"On-water" Michael-type addition reactions promoted by PhSeZnCl

Article abstract of DOI:10.1002/ejoc.201100045

In this communication we report that our reagent PhSeZnCl can be conveniently used to effect Michael addition like reactions of unsaturated ketones and electron-deficient alkynes, leading to synthetically useful β-seleno derivativesand vinyl selenides, respectively. The reactions are effected at room temperature in THF as well as under "on water" conditions. When the addition occurs on a triple bond, good stereoselectivity is observed, and the reaction shows a rate acceleration in water suspension. Copyright

Full text of DOI:10.1002/ejoc.201100045

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100045
“On-Water” Michael-Type Addition Reactions Promoted by PhSeZnCl
Benedetta Battistelli,[a] Testaferri Lorenzo,[a] Marcello Tiecco,[a] and Claudio Santi*[a]
Keywords: Selenium / Zinc / Michael addition / Water chemistry / Nucleophilic addition
In this communication we report that our reagent PhSeZnCl
can be conveniently used to effect Michael addition like re-
actions of unsaturated ketones and electron-deficient alk-
ynes, leading to synthetically useful β-seleno derivatives
and vinyl selenides, respectively. The reactions are effected
at room temperature in THF as well as under “on water”
conditions. When the addition occurs on a triple bond, good
stereoselectivity is observed, and the reaction shows a rate
acceleration in water suspension.
Introduction
The addition of selenolates represents a convenient pro-
cedure to introduce a selenium-containing functionality
into electrophilic organic substrates. It is well known that
once selenium is incorporated into a molecule, it can be
easily manipulated and removed in many different ways by
using mild reaction conditions to usually afford the target
compounds in good yields even with the use of catalytic
amounts of reagents.[1] Conjugate addition is one of the
most important and common bond-forming strategies in
synthetic organic chemistry.[2] Few examples reported that
treatment of α,β-unsaturated carbonyl derivatives with nu-
cleophilic selenium species affords β-seleno derivatives
through Michael-like addition.[3] This reaction has been ap-
Scheme 1. PhSeZnCl in Michael-type reactions.
Results and Discussion
In order to identify the best experimental conditions, pre-
plied to protected α,β-unsaturated lactones,[4] in natural liminary investigations were carried out starting from cy-
product synthesis,[5] and in asymmetric Michael additions clohexen-2-one (2a). The reaction of 1 with electrophile 2a
in the presence of an alkaloid.[6] Seleno-Michael reactions was effected in H2O suspension as well as in THF solution,
were effected by using in situ prepared selenolates starting evaluating the effect of l-proline and DMF as additives.
from the corresponding diselenides in the presence of In-
All the conversions were performed at room temperature,
[8]
TMSCl[7] or Zn/RuCl3 by using ceric(IV) ammonium ni- and the yields reported in Table 1 refer to the amount of
trate[9] in a radical process or β-cyclodextrins[10] as catalysts isolated products after purification by silica gel column
and benzenselenol as the nucleophile. All these procedures chromatography.
suffer from low yields and the disadvantage of using air-
When the reaction was carried out in an on-water sus-
and moisture-sensitive reagents such as selenols. Continuing pension, the reaction was very slow and 4a was obtained in
investigations into the synthetic applicability of zinc sele- only 30% yield after 140 h (Table 1, Entry 1). Nevertheless,
nolates and bench-stable PhSeZnCl (1),[11] we report herein no addition products were observed when the reaction was
the results of some Michael-type addition reactions on con- carried out in THF (Table 1, Entry 4), and in both cases the
jugated alkenes 2a–g and electron-deficient alkynes 3a–g to yields increased slightly when DMF (2 equiv.) was added
give the corresponding β-selenocarbonyl derivatives 4a–g (Table 1, Entries 2 and 5).
and vinyl selenides 5/6a–g, respectively (Scheme 1).
l-Proline has been reported to be a powerful catalyst for
a number of asymmetric Michael addition reactions;[12]
however, when it was added to the water suspension
(Table 1, Entry 3) an increase in yield but no significant ste-
reocontrol was observed in the formation of 4a, which was
isolated as a racemic mixture.
[a] Dipartimento di Chimica e Tecnologia del Farmaco, Università
degli Studi di Perugia,
Via del Liceo 1, 06123 Perugia, Italy
Fax: +39-075-5855116
E-mail: santi@unipg.it
We observed that in THF the reaction mixture progress-
ively became yellow, probably indicating the formation of
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100045.
1848
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1848–1851

“On-Water” Michael-Type Addition Reactions Promoted by PhSeZnCl
Table 1. Preliminary investigations.
Table 2. Michael-type addition reaction of conjugated alkenes.
Entry
Solvent
Additive
hν
Time
[h]
Yield
[%][a]
1
2
3
4
5
6
7
8
9
H2O
H2O
H2O
THF
THF
THF
H2O
THF
H2O
none
DMF
l-proline
none
DMF
none
none
DMF
DMF
yes[c]
yes[c]
yes[c]
yes[c]
yes[c]
no
no
no
no
140
140
140
140
24
24
140
24
30
50
42[b]
–
50
90
53
90
51
140
[a] Calculated for the isolated compound. [b] Racemic mixture.
[c] The reaction was carried out in colorless transparent Pyrex glass
under room light.
the unreactive diphenyl diselenide reasonably through a
photoactivated radical mechanism. To support this hypoth-
esis, a THF solution of PhSeZnCl (1 mmol in 1 mL of
THF) was quantitatively converted into the corresponding
diselenide by irradiation for 30 min with a visible-light
lamp. On the basis of these results and to prevent reagent
decomposition, the reaction mixture was protected from
light. Under these conditions (Table 1, Entries 6–9) better
results could be obtained in water as well in THF, and it is
interesting to note that the presence of DMF did not have
any appreciable effects. Unfortunately, under the same con-
ditions, PhSeZnBr[11b] did not lead to the formation of 4a
in water or in THF solution, and in both cases, starting
enone 2a was quantitatively recovered.
With the optimized conditions in hand we explored the
scope of the reaction that appears to be strongly limited by
the nature of the electron-withdrawing group conjugated to
[a] In H2O, 23 °C for 140 h. [b] In THF, 23 °C for 24 h.
the double bond. Only conjugated ketones were sufficiently intermediates play an important role in the synthesis of or-
reactive to afford the corresponding β-phenylseleno deriva- ganoselenium compounds, we decided to investigate elec-
tives. Conjugated esters (with the only exception being tron-deficient alkynes 3a–g as Michael acceptors in the re-
methyl acrylate, which gave the addition product in 10% action with PhSeZnCl for the stereoselective preparation of
yield in THF and 15% yield in water suspension), alde- functionalized alkenes.[14]
hydes, nitro derivatives, nitriles, and selenones were com-
It is known that nucleophilic addition of phenylselenol
pletely unreactive under both above-described reaction con- to alkynes affords, preferentially, the (Z)-vinylic selenides
ditions. The results obtained starting from ketones 2a–g are even if some of these strategies[13] are usually complicated
summarized in Table 2. In all cases, the reactions in water by long conversion times at room temperature. The reaction
suspension were slower than those in THF, affording gen- can be accelerated by increasing the temperature, but in this
erally low yields (Table 2, Entries 1, 2, 4, 7) or no reaction case a mixture of (Z)- and (E)-vinylic selenides is obtained
products (Table 2, Entries 3, 5) even after 140 h. Only ter- in a quite equimolar ratio.[15] The results collected in
minal alkene 2f gave quantitative yield of addition product Table 3 clearly indicate that, in contrast to previous exam-
4f at room temperature after 140 h. In THF, the same reac- ples, nucleophilic addition of PhSeH promoted by
tions afforded β-phenylseleno ketones 4a–g in moderate to PhSeZnCl through a Michael-type reaction of activated al-
good yields after 24 h. All the compounds were purified by kynes in water suspension is faster than that in THF and
flash chromatography on silica gel and fully characterized affords almost quantitative yield of corresponding vinyl sel-
by GC–MS and NMR spectroscopy.
enides 5a–g and 6a–g in 2 h at 23 °C.
Considering that useful procedures to prepare vinylic sel-
In these cases, the reaction was highly stereoselective
enides involve nucleophilic or electrophilic organoselenium (Table 3, Entries 1–3 and 7) or stereospecific (Table 3, En-
addition to terminal or internal alkynes[13] and that these tries 4–6), leading to (Z)-vinylic selenides 5 as the major
Eur. J. Org. Chem. 2011, 1848–1851
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1849

B. Battistelli, T. Lorenzo, M. Tiecco, C. Santi
SHORT COMMUNICATION
Table 3. Michael-type addition reaction of electron-deficient alk-
ynes.
Scheme 2. nOe correlations used to assign the E/Z geometry of
trisubstituted olefins.
Conclusions
In this communication we reported the PhSeZnCl-pro-
moted Michael-type addition reactions of conjugated al-
kenes and alkynes under neutral and mild conditions by
using water as a green solvent. The corresponding β-seleno-
carbonyl compounds and vinylic selenides were obtained in
good yields, and the latter are obtained with good stereose-
lectivity in favor of the (Z) isomer. The different rate accel-
eration observed for the reaction effected under “on-water”
conditions seems to be strongly correlated to the nature of
the substrates and leads us to speculate that water should
play a role in activating the substrate and does not influence
the reactivity of our nucleophilic reagent. The synthetic
strategy described in this communication offers significant
advantages with regard to operation and yields and thus
presents an efficient and eco-friendly alternative to existing
methods. Finally, the reported procedure demonstrates the
synthetic utility of PhSeZnCl as a nucleophilic organoselen-
ium reagent, stressing its versatile applicability under “on-
water” conditions.
[a] In H2O, 23 °C for 2 h. [b] In THF, 23 °C for 24 h. [c] Refluxing
THF for 24 h.
isomer. The reaction products were purified by flash
chromatography and fully characterized by GC–MS and
NMR spectroscopy. The Z/E ratios were calculated by
NMR spectroscopic analysis of the crude mixture, and the
geometry of the double bond was assigned on the basis of
the vicinal olefinic coupling constants for 5b–6b, 5c–6c, and
5d–6d and on the basis of nOe correlations (Scheme 2) ob-
Experimental Section
General Procedure for the Reactions Effected in THF: To a solution
tained by a standard NOESY experiment for compounds of 1 (1.0 mmol) in THF (3 mL), under anhydrous conditions was
added conjugated alkene 2a–g or alkyne 3a–g (1.0 mmol) dissolved
in THF (2 mL). The resulting mixture was stirred at room tempera-
ture in a dark brown vial for 24 h, and the progress of the reaction
was monitored by TLC and GC–MS. The reaction mixture was
then poured into water and extracted with diethyl ether (3ϫ). The
organic phase was dried with Na2SO4 and filtered, and the solvent
was removed under vacuum. All the reaction products were puri-
fied by flash chromatography. The yields reported in Tables 1–3
refer to isolated products and the Z/E ratios were measured on the
crude by NMR spectroscopy. All isolated compounds were fully
5a and 5e–g.
From a synthetic point of view it is interesting to under-
line that the range of electron-deficient alkynes that can be
successfully employed in this reaction is more general than
that observed for alkenes conjugated to an electron-with-
drawing group. Ketones 3a–c as well as esters 3e–f and alde-
hydes 3g were used as conjugating groups for the triple car-
bon–carbon bond. The stereoselectivity for substrates 3a–c
is slightly better in THF, whereas no appreciable difference
was observed in all other examples. Surprisingly, the reac- characterized by GC–MS and 1H NMR and 13C NMR spec-
troscopy.
tion for compound 3e in THF is very slow but can be ac-
celerated by temperature, whereas the corresponding carb-
oxylic acid was completely unreactive under both condi-
tions.
General Procedure for the Reactions Effected under “On-Water”
Conditions: Compound 1 (1.0 mmol) and conjugated alkene 2a–g
or alkyne 3a–g (1.0 mmol) were poured into water (6 mL), and the
1850
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1848–1851

“On-Water” Michael-Type Addition Reactions Promoted by PhSeZnCl
Int. Ed. 2000, 39, 3740; f) D. M. Freudendahl, S. Santoro, S. A.
Shahzad, C. Santi, T. Wirth, Angew. Chem. 2009, 121, 8559;
Angew. Chem. Int. Ed. 2009, 48, 8409; g) C. Santi, S. Santoro,
B. Battistelli, Curr. Org. Chem. 2010, 14, 2442.
mixture was vigorously stirred at room temperature for 140 h (2a–
g) or 2 h (3a–g). The water was extracted with diethyl ether (3ϫ).
The combined organic layers were dried with Na2SO4 and filtered,
and the solvent was removed under vacuum. All the reaction prod-
ucts were purified by flash chromatography. The yields reported in
Tables 1–3 refer to isolated products and the Z/E ratios were mea-
sured on the crude by NMR spectroscopy. All isolated compounds
[2] P. Perlmutter, Conjugate Addition Reactions in Organic Synthe-
sis, Pergamon, Oxford, 1992.
[3] M. Miyashita, A. Yoshikoshi, Synthesis 1980, 664.
[4] P. A. Grieco, M. Miyashita, Tetrahedron Lett. 1974, 15, 1869.
[5] K. Mori, Tetrahedron 1976, 32, 1101.
[6] H. Pluim, H. Wynberg, Tetrahedron Lett. 1979, 20, 1251.
[7] B. C. Ranu, A. Das, Adv. Synth. Catal. 2005, 347, 712.
[8] B. Movassagh, A. Tatar, Synlett 2007, 1954.
[9] C.-M. Chu, S. Gao, M. N. V. Sastry, C.-W. Kuo, C. Lu, J.-T.
Liu, C.-F. Yao, Tetrahedron 2007, 63, 1863.
1
were fully characterized by GC–MS and H NMR and 13C NMR
spectroscopy.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and characterization data for the new
compounds.
[10] B. Srinivas, V. P. Kumar, R. Sridhar, V. P. Reddy, Y. V. D. Nage-
swar, K. R. Rao, Helv. Chim. Acta 2009, 92, 1080.
[11] a) C. Santi, S. Santoro, L. Testaferri, M. Tiecco, Synlett 2008,
1471; b) C. Santi, S. Santoro, B. Battistelli, L. Testaferri, M.
Tiecco, Eur. J. Org. Chem. 2008, 5387; c) S. Santoro, B. Battis-
telli, L. Testaferri, M. Tiecco, C. Santi, Eur. J. Org. Chem. 2009,
4921.
Acknowledgments
Financial support from Ministero Italiano Università e Ricerca
(MIUR, National Projects PRIN2007, Progetto di Ricerca
dЈInteresse Nazionale), Consorzio Interuniversitario Nazionale di
Metodologie e Processi Innovativi di Sintesi (CINMPIS), Bari, and
the University of Perugia is gratefully acknowledged. Technical
contributions of Dr. Gianni Pintus for collecting some of the results
reported in Table 2 are particularly appreciated.
[12] B. List, Tetrahedron 2002, 58, 5573.
[13] a) J. V. Comasseto, J. Organomet. Chem. 1983, 253, 131; b)
O. S. D. Barros, E. S. Lang, C. A. F. de Oliveira, C. Peppe, G.
Zeni, Tetrahedron Lett. 2002, 43, 7921; c) M. J. Dabdoub, V. B.
Dabdoub, M. A. Pereira, Tetrahedron Lett. 2001, 42, 1595; d)
M. J. Dabdoub, A. C. M. Baroni, E. J. Lenardão, T. R. Gianeti,
G. R. Hurtado, Tetrahedron 2001, 57, 4271.
[14] M. J. Dabdoub, T. M. Cassol, A. C. F. Batista, Tetrahedron
Lett. 1996, 37, 9005; J. V. Comasseto, L. W. Ling, N. Petrag-
nani, H. A. Stefani, Synthesis 1997, 373.
[1] a) A. Krief, L. Havesi, Organoselenium Chemistry, Springer,
Berlin, 1988, vol. 1; b) A. Krief in Comprehensive Organometal-
lic Chemistry (Ed.: B. M. Trost), Pergamon, Oxford, 1991, p.
85; c) T. Wirth (Ed.), Topics in Current Chemistry Vol. 208:
Organoselenium Chemistry – Modern Developments in Organic
Synthesis, Springer, Berlin, 2000; d) T. G. Back (Ed.), Organo-
selenium Chemistry – A Practical Approach, Oxford, New York,
2000; e) T. Wirth, Angew. Chem. 2000, 112, 3890; Angew. Chem.
[15] J. V. Comasseto, J. T. B. Ferreira, J. Organomet. Chem. 1981,
216, 287
Received: January 12, 2011
Published Online: February 23, 2011
Eur. J. Org. Chem. 2011, 1848–1851
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1851