A new, easy access to the 6-aminoperhydro-1,4-diazepine scaffold under ultrasound and microwave irradiation

Article abstract of DOI:10.1055/s-2008-1067035

A novel, efficient, and rapid synthesis of the 6-aminoperhydro-1,4- diazepine scaffold is reported. It was promoted by microwave or sequential ultrasound/microwave irradiation under solvent-free conditions or in solution. Protected ethylenediamine derivatives and N-Boc-serinol dimesylate underwent rapid cyclization to give 6-aminoperhydro-1,4-diazepine derivatives in excellent yields and with high selectivity, whereas the same reaction failed or gave negligible yields under conventional heating. Cesium or potassium ions catalyzed the ring closure by coordinating the sulfon-amide groups. All relevant work reported to date in the literature mostly concern about the syntheses of either 1H-tetrahydro-1,4-diazepine-2,5-dione or substituted 1,4-benzodiazepines, while the few published procedures for the preparation of 6-aminoperhydro-1,4- diazepines involved several steps, required long reaction times and afforded low yields. By the present method, access to 6-aminoperhydro-1,4-diazepines becomes much easier and faster.

Full text of DOI:10.1055/s-2008-1067035

PAPER
1879
A New, Easy Access to the 6-Aminoperhydro-1,4-diazepine Scaffold under
Ultrasound and Microwave Irradiation
6
-Aminoperhydro-
l
1,4-dia
e
zepines ssandro Barge,a Silvia Füzerová,b Dharita Upadhyaya,a Davide Garella,a Silvio Aime,b Lorenzo Tei,c
Giancarlo Cravotto*a
a
Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10235 Torino, Italy
Fax +39(011)6707687; E-mail: giancarlo.cravotto@unito.it
Dipartimento di Chimica IFM, Università di Torino, Via P. Giuria 7, 10125 Torino, Italy
Dipartimento di Scienze dell’Ambiente e della Vita, Università del Piemonte Orientale, Via Bellini 25/G, 25100 Alessandria, Italy
b
c
Received 11 December 2007; revised 7 March 2008
particular, the increasing need to provide finely tuned
Abstract: A novel, efficient, and rapid synthesis of the 6-amino-
macrocycles for medicinal chemistry applications makes
it desirable to develop novel and convenient synthetic pro-
cedures for their preparation.
perhydro-1,4-diazepine scaffold is reported. It was promoted by mi-
crowave or sequential ultrasound/microwave irradiation under
solvent-free conditions or in solution. Protected ethylenediamine
derivatives and N-Boc-serinol dimesylate underwent rapid cycliza-
tion to give 6-aminoperhydro-1,4-diazepine derivatives in excellent
yields and with high selectivity, whereas the same reaction failed or
gave negligible yields under conventional heating. Cesium or potas-
sium ions catalyzed the ring closure by coordinating the sulfon-
amide groups. All relevant work reported to date in the literature
mostly concern about the syntheses of either 1H-tetrahydro-1,4-di-
azepine-2,5-dione or substituted 1,4-benzodiazepines, while the
few published procedures for the preparation of 6-aminoperhydro-
1,4-diazepines involved several steps, required long reaction times
and afforded low yields. By the present method, access to 6-ami-
noperhydro-1,4-diazepines becomes much easier and faster.
It is well known that seven-membered heterocyclic com-
pounds lacking a fused aromatic nucleus are difficult to
synthesize.11 Although the literature reports several syn-
thesis of tetrahydro-1,4-diazepine-2,5-dione and substi-
tuted 1,4-benzodiazepines, we found only three references
describing the synthesis of parent 6-aminoperhydro-1,4-
diazepine, a compound that could be used as an interesting
core for the synthesis of potential drugs. A synthetic pro-
cedure has been reported for (R)-6-amino-1-ethyl-4-meth-
ylperhydro-1,4-diazepine, which is the amine moiety of
AS-8112, a novel and potent dopamine (D2 and D3) and
5-HT H3 receptor antagonist, commonly used as an anti-
emetic agent.12 It involved several steps, required a long
reaction time, and afforded extremely low yields of the
desired product. Another paper dealt with a solid-phase
synthesis of the hitherto unreported 3,6-disubstituted 1H-
tetrahydro-1,4-diazepine-2,5-dione by a microwave-
assisted Miller cyclization.13 More recently, the synthesis
and coordination properties of 6-aminoperhydro-1,4-
diazepine14 were described. This route, however, is
lengthy (six steps) and involves the handling of potential-
ly explosive azides. After taking stock of published work,
we decided to develop a general and versatile access to
this class of heterocycles. Relying on our experience in
synthetic procedures involving power ultrasound (US)15
and microwaves (MW),16 alone or combined,17 we decid-
ed to apply them to the synthesis of 6-aminoperhydro-1,4-
diazepine derivatives by cyclization of a protected ethyl-
enediamine derivative with N-Boc-serinol dimesylate in
the presence of alkali metal carbonate (K2CO3 or
Cs2CO3). Thus, aiming to synthesize the 6-aminoperhy-
dro-1,4-diazepine scaffold, we explored four different re-
action conditions: 1) heating in an oil bath under vigorous
magnetic stirring; 2) intense, short sonication (3 min, 120
W) using a probe equipped with a titanium horn, followed
by MW irradiation in an open vessel fitted with a condens-
er (1 h, 350 W, the flask being cooled by circulation of re-
frigerated fluid) (this sequential US/MW irradiation was
repeated 2–3 times); 3) intense, short sonication (3 min,
120 W), followed by MW irradiation in a pressure-resis-
Key words: heterocycles, synthesis, catalysis, cyclizations,
ligands, ring closure
The synthesis of heterocycles can be regarded as an im-
portant factor in the supply of novel drugs, because a het-
erocyclic ring constitutes an essential feature of many
biologically active compounds. Seven-membered hetero-
cycles with two hetero atoms in 1,4 position provide inter-
esting scaffolds for combinatorial chemistry because of
their unique pharmacological activity on the central ner-
vous system – widely popularized in the case of 1,4-ben-
zodiazepines.1 Several substituted analogues of 6-
aminoperhydro-1,4-diazepine are well-known serotonin
and dopamine receptor antagonists.2 In recent years a va-
riety of 1,4-diazepines have been reported as peptidomi-
metic scaffolds,3 as anti-HIV agents,4 as inhibitors of
peptidoglycan synthesis5 and platelet aggregation,6 as in-
hibitors of protein kinase7 and matrix metalloproteinase
(MMPs),8 as 5-HTH3 (5-hydroxytryptamine) receptor an-
tagonists,9 and otherwise as biological tools.10 The search
for efficient peptidomimetics has led to the synthesis of
numerous peptides containing a ring system that acts as a
conformationally constrained core. The identification of
novel ligands having high affinities for various receptors
and enzymes still remains a major goal in biochemistry. In
SYNTHESIS 2008, No. 12, pp 1879–1882
x
x.
x
x
.
2
0
0
8
Advanced online publication: 29.04.2008
DOI: 10.1055/s-2008-1067035; Art ID: T19307SS
© Georg Thieme Verlag Stuttgart · New York

1880
A. Barge et al.
PAPER
tant closed vessel (200 W, 2 h, 150 °C); and 4) solid re- closed vessel (Table 1, entry 3) and under solvent-free
agents and base, after being finely mixed in a mortar, were conditions (Table 1, entry 10).
directly irradiated with MW (4 times for 5 min, 600 W,
Aiming to optimize the procedure, we compared the ef-
with interposed pauses of 1 min). A summary of the re-
fects of different alkali metal carbonates and two organic
sults is shown in Scheme 1 and Table 1.
bases; conditions were according to protocol P3 of
Table 1. Cesium carbonate (Table 2, entry 3) gave the best
R
Boc
O
result, with an overall yield of 93%, immediately followed
by potassium carbonate (75%). Lithium carbonate
(Table 2, entry 1) only yielded by-products, probably be-
cause of concurrent polymerization processes; with trieth-
ylamine and DBU no reaction occurred (Table 2, entries 6
and 7). The addition of a phase-transfer catalyst (tetra-
butylammonium bromide, TBAB Table 2, entry 4) to
Cs2CO3 did not increase the yield nor did it change the
protected/unprotected primary amine ratio. A similar re-
sult was obtained when Cs2CO3 and triethylamine were
used together (Table 2, entry 5). These findings indicate
that the nature of the alkali metal ion significantly affects
the cyclization, the most active one being Cs; Li is proba-
bly too small to promote the reaction.
HN
HN
Table 1
conditions
Ms
O
Ms
Ts
N
N
Ts
Cs2CO3
+
Ts NH HN Ts
R = Boc
R = H
1a
2a
Scheme 1 Synthesis of 6-amino-1,4-ditosylperhydro-1,4-diazepine
An essential precondition for MW to exhibit its promoting
effect was a very high degree of dispersion of solid alkali
carbonate, as was effected by US. We also carried out the
reaction by omitting prior sonication of the reaction mix-
ture. In this case, lower conversions and consequently
lower yields of desired product were obtained. No conver-
sion was observed when only ultrasound was used.
We surmise that sulfonate groups (ethylenediamine sul-
fonamide and N-Boc-serinol dimesylate) are coordinated
by an alkali metal ion, which holds the two moieties close
to each other and brings them in a favorable position for
cyclization to occur. After ring closure and consequent
mesylate removal, the alkali ion, coordinated by the sul-
fonate and Boc carbonyl groups, behaves as a Lewis acid
in promoting the cleavage of the Boc group (Figure 1).
This hypothesis is supported by crude mechanic and dy-
namic calculations which highlight the role of Cs ions in
pulling together the ethylenediamine and serinol moieties,
also indicating that after cyclization, the Cs ion binds to
the carbamate oxygen.
It is a well-established fact that MW speeds up nucleo-
philic substitutions by rapidly and efficiently heating the
reaction mixture and/or stabilizing their more polar tran-
sition states.16 Out of a variety of solvents studied for our
cyclization, DMF and acetonitrile performed best; the lat-
ter was chosen because it can be easily removed during
the workup. We found that all MW-assisted reactions,
whether neat or in solution, gave the Boc-free heterocycle
(except entry 2 in Table 1) as main product in very short
reaction times and excellent isolated yields. Best results
were achieved with acetonitrile in a pressure-resistant
Table 1 A Comparative Study of Conventional versus US/MW and MW-Assisted Cyclization
Entry
Methoda
Solvent
Time
(h)
Temp
(°C)
Ratio
Overall
yield (%)
1/2 b
1
2
P1
P2
P3
P1
P2
P3
P2
P3
P4
P4
MeCN
120
3
reflux
reflux
150
110
110
150
70
5:0
60:0
9:84
19:0
14:62
3:87
0:5
5
60
93
19
76
90
5
MeCN
3
MeCN
2
4
DMF
5
5
DMF
3
6
DMF
2
7
1,4-dioxane
1,4-dioxane
solvent-free
solvent-free, Al2O3
v3
2
8
150
77
30:5
13:74
7:82
35
87
89
9
0.3
0.3
10
71
a Reaction conditions: P1: heating in an oil bath under magnetic stirring; P2: sonication (120 W, 3 min) followed by MW irradiation (350 W,
1 h) in a cooled reactor. This cycle was repeated 2–3 times; P3: sonication (120 W, 3 min) followed by MW irradiation in a pressure-resistant
closed vessel (150 °C, 2 h, 200 W); P4: all reagents were intimately mixed in a mortar, then irradiated with MW (600 W) for 5 min. The irra-
diation was repeated 4 times, with interposed pauses of 1 min.
b 1: 6-Boc-amino-1,4-diazepine; 2: 6-amino-1,4-diazepine.
Synthesis 2008, No. 12, 1879–1882 © Thieme Stuttgart · New York

PAPER
6-Aminoperhydro-1,4-diazepines
1881
materials can be recovered quantitatively. The same result
was observed with N,N¢-dibenzylethylenediamine, in
which no oxygen is available for metal coordination.
Table 2 Effects of Various Bases on MW/US-Assisted Cyclization
of Ditosylethylenediamine with N-Boc-serinol Dimesylatea
Entry Base
Ratio
Conversion Yield
1/2b
(%)
90
75
93
93
91
0
(%)
To conclude, we have developed two novel, easy, and
highly efficient protocols for the synthesis of the 6-ami-
noperhydro-1,4-diazepine scaffold using Cs2CO3 (or al-
ternatively K2CO3) as a base. One is a solvent-free, MW-
assisted protocol; the other employs US/MW irradiation
in acetonitrile. Both procedures afforded the desired het-
erocycle in high yield, without any by-product, whereas
the same reaction failed when carried out under conven-
tional conditions. Advantages of the method are atom
economy, a clean reaction in one step with no side prod-
ucts, and good selectivity for the desired heterocycle.
1
3
3
4
5
6
7
Li2CO3
0:0
0
K2CO3
6:69
9:84
6:87
5:86
0:0
75
93
93
91
0
Cs2CO3
Cs2CO3, TBAB
Cs2CO3, Et3N
Et3N
DBU
0:0
0
0
a In MeCN (closed vessel, 150 °C for 2 h).
b 1: 6-Boc-amino-1,4-diazepine; 2: 6-amino-1,4-diazepine.
All chemicals were purchased either from Sigma–Aldrich Co. or
Lancaster Synthesis GmbH and were used without purification un-
less otherwise stated. NMR spectra were recorded on a Bruker
Avance 300 spectrometer (operating at 7 Tesla). ESI mass spectra
were recorded on a Waters Micromass ZQ apparatus. MW-promot-
ed reactions were carried out in a MicroSYNTH Milestone oven.
The sonochemical apparatus used in the present work was devel-
oped in the authors’ laboratory18 in collaboration with Danacameri-
ni (Torino, Italy).
Cyclization of N,N¢-Ditosylethylenediamine with N-Boc-serinol
Dismesylate
Under Conventional Conditions: N,N¢-Ditosylethylenediamine
(367 mg, 1 mmol) and N-Boc-serinol dimesylate (315 mg, 1 mmol)
were dissolved in the appropriate solvent (50 mL, see Table 1), then
solid Cs2CO3 (3.26 g, 10 mmol) was added. The mixture was stirred
at the temperatures indicated in Table 1, under N2; reaction times
are also listed in Table 1. Finally the solvent was removed under re-
duced pressure and the crude product purified by silica-gel column
chromatography (eluent: hexane–EtOAc, 1:1). The pure product 1
was obtained as a white solid (yields are reported in Table 1).
Figure 1 Coordination of cesium ions to sulfonate (1a) and Boc car-
bonyl groups (1b)
Boc
HN
R
HN
MeCN, Cs2CO3
))) (120 W), 3 min
Ms
X
O
O
Ms
X
+
X
N
N
X
MW (closed vessel),
150 °C, 2 h
Sequential US/MW-Promoted Cyclization (Open Vessel): N,N¢-Di-
tosylethylenediamine (400 mg, 1.09 mmol), N-Boc-serinol dimesy-
late (343 mg, 1.09 mmol), the base Cs2CO3 or K2CO3 (10 mmol)
and DMF (50 mL) were mixed in a 250 mL round-bottomed flask.
The mixture was sonicated for 3 min at 120 W, then placed in MW
oven and irradiated for 1 h at 350 W, the flask being cooled by cir-
culation of refrigerated fluid. The reacted mixture was filtered and
the filtrate was evaporated under reduced pressure to give a crude
oil. The pure crystalline product was obtained as previously de-
scribed.
NH HN
1a R = Boc, X = Ts
1b R = Boc, X = p-Ns
2a R = H, X = Ts
2b R = H, X = p-Ns
for X = Ts, p-Ns,
(no reaction with X = o-Ns and Bz)
Scheme 2 Synthesis of different N,N¢-disubstituted 6-aminoperhy-
dro-1,4-diazepines
In order to evaluate this hypothesis, we replaced the tosyl
groups on the ethylenediamine precursor with either o- or
p-nosyl or benzyl groups, and reacted each of the three de-
rivatives with Boc-serinol dimesylate (Scheme 2). We
found that with p-nosylate, the heterocycle was obtained
in good overall yield (60%, ratio 1/2 = 10:50), whereas
the o-nosyl and benzyl derivatives did not react at all.
These results are fully consistent with our hypothesis. In
the o-nosyl derivative, a nitro group stands in the position
ortho to the sulfonate; thus the alkali metal ion, being co-
ordinated by both the nitro and sulfonate oxygen atoms,
would be kept away from the mesyl group, and so its tem-
plate effect would be nil. Further, the presence of bulky
substituent at the ortho position (o-nosyl groups) does not
favor the coordination of Cs metal ions to sulfonate
groups. As a result, there is no reaction and both starting
Sequential US/MW-Promoted Cyclization (Closed Vessel): N,N¢-
Ditosylethylenediamine (400 mg, 1.09 mmol), N-Boc-serinol dime-
sylate (343 mg, 1.09 mmol), the base Cs2CO3 or K2CO3 (10 mmol),
and the appropriate solvent (50 mL) were placed in a pressure-resis-
tant closed vessel (Milestone). The mixture was sonicated for 3 min
at 120 W, and then irradiated with MW (200 W, 150 °C) for 2 h. Fi-
nally it was cooled and filtered; the filtrate was evaporated under
vacuum and purified by silica gel column chromatography. The
same procedure was applied to N,N¢-di-o-nosyl-, N,N¢-di-p-nosyl-
and N,N¢-dibenzylethylenediamine.
Solvent-Free MW-Promoted Cyclization: N,N¢-Ditosylethylenedi-
amine (400 mg, 1.09 mmol), N-Boc-serinol dimesylate (343 mg,
1.09 mmol), and Cs2CO3 (10 mmol) were mixed together by grind-
ing in an agate mortar (with or without the addition of 3 g of neutral
alumina) and the resulting mixture was irradiated at 600 W for 5
min. During this time, the temperature of the solid reached 75–
80 °C. The irradiation was repeated 4 times, with interposed pauses
Synthesis 2008, No. 12, 1879–1882 © Thieme Stuttgart · New York

1882
A. Barge et al.
PAPER
of 1 min. The mixture was cooled down to r.t., MeOH was added
and resulting mixture was filtered to separate the excess of base.
The filtrate was evaporated under vacuum to yield a crude oil,
which was purified as previously described. Both the N-Boc-pro-
tected and the deprotected heterocycle were obtained as white crys-
talline solids.
meter and to Prof. F. Trotta (University of Torino, Italy) for the
CHN elemental analyses.
References
(1) (a) Archer, G. A.; Sternbach, L. H. Chem. Rev. 1968, 68,
747. (b) Nakanishi, M.; Tahara, T.; Araki, K.; Shiroki, M.;
Tsumagari, T.; Takigawa, Y. J. Med. Chem. 1973, 16, 214.
(2) Hirokawa, Y.; Harada, H.; Yishikawa, T.; Yoshida, N.;
Kato, S. Chem. Pharm. Bull. 2002, 50, 941.
6-tert-Butyloxycarbonylamino-1,4-ditosylperhydro-1,4-diaz-
epine (1)
White crystalline solid: mp 148–149 °C (dec.).
HPLC analysis: Column X-Terra (Waters) RP-C18 4.6 × 150 mm,
5 mm; sample: 1% in H2O–MeCN (1:1), injection volume 10 mL.
Flow: 1 mL/min, detector wavelength: 215, 230, 254 nm; solvent:
H2O–MeCN gradient; time/MeCN (%) = 0/20, 7.5/20, 15/23, 26/
60, 33.5/100, 44/100.
(3) Taillefumier, C.; Thielges, S.; Chapleur, Y. Tetrahedron
2004, 60, 2213.
(4) Janin, Y. L.; Aubertin, A. M.; Chiaroni, A.; Riche, C.;
Monneret, C.; Bisagani, E.; Grierson, D. S. Tetrahedron
1996, 52, 15157.
(5) Spencer, K.; Santosh, N.; Resnick, L. Tetrahedron Lett.
1992, 33, 5485.
(6) Kawakami, Y.; Kitani, H.; Yuasa, S.; Abe, M.; Moriwaki,
M.; Kagoshima, M.; Terasawa, M.; Tahara, T. Eur. J. Med.
Chem. 1996, 31, 683.
(7) Lakatosh, S. A.; Luzikov, Y. N.; Preobrazhenskaya, M. N.
Org. Biomol. Chem. 2003, 1, 826.
(8) Levin, J. I.; Dijoseph, J. F.; Killar, L. M.; Sung, A.; Walter,
T.; Sharr, M. A.; Roth, C. E.; Skotnicki, J. S.; Albright, J. D.
Bioorg. Med. Chem. Lett. 1998, 8, 2657.
(9) Curtis, M. P.; Dwight, W.; Pratt, J.; Cowart, M.; Esbenshade,
T. A.; Kruger, K. M.; Fox, G. B.; Pan, J. B.; Pagano, T. G.;
Hancock, A. A.; Faghih, R.; Bennanni, Y. Arch. Pharm.
Med. Chem. 2004, 337, 219.
(10) Lauffer, D. J.; Mullican, M. D. Biorg. Med. Chem. Lett.
2002, 12, 1225.
(11) Giovannoni, J.; Subra, G.; Amblard, M.; Martinez, J.
Tetrahedron Lett. 2001, 42, 5389.
(12) Hirokawa, Y.; Horikawa, T.; Noguchi, H.; Yamamoto, K.;
Kato, S. Org. Process Res. Dev. 2002, 6, 28.
(13) Lampariello, L. R.; Piras, D.; Rodriquez, M.; Taddei, M.
J. Org. Chem. 2003, 68, 7893.
(14) Romba, J.; Kuppert, D.; Morgenstern, B.; Neiz, C.;
Steinhauser, S.; Weyhermuller, T.; Hegetschweiler, K. Eur.
J. Inorg. Chem. 2006, 314.
(15) Cravotto, G.; Cintas, P. Chem. Soc. Rev. 2006, 35, 180.
(16) (a) Microwaves in Organic Synthesis; Loupy, A., Ed.;
Wiley-VCH: Weinheim, 2006. (b) Herrero, M. A.;
Kremsner, J. M.; Kappe, C. O. J. Org. Chem. 2008, 73, 36.
(c) Hostyn, S.; Maes, B. U. W.; Van Baelen, G.; Gulevskaya,
A.; Meyers, C.; Smits, K. Tetrahedron 2006, 62, 4676.
(17) (a) Cravotto, G.; Cintas, P. Chem. Eur. J. 2007, 13, 1902.
(b) Palmisano, G.; Tagliapietra, S.; Barge, A.; Binello, A.;
Cravotto, G. Synlett 2007, 2041. (c) Cravotto, G.; Boffa, L.;
Lévêque, J.-M.; Estager, J.; Draye, M.; Bonrath, W. Aust. J.
Chem. 2007, 60, 946.
IR (KBr): 3406, 2976, 2930, 2870, 1757, 1709, 1597, 1510, 1454,
1331, 1286, 1159, 1089, 1012, 995, 914, 814, 721, 653 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.64 (d, J = 8.06 Hz, 4 H), 7.30 (d,
J = 8.06 Hz, 4 H), 3.60 (dd, J = 20.86, 5.86 Hz, 2 H), 3.40 (m, 5 H),
3.21 (dd, J = 19.71, 5.13 Hz, 2 H), 2.42 (s, 6 H), 1.44 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 155.9, 144.0, 135.8, 129.9, 126.9,
79.6, 53.2, 52.8, 50.4, 28.4, 21.6.
ESI-HRMS: m/z calcd for [MH+]: 524.1889; found: 524.1877.
Anal. Calcd for C24H33N3O6S2: C, 55.05; H, 6.35; N, 8.02. Found:
C, 54.95; H, 6.28; N, 8.15.
6-Amino-1,4-ditosylperhydro-1,4-diazepine (2)
White crystalline solid; mp 198–199 °C (dec.).
IR (KBr): 3391, 2976, 2872, 1750, 1599, 1495, 1338, 1196, 1161,
1089, 1078, 1012, 933, 816, 790, 767, 657 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.49 (s, 6 H), 3.18 (m, 2 H), 3.38
(m, 2 H), 3.6 (m, 4 H), 4.12 (m, 1 H), 7.35 (d, J = 13.6 Hz, 4 H),
7.71 (d, J = 10.8 Hz, 4 H).
13C NMR (75 MHz, CDCl3): d = 144.2, 130.3, 127.9, 127.3, 55.4,
52.8, 51.6, 21.9.
ESI-HRMS: m/z calcd for [MH+]: 424.1365; found: 424.1350.
Anal. Calcd for C19H25N3O4S2: C, 53.88; H, 5.95; N, 9.92. Found:
C, 53.95; H, 5.75; N, 10.04.
Acknowledgment
The combined US/MW reactor has been developed in collaboration
with Danacamerini sas (Torino, Italy). Financial support from
MIUR (FIRB 2003) and the University of Torino is gratefully ack-
nowledged. D.J.U. thanks ASP (Associazione per lo Sviluppo Sci-
entifico e Tecnologico del Piemonte) and S.F. thanks the European
Network of Excellence EMIL for research fellowships. We are in-
debted to Dr. M. Boccasile (Waters Italia S.p.A., Vimodrone, Italy)
for recording the HRMS on Waters LCT Premier XE Mass Spectro-
(18) Cravotto, G.; Omiccioli, G.; Stevanato, L. Ultrason.
Sonochem. 2005, 12, 213.
Synthesis 2008, No. 12, 1879–1882 © Thieme Stuttgart · New York