Regiocontrolled Halogen Dance of Bromothiophenes and Bromofurans

Article abstract of DOI:10.1021/acs.joc.8b02220

The LDA (lithium diisopropylamide)-promoted regiocontrolled halogen dance of α-bromothiophenes and α-bromofurans is described. Bromothiophenes bearing a diethyl acetal moiety undergo selective deprotonation at the β-position adjacent to the bromo group. In contrast, oxazoline, ester, and amide groups act as directing groups in the initial lithiation step to generate a carbanion at the β-position neighboring the directing group to exclusively give the other regioisomer. These results can be applied to the regiocontrolled halogen dance of bromofuran derivatives.

Full text of DOI:10.1021/acs.joc.8b02220

Note
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
pubs.acs.org/joc
Regiocontrolled Halogen Dance of Bromothiophenes and
Bromofurans
Daichi Mari, Naoki Miyagawa, Kentaro Okano,* and Atsunori Mori
Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan
*
S Supporting Information
ABSTRACT: The LDA (lithium diisopropylamide)-promoted regiocon-
trolled halogen dance of α-bromothiophenes and α-bromofurans is described.
Bromothiophenes bearing a diethyl acetal moiety undergo selective
deprotonation at the β-position adjacent to the bromo group. In contrast,
oxazoline, ester, and amide groups act as directing groups in the initial
lithiation step to generate a carbanion at the β-position neighboring the
directing group to exclusively give the other regioisomer. These results can be
applied to the regiocontrolled halogen dance of bromofuran derivatives.
ultiply substituted thiophenes and furans are found in a
Scheme 1. Regiochemistry in the Halogen Dance
1
−3
M
variety of functional materials,
bioactive com-
4
−6
7−9
pounds,
and pharmaceutically important compounds.
10
Classical methods such as Paal−Knorr synthesis, Gewald
1
1
12
thiophene synthesis, and Feist−Benary synthesis are
powerful methods for the regiocontrolled synthesis of such
heteroaromatic compounds. However, they require preparation
of functionalized acyclic dicarbonyl compounds before
cyclization under heating conditions in the presence of a
strong acid, which therefore limits the scope for substrates.
Substantial efforts have been made to achieve stepwise
regioselective introduction of functional groups after the
formation of these heterocyclic skeletons by employing
different reactivity of the α-/β-positions and different acidity
1
3
of α-/β-proton. However, control of the unsymmetrical
substrates using two β-positions’ reactivity is still difficult
except for the special examples, and it also depends on the
14
nature of the substituents. Recently, the development of
catalyst-controlled Pd-catalyzed C−H arylation and amide-
directed Rh-catalyzed C−H halogenation has reached a
1
5
practical level. A base-mediated halogen dance of bromo-
thiophenes involves the migration of an α-bromo group to a β-
position through intermolecular halogen−lithium ex-
1
6−18
change.
The resulting thienyl lithium species react with
an electrophile to form two chemical bonds in one pot. The
halogen dance of thiophenes and other heteroaromatic
compounds has been utilized as a synthetic tool for
introducing functional groups; however, effects of substituents
on regioselectivity in the halogen dance have not been
investigated. Examples of regioselective halogen dance are
The current study reports on a halogen dance of 2-
bromothiophenes and 2-bromofurans using LDA as a base
for developing reliable and direct access to functionalized
thiophenes and furans in a regioselective manner.
A suitable functional group for the regiocontrolled halogen
dance of 2-bromothiophene derivatives was first explored
19,20
shown in Scheme 1. The 2-bromothiophenes bearing alkyl,
2
1,22
23
aryl,
and trimethylsilylethynyl groups on position 5
undergo 1,2-migration-type halogen dance. To the best of the
authors’ knowledge, 1,3-halogen dance was induced only by
2
4
25
18c
oxadiazole, benzoxazole, or ester moieties.
However,
they require harsh conditions to get converted to other
Received: August 27, 2018
functional groups, making its synthetic application difficult.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b02220
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(
(
Table 1). These substrates were typically treated with LDA
Table 1. Effects of Functional Groups on the
Regioselectivity of the Halogen Dance
a
1.2 equiv) in THF at −78 °C for 1 h, and the reaction was
1
quenched with water. Regioselectivity was evaluated by H
NMR yields of the crude products using 1,1,2,2-tetrachloro-
ethane as an internal standard. We chose 2-bromo-5-
hexylthiophene (1a) because 2-bromo-5-alkylthiophenes have
19,20
been reported to give only 2-alkyl-4-bromothiophenes.
1
Careful inspection of the H NMR spectrum of the crude
material showed that 4-bromo-2-hexylthiophene (2a) formed
exclusively without the generation of 3-bromo-2-hexylthio-
phene (3a). Bromothiophene 1b, having a six-membered cyclic
acetal, was converted to a ca. 2:1 mixture of regioisomers 2b
and 3b with a 68% combined yield and recovery of the starting
bromothiophene 1b (5%). Switching the cyclic acetal 1b to
diethyl acetal 1c led to the exclusive formation of compound
2c, probably, because of the steric hindrance of the acyclic
acetal in the initial deprotonation. A directing group for the
synthesis of another regioisomer was then investigated. The
imine moiety was effective for obtaining the desired isomer 3d
as a major product, but the product ratio was unsatisfactory.
On the basis of the evidence that the sterically demanding
acetal 1c prohibited the deprotonation of the proton
neighboring the acetal, the reaction was then performed with
oxazoline 1e. As expected, the halogen dance took place
1
smoothly to provide regioisomer 3e in 87% H NMR yield
without the detection of the other regioisomer 2e. The
reaction could be performed at −40 or 0 °C to provide the
desired product 3e in almost the same yields. Amide and ester
also worked as directing groups to provide compounds 3f and
3
g in 78% and 75% yields, respectively, with concomitant
26
generation of the minor regioisomer. The use of 2-bromo-5-
formylthiophene (1h) and 2-bromo-5-thiophenecarboxylic
acid (1i) did not provide the corresponding products even
with 3 equiv of LDA, with recovery of the starting thiophenes.
Having found that diethyl acetal and oxazoline were suitable
functional groups for the regiocontrolled halogen dance of
bromothiophenes, we then trapped the resulting anion species
with electrophiles. Upon treatment of bromothiophene bearing
a diethyl acetal 1c with LDA at −78 °C for 1 h, 1,2-migration
of the bromo group took place smoothly, and the generated
thienyl lithium species was trapped with several electrophiles.
Treatment with benzaldehyde provided the corresponding
alcohol 4a in 78% yield (Table 2, entry 1). Trapping of the
resultant anion species with ethyl chloroformate yielded the
corresponding product 4b in 61% yield (entry 2). Similarly,
allyl iodide and cyclohexanone reacted with the thienyl anion
species to provide 4c and 4d in 68% and 52% yields,
respectively (entries 3 and 4). The same reaction was
performed using bromothiophene 1e bearing an oxazoline
moiety, which resulted in 1,3-migration of the bromo group.
The thienyl anion species were trapped with these electrophiles
to give 5a−5d (Table 3, entries 1−4).
The regiocontrolled halogen dance of bromofurans was also
investigated (Scheme 2). In contrast to bromothiophene 1b,
treatment of bromofuran 6 bearing a six-membered cyclic
acetal with LDA resulted in only deprotonation. Subsequent
trapping of the resulting anion species with benzaldehyde
a
Reaction conditions: bromothiophene 1 (1.0 equiv), LDA (1.2
b
1
equiv), THF, −78 °C, 1 h. The yield was determined by H NMR of
the crude material using 1,1,2,2-tetrachloroethane as an internal
c
d
e
27
standard. Not observed. Isolated yield. Reaction temperature: −40
provided compound 7 exclusively. According to a related
f g h
2
8
°C. Reaction temperature: 0 °C. LDA (2 equiv). LDA (3 equiv).
i j
work, the desired regioselective halogen dance proceeded in
the presence of potassium tert-butoxide. Prolonged reaction
time led to a significant reduction of the yield of the product 8,
indicating that the generated furyl anion was a short-lived
Reaction time: 3 h. Reaction time: 30 min.
requisite halogen−lithium exchange because of coordination to
the initially formed furyl lithium species. Similar to the authors’
2
9
reactive species. Potassium tert-butoxide should promote the
B
DOI: 10.1021/acs.joc.8b02220
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 2. Halogen Dance of Bromothiophene Bearing an
Acetal Moiety and Trapping with Electrophiles
Scheme 2. Scope and Limitation of Bromofurans
a
a
Reaction conditions: bromothiophene 1c (1.0 equiv), LDA (1.2
b
c
equiv), THF, −78 °C, 1 h; electrophile. Isolated yield. Reaction
conditions: bromothiophene 1c (1.0 equiv), LDA (1.2 equiv), THF,
−78 °C, 1 h; CuI (1.4 equiv), −78 to 0 °C, 1 h; allyl iodide, −78 °C.
Table 3. Oxazoline-Directed Halogen Dance of
Bromothiophene and Trapping with Electrophiles
a
29% isolated yield with 19% recovery of the starting material
1
1b. These results indicated that the oxazoline and
benzoxazole proved to be effective directing groups for the
smooth 1,3-halogen dance of both 2-bromothiophenes and 2-
bromofurans.
The diethyl acetal and oxazoline moieties were converted to
31
formyl and carboxyl groups, respectively (Scheme 3). Diethyl
Scheme 3. Conversion of Acetal and Oxazoline Moieties to
Formyl and Carboxyl Groups
a
Reaction conditions: bromothiophene 1e (1.0 equiv), LDA (1.2
b
c
equiv), THF, 0 °C, 30 min; electrophile. Isolated yield. Reaction
temperature: −78 °C.
2
5
previous report, the halogen dance of bromofuran 9 bearing
an oxazoline took place smoothly in the absence of potassium
tert-butoxide, and the subsequent treatment of benzaldehyde
provided the desired product 10 in 55% yield. These results
suggested that the oxazoline moiety acted as a directing group
in the initial deprotonation, and the following halogen−lithium
exchange was promoted by coordination of the oxazoline
nitrogen to the furyl lithium and led to the generation of a
acetal 4a was hydrolyzed under acidic conditions to give the
corresponding aldehyde 13 in 82% yield. Conversion of
oxazoline to a carboxyl group was achieved by N-methylation
with MeOTf, and the resultant oxazolium salt was treated with
NaOH/MeOH by refluxing for 10 min, which smoothly
provided the desired carboxylic acid 14 in 80% yield.
In summary, we have demonstrated the regiocontrolled
halogen dance of α-bromothiophenes and α-bromofurans
using LDA as a base. The 2-bromothiophene and 2-
bromofuran derivatives bearing the acetal moieties in position
5 underwent regioselective 1,2-migration of the bromo group,
whereas oxazoline, ester, and amide groups worked as directing
groups to facilitate 1,3-migration of the bromo group. The
established method provides reliable access to functionalized
thiophenes and furans in a regioselective manner.
30
reactive, lower aggregation state. We also performed the
reaction with 2-bromofurans bearing an ethyl ester and an
N,N-diethylamide that promoted 1,3-migration of the bromo
group in the case of thiophenes; however, we did not observe
clean transformation despite further optimization of reaction
conditions. In addition to our successful example of 1,3-
25
halogen dance of benzoxazole-conjugated bromofuran 11a,
its benzothiazole derivative 11b also underwent selective 1,3-
halogen dance to provide the corresponding product 12b in
C
DOI: 10.1021/acs.joc.8b02220
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
mmol, 92%). R = 0.28 (hexane/diethyl ether = 50:1); IR (ATR,
EXPERIMENTAL SECTION
f
■
−1
cm ): 2956, 1469, 1447, 1376, 1366, 1209, 1190, 1096, 1021, 986,
General Experimental Details. Analytical thin layer chromatog-
raphy (TLC) was performed on Merck 60 F aluminum sheets
precoated with a 0.25 mm thickness of silica gel. Melting points (Mp)
were measured on a Yanaco MP-J3 and are uncorrected. Infrared (IR)
spectra were recorded on a Bruker Alpha with an ATR attachment
1
9
71, 923, 795, 777, 641; H NMR (400 MHz, CDCl ): δ 6.93 (d, 1H,
3
2
54
J = 3.6 Hz), 6.87 (d, 1H, J = 3.6 Hz), 5.54 (s, 1H), 3.73 (d, 2H, J =
1
1.4 Hz), 3.60 (d, 2H, J = 11.4 Hz), 1.25 (s, 3H), 0.79 (s, 3H);
13
1
C{ H} NMR (100 MHz, CDCl ): δ 143.1, 129.4, 125.4, 113.1, 97.9,
3
+
7
7.5, 30.3, 23.0, 21.9; HRMS (DART ) m/z: calcd. for C H -
−
1
1
10 14
(
Ge) and are reported in wavenumbers (cm ). H NMR (400 MHz)
79
+
O2 BrS, 276.9898 [M + H] ; found, 276.9885.
-Bromo-2-(diethoxymethyl)thiophene (1c). To a 20 mL test
tube equipped with a Teflon-coated magnetic stirring bar were added
-bromothiophene-2-carbaldehyde (958.2 mg, 5.02 mmol, 1.0 equiv),
ammonium chloride (133.7 mg, 2.50 mmol, 0.50 equiv), ethanol
0.88 mL), and triethyl orthoformate (1.66 mL, 10.0 mmol, 2.0
13
1
and C{ H} NMR (100 MHz) spectra were measured on a JEOL
5
1
ECZ400 spectrometer. Chemical shifts for H NMR are reported in
parts per million (ppm) downfield from tetramethylsilane with the
solvent resonance as the internal standard (CHCl : δ 7.26 ppm,
5
3
tetramethylsilane: δ 0 ppm) and coupling constants are in hertz (Hz).
The following abbreviations are used for spin multiplicity: s = singlet,
d = doublet, t = triplet, q = quartet, sept = septet, m = multiplet, and
(
equiv). The resulting mixture was heated to reflux for 43 h. To the
reaction mixture were further added triethyl orthoformate (0.84 mL,
1
3
1
br = broad. Chemical shifts for C{ H} NMR are reported in ppm
from tetramethylsilane with the solvent resonance as the internal
5.0 mmol, 1.0 equiv) and ethanol (0.29 mL). After stirring for 9 h,
additional ammonium chloride (135.1 mg, 2.52 mmol, 0.50 equiv)
was added and the reaction mixture was then stirred for 15 h, at which
time the solvent was removed under reduced pressure. The residue
was washed with saturated aqueous sodium hydrogen carbonate (8
mL), and the aqueous layer was extracted with diethyl ether (3 mL)
four times. The combined organic extracts were dried over sodium
sulfate and filtered. The filtrate was concentrated under reduced
pressure to give a crude material, which was purified by silica gel
column chromatography (hexane/diethyl ether = 50:1) to provide the
standard (CDCl : δ 77.16 ppm). High-resolution mass spectra
3
(
HRMS) were performed on a JEOL JMS-T100LP AccuTOF LC-
Plus (ESI) with a JEOL MS-5414DART attachment. Unless
otherwise stated, all reactions were conducted in flame-dried
glassware under an inert atmosphere of nitrogen. All workup and
purification procedures were carried out with reagent solvents in air.
Unless otherwise noted, materials were obtained from commercial
suppliers and used without further purification. Flash column
chromatography was performed on Wakogel C-300 (45−75 μm,
Wako Pure Chemical Industries, Ltd.). Recycling preparative SEC-
HPLC was performed with an LC-9201 (Japan Analytical Industry
Co., Ltd.) equipped with preparative SEC columns (JAI-GEL-1H and
JAI-GEL-2H). Anhydrous THF was purchased from Wako Pure
Chemical Industries, Ltd. LDA (ca. 1.5 M in THF/ethylbenzene/
heptane) was purchased from Tokyo Chemical Industry Co., Ltd.
corresponding product as a brown oil (1.24 g, 4.69 mmol, 94%). R =
f
−1
0
1
.35 (hexane/diethyl ether = 50:1); IR (ATR, cm ): 1740, 1735,
374, 1364, 1354, 1229, 1217, 668, 575, 550, 538, 516; H NMR
1
(400 MHz, CDCl ): δ 6.93 (d, 1H, J = 4.0 Hz), 6.82 (dd, 1H, J = 4.0,
3
0
9
.8 Hz), 5.64 (s, 1H), 3.66 (dq, 2H, J = 9.6, 7.2 Hz), 3.56 (dq, 2H, J =
.6, 7.2 Hz), 1.23 (t, 6H, J = 6.8 Hz); C{ H} NMR (100 MHz,
13
1
CDCl ): δ 144.6, 129.6, 125.5, 112.5, 98.1, 61.1, 15.2; HRMS
3
(
Product number: L0171). Molecular sieves 4A were “activated” in
+
81
+
(
2
DART ) m/z: calcd. for C H O BrS, 220.9459 [M − OEt] ; found,
7
8
the following manner: a round-bottom flask containing molecular
sieves was heated in a regular microwave oven (730 W) for 1.5 min
and the flask was immediately evacuated. The above procedure was
repeated three times.
20.9467.
(
E)-1-(5-Bromothiophen-2-yl)-N-(2,6-diisopropylphenyl)-
methanimine (1d). To a 20 mL test tube equipped with a Teflon-
coated magnetic stirring bar were added 5-bromothiophene-2-
carbaldehyde (416.6 mg, 3.71 mmol, 1.3 equiv), 2,6-diisopropylani-
line (524.0 mg, 2.96 mmol, 1.0 equiv), p-toluenesulfonic acid
monohydrate (32.0 mg, 0.17 mmol, 6 mol %), and dichloromethane
(6.0 mL). The resulting mixture was heated to reflux for 1 h, after
which time additional 5-bromothiophene-2-carbaldehyde (236.7 mg,
2.11 mmol, 0.7 equiv) was added to the test tube. The reaction
mixture was heated to reflux for 3 h, at which time the reaction was
quenched with saturated aqueous sodium hydrogen carbonate (3
mL). After partitioned, the aqueous layer was extracted with
dichloromethane (2 mL × 2). The combined organic extracts were
washed with brine (8 mL), dried over sodium sulfate, and filtered.
The filtrate was concentrated under reduced pressure to give a crude
material, which was purified by silica gel column chromatography
(hexane/diethyl ether = 30:1), followed by recrystallization from
hexane/ethanol, to afford the corresponding product as orange
General Procedure for Halogen Dance (Table 1). A flame-
dried 20 mL Schlenk tube equipped with a Teflon-coated magnetic
stirring bar and a rubber septum was charged with 2-bromo-5-
hexylthiophene (1a) (75.4 mg, 0.31 mmol, 1.0 equiv) and anhydrous
THF (2.0 mL). The solution was cooled to −78 °C. LDA (1.5 M,
0
.40 mL, 0.60 mmol, 1.9 equiv) was added dropwise to the Schlenk
tube, and the resulting mixture was stirred at −78 °C for 1 h, at which
time the brown reaction mixture was treated with water (1 mL). After
partitioned, the aqueous layer was extracted with diethyl ether (1 mL)
three times. The combined organic extracts were washed with brine,
dried over sodium sulfate, and filtered. The filtrate was concentrated
under reduced pressure to give a crude material. The yield of
1
compound 2a (0.302 mmol, 99%) was determined by H NMR
analysis using 1,1,2,2-tetrachloroethane (24.1 mg, 0.144 mmol) as an
internal standard by comparing relative values of integration for the
peak observed at 7.00 ppm (one proton) with that of 1,1,2,2-
tetrachloroethane observed at 5.96 ppm. Purification was carried out
by silica gel column chromatography and/or SEC-HPLC.
crystals (696.4 mg, 1.99 mmol, 67%). R = 0.38 (hexane/diethyl ether
f
−
1
= 50:1); Mp 80−83 °C; IR (ATR, cm ): 2962, 2870, 1626, 1456,
1
1418, 1260, 1220, 1163, 1095, 1018, 874, 847, 799, 766, 757; H
Synthesis of Starting Materials (Table 1). 2-(5-Bromothio-
phen-2-yl)-5,5-dimethyl-1,3-dioxane (1b). To a 20 mL round-
bottom flask equipped with a Teflon-coated magnetic stirring bar
were added 5-bromothiophene-2-carbaldehyde (216.8 mg, 1.13
mmol, 1.0 equiv), neopentyl glycol (224.4 mg, 2.15 mmol, 1.9
equiv), p-toluenesulfonic acid monohydrate (9.1 mg, 0.045 mmol, 4
mol %), and toluene (2.4 mL). The resulting mixture was heated to
reflux for 19 h, at which time the reaction was quenched with
saturated aqueous sodium hydrogen carbonate (2 mL). After
partitioned, the aqueous layer was extracted with diethyl ether (5
mL × 1, 2 mL × 2) three times. The combined organic extracts were
dried over sodium sulfate and filtered. The filtrate was concentrated
under reduced pressure to give a crude material, which was purified by
silica gel column chromatography (hexane/diethyl ether = 50:1) to
provide the corresponding product as an orange oil (288.2 mg, 1.04
NMR (400 MHz, CDCl ): δ 8.13 (s, 1H), 7.18−7.07 (m, 5H), 2.95
3
1
3
1
(sept, 2H, J = 6.8 Hz), 1.16 (d, 12H, J = 6.8 Hz); C{ H} NMR (100
MHz, CDCl ): δ 154.2, 148.4, 144.3, 137.9, 131.8, 130.8, 124.6,
3
+
123.2, 118.9, 28.2, 23.6; HRMS (DART ) m/z: calcd. for C H -
N BrS, 350.0578 [M + H] ; found, 350.0592.
1
7
21
7
9
+
2-(5-Bromothiophen-2-yl)-4,4-dimethyl-4,5-dihydrooxazole (1e).
To a 100 mL round-bottom flask equipped with a Teflon-coated
magnetic stirring bar were added 5-bromothiophene-2-carbaldehyde
(1.91 g, 10.0 mmol, 1.0 equiv), 28% ammonium hydroxide (16 mL),
and THF (1.0 mL). After stirring at room temperature for 5 min,
iodine (2.79 g, 11.0 mmol, 1.1 equiv) and THF (2.3 mL) were added
and the resulting mixture was stirred for 1 h. The reaction mixture was
treated with saturated aqueous sodium thiosulfate. After partitioned,
the aqueous layer was extracted with diethyl ether. The combined
organic extracts were washed with water, dried over sodium sulfate,
D
DOI: 10.1021/acs.joc.8b02220
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
+
and filtered. The filtrate was concentrated under reduced pressure to
δ 161.0, 135.1, 133.4, 130.8, 120.0, 61.3, 14.3; HRMS (DART ) m/z:
7
9
+
give a crude 5-bromo-2-cyanothiophene (1.82 g, 9.67 mmol, 97%),
calcd. for C H O BrS, 234.9428 [M + H] ; found, 234.9429.
7 8 2
1
1
which was used to the next reaction without any purification. H
Synthesis of Authentic Samples (Table 1). H NMR spectra of
15b
NMR spectra of this product were identical to those reported in the
3-bromo-N,N-diethylthiophene-2-carboxamide (3f),
ethyl 4-bro-
32
1
33
literature. H NMR (400 MHz, CDCl ): δ 7.39 (d, 1H, J = 3.8 Hz),
mothiophene-2-carboxylate (2g), and ethyl 3-bromothiophene-2-
3
34
7
.10 (d, 1H, J = 3.8 Hz).
A flame-dried 50 mL Schlenk tube equipped with a Teflon-coated
carboxylate (3g) were reported.
2-(4-Bromothiophen-2-yl)-5,5-dimethyl-1,3-dioxane (2b). A 20
mL round-bottom flask equipped with a Teflon-coated magnetic
stirring bar with a Dean−Stark apparatus was charged with 4-bromo-
2-formylthiophene (95.2 mg, 0.50 mmol, 1.0 equiv), neopentyl glycol
(57.4 mg, 0.55 mmol, 1.1 equiv), p-toluenesulfonic acid monohydrate
(4.8 mg, 0.025 mmol, 5 mol %), and toluene (2.0 mL). The resulting
mixture was heated to reflux for 50 h, at which time additional
neopentyl glycol (45.4 mg, 0.44 mmol, 0.9 equiv) was added to the
flask and the resulting mixture was stirred for another 20 h. The
reaction mixture was treated with saturated aqueous sodium hydrogen
carbonate (2 mL). After partitioned, the aqueous layer was extracted
with diethyl ether (6 mL × 1, 2 mL × 2) three times. The combined
organic extracts were dried over sodium sulfate and filtered. The
filtrate was concentrated under reduced pressure to give a crude
material, which was purified by silica gel column chromatography
hexane/diethyl ether = 50:1) to provide the corresponding product
b (105.4 mg, 0.380 mmol, 76%. R = 0.30 (hexane/diethyl ether =
50:1); Mp 71−74 °C; IR (ATR, cm ): 3098, 2956, 2865, 1464,
441, 1378, 1225, 1209, 1180, 1092, 1026, 1013, 986, 966, 923, 874,
52, 830, 792, 780, 738, 558, 544, 515; H NMR (400 MHz, CDCl ):
δ 7.19 (d, 1H, J = 1.2 Hz), 7.06 (d, 1H, J = 1.2 Hz), 5.56 (s, 1H), 3.74
d, 2H, J = 10.6 Hz), 3.61 (d, 2H, J = 10.6 Hz), 1.25 (s, 3H), 0.78 (s,
H); C{ H} NMR (100 MHz, CDCl ): δ 142.7, 127.8, 123.0,
magnetic stirring bar and a rubber septum was charged with
potassium carbonate (89.0 mg, 0.64 mmol, 0.09 equiv), glycerol
(
2
6.4 mL), 5-bromo-2-cyanothiophene (1.35 g, 7.17 mmol, 1.0 equiv),
-amino-2-methyl-1-propanol (1.00 g, 11.2 mmol, 1.6 equiv), and
ethylene glycol (8.6 mL). The resulting mixture was heated to 110 °C
for 27 h, at which time the reaction mixture was treated with saturated
aqueous ammonium chloride (10 mL). After partitioned, the aqueous
layer was extracted with diethyl ether (20 mL × 1, 10 mL × 3, 5 mL ×
1). The combined organic extracts were washed with water (20 mL),
dried over sodium sulfate, and filtered. The filtrate was concentrated
under reduced pressure to give a crude material, which was purified by
silica gel column chromatography (hexane/diethyl ether = 3:1) to
provide the corresponding product as a colorless solid (1.61 g, 6.17
mmol, 86%). R = 0.33 (hexane/diethyl ether = 3:1); Mp 74.6−75.3
f
−
1
°
C; IR (ATR, cm ): 2968, 2928, 1648, 1432, 1353, 1305, 1273,
(
1
1263, 1210, 1063, 1024, 947, 803, 702, 567; H NMR (400 MHz,
2
f
CDCl ): δ 7.33 (br s, 1H), 7.03 (d, 1H, J = 3.6 Hz), 4.08 (s, 2H),
−1
3
13
1
1
1
.37 (s, 6H); C{ H} NMR (100 MHz, CDCl ): δ 156.9, 132.2,
30.6, 130.4, 117.1, 79.5, 68.1, 28.3; HRMS (DART ) m/z: calcd. for
3
1
8
+
1
79
+
3
C H ON BrS, 259.9745 [M + H] ; found, 259.9733.
9
11
5
-Bromo-N,N-diethylthiophene-2-carboxamide (1f). To a 100
(
3
mL round-bottom flask equipped with a Teflon-coated magnetic
stirring bar were added 5-bromothiophene-2-carboxylic acid (989.6
mg, 4.78 mmol, 1.0 equiv), dichloromethane (20 mL), 1-ethyl-3-(3-
13
1
3
+
1
09.2, 97.4, 77.5, 30.3, 23.0, 21.8; HRMS (DART ) m/z: calcd. for
79
2
+
C H O BrS, 276.9898 [M + H] ; found, 276.9884.
1
0
14
(
1
(
dimethylamino)propyl) carbodiimide (1.92 g, 10.0 mmol, 2.1 equiv),
-hydroxybenzotriazole (1.53 g, 10.0 mmol, 2.1 equiv), diethyl amine
1.06 g, 14.6 mmol, 3.1 equiv), and N,N-diisopropylethylamine (1.92
2
-(3-Bromothiophen-2-yl)-5,5-dimethyl-1,3-dioxane (3b). The
title compound was obtained as a light yellow oil in 70% yield
97.9 mg, 0.353 mmol) from 3-bromo-2-formylthiophene (96.2 mg,
.51 mmol) according to the above procedure. R = 0.30 (hexane/
diethyl ether = 50:1); IR (ATR, cm ): 2854, 1537, 1470, 1446, 1396,
363, 1342, 1307, 1201, 1189, 1156, 1091, 1028, 1013, 984, 969, 929,
(
g, 14.9 mmol, 3.1 equiv). The resulting mixture was stirred at room
temperature for 23 h, at which time TLC indicated complete
consumption of the starting carboxylic acid. The reaction mixture was
washed with 1 M hydrochloric acid (20 mL), saturated aqueous
sodium hydrogen carbonate (20 mL), and brine (20 mL). The
organic layer was dried over sodium sulfate, and filtered. The filtrate
was concentrated under reduced pressure to give a crude material,
which was purified by silica gel column chromatography (hexane/
diethyl ether = 3:2) to provide the corresponding product as a light
0
f
−
1
1
8
5
1
76, 755, 716, 620; H NMR (400 MHz, CDCl ): δ 7.30 (d, 1H, J =
3
.4 Hz), 6.94 (d, 1H, J = 5.4 Hz), 5.70 (s, 1H), 3.76 (d, 2H, J = 11.0
1
3
1
Hz), 3.67 (d, 2H, J = 11.0 Hz), 1.30 (s, 3H), 0.79 (s, 3H); C{ H}
NMR (100 MHz, CDCl ): δ 136.0, 129.8, 126.4, 109.3, 97.6, 77.8,
3
+
79
3
2
0.2, 23.0, 21.8; HRMS (DART ) m/z: calcd. for C H O BrS,
10 14 2
+
76.9898 [M + H] ; found, 276.9886.
4-Bromo-2-(diethoxymethyl)thiophene (2c). A 20 mL test tube
equipped with a Teflon-coated magnetic stirring bar and a reflux
condenser was charged with 4-bromo-2-formylthiophene (96.8 mg,
0.51 mmol, 1.0 equiv), ammonium chloride (13.3 mg, 0.25 mmol,
.49 equiv), and EtOH (0.50 mL). To the resulting mixture was
added triethyl orthoformate (0.10 mL, 0.60 mmol, 1.2 equiv), and the
green oil (984.8 mg, 3.76 mmol, 79%). R = 0.25 (hexane/diethyl
f
−1
ether = 2:1); IR (ATR, cm ): 2974, 1607, 1530, 1479, 1433, 1381,
362, 1317, 1280, 1220, 1083, 1049, 968, 840, 803, 734, 693; H
1
1
NMR (400 MHz, CDCl ): δ 7.09 (d, 1H, J = 3.6 Hz), 7.00 (d, 1H, J =
3
1
3
1
3
.6 Hz), 3.53 (q, 4H, J = 7.2 Hz), 1.25 (t, 6H, J = 7.2 Hz); C{ H}
0
NMR (100 MHz, CDCl ): δ 162.5, 140.1, 129.8, 128.6, 116.4, 42.2,
3
+
81
1
+
3.7; HRMS (DART ) m/z: calcd. for C H ON BrS, 263.9881 [M
9 13
+
mixture was heated to 100 °C for 16 h. Another triethyl orthoformate
0.10 mL, 0.60 mmol, 1.2 equiv) was added and the mixture was
H] ; found, 263.9876.
Ethyl 5-Bromothiophene-2-carboxylate (1g). To a 20 mL test
tube equipped with a Teflon-coated magnetic stirring bar were added
-bromothiophene-2-carboxylic acid (470.4 mg, 2.28 mmol, 1.0
(
further stirred at 100 °C for 28 h. Another triethyl orthoformate (0.10
mL, 0.60 mmol, 1.2 equiv) and ethanol (0.30 mL) were added and
the mixture was stirred at 100 °C for 44 h, at which time the organic
solvents were removed under reduced pressure. The residue was
treated with saturated sodium hydrogen carbonate (3 mL), and the
mixture was extracted with diethyl ether (3 mL × 1 then 2 mL × 2)
three times. The combined organic extracts were washed with brine,
dried over sodium sulfate, and filtered. Purification was performed by
silica gel column chromatography (hexane/diethyl ether = 50:1) to
afford the desired acetal 2c (112.3 mg, 0.424 mmol, 84%) as a
5
equiv), ethanol (2.3 mL), and concentrated sulfuric acid (4 drops).
The resulting mixture was heated to reflux for 24 h, at which time
ethanol (1.0 mL) was added to the test tube and the reaction mixture
was stirred for 69 h. The reaction mixture was treated with saturated
aqueous sodium hydrogen carbonate (5 mL). After partitioned, the
aqueous layer was extracted with diethyl ether (3 mL × 2, 2 mL × 1)
three times. The combined organic extracts were washed with brine
(3 mL), dried over sodium sulfate, and filtered. The filtrate was
concentrated under reduced pressure to give a crude material, which
was purified by silica gel column chromatography (hexane/dichloro-
methane = 3:1) to provide the corresponding product as a colorless
colorless oil. R = 0.50 (hexane/diethyl ether = 50:1); IR (ATR,
f
−
1
1
cm ): 1771, 1738, 1717, 643, 611, 590, 572, 556, 543, 535, 515; H
NMR (400 MHz, CDCl ): δ 7.18 (d, 1H, J = 1.6 Hz), 7.01−6.99 (m,
1H), 5.68 (s, 1H), 3.70−3.66 (dq, 2H, J = 9.6, 7.0 Hz), 3.58 (dq, 2H,
J = 9.6, 7.0 Hz), 1.24 (t, 6H, J = 7.2 Hz); C{ H} NMR (100 MHz,
CDCl ): δ 144.3, 127.9, 123.1, 109.2, 97.7, 61.2, 15.2; HRMS
3
oil (325.2 mg, 1.38 mmol, 61%). R = 0.29 (hexane/diethyl ether =
f
−
1
13
1
3
1
:1); IR (ATR, cm ): 1711, 1533, 1417, 1367, 1327, 1280, 1250,
210, 1088, 1049, 1014, 973, 810, 745; H NMR (400 MHz, CDCl ):
1
3
3
+
81
+
δ 7.54 (d, 1H, J = 3.8 Hz), 7.07 (d, 1H, J = 3.8 Hz), 4.33 (q, 2H, J =
(DART ) m/z: calcd. for C H O BrS, 220.9459 [M − OEt] ; found,
7
8
1
3
1
7
.2 Hz), 1.36 (t, 3H, J = 7.2 Hz); C{ H} NMR (100 MHz, CDCl ):
220.9456.
3
E
DOI: 10.1021/acs.joc.8b02220
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
3
-Bromo-2-(diethoxymethyl)thiophene (3c). The title compound
°C for 19 h, at which time the reaction mixture was quenched with
saturated aqueous ammonium chloride (1 mL). After partitioned, the
aqueous layer was extracted with diethyl ether (2 mL) three times.
The combined organic extracts were washed with brine (2 mL), dried
over sodium sulfate, and filtered. The filtrate was concentrated under
reduced pressure to give a crude material, which was purified by silica
gel column chromatography (hexane/diethyl ether = 5:1) to provide
was obtained as a colorless oil in 92% yield (125.7 mg, 0.474 mmol)
from 3-bromo-2-formylthiophene (98.9 mg, 0.52 mmol) according to
the above procedure. R = 0.33 (hexane/diethyl ether = 50:1); IR
ATR, cm ): 2976, 2880, 1739, 1520, 1440, 1368, 1350, 1319, 1190,
158, 1090, 1054, 1004, 867, 708; H NMR (400 MHz, CDCl ): δ
f
−
1
(
1
7
1
3
.26 (d, 1H, J = 5.4 Hz), 6.94 (d, 1H, J = 5.4 Hz), 5.71 (s, 1H), 3.67
(
=
1
2
dq, 2H, J = 9.6, 6.8 Hz), 3.60 (dq, 2H, J = 9.6, 6.8 Hz), 1.24 (t, 6H, J
the title compound as a colorless oil (38.5 mg, 0.148 mmol, 50%). R
= 0.31 (hexane/diethyl ether = 5:1); IR (ATR, cm ): 2967, 1649,
f
6.8 Hz); 13C{ H} NMR (100 MHz, CDCl ): δ 137.3, 130.0, 126.0,
1
−1
3
+
79
08.9, 97.9, 61.9, 15.2; HRMS (DART ) m/z: calcd. for C H O BrS,
1517, 1422, 1353, 1306, 1271, 1202, 1179, 1205, 985, 954, 876, 846,
7
8
+
1
18.9479 [M − OEt] ; found, 218.9488.
814, 751, 701, 678, 616, 583, 526; H NMR (400 MHz, CDCl
3
): δ
(
E)-1-(4-Bromothiophen-2-yl)-N-(2,6-diisopropylphenyl)-
7.47 (d, 1H, J = 1.8 Hz), 7.30 (d, 1H, J = 1.8 Hz), 4.08 (s, 2H), 1.35
1
3
1
methanimine (2d). A 10 mL test tube equipped with a Teflon-coated
magnetic stirring bar was charged with 4-bromo-2-formylthiophene
(
(s, 6H); C{ H} NMR (100 MHz, CDCl ): δ 156.8, 132.5, 131.9,
3
+
126.8, 110.3, 79.7, 68.2, 28.3; HRMS (DART ) m/z: calcd. for
7
9
+
104.3 mg, 0.55 mmol, 1.1 equiv), 2,6-diisopropylaniline (85.2 mg,
C H ON BrS, 259.9745 [M + H] ; found, 259.9743.
9
11
0
0
.48 mmol, 1.0 equiv), p-toluenesulfonic acid monohydrate (15.0 mg,
.079 mmol, 16 mol %), and dichloromethane (1.0 mL). The
2-(3-Bromothiophen-2-yl)-4,4-dimethyl-4,5-dihydrooxazole (3e).
To a 30 mL round-bottom flask equipped with a Teflon-coated
magnetic stirring bar were added 3-bromo-2-formylthiophene (184.7
mg, 0.97 mmol, 1.0 equiv), 28% aqueous ammonium hydroxide (2.6
mL), and THF (2.8 mL). After stirring at room temperature for 10
min, the reaction mixture was treated with iodine (154.4 mg, 0.61
mmol, 0.63 equiv) and the resulting mixture was stirred at room
temperature for 6 h. Iodine (125.8 mg, 0.50 mmol, 0.51 equiv) was
added to the flask, and the reaction mixture was stirred for 3 h, at
which time the reaction mixture was treated with saturated aqueous
sodium thiosulfate (3 mL). After partitioned, the organic layer was
washed with water (10 mL), brine (10 mL), dried over sodium
sulfate, and filtered. The filtrate was concentrated under reduced
pressure to give a crude material (157.0 mg, 0.835 mmol, 86%), which
resulting mixture was heated to reflux for 18 h, at which time the
reaction mixture was treated with saturated aqueous sodium hydrogen
carbonate (2 mL). After partitioned, the aqueous layer was extracted
with dichloromethane (2 mL) three times. The combined organic
extracts were dried over sodium sulfate and filtered. The filtrate was
concentrated under reduced pressure to give a crude material, which
was purified by silica gel column chromatography (hexane/diethyl
ether = 50:1) to provide the corresponding product as a yellow solid
(
5
1
149.0 mg, 0.425 mmol, 88%). R = 0.38 (hexane/diethyl ether =
0:1); Mp 71−74 °C; IR (ATR, cm ): 3088, 2961, 2921, 2869,
626, 1455, 1418, 1219, 1163, 1097, 847, 766; H NMR (400 MHz,
f
−
1
1
CDCl ): δ 8.20 (s, 1H), 7.42 (d, 1H, J = 1.4 Hz), 7.36 (d, 1H, J = 1.4
3
1
Hz), 7.16−7.08 (m, 3H), 2.94 (sept, 2H, J = 6.8 Hz), 1.16 (d, 12H, J
was used in the next reaction without further purification. H NMR
6.8 Hz); 13C{ H} NMR (100 MHz, CDCl ): δ 153.8, 148.2, 143.3,
1
=
(400 MHz, CDCl ): δ 7.55 (d, 1H, J = 5.2 Hz), 7.11 (d, 1H, J = 5.2
3
3
+
137.9, 133.7, 127.5, 124.7, 123.2, 110.6, 28.2, 23.6; HRMS (DART )
Hz).
7
9
+
m/z: calcd. for C H N BrS, 350.0578 [M + H] ; found, 350.0589.
A flame-dried 20 mL Schlenk tube equipped with a Teflon-coated
magnetic stirring bar and a rubber septum was charged with
potassium carbonate (6.0 mg, 0.043 mmol, 0.15 equiv), glycerol
(0.36 mL), 3-bromo-2-cyanothiophene (53.4 mg, 0.28 mmol, 1.0
equiv), 2-amino-2-methyl-1-propanol (50.5 mg, 0.57 mmol, 2.0
equiv), and ethylene glycol (0.30 mL). The resulting mixture was
heated at 110 °C for 49 h, at which time 2-amino-2-methyl-1-
propanol (90.3 mg, 1.01 mmol, 3.6 equiv) was added to the Schlenk
tube. After stirring for 45 h, the reaction mixture was treated with
saturated aqueous ammonium chloride (1 mL). After partitioned, the
aqueous layer was extracted with diethyl ether (2 mL × 1, 1 mL × 3)
four times. The combined organic extracts were washed with brine (2
mL), dried over sodium sulfate, and filtered. The filtrate was
concentrated under reduced pressure to give a crude material, which
was purified by silica gel column chromatography (hexane/diethyl
ether = 3:1), followed by preparative SEC-HPLC, to provide the title
17
21
(
E)-1-(3-Bromothiophen-2-yl)-N-(2,6-diisopropylphenyl)-
methanimine (3d). The title compound was obtained as a yellow
solid in 93% yield (153.8 mg, 0.439 mmol) from 3-bromo-2-
formylthiophene (108.2 mg, 0.57 mmol) and 2,6-diisopropylaniline
(83.8 mg, 0.47 mmol, 1.0 equiv) according to the above procedure. Rf
=
0.26 (hexane/diethyl ether = 100:1); Mp 99−103 °C; IR (ATR,
−
1
cm ): 2959, 1750, 1741, 1734, 1717, 1684, 1654, 1636, 1623, 1617,
1
1
559, 1507, 1457; H NMR (400 MHz, CDCl ): δ 8.34 (d, 1H, J =
.2 Hz), 7.50 (dd, 1H, J = 5.0, 1.2 Hz), 7.18−7.09 (m, 4H), 2.97
3
1
1
3
1
(
sept, 2H, J = 6.8 Hz), 1.19 (d, 12H, J = 6.8 Hz); C{ H} NMR (100
MHz, CDCl ): δ 154.6, 148.6, 138.0, 136.5, 131.2, 130.3, 124.7,
3
+
123.2, 115.8, 28.1, 23.7; HRMS (DART ) m/z: calcd. for C H -
17 21
79
+
N BrS, 350.0578 [M + H] ; found, 350.0561.
-(4-Bromothiophen-2-yl)-4,4-dimethyl-4,5-dihydrooxazole (2e).
To a 25 mL round-bottom flask equipped with a Teflon-coated
magnetic stirring bar were added 4-bromo-2-formylthiophene (96.4
mg, 0.50 mmol, 1.0 equiv), 28% ammonium hydroxide (1.3 mL), and
THF (1.4 mL). After stirring at room temperature for 10 min, iodine
2
compound as a yellow oil (24.8 mg, 0.0954 mmol, 34%). R = 0.29
f
−
1
(hexane/diethyl ether = 3:1); IR (ATR, cm ): 3111, 2966, 2929,
2895, 1646, 1573, 1494, 1291, 1183, 1050, 999, 984, 955, 886, 790;
1
(
151.8 mg, 0.60 mmol, 1.1 equiv) was added to the flask and the
resulting mixture was stirred at room temperature for 3 h. Iodine
105.2 mg, 0.41 mmol, 0.83 equiv) was added to the flask, and the
H NMR (400 MHz, CDCl ): δ 7.35 (d, 1H, J = 5.4 Hz), 7.04 (d, 1H,
3
1
3
1
J = 5.4 Hz), 4.12 (s, 2H), 1.39 (s, 6H); C{ H} NMR (100 MHz,
(
CDCl ): δ 156.8, 132.6, 129.1, 126.1, 113.2, 79.6, 68.0, 28.4; HRMS
3
+
79
+
reaction mixture was stirred for 1.5 h, at which time the reaction
mixture was treated with saturated aqueous sodium thiosulfate (2
mL). After partitioned, the aqueous layer was extracted with diethyl
ether (5 mL × 1, 2 mL × 2) three times. The combined organic
extracts were washed with water (2 mL), brine (2 mL), dried over
sodium sulfate, and filtered. The filtrate was concentrated under
reduced pressure to give a crude material (91.9 mg, 0.489 mmol,
(DART ) m/z: calcd. for C H ON BrS, 259.9745 [M + H] ; found,
9 11
259.9733.
4-Bromo-N,N-diethylthiophene-2-carboxamide (2f). To a 30 mL
round-bottom flask equipped with a Teflon-coated magnetic stirring
bar were added 4-bromothiophene-2-carboxylic acid (104.9 mg, 0.51
mmol, 1.0 equiv), dichloromethane (2.0 mL), 1-ethyl-3-(3-(dimethyl-
amino)propyl) carbodiimide (194.0 mg, 1.0 mmol, 2.0 equiv), 1-
hydroxybenzotriazole (154.8 mg, 1.0 mmol, 2.0 equiv), diethylamine
(106.3 mg, 1.5 mmol, 2.9 equiv), and N,N-diisopropylethylamine
(195.5 mg, 1.5 mmol, 2.9 equiv). The resulting mixture was stirred at
room temperature for 22 h, at which time the reaction mixture was
treated with 1 M aqueous hydrochloric acid (3 mL). After partitioned,
the organic layer was washed with saturated aqueous sodium
hydrogen carbonate (3 mL) and brine (3 mL). The organic solvents
were removed under reduced pressure to give a crude material, which
was purified by silica gel column chromatography (hexane/diethyl
9
7%), which was used in the next reaction without further
1
purification. H NMR (400 MHz, CDCl ): δ 7.54 (d, 1H, J = 1.4
3
Hz), 7.50 (d, 1H, J = 1.4 Hz).
A flame-dried 20 mL Schlenk tube equipped with a Teflon-coated
magnetic stirring bar and a rubber septum was charged with 4-bromo-
2
-cyanothiophene (55.5 mg, 0.30 mmol, 1.0 equiv), potassium
carbonate (3.2 mg, 0.023 mmol, 0.08 equiv), glycerol (0.36 mL), 2-
amino-2-methyl-1-propanol (43.4 mg, 0.49 mmol, 1.6 equiv), and
ethylene glycol (0.30 mL). The resulting mixture was heated at 110
F
DOI: 10.1021/acs.joc.8b02220
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
ether = 3:2), followed by (hexane/diethyl ether = 5:1 to 4:1,
gradient), to provide the title compound as a yellow oil (85.5 mg,
Schlenk tube. After warming to 0 °C for 1 h, the reaction mixture was
cooled to −78 °C and allyl iodide (53 μL, 0.58 mmol, 1.9 equiv) was
added to the Schlenk tube. The resulting mixture was stirred at −78
°C for 3 h, at which time the reaction mixture was treated with water
(1 mL) and 28% aqueous ammonia (2 mL). After partitioned, the
aqueous layer was extracted with diethyl ether (1 mL) three times.
The combined organic extracts were washed twice with 28% aqueous
ammonia (2 mL), brine (2 mL), dried over sodium sulfate, and
filtered. The filtrate was concentrated under reduced pressure to give
a crude material, which was purified by silica gel column
chromatography (hexane/diethyl ether = 50:1), followed by
preparative SEC-HPLC, to provide the title compound as a yellow
0
.326 mmol, 64%). R = 0.21 (hexane/diethyl ether = 4:1); IR (ATR,
f
−
1
cm ): 2974, 1750, 1620, 1612, 1546, 1516, 1455, 1432, 1379, 1363,
1
1338, 1278, 1217, 1175, 838; H NMR (400 MHz, CDCl ): δ 7.30
3
(
1
1
d, 1H, J = 1.2 Hz), 7.15 (d, 1H, J = 1.2 Hz), 3.48 (q, 4H, J = 6.8 Hz),
1
3
1
.21 (t, 6H, J = 6.8 Hz); C{ H} NMR (100 MHz, CDCl ): δ 162.2,
3
+
39.7, 130.0, 125.9, 109.2, 42.3, 13.6; HRMS (DART ) m/z: calcd.
79
+
for C H ON BrS, 261.9901 [M + H] ; found, 261.9897.
9
13
Halogen Dance/Trapping of the Anion Species (Tables 2
and 3). (3-Bromo-5-(diethoxymethyl)thiophen-2-yl)(phenyl)-
methanol (4a). To a flame-dried 20 mL Schlenk tube equipped
with a Teflon-coated magnetic stirring bar and a rubber septum were
added 5-bromo-2-(diethoxymethyl)thiophene (1c) (81.1 mg, 0.31
mmol, 1.0 equiv) and THF (2.0 mL). The resulting solution was
cooled to −78 °C for 30 min, and LDA (0.24 mL, 0.36 mmol, 1.2
equiv) was added to the Schlenk tube dropwise. The reaction mixture
was stirred at −78 °C for 1 h, at which time benzaldehyde (62 μL,
oil (60.7 mg, 0.199 mmol, 68%). R = 0.30 (hexane/diethyl ether =
f
−
1
5
1
0:1); IR (ATR, cm ): 2977, 2886, 1640, 1541, 1481, 1443, 1427,
370, 1337, 1195, 1168, 1123, 1052, 1003, 919, 845, 805, 706; H
1
NMR (400 MHz, CDCl ): δ 6.91 (d, 1H, J = 1.2 Hz), 5.92 (ddt, 1H, J
3
=
17.2, 10.4, 6.4 Hz), 5.63 (s, 1H), 5.18−5.09 (m, 2H), 3.65 (dd, 2H,
J = 9.6, 6.8 Hz), 3.56 (dd, 2H, J = 9.6, 6.8 Hz), 3.48 (ddd, 2H, J = 6.4,
1
3
1
0
−
.60 mmol, 1.9 equiv) was added to the Schlenk tube. After stirring at
78 °C for 1 h, the reaction mixture was treated with water (1 mL).
After partitioned, the aqueous layer was extracted with diethyl ether
1 mL) three times. The combined organic extracts were washed with
1.2, 1.2 Hz), 1.23 (t, 6H, J = 7.2 Hz); C{ H} NMR (100 MHz,
CDCl ): δ 140.8, 137.5, 134.8, 127.9, 117.2, 108.0, 98.0, 61.2, 33.7,
3
+
79
1
5.2; HRMS (DART ) m/z: calcd. for C H O BrS, 258.9792 [M −
1
0
12
+
(
OEt] ; found, 258.9784.
-(3-Bromo-5-(diethoxymethyl)thiophen-2-yl)cyclohexan-1-ol
brine (2 mL), dried over sodium sulfate, and filtered. The filtrate was
concentrated under reduced pressure to give a crude material, which
was purified by silica gel column chromatography (hexane/diethyl
ether = 50:1 to 5:1, gradient) to provide the title compound as a
1
(4d). To a flame-dried 20 mL Schlenk tube equipped with a Teflon-
coated magnetic stirring bar and a rubber septum were added 5-
bromo-2-(diethoxymethyl)thiophene (1c) (76.2 mg, 0.29 mmol, 1.0
equiv) and THF (2.0 mL). The resulting solution was cooled to −78
°C for 30 min, and LDA (0.24 mL, 0.36 mmol, 1.2 equiv) was added
dropwise to the Schlenk tube. The reaction mixture was stirred at −78
°C for 1 h, at which time cyclohexanone (59.4 mg, 0.61 mmol, 2.1
equiv) was added to the Schlenk tube. After stirring at −78 °C for 1 h,
the reaction mixture was treated with water (1 mL). After partitioned,
the aqueous layer was extracted with diethyl ether (1 mL) three times.
The combined organic extracts were washed with brine (2 mL), dried
over sodium sulfate, and filtered. The filtrate was concentrated under
reduced pressure to give a crude material, which was purified by silica
gel column chromatography (hexane/diethyl ether = 10:1), followed
by preparative SEC-HPLC, to provide the title compound as a
yellow solid (88.7 mg, 0.239 mmol, 78%). R = 0.32 (hexane/diethyl
f
−
1
ether = 5:1); Mp 56−57 °C; IR (ATR, cm ): 3381, 2978, 1342,
1
5
200, 1153, 1126, 1087, 1041, 1029, 986, 855, 838, 716, 698, 572,
1
61, 554, 537, 521, 511; H NMR (400 MHz, CDCl ): δ 7.51−7.46
3
(m, 2H), 7.40−7.27 (m, 3H), 6.92 (d, 1H, J = 1.0 Hz), 6.12 (d, 1H, J
=
3.2 Hz), 5.62 (d, 1H, J = 1.0 Hz), 3.66 (dq, 2H, J = 9.6, 6.8 Hz),
3
=
.55 (dq, 2H, J = 9.6, 6.8 Hz), 2.44 (d, 1H, J = 3.2 Hz), 1.224 (t, 3H, J
7.4 Hz), 1.218 (t, 3H, J = 7.4 Hz); C{ H} NMR (100 MHz,
1
3
1
CDCl ): δ 142.7, 142.6, 141.9, 128.7, 128.2, 127.8, 126.5, 107.5, 97.9,
3
+
7
1.7, 61.3, 61.2, 15.2; HRMS (DART ) m/z: calcd. for C H -
14 14
81
+
O2 BrS, 326.9877 [M − OEt] ; found, 326.9885.
Ethyl 3-Bromo-5-(diethoxymethyl)thiophene-2-carboxylate (4b).
To a flame-dried 20 mL Schlenk tube equipped with a Teflon-coated
magnetic stirring bar and a rubber septum were added 5-bromo-2-
colorless solid (55.4 mg, 0.150 mmol, 52%). R = 0.32 (hexane/
f
−
1
diethyl ether = 4:1); Mp 85−86 °C; IR (ATR, cm ): 2976, 2932,
(
diethoxymethyl)thiophene (1c) (101.1 mg, 0.38 mmol, 1.0 equiv)
and THF (2.0 mL). The resulting solution was cooled to −78 °C for
0 min, and LDA (0.31 mL, 0.46 mmol, 1.2 equiv) was added
dropwise to the Schlenk tube. The reaction mixture was stirred at −78
C for 1 h, at which time ethyl chloroformate (73 μL, 0.76 mmol, 2.0
2861, 1446, 1336, 1309, 1258, 1165, 1125, 1083, 1052, 1001, 972,
1
904, 847, 827; H NMR (400 MHz, CDCl ): δ 6.90 (d, 1H, J = 1.2
3
3
Hz), 5.60 (s, 1H), 3.65 (dq, 2H, J = 9.6, 7.0 Hz), 3.56 (dq, 2H, J =
9.6, 7.0 Hz), 2.45 (br s, 1H), 2.16 (dt, 2H, J = 13.2, 4.0 Hz), 1.89 (d,
2H, J = 12.8 Hz), 1.78−1.57 (m, 6H), 1.23 (t, 6H, J = 6.8 Hz);
°
1
3
1
equiv) was added to the Schlenk tube. After stirring at −78 °C for 1 h,
the reaction mixture was treated with water (1 mL). After partitioned,
the aqueous layer was extracted with diethyl ether (1 mL) three times.
The combined organic extracts were washed with brine (2 mL), dried
over sodium sulfate, and filtered. The filtrate was concentrated under
reduced pressure to give a crude material, which was purified by silica
gel column chromatography (hexane/diethyl ether = 20:1) to provide
C{ H} NMR (100 MHz, CDCl ): δ 147.5, 139.6, 130.1, 103.0, 98.0,
3
+
73.5, 61.3, 36.6, 25.2, 21.8, 15.2; HRMS (DART ) m/z: calcd. for
C H O BrS, 317.0211 [M − OEt] ; found, 317.0214.
7
2
9
+
1
3
16
(4-Bromo-5-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)thiophen-2-
yl)(phenyl)methanol (5a). To a flame-dried 20 mL Schlenk tube
equipped with a Teflon-coated magnetic stirring bar and a rubber
septum were added 2-(5-bromothiophen-2-yl)-4,4-dimethyl-4,5-dihy-
drooxazole (1e) (76.9 mg, 0.30 mmol, 1.0 equiv) and THF (2.0 mL).
The resulting solution was cooled to 0 °C for 30 min, and LDA (0.24
mL, 0.36 mmol, 1.2 equiv) was added dropwise to the Schlenk tube.
The reaction mixture was stirred at 0 °C for 30 min, at which time
benzaldehyde (62 μL, 0.60 mmol, 2.0 equiv) was added to the
Schlenk tube. After stirring at 0 °C for 1 h, the reaction mixture was
treated with water (1 mL). After partitioned, the aqueous layer was
extracted with diethyl ether (1 mL) three times. The combined
organic extracts were washed with brine (2 mL), dried over sodium
sulfate, and filtered. The filtrate was concentrated under reduced
pressure to give a crude material, which was purified by silica gel
column chromatography (hexane/diethyl ether = 3:1 to 1:1,
gradient), followed by silica gel column chromatography (hexane/
diethyl ether = 1:1), to provide the title compound as a yellow solid
the title compound as a yellow oil (78.1 mg, 0.232 mmol, 61%). R =
f
−
1
0
1
1
1
.30 (hexane/diethyl ether = 20:1); IR (ATR, cm ): 2978, 1724,
700, 1527, 1456, 1368, 1338, 1314, 1277, 1237, 1190, 1170, 1133,
1
077, 1054, 844, 759, 604; H NMR (400 MHz, CDCl ): δ 7.04 (d,
3
H, J = 0.8 Hz), 5.65 (s, 1H), 4.32 (q, 2H, J = 7.2 Hz), 3.62 (dq, 2H,
J = 9.6, 7.4 Hz), 3.56 (dq, 2H, J = 9.6, 7.4 Hz), 1.35 (t, 3H, J = 6.8
1
3
1
Hz), 1.22 (t, 6H, J = 6.8 Hz); C{ H} NMR (100 MHz, CDCl ): δ
3
1
60.9, 148.7, 130.6, 127.5, 116.2, 97.4, 61.4, 61.3, 15.2, 14.3; HRMS
+
81
+
(DART ) m/z: calcd. for C H O BrS, 292.9670 [M − OEt] ;
1
0
12
3
found, 292.9655.
2
-Allyl-3-bromo-5-(diethoxymethyl)thiophene (4c). To a flame-
dried 20 mL Schlenk tube equipped with a Teflon-coated magnetic
stirring bar and a rubber septum were added 5-bromo-2-(diethoxy-
methyl)thiophene (1c) (78.1 mg, 0.30 mmol, 1.0 equiv) and THF
(
2.0 mL). The resulting solution was cooled to −78 °C for 30 min,
(70.3 mg, 0.192 mmol, 65%). R = 0.31 (hexane/diethyl ether = 1:1);
f
−
1
and LDA (0.24 mL, 0.36 mmol, 1.2 equiv) was added dropwise to the
Schlenk tube. The reaction mixture was stirred at −78 °C for 1 h, at
which time CuI (82.3 mg, 0.43 mmol, 1.4 equiv) was added to the
Mp 104−107 °C; IR (ATR, cm ): 1626, 1457, 1359, 1304, 1261,
1
1107, 1037, 949, 808, 717, 703; H NMR (400 MHz, CDCl ): δ
3
7.45−7.29 (m, 5H), 6.84 (s, 1H), 5.96 (s, 1H), 4.12 (s, 2H), 2.77 (br
G
DOI: 10.1021/acs.joc.8b02220
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
s, 1H), 1.37 (s, 6H); 13C{ H} NMR (100 MHz, CDCl ): δ 157.6,
1
material, which was purified by silica gel column chromatography
3
1
53.6, 142.4, 129.0, 128.7, 128.3, 126.5, 124.3, 112.5, 79.7, 71.6, 67.4,
(hexane/diethyl ether = 3:1 to 3:2, gradient) to provide the title
+
79
2
8.1; HRMS (DART ) m/z: calcd. for C H O N BrS, 366.0163
M + H] ; found, 366.0159.
Ethyl 4-Bromo-5-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-
compound as a yellow solid (89.5 mg, 0.250 mmol, 83%). R = 0.21
1
6
17
2
f
+
−1
[
(hexane/diethyl ether = 3:2); IR (ATR, cm ): 2928, 1631, 1467,
1353, 1312, 1173, 1036, 977, 568, 519; H NMR (400 MHz, CDCl ):
1
3
thiophene-2-carboxylate (5b). To a flame-dried 20 mL Schlenk
tube equipped with a Teflon-coated magnetic stirring bar and a
rubber septum were added 2-(5-bromothiophen-2-yl)-4,4-dimethyl-
δ 6.90 (s, 1H), 4.11 (s, 2H), 1.93−1.59 (m, 11H), 1.37 (s, 6H);
1
3
1
C{ H} NMR (100 MHz, CDCl ): δ 158.4, 157.1, 127.4, 124.0,
3
+
1
12.2, 79.6, 72.5, 67.8, 39.7, 28.4, 25.3, 22.2; HRMS (DART ) m/z:
calcd. for C H O N BrS, 358.0476 [M + H] ; found, 358.0467.
7
9
+
4
,5-dihydrooxazole (1e) (78.0 mg, 0.30 mmol, 1.0 equiv) and THF
1
5
21
2
(2.0 mL). The resulting solution was cooled to −78 °C for 30 min,
Scope and Limitations of Bromofurans (Scheme 2). (2-
Bromo-5-(5,5-dimethyl-1,3-dioxan-2-yl)furan-3-yl)(phenyl)-
methanol (7). To a flame-dried 20 mL Schlenk tube equipped with a
Teflon-coated magnetic stirring bar and a rubber septum were added
2-(5-bromofuran-2-yl)-5,5-dimethyl-1,3-dioxane (6) (78.7 mg, 0.30
mmol, 1.0 equiv) and THF (2.0 mL). The resulting solution was
cooled to −78 °C, and LDA (0.40 mL, 0.60 mmol, 2.0 equiv) was
added dropwise to the Schlenk tube. The reaction mixture was stirred
at −78 °C for 1 h, at which time benzaldehyde (62 μL, 0.60 mmol, 2.0
equiv) was added to the Schlenk tube. After stirring at −78 °C for 1 h,
the reaction mixture was treated with water (1 mL). After partitioned,
the aqueous layer was extracted with diethyl ether (1 mL) three times.
The combined organic extracts were washed with brine (2 mL), dried
over sodium sulfate, and filtered. The filtrate was concentrated under
reduced pressure to give a crude material, which was purified by silica
gel column chromatography (hexane/CH Cl = 1:3 to hexane/
and LDA (0.24 mL, 0.36 mmol, 1.2 equiv) was added dropwise to the
Schlenk tube. The reaction mixture was stirred at −78 °C for 30 min,
at which time ethyl chloroformate (57 μL, 0.60 mmol, 2.0 equiv) was
added to the Schlenk tube. After stirring at −78 °C for 1 h, the
reaction mixture was treated with water (1 mL). After partitioned, the
aqueous layer was extracted with diethyl ether. The combined organic
extracts were washed with saturated aqueous ammonium chloride,
water, brine, dried over sodium sulfate, and filtered. The filtrate was
concentrated under reduced pressure to give a crude material, which
was purified by silica gel column chromatography (hexane/dichloro-
methane = 1:1 to 1:4, gradient) to provide the title compound as a
yellow solid (40.8 mg, 0.123 mmol, 41%). R = 0.52 (hexane/diethyl
f
−
1
ether = 3:2); Mp 65−67 °C; IR (ATR, cm ): 2967, 2931, 1733,
1
1
7
714, 1653, 1638, 1532, 1473, 1465, 1457, 1368, 1337, 1263, 1250,
1
201, 1076, 1045, 1020, 966, 748; H NMR (400 MHz, CDCl ): δ
3
2
2
.67 (s, 1H), 4.35 (q, 2H, J = 7.2 Hz), 4.13 (s, 2H), 1.39 (s, 6H), 1.36
acetone = 3:1, gradient), followed by preparative SEC-HPLC, to give
1
3
1
(t, 3H, J = 7.2 Hz); C{ H} NMR (100 MHz, CDCl ): δ 160.8,
a yellow oil (45.8 mg, 0.130 mmol, 43%). R = 0.27 (hexane/diethyl
3
f
−
1
56.2, 137.2, 135.7, 131.6, 112.8, 79.7, 68.4, 62.0, 28.3, 14.3; HRMS
ether = 3:1); IR (ATR, cm ): 2957, 2856, 1680, 1546, 1537, 1494,
+
79
+
1469, 1461, 1453, 1395, 1366, 1216, 1192, 1153, 1101, 1014, 982,
1
2
15
3
1
found, 331.9947.
963, 948, 920, 823, 730, 700; H NMR (400 MHz, CDCl ): δ 7.44−
3
2
-(5-Allyl-3-bromothiophen-2-yl)-4,4-dimethyl-4,5-dihydrooxa-
7.22 (m, 5H), 6.46 (s, 1H), 5.74 (d, 1H, J = 2.6 Hz), 5.36 (s, 1H),
3.72 (d, 2H, J = 11.4 Hz), 3.57 (d, 2H, J = 11.4 Hz), 2.10 (d, 1H, J =
2.6 Hz), 1.23 (s, 3H), 0.77 (s, 3H); C{ H} NMR (100 MHz,
zole (5c). To a flame-dried 20 mL Schlenk tube equipped with a
Teflon-coated magnetic stirring bar and a rubber septum were added
1
3
1
2
-(5-bromothiophen-2-yl)-4,4-dimethyl-4,5-dihydrooxazole (1e)
CDCl ): δ 152.9, 142.1, 128.6, 127.9, 127.7, 126.0, 120.7, 108.9, 95.7,
3
+
(78.7 mg, 0.30 mmol, 1.0 equiv) and THF (2.0 mL). The resulting
77.5, 68.7, 30.5, 23.0, 21.9; HRMS (DART ) m/z: calcd. for
C H O Br, 366.0467 [M + H] ; found, 366.0460.
17 19 4
7
9
+
solution was cooled to 0 °C for 30 min, and LDA (0.24 mL, 0.36
mmol, 1.2 equiv) was added dropwise to the Schlenk tube. The
reaction mixture was stirred at 0 °C for 30 min, at which time allyl
iodide (56 μL, 0.60 mmol, 2.0 equiv) was added to the Schlenk tube.
After warming to room temperature for 1 h, the reaction mixture was
treated with water (1 mL). After partitioned, the aqueous layer was
extracted with diethyl ether. The combined organic extracts were
washed with brine (2 mL), dried over sodium sulfate, and filtered.
The filtrate was concentrated under reduced pressure to give a crude
material, which was purified by silica gel column chromatography
(3-Bromo-5-(5,5-dimethyl-1,3-dioxan-2-yl)furan-2-yl)(phenyl)-
methanol (8). To a flame-dried 20 mL Schlenk tube equipped with a
Teflon-coated magnetic stirring bar and a rubber septum were added
potassium tertiary butoxide (66.9 mg, 0.60 mmol, 2.0 equiv) and
THF (1.0 mL). The resulting solution was cooled to −78 °C, and
LDA (0.40 mL, 0.60 mmol, 2.0 equiv) was added dropwise to the
Schlenk tube. To the Schlenk tube was added the 2-(5-bromofuran-2-
yl)-5,5-dimethyl-1,3-dioxane (6) (78.5 mg, 0.30 mmol, 1.0 equiv) in
THF (1.0 mL) dropwise. The reaction mixture was stirred at −78 °C
for 15 min, at which time benzaldehyde (62 μL, 0.60 mmol, 2.0
equiv) was added to the Schlenk tube. After stirring at −78 °C for 15
min, the reaction mixture was treated with water (1 mL). After
partitioned, the aqueous layer was extracted with diethyl ether (1 mL)
three times. The combined organic extracts were washed with brine
(2 mL), dried over sodium sulfate, and filtered. The filtrate was
concentrated under reduced pressure to give a crude material, which
was purified by silica gel column chromatography twice (hexane/
acetone = 3:1, then hexane/CH Cl = 1:3 to hexane/acetone = 3:1,
(
hexane/diethyl ether = 3:1), followed by preparative SEC-HPLC, to
provide the title compound as a light green oil (49.1 mg, 0.149 mmol,
−
1
4
2
1
9%). R = 0.39 (hexane/diethyl ether = 3:1); IR (ATR, cm ): 2968,
f
928, 2895, 1635, 1535, 1477, 1428, 1352, 1304, 1275, 1202, 1186,
1
026, 991, 951, 919, 846, 834, 810, 710, 604; H NMR (400 MHz,
CDCl ): δ 6.77 (s, 1H), 5.97−5.86 (m, 1H), 5.22−5.13 (m, 2H), 4.11
3
1
3
1
(
s, 2H), 3.51 (d, 2H, J = 6.4 Hz), 1.38 (s, 6H); C{ H} NMR (100
MHz, CDCl ): δ 156.9, 147.1, 134.6, 130.1, 124.0, 117.9, 112.5, 79.5,
6
3
3
+
79
7.7, 34.3, 28.3; HRMS (DART ) m/z: calcd. for C H ON BrS,
00.0058 [M + H] ; found, 300.0065.
-(4-Bromo-5-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)thiophen-2-
12 15
2
2
+
gradient), followed by preparative SEC-HPLC and preparative TLC,
to provide the title product as a yellow oil (36.0 mg, 0.102 mmol,
1
−
1
yl)cyclohexan-1-ol (5d). To a flame-dried 20 mL Schlenk tube
equipped with a Teflon-coated magnetic stirring bar and a rubber
septum were added 2-(5-bromothiophen-2-yl)-4,4-dimethyl-4,5-dihy-
drooxazole (1e) (78.0 mg, 0.30 mmol, 1.0 equiv) and THF (2.0 mL).
The resulting solution was cooled to −78 °C for 30 min, and LDA
34%). R = 0.32 (hexane/diethyl ether = 2:1); IR (ATR, cm ): 3423,
f
2956, 2861, 1470, 1453, 1395, 1365, 1340, 1309, 1217, 1189, 1124,
1
1097, 1038, 1008, 984, 963, 921, 831, 809, 728, 701, 503; H NMR
(400 MHz, CDCl ): δ 7.45−7.26 (m, 5H), 6.50 (s, 1H), 5.92 (s, 1H),
3
5.36 (s, 1H), 3.69 (d, 2H, J = 11.2 Hz), 3.54 (dd, 2H, J = 10.8, 2.8
1
3
1
(0.24 mL, 0.36 mmol, 1.2 equiv) was added dropwise to the Schlenk
Hz), 2.80 (br s, 1H), 1.21 (s, 3H), 0.75 (s, 3H); C{ H} NMR (100
tube. The reaction mixture was stirred at −78 °C for 30 min, at which
time cyclohexanone (56 μL, 0.54 mmol, 1.8 equiv) was added to the
Schlenk tube. After stirring at −78 °C for 1 h, the reaction mixture
was treated with water (1 mL). After partitioned, the aqueous layer
was extracted with diethyl ether (1 mL) three times. The combined
organic extracts were washed with saturated aqueous ammonium
chloride, water, brine, dried over sodium sulfate, and filtered. The
filtrate was concentrated under reduced pressure to give a crude
MHz, CDCl ): δ 151.4, 151.2, 140.2, 128.6, 128.0, 126.4, 111.5, 98.3,
3
+
95.7, 77.4, 68.1, 30.4, 23.0, 21.9; HRMS (DART ) m/z: calcd. for
7
4
9
+
C H O Br, 366.0467 [M + H] ; found, 366.0466.
1
7
19
(4-Bromo-5-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)furan-2-yl)-
(phenyl)methanol (10). To a flame-dried 20 mL Schlenk tube
equipped with a Teflon-coated magnetic stirring bar and a rubber
septum were added 2-(5-bromofuran-2-yl)-4,4-dimethyl-4,5-dihy-
drooxazole (9) (73.0 mg, 0.30 mmol, 1.0 equiv) and THF (2.0
H
DOI: 10.1021/acs.joc.8b02220
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
mL). The resulting solution was cooled to −40 °C, and LDA (0.24
mL, 0.36 mmol, 1.2 equiv) was added dropwise to the Schlenk tube.
The reaction mixture was stirred at −40 °C for 5 min, at which time
benzaldehyde (62 μL, 0.60 mmol, 2.0 equiv) was added to the
Schlenk tube. After the reaction mixture was let warm to room
temperature and stirred for 30 min, the reaction mixture was treated
with water (1 mL). After partitioned, the aqueous layer was extracted
with diethyl ether (1 mL) three times. The combined organic extracts
were washed with brine (2 mL), dried over sodium sulfate, and
filtered. The filtrate was concentrated under reduced pressure to give
a crude material, which was purified by silica gel column
chromatography (hexane/diethyl ether = 1:1) to provide the title
bromosuccinimide (14.1 g, 79.4 mmol, 1.5 equiv) and the resulting
mixture was stirred at room temperature for 22 h, at which time the
reaction mixture was treated with saturated aqueous sodium
thiosulfate. After partitioned, the aqueous layer was extracted twice
with diethyl ether. The combined organic extracts were washed with
water and filtered. The filtrate was concentrated under reduced
pressure to give a crude material, which was purified by silica gel
column chromatography (hexane/diethyl ether = 5:1) to provide the
title compound as a pale yellow solid (8.67 g, 33.2 mmol, 63%). R =
f
−
1
0.66 (hexane/diethyl ether = 2:1); IR (ATR, cm ): 1504, 1210,
1104, 1039, 1022, 1014, 986, 978, 914, 809, 781, 511, 453; H NMR
1
(400 MHz, CDCl ): δ 6.42 (d, J = 3.4 Hz, 1H), 6.28 (d, J = 3.4 Hz,
3
compound as a yellow solid (58.0 mg, 0.166 mmol, 55%). R = 0.37
1H), 5.41 (s, 1H), 3.74 (d, J = 11.0 Hz, 2H), 3.59 (d, J = 11.0 Hz,
f
−
1
13
1
(
1
hexane/diethyl ether = 1:2); IR (ATR, cm ): 3224, 2966, 2349,
658, 1187, 1140, 1045, 1010, 972, 954, 818, 725, 700; H NMR
2H), 1.26 (s, 3H), 0.78 (s, 3H); C{ H} NMR (100 MHz, CDCl ):
3
1
δ 153.0, 122.3, 112.1, 110.2, 95.7, 77.5, 30.5, 23.0, 21.9; HRMS
+
79
+
(
400 MHz, CDCl ): δ 7.47−7.31 (m, 5H), 6.18 (s, 1H), 5.87 (d, 1H,
(DART ) m/z: calcd. for C H O Br, 261.0126 [M + H] ; found,
3
10 14 3
J = 3.2 Hz), 4.11 (s, 2H), 3.02 (d, 1H, J = 3.2 Hz), 1.36 (s, 6H);
261.0118.
13
1
C{ H} NMR (100 MHz, CDCl ): δ 160.3, 154.6, 140.4, 139.2,
2-(5-Bromofuran-2-yl)-4,4-dimethyl-4,5-dihydrooxazole (9). A
500 mL round-bottom flask equipped with a Teflon-coated magnetic
stirring bar was charged with 5-bromo-2-furaldehyde (8.75 g, 50.0
mmol, 1.0 equiv), 2-amino-2-methyl-1-propanol (9.04 g, 102 mmol,
2.0 equiv), and dichloromethane (300 mL). After the resulting
solution was stirred at 40 °C for 30 min, activated MS 4 Å (75.7 g)
was added to the flask. The reaction mixture was stirred at 40 °C for
15 h, and N-bromosuccinimide (17.9 g, 101 mmol, 2.0 equiv) was
added. The resulting mixture was stirred at 40 °C for 6 h, at which
time the reaction mixture was filtered through a pad of Celite. The
filtrate was washed with saturated aqueous sodium thiosulfate, water,
and brine. The organic layer was dried over sodium sulfate and
filtered. The filtrate was concentrated under reduced pressure to give
a crude material, which was purified by silica gel column
chromatography (hexane/diethyl ether = 4:1 to 2:3, gradient) to
provide the title compound as an ocher solid (6.71 g, 27.5 mmol,
3
1
28.6, 128.4, 126.8, 113.8, 105.3, 79.6, 69.3, 67.3, 28.1; HRMS
+
79
+
(DART ) m/z: calcd. for C H O N Br, 350.0392 [M + H] ;
16 17 3
found, 350.0386.
2
-(3-Bromofuran-2-yl)benzo[d]thiazole (12b). A flame-dried 20
mL Schlenk tube equipped with a Teflon-coated magnetic stirring bar
and a rubber septum was charged with 2-(5-bromo-2-furanyl)-
benzothiazole (11b) (84.8 mg, 0.30 mmol, 1.0 equiv) and anhydrous
THF (2.0 mL). The solution was cooled to −78 °C. LDA (0.24 mL,
0.36 mmol, 1.2 equiv) was added dropwise to the Schlenk tube and
the resulting mixture was stirred at −78 °C for 30 min, at which time
the brown reaction mixture was treated with water (1 mL). After
partitioned, the aqueous layer was extracted with diethyl ether (1 mL)
three times. The combined organic extracts were washed with brine,
dried over sodium sulfate, and filtered. The filtrate was concentrated
under reduced pressure to give a crude material, which was purified by
silica gel column chromatography (hexane/methyl acetate = 20:1) to
provide the title compound as a yellow solid (24.4 mg, 0.0871 mmol,
55%). R = 0.36 (hexane/diethyl ether = 2:3); Mp 71−72 °C; IR
f
−1
(ATR, cm ); 3073, 2965, 1677, 1479, 1367, 1217, 1094, 1024, 976,
1
2
9%). R = 0.17 (hexane/methyl acetate = 20:1); Mp 81−83 °C; IR
922, 800; H NMR (400 MHz, CDCl
6.41 (d, 1H, J = 3.6 Hz), 4.08 (s, 2H), 1.37 (s, 6H); C{ H} NMR
(100 MHz, CDCl ): δ 153.5, 144.8, 125.9, 116.3, 113.4, 79.2, 67.9,
3
): δ 6.87 (d, 1H, J = 3.6 Hz),
f
−
1
13
1
(ATR, cm ): 1573, 1501, 1450, 1428, 1384, 1315, 1064, 1027, 1012,
1
9
32, 922, 885, 752, 725, 691, 672; H NMR (400 MHz, CDCl ): δ
3
3
+
79
8
.14 (d, 1H, J = 8.4 Hz), 7.93 (d, 1H, J = 8.4 Hz), 7.60 (d, 1H, J = 2.0
28.3; HRMS (DART ) m/z: calcd. for C
+ H] ; found, 243.9985.
9
H
11
O
2
N Br, 243.9973 [M
1
3
1
+
Hz), 7.52 (m, 1H), 7.43 (m, 1H), 6.69 (d, 1H, J = 2.0 Hz); C{ H}
NMR (100 MHz, CDCl ): δ 155.1, 153.0, 145.5, 144.7, 134.4, 126.7,
2-(5-Bromofuran-2-yl)benzo[d]thiazole (11b). To a flame-dried
50 mL Schlenk tube equipped with a Teflon-coated magnetic stirring
bar and a rubber septum were added 5-bromofuran-2-carbaldehyde
(1.75 g, 9.97 mmol, 1.0 equiv), 2-aminothiophenol (1.36 g, 10.9
mmol, 1.1 equiv), and anhydrous xylene (30 mL). After stirring at 120
°C for 30 min, the resulting solution was treated with activated carbon
(1.22 g). The resulting mixture was stirred under an oxygen balloon at
120 °C for 13 h, then treated with water (10 mL). The mixture was
filtered through a pad of Celite and the filter cake was washed with
diethyl ether (40 mL). The filtrate was washed with water (20 mL)
and brine (10 mL), dried over sodium sulfate, and filtered. The filtrate
was concentrated under reduced pressure to give a crude material,
which was recrystallized from ethanol to provide the title compound
3
+
1
25.7, 123.6, 121.6, 116.7, 103.1; HRMS (DART ) m/z: calcd. for
81
+
C H O BrNS, 281.9411 [M + H] ; found, 281.9398.
11
5
Synthesis of Starting Materials (Scheme 2). 2-(Furan-2-yl)-
,5-dimethyl-1,3-dioxane. A 100 mL round-bottom flask equipped
with a Teflon-coated magnetic stirring bar was charged with furfural
5
(
(
4.97 mL, 60 mmol, 1.0 equiv), toluene (72 mL), neopentyl glycol
6.25 g, 60 mmol, 1.0 equiv), and p-toluene sulfonic acid
monohydrate (114.2 mg, 0.60 mmol, 1 mol %). The flask was fitted
with a Dean−Stark apparatus, and the mixture was heated to reflux for
5
h. The mixture was evaporated under reduced pressure. The residue
was filtered through a pad of Celite. The filtrate was partitioned
between diethyl ether and water. The organic layer was dried over
sodium sulfate and filtered. The filtrate was concentrated under
reduced pressure to give a crude material, which was purified by silica
gel column chromatography (hexane/diethyl ether = 5:1) to provide
1
as a brown solid (1.66 g, 5.93 mmol, 59%). H NMR spectra of this
3
5
product were identical to those reported in the literature. R = 0.68
f
−
1
(hexane/methyl acetate = 3:1); Mp 120−122 °C; IR (ATR, cm ):
3100, 1504, 1455, 1314, 1229, 1020, 1011, 925, 904, 786, 752, 723,
672, 664, 651, 632, 615; H NMR (400 MHz, CDCl ): δ 8.05 (d, 1H,
the title product as a colorless oil (9.64 g, 52.9 mmol, 88%). R = 0.45
f
−1
1
(
1
hexane); IR (ATR, cm ): 1472, 1395, 1364, 1218, 1150, 1104,
024, 987, 971, 953, 933, 917, 884, 813, 781, 740, 599; H NMR (400
3
1
J = 8.2 Hz), 7.90 (d, 1H, J = 8.2 Hz), 7.50 (m, 1H), 7.40 (m, 1H),
1
3
1
MHz, CDCl ): δ 7.41−7.39 (m, 1H), 6.45 (d, J = 3.2 Hz, 1H), 6.36
7.14 (d, 1H, J = 3.4 Hz), 6.50 (d, 1H, J = 3.4 Hz); C{ H} NMR
3
(
(
dd, J = 3.2, 2.0 Hz, 1H), 5.47 (s, 1H), 3.75 (d, J = 11.0 Hz, 2H), 3.61
(100 MHz, CDCl ): δ 156.4, 153.7, 150.6, 134.3, 126.7, 125.5, 125.3,
3
d, J = 11.0 Hz, 2H), 1.28 (s, 3H), 0.78 (s, 3H); 13C{ H} NMR (100
1
+
123.3, 121.7, 114.6, 113.6; HRMS (DART ) m/z: calcd. for
C H O BrNS, 279.9432 [M + H] ; found, 279.9445.
7
9
+
MHz, CDCl ): δ 151.0, 142.6, 110.3, 107.5, 96.2, 77.6, 30.5, 23.0,
3
11 5
+
2
1.9; HRMS (DART ) m/z: calcd. for C H O , 183.1021 [M +
Conversion of Acetal and Oxazoline Moieties (Scheme 3). 4-
Bromo-5-(hydroxy(phenyl)methyl)thiophene-2-carbaldehyde (13).
To a 20 mL round-bottom flask equipped with a Teflon-coated
magnetic stirring bar were added (3-bromo-5-(diethoxymethyl)-
thiophen-2-yl)(phenyl)methanol (4a) (37.5 mg, 0.10 mmol, 1.0
equiv), p-toluenesulfonic acid monohydrate (2.1 mg, 0.011 mmol, 11
mol %), water (1.0 mL), and acetone (1.0 mL). The resulting solution
1
0
15
3
+
H] ; found, 183.1018.
-(5-Bromofuran-2-yl)-5,5-dimethyl-1,3-dioxane (6). A flame-
2
dried 200 mL Schlenk tube equipped with a Teflon-coated magnetic
stirring bar and a rubber septum was charged with 2-(furan-2-yl)-5,5-
dimethyl-1,3-dioxane (9.64 g, 52.9 mmol, 1.0 equiv) and THF (150
mL). After cooling to 0 °C, the solution was treated with N-
I
DOI: 10.1021/acs.joc.8b02220
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
was stirred at room temperature for 75 min, at which time the
reaction mixture was treated with saturated aqueous sodium hydrogen
carbonate (1 mL). After partitioned, the aqueous layer was extracted
with diethyl ether (6 mL × 1, 2 mL × 2). The combined organic
extracts were washed with brine (2 mL), dried over sodium sulfate,
and filtered. The filtrate was concentrated under reduced pressure to
give a crude material, which was purified by silica gel column
chromatography (hexane/diethyl ether = 3:1), followed by prepara-
tive SEC-HPLC, to provide the title product as a colorless oil (24.5
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(
mg, 0.0824 mmol, 82%). R = 0.25 (hexane/diethyl ether = 3:1); IR
f
−1
(
(
6
ATR, cm ): 1667, 1452, 1223, 1140, 1038, 1024, 846, 722, 700,
67, 594, 575, 568, 544, 535, 522, 503; H NMR (400 MHz, CDCl ):
1
3
δ 9.82 (s, 1H), 7.60 (s, 1H), 7.50−7.45 (m, 2H), 7.42−7.32 (m, 3H),
1
3
1
6
.12 (d, 1H, J = 3.2 Hz), 2.59 (d, 1H, J = 3.2 Hz); C{ H} NMR
(
1
2
100 MHz, CDCl ): δ 182.2, 153.5, 141.6, 140.6, 138.6, 129.0, 128.9,
3
+
79
26.9, 108.9, 72.4; HRMS (DART ) m/z: calcd. for C H O BrS,
12 10 2
+
96.9585 [M + H] ; found, 296.9599.
3
-Bromo-5-(hydroxy(phenyl)methyl)thiophene-2-carboxylic
Acid (14). To an oven-dried 20 mL test tube equipped with a Teflon-
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4,5-dihydrooxazol-2-yl)thiophen-2-yl)(phenyl)methanol (5a) (36.6
mg, 0.10 mmol, 1.0 equiv), dichloromethane (1.0 mL), and methyl
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stirred at room temperature for 2 h, at which time the reaction
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treated with 6 M aqueous sodium hydroxide (0.65 mL) and methanol
(
7) Anti-inflammatory drug: Gans, K. R.; Galbraith, W.; Roman, R.
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(
8) Thiophenes: (a) Fobare, W. F.; Solvibile, W. R.; Robichaud, A.
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f
1
7, 5353. (b) Bey, E.; Marchais-Oberwinkler, S.; Negri, M.; Kruchten,
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.45 (dichloromethane/methanol = 4:1); Mp 127−132 °C; IR (ATR,
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−1
cm ): 1715, 1697, 1682, 1521, 1508, 1456, 1339, 1262, 1223, 1022,
8
6
1
64, 854, 844, 829, 818, 796, 781, 759, 742, 701, 683, 673, 664, 646,
1
12; H NMR (400 MHz, CDCl ): δ 7.45−7.33 (m, 5H), 6.88 (d,
3
1
3
1
H, J = 0.8 Hz), 5.98 (d, 1H, J = 0.8 Hz), 2.13 (br s, 1H); C{ H}
(
17β-HSD1) Inhibitory Activity and Selectivity. J. Med. Chem. 2009,
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81
+
12
10
3
ASSOCIATED CONTENT
Supporting Information
■
*
S
4
(
977.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b02220.
9) Fused thiophenes: (a) Jones, C. D.; Jevnikar, M. G.; Pike, A. J.;
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13
H and C NMR spectra for all new compounds (PDF)
2
hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]-
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Methoxyureidophenyl Moiety at the 6-Position: A Highly Potent
and Orally Bioavailable Non-Peptide Antagonist for the Human
Luteinizing Hormone-Releasing Hormone Receptor. J. Med. Chem.
AUTHOR INFORMATION
Corresponding Author
E-mail: okano@harbor.kobe-u.ac.jp.
■
*
ORCID
Kentaro Okano: 0000-0003-2029-8505
Atsunori Mori: 0000-0002-1163-264X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by JSPS KAKENHI Grant
Numbers JP16K05774 in Scientific Research (C), JP16H-
■
2
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̈
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̈
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̈
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