); 13
C
NMR (100 MHz, CDCl3) d 147.0 (CH, major), 146.1 (CH, minor), 107.3
oil (0.423 g, 69%): 1H NMR (400 MHz, CDCl3)
d
7.49e7.45 (m,1.66H),
(CH, minor), 103.4 (CH, major), 59.6 (CH3, minor), 56.0 (CH3, major),
31.7 (CH2, minor), 31.4 (CH2, major), 30.6 (CH2, major), 29.7 (CH2,
minor), 27.8 (CH2, major), 24.0 (CH2, minor), 22.7 (CH2, major), 22.5
(CH2, minor), 14.24 (CH3, minor), 14.23 (CH3, major); IR (ATR) 2924,
2855, 1655, 1464, 1209, 1107, 931 cmꢁ1; HRMS (ESI) m/z calcd for
C8H15K (M þ K e H2O)þ 150.0805, found 150.0804.
7.36e7.26 (m, 5.66H), 7.22e7.15 (m, 1.83H), 6.33 (s, 1H), 6.12 (s,
0.83H), 3.69 (s, 3H), 3.64 (s, 2.49H), 2.61 (t, J ¼ 7.7 Hz, 2H), 2.43 (t,
J ¼ 7.3 Hz, 1.66H), 2.21e2.13 (m, 3.66H), 1.97e1.92 (m, 1.83H),
1.68e1.54 (m, 3.66H); 13C NMR (100 MHz, CDCl3)
d 145.9 (CH,
major), 144.8 (CH, minor), 139.4 (C, major), 137.0 (C, minor), 128.5
(CH, major), 128.22 (CH, minor), 128.16 (CH, minor), 126.3 (CH,
minor), 126.2 (CH, major), 125.8 (CH, major), 118.8 (C, major), 115.2
(C, minor), 84.8 (C, major), 84.5 (C, minor), 68.6 (CH, minor), 68.3
(CH, major), 60.3 (CH3, minor), 60.1 (CH3, major), 31.3 (CH2, minor),
27.3 (CH2, minor), 27.2 (CH2, major), 26.2 (CH2, major), 18.4 (CH2,
major), 17.7 (CH2, minor); IR (ATR) 3293, 2931, 1646, 1455, 1221,
1130, 760 cmꢁ1; HRMS (ESI) m/z calcd for C14H17O (M þ H)þ
201.1274, found 201.1272.
4.2.2. Representative procedure for peroxidation of enol ethers
(peroxide 5a)
To a foil-covered flask containing acetone (6 mL, sparged with
oxygen for 5 min) was added N-hydroxyphthalimide (NHPI,
0.059 g, 0.36 mmol). The flask was then sealed, and the
(methoxymethylene)cyclohexane (4a, 0.038 g, 0.30 mmol) was
injected by syringe. The reaction mixture was stirred under a
balloon filled with O2 in the dark for 16 h, then concentrated in
vacuo. The resulting solid was suspended in dichloromethane
(6 mL) and the suspension was filtered through a 2-cm plug of
Celite. The filtered solid was washed with dichloromethane
(12 mL), and the combined filtrates were concentrated in vacuo.
Purification of the resulting solid by flash column chromatography
(30:70 EtOAc:hexanes) afforded peroxide 5a as a white solid
(0.063 g, 66%). No melting point was obtained because peroxide 5a
decomposed at a temperature of 150e156 ꢀC: 1H NMR (400 MHz,
4.2.1.8. (2-Methoxyvinyl)benzene (4i). Following the representative
procedure for the synthesis of enol ethers, (methoxymethyl)tri-
phenylphosphonium chloride (4.11 g, 12.0 mmol), potassium tert-
butoxide (0.673 g, 12.0 mmol), and benzaldehyde (1.02 mL,
10.0 mmol) were combined in THF (50 mL) to give (2-
methoxyvinyl)benzene (4i) as a mixture of diastereomers in a
1.00:0.59 ratio as a colorless oil (1.11 g, 83%): 1H NMR (400 MHz,
CDCl3)
d 7.61e7.52 (m, 1.18H), 7.31e7.19 (m, 5.18H), 7.17e7.10 (m,
1.59H), 7.04 (d, J ¼ 13.0 Hz, 1H), 6.13 (d, J ¼ 7.1 Hz, 0.59H), 5.81 (d,
CDCl3)
2.10e2.01 (m, 1H), 1.95e1.86 (m, 1H), 1.81e1.65 (m, 3H), 1.62e1.45
(m, 4H), 1.30e1.15 (m, 1H); 13C NMR (100 MHz, CDCl3)
164.7 (C),
135.2 (CH),128.8 (C),124.2 (CH),114.1 (CH), 84.1 (C), 60.4 (CH3), 28.1
d 9.86 (s, 1H), 7.92e7.77 (m, 4H), 4.97 (s, 1H), 3.61 (s, 3H),
J ¼ 13.0 Hz, 1H), 5.22 (d, J ¼ 7.1 Hz, 0.59H), 3.77 (s, 1.77H), 3.68 (s,
3H); 13C NMR (100 MHz, CDCl3)
d
149.0 (CH, major), 148.1 (CH,
d
minor), 136.5 (C, major), 136.0 (C, minor), 128.7 (CH, major), 128.3
7

T.E. Anderson, A.A. Andia and K.A. Woerpel
Tetrahedron 82 (2021) 131874
(CH2), 26.1 (CH2), 25.7 (CH2), 20.9 (CH2), 20.6 (CH2); IR (ATR) 3303,
major), 60.7 (CH3, major), 60.2 (CH3, minor), 21.2 (CH3, major); 18.7
2944, 1786, 1721, 1370, 1205, 968 cmꢁ1; HRMS (ESI) m/z calcd for
(CH3, minor); IR (ATR) 3489, 3333, 1785, 1717, 1378, 1124, 877 cmꢁ1
;
C
16H19NNaO6 (M þ Na)þ 344.1105, found 344.1106.
HRMS (ESI) m/z calcd for C18H17NNaO6 (M þ Na)þ 366.0948, found
366.0949.
4.2.2.1. Peroxide 5b. Following the representative procedure for the
peroxidation of enol ethers, (methoxymethylene)-heptane (4b,
0.047, 0.33 mmol), NHPI (0.065 g, 0.40 mmol), and acetone (7 mL)
were combined to afford peroxide 5b as a white solid (0.055 g,
4.2.2.5. Peroxide 5f. Following the representative procedure for the
peroxidation of enol ethers, (1-methoxyhepta-1,6-dien-2-yl)ben-
zene (4f, 0.060 g, 0.30 mmol), NHPI (0.059 g, 0.360 mmol), and
acetonitrile (6 mL) were combined to afford peroxide 5f as a
1.00:0.12 mixture of diastereoemers as a white solid (0.047 g, 39%):
49%): mp ¼ 98e100 ꢀC; 1H NMR (400 MHz, CDCl3)
d 9.88 (s, 1H),
7.93e7.77 (m, 4H), 5.08 (m, 1H), 3.61 (s, 3H), 1.81e1.62 (m, 4H),
1.57e1.41 (m, 4H), 0.98e0.88 (m, 6H); 13C NMR (100 MHz, CDCl3)
mp ¼ 146e151 ꢀC; 1H NMR (400 MHz, CDCl3)
d 10.49 (s, 0.12 H),
d
164.8 (C), 135.2 (CH), 128.9 (C), 124.2 (CH), 115.1 (CH), 86.6 (C),
10.24 (s,1H), 7.94e7.75 (m, 4.48H), 7.69e7.64 (m, 0.24 H), 7.59e7.53
(m, 2H), 7.41e7.26 (m, 3.36H), 5.84e5.63 (m, 1.12H), 5.36 (s, 1H),
5.30 (s, 0.12H), 5.05e4.84 (m, 2.24H), 3.63e3.57 (m, 3.36H),
2.27e2.00 (m, 4.48H), 1.64e1.51 (m, 1.12H), 1.28e1.16 (m, 1.12H);
60.6 (CH3), 35.4 (CH2), 32.2 (CH2), 16.7 (CH2), 16.5 (CH2), 15.1 (CH3),
14.9 (CH3); IR (ATR) 3349, 2961, 1719, 1376, 1188, 1113, 968 cmꢁ1
;
HRMS (ESI) m/z calcd for C17H23NNaO6 (M þ Na)þ 360.1418, found
360.1425.
13C NMR (100 MHz, CDCl3)
d 164.9 (C, minor),164.7 (C, major),139.3
(C, minor), 138.8 (CH, major), 138.6 (CH, minor), 135.9 (C, major),
135.3 (CH, minor), 135.2 (CH, major), 128.8 (C, minor), 128.7 (C,
major),128.2 (CH, minor),127.9 (CH, major),127.8 (CH, major),127.6
(CH, minor), 127.4 (CH, major), 127.2 (CH, minor), 124.3 (CH, minor),
124.2 (CH, major), 114.79 (CH2, major), 114.77 (CH2, minor), 113.9
(CH, major), 113.8 (CH, minor), 88.5 (C, minor), 87.7 (C, major), 61.1
(CH3, minor), 60.8 (CH3, major), 34.0 (CH2, minor), 33.9 (CH2, ma-
jor), 32.9 (CH2, major), 32.0 (CH2, minor), 22.0 (CH2, minor), 21.8
4.2.2.2. Peroxide 5c. Following the representative procedure for
the peroxidation of enol ethers, 4-(methoxymethylene)cyclo-
hexan-1-one (4c, 0.048 g, 0.34 mmol), NHPI (0.066 g, 0.41 mmol),
and acetone (7 mL) were combined to afford peroxide 5c as a white
solid (0.075 g, 66%): mp ¼ 69e75 ꢀC; 1H NMR (400 MHz, CDCl3)
d
10.3 (s, 1H), 7.95e7.80 (m, 4H), 5.13 (s, 1H), 3.64 (s, 3H), 2.77 (dt,
J ¼ 6.1, 14.3 Hz, 1H), 2.65e2.53 (m, 1H), 2.48e2.39 (m, 1H),
2.37e2.19 (m, 4H), 2.05e1.95 (m, 1H); 13C NMR (100 MHz, CDCl3)
(CH2, major); IR (ATR) 3335, 2936, 1716, 1377, 1116, 906, 877 cmꢁ1
;
d
211.0 (C), 164.8 (C), 135.4 (CH), 128.7 (C), 124.4 (CH), 113.2 (CH),
HRMS (ESI) m/z calcd for C22H23NNaO6 (M þ Na)þ 420.1418, found
82.8 (C), 60.2 (CH3), 36.2 (CH2), 35.9 (CH2), 28.2 (CH2), 25.6 (CH2); IR
(ATR) 3340, 2942, 1724, 1374, 1187, 971, 896 cmꢁ1; HRMS (ESI) m/z
calcd for C16H17NNaO7 (M þ Na)þ 358.0897, found 358.0900.
420.1414.
4.2.2.6. Peroxide 5g and ketone 5g’. Following the representative
procedure for the peroxidation of enol ethers, (1-methoxy-3-
methylbut-1-en-2-yl)benzene (4g, 0.053 g, 0.30 mmol), NHPI
(0.059 g, 0.36 mmol), and acetonitrile (6 mL) were combined to
afford peroxide 5g as a mixture of a pair of diastereomers and ke-
tone 5g′ in a 1.00:0.79:0.50 ratio as a white solid (0.076 g, 68%):
4.2.2.3. Peroxide 5d. Following the representative procedure for
the peroxidation of enol ethers, 1-methoxy-2-methylhepta-1,6-
diene (4d, 0.043 g, 0.307 mmol), NHPI (0.060 g, 0.368 mmol), and
acetone (6 mL) were combined to afford peroxide 5d as a 1.00:0.85
mixture of diastereomers as
a
white solid (0.046 g, 45%):
mp ¼ 51e55 ꢀC; 1H NMR (400 MHz, CDCl3)
d 10.32e10.25 (m,
mp ¼ 146e151 ꢀC; 1H NMR (400 MHz, CDCl3)
d
9.99 (s, 1H), 9.88 (s,
1.79H), 8.26e8.20 (m, 1H), 7.92e7.74 (m, 9.16H), 7.69e7.60 (m,
4.08H), 7.55e7.49 (m, 1H), 7.42e7.24 (m, 5.37H), 5.80 (s, 0.5H), 5.69
(s, 0.79H), 5.52 (s, 1H), 3.86 (s, 1.5H), 3.69 (s, 3H), 3.66 (s, 2.37),
2.59e2.43 (m, 1.79H), 1.12 (d, J ¼ 7.0 Hz, 3H), 1.07 (d, J ¼ 6.9 Hz,
2.37H), 0.92 (d, J ¼ 6.9 Hz, 2.37H), 0.79 (d, J ¼ 7.0 Hz, 3H); 13C NMR
0.85H), 7.92e7.79 (m, 7.4H), 5.90e5.76 (m, 1.85H), 5.09e4.92 (m,
5.55H), 3.63e3.61 (m, 5.55H), 2.15e2.01 (m, 3.7H), 1.91e1.45 (m,
7.4H),1.37 (s, 2.55H),1.25 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 164.8
(C, major), 164.7 (C, minor), 138.9 (CH, major), 138.8 (CH, minor),
135.2 (CH, major), 135.2 (CH, minor), 128.8 (C, major), 128.8 (C,
minor), 124.21 (CH, major), 124.20 (CH, minor), 114.8 (2CH2, major,
minor), 114.5 (CH, minor), 114.0 (CH, major), 85.11 (C, minor), 85.07
(C, major), 60.4 (CH3, minor), 60.2 (CH3, major), 34.3 (CH2, major),
34.1 (CH2, minor), 33.2 (CH2, major), 30.5 (CH2, minor), 22.1 (CH2,
major), 21.7 (CH2, minor), 18.6 (CH3, minor), 14.8 (CH3, major); IR
(ATR) 3345, 2948, 1719, 1377, 1116, 972, 877 cmꢁ1; HRMS (ESI) m/z
calcd for C17H21NNaO6 (M þ Na)þ 358.1261, found 358.1259.
(100 MHz, CDCl3)
d 190.4 (5g′ C), 164.8 (5g C, major), 164.7 (5g C,
minor), 163.4 (5g′ C), 139.4 (5g C, major), 136.9 (5g C, minor), 135.22
(5g CH, major), 135.17 (5g CH, minor), 134.8 (5g′ CH), 134.5 (5g′ C),
134.2 (5g′ CH), 133.7 (5g′ C), 129.9 (5g′ CH, major), 129.00 (5g′ C),
128.97 (5g C, major), 128.8 (5g C, minor), 128.7 (5g′ CH), 127.9 (5g
CH, major), 127.61 (5g CH, minor), 127.59 (5g CH, minor), 127.42 (5g
CH, minor), 127.37 (5g CH, major), 127.36 (5g CH, major), 124.2 (5g
CH, major), 124.1 (5g CH, minor), 123.9 (5g′ CH), 114.0 (5g CH, mi-
nor), 113.9 (5g CH, major), 107.8 (5g′ CH), 90.4 (5g C, major), 89.9
(5g C, minor), 61.7 (5g CH3, major), 61.1 (5g CH3, minor), 57.7 (5g′
CH3), 35.2 (5g CH, minor), 33.9 (5g CH, major), 18.2 (5g CH3, major),
18.0 (5g CH3, major), 17.9 (5g CH3, minor), 17.6 (5g CH3, minor); IR
(ATR) 3344,1723,1372,1186, 966, 876, 747 cmꢁ1; 5g HRMS (ESI) m/z
calcd for C20H21NNaO6 (M þ Na)þ 394.1261, found 394.1260; 5g’
HRMS (ESI) m/z calcd for C17H13NNaO5 (M þ Na)þ 335.0719, found
335.0721.
4.2.2.4. Peroxide 5e. Following the representative procedure for
the peroxidation of enol ethers, (1-methoxyprop-1-en-2-yl)ben-
zene (4e, 0.044 g, 0.30 mmol), NHPI (0.059 g, 0.36 mmol), and
acetone (6 mL) were combined to afford peroxide 5e as a 1.00:0.39
mixture of diastereomers as a white solid (0.064 g, 63%). The
peroxide was purified by flash column chromatography and char-
acterized as a 1.0:0.11 mixture of diastereomers: mp ¼ 126e130 ꢀC;
1H NMR (400 MHz, CDCl3)
d 9.99 (s, 0.11H), 9.88 (s, 1H), 7.92e7.77
(m, 4.44H), 7.71e7.67 (m, 2H), 7.63e7.69 (m, 0.22H), 7.41e7.27 (m,
3.33H), 5.42 (s, 1H), 5.37 (s, 0.11H), 3.66e3.60 (m, 3.33H), 1.80 (s,
4.2.2.7. Peroxide 5h. Following the representative procedure for
the peroxidation of enol ethers, (1-methoxyhept-1-en-6-yn-2-yl)
benzene (4h, 0.061 g, 0.31 mmol), NHPI (0.059 g, 0.36 mmol), and
acetonitrile (6 mL) were combined to afford peroxide 5h as a
1.00:0.42 mixture of diastereomers as a white solid (0.066 g, 55%):
d 10.94 (s, 0.42H),
10.28 (s, 1H), 7.93e7.78 (m, 5.68H), 7.68e7.64 (m, 0.84H), 7.59e7.55
(m, 2H), 2.41e2.27 (m, 4.26H), 5.37 (s, 1H), 5.30 (s, 0.42H), 3.62 (s,
3H), 1.71 (s, 0.33H)); 13C NMR (100 MHz, CDCl3)
d 164.7 (C, minor),
164.5 (C, major),141.2 (C, minor),137.9 (C, major),135.2 (CH, minor),
135.1 (CH, major), 128.9 (C, minor), 128.8 (C, major), 128.4 (CH,
minor), 128.3 (CH, major), 128.1 (CH, major), 127.9 (CH, minor),
127.6 (CH, major), 126.6 (CH, minor), 124.2 (CH, minor), 124.1 (CH,
major), 113.4 (CH, major), 112.5 (CH, minor), 86.7 (C, minor), 86.4 (C,
mp ¼ 149e153 ꢀC; 1H NMR (400 MHz, CDCl3)
8

T.E. Anderson, A.A. Andia and K.A. Woerpel
Tetrahedron 82 (2021) 131874
3H), 3.58 (s, 1.26H), 2.38e2.07 (m, 5.68H), 1.96 (t, J ¼ 2.6 Hz, 1H),
1.88 (t, J ¼ 2.6 Hz, 0.42H), 1.77e1.57 (m, 1.42H), 1.44e1.32 (m, 1H),
4.2.2.11. Peroxides 5n and 5n’. Following the representative pro-
cedure for the peroxidation of enol ethers, 1-methoxyhept-1-ene
(4n, 0.040 g, 0.31 mmol), NHPI (0.059 g, 0.36 mmol), and acetoni-
trile (6 mL) were combined to afford peroxides 5n and 5n′ as a
mixture of regoisomers and diastereomers in a 1.0:0.92:0.59:0.43
1.30e1.18 (m, 0.42H); 13C NMR (100 MHz, CDCl3)
d 164.8 (C, minor),
164.6 (C, major), 139.0 (C, minor), 135.7 (C, major), 135.3 (CH, mi-
nor), 135.2 (CH, major), 128.9 (C, minor), 128.8 (C, major), 128.3 (CH,
minor), 127.90 (CH, major), 127.87 (CH, major), 127.7 (CH, minor),
127.5 (CH, major), 127.2 (CH, minor), 124.3 (CH, minor), 124.1 (CH,
major), 113.73 (CH, minor), 113.70 (CH, major), 88.4 (C, minor), 87.6
(C, major), 84.5 (C, major), 84.3 (C, minor), 68.62 (CH, major), 68.56
(CH, minor), 61.1 (CH3, minor), 60.7 (CH3, major), 32.4 (CH2, major),
31.6 (CH2, minor), 22.1 (CH2, minor), 21.8 (CH2, major), 18.8 (CH2,
minor), 18.6 (CH2, major); IR (ATR) 3338, 3298, 1716, 1378, 1132,
973, 877 cmꢁ1; HRMS (ESI) m/z calcd for C22H25N2O6 (M þ NH4)þ
413.1707, found 413.1701.
ratio as
a colorless oil (0.037 g, 36%). The identity of the
regioisomers was assigned by comparison of the acetal carbon
chemical shifts to other peroxide products: 1H NMR (400 MHz,
CDCl3)
d 9.97e9.83 (m, 2.35H), 9.07e9.00 (s, 0.59H), 7.90e7.75 (m,
11.76H), 5.21 (d, J ¼ 4.2 Hz, 0.92H), 5.05 (d, J ¼ 7.0 Hz, 1H), 4.94 (d,
J ¼ 4.7 Hz, 0.59H), 4.89 (d, J ¼ 7.6 Hz, 0.43H), 4.36e4.25 (m, 1.02H),
4.18e4.10 (m, 1.92H), 3.73e3.68 (m, 5.76H), 3.59 (s, 1.29H), 3.50 (s,
1.77H), 1.97e1.26 (m, 23.52H), 0.95e0.87 (8.82H); 13C NMR
(100 MHz, CDCl3)
d 164.8 (C, 5n′ minor), 164.6 (C, 5n major), 164.5
(C, 5n minor), 164.2 (C, 5n′ major), 135.12 (CH, 5n major), 135.11
(CH, 5n minor), 135.0 (CH, 5n′ minor), 134.8 (CH, 5n′ major), 129.0
(C, 5n′ major), 128.84 (C, 5n major), 128.82 (C, 5n minor), 128.78 (C,
5n′ minor), 124.11 (CH, 5n major), 124.07 (CH, 5n minor), 124.0 (CH,
5n′ minor),123.8 (CH, 5n′ major),111.7 (CH, 5n major),111.0 (CH, 5n
minor), 108.4 (CH, 5n′ major), 107.7 (CH, 5n′ minor), 86.6 (CH, 5n′
major), 85.5 (CH, 5n′ minor), 84.2 (CH, 5n minor), 83.6 (CH, 5n
major), 58.9 (CH3, 5n minor), 57.4 (CH3, 5n′ major), 56.8 (CH3, 5n′
minor), 56.7 (CH3, 5n major), 32.1 (CH2, 5n′ minor), 31.81 (CH2, 5n
minor), 31.78 (CH2, 5n′ major), 31.76 (CH2, 5n major), 30.0 (CH2, 5n′
minor), 28.0 (CH2, 5n major), 27.7 (CH2, 5n′ major), 26.8 (CH2, 5n
minor), 25.7 (CH2, 5n minor), 25.2 (CH2, 5n major), 25.0 (CH2, 5n′
major), 23.7 (CH2, 5n′ minor), 22.7 (CH2, 5n major), 22.62 (CH2, 5n
minor, 5n′ minor), 22.60 (CH2, 5n′ major), 14.23 (CH3, 5n′ major),
14.21 (CH3, 5n’ minor),14.19 (CH3, 5n major),14.19 (CH3, 5n minor);
IR (ATR) 3384, 2930, 1724, 1374, 1187, 971, 876 cmꢁ1; HRMS (ESI) m/
z calcd for C16H22NO6 (M*)þ 324.1442, found 324.1439.
4.2.2.8. Peroxide 5i. Following the representative procedure for the
peroxidation of enol ethers, (2-methoxyvinyl)benzene (4i, 0.073 g,
0.5455 mmol), NHPI (0.107 g, 0.6546 mmol), and acetone (11 mL)
were combined to afford peroxide 5i as a 1.00:0.77 mixture of di-
astereomers as a white solid (0.100 g, 56%). The peroxide was pu-
rified by flash column chromatography and characterized as a
1.0:1.0 mixture of diastereomers: mp ¼ 123e130 ꢀC; 1H NMR
(400 MHz, CDCl3)
d 9.97 (s, 1H), 9.60 (s, 1H), 7.92e7.76 (m, 8H),
7.55e7.51 (m, 2H), 7.48e7.44 (m, 2H), 7.42e7.34 (m, 6H), 5.45 (d,
J ¼ 3.8 Hz,1H), 5.31 (d, J ¼ 3.8 Hz,1H), 5.29 (d, J ¼ 7.1 Hz,1H), 5.17 (d,
J ¼ 7.1 Hz, 1H), 3.71 (s, 3H), 3.60 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
164.7 (C), 164.4 (C), 135.5 (C), 135.1 (CH), 135.0 (CH), 134.4 (C),
129.2 (CH), 128.98 (C), 128.97 (C), 128.9 (CH), 128.8 (CH), 128.56
(CH), 128.55 (CH), 128.4 (CH), 124.1 (CH), 124.0 (CH), 110.9 (CH),
110.0 (CH), 86.7 (CH), 86.5 (CH), 58.7 (CH3), 57.7 (CH3); IR (ATR)
3308, 1716, 1376, 1188, 1156, 981, 877 cmꢁ1; HRMS (ESI) m/z calcd
for C17H15NNaO6 (M þ Na)þ 352.0792, found 352.0799.
Declaration of competing interest
4.2.2.9. Peroxide 5j. To a solution of NHPI (0.111 g, 0.683 mmol) in
acetone (10 mL, sparged with O2 for 5 min) was added ethyl vinyl
ether (0.041 g, 0.569 mmol). The reaction mixture was stirred un-
der an O2 balloon in front of blue light for 16 h, then concentrated in
vacuo. The resulting solid was resuspended in dichloromethane
(10 mL) and the suspension was filtered through a Celite plug. The
filtered solid was washed with dichloromethane (20 mL), and the
combined filtrates were concentrated in vacuo. Purification of the
resulting solid by flash column chromatography (30% EtOAc/hex-
anes) afforded peroxide 5j as a colorless oil (0.073 g, 48%): 1H NMR
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgements
This research was supported by the National Institute of General
Medical Sciences of the National Institutes of Health
(1R01GM118730). NMR spectra acquired with the Bruker Avance
400 and 500 NMR spectrometers were supported by the National
Science Foundation (CHE-01162222). The authors thank Dr. Chin
Lin (NYU) for his assistance with NMR spectroscopy and mass
spectrometry, as well as the NYU Genomics Core Facility for use of
their Tecan Spark Microplate Reader.
(400 MHz, CDCl3)
d
9.09 (s, 1H), 7.89e7.75 (m, 4H), 5.21 (dd, J ¼ 4.1,
7.1 Hz, 1H), 4.41 (dd, J ¼ 4.1, 11.4 Hz, 1H), 4.30 (dd, J ¼ 7.1, 11.4 Hz,
1H), 3.97 (dq, J ¼ 7.1, 9.6 Hz, 1H), 3.67 (dq, J ¼ 7.1, 9.6 Hz, 1H), 1.23 (t,
J ¼ 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 163.9 (C), 135.0 (CH),
128.9 (C), 124.0 (CH), 103.8 (CH), 75.6 (CH2), 65.0 (CH2), 15.2 (CH3);
IR (ATR) 2978,1720,1374,1186,1116,1020, 877 cmꢁ1; HRMS (ESI) m/
z calcd for C12H13NNaO6 (M þ Na)þ 290.0635, found 290.0640.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131874.
4.2.2.10. Peroxide 5k. Following the representative procedure for
the peroxidation of enol ethers, (cyclohexylidenemethoxy)trime-
thylsilane (4k, 0.038 g, 0.181 mmol), NHPI (0.035 g, 0.217 mmol)
and acetonitrile (3.6 mL) were combined to afford peroxide 5k as a
white solid (0.037 g, 54%). No melting point was obtained because
peroxide 5k decomposed at a temperature of 158e164 ꢀC; 1H NMR
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