An effective synthetic entry to fused benzimidazoles via iodocyclization

Article abstract of DOI:10.1002/adsc.201100038

A protocol for the synthesis of the fused heterocyclic polycyclic compounds pyrrole[1,2-a]benzimidazoles, piperidine[1,2-a]benzimidazoles and oxa-fused benzimidazoles using iodine and silver nitrate by an exo-dig or endo-dig cyclization pathway at room te

Full text of DOI:10.1002/adsc.201100038

COMMUNICATIONS
DOI: 10.1002/adsc.201100038
An Effective Synthetic Entry to Fused Benzimidazoles via
Iodocyclization
Xu Zhang,a,b Yu Zhou,a Hengshuai Wang,a Diliang Guo,a,b Deju Ye,a Yungen Xu,b
Hualiang Jiang,a and Hong Liua,b,*
a
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555
Zuchongzhi Road, Shanghai 201203, Peopleꢀs Republic of China
Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, Peopleꢀs
b
Republic of China
Fax : (+86)-21-5080-7042; phone: (+86)-21-5080-7042; e-mail: hliu@mail.shcnc.ac.cn
Received: January 16, 2011; Published online: June 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100038.
Abstract: A protocol for the synthesis of the fused
heterocyclic polycyclic compounds pyrrole[1,2-
a]benzimidazoles, piperidine[1,2-a]benzimidazoles
Although fused benzimidazoles are important
building block in synthetic chemistry, available strat-
egies for the synthesis of these compounds are limit-
ed. Oxygen- or nitrogen-containing fused benzimida-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
and oxa-fused benzimidazoles using iodine and
silver nitrate by an exo-dig or endo-dig cyclization
pathway at room temperature has been developed.
Silver nitrate is a key additive for improving the
yield, and the improvement is a result of this addi-
tive eliminating the influence of iodine ions (IÀ),
which would otherwise lead to the formation of bis-
iodine by-products. Cyclizations involving terminal
and substituted alkynes were performed. Further
functionalizations demonstrated that the iodo deriv-
atives obtained are potential synthetic intermedi-
ates that can increase the molecular complexity.
À
zoles have been synthesized by C H bond activa-
tion,[3] rhodium-catalyzed cyclization,[4] solid-phase
synthesis,[5] radical cyclization,[6a] CuI/I2-promoted
electrophilic tandem cyclization.[6b] Most of the meth-
ods used for the synthesis of fused benzimidazoles re-
quire harsh reaction conditions. Therefore, it is imper-
ative to develop a novel and convenient method re-
quiring mild reaction conditions for the synthesis of
fused benzimidazoles.
Recently, electrophilic cyclizations of functionally
substituted alkynes have attracted considerable atten-
tion because they can help in the preparation of vari-
ous heterocyclic and carbocyclic compounds that are
Keywords: cyclization; fused benzimidazoles;
iodine; silver nitrate
Fused benzimidazoles constitute an important class of
heterocyclic scaffolds used in drug discovery and dye
chemistry.[1] Harb et al. prepared a molecule (1) with
antibacterial activity, which showed marked activity
against Gram-positive and Gram-negative bacteria.[1e]
Additionally, fused benzimidazole moieties have been
found in other bioactive molecules such as lipid per-
oxidation inhibitor (2) that potently inhibit NADPH-
induced lipid peroxidation and Fe2+-induced lipid per-
oxidation.[1d] Fused benzimidazole moieties are also
used in dye chemistry, as reported by Libeer et al.,
and in quaternary ammonium salts (3), and their ana-
logues are used for sensitizing photographic silver
halide emulsions.[2] (Figure 1)
Figure 1. The related structures of fused benzimidazoles.
Adv. Synth. Catal. 2011, 353, 1429 – 1437
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1429

Xu Zhang et al.
COMMUNICATIONS
Scheme 1. Synthesis of fused tricyclic benzimidazoles.
useful intermediates in the synthesis of natural prod- creased the yield to 66% and 78%, respectively
ucts and pharmaceuticals.[7] In electrophilic cycliza- (Table 1, entries 2 and 3); however, the by-product C1
tion, iodine has been found to be an important and was also formed with 13–22% yields. Besides, we also
versatile element for the synthesis of functionalized
heterocycles such as isoquinolines,[7g,h] indoles,[7d] chro-
Table 1. Iodine-mediated cyclization: optimiazion of the re-
mones,[7c] and other heterocycles.[7a,8] Although iodo-
action conditions.[a]
cyclization-based protocols can be successfully used
for the preparation of iodinated alkenes, there are
some inherent disadvantages such as the formation of
bis-iodine by-products.[7g,h,i]
In view of the valuable uses of iodinated alkenes in
the production of asymmetrically substituted olefins,
it is very important to develop more effective proto-
Entry Electrophile
(equiv.)
Solvent Base
Yield [%]
cols to prepare single-isomer iodinated products. In
this paper, we present our recent findings on the
regio- and stereo-controlled synthesis of fused iodo-
benzimidazoles in the presence of AgNO3, which is
an important additive for improving the yield of prod-
ucts.[9] It is thought that this improvement is a result
of AgNO3 preventing the formation of bis-iodine by-
products (Scheme 1).
The requisite cyclization precursors benzimidazoles
(A) were readily synthesized by previously reported
methods from o-phenylenediamines and various ace-
tylenic acids through a condensation reaction and
subsequent cyclization reaction involving acetic
acid.[10]
Initially, 2-(but-3-ynyl)-1H-benzo[d]imidazole (A1)
was chosen as the model substrate for investigating
the optimum reaction conditions, including solvents,
reaction temperatures, reaction times, and amounts of
AgNO3. As shown in Table 1, we first studied the re-
actions of A1 with I2 (3.0 equiv.) in THF at room tem-
perature in the presence of a variety of bases
(3.0 equiv.) for 2 h (Table 1, entries 1–6). Under base-
free conditions, this protocol gave the desired fused
benzimidazole product B1 in 44% yield and the bis-
iodine by-product C1 in 43% yield (Table 1, entry 1).
The addition of inorganic bases could increase the
yields of B1, for example, NaHCO3 and Na2CO3 in-
B1
44
C1
1
2
3
4
5
6
I2 (3.0)
I2 (3.0)
I2 (3.0)
I2 (3.0)
I2 (3.0)
I2 (3.0)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
–
44
22
13
NaHCO3 66
Na2CO3 78
NaOH
Et3N
AcONa 58
Na2CO3 trace trace
Na2CO3 trace trace
Na2CO3 79
Na2CO3 71
Na2CO3 45
trace trace
0
0
29
7
NBS
N
8
NIS(3.0)
ACHTUNGTRENNUNG
9
I2 (1.5)
I2 (1.0)
I2 (0.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
13
12
0
14
15
10
11
12
13
14
CH2Cl2 Na2CO3 71
MeCN Na2CO3 74
MeOH Na2CO3 trace trace
15[b] I2 (1.5)
16[b,c] I2 (1.5)
17[d] I2 (1.5)
THF
THF
THF
Na2CO3 21
Na2CO3 64
Na2CO3 75
Na2CO3 93
Na2CO3 80
Na2CO3 88
4
11
13
0
11
0
18
19
20
21
I2 ACTHUNGTRENU(NG 1.5)/AgNO3 ACHTUNGERTN(NUNG 1.0) THF
I2 (1.5)/AgNO3 (0.5) THF
I2 (1.5)/AgNO3 (1.5) THF
AgNO3 (1.0)
THF
Na2CO3
0
0
[a]
A1 (0.3 mmol), electrophile, base 0.9 mmol, room tem-
perature, 2 h.
The reaction temperature was 08C.
The reaction time was prolonged to 16 h.
The reaction time was prolonged to 4 h.
[b]
[c]
[d]
1430
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1429 – 1437

An Effective Synthetic Entry to Fused Benzimidazoles via Iodocyclization
investigated the use of other inorganic and organic when R3 was hydrogen, five membered ring-closure
bases such as NaOH, Et3N, and AcONa, but some of products were obtained, however, when R3 was a
them dramatically decreased the yields of the prod- phenyl or substituted phenyl group, six-membered
ucts and even inhibited the reaction or substrate con- products were received, perhaps due to electronic ef-
version (Table 1, entries 4–6). Other electrophiles, in- fects. In addition, replacement of the benzimidazole
cluding NBS and NIS, were screened in THF at room ring with a naphthoimidazole ring also gave a good
temperature for 2 h. The results showed that iodine yield (Table 2, entry 9). However, when we inter-
was the most effective electrophile (Table 1, en- changed the benzimidazole ring with a benzothiazole
tries 1–8). In addition, when the amount of iodine was heterocycle, the transformation did not occur under
decreased from 3.0 to 1.5 equiv., the yield and selec- the above-mentioned optimum conditions (Table 2,
tivity of the target compound were found to have entry 10).
been improved (79% yield, Table 1, entry 9). Howev-
er, any further decrease in the amount of iodine did used it to synthesize piperidineAHCNUTGTRENNUNG
To further explore the scope of this cyclization, we
[1,2-a]benzimidazoles
not lead to better yields (Table 1, entries 10 and 11). and oxa-fused benzimidazoles (B11–B30) by using the
Subsequently, we screened different solvents, and the compounds A11–A30 as the starting materials. As
results showed that THF is the most suitable for this shown in Table 3, the tolerance of the cyclization
reaction (Table 1, entries 9, 12–14). Decreasing the system was remarkable, and moderate to excellent
temperature or prolonging the reaction time did not yields of the desired products were obtained (Table 3,
improve the yield and selectivity of the products entries 1–18). First, various piperidineACHTUNTRGNEUNG[1,2-a]benzimi-
(Table 1, entries 15–17). The formation of the by- dazoles were prepared and excellent yields were ob-
product C1 resulted in a decrease in the yield of the tained when R1 was hydrogen or methyl, chloro and
desired product, and therefore, we tried to improve methoxycarbonyl groups (Table 3, entries 1–4). When
the yield and selectivity of this transformation by R3 was a phenyl group, substituted phenyl group, or
adding an additive. To our surprise, when AgNO3 3-pyridyl group, the reaction proceeded well to form
(1.0 equiv.) was employed, we obtained good yield intriguing cyclized products. However, the transfor-
and selectivity; and the target product B1 was ob- mation needed a longer time to complete the sub-
tained in 93% yield and C1 was not detected (Table 1, strate conversion (60 h) (Table 3, entries 5–12). Fur-
entry 18). However, further investigations showed thermore, various substituted oxa-fused benzimida-
that increasing or decreasing the amount of AgNO3 zoles were obtained in good yields (Table 3, en-
did not give better yields (Table 1, entries 19 and 20). tries 13–17). When R1 was hydrogen or a chloro
Additionally, no product was detected in the absence group, and R3 was hydrogen (Table 3, entries 13 and
of silver nitrate (Table 1, entry 21). Briefly, the opti- 14), good yields were obtained, but a duration of 4 h
mum results were obtained when A1 (0.30 mmol) was was needed to complete the substrate conversion.
treated with 1.5 equiv. of iodine, 3.0 equiv. of Na2CO3, When R3 was a methyl group, although the reactions
and 1.0 equiv. of AgNO3 and THF was used as the proceeded well to form oxa-cyclized products, the
solvent at room temperature for 2 h.
To evaluate the scope of the proposed methods, we (Table 3, entries 15–17). 2-(Pent-4-ynyl)-1H-naphtho-
attempted to investigate the cyclization of a variety of [2,3-d]imidazole (A28) was tolerated in the reaction,
transformation needed a much longer time (36 h)
AHCTUNGTRENNUNG
substituted benzimidazoles (A) under the above-men- and a good yield was obtained (Table 3, entry 18).
tioned optimum conditions. As shown in Table 2, the However, introducing several substituents at the R3
protocol was tolerant to the substituents at the posi- position of the annelated substrates led to a drastic
tion of the R1 group, including H, methyl and chloro decrease in the yields of the desired products under
groups (Table 2, entries 1–3). Good yield was also ob- the optimum reaction conditions, presumably due to
tained when an alkyl group was introduced at the R2 the steric effects (Table 3, entries 19 and 20).
position (Table 2, entry 4). Additionally, the introduc-
In principle, the cyclization of alkynes possessing a
tion of some substituents at the terminal position of nucleophile group in proximity to the triple bond can
the alkynyl groups of various benzimidazoles was also yield various heterocycles via different ring-closing
investigated (Table 2, entries 5–8). When R3 was a pathways. As shown in Scheme 2, there are two possi-
phenyl or substituted phenyl group with an electron- ble mechanisms for this transformation, which give
donating group, the transformation proceeded well to three possible products: pathway A, the exo-dig cycli-
form intriguing target products; however, a longer zation process yields products B or D; pathway B, the
time (12 h) was needed to complete the substrate con- endo-dig cyclization process leads to the formation of
version (Table 2, entries 5–7). Introducing a substitut- a product E. However, with our strategies, only E5–
ed phenyl group with an electron-withdrawing group E7 – via the endo-dig cyclization pathway – were ob-
(4-CF3Ph) at the R3 position resulted in a dramatic tained, and others were performed via the exo-dig
decrease in the yield of the product, presumably due cyclization pathway. All the fused benzimidazoles syn-
to electronic effects (Table 2, entry 8). To our surprise, thesized were characterized by 1H NMR, 13C NMR
Adv. Synth. Catal. 2011, 353, 1429 – 1437
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1431

Xu Zhang et al.
COMMUNICATIONS
Table 2. Iodine-mediated synthesis of pyrroleACTHNUTRGNEUNG
[1,2-a]benzimidazoles.[a]
Entry
1
R1
H
R2
H
R3
H
Product B
Yield [%]
94
B1
B2
2
3
CH3
Cl
H
H
H
H
90
94
B3
B4
4
H
H
hexyl
H
H
92
90
5[b]
E5
E6
6[b]
Cl
H
H
H
82
90
7[b]
E7
E8
8[b]
H
H
trace
Substrate A
Product B
9
B9
92
10
B10
trace
[a]
The reaction was carried out in the presence of 1.5 equiv. of I2, 3.0 equiv. of Na2CO3, 1.0 equiv. of AgNO3 and THF as the
solvent at room temperature for 2 h.
The reaction time was prolonged to 12 h.
[b]
1432
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1429 – 1437

An Effective Synthetic Entry to Fused Benzimidazoles via Iodocyclization
[1,2-a]benzimidazoles and oxa-fused benzimidazoles.[a]
Table 3. Iodine-mediated synthesis of piperidineCAHTUNGTRENNUNG
Entry
1
R1
H
R3
H
X
Time [h]
2
Product B
Yield [%]
93
CH2
B11
B12
B13
2
3
CH3
Cl
H
H
CH2
CH2
2
2
91
90
4
5
COOCH3
H
CH2
CH2
2
B14
B15
93
81
H
60
6
H
CH2
60
B16
84
7
H
H
H
H
CH2
CH2
CH2
CH2
60
60
60
60
B17
B18
B19
B20
55
71
70
85
8
9
10
Adv. Synth. Catal. 2011, 353, 1429 – 1437
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1433

Xu Zhang et al.
COMMUNICATIONS
Table 3. (Continued)
Entry
11
R1
R3
X
Time [h]
60
Product B
Yield [%]
71
CH3
CH2
B21
B22
12
Cl
CH2
60
84
13
14
15
16
17
H
H
O
O
O
O
O
4
B23
B24
B25
B26
B27
62
76
88
82
81
Cl
H
4
H
CH3
CH3
CH3
36
36
36
CH3
Cl
Substance A
Product B
18
19
2
B28
B29
B30
88
60
36
trace
trace
20
[a]
The reaction was carried out in the presence of 1.5 equiv. of I2, 3.0 equiv. of Na2CO3, 1.0 equiv. of AgNO3 and the use of
THF as the solvent at room temperature in 2 h.
and MS data. Besides, the structures of B1, E5 and to form the I-alkyne p-complex F; subsequently,
B17 were determined by X-ray diffraction (XRD) attack of the nitrogen atom at the electron-deficient
studies (Figure 2, see the Supporting Information for triple bonds leads to intermediates G or G’ via the
details).[11]
exo- dig or endo-dig ring-closing pathway, which is
A plausible mechanism for the formation of fused followed by proton transfer to produce the target
benzimidazoles via iodocyclization is depicted in products B or E. We hypothesize that iodocyclization
Scheme 3. First, the carbon-carbon triple bonds of the to form fused benzimidazoles goes by an ionic mecha-
substrate A are activated by coordination with iodine nism.[12] Adding silver nitrate would assist an ionic re-
1434
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1429 – 1437

An Effective Synthetic Entry to Fused Benzimidazoles via Iodocyclization
Scheme 2. Intramolecular cyclization of A1.
Figure 2. X-ray crystal structures of B1, E5 and B17.
action and eliminate iodide ion in the reaction solu- the presence of the halogen functionality, especially
tion to prevent iodide ion attacking intermediate F the iodo group, in the heterocyclic products renders
forming bis-iodine by-products in the form of silver the products useful as substrates for both the efficient
iodide.
preparation of interesting bioactive molecules and the
The synthesis of iodo-benzimidazoles has attracted construction of a compound library for drug screen-
much attention because they are generally considered ing.
as important building blocks for several drug mole-
cules and natural products (Scheme 4). For example,
the Suzuki coupling of B1 with phenylboronic acid
can easily afford H in 94% yield. Compound B1 un-
Experimental Section
dergoes a Sonogashira coupling reaction with 1-ethyn-
yl-4-methylbenzene to give the corresponding I in
Typical Procedure for Synthesis of the Substrates (A1
as an Example)
88% yield. Further studies involving the application
To a solution of substituted or unsubstituted 1,2-phenylene-
of these intriguing iodo-benzimidazoles are under in-
diamine[13a] (2.0 mmol) in methanol (20 mL) was added 4-
vestigation in our laboratory, and the results will be
pentynoic acid[13b] (1.0 equiv.) and EDCI (1.1 equiv.). The re-
reported in due course.
action mixture was stirred at room temperature for 4–5 h
In summary, we have developed an approach to
while being monitored by TLC. The solvent was concentrat-
ed under vacuum and the amide intermediate derivatives
were precipitated by the addition of water. After filtration,
the solid was dried. Then the solid was dissolved in neat
synthesize various fused benzimidazoles via iodine-in-
duced cyclization. These reactions are run under mild
conditions, are tolerant to various substituted sub-
strates, and can generally provide fused benzimida-
acetic acid, and stirred at 908C under N2 for 5 h. The acetic
zole products in good to excellent yields. In addition, acid was distilled off; the residue was dissolved in ethyl ace-
Adv. Synth. Catal. 2011, 353, 1429 – 1437
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1435

Xu Zhang et al.
COMMUNICATIONS
General Procedure for Synthesis of B1–B28, E5–E7
(B1 as an Example)
To a solution of 0.3 mmol of A1 in 10 mL of THF were
added 0.45 mmol of iodine, 0.9 mmol of Na2CO3 and
0.3 mmol AgNO3. The mixture was stirred at room tempera-
ture, after the starting materials had been completely con-
sumed as monitored by TLC, the solvent was removed
under reduced pressure, and the residue was taken up in
EtOAc and washed with saturated Na2S2O3, brine, dried
over anhydrous Na2SO4. The solvent was removed under re-
duced pressure, and the residue was purified by a flash
column chromatography to provide B1.
Acknowledgements
We gratefully acknowledge financial support from the Na-
tional Natural Science Foundation of China (Grants
21021063, 20872153 and 81025017)
References
[1] a) T. Roth, M. L. Morningstar, P. L. Boyer, S. H.
Hughes, R. W. Buckheit Jr, C. J. Michejda, J. Med.
Chem. 1997, 40, 4199; b) W. Wienen, N. Hauel, J. C. A.
Van Meel, B. Narr, U. Ries, M. Entzeroth, Br. J. Phar-
macol. 1993, 110, 245; c) I. Islam, E. B. Skibo, R. T.
Dorr, D. S. Alberts, J. Med. Chem. 1991, 34, 2954; d) G.
Domany, T. Gizur, A. Gera, Eur. J. Med. Chem. 1998,
33, 181; e) A. E. A. Harb, F. H. Mostafa, S. A. Metwal-
ly, Arch. Pharm. Res. 1990, 13, 187; f) M. J. Libeer, H.
Depoorter, G. V. Mierlo, R. G. Lemahieu, U.S. Patent
3,931,156, 1976; g) K. M. Dawood, B. F. Abdel-Wahab,
Arkivoc 2010, i, 333–389.
Scheme 3. A plausible mechanism for the iodocyclization.
tate (EtOAc), and washed by saturated NaHCO3, brine,
dried over anhydrous Na2SO4. Evaporation of the solvent
followed by chromatography on a silica gel column with
Petro Ether (PE)/EtOAc (4/1, v/v) as eluent to give the de-
sired 2-(but-3-ynyl)-1H-benzo[d]imidazole (A1): 1H NMR
(300 MHz, CDCl3): d=2.13–2.15 (m, 1H, CH), 2.73–2.79
(m, 2H, CH2), 3.18 (t, J=6.9 Hz, 2H, CH2), 7.24–7.28 (m,
2H, ArH), 7.57–7.60 (m, 2H, ArH); 13C NMR (100 MHz,
CDCl3): d=17.3, 28.3, 70,3, 83.2, 122.5, 152.8; ESI-MS:
m/z=171 [M + H]+; HR-MS (ESI): m/z=171.0920, calcd.
for C11H11N2 [M+H]+: 171.0922.
[2] For example see: a) A. J. Charlson, J. S. Harrington,
Carbohydr. Res. 1972, 43, 383; b) R. Zhou, E. B. Skibo,
J. Med. Chem. 1996, 39, 4321.
[3] K. L. Tan, A. Vasudevan, R. G. Bergman, J. A. Ellman,
A. J. Souers, Org. Lett. 2003, 5, 2131.
[4] D. Anastasiou, E. M. Campi, H. Chaouk, W. R. Jack-
son, Tetrahedron 1992, 48, 7467.
Scheme 4. Diversification of fused indo-benzimidazoles.
1436
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1429 – 1437

An Effective Synthetic Entry to Fused Benzimidazoles via Iodocyclization
[5] S. M. Allin, W. R. Bowman, R. Karim, S. S. Rahman,
Tetrahedron 2006, 62, 4306.
[6] a) F. Aldabbagh, W. R. Bowman, Tetrahedron 1999, 55,
4109; b) H. C. Ouyang, R. Y. Tang, P. Zhong, X. G.
Zhang, J. H. Li, J. Org. Chem. 2011, 76, 223.
[9] M. Alvarez-Corral , M. MuÇoz-Dorado , I. Rodrꢂguez-
Garcꢂa, Chem. Rev. 2008, 108, 3174.
[10] A. Bꢃttner, K. Seifert, T. Cottin, V. Sarli, L. Tzagkar-
oulaki, S. Scholz, A. Giannis, Bioorg. Med. Chem. 2009,
17, 4943.
[11] CCDC 775526 contains the supplementary crystallo-
graphic data for B1, CCDC 817289 contains the supple-
mentary crystallographic data for B5 and CCDC
775527 contains the supplementary crystallographic
data for B17. These data can be obtained free of
charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[12] V. L. Heasley, D. F. Shellhamer, L. E. Heasley, D. B.
Yaeger, G. E. Heasley, J. Org. Chem. 1980, 45, 4649–
4652.
[13] a) Dimethyl 4,5-diaminophthalate was prepared via the
modified synthesis method reported by R. L. Williams,
and his colleagues: R. L. Williams, S. W. Shalaby, J.
Heterocycl. Chem. 1973, 10, 891. Other o-phenylenedi-
[7] a) D. Yue, C. N. Della, R. C. Larock, Org. Lett. 2004, 6,
1581; b) S. Mehta, J. P. Waldo, R. C. Larock, J. Org.
Chem. 2009, 74, 1141; c) C. Zhou, A. V. Dubrovsky,
R. C. Larock, J. Org. Chem. 2006, 71, 1626; d) D. Yue,
T. Yao, R. C. Larock, J. Org. Chem. 2006, 71, 62; e) T.
Yao, M. A. Campo, R. C. Larock, J. Org. Chem. 2005,
70, 3511; f) T. Yao, R. C. Larock, J. Org. Chem. 2005,
70, 1432; g) D. Fischer, H. Tomeba, N. K. Pahadi, N. T.
Patil, Z. Huo, Y. Yamamoto, J. Am. Chem. Soc. 2008,
130, 15720; h) D. Fischer, H. Tomeba, N. K. Pahadi,
N. T. Patil, Z. Huo, Y. Yamamoto, Angew. Chem. 2007,
119, 4848; Angew. Chem. Int. Ed. 2007, 46, 4764; i) G.
Raffa, S. Belot, G. Balme, N. Monteiro, Org. Biomol.
Chem. 2011, 9, 1474.
[8] a) I. Aillaud, E. Bossharth, D. Conreaux, P. Desbordes,
N. Monteiro, G. Balme, Org. Lett. 2006, 8, 1113;
b) Z. A. Khan, T. Wirth, Org. Lett. 2009, 11, 229; c) J.
Barluenga, D. Palomas, E. Rubio, J. M. Gonzalez, Org.
Lett. 2007, 9, 2823; d) Y. Xie, X. Liu, L. Wu, Y. Han, L.
Zhao, M. Fan, Y. Liang, Eur. J. Org. Chem. 2008, 1013.
AHCTUNGTREGaNNNU mines are commercially available. b) Various acetylen-
ic acids containing oxygen were synthesized from alky-
nols and ethyl 2-bromoacetate; various substituted ace-
tylenic acids were prepared by Sonogashira coupling
reactions between acetylenic ester and iodobenzene or
substituted iodobenzenes. The details of operation are
given in the Supporting Information.
Adv. Synth. Catal. 2011, 353, 1429 – 1437
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1437