Iodine-mediated electrophilic cyclization of 2-alkynylbenzaldoximes leading to the formation of iodoisoquinoline N-oxides

Article abstract of DOI:10.1016/j.tetlet.2008.07.061

Reaction of 2-alkynylbenzaldoximes 1 with 5 equiv of iodine in EtOH at room temperature gives the corresponding iodoisoquinoline N-oxides 2 in good to excellent yields. The cyclization proceeds very smoothly and quickly without any additives such as bases

Full text of DOI:10.1016/j.tetlet.2008.07.061

Tetrahedron Letters 49 (2008) 5531–5533
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iodine-mediated electrophilic cyclization of 2-alkynylbenzaldoximes
leading to the formation of iodoisoquinoline N-oxides
*
Zhibao Huo, Hisamitsu Tomeba, Yoshinori Yamamoto
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of 2-alkynylbenzaldoximes 1 with 5 equiv of iodine in EtOH at room temperature gives the
corresponding iodoisoquinoline N-oxides 2 in good to excellent yields. The cyclization proceeds very
smoothly and quickly without any additives such as bases under very mild reaction conditions.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 9 June 2008
Revised 30 June 2008
Accepted 9 July 2008
Available online 12 July 2008
Keywords:
Electrophilic cyclization
Iodonium ion
Iodine
Isoquinoline N-oxide
2-Alkynylbenzaldoxime
Isoquinoline
Isoquinoline N-oxides are an important class of compounds be-
cause of their wide utility.1 They have been considered as very use-
ful intermediates for isoquinolines and their derivatives and are
often seen as building blocks in biologically active compounds
and functional materials.2 Recently, isoquinoline N-oxides have
been utilized as backbones of chiral ligands for asymmetric trans-
formations, and several new compounds have been synthesized.3
Due to their potential importance, several synthetic methods from
2-alkynylbenzaldoximes have been developed (Eq. 1). For example,
Sakamoto et al.4 reported the reaction of 2-alkynylbenzaldoximes
in the presence of potassium carbonate in ethanol/water at 60 °C
(Eq. 1). Shin et al.5 reported that silver trifluoromethanesulfonate
catalyzed the cyclization of 2-alkynylbenzaldoxime derivatives
into the corresponding isoquinoline N-oxides in CH2Cl2 (Eq. 1).
However, an analogous transformation via iodine-mediated elec-
trophilic cyclization of 2-alkynylbenzaldoximes has not been
developed.
Previously, we reported the synthesis of 1,2-dihydroisoquino-
line skeletons via AgOTf-catalyzed direct addition of pronucleo-
philes to o-alkynylarylaldimines6 and via three-component
coupling reaction with ortho-alkynylbenzaldehydes, primary
amines and pronucleophiles in the presence of molecular sieves.7
More recently, we reported8 an entirely new method for the syn-
thesis of 1,3,4-trisubstituted isoquinolines through iodine-medi-
ated electrophilic cyclization of 2-alkynyl benzyl azides (Eq. 2). It
occurred to us that iodine-mediated cyclization of 2-alkynylbenz-
aldoximes 1 might produce iodoisoquinoline N-oxides 2 (Eq. 3).
With this in mind, we examined the iodine-mediated cyclization
reaction of various 2-alkynylbenzaldoximes, and found that the
reaction proceeded very smoothly to give the desired iodoisoquino-
line N-oxides 2 in good to high yields (Eq. 3).
K2CO3
R1
R
R1
EtOH/H2O, 60 o
C
R
O
ð1Þ
N
or
N
OH
AgOTf, CH2Cl2, rt
I
R1
X
R1
X
I2 (5 equiv)
ð2Þ
N
N3
base (1 equiv)
CH2Cl2, rt, 24 h
R2
R2
X = C, N
I
R
R1
R1
I2 (5 equiv)
R
O
ð3Þ
EtOH, rt, 15 min
N
N
OH
1
3
Initially, we tested the reaction of substrate 1a in order to opti-
mize the reaction conditions, and the results are summarized in
Table 1. Cyclization of 1a using 5 equiv of iodine and 1 equiv of
NaHCO3 as a base in CH3NO2 at room temperature for 15 min
* Corresponding author. Tel.: +81 22 795 6581; fax: +81 22 795 6784.
E-mail address: yoshi@mail.tains.tohoku.ac.jp (Y. Yamamoto).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.061

5532
Z. Huo et al. / Tetrahedron Letters 49 (2008) 5531–5533
Table 1
Table 2
Effect of iodo reagent and solvent on the formation of iodoisoquinoline N-oxide 2a
Iodine-mediated cyclization of 2-alkynylbenzaldoximes
1
to iodoisoquinoline N-
from 1aa
oxides 2a
Entry
Iodo reagent
Solvent
Time (min)
Yield of 2ab (%)
Entry Substrate
Product (2)
Yield Mp
of 2,b (°C)
(%)
1
2
3
4
5
6
7
8
I2
I2
NIS
NIS
ICl
I2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
EtOH
15
15
30
60
60
15
15
150
81c
82
(11)c
(15)
Mixtured
(94)
26e
OMe
OMe
I
1
86
80
206–207
198–199
1b
2b
I2
I2
H2O
EtOH
f
N
(69)
N
N
O
O
O
OH
OH
a
The reaction of 1a was carried out in the presence of 5 equiv of iodo reagent at
room temperature except as otherwise indicated.
CF3
b
1H NMR yield was determined using 1,4-dioxane as an internal standard. Iso-
CF3
I
lated yield is shown in parentheses.
2c
1c
c
One equiv of NaHCO3 was used.
A mixture of iodo- and chloro-substituted isoquinoline N-oxides was obtained.
Reaction temperature was 100 °C.
Two equivalents of iodine were used.
2
d
e
N
f
provided the desired iodoisoquinoline N-oxide 2a in 81% NMR
yield (entry 1). To our surprise, the cyclization also proceeded
smoothly without a base, giving the product in 82% NMR yield
(entry 2). N-iodosuccinimide (NIS) was inefficient and gave the
product in lower yields (entries 3 and 4). Use of ICl led to a mixture
of iodo- and chloro-substituted isoquinoline N-oxides (entry 5).
The use of ethanol, instead of nitromethane, gave the product 2a
in a higher yield (entry 6). The use of water as a solvent gave a very
low yield even after increasing the reaction temperature up to
100 °C (entry 7). Decreasing the amount of iodine from 5 to 2 equiv
also resulted in a lower yield (entry 8).
I
I
I
I
1d
2d
3
4
5
6
71
65
92
90
75
199–200
192–193
205–206
200–201
249–250
N
N
N
N
N
N
OH
C4H9
1e
1f
2e
2f
C4H9
O
OH
Ph
I
Ph
Ph
Iodo reagent (5 equiv)
Ph
N
N
ð4Þ
OH
OH
solvent, rt, time
O
N
N
OH
O
1a
2a
2g
1g
The scope of the intramolecular cyclization of 2-alkynylbenz-
aldoximes is summarized in Table 2.9 Arylacetylenes bearing
methoxy and trifluoromethyl groups 1b and 1c on the aromatic
ring afforded the corresponding cyclized products 2b and 2c,
respectively, in good yields, indicating that the substituents on
the aromatic ring did not exert a significant influence upon the
cyclization (entries 1 and 2). The reactions of 1d, 1e, and 1f, having
cyclohexyl, n-butyl, and benzyl groups at the alkyne terminus,
under the standard conditions, proceeded smoothly to give the de-
sired products 2d, 2e, and 2f, respectively, in good to high yields
(entries 3–5). The cyclization of 1g afforded the desired product
2g in a high yield (entry 6). The 2-alkynylbenzaldoximes 1h and
1i, in which the aromatic ring was substituted with RO groups,
gave the corresponding iodoisoquinoline N-oxides 2h and 2i in
good to high yields (entries 7 and 8). Replacing a carbon atom of
the aromatic ring with a nitrogen atom did not affect the cycliza-
tion; the reaction proceeded very smoothly to afford the product
2j in 72% yield, although a prolonged reaction time was required
(entry 9). Iodoisoquinoline N-oxide 2k was not obtained from
ketoxime 1k under the present conditions (entry 10).
O
I
Ph
1h
MeO
MeO
MeO
Ph
2h
7
N
N
MeO
OH
O
I
Ph
Ph
O
O
O
O
8
85
274–275
236–237
—
1i
OH
2i
N
N
O
I
Ph
N
9
72c
N
Ph
O
1j
2j
N
N
N
N
OH
Ph
I
A plausible mechanism for the formation of iodoisoquinoline N-
oxides 2 via iodine-mediated electrophilic cyclization of 2-alkynyl-
benzaldoximes 1 is illustrated in Scheme 1. Coordination of the
iodonium cation to the alkyne activates the triple bond toward
nucleophilic attack of the oxime nitrogen, leading to the iodo-
isoquinoline intermediate. Subsequent elimination of a proton
results in the formation of iodoisoquinoline N-oxide 2.
Ph
O
d
10
—
1k
2k
OH
Me
Me
a
The reactions of 1 (0.3 mmol) in the presence of iodine (5 equiv) were carried
out at room temperature in EtOH for 15 min.
b
Isolated yields.
Reaction time was 30 min.
Starting material decomposed at 60 °C.
c
We were also interested in further manipulation of compounds
2. For example, a
-cyanation using TMSCN is known (Eq. 5),10 and
d

Z. Huo et al. / Tetrahedron Letters 49 (2008) 5531–5533
5533
2. (a) Dzierszinski, F.; Coppin, A.; Mortuaire, M.; Dewally, E.; Slomianny, C.;
Ameisen, J.-C.; Debels, F.; Tomavo, S. Antimicrob. Agent. Chemother. 2002, 46,
3197; (b) Kletsas, D.; Li, W.; Han, Z.; Papadopoulos, V. Biochem. Pharmacol.
2004, 67, 1927; (c) Mach, U. R.; Hackling, A. E.; Perachon, S.; Ferry, S.;
Wermuth, C. G.; Schwartz, J.-C.; Sokoloff, P.; Stark, H. ChemBioChem 2004, 5,
508; (d) Muscarella, D. E.; O’Brian, K. A.; Lemley, A. T.; Bloom, S. E. Toxicol. Sci.
2003, 74, 66.
I
R
I2
R
O
N
N
OH
1
2
3. (a) Petrowitsch, T.; Eilbracht, P. Synlett 1997, 287; (b) Derdau, V.; Laschat, S.;
Jones, P. G. Heterocycles 1998, 48, 1445; (c) Kerr, W. J.; Kirk, G. G.; Middlemiss,
D. Synlett 1995, 1085; (d) Hamuro, Y.; Geib, S. J.; Hamilton, A. D. J. Am. Chem.
Soc. 1996, 118, 7529; (e) O’Neil, I. A.; Turner, C. D.; Kalindjian, S. B. Synlett 1997,
777; (f) Derdau, V.; Laschat, S.; Hupe, E.; König, W. A.; Dix, I.; Jones, P. G. Eur. J.
Inorg. Chem. 1999, 1001.
I+
- H+
I
I
R
R
4. (a) Sakamoto, T.; Kondo, Y.; Miura, N.; Hayashi, K.; Yamanaka, H. Heterocycles
1986, 24, 2311; (b) Sakamoto, T.; Numata, A.; Kondo, Y. Chem. Pharm. Bull.
2000, 48, 669.
N
N
OH
OH
5. The following paper was published during the preparation of the present
manuscript: Yeom, H.-S.; Kim, S.; Shin, S. Synlett 2008, 924.
Scheme 1. A plausible mechanism for the formation of 2.
6. Asao, N.; Yudha, S.; Nogami, T.; Yamamoto, Y. Angew. Chem. Int. Ed. 2005, 44,
5526.
7. Asao, N.; Iso, K.; Yudha, S. Org. Lett. 2006, 8, 4149.
8. Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Yamamoto, Y. Angew. Chem.
Int. Ed. 2007, 46, 4764.
we thought that application of this
a
-cyanation to our iodoisoquin-
oline N-oxides would lead to formation of 1,3,4-trisubstituted iso-
quinolines. The reactions of iodoisoquinoline N-oxides 2a, 2f, and
2g were carried out in THF at 75 °C for 30 min in the presence of
TMSCN and DBU to give the desired cyanoisoquinolines 3a, 3f,
and 3g in high yields (Eq. 6).11
9. The procedure for the synthesis of isoquinoline N-oxide 2ais as follows. To a
5 mL screw capped vial equipped with a magnetic stirring bar were added 2-
phenylalkynylbenzaldoxime (66.4 mg, 0.3 mmol), iodine (380.7 mg, 1.5 mmol)
and dry ethanol (3 mL) under an argon atmosphere. The reaction mixture was
stirred at room temperature for 15 min, and the progress of the reaction was
monitored by TLC (hexane/ethyl acetate; 2:1). After complete consumption of
the starting material, saturated aqueous Na2S2O3 was added, and stirring was
continued for 5–15 min. The mixture was extracted with CH2Cl2 (2 ꢀ 20 mL)
and dried over anhydrous magnesium sulfate. The solvent was removed under
reduced pressure, and the residue was purified by column chromatography
(silica gel, CH2Cl2/EtOH; 50/1–5/1) to afford product 2a in 94% yield (97.9 mg).
Mp: 230–231 °C; 1H NMR (500 MHz, CDCl3): d 7.41–7.37 (m, 2H), 7.58–7.48 (m,
3H), 7.70–7.61 (m, 3H), 8.08 (d, J = 8.0 Hz, 1H), 8.86 (s, 1H); 13C NMR (75 MHz,
CDCl3): 101.79, 125.21, 128.37, 128.64, 129.42, 129.58, 129.76, 130.33, 131.72,
TMSCN (1.2 equiv)
DBU (2.2 equiv)
N
ð5Þ
N
THF, reflux, 30 min
97%
O
CN
I
I
TMSCN (1.5 equiv)
DBU (3.3 equiv)
R
R
O
132.54, 136.78, 137.21, 151.04; IR (KBr) 1307, 1171, 1119, 773, 752 cmꢁ1
;
N
HRMS (EI) calcd for C15H10INO ([M+Na]+) 369.9705. Found. 369.9699.
THF, 75 oC, 30 min
N
10. Miyashita, A.; Kawashima, T.; Iijima, C.; Higashino, T. Heterocycles 1992, 33,
211.
CN
, 84% (mp: 161-162 oC)
3f, 88% (mp: 138-139 oC)
3g
2a
3a
, R = Ph
, R = Bn
11. The procedure for the synthesis of cyanoisoquinoline 3a from 2a is as follows.
To a 5 mL screw capped vial equipped with a magnetic stirring bar were added
compound 2a (104.1 mg, 0.3 mmol), TMSCN (0.06 mL, 0.45 mmol), DBU
(0.15 mL, 0.99 mmol) and THF (3 mL). The reaction mixture was stirred at
75 °C for 30 min, and the progress of the reaction was monitored by TLC
(hexane/ethyl acetate; 5:1). After complete consumption of the starting
material, the reaction mixture was cooled to room temperature, saturated
aqueous NH4Cl was added, and stirring was continued for 5–15 min. The
mixture was extracted with CH2Cl2 (2 ꢀ 20 mL) and dried over anhydrous
magnesium sulfate. The solvent was removed under reduced pressure, and the
residue was purified by column chromatography (silica gel, hexane/ethyl
acetate; 20/1–5/1) to afford product 3a in 84% yield (89.3 mg). Mp: 161–
162 °C; 1H NMR (500 MHz, CDCl3): d 7.55–7.46 (m, 3H), 7.64–7.59 (m, 2H),
7.86 (t, J = 8.0 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 8.35 (d, J = 8.0 Hz, 2H); 13C NMR
(75 MHz, CDCl3): 103.84, 115.13, 125.75, 127.90, 128.07, 128.90, 129.67,
130.28, 133.29, 133.45, 134.25, 139.10, 142.08, 157.83. IR (KBr) 2228, 1537,
1264, 916, 766, 744 cmꢁ1; HRMS (EI) calcd for C16H9IN2 ([M+Na]+) 378.9708.
Found. 378.9703.
2f
2g, R = Cyclohexenyl
, 92% (mp: 108-109 oC)
ð6Þ
In conclusion, we have developed a new and efficient procedure
for the synthesis of 3,4-disubstituted iodoisoquinoline N-oxides
from 2-alkynylbenzaldoximes. We also demonstrated that 1,3,4-
trisubstituted isoquinolines may be derived from these iodo-
isoquinoline N-oxides. Further studies to extend the scope of this
procedure are in progress in our laboratory.
References and notes
1. Bentley, K. W. In The Isoquinoline Alkaloids; Harwood Academic: Amsterdam,
1998; Vol. 1.