A practical synthesis of 4-chloro-3-(hydroxymethyl)pyridine by regioselective one-pot lithiation/formylation/reduction of 4-chloropyridine

Article abstract of DOI:10.1055/s-1999-3551

4-Chloro-3-(hydroxymethyl)pyridine was prepared and isolated as its hydrochloride in 85% yield from 4-chloropyridine by formylation with dimethylformamide of the corresponding 3-lithium salt, followed by in situ reduction of the resulting 4-chloro-3-formylpyridine through a crossed- Cannizzaro reaction with aqueous formaldehyde.

Full text of DOI:10.1055/s-1999-3551

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Domenico Albanese,a Michele Penso,*a Maurizio Zenonib
a CNR-CSSSSO and Dipartimento di Chimica Organica e Industriale dell'Università, Via Golgi 19, I-20133 Milano, Italy
Fax +39(2)2364369; Eꢀmail: michele.penso@unimi.it
b ACSꢀDobfar, Via Addetta 8, I-20067 Tribiano, Italy
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$EVWUDFWꢊ4-Chloro-3-(hydroxymethyl)pyridine was prepared and
isolated as its hydrochloride in 85% yield from 4-chloropyridine by
formylation with dimethylformamide of the corresponding 3-lithi-
um salt, followed by in situ reduction of the resulting 4-chloro-3-
formylpyridine through a crossed-Cannizzaro reaction with aque-
ous formaldehyde.
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.H\ꢄZRUGVꢊꢄ4-Chloro-3-hydroxymethylpyridine, crossed Canniz-
zaro reaction, regioselective lithiation, aromatic formylation, 4-
chloro-3-formylpyridine
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4-Chloro-3-(hydroxymethyl)pyridine ꢇꢋꢈ can be used as a
starting material for the preparation of several polyfunc-
tionalized molecules which can be linked to cephalospor-
ins, generating a new class of antibiotics that show
interesting antimicrobial activities.1,2
a) H2SO4-HNO3, ∆; 83%. b) PCl3, CHCl3, ∆; 81%. c) KHCO3, H2O,
0 °C; 100%. d) KMnO4, H2O, 90 °C; 41%. e) LDA, THF, CO2 gas, -78 °C.
f) HCl aq, 89% from 4. g) SOCl2, ∆. h) MeOH, 0-20 °C; 90%.
i) LAH, Et2O, 0 °C.
To our surprise, a literature search revealed only few re-
ports on the synthesis of the target compound ꢋ or its di-
rect precursor, e.g. methyl 4-chloronicotinate ꢇꢌꢈ. One
procedure3 involves the use of 3-picoline Iꢀoxide ꢇꢀꢈꢄas a
cheap starting material, which is transformed into methyl
4-chloronicotinate ꢇꢌꢈꢄ through the steps described in
Scheme 1. Even if this synthesis is easy to conduct on a
laboratory scale, it does not result in a viable process as a
consequence of the low overall yield obtained. An alterna-
tive route to ꢌꢄis the selective C-3 lithiation of 4-chloropy-
ridine ꢇꢃꢈ with lithium diisopropylamide (LDA) in THF at
–78 °C and carboxylation with anhydrous carbon dioxide
to give 4-chloronicotinic acid ꢇꢆꢈ,4 followed by esterifica-
tion. The last and crucial step of both procedures is the re-
duction of ꢌ with lithium aluminum hydride.5 After
several attempts to optimize this reaction we concluded
that methyl 4-chloronicotinate ꢇꢌꢈ, due to its low stability,
is not a good starting material for the preparation of ꢋ. Ac-
tually, ꢌꢄpolymerizesꢄvery rapidly and the reduction, re-
ported to proceed in 74% yield,5 gave in our hands only
lower yields of an impure product.
by treating ꢃ with LDA (1.1 mol equiv) in THF at –78 °C,
was carried out by addition of 1.23 mol equivalents of
DMF at –78 °C followed by quenching with water. Under
these reaction conditions the only product recovered from
the organic layer after extraction with dichloromethane
and standard aqueous workup, although in low yield
(< 50%), is the desired alcohol ꢋ. This alcohol, together
with the lithium salt of 4-chloronicotinic acid (recovered
from the aqueous layer), are derived from the intermediate
aldehyde ꢎꢄ through a Cannizzaro disproportionation
which is promoted by the aqueous LiOH formed by the
hydrolysis of LDA.7 Although the synthetic utility of this
process is limited because only 50% of the aldehyde can
form the corresponding alcohol, the yield can be greatly
improved by quenching the reaction mixture with an alde-
hyde more reactive than ꢎ. The formylation step was
therefore followed by the addition of an aqueous 40% (w/
v) formaldehyde solution (1.5 mol equiv). Formaldehyde
participates in the reduction of the generated aldehyde ꢎ
through a crossed Cannizzaro reaction,8,9 producing lithi-
um formate as byproduct.
Gribble and Saulnier6 had reported the regioselective sily-
lation of 4-chloropyridine at C-3 position to give 4-chlo-
ro-3-trimethylsilylpyridine in 92% yield by lithiation with
LDA and reaction with trimethylsilyl chloride. We could
therefore devise a more efficient route to ꢋ via the regiose-
lective lithiation of ꢃ with LDA4 followed by formylation
affording directly ꢋ. In an initial experiment the formyla-
tion of ꢍꢄ(Scheme 2), prepared as previously described4,6
After extraction with dichloromethane and standard aque-
ous workup, the pyridine hydrochloride ꢂ was prepared by
treatment with anhydrous hydrogen chloride at 0 °C in an
overall yield of 85%. Finally, the free base ꢋ was obtained
Synthesis 1999, No. 8, 1294–1296 ISSN 0039-7881 © Thieme Stuttgart · New York

6+257ꢄ3$3(5
A Practical Synthesis of 4-Chloro-3-(hydroxymethyl)pyridine
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a dropping funnel with a pressure-equalizing side tube. The appara-
tus was cooled to –78 °C with a dry ice-acetone bath and a 2 M LDA
solution in THF (58 mL, 0.116 mol) was introduced via a cannula
and vigorously stirred under argon for 10 min. A solution of 4-chlo-
ropyridine ꢇꢃ; 11.94 g, 0.105 mol) in anhyd THF (50 mL) was added
dropwise over 15 min and the mixture became orange/brick red co-
loured. After stirring for 1 h at –78 °C, anhyd DMF (10 mL, 0.129
mol) was added by a syringe over 12 min and the mixture was
stirred for 1 h. The conversion of the substrate ꢃ into the aldehyde ꢎ
was monitored by 1H NMR analysis as follows. A sample (200 mL)
was diluted with Et2O (200 mL) and hydrolyzed with H2O (200 mL),
the organic phase was separated, dried over molecular sieves (0.4
nm) and evaporated at 30 °C, diluted with CDCl3 (0.7 mL) and its
1H NMR spectrum was recorded.
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Cl
Cl
Li
CHO
a
b
N
4
N
7
N
8
Cl
Cl
CH2OH
CH2OH
c, d
[8]
e
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N
HCl
9
N
6
1H NMR (CDCl3/TMS): d = 7.41 (d, 1 H, E = 5.4 Hz), 8.65 (d, 1 H,
E = 5.4 Hz), 9.02 (s, 1 H), 10.48 (s, 1 H).
a) LDA, THF, -78 °C, 1 h. b) DMF, -78 °C, 1 h. c) CH2O, H2O, 25 °C, 1.5 h.
d) HClgas, CH2Cl2, 0 °C, 15 min. e) KHCO3, H2O, 0 °C; 100%
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After completion of the formylation, an aqueous solution (40% w/
v) of formaldehyde (12 mL, 0.158 mol) was added at once, the tem-
perature was allowed to rise to 25 °C and the mixture was vigorous-
ly stirred at this temperature for 90 min. The liquid phase was
decanted and the remaining solid was washed with CH2Cl2 (2 x 20
mL) by decanting the CH2Cl2. The organic-aqueous mixture thus
obtained was evaporated at 50 °C under vacuum (20 mbar) then at
20 °C (0.001 mbar). The residue was dissolved in CH2Cl2 (150 mL)
and washed with H2O (4 x 20 mL) and half saturated NaCl solution
(40 mL), dried (MgSO4) and evaporated under vacuum to 70 mL.
This solution was cooled in an ice bath to 0 °C and anhyd gaseous
HCl was bubbled in for 15 min. After 3–4 min light brown crystals
formed and were filtered after 30 min, washed with ice cold CH2Cl2
(20 mL) and dried under vacuum (20 mbar) at 40 °C; yield:16.0 g
(85%); mp 145 °C.
in quantitative yield by treatment of an aqueous solution
of ꢂ with potassium hydrogen carbonate.
4-Chloro-3-formylpyridine ꢇꢎꢈ can be obtained from the
crude product of the formylation reaction by acidification
with aqueous 10% acetic acid, extraction with dichlo-
romethane and usual aqueous workup. The crude alde-
hyde ꢎ was characterised by 1H NMR analysis, but it was
unstable and hence was not subjected to further purifica-
tion.
In conclusion we have developed a large scale, high yield,
one-pot procedure for the preparation of 4-chloro-3-hy-
droxymethylpyridine ꢇꢋꢈ, using a combination of direct
regioselective lithiation/formylation and crossed Canniz-
zaro reduction of 4-chloropyridine ꢇꢃꢈ.
1H NMR (DMSOꢀq6): d = 4.67 (s, 2 H), 6.12 (br s, 2 H), 8.18 (d, 1
H, E = 6.1 Hz), 8.79 (s, 1 H), 8.83 (d, 1 H, E = 6.1 Hz).
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A sample of the hydrochloride ꢂ was dissolved in cold H2O and neu-
tralized with 1 equivalent of KHCO3. The free base ꢋ was recovered
in quantitative yield by extraction with CH2Cl2, drying (MgSO4)
and evaporation of the solvent under vacuum; mp 82–83 °C.
1H NMR (CDCl3/TMS): d = 2.69 (br s, 1 H), 4.81 (s, 2 H), 7.29 (d,
1 H, E = 5.3 Hz), 8.40 (d, 1 H, E = 5.3 Hz), 8.65 (s, 1 H).
Commercial 4-chloropyridine hydrochloride was used as pur-
chased. A commercial 2 M solution of lithium diisopropylamide
(LDA) in THF was used. Commercial solvents were of anal grade:
THF (H2O ≤ 0.05%) and DMF (H2O ≤ 0.01%). Melting points were
1
determined on a Büchi 535 apparatus and are corrected. H NMR
spectra were recorded on a Bruker WP 80 SY or 300 AC spectrom-
eter using TMS as external reference; d are in ppm and E values are
in Hz. GC/MS analyses were performed on a HP5 (30 m x 0.25 mm,
0.25 mm) column, using a Varian Saturn 3 detector.
GC/MS (EI): m/z = 144.
Anal. calcd for C6H6ClNO: C, 50.19; H, 4.21; N, 9.76. Found: C,
50.11; H, 4.26; N, 9.85.
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To a solution of KHCO3 (20 g, 0.2 mol) in distilled H2O (40 mL)
cooled at 0 °C was added portionwise 4-chloropyridine hydrochlo-
ride (30 g, 0.2 mol) over 10 min. The heterogeneous mixture was
extracted with CH2Cl2 (5 x 30 mL). The combined organic phases
were washed with brine (10 mL) and dried (MgSO4). After evapo-
ration of the solvent under vacuum (40 mbar) at 20 °C, the free base
ꢃ (21.86 g, 96%) was obtained as an oil.
1H NMR (CDCl3/TMS): d = 7.25 (d, 2 H, E = 4.8 Hz), 8.46 (d, 2 H,
E = 4.8 Hz).
1H NMR (DMSOꢀq6/TMS): d = 7.45 (dd, 2 H, E = 1.5, 4.6 Hz), 8.54
(dd, 2 H, E = 1.5, 4.6 Hz).
Financial support by MURST and CNR is gratefully acknowledged.
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(1) Kawabata, K.; Yamamoto, H.; Eikyu, Y.; Okuda, S.;
Takasugi, H. W.O. Patent 12 889 ꢀꢂꢂꢍ; 8ur€ꢃꢁ6i†‡ꢂꢃ ꢀꢂꢂꢍ,
!%, 293 226.
(2) Cho, I.-S.; Hecker, S.; Glinka, T. W.O. Patent 13 772 ꢀꢂꢂꢍ;
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(3) Leroy, F.; Després, P.; Bigan, M.; Blondeau, D. T’‡uꢃꢁ
8‚€€ˆꢃꢁꢀꢂꢂꢋ, !%, 2257.
(4) Guillier, F.; Nivoliers, F.; Godard, A.; Marsais, F.; Quéguiner,
G.; Siddiqui, M. A.; Snieckus, V. EꢃꢁPꢂtꢃꢁ8ur€ꢃꢄꢀꢂꢂꢌ, %ꢄ, 292.
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8ur€ꢃ ꢀꢂꢍꢆ, "', 3268.
ꢃꢅ&KORURꢅꢆꢅIRUP\OS\ULGLQHꢄꢇꢎꢈꢄ
A 500 mL 4-necked round bottomed flask was dried at 110 °C for 1
h and then allowed to cool to r.t. under argon. The flask was assem-
bled with a mechanical stirrer, an argon inlet, a rubber septum and
Synthesis 1999, No. 8, 1294–1296 ISSN 0039-7881 © Thieme Stuttgart · New York

ꢀꢁꢂꢋ
D. Albanese et al.
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(6) Gribble, G. W.; Saulnier, M. G. Ur‡ꢂhurqꢂ‚ꢁGr‡‡ꢃ ꢀꢂꢎꢏ, ! ,
4137.
(7) Geissman, T. A. PꢂtꢃꢁSrhp‡ꢃ ꢀꢂꢃꢃ, !, 94.
(8) Ref. 7, p 109.
Article Identifier:
1437-210X,E;1999,0,08,1294,1296,ftx,en;H01899SS.pdf
(9) Davidson, D.; Weiss, M. PꢂtꢃꢁT’‡uꢃꢅꢁ8‚yyꢃꢁW‚yꢃꢁ$ ꢀꢂꢍꢆ, 590.
Synthesis 1999, No. 8, 1294–1296 ISSN 0039-7881 © Thieme Stuttgart · New York