Arylmaleic anhydrides via Heck arylation of fumaric acid

Article abstract of DOI:10.1016/j.tetlet.2010.05.023

Palladium-catalyzed arylation of fumaric acid with aryl iodides is found to be a very simple, economic and scalable approach to arylmaleic anhydrides. The reaction is facilitated by the presence of donor moieties on the aryl fragment and does not occur wi

Full text of DOI:10.1016/j.tetlet.2010.05.023

Tetrahedron Letters 51 (2010) 3633–3635
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Arylmaleic anhydrides via Heck arylation of fumaric acid
*
Alexander I. Roshchin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospekt 47, 119991 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium-catalyzed arylation of fumaric acid with aryl iodides is found to be a very simple, economic
and scalable approach to arylmaleic anhydrides. The reaction is facilitated by the presence of donor moi-
eties on the aryl fragment and does not occur with strong acceptor groups.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 12 March 2010
Revised 26 April 2010
Accepted 7 May 2010
Available online 12 May 2010
Keywords:
Palladium
Heck reaction
Fumaric acid
2-Arylmaleic anhydrides
1. Introduction
A few other protocols for the Heck arylation have been devel-
oped, including the K2CO3–H2O–DMF–PdCl2 system,19 which al-
Arylmaleic anhydrides are useful reagents, which can be
converted, for example, into various polycyclic adducts,1–3 3-aryl-
furan-2(5H)-ones,4 6-aryl-3-oxauracils,5 or 2-chloro-3-arylmalei-
mides.6 The substituted maleic anhydride moiety is sometimes
associated with biological activity.7–9
lowed minimization of the palladium loading and the use of
highly hydrophilic olefin substrates such as acrylic acid. Using this
system we previously achieved fine and scale-up catalytic aryla-
tion of fumaric acid with 4- and 2-iodoanisoles to give the corre-
sponding arylmaleic acids in high yields.1
The title compounds have been obtained by a number of meth-
ods; examples include condensations of aryl
a-oxoacetates with
2. Results and discussion
cyanoacetic ester,10 with the Emmons reagent,3 or, quite recently,
with Ac2O in a TiCl4–Bu3N system.11 Another modern approach in-
volves the palladium-catalyzed double carbonylation of terminal
aryl acetylenes.12,13 As reported, these synthetic methods are quite
efficient, however they are limited by the availability of the start-
ing materials.
Here we present our further results on the scope and limitations
of this synthetic method. Thus, a set of aryl iodides (including some
hetaryl halides) bearing different substituents on the aromatic ring
were studied in the palladium-catalyzed arylation of fumaric acid
(Scheme 1). The isolated yields of the final products, arylmaleic
anhydrides, are summarized in Table 1.
The effect of substituents on the reactivity of ArI is the most sur-
prising feature of this reaction. It was found that p-donor moieties
on the aryl fragment markedly facilitate the arylation, while accep-
tor groups, even more markedly, retard it. The data obtained sug-
gest the following reactivity sequence:
Another approach using the Meerwein arylation of maleic acid
derivatives4,14,15 is straightforward, but tends to give substantial
amounts of byproducts, including diarylated olefins. Similar results
have been reported for the palladium-catalyzed arylation of maleic
anhydride with an aryl diazonium fluoroborate.16
In 1978, Heck and coworkers found that the reaction of iodo-
benzene with diethyl fumarate in an Et3N–Pd(OAc)2–o-Tol3P sys-
tem gave rise to 2-phenylmaleic ester in 80% yield.17 This
inversion of the olefin configuration results from the typical stereo-
chemical requirements of the reaction mechanism (Scheme 1):
intermediate 1 is formed by syn-addition of Ar-PdI to the olefin
and the following step, b-hydride elimination, requires a syn-
arrangement of the IPd–C–C–H fragment.18
4-AcNH > 4-MeO ꢀ 4-F > 3-MeO > 4-Cl > 4-CN = 2-CN =
2-NO2 = no reaction
No arylated products were obtained with 4-cyano-, 2-cyano-,
and 2-nitroiodobenzenes and 3-bromopyridine; only about 5% of
the product was obtained with 2-bromothiophene, and with
2-iodothiophene only decomposition was observed.
This behavior, although unusual for the Heck reaction and not yet
explained, is not completely without precedent. Similar retarding
* Tel.: +7 499 137 2944; fax: +7 499 135 5328.
E-mail address: rosc71@yandex.ru
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.023

3634
A. I. Roshchin / Tetrahedron Letters 51 (2010) 3633–3635
O
O
OH
O
H
O
O
I
Pd(L2)I
H
R
O
O
O
a
b
HO
OH
O
+
O
Ar
1
R
R
O
HO
Scheme 1. Reagents and conditions: (a) PdCl2 (0.4 mol %), Ph3P (1.6 mol %), K2CO3, DMF–H2O or dioxane–H2O, 100 °C, 2.5–48 h; (b) 200–300 °C, 0.5–2 Torr or Ac2O, 100 °C,
0.5 h.
Table 1
tor substituents, under Heck conditions,17 has not been reported to
date.
Yields of 2-arylmaleic anhydrides from aryl iodides and fumaric acid
Entry
1
Ar-X
Method
B
Time (h)
2.5
Yielda (%)
74
The arylation of fumaric acid is also sensitive to steric hindrance
in the aryl fragment; for the 2-methoxy moiety this effect is com-
parable with its electronic promoting influence. With mono-iodo-
ortho-xylene,22 comprised of a 4:1 mixture of 3,4- and 2,3-dimeth-
yliodobenzenes, the arylation product was only obtained from the
3,4-isomer, while both the minor isomer and the mono-iodo-para-
xylene (2,5-dimethyliodobenzene) were found to be unreactive.
These data can be summarized in the following sequence:
O
N
I
2
3
A
A
4
4
79
76
O
F
I
I
3,4-dimethoxy > 2-MeO ꢀ 2,5-dimethoxy ꢀ 3-MeO ꢀ
I
3,4-dimethyl > 2,5-dimethyl = 2,3-dimethyl = no reaction
4
5
Ab
12
3
75
70
In conclusion, the palladium-catalyzed reaction of aryl iodides
with fumaric acid represents a simple and very economical method
to obtain a variety of arylmaleic anhydrides. We are working to
give further theoretical explanation of the observed substituent ef-
fects, and also to employ the newly available arylmaleic anhy-
drides for the synthesis of polycyclic systems.
O
O
I
B
O
O
I
6
7
Bb
A
20
18
58
3. Typical experimental procedure
O
I
I
79c
A mixture of fumaric acid (1.45 g, 12.5 mmol), K2CO3 (3.45 g,
25 mmol), Ph3P (0.055 g, 0.20 mmol, 1.6 mol %), DMF (12 mL),
H2O (12 mL), and PdCl2 (0.5 mL of a 0.1 M aq soln, 0.05 mmol,
0.4 mol %) was stirred under argon at 100–105 °C (Table 1).23 The
solvents were evaporated in vacuo, the residue washed with EtOAc
(26 mL), dried, suspended in water (15 mL) and treated with concd
aq HCl (5 mL) to give a precipitate of the crude arylmaleic acid,
which was dried in air.24 Method A: the precipitate was sublimed
at 0.5–2 Torr and 200–300 °C, followed, if required, by crystalliza-
tion from toluene or a toluene–hexane mixture. Method B: a mix-
ture of the crude arylmaleic acid and Ac2O (3 mL/g) was heated at
100 °C for 30 min followed by solvent evaporation in vacuo and
crystallization from toluene.
I
8
B
48
59
9
A
A
48
20
—
O
I
I
10
76
11
12
13
A
A
A
26
10
48
51
5
Cl
4. Characterization data of arylmaleic anhydrides
N-[4-(2,5-Dioxo-2,5-dihydrofuran-3-yl)phenyl]acetamide (Table1,
entry 1). Yellow crystals (MeCN or AcOH), mp 254 °C dec. 1H NMR
(300 MHz, (CD3)2SO) d: 2.09 (s, 3H, Ac), 7.55 (s, 1H, @CH), 7.75
(d, 2H, J = 9 Hz, Ar), 8.03 (d, 2H, J = 9 Hz, Ar), 10.33 (s, 1H, NH).
MS (EI) m/z: 231 (39%, MÅ+), 189 (61%, M–CH2CO), 159 (3%,
M–CO–CO2), 117 (100%). Anal. Calcd for C12H9NO4 (231.20):
C, 62.34; H, 3.92; N, 6.06. Found: C, 62.43; H, 4.01; N, 6.00.
3-(4-Methoxyphenyl)furan-2,5-dione1,4,13,14,16 (entry 2). Yellow
crystals (toluene + hexane), mp 145 °C with partial sublimation,
lit.25 mp 143–144 °C. 1H NMR (250 MHz, CDCl3) d: 3.90 (s, 3H,
OMe), 6.83 (s, 1H, @CH), 7.01 (d, 2H, J = 9 Hz, Ar), 7.98 (d, 2H,
J = 9 Hz, Ar).
Br
S
N
—
I
a
b
c
Isolated product was of satisfactory purity according to the NMR spectrum.
1,4-Dioxane was used instead of DMF.23
A 4:1 mixture of 3,4- and 2,3-dimethyliodobenzenes resulting from the iodin-
ation of ortho-xylene22 was used. Only the major 3,4-isomer participates in the
reaction, and the yield of the product is based on its content.
influence of acceptor moieties was observed in palladium-catalyzed
arylations of maleimides20 and cinnamonitrile21 in a base–Bu4NCl–
DMF system. Arylation of fumarate with aryl iodides, bearing accep-
3-(4-Fluorophenyl)furan-2,5-dione12 (entry 3). Colorless shiny
crystals (toluene + hexane), mp 114 °C with partial sublimation,

A. I. Roshchin / Tetrahedron Letters 51 (2010) 3633–3635
3635
1H NMR (250 MHz, CDCl3) d: 6.98 (s, 1H, @CH), 7.21 (m, 2H, Ar),
8.02 (m, 2H, Ar). 13C NMR (62.9 MHz, CDCl3) d: 116.82
(300 MHz, CDCl3) d: 7.02 (s, 1H, @CH), 7.52 (d, 2H, J = 9 Hz, Ar),
7.95 (d, 2H, J = 9 Hz, Ar).
(d, J = 11 Hz), 123.26, 124.06, 131.57 (d, J = 4.5 Hz), 145.71 (CAr
,
3-(2-Thienyl)furan-2,5-dione (entry 12). Yellow crystals, mp
127–129 °C. 1H NMR (250 MHz, CDCl3) d: 6.76 (s, 1H, @CH), 7.26
(t, 1H, J = 5 Hz, Ar-H4), 7.75 (d, 1H, J = 5 Hz, Ar-H), 8.03 (d, 1H,
J = 4 Hz, Ar-H). MS (EI) m/z: 180 (88%, MÅ+), 136 (4%, M–CO2), 108
(100%, M–CO–CO2). Anal. Calcd for C8H4O3S (180.18): C, 53.33; H,
2.24; S, 17.80. Found: C, 53.20; H, 2.32; S 17.69.
@C<), 163.29, 163.49, 164.63, 167.37 (CO, CF). MS (EI) m/z: 192
(43%, M+), 120 (100%, M–CO–CO2).
3-(2-Methoxyphenyl)furan-2,5-dione1,25 (entry 4). Bright yel-
low crystals (toluene + hexane), mp 134–136 °C with partial subli-
mation, lit.25 mp 135–136 °C. 1H NMR (250 MHz, CDCl3) d: 3.98
(s, 3H, OMe), 7.00–7.15 (m, 2H, Ar), 7.38 (s, 1H, @CH), 7.52
(t, 1H, J = 8 Hz, Ar), 8.34 (dd, 1H, J = 8 Hz, J = 1 Hz, Ar).
References and notes
3-(3,4-Dimethoxyphenyl)furan-2,5-dione (entry 5). Orange
crystals (toluene), mp 171.5–172.5 °C. 1H NMR (300 MHz, CDCl3)
d: 3.97 (s, 3H, OMe), 3.98 (s, 3H, OMe), 6.86 (s, 1H, @CH), 6.98 (d,
1H, J = 9 Hz, Ar-H5), 7.51 (d, 1H, J = 2 Hz, Ar-H2), 7.72 (dd, 1H,
J = 2 Hz, J = 9 Hz, Ar-H6). MS (EI) m/z: 234 (46%, MÅ+), 162 (100%,
M–CO–CO2), 147 (43%). Anal. Calcd for C12H10O5 (234.20): C,
61.54; H, 4.30. Found: C, 61.38; H, 4.34.
3-(2,5-Dimethoxyphenyl)furan-2,5-dione (entry 6). Dark red
crystals (toluene), mp 167–169 °C. 1H NMR (300 MHz, CDCl3) d:
3.84 (s, 3H, OMe), 3.94 (s, 3H, OMe), 6.96 (d, 1H, J = 9 Hz, Ar-H3),
7.08 (dd, 1H, J = 9 Hz, J = 3 Hz, Ar-H4), 7.41 (s, 1H, @CH), 7.95
(d, 1H, J = 3 Hz, Ar-H6). MS (EI) m/z: 234 (78%, MÅ+), 175 (6%,
M–CO–OCH3), 162 (100%, M–CO–CO2), 147 (84%), 119 (20%). Anal.
Calcd for C12H10O5 (234.20): C, 61.54; H, 4.30. Found: C, 61.44;
H, 4.22.
1. Roshchin, A. I.; Kuznetsov, Y. V.; Polunin, E. V. Russ. Chem. Bull. 2007, 56, 509–
512 (Izvestiya Akademii Nauk. Seriya Khimicheskaya 2007, 56, 491–494).
2. Muraoka, O.; Tanabe, G.; Higashiura, M.; Minematsu, T.; Momose, T. J. Chem.
Soc., Perkin Trans. 1 1995, 1437–1443.
3. Adams, D. L.; Vaughan, W. R. J. Org. Chem. 1972, 37, 3906–3913.
4. Kar, A.; Argade, N. P. Synthesis 2005, 2284–2286.
5. MacMillan, J. H.; Washburne, S. S. J. Heterocycl. Chem. 1975, 12, 1215–1220.
6. Augustin, M.; Faust, J.; Köhler, M. J. Prakt. Chem. 1983, 326, 293–300.
7. Slade, R. M.; Branchaud, B. P. J. Org. Chem. 1998, 63, 3544–3549.
8. Bit, R. A.; Davis, P. D.; Elliott, L. H.; Harris, W.; Hill, C. H.; Keech, E.; Kumar, H.;
Lawton, G.; Maw, A.; Nixon, J. S.; Vesey, D. R.; Wadsworth, J.; Wilkinson, S. E. J.
Med. Chem. 1996, 36, 21–29.
9. Adlington, R. M.; Baldwin, J. E.; Cox, R. J.; Pritchard, G. J. Synlett 2002, 820–822.
and references therein.
10. Rondestvedt, C. S., Jr.; Filbey, A. H. J. Org. Chem. 1954, 19, 119–123.
11. Kishorebabu, N.; Periasamy, M. Tetrahedron Lett. 2006, 47, 2107–2109.
12. Li, J.; Li, G.; Jiang, H.; Chen, M. Tetrahedron Lett. 2001, 42, 6923–6924.
13. Gabriele, B.; Veltri, L.; Salerno, G.; Costa, M.; Chiusoli, G. P. Eur. J. Org. Chem.
2003, 1722–1728. and references therein.
3-(3,4-Dimethylphenyl)furan-2,5-dione (entry 7). Pale yellow
crystals (toluene), mp 151–153 °C with partial sublimation, 1H
NMR (300 MHz, CDCl3) d: 2.35 (two overlapping s, 6H, 2Me), 6.90
(s, 1H, @CH), 7.27 (d, 1H, J = 8 Hz, Ar-H), 7.73 (m, 2H, Ar-H). MS
(EI) m/z: 202 (36%, MÅ+), 187 (5%, M–Me), 130 (100%, M–CO–
CO2), 115 (60%). Anal. Calcd for C12H10O3 (202.21): C, 71.28; H,
4.98. Found: C, 71.26; H, 5.11.
14. Rondestvedt, C. S., Jr.; Vogl, O. J. Am. Chem. Soc. 1955, 77, 2313–2315.
15. Nikitin, K. V.; Andryukhova, N. P. Chem. Heterocycl. Compd. 2004, 40, 561–569
(Khim. Geterotsikl. Soedin. 2004, 40, 670–678).
16. Burtoloso, A. C. B.; Garsia, A. L. L.; Miranda, K. C.; Correia, C. R. D. Synlett 2006,
3145–3149.
17. Cortese, N. A.; Ziegler, C. B., Jr.; Hrnjez, B. J.; Heck, R. F. J. Org. Chem. 1978, 43,
2952–2958.
18. Other products were biphenyl (11%) and diethyl 2-phenylfumarate (6%); the
amount of the latter increased if no phosphine ligand was added.17 Actually,
elimination of Pd and H is not necessarily a concerted syn-stereospecific
process and sometimes proceeds even when these atoms are fixed in an anti-
configuration.16,20
3-(Acenaphthen-5-yl)furan-2,5-dione (entry 8). Yellow crystals
(toluene + hexane), mp 153–155 °C. 1H NMR (300 MHz, CDCl3) d:
3.47 (s, 4H, 2CH2), 7.16 (s, 1H, @CH), 7.42 (d, 1H, J = 7 Hz, Ar-H),
7.44 (d, 1H, J = 7 Hz, Ar-H), 7.63 (t, 1H, J = 7 Hz, Ar-H), 7.80 (d,
1H, J = 7 Hz, Ar-H), 8.05 (d, 1H, J = 7 Hz, Ar-H). MS (EI) m/z: 250
(46%, MÅ+), 222 (14%, M–CO), 194 (7%), 178 (100%, M–CO–CO2).
Anal. Calcd for C16H10O3 (250.25): C, 76.79; H, 4.03. Found: C,
76.62; H, 4.17.
19. Bumagin, N. A.; More, P. G.; Beletskaya, I. P. J. Organomet. Chem. 1989, 371, 397–
401.
20. Roshchin, A. I.; Polunin, E. V. Mendeleev Commun. 2008, 18, 332–333.
21. Moreno-Manas, M.; Pleixats, R.; Roglans, A. Synlett 1997, 1157–1158.
22. Wirth, H. O.; Königstein, O.; Kern, W. Ann. Chem. 1960, 634, 84–104.
23. In a few runs, 1,4-dioxane was used instead of DMF, with no marked difference
in the results.
24. Precipitation might take from 3 h at rt to 2 d at 4 °C. The crude acid was often
contaminated with fumaric acid and inorganic salts; no arylfumaric acid was
detected by NMR.
25. Rondestvedt, C. S., Jr.; Kalm, M. J.; Vogl, O. J. Am. Chem. Soc. 1956, 78, 6115–
6120.
26. This compound was also obtained via arylation of diethyl fumarate with
3-iodoanisole using Heck’s17 protocol: Spiegel, D. A.; Njardarson, J. T.; Wood, J.
L. Tetrahedron 2002, 58, 6545–6554.
3-(3-Methoxyphenyl)furan-2,5-dione25,26 (entry 10). Bright yel-
low shiny crystals (toluene), mp 149–150 °C with partial sublima-
tion, lit.25 mp 146–147 °C. 1H NMR (300 MHz, CDCl3) d: 3.88 (s, 3H,
OMe), 7.00 (s, 1H, @CH), 7.12 (d, 1H, J = 8 Hz, Ar), 7.44 (t, 1H,
J = 8 Hz, Ar), 7.52–7.56 (m, 2H, Ar).
3-(4-Chlorophenyl)furan-2,5-dione (entry 11). Colorless crys-
tals (toluene), mp 147 °C, lit.14 mp 149–150 °C. 1H NMR