One-pot oxidative conjugate hydrothiocyanation-hydrosulfenylation of Baylis-Hillman alcohols promoted by a protic ionic liquid

Article abstract of DOI:10.1055/s-2008-1078549

The first example of one-pot oxidative conjugate hydrothiocyanation- hydrosulfenylation of acrylic ester derived Baylis-Hillman alcohols, that is, methyl 3-aryl-3-hydroxy-2-methylene-propanoate, is reported. The reaction involves protic ionic liquid [Hmim]HSO₄-mediated oxidation of Baylis-Hillman alcohols with NaNO₃ to give methyl (E)-α-formylcinnamates followed by conjugate addition of sulfur-centered nucleophiles (NH₄SCN/PhSH) to afford the corresponding methyl β-thiocyanato (or β-phenylsulfenyl)-α-formylhydrocinnamates diastereoselectively in 74-87% yields in a one-pot procedure. After isolation of the product, the ionic liquid [Hmim]HSO₄ could be easily recycled for further use without any loss of efficiency. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078549

LETTER
1789
One-Pot Oxidative Conjugate Hydrothiocyanation–Hydrosulfenylation of
Baylis–Hillman Alcohols Promoted by a Protic Ionic Liquid
Conjugate
H
ydr
a
othiocyana
l
tion–Hydrosu
D
lfenylation of Bay
h
lis–Hillman
a
A
lcohols r Singh Yadav,* Rajesh Patel, Vishnu Prabhakar Srivastava
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211002, India
Fax +91(532)2460533; E-mail: ldsyadav@hotmail.com
Received 26 March 2008
are well known in various areas of organosulfur chemistry
and are of considerable importance from both chemical
and biological viewpoints.
Abstract: The first example of one-pot oxidative conjugate hydro-
thiocyanation–hydrosulfenylation of acrylic ester derived Baylis–
Hillman alcohols, that is, methyl 3-aryl-3-hydroxy-2-methylene-
propanoate, is reported. The reaction involves protic ionic liquid
[Hmim]HSO4-mediated oxidation of Baylis–Hillman alcohols with
NaNO3 to give methyl (E)-a-formylcinnamates followed by conju-
gate addition of sulfur-centered nucleophiles (NH4SCN/PhSH) to
afford the corresponding methyl b-thiocyanato (or b-phenylsulfe-
nyl)-a-formylhydrocinnamates diastereoselectively in 74–87%
yields in a one-pot procedure. After isolation of the product, the ion-
ic liquid [Hmim]HSO4 could be easily recycled for further use with-
out any loss of efficiency.
The thioether structural fragment is an important molecu-
lar tool as bioisosteric replacements in rational drug de-
sign.9 Organic thiocyanates, representing a masked
marcapto group, are useful scaffolds for synthesis of var-
ious heterocycles; some of which exhibit herbicidal and
other important biological activity.10 The thiocyanato
group is a prominent functional motif found in certain an-
ticancer natural products formed by deglycosylation of
glucosinolates derived from cruciferous vegetables.11 Fur-
thermore, b-sulfenylated carbonyl compounds are an im-
portant class of synthons for a wide variety of compounds
and thus enhance the versatility of molecules containing
sulfur functionalities.12 Hence, the development of a sim-
ple, convenient, and efficient methodology for their syn-
thesis is highly desirable. Herein, Baylis–Hillman
chemistry has been applied for this purpose (Scheme 1).
Key words: Baylis–Hillman alcohols, conjugate addition, oxida-
tion, protic ionic liquids, methyl cinnamates, stereoselective synthe-
sis
The Baylis–Hillman reaction is a synthetically useful
method for carbon–carbon bond-forming reactions yield-
ing functionalized allylic alcohols,1 thereby providing
handles for further manipulation in a multitude of synthet-
ic organic transformations.2 The Baylis–Hillman (BH) al-
cohols, particularly in the form of their modified version
(e.g., acetyl derivatives), have been utilized as carbon
electrophiles, and their derivatizations with various nu-
cleophilic reagents, including thiocyanates, alkyl or aryl
thiolates, providing a wide range of potential synthetic in-
termediates and precursors for the synthesis of a variety of
biologically active natural and unnatural products, have
been well documented in the literature.3–5 The BH alco-
hols have been employed as Michael acceptors to produce
functionalized aldol products with oxygen, sulfur, nitro-
gen, and carbon-centered nucleophiles.6 Quite recently,
Yadav and co-workers have reported oxidative conjugate
addition of carbon-centered nucleophiles to acrylic ester
derived BH alcohols.7 However, there has been no report
on oxidative conjugate addition of sulfur-centered nucleo-
philes to acrylic ester derived BH alcohols.
To design a catalyst with high activity and selectivity, and
which is benign to environment and easily recovered, is an
interesting and rapidly developing area of chemistry. Ion-
ic liquids (IL) have attracted considerable interest as envi-
ronmentally benign reaction media, catalysts, and
reagents and are easy to recycle.13 Recently, protic ionic
liquids (PIL) have been deemed as promising alternatives
for acid-catalyzed reactions and play a dual solvent–cata-
lyst role in a variety of reactions including esterification
of carboxylic acids, protection of alcohols and carbonyl
groups, oxidation of alcohols, alcohol dehydrodimeriza-
tion, pinacol–benzopinacol rearrangement, in Mannich
reactions, and cleavage of ethers.14
N
N
H
OH
HSO4
COOMe
O
COOMe
The conjugate addition of sulfur-centered nucleophiles to
a,b-unsaturated carbonyl compounds, constituting a key
reaction in biosynthetic processes as well as in organic
synthesis,8 is one of the most important methods for the
synthesis of b-sulfur functionalized carbonyl compounds.
Sulfur functionalities, such as thiocyanate and thioether,
NaNO3, 80 °C, 1–3 h
1
2
SPh
SCN
COOMe
O
COOMe
NH4SCN or PhSH
r.t., 2–3 h
or
O
3
4
SYNLETT 2008, No. 12, pp 1789–1792
0
1
.0
7
.2
0
0
8
Advanced online publication: 02.07.2008
DOI: 10.1055/s-2008-1078549; Art ID: D09508ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Protic ionic liquid promoted oxidative conjugate addition
to BH alcohols

1790
L. D. S. Yadav et al.
LETTER
The continued interest of synthetic chemists in the BH re- precedent,17 the syn configuration was conclusively as-
action and our ongoing efforts to devise one-pot protocols signed to 3 and 4, as the coupling constant (J2,3 = 3.9 Hz)
involving conjugate addition15 has encouraged us to de- for them was lower than that for the minor anti isomer
velop the present protic ionic liquid promoted oxidative (J = 7.8 Hz). Moreover, the syn configuration of 4 was
sulfur functionalization of BH alcohols, which opens a also established by its oxidation and subsequent thermal
new aspect of their synthetic utility (Table 1).
syn-elimination of the resulting sulfoxide.18 The oxidation
of 4 with 1-(4-diacetoxyiodobenzyl)-3-methylimidazoli-
um tetrafluoroborate afforded the corresponding sulfox-
ide,19 which underwent syn-elimination in boiling toluene
to furnish methyl (Z)-a-formylcinnamate. This observa-
tion unequivocally proves the syn configuration of 4.
Table 1 One-Pot Oxidative Conjugate Hydrothiocyanation–Hydro-
sulfenylation of BH Alcohols
The methyl (E)-a-substituted cinnamates possess interest-
ing as well as important biological profiles.20 Previously,
methyl (E)-a-methyl/cyanomethylcinnamates have been
synthesized utilizing BH alcohols as well as their acetyl
derivatives.4a,21 However, synthesis of methyl (E)-a-
formylcinnamates 2 is hitherto unknown in rich literature
of Baylis–Hillman chemistry. The present method pro-
vides an easy access to compound 2 from unmodified BH
alcohols with sole E-stereoselectivity in a one-pot reac-
tion using the NaNO3–[Hmim]HSO4 reagent–solvent sys-
tem (Table 2).22
Entry R1
Nucleophile
NH4SCN
PhSH
R2
Time (h) Yield (%)a,b
3a
4a
3b
4b
3c
4c
3d
4d
3e
4e
3f
H
CN
Ph
3.5
4
78
81
80
84
86
87
83
85
82
80
74
76
H
4-Me
4-Me
2-MeO
2-MeO
3-Br
3-Br
4-Cl
NH4SCN
PhSH
CN
Ph
3
4
NH4SCN
PhSH
CN
Ph
3.5
4
Table 2 Synthesis of Methyl (E)-a-Formylcinnamate 2 from BH
Alcohols
OH
NH4SCN
PhSH
CN
Ph
5.5
4
COOMe
COOMe
[Hmim]HSO4
NaNO3, 80 °C
R
R
ONO2
NH4SCN
PhSH
CN
Ph
5
1
4-Cl
4
COOMe
O
R
4-O2N
4-O2N
NH4SCN
PhSH
CN
Ph
6
4f
5.5
2
a Yield refers to pure products after column chromatography.
b All compounds gave C, H, and N analyses within 0.36% and satis-
factory spectral (IR, 1H NMR, 13C NMR and EIMS) data.
Product
2a
R
Time (h)
Yield (%)a
Ph
1.5
1.3
1.5
2.5
2
80
83
81
78
76
73
2b
4-MeC6H4
2-MeOC6H4
3-BrC6H4
The present one-pot procedure for oxidative hydrothiocy-
anation–hydrosulfenylation involves stirring an equimo-
lar mixture of NaNO3 and BH alcohol 1 in 1-
methylimidazolium hydrogen sulfate [Hmim]HSO4 at
80 °C for 1–3 hours followed by addition of 1.1 equiva-
lents of NH4SCN or PhSH and stirring at room tempera-
ture for a further 2–3 hours to afford the corresponding b-
thiocyanated product 3 in 74–86% yields or b-sulfenylat-
ed compounds 4 in 76–87% yields (Table 1).16 The pro-
cess proceeds through the formation of isolable methyl
2c
2d
2e
4-ClC6H4
2f
4-O2NC6H4
3
a Yields of isolated and purified products.
(E)-a-formylcinnamate 2. The formation of 3 and 4 was The E-stereochemistry of molecules 2 was assigned on the
1
highly diastereoselective in favor of the syn isomers. The basis of H NMR spectra and literature precedent.21a,23
diastereomeric ratios in the crude isolates were deter- Furthermore, strong NOE were observed between the al-
1
mined by H NMR spectroscopy to note any inadvertent dehydic proton and the ortho protons of the aromatic ring
alteration of these ratios during subsequent purification. of compounds 2, which unequivocally proves their E-ste-
1
As determined by H NMR spectroscopy, the crude iso- reochemistry. For example, when aldehydic proton of 2f
lates of 3 and 4 were found to be diastereomeric mixtures was irradiated, 21.3% NOE was observed at ortho protons
containing 89–93% and 91–94% of the syn isomer, re- of its aromatic ring. This clearly shows the E-stereochem-
spectively. On the basis of 1H NMR spectra and literature istry of 2f.
Synlett 2008, No. 12, 1789–1792 © Thieme Stuttgart · New York

LETTER
Conjugate Hydrothiocyanation–Hydrosulfenylation of Baylis–Hillman Alcohols
1791
O
N
COOMe
O
OH
OH2
COOMe
–O
O
COOMe
[Hmim]HSO4
NaNO3
H
– H2O
O
O
N
1
SCN
SPh
NO2
+
COOMe
COOMe
O
COOMe
NO
– HNO2
NH4SCN
or PhSH
or
O
O
H2O
3
4
2
Scheme 2 Plausible mechanism for the formation of 3 and 4
P. Angew. Chem. Int. Ed. 2000, 39, 3049. (d) Basavaiah,
D.; Rao, P. D. Tetrahedron 1996, 52, 8001. (e) Drewes, S.
E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653.
We also attempted the oxidative conjugate hydrothiocya-
nation–hydrosulfenylation using NaNO3–[Hmim]NO3 as
well as NaNO3–[Hmim]H2PO4 separately under the same
reaction conditions (Table 1). The reaction was unsuc-
cessful in the former case indicating the need for an acidic
hydrogen which is absent in [Hmim]NO3 to catalyze the
oxidation of the BH alcohols into methyl (E)-a-formyl-
cinnamate 2 (Scheme 2). However, the reaction proceed-
ed with the NaNO3–[Hmim]H2PO4 system but relatively
low yields of 3 and 4 (26–37%) were obtained. This is
probably due to the lower Brønsted acidity associated
with [H2PO4]. Thus [Hmim]HSO4 plays a dual role, that
is, as an acid catalyst and solvent for both oxidation as
well as hydrothiocyanation–hydrosulfenylation.
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2002, 43, 4305. (d) Kamimura, A.; Morita, R.; Matsuura,
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Singh, A. P.; Basak, A. K. Tetrahedron Lett. 2007, 48, 4169.
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2; Patai, S., Ed.; Wiley: New York, 1974, 589. (b) Clark, J.
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After isolation of the product, the ionic liquid
[Hmim]HSO4 could be recycled for four times up to a
minimum of 73% recovery and reused without loss of ef-
ficiency. The requisite BH alcohols and protic ionic liq-
uids were prepared employing known methods.24,25
In summary, we have documented the first example of the
one-pot oxidative conjugate addition of sulfur-centered
nucleophiles to methyl acrylate derived BH alcohols us-
ing the NaNO3–[Hmim]HSO4 system to afford methyl b-
thiocyanato (or b-phenylsulfenyl)-a-formylhydrocin-
namates, diastereoselectively. Furthermore, application of
the same reagent–solvent system for the one-pot isomer-
ization–oxidation of BH alcohols to afford methyl (E)-a-
formylcinnamates has also been demonstrated.
Acknowledgment
We sincerely thank SAIF, Punjab University, Chandigarh, for pro-
viding microanalyses and spectra. One of us (R.P.) is grateful to the
CSIR, New Delhi, for the award of a Junior Research Fellowship.
References and Notes
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W. J. Tetrahedron Lett. 1995, 36, 2949. (d) Metzer, J. B. In
Comprehensive Heterocyclic Chemistry, Vol. 6; Katritzky,
A., Ed.; Pergamon: Oxford, 1984, 235. (e) Newman, A. A.
In Chemistry and Biochemistry of Thiocyanic Acid and Its
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2007, 36, 1581. (b) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. Rev. 2003, 103, 811. (c) Langer,
Synlett 2008, No. 12, 1789–1792 © Thieme Stuttgart · New York

1792
L. D. S. Yadav et al.
LETTER
Calcd (%) for C12H11NO3S: C, 57.82; H, 4.45; N, 5.62.
Derivatives; Academic Press: New York, 1975.
(11) Mehta, R. G.; Liu, J.; Constantinou, A.; Thomas, C. F.;
Hawthorne, M.; You, M.; Gerhaeusers, C.; Pezzuto, J. M.;
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2007, 1118. (f) Zhao, G.; Jiang, T.; Gao, H.; Han, B.; Huang,
J.; Sun, D. Green Chem. 2004, 6, 75.
Found: C, 57.56; H, 4.57; N, 5.43.
Compound 4f: yellowish solid, yield 76%, mp 132–133 °C.
IR (KBr): 3055, 2932, 1746, 1721, 1586, 1520, 1345, 1280,
1186, 760, 710 cm–1. 1H NMR (400 MHz, CDCl3, TMS):
d = 3.72 (dd, 1 H, J = 3.9, 2.1 Hz, 2-H), 3.81 (s, 3 H,
MeOCO), 4.68 (d, 1 H, J = 3.9 Hz, 3-H), 7.24–8.27 (m,
9Harom), 9.54 (d, 1 H, J = 2.1 Hz, CHO). 13C NMR (100
MHz, CDCl3, TMS): d = 30.6, 52.7, 64.2, 121.6, 124.9,
127.4, 129.2, 129.8, 135.8, 148.2, 149.4, 169.0, 198.3. MS
(EI): m/z = 345 [M+]. Anal. Calcd (%) for C17H15NO5S: C,
59.12; H, 4.38; N, 4.06. Found: C, 59.33; H, 4.74; N, 3.89.
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(16) General Procedure for the Synthesis of Methyl b-
Thiocyanato-a-formylhydrocinnamates 3 and Methyl b-
Phenylsulfenyl-a-formylhydrocinnamates 4
(20) (a) Watanabe, T.; Hayashi, K.; Yoshimatsu, S.; Sakai, K.;
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1725.
(22) General Procedure for the Synthesis of Methyl (E)-a-
Formylcinnamates 2
A mixture of BH alcohol 1 (1 mmol) and NaNO3 (1 mmol)
was stirred in 1 mL of [Hmim]HSO4 at 80 °C for 1–3 h
(Table 2). The reaction mixture was cooled to r.t. and
NH4SCN or PhSH (1.1 mmol) was added. The mixture was
further stirred at r.t. for 2–3 h. After completion of the
reaction (monitored by TLC), the product was extracted with
EtOAc (3 × 10 mL). The combined extract was dried over
MgSO4, filtered, concentrated under reduced pressure, and
purified by silica gel column chromatography (hexane–
EtOAc, 8.5:1.5) to afford the desired product 3 or 4. After
isolation of the product, the remaining ionic liquid was
washed with Et2O (2 × 10 mL) to remove any organic
impurity, then H2SO4 (2.1 mmol in the case of compound 3
and 1 mmol in the case of 4) was added, the mixture was
stirred at 80 °C for 1 h, and cooled to about –5 °C in an ice–
salt bath. The precipitated solid [Na2SO4, (NH4)2SO4] was
filtered out, and the filtrate was dried under vacuum to afford
the IL [Hmim]HSO4, which was used in subsequent runs.
Data of Representative Compounds
Compound 3a: white solid, yield 78%, mp 104–105 °C. IR
(KBr): 3026, 2115, 1745, 1718, 1603, 1578, 1460, 1284,
1194, 764, 714 cm–1. 1H NMR (400 MHz, CDCl3, TMS):
d = 3.68 (dd, 1 H, J = 3.9, 2.1 Hz, 2-H), 3.82 (s, 3 H,
MeOCO), 4.86 (d, 1 H, J = 3.9 Hz, 3-H), 7.14–7.32 (m, 5
Harom), 9.56 (d, 1 H, J = 2.1 Hz, CHO). 13C NMR (100 MHz,
CDCl3, TMS): d = 36.6, 63.9, 52.8, 112.4, 126.9, 128.6,
129.2, 140.9, 169.1, 198.3. MS (EI): m/z = 249 [M+]. Anal.
A stirred solution of BH alcohols 1 (1 mmol) and NaNO3 (1
mmol) in 1 mL of [Hmim]HSO4 was heated at 80 °C for 1–
3 h (Table 2). The reaction progress was monitored by TLC.
Upon completion, the reaction mixture was cooled to r.t. and
extracted with EtOAc (3 × 10 mL).The combined organic
phase was dried over MgSO4, filtered, and evaporated under
reduced pressure. The resulting crude product was purified
by silica gel column chromatography using a gradient
mixture of hexane–EtOAc (8:2) as eluent to give the pure
cinnamates 2. The remaining ionic liquid was recycled for
subsequent runs as described above using H2SO4 (1 mmol).16
Data of Representative Compound
Compound 2a: white solid, yield 80%, mp 91–92 °C. IR
(KBr): 3076, 2809, 2740, 1724, 1684, 1578, 1462, 1286,
1190, 760, 712 cm–1. 1H NMR (400 MHz, CDCl3, TMS):
d = 3.87 (s, 3 H, MeOCO), 7.48–7.70 (m, 3 Harom), 7.86 (s, 1
H, CHPh), 8.04–8.12 (m, 2 Harom), 9.66 (s, 1 H, CHO). 13
NMR (100 MHz, CDCl3, TMS): d = 52.6, 127.7, 129.4,
130.2, 131.3, 134.7, 154.6, 167.9, 187.6. MS (EI):
C
m/z = 190 [M+]. Anal. Calcd (%) for C11H10O3: C, 69.46; H,
5.30. Found: C, 69.81; H, 5.14.
(23) Basavaiah, D.; Hyma, R. S.; Kumaragurubaran, N.
Tetrahedron 2000, 56, 5905.
(24) Mehdi, H.; Bodor, A.; Lantos, D.; Horváth, I. T.; de Vas, D.
E.; Binnemans, K. J. Org. Chem. 2007, 72, 1517.
(25) Cai, J.; Zhou, Z.; Zhao, G.; Tang, C. Org. Lett. 2002, 4,
4723.
Synlett 2008, No. 12, 1789–1792 © Thieme Stuttgart · New York

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