Lithium butylchalcogenolate induced Michael-aldol tandem sequence: easy and rapid access to highly functionalized organochalcogenides and unsaturated compounds

Article abstract of DOI:10.1016/j.tetlet.2009.02.158

Lithium ⁿbutylchalcogenolates are generated in situ by reacting the elements (S, Se, and Te) with ⁿbutyllithium at 0 °C. Reaction of the lithium alkylchalcogenolates with activated alkenes and aldehydes gives the corresponding aldol

Full text of DOI:10.1016/j.tetlet.2009.02.158

Tetrahedron Letters 50 (2009) 2181–2184
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Tetrahedron Letters
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Lithium butylchalcogenolate induced Michael-aldol tandem sequence:
easy and rapid access to highly functionalized organochalcogenides
and unsaturated compounds
*
Artur F. Keppler, Rogério A. Gariani, Danilo G. Lopes, João V. Comasseto
Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, 05508-900 São Paulo, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Lithium nbutylchalcogenolates are generated in situ by reacting the elements (S, Se, and Te) with nbutyl-
lithium at 0 °C. Reaction of the lithium alkylchalcogenolates with activated alkenes and aldehydes gives
the corresponding aldol adducts. The selenium-containing products give Morita–Baylis–Hillman adducts
after the oxidation/elimination of the selenoxide. The whole sequence can be performed in a one-pot
procedure.
Article history:
Received 16 January 2009
Revised 11 February 2009
Accepted 19 February 2009
Available online 25 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The addition of chalcogenols or metal alkyl chalcogenolates to
activated alkenes is a useful method to prepare functionalized
alkylchalcogenides.1 A serious drawback of this methodology is
the use of alkylchalcogenols or dialkylchalcogenides as starting
materials, since these compounds are volatile and very bad smell-
ing. Recently we demonstrated that alkylchalcogenols, generated
in situ by reacting commercial alkyllithiums and elemental sulfur,
selenium and tellurium, react with activated alkenes to give func-
tionalized dialkylchalcogenides in good yields.1 This protocol con-
stitutes an important advance in preparative organochalcogen
chemistry, since it allows the preparation of non-volatile products
starting from easily available and friendly precursors. It is espe-
cially important in the context of the sulfur chemistry, since lith-
ium alkylthiolates, which are widely used in synthesis,
surprisingly continue to be generated by deprotonation of foul
smelling alkylthiols.2
Application of our protocol to activated alkenes and capture of
the intermediate enolate with an aldehyde, followed by sulfoxide
or selenoxide elimination would constitute a simple and efficient
one-pot access to Baylis–Hillman adducts (Scheme 1).3 In addition,
the tellurium containing products are precursors of functionalized
reactive organometallics, as recently demonstrated by our group.4
In this Letter we disclose our preliminary results on the reaction
sequence shown in Scheme 1 and in Table 1.
nBuLi to a suspension of the chalcogen in THF under nitrogen at
0 °C. The limpid solution was cooled to ꢀ70 °C and then equimolar
amounts of freshly distilled benzaldehyde, and after 5 min, the
activated alkene were added. The mixture was then allowed to
reach room temperature to give the adducts in the isolated yields
as shown in Table 1.5 No additive was needed to promote the con-
densation reaction.3 As can be observed, the reaction works well
with the three chalcogens. In one case (Table 1, entry 3) a two-
substituted olefin was used, with a good yield being obtained.
The products are almost odorless oils, stable to the light and air,
and can be purified by column chromatography. When stored un-
der refrigeration the sulfides and selenides do not degrade to an
observable extent. The tellurides are less stable and after some
days some degree of decomposition can be detected by the darken-
ing of the samples. However, by taking the proper care, evaporat-
ing the solvent immediately after the work-up, even the
tellurides can be safely manipulated in the presence of the light
and the air. It is worth mentioning that during the reaction course,
no bad smell typical of butylthiol, -selenol, or dibutylditelluride
was detected.
The best yield was achieved when lithium butylselenolate and
acrylonitrile were reacted (Table 1, entry 5). It is well known that
the selenoxide syn-elimination reaction occurs under much milder
conditions than the sulfoxide syn-elimination;6 while the sulfoxide
syn-elimination requires reflux at about 120 °C to occur,7 the selen-
oxide syn-elimination proceeds at room temperature or below.8
This fact is especially important if we intend to apply this protocol
in the synthesis of more complex and sensitive substrates. In view
of this we concentrated our efforts in the reaction involving the
lithium butylselenolate to test the influence of the aldehyde in
the reaction yield and to obtain the butyl selenides for further sel-
enoxide elimination.
Initially we investigated the best experimental conditions to
perform the chalcogenation/condensation sequence. Several reac-
tion conditions and sequence of addition of the components were
tested. The best experimental protocol found was to generate the
lithium alkylchalcogenolate by adding an equimolar amount of
* Corresponding author. Tel.: +55 11 3091 2176; fax: +55 11 3815 5574.
E-mail address: jvcomass@iq.usp.br (J.V. Comasseto).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.158

2182
A. F. Keppler et al. / Tetrahedron Letters 50 (2009) 2181–2184
Y0
nBuLi
OLi
OH
Li
EWG
R
EWG
R
[nBuYLi]
EWG
R
EWG
R
[O]
R1
nBuY
R1CHO
R1
Y = Se
nBuY
EWG = electron-withdrawing group
Y = S, Se, Te
Scheme 1. Morita–Baylis–Hillman adducts formation.
Table 1
In Table 2 we can see the result of the reaction sequence using
aromatic aldehydes bearing electron-withdrawing and electron-
donating groups, as well as aliphatic aldehydes. In all cases the
yields were high except for the nitrobenzaldehydes (Table 2, en-
tries 2 and 3). In these cases a darkening of the reaction mixture
was observed. However, it is well known that reaction of com-
pounds bearing the nitrogroup with carbanionic substrates is trou-
blesome. Entry 4 shows that the reaction is sensitive to steric
factors.
Three-component electrochalcogenation reactionsa
Y0
nBuLi, THF, 0 oC
OH
nBuYLi, PhCHO
THF, -70oC to r.t., N2
Y = S, Se, Te
nBuY
EWG
EWG
As mentioned before, the selenoxide syn-elimination reaction is
milder than the analogous sulfoxide syn-elimination. Normally the
selenoxide elimination is performed with substrates bearing aryl
groups linked to the selenium atom, electron-withdrawing substit-
uents enhancing the elimination rate.6,9 However, the presence of
Entry
Chalcogen
(Y0)
Alkene
Aldol product
Yieldb
(%)
OH
nBuTe
O
an acidic proton
a to the organoselenium moiety of the aldol ad-
1
Te
Se
73
78
CO2Me
CO2Me
ducts (Table 2, entries 8–18) facilitates the elimination, which oc-
curred in 74% isolated yield when compound 15 was subjected to
the oxidation reaction with H2O2 in THF at 0 °C for 10 min (Eq.
1), while the oxidation of the same compound with tBuOOH,
Ti(OiPr)4, and DHP10 for 10 min at room temperature gave 19 in
93% isolated yield (Eq. 2).
OMe
1
OH
nBuSe
O
2
3
OMe
2
OH
OH
H2O2, THF, -10 oC
20 min, 74%
OH
r.t.
nBuSe
CN
15
CN
nBuSe
O
Cl
Cl
Se
81
68
CO2Me
19
OMe
ð1Þ
3
tBuOOH, Ti(OiPr)4, DHP
10 min, r.t., 93%
OH
ð2Þ
19
15
nBuS
O
4
S
CO2Me
The oxidation/elimination sequences described in Eqs. 1 and
OMe
2 were performed in a 3 mmol scale and the isolated yields
are in the range expected for the selenoxide syn-elimination reac-
tion.11 A number of reaction conditions are available to perform
this classical transformation.6 In this way, the proper choice of
reagents and reaction conditions can be made, depending on
the substrate structure. The whole reaction sequence, that is,
lithium butylselenolate generation, Michael addition to the acti-
vated alkene, aldol condensation, and selenide oxidation/elimi-
nation can be performed in one-pot operation as shown in Eq.
(3), when compound 15 was transformed into 19 in 61% overall
yield.12
4
OH
nBuTe
nBuSe
nBuS
5
6
Te
Se
S
79
95
79
CN
CN
CN
CN
5
OH
CN
6
1) p-ClPhCHO, -70oC
2) CH2 CHCN, -70oC, 10 min
nBuLi, THF
r.t.
OH
[nBuSeLi]
Se0
19
7
3) -70oC
r.t.
CN
4) Ti(OiPr)4, then tBuOOH,
10 min, r.t.
7
a
All the reactions were performed in THF using stoichiometric amounts of the
alkene, aldehyde, and the lithium butylchalcogenolate in a 3 mmol scale.
61% overall
ð3Þ
b
The yields refer to the isolated products purified by column chromatography.

A. F. Keppler et al. / Tetrahedron Letters 50 (2009) 2181–2184
2183
Table 2
In conclusion, a three-component sequence leading to highly
functionalized alkyl chalcogenides was developed. The reactions
were performed under friendly conditions, which avoid the manip-
ulation of bad smelling alkyl thiols, selenols, and dialkylditellu-
rides. In the case of the selenides, the oxidation/elimination
occurs under very mild conditions and the whole reaction se-
quence can be performed in a one-pot operation, leading to a Mori-
ta–Baylis–Hillman adduct.
Three-component electroselenylation reaction of acrylonitrilea
Se0
nBuLi, THF,
0oC, N2
OH
[nBuSeLi], RCHO
THF, -70oC to r.t.
nBuSe
R
CN
CN
Entry
1
Aldehyde
Aldol productsc
Yieldb (%)
95
Acknowledgments
OH
O
H
The work was supported by FAPESP and CNPq.
nBuSe
nBuSe
nBuSe
8
CN
OH
References and notes
O
H
1. Comasseto, J. V.; Gariani, R. A.; Princival, J. L.; Dos Santos, A. A.; Zinn, F. K. J.
Organomet. Chem. 2008, 693, 2929–2936.
NO2
NO2
2
3
4
40
32
57
2. Comasseto, J. V.; Guarezemini, A. S. Product Class 6: Acyclic alkanethiolates of
group 1, 2 and 13–15 metals. In Science of Synthesis, Houben-Weyl, Methods of
Molecular Transformations; Kambe, N., Ed.; George Thieme: Stuttgart, 2008; Vol.
39, pp 413–435; Comasseto, J. V.; Guarezemini, A. S. Product Class 5:
Alkanethiols. In Science of Synthesis, Houben–Weyl, Mehods of Molecular
Transformations; Kambe, N., Ed.; Georg Thieme: Stuttgart, 2008; Vol. 39, pp
391–411.
3. Lithium phenylselenolate, generated by reacting methyllithium with
diphenyldiselenide, promoted the condensation of tbutylacrylamide with
benzaldehyde. The reaction took 15 h to occur. The selenoxyde syn-
elimination was performed by oxidation of the selenide with H2O2,
taking 12 h to complete. The overall yield of the sequence was 72%:
Kamimura, A.; Omata, Y.; Mitsudera, H.; Kakehi, A. J. Chem. Soc., Perkin
9
CN
OH
O
H
CN
10
11
NO2
NO2
OH Br
O
H
Br
nBuSe
nBuSe
Trans.
1 2000, 4499–4504; A similar sequence was published recently,
CN
OH
which described the transformation of acryloyl chloride into the
corresponding phenylthio esters aldol adducts, by reaction with 3 equiv
of lithium phenylthiolate in the presence of benzaldehyde, assisted by
MgBr2 Et2O. Oxidation of the resulting sulfide with MCPBA, followed by
pyrolysis of the selenoxide in refluxing toluene gave the corresponding
Baylis–Hillman adduct: Tarsis, E.; Gromova, A.; Lim, D.; Zhow, G.;
Coltart, D. M. Org. Lett. 2008, 10, 4819–4822. To our knowledge, similar
aldol condensations with activated alkenes, promoted by metal
alkyltellurolates, were not yet described.
O
H
5
6
87
81
81
88
72
70
83
CN
12
OEt
OEt
O
H
OH
4. (a) Dos Santos, A. A.; Princival, J. L.; Comasseto, J. V.; Barros, S. M. G.; Brainer
Neto, J. E. Tetrahedron 2007, 63, 5167–5172; (b) DosSantos, A. A.; Princival, J. L.;
Comasseto, J. V. Tetrahedron: Asymmetry 2006, 63, 2252; (c) Princival, J. L.;
Barros, S. M. G.; Comasseto, J. V.; Dos Santos, A. A. Tetrahedron Lett. 2005, 46,
4423; d Dos Santos, A. A.; Princival, J. L.; Comasseto, J. V., unpublished results.;
(e) Dos Santos, A. A.; Ferrarini, R. S.; Princival, J. L.; Comasseto, J. V. Tetrahedron
Lett. 2006, 47, 8933; (f) Dos Santos, A. A.; Ferrarini, R. S.; Princival, J. L.;
Comasseto, J. V. J. Braz. Chem. Soc. 2008, 19, 811–812; (g) Vargas, F.; Comasseto,
J. V. J. Organomet. Chem. 2009, 694, 122; For recent reviews, see: (h) Comasseto,
J. V.; Dos Santos, A. A. Phosphorus, Sulfur and Silicon 2008, 183, 939; Dos Santos,
A. A.; Wendler, E. P. Synlett, in press.
nBuSe
nBuSe
CN
13
O
H
OH
7
CN
14
O
H
OH
5. Typical procedure for the electrochalcogenation of activated alkenes: 2-
nBuSe
15
8
(butylselanylmethyl)-3-(4-chlorophenyl)-3-hydroxypropanenitrile (15).
A
CN
OH
250 mL, two-necked, round-bottomed flask was equipped with a magnetic
stirrer and a rubber septum and charged with elemental selenium (0.78 g,
10 mmol), flame-dried twice under a positive Ar0 stream, and then cooled to
room temperature. Freshly distilled THF (150 mL) was transferred to the reaction
flask. nButyllithium (5 mL of a 2 M solution in hexane, 10 mmol) was added
dropwise to the vigorously stirred Se0/THF mixture at room temperature. After
the addition the powder was completely consumed and then the reaction
mixture was cooled to ꢀ70 °C. p-Chlorobenzaldehyde (1.4 g, 10 mmol) in dry
THF (10 mL) was added to the reaction flask. After 5 min, freshly distilled
acrylonitrile (0.69 mL, 10 mmol) was added dropwise. The reaction mixture was
stirred for 10 min at ꢀ70 °C and then it was gradually warmed to room
temperature (c.a. 20 min), after which time the reaction was quenched with
NaHSO3 saturated aqueous solution (200 mL). The product was extracted with
ethyl acetate (3 ꢁ 40 mL). The combined organic layers were washed with brine,
dried over MgSO4, and concentrated under reduced pressure. Column
chromatography (3:1 hexane/AcOEt) of the crude oil on silica gel afforded 15
as a pale yellow oil. Yield 2.91 g (88%). Mixture of diastereomers (1:0.7): 1H NMR
(CDCl3, 300 MHz) d 0.91 (t, J = 7,5 Hz, 3H), 1.39 (sx, J = 7.5 Hz, 2H), 1.63 (qt,
J = 7.5 Hz, 2H), 2.68–2.82 (m, 5H), 3.00–3.19 (m, 1H), 4.92 (d, J = 6.5 Hz, 1H), 7.
34–7.36 (m, 4H). 13C NMR (CDCl3, 125 MHz) d 13.5, 20.3, 21.3, 22.8, 25.3, 25.4,
32.3, 42.1, 42.6, 72.5, 72.8, 119.0, 119.3, 127.4, 127.8, 128.9, 129.0, 134.6, 134.7,
Cl
Cl
O
H
O
9
O
nBuSe
nBuSe
nBuSe
CN
16
17
OH
O
H
10
CN
OH
O
H
11
CN
18
a
All the reactions were performed in THF using stoichiometric amounts of
alkene, aldehyde, and the lithium butylchalcogenolate in a 3 mmol scale. Com-
pound 15 was prepared in a 10 mmol scale.
137.9, 138.5. 125Se NMR (CDCl3, 500 MHz) d 161.8, 163.4. IR (film) , cmꢀ1 3442,
m
2958, 2929, 2872, 2246, 1907, 1787, 1701, 1597, 1491, 1091, 1013, 839. HRMS
calc. for [C14H18ClNOSeNa]+: 354.0139. Found: 354.0123.
6. Back, T. G.. Organoselenium Chemistry, A Practical Approach; Oxford University
Press: Oxford, 1999.
7. Trost, B. M.; Salzmann, T. N. J. Am. Chem. Soc. 1973, 95, 6840–6842.
8. Reich, J. H. J. Org. Chem. 1975, 40, 2570.
b
The yields refer to the isolated products purified by column chromatography.
All prepared compounds were subjected to the selenoxide syn-elimination to
c
eliminate a stereogenic center facilitating the product analysis. No attempts were
made to improve the yields of this step, except for the oxidation–elimination
reaction of compounds 2 and 15.

2184
A. F. Keppler et al. / Tetrahedron Letters 50 (2009) 2181–2184
9. Sharpless, K. B.; Young, M. W. J. Org. Chem. 1975, 40, 947–949.
10. Cuñat, A. C.; Martin, D. D.; Ley, S. V.; Montgomery, F. J. J. Chem. Soc., Perkin
Trans. 1 1996, 611.
11. (a) Clive, D. L. J. Tetrahedron 1978, 34, 1049–1132; (b) Reich, H. J. In Oxidation in
Organic Synthesis; Trahanovsky, W. S., Ed.; Academic Press: New York, 1978; pp
1–130.
4.5 mmol) were added. After 10 min., tBuOOH (0.5 mL of a 5.5 M aq solution,
3.0 mmol) was added dropwise to the reaction mixture, which was stirred for
10 min. After this period, 5.0 g of flash silica gel was added to the reaction flask
and the solvent was removed under reduced pressure. The solid was filtered
through a flash silica cake using CH2Cl2 (2 ꢁ 30 mL). The filtrate was washed
with brine, dried over MgSO4, and concentrated under reduced pressure.
Column chromatography of the crude oil in flash silica gel eluting with hexane/
ethyl acetate (2:1) afforded 19 as a colorless oil. Yield 0.35 g (61%). 1H NMR
(500 MHz, CDCl3): d 5.30 (s, 1H), 6.05 (s, 1H), 6.12 (s, 1H), 7.33–7.40 (m, 4H).
13C NMR (125 MHz, CDCl3): d 73.4, 116.8, 125.9, 127.9, 129.0, 130.3, 134.7,
12. One-pot
preparation
of
a
Baylis–Hillman
adduct
through
an
electroselenylation followed by oxidation/elimination. 2-((4-chlorophenyl)-
(hydroxy)methyl)acrylonitrile (19). The procedure described above5 was
repeated in a 3 mmol scale. After the addition of the p-chlorobenzaldehyde
and the acrylonitrile, the mixture was heated to room temperature as
described above5 and then Ti(OiPr)4 (0.07 mL, 0.3 mmol), and DHP (1.5 mL,
137.7. IR (film)
818.
m
, cmꢀ1 3467, 3119, 3034, 2872, 2233, 1905, 1489, 1399, 1069,