In situ generation of n-butanethiol and its reaction with electron-deficient olefines

Article abstract of DOI:10.1080/00397910701820897

n-Butanethiol is generated in situ by sequential addition of n-butyllithium and water to elemental sulfur. The n-butanethiol formed was reacted with electron-deficient olefines to give Michael-type addition products in good yields. The method avoids the manipulation of the bad-smelling n-butanethiol. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701820897

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In Situ Generation of n‐Butanethiol and Its
Reaction with Electron‐Deficient Olefines
Rogério A. Gariani a , Alcindo A. Dos Santos b & João V. Comasseto a
a Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
b Departamento de Química, Universidade Federal de São Carlos, São
Carlos, Brazil
Published online: 15 Feb 2008.
To cite this article: Rogrio A. Gariani , Alcindo A. Dos Santos & Joo V. Comasseto (2008) In Situ Generation
of n‐Butanethiol and Its Reaction with Electron‐Deficient Olefines, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:5, 789-795, DOI:
10.1080/00397910701820897
To link to this article: http://dx.doi.org/10.1080/00397910701820897
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Synthetic Communicationsw, 38: 789–795, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701820897
In Situ Generation of n-Butanethiol and Its
Reaction with Electron-Deficient Olefines
1
Rogerio A. Gariani, Alcindo A. Dos Santos, and
2
´
Joa˜o V. Comasseto1
1
´
Instituto de Quımica, Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil
2
´
Departamento de Quımica, Universidade Federal de Sa˜o Carlos,
Sa˜o Carlos, Brazil
Abstract: n-Butanethiol is generated in situ by sequential addition of n-butyllithium
and water to elemental sulfur. The n-butanethiol formed was reacted with electron-
deficient olefines to give Michael-type addition products in good yields. The method
avoids the manipulation of the bad-smelling n-butanethiol.
Keywords: Michael addition, thiols, a,b-unsaturated carbonyl compound
INTRODUCTION
Alkanethiols are compounds widely used in organic synthesis. Among the uses
of this class of compounds, we focus on their Michael-type addition reaction to
electron-deficient olefines.[1] A serious limitation for the use of alkanethiols in
that and other reactions is their bad smell. However, in view of their peculiar
reactivity, they are continuously used for synthetic purposes. A similar
problem is encountered in selenium[2] and tellurium[3] chemistry. In the case
of the tellurium compounds, the organotellurols are so sensitive to the air
oxydation that these compounds cannot be isolated.[3] The diorganoditellurides
are used instead and transformed in situ into organotellurolates or organotellur-
ols. Even the dialkaneditellurides are so bad smelling that their use must be
Received in the USA September 5, 2007
Address correspondence to Joa˜o V. Comasseto, Instituto de Quımica, Universidade
´
de Sa˜o Paulo, Av. Prof. Lineu Prestes, 748 Cx.P. 26077, Sa˜o Paulo 05599-970, Brazil.
E-mail: jvcomass@iq.usp.br
789

790
R. A. Gariani, A. A. Dos Santos, and J. V. Comasseto
avoided to introduce tellurium into organic molecules. Because of this limit-
ation, some time ago, we divised a practical method to generate and to use alka-
neselenols and tellurols in situ.[4] This strategy consists in the reaction of
elemental selenium or tellurium with a commercialy available alkyllithium
and then the addition of a proton source (water or ethanol) to the lithium alka-
nechalcogenate formed. This methodology was employed in the hydrochalco-
genation of electron-deficient olefines, leading to the functionalized
alkaneselenides and tellurides.[4] In past years, this methodology has been con-
tinuously used with success to prepare vinyl[4,5] and alkyltellurides.[6] Keeping
in mind the bad smell of the alkanethiols, we wondered if this method could be
also applied for the in situ preparation of alkanethiols and their Michael-type
addition to electron-deficient olefines. It is surprising that the use of
elemental sulfur and a commercialy available alkyllithium is not commonly
used to generate lithium alkanethiolates in situ, although the reaction of orga-
nolithium with elemental sulfur has been long known to prepare orga-
nothiols.[7] The method of choice to generate alkanethiolates continues to be
the reaction of alkanethiols with alkyllithiums, notwithstanding the volatility
and the bad smell of the alkanethiols.
RESULTS AND DISCUSSION
To test the feasibility of the in situ generation and the Michael-type addition of
alkanethiols to electron-deficient olefines, we added commercial n-butyl-
lithium in hexane to a stirred suspension of elemental sulfur in freshly
distilled tetrahydrofuran at 08C under nitrogen. At the beginning of the
addition, the reaction mixture turned orange. When a stoichiometric amount
of n-butyllithium was added, a limpid colorless solution was formed. To
this solution, 2 equivalents of deoxygenated water and 2-cyclohexen-1-one
were added. After 30 min, all the cyclohexenone had been consumed. The
analysis of the product after column chromatography revealed that
3-(butylthio)cyclohexanone was formed in a 98% yield (Scheme 1).
Scheme 1. In situ formation of n-butanethiol and its reaction with 2-cyclohexen-
1-one.

In Situ Generation of n-Butanethiol
791
It is worth mentioning that during all the operations described previously,
the peculiar bad smell of n-butanethiol was not detected. Another fact to be
mentioned is that no additive was necessary to promote this Michael-type
addition. In recent years, a number of articles were published on the
addition of alkanethiols to electron-deficient olefines.[8] In all cases, the alka-
nethiols were used in combination with other agents, which in some cases are
expensive or present acidic or basic character. [For a review, see Ref. 8a.]
Repeating of the reaction using 2-cyclohexen-1-one and lithium butanethio-
late in anhydrous medium gave the product 3-(butylthio)cyclohexanone in
only 50% yield. This indicates that the presence of water is mandatory for
the success of the addition reaction.
In view of the practicality of our approach, we investigated the thiolation
of different substrates to establish the scope and limitations of the method.
Table 1 shows the obtained results. As can be observed, unhindered enones
give excellent yields of the Michael adducts (entries 1–3). Enones with
some degree of steric hindrance give less satisfactory yields (entries 4 and 5).
The yields are, however, still comparable with those of similar compounds
prepared by Michael-type reactions of alkanethiols using other thiolation
methods. [For example, see Ref. 8f.] Unsaturated ester (entry 6) and nitrile
(entry 7) also gave good yields of the Michael adduct. Unsaturated aldehydes
(entries 8 and 9) also reacted, but the product had to be reduced in situ in
view of the instability of the resulting 3-butylthioaldehyde. The resulting
alcohols were isolated in 50% yield. Finally, the thiolation of ethylpropiolate
(entry 10) gave the corresponding Z-vinylic sulfide in 80% yield.
In summary, the Michael-type reaction of electron-deficient olefines can
be performed with n-butanethiol generated in situ from elemental sulfur and n-
butyllithium, avoiding the manipulation of bad-smelling alkanethiols.
EXPERIMENTAL
Materials
All reagents and solvents used were previously purified and dried as reported
in the literature.[9] THF was distilled from sodium/benzophenone under
nitrogen immediately before use. n-Butyllithium was titrated using 1,10-phe-
nanthroline as the indicator prior to use. Column chromatography separations
were performed with Merck 60 (70–230 mesh) silica gel. Elemental sulfur
was purchased from Aldrich Chemical Co.
Analysis
[1]H and 13C NMR spectra were obtained on a Bruker DRX 500 spectrometer
using CDCl3 as the solvent, and the chemical shifts are given in parts per

792
R. A. Gariani, A. A. Dos Santos, and J. V. Comasseto
Table 1. In situ generation of n-butanethiol and the addition to electron-deficient
olefines
Registry
number
Entry
1
Substrate
Producta
Yieldb (%)
93
Ref.
—
69688-97-7
2
3
98, 50d 505062-31-7
—
—
97
66
50987-48-9
4
—
[12a]
5
6
64
78
21205-11-8
68298-26-0
—
—
7
8
90
51771-37-0
26901-99-5
—
—
50c
(continued)

In Situ Generation of n-Butanethiol
Table 1. Continued
793
Registry
number
Entry
9
Substrate
Producta
Yieldb (%)
50c
Ref.
—
[12b]
10
80
875822-74-5
—
aAll products gave satisfactory analytical data, which agree with the proposed
structures.
bYield of the isolated product after column chromatography in silica gel eluting with
hexane–ethyl acetate (20:1).
cThe aldehyde initially formed was reduced in situ with sodium borohydride in
ethanol.
dYield of the reaction of lithium butanethiolate in anhydrous medium.
million (ppm) relative to tetramethylsilane as an internal reference. Infrared
spectra were recorded with a KBr cell on a FTIR Bomem MB 100
spectrophotometer.
Typical Procedure
Preparation of 3-(Butylthio)cyclohexanone
A 50-mL, two-necked, round-bottomed flask was equipped with a
magnetic stirrer and a rubber septum, flame-dried twice under a positive
nitrogen stream under a nitrogen atmosphere, and then cooled to room temp-
erature. Elemental sulfur (0.20 g, 6.0 mmol) was transferred to the reaction
flask followed by freshly distilled THF (10 mL). n-Butyllithium (5.47 mL
of a 1.17 mol/L solution in hexane, 6.4 mmol) was added dropwise to the vig-
orously stirred S8/THF mixture at 08C. After the addition, the powder was
completely consumed. Deoxygenated water (0.27 mL, 15.0 mmol) was
slowly added to the thiolate solution. The resulting colorless solution was
stirred for 10 min, and then 2-cyclohexen-1-one (0.58 mL, 6.0 mmol) was
added in one portion. The solution was stirred for additional 30 min. After
the reaction was complete, the reaction mixture was quenched with 5 mL of
water. The product was extracted with ethyl acetate (3 ꢀ 20 mL). The
combined organic layers were dried over magnesium sufate and concentrated
under reduced pressure. Column chromatography (20:1 hexane/ethyl acetate)
1
of the crude oil on silica gel afforded a colorless oil. Yield 1.10 g (98%). H

794
R. A. Gariani, A. A. Dos Santos, and J. V. Comasseto
NMR: (500 MHz, CDCl3, ppm) d 0.91 (t, J ¼ 7.0 Hz, 3H), 1.40 (sx,
J ¼ 7.5 Hz, 2H), 1.56 (qt, J ¼ 7.5 Hz, 2H), 1.69–1.75 (m, 2H), 2.10–2.17
(m, 2H), 2.28–2.40 (m, 3H), 2.55 (t, J ¼ 7.5 Hz, 2H), 2.68–2.73 (m, 1H),
3.03–3.08 (m, 1H). 13C NMR: (125 MHz, CDCl3, ppm) d 208.8, 48.1, 42.6,
40.8, 31.6, 31.5, 30.1, 24.1, 21.9, 13.5. IR (cm21) 2956, 2934, 2869, 1714,
1221.
Data
1
(a) H NMR (300 MHz, CDCl3): d 0.86–0.96 (m, 3H), 0.98–1.02 (m, 3H),
1.32–1.59 (m, 10H), 1.77–2.08 (m, 5H), 2.26–2.32 (m, 1H), 2.40–2.60
(m, 4H). 13C NMR (75 MHz, CDCl3): d 13.5, 22.0, 22.1, 23.7, 27.1, 27.7,
29.4, 31.3, 34.5, 36.5, 46.6, 52.2, 57.8, 210.4. IR (cm21): 1121, 1456, 1711,
2871, 2928, 2957. HRMS calc. for [C14H26OS þ Na]þ: 247, 1132. Found:
1
247, 1128. (b) H NMR (300 MHz, CDCl3): d 0,82 (t, 7.2 Hz, 3H), 1.22–
1.50 (m, 4H), 1.99–2.15 (m, 2H), 2.22–2.36 (m, 2H), 3.51–3.74 (m, 2H),
3.95 (t, 7.5 Hz, 1H), 7.18–7.33 (m, 5H). 13C NMR (75 MHz, CDCl3): d
142.5, 128.3, 127.6, 126.9, 60.4, 46.3, 39.0, 31.2, 30.5, 21.8, 13.4. IR
(cm21): 3360, 2957, 2872, 1948, 1882, 1806, 1453, 1042, 759, 700. HRMS
calc. for [C13H20OS þ H]þ: 243, 1782. Found: 243, 1776.
ACKNOWLEDGMENTS
The authors acknowledge CNPq and FAPESP for support. R. A. Gariani
thanks CAPES for a PhD fellowship.
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