Synthesis of furo[2,3-f]isoquinolines by aromatic Claisen rearrangement and subsequent cyclization

Article abstract of DOI:10.1055/s-2006-958954

Furo[2,3-f]isoquinolines were prepared by reacting isoquinolin-5-ol with an allyl bromide. Reaction between the sodium salt of isoquinolinol and and allyl bromide led to the formation of an allyloxyisoquinoline, which was thermally rearranged. The resulta

Full text of DOI:10.1055/s-2006-958954

284
PAPER
Synthesis of Furo[2,3-f]isoquinolines by Aromatic Claisen Rearrangement and
Subsequent Cyclization
S
ynthesisof Furo[2,3-
e
]isoquinoli
rnes cedes Törincsi, Pál Kolonits, Endre Pálosi, Lajos Novák *
Institute for Organic Chemistry, Budapest University of Technology and Economics, Research Group for Alkaloid Chemistry,
Hungarian Academy of Sciences, Gellért tér 4, 1111 Budapest, Hungary
Fax +36(1)4533297; E-mail: lnovak@mail.bme.hu
Received 26 July 2006; revised 9 October 2006
R3
Abstract: Furo[2,3-f]isoquinolines were prepared by reacting iso-
quinolin-5-ol with an allyl bromide. Reaction between the sodium
salt of isoquinolinol and and allyl bromide led to the formation of
an allyloxyisoquinoline, which was thermally rearranged. The re-
sultant allylisoquinoline was then subjected to acid-catalyzed cycli-
zation to afford the title compound.
OH
R2
R1
R1 R2
O
R4
a
b
+
R3
N
N
1
2
3
Br
Key words: furo[2,3-f]isoquinoline, allyl aryl ethers, Claisen rear-
rangement, ring closure, sonochemical conditions
R4
R3
R4
R3
R2
R1
OH
O
c
R2
Derivatives of furo[3,2-f]isoquinolines were recently
found to possess phosphodiesterase IV inhibitor activity.1
Some of them are considered to be anti-inflammatory and/
or anti-arteriosclerotic agents. The structural isomer fu-
ro[2,3-f]isoquinoline has not received as much attention –
only one synthetic method has so far been reported for the
preparation of highly substituted derivatives.2
R1
N
N
4
5
Scheme 1 Reagents and conditions: (a) NaH, DME, r.t.; (b) chloro-
benzene, reflux; or microwave oven, 120 °C; (e) H2SO4, 100 °C.
which then underwent a homo[1,5]-H shift to yield com-
pound 6. A [1,5]-H shift on compound 6 led to the forma-
tion of 4b. Acid-catalyzed intramolecular cyclization of
the latter furnished 5b (Table 1, entries 2, 6 and 11).
Our interest in the preparation of new heterocyclic com-
pounds which might be promising in the treatment of psy-
chiatric disorders prompted us to elaborate novel methods
for the synthesis of furo[2,3-f]isoquinoline derivatives.
We now report a method for the preparation of furoiso-
quinolines 5a,b and their cycloalkano analogues 5c,d.
The above type of abnormal Claisen rearrangement (3b →
4b) was first reported by Lauer and Filbert.6 The mecha-
nism of these reactions has been identified as the result of
consecutive processes: Claisen rearrangement followed
by 1,5-hydrogen shifts.7
For the preparation of compounds 5a–d we used the
Claisen rearrangement of allyl aryl ethers. This thermal
sigmatropic rearrangement is one of the most effective
methods in the construction of carbon–carbon bonds.3
From the microwave-assisted reaction of 3b we also iso-
lated the product of the [3,3]-sigmatropic rearrangement
(4c). The isolation of this intermediate supports the pro-
posed mechanism.
The syntheses of 5a–d are depicted in Scheme 1. Treat-
ment of isoquinolin-5-ol (1) with sodium hydride afforded
the corresponding anion which was then reacted with allyl
bromide 2a. The ether 3a4 formed was subjected to micro-
wave irradiation assisted [3,3] rearrangement to yield
compound 4a.5 Acid-catalyzed intramolecular cyclization
of the latter afforded furo[2,3-f]isoquinoline 5a (Table 1,
entries 1, 5 and 10).
Under similar conditions, the reaction between compound
1 and 3-bromocyclohex-2-enol (2c) gave the expected
ether 3c, which was then rearranged by heating in chlo-
robenzene. The reaction took place at 132 °C over 30
hours. The microwave-accelerated rearrangement reac-
tion worked at a temperature below 120 °C and needed
only five hours. Microwave heating was superior to con-
ventional external heating in this rearrangement reaction
(Table 1, entries 6 and 8).
Likewise, reaction between the sodium salt of 1 and meth-
allyl chloride afforded ether 3b. However, thermal rear-
rangement of the latter yielded an unexpected product 4b.
A plausible scheme for the formation of compound 4b
was based on the consecutive rearrangement reaction de-
picted in Scheme 2. In the initial step the [3,3]-sigmatrop-
ic rearrangement of ether 3b afforded intermediate 4c
Acid-catalyzed intramolecular cyclization of the isolated
4d yielded an approximately 1:1 mixture of stereoisomers
(5c). Small amounts of this mixture were separated by
preparative HPLC and the stereochemistry of isomers was
established by extensive 1H and 13C NMR studies. For ex-
ample, in the cis-fused isomer we saw an NOE interaction
between the 6b proton and the 10a proton (3.39 and 4.91,
SYNTHESIS 2007, No. 2, pp 0284–0288
x
x
.
x
x
.2
0
0
7
Advanced online publication: 21.12.2006
DOI: 10.1055/s-2006-958954; Art ID: T11606SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Furo[2,3-f]isoquinolines
285
Table 1 Compounds Prepared by the Rearrangement of 3a–d and Subsequent Cyclization
Entry
Substrate Product
R1
H
R2
R3
H
R4
H
H
H
H
H
H
Temp (°C)
Time (h)
Yielda (%)
1
2
3
4
5
6
2a
2b
2c
2d
3a
3b
3a
3b
3c
3d
4a
4b
H
r.t.
48
48
48
48
6
48
62
58
52
44
Me
H
Me
H
r.t.
(CH2)3
(CH2)4
H
r.t.
H
r.t.
H
H
H
120b
Me
Me
132c
120b
30
6
74
72
7
8
3b
3c
4c
H
H
Me
H
Me
H
120b
6
Trace amounts
4d
(CH2)3
132c
120b
30
6
64
70
9
10
11
12
13
3d
4a
4b
4d
4e
4e
5a
5b
5c
5d
H
(CH2)4
H
H
120b
100
100
100
100
6
1
1
1
1
42
45
87
82
52
H
H
H
H
Me
H
H
Me
H
(CH2)3
(CH2)4
H
H
a Isolated and unoptimized yields.
b Method B (in microwave oven).
c Method A (in chlorobenzene).
Solvents were used as received from commercial vendors and no
further attempts were made to purify or dry them. Melting points
were determined on a Büchi apparatus and are uncorrected. H
H
O
1
[3,3]
homo-[1,5]-H
3b
NMR and 13C NMR spectra were obtained on a Bruker DRX-500
spectrometer operating at 500 MHz and 125 MHz, respectively. All
NMR spectra are reported in ppm relative to TMS. Merck precoated
silica gel 60 F254 plates were used for TLC and Kieselgel 60 for col-
umn chromatography. Solvents were mixed on a v/v basis. HPLC
chromatographic analyses and separations were performed with a
Waters 600 equipped with a photodiode array detector 990. The sta-
tionary phase for compound 5c was SupelcosilTM SPLC-18-DB,
250 × 10 mm. For compound 5d the stationary phase was Waters
Symmetry C18, 150 × 3.9 mm. For the separation of the isomers of
5c we used a SupelcosilTM PLC-18 column, 250 × 21.2 mm, eluents
MeOH–H2O, 7:3. Microwave-accelerated reactions were conducted
in an CEM Focused MicrowaveTM synthesis System (CEM Corpo-
ration, Metthews, NC, USA).
N
6
H
H2C
O
[1,5]-H
4b
N
7
Scheme 2
respectively). This coupling was absent in the case of the
corresponding trans-isomer.
3-Bromocyclohex-1-ene (2c)9 and 3-bromocyclohept-1-ene (2d)10
were prepared using literature procedures.
The reaction between 1 and 3-bromocyclohept-1-ene (2d)
gave similar results (Table 1, entries 4, 9 and 13). The ini-
tially formed ether 3d was irradiated with microwaves and
the rearrangement product 4e was submitted to acid-cata-
lyzed cyclization. An approximately 3:1 mixture of ste-
reoisomers 5d was isolated and the isomers were
separated by preparative HPLC.
Preparation of Ethers 3; General Procedure
To a cold stirred suspension of NaH (10 mmol, 63.7% in mineral
oil) in DME (40 mL) a soln of isoquinolin-5-ol (1: 1.16 g, 8 mmol)
in DME (150 mL) was added dropwise and the resulting mixture
was stirred at 0 °C for 2 h. To this mixture was added dropwise the
appropriate bromine (2: 10 mmol) and stirring was continued at r.t.
for 48 h. The reaction mixture was quenched with sat. aq NaCl (150
mL) and extracted with EtOAc (3 × 100 mL). The combined organ-
ic layers were washed with 1N NaOH soln and H2O and then dried
over MgSO4. Evaporation of the solvent under reduced pressure
provided a residue which was purified by column chromatography
on silica gel (acetone–CH2Cl2, 4:1).
In summary, furo[2,3-f]isoquinoline derivatives 5a–d
have been prepared from isoquinolin-5-ol (1) and allyl
bromides 2a–d. This convenient process involves the re-
arrangement reaction of ethers 3a–d, followed by acid-
catalyzed cyclization of the products 4a–d.8 The present
synthetic scheme would enable access to a variety of furo-
isoquinolines, which would have interesting biological
properties.
Synthesis 2007, No. 2, 284–288 © Thieme Stuttgart · New York

286
M. Törincsi et al.
PAPER
5-Allyloxyisoquinoline (3a)
Yield: 48%; light brown oil; Rf = 0.62 (CH2Cl2–acetone, 2:1).
Method B: Ether 3 (10 mmol) was heated at 120 °C for 6 h in a mi-
crowave oven. After cooling, the reaction mixture was dissolved in
a mixture of CH2Cl2–acetone (5:1) and purified by column chroma-
tography (CH2Cl2–acetone, 5:1).
1H NMR (CDCl3): d = 4.71 (d, J = 4.0 Hz, 2 H, O-CH2), 5.35 (dd,
J = 10.5, 1.2 Hz, 1 H, H-3¢), 5.52 (dd, J = 17.5, 1.3 Hz, 1 H, H-3¢),
6.16 (m, 1 H, H-2¢), 6.98 (d, J = 7.6 Hz, 1 H, H-6), 7.47 (t, J = 8 Hz,
1 H, H-7), 7.53 (d, J = 8.2 Hz, 1 H, H-8), 8.05 (d, J = 6.0 Hz, 1 H,
H-4), 8.53 (d, J = 6.0 Hz, 1 H, H-3), 9.20 (s, 1 H, H-1).
13C NMR (CDCl3): d = 69.07 (C-1¢), 108.83 (C-6), 115.10 (C-4),
117.86 (C-3¢), 119.46 (C-8), 127.31 (C-7), 128.59 (C-4a), 129.49
(C-8a), 132.73 (C-2¢), 142.67 (C-3), 151.82 (C-1), 153.33 (C-5).
6-Allylisoquinolin-5-ol (4a)
Method B: Yield: 44%; yellow crystals; mp 108–112 °C; Rf = 0.4
(CH2Cl2–acetone, 2:1).
1H NMR (CDCl3): d = 3.69 (d, J = 6.3 Hz, 2 H, H-1¢), 5.15 (d,
J = 6.3 Hz, 2 H, H-3¢), 5.17 (m, 1 H, H-3¢), 6.05 (m, 1 H, H-2¢), 7.41
(d, J = 8.4 Hz, 1 H, H-7), 7.52 (d, J = 8.4 Hz, 1 H, H-8), 8.14 (d,
J = 6.0 Hz, 1 H, H-4), 8.42 (d, J = 6.0 Hz, 1 H, H-3), 9.15 (s, 1 H,
H-1), 9.2 (br s, 1 H, OH).
Anal. Calcd for C12H11NO: C, 77.81; H, 5.99; N, 7.56. Found: C,
77.74; H, 6.23; N, 7.23.
13C NMR (CDCl3): d = 35.26 (C-1¢), 115.89 (C-4), 116.80 (C-3¢),
119.51 (C-8), 125.33 (C-6), 128.74 (C-4a and C-8a), 130.38 (C-7),
135.80 (C-2¢), 140.99 (C-3), 149.40 (C-5), 151.35 (C-1).
5-(3-Methylbut-2-enyloxy)isoquinoline (3b)
Yield: 62%; yellow oil; Rf = 0.81 (CH2Cl2–acetone, 2:1).
1H NMR (CDCl3): d = 1.77 (s, 3 H, CH3), 1.82 (s, 3 H, CH3), 4.68
(d, J = 6.5 Hz, 2 H, O-CH2), 5.58 (t, J = 6.5 Hz, 1 H, H-2¢), 6.98 (d,
J = 7.5 Hz, 1 H, H-6), 7.47 (t, J = 8.0 Hz, 1 H, H-7), 7.48 (d, J = 8.0
Hz, 1 H, H-8), 8.04 (d, J = 5.8 Hz, 1 H, H-4), 8.50 (d, J = 8.5 Hz, 1
H, H-3), 9.19 (s, 1 H, H-1).
13C NMR (CDCl3): d = 18.25 (CH3), 25.73 (CH3), 65.14 (C-1¢),
108.43 (C-6), 114.99 (C-4), 118.77 (C-8), 118.99 (C-2¢), 127.08 (C-
7), 128.35 (C-4a), 129.09 (C-8a), 137.91 (C-3¢), 141.88 (C-3),
151.18 (C-1), 153.25 (C-5).
Anal. Calcd for C12H11NO: C, 77.81; H, 5.99; N, 7.56. Found: C,
77.54; H, 6.20; N, 7.28.
6-(2-Methylbut-3-en-2-yl)isoquinolin-5-ol (4b)
Yield: Method A: 74%; Method B: 72%; brown crystalline solid;
mp 121–123 °C; Rf = 0.59 (CH2Cl2–acetone, 2:1).
1H NMR (CDCl3): d = 1.54 (s, 6 H, 2 CH3), 5.44 (d, J = 10.5 Hz, 1
H, H-3¢), 5.50 (d, J = 17.7 Hz, 1 H, H-3¢), 6.30 (dd, J = 17.7, 10.5
Hz, 1 H, H-2¢), 6.70 (br s, 1 H, OH), 7.54 (d, J = 8.7 Hz, 1 H, H-8),
7.56 (d, J = 8.7 Hz, 1 H, H-7), 7.98 (d, J = 5.9 Hz, 1 H, H-4), 8.48
(d, J = 5.9 Hz, 1 H, H-3), 9.17 (s, 1 H, H-1).
Anal. Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found: C,
79.02; H, 6.83; N, 6.33.
13C NMR (CDCl3): d = 26.93 (CH3), 40.69 (C-1¢), 114.44 (C-3¢),
115.24 (C-4), 119.35 (C-8), 125.56 (C-7), 128.42 (C-4a), 128.69
(C-8a), 129.33 (C-6), 142.33 (C-3), 147.36 (C-2¢), 149.05 (C-5),
151.64 (C-1).
5-(Cyclohex-2-enyloxy)isoquinoline (3c)
Yield: 58%; yellow oil; Rf = 0.75 (CH2Cl2–acetone, 2:1).
1H NMR (CDCl3): d = 1.66 (m, 1 H, H-5¢), 1.89 (m, 1 H, H-5¢), 1.98
(m, 2 H, H-6¢), 2.02 (m, 1 H, H-4¢), 2.14 (m, 1 H, H-4¢), 4.94 (br s,
1 H, H-1¢), 5.93 (d, J = 10.3 Hz, 1 H, H-2¢), 5.98 (md, J = 10.3 Hz,
1 H, H-3¢), 7.00 (d, J = 7.3 Hz, 1 H, H-6), 7.43 (m, 1 H, H-7), 7.45
(m, 1 H, H-8), 8.02 (d, J = 5.8 Hz, 1 H, H-4), 9.17 (s, 1 H, H-1).
13C NMR (CDCl3): d = 18.98 (C-5¢), 25.04 (C-4¢), 28.19 (C-6¢),
71.19 (C-1¢), 109.50 (C-6), 115.05 (C-4), 118.66 (C-8), 125.26 (C-
2¢), 126.97 (C-7), 128.85 (C-4a), 129.29 (C-8a), 132.19 (C-3¢),
141.95 (C-3), 151.25 (C-1), 152.20 (C-5).
Anal. Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found: C,
78.51; H, 6.82; N, 6.32.
6-(3-Methylbut-3-en-2-yl)isoquinolin-5-ol (4c)
Method B: Yield: trace amounts; brown crystalline solid; mp 95–
103 °C. Rf = 0.39 (CHCl3–acetone, 10:1).
1H NMR (CDCl3): d = 1.47 (d, J = 7.0 Hz, 3 H, CH3), 1.67 (s, 3 H,
CH3), 3.96 (q, J = 6.9 Hz, 1 H, H-1¢), 5.09 (s, 1 H, H-3¢), 5.14 (s, 1
H, H-3¢), 7.43 (d, J = 8.4 Hz, 1 H, H-7), 7.54 (d, J = 8.4 Hz, 1 H,
H-8), 8.12 (d, J = 5.9 Hz, 1 H, H-4), 8.20 (br s, 1 H, OH), 8.43 (d,
J = 5.8 Hz, 1 H, H-3), 9.15 (s, 1 H, H-1).
13C NMR (CDCl3): d = 18.76 (CH3), 21.99 (CH3), 41.65 (C-1¢),
111.32 (C-3¢), 115.78 (C-4), 119.48 (C-8), 128.11 (C-7), 128.49 (C-
4a), 129.42 (C-6), 140.68 (C-3), 148.75 (C-5), 148.93 (C-8a),
150.88 (C-1).
Anal. Calcd for C15H15NO: C, 79.97; H, 6.71; N, 6.22. Found: C,
79.74; H, 6.83; N, 6.03.
5-[(Z)-Cyclohept-2-enyloxy]isoquinoline (3d)
Yield: 52%; yellow crystalline solid; mp 54–58 °C; Rf = 0.58
(CH2Cl2–acetone, 2:1).
1H NMR (CDCl3): d = 1.46 (m, 1 H, H-5¢), 1.73 (m, 1 H, H-6¢), 1.75
(m, 1 H, H-5¢), 1.93 (m, 1 H, H-7¢), 2.11 (m, 1 H, H-6¢), 2.15 (m, 2
H, H--4¢, H-7¢), 2.28 (m, 1 H, H-4¢), 5.07 (d, J = 10.2 Hz, 1 H, H-
1¢), 5.89 (m, 1 H, H-2¢), 5.92 (m, 1 H, H-3¢), 6.94 (d, J = 7.4 Hz, 1
H, H-6), 7.46 (m, 1 H, H-7), 7.50 (m, 1 H, H-8), 8.03 (d, J = 5.8 Hz,
1 H, H-4), 8.51 (d, J = 5.8 Hz, 1 H, H-3), 9.19 (s, 1 H, H-1).
13C NMR (CDCl3): d = 26.51 (C-5¢), 27.42 (C-6¢), 28.55 (C-4¢),
32.98 (C-7¢), 77.79 (C-1¢), 109.87 (C-6), 115.27 (C-4), 119.00 (C-
8), 127.30 (C-7), 129.07 (C-4a), 129.68 (C-8a), 131.66 (C-3¢),
134.94 (C-2¢), 142.56 (C-3), 151.82 (C-1), 152.44 (C-5).
Anal. Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found: C,
78.61; H, 6.86; N, 6.62.
6-(Cyclohex-2-enyl)isoquinolin-5-ol (4d)
Yield: Method A: 64%; Method B: 70%; brown crystalline solid;
mp 149–152 °C; Rf = 0.63 (CH2Cl2–acetone, 2:1).
1H NMR (CDCl3): d = 1.69 (m, 2 H, H-4¢, H-5¢), 1.83 (m, 1 H, H-
5¢), 2.08 (m, 1 H, H-4¢), 2.17 (br s, 2 H, H-6¢), 3.92 (br s, 1 H, H-1¢),
5.87 (d, J = 10.0 Hz, 1 H, H-2¢), 6.12 (d, J = 7.8 Hz, 1 H, H-3¢),7.43
(d, J = 8.4 Hz, 1 H, H-7), 7.52 (d, J = 8.4 Hz, 1 H, H-8), 7.6 (br s, 1
H, OH), 8.12 (d, J = 5.9 Hz, 1 H, H-4), 8.43 (d, J = 8.4 Hz, 1 H, H-
3), 9.15 (s, 1 H, H-1).
13C NMR (CDCl3): d = 21.45 (C-5¢), 24.93 (C-6), 30.12 (C-4¢),
38.04 (C-1¢), 115.58 (C-4), 119.07 (C-8), 128.02 (C-8a), 128.30 (C-
4a), 128.88 (C-2¢), 129.18 (C-7), 130.31 (C-6), 131.14 (C-3¢),
140.24 (C-3), 148.51 (C-5), 150.56 (C-1).
Anal. Calcd for C16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C,
79.94; H, 6.83; N, 6.07.
Rearrangement of Ethers 3a–d; General Procedure
Method A: A soln of ether 3 (5 mmol) in chlorobenzene (50 mL)
was heated at reflux for 30 h. The solvent was evaporated under re-
duced pressure and the crude product was purified by column chro-
matography on silica gel (CH2Cl2–acetone, 9:1).
Synthesis 2007, No. 2, 284–288 © Thieme Stuttgart · New York

PAPER
Synthesis of Furo[2,3-f]isoquinolines
287
Anal. Calcd for C15H15NO: C, 79.97; H, 6.71; N, 6.22. Found: C,
79.53; H, 6.92; N, 6.01.
(d, J = 6 Hz, 1 H, H-1), 8.46 (d, J = 6 Hz, 1 H, H-2), 9.20 (br s, 1 H,
H-4).
13C NMR (CDCl3): d = 20.29 (C-9), 21.76 (C-8), 27.40 (C-10),
28.16 (C-7), 41.31 (C-6b), 83.89 (C-10a), 114.52 (C-1), 120.00 (C-
5), 123.07 (C-11b), 123.25 (C-6), 129.06 (C-4a), 131.57 (C-6a),
142.03 (C-2), 152.38 (C-4), 153.93 (C-11a).
6-(Cyclohept-2-enyl)isoquinolin-5-ol (4e)
Method B: Yield: 42%; yellow solid; mp 74–78 °C; Rf = 0.45
(CH2Cl2–acetone, 2:1).
1H NMR (CDCl3): d = 1.50 (m, 1 H, H-5¢), 1.65 (m, 1 H, H-6¢), 1.81
(m, 1 H, H-5¢), 1.88 (m, 2 H, H-7¢), 1.94 (m, 1 H, H-6¢), 2.21 (m, 1
H, H-4¢), 2.31 (m, 1 H, H-4¢), 4.15 (m, 1 H, H-1¢), 5.78 (d, J = 8.4
Hz, 1 H, H-2¢), 5.97 (m, 1 H, H-3¢), 7.48 (d, J = 8.5 Hz, 1 H, H-7),
7.53 (d, J = 8.5 Hz, 1 H, H-8), 8.13 (d, J = 6.0 Hz, 1 H, H-4), 8.43
(d, J = 6.0 Hz, 1 H, H-3), 9.1 (br s, 1 H, OH), 9.14 (s, 1 H, H-1).
13C NMR (CDCl3): d = 27.13 (C-5¢), 28.88 (C-4¢), 29.89 (C-6¢),
34.67 (C-7¢), 41.72 (C-1¢), 115.97 (C-4), 119.73 (C-8), 128.37 (C-
8a), 128.54 (C-7), 128.92 (C-4a), 132.92 (C-6), 133.81 (C-3¢),
135.10 (C-2¢), 141.10 (C-3), 147.82 (C-5), 151.30 (C-1).
Anal. Calcd for C15H15NO: C, 79.97; H, 6.71; N, 6.22. Found: C,
79.72; H, 6.89; N, 5.97.
trans-Isomer: tR = 11.66 (MeOH–H2O–H3PO4, 4:6:0.05).
1H NMR (CDCl3): d = 1.28 (m, 1 H, H-9), 1.48 (m, 1 H, H-9), 1.67
(m, 1 H, H-10), 1.83 (m, 2 H, H-8), 2.00 (m, 2 H, H-7), 2.16 (m, 1
H, H-10), 3.13 (br s, 1 H, H-6b), 4.83 (br s, 1 H, H-10a), 7.22 (d,
J = 8.2 Hz, 1 H, H-6), 7.41 (d, J = 8.2 Hz, 1 H, H-5), 7.96 (d, J = 6
Hz, 1 H, H-1), 8.46 (d, J = 6 Hz, 1 H, H-2), 9.14 (s, 1 H, H-4).
13C NMR (CDCl3): d = 17.17 (C-9), 29.21 (C-7), 31.80 (C-6b),
32.42 (C-8), 33.33 (C-10), 71.66 (C-10a), 114.86 (C-1), 117.92 (C-
5), 124.20 (C-6a), 126.93 (C-11b), 128.43 (C-6), 128.57 (C-4a),
142.17 (C-2), 150.42 (C-11a), 151.68 (C-4).
Anal. Calcd for C16H17NO (239.31): C, 80.30; H, 7.16; N, 5.85.
Found: C, 79.98; H, 6.77; N, 6.07.
Furo[2,3-f]isoquinolines (5a–d); General Procedure
Anal. Calcd for C15H15NO: C, 79.97; H, 6.71; N, 6.22. Found: C,
80.02; H, 6.47; N, 5.98.
A mixture of compound 4 (1 mmol) and concd H2SO4 (0.1 g, 2.1
mmol) was heated in a water bath for 1 h. After cooling, the reaction
mixture was poured onto ice (10 g), basified using 1 N NaOH (7
mL) and extracted with CHCl3 (3 × 20 mL). The combined organic
layers were washed with H2O, dried (MgSO4) and the solvent was
evaporated in vacuo. The residue was purified by column chroma-
tography using CH2Cl2–acetone (5:1) as eluent.
7,8,9,10,11,11a-Hexahydro-6bH-cyclohepta[4,5] furo[2,3-f]iso-
quinoline (5d)
Yield: 52%; yellow crystalline solid mp 32–39 °C; Rf = 0.73
(CH2Cl2–acetone, 2:1).
trans-Isomer: tR = 4.4 min (MeOH–H2O, 4:1).
1H NMR (CDCl3): d = 1.25 (m, 1 H, H-9), 1.38 (m, 1 H, H-10), 1.53
(m, 1 H, H-10), 1.64 (m, 1 H, H-9), 1.80 (m, 2 H, H-7, H-11), 2.09
(m, 1 H, H-8), 2.14 (m, 2 H, H-7, H-11), 2.40 (m, 1 H, H-8), 3.18
(m, 1 H, H-6b), 4.95 (m, 1 H, H-11a), 7.30 (d, J = 8.3 Hz, 1 H, H-
6) 7.43 (d, J = 8.3 Hz, 1 H, H-5), 7.94 (d, J = 5.8 Hz, 1 H, H-1),
8.48 (d, J = 5.8 Hz, 1 H, H-2), 9.12 (s, 1 H, H-4).
13C NMR (CDCl3): d = 24.40 (C-10), 26.21 (C-9), 29.21 (C-8),
32.14 (C-6b), 35.51 (C-7), 36.70 (C-11), 73.31 (C-11a), 114.89 (C-
1), 118.29 (C-5), 124.20 (C-6a), 128.26 (C-12b), 128.36 (C-4a),
128.60 (C-6), 142.49 (C-2), 148.04 (C-12a), 151.52 (C-4).
2,3-Dihydro-2-methylfuro[2,3-f]isoquinoline (5a)
Yield: 45%; yellow oil; Rf = 0.68 (CH2Cl2–acetone, 2:1).
1H NMR (CDCl3): d = 1.55 (d, J = 16.3 Hz, 3 H, CH3), 2.99 (dd,
J = 15.6, 7.6 Hz, 1 H, H-3), 3.50 (dd, J = 15.6, 9.2 Hz, 1 H, H-3),
5.15 (m, 1 H, H-2), 7.40 (d, J = 8.2 Hz, 1 H, H-4), 7.45 (d, J = 8.2
Hz, 1 H, H-5), 7.70 (d, J = 5.8 Hz, 1 H, H-9), 8.44 (d, J = 5.8 Hz, 1
H, H-8), 9.17 (s, 1 H, H-6).
13C NMR (CDCl3): d = 21.99 (CH3), 37.88 (C-3), 80.78 (C-2),
114.43 (C-9), 119.57 (C-5), 122.63 (C-9a), 124.36 (C-4), 124.79
(C-3a), 129.02 (C-5a), 142.22 (C-8), 152.31 (C-6), 153.85 (C-9b).
Anal. Calcd for C16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C,
80.04; H, 6.77; N, 5.91.
Anal. Calcd for C12H11NO: C, 77.81; H, 5.99; N, 7.56. Found: C,
77.52; H, 6.09; N, 7.79.
cis-Isomer: tR = 5.24 min (MeOH–H2O, 4:1).
2,3-Dihydro-2,2,3-trimethylfuro[2,3-f]isoquinoline (5b)
Yield: 87%; yellow crystalline solid; mp 55–57 °C; Rf = 0.73
(CH2Cl2–acetone, 2:1).
1H NMR (CDCl3): d = 1.29 (d, J = 7.2 Hz, 3 H, CH3), 1.39 (s, 3 H,
CH3), 1.55 (s, 3 H, CH3), 3.33 (q, J = 7.2 Hz, 1 H, H-3), 7.37 (d,
J = 8.2 Hz, 1 H, H-4), 7.48 (d, J = 8.2 Hz, 1 H, H-5), 7.71 (d, J = 5.8
Hz, 1 H, H-9), 8.44 (d, J = 5.8 Hz, 1 H, H-8), 9.18 (s, 1 H, H-6).
13C NMR (CDCl3): d = 15.11 (CH3), 22.18 (CH3), 28.48 (CH3),
46.45 (C-3), 91.08 (C-2), 114.62 (C-9), 119.47 (C-5), 122.88 (C-
9a), 123.63 (C-4), 129.16 (C-5a), 130.34 (C-3a), 142.05 (C-3),
152.33 (C-6), 152.36 (C-9b).
1H NMR (CDCl3): d = 3.76 (m, 1 H, H-6b), 5.18 (m, 1 H, H-11a),
7.35 (d, J = 8.2 Hz, H-6), 7.42 (d, J = 8.2 Hz, H-5), 7.70 (d, J = 5.8
Hz, 1 H, H-1), 8.44 (d, J = 5.8 Hz, 1 H, H-2), 9.18 (s, 1 H, H-4).
13C NMR (CDCl3): d = 47.18 (C-6b), 88.25 (C-11a), 114.63 (C-1),
122.47 (C-6a), 123.74 (C-6), 129.14 (C-12b), 129.25 (C-4a), 142.20
(C-2), 152.29 (C-4), 153.25 (C-12a).
Anal. Calcd for C16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C,
80.44; H, 6.79; N, 5.52.
Acknowledgment
Anal. Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found: C,
78.56; H, 6.80; N, 6.72.
This work was supported by the Hungarian OTKA Foundation
(T42515) and NKFP program contract MediChem II (Hungarian
Ministry of Education). We would like to thank Csilla Hegyi and
Sarolta Pilbak for the HPLC separations.
6b,7,8,9,10,10a-Hexahydrobenzofuro[2,3-f]isoquinoline (5c)
Yield: 82%; light brown crystals; Rf = 0.8 (CH2Cl2–acetone, 2:1).
cis-Isomer: tR = 14.19 min (MeOH–H2O–H3PO4, 4:6:0.05).
References
1H NMR (CDCl3): d = 1.40 (m, 1 H, H-8), 1.55 (m, 4 H, H-7, H-8,
2 H-9)C7, C8-H, and 2 C9-H), 1.92 (m, 2 H, H-7, H-10), 2.10 (m, 1
H, H-10), 3.39 (q, J = 7.2 Hz, 1 H, H-6b), 4.91 (m, 1 H, H-10a),
7.43 (d, J = 8.1 Hz, 1 H, H-6), 7.51 (d, J = 8.1 Hz, 1 H, H-5), 7.74
(1) Yasuhiko, K.; Matsumoto, T.; Fujii, N. PCT Int. Appl.
20030103, Chem. Abstr. 2005, 138: 73247.
(2) Roger, R.; Guillaumel, J.; Demerseman, P.; Platzer, N.;
Buisson, J.-P. Bull. Soc. Chim. Fr. 1972, 4201.
Synthesis 2007, No. 2, 284–288 © Thieme Stuttgart · New York

288
M. Törincsi et al.
PAPER
(3) For excellent monographs on the Claisen rearrangement,
see: (a) Tarbell, D. S. Org. React. 1944, 2, 2. (b) Ziegler, F.
E. Acc. Chem. Res. 1977, 10, 227. (c) Murray, A. W. Org.
React. Mech. 1980, 517. (d) Lutz, R. P. Chem. Rev. 1984,
84, 205. (e) Ziegler, F. E. Chem. Rev. 1988, 88, 1423.
(f) Nubbemeyer, U. Synthesis 2003, 961. (g) Castro, A. M.
M. Chem. Rev. 2004, 104, 2939.
(4) Some ethers of isoquinolin-5-ol expressed strong
bactericidal activity on Helicobacter pylori: Yoshida, Y.;
Barrett, D.; Azami, H.; Morinaga, C.; Matsumoto, S.;
Matsumoto, Y.; Takasugi, H. Bioorg. Med. Chem. 1999, 7,
2647.
(5) In recent years there has been an increasing interest in the
use of microwave irradiation to heat chemical reactions,
see: (a) Farand, J. A.; Denissova, I.; Barriault, L.
Heterocycles 2004, 62, 735. (b) Kotha, S.; Mandal, K.; Deb,
A. C.; Banerjee, S. Tetrahedron Lett. 2004, 45, 9603.
(c) Rao, V. V.; Reddy, G. V.; Yadla, R.; Narsaiah, B.; Rao,
P. S. ARKIVOC 2005, (iii), 211. (d) Jacob, A. M.; Moody,
C. J. Tetrahedron Lett. 2005, 46, 8823. (e) Kremsner, J. M.;
Kappe, C. O. J. Org. Chem. 2006, 71, 4651; and references
cited therein.
(7) (a) Hurd, C. D.; Pollack, M. A. J. Org. Chem. 1939, 3, 550.
(b) Marwell, E. N. J. Org. Chem. 1960, 25, 676. (c) Lauer,
W. M.; Douldoras, G. A.; Hileman, R. E.; Lupino, R. J. Org.
Chem. 1961, 26, 4785. (d) Marwell, E. N.; Anderson, D. R.;
Ong, J. J. Org. Chem. 1962, 27, 1109. (e) Roberts, R. M.;
Landolt, R. G.; Greene, R. N.; Heyer, E. W. J. Am. Chem.
Soc. 1967, 89, 1404. (f) Scheinmann, F.; Barner, R.;
Schmid, H. Helv. Chim. Acta 1968, 51, 1603. (g) Rhoads,
S. J.; Raulins, N. R. Org. React. 1974, 22, 1. (h) Schobert,
R.; Siegfried, S.; Gordon, G.; Mulholland, D.;
Nieuwenhuyzen, M. Tetrahedron Lett. 2001, 42, 4561.
(8) The Claisen rearrangement and subsequent cyclization
under acidic conditions has been widely used for the
preparation of cyclic compounds. For general reviews and
selected examples, see: (a) Corey, E. J.; Cheng, X.-M. The
Logic of Chemical Synthesis; Wiley & Sons: New York,
1989. (b) Nicolaou, K. C.; Sorensen, E. J. Classics in Total
Synthesis; VCH: Weinheim, 1996. (c) Robinson, B. Chem.
Rev. 1969, 69, 227. (d) Rischke, H.; Wilcock, J. D.;
Winterfeldt, E. Chem. Ber. 1973, 106, 3106. (e) Murray, R.
D. H.; Forbes, I. T. Tetrahedron 1978, 34, 1411. (f)Mohan,
C.; Kumar, V.; Mahajan, M. P. Tetrahedron 2004, 45, 6075.
(g) Miyata, O.; Takeda, N.; Kimura, Y.; Takemoto, Y.;
Tohnai, N.; Miyata, M.; Naito, T. Tetrahedron 2006, 62,
3629.
(6) Lauer, W. M.; Filbert, W. F. J. Am. Chem. Soc. 1936, 58,
1388.
(9) Cox, R. A.; Swallow, A. J. J. Chem. Soc. 1958, 3727.
(10) Dondas, H. A.; Grigg, R.; Thibault, S. Tetrahedron 2001, 57,
7035.
Synthesis 2007, No. 2, 284–288 © Thieme Stuttgart · New York