An efficient synthesis of N-substituted 3-nitrothiophen-2-amines

Article abstract of DOI:10.3762/bjoc.11.185

A novel protocol for the synthesis of 3-nitro-N-aryl/alkylthiophen-2-amines in good yields from the reaction of α-nitroketene N,S-aryl/alkylaminoacetals and 1,4-dithiane-2,5-diol in the presence of K₂CO₃ in refluxing ethanol is descr

Full text of DOI:10.3762/bjoc.11.185

An efficient synthesis of
N-substituted 3-nitrothiophen-2-amines
Sundaravel Vivek Kumar1, Shanmugam Muthusubramanian1, J. Carlos Menéndez*2
and Subbu Perumal*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 1707–1712.
1Department of Organic Chemistry, School of Chemistry, Madurai
Kamaraj University,Madurai – 625021, Tamil Nadu, India and
2Departmento de Química Orgánica y Farmacéutica, Facultad de
Farmacia, Universidad Complutense, 28040 Madrid, Spain
doi:10.3762/bjoc.11.185
Received: 21 April 2015
Accepted: 31 August 2015
Published: 22 September 2015
Email:
J. Carlos Menéndez* - josecm@farm.ucm.es;
Subbu Perumal* - subbu.perum@gmail.com
Associate Editor: T. J. J. Müller
© 2015 Vivek Kumar et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
C–C bond generation; nitroarenes; nitroketene acetals; sulfur
heterocycles
Abstract
A novel protocol for the synthesis of 3-nitro-N-aryl/alkylthiophen-2-amines in good yields from the reaction of α-nitroketene
N,S-aryl/alkylaminoacetals and 1,4-dithiane-2,5-diol in the presence of K2CO3 in refluxing ethanol is described. This transforma-
tion generates two C–C bonds in a single operation and presumably proceeds through a reaction sequence comprising
2-mercaptoacetaldehyde generation, nucleophilic carbonyl addition, annelation and elimination steps.
Introduction
Thiophenes constitute an important class of heterocyclic com- medication for osteoporosis [6] (Figure 1). Other interesting
pounds, and are embedded in natural [1] and unnatural [2] properties identified in 2-aminothiophene derivatives include
organic molecules with diverse biological activities. Among GluR6 antagonism [7], antiviral and antitumor activities [8-10],
them, many 2-aminothiophenes have reached the market or inhibition of p53-MDM2 interactions [11] and protein-tyrosine
have undergone extensive pharmacological studies. Represen- phosphatase 1B inhibition [12]. Furthermore, 2-aminothio-
tative examples are the neuroleptic olanzapine [3], the 2A3BT phenes have potential applications in the field of functional ma-
family of allosteric modulators of the A1 adenosine receptor, terials such as liquid crystals [13], nonlinear optical materials
derived from 2-amino-3-benzoylthiophene and compounds such (NLOs) [14], organic solar cells [15], photonic polymers [16]
as PD-81,723 and T-62 [4], the non-steroidal anti-inflammatory and electroluminescent materials [17]. Nitrothiophenes are also
tinoridine [5] and ranelic acid, whose strontium salt is used as a important as chemotherapeutic agents and in a few cases both
1707

Beilstein J. Org. Chem. 2015, 11, 1707–1712.
functional groups are combined in the same molecule. For acetamide [26]; (ii) 3-nitrothiophene with Grignard reagents
instance, compound I (Figure 1) is an antitubercular agent that [27] and (iii) 3-bromo-2-silylthiophene with aldehydes [28].
acts by releasing nitric oxide following activation by F420- The major drawback of these methods is that none of them
dependent nitroreductase DDN [18]. However, the pharmaco- allow the simultaneous introduction of 2-amino and 3-nitro
logical study of this class of compounds is hampered by limita- substituents (see Scheme 1d for a representative example).
tions in existing synthetic methodologies, particularly in the
direct preparation of N-substituted amino derivatives.
Figure 1: Selected examples of biologically active 2-aminothiophene
derivatives.
Scheme 1: Some strategies for the synthesis of 2-aryl/alkylaminothio-
phenes and 3-nitrothiophenes.
2-Aminothiophenes have traditionally been synthesized from
mercapto- or halogen-substituted thiophenes through nucleo-
philic displacements [19]. More recently, these derivatives have
been assembled from acyclic starting materials by methods such Multiple bond-forming transformations [29-31] are very attrac-
as i) reaction of lithiated 1-alkynes or allenes with substituted tive because of the high synthetic efficiency associated to the
phenyl isothiocyanates [20], ii) treatment of N-allylbenzotria- formation of several bonds in a single operation. The corres-
zole with substituted phenylisothiocyanates [21] and ponding reduction in the number of isolation and purification
iii) reaction between phenyl isothiocyanate and electron-defi- steps and hence in the use of organic solvents and chromato-
cient allenes catalyzed by PPh3 [22] (Scheme 1a–c). On the graphic stationary phases helps to achieve one of the main goals
other hand, studies on the synthesis of 3-nitrothiophenes are of green chemistry [32]. In this context, we wish to report
scarce. One of the traditional methods involves electrophilic herein a new and efficient synthesis of 3-nitro-N-aryl/alkyl-
aromatic substitution reactions of thiophenes, which introduces thiophen-2-amines based on domino reactions between
substituents at the 2- and 5-positions, but with some drawbacks α-nitroketene N,S-aryl/alkylaminoacetals and 1,4-dithiane-2,5-
associated with the lack of regioselectivity and difficult isomer diol, the dimer of 2-mercaptoacetaldehyde (Scheme 2). This
separation [23]. Other methods for the synthesis of 2,3-disubsi- work emerges as a continuation of our recent efforts directed
tuted thiophenes include the reactions of (i) 1,4-dithiane-2,5- towards the construction of biologically relevant heterocycles
diol with nitroalkenes [24], activated nitriles [25] and cyano- employing multiple bond-forming transformations [33-40].
1708

Beilstein J. Org. Chem. 2015, 11, 1707–1712.
Table 1: Optimization of the synthesis of compound 3ea.
Scheme 2: Our plan for the synthesis of N-substituted 3-nitrothiophen-
2-amines.
Entry
Base (1 equiv)
Solvent
Time, min Yield, %b
1
–
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
DMF
60
180
25
25
25
30
25
30
30
25
25
25
25
25
30
30
30
30
25
25
25
30
0b,c
62b
88
76
64
0
2
TEA
Results and Discussion
3
TEA
In a preparatory study, the optimization of the reaction between
(E)-4-methyl-N-(1-(methylthio)-2-nitrovinyl)aniline (1e,
1 mmol) and 1,4-dithiane-2,5-diol (2, 0.5 mmol, 1 equiv) was
performed. Initially, this model reaction was attempted in
ethanol and in the absence of base, with negative results
(Table 1, entry 1). In the presence of TEA (1 equiv), it gave
62% yield (Table 1, entry 2), which was increased to 88% when
the reaction was performed in refluxing ethanol for 25 min
(Table 1, entry 3). In both cases, work-up had the advantage
of being very simple. After completion of the reaction, the
mixture was poured into water and the precipitated solid was
filtered and washed with ethanol to give the pure
3-nitro-N-(p-tolyl)thiophen-2-amine (3e) without the need
for chromatography. Then the model reaction was further
investigated by employing alternative bases such as 1,4-diazabi-
cyclo[2.2.2]octane (DABCO, Table 1, entry 4), 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU, Table 1, entry 5), pyridine
(Table 1, entry 6), N,N-dimethylaminopyridine (DMAP,
Table 1, entry 7), piperidine (Table 1, entry 8), L-proline
(Table 1, entry 9), potassium carbonate (Table 1, entry 10),
sodium carbonate (Table 1, entry 11) and caesium carbonate
(Table 1, entry 12). After identifying potassium carbonate as the
optimal base in refluxing ethanol (93% yield), alternative
4
DABCO
DBU
5
6
pyridine
DMAP
piperidine
L-proline
K2CO3
Na2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3d
K2CO3e
K2CO3f
K2CO3g
7
44
0
8
9
0
10
11
12
13
14
15
16
17
18
19
20
21
22
93
83
90
88
86
53
trace
22
48
94
93
94
88
CH3CN
THF
1,4-dioxane
water
EtOH
EtOH
EtOH
EtOH
aAll reactions were performed with a mixture of 1e (1 mmol) and 2
(0.5 mmol). bIsolated yield after washing with cold ethanol. cReaction
performed at room temperature. d75 mol %. e50 mol %. f25 mol %.
g20 mol %.
solvents such as methanol (Table 1, entry 13), N,N-dimethyl- Scheme 3 and Table 2). The starting materials 1 were readily
formamide (Table 1, entry 14), acetonitrile (Table 1, entry 15), available by refluxing in ethanol the suitable primary amine
tetrahydrofuran (Table 1, entry 16), 1,4-dioxane (Table 1, entry and 1,1-bis(methylthio)-2-nitroethylene. Regarding aryl
17) and water (Table 1, entry 18) were examined, without substituents, the thiophene synthesis was compatible with
affording additional improvements. Finally, the use of substoi- the presence of unsubstituted phenyl rings (compound 3e) and
chiometric amounts of base was examined (Table 1, entries phenyl substituents bearing moderately electron-withdrawing
19–21), leading to the conclusion that 0.25 equivalents of potas- groups such as m- and p-halogens and m-trifluoroalkyl
sium carbonate were sufficient to promote the desired transfor- substituents (compounds 3a–d and 3l–n), although substrates 1
mation, but lower amounts led to longer reaction times and with aryl rings bearing strongly electron-withdrawing groups
diminished yields (Table 1, entry 22). All reactions included in such as p-nitro, p-cyano and p-trifluoromethyl failed to afford
Table 1 were performed under heating at reflux temperature of the final products. Furthermore, it was gratifying to observe that
the respective solvents used, except reactions corresponding to our method was compatible with the presence of electron-
entries 1 and 2, which were performed at room temperature.
releasing substituents at the aromatic ring, including alkyl
(compounds 3f–h, 3j, 3o and 3q) and alkoxy (compounds 3i, 3k
The scope and generality of this transformation was investi- and 3p) substituents, even at the more hindered ortho-positions
gated by examining the reaction between a variety of (3j, 3k, 3q). The preparation of a compound bearing a 1-naph-
α-nitroketene N,S-anilinoacetals 1 with 1,4-dithiane-2,5-diol (2, thylamino substituent (compound 3r) also proceeded unevent-
1709

Beilstein J. Org. Chem. 2015, 11, 1707–1712.
fully. We also investigated the reactions of α-nitroketene N,S- confirmed unambiguously by a single-crystal X-ray crystallo-
alkylaminoacetals and 1,4-dithiane-2,5-diol (2). These reac- graphic study [41] of 3p (Figure 2).
tions provided the desired 2-(alkylamino)-3-nitrothiophenes in
excellent yields, albeit with the need for longer reaction times.
The method allowed the preparation of compounds bearing
linear (compounds 3s–u) and α-branched alkyl substituents
(compounds 3v, 3x). Benzyl substituents could also be accom-
modated, as shown by the efficient preparation of 3y and 3z.
Figure 2: X-ray diffraction study of compound 3p.
Scheme 3: Synthesis of N-substituted 3-nitrothiophen-2-amines.
The transformation leading to compounds 3 presumably
proceeds through the initial formation of 2-mercaptoacetal-
dehyde (4) from the base-promoted decomposition of 1,4-
Table 2: Scope of the 2-amino-3-nitrothiophene synthesis.
dithiane-2,5-diol (2). This would be followed by a formal
Compound
R
Time, min
Yield, %
[3 + 2] annexation via nucleophilic addition of compounds 1 to
the carbonyl of intermediate 4 followed by addition of the thio-
late anion onto the iminium functionality thus generated to give
5. Subsequent elimination of methylmercaptan and water
furnishes the product 3 (Scheme 4).
3a
3b
3c
3d
3e
3f
4-FC6H4
25
25
25
25
24
23
23
22
20
22
25
24
24
25
24
22
90
92
91
93
94
94
95
93
96
93
91
94
90
89
94
95
82
91
93
95
98
93
94
95
92
96
4-ClC6H4
4-BrC6H4
4-IC6H4
C6H5
4-MeC6H4
4-EtC6H4
4-iPrC6H4
4-MeOC6H4
2-MeC6H4
2-MeOC6H4
3-FC6H4
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3-BrC6H4
3-F3CC6H4
3-MeC6H4
3-MeOC6H4
2,4-Me2C6H3 23
1-naphthyl
Me
25
Scheme 4: Proposed reaction sequence leading to the formation of 3.
3s
3t
205
190
190
205
190
190
180
180
n-Pr
3u
3v
3w
3x
3y
3z
n-Bu
Conclusion
iPr
In conclusion, we have developed a very efficient synthesis of a
synthetically and biologically relevant class of push–pull hete-
rocyclic compounds under mild conditions and starting from
simple acyclic substrates and catalysts. Previously, these com-
pounds were available only through multistep sequences, most
notably one involving as the final step an SNAr reaction with
cyclopropyl
cyclohexyl
Bn
(R)-α-MeBn
The structure of the 3-nitro-N-arylthiophen-2-amines 3 was the amine and having the serious limitation of requiring the
deduced from one- and two-dimensional NMR spectroscopic, presence of an additional strong electron-withdrawing group at
microanalytical and mass spectral data, as detailed for 3c as a C-5 [42-44]. Our protocol requires only two steps (including the
representative example (see Supporting Information File 1) and preparation of starting materials 1) and generates two C–C
1710

Beilstein J. Org. Chem. 2015, 11, 1707–1712.
12.Andersen, H. S.; Olsen, O. H.; Iversen, L. F.; Sørensen, A. L. P.;
Mortensen, S. B.; Christensen, M. S.; Branner, S.; Hansen, T. K.;
Lau, J. F.; Jeppesen, L.; Moran, E. J.; Su, J.; Bakir, F.; Judge, L.;
Shahbaz, M.; Collins, T.; Vo, T.; Newman, M. J.; Ripka, W. C.;
Møller, N. P. H. J. Med. Chem. 2002, 45, 4443–4459.
doi:10.1021/jm0209026
bonds through a sequence of reactions that comprise up to five
individual steps and proceeds in excellent yields (93% in
average for 26 examples) and atom economies.
Supporting Information
13.Romiszewski, J.; Puterová-Tokarová, Z.; Mieczkowski, J.; Gorecka, E.
New J. Chem. 2014, 38, 2927–2934. doi:10.1039/c4nj00298a
14.Borbone, F.; Caruso, U.; Diana, R.; Panunzi, B.; Roviello, A.;
Tingoli, M.; Tuzi, A. Org. Electron. 2009, 10, 53–60.
doi:10.1016/j.orgel.2008.10.004
Supporting Information File 1
Experimental procedures, characterization data, details of
the NMR structural determination of 3c and copies of
1H NMR, 13C NMR and ESI mass spectra of all new
compounds 1 and 3.
15.Stylianakis, M. M.; Mikroyannidis, J. A.; Kymakis, E.
Sol. Energy Mater. Sol. Cells 2010, 94, 267–274.
doi:10.1016/j.solmat.2009.09.013
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-185-S1.pdf]
16.Yuquan, S.; Yuxia, Z.; Zao, L.; Jianghong, W.; Ling, Q.; Shixiong, L.;
Jianfeng, Z.; Jiayun, Z. J. Chem. Soc., Perkin Trans. 1 1999,
3691–3695. doi:10.1039/A904945B
17.Su, Y. Z.; Lin, J. T.; Tao, Y.-T.; Ko, C.-W.; Lin, S.-C.; Sun, S.-S.
Chem. Mater. 2002, 14, 1884–1890. doi:10.1021/cm011671e
18.Hartkoorn, R. C.; Ryabova, O. B.; Chiarelli, L. R.; Riccardi, G.;
Makarov, V.; Cole, S. T. Antimicrob. Agents Chemother. 2014, 58,
2944–2947. doi:10.1128/AAC.02693-13
Acknowledgements
S.P. thanks DST-SERB New Delhi, for Major Research Project
(SR/S1/OC-50/2011) and the UGC, New Delhi for the award of
a BSR Faculty Fellowship. JCM thanks MINECO for financial
support through grant CTQ2012-33272-BQU.
19.King, F. D.; Walton, D. R. M. J. Chem. Soc., Chem. Commun. 1974,
256–257. doi:10.1039/c39740000256
20.Tarasova, O. A.; Klyba, L. V.; Vvedensky, V. Yu.; Nedolya, N. A.;
Trofimov, B. A.; Brandsma, L.; Verkruijsse, H. D. Eur. J. Org. Chem.
1998, 253–256.
References
1. Koike, K.; Jia, Z.; Nikaib, T.; Liu, Y.; Zhao, Y.; Guo, D. Org. Lett. 1999,
doi:10.1002/(SICI)1099-0690(199802)1998:2<253::AID-EJOC253>3.0.
CO;2-E
1, 197–198. doi:10.1021/ol9905295
2. Fevig, T. L.; Phillips, W. G.; Lau, P. H. J. Org. Chem. 2001, 66,
2493–2497. doi:10.1021/jo001376y
21.Katritzky, A. R.; Wang, X.; Denisenko, A. J. Org. Chem. 2001, 66,
2850–2853. doi:10.1021/jo001159x
3. Meltzer, H. Y.; Fibiger, H. C. Eur. Neuropsychopharmacol. 1996, 14,
83–85. doi:10.1016/0893-133X(95)00197-L
22.Virieux, D.; Guillouzic, A.-F.; Cristau, H.-J. Heteroat. Chem. 2007, 18,
312–315. doi:10.1002/hc.20300
4. Valant, C.; Aurelio, L.; Devine, S. M.; Ashton, T. D.; White, J. M.;
Sexton, P. M.; Christopoulos, A.; Scammells, P. J. J. Med. Chem.
2012, 55, 2367–2375. doi:10.1021/jm201600e
23.Gronowitz, S.; Hörnfeldt, A.-B. Thiophenes; Elsevier Academic Press:
San Diego, CA, 2004.
24.O’ Connor, C. J.; Roydhouse, M. D.; Przybył, A. M.; Wall, M. D.;
Southern, J. M. J. Org. Chem. 2010, 75, 2534–2538.
doi:10.1021/jo902656y
5. Shimada, O.; Yasuda, H. Agents Actions 1986, 19, 208–214.
doi:10.1007/BF01966208
6. Meunier, P. J.; Roux, C.; Seeman, E.; Ortolani, S.; Badurski, J. E.;
Spector, T. D.; Cannata, J.; Balogh, A.; Lemmel, E.-M.;
Pors-Nielsen, S.; Rizzoli, R.; Genant, H. K.; Reginster, J.-Y.
N. Engl. J. Med. 2004, 350, 459–468. doi:10.1056/NEJMoa022436
7. Briel, D.; Rybak, A.; Kronbach, C.; Unverferth, K. Eur. J. Med. Chem.
2010, 45, 69–77. doi:10.1016/j.ejmech.2009.09.025
8. Stephens, C. E.; Felder, T. M.; Sowell, J. W., Sr.; Andrei, G.;
Balzarini, J.; Snoeck, R.; De Clercq, E. Bioorg. Med. Chem. 2001, 9,
1123–1132. doi:10.1016/S0968-0896(00)00333-3
25.Ma, L.; Yuan, L.; Xu, C.; Li, G.; Tao, M.; Zhang, W. Synthesis 2013, 45,
45–52. doi:10.1055/s-0032-1316821
26.Wang, K.; Nguyen, K.; Huang, Y.; Dömling, A. J. Comb. Chem. 2009,
11, 920–927. doi:10.1021/cc9000778
27.Blatt, A.; Bach, S.; Kresch, L. J. Org. Chem. 1957, 22, 1693–1695.
doi:10.1021/jo01363a604
28.Devarie-Baez, N. O.; Shuhler, B. J.; Wang, H.; Xian, M. Org. Lett.
2007, 9, 4655–4658. doi:10.1021/ol702149c
29.Coquerel, Y.; Boddaert, T.; Presset, M.; Mailhol, D.; Rodriguez, J.
Multiple Bond-Forming Transformations: The Key Concept toward
Eco-Compatible Synthetic Organic Chemistry. In Ideas in Chemistry
and Molecular Sciences: Advances in synthetic chemistry;
Pignataro, B., Ed.; Wiley-VCH: Weinheim, 2010; Vol. 1, pp 187–202.
doi:10.1002/9783527630554.ch9
9. Romagnoli, R.; Baraldi, P. G.; Pavani, M. G.; Tabrizi, M. A.; Preti, D.;
Fruttarolo, F.; Piccagli, L.; Jung, M. K.; Hamel, E.; Borgatti, M.;
Gambari, R. J. Med. Chem. 2006, 49, 3906–3915.
doi:10.1021/jm060355e
10.Romagnoli, R.; Baraldi, P. G.; Carrion, M. D.; Cara, C. L.; Preti, D.;
Fruttarolo, F.; Pavani, M. G.; Tabrizi, M. A.; Tolomeo, M.; Grimaudo, S.;
Di Cristina, A.; Balzarini, J.; Hadfield, J. A.; Brancale, A.; Hamel, E.
J. Med. Chem. 2007, 50, 2273–2277. doi:10.1021/jm070050f
11.Wang, W.; Lv, D.; Qiu, N.; Zhang, L.; Hu, C.; Hu, Y.
Bioorg. Med. Chem. 2013, 21, 2886–2894.
30.Menéndez, J. C. Curr. Org. Chem. 2013, 17, 1919–2064.
doi:10.2174/1385272811317180002
31.Rodriguez, J.; Bonne, D., Eds. Stereoselective multiple bond-forming
transformations in organic synthesis; John Wiley and Sons, Inc., 2015.
doi:10.1002/9781119006220
doi:10.1016/j.bmc.2013.03.070
32.Cioc, R. C.; Ruijter, E.; Orru, R. V. A. Green Chem. 2014, 16,
2958–2975. doi:10.1039/c4gc00013g
1711

Beilstein J. Org. Chem. 2015, 11, 1707–1712.
33.Indumathi, S.; Perumal, S.; Menéndez, J. C. J. Org. Chem. 2010, 75,
472–475. doi:10.1021/jo9021327
34.Prasanna, P.; Balamurugan, K.; Perumal, S.; Menéndez, J. C.
Green Chem. 2011, 13, 2123–2129. doi:10.1039/c0gc00952k
35.Gunasekaran, P.; Balamurugan, K.; Sivakumar, S.; Perumal, S.;
Menéndez, J. C.; Almansour, A. I. Green Chem. 2012, 14, 750–757.
doi:10.1039/c2gc16517a
36.Gunasekaran, P.; Indumathi, S.; Perumal, S. RSC Adv. 2013, 3,
8318–8325. doi:10.1039/c3ra00136a
37.Muthusaravanan, S.; Sasikumar, C.; Bala, B. D.; Perumal, S.
Green Chem. 2014, 16, 1297–1304. doi:10.1039/C3GC42150C
38.Vivek Kumar, S.; Prasanna, P.; Perumal, S. Tetrahedron Lett. 2013,
54, 6651–6655. doi:10.1016/j.tetlet.2013.09.123
39.Muthusaravanan, S.; Bala, B. D.; Perumal, S. Tetrahedron Lett. 2013,
54, 5302–5306. doi:10.1016/j.tetlet.2013.07.091
40.Gunasekaran, P.; Perumal, S.; Menéndez, J. C.; Mancinelli, M.;
Ranieri, S.; Mazzanti, A. J. Org. Chem. 2014, 79, 11039–11050.
doi:10.1021/jo502047n
41.Cambridge Crystallographic Data Centre (CCDC) reference for
compound 3p: 1000701.
42.Consiglio, G.; Frenna, V.; Guernelli, S.; Macaluso, G. ARKIVOC 2002,
No. xi, 104–117.
43.Morley, J. O.; Matthews, T. P. Org. Biomol. Chem. 2006, 4, 359–366.
doi:10.1039/B514441H
44.Sarkar, P.; Maiti, S.; Ghosh, K.; Sengupta (Bandyopadhyay), S.;
Butcher, R. J.; Mukhopadhyay, C. Tetrahedron Lett. 2014, 55,
996–1001. doi:10.1016/j.tetlet.2013.12.068
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.11.185
1712