Synthetic studies of substituted pyridine aldehydes as intermediates for the synthesis of toddaquinoline, its derivatives and other natural products

Article abstract of DOI:10.3987/COM-11-12239

The synthesis of substituted 2-bromopyridine aldehydes as intermediates in our planned approach to toddaquinoline, its derivatives and other natural products is reported. The DMF-formylation method of pyridine ring, the Vilsmeier-Haack procedure and the b

Full text of DOI:10.3987/COM-11-12239

HETEROCYCLES, Vol. 83, No. 9, 2011
1989
HETEROCYCLES, Vol. 83, No. 9, 2011, pp. 1989 - 2000. © The Japan Institute of Heterocyclic Chemistry
Received, 18th April, 2011, Accepted, 14th July, 2011, Published online, 21st July, 2011
DOI: 10.3987/COM-11-12239
SYNTHETIC STUDIES OF SUBSTITUTED PYRIDINE ALDEHYDES AS
INTERMEDIATES FOR THE SYNTHESIS OF TODDAQUINOLINE, ITS
DERIVATIVES AND OTHER NATURAL PRODUCTS
Georgeta Serban,a* Hitoshi Abe,b and Yasuo Takeuchic
a) Faculty of Medicine and Pharmacy, University of Oradea, Pharmaceutical
Chemistry Department, Nicolae Jiga 29, Oradea 410028, Romania, b) Faculty of
Engineering, University of Toyama, Department of Environmental Applied
Chemistry, Toyama 930-8555, Japan, c) Faculty of Pharmaceutical Sciences,
Okayama University, Department of Synthetic and Medicinal Chemistry,
Okayama 700-8530, Japan; E-mail: getaserban_2000@yahoo.com
Abstract – The synthesis of substituted 2-bromopyridine aldehydes as
intermediates in our planned approach to toddaquinoline, its derivatives and other
natural products is reported. The DMF-formylation method of pyridine ring, the
Vilsmeier-Haack procedure and the bromination of pyridine ring respectively,
were studied in order to synthesize the above mentioned compounds. The
successful methods (DMF-formylation and bromination of pyridine ring) provided
the 2-bromo-4-formyl-5-tosyloxypyridine Ib and 5-benzyloxy-2,4,6-tribromo-
nicotinaldehyde Ia under relatively mild conditions and in good yields.
INTRODUCTION
Toddaquinoline, a benzo[h]quinoline alkaloid featuring a unique tetracyclic skeleton, was isolated in
1993 from the root bark of Toddalia asiatica, a constituent of many Asian folk medicines.1a,b In
connection with our efforts to develop new and useful methods for the preparation of the Toddalia
asiatica alkaloids2 and other natural products, our need for syntheses led us to prepare functionalized
pyridine aldehydes type I, particularly molecules that bear bromine and hydroxyl functional groups.
R"
O
R'
OR
R'"
Ia R = protective group
Ib R = protective group
R' = CHO
R" = CHO
O
Br
N
R", R'" = H or leaving groups R', R'" = H or leaving groups
N
OH
I
toddaquinoline

1990
HETEROCYCLES, Vol. 83, No. 9, 2011
RESULTS AND DISCUSSION
Taking into account the chemical literature concerning the pyridines being substituted with formyl or
bromine group respectively, we focused on the possibilities of obtaining the substituted 2-bromopyridine
aldehydes I and our synthetic approach is based on the four routes as shown in the retrosynthetic analysis
(Scheme 1).
OR
N
R'"
electrophilic aromatic bromination
or lithium-bromine exchange
route D
Vilsmeier-Haack
formylation
DMF-formylation
OR
R'"
OR
R'"
OR
R'"
route A
route B
Br
N
Br
N
Br
N
I
CO2Ph
route C
Vilsmeier-Haack
formylation
OR
R'"
OR
R'"
CO2Ph
OR
R'"
OR
or
or
Br
N
Br
N
Br
N
Br
N
R'"
X
CO2Ph
CO2Ph
Ph
Scheme 1. Retrosynthesis of compounds I
Pyridine ring formylation by DMF (route A)
Lithiation of aromatic and heteroaromatic compounds has been widely used to introduce various
functional groups. This reaction is a very efficient functionalization method since electrophilic
substitutions are often difficult on π-deficient heterocycles. 2-Bromopyridine aldehyde and its derivatives
are valuable intermediates in heterocyclic chemistry. o-Bromopyridine aldehydes have been prepared by
ortho-metalation of bromopyridines with lithium diisopropylamide LDA followed by electrophilic
substitution with DMF.3a-c Based upon the fact that the ortho-metalation procedure studied previously in
our laboratory2 is a useful route for the synthesis of various 2-bromopyridine aldehydes, our first strategy
involved the pyridine ring formylation by DMF (route A). Subsequently the protection of hydroxyl group
as benzyl,4 mesyl and tosyl,5 we started to investigate the reaction of 2-bromo-5-hydroxypyridine with
LDA and DMF under various conditions.

HETEROCYCLES, Vol. 83, No. 9, 2011
1991
Since in our previous studies the formylation of pyridine ring worked very well when 3 eq LDA/4 eq
DMF/THF/-78 °C were used,2 in this case the first experiments using as starting materials 2-bromo-5-
benzyloxypyridine 2 and 2-bromo-5-mesyloxypyridine 3 respectively, did not give the expected
formylated products except the recovery of the starting materials in very high yields. Different
experimental conditions still did not improve the result. Further we used 2-bromo-5-tosyloxypyridine 4 as
starting material for the pyridine ring formylation by DMF (Scheme 2).
OBn
BnCl, K2CO3
OHC
Br
DMF, rt, 77%
Br
N
OR
i) LDA, THF
ii) DMF
2
OH
N
OMs
OTs
MsCl, Et3N, Py
CH2Cl2, rt, 99%
R = Bn, Ms
Br
N
Br
Br
N
1
3
CHO
OTs
TsCl, Et3N
LDA, DMF
18-53%
CH2Cl2, rt, 94%
N
Br
N
4
Ib
Scheme 2. Formylation by DMF of compound 1
The formylation of 2-bromo-5-tosyloxypyridine 4 proved to be also troublesome in the above mentioned
experimental conditions giving only the starting material in a very high yield (table 1, run 1). A higher
reaction temperature (-80 °C→-40 °C) did not give a better result (run 2). By increasing the amount of
deprotonation agent to 10 eq of LDA, the reaction proceeded in one case (run 3). When the reaction
conditions of run 3 were applied again, the result could not be reproduced in the next experiments. Only
when a different solvent (THF→ether) and higher amounts of deprotonation agent/formylation agent (10
eq LDA/4-8 eq DMF) were used, the formyl compound was obtained in a moderate to good yield (run 4-
6).
Table 1. The results of the formylation of compound 4
yield (%)
Run
temp (oC)
LDA (eq/time)
DMF (eq/time) solvent
4
Ib
THF
4/1h
1.
2.
3.
4.
5.
6.
3/1h
-78
-40
-80
-75
-78
-80
96
97
-
43
-
-
-
-
43
18
43
53
THF
THF
Et2O
Et2O
Et2O
3/2h
4/1.5h
4/1h
4/1h
6/1h
8/1h
10/1.5h
10/1.5-2h
10/2h
10/1.5-2h

1992
HETEROCYCLES, Vol. 83, No. 9, 2011
13
The position of formyl group of the compound Ib was assigned by one- (1H-NMR, C-NMR) and two-
dimensional experiments (HMBC), which showed the correlation of formyl hydrogen with C3, C4 and C5
of the pyridine ring meaning that deprotonation/formylation proceeded on the ortho-position of the
functional group containing oxygen.6a-b
Pyridine ring formylation by Vilsmeier-Haack procedure (route B-C)
The Friedel-Crafts acylation and Vilsmeier formylation, which are important methods for the preparation
of aryl ketones and aldehydes, fail in the pyridine series, making many 3-pyridine ketones and 3-pyridine
carboxaldehydes difficult to prepare.7a In the last years, there have been developed synthesis of
substituted pyridines via N-acyldihydropyridine or N-alkylpyridinium salts intermediates.7-e The 1,2- and
1,4-dihydropyridine have proven to be valuable intermediates for the preparation of interesting
heterocyclic compounds. Meanwhile, 1,2-dihydropyridines that do not contain electron-withdrawing
substituents on the ring are unstable, N-acyl-1,2-dihydropyridine are stabilized by the acyl group.8a,b The
β-position of a 1-acyldihydropyridine is electron rich and susceptible to electrophilic attack. Shono9
described one example of β-formylation of 1-acyl-1,4-dihydropyridine and Comins reported the β-
formylation of some substituted 1-(phenoxycarbonyl)-1,2-dihydropyridines via Vilsmeier-Haack reaction.
The regiospecific β-formylation of 1-acyldihydropyridines has considerable potential for the synthesis of
substituted 3-pyridine carboxaldehydes.7a,b
The preparation of compound Ia requires a method for the synthesis of N-acyl-6-bromo-3-hydroxy-1,2-
dihydropyridine (route B). Comins synthesized the 3-substituted 1-(phenoxycarbonyl)-1,2-
dihydropyridines using Fowler’s method by the reaction of several 3-substituted pyridines with phenyl
chloroformate and sodium borohydride in methanol at -78 °C.7a Although Fowler and Comins have
developed excellent procedures for the preparation of N-carboxyalkyl and N-carboxyphenyl 1,2-
dihydropyridines, when these procedures were applied to 2-bromo-5-mesyloxypyridine 3 and 2-bromo-5-
tosyloxypyridine 4 respectively, no reaction was found to occur and we recovered the unreacted starting
material in every cases. The change of solvent (methanol→ether), higher amounts of reductive agent or
acylation agent (concentration of sodium borohydride and phenyl chloroformate ranging from 1.3 eq and
1 eq, respectively to 2.5-3 eq) or varying the reaction temperature did not provide the desired N-acyl-6-
bromo-3-hydroxy-1,2-dihydropyridine, the key intermediate for the formylation step (Scheme 3).
Further we studied the use of pyridinium salts as activated electrophilic substrates for reduction. The
intermediate generated by the reduction of such salts can be reacted successfully with a range of different
electrophiles (e.g. carbonyl compounds to give N-acyldihydropyridine).10 There are very few examples of
2-bromopyridine being N-alkylated using a suitable alkyl chain, the reluctance of 2-halopyridines to
undergo alkylation with normal type of alkyl halides and tosylates being known.7d-e Thus, we decided to
try the benzyl halides which have been used to synthesize N-benzylpyridinium salts in other examples11a-b

HETEROCYCLES, Vol. 83, No. 9, 2011
1993
and the N-alkylation was achieved in good yield when benzyl bromide was used (route C, Scheme 3).
Having the 2-bromo-5-hydroxy-N-benzylpyridinium bromide 5 and 2-bromo-5-benzyloxy-N-
benzylpyridinium bromide 6 in hands we focused on the reduction of the pyridinium salts. Earlier reports
on the reduction of some pyridinium salts indicated that the selective formation of single dihydro isomer
is difficult and dependent on temperature, pH and the nature of the reducing agent.12a-b Thus, the
reduction of 2-bromo-5-hydroxy-N-benzylpyridinium bromide 5 by sodium borohydride, lithium
aluminium hydride and sodium cyanoborohydride proved unsuccessful, in as much as many organic
products very difficult to separate could be extracted from the reaction mixture.
With this background information, we carried out detailed studies on the reduction of 2-bromo-5-
benzyloxy-N-benzylpyridinium bromide 6 by sodium dithionite in alkaline medium, sodium borohydride
and tributyltin hydride. Working under various conditions, attempts to obtain 1,2- or 1,4-dihydropyridines
were disappointing, the only compound obtained being the hydrolysis product 5-benzyloxy-N-
benzylpyridine-2-one 7.
O
Bn
Na2S2O4
or NaBH4
or Bu3SnH
O
N
OR
OR
OR
NaBH4
BnBr, 120 °C
toluene
85-97%
Bn
PhOCOCl
7
Br
N
Br
N
Br
N
O
Bn
1-4
NaBH3CN
Br
CO2Ph
Bn
MeOH
65-93%
R = Ms, Ts
N
5
6
R = H, 56%
R = Bn, 57%
Bn
8
Scheme 3. N-Acylation/reduction and N-alkylation/reduction studies on compounds 1-4
Selective sodium cyanoborohydride reduction in the nitrogen heterocyclic area and the conversion of
certain pyridinium salts to the corresponding 1,2,5,6-tetrahydropyridines have been studied.13 The
conversion
of
1,2,5,6-tetrahydropyridines
to
dihydropyridines
by
bromination/double
dehydrobromination with ethyl aluminium dichloride in HMPA under mild conditions is also known.11b
Despite our efforts, the reduction of 6 by sodium cyanoborohydride in methanol at reflux or at room
temperature gave the corresponding debrominated 1,2,5,6-tetrahydropyridine 8, not useful for
bromination/double dehydrobromination step (Scheme 3).
Pyridine ring bromination (route D)
Our last approach for the preparation of compound Ia employed a bromination of the pyridine ring
carrying the formyl group (route D, Scheme 4). The intermediate 5-benzyloxynicotinaldehyde 11,
prepared from 3,5-dibromopyridine 9 by a method previously described,14a-b after acetalization with
ethylene glycol in toluene15 yielded the corresponding 5-benzyloxynicotinaldehyde acetal 12. Since our

1994
HETEROCYCLES, Vol. 83, No. 9, 2011
experiments concerning the bromination of acetal 12 failed via electrophilic aromatic substitution
(Br2/K2CO3, Br2/AcOH, benzyltrimethylammonium tribromide BTMABr3)16a-d and also via lithium-
bromine exchange procedure (LDA/NBS, n-BuLi/NBS, n-BuLi/DBTCE dibromo tetrachloroethane, n-
BuLi/LiDMAE/NBS, n-BuLi/LiDMAE/DBTCE),17a-b catalytic Pd/C hydrogenolysis of compound 12 in
methanol18 gave debenzylated product 13 in a very good yield.
Br
Br
Br
OBn
OHC
OBn
(CH2OH)2, toluene
TsOH, 110°C, 90%
BnONa, DMF
65°C, 66%
BuLi, THF, -100°C
DMF, -100°C to -60°C
69%
N
N
N
9
10
11
Br2, 10% NaOH
rt, 15%
O
O
O
Br
OBn
OH
OH
Br
O
O
H2, 10% Pd-C
MeOH, rt, 98%
O
BTMABr3, Et3N
N
N
Br
N
CH2Cl2-MeOH
-50°C to -35°C, 68%
12
13
14
O
Br
Br
OBn
Br
OHC
Br
OBn
BnBr, K2CO3
DMF, rt, 84%
10% HCl, THF
65°C, 86%
O
Br
N
N
Br
Ia
15
Scheme 4. Synthesis of 5-benzyloxy-2,4,6-tribromonicotinaldehyde Ia
Table 2. The results of the bromination of compound 13
yield (%)
Br2 (eq)
BTMABr3 (eq)
temp (oC)
Run
base (eq)
time (h)
13
14
Na2CO3
NaOH
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
rt
2
1
1
-
-
-
17
1
10
-
-
rt
15
16
0
rt
0
-
2
-
NaOH
-
1.1
1.01
1.01
1.01
3
4
4
23
many spots
-
-
1.5
3.5
1.5
3
6
22
10
37
48
68
-
-45
-
-
-
-
-78
-
-40
-
-35
-
40 min
3
Et3N (6)
-50 to -35
-
Out of the bromination reagents tried the best was benzyltrimethylammonium tribromide BTMABr3
which reacted with hydroxypyridine 13 in dichloromethane-methanol mixture. Various reaction
conditions were experimented and good yields of the bromo compound 14 were obtained when a base
(Et3N) was employed in order to neutralize a generating hydrogen bromide. Reaction of equimolar

HETEROCYCLES, Vol. 83, No. 9, 2011
1995
amounts of 3-hydroxypyridine 13 and bromine in the presence of a 10% aqueous solution of sodium
hydroxide19a-b gave the brominated hydroxypyridine 14 only in low yield (15%). The results are
summarized in the table 2.
In the next steps, the hydroxyl function was protected using the benzyl group4 which proved to be a good
leaving group for deprotection method and the acetal group of 15 was removed by 10% HCl in THF20 to
afford the 5-benzyloxy-2,4,6-tribromonicotinaldehyde Ia, a good intermediate for the synthesis of
toddaquinoline and its derivatives.
In conclusion, we have developed highly practical and efficient syntheses of substituted 2-bromopyridine
aldehydes Ia and Ib without using very expensive or dangerous reagents.
Due to reluctance of 2-bromopyridine for the introduction of substituents on its π-deficient aromatic ring,
different synthetic pathways were studied: DMF-formylation method of pyridine ring, Vilsmeier-Haack
formylation of N-acyl-1,2-dihydropyridine (starting from N-acyldihydropyridine or N-alkylpyridinium
salts) and bromination of pyridine ring. The successful methods provided the 2-bromo-4-formyl-5-
tosyloxypyridine Ib from 2-bromo-5-hydroxypyridine in 2 steps by DMF formylation method and 5-
benzyloxy-2,4,6-tribromonicotinaldehyde Ia from 3,5-dibromopyridine in 7 steps by means of
benzyltrimethylammonium tribromide under relatively mild conditions and in good yields. To the best of
our knowledge, this is the first attempt of hydroxypyridines bromination using BTMABr3 as bromination
reagent. The 2-bromopyridine aldehydes Ia and Ib are very good intermediates in the synthesis of
toddaquinoline, its derivatives and other natural products.
EXPERIMENTAL
General: Melting points were measured on a micro-melting point hot-stage apparatus (Yanagimoto) and
1
are uncorrected. The IR spectra were recorded using a JASCO FTIR-350 spectrophotometer. The H-
NMR spectra in deuteriochloroform were recorded by a Mercury-300, VXR-500 or Varian Unity INOVA
AS-600 spectrometer. The NMR spectral data are reported in parts per million downfield from the
internal standard (tetramethylsilane, δ 0.0). The FAB-MS were obtained using a VG AutoSpec
spectrometer with m-nitrobenzyl alcohol as the matrix. The elemental analysis was performed using a
Yanaco MT-5 analyzer. Column chromatography was carried out with Merck silica gel (230-400 mesh).
The TLC analysis was performed on Kieselgel 60 F254 (Merck) plates. All the experiments were carried
out in an argon atmosphere, unless otherwise noted.
Substrates: 2-bromo-5-benzyloxypyridine 2,4 2-bromo-5-tosyloxypyridine 4, 2-bromo-4-formyl-5-
tosyloxypyridine Ib,6b 3-bromo-5-benzyloxypyridine 10, and 3-formyl-5-benzyloxypyridine 1114a,b are
known compounds.

1996
HETEROCYCLES, Vol. 83, No. 9, 2011
2-Bromo-5-mesyloxypyridine (3). To a solution of 2-bromo-5-hydroxypyridine (1) (0.3 g, 1.72 mmol) in
dry CH2Cl2 (20 mL), Et3N (1.19 mL, 8.62 mmol) was added. The mixture was cooled at 0 °C and MsCl
(0.4 mL, 5.17 mmol) was added dropwise under stirring and then pyridine (0.15 mL, 1.72 mmol). The
reaction mixture was stirred for 4 h at rt and then poured into ice water, neutralized with saturated
aqueous solution of NaHCO3 and extracted with CH2Cl2. The solvent was removed under reduced
pressure and the residue (0.52 g) was purified by column chromatography on silica gel. Elution with
hexane-CH2Cl2 (2:1) gave the mesyloxypyridine 3 (0.433 g, 99%) as colourless prisms; mp 87.5-88.5 °C
(Et2O). IR (KBr) cm-1: 1570, 1370. 1H-NMR (300 MHz, CDCl3) δ: 8.34 (dd, 1H, Py-H, J = 1.2; 2.1 Hz),
7.55 (d, 1H, Py-H, J = 1.2 Hz), 7.54 (d, 1H, Py-H, J = 2.1 Hz), 3.23 (s, 3H, CH3). LRMS (FAB, positive
ion mode) m/z 252, 254 (M+H)+. Anal. Calcd for C6H6BrNO3S: C, 28.59; H, 2.40; N, 5.56. Found C,
28.52; H, 2.38; N, 5.47.
2-Bromo-4-formyl-5-tosyloxypyridine (Ib). To a LDA solution prepared from n-BuLi (hexane solution,
2 mL, 3.14 mmol) and i-Pr2NH (0.5 mL, 3.55 mmol) in Et2O (5 mL) at -80 °C for 1 h under Ar
atmosphere, 2-bromo-5-tosyloxypyridine 4 (0.1 g, 0.304 mmol) solved in dry Et2O (8 mL) was added
slowly and the mixture was stirred for 1.5-2 h at -80 °C. Dry DMF (0.2 mL, 2.57 mmol) was added drop
by drop. After 1 h of stirring at -80 °C, the mixture was hydrolyzed with a 10% degassed aqueous
solution of KH2PO4 (30 mL) and allowed to warm up to rt and extracted with Et2O. The combined
organic layers were washed with brine, dried (Na2SO4), evaporated and purified by column
chromatography on silica gel. Elution with hexane-Et2O (5:1) gave the formylated product Ib (0.057 g,
1
53%) as colorless prisms, mp 105-107 °C (hexane-Et2O). IR (KBr) cm-1: 1700, 1590, 1380, 1180. H-
NMR (500 MHz, CDCl3) δ: 10.04 (s, 1H, CHO), 8.11 (s, 1H, Py-H6), 7.86 (s, 1H, Py-H3), 7.73 (d, 2H,
Ar-H, J = 8 Hz), 7.39 (d, 2H, Ar-H, J = 8 Hz), 2.49 (s, 3H, CH3). 13C-NMR (150 MHz, CDCl3) δ: 184.98
(CHO), 147.25 (C, C-Ar), 146.53 (CH, C6-Py), 145.26 (C, C2-Py), 140.49 (C, C5-Py), 136.84 (C, C4-Py),
130.49 (CH, 2C-Ar), 130.26 (C, C-Ar), 128.62 (CH, 2C-Ar), 125.77 (CH, C3-Py), 21.82 (CH3). MS (FAB,
positive ion mode) m/z 356, 358 (M+H)+. Anal. Calcd for C13H10BrNO4S: C, 43.84; H, 2.83; N, 3.93.
Found: C, 44.19; H, 3.04; N, 3.79.
2-Bromo-5-hydroxy-N-benzylpyridinium bromide (5). To a solution of pyridine 1 (0.25 g, 1.43 mmol)
in toluene (70 mL), BnBr (0.17 mL, 1.43 mmol) was added and the mixture was heated under reflux for
70 h. The solvent was removed under reduced pressure to furnish 2-bromo-5-hydroxy-N-
benzylpyridinium bromide (5) (0.283 g, 56%) as white powder after washing with cold Et2O. mp 190-
194 °C (EtOH). IR (KBr) cm-1: 3440, 3070, 1610, 1495, 1320. 1H-NMR (300 MHz, DMSO) δ: 12.18 (s,
1H, OH), 8.91 (d, 1H, Py-H, J = 2.8 Hz), 8.27 (d, 1H, Py-H, J = 9.1 Hz), 7.90 (dd, 1H, Py-H, J = 2.8; 9.1
Hz), 7.43-7.26 (m, 5H, Ph-H), 5.91 (s, 2H, CH2-Ph). LRMS (M-Br)+ 264, 266. Anal. Calcd for
C12H11Br2NO: C, 41.77; H, 3.21; N, 4.06. Found: C, 42.03; H, 3.34; N 3.97.

HETEROCYCLES, Vol. 83, No. 9, 2011
1997
2-Bromo-5-benzyloxy-N-benzylpyridinium bromide (6). To a solution of pyridine 2 (1 g, 3.78 mmol)
in toluene (70 mL), BnBr (0.67 mL, 5.68 mmol) was added and the mixture was heated under reflux for
66 h. The solvent was removed and a liquid residue which crystallized in time was obtained. The crystals
were filtered and washed with cold Et2O, giving the product 6 (0.982 g, 57%) as colourless cubic crystals.
mp 142-144 °C (EtOH). IR (KBr) cm-1: 3060, 1615, 1510, 1260. 1H-NMR (300 MHz, DMSO) δ: 9.45 (d,
1H, Py-H, J = 3 Hz), 8.46 (d, 1H, Py-H, J = 9.3 Hz), 8.31 (dd, 1H, Py-H, J = 3; 9.3 Hz), 7.52-7.28 (m,
10H, Ph-H), 5.97 (s, 2H, N-CH2-Ph), 5.39 (s, 2H, O-CH2-Ph). LRMS (M-Br)+ 354, 356. Anal. Calcd for
C19H17Br2NO: C, 52.44; H, 3.94; N, 3.22 Found C, 52.28; H, 4.01; N, 3.55.
3-Benzyloxy-N-benzyl-1,2,5,6-tetrahydropyridine (8). To a solution of N-benzylpyridinium bromide 6
(0.05g, 0.11 mmol) in dry MeOH (10 mL), NaBH3CN (0.014 g, 0.22 mmol) was added and the mixture
was stirred for 22 h at rt. The mixture was poured into cold water, basified with saturated aqueous
solution of NaHCO3 and extracted with AcOEt. The combined organic extracts were washed with brine,
dried over anhydrous Na2SO4 and evaporated. The residue (0.05 g), purified by column chromatography
on silica gel (hexane-AcOEt 15:1) gave the tetrahydropyridine 8 (0.021 g, 65%) as pale yellow oil. IR
(NaCl) cm-1: 3050, 1680, 1500, 1450, 1220, 1180. 1H-NMR (300 MHz, CDCl3) δ: 7.39-7.28 (m, 10H, Ph-
H), 4.79 (t, 1H, Py-H, J = 3.7 Hz), 4.72 (s, 2H, O-CH2-Ph), 3.66 (s, 2H, N-CH2-Ph), 3.03 (d, 2H, Py-H, J
= 0.9 Hz), 2.60 (t, 2H, Py-H, J = 5.8 Hz ), 2.52-2.24 (m, 2H, Py-H). LRMS (FAB, positive ion mode) m/z
280 (M+H)+. HRMS (FAB) calcd for C19H22NO+: 280.1701, found 280.1708 (M+H)+.
5-Benzyloxypyridine-3-acetal (12). 3-Formyl-5-benzyloxypyridine (11) (0.27 g, 1.28 mmol) was
dissolved in 25 mL of dry toluene. p-TsOH monohydrate (0.30 g, 1.6 mmol) was added and the mixture
was stirred at 90 °C for 15 min. Ethylene glycol (0.35 mL, 6.29 mmol) was added and stirring was
continued for 5 h at 110 °C. After the reaction was completed (TLC), the reaction mixture was cooled
down, treated with saturated aqueous solution of NaHCO3 and extracted with CH2Cl2. The combined
extracts were washed with brine, dried over anhydrous K2CO3 and evaporated. The yellow liquid residue
(0.49 g) was purified by column chromatography on silica gel (hexane-AcOEt 2:1) to give the acetal 12
(0.297 g, 90%) as a colourless oil which crystallized in time as white prisms. mp 37-39 °C (crude). IR
1
(KBr) cm-1: 2845, 1590, 1460, 1290, 970. H-NMR (300 MHz, CDCl3) δ: 8.38 (d, 1H, Py-H, J = 3 Hz),
8.32 (d, 1H, Py-H, J = 1.2 Hz), 7.45-7.32 (m, 6H, Ar-H, Py-H), 5.84 (s, 1H, CH-acetal), 5.11 (s, 2H, O-
CH2-Ph), 4.13-4.01 (m, 4H, O-CH2-CH2-O). LRMS (FAB, positive ion mode) m/z 258 (M+H)+. HRMS
+
(FAB) calcd for C15H16NO3 : 258.1130, found 258.1134 (M+H)+.
5-(1,3-Dioxolan-2-yl)pyridin-3-ol (13). A solution of pyridine 12 (0.61 g, 2.39 mmol) and 10% Pd on C
(0.101 g) in MeOH (100 mL) was hydrogenated for 27 h at rt. The reaction mixture was filtered, washed
through with MeOH and the filtrate was concentrated under reduced pressure to afford the compound 13
(0.393 g, 98%) as colourless prisms. mp 142-145 °C (CHCl3). IR (KBr) cm-1: 2845, 2810-2300, 1595,

1998
HETEROCYCLES, Vol. 83, No. 9, 2011
1
1460, 1190, 970. H-NMR (300 MHz, CDCl3) δ: 8.23 (d, 1H, Py-H, J = 2.7 Hz), 8.21 (d, 1H, Py-H, J =
1.8 Hz), 7.39-7.38 (m, 1H, Py-H), 5.84 (s, 1H, CH-acetal), 4.13-4.08 (m, 2H, O-CH2-CH2-O), 4.06-4.01
(m, 2H, O-CH2-CH2-O). LRMS (FAB, positive ion mode) m/z 168 (M+H)+. Anal. Calcd for C8H9NO3: C,
57.48; H 5.43; N, 8.38; Found C, 57.14; H, 5.20; N, 8.27.
2,4,6-Tribromo-5-(1,3-dioxolan-2-yl)pyridin-3-ol (14). To a solution of pyridin-3-ol 13 (0.16 g, 0.99
mmol) in CH2Cl2-MeOH (20 mL-9 mL), dry Et3N (0.9 mL, 5.95 mmol) was added and the reaction
mixture was stirred for a few minutes at -50 °C. After that BTMABr3 (1.54 g, 3.97 mmol) solved in 20
mL of CH2Cl2 was added dropwise. The temperature was increased from -50 °C to -35 °C during 3 h,
after that 10% Na2S2O3 solution was added and the mixture was extracted with CH2Cl2. The combined
organic extracts were washed with brine, dried (anhydrous K2CO3) and evaporated and the residue
purified by column chromatography on silica gel (CH2Cl2-MeOH 50:1) gave the tribromopyridine 14
(0.273 g, 68%) as a white powder. mp 192.5-193.5 °C (CHCl3). IR (KBr) cm-1: 3400-3200, 2845, 1540,
1430, 1160, 960. 1H-NMR (300 MHz, CDCl3) δ: 6.25 (s, 1H, CH-acetal), 4.35-4.27 (m, 2H, O-CH2-CH2-
13
O), 4.16-4.08 (m, 2H, O-CH2-CH2-O). C-NMR (125 MHz, CDCl3) δ: 144.64 (C), 128.58 (C), 127.21
(C), 125.72 (C), 119.04 (C), 100.45 (CH), 62.96 (2C, CH2). LRMS (FAB, positive ion mode) m/z 402,
404, 406, 408 (M+H)+. Anal. Calcd for C8H6Br3NO3: C, 23.79; H, 1.50; N, 3.47; Found C, 23.75; H, 1.44;
N, 3.32.
3-Benzyloxy-2,4,6-tribromo-5-(1,3-dioxolan-2-yl)pyridine (15). To a solution of tribromopyridine 14
(0.68 g, 1.7 mmol) in dry DMF (70 mL) at 0 °C, anhydrous K2CO3 (0.47 g, 3.4 mmol) and a catalytic
amount of KI (0.1 g) were added. The reaction mixture was stirred for 30 min at 0 °C and for another 30
min at rt, then was treated with BnBr (0.58 g, 3.4 mmol) for 6 h at rt. When the reaction was completed,
cold water was added and the reaction mixture was extracted with CH2Cl2 and dried over anhydrous
K2CO3. The solvent was removed under reduced pressure and the red liquid residue (1.52 g) was purified
by column chromatography on silica gel (hexane-AcOEt 10:1) to give the benzyloxypyridine 15 (0.701 g,
1
84%) as colourless oil. IR (KBr) cm-1: 2860, 1520, 1420, 1220, 1030, 965. H-NMR (300 MHz, CDCl3)
δ: 7.59-7.53 (m, 2H, Ar-H), 7.46-7.38 (m, 3H, Ar-H), 6.30 (s, 1H, CH-acetal), 5.05 (s, 2H, CH2Ph), 4.37-
4.32 (m, 2H, O-CH2-CH2-O), 4.12-4.08 (m, 2H, O-CH2-CH2-O). LRMS (FAB, positive ion mode) m/z
+
492, 494, 496, 498 (M+H)+. HRMS (FAB) calcd for C15H13Br3NO3 : 495.8352, found 495.8385 (M+H)+.
5-Benzyloxy-2,4,6-tribromo-3-formylpyridine (Ia). To a solution of acetal 15 (0.74 g, 1.49 mmol) in
THF (70 mL) was added 10% HCl (50 mL) and the reaction mixture was stirred for 3.5 h at 65 °C. After
the reaction was completed (TLC), saturated aqueous solution of NaHCO3 was added and the mixture
was extracted with AcOEt. The combined organic extracts were washed with brine, dried over anhydrous
K2CO3 and evaporated under reduced pressure. The solid residue was purified by column
chromatography on silica gel (hexane-AcOEt 20:1) to give the formylpyridine Ia (0.58 g, 86%) as

HETEROCYCLES, Vol. 83, No. 9, 2011
1999
1
colourless needles. mp 122.5-125 °C (Et2O-hexane). IR (KBr) cm-1: 1700, 1525, 1500, 1220, 1030. H-
NMR (300 MHz, CDCl3) δ: 10.17 (s, 1H, CHO), 7.58-7.52 (m, 2H, Ar-H), 7.44-7.41 (m, 3H, Ar-H), 5.10
(s, 2H, CH2Ph). LRMS (FAB, positive ion mode) m/z 448, 450, 452, 454 (M+H)+. Anal. Calcd for
C13H8Br3NO2: C, 34.70; H 1.79; N, 3.11. Found C, 34.93; H, 1.81; N, 3.07.
ACKNOWLEDGEMENTS
The authors are grateful to SC NMR Laboratory of Okayama University for the use of the facilities. We
also wish to thank the Japan Society for the Promotion of Science (JSPS) for a postdoctoral fellowship for
G.S. and financial support. Many thanks to Prof. I. Grosu, UBB Cluj-Napoca Romania, for his helpful
suggestions and comments during the preparation of this paper.
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