An improved synthesis of pyridoxine via [2+2+2] cyclization of acetylenes and nitriles

Article abstract of DOI:10.1055/s-2005-864834

An improved synthesis of pyridoxine (vitamin B₆) is reported. The key step involves the light-promoted [2+2+2] cyclization of 3,3-bissilyl-di-2-propynyl ethers and acetonitrile in the presence of [cpCo(cod)] (1 mol%) as a catalyst. Convenient oxidation and iodination procedures are elaborated to transfer 3-silylpyridines into corresponding 3-hydroxy- and 3-iodo-derivatives.

Full text of DOI:10.1055/s-2005-864834

1188
LETTER
An Improved Synthesis of Pyridoxine via [2+2+2] Cyclization of Acetylenes
and Nitriles
An
Improved
Synt
n
hesis of Pyri
d
doxine via [2
r
+2+2]
C
e
yclization
o
y
f
A
cetylenes and N
G
itriles utnov,a Vladimir Abaev,a Dmitry Redkin,a Christine Fischer,a Werner Bonrath,b Barbara Heller*a
a
Leibniz-Institut für Organische Katalyse an der Universität Rostock e.V., Buchbinderstrasse 5–6, 18055 Rostock, Germany
Fax +49(381)4669324; E-mail: barbara.heller@ifok.uni-rostock.de
b
DSM Nutritional Products Ltd. 214/0.71, Wurmisweg 576, 4303 Kaiseraugst, Switzerland
Received 21 December 2004
source of energy for the catalyst activation which allows
to carry out the reaction under mild conditions: ambient
temperature and pressure, possibility to use water as a re-
action medium, substrate to catalyst ratio up to 10000:1.
Abstract: An improved synthesis of pyridoxine (vitamin B6) is re-
ported. The key step involves the light-promoted [2+2+2] cycliza-
tion of 3,3-bissilyl-di-2-propynyl ethers and acetonitrile in the
presence of [cpCo(cod)] (1 mol%) as a catalyst. Convenient oxida-
tion and iodination procedures are elaborated to transfer 3-silyl- The method might provide a basis for the improved
pyridines into corresponding 3-hydroxy- and 3-iodo-derivatives.
preparation of silylated pyridines. On the other hand, we
envisaged a possibility to use organosilicon groups other
than (CH3)3Si as a masked equivalent of hydroxy group.
As it was recently reviewed,5 alkoxy-containing (OR)nR-
Si groups undergo the oxidation sufficiently easier than
R3Si ones in many cases. That fact could ease the task of
the direct oxidation of sensitive substrates like pyridoxine
precursors.
Key words: pyridines, alkynes, nitriles, cyclizations, vitamins
Since the discovery of the Co(I)-catalyzed [2+2+2] cy-
clization of acetylenes and nitriles,1 many attempts were
made to employ this reaction for the synthesis of impor-
tant natural pyridine derivatives. In particular, two groups
(Schleich et al.2 and Vollhardt et al.3) reported indepen-
dently from each other on the synthesis of pyridoxine (vi-
tamin B6) almost simultaneously in the mid 1980s.
To prove this hypothesis, we prepared 3,3-bis(dimethyl-
isopropoxysilyl)-di-2-propynyl ether (1) through the di-
lithiation of dipropargyl ether followed by treatment
with chlorodimethylisopropoxysilane6 (Scheme 1). The
disilylated product 1 was isolated with good yield (60%)
along with some amount (6%) of the monosilylated
product 2.
The key steps of both approaches included the cobalt-cat-
alyzed (with cobaltocene or [cpCo(CO)2] as catalysts)
[2+2+2] cyclization of dimetalated dipropargyl ethers and
acetonitrile under harsh conditions (under pressure or at
139 °C), which sometimes led to reasonable decomposi-
tion of starting acetylenes and ultimate pyridines during
the reaction. Subsequent selective protiodesilylation of
(CH3)3Si or (CH3)3Sn groups in position 6 of the 3,6-di-
metalated products furnished 3-monometalated pyridines.
The last step of both methods, an oxidation of the Si(Sn)–
C bond, also caused some difficulties because of many
side reactions with the strained oxygen-containing anel-
lated ring. Although the total yields of pyridoxine did not
exceed 6%, it is a fundamental result to demonstrate the
principal possibility of vitamin B6 preparation via the
[2+2+2] cyclization.
2 BuLi,
O
2 (CH3)2(Oi-Pr)SiCl
Si
Si O
+
O
O
O
Et2O
Si
O
1
2
Scheme 1 Preparation of 3,3-bis(dimethylisopropoxysilyl)-di-2-
propynyl ether (1)
Having the disilylated ether 1 in hands, we investigated its
The aim of our project was to modify the substrates and [2+2+2] cyclization with acetonitrile in the presence of
conditions of the Co(I)-catalyzed [2+2+2] cyclization as [cpCo(cod)] (Scheme 2).
well as to elaborate practical synthetic procedures for the
oxidation of Si-C bond in pyridoxine-like compounds.
Our recent studies of the h5-cyclopentadienyl-h4-cyclooc-
ta-1,5-diene-cobalt(I) [cpCo(cod)]-catalyzed [2+2+2] cy-
clization of acetylenes and nitriles into pyridine core led
to the elaboration of highly efficient procedure for the re-
action.4 The irradiation with visible light (l = 350–500
nm) or, alternatively, sun light was found to be a powerful
O
O
Si
O
hv MeCN
Si
O
[cpCo(cod)], hexane
Si
O
N
Si
O
3
1
(81%)
Scheme 2 [2+2+2] Cyclization to disilylated pyridine 3
SYNLETT 2005, No. 7, pp 1188–1190
0
2.
0
5.
2
0
0
5
Advanced online publication: 14.04.2005
DOI: 10.1055/s-2005-864834; Art ID: G48004ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
An Improved Synthesis of Pyridoxine via [2+2+2] Cyclization of Acetylenes and Nitriles
1189
The conditions of the reaction were mild. After 20 hours hydroperoxide anion followed by intramolecular oxida-
under reflux in hexane solution and irradiation with two tive rearrangement of peroxysilane.
460 W Phillips HPM 12 lamps in the presence of only 1
The dibromide 6 was easily converted into pyridoxine by
mol% of [cpCo(cod)] as a catalyst, disilylated pyridine 3
a well-known two-step synthetic procedure.2
was isolated by vacuum distillation in high yield (81%).7
Another facile access to pyridoxine involved the iodina-
The silyl group beside the N-atom was then smoothly
tion key stage (Scheme 5).
eliminated by heating in isopropanol, and the resulted 3-
monosilylpyridine 4 was isolated by distillation with 75%
O
O
yield (Scheme 3).8 As a reason of this regioselectivity we
see the influence of the nitrogen atom. Due to this hetero-
atom, the carbon in the 2-position of pyridine 3 is more
electropositive than that in the 5-position and is therefore
less prone to stabilizing an anionic species.
Si
I
I2, KF, PhNO2
DMFA
N
N
8
7
(72%)
Scheme 5 Iodination of 3-trimethylsilylpyridine 7
O
OH
O
O
3-Trimethylsilylpyridine 7 was prepared by cyclization of
3,3-bis(trimethylsilyl)-di-2-propynyl ether and acetoni-
trile under conditions analogous to those described for py-
ridine 3 in 86% yield with subsequent protiodesilylation
in methanol. The iodination proceeds smoothly in DMFA
at 80 °C for 10 hours in the presence of KF and nitroben-
zene to give 3-iodopyridine 8 which was earlier reported
as a key compound for the synthesis of pyridoxine.3 The
addition of both KF and nitrobenzene is crucial for the
reaction.11 Since the single electron transfer (SET) com-
plexation–oxidation (reduction) processes have become a
common concept in the metallorganic chemistry, we
would suppose that such redox activation of 3-silylpyri-
dine 7 with KF and iodine with nitrobenzene influences
sufficiently the energetic profile of the reaction and
decreases its activation energy.
O
Si
Si
70 °C, 12 h
N
Si
N
O
4
3
(75%)
Scheme 3 Preparation of monosilylated pyridine 4
The oxidation of Si-Caryl bond is still a challenge for prac-
tical chemistry. Only few examples of it have been report-
ed to date.9 We applied several oxidizing systems (for
example H2O2 + KF in DMF, PhCOOOH + K2CO3 + KF
in DMF) for the oxidation of Si-C bond in the compound
4. However, most of the attempts resulted in protiode-
silylation reaction and (or) oxidation of alkyl side chains.
Fortunately, the oxidation with potassium t-butylhydro-
peroxide in anhydrous DMF without addition of fluorides
afforded 3-hydroxypyridine 5 which was transformed in
In conclusion, we succeeded in elaboration of efficient
procedures for the preparation of vitamin B6 via the
[2+2+2] cocyclization reaction. The utilization of [cp-
Co(cod)] as a catalyst under irradiation with visible light
appeared to be superior to catalysis with cobaltocene and
[cpCo(CO)2], and the modification of organosilicon aux-
iliary allowed direct oxidation of highly sensitive 3-si-
lylpyridines into pyridoxine precursors. Alternatively, a
direct iodination of the 3-silylpyridines is now possible to
get access to vitamin B6.
situ into dibromo derivative
6
with 35% yield
(Scheme 4).10
Br
O
t-BuOOH,
O
O
Si
KH
HBr
HO
HO
Br
DMF, 5 °C
N
HBr
N
N
4
6
5
Acknowledgment
OOK
OK
O
O
O
O
O
This work was supported by DSM Nutritional Products (formely
Roche Vitamins Ltd.). We are grateful to Beate Friedrich for
technical assistance, and Hannelore Baudisch for analytical measu-
rements.
Si
Si
_
N
N
O
O
References
O
O
O
Si
Si
O
(1) (a) Yamazaki, H.; Wakatsuki, Y. Tetrahedron Lett. 1973, 36,
3383. (b) Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl.
1984, 23, 539. (c) Bönnemann, H. Angew. Chem., Int. Ed.
Engl. 1985, 24, 248. (d) Schore, N. E. Chem. Rev. 1988, 88,
1081. (e) Grotjahn, D. B. In Comprehensive Organometallic
Chemistry II, Vol. 12; Hegedus, L. S., Ed.; Pergamon:
Oxford, 1995, 741.
N
N
Scheme 4 Oxidation of monosilylated pyridine 4
Possible mechanism of the reaction includes a replace-
ment of isopropoxy group with highly nucleophilic t-butyl
Synlett 2005, No. 7, 1188–1190 © Thieme Stuttgart · New York

1190
A. Gutnov et al.
LETTER
(2) Geiger, R. E.; Lalonde, M.; Stoller, H.; Schleich, K. Helv.
Chim. Acta 1984, 67, 1274.
(3) Parnell, C. A.; Vollhardt, K. P. C. Tetrahedron 1985, 41,
5791.
(4) (a) Heller, B.; Oehme, G. J. Chem. Soc., Chem. Commun.
1995, 179. (b) Heller, B.; Sundermann, B.; Buschmann, H.;
Drexler, H.-J.; You, J.; Holzgrabe, U.; Heller, E.; Oehme, G.
J. Org. Chem. 2002, 67, 4414. (c) Heller, B.; Sundermann,
B.; Fischer, C.; You, J.; Chen, W.; Drexler, H.-J.; Knochel,
P.; Bonrath, W.; Gutnov, A. J. Org. Chem. 2003, 68, 9221.
(d) Gutnov, A.; Heller, B.; Fischer, C.; Drexler, H.-J.;
Sundermann, B.; Sundermann, C. Angew. Chem. Int. Ed.
2004, 43, 3795.
(9) (a) Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1980,
102, 5253. (b) Prouilhac-Cros, S.; Babin, P.; Bennetau, B.;
Dunogues, J. Bull. Soc. Chim. Fr. 1995, 132, 513.
(c) Suginome, M.; Matsunaga, S.-I.; Ito, Y. Synlett 1995,
941. (d) Sunderhaus, J. D.; Lam, H.; Dudley, G. B. Org. Lett.
2003, 5, 4571.
(10) KH (1.575 g, 39.26 mmol) was suspended in DMF (20 mL)
at 0 °C. Then, t-BuOOH (6.5 mL, 39 mmol, 6 M solution in
nonane) was added dropwise to the slurry within 10 min so
that the reaction temperature did not exceed 5 °C. After the
addition, the mixture was stirred additionally for 10 min at 5
°C until the evolution of hydrogen ceased. The solution of 6-
methyl-7-(dimethylisopropoxysilyl)-1,3-dihydrofuro[3,4-
c]pyridine (4, 3.23 g, 12.86 mmol) in DMF (3 mL) was
added dropwise to the reaction mixture within 30 min at 5 °C
under vigorous stirring. The reaction mixture was stirred for
additional 30 min. At this point the color turned to brown,
and the reaction mixture was evaporated to dryness in high
vacuum. The remaining solids were dissolved in hot HOAc
(10 mL) followed by addition of HBr (25 mL, 48% in H2O).
The solution was brought to reflux, and 13 mL of liquids
were distilled off at atmospheric pressure. The remaining
solution was left overnight at 5 °C. The precipitated
hydrobromide was filtered off, washed with acetone, and
then air dried. The crude salt was recrystallized from HOAc
(8 mL) to give 1.68 g (35% yield) of the product 6 as beige
crystals with mp 228 °C. 1H NMR (400 MHz, CD3OD): d =
(5) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599.
(6) Krolevets, A. A.; Antipova, V. V.; Popov, A. G.; Adamov,
A. V. J. Gen. Chem. USSR 1988, 58, 2023.
(7) 3,3-Bis(dimethylisopropoxysilyl)-di-2-propynyl ether (1,
9.1 g, 10 mL, 27.85 mmol) and MeCN (5 mL) were
dissolved in hexane (130 mL). Then, [cpCo(cod)] (65 mg,
0.28 mmol, 1 mol%) was added to the solution, and the
reaction mixture was stirred under reflux for 20 h under two
460 W Phillips HPM 12 lamps’ irradiation. The reaction
mixture was evaporated in vacuum, and the residue was
distilled. A fraction with bp 119–122 °C (2·10–3 mbar) was
collected to give 8.29 g (81% yield) of compound 3 as a
colorless oil. 1H NMR (400 MHz, CDCl3): d = 5.06 (m, 2 H),
5.04 (m, 2 H), 4.03–3.94 (m, 2 H), 2.55 (s, 3 H), 1.09 (d, J =
6.1 Hz, 6 H), 1.07 (d, J = 6.1 Hz, 6 H), 0.31 (s, 6 H), 0.28 (s,
6 H). 13C NMR (100 MHz, CDCl3): d = 159.24, 157.46,
152.28, 136.75, 123.03, 73.42, 71.28, 64.84, 64.68, 25.75,
24.92, 0, –2.23. MS (70 eV): m/z (%) = 368 (2) [M+], 352
(11), 325 (100), 312 (34), 294 (24), 74 (28), 43 (23).
(8) Bissilylated pyridine 3 (5.565 g, 15.14 mmol) was stirred for
12 h at 70 °C in absolute i-PrOH (10 mL). The solvent was
evaporated, and the residue was distilled in vacuo to give
2.85 g (75% yield) of the product 4 with bp 74–77 °C
(8·10–3 mbar). 1H NMR (400 MHz, CDCl3): d = 8.29 (s, 1 H),
5.09 (m, 2 H), 4.96 (m, 2 H), 4.03–3.97 (m, 1 H), 2.56 (s,
3 H), 1.12–1.1 (m, 6 H), 0.33 (m, 6 H). 13C NMR (100 MHz,
CDCl3): d = 160.09, 155.04, 141.61, 130.98, 124.11, 74.1,
70.19, 64.84, 25.38, 24.98, 0.003. MS (70 eV): m/z (%) =
251 (5) [M+], 236 (10), 208 (100), 194 (37), 176 (18), 75
(18).
8.34 (s, 1 H), 4.74 (s, 2 H), 4.73 (s, 2 H), 2.61 (s, 3 H). 13
C
NMR (100 MHz, CD3OD): d = 154.8, 145.2, 143.3, 137.1,
134.4, 25.5, 21.2, 16.3. MS (70 eV): m/z (%) = 296 (4)
[M+ – Br], 248 (2), 215 (37), 134 (67), 106 (100), 80 (50), 65
(50), 39 (74).
(11) The solution of the pyridine 7 (228 mg, 1.1 mmol), dried KF
(198 mg, 3.4 mmol), nitrobenzene (0.35 mL, 3.4 mmol) in
DMF (3 mL) was treated with iodine (863 mg, 3.4 mmol),
and the mixture stirred for 10 h at 80 °C. Then reaction was
quenched by addition of 5% solution of Na2SO3 in H2O after
cooling and extracted with Et2O. The organic phase was
dried over Na2SO4, solvents were removed in vacuum, and
the oily residue was purified on silica (Et2O) to give 206 mg
(72% yield) of the iodide 8 as colorless crystals. 1H NMR
(400 MHz, CDCl3): d = 8.21 (s, 1 H), 5.21 (s, 2 H), 4.92 (s,
2 H), 2.70 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 158.1,
155.1, 141.2, 133.4, 89.6, 78.3, 73.7, 28.1. MS (70 eV): m/z
(%) = 261 (100) [M+], 233 (50), 205 (15), 133 (11), 106 (51),
77 (29), 63 (12), 51 (16).
Synlett 2005, No. 7, 1188–1190 © Thieme Stuttgart · New York