One-pot sequential synthesis of isocyanates and urea derivatives via a microwave-assisted Staudinger-aza-Wittig reaction

Article abstract of DOI:10.3762/bjoc.9.274

A fast and efficient protocol for the synthesis of N,N'-disubstituted urea derivatives from alkyl halides and primary or secondary amines has been developed. The synthetic pathway combines nucleophilic substitutions and a Staudinger-aza-Wittig reaction in the presence of polymer-bound diphenylphosphine under 14 bar of CO2 pressure and has been performed in a one-pot two-step process. The protocol has been optimized under microwave irradiation and the scale-up experiment has been conducted under conventional conditions in a Parr reactor. The final compounds were isolated after simple filtration in almost quantitative overall yields which makes this procedure facile and rapid to execute.

Full text of DOI:10.3762/bjoc.9.274

One-pot sequential synthesis of isocyanates and
urea derivatives via a microwave-assisted
Staudinger–aza-Wittig reaction
Diego Carnaroglio1, Katia Martina1, Giovanni Palmisano2, Andrea Penoni2,
Claudia Domini3 and Giancarlo Cravotto*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2378–2386.
1Dipartimento di Scienza e Tecnologia del Farmaco, University of
Turin, Via Pietro Giuria 9, 10125 Torino, Italy; Fax +390116707687;
Tel: +390116707684, 2Dipartimento di Scienza e Alta Tecnologia,
University of Insubria, Via Valleggio 11, 22100 Como, Italy and
3Department of Chemistry, Universidad Nacional del Sur, Av. Alem
1253, B8000CPB, Bahía Blanca, Buenos Aires, Argentina
doi:10.3762/bjoc.9.274
Received: 02 August 2013
Accepted: 17 October 2013
Published: 06 November 2013
Associate Editor: B. Stoltz
Email:
Giancarlo Cravotto* - giancarlo.cravotto@unito.it
© 2013 Carnaroglio et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
isocyanates; microwave-assisted reaction; one-pot reaction; tandem
Staudinger–aza-Wittig reaction; urea derivatives
Abstract
A fast and efficient protocol for the synthesis of N,N'-disubstituted urea derivatives from alkyl halides and primary or secondary
amines has been developed. The synthetic pathway combines nucleophilic substitutions and a Staudinger–aza-Wittig reaction in the
presence of polymer-bound diphenylphosphine under 14 bar of CO2 pressure and has been performed in a one-pot two-step process.
The protocol has been optimized under microwave irradiation and the scale-up experiment has been conducted under conventional
conditions in a Parr reactor. The final compounds were isolated after simple filtration in almost quantitative overall yields which
makes this procedure facile and rapid to execute.
Introduction
The industrial and commercial impact of isocyanates (R–NCO) agrochemicals and pharmaceuticals. The isocyanate group is
is steadily growing. In particular, the polyurethane output has also widely used as a precursor to several bioactive compounds
undergone yearly increases of 5% over the last decade [1]. and drugs that contain urea and carbamate moieties [2].
Isocyanates play a relevant role as chemical intermediates in the Isocyanates were discovered by Wurtz in 1849 [3], and more
manufacturing of thermoplastic foams, elastomers, adhesives, than 20 methods for the preparation of R–NCO have now been
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Beilstein J. Org. Chem. 2013, 9, 2378–2386.
listed and classified according to the reactions involved [4,5]. (SynthWave by Milestone) and is well suited for parallel
The old procedure that entails reactions between primary or sec- syntheses at any reaction temperature and gas pressure (up to
ondary amines or amides with phosgene, is the most commonly 300 °C and 200 bar). We aimed to successfully reduce the reac-
used and it is described in papers [6,7] and reviews [8]. The tion time and the reagent excess, and to employ poorly reactive
main drawbacks of this method are the extremely high toxicity substrates and volatile, solid and supported reagents. In
of phosgene and the generation of a large amount of corrosive summary, we herein report an optimized protocol for a
HCl. Moreover, the high temperature required by this process MW-assisted Staudinger–aza-Wittig reaction with polymer-
(>250 °C) makes the synthesis of lower molecular weight com- bound diphenylphosphine (PS-PPh2) in a CO2 atmosphere. The
pounds impossible.
study also aimed to prepare a series of symmetric and asym-
metric alkyl/aryl urea derivatives in a one-pot, sequential syn-
Apart from the catalytic carbonylation of nitro compounds, thesis of urea derivatives from alkyl bromides. With the aim to
which is one of the most interesting alternatives for the syn- verify the feasibility of the method under conventional heating,
thesis of aromatic isocyanates, other alternative greener, non- the protocol was tested in a Parr reactor (90 mL) for an easier
phosgene routes to isocyanates have also been developed [9]. scale-up.
Of these, the Curtius, Hoffman and Lossen rearrangements have
been used quite often in the past and are still used for specific Results and Discussion
applications [10-13]. The Staudinger–aza-Wittig reactions have The Staudinger–aza-Wittig reaction is extremely versatile and
played a pivotal role in the construction of cyclic and acyclic can be used for the synthesis of many products. However, the
compounds [14-19]. The replacement of phosgene by carbon byproduct of this reaction is triphenylphosphine oxide, which is
dioxide (CO2), which is nontoxic, abundant, and economical, is difficult to remove. It is known that this reaction can be
the main advantage of this reaction. The mechanism of this performed in a heterogeneous system using PS-PPh2. Despite
transformation passes through iminophosphoranes that are the higher costs for the reagent, the use of PS-PPh2 has the
versatile intermediates and can react with CO2 to generate advantage of a much easier reaction work-up [33-38]. A
isocyanates [20]. This reaction is compatible with a large polymer regeneration procedure was described by Marsura et al.
number of functional groups and therefore has various uses in [35], however a quasi-stoichiometric amount makes the recy-
organic synthesis and can also be exploited for the preparation cling step unneccessary. With the aim to overcome cost limita-
of heterocyclic compounds. Isocyanate derivatives can be gen- tions we recently described the preparation of triphenylphos-
erally obtained in good yields. However, it is necessary to avoid phine-loaded cross-liked cyclodextrin complexes as recyclable
the traditional triphenylphosphine to obtain high purity prod- green catalyst [39]. The reactivity of polystyrene-supported
ucts [21].
reagents strongly depends on the choice of solvent that can
influence polymer swelling [40]. Solvent choice is therefore an
So called “enabling techniques”, mainly non-conventional important issue as it must allow the supported reagent to work
energy sources such as microwaves (MW) and ultrasound (US), in a friendly environment and, at the same time, facilitate the
can dramatically enhance reaction rates in organic synthesis reaction outcome. In the first part of this work, we have focused
[22,23]. Kinetics and yields of any chemical modification are on the development of a MW promoted protocol for isocyanate
strongly improved by the optimal heat and mass transfer synthesis with the aim of reducing reaction time and decreasing
provided by dielectric heating and sonochemical conditions the amount of solid supported PS-PPh2, which is usually added
[24,25]. In general, MW in organic synthesis is a valid response in large excess. The conversion of benzyl azide to benzyl
to problems regarding long reaction times and a high reagent isocyanate (Scheme 1) was selected as the model reaction and it
excess. The use of dielectric heating to promote chemical reac- was performed both under conventional conditions and under
tions has become well established as a reliable technique which MW irradiation. Various solvents were compared at a number
can be applied on a range of scales [26]. Despite MW irradi- of temperatures thanks to the versatility of the SynthWave
ation being commonly used in organic synthesis, only few reactor, which provides multiple-sample racks. Experiments
publications describe this technique with gaseous reagents in were performed at 90, 70 and 50 °C at 14.5 bar of CO2 pres-
closed vessels and in heterogeneous gas-phase reactions that are sure.
important for industrial processes [27-31]. The aim of the
present work is the development of new green and efficient syn- As shown in Table 1, the reaction showed complete conversion
thetic procedures for easier access to isocyanates and urea when performed in toluene at 70 °C. The purity of the com-
libraries using a renewable carbon resource like CO2. Since pound was also slightly higher than that of the reacition at
CO2 requires a large energy input to be transformed [32], we 90 °C. The conversion was not complete at 50 °C. Conversion
have studied a synthetic procedure which uses a MW reactor was low in THF and the isocyanate was present only as trace
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Beilstein J. Org. Chem. 2013, 9, 2378–2386.
In order to optimize the reaction conditions, another study was
pursued in MeCN and toluene, and a number of different reac-
tions were performed at 50 °C. As shown in Table 2, we
confirm that the reaction was faster in MeCN than in toluene
and that even full conversion was obtained after 1.5 h in many
cases. An important goal was to reduce the PS-PPh2 excess
from 5 to 1.5 equiv, with excellent results only in MeCN
Scheme 1: Synthesis of benzyl isocyanate.
among side-products. MeCN, like toluene allowed a higher (Table 2) under MW irradiation. When the reaction was carried
conversion and a higher yield to be achieved, even in compari- out in the Parr reactor, the highest conversion was 93% with
son with DMF. In MeCN, there was a complete conversion 2 equiv PS-PPh2.
even at 50 °C in 4 h. The influence of the CO2 pressure on the
reaction rate was evident by the poor conversion (40%) that was To confirm the versatility of our protocol, the method was
observed when the reaction was performed with 1 bar CO2 at extended to include a number of different substrates and the
50 °C in an oil bath. In contrast, the conversion reached 93% in obtained isocyanates were also used for the synthesis of urea
a Parr reactor with 14 bar CO2. At room temperature with 1 bar derivatives via the reaction with (±)-1-phenylethylamine 3 (see
CO2 the reaction occurs within 24 h.
Scheme in Table 3). Seven different azido-derivatives were
Table 1: Synthesis of benzyl isocyanate.a
entry
solvent
reaction conditions
conversionb(%)
yieldb(%)
1
2
toluene
toluene
toluene
THF
90 °C, MW, CO2 (14.5 bar)
70 °C, MW, CO2 (14.5 bar)
50 °C, MW, CO2 (14.5 bar)
70 °C, MW, CO2 (14.5 bar)
70 °C, MW, CO2 (14.5 bar)
70 °C, MW, CO2 (14.5 bar)
50 °C, MW, CO2 (14.5 bar)
50 °C, CO2 (1 bar)
>99
96
75
84
6
82
78
3
50
25
4
DMF
95
80
5
MeCN
MeCN
MeCN
MeCN
MeCN
>99
>99
41
85
7
94
8c
9
25
rt, CO2 (1 bar)
25 (95)d
93
21 (85)d
89
10e
50 °C, CO2 (14 bar)
aUnless otherwise stated, reactions were performed in the presence of PS-PPh2 (5 equiv), reaction time 4 h. bDetermined by GC–MS. cThe reaction
was performed in an oil bath. dReaction time 24 h. eThe reaction was performed in a Parr reactor.
Table 2: Synthesis of benzyl isocyanate.a
entry
solvent
PS-PPh2 (equiv)
time (h)
conversionb (%)
yieldb (%)
1
2
toluene
toluene
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
5
5
4
2
82
71
78
71
54
94
96
97
76
97
95
88
98
82
76
3
2
2
66
4
5
4
>99
>99
>99
80
5
5
2
6
5
1.5
1
7
5
8
3
1.5
1.5
1.5
1.5
1.5
1.5
>99
>99
93
9
2
10c
11
12c
13
2
1.5
1.5
1
>99
88
80
aReactions were carried out in a MW reactor: 1, PS-PPh2, CO2 (14.5 bar) 50 °C. bDetermined by GC–MS. cReactions were carried out in a Parr
reactor (90 mL): 1, PS-PPh2, CO2 (14 bar) 50 °C.
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Beilstein J. Org. Chem. 2013, 9, 2378–2386.
Table 3: Synthesis optimization of urea derivatives.a
entry
1
R–N3
product
yieldb (%)
98
1
10
10
11
12
1c
2
1
79
90
92
4
5
3
4
97
6
7
13
14
15
5
6
97
98
8
7
94
9
16
aReactions were carried out in a MW reactor: azido derivative, PS-PPh2 (1.5 equiv), CO2 (14.5 bar), 50 °C, 1.5 h, then 3 (2 equiv) 70 °C, 3 h.
bIsolated yield. cThe reaction was performed in a Parr reactor.
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Beilstein J. Org. Chem. 2013, 9, 2378–2386.
synthesized from the alkyl halide and reacted via temperatures. Furthermore, NaBr generated during the nucleo-
Staudinger–aza-Wittig reactions. After the PS-PPh2 was philic substitution is insoluble and can be removed by filtration
filtered, the isocyanate solution was directly subjected to an as can the NaN3 excess. These factors allow the work-up proce-
addition of 2 equiv of 3 and heated up to 70 °C in the MW dure to be simplified and pure azido derivative solutions were
reactor for 3 h. Primary alkyl and benzyl azide derivatives were obtained by filtration. Benzyl azide was successfully obtained
compared to secondary ones, and the compatibility of the from benzyl bromide after the reaction in a MW reactor at 95
protocol towards different functional groups was also °C for 3 h. After filtration, the benzyl azide solution was
considered. The results obtained are given in Table 3 directly converted into the urea compound by MW irradiation at
and show the yield of urea derivatives after purification 70 °C for 3 h in the presence of CO2, PS-PPh2 and benzy-
from the amine excess by using Dowex® 50WX8-200. This lamine. The desired product was obtained in almost quantitat-
synthetic protocol is versatile and highly efficient with ive yields.
both primary and secondary azido derivatives as well as alkoxy
and amido groups. The one-pot, two-step procedure afforded The robustness of this MW-promoted sequential one-pot proce-
urea derivatives in high yield and purity via the isocyanate dure was established by synthesizing a set of 13 different urea
intermediate. To broaden the scope of the study, the reaction derivatives. A small set of five different primary and secondary
was repeated in a bigger scale (80 mL) in a Parr reactor at the alkyl and benzyl azides were synthesized. Besides the azido
same pressure. Despite the good conversion (about 93%), the derivatives synthesized from 17–19, the two volatile azides
product purity was slightly lower than that of the MW-assisted synthesized from 20 and 21 (n-butyl and allyl azide, respective-
reaction.
ly) were obtained under N2 pressure. After filtration they were
converted into the urea compound. The procedure was
To expand the scope of this method, a sequential one-pot syn- performed in parallel and under 14.5 bar of CO2 and even the
thesis from the alkyl bromide to the urea derivative was carried volatile allyl and butyl azide reacted successfully. The results
out without isolating the intermediates. The aim of this part of reported in Table 4 show that all final products were obtained in
the work was the synthesis of the azido derivatives and their excellent to almost quantitative yield.
subsequent conversion to urea via the Staudinger–aza-Wittig
reaction and one-pot amine addition. The combination of reac- Conclusion
tants in a one-pot fashion can lead to undesired side-product In conclusion, a MW-assisted, one-pot sequential protocol for
formation and, consequently, a lower yield. Therefore, the the synthesis of urea derivatives from alkyl bromides has been
choice of the right solvent and reaction conditions is the key to described. This study has proven that in acetonitrile under high
the success of this transformation.
CO2 pressure the Staudinger–aza-Wittig reaction in presence of
PS-PPh2 is strongly promoted. Excellent results have been
Our initial attempts focused on the synthesis of azido deriva- obtained under MW irradiation in a closed vessel also with
tives in MeCN. Although generally performed in DMF, the SN2 gaseous reagents. The optimized procedure benefited from the
reaction of alkyl bromide with NaN3 can also be performed in use of a quasi-stoichiometric amount of PS-PPh2 and can be
MeCN. NaN3 is insoluble in MeCN at room temperature applied for the efficient, safe, rapid, and cost-effective produc-
(<0.005 g/100 mL), but its solubility increases at higher tion of urea derivative libraries.
Table 4: One-pot MW-assisted synthesis of a set of urea derivatives.a
entry
1
R–Br
R–NH2
product
yieldb (%)
98
17
22
27
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Beilstein J. Org. Chem. 2013, 9, 2378–2386.
Table 4: One-pot MW-assisted synthesis of a set of urea derivatives.a (continued)
2
3
17
17
98
23
28
98
24
22
29
4
5
97
18
18
10
23
24
94
30
6
7
8
9
18
18
18
98
31
98
25
32
98
26
22
33
89
19
19
34
10
11
23
24
3
89
35
19
20
88
36
12c
85
37
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Beilstein J. Org. Chem. 2013, 9, 2378–2386.
Table 4: One-pot MW-assisted synthesis of a set of urea derivatives.a (continued)
13c
3
83
21
38
aReactions were carried out in a MW reactor: alkyl bromide, NaN3 (2 equiv), MeCN, 95 °C, 3 h ; then PS-PPh2 (1.5 equiv), CO2 (14.5 bar), amine
(2 equiv), at 50 °C 1.5 h then 70 °C 3 h. bIsolated yield. cR–N3 was synthesized in DMF and MeCN was then added.
Experimental
200 W) under N2 (2 bar) and magnetic stirring. The solvent was
All chemicals were purchased from Sigma-Aldrich (solvents then evaporated under vacuum, the residue was dissolved in
from Carlo Erba SpA) and used without further purification. MeOH and Dowex® 50WX8-200 was added. The mixture was
Solid diphenylphosphino-polystyrene (PS-PPh2) was purchased stirred at rt for 15 min. The mixture was then filtered on paper
from Novabiochem® (Cas-No: 39319-11-4, loading ca. and the solvent was evaporated under vacuum.
1.2 mmol/g). Reactions were monitored by TLC on Merck 60
F254 (0.25 mm) plates, which were visualized by UV inspec- Representative “multi-pot” procedure for the synthesis of
tion and/or by heating after a spraying with 5% H2SO4 in urea derivatives: NaN3 (0.477 mmol) was added to a solution
ethanol or phosphomolybdic acid. MW-promoted reactions of alkyl bromide (0.318 mmol) in MeCN (1.5 mL). The mix-
were carried out in a SynthWave (Milestone, Italy). NMR ture was irradiated by MW for 3 h at 95 °C (average power
spectra were recorded on a Bruker Avance 300 (300 MHz and 240 W) under N2 (2 bar) and magnetic stirring. After the reac-
75 MHz for 1H and 13C, respectively) at 25 °C; chemical shifts tion, the mixture was cooled to rt, filtered on paper, and
were calibrated to the residual proton and carbon resonances of PS-PPh2 (0.477 mmol) and amine (0.636 mmol) were sequen-
the solvents: CDCl3 (δH = 7.26, δC = 77.16) or CD3OD (δH = tially added. The mixture was irradiated by MW for 1.5 h at
3.31, δC = 49.00). GC–MS analyses were performed in a GC 50 °C (average power 70 W) and 3 h at 70 °C (average power
Agilent 6890 (Agilent Technologies, USA) that was fitted with 200 W) under CO2 (14.5 bar) and magnetic stirring. Then, the
a mass detector Agilent Network 5973, using a 30 m long capil- mixture was filtered on a cartridge to remove the polymer-
lary column, i.d. of 0.25 mm and film thickness 0.25 μm. GC bound diphenylphosphine oxide. The solvent was then evapo-
conditions were: injection split 1:20, injector temperature rated under vacuum, the residue was dissolved in MeOH and
250 °C, detector temperature 280 °C. Gas carrier: helium Dowex® 50WX8-200 was added. The mixture was stirred at rt
(1.2 mL/min), temperature program: from 70 °C (2 min) to for 15 min. Finally, the mixture was filtered on paper and the
300 °C at 5 °C/min. HRMS was determined using MALDI-TOF solvent was evaporated under vacuum. When the reaction was
mass spectra (Bruker Ultraflex TOF mass spectrometer).
performed in a Parr reactor, PS-PPh2 (6.36 mmol) was added to
a solution of alkyl azide (3.18 mmol) and amine (6.36 mmol) in
MeCN (80 mL). The solution was heated 3 h at 70 °C under
General procedures
Representative procedure for alkyl isocyanate synthesis CO2 (14.5 bar). The mixture was filtered on a cartridge to
from alkyl azide: PS-PPh2 (0.477 mmol) was added to a solu- remove the polymer-bound diphenylphosphine oxide and the
tion of alkyl azide (0.318 mmol) in MeCN (1.5 mL). The mix- residual polymer-bound diphenylphosphine. The solvent was
ture was irradiated by MW for 1.5 h at 50 °C (average power then evaporated under vacuum, the residue was dissolved in
70 W) under CO2 (14.5 bar) and magnetic stirring. After the MeOH and Dowex® 50WX8-200 was added. The mixture was
reaction, the mixture was filtered on a cartridge. When the reac- stirred at rt for 15 min. Finally, the mixture was filtered on
tion was performed in a Parr reactor, PS-PPh2 (6.36 mmol) was paper and the solvent was evaporated under vacuum.
added to a solution of alkyl azide (3.18 mmol) in MeCN
(80 mL). The solution was heated for 2 h at 50 °C under CO2
Supporting Information
(14.5 bar). After the reaction, the mixture was filtered on a
cartridge.
Supporting Information File 1
Detailed analytical data of the prepared compounds and a
Representative procedure for urea synthesis from alkyl
isocyanate: The amine (0.636 mmol) was added to a solution of
alkyl isocyanate (0.318 mmol) in MeCN (1.5 mL). The solu-
tion was irradiated by MW for 3 h at 70 °C (average power
collection of NMR spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-274-S1.pdf]
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Beilstein J. Org. Chem. 2013, 9, 2378–2386.
23.Cravotto, G.; Cintas, P. The Combined Use of Microwaves and
Ultrasound. In Methods and Practice, Microwaves in Organic
Synthesis, 3rd ed.; De La Hoz, A.; Loupy, A., Eds.; Springer: U.S.A.,
2012.
Acknowledgements
This work was funded by the Compagnia di San Paolo –
University of Turin (Progetti di Ricerca di Ateneo 2011, grant
D15E11001710003).
24.Cravotto, G.; Cintas, P. Chem.–Eur. J. 2007, 13, 1902–1909.
doi:10.1002/chem.200601845
25.Cintas, P.; Carnaroglio, D.; Rinaldi, L.; Cravotto, G. Chim. Oggi 2012,
30 (3), 33–35.
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