Tandem electrophilic cyclization-[3+2] cycloaddition-rearrangement reactions of 2-alkynylbenzaldoxime, DMAD, and Br2

Article abstract of DOI:10.1021/jo802076k

Tandem electrophilic cyclization-[3+2] cycloaddition-rearrangement reactions of 2-alkynylbenzaldoximes, DMAD, and bromine are described, which afford the unexpected iso-quinoline-based azomethine ylides in good to excellent yields. The products could be f

Full text of DOI:10.1021/jo802076k

compounds,6,7 we became interested in developing novel and
efficient methods to construct the new 1,2-dihydroisoquinoline
or isoquinoline-based structures, with a hope of finding more
active hits or leads for our particular biological assays. Herein,
we would like to disclose our recent efforts toward the synthesis
of isoquinoline-based structures via tandem electrophilic cy-
clization-[3+2] cycloaddition-rearrangement reactions of
2-alkynylbenzaldoximes with DMAD. The products could be
further elaborated via transition metal catalyzed cross-coupling
reactions.
Tandem Electrophilic Cyclization-[3+2]
Cycloaddition-Rearrangement Reactions of
2-Alkynylbenzaldoxime, DMAD, and Br2
Qiuping Ding,† Zhiyong Wang,† and Jie Wu*,†,‡
Department of Chemistry, Fudan UniVersity,
220 Handan Road, Shanghai 200433, China, and State Key
Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
The electrophilic cyclization of heteroatomic nucleophiles
such as oxygen, nitrogen, sulfur, and phosphorus with tethered
jie_wu@fudan.edu.cn
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G.-W.; Li, J.-X. Org. Biomol. Chem. 2006, 4, 4063. (l) Diaz, J. L.; Miguel, M.;
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ReceiVed September 18, 2008
Tandem electrophilic cyclization-[3+2] cycloaddition-rear-
rangement reactions of 2-alkynylbenzaldoximes, DMAD, and
bromine are described, which afford the unexpected iso-
quinoline-based azomethine ylides in good to excellent
yields. The products could be further elaborated via pal-
ladium-catalyzed cross-coupling reactions to generate highly
functionalized isoquinoline-based stable azomethine ylides.
Methodology development and library approaches to the
discovery of small-molecule enzyme inhibitors or receptor
ligands are well-established.1 Among the strategies used for the
construction of small molecules, design and synthesis of natural
product-like compounds via tandem reactions have attracted
much attention, and the development of tandem reactions has
been a fertile area in organic synthesis.2 As a privileged
fragment, the 1,2-dihydroisoquinoline (including isoquinoline)
core is found in many natural products and pharmaceuticals that
exhibit remarkable biological activities.3 Typical examples
include papaverine (smooth muscle relaxant),3e saframycin-B
(antitumor agent),3f indenoisoquinoline (topoisomerase
I
inhibitor),3g and narciclasine (antitumor agent).3h Many efforts
continue to be given to the development of new 1,2-dihydroiso-
quinoline or isoquinoline-based structures and new methods for
their constructions.4-6 As part of a program in our laboratory
for the expeditious synthesis of biologically relevant heterocyclic
(7) (a) Ding, Q.; Wu, J. AdV. Synth. Catal. 2008, 350, 1850. (b) Gao, K.;
Wu, J. Org. Lett. 2008, 10, 2251. (c) Ding, Q.; Wu, J. J. Comb. Chem. 2008,
10, 541. (d) Wang, Z.; Fan, R.; Wu, J. AdV. Synth. Catal. 2007, 349, 1943. (e)
Zhang, L.; Wu, J. AdV. Synth. Catal. 2007, 349, 1047.
(8) For selected examples, see: (a) Bi, H.-P.; Guo, L.-N.; Duan, X.-H.; Gou,
F.-R.; Huang, S.-H.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2007, 9, 397. (b) Sniady,
A.; Wheeler, K. A.; Dembinski, R. Org. Lett. 2005, 7, 1769. (c) Liu, Y.-H.;
Song, F.-J.; Cong, L. Q. J. Org. Chem. 2005, 70, 6999. (d) Peng, A. Y.; Ding,
Y. X. Org. Lett. 2004, 6, 1119. (e) Yue, D.; Yao, T.; Larock, R. C. J. Org.
Chem. 2005, 70, 10292. (f) Flynn, B. L.; Verdier-Pinard, P.; Hamel, E. Org.
Lett. 2001, 3, 651. (g) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905. (h)
Hessian, K. O.; Flynn, B. L. Org. Lett. 2003, 5, 4377. (i) Arcadi, A.; Cacchi, S.;
Giuseppe, S. D.; Fabrizi, G.; Marinelli, F. Org. Lett. 2002, 4, 2409. (j) Huang,
Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67, 3437. (k) Yao, T.;
Larock, R. C. J. Org. Chem. 2003, 68, 5936. (l) Yao, T.; Campo, M. A.; Larock,
R. C. Org. Lett. 2004, 6, 2677. (m) Yue, D.; Della, C. N.; Larock, R. C. Org.
Lett. 2004, 6, 1581. (n) Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 1432.
(o) Barluenga, J.; Trincado, M.; Marco-Arias, M.; Ballesteros, A.; Rubio, E.;
Gonzalez, J. M. Chem. Commun. 2005, 2008.
† Fudan University.
‡ Chinese Academy of Sciences.
(1) (a) Walsh, D. P.; Chang, Y.-T. Chem. ReV. 2006, 106, 2476. (b) Arya,
P.; Chou, D. T. H.; Baek, M.-G. Angew. Chem., Int. Ed. 2001, 40, 339. (c)
Schreiber, S. L. Science 2000, 287, 1964.
(2) For selected examples, see: (a) Denmark, S. E.; Thorarensen, A. Chem.
ReV. 1996, 96, 137. (b) Porco, J. A., Jr.; Schoenen, F. J.; Stout, T. J.; Clardy, J.;
Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 7410. (c) Molander, G. A.; Harris,
C. R. J. Am. Chem. Soc. 1996, 118, 4059. (d) Chen, C.; Layton, M. E.; Sheehan,
S. M.; Shair, M. D. J. Am. Chem. Soc. 2000, 122, 7424. (e) Shi, F.; Li, X.; Xia,
Y.; Zhang, L.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 15503.
10.1021/jo802076k CCC: $40.75
Published on Web 12/04/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 921–924 921

TABLE 1. Condition Screening for Tandem Electrophilic
Cyclization-[3+2] Cycloaddition Reactions of
2-Alkynylbenzaldoximea
SCHEME 1. Proposed Tandem Electrophilic
Cyclization-[3+2] Cycloaddition of 2-Alkynylbenzaldoxime
entry
base
none
DABCO
DBU
pyridine
Et3N
KOH
solvent
time (h)
yield (%)b
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
(CH2Cl)2
DMF
24
24
24
24
24
6
0
5
trace
trace
trace
6
alkynes has proven to be an effective method of preparing a
large variety of heterocyclic ring systems.8,9 The electrophiles
such as iodine, bromine, ICl, and NBS were commonly used in
the reaction since the resulting iodine- or bromo-containing
products are readily elaborated to more complex products by
using known organopalladium chemistry. Meanwhile, it was
found that 2-alkynylbenzaldehyde was a versatile building block
in tandem reactions for construction of heterocycles.10 Prompted
by the results, we envisioned that 2-alkynylbenzaldoxime might
be utilized as starting material for synthesis of N-heterocycles
due to the structural similarity with 2-alkynylbenzaldehyde.
Recently, we discovered that 2-alkynylbenzaldoxime 1 would
be converted to isoquinoline N-oxide A via electrophilic
cyclization7a in the presence of electrophiles such as iodine or
bromine. The resulting compound A might undergo dipolar
cycloaddition in the presence of dipolarophiles leading to the
fused 1,2-dihydroisoquinoline derivatives B (Scheme 1). After
further transformation, functionalized fused 1,2-dihydroiso-
quinolines C could be generated via palladium-catalyzed cross-
coupling reactions. It is well-known that the [3+2] cycloaddition
reaction is a useful tool for constructing five-membered
heterocyclic compounds.11 To verify the practicability of this
projected route, we started to investigate the possibility for one-
pot tandem electrophilic cyclization-[3+2] cycloaddition of
2-alkynylbenzaldoxime 1.
NaOH
LiOH
6
15
70
31
67
67
40
18
87
82
88
74
10
51
79
66
72
24
24
24
24
24
24
18
18
24
24
24
24
24
24
24
9
Na2CO3
Cs2CO3
K2CO3
NaHCO3
KF
K2HPO4
K3PO4
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
10
11
12
13
14
15
16
17
18
19
20
21
22
CH3CN
CH3NO2
THF
toluene
a Reaction conditions: 2-alkynylbenzaldoxime 1a (0.30 mmol),
dimethyl but-2-ynedioate (1.0 equiv), bromine (1.0 equiv), base (1.2
equiv), solvent (2.0 mL). b Isolated yield based on 2-alkynyl-
benzaldoxime 1a.
entry 1). We reasoned that during the electrophilic cyclization
process, the in situ generated HBr might inhibit the reaction.
Thus, the addition of base would benefit the reaction. Different
bases were then screened and NaOAc was demonstrated as the
best choice. Under these conditions, a product was isolated in
88% yield (Table 1, entry 16). However, after careful identifica-
tion, the structure of this product was recognized as compound
2a instead of the desired fused 1,2-dihydroisoquinoline B1. We
also tested other solvents, such as 1,2-dichloroethane, DMF,
CH3CN, and THF (Table 1, entries 17-22). However, only
inferior results were observed. According to the previous
report,13 the fused 1,2-dihydroisoquinoline B1 was generated
as intermediate in the reaction process, which then underwent
rearrangement leading to the unexpected compound 2a.13
The scope of this reaction was then investigated under the
optimized conditions (NaOAc, CH2Cl2, rt), and the results are
summarized in Table 2. For all cases, 2-alkynylbenzaldox-
ime 1 reacted with dimethyl acetylene dicarboxylate and
bromine leading to the corresponding products 2 in good to
excellent yields. For instance, reaction of 2-alkynylbenzaldoxime
1b under the standard conditions gave rise to the corresponding
product 2b in 63% yield (Table 2, entry 2). Lower yield was
obtained when compound 1c was utilized as substrate (Table
2, entry 3, 42% yield). Reaction of 2-alkynylbenzaldoxime 1d,
Initially, a set of experiments were carried out with 2-alky-
nylbenzaldoxime (1a) and dimethyl acetylene dicarboxylate
(DMAD) as model substrates in the presence of bromine. No
desired product B1 was generated when the reaction was
performed at room temperature in dichloromethane (Table 1,
(9) For reviews, see: (a) Larock, R. C. In Acetylene Chemistry; Diederich,
F., Stang, P. J., Tykwinski, R. R., Eds.; Wiley-VCH: Weinheim, Germany, 2005;
pp 51-99. (b) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104,
3079. (c) Zeni, G.; Larock, R. C. Chem. ReV. 2006, 106, 4644.
(10) Selected examples for metal-catalyzed cyclization of 2-alkynylbenzal-
dehyde: (a) Beeler, A. B.; Su, S.; Singleton, C. A.; Porco, J. A., Jr. J. Am. Chem.
Soc. 2007, 129, 1413, and references cited therein. (b) Asao, N. Synlett 2006,
1645. (c) Nakamura, I.; Mizushima, Y.; Gridnev, I. D.; Yamamoto, Y. J. Am.
Chem. Soc. 2005, 127, 9844. (d) Kim, N.; Kim, Y.; Park, W.; Sung, D.; Gupta,
A.-K.; Oh, C.-H. Org. Lett. 2005, 7, 5289. (e) Sato, K.; Asao, N.; Yamamoto,
Y. J. Org. Chem. 2005, 70, 8977. (f) Asao, N.; Sato, K.; Menggenbateer;
Yamamoto, Y. J. Org. Chem. 2005, 70, 3682. (g) Kusama, H.; Funami, H.;
Takaya, J.; Iwasawa, N. Org. Lett. 2004, 6, 605. (h) Asao, N.; Aikawa, H.;
Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 7459. (i) Asao, N.; Aikawa, H.;
Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 7458.
(11) For reviews, see: (a) Husinec, S.; Savic, V. Tetrahedron: Asymmetry
2005, 16, 2047. (b) Kanemasa, S. Synlett 2002, 1371. (c) Gothelf, K. V.;
Jørgensen, K. A. Chem. ReV. 1998, 98, 863. (d) Pichon, M.; Figadere, B.
Tetrahedron: Asymmetry 1996, 7, 927.
(12) We thank the referee’s helpful suggestion for structure identification of
compound 2.
(13) Coskun, N.; Tuncman, S. Tetrahedron 2006, 62, 1345.
922 J. Org. Chem. Vol. 74, No. 2, 2009

TABLE 2. Tandem Electrophilic Cyclization-[3+2]
Cycloaddition-Rearrangement Reactions of 2-Alkynylbenzaldoximes
with DMADa
TABLE 3. Synthesis of Functionalized Isoquinoline-Based
Azomethine Ylides via Palladium-Catalyzed Suzuki Reactionsa
a Reaction conditions: substrate 2 (0.25 mmol), arylboronic acid (1.2
equiv), PdCl2(PPh3)2 (10 mol %), K2CO3 (2.0 equiv), DMF/H2O (2.0
mL, 5/1), rt, 12 h. b Isolated yield based on compound 2. PMP:
p-methoxyphenyl.
group), reactions also proceeded well to give rise to the
corresponding products in good yields (Table 2, entries 7-9).
As mentioned above, the resulting bromo-containing products
2 could be easily functionalized by using known organopalla-
dium chemistry. Due to their easy handling and long shelf life,
arylboronic acid derivatives would be the starting materials of
choice. Thus, we started to explore the possibility of the
Suzuki-Miyaura coupling reaction14 by using the bromo-
substituted azomethine ylide 2 as an electrophile for the
synthesis of functionalized isoquinoline-based azomethine ylides.
The reactions were performed at room temperature catalyzed
by PdCl2(PPh3)2 (10 mol %) in DMF-H2O in the presence of
potassium carbonate as base (Table 3). We found that all
reactions proceeded smoothly to generate the desired product
3 in good to excellent yields.
a Reaction conditions: 2-alkynylbenzaldoxime
dimethyl but-2-ynedioate (1.0 equiv), bromine (1.0 equiv), NaOAc (1.2
equiv), CH2Cl2 (2.0 mL), rt, 18-24 h. b Isolated yield based on
2-alkynylbenzaldoxime 1. PMP: p-methoxyphenyl.
1
(0.30 mmol),
DAMA, and bromine afforded the isoquinoline-based azome-
thine ylide 2d in almost quantitative yield (Table 2, entry 4,
98% yield). The structure of compound 2d was also verified
by X-ray illustration (for details, see the Supporting Informa-
tion). In addition, it seems that the groups attached on the
aromatic ring of 2-alkynylbenzaldoxime 1 affect the reaction
markedly. Compared to the electron-donating group, a better
result was observed with an electron-withdrawing group attached
on the aromatic ring of 2-alkynylbenzaldoxime 1. For example,
88% yield of product 2e was observed when fluoro-substituted
2-alkynylbenzaldoxime 1e was employed in the reaction (Table
2, entry 5), while 52% yield of product 2f was generated when
substrate 1f was used under the same conditions (Table 2, entry
6). When R2 was replaced by alkyl groups (butyl or cyclopropyl
In conclusion, we have described an efficient route for the
synthesis of isoquinoline-based azomethine ylides starting from
(14) For recent reviews, see: (a) Miyaura, N. Top. Curr. Chem. 2002, 219,
11. (b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (c) Littke, A. F.; Fu,
G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
J. Org. Chem. Vol. 74, No. 2, 2009 923

General Procedure for the Synthesis of Functionalized
Isoquinoline-Based Azomethine Ylides via Palladium-Catalyzed
Suzuki Reactions. A solution of compound 2 (0.25 mmol),
ArB(OH)2 (0.30 mmol, 1.2 equiv), K2CO3 (0.5 mmol, 2.0 equiv),
and PdCl2(PPh3)2 (0.025 mmol, 10 mol %) in H2O/DMF (1:5, 2.0
mL) was stirred at room temperature overnight. After completion
of the reaction as indicated by TLC, the solvent was diluted with
EtOAc (30 mL), washed with aqueous HCl (1.0 M, 10 mL), and
dried by anhydrous Na2SO4. Evaporation of the solvent followed
by purification on silica gel provided the corresponding compound
3. Selected example, compound 3a: yield 78%; 1H NMR (400 MHz,
CDCl3) δ 3.43 (s, 3H), 3.74 (s, 3H), 6.96 (br, 1H), 7.00 (d, J ) 7.8
Hz, 1H), 7.09 (t, J ) 7.3 Hz, 1H), 7.20-7.32 (m, 5H), 7.37 (t, J
) 7.8 Hz, 1H), 7.43 (d, J ) 7.3 Hz, 1H), 7.71 (d, J ) 8.3 Hz, 1H),
7.89 (t, J ) 7.3 Hz, 1H), 7.97 (t, J ) 8.3 Hz, 1H), 8.28 (d, J ) 7.8
Hz, 1H), 9.36 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 50.3, 51.7,
126.4, 126.8, 127.4, 127.5, 128.0, 128.3, 128.5, 129.2, 129.4, 129.7,
130.0, 130.2, 131.3, 133.6, 136.3, 138.3, 138.4, 148.7, 153.9, 168.1,
171.8; HRMS calcd for C27H21NO5 [M + H]+ 440.1498, found
440.1508. (For details, please see the Supporting Information.)
2-alkynylbenzaldoximes, DMAD, and bromine via tandem
electrophilic cyclization-[3+2] cycloaddition-rearrangement
reactions. These products could be further elaborated by
Suzuki-Miyaura couplings to introduce more diversity. The
efficiency of this method combined with the operational
simplicity of the present process makes it potentially attractive
for library construction. The focused library generation and
screening for biological activity of these small molecules are
under investigation in our laboratory.
Experiment Section
General Procedure for Tandem Electrophilic Cycliza-
tion-[3+2] Cycloaddition-rearrangement Reactions of DMAD
with 2-Alkynylbenzaldoxime. Br2 (0.30 mmol, 1.0 equiv) in 2.0
mL of CH2Cl2 was added to a mixture of 2-alkynylbenzaldoxime
1 (0.30 mmol) and NaOAc (0.36 mmol, 1.2 equiv) in CH2Cl2 (2.0
mL). After 5 min, dimethyl acetylene dicarboxylate (DMAD) (0.60
mmol, 2.0 equiv) was added, and the reaction was stirred at room
temperature. After completion of the reaction as indicated by TLC,
the solvent was diluted with CH2Cl2 (10 mL), washed with saturated
aqueous NaS2O3 (20 mL), and dried by anhydrous Na2SO4.
Evaporation of the solvent followed by purification on silica gel
provided the corresponding product 2. Selected example, compound
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20772018), Shanghai
Pujiang Program, and Program for New Century Excellent
Talents in University (NCET-07-0208) is gratefully acknowledged.
1
2a: yield 88%; H NMR (400 MHz, CDCl3) δ 3.46 (s, 3H), 3.73
(s, 3H), 7.34 (d, J ) 7.3 Hz, 1H), 7.44-7.48 (m, 1H), 7.49-7.53
(m, 3H), 7.97 (t, J ) 8.3 Hz, 1H), 8.22 (t, J ) 8.0 Hz, 1H), 8.28
(d, J ) 7.8 Hz, 1H), 8.46 (d, J ) 8.8 Hz, 1H), 9.33 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 50.4, 51.8, 124.3, 127.3, 127.5, 127.6,
128.3, 128.4, 128.9, 130.4, 130.6, 131.0, 132.6, 137.9, 138.0, 150.0,
154.4, 167.9, 171.6; HRMS calcd for C21H16BrNO5 [M + H]+
442.0290, found 442.0301.
Supporting Information Available: Experimental proce-
dures, characterization data, and copies of 1H and 13C NMR of
compounds 2 and 3. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO802076K
924 J. Org. Chem. Vol. 74, No. 2, 2009