A variety  of alpha,beta-unsaturated ketones can be easily converted, at room temperature, into beta-nitro ketones by nitration with solid supported nitrite (SSN) and in the presence
of acetic acid and cyclopentyl methyl ether

A. Palmieri

A. Perosa

M. Selva

R. Ballini

S. Gabrielli

Green Chemistry

Archivio Ricerca Ca'Foscari

Green Chemistry Dynamic Article Links
Cite this: Green Chem., 2011, 13, 2026
www.rsc.org/greenchem COMMUNICATION
Eco-friendly synthesis of b-nitro ketones from conjugated enones: an
important improvement of the Miyakoshi procedure†
Serena Gabrielli,a Alessandro Palmieri,a Alvise Perosa,b Maurizio Selvab and Roberto Ballini*a
Received 27th May 2011, Accepted 20th June 2011
DOI: 10.1039/c1gc15616k
A variety of a,b-unsaturated ketones can be easily con-
verted, at room temperature, into b-nitro ketones by nitra-
tion with solid supported nitrite (SSN) and in the presence
of acetic acid and cyclopentyl methyl ether.
Nitroalkanes are one of the most fundamental classes of
substrates in organic chemistry.1 This is mainly due to the
fact that (i) they allow the easy formation of new carbon–
carbon and carbon–heteroatom bonds under very mild reaction
conditions,2,3 (ii) the nitro group can be converted into a plethora
of other functionalities,4 and (iii) they are the key starting
material for the preparation of a variety of ﬁne chemicals.5
Thus, the easy accessibility to nitroalkanes remains an impor-
tant goal, especially for those functionalized ones.6 In this con-
text, of great interest are the b-nitro ketones 1 because these kind
of derivatives, or their protected ones, have been demonstrated
to be important building blocks in organic synthesis.7 These
molecules can be obtained (Fig. 1) from three different sources:
(i) by halo-nitro displacement of b-halocarbonyl derivatives
2 (way a),8a (ii) via C,C-cross-coupling of nitroalkanes 3 and
their silyl derivatives 4 (Ioffe procedure, way b),8b or (iii) by the
historical Miyakoshi procedure8c that involves the nitration of
conjugated enones 5 using sodium nitrite and acetic acid, in
THF as solvent (way c). Although each of the above methods
gives access to different interesting molecular structures, way c
remains the most used one.
Above all, the Miyakoshi procedure shows important draw-
backs because it seems to be limited just to a,b-unsaturated
ketones having simple molecular frames, gives moderate yields,
needs the presence of organic volatile solvents such as THF9
and, moreover, the methodology requires a tedious and non
eco-sustainable work-up. Thus, in order to avoid the above
limitations, new improvements of this classical method for the
preparation of the title compounds would be encouraged.
aGreen Chemistry Group, School of Science and Technology, Chemistry
Division, University of Camerino, Via S. Agostino 1, 62032, Camerino,
Italy. E-mail: roberto.ballini@unicam.it; Fax: +39 0737 402297;
Tel: +39 0737 402270
bDipartimento di Scienze Molecolari e Nanosistemi, Universita` Ca’
Foscari Venezia, Dorsoduro 2137, 30123, Venezia, Italy.
E-mail: selva@unive.it; Tel: +39 041 2348687
† Electronic supplementary information (ESI) available: See DOI:
10.1039/c1gc15616k
Fig. 1 Main synthetic pathways for the synthesis of b-nitro ketones 1.
In the course of the last few years, solid supported reagents
(SSR) have attracted growing interest since they have demon-
strated a great versatility as powerful promoters in a wide
number of reactions,10 increasing the chemical reactivity and
simplifying the classical work-up step into an easy ﬁltration,
with the consequent minimization of the use of solvents.11
On the other hand, recently, it has been demonstrated that
reactions conducted in cyclopentyl methyl ether (CPME), as
a new emerging “green solvent”, in contrast to tetrahydrofuran,
are comparativelymore favourable in terms of eco-sustainability
and efﬁciency, and with consequent reduction of both exposure
and ﬂammability safety problems.12
In our laboratory in recent years, we have found that the
reactivity and the chemical potentialities of the aliphatic nitro
compounds often increase by the use of SSR.13 Based on
these experiences and following our research projects on the
chemistry of aliphatic nitro compounds, we have now developed
an improved general procedure for the nitration of conjugated
enones, employing solid supported nitrite (SSN).14 Thus, ﬁrstly
we tested, as model reaction, the nitration of the compound 5a
checking different amounts of both SSN and acetic acid on a
variety of solvents, including CPME.
As reported in Table 1, the best yield (89%) was obtained
using 3 equivalents of nitrite on polymer, and 5 equivalents of
acetic acid on CPME (entry f).
Encouraged by this excellent result and in order to explore
the general applicability of our methodology, we submitted a
variety of a,b-unsaturated ketones under the optimized reaction
conditions.
As reported in Table 2, the reaction gives important yields
(60–89%) with a variety of enones, including furyl and aryl vinyl
2026 | Green Chem., 2011, 13, 2026–2028 This journal is © The Royal Society of Chemistry 2011
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Table 1 Optimization studies
Entry
eq. Nitrite on
polymer (SSN) eq. AcOH Solvent Yield (%)a of 1a
a 1 2 CPME 15
b 1 2 CPME 30
c 2 4 CPME 68
d 3 4 CPME 63
e 4 5 THF 80
f 3 5 CPME 89
g 3 6 CPME 70
h 3 5 EtOAc 55
i 3 5 DCM 65
a Yield of pure isolated product.
Table 2 Nitration of different unsaturated ketones
R R1 Reaction time (h) Yield (%)a of 1
a Ph(CH2)2 H 30 89
b n-C8H17 H 30 72
c PhC6H4 H 24 82
d Ph H 24 86
e p-MeOC6H4 H 30 82
f p-CF3C6H4 H 27 77
g c-C6H11 H 30 75
h 2-furyl H 30 75
i Cl(CH2)5 H 30 75
j Et H 24 84
k n-Bu Me 48 60
a Yield of pure isolated product.
ketones, independently from the nature of the alkyl group (R)
or the presence of other functionalities in the phenyl ring (1c, 1e
and 1f).
However, of particular importance is the success obtained by
the nitration of the hindered enone 5k performed in consistent
yield (60%). The latter example is of great importance, because,
to the best of our knowledge, it is the ﬁrst report of the
nitration of substituted vinyl ketones, allowing an easy access
to secondary nitro compounds, which are difﬁcult to obtain by
other methods.
Conclusions
In conclusion, by our method the Miyakoshi procedure has
been signiﬁcantly improved both in terms of efﬁciency and eco-
sustainability. In fact, higher yields have been obtained using a
greener solvent (CPME) and the procedure works well even with
complex conjugated enones, including substituted vinyl ketones.
Furthermore, it is possible to preserve other functionalities,
minimizing the work-up step into an easy ﬁltration and evap-
oration of both solvent and acetic acid, avoiding any classical,
tedious aqueous work-up and the use of any drying salts, with
the consequent drastic decrease of E-factor.
Experimental
General procedure for the synthesis of compounds 1a–k
Batch reaction was carried out by stirring a mixture of ketone
5 (1 mmol), SSN (3 mmol), acetic acid (5 mmol) and CPME
(3 mL). The reaction was allowed to stir for the appropriate
time (see Table 2) at room temperature. After the reaction was
completed, the resin was ﬁltered off and washed with EtOAc
(5 mL), then the solvent was removed under vacuum, and the
crude product 1 was puriﬁed by ﬂash chromatography column
(hexanes : EtOAc = 85 : 15).
Acknowledgements
The authors thanks the Universities of Camerino and Ca’
Foscari Venezia and MIUR-Italy (FIRB National Project
“Metodologie di nuova generazione nella formazione di legami
carbonio-carbonio e carbonio-eteroatomo in condizioni eco-
sostenibili”, e PRIN National Project “Sintesi organiche
ecosostenibili mediate da nuovi sistemi catalitici”) for ﬁnancial
support.
Notes and references
1 (a) G. Rosini and R. Ballini, Synthesis, 1988, 833; (b) N. Ono, The
Nitro Group in Organic Synthesis, Wiley-VCH, New York, 2001.
2 (a) G. Rosini, in Comprehensive Organic Synthesis, ed. B. M.
Trost, Pergamon, Oxford, 1991, vol. 2, pp. 321; (b) F. A. Luzzio,
Tetrahedron, 2001, 57, 915.
3 (a) R. Ballini, G. Bosica, D. Livi, A. Palmieri, R. Maggi and G.
Sartori, Tetrahedron Lett., 2003, 44, 2271; (b) R. Ballini, G. Bosica,
D. Fiorini, A. Palmieri and M. Petrini, Chem. Rev., 2005, 105, 933.
4 (a) D. Seebach, E. W. Colvin, F. Leher and T. Weller, Chimia, 1979,
33, 1; (b) R. Ballini and M. Petrini, Tetrahedron, 2004, 60, 1017.
5 See for example: (a) G. Rosini, R. Ballini and M. Petrini, Angew.
Chem., Int. Ed. Engl., 1986, 25, 941; (b) G. Rosini, R. Ballini, M.
Petrini and E. Marotta, Org. Prep. Proced. Int., 1990, 22, 707; (c) R.
Ballini, L. Barboni, G. Bosica and M. Petrini, Synlett, 2000, 391;
(d) R. Ballini and A. Rinaldi, Tetrahedron Lett., 1994, 35, 9247;
(e) R. Ballini, in Studies in Natural Products Chemistry, ed. Atta-ur-
Rahman, Elsevier, Amsterdam, 1997, vol. 19, pp. 117.
6 See for example: (a) R. Ballini, A. Palmieri and P. Righi,Tetrahedron,
2007, 63, 12099; (b) R. Ballini, Synlett, 1999, 1009; (c) R. Ballini, L.
Barboni and G. Giarlo, J. Org. Chem., 2004, 69, 6907; (d) R. Ballini,
L. Barboni and A. Palmieri, Synlett, 2007, 3019; (e) R. Ballini, L.
Barboni and A. Palmieri, Green Chem., 2008, 10, 1004.
7 See for example: (a)G.Rosini, R. Ballini andP. Sorrenti,Tetrahedron,
1983, 39, 4127; (b) R. O¨hrlein, W. Schwab, R. Ehrler and V. Ja¨ger,
Synthesis, 1986, 535; (c) R. Ballini and G. Bartoli, Synthesis, 1993,
965; (d) A. P. Kozikowski and L.-P. Wu, Synlett, 1991, 465; (e) J. K.
Addo, P. Teesdale-Spittle and J. O. Hoberg, Synthesis, 2005, 1923;
(f) P. C. Silva, J. S. Costa and V. L. P. Pereira, Synth. Commun., 2001,
31, 595; (g) F. A. Luzzio and R. W. Fitch, J. Org. Chem., 1999, 49,
6508.
8 (a) H. H. Baer, S.-H. L. Chiu and D. C. Shield, Can. J. Chem., 1973,
51, 2828; (b) R. A. Kunetsky, A. D. Dilman, K. P. Tsvaygboym, S. L.
Ioffe, Y. A. Strelenko and V. A. Tartakovsky, Synthesis, 2003, 1339;
(c) T. Miyakoshi, S. Saito and J. Kumanotani, Chem. Lett., 1981,
1677.
9 K.Alfonsi, J. Colberg, P. J.Dunn,T. Fevig, S. Jennings, T.A. Johnson,
H. P. Kleine, C. Knight, M. A. Nagy, D. A. Perry and M. Stefaniak,
Green Chem., 2008, 10, 31.
10 A. Solinas and M. Taddei, Synthesis, 2007, 2409.
11 S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson, A. G. Leach,
D. A. Longbottom, M. Nesi, J. S. Scott, R. I. Storer and S. J. Taylor,
J. Chem. Soc., Perkin Trans. 1, 2000, 3815.
12 (a) K. Watanabe, N. Yamagiwa and Y. Torisawa, Org. Process Res.
Dev., 2007, 11, 251; (b) R. K. Henderson, C. Jime´nez-Gonza´lez, D.
This journal is © The Royal Society of Chemistry 2011 Green Chem., 2011, 13, 2026–2028 | 2027
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J. C. Constable, S. R. Alston, G. G. A. Inglis, G. Fisher, J. Sherwood,
S. P. Binks and A. D. Curzons, Green Chem., 2011, 13, 854.
13 (a) R. Ballini, D. Fiorini, M. V. Gil and A. Palmieri, Green Chem.,
2003, 5, 475; (b) R. Ballini, D. Fiorini, R. Maggi, C. Oro, A. Palmieri
and G. Sartori, Synlett, 2006, 1849; (c) R. Ballini and A. Palmieri,
Adv. Synth. Catal., 2006, 348, 1154; (d) R. Ballini, L. Barboni and A.
Palmieri, Synlett, 2007, 3019; (e) R. Ballini, G. Bosica, A. Palmieri,
F. Pizzo and L. Vaccaro, Green Chem., 2008, 10, 541; (f) R. Ballini,
A. Palmieri, M. Abdul, Karim Talaq and S. Gabrielli, Adv. Synth.
Catal., 2009, 351, 2611; (g) A. Palmieri, S. Gabrielli and R. Ballini,
Adv. Synth. Catal., 2010, 352, 1485; (h) A. Palmieri, S. Gabrielli and
R. Ballini, Chem. Commun., 2010, 46, 6165.
14 The nitrite on polymer support (Amberlite R©IRA 900 NO2-form)
was purchased from Sigma-Aldrich and used directly without any
manipulation. The promoter containing ~14% of water and has a
loading of ~4 mmol g-1 of NO2.
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Eco-friendly synthesis of beta-nitro ketones from conjugated enones: an important improvement of the Miyakoshi procedure

PEROSA, Alvise

SELVA, Maurizio

Archivio istituzionale della ricerca - Università degli Studi di Venezia Ca' Foscari

Green Chemistry Dynamic Article LinksCite this: Green Chem., 2011, 13, 2026www.rsc.org/greenchem COMMUNICATIONEco-friendly synthesis of b-nitro ketones from conjugated enones: animportant improvement of the Miyakoshi procedure†Serena Gabrielli,a Alessandro Palmieri,a Alvise Perosa,b Maurizio Selvab and Roberto Ballini*aReceived 27th May 2011, Accepted 20th June 2011DOI: 10.1039/c1gc15616kA variety of a,b-unsaturated ketones can be easily con-verted, at room temperature, into b-nitro ketones by nitra-tion with solid supported nitrite (SSN) and in the presenceof acetic acid and cyclopentyl methyl ether.Nitroalkanes are one of the most fundamental classes ofsubstrates in organic chemistry.1 This is mainly due to thefact that (i) they allow the easy formation of new carbon–carbon and carbon–heteroatom bonds under very mild reactionconditions,2,3 (ii) the nitro group can be converted into a plethoraof other functionalities,4 and (iii) they are the key startingmaterial for the preparation of a variety of ﬁne chemicals.5Thus, the easy accessibility to nitroalkanes remains an impor-tant goal, especially for those functionalized ones.6 In this con-text, of great interest are the b-nitro ketones 1 because these kindof derivatives, or their protected ones, have been demonstratedto be important building blocks in organic synthesis.7 Thesemolecules can be obtained (Fig. 1) from three different sources:(i) by halo-nitro displacement of b-halocarbonyl derivatives2 (way a),8a (ii) via C,C-cross-coupling of nitroalkanes 3 andtheir silyl derivatives 4 (Ioffe procedure, way b),8b or (iii) by thehistorical Miyakoshi procedure8c that involves the nitration ofconjugated enones 5 using sodium nitrite and acetic acid, inTHF as solvent (way c). Although each of the above methodsgives access to different interesting molecular structures, way cremains the most used one.Above all, the Miyakoshi procedure shows important draw-backs because it seems to be limited just to a,b-unsaturatedketones having simple molecular frames, gives moderate yields,needs the presence of organic volatile solvents such as THF9and, moreover, the methodology requires a tedious and noneco-sustainable work-up. Thus, in order to avoid the abovelimitations, new improvements of this classical method for thepreparation of the title compounds would be encouraged.aGreen Chemistry Group, School of Science and Technology, ChemistryDivision, University of Camerino, Via S. Agostino 1, 62032, Camerino,Italy. E-mail: roberto.ballini@unicam.it; Fax: +39 0737 402297;Tel: +39 0737 402270bDipartimento di Scienze Molecolari e Nanosistemi, Universita` Ca’Foscari Venezia, Dorsoduro 2137, 30123, Venezia, Italy.E-mail: selva@unive.it; Tel: +39 041 2348687† Electronic supplementary information (ESI) available: See DOI:10.1039/c1gc15616kFig. 1 Main synthetic pathways for the synthesis of b-nitro ketones 1.In the course of the last few years, solid supported reagents(SSR) have attracted growing interest since they have demon-strated a great versatility as powerful promoters in a widenumber of reactions,10 increasing the chemical reactivity andsimplifying the classical work-up step into an easy ﬁltration,with the consequent minimization of the use of solvents.11On the other hand, recently, it has been demonstrated thatreactions conducted in cyclopentyl methyl ether (CPME), asa new emerging “green solvent”, in contrast to tetrahydrofuran,are comparativelymore favourable in terms of eco-sustainabilityand efﬁciency, and with consequent reduction of both exposureand ﬂammability safety problems.12In our laboratory in recent years, we have found that thereactivity and the chemical potentialities of the aliphatic nitrocompounds often increase by the use of SSR.13 Based onthese experiences and following our research projects on thechemistry of aliphatic nitro compounds, we have now developedan improved general procedure for the nitration of conjugatedenones, employing solid supported nitrite (SSN).14 Thus, ﬁrstlywe tested, as model reaction, the nitration of the compound 5achecking different amounts of both SSN and acetic acid on avariety of solvents, including CPME.As reported in Table 1, the best yield (89%) was obtainedusing 3 equivalents of nitrite on polymer, and 5 equivalents ofacetic acid on CPME (entry f).Encouraged by this excellent result and in order to explorethe general applicability of our methodology, we submitted avariety of a,b-unsaturated ketones under the optimized reactionconditions.As reported in Table 2, the reaction gives important yields(60–89%) with a variety of enones, including furyl and aryl vinyl2026 | Green Chem., 2011, 13, 2026–2028 This journal is © The Royal Society of Chemistry 2011Downloaded by UNIVERSITA CA FOSCARI DI VENEZIA on 12 August 2011Published on 07 July 2011 on http://pubs.rsc.org | doi:10.1039/C1GC15616KView OnlineTable 1 Optimization studiesEntryeq. Nitrite onpolymer (SSN) eq. AcOH Solvent Yield (%)a of 1aa 1 2 CPME 15b 1 2 CPME 30c 2 4 CPME 68d 3 4 CPME 63e 4 5 THF 80f 3 5 CPME 89g 3 6 CPME 70h 3 5 EtOAc 55i 3 5 DCM 65a Yield of pure isolated product.Table 2 Nitration of different unsaturated ketonesR R1 Reaction time (h) Yield (%)a of 1a Ph(CH2)2 H 30 89b n-C8H17 H 30 72c PhC6H4 H 24 82d Ph H 24 86e p-MeOC6H4 H 30 82f p-CF3C6H4 H 27 77g c-C6H11 H 30 75h 2-furyl H 30 75i Cl(CH2)5 H 30 75j Et H 24 84k n-Bu Me 48 60a Yield of pure isolated product.ketones, independently from the nature of the alkyl group (R)or the presence of other functionalities in the phenyl ring (1c, 1eand 1f).However, of particular importance is the success obtained bythe nitration of the hindered enone 5k performed in consistentyield (60%). The latter example is of great importance, because,to the best of our knowledge, it is the ﬁrst report of thenitration of substituted vinyl ketones, allowing an easy accessto secondary nitro compounds, which are difﬁcult to obtain byother methods.ConclusionsIn conclusion, by our method the Miyakoshi procedure hasbeen signiﬁcantly improved both in terms of efﬁciency and eco-sustainability. In fact, higher yields have been obtained using agreener solvent (CPME) and the procedure works well even withcomplex conjugated enones, including substituted vinyl ketones.Furthermore, it is possible to preserve other functionalities,minimizing the work-up step into an easy ﬁltration and evap-oration of both solvent and acetic acid, avoiding any classical,tedious aqueous work-up and the use of any drying salts, withthe consequent drastic decrease of E-factor.ExperimentalGeneral procedure for the synthesis of compounds 1a–kBatch reaction was carried out by stirring a mixture of ketone5 (1 mmol), SSN (3 mmol), acetic acid (5 mmol) and CPME(3 mL). The reaction was allowed to stir for the appropriatetime (see Table 2) at room temperature. After the reaction wascompleted, the resin was ﬁltered off and washed with EtOAc(5 mL), then the solvent was removed under vacuum, and thecrude product 1 was puriﬁed by ﬂash chromatography column(hexanes : EtOAc = 85 : 15).AcknowledgementsThe authors thanks the Universities of Camerino and Ca’Foscari Venezia and MIUR-Italy (FIRB National Project“Metodologie di nuova generazione nella formazione di legamicarbonio-carbonio e carbonio-eteroatomo in condizioni eco-sostenibili”, e PRIN National Project “Sintesi organicheecosostenibili mediate da nuovi sistemi catalitici”) for ﬁnancialsupport.Notes and references1 (a) G. Rosini and R. Ballini, Synthesis, 1988, 833; (b) N. Ono, TheNitro Group in Organic Synthesis, Wiley-VCH, New York, 2001.2 (a) G. Rosini, in Comprehensive Organic Synthesis, ed. B. M.Trost, Pergamon, Oxford, 1991, vol. 2, pp. 321; (b) F. A. Luzzio,Tetrahedron, 2001, 57, 915.3 (a) R. Ballini, G. Bosica, D. Livi, A. Palmieri, R. Maggi and G.Sartori, Tetrahedron Lett., 2003, 44, 2271; (b) R. Ballini, G. Bosica,D. Fiorini, A. Palmieri and M. Petrini, Chem. Rev., 2005, 105, 933.4 (a) D. Seebach, E. W. Colvin, F. Leher and T. Weller, Chimia, 1979,33, 1; (b) R. Ballini and M. Petrini, Tetrahedron, 2004, 60, 1017.5 See for example: (a) G. Rosini, R. Ballini and M. Petrini, Angew.Chem., Int. Ed. Engl., 1986, 25, 941; (b) G. Rosini, R. Ballini, M.Petrini and E. Marotta, Org. Prep. Proced. Int., 1990, 22, 707; (c) R.Ballini, L. Barboni, G. Bosica and M. Petrini, Synlett, 2000, 391;(d) R. Ballini and A. Rinaldi, Tetrahedron Lett., 1994, 35, 9247;(e) R. Ballini, in Studies in Natural Products Chemistry, ed. Atta-ur-Rahman, Elsevier, Amsterdam, 1997, vol. 19, pp. 117.6 See for example: (a) R. Ballini, A. Palmieri and P. Righi,Tetrahedron,2007, 63, 12099; (b) R. Ballini, Synlett, 1999, 1009; (c) R. Ballini, L.Barboni and G. Giarlo, J. Org. Chem., 2004, 69, 6907; (d) R. Ballini,L. Barboni and A. Palmieri, Synlett, 2007, 3019; (e) R. Ballini, L.Barboni and A. Palmieri, Green Chem., 2008, 10, 1004.7 See for example: (a)G.Rosini, R. Ballini andP. Sorrenti,Tetrahedron,1983, 39, 4127; (b) R. O¨hrlein, W. Schwab, R. Ehrler and V. Ja¨ger,Synthesis, 1986, 535; (c) R. Ballini and G. Bartoli, Synthesis, 1993,965; (d) A. P. Kozikowski and L.-P. Wu, Synlett, 1991, 465; (e) J. K.Addo, P. Teesdale-Spittle and J. O. Hoberg, Synthesis, 2005, 1923;(f) P. C. Silva, J. S. Costa and V. L. P. Pereira, Synth. Commun., 2001,31, 595; (g) F. A. Luzzio and R. W. Fitch, J. Org. Chem., 1999, 49,6508.8 (a) H. H. Baer, S.-H. L. Chiu and D. C. Shield, Can. J. Chem., 1973,51, 2828; (b) R. A. Kunetsky, A. D. Dilman, K. P. Tsvaygboym, S. L.Ioffe, Y. A. Strelenko and V. A. Tartakovsky, Synthesis, 2003, 1339;(c) T. Miyakoshi, S. Saito and J. Kumanotani, Chem. Lett., 1981,1677.9 K.Alfonsi, J. Colberg, P. J.Dunn,T. Fevig, S. Jennings, T.A. Johnson,H. P. Kleine, C. Knight, M. A. Nagy, D. A. Perry and M. Stefaniak,Green Chem., 2008, 10, 31.10 A. Solinas and M. Taddei, Synthesis, 2007, 2409.11 S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson, A. G. Leach,D. A. Longbottom, M. Nesi, J. S. Scott, R. I. Storer and S. J. Taylor,J. Chem. Soc., Perkin Trans. 1, 2000, 3815.12 (a) K. Watanabe, N. Yamagiwa and Y. Torisawa, Org. Process Res.Dev., 2007, 11, 251; (b) R. K. Henderson, C. Jime´nez-Gonza´lez, D.This journal is © The Royal Society of Chemistry 2011 Green Chem., 2011, 13, 2026–2028 | 2027Downloaded by UNIVERSITA CA FOSCARI DI VENEZIA on 12 August 2011Published on 07 July 2011 on http://pubs.rsc.org | doi:10.1039/C1GC15616KView OnlineJ. C. Constable, S. R. Alston, G. G. A. Inglis, G. Fisher, J. Sherwood,S. P. Binks and A. D. Curzons, Green Chem., 2011, 13, 854.13 (a) R. Ballini, D. Fiorini, M. V. Gil and A. Palmieri, Green Chem.,2003, 5, 475; (b) R. Ballini, D. Fiorini, R. Maggi, C. Oro, A. Palmieriand G. Sartori, Synlett, 2006, 1849; (c) R. Ballini and A. Palmieri,Adv. Synth. Catal., 2006, 348, 1154; (d) R. Ballini, L. Barboni and A.Palmieri, Synlett, 2007, 3019; (e) R. Ballini, G. Bosica, A. Palmieri,F. Pizzo and L. Vaccaro, Green Chem., 2008, 10, 541; (f) R. Ballini,A. Palmieri, M. Abdul, Karim Talaq and S. Gabrielli, Adv. Synth.Catal., 2009, 351, 2611; (g) A. Palmieri, S. Gabrielli and R. Ballini,Adv. Synth. Catal., 2010, 352, 1485; (h) A. Palmieri, S. Gabrielli andR. Ballini, Chem. Commun., 2010, 46, 6165.14 The nitrite on polymer support (Amberlite R©IRA 900 NO2-form)was purchased from Sigma-Aldrich and used directly without anymanipulation. The promoter containing ~14% of water and has aloading of ~4 mmol g-1 of NO2.2028 | Green Chem., 2011, 13, 2026–2028 This journal is © The Royal Society of Chemistry 2011Downloaded by UNIVERSITA CA FOSCARI DI VENEZIA on 12 August 2011Published on 07 July 2011 on http://pubs.rsc.org | doi:10.1039/C1GC15616KView Online

Serena Gabrielli

Alessandro Palmieri

Alvise Perosa

Maurizio Selva

Roberto Ballini

Crossref

Eco-friendly synthesis of β-nitro ketones from conjugated enones: an important improvement of the Miyakoshi procedure

A variety of alpha,beta-unsaturated ketones can be easily converted, at room temperature, into beta-nitro ketones by nitration with solid supported nitrite (SSN) and in the presence of acetic acid and cyclopentyl methyl ether

GABRIELLI, Serena

PALMIERI, Alessandro

BALLINI, Roberto

Perosa A.

Selva M.

Archivio istituzionale della ricerca - Università di Camerino

Green Chemistry Dynamic Article LinksCite this: Green Chem., 2011, 13, 2026www.rsc.org/greenchem COMMUNICATIONEco-friendly synthesis of b-nitro ketones from conjugated enones: animportant improvement of the Miyakoshi procedure†Serena Gabrielli,a Alessandro Palmieri,a Alvise Perosa,b Maurizio Selvab and Roberto Ballini*aReceived 27th May 2011, Accepted 20th June 2011DOI: 10.1039/c1gc15616kA variety of a,b-unsaturated ketones can be easily con-verted, at room temperature, into b-nitro ketones by nitra-tion with solid supported nitrite (SSN) and in the presenceof acetic acid and cyclopentyl methyl ether.Nitroalkanes are one of the most fundamental classes ofsubstrates in organic chemistry.1 This is mainly due to thefact that (i) they allow the easy formation of new carbon–carbon and carbon–heteroatom bonds under very mild reactionconditions,2,3 (ii) the nitro group can be converted into a plethoraof other functionalities,4 and (iii) they are the key startingmaterial for the preparation of a variety of fine chemicals.5Thus, the easy accessibility to nitroalkanes remains an impor-tant goal, especially for those functionalized ones.6 In this con-text, of great interest are the b-nitro ketones 1 because these kindof derivatives, or their protected ones, have been demonstratedto be important building blocks in organic synthesis.7 Thesemolecules can be obtained (Fig. 1) from three different sources:(i) by halo-nitro displacement of b-halocarbonyl derivatives2 (way a),8a (ii) via C,C-cross-coupling of nitroalkanes 3 andtheir silyl derivatives 4 (Ioffe procedure, way b),8b or (iii) by thehistorical Miyakoshi procedure8c that involves the nitration ofconjugated enones 5 using sodium nitrite and acetic acid, inTHF as solvent (way c). Although each of the above methodsgives access to different interesting molecular structures, way cremains the most used one.Above all, the Miyakoshi procedure shows important draw-backs because it seems to be limited just to a,b-unsaturatedketones having simple molecular frames, gives moderate yields,needs the presence of organic volatile solvents such as THF9and, moreover, the methodology requires a tedious and noneco-sustainable work-up. Thus, in order to avoid the abovelimitations, new improvements of this classical method for thepreparation of the title compounds would be encouraged.aGreen Chemistry Group, School of Science and Technology, ChemistryDivision, University of Camerino, Via S. Agostino 1, 62032, Camerino,Italy. E-mail: roberto.ballini@unicam.it; Fax: +39 0737 402297;Tel: +39 0737 402270bDipartimento di Scienze Molecolari e Nanosistemi, Università Ca’Foscari Venezia, Dorsoduro 2137, 30123, Venezia, Italy.E-mail: selva@unive.it; Tel: +39 041 2348687† Electronic supplementary information (ESI) available: See DOI:10.1039/c1gc15616kFig. 1 Main synthetic pathways for the synthesis of b-nitro ketones 1.In the course of the last few years, solid supported reagents(SSR) have attracted growing interest since they have demon-strated a great versatility as powerful promoters in a widenumber of reactions,10 increasing the chemical reactivity andsimplifying the classical work-up step into an easy filtration,with the consequent minimization of the use of solvents.11On the other hand, recently, it has been demonstrated thatreactions conducted in cyclopentyl methyl ether (CPME), asa new emerging “green solvent”, in contrast to tetrahydrofuran,are comparatively more favourable in terms of eco-sustainabilityand efficiency, and with consequent reduction of both exposureand flammability safety problems.12In our laboratory in recent years, we have found that thereactivity and the chemical potentialities of the aliphatic nitrocompounds often increase by the use of SSR.13 Based onthese experiences and following our research projects on thechemistry of aliphatic nitro compounds, we have now developedan improved general procedure for the nitration of conjugatedenones, employing solid supported nitrite (SSN).14 Thus, firstlywe tested, as model reaction, the nitration of the compound 5achecking different amounts of both SSN and acetic acid on avariety of solvents, including CPME.As reported in Table 1, the best yield (89%) was obtainedusing 3 equivalents of nitrite on polymer, and 5 equivalents ofacetic acid on CPME (entry f).Encouraged by this excellent result and in order to explorethe general applicability of our methodology, we submitted avariety of a,b-unsaturated ketones under the optimized reactionconditions.As reported in Table 2, the reaction gives important yields(60–89%) with a variety of enones, including furyl and aryl vinyl2026 | Green Chem., 2011, 13, 2026–2028 This journal is © The Royal Society of Chemistry 2011Downloaded by University of Camerino on 03 February 2012Published on 07 July 2011 on http://pubs.rsc.org | doi:10.1039/C1GC15616KView Online / Journal Homepage / Table of Contents for this issueTable 1 Optimization studiesEntryeq. Nitrite onpolymer (SSN) eq. AcOH Solvent Yield (%)a of 1aa 1 2 CPME 15b 1 2 CPME 30c 2 4 CPME 68d 3 4 CPME 63e 4 5 THF 80f 3 5 CPME 89g 3 6 CPME 70h 3 5 EtOAc 55i 3 5 DCM 65a Yield of pure isolated product.Table 2 Nitration of different unsaturated ketonesR R1 Reaction time (h) Yield (%)a of 1a Ph(CH2)2 H 30 89b n-C8H17 H 30 72c PhC6H4 H 24 82d Ph H 24 86e p-MeOC6H4 H 30 82f p-CF3C6H4 H 27 77g c-C6H11 H 30 75h 2-furyl H 30 75i Cl(CH2)5 H 30 75j Et H 24 84k n-Bu Me 48 60a Yield of pure isolated product.ketones, independently from the nature of the alkyl group (R)or the presence of other functionalities in the phenyl ring (1c, 1eand 1f).However, of particular importance is the success obtained bythe nitration of the hindered enone 5k performed in consistentyield (60%). The latter example is of great importance, because,to the best of our knowledge, it is the first report of thenitration of substituted vinyl ketones, allowing an easy accessto secondary nitro compounds, which are difficult to obtain byother methods.ConclusionsIn conclusion, by our method the Miyakoshi procedure hasbeen significantly improved both in terms of efficiency and eco-sustainability. In fact, higher yields have been obtained using agreener solvent (CPME) and the procedure works well even withcomplex conjugated enones, including substituted vinyl ketones.Furthermore, it is possible to preserve other functionalities,minimizing the work-up step into an easy filtration and evap-oration of both solvent and acetic acid, avoiding any classical,tedious aqueous work-up and the use of any drying salts, withthe consequent drastic decrease of E-factor.ExperimentalGeneral procedure for the synthesis of compounds 1a–kBatch reaction was carried out by stirring a mixture of ketone5 (1 mmol), SSN (3 mmol), acetic acid (5 mmol) and CPME(3 mL). The reaction was allowed to stir for the appropriatetime (see Table 2) at room temperature. After the reaction wascompleted, the resin was filtered off and washed with EtOAc(5 mL), then the solvent was removed under vacuum, and thecrude product 1 was purified by flash chromatography column(hexanes : EtOAc = 85 : 15).AcknowledgementsThe authors thanks the Universities of Camerino and Ca’Foscari Venezia and MIUR-Italy (FIRB National Project“Metodologie di nuova generazione nella formazione di legamicarbonio-carbonio e carbonio-eteroatomo in condizioni eco-sostenibili”, e PRIN National Project “Sintesi organicheecosostenibili mediate da nuovi sistemi catalitici”) for financialsupport.Notes and references1 (a) G. Rosini and R. Ballini, Synthesis, 1988, 833; (b) N. Ono, TheNitro Group in Organic Synthesis, Wiley-VCH, New York, 2001.2 (a) G. Rosini, in Comprehensive Organic Synthesis, ed. B. M.Trost, Pergamon, Oxford, 1991, vol. 2, pp. 321; (b) F. A. Luzzio,Tetrahedron, 2001, 57, 915.3 (a) R. Ballini, G. Bosica, D. Livi, A. Palmieri, R. Maggi and G.Sartori, Tetrahedron Lett., 2003, 44, 2271; (b) R. Ballini, G. Bosica,D. Fiorini, A. Palmieri and M. Petrini, Chem. Rev., 2005, 105, 933.4 (a) D. Seebach, E. W. Colvin, F. Leher and T. Weller, Chimia, 1979,33, 1; (b) R. Ballini and M. Petrini, Tetrahedron, 2004, 60, 1017.5 See for example: (a) G. Rosini, R. Ballini and M. Petrini, Angew.Chem., Int. Ed. Engl., 1986, 25, 941; (b) G. Rosini, R. Ballini, M.Petrini and E. Marotta, Org. Prep. Proced. Int., 1990, 22, 707; (c) R.Ballini, L. Barboni, G. Bosica and M. Petrini, Synlett, 2000, 391;(d) R. Ballini and A. Rinaldi, Tetrahedron Lett., 1994, 35, 9247;(e) R. Ballini, in Studies in Natural Products Chemistry, ed. Atta-ur-Rahman, Elsevier, Amsterdam, 1997, vol. 19, pp. 117.6 See for example: (a) R. Ballini, A. Palmieri and P. Righi, Tetrahedron,2007, 63, 12099; (b) R. Ballini, Synlett, 1999, 1009; (c) R. Ballini, L.Barboni and G. Giarlo, J. Org. Chem., 2004, 69, 6907; (d) R. Ballini,L. Barboni and A. Palmieri, Synlett, 2007, 3019; (e) R. Ballini, L.Barboni and A. Palmieri, Green Chem., 2008, 10, 1004.7 See for example: (a) G. Rosini, R. Ballini and P. Sorrenti, Tetrahedron,1983, 39, 4127; (b) R. Öhrlein, W. Schwab, R. Ehrler and V. Jäger,Synthesis, 1986, 535; (c) R. Ballini and G. Bartoli, Synthesis, 1993,965; (d) A. P. Kozikowski and L.-P. Wu, Synlett, 1991, 465; (e) J. K.Addo, P. Teesdale-Spittle and J. O. Hoberg, Synthesis, 2005, 1923;(f) P. C. Silva, J. S. Costa and V. L. P. Pereira, Synth. Commun., 2001,31, 595; (g) F. A. Luzzio and R. W. Fitch, J. Org. Chem., 1999, 49,6508.8 (a) H. H. Baer, S.-H. L. Chiu and D. C. Shield, Can. J. Chem., 1973,51, 2828; (b) R. A. Kunetsky, A. D. Dilman, K. P. Tsvaygboym, S. L.Ioffe, Y. A. Strelenko and V. A. Tartakovsky, Synthesis, 2003, 1339;(c) T. Miyakoshi, S. Saito and J. Kumanotani, Chem. Lett., 1981,1677.9 K. Alfonsi, J. Colberg, P. J. Dunn, T. Fevig, S. Jennings, T. A. Johnson,H. P. Kleine, C. Knight, M. A. Nagy, D. A. Perry and M. Stefaniak,Green Chem., 2008, 10, 31.10 A. Solinas and M. Taddei, Synthesis, 2007, 2409.11 S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson, A. G. Leach,D. A. Longbottom, M. Nesi, J. S. Scott, R. I. Storer and S. J. Taylor,J. Chem. Soc., Perkin Trans. 1, 2000, 3815.12 (a) K. Watanabe, N. Yamagiwa and Y. Torisawa, Org. Process Res.Dev., 2007, 11, 251; (b) R. K. Henderson, C. Jiménez-González, D.This journal is © The Royal Society of Chemistry 2011 Green Chem., 2011, 13, 2026–2028 | 2027Downloaded by University of Camerino on 03 February 2012Published on 07 July 2011 on http://pubs.rsc.org | doi:10.1039/C1GC15616KView OnlineJ. C. Constable, S. R. Alston, G. G. A. Inglis, G. Fisher, J. Sherwood,S. P. Binks and A. D. Curzons, Green Chem., 2011, 13, 854.13 (a) R. Ballini, D. Fiorini, M. V. Gil and A. Palmieri, Green Chem.,2003, 5, 475; (b) R. Ballini, D. Fiorini, R. Maggi, C. Oro, A. Palmieriand G. Sartori, Synlett, 2006, 1849; (c) R. Ballini and A. Palmieri,Adv. Synth. Catal., 2006, 348, 1154; (d) R. Ballini, L. Barboni and A.Palmieri, Synlett, 2007, 3019; (e) R. Ballini, G. Bosica, A. Palmieri,F. Pizzo and L. Vaccaro, Green Chem., 2008, 10, 541; (f) R. Ballini,A. Palmieri, M. Abdul, Karim Talaq and S. Gabrielli, Adv. Synth.Catal., 2009, 351, 2611; (g) A. Palmieri, S. Gabrielli and R. Ballini,Adv. Synth. Catal., 2010, 352, 1485; (h) A. Palmieri, S. Gabrielli andR. Ballini, Chem. Commun., 2010, 46, 6165.14 The nitrite on polymer support (Amberlite R©IRA 900 NO2-form)was purchased from Sigma-Aldrich and used directly without anymanipulation. The promoter containing ~14% of water and has aloading of ~4 mmol g-1 of NO2.2028 | Green Chem., 2011, 13, 2026–2028 This journal is © The Royal Society of Chemistry 2011Downloaded by University of Camerino on 03 February 2012Published on 07 July 2011 on http://pubs.rsc.org | doi:10.1039/C1GC15616KView Online

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Eco-friendly synthesis of beta-nitro ketones from conjugated enones: an important improvement of the Miyakoshi procedure

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Archivio istituzionale della ricerca - Università di Camerino