A Catalytic Peterson-like Synthesis of Alkenyl Nitriles

Article abstract of DOI:10.1021/acs.orglett.6b01121

A heterogeneous fluoride catalyst was found to enable the straightforward formation of alkenyl nitriles from the reaction of aldehydes and simple or substituted acetonitriles, in the presence of commercially available silazanes and in solvent-free conditions. The protocol afforded the products in good to excellent yields with selectivity values dependent on the nature of the substrates. It represents an alternative to classic approaches using stoichiometric strong bases, and the catalyst can be easily recovered and reused for consecutive cycles.

Full text of DOI:10.1021/acs.orglett.6b01121

Letter
pubs.acs.org/OrgLett
A Catalytic Peterson-like Synthesis of Alkenyl Nitriles
Daniela Lanari,*,† Matteo Alonzi,‡ Francesco Ferlin,‡ Stefano Santoro,‡ and Luigi Vaccaro*,‡
†Dipartimento di Scienze Farmaceutiche, Universita
̀
di Perugia, Via del Liceo, 1 - 06123 Perugia, Italy
‡Laboratory of Green Synthetic Organic Chemistry, CEMIN − Dipartimento di Chimica, Biologia e Biotecnologie, Universita
̀
di
Perugia, Via Elce di Sotto, 8 - 06123 Perugia, Italy
S
* Supporting Information
ABSTRACT: A heterogeneous fluoride catalyst was found to enable
the straightforward formation of alkenyl nitriles from the reaction of
aldehydes and simple or substituted acetonitriles, in the presence of
commercially available silazanes and in solvent-free conditions. The
protocol afforded the products in good to excellent yields with
selectivity values dependent on the nature of the substrates. It
represents an alternative to classic approaches using stoichiometric
strong bases, and the catalyst can be easily recovered and reused for consecutive cycles.
Scheme 1. Amb-F Catalyzed Synthesis of Alkenyl Nitriles
Using Aldehydes and Nitriles
lkenyl nitriles represent important building blocks in
Asynthetic organic chemistry, particularly as electrophilic
partners in nucleophilic conjugate addition reactions.1 Moreover,
alkenyl nitriles are found in a number of natural products,2
especially nitrilosides, and pharmaceutically important com-
pounds,3 such as the anti-HIV non-nucleoside reverse tran-
scriptase inhibitor rilpivirine4 and the antiparkinson agent
entacapone.5 The standard procedure for the preparation of
alkenyl nitriles employs sodium or potassium hydroxide to
promote the condensation between acetonitrile and carbonyl
compounds.6 However, side reactions are common under these
conditions. These include the aldol reaction (for enolizable
carbonyl compounds), the self-condensation of nitriles, and the
Cannizzaro reaction. It is not surprising then that considerable
research efforts have been devoted to the definition of more
efficient methodologies for the preparation of alkenyl nitriles.7
Among these, particularly interesting procedures are those based
on the Wittig−Horner7c,o and the Peterson reactions,7m the
carbocyanation of alkynes,7l and the iron-catalyzed oxidative
functionalization of alkenes.7j However, most of these procedures
sufferfromseriousdrawbacks, suchastheuseoftoxicreagents,the
need for stoichiometric organometallic reagents, and the
frequently observed unsatisfactory yields.
In this letter, we present a novel, simple, and mild protocol for
theolefinationreactiontowardthesynthesisofalkenylnitriles1or
8, starting from aldehydes 2 and acetonitrile 3 or substituted
acetonitriles 7 (Scheme 1). This novel approach is based on the
ability of a fluoride ion to activate a Si−N bond.8 The reaction
works efficiently in the absence of an additional reaction medium
(solvent-free conditions, SolFC) and involves the use of silazanes
4−5 as trimethylsilyl sources and the use of a polystyrene
supported tetraalkylammonium fluoride (amberlyst fluoride,
Amb-F,6)asthecatalyst.Thisprotocoloffersthegreatadvantages
of using simple nitriles as a reactant without any time-consuming
andcostlyfunctionalizationandavoidingtheuseofhighlyreactive
organometallic reagents or superbases. Moreover, the use of a
solid catalyst simplifies the purification and allows the recovery
and recycle of the fluoride ion source.
We first focused on the scope of the reaction between
unsubstituted acetonitrile and a wide range of aromatic and
heteroaromatic aldehydes (Table 1). Either N-methyl-N-
trimethylsilylacetamide (MTSA, 4) or N,O-bis-trimethylsilyl-
acetamide (BSA, 5) were used as silazane bases, with 4 generally
giving better results, especially in terms of a clean reaction profile
and ease of purification of the reaction mixture. The reaction
affords the products in good to excellent yields (up to 93%), and
bothelectron-rich(Table1,entries1−5and10−12)andelectron-
poor aldehydes (Table 1, entries 6−8 and 13) could be used as
substrates. The reaction with 4-bromobenzaldehyde (2f) (Table
1,entry6)requiredanincreasedamountofacetonitrile,becauseof
the competing nucleophilic addition of the silazane on the
carbonyl. Anyway, it should be noted that highly concentrated
conditions are crucial for the efficiency of the process, and a larger
excess of 3 is detrimental to the reactivity.
Cinnamaldehyde (2i) was also employed, showing a complete
preference for carbonyl olefination over conjugate addition
(Table 1, entry 9). Olefination of aromatic heterocyclic aldehydes
2k−m proved to be very satisfying (Table 1, entries 11−13),
especially with 2-pyridinecarboxaldehyde (2m) (Table 1, entry
13). The reaction with indole-3-carboxaldehyde (2n) (Table 1,
Received: April 18, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01121
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Organic Letters
Letter
the relatively acidic nitrogen, as revealed by GC-MS analysis. Use
ofanexcessof4equivof4ledtocomplexreactionmixtures. These
results indicate the involvement of a strong base in the reaction.
A slight preference for the formation of the E isomer was
generally observed, with the selectivity depending on the
substrate. The highest levels of selectivity were found for the
reactions of pentamethylbenzaldehyde (2e) (Table 1, entry 5)
and pyridine-2-carboxaldehyde (2m) (Table 1, entry 13). The
generally moderate selectivity might be ascribed to the limited
steric hindrance exerted by acetonitrile. Indeed, performing the
reaction withbulkiernitrilesgivesmuchhigher levelsofselectivity
(vide infra).
Table 1. Amb-F-Catalyzed Preparation of Alkenylnitriles 1
from Aromatic Aldehydes 2 Using Silazanes 4 or 5 under
SolFC
a
Having established the scope of the reaction with acetonitrile
(3) we decided to investigate whether the protocol could be
extended to substituted acetonitriles 7 to afford trisubstituted
alkenylnitriles (Table 2).
Thereactionpromotedbysilazane4worksefficientlyonbenzyl
nitriles, with yields ranging from good to excellent (68%−99%).
Electron-rich and -poor aromatic aldehydes, as well as
heteroaromatic aldehydes, could be used in combination with
substitutedorunsubstitutedbenzylnitriles.Theuseofanexcessof
nitrile was not necessary in this case, as all the reactions could be
carried out with equimolar amounts of the two coupling partners.
As expected, the higher steric demands of benzyl nitriles lead to
much higher selectivity compared to the reactions with
acetonitrile. Indeed, in most of the cases only one of the two
possible geometrical isomers was detected.9 The methodology
could be extended also to alkyl-substituted acetonitriles (Table 2,
entries 12−13) and alkyl aldehydes (Table 2, entries 14−15).
We also tested whether this protocol could be applied to
ketones, subjecting acetophenone (9) to normal reaction
conditions using silazane 4 and acetonitrile (3) as coupling
partners (Scheme 2). Gratifyingly, the product was obtained in
90% yield after 2.5 h with an E/Z ratio of 7.2:1. In line with the
hypothesis that the selectivity depends on the steric hindrance of
the reactants, the isomer ratio observed for this reaction lies in
between the average ratio of the reactions between aldehydes and
acetonitrileandthatobtainedforreactionsbetweenaldehydesand
benzyl nitriles.
Atentative mechanism for the reaction isreported in Scheme3.
The process is initiated by the fluoride anion mediated activation
of the silazane,10 to generate a basic amide (11). Here we should
mention that no reaction occurred without catalyst 6. Additional
proof of the activation of the silazane, with the likely formation of
intermediate11,istheformationofthesideproductderivingfrom
the addition of the silazane on the carbonyl moiety when the
reaction is performed on highly electrophilic aldehydes such as 4-
bromobenzaldehyde (2f).
Amide 11 is inturn responsible for deprotonating acetonitrile 3
(or nitriles 7), with the assistance of the cationic resin which
stabilizes the generated carbanion 12. At this stage, the reaction is
likely to proceed through two possible pathways: namely, direct
attack of the carbanion on the carbonyl substrate, with the
assistance of a trimethylsilyl group in stabilizing the negative
charge onthe oxygen (from 12 to 15 inScheme 3), or through the
formation of trimethylsilylacetonitrile intermediate 16. The latter
is known to react with aldehydes to give the corresponding β-
trimethylsilyloxynitriles 15, in different reaction conditions.11
Accordingly, we believe that also this process may proceed
throughafluorideionactivatedsiliconpentavalentspeciesderived
from the attack of the fluoride ion on 16.
a
Reaction conditions: 2 (0.5 mmol), 3 (5 mmol, 10 equiv), 4 or 5 (1
b
c
mmol, 2 equiv). 20 equiv of 3. Deprotonation/silylation of 2 (no
formation of product 1).
entry 14) and pyrrole-2-carboxaldehyde (2o) (Table 1, entry 15)
led to the immediate and irreversible deprotonation/silylation of
In several cases, we observed the formation of intermediate 15
in the reaction mixtures, especially in the early stages of the
B
DOI: 10.1021/acs.orglett.6b01121
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Table2. Amb-F-CatalyzedPreparationofAlkenylnitriles8fromAldehydes2andSubstitutedAcetonitriles7, UsingSilazane4under
a
SolFC
a
b
c
Reaction conditions: 2 (0.5 mmol), 7 (0.5 mmol), 4 (1 mmol, 2 equiv). Determined by gas chromatography. The minor isomer was not detected.
Reaction conducted at 80 °C. 10 equiv of nitrile were used.
d
e
Scheme 2. Amb-F-Catalyzed Olefination of Acetophenone (9)
with Acetonitrile (3) under SolFC
Scheme 3. Proposed Mechanism for the Reported Peterson-
like Olefination
reaction, confirming its involvement in the reaction mechanism.
Finally, activation of the second equivalent of the silazane should
provide both the base and an electrophilic silyl group to readily
provide the β-elimination product 1. It is important to note that 2
equivofsilazanearenecessaryforthereactiontogotocompletion.
To further prove the role of 15 as an intermediate, we first
synthesized15a(R=p-MeO-C6H4-)(Scheme3)byreactionofp-
anisaldehyde 2a with trimethylsilylacetonitrile 16, in SolFC and
with 10 mol % of Amb-F 6 as the catalyst. The reaction went to
completion in 5 min. Then, intermediate 15a was treated with 1
equivofsilazane4andacatalyticamountofAmb-F6.Thereaction
C
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a
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89
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87
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such a coupling in test compound 8b (14.3 Hz) is typical of the Z-isomer
according to literature data. For references, see: Sanna, P.; Carta, A.;
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mmol, 2 equiv); between each run the catalyst was washed 3 times
with dichloromethane, dried with a nitrogen flow, and directly reused.
b
Determined by gas chromatography.
quickly afforded product 1a in good yield (83%), also confirming
the role of the second equivalent of silazane.12
To establish that the fluoride ion is restored to the catalyst, we
tested the possibility of using catalyst 6 for three consecutive
reaction runs (Table 3). Complete retention of the activity was
observed. Moreover, the composition of the catalyst did not show
any appreciable modification, as revealed by elemental analysis.
Thesearchforsimple,effective,andinexpensivemethodologies
for the synthesis of valuable products or intermediates is a topic of
great importance;13 herein, we reported a mild, simple, and
efficient protocol for the synthesis of alkenyl nitriles starting from
aldehydes and simple or substituted acetonitriles. The reaction
requires solvent-free conditions and makes use of a commercially
available and bench stable catalyst (Amberlyst Fluoride) and
silazanes. Preliminaryresultsshowthattheprotocolalsoworkson
ketones, but further investigations are necessary to explore the
scope of the reaction. Finally, the reaction mechanism has been
discussed with support from experiments.
ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b01121.
Characterization data and copies of the 1H and 13C NMR
spectra for all compounds 1a−m, 8a−o, and 10 (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: luigi.vaccaro@unipg.it.
*E-mail: daniela.lanari@unipg.it.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.S. gratefully acknowledges the MIUR for financial support
through the fellowship PGR123GHQY. Ms. Florence Valtin
(Erasmus visiting student from the University of Namur) is
gratefully acknowledged for preliminary experiments.
(11) (a) Kawanami, Y.; Yuasa, H.; Toriyama, F.; Yoshida, S.; Baba, T.
Catal. Commun. 2003, 4, 455. (b) Latouche, R.; Texier-Boullet, F.;
Hamelin, J. Tetrahedron Lett. 1991, 32, 1179. (c) Palomo, C.; Aizpurua, J.
́
M.; Lopez, M. C.; Lecea, B. J. Chem. Soc., Perkin Trans. 1 1989, 1692.
(12) We cannot exclude at this stage that the process is initiated by the
formation of HF2− and carbanion 12: Christe, K. O.; Wilson, W. W. J.
Fluorine Chem. 1990, 47, 117.
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D
DOI: 10.1021/acs.orglett.6b01121
Org. Lett. XXXX, XXX, XXX−XXX