O-tetrahydropyran-2-yloxy (O-THP) as an ortho-directing group in the lithiation of pyridines

Article abstract of DOI:10.1055/s-2006-947340

Herein we report regioselective deprotonations of 3- and 4-(tetrahydropyran-2-yloxy)pyridine with n-butyllithium. Trapping the lithiated species with various electrophiles afforded functionalized pyridines in good yields. A one-pot procedure also allowed

Full text of DOI:10.1055/s-2006-947340

1908
LETTER
O-Tetrahydropyran-2-yloxy (O-THP) as an ortho-Directing Group in the
Lithiation of Pyridines
ortho-Directing
G
a
roup in the
b
Lithiation
o
a
f
Pyridine
s
h Azzouz, Laurent Bischoff,* Corinne Fruit, Francis Marsais
Laboratoire de Chimie Organique Fine et Hétérocyclique, IRCOF, INSA Rouen, CNRS UMR 6014, B.P. 08, 76131 Mont-Saint-Aignan
Cedex, France
Fax +33(2)35522962; E-mail: laurent.bischoff@insa-rouen.fr
Received 30 March 2006
excess of n-butyllithium (1.5 molar equiv). It is note-
Abstract: Herein we report regioselective deprotonations of 3- and
worthy that no trace of addition of the alkyllithium species
on the pyridine ring was observed and the reaction led to
cleanly ortho-metallated species. Indeed, deuteration of 1
4-(tetrahydropyran-2-yloxy)pyridine with n-butyllithium. Trapping
the lithiated species with various electrophiles afforded functional-
ized pyridines in good yields. A one-pot procedure also allowed the
double functionalization at C4 and C2 in the case of 3-O-THP-pyri- under these conditions was achieved in 90% yield.
dine. The ortho-metallating ability of this group was examined in
The lithium chelate is subsequently trapped by suitable
comparison with other well-known oxygen-based ortho-directing
electrophiles showing regioselectivity of the lithiation
(Table 1). In all cases, only one isomer was obtained with
functionalization at C4.
groups.
Key words: acetals, pyridines, metallations, lithium, organometal-
lic reagents
O
O
O
The directed ortho-metallation is a powerful methodology
for functionalization of aromatic and heteroaromatic com-
pounds since lithiated derivatives display a high reactivity
toward a wide range of electrophiles.1 While numerous
ortho-directing groups such as the methoxy group, meth-
oxymethoxy group (MOM)2 or O-carbamoyl group3 have
been widely studied in benzene series, only few examples
of ortho-lithiated O-tetrahydropyran-2-yloxy (O-THP)
group were reported. For instance, di-(O-THP)hydro-
quinone and (O-THP)phenol were metallated by n-butyl-
lithium and trapped by carbon dioxide and ethylene oxide,
respectively.4a ortho-Lithiation of (O-THP)phenol deriva-
tives was also a key step in a tri-O-thymotide synthesis.4b
For pyridine, the ortho-lithiation of the O-THP group still
remaines unexplored. Since the easy removal of the THP
group for the formation of pyridinol, which greatly en-
hances its synthetic application, it therefore appeared to us
interesting to determine the efficiency of O-THP as ortho-
directing group in metallation reaction.
Li
E
O
O
O
E+
n-BuLi, THF
–78 °C
N
N
N
1
2–6
Scheme 1 Lithiation and electrophilic trapping of 3-(O-THP)pyri-
dine
Table 1 Deprotonation of 3-(O-THP)pyridine Using n-Butyl-
lithium and Trapping with Various Electrophiles
Entry
Electrophile
D2O
–E
Compd Yield (%)a
1
2
3
4
–D
–I
2
3
4
90
88
65
67
I2
PhSSPh
–SPh
4-Anisaldehyde –CH(OH)C6H4-p- 5
OMe
In order to study the regioselectivity of the metallation re-
action, 3-O-THP pyridine (1) was first studied. Because
the classical DHP/H+ pathway could not be envisaged, 3-
O-THP pyridine (1) is conveniently produced from 3-hy-
droxypyridine by treatment with 2-hydroxytetrahydro-
pyran under Mitsunobu conditions (triethylphosphine,
diethyl azadicarboxylate in THF) as we recently de-
scribed.5 The O-THP group was thus tested as ortho-di-
recting group in the metallation reaction.
5
DMF
–CHO
6
89
a Isolated yield after flash chromatography.
The trapping reaction led to deuteration, halogenation,
sulfenylation, hydroxyalkylation or formylation. The con-
version, observed by 1H NMR spectroscopy on the crude
reaction mixture, was >80%, very low amounts of starting
material being detected. Furthermore, iodopyridine 3
would allow further substitutions or cross-coupling
reaction.
As depicted in Scheme 1, metallation of pyridine 1 was
successfully achieved. A typical procedure involved, in
THF at –78 °C, the use of 1 in the presence of a slight
The ability of the O-THP group for ortho-lithiation could
be easily explained by a chelation of the lithium owing to
the endocyclic oxygen atom of the heterocycle. Likewise,
the acidity of the labile proton is enhancing due to the
SYNLETT 2006, No. 12, pp 1908–1912
0
1
.0
8
.2
0
0
6
Advanced online publication: 24.07.2006
DOI: 10.1055/s-2006-947340; Art ID: D09606ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
ortho-Directing Group in the Lithiation of Pyridine
1909
electron-withdrawing character of the oxygen atom. The sulfenylation at C4 followed by deuteration at C2 (com-
role of this complex-induced proximity effect (CIPE) in pound 10), then a double functionalization was performed
metallation reactions was recently thoroughly discussed.6 (Scheme 3). The pyridinol was further deprotected from
the crude reaction mixture as described above. This
procedure led to compound 11 with a 74% overall yield of
isolated pure material.
The yields obtained for compounds 4 and 5 after column
chromatography are lower than those expected, consider-
ing the good conversions observed before purification.
This can be explained by partial hydrolysis of the THP
group on silica gel. Thus, we evaluated the possibility of
SPh
O-THP
OH
OH
OMe
cleavage of the O-THP group after functionalization of
the pyridine. We observed (Scheme 2) that an aqueous
hydrolysis can be carried out under mild conditions, i.e. 3
molar HCl in a 1:1 mixture of dioxane–H2O at room tem-
perature. A typical procedure for a tandem functionaliza-
tion–deprotection was achieved by simply hydrolyzing
the crude reaction under these mild acidic conditions. In
this way, the expected pyridinol hydrochloride was recov-
ered from the aqueous layer upon lyophylization.
i, ii, iii
74 %
·HCl
N
N
1
11
Scheme 3 One-pot double deprotonation–electrophilic trapping
sequence of 3-(O-THP)pyridine.
Reagents and conditions: i) 1.2 equiv n-BuLi, THF, –78 °C, then
PhSSPh; ii) 1.5 equiv n-BuLi, THF, –78 °C, then anisaldehyde;
iii) 3 M HCl, H2O–dioxane = 1:1, r.t.
E
These results showed that successive metallations oc-
curred at C4 and at subsequent C2 position, without
adding n-BuLi onto the electron-deficient pyridine ring.
O-THP
OH
·HCl
i, ii
N
N
The ortho-directing ability of the O-THP group in lithia-
tion reactions was achieved by carrying out competitive
experiments. The competitive efficiencies of ortho-lithia-
tions within different O-protected pyridinols were estab-
lished by a series of reactions in which two different
substrates (1 mmol each) were allowed to react with n-
BuLi (2 or 3 mmol) in THF. The reactions were quenched
with a deuterium source. A typical competition is shown
in Scheme 4. Signifiant differences for competitive effi-
ciencies in directed ortho-lithiations for O-protected pyri-
dinol were observed. The O-THP-methoxy pair was
allowed to compete and it was found that only O-THP
pyridine (1) underwent lithiation. This is consistent with a
better lithium-chelation ability of the O-THP compared to
the OMe group. For the carbamoyl group, the deprotona-
tion occured at 97%, while the O-THP group led to 43%
deuteration at C4. These two experiments rank the O-THP
group between methoxy and O-diethylcarbamate, in terms
of ortho-directing ability.
1
7–9
Scheme 2 One-pot lithiation, electrophilic trapping and deprotec-
tion of 3-(O-THP)pyridine.
Reagents and conditions: i) n-BuLi, –78 °C, then E+, –78 °C; ii) 3 M
HCl in dioxane–H2O, 2 h at r.t.
Table 2 Synthesis of 3-Pyridinols Functionalized at C4
Entry Electrophile
–E
Compd Yield (%)
1
2
PhSSPh
–SPh
7
8
75
67
4-Anisaldehyde –CH(OH)C6H4-p-
OMe
3
MeI
–Me
9
96
As shown in Table 2, this one-pot methodology gave good
yields of very pure pyridinol hydrochlorides, which were
obtained without further purification. This was rendered
feasible by a quantitative metallation, since no trace of 3-
hydroxypyridine was observed. For this purpose, we used
a larger excess (2 mol equiv) of n-BuLi.
D
OTHP
OMe
OTHP
OMe
i, ii
N
N
N
N
As far as the regioselectivity is concerned, according to
the lithiation of 3-methoxymethyloxy pyridine with tert-
butyllithium published earlier,7 metallation of 1 was only
effected at the C4 carbon, and no trace of the other regio-
isomer was observed. We then focused our attention to-
wards the possibility of subsequent functionalization at
the C2 carbon. To achieve 2-deprotonation of 1, blocking
of the 4-position is necessary. A one-pot procedure for a
straight double functionalization was performed by using
a slight excess of n-BuLi in each deprotonation step. In-
deed, a first metallation-trapping sequence allowed the
functionalization at the C4 position, and a subsequent,
1
2
D
D
OTHP
OCONEt2
iii, iv
OTHP
OCONEt2
N
1
N
N
2
N
12
43%
97%
Scheme 4 Competition experiments between O-THP and other
oxygen-based ortho-directing groups.
Reagents and conditions: i) 2 mmol n-BuLi (for 1 mmol of 1 + 1
mmol 3-methoxypyridine), THF, –40 °C, 1 h; ii) D2O; iii) 3 mmol n-
BuLi (for 1 mmol of 1 + 1 mmol 3-diethylcarbamoyl pyridine),
one-pot repetition of this protocol led to a second sub- TMEDA, THF, –78 °C; iv) EtOD.
stitution at the C2 position. This was first tested by
Synlett 2006, No. 12, 1908–1912 © Thieme Stuttgart · New York

1910
R. Azzouz et al.
LETTER
As the O-THP group seemed to exhibit a very good ability mate. The 3- and 4-(tetrahydropyran-2-yloxy)pyridines
for directing ortho-metallation, we subsequently exam- are metallated with complete regioselectivity at, respec-
ined the possibility of deprotonating at the C3 carbon, us- tively, C4 and C3 positions to afford products in good
ing 4-O-THP pyridine 13.5 This position is generally more yields. In addition, a new one-pot procedure easily led to
difficult to deprotonate, due to less favorable electronic 2,4-disubstituted pyridin-3-ols in good yields. Further
effects of the nitrogen atom. We were pleased to notice research is focused on asymmetric O-alkyl group and
that using the same reaction conditions, the lithiation only develops the approach into synthetically interesting
occurred at the C3 carbon. The metallated species were methodology.
trapped with suitable electrophiles (Scheme 5), as listed in
Table 3.
NMR spectra were recorded on a 300 MHz Bruker Avance. All
chemical shifts are given in ppm. Rf given for TLC analyses were
measured on silica gel Merck Kieselgel F254 aluminum plates. Melt-
ing points are uncorrected.
OTHP
OTHP
O
E
E
i, ii
Typical Procedure for the Metallation of Compounds 1 and 13
To a solution of 300 mg (1.67 mmol) of 3-tetrahydropyran-2-yloxy
pyridine (1) in THF (16 mL) at –78 °C were added dropwise 1.62
mL (2.51 mmol) of a 1.6 M solution of n-BuLi in hexanes. After 30
min stirring at this temperature, the electrophile (1 M in THF) was
added dropwise. After 1 h stirring at –78 °C, 15 mL of 10% NH4Cl
were added and the crude material was obtained by extractive work-
up with Et2O. Purification was subsequently achieved by means of
column chromatography through silica gel using 1% Et3N in the
eluent (compounds 2–6). In the case of more acid-sensitive com-
pounds 14–16, basic alumina was used for column chromatography.
N
N
N
13
14a–16a
THP
14b–16b
Scheme 5 Deprotonation of 4-O-THP pyridine: obtention of N-
THP by-products.
Reagents and conditions: i) 1.5 equiv n-BuLi, THF, –78 °C; ii) elec-
trophile, THF, –78 °C.
Table 3 Isolated Yields for the Trapping of Lithiated 4-(O-THP)py-
ridine
4-Deuterio-3-tetrahydropyran-2-yloxy Pyridine (2)
Entry Electrophile
Compd
Yield (%) Ratio O-THP/
N-THP
From 300 mg (1.67 mmol) of 1 and 150 mL (8.3 mmol) D2O, 270
mg of compound 2 were obtained (90%) as a pale brown oil. TLC
(cyclohexane–EtOAc, 1:3, 1% Et3N): Rf = 0.65. 1H NMR (CDCl3):
d = 1.50–2.00 (6 H, m), 3.50–3.70 (2 H, m), 5.37 (1 H, t, J = 3.0
Hz), 7.14 (1 H, d, J = 4.7 Hz), 8.17 (1 H, d, J = 4.7 Hz), 8.35 (1 H,
s). 13C NMR: d = 18.8, 25.4, 30.5, 62.4, 97.0, 124.2, 140.0, 143.0,
162.7. MS (CI): m/z = 97, 85, 181.
1
2
3
EtOD
14a,b
15a,b
16a
92
50
68
71:29
48:52
100:0
I2
4-Anisaldehyde
4-Iodo-3-tetrahydropyran-2-yloxy Pyridine (3)
From 200 mg (1.12 mmol) of 1 and 426 mg (1.68 mmol) I2, 300 mg
of compound 3 were obtained (88%) as a pale brown powder; mp
Nevertheless, the THP protecting group is very labile, es-
pecially when linked to oxygen at the C2 or C4 on pyrid-
inols.5 During the course of the metallation of 4-O-THP
1
90 °C; TLC (cyclohexane–EtOAc, 1:3, 1% Et3N): Rf = 0.93. H
pyridine, we obtained a side product resulting from a NMR: d = 1.50–2.00 (6 H, m), 3.50–3.70 (2 H, m), 5.54 (1 H, dd,
J = 2.6, 2.3 Hz), 7.65 (1 H, d, J = 4.9 Hz), 7.82 (1 H, d, J = 4.9 Hz),
transposition of THP from the oxygen atom to the nitro-
gen atom of pyridine. This rearrangement should occur af-
ter the trapping, since the functionalization at C3 was
8.26 (1 H, s) 13C NMR (CDCl3): d = 20.1, 25.5, 30.2, 63.2, 88.8,
95.8, 132.7, 139.3, 143.0, 164.1. MS (CI): m/z = 85, 96, 222, 306.
quantitative in each case, according to the NMR spectra of
the crude materials. Presumably, the lithiated 4-O-THP
4-Phenylsulfanyl-3-tetrahydropyran-2-yloxy Pyridine (4)
From 200 mg (1.12 mmol) of 1 and 367 mg (1.68 mmol) PhSSPh,
209 mg of 4 were obtained (65%) as a pale brown oil. TLC
pyridine is stable enough to be synthesized without rear-
rangement, as long as the lithium is involved in the C–Li (CH2Cl2–EtOAc, 1:1, 1% Et3N): Rf = 0.6. 1H NMR (CDCl3):
d = 1.50–2.00 (6 H, m), 3.50–3.70 (2 H, m), 5.52 (1 H, dd, J = 3.0,
bond. Though, it may become labile and lead to N-THP
by-products once the lithium species was trapped by the
electrophile. At this time, the lithium is only chelated by
the O-THP, without being bound to the carbon atom of the
m/z = 85, 204, 260, 288.
pyridine. In order to confirm this hypothesis, we used an
2.6 Hz), 6.48 (1 H, d, J = 5.0 Hz), 7.40–7.50 (5 H, m), 7.92 (1 H, d,
J = 5.0 Hz), 8.26 (1 H, s). 13C NMR: d = 20.2, 25.5, 30.2, 63.2, 96.3,
122.2, 125.6, 127.1, 129.5, 136.4, 139.0, 142.0, 157.9. MS (CI):
aldehyde as the electrophile (entry 3), so as to still permit
the chelation of the lithium cation by the alcoholate thus
obtained. In this case, no N-THP by-product was ob-
served.
4-(4-Methoxyphenylhydroxymethyl)-3-tetrahydropyran-2-
yloxy Pyridine (5)
From 300 mg (1.67 mmol) of 1 and 304 mL (2.5 mmol) p-anisalde-
hyde, 351 mg of 5 were obtained (67%) as a pale yellow powder;
1
mp 102 °C; TLC (EtOAc, 1% Et3N): Rf = 0.4. H NMR (CDCl3):
In summary, we reported a new and efficient ortho-direct-
ing group to extend the scope of the functionalization of
pyridines. This methodology used the O-THP both as an
ortho-directing and protecting group, since it can be easily
cleaved after the functionalization step, in much milder
conditions than the methoxy group or a tertiary carba-
d = 1.60–2.00 (6 H, m), 3.50–3.70 (2 H, m), 3.71 (3 H, s), 5.41 (1
H, dd, J = 2.6, 2.3 Hz), 5.97 (1 H, s), 6.78 (2 H, d, J = 8.7 Hz), 7.20
(2 H, d, J = 8.7 Hz), 7.37 (1 H, d, J = 4.9 Hz), 8.22 (1 H, d, J = 4.9
Hz), 8.32 (1 H, s). 13C NMR: d = 19.8, 25.3, 30.4, 55.7, 62.8, 70.5,
97.5, 114.2, 127.5, 128.7, 134.8, 135.0, 137.3, 141.9, 159.6. MS
(CI): m/z = 85, 232, 298, 316
Synlett 2006, No. 12, 1908–1912 © Thieme Stuttgart · New York

LETTER
ortho-Directing Group in the Lithiation of Pyridine
1911
4-Formyl-3-tetrahydropyran-2-yloxy Pyridine (6)
From 160 mg (0.89 mmol) of 1 and 140 mL DMF (1.78 mmol), 160
mg of compound 6 were obtained (89%) as brown oil. H NMR
(CDCl3): d = 1.50–2.00 (6 H, m), 3.65 (1 H, m), 3.90 (1 H, m), 5.66
(1 H, t, J = 2.9 Hz), 7.61 (1 H, d, J = 4.89 Hz), 8.42 (1 H, d, J = 4.89
Hz), 8.76 (1 H, s), 10.58 (1 H, s). 13C NMR: d = 18.8, 25.2, 30.4,
62.8, 97.6, 120.0, 130.0, 140.3, 143.7, 153.9, 189.6.
Hz), 7.28 (1 H, d, J = 8.7 Hz), 7.43 (1 H, s), 7.50 (5 H, m), 7.82 (1
H, d, J = 5.8 Hz). 13C NMR: d = 55.4, 70.9, 113.9, 114, 119.9,
128.2, 128.4, 130.6, 130.8, 134, 135.6, 136, 145.4, 147.4, 159.1.
HRMS: m/z calcd for C19H18NO3S [M]+: 340.0991; found:
340.1007.
1
Competition Experiments
Competition experiment involving 3-methoxy and 3-(O-THP)pyri-
2-Deuterio-4-phenylsulfanyl-3-tetrahydropyran-2-yloxy
Pyridine (10)
dine was conducted using the experimental conditions described for
2.
From 200 mg (1.12 mmol) of 1, after successive treatments with n-
BuLi (1.34 mmol), PhSSPh (330 mg, 1.46 mmol), then n-BuLi
(1.68 mmol) and D2O (0.1 mL, 5.6 mmol), 190 mg were obtained
(59%) after column chromatography as a pale brown oil. 1H NMR
(CDCl3): d = 1.50–2.00 (6 H, m), 3.50–3.70 (2 H, m), 5.52 (1 H, t,
J = 2.6 Hz), 6.45 (1 H, d, J = 4.5 Hz), 7.40–7.50 (5 H, m), 7.92 (1
H, d, J = 4.5 Hz). MS (CI): m/z = 85, 205, 289.
Competition Experiment with the Carbamate
From 100 mg (0.56 mmol) of 1 and 110 mg (0.56 mmol) of 3-O-di-
ethylcarbamoylpyridine, 150 mg of the following mixture were ob-
1
tained as a colorless oil. H NMR (CDCl3): d = 1.23 (6 H, 2 t,
J = 7.1 Hz), 1.50–2.00 (6 H, m), 3.42 (4 H, 2q, J = 7.0 Hz), 3.61 (1
H, m), 3.86 (1 H, m), 5.44 (1 H, t, J = 2.9 Hz), 7.20 (1 H, dd, J = 8.5,
4.5 Hz), 7.30 (1 H, d, J = 4.3 Hz), 7.38 (0.57 H, H4 of the THP
ether, ddd, J = 8.3, 2.8, 1.3 Hz), 7.52 (0.03 H, H4 of the carbamate,
ddd, J = 8.1, 4.3, 1.1 Hz), 8.10 (1 H, d, J = 4.2 Hz), 8.41 (1 H, s),
8.43 (1 H, s), 8.43 (1 H, d, J = 4.3 Hz).
Procedure for Subsequent Deprotection
After metallation (with 2 mol equiv n-BuLi 45 min at –78 °C) and
electrophilic trapping (45 min at –78 °C), the crude material was
taken up in dioxane and an equal volume of 6 M aq HCl was added.
After 2 h stirring at r.t., solvents were evaporated in vacuo and the
residue was dissolved in H2O, washed with Et2O and lyophilized to
afford pure 7–9 as their hydrochlorides.
3-Deuterio-4-tetrahydropyran-2-yloxy Pyridine (14a)
From 100 mg (0.56 mmol) of 13 and 160 mL (2.79 mmol) EtOD, 65
mg of 14a (65%) were obtained. 1H NMR: d = 1.50–2.00 (6 H, m),
3.50–3.70 (2 H, m), 5.46 (1 H, t, J = 2.8 Hz), 6.88 (1 H, d, J = 5.6
Hz), 8.36 (1 H, s), 8.37 (1 H, d, J = 5.6 Hz). 13C NMR: d = 18.7,
25.5, 30.2, 69.3, 93.7, 131.6, 153.1, 164.0.
3-Hydroxy-4-phenylsulfanyl Pyridine Hydrochloride (7)
From 150 mg (0.84 mmol) of 1 and 364 mg (1.67 mmol) diphenyl-
disulfide, 150 mg of compound 7 were obtained (75%) as a white
powder; mp 238 °C. 1H NMR (DMSO): d = 6.85 (1 H, d, J = 6.21
Hz), 7.67 (5 H, m), 8.13 (1 H, d, J = 6.21 Hz), 8.19 (1 H, s). 13C
NMR: d = 121.8, 125.6, 127, 131.8, 132.0, 133.7, 136.7, 150.2,
151.8. MS (FAB+): m/z = 204, 185, 93, 75. HRMS: m/z calcd for
C11H9NOS [M]+: 203.0404; found: 203.0405.
3-Deuterio-1-tetrahydropyran-2-yloxy Pyridin-4-one (14b)
From the previous experiment, 27 mg of 14b (27%) were obtained
by crystallization as a white solid. 1H NMR (CDCl3): d = 1.50–2.00
(6 H, m), 3.60–4.10 (2 H, m), 4.78 (1 H, dd, J = 10.0, 2.2 Hz), 6.32
(1 H, d, J = 8.1 Hz), 7.41 (2 H, m). 13C NMR: d = 22.9, 24.9, 32.3,
69.3, 91.7, 118.5, 118.7, 137.4, 137.5, 180.2.
3-Hydroxy-4-(4-methoxyphenylhydroxymethyl) Pyridine
Hydrochloride (8)
3-Iodo-4-tetrahydropyran-2-yloxy Pyridine (15a)
From 150 mg (0.84 mmol) of 1 and 200 mL 4-anisaldehyde, 150 mg
of compound 8 were obtained (67%) as a light brown powder; mp
82 °C. 1H NMR (D2O): d = 3.71 (3 H, s), 6.10 (1 H, s), 6.87 (1 H, d,
J = 8.8 Hz), 7.25 (1 H, d, J = 8.8 Hz), 8.12 (1 H, d, J = 6.2 Hz), 8.13
(1 H, s), 8.29 (1 H, d, J = 6.2 Hz). 13C NMR: d = 55.6, 69.5, 114.5,
124.2, 127.9, 129.2, 132.3, 133.4, 150.6, 152.8, 159.2. MS (FAB+):
m/z = 232, 214, 185, 93, 75. HRMS: m/z calcd for C13H13NO3 [M]+:
231.0891; found: 231.0895.
From 100 mg (0.56 mmol) of 13 and 210 mg (0.83 mmol) I2, 40 mg
of 15a were obtained (24%) as a brown oil. H NMR (CDCl3):
d = 1.50–2.00 (6 H, m), 3.50–3.70 (2 H, m), 5.61 (1 H, t, J = 2.9
Hz), 6.94 (1 H, d, J = 5.6 Hz), 8.28 (1 H, d, J = 5.6 Hz), 8.71 (1 H,
1
s).
3-Iodo-1-tetrahydropyran-2-yloxy Pyridin-4-one (15b)
From the previous experiment, 45 mg of 15b (26%) were obtained
1
by crystallization as a yellow solid. H NMR (CDCl3): d = 1.50–
3-Hydroxy-4-methyl Pyridine Hydrochloride (9)
2.00 (6 H, m), 3.60 (1 H, m), 4.11 (1 H, m), 4.79 (1 H, dd, J = 10.0,
2.1 Hz), 6.33 (1 H, d, J = 7.5 Hz), 7.41 (1 H, dd, J = 7.5, 2.4 Hz),
8.00 (1 H, d, J = 2.4 Hz). 13C NMR: d = 21.5, 23.5, 31.1, 68, 90.1,
91.9, 113, 135.8, 141.4, 174.3. MS (CI): m/z = 306, 222, 180, 96,
85, 73.
From 105 mg (0.59 mmol) of 1 and 55 mL iodomethane (0.88
mmol), 82 mg of compound 9 were obtained (96%) as a brown
paste. 1H NMR (DMSO): d = 2.41 (3 H, s), 7.86 (1 H, d, J = 5.6 Hz),
8.34 (1 H, d, J = 5.6 Hz), 8.42 (1 H, s). 13C NMR: d = 17.3, 127.2,
129.3, 132.9, 146.6, 155.9.
3-(4-Methoxyphenylhydroxymethyl)-4-tetrahydropyran-2-
yloxy Pyridine (16a)
From 100 mg (0.56 mmol) of 13 and 100 mL (0.83 mmol) of 4-anis-
3-Hydroxy-2-(4-methoxyphenyl)hydroxymethyl-4-phenylsulfa-
nyl Pyridine Hydrochloride (11)
1
From 100 mg (0.56 mmol) of 1, n-BuLi (1.12 mmol, 45 min at
–78 °C), 244 mg diphenyldisulfide (1.12 mmol, 45 min at –78 °C),
135 mL 4-anisaldehyde (1.12 mmol, 45 min at –78 °C), then hydro-
lyzing as described for 7–9, 156 mg of compound 11 were obtained
(74%) as a white powder; mp 112 °C. 1H NMR (DMSO): d = 3.65
(3 H, s), 6.17 (1 H, s), 6.48 (1 H, d, J = 5.8 Hz), 6.83 (1 H, d, J = 8.7
aldehyde, 120 mg of 16a were obtained (68%) as a white oil. H
NMR (CDCl3): d = 1.50–2.00 (6 H, m), 3.47 (2 H, m), 3.71 (3 H, s),
5.44 (1 H, m), 5.90 (1 H, s), 6.78 (2 H, d, J = 8.8 Hz), 6.94 (1 H, d,
J = 5.6 Hz), 7.22 (2 H, d, J = 8.8 Hz), 8.34 (1 H, d, J = 5.6 Hz), 8.56
(1 H, s). 13C NMR: d = 19.3, 25.9, 30, 55.7, 65.3, 69.2, 96, 103,
114.1, 118.1, 128.5, 130.3, 148,150.6, 159, 172.7.
Synlett 2006, No. 12, 1908–1912 © Thieme Stuttgart · New York

1912
R. Azzouz et al.
LETTER
(4) (a) Stern, R.; English, J. Jr.; Cassidy, H. G. J. Am. Chem.
References
Soc. 1957, 79, 5797. (b) Harris, T. D.; Oruganti, S. R.;
Davis, L. M.; Keehu, P. M.; Green, B. S. Tetrahedron 1987,
43, 1519.
(1) Mongin, F.; Quéguiner, G. Tetrahedron 2001, 57, 4059.
(2) (a) Schlosser, M. In Organometallics in Synthesis, 2nd ed.;
Schlosser, M., Ed.; Wiley: Chichester UK, 2002, 1–352.
(b) Clayden, J. In The Chemistry of Organolithium
Compounds; Rappoport, Z.; Marek, I., Eds.; Wiley:
Chichester UK, 2004, 495–646.
(5) Azzouz, R.; Bischoff, L.; Fouquet, M.-H.; Marsais, F.
Synlett 2005, 2808.
(6) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew.
Chem. Int. Ed. 2004, 43, 2206.
(3) Miah, M. A. J.; Snieckus, V. J. Org. Chem. 1985, 50, 5438.
(7) Winkle, M. R.; Ronald, R. C. J. Org. Chem. 1982, 47, 2101.
Synlett 2006, No. 12, 1908–1912 © Thieme Stuttgart · New York