Synthesis of new fused isoquinolines via Reissert compounds

Article abstract of DOI:10.1002/jhet.5570450615

(Chemical Equation Presented) Reissert compounds 2 derived from isoquinoline, chlomformates and TMS-cyanide were alkylated in position 1. The resulting alkylation products 3 as well as the precursors 2 reacted with Grignard reagents affording imidazoisoquinolines 4, 5, 7 and 8 by addition to the cyano group and Grignard reduction or by twofold addition to the cyano group, respectively. In both cases the alcohol of the 2-alkoxycarbonyl moiety was eliminated by attack of the N-atom at the carbonyl carbon atom. Under acid conditions, 1-benzylated Reissert compound 3h cyclised by attack of the resulting N-acyliminium C-atom at the o-position of the benzyl ring to form tetracyclic 1,3-bridged tetrahydroisoquinolines 10 and 11. Bromocyclisation of 1-allyl-2-menthyloxycarbonyl-substituted Reissert compounds 3b, c led to tricyclic dibromo products 12, in which the menthol moiety was split off and addition to the enamine double bond occurred. A 2-menthyloxycarbonyl group in Reissert compounds 2a and 3 failed to exert an asymmetric induction in all cases.

Full text of DOI:10.1002/jhet.5570450615

Nov-Dec 2008
1651
Synthesis of New Fused Isoquinolines Via Reissert Compounds
Christian Fuchs, Christoph Bender, Burkhard Ziemer, Jürgen Liebscher*
Institute of Chemistry, Humboldt-University Berlin,
Brook-Taylor-Str. 2, D-12489 Berlin, Germany, e-mail: liebscher@chemie.hu-berlin.de
Received April 14, 2008
Br
OMe
N
NH
NH
O
N
OR
R1
R2
N
O
OMe
R1
H2NOC
NC
R´
CN
O
O
3
7
11
12
Br
Reissert compounds 2 derived from isoquinoline, chloroformates and TMS-cyanide were alkylated in
position 1. The resulting alkylation products 3 as well as the precursors 2 reacted with Grignard reagents
affording imidazoisoquinolines 4, 5, 7 and 8 by addition to the cyano group and Grignard reduction or by
twofold addition to the cyano group, respectively. In both cases the alcohol of the 2-alkoxycarbonyl moiety
was eliminated by attack of the N-atom at the carbonyl carbon atom. Under acid conditions, 1-benzylated
Reissert compound 3h cyclised by attack of the resulting N-acyliminium C-atom at the o-position of the
benzyl ring to form tetracyclic 1,3-bridged tetrahydroisoquinolines 10 and 11. Bromocyclisation of 1-allyl-2-
menthyloxycarbonyl-substituted Reissert compounds 3b, c led to tricyclic dibromo products 12, in which the
menthol moiety was split off and addition to the enamine double bond occurred. A 2-menthyloxycarbonyl
group in Reissert compounds 2a and 3 failed to exert an asymmetric induction in all cases.
J. Heterocyclic Chem., 45, 1651 (2008).
INTRODUCTION
phosphineoxide-derived Lewis acids as chiral catalyst
[5,6]. As 1-alkylisoquinolines are difficult to obtain and
mainly commercially unavailable, the reversed synthetic
sequence, i.e. firstly to transforming isoquinoline into
Reissert compounds and then introducing the alkyl
substituent by stereoselective alkylation would be a useful
alternative. We further sought to introduce substituents in
position 1 of Reissert compounds which allow fused
isoquinolines to be established, such as imidazo[5,1-a]-
isoquinolines, 1,4-oxazino[5,1-a]isoquinolines and 1,3-
bridged isoquinolines.
Reissert compounds, i.e. N-acyl-1-cyano-1,2-dihydro-
isoquinolines, have been known for more than 100 years
[1]. They are formed from isoquinolines or similar N-6-
ring-heterocycles, acyl chlorides or acid anhydrides and
cyanide via intermediate N-acyliminium salts. This
reaction was originally used to transform acyl chlorides
into aldehydes by final acid hydrolysis of the Reissert
compounds. Following this, Reissert compounds were
also recognized as useful intermediates for cyclic amino
acids (benzo-annellated pipecolinic acids). Because of
their acidity in position 1, Reissert compounds can be
RESULTS AND DISCUSSION
deprotonated and finally alkylated establishing
a
The 2-(R)-menthyloxycarbonyl Reissert compound 2a
(R = (R)-menthyl) was previously assigned by us to exist
as a pure 1-(S)-diastereomer by comparison of measured
data of optical rotation with calculated values [4].
However, as we achieved only modest asymmetric
inductions when isoquinolinium salts derived from
menthyloxycarbonyl chloride and isoquinoline were
reacted with nucleophiles other than cyanide [7],
investigation of the configuration of the Reissert
compound 2a was revisited. H1 NMR spectrum of 2a (R =
(R)-menthyl) in DMSO-d6, rather than chloroform as in
our original publication, showed two sets of signal at 25
°C, 40 °C and 70 °C, i.e. no coalescence occurred.
Furthermore, HPLC at a chiral phase revealed two peaks
of identical integration. Finally, we succeeded in
obtaining single crystals from the Reissert compound 2a
(R = (R)-menthyl) useful for X-ray crystal analysis. As
quaternary C-centre. Furthermore, they can serve as
intermediates in the synthesis of condensed isoquinolines
[2]. Asymmetric routes to condensed isoquinolines are
interesting in the synthesis of natural products [3]. We
became interested to apply such 1-alkylated 2-acyl-1-
cyano-1,2-dihydroisoquinolines in intramolecular
cyclisations in order to establish annellated dihydro-
isoquinolines. As one option, the chiral Reissert
compound 2a (R = (R)-menthyl) was chosen, which we
recently made available by reaction of isoquinoline with
chloro (-)-menthylformate and trimethylsilyl cyanide in
the presence of AlCl3 [4]. We expected that alkylation of
such Reissert compounds could be stereoselective because
of the presence of the menthyloxycarbonyl substituent.
Recently, chiral 1-alkylated Reissert compounds became
available by Shibasaki et al. carrying out asymmetric
Reissert reactions of 1-alkylisoquinolines using BINOL-

1652
C. Fuchs, C. Bender, B. Ziemer, J. Liebscher
Vol 45
Scheme 1
can be seen (Fig. 1), the compound exists as a 1:1 mixture
of epimers even in the single crystal. All of these results
request that our original configurational assignment [4] of
the Reissert compound 2a has to be revised. Instead of
being a single 1-(S)-isomer, the compound is in fact a 1:1
mixture of 1-(S)/1(R) epimers (Fig. 1), i.e. the menthyl-
oxycarbonyl group does not give any asymmetric
induction in the addition of the cyanide to position 1 of
isoquinoline in the formation of the Reissert product 2a.
This information was recently confirmed by Gibson et al.
by NMR-investigations [8].
ClCOOR/
AlCl3/TMSCN
N
N
OR
CH2Cl2
CN
O
1
2a (R = (R)-menthyl)
2b (R = Me)
NaH/DMF
R1-X
MgBr
THF, 0-23°C, 2 d
0°C, 2h
N
OR
N
O
R1
CN
O
NH
3
3-4 equ. R2Mg-Br
Et2O, rt
4 (57%)
N
O
N
O
3-4h
+
CN
O
CN
O
2a
N
O
N
O
NH
R1
R2
N
5 (33%)
O3
6
(R2=Me)
40-66%
N3
O4
(R2=Et)
27-39%
N2
N4
O2
N1
O1
N
N
NH
O
R1
R2
R2
O
R1
R2
NH
7
8
Figure 1. X-ray crystal analysis of Reissert product 2a [23].
Regardless of this fact, we employed Reissert
compound 2a (R = (R)-menthyl) in alkylation reactions at
position 1, taking into consideration that the possibility of
the chiral auxiliary eventually giving an asymmetric
induction in the reaction, when the site of attack is more
congested. This is somewhat similar to the known
The expected alkylation products 3 were obtained in
both procedures, althoug NaH in DMF at 0 °C gave
much better yields (Table 1). Two sets of signals were
found in the NMR spectra of compounds 3 which
gave coalescence upon heating to 50 °C, suggesting
the existence of rotamers, as found before with
reaction of 2a
with pivalaldehyde affording
2-methoxycarbonyl-tetrahydroisoquinolines
[17].
stereoselective formation of 1-(1-hydroxyalkyl)-1,2-
isoquinolines [8]. Several bases, such as phenyl-Li [9],
nBu-Li [10], Na in xylene [11], KOH or NaOH under
PTC [12], NaH [13], LDA [12,14], or tBuOK [15] were
reported to achieve deprotonation of Reissert compounds
at position 1 of the isoquinoline. Deprotonation-alkylation
under phase transfer catalysis with chiral quaternary
ammonium salts allowed stereoselective introduction of
alkyl groups [16]. We deprotonated Reissert compounds
2a with LDA in THF at -78 °C, similar to a previously
used methylation protocol [4] or with NaH in DMF at 0
°C, and treated the resulting benzyl anions with alkylating
reagents.
However, an almost racemic product was found when
the (R)-menthyloxycarbonyl moiety was split off in a
later transformation (v. s. formation of 8b). Thus,
unlike previous claims (the compound 13 of reference
[4] was erroneously assigned as a single diastereomer)
the alkylation of the Reissert compounds 2 did not
occur stereoselectively, i.e. the products 3 are 1:1
epimers as their precursors 2. Regardless of the non-
stereoselective formation of alkylation products 3, we
tried to explore their synthetic potential at the
functionality in the 1-alkyl group for building up more
complex fused isoquinoline systems.

Nov-Dec 2008
Synthesis of New Fused Isoquinolines Via Reissert Compounds
1653
Table 1
Table 2
Imidazoisoquinolines 7 and 8
1-Alkyl-1-cyano-2-(R)-menthyloxycarbonyl)-1,2-dihydroisoquinolines
3a-f (R = (R)-menthyl) and corresponding 2-methoxcarbonyl
compounds 3g, h (R = Me).
Product
R1
R2
R
yield (%)
in reactant 3
(R)-menthyl
Me
3
R
R1
X
Yield
(%)
7a
7b
8a
8b
Allyl
Bn
Et
39%
27%
66%
40%[a]
65%
51%
Et
a
b
c
(R)-Menthyl
(R)-Menthyl
(R)-Menthyl
(R)-Menthyl
n-Bu
Allyl
Methallyl
Bn
I
95
97
99
n-Bu
Bn
Me
Me
(R)-menthyl
(R)-menthyl
Me
Br
Cl
Cl
NEt3
Cl-
Cl
Br
Br
Cl
d
90[a]
69[a,
b]
8c
Bn
Allyl
Me
+
[a] 14 % ee, could be increased by recrystallisation, where the racemate
crystallized preferably, thus increasing the ee in the mother liquor.
e
f
g
h
(R)-Menthyl
(R)-Menthyl
Me
2-BrBn
3-MeOBn
Allyl
82
89
82
86
Me
Bn
Non-alkylated Reissert compounds 2 can undergo a
similar transformation into imidazo[5,1-a]isoquinolin-3-
ones, as shown in the formation of the diallyl product 4
(55 % yield) upon treatment of 2a with allyl magnesium
[a] equimolar quantities of 2 and alkylating reagent were used [b]
product contained 28 % of reactant 2
For convenience, 1-alkylated Reissert compounds 3h
and 3g bearing a non-chiral methoxycarbonyl moiety at
the N-atom were also included.
Treatment of 3 with Grignard reagents showed an
interesting dependence of the outcome of the reaction on
the type of incoming substituent. Methyl and allyl
magnesium bromide gave the racemic trisubstituted
imidazo[5,1-a]isoquinolinone 8 by incorporating two allyl
or methyl groups into the product. On the other hand, only
one ethyl group was introduced when 3 were reacted with
N1
O1
N2
ethyl magnesium bromide and
a further Grignard
Figure 2. X-ray structure of imidazoisoquinoline 7a [23].
reduction took place rather than a Grignard addition. Thus
a corresponding diethyl product 8 (R2 = Et) was only
found in traces (3 % yield) while 7 was obtained as major
product. In both cases it can be assumed that the Reissert
compounds 3 react primarily by addition of the Grignard
reagent to the cyano group. This is followed by the
resulting imine anion attacking the carbamate moiety at
position 2 by cyclisation and elimination of menthol or
methanol, affording imidazo[5,1-a]isoquinolinones 6. The
imine moiety of intermediate imidazoisoquinolinone 6
seems to be sterically shielded as a result of the
occurrence of a Grignard reduction to 7 rather than a 1,2-
addition taking place with ethyl magnesium bromide. If
methyl or allyl magnesium bromide were used, no
Grignard reduction was possible per se, and thus a second
addition of the Grignard reagent occurred affording
trialkyl products 8. The structures of the imidazo[5,1-a]-
isoquinolinones 7 and 8 were confirmed by several X-ray
crystal analyses (see Figures 2-5). The trans-configuration
of the alkyl substituents in compounds 7 can be
understood by an attack of the Grignard-reagent in the
Grignard-reduction of the intermediate 6 from the convex
side of the bicyclic system.
N1
O1
N2
Figure 3. X-ray structure of imidazoisoquinoline 7b [23].
N1
O1
N2
Figure 4. X-ray structure of imidazoisoquinoline 8b [23].

1654
C. Fuchs, C. Bender, B. Ziemer, J. Liebscher
Vol 45
1-Benzylisoquinolines can be used to establish 1,3-
bridged isoquinolines by intramolecular Mannich-type
reaction [19]. This cyclisation however, has rarely been
applied to Reissert compounds until now [20]. We treated
the 1-(3-methoxybenzyl)-substituted Reissert compound
3f with methyl triflate in dichloromethane (Method A).
Our aim was the introduction of a methyl group in
position 6 and subsequent cyclisation, but instead we
obtained the dibenzo-9-azabicyclo[3.3.1]nonane 10,
which lacked a methyl group. Presumably the enamine
moiety of 3h was protonated by catalytic traces of triflic
acid, followed by the resulting N-acyliminium salt 9
undergoing an intramolecular Mannich reaction at
position 4 of the 3-methoxybenzyl substituent, thus giving
product 10. When the Reissert compound 3f was treated
with phosphoric acid in formic acid (Method B) and the
resulting mixture worked up under aqueous conditions,
hydrolysis of the cyano group and the carbamate took
place resulting in the formation of dibenzo-9-azabicyclo-
[3.3.1]nonane 11. The structure of the cyclisation product
11 was unambiguously assigned by X-crystal structure
analysis (as hydrochloride, see Fig. 6)
In order to verify a novel access to 1,4-oxazino[5,1-
a]-isoquinolines we submitted 1-allyl and 1-methallyl-
substituted Reissert compounds 3b and 3c to bromo
cyclisation in methanol/dichloromethane as solvent. The
1,4-oxazino[5,1-a]isoquinolines 12 were formed where
bromine and methoxide were also added to the acyl
enamine moiety. The latter addition was previously
observed with Reissert compounds which could not
undergo cyclisation [21]. The application of yridinium
tribromide (Method C) turned out to be advantageous
O1
N1
N2
Figure 5. X-ray structure of imidazoisoquinoline 8c [23].
bromide. Interestingly, the 1-allyl imidazo[5,1-a]iso-quino-
lin-3(2H)-one 5 was obtained as a by-product in 30 % yield,
which was obviously formed by 1,3-H shift in the
intermediate cyclisation product 6 (R1 = H, R2 = allyl). The
Grignard reagent-mediated formation of imidazo[5,1-a]-
isoquinolin-3-ones 4, 5, 7 and 8 represents a new access to
this ring system. So far, cyclisation of Reissert compounds
to imidazo[5,1-a]isoquinolines was implemented by the
application of hydrogen peroxide, giving corresponding 1,3-
diones [6]. A Reissert compound derived from N,N-
dimethyl nicotinamide could be transformed to
hexahydroimidazo[1,5-a]pyridine by reduction with Mg in
a
methanol [18].
Scheme 2
N+ O-(R)-Menthyl
N
O-(R)-Menthyl
NC
NC
O
O
Method A:
MeOTf, CH2Cl2,
rt, 12 d
Method B:
1. 85% H3PO4/HCOOH
2. H2O
OMe
OMe
3f
Method B
9
50%
Method A
65 %
N1
O1
NH
N
O2
OMe
H2NOC
OMe
CO2-(R)-Menthyl
NC
N2
11
10
Br
Method C:
Br2
OMe
Figure 6 X-ray structure of 11 (as hydrochloride, anion not shown) [23]
Method D:
py.HBr3
N
O-(R)-Menthyl
N
O
NC
R´
NC
R´
O
O
MeOH / CH2Cl2
O1
O2
Br1
Br
N1
3b, c
12a (R´=H): 35% Method C
12b (R´=Me): 66% Method D
N2
O3
Br
OMe
N
z
Br2
NC
O
13
Figure 7 X-ray structure of oxazinoisoquinoline 12a [23]

Nov-Dec 2008
Synthesis of New Fused Isoquinolines Via Reissert Compounds
1655
EXPERIMENTAL
Br2
1H NMR and 13C NMR spectra were recorded at 300 MHz
and 75.5 MHz, respectively, on a Bruker AC-300 with TMS as
internal standard. ESI-mass spectra were measured with Varian
CH-7a MAT (EI 70 eV) LDQ FT Finnigan ESI with MeOH as
solvent. Silica gel 60 (0.04-0.063 mm, Merck) was used for
preparative column chromatography and a Chiracel-OD-column
for chiral HPLC. Unless otherwise mentioned, chemicals were
purchased. Compounds 2 (R = Me, (R)-menthyl) were obtained
adopting reported procedures [4,24] (v. i.). Compound 2b was
reported before [24], but higher yields were obtained using the
AlCl3-assisted method with TMSCN.
O3
O2
N1
Br1
O1
N2
Figure 8 X-ray structure of oxazinoisoquinoline 12b [23].
General Procedure for the Synthesis of Alkylated
Reissert Compounds 3. Reissert compound 2 (339 mg, 1.00
mmol) and alkylating reagent R1-X (1.10 mmol) were dissolved in
dry DMF (1 mL) and stirred under argon in an ice-bath. NaH (48
mg of a 60% suspension in mineral oil, 1.20 mmol) was added.
Equimolar quantities of R1-X led to incomplete conversion, i.e.
products 3 contained starting materials 2, which could not be
removed by chromatography. The mixture became slightly brown,
while a gas (H2) evolved. After 2 h, excess of NaH was destroyed
by addition of MeOH. After dilution with DCM (5 mL), the DMF
was extracted by washing twice with water (5 mL). The DCM
layer was dried with MgSO4 and evaporated to dryness under
reduced pressure. If necessary, the product can be purified by
column chromatography with silica gel and DCM or cyclohexane/
EtOAc (7:3). The substances are slightly coloured oils.
over elemental bromine (Method D) in this synthesis.
A plausible explanation of this reaction outcome could
be the transformation of the alkene double bond of the
allyl moiety of 3 into a bromonium ion. Subsequent
intramolecular attack at the carbonyl oxygen (rather
than at the cyano nitrogen atom – Ritter-type reaction)
atom would follow forming the oxazino ring, while the
menthyloxy moiety is split off. The structure of the
1,4-oxazino[5,1-a]isoquinolines 12 were proved by X-
ray crystal analysis (see Figures 7, 8). It reveals that
the bromine atom is found at the concave side of the
bowl shaped 1,4-oxazino[5,1-a]isoquinoline ring
system. Since attack at bowl shaped ring systems
occurs preferably from the convex side, it can be
assumed that the bromo alkoxide addition to the
enamine moiety occurred prior to the formation of the
oxazine ring. This assumption is supported by the fact
that we were able to isolate small quantities of the
non-cyclised addition product 13. Syntheses of the
1,4-oxazino[5,1-a]isoquinoline system are rare and so
far this heterocycle has been obtained starting from
1-(2-hydroxyalkyl)-tetrahydroisoquinolines and
chloroformate [22].
1-(n-Butyl)-1-cyano-2-[(R)-menthyloxycarbonyl]-1,2-di-
hydroisoquinoline (3a). The product was obtained in 95%
1
yield following the general procedure using n-butyl iodide. H-
NMR (CDCl3): ꢀ = 0.60-2.20 (m, 27 H, menthyl + butyl); 2.53
(m, 1 H, butyl); 4.84 (m, 1 H, CH-O); 5.63 (t, 1 H, J = 6.89 Hz,
CHCH-N); 6.97 (m, 2 H); 7.23 (m, 2 H); 7.52 ppm (m, 1 H).
13C-NMR (CDCl3): ꢀ = 13.7; 16.1; 20.7; 21.9; 22.0; 23.2; 25.0;
26.3; 31.4; 34.0; 40.9; 47.1; 59.9; 77.8; 105.2 (CH-CH-N);
119.1 (CN); 124.6-129.1 (aromatic C and CH); 151.8 ppm (CO).
Anal. Calcd. for C25H34N2O2 (394.55): C, 76.10; H, 8.69; N,
7.10. Found: C, 75.81; H, 8.96; N, 6.92.
1-Allyl-1-cyano-2-[(R)-menthyloxycarbonyl]-1,2-dihydro-
isoquinoline (3b). The product was obtained in 97 % yield
1
following the general procedure using allyl bromide. H-NMR
(CDCl3): ꢀ = 0.6-2.3 (m, 18 H, menthyl); 2.70-2.85 (m, 1 H,
=CHCH2); 3.15-3.35 (m, 1 H, =CHCH2); 4.75-4.95 (m, 1 H,
CH-O); 4.95-5.15 (m, 2 H); 5.64 (m, 2 H); 6.80-7.60 ppm (m,
5H, 4CHar + CHCH-N). 13C-NMR (CDCl3): ꢀ = 16.3; 20.8; 22.0;
23.4; 26.5; 31.6; 34.2; 41.1; 45.7 (=CHCH2); 47.3; 59.8 (Cq);
78.2 (CHO); 105.4 (CH-CH-N); 118.6 (CN); 121.5 (=CH2);
125-130 (aromatic C and CH); 152.0 ppm (C=O). HRMS (ESI)
m/z: Calc. for C24H30N2O2+H+ 379.2380, found 379.2380. Anal.
Calcd. for C24H30N2O2 (378.51): C, 76.10; H, 8.69; N, 7.10.
Found: C, 75.81; H, 8.96; N, 6.92.
1-Cyano-1-(2-methylallyl)-2-[(R)-menthyloxycarbonyl]-
1,2-dihydroisoquinoline (3c). The product was obtained in 99
% yield following the general procedure using methallyl chloride.
1H-NMR (CDCl3): ꢀ = 0.6-2.2 (m, 21H), menthyl + methyl), 2.71
(d, 1 H, J = 13.0 Hz, CH2), 3.06 (d, 1 H, J = 13.0 Hz, CH2), 4.53 (s,
1 H, =CH2), 4.80(m, 2 H, =CH2, CH-O), 5.63 (d, 1 H, J = 8.1 Hz,
CHCH-N), 6.84 (d, 1 H, J = 7.9 Hz, CHar), 6.96 (m, 1H, CHar), 7.18
(m, 2 H, CHar), 7.54 ppm (m, 1H, CHar). 13C-NMR (CDCl3): ꢀ =
15.6; 20.6; 21.8; 23.0; 23.3; 26.2; 31.3; 33.9; 40.8; 46.9; 47.6; 59.4
(Cq); 77.8 (CHO); 105.5 (CH-CH-N); 117.9 (CN); 118.9 (=CH2);
In summary, we revised configurational assignment of
the Reissert compound 2a obtained from (-)-(R)-
menthylchloroformate and isoquinoline as a 1:1 epimeric
mixture. Alkylation of this Reissert compound at position
1 gave products 3 with no or marginal diastereo-
selectivities. Reissert compounds 2 and 3 could be used to
establish a number of new condensed isoquinolines, thus
reaction with Grignard-reagents has afforded imidazoiso-
quinolines 4, 7, 8 in a new connective scheme. Under acid
conditions, 1-(3-methoxybenzyl)-substituted Reissert
compound 2f underwent intramolecular Mannich
reactions to tetracyclic isoquinolines similar to naturally
occurring alkaloids.
Bromocyclisation of 1-allyl-
substituted Reissert compounds in methanol incorporated
two bromo atoms and methoxide, affording new
oxazinoisoquinolins 12 in a novel synthetic scheme.

1656
C. Fuchs, C. Bender, B. Ziemer, J. Liebscher
Vol 45
124.4; 124.8; 126.7; 127.2 ; 128.7; 128.9; 129.2; 138.2; 151.7 ppm
(CO). HRMS (EI) m/z: Calc. for C25H32N2O2: 392.2464, found
392.2465. Anal. Calcd. for C25H32N2O2 (392.53): C, 76.49; H,
8.22; N, 7.14. Found: C, 76.21; H, 8.41; N, 7.33.
(CDCl3): ꢀ = 3.32 (d, J = 13.20 Hz, 1.4 H, PhCH2); 3.61 – 3.76
(m, 1.6 H, PhCH2); 3.91 (s, 3 H, MeO); 5.46 (d, J = 8.43 Hz,1
H, PhCH); 6.92 (d, J = 9.35 Hz, 1H, CHN), 6.62 – 7.34 ppm (m,
9 H, aryl). 13C-NMR (CDCl3): ꢀ = 45.5 (CH2Ph); 54.1 (OCH3);
61.1 (C1); 78.1; 105.7 (CH=CH-N); 118.5 (CN); 124.2; 124.9;
127.3; 127.7, 128.1, 129.2; 129.5, 130.8, 132.8, 152.9 ppm
(CO). Anal. Calcd. for C19H16N2O2 (304.34): C, 74.98; H, 5.30;
N, 9.20. Found: C, 75.07; H, 5.28; N, 9.04.
Imidazo[5,1-a]isoquinolines 4 and 5 by Reaction of
Reissert Compounds 2b with Allyl Magnesium Bromide.
Reissert compound 2b (1.00 mmol) was dissolved in dry THF
(20 mL) and cooled to 0°C. Allylmagnesium chloride solution
(2.0 M in THF, 5 mL, 10 eq.) was added drop by drop under
stirring. The solution became turbid. After stirring for 2 days,
excess of Grignard reagent was destroyed by cautious addition
of saturated aq. NH4Cl solution (20 mL). The phases were
separated, and the aqueous phase extracted three times with
EtOAc (50 mL). The combined organic layers were dried over
MgSO4. The solution was then evaporated to dryness under
reduced pressure. Separation of by-products by column-
chromatography DCM/acetone 8:2) yielded 4 (120 mg, 0.568
mmol, 57%) as a yellow-brown oil and 5 (75 mg, 0.33 mmol,
33%) as a brown oil. 4 Rf: 0.44 (DCM/acetone 8:2), 5 Rf: 0.09
(DCM/(acetone 8:2)
1-Benzyl-1-cyano-2-[(R)-menthyloxycarbonyl]-1,2-dihy-
droisoquinoline (3d). The product was obtained in 74 % yield
following the general procedure but using equimolar quantities
of reactant 2 and benzyl chloride. If benzyltriethylammonium
chloride was used under the same conditions 69 % of 3d was
1
obtained together with 28 % of starting material 2. H-NMR
(CDCl3): ꢀ = 0.6-2.3 (m, 18 H, menthyl); 3.31 (t, 1 H, J = 12.6
Hz, ArCH); 3.60-3.95 (m, 1 H, ArCH); 4.70-5.00 (m, 1 H, CH-
O); 5.42 (d, d, 1 H, J1 = 7.18 Hz, J2 = 8.12 Hz); 6.60-7.50 ppm
(m, 9H, CHar). 13C-NMR (CDCl3): ꢀ = 16.2; 20.9; 22.0; 23.2;
26.5; 31.5; 34.1; 41.0; 46.0 (CH2Ph); 47.1; 60.8 (C-CN); 78.1;
105.4 (CH-CH-N); 118.8 (CN); 124.3; 124.7; 127.0; 127.2;
127.3; 127.6; 127.9; 128.0; 129.4; 130.8; 132.9; 152.0 ppm
(CO). HRMS (EI): Calc. for C28H32N2O2: 428.2464, found:
428.2465. Anal. Calcd. for C28H32N2O2 (428.57): C, 78.47; H,
7.53; N, 6.54. Found: C, 78.27; H, 7.80; N, 6.33.
1-(2-Bromobenzyl)-1-cyano-2-[(R)-menthyloxycarbonyl]-
1, 2-dihydroisoquinoline (3e). The product was obtained in 82
% yield following the general procedure using 2-bromobenzyl
1
bromide. H-NMR (CDCl3): ꢀ = 0.6-2.3 (m, 18 H, menthyl);
3.46 (m, 1 H, ArCH); 3.95 (m, 1 H, ArCH); 4.86 (m, 1 H, CH-
O); 5.56 (d, 1 H, J = 7.93 Hz); 6.70-7.50 ppm (m, 9H, CHar).
13C-NMR (CDCl3): ꢀ = 16.1; 20.9; 22.0; 23.1; 26.4; 31.5; 34.0;
41.0; 43.8; 47.0; 47.1; 53.5; 60.9; 78.2; 105.9 (CH-CH-N);
118.4 (CN); 124.5-132.9 (aromatic C and CH); 151.9 ppm (CO).
HRMS (EI): Calc. for C28H31BrN2O2: 506.1569, found:
506.1569. Anal. Calcd. for C28H31BrN2O2 (507.46): C, 66.27; H,
6.16; N, 5.52. Found: C, 66.02; H, 6.38; N, 5.29.
1,1-Diallyl-1,2-dihydroimidazo[5,1-a]isoquinolin-3(10bH)-one
(4). H-NMR (CDCl3): ꢀ = 2.20-2.30 (m, 1H); 2.45-2.60 (m,
1
2H); 2.65-2.75 (m, 1H); 4.60-5.00 (m, 2 H); 5.11 (d, 1 H); 5.16
(d, 1H, J = 4.49 Hz); 5.85-6.00 (m, 1 H); 6.68 (d, 1H, J = 4.49
Hz); 6.88-6.95 (m, 1H); 6.98-7.15 ppm (m, 3H). 13C-NMR
(CDCl3): ꢀ = 40.6 (CH2); 43.2 (CH2); 60.4 (CH); 64.7 (Cq);
105.8; 119.6 (=CH2); 120.2 (=CH2); 122.9; 124.5; 125.8; 126.4;
128.1; 131.3; 132.6; 132.9; 156.9 ppm (CO). Anal. Cald. For
C17H18N2O (266.34): C: 76.66, H: 6.81, N: 10.52. Found: C:
76.41, H. 6.97, N: 10.66.
1-Allylimidazo[5,1-a]isoquinolin-3(2H)-one (5). 1H-NMR
(CDCl3): ꢀ = 3.59 (m, 2 H, CH2-CH=CH2); 5.05-5.20 (m, 2 H,
=CH2); 5.85-6.00 (m, 1 H, -CH=CH2); 6.19 (d, 1 H, J = 7.61 Hz,
CH); 7.11-7.27 (m, 3 H, ArH); 7.30 (d, 1 H, J = 7.61 Hz, CH);
7.50-7.55 (m, 1H, ArH); 11.26 ppm (s, 1H, NH). 13C-NMR
(CDCl3): ꢀ = 30.4 (CH2); 110.4 (Cq-NH); 111.8; 115.4; 117.3
(=CH2); 120.3; 122.5; 125.9; 126.7; 127.0; 127.8; 129.0; 132.8;
148.9 ppm (CO). Anal. Calcd. for C14H12N2O (224.26): C:
74.98, H: 5.39, N: 12.49. Found: C: 74.72, H. 5.53, N: 12.36.
Imidazo[5,1-a]isoquinolines 7 and 8 by Reaction of
1-Cyano-1-(3-methoxybenzyl)-2-[(R)-menthyloxycarbonyl]-
1,2-dihydroisoquinoline (3f). The product was obtained in 89
% yield following the general procedure using 3-methoxybenzyl
bromide. 1H-NMR (CDCl3): ꢀ = 0.7-2.3 (m, 18 H, menthyl); 3.28
(m, 1 H, ArCH); 3.61 (d, 3 H, OCH3); 3.65-3.90 (m, 1 H, ArCH);
4.92 (m, 1 H, CH-O); 5.43 (dd, 1 H, J1 = 7.74 Hz, J2 = 8.12 Hz);
6.20+6.26 (s+s, 1H, CHar); 6.42 (d, J = 7.36 Hz, CHar); 6.65-6.85
(m, 2H, CHar); 6.94 (m, 1H, CHar); 7.0-7.5 ppm (m, 4H, CHar).
13C-NMR (CDCl3): ꢀ = 16.2; 20.9; 22.9; 23.2; 26.5; 31.5; 34.1;
41.0; 46.0 (CH2Ph); 47.1; 54.9 (OCH3); 60.8 (C1); 78.1; 105.3
(CH-CH-N); 113.7; 115.7; 118.8 (CN); 123.1; 124.4; 124.7;
127.2; 128.0; 128.8; 128.9; 129.4; 129.6; 134.3; 152.0 ppm (CO).
HRMS (EI) m/z: Calc. for C29H34N2O3 458.2569, found 458.2570.
Anal. Calcd. for C29H34N2O3 (458.59): C, 75.95; H, 7.47; N, 6.11.
Found: C, 75.77; H, 7.68; N, 5.87.
Alkylated Reissert Compounds
3
with Grignard
Reagents. Alkylated Reissert compound 3 (1.00 mmol) was
dissolved in dry Et2O (5 mL). Grignard reagent (3.00 mmol for
single addition, 4.00 mmol for double addition, as solution in
Et2O or THF) was added drop by drop under stirring. The
solution became turbid. After 3 h, excess of Grignard reagent
was destroyed by cautious addition of MeOH. The reaction
mixture was evaporated to dryness under reduced pressure,
taken up in EtOAc and the product was separated from by-
products by column chromatography (EtOAc/cyclohexane 1:1).
Final purification was done by crystallization from EtOAc by
evaporation to yield colourless crystals.
1-Allyl-1-cyano-1-2-methoxycarbonyl-1,2-dihydroiso-
quinoline (3g).
The product was obtained in 82 % yield
following the general procedure using 1-cyano-2-methoxy-
carbonyl-1,2-dihydroquinoline and allyl bromide. 1H-NMR
(CDCl3): ꢀ = 3.00 (dd, J1 = 1.38 Hz, J2 = 178.0 Hz, 1 H, PhCH2),
3.02 (dd, J1 = 1.38 Hz, J2 = 178.0 Hz, 1 H, PhCH2) 3.92 (s, 3 H,
MeO); 4.97 - 5.16 (2 H, m, =CH2), 5.50 – 5.62 (m, 1 H, CH=),
5.65 (d, J = 11.2 Hz, 1H, Ph-CH), 6.88 (d, J = 11.2 Hz, 1 H,
=CHN); 6.98 – 7.03, m, 1H, ArH); 7.20 – 7.32 (m, 2 H, ArH); 7.52
– 7.59 ppm (m, 1 H, ArH). Anal. Calcd. for C15H14N2O2 (254.28):
C, 70.85; H, 5.55; N, 11.02. Found: C, 70.76; H, 5.68; N, 10.96.
1-Benzyl-1-cyano-2-methoxycarbonyl-1,2-dihydroiso-
quinoline (3h). The product was obtained in 86 % yield
following the general procedure using 1-cyano-2-methoxy-
carbonyl-1,2-dihydroquinoline and benzyl chloride. 1H-NMR
Allyl-1-ethyl-1,2-dihydroimidazo[5,1-a]isoquinolin-
3(10bH)-one (7a). Following the general procedure 39 % yield
1
was obtained starting from the methyl carbamate (R = Me). H-
NMR (CDCl3): ꢀ = 1.18 (t, 3H, J = 7.41 Hz, CH3); 1.90-2.20 (m,
2H, ethyl); 2.39 (dq, 2H, J1 = 14.36 Hz, J2 = 7.19 Hz); 4.09 (m,
1H); 4.88-5.02 (m, 2H, =CH2); 5.66-5.82 (m, 2H, =CH-, NH);

Nov-Dec 2008
Synthesis of New Fused Isoquinolines Via Reissert Compounds
1657
5.86 (d, 1H, J = 7.43 Hz, 1H); 6.87 (d, 1H, J = 7.42 Hz); 7.06-
7.14 (m, 2H, ArH); 7.15-7.26 ppm (m, 2H, ArH). 13C-NMR
(CDCl3): ꢀ = 12.2 (CH3); 24.1 (CH2); 39.7 (CH2); 63.5 (Cq);
64.3 (CH); 107.7 (CH); 118.7 (CH2); 122.2 (CH); 122.5 (CH);
125.1 (CH); 126.7 (CH); 127.7 (CH); 131.1 (Cq); 132.6 (CH);
134.8 (Cq); 157.1 ppm (CO). Mp: 168-171 °C. HRMS (ESI)
m/z: Calcd. for C16H19N2O [M + H]+: 255.1492, found 255.1497.
Anal. Calcd. for C16H18N2O (254.33): C, 75.56; H, 7.13; N,
11.01. Found: C, 75.48; H, 7.33; N, 10.95.
Benzyl-1-ethyl-1,2-dihydroimidazo[5,1-a]isoquinolin-3-
(10bH)-one (7b). Following the general procedure 27 % yield
were obtained starting from the methyl carbamate (R = Me). 1H-
NMR (CDCl3): ꢀ = 1.19 (t, 3H, J = 7.39 Hz, CH3); 2.00-2.30 (m,
2H, ethyl CH2); 2.69 (d,1H, J = 13.12 Hz, ArCH2); 3.06 (d, 1H,
J = 13.13 Hz, ArCH2); 4.14 (dd, J1 = 10.82 Hz, J2 = 2.30 Hz,
1H); 5.23 (d, 1H, J = 7.48 Hz), 6.57 (d, 1H, J = 7.47 Hz); 4.60-
6.20 (br s, 1H, NH); 6.63-6.70 (m, 2H, ArH); 6.81-6.89 (m, 1H,
ArH); 6.98-7.06 (m, 2H, ArH); 7.09-7.17 (m, 1H, ArH); 7.17-
7.26 ppm (m, 3H, ArH). 13C-NMR (CDCl3): ꢀ = 12.4 (CH3);
24.0 (CH2); 43.0 (ArCH2); 64.6 (Cq); 66.0 (CH); 106.7 (CH);
123.1 (ArH); 123.1 (ArH); 124.8 (ArH); 126.3 (ArH); 126.8
(ArH); 127.3 (ArH); 127.9 (ArH); 130.7 (ArH); 132.3 (Cq);
133.5 (Cq); 135.5 (Cq); 157.6 ppm (CO). Mp: 224-226 °C.
HRMS (ESI) m/z: Calcd. for C20H21N2O [M + H]+: 305.1648,
found 305.1655. Anal. Calcd. for C20H20N2O (304.39): C, 78.92;
H, 6.62; N, 9.20. Found: C, 78.77; H, 6.73; N, 9.02.
using the achiral starting material (R = Me) provided 51 % yield of
the racemic product. H-NMR (CDCl3): ꢀ = 2.32-2.44 (m, 1 H);
1
2.45-2.56 (m, 1 H); 2.73-86 (m, 1H); 2.77 (d, J = 12.29 Hz, 1H,
ArCH2); 3.00-3.11 (m, 1H); 3.31 (d, J = 12.41 Hz, 1H, ArCH2);
4.77-4.86 (m, 1H); 4.88-4.98 (m, 2H); 5.30-5.41 (m, 2H); 5.41-
5.58 (m, 1H); 5.93-6.15 (m, 2H); 6.39 (d, 1H, J = 7.59 Hz); 6.59-
6.65 (m, 2H); 6.67-6.73 (m, 1H); 6.96-7.05 (m, 2H); 7.09-7.25 (m,
3H); 7.29-7,35 ppm (m, 1H). 13C-NMR (CDCl3): ꢀ = 39.5 (CH2);
41.9 (CH2); 46.3 (CH2); 68.3 (Cq); 68.9 (Cq); 104.4 (CH); 119.3
(CH2); 120.1 (CH2); 123.0 (CH); 124.9 (CH); 125.2 (CH); 125.9
(CH); 126.2 (CH); 127.1 (CH); 127.8 (CH); 130.4 (Cq); 131.0
(CH); 131.2 (CH); 133.2 (CH); 133.5 (Cq); 135.2 (Cq); 157.3 ppm
(CO). Mp: 162-164 °C. Anal. Calcd. for C24H24N2O (356.46): C,
80.87; H, 6.79; N, 7.86. Found: C, 81.01; H, 6.71; N, 7.65.
N-[(R)-Menthyloxycarbonyl]-2-methoxy-5,6,11,12-tetra-
hydro-dibenzo[a,e]cyclooctene-5,11-imin-11-carbonitrile (10)
(Method A). To a solution of 3f (235 mg, 0.51 mmol) in DCM
(10 mL) methyl triflate (60 μL, 0.53 mmol) was added. After 12
days at rt some colourless solid separated which was dissolved by
addition of some MeOH. The solution was washed with aqueous
saturated solution of NaHCO3 (5 mL). The solvent was distilled
off, the remaining slightly yellow foam (201 mg) was purified by
column chromatography (DCM) yielding 152 mg (65%) product
10. Almost colourless oil, Rf = 0.70 (DCM). 1H-NMR (CDCl3): ꢀ
= 0.5 – 2.3 (m, 18H, menthyl); 2.91 (d, 1 H, J = 16.5 Hz, ArCH);
3.21 (m, 1 H, ArCH); 3.58 (m, 1 H, ArCH); 3.72 (s, 3 H, OCH3);
4.07 (m, 1 H, ArCH); 4.76 (m, 1 H, CH-O); 5.75 (m, 1H, CH-N);
6.50 (s, 1H); 6.76 (m, 1 H, CHar); 7.00-7.15 (m, 2H, CHar); 7.22
(m, 1H, CHar); 7.30 (m, 1H, ); 7.70-7.80 (m, 1H). 13C-NMR
(CDCl3): ꢀ = 15.9; 20.6; 22.0; 23.2; 26.1; 31.4; 34.1; 36.5; 41.1;
47.1; 51.8; 55.1 (OCH3); 77.5; 113.1; 113.5; 120.6 (CN); 126.7-
133.6 (aromatic C and CH); 154.8; 155.6. HRMS (EI) m/z: Calcd.
for C29H35N2O3 [M + H]+: 459.2642, found 459.2649. Anal. Calcd.
for C29H34N2O3 (458.59): C, 75.95; H, 7.47; N, 6.11. Found: C,
76.02; H, 7.70; N, 6.03.
10b-(n-Butyl)-1,1-dimethyl-1,2-dihydroimidazo[5,1-a]-
isoquinolin-3(10bH)-one (8a). Following the general
procedure 66 % yield were obtained starting from the (R)-
1
menthyl carbamate [R = (R)-menthyl)]. H-NMR (CDCl3): ꢀ =
0.76 (t, 3 H, J = 7,22 Hz, CH3); 0.95-1.25 (m, 3 H, Butyl); 1,21
(s, 3 H, CH3); 1.35-1.70 (m, 2 H, Butyl); 1.61 (s, 3 H, CH3);
1.90-2.10 (m, 1 H, Butyl); 5.56 (d, 1 H, J = 7.58 Hz); 5.60-6.00
(br s, 1H, NH); 6.86 (d, 1 H, J = 7.56 Hz); 6.92-7.04 (m, 2H,
ArH); 7.04-7.18 ppm (m, 2H, ArH). 13C-NMR (CDCl3): ꢀ =
13.9 (CH3); 22.8 (CH3); 23.1 (CH2); 25.6 (CH2); 27.6 (CH3);
40.1 (CH2); 63.8 (Cq); 67.9 (Cq); 105.3 (CH); 123.6 (CH); 124.4
(CH); 125.0 (CH); 126.1 (CH); 127.4 (CH); 132.2 (Cq); 132.3
(Cq); 157.6 ppm (CO). Oil. HRMS (ESI) m/z: Calcd. for
C17H23N2O [M + H]+: 271.1805, found 271.1807. Anal. Calcd.
for C17H22N2O (270.37): C, 75.52; H, 8.20; N, 10.36. Found: C,
75.27; H, 8.43; N, 10.08.
2-Methoxy-5,6,11,12-tetrahydro-dibenzo[a,e]cyclooctene-
5,11-imin-11-carbamide (11). (Method B). 85% H3PO4 (2
mL) was added to a solution of 3g (235 mg, 0.51 mmol) in 99%
AcOH (6 mL). The solution was heated to 100°C for 15 h. After
dilution with water (10 mL), the solution was stirred in an ice-
bath and 3 M aqueous NaOH (60 mL) added dropwise. The pH
rose to about 14.
A colourless substance separated and
disappeared after extraction with CHCl3 (3 x 10 mL). The
combined organic layers were dried with MgSO4 and evaporated
to dryness with a rotary evaporator. A slightly yellow solid (109
mg, 73%) remained. It was dissolved in MeOH (about 5 mL) by
boiling, filtered hot and cooled to -24 °C. A white solid
substance seperated, which was centrifuged off, washed with
MeOH and dried. Yield 31 mg (21%) of a white powder, mp =
10b-Benzyl-1,1-dimethyl-1,10b-dihydro-2H-imidazo[5,1-a]-
isoquinolin-3-one (8b). Following the general procedure 40 %
yield of optically active product (ee = 14 %) were obtained
starting from the menthyl carbamate (R = (R) menthyl). 65 % of
racemic material was obtained, when the non-chiral starting
material (R = Me) was used. 1H-NMR (CDCl3): ꢀ = 1.32 (s, 3 H,
CH3); 1.77 (s, 3 H, CH3); 2.77 (d, 1H, J = 12.65 Hz, ArCH2);
3.34 (d, 1H, J = 12.66 Hz, ArCH2); 4.40-5.60 (br s, 1H, NH);
4.93 (d, 1H, J = 7.57 Hz); 6.44 (d, 1H, J = 7.56 Hz); 6.60-6.67
(m, 2H, ArH); 6.69-6.75 (m, 1H, ArH); 6.95-7.05 (m, 2H, ArH);
7.08-7.25 ppm (m, 4H, ArH). 13C-NMR (CDCl3): ꢀ = 22.9
(CH3); 27.6 (CH3); 45.2 (CH2); 64.2 (Cq); 69.1 (Cq); 104.8
(CH); 123.3 (CH); 124.8 (CH); 125.1 (CH); 126.1 (CH); 126.2
(CH); 127.3; 127.9; 130.8; 131.0; 133.2; 135.9; 157.1 ppm
(CO). Mp: 231.0-234 °C. HRMS (ESI) m/z: Calcd. for
C20H20N2ONa [M + Na]+: 327.1468, found 327.14.77. Anal.
Calcd. for C20H20N2O (304.39): C, 78.92; H, 6.62; N, 9.20.
Found: C, 79.07; H, 6.53; N, 9.09.
1
249-251 °C (MeOH). H-NMR (CDCl3): ꢀ = 2.65 (d, 1 H, J =
15.86 Hz); 3.11 (m, 2 H); 3.38 (dd, 1 H, J1 = 16.06 Hz, J2 = 5.29
Hz); 3.60 (s, 3 H, OCH3); 4.40 (d, 1 H, J = 4.53 Hz); 6.51 (d, 1
H, J = 2.26 Hz); 6.65 (dd, 1H, J1 = 8.31 Hz; J2 = 2.64 Hz); 6.92
(m, 1 H); 7.04 (m, 2H); 7.09 (d, 1H, J = 8.50 Hz); 7.15 (m, 1H,
NH); 7.32 (m, 1H, NH); 7.44 (m, 1H). 13C-NMR (CDCl3): ꢀ =
38.2 (CH2); 40.5 (CH2); 50.2 (CH); 55.3 (OCH3); 59.4 (Cq);
112.8 (CCONH2); 113.8 (CCONH2); 125.0 (CarH); 126.3 (CarH);
127.3 (CarH); 127.7 (CarH); 129.7; 131.5 (Cq); 133.6 (Cq); 135.6
(Cq); 138.2 (Cq); 177.1 (CONH2). HRMS (ESI) m/z: Calcd. for
C18H19N2O2 [M + H]+: 295.1441, found 295.1444. Anal. Calcd.
for C18H18N2O2 (294.14): C, 73.45; H, 6.16; N, 9.52. Found: C,
73.35; H, 6.22; N, 9.33.
1,1-Diallyl-10b-benzyl-1,2-dihydroimidazo[5,1-a]iso-
quinolin-3(10bH)-one (8c). Following the general procedure

1658
C. Fuchs, C. Bender, B. Ziemer, J. Liebscher
Vol 45
7-Bromo-2-bromomethyl-6-methoxy-1,6,7,11b-tetrahydro-
2H[1,3]oxazino[4,3-a]isoquinoline-4-on-11b-carbonitrile (12a)
(Method C). solution of the allyl-substituted Reissert
Acknowledgement. Donations of chemicals by Bayer
Services GmbH & Co. OHG, BASF AG, Sasol GmbH is
gratefully acknowledged.
A
compound 3a (385 mg, 1.0 mmol) in CH2Cl2 (7 mL) and methanol
(0.5 mL, 12 mmol) was stirred under argon in an ice bath. A
solution of bromine (332 mg, 2.1 mmol) in CH2Cl2 (2 mL) was
added dropwise over a period of 15 min. After stirring for 15 min,
the solution was washed with water (3 x 10 mL) and satd. aqu.
NaHCO3 (10 mL). The organic layer was dried (Na2SO4) and the
solvent distilled off. The remaining light yellow oil was purified
by column chromatography (AcOEt/cyclohexane 3:7) and the
resulting colorless foam was recrystallized from ethyl acetate.
Yield 35 %. Clear colourless crystals, mp = 207-209 °C
(decomposition), Rf = 0.46 (cyclohexane/EtOAc 7:3), chiral
HPLC: 28.1 min (100%, isopropanol/hexane 20:80). 1H-NMR
(DMSO-d6): ꢀ = 2.27 (m, 1 H, CH2CN); 3.35 (m, 1 H, CH2CN);
3.43 (s, 3 H, OCH3); 3.81-4.01 (m, 2 H, CH2Br); 5.11 (m, 1 H);
5.65 (d, 1 H, J = 2.26 Hz, CHOMe); 6.07 (d, 1H, J = 2.26 Hz,
CHBr); 7.50-7.71 ppm (m, 4H, CHar). 13C-NMR (DMSO-d6): ꢀ =
36.0 (CH2); 38.8 (CH2); 45.8 (CHBr); 52.9 (Cq); 57.7 (OCH3);
74.6 (CH-O); 84.9 (C-O CH3); 120.5 (CN); 127.3 (CarH); 130.5
(Car, q); 131.2 (CarH); 131.6 (CarH); 131.9 (CarH); 132.7 (Car, q);
151.7 ppm (CO). Anal. Calcd. for C15H14Br2N2O3 (430.09): C:
41.89, H: 3.23, N: 6.51. Found: C: 41.77, H: 3.48, N: 6.31
REFERENCES
[1] Reissert, A., Ber. Dtsch. Chem. Ges., 1905, 38, 1603;
Mosettig, E. and Mozingo, R., Organic Reactions, 1947, 4, 362;
Mcewen, W. E. and Cobb, R. L., Chem. Rev., 1955, 55, 511.
[2] Langer, P., Eur. J. Org. Chem., 2007, 2233; Schöpf, C. and
Thierfelder, K., Liebigs Ann. Chem., 1932, 497, 22.
[3] Munchhof, M. J. and Meyers, A. I., J. Org. Chem., 1996, 61,
4607.
[4] Sieck, O., Schaller, S., Grimme, S. and Liebscher, J., Synlett,
2003, 337.
[5] Takamura, M., Funabashi, K., Kanai, M. and Shibasaki, M.,
J. Am. Chem. Soc., 2000, 122, 6327.
[6] Funabashi, K., Ratni, H., Kanai, M. and Shibasaki, M., J. Am.
Chem. Soc., 2001, 123, 10784.
[7] Bender, C., PhD-Thesis, Humboldt-University Berlin, 2007.
[8] Gibson, H. W., Berg, M. A. G., Dickson, J. C., Lecavalier, P.
R., Wang, H. and Merola, J. S., J. Org. Chem., 2007, 72, 5759.
[9] Popp, F. D. and Gibson, H. W., J. Heterocycl. Chem., 1964,
1, 51; Walters, L. R., Iver, N. T. and McEven, W. E., J. Am. Chem. Soc.,
1958, 80, 1177; Boekelheide, V. and Godfrey, J. C., J. Amer. Chem.
Soc., 1953, 75, 3679.
7-Bromo-2-bromomethyl-2-methyl-6-methoxy-1,6,7,11b-
tetrahydro-2H[1,3]oxazino[4,3-a]isoquinoline-4-on-11b-
carbonitrile (12b) (Method D). To a solution of the Reissert
compound 3 (1.00 mmol) in DCM (5 mL) and MeOH (0.4 mL;
10 mmol) solid pyridiumhydrobromide-perbromide (3.00 mmol,
90% techn.) was added at 0°C and the solution was stirred at
0°C for 1 h. After washing with sat. aq. NaHCO3 (5 mL), 5%
Na2S2O3 (5 mL), and sat. aq. NaCl (5 mL), the solution was
dried with MgSO4 and evaporated to dryness under reduced
pressure. Purification by column chromatography (DCM or
EtOAc/cyclohexane 1:3) yielded white foams, which could be
crystallized from EtOAc. Yield 66 %. White crystals, mp = 160-
[10] Kubo, A., Nakahara, S., Inaba, K. and Kitahara, Y., Chem.
Pharm. Bull., 1986, 34, 4056; Kant, J. and Popp, F. D., J. Heterocycl.
Chem., 1985, 22, 1065.
[11] Boekelheide, V. and Ainsworth, C., J. Amer. Chem. Soc.,
1950, 72, 2134.
[12] Skiles, J. W. and Cava, M. P., Heterocycles, 1978, 9, 653.
[13] Kovacs, L. and Kerekes, P., Acta Chim. Hungarica, 1985,
120, 103; Popp, F. D. and Wefer, J. M., J. Heterocycl. Chem., 1967, 4,
183; Reimann, E., Grasberger, F. and Polborn, K., Monatsh. Chem.,
2003, 134, 991.
[14] Lorsbach, B. A., Bagdanoff, J. T., Miller, R. B. and Kurth,
M. J., J. Org. Chem., 1998, 63, 2244.
[15] Uff, B. C., Budhram, R. S., Consterdine, M. F., Hicks, J. K.,
Slingsby, B. P. and Pemblington, J. A., J. Chem. Soc., Perkin Trans. 1,
1977, 2018.
[16] Brozda, D., Hoffman, K. and Rozwadowska, M. D.,
Heterocycles, 2006, 67, 119.
[17] Ullah, E., Rotzoll, S., Schmidt, A., Michalik, D. and Langer,
P., Tetrahedron Lett., 2005, 46, 8997.
[18] Ichikawa, E., Suzuki, M., Yabu, K., Albert, M., Kanai, M.
and Shibasaki, M., J. Am. Chem. Soc., 2004, 126, 11808.
[19] Wanner, K. T., Beer, H., Hofner, G. and Ludwig, M., Eur. J.
Org. Chem., 1998, 2019; Youte, J. J., Barbier, D., Al-Mourabit, A.,
Gnecco, D. and Marazano, C., J. Org. Chem., 2004, 69, 2737; Battersby,
A. R. and Binks, R., J. Chem. Soc., 1955, 2888; Lee, K. H. and Soine, T.
O., J. Pharm. Sci., 1968, 57, 1922.
[20] Dyke, S. F., White, A. W. C. and Hartley, D., Tetrahedron,
1973, 29, 857; Yamada, K., Takeda, M., Itoh, N., Ohtsuka, H.,
Tsunashima, A. and Iwakuma, T., Chem. Pharm. Bull., 1982, 30, 3197.
[21] Sugiura, M., Asai, K., Hamada, Y., Hatano, K., Kurono, Y.,
Suezawa, H. and Hirota, M., Chem. Pharm. Bull., 1997, 45, 928.
[22] Sohár, P., Lázár, L., Fülöp, F., Bernáth, G. and Kóbor, J.,
Tetrahedron, 1992, 48, 4937; Lázár, L., Fülöp, F., Dombi, G., Bernáth,
G., Argay, G. and Kálmán, A., Tetrahedron, 1990, 46, 4039.
[23] Full details have ben deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no CCDC
653654 for 2a, CCDC 653660 for 7a, CCDC 653659 for 7b, CCDC
653656 for 8b,CCDC 653661 for 8c, CCDC 653657 for 11, CCDC
653655 for 12a, CCDC for 12b.
162 °C, [ꢁ]20 = +21.5° (c = 1, CH2Cl2), Rf = 0.31 (CH2Cl2).
D
1
Chiral HPLC: 22.5 min (100%, isopropanol/hexane 20:80). H-
NMR (CDCl3): ꢀ = 1.99 (s, 1 H, CH3); 2.72 (m, 2 H, CH2); 3.51
(m, 2 H, CH2Br); 3.53 (s, 3 H, OCH3); 5.21 (d, 1 H, J = 2.27 Hz,
CHOMe); 6.08 (d, 1 H, J = 2.27 Hz, CHBr); 7.35-7.55 ppm (m,
4H, CHar). 13C-NMR (CDCl3): ꢀ = 25.8 (CH3); 41.3 (CH2); 44.0
(CH2Br); 44.4 (CHBr); 50.6 (Cq); 57.5 (OCH3); 79.1 (C-O); 83.9
(C-O); 119.3 (CN); 126.1; 130.0; 130.2; 130.3; 130.8; 131.2;
152.0 ppm (CO). Anal. Calcd. for C16H16Br2N2O3 (444.12): C:
43.27, H: 3.63, N: 6.31. Found: C: 43.28, H: 3.78, N: 6.20.
1-Allyl-4-bromo-1-cyano-2-[(R)-menthyloxycarbonyl]-
3-methoxy-1,2,3,4-tetrahydroisoquinoline (13). Small
quantities of the product (yield not determined) were obtained,
when only one equivalent of bromine was used in Method C. 1H-
NMR (CDCl3): ꢀ = 0.60-2.30 (m, 18 H, menthyl), 3.10-3.70 (m,
5 H, OCH3, CH2), 4.76-5.02 (m, 2 H), 5.02-5.13 (m, 1 H), 5.14-
5.20 (m, 1 H), 5.40-5.70 (m, 1 H, OCH), 5.85-6.00 (br s, 1H);
7.28-7.44 (m, 3 H, CHar); 7.48-7.58 ppm (m, 1 H, CHar). 13C-
NMR (CDCl3): ꢀ = 15.5; 20.6; 20.9; 21.9; 22.6: 26.0; 31.4; 33.9;
34.0; 40.6; 41.0; 44.1; 46.8; 47.3; 56.1; 77.9 (CHO); 85.2
(NCHO); 119.3; 120.8; 127.0; 125-130 (aromatic C and CH);
154.8 ppm (C=O). HRMS (ESI) m/z: Calcd. for C25H33BrN2O3K
[M
+
K]+: 527.1306, found 527.1321. Anal. Calcd. for
C25H33BrN2O3 (489.44): C, 61.35; H, 6.80; N, 5.72. Found: C:
61.18, H: 6.78, N: 5.56.
[24] Popp, F. D., Katz, L. E., Klinowski, C. W. and Wefer, J. M.,
J. Org. Chem., 1968, 33, 4447.