Synthesis of the disubstituted maleic anhydride frame using a novel tandem radical-polar reaction

Article abstract of DOI:10.1055/s-0029-1217569

An unreported 5-endo-trig atom-transfer radical cyclization of cyclic N-α-dichloroacyl-ketene-N,S-acetals, which evolves as a tandem radical-polar process, is described. The reaction, which is carried out in the presence of a Cu(I) complex catalyst (10 mol%) and an inorganic base (i.e., carbonate), can be exploited as the key step for a novel, short, and versatile synthesis of the 3,4-disubstituted maleic anhydride nucleus. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217569

2172
LETTER
Synthesis of the Disubstituted Maleic Anhydride Frame Using a Novel Tandem
Radical–Polar Reaction
Synthesis of the
Disub
a
stitute
d
Ma
r
leic
A
nh
i
ydride
e
Fram
e
lla Pattarozzi,*a Franco Ghelfi,a Fabrizio Roncaglia,a Ugo M. Pagnoni,a Andrew F. Parsonsb
a
Dipartimento di Chimica, Università degli Studi di Modena e Reggio Emilia, via Campi 183, 41100 Modena, Italy
Fax +39(059)373543; E-mail: mariella.pattarozzi@unimore.it
b
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 28 April 2009
these reactions, the radicals 1, formed according to
Scheme 1, can add to the C=C bond generating the cyclic
radicals exo-2 (from 10 and 11) and endo-2 (from 10),
which react further with the redox catalyst in its oxidized
Abstract: An unreported 5-endo-trig atom-transfer radical cycliza-
tion of cyclic N-a-dichloroacyl-ketene-N,S-acetals, which evolves
as a tandem radical–polar process, is described. The reaction, which
is carried out in the presence of a Cu(I) complex catalyst (10 mol%)
and an inorganic base (i.e., carbonate), can be exploited as the key state, returning it under the active reduced form. The reac-
step for a novel, short, and versatile synthesis of the 3,4-disubstitut-
ed maleic anhydride nucleus.
tion proceeds through the irreversible halogen-atom trans-
fer from the CuX2 complex to the intermediates 2, with
formation of the corresponding fully halogenated prod-
ucts 3 (Scheme 1, path i). In the 5-endo cyclization of N-
vinyl-a-haloamides it has been suggested that the a-amido
radical endo-20 can evolve also via a radical–polar cross-
Key words: cyclizations, imides, radical reactions, sulfur, tandem
reactions
The cyclization of N-allyl (11) or N-vinyl (10) carbamoyl over (Scheme 1, path ii),10 due to its tendency to undergo
methyl radicals is a well-consolidated practice for the con- oxidation to the acyliminium ion 4 through a single elec-
struction of g-lactams, via a 5-exo- or a 5-endo-trig route, tron transfer to CuX2.11 In this case, a halogen atom can be
respectively (Scheme 1).1 However, for N-vinyl radicals inserted through a process akin to the second step of an
10, the regioselectivity of the cyclization can change to af- SN1 mechanism, or, if a b-hydrogen is present, the reac-
ford b-lactams through an alternative 4-exo-trig attack. tion can proceed by an E1-type mechanism affording an
According to Baldwin’s rules,2 the 5-endo radical cycliza- unsaturated g-lactam. However, we believe that the cation
tion (RC) is hampered with respect to the 4-exo mode, yet 4 can also be formed from the chlorolactams derived from
in many cases the five-membered ring is isolated as the the ATRC cycle (Scheme 1, path iii).12
main or the sole product.3 Studies exploring the effect of
temperature and solvent on the regiochemistry of the
process4 indicate that the 4-exo cyclization is kinetically
favored, but reversible.5 The course of the reaction is
strongly influenced by the stability of the cyclic radical in-
termediates 20. Although the exo-20 adduct is formed first,
in the absence of adjacent radical-stabilizing groups (i.e.,
Ph, SR) it is converted through the carbamoyl methyl rad-
icals 10 into the more stable endo-20.6 In any case, a sub-
stituent on the amide nitrogen, acting as a cyclization
auxiliary (CA), is required. Its function is to cause the
molecule to adopt a conformation whereby the radical
center is positioned in close proximity to the radicophile.7
X
( )n
( )n
O
N
O
N
CA
CA
1n
(X = Cl, Br)
Cu(I)X
Cu(II)X2
X
( )n
( )n
N
N
N
O
O
O
CA
CA
CA
n = 0 4-exo
n = 1 5-exo
n = 0 4-exo
n = 1 5-exo
–H+
By far the most common method of preparing radicals 1 is
by homolytic cleavage of the Ca-halogen bond in N-allyl-
or N-vinyl-a-haloamides with Bu3SnH, in the presence of
a radical initiator.8 However, this methodology comes
down with grave flaws, including the toxicity of organotin
derivatives and the reductive nature of the process. These
problems have been conveniently circumvented by the
atom-transfer radical cyclization (ATRC) of the same
substrates, promoted by transition metals (TMC), usually
Cu(I) complexes with polydentate nitrogen ligands.9 In
3n
2n
or/and
or/and
ii) radical-polar
crossover
i)
ATRC
X
Cu(II)X2
N
N
O
O
N
O
CA
CA
CA
n = 0 5-endo
n = 0 5-endo
4
iii)
Scheme 1 Cu(I)-catalyzed RC of N-allyl (n = 1) and N-vinyl (n = 0)
a-halo-amides
The TMC-ATRC of N-vinyl-a-haloamides10b,c is catalyti-
cally less efficient than for N-allyl-a-haloamides,13 prob-
ably owing to the release of HCl in the reaction medium,
consequently these reactions require larger amounts of the
SYNLETT 2009, No. 13, pp 2172–2176
x
x
.x
x
.2
0
0
9
Advanced online publication: 15.07.2009
DOI: 10.1055/s-0029-1217569; Art ID: G14409ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of the Disubstituted Maleic Anhydride Frame
2173
Cu(I) complex, typically 30–50 mol% against 5–10 Herein we report the positive preliminary results concern-
mol%.
ing the viability of the process, from the reactions of eas-
ily accessible cyclic ketene-N,S-acetals 5a,b, which have
been chosen in order to clarify the effect of the ring size
on the ATRC.
In our group, the Cu(I)-catalyzed 5-exo ATRC of N-allyl-
a-perchloroamides has been extensively studied and used,
jointly with the MeONa-mediated functional rearrange-
ment (FR) of the resulting chlorolactams, for the synthesis 3-(2,2-Dichlorobutanoyl)-2-ethylidene-1,3-thiazolidine
of the 3,4-dialkyl-substituted maleic anhydride nucleus,14 (5a) and 3-(2,2-dichlorobutanoyl)-2-ethylidene-1,3-thiaz-
typical framework of valuable natural products.15 Since ine (5b) were first prepared by N-acylation,14b,18 using
the stereoselectivity of the ATRC cannot be exactly con- 2,2-dichlorobutanoyl chloride, of 2-ethyl-1,3-thiazoline
trolled,16 the formation of an unwanted diastereomer leads (46%) and 2-ethyl-5,6-dihydro-4H-1,3-thiazine (71%),
to a loss of efficiency that can limit the scope of the meth- respectively, which in turn were prepared according to lit-
od.
erature methods.19
As part of a program to develop new and more versatile Our initial experiments examined the RC of 5a,b under
routes towards chaetomellic anhydrides and their homo- our classical reaction conditions: CuCl (10 mol%) with
logues, we planned to study the preparation of 3,4-dialkyl- N,N,N¢,N¢-tetramethylethylenediamine (TMEDA, 20
substituted maleic anhydrides through the Cu(I)-catalyzed mol%) or N,N,N¢,N¢N¢¢-pentamethyldiethylenetriamine
RC of the N-a-perchloroacyl cyclic ketene-N,S-acetals 5, (PMDETA, 10 mol%) in MeCN. Unfortunately, a com-
according to Scheme 2, in order to overcome the stereose- plete lack of reactivity was observed even after 16 hours
lectivity problem of the 5-exo. Interestingly, in this new at 40–60 °C. We ascribed the reason for these dishearten-
synthetic approach the CA is already included into the ing results to the release of HCl into the reaction mixture,
structure of the cyclic ketene acetal.
an event which is known to disrupt the redox cycle.7,10b To
solve this problem, we repeated the same reactions with a
higher amount of catalyst (30 mol%) and the concomitant
use of an inorganic base, such as K2CO3 (2 equiv). To our
great satisfaction, both the enamides 5a,b reacted com-
pletely, when the reaction mixture was stirred overnight at
room temperature.
Me
Cl Cl
Et
Cl
Me
S
Me
CuCl
ligand
Et
Cl
S
4-exo
Et
N
S
( )n
O
N
N
( )n
( )n
O
6
O
7
5a n = 1
5b n = 2
5-endo
Ketene-N,S-acetal 5a afforded a very complex mixture of
products, from which four main components were isolated
using chromatography: the dimer 13a (19%), the symmet-
ric disulfide 14a (9%), the symmetric C–C dimer 15a, as
separable mixture of meso/dl diastereomers (15%), and
the thioester 16a (12%), in a combined overall yield of
55% (Figure 1).
Me
Me
Me
Cl
Cl
Cl
Et
Et
Et
Cl
S
S
S
N
N
N
O
O
O
( )n
( )n
( )n
Me
9
10
8
Me
Et
Et
O
O
O
Et
Me
O
O
N
Me
O
O
12
11
Et
Et
N
R
O
S
Me
( )n
Et
N
S
Scheme 2
Me
N
O
( )n
O
O
( )n
N
O
13
14
( )n
S
( )n
As far as we are aware, the cyclization of a carbamoyl me-
thyl radical intermediate of type 6 has not been reported.
There is only one example of a RC of a cyclic ketene-N,S-
acetal, which concerns the Bu3SnH/AIBN-mediated 6-
endo-trig cyclization of b-haloenamides.17 It should be
noted that ketene-N,S-acetals contain a highly nucleo-
philic C=C bond due to the combined electron-donating
effects of the enamine and the vinyl thioether groups.
S
O
N
Me
S
S
Et
O
Cl Cl
Et
H
Et
N
( )n
Me
S
Et
N
O
( )n
O
15
16
Figure 1 Products of the ATRC of 5a (n = 1) and 5b (n = 2)
Under the same reaction conditions, 5b gave a much bet-
ter result. In fact, it was converted into a 9:1 mixture (by
1H NMR spectroscopy) of dimers 13b and 14b, which, af-
ter chromatography, were recovered in 74% and 8% yield,
respectively. Only traces of thioester 16b were indicated
by the H NMR spectrum of the crude reaction product
and there was no evidence of dimer 15b.
In the ATRC of 5, we expected a high 5-endo regioselec-
tivity, due to the greater stability of the cyclic radical in-
termediate 8 compared to 7. Indeed, the 5-endo radical 8
is adjacent to two radical-stabilizing groups: the a-acyl-
amino and the alkylthio group. In principle, radical 8
could react to afford adducts 9 or/and 10, which can con-
verge first to a 3,4-dialkyl-substituted maleimide 11 and,
from here, to the anhydride 12, under appropriate hydro-
lytic conditions.
1
Synlett 2009, No. 13, 2172–2176 © Thieme Stuttgart · New York

2174
M. Pattarozzi et al.
LETTER
Table 1 ATRC of 5ba
13b
silicasulfuric acid (2 equiv)
Entry Ligand (mol%)
Conversion (%)b Yield (%)c
NaNO3 (2 equiv)
wet SiO2 60% w/w
CH2Cl2, 40 °C, 17 h
13b
74
14b
8
16b
traces
traces
n.d.
6
1d
2
PMDETA (30)
PMDETA (10)
PMDETA (5)
PMDETA (10)
PMDETA (10)
TMEDA (20)
bpy (20)
100
100
33
14b
+
Me
69
15
n.d.
9
Me
Et
Me
H2SO4–AcOH (1:1)
140 °C, 65 h
Et
Et
3e
4f
5g
6
n.d.
17
O
O
O
O
O
N
N
O
O
64
S
( )2
S
( )2
12 (60%)
100
100
100
100
73
9
2
O
O
17
69
23
18
14
traces
2
Scheme 3 Conversion of 13b into the maleic anhydride 12
7
72
hydrolytic step. Indeed, both 13b and 14b already contain
the maleimide skeleton, a more evolved structure com-
pared to the expected product 10. While the reductive
dimerization product 14b requires a simple hydrolysis for
its conversion into the maleic anhydride 12, compound
13b requires prior cleavage of the S,S-acetal to give the
corresponding C=O bond. This was performed by reac-
tion with silica-sulfuric acid and NaNO3, with the recov-
ery of the two adducts 14b and 17 in 40% and 25% yield,
respectively.21,22 So, this procedure, which was not opti-
mized, allows the main product derived from ATRC of 5b
8h
TMEDA (20)
80
traces
a Reaction conditions: 5b (2 mmol), CuCl (10 mol%), K2CO3 (2
mmol), MeCN (3 mL), 17 h, r.t. (25–30 °C).
b Determined from the 1H NMR spectrum of the crude product.
c Isolated yields.
d CuCl (30 mol%).
e CuCl (5 mol%).
f K2CO3 (1 mmol).
g MeCN (1.5 mL).
h Na2CO3 (2 mmol).
Most likely, products 13 and 14 arise from the expected to be converted into a dimaleimide, avoiding the use of
radical–polar-crossover product 10, with subsequent toxic mercury-containing reagents.
opening of the 1,3-thiazoline or 1,3-thiazine ring and
dimerization processes.
We then carried out the conversion of the dimer 13b into
the maleic anhydride 12 through two subsequent steps:
After these preliminary results, because of the problems dithioacetal oxidative cleavage and acidic hydrolysis of
associated with the reaction of enamide 5a [a complex reac- the crude intermediates 14b and 17 using H2SO4–acetic
tion mixture, compared to 5b, a lower yield of products acid at high temperature (140 °C, Scheme 3), obtaining 12
(55% vs. 82%) and higher instability], we focused our at- in good overall yield (60%).23
tention on ketene-N,S-acetal 5b.20
In summary, we report the first regioselective 5-endo
Importantly, the quantity of the Cu(I) catalyst can be re- ATRC of ketene-N,S-acetals 5, using a catalytic amount
duced to 10 mol%, without affecting the overall result (10 mol%) of Cu(I) halide complexes. The lack of reactiv-
(Table 1, entry 2). The key role played by the base was ity due to the release of HCl in the reaction mixture can be
verified by using only 1 equivalent of K2CO3 (Table 1, en- easily solved with the concomitant use of an inorganic
try 4): in this case the reaction was incomplete. Although base (i.e., carbonate). The overall process is a clear and
we have not yet completely clarified the reaction mecha- particularly efficient example of a tandem radical–polar
nism, it is evident that 2 equivalents of the base are re- reaction.24 In fact, from enamide 5b two products, 13b
quired to neutralize the 2 equivalents of HCl released and 14b, which already contain the latent maleic anhy-
during the process. Moreover, the reaction can be carried dride nucleus, were recovered in excellent yield (94%).
out using a more concentrated solution with the same ef- Studies aimed at clarifying the reaction mechanism are
ficiency (Table 1, entry 5). The effectiveness of the three currently under investigation, along with the use of
multidentate nitrogen ligands TMEDA, PMDETA, or ketene-N,O-acetals and ketene-N,N-acetals analogues of
2,2¢-bipyridyl (bpy) gave comparable results as far as re- 5. Moreover, the smooth conversion of both 13b and 14b
activity, product distribution and yields are concerned into the disubstituted maleic anhydride 12 offers a new
(Table 1, entries 2 and 6, 7). Finally, we were pleased to and versatile synthetic pathway, which could allow the
verify that the less expensive Na2CO3 can be used in place preparation of analogues of chaetomellic anhydride in two
of K2CO3, to give an optimum 94% combined yield (Ta- steps, starting from the appropriate enamide. Finally, we
ble 1, entry 8).
believe that the incorporation of an inorganic base could
be applied to the Cu(I)-mediated ATRC of simple N-
vinyl-a-haloamides, which in turn could lead to the use of
much lower quantities of catalyst than currently required.
These results are extremely interesting because the two
main products obtained, in excellent yields, from the
RC of 5b could, in principle, be converted into our target
3,4-dialkyl-substituted maleic anhydride through a single
Synlett 2009, No. 13, 2172–2176 © Thieme Stuttgart · New York

LETTER
Synthesis of the Disubstituted Maleic Anhydride Frame
2175
(18) 3-(2,2-Dichlorobutanoyl)-2-ethylidene-1,3-thiazolidine
(5a)
Acknowledgment
Yellow oil. Rf = 0.64 (PE–Et2O, 1:1). 1H NMR (200 MHz,
CDCl3): d = 1.23 (t, J = 7.1 Hz, 3 H, CH3), 1.74 (d, J = 6.8
Hz, 3 H, CH3), 2.50 (q, J = 7.1 Hz, 2 H, CH2), 3.05 (t, J = 6.2
Hz, 2 H, CH2), 4.48 (t, J = 6.2 Hz, 2 H, CH2), 6.26 (q, J = 7.1
Hz, 1 H, CH) ppm. 13C NMR (50 MHz, CDCl3): d = 9.6,
15.8, 28.1, 39.4, 53.1, 87.2, 109.1, 135.0, 162.3 ppm. MS
(EI, 70 eV): m/z (%) = 253 (22) [M]+, 218 (100), 190 (28).
IR (film): 1670 (C=O) cm–1.
We thank the Ministero dell’Istruzione, dell’Università e della
Ricerca (MIUR) for financial assistance.
References and Notes
(1) Giese, B.; Kopping, B.; Göbel, T.; Dickhaut, J.; Thoma, G.;
Kulicke, K. J.; Trach, F. Organic Reactions, Vol. 48;
Paquette, L. A., Ed.; Wiley: New York, 1996, 301.
(2) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976,
734. (b) Beckwith, A. L. J.; Easton, C. J.; Serelis, A. K.
J. Chem. Soc., Chem. Commun. 1980, 482.
(3) For reviews, see: (a) Parsons, A. F. C. R. Acad. Sci., Ser. IIc
2001, 4, 391. (b) Ishibashi, H.; Sato, T.; Ikeda, M. Synthesis
2002, 695.
(4) (a) Ishibashi, H.; Higuchi, M.; Ohba, M.; Ikeda, M.
Tetrahedron Lett. 1998, 39, 75. (b) Bryans, J. S.; Chessum,
N. E. A.; Parsons, A. F.; Ghelfi, F. Tetrahedron Lett. 2001,
42, 2901.
(5) For the sake of completeness the question is debated, since
recent computational studies on the cyclization of N-vinyl-
carbamoyl methyl radicals suggest that the 5-endo mode is
not only thermodynamically favored, but also kinetically
favored: Chatgilialoglu, C.; Ferreri, C.; Guerra, M.;
Timokhin, V.; Froudakis, G.; Gimisis, T. J. Am. Chem. Soc.
2002, 124, 10765.
3-(2,2-Dichlorobutanoyl)-2-ethylidene-1,3-thiazine (5b)
Yellowish oil. Rf = 0.56 (PE–Et2O, 1:1). 1H NMR (400
MHz, CDCl3): d = 1.19 (t, J = 7.1 Hz, 3 H, CH3), 1.84 (d,
J = 6.8 Hz, 3 H, CH3), 2.08 (br m, 2 H, CH2), 2.49 (q, J = 7.1
Hz, 2 H, CH2), 2.85 (br m, 2 H, CH2), 4.22 (br m, 2 H, CH2),
6.07 (br m, 1 H, CH) ppm. 13C NMR (100 MHz, CDCl3):
d = 9.7, 14.4, 26.3, 29.5, 40.1, 49.8, 85.7, 130.6, 132.2,
163.5 ppm. MS (EI, 70 eV): m/z (%) = 267 (2) [M]+, 232
(42), 156 (96), 128 (100). IR (film): 1669 (C=O) cm–1.
(19) Fuganti, C.; Gatti, F. G.; Serra, S. Tetrahedron 2007, 63,
4762.
(20) Typical Procedure for the ATRC
Compound 5b (2 mmol, 536 mg), CuCl (10 mol%, 20 mg),
and Na2CO3 (2 mmol, 212 mg) were weighed into a Schlenk
tube, then dry MeCN (3 mL) and TMEDA (20 mol%, 60 mL)
were added under Ar. The mixture was stirred at 30 °C and
after 17 h diluted with H2O and extracted with CH2Cl2 (3 ×
25 mL). The combined organic layers were concentrated
under vacuum. Chromatography of the crude product on
silica, eluting with a PE–Et2O gradient from 9:1 to 4:6,
afforded 1-{3-[(7-ethyl-8-methyl-6-oxo-3,4-dihydro-2H-
pyrrolo[2,1-b][1,3]thiazin-6 (8aH)-yl)sulfanyl]propyl}-3-
ethyl-4-methyl-1H-pyrrole-2,5-dione (13b) as yellow oil
(327 mg, 80%) and 1,1¢-(disulfanediyldipropane-2,1-
diyl)bis(3-ethyl-4-methyl-1H-pyrrole-2,5-dione) (14b) as
orange oil (60 mg, 14%).
(6) Ishibashi, H. Chem. Rec. 2006, 6, 23.
(7) Ghelfi, F.; Parsons, A. F. J. Org. Chem. 2000, 65, 6249.
(8) (a) Curran, D. P. Comprehensive Organic Synthesis, Vol. 4;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991, 779. (b) Gilbert, B. C.; Parsons, A. F. J. Chem. Soc.,
Perkin Trans. 2 2002, 367. (c) Majumdar, K. C.; Basu,
P. K.; Chattopadhyay, S. K. Tetrahedron 2007, 63, 793.
(9) Clark, A. J. Chem. Soc. Rev. 2002, 31, 1; besides Cu(I),
Ru(II) has also been significantly employed.
Compound 13b: Rf = 0.12 (PE–Et2O, 1:1). 1H NMR (400
MHz, CDCl3): d = 0.92 (t, J = 7.6 Hz, 3 H, CH3), 0.98 (t,
J = 7.6 Hz, 3 H, CH3), 1.44 (q t, J = 13.2 Hz, 3.0 Hz, 1 H,
CHaxH), 1.51 (quin, J = 7.0 Hz, 2 H, CH2), 1.62–1.77 (m, 2
H, CH2), 1.78–1.90 (m, 1 H, CHeqH), 1.80 (s, 3 H, CH3), 1.88
(s, 3 H, CH3), 2.17 (q, J = 7.6 Hz, 2 H, CH2), 2.24 (q, J = 7.6
Hz, 2 H, CH2), 2.54 (br d t, J = 13.2 Hz, 1 H, CHeqH), 2.94
(t d, J = 13.2, 3.0 Hz, 1 H, CHaxH), 3.17 (t d, J = 13.2, 3.0
Hz, 1 H, CHaxH), 3.29 (t, J = 7.0 Hz, 2 H, CH2), 4.11 (br d,
J = 13.2 Hz, 1 H, CHeqH) ppm. 13C NMR (100 MHz,
CDCl3): d = 8.4, 10.2, 12.6, 13.1, 17.0, 26.2, 26.8, 27.7,
27.9, 35.6, 37.0, 73.8, 134.5, 136.5, 142.1, 150.1, 167.6,
171.6, 172.1 ppm. HRMS: m/z calcd for C20H28N2NaO3S2
[M + Na]+ 431.1434; found: 431.1438. IR (film): 1685
(C=O) cm–1.
(10) (a) Lampard, C.; Murphy, J. A.; Lewis, N. J. Chem. Soc.,
Chem. Commun. 1993, 295. (b) Davies, D. T.; Kapur, N.;
Parsons, A. F. Tetrahedron Lett. 1999, 40, 8615. (c) Clark,
A. J.; Dell, C. P.; Ellard, J. M.; Hunt, N. A.; McDonagh,
J. P. Tetrahedron Lett. 1999, 40, 8619.
(11) The radical–polar crossover has also been proposed for Ni,
Mn(III), Bu3SnH, and Ce(IV) promoted RC of enamides:
(a) Cassayre, J.; Quiclet-Sire, B.; Saunier, J.-B.; Zard, S. Z.
Tetrahedron 1998, 54, 1029. (b) Davies, D. T.; Kapur, N.;
Parsons, A. F. Tetrahedron Lett. 1998, 39, 4397.
(c) Ishibashi, H.; Matsukida, H.; Toyao, A.; Tamura, O.;
Takeda, Y. Synlett 2000, 1497. (d) Clark, A. J.; Dell, C. P.;
McDonagh, J. M.; Geden, J.; Mawdsley, P. Org. Lett. 2003,
5, 2063.
(12) Friestad, G. K.; Wu, Y. Org. Lett. 2009, 11, 819.
(13) Benedetti, M.; Forti, L.; Ghelfi, F.; Pagnoni, U. M.; Ronzoni,
R. Tetrahedron 1997, 53, 14031.
(14) (a) Bellesia, F.; Danieli, C.; De Buyck, L.; Galeazzi, R.;
Ghelfi, F.; Mucci, A.; Orena, M.; Pagnoni, U. M.; Parsons,
A. F.; Roncaglia, F. Tetrahedron 2006, 62, 746. (b) Ghelfi,
F.; Pattarozzi, M.; Roncaglia, F.; Parsons, A. F.; Felluga, F.;
Pagnoni, U. M.; Valentin, E.; Mucci, A.; Bellesia, F.
Synthesis 2008, 3131.
Compound 14b: Rf = 0.33 (PE–Et2O, 1:1). 1H NMR (400
MHz, CDCl3): d = 1.12 (t, J = 7.6 Hz, 6 H, 2 CH3), 1.90–
2.00 (m, 4 H, 2 CH2), 1.95 (s, 6 H, 2 CH3), 2.39 (q, J = 7.6
Hz, 4 H, 2 CH2), 2.64 (t, J = 7.0 Hz, 4 H, 2 CH2), 3.56 (t,
J = 7.0 Hz, 4 H, 2 CH2) ppm. 13C NMR (100 MHz, CDCl3):
d = 8.5, 12.6, 17.1, 28.3, 36.0, 36.7, 136.5, 142.2, 171.8,
172.2 ppm. HRMS: m/z calcd for C20H28N2NaO4S2
[M+Na]+: 447.1383; found: 447.1385. IR (film): 1700
(C=O) cm–1.
(15) Chen, X.; Zheng, Y.; Shen, Y. Chem. Rev. 2007, 107, 1777.
(16) Ghelfi, F.; Bellesia, F.; Forti, L.; Ghirardini, G.; Grandi, R.;
Libertini, E.; Montemaggi, M. C.; Pagnoni, U. M.; Pinetti,
A. Tetrahedron 1999, 55, 5839.
All other compounds show spectral data (1H NMR, 13
C
NMR, HRMS, and IR) consistent with their structures.
(21) (a) Hajipour, A. R.; Zarei, A.; Khazdooz, L.; Ruoho, A. E.
Synthesis 2006, 1480. (b) Zolfigol, M. A. Tetrahedron 2001,
57, 9509.
(17) Zhou, A.; Njogu, M. N.; Pittman, C. U. Jr. Tetrahedron
2006, 62, 4093.
Synlett 2009, No. 13, 2172–2176 © Thieme Stuttgart · New York

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M. Pattarozzi et al.
LETTER
cooled down to r.t. Et2O (10 mL) was added, and the
(22) 1-[3-({[3-(3-Ethyl-4-methyl-2,5-dioxo-2,5-dihydro-1H-
pyrrol-1-yl)propyl]sulfonyl}sulfanyl)propyl]-3-ethyl-4-
methyl-1H-pyrrole-2,5-dione (17)
suspension was stirred at r.t. for 30 min and then filtered.
The solid was washed with Et2O (3 × 10 mL), then the
combined organic layers were concentrated under vacuum
into a Schlenk tube. Glacial AcOH (1.5 mL) and 2 M aq
H2SO4 (1.5 mL) were added to the crude product, then the
tube was closed with a screw cap. The mixture was stirred at
140 °C for 65 h and then cooled down to r.t. Water (15 mL)
was added, and the solution was extracted with Et2O (4 × 20
mL). The solvent was removed under vacuum.
Chromatography of the crude product on silica, eluting with
a PE–Et2O gradient from 9:1 to 5:5, afforded 3-ethyl-2-
methyl maleic anhydride (12, 61 mg, 60%).
Characterizations were in agreement with literature values:
Poigny, S.; Guyot, M.; Samadi, M. J. Chem. Soc., Perkin
Trans. 1 1997, 2175.
Yellow oil. Rf = 0.10 (PE–Et2O, 1:1). 1H NMR (400 MHz,
CDCl3): d = 1.11 (t, J = 7.6, 6 H, 2 CH3), 1.94 (s, 6 H,2 CH3),
2.00 (quin, J = 6.8 Hz, 2 H, CH2), 2.14 (quin, J = 7.2 Hz, 2
H, CH2), 2.38 (br q, J = 7.6 Hz, 4 H, 2 CH2), 3.07 (br t,
J = 6.8 Hz, 2 H, CH2), 3.31 (br t, J = 7.2 Hz, 2 H, CH2), 3.57
(br t, J = 6.8 Hz, 2 H, CH2), 3.61 (br t, J = 7.2 Hz, 2 H, CH2)
ppm. 13C NMR (100 MHz, CDCl3): d = 8.4, 12.5, 17.0, 23.4,
28.9, 33.5, 35.8, 36.1, 60.2, 136.6, 136.7, 142.28, 142.32,
171.6, 171.7, 172.0, 172.1 ppm. HRMS: m/z calcd for
C20H29N2O6S2 [M + H]+: 457.1462; found: 457.1470. IR
(film): 1700 (C=O) cm–1.
(23) Compound 13b (0.73 mmol, 300 mg), wet SiO2 60% (w/w,
365 mg), NaNO3 (1.46 mmol, 124 mg), and silica-sulfuric
acid (1.46 mmol, 400 mg) were weighed into a vial, then
CH2Cl2 (3 mL) was added. The vial was closed with a screw
cap, and the mixture was stirred at 45 °C for 17 h and then
(24) Albert, M.; Fensterbank, L.; Lacôte, E.; Malacria, M. Top.
Curr. Chem. 2006, 264, 1.
Synlett 2009, No. 13, 2172–2176 © Thieme Stuttgart · New York

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