Improved condensation of 2-pyridyllithium intermediates with aldehydes: Application for the Synthesis of 2 (polyhydroxyalkyl)pyridines

Article abstract of DOI:10.2174/157017809787003214

The scope and the limitations of 3-chloro-2-pyridinyl lithium condensation to aldehydes were envisioned depending on metallation conditions or condensation time and temperatures. The procedure was applied to various aromatic, aliphatic or functionalized a

Full text of DOI:10.2174/157017809787003214

50
Letters in Organic Chemistry, 2009, 6, 50-56
Improved Condensation of 2-pyridyllithium Intermediates with
Aldehydes: Application for the Synthesis of 2-(polyhydroxyalkyl)pyridines
Corinne Comoy, Julien Pétrignet, Estelle Banaszak, Anthony Chartoire and Yves Fort*
SRSMC, Nancy-Université, CNRS, B.P. 239, Boulevard des Aiguillettes, F-54506 Vandoeuvre-lès-Nancy, France
Received May 27, 2008: Revised October 16, 2008: Accepted October 19, 2008
Abstract: The scope and the limitations of 3-chloro-2-pyridinyl lithium condensation to aldehydes were envisioned de-
pending on metallation conditions or condensation time and temperatures. The procedure was applied to various aromatic,
aliphatic or functionalized aldehydes to afford a new and efficient access to 2-(polyhydroxyalkyl)pyridines.
Keywords: Regioselective lithiation, [n-BuLi/LiDMAE] superbase, 2-pyridinyllithium, 2-(polyhydroxyalkyl)pyridines.
INTRODUCTION
metallation was explained by a strong complexation between
lithium, heteroatom (Cl), pyridinic nitrogen and dimethy-
laminoethoxide in a specific lithiated aggregate [10].
Nucleophilic addition using organolithium species is
known to be useful in carbon-carbon bond formation [1].
Classically applied to aromatic or non-enolisable aldehydes
this organic sequence is described as a powerful method of
functionalization [2-4] but the efficient use of functional
aldehydes is rarely reported. Furthermore, in heterocyclic
series, a basic problem limiting applications results from
additional complexation phenomena which impose the use of
an excess (2-4 eq) of organolithium to reach the complete
formation of lithiated intermediates. Consequently, the same
excess of trapping agent (electrophile) has to be used to fur-
nish condensation products. In these basic conditions, reac-
tive aliphatic aldehydes are prone to side-reactions such as
enolisation or polycondensation. It then appears that adapted
reaction conditions have to be determined to reach accept-
able yields.
Cl
Cl
[n-BuLi/LiDMAE], hexane
then E+, THF
Cl
N
E
N
2
E = SiMe3, Br, Cl, I, SMe, ...
Li
Li O
N
N
n
Scheme 1. Selective functionalization of 3-chloropyridine induced
by [n-BuLi/LiDMAE] superbase.
In this previous study, we described the regioselective C-
2 functionalization of 3-chloropyridine (2) performed by a
metallation at -60°C for 1h, in hexane as solvent, with super-
base [n-BuLi/LiDMAE] (3 eq). Condensation reactions were
afforded using various representative electrophiles, one was
a carbonyl reagent (tBuCHO, 60% isolated yield). In agree-
ment with these results, we reported here a detailed investi-
gation to extend the scope of this condensation using a vari-
ety of functionalized aldehydes. The best determined condi-
tions led us to define an improved protocol for introducing
polyhydroxylated moieties on pyridinic ring allowing the
synthesis of 1a-b.
In our continuous effort to develop new heterocyclic syn-
thons [5,6], our group is now interested in the preparation of
functionalized heterocycles as precursors for fused polyhet-
erocycles synthesis [7,8]. In this context, we focused our
attention on the preparation of 2-(polyhydroxyalkyl)
pyridines (1a-b) (Fig. 1) via a regioselective functionaliza-
tion of 3-chloropyridine (2) using reactive aldehyde conden-
sation to indroduce the expected (poly)hydroxyalkyl chain
on pyridinic moiety.
Cl
OH
1a,b X = H, OH
RESULTS AND DISCUSSION
N
X
At first, we decided to reinvestigate the functionalization
by aldehydic electrophiles and we studied the reactivity of 3-
chloropyridine (2) under various metallation conditions fol-
lowed by condensation with benzaldehyde (used as model).
In Table 1, we report the more significant results of this pre-
liminary study. The completion of the reaction was attested
by GC analysis using internal standard method (undecane).
OH
Fig. (1). 2-(Polyhydroxyalkyl)pyridines 1a-b.
Some of our previous investigations displayed the use-
fulness of the monomeric [n-BuLi/LiDMAE] superbase [5]
(DMAE: 2-(dimethylaminoethanol)) in an apolar solvent
(toluene or hexane) to perform regioselective C-2-lithiation
of 3-chloropyridine (2) (Scheme 1) [9]. The exclusive C-2-
Using previously described conditions [9] (entry 1), met-
allation was carried out with 3 equivalents of superbase, at -
60°C for 1h then the condensation with benzaldehyde (3 eq)
led to the expected derivative (3a) in good yield (75%). In
these conditions, no trace of starting material was recovered.
*Address correspondence to this author at the SRSMC, Nancy-Université,
CNRS, B.P. 239, Boulevard des Aiguillettes, F-54506 Vandoeuvre-lès-
Nancy, France, E-mail : yves.fort@sor.uhp-nancy.fr
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

Improved Condensation of 2-pyridyllithium Intermediates with Aldehydes
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
51
Table 1. Optimization of the 2-lithio-3-chloropyridine Con-
densation to Benzaldehyde
medium, induced a significant decrease of yields in 3a (for
example 47-41 % versus 75%, entries 3, 4 versus 1 – starting
material was recovered), while the use of 2 equivalents of
superbase showed only a weak decreased yield (entry 2,
71%). However, a small excess (2.5 equivalents) of aldehyde
was required to optimize this latter metallation-condensation
sequence.
Cl i) [n-Buli/LiDMAE] (n eq),
Cl
hexane, T°C, 1h
Ph
ii) PhCHO (n eq), THF, -78°C, 1h
iii) H2O, -20°C
N
N
2
3a
OH
Variations of metallation temperature were also studied
and we observed a large increase of isolated yield (85% ver-
sus 75%, entries 1 versus 14) when the metallation is con-
ducted at -45°C for 1h. As outlined in Table 1, 3 equivalents
of superbase were then required to totally succeed in lithiat-
ing the 3-chloropyridine (2). Note that entry 15 is also of
interest in a synthetic purpose since an 80% yield was ob-
tained by using respectively 2 equivalents of base and 2.5
equivalents of aldehyde under the same temperature condi-
tions.
Entry
Metallation Conditions
PhCHO
Yieldsa,b
(%)
Base (eq)
T(°C)
(eq)
1
2
3.0
2.0
1.0
1.5
2.0
2.0
2.0
1.0
1.5
1.5
2.0
2.0
3.0
3.0
2.0
-60°C
-60°C
-60°C
-60°C
-60°C
-60°C
-30°C
-45°C
-45°C
-45°C
-45°C
-45°C
-45°C
-45°C
-45°C
3.0
2.5
1.2
2.0
4.0
6.0
2.5
1.2
2.0
3.0
2.5
4.0
3.5
3.0
2.5c
75
71
47
41
51
54
63
45
51
45
77
66
84
85
80
3
4
5
6
7
To illustrate the generality of the procedure, we next
studied the condensation of various aromatic aldehydes. The
expected aryl pyridinyl methanols (3a-f) were produced in
good to excellent yields (74–88%) (Table 2). It is interesting
to note that additional heteroatoms on phenyl group (OMe,
NMe2) seem to induce no disturbance on the lithium aggre-
gate since any increasing of superbase amount is needed to
obtain high yields.
8
9
10
11
12
13
14
15
We then examined the reaction using alkenyl aldehydes.
Such carbonyl reagents generally present disadvantage to
easily lead to unexpected polymerization under basic condi-
tions. We were pleased to observe that condensation of 3-
chloro-2-lithiopyridine with acroleine or dimethyl acroleine
aReactions performed on 2.67 mmoles of 3-chloropyridine. bIsolated yields after silica
gel chromatography. c3h were required for condensation.
We also noted that metallations performed with only 1 or 1.5
equivalent of [n-BuLi/LiDMAE] to limit excess of base in
Table 2. Preparation of Substituted Pyridinylmethanols (3-7)a
i) [n-Buli/LiDMAE] (3 eq),
hexane, -45°C, 1h
Cl
Cl
R
N
ii) RCHO (3 eq), THF, -78°C, 1h
iii) H2O, -20°C
N
2
3-7
OH
Yields (%)b
R
Yields (%)b
R
3a
3b
3c
85
3f
4
74
Br
87
88
65
78
MeO
Me
5
Me
OMe
Me
OMe
3d
3e
79
78
6c
7c
71
85
Me
Me
NMe2
aReactions performed on 2.67 mmoles of 3-chloropyridine. bIsolated yields after silica gel chromatography. c2 eq of superbase at -45°C for 1h then 2.5 eq RCHO at -78°C for 3h.

52
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Comoy et al.
at -78°C afforded the expected allylic alcohols (4) and (5) in
good yields (65 and 78% respectively). In these conditions,
no trace of 1,4-adduct resulting from a conjugate addition
was isolated. In connection with our target to condense func-
tionalized aldehydes, we also examined the condensation of
representative enolisable aldehydes. To limit competitive
side-reactions, we decided to use the previously determined
lower efficient excess of superbase (entry 15, Table 1). Con-
sequently, experiments carrying out with 2 equivalents of [n-
BuLi/LiDMAE] superbase in n-hexane at -45°C for 1h fol-
lowing by addition of aldehyde (2.5 eq) at -78°C for 3h were
applied to i-butyraldehyde and propanal to afford the ex-
pected pyridinyl alcohols (6) and (7) in excellent isolated
yields (71 and 85% respectively). These interesting results
contrast with classical experiments described in the literature
and validate our systematic study. Under used conditions, it
could be postulated that formed lithiated aggregates possess
a high nucleophilicity and a low basicity which favor the
condensation process to the detriment of side basic reactions.
catalytic amount of CBr4 in MeOH to give the expected
pyridinylpropanetriol (1b) in quantitative yield [13]. Note
that compounds (12) and (1b) were isolated as a mixture of
diastereoisomers.
i) nBuLi (1.3 eq), THF,
HMPT (2.2 eq), -30°C
then 1h, 0°C
Cl
Cl
N
N
ii) MOMCl (1.3 eq),
4h, RT
OH
OMOM
4
11
K3FeCN6 (3 eq), K2CO3 (3 eq),
tBuOH/H2O : 1/1,
OsO4 (0.04 eq), 24h, RT
82%
(2 steps)
Cl
CBr4 (10%),
MeOH, 18h, ꢀ
Cl
OH
OH
OH
quantitative yield
N
N
OH
OH
OMOM
1b
12
Next, we envisioned to examine the efficiency of these
conditions in the presence of sensitive functionalized elec-
trophiles. Condensation of 3-O-substituted propanals (9a-c)
led to pyridinylpropanols (10a-c) in moderate yields (40-
44%) and allowed the introduction of a silyl ether, an ester or
an O-benzyl groups respectively (Scheme 2). The decrease
of the isolated yield could be interpreted by the introduction
of an additional complexing atom (in the electrophile) pro-
ducing desaggregation processes before condensation and
consequently a variation of nucleophilicity/basicity ratio of
the lithiated species. The steric entrance of the ether part
could also be taking into account.
Scheme 3. Synthesis of 1-(3-chloropyridin-2-yl)propan-1,2,3-triol
(1b).
In summary, we have described an improved procedure
for the regioselective lithiation of 3-chloropyridine using the
superbase [n-BuLi/LiDMAE] followed by the efficient con-
densation of the pyridinyl lithium intermediate with various
functionalized and/or reactive aldehydes. This optimized
procedure was applied to 3-O-protected hydroxypropanals to
allow the efficient preparation of the 2-(polyhydroxypropyl)
pyridines 1a-b in good overall yields (35 and 53% yield re-
spectively) starting from 3-chloropyridine.
Cl
Cl
i) [n-Buli/LiDMAE] (2 eq),
hexane, -45°C, 1h
EXPERIMENTAL
General
1H and 13C NMR spectra were recorded at 400 or 250 and
100 MHz respectively with CDCl3 as solvent and TMS as
N
N
ii)
9a-c
OR'
O
(2.5 eq),
THF, -78°C, 3h
iii) H2O, -20°C
OH
OR'
2
10a R' = SitBuPh2, 44%
10b R' = C(O)tBu, 43%
10c R' = Bn,
1
internal standard (for H NMR). HRMS spectra were re-
40%
corded on a BRUKER micrOTOF-Q spectrometer. MS were
recorded on a SHIMADZU GCMS-QP2010 spectrometer.
Elemental analysis are realized on a Thermofinnigan
FlashEA 1112 instrument. Melting temperatures are uncor-
rected.
Cl
for R' = C(O)tBu
tBuOK (8.7 eq), H2O (2.2 eq)
N
Et2O, RT, 3h
OH
OH
1a
81%
Scheme 2. Synthesis of 1-(3-chloropyridin-2-yl)propan-1,3-diol
(1a).
Materials and Solvents
All reagents were commercially available and were puri-
fied by distillation when necessary. n-BuLi was used as a
commercial 1.6 M solution in hexanes. 2-(Dimethyl-
amino)ethanol (DMAE) was distilled and stored over mo-
lecular sieves before use. Toluene and THF were distilled
and stored on sodium wire before use.
Deprotection of hydroxyl moiety was next performed
starting from ester (10b) in the presence of potassium t-
butylate and water [11]. The expected pyridinylpropan-1,3-
diol (1a) was then isolated in 81% yield.
Finally, the synthesis of the chlorinated pyridinyl-propan-
1,2,3-triol (1b) was achieved starting from the previou-
sly prepared 1-(3-chloropyridin-2-yl)-prop-2-en-1-ol (4)
(Scheme 3). Our reaction way involved an O-protection of
allylic alcohol (4) that was performed in THF with n-BuLi
(1.3 eq) as base in the presence of HMPA (2.2 eq) and
chloromethyl methyl ether (MOMCl, 1.3 eq), followed by
bishydroxylation of the alkene (11) as main step [12] to lead
to the polyhydroxyalkylpyridine (12) in excellent yield (82%
for 2 steps). Cleavage of MOM-protection was afforded by
General Procedure for Preparation of Derivatives (3-5)
A solution of 2-(dimethylamino)ethanol (DMAE) (0.8
mL, 8.0 mmol, 3.0 eq) in anhydrous hexane (25.0 mL) was
cooled at ca. -5°C then n-BuLi (10.0 mL, 16.0 mmol, 6.0 eq)
was added dropwise under a nitrogen atmosphere. After stir-
ring for 15 minutes at 0°C, the reaction medium was cooled
at -45°C. 3-Chloropyridine (2) (303 mg, 2.67 mmol, 1.0 eq)
in hexane (5.0 mL) was added dropwise. After stirring for 1

Improved Condensation of 2-pyridyllithium Intermediates with Aldehydes
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
53
h at -45°C, a solution of the appropriate electrophile (8.0
mmol, 3.0 eq) in anhydrous THF (10.0 mL) was added
dropwise. After stirring at -78°C for 1h, hydrolysis was per-
formed with H2O (30.0 mL) at -20°C. The aqueous phase
was then extracted with ethyl acetate (20.0 mL). After drying
(MgSO4), filtration and solvent evaporation, the crude prod-
uct was purified by column chromatography on silica gel
(Geduran Si 60, 63–200 μm).
(NaCl) ꢁ 3429, 2837, 1609, 1485, 1264 ; MS (EI) m/z 249
(M+, 16), 218 (100), 136 (23), 107 (32), 77 (25).
1-(3-Chloropyridin-2-yl)-1-(4-methoxyphenyl)methanol
(3d)
1-(3-Chloropyridin-2-yl)-1-(4-methoxyphenyl)methanol
(3d) was prepared according to the general method described
herein with p-anisaldehyde (1088 mg, 8.0 mmol, 3.0 eq) as
electrophile. Purification on silica gel was performed with a
mixture hexane/AcOEt : 8/2 and yielded the expected com-
pound (3d) (526 mg, 79%) as a white solid ; mp 107-109 °C
1-(3-Chloropyridin-2-yl)-1-phenylmethanol (3a)
1-(3-Chloropyridin-2-yl)-1-phenylmethanol (3a) was
prepared according to the general method described herein
with benzaldehyde (848 mg, 8.0 mmol, 3.0 eq) as electro-
phile. Purification on silica gel was performed with a mix-
ture hexane/AcOEt : 9/1 as eluent and led to the expected
pyridinyl compound (3a) (498 mg, 85%) as a white solid ;
1
; H NMR ꢀH 3.77 (s, 3H, O-CH3), 5.19-5.23 (m, 1H,
CHOH), 5.95 (s, 1H, CHOH), 6.81-6.85 (m, 2H, HAr), 7.18-
7.28 (m, 3H, H5, HAr), 7.65 (dd, J = 7.9 Hz, J’ = 1.4 Hz, 1H,
H4), 8.54 (dd, J = 4.8 Hz, J’ = 1.4 Hz, 1H, H6) ; 13C NMR ꢀC
55.4 (O-CH3), 71.8 (CHOH), 114.0 (CAr), 123.8 (C5), 129.0
(CAr), 130.0 (C3), 134.2 (CAr), 137.9 (C4), 146.3 (C6), 157.9
(C2), 159.3 (CAr-O) ; IR (NaCl) ꢁ 3189, 2995, 1608, 1428,
1247 ; MS (EI) m/z 249 (M+, 68), 232 (13), 141 (12), 136
(100), 113 (32), 94 (18), 77 (25).
1
mp 68-70 °C ; H NMR ꢀH 5.27 (d, J = 4.0 Hz, 1H, OH),
6.00 (d, J = 4.0 Hz, 1H, CHOH), 7.21-7.33 (m, 6H, HAr, H5),
7.67 (dd, J = 7.9 Hz, J’ = 1.4 Hz, 1H, H4), 8.56 (dd, J = 4.8
Hz, J’= 1.4 Hz, 1H, H6) ; 13C NMR ꢀC 72.1 (CHOH), 123.8
(C5), 127.6 (CAr), 127.9 (CAr), 128.5 (C3), 137.9 (C4), 141.8
(CAr), 146.2 (C6), 158.5 (C2) ; IR (NaCl) ꢁ 3426, 3058, 1425,
1295, 1258 ; MS (EI) m/z 220 ([M+1]+, 3), 218 ([M-1]+,
100), 201 (7), 142 (31), 113 (51), 77 (45) ; ESI-HRMS
calcd for C12H10ClNO (M+Na)+ : 242.0343, found: 242.0364.
1-(3-Chloropyridin-2-yl)-1-(4-N,N’-dimethylamino
phenyl)methanol (3e)
1-(3-Chloropyridin-2-yl)-1-(4-N,N’-dimethylaminophe-
nyl)methanol (3e) was prepared according to the general
method described herein with N,N’-dimethylaminoben-
zaldehyde (1192 mg, 8.0 mmol, 3.0 eq) as electrophile. Puri-
fication on silica gel was performed with a mixture hex-
ane/AcOEt : 8/2 and yielded the expected compound (3e)
(547 mg, 78%) as a white solid ; mp 125-127 °C ; 1H NMR
ꢀH 2.91 (s, 6H, N(CH3)2), 5.12 (d, J = 7.5 Hz, 1H, CHOH),
5.93 (d, J = 7.5 Hz, 1H, CHOH), 6.68 (d, J = 8.9 Hz, 2H,
HAr), 7.17-7.26 (m, 3H, H5, HAr), 7.66 (dd, J = 7.9 Hz, J’ =
1.4 Hz, 1H, H4), 8.54 (dd, J = 4.8 Hz, J’ = 1.4 Hz, 1H, H6) ;
13C NMR ꢀC 40.7 (N(CH3)2), 72.0 (CHOH), 112.5 (CAr),
123.6 (C5), 128.6 (CAr), 129.7 (CAr), 130.0 (C3), 137.8 (C4),
146.2 (C6), 150.3 (CAr-N), 158.3 (C2) ; IR (NaCl) ꢁ 3368,
2889, 1613, 1359, 1261 ; MS (EI) m/z 262 (M+, 36), 245
(18), 150 (100), 122 (12), 107 (7), 77 (7).
1-(3-Chloropyridin-2-yl)-1-(2-methoxyphenyl)methanol
(3b)
1-(3-Chloropyridin-2-yl)-1-(2-methoxyphenyl)methanol
(3b) was prepared according to the general method described
herein with o-anisaldehyde (1088 mg, 8.0 mmol, 3.0 eq) as
electrophile. Purification on silica gel was performed with a
mixture hexane/AcOEt : 8/2 and yielded the expected
pyridinyl compound (3b) (580 mg, 87%) as a white solid ;
mp 115-117 °C ; 1H NMR ꢀH 3.87 (s, 3H, O-CH3), 5.11 (d, J
= 6.5 Hz, 1H, CHOH), 6.41 (d, J = 6.5 Hz, 1H, CHOH),
6.82-6.92 (m, 3H, HAr), 7.20-7.28 (m, 2H, H5, HAr), 7.68 (dd,
J = 7.9 Hz, J’ = 1.4 Hz, 1H, H4), 8.56 (dd, J = 4.8 Hz, J’ =
1.4 Hz, 1H, H6) ; 13C NMR ꢀC 55.8 (O-CH3), 66.9 (CHOH),
111.2 (CAr), 120.7 (CAr), 123.6 (C5), 128.3 (CAr), 129.3 (CAr),
129.8 (CAr), 130.3 (C3), 138.0 (C4), 145.6 (C6), 157.7 (C2),
157.8 (CAr-O) ; IR (NaCl) ꢁ 3205, 1599, 1424, 1287, 1244 ;
MS (EI) m/z 249 (M+, 16), 218 (100), 136 (23), 107 (32), 77
(25). Anal. calcd for (C13H12NO2Cl) C : 62.53; H : 4.84; N :
5.61, Found C : 62.40; H : 4.79; N : 5.60.
1-(2-Bromophenyl)-1-(3-chloropyridin-2-yl)methanol (3f)
1-(2-Bromophenyl)-1-(3-chloropyridin-2-yl)methanol
(3f) was prepared according to the general method described
herein with 2-bromobenzaldehyde (1480 mg, 8.0 mmol, 3.0
eq) as electrophile. Purification on silica gel was performed
with a mixture hexane/AcOEt : 8/2 and yielded the expected
pyridinyl compound (3f) (590 mg, 74%) as a white solid ;
1-(3-Chloropyridin-2-yl)-1-(3-methoxyphenyl)methanol
(3c)
1
mp 127-131°C ; H NMR ꢀH 5.17 (s, 1H, CHOH), 6.41 (s,
1-(3-Chloropyridin-2-yl)-1-(3-methoxyphenyl)methanol
(3c) was prepared according to the general method described
herein with m-anisaldehyde (1088 mg, 8.0 mmol, 3.0 eq) as
electrophile. Purification on silica gel was performed with a
mixture hexane/AcOEt : 8/2 and yielded the expected
pyridinyl compound (3c) (586 mg, 88%) as a white solid ;
1H, CHOH), 6.82 (dd, J = 7.9 Hz, J’ = 1.9 Hz, 1H, HAr),
7.11-7.16 (m, 2H, H5, HAr), 7.31 (dd, J = 7.9 Hz, J’ = 4.8 Hz,
1H, HAr), 7.61 (d, J = 7.6 Hz, 1H, HAr), 7.70 (d, J = 7.6 Hz,
1H, H4), 8.59 (d, J = 4.6 Hz, 1H, H6) ; 13C NMR ꢀC 71.5
(CHOH), 124.1 (C5), 125.3 (CAr-Br), 127.8 (CAr), 128.8
(CAr), 129.6 (C3), 130.7 (CAr), 133.3 (CAr), 138.1 (C4), 140.7
(CAr), 145.8 (C6), 156.8 (C2) ; IR (NaCl) ꢁ 3200, 1590, 1410,
1280, 1250 ; MS (EI) m/z 298 (M+, 26), 283.1 (25), 282.5
1
mp 113-115 °C ; H NMR ꢀH 3.78 (s, 3H, O-CH3), 4.40-
4.51 (m, 1H, CHOH), 5.97 (s, 1H, CHOH), 6.72-7.02 (m,
3H, HAr), 7.17-7.25 (m, 2H, H5, HAr), 7.68 (dd, J = 7.9 Hz, J’
= 1.4 Hz, 1H, H4), 8.53 (dd, J = 4.8 Hz, J’ = 1.4 Hz, 1H, H6)
(18), 261 (100), 218 (8)
; ESI-HRMS calcd for
C12H9BrClNO (M+Na)+ : 319.9448, found: 319.9460.
;
13C NMR ꢀC 55.4 (O-CH3), 72.1 (CHOH), 113.4 (CAr),
1-(3-Chloropyridin-2-yl)prop-2-en-1-ol (4)
120.0 (CAr), 124.0 (C5), 129.6 (CAr), 130.2 (C3), 138.0 (C4),
143.5 (CAr), 146.4 (C6), 157.5 (C2), 159.8 (CAr-O) ; IR
1-(3-Chloropyridin-2-yl)prop-2-en-1-ol (4) was prepared
according to the general method described herein with ac-

54
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Comoy et al.
1-(3-Chloropyridin-2-yl)propan-1-ol (7)
roleine (448 mg, 8.0 mmol, 3.0 eq) as electrophile. Purifica-
tion on silica gel was performed with a mixture hex-
ane/AcOEt : 9/1 as eluent and yielded the expected cou-
The base [n-BuLi/LiDMAE] was prepared according to
the general procedure described herein with n-BuLi (10.0
mL, 16.0 mmol, 4.0 eq) and DMAE (0.8 mL, 8.0 mmol, 2.0
eq) in anhydrous hexane (25.0 mL). A solution of 3-
chloropyridine (2) (454 mg, 4.0 mmol, 1.0 eq) in hexane (5.0
mL) was then added. The reaction mixture was stirred for 1 h
at -45°C. After cooling at -78°C, a solution of propanal (580
mg, 10.0 mmol, 2.5 eq) in THF (10.0 mL) was added drop-
wise. After 3 h at -78°C, hydrolysis was performed with H2O
(15.0 mL), the aqueous phase was extracted with methylene
chloride (CH2Cl2) (2 x 20.0 mL). After drying (MgSO4),
filtration and solvent evaporation, the crude product was
purified by column chromatography on silica gel with a mix-
ture hexane/AcOEt : 8/2 as eluent. The expected compound
1
pound (4) (294 mg, 65%) as a yellow liquid ; H NMR ꢀH
4.65 (s, 1H, OH), 5.11 (d, J = 10.2 Hz, 1H, CHOH), 5.33-
5.43 (m, 2H, CH=CH2), 5.88-5.91 (m, 1H, CH=CH2), 7.16
(dd, J = 8.0 Hz, J’= 4.7 Hz, 1H, H5), 7.65 (dd, J = 8.0 Hz,
J’= 1.4 Hz, 1H, H4), 8.41 (d, J = 4.7 Hz, J =1.4 Hz, 1H, H6) ;
13C NMR ꢀC 71.1 (CHOH), 116.4 (CH2), 124.0 (C5), 132.0
(C3), 137.5 (C4), 138.0 (CH), 146.7 (C6), 157.0 (C2) ; IR
(NaCl) ꢁ 3600, 3100, 2850, 1600, 1250 ; MS (EI) m/z 169
(M+, 7), 152 (96), 113 (83), 78 (100) ; Anal. calcd for
C8H8ClNO C : 56.65; H : 4.75; N : 8.26 ; found C : 56.77 ;
H : 4.84; N : 8.16.
1-(3-Chloropyridin-2-yl)-3-methylbut-2-en-1-ol (5)
1
(7) (583 mg, 85%) was afforded as a colorless liquid ; H
1-(3-Chloropyridin-2-yl)-3-methylbut-2-en-1-ol (5) was
prepared according to the general method described herein
with 3,3-dimethylacroleine (672 mg, 8.0 mmol, 3.0 eq) as
electrophile. Purification on silica gel was performed with a
mixture hexane/AcOEt : 8/2 and yielded the expected com-
NMR ꢀH 0.99 (t, J = 7.5 Hz, 3H, CH2-CH3), 1.55-1.67 (m,
1H, CH2-CH3), 1.88-1.95 (m, 1H, CH2-CH3), 4.25 (d, J = 7.5
Hz, 1H, CHOH), 4.95-5.02 (m, 1H, CHOH), 7.20 (dd, J =
7.9 Hz, J’ = 4.8 Hz, 1H, H5), 7.70 (dd, J = 7.9 Hz, J’ = 1.4
Hz, 1H, H4), 8.50 (dd, J = 4.8 Hz, J’ = 1.4 Hz, 1H, H6) ; 13
C
1
pound (5) (411 mg, 78%) as a yellow liquid ; H NMR ꢀH
NMR ꢀC 9.6 (CH3), 29.9 (CH2), 71.0 (CH), 123.3 (C5), 135.9
(C3), 137.4 (C4), 146.2 (C6), 158.1 (C2) ; IR (NaCl) ꢁ 3300,
2965, 1399 ; MS (EI) m/z 172 ([M+1]+, 33), 154 (18), 142
(100), 114 (15), 78 (41), 51 (24).
1.74 (d, J = 1.4 Hz, 3H, CH3), 1.93 (d, J = 1.4 Hz, 3H, CH3),
4.65-4.85 (m, 1H, OH), 5.01-5.09 (m, 1H, CH=C), 5.65 (d, J
= 9.3 Hz, 1H, CHOH), 7.20 (dd, J = 7.9 Hz, J’= 4.8 Hz, 1H,
H5), 7.68 (dd, J = 7.9 Hz, J’ = 1.4 Hz, 1H, H4), 8.46 (dd, J =
4.8 Hz, J’ = 1.4 Hz, 1H, H6) ; 13C NMR ꢀC 18.4 (CH3), 25.7
(CH3), 67.0 (CHOH), 123.2 (C5), 124.5 (CH-C(CH3)2), 129.4
(C3), 136.8 (C4), 137.4 (C(CH3)2), 146.1 (C6), 158.1 (C2) ; IR
(NaCl) ꢁ 3418, 2914, 1428, 1274 ; MS (EI) m/z 198 ([M+1]+,
12), 196 (15), 180 (100), 164 (26), 142 (26), 113 (32), 78
(25), 51 (10).
Preparation of Functionalized Aldehydes (9a-c)
3-(t-Butyldiphenylsilanoxy)propan-1-ol (8a)
Preparation of 3-(t-butyldiphenylsilanoxy)propan-1-ol
(8a) is described in literature [14]. The spectroscopic data
are in conformity with literature.
1-(3-Chloropyridin-2-yl)-2-methylpropan-1-ol (6)
3-Hydroxypropyle 2,2-dimethylpropanoate (8b)
The base [n-BuLi/LiDMAE] was prepared according to
the general procedure described herein with n-BuLi (10.0
mL, 16.0 mmol, 4.0 eq) and DMAE (0.8 mL, 8.0 mmol, 2.0
eq) in anhydrous hexane (25.0 mL). A solution of 3-
chloropyridine (2) (454 mg, 4.0 mmol, 1.0 eq) in hexane (5.0
mL) was then added. The reaction mixture was stirred for 1 h
at -45°C. After cooling at -78°C, a solution of isobutyralde-
hyde (720mg, 10.0 mmol, 2.5 eq) in THF (10.0 mL) was
added dropwise. After 3 h at -78°C, hydrolysis was per-
formed with H2O (15.0 mL), the aqueous phase was ex-
tracted with methylene chloride (CH2Cl2) (2 x 20.0 mL).
After drying (MgSO4), filtration and solvent evaporation, the
crude product was purified by column chromatography on
silica gel with a mixture hexane/ AcOEt : 85/15 and yielded
the expected compound (6) (527 mg, 71%) as a yellow liq-
To a mixture of 1,3-propanediol (10.0 g, 131.6 mmol, 1.0
eq) and pyridine (26.0 g, 329.0 mmol, 2.5 eq) in CH2Cl2
(70.0 mL), at -10°C and under nitrogen atmosphere, was
added dropwise a solution of pivaloyle chloride (15.9 g,
131.6 mmol, 1.0 eq) in CH2Cl2 (30.0 mL). The reaction mix-
ture was stirred for 2 h at -10°C. After dilution with CH2Cl2
(100.0 mL), drying (MgSO4), filtration and solvent evapora-
tion, the crude product was purified by column chromatog-
raphy on silica gel (eluent hexane/AcOEt : 7/3) to yield the
expected derivative (8b) (14.3 g, 68%) as a colorless liquid ;
1H NMR ꢀH 1.21 (s, 9H, C(CH3)3), 1.87 (qu, J = 4.8 Hz, 2H,
CH2-CH2-CH2), 2.22-2.56 (m, 1H, CH2-OH), 3.68 (t, J = 5.8
Hz, 2H, CH2-OH), 4.23 (t, J = 4.8 Hz, 2H, CH2-O-) ; 13C
NMR ꢀC 27.2 (C(CH3)3), 31.8 (CH2-CH2-CH2), 38.8
(C(CH3)3), 58.9 (CH2OH), 61.4 (CH2-O-), 179.1 (O-CO) ;
IR (NaCl) ꢁ 3444, 2969, 1713, 1286, 1160 ; MS (EI) m/z
161 ([M+1]+, 16), 142 (12), 103 (14), 85 (11), 69 (6), 59
(10), 57 (100).
1
uid ; H NMR ꢀH (CDCl3, D2O) 0.73 (d, J = 6.8 Hz, 3H,
CH3), 1.11 (d, J = 6.8 Hz, 3H, CH3), 2.12-2.22 (m, 1H,
CH(CH3)2), 4.13-4.16 (m, 1H, CHOH), 7.20 (dd, J = 7.9 Hz,
J’ = 4.8 Hz, 1H, H5), 7.68 (dd, J = 7.9 Hz, J’= 1.4 Hz, 1H,
H4), 8.46 (dd, J = 4.8 Hz, J’ = 1.4 Hz, 1H, H6) ; 13C NMR ꢀC
15.3 (CH3), 19.9 (CH3), 33.0 (CH(CH3)2), 73.9 (CHOH),
123.2 (C5), 129.6 (C3), 137.4 (C4), 146.0 (C6), 158.5 (C2) ;
IR (NaCl) ꢁ 3448, 1578, 1289, 1254 ; MS (EI) m/z 186
([M+1]+, 3), 142 (100), 114 (12), 78 (37), 51 (22) ; ESI-
HRMS calcd for C9H12ClNO (M+Na)+ : 208.0500, found :
208.0515.
3-Benzoxypropan-1-ol (8c)
A solution of 1,3-propanediol (10.0 g, 131.6 mmol, 1.0
eq) in THF (10 mL) was added dropwise to a suspension of
freshly washed sodium hydride (NaH, 65% suspension in
mineral oil) (4.86 g, 131.6 mmol, 1.0 eq) in THF (10 mL) at
0°C under nitrogen atmosphere. After stirring for 1 h at 0°C,
benzyle bromide (22.5 g, 131.6 mmol, 1.0 eq) was added
dropwise. The reaction mixture was then stirred at room

Improved Condensation of 2-pyridyllithium Intermediates with Aldehydes
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
55
temperature overnight. The crude solution was then washed
with a saturated ammonium chloride solution, the aqueous
layer was extracted with Et2O (2 x 10.0 mL). After drying
(MgSO4), filtration and solvent evaporation, the crude prod-
uct was purified by column chromatography on silica gel
(eluent hexane/AcOEt : 5/5) to yield the expected 3-
benzoxypropan-1-ol (8c) (8.8 g, 40%) as a white gummy.
The spectroscopic data are in conformity with literature [15].
3-Hydroxy-3-(3-chloropyridin-2-yl)propyle 2,2-dimethyl
propanoate (10b)
3-Hydroxy-3-(3-chloropyridin-2-yl)propyle
2,2-di
methyl-propanoate (10b) is prepared according to the proce-
dure described above for the compound (7) using 3-
oxopropyle 2,2-dimethylpropanoate (9b) (1.58 g, 10.0 mmol,
2.5 eq). Purification on silica gel was performed with a mix-
ture hexane/AcOEt : 8/2 and yielded the expected pyridinyl
ester (10b) (467 mg, 43%) as a yellow gummy ; 1H NMR ꢀH
1.19 (s, 9H, C(CH3)3), 1.77-1.84 (m, 1H, CH2-CHOH), 2.16-
2.25 (m, 1H, CH2-CHOH), 4.29-4.38 (m, 3H, CHOH, CH2-
O-), 5.16 (dt, J = 8.6 Hz, J’ = 3.1 Hz, 1H, CHOH), 7.23 (dd,
J = 7.9 Hz, J’ = 4.8 Hz, 1H, H5), 7.70 (dd, J = 7.9 Hz, J’ =
1.4 Hz, 1H, H4), 8.48 (dd, J = 4.8 Hz, J’ = 1.4 Hz, 1H, H6) ;
13C NMR ꢀC 27.5 (C(CH3)3), 36.4 (C(CH3)3), 41.0 (CH2-
CHOH), 61.2 (CH2-O), 67.2 (CHOH), 124.0 (C5), 129.4
(C3), 137.9 (C4), 146.8 (C6), 158.5 (C2), 179.1 (O-CO) ; IR
(NaCl) ꢁ 3440, 2971, 1727, 1285, 1160 ; MS (EI) m/z 269
([M-2]+, 100), 254 (7), 167 (18), 140 (25), 77 (10), 57 (35).
3-(t-Butyldiphenylsilanoxy)propanal (9a)
Preparation of 3-(t-butyldiphenylsilanoxy)propanal (9a)
is described in literature [14]. The spectroscopic data are in
conformity with literature.
3-Oxopropyle 2,2-dimethylpropanoate (9b)
To a solution of IBX [16] (9.6 g, 34.4 mmol, 1.1 eq) in
DMSO (70.0 mL) was added derivative (8b) (5.0 g, 31.2
mmol, 1.0 eq) at one go, under nitrogen atmosphere. After
stirring for 18 h at RT, hydrolysis was performed with H2O
(70.0 mL), then the aqueous phase was extracted with Et2O
(2 x 200.0 mL). After drying (MgSO4), filtration and solvent
evaporation, the crude product was purified by column
chromatography on silica gel (eluent hexane/AcOEt : 7/3) to
yield the expected 3-oxopropyle 2,2-dimethylpropanoate
(9b) (3.65 g, 74%) as a colorless liquid ; 1H NMR ꢀH 1.19 (s,
9H, C(CH3)3), 2.77 (dt, J = 6.2 Hz, J’ = 1.7 Hz, 2H, CH2-
CHO), 4.41 (t, J = 6.2 Hz, 2H, CH2-O-), 9.80 (t, J = 1.7 Hz,
1H, CHO) ; 13C NMR ꢀC 27.2 (C(CH3)3), 38.8 (C(CH3)3),
42.9 (CH2CHO), 58.1 (CH2O), 179.1 (O-CO), 199.7 (CHO) ;
IR (NaCl) ꢁ 2975, 1729, 1284, 1157 ; MS (EI) m/z 159
([M+1]+, 13), 130 (7), 103 (4), 85 (9), 69 (10), 57 (100).
3-Benzyloxy-1-(3-chloropyridin-2-yl)propan-1-ol (10c)
3-Benzyloxy-1-(3-chloropyridin-2-yl)propan-1-ol (10c)
was prepared according to the procedure described above for
the compound (7) using 3-benzoxypropanal (9c) (1.64 g,
10.0 mmol, 2.5 eq). Purification on silica gel was performed
with a mixture hexane/Et2O : 9/1 and yielded the expected
1
pyridinyl ether (10c) (445 mg, 40%) as a yellow liquid ; H
NMR ꢀH 1.77-1.94 (m, 1H, CH2CH2OBn), 2.17-2.33 (m, 1H,
CH2CH2OBn), 3.63-3.86 (m, 2H, CH2CH2OBn), 4.30-4.40
(m, 1H, CHOH), 4.52 (s, 2H, OCH2Ph), 5.22-5.25 (m, 1H,
CHOH), 7.20 (dd, J = 7.9 Hz, J’ = 4.8 Hz, 1H, H5), 7.26-
7.34 (m, 5H, HAr), 7.70 (dd, J = 7.9 Hz, J’ = 1.4 Hz, 1H, H4),
8.47 (dd, J = 4.8 Hz, J’ = 1.4 Hz, 1H, H6) ; 13C NMR ꢀC 37.0
(CHCH2), 67.2 (CH2CH2O), 68.0 (CHOH), 73.5 (OCH2Ph),
123.7 (C5), 127.7 (CHAr), 127.8 (CHAr), 128.6 (CHAr), 129.5
(C3), 137.7 (C4), 138.8 (CAr), 146.6 (C6), 158.9 (C2) ; IR
(NaCl) ꢁ 3435, 2860, 1688, 1264, 1099 ; MS (EI) m/z 277
[M+, 1), 242 (6), 143 (100), 127 (19), 91 (40).
3-Benzoxypropanal (9c)
3-Benzoxypropanal (9c) is prepared according to the pro-
cedure described above for the aldehyde (9b) using com-
pound (8c) (4.15 g, 25.0 mmol, 1.0 eq) and IBX (7.7 g, 27.5
mmol, 1.1 eq). Purification on silica gel was performed with
a mixture hexane/AcOEt : 7/3 and yielded the expected 3-
benzoxypropanal (9c) (3.48 g, 85%) as a yellow liquid. The
spectroscopic data are in conformity with literature [15].
1-(3-Chloropyridin-2-yl)propan-1,3-diol (1a)
3-(t-Butyldiphenylsilanoxy)-1-(3-chloropyridin-2-yl) pro-
pan-1-ol (10a)
A suspension of potassium t-butyloxyde (974 mg, 8.7
mmol, 8.7 eq) in H2O (40 ꢂL, 2.2 mmol, 2.2 eq) and Et2O
(17.0 mL) was cooled at 0°C. After stirring for 5 min at 0°C,
ester (10b) (271 mg, 1.0 mmol, 1.0 eq) was added. The reac-
tion medium was stirred at RT for 3h. Then, the reaction
solution was washed with iced water and the aqueous phase
was neutralized using a HCl solution then a saturated Na-
HCO3 aqueous solution. After extraction with CH2Cl2 (3 x
20 mL), drying (MgSO4), filtration and solvent evaporation,
the crude product was purified by column chromatography
on silica gel (eluent hexane/AcOEt : 3/7) to afford the ex-
pected diol (1a) (151 mg, 81%) as a brown solid ; mp 101-
3-(t-Butyldiphenylsilanoxy)-1-(3-chloropyridin-2-yl)-
propan-1-ol (10a) was prepared according to the procedure
described above for the compound (7) using 3-(t-
butyldiphenylsilanoxy)propanal (9a) (3.12 g, 10.0 mmol, 2.5
eq). Purification on silica gel was performed with a mixture
hexane/AcOEt : 9/1 and yielded the expected pyridinyl de-
1
rivative (10a) (752 mg, 44%) as a white gummy; H NMR
ꢀH 1.06 (s, 9H, C(CH3)3), 1.59-1.76 (m, 1H, CH2CH2OSi),
2.04-2.20 (m, 1H, CH2-CH2OSi), 3.77-3.85 (m, 1H,
CH2CH2OSi), 3.94-4.05 (m, 1H, CH2CH2OSi), 4.27 (d, J =
7.5 Hz, 1H, CHOH), 5.32 (dt, J = 8.7 Hz, J’ = 2.4 Hz, 1H,
CHOH), 7.17 (dd, J = 7.9 Hz, J’ = 4.8 Hz, 1H, H5), 7.32-
7.36 (m, 6H, HAr), 7.60-7.70 (m, 5H, HAr, H4), 8.45 (dd, J =
4.8 Hz, J’ = 1.4 Hz, 1H, H6) ; 13C NMR ꢀC 19.5
(SiC(CH3)3), 27.2 (CH3), 40.0 (CH2-CH2OSi), 61.1 (CH2-
CH2OSi), 67.7 (CH-OH), 123.7 (C5), 128.0 (CHAr), 129.9
(C3), 134.1 (CAr), 135.9 (CHAr), 137.8 (C4), 146.7 (C6), 159.3
(C2) ; IR (NaCl) ꢁ 3445, 1589, 1428, 1263, 1110 ; MS (EI)
m/z 313 (3), 229 (16), 199 (100), 181 (9), 77 (10), 55 (25).
1
103 °C ; H NMR ꢀH 1.64-1.84 (m, 1H, CH2CH2OH), 2.11-
2.27 (m, 1H, CH2CH2OH), 2.70-2.92 (s, 1H, CH2OH), 3.80-
4.08 (m, 2H, CH2CH2OH), 4.62-4.80 (s, 1H, CHOH), 5.16-
5.32 (s, 1H, CHOH), 7.24 (dd, J = 7.9 Hz, J = 4.8 Hz, 1H,
H5), 7.71 (dd, J = 7.9 Hz, J’ = 1.4 Hz, 1H, H4), 8.49 (dd, J =
4.8 Hz, J’ = 1.4 Hz, 1H, H6) ; 13C NMR ꢀC 38.7 (CH2), 61.2
(CH2O), 69.9 (CHOH), 123.8 (C5), 129.1 (C3), 137.8 (C4),
146.4 (C6), 158.1 (C2) ; IR (NaCl) ꢁ 3313, 1577, 1417, 1261,
1174 ; MS (EI) m/z 187 (M+, 1), 156 (8), 142 (100), 113

56
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Comoy et al.
(16), 78 (20) ; ESI-HRMS calcd for C8H10ClNO2 (M+Na)+ :
1-(3-Chloropyridin-2-yl)propan-1,2,3-triol (1b)
210.0311, found: 210.0292.
To a solution of compound (12) (151 mg, 0.61 mmol) in
MeOH (3 mL) was added CBr4 (20 mg, 10%). The mixture
was then refluxed during 18h. After evaporation of the sol-
vent and chromatography on silica gel (eluent
CH2Cl2/MeOH : 95/5), the expected triol (1b) was obtained
as a white solid (124 mg, quantitative yield) : mp 129-
131°C; 1H NMR (MeOH-d4) ꢀH 3.69-3.85 (m, 2H, CH2OH),
3.97-4.07 (m, 1H, CHOH), 5.18 (d, J = 7.1 Hz 1H, CHOH),
7.32 (dd, J = 8.0 Hz, J’ = 4.8 Hz, 1H, H5), 7.84 (dd, J = 8.0
Hz, J’ = 1.6 Hz, 1H, H4), 8.52 (dd, J = 4.8 Hz, J’ = 1.6 Hz,
1H, H6) ; 13C NMR ꢀC 64.3 (CH2OH), 71.6 (CHOH), 75.5
(CHOH), 125.1 (C5), 132. 7 (C3), 138.8 (C4), 148.4 (C6),
158.7 (C2) ; IR (NaCl) ꢂ 3390, 1583, 1086, 1038 ; MS (CI)
m/z 204 ([M + 1]+, 9), 172 (13), 156 (11), 142 (100), 114
(15), 78 (42) ; ESI-HRMS calcd for C8H10ClNO3 (M+Na)+ :
226.0241, found : 226.0259.
3-Chloro-2-(methoxymethoxyprop-2-en-1-yl)pyridine (11)
A solution of 1-(3-chloropyridin-2-yl)prop-2-en-1-ol (4)
(225 mg, 1.33 mmol, 1.0 eq) in a mixture THF (15.0 mL) /
HMPT (0.53 mL, 2.93 mmol, 2.2 eq) was cooled at -30°C
under nitrogen atmosphere. Then n-BuLi (1.1 mL, 1.73
mmol, 1.3 eq) was added dropwise, the reaction medium was
stirred for 1 h at 0°C. Methoxymethyle chloride (0.13 mL,
1.73 mmol, 1.3 eq) was added carefully, then the reaction
solution was stirred for 4 h at RT. Hydrolysis was performed
with a saturated NaHCO3 solution (10.0 mL), the aqueous
phase was extracted using CH2Cl2 (3 x 10.0 mL). After dry-
ing (MgSO4), filtration and solvent evaporation, the crude
product (11) was used without purification in the next step.
An analytical quantity was purified for spectroscopic data ;
1H NMR ꢀH 3.36 (s, 3H, CH3), 4.67 (d, J = 6.8 Hz, 1H,
CH2O), 4.85 (d, J = 6.8 Hz, 1H, CH2O), 5.33 (d, J = 10.2 Hz,
1H, CHO), 5.46 (d, J = 17.2 Hz, 1H, CH2=CH), 5.69 (d, J =
7.2 Hz, 1H, CH2=CH), 6.06-6.15 (m, 1H, CH=CH2), 7.20
(dd, J = 8.1 Hz, J’ = 4.6, 1H, H5), 7.70 (dd, J = 8.1 Hz, J’ =
1.3 Hz, 1H, H4), 8.58 (dd, J = 4.6 Hz, J’ = 1.3 Hz, 1H, H6).
ACKNOWLEDGEMENTS
We gratefully acknowledge financial support from CNRS
and Nancy-Université, UHP. We thank Sandrine Adach and
François Dupire for performing elemental analyses and re-
cording mass spectra.
3-(3-Chloropyridin-2-yl)-3-methoxymethoxypropane-1,2-
diol (12)
Potassium ferrocyanate K3FeCN6 (1.316 g, 4.0 mmol, 3.0
eq) and potassium carbonate K2CO3 (552 mg, 4.0 mmol, 3.0
REFERENCES
[1]
Clayden, J. Tetrahedron Organic Chemistry Series - Organolithi-
ums: Selectivity for Synthesis: EdPergamon, 2002; Vol. 23.
Voitenko, Z.V.; Kysil, A.I.; Wolf, J.G. C. R. Chimie, 2007, 10, 813.
Granander, J.; Eriksson, J.; Hilmersson, G. Tetrahedron Asymme-
try, 2006, 17, 2021.
eq) were added to
a
solution of 3-chloro-2-
(methoxymethoxyprop-2-en-1-yl)pyridine (11) (284 mg,
1.33 mmol, 1.0 eq) in a mixture t-butanol (20.0 mL) and
water (20.0 mL). Then osmium tetroxide (OsO4) was added
carefully (2.5wt% solution in t-butanol, 0.71 mL, 54 ꢁmol,
0.04 eq). The reaction solution was allowed to stir for 24 h at
RT, then the reaction was quenched by addition of solid
Na2SO3 until saturation and a saturated aqueous solution of
Na2SO3 (20.0 mL). The aqueous phase was extracted with
CH2Cl2 (3 x 20.0 mL). After drying (MgSO4), filtration and
solvent evaporation, the crude product was purified by col-
umn chromatography on silica gel (eluent hexane/AcOEt:
7/3). The expected compound (12) (270 mg, 82%) was ob-
[2]
[3]
[4]
Fort, Y.; Gros, P.; Rodriguez, A. Tetrahedron Asymmetry, 2001,
12, 2631.
[5]
[6]
Gros, P.; Fort, Y. Eur. J. Org. Chem., 2002, 20, 3375.
Desmarets, C.; Schneider, R.; Fort, Y. Tetrahedron Lett., 2001, 42,
247.
[7]
[8]
Comoy, C.; Banaszak, E.; Fort, Y. Tetrahedron, 2006, 62, 6036.
Banaszak, E.; Comoy, C.; Fort, Y. Tetrahedron Lett., 2006, 47,
6235.
[9]
[10]
Choppin, S.; Gros, P.; Fort, Y. Eur. J. Org. Chem., 2001, 4, 603.
Gros, P.; Choppin, S.; Mathieu, J.; Fort, Y. J. Org. Chem., 2002,
67, 234.
1
[11]
[12]
Gassman, P.G.; Schenk, W.N. J. Org. Chem., 1977, 42, 918.
Sammakia, T.; Hurley, T.B.; Sammond, D.M.; Smith, R.S.;
Sobolov, S.B.; Oeschberg, T.R. Tetrahedron Lett., 1996, 37, 4427.
Shih-Yuan Lee, A.; Hu, Y.-J.; Chu, S.-F. Tetrahedron, 2001, 57,
2121.
(a) Holmes, A.; Hughes, A.; Smith, A. J. Chem. Soc. Perkin Trans.
1, 1993, 1, 633 ; (b) Caprio, V.; Brimble, M.A.; Furkert, D.P. Tet-
rahedron, 2001, 57, 4023.
tained as a white amorphous solid ; H NMR ꢀH 2.52-2.66
(m, 2H, OH), 3.31 (s, 3H, CH3), 3.74 (dd, J = 5.1 Hz, J’ =
1.3 Hz, 2H, CH2OH), 4.16-4.25 (m, 1H, CHOH), 4.62 (d, J =
6.8 Hz, 1H, CH2OCH3), 4.73 (d, J = 6.8 Hz, 1H, CH2OCH3),
5.35 (d, J = 5.1 Hz, 1H, CH-O), 7.23 (dd, J = 7.9 Hz, J’ =
4.8 Hz, 1H, H5), 7.73 (dd, J = 7.9 Hz, J’ = 1.4 Hz, 1H, H4),
8.55 (dd, J = 4.8 Hz, J’ = 1.4 Hz, 1H, H6) ; 13C NMR ꢀC 56.1
(CH3), 63.6 (CH2OH), 73.6 (CH-O), 75.4 (CH-O), 96.3 (O-
CH2-O), 124.2 (C5), 132.3 (C3), 137.9 (C4), 147.6 (C6), 155.3
(C2) ; IR (NaCl) ꢂ 3553, 3206 ; MS (EI) m/z 244 ([M-3]+, 1),
230 (2), 214 (4), 187 (6), 156 (12), 142 (100), 117 (58), 89
(22), 78 (14), 59 (17).
[13]
[14]
[15]
[16]
(a) Davies, F.; Qi, H. Tetrahedron Lett., 1996, 37, 4345; (b) Cheng,
H.S.; Loh, T.P. J. Am. Chem. Soc., 2003, 125, 4990.
(a) Dess, D.B.; Martin, J.C. J. Org. Chem., 1983, 48, 4155; (b)
Ireland, R.E.; Liu, L. J. Org. Chem., 1993, 58, 289.