Uncatalyzed and solvent-free multicomponent process for the synthesis of biphenyl-2-carbonitrile derivatives

Article abstract of DOI:10.1021/ol062253o

(Diagram presented) An innovative route to prepare a number of variously substituted new biphenyl derivatives is presented here. The protocol avoids the use of a catalyst, an organic solvent, and dry conditions.

Full text of DOI:10.1021/ol062253o

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5741-5744
Uncatalyzed and Solvent-Free
Multicomponent Process for the
Synthesis of Biphenyl-2-carbonitrile
Derivatives
Francesco Fringuelli, Rugiada Girotti, Oriana Piermatti, Ferdinando Pizzo,* and
Luigi Vaccaro*
CEMIN - Dipartimento di Chimica, UniVersita` di Perugia, Via Elce di Sotto, 8,
I-06123 Perugia, Italy
luigi@unipg.it; pizzo@unipg.it
Received September 11, 2006
ABSTRACT
An innovative route to prepare a number of variously substituted new biphenyl derivatives is presented here. The protocol avoids the use of
a catalyst, an organic solvent, and dry conditions.
Biphenyls represent a key structural motif in a large number
of compounds used as pharmaceuticals, agrochemicals, dyes,
chiral ligands for metal catalysts, liquid crystals, organic
semiconductors, and materials for molecular recognition
devices.1 Furthermore, the biaryl subunit is present in an
extensive range of natural products.1
The most widely employed method for their preparation
involves a cross-coupling reaction of aryl halides, or their
synthetic equivalent such as triflates, with aryl metal
compounds.2 In addition, progress has been recently made
in the palladium-catalyzed direct arylation of simple arenes.3
Among all the possible organometallics, tin (Stille cou-
pling),4 boron derivatives (Suzuki-Miyaura coupling),5 and
to a lesser extent organozinc (Negishi coupling), organo-
magnesium (Kumada coupling), and organosilicon reagents
(Hiyama) have been the most frequently used.3 To promote
these coupling reactions, various metal catalysts have been
used and particular attention has been paid to palladium
complexes.3,6 The uncatalyzed synthesis of the biphenyl
system has been scarcely investigated,7 and solvent-free
conditions (SolFC) have never been used.
Considering the importance of this class of compounds,
the development of a green approach for their synthesis is
desirable.
As a continuation of our studies on the use of water8 and
SolFC9 in organic synthesis, we are currently involved in a
project aimed at the definition of an innovative synthesis of
(1) Bringmann, G.; Gunther, C.; Schupp, O.; Tesler S. In Progress in
the Chemistry of Organic Natural Products; Herz, W., Falk, H., Kirby, G.
W., Moore, R. E., Eds.; Springer-Verlag: New York, 2001; Vol. 81, pp
1-293.
(2) (a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; De Meijere,
A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004. (b) Cross-Coupling
Reactions. A Practical Guide. In Top. Curr. Chem.; Miyaura, N., Ed.;
Springer-Verlag: Berlin, 2002; Vol. 219.
(3) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006, 1253-1264.
(4) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50,
1-652.
(5) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359-1469.
(6) Tsuji, J. Palladium Reagents and Catalysts: New PerspectiVes for
the 21st Century; Wiley: Chichester, U.K., 2004.
(7) Becht, J.-M.; Gissot, A.; Wagner, A.; Miosjkowki, C. Chem.-Eur.
J. 2003, 9, 3209-3215.
(8) As representative examples, see: (a) Fringuelli, F.; Pizzo, F.; Vaccaro,
L. J. Org. Chem. 2004, 67, 2315-2321. (b) Fringuelli, F.; Pizzo, F.;
Tortoioli, S.; Vaccaro, L. Org. Lett. 2005, 7, 4411-4414 and literature cited
therein.
(9) As representative examples, see: (a) Fringuelli, F.; Pizzo, F.;
Vittoriani, C.; Vaccaro, L. Chem. Commun. 2004, 2756-2757. (b)
Fringuelli, F.; Girotti, R.; Pizzo, F.; Vaccaro, L. AdV. Synth. Catal. 2006,
348, 297-300 and literature cited therein.
10.1021/ol062253o CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/09/2006

2-substituted biphenyls under SolFC, via a metal-free mul-
ticomponent strategy, which starting from an aryl aldehyde
is based on the construction of the second aryl ring by a (1)
Knoevenagel reaction, (2) Diels-Alder cycloaddition, and
(3) final aromatization process (Scheme 1).
Scheme 2. Aromatization Process of Cycloadduct 5a
Scheme 1. Multicomponent Approach under SolFC to the
Biphenyl System
entries 1-4) and the other on a multicomponent procedure
performed in water or under SolFC (Table 1, entries 5 and
6). In the latter case, the result obtained was excellent; in
fact, when the heterogeneous mixture of 1a, 2, and 4a under
SolFC was left under vigorous stirring at room temperature
for 10 h, cycloadduct 5a was isolated in 85% yield (Table
1, entry 6). All the experiments have been performed by
using 1a:2:4a 1:1.5:2.0 molar ratios.
To convert 5a to biphenyl 6a, we have tried many
procedures, always obtaining unsatisfactory results. We have
found that when 5a was treated with 2.0 molar equiv of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) under SolFC in the
presence of O2 (0.5 bar) at 60 °C for 0.5 h, 4,5-dimethyl-
1,1′-biphenyl-2,4′-dicarbonitrile (6a) was isolated in a sat-
isfactory 77% yield (Scheme 2).
To our knowledge, this synthetic approach has been
realized in organic solvent and only for the preparation of
4′-methyl-1,1′-biphenyl-2-carbonitrile, but the yield was
unsatisfactory.10 We maintain that this approach could furnish
under SolFC a valid synthetic tool for the preparation of 1,1′-
biphenyl-2-carbonitriles.
In this communication, we report the synthesis of biphenyl-
2-carbonitrile derivatives 6a-o by using aryl aldehydes 1a-
k,o, nitroacetonitrile 2, and the 1,3-butadienes 4a-d. This
class of biphenyls is an important target: they are little
known and commonly prepared by Suzuki-Miyaura cou-
pling.11
The study was then extended to a variety of aldehydes
1b-k and to 1,3-dienes 4a-c (Table 2 and Scheme 3).
We have initially verified the feasibility of the process by
preparing 4,5-dimethyl-1,1′-biphenyl-2,4′-dicarbonitrile (6a),
studying (a) the preparation of cycloadduct 5a (Table 1) and
then (b) its aromatization (Scheme 2).
Scheme 3. Multicomponent Processes on 1b by Using
Isoprene (4b) and (E)-Piperylene (4c)
Table 1. Optimization of the Synthesis of the Intermediate 5a
at 30 °C
The multicomponent reaction among 1b-f,h,i,k, 2, and
4a allowed at 30-60 °C in 5-20 h the corresponding
cycloadducts 5b-f,h,i,k to be isolated (Table 2, entries 1-5,
7, 8, and 10). In the case of electron-rich aldehydes 1g and
1j, the Knoevenagel condensation was performed at 30 °C,
and to complete the Diels-Alder cycloaddition step in
reasonable time (3 h), the temperature was raised to 120 °C
(Table 2, entries 6 and 9). In all cases, the yields were
excellent.12
reaction
medium
time
(h)
yield
(%)a
entry
reactants
product
1
2
3
4
5
6
water
SolFC
water
SolFC
water
SolFC
1a, 2
1a, 2
3a, 4a
3a, 4a
1a, 2, 4a
1a, 2, 4a
12
3
10
10
12
10
-
-
75
84
90
72
85
3a
5a
5a
5a
5a
a Isolated yield.
In addition, the reactions among 1b, 2, and isoprene (4b)
or (E)-piperylene (4c) were also performed to evaluate the
regio- and stereoselectivity of the process (Scheme 3). In
the first case, para adduct 5l was exclusively formed and
isolated in 80% yield, whereas with 4c the exo/endo adducts
5m/5n were formed in a 75:25 ratio and isolated in 85%
yield.
The aromatization of adducts 5b-n was performed at 60
°C, generally in the presence of 2.0 molar equiv of DBU,
under an O2 atmosphere (0.5 bar) and SolFC. Biphenyl-2-
To optimize the synthesis of 5a, we have used two
approaches, one based on a step-by-step process (Table 1,
(10) Noda, Y.; Akiba, Y.; Kashima, M. Synth. Commun. 1996, 26, 4633-
4639.
(11) (a) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000,
39, 4153-4155. (b) Yamada, Y. M. A.; Takeda, K.; Takahashi, H.; Ikegami,
S. Org. Lett. 2002, 4, 3371-3374. (c) Tewari, A.; Hein, M.; Zapf, A.; Beller,
M. Synthesis 2004, 935-941. (d) Wang, G. T. et al. Bioorg. Med. Chem.
Lett. 2005, 15, 153-158.
5742
Org. Lett., Vol. 8, No. 25, 2006

Table 2. Multicomponent Synthesis of 5b-k Using 1b-k, 2,
and 4a under SolFC
Table 3. Multicomponent Synthesis of 6b-n under SolFC at
60 °C
a Yield of isolated pure product.
carbonitriles 6b-n were isolated in 0.5-7 h in satisfactory
to excellent yields (Table 3).13
We have also prepared the 4′-methyl-1,1′-biphenyl-2-
carbonitrile (6o) that is the precursor of angiostein II
antagonists (Scheme 4).11,14
In this case, due to the significant tendency of benzylidene
3o to give the retro Knoevenagel reaction at 110 °C, even
in the presence of traces of water, the synthesis of 5o was
accomplished in a two-step procedure. After the completion
of the condensation of p-methyl-benzaldehyde (1o) with 2
under SolFC (30 °C, 4 h), the resulting solid benzylidene
3o was washed with water, rigorously dried under a vacuum,
and then treated with sulfone 4d at 110 °C for 12 h. The
corresponding cycloadduct 5o was obtained in 75% yield
a Yield of isolated pure product. b 4.0 molar equiv of DBU. c 6m/6n 57:
43. 6m: X ) CN. 6n: X ) NO2. d Overall yield for 6m/6n
after silica gel column chromatography. The final aromati-
zation furnished the desired 4′-methyl-1,1′-biphenyl-2-car-
bonitrile (6o) in 65% yield.
Org. Lett., Vol. 8, No. 25, 2006
5743

on the crude products, and (c) isolate the pure biphenyls 6
by recrystallization to reduce the use of costly organic
solvents.
Scheme 4. Multicomponent Synthesis of
4′-Methyl-1,1′-biphenyl-2-carbonitrile (6o)
Finally, 4-cyano-benzaldehyde (1a) (40 mmol) was charged
in a metallic reactor equipped with a mechanical stirrer, and
at 30 °C, nitroacetonitrile (2) (40 mmol) and diene 4a (40
mmol) were subsequently added. After 10 h, the formation
of cycloadduct 5a was complete and DBU (80 mmol) was
added in situ. The reactor was then sealed and left under
mechanical stirring for 12 h at 30 °C under an O2 atmosphere
(0.5 bar). The final biphenyl 6a was isolated as a pure
compound after filtration of the reaction mixture through a
silica gel pad (sample/silica gel, 1:1 ratio) and recrystalli-
zation from acetone, in a satisfactory 72% overall yield (see
Supporting Information).
Working on a typical laboratory scale (1-2 mmol) and
with equimolar amounts of reagents, magnetic stirring was
not sufficient to ensure their necessary mixing, allowing a
maximum 80% conversion. Therefore, the use of oversto-
ichiometric amounts of nitroacetonitrile (2) and diene 4 was
necessary to complete the reactions. Consequently, although
the chemical efficiency of the process has been improved,
its “greenness” has been lowered.
In conclusion, the approach to biphenyl systems presented
herein avoids the use of a catalyst, an organic solvent, and
dry conditions and makes the purification of the final
products very simple. This protocol represents a promising
green route to this class of compounds.
We have therefore investigated the possibility of improving
the environmental efficiency of this process.
We have planned to (a) operate on a large scale that would
enable the use of the more efficient mechanical stirrer,
allowing operation with equimolar amounts of 2 and 4, (b)
perform the aromatization of cycloadducts 5 in the same pot
Acknowledgment. The Universita` degli Studi di Perugia
and the Ministero dell’Istruzione dell’Universita` e della
Ricerca (MIUR) are thanked for financial support. COFIN
2004; COFINLAB 2001 (CEMIN); FIRB: “Progettazione,
preparazione e valutazione biologica e farmacologica di
nuove molecole organiche quali potenziali farmaci innova-
tivi”.
(12) General Procedure for the Preparation of Diels-Alder Adducts.
A screw-capped vial equipped with a magnetic stirrer was charged with
the aldehydes 1a-k, nitroacetonitrile 2 (1.5 molar equiv), and dienes 4a-c
(2.0 molar equiv). The resulting mixture was left under magnetic stirring
for the time and at the temperatures reported in Tables 1 and 2 and in
Scheme 3. Cycloadducts 5a-n were isolated after silica gel column
chromatography of the final mixture.
(13) General Procedure for the Preparation of Biphenyls 6a-o. A
screw-capped vial equipped with a magnetic stirrer was charged with
cycloadducts 5a-o and DBU (2.0 molar equiv). The resulting mixture was
left under O2 (0.5 bar) under magnetic stirring at 60 °C for the time reported
in Table 3 and Schemes 2 and 4. Biphenyls 6a-o were isolated after silica
gel column chromatography of the final mixture.
Supporting Information Available: General experimen-
tal procedures and characterization data (1H NMR, 13C NMR,
IR, Rf, mp, GC-MS analyses) for all compounds, copies of
1H NMR and 13C NMR for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(14) Yamada, Y. M. A.; Takeda, K.; Takahashi, H.; Ikegami, S. Org.
Lett. 2002, 4, 3371-3374 and literature cited therein.
OL062253O
5744
Org. Lett., Vol. 8, No. 25, 2006