PBr3-mediated unexpected reductive deoxygenation of α-aryl-pyridinemethanols: Synthesis of arylmethylpyridines

Article abstract of DOI:10.1016/j.tet.2016.02.005

PBr₃-mediated reductive deoxygenation of α-aryl-pyridinemethanols to provide arylmethylpyridines is described, the alcohol substrate scope is explored, free radical trap TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) is introduced, and the hydrogen source of the methylene product is defined. The unexpected reaction enabled us to prepare previously inaccessible, novel EP₁ antagonists.

Full text of DOI:10.1016/j.tet.2016.02.005

Tetrahedron 72 (2016) 1566e1572
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
PBr3-mediated unexpected reductive deoxygenation of
pyridinemethanols: synthesis of arylmethylpyridines
a-aryl-
*
Yosuke Nishigaya, Kentaro Umei, Daisuke Watanabe, Yasushi Kohno, Shigeki Seto
Watarase Research Center, Discovery Research Headquarters, Kyorin Pharmaceutical Co., Ltd., 1848, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi
329-0114, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
PBr3-mediated reductive deoxygenation of a-aryl-pyridinemethanols to provide arylmethylpyridines is
Received 19 December 2015
Received in revised form 30 January 2016
Accepted 2 February 2016
Available online 4 February 2016
described, the alcohol substrate scope is explored, free radical trap TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy) is introduced, and the hydrogen source of the methylene product is defined. The un-
expected reaction enabled us to prepare previously inaccessible, novel EP1 antagonists.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
PBr3
Reductive deoxygenation
Arylmethylpyridine
Free radical
a
-Aryl-pyridinemethanol
1. Introduction
product 1a or 2. Next, we examined the reductive deoxygenation of
the
a-aryl-pyridinemethanol 8a, which was prepared from the
The arylmethylpyridine skeleton exhibits pharmaceutically
important biological activity and has been shown to act as a PDE4
inhibitor,1 a p38 kinase inhibitor,2 a SGLT2 inhibitor,3 a thyroid
coupling reaction of the Grignard adduct of 5 with formylpyridine 7
followed by the removal of Boc protection of the amino group by
treatment with trifluoroacetic acid (see Supplementary data for the
hormone
b
receptor agonist,4 and an EP1 antagonist.5
For the synthesis of arylmethylpyridines, it is crucial to con-
struct a methylene linkage. Recent developments in approaches to
coupling aryl halide or aryl metal complex with pyridylmethyl
derivative using a transition metal catalyst, such as Pd,6e9 Co,10 or
Ni,11,12 enable the direct construction of methylene linkages. A
stepwise approach is also common; for example, building up a-
aryl-pyridinemethanols by a coupling reaction of Grignard reagent
with formylpyridine and subsequent reductive deoxygenation re-
action to provide the desired arylmethylpyridines.13e21
In the course of our drug research program, we needed to syn-
thesize arylmethylpyridine 1a as a key intermediate of EP1 antago-
nist.5 Our initial attempts for the synthesis of 1a are summarized in
Scheme 1. First, we examined the construction of the methylene
linkage of 1a using a coupling reaction, for example, the Suzuki
coupling reaction6 of boronic acid 3 with
a-bromomethylpyridine 4
in the presence of PdCl2(PPh3)2 and K3PO4 in DMF at room tem-
perature; and the Negishi coupling reaction7 of bromide 5 with zinc
reagent 6 using Pd(OAc)2 and S-Phos in THF at rt. Unfortunately,
however, these reactions failed to provide the desired methylene
* Corresponding author. Tel.: þ81 280 57 1551; fax: þ81 280 57 2336; e-mail
Scheme 1. Initial attempts to synthesize 1 and 2.
address: shigeki.seto@mb.kyorin-pharm.co.jp (S. Seto).
http://dx.doi.org/10.1016/j.tet.2016.02.005
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

Y. Nishigaya et al. / Tetrahedron 72 (2016) 1566e1572
1567
synthesis of 8a). However, treatment of alcohol 8a with trime-
thylsilyl iodide13 or triethylsilane-trifluoroacetic acid14,15b did not
provide the desired product 1a, presumably due to the low reactivity
of the oxygen atom, which can be caused by an electron-
withdrawing effect of the picolyl group.13a Interestingly, a palla-
dium-catalyzed hydrogenation reaction15 of 8a afforded the de-
sired product 1a, but the reaction was very slow and the starting
material 8a remained in 70% yield after 6 h reaction.
Table 1
Reductive deoxygenation of
a
-aryl-pyridinemethanols
Entry Alcohol (8aen)
Methylene (1aen)
Yield (%) of 1aen
On the basis of the results of the palladium-catalyzed hydro-
genolysis of 8a in the presence of zinc bromide (Scheme 1, entry 3),
we envisioned that the replacement of the OH group to a better
leaving group, such as bromide atom, could promote the hydro-
genolysis reaction to provide 1a. Thus, we tried to convert hy-
droxide 8a to bromide 9 by treatment with PBr3 in chloroform at
80 ꢀC for 2 h. To our surprise, methylene 1a was directly afforded in
74% yield without producing bromide 9 (Scheme 2). Changing the
solvent to THF also provided 1a in 78% yield, but the reaction did
not proceed when toluene was used as a solvent, probably because
of the low solubility of 8a in toluene. Although there have been two
reports on PBr3-induced deoxygenation reactions of allylic alco-
hols,22,23 this reaction proceeds with a completely different re-
action mechanism, as we discuss later in this paper.
1
74(CHCl3)
78(THF)
0(toluene)
2
44
3
4
59
52
5
6
7
73þ26(10)
0
Scheme 2. Unexpected reductive deoxygenation.
2. Results and discussion
The unexpected and successful one-step formation of methy-
lene 1a from alcohol 8a inspired us to further apply the PBr3-me-
diated dehydrogenation reaction to the synthesis of 1bed, the key
intermediates of EP1 antagonists (see Supplementary data for the
synthesis of 8bed). The electron-donating group (OMe) at the C6
position of the 2-aminobenzothiazolyl group afforded the desired
methylene product 1b in a less satisfactory yield (44%). The de-
hydrogenation reaction of the electron-withdrawing groups (F, Br)
and subsequent removal of the Boc group with trifluoroacetic acid
afforded the desired products 1c and 1d in 59% and 52% yields,
respectively (entries 3 and 4).
0þ95(11)
8
9
88
90
To explore the scope of this transformation, we investigated the
effect of the 2-aminobenzothiazole group and picolyl ester group
attached to the left and right parts, respectively (Table 1, entries
5e14). First, we focused on replacing the 2-aminobenzothiazole
group on the left-side part (entries 5 and 6). Practically speaking,
the 2-aminobenzothiazole group can be successfully replaced with
10
81
11
12
13
55
the phenyl group (entry 5). The deoxygenation reaction of a-phe-
nylpyridinemethanol 8e afforded the desired methylene product 1e
in 73% yield as well as the THF ring-opening adduct24 10 in 26%
yield (entry 5). However, when the substrate with the cyclohexyl
group was used, no desired methylene product 1f was observed,
implying that the aromatic ring appeared to be necessary for the
reaction (entries 5 vs 6).
Next, we investigated the effects of the ester group and nitrogen
atom on the right-side picolyl ester part (entries 7e9). Replacing
the pyridyl with the phenyl ring did not provide the desired
methylene product 1g; instead, the major product was the dimeric
ether 11 in 95% yield (entry 7). To determine the effect of an external
complex
51
(continued on next page)

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Y. Nishigaya et al. / Tetrahedron 72 (2016) 1566e1572
Table 1 (continued )
condition.). Interestingly, no sign of methylene 1i, 1e, or 1g was
detected in any of the three cases. Furthermore, the reaction of 8i
afforded TEMPO adduct 12 in 37% yield with the recovery of the
starting material 8i in 33% yield. These results support that our
present reductive deoxygenation reaction involves biarylmethyl
radical intermediate. Meanwhile, the reaction of 8e with TEMPO
provided bromide 13 in 57% yield as the main product. In addition,
the reactions of 8e and 8g provided the same byproducts at the
reaction without TEMPO as shown in Table 1, THF adduct 10, and
dimeric ether 11, respectively, which could form through the car-
bocation intermediate.
Entry Alcohol (8aen)
Methylene (1aen)
Yield (%) of 1aen
14
45
To investigate the hydrogen source of the methylene moiety, we
tried to incorporate deuterium through three approaches (Scheme
4. See the Supplementary data for condition.). We first treated 8i
with PBr3 in deuterated tetrahydrofuran (THF-d8), but we did not
obtain any deuterated product, as determined by 1H NMR and MS
(path A, Scheme 4). Next, quenching the reaction by D2O after
treatment of 8i with PBr3 in THF afforded the same result, which
means the methylene proton does not come from the aqueous
workup process (path B, Scheme 4). Finally, all that is left is 8i as
a plausible hydrogen source of this transformation (path C, Scheme
4). Interestingly, the reaction of deuterium-labeled 8ieD, which
was prepared by the treatment of 8i with CD3OD and subsequent
pyridine, we examined the reaction of 8g with PBr3 in THF in the
presence of one equivalent of pyridine. However, the methylene 1g
was not detected, only 11 was obtained in 94% yield. These results
suggested that the internal pyridine moiety of the substrate is key
to the reductive deoxygenation reaction. In contrast, the removal of
the ester moiety did not affect the reaction yield and provided the
desired methylene products in 88% and 90% yields, respectively
(entries 8 and 9). Next, the effects of the position of the nitrogen
atom in the right-side pyridine nucleus were investigated (entries
8e13). The moving position of the nitrogen atom to position 4 in the
ring (4-pyridyl) maintained the reaction yield (81% and 55%, entries
10 and 11, respectively). However, the reaction did not proceed
when 3-pyridyl isomer 8l was used (entry 12). Interestingly, pyr-
idazinyl derivative 8m, which has two nitrogen atoms in the ring,
was a suitable substrate for the reaction, and led to the corre-
sponding methylene product 1m in 51% yield (entry 13). These
results suggest that the 2- or 4-position of the nitrogen atom in the
ring is crucial for this transformation, and they express a contrary
view to the results of carbocation-mediated TMSI-induced de-
hydrogenation reaction.13a Meanwhile, the reaction can be applied
to not only secondary but also tertiary alcohols, such as 8n, which
provided the desired methane product 1n in 45% yield (entry 14).
To determine whether the reaction proceeds via a radical
pathway, we treated the alcohols 8i, 8e, and 8g with PBr3 in the
presence of a radical inhibitor, TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy) (Scheme 3. See the Supplementary data for
removal of the solvent, provided
D
-incorporated product at
a posi-
tion 1ieD (80%, 1:1 mixture of -D and
a
a-H). This indicated that the
hydrogen originates from an in situ hydrogen source, such as al-
cohol 8i, trace water content in the reaction system.
Scheme 4. Deuterium incorporation study.
To explore PBr3 alternatives for the reductive deoxygenation
reaction, we performed two sets of experiments as shown in
Scheme 5. Neither of them provided the methylene 1e. The reaction
of 8e with bromine afforded the bromide 13 and the ketone 14 in
Scheme 3. TEMPO experiment.
Scheme 5. Studies of PBr3 alternatives.

Y. Nishigaya et al. / Tetrahedron 72 (2016) 1566e1572
1569
38% and 31% yields, respectively, and did not afford 1e at all. In-
3. Conclusions
In conclusion, we developed a new approach to synthesizing
terestingly, treatment of 13 with PBr3 in an open-air atmosphere
afforded the methylene 1e in 90% yield. The hydrogen source of this
reaction was probably a small amount of water contained in the
open air. Meanwhile, the reaction of 8e with PCl3 gave the chloride
15 in 98% yield. To determine the possibility that PCl3 induced
a radical reaction in the presence of oxygen,25 the reaction was also
performed in an open-air atmosphere. However, the reductive
deoxygenation reaction did not occur, and 15 was obtained in only
a 95% yield. Although it is difficult at this stage to specify the radical
initiators involved in this reductive deoxygenation reaction, PBr3 is
crucial for this transformation.
On the basis of these findings, a plausible mechanism is pro-
posed in Scheme 6. The biarylmethyl radical D initiated from C or
G by thermal conditions could abstract a hydrogen from internal
ROH, such as the starting substrate A, H2O, to form the desired
methylene product B. Both byproducts, J and L, could be pro-
duced through the carbocation intermediate F, via THF in-
termediate adduct K and the additional alcohol A adduct I,
respectively.
arylmethylpyridines
by
an
unexpected
PBr3-mediated
reductive deoxygenation reaction of
a
-aryl-pyridinemethanols.
This free-radical reaction led to successful results in the re-
ductive deoxygenation of electron-deficient pyridinemethanols,
and in the preparation of previously inaccessible, novel EP1
antagonists.
4. Experimental section
4.1. General
Melting points were determined with an OptiMelt and are un-
corrected. 1H NMR and 13C NMR spectra were measured in CDCl3 or
DMSO-d6 with TMS and the solvent peak as internal standards, on
a JEOL ECA-400 (400 MHz) spectrometer. Mass spectra (MS) were
obtained on a Hitachi M-2000 mass spectrometer. Column chro-
matography was carried out on Merck silica gel 60. Analytical thin-
layer chromatography (TLC) was performed on Merck precoated
silica gel 60F254 plates, and the compounds were visualized by UV
illumination (254 nm) or by heating after spraying with phospho-
molybdic acid in ethanol. See the Supplementary data for the
synthesis of 8aen.
4.2. Methyl 6-((2-amino-6-chlorobenzo[d]thiazol-4-yl)
methyl)pyridine-2-carboxylate (1a); typical procedure
To a mixture of methyl 6-((2-amino-6-chlorobenzo[d]thiazol-
4-yl) (hydroxy)methyl)pyridine-2-carboxylate (8a, 50.0 mg,
0.143 mmol) in THF (1.4 mL) was added PBr3 (40 mL, 0.424 mmol).
The mixture was stirred at room temperature for 0.5 h, and then
heated at 80 ꢀC for 2 h. After cooling in an icewater bath, the
reaction was quenched by adding water. The pH of the mixture
was adjusted to 11 by the addition of sodium carbonate, and the
mixture was then extracted with ethyl acetate. The organic layer
was dried over anhydrous Na2SO4, and evaporated in vacuo. The
residue was collected by filtration and washed with hexane/ethyl
acetate (1:1) to give 1a (37.2 mg, 78%) as a colorless solid. Mp
230e233 ꢀC. 1H NMR (400 MHz, DMSO-d6)
s), 7.03 (1H, d, J¼1.8 Hz), 7.35 (1H, dd, J¼6.7, 1.8 Hz), 7.65e7.72
(3H, m), 7.83e7.90 (2H, m). 13C NMR (100 MHz, DMSO-d6)
52.3,
d 3.87 (3H, s), 4.37 (2H,
d
Scheme 6. Plausible mechanism.
54.9, 119.0, 122.6, 124.4, 126.1, 126.4, 129.2, 132.2, 138.0, 147.0,
150.4, 160.4, 165.3, 166.9. IR (ATR) nmax 3122, 1728, 1639, 1587,
1531, 1438, 1404, 1287, 1227, 1144, 993 cmꢁ1. MS (EI) 333 (Mþ).
HRMS (EI) calcd for
333.0323.
Finally, we completed the synthesis of EP1 antagonist 18
(Scheme 7). A Sandmeier reaction of amine 1a afforded iodide 16 in
71% yield. Coupling the reaction of 16 with morpholine, along with
subsequent hydrolysis, provided the corresponding carboxylic acid
18, an EP1 antagonist, in 93% yield.
C
15H12ClN3O2S (Mþ) 333.0339, found
4.3. Methyl 6-((2-amino-6-methoxybenzo[d]thiazol-4-yl)
methyl)pyridine-2-carboxylate (1b)
Following the typical procedure for 1a using methyl 6-((2-
amino-6-methoxybenzo[d]thiazol-4-yl)
dine-2-carboxylate (8b, 100 mg, 0.290 mmol) and PBr3 (27
0.29 mmol) gave 1b (41.9 mg, 44%) as a pale yellow solid. Mp
185e186 ꢀC. 1H NMR (400 MHz, DMSO-d6)
3.72 (3H, s), 3.86 (3H,
(hydroxyl)methyl)pyri-
mL,
d
s), 4.11 (2H, s), 7.09 (1H, s), 7.19 (2H, s), 7.30 (1H, dd, J¼6.7, 2.4 Hz),
7.34 (1H, s), 7.80e7.90 (2H, m). 13C NMR (100 MHz, DMSO-d6)
d
38.2, 52.3, 56.0, 103.8, 119.5, 122.4, 125.0, 126.2, 129.9, 137.7, 146.5,
146.9, 152.2, 161.1, 165.0, 165.3. IR (ATR) nmax 1725, 1633, 1590, 1540,
1458, 1427, 1298, 1250, 1228, 1133, 1044, 993 cmꢁ1. MS (EI) 329 (M
þ). HRMS (EI) calcd for C16H15N3O3S (M þ) 329.0834, found
329.0847.
Scheme 7. Synthesis of EP1 antagonist 18.

1570
Y. Nishigaya et al. / Tetrahedron 72 (2016) 1566e1572
4.4. Methyl 6-((2-amino-6-fluorobenzo[d]thiazol-4-yl)
methyl)pyridine-2-carboxylate (1c); typical procedure
147.4, 161.7, 165.9. IR (ATR) nmax 3028, 2951, 1741, 1721, 1587, 1495,
1453, 1435, 1317, 1287, 1225, 1132, 1085 cmꢁ1. MS (ESI) 228 (MþH)þ
HRMS (ESI) calcd for C14H14NO2 (MþH)þ 228.10245, found
228.10320
To a mixture of methyl 6-((2-(tert-butoxycarbonylamino)-6-
fluorobenzo[d]thiazol-4-yl)
(hydroxyl)methyl)pyridine-2-
carboxylate (8c, 4.45 g, 10.3 mmol) in THF (100 mL) was added
PBr3 (3.00 mL, 31.8 mmol). The mixture was stirred at room tem-
perature for 0.5 h and then heated at 80 ꢀC for 2 h. After cooling in
an ice-water bath, the reaction was quenched by adding water. The
pH of the mixture was adjusted to 11 by the addition of sodium
carbonate, and the mixture was then extracted with ethyl acetate.
The organic layer was dried over anhydrous Na2SO4, and evapo-
rated in vacuo. The residue was dissolved in methylene chloride
(50 mL) and added trifluoroacetic acid (7.70 mL, 0.104 mol). After
stirring at room temperature for 24 h, the mixture was poured into
1 M aqueous solution of potassium carbonate (150 mL). The mix-
ture was extracted with ethyl acetate. The organic layer was dried
over anhydrous Na2SO4, and evaporated in vacuo. The residue was
purified by NH silica gel column chromatography (hexane/ethyl
acetate, 3:1) to give 1c (1.94 g, 59%) as a yellow solid. Mp
4.6.2. Methyl
6-((4-bromobutoxy)
(phenyl)methyl)picolinate
(10). 1H NMR (400 MHz, CDCl3)
d
1.76e1.85 (2H, m), 1.97e2.06 (2H,
m), 3.44 (2H, t, J¼6.7 Hz), 3.48e3.55 (1H, m), 3.57e3.64 (1H, m),
3.99 (3H, s), 5.65 (1H, s), 7.24 (1H, t, J¼7.3 Hz), 7.31 (2H, t, J¼7.3 Hz),
7.44 (2H, d, J¼7.3 Hz), 7.68 (1H, d, J¼7.9 Hz), 7.82 (1H, t, J¼7.9 Hz),
8.00 (1H, d, J¼7.9 Hz). 13C NMR (100 MHz, CDCl3)
d 28.5, 29.7, 33.6,
52.9, 68.4, 84.4, 124.0, 124.0, 126.5, 127.7, 128.4, 137.8, 140.8, 147.1,
162.7, 165.7. IR (ATR) nmax 2950, 2869, 1742, 1722, 1587, 1494, 1454,
1436, 1320, 1275, 1193, 1135, 1082 cmꢁ1. MS (ESI) 378 (MþH)þ.
HRMS (ESI) calcd for C18H20BrNO3 (MþH)þ 378.07048, found
378.07137.
4.7. 2-Benzylpyridine (1h)
Following the typical procedure for 1e using phenyl(pyridin-2-
212e215 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d
3.87 (3H, s), 4.38 (2H,
yl)methanol (8h, 50.0 mg, 0.270 mmol) and PBr3 (77 mL,
s), 6.85 (1H, dd, J¼10.3, 2.4 Hz), 7.35 (1H, dd, J¼7.3, 2.4 Hz), 7.48 (1H,
0.811 mmol) gave 1h (40.3 mg, 88%) as a colorless oil. 1H NMR
dd, J¼8.5, 2.4 Hz), 7.54 (2H, br s), 7.83e7.90 (2H, m). 13C NMR
spectroscopic data are identical to those reported in the litera-
(100 MHz, DMSO-d6)
d
52.3, 59.7, 106.2 (d, J¼27.7 Hz), 113.4 (d,
ture.26 1H NMR (400 MHz, CDCl3)
d 4.16 (2H, s), 7.08e7.13 (2H, m),
J¼23.8 Hz), 122.6, 126.4, 128.9 (d, J¼8.6 Hz), 131.6 (d, J¼11.4 Hz),
137.9, 147.0, 148.2, 156.9 (d, J¼236.5 Hz), 160.4, 165.3, 166.0 (d,
J¼1.9 Hz). IR (ATR) nmax 3147, 1728, 1635, 1539, 1451, 1287, 1228,
1140, 1084, 995 cmꢁ1. MS (EI) 317 (Mþ). HRMS (EI) calcd for
7.19e7.33 (5H, m), 7.56 (1H, ddd, J¼7.3, 7.3, 1.8 Hz), 8.55 (1H, dd,
J¼5.5, 1.8 Hz). 13C NMR (100 MHz, CDCl3)
d 44.7, 121.2, 123.1, 126.3,
128.6, 129.1, 136.5, 139.5, 149.3, 161.0. IR (ATR) nmax 3027, 2923,
1588, 1569, 1473, 1433, 1147, 1092, 1049 cmꢁ1. MS (ESI) 170 (MþH)þ.
HRMS (ESI) calcd for C12H12N (MþH)þ 170.09697, found 170.09744.
C
15H15FN3O3S (Mþ) 317.0634, found 317.0666.
4.5. Methyl 6-((2-amino-6-bromobenzo[d]thiazol-4-yl)
4.8. 2-(4-Methoxybenzyl)pyridine (1i)
methyl)pyridine-2-carboxylate (1d)
Following the typical procedure for 1e using (4-methoxyphenyl)
Following the typical procedure for 1c using methyl 6-((6-
(pyridin-2-yl)methanol (8i, 50.0 mg, 0.232 mmol) and PBr3 (67 mL,
bromo-2-(tert-butoxycarbonylamino)benzo[d]thiazol-4-yl)
(hy-
0.705 mmol) gave 1i (41.5 mg, 90%) as a colorless oil. 1H NMR
droxyl)methyl)pyridine-2-carboxylate (8d, 3.80 g, 7.70 mmol) and
PBr3 (2.20 mL, 23.3 mmol) gave 1d (1.52 g, 52%) as a yellow solid.
spectroscopic data are identical to those reported in the litera-
ture.27 1H NMR (400 MHz, CDCl3)
d 3.78 (3H, s), 4.10 (2H, s), 6.84
Mp 225e228 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d
3.87 (3H, s), 4.37
(2H, d, J¼8.5 Hz), 7.07e7.12 (2H, m), 7.18 (2H, d, J¼8.5 Hz), 7.56 (1H,
(2H, s), 7.15 (1H, d, J¼1.8 Hz), 7.35 (1H, dd, J¼6.7, 2.4 Hz), 7.69 (2H, br
ddd, J¼7.3, 7.3, 1.8 Hz), 8.54 (1H, d, J¼4.3 Hz). 13C NMR (100 MHz,
s), 7.79 (1H, d, J¼1.8 Hz), 7.82e7.90 (2H, m). 13C NMR (100 MHz,
CDCl3)
d 43.8, 55.2, 114.0, 121.1, 122.9, 130.0, 131.6, 136.5, 149.3,
DMSO-d6)
d
52.3, 59.7, 112.0, 121.7, 122.6, 126.4, 128.7, 129.7, 132.8,
158.4, 161.4. IR (ATR) nmax 3005, 2932, 2835, 1610, 1587, 1568, 1509,
138.0, 147.0, 150.9, 160.4, 165.3, 166.9. IR (ATR) nmax 3385, 3336,
3135, 1728, 1636, 1528, 1436, 1398, 1286, 1228, 1142, 1096 cmꢁ1. MS
(ESI) 377 (MþH)þ. HRMS (ESI) calcd for C15H13BrN3O2S (MþH)þ
377.99118, found 377.99206.
1471, 1434, 1300, 1233, 1176, 1107, 1033 cmꢁ1. MS (ESI) 200 (MþH)þ.
HRMS (ESI) calcd for
200.10797.
C
13H14NO (MþH)þ 200.10754, found
4.9. 4-Benzylpyridine (1j)
Following the typical procedure for 1e using phenyl(pyridin-4-
4.6. Methyl 6-benzylpicolinate (1e) and Methyl 6-((4-
bromobutoxy) (phenyl)methyl)picolinate (10) typical
procedure
yl)methanol (8j, 50.0 mg, 0.270 mmol) and PBr3 (77
mL,
0.811 mmol) gave 1j (37.0 mg, 81%) as a slightly yellow oil. 1H NMR
To a mixture of methyl 6-(hydroxy(phenyl)methyl)picolinate
spectroscopic data are identical to those reported in the litera-
(8e, 30.0 mg, 0.123 mmol) in THF (1.2 mL) was added PBr3 (36
mL,
ture.28 1H NMR (400 MHz, CDCl3)
d 3.97 (2H, s), 7.10 (2H, d,
0.379 mmol). The mixture was stirred at room temperature for
0.5 h, and then heated at 80 ꢀC for 2 h. After cooling in an icewater
bath, the reaction was quenched by adding water. The pH of the
mixture was adjusted to 11 by the addition of sodium carbonate,
and the mixture was then extracted with ethyl acetate. The organic
layer was dried over anhydrous Na2SO4, and evaporated in vacuo.
The crude material was purified by flash column chromatography
on silica gel (Hexane:AcOEt¼3:1) to give 1e (20.5 mg, 73%) as
a colorless oil and 10 (12.3 mg, 26%) as a colorless oil.
J¼5.5 Hz), 7.17 (2H, d, J¼7.3 Hz), 7.24 (1H, t, J¼7.3 Hz), 7.29e7.35
(2H, m), 8.49 (2H, d, J¼5.5 Hz). 13C NMR (100 MHz, CDCl3)
d 41.2,
124.1, 126.6, 128.7, 129.0, 138.8, 149.8, 150.0. IR (ATR) nmax 3065,
3027, 2918, 1596, 1559, 1494, 1414, 1219, 1070 cmꢁ1. MS (ESI) 170
(MþH)þ. HRMS (ESI) calcd for C12H12N (MþH)þ 170.09697, found
170.09641.
4.10. Ethyl 4-benzylpicolinate (1k)
Following the typical procedure for 1e using ethyl 4-(hydrox-
y(phenyl)methyl)picolinate (8k, 30.0 mg, 0.117 mmol) and PBr3
4.6.1. Methyl 6-benzylpicolinate (1e). 1H NMR (400 MHz, CDCl3)
d
4.01 (3H, s), 4.30 (2H, s), 7.21 (1H, d, J¼7.3 Hz), 7.23e7.35 (5H, m),
(36
NMR (400 MHz, CDCl3)
q, J¼7.3 Hz), 7.17 (2H, d, J¼7.3 Hz), 7.22e7.36 (4H, m), 7.99 (1H, s),
m
L, 0.379 mmol) gave 1k (15.6 mg, 55%) as a colorless oil. 1H
7.70 (1H, t, J¼7.3 Hz), 7.97 (1H, d, J¼7.3 Hz). 13C NMR (100 MHz,
d
1.43 (3H, t, J¼7.3 Hz), 4.04 (2H, s), 4.46 (2H,
CDCl3)
d 44.6, 52.9, 122.9, 126.5, 126.6, 128.7, 129.3, 137.3, 138.8,

Y. Nishigaya et al. / Tetrahedron 72 (2016) 1566e1572
1571
8.63 (1H, d, J¼4.9 Hz). 13C NMR (100 MHz, CDCl3)
d
14.3, 41.2, 61.9,
1716, 1580, 1435, 1323, 1267, 1196, 1134, 1080, 978 cmꢁ1. MS (EI) 444
(Mþ). HRMS (EI) calcd for C15H10ClIN2O2S (Mþ) 444.9196, found
444.9162.
125.6, 126.9, 127.2, 128.8, 129.0, 138.3, 148.4, 149.9, 151.4, 165.4. IR
(ATR) nmax 2981, 1737, 1713, 1595, 1559, 1495, 1421, 1366, 1294, 1193,
1120,1095,1021 cmꢁ1. EIMS (ESI) 242 (MþH)þ. HRMS (ESI) calcd for
C
15H16NO2 (MþH)þ 242.11810, found 242.11797.
4.15. Methyl 6-((6-chloro-2-morpholinobenzo[d]thiazol-4-yl)
methyl)picolinate (17)
4.11. 2-Benzylpyrazine (1m)
To a solution of methyl 6-((6-chloro-2-iodobenzo[d]thiazol-4-
yl)methyl)picolinate (16, 51.0 mg, 0.114 mmol) in THF (1.0 mL)
was added morpholine (0.1 mL), and the mixture was heated at
140 ꢀC, for 15 min using microwave oven. After cooling to rt, the
mixture was evaporated in vacuo. The residue was triturated with
diisopropyl ether, and the precipitate was corrected by filtration to
provide 17 (21.5 mg, 46%) as a colorless solid. Mp 126e128 ꢀC. 1H
Following the typical procedure for 1e using phenyl(pyrazin-2-
yl)methanol (8m, 30.0 mg, 0.161 mmol) and PBr3 (46
mL,
0.484 mmol) gave 1m (14.0 mg, 51%) as a slightly yellow oil. 1H
NMR spectroscopic data are identical to those reported in the lit-
erature.29 1H NMR (400 MHz, CDCl3)
d
4.18 (2H, s), 7.21e7.36 (5H,
m), 8.41 (1H, d, J¼2.4 Hz), 8.47 (1H, d, J¼1.2 Hz), 8.51 (1H, dd, J¼2.4,
1.2 Hz). 13C NMR (100 MHz, CDCl3)
42.0, 126.8, 128.8, 129.0, 138.1,
d
NMR (400 MHz, CDCl3)
d
3.59 (4H, t, J¼4.8 Hz), 3.82 (4H, t,
142.4, 144.1, 144.8, 156.5. IR (ATR) nmax 3029, 2924, 1603, 1576, 1526,
1495, 1473, 1453, 1401, 1310, 1231, 1126, 1056, 1017 cmꢁ1. MS (ESI)
171 (MþH)þ. HRMS (ESI) calcd for C11H11N2 (MþH)þ 171.09222,
found 171.09196.
J¼4.8 Hz), 4.02 (3H, s), 4.59 (2H, s), 7.16 (1H, d, J¼2.4 Hz), 7.31 (1H, d,
J¼7.9 Hz), 7.48 (1H, d, J¼2.4 Hz), 7.67 (1H, t, J¼7.9 Hz), 7.97 (1H, d,
J¼7.9 Hz). 13C NMR (100 MHz, CDCl3)
d 40.6, 48.5, 52.9, 66.2, 119.0,
122.9, 126.8, 127.2, 127.8, 130.9, 131.8, 137.3, 147.3, 150.1, 161.1, 166.0,
168.2. IR (ATR) nmax 1713, 1583, 1537, 1436, 1397, 1299, 1229, 1113,
1032 cmꢁ1
.
MS (ESI) 404 (MþH)þ. HRMS (ESI) calcd for
4.12. 2-(1-Phenylethyl)pyridine (1n)
C
19H19ClN3O3S (MþH)þ 404.08356, found 404.08355.
Following the typical procedure for 1e using 1-phenyl-1-(pyr-
idin-2-yl)ethanol (8n, 50.0 mg, 0.251 mmol) and PBr3 (72
mL,
4.16. 6-((6-Chloro-2-morpholinobenzo[d]thiazol-4-yl)
methyl)picolinic acid (18)
0.758 mmol) gave 1n (20.6 mg, 45%) as a colorless oil. 1H NMR
spectroscopic data are identical to those reported in the litera-
ture.30 1H NMR (400 MHz, CDCl3)
d
1.70 (3H, d, J¼7.3 Hz), 4.29 (1H,
To an ice cold solution of methyl 6-((6-chloro-2-
morpholinobenzo[d]thiazol-4-yl)methyl)picolinate (17, 13.3 mg,
32.9 mM) in THF-MeOH (1.5 mL, 2:1 v/v) was added 1 M aqueous
q, J¼7.3 Hz), 7.05e7.13 (2H, m), 7.17e7.23 (1H, m), 7.27e7.38 (4H,
m), 7.55 (1H, ddd, J¼7.3, 7.3, 1.8 Hz), 8.56 (1H, d, J¼4.9 Hz). 13C NMR
(100 MHz, CDCl3)
d 20.7, 47.4, 121.2, 122.1, 126.3, 127.7, 128.4, 136.4,
solution of NaOH (0.5 mL), and the solution was heated at 100 ꢀC for
5 min using microwave oven. The pH of the mixture was adjusted to
three by the addition of citric acid and evaporated in vacuo. The
precipitate was corrected by filtration to give 18 (12.0 mg, 93%) as
a colorless solid. Mp 118e121 ꢀC. 1H NMR (400 MHz, DMSO-d6)
145.1, 149.1, 165.0. IR (ATR) nmax 2968, 2930, 1589, 1568, 1493, 1472,
1431, 1370, 1149, 1045, 1028 cmꢁ1. MS (ESI) 184 (MþH)þ. HRMS
(ESI) calcd for C13H14N (MþH)þ 184.11262, found 184.11357.
4.13. Dimethyl 3,30-(oxybis(phenylmethylene))dibenzoate (11)
d
3.54 (4H, t, J¼4.8 Hz), 3.71 (4H, t, J¼4.8 Hz), 4.40 (2H, s), 7.17 (1H,
d, J¼2.4 Hz), 7.47e7.51 (1H, m), 7.81 (1H, d, J¼2.4 Hz), 7.84e7.87
(2H, m), 13.07 (1H, s). 13C NMR (100 MHz, DMSO-d6)
40.0, 48.0,
Following the typical procedure for 1e using methyl 3-
(hydroxy(phenyl)methyl)benzoate (8g, 50.0 mg, 0.206 mmol) and
d
65.4, 119.3, 122.4, 124.9, 126.5, 130.7, 131.6, 137.8, 148.2, 148.2, 149.9,
159.8, 166.2, 168.4. IR (ATR) nmax 1713, 1585, 1536, 1437, 1341, 1289,
1230, 1111, 1031 cmꢁ1. MS (ESI) 390 (MþH)þ. HRMS (ESI) calcd for
PBr3 (59
oil. 1H NMR (400 MHz, CDCl3)
(12H, m), 7.66 (2H, d, J¼7.3 Hz), 7.96 (2H, d, J¼7.3 Hz), 8.14 (2H, s).
13C NMR (100 MHz, CDCl3)
52.2, 54.3, 128.3, 128.3, 128.7, 128.7,
mL, 0.621 mmol) gave 11 (45.6 mg, 95%) as a slightly yellow
d
3.91 (6H, s), 6.30 (2H, s), 7.26e7.47
C
18H17ClN3O3S (MþH)þ 390.06791, found 390.06758.
d
129.2, 129.4, 130.5, 132.9, 140.5, 141.5, 166.5. IR (ATR) nmax 3029,
2950, 1719, 1605, 1586, 1494, 1432, 1284, 1196, 1170, 1107,
1083 cmꢁ1. MS (ESI) 467 (MþH)þ. HRMS (ESI) calcd for C30H27O5
(MþH)þ 467.18585, found 467.18606.
Supplementary data
Supplementary data (NMR spectra for all compounds and full
experimental details of
a-aryl-pyridinemethanols are provided)
4.14. Methyl 6-((6-chloro-2-iodobenzo[d]thiazol-4-yl)methyl)
picolinate (16)
associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2016.02.005.
To a suspension of methyl 6-((2-amino-6-chlorobenzo[d]thia-
zol-4-yl)methyl)pyridine-2-carboxylate (1a, 3.37 g, 10.1 mmol) in
acetonitrile (45 mL) was added p-toluenesulfonic acid mono-
hydrate (5.77 g, 30.3 mmol), and subsequently added a solution of
sodium nitrate (1.41 g, 20.4 mmol) and potassium iodide (4.20 g,
25.3 mmol) in H2O, and the mixture was stirred at rt, for 24 h. The
pH of the mixture was adjusted to 11 by the addition of sodium
carbonate, and the mixture was then extracted with ethyl acetate.
The organic layer was dried over anhydrous Na2SO4, and evapo-
rated in vacuo. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate, 3:1) to give 16 (3.20 g, 71%)
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