1-(2-Pyridyl)-2-propen-1-ol: a multipurpose reagent in organic synthesis

Article abstract of DOI:10.1016/j.tet.2009.06.044

A peculiar thermal behaviour of hydroxyallylpyridyl derivatives, likely associated to the weak acidity of the 'picoline-type' hydrogen atom and responsible for the formation of allyl inversion products, has been reported. The 'mobility' of the same hydrog

Full text of DOI:10.1016/j.tet.2009.06.044

Tetrahedron 65 (2009) 7048–7055
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1-(2-Pyridyl)-2-propen-1-ol: a multipurpose reagent in organic synthesis
*
*
Donatella Giomi , Michela Piacenti, Renzo Alfini, Alberto Brandi
`
Dipartimento di Chimica Organica ‘Ugo Schiff’, Laboratorio di Progettazione, Sintesi e Studio di Eterocicli Biologicamenti Attivi (HeteroBioLab), Universita di Firenze,
Polo Scientifico e Tecnologico, Via della Lastruccia 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 3 April 2009
Received in revised form 20 May 2009
Accepted 11 June 2009
Available online 18 June 2009
A peculiar thermal behaviour of hydroxyallylpyridyl derivatives, likely associated to the weak acidity of
the ‘picoline-type’ hydrogen atom and responsible for the formation of allyl inversion products, has been
reported. The ‘mobility’ of the same hydrogen atom allowed the unprotected title compound to behave
regioselectively as C-1, C-2 or C-3 carbon nucleophile depending on the thermal or base-promoted ex-
perimental conditions and on the kind of electrophile; moreover, the corresponding Hantzsch-type
pyridine tautomer displayed a biomimetic ability to transfer hydrogen to aromatic and heteroaromatic
nitro derivatives.
Keywords:
Allyl pyridyl alcohol derivatives
Nucleophilic substitutions
Ó 2009 Elsevier Ltd. All rights reserved.
Hantzsch ester 1,4-dihydropyridine mimics
Nitro derivatives metal-free reductions
1. Introduction
1a–c,5 likely ascribed to the weak acidity of the picoline-type hy-
drogen atom, we decided to gain better insight into the thermal
The wide range of synthetic applications of
and alkylpyridines mainly arise from the weak acidity of the alkyl
protons, easily removed in base-catalysed processes. The presence
a
- and
g
-picolines
isomerisation processes as well as the possibility to exploit the
above compounds as carbon nucleophiles in reactions with differ-
ent electrophilic counterparts. On the other hand, a new reactivity
of 1a as a hydrogen donor towards aromatic and heteroaromatic
nitro derivatives,6 again amenable to the ‘mobility’ of the picoline-
type hydrogen atom, has been investigated.
of the nitrogen atom makes the alkyl substitutents in the
positions more reactive with respect to the corresponding benzene
derivatives. As a consequence, treatment of - and -alkylpyridines
a- and g-
a
g
with strong bases, such as sodium amide in liquid ammonia or
organolithiums, results in an essentially quantitative deprotonation
affording stabilized carbanions, as a result of charge delocalisation
on the ring nitrogen. These intermediates are able to react with
a wide range of electrophiles, such as alkyl halides and tosylates,
acyl halides, carbon dioxide, aldehydes, ketones, etc., in a large
array of different reactions.1
2. Results and discussion
By heating a solution of allyl alcohol 1a7 in chloroform in
a sealed tube at 110 ꢀC for 48 h, we observed the complete disap-
pearance of the starting material with the resultant formation of
2-propionylpyridine (2)8 in 90% yield (Scheme 1).9
Moreover, the one-pot isomerization of allyl alcohols to the
corresponding saturated carbonyl compounds is a very attractive
synthetic approach, corresponding to an internal redox process
with total atom economy.2 Even though some thermal conversions
at high temperatures or in the presence of mineral acids or bases
are reported,3 the above rearrangement has been mainly and effi-
ciently performed under catalysis of transition-metal complexes.4
On this ground and in the light of preliminary data supporting
a peculiar thermal behaviour for allyl pyridyl alcohol derivatives
CHCl3
N
N
110 °C, 48h
O
OH
1a
2 90%
Scheme 1. Thermal isomerization of alcohol 1a.
In contrast, the acetyl derivative 1b,10 the tert-butyldimethylsilyl
ether 1c11 and the new acryloyl derivative 1d proved to be more
stable. While 1c was synthesized according to the Uenishi pro-
cedure, 1b and 1d were prepared in 85% and 94% yields by treat-
ment of the alcohol 1a with acetic anhydride and acryloyl chloride,
respectively, in the presence of triethylamine and a catalytic
amount of 4-dimethylaminopyridine at 0 ꢀC (Experimental
* 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/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.044

D. Giomi et al. / Tetrahedron 65 (2009) 7048–7055
7049
CHCl3, 110 °C
12-14d
xylene, 160 °C
7-14d
+
N
N
N
N
OR
OR
OR
OR
3b 62%
3c
1b R = Ac
3b 21%
3c 36%
3d 20%
4b 47%
4c 13%
4d 29%
1c R = TBDMS
3d 68%
1d R = COCH=CH2
Scheme 2. Thermal isomerization of compounds 1b–d.
section). When 1b was heated at 110 ꢀC in a sealed tube for 12 days,
the vinyl acetate 3b was obtained in 62% yield. On the other hand,
by heating 1b in xylene at 160 ꢀC for 14 days the diastereomeric
vinyl acetates 3b and 4b were isolated in 21% and 47% yields, re-
spectively (Scheme 2). When submitted to heating in xylene at
160 ꢀC, compound 3b was recovered completely unchanged, ruling
out the possibility of its thermal isomerization into 4b. The tert-
butyldimethylsilyl ether 1c appeared perfectly stable in chloroform
at 110 ꢀC for weeks and only after 10 days at 160 ꢀC in xylene was
partially converted (ca. 66%, 1H NMR) into 3c and 4c, isolated by
flash column chromatography in 36% and 13% yields, respectively
(Scheme 2).12 As observed for 1b, when the acryloyl derivative 1d
was heated at 110 ꢀC in chloroform in a sealed tube for 14 days only
compound 3d was recovered in 68% yield whereas, operating in
xylene at 160 ꢀC for 7 days, the two diastereomers 3d and 4d were
isolated respectively in 20% and 29% yields (Scheme 2). As com-
pound 3b, also the (Z) isomers 3c,d resulted completely stable in
xylene at 160 ꢀC.
intramolecular operating mechanism. In particular, the higher en-
ergy pathway associated with the intramolecular sigmatropic hy-
drogen shift leading to diastereomers 4b–d, could justify the
exclusive formation of 3b and 3d at lower temperature. The higher
reactivity of 1a with respect to 1b–d could be likely ascribed to the
contribution of an intramolecular hydrogen bond between the OH
group and the ring nitrogen, which could favour the initial proton
abstraction. Moreover, the poor reactivity of 1c with respect to 1b
and 1d could be justified by the presence of the strongly electron-
donating silyl ether group, unable to stabilize a vicinal negative
charge.
On the basis of this new reactivity of 1a–d, and their likely be-
haviour as enamines or, even vinilogous enamines, we investigated
their reactions towards different electrophiles.
The studies were rapidly focused on alcohol 1a, because,
working under neutral thermal conditions, the less reactive oxy-
gen-protected derivatives 1b–d required long reaction times and
drastic conditions leading to complex reaction mixtures.
Alcohol 1a was totally inert towards benzaldehyde and fur-
aldehyde at 110 ꢀC, in toluene or chloroform in a sealed tube, while
the reaction with an excess (3 equiv) of 2-pyridyl carbaldehyde (9)
in dry toluene at 70 ꢀC for 24 h gave an almost 1:1 mixture of the
diastereomeric diols 10a,b, isolated in 50% yield, along with a minor
amount of pyridyl ketone 2 (7%)13 (Scheme 4).
The structures of (Z) and (E) diastereomers were easily assigned
on the basis of NOESY-1D experiments; moreover the quartet of the
H-2 proton (J¼7.1 Hz and 7.4–7.5 Hz, respectively) appears at higher
frequencies in diastereomers 3b–d (d 5.98–6.63) with respect to
4b–d (d 5.29–5.80), likely due to the anisotropy of the pyridine ring.
A mechanistic rational of the above results could be proposed
taking into account the weak acidity of the ‘picoline-type’ hydrogen
atom on the C-1 carbon of the allyl residue of compounds 1a–d. A
1,3-proton shift can give rise to the fully conjugated diastereomeric
enamines (Z)-5a–d and (E)-6a–d. While 5a–d could evolve into the
(Z) enol derivatives 3b–d and ketone 2 (coming from the corre-
sponding enol form) by simple intermolecular proton transfer, 6a–
d could give rise to the (E) isomers 4b–d, as well as compound 2,
through a [1,5] sigmatropic hydrogen shift involving the higher
energy s-cis conformers (E)-7a–d. When R¼H also the tautomer 8a
can form (Scheme 3).
N
OH
1a
2 7%
+
toluene
N
CHO
70 °C, 24 h
N
OH
9
10a,b 50% syn/anti 1:1
Scheme 4. Reaction of 1a with 2-pyridyl carbaldehyde (9).
The vicinal diols 10a,b are the products of an aldol reaction
occurring through nucleophilic attack of the C-1 carbon atom of the
allyl residue of 1a (via enamines 5a and 6a) on the carbonyl group
of 9. The stability of diols, not undergoing H2O elimination, could be
likely due to intramolecular hydrogen bonds between the OH
groups and the pyridine rings nitrogen atoms.
1a-d
2
OR
3b-d
N
H
N
OR
H
(E )-6a-d
The enamine reactivity in aldol type reactions, therefore, seems
to be limited to activated aromatic aldehydes. Switching to study
the alkylation with halides, the thermal reaction of 1a with an
excess of allyl bromide 11 in dry toluene at 70 or 110 ꢀC for 24–48 h
led to the exclusive formation of ketone 2. Nevertheless, operating
in the presence of bases alkylation products were obtained. By
treatment with an equivalent amount of sodium hydride at room
temperature in THF, 1a reacted with allyl bromides 11, 13 and 15 in
24 h to give compounds 12,14 14 and 16, in 75%,12 71% and 81%
yields, respectively. The products 12, 14 and 16 result from the
nucleophilic substitution of bromides by the C-2 carbon of the allyl
moiety of 1a (Scheme 5). In such reaction conditions, operating at
room temperature, the formation of ketone 2 was almost com-
pletely avoided allowing the isolation of the substitution products
in satisfactory yields.
(Z )-5a-d
R=H
H
H
[1,5]
2
OR
N
H
4b-d
N
H
O
8a
(E)-7a-d
Scheme 3. Proposed mechanism for thermal isomerization of 1a–d.
This mechanistic assumption allowed us to explain the experi-
mental results. While the enol forms coming from the free alcohol
1a, immediately evolve into pyridyl ketone 2, the protected alcohols
1b–d afford different enol derivatives 3b–d or 4b–d, depending on
the reaction conditions and, consequently, on the inter- or
A reasonable mechanistic hypothesis could involve the forma-
tion of the enolate 19 as reactive species from the deprotonated
alcohol 17, via the mesomeric allyl anions 18 (Scheme 6).

7050
D. Giomi et al. / Tetrahedron 65 (2009) 7048–7055
Cl
1a
Cl
N
N
Br
Br
Br
1a
N
NaH, THF
rt, 24h
2 52%
2 <5%
2 55%
+
N
O
toluene
70 °C, 48h
N
N
11
13
15
12 75%
O
Cl
20
21 19%
1a
CN
N
NC
N
N
1a
N
NaH, THF
rt, 24h
+
+
N
toluene
70 °C, 48h
O
CN
N
N
14 71%
O
O
23 44%
22
1a
O2N
NO2
1a
N
NaH, THF
rt, 24h
O
NaH, toluene
70 °C, 6 d
N
N
Cl
16 81%
24
25 15%
Scheme 5. Reactions of 1a with allyl bromides.
Scheme 7. Reactions of 1a with heterocyclic electrophiles.
attack on ribopyranoside derivatives,17 a repulsive dipolar in-
teraction due to the proximity of the lone pair of an heteroatom
could hamper the approach of the incoming nucleophile. An anal-
ogous repulsive effect involving the nitrogen lone pair could be
invoked to explain the lower reactivity of 2-cyanopyridine with
respect to the 4-cyano derivative in nucleophilic aromatic sub-
stitutions with lithium amides,18 as well as the weaker acidity de-
termined in THF of 2-picoline compared with the 4-isomer.19
Unfortunately, alcohol 1a was absolutely inert towards mono-
and bis-halo substituted pyrazines, pyrimidines, and pyridines and
even rising the reaction temperature to 110 ꢀC the exclusive iso-
merisation into ketone 2 was observed.
The anomalous behaviour of 2-chloro-3-nitropyridine (24) in
the substitution reaction with 1a allowed, however, the discovery
of another reaction path for 1-(2-pyridyl)-2-propen-1-ol (1a). In
fact, when pure samples of 1a were allowed to react with an excess
(5 equiv) of 24 in toluene at 110 ꢀC for 18 h, the amino compound
26 was obtained as the only reaction product isolated in 31% yield
(Table 1, entry 1).6
The structure of compound 26, and the lack in the reaction
mixture of any rearrangement product of 1-(2-pyridyl)-2-propen-
1-ol (1a), together with the absence of side products,6 suggested
that 26 derived from a very straightforward redox process of 1a
able to reduce the nitro group of 2-chloro-3-nitropyridine to the
corresponding amino function which adds to the pyridyl vinyl ke-
tone 28, the product of oxidation of alcohol 1a. In the light of the
proposed mechanistic hypothesis (see below) 3 equiv of 1a are
necessary to reduce 2-chloro-3-nitropyridine to 2-chloro-3-ami-
nopyridine and then the yield of the reaction should be calculated
as 93% (Scheme 8). The excess of the unstable pyridyl vinyl ketone
likely undergoes polymerization under the reaction conditions.
The mechanistic rationale for this new behaviour of 1a as re-
ducing agent can be ascribed again to the weak acidity of the ‘pic-
oline-type’ hydrogen atom, likely involving the 1,4-dihydropyridine
tautomeric form 8a able to react as Hantzsch ester (HEH) mimic in
metal-free redox processes. Hydrogen transfer to 24 could produce
the vinyl ketone 28 and nitroso pyridine 29; the involvement of two
more molecules of 1a could then allow the formation of the amino
derivative 31 able to give aza-Michael addition to 28 affording 26
through a novel domino process (Scheme 8).6
Considering the easy isomerisation of allyl alcohols into the
corresponding ketones by treatment with bases,3b,c the above
alkyation derivatives might derive also from ketone 2, as the first
reaction product, via enolate formation and nucleophilic sub-
stitution. In fact, in the same reaction conditions, compound 2 gave
similar results under deprotonation with NaH. However, the re-
covery of unreacted alcohol 1a in the reaction with allyl bromide (11,
Scheme 5) after 24 h (Experimental section) seems to rule out the
conversion of alcohol into ketone 2 before nucleophilic substitution.
As previously observed with aldehydes, the non catalysed
thermal reactions of allyl pyridine 1a as carbon nucleophile seem to
require highly activated electrophiles. For this reason heterocyclic
electrophiles were investigated. When 1a was allowed to react in
a sealed tube with an excess (8 equiv) of 3,6-dichloropyridazine
(20) in anhydrous toluene at 70 ꢀC for 48 h the substitution product
21 was isolated by flash column chromatography in 19% yield, along
with a significant amount (ca. 52%) of the volatile pyridyl ketone 2
(Scheme 7). Analogously, treatment of 1a with 2 equiv of 4,5-
dicyanopyridazine (DCP)15 (22) gave, together with minor amount
of ketone 2 (<5%, 1H NMR), compound 23, coming from nucleo-
philic attack on DCP and HCN elimination, in 44% yield (Scheme 7).
Attempts to improve the formation of compounds 21 and 23 by
varying the experimental conditions (amounts of electrophile,
solvent, reaction temperature) were unsuccessful likely due to the
competitive isomerization affording compound 2.
A peculiar behaviour was observed with 2-chloro-3-nitro-
pyridine (24). Nucleophilic substitution product 25 was isolated in
poor 15% yield, together with ketone 2 as the major product (55%
yield), only after longer reaction times (six days) and addition of
1.3 equiv of NaH (Scheme 7).16
Compounds 21, 23 and 25 derive from nucleophilic attack of the
C-3 carbon atom of the allyl residue of alcohol 1a on the electro-
philic C-3, C-4, and C-2 carbons, respectively, of 20, 22 and 24 fol-
lowed by leaving group elimination. The products are the results of
a ‘vinylogous picolination’ that is unprecedented, to our knowledge,
in the literature. The sizeable enhancement of reactivity observed
for 4,5-dicyanopyridazine (22) could be tentatively associated to
the presence of the leaving group (the CN group, in this case) in
g-
position with respect to the nitrogen atom, rather than in -posi-
a
tion as in compounds 20 and 24. Likely, as reported for nucleophilic
R
Na+
RBr
Na+
Na+
OH
NaH
1a
N
N
N
N
N
Na+
O
OH
O
O
17
18
19
12,14,16
Scheme 6. Proposed mechanism accounting for the formation of 12, 14 and 16.

D. Giomi et al. / Tetrahedron 65 (2009) 7048–7055
7051
Table 1
A different behaviour was observed with nitro alkenes. In fact,
when alcohol 1a was reacted with trans- -nitrostyrene (38a) in
toluene at 110 ꢀC for 18 h, the reduction process did not occur either
for the NO2 group or for the C]C double bond, and only the con-
jugate addition product 39a was isolated in 30% yield along with
ketone 2 (Scheme 9).
Thermal reactions of 1a with nitro derivatives (RNO2)a
b
Entry
RNO2
O2N
Cl
T (ꢀC) Time
Products
Yieldb,c
31 (93)
%
H
N
1
110 18 h
N
N
p-Bromonitrostirene (38b)21 gave similar results leading to 39b
in 19% yield. Again, the formation of 39a,b could be ascribed to the
reactivity of 1a as vinylogous picoline C-3 carbon nucleophile, now
able to give conjugate addition to the electrophilic nitro alkenes
38a,b.
O
Cl
N
24
26
O2N
H
N
2
3
70 48 h
15 (45)
10 (30)
N
N
N
Cl
Cl
O
O
N
Cl
Cl
32
33
3. Conclusions
O2N
H
N
In summary, the reported results clearly show a peculiar ther-
mal behaviour of hydroxyallylpyridyl derivatives likely associated
to the weak acidity of the ‘picoline-type’ hydrogen atom and re-
sponsible for the formation of allyl inversion products. In fact, the
alcohol 1a and its oxygen protected derivatives 1b–d can be easily
isomerised to ketone 2 and vinyl derivatives 3b–d and 4b–d, re-
spectively, under thermal neutral conditions.
From a synthetic viewpoint, the allyl alcohol 1a can behave
regioselectively as C-1, C-2 or C-3 carbon nucleophile depending on
the experimental conditions and the electrophilic counterparts.
In particular, reactivity as C-1 carbon nucleophile was ob-
served in the thermal aldol reaction with pyridine carbaldehyde,
while allyl bromides, in the presence of NaH at room tempera-
ture, afforded in good yields the corresponding propionylpyr-
idines allyl substituted at position 2 of the lateral chain through
reaction of the C-2 carbon atom. On the other hand, treatment of
1a with activated heterocyclic electrophiles as well as nitro-
alkenes allowed a ‘vinylogous picolination’, via nucleophilic at-
tack of the C-3 carbon of the allyl moiety of 1a, leading to new
110 18 h
Cl
34
35
Cl
O2N
H
N
4
150d 4 h
11 (33)
N
O
36
37
a
Reactions performed in a sealed tube in toluene with an excess (5 equiv) of RNO2
to reduce the competitive thermal isomerisation of 1a to ethyl ketone 2.
b
Isolated yields.
c
Yields in brackets refer to a reaction stoichiometry 1a/RNO2 3:1, according to the
proposed mechanism.
d
Reaction performed in xylene with 9 equiv of nitrobenzene.
, H2O
N
28 O
N=O
Cl
polyfunctionalized nitrogen heterocycles and
b-substituted
1a
8a
24
+
N
29
nitroalkanes, respectively. Moreover, a new reactivity as 1,4-
dihydropyridine HEH mimic allowed the metal-free reduction of
the nitro group of aromatic and heteroaromatic nitro derivatives
leading to aminoalkyl pyridyl ketones through domino processes
involving direct trapping of the produced amino species. Mech-
anistic hypothesis have been proposed to rationalize the experi-
mental results.
These new complementary features of reactivity of alcohol 1a
appear quite intriguing from a synthetic viewpoint and encourage
further studies to find conditions which reduce the drawbacks of
the processes, mainly reaction yields, and to expand the synthetic
application of the new synthesized products.
1a
28
NH2
Cl
NHOH
28
1a
26
N
N
Cl
28, H2O
31
30
Scheme 8. Mechanistic hypothesis accounting for the formation of compound 26.
The synthetic potential of alcohol 1a as reducing agent was
tested with other nitro derivatives. Chloronitropyridine 32 was able
to react at lower temperature, likely due to reduced steric hin-
drance, leading to the amino ketone 33, albeit in lower yield (45%,
Table 1, entry 2).
4. Experimental section
4.1. General
Operating at higher temperatures, less activated nitroarenes
were also reduced to the corresponding amino derivatives. 3,5-
Dichloro-1-nitrobenzene (34) was allowed to react at 110 ꢀC for 18 h
with 1a to give amino compound 35 (Table 1, entry 3) while nitro-
benzene (36) was converted into 3720 only by heating in xylene at
150 ꢀC for 4 h (Table 1, entry 4).
Melting points were taken on a Bu¨chi 510 apparatus and are
uncorrected. Silica gel plates (Merck F254) and silica gel 60 (Merck,
230–400 mesh) were used for TLC and flash chromatographies (FC),
respectively; petroleum ether (PE) employed for chromatographic
workup refers to the fractions of bp 40–70 ꢀC. IR spectra were
recorded with a Perkin–Elmer Spectrum BX FT-IR System spectro-
photometer. 1H and 13C NMR spectra were recorded in CDCl3 so-
lutions with Varian-Gemini and Varian Mercuryplus 400
instruments, operating at 200 and 50 MHz and 400 and 100 MHz,
respectively. Elemental analyses were performed in our De-
partment with a Perkin–Elmer 2400 analyzer.
Ar
NO2
toluene
Ar
38a,b
1a
N
110 °C, 18h
NO2
39a 30%
Ar = 4-Br-C6H4 39b 19%
O
Unless otherwise stated, the thermal reactions were performed
in a sealed tube (Pyrex N. 13). In the following reactions, the re-
agents used in large excess to reduce the competitive thermal
isomerisation of alcohol 1a to ethyl ketone 2 were recovered via FC.
Ar = Ph
Scheme 9. Reactions of 1a with nitroalkenes.

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D. Giomi et al. / Tetrahedron 65 (2009) 7048–7055
4.2. Preparation of derivatives 1b and 1d. General procedure
136.1 (d),145.4 (s),149.2 (d),152.8 (s), 169.9 (s); m/z (EI) 177 (4, Mþ),
135 (78), 106 (31), 79 (100%).
Acetic anhydride (0.613 g, 0.566 mL, 6.0 mmol) or acryloyl
chloride (0.543 g, 0.487 mL, 6.0 mmol), triethylamine (0.911 g,
1.25 mL, 9.0 mmol) and DMAP (0.073 g, 0.6 mmol) were added at
0 ꢀC to a solution of alcohol 1a (0.405 g, 3 mmol) in dry dichloro-
methane (17 mL). After 5 h at room temperature, the reaction
mixture was quenched with a saturated aqueous solution of
NaHCO3 (17 mL) and extracted with dichloromethane (3ꢁ30 mL).
The extract was washed with water (30 mL) and brine (30 mL),
dried over Na2SO4 and evaporated to dryness under reduced
pressure giving a reaction crude which was resolved by FC.
4.3.4. tert-Butyl(dimethyl)silyl (1Z)-1-(2-pyridyl)-1-propenyl ether
(3c) and tert-butyl(dimethyl)silyl (1E)-1-(2-pyridyl)-1-propenyl
ether (4c)
The reaction crude coming from heating 1c at 160 ꢀC for 10 days
was resolved by FC (PE/EtOAc 50:1). The first band gave compound
4c (0.023 g, 9% absolute yield) as colourless oil; [Found: C, 67.04; H,
8.90; N, 5.98. C14H23NSiO requires: C, 67.42; H, 9.29; N, 5.62%.] Rf
(PE/EtOAc 50:1) 0.22; nmax (film) 3043, 2966, 2941, 2864,1647,1581,
1331 cmꢂ1
; dH (200 MHz) 0.08 [s, 6H, Si(CH3)2], 0.94 [s, 9H, C(CH3)3],
1.93 (d, J¼7.3 Hz, 3H, CH3), 5.29 (q, J¼7.4 Hz, 1H, ]CHCH3), 7.15 (dd,
J¼7.6 and 5.1 Hz, 1H, 5-H), 7.49 (d, J¼8.0 Hz, 1H, 3-H), 7.68 (ddd,
J¼7.8, 7.8, and 1.8 Hz, 1H, 4-H), 8.59 (d, J¼5.0 Hz, 1H, 6-H); dC
(50 MHz) ꢂ4.6 (q), 12.7 (q), 18.1 (s), 25.8 (q), 109.0 (d), 121.9 (d),
122.5 (d), 135.9 (d), 147.9 (s), 148.2 (d), 156.7 (s).
4.2.1. 1-(2-Pyridyl)-2-propenyl acetate (1b)7
Colourless oil (0.505 g, 95%); Rf (PE/EtOAc 3:1) 0.33.
4.2.2. 1-(2-Pyridyl)-2-propenyl acrylate (1d)
Colourless oil (0.539 g, 94%); [Found: C, 69.91; H, 5.83; N, 7.34.
C11H11NO2 requires: C, 69.83; H, 5.86; N, 7.40%.] Rf (PE/EtOAc 7:1)
The second band afforded derivative 3c (0.064 g, 26% absolute
yield) as colourless oil; [Found: C, 67.02; H, 9.61; N, 6.00. C14H23NSiO
requires: C, 67.42; H, 9.29; N, 5.62%.] Rf (PE/EtOAc 50:1) 0.18; nmax
0.39; nmax (film) 3087, 3014, 2990, 1728, 1590, 1405, 1186 cmꢂ1
; dH
(200 MHz) 5.32 (br d, J¼10.3 Hz, 1H, CHCH]CH2), 5.41 (br d,
J¼17.2 Hz, 1H, CHCH]CH2), 5.89 (dd, J¼10.3 and 1.5 Hz, 1H,
COCH]CH2), 6.06–6.31 (m, 2H, 2ꢁCH]CH2), 6.38 (d, J¼6.2 Hz, 1H,
CHCH]CH2), 6.50 (dd, J¼17.4 and 1.6 Hz, 1H, COCH]CH2), 7.22 (dd,
J¼7.0 and 5.5 Hz,1H, 5-H), 7.38 (d, J¼7.7 Hz,1H, 3-H), 7.70 (ddd, J¼7.7,
7.7 and 1.8 Hz,1H, 4-H), 8.61 (d, J¼4.4 Hz, 1H, 6-H); dC (50 MHz) 76.9
(d),117.7 (t),121.0 (d),122.7 (d),128.0 (d),131.3 (t),134.8 (d),136.7 (d),
149.3 (d), 157.9 (s), 164.8 (s); m/z (EI) 189 (4, Mþ), 118 (100%).
(film) 3054, 2956, 2929, 2858, 1653, 1584, 1472, 1326 cmꢂ1
; dH
(200 MHz) 0.04 [s, 6H, Si(CH3)2], 1.02 [s, 9H, C(CH3)3], 1.79 (d,
J¼7.3 Hz, 3H, CH3), 5.98 (q, J¼7.1 Hz, 1H, ]CHCH3), 7.12 (dd, J¼7.6
and 5.0 Hz,1H, 5-H), 7.45 (d, J¼8.0 Hz,1H, 3-H), 7.63 (ddd, J¼7.8, 7.8,
and 1.7 Hz, 1H, 4-H), 8.50 (d, J¼4.9 Hz, 1H, 6-H); dC (50 MHz) ꢂ3.9
(q),11.8 (q),18.35 (s), 25.9 (q),108.8 (d),119.4 (d),121.9 (d),136.1 (d),
148.7 (d), 148.75 (s), 156.2 (s).
The slowest moving band gave unreacted 1c (Rf¼0.13, 0.072 g,
29%).
4.3. Thermal isomerizations of compounds 1a–d. General
procedure
4.3.5. (1Z)-1-(2-Pyridyl)-1-propenyl acrylate (3d)
Chromatographic resolution (PE/EtOAc 8:1) of the reaction
crude obtained by heating 1d at 110 ꢀC for 14 days led to compound
3d (0.128 g, 68%) as a colourless oil; [Found: C, 69.46; H, 5.70; N,
7.37. C11H11NO2 requires: C, 69.83; H, 5.86; N, 7.40%.] Rf (PE/EtOAc
8:1) 0.29; nmax (film) 3055, 3008, 2983, 2918, 1741, 1584, 1470, 1404,
A solution of the allyl pyridyl derivative (1.0 mmol) in chloro-
form or xylene (2 mL) was heated in a sealed tube at 110 ꢀC or
160 ꢀC, respectively, for the reported time. After evaporation to
dryness, the reaction crude was subjected to FC.
1238, 1160 cmꢂ1
;
dH (200 MHz) 1.78 (d, J¼7.0 Hz, 3H, CH3), 6.04 (dd,
4.3.1. 2-Propionylpyridine (2)8
FC (PE/EtOAc 6:1) of the reaction crude obtained by heating 1a
at 110 ꢀC for 2 days gave compound 2 (Rf¼0.51, 0.122 g, 90%).
J¼10.3 and 1.4 Hz, 1H, COCH]CH2), 6.38 (dd, J¼17.2 and 10.2 Hz,
1H, COCH]CH2), 6.63 (q, J¼7.1 Hz, 1H, ]CHCH3), 6.65 (dd, J¼17.3
and 1.2 Hz, 1H, COCH]CH2), 7.16 (dd, J¼7.5 and 4.8 Hz, 1H, 5-H),
7.27 (d, J¼7.7 Hz, 1H, 3-H), 7.64 (ddd, J¼7.7, 7.7, and 1.5 Hz, 1H, 4-H),
8.55 (d, J¼4.6 Hz, 1H, 6-H); dC (50 MHz) 11.4 (q), 116.6 (d), 118.2 (d),
122.4 (d), 127.3 (d), 132.7 (t), 136.7 (d), 145.8 (s), 149.1 (d), 151.8 (s),
163.7 (s); m/z (CI) 190 (48, MHþ), 189 (2, Mþ), 136 (100%).
4.3.2. (1Z)-1-(2-Pyridyl)-1-propenyl acetate (3b)
Purification by FC (PE/EtOAc 6:1) of the residue coming from
heating 1b at 110 ꢀC for 12 days led to compound 3b (0.110 g, 62%)
as a colourless oil; [Found: C, 68.02; H, 6.13; N, 8.09. C10H11NO2
requires: C, 67.78; H, 6.26; N, 7.90%.] Rf (PE/EtOAc 6:1) 0.33; nmax
4.3.6. (1E)-1-(2-Pyridyl)-1-propenyl acrylate (4d)
(film) 3055, 3008, 2919, 1759, 1585, 1470, 1432, 1370, 1205 cmꢂ1
;
Operating as above, chromatographic resolution of the reaction
crude obtained by heating 1d at 160 ꢀC for 7 days allowed the
isolation of, along with compound 3d (Rf¼0.29, 0.038 g, 20%), the
diastereomer 4d (0.055 g, 29%) as colourless oil; [Found: C, 69.57;
H, 5.58; N, 7.19. C11H11NO2 requires: C, 69.83; H, 5.86; N, 7.40%.] Rf
(PE/EtOAc 8:1) 0.23; nmax (film) 3048, 3011, 2976, 1735, 1578, 1468,
dH (400 MHz) 1.76 (d, J¼7.2 Hz, 3H, CH3), 2.34 (s, 3H, OCOCH3), 6.56
(q, J¼7.1 Hz, 1H, ]CHCH3), 7.17 (dd, J¼7.5 and 4.9 Hz, 1H, 5-H), 7.30
(d, J¼8.0 Hz, 1H, 3-H), 7.66 (ddd, J¼7.8, 7.8, and 1.5 Hz, 1H, 4-H),
8.54 (d, J¼4.9 Hz, 1H, 6-H); dC (100 MHz) 11.5 (q), 20.5 (q), 117.1 (d),
118.5 (d), 122.6 (d), 137.1 (d), 145.7 (s), 148.7 (d), 151.7 (s), 168.7 (s);
m/z (EI) 177 (3, Mþ), 135 (82), 106 (29), 79 (100%).
1411, 1231, 1172 cmꢂ1
;
dH (200 MHz) 2.04 (d, J¼7.3 Hz, 3H, CH3),
5.80 (q, J¼7.4 Hz, 1H, ]CHCH3), 5.94 (dd, J¼10.3 and 1.2 Hz, 1H,
COCH]CH2), 6.27 (dd, J¼17.2 and 10.3 Hz, 1H, COCH]CH2), 6.54
(dd, J¼17.2 and 1.3 Hz, 1H, COCH]CH2), 7.19 (dd, J¼7.6 and 4.7 Hz,
1H, 5-H), 7.38 (d, J¼8.0 Hz,1H, 3-H), 7.70 (ddd, J¼7.8, 7.8, and 1.5 Hz,
1H, 4-H), 8.63 (d, J¼4.5 Hz, 1H, 6-H); dC (50 MHz) 12.7 (q), 118.4 (d),
122.5 (d), 122.6 (d), 127.8 (d), 132.2 (t), 136.1 (d), 145.0 (s), 149.1 (d),
152.7 (s), 164.9 (s); m/z (CI) 190 (39, MHþ), 189 (3, Mþ), 136 (100%).
4.3.3. (1E)-1-(2-Pyridyl)-1-propenyl acetate (4b)
Operating as above, chromatographic resolution of the reaction
crude obtained by heating 1b at 160 ꢀC for 14 days allowed the
isolation of, along with compound 3b (Rf¼0.33, 0.038 g, 21%), the
diastereomer 4b (0.084 g, 47%) as colourless oil; [Found: C, 68.15; H,
6.01; N, 8.22. C10H11NO2 requires: C, 67.78; H, 6.26; N, 7.90%.] Rf (PE/
EtOAc 6:1) 0.24; nmax (film) 3048, 3012, 2911, 1741, 1580, 1451,
1210 cmꢂ1
;
dH (400 MHz) 2.00 (d, J¼7.6 Hz, 3H, CH3), 2.21 (s, 3H,
4.4. 1,2-Di(2-pyridyl)-3-butene-1,2-diol (10a,b)
OCOCH3), 5.75 (q, J¼7.5 Hz, 1H, ]CHCH3), 7.18 (ddd, J¼7.6, 4.8, and
1.0 Hz,1H, 5-H), 7.37 (ddd, J¼8.0,1.0, and 1.0 Hz,1H, 3-H), 7.69 (ddd,
J¼7.8, 7.8, and 1.9 Hz, 1H, 4-H), 8.63 (ddd, J¼4.9, 1.8, and 1.0 Hz, 1H,
6-H); dC (100 MHz) 12.7 (q), 20.8 (q), 118.2 (d), 122.5 (d), 122.7 (d),
A mixture of alcohol 1a (0.068 g, 0.5 mmol) and 2-pyridyl carb-
aldehyde (9) (0.161 g, 0.14 mL, 1.5 mmol) in anhydrous toluene
(1 mL) was heated at 70 ꢀC for 24 h. Chromatographic resolution (PE/

D. Giomi et al. / Tetrahedron 65 (2009) 7048–7055
7053
EtOAc 6:1) of the residue left by evaporation to dryness gave, after
the isolation of ketone 2 (Rf ¼ 0.36, 0.005 g, 7%), a 1:1 mixture of
compounds 10a,b (0.061 g, 50%) as pale yellow solid; [Found: C,
69.27; H, 6.08; N, 11.51. C14H14N2O2 requires: C, 69.41; H, 5.82; N,
11.56%.] Rf (PE/EtOAc 6:1) 0.14; nmax (KBr) 3158, 2890, 1597, 1571,
3H, CH3), 2.30 (m, 2H, 3-CH2), 4.09 (sextet, J¼6.9 Hz,1H, 2-H), 5.12 (t,
J¼7.1 Hz,1H, 4-H), 7.46 (m,1H, 50-H), 7.85 (ddd, J¼7.8, 7.8, and 1.5 Hz,
1H, 40-H), 8.04 (d, J¼8.0 Hz,1H, 30-H), 8.69 (d, J¼4.8 Hz,1H, 60-H); dC
(50 MHz) 16.1 (q), 17.7 (q), 25.7 (q), 31.6 (t), 39.8 (d), 121.7 (d), 122.3
(d), 126.8 (d), 133.2 (s), 136.8 (d), 148.8 (d), 153.1 (s), 205.3 (s); m/z
(EI) 203 (1, Mþ), 188 (2), 175 (11), 160 (9), 106 (11), 79 (100%).
1468,1061 cmꢂ1
;
dH (400 MHz) 4.98 (s,1H,1-H), 5.00 (dd, J¼10.7 and
1.8 Hz,1H, 4-H), 5.10 (s,1H,1-H), 5.21 (dd, J¼10.6 and 1.7 Hz,1H, 4-H),
5.26 (dd, J¼17.2 and 1.8 Hz,1H, 4-H), 5.36 (v br s, 2H, 2ꢁOH), 5.41 (dd,
J¼17.2 and 1.6 Hz, 1H, 4-H), 5.80 (v br s, 2H, 2ꢁOH), 6.32 (dd, J¼17.1
and 10.6 Hz, 1H, 3-H), 6.55 (dd, J¼17.1 and 10.6 Hz, 1H, 3-H), 7.04–
7.09 (m, 2H, Ar-2H), 7.18–7.23 (m, 2H, Ar-2H), 7.57–7.64 (m, 4H, Ar-
4H), 7.62–7.76 (m, 4H, Ar-4H), 8.30–8.32 (m, 2H, Ar-2H), 8.45–8.49
(m, 2H, Ar-2H); dC (100 MHz) 76.4 (d), 78.0 (d), 78.1 (s), 78.5 (s),
114.65 (t),114.75 (t),121.3 (d),121.4 (d),122.0 (d),122.15 (d),122.2 (d),
122.25 (d), 122.3 (d), 122.4 (d), 136.8 (d), 136.95 (d), 137.1 (d), 137.5
(d),139.2 (d),141.2 (d),146.7 (d),146.8 (d),146.9 (d),146.95 (d),160.3
(s), 161.4 (s), 163.3 (s), 164.0 (s).
4.6. 3-(6-Chloropyridazin-3-yl)-1-(2-pyridyl)-1-
propanone (21)
5'
4''
6'
Cl
4'
3''
5''
6''
2
1
3
N
1'
2''
N
N
2'
3'
1''
O
The reaction mixture obtained by heating 3,6-dichloropyr-
idazine (20) (1.192 g, 8 mmol) and alcohol 1a (0.135 g, 1 mmol) in
anhydrous toluene (2 mL) at 70 ꢀC for 48 h was resolved by FC (PE/
EtOAc 1:1) to afford, after the isolation of ketone 2 (Rf¼0.82,
0.070 g, 52%), compound 21 (0.048 g, 19%) as a white solid, mp 92–
93 ꢀC (from pentane); [Found: C, 57.81; H, 3.98; N, 16.71.
C12H10ClN3O requires: C, 58.19; H, 4.07; N,16.97%.] Rf (PE/EtOAc 1:1)
4.5. Reactions of 1a with allyl bromides 11, 13, and 15. General
procedure
A solution of alcohol 1a (0.068 g, 0.5 mmol) in anhydrous THF
(1 mL) was added dropwise, under nitrogen, at room temperature
to a solution of NaH (0.012 g, 0.5 mmol) in the same solvent
(0.25 mL). The reaction mixture was stirred at room temperature
for 2 h and then the suitable allyl bromide (1 mmol) was added. The
resulting mixture (which turned red during the addition) was
stirred at room temperature overnight and then decomposed with
aqueous hydrochloride (10%, 0.5 mL) and water (1 mL). Extraction
with diethyl ether (3ꢁ3 mL), evaporation to dryness, and prolonged
evacuation gave pure alkylation products.
0.28; nmax (KBr) 3087, 3049, 2921, 1701, 1676, 1581, 1437 cmꢂ1
; dH
(400 MHz) 3.74 (t, J¼7.2 Hz, 2H, 2-CH2), 4.56 (t, J¼7.2 Hz, 2H, 3-
CH2), 6.90 (d, J¼9.7 Hz, 1H, 40-H), 7.15 (d, J¼9.7 Hz, 1H, 50-H), 7.45
(ddd, J¼7.6, 4.8, and 1.3 Hz, 1H, 500-H), 7.85 (ddd, J¼7.7, 7.7, and
1.6 Hz, 1H, 400-H), 8.04 (dd, J¼7.8 and 1.2 Hz, 1H, 300-H), 8.65 (ddd,
J¼4.8, 1.5, and 0.9 Hz, 1H, 600-H); dC (100 MHz) 36.2 (t), 47.65 (t),
121.8 (d), 127.35 (d), 131.8 (d), 133.5 (d), 137.0 (d), 137.3 (s), 149.0 (d),
152.9 (s), 158.9 (s), 199.0 (s).
4.7. 5-[3-Oxo-3-(2-pyridyl)propyl]-4-pyridazinecarbo-
nitrile (23)
4.5.1. 2-Methyl-1-(2-pyridyl)-4-penten-1-one (12)14
Compound 12 (0.050 g, 57%) was obtained as a pale yellow oil;
[Found: C, 75.08; H, 7.74; N, 7.68. C11H13NO requires: C, 75.40; H,
7.48; N, 7.99%.] nmax (film) 3076, 3055, 2975, 2932, 1699, 1641,
3
4''
N
4
NC
2
1
3''
3'
N
N
5''
6''
5
1583 cmꢂ1
;
dH (200 MHz) 1.20 (d, J¼7.0 Hz, 3H, CHCH3), 2.40 (m,
2''
2'
1''
1'
6
O
2H, 3-CH2), 4.18 (sextet, J¼7.0 Hz, 1H, 2-H), 5.00 (m, 2H, 5-CH2),
5.80 (m, 1H, 4-H), 7.47 (m, 1H, 50-H), 7.85 (ddd, J¼7.7, 7.7, and 1.5 Hz,
1H, 40-H), 8.05 (d, J¼7.9 Hz, 1H, 30-H), 8.70 (d, J¼4.4 Hz, 1H, 60-H); dC
(50 MHz) 16.3 (q), 37.1 (t), 38.8 (d), 116.4 (t), 122.3 (d), 126.9 (d),
136.0 (d), 136.8 (d), 148.8 (d), 152.9 (s), 204.7 (s); m/z (EI) 175 (2,
Mþ), 160 (16), 147 (17), 106 (19), 79 (100%).
4,5-Dicyanopyridazine (22) (0.130 g, 1 mmol) was added to a so-
lution of alcohol 1a (0.068 g, 0.5 mmol) in anhydrous toluene (1 mL)
and. the resulting mixture was heated at 70 ꢀC for 48 h. The crude
product left by evaporation to dryness was subject to FC (PE/EtOAc
1:1) to afford compound 23 (0.053 g, 44%) as a pale orange solid, mp
89–90 ꢀC (from diethyl ether/dichloromethane); [Found: C, 65.44; H,
4.22; N, 23.21. C13H10N4O requires: C, 65.54; H, 4.23; N, 23.52%.] Rf
(PE/EtOAc 1:1) 0.28; nmax (KBr) 3071, 3051, 2930, 2236, 1698, 1583,
Neutralization of the aqueous phase with a saturated solution of
NaHCO3, and extraction with diethyl ether (3ꢁ3 mL) allowed the
recovery of unreacted 1a (0.016 g, 24%).
1567, 1362 cmꢂ1
;
dH (400 MHz) 3.31 (t, J¼7.1 Hz, 2H, 10-CH2), 3.76 (t,
4.5.2. 2-Methyl-1-(2-pyridyl)-4-hexen-1-one (14)
J¼7.1 Hz, 2H, 20-CH2), 7.50 (ddd, J¼7.6, 4.8, and 1.3 Hz,1H, 500-H), 7.85
(ddd, J¼7.7, 7.7, and 1.7 Hz, 1H, 400-H), 8.02 (dd, J¼7.8 and 1.2 Hz, 1H,
300-H), 8.65 (ddd, J¼4.8, 1.6, and 0.9 Hz, 1H, 600-H), 9.23 (d, J¼1.0 Hz,
1H, 3-H), 9.42 (d, J¼1.0 Hz, 1H, 6-H); dC (100 MHz) 25.8 (t), 36.8 (t),
113.35 (s), 113.6 (s), 121.9 (d), 127.7 (d), 137.1 (d), 143.5 (s), 149.1 (d),
150.2 (d),152.3 (s),152.65 (d),198.5 (s); m/z (EI) 238 (11, Mþ), 222 (5),
210 (13), 209 (26), 132 (31), 106 (24), 79 (100), 78 (92), 51 (95%).
Compound 14 was obtained (0.067 g, 71%) as pale orange oil;
[Found: C, 75.81; H, 8.25; N, 7.15. C12H15NO requires: C, 76.16; H,
7.99; N, 7.40%.] nmax (film) 3054, 3018, 2969, 2934, 1697, 1583,
1456 cmꢂ1
;
dH (200 MHz) 1.17 (d, J¼7.0 Hz, 3H, CHCH3), 1.59 (m, 3H,
6-CH3), 2.09–2.53 (m, 2H, 3-CH2), 4.11 (sextet, J¼6.9 Hz, 1H, 2-H),
5.42 (m, 2H, 4-H and 5-H), 7.46 (m, 1H, 50-H), 7.84 (ddd, J¼7.8, 7.8,
and 1.4 Hz, 1H, 40-H), 8.04 (d, J¼8.0 Hz, 1H, 30-H), 8.69 (d, J¼4.0 Hz,
1H, 60-H); dC (50 MHz) (the values in square brackets refer to some
resonances of the minor diastereomer) [12.9 (q)], 16.3 (q), 17.9 (q),
[30.4 (t)], 36.1 (t), 39.4 (d), 122.2 (d), [125.5 (d)], 126.6 (d), 126.8 (d),
[127.4 (d)], 128.2 (d), 136.6 (d), 148.6 (d), 152.8 (s), 204.7 (s); m/z (EI)
189 (5, Mþ), 161 (18), 146 (14), 106 (30), 91 (80), 79 (100%).
4.8. 3-(3-Nitro-2-pyridyl)-1-(2-pyridyl)-1-propanone (25)
4'
4''
3'
2'
O2N
3''
5'
6'
5''
6''
2
1
3
2''
N
N
1''
1'
4.5.3. 2,5-Dimethyl-1-(2-pyridyl)-4-hexen-1-one (16)
O
Compound 16 was obtained (0.082 g, 81%) as pale orange oil;
[Found: C, 76.49; H, 8.64; N, 6.54. C13H17NO requires: C, 76.81; H,
2-Chloro-3-nitropyridine (24) (0.396 g, 2.5 mmol) was added to
a solution of alcohol 1a (0.068 g, 0.5 mmol) and NaH (0.016 g,
0.67 mmol) in anhydrous toluene (1 mL), previously stirred at room
8.43; N, 6.89%.] nmax (film) 3054, 2970, 2930, 1697, 1583, 1456 cmꢂ1
;
dH (200 MHz) 1.18 (d, J¼7.0 Hz, 3H, CHCH3), 1.58 (s, 3H, CH3), 1.64 (s,

7054
D. Giomi et al. / Tetrahedron 65 (2009) 7048–7055
temperature for three hours. The reaction mixture was then heated
at 70 ꢀC for six days. The resulting crude was treated with aqueous
hydrochloride (10%, 0.5 mL) and water (1 mL) and extracted with
dichloromethane (3ꢁ5 mL). The crude product left by evaporation
to dryness was subjected to FC with PE/EtOAc 2:1 as eluent leading
to ketone 2 (Rf¼0.70, 0.027 g, 40%) and with PE/EtOAc 1:2 to isolate
the nitro derivative 25 (0.020 g, 15%) as a pale orange solid, mp
144–145 ꢀC (from ethyl acetate); [Found: C, 60.37; H, 4.24; N, 16.10.
C13H11N3O3 requires: C, 60.70; H, 4.31; N, 16.33%.] Rf (PE/EtOAc 1:2)
0.24; nmax (KBr) 3120, 3052, 2923, 1694, 1679, 1598, 1523,
110 ꢀC for 18 h afforded ketone 2 (Rf¼0.49, 0.009 g, 13%) and com-
pound 35 (0.015 g, 10%) as pale yellow oil; Rf (PE/EtOAc 4:1) 0.21;
nmax (film) 3395, 3057, 2916, 1694, 1590, 1569 cmꢂ1
; dH (400 MHz)
3.49 (m, 2H, 2-CH2), 3.55 (m, 2H, 3-CH2), 4.41 (br s, 1H, NH), 6.49 (d,
J¼1.6 Hz, 2H, 20-H and 60-H), 6.63 (t, J¼1.7 Hz, 1H, 40-H), 7.49 (ddd,
J¼7.7, 4.7, and 1.2 Hz, 1H, 500-H), 7.84 (ddd, J¼7.8, 7.8, and 1.6 Hz, 1H,
400-H), 8.04 (dd, J¼7.8 and 1.0 Hz, 1H, 300-H), 8.69 (ddd, J¼4.8, 1.8.
and 1.0 Hz, 1H, 600-H); dC (100 MHz) 37.0 (t), 38.8 (t), 111.0 (d), 117.0
(d), 121.9 (d), 127.5 (d), 135.5 (s), 137.1 (d), 149.0 (d), 149.5 (s), 152.9
(s), 200.6 (s); HRMS (ESI): MNaþ, found 317.0222. C14H12Cl2N2NaO
requires 317.0219.
1355 cmꢂ1
;
dH (400 MHz) 3.86 (t, J¼6.0 Hz, 2H, 2-CH2), 4.49 (t,
J¼6.0 Hz, 2H, 3-CH2), 6.28 (dd, J¼7.7 and 6.6 Hz, 1H, 50-H), 7.48
(ddd, J¼7.7, 4.7, and 1.4 Hz, 1H, 500-H), 7.83 (ddd, J¼7.7, 7.7, and
1.6 Hz,1H, 400-H), 7.98 (ddd, J¼7.7,1.1, and 1.1 Hz,1H, 300-H), 8.07 (dd,
J¼6.6 and 2.1 Hz, 1H, 60-H), 8.30 (dd, J¼7.7 and 2.0 Hz, 1H, 40-H),
8.65 (ddd, J¼4.7, 1.6, and 1.0 Hz, 1H, 600-H); dC (100 MHz) 36.35 (t),
47.0 (t), 102.9 (d), 121.6 (d), 127.7 (d), 136.9 (d), 138.6 (s), 138.8 (d),
146.1 (d),149.2 (d),152.4 (s), 154.4 (s),199.6 (s); m/z (EI) 257 (1, Mþ),
212 (13), 133 (62), 132 (42), 105 (88), 80 (49), 78 (100%).
4.9.4. 3-Anilino-1-(2-pyridyl)-1-propanone (37)20
Chromatographic resolution (PE/EtOAc 3:1) of the crude
obtained by heating 1a and 36 (0.554 g, 0.46 mL, 4.5 mmol) in xy-
lene at 150 ꢀC for 4 h afforded ketone 2 (Rf¼0.59, 0.010 g, 15%) and
amino ketone 37 (0.013 g, 11%) as a pale solid, mp 78–79 ꢀC (from
methanol–ether); Rf (PE/EtOAc 3:1) 0.28; dH (400 MHz) 3.62 (m, 4H,
2-CH2 and 3-CH2), 5.45 (br s, 1H, NH), 6.81–6.85 (m, 3H, Ar-3H),
7.19–7.23 (m, 2H, Ar-2H), 7.47 (ddd, J¼7.6, 4.9, and 1.2 Hz, 1H, 50-H),
7.83 (ddd, J¼7.7, 7.7, and 1.8 Hz, 1H, 40-H), 8.03 (dd, J¼7.8 and 1.2 Hz,
1H, 30-H), 8.65 (ddd, J¼4.8, 2.0. and 0.8 Hz, 1H, 60-H); dC (100 MHz)
36.8 (t), 40.7 (t), 114.8 (d), 119.5 (d), 121.8 (d), 127.4 (d), 129.4 (d),
136.95 (d), 149.0 (d), 149.05 (s), 152.95 (s), 200.6 (s).
4.9. Reactions of 1a with nitro derivatives 24, 32, 34, 36, and
38a,b. General procedure
Alcohol 1a (0.068 g, 0.5 mmol) was heated at 70 or 110 ꢀC in
toluene or xylene (1 mL) with the suitable nitro compound until its
complete disappearance. Removal of the solvent in vacuo and pu-
rification by FC allowed, after the recovery of unreacted nitro
compound, to isolate the reaction products along with different
amounts of ketone 2.
4.9.5. 5-Nitro-4-phenyl-1-(2-pyridyl)-1-pentanone (39a)
The reaction mixture obtained by heating 1a and 38a (0.373 g,
2.5 mmol) in toluene at 110 ꢀC for 18 h was resolved with PE/EtOAc
4:1, leading to ketone 2 (Rf¼0.49, 0.021 g, 30%) and compound 39a
(0.043 g, 30%) as a pale oil; Rf (PE/EtOAc 4:1) 0.16; nmax (film) 3053,
2922,1695, 1541, 1379 cmꢂ1
; dH (400 MHz) 2.16 (m, 2H, 3-CH2), 3.14
4.9.1. 3-[(2-Chloro-3-pyridyl)amino]-1-(2-pyridyl)-1-
(m, 2H, 2-CH2), 3.60 (m, 1H, 4-H), 4.63 (AB part of an ABX system,
J¼12.2 and 7.7 Hz, 2H, 5-CH2), 7.22–7.36 (m, 5H, Ph), 7.43 (ddd,
J¼7.6, 4.8, and 1.0 Hz, 1H, 50-H), 7.80 (ddd, J¼7.7, 7.7, and 1.7 Hz, 1H,
40-H), 7.98 (ddd, J¼7.8, 1.2 and 1.2 Hz, 1H, 30-H), 8.60 (ddd, J¼4.6, 1.7,
and 0.9 Hz, 1H, 60-H); dC (100 MHz) 27.1 (t), 35.0 (t), 43.75 (d), 80.8
(t), 121.7 (d), 127.2 (d), 127.6 (d), 127.8 (d), 128.9 (s), 129.0 (d), 136.9
(d), 148.9 (d), 153.0 (s), 200.7 (s); HRMS (ESI): MHþ, found 285.1237.
C16H17N2O3 requires 285.1234.
propanone (26)
See Ref. 6.
4.9.2. 3-[(6-Chloro-3-pyridyl)amino]-1-(2-pyridyl)-1-
propanone (33)
4''
3''
5''
6''
H
N
4'
2
1
3
3'
2'
5'
6'
Cl
2''
N
1''
O
4.9.6. 5-Nitro-4-(4-bromophenyl)-1-(2-pyridyl)-1-
pentanone (39b)
N
1'
The reaction mixture obtained by heating 1a and 32 (0.396 g,
2.5 mmol) in toluene at 70 ꢀC for 48 h was resolved with PE/EtOAc
2:1, leading to ketone 2 (Rf¼0.70, 0.013 g, 19%) and compound 33
(0.020 g, 15%) as ivory coloured needles, mp 112–113 ꢀC (from n-
hexane/acetone); [Found: C, 59.53; H, 4.53; N, 15.77. C13H12ClN3O
requires: C, 59.66; H, 4.62; N, 16.06%.] Rf (PE/EtOAc 2:1) 0.14; nmax
Operating as above with 38b (0.570 g, 2.5 mmol), chromato-
graphic resolution (PE/EtOAc 3:1) gave ketone 2 (Rf¼0.59, 0.012 g,
18%) and compound 39b (0.035 g, 19%) as a pale yellow oil; Rf (PE/
EtOAc 3:1) 0.21; nmax (film) 3051, 2926, 1690, 1546, 1383 cmꢂ1
; dH
(400 MHz) 2.12 (m, 2H, 3-CH2), 3.12 (m, 2H, 2-CH2), 3.58 (m, 1H, 4-
H), 4.61 (AB part of an ABX system, J¼12.5 and 7.6 Hz, 2H, 5-CH2),
7.11 (m, 2H, Ar-2H), 7.43–7.46 (m, 3H, 50-H and Ar-2H), 7.81 (ddd,
J¼7.7, 7.7, and 1.8 Hz, 1H, 40-H), 7.98 (ddd, J¼7.8, 1.0 and 1.0 Hz, 1H,
30-H), 8.60 (ddd, J¼4.7, 1.7. and 0.9 Hz, 1H, 60-H); dC (100 MHz) 27.1
(t), 34.8 (t), 43.2 (d), 80.5 (t), 121.7 (d), 127.3 (d), 129.1 (s), 129.4 (d),
132.0 (s), 132.2 (d), 136.9 (d), 148.9 (d), 152.9 (s), 200.5 (s); HRMS
(ESI): MHþ, found 363.0342. C16H16BrN2O3 requires 363.0339.
(KBr) 3395, 3055, 2858, 1690, 1585, 1459, 1326 cmꢂ1
; dH (400 MHz)
3.54 (m, 2H, 2-CH2), 3.58 (m, 2H, 3-CH2), 4.25 (br s,1H, NH), 6.93 (dd,
J¼8.6 and 3.1 Hz, 1H, 40-H), 7.08 (d, J¼8.6 Hz, 1H, 50-H), 7.50 (m, 1H,
500-H), 7.80 (d, J¼2.9 Hz, 1H, 20-H), 7.86 (ddd, J¼7.7, 7.7, and 1.7 Hz,
1H, 400-H), 8.05 (d, J¼7.8 Hz, 1H, 300-H), 8.68 (d, J¼4.3 Hz, 1H, 600-H);
dC (100 MHz) 37.2 (t), 39.4 (t),122.2 (d),122.7 (d),124.4 (d),127.9 (d),
135.0 (d), 137.4 (d), 139.3 (s), 143.3 (s), 149.4 (d), 153.2 (s), 200.9 (s).
Acknowledgements
4.9.3. 3-(3,5-Dichloroanilino)-1-(2-pyridyl)-1-propanone (35)
4''
Mrs. B. Innocenti and Mr. M. Passaponti are acknowledged for
technical support. Authors thank Ministry of University and Re-
search (MIUR Rome-Italy) for financial support (PRIN project).
3''
5''
6''
H
N
6'
2
1
3
1'
2'
Cl
2''
N
5'
4'
1''
O
3'
Cl
References and notes
Chromatographic resolution (PE/EtOAc 4:1) of the crude
1. (a) Uff, B. C. In Comprehensive Heterocyclic Chemistry; Boulton, A. J., McKillop, A.,
obtained by heating 1a and 34 (0.48 g, 2.5 mmol) in toluene at
Eds.; Pergamon: Oxford, UK, 1984; Vol. 2, pp 329–335; (b) Dennis, N. In

D. Giomi et al. / Tetrahedron 65 (2009) 7048–7055
7055
Comprehensive Heterocyclic Chemistry II; McKillop, A., Ed.; Pergamon: Oxford,
UK, 1996; Vol. 5, pp 101–104.
2. (a) Trost, B. M.; Kulawiec, R. J. J. Am. Chem. Soc. 1993, 115, 2027–2036; (b) Trost,
B. M. Acc. Chem. Res. 2002, 35, 695–705.
3. (a) Andrist, A. H.; Slivon, L. E.; Graas, J. E. J. Org. Chem. 1978, 43, 634–637;
(b) Yanovskaya, L. A.; Shakhidaystov, Kh. Russ. Chem. Rev. 1970, 39, 859–
874; (c) Dimmel, D. R.; Fu, W. Y.; Gharpure, S. B. J. Org. Chem. 1976, 41,
3092–3096.
4. For reviews on metal catalysed isomerization of allyl alcohols, see: (a) Van der
Drift, R. C.; Bouwman, E.; Drent, E. J. Organomet. Chem. 2002, 650, 1–24; (b)
Bellemin-Laponnaz, S.; Le Ny, J.-P. C. R. Chimie 2002, 5, 217–224; (c) Uma, R.;
Cre´visy, C.; Gre´e, R. Chem. Rev. 2003, 103, 27–51.
11. Uenishi, J.; Hiraoka, T.; Yuyama, K.; Yonemitsu, O. Heterocycles 2000, 52, 719–732.
12. The reported yields were determined on the basis of the recovered starting
material.
13. Ketone 2 (a volatile liquid, 50 ꢀC/4 Torr, see Ref. 8), was sometimes lost upon
evaporation to dryness under reduced pressure.
14. Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 17180–17181.
15. Di Sterfano, L: Castke. R.N.J. Heterocycl. Chem. 1968, 5, 53–59; For the electro-
philic behaviour of 22, see: Cecchi, M.: Micoli, A.: Giomi, D. Tetrahedron 2006,
62, 12281–12287.
16. This result is somewhat in contrast with that reported in our preliminary
communication (see Ref. 5). In fact, it was never possible to repeat the synthesis
of 25 in the simple thermal conditions as reported before. The observed dif-
ference is likely due to impurities of bases deriving from the work-up of alcohol
1a carried out by the previous student.
5. Giomi, D.; Piacenti, M.; Brandi, A. Tetrahedron Lett. 2004, 45, 2113–2115.
6. Giomi, D.; Alfini, R.; Brandi, A. Tetrahedron Lett. 2008, 49, 6977–6979.
7. Uenishi, J.; Hiraoka, T.; Hata, S.; Nishiwaki, K.; Yonemitsu, O. J. Org. Chem. 1998,
63, 2481–2487.
17. Vasudeva, P. K.; Nagarajan, M. Tetrahedron 1996, 52, 5607–5616.
18. Penney, J. M. Tetrahedron Lett. 2004, 45, 2667–2669.
8. Sato, N.; Narita, N. Synthesis 2001, 1551–1555.
19. Fraser, R. R.; Mansour, T. S.; Savard, S. J. Org. Chem. 1985, 50, 3232–3234.
20. Kano, S.; Ebata, T.; Shibuya, S. Chem. Pharm. Bull. 1979, 27, 2450–2455.
21. Dominguez, X. A.; Slim, J.; Elizondo, A. J. Am. Chem. Soc. 1953, 75, 4581–4582.
9. The same transformation was observed by heating at 70 ꢀC for three days.
10. For the synthesis of 1b in enantiopure form, see Ref. 7.