CuI/I2-promoted electrophilic tandem cyclization of 2-ethynylbenzaldehydes with ortho -benzenediamines: Synthesis of iodoisoquinoline-fused benzimidazoles

Article abstract of DOI:10.1021/jo102060j

An efficient tandem route to the synthesis of iodoisoquinoline-fused benzimidazole derivatives including an iodocyclization strategy has been developed. In the presence of CuI, a variety of 2-ethynylbenzaldehydes underwent the tandem reaction with benzenediamines and iodine to afford the corresponding iodoisoquinoline-fused benzimidazoles in moderate to good yields.

Full text of DOI:10.1021/jo102060j

pubs.acs.org/joc
CuI/I2-Promoted Electrophilic Tandem Cyclization of
2-Ethynylbenzaldehydes with ortho-Benzenediamines: Synthesis of
Iodoisoquinoline-Fused Benzimidazoles
Huang-Che Ouyang,† Ri-Yuan Tang,† Ping Zhong,*,† Xing-Guo Zhang,†,‡ and
Jin-Heng Li*,†,‡
†College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China, and
‡Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education),
Hunan Normal University, Changsha 410081, China
zhongp0512@163.com; jhli@hunnu.edu.cn
Received October 19, 2010
An efficient tandem route to the synthesis of iodoisoquinoline-fused benzimidazole derivatives
including an iodocyclization strategy has been developed. In the presence of CuI, a variety of
2-ethynylbenzaldehydes underwent the tandem reaction with benzenediamines and iodine to afford
the corresponding iodoisoquinoline-fused benzimidazoles in moderate to good yields.
Introduction
modification of the benzimidazoisoquinolines prepared by
these routes is difficult.
Among the multitude of heterocyclic compounds, isoqui-
noline-fused benzimidazoles have attracted considerable
interest due to their outstanding biological activities, such
as anti-HIV-1, anticancer, antimicrobial, and antifungal
properties.1 The importance of isoquinoline-fused benzimi-
dazoles has resulted in the development of two synthetic
routes for their preparation: one involves introduction of
substituents onto a preexisting benzimidazole ring2 and the
other is the tandem reactions of benzenediamines with
2-ethynylbenzaldehyde3 or with pyran-2-one derivatives.4
However, a significant problem for drug discovery is that
Iodocyclization technology5-7 has undoubtedly become
one of the most powerful methods for the synthesis of iodo-
containing cyclic compounds which can be modified easily
by introducing diverse functional groups through the cross-
coupling reactions. 2-Ethynylbenzaldehyde, an intriguing
substrate, has been applied to the synthesis of diverse poly-
cyclic compounds8 and is a good electrophilic cyclization species
for iodocyclization.7 As a continuing interest in expanding the
synthetic application of 2-ethynylbenzaldehydes,9 we report here
an efficient protocol for the synthesis of iodoisoquinoline-fused
benzimidazoles by copper-promoted tandem cyclization of
2-ethynylbenzaldehydes with o-benzenediamines and iodine
(Scheme 1).
(1) (a) Rida, S. M.; El-Hawash, S. A. M.; Fahmy, H. T. Y.; Hazzaa, A. A.;
El-Meligy, M. M. M. Arch. Pharmacal. Res. 2006, 29, 826. (b) Deady, L. W.;
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P.; Goel, A.; Ram, V. J. Eur. J. Org. Chem. 1998, 2083.
Results and Discussion
The reaction between o-benzenediamine (1a) and 2-(phenyl-
ethynyl)benzaldehyde (2a) was investigated to optimize
the reaction conditions (Table 1). Initially, the reaction between
(3) (a) Dyker, G.; Stirner, W.; Henkel, G. Eur. J. Org. Chem. 2000, 8,
1433. (b) Okamoto, N.; Sakurai, K.; Ishikur, M.; Takeda, K.; Yanada, R.
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Chiba, H.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2009, 74, 6299.
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2001, 30, 1262.
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Synlett 2006, 14, 2159. (c) da Silva, F. M.; Jones, J., Jr.; de Mattos, M. C. S.
Curr. Org. Synth. 2005, 2, 393. (d) Kitagawa, O.; Inoue, T.; Taguchi, T. Rev.
Heteroatom Chem. 1996, 15, 243. (e) Larock, R. C. Acetylene Chem. 2005, 51.
(f) Luo, P.; Tang, R.; Zhong, P.; Li, J. Chin. J. Org. Chem. 2009, 29, 1924.
DOI: 10.1021/jo102060j
r
Published on Web 12/10/2010
J. Org. Chem. 2011, 76, 223–228 223
2010 American Chemical Society

Ouyang et al.
JOCArticle
SCHEME 1
TABLE 1. Screening Conditionsa
entry [Cu] (mol %) [I] (equiv)
solvent
DMSO
T (°C) yield (%)
aldehyde 1a and diamine 2a was tested in the presence of NIS
(N-iodosuccimide) in DMSO at 80 °C for 20 h; however, only a
trace amount of the target product 3 was observed (entry 1). To
our delight, the yield was enhanced to 51% when CuI
(10 mol %) was added (entry 2). It is noteworthy that the
structure of 3 was unambiguously confirmed by X-ray single-
crystal diffraction analysis.10 The effect of the reaction tempera-
ture was also examined, and higher temperatures were found to
be more effective (entries 2-4). For example, the reaction at
120 °C gave the target product 3 in 60% yield (entry 4). We
disclosed that the yield was lowered at a loading of 2 equiv NIS
(entry 5). Subsequently, a number of solvents, such as toluene,
CH2ClCH2Cl, CH3CN, dioxane, DMF, NMP, and DMA,
were investigated in the presence of 10 mol % of CuI and 1
equiv of NIS, but they were inferior to DMSO to some extent in
1
2
3
4
5
6
7
8
NIS (1)
NIS (1)
NIS (1)
NIS (1)
NIS (2)
NIS (1)
NIS (1)
NIS (1)
NIS (1)
NIS (1)
NIS (1)
NIS (1)
ICl (1)
I2 (1)
I2 (1.5)
I2 (2)
I2 (2.5)
I2 (2)
I2 (2)
I2 (2)
I2 (2)
I2 (2)
I2 (2)
80
80
trace
51
53
60
48
31
10
32
47
50
56
55
58
55
65
74
75
55
60
69
66
67
53
70
74
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
Cu(OTf)2 (10)
CuCl2 (10)
CuBr (10)
Cu2O (10)
CuI (5)
DMSO
DMSO
DMSO
DMSO
toluene
CH2ClCH2Cl
CH3CN
dioxane
DMF
100
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
NMP
DMA
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
(6) For selected recent papers on the electrophilic halogenocyclizations of
alkynes, see: (a) Stein, A. L.; da Rocha, J.; Menezes, P. He.; Zeni, G. Eur. J.
Org. Chem. 2010, 705. (b) Verma, A. K.; Aggarwal, T.; Rustagi, V.; Larock,
R. C. Chem. Commun. 2010, 4064. (c) Schumacher, R. F.; Rosario, A. R.;
Souza, A. C. G.; Menezes, P. H.; Zeni, G. Org. Lett. 2010, 12, 1952. (d) Huo,
Z.; Gridnev, I. D.; Yamamoto, Y. J. Org. Chem. 2010, 75, 1266. (e) Zhang,
X.; Yao, T.; Campo, M. A.; Larock, R. C. Tetrahedron 2010, 66, 1177. (f)
Chen, Y.; Cho, C.-H.; Shi, F.; Larock, R. C. J. Org. Chem. 2009, 74, 6802. (g)
Manarin, F.; Roehrs, J. A.; Gay, R. M.; Brandao, R.; Menezes, P. H.;
Nogueira, C. W.; Zeni, G. J. Org. Chem. 2009, 74, 2153. (h) Mehta, S.;
Waldo, J. P.; Larock, R. C. J. Org. Chem. 2009, 74, 1141. (i) Ding, Q.; Wang,
Z.; Wu, J. J. Org. Chem. 2009, 74, 921. (j) Chen, Y.; Cho, C.-H.; Larock, R. C.
Org. Lett. 2009, 11, 173. (k) Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil,
N. T.; Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc. 2008, 130, 15720. (l) Li, P.;
Chai, Z.; Zhao, G.; Zhu, S.-Z. Synlett 2008, 2547. (j) Ding, Q.; Wu, J. Adv.
Synth. Catal. 2008, 350, 1850. (m) Wen, S.-G.; Liu, W.-M.; Liang, Y.-M.
J. Org. Chem. 2008, 73, 4342. (n) Xie, Y.-X.; Liu, X.-Y.; Wu, L.-Y.; Han, Y.;
Zhao, L.-B.; Fan, M.-J.; Liang, Y.-M. Eur. J. Org. Chem. 2008, 1013. (o)
Huang, X.; Fu, W.; Miao, M. Tetrahedron Lett. 2008, 49, 2359. (p) Just,
Z. W.; Larock, R. C. J. Org. Chem. 2008, 73, 2662. (q) Du, H.-A.; Zhang,
X.-G.; Tang, R.-Y.; Li, J.-H. J. Org. Chem. 2009, 74, 7844. (r) Jiang, T.-S.;
Zhang, X.-G.; Li, J.-H. Synthesis 2009, 3029. (s) Crone, B.; Kirsch, S. F.;
Umland, K.-D. Angew. Chem., Int. Ed. 2010, 49, 4661. For special papers,
see: (t) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M.
J. Am. Chem. Soc. 2003, 125, 9028. (u) Barluenga, J.; Vazquez-Villa, H.;
Ballesteros, A.; Gonzalez, J. M. Org. Lett. 2003, 5, 4121. (v) Barluenga, J.;
Trincado, M.; Rubio, E.; Gonzalez, J. M. Angew. Chem., Int. Ed. 2003, 42,
2406. (w) Barluenga, J.; Trincado, M.; Rubio, E.; Gonzalez, J. M. Angew.
Chem., Int. Ed. 2006, 45, 3140. (x) Barluenga, J.; Palomas, D.; Rubio, E.;
Gonzalez, J. M. Org. Lett. 2007, 9, 2823 and references cited therein. (y)
Mancuso, R.; Mehta, S.; Gabriele, B.; Salerno, G.; Jenks, W. S.; Larock,
R. C. J. Org. Chem. 2010, 75, 897.
CuI (20)
I2 (2)
I2 (2)
25b CuI (10)
aReaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), [I], and [Cu] in
solvent (2 mL) for 24 h under air atmosphere. bUnder argon atmosphere.
terms of yields (entries 6-12). Two other electrophilic reagents,
ICl and I2, were employed to screen the reaction (entries 13 and
14). The results showed that both ICl and I2 were also efficient
for the reaction catalyzed by CuI at 120 °C in DMSO, giving the
product 3in 58% and 55% yields, respectively. Gratifyingly, the
higher yield was obtained when the amount of I2 was increased:
up to 74% yield using 2 equiv of I2 and 75% yield at 2.5 equiv of
I2 (entries 15-17). Finally, a series of other copper catalysts,
such as Cu(OTf)2, CuCl2, CuBr, and Cu2O, were evaluated
(entries 18-21). These copper reagents, when combined with I2
(2 equiv) and DMSO at 120 °C, were less efficient than CuI on
the basis of yields. It is noted that identical results are obtained
at 20 mol % CuI (entry 24), and the yield is decreased to
67% at 5 mol % of CuI (entry 22). To our surprise, the reaction
could be conducted without Cu catalysts although the yield of
the desired product 3 was decreased to some extent (53%
yield, entry 23). Notably, the reaction under either air or
argon atmosphere afforded the same results (entries 16
and 25).
(7) For special papers, see: (a) Barluenga, J; V1zquez-Villa, H.; Merino,
I.; Ballesteros, A.; Gonz1lez, J. M. Chem.;Eur. J. 2006, 12, 5790. (b) Yue,
ꢀ
D. W.; Della Ca, N.; Larock, R. C. J. Org. Chem. 2006, 71, 3381. (c)
ꢀ
Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M. Org. Lett.
2003, 5, 4121. (d) Yue, D. W.; Della Ca, N.; Larock, R. C. Org. Lett. 2004, 6,
ꢀ
ꢁ
1581.
(8) For selected papers, see: (a) Asao, N.; Takahashi, K.; Lee, S.;
Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 12650. (b) Asao,
N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 10921.
(c) Asao, N.; Kasahara, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2003, 42,
3504. (d) Asao, N.; Aikawa, H.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126,
7458. (e) Dyker, G.; Hildebrandt, D.; Liu, J.; Merz, K. Angew. Chem., Int.
Ed. 2003, 42, 4399.
(9) (a) Tang, R.-Y.; Li, J.-H. Chem.;Eur. J. 2010, 16, 4733. (b) Zhao, X.;
Zhang, X.-G.; Tang, R.-Y.; Deng, C.-L.; Li, J.-H. Eur. J. Org. Chem. 2010,
4211.
As shown in Table 2, the scope of both 2-ethynylbenzal-
dehydes 1 and diamines 2 partners for the tandem cyclization
reaction was explored under the standard reaction condi-
tions. We initially investigated the reactions of diamines
2b-e with 2-ethynylbenzaldehyde (1a), CuI, and I2 (entries
1-4). The results demonstrated that electron-donating
groups diamines were suitable substrates (entries 1 and 2),
but diamines with electron-withdrawing groups displayed
(10) See the detailed data in the Supporting Information.
224 J. Org. Chem. Vol. 76, No. 1, 2011

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TABLE 2. CuI-Catalyzed Tandem Iodocyclization of 2-Alkynylbenzaldehydes (1) with Diamines (2) and Iodinea
aReaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), I2 (2 equiv), and CuI (10 mol %) in DMSO (2 mL) at 120 °C for 24 h under air atmosphere.
b5-Me/6-Me = 1.3:1. cInterestingly, only an isomer was isolated.
less activity in terms of yields (entries 3 and 4). While
4-methylbenzene-1,2-diamine (2b) reacted with 2-ethynyl-
benzaldehyde (1a), CuI, and I2 to afford the target product 4
in 62% yield (entry 1), CF3-substituted diamine 2e gave a low
yield under the same conditions (entry 4). Notably, both
diamines 2b and 2e provided two regioisomers. Subse-
quently, the reaction between various 2-ethynylbenzalde-
hydes 1 and o-benzenediamines 2 were examined in the
presence of I2 and CuI (entries 5-16). We were pleased to
find that several functional groups, such as Me, MeO,
OCH2O, Cl, and F groups, were tolerated (entries 5-10).
Substrate 1e bearing a chloro group, for instance, was
reacted with diamines 2a or 2c, I2, and CuI smoothly in
72% and 48% yields, respectively (entries 8 and 9). It was
noteworthy that a moderate yield was still achieved from
6-(phenylethynyl)benzo[d][1,3]dioxole-5-carbaldehyde (1d)
(entry 7). To our delight, two heteroaromatic aldehydes 1g
and 1h could undergo the cyclization reaction, providing two
interesting heterocycle-containing products in low to mod-
erate yields (entries 11 and 12). It was found that substrates
1i-k, having a methyl-substituted phenyl group at the
terminal alkyne, were suitable for this cyclization reaction
under the standard conditions (entries 13-15). Gratifyingly,
in the presence of CuI aliphatic alkyne 1l displayed greater
activity to successfully react with diamine 2a and I2 leading
to a moderate yield (entry 16).
The synthesis of other haloisoquinoline-fused benzimida-
zoles using N-halosuccimide (NXS) was tested (Scheme 2). In
the presence of CuI, treatment of 2-ethynylbenzaldehyde (1a)
with o-benzenediamine (2a) and NBS (N-bromosuccimide)
J. Org. Chem. Vol. 76, No. 1, 2011 225

Ouyang et al.
JOCArticle
SCHEME 2. CuI-Catalyzed Tandem Bromocyclization of
2-Ethynylbenzaldehyde (1a) with o-Benzenediamine (2a) and
N-Halosuccimide (NXS)
SCHEME 4. Possible Mechanism
SCHEME 3. Controlled Experiments
could improve the yield of product 3 from 53% to 74%
(entries 16 and 23 in Table 1). We also found that CuI plays a
crucial role among the cyclization using NIS (entries 1 and 4
in Table 1). Based on the controlled experiments and the
possible mechanism, we deduce that CuI has some important
roles including: (1) catalyst or/and promoter for the catalytic
oxidation cyclization of intermediate A leading to intermedi-
ate B and (2) complexation of the carbon-carbon triple
bond to activate it.
As shown in Scheme 5, the reactions of the product 3 with
phenylboronic acid, phenylacetylene or 1-methyl-4-vinyl-
benzene were examined under the previously reported reac-
tion conditions.12-14 To our delight, substrate 3 smoothly
underwent the Suzuki,12 Sonogashira,13 and Heck14 cou-
pling reactions, respectively, in excellent yields.
In summary, we have developed a new electrophilic tan-
dem cyclization protocol for the synthesis of haloisoquino-
line-fused benzimidazoles via CuI-promoted tandem
cyclization of 2-ethynylbenzaldehydes with o-benzenedia-
mines and iodine. This protocol allows the formation of
two heterocyclic rings in a one-pot reaction through the
electrophilic annulation. Most importantly, these isoquino-
line-fused benzimidazoles with a halo group would be useful
introduction of various functional groups, which should be
significant for drug discovery.
afforded bromoisoquinoline-fused benzimidazole 20 in 45%
yield. However, NCS (N-chlorosuccimide) has no activity.
To understand this mechanism, some controlled experi-
ments were carried out (Scheme 3). The reported results
demonstrated that without catalysts the reaction could take
place although the corresponding isoquinoline-fused benzi-
midazoles were obtained in low yield using PhNO2 solvent
under heat conditions (120 or 150 °C).3a,b However, only a
trace of isoquinoline-fused benzimidazole 22 was observed in
DMSO without catalyst. Gratifyingly, CuI could promote
the reaction: product 22 was isolated in 34% yield at 10 mol
% of CuI and 60% yield at 2 equiv of CuI. Notably, substrate
22 could not be converted into iodoisoquinoline-fused ben-
zimidazole 3 under the present standard conditions.
The reactions of substrate 1a with CuI or I2 were con-
ducted without diamines after 15 min, and then determined
by 13C NMR analysis.10 The results showed that the presence
of CuI could affect the chemical shift to some extent in the
13C NMR spectra. Interestingly, in the presence of I2 some
intermediates besides substrate 1a were observed: one is an
iodonium ion.
Therefore, a possible mechanism as outlined in Scheme 4
was proposed on the base of the present results and the
reported mechanism.3,5-7,11 Initially, complexation of
2-ethynylbenzaldehyde (1) with CuI gives intermediate A.
copper/iodine-catalyzed oxidative cyclization of intermedi-
ate A with o-benzenediamine (2) takes place,3,11 followed by
I2 added to a triple bond leading to intermediate B.5-7
Finally, intermediate B undergoes the electrophilic cycliza-
tion to afford the target cyclization product.
Experimental Section
Typical Experimental Procedure for the Cu-Catalyzed Elec-
trophilic Tandem Cyclization. 2-Ethynylbenzaldehyde 1 (0.2
mmol), o-benzenediamine 2 (0.2 mmol), I2 (2 equiv), CuI
(10 mol %), and DMSO (2 mL) were added to a two-neck flask
in turn. Then the solution was stirred at 120 °C for 24 h until
complete consumption of starting material as monitored by
TLC and GC-MS analysis. After the reaction was finished, the
mixture was washed with saturated Na2S2O3 solution, extracted
with EtOAc, dried over anhydrous Na2SO4, and evaporated in
vacuum. The residue was purified by flash column chromatog-
raphy on silica gel (EtOAc/petroleum ether) to afford the
desired product.
It was found that the iodocyclization reaction could take
place without Cu catalysts; however, the presence of CuI
(12) Li, J.-H.; Liu, W.-J.; Xie, Y.-X. J. Org. Chem. 2005, 70, 5409.
(13) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 44, 4467. (b) Dieck, H. A.; Heck, R. F. J. Organomet. Chem. 1975, 93,
259. (c) Cassar, L. J. Organomet. Chem. 1975, 93, 253.
(14) (a) Grasa, A. G.; Singh, R.; Stevens, E. D.; Nolan, S. P. J. Organo-
met. Chem. 2003, 687, 269. (b) Jeffery, T. Tetrahedron 1996, 52, 10113.
(c) Selvakumar, K.; Zapf, A.; Beller, M. Org. Lett. 2002, 4, 3031.
ꢀ
(11) (a) Balogh-Hergovich, E; Bodnar, G.; Speier, G. Acta Chim. Acad.
ꢀ
Sci. Hung. 1981, 108, 37. (b) Speier, G.; Parkanyi, L. J. Org. Chem. 1986, 51,
218.
ꢀ
ꢀ
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SCHEME 5. Applications in Organic Synthesis
1
Compound 3: red solid; mp 199.5-201.3 °C; H NMR (300
MHz, CDCl3) δ 8.88 (d, J = 7.5 Hz, 1H), 8.15 (m, J = 8.0 Hz,
1H), 7.94 (d, J = 8.1 Hz, 1H), 7.75-7.67 (m, 6H), 7.48-7.45 (m,
2H), 7.33 (t, J = 7.5 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 147.5, 143.6, 139.6, 138.5, 132.5, 132.4,
131.0, 130.8, 130.3, 129.9, 129.6, 128.7, 125.2, 124.5, 122.4,
121.7, 119.5, 114.0, 87.0; LRMS (EI, 70 eV) m/z 420 (Mþ,
100), 292 (52); HRMS (EI) for C21H13IN2 (Mþ) calcd
420.0123, found 420.0126.
(EI, 70 eV) m/z 488 (Mþ, 100), 360 (33); HRMS (EI) for
C22H12F3IN2 (Mþ) calcd 487.9997, found 487.9998.
Compound 8: yellow solid; mp 228.6-230.5 °C; 1H NMR (300
MHz, CDCl3) δ 8.77 (d, J = 8.1 Hz, 1H), 7.95-7.90 (m, 2H),
7.69-7.68 (m, 3H), 7.54 (d, J = 8.1 Hz, 1H), 7.48-7.46 (m, 2H),
7.34 (t, J = 7.5, 1H), 6.92 (t, J = 7.5 Hz, 1H), 5.81 (d, J = 8.7
Hz, 1H), 2.62 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 147.8,
143.9, 141.6, 139.7, 138.7, 132.5, 132.3, 131.0, 130.3, 130.2,
130.0, 129.6, 125.2, 124.4, 121.4, 120.3, 119.5, 114.0, 86.9,
22.0; LRMS (EI, 70 eV) m/z 434 (Mþ, 100), 306 (30); HRMS
(EI) for C22H15IN2 (Mþ) calcd 434.0280, found 434.0284.
Compound 9: brown solid; mp 223.7-226.4 °C; 1H NMR (300
MHz, CDCl3) δ 8.26 (s, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.93 (d,
J = 8.1 Hz, 1H), 7.69-7.67 (m, 3H), 7.49-7.45 (m, 2H),
7.35-7.30 (m, 2H), 6.94 (t, J = 7.7 Hz, 1H), 5.83 (d, J = 8.7
Hz, 1H), 4.05 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.0,
147.4, 143.7, 138.6, 137.4, 134.6, 133.1, 130.3, 129.6, 128.8,
127.7, 126.6, 123.6, 121.7, 121.4, 119.6, 114.1, 105.2, 86.7,
56.1; LRMS (EI, 70 eV) m/z 450 (Mþ, 26), 105 (100); HRMS
(EI) for C22H15IN2O (Mþ) calcd 450.0229, found 450.0231.
Compound 4: 5-Me/6-Me = 1.3:1; yellow solid; mp 232.2-
1
233.9 °C; H NMR (300 MHz, CDCl3) δ 8.88-8.86 (m, 2H),
8.21 (d, J = 7.5 Hz, 1H), 8.15-8.13 (m, 2H), 7.82 (d, J = 8.4 Hz,
1H), 7.76-7.68 (m, 10H), 7.51-7.46 (m, 4H), 7.18 (d, J = 8.1
Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 5.67 (d, J = 8.4 Hz, 0.56H),
5.52 (s, 0.44H), 2.44 (s, 1.7H), 2.18 (s, 1.3H); 13C NMR (75
MHz, CDCl3) δ 147.3, 147.0, 143.5, 141.4, 139.6, 138.5, 138.4,
132.7, 132.4, 132.3, 132.2, 131.5, 130.9, 130.8, 130.3, 130.2,
130.0, 129.9, 129.5, 129.4, 128.8, 128.7, 128.2, 126.2, 125.2,
125.0, 123.5, 123.2, 122.4, 122.2, 119.0, 118.8, 114.0, 113.4,
86.8, 21.9, 21.5; LRMS (EI, 70 eV) m/z 434 (Mþ, 100), 305
(20); HRMS (EI) for C22H15IN2 (Mþ) calcd 434.0280, found
434.0285.
1
Compound 10: yellow solid; mp 258.6-259.8 °C; H NMR
(300 MHz, CDCl3) δ 8.23 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H),
7.70-7.63 (m, 4H), 7.47-7.44 (m, 2H), 7.35 (t, J = 8.0 Hz, 1H),
6.91 (t, J = 8.4 Hz, 1H), 6.17 (s, 2H), 5.80 (d, J = 8.4 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 151.1, 148.9, 147.5, 143.8, 138.7,
138.3, 130.8, 130.3, 130.0, 129.6, 129.4, 124.5, 121.1, 119.2,
118.0, 114.0, 111.3, 103.1, 102.2, 86.2; LRMS (EI, 70 eV) m/z
464 (Mþ, 100), 336 (23); HRMS (EI) for C22H13IN2O2 (Mþ)
calcd 464.0022, found 464.0025.
Compound 5: yellow solid; mp 248.2-249.0 °C; 1H NMR (300
MHz, CDCl3) δ 8.84 (d, J = 7.2 Hz, 1H), 8.20-8.13 (m, 1H),
7.75-7.67 (m, 6H), 7.57-7.46 (m, 2H), 5.50 (s, 1H), 2.34 (s, 3H),
2.05 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 147.0, 142.4, 139.7,
138.7, 132.2, 130.8, 130.7, 130.6, 130.5, 130.1, 130.0, 129.5,
129.4, 128.6, 125.0, 122.7, 119.4, 114.1, 86.1, 20.7, 20.3; LRMS
(EI, 70 eV) m/z 448 (Mþ, 100); HRMS (EI) for C23H17IN2 (Mþ)
calcd 448.0436, found 448.0439.
1
Compound 11: brown solid; mp 224.2-225.9 °C; H NMR
Compound 6: yellow solid; mp 292.2-292.4 °C; 1H NMR (500
MHz, CDCl3) δ 8.91 (d, J = 7.9 Hz, 1H), 8.19 (d, J = 8.0 Hz,
1H), 8.02 (s 1H), 7.84-7.73 (m, 5H), 7.48 (d, J = 7.0 Hz, 2H),
5.78 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 148.7, 142.2, 139.1,
137.6, 132.8, 132.7, 132.2, 130.9, 130.0, 129.8, 129.6, 129.3,
129.1, 125.7, 125.6, 121.7, 120.1, 115.6, 88.2; LRMS (EI, 70
eV) m/z 488 (Mþ, 100), 326 (42); HRMS (EI) for C21H11Cl2IN2
(Mþ) calcd 487.9344, found 487.9349.
(300 MHz, CDCl3) δ 8.84 (s, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.88
(d, J = 8.1 Hz, 1H), 7.70-7.61 (m, 4H), 7.49-7.47 (m, 2H), 7.33
(t, J = 7.5 Hz, 1H), 6.92 (t, J = 7.5, 1H), 5.79 (d, J = 8.7 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 145.3, 142.6, 138.9, 137.2,
133.9, 130.1, 129.9, 129.5, 128.8, 128.6, 123.7, 123.3, 122.3,
121.0, 118.7, 113.0, 84.5; LRMS (EI, 70 eV) m/z 454 (Mþ,
100), 326 (31); HRMS (EI) for C21H12ClIN2 (Mþ) calcd
453.9734, found 453.9737.
1
Compound 7: yellow solid mp 273.2-274.1 °C; 1H NMR (300
MHz, CDCl3) δ 8.89 (d, J = 8.1 Hz, 1H), 8.22-8.20 (m, 2H),
7.85-7.71 (m, 5H), 7.52-7.28 (m, 2H), 7.19 (d, J = 8.7 Hz, 1H),
5.87 (d, J = 9.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 149.1,
143.3, 139.4, 138.2, 132.7, 132.6, 131.7, 130.7, 129.9, 129.8,
Compound 12: yellow solid; mp 285.5-291.6 °C; H NMR
(500 MHz, CDCl3) δ 8.84 (s, 1H), 8.19 (d, J = 7.5 Hz, 1H),
7.72-7.70 (m, 3H), 7.65-7.64 (m, 2H), 7.46-7.47 (m, 2H), 5.49
(s, 1H), 2.33 (s, 3H), 2.05 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
144.8, 141.3, 138.9, 137.5, 133.8, 133.1, 133.0, 130.3, 129.7,
129.6, 129.3, 129.1, 128.9, 128.5, 127.9, 123.2, 118.5, 113.1,
83.8, 19.5, 19.3; LRMS (EI, 70 eV) m/z 482 (Mþ, 100), 356
2
129.1, 126.8 (q, JC-F = 32.5 Hz, 1C), 125.4, 124.5 (q,
1JC-F = 273.5 Hz, 1C), 122.3, 118.3, 117.2, 114.5, 88.1; LRMS
J. Org. Chem. Vol. 76, No. 1, 2011 227

Ouyang et al.
JOCArticle
(26); HRMS (EI) for C23H16ClIN2 (Mþ) calcd 482.0047, found
482.0050.
1H), 3.64 (t, J = 8.0 Hz, 2H), 1.83-1.77 (m, 2H), 1.62-1.59 (m,
2H), 1.36-1.30 (m, 2H), 1.22-1.18 (m, 4H), 0.87 (t, J = 7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 147.6, 143.2, 140.5, 132.7,
132.2, 131.3, 130.5, 128.2, 125.4, 125.0, 122.6, 121.4, 120.0,
114.5, 87.2, 38.3, 31.4, 28.9, 26.7, 22.6, 14.0; LRMS (EI, 70
eV) m/z 428 (Mþ, 21), 301 (38), 231 (100); HRMS (EI) for
C21H21IN2 (Mþ) calcd 428.0749, found 428.0746.
1
Compound 13: brown solid; mp 206.2-207.1 °C; H NMR
(300 MHz, CDCl3) δ 8.54 (d, J = 8.7 Hz, 1H), 8.19-8.15 (m,
1H), 7.91 (d, J = 8.1 Hz, 1H), 7.70-7.69 (m, 3H), 7.49-7.45 (m,
3H), 7.36 (t, J = 7.8 Hz, 1H), 6.96 (t, J = 8.0 Hz, 1H), 5.82 (d,
J = 8.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 162.5 (d,
1JC-F = 248.7 Hz, 1C), 146.7 (d, 4JC-F = 3.8 Hz, 1C), 143.6,
139.0, 138.3, 135.2 (d, 3JC-F = 8.8 Hz, 1C), 130.9, 130.4, 129.9,
129.6, 129.0, 124.7, 123.7 (d, 3JC-F = 8.8 Hz, 1C), 122.3, 119.8,
119.4 (d, 2JC-F = 23.8 Hz, 1C), 114.0, 110.3 (d, 2JC-F = 23.8
Hz, 1C), 85.6; LRMS (EI, 70 eV) m/z 438 (Mþ, 100), 310 (43),
155 (25); HRMS (EI) for C21H12FIN2 (Mþ) calcd 438.0029,
found 438.0031.
1
Compound 20: yellow solid; mp 205.5-206.1 °C; H NMR
(300 MHz, CDCl3) δ 8.92 (d, J = 8.1 Hz, 1H), 8.21 (d, J = 7.5
Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.78-7.66 (m, 5H), 7.53-7.51
(m, 2H), 7.38-7.33 (m, 1H), 6.92 (t, J = 8.1 Hz, 1H), 5.92 (d,
J = 8.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 147.0, 143.8,
136.2, 134.8, 130.9, 130.7, 130.5, 130.3, 129.9, 129.5, 128.7,
127.3, 125.2, 124.5, 123.0, 121.4, 119.7, 113.8, 108.5; LRMS
(EI, 70 eV) m/z 374 (Mþ þ 2, 97), 373 (57), 372 (Mþ, 100), 292
(42); HRMS (EI) for C21H13BrN2 (Mþ) calcd 372.0262, found
372.0265.
1
Compound 14: brown solid; mp 237.1-237.8 °C; H NMR
(300 MHz, CDCl3) δ 9.14-9.07 (m, 2H), 7.94 (d, J = 8.1 Hz,
1H), 7.74-7.72 (m, 3H), 7.67-7.64 (m, 1H), 7.53-7.51 (m, 2H),
7.40 (t, J = 7.8 Hz, 1H), 7.00 (t, J = 7.8 Hz, 1H), 5.89 (d, J = 7.8
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 152.8, 147.1, 146.8,
144.1, 143.3, 137.8, 133.2, 130.8, 130.7, 130.6, 129.8, 129.6,
125.0, 123.4, 122.4, 119.8, 118.4, 114.2, 90.3; LRMS (EI, 70
eV) m/z 421 (Mþ, 100), 293 (20); HRMS (EI) for C20H12IN3
(Mþ) calcd 421.0076, found 421.0080.
Compound 22:3a,b yellow solid; mp 173.2-174.5 °C; 1H NMR
(500 MHz, CDCl3) δ 8.92-8.90 (m, 1H), 8.02 (d, J = 8.0 Hz,
1H), 7.73-7.68 (m, 3H), 7.65-7.60 (m, 5H), 7.40 (t, J = 7.5 Hz,
1H), 7.01 (t, J = 7.5 Hz, 1H), 6.92 (s, 1H), 6.49 (d, J = 8.5 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 148.2, 144.0, 137.4, 134.6,
131.6, 130.2, 129.9, 129.4, 129.0, 128.0, 126.6, 125.2, 124.3,
121.3, 119.6, 114.1, 112.7; LRMS (EI, 70 eV) m/z 294 (Mþ, 100).
Compound 15: yellow solid; mp 254.9-256.6 °C; IR (KBr,
1
1
cm-1) 1522, 1445, 1416, 1267, 753, 708; H NMR (300 MHz,
Compound 23: yellow solid; mp 265.4-266.1 °C; H NMR
CDCl3) δ 7.90 (d, J = 8.1 Hz, 1H), 7.70-7.57 (m, 5H),
7.47-7.45 (m, 2H), 7.36 (t, J = 7.5 Hz, 1H), 6.92 (t, J = 7.7
Hz, 1H), 5.90 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
144.9, 144.1, 141.5, 138.8, 137.2, 130.4, 130.3, 130.1, 129.9,
129.7, 129.0, 125.0, 124.2, 121.2, 119.4, 114.2; LRMS (EI, 70
eV) m/z 426 (Mþ, 100), 298 (31); HRMS (EI) for C19H11IN2S
(Mþ) calcd 425.9688, found 425.9695.
(500 MHz, CDCl3) δ 8.99 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.5
Hz, 1H), 7.68-7.66 (m, 1H), 7.60-7.57 (m, 2H), 7.38-7.33 (m,
7H), 7.25-7.22 (m, 4H), 6.94-6.91 (m, 1H), 6.00 (d, J = 8.5 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 147.8, 144.2, 133.7, 132.7,
131.5, 130.7, 129.9, 129.2, 128.8, 128.0, 127.8, 127.3, 126.4,
125.1, 124.2, 121.3, 119.6, 114.1, 112.6; LRMS (EI, 70 Ev) m/z
370 (Mþ, 100); HRMS (EI) for C27H18N2 (Mþ) calcd 370.1470,
found 370.1465.
1
Compound 16: brown solid; mp 229.9-231.1 °C; H NMR
1
(300 MHz, CDCl3) δ 8.88 (d, J = 7.2 Hz, 1H), 8.16 (d, J = 7.5
Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.75-7.70 (m, 2H), 7.50-7.47
(m, 2H), 7.38-7.34 (m, 3H), 6.96 (t, J = 8.0 Hz, 1H), 5.92 (d,
J = 8.4 Hz,1H), 2.59 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
147.6, 143.8, 140.5, 139.9, 135.7, 132.5, 132.4, 131.0, 130.9, 130.3,
129.7, 128.6, 125.2, 124.5, 122.6, 121.6, 119.6, 114.2, 87.2, 21.7;
LRMS (EI, 70 eV) m/z 434 (Mþ, 100), 306 (33); HRMS (EI) for
C22H15IN2 (Mþ) calcd 434.0280, found 434.0285.
Compound 24: yellow solid; mp 232.1-233.0 °C; H NMR
(500 MHz, CDCl3) δ 8.91 (d, J = 8.0 Hz, 1H), 8.34 (d, J = 8.0
Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.80-7.66 (m, 7H), 7.38 (t,
J = 7.5 Hz, 1H), 7.28-7.22 (m, 5H), 6.99 (t, J = 7.5 Hz, 1H),
6.28 (d, J = 8.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 147.3,
144.3, 140.6, 133.9, 131.2, 130.8, 130.4, 130.1, 130.0, 129.1,
128.4, 128.3, 125.9, 125.1, 124.6, 123.0, 121.7, 119.7, 114.1,
106.7, 97.1, 84.3; LRMS (EI, 70 eV) m/z 394 (Mþ, 100); HRMS
(EI) for C29H18N2 (Mþ) calcd 394.1469, found 394.14696.
Compound 17: red solid; mp 226.3-227.8 °C; 1H NMR (300
MHz, CDCl3) δ 8.26 (s, 1H), 8.07 (d, J = 9.0 Hz, 1H), 7.94 (d,
J = 8.1 Hz, 1H), 7.47 (d, J = 7.9 Hz, 2H), 7.36-7.29 (m, 4H),
6.96 (t, J = 8.0 Hz, 1H), 5.92 (d, J = 8.4 Hz, 1H), 4.06 (s, 3H),
2.59 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 159.9, 147.2, 143.6,
140.3, 137.5, 135.7, 134.3, 131.1, 130.2, 130.0, 126.6, 124.5,
123.4, 121.6, 121.3, 119.4, 114.3, 105.1, 87.0, 56.1, 21.7; LRMS
(EI, 70 eV) m/z 464 (Mþ, 100); HRMS (EI) for C23H17IN2O
(Mþ) calcd 464.0386, found 464.0389.
1
Compound 25: yellow solid; mp 241.7-243.2 °C; H NMR
(500 MHz, CDCl3) δ 8.99-8.97 (m, 1H), 8.16-8.14 (m, 1H),
7.96 (d, J = 8.0 Hz, 1H), 7.70-7.69 (m, 2H), 7.59-7.57 (m, 3H),
7.50-7.49 (m, 2H), 7.28 (t, J = 7.5 Hz, 1H), 7.19-7.18 (m, 2H),
7.11-7.10 (m, 2H), 6.92-6.91 (m, 1H), 6.83 (d, J = 17.0 Hz,
1H), 6.50 (d, J = 16.5 Hz, 1H), 6.02 (d, J = 8.0 Hz, 1H), 2.33 (s,
1H); 13C NMR (125 MHz, CDCl3) δ 147.5, 144.1, 137.8, 136.6,
134.3, 130.5, 130.0, 129.7, 129.3, 127.8, 126.2, 125.5, 125.4,
124.1, 121.5, 121.2, 119.5, 114.1, 21.2; LRMS (EI, 70 eV) m/z
410 (Mþ, 100); HRMS (EI) for C30H22N2 (Mþ) calcd 410.1783,
found 410.1781.
1
Compound 18: brown solid; mp 243.5-245.8 °C; H NMR
(300 MHz, CDCl3) δ 8.85 (s, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.90
(d, J = 8.1 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 7.6 Hz,
2H), 7.36-7.26 (m, 3H), 6.96 (t, J = 8.7 Hz, 1H), 5.89 (d, J = 8.4
Hz, 1H), 2.59 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 146.3,
143.7, 140.6, 140.1, 135.4, 134.8, 134.1, 131.1, 130.9, 130.8,
130.3, 129.6, 124.7, 124.3, 123.3, 122.0, 119.7, 114.2, 85.8,
21.7; LRMS (EI, 70 eV) m/z 468 (Mþ, 100), 340 (29); HRMS
(EI) for C22H14ClIN2 (Mþ) calcd 467.9890, found 467.9895.
Compound 19: red oil; 1H NMR (500 MHz, CDCl3) δ 8.78 (d,
J = 7.5 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz,
1H), 7.78 (d, J = 8.5 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.57 (t,
J = 7.5 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.33 (t, J = 7.5 Hz,
Acknowledgment. We thank the Natural Science Founda-
tion of China (Nos. 20872112 and 20972114) and Zhejiang
Provincial Natural Science Foundation of China (Nos.
Y407116 and Y4080169) for financial support.
Supporting Information Available: Copies of spectra and the
crystallographic data of product 3. This material is available free
of charge via the Internet at http://pubs.acs.org.
228 J. Org. Chem. Vol. 76, No. 1, 2011