Solvent-dependent oxidations of 5- and 6-azaindoles to trioxopyrrolopyridines and functionalised azaindoles

Article abstract of DOI:10.1039/b719776d

A regioselective synthesis of 4,7-dimethoxy 5- and 6-azaindoles 2 has been achieved, based on the appropriate choice of ortho-directing or ortho-repulsing groups in the formylation of a pyridine ring. Studies on the regioselectivity of the formylation step and on the preparation of azidoacrylate intermediates 4 are described in this paper. The reactivity of the 5- and 6-azaindole structures towards BBr₃-mediated selective monodemethylation and oxidative demethylation reactions were also investigated. The regioselectivity of the deprotection was confirmed using a chemical approach. Oxidation reactions were then carried out on either dimethoxy- or hydroxymethoxyazaindoles, in different solvents, using [bis(trifluoroacetoxy)iodo]benzene. In acetonitrile-water, trioxopyrrolopyridines 12 were obtained, whereas the formation of functionalised azaindoles 17 was observed in acetonitrile-methanol. The tautomeric structure of the trioxopyrrolopyridines was proved by X-ray diffraction analysis. The Royal Society of Chemistry.

Full text of DOI:10.1039/b719776d

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Solvent-dependent oxidations of 5- and 6-azaindoles to trioxopyrrolopyridines
and functionalised azaindoles†
Zahia Mahiout,a,b Thierry Lomberget,a,b Sylvie Goncalvesa,b and Roland Barret*a,b
Received 2nd January 2008, Accepted 7th February 2008
First published as an Advance Article on the web 28th February 2008
DOI: 10.1039/b719776d
A regioselective synthesis of 4,7-dimethoxy 5- and 6-azaindoles 2 has been achieved, based on the
appropriate choice of ortho-directing or ortho-repulsing groups in the formylation of a pyridine ring.
Studies on the regioselectivity of the formylation step and on the preparation of azidoacrylate
intermediates 4 are described in this paper. The reactivity of the 5- and 6-azaindole structures towards
BBr3-mediated selective monodemethylation and oxidative demethylation reactions were also
investigated. The regioselectivity of the deprotection was confirmed using a chemical approach.
Oxidation reactions were then carried out on either dimethoxy- or hydroxymethoxyazaindoles, in
different solvents, using [bis(trifluoroacetoxy)iodo]benzene. In acetonitrile–water,
trioxopyrrolopyridines 12 were obtained, whereas the formation of functionalised azaindoles 17 was
observed in acetonitrile–methanol. The tautomeric structure of the trioxopyrrolopyridines was proved
by X-ray diffraction analysis.
Introduction
Results and discussion
The synthesis and functionalisation of the indole ring continues to
interest organic chemists, due to its widespread occurrence in many
natural products and biologically active molecules.1 More recently,
azaindoles have proved to be of prime importance to medicinal
chemists, and the growing interest of the scientific community and
pharmaceuticals firms in this core structure has resulted in a drive
to develop new methods for its preparation.2
Synthesis of dimethoxyazaindoles
A synthetic strategy for the regioselective preparation of the 5-
and 6-azaindoles 2 has been developed in our group,6 and is based
on an appropriate functionalisation of the pyridine ring followed
by the de novo pyrrolidine ring formation via the Hemetsberger
reaction (Fig. 2).7
As part of a project directed towards the design of new purine
bases,3 we planned to obtain the 5- and 6-azaquinone indoles
1 (3,7- and 3,9-dideazapurines, respectively) from the di- and
monomethoxy 5- and 6-azaindoles 2 and 3 (Fig. 1).4
Fig. 1 Strategy to 5- and 6-azaquinone indoles 1.
Upon searching the literature, we found that preparations of
azaquinones are scarce,5 and that the synthesis of an azaquinone
indole had not previously been described. This encouraged us to
develop a synthetic route towards such a structure, the results of
which are reported herein.
Fig. 2 Access to 5- and 6-aza dimethoxyindoles 2.
For this selective approach to be possible, we required access to
the dimethoxy 3- and 4-formyl pyridines 5a and 6a, precursors of
the azidoacrylates 4 (Fig. 2). To this end, we envisaged performing
a metalation–formylation procedure on 2,5-dimethoxypyridine
8a, a substrate which was easily obtained in three steps from 2-
methoxypyridine (Scheme 1).
Commercially available 2-methoxypyridine was first bromi-
nated at the para position using N-bromosuccinimide (NBS) in
a polar solvent.8 Halogen–lithium exchange followed by an in situ
aLaboratoire de Chimie The´rapeutique, Universite´ de Lyon, Lyon, F-69003,
France
bUniversite´ Lyon 1, ISPB, INSERM U863, IFR 62, 8 avenue Rockefeller,
F-69373, Lyon cedex 08, France. E-mail: barret@sante.univ-lyon1.fr;
Fax: +33 478 777 549; Tel: +33 478 777 542
† Electronic supplementary information (ESI) available: Additional exper-
imental procedures and characterisation data; 1H and 13C NMR spectra;
crystal structure data. See DOI: 10.1039/b719776d
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“ortho-repulsing” properties of the TIPS group during metalation
reactions (Scheme 2). In this case, a small amount (less than 10%)
of the starting material 8c was detected and separated from the
desired product 5c by flash chromatography.
Deprotections of the MOM and TIPS ethers were carried out
under the appropriate conditions (acidic medium for 6b and a
fluoride source for 5c) to afford the free pyridinols 9 and 10. These
were methylated under basic conditions to give the desired 2,5-
dimethoxy-4-formylpyridine 6a and its 3-formyl regioisomer 5a in
excellent yields (Scheme 3).
Scheme 1 Synthesis of formylation precursors 8. Reagents and conditions:
a) NBS 1.2 equiv, CH3CN, reflux, 16 h, 81%; b) 1) n-BuLi 1.5 equiv, THF,
−78 ◦C, 30 min. 2) B(OMe)3 1.5 equiv, −78 ◦C, 2 h. 3) peracetic acid 1.5
equiv, 0 ◦C, 1 h, 7, 83%; c) R = Me: K2CO3 1.5 equiv, DMF, 50 ◦C, 10 min
then MeI 1.0 equiv, 3 h 30 min, 8a, 86%. R = MOM: NaH 1.2 equiv, DMF,
rt, 45 min then MeOCH2Cl 1.15 equiv, 3h, 8b, 92%. R = TIPS: imidazole
2.1 equiv, DMF, (i-Pr)3SiCl 1.2 equiv, rt, 24 h, 8c, quantitative.
trapping with trimethylborate afforded the corresponding borane,
which was oxidised to give 5-hydroxy 2-methoxypyridine 7, after a
reductive work-up.9 Dimethoxypyridine 8a was then obtained by
methylation of pyridinol 7 under basic conditions (Scheme 1).
Although metalation reactions10 of 2-methoxypyridine have
been studied by several research groups,11 no examples of the
metalation/functionalisation of substrate 8a have been described
in the literature. In order to explore this area, we prepared further
substrates bearing other groups such as methoxymethoxyl (MOM)
(8b) and triisopropylsilyl (TIPS) (8c) groups (Scheme 1), and
studied their behaviour towards the lithiation step.
We then proceeded to investigate on substrates 8 the lithium-
based metalation procedure developed by Que´guiner and co-
workers.11b Lithiation was performed at 0 ◦C by using methyl-
lithium and a catalytic amount of diisopropylamine (DIPA),
followed by an electrophilic quench with N-formylpiperidine.
When applied to the dimethoxy substrate 8a, this method led to
Scheme 3 Access to 3- and 4-formyldimethoxypyridines 5a and 6a.
Reagents and conditions: e) 3 N aq HCl, THF, 50 ◦C, 3 h, 95%; f) TBAF
1.5 equiv, THF, 0 ◦C to rt, 2 h, 92%; g) K2CO3 1.5 equiv, DMF, 50 ◦C,
10 min then MeI 1.0 equiv, 3 h, 6a, 89% and 5a, 96%.
1
We then turned our attention to the preparation of the azi-
doacrylates 4. Our first attempt involved a condensation reaction
between 3-formylpyridine 5a and an excess of methyl azidoacetate,
an 81:19 mixture (determined from the H NMR of the crude
product) of the 4- and 3-formyl derivatives 6a and 5a. These
were isolated after chromatographic separation in 55% and 15%
yields, respectively (Scheme 2). The use of the ortho-directing12
MOM group13 enhanced the proportion of the 4-isomer, as
compound 6b was obtained from 8b with a 62% isolated yield.14
Further investigation of the reaction in the presence of other
ortho-directing groups such as tetrahydropyranyl ether15 or N,Nꢀ-
diethyl carbamate12a were less satisfactory (lower regioselectivity
or degradation of starting material without metalation of the
pyridine ring, respectively).
◦
in the presence of sodium methoxide as the base, at 0 C. These
conditions led to the formation of a mixture of the expected
azidoacrylate 4a, together with azidoalcohol 11a in a 28:72 ratio
(Scheme 4).17
Scheme 2 Formylation of 5-substituted 2-methoxypyridines 8. Reagents
and conditions: d) 1) MeLi 1.8 equiv, DIPA 2 mol%, THF, 0 ◦C, 3 h. 2)
N-formylpiperidine 1.8 equiv, −40 ◦C, 2 h.
The same metalation–electrophilic quench conditions were
then applied to substrate 8c, which was protected with the
sterically hindered triisopropyl group. This resulted in the exclusive
formation of compound 5c with a 64% isolated yield,16 showing the
Scheme 4 Azidoalcohol 11a versus azidoacrylate 4a formation from
3-formylpyridine 5a. Reagents and conditions: h) MsCl 5 equiv, Et3N 10
equiv, CH2Cl2, rt, 15h, 84%.
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Azidoacrylate 4a was easily separated from the azidoalcohol
11a by flash chromatography, and the latter was converted into
4a in good yield by reaction with methanesulfonyl chloride in the
presence of excess triethylamine (in situ basic elimination of the
mesylate).
In an attempt to obtain exclusively 4a from the condensation
reaction, we varied the reagent addition time and the reaction
temperature. Adding the reagents over 30 seconds (instead of
5 minutes) at the same temperature, a higher proportion of
azidoacrylate 4a was observed (ratio 11a/4a 46:54), showing
that exothermicity of the reaction may influence the product
distribution.
tive oxidising reagents.19 We first attempted the transformation
of dimethoxy-5-azaindole 2a with the commercially available
[bis(trifluoroacetoxy)iodo]benzene (PIFA).20 Four equivalents of
the oxidising reagent were necessary for a complete conversion of
the starting material. This resulted in the surprising formation
of trioxopyrrolopyridine 12a with an excellent yield of 97%
(Scheme 6).21
At a lower temperature (−20 ◦C), the slow addition (over
a 45 min period) of a methanolic solution of 5a and methyl
azidoacetate onto sodium methoxide in methanol resulted in the
selective formation of the kinetic product 11a with a modest 46%
isolated yield (Scheme 4).18 When the reaction was carried out at
30 ◦C, with a fast addition of the reagents, however, the exclusive
formation of the desired acrylate 4a was observed.
Following this optimised procedure, azidoacrylates 4a and
4b were obtained in 57% and 51% isolated yields respectively
(Scheme 5). The 5- and 6-azaindoles 2 could then be prepared in
moderate to good yield by the Hemetsberger thermolysis reaction.
Suspensions of the corresponding acrylates 4 were heated at reflux
in xylene for one hour, then the reaction mixture was cooled slowly
to crystallise the products. Due to large solubility differences
between compounds 2a and 2c, complete crystallisation of 5-
azaindole occurred at room temperature, whereas only◦ partial
crystallisation of the 6-aza isomer was observed at −20 C. Ad-
ditional flash chromatography of the supernatant was necessary
for complete recovery of compound 2c. N1 functionalisation of
the azaindoles is also feasible, as shown by the benzylation of the
5-aza derivative to compound 2b (Scheme 5).
Scheme 6 PIFA-mediated oxidations of dimethoxy-5- and 6-azaindoles
2 to trioxopyrrolopyridines 12. Reagents and conditions: l) PIFA 4 equiv,
CH3CN–water 1:1, rt, 4 h.
This oxidation reaction was also successful when applied to N-
benzyl-protected 5-azaindoles and in the 6-azaindole series, as the
corresponding trioxo compounds 12b and 12c were obtained in
good yields (Scheme 6).
The identity of the oxidised product was confirmed by high-
resolution mass spectroscopy, infrared spectroscopy and NMR,
this last technique being essential in determining the tautomeric
form of the compound in solution. We observed three peaks at
158.7, 160.0 and 160.7 ppm in the 13C spectrum, similar to those
of the amide, rather than the 180–190 ppm usually associated with
a quinone (Fig. 3).
Scheme 5 Synthesis of dimethoxy 5- and 6-azaindoles 2. Reagents and
conditions: i) MeONa 4.1 equiv, methyl azidoacetate 3.8 equiv, MeOH,
30 ◦C, 2 h; j) Xylene, 140 ◦C, 1 h; k) NaH 1.2 equiv, DMF, 50 ◦C, 3 h
30 min, then BnBr 1.1 equiv, 50 ◦C, 2 h.
Fig. 3 Tautomeric forms of compound 12a.
Evaporation of an acetone solution of 12a provided a single
crystal for a X-ray diffraction analysis‡ (Fig. 4). These results
supported the spectroscopic data, confirming that the major
tautomer form was the 4,6,7-trioxopyrrolopyridine compound
rather than the 6-hydroxyazaquinone indole (Fig. 3).
Oxidation of dimethoxyazaindoles
Continuing our strategy for the preparation of the azaquinone
indoles 1, we then studied their behaviour under oxidising condi-
tions (Fig. 1). We thought it was possible that the behaviour of the
dimethoxyazaindoles towards oxidative demethylation conditions
may be similar to that of their carbon congeners.4
Among the numerous methods of oxidation available to us,
we focused our attention on hypervalent iodine reagents. These
have proved to be essential in modern organic chemistry, be-
ing of great synthetic value as mild and highly chemoselec-
¯
‡ Crystal data for 12a: C9H6N2O5, M = 222.16; triclinic, space group P1,
◦
˚
a = 5.35, b = 8.79, c = 10.58 A, a = 111.47, b = 94.77, c = 94.31 ,
3
V = 458.78(1) A , Z = 2, dx = 1.608 g cm−3, l = 0.14 mm−1, Tmin,max
=
˚
0.991, 0.992; T = 293 K, 3192 measured reflections, 2078 independent
reflections (Rint = 0.042), 1005 reflections with I > 2.0r(I). R[F2
>
2r(F2)] = 0.047, xR(F2) = 0.057, S = 1.06. CCDC reference number
641655. For crystallographic data in CIF or other electronic format see
DOI: 10.1039/b719776d.
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substrate 2c required only 2.5 equiv of BBr3 to give a 8:92 mixture
of 2c and monodemethylated product 3c.
We were not able to obtain a single crystal of a quality
suitable for X-ray diffraction analysis of the mono-demethylated
products 3a and 3c. In order to confirm the regioselectivity of the
demethylation, we took advantage of the regioselective synthesis
of formyl pyridines that we have previously developed.
Reaction of the TIPS ether of 3-formyl pyridine 5c with
◦
methyl azidoacetate under basic conditions at 0 C afforded the
azido methyl acrylate 13,26 which was subsequently submitted
to thermolysis conditions. Cleavage of the orthogonal TIPS
protecting group on the resulting indole 14 with a fluoride
source then provided indirect chemical proof of the selectivity
of the demethylation, as 7-hydroxy-4-methoxy-5-azaindole 3a was
obtained (Scheme 8).
Fig. 4 ORTEP view of the crystal structure of 12a. Ellipsoids are
represented at the 30% probability level.
The bond lengths observed in the X-ray crystal structure22
allowed us to determine without any doubt that we had isolated
the trioxo tautomer. All three carbon–oxygen bond lengths on
the pyridine ring were in good agreement with that expected for
=
a carbonyl group C O; each bond of the pyridine ring, except
the junction C(7)–C(13), was a single bond (whereas C(8)–N(3)
in the hydroxyquinone form should be a double bond), and the
proton H(2) located on N(3) was unambigously detected from the
˚
diffraction data (bond length = 0.88 A) and formed a hydrogen
bond with O(4) of another molecule of the cell packing. This last
observation provides convincing proof for the trioxo tautomeric
form (Fig. 4).23
Oxidation of hydroxymethoxyazaindoles
In an attempt to increase the efficiency of the transformation, we
then assessed whether we could obtain trioxopyrrolopyridines 12
from monohydroxy azaindoles 3 with a reduced amount of the
oxidising agent.24
To this end, hydroxymethoxy azaindole substrates were pre-
pared by demethylation of dimethoxy-5- and 6-azaindoles.
Dimethoxyazaindoles 2a and 2c were treated with optimised
equivalents of boron tribromide in dichloromethane to afford
the monodemethylated products 3a and 3c in 57 and 55% yield,
respectively, after optimisation (Scheme 7).25
Scheme 8 Access to 7-OTIPS-protected 5-azaindole 7 and TBAF depro-
tection. Reagents and conditions: o) Methyl azidoacetate 3.8 equiv, MeONa
4.1 equiv, MeOH, 0 ◦C, 2 h, 20%; p) Xylene, 140 ◦C, 1 h, 77%; q) TBAF,
1.5 equiv, THF, 0 ◦C to rt, 2 h, 92%.
The same strategy was applied to confirm the regioselectivity of
the demethylation of 2c upon treatment with BBr3. In this case,
however, the three-step sequence, which concluded with an acidic
hydrolysis of the methoxymethyl (MOM) ether group, afforded 3c
in a very disappointing 5% overall yield from the 4-formylpyridine
6b (Scheme 9). The low yield when R = Me is explained by the
poor stability of compound 15a in solution, combined with the
unexpectedly low-yielding indole ring formation.
We then attempted to improve the yield of the azidoacrylate
formation by using the more stable tert-butyl azidoacetate.27
After the exclusive formation of the azidoalcohol (11b) at low
temperature, treatment with methanesulfonyl chloride in the
presence of excess triethylamine gave the tert-butyl azidoacrylate
15b in 54% yield over the two steps (Scheme 9).
Scheme 7 Selective demethylation of dimethoxy 5- and 6-azaindoles 2
The Hemetsberger reaction then afforded the expected indole
16b in a good 72% yield. To obtain the monohydroxy compound
3c, hydrolysis of the MOM ether combined with an in situ
transesterification (R = t-Bu to R = Me) was achieved by a simple
treatment of the indole with concentrated hydrochloric acid in
methanol. In this way, 3c was obtained in an improved 19% overall
yield from the 4-formylpyridine 6b.
With the hydroxymethoxy azaindoles 3a and 3c in hand, we
proceeded to study their behaviour when oxidised by PIFA. In
contrast to the dimethoxyazaindole substrates, we found that
into hydroxymethoxy azaindoles 3. Reagents and conditions: m) BBr3
5
equiv, CH2Cl2, −78◦C to rt, 16 h; n) BBr3 2.5 equiv, CH2Cl2, −78 ◦C to
rt, 16 h.
This Lewis acid-promoted demethylation reaction proved to be
very substrate-sensitive. When 5-azaindole 2a was treated with
2.5 equiv of BBr3, a 70:30 mixture of the starting material and
1
monodemethylated product 3a (determined by H NMR of the
crude product) was obtained. With 5 equiv BBr3, a mixture of
2a/3a in a 16:84 ratio was formed. By comparison, the 6-aza
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Scheme 9 Access to 4-OMOM-protected 6-azaindoles 16 and acidic
deprotection. Reagents and conditions: R = Me: r) MeONa 4.1 equiv,
MeOH, 30 ◦C, 2 h, 21%; s) Xylene, 140 ◦C, 2 h, 31%; t) HCl 3M, THF,
50◦C, 3 h, 77%. R = t-Bu: r) 1) i-PrONa 2.0 equiv, i-PrOH, −30 ◦C, 4 h.
2) MsCl 5.0 equiv, Et3N 10.0 equiv, CH2Cl2, 45 ◦C, 1 h, 54% over 2 steps;
s) Xylene, 140 ◦C, 2 h, 72%; t) Conc. HCl, MeOH, rt, 4.5 h then 50 ◦C,
20 h, 49%.
the reaction required only one equivalent of oxidising agent for
complete conversion of the substrate. When a 1:1 acetonitrile–
water solvent mixture was employed, trioxopyrrolopyridines 12a
and 12c were obtained in excellent 95 and 99% yields, respectively
(Scheme 10).
Fig. 5 Plausible mechanism for the PIFA-mediated oxidation of hydrox-
ymethoxy-5- and 6-azaindoles 3.
The fate of the resulting intermediate would then depend on the
nature of the R group: (a) where R = Me, a simple enolisation of
the ketone at the 7-position gives the hydroxydimethoxyazaindole
17; (b) where R = H, an overoxidation occurs28 that leads, after
enolisation at the 4-position, to the trioxopyrrolopyridines 12.
A similar mechanism could be proposed for the oxidations
of dimethoxyazaindoles 2 into pyrrolopyridines 12,29 according
to Kita’s mechanism for the oxidative demethylation of para-
dimethoxy aromatic rings into para-quinones.20
Conclusions
In summary, we have described a regioselective synthesis of
dimethoxy-5- and 6-azaindoles starting from a common substrate
7. The reactivity of these nitrogen-containing heterocycles towards
Lewis acid-promoted demethylation reactions and PIFA-mediated
oxidative demethylations was investigated. The structures of the
novel trioxopyrrolopyridine products were proved by crystallo-
graphic and spectroscopic means.
Scheme 10 Solvent-dependent oxidations of hydroxymethoxy-5- and
6-azaindoles 3. Reagents and conditions: u) PIFA 1 equiv, CH3CN–water
1:1, rt, 1 h; v) PIFA 1 equiv, CH3CN–methanol 1:1, rt, 1 h.
We have also demonstrated the utility of these unprecedented
oxidation reactions of dimethoxy- and hydroxymethoxyazaindoles
as entries to trioxopyrrolopyridines and functionalised azaindoles.
When water was replaced by methanol, formation of the
functionalised 5- and 6-azaindoles 17a and 17c was observed,
resulting from incorporation of a solvent-derived methoxy group
into the 6- and 5-positions, respectively (Scheme 10).
In light of this last result, we can suggest a mechanism for the
PIFA-mediated oxidations (figure 5). We propose that the first
step consists of the activation of the pyridinol by coordination
with a PIFA molecule. This is facilitated by the release of a
trifluoroacetate anion. This activation would then favor the attack
of a solvent molecule (either water or methanol) on the 4-position,
thus forming an (hemi)acetal. The electrophilic character of the
6-position, a to the nitrogen atom, could be the driving force for
a second nucleophilic attack by the solvent. There is literature
precedence for a similar reaction in an azaquinone structure.5e
Experimental
Unless otherwise indicated, all reactions were carried out under
a positive pressure of argon and with oven-dried glassware.
Melting points were measuredonaBarnstead Electrothermal 9200
melting point apparatus and are uncorrected. Infrared spectra
(IR) were recorded on a Perkin-Elmer FT-IR SPECTRUM ONE
spectrometer (film or 1% in KBr). Proton nuclear magnetic
resonance (1H NMR) spectra were recorded on Bruker ALS300
and DRX 300 Fourier transform spectrometers, using an internal
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deuterium lock, operating at 300 MHz. Chemical shifts are
reported in parts per million (ppm) relative to internal standard
General experimental procedure for the methylation of pyridinols:
preparation of 2,5-dimethoxypyridine 8a
(tetramethylsilane, dH = 0.00; CDCl3, dH = 7.26; acetone-d6, dH
=
To a solution of 5-hydroxy-2-methoxypyridine 7 (1.877 g,
15 mmol) in DMF (45 mL) at room temperature was added K2CO3
(3.110 g, 22.5 mmol). The mixture was stirred at 50 ◦C for 10 min,
then methyl iodide (935 lL, 15 mmol) was added. The reaction
mixture was then stirred for 3 h 30 min at 50 ◦C. After addition of
water (50 mL) and EtOAc (100 mL) and decantation, the aqueous
phase was extracted with EtOAc (2 × 100 mL) and the organic
phase was dried over Na2SO4. After filtration and removal of the
solvents under reduced pressure, the residue was purified by flash
chromatography (PE–EtOAc 70:30) to afford 8a (1.790 g, 86%) as
a yellow liquid.
2.05 and DMSO-d6, dH = 2.50).30 Data are presented as follows:
chemical shift (d, ppm), integration, multiplicity (s = singlet, d =
doublet, t = triplet, q = quadruplet, m = multiplet, br = broad),
coupling constant (reported in Hz), assignment. Atom numbering
refers to pyridine and indole nomenclatures. Carbon magnetic
resonance (13C NMR) spectra were recorded on Bruker AC200
and DRX 300 Fourier transform spectrometers, using an internal
deuterium lock, operating at 50 MHz and 75 MHz respectively.
Chemical shifts are reported in parts per million (ppm) relative
to internal standard (tetramethylsilane, dC = 0.00; CDCl3, dC
=
77.16; acetone-d6, dC = 29.84 and DMSO-d6, dC = 39.52). Carbon
multiplicities (indicated in parentheses) were determined by DEPT
experiments. Electron-spray low-resolution mass spectra were
recorded on a Thermo ALCQ Advantage spectrometer. Gas
chromatography coupled with low-resolution mass spectroscopy
(GC-MS) were recorded on a Thermo Focus GC (fused silica
column, diameter 0.25 mm, length 15 m, coated with TR5M5,
mmax (film)/cm−1 3583, 2947, 2838, 1738, 1611, 1576, 1493, 1464,
1382, 1253, 1185, 1039, 828 and 742; dH (300 MHz; CDCl3) 3.81
(3H, s, OCH3), 3.89 (3H, s, OCH3), 6.69 (1H, d, J = 9.0, ArH3),
7.21 (1H, dd, J = 9.0 and J = 3.0, ArH4) and 7.80 (1H, d, J =
3.0, ArH6); dC (75 MHz; CDCl3) 53.4 (CH3), 56.2 (CH3), 111.0
(CH), 126.7 (CH), 131.0 (CH), 151.1 (C) and 158.7 (C); GC-MS
•
(retention time: 3.97 min) m/z (EI) 139 (M+ , 96%), 138 (100), 96
◦
thickness 0.25 lm, initial temperature for 2 min: 70 C, heating
(48) and 54 (44).
◦
rate 15 C min−1) DSQ spectrometer operating at 70 eV. High-
resolution mass spectra were recorded on a Thermoquest Finnigan
MAT 95 XL spectrometer (for chemical ionisations, isobutane was
used). Elemental analyses were performed by the Service Central
d’Analyses du CNRS, Solaize, France.
2-Methoxy-5-(triisopropylsilanyloxy)pyridine 8c
To a solution of 5-hydroxy-2-methoxypyridine 7 (2.503 g,
20 mmol) and imidazole (2.859 g, 42 mmol) in DMF (60 mL) at
room temperature was added triisopropylsilyl chloride (5.2 mL,
24 mmol). The reaction mixture was stirred for 20 h, after
which water (50 mL) and EtOAc (100 mL) were added. After
decantation, the aqueous phase was extracted with EtOAc (2 ×
100 mL) and the organic phase was dried over Na2SO4. After
filtration and removal of the solvents under reduced pressure, the
residue was purified by flash chromatography (PE–EtOAc 90:10)
to afford 8c (6.336 g, quantitative) as a pale yellow liquid.
Product purification by flash column chromatography was
˚
performed using Merck Kieselgel 60 A (40–63 lm). Analytical
thin layer chromatography (TLC) was carried out using Merck
commercial aluminium sheets coated (0.2 mm layer thickness) with
Kieselgel 60 F254, with visualization by ultraviolet and anisalde-
hyde stain solution. N,N-dimethylformamide (HPLC grade) was
used as received without purification. THF (anhydrous analytical
grade, stored over molecular sieves) was purchased from Carlo
Erba Chemicals. Dichloromethane was distilled over calcium
hydride prior to use. Diisopropylamine was distilled over sodium
hydride prior to use. Methanol and isopropanol were distilled over
sodium prior to use. Petroleum ether (PE) refers to the 40–60 ◦C
boiling point fraction. MeLi and n-BuLi solutions were titrated
using N-benzylbenzamide.31 All other chemical reagents were used
as received.
mmax (film)/cm−1 2945, 2893, 2867, 2727, 1743, 1724, 1607, 1584,
1573, 1488, 1464, 1432, 1378, 1256, 1195, 1115, 1060, 1031, 997,
912, 883, 818 and 688; dH (300 MHz; CDCl3) 1.08 (18H, d, J =
6.8, (CH(CH3)2)3), 1.16–1.28 (3H, m, (CH(CH3)2)3), 3.87 (3H, s,
OCH3), 6.61 (1H, d, J = 8.9, ArH3), 7.1((1H, dd, J = 8.9 and J =
3.0, ArH4) and 7.79 (1H, d, J = 3.0, ArH6); dC (75 MHz; CDCl3)
12.6 (CH), 17.8 (CH3), 53.4 (CH3), 110.8 (CH), 131.1 (CH), 136.8
(CH), 147.4 (C) and 158.6 (C); GC-MS (retention time: 9.83 min)
5-Hydroxy-2-methoxypyridine 7 and 2-methoxy-5-(methoxy-
methoxy)pyridine 8b were prepared according to known
procedures.9 Methyl- and tert-butyl azidoacetate were prepared
from methyl- and tert-butyl bromoacetate and sodium azide
according to a literature procedure.32
•
m/z (EI) 281 (M+ , 22%), 238 (62), 210 (50), 182 (100) and 168
(58).
Typical experimental procedure for the formylation of
5-substituted 2-methoxypyridines 8: preparation of 5a and 6a
To a solution of 2,5-dimethoxypyridine 8a (417 mg, 3.0 mmol)
in anhydrous THF (10 mL) was added diisopropylamine (10 lL,
5-Bromo-2-methoxypyridine
◦
To a solution of 2-methoxypyridine (10.91 g, 100 mmol) in CH3CN
(300 mL) was added N-bromosuccinimide (21.36 g, 120 mmol).
The mixture was then heated at reflux (90 ◦C) for 9 h. After cooling
down to rt, the mixture was filtered over a pad of silica (3 cm
thick, washing with PE–Et2O 80:20) and, after evaporation of
the filtrate under reduced pressure, the crude oil was purified by
flash chromatography (PE–Et2O 95:5) to afford the title compound
(15.212 g, 81%) as a colorless oil.
0.06 mmol). The mixture was then cooled to −40 C and MeLi
(1.6 M solution in Et2O, 3.4 mL, 5.4 ◦mmol) was slowly added.
The resulting mixture was stirred at 0 C for 3 h, then cooled to
◦
−40 C and N-formylpiperidine (600 lL, 5.4 mmol) was added.
The mixture was stirred at −40 ◦C for 2 h then quenched by
careful addition of a solution of 37% aqueous HCl (3 mL) in THF
(7 mL). The temperature was raised to 20 ◦C, then water (30 mL)
and EtOAc (150 mL) were added. The pH of the resulting mixture
was then adjusted to 8–9 with solid K2CO3. After decantation,
Spectral data were identical to those reported in the literature.8
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the aqueous phase was extracted with EtOAc (2 × 20 mL). After
drying of the combined organic phases with Na2SO4 and filtration,
the solvents were removed under reduced pressure. The resulting
crude product was purified by flash chromatography (PE–EtOAc
96:4 to 80:20).
17.8 (CH3), 53.9 (CH3), 118.3 (C), 127.6 (CH), 144.2 (CH), 147.9
(C), 159.3 (C) and 189.3 (CH); m/z (CI) 311 (23%) and 310 (MH+,
100); HRMS (CI) found (MH+) 310.1838, C16H28NO3Si requires
310.1838.
Typical experimental procedure for the acidic deprotection of 6b:
5-hydroxy-2-methoxy-pyridine-4-carbaldehyde 9
The less polar fraction was 2,5-dimethoxypyridine-3-
carbaldehyde◦5a (77 mg, 15% yield, colorless solid).
Mp 64–66 C; Anal. found C, 57.4; H, 5.5; N, 8.35. C8H9NO3
requires C, 57.5; H, 5.4; N, 8.4; mmax (KBr)/cm−1 3461, 3055, 2953,
2875, 1679, 1611, 1577, 1488, 1445, 1432, 1411, 1382, 1305, 1290,
1258, 1211, 1172, 1044, 1012, 955, 904, 800, 752 and 737; dH
(300 MHz; CDCl3) 3.84 (3H, s, OCH3), 4.03 (3H, s, OCH3), 7.66
(1H, d, J = 3.3, ArH), 8.10 (1H, d, J = 3.3, ArH) and 10.35
(1H, s, CHO); dC (75 MHz; CDCl3) 53.9 (CH3), 56.2 (CH3), 117.9
(C), 121.0 (CH), 140.5 (CH), 151.4 (C), 159.4 (C) and 189.1 (CH).
The more polar fraction was 2,5-dimethoxypyridine-4-
carbaldehyde 6a (279 mg, 56% yield, yellow solid).
To
a solution of 2-methoxy-5-(methoxymethoxy)pyridine-4-
carbaldehyde 6b (986 mg, 5 mmol) in THF (10 mL) was added
3 N aqueous HCl (15 mL) and the resulting mixture was stirred
at 50 ◦C for 3 h. After this time, the mixture was cooled to
room temperature and water (100 mL) was added followed by
neutralisation (pH 7–8) with solid K2CO3. The aqueous phase was
extracted with EtOAc (3 × 100 mL). After drying of the organic
phase over Na2SO4, filtration and removal of the solvents under
reduced pressure, the residue was purified by flash chromatography
(PE–EtOAc 70:30) to afford 9 (725 mg, 95%) as a yellow powder.
Mp 136–137 ◦C; mmax (KBr)/cm−1 3436, 2925, 2616, 1691, 1677,
1472, 1449, 1424, 1394, 1324, 1298, 1229, 1119, 1048, 921, 854, 830
and 733; dH (300 MHz; CDCl3) 3.93 (3H, s, OCH3), 6.93 (1H, d,
J = 0.5, ArH3), 8.08 (1H, s, ArH5), 9.46 (1H, s, ArOH) and 9.97
(1H, d, J = 0.5, CHO); dC (75 MHz; CDCl3) 54.2 (CH3), 111.6
(CH), 127.7 (C), 137.3 (CH), 149.0 (C), 158.4 (C) and 196.6 (CH);
m/z (ESI+) 186 (M + CH3OH + H+, 100%), 168 (46) and 154
Mp 98–100 ◦C; mmax (KBr)/cm−1 3362, 2976, 2914, 1697, 1616,
1563, 1485, 1456, 1446, 1436, 1396, 1381, 1314, 1277, 1242, 1220,
1190, 1040, 1011, 930, 883, 873 and 742; dH (300 MHz; CDCl3)
3.91 (3H, s, OCH3), 3.97 (3H, s, OCH3), 7.08 (1H, s, ArH), 8.01
(1H, s, ArH) and 10.43 (1H, s, CHO); dC (75 MHz; CDCl3) 53.9
(CH3), 56.7 (CH3), 107.8 (CH), 131.5 (CH), 133.3 (C), 151.0 (C),
•
159.1 (C) and 189.2 (CH); m/z (EI) 167 (M+ , 100%), 166 (75) and
•
44 (88); HRMS (EI) found (M+ ) 167.0580, C8H9NO3 requires
•
(MH+, 49); HRMS (EI) found (M+ ) 153.0421, C7H7NO3 requires
167.0582.
153.0426.
2-Methoxy-5-(methoxymethoxy)pyridine-4-carbaldehyde 6b
Typical experimental procedure for the fluoride-promoted
deprotection of 5c: preparation of 5-hydroxy-2-methoxypyridine-
3-carbaldehyde 10
Compound 6b was prepared according to the same procedure
as for compounds 5a/6a, scale: 2-methoxy-5-methoxymethoxy-
pyridine (1.523 g, 9.0 mmol), THF (30 mL), diisopropylamine
(30 lL, 0.18 mmol), MeLi 1.6 M in Et2O (10.2 mL, 16.2 mmol),
N-formylpiperidine (1.8 mL, 16.2 mmol). The crude product was
purified by flash chromatography (PE–EtOAc 90:10 to 80:20) to
afford 6b (1.083 g, 61%) as a yellow solid.
Tetra-n-butylammonium fluoride (1 M solution in THF, 15 mL,
15 mmol) was added to a stirred solution of 2-methoxy-
5-(triisopropylsilanyloxy)pyridine-3-carbaldehyde 5c (3.095 g,
◦
10 mmol) in anhydrous THF (15 mL) at 0 C. The temperature
was allowed to rise to room temperature and the resulting mixture
for stirred for 2 h. After addition of water (15 mL) and EtOAc
(50 mL) and decantation, the aqueous phase was extracted with
EtOAc (2 × 50 mL). The combined organic phases were washed
with water (2 × 50 mL) and dried over Na2SO4. After filtration
and removal of the solvents under reduced pressure, the residue
was purified by flash chromatography (PE–EtOAc 50:50) to afford
10 (1.408 g, 92%) as a white solid.
◦
Mp 39–40 C; mmax (KBr)/cm−1 3369, 2973, 2930, 1739, 1699,
1609, 1486, 1380, 1235, 1195, 1155, 1083, 1032, 986 and 930; dH
(300 MHz; CDCl3) 3.53 (3H, s, OCH3), 3.91 (3H, s, OCH3), 5.25
(2H, s, CH2OCH3), 7.07 (1H, s, ArH), 8.23 (1H, s, ArH), 10.43
(1H, s, CHO); dC (75 MHz; CDCl3) 54.1 (CH3), 56.7 (CH3), 96.3
(CH2), 107.6 (CH), 134.3 (C), 136.0 (CH), 149.0 (C), 159.9 (C)
and 189.2 (CH); m/z (CI) 199 (10%), 198 (MH+, 100) and 89 (15);
HRMS (CI) found (MH+) 198.0766, C9H12NO4 requires 198.0766.
Mp 104–105 ◦C; Anal. found C, 54.6; H, 4.6; N, 9.05. C7H7NO3
requires C, 54.9; H, 4.6; N, 9.15; mmax (KBr)/cm−1 3466, 3084, 3007,
2962, 2888, 1674, 1312, 1588, 1483, 1460, 1426, 1390, 1323, 1307,
1283, 1226, 1207, 1170, 1132, 1049, 995, 897, 751 and 743; dH
(300 MHz; CDCl3) 4.03 (3H, s, OCH3), 5.09 (1H, br s, ArOH),
7.64 (1H, d, J = 3.2, ArH), 8.07 (1H, d, J = 3.2, ArH) and 10.33
(1H, s, CHO); dC (50 MHz; CDCl3) 54.1 (CH3), 118.2 (C), 124.3
(CH), 140.9 (CH), 148.2 (C), 159.3 (C) and 190.2 (CH); m/z (ESI+)
200 (66%), 186 (M + CH3OH + H+, 100) and 154 (MH+, 59); m/z
(ESI−) 152 (M − H−, 100%) and 137 (44).
2-Methoxy-5-(triisopropylsilanyloxy)pyridine-3-carbaldehyde 5c
Compound 5c was prepared according to the same procedure as
for compounds 5a/6a, scale: 2-methoxy-5-triisopropylsilanyloxy-
pyridine (2.815 g, 10.0 mmol), THF (35 mL), diisopropylamine
(30 lL, 0.2 mmol), MeLi (1.5 M in Et2O, 12.0 mL, 18.0 mmol),
N-formylpiperidine (2.0 mL, 18.0 mmol). The crude product was
purified by flash chromatography (PE–EtOAc 98:2 to 96:4) to
afford 5c (1.965 g, 64%) as a yellow oil.
mmax (film)/cm−1 2943, 2893, 2868, 2748, 1742, 1691, 1602, 1569,
1474, 1430, 1383, 1286, 1244, 1211, 1048, 1018, 1003, 910, 882,
844, 801, 755, 690, 665 and 587; dH (300 MHz; CDCl3) 1.10 (18H,
d, J = 6.8, (CH(CH3)2)3), 1.18–1.30 (3H, m, (CH(CH3)2)3), 4.02
(3H, s, OCH3), 7.61 (1H, d, J = 3.1, ArH), 8.04 (1H, d, J = 3.1,
ArH) and 10.32 (1H, s, CHO); dC (50 MHz; CDCl3) 12.5 (CH),
2,5-Dimethoxypyridine-4-carbaldehyde 6a from 5-hydroxy-2-
methoxy-pyridine-4-carbaldehyde 9
Compound 6a was prepared according to the same proce-
dure as for compound 8a, scale: 5-hydroxy-2-methoxypyridine-
4-carbaldehyde 9 (718 mg, 4.7 mmol), DMF (15 mL), K2CO3
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(971 mg, 7.05 mmol), methyl iodide (295 lL, 4.7 mmol). The
crude product was purified by flash chromatography (PE–EtOAc
70:30) to afford 6a (1.930 g, 96%) as a pale yellow solid.
(100) and 88 (37); HRMS (CI) found (MH+) 283.1044, C11H15N4O5
requires 283.1042.
Typical experimental procedure for the preparation of
azidoacrylates: 2-azido-3-(2,5-dimethoxypyridin-3-yl)acrylic acid
methyl ester 4a
2,5-Dimethoxypyridine-3-carbaldehyde 5a from 5-hydroxy-2-
methoxy-pyridine-3-carbaldehyde 10
Sodium metal (189 mg, 8.2 mmol) was added to anhydrous
methanol (4 mL) at 0 ◦C and the resulting mixture was stirred
until the metal completely dissolved. To this preformed sodium
methoxide solution at 30 ◦C was quickly added (within 30
seconds) a solution of aldehyde 5a (335 mg, 2.0 mmol) and methyl
azidoacetate (1.055 g, 7.6 mmol) in methanol (6 mL). The mixture
was stirred at 30 ◦C for 2 h, then poured onto crushed ice (40 g, in
an open beaker) and left for one hour in a refrigerator at 4 ◦C. The
product was recovered by filtration on a sintered glass funnel (no.
4) and dried under vacuum to afford 4a (315 mg, 57%) as an
off-white powder.
Compound 5a was prepared according to the same proce-
dure as for compound 8a, scale: 5-hydroxy-2-methoxypyridine-
3-carbaldehyde 10 (1.838 g, 12 mmol), DMF (36◦mL), K2CO3
(2.488 g, 18 mmol). The mixture was stirred at 50 C for 10 min
and then methyl iodide (295 lL, 4.7 mmol). The crude product was
purified by flash chromatography (PE–EtOAc 70:30) to afford 5a
(693 mg, 89%) as a pale yellow powder.
Condensation reaction between 3-formyl pyridine 5a and methyl
azidoacetate
Sodium metal (226 mg, 9.84 mmol) was added to anhydrous
methanol (6 mL) at 0 ◦C and the resulting mixture stirred until the
metal completely dissolved. To this preformed sodium methoxide
solution at 0 ◦C was slowly added (over a 5 min period) a solution
in methanol (6 mL) of aldehyde 5a (401 mg, 2.4 mmol) and methyl
azidoacetate (1.055 g, 3.8 mmol). The mixture was stirred at 0 ◦C
for 3 h, then poured onto crushed ice (40 g, in an open beaker)
2-Azido-3-(2,5-dimethoxypyridin-4-yl)acrylic acid methyl ester 4b
Compound 4b was prepared according to the same procedure
as for compound 4a, scale: sodium metal (189 mg, 8.2 mmol),
anhydrous methanol (4 mL), methanol (6 mL), aldehyde (335 mg,
2 mmol), methyl azidoacetate (875 mg, 7.6 mmol), to afford 4b as
a yellow powde (268 mg, 51%).
◦
and left for one hour in a refrigerator at 4 C. The product was
Mp 117–118 ◦C (decomposed); mmax (KBr)/cm−1 3439, 3108,
2946, 2925, 2851, 2127, 1716, 1602, 1548, 1487, 1463, 1435, 1384,
1322, 1281, 1254, 1214, 1189, 1082, 1044, 1014, 888 and 739; dH
(300 MHz; acetone-d6) 3.84 (3H, s, OCH3), 3.92 (3H, s, OCH3),
3.93 (3H, s, OCH3), 7.12 (1H, s, CH), 7.50 (1H, s, ArH), 7.89
(1H, s, ArH); dC (75 MHz; acetone-d6) 53.6 (CH3), 53.6 (CH3),
57.2 (CH3), 111.1 (CH), 116.1 (CH), 130.3 (CH), 130.5 (C), 133.3
recovered by filtration on a sintered glass funnel (no. 4) and
dried under vacuum to give a pale yellow solid (315 mg). This
1
product consisted of a 28:72 mixture (determined by H NMR)
of azidoacrylate 4a and azidoalcohol 11a, respectively. The crude
product was purified by flash chromatography (PE–AcOEt 70:30,
the solid was adsorbed onto silica).
The less polar fraction was 2-azido-3-(2,5-dimethoxypyridin-3-
yl)acrylic acid methyl ester 4a (87 mg, pale yellow powder, 14%
yield).
•
(C), 149.3 (C), 159.4 (C) and 164.0 (C); m/z (EI) 264 (M+ , 53%),
•
204 (49), 177 (58), 64 (54) and 59 (100); HRMS (EI) found (M+ )
264.0856, C11H12N4O4 requires 264.0859.
Mp 123–124 ◦C; mmax (KBr)/cm−1 3088, 2986, 2941, 2853, 2120,
1702, 1611, 1571, 1470, 1440, 1400, 1382, 1347, 1303, 1279, 1261,
1214, 1182, 1146, 1082, 1019 and 962. dH (300 MHz; DMSO-d6)
3.81 (3H, s, OCH3), 3.86 (3H, s, OCH3), 3.87 (3H, s, OCH3), 7.03
(1H, s, CH), 7.89 (1H, d, J = 3.0, ArH) and 8.13 (1H, d, J =
3.0, ArH); dC (75 MHz; DMSO-d6) 53.3 (CH3), 53.8 (CH3), 56.2
(CH3), 115.7 (C), 116.0 (CH), 125.3 (CH), 127.3 (C), 132.7 (CH),
150.4 (C), 155.2 (C) and 163.0 (C); m/z (CI) 265 (MH+, 31%), 238
(14) and 237 (MH+-N2, 100); HRMS (CI) found (MH+) 265.0938,
C11H13N4O4 requires 265.0937.
4,7-Dimethoxy-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid
methyl ester 2a
The reaction was carried out in a 100 mL round-bottomed flask,
open to the atmosphere via a condenser and an addition funnel.
To hot xylene (13 mL) at 140 ◦C was slowly added with vigorous
stirring a suspension of acrylate 4a (423 mg, 1.6 mmol) in xylene
(27 mL). Once the addition was complete, the mixture was stirred
for 1 h at 140 ◦C, then slowly cooled down to room temperature
overnight without stirring. After the complete crystallisation of
the solid, the supernatant was removed and the solid dried under
high vacuum to give 5-azaindole 2a (310 mg, 82%) as pale pink
crystals.
The more polar fraction was 2-azido-3-(2,5-dimethoxypyridin-
3-yl)-3-hydroxypropionic acid methyl ester 11a (205 mg, white
powder, 20% yield).
Mp 145–146 ◦C; mmax (KBr)/cm−1 3413, 3153, 2965, 2935, 2130,
2098, 1742, 1589, 1484, 1435, 1405, 1351, 1274, 1295, 1214, 1250,
1205, 1068, 1043, 1014, 1008, 947 and 817; dH (300 MHz; DMSO-
d6) 3.78 (3H, s, OCH3), 3.79 (3H, s, OCH3), 3.84 (3H, s, OCH3),
4.17 (1H, d, J = 2.3, CHN3), 5.31 (1H, dd, J = 5.0 and J = 2.3,
CHOH), 6.23 (1H, d, J = 5.0, disappears after D2O addition, OH),
7.46 (1H, d, J = 3.0, ArH), 7.80 (1H, d, J = 3.0, ArH); dC (75 MHz;
DMSO-d6) 52.7 (CH3), 53.4 (CH3), 56.0 (CH3), 64.0 (CH), 68.5
(CH), 124.1 (CH), 124.3 (C), 129.6 (CH), 151.1 (C), 153.6 (C) and
169.1 (C); m/z (CI) 283 (MH+, 32%), 265 (MH+-H2O, 25), 168
Mp 192–193 ◦C; Anal. found C, 55.8; H, 5.3; N, 11.65.
C11H12N2O4 requires C, 55.95; H, 5.1; N, 11.85; mmax (KBr)/cm−1
3437, 3300, 2948, 2924, 1702, 1619, 1593, 1537, 1499, 1465, 1446,
1429, 1360, 1307, 1258, 1208, 1157, 1098, 1087, 984, 853 and 754;
dH (300 MHz; DMSO-d6) 3.84 (3H, s, OCH3), 3.90 (3H, s, OCH3),
3.92 (3H, s, OCH3), 7.10 (1H, s, ArH), 7.47 (1H, s, ArH) and 12.57
(1H, br s, NH); dC (75 MHz; DMSO-d6) 51.9 (CH3), 52.8 (CH3),
56.4 (CH3), 106.5 (CH), 113.0 (C), 120.4 (CH), 127.5 (C), 134.2
(C), 140.0 (C), 152.8 (C) and 160.9 (C); m/z (CI) 238 (12%) and
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237 (MH+, 100); HRMS (CI) found (MH+) 237.0874, C11H13N2O4
requires 237.0875.
added in one portion [bis(trifluoroacetoxy)iodo]benzene (PIFA)
(86 mg, 0.2 mmol). After stirring for one hour, a further portion of
PIFA (86 mg, 0.2 mmol) was added. This procedure was repeated
two more times, after 2 h and 3 h reaction time, so that a total of
four equivalents (344 mg, 0.8 mmol) of PIFA were used. One hour
after the last PIFA addition, the mixture was filtered on a sintered
glass funnel filled with a pad of silica gel 1 cm thick, washing with
EtOAc. After evaporation of the filtrate under reduced pressure,
the residue was purified by flash chromatography (PE–EtOAc
50:50) to afford a pink solid. This solid was then washed with
dichloromethane to give the trioxo compound 12a (43 mg, 97%)
as a pale yellow solid.
4,7-Dimethoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
methyl ester 2c
The reaction was carried out in a 50 mL round-bottomed flask,
open to the atmosphere via a condenser and an addition funnel. To
hotxylene (8 mL) at 140 ◦C was slowly added with vigorous stirring
a solution of acrylate 4b (264 mg, 1.0 mmol) in xylene (16 mL).
Once the addition was complete, the mixture was stirred for 1 h
at 140 ◦C, then cooled to room temperature over 4 h and kept in
a freezer at −20 ◦C overnight. The supernatant was removed and
the solid dried under high vacuum to give 6-azaindole 2c (73 mg,
31%) as a pale yellow powder. The supernatant was purified by
flash chromatography (PE–EtOAc 50:50) to afford 2c (61 mg,
26%) as a pale yellow powder; overall yield = 57%.
Mp 269–270 ◦C; mmax (KBr)/cm−1 3210, 3137, 2924, 2853, 1690,
1554, 1455, 1432, 1287, 1229, 1138, 1096, 974, 927 and 799; dH
(300 MHz; DMSO-d6) 3.85 (3H, s, OCH3), 7.16 (1H, s, H3), 11.54
(1H, s, H5) and 14.00 (1H, br s, H1); dC (75 MHz; DMSO-d6)
52.4 (CH3), 113.3 (CH), 123.9 (C), 130.3 (C), 132.8 (C), 158.7 (C),
160.0 (C), 160.7 (C) and 166.5 (C); m/z (ESI+) 463 (48%), 445 (54),
427.1 (2M + H+, 29), 222.9 (MH+, 100), 209 (24); HRMS (ESI+)
found (M + Na+) 245.0174, C9H6N2O5Na requires 245.0174.
The single crystal for the X-ray diffraction analysis was obtained
as follows: a solution of compound 12a (1 mg) in acetone (0.7 mL)
was allowed to stand for three days at room temperature (20 ◦C)
in a test tube (without capping). The resulting colorless needle
(0.06 × 0.07 × 0.21 mm) was then analyzed on a Nonius Kappa
CCD diffractometer at 293 K. CCDC reference number 641655.
For crystallographic data in CIF or other electronic format see
DOI: 10.1039/b719776d.†
Mp 169–170 ◦C; mmax (KBr)/cm−1 3306, 2994, 2939, 1713, 1511,
1470, 1448, 1340, 1320, 1288, 1234, 1202, 1097, 992, 827 and
747; dH (300 MHz; DMSO-d6) 3.86 (3H, s, OCH3), 3.88 (3H, s,
OCH3), 3.96 (3H, s, OCH3), 7.07 (1H, s, ArH), 7.27 (1H, s, ArH)
and 12.62 (1H, br s, NH); dC (75 MHz; DMSO-d6) 52.0 (CH3),
52.8 (CH3), 55.9 (CH3), 104.9 (CH), 114.7 (CH), 123.0 (C), 124.8
(C), 129.0 (C), 145.7 (C), 146.4 (C) and 161.0 (C); m/z (EI) 236
•
•
•
•
(M+ , 100%), 221 (M+ − CH3 , 7), 204 (M+ − CH3OH, 53), 189
•
•
•
(M+ − CH3OH − CH3 , 54); HRMS (EI) found (M+ ) 236.0798,
C11H12N2O4 requires 236.0797.
1-Benzyl-4,7-dimethoxy-1H-pyrrolo[3,2-c]pyridine-2-carboxylic
acid methyl ester 2b
Experimental procedure for the oxidation of 7-hydroxy 4-methoxy
5-azaindole 3a: preparation of compound 12a
To a solution of 5-azaindole 2a (100 mg, 0.42 mmol) in DMF
(3 mL) at room temperature, was added in one portion sodium
hydride (60% dispersion in mineral oil, 20 mg, 0.50 mmol). The
To a solution of 5-azaindole 3a (22 mg, 0.1 mmol) in a 1:1
acetonitrile–water mixture (8 mL) at room temperature was added
in one portion [bis(trifluoroacetoxy)iodo]benzene (PIFA) (44 mg,
0.1 mmol). After stirring for one hour, the resulting mixture
was filtered off on a sintered glass funnel filled with a pad of
silica gel 1 cm thick, washing with EtOAc. After evaporation
of the filtrate under reduced pressure, the residue was purified
by flash chromatography (PE–EtOAc 50:50) to afford the trioxo
compound 12a (19 mg, 95%) as an orange solid.
◦
mixture was heated to 50 C and stirred for 3 h 30 min. Benzyl
bromide (50 lL, 0.42 mmol) was then added and the resulting
mixture stirred for an additional 2 h at 50 ◦C. After cooling to
room temperature, water (10 mL) was added and the aqueous
phase extracted with EtOAc (3 × 20 mL). The organic phases
were dried over Na2SO4, filtered and the solvents removed under
reduced pressure. The resulting crude product was purified by
flash chromatography (PE–EtOAc 70:30) to afford compound 2b
(101 mg, 74%) as a white powder.
Mp 121–122 ◦C; mmax (KBr)/cm−1 3435, 3028, 3008, 2940, 1712,
1657, 1606, 1520, 1483, 1452, 1437, 1400, 1362, 1312, 1269, 1234,
1203, 1101, 1066, 1011, 985, 857, 749 and 727; dH (300 MHz;
DMSO-d6) 3.79 (3H, s, OCH3), 3.82 (3H, s, OCH3), 3.94 (3H, s,
OCH3), 6.04 (2H, s, CH2Ph), 6.93 (2H, d, J = 7.0, CH2o-ArH),
7.17–7.29 (3H, m, CH2ArH), 7.30 (1H, s, ArH) and 7.54 (1H, s,
ArH); dC (75 MHz; DMSO-d6) 49.3 (CH2), 52.0 (CH3), 53.0 (CH3),
56.6 (CH3), 109.4 (CH), 111.9 (C), 122.0 (CH), 125.9 (CH), 127.0
(CH), 127.0 (C), 128.5 (CH), 134.5 (C), 139.2 (C), 140.5 (C), 153.1
(C) and 160.9 (C); m/z (ESI+) 328 (19%), 327 (MH+, 100); HRMS
(ESI+) found (MH+) 327.1347, C18H19N2O4 requires 327.1345.
Typical experimental procedure for the oxidation of
N-benzyl-4,7-dimethoxy 5-azaindole 2b: preparation of
1-Benzyl-4,6,7-trioxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-
c]pyridine-2-carboxylic acid methyl ester 12b
To a solution of N-benzyl-5-azaindole 2b (68 mg, 0.21 mmol) in a
1:1 acetonitrile–water mixture (23 mL) at room temperature was
added in one portion [bis(trifluoroacetoxy)iodo]benzene (PIFA)
(359 mg, 0.84 mmol). After stirring for 4 h, the resulting mixture
was filtered off on a sintered glass funnel filled with a pad of
silica gel 1 cm thick, washing with EtOAc. After evaporation of
the filtrate under reduced pressure, the residue was purified by
flash chromatography (PE–EtOAc 70:30) to afford compound 12b
(53 mg, 81%) as a pale brown solid.
Experimental procedure for the oxidation of 4,7-dimethoxy
5-azaindole 2a: 4,6,7-trioxo-4,5,6,7-tetrahydro-1H-
pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester 12a
Mp 208–209 ◦C; mmax (KBr)/cm−1 3205, 3120, 2924, 2853, 1728,
1710, 1674, 1526, 1489, 1454, 1425, 1382, 1255, 1186, 1119, 1078,
945, 737 and 707; dH (300 MHz; DMSO-d6) 3.79 (3H, s, OCH3),
To a solution of 5-azaindole 2a (47 mg, 0.2 mmol) in a 1:1
acetonitrile–water mixture (16 mL) at room temperature was
1372 | Org. Biomol. Chem., 2008, 6, 1364–1376
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5.99 (2H, s, CH2Ph), 7.13 (2H, d, J = 6.4, CH2o-ArH), 7.25–7.30
(3H, m, CH2ArH), 7.32 (1H, s, H3) and 11.70 (1H, s, H5); dC
(75 MHz; DMSO-d6) 49.7 (CH2), 52.5 (CH3), 115.3 (CH), 123.5
(C), 126.7 (CH), 127.4 (CH), 128.5 (CH), 129.5 (C), 132.0 (C),
136.8 (C), 158.5 (C), 159.7 (C), 160.3 (C) and 167.1 (C); m/z (ESI+)
648 (32%), 647 (2M + Na+, 100), 335 (M + Na+, 11), 313 (MH+, 8);
HRMS (ESI+) found (M + Na+) 335.0647, C16H12N2O5Na requires
335.0644.
Mp 183–184 ◦C (decomposed); mmax (KBr)/cm−1 3315, 2924,
2854, 1711, 1628, 1601, 1541, 1497, 1442, 1389, 1327, 1278, 1208,
1161, 1093, 1071, 989, 936, 829, 749 and 708; dH (300 MHz;
DMSO-d6) 3.86 (3H, s, OCH3), 3.88 (3H, s, OCH3), 7.09 (1H, s,
ArH), 7.34 (1H, s, ArH), 9.28 (1H, br s, ArOH) and 12.07 (1H, br s,
NH); dC (50 MHz; DMSO-d6) 51.9 (CH3), 52.6 (CH3), 106.3 (CH),
113.1 (C), 123.0 (CH), 126.8 (C), 134.0 (C), 136.7 (C), 151.8 (C)
and 161.0 (C); m/z (CI) 223 (MH+, 100%), 85 (10), 79 (20); HRMS
(CI) found (MH+) 223.0720, C10H11N2O4 requires 223.0719.
Preparation of compound 12c from 4,7-dimethoxy-6-azaindole 2c:
4,5,7-trioxo-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-
carboxylic acid methyl ester 12c
Preparation of compound 3c from monodemethylation of
4,7-dimethoxyazaindole 2c. 4-Hydroxy-7-
methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
methyl ester 3c
Compound 12c was prepared according to the same procedure
as for compound 12b, scale: 6-azaindole 2c (50 mg, 0.21 mmol),
[bis(trifluoroacetoxy)iodo]benzene (PIFA) (365 mg, 0.85 mmol),
1:1 acetonitrile–water mixture (16 mL). The crude product was
purified by flash chromatography (PE–EtOAc 50:50) to afford 12c
(27 mg, 57%) as a yellow powder.
Compound 3c was prepared according to the same procedure
as for compound 3a, scale: 6-azaindole 2c (25 mg, 0.10 mmol),
dichloromethane (2 mL), 1 M solution BBr3 in CH2Cl2 (266 lL,
0.26 mmol). The crude product was purified by flash chromatog-
raphy (PE–Et2O 30:70) to afford 3c (13 mg, 55%) as a yellow
powder.
Mp 261–262 ◦C; mmax (KBr)/cm−1 3436, 3203, 3124, 2925, 2854,
1691, 1561, 1503, 1483, 1425, 1395, 1331, 1276, 1234, 1140, 1101,
990, 932, 809 and 774; dH (300 MHz; DMSO-d6) 3.84 (3H, s,
OCH3), 7.18 (1H, s, H3), 11.73 (1H, br s, H6) and 14.06 (1H,
very br s, H1); dC (75 MHz; DMSO-d6) 52.2 (CH3), 112.5 (CH),
124.3 (C), 129.7 (C), 132.7 (C), 157.3 (C), 159.2 (C), 160.2 (C)
and 171.1 (C); m/z (ESI+) 468 (22%), 467 (2M + Na+, 100), 245
(M + Na+, 15); m/z (ESI−) for C9H5N2O5 221 (M − H−, 100%);
HRMS (ESI+) found (M + Na+) 245.0177, C9H6N2O5Na requires
245.0174.
Mp 203–204 ◦C (decomposed); mmax (KBr)/cm−1 3325, 2924,
2852, 1709, 1512, 1449, 1413, 1333, 1262, 1199, 1090, 1063, 820,
776 and 747; dH (300 MHz; DMSO-d6) 3.86 (3H, s, OCH3), 3.92
(3H, s, OCH3), 7.16 (1H, s, ArH), 7.17 (1H, s, ArH), 9.41 (1H, s,
ArOH) and 12.42 (1H, br s, NH); dC (75 MHz; DMSO-d6) 52.0
(CH3), 52.7 (CH3), 105.5 (CH), 117.6 (CH), 123.2 (C), 124.9 (C),
128.5 (C), 143.1 (C), 145.2 (C) and 161.1 (C); m/z (ESI+) 223
(MH+, 100%), 209 (24), 191 (23); m/z (ESI−) 425 (100%), 237
(27), 221 (M − H−, 30); HRMS (ESI+) found (MH+) 223.0717,
C10H11N2O4 requires 223.0719.
Preparation of compound 12c from 4-hydroxy-7-methoxy
6-azaindole 3c
Compound 12c was also prepared according to the same
procedure as for compound 12a (from 7-hydroxy 4-methoxy
5-azaindole 3a), scale: 6-azaindole 3c (30 mg, 0.134 mmol),
[Bis(trifluoroacetoxy)iodo]benzene PIFA (59 mg, 0.137 mmol),
1:1 acetonitrile–water mixture (8 mL). The crude product was
purified by flash chromatography (PE–EtOAc 40:60) to afford 12c
(29.5 mg, 99%) as an orange powder.
2-Azido-3-(2-methoxy-5-(triisopropylsilanyloxy)pyridin-3-
yl)acrylic acid methyl ester 13
Sodium metal (540 mg, 23.5 mmol) was dissolved in anhydrous
methanol (17 mL) at 0 ◦C under argon. To this preformed
sodium methoxide solution at 0 ◦C was quickly added a solution
of aldehyde 5c (1.77 g, 5.7 mmol) and methyl azidoacetate
(2.50 g, 21.7 mmol) in methanol (17 mL). The mixture was
◦
stirred at 25 C for two h, then poured onto crushed ice (120 g)
Typical experimental procedure for the BBr3 monodemethylation
of 4,7-dimethoxyazaindole 2a: preparation of 7-hydroxy-4-
methoxy-1H-pyrrolo[3,2-c]pyridine-2-carboxylic
acid methyl ester 3a
and held for 1 h at 4 ◦C. After addition of dichloromethane
(100 mL) and decantation, the aqueous phase was extracted with
dichloromethane (3 × 150 mL). The organic phases were washed
with water (2 × 150 mL) and dried over Na2SO4. After filtration
and removal of the solvent under reduced pressure, the residue
was purified by flash chromatography (PE–EtOAc 70:30) to afford
acrylate 13 (457 mg, 20%) as an orange solid.
To a cooled (−78 ◦C) solution of dimethoxy-5-azaindole 2a
(25 mg, 0.10 mmol) in dichloromethane (2 mL) was added
dropwise a 1 M solution of BBr3 in dichloromethane (535 lL,
0.53 mmol). The mixture was then stirred at room temperature for
16 h. Methanol (2 mL) was added dropwise and the solvent was
removed in vacuuo. Water (4 mL) was added to the residue and the
pH of this solution was carefully adjusted to pH 7 (controlled with
a calibrated pH meter) with 0.5 M sodium hydroxide solution.
The aqueous phase was extracted with EtOAc (3 × 10 mL)
and, after drying over Na2SO4, the solvent was removed under
reduced pressure. The resulting crude product was purified by
flash chromatography (PE–Et2O 20:80) to afford compound 3a
(13.5 mg, 57%) as a yellow solid.
Mp 61–63 ◦C (decomposed); mmax (KBr)/cm−1 3409, 3093, 2946,
2892, 2867, 2123, 1716, 1612, 1589, 1564, 1468, 1437, 1425, 1403,
1379, 1290, 1277, 1260, 1227, 1141, 1086, 1026, 1009, 901, 883,
864, 834, 748, 740 and 692; dH (300 MHz; CDCl3) 1.12 (18H, br
d, J = 6.8, (CH(CH3)2)3), 1.26 (3H, m, (CH(CH3)2)3), 3.91 (3H, s,
OCH3), 3.94 (3H, s, OCH3), 7.18 (1H, s, CH), 7.77 (1H, d, J = 3.0,
ArH) and 8.15 (1H, d, J = 3.0, ArH); dC (50 MHz; CDCl3) 12.6
(CH), 17.9 (CH3), 53.0 (CH3), 53.8 (CH3), 116.2 (C), 118.0 (CH),
126.7 (C), 130.3 (CH), 138.2 (CH), 147.1 (C), 156.0 (C) and 163.8
(C); m/z (ESI) 407 (MH+, 12%), 380 (23), 379 (MH+-N2, 100).
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4-Methoxy-7-triisopropylsilanyloxy-1H-pyrrolo[3,2-c]pyridine-2-
7-Methoxy-4-methoxymethoxy-1H-pyrrolo[2,3-c]pyridine-2-
carboxylic acid methyl ester 14
carboxylic acid methyl ester 16a
A solution of azidoacrylate 13 (369 mg, 0.9 mmol) in dry xylene
Compound 16a was prepared according to the same procedure as
for compound 2a, scale: azidoacrylate 15a (36.6 mg, 0.12 mmol),
xylene (11 mL). The crude product was purified by flash chro-
matography (PE–EtOAc 70:30) to afford 16a as a yellow powder
(10.1 mg, 31%).
◦
(32 mL) was added dropwise onto hot (140 C) xylene (18 mL).
After addition, the mixture was heated at 140 ◦C for 1 h and then
cooled down to room temperature. The xylene solution was then
chromatographed over silica gel (eluent PE–EtOAc 90:10) to give
5-azaindole 14 (266 mg, 77%) as a pale yellow solid.
Mp 119–120 ◦C; mmax (KBr)/cm−1 3322, 3299, 1716, 1706, 1510,
1443, 1333, 1314, 1299, 1274, 1227, 1206, 1163, 1149, 1092, 1055,
979, 917, 779 and 750; dH (300 MHz; CDCl3) 3.55 (3H, s, OCH3),
3.96 (3H, s, OCH3), 4.07 (3H, s, OCH3), 5.26 (2H, s, CH2OCH3),
7.25 (1H, d, J = 2.3, H3), 7.54 (1H, s, H5) and 9.21 (1H, br s,
NH); dC (50 MHz; CDCl3) 52.3 (CH3), 53.3 (CH3), 56.3 (CH3),
96.1 (CH2), 105.8 (CH), 120.9 (CH), 123.1 (C), 126.5 (C), 128.5
(C), 143.7 (C), 147.4 (C) and 161.7 (C); m/z (ESI+) 268 (13%),
267 (MH+, 100), 223 (15); HRMS (CI) found (MH+) 267.0987,
C12H15N2O5 requires 267.0981.
Mp 134–135 ◦C; mmax (KBr)/cm−1 3423, 3114, 2969, 2943, 2866,
1723, 1606, 1546, 1497, 1460, 1432, 1382, 1352, 1309, 1296,
1275, 1239, 1215, 1189, 1178, 1083, 1011, 885, 850 and 833; dH
(300 MHz; CDCl3) 1.13 (18H, d, J = 7.2, (CH(CH3)2)3), 1.33 (3H,
m, (CH(CH3)2)3), 3.95 (3H, s, OCH3), 4.03 (3H, s, OCH3), 7.27
(1H, d, J = 2.3, H3), 7.50 (1H, s, H6) and 8.91 (1H, br s, NH); dC
(50 MHz; CDCl3) 12.8 (CH), 18.0 (CH3), 52.2 (CH3), 53.3 (CH3),
108.0 (CH), 114.1 (C), 126.5 (C), 126.8 (CH), 135.6 (C), 135.9 (C),
153.7 (C) and 161.8 (C); m/z (ESI+) 380 (24%), 379 (MH+, 100),
365 (13); m/z (ESI−) 378 (31%), 377 (M-H−, 100); HRMS (ESI+)
found (MH+) 379.2052, C19H31N2O4Si requires 379.2053.
Acidic deprotection of the MOM-protected 6-azaindole 16a:
preparation of 4-hydroxy-7-methoxy 6-azaindole 3c
To a solution of 6-azaindole 16a (80 mg, 0.30 mmol) in THF (1 mL)
was added 3 N aqueous HCl (1.1 mL) and the resulting mixture
was stirred at 50 ◦C for 3 h. After this time, the mixture was cooled
to room temperature and water (10 mL) was added followed by
neutralisation (pH 7–8) with solid K2CO3. The aqueous phase was
then extracted with EtOAc (3 × 10 mL). After drying of the organic
phase over Na2SO4, filtration and removal of the solvents under
reduced pressure, the residue was purified by flash chromatography
(PE–EtOAc 40:60) to afford 3c (52 mg, 77%) as an orange solid.
Fluoride-promoted deprotection of the TIPS-protected 5-azaindole
14: preparation of 7-hydroxy-4-methoxy 5-azaindole 3a
A 1 M solution of tetra-n-butylammonium fluoride in THF
(1.15 mL, 1.15 mmol) was added to a stirred solution of 5-
azaindole 14 (290 mg, 0.76 mmol) in anhydrous THF (1.2 mL)
at 0 ◦C under argon. The temperature was allowed to rise to room
temperature and the resulting mixture for stirred for 35 minutes.
After addition of water (1.5 mL) and EtOAc (10 mL), the aqueous
phase was extracted with EtOAc (2 × 10 mL). The combined
organic phases were washed with water (2 × 10 mL) and dried over
Na2SO4. After filtration and removal of the solvent under reduced
pressure, the residue was purified by flash chromatography (PE–
EtOAc 40:60) to afford 3a (157 mg, 92%) as an orange solid.
2-Azido-3-(2-methoxy-5-(methoxymethoxy)pyridin-4-yl)acrylic
acid tert-butyl ester 15b
Formation of the azidoalcohol 11b: Sodium hydride (60% dis-
persion in oil, 60 mg, 1.52 mmol) was added portionwise to
cold (−30 ◦C) isopropanol (4.5 mL). To the resulting sodium
isopropoxide solution was then added solid aldehyde 6b (150 mg,
0.76 mmol) until completely dissolved. A solution of tert-butyl
azidoacetate (477 mg, 3.04 mmol) in isopropanol (0.8 mL) was
then added dropwise to the reaction mixture. After stirring for 4 h
at −30 ◦C, water (15 mL) was added. The mixture was allowed to
warm to room temperature, then the aqueous phase was extracted
with EtOAc (3 × 15 mL) and the combined organic phases dried
over Na2SO4. After filtration and removal of the solvent under
reduced pressure, the residue was purified by flash chromatography
(PE–EtOAc 70:30) to afford azidoalcohol 11b (170 mg, 63%) as a
yellow oil. This compound 11b was obtained as a 1:1 mixture of
two diastereomers: dia1 and dia2.
2-Azido-3-(2-methoxy-5-(methoxymethoxy)pyridin-4-yl)acrylic
acid methyl ester 15a
Sodium metal (95 mg, 4.1 mmol) was dissolved in anhydrous
methanol (3 mL) at 0 ◦C under argon. To this preformed sodium
methoxide solution at 0 ◦C was quickly added a solution of
aldehyde 6b (199 mg, 1.0 mmol) and methyl azidoacetate (440 mg,
3.8 mmol) in methanol (3 mL). The mixture was stirred at 30 ◦C
fo◦r 1 h, then poured onto crushed ice (20 g) and held for 1 h at
4 C. The product 15a was recovered by filtration on a sintered
glass funnel as a pale yellow solid (60.6 mg, 21%).
Mp 78–79 ◦C (decomposed); mmax (KBr)/cm−1 3418, 3105, 2956,
2856, 2129, 1716, 1618, 1606, 1546, 1482, 1434, 1381, 1319, 1275,
1260, 1219, 1202, 1155, 1084, 1039, 989 and 962; dH (300 MHz;
CDCl3) 3.51 (3H, s, OCH3), 3.91 (3H, s, OCH3), 3.93 (3H, s,
OCH3), 5.15 (2H, s, CH2OCH3), 7.15 (1H, s, CH), 7.55 (1H, s,
ArH), 8.04 (1H, s, ArH); dC (50 MHz; CDCl3) 53.4 (CH3), 53.7
(CH3), 56.4 (CH3), 96.4 (CH2), 110.6 (CH), 116.0 (CH), 129.5 (C),
133.8 (CH), 134.1 (C), 146.5 (C), 159.5 (C) and 163.5 (C); m/z
(ESI) 295 (MH+, 7%), 267 (MH+ − N2, 69), 223 (41), 191 (100),
177 (36).
dH (300 MHz; DMSO-d6) 1.20 (9H, s, t-Bu dia1), 1.48 (9H, s,
t-Bu dia2), 3.39 (3H, s, OCH3 dia 1), 3.42 (3H, s, OCH3 dia 2),
3.80 (3H, s, OCH3 dia 1), 3.81 (3H, s, OCH3 dia 2), 3.93–3.97 (2H,
m, CHN3 for both dia), 5.14–5.24 (5H, m, CH2OCH3 for both
dia + CHOH for dia1), 5.39 (dd, J = 5.3–2.6, 1H, CHOH for
dia2), 6.24 (1H, d, J = 5.3, disappears after D2O addition, OH for
dia1), 6.37 (1H, d, J = 5.3, disappears after D2O addition, OH for
dia2), 6.83(1H, s, ArH for dia1), 6.90(1H, s, ArH for dia2), 7.88
(1H, s, ArH for dia1) and 7.90 (1H, s, ArH for dia2); dC (75 MHz;
DMSO-d6) 27.3 (CH3), 27.7 (CH3), 53.2 (CH3), 53.2 (CH3), 55.9
1374 | Org. Biomol. Chem., 2008, 6, 1364–1376
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(CH3), 56.0 (CH3), 63.3 (CH), 64.1 (CH), 68.9 (CH), 69.4 (CH),
82.0 (C), 82.4 (C), 95.1 (CH2), 95.6 (CH2), 108.4 (CH), 108.5 (CH),
131.8 (CH), 132.4 (CH), 143.3 (C), 143.9 (C), 144.8 (C), 145.3 (C),
158.7 (C), 158.8 (C), 166.6 (C) and 167.4 (C). (It was impossible to
assign with certainty signals for both diastereomers); m/z (ESI+)
formed whose Rf matched that of compound 3c. After this time, the
mixture was evaporated to dryness. Water (4 mL) was then added
to the residue and the pH of this solution was carefully adjusted
to pH 7 (controled with a calibrated pH meter) with 0.5 M sodium
hydroxide solution. The aqueous phase was then extracted with
EtOAc (4 × 15 mL) and, after drying over Na2SO4, the solvent
was removed under reduced pressure. The resulting crude product
was purified by flash chromatography (cyclohexane–EtOAc 60:40)
to afford compound 3c (17 mg, 49%) as a light brown solid.
731 (2M + Na+, 14%), 377 (M + Na+, 54), 355 (MH+, 100), 299
+
=
(MH − isobutene (CH3)2C CH2, 36).
Formation and in situ elimination of the mesylate of compound
11b: formation of azidoacrylate 15b: To a solution of 11b (649 mg,
1.83 mmol) in dichloromethane (50 mL) at 45 ◦C was added
quickly methanesulfonyl chloride (710 ll, 9.19 mmol) and then
triethylamine◦ (2.6 ml, 18.30 mmol). The reaction mixture was
stirred at 45 C for 1 h then cooled to room temperature. After
addition of a saturated aqueous solution of NaHCO3 (50 mL)
and decantation, the aqueous phase was extracted with CH2Cl2
(3 × 100 mL). The organic phases were washed with brine (2 ×
100 mL) and dried over Na2SO4. After filtration and removal of
the solvent under reduced pressure, the residue was purified by
flash chromatography (PE–EtOAc 80:20) to afford azidoacrylate
15b (527 mg, 85%) as a yellow solid.
Typical experimental procedure for the oxidation of 7-hydroxy-4-
methoxy 5-azaindole 3a: Preparation of 7-hydroxy-4,6-dimethoxy-
1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester 17a
To a solution of 3a (26 mg, 0.11 mmol) in a 1:1 acetonitrile–
methanol mixture (18 mL) at room temperature was added in
one portion [bis(trifluoroacetoxy)iodo]benzene (PIFA) (50 mg,
0.11 mmol). After stirring at room temperature for 4 h, the
resulting mixture was filtered off on a sintered glass funnel filled
with a pad of silica gel 1 cm thick, washing with EtOAc. After
evaporation of the filtrate under reduced pressure, the residue was
purified by flash chromatography (cyclohexane–EtOAc 70:30) to
afford 17a (25 mg, 85%) as a yellow powder.
◦
Mp 63–64 C; mmax (KBr)/cm−1 3435, 2924, 2116, 1712, 1605,
1484, 1384, 1277, 1217, 1200, 1153, 1078, 1037, 995 and 886; dH
(300 MHz; DMSO-d6) 1.54 (9H, s, t-Bu), 3.43 (3H, s, OCH3), 3.81
(3H, s, OCH3), 5.20 (2H, s, CH2OCH3), 6.99 (1H, s, CH), 7.44
(1H, s, ArH) and 8.02 (1H, s, ArH); dC (75 MHz; DMSO-d6) 27.6
(CH3), 53.3 (CH3), 56.1 (CH3), 83.8 (C), 96.5 (CH2), 109.5 (CH),
114.1 (CH), 130.9 (C), 133.8 (C), 134.6 (CH), 145.9 (C), 158.7 (C)
and 161.0 (C); m/z (ESI+): 359 (MNa+, 12%), 337 (MH+, 26), 309
Mp 199–200 ◦C; mmax (KBr)/cm−1 3501, 3373, 2951, 2853, 1702,
1675, 1653, 1612, 1537, 1497, 1470, 1446, 1416, 1377, 1329, 1310,
2289, 2211, 1228, 1042, 977 and 748; dH (300 MHz; DMSO-d6)
3.83 (3H, s, OCH3), 3.90 (3H, s, OCH3), 3.93 (3H, s, OCH3), 7.02
(1H, d, J = 2.0, H3), 8.41 (1H, s, ArOH) and 11.63 (1H, s, NH);
dC (75 MHz; DMSO-d6) 51.8 (CH3), 52.8 (CH3), 53.6 (CH3), 106.4
(CH), 108.6 (C), 119.5 (C), 126.7 (C), 136.5 (C), 145.53 (C), 148.2
(C) and 161.1 (C); m/z (CI) 254 (13%), 253 (MH+, 100); HRMS
(CI) found (MH+) 253.0820, C11H13N2O5 requires 253.0824.
(MH+ − N2, 26), 253 (MH+ − N2 − isobutene (CH3)2C CH2,
=
100), 177 (43).
7-Methoxy-4-methoxymethoxy-1H-pyrrolo[2,3-c]pyridine-2-
carboxylic acid tert-butyl ester 16b
Oxidation of 4-hydroxy-7-methoxy 6-azaindole 3c: Preparation of
4-hydroxy-5,7-dimethoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic
acid methyl ester 17c
Compound 16b was prepared according to the same procedure as
for compound 2a, scale: azidoacrylate 15b (72 mg, 0.21 mmol),
xylene (7.2 mL), reaction time 2 h. The crude product was purified
by flash chromatography (PE–EtOAc 70:30) to afford 16b (47 mg,
72%) as a yell◦ow powder.
Compound 17c was prepared according to the same procedure
as for compound 17a, scale: azaindole 3c (50 mg, 0.22 mmol),
PIFA (97 mg, 0.22 mmol), 1:1 acetonitrile–methanol mixture
(18 mL). The crude product was purified by flash chromatography
(cyclohexane–EtOAc 60:40) to afford 17c (30 mg, 53%) as a yellow
powder.
Mp 93–94 C; mmax (KBr)/cm−1 3307, 2979, 2936, 1713, 1620,
1587, 1506, 1445, 1408, 1370, 1336, 1300, 1278, 1227, 1208, 1154,
1093, 1059, 973 and 923; dH (300 MHz; DMSO-d6) 1.56 (9H, s,
t-Bu), 3.43 (3H, s, OCH3), 3.97 (3H, s, OCH3), 5.24 (2H, s,
CH2OCH3), 7.03 (s, 1H, ArH), 7.40 (1H, s, ArH) and 12.44 (1H,
br s, NH); dC (75 MHz; DMSO-d6) 27.9 (CH3), 52.9 (CH3), 55.8
(CH3), 81.6 (C), 95.4 (CH2), 104.5 (CH), 119.7 (CH), 122.8 (C),
125.7 (C), 131.0 (C), 142.9 (C), 147.0 (C) and 159.8 (C); m/z
(ESI+) 308 (MH+, 46%), 252 (100), 222 (48); HRMS (EI) found
Mp 176–177 ◦C; mmax (KBr)/cm−1 3435, 3323, 2951, 1715, 1644,
1598, 1526, 1507, 1451, 1416, 1354, 1328, 1291, 1250, 1210, 1184,
1125, 1095, 1039, 1000, 977, 907 and 770; dH (300 MHz; DMSO-
d6) 3.85 (3H, s, OCH3), 3.86 (3H, s, OCH3), 3.96 (3H, s, OCH3),
7.08 (1H, d, J = 2.0, H3), 8.63 (1H, s, ArOH) and 12.10 (1H, s,
NH); dC (75 MHz, DMSO-d6): 52.0 (CH3), 52.9 (CH3), 54.0 (CH3),
104.7 (CH), 119.1 (C), 125.8 (C), 127.8 (C), 129.9 (C), 140.4 (C),
140.9 (C) and 161.2 (C); m/z (ESI+) 293 (21%), 253 (MH+, 100),
238 (27), 223 (28), 209 (25); HRMS (ESI+) found (MH+) 253.0822,
C11H13N2O5 requires 253.0824.
•
(M+ ) 308.1370, C15H20N2O5 requires 308.1372.
Acidic deprotection and in situ transesterification of the
MOM-protected 6-azaindole 16b: preparation of
4-hydroxy-7-methoxy-6-azaindole 3c
Acknowledgements
To a solution of 6-azaindole 16b (48 mg, 0.16 mmol) in methanol
(4 mL) was added 3 N aqueous HCl (1 mL) and the resulting
mixture stirred at 25 ◦C for 4 h 30 min: after this time, TLC analysis
showed the complete consumption of the starting material. The
The authors would like to thank Dr Erwann Jeanneau (Centre de
Diffractome´trie Henri Longchambon, Universite´ Claude Bernard
Lyon 1) for X-ray diffraction analysis of compound 12a, Dr Sylvie
Radix for preliminary studies concerning the formylation step of
◦
reaction was then heated to 50 C for 20 h. A new product was
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Org. Biomol. Chem., 2008, 6, 1364–1376 | 1375
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precursor 8c and Dr Christopher McKay for his advice concerning
the preparation of this paper. ZM also thanks the Ministe`re de
l’Enseignement Supe´rieur et de la Recherche for a PhD fellowship.
Compounds, ed. Z. Rappaport and I. Marek, Wiley, Chichester, 2004,
495; (d) G. W. Gribble, in Science of Synthesis, vol. 8a, ed. M. Majewski
and V. Snieckus, Thieme, Stuttgart, 2006, 357.
13 For a precedent on the ortho-directing properties of the MOM ether
group during the metalation of a pyridine ring, see: (a) R. C. Ronald
and M. R. Winkle, Tetrahedron, 1983, 39, 2031; (b) See ref. 9; (c) M.
Schlosser, in Organometallics in Synthesis, 2nd edn, ed. M. Schlosser,
Wiley, Chichester, 2002, pp. 1–352.
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16 No trace of the 4-formyl pyridine derivative was detected by 1H NMR
of the crude product.
17 Determined by 1H NMR of the crude product.
18 The 11a/4a ratio was determined by 1H NMR of the white solid which
was obtained after quenching the reaction at −20 ◦C with ice, warming
up to 4 ◦C over 1 h (in a refrigerator) and filtration of the resulting
precipitate on a 0.45 lm glass fiber membrane.
19 For leading references on hypervalent iodine(III) reagents, see: (a) A.
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21 It should be noted that a low yield (19%) of compound 12a was
obtained using 3 equivalents of cerium ammonium nitrate (CAN) in
an acetonitrile–water medium.
˚
˚
22 Atom distances: C(6)–O(2): 1.210(3) A; C(8)–O(4): 1.213(3) A; C(10)–
˚
˚
O(1): 1.203(4) A; N(3)–H(2): 0.88 A.
23 There are examples in the literature of similar trioxo structures (only
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26 When the condensation reaction between 5c and methyl azidoacetate
was carried out at 30 ◦C, an intense degradation of the reaction mixture
was observed and no trace of the desired acrylate 13 was isolated.
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28 Oxidation reactions with PIFA were carried out in open vessels, using
non-degassed solvents.
29 It is noteworthy that the PIFA-mediated (4 equiv) oxidation reaction
of dimethoxyazaindoles 2 in methanol–acetonitrile did not lead to the
formation of functionalised azaindoles 17.
30 H. E. Gottlieb, V. Kotlyar and A. Nudelman, J. Org. Chem., 1997, 62,
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1376 | Org. Biomol. Chem., 2008, 6, 1364–1376
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