Cyclization reactions of anode-generated amidyl radicals

Article abstract of DOI:10.1021/jo402623r

Amidyl radicals have been generated from amides under mild conditions electro-oxidatively. Their reactivity toward electron-rich double bonds to form five- and six-membered rings has been demonstrated experimentally and explored with density functional theory (DFT) calculations (UB3LYP/6-31G(d,p)).

Full text of DOI:10.1021/jo402623r

Article
pubs.acs.org/joc
Cyclization Reactions of Anode-Generated Amidyl Radicals
Hai-Chao Xu,†,§ John M. Campbell,‡,§ and Kevin D. Moeller*,‡
†Department of Chemistry and Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen, Fujian 361005, China
‡Department of Chemistry, Washington University in St. Louis, St. Louis, Missouri 63130, United States
S
* Supporting Information
ABSTRACT: Amidyl radicals have been generated from
amides under mild conditions electro-oxidatively. Their
reactivity toward electron-rich double bonds to form five-
and six-membered rings has been demonstrated experimentally
and explored with density functional theory (DFT) calcu-
lations (UB3LYP/6-31G(d,p)).
amines13 and sulfonamides14 with electron-rich olefins at room
temperature to afford N-heterocycles. We report here that
INTRODUCTION
Nitrogen-centered radicals are potentially important reactive
■
intermediates for synthetic organic chemistry.1 In particular, the
electrochemical methods can also be applied to generate amidyl
radicals directly from amides under mild conditions. Amidyl
cyclization of nitrogen-centered radicals onto carbon−carbon
double bonds provides a promising route to biologically
important N-heterocycles. Among the various kinds of
radicals synthesized in this fashion readily add to olefins to
generate lactams.
We envisioned that anodic oxidation of amide 1 would lead
nitrogen-centered radicals, amidyl radicals have attracted
to amidyl radical 2 (see Scheme 2).15 Intramolecular addition
attention due to their high reactivity and electrophilic nature.2
The generation of amidyl radicals frequently involves the
cleavage of an N-halogen,3 N−N,4 N−O,2,5 or N−S6 bond
(Scheme 1). Studer and co-workers have shown that amidyl
Scheme 2. Proposed Intramolecular Anodic Coupling of
a
Amides and Olefins
Scheme 1. Generation of Amidyl Radicals by Fragmentation
Reactions and Chemical Oxidation
radicals may be generated by hydrogen atom abstraction from
an amide.7 Many of these approaches involve the use of toxic
tin compounds, and the precursors for such fragmentation
reactions are often not stable. In addition, the highly
electrophilic nature of these amide derivatives can cause
undesirable side-reactions.
a
X,Y = electron donating groups
Recently, the generation of amidyl radicals directly from
amides through chemical oxidation has been reported.8,9 These
methods avoid the preparation of amide derivatives and have
therefore increased the synthetic utility of amidyl radicals.
However, the reactions frequently require an excess of the
chemical oxidant and high temperatures, a situation that
imposes limitations on the synthetic utility of the reactions.
Hence, the development of a more general and gentle process
for the generation of amidyl radicals is of great importance.
Electrochemistry has been demonstrated as an easily
implemented,10 reagentless, and mild method for the
generation of reactive intermediates such as radicals and radical
ions.11,12 For example, we have previously shown that an anodic
oxidation reaction can be used to oxidatively couple primary
of the radical onto an appropriately positioned double bond
would give cyclized radical 3. A second single-electron
oxidation followed by solvent (MeOH) trapping of the
subsequent cation would afford the final product 4. Lactams
like 4 are pyroglutamate derivates that form the core structure
of many biologically active compounds such as (−)-dysibe-
taine,16 salinosporamide A,17 lactasystin,18 and stephacidin A19
(Figure 1). The method is intriguing in that it has the potential
to readily form the key tetrasubstituted carbon that lies at the
center of such structures.
Received: November 26, 2013
Published: December 11, 2013
© 2013 American Chemical Society
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The methyl ester 7a was derived from hydrolysis of 6a. It is
not known whether this hydrolysis reaction occurred with
adventitious water in the electrolysis medium or during the
workup following the reaction. Compound 6a can be readily
hydrolyzed to the synthetically more relevant methyl ester 7a in
the presence of N-chlorosuccinimide (NCS) (Scheme 3).20
Scheme 3. Hydrolysis of 6a
Figure 1. Selected examples of biologically active lactams.
Although the electrolysis reactions in this work were carried
out using a potentiostat to maintain constant current, simpler
power supplies can also be used. For example, oxidation of 5a
with a 6-V lantern battery (see the Supporting Information for
more details) as the power source afforded 6a and 7a in 81 and
3% yield, respectively (Table 1, entry 2).
Under the same electrolysis conditions used for entry 1,
oxidation of N-phenyl amide 5b afforded the desired lactam 6b
in 87% yield (Table 1, entry 4). Cyclizations that employed
other substituents on the amidyl nitrogen were not as
successful. When unsubstituted amide 5c was used as a
substrate for the reaction, a complex mixture of products that
could not be characterized was obtained (Table 1, entry 5).
Oxidation of the N-methyl amide 5d gave iminolactone 8d in
75% yield (entry 6).15
RESULTS AND DISCUSSION
■
Identification of Suitable Substrates. Our study began
with the identification of suitable amides for the cyclization. To
this end, a series of amides 5a−d were prepared and submitted
to the electrolysis reaction (Table 1). Initially, a ketene
dithioacetal was chosen as the olefinic coupling partner for the
reactions because of its excellent reactivity in previously studied
anodic cyclizations.13,14
Table 1. Identification of Suitable Amides for the
Cyclizations
The difference between the successful reactions and
unsuccessful reactions appears to be related to the pKa of the
starting amide. O-Benzyl hydroxamates and N-phenyl amides
have pKa’s lower than that of methanol.21 Thus, when exposed
to the basic reaction conditions employed for the electrolysis,
amides 5a and 5b exist as their anionic conjugate bases. The
half-wave oxidation potential (Ep/2) of an O-benzyl hydrox-
amate anion and an N-phenyl amide anion were measured by
cyclic voltammetry to be 0.52 and 0.80 V, respectively, vs a Ag/
AgCl reference electrode. These oxidation potentials are lower
than that of the ketene dithioacetal (Ep/2 = 1.06 V vs Ag/AgCl)
and indicate that the initial oxidation of 5a and 5b occurs at the
amide anion rather than the olefin generating amidyl radical 2
(Scheme 2).
The half-wave oxidation potentials of substrates 5a and 5b
were measured to be 0.40 and 0.71 V vs Ag/AgCl, respectively.
The observation that these compounds exhibit an oxidation
potential lower than any of their isolated functional groups is
consistent with an oxidation step that is followed by a fast
cyclization. The cyclization consumes the oxidized product at
the electrode surface and thus lowers the observed potential.13
The primary amide in 5c and the N-methyl amide in 5d, on
the other hand, are less acidic than methanol, and their neutral
forms are oxidized at higher potentials (Ep/2 > 1.5 V vs Ag/
AgCl) than the ketene dithioacetal. As a result, the electrolysis
of these substrates begins with the oxidation of the olefin to a
radical cation followed by trapping with the nucleophilic
oxygen of the neutral amide to ultimately give the iminolactone
8.15
entry
1
substrate
product, yield (%)
b
5a, R = OBn
5a, R = OBn
5a, R = OBn
5b, R = Ph
5c, R = H
6a, 80
7a, 8
8a, ND
8a, ND
8a, 88
c
2
6a, 81
7a, 3
d
3
6a, ND
6b, 87
6c, ND
6d, ND
7a, ND
7b, ND
7c, ND
7d, ND
4
5
6
8b, ND
8c, ND
8d, 75
5d, R = Me
a
Reticulated vitreous carbon anode, platinum wire cathode, MeOH,
0.1 M Et4NOTs, 0.5 equiv of LiOMe, 6 mA, 2.0−2.2 F/mol, room
temperature. Not detected. A 6-V lantern battery was used as the
b
c
d
power source. 2,6-Lutidine (6 equiv) was used as base.
Anodic oxidation of O-benzyl hydroxamate 5a was
conducted in an undivided cell (a three-necked round-
bottomed flask) equipped with a reticulated vitreous carbon
(RVC) anode and a platinum wire cathode (see the Supporting
Information for more details). The electrolysis was conducted
in a methanol solution with the use of Et4NOTs as the
electrolyte and 0.5 equiv of LiOMe as a base. Under these
conditions, a constant current of 6 mA was passed through the
cell at room temperature to afford the desired product 6a in
80% yield along with methyl ester 7a in 8% yield (Table 1,
entry 1). The reaction required 2 F/mol of charge. During the
electrolysis, acid was produced at the anode, and an equal
amount of base (methoxide) was produced at the cathode
because of the reduction of methanol solvent. In this way, the
reaction remained at the initial basic pH established by the
substoichiometric amount of LiOMe added.
The necessity of deprotonation of the amide prior to the
electrolysis was demonstrated by the use of less basic
conditions. When lithium methoxide was replaced with 2,6-
lutidine as a base, the electrolysis of 5a did not yield the desired
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lactam 6a. Instead, iminolactone 8a was isolated in an 88%
yield (Table 1, entry 3). Under these conditions, the O-benzyl
hydroxamate remained neutral. Hence, the reaction under the
less basic conditions most likely started with the oxidation of
the electron-rich olefin instead of the amide.
Exploration of Diastereoselectivity and Ring Size
Limitations. Next, questions concerning the diastereoselectiv-
ity of the reactions and the size of the rings that could be
formed were probed. The diastereoselectivity of the reaction
was examined by placing a methyl group on the chain
connecting the amide and the electron-rich olefin (Table 2,
The oxidation potential of 9c (Ep/2 = 0.52 V vs Ag/AgCl) is
the same as that of an isolated O-benzyl hydroxamate and much
higher than the potentials measured for 5a (Ep/2 = 0.40 V vs
Ag/AgCl) and 9a (Ep/2 = 0.41 V vs Ag/AgCl). These
observations indicate that the seven-membered ring cyclization
is much slower than the five- and six-membered ring
cyclizations and too slow to compete with the dimerization
reaction.
While the O-benzyl hydroxamate cyclized nicely to form six-
membered ring products, oxidation of the N-phenyl amide 9d
afforded a complex mixture of products (Table 2, entry 4).
Neither the desired δ-lactam nor the methyl ester was detected.
Extension to Other Electron-Rich Olefins. With the
initial success of the reactions in hand, attention was turned to
the nature of the olefin used for the cyclization. In this regard, it
is important to note that the desired cyclization reactions are
two electron oxidation processes. In such reactions, the removal
of a second electron from the cyclic product is critical (Scheme
2, oxidation of radical 3). This second oxidation is best
facilitated by electron-donating substituents on the olefin.
When this requirement is not satisfied sufficiently, the
cyclizations are less successful.23
Table 2. Electrolysis of 9a−d
entry
substrate
product, yield (%)
1
2
3
4
9a, n = 1, R1 = OBn, R2 = Me 10a, 78
9b, n = 2, R1 = OBn, R2 = H 10b, 73
11a, 8
12a, ND
12b, ND
11b, 10
b
9c, n = 3, R1 = OBn, R2 = H 10c, ND 11c, ND 12c, 74 (85)
9d, n = 2, R1 = Ph, R2 = H 10d, ND 11d, ND 12d, ND
For the current study, coupling reactions with both vinyl
sulfides and enol ethers were explored (Table 3). These olefins
a
Reticulated vitreous carbon anode, platinum wire cathode, MeOH,
b
0.1 M Et4NOTs, 0.5 equiv of LiOMe, 6 mA, 2.0−2.2 F/mol. The
reaction was conducted at 65 °C.
Table 3. Cyclizations with Vinyl Sulfides and Enol Ethers
entry 1). In this case, the reaction led to a 78% yield of 10a,
along with 8% of methyl ester 11a, both as a single
diastereomer. The stereochemistry of the products was assigned
in analogy to earlier cyclizations.13,14 Hence, the oxidative
cyclization allows for the generation of the tetrasubstituted
carbon with complete control over relative stereochemistry.
Cyclization to form the more challenging six-membered ring
product with concomitant formation of a tetrasubstituted
carbon was also successful with the use of the O-benzyl
hydroxamate. The oxidation of 9b provided 10b and 11b in 73
and 10% yield, respectively (Table 2, entry 2). The oxidation
potential of 9b was measured under the reaction conditions to
be 0.41 V (Ep/2 vs Ag/AgCl), similar to that of substrate 5a
(Ep/2 = 0.40 V vs Ag/AgCl). This observation suggests that the
six-membered ring cyclization is still very fast.
entry
substrate
n, X, R
T (°C)
product, yield (%)
a
b
1
2
3
4
5
6
7
15a
15a
15b
15c
15d
15e
15f
1, S, Me
1, S, Me
1, O, Me
2, S, Me
2, O, Me
2, S, H
25
65
16a, 60
17a, ND
17a, ND
16a, 88
16b, 41
d
c
25
17b, ND
17c, 68
17d, 51
17e, 3
d
25
16c, ND
16d, ND
16e, 55
16f, 8
d
25
d
25
d
2, O, H
25
17f, 17
a
An 11% yield of the product hydrolyzed to an aldehyde was obtained.
Not detected. A trace amount of the product hydrolyzed to an
aldehyde was obtained. Heating the reaction did not improve the
yield of the cyclized product.
b
c
d
Attempts to form a seven-membered ring product from the
oxidation of substrate 9c failed (Table 2, entry 3). Instead,
methyl ester 12c was isolated in 74% yield. Running the
reaction at higher temperature did not improve the cyclization.
The formation of 12c could be explained by the known
dimerization of the N-alkoxyamidyl radical 13 to give a
hydrazide 14 (Scheme 4).8e,22 Decomposition of 14 under the
reaction conditions led to the methyl ester 12c and benzyl
alcohol. Benzyl alcohol was observed in the 1H NMR spectrum
of the crude reaction mixture.
exhibit oxidation potentials higher than ketene dithioacetals,
and so do not interfere with the oxidation of the amide anion.
Both have proven to be successful coupling partners for past
anodic cyclizations.12 The electrolysis of vinyl sulfide substrate
15a at room temperature led to the desired lactam product 16a
in a 60% isolated yield (entry 1). The yield improved to 88% by
carrying out the electrolysis at higher temperature (entry 2).
Anodic oxidation of enol ether 15b was less successful. In
this case, the anodic cyclization gave rise to a 41% yield of
lactam 16b at room temperature. A small amount of aldehyde
and benzyl alcohol was also observed in the 1H NMR spectrum
of the crude reaction mixture. The formation of benzyl alcohol
suggested that the dimerization reaction was competing with
the cyclization. In this case, running the reaction at higher
temperature (65 °C) did not improve the cyclization.
Scheme 4. Proposed Pathway for the Conversion of an
Amidyl Radical to a Methyl Ester
Attempts to form six-membered rings with either the vinyl
sulfide 15c or the enol ether 15d were not successful (Table 3,
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entries 4 and 5). In both cases, only methyl esters 17c or 17d
were obtained from the reaction, indicating that the radical−
radical dimerization was the dominant pathway.
Electrolysis of the less hindered substrates 15e and 15f did
lead to the cyclized products 16e and 16f in 55 and 8% yield,
respectively (Table 3, entries 6 and 7). Methyl esters 17e and
17f were also obtained suggesting that the radical−radical
dimerization pathway was still competing with the cyclization.
Computational Results.24 To better understand the
synthetic observations made, we turned to computational
methods to probe the reactivity and limitations of amidyl
radicals. Density functional theory has been utilized to
successfully investigate the structure and energetics of open-
shell molecules,25 although it does carry with it some significant
limitations.26 We have endeavored to maintain a close link
between our computational findings and the experimental
results.
We first set out to corroborate our mechanistic under-
standing of the cyclizations. Transition structures for the
cyclization of O-benzyl hydroxamate radicals and N-phenyl
amidyl radicals were located at the DFT level of theory
(UB3LYP/6-31G(d,p)).27 The intrinsic reaction coordinates
(IRC) before and after the transition structures were computed
(Figures 2 and 3). Analysis of the unpaired spin density
Figure 3. Intrinsic reaction coordinate around the transition structure
for the addition of N-phenyl amidyl radical to a ketene dithioacetal.
The color maps represent the unpaired electron spin density,
expressed in units of unpaired electrons per cubic bohr ((eα − eβ)/
3
ao ), mapped onto the total electron density surface.
Table 4. Calculated Reaction Energetics for Amidyl Radical
Cylizations with Ketene Dithioacetal
cyclization
(kcal/mol)
H abstraction
(kcal/mol)
entry
radical
ΔG‡
ΔG
ΔG‡
ΔG
a
1
2
3
4
18a, n = 1, R = Ph
18b, n = 1, R = OBn
18c, n = 2, R = Ph
18d, n = 2, R = OBn
10.7
15.8
15.0
16.8
−6.1
−1.6
0.1
NA
NA
NA
NA
13.4
18.5
−13.2
−2.7
1.3
a
Not applied.
Figure 2. Intrinsic reaction coordinate around the transition structure
for the addition of an O-benzyl hydroxamate amidyl radical to a ketene
dithioacetal. The color maps represent the unpaired electron spin
density, expressed in units of unpaired electrons per cubic bohr ((eα −
activation energy (ΔG‡ = 15.8 kcal/mol) and was less exergonic
(ΔG = −1.6 kcal/mol). Both of these cyclizations were
experimentally successful and led to a good yield of the cyclized
product.
3
eβ)/ao ), mapped onto the total electron density surface.
distribution in the structures in the IRC curves showed that the
radical was localized primarily at the nitrogen in all structures
leading to the transition structure. These calculations along
with the cyclic voltammetry studies suggested that the
cyclizations followed a radical type mechanism, as depicted in
Scheme 2.
Next, we computationally explored the energetics of the
cyclizations presented in Figures 2 and 3 (Table 4). After
optimization of the product and reactant radical species and
incorporation of the thermal energy contributions, the coupling
of an N-phenyl amidyl radical to a ketene dithioacetal to form a
five-membered ring was found to have an activation energy of
10.7 kcal/mol and was exergonic by −6.1 kcal/mol (Table 4,
entry 1). The analogous coupling of an O-benzyl hydroxamate
radical to a ketene dithioacetal was found to have a higher
When six-membered ring cyclizations were attempted,
couplings involving N-phenyl amidyl radicals were not
experimentally successful, while couplings involving O-benzyl
hydroxamate radicals were. We suspected that this was due to a
competing 1,5-H abstraction, which is a known reaction
pathway for amidyl radicals.6c,28 Our calculations seemed to
indicate that 1,5-H abstraction was indeed the problem with N-
phenyl amidyl radical reactions (entry 3). 1,5-H abstraction was
found to have an activation energy lower than cyclization for
the N-phenyl amidyl radical 18c. These results probably explain
why the electrolysis of 9d gave no cyclized product (Table 2,
entry 4). For the analogous reaction involving the O-benzyl
hydroxamate radical 18d (entry 4), the cyclization had a lower
activation energy than 1,5-H abstraction, which would allow for
a successful cyclization. These results are consistent with the
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experimental observation that the electrolysis 9b afforded good
yield of the cyclized product (Table 2, entry 2).
dithiane radical will drain the equilibrium between the cyclic
and acyclic radicals toward the desired product.
We also investigated the energetics of the dimerization
pathway of the O-benzyl hydroxamate radical (conversion of 13
to 14, Scheme 4). This reaction was calculated to be highly
exothermic (ΔG = −15.2 kcal/mol). However, no transition
structure could be located, probably because of the very small
barrier associated with radical−radical combination reactions.29
A computational analysis of the coupling of O-benzyl
hydroxamate radicals with enol ethers and vinyl sulfides also
gave some helpful insights into the cyclization reactions (Table
5). The coupling of either an enol ether or a vinyl sulfide to an
Our computational findings, along with the experimental
results, indicate that the exothermicity of the radical cyclization
is a significant consideration. We propose that the best way to
ensure a successful cyclization is to design the reaction such
that the cyclized radical intermediate is close to or lower in
energy than the uncyclized amidyl radical. This can be achieved
by appropriately substituting the olefin in a way that best
stabilizes the cyclized radical, or alternatively by relieving the
steric strain of the cyclized radical.
Competition Experiments. Unlike the sulfonamide anion
(Ep/2 = 0.90 V vs Ag/AgCl) studied previously,14 the O-benzyl
hydroxamate anion (Ep/2 = 0.52 V vs Ag/AgCl) in this work is
oxidized at a significantly lower potential than the ketene
dithioacetal (Ep/2 = 1.06 V vs Ag/AgCl). In the case of the
sulfonamide anion, competition studies were used to
demonstrate that the N-localized radical underwent a reversible
intramolecular electron transfer to generate a radical cation
localized at the ketene dithioacetal.14c We wanted to see if this
equilibrium still played a role in amidyl radical reactions.
To this end, competition substrate 23 was synthesized
(Scheme 5). The electrolysis of 23 may lead to two mechanistic
Table 5. Calculated Energetics for Cyclizations with Vinyl
Sulfides and Enol Ethers
entry
radical
ΔG‡ (kcal/mol) ΔG (kcal/mol)
1
2
3
4
5
6
19a, n = 1, X = S, R = Me
19b, n = 1, X = O, R = Me
19c, n = 2, X = S, R = Me
19d, n = 2, X = S, R = H
19e, n = 2, X = O, R = Me
19f, n = 2, X = O, R = H
14.9
14.3
16.4
14.0
15.3
13.1
−1.1
0.8
Scheme 5. Competition Experiment Design
4.2
−1.0
5.1
1.3
O-benzyl hydroxamate to form six-membered rings was not
successful when the olefin was trisubstituted. However, when
the olefin was only disubstituted, some of the desired cyclized
product was obtained. The calculations indicate that the
experimental observations are perhaps best explained by the
exothermicity of the cyclization reaction. When the cyclization
is endergonic (entries 3 and 5), the reaction leads to the
formation of the unwanted methyl ester (see experimental
results in Table 3). When the cyclization is exergonic (entry 4),
the reaction leads to the formation of the cyclized product.
In an exergonic cyclization, cyclized radical 3 (Scheme 2) will
be present in a higher concentration than the noncyclized
radical 2. The increased concentration of 3 facilitates its
oxidation, which is critical to the electrolysis reaction.23 An
increased energetic preference for 3 also avoids unwanted side-
reactions arising from 2 such as dimerization.
In the case of entry 6, calculations predicted that the cyclic
radical was slightly higher in energy that the acyclic amidyl
radical (ΔGcyclization = 1.3 kcal/mol). In this case, only a small
amount of cyclized product was obtained experimentally (Table
3, entry 7). This observation cannot be generally applied,
however.
Computational analysis also suggests that the energy
difference between the acyclic amidyl radical and the cyclized
radical is small for reactions that originate from the coupling of
a ketene dithioacetal to an O-benzyl hydroxamate to form a six-
membered ring. For example, the cyclization originating from
18d was calculated to be endergonic by 1.3 kcal/mol (Table,
entry 4). In this case, the cyclization leads to a good yield of the
desired product (Table 2, entry 2). Assuming that the
computational results are reliable, we suspect that for 18d the
ease with which the cyclic radical is oxidized plays a large role in
the success of the cyclization. The efficient oxidation of the
pathways. First, amidyl radical 24 may couple to the olefin to
give intermediate 26 with no intramolecular electron transfer.
Alternatively, an intramolecular single electron transfer from
the closely positioned olefin to the amidyl radical may occur to
form 25. In this case, trapping of the radical cation by the
alcohol would afford intermediate 27. Both intermediates 26
and 27 undergo a second single electron oxidation at the anode,
which ultimately leads to the formation of the final product(s)
from each pathway. Once the final products are formed, the
reaction is over as the final products cannot convert back to the
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open-shell intermediates. The outcome of the reaction is
determined by the equilibrium between open-shell intermedi-
ates 24, 25, 26, and 27.
ketene dithioacetal and the first single electron oxidation took
place at the electron-rich olefin.
The experimental results for the electrolysis of 23 are shown
in Table 6. We chose lithium perchlorate as the electrolyte for
CONCLUSION
■
Amidyl radicals can be generated anodically from O-benzyl
hydroxamates and N-phenyl amides under mild conditions.
These amidyl radicals undergo cyclization reactions with
electron-rich olefins to form both γ- and δ-lactam structures
found in a number of biologically active natural products. The
radical nature of the cyclizations was supported by cyclic
voltammetry data and DFT calculations. The success of these
reactions depends on controlling the energetics of the
cyclization relative to the competing pathways of radical−
radical dimerization and H-abstraction. The relative energetics
of these reaction pathways can be modulated to favor
cyclization through the appropriate selection of the amide
and olefin substituents. In general, ketene dithioacetal groups
were found to be the most effective coupling partners for the
reactions.
Table 6. Competition Experiment Results
yield (%)
entry current (mA) temp. (°C)
base
28
29
30 31
1
2
3
4
5
6
6
45
25
0
LiOMe
65
58
52
25
1
0
0
0
0
3
2
2
0
0
LiOMe
6
LiOMe
2
5
EXPERIMENTAL SECTION
40
6
0
LiOMe
24
38
6
■
25
2,6-lutidine
12
Electrolysis Procedure. A methanol or methanol/tetrahydrofuran
solution containing the electrolysis substrate (80−120 mg, 0.03 M)
and electrolyte (lithium perchlorate or tetraethylammonium tosylate,
0.1 M) was prepared in a three-necked round-bottom flask under
argon atmosphere. If desired for the reaction conditions, lithium
methoxide (0.5 equiv, 1 M in methanol) was added to the solution. A
reticulated vitreous carbon anode and a platinum cathode were
inserted into the solution, and the flask was sonicated for 30 s.
Electrolysis was performed with stirring at a constant current of 6.0
mA until 2.2 F/mol of electric charge had been passed through the
solution, unless otherwise noted. Thin layer chromatography was used
to monitor reaction progress. If the electrolysis reaction was carried
out at a higher current, a room-temperature water bath was used to
keep the reaction from heating. See the Supporting Information for
more details of the electrolysis setup.
If lithium perchlorate was used as the electrolyte, water and ether
were added to the reaction upon completion. The organic layer was
separated, and the aqueous layer was extracted twice with ether. The
combined organic extracts were dried with anhydrous magnesium
sulfate and concentrated under reduced pressure.
If tetraethylammonium tosylate was used as the electrolyte, the
reaction solvent was removed under reduced pressure without
performing an extraction.
this electrolysis reaction. As demonstrated in our previous
competition experiments, this change permits the alcohol-
trapping pathway to be more competititive.14c Results obtained
using the standard conditions presented throughout this paper
(constant current of 6 mA, room temperature) are shown in
entry 2. Product 28, arising from the amide-cyclization
pathway, was obtained in a 58% yield. A small amount of the
undesired amide-trapping product 31 was also obtained. It was
found that the yield of the amide-cyclization products could be
improved marginally by heating the reaction (entry 1).
Alcohol-trapping products 29 and 30 were not detected until
the reaction was run at 0 °C (entry 3). Increasing the current
(that is, the rate of oxidation) also led to higher yields of
alcohol-trapping products. At a current of 40 mA and a
temperature of 0 °C, alcohol-trapping products 29 and 30
become the most abundant products, with a combined yield of
30% (entry 4). Under these conditions, amide-cyclization was
reduced to a 25% yield.
These results indicate that amidyl radicals behave similarly to
the previously studied sulfonamide radicals.14c The formation
of both radicals in the presence of the electron-rich olefin
allows for an intramolecular electron transfer reaction and the
reversible formation of a radical cation intermediate. The
alcohol-trapping pathway for the radical cation is the kinetically
favored pathway and may be selected for through the use of low
temperature and high current conditions. The higher current
helps intermediate 27 to be oxidized quickly before the
cyclization can reverse to regenerate intermediate 25. The
amidyl radical cyclization pathway appears to be thermody-
namically favored, and may be selected for through the use of
high temperature and low current conditions. These conditions
facilitate equilibration to the thermodynamically favored
intermediate 26 prior to oxidation to the final product.
Alcohol-trapping products were most effectively obtained
through the use of less basic conditions (Table 6, entry 5).
When 2,6-lutidine was substituted for lithium methoxide, the
reaction led to almost no amide cyclization products and a
combined 50% yield of alcohol-trapping products. Under these
conditions, the amide oxidizes at higher potential than the
The crude residue was purified via column chromatography through
silica gel with hexanes and ethyl acetate. Compounds containing a
ketene dithioacetal moiety were stable to chromatography. However,
electrolysis products containing a dithioacetal were not. For these
compounds, packing the column with triethylamine (1% by wt)
prevented decomposition.
Cyclic Voltammetry. A solution of methanol containing the
substrate (0.025 M) and electrolyte (tetraethylammonium tosylate, 0.1
M) was prepared. Lithium methoxide (0.6 equiv, 1 M solution in
methanol) was added, if desired. Cyclic voltammetry was performed
on a BAS Cell Stand (model C1B-120) using a glassy carbon working
electrode (3 mm diameter), a platinum counter electrode, and a Ag/
AgCl reference electrode. The potential sweep was performed at a rate
of 25 mV/s, with the sweep beginning in the positive direction. This
produced an irreversible oxidation wave, and the half-wave oxidation
potential (Ep/2) was reported as the oxidation potential of the
substrate.
General Methods. Unless otherwise noted, reactions described
herein were performed in flame-died glassware under a dry argon
atmosphere. Tetrahydrofuran was distilled from benzophenone and
sodium prior to use. Triethylamine was distilled from calcium hydride.
Dichloromethane was distilled from calcium hydride. All other
384
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The Journal of Organic Chemistry
Article
solvents, reagents, and starting materials were purchased commercially
and used without further purification.
(ESI-FTICR) m/z (M + H)+ calcd for C18H26NO3S2 368.1349, found
368.1348.
Compounds reported in this work were characterized by NMR, FT-
Methyl 1-(benzyloxy)-2,3-dimethyl-5-oxo-2-pyrrolidinecarboxy-
late (11a). Isolated as a single diastereomer in the form of a white,
crystalline solid (mp 77−81 °C): IR (neat, cm−1) 1737, 1727, 754,
701; 1H NMR (300 MHz, CDCl3) δ 7.44−7.33 (m, 5H), 5.17 (d, J =
9.9 Hz, 1H, A of AB pattern), 5.08 (d, J = 9.9 Hz, 1H, B of AB
pattern), 3.76 (s, 3H), 2.62 (dd, J = 16.8, 8.7 Hz, 1H), 2.50−2.42 (m,
1H), 1.97 (dd, J = 16.8, 6.6, 1H), 1.31 (s, 3H), 1.08 (d, J = 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 173.4, 172.2, 135.5, 129.7, 128.9,
128.6, 78.4, 69.5, 53.0, 35.1, 32.9, 15.7, 15.0; HRMS (ESI-TOF) m/z
(M + H)+ calcd for C15H20NO4 278.1387, found 278.1386.
Methyl 1-(benzyloxy)-2-methyl-6-oxo-2-piperidinecarboxylate
1
IR, and ESI-MS. H and 13C NMR spectra were collected on either a
300 or 600 MHz spectrometer, with chemical shifts reported in ppm as
1
referenced to an internal TMS standard (δ = 0.00 ppm for both H
and 13C NMR).
Characterization of Electrolysis Products. 1-(Benzyloxy)-5-(2-
methoxy-1,3-dithian-2-yl)-5-methyl-2-pyrrolidinone (6a). Isolated as
a white, crystalline solid (mp 104−109 °C): IR (neat, cm−1) 1713,
1375, 1066, 754, 699; 1H NMR (300 MHz, CDCl3) δ 7.49−7.26 (m,
5H), 5.21 (d, J = 9.6 Hz, 1H, A of AB pattern), 5.05 (d, J = 9.6 Hz, 1H,
B of AB pattern), 3.56 (s, 3H), 2.98−2.78 (m, 4H), 2.67−2.59 (m,
1H), 2.54−2.41 (m, 1H), 2.28−2.19 (m, 1H), 1.99−1.74 (m, 3H),
1.56 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 172.2, 135.8, 129.4,
128.6, 128.5, 101.4, 77.6, 72.7, 72.7, 53.1, 28.5, 27.1, 22.5, 22.0; HRMS
(ESI-FTIRC) m/z (M + H)+ calcd for C17H24NO3S2 354.1192, found
354.1189.
1-(Benzyloxy)-5-(2-methoxy-1,3-dithian-2-yl)-5-methyl-2-pyrroli-
dinone (6b). Isolated as a yellow, crystalline solid (mp 123−140 °C):
IR (neat, cm−1) 1697, 1362, 1086, 698; 1H NMR (300 MHz, CDCl3)
δ 7.38−7.21 (m, 5H), 3.34 (s, 3H), 3.00−2.68 (m, 6H), 2.50−2.40 (m,
1H), 2.06−1.75 (m, 3H), 1.69 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
176.9, 138.6, 128.5, 127.8, 103.0, 52.0, 31.4, 30.7, 29.1, 28.6, 25.1, 21.7;
HRMS (ESI-TOF) m/z (M + H)+ calcd for 324.1086, found
324.1100.
1
(11b). IR (neat, cm−1) 1739, 1678, 756, 699; H NMR (300 MHz,
CDCl3) δ 7.50−7.28 (m, 5H), 5.10 (d, J = 9.6 Hz, 1H, A of AB
pattern), 4.88 (d, J = 9.6 Hz, 1H, B of AB pattern), 3.74 (s, 3H), 2.57−
2.51 (m, 2H), 2.22−2.15 (m, 1H), 1.99−1.89 (m, 1H), 1.79−1.70 (m,
2H), 1.59 (s, 3H), 1.59 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.4,
170.1, 135.6, 129.6, 128.7, 128.6, 128.6, 69.1, 53.0, 36.2, 33.5, 23.0,
18.3; HRMS (ESI-TOF) m/z (M + Na)+ cald for C14H17NO4Na
286.1055, found 286.1051.
Methyl 6-(1,3-dithian-2-ylidene)heptanoate (12c). Isolated as a
1
clear, green-yellow oil: IR (neat, cm−1) 1737, 1434, 1192; H NMR
(300 MHz, CDCl3) δ 3.60 (s, 3H), 2.82−2.76 (m, 4H), 2.33−2.25 (m,
4H), 2.09−2.03 (m, 2H), 1.83 (s, 3H), 1.62−1.51 (m, 2H), 1.41−1.31
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 174.2, 140.2, 119.8, 51.6,
35.5, 34.1, 30.4, 30.3, 27.5, 25.2, 24.7, 20.3; HRMS (ESI-TOF) m/z
(M + Na)+ calcd for C12H20O2S2Na 283.0802, found 283.0797.
1-(Benzyloxy)-5-[methoxy(methylthio)methyl]-5-methyl-2-pyrro-
lidinone (16a). Isolated as a 5:1 mixture if diastereomers in the form
of a yellow, crystalline solid (mp 83−90 °C): IR (neat, cm−1) 1714,
Methyl 1-(benzyloxy)-2-methyl-5-oxo-2-pyrrolidinecarboxylate
1
(7a). IR (neat, cm−1) 1740, 1718, 1454, 756, 698; H NMR (300
MHz, CDCl3) δ 7.48−7.30 (m, 5H), 5.12, (d, J = 10.2 Hz, 1H, A of
AB pattern), 5.06 (d, J = 10.2 Hz, 1H, B of AB pattern), 3.77 (s, 3H),
2.58−2.35 (m, 2H), 2.30−2.21 (m, 1H), 2.00−1.89 (m, 1H), 1.47 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 173.2, 173.0, 135.4, 129.9, 129.0,
128.7, 78.6, 66.0, 53.1, 29.1, 26.7; HRMS (ESI-TOF) m/z (M + Na)+
calcd for 286.1055, found 286.1051.
(Benzyloxy)[5-(2-methoxy-1,3-dithian-2-yl)-5-methyl-4,5-dihy-
dro-3H-fur-2-ylidene]amine (8a). Isolated as a 4:1 mixture of
isomers: IR (neat, cm−1) 1674, 1453, 1052, 732, 698; 1H NMR
(300 MHz, CDCl3) δ 7.43−7.22 (m, 5H), 4.97 (s, major, 1.6H), 4.93
(s, minor, 0.4H), 3.54 (s, major, 2.4H), 3.52 (s, minor, 0.6H), 3.02−
2.56 (m, 7H), 1.97−1.76 (m, 3H), 1.57 (s, major, 2.4H), 1.50 (s,
minor, 0.6H); 13C NMR (75 MHz, CDCl3, only data for major isomer
are given) δ 159.2, 138.8, 128.5, 128.0, 127.6, 100.6, 96.9, 75.9, 53.1,
31.9, 28.0, 27.7, 26.7, 23.0, 22.9; HRMS (ESI-TOF) m/z (M + H)+
calcd for C17H24NO3S2 354.1192, found 354.1192.
1
1453, 1092, 755, 698; H NMR (300 MHz, CDCl3) δ 7.50−7.28 (m,
5H), 5.22 and 5.13 (minor and major, respectively; d, J = 9.9 Hz, 1H,
A of AB pattern), 4.96 and 4.93 (major and minor, respectively; d, J =
9.9 Hz, 1H, B of AB pattern), 4.33 (major, s, 1H), 4.28 (minor, s, 1H),
3.45 (minor, s, 3H), 3.41 (major, s, 3H), 2.60−2.33 (m, 1H), 2.27−
2.20 (m, 2H), 2.18 (major, s, 3H), 2.14 (minor, s, 3H), 1.71−1.60 (m,
1H), 1.35 (minor, s, 3H), 1.31 (major, s, 3H); 13C NMR (75 MHz,
CDCl3) δ 173.1, 135.7, 129.6, 128.9, 128.6, 94.0, 78.4, 67.5, 58.3, 27.3,
25.5, 23.5, 15.5; HRMS (ESI-TOF) m/z (M + Na)+ calcd for
C15H21NO3SNa 318.1140, found 318.1136.
1-(Benzyloxy)-5-(dimethoxymethyl)-5-methyl-2-pyrrolidinone
(16b). IR (neat, cm−1) 1712, 1076, 699; 1H NMR (300 MHz, CDCl3)
δ 7.45−7.35 (m, 5H), 5.19 (d, J = 9.9 Hz, 1H, A of AB pattern), 4.91
(d, J = 9.9 Hz, 1H, B of AB pattern), 4.22 (s, 1H), 4.38 (s, 3H), 4.35
(s, 3H), 3.46−2.17 (m, 3H), 1.58−1.47 (m, 1H), 1.19 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 173.4, 135.7, 129.6, 128.9, 128.6, 108.6,
78.5, 65.6, 59.1, 57.6, 27.5, 23.9, 21.9; HRMS (ESI-TOF) m/z (M +
Na)+ calcd for C15H21NO4Na 302.1368, found 302. 1375.
1-(Benzyloxy)-2-methyl-5-oxo-2-pyrrolidinecarbaldehyde. Iso-
lated as a clear, yellow oil: IR (neat, cm−1) 1707, 1065, 699; 1H
NMR (300 MHz, CDCl3) δ 9.23 (s, 1H), 7.43−7.34 (m, 5H), 5.00 (s,
2H), 2.41 (t, J = 7.8 Hz, 2H), 2.16−2.07 (m, 1H), 1.82−1.72 (m, 1H),
1.33 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 198.9, 172.7, 135.0,
129.9, 129.3, 128.9, 78.7, 69.4, 26.1, 25.1, 17.3; HRMS (ESI-TOF) m/
z (M + H)+ calcd for C13H16NO3 234.1125, found 234.1126.
1-(Benzyloxy)-6-[methoxy(methylthio)methyl]-2-piperidinone
(16e). Isolated as a 5:1 mixture of diastereomers in the form of a
yellow, crystalline solid (mp 68−76 °C): IR (neat, cm−1) 3467, 2923,
1700; 1H NMR (300 MHz, CDCl3) δ 7.48−7.33 (m, 5H), 5.01 (d, J =
10.8 Hz, 1H, A of AB pattern), 4.93 (d, J = 10.8 Hz, 1H, B of AB
pattern), 4.75 (d, J = 2.6 Hz, 0.83H), 4.72 (d, J = 3.9 Hz, 0.17H), 3.74
(dt, J (d) = 3.9 Hz, J (t) = 6.9 Hz, 0.17H), 3.56 (dt, J (d) = 2.5 Hz, J
(t) = 6.0 Hz, 0.83H), 3.44 (s, 3H), 2.54−2.40 (m, 2H), 2.16 (s, 0.5H),
2.15 (s, 2.5H), 2.05−1.8 (m, 3H), 1.62−1.46 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 169.2, 135.5, 129.5, 128.8, 128.5, 88.8, 76.1, 64.6,
58.0, 33.5, 23.6, 19.0, 15.1; HRMS (ESI-TOF) m/z (M + Na)+ calcd
for C15H21NO3SNa 296.1315, found 296.1316.
N-Methyl[5-(2-methoxy-1,3-dithian-2-yl)-5-methyl-4,5-dihydro-
3H-fur-2-ylidene]amine (8d). Isolated as a clear, yellow oil. Isolated as
1
a single isomer: IR (neat, cm−1) 1714, 1126, 1062; H NMR (300
MHz, CDCl3) δ 3.53 (s, 3H), 3.19−2.71 (m, 4H), 2.89 (s, 3H), 2.63−
2.50 (m, 3H), 2.02−1.77 (m, 3H), 1.46 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 163.4, 100.0, 93.4, 53.7, 34.7, 32.2, 28.8, 27.4, 27.0, 23.8,
22.6; HRMS (ESI-TOF) m/z (M + H)+ calcd for C11H20NO2S2
262.0930, found 262.0936.
1-(Benzyloxy)-5-(2-methoxy-1,3-dithian-2-yl)-4,5-dimethyl-2-pyr-
rolidinone (10a). Isolated as a single diastereomer: IR (neat, cm−1)
1
1706, 1376, 1080; H NMR (300 MHz, CDCl3) δ 7.50−7.47 (m,
2H), 7.37−7.33 (m, 3H), 5.25 (d, J = 9.6 Hz, 1H, A of AB pattern),
5.05 (d, J = 9.6 Hz, 1H, B of AB pattern), 3.58 (s, 3H), 2.94−2.71 (m,
6H), 2.01−1.76 (m, 3H), 1.44 (s, 3H), 1.10 (d, J = 6.9 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 171.2, 135.7, 129.4, 128.6, 128.5, 102.7,
77.4, 75.3, 53.0, 36.5, 30.7, 28.4, 28.1, 22.4, 19.3, 16.1; HRMS (ESI-
FTICR) m/z (M + H)+ calcd for C18H26NO3S2 368.1349, found
368.1344.
1-(Benzyloxy)-6-(2-methoxy-1,3-dithian-2-yl)-6-methyl-2-piperi-
dinone (10b). Isolated as a clear, colorless gum: IR (neat, cm−1) 1671,
1
1332, 1085, 734, 698; H NMR (300 MHz, CDCl3) δ 7.49−7.47 (m,
2H), 7.34−7.26 (m, 3H), 5.20 (d, J = 9.6 Hz, 1H, A of AB pattern),
4.83 (d, J = 9.6 Hz, 1H, B of AB pattern), 3.54 (s, 3H), 2.91−2.80 (m,
4H), 2.49−2.40 (m, 3H), 1.96−1.78 (m, 4H), 1.62 (m, appears as a
singlet, 4H); 13C NMR (75 MHz, CDCl3) δ 170.5, 136.1, 129.2, 128.4,
128.3, 102.9, 73.7, 53.0, 35.5, 34.2, 28.4, 28.1, 22.4, 22.2, 18.2; HRMS
1-(Benzyloxy)-6-(dimethoxymethyl)-2-piperidinone (16f). Isolated
as a white, crystalline solid (mp 80−90 °C): IR (neat, cm−1) 3468,
385
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The Journal of Organic Chemistry
Article
1
2918, 2848, 1723, 1700; H NMR (600 MHz, CDCl3) δ 7.46−7.42
1.73 (m, 6H), 1.63 (s, 1H), 1.57 (dt, J (d) = 13.2 Hz, J (t) = 3.9 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 157.9, 139.1, 128.1, 127.6, 127.2,
95.6, 89.9, 75.4, 62.8, 31.5, 30.8, 26.2, 26.1, 25.6, 24.8, 21.8; HRMS
(ESI-FTICR) m/z (M + H)+ calcd for 366.1192, found 366.1191.
(Electrolysis Product 31). Isolated as a clear, colorless oil: IR (neat,
cm−1) 3422, 2932, 1701, 1695, 1690; 1H NMR (600 MHz, DMSO-d6)
δ 7.65−7.30 (m, 5H), 5.09 (d, J = 9.6 Hz, A of AB pattern, 1H), 5.02
(d, J = 9.6 Hz, B of AB pattern, 1H), 4.46 (t, J = 5.2 Hz, not present
after addition of D2O, 1H), 3.58 (s, 3H), 3.41−3.32 (2H), 3.10−2.98
(m, 2H), 2.96−2.88 (m, 2H), 2.56−2.51 (m, 1H), 2.37−2.25 (m, 2H),
2.22−2.14 (m, 1H), 2.11−2.02 (m, 1H), 2.00−1.92 (m, 1H), 1.80−
1.68 (m, 2H), 1.43−1.33 (m, 1H), 1.27−1.15 (m, 1H); 13C NMR (75
MHz, DMSO-d6) δ 172.0, 135.5, 128.5, 128.2, 128.1, 99.9, 75.6, 74.6,
60.6, 52.7, 28.3 (two overlapping signals), 28.0, 26.6, 26.0, 24.8
(broad), 21.9; HRMS (ESI-TOF) m/z (M + Na)+ calcd for
C19H27NO4S2Na 420.1277, found 420.1274.
(m, 2H), 7.40−7.33 (m, 3H), 5.00 (d, J = 10.8 Hz, 1H, A of AB
pattern), 4.96 (d, J = 10.8 Hz, 1H, B of AB pattern), 4.59 (d, J = 3 Hz,
1H), 3.47 (s, 3H), 4.46−3.42 (m, 1H), 3.41 (s, 3H), 2.44 (t, J = 7.2
Hz, 2H), 2.04−1.97 (m, 1H), 1.97−1.89 (m, 1H), 1.77−1.69 (m, 1H),
1.56−1.48 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 169.0, 135.5,
129.5, 128.7, 128.5, 104.5, 75.9, 61.7, 58.0, 56.6, 33.4, 22.3, 18.8;
HRMS (ESI-TOF) m/z (M + Na)+ calcd for C15H21NO4Na 280.1543,
found 280.1553.
Methyl 5-methyl-6-(methylthio)-5-hexenoate (17c). Isolated as a
3:2 mixture of isomers in the form of a clear, colorless oil: IR (neat,
cm−1) 2950, 2920, 1738, 1624, 1436; H NMR (300 MHz, CDCl3) δ
1
5.64 (s, 0.4H), 5.61 (s, 0.6H), 3.67 (s, 3H), 2.33 (t, J = 7.8 Hz, 0.8H),
2.29 (t, J = 7.5 Hz, 1.2H), 2.25 (s, 1.8H), 2.22 (s, 1.2H), 2.19 (t, J =
8.1 Hz, 0.8H), 2.09 (t, J = 7.5 Hz, 1.2), 1.82−1.67 (m, 5H); 13C NMR
(75 MHz, CDCl3) δ 174.0, 135.7, 134.9, 121.5, 121.2, 51.5, 38.4, 33.4,
33.5, 33.3, 32.8, 22.9, 22.7, 22.5, 17.6, 17.3, 17.2; HRMS (ESI-FTIRC)
m/z (M + H)+ calcd for C9H17O2S 189.0943, found 189.0944.
Methyl 6-methoxy-5-methyl-5-hexenoate (17d). Isolated as a 3:2
mixture of isomers: IR (neat, cm−1) 2950, 2934, 1739, 1684, 1455,
1437; 1H NMR (300 MHz, CDCl3) δ 5.77 (s, 1H), 3.67 (s, 3H), 3.54
(s, 1.8H), 3.50 (1.2H), 2.29 (q, J = 7.5 Hz, 2H), 2.09 (t, J = 7.2 Hz,
0.8H), 1.90 (t, J = 7.2 Hz, 1.2H), 1.71 (quintet, J = 7.2 Hz, 2H), 1.58
(s, 1.8H), 1.52 (s, 1.2H); 13C NMR (75 MHz, CDCl3) δ 174.3, 174.2,
142.5, 142.4, 112.9, 112.6, 59.3, 59.2, 51.5, 51.4, 33.5, 33.3, 33.2, 28.1,
23.1, 22.5, 17.0, 12.5; HRMS (ESI-TOF) m/z (M + Na)+ calcd for
C9H16O3Na 195.0992, found 195.1000.
Synthesis of Electrolysis Substrates. Ethyl 4-(1,3-dithian-2-
ylidene)valerate. For the synthesis of the title compound from ethyl
levulinate, see ref 15.
1-(O-Benzyloxyamino)-4-(1,3-dithian-2-ylidene)-1-pentanone
(5a). To a suspension of O-benzylhydroxylamine hydrochloride
(0.72g, 4.5 mmol) in tetrahydrofuran (15 mL) was added lithium
bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 15 mL, 15 mmol)
at −78 °C. The resulting mixture was stirred at 0 °C until a clear
solution was obtained. The reaction was cooled down to −78 °C, and
ethyl 4-(1,3-dithian-2-ylidene)valerate (0.74 g, 3.0 mmol) in
tetrahydrofuran (3 mL) was added. The reaction was stirred at the
same temperature for 5 h. Water and ether were added. The organic
phase was separated, and the aqueous phase was extracted with ether
twice. The combined organic extracts were dried over anhydrous
magnesium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by chromatography on silica gel with a 3:1
mixture of ether:hexane to give the title compound as a white,
crystalline solid (0.69 g, 71% yield, mp 87−90 °C): IR (neat, cm−1)
Methyl 6-(methylthio)-5-hexenoate (17e). Tentatively assigned on
the basis of 1H NMR data. Isolated as a 3:2 mixture of trans:cis
1
isomers: H NMR (300 MHz, CDCl3) δ 6.01 (d, J = 15 Hz, 0.6H,
major isomer), 5.93 (d, J = 9.6 Hz, 0.4H, minor isomer), 5.56−5.20
(m, 1H), 3.67 (s, 3H), 2.33 (q, J = 7.5 Hz, 2H), 2.27 (s, 1.2H, minor
isomer), 2.23 (s, 1.8H, major isomer), 2.15 (quintet, J = 7.2 Hz, 2H),
1.74 (quintet, J = 7.2 Hz, 0.8H, minor isomer), 1.72 (quintet, J = 7.2
Hz, 1.2H, major isomer).
1
3187, 1655, 749, 698; H NMR (300 MHz, CDCl3) δ 9.19 and 8.33
(2s, 1H), 7.34−7.26 (m, 5H), 4.84 (s, 2H), 2.82−2.75 (m, 4H), 2.60
(t, J = 7.8 Hz, 2H), 2.36−2.00 (m, 4H), 1.84 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 170.4, 137.7, 135.7, 129.5, 128.8, 121.6, 78.3, 31.7,
30.3, 30.1, 24.9, 20.3; HRMS (ESI-TOF) m/z (M + Na)+ calcd for
C16H21NO2S2Na 346.0905, found 346.0911.
1-Anilino-4-(1,3-dithian-2-ylidene)-1-pentanone (5b). To a sol-
ution of ethyl 4-(1,3-dithian-2-ylidene)valerate in tetrahydrofuran and
water (3:1 ratio) was added lithium hydroxide monohydrate. The
reaction mixture was stirred overnight and then treated with 1 M
aqueous HCl until to adjust the pH to 1. The reaction mixture was
extracted three times with diethyl ether. The organic extracts were
combined, dried over anhydrous magnesium sulfate, filtered, and
concentrated under a vacuum.
Methyl 6-methoxy-5-hexenoate (17f). Isolated as a 2:1 mixture of
isomers in the form of an unstable, clear, colorless oil: IR (neat, cm−1)
3033, 2998, 2950, 1738, 1655, 1453, 1437; 1H NMR (300 MHz,
CDCl3) δ 6.29 (d, J = 12.6 Hz, 0,67H), 5.90 (d, J = 6.3 Hz, 0.33H),
4.68 (dt, J (d) = 12.6 Hz, J (d) = 7.5 Hz, 0.67H), 4.31 (dt, J (d) = 6.3
Hz, J (t) = 7.2 Hz, 0.33H), 3.67 (s, 3H), 3.57 (s, 1H), 3.50 (s, 2H),
2.32 (t, J = 7.5 Hz, 0.67H), 2.31 (t, J = 7.5 Hz, 1.33H), 2.10 (q, J = 7.5
Hz, 0.67H), 1.97 (q, J = 7.5 Hz, 1.33H), 1.68 (quintet, J = 7.5 Hz,
2H); 13C NMR (150 MHz, CDCl3) δ 174.3, 174.2, 147.8, 146.9,
105.5, 101.7, 59.5, 55.9, 51.5, 51.4, 33.5, 33.2, 27.1, 25.8, 25.0, 23.3;
HRMS (ESI-FTIRC) m/z (M + H)+ calcd for C8H15O3 159.1016,
found 159.1012.
(Electrolysis Product 28). Isolated as a clear, amorphous gum: IR
1
(neat, cm−1) 2955, 2930, 1710, 1497, 1454, 1423, 1411; H NMR
To a solution of the residue (assumed to be 4-(1,3-dithian-2-
ylidene)valeric acid, 0.57g, 2.6 mmol), aniline (0.48 g, 5.2 mmol) and
4-dimethylaminopyridine (0.032 g, 0.26 mmol) in dichloromethane
was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydro-
chloride (EDC·HCl, 0.75 g, 3.9 mmol) at room temperature. The
reaction was stirred overnight. Ether and 1 M hydrochloric acid were
added. The organic phase was separated and washed with 1 M
hydrochloric acid twice. The combined aqueous phase was extracted
with dichloromethane. The organic extracts were combined, dried over
magnesium sulfate, filtered, and concentrated under reduced pressure.
The residue was chromatographed on silica gel to afford the desired
product as a white, crystalline solid (0.65 g, 85% yield, mp 101−106
(300 MHz, CDCl3) δ 7.54 (d, J = 7.5 Hz, 2H), 7.40−7.27 (m, 3H),
5.54 (d, J = 9.3 Hz, 1H, A of AB pattern), 5.23 (d, J = 9.3 Hz, 1H, B of
AB pattern), 4.01 (t, J = 5.4 Hz, 2H), 3.29−3.06 (m, 2H), 2.78−2.50
(m, 4H), 2.35−2.20 (m, 2H), 2.20−2.02 (m, 2H), 1.95 (t, J = 13.2 Hz,
1H), 1.88−1.69 (m, 2H), 1.62 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 171.7, 135.7, 129.5, 128.31, 128.28, 96.6, 76.8, 67.0, 62.5, 30.3, 27.8,
26.6, 26.1, 26.0, 24.8, 21.9; HRMS (ESI-TOF) m/z (M + Na)+ calcd
for C18H23NO3S2Na 388.1017, found 388.1012.
(Electrolysis Product 29). Isolated as a clear, colorless oil: IR (neat,
cm−1) 2952, 2926, 2874, 1672; 1H NMR (300 MHz, CDCl3) δ 7.60−
7.50 (m, 2H), 7.41−7.29 (m, 3H), 5.26 (d, J = 9.2 Hz, A of AB
pattern, 1H), 5.14 (d, J = 9.2 Hz, B of AB pattern, 1H), 4.13 (dt, J (d)
= 6.6 Hz, J (t) = 8.1 Hz, 1H), 4.07−3.98 (m, 1H), 3.4−3.18 (m, 2H),
2.97−2.62 (m, 4H), 2.47−1.69 (m, 8H); 13C NMR (75 MHz, CDCl3)
δ 167.1, 135.7, 129.4, 128.4 (two overlapping peaks), 87.9, 80.7, 77.6,
70.4, 36.0, 29.21, 29.18, 28.8, 28.6, 26.0, 23.2; HRMS (ESI- FTIRC)
m/z (M + H)+ calcd for C18H24NO3S2 366.1192, found 366.1192.
(Electrolysis Product 30). Isolated as a white, crystalline solid (mp
126−132 °C): IR (neat, cm−1) 2952, 2918, 2867, 1672; 1H NMR (300
MHz, CDCl3) δ 7.44−7.18 (m, 5H), 5.02 (s, 2H), 4.08−3.88 (m, 2H),
3.36−3.20 (m, 1H), 3.12−2.98 (m, 1H), 2.81−2.56 (m, 4H), 2.23−
1
°C): IR (neat, cm−1) 3297, 1659, 1599, 1544, 1498, 1442, 755; H
NMR (300 MHz, CDCl3) δ 7.83 (br, 1H), 7.51 (d, J = 8.1 Hz, 2H),
7.30−7.25 (m, 2H), 7.07 (t, J = 7.5 Hz, 1H), 2.87−2.72 (m, 6H),
2.46−2.41 (m, 2H), 2.11−2.03 (m, 2H), 1.90 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 171.0, 138.3, 137.7, 129.1, 124.4, 121.7, 120.3, 36.0,
31.9, 30.3, 30.1, 24.9, 20.3; HRMS (ESI-TOF) m/z (M + H)+ calcd
for C15H19NOS2 294.0981, found 294.0989.
4-(1,3-Dithian-2-ylidene)valeramide (5c). To a solution of ethyl 4-
(1,3-dithian-2-ylidene)valerate in tetrahydrofuran and water (3:1 ratio)
was added lithium hydroxide monohydrate. The reaction mixture was
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Article
stirred overnight and then treated with 1 M aqueous HCl until to
adjust the pH to 1. The reaction mixture was extracted three times
with diethyl ether. The organic extracts were combined, dried over
anhydrous magnesium sulfate, filtered, and concentrated under a
vacuum.
mmol) at room temperature under argon atmosphere. The reaction
was stirred overnight. Ether and 1 N hydrochloric acid were added.
The organic phase was separated, and aqueous phase was extracted
with dichloromethane. The combined organic solution was dried over
anhydrous magnesium sulfate and concentrated. The residue was
purified by flash chromatography (silica gel, eluting with ether/hexane,
3/1) to provide the title compound as a clear, colorless oil (395 mg,
To a solution of the residue (assumed to be 4-(1,3-dithian-2-
ylidene)valeric acid, 0.44 g, 2.0 mmol) in tetrahydrofuran (5 mL) was
added triethylamine (0.29 mL, 2.1 mmol). The solution was cooled to
0 °C, and ethyl choroformate (0.20 mL, 2.1 mmol) was added. The
reaction was stirred at the same temperature for 0.5 h. Ammonium
hydroxide (28−30% in water, 2.5 mL) was added. The resulting
reaction mixture was stirred overnight. Dichloromethane and water
were added. The organic phase was separated and washed with 1 N
sodium hydroxide, dried over anhydrous magnesium sulfate, and
filtered. The solvent was removed in vacuo to give the desired product
as a colorless solid (0.35 g, 82%): IR (neat, cm−1) 3345, 3185, 1667,
1
85%): IR (neat, cm−1) 3183, 1654, 745, 698; H NMR (300 MHz,
CDCl3) δ 8.39 (br, 1H), 7.37−7.35 (m, 5H), 4.93−4.83 (m, 2H),
3.66−3.63 (m, 1H), 2.87−2.76 (m, 4H), 2.13−2.04 (m, 4H), 1.75 (s,
3H), 0.99 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 169.7,
140.7, 135.7, 129.4, 128.7, 121.4, 78.3, 53.8, 38.6, 34.7, 30.3, 30.0, 25.1,
18.5, 15.1; HRMS (ESI-TOF) m/z (M + H)+ calcd for C17H24NO2S2
338.1243, found 338.1245.
Ethyl 5-(1,3-dithian-2-ylidene)hexanoate. The title compound
was prepared from ethyl 5-oxohexanoate by following literature
procedure used for the synthesis of ethyl 4-(1,3-dithian-2-ylidene)-
valerate and was obtained in a 75% yield: IR (neat, cm−1) 1732, 1244,
1147; 1H NMR (300 MHz, CDCl3) δ 4.12 (q, J = 6.9 Hz, 2H), 2.88−
2.81 (m, 4H), 2.38 (t, J = 7.5 Hz, 2H), 2.88 (t, J = 7.5 Hz, 2H), 2.14−
2.06 (m, 2H), 1.89 (s, 3H), 1.78−1.67 (m, 2H), 1.25 (t, J = 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 173.5, 139.0, 120.7, 60.3, 31.2,
33.9, 30.4, 30.2, 25.1, 23.2, 20.2, 14.4; HRMS (ESI-TOF) m/z (M +
H)+ calcd for C12H21O2S2 261.0977, found 261.0978.
1
1643, 909; H NMR (300 MHz, CDCl3) δ 6.28 (br, 1H), 5.89 (br,
1H), 2.90−2.85 (m, 4H), 2.67 (t, J = 8.1 Hz, 2H), 2.31 (t, J = 8.1 Hz,
2H), 2.16−2.08 (m, 2H), 1.92 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
175.4, 138.0, 121.3, 34.3, 31.9, 30.3, 30.1, 24.9, 20.2; HRMS (ESI-
TOF) m/z (M + H)+ calcd for C9H16NOS2 218.0668, found 218.0671.
4-(1,3-Dithian-2-ylidene)-1-(methylamino)-1-pentanone (5d). To
a solution of ethyl 4-(1,3-dithian-2-ylidene)valerate in tetrahydrofuran
and water (3:1 ratio) was added lithium hydroxide monohydrate. The
reaction mixture was stirred overnight and then treated with 1 M
aqueous HCl until to adjust the pH to 1. The reaction mixture was
extracted three times with diethyl ether. The organic extracts were
combined, dried over anhydrous magnesium sulfate, filtered, and
concentrated under a vacuum.
1-(O-Benzyloxyamino)-5-(1,3-dithian-2-ylidene)-1-hexanone
(9b). The title compound was obtained in a 67% yield (0.52 g) from
ethyl 5-(1,3-dithian-2-ylidene)hexanoate (0.78 g, 3.0 mmol) by
following the procedure employed for the synthesis of 6a. Isolated
1
as a clear, yellow oil: IR (neat, cm−1) 3186, 1655, 748, 698; H NMR
(300 MHz, CDCl3) δ 8.07 (s, 1H), 7.39 (s, 5H), 4.92 (s, 2H), 2.88−
2.78 (m, 4H), 2.36 (t, J = 7.5 Hz, 2H), 2.13−2.02 (m, 4H), 1.88 (s,
3H), 1.80−1.70 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 171.0, 139.3,
135.7, 129.4, 128.8, 120.5, 78.3, 35.3, 32.8, 30.4, 30.3, 25.0, 23.7, 20.2;
HRMS (ESI-TOF) m/z (M + Na)+ calcd for C17H23NO2S2Na
360.1072, found 360.1068.
Methyl 6-(1,3-dithian-2-ylidene)heptanoate. The title compound
was prepared from methyl 6-oxoheptanoate by following literature
procedure used for the synthesis of ethyl 4-(1,3-dithian-2-ylidene)-
valerate and was isolated in 64% yield. For characterization and
spectral data, see electrolysis product 12c.
To a solution of the residue (assumed to be 4-(1,3-dithian-2-
ylidene)valeric acid, 0.287 g, 1.32 mmol) in dichloromethane were
added triethylamine (0.20 mL, 1.45 mmol), N-(3-dimethylamino-
propyl)-N′-ethylcarbodiimide hydrochloride (EDC·HCl, 0.274 g, 1.45
mmol), 4-dimethylaminopyridine (0.016 g, 0.13 mmol), and methyl-
amine hydrochloride (0.096 g, 1.4 mmol). The reaction was stirred
overnight and quenched with 1 N hydrochloric acid. The organic
phase was separated, dried over anhydrous magnesium sulfate, and
concentrated. The residue was chromatographed through silica gel to
afford the desired compound as a white, crystalline solid (0.219 g, 72%,
1
mp 97−102 °C): IR (neat, cm−1) 3305, 1642, 1557; H NMR (300
1-(O-Benzyloxyamino)-6-(1,3-dithian-2-ylidene)-1-heptanone
(9c). The title compound was prepared from methyl 6-(1,3-dithian-2-
ylidene)heptanoate using the same procedure for the synthesis of 6a.
Hence, starting with 3.0 mmol of methyl 6-(1,3-dithian-2-ylidene)-
heptanoate, the desired product was obtained as a white, crystalline
solid (0.69 g, 65% yield, mp 110−114 °C): IR (neat, cm−1) 3194,
3062, 3029, 1658, 698; 1H NMR (300 MHz, CDCl3) δ 8.52 (br, 1H),
7.36 (s, 5H), 4.87 (s, 2H), 2.85−2.77 (m, 4H), 2.32 (t, J = 7.8 Hz,
2H), 2.11−2.03 (m, 4H), 1.86 (s, 3H), 1.61−1.54 (m, 2H), 1.42−1.38
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 171.1, 140.3, 135.6, 129.4,
128.8, 119.7, 78.4, 48.7, 35.5, 33.9, 33.3, 30.5, 30.3, 27.4, 25.2, 20.3;
HRMS (ESI-TOF) m/z (M + Na)+ calcd for C18H25NO2S2 374.1224,
found 374.1221.
1-Anilino-5-(1,3-dithian-2-ylidene)-1-hexanone (9d). To a solu-
tion of ethyl 5-(1,3-dithian-2-ylidene)hexanoate (0.47g, 1.8 mmol) in
tetrahydrofuran (6 mL) and water (2 mL) was added lithium
hydroxide monohydrate (0.38 g, 9.0 mmol). The reaction mixture was
stirred overnight. 1 N hydrochloric acid was added to adjust the pH of
the aqueous solution to 1. Ether was then added, and organic phase
was separated. The aqueous phase was exacted with ether twice. The
organic extracts were combined, dried over anhydrous magnesium
sulfate, filtered, and concentrated under a vacuum to give a white solid.
This white solid (assumed to be 5-(1,3-dithian-2-ylidene)hexanoic
acid) was dissolved in dichloromethane (5 mL). Aniline (0.33 g, 3.6
mol), 4-dimethylaminopyridine (22 mg, 0.18 mmol), and N-(3-
dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC·
HCl, 0.52 g, 2.7 mmol) were added. The resulting mixture was
stirred overnight. 1 N hydrochloric acid was added. The organic phase
was separated and washed with 1 N hydrochloric acid twice. The
combined aqueous phase was extracted with dichloromethane. The
MHz, CDCl3) δ 6.01 (br, 1H), 2.90−2.84 (m, 4H), 2.81 (s, 1.5 H),
2.79 (s, 1.5 H), 2.69−2.64 (m, 2H), 2.29−2.24 (m, 2H), 2.16−2.08
(m, 2H), 1.91 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.1, 138.3,
121.2, 34.9, 32.2, 30.3, 30.2, 26.6, 24.9, 20.2; HRMS (ESI-TOF) m/z
(M + H)+ calcd for C10H18NOS2 232.0824, found 232.0826.
4-(1,3-Dithian-2-ylidene)-3-methylvaleric acid. To a solution of 2-
trimethylsilyl-1,3-dithiane (3.84 g, 20 mmol) in tetrahydrofuran (40
mL) was added n-butyllithium (1.6 M in hexanes, 12.5 mL, 20 mmol)
at −78 °C under argon atmosphere. The solution was stirred at the
same temperature for 0.5 h and then 0 °C for 0.5 h. 3-Methyl-4-
oxopentanoic acid (1.30 g, 10 mmol) in tetrahydrofuran (5 mL) was
added at −78 C. The reaction was allowed to warm to room
temperature gradually and stirred overnight. Water and ether were
added. The aqueous phase was separated and acidified by 1 N
hydrochloric acid to pH 2. The solution was exacted with ether twice.
The combined organic extracts were dried over magnesium sulfate,
filtered, and concentrated. The residue was chromatographed on silica
gel (eluting with ether:hexane = 1:2) to give the desired product (0.40
g, 17%): IR (neat, cm−1) 1705, 1297, 911; 1H NMR (300 MHz,
CDCl3) δ 3.74−3.61 (m, 1H), 2.83−2.77 (m, 4H), 2.37−2.23 (m,
2H), 2.08−2.94 (m, 2H), 1.73 (s, 3H), 0.97 (d, J = 6.9 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 197.3, 140.4, 121.6, 39.5, 34.5, 30.4, 30.1,
25.1, 18.5, 15.1; HRMS (ESI-TOF) m/z (M + H)+ calcd for
C10H16O2S2 233.0664, found 233.0665.
1-(O-Benzyloxyamino)-4-(1,3-dithian-2-ylidene)-3-methyl-1-pen-
tanone (9a). To a solution of 4-(1,3-dithian-2-ylidene)-3-methyl-
valeric acid (320 mg, 1.38 mmol) in dichloromethane (3 mL) were
added triethylamine (0.20 mL, 1.44 mmol), N-(3-dimethylamino-
propyl)-N′-ethylcarbodiimide hydrochloride (EDC·HCl, 291 mg, 1.52
mmol), and O-benzylhydroxylamine hydrochloride (253 mg, 1.58
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Article
organic phases were combined, dried over anhydrous magnesium
sulfate, and concentrated. The residue was purified by flash
chromatography (silica gel, eluting with ether/hexane, 1:1) to provide
the title compound as a yellow, crystalline solid (0.39 g, 70%, mp 75−
78 °C): IR (neat, cm−1) 3297, 1659, 1599, 1543, 1498, 1442, 755; 1H
NMR (300 MHz, CDCl3) δ 7.81 (s, 1H), 7.56 (d, J = 8.1 Hz, 2H),
7.33 (m, 2H), 7.12 (t, J = 7.5 Hz, 1H), 2.91−2.84 (m, 4H), 2.47 (t, J =
7.2 Hz, 2H), 2.37 (t, J = 7.5 Hz, 2H), 2.17−2.07 (m, 2H), 1.94 (s,
3H), 1.92−1.85 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 171.5, 139.5,
138.3, 129.1, 124.3, 120.5, 120.2, 37.1, 35.3, 30.5, 30.3, 25.1, 23.8, 20.3;
HRMS (ESI-TOF) m/z (M + Na)+ calcd for C16H21NOS2Na
330.0957, found 330.0959.
3H); 13C NMR (75 MHz, CDCl3) δ 175.3, 170.6, 143.1, 142.6, 135.8,
129.4, 129.4, 128.7, 78.3, 59.4, 32.3, 31.9, 29.9, 24.5, 17.2, 12.7; HRMS
(ESI-TOF) m/z (M + Na)+ calcd for C14H19NO3Na 272.1263, found
272.1261.
1-(Benzyloxy)-6-hydroxy-6-methyl-2-piperidinone. 4-Acetylbuty-
ric acid (1 mL, 8.124 mmol, 1 equiv) and N-(3-Dimethylamino-
propyl)-N-ethylcarbodiimide hydrochloride (EDC·HCl, 1.868 g, 9.749
mmol, 1.2 equiv) were combined in a flask under an argon
atmosphere, suspended in dichloromethane (17 mL), and cooled to
0 °C. The suspension was then treated with triethylamine (2.19 mL,
16.25 mmol, 2 equiv), stirred at room temperature for 30 min, and
cooled back to 0 °C. O-Benzylhydroxylamine hydrochloride (1.310 g,
8.124 mmol, 1 equiv) was added, and the reaction was warmed to
room temperature and stirred overnight. The following morning,
hydrochloric acid (3 M) was added until a pH of 4 was reached, and
the reaction was extracted three times with dichloromethane. The
combined organic extracts were dried over anhydrous magnesium
sulfate, concentrated under reduced pressure, and chromatographed
through silica gel with a mixture of hexanes and ethyl acetate to give
the desired product as a white, crystalline solid (0.8031 g, 42%, mp
97−100 °C): IR (neat, cm−1) 3317, 2946, 2886, 1707, 1685, 1654,
1637, 1630, 1454; 1H NMR (300 MHz, CDCl3) δ 7.53−7.45 (m, 2H),
7.43−7.34 (m, 3H), 5.13 (d, J = 9.6 Hz, 1H, A of AB pattern), 4.87 (d,
J = 9.6 Hz, 1H, B of AB pattern), 2.91−2.84 (m, 0.7H), 2.60−2.39 (m,
2H), 2.13−1.86 (m, 3H), 1.76−1.64 (m, 1H), 1.61 (s, 3H), 1.57−1.53
(m, 0.3H); 13C NMR (75 MHz, CDCl3) δ 170.1, 135.3, 129.5, 128.7,
128.5, 88.7, 78.2, 37.2, 33.8, 27.2, 17.0; HRMS (ESI-FTIRC) m/z (M
+ Na)+ calcd for C13H17NO3Na 236.1281, found 236.1280.
Ethyl 4-methyl-5-(methylthio)-4-pentenoate. To a suspension of
(methylthiomethyl)triphenylphosphonium chloride (10.7 g, 30 mmol)
in tetrahydrofuran (100 mL) was added a n-butyllithium solution (1.6
M in hexanes, 18.7 mL, 30 mmol) at 0 °C under argon atmosphere.
After the addition was complete, the clear solution was stirred at 0 °C
for 30 min and then treated with ethyl levulinate (S-47, 4.2 mL, 30
mmol). The reaction was warmed to room temperature and then
stirred overnight. The reaction was cooled to 0 °C, and brine and ether
were added. The organic phase was separated, and the aqueous layer
was extracted with ether. The combined organic layers were dried over
magnesium sulfate and concentrated. Chromatography on silica gel
gave the title compound as a colorless oil (2.5 g, 45%): IR (neat, cm−1)
1
1732, 1372, 1157; H NMR (300 MHz, CDCl3) δ 5.62 (s, 1H), 4.09
(q, J = 7.2 Hz, 2H), 2.44−2.32 (m, 4H), 2.21 (s, 3H), 1.69 (m, 3H),
1.22 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.2, 134.1,
121.8, 60.5, 34.4, 33.2, 17.8, 17.3, 14.4; HRMS (ESI-TOF) m/z (M +
H)+ calcd for C9H17O2S 189.0944, found 189.0944.
1-(O-Benzyloxyamino)-5-methyl-6-(methylthio)-5-hexen-1-one
(15c). (Methylthiomethyl)triphenylphosphonium chloride (0.7324 g,
3.113 mmol, 1 equiv), was suspended in 8 mL of tetrahydrofuran
under an argon atmosphere, cooled to 0 °C, and treated with n-
butyllithium. After stirring for 30 min at 0 °C, 1-(benzyloxy)-6-
hydroxy-6-methyl-2-piperidinone was added to the reaction as a
solution in 10 mL of tetrahydrofuran. The reaction was warmed to
room temperature and stirred for 41 h. Saturated aqueous ammonium
chloride was added to quench the reaction. The reaction was extracted
three times with diethyl ether. The combined organic extracts were
dried over anhydrous magnesium sulfate, concentrated under reduced
pressure, and chromatographed with a 1:1 mixture of hexanes:ethyl
acetate to give the desired product as a colorless oil (0.7480 g, 86%):
1-(O-Benzyloxyamino)-4-methyl-5-(methylthio)-4-penten-1-one
(15a). The title compound was synthesized from ethyl 4-methyl-5-
(methylthio)-4-pentenoate using the same procedure for the synthesis
of 6a. Hence, starting with 1.7 mmol of ethyl 4-methyl-5-(methylthio)-
4-pentenoate, the title compound was obtained as a white solid with a
melting point close to room temperature (0.41 g, 91% yield, mp ≤ 35
1
°C): IR (neat, cm−1) 3185, 1654, 750, 698; H NMR (300 MHz,
CDCl3) δ 9.21, 8.99, 8.25 (3s, br, 1H), 7.34 (s, 5H), 5.61 (s, 1H), 4.84
(s, 2H), 2.42−2.11 (m, 7H), 1.70, 1.66 (2s, 3H); 13C NMR (75 MHz,
CDCl3) δ 170.5, 135.6, 133.8, 129.4, 128.8, 122.3, 78.3, 34.7, 31.9,
23.0, 17.8, 17.3; HRMS (ESI-TOF) m/z (M + Na)+ calcd for
C14H19NO2SNa 288.1034, found 288.1036.
Ethyl 5-methoxy-4-methyl-4-pentenoate. To a suspension of
methoxymethyltriphenylphosphonium chloride (2.16 g, 15.0 mmol) in
tetrahydrofuran (50 mL) was added sodium bis(trimethylsilyl)amide
(1.0 M in tetrahydrofuran, 15.0 mL, 15.0 mmol) at 0 °C. The dark red
solution was stirred at the same temperature for 0.5 h and then treated
with ethyl levulinate. The reaction was allowed to warm to room
temperature slowly and stirred overnight. Brine was added, followed
by ether. The organic layer was separated and aqueous layer extracted
twice with ether. The combined organic layers were dried with
anhydrous magnesium sulfate and concentrated in vacuo. Chromatog-
raphy through silica gel gave the title compound as a mixture of
1
IR (neat, cm−1) 3186, 3064, 3030, 2957, 2920, 2872, 1654, 1507; H
NMR (300 MHz, CDCl3) δ 8.20−7.64 (2 bs, 1H), 7.39 (s, 5H), 5.66−
5.51 (m, 1H), 4.98−4.74 (bs, 2H), 2.46−1.89 (m, 7H), 1.86−1.64 (m,
5H); 13C NMR (75 MHz, CDCl3) δ 170.9, 135.6, 135.5, 134.9, 129.0,
128.4, 121.3, 121.0, 77.9, 38.3, 32.8, 32.5, 32.3, 23.5, 23.0, 22.6, 17.6,
17.2, 17.0; HRMS (ESI-FTIRC) m/z (M + H)+ calcd for C15H22NO2S
280.1355, found 280.1366.
1-(O-Benzyloxyamino)-6-methoxy-5-methyl-5-hexen-1-one
(15d). Methoxymethyltriphenylphosphonium chloride (3.238 g, 9.735
mmol, 3 equiv) was suspended in tetrahydrofuran (5 mL) under an
argon atmosphere, cooled to 0 °C, and treated with lithium
bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 9.74 mL, 9.735
mmol, 3 equiv). The reaction mixture was stirred at 0 °C for 30 min
and treated with 1-(benzyloxy)-6-hydroxy-6-methyl-2-piperidinone
(0.7636 g, 3.245 mmol, 1 equiv) as a solution in tetrahydrofuran
(20 mL) and warmed to room temperature. After stirring overnight,
the reaction was quenched with saturated aqueous ammonium
chloride and extracted three times with diethyl ether. The combined
organic extracts were dried over anhydrous magnesium sulfate,
concentrated under reduced pressure, and chromatographed with a
1:1 mixture of hexanes and ethyl acetate to give the desired product as
a yellow oil and a 3:2 mixture of isomers (0.7007 g, 82%): IR (neat,
cm−1) 3190, 2933, 2837, 1681, 1655, 1508, 1497, 1455; 1H NMR (300
MHz, CDCl3) δ 8.78−7.54 (2 bs, 1H), 7.39 (s, 5H), 5.82−5.64 (m,
1H), 4.97−4.69 (bs, 2H), 3.52 (s, 1.8H), 3.35 (s, 1.2H), 2.51−1.79
(m, 4H), 1.79−1.61 (m, 2H), 1.55 (s, 1.8H), 1.49 (s, 1.2H); 13C NMR
(75 MHz, CDCl3) δ 171.5, 171.1, 142.3, 142.2, 135.7, 129.2, 128.5,
113.2, 112.7, 77.9, 59.14, 59.07, 33.2, 32.3, 27.8, 23.6, 23.0, 16.9, 12.5;
1
isomers (1.60 g, 62%): IR (neat, cm−1) 1735, 1685, 1207, 1129; H
NMR (300 MHz, CDCl3, isolates as a 2.7:1 mixture of two isomers) δ
5.81, 5.75 (2s with fine couplings, 1H), 4.11 (q, J = 6.9 Hz, 2H), 3.53,
3.51 (2s, 3H), 2.39−2.17 (m, 4H), 1.58, 1.53 (2s with fine couplings,
3H), 1.24 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.6,
173.4, 142.8, 142.7, 112.3, 112.1, 60.3, 59.4, 33.6, 32.7, 29.6, 24.8, 17.2,
14.4, 12.6; HRMS (ESI-TOF) m/z (M + Na)+ calcd for C9H16O3Na
195.0992, found 195.0985.
1-(O-Benzyloxyamino)-5-methoxy-4-methyl-4-penten-1-one
(15b). The title compound was prepared from ethyl 5-methoxy-4-
methyl-4-pentenoate by following the procedure employed for the
synthesis of 6a. Starting with 3.2 mmol of ethyl 5-methoxy-4-methyl-4-
pentenoate, the desired product was isolated as a white oil (0.52 g,
1
65% yield): IR (neat, cm−1) 3187, 1656, 1207, 1129, 750, 698; H
NMR (300 MHz, CDCl3, isolated as a 2:1 mixture of isomers) δ 9.13
(major) and 9.08 (minor) (2s, br, 1H), 7.34 (s, 5H), 5.77 (major) and
5.65 (minor) (2s, 1H), 4.84 (s, 2H), 3.47 (major) and 3.38 (minor)
(2s, 3H), 2.28−2.12 (m, 4H), 1.53 (major) and 1.47 (minor) (2s,
388
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The Journal of Organic Chemistry
Article
HRMS (ESI-FTIRC) m/z (M + Na)+ calcd for C15H21NO3Na
286.1418, found 286.1414.
organic extracts were combined, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The crude residue
was chromatographed through silica gel with a 3:1 mixture of
hexanes:ethyl acetate to give the title compound as a 1:1 mixture of
isomers in the form of a clear, colorless oil (0.7560 g, 65%): IR (neat,
Glutaraldehydic acid. 5-Hexenoic acid (2.074 g, 18.17 mmol) was
dissolved in dichloromethane to a concentration of 0.2 M and cooled
to −78 °C. Ozone was blown over the surface of the solution until a
dark blue color was obtained after approximately 30 min. Solution was
then purged with oxygen until excess ozone had dissipated and blue
color had diminished. Dimethyl sulfide (10 equiv) was added, and the
reaction was allowed to slowly warm from −78 °C to room
temperature over the course of several hours. After 10 h, the solvent
was removed in a vacuum, and the residue was chromatographed
through a short column of silica gel with hexanes and ethyl acetate to
give the desired product as a colorless oil (1.999 g, 95% yield): IR
(neat, cm−1) 3418, 3184, 2949, 2740, 17.6, 1410; 1H NMR (300 MHz,
CDCl3) δ 9.79 (s, 1H), 2.57 (t, J = 7.2, 2H), 2.44 (t, J = 7.2 Hz, 2H),
1.97 (q, J = 7.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 202.2, 179.0,
42.7, 32.9, 17.0; HRMS (ESI-TOF) m/z (M + Na)+ calcd for
C5H8O3Na 139.0366, found 139.0361.
1
cm−1) 3036, 3001, 2937, 2667, 1708, 1656, 1455, 1442, 1412; H
NMR (300 MHz, CDCl3) δ 11.33 (bs, 1H), 6.30 (d, J = 12.6, 0.5H),
5.91 (d, J = 6.3 Hz, 0.5H), 4.68 (dt, J (d) = 12.6 Hz, J (t) = 7.2 Hz,
0.5H), 4.31 (dt, J (d) = 6.9 Hz, J (t) = 7.5 Hz, 0.5H), 3.58 (s, 1.5H),
3.51 (s, 1.5H), 2.37 (t, J = 7.5 Hz, 0.5H), 2.36 (t, J = 7.5 Hz, 0.5H),
2.12 (q, J = 7.2 Hz, 0.5H), 2.00 (q, J = 7.2 Hz, 0.5H), 1.69 (quintet, J =
7.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 180.5, 180.4, 147.9, 147.1,
105.3, 101.6, 59.4, 55.8, 33.5, 33.2, 27.1, 25.6, 24.6, 23.2; HRMS (ESI-
TOF) m/z (M + H)+ calcd for C7H13O3 145.0859, found 145.0860.
1-(O-Benzyloxyamino)-6-methoxy-5-hexen-1-one (15f). 6-Me-
thoxy-5-hexenoic acid (0.3102 g, 2.152 mmol, 1 equiv), N-(3-
dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC·
HCl, 0.6187 g, 3.228 mmol, 1.5 equiv), and O-benzylhydroxylamine
hydrochloride (0.5152 g, 3.228 mmol, 1.5 equiv) were added to the
same flask and suspended in dichloromethane under an argon
atmosphere. The suspension was cooled to 0 °C and treated with
triethylamine (0.45 mL, 3.228 mmol, 1.5 equiv). After the reaction
mixture was stirred for 30 min, another 0.45 mL of triethylamine was
added. The reaction mixture was warmed to room temperature and
stirred overnight. The next morning, 3 N hydrochloric acid was added
until the reaction reached pH 4. The aqueous layer was extracted three
times with dichloromethane. The organic extracts were combined,
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The resulting residue was dissolved in diethyl ether
and washed with aqueous sodium bicarbonate until unreacted starting
material was removed from organic layer. The organic layer was then
separated, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The resulting residue was chromatographed
through a short silica gel column with a 1:2 ratio of hexanes:ethyl
acetate to give the desired compound as a colorless oil (0.3595 g,
67%): IR (neat, cm−1) 3192, 3091, 3061, 3032, 2995, 2935, 2959,
6-(Methylthio)-5-hexenoic acid. (Methylthiomethyl)-
triphenylphosphonium chloride (6.799 g, 18.95 mmol, 2.2 equiv)
was suspended in tetrahydrofuran (30 mL) under an argon
atmosphere, cooled to 0 °C, and treated with sodium bis-
(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 18.95 mL, 18.95
mmol, 2.2 equiv). The resulting solution was stirred for 30 min at 0 °C
and treated with glutaraldehydic acid (1.000 g, 8.614 mmol, 1 equiv).
The reaction was allowed to warm to room temperature and stirred for
6 h. Water and diethyl ether were added. The layers were separated,
and the aqueous layer washed twice with diethyl ether. The aqueous
layer was then acidified with hydrochloric acid (3 N) to pH 4 and
extracted three times with diethyl ether. The organic extracts were
combined, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The resulting residue was chromatographed
through a short silica gel column with a 2:1 ratio of hexanes to ethyl
acetate to give the desired compound as a clear, colorless oil and a 3:2
ratio of isomers (1.063 g, 77%): IR (neat, cm−1) 3012, 2921, 2668,
1
1708, 1610, 1435, 1413; H NMR (300 MHz, CDCl3) δ 11.75 (bs,
1
1H), 6.01 (d, J = 15.0 Hz, 0.6H), 5.93 (d, J = 9.3 Hz, 0.4H), 5.43 (m,
1H), 2.37 (q, J = 6.9 Hz, 2H), 2.27 (s, 1.2H), 2.23 (s, 1.8H), 2.21−
2.11 (m, 2H), 1.81−1.66 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
180.3, 128.2, 127.1, 125.4, 125.2, 33.4, 33.3, 28.3, 24.4, 23.9; HRMS
(ESI-TOF) m/z (M + H)+ calcd for C7H13O2S 161.0631, found
161.0633.
1656; H NMR (300 MHz, CDCl3) δ 8.45−7.72 (2 bs, 1H), 7.39 (s,
5H), 6.25 (d, J = 12.9 Hz, 0.67H), 5.90 (d, J = 6.3 Hz, 0.33H), 4.99−
4.86 (bs, 2H), 4.72−4.56 (m, 0.67H), 4.29 (q, J = 7.2 Hz, 0.33H), 3.49
(bs, 3H), 2.35 (t, J = 7.8 Hz, 0.67H), 2.13−2.06 (m, 2H), 1.95 (q, J =
7.2 Hz, 1.33H), 1.68 (quintet, J = 7.2 Hz, 2H); 13C NMR (150 MHz,
CDCl3) δ 171.4, 171.0, 147.7, 146.9, 135.5, 129.2, 128.6, 105.7, 101.8,
78.1, 59.4, 55.9, 32.4, 32.3, 27.1, 26.2, 25.4, 23.0; HRMS (ESI-TOF)
m/z (M + H)+ calcd for C14H20NO3 250.1438, found 250.1437.
1-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-7-hydroxy-4-hepta-
none. (CAS No. 1218900-86-7). tert-Butyl(3-iodoopropoxy)-
dimethylsilane (1.425 g, 4.746 mmol, 1 equiv) was dissolved in
diethyl ether (6 mL) under an argon atmosphere, cooled to −78 °C,
and treated with tert-butyllithium (1.7 M in hexanes, 5.9 mL, 10.0
mmol, 2.1 equiv). The solution was stirred at −78 °C for 30 min and
then at room temperature for 45 min. In a separate flask, δ-
butyrolactone was dissolved in tetrahydrofuran (6 mL) under an argon
atmosphere, cooled to −78 °C, and treated with the prepared lithium
reagent. The reaction was stirred at −78 °C for 15 min and then
poured into water (25 mL). The mixture was extracted three times
with diethyl ether. The combined organic extracts were dried over
anhydrous magnesium sulfate, concentrated under reduced pressure,
and chromatographed through silica gel with a mixture of 1:1
hexanes:ethyl acetate to give the desired compound as a colorless oil
(0.7886 g, 64%). Spectral data for the title compound have been
previously reported.30
1-(O-Benzyloxyamino)-6-(methylthio)-5-hexen-1-one (15e). The
title compound was prepared according to the procedure for the
synthesis of 15f. The starting material was totally consumed in the
reaction, and so no bicarbonate wash was performed. However, two
acid washes (hydrochloric acid, pH 2) of the crude mixture were
required to remove other impurities. Thus, beginning with 0.7125 g of
6-(methylthio)-5-hexenoic acid, 0.9837 g of the desired product was
obtained as a colorless oil and a 3:2 mixture of isomers (83%): IR
(neat, cm−1) 3189, 3090, 3063, 2982, 2921, 2868, 1656, 1514, 1497,
1454, 1437; 1H NMR (300 MHz, CDCl3) δ 8.26−7.61 (bs, 1H), 7.39
(s, 5H), 5.95 (d, J = 14.1 Hz, 0.4H), 5.91 (d, J = 9.3 Hz, 0.6H), 5.93−
5.66 (m, 1H), 5.01−4.72 (bs, 2H), 2.51−2.30 (bm, 0.4H), 2.25 (s,
1.2H), 2.22 (s, 1.8H), 2.19−1.97 (m, 3.6H), 1.81−1.66 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 170.9, 135.4, 128.9, 128.4, 128.3, 128.3,
127.7, 127.2, 125.6, 124.6; HRMS (ESI-TOF) m/z (M + Na)+ calcd
for C14H19NO2SNa 266.1209, found 266.1210.
6-Methoxy-5-hexenoic acid. Methoxymethyltriphenylphospho-
nium chloride (4.077 g, 11.54 mmol, 2.2 equiv) was suspended in
tetrahydrofuran (10 mL) under an argon atmosphere, cooled to 0 °C,
and treated with sodium bis(trimethylsilyl)amide (1.0 M in
tetrahydrofuran, 11.5 mL, 11.54 mmol, 2.2 equiv). The resulting
solution was stirred at 0 °C for 30 min and then treated with
glutaraldehydic acid (0.6089 g, 5.244 mmol, 1 equiv) as a solution in 3
mL of tetrahydrofuran. The reaction was stirred at room temperature
for 6 h, and then water and diethyl ether were added. The layers were
separated, and the aqueous layer was washed twice with diethyl ether.
The aqueous layer was then acidified with 3 N hydrochloric acid to pH
3, whereupon it was extracted three times with diethyl ether. The
1-(Benzyloxy)-5-hydroxy-5-[3-[[(1,1-dimethyl)dimethylsilyl]oxy]-
propyl]-2-pyrrolidinone. 1-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-7-
hydroxy-4-heptanone (CAS No. 1218900-86-7, 0.4152 g, 1.594 mmol)
was dissolved in acetonitrile (6 mL) under argon. N-Methylmorpho-
line N-oxide (1.540 g, 12.73 mmol), water (0.14 mL, 7.96 mmol), and
tetrapropylammonium perruthenate (0.0577 g, 0.1591 mmol) were
added to the flask, and the reaction was stirred at room temperature
for 5 h. Isopropyl alcohol (1.2 mL, 15.91 mmol) was added, and the
reaction was stirred for 30 min to quench the reaction. The solvent
389
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The Journal of Organic Chemistry
Article
was removed under reduced pressure, and the resulting residue was
filtered through silica gel (packed with 1 wt % acetic acid) with ethyl
acetate. The filtered solution was concentrated under reduced
pressure; 13C NMR analysis showed no aldehyde present in the
crude residue, and the crude residue was dried under a vacuum
overnight. The following day, the residue was dissolved in dichloro-
methane (6.1 mL) under argon. N-(3-Dimethylaminopropyl)-N-
ethylcarbodiimide hydrochloride (EDC·HCl, 0.3056 g, 1.594 mmol)
and O-benzylhydroxylamine hydrochloride (0.2544 g, 1.594 mmol)
were added to the flask. The suspension was cooled to 0 °C and
treated with triethylamine (0.21 mL, 1.59 mmol). The reaction was
stirred at room temperature for 30 min and then cooled back to 0 °C
and treated with more triethylamine (0.42 mL, 3.19 mmol). The
reaction was allowed to stir overnight (approximately 16 h), and then
water was added. The aqueous layer was adjusted to pH = 6−7 with 3
N aqueous hydrochloric acid. The layers were separated without
vigorous mixing. The aqueous layer was extracted twice with
dichloromethane. The combined organic extracts were dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The resulting residue was chromatographed through silica
with hexanes and ethyl acetate (successive ratios of 2:1, 1:1, and then
1:2, hexanes:ethyl acetate) to give the desired product as an
amorphous, yellow, waxy solid (0.2299 g, 38%, two steps): IR (neat,
FTIRC) m/z (M + Na)+ calcd for C18H25NO3S2Na 390.1168, found
390.1160.
ASSOCIATED CONTENT
* Supporting Information
■
S
A general procedure for electrolysis reactions, NMR spectra of
new compounds, and detailed computational results. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: moeller@wuchem.edu.
■
Author Contributions
§H.-C. Xu and J. M. Campbell contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the National Science Foundation,
Grant CHE 1151121. Calculations were performed at Yale
University using the Gaussian 09 suite of programs licensed to
the research group of Jonathan A. Ellman.
1
cm−1) 3345, 2954, 2928, 2884, 2856, 1690; H NMR (300 MHz,
CDCl3) δ 7.53−7.44 (m, 2H), 7.42−7.31 (m, 3H), 5.15 (d, J = 9.9 Hz,
1H, A of AB pattern), 5.08 (d, J = 9.9 Hz, 1H), 4.14 (s, 1H), 3.76−
3.52 (m, 2H), 2.61−2.42 (m, 1H), 2.37−2.21 (m, 1H), 2.14−1.95 (m,
3H), 1.84−1.63 (m, 3H), 0.91 (s, 9H), 0.08 (s, 6H); 13C NMR (75
MHz, CDCl3) δ 171.0, 135.2, 129.4, 128.6, 128.4, 90.8, 78.8, 63.2,
35.1, 29.6, 26.5, 26.1, 25.9, 18.3, −5.4; HRMS (ESI-FTIRC) m/z (M +
Na)+ calcd for C20H33NO4SiNa 402.2071, found 402.2069.
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a clear, yellow, viscous oil (0.4594 g, 100%, or 43% over two steps): IR
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1
(neat, cm−1) 3202, 2933, 2871, 1660, 1517, 1497, 1453, 1422; H
NMR (500 MHz, CDCl3) δ 8.17−7.60 (2 bs, 1H, exchanges with
D2O), 7.39 (s, 5H), 4.99−4.75 (bs, 2H), 3.64−3.59 (m, 2H, becomes
t after addition of D2O, J = 5.9 Hz), 2.93−2.82 (m, 4H), 2.64 (t, J =
7.8 Hz, 2H), 2.54−2.44 (bm, 0.5H), 2.39 (t, J = 7.2 Hz, 2H), 2.23−
2.07 (m, 3.5H), 1.80−1.72 (bs, 1H, exchanges with D2O), 1.66
(quintet, J = 6.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 170.1, 141.3,
135.4, 129.3, 128.6 (two overlapping peaks), 122.8, 78.1, 61.9, 31.8,
30.7, 30.1 (two overlapping peaks), 29.7, 29.3, 24.6; HRMS (ESI-
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(24) Density functional theory (DFT) was used to perform all
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391
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