Synthesis of β-Cyano Ketones Promoted by a Heterogeneous Fluoride Catalyst

Full text of DOI:10.1002/adsc.201600287

FULL PAPERS
DOI: 10.1002/adsc.201600287
Synthesis of b-Cyano Ketones Promoted by a Heterogeneous
Fluoride Catalyst
Giacomo Strappaveccia,a Tommaso Angelini,a Luca Bianchi,a Stefano Santoro,a
Oriana Piermatti,a Daniela Lanari,b,* and Luigi Vaccaroa,*
a
Laboratory of Green Synthetic Organic Chemistry, CEMIN - Dipartimento di Chimica, Biologia e Biotecnologie,
Universitꢀ di Perugia Via Elce di Sotto, 8, 06123 Perugia, Italy
Fax : (+39)-075-585-5560; phone: (+39)-075-585-5541; e-mail: luigi.vaccaro@unipg.it
Dipartimento di Scienze Farmaceutiche, Universitꢀ di Perugia, Via del Liceo, 06123 Perugia, Italy
b
E-mail: daniela.lanari@unipg.it
Received: March 15, 2016; Revised: April 6, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600287.
Introduction
the b-azidation of a,b-unsaturated ketones catalyzed
by PS-DABCOF2,[15] a bis-ammonium fluoride salt of
À ꢀ
Organic nitriles (R C N) are versatile compounds 1,4-diazabicyclo[2.2.2]octane supported on gel type
that can be transformed into different classes of mole- polystyrene resin,[16] and the b-azidation of carboxylic
cules such as amines, carboxylic acids, amides, esters, acids catalyzed by PS-DABCOF,[17] the mono-ammo-
aldehydes, heterocycles, etc.[1] Moreover, active phar- nium fluoride derivative of 1,4-diazabicyclo[2.2.2]oc-
maceutical ingredients (APIs) often contain a nitrile tane supported on a gel type polystyrene.
functionality that plays a pivotal role in the corre-
It is known that the efficiency of these processes is
based on the strong affinity of fluoride ion for silicon
sponding biological activity.[2]
The conjugate addition of cyanide ion to a,b-unsa- atom. In fact, the fluoride ion can interact with silyl
turated ketones has been studied using different types compounds forming a pentavalent silicon species,
of cyanide sources such as acetone cyanohydrin,[3] where a nucleophile is activated to react with an elec-
benzophenone cyanohydrin,[4] malononitrile,[5] potassi- trophilic center.[18]
um hexacyanoferrate(II),[6] tributylsilyl cyanide[7] and
Our research group is also interested in the study
trimethylsilyl cyanide (TMSCN).[8] Several catalytic of the synergic combination of solvent-free conditions
systems have been used to promote this pro- (SolFC) and polymer-supported organocatalysts as an
cess,
including
quinidinium
salts,[3a,b]
metal effective approach to define chemically and environ-
complexes,[3c,7,8a,b,d,h,9] CsF,[8c,g] phosphonates,[4,8e] ce- mentally efficient synthetic protocols.[19,20] We have
sium[8f] and potassium carbonate,[5] as well as KOH.[6] also proved that the use of flow technology to replace
Microwave activation has been also adopted.[8i] How- classic mechanical stirring may very efficiently maxi-
ever, to the best of our knowledge, there is no report mize the advantages of both SolFC and heterogene-
on the use of a heterogeneous and potentially recov- ous catalysis, by preserving the catalytic efficiency
erable catalytic system.
and minimizing the waste production.[21]
The definition of efficient and environmentally
In this paper, we report a straightforward and effi-
friendly chemical protocols is of wide interest for or- cient protocol for the conjugate addition of cyanide to
ganic synthesis. In this context, our group is contribu- a,b-unsaturated ketones 1a–j, an oxazolidinone 1k
ting to the development of new efficient procedures and an ester 1l, using TMSCN as cyanide source and
allowing the minimization of costly purification steps Amb-F as solid catalyst under SolFC.
(i.e., extractions, chromatographic separations, etc.),
and waste production[10] (E-factor).[11]
In recent years, we have focused our attention on Results and Discussion
processes proceeding via fluoride activation of silicon
pronucleophiles[12] in various types of addition reac- The addition of TMSCN to (E)-hept-3-en-2-one (1a)
tions. A few examples are the Mukaiyama aldol reac- was chosen as the representative process to optimize
tion[13] catalyzed by Amberliteꢁ IRA 900F (Amb-F), reaction conditions. The obtained results are summar-
a commercially available tetramethylammonium fluo- ized in Table 1.
ride salt supported on a porous type polystyrene,[14]
Adv. Synth. Catal. 0000, 000, 0 – 0
1
ꢂ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
liteꢁ IRA 400F (a gel-type polystyrene resin) and
Amberliteꢁ IRA 900F (a macroreticular polystyrene
resin) (Table 1, entry 2 vs. 6). The main difference be-
tween these two catalysts resides in their polymeric
structure, which results in a completely different ac-
cessibility to the catalytic sites and efficiency, as also
previously observed in other processes.[15b]
Table 1. Optimization of the reaction conditions for the re-
action between (E)-hept-3-en-2-one (1a) and TMSCN.
In this study, Amb-F was confirmed to be one of
the most effective fluoride sources under solvent-free
À
conditions, being able to efficiently activate Si C,
Si N, and Si O bonds.
[12,13,15b,19]
En- Medium
try
Catalyst
(10 mol%)
Conversion 2a:3a
À
À
[%][a]
ratio
In order to further optimize the reaction conditions,
the catalyst loading was reduced to 5 mol%, obtaining
a lower selectivity, with the formation of a 30:70 mix-
ture of 2a:3a (Table 1, entry 10). Finally, diminishing
the quantity of TMSCN caused incomplete conver-
sion (Table 1, entry 11 vs. entry 6).
The reaction conditions used in Table 1 entry 6,
were extended to substrates 1a–l (Table 2). Under the
optimized conditions alkyl a,b-unsaturated ketones
gave the corresponding b-cyano ketones 3 in high
yields (86–99%) (Table 2, entries 1–3, 5, and 6). The
lower reactivity observed with 4-methylpent-3-en-2-
one (1d) (Table 2, entry 4) can be ascribed to the
steric hindrance at the b-position. Aromatic enones
gave good results, with yields ranging from 73 to 95%
(Table 2, entries 7–10). In the case of (E)-4-phenyl-
but-3-en-2-one (1g) (Table 2, entry 7), additional pu-
rification was needed to isolate pure product 3g (see
1
2
3
4
5
6
7
8
9
SolFC
SolFC
SolFC
SolFC
SolFC
SolFC
H2O (0.5M)
KF/Al2O3
Amb 400 F
PS-DABCOF2 71
PS-DABCOF 88
TBAF/SiO2
Amb-F
85
60
>99:0
>99:0
>99:0
43:57
70
20:80
100
40
48
82
100
90
0:>99
>99:0
0:>99
0:>99
30:70
Amb-F
CH2Cl2 (0.5M) Amb-F
CH3CN (0.5M) Amb-F
10[b] SolFC
11[c] SolFC
Amb-F
Amb-F
0:>99
[a]
Remaining material was unreacted 1a.
[b]
Reaction performed with 5 mol% of Amb-F for 24 h;
performing the same reaction at 808C did not give any
appreciable difference.
[c]
Reaction performed with 1 equiv. of TMSCN for 24 h.
Several heterogeneous fluoride sources have been the Supporting Information). Other Michael accept-
tested and compared. KF on alumina, Amberliteꢁ ors were also tested. (E)-3-(But-2-enoyl)oxazolidin-2-
IRA 400F (Amb-400F, tetramethylammonium fluo- one (1k) (Table 2, entry 11), gave the corresponding
ride supported on a gel type polystyrene) and PS- b-cyano derivative 3k in 75% yield after purification
DABCOF2 selectively promoted the 1,2-addition on (see the Supporting Information). Although (E)-
the carbonyl group, giving exclusively the correspond- methyl but-2-enoate (1l) (Table 2, entry 12) is a very
ing cyanohydrin trimethylsilyl ether 2a (Table 1, en- unreactive substrate in Michael additions,[17] the cor-
tries 1–3). PS-DABCOF gave a 43:57 mixture of 2a responding product 3l was obtained in 96% yield. In
and 3a (Table 1, entry 4). Interestingly, tetrabutylam- all these cases, except for 3g and 3k, products have
monium fluoride (TBAF) on silica gave a 20:80 mix- been isolated in pure form just after filtration of the
ture of 2a and 3a (Table 1, entry 5).
catalyst. The corresponding E-factor values range
Among the tested catalysts, only Amb-F afforded from 9 to 29.
product 3a selectively and with full conversion
The catalyst recovered from filtration of the reac-
(Table 1, entry 6). Amb-F was also tested in different tion mixture was reused in the representative reaction
media such as water, dichloromethane and acetoni- with substrate 1a. Unfortunately, a drop in the cata-
trile, but in all cases the conversion was lower than lyst efficiency was immediately observed in the
under SolFC, highlighting how SolFC are essential to second run and, although full conversion was ach-
achieve sufficient reactivity and selectivity (Table 1, ieved after the same time (3 h), an 80/20 mixture of
entries 7–9 vs. entry 6).
2a/3a was isolated. Even after a prolonged reaction
The efficiency of the different solid fluoride sources time, no changes were observed in the product distri-
strongly depends on the counter ion, especially if bution. Comparing these results with those obtained
polymer-supported, that has an influence on the avail- when 5 mol% of Amb-F was used (Table 1, entry 10),
ability and nucleophilicity of the fluoride ion towards we speculated that the fluoride content is lower in the
silicon atom. This is not surprising, also on the basis recovered catalyst.
of our previous experience on the influence of the
In agreement with previous similar observa-
solid polymeric support on the efficiency of an immo- tions,[15,19] elemental analysis of the recovered used
bilized catalyst.[12,15,17,19,20,22] A striking example is catalyst proved that the nitrogen content is higher
given by the different efficiency showed by Amber- than in fresh Amb-F. In addition, quantitative analysis
Adv. Synth. Catal. 0000, 000, 0 – 0
2
ꢂ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
Table 2. Substrate scope for conjugate addition of cyanide to
a,b-unsaturated compounds.
by ionic exchange HPLC proved that fluoride content
is reduced by ca. 70% in the recovered catalyst com-
pared to fresh Amb-F.
This can be justified by a partial fluoride/cyanide
anions exchange with formation of trimethylsilyl fluo-
ride (TMSF) and Amb-CN, which is not able to pro-
mote the formation of 3. We have observed a similar
scenario in the related azidation reaction.[15,17] The re-
sulting lower selectivity observed using the recovered
catalyst can be therefore ascribed to the different nu-
cleophilicity and/or affinity of cyanide and fluoride
ions for silicon.
As a test to gain some insights into the reaction
mechanism, 1a and TMSCN were left to react for
only 1.5 h in the presence of fresh catalyst. The result-
ing quenched reaction mixture showed a 60% conver-
sion of 1a to an 80:20 mixture of cyanohydrin trime-
thylsilyl ether 2a and b-cyano ketone 3a. This result
suggests that formation of 2a is a reversible process
under the reaction conditions. In order to assess this
hypothesis, 2a has been prepared with a different
method[23] and heated at 608C in the presence of
Amb-F. After 1 hour, a complete conversion of 2a to
3a was observed.
Therefore, we can conclude that addition of
TMSCN to a,b-unsaturated ketones is a stepwise pro-
cess. We can suggest that an initial 1,2-addition of cya-
nide to the a,b-unsaturated ketone 1 occurs giving the
cyanohydrin trimethylsilyl ether 2 (Scheme 1, step a).
In the presence of an efficient fluoride catalyst, for-
mation of 2 is reversible, leading again to ketone
À
1 through the activation of the Si O bond (Scheme 1,
step b). Finally, the formation of b-cyano ketones 3 is
irreversible (Scheme 1, step c). Different fluoride
sources show variable selectivities depending on their
À
ability to efficiently activate the Si O bond
(Scheme 1, step b). Similarly, recovered Amb-F cata-
lyst features a lower fluoride availability, which results
À
in a reduced efficiency in promoting Si O bond acti-
vation and therefore in a poorer selectivity.
[a]
Reaction performed with 1.5 equiv. of TMSCN and 20
[b]
mol% of Amb-F.
Product purified by flash column
[c]
chromatography on silica gel. Reaction performed with
3 equiv. of ethyl acetate to avoid stirring problems.
Scheme 1. Plausible reaction mechanism for the fluoride-cat-
alyzed reaction of TMSCN ion with 1.
Adv. Synth. Catal. 0000, 000, 0 – 0
3
ꢂ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
Table 4. Amb-F recycling for the cyanide shift step.
Considering these findings and results previously
obtained in our group, we also investigated the possi-
bility to pursue the synthesis of b-cyano ketones by
a two-step process applying flow techniques.
In recent years, our research group has developed
several protocols based on the use of a flow ap-
proach,[21,24] allowing the minimization of waste pro-
duction and improving the efficiency of the use of
a heterogeneous recoverable catalyst under SolFC.
This technology is offering several opportunities for
the definition of successful innovative synthetic strat-
egies.[21,24,25] One advantage, among the others, is that
different steps of a synthesis can be run in a sequence,
Entry Run Yield [%] Time [h] (Batch) Time [h] (Flow)
1
2
3
4
1st
90
87
87
88
1
1
2nd
3rd
4th
24
36
80
12
14
18
without the isolation of intermediates. Moreover, the system showed lower reactivity after each recycle.
isolation procedure can be optimized, diminishing the Thus, to reach complete conversion, the reaction time
solvent usage and, consequently, the E-factor value.[21] had to be increased to 24 h in the second run
In addition, in this way mechanical degradation of the (Table 4, entry 2), 36 h in the third (Table 4, entry 3),
heterogeneous catalyst is avoided, as well as the con- and 80 h it the fourth run (Table 4, entry 4). This be-
tact with air or humidity, achieving a longer life time haviour is in agreement with the observed fluoride
of the catalyst and a better recyclability.[21–24]
loss.
On the basis of these findings and our previously
Recently, we reported the synthesis of cyanohydrin
trimethylsilyl ethers 2 catalyzed by polystyrene-sup- reported results,[22] we proceeded to implement the
ported triphenylphosphine (PS-TPP), using a continu- two-step flow procedure. 20 mmol of 1 and 22–
ous flow reactor, managing to recycle the catalyst for 30 mmol of TMSCN were charged into a glass column
several times without any decrease in reactivity.[23] functioning as a reservoir, while 5 mol% of PS-TPP
Thus, we reasoned that this reaction could be com- and 10–20 mol% of Amb-F were charged into two
bined with the Amb-F catalyzed cyanide shift (1,2- to separate glass columns. A schematic diagram of the
1,4-) to allow the synthesis of b-cyano ketones 3 from reactor is presented in Figure 1. The reagents were
a,b-unsaturated ketones 1 in a two-step procedure in continuously pumped through the PS-TPP catalyst for
a continuous flow reactor (Table 3).
4–6 h, until complete conversion to intermediate 2
An important requirement of this reaction plan is was achieved. Then, 2 was collected in the reservoir
the ability of Amb-F to continuously catalyze the cya- and a small quantity (2ꢃ1 mL) of ethyl acetate was
nide shift without considerable loss of activity. Thus, cyclically pumped through the system for 15 min in
we first tested the recyclability of Amb-F in the con-
version of cyanohydrin trimethylsilyl ether 2a to b-
cyano ketone 3a for four consecutive reaction runs
(Table 4). Although complete conversions and good
yields were obtained over four consecutive runs, the
Table 3. Two steps synthesis of b-cyano ketones in flow.
Entry Product Time 1st
step [h]
Time 2nd
step [h]
Yield
[%]
E-
factor
1[a]
2
3a
3e
3f
3g
3h
4
4
6
5
6
1
5
24
1
1
90
94
89
93
94
1.1
0.8
1.2
1.1
0.8
3
4[b]
5[b]
[a]
[b]
Reaction performed with 1.1 equiv. of TMSCN.
Reaction performed with 1.5 equiv. of TMSCN and
20 mol% of Amb-F.
Figure 1. Flow apparatus for the two-steps synthesis of b-
cyano ketones.
Adv. Synth. Catal. 0000, 000, 0 – 0
4
ꢂ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
before use. GC analyses were performed by using a Hew-
lett–Packard HP 5890A equipped with a capillary column
DB-35 MS (30 m, 0.53 mm), FID detector and helium as the
carrier gas. GC-EI-MS analyses were carried out by using
a Hewlett–Packard HP 6890N Network GC system/5975
Mass Selective Detector equipped with an electron impact
ionizer at 70 eV. All 1H NMR and 13C NMR spectra were re-
corded at 200 MHz or 400 MHz, and at 50.3 or 100.6 MHz
respectively, using a Bruker DRX-ADVANCE 200 MHz
spectrometer and a Bruker DRX-ADVANCE 400 MHz
spectrometer. The deuterated solvent used was CDCl3, and
TMS was employed as the internal standard. Chemical shifts
were reported in ppm and coupling constants in hertz. Ele-
mental analyses were realized by using a FISONS instru-
ment EA 1108 CHN. All the detailed experimental proce-
dures, characterization data of compounds 3a–l along with
order to wash PS-TPP, valves and tubes, and collected
in the reservoir with 2. Next, this solution was
pumped through Amb-F for 1–24 h, until complete
conversion to product 3 was achieved.[26] Finally, prod-
uct 3 was transferred in the reservoir and the catalyst
and the system were washed again with ethyl acetate
(2ꢃ1 mL). After distillation and recovery of the sol-
vent (3.1–3.2 mL of EtOAc out of the 4 mL used),
pure 3 were obtained in excellent yields (89–94%)
and E-factor values (0.8–1.2). The procedure was re-
peated 3 times in the reaction with substrate 1a in
order to evaluate the recyclability of Amb-F under
flow conditions (see Table 4). Despite an increase in
the reaction time, this was substantially shorter com-
pared to the batch procedure, giving at the 4th run in
flow a complete conversion in only 18 h, compared to
the 80 h required in batch conditions (Table 4,
entry 4).
These results prove that the catalyst is more stable
in the flow apparatus, where it retains higher activity
compared to the batch reaction due to limited loss of
fluoride as TMSF. Indeed, quantitative analysis by
ionic exchange HPLC proved that after the 4th run in
flow the recovered catalyst still contains 50% of the
starting fluoride ion. For comparison, ca. 70% of the
fluoride is already lost after the first run in batch.
1
copies of the H and 13C NMR spectra are given in the Sup-
porting Information.
Typical Procedure for the Preparation of 2a[23]
In a screw-capped vial, equipped with a magnetic stirrer,
polystyrene-supported
0.025 mmol,
triphenylphosphine
(0.008 g,
(1a)
3.2 mmolgÀ1),
(E)-hept-3-en-2-one
(0.065 mL, 0.5 mmol), and TMSCN (0.075 mL, 0.6 mmol)
were consecutively added and the resulting mixture was left
under stirring at 608C. After 4 h, Et2O (1 mL) was added,
the catalyst was filtered off and the solvent was removed
under vacuum. Pure (E)-2-methyl-2-[(trimethylsilyl)oxy]-
hept-3-enenitrile (2a) was obtained as an oil; yield: 0.104 g
(99%).
Conclusions
Typical Procedure for the Conjugate Addition of
Cyanide to a,b-Unsaturated Ketones
In conclusion, we have developed a straightforward
and environmentally benign protocol to isolate pure
b-cyano ketones without any purification step. Sol-
vent-free conditions proved to be an efficient tool to
obtain a good reactivity and selectivity while worse
results were observed in other reaction media. Utiliz-
ing the SolFC and Amberliteꢁ IRA 900 F (Amb-F) as
catalyst, b-cyano ketones 3a–j were obtained in
a one-step procedure in good yields (73–99%) and
very low E-factor values (9–22). Nitriles 3k and 3l,
featuring an amide and an ester group, respectively,
were obtained with the same protocol. Furthermore,
a flow apparatus was set up, in order to optimize the
recycling of Amb-F. Using a two-step procedure, a sig-
nificant improvement of the catalyst recyclability,
compared to batch conditions, was obtained. More-
over, the flow technique permitted a substantial re-
duction in the E-factor valuesfor the conjugate addi-
tion of cyanide to ketones.
In a screw-capped vial, equipped with a magnetic stirring
bar, Amb-F (19 mg, 0.05 mmol, 2.6 mmolgÀ1), (E)-hept-3-
en-2-one (1a) (56 mg, 0.065 mL, 0.5 mmol) and TMSCN
(51 mg, 0.069 mL, 0.55 mmol) were consecutively added and
the resulting mixture was left under stirring at 608C. After
3 h, EtOAc (1 mL) was added, the catalyst was filtered off
and the solvent was removed under vacuum. Pure 4-oxo-2-
propylpentanenitrile (3a) was obtained as an oil; yield:
69 mg (99%).
Representative E-Factor Calculations
Batch
procedure
(0.5 mmol):
[(E)-hept-3-en-2-one
(56 mg)+TMSCN (51 mg)+washing EtOAc (900 mg)+
Amb-F (19 mg)Àproduct (69 mg)]/product (69 mg)=14.
Flow
procedure
(20 mmol):
[(E)-hept-3-en-2-one
(2243 mg)+TMSCN
(2183 mg)+washing
EtOAc
(722 mg)Àproduct (2506 mg)]/product (2505 mg)=1.1.
Acknowledgements
Experimental Section
We gratefully acknowledge the Universitꢀ degli Studi di Peru-
gia for financial support. S.S. gratefully acknowledges the
MIUR for financial support through the fellowship
PGR123GHQY, funded within “Programma Giovani Ricer-
catori, Rita Levi Montalcini”.
General Remarks
Unless otherwise stated, all chemicals were purchased and
used without any further purification. Amb-F was dried
Adv. Synth. Catal. 0000, 000, 0 – 0
5
ꢂ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
References
(or macroporous) polystyrene is a polymer matrix
which has a permanent porous network.
[1] a) M.-X. Wang, Top. Catal. 2005, 35, 117–130; b) D.
Enders, J. P. Shilvock, Chem. Soc. Rev. 2000, 29, 359–
373; c) R. J. H. Gregory, Chem. Rev. 1999, 99, 3649–
3682.
[15] a) T. Angelini, D. Lanari, R. Maggi, F. Pizzo, G. Sartori,
L. Vaccaro, Adv. Synth. Catal. 2012, 354, 908–916; b) L.
Castrica, F. Fringuelli, L. Gregoli, F. Pizzo, L. Vaccaro,
J. Org. Chem. 2006, 71, 9536–9539.
[2] F. F. Fleming, L. Yao, P. C. Ravikumar, L. Funk, B. C.
Shook, J. Med. Chem. 2010, 53, 7902–7917.
[16] A gel type polystyrene is a polymer matrix which does
not have a permanent porous network.
[17] T. Angelini, S. Bonollo, D. Lanari, F. Pizzo, L. Vaccaro,
Org. Lett. 2012, 14, 4610–4613.
[18] a) S. Rendler, M. Oestreich, Synthesis 2005, 1727–1747;
b) A. D. Dilman, S. L. Ioffe, Chem. Rev. 2003, 103, 733–
772; c) C. Chuit, R. J. P. Curriu, C. Reye, J. C. Young,
Chem. Rev. 1993, 93, 1371–1448.
[3] a) H. Kawai, S. Okusu, E. Tokunaga, H. Sato, M. Shiro,
N. Shibata, Angew. Chem. 2012, 124, 5043–5046;
Angew. Chem. Int. Ed. 2012, 51, 4959–4962; b) B. A.
Provencher, K. J. Bartelson, Y. Liu, B. M. Foxman, L.
Deng, Angew. Chem. 2011, 123, 10753–10757; Angew.
Chem. Int. Ed. 2011, 50, 10565–10569; c) Y. Kawasaki,
A. Fujii, Y. Nakano, S. Sakaguchi, Y. Ishii, J. Org.
Chem. 1999, 64, 4214–4216.
[19] E. Ballerini, P. Crotti, I. Frau, D. Lanari, F. Pizzo, L.
Vaccaro, Green Chem. 2013, 15, 2394–2400.
[4] Y.-F. Wang, W. Zeng, M. Sohail, J. Guo, S. Wu, F.-X.
[20] S. Bonollo, D. Lanari, J. M. Longo, L. Vaccaro, Green
Chem. 2012, 14, 164–169.
Chen, Eur. J. Org. Chem. 2013, 4624–4633.
[5] S. Lin, Y. Wei, F. Liang, Chem. Commun. 2012, 48,
9879–9881.
[21] L. Vaccaro, D. Lanari, A. Marrocchi, G. Strappaveccia,
Green Chem. 2014, 16, 3680–3704.
[6] a) Z. Li, J. Yin, T. Li, G. Wen, X. Shen, J. Yang, Tetra-
hedron 2014, 70, 5619–5625; b) Z. Li, Y. Zhang, R. Li,
B. Ma, J. Yang, Synlett 2012, 2567–2571.
[22] a) E. Ballerini, M. Curini, D. Gelman, D. Lanari, O.
Piermatti, F. Pizzo, S. Santoro, L. Vaccaro, ACS Sus-
tainable Chem. Eng. 2015, 3, 1221–1226; b) M. Tassi, E.
Bartollini, P. Adriaensens, L. Bianchi, B. Barkakaty, R.
Carleer, J. Chen, D. K. Hensley, A. Marrocchi, L. Vac-
caro, RSC Adv. 2015, 5, 107200–107208; c) A. Marroc-
chi, P. Adriaensens, E. Bartollini, B. Barkakati, R. Carl-
eer, J. Chen, D. K. Hensley, C. Petrucci, M. Tassi, L.
Vaccaro, Eur. Polym. J. 2015, 75, 391–401; d) M.
Alonzi, M. P. Bracciale, A. Broggi, D. Lanari, A. Mar-
rocchi, M. L. Santarelli, L. Vaccaro, J. Catal. 2014, 309,
260–267.
[7] Y. Tanaka, M. Kanai, M. Shibasaki, J. Am. Chem. Soc.
2008, 130, 6072–6073.
[8] a) J. Zhang, X. Liu, R. Wang, Chem. Eur. J. 2014, 20,
4911–4915; b) N. Kurono, N. Nii, Y. Sakaguchi, M.
Uemura, T. Ohkuma, Angew. Chem. 2011, 123, 5655–
5658; Angew. Chem. Int. Ed. 2011, 50, 5541–5544; c) Y.
Jingya, C. Fuxue, Chin. J. Chem. 2010, 28, 981–987;
d) Y. Tanaka, M. Kanai, M. Shibasaki, J. Am. Chem.
Soc. 2010, 132, 8862–8863; e) J. Yang, S. Wu, F.-X.
Chen, Synlett 2010, 2725–2728; f) J. Yang, Y. Shen, F.-
X. Chen, Synthesis 2010, 1325–1333; g) J. Yang, Y.
Wang, S. Wu, F.-X. Chen, Synlett 2009, 3365–3367; h) Y.
Tanaka, M. Kanai, M. Shibasaki, Synlett 2008, 2295–
2298; i) H. Iida, T. Moromizato, H. Hamana, K. Matsu-
moto, Tetrahedron Lett. 2007, 48, 2037–2039; j) I. I.
Gerus, I. S. Kruchok, V. P. Kukhar, Tetrahedron Lett.
1999, 40, 5923–5926.
[23] G. Strappaveccia, D. Lanari, D. Gelman, F. Pizzo, O.
Rosati, M. Curini, L. Vaccaro, Green Chem. 2013, 15,
199–204.
[24] a) E. Ballerini, R. Maggi, F. Pizzo, D. Gelman, O. Pier-
matti, L. Vaccaro, Org. Process Res. Dev. 2016, 20, 474–
479; b) V. R. Jumde, E. Petricci, C. Petrucci, N. Santillo,
M. Taddei, L. Vaccaro, Org. Lett. 2015, 17, 3990–3993;
c) C. Petrucci, M. Cappelletti, O. Piermatti, M. Noc-
chetti, Pica, F. Pizzo, L. Vaccaro, J. Mol. Catal. A 2015,
401, 27–34; d) C. Petrucci, G. Strappaveccia, F. Giac-
alone, M. Gruttadauria, F. Pizzo, L. Vaccaro, ACS Sus-
tainable Chem. Eng. 2014, 2, 2813–2819.
[9] T. Onhkuma, N. Kurono, Synlett 2012, 1865–1881.
[10] C. Pavia, E. Ballerini, L. A. Bivona, F. Giacalone, C.
Aprile, L. Vaccaro, M. Gruttadauria, Adv. Synth. Catal.
2013, 355, 2007–2018.
[11] R. A. Sheldon, Chem. Commun. 2008, 3352–3365.
[12] F. Fringuelli, D. Lanari, F. Pizzo, L. Vaccaro, Eur. J.
Org. Chem. 2008, 3928–3932.
[25] a) C. J. Mallia, I. R. Baxendale, Org. Process Res. Dev.
2016, 20, 327–360; b) R. Porta, M. Benaglia, A. Puglisi,
Org. Process Res. Dev. 2016, 20, 2–25; c) H. P. L. Gem-
oets, Y. Su, M. Shang, V. Hessel, R. Luque, T. Noꢄl,
Chem. Soc. Rev. 2016, 45, 83–117; d) B. Gutmann, D.
Cantillo, C. O. Kappe, Angew. Chem. 2015, 127, 6788–
6832; Angew. Chem. Int. Ed. 2015, 54, 6688–6728; e) R.
Munirathinam, J. Huskens, W. Verboom, Adv. Synth.
Catal. 2015, 357, 1093–1123; f) C. Wiles, P. Watts, Green
Chem. 2014, 16, 55–62.
[13] F. Fringuelli, D. Lanari, F. Pizzo, L. Vaccaro, Green
Chem. 2010, 12, 1301–1305.
[14] Amberlite IRA900F (Amb-F) is a trimethylammonium
fluoride on macroreticular polystyrene resin which is
commercially available from Aldrich as “Fluoride on
polymer support” or as “Fluoride on Amberlyst A-26”.
Commercially available Amb-F is a hygroscopic solid
which contains ca. 20 wt% of water. In general, we
have used water-free Amb-F, obtained by drying the
commercial product under vacuum. A macroreticular
[26] The small amount of ethyl acetate, 2 mL for 20 mmol
of reagents, does not affect the reactivity for the follow-
ing step (cyanide shift).
Adv. Synth. Catal. 0000, 000, 0 – 0
6
ꢂ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
Synthesis of b-Cyano Ketones Promoted by
7
a Heterogeneous Fluoride Catalyst
Adv. Synth. Catal. 2016, 358, 1 – 7
Giacomo Strappaveccia, Tommaso Angelini, Luca Bianchi,
Stefano Santoro, Oriana Piermatti, Daniela Lanari,*
Luigi Vaccaro*
Adv. Synth. Catal. 0000, 000, 0 – 0
7
ꢂ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!