Reduction of different electron-poor N-heteroarylhydrazines in strong basic conditions

Article abstract of DOI:10.1002/chem.200600282

The first application of the Wolff-Kishner reduction methodology to electron-poor heteroaromatic compounds is reported. Hydrazino-containing heterocycles with hydrazone-type tautomery have been reduced under basic conditions. This novel chemistry was successfully applied to mono-dehalogenate a number of electron-poor heterocycles in a regioselective manner. According to the experimental results, this reductive process is a base-catalyzed reaction that takes only place in the presence of air, probably through an oxygen-assisted mechanism. As consequence of the specific features of this kind of hydrazone/enehydrazine tautomers, the overall outcome of the process is the synthesis of a Shapirotype reduction product by simply using a milder version of the Huang-Minlon methodology.

Full text of DOI:10.1002/chem.200600282

DOI: 10.1002/chem.200600282
Reduction of Different Electron-Poor N-Heteroarylhydrazines in Strong
Basic Conditions
[
a]
[b]
[b]
Asier Unciti-Broceta,* María J. Pineda de las Infantas, Miguel A. Gallo, and
[
b]
Antonio Espinosa*
In memory of Lucía
Abstract: The first application of the
Wolff–Kishner reduction methodology
to electron-poor heteroaromatic com-
pounds is reported. Hydrazino-contain-
ing heterocycles with hydrazone-type
tautomery have been reduced under
basic conditions. This novel chemistry
was successfully applied to mono-deha-
logenate a number of electron-poor
manner. According to the experimental
results, this reductive process is a base-
catalyzed reaction that takes only place
in the presence of air, probably
through an oxygen-assisted mechanism.
As consequence of the specific features
of this kind of hydrazone/enehydrazine
tautomers, the overall outcome of the
process is the synthesis of a Shapiro-
type reduction product by simply using
a milder version of the Huang–Minlon
methodology.
Keywords: heterocycles
·
hydra-
zone-type tautomery · hydrodehalo-
genation · reaction mechanisms ·
regioselectivity
heterocycles
in
a
regioselective
Introduction
the transformation of carbonyl-containing compounds to the
corresponding hydrazones as intermediates in the Wolff–
Kishner-type reduction (Scheme 1).
[4]
The reduction of chloroarenes has been studied under a va-
riety of conditions including free radical, catalytic and trans-
fer hydrogenation, oxidative, and metal-catalyzed hydride
delivery. In particular, the hydrodehalogenation of elec-
tron-poor heteroaromatic compounds is usually achieved by
[1]
[1a,d,e,2]
catalytic hydrogenolysis and metal catalysis.
However,
these methods do not distinguish between different halogen-
ated positions, giving rise to completely dechlorinated aro-
Scheme 1. The Huang–Minlon methodology of the Wolff–Kishner reduc-
tion.
[4c,d]
[1d]
matic compounds with a few exceptions.
Hydrazine is widely used as a reagent in synthetic organic
[3]
chemistry but is probably most frequently associated with
Although this reaction is well known, it has never been
used before for the reduction of chloro-containing heterocy-
cles. In a few reports hydrazine was used as one of the reac-
[
a] Dr. A. Unciti-Broceta
[5,6]
School of Chemistry, University of Edinburgh
The Kingꢀs Buildings, West Mains Road
Edinburgh, EH9 3 JJ (UK)
Fax : (+44)131-650-6453
E-mail: asier.ub@ed.ac.uk
tants to reduce halogenated aromatic compounds.
How-
[5]
[6]
ever, oxidative agents or palladium catalysts, instead of
basic conditions, were used to complete the hydrodehaloge-
nations.
[7]
[
b] Prof. M. J. Pineda de las Infantas, Prof. M. A. Gallo,
Prof. A. Espinosa
By chance, we observed that applying different alkox-
ides to 2-chloro-3-hydrazino-5-azaquinoxaline (2)
Scheme 2) led not only to the substitution of the chloro
Departamento de Química FarmacØutica y Orgµnica
Universidad de Granada, Facultad de Farmacia
Campus Cartuja s/n, 18071 Granada (Spain)
Fax : (+34)958-243-845
(
ligand in the 2-carbon position, but also to the reduction of
the hydrazine group. The resulting structures 3a–f were con-
firmed by NMR spectroscopy and mass spectrometric analy-
E-mail: aespinos@ugr.es
1754
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Chem. Eur. J. 2007, 13, 1754 – 1762

FULL PAPER
milder conditions and shorter
reaction time than even those
used in the Huang–Minlon
[4c]
modification
were required.
Also, the C3 position of the re-
sulting compound was reduced
to an aromatic methine, a Sha-
[8]
[8,9]
piro and Bamford–Stevens
reduction product (Scheme 3),
instead of a methylene. These
questions together with some
Scheme 2. Unexpected reduction of the hydrazine group of compound 2.
[10]
references,
which described
the decomposition of N-hetero-
aryl-N’-tosylhydrazines in basic conditions without studying
the mechanism in depth, stimulated our interest in the reac-
tion mechanism.
sis. Additionally, the molecular structure of compound 3d
was assigned by X-ray crystallography, which verified the re-
duced position (Figure 1).
From a synthetic point of view, the applicability of this
new process was very promising due to the advantages of
using a two-step procedure: i) nucleophilic aromatic substi-
tution (S Ar) of the more electrophilic halogenated position
N
with hydrazine, and ii) exclusive reduction of the substituted
position using basic conditions. This new synthetic pathway
could permit the dechlorination of electron-poor nitrogen-
containing heterocycles without the drawbacks that previous
strategies have presented, such as the lack of regioselectivity
and the use of toxic and expensive catalysts. Thus, further
studies were carried out.
Figure 1. Molecular structure of 3d (ORTEP diagram).
Results and Discussion
Regioselective synthesis of both 2- and 3-alkoxypyrido[2,3-
A
C
H
T
R
E
U
N
G
[
11]
Initially, we assumed this reduction should follow the
Wolff–Kishner-type mechanism from the hydrazone-type
tautomer of compound 2 (Scheme 2). However, much
b]pyrazines from 2,3-dichloropyrido[2,3-b]pyrazine 1: The
A
H
R
U
G
reduction was driven by the nucleophilic attack of hydrazine
monohydrate to the more electrophilic position of 2,3-
dichloropyrido[2,3-b]pyrazine (1; Scheme 4). The pyrido-
A
H
R
U
ring nitrogen atom dictates the regiochemistry of the reac-
tion, inducing a different electrophilicity between the 2- and
the 3-carbon positions of the compound 1. The heterocycle
2, which presents a hydrazone-type tautomer, was then re-
duced under basic conditions using either alkoxides or
sodium hydroxide. The different alkoxides were prepared in
situ by using the corresponding alcohols and sodium hydride
before being added to a solution of compound 2 in the same
alcohol.
Abstract in Spanish: Se presenta la primera aplicación de la
metodología usada en la reducción de Wolff-Kishner para
compuestos heteroaromµticos p-deficientes. Mediante el
empleo de medio bµsico fuerte se ha conseguido la reducción
del grupo hidrazino de distintos compuestos heterocíclicos
con una característica comffln: la presencia de un tautómero
hidrazona. Este comportamiento nunca antes descrito se ha
aplicado satisfactoriamente en la deshalogenación indepen-
diente y regioselectiva de distintas posiciones halogenadas de
compuestos heterocíclicos p-deficientes. De acuerdo con los
datos experimentales presentados, este proceso reductivo se
cataliza por medio de bases fuertes y fflnicamente tiene lugar
en sistemas abiertos, a travØs de un mecanismo en el que pro-
bablemente interviene el oxígeno del aire. Debido a las espe-
ciales características de esta clase de tautómeros enehidraci-
no/hidrazónicos, el resultado global del proceso es la síntesis
del producto que se obtendría a travØs de la reducción de
Shapiro usando, simplemente, una versión mµs suave de la
modificación de Huang-Minlon.
Primary alkoxides and sodium hydroxide behaved as a
strong base for the reduction of the 3-carbon position and as
a nucleophile for the S Ar of the chloro at the 2-carbon po-
N
sition, to give rise to the 2-alkoxy derivatives 3a–f in good
[12]
overall yields (71–83%). Nucleophilic substitutions occur-
red regardless of the temperature at which the reactions
[13]
were carried out.
However, when sodium isopropoxide in 2-propanol (sec-
ondary alkoxide) and potassium tert-butoxide (tertiary alk-
oxide) in tert-butyl alcohol were tested as reagents, the cor-
responding reactions did not provide the expected com-
pounds in good yields.
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1755

A. Unciti-Broceta, A. Espinosa et al.
solvents (Table 1). Sodium car-
bonate was not basic enough to
accomplish the reaction, where-
as sodium methoxide in metha-
nol produced the fastest reduc-
tion. The use of sodium meth-
oxide in non-protic solvents did
not allow the reductive process.
The final compounds 7a,b,
which contain
a
deuterium
[
8,9]
atom at the 2-carbon position,
Scheme 3. General Shapiro and Bamford–Stevens reduction.
Table 1. Influence of bases for the compound 5a (1 mmol) reduction.
[
a]
[b]
[b]
Base
Solvent
(40 mL)
Product
Yield[%]
Time
(2 equiv)
Time
(6 equiv)
A
H
R
N
A
H
R
U
G
ACHTREUNG
Na CO
NaOHH
NaOD
NaOMe
NaOMe
NaOMe
2
3
H
2
2
2
O
O
O
–
–
–
–
6a
7a
6a
–
88–90
85–88
82–84
–
>2 h
~20 min
~30 min
1–2 min
–
D
MeOH
THF
>2 h
15–20 min
–
Scheme 4. Synthesis of 2-alkoxypyrido
b R=Me; 3c R=Et; 3d R=Pr; 3e R=Allyl; 3 f R=Benzyl). Reagents
and conditions: a) NH NH ·H O (2 equiv), EtOH, 08C, 1 h, 78%; b)
A
H
R
U
G
3
2
2
2
dioxane
–
–
–
–
HNa (60% in mineral oil, 6 equiv), ROH, 60–1208C, 2–30 min, 71–83%.
NaOCD
NaOEt
NaOiPr
KOtBu
3
CD
3
OD
7b
6b
6c
6a
80–82
76–81
74–80
71–75
~30 min
30–40 min
>2 h
~5 min
2–3 min
~10 min
~15 min
EtOH
iPrOH
tBuOH
To exploit the potential of this methodology, the 3-alkoxy
isomers 6a–c were synthesized (Scheme 5). The dichloro
compound 1 was first mono-substituted by alkoxides and
then reduced following the above methodology. Compound
>2 h
[
a] Yield of isolated product after column chromatography. [b] All the re-
actions were performed by stirring (500 rpm) at room temperature
~258C) using 2 and 6 equivalents of base. The reaction times are not op-
(
timized.
1
was dissolved in the appropriate alcohol and treated with
sodium hydrogen carbonate to selectively give rise to 2-
chloro-3-alkoxy-pyrido[2,3-b]pyrazines 4a–c. Following
AHCTREUNG
treatment with hydrazine, which led to the formation of hy-
drazones 5a–c, reductions were achieved by using basic con-
ditions to obtain the 3-alkoxy derivatives 6a–c in excellent
overall yields (89–94%).
were obtained by using deuterated solvents (Scheme 6). Sur-
prisingly, sodium [D ]methoxide caused the methoxy group
3
at the 3-carbon position to be substituted by a [D ]methoxy
3
To identify the best base for the reductive step, compound
5
a (R=Me) was treated with a variety of bases in different
Scheme 6. Synthesis of the deuterated derivatives 7a,b. Reagents and
conditions: a) HNa (60% in mineral oil, 6 equiv), D
2
O, 60 8C, 30 min,
8
5%; b) HNa (60% in mineral oil, 6 equiv), CD OD, 608C, 5 min, 80%.
3
moiety. Using sodium ethoxide and sodium isopropoxide
gave rise to the same S Ar reaction, but neither potassium
N
tert-butoxide nor sodium hydroxide could affect this substi-
tution. It is, thus, clear that the primary and secondary alk-
oxides can generate undesired products due to their higher
nucleophilicity.
Scheme 5. Synthesis of 3-alkoxypyrido
b R=Et; 6c R=iPr). Reagents and conditions: a) NaHCO
ROH, 30 min at room temperature, then 60–788C for 1–2 h, 83–94%; b)
NH NH ·H O (2 equiv), acetonitrile, reflux temperature, 1 h, 88–91%; c)
HNa (60% in mineral oil, 6 equiv), ROH, reflux temperature, 5 min, 89–
4%.
ACHTREUNG
6
3
2
2
2
Complete dehalogenation of 2,3-dichloropyrido
A
H
R
U
G
9
azine (1) could be achieved by refluxing with an excess of
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Chem. Eur. J. 2007, 13, 1754 – 1762

Reduction of Different Electron-Poor N-Heteroarylhydrazines
FULL PAPER
hydrazine monohydrate in 2-propanol followed by addition
of a base (Scheme 7).
By employing the single-pot procedure shown in Scheme 9,
in which water, hydrazine, and sodium hydroxide were used
as the only reagents and solvents, the pure final product 16
[15]
was obtained in quantitative yield.
Scheme 7. Synthesis of 5-azaquinoxaline 9. Reagents and conditions: a)
NH
2
NH
2
·H
2
O (6 equiv), iPrOH, reflux temperature, 3 h, 85%; b) NaOH
O, reflux temperature, 25 min, 94%; c) HNa (60% in miner-
(
6 equiv), H
2
al oil, 6 equiv), MeOH, reflux temperature, 10 min, 91%.
Reduction of the 6-carbon position of several halogenated
purines: With the aim of establishing the full potential of
this methodology, other halogenated heterocycles were
tested. Both 6-bromo- and 6-chloropurine were reduced by
using the same synthetic pathway as was previously men-
tioned (Scheme 8). Compound 12 was obtained from both
Scheme 9. Regioselective synthesis of 2-chloropurine 16. Reagents and
conditions: a) NH NH ·H O (2 equiv), H O, reflux temperature, 30 min;
2
2
2
2
b) NaOH(12 equiv), reflux temperature, 3.5 h, 100% two steps.
The regioselective reduction is favored by the low electro-
philicity of the 2-carbon position of the purine ring, which
avoids the feasible nucleophilic substitution in spite of the
basic conditions. Notably, when sodium hydroxide was utiliz-
ed, the yield was much better than when sodium methoxide
was used.
Behavior of several N-phenylhydrazines under strong basic
conditions: Up until this point we had studied the reduction
of N-heteroarylhydrazines with hydrazone-type tautomery.
With the aim of understanding the mechanism of the reduc-
tion process, a set of N-phenylhydrazines was tested under
the same reduction conditions to determine the importance
of the pyridine-type nitrogen presence.
As expected, under the same basic conditions none of the
phenyl derivatives were reduced even though reaction times
were increased (Scheme 10). The lack of reactivity of these
N-phenylhydrazines confirms the requirement of an endocy-
Scheme 8. Synthesis of purine 13. Reagents and conditions: a)
NH
NH
2
NH
NH
2
·H
·H
2
O (2 equiv), EtOH, reflux temperature, 30 min, 93%; b)
O (2 equiv), EtOH, reflux temperature, 2 h, 95%; c) NaOH
2
2
2
(
2
6 equiv), H O, reflux, 12 h, 100%; d) HNa (60% in mineral oil, 6 equiv),
MeOH, reflux, 8 h, 67%.
starting materials through reaction with hydrazine and re-
duced into purine 13 by using basic conditions. This hetero-
cyclic system is less prone to undergoing S Ar reactions
N
than the azaquinoxaline ring, and thus longer times for both
the substitution and reduction steps were required. Conse-
quently, a direct relationship between the electrophilic char-
acter of the ring and the ease of reducing the hydrazone
group was apparent.
At this stage of our research we investigated more chal-
lenging applications. We were attracted by the difficult re-
gioselective reduction of 2,6-dichloropurine into 2-chloro-
purine, an interesting non-commercially available synthon in
medicinal chemistry. In the only report of this reduction, use
of aqueous sodium acetate and 10% Pd/charcoal under a
Scheme 10. Non-reaction of a set of N-phenylhydrazines under strong
basic conditions. (17a R =Cl, R =R =R =H; 17b R =Cl, R =R =
1
2
3
4
2
1
3
4
3
1
2
4
2
1
3
4
R =H; 17c R =Cl, R =R =R =H; 17d R =Br, R =R =R =H; 17e
3
1
2
4
3
1
2
4
3
R =Br, R =R =R =H; 17 f R =Et, R =R =R =H; 17g R =OMe,
1
2
4
2
4
1
3
R =R =R =H; 17h R =R =NO
tions: a) NaOH(6 equiv), H O, reflux temperature, 24 h; b) HNa (60%
in mineral oil, 6 equiv), MeOH, reflux temperature, 24 h.
2
, R =R =H). Reagents and condi-
2
[14]
hydrogen atmosphere gave 2-chloropurine in 40% yield.
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1757

A. Unciti-Broceta, A. Espinosa et al.
clic nitrogen atom in the a-position relative to the carbon
atom attached to the hydrazine/hydrazone group.
not possible to isolate the dihydroheteroaryl intermediate in
any of the samples. Consequently, other alternative mech-
anisms were considered.
[18]
Mechanistic aspects of the novel reaction: The Wolff–Kish-
Despite the fact that the Bamford–Stevens reaction is
achieved in milder conditions than the Shapiro one, its
mechanism was ruled out as it was confirmed that the reduc-
tion of hydrazine-containing heterocycles could only be ach-
ieved in the presence of protic solvents. Moreover, to ac-
complish the Bamford–Stevens reaction it is essential a
good leaving group, like the tosyl group, is attached to the
ner-type reduction mechanism has been studied for almost a
[
4,16]
century.
tautomerization of hydrazone 19 into its alkyl diimide 21
It is accepted that the reaction begins with the
[4d,16]
form (Scheme 11) mediated by basic conditions.
The
[8,9,19]
hydrazone.
Although the Shapiro reduction also requires a good leav-
ing group attached to the hydrazone, the special acidic prop-
erties of this kind of compounds allow an oxygen-assisted
variant of this mechanism to be considered as a possible al-
ternative. The acidity measurements in DMSO reported by
Bordwell et al. for the NÀHgroups of 2-pyridone 30 (pK =
a
[20]
1
7.0)
and of some hydrazones (acetophenone phenylhy-
drazone 31, pK =21.6, benzaldehyde phenylhydrazone 32,
a
pK =21.1 and 9-fluorenone phenylhydrazone 33, pK =
a
a
[
21]
1
4.9) are evidence for regarding that the endocyclic NÀH
Scheme 11. The Wolff–Kishner reduction mechanism.
of the hydrazone-tautomer derivatives presented in this
[
22]
work
must have similar acidic properties, if not higher,
than the hydrazone amine group (Scheme 12).
[16b]
demonstration by Szmant et al.
that this reaction is first
order with respect to base concentration led to a mechanis-
[16c–g]
tic proposal
that is now largely reproduced in every or-
ganic chemistry textbook.
The novel reduction presented within this article has the
same kinetic features as the Wolff–Kishner-type reduction,
despite the new method needing much milder conditions to
be achieved. The catalytic role of the base in N-heteroaryl-
hydrazine reductions was verified in all the samples shown
in this work by using less than one equivalent of base
(
except in those where it was also produced a S Ar, in
N
which less than two equivalents of base was used). The ex-
perimental results demonstrated that, as in the Wolff–Kish-
ner reduction, reaction kinetics are undoubtedly influenced
by the concentration of base. The reaction rate of the syn-
thesis of 2-chloropurine 16 was the most influenced by the
base concentration. In addition, after this reaction was com-
pleted, the neutralization of the resulting mixture disclosed
no base was consumed during the reaction.
Scheme 12. Comparison among the acidity measurements in DMSO of
several related compounds.
Although the kinetic features of the hydrazino-containing
heterocycle reduction are comparable to that of the Wolff-
Kishner reaction, the resulting product is the one expected
when using the Shapiro or the Bamford–Stevens methodolo-
gy. Therefore, if the reduction took place by the Wolff–Kish-
ner mechanism, the non-aromatic dihydroheteroaryl inter-
mediate produced through this mechanism should be subse-
quently oxidized by the oxygen present in the air. For this
reason the reaction was realized in absence of air to disclose
the importance of the oxygen in the synthetic process.
When the reactions were carried out under nitrogen at-
However, it was not possible to isolate any heteroaryldi-
azene intermediate of the compounds presented in this ar-
[23]
A
H
R
U
G
ticle. Hence, although we propose that the mechanism
whereby the reduction of these compounds occurs must
start with the abstraction of the endocyclic NÀHproton of
the hydrazone-type tautomer 34 (Scheme 13), there are not
enough experimental data to conclude a reliable mechanistic
proposal.
So far four empirically verified facts disclose the main re-
action requirements: 1) the base has a catalytic role; 2) only
N-heteroarylhydrazines with a hydrazone-type tautomery
are reduced under basic conditions; 3) the use of protic sol-
[17]
mosphere in degasified solvent, the synthesis of the final
products was not achieved. Although these experiments con-
firmed the implication of the oxygen in the process, it was
1758
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Chem. Eur. J. 2007, 13, 1754 – 1762

Reduction of Different Electron-Poor N-Heteroarylhydrazines
FULL PAPER
eluent. Evaporations were carried out in vacuo in a rotary evaporator.
Melting points (m.p.) were determined in open capillaries on a melting
point apparatus and are uncorrected. NMR spectra were obtained in
CDCl
3
, [D
6
]DMSO, [D
6
]acetone or CD
3
CN solutions on a 300.13 MHz
1
13
HNMR spectrometer and a 75.58 MHz
C NMR spectrometer, and
chemical shifts (ppm) are reported relative to the solvent peak. Signals
are designated as follows: s, singlet; bs, broad singlet; d, doublet; dd,
doublet of doublet; t, triplet; q, quadruplet; sp, septuplet; m, multiplet.
Coupling constants (J) are expressed in Hertz. All the solids were recrys-
tallized from water before elemental analyses were carried out. HPLC
analyses were carried out in analytical instrument equipped with a UV
detector. Eluents used were analytical grade. Mass spectra were obtained
by Electron Impact at 70 eV on low (MS (EI)) and high (HRMS (EI))
resolution mass spectrometers.
Scheme 13. Preliminary proposal for mechanism.
vents is indispensable for achieving the reduction; and 4)
the synthetic process is only effective in the presence of air.
Therefore, at this early stage of the research it is expedient
to suggest just a simple preliminary proposal (Scheme 13)
supported by the confirmed requirements of the overall pro-
cess.
Procedure for the preparation of 2,3-dichloropyrido[2,3-b]pyrazine (1):
A
H
R
U
G
Compound 1 was prepared from commercially available 2,3-diaminopyri-
[11]
dine as previously described.
Procedure for the preparation of 2-chloro-3-hydrazinopyrido[2,3-b]pyra-
A
H
R
U
G
zine (2): A solution of hydrazine monohydrate (0.116 mL, 2 mmol) in
ethanol (5 mL) was added dropwise to a cooled solution of 1 (0.2 g,
Conclusions and Outlook
1
mmol) in ethanol (10 mL) at 0 C. The mixture was stirred for 1 h. The
resulting precipitate was filtered and washed with ethanol (10 mL),
CH Cl (10 mL), and diethyl ether (10 mL). Compound 2 was obtained
as a yellow solid (78%); m.p. >3008C; HNMR (300 MHz, CD
d=8.90–8.81 (m, 1H), 8.22–8.15 (m, 1H), 7.73 (bs, 1H), 7.49–7.42 (m,
H), 4.48 ppm (bs, 2H); HRMS (EI): calcd for C H N Cl ([M]
7 6 5
95.031173, found 195.031275 (deviation À0.5 ppm).
In conclusion, a new application of the Wolff–Kishner re-
duction methodology has been achieved. For the first time,
hydrazino-containing heterocycles with a hydrazone-type
tautomery have been reduced under basic conditions. A new
way to monodehalogenate electron-poor heterocycles in a
regioselective manner has been provided. This simple two-
step procedure is metal-free, inexpensive, highly efficient,
and displays low-toxicity. In addition, this strategy has been
proven to selectively generate different isomers from the
same building block and consequently it could be used as a
valuable tool to obtain diversity in small-molecule com-
2
2
1
3
CN):
+
1
1
Procedures for the preparation of the reduced and substituted derivatives
3
a–f
1
H-Pyrido[2,3-b]pyrazin-2-one (3a): Sodium hydroxide (0.24 g, 6 mmol)
A
H
R
U
G
was added to water (20 mL) and the suspension was stirred at room tem-
perature until complete dissolution. Then the hydrazino derivative 2
(195.6 mg, 1 mmol) was added, and the resulting mixture was stirred at
6
08C for 15 min. The solvent was evaporated and the crude residue was
purified by flash chromatography (ethyl acetate/hexane 1:1). Compound
a was obtained as a light brown solid (81%); m.p. >3008C; R =0.15
]DMSO): d=12. 60 (bs,
(H,H)=1.7 Hz, 1H), 8.42 (s, 1H), 7.78
[24]
pound library synthesis.
3
f
According to the experimental results shown within this
paper, the reduction of electron-poor N-heteroarylhydra-
zines is a base-catalyzed reaction that takes only place in
the presence of air, probably through an oxygen-assisted
mechanism. As a consequence of the specific features of this
kind of hydrazone/enehydrazine tautomers, the overall out-
come of the process is the synthesis of a Shapiro-type reduc-
tion product by simply using a milder version of the Huang–
Minlon methodology. Further investigations on the study of
the full mechanism involved in this reaction are ongoing in
our laboratory.
Nevertheless, one of the most promising features of this
reaction is the reactivity inversion of the reduced carbon
atom. Through the simple and mild methodology used for
this novel reduction, the most electrophilic position of an
electron-poor heterocycle is transformed into a position
with nucleophilic character. Therefore, the presented re-
search work could be only the first step in the applications
of this reaction mechanism.
1
(
hexanes/EtOAc 1:2); HNMR (300 MHz, [D
6
3
3
ACHTREUNG
1H), 8.58 (dd, J
A
H
R
U
G
3
3
3
ACHTREUNG
(
8
(
dd,
.2 Hz, J
CH), 154.3, 144.8 (CH), 142.7, 127.7, 125.4 (CH), 124.6 ppm (CH);
J
A
H
R
U
G
J
A
H
R
U
G
J
(H,H)=
3
13
+
HRMS (EI): calcd for C
7 5 3
H N O ([M] ) 147.043262, found 147.042967
(deviation 2.0 ppm); elemental analysis calcd (%) for C H N O: C 57.14,
7
5
3
H3.64, N 28.56; found: C 57.42, H3.80, N 28.34.
2-Methoxypyrido[2,3-b]pyrazine (3b): A dispersion of sodium hydride
60% in mineral oil, 0.24 mg, 6 mmol) was added portionwise to metha-
AHCTREUNG
(
nol (20 mL), and the mixture was stirred for 10 min at room temperature.
Then the hydrazino derivative 2 (195.6 mg, 1 mmol) was added and the
resulting mixture was stirred at 608C for 2 min. The solvent was evapo-
rated and the crude residue was purified by flash chromatography (ethyl
acetate/hexane 2:3). Compound 3b was obtained as a white solid (71%);
1
m.p. 70–728C;
CDCl ): d=8.92 (dd,
H), 8.19 (dd,
R
f
=0.27 (hexanes/EtOAc 1:2); HNMR (300 MHz,
3
3
ACHTREUNG
3
J(H,H)=4.3 Hz, J(H,H)=1.8 Hz, 1H), 8.65 (s,
A
H
R
U
G
3
3
3
1
J
A
H
R
U
G
J(H,H)=1.8 Hz, 1H), 7.60 (dd, J-
A
H
R
U
G
3
ACHTREUNG
13
A
H
R
U
G
J
3
1
(
3
8 7 3
H N O
+
8
7 3
H N
5
9.44, H4.60, N 25.88.
2
-Ethoxypyrido[2,3-b]pyrazine (3c): A dispersion of sodium hydride
ACHTREUNG
(
(
60% in mineral oil, 0.24 mg, 6 mmol) was added portionwise to ethanol
20 mL), and the mixture was stirred for 10 min at room temperature.
Experimental Section
Then the hydrazino derivative 2 (195.6 mg, 1 mmol) was added and the
resulting mixture was stirred at 608C for 10 min. The solvent was evapo-
rated and the crude residue was purified by flash chromatography (ethyl
General methods: All reactions were monitored by thin-layer chromatog-
raphy (TLC) carried out on precoated aluminum sheets by using UV
light as a visualizing agent. Flash chromatography was performed with
acetate/hexane 2:3). Compound 3c was obtained as a light yellow solid
1
2
30–240 mesh silica gel, and the solvent mixture in brackets was used as
(83%); m.p. 67–698C;
R
f
=0.35 (Hexanes/EtOAc 1:2); HNMR
Chem. Eur. J. 2007, 13, 1754 – 1762
ꢁ 2007 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
www.chemeurj.org
1759

A. Unciti-Broceta, A. Espinosa et al.
3
3
1
3
3
ACHTREUNG
(
300 MHz, CDCl
.63 (s, 1H), 8.16 (dd,
3
): d=8.92 (dd, J
A
H
R
U
G
A
H
R
U
G
HNMR (300 MHz, CDCl
3
): d=8.97 (dd,
J
A
H
E
N
J(H,H)=
3
3
3
3
ACHTREUNG
8
J
A
H
E
N
(H,H)=8.3 Hz, J
(H,H)=4.3 Hz, 1H), 4.53 (q,
1.9 Hz, 1H), 8.28 (dd, J
A
H
R
U
G
3
3
3
3
3
ACHTREUNG
13
J
A
C
H
T
R
E
U
N
G
(H,H)=8.3 Hz,
J
A
C
H
T
R
E
U
N
G
J
J
A
H
R
U
G
J
3
1
1
(
1
.47 ppm (t,
J
A
C
H
T
R
E
U
N
G
3
3
+
3
8 6 3
); HRMS (EI): calcd for C H N OCl ([M] )
+
CH
2
), 14.3 ppm (CH
75.074562, found 175.074155 (deviation 2.3 ppm); elemental analysis
O: C 61.70, H5.18, N 23.99; found: C 61.64, H
3 9 9 3
); HRMS (EI): calcd for C H N O ([M] )
2
ACHTREUNG
9 9 3
calcd (%) for C H N
5
.40, N 23.66.
(
2
-Propoxypyrido
A
C
H
T
R
E
U
N
G
[2,3-b]pyrazine (3d): A dispersion of sodium hydride
was stirred for 2 h at reflux temperature. Then the solvent was evaporat-
ed and the crude residue was purified by flash chromatography (ethyl
(
60% in mineral oil, 0.24 mg, 6 mmol) was added portionwise to propa-
nol (20 mL), and the mixture was stirred for 10 min at room temperature.
Then the hydrazino derivative 2 (195.6 mg, 1 mmol) was added, and the
resulting mixture was stirred at 608C for 15 min. The solvent was evapo-
rated and the crude residue was purified by flash chromatography (ethyl
acetate/hexane 1:5). Compound 4b was obtained as a white solid (94%);
1
m.p. 128–1308C; R
f
=0.58 (Hexanes/EtOAc 1:2); HNMR (300 MHz,
3
3
ACHTREUNG
CDCl ): d=8.97 (dd,
3
J
A
H
R
U
G
J(H,H)=1.9 Hz, 1H), 8.28 (dd,
3
3
3
3
J
A
H
R
U
G
J
A
H
R
U
G
J(H,H)=8.3 Hz, J-
A
H
R
U
G
3
ACHTREUNG
3
acetate/hexane 1:3). Compound 3d was obtained as a light brown solid
A
H
R
U
G
J
1
13
(
(
74%); m.p. 75–788C;
300 MHz, CDCl ): d=8.90 (dd, J
.64 (s, 1H), 8.15 (dd,
R
f
=0.4 (Hexanes/EtOAc 1:2); HNMR
A
T
E
G
3
3
3
ACHTREUNG
A
H
R
U
G
151.7, 141.0, 136.9 (CH), 133.1, 123.0 (CH), 65.0 (CH
MS (EI): m/z: 209 ([M] ); 211 ([M+2]).
2
), 14.3 Hz (CH
3
);
3
3
3
+
8
J
A
H
R
U
G
3
3
3
ACHTREUNG
J
A
C
H
T
R
E
U
N
G
(H,H)=8.3 Hz,
.93–1.81 (m, 2H), 1.05 ppm (t,
75 MHz, CDCl ): d=157.9, 149.7 (CH), 148.7, 143.1 (CH), 136.2 (CH),
35.7, 125.2 (CH), 68.8 (CH ), 22.1 (CH ), 10.5 ppm (CH ); HRMS (EI):
O ([M] ) 189. 090212, found 189.089995 (deviation
.2 ppm); elemental analysis calcd (%) for C10 O: C 63.48, H5.86,
N 22.21; found: C 63.10, H5.99, N 22.02.
-Allyloxypyrido[2,3-b]pyrazine (3e): A dispersion of sodium hydride
60% in mineral oil, 0.24 mg, 6 mmol) was added portionwise to allyl al-
J
A
C
H
T
R
E
U
N
G
J
(H,H)=6.7 Hz, 2H),
2-Chloro-3-isopropoxypyrido[2,3-b]pyrazine (4c): Sodium hydrogen car-
A
H
E
G
3
13
1
(
1
J
A
H
R
U
G
bonate (92 mg, 1.1 mmol) was added to a stirred solution of compound 1
(200 mg, 1 mmol) in 2-propanol (10 mL) at room temperature. The mix-
ture was stirred for 4 h at reflux temperature. Then the solvent was
evaporated and the crude residue was purified by flash chromatography
(ethyl acetate/hexane 1:5). Compound 4c was obtained as a white solid
3
2
2
3
+
Calcd for C10
1
11 3
H N
11 3
H N
1
(94%); m.p. 108–1118C; R =0.62 (hexanes/EtOAc 1:2); HNMR
f
3
3
ACHTREUNG
(
8
8
300 MHz, CDCl
3
): d=8.97 (dd, J
A
H
R
U
G
(H,H)=1.9 Hz, 1H),
2
(
ACHTREUNG
3
3
3
ACHTREUNG
.28 (dd,
J
A
H
R
U
G
J(H,H)=1.9 Hz, 1H), 7.55 (dd, J(H,H)=
A
H
R
U
G
3
3
.3 Hz, J
A
H
R
U
G
cohol (20 mL), and the mixture was stirred for 10 min at room tempera-
ture. Then the hydrazino derivative 2 (195.6 mg, 1 mmol) was added and
the resulting mixture was stirred at 608C for 15 min. The solvent was
evaporated and the crude residue was purified by flash chromatography
1
3
A
H
R
U
G
1
2
3
+
MS (EI): m/z 223 ([M] ); 225 ([M+2]).
(
ethyl acetate/hexane 1:3). Compound 3e was obtained as a light brown
Procedures for the preparation of the 3-alkoxy-2-hydrazino derivatives
5a–c
1
solid (77%); m.p. 72–738C; R
f
3
=0.4 (hexanes/EtOAc 1:2); HNMR
3
ACHTREUNG
(
300 MHz, CDCl
3
): d=8.83 (dd, J
A
H
R
U
G
2
-Hydrazino-3-methoxypyrido
drate (0.116 mL, 2 mmol) was added to a solution of 4a (191 mg,
mmol) in acetonitrile (10 mL), and the mixture was stirred at reflux
A
H
R
U
G
3
3
ACHTREUNG
8
.68 (s, 1H), 8.17 (dd,
J
A
H
R
U
G
3
3
ACHTREUNG
J
A
C
H
T
R
E
U
N
G
(H,H)=8.3 Hz, J
H), 5.36–5.31 (m, 1H), 5.01–4.98 ppm (m, 2H); C NMR (75 MHz,
CDCl ): d=156.4, 148.6 (CH), 143.9, 143.7, 138.9, 137.6 (CH), 130.7,
23.8 (CH), 10.3 (CH), 8.3 ppm (CH); HRMS (EI): calcd for C10
(H,H)=4.3 Hz, 1H), 6.19–6.06 (m, 1H), 5.51–5.44 (m,
1
1
3
1
temperature for 1 h. Then the solvent was evaporated and the crude resi-
3
due was purified by flash chromatography (ethyl acetate). Compound 5a
1
H
9
N
3
O
1
was obtained as a light yellow solid (88%); m.p. 126–1288C. HNMR
+
(
[M] ) 187.074562, found 187.074828 (deviation À1.4 ppm); elemental
(
1
300 MHz, [D
H), 7.43 (bs, 1H), 4.12 (s, 3H), 2.86 ppm (s, 2H); C NMR (75 MHz,
CD COCD ): d=154.9, 146.9, 146.8 (CH), 145.2, 141.7, 134.0 (CH), 122.2
(CH), 53.9 ppm (CH
3-Ethoxy-2-hydrazinopyrido
6
]acetone): d=8.80 (bs, 1H), 8.57 (bs, 1H), 8.05–7.95 (m,
analysis calcd (%) for C10 O: C 64.16, H4.85; N 22.45; found: C
6
H
9
N
3
13
4.00, H5.16, N 22.11.
3
3
+
2
-Benzyloxypyrido[2,3-b]pyrazine (3 f): A dispersion of sodium hydride
A
C
H
T
R
E
U
N
G
3
); MS (EI): m/z: 191 ([M] ).
(
60% in mineral oil, 0.24 mg, 6 mmol) was added portionwise to benzylic
ACHTREUNG
[2,3-b]pyrazine (5b): Hydrazine monohy-
alcohol (20 mL), and the mixture was stirred for 30 min at room tempera-
ture. Then the hydrazino derivative 2 (195.6 mg, 1 mmol) was added, and
the resulting mixture was stirred at 1208C for 60 min. The solvent was
evaporated and the crude residue was purified by flash chromatography
drate (0.116 mL, 2 mmol) was added to a solution of 4b (205 mg,
1 mmol) in acetonitrile (10 mL) and the mixture was stirred at reflux
temperature for 1 h. Then the solvent was evaporated and the crude resi-
due was purified by flash chromatography (ethyl acetate). Compound 5b
1
(
ethyl acetate/hexane 1:3). Compound 3 f was obtained as a light brown
was obtained as a light brown solid (91%); m.p. 120–1268C. HNMR
1
3
solid (71%); m.p. 67–698C; R
(
f
3
=0.5 (Hexanes/EtOAc 1:2); HNMR
(300 MHz, CD CN): d=8.62 (sa, 2H), 8.07 (d,
J(H,H)=8.1 Hz, 1H),
A
H
R
U
G
3
3
3
3
3
ACHTREUNG
300 MHz, CDCl
.71 (s, 1H), 8.21 (dd,
3
): d=8.94 (dd, J
A
H
R
U
G
A
H
R
U
G
7.48 (dd,
J
A
H
R
U
G
J
A
H
R
U
(H,H)=4.5 Hz, 1H), 4.69 (q,
(H,H)=7.0 Hz, 3H); C NMR (75 MHz, CD CN):
J
(H,H)=
3
3
3
ACHTREUNG
13
8
J
A
H
R
U
G
A
H
R
U
G
7.0 Hz, 2H), 1.55 (t, J
3
3
3
ACHTREUNG
J
A
C
H
T
R
E
U
N
G
(H,H)=8.3 Hz, J
H), 5.54 ppm (s, 2H); C NMR (75 MHz, CDCl
CH), 148.8, 142.9 (CH), 136.3 (CH), 135.8, 135.6, 128.7 (CH), 128.6
CH), 128.5 (CH), 125.4 (CH), 68.9 ppm (CH ); HRMS (EI): calcd for
O ([M] ) 237.090212, found 237.089768 (deviation 1.9 ppm); el-
d=165.3, 155.6, 147.24 (CH), 142.2, 134.4 (CH), 134.3, 122.6 (CH), 63.9
1
3
+
3
(
(
3
): d=157.4, 150.1
(CH ), 14.0 Hz (CH ); MS (EI): m/z: 205 ([M] ).
2
3
3
-Isopropoxy-2-hydrazinopyrido
drate (0.116 mL, 2 mmol) was added to a solution of 4c (205 mg,
mmol) in acetonitrile (10 mL) and the mixture was stirred at reflux
A
H
R
U
G
2
+
14 11 3
C H N
1
11 3
emental analysis calcd (%) for C14H N O: C 70.87, H4.67, N 17.71;
temperature for 1 h. Then the solvent was evaporated and the crude resi-
found: C 71.04, H4.43, N 17.88.
due was purified by flash chromatography (ethyl acetate). Compound 5c
1
Procedures for the preparation of the 3-alkoxy-2-chloro derivatives 4a–c
-Chloro-3-methoxypyrido[2,3-b]pyrazine (4a): Sodium hydrogen car-
bonate (92 mg, 1.1 mmol) was added to a stirred solution of compound 1
200 mg, 1 mmol) in methanol (10 mL) cooled at 08C. The mixture was
was obtained as a light brown solid (87%); m.p. 110–1158C. HNMR
3
(
7
7
300 MHz, CD
3
CN): d=8.62 (sa, 2H), 8.07 (d,
J(H,H)=8.1 Hz, 1H),
A
H
R
U
2
ACHTREUNG
3
3
3
ACHTREUNG
.48 (dd,
.0 Hz, 2H), 1.55 ppm (t,
CN): d=165.3, 155.6, 147.24 (CH), 142.2, 134.4 (CH), 134.3, 122.6
J
A
H
R
U
G
J
A
H
R
U
G
J
(H,H)=
3
ACHTREUNG
13
J
(H,H)=7.0 Hz, 3H); C NMR (75 MHz,
(
CD
2 3
CH), 63.9 (CH ), 14.0 ppm (CH ); MS (EI): m/z: 219 ([M] ).
3
stirred for 30 min at room temperature and then 1 h at 608C. Then the
solvent was evaporated and the crude residue was purified by flash chro-
matography (ethyl acetate/hexane 1:4). Compound 5a was obtained as a
+
(
Procedures for the preparation of the reduced compounds 6a–c: A dis-
white solid (83%); m.p. 130–1328C; R
f
=0.55 (hexanes/EtOAc 1:2);
persion of sodium hydride (60% in mineral oil, 0.24 mg, 6 mmol) was
1760
www.chemeurj.org
ꢁ 2007 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1754 – 1762

Reduction of Different Electron-Poor N-Heteroarylhydrazines
FULL PAPER
added portionwise to the adequate alcohol (20 mL) and the mixture was
stirred for 10 min at room temperature. Then the corresponding hydrazi-
no derivative (1 mmol) was added and the resulting mixture was stirred
at 608C for 5 min. The solvent was evaporated and the crude residue was
purified by flash chromatography (ethyl acetate/hexane 2:3).
Procedure for the preparation of pyrido[2,3-b]pyrazine (9): A dispersion
A
H
T
E
U
G
of sodium hydride (60% in mineral oil, 0.24 mg, 6 mmol) or sodium hy-
droxide (0.24 mg, 6 mmol) was added portionwise to methanol or water
(20 mL), and the mixture was stirred for 10 min at room temperature.
Then the dihydrazino derivative 8 (0.191 mg, 1 mmol) was added and the
resulting mixture was stirred at reflux temperature for 10–25 min. The
solvent was evaporated and the crude residue was purified by flash chro-
matography (ethyl acetate/hexane 2:3). Compound 9 was obtained as a
3
-Methoxypyrido
A
C
H
T
R
E
U
N
G
[2,3-b]pyrazine (6a): Compound 6a was obtained as a
white solid (89%); m.p. 69–718C;
R
f
=0.27 (Hexanes/EtOAc 1:2);
1
3
3
ACHTREUNG
HNMR (300 MHz, CDCl
3
): d=8.99 (dd,
J
A
H
R
U
G
J
3
3
ACHTREUNG
f
light brown solid (89%); m.p. 88–908C; R =0.55 (hexanes/EtOAc 1:2);
1
.8 Hz, 1H), 8.57 (s, 1H), 8.37 (dd,
J
A
H
R
U
G
J
1
3
3
ACHTREUNG
3
3
ACHTREUNG
HNMR (300 MHz, CDCl
3
): d=9.16 (dd,
J
A
H
R
U
1
H), 7.55 (dd, J
A
C
H
T
R
E
U
N
G
(H,H)=8.2 Hz, J
3
ACHTREUNG
3
1
3
1.9 Hz, 1H), 9.05 (d,
J
(H,H)=1.8 Hz, 1H), 8.92 (s, 1H), 8.45 (dd, J-
(H,H)=1.9 Hz, 1H), 7.71 ppm (dd,
J(H,H)=4.2 Hz, 1H); C NMR (75 MHz, CDCl
3
C NMR (75 MHz, CDCl
3
3
3
ACHTREUNG
A
H
R
U
G
J
A
H
R
U
G
J
(
C
3
3
13
+
A
H
R
U
G
8
H
7
N
3
O ([M] ) 161.058912, found 161.059078 (deviation À1.0 ppm); el-
1
emental analysis calcd (%) for C
found: C 59.66, H4.22, N 26.12.
8 7 3
H N O: C 59.62, H4.38, N 26.07;
+
(
7 5 3
EI): m/z: 131.1 ([M] ); elemental analysis calcd (%) for C H N : C
6
4.11, H3.84, N 32.04; found: C 64.09, H4.05, N 32.01.
3
-Ethoxypyrido
A
C
H
T
R
E
U
N
G
[2,3-b]pyrazine (6b): Compound 6b was obtained as a
Procedures for the preparation of 6-hydrazinopurine (12)
light brown solid (94%); m.p. 68–698C; R
f
=0.35 (hexanes/EtOAc 1:2);
1
3
3
ACHTREUNG
From 6-bromopurine (10): Hydrazine monohydrate (0.116 mL, 2 mmol)
was added to a solution of 6-bromopurine 10 (0.199 g, 1 mmol) in ethanol
(15 mL). The mixture was stirred and heated at reflux temperature for
30 min. The resulting precipitate was filtered and washed with ethanol
HNMR (300 MHz, CDCl
3
): d=8.97 (dd,
J
A
H
R
U
G
J
3
3
ACHTREUNG
1
.8 Hz, 1H), 8.54 (s, 1H), 8.36 (dd,
J
A
H
R
U
G
3
3
ACHTREUNG
3
1
H), 7.52 (dd,
J
A
C
H
T
R
E
U
N
G
(H,H)=8.3 Hz,
J
3
ACHTREUNG
13
A
C
H
T
R
E
U
N
G
(H,H)=7.1 Hz, 2H), 1.50 ppm (t,
J
(
2 2
10 mL), CH Cl (10 mL), and diethyl ether (10 mL). Compound 12 was
(
75 MHz, CDCl
3
obtained as a white solid (93%); m.p. 246–2508C (decomp) [lit. [25] m.p.
246–247.58C (decomp)].
1
C
22.2 (CH), 122.1, 63.4 (CH
2
3
+
9
H
9
N
3
O ([M] ) 175.074562, found 175.074804 (deviation À1.4 ppm); el-
emental analysis calcd (%) for C
found: C 61.77, H5.20, N 23.96.
9
H
9
N
3
O: C 61.70, H5.18, N 23.99;
From 6-chloropurine (11): Hydrazine monohydrate (0.116 mL, 2 mmol)
was added to a solution of 11 (0.154 g, 1 mmol) in ethanol (15 mL). The
mixture was stirred and heated at reflux temperature for 2 h. The result-
3
-Isopropoxypyrido
A
C
H
T
R
E
U
N
G
[2,3-b]pyrazine (6c): Compound 6c was obtained as a
ing precipitate was filtered and washed with ethanol (10 mL), CH
2 2
Cl
light brown solid (94%); m.p. 66–678C; R
f
=0.41 (hexanes/EtOAc 1:2);
1
3
3
ACHTREUNG
(10 mL), and diethyl ether (10 mL). Compound 12 was obtained as a
HNMR (300 MHz, CDCl
3
): d=8.85 (dd,
J
A
H
R
U
G
J
[
25]
3
3
ACHTREUNG
white solid (95%); m.p. 246–2488C (decomp) [lit.
(decomp)]; HNMR (300 MHz, [D
6
m.p. 246–247.58C
]DMSO): d=12.85 (bs, 1H), 8.73 (bs,
1H), 8.17 (s, 1H), 8.08 (s, 1H), 4.62 ppm (bs, 2H); HR (LSIMS): calcd
1
.8 Hz, 1H), 8.54 (s, 1H), 8.11 (dd,
J
A
H
R
U
G
1
3
3
ACHTREUNG
3
1
H), 7.48 (dd,
J
A
C
H
T
R
E
U
N
G
(H,H)=8.3 Hz,
J
3
ACHTREUNG
13
A
C
H
T
R
E
U
N
G
(H,H)=6.2 Hz, 1H), 1.40 ppm (d,
J
+
for C
5 6 6
H N ([M] ) 150.065376, found 150.065394 (deviation 0.1 ppm).
(
75 MHz, CDCl
3
[
26]
Procedures for the preparation of purine (13): m.p. 214–2168C [lit.
1
22.2 (CH), 122.1, 70.8 (CH), 22.1 ppm (CH
3
11 3
H N O
1
+
f
m.p. 214–2178C]; R =0.3 (MeOH/DCM 1:9); HNMR (300 MHz,
(
[M] ) 189. 090212, found 189.089972 (deviation 1.2 ppm); elemental
analysis calcd (%) for C10 O: C 63.48, H5.86, N 22.21; found: C
3.05, H5.97, N 22.01.
[
D
6
]DMSO): d=12.8–11.3 (bs, 1H), 9.09 (s, 1H), 8.88 ppm (s, 1H);
C NMR (75 MHz, [D ]DMSO): d=154.5, 151.8 (CH), 145.9 (CH), 145.3
CH), 130.2 ppm; HR (LSIMS): calcd for C
found 120.043596 (deviation À1.0 ppm).
Method a: Sodium hydroxide (0.24 g, 6 mmol) was added to water
20 mL), and the mixture was stirred to solution for 5 min at room tem-
11 3
H N
1
3
6
6
+
(
5 4 4
H N ([M+H]) 120.043722,
Procedures for the preparation of the deuterated compounds: A disper-
sion of sodium hydride (60% in mineral oil, 0.24 mg, 6 mmol) was added
portionwise to the corresponding deuterated solvent (15 mL), and the
mixture was stirred for 20 min at room temperature. Then the hydrazino
derivative 5a (0.161 mg, 1 mmol) was added and the resulting mixture
was stirred at room temperature for 5–30 min. The solvent was evaporat-
ed and the crude residue was purified by flash chromatography (ethyl
acetate/hexane 2:3).
(
perature. Then the hydrazino derivative 12 (0.149 g, 1 mmol) was added
and the resulting mixture was stirred at reflux temperature for 12 h.
After cooling to room temperature, the crude reaction mixture was neu-
tralized with HCl 1n (~6 mL) and extracted with ethyl acetate (3”
2
0 mL). Then the organic layer were collected and dried over sodium sul-
2
-Deuterio-3-methoxypyrido
ACHTREUNG
fate anhydrous and next distilled under vacuum to provide pure com-
pound 13 as a white solid (95%).
tained as a light yellow solid (91%); m.p. 70–738C; R
f
3
1
EtOAc 1:2); HNMR (300 MHz, CDCl
3
): d=8.92 (dd, J
ACHTREUNG
Method b: A dispersion of NaH(60% in mineral oil, 0.24 mg, 6 mmol)
was added portionwise to methanol (20 mL), and the mixture was stirred
for 10 min at room temperature. Then the hydrazino derivative 12
3
3
3
ACHTREUNG
J
A
C
H
T
R
E
U
N
G
(H,H)=1.9 Hz, 1H), 8.31 (dd, J
A
H
R
U
G
3
3
ACHTREUNG
7
.47 (dd,
J
A
C
H
T
R
E
U
N
G
(H,H)=8.2 Hz,
J
1
3
C NMR (75 MHz, CDCl
3
(
0.149 g, 1 mmol) was added and the resulting mixture was stirred at
3
reflux temperature for 8 h. The solvent was evaporated and the crude
was neutralized with aqueous HCl 1n (~11 mL) and extracted with ethyl
acetate (3x20 mL). Then the organic layers were combined and the crude
residue was purified by flash chromatography (dichloromethane/metha-
nol 14:1). Compound 13 was obtained as a white solid (67%).
+
(
EI): m/z: 162.1 ([M] ).
-([D ]Methoxy)-pyrido
obtained as a white solid (81%); m.p. 67–698C; R
3
3
A
C
H
T
R
E
U
N
G
[2,3-b]pyrazine-2-[D] (7b). Compound 7b was
f
=0.24 (hexanes/
1
3
3
EtOAc 1:2); HNMR (300 MHz, CDCl ): d=8.97 (bs, 1H), 8.36 (dd, J-
3
3
ACHTREUNG
A
C
H
T
R
E
U
N
G
(H,H)=8.2 Hz,
J
A
C
H
T
R
E
U
N
G
(H,H)=1.9 Hz, 1H), 7.53 ppm (dd,
J
Procedure for the preparation of 2-chloropurine 16 from 2,6-dichloropur-
ine (14): Hydrazine monohydrate (0.116 mL, 2 mmol) was added to a so-
lution of 2,6-dichloropurine 14 (0.189 g, 1 mmol) in water (20 mL) and
the mixture was stirred at reflux temperature for 30 min. Then, sodium
hydroxide (0.48 g, 12 mmol) was added to the reaction, and the mixture
was stirred at room temperature for 3.5 h. An analytical HPLC was car-
ried out showing that the reaction was completed. A unique peak was de-
tected, using a UV detector (254 nm), corresponding to the desired com-
pound. After cooling to room temperature, the crude reaction mixture
was neutralized with aqueous HCl 1n (~11 mL) and extracted with ethyl
acetate (3”20 mL). Then the organic layers were combined and dried
3
13
J(H,H)=4.4 Hz, 1H); C NMR (75 MHz, CDCl
3
A
C
H
T
R
E
U
N
G
(
(
+
3
CH), 53.9 ppm (sp, CH , J=80 Hz); MS (EI): m/z: 165.1 ([M] ).
Procedure for the preparation of the dihydrazino derivative 8: Hydrazine
monohydrate (0.348 mL, 6 mmol) was added to a solution of 1 (0.2 g,
1
mmol) in 2-propanol (20 mL). The mixture was stirred at room temper-
ature for 3 h. The resulting precipitate was filtered and washed with etha-
nol (10 mL), CH Cl (10 mL), and diethyl ether (10 mL). Compound 8
was obtained as a yellow solid (85%); m.p. >3008C; MS (EI): m/z: 191.2
2
2
+
(
[M] ).
Chem. Eur. J. 2007, 13, 1754 – 1762
ꢁ 2007 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
www.chemeurj.org
1761

A. Unciti-Broceta, A. Espinosa et al.
over anhydrous sodium sulphate and dried in vacuo to provide pure com-
[7] A. Unciti-Broceta, PhD thesis, Universidad de Granada (Spain),
2004.
pound 16 as a light yellow solid (97%); m.p. 233–2358C [lit. [27] m.p.
1
2
31–2348C];
R
f
=0.4 (MeOH/DCM 1:9);
HNMR (300 MHz,
[8] R. H. Shapiro, Org. React. 1976, 23, 405–507.
[9] W. R. Bamford, T. S. Stevens, J. Chem. Soc. 1952, 4735–4740.
[10] G. Adembri, A. Camparini, F. Ponticelli, P. Tedeschi, J. Chem. Soc.
Perkin Trans. 1 1975, 5, 2190–2195; A. Gomtsyan et al., J. Med.
Chem. 2005, 48, 744–752.
1
3
[
D
6
]DMSO): d=9.04 (s, 1H), 8.68 ppm (s, 1H); C NMR (75 MHz,
]DMSO): d=157.7 (CH), 152.6 (CH), 147.8 (CH), 146.9, 128.6 ppm;
[
D
6
+
HRMS (EI): calcd for C
5 3 4
H ClN ([M] ) 154.004624, found 154.004474
(
deviation 1.0 ppm).
[
11] Compound 1 was synthesized as decribed: A. Unciti-Broceta, M. J.
Pineda-de-las-Infantas, J. J. Díaz-Mochón, R. Romagnoli, P. G. Bar-
aldi, M. A. Gallo; A. Espinosa, J. Org. Chem. 2005, 70, 2878–2880.
12] Reactions were monitored by TLC. All the reductions were ach-
ieved in less than 1 h.
13] The reduction was very quick in all the experiments at the corre-
sponding reflux temperature of each alcohol. However, the bigger
the substituent R, the longer the time and the higher the tempera-
ture needed to complete the reaction.
To verify the process, 6-chloro-2-hydrazinepurine 15 was isolated one
time by filtration. Compound 15 was obtained as a white solid (98%);
1
m.p. >3008C [lit. [27] m.p. >3008C]; HNMR (300 MHz, [D
6
]DMSO):
[
[
d=9.12 (bs, 1H), 8.12 (s, 1H), 4.92 ppm (bs, 2H); HR (LSIMS): calcd
+
for C
5
H
5
ClN
6
([M] ) 184.026422, found 184.026904 (deviation À2.6 ppm).
X-ray crystallographic study of compound 3d: Crystallographic data
were collected at 297 K using graphite-monochromated MoKa radiation
(
l=0.71073 Š). The structure was solved by direct methods using the
[
28]
program SHELXS97
and all non-hydrogen atoms were refined with
[
[
14] S. R. Breshears, S. S. Wang, S. G. Bechtolt, B. E. Christensen, J. Am.
Chem. Soc. 1959, 81, 3789–3792.
anisotropic thermal parameters by full-matrix least squares techniques of
2
[29]
F
using the program SHELXL97. Hydrogen atoms were inserted in
15] The reaction was monitored by HPLC.
calculated positions and refined isotropically. Molecular graphics were
[
30]
[16] a) D. Todd, J. Am. Chem. Soc. 1949, 71, 1356–1358; b) H. H.
Szmant, H. F. Hangsberger, T. J. Butler, W. B. Barie, J. Am. Chem.
Soc. 1952, 74, 2724–2728; c) H. H. Szmant, Angew. Chem. 1968, 80,
141–149; Angew. Chem. Int. Ed. Engl. 1968, 7, 120–128; d) H. H.
Szmant, C. E. Alciaturi, J. Org. Chem. 1977, 42, 1081–1083; e)
Szmant, C. A. Birke, M. P. Lau, J. Am. Chem. Soc. 1977, 99, 1863–
1871; f) H. H. Szmant, C. E. Alciaturi, J. Solution Chem. 1978, 7,
obtained from ORTEP-3 v1.08. Relevant crystal data: colorless prisms,
crystal size 0.35”0.32”0.12 mm, formula C10 O, M =189.22, system
monoclinic, space group P2(1)/c, unit cell dimensions a=11.7758(10), b=
H
11
N
3
r
3
1
1.2035(10), c=7.3807(7) Š, b=98.1130(10)8, V=963.99(15) Š , Z=4, m-
À1
À3
A
C
H
T
R
E
U
N
G
(MoKa)=0.088 mm
,
1
calcd =1.304 Mgm
,
F
ACHTREUNG
unique reflections 2248/1804 (R
AHCTREUNG
2
1
A
H
R
U
G
2
2
9
69–281; g) D. F. Taber, S. J. Stachel, Tetrahedron Lett. 1992, 33,
03–906.
CCDC-286167 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data request/cif.
[
[
17] The air present in the solvents was removed by bubbling a stream of
nitrogen through the corresponding solvent for 30 min.
18] According to: D. L. Smith, P. J. Elving, J. Am. Chem. Soc. 1961, 83,
1
412–1420; it should be possible to isolate 1,6-dihydropurine before
its oxidation into purine by avoiding the exposure to air and neutral-
izing the reaction mixture.
19] R. H. Shapiro, M. J. Heath, J. Am. Chem. Soc. 1967, 89, 5734–5735;
R. H. Shapiro, E. C. Hornaman, J. Org. Chem. 1974, 39, 2302–2303.
[20] F. G. Bordwell, D. L. Singer, A. V. Satish, J. Am. Chem. Soc. 1993,
115, 3543–3547.
Acknowledgements
[
A.U.B. is grateful to Ramon Areces Foundation and NOX for funding.
We thank Gianluca Sechi, Adam Belsom and, especially, Dr. Juan J.
Díaz-Mochón for their helpful discussions.
[
[
21] F. G. Bordwell, unpublished results.
22] The heterocyclic systems of the compounds reduced in this article
are much more electron-poor than the 2-pyridone ring.
[
1] a) R. Nakao, H. Rhee, Y. Uozumi, Org. Lett. 2005, 7, 163–165;
b) X. Bei, A. Hagemeyer, A. Volpe, R. Saxton, H. Turner, A.
Guram. S, J. Org. Chem. 2004, 69, 8626–8633; c) R. J. Jr., Rahaim,
R. E. Jr., Maleczka, Tetrahedron Lett. 2002, 43, 8823–8826, and ref-
erences therein. For a recent and effective method, see: d) P. X.
Wang, F. W. Moser, PCT Int. Appl. WO 05/068403. For a review of
metal-catalyzed reductions of organic halides, see: e) F. Alonso, I. P.
Beletskaya, M. Yus, Chem. Rev. 2002, 102, 4009–4091.
[
19]
[
23] According to the literature, the aromatic heteroaryldiazene deriv-
ative would be the expected intermediate produced through a Sha-
piro-type reduction mechanism in this kind of compounds.
[
24] For a review of rational and maximal structure proliferation from
simple aromatic and heterocyclic starting material, see: M. Schloss-
er, Angew. Chem. 2005, 117, 380–398; Angew. Chem. Int. Ed. 2005,
4
4, 376–393.
25] J. A. Montgomery, L. B. Holum, J. Am. Chem. Soc. 1957, 79, 2185–
188.
[
[
2] For chloropyridines reductions, see: a) J. Cheng, C. Zhang, E. D.
Stevens S. Izenwasser, D. Wade S. Chen, D. Paul, M. L. Trudell, J.
Med. Chem. 2002, 45, 3041–3047; b) S. Connon, A. F. Hegarty, Tet-
rahedron Lett. 2001, 42, 735–737; c) P. L. Kotian, F. I. Carroll, Synth.
Commun. 1995, 25, 63–71. For chloroquinoxalines reductions, see:
d) W. C. Jr., Lumma, R. D. Hartman, W. S. Saari, E. L. Engelhardt,
J. Med. Chem. 1981, 24, 93–101.
2
[
[
26] Merck Index 13, 8033.
27] S. R. Breshears, S. S. Wang, S. G. Bechtolt, B. E. Christensen, J. Am.
Chem. Soc. 1959, 81, 3789–3792.
[28] G. M. Sheldrick, SHELXS97, Program for the Solution of Crystal
Structures, University of Gçttingen, Gçttingen (Germany), 1997.
[29] G. M. Sheldrick, SHELXL97, Program for the Refinement of Crys-
tal Structures, University of Gçttingen, Gçttingen (Germany), 1997.
[30] a) M. N. Burnett, C. K. Johnson, ORTEP-III: Oak Ridge Thermal
Ellipsoid Plot Program for Crystal Structure Illustrations, Oak
Ridge National Laboratory Report ORNL-6895 (USA), 1996;
b) L. J. Farrugia, Ortep-3 for Windows, J. Appl. Crystallogr. 1997,
[
[
3] For a review of the applications of hydrazine in organic chemistry,
see: B. A. Roden, Hydrazine, in Encyclopedia of Reagents for Or-
ganic Synthesis, Vol. 4 (Ed.: L. A. Paquette), Wiley, Chichester, UK,
995, pp. 2680–2684.
4] a) N. Kishner, Zh. Russ. Fiz.-Khim. O-va. Chast Khim. 1911, 43,
82; b) L. Wolff, Justus Liebigs Ann. Chem. 1912, 394, 86; c) Huang-
1
5
3
0, 565.
Minlon, J. Am. Chem. Soc. 1946, 68, 2487. For a review, see d) O.
Hutchins, M. K. Hutchins, Comp. Org. Syn. 1991, 8, 327–343.
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Recl. Trav. Chim. Pays-Bas 1953, 72, 569.
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Lett. 2003, 44, 7191–7195.
[
[
Received: February 28, 2006
Revised: July 27, 2006
Published online: December 5, 2006
1762
www.chemeurj.org
ꢁ 2007 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1754 – 1762