Synthesis of isoquinolinium-2-yl amides via silver(I)-catalyzed ring closure of N′-(2-alkynylbenzylidene)hydrazides

Article abstract of DOI:10.1055/s-0030-1260219

An efficient one-pot protocol for the synthesis of isoquinolinium-2-yl amides starting from readily available hydrazides and 2-alkynylbenzaldehydes is described. The key step of the protocol is a silver(I)-catalyzed ring-closure of N-(2-alkynylbenzylidene)hydrazides that are generated in situ. Isoquinolinium-2-yl amides derived from tert-butoxycarbonyl hydrazide could be further deprotected, delivering 2-aminoisoquinolinium trifluoroacetates. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260219

PAPER
3371
Synthesis of Isoquinolinium-2-yl Amides via Silver(I)-Catalyzed Ring Closure
of N¢-(2-Alkynylbenzylidene)hydrazides
S
ilver(I)-Catalyzed
s
Synthesi
e
s
of Isoquin
v
olinium-2-y
o
l
A
mides lod A. Peshkov, Olga P. Pereshivko, Sofie Van Hove, Denis S. Ermolat’ev,* Erik V. Van der Eycken*
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, Katholieke Universiteit Leuven,
Celestijnenlaan 200F, 3001 Leuven, Belgium
Fax +32(16)327990; E-mail: denis.ermolatev@chem.kuleuven.be; E-mail: erik.vandereycken@chem.kuleuven.be
Received 26 June 2011; revised 21 July 2011
that provides general access to isoquinolinium-2-yl
Abstract: An efficient one-pot protocol for the synthesis of iso-
amides of type 10.
quinolinium-2-yl amides starting from readily available hydrazides
and 2-alkynylbenzaldehydes is described. The key step of the pro-
tocol is a silver(I)-catalyzed ring-closure of N¢-(2-alkynylben-
zylidene)hydrazides that are generated in situ. Isoquinolinium-2-yl
Initially, we prepared N¢-(2-alkynylbenzylidene)hy-
drazide 8a via reaction between 2-(phenylethynyl)benzal-
dehyde (11a) and tert-butoxycarbonyl hydrazide (12a;
amides derived from tert-butoxycarbonyl hydrazide could be fur-
ther deprotected, delivering 2-aminoisoquinolinium trifluoroace-
tates.
R3
R1
N
- cleaved bond
- forming bonds
Key words: alkynes, hydrazides, isoquinolines, annulation, ylides,
silver catalysis
R2
E+ (or LA)
1
In recent years, a cluster of reports devoted to the synthe-
sis of various isoquinoline derivatives involving 6-endo-
dig ring-closure of alkynylimines 1 have appeared in the
literature (Scheme 1). The pioneering work of Larock and
co-workers describes efficient protocols involving Lewis
acid catalysts (AgI, CuI, Pd0, PdII) or electrophilic reagents
(I2, ICl, PhSeCl, ArSCl) that cyclize N-tert-butyl-2-alky-
nylaryl aldimines 2 into isoquinolines 3.1 One C–N bond
or C–N and C–E (E = I, Br, SPh etc.) bonds are efficiently
formed in these processes, however, this is accompanied
by the cleavage of another C–N bond with concomitant
liberation of isobutene.2 In contrast, Lewis acid-catalyzed
tandem reactions involving external nucleophiles deliver
1,2-dihydroisoquinolines 4 without cleavage of any group
(Scheme 1).3
N
N
I2, NaOCO2Me
+
Ph
MeCN, r.t., 0.5 h
I
Ph
2
3
NO2
Ph
N
AgOTf
(3 mol%)
Ph
Ph
NO2
+
N
DCE
80 °C, 6 h
Ph
4
Scheme 1
OH
AgOTf
(5 mol%)
R1
O
N
R1
N
Other examples of atom-economical processes are the
Lewis acid catalyzed4 or electrophile-mediated5 cycliza-
tion of 2-alkynylbenzaldoximes 5 into isoquinoline 2-ox-
ides 6 and 7, respectively (Scheme 2). The electrophile-
mediated6 cyclization of N¢-(2-alkynylbenzylidene)hy-
drazides 8 into isoquinolinium-2-yl amides 9 is also well-
established (Scheme 2). However, a general protocol for
the preparation of isoquinolinium-2-yl amides 10 via
Lewis acid-catalyzed cyclization of N¢-(2-alkynylben-
zylidene)hydrazides is not described in the literature, al-
though a great number of efficient one-pot/tandem
procedures are reported in which compounds of type 6, 7,
9, or 10 are generated in situ and used as highly reactive
intermediates.7–9 In order to fill this gap, we herein de-
scribe an optimized protocol for the silver(I)-catalyzed
ring-closure of N¢-(2-alkynylbenzylidene)hydrazides 8
CH2Cl2, r.t.
R2
R2
6
5
O
R1
N
Br2
5
R2
CH2Cl2, r.t.
Br
7
H
N
N
N
R3
R1
N
R3
R1
I2
R2
CH2Cl2, r.t.
R2
I
9
8
N
AgI cat.
R1
N
R3
8
R2
focus of this work
10
SYNTHESIS 2011, No. 20, pp 3371–3374
x
x.
x
x
.
2
0
1
1
Advanced online publication: 08.09.2011
DOI: 10.1055/s-0030-1260219; Art ID: Z64411SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

3372
V. A. Peshkov et al.
PAPER
Scheme 3). This reaction proceeds efficiently within five ated that delivered the desired isoquinolinium-2-yl amide
hours in acetonitrile at 80 °C, delivering 8a in 92% yield. 10a in good yields. The best result was obtained with sil-
ver triflate (Table 1, entry 2); copper(II) triflate was found
to be less efficient (Table 1, entry 5).
We then performed a catalyst screening for the cyclization
of N¢-(2-alkynylbenzylidene)hydrazide 8a into isoquino-
linium-2-yl amide 10a. Several silver(I) salts were evalu- With these preliminary results in hand, we evaluated the
possibility of performing the formation and subsequent
cyclization of N¢-(2-alkynylbenzylidene)hydrazide 8a in a
one-pot fashion. Gratifyingly, by applying a one-pot pro-
H
N
O
NH2NHBoc (12a)
N
Boc
tocol, the target isoquinolinium-2-yl amide 10a was ob-
tained in a good overall yield of 62% (Table 2, entry 1).
We then investigated the scope of the one-pot procedure
by employing various hydrazides 12 (Table 2).10 To our
satisfaction, all reactions worked well and provided the
target isoquinolinium-2-yl amides 10a–j in good to excel-
lent yields. The lower yields in the reactions with tert-bu-
toxycarbonyl hydrazide (12a) could probably be ascribed
to the less electron-withdrawing character of the Boc
group, implying that the negative charge in the formed
isoquinolinium-2-yl amides 10a, 10i, and 10j is less stabi-
lized (Table 2, entries 1, 9, and 10).
MeCN, 80 °C
5 h, 92%
Ph
Ph
11a
8a
Scheme 3
Table 1 Catalyst Screening for the Ring Closure of N¢-(2-Alkynyl-
benzylidene)hydrazide 8a into Isoquinolinium-2-yl Amide 10a
H
catalyst
N
N
(10 mol%)
N
Boc
N
Boc
MeCN
80 °C, 3 h
Ph
Ph
10a
8a
Finally, we attempted Boc-deprotection of the isoquino-
linium-2-yl amides 10a, 10i, and 10j. By treatment with
trifluoroacetic acid (TFA) in dichloromethane (1:2) at
room temperature for three hours, the 2-aminoisoquino-
linium trifluoroacetates 13a–c were obtained in good
yields (Table 3).11
Entry
Catalyst (10 mol%)
AgOOCCF3
AgOTf
Yield (%)a
1
2
3
4
5
74
80
AgSbF6
77
In conclusion, we have elaborated a protocol for the
synthesis of isoquinolinium-2-yl amides via silver(I)-cat-
alyzed ring-closure of N¢-(2-alkynylbenzylidene)hy-
drazides. The current report is the first focused study of
this transformation, which was previously described only
AgNO3
74
Cu(OTf)2
17 (70)b
a Isolated yield.
b Yield of recovered 8a given in parenthesis.
Table 2 One-Pot Synthesis of Isoquinolinium-2-yl Amides 10
H
R1
AgOTf
(10 mol%)
R1
N
R1
N
NH2NHR3 (12)
N
R3
O
N
R3
MeCN
conditions
MeCN
80 °C, 1.5–3 h
R2
R2
R2
11
8
R2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
10
Entry
11
R1
H
H
H
H
H
F
12
R3
Conditionsa
Product
10a
10b
10c
Yield (%)b
1
2
11a
11a
11a
11a
11a
11b
11b
11b
11c
11a
12a
12b
12c
12d
12e
12d
12e
12f
12a
12a
Boc
Ac
A
A
A
A
B
C
B
B
A
A
62
80
70
76
99
89
97
80
70
53
3
formyl
COBn
Ts
4
10d
10e
5
6
COBn
Ts
10f
7
F
10g
10h
10i
8
F
p-Tol
Boc
Boc
9
H
H
3-thienyl
Bu
10
10j
a Conditions A: 80 °C, 3–5 h; B: 80 °C, 15 min; C: 100 °C, 5 h.
b Isolated yield based on 11.
Synthesis 2011, No. 20, 3371–3374 © Thieme Stuttgart · New York

PAPER
Silver(I)-Catalyzed Synthesis of Isoquinolinium-2-yl Amides
3373
1H NMR (300 MHz, CDCl3): d = 10.38 (s, 1 H), 8.37–8.26 (m, 1 H),
8.05–7.94 (m, 3 H), 7.92–7.80 (m, 1 H), 7.71–7.54 (m, 5 H).
Table 3 Boc-Deprotection of Isoquinolinium-2-yl Amides 10a, 10i,
and 10j to 2-Aminoisoquinolinium Trifluoroacetates 13a–c
13C NMR (75 MHz, CDCl3): d = 142.43, 142.39, 135.2, 134.9,
CF3COO
131.3, 131.1, 129.9, 129.53, 129.49, 129.3, 127.4, 126.8, 126.7.
CH2Cl2–TFA
NH2
R2
N
(2:1)
N
MS (ESI): m/z = 221.7 [C15H13N2]+.
N
Boc
r.t., 3 h
R2
10
13
Product
13a
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are spectral data for all compounds and copies of NMR spectra.
Entry
10
R2
Yield (%)a
1
2
3
10a
10i
10j
Ph
52
57
49
Acknowledgment
3-thienyl
Bu
13b
Support was provided by the Fund for Scientific Research (FWO),
Flanders, and by the Research Fund of the Katholieke Universiteit
Leuven. P.V.A. is grateful to the EMECW (Triple I) for obtaining a
doctoral scholarship.
13c
a Isolated yield.
as part of a complex one-pot/tandem process. A signifi-
cant expansion of the hydrazide substrate scope has been
achieved.
References
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1H and 13C NMR spectra were recorded with Bruker Avance 300 in-
struments. The 1H and 13C chemical shifts are reported in parts per
million (ppm) relative to TMS using the residual solvent signal as
the internal reference. Mass spectra were recorded with a Thermo
Finnigan LCQ Advantage apparatus (ESI).
One-Pot Synthesis of Isoquinolinium-2-yl Amides 10; Typical
Procedure
2-(Phenylethynyl)benzaldehyde (11a; 206 mg, 1 mmol) and tert-
butoxycarbonyl hydrazide (12a; 145 mg, 1.1 mmol) were dissolved
in anhydrous MeCN (3.5 mL). The reaction mixture was heated at
80 °C for 5 h in a glass tube with a screw-cap. AgOTf (26 mg, 0.1
mmol) was added and the reaction mixture was degassed and
flushed with argon. After heating at 80 °C for 3 h, the reaction mix-
ture was directly loaded onto a silica gel column and purified by
column chromatography (EtOAc–MeOH, 9:1), to provide iso-
quinolinium-2-yl amide (10a).
tert-Butoxycarbonyl(3-phenylisoquinolinium-2-yl)amide (10a)
Yield: 199 mg (62%).
1H NMR (300 MHz, CDCl3): d = 9.37 (s, 1 H), 8.08–8.01 (m, 1 H),
7.98–7.90 (m, 2 H), 7.89–7.81 (m, 1 H), 7.80–7.71 (m, 1 H), 7.70–
7.63 (m, 2 H), 7.50–7.40 (m, 3 H), 1.38 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 163.9, 148.3, 148.0, 134.8, 133.5,
129.6, 129.5, 129.4, 128.1, 127.9, 127.5, 126.6, 125.8, 77.3, 28.8.
MS (ESI): m/z = 321.8 [M + H]+.
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Boc-Deprotection of Isoquinolinium-2-yl Amides 10 To Give 2-
Aminoisoquinolinium Trifluoroacetates 13; Typical Procedure
Isoquinolinium-2-yl amide (10a; 192 mg, 0.6 mmol) was dissolved
in CH2Cl2 (4 mL) and TFA (2 mL) was added. The reaction mixture
was stirred at r.t. for 3 h and then concentrated under reduced pres-
sure. The residue was diluted with CH2Cl2 and loaded onto a short
pad of silica for flash chromatography (EtOAc–MeOH, 4:1), pro-
viding 2-aminoisoquinolinium trifluoroacetate (13a).
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2-Amino-3-phenylisoquinolinium Trifluoroacetate (13a)
Yield: 104 mg (52%).
Synthesis 2011, No. 20, 3371–3374 © Thieme Stuttgart · New York

3374
V. A. Peshkov et al.
PAPER
(10) So far, only the application of tosyl hydrazide (12e) was
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Synthesis 2011, No. 20, 3371–3374 © Thieme Stuttgart · New York