(2-Pyridyl)phenyl methanol: A new reagent for metal-free reduction of nitro aromatic compounds

Article abstract of DOI:10.1016/j.tet.2010.11.008

As previously reported for 1-(2-pyridyl)-2-propen-1-ol, (2-pyridyl)phenyl methanol is able to react as hydrogen donor towards nitro aromatic and heteroaromatic compounds. Operating in the presence of methyl acrylate as an aza-Michael acceptor, a domino process involving reduction and conjugate addition steps allows the one pot formation of β-amino esters. The crucial role of the pyridine nucleus in making this purely thermal reactivity of carbinols possible has been shown.

Full text of DOI:10.1016/j.tet.2010.11.008

Tetrahedron 67 (2011) 167e172
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Tetrahedron
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(2-Pyridyl)phenyl methanol: a new reagent for metal-free reduction of nitro
aromatic compounds
*
*
Donatella Giomi , Renzo Alfini, Alberto Brandi
ꢀ
Dipartimento di Chimica ‘Ugo Schiff’, Laboratorio di Progettazione, Sintesi e Studio di Eterocicli Biologicamenti Attivi (HeteroBioLab), Universita di Firenze,
Polo Scientifico e Tecnologico, Via della Lastruccia 3-13, I-50019 Sesto Fiorentino, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 July 2010
Received in revised form 14 October 2010
Accepted 1 November 2010
Available online 5 November 2010
As previously reported for 1-(2-pyridyl)-2-propen-1-ol, (2-pyridyl)phenyl methanol is able to react as
hydrogen donor towards nitro aromatic and heteroaromatic compounds. Operating in the presence of
methyl acrylate as an aza-Michael acceptor, a domino process involving reduction and conjugate addition
steps allows the one pot formation of
this purely thermal reactivity of carbinols possible has been shown.
Ó 2010 Elsevier Ltd. All rights reserved.
b-amino esters. The crucial role of the pyridine nucleus in making
Keywords:
Pyridyl carbinols
Hantzsch ester 1,4-dihydropyridine mimics
Nitro derivatives
Metal-free reductions
1. Introduction
solvents, with inexpensive catalysts, etc.) and in many cases ex-
tremely high enantioselectivities.6 On this basis, new metal-free
organocatalytic strategies based on the use of small molecules as
organocatalysts and 1,4-dihydropyridine systems as hydrogen do-
nors have been described.7
In biological systems, reductions proceed smoothly under mild
conditions in cascade processes involving metalloenzymes and or-
ganic hydride reduction cofactors, such as nicotinamide adenine di-
nucleotide(NADH)andthecorrespondingphosphateester(NADPH).1
In order to understand the mechanism of the hydride transfer, many
1,4-dihydropyridinederivativeshavebeenextensivelyinvestigatedas
NADH models for the reduction of unsaturated organic compounds2
in the absence of metal ions, under thermal or Brùnsted acid-cata-
lyzed conditions. In particular, after the pioneering works of Braude
andDittmer,3 noteworthyresultsinthelast50yearsdemonstratethat
Hantzsch ester (HEH) and other 1,4-dihydropyridine systems work as
efficient and versatile reducing agents.4
Moreover, even if the most common methods applied for the
reduction of organic compounds exploit metal catalysts in con-
junction with a hydrogen source, in the last decade great attention
has been devoted to the development of organocatalysis,5 namely
the acceleration of chemical reactions through the addition of
a substoichiometric amount of an organic compound, which does
not contain a metal atom. This combines significant preparative
advantages (reactions performed under aerobic conditions, in wet
Concerning nitro compounds, their synthetic applications and,
hence, their reduction processes have been extensively reviewed.8
The reduction of aromatic nitro derivatives to amines has been
mainly performed with metals and acid, by catalytic hydrogenation,
or with hydrides and various catalysts.9 Aniline derivatives have
also been obtained in alcoholic media in the presence of dodeca-
carbonyltriiron10 or bases,11 although in the last case different re-
action products were isolated depending on the experimental
conditions. Recently, hydrogenation of nitrobenzene to give aniline
has been performed in the presence of fullerene, as a non-metal
catalyst for the activation of molecular hydrogen, under UV irra-
diation or by heating under a high pressure of H2.12 Only few ex-
amples of purely thermal metal-free reductions of aromatic nitro
derivatives exploiting 9,10-dihydroanthracene13 or 1,4-dihy-
dropyridine systems3,14,15 as hydrogen source have been reported.
In this context, we recently described a surprising reactivity of 1-
(2-pyridyl)-2-propen-1-ol as 1,4-dihydropyridine HEH mimic for the
metal-free reduction of nitro groups to amino functions in aromatic
and heteroaromatic nitro compounds.16,17 A low chemical efficiency
of the reduction was, however, observed due to competitive thermal
isomerization of the allyl alcohol into the corresponding ethyl ketone.
Other pyridyl carbinols were taken into consideration to avoid such
* Corresponding authors. Tel.: þ39 055 4573475; fax: þ39 055 4573575
(D.G.); Tel.: þ39 055 4573485; fax: þ39 055 4573572 (A.B.); e-mail addresses:
donatella.giomi@unifi.it (D. Giomi), alberto.brandi@unifi.it (A. Brandi).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.008

168
D. Giomi et al. / Tetrahedron 67 (2011) 167e172
drawbacks and, in this paper, (2-pyridyl)phenyl methanol (1)18
demonstrated its efficiency as hydrogen donor.
H
N
N
H
N
H
2. Results and discussion
OH
1
OH
1a
O
1b
As aromatic amines are often quite unstable compounds, they
are preferably trapped during their synthesis. Indeed, in a pre-
liminary study,16 (2-pyridyl)phenyl methanol (1) and 2-chloro-3-
nitropyridine (2) completely disappeared after heating in toluene
at 110 ꢀC for 96 h, leading to a complex reaction mixture mainly
containing ketone 318a,18d,19 and only trace amounts of 3-amino-2-
chloropyridine (4). It is likely that the free amine, coming from the
reduction of 2, undergoes different competitive reaction pathways.
Among them, however, the condensation of 4 with ketone 3 should
be ruled out as the corresponding product was never observed in
the reaction crude.
Fig. 1. Tautomeric forms of alcohol 1.
from the reaction mixture mainly containing the starting reagents
(Scheme 3). This result clearly showed the key role of the pyridine
ring in promoting the reactivity of 1 as a reducing agent.
CO2Me
O2N
NO2
Cl
(4 equiv)
+
no reactivity
N
toluene, 110 °C, 96 h
or
OH
Performing the above reaction in the presence of methyl acry-
late as aza-Michael acceptor, the amino ester 5 was isolated in 65%
xylene, 150 °C, 24 h
8 (3 equiv)
2
yield.16 Thus, the method provided an excellent access to
b
-amino
Scheme 3. Reactions of carbinol 8 with 2-chloro-3-nitropyridine (2).
esters in a domino multicomponent process.
b-Amino acids and
their derivatives are valuable synthetic intermediates.20 The re-
action was then optimized using an excess of methyl acrylate (see
Experimental section) in acetonitrile to favour the trapping of the
free amine (Scheme 1). Careful chromatographic separation
allowed isolation of amino derivatives 4 and 5 in 8 and 68% yields,
respectively, along with ketone 3 (recovered in 89% yield, based on
reacted alcohol 1). Attempts to complete the conversion of 4 into 5
by operating with a larger excess of acrylate or by addition of
a catalytic amount of acetic acid were unsuccessful.
Reactions of other nitro heterocycles with alcohol 1 were
studied to demonstrate the generality of the process (Table 1).
Under the same reaction conditions, a complex reaction mixture
was obtained from the isomeric 2-chloro-5-nitropyridine (9): the
amino ester 10 was isolated in only 30% yield, with ketone 3 re-
covered in 84% yield (Table 1, entry 2). The switch to acetonitrile as
solvent did not change the poor result, probably due to side re-
actions of the formed 5-amino-2-chloropyridine.24
CO2Me
NO2
Cl
NH2
NH
Cl
MeCN, 110 °C, 96 h
+
+
N
N
N
Cl
N
CO2Me
OH
1
2
4 8%
5 68%
N
O
3 (89%)
Scheme 1. Reaction of alcohol 1 with 2-chloro-3-nitropyridine (2).
From a mechanistic viewpoint, the reaction stoichiometry (alco-
hol/nitro derivative ratio at least 3:1), associated with the recovery of
ketone 3, seems to confirm the hypothesis of a domino process. Al-
cohol 1 acts as a reducing agent able to transform 2-chloro-3-nitro-
pyridine (2), viathe nitrosoandhydroxylaminointermediates6and7,
into the amino derivative 4, converted into the final product through
aza-Michael addition to methyl acrylate (Scheme 2).
On the basis of the interest in 4-aminopyridine in the pharma-
cological domain,25 and with the aim to test monofunctional
nitropyridines to limit competitive pathways, 4-nitropyridine
(11)26 was allowed to react with 1. However, a completely different
behaviour was observed. Operating in acetonitrile at 110 ꢀC, only
the pyridone derivative 12 was isolated in 57% yield (Table 1, entry
3).27 Control experiments showed that the same compound formed
O
N
OH
NH
CO2Me
NH2
Cl
NH
Cl
1
1
1
2
N
6
Cl
N
7
Cl
N
4
N
5
CO2Me
3
, H2O
3
3, H2O
Scheme 2. Mechanistic rationale accounting for the formation of compound 5.
Such reactivity of alcohol 1 could be ascribed to its behaviour as
a HEH mimic16,17 through the involvement of a 1,4-dihydropyridine
tautomer 1b generated as a consequence of the mobility of the
hydrogen atom of the methanol residue (Fig. 1).
Moreover, the crucial role of the pyridine ring is demonstrated
in the lack of reactivity towards 2-chloro-3-nitropyridine (2) of the
apparently analogous nitrophenyl derivative 8.21 In toluene at
110 ꢀC or in xylene at 150 ꢀC, alcohol 8 was only poorly converted to
4-nitrobenzophenone,22,23 and reduction products were absent
also in absence of 1, likely due to the hydrolysis of 4-nitropyridine
to 4-pyridone28,29 followed by aza-Michael addition to methyl ac-
rylate. However, 4-nitropyridine (11) was recovered unchanged
after heating at 110 ꢀC in dry toluene in the presence of alcohol 1
and molecular sieves.
Better results were obtained with monofunctionalized nitro het-
erocycles, such as 5-nitroquinoline (13) and 6-nitroquinoline (15)
which gave, in acetonitrile as solvent, the valuable
b-amino esters 14
and 16 in 57 and 55% yields, respectively (Table 1, entries 4 and 5).

D. Giomi et al. / Tetrahedron 67 (2011) 167e172
169
Table 1
Reduction of nitroarenes to aminoarenes and aza-Michael addition to methyl acrylate
Entry
Reagent
NO2
Cl
Reaction conditionsa
Product
Yieldb
NH2
NH
Cl
MeCN
110 ꢀC, 96 h
4 8%
5 68%
+
1
N
4
Cl
N
5
CO2Me
N
2
H
N
NO2
toluene
CO2Me
2
30%
57%
110 ꢀC, 63 h
9
Cl
N
10
Cl
N
O
N
NO2
N
MeCN
110 ꢀC, 43 h
3c
12
11
CO2Me
CO2Me
NO2
HN
MeCN
110 ꢀC, 6 days
4
57%
14
N
13
N
H
N
NO2
MeCN
CO2Me
5
6
55%
63%
110 ꢀC, 7 days
N
15
16
N
CO2Me
NO2
HN
MeCN
110 ꢀC, 10 days,
20 mol % AcOH
18
17
CO2Me
NO2
HN
Toluene
110 ꢀC, 67 h,
20 mol % AcOH
7
15%
19
20
Cl
Cl
Cl
Cl
Me
NO2
Me
Xylene
150 ꢀC, 46 h
8c, d
29%
48%
21
N
N
22
O
OCOMe
Ph
NO2
Ph
NH2
Toluene
110 ꢀC, 64 h
9d
23
24
N
N
CO2Et
CO2Et
O
O
a
(2-Pyridyl)phenyl methanol (1) (3.5 equiv), methyl acrylate (4 equiv), screw-cap tube (Pyrex N. 15). Reaction times refer to disappearance of starting nitro derivative.
Isolated yields.
The reaction product is not related to the reduction process.
Reaction performed without methyl acrylate.
b
c
d
Nitrobenzene derivatives could be also reduced by alcohol 1. The
recovered unchanged after heating with an excess of 1 in toluene at
110 ꢀC for 96 h, while when operating in xylene at 150 ꢀC only the
acetate 22 was isolated in 29% yield (Table 1, entry 8). It is likely that
thermal decomposition of the isoxazole 21 prevails in these condi-
tions, showingits reactivityasa maskedacetate.31 Nucleophilic attack
of the alcohol 1 on the C-5 carbon atom of the isoxazole ring and
subsequent ring opening gave the acetate 22.
reactions were performed in the presence of 20 mol % of AcOH to
favour the aza-Michael addition.20,30 Nitrobenzene (17) gave the
b
-anilino ester 18 in 63% yield by prolonged heating in MeCN (10
days, Table 1, entry 6), whereas the more activated dichloro de-
rivative 19 was more quickly converted in toluene into the amino
ester 20, isolated in only 15% yield (Table 1, entry 7).
The reactivity of 1 was also tested towards available heterocycles
like nitroisoxazoles. 3,5-Dimethyl-4-nitroisoxazole (21) was
In contrast, a chemoselective reduction of the NO2 group of the
nitro ester 2332 leading to the corresponding amino isoxazole 24 in

170
D. Giomi et al. / Tetrahedron 67 (2011) 167e172
48% yield was achieved (Table 1, entry 9). Attempts to convert 24
into the corresponding -amino ester operating in the presence of
methyl acrylate were unsuccessful, likely due to the less nucleo-
philic character of the amino function.
4. Experimental section
4.1. General
b
€
To evaluate the potential of (2-pyridyl)phenyl methanol (1) in
the reduction of nitro aromatics and heteroaromatics, its reactivity
towards the poorly activated nitrobenzene (17) was compared with
that of Hantzsch ester 25. When nitrobenzene was heated in
a screw-cap tube with an excess of 25 (3 equiv) in toluene or MeCN,
after 72 h at 70 ꢀC the reaction mixture appeared unchanged.
Raising the temperature to 110 ꢀC for 5 days, the conversion of 25
into the corresponding pyridine derivative 26 was the only signif-
icant process,33 and only trace amounts of aniline were observed
(GCeMS) along with unreacted 17. Operating under the same
conditions described for alcohol 1 (MeCN, in the presence of methyl
acrylate and AcOH as catalyst), after 5 days at 110 ꢀC, 18 was com-
pletely absent in the reaction mixture containing pyridine 26 and
nitrobenzene (17). The same result was also observed when the
more activated 2-chloro-3-nitropyridine (2) was heated with ester
25 and methyl acrylate at 110 ꢀC in MeCN for 4 days: only unreacted
2 and the aromatic derivative 26 were detected in the reaction
mixture.
Melting points were taken on a Buchi 510 apparatus and are
uncorrected. Silica gel plates (Merck F254) and silica gel 60 (Merck,
230e400 mesh) were used for TLC and flash chromatographies
(FCs), respectively; petroleum ether (PE) employed for crystalliza-
tions and chromatographic workup refers to the fractions of bp
30e50 and 40e70 ꢀC, respectively. IR spectra were recorded with
a PerkineElmer Spectrum BX FT-IR System spectrophotometer. 1H
and 13C NMR spectra were recorded in CDCl3 solutions with a Var-
ian Mercuryplus 400 instrument, operating at 400 and 100 MHz,
respectively. Elemental analyses were performed with a Per-
kineElmer 2400 analyzer.
Accurate mass spectra were recorded on an LTQ-Orbitrap high-
resolution mass spectrometer (Thermo, San Jose, CA, USA), equip-
ped with a conventional ESI source.
4.2. Reaction of 1 with nitro derivatives 2, 9, 11, 13. General
procedure
Nitro compound (0.5 mmol), alcohol 1 (0.324 g, 1.75 mmol) and
methyl acrylate (0.180 mL, 2 mmol) were mixed in toluene or ace-
tonitrile (1 mL) degassed by several vacuumenitrogen cycles to
reduce the air oxidation of alcohol 1 to ketone 3. The resulting
mixture was heated at 110 ꢀC in a screw-cap tube (Pyrex N. 15) until
the disappearance of the starting nitro compound. Removal of the
EtO2C
Me
CO2Et
Me
EtO2C
Me
CO2Et
Me
N
H
N
25
26
solvent in vacuo and purification by FC gave the b-amino esters and
ketone 3. The excess alcohol 1 was recovered and recycled.
The lack of reactivity of the Hantzsch ester is remarkable, as this
popular reagent has been employed in a vast array of hydrogen
transfer reductions,4,7 and provides even more interest in (2-pyr-
idyl)phenyl methanol (1) as a new reducing agent. An explanation
of the different reactivity is rather premature, although a brief
structural comparison of the two compounds shows the presence
of sterically bulky substituents in the dihydropyridine ring of
Hantzsch ester that might slow down its reactivity compared to 1.
4.2.1. 3-Amino-2-chloropyridine (4). In the reaction crude obtained
by heating 2-chloro-3-nitropyridine (2) (0.079 g, 0.5 mmol) and
alcohol 1 (0.324 g, 1.75 mmol) in toluene (1 mL) at 110 ꢀC for 96 h,
without methyl acrylate, ketone 3 was the predominant product
(ca. 90%, 1H NMR spectroscopy) while only trace amounts of amine
4 (ca. 5%, 1H NMR spectroscopy) were detected.
3. Conclusions
4.2.2. Methyl 3-[(2-chloro-3-pyridyl)amino]propanoate (5). The re-
action mixture obtained by heating 2-chloro-3-nitropyridine (2)
(0.079 g, 0.5 mmol), alcohol 1 (0.324 g, 1.75 mmol) and methyl ac-
rylate (0.180 mL, 2 mmol) in acetonitrile (1 mL) at 110 ꢀC for 96 h,
was resolved by FC (DCM/EtOAc 100:3), leading to ketone 3
(Rf¼0.43, 0.244 g, 89% referred to reacted 1), 3-amino-2-chlor-
opyridine (4) (Rf¼0.20, 0.005 g, 8%) and compound 5 (Rf¼0.18,
0.073 g, 68%) as a dark yellow oil: IR (film) 3402, 3059, 2954, 2918,
The above results demonstrate the ability of pyridyl carbinol 1 to
react as hydrogen donor towards nitro aromatic and hetero-
aromatic derivatives. The observed reactivity extends that already
reported for 1-(2-pyridyl)-2-propen-1-ol.16,17 Pyridyl carbinol 1
proves to be a superior reagent for this chemistry, as the re-
placement of the vinyl group with the phenyl ring prevents com-
petitive reactions observed for pyridylpropenol, such as thermal
isomerisation or nucleophilic substitutions/additions, allowing the
use of almost stoichiometric amounts of the reducing agent.
Moreover, the oxidation product, ketone 3, can be recovered and
recycled through reduction with NaBH4.34
1734, 1586, 1495, 1176 cmꢁ1
;
1H NMR
d
2.66 (t, J¼6.4 Hz, 2H,
CH2CO2Me), 3.50 (t, J¼6.4 Hz, 2H, CH2NH), 3.71 (s, 3H, OCH3), 4.90
(br s, 1H, NH), 6.95 (dd, J¼8.0 and 1.5 Hz, 1H, 4-H), 7.12 (dd, J¼8.0
and 4.7 Hz, 1H, 5-H), 7.73 (dd, J¼4.7 and 1.4 Hz, 1H, 6-H); 13C NMR
d
33.4 (t), 38.7 (t), 52.0 (q), 117.7 (d), 123.5 (d), 136.2 (d), 136.9 (s),
Despite the isolation of the free amines being impractical, op-
erating in the presence of methyl acrylate as aza-Michael acceptor,
a domino process involving reduction and conjugate addition al-
140.4 (s), 172.1 (s). HRMS (ESI): MHþ, found 215.0582,
C9H1235ClN2O2 requires 215.0586.
lows the one pot formation of
b
-amino esters as the product of
4.2.3. Methyl 3-[(6-chloro-3-pyridyl)amino]propanoate (10). The
crude obtained by heating alcohol 1 (0.324 g, 1.75 mmol), com-
pound 9 (0.079 g, 0.5 mmol) and methyl acrylate (0.180 mL,
2 mmol) in toluene (1 mL) for 63 h was subjected to FC with DCM/
EtOAc 20:1 as eluent leading to ketone 3 (Rf¼0.47, 0.229 g, 84%
referred to reacted 1) and with DCM/EtOAc 6:1 to isolate com-
pound 10 (Rf¼0.23, 0.032 g, 30%) as ivory needles, mp 86e87 ꢀC
(from PE/Et2O 4:1); [found: C, 50.08; H, 4.96; N, 12.97.
C9H11ClN2O2 requires: C, 50.36; H, 5.17; N, 13.05%]. IR (KBr) 3397,
3051, 2947, 2890, 2853, 1723, 1594, 1461, 1441, 1209 cmꢁ1; 1H NMR
multicomponent reactions (3-MCR)35 involving alcohol 1, the nitro
compound, and methyl acrylate. Comparing the reactivity of car-
binols 1 and 8, the crucial role of the pyridine nucleus to make this
purely thermal reactivity of 1 possible is well evidenced. Moreover,
the reducing ability of 1 is even more striking if compared with the
inertness of Hantzsch ester 25 in reducing 2-chloro-3-nitropyridine
(2) and nitrobenzene (17) in purely thermal conditions.
In the light of the great interest associated with multicompo-
nent and organocatalytic metal-free processes, further studies are
underway in our laboratories to test the reactivity of pyridyl car-
binols as reducing agents towards different substrates.
d
2.62 (t, J¼6.1 Hz, 2H, CH2CO2Me), 3.43 (q, J¼6.2 Hz, 2H, CH2NH),
3.71 (s, 3H, OCH3), 4.16 (br s, 1H, NH), 6.88 (dd, J¼8.4 and 3.3 Hz,

D. Giomi et al. / Tetrahedron 67 (2011) 167e172
171
1H, 4-H), 7.09 (d, J¼8.3 Hz, 1H, 5-H), 7.77 (d, J¼3.4 Hz, 1H, 2-H); 13
C
acid (0.006 g, 0.006 mL, 0.1 mmol) in toluene (1 mL) at 110 ꢀC for
67 h afforded compound 20 (Rf¼0.32, 0.019 g, 15%) as a pale yellow
oil; [found: C, 48.79; H, 4.83; N, 5.75. C10H11Cl2NO2 requires: C,
48.41; H, 4.47; N, 5.65%]. IR (film) 3394, 3102, 2951, 1731, 1594,
NMR d 33.3 (t), 39.2 (t), 51.9 (q), 122.4 (d), 124.1 (d), 134.7 (d), 139.4
(s), 142.7 (s), 172.4 (s).
4.2.4. Methyl 3-[4-oxo-1-(4H)-pyridyl]propanoate (12)36. 4-Nitro-
pyridine (11) (0.062 g, 0.5 mmol), alcohol 1 (0.324 g, 1.75 mmol)
and methyl acrylate (0.180 mL, 2 mmol) were heated in MeCN
(1 mL) at 110 ꢀC for 43 h. Chromatographic resolution (EtOAc/
MeOH/NEt3 7:2:2) gave alcohol 1 and ketone 3 as a 3:1 mixture (1H
NMR spectroscopy) (Rf¼0.86, 0.310 g) and compound 12 (Rf¼0.33,
0.052 g, 57%) as a pale yellow oil. IR (film) 3004, 2956, 1737, 1641,
1572 cmꢁ1
;
1H NMR
d
2.61 (t, J¼6.2 Hz, 2H, CH2CO2Me), 3.41 (t,
J¼6.2 Hz, 2H, CH2NH), 3.71 (s, 3H, OCH3), 4.23 (br s,1H, NH), 6.46 (d,
J¼1.8 Hz, 2H, 2-H and 6-H), 6.67 (t, J¼1.8 Hz, 1H, 4-H); 13C NMR
d
33.3 (t), 39.0 (t), 51.9 (q), 111.0 (d), 117.3 (d), 135.5 (s), 149.2 (s),
172.4 (s).
Ketone 3 was recovered with DCM/EtOAc 3:1 as eluent (Rf¼0.74,
0.216 g, 79% referred to reacted 1).
1578, 1190 cmꢁ1; 1H NMR
d
2.78 (t, J¼6.3 Hz, 2H, CH2CO2Me), 3.69
(s, 3H, OCH3), 4.09 (t, J¼6.3 Hz, 2H, CH2NH), 6.35 (d, J¼7.8 Hz, 2H, 3-
4.2.9. Phenyl-2-pyridylmethyl acetate (22)39. Operating as above,
but without methyl acrylate, chromatographic resolution (PE/
EtOAc 3:1) of the material obtained by heating carbinol 1 (0.324 g,
1.75 mmol) and compound 21 (0.072 g, 0.5 mmol) in xylene (1 mL)
at 150 ꢀC for 46 h allowed the isolation of, along with ketone 3
(Rf¼0.40, 0.163 g, 51% referred to 1) coming from oxidation of al-
cohol 1, derivative 22 (Rf¼0.14, 0.031 g, 29%) as a pale yellow oil; 1H
H and 5-H), 7.35 (d, J¼7.8 Hz, 2H, 2-H and 6-H); 13C NMR
d 35.0 (t),
51.9 (t), 52.3 (q), 118.8 (d), 139.9 (d), 170.5 (s), 178.7 (s). HRMS (ESI):
MHþ, found 182.0814, C9H12NO3 requires 182.0817.
4.2.5. Methyl 3-(5-quinolylamino)propanoate (14). The residue com-
ing from heating alcohol 1 (0.324 g, 1.75 mmol), 5-nitroquinoline
(13) (0.087 g, 0.5 mmol) and methyl acrylate (0.180 mL, 2 mmol) at
110 ꢀC in MeCN (1 mL) for 6 days, was resolved by FC with PE/EtOAc
3:1 as eluent leading to ketone 3 (Rf¼0.43, 0.242 g, 88% referred to
reacted 1) and with PE/EtOAc 1:1 to isolate compound 14 (Rf¼0.18,
0.065 g, 57%) as yellow needles, mp 79e80 ꢀC (from PE/Et2O 3:1);
[found: C, 67.72; H, 6.41; N, 12.29. C13H14N2O2 requires: C, 67.81; H,
6.13; N, 12.17%]. IR (KBr) 3269, 3085, 2946, 1729, 1583, 1204,
NMR
d
2.18 (s, 3H, CH3), 6.86 (s, 1H, CHOCOCH3), 7.17 (ddd, J¼7.6,
4.9, and 1.0 Hz, 1H, 5-H), 7.25e7.34 (m, 3H, Ar-3H), 7.39e7.42 (m,
3H, Ar-2H and 3-H), 7.67 (ddd, J¼7.6, 7.6, and 1.8 Hz, 1H, 4-H), 8.56
(br d, J¼4.8 Hz,1H, 6-H); 13C NMR
d 21.2 (q), 77.8 (d), 121.0 (d), 122.7
(d), 127.3 (d), 128.2 (d), 128.55 (d), 136.9 (d), 138.9 (s), 149.3 (d),
159.1 (s), 169.9 (s).
The slowest moving bands led to unreacted 1 (Rf¼0.07, 0.099 g).
1119 cmꢁ1; 1H NMR
d
2.75 (t, J¼6.4 Hz, 2H, CH2CO2Me), 3.59 (m, 2H,
CH2NH), 3.71 (s, 3H, OCH3), 4.97 (br s, 1H, NH), 6.63 (d, J¼7.6 Hz, 1H,
6-H), 7.30 (dd, J¼8.4 and 4.3 Hz, 1H, 3-H), 7.48e7.57 (m, 2H, 7-H and
8-H), 8.16 (d, J¼8.3 Hz, 1H, 4-H), 8.85 (dd, J¼4.3 and 1.4 Hz, 1H, 2-H);
4.2.10. Ethyl 4-amino-3-phenylisoxazole-5-carboxylate (24)40. The
reaction mixture obtained by heating compound 23 (0.132 g,
0.5 mmol) and alcohol 1 (0.324 g, 1.75 mmol) in toluene (1 mL) at
110 ꢀC for 64 h, without methyl acrylate, was resolved by FC (DCM/
EtOAc 120:1) to give amino ester 24 (Rf¼0.44, 0.056 g, 48%) as pale
yellow needles, mp 62e63 ꢀC (from n-hexane) (lit.40 61e62 ꢀC); 1H
13C NMR
d 33.1 (t), 39.5 (t), 51.8 (q),104.7 (d), 118.7 (s), 118.8 (d), 119.4
(d), 128.8 (d), 130.2 (d), 143.1 (s), 149.2 (s), 150.0 (d), 172.9 (s).
4.2.6. Methyl 3-(6-quinolylamino)propanoate (16). Operating as
above with compound 15 (0.087 g, 0.5 mmol) for 7 days, chro-
matographic resolution with DCM/EtOAc 4:1 as eluent gave
ketone 3 (Rf¼0.61, 0.230 g, 84% referred to reacted 1) while the use
of EtOAc/DCM 3:1 gave derivative 16 (Rf¼0.20, 0.063 g, 55%) as
a pale yellow oil; [found: C, 67.47; H, 6.35; N, 11.83. C13H14N2O2
requires: C, 67.81; H, 6.13; N, 12.17%]. IR (film) 3393, 3266, 3024,
NMR
d
1.42 (t, J¼7.0 Hz, 3H, OCH2CH3), 4.45 (q, J¼7.0 Hz, 2H,
OCH2CH3), 4.68 (br s, 2H, NH2), 7.48e7.61 (m, 3H, Ar-3H), 7.68e7.83
(m, 2H, Ar-2H).
The slowest moving bands gave ketone 3 (Rf¼0.20, 0.230 g, 85%
referred to reacted 1).
Acknowledgements
2950, 1734, 1624, 1174 cmꢁ1
;
1H NMR
d
2.70 (t, J¼6.3 Hz, 2H,
CH2CO2Me), 3.57 (q, J¼6.1 Hz, 2H, CH2NH), 3.72 (s, 3H, OCH3), 4.37
(br s, 1H, NH), 6.72 (d, J¼2.7 Hz, 1H, 5-H), 7.09 (dd, J¼9.2 and
2.5 Hz, 1H, 7-H), 7.26 (dd, J¼8.4 and 4.1 Hz, 1H, 3-H), 7.87 (d,
J¼9.3 Hz, 1H, 8-H), 7.10 (dd, J¼8.4 and 1.3 Hz, 1H, 4-H), 8.62 (dd,
Mrs. B. Innocenti and Mr. M. Passaponti are acknowledged for
technical support. Authors thank the Centro Interdipartimentale di
Spettrometria di Massa (CISM) of the University of Firenze for the
HRMS analyses and Ministry of University and Research (MIUR
Rome-Italy) for financial support (PRIN2008BRXNTY).
J¼4.1 and 1.5 Hz, 1H, 2-H); 13C NMR
d 33.3 (t), 39.3 (t), 51.8 (q),
103.1 (d), 121.3 (d), 121.4 (d), 130.0 (s), 130.3 (d), 133.7 (d), 143.3
(s), 145.5 (s), 146.3 (d), 172.6 (s).
Supplementary data
4.2.7. Methyl 3-anilinopropanoate (18)37. The reaction mixture
obtained by heating alcohol 1 (0.324 g, 1.75 mmol), nitrobenzene
(17) (0.062 g, 0.052 mL, 0.5 mmol), methyl acrylate (0.180 mL,
2 mmol) and glacial acetic acid (0.006 g, 0.006 mL, 0.1 mmol) in
acetonitrile (1 mL) at 110 ꢀC for 10 days was resolved with DCM/
EtOAc 100:1 as eluent to give compound 18 (Rf¼0.19, 0.056 g, 63%)
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.11.008.
References and notes
as a yellow sticky solid (lit.37 mp 37e38 ꢀC); 1H NMR
d 2.64 (t,
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