Mild Condition for the Deoxygenation of α-Heteroaryl-Substituted Methanol Derivatives

Article abstract of DOI:10.1021/acs.joc.1c00067

A mild condition via PPh3/I2/imidazole for the deoxygenation of substituted methanol derivatives has been identified. This metal-free process was found to proceed well on secondary or tertiary alcohols substituted with one or two heteroaryl groups, and it tolerates acid-sensitive heterocycles. This condition works for methanol derivatives substituted with 2-pyridyl, 4-pyridyl, or other heterocyclic groups, allowing the negative charge formed during the reaction to resonate to a nitrogen atom. Methanol derivatives substituted with 3-pyridyl or heterocyclic groups that do not allow the negative charge formed during the reaction to resonate to a nitrogen atom will not undergo deoxygenation under this condition.

Full text of DOI:10.1021/acs.joc.1c00067

pubs.acs.org/joc
Article
Mild Condition for the Deoxygenation of α‑Heteroaryl-Substituted
Methanol Derivatives
Na Meng,* Wensheng Yu,* Takao Suzuki, Maofen Chen, Zhiqi Qi, Bin Hu, Jianming Bao,
John S. Debenham, Robert Mazzola, and Joseph L. Duffy
Cite This: J. Org. Chem. 2021, 86, 5560−5567
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A mild condition via PPh3/I2/imidazole for the
deoxygenation of substituted methanol derivatives has been
identified. This metal-free process was found to proceed well on
secondary or tertiary alcohols substituted with one or two
heteroaryl groups, and it tolerates acid-sensitive heterocycles.
This condition works for methanol derivatives substituted with 2-
pyridyl, 4-pyridyl, or other heterocyclic groups, allowing the
negative charge formed during the reaction to resonate to a nitrogen atom. Methanol derivatives substituted with 3-pyridyl or
heterocyclic groups that do not allow the negative charge formed during the reaction to resonate to a nitrogen atom will not undergo
deoxygenation under this condition.
have not expanded their substrates to α-heteroaryl-substituted
methanol derivatives. Currently, there is no general method to
prepare heteroaryl and aryl or bisheteroaryl-substituted
methane derivatives. The deoxygenation of α-heteroaryl-
substituted methanol derivatives has not been well studied.
In 2016, Nishigaya et al. reported a PBr3-mediated
deoxygenation of α-aryl-2-pyridine methanols to provide α-
aryl-2-pyridinyl-methylenes in 44−91% yields.7 However, this
condition does not work if the aryl group is replaced with a
cyclohexyl group. The author speculated that the aryl group is
necessary for this condition. In addition, the usage of PBr3 in
this condition limits its application to nonacid-sensitive
substrates. It also does not tolerate PBr3-sensitive heteroaryl-
substituted methanol derivatives. A more general and milder
deoxygenation method for the deoxygenation of α-heteroaryl-
substituted methanol derivatives is highly desirable. Herein, we
report a mild condition of PPh3/I2/imidazole for the
deoxygenation of α-heteroaryl-substituted methanol deriva-
tives.
INTRODUCTION
■
Deoxygenation is an important reaction in organic synthesis.
Barton−Maccombie deoxygenation is one of the methods that
has been widely used.1 Another commonly used method
utilizes trifluoroacetic acid and triethylsilane to remove the
hydroxyl group.2 This method uses strong acidic conditions
and cannot be applied to acid-sensitive substrates. The metal-
free iodine-mediated deoxygenation of alcohols has been
reported. In 1976, Bohlmann et al. reported that the
corresponding hydrocarbons were unexpectedly obtained in
24−95% yields when they tried to convert the allyl primary
alcohols or dibenzyl secondary alcohols to iodides under
triphenyl phosphine and iodine conditions.3 In 1984,
Furukawa et al. reported that, under triphenyl phosphine and
iodine conditions, benzyl alcohols with no β-hydrogen gave the
corresponding iodides as intermediates, which were reduced in
situ by the hydrogen iodide produced, giving the correspond-
ing alkanes in 26−83% yields.4 For substrates with β-
hydrogens, the corresponding elimination products were
formed. In 1998, Rauter et al. reported an interesting iodide-
mediated deoxygenation reaction of α-hydroxy sugar, lactone,
or amide.5 When these substrates were treated with triphenyl
phosphine (4 equiv), imidazole (4 equiv), and iodine (3 equiv)
in toluene at 60 °C for 3.5 h, the corresponding alkane
products were obtained in 51−74% yields. In 2018, Pichon et
al. reported a similar condition with pyridine replacing
imidazole and a lower amount of iodine (0.5 equiv) and
triphenyl phosphine (1.5 equiv).6 The substrate scope was
expanded to the primary and secondary alcohols with a variety
of electron-withdrawing groups, such as ketones, esters,
amides, imides, and nitrile groups, at the α-position. The
yields were 51−93%. Interestingly, all the reported methods
RESULTS AND DISCUSSION
■
α-Heteroaryl-substituted methane derivatives are important
scaffolds in drug discovery. During our research, we often need
to convert α-heteroaryl-substituted methanol derivatives to the
corresponding alkanes to test their biological activities. The
Received: January 10, 2021
Published: March 30, 2021
https://doi.org/10.1021/acs.joc.1c00067
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 5560−5567
5560

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
existing conditions often do not work. To identify a proper
condition for this conversion, we explored the condition of
PPh3/I2/imidazole to the conversion of 1 to 2, and the results
are summarized in Table 1. When 1 was treated with PPh3/I2/
significantly reduced the yield of 2 to 19%. The corresponding
iodide (35) was isolated in a 78% yield. Reducing the amount
of both I2 and imidazole (entry 4) did not affect the yield. No
corresponding iodide is obtained. Interestingly, reducing the
amount of PPh3 to 1.2 equiv afforded 92% yield (entry 5). The
reason for the improved yield in entry 5 was due to the less
amount of triphenylphosphine added, which led to an easier
purification. Repeating the same condition of entry 5 at a lower
temperature of 50 °C gave a lower yield of 2 (entry 6). 52% of
the corresponding iodide (31) was also obtained. The reaction
condition of entry 5 seems to be the best condition for this
conversion.
Table 1. Optimization of the PPh3/I2/Imidazole
Deoxygenation Condition
With the best reaction condition identified, we explored the
substrate scope of this reaction. The results are summarized in
Table 2. Compound 3 was reported to be tested in the PBr3-
mediated deoxygenation condition and no corresponding
alkane product was obtained.7 However, it afforded the
corresponding alkane product 4 in 87% yield under the
PPh3/I2/imidazole condition. Compound 5 is the 4-pyridyl
analogue of 1 and afforded 8 in 50% yield. During this
reaction, 29% of 5 was recovered. 2-Pyridyl and CF3 group-
substituted methanol derivative 7 and its 4-pyridyl analogue 9
all worked well under this condition and gave 8 and 10 in 55
and 74% yields, respectively. The substrates tested so far (1, 3,
5, 7, and 9) are all methanol derivatives substituted with a
heterocyclic group and an alkyl group. Substrates substituted
entry PPh3 (equiv) I2 (equiv) imidazole (equiv)
temp
rt
reflux
50 °C
reflux
reflux
50 °C
yield (%)
1
2
3
4
5
6
2.8
2.8
2.8
2.8
1.2
1.2
2.4
2.4
2.4
1.2
1.2
1.2
2.6
2.6
2.6
1.5
1.5
1.5
0.0
78
19
82
92
40
imidazole in THF at 25 °C (entry 1), no reaction occurred.
However, when the reaction temperature was increased to the
reflux temperature, deoxygenated product 2 was obtained in a
78% yield (entry 2). No elimination product was observed in
this reaction. Lowering the reaction temperature to 50 °C
Table 2. Deoxygenation of α-Heteroaryl-Substituted Methanol Derivatives
5561
https://doi.org/10.1021/acs.joc.1c00067
J. Org. Chem. 2021, 86, 5560−5567

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
by a heterocyclic and a phenyl group were also tested.
Compound 11 is a 2-pyrazinyl- and a phenyl-substituted
methanol derivative. It gave the corresponding deoxygenated
product 12 in 46% yield. Methanol derivatives substituted with
a thiazole and a phenyl group (13) were tested, and they
afforded the corresponding alkane product 14 in 53% yield.
1,2,4-Triazole-3-thiol- and phenyl-substituted methanol deriv-
ative 15 worked well under this condition and gave 16 in 62%
yield. In addition, the methanol derivative substituted by two
heteroaryl groups was tested. Compound 17 was a methanol
derivative substituted with a 1,2,4-triazolyl and a 3-pyridyl
group. The desired alkane product 18 was obtained in 60%
yield. Trisubstituted methanol derivatives, such as tertiary
alcohol 19, were further tested under this condition. The
desired deoxygenated product 20 was obtained in 52% yield.
An elimination side product, 2-(1-phenylvinyl)pyridine, was
obtained as well in 41% yield. This method worked on the
polycyclic heteroarene-substituted methanol derivatives as
well. Quinoxaline analogue (21) gave the corresponding
deoxygenated product 22 in 42% yield. Quinoline analogue
(23) gave the corresponding deoxygenated product 24 in 43%
yield.
Table 3. 3-Pyridyl-Substituted Methanol Derivatives and
Their Presumed Side Products
The PPh3/I2/imidazole-mediated condition worked well for
converting a variety of heterocyclic and alkyl, heterocyclic and
phenyl, or bisheterocyclic-substituted methanol derivatives to
their corresponding deoxygenated alkane products. Interest-
ingly, we observed that 3-pyridyl-substituted methanol
derivatives did not work under this condition. For example,
while the 2-pyridyl (1) and 4-pyridyl (5) derivatives worked
well, the corresponding 3-pyridine derivative (25) did not give
any desired deoxygenated alkane product. Instead, 42% of 25
remained. The other side products were speculated to be the
corresponding iodide (25a, 28%) and the elimination product
(25b, 25%) by liquid chromatography−mass spectrometry
(LC−MS). Another example is that 26, unlike its 2-pyridyl (7)
and 4-pyridyl (9) derivatives, did not give any desired alkane
product. Besides 77% of 26 remained on LC−MS, the
corresponding iodide (26a, 23%) was also observed. To
confirm the observation that 3-pyridyl-substituted methanol
derivatives do not work under the PPh3/I2/imidazole
condition, we tested more 3-pyridyl-substituted derivatives,
and the results are summarized in Table 3. Compound 27 did
not give any deoxygenated product. The corresponding iodide
27a was isolated in 78% yield. Compound 28 gave a messy
reaction and no major product was observed on LC−MS.
Compound 29 gave a reaction mixture containing 29 (20%)
and the presumed iodide 29a (80%) on LC−MS. Compound
30 provided a similar result as 25. The LC−MS of the crude
reaction mixture showed 9% of 30, 49% of the presumed
iodide 30a, and 41% of the presumed elimination product 30b.
Compound 31 gave solely one product, which was presumably
the elimination product 31a, as determined by LC−MS. One
exception is that 17 is a 3-pyridyl-substituted analogue, but it
worked well under the PPh3/I2/imidazole condition (Table 1).
We speculated it as due to the presence of the 1,2,4-triazolyl
group. When the 1,2,4-triazolyl group was replaced with a
pyrazol-4-yl group (32), interestingly, the substrate did not
give any desired alkane product under the same condition and
only 32 remained. We also observed examples of heterocyclic-
substituted methanol derivatives that are not a 3-pyridyl
derivative but do not work under the PPh3/I2/imidazole
condition. Compound 33 is one of them and no reaction
occurred under the PPh3/I2/imidazole condition.
A speculated reaction mechanism is listed in Figure 1. The
reaction begins with the formation of triphenoxyphosphorus
intermediate 34. The triphenoxyphosphorus group was
replaced by the iodide to form intermediate 35 and
triphenylphosphine oxide. This step can be confirmed by the
observation of the formation as well as the isolation of
triphenylphosphine oxide in all reactions. The attack of the
iodide ion on iodide 35 generated iodine and a negative charge
on 36. The negative charge on 36 can be resonated to the
nitrogen atom of 37. Dehalogenation by the iodide ion has
been reported for α-halo ketones.8 The reaction was believed
to occur via an enol intermediate. Without the carbonyl group
next to the iodide, the enol intermediate could not be formed,
and the dehalogenation reaction would not occur. In the
deoxygenation reaction of α-heteroaryl-substituted methanol
derivatives via the I2/PPh3/imidazole condition, we speculate
that the presence of a nitrogen in the 2-position or 4-position
of the heteroaryl group could facilitate the dehalogenation by
the iodine ion, as resonance structures (36 and 37) can be
formed and the transition states can be stabilized. This is
similar to the mechanism of the dehalogenation reaction of α-
halo ketones by the iodide ion. The protonation of 37 will give
the corresponding deoxygenated products. For 3-pyridine
analogues, resonance structures are not stable and therefore
the iodide intermediates cannot undergo de-iodination and
they will remain in the reaction. If a α-proton is presented,
elimination could happen to form the alkene as well. These are
5562
https://doi.org/10.1021/acs.joc.1c00067
J. Org. Chem. 2021, 86, 5560−5567

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Figure 1. Speculated reaction mechanism.
actually the cases and the corresponding iodide intermediates
and alkene side products were isolated from a majority of the
reactions with 3-pyridyl-substituted methanol derivatives. This
mechanism could explain why 17 could undergo the
deoxygenation reaction but 32 could not. As the 1,2,4-triazolyl
group in 17 behaved like a 2-pyridyl group, but the pyrazol-4-yl
group in 32 behaved like a 3-pyridyl group. The substituted
imidazole group in 33 also behaved like a 3-pyridyl group, so it
also could not undergo the deoxygenation reaction.
CONCLUSIONS
■
In summary, a mild reaction condition via PPh3/I2/imidazole
for the deoxygenation of α-heteroaryl-substituted methanol
derivatives has been identified. This metal-free process was
found to proceed well on secondary and tertiary alcohols with
a variety of heteroaryl substrates, including acid-sensitive
heterocycles. It is mild enough to tolerate boronic ester. Our
condition can be applied to a wide range of methanol
derivatives, such as 2- or 4-pyridyl group, including those
heterocyclic groups allowing the negative charge formed
during the reaction to resonate to a nitrogen atom that were
scarcely addressed previously.
Based on the above mechanism, only catalytic iodine is
required. To prove this mechanism, we tested the reaction with
catalytic iodine, and the results are summarized in Table 4.
Table 4. Reaction Conditions with Catalytic Amount of
Iodine
EXPERIMENTAL SECTION
■
General Information. 13, 15, and 17 (all known compounds)
were from Merck Building Block Collection (MBBC) and used
without further purification. The other α-heteroaryl-substituted
methanol derivatives were prepared by laboratory preparation.
NMR spectra were recorded using a 400 MHz (100 MHz for 13C
NMR) or 500 MHz (125 MHz for 13C NMR) NMR spectrometer.
Abbreviations for signal coupling are as follows: s, singlet; d, doublet;
t, triplet; and m, multiplet. The chemical shifts are referenced to
entry
I2 (equiv)
time (h)
yield (%)
1
1
2
3
4
5
0.5
0.3
0.2
0.5
0.3
16
16
16
52
52
67
53
2.0
70
61
signals at H NMR: 2.5 ppm (DMSO-d6), 3.3 ppm (methanol-d4),
and 7.26 ppm (CDCl3); 13C NMR: 39.6 ppm (DMSO-d6), 47.0 ppm
(methanol-d4), and 77.0 ppm (CDCl3), respectively, and DMSO-d6,
methanol-d4, and CDCl3 were used as solvents with TMS as the
internal standard. Mass spectra were recorded on a liquid chromato-
graph−mass spectrometer and equipped with an XtimateC18
(internal diameter: 2.1 mm, length: 30 mm). The data of HRMS
were obtained on a high-resolution mass spectrometer (LC−MS-IT-
TOF). Analytical thin-layer chromatography was performed on 0.20
mm silica gel plates (GF254) using UV light as a visualizing agent.
Thin-layer chromatography was conducted using silica gel (100−200
mesh) along with the solvent as indicated. All reagents not listed in
the Supporting Information were obtained from commercial sources.
All reactions were carried out under a nitrogen atmosphere in dried
glassware. All heated reactions were performed with a Parallel Heating
Reactor (WIGGENS, WH220-R).
Interestingly, 67% of 2 was obtained when 0.5 equiv iodine was
used after 16 h. When the amount of iodine was further
lowered to 0.3 equiv, 53% of 2 was obtained. However, the
yield of 2 significantly dropped to 2% when only 0.2 equiv
iodine was used after 16 h. In the above three reactions, 1 was
not completely consumed. We extended the reaction time to
52 h to push the reaction to completion. However, extending
the reaction time did not help much to increase the yield of 2,
instead, side products started to show up. The yield of 2 was
70% for the reaction with 0.5 equiv iodine and 61% for the
reaction with 0.3 equiv iodine. These reaction results support
our proposed reaction mechanism. Interestingly, even though
theoretically only the catalytic amount of iodine is needed,
when the amount of iodine is less than 1.2 equiv, the reaction
becomes slower which leads to a longer reaction time and
appearance of side products. The reaction condition with 1.2
equiv iodine retains the optimized reaction condition and
offers the highest yields.
Synthesis of Substrates. Synthesis of Methyl-6-(cyclohexyl-
(hydroxy)methyl) Picolinate (3). To a solution of 6-bromopicoli-
naldehyde (1.00 g, 5.38 mmol) in THF (10.0 mL) at −15 °C was
dropwise added cyclohexylmagnesium chloride (5.91 mL, 5.91 mmol,
1 M in THF) under N2 protection.7 The reaction mixture was stirred
at −15 °C for 3 h under N2 protection. Then, the reaction mixture
was quenched with 1 N HCl (5 mL) and stirred for an additional 2 h
at 25 °C. After that, the pH was adjusted to 8 with 1 N NaOH. The
aqueous solution was extracted with EtOAc (15 mL × 3). The
combined organic layers were dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (pet. ether: EtOAc = 3:1) to afford
5563
https://doi.org/10.1021/acs.joc.1c00067
J. Org. Chem. 2021, 86, 5560−5567

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(6-bromopyridin-2-yl) (cyclohexyl) methanol (3a) as yellow oil (700
mg, 45.8% yield). 1H NMR (500 MHz, CDCl3): δ 7.53 (t, J = 8.0 Hz,
1H), 7.38 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 4.47 (t, J = 6.0
Hz, 1H), 3.27 (d, J = 6.5 Hz, 1H), 1.61−1.75 (m, 5H), 1.09−1.27 (m,
5H); MS (ESI) m/z: [M + H]+, 269.9; 271.9.
ether/EtOAc = 3:1) to provide 2, 2, 2-trifluoro-1-(pyridin-4-yl)
ethan-1-ol (9) (2.50 g, 76.0% yield) as yellow oil. H NMR (500
MHz, CDCl3): δ 8.57 (m, J = 6.5 Hz, 2H), 7.50 (d, J = 5.5 Hz, 2H),
5.88 (br s, 1H), 5.08 (q, J = 6.5 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 149.2, 144.4, 125.4, 122.7, 71.2 (q, J = 32.2 Hz); HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C7H7F3NO, 178.0474; found,
178.0480.
1
To a solution of 3a (700 mg, 2.59 mmol) in MeOH (10.0 mL) at
25 °C were added TEA (1.08 mL, 7.77 mmol) and Pd(dppf)Cl2 (190
mg, 0.259 mmol). Then, the reaction mixture was stirred at 80 °C for
2 h under 50 psi of CO. The reaction mixture was concentrated and
H2O (15 mL) was added. It was extracted with EtOAc (15 mL × 3).
The combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (pet. ether/EtOAc =
3:1) to afford methyl-6-(cyclohexyl(hydroxy)methyl) picolinate (3)
as yellow oil (380 mg, 55.9% yield). 1H NMR (500 MHz, DMSO-d6):
δ 8.02 (d, J = 7.5 Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0
Hz, 1H), 4.62 (t, J = 5.5 Hz, 1H), 3.99 (s, 3H), 3.82−3.83 (m, 1H),
1.65−1.76 (m, 6H), 1.40−1.51 (m, 1H), 1.15−1.25 (m, 2H), 1.01−
1.13 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.6, 162.1,
146.7, 137.2, 124.5, 123.7, 52.8, 44.9, 29.7, 26.8, 26.3, 26.0; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C14H20NO3, 250.1438; found,
250.1434.
Synthesis of Phenyl(pyrazin-2-yl) Methanol (11). To a solution of
2-iodopyrazine (1.00 g, 4.85 mmol) in THF (10.0 mL) was added
butylmagnesium chloride-lithium chloride (3.24 mL, 4.85 mmol, 1.5
M in THF) at −78 °C under N2 protection.12 Then, the reaction
mixture was stirred for 0.5 h at −78 °C. Benzaldehyde (618 mg, 5.83
mmol) was added to the reaction mixture at −78 °C under N2
protection and stirred for 2 h. The reaction mixture was quenched
with aq. NH4Cl (20 mL). Then, the mixture was extracted with
EtOAc (20 mL × 3) and dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
Prep-HPLC (TFA) to give phenyl(pyrazin-2-yl) methanol (11) as
1
yellow oil (800 mg, 84.0% yield). H NMR (CDCl3, 500 MHz): δ
8.46 (d, J = 1.0 Hz, 1H), 8.40 (t, J = 2.0 Hz, 1H), 8.36 (d, J = 2.5 Hz,
1H), 7.10−7.30 (m, 5H), 5.75 (s, 1H), 4.28 (br s, 1H); 13C{1H}
NMR (100 MHz, CDCl3): δ 156.8, 143.5, 143.4, 142.8, 141.8, 128.9,
128.3, 126.9, 74.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C11H11N2O, 187.0866; found, 187.0872.
Synthesis of (2-Fluoropyridin-3-yl)(1-((2-(trimethylsilyl)ethoxy)-
methyl)-1H-1,2,4-triazol-3-yl) (17). To a solution of 3-bromo-1H-
1,2,4-triazole (2.00 g, 13.5 mmol) and triethylamine (5.55 mL, 40.6
mmol) in DCM (5.00 mL) was added SEM-Cl (4.79 mL, 27.0 mmol)
at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The
reaction was concentrated, and the residue was purified by flash
chromatography on silica gel (pet. ether/EtOAc = 5:1) to give 3-
bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (17a)
(3.00 g, 10.2 mmol, 76.0% yield) as colorless oil. MS (ESI) m/z:
[M-Boc + 42]+, 219.9; 221.9.
Synthesis of tert-Butyl-4-(hydroxy(pyridin-4-yl)methyl)-
piperidine-1-carboxylate (5). To a solution of piperidin-4-yl-
(pyridin-4-yl) methanol were added 4-toluene sulfonate (1.00 g,
2.74 mmol) in THF (8.00 mL) and Na2CO3 (872 mg, 8.23 mmol)
and Boc2O (764 mg mL, 3.29 mmol) in water (8.00 mL) at 25 °C.9
Then, the reaction mixture was stirred at 25 °C for 16 h. The mixture
was diluted with water (10 mL) and extracted with EtOAc (20 mL ×
2). The combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash silica gel chromatography (pet. ether/EtOAc = 5:3)
to give tert-butyl-4-(hydroxy(pyridin-4-yl)methyl)piperidine-1-car-
1
boxylate (5) as colorless oil (500 mg, 62.3% yield). H NMR (500
MHz, CDCl3): δ 8.56 (d, J = 6.0 Hz, 2H), 7.23 (d, J = 6.0 Hz, 2H),
4.50−4.60 (m, 1H), 4.13−4.15 (m, 1H), 2.50−2.62 (m, 2H), 2.25−
2.30 (m, 1H), 1.73−1.74 (m, 2H), 1.43−1.63 (s, 9H), 1.25−1.35 (m,
4H); 13C{1H} NMR (100 MHz, CDCl3): δ 154.7, 151.8, 149.8,
121.6, 79.5, 43.2, 28.4, 28.3, 27.3; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C16H25N2O3, 293.1860; found, 293.1860.
To a solution of 17a (1.33 g, 4.80 mmol) in THF (10.0 mL) was
added n-butyllithium (3.20 mL, 7.99 mmol) at −78 °C under N2
protection. The reaction mixture was stirred for 0.5 h at −78 °C. 2-
Fluoronicotinaldehyde (500 mg, 4.00 mmol) was added to the
mixture and stirred at −78 °C for 2 h under N2 protection. The
reaction mixture was quenched with sat. aq. NH4Cl (10 mL) and
extracted with EtOAc (20 mL × 3). The combined organic layers
were dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel (pet. ether/EtOAc = 1:1) to give (2-fluoropyridin-3-yl)
(1-((2-(trimethylsilyl) ethoxy) methyl)-1H-1,2,4-triazol-3-yl) meth-
Synthesis of 2, 2, 2-Trifluoro-1-(pyridin-2-yl) Ethanol (7). To a
solution of picolinaldehyde (1.20 g, 11.2 mmol) and trimethyl
(trifluoromethyl) silane (1.91 g, 13.4 mmol) in THF (20.0 mL) at 0
°C was added TBAF (0.560 mL, 0.560 mmol, 1 M in THF)
dropwise.10 The reaction was stirred at 0 °C for 1 h, then allowed to
warm to 25 °C, and stirred overnight. Then, 1 N HCl (5 mL) was
added to the reaction mixture and stirred for an additional 2 h at 25
°C. After that, the pH was adjusted to 8 with 1 N NaOH. The
aqueous solution was extracted with EtOAc (15 mL × 3). The
combined organic layers were dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (pet. ether/EtOAc = 20:1) to give
2,2,2-trifluoro-1-(pyridin-2-yl) ethanol (7) as yellow oil (1.60 g, 81%
1
anol (17) as a white solid (480 mg, 34.4% yield). H NMR (500
MHz, CDCl3): δ 8.20−8.21 (m, 1H), 8.06 (t, J = 5.5 Hz, 1H), 7.82 (s,
1H), 7.26−7.28 (m, 1H), 6.28 (s, 2H), 3.51−3.60 (m, 2H), 0.83−
0.87 (m, 2H), 0.02 (s, 9H). MS (ESI) m/z: [M + H]+, 325.1.
Synthesis of Phenyl-1-(pyridin-2-yl)ethanol (19). To a solution of
phenyl-(pyridin-2-yl) methanone (1.85 g, 10.1 mmol) in THF (10
mL) was added methylmagnesium bromide (3.37 mL, 10.1 mmol, 3
M in THF) at 0 °C under N2 protection.13 The reaction mixture was
warmed to 25 °C and stirred for 16 h. The reaction was then
quenched with aq. NH4Cl (10 mL). The aqueous layer was extracted
with EtOAc (2 × 20 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography on silica
gel (pet. ether/EtOAc = 9:1) to give 1-phenyl-1-(pyridin-2-yl)
1
yield). H NMR (500 MHz, CDCl3): δ 8.46 (d, J = 5.0 Hz, 1H),
7.60−7.64 (m, 1H), 7.09−7.25 (m, 2H), 5.25−5.4 (m, 1H), 4.75−
4.80 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 151.0, 148.3,
137.2, 125.5, 124.5, 122.6, 70.86 (q, J = 31.6 Hz); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C7H7F3NO, 178.0474; found, 178.0475.
Synthesis of 2,2,2-Trifluoro-1-(pyridin-2-yl) Ethanol (9). To a
solution of isonicotinaldehyde (2.00 g, 18.7 mmol) and trimethyl
(trifluoromethyl)silane (3.19 g, 22.4 mmol) in THF (20 mL) at 25
°C was added TBAF (0.934 mL, 0.934 mmol, 1 M in THF)
dropwise.11 The reaction mixture was stirred for 1 h at 0 °C, then
allowed to warm to 25 °C, and again stirred for 16 h. Then, 1 N HCl
(5 mL) was added to the reaction mixture and stirred for an
additional 2 h at room temperature. After that, the pH was adjusted to
8 with 1 N NaOH. The aqueous solution was extracted two times
with EtOAc (30 mL × 2). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel (pet.
1
ethanol (19) as a white solid (1.20 g, 59.6% yield). H NMR (500
MHz, CDCl3): δ 8.56 (d, J = 4.5 Hz, 1H), 7.68 (dt, J = 1.5 Hz, 8.0
Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.32−7.37 (m, 3H), 7.22−7.28 (m,
2H), 5.90 (br s, 1H), 2.00 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 164.8, 147.4, 147.1, 137.0, 128.2, 126.9, 125.9, 122.1,
120.3, 75.1, 29.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C13H14NO, 200.1070; found, 200.1071.
Phenyl(quinoxalin-2-yl) Methanol (21). To a solution of quinoxa-
line-2-carbaldehyde (100 mg, 0.632 mmol) in THF (2.00 mL) at 0 °C
was added phenylmagnesium bromide (0.695 mL, 0.695 mmol, 1 M
in Et2O) under N2 protection.14 Then, the reaction mixture was
5564
https://doi.org/10.1021/acs.joc.1c00067
J. Org. Chem. 2021, 86, 5560−5567

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
stirred at 0 °C for 4 h. The reaction was quenched with 2 ml H2O and
extracted with EtOAc (5 mL × 3). The combined organic layers were
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by Prep-TLC (SiO2, pet.
ether/EtOAc = 3:1) to provide phenyl(quinoxalin-2-yl) methanol
(110 mg, 73.6% yield) as yellow oil.
Tert-Butyl-4-(pyridin-4-ylmethyl)piperidine-1-carboxylate (6).
Tert-Butyl-4-(pyridin-4-ylmethyl)piperidine-1-carboxylate (6) was
prepared according to the general method. The crude product was
purified by Prep-HPLC (Neu) to afford the title compound as yellow
oil (50.0 mg, 50.0% yield). 1H NMR (CDCl3, 500 MHz): δ 8.50 (d, J
= 4.5 Hz, 2H), 7.07 (d, J = 5.0 Hz, 2H), 3.95−4.15 (m, J = 4.0 Hz,
2H), 2.61−2.70 (m, 2H), 2.45−2.55 (m, 2H), 1.68−1.75 (m, 1H),
1.54−1.65 (m, 2H), 1.45 (s, 9H), 1.14−1.17 (m, 2H); 13C{1H} NMR
(100 MHz, CDCl3): δ 154.7,149.6, 149.1, 124.5, 79.3, 42.4, 37.3,
31.8, 28.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H25N2O2,
277.1911; found, 277.1915.
1H NMR (400 MHz, CDCl3): δ 8.74 (s, 1H), 8.09−8.17 (m, 2H),
7.75−7.83 (m, 2H), 7.36−7.46 (m, 5H), 6.03 (s, 1H), 5.14 (br s,
1H); 13C{1H} NMR (100 MHz, CDCl3): δ 155.5, 144.3, 141.9,
141.4, 140.4, 130.5, 129.9, 129.3, 128.9, 128.8, 128.5, 127.3, 74.4;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H13N2O, 237.1022;
found, 237.1021.
2-(2,2,2-Trifluoroethyl) Pyridine (8). 2-(2,2,2-trifluoroethyl) pyr-
idine (8) was prepared according to the general method. The crude
mixture was purified by Prep-TLC (SiO2, pet. ether/EtOAc = 5:1) to
Phenyl(quinolin-2-yl)methanol (23). To a solution of quinoline-2-
carbaldehyde (100 mg, 0.636 mmol) in THF (2.00 mL) at 0 °C was
added phenylmagnesium bromide (0.700 mL, 0.700 mmol, 1 M in
Et2O) under N2 protection.15 Then, the reaction mixture was stirred
at 0 °C for 4 h. The reaction was quenched with 2 mL of H2O and
extracted with EtOAc (5 mL × 3). The combined organic layers were
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by Prep-TLC (SiO2, pet.
ether/EtOAc = 3:1) to provide phenyl (quinolin-2-yl)methanol (50.0
1
afford the title compound as colorless oil (53.0 mg, 55.0% yield). H
NMR (400 MHz, methanol-d4): δ 8.93 (d, J = 6.0 Hz, 1H), 8.65−
8.72 (m, 1H), 8.11−8.32 (q, J = 10.0 Hz 2H), 4.12−4.20 (m, 2H);
13C{1H}NMR (125 MHz, CDCl3): δ 150.7, 149.8, 137.0, 126.5,
124.6, 123.1, 42.8 (q, J = 29.1); HRMS (ESI-TOF) m/z: [M + H]+
calcd for C7H7F3N, 162.0525; found, 162.0523.
4-(2,2,2-Trifluoroethyl) Pyridine (10). 4-(2,2,2-Trifluoroethyl)
pyridine (10) was prepared according to the general method. The
crude mixture was purified by Prep-TLC (SiO2, pet. ether/EtOAc =
1:1) to afford the title compound as colorless oil (68.0 mg, 74.0%
yield). 1H NMR (500 MHz, methanol-d4): δ 8.84 (d, J = 6.0 Hz, 2H),
8.00 (d, J = 6.0 Hz, 2H), 3.95 (q, J = 10.0 Hz, 2H); 13C{1H} NMR
(125 MHz, CDCl3): δ 150.1, 138.9, 126.2, 125.1, 123.9, 39.8 (q, J =
29.2 Hz); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C7H7F3N,
162.0525; found, 162.0530.
2-Benzylpyrazine (12). 2-Benzylpyrazine (12) was prepared
according to the general method. The crude product was purified
by flash chromatography on silica gel (pet. ether/EtOAc = 3:1) to
afford the title compound as yellow oil (200 mg, 46.0% yield).1H
NMR (500 MHz, CDCl3): δ 8.51 (d, J = 1.5 Hz, 1H), 8.48−8.50 (m,
1H), 8.42 (d, J = 2.0 Hz, 1H), 7.33 (t, J = 7.5 Hz, 2H), 7.25−7.29 (m,
3H), 4.18 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 156.5,
144.7, 144.0, 142.3, 138.0, 129.0, 128.7, 126.7, 41.9; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C11H11N2, 171.0917; found,
171.0922.
2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-
thiazole (14). 2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-
benzyl)thiazole (14) was prepared according to the general method.
The crude product was purified by flash chromatography on silica gel
(pet. ether/EtOAc = 3:1) to afford the title compound as yellow oil
(100 mg, 53.0% yield). 1H NMR (500 MHz, methanol-d4): δ 7.72 (t,
J = 5.0 Hz, 3H), 7.48 (d, J = 3.5 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H),
4.39 (s, 2H), 1.36 (s, 12H); 13C{1H} NMR (100 MHz, methanol-d4):
δ 170.9, 141.4, 141.0, 134.7, 127.9, 119.5, 83.6, 38.4, 23.7; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C16H21BNO2S, 302.1381; found,
302.1380.
1
1
mg, 33.4% yield) as yellow oil. H NMR (400 MHz, CDCl3) H
NMR (500 MHz, DMSO-d6): δ 8.58 (d, J = 8.0 Hz, 1H), 8.19 (d, J =
9.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.89 (t, J = 7.5 Hz, 1H), 7.79
(d, J = 8.5 Hz, 1H), 7.70 (t, J = 7.0 Hz, 1H), 7.52 (d, J = 7.5 Hz, 2H),
7.36 (t, J = 7.5 Hz, 2H), 7.25−7.26 (m, 1H), 6.04 (s, 1H); 13C{1H}
NMR (100 MHz, DMSO-d6): δ 163.7, 154.9, 146.5, 143.8, 143.1,
131.8, 131.3, 131.1, 128.9, 128.8, 128.1, 127.9, 127.7, 127.0, 119.8,
75.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H14NO,
236.1070; found, 236.1074.
General Procedure for the Synthesis of Deoxygenated α-
Heteroaryl-Substituted Methanol Derivatives. To a mixture of
α-heteroaryl-substituted methanol derivatives (1 equiv) in THF (2
mL/100 mg) were added triphenylphosphine (1.2 equiv), imidazole
(1.5 equiv), and I2 (1.2 equiv) at 25 °C under N2 protection. Then,
the reaction mixture was stirred at the reflux temperature under N2
protection for 16 h. After cooling to room temperature, the mixture
was diluted with water and extracted by EtOAc twice. The combined
organic layers were dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
chromatography, Prep-TLC, or Prep-HPLC to afford the dehydroxy
product.
Synthesis of tert-Butyl-4-(pyridin-2-ylmethyl)piperidine-1-car-
boxylate (2). To a mixture of compound 1 (100 mg, 0.342 mmol)
in THF (2 mL) were added triphenylphosphine (108 mg, 0.410
mmol), imidazole (34.9 mg, 0.513 mmol), and I2 (104 mg, 0.410
mmol) at 25 °C under N2 protection. Then, the reaction mixture was
stirred at the reflux temperature under N2 protection for 16 h. The
mixture was diluted with water (5 mL) and extracted with EtOAc (10
mL × 2). The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by Prep-TLC (SiO2, pet. ether/EtOAc = 1:1) to
give compound 2 as yellow oil (870 mg, 92.0% yield). 1H NMR (500
MHz, CDCl3): δ 8.55 (d, J = 4.0 Hz, 1H), 7.57−7.61 (m, 1H), 7.09−
7.13 (m, 2H), 4.07−4.08 (m, 2H), 2.67−2.72 (m, 4H), 1.95−1.98
(m, 1H), 1.55−1.70 (m, 2H), 1.45 (s, 9H), 1.18−1.22 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ 160.1, 154.8, 149.3, 136.1,
5-Benzyl-4-Methyl-4H-1,2,4-triazole-3-thiol (16). 5-Benzyl-4-
methyl-4H-1,2,4-triazole-3-thiol (16) was prepared according to the
general method. The crude product was purified by Prep-TLC (SiO2,
EtOAc/MeOH = 100:1) to afford the title compound as a yellow
1
solid (57.0 mg, 62.0% yield). H NMR (400 MHz, CDCl3): δ 7.31−
7.38 (m, 3H), 7.18−7.20 (m, 2H), 4.06 (s, 2H), 3.39 (s, 3H);
13C{1H} NMR (100 MHz, methanol-d4): δ 151.9, 134.2, 128.6, 128.2,
123.6, 121.1, 79.2, 45.2, 36.7, 31.9, 28.4; HRMS (ESI-TOF) m/z: [M
127.0, 31.0, 29.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C10H12N3S, 206.0746, found 206.0750. mp: 149−151 °C.
+ H]+ calcd for C16H25N2O2, 277.1911; found, 277.1915.
Methyl-6-(cyclohexylmethyl) Picolinate (4). Methyl-6-(cyclohex-
ylmethyl) picolinate (4) was prepared according to the general
method. The crude mixture was purified by Prep-TLC (SiO2, pet.
ether/EtOAc = 3:1) to afford the title compound as yellow oil (162
mg, 87.0% yield).1H NMR (500 MHz, CDCl3): δ 7.95 (d, J = 7.5 Hz,
1H), 7.72 (t, J = 7.5 Hz, 1H), 7.27−7.30 (m, 1H), 4.00 (s, 3H), 2.77
(d, J = 7.0 Hz, 2H), 1.69−1.79 (m, 1H), 1.61−1.66 (m, 5H), 1.19−
1.23 (m, 3H), 0.99−1.18 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3): δ 166.1, 161.8, 147.6, 136.6, 126.9, 122.5, 52.8, 46.0, 38.4,
32.9, 26.4, 26.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C14H20NO2, 234.1489; found, 234.1485.
2-Fluoro-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-tria-
zol-3-yl)methyl) Pyridine (18). 2-Fluoro-3-((1-((2-(trimethylsilyl)-
ethoxy)methyl)-1H-1,2,4-triazol-3-yl)methyl) pyridine (18) was
prepared according to the general method. The crude product was
purified by Prep-HPLC (TFA) to afford the title compound as a white
solid (53.0 mg, 60.0% yield). 1H NMR (500 MHz, CDCl3): δ 8.14 (d,
J = 4.5 Hz, 1H), 7.85 (s, 1H), 7.72 (t, J = 8.5 Hz, 1H), 7.17−7.19 (m,
1H), 5.51 (s, 2H), 4.24 (s, 2H), 3.53−3.57 (m, 2H), 0.82−0.86 (m,
2H), 0.02 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 164.0,
161.6, 154.6, 152.1, 148.1, 142.8, 123.2, 119.2 (d, J = 30.5 Hz), 68.7,
5565
https://doi.org/10.1021/acs.joc.1c00067
J. Org. Chem. 2021, 86, 5560−5567

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
26.5, 19.2, 0.00. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C14H22FN4OSi, 309.1541; found, 309.1546. mp: 36.8−38.2 °C.
2-(1-Phenylethyl) Pyridine (20). 2-(1-Phenylethyl) pyridine (20)
was prepared according to the general method. The crude product
was purified by Prep-HPLC (TFA) to afford the title compound as
Jianming Bao − Merck & Company, Inc., Kenilworth, New
Jersey 07033, United States
John S. Debenham − Merck & Company, Inc., Kenilworth,
New Jersey 07033, United States; orcid.org/0000-0002-
9327-2835
Robert Mazzola − Merck & Company, Inc., Kenilworth, New
Jersey 07033, United States
1
yellow oil (240 mg, 52.0% yield). H NMR (500 MHz, CDCl3): δ
8.81 (d, J = 5.0 Hz, 1H), 8.05 (t, J = 8.0 Hz, 1H), 7.50−7.53 (m, 1H),
7.44 (d, J = 8.0 Hz, 1H), 7.18−7.29 (m, 5H), 4.73 (q, J = 7.5 Hz,
1H), 1.74 (d, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
162.1, 143.7, 142.7, 140.4, 129.1, 127.8 (d, J = 60 Hz), 124.4, 123.7,
43.2, 20.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H14N,
184.1121; found, 184.1125.
Joseph L. Duffy − Merck & Company, Inc., Kenilworth, New
Jersey 07033, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00067
2-Benzylquinoxaline (22). 2-Benzylquinoxaline (22) was prepared
according to the general method. The crude mixture was purified by
Prep-TLC (SiO2, pet. ether/EtOAc = 1:1) to afford the title
Notes
1
compound as colorless oil (20.0 mg, 43.0% yield). H NMR (500
The authors declare no competing financial interest.
MHz, CDCl3): δ 8.66 (s, 1H), 8.01 (t, J = 7.5 Hz, 2H), 7.66−7.70 (m,
2H), 7.26 (d, J = 4.5 Hz, 3H), 7.19 (d, J = 6.5 Hz, 2H), 4.32 (s, 2H);
13C{1H} NMR (125 MHz, CDCl3): δ 155.8, 145.9, 142.1, 141.2,
137.9, 130.1, 129.1, 129.0, 128.8, 126.9, 43.0; HRMS (ESI-TOF) m/
z: [M + H]+ calcd for C15H14N2, 221.1073; found, 221.1076.
2-Benzylquinoxaline (24). 2-Benzylquinoxaline (24) was prepared
according to the general method. The crude mixture was purified by
Prep-TLC (SiO2, pet. ether/EtOAc = 1:1) to afford the title
REFERENCES
■
(1) Barton, D. H. R.; McCombie, S. W. A New Method for the
Deoxygenation of Secondary Alcohols. J. Chem. Soc., Perkin Trans. 1
1975, 1574−1585.
(2) Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Applications of
Ionic Hydrogenation to Organic Synthesis. Synthesis 1974, 1974,
633−651.
1
compound as colorless oil (20.0 mg, 43.0% yield). H NMR (500
MHz, CDCl3): δ 8.05 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H),
7.64−7.71 (m, 2H), 7.45 (t, J = 7.5 Hz, 1H), 7.17−7.26 (m, 6H),
4.31 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 161.2, 147.7,
139.1, 136.5, 129.4, 129.2, 128.9, 128.6, 127.5, 126.7, 126.4, 125.9,
121.5, 45.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H14N,
220.1121; found, 220.1127.
3-Neopentylpyridine. 3-Neopentylpyridine was prepared accord-
ing to the general method. However, 3-neopentylpyridine was not
isolated, and its corresponding iodide product (27a) was isolated in
78.0% yield as colorless oil. 1H NMR (500 MHz, CDCl3): δ 8.57 (d, J
= 2.0 Hz, 1H), 8.45−8.47 (m, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.21−
7.24 (m, 1H), 5.00 (s, 1H), 1.11 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3): δ 149.2, 148.7, 137.8, 122.8, 47.3, 37.0, 28.2; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C10H15IN, 276.0244; found,
276.0240.
(3) Bohlmann, F.; Staffeldt, J.; Skuballa, W. Notiz uber die
̈
Umwandlung von Allylalkoholen in Kohlenwasserstoffe. Chem. Ber.
1976, 109, 1586−1588.
(4) Furukawa, I.; Zhou, B.; Hashimoto, S. Reaction of Alcohols with
Triphenylphosphine Diiodide. Nippon Kagaku Kaishi 1984, 1984,
1208−1212.
(5) Rauter, A. P.; Fernandes, A. C.; Figueiredo, J. A. A Novel
Deoxygenation of Hydroxy Groups Activated by a Vicinal Carbonyl
Group via Reaction with Ph3P/I2/Imidazole. J. Carbohydr. Chem.
1998, 17, 1037−1045.
(6) Pichon, M. M.; Stauffert, F.; Addante-Moya, L. G.; Bodlenner,
A.; Compain, P. Metal-Free Iodine-Mediated Deoxygenation of
Alcohols in the Position α to Electron-Withdrawing Groups. Eur. J.
Org. Chem. 2018, 2018, 1538−1545.
(7) Nishigaya, Y.; Umei, K.; Watanabe, D.; Kohno, Y.; Seto, S. PBr3-
mediated unexpected reductive deoxygenation of α-aryl-pyridineme-
thanols: synthesis of arylmethylpyridines. Tetrahedron 2016, 72,
1566−1572.
(8) Gemal, A. L.; Luche, J. L. Haloketone dehalogenation by iodide
ion. Tetrahedron Lett. 1980, 21, 3195−3198.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00067.
(9) Fish, P. V.; Mark, D. A.; Fray, M. J.; Alan, S.; Florian, W.; Gavin,
A. W. 4-Piperidines and 3-pyrrolidines as dual serotonin and
noradrenaline reuptake inhibitors: Design, synthesis and structure−
activity relationships. Bioorg. Med. Chem. Lett. 2009, 19, 2829−2834.
(10) Kelly, C. B.; Michael, A. M.; Trevor, A. H.; Madison, H. F.;
Nicholas, E. L. Oxidation of α-Trifluoromethyl Alcohols Using a
Recyclable Oxoammonium Salt. J. Org. Chem. 2012, 77, 8131−8141.
(11) (a) Sun, J.; Xinhua, P.; Hao, G. Photoinduced additive-free
trifluoromethylation of aromatic aldehydes with TMSCF3. Tetrahe-
dron Lett. 2015, 56, 797−800. (b) Funabiki, K.; Ayaka, H.;
Ryunosuke, K.; Toshiyasu, I.; Yashuhiro, K. One-Pot and
Reducible-Functional-Group-Tolerant Synthesis of α-Aryl- and α-
Heteroaryl-α-Trifluoromethyl Alcohols via Tandem Trifluoroacetyla-
tion and MPV Type Reduction. Eur. J. Org. Chem. 2019, 2019, 5978−
5984.
1H NMR and 13C{1H} NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Na Meng − IDSU, WuXi AppTec Company, Ltd., Shanghai
200131, China; orcid.org/0000-0001-7674-7395;
Email: meng_na@wuxiapptec.com
Wensheng Yu − Merck & Company, Inc., Kenilworth, New
Jersey 07033, United States; orcid.org/0000-0001-5978-
9454; Email: wensheng.yu@merck.com
Authors
Takao Suzuki − IDSU, WuXi AppTec Company, Ltd.,
Shanghai 200131, China
Maofen Chen − IDSU, WuXi AppTec Company, Ltd.,
Shanghai 200131, China
Zhiqi Qi − IDSU, WuXi AppTec Company, Ltd., Shanghai
200131, China
Bin Hu − IDSU, WuXi AppTec Company, Ltd., Shanghai
200131, China
̂
(12) Lepretre, A.; Alain, T.; Nelly, P.; Guy, Q. Syntheses in the
Nitrogen π-Deficient Heterocycles Series Using a Barbier Type
Reaction Under Sonication. Diazines. Part 29. Tetrahedron 2000, 56,
3709−3715.
(13) Xun, X.; Man, Z.; Jianzhong, X.; Tao, H.; Ming, Z.; Guofeng,
L.; Liang, H. Difunctionalization of Alkenylpyridine N-Oxides by the
Tandem Addition/Boekelheide Rearrangement. Org. Lett. 2019, 21,
8266−8269.
5566
https://doi.org/10.1021/acs.joc.1c00067
J. Org. Chem. 2021, 86, 5560−5567

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(14) Higashino, T.; Masami, G.; Eisaku, H. Studies on the Reaction
of π-Deficient Heterocycles with Aromatic Aldehyde in the Presence
of Cyanide Ion. Chem. Pharm. Bull. 1976, 24, 238−252.
(15) Nakano, Y.; Michael, J. B.; Andrew, J. M.; Braddock, A. S.;
Megan, M. C.; Kyle, F. B.; Tianyu, Z.; Todd, K. H. Photoenzymatic
Hydrogenation of Heteroaromatic Olefins Using ‘Ene’-Reductases
with Photoredox Catalysts. Angew. Chem., Int. Ed. 2020, 59, 10484−
10488.
5567
https://doi.org/10.1021/acs.joc.1c00067
J. Org. Chem. 2021, 86, 5560−5567