A synthetic approach to 2,3,4-substituted pyridines useful as scaffolds for tripeptidomimetics

Article abstract of DOI:10.1016/j.tet.2004.05.048

The synthesis of 2,3,4-substituted pyridine derivatives useful as scaffolds in the development of peptidomimetics is described. The use of a variety of electrophiles in a halogen-dance reaction to produce 3-alkyl-2-fluoro-4-iodo- pyridine derivatives as 'functionalized scaffolds' and the possibility to differentiate between the reactivities of the two halogen handles have been explored. Coupling of amino acid derivatives in the 4-position of the pyridine was found to proceed efficiently by conversion of iodo-pyridine to a Grignard derivative, which was allowed to react with a protected amino aldehyde. Substitution of fluorine in the 2-position of the pyridine was found to be facile with alkoxide nucleophiles, whereas amines were much less reactive.

Full text of DOI:10.1016/j.tet.2004.05.048

Tetrahedron 60 (2004) 6113–6120
A synthetic approach to 2,3,4-substituted pyridines useful as
scaffolds for tripeptidomimetics
†
Stina Saitton,a,b Jan Kihlbergb and Kristina Luthmana
,
,
*
a
¨
¨
Department of Chemistry, Medicinal Chemistry, Goteborg University, SE-412 96 Goteborg, Sweden
b
˚
˚
Department of Chemistry, Organic Chemistry, Umea University, SE-901 87 Umea, Sweden
Received 11 March 2004; revised 27 April 2004; accepted 20 May 2004
Available online 10 June 2004
Abstract—The synthesis of 2,3,4-substituted pyridine derivatives useful as scaffolds in the development of peptidomimetics is described.
The use of a variety of electrophiles in a halogen-dance reaction to produce 3-alkyl-2-fluoro-4-iodo-pyridine derivatives as ‘functionalized
scaffolds’ and the possibility to differentiate between the reactivities of the two halogen handles have been explored. Coupling of amino acid
derivatives in the 4-position of the pyridine was found to proceed efficiently by conversion of iodo-pyridine to a Grignard derivative, which
was allowed to react with a protected amino aldehyde. Substitution of fluorine in the 2-position of the pyridine was found to be facile with
alkoxide nucleophiles, whereas amines were much less reactive.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
to which appropriate amino acids and side chain moieties
should be attached in the 2-, 3- and 4-positions (Fig. 1). The
suggested scaffold provides a rigid framework with a well
defined geometry due to the aromaticity of the pyridine ring.
There are no remaining amide bonds in the peptidomimetic;
a feature that is desirable when developing new bioactive
compounds. The nitrogen atom of the pyridine ring is
positioned to mimic the electrostatics of the carbonyl
oxygen of the original amide bond between the second and
third residues of a tripeptide (Fig. 1). The middle amino acid
of the tripeptide sequence is represented by the pyridine
ring, which carries a side chain equivalent in position 3. The
N-terminal amino acid moiety is attached to the 4-position
of the pyridine ring via a carbonyl group, and the C-terminal
amino acid moiety is attached to the 2-position via an amino
or ether bridge. Here we report our findings towards the
development of a facile synthetic strategy to produce these
compounds. A main goal has been to allow the use of
derivatives of the natural amino acids as building blocks,
Peptides are known to influence many vital physiological
processes and thereby they constitute important lead
compounds in medicinal chemistry research. However,
poor pharmacokinetic properties such as low oral bio-
availability and rapid enzymatic degradation make most
peptides unsuitable as drugs. In addition, the conformational
flexibility of peptides may reduce the receptor selectivity.
These problems can be addressed by the design and
synthesis of small rigid molecules known as peptidomi-
metics. In the interaction between a peptide and its receptor
or enzyme, the peptide backbone serves as a scaffold which
positions important amino acid side chains in defined spatial
positions. One approach towards the development of
peptidomimetics is to find rigid and physiologically stable
structures that can replace the peptide backbone, i.e.
providing a molecular framework to which the recognition
elements can be anchored and correctly presented for the
target structure.1,2
We have for some time been interested in the development
of a general scaffold useful in mimetics of biologically
active tripeptides or tripeptide sequences. A computer based
design proposed a trisubstituted pyridine ring as a scaffold
Keywords: Peptidomimetic; Pyridine; Scaffold; Grignard reaction;
Halogen-dance.
*
Corresponding author. Tel.: þ46-31-7722894; fax: þ46-31-7723840;
e-mail address: luthman@chem.gu.se
Present address: AstraZeneca R & D Molndal, SE-431 83 Molndal,
Sweden.
Figure 1. The proposed pyridine based tripeptidomimetic scaffold
compared with a general tripeptide. R1-R3 are amino acid side-chains,
X¼NH or O.
†
¨
¨
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.048

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S. Saitton et al. / Tetrahedron 60 (2004) 6113–6120
thereby obtaining the correct stereochemistry of peptides
and providing ready access to a variety of different
tripeptidomimetic sequences.
Table 1. Introduction of substituents at the 3-position in the pyridine
template
2. Results and discussion
2.1. Retrosynthetic analysis
Entry
Electrophile
H2O
MeI
R-group
Product
Yield (%)
The synthetic strategy was based on an appropriately
substituted pyridine derivative that should allow selective
synthetic manipulations in one position without disturbing
the others. This requirement was fulfilled by the 3-alkyl-2-
fluoro-4-iodopyridine scaffold 1 (the ‘functionalized
scaffold’), as shown in the retrosynthetic analysis (Fig. 2).
A fluorine atom activates the 2-position for nucleophilic
substitution. For example, a-amino or a-hydroxy acid
derivatives with an appropriately protected carboxylic acid
functionality could be used as nucleophiles. The iodine in
the 4-position of the pyridine ring could be envisioned to be
useful in metal catalyzed coupling reactions with amino
acid derivatives such as Weinreb’s amides, amino acid
chlorides or amino aldehydes. Thus, this synthetic strategy
allows the use of natural amino acids as reagents for the
substituents in the 2- and 4-positions of the pyridine
scaffold. The side chain equivalent in the 3-position is
attached by alkylation with an electrophile, which might
limit the possibilities of making functionalized scaffolds
corresponding to all natural amino acids. Regardless of this
limitation, use of the functionalized pyridine scaffold with
its two halogen handles with different reactivities seemed
1
2
3
4
5
6
7
8
9
10
H
Me
Bn
1a
1b
1c
1d
1e
1f
1g
1h
1i
80
89
BnBr
71
Isobutyl halide
Isobutyric aldehyde
Methallyl bromide
Acetaldehyde
Ethyl bromoacetate
Allyl bromide
Ethyl acrylate
Isobutyl
,0b
96
Me2CHCH(OH)
Isobutylene
MeCH(OH)
CH2COOEt
Allyl
93
51
13c
87
CH2CH2COOEt
1j
,0
aReaction conditions: 2-fluoro-3-iodopyridine was reacted with LDA in
THF at 278 8C for 1 h before the electrophile was added as a solution in
THF.
b
Isobutyl bromide and isobutyl iodide with or without TMEDA at 278 8C
to 230 8C were used as electrophiles.
See Scheme 1 for synthesis of the corresponding methyl ester.
c
1b,3 which in our application correspond to glycine (R¼H)
and alanine (R¼Me), side chain equivalents of phenyl-
alanine (R¼Bn), leucine (R¼isobutylene), threonine (R¼
CH(OH)CH3) and the methyl ester of aspartic acid
(R¼CH2COOMe) have successfully been introduced
(Table 1 and Scheme 1). Treatment of the lithiated scaffold
with benzyl bromide smoothly introduced a benzyl
substituent thus producing the functionalized scaffold 1c,
corresponding to the phenylalanine side chain, in 71% yield.
The direct introduction of an isobutyl group to afford the
leucine mimetic 1d proved unsuccessful using isobutyl
bromide or isobutyl iodide as electrophiles, with or without
the addition of TMEDA. However, when using isobutyric
aldehyde, the expected alcohol 1e was afforded in 96%
yield. Removal of the hydroxyl group either directly or after
modification to the tosylate5 was not successful. Attempted
catalytic hydrogenation in the presence of acid6 or reduction
with a variety of reagents (Et3SiH/TFA, NaBH4/TFA-
AcOH,7 HCOOH/triflic acid,8 NaCNBH3/BF3·Et2O,9
LiAlH410 at various temperatures or LiEt3BH·THF11) either
resulted in the isolation of unreacted starting material, or the
deiodinated starting material, or gave esters formed from
reactions of the alcohol with the different acids present. In
one case, after refluxing the tosylate in toluene with DBU,12
the elimination product was isolated in 55% yield. These
findings indicated that the removal of the hydroxyl group
would require several steps with possibilities of side
reactions such as deiodination and this approach was
therefore abandoned. Instead, the introduction of an isobutyl
like
tripeptidomimetics.
a
promising approach for preparation of
Figure 2. Retrosynthetic analysis of the tripeptidomimetic. R1-R3 are
amino acid side-chains, X¼NH or O, Y¼N(OMe)(Me), Cl or H.
2.2. Synthesis of the functionalized scaffold
The functionalized scaffold 1 was obtained in two steps
starting from commercially available 2-fluoropyridine
according to the procedure by Queguiner.3 2-Fluoro-3-
iodopyridine was synthesized from 2-fluoropyridine in 78%
yield by reaction with LDA followed by addition of I2
(Table 1).4 In the following step, treatment with LDA is
associated with a phenomenon commonly referred to as a
‘halogen dance’, whereby iodine migrates to the 4-position
and the subsequently added electrophile is attached to the
3-position of the pyridine ring. The alkylating agents that
are used should mimic the side chain of the middle amino
acid of a tripeptide sequence.
Scheme 1. Reagents and conditions: O3, NaOH in MeOH, CH2Cl2, 278 8C,
15 min.
In addition to the previously reported compounds 1a3 and

S. Saitton et al. / Tetrahedron 60 (2004) 6113–6120
6115
equivalent was performed by using 2-methyl-2-propenyl
bromide as electrophile. Thereby a methallyl group was
successfully introduced to afford 1f in 93% yield. Since
catalytic hydrogenation resulted in extensive deiodination
of 1e, no attempts to reduce the double bond at this stage
were made. The hydrogenation is however not expected to
be problematic after substitution of the iodine has been
accomplished. The side chain corresponding to threonine
was introduced by using acetaldehyde as electrophile to
afford 1g in 51% yield. The ester 1h, corresponding to an
aspartic acid residue, was isolated in only 13% yield after
reaction with ethyl bromoacetate. To improve the yield, the
desired product was instead synthesized in a two-step
procedure; first an allyl group was introduced by using allyl
bromide as electrophile to afford 1i in 87% yield. The allyl
group was then treated with ozone and methanolic sodium
hydroxide in dichloromethane to afford the methyl ester 1k
in 71% yield (Scheme 1).13 Attempts to introduce the side
chain corresponding to glutamic acid by using ethyl acrylate
as electrophile to afford 1j were unsuccessful. However, the
allyl substituent in 1i could be useful as precursor for side
chain equivalents of asparagine (via ester 1k), glutamine
and glutamate (via the primary alcohol). In subsequent
studies of the reactivities of fluorine and iodine at the 2- and
4-positions of the functionalized scaffold, the methyl
derivative 1b was used.
similar couplings. However, although a range of Pd-
catalysts [Pd(PPh3)4, Pd(OAc)2, (PPh3)2PdCl2, Pd2(dba)3],
ligands [dppf, dppe, P(t-Bu)3, AsPh3], co-catalysts and
additives [CuI, CuCl, CuO, LiCl], solvents [benzene,
DMSO, CHCl3, DMF] and reaction temperatures [25, 60
and 80 8C] were explored, the desired coupling reaction
between the pyridine scaffold and an amino acid chloride
was never realized.
The disappointing results from the Stille reactions led us to
investigate the reactivity of the 4-lithiated scaffold. It was
found that the Weinreb’s amide of Eoc-protected phenyl-
alanine could be coupled to 1b by using 2 equiv. of BuLi in
the presence of TMEDA. The use of TMEDA was found to
be required but even so, the yield was only around 10%. An
aldehyde, Ts-Pro-CHO,21,22 showed higher reactivity and
coupling under the same conditions, and by using 2 equiv.
of the pyridine derivative, the reaction proceeded in
approximately 60% yield. Finally, a pyridine Grignard
derivative proved to be excellent for the coupling reaction in
the 4-position of the pyridine.23 Reaction of 1 equiv. of 1b
with iPrMgCl in THF at room temperature followed by the
addition of Ts-Pro-CHO afforded the desired product 4 in
72% yield (Scheme 3). The reaction proceeded very cleanly
and no additional purification was needed after work-up by
extraction. 13C NMR spectra of the crude product show
signals for CH–OH at d 71.26 and 71.22, respectively,
which indicates that the two diastereomers were formed in
equal amounts.
2.3. Introduction of the N-terminal amino acid moiety
The next step to explore was the possibility of introducing
an amino acid moiety in the 4-position of the pyridine ring
where the functionalized scaffold carries an iodine handle.
The first approach was to perform the coupling via the
corresponding tin derivative in a palladium catalyzed Stille
cross-coupling reaction with an amino acid chloride.14–16
Although this is a thoroughly explored reaction also for
pyridine derivatives,17–19 to our knowledge only one
example of a Stille coupling with amino acid chlorides
has previously been reported.20 The trialkyl tin derivatives 2
and 3 were synthesized by reaction of 1b with BuLi in THF
at 278 8C followed by the addition of trialkyl tin chloride
(Scheme 2). A test reaction between 2 and 3-phenyl-
propionyl chloride succeeded at the first attempt using
Pd(PPh3)4 as catalyst and CuI as additive producing the
desired product in approximately 40% yield. Considerable
effort was thereafter made to use amino acid chlorides such
as Ts-Pro-COCl, Fmoc-Phe-COCl or Eoc-Phe-COCl in
Scheme 3. Reagents and conditions: (1) iPrMgCl, THF, rt, 1.5 h; (2) Ts-
Pro-CHO, rt, o.n.
Encouraged by these results, use of a Boc-protected amino
aldehyde instead of the tosyl protected one was also
attempted. It was found that the reaction proceeded nicely
with Boc-Pro-CHO‡ providing 5 in 86% yield with a
1
diastereomeric ratio of 1:3 according to H NMR analysis.
To afford the desired amino acid moiety in the 4-position,
alcohol 5 was oxidized using Dess–Martin periodinane to
give ketone 6 in 74% yield (Scheme 4). The optical purity of
Scheme 4. Reagents and conditions: (i) (1) iPrMgCl, THF, rt, 1 h; (2) Boc-
Pro-CHO, rt, o.n. (ii) Dess–Martin periodinane, CH2Cl2, rt, 3 h.
Scheme 2. Reagents and conditions: (i) (1) BuLi, THF, 278 8C, 1 h; (2)
R3SnCl, 278 8C, 1–1.5 h. (ii) Ts-ProCOCl, Pd-catalyst, co-catalyst,
additive, solvent and temperature were varied as specified in the text.
‡
Boc-Pro-CHO was synthesized according to Ref. 22 or obtained
commercially from Aldrich.

6116
S. Saitton et al. / Tetrahedron 60 (2004) 6113–6120
6 was confirmed by chiral HPLC analysis on a Pirkle
Covalent (S,S)-Whelk-O 1 10/100 Krom Fec column using
dichloromethane–isopropanol–heptane (48:4:48) as eluent.
A single peak was observed in the chromatogram for 6
which was compared to a chromatogram obtained from the
racemate.§
Scheme 6. Reagents and conditions: NaH, THF, rt to 60 8C, o.n.
2.4. Introduction of the C-terminal amino acid moiety
with NaH in a 0.2 M solution in THF (higher concentration
caused problems with polymerization) at 60 8C (Scheme 6).
It was important not to have an excess of NaH, since that
resulted in deiodination of the starting material. However,
even though the ether 9 was isolated in a satisfactory 80%
yield, it was found both by chiral HPLC analysis and by
measurement of optical rotation that the optical activity of
the product was lost under these reaction conditions. To
examine whether the racemization of the product was
caused by the excess of nucleophile, 1 equiv. of L- and
D-methyl lactate, respectively, were reacted with 1b using
KH as base. Chiral HPLC analysis (MTBE–heptane 5:95)
showed that even when the reaction was stopped after
30 min at room temperature (before complete consumption
of the starting material), the product was almost completely
racemized (er 56:44).
The introduction of amino acid equivalents in the 2-position
of the functionalized scaffold by nucleophilic substitution of
fluorine was thereafter investigated. At first, the reactivity of
nitrogen versus oxygen nucleophiles was compared using
glycine aldehyde dimethyl acetal and the corresponding
alcohol analogue (Scheme 5). It was found that the amine
required quite harsh reaction conditions; the substitution
was performed using the amino acetal as solvent at 140 8C.
The reaction was stopped after 4.5 h when a byproduct was
detected by TLC and the product 7 was isolated in 58%
yield. The byproduct was isolated in 4% yield and found to
be the 4-substituted derivative, i.e. the 4-iodo group had
been substituted instead of the fluorine atom.{ The
glycolaldehyde dimethylacetal was tested and found to
react considerably faster than the amino analogue; after
deprotonation by NaH the substitution went smoothly at
room temperature in THF and the expected product 8 was
isolated in 86% yield. The poor reactivity of amino acid
analogues under these conditions was confirmed by a test
reaction with the amino acid glycine in DMF. After 20 h at
140 8C the starting material was still intact according to
TLC analysis.
It was not possible to use the ethyl ester of glycolic acid as a
nucleophile together with NaH due to problems with
polymerization. This was not unexpected as there is less
steric hindrance in the glycolate compared to the lactate.
Another route for the introduction of a glycolate ester was
therefore employed. Use of allyl alcohol together with NaH
in THF allowed a smooth reaction to take place at room
temperature and the allyl ether 10 was isolated in 86% yield.
The methyl ester 11 could then be afforded from the alkene
in 76% yield by treatment with ozone and NaOH/MeOH in
CH2Cl2 (Scheme 7).
Scheme 5. Reagents and conditions: (i) glycine aldehyde dimethyl acetal,
140 8C, 4.5 h. (ii) glycol aldehyde dimethyl acetal, NaH, THF, rt, o.n.
The above findings indicated that considerable problems
would probably be experienced using regular amino acids as
nucleophiles in the substitution at the 2-position of the
scaffold. In addition, the conversion of the acetal function-
ality of 8 into an aldehyde or ester was unsuccessful
although several different reaction conditions were explored
[CrO3/AcOH,24 Oxonew/wet Al2O3,25 trichloroisocyanuric
acid,26 AcOH/H2O,27 wet SiO2/oxalic acid or H2SO4,28,29
Amberlitew IR-120,30 formic acid,31 Amberlystw 15,30
TiCl4/LiI,32 pTsOH,33 BF3·Et2O/LiI,34 ozone35]. The syn-
thesis of derivatives with an ether bridge between the
pyridine ring and the amino acid residue in the 2-position
was therefore further explored. It was found that L-ethyl
lactate could be used as nucleophile after deprotonation
Scheme 7. Reagents and conditions: (i) Allyl alcohol, NaH, THF, rt, 0.5 h.
(ii) O3, NaOH in MeOH, CH2Cl2, 278 8C, 1.5 h.
3. Conclusion
We have developed a synthetic strategy towards trisubsti-
tuted pyridine derivatives based on a functionalized scaffold
that provides the possibility of selective manipulation of one
position without disturbing the others. Efficient introduction
of substituents in the 3- and 4-positions of the pyridine
scaffold has been accomplished, whereas more work is
needed to provide access to chiral amino acid derived
nucleophiles suitable for substitution in the 2-position.
§
The racemate was produced by treatment of 6 with DBU in refluxing
{ THF.
1
According to H NMR and 19F NMR analysis.

S. Saitton et al. / Tetrahedron 60 (2004) 6113–6120
6117
4. Experimental
was purified by flash chromatography (EtOAc–heptane
1:10 then 1:5) to yield 1e (1.27 g, 96%) as a non-viscous,
1
4.1. General data
colorless oil; H NMR (CDCl3) d 7.63 (d, 1H, J¼5.3 Hz),
7.58 (d, 1H, J¼5.3 Hz), 4.56 (d, 1H, J¼9.1 Hz), 3.03 (br s,
1H), 2.24 (m, 1H), 1.11 (d, 3H, J¼6.7 Hz), 0.75 (d, 3H,
THF was distilled from potassium/sodium. 1H and 13C
NMR spectra were obtained on a Bruker DRX-400
(399.53 MHz) or a JEOL Eclipse 400 (399.78 MHz)
spectrometer using residual peak of solvent as internal
reference; CDCl3 [CHCl3 dH 7.26, CDCl3 dC 77.0]. TLC
analysis was performed on Silica Gel F254 (Merck) and
detection was carried out by examination under UV light
and staining with phosphomolybdic acid. Flash column
chromatography was performed on Silica Gel (Matrex,
J¼6.7 Hz); 13C NMR (CDCl3) d 159.61 (d, JC–F
244.5 Hz), 145.75 (d, JC–F¼16.8 Hz), 132.94 (d, JC–F
4.0 Hz), 128.65 (d, JC–F¼27.6 Hz), 113.01 (d, JC–F
¼
¼
¼
5.4 Hz), 81.36 (d, JC–F¼3.7 Hz), 33.66 (d, JC–F¼2.7 Hz),
19.20, 18.97; IR (CH2Cl2 cast) 3389 (br), 3083 (w), 2961,
2871, 1581, 1539, 1444, 1401 cm21; HRMS (EIþ) calcd for
C9H11FINO (M)þ 294.9869, found 294.9871.
˚
60 A, 35–70 mm, Grace Amicon). Chiral HPLC chroma-
4.2.3. 2-Fluoro-4-iodo-3-(2-methyl-allyl)-pyridine (1f).
LDA (4.48 mmol) was prepared and reacted with 2-fluoro-
3-iodopyridine (4.48 mmol) as described above. After the
addition of 3-bromo-2-methyl-1-propene (0.47 mL,
4.48 mmol), the reaction was stirred for 2 h at 278 8C and
then for 2.5 h at 245 8C. Work-up as described above
afforded 1.22 g of a yellow-brown clear light crude oil.
Purification by distillation at reduced pressure afforded 1f
(1.15 g, 93%) as a non-viscous, colorless oil, which
tography was performed on a Pirkle Covalent (S,S)-Whelk-
O 1 10/100 Krom Fec column. After work-up, all organic
phases were dried with MgSO4. All new compounds were
1
determined to be .95% pure by H NMR and 13C NMR
spectroscopy. For the synthesis of compounds 1a and 1b see
Ref. 3.
4.2. General procedure for the synthesis of 2-fluoro-4-
iodo-3-substituted pyridine derivatives
1
solidified upon standing: mp 38–40 8C; H NMR (CDCl3)
d 7.69 (dd, 1H, J¼5.2 Hz, 0.7 Hz), 7.60 (d, 1H, J¼5.2 Hz),
4.80 (m, 1H), 4.41 (m, 1H), 3.44 (s, 2H), 1.78 (s, 3H); 13C
NMR (CDCl3) d 160.52 (d, JC–F¼242.5 Hz), 145.42 (d,
JC–F¼15.8 Hz), 140.60, 132.46 (d, JC–F¼4.4 Hz), 125.86
(d, JC–F¼32.3 Hz), 115.13 (d, JC–F¼4.4 Hz), 112.09, 40.60
(d, JC–F¼1.3 Hz), 22.90; IR (CH2Cl2 cast) 3082 (w), 2974
(w), 1581, 1547, 1444, 1403 cm21; HRMS (CI) calcd for
C9H10FIN (MþH)þ 277.9842, found 277.9837. Anal. calcd
for C9H9FIN: C, 39.1; H, 3.3; N, 5.1. Found: C, 39.3; H, 3.4;
N, 5.2.
LDA was prepared by the addition of diisopropylamine
(0.63 mL, 4.48 mmol) to freshly distilled THF (10 mL) in a
dry two-necked round bottomed flask kept under nitrogen
atmosphere. The solution was cooled to 278 8C before
1.6 M n-BuLi in hexane (2.80 mL, 4.48 mmol) was added
and the resulting clear, colorless solution was stirred for
15 min. 2-Fluoro-3-iodopyridine (1.00 g, 4.48 mmol) was
added as a solution in THF (2 mL) whereby the reaction
immediately turned bright yellow. The mixture was stirred
for 1 h at 278 8C before the electrophile (4.48 mmol) was
added with syringe (neat or as a solution in THF). After the
indicated reaction times (see below), the mixture was
quenched by the addition of H2O and extracted into
Et2O. The pooled organic phases were washed with brine,
dried and evaporated to yield the crude product.
4.2.4. 1-(2-Fluoro-4-iodo-pyridin-3-yl)-ethanol (1g).
LDA (0.49 mmol) was prepared and reacted with 2-fluoro-
3-iodopyridine (0.45 mmol) as described above. After the
addition of acetaldehyde (0.028 mL, 0.49 mmol), the
reaction was stirred for 2 h at 278 8C. Work-up as described
above afforded a crude oil which was purified by flash
chromatography (EtOAc–heptane 1:5) to yield 1g (62 mg,
51%) as an oil; 1H NMR (CDCl3) d 7.73 (d, 1H, J¼5.2 Hz),
7.64 (d, 1H, J¼5.2 Hz), 5.16 (q, 1H, J¼6.7 Hz), 1.59 (dd,
3H, J¼6.7, 1.2 Hz); 13C NMR (CDCl3) d 159.99 (d,
JC–F¼242.9 Hz), 146.14 (d, JC–F¼17.2 Hz), 132.97 (d,
JC–F¼4.4 Hz), 129.72 (d, JC–F¼27.3 Hz), 110.97 (d,
4.2.1. 3-Benzyl-2-fluoro-4-iodo-pyridine (1c). LDA
(20 mmol) was prepared and reacted with 2-fluoro-3-
iodopyridine (18 mmol) as described above. After the
addition of benzyl bromide (2.4 mL, 20 mmol), the reaction
was allowed to reach room temperature while stirred over
night. Work-up as described above afforded a crude product
which was purified by flash chromatography (EtOAc–
heptane 1:10) to yield 1c (4.0 g, 71%) as a yellow oil; d 1H
NMR (CDCl3) 7.75–7.71 (m, 1H), 7.67–7.63 (m, 1H),
7.33–7.20 (m, 5H), 4.19 (s, 2H); 13C NMR (CDCl3) d
160.68 (d, JC–F¼242.2 Hz), 145.63 (d, JC–F¼16.2 Hz),
137.26, 132.69 (d, JC–F¼4.4 Hz), 128.53 (4 C:s), 127.12 (d,
JC–F¼32.3), 126.68, 114.88 (d, JC–F¼4.0 Hz), 38.63; IR
(neat) 2360 (w), 1579, 1544, 1441, 1394 cm21; HRMS
(FABþ) calcd for C12H9FIN (MþH)þ 313.9842, found
313.9845.
JC–F¼5.4 Hz), 72.92 (d, JC–F¼2.7 Hz), 22.23 (d, JC–F
¼
2.4 Hz); IR (CH2Cl2 cast) 3360 (br), 3084 (w), 2976, 2929,
1580, 1546, 1443, 1402 cm21; HRMS (FABþ) calcd for
C7H8FINO (MþH)þ 267.9635, found 267.9641.
4.2.5. 3-Allyl-2-fluoro-4-iodo-pyridine (1i). LDA
(4.93 mmol) was prepared and reacted with 2-fluoro-3-
iodopyridine (4.48 mmol) as described above. After the
addition of allyl bromide (0.43 mL, 4.93 mmol), the
reaction was allowed to reach room temperature over
night. Work-up as described above afforded a brown crude
oil which was purified by distillation under reduced pressure
to afford 1i (1.03 g, 87%) as an oil; 1H NMR (CDCl3) d 7.70
(d, 1H, J¼5.2 Hz), 7.62 (d, 1H, J¼5.2 Hz), 5.86 (ddt, 1H,
J¼16.6, 10.2, 6.2 Hz), 5.15–5.07 (m, 2H), 3.55 (app dq, 2H,
4.2.2. 1-(2-Fluoro-4-iodo-pyridin-3-yl)-2-methyl-pro-
pan-1-ol (1e). LDA (4.48 mmol) was prepared and reacted
with 2-fluoro-3-iodopyridine (4.48 mmol) as described
above. After the addition of isobutyraldehyde (0.41 mL,
4.48 mmol), the reaction was stirred for 2 h at 278 8C.
Work-up as described above afforded a crude product which
J¼6.2, 1.4 Hz); 13C NMR (CDCl3)
d 160.46 (d,
JC–F¼242.8 Hz), 145.46 (d, JC–F¼15.8 Hz), 132.51 (d,

6118
S. Saitton et al. / Tetrahedron 60 (2004) 6113–6120
JC–F¼4.7 Hz), 132.46, 125.98 (d, JC–F¼32.3 Hz), 117.19,
114.25 (d, JC–F¼4.4 Hz), 37.20 (d, JC–F¼1.4 Hz); IR
(CH2Cl2 cast) 3303 (w), 3081, 2981, 2921, 1639, 1580,
1544, 1444, 1401 cm21; HRMS (FABþ) calcd for C8H8FIN
(MþH)þ 263.9685, found 263.9697.
1H NMR (CDCl3) d 7.93 (d, 1H, J¼4.7 Hz), 7.15 (dd, 1H,
J¼4.7, 2.6 Hz), 2.30 (d, 3H, J¼1.6 Hz), 1.56–1.45 (m, 6H),
1.32 (sextet, 6H, J¼7.3 Hz), 1.16–1.09 (m, 6H), 0.88 (t, 9H,
J¼7.3 Hz); 13C NMR (CDCl3) d 161.78 (d, JC – F
243.5 Hz), 160.01 (d, JC–F¼1.0 Hz), 143.29 (d, JC–F
12.5 Hz), 128.89 (d, JC–F¼4.0 Hz), 125.62 (d, JC–F
26.6 Hz), 28.95 (3 C:s), 27.92 (3 C:s), 17.25 (d, JC–F
¼
¼
¼
¼
4.2.6. Methyl 2-(2-fluoro-4-iodo-pyridin-3-yl)-acetate
(1k). The allyl derivative 1i (24 mg, 0.091 mmol) was
dissolved in CH2Cl2 (2 mL). NaOH (0.46 mmol) was added
as a 2.5 M solution in MeOH and the reaction was cooled to
278 8C, whereafter ozone was passed through the solution
which immediately turned orange. After 15 min, the
solution turned blue and the ozone generator was switched
off to allow oxygen to pass through the reaction mixture
until the color disappeared. After addition of H2O–Et2O
(1:1, 2 mL) the reaction was allowed to reach room
temperature. The mixture was extracted into Et2O, the
combined organic phases were washed with brine, dried and
evaporated to afford a crude oil which was purified by flash
chromatography (EtOAc–heptane 1:9) to yield 1k (19 mg,
1.7 Hz), 13.56 (3 C:s), 10.29 (3 C:s); HRMS (FABþ) calcd
for C18H33FNSn (MþH)þ 402.1619, found 402.1624.
4.5. 1-(2-Fluoro-3-methyl-pyridin-4-yl)-1-[(S)-1-
(p-toluylsulfonyl)-pyrrolidin-2-yl]methanol (4)
The pyridine derivative 1b (100 mg, 0.42 mmol) was
dissolved in freshly distilled THF (1 mL) and kept under
nitrogen atmosphere. Isopropyl magnesium chloride
(0.21 mL, 0.42 mmol, 2.0 M in THF) was added with
syringe. A white precipitate was formed immediately. After
1.5 h, Ts-Pro-CHO (0.11 g, 0.42 mmol) was added with
syringe as a solution in THF (1 mL). The reaction mixture
turned clear and was stirred at room temperature over night
before it was quenched by the addition of H2O (2 mL). The
mixture was extracted into CH2Cl2, dried and evaporated to
yield 4 (111 mg, 72%) as a solid with dr 1:1 according to
13C NMR analysis; d 1H NMR (CDCl3) 7.96 (d, 1H,
J¼5.2 Hz), 7.67 (d, 2H, J¼8.3 Hz), 7.38 (d, 1H, J¼5.2 Hz),
7.28 (d, 2H, J¼8.3 Hz), 5.55 (d, 1H, J¼2.0 Hz), 3.85 (br s,
1H), 3.66–3.60 (m, 1H), 3.48–3.40 (m, 1H), 3.34–3.26 (m,
1H), 2.37 (s, 3H), 2.33 (s, 3H), 1.91–1.78 (m, 2H), 1.28–
1
71%) as a white solid; H NMR (CDCl3) d 7.78 (d, 1H,
J¼5.2 Hz), 7.65 (d, 1H, J¼5.2 Hz), 3.87 (s, 2H), 3.74 (s,
3H); 13C NMR (CDCl3) d 169.05, 160.64 (d, JC–F
243.5 Hz), 146.52 (d, JC–F¼15.8 Hz), 132.39 (d, JC–F
¼
¼
4.0 Hz), 121.65 (d, JC–F¼32.7 Hz), 115.16, 52.52, 38.70;
IR (CH2Cl2 cast) 2951 (w), 1737 (s), 1584, 1540, 1435,
1399 cm21; HRMS (FABþ) calcd for C8H8FINO2 (MþH)þ
295.9584, found 295.9579.
4.3. 2-Fluoro-3-methyl-4-trimethylstannyl-pyridine (2)
1.11 (m, 2H); 13C NMR (CDCl3) d 162.04 (d, JC–F
236.8 Hz), 153.34 (d, JC–F¼5.4 Hz), 144.02 (d, JC–F
¼
¼
The pyridine derivative 1b (3.1 g, 13 mmol) was dissolved
in THF (30 mL) and the solution was cooled to 278 8C.
BuLi (1.6 M, 9.1 mL) was added dropwise and the reaction
was stirred for 1 h before trimethyl tin chloride (2.9 g,
14 mmol) was added as a solution in THF (15 mL). The
reaction was stirred for 1 h before it was allowed to reach
room temperature. H2O was added and the mixture was
extracted into Et2O, dried and evaporated to yield a crude
yellowish oil which was purified by sublimation under
vacuum to collect most of the starting material as crystals,
followed by flash chromatography (CH2Cl2 –MeOH–
hexane 8:1:10) of the remaining oil to afford 2 (1.9 g,
52%) as an oil; 1H NMR (CDCl3) d 7.95 (d, 1H, J¼4.9 Hz),
7.17 (dd, 1H, J¼4.9, 2.6 Hz), 2.33 (d, 3H, J¼1.5 Hz), 0.38
(s, 9H); 13C NMR (CDCl3) d 161.73 (d, JC–F¼243.5 Hz),
15.2 Hz), 143.85, 133.67, 129.78 (2 C:s), 127.30 (2 C:s),
119.00 (d, JC–F¼3.7 Hz), 116.06 (d, JC–F¼31.7 Hz), 71.26
(CH–OH), 71.22 (CH–OH), 62.94, 50.34, 24.84, 24.71,
21.35, 10.54; IR (CH2Cl2 cast) 3297 (br), 2953, 2872, 1611,
1567, 1453, 1410, 1344, 1157 cm21; HRMS (FABþ) calcd
for C18H22FN2O3S (MþH)þ 365.1335, found 365.1333.
4.6. 1-((S)-1-tert-Butoxycarbonylpyrrolidin-2-yl)-1-[(2-
fluoro-3-methyl-pyridin-4-yl)]-methanol (5)
The pyridine derivative 1b (100 mg, 0.42 mmol) was
dissolved in freshly distilled THF (1 mL) and kept under
nitrogen atmosphere. Isopropyl magnesium chloride
(0.21 mL, 0.42 mmol, 2.0 M in THF) was added with
syringe. A white precipitate was formed immediately. After
1 h, Boc-Pro-CHO (84 mg, 0.42 mmol) was added as a
solution in THF (0.5 mL). The reaction mixture turned clear
and was stirred at room temperature over night before it was
quenched by the addition of H2O. The mixture was
extracted into Et2O, the combined organic phases were
washed with brine, dried and evaporated to yield a crude
yellow oil (dr 1:3 according to 1H NMR analysis).
Purification by flash chromatography (EtOAc–heptane 1:3
then 1:1) afforded the diastereomeric alcohols of 5 (113 mg,
86% combined yield) as a colorless oil. Partial separation
allowed the isolation of respective pure isomer for
characterization: Major isomer [a]D¼214.2 (c 1.0,
159.44, 143.42 (d, JC–F¼12.5 Hz), 128.25 (d, JC–F
4.0 Hz), 125.51 (d, JC – F¼26.9 Hz), 16.91 (d, JC –F
¼
¼
1.7 Hz), 28.72 (3 C:s); HRMS (FABþ) calcd for
C9H15FNSn (MþH)þ 276.0211, found 276.0215.
4.4. 2-Fluoro-3-methyl-4-tributylstannyl-pyridine (3)
The pyridine derivative 1b (2.2 g, 8.0 mmol) was dissolved
in THF (30 mL) and the solution was cooled to 278 8C.
BuLi (1.6 M, 5.5 mL) was added and the reaction was
stirred for 1 h before tributyl tin chloride (2.2 mL,
8.8 mmol) was added. The reaction was stirred for 1.5 h
before it was quenched with H2O (50 mL) and allowed to
reach room temperature. The mixture was extracted into
Et2O, dried and evaporated to yield a crude semi-solid
which was purified by flash chromatography (Et2O–hexane
1:19) to afford 3 (2.4 g, 75%) as a non-viscous, colorless oil;
1
CH2Cl2); H NMR (CDCl3) d 7.99 (s, 1H), 7.26 (s, 1H),
4.84 (d, 1H, J¼7.9 Hz), 4.18–4.09 (m, 1H), 3.50–3.23 (m,
2H), 2.26 (s, 3H), 1.83–1.57 (m, 3H), 1.47 (s, 9H), 1.38–
1.26 (m, 1H); 13C NMR (CDCl3) d 162.24 (d, JC–F¼237.1),
158.23, 154.46 (d, JC – F¼4.7 Hz), 144.32 (d, JC – F
¼

S. Saitton et al. / Tetrahedron 60 (2004) 6113–6120
6119
15.5 Hz), 120.17, 117.41 (d, JC–F¼31.7 Hz), 81.16, 74.12.
63.55, 47.64, 28.31 (3 C:s), 28.09, 24.02, 10.83; IR (CH2Cl2
cast) 3372 (br), 3054 (w), 2977, 2934, 2886, 2360, 2341,
1682, 1404 cm21; HRMS (FABþ) calcd for C16H24FN2O3
(MþH)þ 311.1771, found 311.1768. Minor isomer
6H), 2.26 (s, 3H); 13C NMR (CDCl3) d 155.72, 145.34,
123.65, 120.12, 111.87, 102.80, 54.25 (2 C:s), 43.31, 21.80;
IR (CH2Cl2 cast) 3399 (w), 2978 (w), 2936 (w), 2360, 2340,
1691, 1567, 1398 cm21; HRMS (FABþ) calcd for
C10H16IN2O2 (MþH)þ 323.0257, found 323.0232.
1
[a]D¼234.8 (c 1.0, CH2Cl2); H NMR (CDCl3) d 8.01 (s,
1H), 7.33 (s, 1H), 5.41 (s, 1H), 4.27–3.89 (m, 1H), 3.71–
3.01 (m, 3H), 2.31 (s, 3H), 1.99–1.56 (m, 4H), 1.52–1.48
(m, 9H); 13C NMR (CDCl3) d 162.16 (d, JC–F¼237.8 Hz),
155.85 (br), 153.86, 143.93 (d, JC–F¼12.1 Hz), 119.46,
116.42 (br), 80.49, 70.27, 61.21 (br), 48.09, 28.52 (3 C:s),
25.76, 24.05, 10.94; IR (CH2Cl2 cast) 3371 (br), 2978, 2921,
2889, 2358, 2339, 1692, 1403 cm21; HRMS (FABþ) calcd
for C16H24FN2O3 (MþH)þ 311.1771, found 311.1773.
4.9. 2-(2,2-Dimethoxy-ethoxy)-4-iodo-3-methyl-pyridine
(8)
Glycol aldehyde dimethyl acetal (1.1 g, 10 mmol) was
dissolved in THF (2.5 mL) and NaH (0.25 g, 5.8 mmol, 55%
in mineral oil) was added carefully. After the gas evolution
ceased, the pyridine derivative 1b (0.50 g, 2.1 mmol) was
added as a solution in THF (2.5 mL). The reaction was
stirred over night before it was quenched by the addition of
H2O and extracted into CH2Cl2. The combined organic
phases were dried and evaporated to yield a crude oil which
was purified by flash chromatography (EtOAc–heptane
1:10) to afford 8 (0.59 g, 86%) as a non-viscous, colorless
oil; 1H NMR (CDCl3) d 7.56 (d, 1H, J¼5.3 Hz), 7.29 (d, 1H,
J¼5.3 Hz), 4.75 (t, 1H, J¼5.4 Hz), 4.34 (d, 2H, J¼5.4 Hz),
3.43 (s, 6H), 2.34 (s, 3H); 13C NMR (CDCl3) d 160.39,
143.85, 127.66, 125.17, 112.89, 101.74, 65.34, 53.89 (2
C:s), 20.60; IR (CH2Cl2 cast) 3042 (w), 2952, 2831, 1563,
1445, 1411, 1386, 1135, 1077 cm21; HRMS (FABþ) calcd
for C10H15INO3 (MþH)þ 324.0097, found 324.0099.
4.7. (S)-4-(1-tert-Butoxycarbonylpyrrolidin-2-oyl)-2-
fluoro-3-methyl-pyridine (6)
The diastereomeric mixture of 5 (30 mg, 0.097 mmol) was
dissolved in dry CH2Cl2 (1 mL). Dess–Martin periodinane
(0.41 mL, 0.19 mmol) was added as a 15% wt solution in
CH2Cl2. The reaction was stirred for 3 h at room
temperature before it was quenched with Na2S2O3 (0.28 g,
1.13 mmol) dissolved in NaHCO3 (aq. sat.). The mixture
was extracted into Et2O, the combined organic phases were
washed with NaHCO3 (aq. sat.) and brine, dried and
evaporated to yield 6 (22 mg, 74%) as an oil: [a]D¼23.5 (c
1
1.0, MeOH); H NMR (CDCl3) d major [minor] rotamer
4.10. (R,S)-Ethyl 2-(4-Iodo-3-methyl-pyridin-2-yloxy)-
propanoate (9)
(ratio 3:2) 8.11 [8.16] (d, 1H, J¼5.1 Hz), 7.40 [7.27] (d, 1H,
J¼5.1 Hz), 4.94–4.85 (m, 1H), 3.71–3.39 (m, 2H), 2.31 (s,
3H), 2.23–2.11 (m, 1H), 2.03–1.76 (m, 3H), 1.44 [1.38] (s,
9H); 13C NMR (CDCl3) d major [minor] rotamer (ratio 3:2)
202.39 [200.69], 162.72 [162.87] (d, JC–F¼239.8 Hz),
154.48 [153.52], 149.32 [148.47], 144.68 [144.94] (d,
JC–F¼14.8 Hz), 119.09 [118.85], 118.40 [118.08], 80.13
[80.42], 63.85, 46.82 [46.67], 28.82 [29.37], 28.33 (3 C:s),
24.32 [23.11], 11.35 [11.54]; IR (CH2Cl2 cast) 3038 (w),
2977, 2934, 2882, 1693, 1602, 1556, 1402 cm21; HRMS
(FABþ) calcd for C16H22FN2O3 (MþH)þ 309.1614, found
309.1617. Chiral HPLC using CH2Cl2–iPrOH–heptane
(48:4:48) as eluent, retention time 5.1 min.
L-Ethyl lactate (2.5 g, 21 mmol) was dissolved in THF
(100 mL) and 55% NaH in mineral oil (0.46 g, 10 mmol)
was added carefully. The reaction was allowed to stir until
the gas evolution ceased (almost 2 h) and the solution was
clear with no solid particles before the pyridine derivative
1b (1.0 g, 4.2 mmol) was added as a solution in THF
(15 mL). The reaction was heated to 60 8C and allowed to
stir over night before it was cooled to room temperature,
quenched with H2O and extracted into Et2O. The combined
organic phases were washed with brine, dried and
evaporated to yield a crude oil which was purified by flash
chromatography (CH2Cl2 –MeOH–heptane 5:1:50) to
afford the racemate 9 (1.1 g, 80%) as a non-viscous,
The racemate of 6 was produced by treating 6 (2 mg,
6.5 mmol) with DBU (10 mL, 65 mmol) in refluxing THF for
7 h: Chiral HPLC using CH2Cl2–iPrOH–heptane (48:4:48)
as eluent, retention time 4.3 and 5.1 min, respectively.
1
colorless oil; d H NMR (CDCl3) 7.49 (d, 1H, J¼5.3 Hz),
7.27 (d, 1H, J¼5.3 Hz), 5.23 (q, 1H, J¼7.0 Hz), 4.17 (q, 2H,
J¼7.1 Hz), 2.37 (s, 3H), 1.59 (d, 3H, J¼7.0 Hz), 1.22 (t, 3H,
J¼7.1 Hz); 13C NMR (CDCl3) d 172.15, 159.64, 143.55,
127.83, 124.87, 112.98, 70.36, 60.78, 20.45, 17.53, 14.03;
IR (CH2Cl2 cast) 3044 (w), 2984, 2938, 1752, 1561, 1402,
1177, 1098 cm21; HRMS (FABþ) calcd for C11H15INO3
(MþH)þ 336.0097, found 336.0092.
4.8. 2-(2,2-Dimethoxyethylamino)-4-iodo-3-methyl-
pyridine (7)
The pyridine derivative 1b (0.10 g, 0.42 mmol) was
dissolved in glycine aldehyde dimethyl acetal (0.23 mL,
2.1 mmol) and heated to 140 8C. After 1.5 h, more amine
(0.23 mL, 2.1 mmol) was added. The reaction was stopped
after 4.5 h when the formation of a by-product was detected
by TLC. After cooling, the mixture was diluted with CH2Cl2
(5 mL) and washed with 0.05 M HCl, H2O and brine. The
organic phase was dried and evaporated to yield a brown
solid which was purified by flash chromatography
(CH2Cl2 –MeOH–hexane 5:1:20) to afford 7 (79 mg,
4.11. 2-Allyloxy-4-iodo-3-methyl-pyridine (10)
Allyl alcohol (0.50 mL, 7.4 mmol) was dissolved in THF
(4 mL) and NaH (0.14 g, 3.6 mmol, 60% in mineral oil) was
added carefully. After the gas evolution ceased the pyridine
derivative 1b (0.35 g, 1.5 mmol) was added as a solution in
THF (2 mL). The reaction was allowed to stir at room
temperature for 0.5 h before it was quenched with H2O and
extracted into EtOAc. The combined organic phases were
washed with brine, dried and evaporated to yield a crude
product which was purified by flash chromatography
1
58%) as a white semi-solid; d H NMR (CDCl3) 7.55 (d,
1H, J¼5.3 Hz), 7.03 (d, 1H, J¼5.3 Hz), 4.77–4.55 (m, 1H),
4.52 (t, 1H, J¼5.5 Hz), 3.59 (app t, 2H, J¼5.5 Hz), 3.41 (s,

6120
S. Saitton et al. / Tetrahedron 60 (2004) 6113–6120
4. Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G. Tetrahedron
1993, 49, 49–64.
(EtOAc–heptane 1:20) to afford 10 (0.35 g, 86%) as a
1
colorless oil; d H NMR (CDCl3) 7.57 (d, 1H, J¼5.3 Hz),
5. Kabalka, G.; Varma, M.; Varma, R. S.; Srivastava, P. C.;
Knapp, F. F. J. Org. Chem. 1986, 51, 2386–2388.
6. Burdeska, K. Synthesis 1982, 940–942.
7.28 (d, 1H, J¼5.3 Hz), 6.08 (ddt, 1H, J¼17.2, 10.4,
5.2 Hz), 5.38 (ddt, 1H, J¼17.2, 1.6, 1.6 Hz), 5.23 (ddt, 1H,
J¼10.4, 1.6, 1.6 Hz), 4.82 (ddd, 2H, J¼5.2, 1.6, 1.6 Hz),
2.35 (s, 3H); 13C NMR (CDCl3) d 160.51, 143.86, 133.42,
127.35, 125.08, 116.94, 112.76, 66.86, 20.60; IR (CH2Cl2
cast) 3080 (w), 2988 (w), 2936, 1563, 1401, 1334, 1259,
1175, 1007 cm21; HRMS (FABþ) calcd for C9H11INO
(MþH)þ 275.9885, found 275.9883.
7. Maddaford, S. P.; Charlton, J. L. J. Org. Chem. 1993, 58,
4132–4138.
8. Olah, G. A.; Wu, A. H.; Farooq, O. J. Org. Chem. 1988, 53,
5143–5145.
9. Srikrishna, A.; Viswajanani, R.; Sattigeri, J. A.; Yelamaggad,
C. V. Tetrahedron Lett. 1995, 36, 2347–2350.
10. Krishnamurthy, S. J. Org. Chem. 1980, 45, 2550–2551.
11. Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1976, 41,
3064–3066.
4.12. Methyl (4-iodo-3-methyl-pyridin-2-yloxy)-acetate
(11)
12. Zanoni, G.; Vidari, G. J. Org. Chem. 1995, 60, 5319–5323.
13. Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58,
3675–3680.
The pyridine derivative 10 (52 mg, 0.19 mmol) was
dissolved in CH2Cl2 (2 mL) and NaOH in MeOH (2.5 M,
0.40 mL) was added. The solution was cooled to 278 8C
before ozone was bubbled through. The reaction turned
dark-yellow immediately and the color disappeared
gradually until it was clear and colorless with a yellow
precipitate after 80 min. The ozone generator was switched
off after another 10 min when the reaction turned blue and
O2 was allowed to pass through until the solution was
colorless. H2O–Et2O (1:1, 2 mL) was added and the
mixture was allowed to reach room temperature. Additional
H2O was added and the reaction mixture was extracted into
Et2O. The combined organic phases were washed with
brine, dried and evaporated to yield 11 (44 mg, 76%) as an
oil; d 1H NMR (CDCl3) 7.53 (d, 1H, J¼5.3 Hz), 7.32 (d, 1H,
J¼5.3 Hz), 4.88 (s, 2H), 3.75 (s, 3H), 2.39 (s, 3H); d 13C
NMR (CDCl3) 169.61, 159.53, 143.65, 128.26, 125.11,
113.22, 62.74, 51.98, 20.49; IR (CH2Cl2 cast) 2998 (w),
14. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508–524.
15. Mitchell, T. N. Synthesis 1992, 803–815.
16. Farina, V. Pure Appl. Chem. 1996, 68, 73–78.
17. Yamamoto, Y.; Tanaka, T.; Ouchi, H.; Miyakawa, M.; Morita,
Y. Heterocycles 1995, 41, 817–825.
18. Gronowitz, S.; Bjork, P.; Malm, J.; Hornfeldt, A. B.
J. Organomet. Chem. 1993, 460, 127–129.
19. Bjork, P.; Malm, J.; Hornfeldt, A. B.; Gronowitz, S.
Heterocycles 1997, 44, 237–253.
20. Crisp, G.; Bubner, T. P. Synth. Commun. 1990, 20,
1665–1670.
21. Berry, M. B.; Craig, D. Synlett 1992, 41–44.
22. Fehrentz, J.-A.; Castro, B. Synthesis 1983, 676–678.
23. Trecourt, F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.;
Queguiner, G. Tetrahedron Lett. 1999, 40, 4339–4342.
24. Pistia, G.; Hollingsworth, R. I. Carbohydr. Res. 2000, 328,
467–472.
2951, 1762, 1567, 1428, 1397, 1215, 1175, 1073 cm21
;
HRMS (FABþ) calcd for C9H11INO3 (MþH)þ 307.9784,
25. Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O. Synlett
1999, 777–779.
found 307.9792.
26. Benincasa, M.; Grandi, R.; Ghelfi, F.; Pagnoni, U. M. Synth.
Commun. 1995, 25, 3463–3470.
Acknowledgements
27. Levchine, I.; Rajan, P.; Borloo, M.; Bollaert, W.; Haemers, A.
Synthesis 1994, 37–39.
We thank the Norwegian Research Council and the Swedish
Research Council for financial support of this project and
28. Huet, F.; Lechevallier, A.; Pellet, M.; Conia, J. M. Synthesis
1978, 63–65.
29. Huet, F. Synthesis 1978, 624–624.
˚
Umea University for providing laboratory facilities. We also
thank Tobias Stenstrom for skillful laboratory assistance.
¨
30. Coppola, G. M. Synthesis 1984, 1021–1023.
31. Celanire, S.; Salliot-Maire, I.; Ribereau, P.; Godard, A.;
Queguiner, G. Tetrahedron 1999, 55, 9269–9282.
32. Balme, G.; Gore, J. J. Org. Chem. 1983, 48, 3336–3338.
33. Imamura, H.; Shimizu, A.; Sato, H.; Sugimoto, Y.; Sakuraba,
S.; Nakajima, S.; Abe, S.; Miura, K.; Nishimura, I.; Yamada,
K.; Morishima, H. Tetrahedron 2000, 56, 7705–7713.
34. Mandal, A. K.; Shrotri, P. Y.; Ghogare, A. D. Synthesis 1986,
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References and notes
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