Regioselective Reaction of Heterocyclic N-Oxides, an Acyl Chloride, and Cyclic Thioethers

Article abstract of DOI:10.1021/acs.joc.7b02457

Treatment of electron deficient pyridine N-oxides with 4-nitrobenzoyl chloride and a cyclic thioether in the presence of triethylamine leads to the corresponding 2-functionalized product in up to a 74% isolated yield. The transformation can also be accomplished with alternative nitrogen containing heterocycles, including quinolines, pyrimidines, and pyrazines. To expand the scope of the transformation, diisopropyl ether can be used as the reaction medium to allow for the use of solid thioether substrates.

Full text of DOI:10.1021/acs.joc.7b02457

Note
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
pubs.acs.org/joc
Regioselective Reaction of Heterocyclic N‑Oxides, an Acyl Chloride,
and Cyclic Thioethers
†
†
†
†
‡
Przemyslaw Frei, D. Heulyn Jones, Steven T. Kay, Jayde A. McLellan, Blair F. Johnston,
Alan R. Kennedy,† and Nicholas C. O. Tomkinson*,†
†WestCHEM, Department of Pure and Applied Chemistry, Thomas Graham Building, University of Strathclyde,
2
95 Cathedral Street, Glasgow G1 1XL, United Kingdom
‡
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street,
Glasgow G4 0RE, United Kingdom
*
S Supporting Information
ABSTRACT: Treatment of electron deficient pyridine N-oxides
with 4-nitrobenzoyl chloride and a cyclic thioether in the pres-
ence of triethylamine leads to the corresponding 2-functionalized
product in up to a 74% isolated yield. The transformation can
also be accomplished with alternative nitrogen containing hetero-
cycles, including quinolines, pyrimidines, and pyrazines. To expand the scope of the transformation, diisopropyl ether can be used as
the reaction medium to allow for the use of solid thioether substrates.
itrogen containing heterocycles including pyridines,
N-oxides in the presence of a nucleophile. For example, PyBroP
N
quinolines, pyrazines, and pyrimidines are embedded in
many molecules of agrochemical and pharmaceutical significance.
has been shown to be an excellent reagent in facilitating the addi-
tion of a thiol to the 2-position of a pyridine N-oxide. More
1
8
Methods for either the generation or selective functionalization of
recent methods for the sulfonylation of quinoline and pyridine
9
2−4
N-oxides through reaction with sodium sulfonates, sulfonyl
these heterocycles are therefore of great interest. 2-Substituted
derivatives represent an important subset of this family that
show a broad spectrum of biological activities as exemplified by
nexium, pirfenidone, boscalid, and lunesta (Figure 1), which
10
11
hydrazides, or sulfonyl chlorides have further expanded this
toolbox.
We recently described a simple and effective regioselective
three-component coupling reaction of a pyridine N-oxide 1, an
acyl chloride, and THF, which led to the corresponding
12
2
-functionalized pyridine 2 (Scheme 1). We were interested
Scheme 1. Different Reactivity of Ethers and Thioethers
Figure 1. Examples of 2-heteroatom-substituted pyridine derivatives
with biological activity.
contain carbon, oxygen, chlorine, and nitrogen substitution at
the 2-position, respectively.
5
in discovering if a similar transformation could be performed
using tetrahydrothiophene as a method for preparing 2-thio-
substituted pyridine derivatives. The reaction of 3-cyanopyr-
When compared to the introduction of nitrogen and
6
oxygen heteroatoms at the 2-position of nitrogen containing
heterocycles, the addition of a sulfur atom is a substantially less
developed area. Two principal approaches have been developed
1
idine N-oxide 1a (R = 3-CN) with 4-nitrobenzoyl chloride
for the introduction of a sulfur heteroatom: (1) an S Ar reac-
N
tion on a 2-halo derivative, which is an effective strategy for elec-
Received: September 27, 2017
7
tron deficient substrates, and (2) the activation of heterocyclic
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b02457
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
2
(
R = 4-NO C H , 2.2 equiv) and triethylamine (2.2 equiv) in
Table 2. Reaction of Alternative Heterocyclic N-Oxides
2
6
4
tetrahydrothiophene (0.2 M) at 50 °C overnight did not give 3,
the product analogous to that observed using THF. Instead, the
-substituted pyridine 4a (R = 3-CN) was isolated in an
1
2
excellent 74% yield. With this transformation, a chloride had
been incorporated into the product rather than a molecule of
4-nitrobenzoate. Introduction of the chloride group provided
greater potential for further functionalization, and we believed
this represented a promising new transformation. Within this
manuscript we describe the scope and limitations of this pro-
cess, expand the transformation to encompass alternative nitro-
gen containing heterocycles, and show that the reaction can be
performed effectively in ethereal solvents, allowing a significant
reduction in the amount of sulfide nucleophile used.
Having showed the reaction was effective using 3-cyanopyridine
N-oxide 1a as the substrate under the same conditions devel-
12
oped for the reaction of THF, we went on to examine alterna-
tive pyridine N-oxide substrates (Table 1). While 4-cyanopyridine
a
Table 1. Reaction of Pyridine N-Oxide Substrates
b
entry
N-oxide
R
product
yield (%)
Despite the success observed in the reaction of the N-oxide
substrates shown in Tables 1 and 2, a drawback of the overall
transformation was using sulfide as the reaction medium. This
presented two distinct disadvantages to the process. First, the
sulfide was used in vast excess; for example, in the reaction
of tetrahydrothiophene with 3-cyanopyridine N-oxide 1a the
sulfide was present in a 57 equiv excess (Table 1, entry 1).
Second, the transformation was limited to sulfides which were
liquids at 50 °C. We therefore sought to discover if a suitable
solvent could be found to overcome these challenges (Table 3).
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
3-CN
4-CN
3-Cl
4a
4b
4c
4d
4e
4f
74
28
51
39
37
4-Cl
3-NO2
4-NO2
c
0
1g
1h
1i
2-CF , 5-CN
4g
4h
4i
60
3
d
H
0
d
2-Cl, 6-Cl
0
a
Reactions carried out at 0.2 M with 2.2 equiv of 4-nitrobenzoyl
chloride. Isolated yield. Starting material recovered. Product of
O-benzoylation observed.
b
c
d
a
Table 3. Optimization of the Reaction Solvent
N-oxide 1b was a less effective substrate, the product was easily
purified by column chromatography (entry 2, 28%). 3-Chloro-
and 4-chloropyridine N-oxide 1c and 1d also gave the expected
products in 51% and 39% yields, respectively (entries 3 and 4).
In addition, the disubstituted substrate 1g gave 4g in an excel-
lent 60% yield (entry 7), providing an improved entry to a
scaffold known to be a potent TRPV1 antagonist. The transfor-
mation requires an electron withdrawing group on the pyridine to
proceed (1h, entry 8), although in an extreme case (4f, entry 6)
this prevents O-benzoylation, presumably due to the reduced
nucleophilicity of the N-oxide. Blocking the 2-position of the
pyridine ring resulted in O-benzoylation, but this product did
not lead to the 4-substituted derivative (entry 9).
b
entry
solvent
yield (%)
13
1
2
3
4
5
6
7
8
9
toluene
acetonitrile
THF
0
not isolated
not isolated
acetone
14
26
44
51
42
53
eucalyptol
t-butylmethyl ether
diethyl ether
dibutyl ether
diisopropyl ether
Encouraged by the excellent reactivity shown by pyridine
N-oxide substrates, we went on to examine alternative nitrogen
containing heterocycles within the transformation (Table 2).
Electron deficient quinoline N-oxides smoothly delivered the
a
Reactions carried out at 0.2 M with 2.2 equiv of 4-nitrobenzoyl
b
chloride. Isolated yield.
2
-substituted products (entries 1 and 2). 1,4-Pyrazine N-oxides
(
entries 3 and 4) and a pyrimidine N-oxide (entry 5, 63%) were
Toluene proved ineffective, returning only starting material
after reaction at 50 °C overnight. Both acetonitrile (entry 2)
and THF (entry 3) showed the presence of the desired product
4a in the crude reaction mixture along with a number of
also effective substrates. The transformation therefore appears
to be effective across a range of heterocyclic N-oxides, leading
to functionalized products with excellent opportunities for fur-
ther elaboration.
14
unidentified co-products that incorporated the solvent. Given
B
DOI: 10.1021/acs.joc.7b02457
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
the promise of THF, we postulated that a more hindered
ether may prove effective as the solvent. We initially examined
eucalyptol which gave the product in a 26% isolated yield (entry 5).
We also examined a series of acyclic ethers with different steric
demands (entries 6−9). From this study, diisopropyl ether
emerged as the most effective solvent, which was easy to handle
at the operating temperature of the reaction (entry 9, 53%).
While this gave the product in a yield lower than when using
the sulfide as the reaction solvent (Table 1, entry 1, 74%), the
reduction to 5 equiv of sulfide provided distinct benefits.
Having discovered a suitable solvent with which to undertake
the reaction, we were able to explore the effect of changing the
thioether substrate (Table 4). Crucially, adoption of a solvent
allowed the use of solid thioether substrates (e.g., entry 7).
Two key findings came from this part of the investigation.
We were able to isolate products from the reaction of 3- and
4-membered thioethers which provided 2-substituted pyridine
products (entries 1−3). This was in stark contrast to previous
investigations where we were unable to isolate a product from
the reaction using either epoxides or oxiranes. In addition, the
ring size of the nucleophilic sulfide dictated which product was
obtained from the reaction. Using the strained cyclohexene
sulfide (entry 1) and thiirane (entry 2), the product from the
transformation was 4-nitrobenzoate 3. With less strained 5- and
6-membered ring sulfides as substrates the product was the cor-
responding chloride 4 (entries 5−8). Using thietane as the
substrate gave mixtures of both the 4-nitrobenzoate 3 and the
chloride product 4, the ratio of which could be altered by
changing the reaction temperature (entries 3 and 4).
12
Table 4. Alternative Thioether Substrates
The unexpected change in reaction outcome based upon the
structure of the sulfide is intriguing and provides insight into
the reaction mechanism. A potential mechanistic course for the
process is presented in Scheme 2. O-Benzoylation of 1a
followed by deprotonation leads to the carbene intermediate 13
which can combine with the sulfide to generate the ylide 14.
Sulfur ylides are more stable than their corresponding oxygen
15
variants, which could provide the reason for the product diver-
gence when changing from cyclic ethers to cyclic thioethers and
for the effect of different thioether substrates. Ylides derived
from more strained sulfur nucleophiles will be less stable. There-
fore, the reaction follows path A, eliminating 4-nitrobenzoate fol-
lowed by recombination through ring opening to give the
product 3a. Increasing the stability of the ylide through use of a
less strained sulfide (Table 4, entries 5−8) slows the elimina-
tion of 4-nitrobenzoate and allows for selective ring opening
with the more nucleophilic chloride ion which leads to 4a
16
(
path B). Consistent with this proposal, in reactions where
mixtures of 3a and 4a are observed, reducing the temperature
provides increased amounts of 4a (Table 4, entries 3 and 4).
The introduction of a chloride instead of a 4-nitrobenzoate in
the reaction products was unexpected at the start of this work;
however, chloride is an extremely versatile functional group
(
(
(
Table 5). We examined the addition of a series of nitrogen
entry 1, 97%, and entry 2, 36%), oxygen (entry 3, 97%), sulfur
entry 4, 96%, and entry 5, 34%), phosphorus (entry 6, 32%),
and carbon nucleophiles (entry 7, 88%) to 4a to explore the
flexibility of the transformation in synthesis. Overall, the product
from this novel coupling process provides an effective substrate
for further transformations to introduce diversity.
In summary, we have developed a simple and effective
method for the regioselective functionalization of heterocyclic
N-oxides through the reaction with 4-nitrobenzoyl chloride and
a
b
Reaction carried out at 25 °C. Product isolated as an inseparable
1
:1 mixture of regioisomers.
Scheme 2. Potential Mechanism for the Pyridine N-Oxide Functionalization
C
DOI: 10.1021/acs.joc.7b02457
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(
(
THT) (0.2 M), after purification via flash column chromatography
dry loading, petroleum ether/EtOAc 10:1 isocratic), afforded the title
Table 5. Functionalization of Pyridine Products
−1
compound 4a (138 mg, 0.61 mmol, 74%) as a yellow oil: IR (ATR)/cm
3
1
061, 2936, 2864, 2222, 1571, 1549, 1443, 1391; H NMR
(
(
400 MHz, CDCl ) δ 8.57 (dd, J = 4.9 Hz, J = 1.8 Hz, 1H), 7.79
dd, J = 7.7 Hz, J = 1.8 Hz, 1H), 7.07 (dd, J = 7.7 Hz, J = 4.9 Hz, 1H),
3
entry
nucleophile
product
yield (%)
3
.58 (t, J = 6.3 Hz, 2H), 3.31 (t, J = 6.9 Hz, 2H), 1.99−1.86 (m, 4H);
a
13
1
NaN3
17
18
19
20
21
22
23
97
36
97
96
34
32
88
C NMR (101 MHz, CDCl ) δ 163.0, 152.2, 140.7, 118.6, 115.6,
3
b
2
morpholine
1
07.7, 44.5, 31.6, 29.4, 26.6; LRMS (ES + APCI) m/z calcd for
c
35
+
3
NaOAc
KSAc
C H ClN S 226.0, found 227.0 [M + H] ; HRMS (ESI-TOF) m/z
[M + H] calcd for C H ClN S 227.0410, found 227.0408.
10 12 2
2-((4-Chlorobutyl)thio)isonicotinonitrile (4b). Following General
Procedure A, 4-cyanopyridine N-oxide (100 mg, 0.83 mmol) and
4-nitrobenzoyl chloride (339 mg, 1.83 mmol) in THT (0.2 M), after
purification via flash column chromatography (dry loading, petroleum
10 11 2
d
+
35
4
e
5
4-MeOC H SH
6
4
f
6
P(OEt)3
KCN
g
7
a
b
c
NaN , DMF, 80 °C, 48 h. Morpholine, rt, 48 h. NaOAc, DMF,
3
ether/EtOAc 10:1 isocratic), afforded the title compound 4b (52 mg,
d
e
8
0 °C, 48 h. KSAc, KI, DMF, 80 °C, 48 h. 4-MeOC H CH SH,
−1
6
4
2
0
.23 mmol, 28%) as a yellow oil: IR (ATR)/cm 3050, 2925, 2853,
f
g
Cs CO , DMF, 80 °C, 48 h. P(OEt) , 160 °C, 48 h. KCN, KI,
1
2
3
3
2237, 1584, 1530, 1458, 1365; H NMR (400 MHz, CDCl ) δ 8.55
3
DMF, rt, 18 h.
(
1
d, J = 5.1 Hz, 1H), 7.38−7.36 (m, 1H), 7.15 (dd, J = 5.1 Hz, J =
.4 Hz, 1H), 3.57 (t, J = 6.3 Hz, 2H), 3.22 (t, J = 7.0 Hz, 2H), 1.97−1.83
13
cyclic sulfide under basic conditions. The transformation results
in yields higher than that of the related process involving cyclic
ethers and is tolerant of a greater range of substrates. Thioethers
within a strained 3- or 4-membered ring provide access to an
alternative ester product. It is believed the divergence in the
reaction pathways is due to the formation of a less-stable ylide
intermediate when using thiirane or thietane derivatives as the
reactive sulfide. Thioethers are significantly more reactive than
ethers within this transformation such that ethers are effective
solvents for the reaction, allowing the use of solid sulfides within
the process. The products can be used in a variety of substi-
tution reactions, suggesting they could be useful in the forma-
tion of nitrogen containing heterocycles of pharmaceutical and
agrochemical interest. For example, 2-thio-substituted pyridine
(m, 4H); C NMR (101 MHz, CDCl ) δ 161.5, 150.3, 124.0, 120.4,
120.0, 116.4, 44.5, 31.6, 29.3, 26.7; LRMS (ES + APCI) m/z calcd for
C H ClN S 226.0, found 226.9 [M + H] ; HRMS (ESI-TOF) m/z
3
35
10 11
+
2
+
35
[
M + H] calcd for C H ClN S 227.0410, found 227.0406.
10 12 2
3
-Chloro-2-((4-chlorobutyl)thio)pyridine (4c). Following General
Procedure A, 3-chloropyridine N-oxide (108 mg, 0.83 mmol) and
-nitrobenzoyl chloride (339 mg, 1.83 mmol) in THT (0.2 M), after
4
purification via flash column chromatography (dry loading, petroleum
ether/EtOAc 10:1 isocratic), afforded the title compound 4c (100 mg,
0.42 mmol, 51%) as a yellow oil: IR (ATR)/cm 3044, 2929, 2864,
1566, 1434, 1387; H NMR (400 MHz, CDCl ) δ 8.33 (dd, J = 4.7 Hz,
J = 1.5 Hz, 1H), 7.53 (dd, J = 7.8 Hz, J = 1.5 Hz, 1H), 6.95 (dd, J =
7
2
−1
1
3
.8 Hz, J = 4.7 Hz, 1H), 3.58 (t, J = 7.0 Hz, 2H), 3.23 (t, J = 7.0 Hz,
1
3
H), 1.99−1.84 (m, 4H); C NMR (101 MHz, CDCl ) δ 157.4,
3
1
47.1, 135.9, 129.3, 119.7, 44.6, 31.8, 29.3, 26.7; LRMS (ES + APCI)
3
5
+
17
m/z calcd for C H11 Cl NS 235.0, found 235.9 [M + H] ; HRMS
9 2
N-oxides have been shown to have antibiotic activity. We are
currently engaged in exploiting this transformation in discovery
research and will report on our findings in due course.
+
35
(
ESI-TOF) m/z [M + H] calcd for C H Cl NS 236.0067, found
9 12 2
2
36.0063.
-Chloro-2-((4-chlorobutyl)thio)pyridine (4d). Following General
Procedure A, 4-chloropyridine N-oxide (108 mg, 0.83 mmol) and
-nitrobenzoyl chloride (339 mg, 1.83 mmol) in THT (0.2 M), after
4
EXPERIMENTAL SECTION
4
■
General Procedure A. The appropriate pyridine N-oxide (1.0 equiv)
and 4-nitrobenzoyl chloride (2.2 equiv) were added to a 20 mL flame-
dried microwave vial. The pressure was carefully restored using
a nitrogen/argon balloon. The appropriate cyclic thioether (0.2 M)
was introduced, and the mixture was cooled to 0 °C. Triethylamine
purification via flash column chromatography (dry loading, petroleum
ether/EtOAc 10:1 isocratic), afforded the title compound 4d (77 mg,
0.33 mmol, 39%) as a yellow oil: IR (ATR)/cm 3042, 2933, 2864,
−1
1
1562, 1540, 1452, 1355; H NMR (400 MHz, CDCl ) δ 8.29 (d, J =
3
5.4 Hz, 1H), 7.18−7.16 (m, 1H), 6.97 (dd, J = 5.4 Hz, J = 1.9 Hz, 1H),
3.57 (t, J = 7.0 Hz, 2H), 3.20 (t, J = 7.0 Hz, 2H), 1.97−1.82 (m, 4H);
(
2.2 equiv) was added during rapid stirring of the reaction mixture.
13
Following completion of the addition, the cooling bath was removed
and the mixture was stirred for 5 min at room temperature before
being heated to 50 °C overnight. Ethyl acetate (EtOAc) (5 mL) was
added to the mixture, and the mixture was transferred to a round-
bottomed flask. The volatiles were removed under reduced pressure.
The compounds were purified by flash column chromatography eluted
with the stated solvent systems.
C NMR (101 MHz, CDCl ) δ 161.0, 150.1, 143.9, 122.0, 120.0, 44.6,
3
3
5
31.7, 29.4, 26.8; LRMS (ES + APCI) m/z calcd for C
235.0, found 235.9 [M + H] ; HRMS (ESI-TOF) m/z [M + H] calcd
for C H12 Cl NS 236.0067, found 236.0063.
9 2
2-((4-Chlorobutyl)thio)-3-nitropyridine (4e). Following General
Procedure A, 3-nitropyridine N-oxide (116 mg, 0.83 mmol) and
4-nitrobenzoyl chloride (339 mg, 1.83 mmol) in THT (0.2 M), after
purification via flash column chromatography (dry loading, petroleum
ether/EtOAc 8:1 isocratic), afforded the title compound 4e (75 mg,
0.30 mmol, 37%) as a yellow oil: IR (ATR)/cm 3076, 2931, 2860,
1584, 1554, 1510, 1396, 1329; H NMR (400 MHz, CDCl ) δ 8.68
(dd, J = 4.6 Hz, J = 1.7 Hz, 1H), 8.48 (dd, J = 8.2 Hz, J = 1.7 Hz, 1H),
7.19 (dd, J = 8.2 Hz, J = 4.6 Hz, 1H), 3.59 (t, J = 7.0 Hz, 2H), 3.26
(t, J = 7.0 Hz, 2H), 2.01−1.85 (m, 4H); C NMR (101 MHz, CDCl3)
δ 158.1, 153.2, 142.3, 133.9, 118.7, 44.6, 31.9, 29.8, 26.2; LRMS (ES +
APCI) m/z calcd for C H ClN O S 246.0, found 246.9 [M + H] ;
HRMS (ESI-TOF) m/z [M + H] calcd for C H ClN O S
H
11 Cl
NS
9
2
+
+
35
General Procedure B. The appropriate pyridine N-oxide (1.0 equiv)
and 4-nitrobenzoyl chloride (2.2 equiv) were added to a 20 mL flame-
dried microwave vial. The pressure was carefully restored using a
nitrogen/argon balloon. Diisopropyl ether (0.4 M) and the appropriate
cyclic thioether (5.0 equiv) were introduced, and the mixture was
cooled to 0 °C. Triethylamine (2.2 equiv) was added during rapid
stirring of the reaction mixture. Following completion of the addition,
the cooling bath was removed and the mixture was stirred for 5 min at
room temperature before being heated to 50 °C overnight. EtOAc
−1
1
3
13
35
+
9
11
2
2
+
35
(
5 mL) was added to the mixture, and the mixture was transferred to a
9
12
2
2
round-bottomed flask. The volatiles were removed under reduced
pressure.The compounds were purified by flash column chromatog-
raphy eluted with the stated solvent systems.
247.0308, found 247.0310.
1
9
5-Cyano-2-(trifluoromethyl)pyridine 1-Oxide (1g). To a stirred
mixture of 6-(trifluoromethyl)nicotinonitrile (1.00 g, 5.81 mmol) and urea-
hydrogen peroxide addition complex (UHP) (1.15 g, 12.21 mmol) in
CH Cl (15 mL) was added trifluoroacetic anhydride (TFAA) (1.7 mL,
2
-((4-Chlorobutyl)thio)nicotinonitrile (4a). Following General
Procedure A, 3-cyanopyridine N-oxide (100 mg, 0.83 mmol) and
-nitrobenzoyl chloride (339 mg, 1.83 mmol) in tetrahydrothiophene
2
2
4
12.21 mmol) at 0 °C under an argon atmosphere. The reaction
D
DOI: 10.1021/acs.joc.7b02457
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The Journal of Organic Chemistry
Note
−
1
mixture was allowed to stir at room temperature for 0.5 h. Excess
peroxide was destroyed by the addition of 10% aqueous potassium
iodide solution (50 mL). The organic phase was washed with saturated
a yellow solid: mp 123−125 °C; IR (ATR)/cm 3113, 3081, 2957,
1
2933, 2220, 1716, 1607, 1567, 1519, 1385; H NMR (400 MHz,
CDCl ) δ 8.52 (dd, J = 4.9 Hz, J = 1.8 Hz, 1H), 8.34−8.22 (m, 2H),
3
1
0% aqueous Na S O solution (50 mL) and water (50 mL), dried
8.27−8.22 (m, 2H) 7.80 (dd, J = 7.7 Hz, J = 1.8 Hz, 1H), 7.08 (dd, J =
7.7 Hz, 4.9 Hz, 1H), 4.52 (t, J = 7.0 Hz, 2H), 3.45 (t, J = 7.0 Hz, 2H),
2
2
3
over MgSO , and filtered. The filtrate was concentrated under reduced
4
pressure before the residue was triturated by diethyl ether to afford the
2.26 (app quint, J = 7.0 Hz, 2H); 13C NMR (101 MHz, CDCl ) δ
3
title compound 1g as an off-white solid (571 mg, 3.04 mmol, 52%): mp
164.7, 162.6, 152.2, 150.8, 140.8, 135.7, 130.9, 123.8, 118.8, 115.5,
−1
9
1
8
4−96 °C; IR (ATR)/cm 3031, 2988, 2243, 1605, 1549, 1389, 1277,
107.8, 64.6, 28.6, 26.8; LRMS (ES + APCI) m/z calcd for
1
+
155; H NMR (500 MHz, CDCl ) δ 8.49 (br s, 1H), 7.80 (d, J =
C H N O S 343.1, found 344.0 [M + H] ; HRMS (ESI-TOF)
3
16 13
3
4
13
+
.5 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H); C NMR (125 MHz, CDCl3)
m/z [M + H] calcd for C H N O S 344.0705, found 344.0708.
16 14 3 4
δ 143.8, 126.0, 125.9−125.8 (m, 1C), 122.6, 119.2 (q, J = 271.6 Hz),
2-((3-Chloropropyl)thio)nicotinonitrile (4l). Following General
Procedure B, with stirring at 25 °C overnight, 3-cyanopyridine N-oxide
(100 mg, 0.83 mmol), 4-nitrobenzoyl chloride (339 mg, 1.83 mmol), and
thietane (308 mg, 4.15 mmol) in diisopropyl ether (0.4 M), after
purification via flash column chromatography (dry loading, petroleum
ether/EtOAc 5:1 isocratic), afforded the title compound 4l (100 mg,
FC
1
15.8, 113.1; 19F NMR (471 MHz, CDCl ) δ −69.6 (s, 3F); LRMS
3
+
(
ES + APCI) m/z calcd for C H F N O 188.0, found 187.1 [M + H] ;
HRMS (ESI-TOF) m/z [M + H] calcd for C H F N O 189.0276,
7
3
3
2
+
7
4
3
2
found 189.0274.
-((4-Chlorobutyl)thio)-6-(trifluoromethyl)nicotinonitrile (4g).
2
−1
Following General Procedure A, compound 1g (100 mg, 0.53 mmol)
and 4-nitrobenzoyl chloride (218 mg, 1.17 mmol) in THT (0.2 M), after
purification via flash column chromatography (dry loading, petroleum
ether/CH Cl 3:1 isocratic), afforded the title compound 4g (94 mg,
0.47 mmol, 57%) as a yellow oil: IR (ATR)/cm 3063, 2955, 2222,
1
1571, 1551, 1441, 1391; H NMR (400 MHz, CDCl ) δ 8.57 (dd, J =
3
4.9 Hz, J = 1.8 Hz, 1H), 7.79 (dd, J = 7.7 Hz, J = 1.8 Hz, 1H), 7.08
(dd, J = 7.7 Hz, J = 4.9 Hz, 1H), 3.60 (t, J = 7.0 Hz, 2H), 3.42 (t, J =
2
2
−1
13
0
2
.32 mmol, 60%) as a yellow oil: IR (ATR)/cm 3079, 2940, 2869,
230, 1579, 1361, 1333, 1143; H NMR (500 MHz, CDCl ) δ 7.96
7.0 Hz, 2H), 2.20 (app quint, J = 7.0 Hz, 2H); C NMR (101 MHz,
1
CDCl ) δ 162.6, 152.3, 140.7, 118.7, 115.5, 107.7, 43.5, 32.0, 27.4;
3
3
3
5
(
d, J = 7.5 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 3.58 (t, J = 6.5 Hz, 2H),
LRMS (ES + APCI) m/z calcd for C H ClN S 212.0, found 212.9
[M + H] ; HRMS (ESI-TOF) m/z [M + H] calcd for C H ClN2S
9 10
9 9 2
13
+
+
35
3
.33 (t, J = 6.5 Hz, 2H), 1.98−1.89 (m, 4H); C NMR (125 MHz,
CDCl ) δ 164.6, 150.2 (q, J = 36.1 Hz, 1C), 142.3, 120.7 (q, JFC
=
213.0248, found 213.0248.
3
FC
2
2
73.9 Hz, 1C), 115.1 (q, J = 2.8 Hz, 1C), 114.5, 110.4, 44.3, 31.6,
2-((5-Chloropentyl)thio)nicotinonitrile (4m). Following General
Procedure B, 3-cyanopyridine N-oxide (100 mg, 0.83 mmol),
4-nitrobenzoyl chloride (339 mg, 1.83 mmol), and thiane (424 mg,
4.15 mmol) in diisopropyl ether (0.4 M), after purification via flash
column chromatography (dry loading, petroleum ether/EtOAc 8:1
isocratic), afforded the title compound 4m (66 mg, 0.28 mmol, 33%)
FC
9.9, 26.5; 19F NMR (471 MHz, CDCl ) δ −69.1 (s, 3F); LRMS
3
35
(
ES + APCI) m/z calcd for C H ClF N S 294.0, found 295.0
11 10 3 2
+
+
35
11
[
M + H] ; HRMS (ESI-TOF) m/z [M + H] calcd for C H ClF N S
11
3
2
2
95.0284, found 295.0280.
-((3-Cyanopyridin-2-yl)thio)cyclohexyl 4-Nitrobenzoate (3j).
Following General Procedure B, 3-cyanopyridine N-oxide (100 mg,
2
−
1
as a yellow solid: mp 28−30 °C; IR (ATR)/cm 3059, 2988, 2949,
1
0
7
.83 mmol), 4-nitrobenzoyl chloride (339 mg, 1.83 mmol), and
-thiabicyclo[4.1.0]heptane (476 mg, 4.17 mmol) in diisopropyl
2925, 2853, 2224, 1571, 1545, 1391; H NMR (400 MHz, CDCl )
3
δ 8.57 (dd, J = 4.9 Hz, J = 1.8 Hz, 1H), 7.79 (dd, J = 7.7 Hz, J =
1.8 Hz, 1H), 7.07 (dd, J = 7.7 Hz, J = 4.9 Hz, 1H), 3.55 (t, J = 7.0 Hz,
ether (0.4 M), after purification via flash column chromatography
(
dry loading, petroleum ether/EtOAc 5:1 isocratic), afforded the title
2H), 3.28 (t, J = 7.0 Hz, 2H), 1.88−1.73 (m, 4H), 1.66−1.57 (m, 2H);
−1
13
compound 3j (182 mg, 0.48 mmol, 57%) as a yellow oil: IR (ATR)/cm
C NMR (101 MHz, CDCl ) δ 163.3, 152.2, 140.7, 118.5, 115.7,
3
3
050, 2933, 2856, 2224, 1720, 1571, 1525, 1391, 1346, 1264;
107.7, 44.9, 32.2, 30.0, 28.6, 26.2; LRMS (ES + APCI) m/z calcd for
1
35
+
H NMR (500 MHz, CDCl ) δ 8.62 (dd, J = 5.0 Hz, J = 1.5 Hz, 1H),
C H ClN S 240.0, found 241.1 [M + H] ; HRMS (ESI-TOF)
3
11 13 2
+
35
8.18 (d, J = 9.0 Hz, 2H), 8.03 (d, J = 9.0 Hz, 2H), 7.73 (dd, J = 8.0 Hz,
m/z [M + H] calcd for C H ClN S 241.0566, found 241.0567.
11 14 2
J = 1.5 Hz, 1H), 7.08 (dd, J = 8.0 Hz, J = 5.0 Hz, 1H), 5.19 (td, J =
2-((2-((2-Chloroethyl)thio)ethyl)thio)nicotinonitrile (4n). Follow-
ing General Procedure B, 3-cyanopyridine N-oxide (100 mg, 0.83 mmol),
4-nitrobenzoyl chloride (339 mg, 1.83 mmol), and 1,4-dithiane
(500 mg, 4.15 mmol) in diisopropyl ether (0.4 M), after purification
via flash column chromatography (dry loading, petroleum ether/
EtOAc 7:1 isocratic), afforded the title compound 4n (78 mg, 0.30 mmol,
9
.0 Hz, J = 4.0 Hz, 1H), 4.43 (td, J = 9.0 Hz, J = 4.0 Hz, 1H),
13
2
.37−2.23 (m, 2H), 1.90−1.66 (m, 4H), 1.61−1.51 (m, 2H);
C
NMR (125 MHz, CDCl ) δ 163.8, 162.4, 152.1, 150.6, 140.9, 135.8,
3
1
30.8, 123.5, 119.0, 115.4, 108.1, 77.4, 75.9, 46.5, 31.3, 25.1, 23.4;
LRMS (ES + APCI) m/z calcd for C H N O S 383.1, found 384.2
19
17
3
4
+
+
−1
[M + H] ; HRMS (ESI-TOF) m/z [M + H] calcd for C H N O S
36%) as an off-white solid: mp 58−60 °C; IR (ATR)/cm 3057,
19
18
3
4
1
384.1018, found 384.1019.
2964, 2946, 2929, 2222, 1571, 1553, 1437, 1393; H NMR (400 MHz,
2
-((3-Cyanopyridin-2-yl)thio)ethyl 4-Nitrobenzoate (3k). Follow-
CDCl ) δ 8.62 (dd, J = 4.9 Hz, J = 1.8 Hz, 1H), 7.82 (dd, J = 7.7 Hz,
3
ing General Procedure B, with stirring at 25 °C overnight, 3-cyanopyridine
J = 1.8 Hz, 1H), 7.11 (dd, J = 7.7 Hz, J = 4.9 Hz, 1H), 3.75−3.69
N-oxide (100 mg, 0.83 mmol), 4-nitrobenzoyl chloride (339 mg,
(m, 2H), 3.48−3.42 (m, 2H), 3.04−2.98 (m, 2H), 2.90−2.85 (m, 2H);
13
1
.83 mmol), and thiirane (250 mg, 4.15 mmol) in diisopropyl ether
0.4 M), after purification via flash column chromatography (dry loading,
petroleum ether/EtOAc 5:1 isocratic), afforded the title compound 3k
C NMR (101 MHz, CDCl ) δ 162.3, 152.4, 140.9, 119.0, 115.4,
3
(
107.8, 43.1, 34.0, 31.6, 30.1; LRMS (ES + APCI) m/z calcd for
3
5
+
C H ClN S 258.0, found 259.0 [M + H] ; HRMS (ESI-TOF)
10
11
2 2
+
35
(
(
112 mg, 0.34 mmol, 41%) as an off-white solid: mp 132−134 °C; IR
m/z [M + H] calcd for C H ClN S 259.0130, found 259.0129.
10 12 2 2
−1
ATR)/cm 3109, 3078, 2921, 2853, 2224, 1714, 1608, 1569, 1525,
2-((5-Chloropentan-2-yl)thio)nicotinonitrile and 2-((4-Chloropentyl)-
thio)nicotinonitrile (4o). Following General Procedure B, 3-cyanopyr-
idine N-oxide (100 mg, 0.83 mmol), 4-nitrobenzoyl chloride (339 mg,
1.83 mmol), and 2-methyltetrahydrothiophene (426 mg, 4.15 mmol)
in diisopropyl ether (0.4 M), after purification via flash column
chromatography (dry loading, petroleum ether/EtOAc 10:1 isocratic),
afforded the title compound 4o (90 mg, 0.38 mmol, 45%) as a yellow
1
1
1
7
391; H NMR (400 MHz, CDCl ) δ 8.56 (dd, J = 4.9 Hz, J = 1.8 Hz,
3
H), 8.28 (d, J = 9.0 Hz, 2H), 8.20 (d, J = 9.0 Hz, 2H), 7.83 (dd, J =
.7 Hz, J = 1.8 Hz, 1H), 7.11 (dd, J = 7.7 Hz, J = 4.9 Hz, 1H), 4.65
13
(
t, J = 6.4 Hz, 2H), 3.70 (t, J = 6.4 Hz, 2H); C NMR (101 MHz,
CDCl ) δ 164.6, 161.8, 152.3, 150.8, 141.0, 135.4, 130.9, 123.7, 119.2,
3
1
15.3, 107.9, 64.1, 28.7; LRMS (ES + APCI) m/z calcd for
+
−1
C H N O S 329.0, found 330.0 [M + H] ; HRMS (ESI-TOF) m/z
oil in a 1:1 mixture of regioisomers: IR (ATR)/cm 3056, 2959,
15
11
3
4
+
1
[
M + H] calcd for C H N O S 330.0543, found 330.0545.
2925, 2224, 1573, 1551, 1443, 1391; H NMR (400 MHz, CDCl )
15
12
3
4
3
3
-((3-Cyanopyridin-2-yl)thio)propyl 4-Nitrobenzoate (3l). Follow-
δ 8.58−8.54 (m, 2H), 7.80−7.76 (m, 2H), 7.09−7.03 (m, 2H), 4.18−4.01
ing General Procedure B, 3-cyanopyridine N-oxide (100 mg, 0.83 mmol),
-nitrobenzoyl chloride (339 mg, 1.83 mmol), and thietane (308 mg,
.15 mmol) in diisopropyl ether (0.4 M), after purification via flash
(m, 2H), 3.57 (t, J = 6.4 Hz, 1H), 3.32−3.26 (m, 3H), 2.04−1.80
13
4
4
(m, 8H), 1.52 (d, J = 6.4 Hz, 4H), 1.45 (d, J = 6.4 Hz, 2H); C NMR
(101 MHz, CDCl ) δ 163.3, 163.1, 152.2, 140.8, 140.7, 118.6, 118.5, 115.7,
3
column chromatography (dry loading, petroleum ether/EtOAc 5:1
isocratic), afforded the title compound 3l (48 mg, 0.14 mmol, 17%) as
107.7, 107.6, 58.2, 44.8, 39.8, 39.2, 33.8, 30.1, 29.7, 26.4, 25.5, 21.3 (2 C
3
5
missing); LRMS (ES + APCI) m/z calcd for C H ClN S 240.0,
11 13 2
E
DOI: 10.1021/acs.joc.7b02457
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
+
+
found 241.0 [M + H] ; HRMS (ESI-TOF) m/z [M + H] calcd for
of pyrazine-2-carbonitrile (1.00 g, 9.51 mmol) in CH Cl (25 mL) at
2
2
35
C H ClN S 241.0561, found 241.0562.
-Cyanoquinoline N-Oxide. m-Chloroperoxybenzoic acid (<77%,
.35 g, 7.79 mmol) was added portion-wise to a solution of
0 °C. Following completion of the addition, the reaction mixture was
stirred overnight at room temperature, and the reaction was
subsequently quenched with a saturated aqueous solution of potassium
carbonate (30 mL). The resulting layers were separated before the
aqueous layer was extracted with chloroform (5 × 40 mL). The
1
1
3
14
2
1
8
1
3
-cyanoquinoline (1.00 g, 6.49 mmol) in CH Cl (17 mL) at 0 °C.
2
2
Following completion of the addition, the reaction mixture was stirred
overnight at room temperature, and the reaction was subsequently
quenched with a saturated aqueous solution of potassium carbonate
combined organic extracts were washed with NaHCO (50 mL) and
3
brine (50 mL) before being dried, filtered, and concentrated under
reduced pressure. Further purification via flash column chromatog-
raphy (dry loading, petroleum ether/EtOAc 3:1 isocratic) afforded the
title compound as an off-white solid (240 mg, 1.98 mmol, 21%): mp
(
30 mL). The resulting layers were separated before the aqueous layer
was extracted with chloroform (5 × 40 mL). The combined organic
extracts were washed with NaHCO (50 mL) and brine (50 mL)
before being dried, filtered, and concentrated under reduced pressure.
Further purification via flash column chromatography (dry loading,
petroleum ether/EtOAc 3:1 isocratic) afforded the title compound as
an off-white solid (473 mg, 2.78 mmol, 43%): mp 156−158 °C;
IR (ATR)/cm 3042, 2936, 2237, 1580, 1495, 1372, 1331, 1229;
H NMR (500 MHz, CDCl ) δ 8.74 (d, J = 8.5 Hz, 1H), 8.60 (s, 1H),
3
−1
140−142 °C; IR (ATR)/cm 3059, 3013, 2903, 2200, 1579, 1456,
1
1415, 1279; H NMR (500 MHz, CDCl ) δ 8.53 (d, J = 4.0 Hz, 1H),
3
8.37 (d, J = 1.5 Hz, 1H), 8.22 (dd, J = 4.0 Hz, J = 1.5 Hz, 1H);
13
C NMR (125 MHz, CDCl ) δ 148.7, 138.3, 136.7, 134.2, 113.7;
3
−1
LRMS (ES + APCI) m/z calcd for C H N O 121.0, found 122.1
5 3 3
1
+
+
[M + H] ; HRMS (ESI-TOF) m/z [M + H] calcd for C H N O
5 4 3
3
8
.05 (s, 1H), 7.98−7.90 (m, 2H), 7.78 (app t, J = 7.5 Hz, 1H);
121.0271, found 121.0270.
1
3
C NMR (101 MHz, DMSO-d ) δ 143.5, 134.9, 133.5, 130.6, 129.9,
3-((4-Chlorobutyl)thio)pyrazine-2-carbonitrile (8). Following Gen-
eral Procedure A, 3-cyanopyrazine N-oxide (100 mg, 0.83 mmol) and
4-nitrobenzoyl chloride (338 mg, 1.82 mmol) in THT (0.2 M), after
purification via flash column chromatography (dry loading, petroleum
ether/EtOAc 6:1 isocratic), afforded the title compound 8 (105 mg,
0.46 mmol, 56%) as a yellow oil: IR (ATR)/cm 3070, 2927, 2864,
2230, 1514, 1430, 1357, 1196; H NMR (500 MHz, CDCl ) δ 8.52
(d, J = 2.5 Hz, 1H), 8.32 (d, J = 2.5 Hz, 1H), 3.58 (t, J = 6.5 Hz, 2H),
6
1
29.2, 129.1, 120.2, 115.1, 107.3; LRMS (ES + APCI) m/z calcd
+
for C H N O 170.1, found 171.0 [M + H] ; HRMS (ESI-TOF) m/z
10
6
2
+
[
M + H] calcd for C H N O 171.0558, found 171.0560.
10 7 2
2
-((4-Chlorobutyl)thio)quinoline-3-carbonitrile (6). Following
−
1
General Procedure A, 3-cyanoquinoline N-oxide (100 mg, 0.59 mmol)
and 4-nitrobenzoyl chloride (241 mg, 1.29 mmol) in THT (0.2 M),
after purification via flash column chromatography (dry loading,
petroleum ether/EtOAc 10:1 isocratic), afforded the title compound 6
1
3
1
3
3.29 (t, J = 6.5 Hz, 2H), 1.98−1.88 (m, 4H); C NMR (125 MHz,
−1
(
102 mg, 0.37 mmol, 63%) as a yellow oil: IR (ATR)/cm 3050,
CDCl ) δ 161.4, 146.0, 139.6, 128.4, 114.5, 44.3, 31.5, 29.4, 26.4;
3
1
35
10
2
933, 2860, 2224, 1614, 1584, 1556, 1333; H NMR (500 MHz,
LRMS (ES + APCI) m/z calcd for C H ClN S 227.0, found 228.0
9
3
+
+
35
CDCl ) δ 8.32 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.82−7.74 (m, 2H),
[M + H] ; HRMS (ESI-TOF) m/z [M + H] calcd for C H ClN3S
3
9 11
7
2
.52 (ddd, J = 8.0 Hz, J = 7.0 Hz, J = 1.0 Hz, 1H), 3.63 (t, J = 6.5 Hz,
228.0362, found 228.0366.
13
18
H), 3.43 (t, J = 6.5 Hz, 2H), 2.05−1.93 (m, 4H); C NMR
3-Chloropyrazine N-Oxide. m-Chloroperoxybenzoic acid (<77%,
1.80 g, 10.50 mmol) was added portion-wise to a solution of
2-chloropyrazine (1.00 g, 8.73 mmol) in CH Cl (23 mL) at 0 °C.
(
125 MHz, CDCl ) δ 158.7, 148.7, 142.6, 133.0, 128.4, 128.3, 126.8,
3
123.9, 115.9, 106.3, 44.5, 31.7, 29.5, 26.5; LRMS (ES + APCI) m/z calcd
2
2
35
13
+
for C H ClN S 276.0, found 277.0 [M + H] ; HRMS (ESI-TOF)
m/z [M + H] calcd for C H ClN S 277.0566, found 277.0570.
Following completion of the addition, the reaction mixture was stirred
overnight at room temperature, and the reaction was subsequently
quenched with a saturated aqueous solution of potassium carbonate
(30 mL). The resulting layers were separated before the aqueous layer
was extracted with chloroform (5 × 40 mL). The combined organic
14
2
+
35
14
14
2
1
8
3
-Chloroquinoline N-Oxide.
<77%, 1.27 g, 7.36 mmol) was added portion-wise to a solution of
-chloroquinoline (1.00 g, 6.13 mmol) in CH Cl (16 mL) at 0 °C.
m-Chloroperoxybenzoic acid
(
3
2
2
Following completion of the addition, the reaction mixture was stirred
overnight at room temperature, and the reaction was subsequently
quenched with a saturated aqueous solution of potassium carbonate
extracts were washed with NaHCO (50 mL) and brine (50 mL)
3
before being dried, filtered, and concentrated under reduced pressure.
Further purification via flash column chromatography (dry loading,
petroleum ether/EtOAc 5:1 isocratic) afforded the title compound
as an off-white solid (970 mg, 7.46 mmol, 85%): mp 97−99 °C;
(
30 mL). The resulting layers were separated before the aqueous layer
was extracted with chloroform (5 × 40 mL). The combined organic
extracts were washed with NaHCO (50 mL) and brine (50 mL)
−1
1
IR (ATR)/cm 3053, 3005, 2979, 1582, 1445, 1409, 1272; H NMR
3
before being dried, filtered, and concentrated under reduced pressure to
afford the title compound as a pale yellow solid (1.04 g, 5.81 mmol, 95%):
(500 MHz, CDCl ) δ 8.25 (d, J = 4.0 Hz, 1H), 8.15 (d, J = 1.5 Hz,
1H), 8.01 (dd, J = 4.0 Hz, J = 1.5 Hz, 1H); C NMR (125 MHz,
3
13
−1
mp 118−120 °C; IR (ATR)/cm 3066, 2921, 2851, 1580, 1556, 1361,
CDCl ) δ 151.9, 146.1, 133.7, 133.3; LRMS (ES + APCI) m/z calcd
3
1
35
+
1
216; H NMR (400 MHz, CDCl ) δ 8.66 (d, J = 8.4 Hz, 1H), 8.51
for C H3 ClN O 130.0, found 131.0 [M + H] ; HRMS (ESI-TOF)
3
4 2
+
35
(
7
1
d, J = 1.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.76−7.70 (m, 2H),
m/z [M + H] calcd for C H ClN O 130.9914, found 130.9915.
4 4 2
13
.69−7.63 (m, 1H); C NMR (101 MHz, CDCl ) δ 140.6, 135.5, 130.5,
2-Chloro-3-((4-chlorobutyl)thio)pyrazine (9). Following General
Procedure A, 3-chloropyrazine N-oxide (100 mg, 0.77 mmol) and
4-nitrobenzoyl chloride (315 mg, 1.69 mmol) in THT (0.2 M), after
purification via flash column chromatography (dry loading, petroleum
ether/CH Cl 3:1 isocratic), afforded the title compound 9 (98 mg,
3
29.9, 129.8, 127.6, 127.5, 124.5, 119.9; LRMS (ES + APCI) m/z calcd
3
5
+
for C H6 ClNO 179.0, found 179.9 [M + H] ; HRMS (ESI-TOF) m/z
9
+
35
9 7
[M + H] calcd for C H ClNO 179.0132, found 179.0133.
3
-Chloro-2-((4-chlorobutyl)thio)quinoline (7). Following General
Procedure A, 3-chloroquinoline N-oxide (100 mg, 0.56 mmol) and
-nitrobenzoyl chloride (229 mg, 1.23 mmol) in THT (0.2 M), after
2
2
−1
0.42 mmol, 54%) as a yellow oil: IR (ATR)/cm 3046, 2927, 2866,
1528, 1497, 1432, 1337, 1143; H NMR (500 MHz, CDCl ) δ 8.29
1
4
3
purification via flash column chromatography (dry loading, petroleum
(d, J = 2.5 Hz, 1H), 8.01 (d, J = 2.5 Hz, 1H), 3.58 (t, J = 6.5 Hz, 2H),
13
ether/CH Cl 2:1 isocratic), afforded the title compound 7 (99 mg,
3.20 (t, J = 6.5 Hz, 2H), 1.99−1.85 (m, 4H); C NMR (125 MHz,
2
2
−1
0
1
.35 mmol, 62%) as a yellow oil: IR (ATR)/cm 3053, 2914, 2847,
579, 1523, 1469, 1383; H NMR (500 MHz, CDCl ) δ 7.97 (s, 1H),
CDCl ) δ 156.6, 146.5, 141.8, 137.9, 44.5, 31.7, 29.6, 26.3; LRMS
3
1
35
+
(ES + APCI) m/z calcd for C H Cl N S 236.0, found 236.4 [M + H] ;
HRMS (ESI-TOF) m/z [M + H] calcd for C H Cl N S 237.0020,
8 11 2 2
3
8 10 2 2
+
35
7
3
(
.93 (d, J = 8.5 Hz, 1H), 7.68−7.62 (m, 2H), 7.45 (app t, J = 7.0 Hz, 1H),
.63 (t, J = 6.5 Hz, 2H), 3.38 (t, J = 6.5 Hz, 2H), 2.05−1.94
m, 4H); 13C NMR (125 MHz, CDCl ) δ 157.5, 146.4, 133.9, 129.8,
found 237.0024.
18
5-Chloropyrimidine N-Oxide. m-Chloroperoxybenzoic acid
(<77%, 1.81 g, 10.50 mmol) was added portion-wise to a solution of
5-chloropyrimidine (1.00 g, 8.73 mmol) in CH Cl (23 mL) at 0 °C.
3
1
28.0, 127.2, 126.9, 126.4, 126.1, 44.7, 31.9, 29.6, 26.6; LRMS (ES +
35
+
APCI) m/z calcd for C H Cl NS 285.0, found 285.9 [M + H] ;
HRMS (ESI-TOF) m/z [M + H] calcd for C H Cl NS 286.0224,
13
13
2
2
2
+
35
14
Following completion of the addition, the reaction mixture was stirred
overnight at room temperature, and subsequently the reaction was
quenched with a saturated aqueous solution of potassium carbonate
(30 mL). The resulting layers were separated before the aqueous layer
13
2
found 286.0227.
-Cyanopyrazine N-Oxide.
<77%, 1.97 g, 11.42 mmol) was added portion-wise to a solution
1
8
3
m-Chloroperoxybenzoic acid
(
F
DOI: 10.1021/acs.joc.7b02457
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
was extracted with chloroform (5 × 40 mL). The combined organic
pressure to afford the crude product. Further purification was performed
via flash column chromatography (petroleum ether/EtOAc 1:1 isocratic)
to afford the title compound 18 (38 mg, 0.14 mmol, 36%) as a yellow oil:
extracts were washed with NaHCO (50 mL) and brine (50 mL)
3
before being dried, filtered, and concentrated under reduced pressure.
Further purification via flash column chromatography (dry loading,
petroleum ether/EtOAc 3:1 isocratic) afforded the title compound
as an off-white solid (874 mg, 6.72 mmol, 77%): mp 108−109 °C;
−1
IR (ATR)/cm 3072, 2934, 2853, 2804, 2222, 1573, 1549, 1391, 1166;
1
H NMR (500 MHz, CDCl ) δ 8.55 (dd, J = 5.0 Hz, J = 1.5 Hz, 1H),
3
7
5
.77 (dd, J = 7.5 Hz, J = 1.5 Hz, 1H), 7.05 (dd, J = 7.5 Hz, J =
.0 Hz, 1H), 3.70 (t, J = 5.0 Hz, 4H), 3.29 (t, J = 7.5 Hz, 2H),
−1
1
IR (ATR)/cm 3026, 3003, 2879, 1569, 1519, 1406, 1249; H NMR
(
500 MHz, CDCl ) δ 8.85 (s, 1H), 8.39 (s, 1H), 8.19 (s, 1H);
3
2.46−2.40 (m, 4H), 2.37 (t, J = 7.5 Hz, 2H), 1.81−1.73 (m, 2H),
1
3
1
3
C NMR (125 MHz, CDCl ) δ 148.1, 143.6, 142.2, 130.8; LRMS
3
1.69−1.62 (m, 2H); C NMR (101 MHz, CDCl ) δ 163.4, 152.2,
3
3
5
+
(ES + APCI) m/z calcd for C H3 ClN O 130.0, found 130.8 [M + H] ;
4 2
140.7, 118.5, 115.7, 107.6, 67.1, 58.5, 53.8, 30.2, 27.2, 25.8; LRMS
(ES + APCI) m/z calcd for C H N OS 277.1, found 278.1 [M + H] ;
HRMS (ESI-TOF) m/z [M + H] calcd for C H N OS 278.1322,
+
35
4
HRMS (ESI-TOF) m/z [M + H] calcd for C H ClN O 131.0007,
+
4
2
14
19
3
found 130.9996.
-Chloro-4-((4-chlorobutyl)thio)pyrimidine (10). Following Gen-
+
14
20
3
5
found 278.1323.
-((3-Cyanopyridin-2-yl)thio)butyl Acetate (19). To a microwave
eral Procedure A, 5-chloropyrimidine N-oxide (100 mg, 0.77 mmol)
and 4-nitrobenzoyl chloride (315 mg, 1.69 mmol) in THT (0.2 M),
after purification via flash column chromatography (dry loading,
petroleum ether/CH Cl 1:1 isocratic), afforded the title compound 10
4
vial charged with compound 4a (100 mg, 0.44 mmol) in a solution
of DMF (1.8 mL) was added sodium acetate (218 mg, 2.65 mmol).
The reaction mixture was heated to 80 °C for 48 h before being allowed
2
2
−1
(
2
114 mg, 0.48 mmol, 63%) as a yellow oil: IR (ATR)/cm 3040,
936, 2866, 1543, 1415, 1370, 1132; H NMR (500 MHz, CDCl )
to cool to room temperature. A 1:1 mixture of EtOAc/H O (10 mL)
2
1
3
was added; the layers were separated, and the aqueous phase was
extracted with EtOAc (3 × 10 mL). The combined organic extracts were
δ 8.82 (s, 1H), 8.38 (s, 1H), 3.58 (t, J = 6.5 Hz, 2H), 3.20 (t, J =
1
3
6
.5 Hz, 2H), 1.99−1.86 (m, 4H); C NMR (125 MHz, CDCl3)
washed with brine (10 mL), dried over MgSO , filtered, and concen-
4
δ 167.9, 155.3, 152.8, 128.9, 44.4, 31.7, 29.1, 26.5; LRMS (ES + APCI)
m/z calcd for C H Cl N S 236.0, found 237.0 [M + H] ; HRMS
ESI-TOF) m/z [M + H] calcd for C H Cl N S 237.0020, found
trated under reduced pressure to afford the title compound 19 (107 mg,
35
+
−1
8
10
2
2
0
2
.43 mmol, 97%) as a yellow oil: IR (ATR)/cm 3065, 2946, 2864,
+
35
(
1
8
11
2
2
224, 1731, 1573, 1549, 1391, 1233; H NMR (400 MHz, CDCl )
3
2
37.0025.
,6-Dichloropyridine N-Oxide. m-Chloroperoxybenzoic acid
<77%, 1.40 g, 8.10 mmol) was added portion-wise to a solution of
,6-dichloropyridine (1.00 g, 6.76 mmol) in CH Cl (18 mL) at 0 °C.
δ 8.56 (dd, J = 4.8 Hz, J = 1.6 Hz, 1H), 7.78 (dd, J = 8.0 Hz, J =
1
8
2
1
3
.6 Hz, 1H), 7.06 (dd, J = 8.0 Hz, J = 4.8 Hz, 1H), 4.13−4.08 (m, 2H),
(
2
13
.32−3.28 (m, 2H), 2.05 (s, 3H), 1.84−1.77 (m, 4H); C NMR
2
2
(101 MHz, CDCl ) δ 171.3, 163.2, 152.2, 140.7, 118.6, 115.7, 107.7, 63.9,
3
Following completion of the addition, the reaction mixture was stirred
overnight at room temperature, and subsequently the reaction was
quenched with a saturated aqueous solution of potassium carbonate
2
2
9.8, 27.9, 25.9, 21.1; LRMS (ES + APCI) m/z calcd for C H N O S
12 14 2 2
50.1, found 251.0 [M + H] ; HRMS (ESI-TOF) m/z [M + H] calcd
+
+
for C H N O S 251.0849, found 251.0850.
12
15
2
2
(
30 mL). The resulting layers were separated before the aqueous layer
S-(4-((3-Cyanopyridin-2-yl)thio)butyl) Ethanethioate (20). To a
microwave vial charged with compound 4a (50 mg, 0.22 mmol) in a
solution of DMF (1.1 mL) were added potassium thioacetate (152 mg,
was extracted with chloroform (5 × 40 mL). The combined organic
extracts were washed with NaHCO (50 mL) and brine (50 mL)
3
before being dried, filtered, and concentrated under reduced pressure.
Further purification via flash column chromatography (dry loading,
petroleum ether/EtOAc 5:1 isocratic) afforded the title compound
as an off-white solid (420 mg, 2.58 mmol, 38%): mp 135−137 °C; IR
1
.32 mmol) and potassium iodide (8.2 mg, 0.04 mmol). The reaction
mixture was heated to 80 °C for 48 h before being allowed to cool to
room temperature. A 1:1 mixture of EtOAc/H O (10 mL) was added;
2
−1
1
the layers were separated, and the aqueous phase was extracted with
EtOAc (3 × 10 mL). The combined organic extracts were washed with
(
ATR)/cm 3081, 2960, 2866, 1532, 1447, 1365, 1264, 1143; H
NMR (500 MHz, CDCl ) δ 7.45 (d, J = 8.0 Hz, 2H), 7.12 (t, J =
3
.0 Hz, 1H); 1 C NMR (101 MHz, CDCl ) δ 143.9, 125.2, 124.6;
3
brine (10 mL), dried over MgSO , filtered, and concentrated under
4
8
3
35
reduced pressure to afford the title compound 21 (56 mg, 0.21 mmol,
LRMS (ES + APCI) m/z calcd for C H Cl NO 163.0, found 164.1
5
3
2
−1
+
+
35
96%) as a yellow oil: IR (ATR)/cm 3063, 2923, 2851, 2222, 1683,
[
M + H] ; HRMS (ESI-TOF) m/z [M + H] calcd for C H Cl NO
5 4 2
1
1
571, 1549, 1391, 1138; H NMR (400 MHz, CDCl ) δ 8.56 (dd, J =
3
1
63.9664, found 163.9662.
-((4-Azidobutyl)thio)nicotinonitrile (17). A microwave vial, placed
under an inert atmosphere, was charged with a solution of 4a (50 mg,
.22 mmol) in dimethylformamide (DMF) (0.9 mL). Sodium azide
86 mg, 1.33 mmol) was added to this solution. The reaction mixture
4.8 Hz, J = 1.6 Hz, 1H), 7.78 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H), 7.06 (dd,
2
J = 7.6 Hz, J = 4.8 Hz, 1H), 3.27 (t, J = 7.2 Hz, 2H), 2.91 (t, J = 7.2 Hz,
1
3
2
H), 2.32 (s, 3H), 1.85−1.69 (m, 4H); C NMR (101 MHz, CDCl3)
0
(
δ 195.9, 163.1, 152.2, 140.7, 118.6, 115.7, 107.6, 30.8, 29.6, 28.8, 28.6,
2
2
8.4; LRMS (ES + APCI) m/z calcd for C H N OS 266.1, found
12 14 2 2
67.0 [M + H] ; HRMS (ESI-TOF) m/z [M + H] calcd for
was stirred at 80 °C for 48 h before being cooled to room temperature.
+
+
A 1:1 mixture of EtOAc/H O (10 mL) was added; the layers were
2
C H N OS 267.0620, found 267.0621.
separated, and the aqueous phase was extracted with EtOAc (3 × 10 mL).
The combined organic extracts were washed with brine (10 mL), dried
12 15
2
2
2
-((4-((4-Methoxyphenyl)thio)butyl)thio)nicotinonitrile (21). To a
microwave vial charged with compound 4a (50 mg, 0.22 mmol) in a
solution of DMF (1.1 mL) was added 4-methoxybenzenethiol (63 mg,
0.44 mmol) and cesium carbonate (216 mg, 0.66 mmol). The reaction
mixture was heated to 80 °C for 48 h before being allowed to cool to
over MgSO , filtered, and concentrated under reduced pressure to
4
afford the title compound 17 (50 mg, 0.21 mmol, 97%) as a yellow oil:
−1
1
IR (ATR)/cm 3057, 2931, 2862, 2224, 1573, 1551, 1391; H NMR
(
500 MHz, CDCl ) δ 8.57 (dd, J = 5.0 Hz, J = 2.0 Hz, 1H), 7.79
3
room temperature. A 1:1 mixture of EtOAc/H O (10 mL) was added;
(
3
1
dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 7.07 (dd, J = 8.0 Hz, J = 5.0 Hz, 1H),
2
the layers were separated, and the aqueous phase was extracted with
EtOAc (3 × 10 mL). The combined organic extracts were washed with
.33 (t, J = 7.0 Hz, 2H), 3.29 (t, J = 7.0 Hz, 2H), 1.87−1.80 (m, 2H),
13
.79−1.72 (m, 2H); C NMR (101 MHz, CDCl ) δ 163.0, 152.2,
3
brine (10 mL), dried over MgSO , filtered, and concentrated under
1
40.7, 118.6, 115.6, 107.7, 51.1, 29.6, 28.1, 26.6; LRMS (ES + APCI) m/z
4
+
reduced pressure to afford the title compound 23 (25 mg, 0.08 mmol,
calcd for C H N S 233.1, found 234.0 [M + H] ; HRMS (ESI-TOF)
10
11
5
−
1
+
3
2
4%) as an off-white solid: mp 38−40 °C; IR (ATR)/cm 3066,
m/z [M + H] calcd for C H N S 234.0808, found 234.0809.
10
12
5
1
949, 2830, 2220, 1571, 1553, 1493, 1395, 1235; H NMR (400 MHz,
2
-((4-Morpholinobutyl)thio)nicotinonitrile (18). To a microwave
CDCl ) δ 8.55 (dd, J = 5.2 Hz, J = 1.6 Hz, 1H), 7.77 (dd, J = 7.6 Hz,
vial charged with compound 4a (95 mg, 0.38 mmol) was added
morpholine (60 μL, 0.66 mmol). The reaction mixture was stirred at
room temperature for 48 h. The solvent was removed under reduced
3
J = 1.6 Hz, 1H), 7.34 (d, J = 8.8 Hz, 2H), 7.05 (dd, J = 7.6 Hz, J =
5.2 Hz, 1H), 6.83, (d, J = 8.8 Hz, 2H), 3.80 (s, 3H), 3.25 (t, J = 7.2 Hz,
2H), 2.85 (t, J = 7.2 Hz, 2H), 1.90−1.81 (m, 2H), 1.77−1.68 (m, 2H);
pressure. A 1:1 mixture of EtOAc/H O (10 mL) was added; the layers
2
13
were separated, and the aqueous phase was extracted with EtOAc
C NMR (101 MHz, CDCl ) δ 163.2, 159.1, 152.2, 140.7, 133.5,
3
(
(
3 × 10 mL). The combined organic extracts were washed with brine
126.4, 118.5, 115.7, 114.7, 107.6, 55.5, 35.5, 29.8, 28.4, 28.1; LRMS (ES +
+
10 mL), dried over MgSO , filtered, and concentrated under reduced
APCI) m/z calcd for C H N OS 330.1, found 331.0 [M + H] ; HRMS
4
17 18
2
2
G
DOI: 10.1021/acs.joc.7b02457
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
+
(
3
ESI-TOF) m/z [M + H] calcd for C H N OS 331.0939, found
31.0936.
17
19
2
2
REFERENCES
■
(
5
1) (a) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014,
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Diethyl (4-((3-Cyanopyridin-2-yl)thio)butyl)phosphonate (22).
To a microwave vial charged with compound 4a (50 mg, 0.22 mmol)
was added triethyl phosphite (484 mg, 2.92 mmol). The reaction
mixture was heated to 160 °C for 48 h before being allowed to cool to
room temperature. A 1:1 mixture of EtOAc/H O (10 mL) was added;
the layers were separated, and the aqueous phase was extracted with
EtOAc (3 × 10 mL). The combined organic extracts were washed with
brine (10 mL), dried over MgSO , filtered, and concentrated under
reduced pressure. Further purification via flash column chromatog-
raphy (dry loading, petroleum ether/EtOAc 3:1 isocratic) afforded
the title compound 24 (23 mg, 0.07 mmol, 32%) as an orange oil:
(
(
2
(
(
4
−1
IR (ATR)/cm 3047, 2931, 2867, 2222, 1573, 1551, 1391, 1231,
017, 956; H NMR (500 MHz, CDCl ) δ 8.56 (d, J = 4.0 Hz, 1H),
.77 (d, J = 7.5 Hz, 1H), 7.05 (dd, J = 7.5 Hz, J = 4.0 Hz, 1H),
1
1
7
4
(
(
6
1
3
2
34−242. (b) Ye, F.; Haddad, M.; Ratovelomanana-Vidal, V.; Michelet, V.
Org. Lett. 2017, 19, 1104−1107. (c) Bugaenko, D. I.; Yurovskaya, M. A.;
Karchava, A. V. J. Org. Chem. 2017, 82, 2136−2149. (d) Keylor, M. H.;
Niemeyer, Z. L.; Sigman, M. S.; Tan, K. L. J. Am. Chem. Soc. 2017, 139,
.18−4.02 (m, 4H), 3.27 (t, J = 6.0 Hz, 2H), 1.88−1.72 (m, 6H), 1.32
t, J = 6.0 Hz, 6H); 1 C NMR (101 MHz, CDCl ) δ 163.1, 152.2
3
3
d, JPC = 18.5 Hz, 1C), 140.7 (d, JPC = 9.0 Hz, 1C), 118.6, 115.6, 107.6,
1
0613−10616. (e) Ali, W.; Dahiya, A.; Pandey, R.; Alam, T.; Patel, B. K. J.
2.0−60.4 (m, 2C), 31.2−28.3 (m, 3C), 22.3 (d, J = 107.5 Hz, 1C),
PC
6.6 (d, J = 66.8 Hz, 2C); 31P NMR (202 MHz, CDCl ) δ 35.2−28.5
Org. Chem. 2017, 82, 2089−2096. (f) Lan, X.-B.; Li, Y.; Li, Y.-F.; Shen,
PC
3
D.-S.; Ke, Z.; Liu, F.-S. J. Org. Chem. 2017, 82, 2914−2925.
(
m, 1P); LRMS (ES + APCI) m/z calcd for C H N O PS 328.1,
14 21 2 3
+
+
(6) For selected recent contributions to the area, see: (a) Wang, D.;
Wang, Y.; Zhao, J.; Shen, M.; Hu, J.; Liu, Z.; Li, L.; Xue, F.; Yu, P. Org.
Lett. 2017, 19, 984−987. (b) Fier, P. S. J. Am. Chem. Soc. 2017, 139,
found 328.7 [M + H] ; HRMS (ESI-TOF) m/z [M + H] calcd for
C H N O PS 329.1089, found 329.1087.
14
22
2
3
2
-((4-Cyanobutyl)thio)nicotinonitrile (23). A microwave vial
9
499−9502. (c) Yang, X.; Hu, F.; Wang, Y.; Yang, C.; Zou, X.; Liu, J.;
placed under an inert atmosphere was charged with a solution of 4a
50 mg, 0.22 mmol) in DMF (0.8 mL). To this solution were added
potassium cyanide (29 mg, 0.44 mmol) and potassium iodide (2.2 mg,
.01 mmol). The reaction mixture was stirred at room temperature for
8 h. A 1:1 mixture of EtOAc/H O (10 mL) was added; the layers
Zhang, Q. Chem. Commun. 2017, 53, 7497−7500. (d) Takise, R.;
(
Isshiki, R.; Muto, K.; Itami, K.; Yamaguchi, J. J. Am. Chem. Soc. 2017,
1
39, 3340−3343. (e) Duret, G.; Quinlan, R.; Yin, B.; Martin, R. E.;
Bisseret, P.; Neuburger, M.; Gandon, V.; Blanchard, N. J. Org. Chem.
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7) For an example, see: Sreedhar, B.; Reddy, P. S.; Reddy, M.
0
1
2
2
were separated, and the aqueous phase was extracted with EtOAc
(
(
3 × 10 mL). The combined organic extracts were washed with brine
(
10 mL), dried over MgSO , filtered, and concentrated under reduced
4
Synthesis 2009, 1732−1738.
pressure to afford the title compound 25 (42 mg, 0.19 mmol, 88%) as
a yellow oil: IR (ATR)/cm 3055, 2936, 2856, 2243, 2222, 1571,
551, 1391; H NMR (400 MHz, CDCl ) δ 8.57 (dd, J = 4.8 Hz,
J = 1.6 Hz, 1H), 7.79 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H), 7.08 (dd, J =
.6 Hz, J = 4.8 Hz, 1H), 3.30 (t, J = 6.8 Hz, 2H), 2.42 (t, J = 6.8 Hz, 2H),
.95−1.78 (m, 4H); C NMR (101 MHz, CDCl ) δ 162.6, 152.3,
40.8, 119.4, 118.8, 115.5, 107.7, 29.0, 28.4, 24.5, 16.9; LRMS
−1
(8) Londregan, A. T.; Jennings, S.; Wei, L. Org. Lett. 2011, 13, 1840−
1
1
(
843.
1
3
9) (a) Sumunnee, L.; Buathongjan, C.; Pimpasri, C.; Yotphan, S.
Eur. J. Org. Chem. 2017, 1025−1032. (b) Fu, W.-K.; Sun, K.; Qu, C.;
Chen, X.-L.; Qu, L.-B.; Bi, W.-Z.; Zhao, Y.-F. Asian J. Org. Chem. 2017,
7
1
1
13
3
6
, 492−495. (c) Wang, R.; Zeng, Z.; Chen, C.; Yi, N.; Jiang, J.; Cao, Z.;
+
(
ES + APCI) m/z calcd for C H N S 217.1, found 218.0 [M + H] ;
HRMS (ESI-TOF) m/z [M + H] calcd for C H N S 218.0746,
Deng, W.; Xiang, J. Org. Biomol. Chem. 2016, 14, 5317−5321. (d) Du,
B.; Qian, P.; Wang, Y.; Mei, H.; Han, J.; Pan, Y. Org. Lett. 2016, 18,
4144−4147.
11
11
3
+
11
12
3
found 218.0744.
(
10) Su, Y.; Zhou, X.; He, C.; Zhang, W.; Ling, X.; Xiao, X. J. Org.
Chem. 2016, 81, 4981−4987.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b02457.
■
(11) (a) Sun, K.; Chen, X.-L.; Li, X.; Qu, L.-B.; Bi, W.-Z.; Chen, X;
Ma, H.-L.; Zhang, S.-T.; Han, B.-W.; Zhao, Y.-F.; Li, C.-J. Chem.
Commun. 2015, 51, 12111−12114. (b) Wu, Z.; Song, H.; Cui, X.; Pi,
C.; Du, W.; Wu, Y. Org. Lett. 2013, 15, 1270−1273.
S
(
12) Jones, D. H.; Kay, S. T.; McLellan, J. A.; Kennedy, A. R.;
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13) Tran, P.-T.; Kim, H. S.; Ann, J.; Kim, S.-E.; Kim, C.; Hong, M.;
NMR spectra for all reported compounds (PDF)
X-ray data for 3-chloropyrazine 1-oxide (CIF)
(
Hoang, V.-H.; Ngo, V. T. H.; Hong, S.; Cui, M.; Choi, S.; Blumberg, P.
M.; Frank-Foltyn, R.; Bahrenberg, G.; Stockhausen, T.; Christoph, T.;
Lee, J. Bioorg. Med. Chem. Lett. 2015, 25, 2326−2330.
AUTHOR INFORMATION
Corresponding Author
E-mail: Nicholas.Tomkinson@strath.ac.uk.
■
(
14) For a related reaction involving acetonitrile, see: Tagawa, Y.;
*
Tanaka, J.; Hama, K.; Goto, Y.; Hamana, M. Tetrahedron Lett. 1996,
ORCID
37, 69−72. For a related reaction involving THF, see ref 12.
(
15) Nitrogen, Oxygen, and Sulfur Ylide Chemistry: A Practical
Blair F. Johnston: 0000-0001-9785-6822
Alan R. Kennedy: 0000-0003-3652-6015
Nicholas C. O. Tomkinson: 0000-0002-5509-0133
Approach in Chemistry; Clarke, J. S., Ed.; Oxford University Press:
Oxford, U.K., 2002.
(16) Kiyooka, S.-i.; Kaneno, D.; Fujiyama, R. Tetrahedron 2013, 69,
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4247−4258.
The authors declare no competing financial interest.
(17) O’Donnell, G.; Poeschl, R.; Zimhony, O.; Gunaratnam, M.; Moreira,
J. B. C.; Neidle, S.; Evangelopoulos, D.; Bhakta, S.; Malkinson, J. P.;
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(18) Duric, S.; Tzschucke, C. C. Org. Lett. 2011, 13, 2310−2313.
ACKNOWLEDGMENTS
■
The authors thank CRUK and the EPSRC for financial support
and the EPSRC Mass Spectrometry Service, Swansea, for high-
resolution spectra.
(19) Kiss, L. E.; Ferreira, H. S.; Torrao
N.; Soares-da-Silva, P.; Learmonth, D. A. J. Med. Chem. 2010, 53,
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̃
́
, L.; Bonifacio, M. J.; Palma, P.
3
H
DOI: 10.1021/acs.joc.7b02457
J. Org. Chem. XXXX, XXX, XXX−XXX