Electrochemically initiated tandem and sequential conjugate addition processes: One-pot synthesis of diverse functionalized isoindolinones

Article abstract of DOI:10.1002/adsc.201200065

A tandem aldol-heterocyclization-rearrangement reaction and one-pot sequential Michael addition allowed a direct access to highly functionalized 3-isoindolinones containing quaternary carbon centers. The desired products are obtained under mild conditions and in short reaction times by galvanostatic electrolysis in a divided cell. A further tandem intramolecular heterocyclization reaction leading to synthetically relevant hemiaminal derivatives has been established with suitable Michael acceptors. Copyright

Full text of DOI:10.1002/adsc.201200065

COMMUNICATIONS
DOI: 10.1002/adsc.201200065
Electrochemically Initiated Tandem and Sequential Conjugate
Addition Processes: One-Pot Synthesis of Diverse Functionalized
Isoindolinones
Pasqualmorica Antico,a Vito Capaccio,a Antonia Di Mola,b Antonio Massa,a,*
and Laura Palombia,*
a
Dipartimento di Chimica e Biologia, Universitꢀ di Salerno, Via Ponte Don Melillo, 84084 Fisciano (Sa), Italy
Fax : (+39)-089-969-603; phone: (+39)-089-969-575; e-mail: amassa@unisa.it or lpalombi@unisa.it
Dipartimento di Scienze Farmaceutiche, Universitꢀ di Salerno, Via Ponte Don Melillo, 84084 Fisciano (Sa), Italy
b
Received: February 1, 2012; Revised: March 9, 2012; Published online: June 5, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200065.
Abstract: A tandem aldol–heterocyclization–rear-
rangement reaction and one-pot sequential Michael
addition allowed a direct access to highly function-
alized 3-isoindolinones containing quaternary
carbon centers. The desired products are obtained
under mild conditions and in short reaction times
by galvanostatic electrolysis in a divided cell. A fur-
ther tandem intramolecular heterocyclization reac-
tion leading to synthetically relevant hemiaminal
derivatives has been established with suitable Mi-
chael acceptors.
On these grounds, some research groups in the
electro-organic area are currently exploring the possi-
bility to perform domino reactions by means of elec-
trochemical activation, so combining virtues and ben-
efits of both strategies in solving specific synthetic
issues.[4]
Hitherto, most of the domino reactions induced in
an electrochemical way are Knoevenagel–Michael
processes that have been successfully exploited in the
synthesis of biologically relevant heterocyclic com-
pounds, such as bis-tetronic acids,[5] bispyrazoles,[6] 2-
amino-4H-chromenes and their derivatives[7] etc.
Recently, inspired by the interesting works of Ram-
strçm et al.,[8] one of the authors and co-workers suc-
cessfully assessed a base-promoted tandem reaction
to directly access 3-functionalized isoindolinone scaf-
folds containing dicarbonyl moieties, by aldol addition
to 2-cyanobenzaldheyde (2-CNC6H4CHO), followed
Keywords: electrosynthesis; hemiaminals; isoindoli-
nones; one-pot Michael addition; tandem reactions
Due to the ever-increasing concern for the environ- by heterocyclization and rearrangement via an aza-
ment and health, the search for new synthetic meth- Michael reaction (Scheme 1).[9]
odologies remains a task of great interest for the or-
ganic chemistry community, especially for the isoindolin
achievement of building block molecules with applica- natural[10] and pharmaceutical products,[11] therefore
tions in biological and medicinal chemistry. straightforward methods to assemble related struc-
As well documented in the literature, the
AHCTUNGTRENNUNG
As well established by several literature reports, tures incorporating suitable functionalities for further
many advantages in terms of sustainability and green molecular processing, are still highly desirable.
chemistry, are offered by domino or tandem[1] reac-
In the light of the above considerations and follow-
tions and one-pot multicomponent[2] processes that ing on from our previous investigations on the galva-
[12]
À
provide valuable synthetic targets while avoiding in- nostatic activation of C H acid compounds, we en-
convenient multistep protocols and tedious purifica- visaged the chance to design an electrochemical ver-
tion of intermediates.
sion of this useful tandem reaction and further specu-
On the other hand, the electrochemical methodolo- lated on the electrocatalytic method for exploring the
gy also stands out as a powerful tool to induce useful possible second reactivity of the isoindolinone skele-
chemical transformations with reduced waste produc- ton with alkylating agents.
tion and improved atom economy thanks to the use
Herein we present the scope and limitations of the
of the practically mass-free electron as reagent or cat- electroreductively-catalyzed tandem reaction of 1,3-
alyst.[3]
dicarbonyl compounds and 2-CNC6H4CHO and a se-
Adv. Synth. Catal. 2012, 354, 1717 – 1724
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1717

Pasqualmorica Antico et al.
COMMUNICATIONS
Scheme 1. Proposed reaction pathway for the base-catalyzed synthesis of isoindolinones.
optimized conditions (Table 1, entry 4), in 87% isolat-
ed yield.
Quite interestingly, with respect to the conventional
chemical method,[9] the electrochemical approach al-
lowed for lower catalyst loading (4% of electricity vs.
100% Et3N) and shorter reaction time (0.75 h vs.
18 h).[13]
With this result in hand, we felt encouraged to ex-
plore the substrate scope for this process, so a series
of symmetrical and unsymmetrical 1,3-dicarbonyl
Scheme 2. Electrochemically induced tandem reaction of 1a.
quential one-pot addition to Michael acceptors lead- compounds (1b–l) was electrolyzed in the presence of
ing to isoindolinone derivatives containing quaternary 2-CNC6H4CHO accordingly to the optimized condi-
carbon centers.
tions reported in Table 1, entry 4 (Scheme 3).
The effectiveness of the electrochemical route was
As showed in Table 2, the scope of this electrocata-
firstly checked using dimethyl malonate (1a) as a ref- lytic reaction may be successfully extended to the use
erence compound (Scheme 2) and performing the of both b-diesters, b-keto esters and b-diketones af-
electrolysis in the presence of 2-CNC6H4CHO under fording the isoindolinone derivatives with very satis-
a variety of conditions as reported in Table 1.
factory yields and complete chemo- and regioselectiv-
Since no conversion of starting materials was ob- ity in almost all the cases.
served by performing the electrolysis in an undivided
Interestingly, excellent conversions of starting ma-
cell (entry 1), the following experiments were carried terials and short reaction times were observed with
out in the cathodic side of a U-shaped two-compart- the class of malonates, regardless of the steric hin-
ments cell fitted with a glass (G-4) separator septum; drance of the two alkyl substituents (1b–e); converse-
this strategy proved to be successful as the tandem re- ly, significant drops in reactivity or selectivity were
action efficiently took place affording 2a, under the noticed when electrogenerated enolates arising from
Table 1. Electrochemically induced tandem reaction of 2-CNC6H4CHO and 1a.
Entry
Electrolysis
method[a]
Current density
D [mA/cm2]
Current quantity
[F/mmol of 1a]
Reaction
time [h]
Yield [%]
of 3a[b]
1
A
B
B
B
2
2
2
5
0.1
24
–
2
0.08
0.08
0.04
0.5
0.5
0.75
76
83
87
3[c]
4[c]
[a]
Method A: a solution of 1a (1 mmol) in CH3CN/TEABF4 (3 mL/0.1 mmol) was electrolyzed in an undivided cell, at room
temperature, using Pt anode and cathode, under galvanostatic conditions. At the end of electrolysis 2-CNC6H4CHO was
added and the reaction prolonged for 24 h. Method B: 1a (1 mmol) in CH3CN/TEABF4 (3 mL/0.08 mmol (entries 2 and 3)
or 0.04 mmol (entry 4)) was electrolyzed at the cathodic compartment of a U-divided cell, Pt anode and cathode, under
galvanostatic conditions. 2-CNC6H4CHO (1 mmol) was added after the potential was switched off.
Yields refer to chromatographically pure 2a
[b]
[c]
Electrolyses were performed in the presence of 2-CNC6H4CHO (1 mmol).
1718
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 1717 – 1724

Electrochemically Initiated Tandem and Sequential Conjugate Addition Processes
highly enolizable active methylene compounds (1f–h)
or b-keto esters (1i–l) were used as nucleophiles.
However, in these cases, convenient increases in re-
action rate and yield could be achieved upon per-
forming the electrolysis under neat conditions
(Table 2, entries 7, 10–13).
By comparing selected data collected for 1d, 1f and
1h with the those obtained using the conventional
base-promoted method we could further remark sev-
eral differences of the electro-induced method with
respect to the chemical one. Substrate 1d, for exam-
ple, which displays very high reactivity and selectivity
under electrochemical conditions (Table 2, entry 3),
suffered a strong dependence on the steric hindrance
of the ester substituents when standard chemical con-
ditions were used: in such a case, 1d showed a very
low conversion (<15%) after long reaction times
(18 h). Again, while the attempt to obtain isoindolin-
AHCTUNGTRENNUNG
Scheme 3. Electrochemically induced tandem reaction of
1b–l.
Table 2. Electrochemically induced tandem reaction of 2-CNC6H4CHO and 1b–l.
Entry Substrate
Product
Reaction
time [h]
Yield
[%][a]
dr[b]
Et3N (stoich.)
Reaction Yield [%]
1
time
(dr)
1
1b
1c
1d
1e
1f
2b
0.5
0.5
0.5
2.5
1
73
–
–
–
–
–
2
2c
93
3[c]
2d
98
18 h
18 h
18 h
<15
dec.
64
4
2e
65
5
2f (3f)
59 (20)[d]
6
1g
1g
2g
2g
21
7
52
65
–
–
7[e,f]
8
1h
2h (4h)
1
– (84)[g]
–
Adv. Synth. Catal. 2012, 354, 1717 – 1724
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1719

Pasqualmorica Antico et al.
Et3N (stoich.)
COMMUNICATIONS
Table 2. (Continued)
Entry Substrate
Product
Reaction
time [h]
Yield
[%][a]
dr[b]
1
Reaction
time
Yield [%]
(dr)
9
1i
1i
1j
2i
2i
2j
12
5
70
74
71
50:50
50:50
50:50
10[e]
11[e]
5
12[e]
1k
1l
2k
2l
4
1
84
53:47
13[e]
92
70:30 (85:15)[h] 18 h
87 (60:40)
[a]
Yields refer to chromatographically pure products.
[b]
[c]
1
Diastereoisomeric ratios have been calculated on the ground of H NMR spectra on crude products.
This reaction performed on 3 mmol scale of 2-CNC6H4CHO using D=15 mA/cm2 led to the product 2d in 95% isolated
yield.
[d]
[e]
[f]
Value in parentheses refers to isolated product 3f.
Electrolysis was performed using solvent-free conditions: see Experimental Section for details.
This reaction was performed on a 3-mmol scale of 2-CNC6H4CHO using D=15 mA/cm2 and led to the product 2 in 67%
isolated yield.
Value in parentheses refers to isolated product 4h (isolated yield calculated with respect to 1h).
Value in parenthesis refers to dr after recrystallization.
[g]
[h]
materials, the electrochemical route allowed us to
achieve the desired product (Table 2, entry 5) in rea-
sonable yield. Conversely, the electrolysis of 1,3-cyclo-
hexanedione 1h in the presence of 2-CNC6H4CHO
did not afford isoindolinone 2h in appreciable yield,
rather leading to the product 4h as a result of an elec-
tro-initiated cascade Knoevenagel–Michael reaction
process.
Given the presence of several adjoined functionali-
ties and reactive sites, the isoindolinone derivatives of
type 2 also intrigued us as potential building blocks
for the quick assembly of heterocyclic frameworks
with enhanced molecular diversity.
Taking into account our preceding investigations on
the electro-catalyzed Michael and related addition re-
Scheme 4. Electrochemically induced Michael addition of 5a
actions,[14] several isoindolinone derivatives 2 were to isoindolinone derivatives 2.
submitted to electrolysis under the conditions report-
ed in Scheme 3 and tested in the conjugate addition
to tert-butyl acrylate 5a – chosen as a model Michael of the Michael adducts 6, with good to excellent
acceptor.
yields, in short reaction times and under mild condi-
As indicated in Scheme 4, we were pleased to ob- tions for almost all the substrates.
serve that the process turned out completely chemo-
Indeed, as already noted for the tandem process,
and regioselective, leading to the exclusive formation the moderate reactivity of the isoindolinone deriva-
1720
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 1717 – 1724

Electrochemically Initiated Tandem and Sequential Conjugate Addition Processes
reoselective as the product 6la was achieved with a dr
>95:5, irrespective of the diastereomeric ratio of the
starting material 2l.[16]
With these results in hand, we focused our next ef-
forts to ascertain whether both these cathodically-ini-
tiated processes could be paired in a one-pot proce-
dure directly leading to isoindolinone derivatives 6.
To this end, active methylene compounds 1a, d
were electrolyzed in the presence of 2-CNC6H4CHO
and Michael acceptors 5a–c were subsequently added
to the cathodic compartment after 0.08 F/mol of elec-
tricity had been passed (Scheme 5).
Scheme 5. Electrochemically initiated tandem reaction and
one-pot sequential Michael addition.
tive 2g confirmed the reduced nucleophilic ability of
To our delight, highly functionalized isoindolinone
electro-generated enolates arising from highly enoliz- derivatives 6 containing quaternary carbon centers
able active methylene compounds.[15]
were smoothly achieved as exclusive reaction prod-
Notably, concerning the stereochemical aspects, the ucts in 67–85% overall yields (Table 3), with no signif-
electro-catalyzed process proved to be highly diaste- icant loss in selectivity with respect to the above two-
Table 3. Electrochemically-induced isoindolinones synthesis and sequential one-pot Michael addition to 5a–c.
Entry
Substrate 1
5
6
Reaction time [h][a]
Yield[b]
85%
1[c]
1a
5a
6aa
6ab
6ac
18
2[c]
1a
1a
5b
5c
5
2
83%
67%
3[c]
4[d]
1d
1d
1d
5a
5b
5c
6da
6db
6dc
1
2
2
91%
75%
76%
5[d]
6[d]
[a]
Reaction time refers to the overall process of synthesis of 6.
Yields refer to chromatographically pure products.
Current density: 4 mA/cm2.
[b]
[c]
[d]
Current density: 2 mA/cm2.
Adv. Synth. Catal. 2012, 354, 1717 – 1724
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1721

Pasqualmorica Antico et al.
COMMUNICATIONS
À
In conclusion, the electrochemical activation of C
H acid compounds proved to be an efficient, selective
and convenient strategy to accomplish the synthesis
of 3-substitued isoindolinones via tandem reactions
with 2-CNC6H4CHO. The products are obtained in
good to high yields, under mild conditions and short
reaction times, by constant current electrolysis, using
a catalytic amount of electricity. Compared with the
conventional base-catalyzed procedure, the electro-
chemical method can, in turn, be considered as
a viable alternative with promising features of versa-
tility or even the only route to obtain the desired
products.
A further study on the second reactivity of these
valuable compounds successfully proved the effective-
ness of the electrochemical activation to also promote
a sequential one-pot conjugate addition to activated
olefins providing highly functionalized isoindolinones
Scheme 6. Electrochemically initiated one-pot access to tri-
cyclic hemiaminal derivatives.
step synthesis. In such a way, that is, bypassing the iso- containing quaternary carbon centers. Furthermore,
lation of isoindolinone intermediates 2, an important the direct one-pot access to tricyclic hemiaminal de-
improvement in terms of simplicity, reduction of rivatives 7 in highly diastereoselective fashion has
waste disposal and solvent/electrolyte amount has been demonstrated as a consequence of an electroca-
been demonstrated.
talytic process constituted by two-sequential tandem
A further useful finding on this subject was dis- reactions.
closed by us using an appropriate dielectrophile as
the acceptor. As is well-known, in the presence of
amidomalonates, a,b-unsaturated aldehydes display Experimental Section
a sequential reactivity which gives access to cyclic
hemiaminals, an important class of heterocyclic com- General Remarks
pounds with a wide range of synthetic applications.[17]
Reaction times and conditions are detailed in the respective
A similar tricyclic skeleton is found, for example, in
indolizidine-based biologically active compounds.[18]
In order to assess whether a similar reactivity could
be found with isoindolinone derivatives, acrolein was
added to the electrolyzed solutions of 1 and 2-
CNC6H4CHO. As shown in Scheme 6, jointly to the
1,2-addition, we were pleased to observe a further
cyclization involving the amidic group of the isoindo-
linone moiety to give the unprecedented tricyclic iso-
indolinone derivatives 7 with the hemiaminal func-
tionality, a feature that can open the way to new in-
teresting synthetic investigations. As expected this
finding was achieved as the overall goal of a one-pot
process of two sequential electro-induced tandem re-
actions.
tables. Constant current electrolyses were performed using
using a Hewlett–Packard DC Power Supply Model E3612A
.The experiments were carried out in a U-divided glass cell
separated through a porous G-4 glass plug. Platinum spirals
(apparent area 2.5 or 5 cm2) were used as anode and cath-
ode. In all the experiments the anolyte was constituted by
a solution of TEABF4 0.1M in CH3CN.
Typical Experimental Procedure for
Electrochemically Induced Synthesis of
Isoindolinones in CH3CN (2a–f)
A solution of 1 (1.1 mmol) and 2-CNC6H4CHO (1.0 mmol)
in CH3CN/TEABF4 (0.6 mL/0.04 mmol) was electrolyzed at
room temperature, under galvanostatic conditions (current
density and quantity as reported in Table 2). At the end of
Remarkably, in all the cases examined, products 7 the electrolysis, the reaction was prolonged at room temper-
ature under magnetic stirring until TLC disappearance of 2-
CNC6H4CHO. The mixture was then concentrated under
vacuum and purified by silica gel chromatography (CH3Cl:
AcEt=9:1).
were obtained with a high level of diastereoisomeric
purity. Preliminary 2D NMR experiments (ROESY
and NOESY) showed cross-peaks between the hydro-
gen atom on the hydroxy functionality and the one on
the isoindolinone moiety so indicating that, in the
most abundant diastereoisomer, the asymmetric
atoms should have the configurations (RR, SS) (see
Supporting Information for details). Moreover, Spar-
tan calculations indicated that the diastereoisomer
(RR, SS) form is ca. 4 kcal/mol more stable than the
other (RS, SR) form.
Typical Experimental Procedure for Electrohemically
Induced Synthesis of Isoindolinones under Solvent-
Free Conditions (2g–l)
A solution of 1 (0.5 mL), 2-CNC6H4CHO (1.0 mmol) and
TEABF4 (0.05 mmol) was electrolyzed at room temperature,
under galvanostatic conditions (current density and quantity
1722
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 1717 – 1724

Electrochemically Initiated Tandem and Sequential Conjugate Addition Processes
as reported in Table 1). At the end of the electrolysis, the re-
action was prolonged at room temperature under magnetic
stirring until TLC disappearance of 2-CNC6H4CHO. The
mixture was then concentrated under vacuum and purified
as reported above.
c) B. Jiang, T. Rajale, W. Wever, S.-J. Tu, G. Li, Chem.
Asian J. 2010, 5, 2318–2335; d) S. Fustero, M. Sanchez-
Rosello, C. del Pozo, Pure Appl. Chem. 2010, 82, 669–
677; e) Y.-F. Han, M. Xia, Curr. Org. Chem. 2010, 14,
379–413.
[3] For recent reviews, see: a) B. A. Frontana-Uribe, R. D.
Little, J. G. Ibanez, A. Palma, R. Vasquez-Medrano,
Green Chem. 2010, 12, 2099–2119; b) M. Okimoto, Y.
Takahashi, Curr. Org. Synth. 2004, 1, 233–251; c) Y. N.
Ogibin, M. N. Elinson, G. I. Nikishin, Russ. Chem. Rev.
2009, 78, 89–140.
[4] a) S. R. Nambiar, K. P. Prathish, G. Karthik, T. P. Rao,
Biosens. Bioelectron. 2011, 26, 3920–3926; b) M. N. Eli-
nson, A. S. Dorofeev, S. K. Feducovich, R. F. Nasybul-
lin, S. V. Gorbunov, G. I. Nikishin, Electrochem.
Commun. 2006, 8, 1567–1571; c) L. Zhang, Z. Zha, Z.
Zhang, L. Yunfeng, Z. Wang, Chem. Commun. 2010,
46, 7196–7198.
Typical Experimental Procedure for
Electrochemically Initiated Tandem Reaction and
One-Pot Sequential Michael Addition (6)
A solution of 1 (1.0 mmol) and 2-CNC6H4CHO (1.0 mmol)
in CH3CN/TEABF4 (0.6 mL/0.08 mmol) was electrolyzed at
room temperature, under galvanostatic conditions (current
density and quantity as reported in Table 3). At the end of
the electrolysis, the reaction was prolonged at room temper-
ature under magnetic stirring until TLC disappearance of 2-
CNC6H4CHO; The Michael acceptor 5a–c (1.05 mmol) was
subsequently added. The mixture was kept under stirring up
to completion of the reaction (TLC disappearance of isoin-
dolinone intermediate), concentrated under vacuum and pu-
rified as reported above.
[5] Z.-Z. Zhang, N.-T. Zhang, L.-M. Hu, Z.-Q. Wei, C.-C.
Zeng, R.-G. Zhong, Y. B. Shec, RSC Adv. 2011, 1,
1383–1388.
[6] M. N. Elinson, A. S. Dorofeev, R. F. Nasybullin, G. I.
Nikishin, Synthesis 2008, 1933–1937.
[7] M. N. Elinson, A. S. Dorofeev, F. M. Miloserdov, A. I.
Ilovaisky, S. K. Feducovich, P. A. Belyakov, G. I. Ni-
kishin, Adv. Synth. Catal. 2008, 350, 591–601.
Typical Experimental Procedure for
Electrochemically Initiated Single-Step Synthesis of
Hemiaminal Derivatives (7)
A solution of 1 (1.0 mmol) and 2-CNC6H4CHO (1.0 mmol)
in CH3CN/TEABF4 (0.6 mL/0.08 mmol) was electrolyzed at
room temperature, under galvanostatic conditions (current
density and quantity as reported in Table 3). At the end of
the electrolysis, the reaction was prolonged at room temper-
ature under magnetic stirring until TLC disappearance of 2-
CNC6H4CHO; acrolein (1.2 mmol) was subsequently added.
The mixture was kept under stirring up to completion of the
reaction (TLC disappearance of isoindolinone intermedi-
ate), concentrated under vacuum and purified as reported
above.
[8] a) M. Angelin, M. Rahm, A. Fischer, T. Brinck, O.
Ramstrom, J. Org. Chem. 2010, 75, 5882–5887; b) M.
Angelin, P. Vongvilai, A. Fischer, O. Ramstrom, Chem.
Commun. 2008, 768–770; c) M. Angelin, A. Fischer, O.
Ramstrom, J. Org. Chem. 2008, 73, 3593–3595.
[9] V. More, A. Di Mola, M. Perillo, P. De Capraris, R.
Filosa, A. Pedulo, A. Massa, Synthesis 2011, 3027–3031.
[10] For some naturally occurring substances see: a) V. Fa-
jardo, V. Elango, B. K. Cassels, M. Shamma, Tetrahe-
dron Lett. 1982, 23, 39–42; b) H. A. Priestap, Phyto-
chemistry 1985, 24, 848–852; c) J.-M. Ferland, C. A. De-
merson, L. G. Humber, Can. J. Chem. 1985, 63, 361–
365.
[11] a) Z.-P. Zhuang, M.-P. Kung, M. Mu, H. F. Kung, J.
Med. Chem. 1998, 41, 157–168; b) I. Takahashi, T. Ka-
wakami, E. Hirano, H. Yokota, H. Kitajima, Synlett
1996, 353–355; c) I. Pendrak, S. Barney, R. Wittrock,
D. M. Lambert, W. D. Kingsbury, J. Org. Chem. 1994,
59, 2623–2625; d) E. De Clercq, J. Med. Chem. 1995,
38, 2491–2517; e) F. Pin, S. Comesse, M. Sanselme, A. J.
Daiech, J. Org. Chem. 2008, 73, 1975–1977; f) J. S.
Yadav, B. V. S. Reddy, Tetrahedron Lett. 2002, 43, 1905–
1907.
Acknowledgements
This work was supported by research grants from MIUR.
The authors are very grateful to Dr. Patrizia Oliva for techni-
cal assistance in 2D NMR experiments.
References
[12] a) L. Palombi, Catal. Commun. 2011, 12, 485–488; b) L.
Palombi, M. Feroci, M. Orsini, A. Inesi, Chem.
Commun. 2004, 1846–1847; c) L. Palombi, M. Feroci,
M. Orsini, L. Rossi, A. Inesi, Tetrahedron Lett. 2002,
43, 2881–2884.
[13] It has to be noted that, using a sub-stoichiometric
amount of Et3N (20%), only 40% of conversion of
starting materials is observed after 24 h (unpublished
results).
[14] a) M. Feroci, M. Orsini, L. Palombi, A. Inesi, Green
Chem. 2007, 9, 323–325; b) T. Caruso, M. Feroci, A.
Inesi, M. Orsini, A. Scettri, L. Palombi, Adv. Synth.
Catal. 2006, 348, 1942–1947; c) L. Palombi, M. Feroci,
[1] For selected reviews and discussion on the taxonomy of
one-pot multistep chemical elaborations, see: a) D. E.
Fogg, Eduardo N. dos Santos, Coord. Chem. Rev. 2004,
248, 2365–2379; b) A. J. McCarroll, J. C. Walton,
Angew. Chem. 2001, 113, 2282–2307; Angew. Chem. Int.
Ed. 2001, 40, 2224–2248; c) S. F. Mayer, W. Kroutil, K.
Faber, Chem. Soc. Rev. 2001, 30, 332–339; d) L. F.
Tietze, Chem. Rev. 1996, 96, 115–136.
[2] For selected recent reviews on multicomponent reac-
tions, see: a) E. Ruijter, R. Scheffelaar, R. V. A. Orru,
Angew. Chem. 2011, 123, 6358–6371; Angew. Chem. Int.
Ed. 2011, 50, 6234–6246; b) I. Akritopoulou-Zanze,
S. W. Djuric, Top. Heterocycl. Chem. 2010, 25, 231–287;
Adv. Synth. Catal. 2012, 354, 1717 – 1724
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1723

Pasqualmorica Antico et al.
COMMUNICATIONS
M. Orsini, A. Inesi, Tetrahedron: Asymmetry 2002, 13,
2311–2316; d) L. Palombi, M. Feroci, M. Orsini, L.
Rossi, A. Inesi, Tetrahedron: Asymmetry 2001, 12,
2331–2335.
A. Moyano, R. Rios, J. Vesely, Tetrahedron 2011, 67,
8942–8950; c) L. You, R. S. Long, V. M. Lynch, E. V.
Anslyn, Chem. Eur. J. 2011, 17, 11017–11023; d) L.
Huck, J. F. Gonzalez, E. de La Cuesta, J. C. Menendez,
C. Avendano, Org. Biomol. Chem. 2011, 9, 6271–6277;
e) S. Pathak, A. Kundu, A. Pramanik, Tetrahedron Lett.
2011, 52, 5180–5183; f) O. S. Miljanic, Nat. Chem. 2011,
3, 909–991.
[15] For a recent report on the nucleophilicity scales, see:
H. Mayr, A. R. Ofial, J. Phys. Org. Chem. 2008, 21,
584–595.
1
[16] The dr value has been determined by H NMR on the
crude product (see the Supporting Information).
[17] a) J. Franzꢂn, A. Fisher, Angew. Chem. 2009, 121, 801–
805; Angew. Chem. Int. Ed. 2009, 48, 787–791; b) S. Cꢃ-
halovꢀ, G. Valero, J. Schimer, M. Humpl, M. Dracꢃnsky,
[18] A. Mertens, J H. Zilch, B. Kdnigj, W. Schuer, T. Poll W.
Kampe, H. Seide, U. Leser, H. Leinert, J. Med. Chem.
1993, 36, 2526–2635.
1724
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 1717 – 1724