N-Metalated imines by reaction of 1,1-diethoxybut-2-ene with aromatic nitriles, as useful intermediates for the synthesis of substituted pyrimidines and cyclopentenones

Article abstract of DOI:10.1039/b719462e

A new approach to the synthesis of pyrimidines and cyclopentenones is described. The method exploits the reactivity of α,β-unsaturated acetals with aromatic nitriles in the presence of the Schlosser's superbase LIC-KOR. The Royal Society of Chemistry.

Full text of DOI:10.1039/b719462e

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N-Metalated imines by reaction of 1,1-diethoxybut-2-ene with aromatic
nitriles, as useful intermediates for the synthesis of substituted
pyrimidines and cyclopentenoneswz
Marco Blangetti,a Annamaria Deagostino,a Cristina Prandi,*a Chiara Zavattaroab
and Paolo Venturello*a
Received (in Cambridge, UK) 20th December 2007, Accepted 29th January 2008
First published as an Advance Article on the web 7th February 2008
DOI: 10.1039/b719462e
A new approach to the synthesis of pyrimidines and cyclopente-
nones is described. The method exploits the reactivity of
a,b-unsaturated acetals with aromatic nitriles in the presence
of the Schlosser’s superbase LIC-KOR.
monolithio- and dilithiobutadienes has been developed in
order to synthesize substituted pyridines and pyrroles.11
Herein we would like to report a novel and synthetically
useful reaction pattern of 1,1-diethoxybut-3-ene with nitriles
in the presence of Schlosser’s superbase LIC-KOR,12 that
afford N-containing heterocycles as the final products. More-
over, highly functionalized cyclopentenones can be also iso-
lated by slightly modifying the synthetic procedure.
The synthetic community dedicates much effort to the inves-
tigation of new approaches to those derivatives that are related
to the synthesis of natural products, pharmaceuticals, and
functional materials. Among these, pyrimidines and cyclopen-
tenones play a significant role. Most of the synthetic routes to
pyrimidine derivatives usually involve methodologies based on
the condensation reaction of 1,3-dicarbonyl compounds with
amidines (Pinner synthesis),1 or with an aryl aldehyde and
urea (Biginelli synthesis).2 Moreover, recent approaches to
substituted derivatives exploit cross-coupling chemistry.3 Re-
cently, it has been reported that the trapping of highly
activated amide derivatives with weakly nucleophilic nitriles
directly provides the corresponding pyrimidine derivatives.4
Equally significant is the development of synthetically useful
methods for the preparation of cyclopentyl derivatives. In
particular, cyclopentenones exhibit characteristic biological
activity and are useful for the versatility of their chemical
features, and for their application in natural product synthesis.
The methods reported for the cyclopentenone ring formation
mainly involve the intramolecular aldol reaction of suitable
1,4-dicarbonyl compounds,5 Nazarov cyclization of dienones,6
insertion reaction of an intermediate alkylidene carbene,7
Pauson–Khand reactions,8 and the tandem Michael addi-
tion–carbene insertion reactions of a b-ketoethynyl (phenyl)-
iodonium salts.9 Among the various syntheses for N-contain-
ing heterocycles, the addition of organolithium reagents to
nitriles provides an alternative and fundamental synthetic
method. In this context, 2-arylpyrroles have been prepared
from 2-lithio-N,N-dibenzylcyclopropylamine and nitriles,10
while a novel cycloaddition reaction of aromatic nitriles with
Metalation of 1,1-diethoxybut-2-ene 1 with 3 equiv. of LIC-
KOR base afforded the (1-ethoxybuta-1,3-dienyl)metal (metal
= Li or K) as a purple red solution.13 Addition of 1 equiv. of a
nitrile to the above reagent caused the addition reaction and
the color was discharged within a few seconds. The reaction
mixture was then stirred at ꢀ78 1C for 2 h, and the expected
imine 2 was isolated, as the E pure isomer, in high yield upon
quenching at this temperature (Scheme 1).y
In Table 1 are reported the results concerning the prepara-
tion of various imine derivatives.
In order to direct the reaction pattern towards new path-
ways, we have then investigated different experimental condi-
tions. We were especially interested in promoting the trapping
of the metalated imine intermediate, that can be in principle be
accomplished according to an intra- or intermolecular ap-
proach. During this systematic investigation we envisioned
that a new three-component synthesis of the pyrimidine ring
could be planned on the basis of the disconnection approach
shown in Scheme 2, that hints the use of a metalated diene as a
nucleophile and of two nitriles as electrophiles (1,6-, 2,3-, and
4,5-bond forming reactions).
When the crotonaldehyde acetal 1 was reacted under nitro-
gen with 2 equiv. of benzonitrile in THF for 2 h at ꢀ78 1C in
the presence of the LIC-KOR base, and then for 2 h at room
temperature, 5-ethoxy-2,4-diphenyl-6-vinylpyrimidine (7, Ar
= Ph) was produced in 80% yield. As illustrated in Scheme 3,
the initially formed N-metalketimine 3, as the reaction tem-
perature increases, adds to a second molecule of organonitrile
and gives a new N-metalketimine intermediate 4. Finally, an
intramolecular cyclization leads to the metal 5-ethoxy-2,6-
a
`
Dipartimento di Chimica Generale e Chimica Organica, Universita di
Torino, Via P. Giuria, 7, I-10125 Torino, Italy. E-mail:
cristina.prandi@unito.it. E-mail: paolo.venturello@unito.it; Fax:
+39 0112367646; Tel: +39 0116707645(7646)
b Institute of Organic Chemistry, RWTH Aachen, Landoltweg 1,
D-52074 Aachen, Germany
w Electronic supplementary information (ESI) available: Character-
ization data for all products, copies of 1H and 13C NMR spectra for all
isolated compounds. See DOI: 10.1039/b719462e
z Partially taken from the PhD research project of MB.
Scheme 1 Generation and reaction of 1-ethoxybuta-1,3-diene with
nitriles affording imine derivatives.
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Table 1 Synthesis of imines starting from 1,1-diethoxybut-2-ene 1a
Table 2 Synthesis of pyrimidines 7 starting from 1a
Nitriles
Product
Yieldb (%)
Reactant
Product
Yieldb (%)
65
72
47
84
82
63
74
81
65
82
a
Reaction conditions: t-BuOK (3.0 equiv.); BuLi (3.0 equiv.); 1
b
(1.0 equiv.); THF (20.0 mL); . Isolated yield.
diphenyl-4-vinyl-4H-pyrimidin-1-ide intermediate (5, Ar =
Ph), which upon quenching with aqueous NH4Cl affords
pyrimidine 7, probably via aerial oxidationz.8
a
Reaction conditions: t-BuOK (3.0 equiv.); BuLi (3.0 equiv.);
b
1 (1.0 equiv.); THF (20.0 mL); ArCN (2.5 equiv.). Isolated yield.
The synthesis was successfully carried out with benzonitrile
and with aryl nitriles bearing electron donating and electron
withdrawing substituents. The results obtained using different
organonitriles are reported in Table 2.
Successively, to examine a broader synthetic applicability of
the N-metalketimine, we attempted the acidic hydrolysis of
both the enol ether and iminic function of ketimine inter-
mediate 2, in order to obtain 1,2-dicarbonyl derivatives. Un-
fortunately, after treatment with Amberlyst-15 in wet CHCl3,
or with aqueous 1N HCl (H2O : THF = 1 : 1), only the
product of imine hydrolysis was recovered.**
Finally, in order to tune the reactivity of imine group, we
examined the trapping of the N-metalketimine intermediate
with benzoyl chloride, followed by acidic hydrolysis with
Amberlyst-15 in wet CHCl3. Reaction yield, and products
Scheme 4 Synthesis of substituted cyclopentenones.
Table 3 Synthesis of protected dienyl imines 9a and substituted
cyclopentenones 12b starting from 1
Nitriles
Product 5 (Yield %)c
Product 6 (Yield %)c
Scheme 2 Disconnection approach resulting in a three-component
pyrimidine synthesis.
(92)
(64)
(95)
(72)
(0)
a
Reaction conditions: t-BuOK (3.0 equiv.); BuLi (3.0 equiv.); 1 (1.0
equiv.); THF (20.0 mL); ArCN (1.1 equiv.); PhCOCl (2.2 equiv.).
b
c
5 (0.5 mmol); CH2Cl2 (2 mL); Amberlyst-15 (cat.). Isolated yield.
Scheme 3 One-pot synthesis of substituted pyrimidine derivatives.
1690 | Chem. Commun., 2008, 1689–1691
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filtration and evaporation of the solvent, the crude products were
purified by column flash chromatography.
obtained according to the mechanism proposed in Scheme 4,
are reported in Table 3.wwzz
In summary, a new synthesis for a series of derivatives of
potentially valuable biological interest has been developed by
the one-pot reaction of an a,b-unsaturated acetal with
aromatic nitriles in the presence of LIC-KOR superbase.
This work was supported by the Universita di Torino and
the MIUR.
1 (a) A. Pinner, Ber. Dtsch. Chem. Ges., 1890, 23, 2919; (b) A. Pinner,
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y General procedure for the syntheses of dienyl imines 2: a solution of
freshly sublimated t-BuOK (6 mmol, 672 mg, 3.0 equiv.) in 20 mL of
THF was refrigerated to ꢀ78 1C under nitrogen. 1,1-diethoxybut-2-
ene 1 (2 mmol, 288 mg) in 2 mL of THF and BuLi (1.6 M in hexanes,
6 mmol, 3.75 mL, 3.0 equiv.) were then quickly added and the mixture
was stirred for 2 h. During this time the temperature was allowed to
raise to ꢀ40 1C. Afterwards the reaction was cooled again to ꢀ78 1C
and the appropriate nitrile (2.2 mmol, 1.1 equiv.) in 5 mL of THF was
added. The resulting mixture was stirred at ꢀ78 1C for 1 h. Then, a
saturated NH4Cl aqueous solution (20 mL) was added, the mixture
extracted with Et2O (3 ꢂ 20 mL), the organic layers collected, washed
with H2O (10 mL), brine (2 ꢂ 20 mL), and dried over anhydrous
K2CO3. After filtration and evaporation of the solvent, the crude
products were purified by flash column chromatography.
z The last step of mechanism, namely the conversion of dihydropyr-
imidine 6 into pyrimidine 7, could be perhaps as well attributed to
metal hydride elimination, as proposed by Z. Xi and colleagues in the
articles that we have quoted in ref. 11. At the moment we have no
experimental evidence in order to support such an hypothesis.
8 General procedure for the syntheses of pyrimidines 7: the procedure in
detail follows what specified for the preparation of imines 2, up to the
generation of metalated 1-ethoxybuta-1,3-diene. Afterwards the reac-
tion was cooled again to ꢀ78 1C and a solution of the appropriate
nitrile (5.0 mmol, 2.5 equiv.) in 5 mL of THF was added. The resulting
mixture was stirred at ꢀ78 1C for 1 h, after which the temperature was
allowed to raise to rt and the reaction stirred overnight. Then, a
saturated NH4Cl aqueous solution (20 mL) was added, the mixture
extracted with Et2O (3 ꢂ 20 mL), the organic layers collected, washed
with H2O (10 mL), brine (2 ꢂ 20 mL), and dried over anhydrous
K2CO3. After filtration and evaporation of the solvent, the crude
products were purified by flash column chromatography.
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** Probably derivatives 2 do not release both masked carbonyl
functions since an unstable charged intermediates has to be considered
inspecting the mechanistic hydrolysis path.
12 B. L. Williamson, R. R. Tykwinski and P. J. Stang, J. Am. Chem.
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ww General procedure for the syntheses of protected dienyl imines 9: the
procedure in detail follows what specified for the preparation of imines
2 up to the genration of metalated 1-ethoxybuta-1,3-diene. Afterwards
the reaction was refrigerated again to ꢀ78 1C and a solution of the
appropriate nitrile (2.2 mmol, 1.1 equiv.) in 5 mL of THF was added.
The resulting mixture was stirred at ꢀ78 1C for 1 h, then PhCOCl (4.4
mmol, 2.2 equiv.) was added dropwise. Then, a saturated NH4Cl
aqueous solution (20 mL) was added, the mixture was extracted with
Et2O (3 ꢂ 20 mL), the organic layers collected, washed with H2O (10
mL), brine (2 ꢂ 20 mL), and dried over anhydrous K2CO3. After
filtration and evaporation of the solvent, the crude products were
purified by flash column chromatography. zz General procedure for the
syntheses of cyclopentenones 12: a solution of protected dienyl imine
(0.5 mmol) in CH2Cl2 (2 mL) was stirred in the presence of Amberlyst-
15s and the reaction progress monitored by TLC. When the reaction
was complete, a small amount of anhydrous K2CO3 was added. After
13 C. Tanguy, P. Bertus, J. Szymoniak, O. V. Larionov and A. de
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