Silver(I)-catalyzed direct route to isoquinoline-N-oxides

Article abstract of DOI:10.1055/s-2008-1042936

Silver trifluoromethanesulfonate efficiently catalyzes the cyclization of 2-alkynylbenzaldoxime derivatives into the corresponding isoquinoline-N-oxides. The current protocol provides a direct route to the latter skeleton under a very mild reaction condition. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042936

924
LETTER
Silver(I)-Catalyzed Direct Route to Isoquinoline-N-Oxides
D
irec
t
Route to Iso
y
quinoline-
N
-
Oxides n-Suk Yeom,a Sunghwan Kim,b Seunghoon Shin*a
a
Department of Chemistry, Hanyang University, Seoul 133-791, Korea
Fax +82(2)22990762; E-mail: sshin@hanyang.ac.kr
Korea Basic Science Institute, 804-1 Yangcheong-Ri, Ochang-Myun, Cheongwon-Gun, Chungcheongbuk-Do 363-883, Korea
b
Received 18 December 2007
Abstract: Silver trifluoromethanesulfonate efficiently catalyzes
the cyclization of 2-alkynylbenzaldoxime derivatives into the corre-
sponding isoquinoline-N-oxides. The current protocol provides a
direct route to the latter skeleton under a very mild reaction condi-
tion.
N+
N+
N+
O–
O–
O–
OMe
Key words: AgOTf, isoquinoline-N-oxide, heterocycles, cyclo-
isomerization
HO
N
OH
N+
N+
O–
N
Electrophilic metal-catalyzed addition of nucleophiles
onto alkyne has witnessed a significant level of develop-
ment recently, leading to diverse novel syntheses of het-
erocycles.1 In this effort, a search for a new reaction
partner has played a pivotal role in the development of
synthetic route to biologically important heterocycles.2 In
particular, isoquinoline derivatives are widespread in nat-
ural products and the development of their efficient cata-
lytic synthesis fits as a suitable goal.3 Isoquinoline-N-
oxides, on the other hand, are an important precursor for
isoquinoline derivatives including pharmaceutically im-
portant 2-amino-functionalized nitrogen heterocycles,4
and more recently they attracted renewed interests be-
cause of their use as a chiral scaffold in Lewis basic orga-
nocatalysis (Figure 1).5 In addition, their utility extends to
materials science because of their interesting optochemi-
cal/physical properties, such as charge-transfer and metal
(Li+/Mg2+) sensor as well as applications as a radical ini-
tiator for atom-transfer radical polymerization (ATRP).6
To our knowledge, however, there is no precedent for di-
rect catalytic synthesis of isoquinoline-N-oxides and most
of their preparation is still conducted by oxidation of par-
ent nitrogen heterocycles, which suffers from poor atom-
economy and/or generality and often are not environmen-
tally friendly.7
O– –O
Ph
Ph
Figure 1 Isoquinoline oxides and related chiral scaffold for asym-
metric allylation of aldehyde
As a part of our ongoing projects on the reactions of sub-
strates having N–O bond in electrophilic metal catalysis,8
Table 1 Cyclization of 1a (R = Ph)a
Entry Catalyst
Conditionsb
Yieldc
(conv.d)
1
2
AuPPh3OTf
70 °C, 12 h
70 °C, 4 h
70 °C, 1 h
r.t., 1.5 h
r.t., 5 h
(>95%)
Au[t-Bu2P(o-biph)]OTf
Au(t-Bu3P)OTf
Au[P(C6F5)3]OTf
Au(IPr)Otf
Au(IMes)OTf
In(OTf)3
83% (>95%)
(>95%)
3
4
(>95%)
5
(>95%)
6
r.t., 0.5 h
70 °C, 2.5 h
70 °C, 24 h
r.t., 12 h
96% (>99%)
(85%)
7
8
Zn(OTf)2
(>95%)
9
Cu(OTf)2
NRe (52%)
NRe (47%)
85% (>95%)
80% (>95%)
83% (>95%)
OH
O–
N
catalyst
N
10
9
CuI
r.t., 12 h
R
AgOTf
r.t., 0.5 h
r.t., 0.5 h
r.t., 0.5 h
R
1
2
10
11
AgSbF6
Scheme 1 Catalytic cycloisomerization into isoquinoline-N-oxides
AgNTf2
a In CH2Cl2 (0.1 M) with 5 mol% of catalyst unless otherwise noted.
b Time required for full consumption of 1a was indicated; reactions at
70 °C were conducted in a sealed tube.
c Isolated yield after chromatography.
SYNLETT 2008, No. 6, pp 0924–0928
Advanced online publication: 11.03.2008
DOI: 10.1055/s-2008-1042936; Art ID: U12607ST
x
x.
x
x.
2
0
0
8
d Conversions are based on the crude 1H NMR spectra.
e No reaction; an unidentified side product was observed.
© Georg Thieme Verlag Stuttgart · New York

LETTER
Direct Route to Isoquinoline-N-Oxides
925
we envisaged a direct formation of isoquinoline N-oxides temperature and it took 12 hours at 70 °C for a complete
from o-alkynylbenzaldoximes would be possible via an conversion into 2a (entry 1). There was a strong ligand de-
appropriate electrophilic metal-catalyzed cyclization pendency in Au(I)-catalyzed cyclization (entries 1–6,
(Scheme 1).9,10 Herein, we report examination of various Table 1) and Au(IMes)Cl/AgOTf turned out to be the
conditions using electrophilic metals and development of most efficient, delivering 2a in 30 minutes at room tem-
a direct silver(I)-catalyzed route to isoquinoline-N-ox- perature in a quantitative conversion (entry 6). We also
ides. The current protocol is significantly more efficient looked at other electrophilic metals and group 11 metals.
than conventional basic or thermal condition in terms of With In(OTf)3 and Zn(OTf)2, the reaction was much slow-
the yield and mildness of reaction conditions.11 It is of er than Au(I) complexes, requiring higher temperature
note that the current protocol is highly regio- (6-endo-dig) (entries 7 and 8). The Cu(II) and Cu(I) salts did not turn
and chemoselective (N- vs. O-nucleophile) so that its out effective at room temperature, producing byproducts
scope nicely complements Pictet–Spengler or Bischler– (entries 9 and 10). Among Ag(I) salts (entries 11–13) ex-
Napieralski reactions for the synthesis of related heterocy- amined, AgOTf (5 mol%)9l turned out to be as effective as
cles.
Au(IMes)Cl/AgOTf under similar conditions: The cy-
clization was slightly faster than Au(I), although the iso-
lated yield was somewhat lower (entry 9). Considering the
benefit of cost effectiveness, we took AgOTf (entry 9)
along with Au(IMes)OTf (entry 6) as our optimized con-
dition.12
We set out our study by examination of various catalysts
for the current reaction using 1a (R = Ph) as substrate
(Table 1). We first looked at various cationic Au(I) com-
plexes. Use of Au(PPh3)Cl (5 mol%) in combination with
equimolar AgOTf resulted in a sluggish reaction at room
Table 2 Scope of the Cyclization into Isoquinoline-N-oxides14
Entry
Substrate (R)
Product
Conditionsa (temp, time)
Yield (%)b
O–
Ph
O–
N
N
Ph
1a
A (r.t., 0.5 h)
B (r.t., 0.5 h)
96
85
1
2a
3-MeO2CC6H4
1b
A (r.t., 1 h)
B (r.t., 2 h)
95
95
2
3
MeO2C
N
2b
2c
2c
O–
3-MeO2C6H4
1c
A (r.t., 1.5 h)
B (r.t., 0.5 h)
83
84
MeO
N
O–
3-O2NC6H4
1d
A (70 °C, 72 h)
B (70 °C, 16 h)
21
80
4
O2N
N
O–
Biphen-4-yl
1e
5
6
B (r.t., 2.5 h)
85
Ph
2d
2f
O–
N
Thien-2-yl
1f
A (r.t., 5 h)
B (r.t., 1 h)
64
75
S
Synlett 2008, No. 6, 924–928 © Thieme Stuttgart · New York

926
H.-S. Yeom et al.
LETTER
Table 2 Scope of the Cyclization into Isoquinoline-N-oxides14 (continued)
Entry
7
Substrate (R)
Product
Conditionsa (temp, time)
Yield (%)b
O–
N
Cyclohexen-1-yl
1g
A (70 °C, 5 h)
B (r.t., 0.5 h)
91
89
2g
2h
2i
O–
N
n-Bu
1h
A (r.t., 0.5 h)
B (r.t., 0.5 h)
92
97
8
n-Bu
O–
N
N
N
H
1i
A (r.t., 1 h)
B (r.t., 0.5 h)
94
97
9
O–
CH2OPiv
1j
A (70 °C, 12 h)
B (r.t., 1 h)
83
86
10
11
OPiv
2j
O–
CH2OTHP
1k
A (70 °C, 12 h)
B (r.t., 0.5 h)
53c
70
OTHP
2k
a Method A: Au(IMes)OTf (5 mol%) in CH2Cl2, Method B: AgOTf (5 mol%) in CH2Cl2.
b Isolated yield (%) after chromatography.
c THP-Deprotected alcohol (26%) was obtained along with 2k.
With the optimization conditions above, a variety of sub- is demonstrated in Scheme 2.4,13 Isoquinoline-N-oxides
strates having aryl and alkyl R substituents were convert- 2a, 2c, and 2h underwent smooth conversion into the re-
ed into the respective isoquinoline N-oxides in an efficient spective 1-cyanoisoquinolines in generally good yields by
manner (Table 2). For example, 1b–d, with different treatment with TMSCN and DBU as base.
ortho-substituted aryl groups, underwent smooth conver-
CN
sion into isoquinoline-N-oxides 2b–d (entries 2–4). Bi-
phenyl, heteroaryl, and alkyl R groups were also well
accommodated in the current reaction (entries 5–11). For
substrate 1j, a potentially competing [3,3]- or [2,3]-sigma-
tropic rearrangement of propargyl pivalate was effectively
suppressed, delivering 2j uneventfully. In general, both
Au(I)- and Ag(I)-based catalysts performed similarly and
Ag(I) catalyst shows better catalytic activity than Au(I)
system when functional group compatibility becomes an
issue (entry 4, 6, and 11). One problem of electrophilic
metal catalysis could be functional group compatibility
with acid-labile protecting group. A substrate with an
acid-sensitive THP protecting group (1k, entry 11) under
Au(I) catalysis (method A) led to 53% of 2k with the for-
mation of 26% of the corresponding alcohol. In contrast,
the same substrate under Ag(I) catalysis (method B) led to
70% isolated yield of 2k with only a trace amount of hy-
drolyzed byproduct, indicating a better functional-group
compatibility of Ag(I) catalyst as compared to the Au(I)-
based catalyst.
O–
TMSCN (1.1 equiv)
DBU (1.5 equiv)
N
N
r.t., 12 h
R
R
2a, R = Ph
3a, 69%
3c, 67%
3c, 84%
2c, R = 2-MeOC6H4
2h, R = n-Bu
Scheme 2
In summary, we report herein direct formation of isoquin-
oline-N-oxides from o-alkynylarylaldoximes under Au(I)
and Ag(I) catalysis. The advantage of an Ag(I)-based sys-
tem is demonstrated in substrates where coordinating at-
oms or acid-labile groups are involved. Future study in
this laboratory will focus on the generation of chiral
ligands based on the isoquinoline-N-oxides utilizing the
current approach.
Acknowledgment
The thus-prepared isoquinoline-N-oxides allow for vari-
ous subsequent transformations and one such opportunity
This work was supported by the research fund of Hanyang Univer-
sity (HY-2006-I). H.-S.Y. thanks the BK21 program for the finan-
cial support.
Synlett 2008, No. 6, 924–928 © Thieme Stuttgart · New York

LETTER
Direct Route to Isoquinoline-N-Oxides
927
(10) For metal-catalyzed tandem cyclization–addition of 2-
References and Notes
alkynyl benzaldimines, see for Ag: (a) Ding, Q.; Ye, Y.;
Fan, R.; Wu, J. J. Org. Chem. 2007, 72, 5439. (b) Asao, N.;
Yudha, S.; Nogami, T.; Yamamoto, Y. Angew. Chem. Int.
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Chem. 2007, 72, 8611. For In: (d) Yanada, R.; Obika, S.;
Kono, H.; Takemoto, Y. Angew. Chem. Int. Ed. 2006, 45,
3822. Without catalyst: (e) Asao, N.; Iso, K.; Yudha, S. S.
Org. Lett. 2006, 8, 4149. Organocatalyzed: (f) Ding, Q.;
Wu, J. Org. Lett. 2007, 9, 4959.
(1) (a) Larock, R. C. In Acetylene Chemistry; Diederich, F.;
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Jones, K.; White, T. D. Org. Lett. 2006, 8, 1929.
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(a) Sakamoto, T.; Numata, A.; Kondo, Y. Chem. Pharm.
Bull. 2000, 48, 669. (b) Sakamoto, T.; Kondo, Y.; Miura,
N.; Hayashi, K.; Yamanaka, H. Heterocycles 1986, 24,
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Choshi, T.; Nobuhiro, J.; Hibino, S. J. Org. Chem. 2001, 66,
8793.
(12) One of the referees suggested the possibility of TfOH
(generated by hydrolysis of metal triflates) acting as acid
catalyst. When 1a was treated with 10% of TfOH in CH2Cl2,
a slow decomposition was observed but none of the
isoquinoline-N-oxide was observed in this case.
(c) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2002, 4, 3127.
Rearrangement into isoquinolone: (d) Robison, M. M.;
Robison, B. L. J. Org. Chem. 1957, 21, 1337. 1,3-Dipolar
cycloaddition: (e) Zhao, B.-X.; Eguchi, S. J. Chem. Soc.,
Perkin Trans. 1 1997, 2973. Ni-Catalyzed alkenylation:
(f) Kanyiva, K. S.; Nakao, Y.; Hiyama, T. Angew. Chem. Int.
Ed. 2007, 46, 8872.
(13) Miyashita, A.; Kawashima, T.; Iijima, C.; Higashino, T.
Heterocycles 1992, 33, 211.
(14) Representative Preparatory Procedure for Isoquinoline
N-oxide 2a (Method B)
To a solution of oxime 1a (20 mg, 0.090 mmol) in CH2Cl2 (1
mL) was added AgOTf (1.2 mg, 0.0045 mmol) and the
mixture was stirred at r.t. for 30 min. The solvent was
removed and the residue was purified by silica gel
chromatography (CH2Cl2–MeOH, 10:1) to give 17.0 mg
(85%) of 2a as a white solid (method A). To a mixture of
Au(IMes)Cl (5 mol%) and AgOTf (5 mol%) in CH2Cl2 (ca.
0.1 M) at r.t. was added substrate. Otherwise, a similar
procedure to method B was followed.
(5) (a) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S.-I. J.
Am. Chem. Soc. 1998, 120, 6419. (b) Shimada, T.; Kina, A.;
Ikeda, S.; Hayashi, T. Org. Lett. 2002, 4, 2799. (c) Malkov,
A. V.; Orsini, M.; Pernazza, D.; Muir, K. W.; Langer, V.;
Meghani, P.; Kočovský, P. Org. Lett. 2002, 4, 1047.
(d) Malkov, A. V.; Dufková, L.; Farrugia, L.; Kočovský, P.
Angew. Chem. Int. Ed. 2003, 42, 3674. (e) Hrdina, R.;
Valterová, I.; Hodačová, J.; Císařová, I.; Kotora, M. Adv.
Synth. Catal. 2007, 349, 822.
(6) (a) Collado, D.; Perez-Inestrosa, E.; Suau, R. J. Org. Chem.
2003, 68, 3574. (b) Collado, D.; Perez-Inestrosa, E.; Suau,
R.; Desvergne, J.-P.; Bouas-Laurent, H. Org. Lett. 2002, 4,
855. (c) Collado, D.; Perez-Inestrosa, E.; Suau, R.;
Navarrete, J. T. L. Tetrahedron 2006, 62, 2927.
Compound 2a: 1H NMR (400 MHz, CDCl3): d = 8.91 (s, 1
H), 7.93–7.76 (m, 4 H), 7.76–7.67 (m, 1 H), 7.67–7.54 (m, 2
H), 7.54–7.38 (m, 3 H). 13C NMR (100 MHz, CDCl3): d =
147.8, 137.7, 133.5, 130.4, 130.1, 129.9, 129.74, 129.70,
129.5, 128.9, 127.3, 125.5, 125.1. HRMS: m/z calcd for
C30H22N2O2Na [2 M + Na]: 465.1573; found: 465.1546.
Compound 2d: 1H NMR (400 MHz, CDCl3): d = 8.83 (s, 1
H), 8.18 (d, J = 8.2 Hz, 1 H), 7.90–7.82 (m, 2 H), 7.82–7.73
(d) Durmaz, Y. Y.; Yilmaz, G.; Yagci, Y. J. Polym. Sci.,
Part A.: Polym. Chem. 2007, 45, 423.
(m, 2 H), 7.71–7.60 (m, 3 H), 7.54 (d, J = 7.3 Hz, 1 H). 13
NMR (100 MHz, CDCl3): d = 149.9, 145.9, 137.0, 134.2,
132.9, 131.2, 130.2, 129.8, 129.7, 128.6, 127.5, 125.5,
C
(7) For catalytic oxidation of isoquinolines using H2O2 as
stoichiometric oxidant, see: (a) Copéret, C.; Adolfsson, H.;
Chiang, J. P.; Yudin, A. K.; Sharpless, K. J. Org. Chem.
1998, 63, 1740. (b) Prasad, M. R.; Kamalakar, G.; Madhavi,
G.; Kulkarni, S. J.; Raghavan, K. V. Chem. Commun. 2000,
1577.
125.0, 124.4. HRMS: m/z calcd for C30H20N2O6Na [2 M +
Na]: 555.1275; found: 555.1280.
Compound 2g: 1H NMR (400 MHz, CDCl3): d = 8.77 (s, 1
H), 7.80–7.64 (m, 2 H), 7.60 (s, 1 H), 7.58–7.48 (m, 2 H),
6.09 (m, 1 H), 2.75–2.43 (m, 2 H), 2.40–2.18 (m, 2 H), 1.94–
1.62 (m, 4 H). 13C NMR (100 MHz, CDCl3): d = 151.0,
137.2, 134.7, 131.8, 130.0, 129.3, 129.2, 129.1, 127.0,
125.0, 123.7, 27.2, 26.2, 22.9, 22.4. HRMS: m/z calcd for
C30H30N2O2Na [2 M + Na]: 473.2199; found: 473.2180.
Compound 2k: 1H NMR (400 MHz, CDCl3): d = 8.82 (s, 1
H), 7.93 (s, 1 H), 7.88–7.78 (m, 1 H), 7.78–7.66 (m, 1 H),
7.66–7.52 (m, 2 H), 5.15 (d of AB, J = 16.5 Hz, 1 H), 4.92
(d of AB, J = 16.5 Hz, 1 H), 4.878 (t, J = 3.5 Hz, 1 H), 4.02–
(8) Yeom, H.-S.; Lee, E.-S.; Shin, S. Synlett 2007, 2292.
(9) For metal-catalyzed approaches to other isoquinoline
derivatives, see (selected examples) for Pd: (a) Ban, Y.;
Wakamatsu, T.; Mori, M. Heterocycles 1977, 6, 1711.
(b) Tietze, L. F.; Schimpf, R. Angew. Chem., Int. Ed. Engl.
1994, 33, 1089. (c) Larock, R. C.; Yum, E. K.; Doty, M. J.;
Shan, K. K. C. J. Org. Chem. 1995, 60, 3270. (d) Roesch,
K. R.; Larock, R. C. J. Org. Chem. 1998, 63, 5306.
(e) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 1553.
(f) Dai, G.; Larock, R. C. Org. Lett. 2001, 3, 4035.
(g) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 553.
(h) Wei, L.-M.; Lin, C.-F.; Wu, M.-J. Tetrahedron Lett.
2000, 41, 1215. (i) Roesch, K. R.; Larock, R. C. J. Org.
Chem. 2002, 67, 86. (j) Cho, C. S.; Patel, D. B. J. Mol.
Catal. A: Chem. 2006, 260, 105. (k) Oikawa, M.; Takeda,
Y.; Naito, S.; Hashizume, D.; Koshino, H.; Sasaki, M.
Tetrahedron Lett. 2007, 48, 4255. For Ag: (l) Huang, Q.;
Hunter, J. A.; Larock, R. C. Org. Lett. 2001, 3, 2973. For
Au: (m) Youn, S. W. J. Org. Chem. 2006, 71, 2521.
3.82 (m, 1 H), 3.48–3.70 (m, 1 H), 2.10–1.50 (m, 6 H). 13
C
NMR (100 MHz, CDCl3): d = 146.7, 136.9, 129.8, 129.5,
129.3, 129.0, 127.3, 125.3, 121.6, 99.8, 64.1, 63.3, 31.2,
26.0, 20.3. HRMS: m/z calcd for C30H34N2O6Na [2 M + Na]:
541.2309; found: 541.2309.
General Experimental Procedure for Cyanation of 2h
into 3h
To a solution of 2h (19 mg, 0.094 mmol) in THF (1 mL) at
Synlett 2008, No. 6, 924–928 © Thieme Stuttgart · New York

928
H.-S. Yeom et al.
LETTER
r.t. was added DBU (21 mL, 0.142 mmol) and TMSCN (14
mL, 0.104 mmol), and the mixture was stirred at r.t.
overnight. The mixture was directly loaded onto a silica gel
column and eluted with EtOAc–hexane (1:10) to give 16.7
mg (84%) of 1-cyano-3-n-butyl-isoquinoline (3h) as a
yellow solid.
J = 8.0 Hz, 1 H), 7.94–7.82 (d, J = 8.0 Hz, 1 H), 7.82–7.65
(m, 3 H), 2.98 (t, J = 7.3 Hz, 2 H), 1.80 (quin, J = 7.3 Hz, 2
H), 1.42 (sext, J = 7.3 Hz, 2 H), 0.97 (t, J = 7.3 Hz, 3 H). 13
NMR (100 MHz, CDCl3): d = 157.6, 137.3, 134.8, 132.1,
129.4, 128.5, 127.5, 125.8, 122.9, 116.7, 38.1, 32.6, 23.0,
14.5.
C
Compound 3h: 1H NMR (400 MHz, CDCl3): d = 8.38 (d,
Synlett 2008, No. 6, 924–928 © Thieme Stuttgart · New York