Efficient organocatalytic α-sulfenylation of substituted piperazine-2,5-diones

Article abstract of DOI:10.1016/j.tetlet.2009.05.031

Organocatalytic α-sulfenylation of substituted piperazine-2,5-diones is reported through the use of cinchona alkaloids as Lewis bases and electrophilic sulfur transfer reagents. 1-Phenylsulfanyl[1,2,4]triazole, a novel sulfur transfer reagent, gave excell

Full text of DOI:10.1016/j.tetlet.2009.05.031

Tetrahedron Letters 50 (2009) 4310–4313
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient organocatalytic
a-sulfenylation of substituted piperazine-2,5-diones
*
Ramin Dubey, Nathan W. Polaske, Gary S. Nichol, Bogdan Olenyuk
Department of Chemistry, The University of Arizona, Tucson, AZ 85721, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 February 2009
Revised 3 May 2009
Accepted 12 May 2009
Available online 19 May 2009
Organocatalytic a-sulfenylation of substituted piperazine-2,5-diones is reported through the use of cin-
chona alkaloids as Lewis bases and electrophilic sulfur transfer reagents. 1-Phenylsulfanyl[1,2,4]triazole,
a novel sulfur transfer reagent, gave excellent product yields with a number of substituted piperazine-
2,5-diones under mild conditions. Catalyst loading, stoichiometry of sulfur electrophile, temperature,
and solvent were optimized to achieve high product yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Organocatalytic
a
-sulfenylation of carbonyl compounds is of
azole (2a)2,4 was used as the electrophilic sulfenylating reagent in
attempts to convert substrates 1a–e to products
considerable synthetic utility because it produces synthetic inter-
mediates useful in a variety of organic transformations.1 To date,
the majority of reported organocatalytic sulfenylations utilized
aldehydes,2 ketones,3 lactones, lactams, and b-dicarbonyl com-
pounds4 as substrates. Despite their simplicity and low catalyst
costs such transformations, to our knowledge, have not been
reported for b-amido esters or diketopiperazines. In this Letter,
3
(Table 1). This reagent is known to give products in high yields
with the variety of aldehydes, ketones, and b-ketoesters.4 However,
with substituted piperazine-2,5-dione 1a, only low yields of the
product 3a were obtained. Therefore, our goal was to improve
the efficiency of this reaction by varying the amount of sulfenylat-
ing reagent 2a and changing the type of catalyst 4a–d (Fig. 2).
In order to obtain higher yields, the loading of the sulfenylating
reagent 2a was increased (Table 1). Despite using an excess of 2a,
the product 3a was still obtained in low yields. Using precursor 1b
without substituent at the N-4 position resulted in significantly
improved yields. Compounds 1c and 1d gave product 3b in low
yields, along with the removal of the substituents at the N-4 posi-
tion. Such a removal could be the result of an attack of the formed
in the trace amounts thiolate anion on acetyl or benzoyl groups of
1c–d. The small quantities of the newly formed 1b could then be
sulfenylated by 2a, producing compound 3b. No product formation
could be observed with substrate 1e. It is believed that the low
reactivity of the N-4 substituted piperazine-2,5-diones is attribut-
able to the steric clash between the approaching sulfenylating
reagent and the substrate, because only the compound lacking
we report the first organocatalytic
piperazine-2,5-diones.
a-sulfenylation of substituted
Direct a-sulfenylation of substituted b-amido esters and diketo-
piperazines could facilitate synthesis of epidithiodiketopiperazines
(ETPs)—an intriguing class of biologically active natural products.5
ETPs are cytotoxic and immunomodulatory constituents produced
by the filamentous fungi Chaetomium and Pithomyces sp. They con-
tain one or two polysulfide-bridged piperazine-2,5-dione frag-
ments and display a broad spectrum of biological activity. Recent
studies have shown that two members of this diverse family, chae-
tocin6 and chetomin7 (Fig. 1), suppress neovascularization in solid
tumors8 by disrupting the expression of VEGF gene mediated by
hypoxia-inducible factor 1
the preparation of ETPs require multistep sequences for the intro-
duction of sulfur.10–13 Direct, catalytic procedure for
-sulfenyla-
a (HIF-1a
).9 All reported methods for
a
tion of piperazine-2,5-diones could prove valuable in the
development of a concise synthetic route to ETPs.
O
Organocatalytic transformation of piperazine-2,5-dione ring
system is more challenging as compared to aldehydes, ketones,
and esters due to its lower reactivity toward electrophilic sulfur re-
agents and greater steric bulk. Hence, the preliminary goal was to
investigate the reactivity of the substituted piperazine-2,5-diones
N
H
S
CH2OH
CH2OH
O
H
S
N
N
HOH2C
O
N
N
O
S
S
O
N
N
N
S
S
S
S
O
a-sulfenylation with
N
under typical conditions of organocatalytic
N
CH2OH
cinchona alkaloids as catalysts. Initially, 1-benzylsulfanyl[1,2,4]tri-
N
N
H
H
O
O
H
H
Chaetocin
Chetomin
* Corresponding author. Tel.: +1 520 626 0754; fax: +1 520 621 8407.
E-mail address: olenyuk@email.arizona.edu (B. Olenyuk).
Figure 1. Epidithiodiketopiperazine fungal metabolites.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.031

R. Dubey et al. / Tetrahedron Letters 50 (2009) 4310–4313
4311
Table 1
Organocatalytic
a-sulfenylation of 1a–e with 1-benzylsulfanyl[1,2,4]triazole 2a and Lewis bases 4a–d
O
O
O
R
O
R
N
Ph
cat., solv.
15 mol%
N
N
S
N
S
+
N
N
N
OEt
OEt
O
O
2a
Ph
1a: R = Me
1b: R = H
1c: R = CH3CO
1d: R = PhCO
1e: R = Ts
3a: R = Me
3b: R = H
High substrate
Solvent
Temp. (°C)
Time (h)
Catalyst
Equiv of 2a
Yielda (%)
1a
1a
1a
CH2Cl2
Toluene
CH2Cl2
rt
rt
rt
rt
120
120
120
48
24
24
24
24
24
72
4a
4a
4d
4d
4c
4c
4c
4a
4b
4a
4a
4a
4a
5.0
5.0
10.0
2.0
2.0
1.5
1.5
2.0
2.0
2.6
2.6
2.6
2.6
46
44
55
93
95
90
20
94
91
10
10
1b
1b
1b
1b
1b
1b
1cb
1cb
1db
1e
CH2Cl2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
rt
À10
À78
À10
À10
rt
À10
72
72
72
rt
10
c
rt
a
Yield of purified product after chromatographic separation.
Compound 3b was obtained as the product.
b
c
No product was formed, as observed by 1H NMR.
N-4 substituent, 1b, gave yields with 2a. This limits the scope of 2a
as an electrophile in sulfenylation of substituted piperazine-2,5-
diones.
In an attempt to improve the substrate scope, we also synthe-
sized 1-(p-methoxybenzyl)sulfanyl[1,2,4]triazole and 1-(p-nitro-
manner similar to 2a, were found to be too unstable for practical
application.
To improve yields, a new sulfenylating reagent 1-phenylsulfa-
nyl[1,2,4]triazole (2b) was tested. This reagent gave excellent
product yield with substrate 1a and was chosen for subsequent
reaction optimizations. First, we screened the reaction conditions
benzyl)sulfanyl[1,2,4]triazole. These reagents, prepared in
a
needed to efficiently carry out the a-sulfenylation with compound
2b. Catalysts, solvents, temperature as well as amounts of sulfeny-
lating reagent 2b were varied in order to improve yields (Table 2).
The sterically bulky compound 1g was selected because its lower
reactivity made it an ideal substrate for screening of sulfenylation
conditions.
Gratifyingly, sulfenylating reagent 2b gave considerably higher
yields than 2a in all reactions with lower amounts of 2b required
for efficient sulfenylation (Table 2). Different catalysts were
screened, to find the most suitable candidate. The readily accessi-
H
H
Et
Et
Ph
Ph
N
N
H
O
O
H
H
H
MeO
N
N
OMe
N
N
4a: (DHQD)2PYR
H
H
Et
Et
Table 2
Optimization of reaction conditions of sulfenylation of 1g with 1-phenylsulfa-
nyl[1,2,4]triazole 2b
N
N
O
H
O
H
H
H
N
N
MeO
OMe
O
O
cat., solv.
15 mol %
N
N
N
N
N
N
S Ph
+
Ot-Bu
Ot-Bu
N
N
N
4b: (DHQD)2PHAL
S
O
O
O
O
R
Ph
1g
2b
3g
H
N
Entry
Solvent
Temp (°C)
Catalyst
Equiv of 2b
Yielda (%)
R'O
1
2
3
4
5
6
CH2Cl2
rt
rt
rt
rt
0
À10
4c
4a
4b
4c
4c
4c
2.0
2.0
2.0
2.0
3.0
3.0
79
60
65
91
97
96
MeO
Toluene
Toluene
Toluene
Toluene
N
4c: R = CH2=CH, R' = H, Quinine
4d: R = Et, R' = H, Dihydroquinine
PhH/PhMe (3:1)
a
Yield of purified product after chromatographic separation.
Figure 2. Cinchona alkaloids used as catalysts.

4312
R. Dubey et al. / Tetrahedron Letters 50 (2009) 4310–4313
ble quinine (4c) was found to be superior to catalysts (DHQD)2PYR
(4a) and (DHQD)2PHAL (4b). This is probably due to the fact that
the tertiary amines in both (DHQD)2PYR (4a) and (DHQD)2PHAL
(4b) are more sterically demanding than quinine. Toluene and ben-
zene/toluene mixture were also found to be superior to dichloro-
methane for obtaining high yields. The higher stability of 2b as
compared to 2a under sulfenylation conditions has facilitated
product isolation, because lesser amount of this reagent was
required to obtain high yields.
Next, to test the substrate scope, the reactivity of 2b with other
substituted piperazine-2,5-diones 1f–j was studied. Compounds
1a and 1f gave excellent yields with 2b (Table 3). Substrates 1h
and 1i with ethyl and benzyl groups at the N-4 position are more
sterically demanding than substrates with a methyl group at that
position. Compounds 1h and 1i were sulfenylated using 2b in high
yields. This shows that 1-phenylsulfanyl[1,2,4]triazole (2b) is able
to efficiently sulfenylate piperazine-2,5-dione substrates under
different reaction conditions. Compound 1j which has a benzyl
Figure 3. The molecular structure of 3g with anisotropic displacement parameters
at 30% probability level.
substituent at the N-4 position and a t-butyl ester at the a-position,
efficient manner. We continue structural modifications of electro-
philic sulfur transfer reagents in order to expand their scope to ste-
rically bulky substrates. Further exploration of the mechanism of
organocatalytic a-sulfenylation and development of its enantiose-
lective variant are currently under investigation.
is the most sterically hindered substrate used in this study. It
showed moderate yield with 2b and quinine 4c as the catalyst.
When (DHQD)2PYR 4a and (DHQD)2PHAL 4b were used, low prod-
uct yield was observed. Presumably the greater steric bulk of 4a
and 4b played a major role in reducing the reaction rate when
these catalysts were used with the bulky substrates. Because qui-
nine is the least expensive organocatalyst among all tested cin-
chona alkaloids, its use in combination with the readily prepared
Acknowledgments
Financial support of the University of Arizona is gratefully
acknowledged. The X-ray diffractometer was purchased with sup-
port of the National Science Foundation (Grant CHE-9610374). We
also thank the National Science Foundation (Grant CHE-0748838)
and the National Institutes of Health (Grant R21 CA129388) for
funding.
2b, provides an economical route to
2,5-diones.
a-sulfenylated piperazine-
Crystallization of product 3g from ethanol at room temperature
provided single crystals suitable for X-ray diffraction analysis.14
The molecular structure of 3g is shown in Figure 3. The compound
3g has crystallized in the centrosymmetric orthorhombic space
group Pbca and the crystal packing shows efficient stacking of
the phenyl and diketopiperazine rings in the solid state. It is
hypothesized that this stacking may provide additional stabiliza-
tion in the transition state of the sulfenylation reaction.
Supplementary data
Synthetic procedures, characterization, and NMR spectra of
compounds 1, 2b and 3 are available. Crystallographic data for
3g have been deposited into the Cambridge Crystallographic Data
Centre (CCDC accession number 721744). These data can be ob-
tained free of charge from http://www.ccdc.cam.ac.uk/data_re-
quest/cif. Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.05.031.
In summary, direct and efficient organocatalytic a-sulfenylation
of substituted piperazine-2,5-diones has been developed. Various
substrates, solvents, and sulfur transfer reagents have been
screened, resulting in high product yields under optimized reaction
conditions. This methodology may be of value for future construc-
tion of the epidithiodiketopiperazine ring system in a rapid and
Table 3
Scope of a-sulfenylation of trisubstituted piperazine-2,5-diones with reagent 2b and 10 mol % of cinchona alkaloids 4a–c
O
O
O
R1
O
R1
O
N
catalyst
N
N
S
N
S Ph
OR3
N
N
OR3
+
N
10 mol%
R2
R2
O
2b
Ph
Entry
Substrate
R1
R2
R3
Solvent
Temp (°C)
Catalyst
Equiv of 2b
Time (h)
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
1f
1a
1g
1h
1h
1i
1i
1b
1j
Me
Me
Me
Et
Me
Me
Me
Et
Me
Et
t-Bu
Et
Et
Et
Et
Et
t-Bu
t-Bu
t-Bu
PhH/PhMe (3:1)
PhH/PhMe (3:1)
PhH/PhMe (3:1)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
À10
À10
À10
rt
rt
rt
rt
rt
rt
rt
4c
4c
4c
3.0
3.0
3.0
3.0
8.0
3.0
8.0
3.0
10.0
2.0
2.0
18
30
48
60
48
60
48
16
72
60
60
3f
3k
3g
3h
3h
3i
3i
3l
3j
3j
99
99
96
77
94
75
95
81
52
5
4c
Et
Et
4cb
4c
Bn
Bn
H
Bn
Bn
Bn
Bn
Bn
Me
Bn
Bn
Bn
4cb
4c
4cb
4a
4b
10
11
1j
1j
Toluene
rt
3j
5
a
Yield of purified product after chromatographic separation.
20 mol % catalyst used.
b

R. Dubey et al. / Tetrahedron Letters 50 (2009) 4310–4313
4313
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14. Crystal data for 3g: C17H22N2O4S, 350.43 g molÀ1
,
colorless crystal
0.72 Â 0.47 Â 0.33 mm3, 220(2) K, Bruker SMART 1000 CCD diffractometer
with a graphite monochromator (thin-slice
x scans, h range from 2.2° to 27.1°),
MoK
k = 0.71073 Å, a = 11.4784(15) Å, b = 16.628(2) Å, c = 18.778(2) Å,
V = 3584.1(8) Å3, Z = 8, calc = 1.299 g cmÀ3 0.203 mmÀ1
2hmax = 27.1°
99.9% complete, reflections collected/unique = 28,216/3954 (Rint = 0.0321),
R1 = 0.0399, wR2 = 0.0928 for 2960 reflections with I > 2 (I). See
Supplementary data for complete X-ray crystallographic information.
a
q
,
l
,
r