A combined RCM-Bischler-Napieralski strategy towards the synthesis of the carbon skeleton of excentricine and related stephaoxocanes

Article abstract of DOI:10.1016/j.tet.2008.08.005

A convenient synthetic approach to a cyclodeca[ij]isoquinoline derivative, which embodies the carbon skeleton of excentricine and related stephaoxocanes, is described. The synthesis involves the combined use of ring closing metathesis and Bischler-Napiera

Full text of DOI:10.1016/j.tet.2008.08.005

Tetrahedron 64 (2008) 9921–9927
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A combined RCM-Bischler–Napieralski strategy towards the synthesis
of the carbon skeleton of excentricine and related stephaoxocanes
*
Enrique L. Larghi, Teodoro S. Kaufman
Instituto de Qu´ımica Rosario (IQUIR, CONICET-UNR), Facultad de Ciencias Bioqu´ımicas y Farmace´uticas, Universidad Nacional de Rosario,
Suipacha 531, S2002LRK Rosario, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 May 2008
Received in revised form 23 July 2008
Accepted 1 August 2008
Available online 9 August 2008
A convenient synthetic approach to a cyclodeca[ij]isoquinoline derivative, which embodies the carbon
skeleton of excentricine and related stephaoxocanes, is described. The synthesis involves the combined
use of ring closing metathesis and Bischler–Napieralski cyclizations for the construction of the homo-
cyclic and nitrogen-bearing rings, respectively.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Stephaoxocanes
Excentricine analogue
Bischler–Napieralski
RCM
Macrolactam cyclization
1. Introduction
The natural sources of the stephaoxocanes are herbaceous pe-
rennial wines or climbers employed in diverse folk medicine sys-
Plants employed as sources of traditional herbal remedies are
currently being scrutinized as part of the great worldwide effort
aimed to identify novel structures, develop new bioactive com-
pounds and turn them into powerful medicines.1 In the past two
decades, plants of the genera Stephania and Cissampelos (Menis-
permaceae) have gained considerable attention; their extracts1a,2
and several alkaloids isolated from them were shown to be
bioactive.2a,3
Phytochemical investigations carried out during the last 15
years in China, Brazil and Japan revealed the existence of the ste-
phaoxocanes, as a small family of eight isoquinoline alkaloids,
characterized by carrying the unique tetracyclic stephaoxocane
skeleton (1a).4a These alkaloids were isolated from Stephania
cepharantha Hayata, Stephania excentrica H. S. Lo, Stephania longa
Lour and Cissampelos glaberrima A. St. Hill, and include compounds
with the nitrogen-bearing heterocyclic ring at the isoquinoline
level (Fig. 1), such as in stephaoxocanidine (1b)4a and eletefine
(1c);4b in addition, they comprise a single example of a dihy-
droisoquinoline-type compound (stephaoxocanine, 2)4c and also
several tetrahydroisoquinolines [excentricine (3a)4d and stepha-
longanines A (3b) and B (3c)]4e and their N-methyl derivatives
[N-methylexcentricine (3d)4f and stephalonganine C (3e)].4e
tems of South America5 and the Far East, including Traditional
Chinese Medicine.6 Their uses include indications as diuretic, an-
tiphlogistic, antirheumatic, antiinflammatory, analgesic and sto-
machic agents, being also prescribed to treat different conditions,
such as dysentery, leukopenia, bleeding, urinary infections, paro-
tiditis, asthma, inflammation and fever.7 Despite their scarcity,
potential biological activity and intriguing structures, little work
has been carried out in the area of synthesis of stephaoxocanes and
their analogues.8
As part of our interest in the study of the synthesis and bio-
logical activity of the stephaoxocanes, we have reported the syn-
theses of 1,9-oxazafluoranthenes 4 and 5,9a–c which embody the
ABC-ring system of the stephaoxocanes and demonstrated that
tricyclic lactone 5 and some of its derivatives are inhibitors of the
enzyme acetylcholinesterase, a therapeutic target for the treatment
of Alzheimer’s disease, their potency being equivalent to that of
a daffodil (Narcissus pseudonarcissus) extract enriched in the ap-
proved anti-Alzheimer’s drug galanthamine.9d
More recently, we have also disclosed the sequential use of ring
closing metathesis (RCM) and Jackson’s cyclization for the prepa-
ration of compounds 6 and 7, which correspond to the carbon
framework of different stephaoxocanes.10
Herein, we describe a modification of our original strategic se-
quence that has culminated in the synthesis of cyclo-
deca[ij]isoquinoline derivative 7, which embodies the carbon
skeleton of the stephaoxocanes, displaying the nitrogenated ring as
* Corresponding author. Tel.: þ54 341 4370477x35; fax: þ54 341 4370477.
E-mail address: kaufman@iquios.gov.ar (T.S. Kaufman).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.005

9922
E.L. Larghi, T.S. Kaufman / Tetrahedron 64 (2008) 9921–9927
R1
Henry
Acylation
MeO
MeO
RCM
MeO
MeO
4
1
5
4a
8a
MeO
MeO
MeO
R2
R2
6
7
3
2
N
A
B
N
O
H
N
H
H
N
N
H
MeO
R
8
9
Bischler-
Napieralski
C
15
14
H
O
O
O
OH
D
10
12
13
11
8
7
R3
OH
OH
3a R= H
1a R1= R2= R3= H
1b R1= H, R2= OMe, R3= OH
1c R1= R2= OMe, R3= OH
2
3d R= Me
MeO
MeO
MeO
HO
CHO
MeO
MeO
CHO
MeO
N
N
MeO
R
1 N
MeO
R2
O
O
Me
O
Me
Claisen
Rearrangement
O
10
9
4
5
Scheme 1. Retrosynthetic analysis of target compound 7.
MeO
MeO
MeO
MeO
OH
N
N
3b R1= β-H, R2= H
3c R1= α-H, R2= H
3e R1= β-H, R2= Me
H
Therefore, the synthesis began with the O-allylation of vanillin
(10) with allyl bromide in refluxing EtOH, in the presence of K2CO3
as base, which afforded the known compound 11 in 99% yield as
shown in Scheme 2.14 In turn, 11 was subjected to a Claisen rear-
rangement in refluxing 1,2-dichlorobenzene as the inert, high
boiling solvent, furnishing 85% of 5-allyl vanillin (12),15 which was
finally submitted to O-methylation of its phenolic moiety with
methyl iodide in refluxing ethanol, with K2CO3 as base, quanti-
tatively providing the projected aldehyde 9.
6
7
Figure 1. Chemical structures of the stephaoxocane skeleton 1a, naturally occurring
stephaoxocanes (1b, 1c, 2 and 3a–e), synthetic tricyclic analogues of the stephaox-
ocanes (4–6) and the proposed target (7).
found in excentricine and stephalonganines A and B. This approach
entails the use of a RCM for the preparation of macrocyclic com-
pounds and Bischler–Napieralski’s isoquinoline synthesis for
accessing the nitrogen-bearing heterocyclic ring.
2
6
4
2'
1
3
1
3
2
5
5
MeO
RO
CHO
MeO
RO
CHO
MeO
MeO
NO2
b
d
1'
2
6
6
4
4
3
1
5
Although RCM has been employed in several strategies towards
the elaboration of isoquinoline derivatives,11 the combined use of
RCM and Bischler–Napieralski cyclization has scarce precedents.12
In principle, however, a sequence containing this association of
synthetic transformations should be advantageous over our pre-
viously described approach to 7,10 resulting in shorter routes to-
wards the target, which may also make less use of protecting
groups or even avoid their utilization.
10 R= H, Vanillin
11 R= CH2-CH=CH2
a
13
12 R= H
c
9
R= Me
f
e
6
2'
1
5
MeO
1'
1"
N
O
2
MeO
MeO
NH2
MeO 4
H
3
2"
3"
4"
6"
7"
5"
8
14
2. Results and discussion
Scheme 2. Reagents and conditions: (a) CH2]CHCH2Br, K2CO3, EtOH, reflux, 4 h (99%);
(b) 1,2-Cl2-C6H4, 185 ꢀC, 13 h (85%); (c) MeI, K2CO3, EtOH, reflux, 6 h (100%); (d) MeNO2,
(H3NCH2CH2NH3)þ2$2AcOꢁ, t-BuOH, 80 ꢀC, 24 h (95%); (e) LiAlH4, THF, 0 ꢀC/reflux,
5 h (90%); (f) 6-heptenoic acid, DCC, DMAP(cat.), ClCH2CH2Cl, 0 ꢀC/reflux, 15 h (54%).
The synthetic plan towards tricycle 7 was based on the retro-
synthetic analysis shown in Scheme 1, which hinged upon the use
of RCM and Bischler–Napieralski cyclizations of precursor 8, to
build the macrocyclic and heterocyclic features of the target. It was
expected that the amide chain of 8 could be easily constructed by
With the allyl benzaldehyde derivative 9 in hand, the next stage
acylation of the
b
-phenethylamino moiety with an
u
-olefin
consisted in the preparation and further acylation of the 3,4-
substituted acyl chloride, while the
b
-ethylamino chain itself could
dimethoxy b-phenethylamine 14. To that end, 9 was reacted with
be prepared by the Henry nitroaldol reaction of a suitably func-
tionalized benzaldehyde derivative.
nitromethane under promotion of ethylenediammonium diac-
etate16 yielding 95% of nitrostyrene 13, to which the E configuration
was assigned, in view of the value of the coupling constant
(J¼13.7 Hz) between both of its vinylic protons. The nitrostyrene
was next subjected to reduction with LiAlH4 in THF, providing
It was considered that the carbon–carbon disconnection
shown in Scheme 1 represented the most convenient alternative
to perform the RCM, since on one hand, this would entail the use
of an allylbenzenoid precursor (9) and on the other, the proximity
of one of the terminal double bonds to the carbonyl oxygen may
affect the cyclization. In fact, there are literature precedents by
the groups of Grubbs and Schrock, indicating that unproductive
metal complexes can result when the terminal double bond is
separated three bonds or less from the carbonyl moiety.13 Finally,
taking into account the neighbourhood of a phenolic group, 9
could be conveniently accessed by a Claisen rearrangement of the
corresponding allyl phenyl ether. In turn, this early intermediate
could result from the inexpensive and commercially available
vanillin (10).
b-phenethylamine 14; however, due to its ready oxidizability,
without further purification the latter was immediately acylated
with 6-hexenoic acid and DCC in refluxing 1,2-dichloroethane un-
der catalysis of DMAP, giving intermediate 8 in 54% overall yield.
Now, the stage was set to carry out the projected cyclizations. A
priori, performing the RCM before the Bischler–Napieralski syn-
thesis was considered less likely to give satisfactory results, since it
entailed the unusual formation of a 14-membered macrolactam
ring, which would then need to be regioselectively cyclized.17
Therefore, 8 was subjected to a Bischler–Napieralski cyclization
with phosphoryl chloride in refluxing acetonitrile, which smoothly

E.L. Larghi, T.S. Kaufman / Tetrahedron 64 (2008) 9921–9927
9923
furnished in almost quantitative yield 1,2-dihydroisoquinoline in-
termediate 15 (Scheme 3), as concluded from the observation of
NOE between H-4 and H-5 and by the value of the 13C NMR reso-
nance of OMe-6 (55.69 ppm); in case of formation of the undesired
dihydroisoquinoline a 4–5 ppm downfield shift of this carbon atom
should have been seen in its spectrum.18a The observed regiose-
lectivity of the reaction most probably stems from the fact that
cyclization para to the activating methoxy group is favoured over
the alternative ring closing reaction, at the position ortho to the
activating methyl ether. In the latter case, steric reasons may hinder
cyclization or lower the degree of activation of the aromatic ring
towards cyclization.18b,c
However, several attempts to perform the RCM of the di-olefin
to obtain 16, en route towards 7, including with the addition of
20 mol % titanium isopropoxide in order to block coordination of
the nitrogen atom of the dihydroisoquinoline to the ruthenium
species,19a met with failure; despite that the interaction of imines
with RCM catalysts leading to ring opening has been reported,19b no
such products were observed, and only unreacted starting material
was recovered.
N-acetyl derivative 17 (from 15), which was observed in its 1H NMR
spectrum as an approximately 1:1 mixture of amide rotamers, due
to hindered rotation around the amide C–N bond, with the
acetamido methyl group resonating at 2.11 and 2.13 ppm.20
Upon submission to reaction with Grubbs II catalyst, compound
17 quite efficiently underwent RCM, affording 68% of the tricyclic
derivative 18, to which the Z configuration was assigned on the
basis of previous observations for an analogous transformation10
andtheobservedvalueof thecouplingconstant(J¼10.8 Hz)between
the vinylic hydrogens H-8 and H-9. After conventional hydro-
genation of the olefinic double bond with pre-reduced Adams cat-
alyst, the resulting acetamide derivative 19 was exposed to a
refluxing mixture of MeOH and 12 N HCl (1:1, v/v),21 yielding the
expected tricycle 7, albeit in unsatisfactory 25% yield.
In view of the meager results of the deacetylation stage and in
order to evaluate the challenging and more direct route towards the
target compound 7, di-olefin 8 was subjected to RCM, furnishing
macrolactam 20 when the reaction was carried out with Grubbs I
catalyst in CH2Cl2 at room temperature. Interestingly, yields were
quite satisfactory (88%), and no need to protect the nitrogen of the
diene-amide precursor was required, as suggested by previous
studies.22a
The stereochemistry of 20 was deduced as E from the value of
the observed coupling constant (J¼17.6 Hz) between the vinylic
protons H-10 and H-11 of the macrocycle. This is consistent with
the observations of Weiler and co-workers on similarly sized lac-
tams, who also found that within this group, the geometry of the
double bond may be predicted.22b As expected, minor amounts of
the corresponding Z-macrolactam (Z-20) were also observed;22b
however, despite being inseparable from E-20, this was considered
not to be an obstacle for the synthesis.
Therefore, 15 was reduced with sodium borohydride and the
resulting tetrahydroisoquinoline was immediately subjected to
acylation with acetic anhydride and DMAP, providing 54% of the
1
2
MeO
MeO
15
14
16
17
MeO
MeO
g
f
3
4
N
O
N
O
H
H
13
5
6
12
11
MeO
7
10
8
N
O
MeO
H
9
20
The literature contains many examples on the preparation of 14-
membered lactam derivatives as intermediates towards natural
products or for studying their properties.23 However, despite the
wide use and recent popularity of the RCM reaction, the synthesis
of these macrolactams employing RCM has few and scattered
precedents. Among them, the group of Hoveyda employed a moly-
bdenum-based (Schrock) catalyst to prepare the cis-macrolactam
unit of fluvirucin B1,24a while Billard and co-workers have synthe-
8
a
21
h
5
4
3a
8a
MeO
MeO
MeO
6
7
MeO
MeO
3
X
N2
N
sized a 14-membered a
-trifluoromethyl lactam24b and the group of
N
MeO
3"
8
1
1'
Danishefsky has recently reported the RCM-mediated preparation
of 14-membered lactones en route to radicicol and aigialomycin
D,24c and the synthesis of a related 14-membered macrolactam.24d
The possibility of sequentially carrying out the RCM and the
hydrogenation of the resulting olefin with Grubbs catalyst as a one-
pot process was explored,25 employing 1,2-dichloroethane as
solvent; however, after performing the hydrogenation of 20 over
the ruthenium catalyst during 24 h (70 ꢀC, H2 at 100 psi), it was
observed that the reaction was not complete and more than one
product was present in the reaction medium. Therefore, the double
bond of 20 was hydrogenated under atmospheric pressure of hy-
drogen, with Adams catalyst in EtOH, uneventfully furnishing 91%
of 21 after 3–5 h at room temperature. Once subjected to the pro-
posed Bischler–Napieralski cyclization, with POCl3 in refluxing
benzene, lactam 21 regioselectively generated the 3,4-dihydro-
isoquinoline derivative 22 in 77% yield. Finally, atmospheric pres-
sure hydrogenation of the dihydroisoquinoline with 10% Pd/C in
MeOH completed the synthesis, furnishing 90% of compound 7, the
spectral data of which were in full agreement with those previously
reported.10
1"
2'
3'
2"
5'
6'
4'
22
15
16
i
b
3
4
3a
5
MeO
MeO
MeO
MeO
2
1
H
6
13a
13b
N
N
6a
7
Ac
13
12
8
10
9
11
7
17
MeO
MeO
MeO
MeO
e
c
d
N
N
Ac
Ac
19
18
In conclusion, two approaches towards the synthesis of tricyclic
compound 7, which embodies the carbon skeleton of excentricine
and related stephaoxocanes, were implemented, using a combined
RCM-Bischler–Napieralski strategy. Starting from the readily
available vanillin, and employing macrolactam 20 as key
intermediate, resulted in an efficient 10 steps sequence towards
Scheme 3. Reagents and conditions: (a) POCl3, MeCN, reflux, 1 h (95%); (b) (1) NaBH4,
THF/MeOH, 0 ꢀC, 1 h; (2) Ac2O, C5H5N, DMAP(cat.), CH2Cl2, 0 ꢀC, 4 h (54% from 15); (c)
Grubbs II catalyst, CH2Cl2, reflux, 22 h (68%); (d) H2 (1 atm), PtO2(cat.), EtOH, RT, 23 h
(99%); (e) 12 N HCl, MeOH (1:1, v/v), sealed tube, 90 ꢀC, 52 h (25%); (f) Grubbs I cat-
alyst, CH2Cl2, RT, 16 h (88%); (g) H2 (1 atm), PtO2(cat.), EtOH, RT, 3–5 h (91%); (h) POCl3,
C6H6, reflux, 27 h (77%); (i) H2 (1 atm), 10% Pd/C(cat.), MeOH, RT, 24 h (90%).

9924
E.L. Larghi, T.S. Kaufman / Tetrahedron 64 (2008) 9921–9927
the target, which was reached in 23% overall yield, without the
need of protective groups.
134.9 (OCH2CH]CH2), 152.5 (C-3), 156.1 (C-4) and 193.5 (CHO). A
solution of aldehyde 11 (3.60 g, 18.8 mmol) in 1,2-dichlorobenzene
(7 mL) was heated at 180–185 ꢀC until complete consumption of
the starting material was verified by TLC (12–16 h). Then, the so-
lution was passed through a short silica gel column, eluting with
hexanes in order to remove the 1,2-dichlorobenzene. Increasing
solvent polarity allowed the elution of ortho-allylphenol 12
(3.042 g, 85%), which was recovered as a solid, mp 82–84 ꢀC (hex-
ane/EtOAc). IR (KBr) nmax: 3250, 2968, 2852, 1675, 1589, 1469, 1303,
3. Experimental
3.1. General conditions
Melting points were taken on an Ernst Leitz Wetzlar model 350
hot-stage microscope and are reported uncorrected. FTIR spectra
were determined employing a Shimadzu Prestige 21 spectrophoto-
meter as solid dispersions in KBr disks, or as thin films held between
NaCl cells. The 1H and 13C NMR spectra were acquired in CDCl3 in
a Bruker Avance spectrometer (300.13 and 75.48 MHz for 1H and
13C, respectively), with tetramethylsilane (TMS) as internal stan-
dard. The chemical shifts are reported in parts per million down-
field from TMS and coupling constants (J) are expressed in hertz.
DEPT 135 and DEPT 90 experiments aided the interpretation and
assignment of the fully decoupled 13C NMR spectra. In special
cases, 2D-NMR experiments (COSY, HMBC, HMQC and J-resolved
spectra) were also employed. Pairs of signals marked with (#) or
1259, 1146, 1072, 912, 849, 734 and 651 cmꢁ1; 1H NMR (
d): 3.46 (br
d, 2H, J¼6.6, ArCH2CH]CH2), 3.96 (s, 3H, OMe), 5.11 (ddd, 1H, J¼1.7,
3.0 and 9.7, ArCH2CH]CH2cis), 5.12 (ddd, 1H, J¼1.7, 3.0 and 17.5,
ArCH2CH]CH2trans), 6.01 (dddd, 1H, J¼6.6, 6.6, 9.7 and 17.5,
ArCH2CH]CH2), 6.26 (s, 1H, OH), 7.31 (s, 2H, H-2 and H-6) and 9.81
(s, 1H, CHO); 13C NMR (
(C-6), 119.2 (ArCH2CH]CH2), 129.0 (C-2), 130.8 (C-1),
d
): 36.3 (ArCH2CH]CH2), 59.1 (OMe), 110.0
132.0 (C-3),
*
*
138.4 (ArCH2CH]CH2), 149.8 (C-5), 152.3 (C-4) and 193.9 (CHO).
Methyl iodide (1.4 mL, 22.5 mmol) was added to a mixture of
allylphenol 12 (2.05 g, 10.66 mmol) and K2CO3 (2.06 g, 14.9 mmol)
in absolute EtOH (20 mL). The resulting suspension was refluxed
until the reaction was completed, as judged by TLC (4 h). Then, the
solids were removed by filtration through Celite, the filtrate
washed with EtOH (3ꢂ5 mL), and the combined organic filtrates
were concentrated under reduced pressure. After addition of EtOAc
(70 mL), the solution was successively washed with 20% aqueous
K2CO3 (2ꢂ15 mL) and brine (2ꢂ15 mL). The organic phase was
dried (Na2SO4) and concentrated in vacuo to give 9 (2.20 g,100%), as
a colourless oil. IR (NaCl) nmax: 3090, 2941, 2836, 1695, 1586, 1486,
with an asterisk ( ) indicate that their assignments may be ex-
*
changed. High-resolution mass spectral data were obtained from
the University of California, Riverside (USA). The reactions were
carried out under dry nitrogen or argon atmosphere, employing
oven-dried glassware.
Reagents were used as received; dry THF and benzene were
prepared by distillation from Na-benzophenone ketyl; anhydrous
pyridine was prepared by distillation after refluxing the reagent 4 h
over pellets of KOH; dry CH2Cl2 and MeCN were prepared by a 4 h
reflux over P2O5 followed by distillation; anhydrous solvents were
stored in dry Young ampoules. In the conventional work-up pro-
cedure, the reaction was diluted with brine (5–10 mL) and the
products were extracted with EtOAc (4–5ꢂ20 mL); the combined
organic extracts were then washed once with brine (5 mL), dried
over Na2SO4 and concentrated under reduced pressure. The residue
was submitted to flash column chromatography with silica gel 60
H. Elution was carried out with hexane/EtOAc mixtures, under
positive pressure and employing gradient of solvent polarity
techniques.
1388, 1299, 1110, 1004, 915, 858 and 655 cmꢁ1; 1H NMR (
d): 3.46 (br
d, 2H, J¼6.6, ArCH2CH]CH2), 3.90 (s, 3H, OMe), 3.92 (s, 3H, OMe),
5.04 (ddd, 1H, J¼1.3, 3.0 and 17.1, ArCH2CH]CH2trans), 5.10 (ddd, 1H,
J¼1.3, 3.0 and 10.0, ArCH2CH]CH2cis), 5.97 (dddd, 1H, J¼6.6, 6.6,
10.0 and 17.1, ArCH2CH]CH2), 7.31 (d, 1H, J¼1.9, H-6),
*
7.33 (d, 1H,
(d): 36.8
J¼1.9, H-2),
*
and 9.87 (s, 1H, CHO); 13C NMR
(ArCH2CH]CH2), 58.7 (OMe-3), 63.6 (OMe-4), 112.0 (C-6), 119.14
(ArCH2CH]CH2), 129.30 (C-2), 135.14 (C-3), 137.2 (C-1), 139.2
(ArCH2CH]CH2), 155.5 (C-5), 156.1 (C-4) and 194.1 (CHO). Spectral
data of compounds 9, 11 and 12 were in good agreement with the
literature.14b
All new compounds gave single spots on TLC plates run in dif-
ferent hexane/EtOAc and CH2Cl2/toluene solvent systems. Chro-
matographic spots were detected by exposure to UV light (254 nm),
followed by spraying with ethanolic ninhydrin (amines) or with
ethanolic p-anisaldehyde/sulfuric acid reagent and careful heating
of the plates for improving selectivity.
3.3. E-1-Allyl-2,3-dimethoxy-5-(20-nitrovinyl)-benzene 13
A
solution of aldehyde 9 (670 mg, 3.25 mmol), MeNO2
(1.05 mL, 19.5 mmol) and anhydrous [NH3CH2CH2NH3]2þ$2AcOꢁ
(59 mg, 0.33 mmol) in dry t-BuOH (15 mL) was heated at 65 ꢀC.
After 17 h, the mixture was concentrated in vacuo; Celite
(200 mg) and EtOAc (20 mL) were added to the oily residue and
the resulting suspension was filtered through a short pad of
Celite. The filter was washed with EtOAc (2ꢂ5 mL) and the
combined filtrates were concentrated under reduced pressure,
yielding a yellow oil, which slowly solidified, affording nitro-
styrene derivative 13 (729 mg, 90%), as a bright yellow solid, mp
76–78 ꢀC. IR (KBr) nmax: 2976, 2834, 1634, 1559, 1490, 1334, 1293,
3.2. 3-Allyl-4,5-dimethoxy-benzaldehyde 9
Allyl bromide (2.1 mL, 24.51 mmol) was added to a stirred sus-
pension of vanillin (10, 2.87 g, 18.85 mmol) and K2CO3 (3.64 g,
26.4 mmol) in absolute EtOH (28 mL). The slurry was refluxed until
complete consumption of the starting material was observed by
TLC. Then, it was filtered through a pad of Celite, the filter was
washed with EtOH (3ꢂ5 mL) and the combined organic filtrates
were concentrated under reduced pressure. After addition of EtOAc
(80 mL), the solution was washed with brine (2ꢂ15 mL); the or-
ganic phase was dried over Na2SO4 and concentrated in vacuo to
give aldehyde 11 (3.61 g, 99%), as an oil. IR (NaCl) nmax: 3100, 2939,
2835, 1684, 1586, 1424, 1394, 1258, 1136, 1033, 995, 809, 731 and
1153, 1007, 970 and 832 cmꢁ1
;
1H NMR (
d
): 3.41 (br d, 2H, J¼6.5,
ArCH2CH]CH2), 3.88 (s, 3H, OMe), 3.90 (s, 3H, OMe), 5.08 (ddd,
1H, J¼1.7, 3.0 and 16.7, ArCH2CH]CH2trans), 5.09 (ddd, 1H, J¼1.7,
3.0 and 10.3, ArCH2CH]CH2cis), 5.95 (dddd, 1H, J¼6.4, 6.4, 10.3
662 cmꢁ1; 1H NMR (
d
): 3.94 (s, 3H, OMe), 4.71 (dt, 2H, J¼2.6 and 5.3,
and 16.7, ArCH2CH]CH2), 6.93 (d, 1H, J¼2.1, H-4),
*
7.01 (d, 1H,
OCH2CH]CH2), 5.35 (ddd, 1H, J¼1.3, 2.6 and 10.5, OCH2CH]CH2),
5.44 (ddd, 1H, J¼1.3, 2.6 and 16.8, OCH2CH]CH2), 6.09 (dddd, 1H,
J¼5.3, 5.3, 10.5 and 16.8, OCH2CH]CH2), 6.97 (d, 1H, J¼8.6, H-3),
7.40 (d, 1H, J¼1.9, H-2), 7.43 (dd, 1H, J¼1.9 and 8.6, H-2) and 9.85 (s,
J¼2.1, H-6),
*
7.51 (d, 1H, J¼13.7, H-20) and 7.93 (d, 1H, J¼13.7,
H-10); 13C NMR (
d): 33.9 (ArCH2CH]CH2), 55.9 (OMe-3), 60.9
(OMe-2), 110.4 (C-4), 116.5 (–CH]CH2), 124.4 (C-6), 125.5 (C-5),
135.0 (C-1), 136.1 (ArCH2CH]CH2),
136.3 (C-10), 139.2 (C-20),
*
*
1H, CHO); 13C NMR (
2), 114.6 (C-5), 121.3 (OCH2CH]CH2), 129.1 (C-6), 132.9 (C-1),
d
): 56.6 (OMe), 72.4 (OCH2CH]CH2), 112.0 (C-
150.8 (C-2) and 153.2 (C-3); HRMS (CI) Calcd for C13H16NO4
*
*
(MHþ): 250.1079; found: 250.1071.

E.L. Larghi, T.S. Kaufman / Tetrahedron 64 (2008) 9921–9927
9925
3.4. Hept-6-enoic acid [2-(3-allyl-4,5-dimethoxy-phenyl)-
ethyl]-amide 8
2H, J¼4.6, 8.6 and 11.4, H-3), 3.79 (s, 3H, OMe-14), 3.86 (s, 3H, OMe-
15), 5.35 (br s, 1H, w1/2¼15 Hz, NH), 5.45 (ddd, 1H, J¼9.4, 15.7 and
17.6, H-10), 5.56 (ddd, 1H, J¼6.5,16.2 and 17.6, H-11) and 6.56 (s, 2H,
A solution of nitrostyrene 13 (857 mg, 3.44 mmol) in THF
(3.5 mL) was introduced via cannula during 5 min into an ice-cooled
suspension of LiAlH4 (784 mg, 20.6 mmol) in anhydrous THF
(27 mL). The system was submitted to reflux during 5 h, then cooled
toroomtemperature, dilutedwithEt2O(10 mL)andcarefullytreated
with H2O (0.81 mL), 15% NaOH (1.16 mL) and saturated KF solution
(2.64 mL). The mixture was stirred for 30 min and then filtered
through Celite. The Celite was washed with Et2O (4ꢂ5 mL) and the
combined organic filtrates were concentrated in vacuo to furnish the
unstable 2-(3-allyl-4,5-dimethoxy-phenyl)-ethylamine 14, as an
oil. IR (NaCl) nmax: 3361, 3299, 2936, 2834, 1639, 1588, 1489, 1290,
H-1 and H-17); 13C NMR (
d): 24.4 (C-7), 26.8 (C-8), 30.4 (C-9), 31.1 (C-
12), 35.3 (C-2), 35.7 (C-6), 39.7 (C-3), 55.8 (OMe-15), 60.9 (OMe-14),
110.2 (C-1), 123.5 (C-17), 131.2 (C-10), 131.3 (C-11),
*
*
134.5 (C-13),#
134.7 (C-16),# 145.3 (C-14), 153.2 (C-15) and 173.3 (C-4); HRMS (CI)
Calcd for C18H26NO3 (MHþ): 304.1913; found: 304.1906. Without
further purification, macrolactam 20 (87 mg, 0.287 mmol) was
dissolved in absolute ethanol (10 mL). The resulting solution was
transferred to a suspension of PtO2 (4 mg, 0.018 mmol) in EtOH
(4 mL) and the reaction was stirred under H2 at atmospheric pres-
sure until complete consumption of the olefin was verified by TLC.
The suspension was filtered through a small pad of Celite and the
filter was washed with EtOH (1 mL); the combined filtrates were
concentrated in vacuo and the residue was chromatographed,
affording amide 21 (80 mg, 91%), as a solid, mp 127–129 ꢀC (hexane/
EtOAc). IR (KBr) nmax: 3269, 2928, 2855,1639,1560,1488,1357,1231,
1148, 1010, 912 and 736 cmꢁ1; 1H NMR (
d): 1.67 (br s, 2H, NH2), 2.68
(t, 2H, J¼6.9, H-20), 2.94 (t, 2H, J¼6.9, H-10), 3.38 (d, 2H, J¼6.5,
ArCH2CH]CH2), 3.79 (s, 3H, OMe), 3.85 (s, 3H, OMe), 5.04 (ddd, 1H,
J¼1.3, 3.0 and 10.1, ArCH2CH]CH2cis), 5.06 (ddd, 1H, J¼1.3, 3.0 and
17.0, ArCH2CH]CH2trans), 5.96 (dddd, 1H, J¼6.5, 6.5, 10.1 and 17.0,
1148 and 1017 cmꢁ1; 1H NMR (
d): 1.18–1.28 (m, 4H, H-9 and H-10),
ArCH2CH]CH2), 6.60 (d, 1H, J¼1.5, H-6)
*
and 6.62 (d, 1H, J¼1.5, H-
1.30–1.41 (m, 2H, H-7), 1.62–1.75 (m, 4H, H-8 and H-11), 2.09–2.19
(m, 2H, H-6), 2.69 (dd, 2H, J¼6.2 and 12.0, H-12), 2.80 (br t, 2H, J¼5.9,
H-2), 3.56 (dd, 2H, J¼5.9 and 11.7, H-3), 3.77 (s, 3H, OMe-14), 3.86 (s,
3H, OMe-15), 5.26 (br s,1H, w1/2¼15 Hz, NH), 6.59 (d,1H, J¼2.0, H-1)
2); d
*
13C NMR ( ): 34.0 (ArCH2CH]CH2), 39.7 (C-20), 43.3 (C-10), 55.7
(OMe-5), 60.6 (OMe-4), 111.1 (C-6), 115.5 (ArCH2CH]CH2), 122.1 (C-
2), 133.7 (C-3), 135.3 (C-1), 137.3 (ArCH2CH]CH2), 145.4 (C-4) and
152.6 (C-5). Without further purification, the crude amine 14
(684 mg, 3.10 mmol) was dissolved in ClCH2CH2Cl (41 mL) and
and 6.63 (d, 1H, J¼2.0, H-17); 13C NMR (
d): 25.0 (C-11), 26.2 (C-7),
26.7 (C-10), 27.0 (2C, C-9 and C-8), 27.6 (C-12), 34.7 (C-2), 36.4 (C-6),
39.6 (C-3), 55.7 (C-15), 60.5 (C-14), 109.8 (C-1), 122.2 (C-17), 133.8
cooled to 0 ꢀC in an ice-water bath. 6-Heptenoic acid (210
mL,
1.55 mmol) and DMAP(cat.) were successively added; the mixture
was stirred for 5 min, and then solution of DCC (478 mg, 2.32 mmol)
in ClCH2CH2Cl (2 mL) was introduced via cannula. The cooling bath
was removed and after the reaction reached room temperature (1 h)
it was submitted to reflux (12 h) until complete consumption of the
starting amine was ascertained by TLC. The solvent was removed
under vacuum, and the oily residue was chromatographed to give
amide 8 (274 mg, 54%), as a colourless oil. IR (NaCl) nmax: 3303, 3078,
2933, 2859, 1729, 1641, 1549, 1490, 1289, 1148, 1011, 911 and
(C-16),
*
135.6 (C-13), 146.2 (C-14), 153.1 (C-15) and 173.2 (C-4);
*
HRMS (CI) Calcd for C18H28NO3 (MHþ): 306.2069; found: 306.2059.
3.6. 5,6-Dimethoxy-2,3,7,8,9,10,11,12,13,13a-decahydro-1H-
cyclodeca[ij]isoquinoline 7 from 3,4-dihydro-isoquinoline
derivative 22
Recently, distilled POCl3 (0.24 mL) was slowly added to
a refluxing solution of amide 21 (18 mg, 0.058 mmol) in anhydrous
benzene (3.0 mL). After 28 h, when the reaction was completed
(TLC), the volatiles were removed under reduced pressure and the
oily residue was alkalinized with aqueous Na2CO3 (2 mL). The
product was extracted with EtOAc (5ꢂ2 mL) and the organic ex-
tracts were combined, dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by column chromato-
graphy, furnishing tricyclic derivative 22 (13 mg, 77%), as an oil. IR
(NaCl) nmax: 2933, 2847,1669, 1590,1464,1311,1293, 1133,1020, 910
733 cmꢁ1
;
1H NMR (
d
): 1.41 (dd, 2H, J¼8.2 and 15.4, H-400),
*
1.65
(ddd, 2H, J¼5.7, 7.9 and 15.4, H-300),
2.06 (br dd, 2H, J¼7.6 and 14.4,
*
H-500), 2.14 (t, 2H, J¼7.6, H-200), 2.74 (t, 2H, J¼7.0, H-20), 3.39 (dt, 2H,
J¼1.4 and 6.6, ArCH2CH]CH2), 3.50 (dd, 2H, J¼7.0 and 12.9, H-10),
3.80 (s, 3H, OMe), 3.85 (s, 3H, OMe), 4.95 (ddd, 1H, J¼1.0, 2.0 and
10.2, H-700cis), 5.00 (ddd,1H, J¼1.0, 2.0 and 17.2, H-700trans), 5.05 (ddd,
1H, J¼1.5, 3.0 and 10.3, ArCH2CH]CH2cis), 5.06 (ddd, 1H, J¼1.5, 3.0
and 17.0, ArCH2CH]CH2trans), 5.44 (br s, w1/2¼15 Hz, NH), 5.78
(dddd,1H, J¼6.7, 6.7,10.3 and 17.0, ArCH2–CH]CH2), 5.95 (dddd,1H,
J¼6.3, 6.3, 10.2 and 17.2, H-600), 6.58 (d, 1H, J¼2.1, H-2) and 6.62 (d,
and 731 cmꢁ1; 1H NMR (
d): 1.42–1.60 (m, 4H, H-8 and H-11), 1.61–
1.75 (m, 4H, H-9 and H-10), 1.76–1.95 (m, 2H, H-12), 2.40–2.70 (m,
2H, H-3), 2.50 (dt, 2H, J¼6.8 and 13.5, H-13), 3.02 (dt, 2H, J¼7.6 and
15.2, H-7), 3.30–3.59 (m, 2H, H-2), 3.78 (s, 3H, OMe-6), 3.89 (s, 3H,
1H, J¼2.1, H-6); 13C NMR (
d
): 25.2 (C-300), 28.5 (C-400), 33.4 (C-500),
34.0 (ArCH2CH]CH2), 35.6 (C-20), 36.6 (C-200), 40.6 (C-10), 55.8
(OMe-5), 60.7 (OMe-4), 110.9 (C-6), 114.7 (]CH2), 115.6 (]CH2),
OMe-5) and 6.63 (s, 1H, H-5); 13C NMR (
d): 22.4 (H-10), 23.3 (H-11),
122.1 (C-2), 133.8 (C-3), 134.6 (C-1), 137.3 (ArCH2CH]CH2),
*
138.4
23.6 (C-7), 25.5 (C-12), 26.3 (C-8), 28.5 (H-9), 28.8 (C-13), 33.7 (C-3),
46.6 (C-2), 55.6 (OMe-5), 60.9 (OMe-6), 108.4 (C-4), 123.9 (C-13b),
135.9 (C-3a),137.6 (C-6a),146.4 (C-5),153.3 (C-6) and 169.8 (C-13a);
HRMS (CI) Calcd for C18H26NO2 (MHþ): 287.19645; found: 288.1957.
Without further purification, dihydroisoquinoline derivative 22
(3.0 mg, 0.0104 mmol) was dissolved in MeOH (1 mL), 10% Pd/C
(1 mg) was added and the resulting suspension was vigorously
stirred 7 h under a H2 atmosphere. The catalyst was separated by
filtration through a short pad of Celite and the filter was washed
with EtOH (6ꢂ1 mL). The filtrates were combined and concentrated
under reduced pressure, affording tetrahydroisoquinoline de-
(CH2CH]CH2),
145.6 (C-4),152.8 (C-5) and 173.0 (C-100); HRMS (CI)
*
Calcd for C20H30NO3 (MHþ): 332.2218; found: 332.2226.
3.5. 14,15-Dimethoxy-4-aza-bicyclo[11.3.1]heptadeca-
1(16),13(17),14-trien-5-one 21
A solution of Grubbs I catalyst (42 mg, 0.05 mmol) in CH2Cl2
(5 mL) was added dropwise, in 90 min, to a refluxing solution of
amide 8 (158 mg, 0.478 mmol) in CH2Cl2 (260 mL). The mixture was
further refluxed during 18 h; then the volatiles were removed under
reduced pressure. The remaining dark oil was chromatographed,
affording macrolactam 20 (128 mg, 88%), as colourless needles, mp
126–128 ꢀC (hexane/EtOAc). IR (KBr) nmax: 3259, 3078, 2934, 2844,
rivative 7 (2.7 mg, 90%), as a solid, mp 216–218 ꢀC. IR (KBr) nmax
3650–3320, 3200–2400, 1588, 1475, 1308, 1235, 1122, 1022, 921,
842, 731 and 644 cmꢁ1 1H NMR (
): 1.21–1.48 (m, 4H, H-9, H-10
:
;
d
1637, 1559, 1485, 1358, 1287, 1143, 1080, 1005 and 665 cmꢁ1
NMR ( ): 1.45–1.56 (m, 2H, H-8), 1.62–1.72 (m, 3H, H-6 and H-7),
2.08 (dt, 1H, J¼8.0 and 9.7, H-6), 2.11 (dd, 2H, J¼5.5 and 13.1, H-9),
2.68 (t, 2H, J¼4.6 and 8.6, H-2), 3.37 (d, 2H, J¼6.5, H-12), 3.40 (ddd,
;
1H
and H-11), 1.52–1.77 (m, 5H, H-8, H-9, H-11 and H-12), 1.80–2.06
(m, 2H, H-8 and H-13), 2.13–2.39 (m,1H, H-13), 2.59 (ddd,1H, J¼3.4,
3.5 and 10.5, H-7), 2.90 (ddd, 1H, J¼3.4, 3.6 and 10.5, H-7), 3.03
(ddd, 2H, J¼3.4, 6.1 and 17.7, H-3), 3.31 (ddd, 1H, J¼3.4, 6.1 and 9.6,
d

9926
E.L. Larghi, T.S. Kaufman / Tetrahedron 64 (2008) 9921–9927
H-2), 3.71 (ddd, 1H, J¼3.4, 6.1 and 9.6, H-2), 3.80 (s, 3H, OMe-6),
3.84 (s, 3H, OMe-5), 4.95 (t, 1H, J¼6.8, H-13a), 6.58 (s, 1H, H-4) and
3.8. 1-(5,6-Dimethoxy-2,3,7,8,9,10,11,12,13,13a-deca-hydro-
cyclodeca[ij]isoquinolin-1-yl)ethanone 19
9.58 (br s, 1H, w1/2¼9 Hz, NH); 13C NMR (
d
): 23.7 (C-9),
*
25.2 (C-10),
25.4 (C-3), 25.8 (C-12), 26.0 (C-7), 27.7 (C-11),
*
28.1 (C-8), 31.5 (C-
A solution of Grubbs II catalyst (3 mg, 3.52 mmol) in CH2Cl2 (2 mL)
13), 37.0 (C-2), 51.4 (C-13a), 55.4 (OMe-5), 60.1 (OMe-6),110.6 (C-4),
was added dropwise during 120 min to a refluxing solution of amide
17 (25.2 mg, 0.0.71 mmol) in CH2Cl2 (35.8 mL) and the mixture was
further refluxed for 24 h. Then, the solution was concentrated under
reduced pressure and the remaining dark oil was chromatographed,
furnishing macrocycle 18 (16 mg, 68%) as a colourless oil, which was
observed as a 2:1 mixture of rotamers by 1H and 13C NMR. IR (NaCl)
nmax: 2933, 2857, 1623, 1600, 1419, 1332, 1234, 1120, 1030, 910 and
124.1 (C-6a),
*
127.8 (C-13b), 134.9 (C-3a), 146.9 (C-6) and 152.1 (C-
*
5); HRMS Calcd for C18H28NO2: 290.2120 (MHþ); found: 290.2124.
Data of 7 were in agreement with the literature.10
3.7. 1-(8-Allyl-1-hex-5-enyl-6,7-dimethoxy-3,4-dihydro-1H-
isoquinolin-2-yl)-ethanone 17
732 cmꢁ1; 1H NMR (
d): 1.02–1.50 (m, 4H, H-11 and H-12), 1.65–2.19
Freshly distilled POCl3 (0.43 mL) was added dropwise to a reflux-
ing solution of amide 8 (92 mg, 0.278 mmol) in anhydrous MeCN
(5.3 mL), and the mixture was stirred (ca. 1 h) until complete con-
sumption of the starting material (TLC). The volatiles were removed
under reduced pressure, the oily residue was diluted with EtOAc
(2 mL) and basified with saturated aqueous NaHCO3 (5 mL). The re-
action products were extracted with EtOAc (5ꢂ2 mL), the organic
extracts were combined, dried over Na2SO4 and concentrated under
reduced pressure. Chromatography of the residue furnished 15
(83 mg, 95%), as an oil. IR (NaCl) nmax: 2935, 2853, 1640, 1591, 1464,
(m, 4H, H-10 and H-13), 2.09 (s, 2H, MeCO), 2.30 (s,1H, MeCO), 2.69–
2.90 (m,1H, H-3), 3.02–3.46 (m, 2H, H-3 and H-4), 3.55–3.65 (m,1H,
H-7), 3.78–3.88 (m, 2H, H-4 and H-7), 3.85 (s, 2H, OMe), 3.86 (s, 3H,
OMe), 3.88 (s,1H, OMe), 5.28 (dd, 0.34H, J¼5.7 and 11.0, H-13a), 5.34
(ddd,1H, J¼5.2,10.8 and 10.9, H-9), 5.81–5.95 (m,1H, H-8), 6.12 (dd,
0.66H, J¼5.4 and 10.4, H-13a), 6.63 (s, 0.66H, H-4) and 6.64 (s, 0.34H,
H-4); 13C NMR (
(C-12),
d
): 20.7 and 21.0 (C-11), 22.0 and 22.4 (MeCO), 25.4
*
*
26.5 and 26.6 (C-7),# 27.9 and 28.8 (C-4),# 29.1 and 29.2 (C-
10),# 35.8 and 37.0 (C-13), 40.2 and 43.2 (C-2), 50.4 and 54.9 (C-13a),
55.7 (OMe-5), 60.6 (OMe-6), 110.3 and 110.8 (C-4), 127.9 and 128.2
1308, 1291, 1139, 1022, 910 and 943 cmꢁ1; 1H NMR (
d): 1.00–1.90 (m,
(C-8),
133.1 (C-6a),
and 169.5 (MeCO); HRMS (CI) Calcd for
*
129.0 and 129.8 (C-9),
145.7 and 146.0 (C-5), 151.2 and 151.4 (C-6), and 169.3
20H28NO3 (MHþ):
*
131.0 (C-13b),
*
131.5 and 131.9 (C-3a),
*
4H, H-20 and H-30), 2.01 (dd, 2H, J¼7.3 and 14.4, H-40), 2.55 (t, 2H,
J¼6.6, H-4), 2.80(t, 2H, J¼7.3, H-10), 3.46(t, 2H, J¼6.6, H-3), 3.63(d, 2H,
J¼5.3, H-100), 3.79 (s, 3H, OMe), 3.91 (s, 3H, OMe), 4.86–5.08 (m, 4H,
*
C
330.2069; found: 330.2062. A solution of 18 (23 mg, 0.068 mmol) in
absolute EtOH (2.0 mL) was submitted to hydrogenation at atmo-
spheric pressure, employing PtO2 (1.1 mg) as catalyst. After 24 h, the
mixture was filtered through a short pad of Celite and the filtrate
was concentrated in vacuo. The residue was chromatographed,
affording compound 19 (23 mg, 99%) as an oil, which was observed
H-60 and H-300), 5.75 (dddd, 1H, J¼6.8, 6.8, 10.6 and 17.0, H-50),
*
5.99
(dddd, 1H, J¼5.3, 5.3, 10.6 and 15.5, H-300),
*
and 6.70 (s, 1H, H-5); 13
C
NMR (d
): 27.9 (C-4), 28.6 (2C, C-20 and C-30), 31.5 (C-100), 33.5 (C-40),
38.5 (C-10), 45.9 (C-3), 55.7 (OMe-6), 60.8 (OMe-7), 109.4 (C-5), 114.4
(C-300),
*
114.6 (C-8a), 115.7 (C-60),
123.2 (C-4a), 131.3 (C-8), 136.9 (C-
*
200),# 137.1 (C-6),138.7 (C-50),# 146.7 (C-7) and 154.0 (C-1); HRMS (CI)
Calcd for C20H28NO2 (MHþ): 314.2120; found: 314.2116. Without
furtherpurification,dihydroisoquinoline15 (80 mg, 0.255 mmol)was
dissolved in a mixture of dry THF (6.1 mL) and anhydrous MeOH
as a 1.4:1 mixture of rotamers by 1H and 13C NMR. IR (NaCl) nmax
:
;
2932, 2859, 1640, 1598, 1482, 1312, 1234, 1120, 1026 and 734 cmꢁ1
1H NMR (
d): 1.03–2.00 (m,10H, H-8, H-9, H-10, H-11 and H-12), 2.08
(s, 1.75H, MeCO), 2.24 (s, 1.25H, MeCO), 2.55–3.60 (m, 8H, H-7, H-13,
H-2 and H-3), 3.80 (s, 3H, OMe-6), 3.86 (s, 3H, OMe-5), 5.19 (dd,
0.58H, J¼5.7 and 10.0, H-13a), 6.04 (dd, 0.42H, J¼5.7 and 10.0, H-13a)
(93 mL); thesolutionwascooled in an ice bathand treated with NaBH4
(22 mg, 0.582 mmol). After consumption of the imine was verified by
TLC, the solvent was removed in vacuo and the resulting white gum
was suspended in CH2Cl2 (4.3 mL), cooled at 0 ꢀC and dry pyridine
(0.23 mL, 2.97 mmol), Ac2O (0.14 mL, 1.54 mmol) and a catalytic
amount of DMAP were successively added. After 5 h, the mixture was
diluted with CH2Cl2 (20 mL) and successively washed with saturated
aqueous solutions of NaHCO3 (5 mL), NH4Cl (5 mL) and NaCl (5 mL).
The organic layer was dried over Na2SO4 and concentrated under
reduced pressure, giving a residue, which was chromatographed,
affording acetamide derivative 17 (54 mg, 54% from 8), as a white
solid, mp 220–222 ꢀC (hexane/EtOAc), which was observed as
and 6.63 (s, 0.58H, H-4) and 6.65 (s, 0.42H, H-4); 13C NMR (
d): 21.8
and 22.4 (MeCO), 23.1 and 23.6 (C-11), 24.5 and 25.0 (C-12), 26.1 and
26.2 (C-10), 26.5 and 26.6 (C-7), 28.0 (2C, C-8, C-9), 28.8 (C-3), 33.6
and 34.2 (C-13), 40.3 and 43.3 (C-2), 48.7 and 53.1 (C-13a), 55.6
(OMe-5), 60.1 and 60.2 (OMe-6), 110.1 and 110.6 (C-4), 128.8 and
129.8 (C-13b), 130.6 and 131.0 (C-3a), 133.6 and 134.9 (C-6a), 146.3
and 146.6 (C-5), 151.2 and 151.4 (C-6), and 169.3 and 169.6 (C]O);
HRMS (CI) Calcd for C20H29NO3 (MHþ): 332.2226; found: 332.2216.
3.9. 3,4-Dihydroisoquinoline 7 from acetamide 19
a roughly 1:1 mixture of rotamers by 1H and 13C NMR. IR (KBr) nmax
2933, 2856, 1641, 1598, 1429, 1339, 1235, 1120, 1028, 911 and
735 cmꢁ1; 1H NMR ( ): 1.30–1.50 (m, 4H, H-20 and H-30),1.60–1.70 (m,
:
Acetamide 19 (17 mg, 0.051 mmol) was dissolved in a 1:1 (v/v)
mixture of MeOH and 12 N HCl (0.94 mL), confined in a sealed
ampoule and subjected to hydrolysis at 95 ꢀC during 20 h. Then, the
reaction mixture was made alkaline with a saturated aqueous
NaHCO3 solution and the products were extracted with Et2O
(5ꢂ5 mL). The organic extracts were combined, dried over Na2SO4
and concentrated under reduced pressure; the residue was chro-
matographed to afford compound 7 (3.65 mg, 25%), as a solid, mp
216–218 ꢀC. The spectral data of this product were in full agreement
with the literature10 and with those recorded for compound 7,
obtained from 22.
d
2H, H-10), 1.96–2.09 (m, 1H, H-40), 2.11 (s, 1.5H, MeCO), 2.13 (s, 1.5H,
MeCO), 2.70–2.99 (m, 2H, H-4), 3.14–3.25 (m,1H, H-3), 3.33–3.42 (m,
0.5H, H-3), 3.50–3.60 (m, 0.5H, H-3), 3.62–3.71 (m, 2H, H-100), 3.79 (s,
3H, OMe-7), 3.84 (s, 3H, OMe-6), 4.66 (dd, 0.5H, J¼4.1 and 7.6, H-1),
4.79 (dd, 0.5H, J¼3.8 and 10.6, H-1), 4.86–5.09 (m, 4H, H-300 and H-60),
5.78 (dddd,1H, J¼6.8, 6.8,10.0 and 16.7, H-200),
5.96 (dddd,1H, J¼6.2,
*
10.3 and 16.7, H-50), 6.56 (s, 0.5H, H-5) and 6.58 (s, 0.5H, H-5); 13C
*
NMR (d
): 21.9 and 22.1 (MeCO), 25.0 and 25.9 (C-20), 26.1 and 27.6 (C-
30), 28.7 (C-100), 29.8 and 30.3 (C-4), 33.5 and 33.6 (C-10), 34.0 and 35.1
(C-3), 35.3 and 35.5 (C-40), 49.0 and 54.4 (C-1), 55.6 (OMe-6), 60.7 and
60.9 (OMe-7),110.7 and 111.2 (C-5),114.3 and 114.8 (C-60),
*
115.33 and
128.9 and 129.0 (C-8a),# 129.4 and 129.8 (C-4a),# 130.2
and 130.6 (C-8),# 136.8 and 137.2 (C-200), 138.4 and 138.9 (C-50),
Acknowledgements
115.4 (C-300),
*
*
*
The authors are thankful to Consejo Nacional de Investigaciones
´ ´
Cientıficas y Tecnicas (CONICET), Universidad Nacional de Rosario
145.7 and 146.1 (C-6), 151.2 and 151.4 (C-7) and 169.4 and 169.7
(MeCO); HRMS (CI) Calcd for C22H32NO3 (MHþ): 358.2382; found:
328.2375.
´
´
´
and Agencia Nacional de Promocion Cientıfica y Tecnologica
(ANPCyT) for financial support (projects Nꢀ 5439, 06-12532 and

E.L. Larghi, T.S. Kaufman / Tetrahedron 64 (2008) 9921–9927
9927
10. Bracca, A. B. J.; Kaufman, T. S. Eur. J. Org. Chem. 2007, 5284.
06-38165). ELL acknowledges CONICET for his post-doctoral
fellowship.
11. For examples on the synthesis of isoquinoline derivatives employing RCM, see:
(a) Kuznetsov, N. Yu.; Lyssenko, K. A.; Peregudov, A. S.; Bubnov, Yu. N. Russ.
Chem. Bull. 2007, 56, 1569; (b) Mori, M.; Wakamatsu, H.; Tonogaki, K.; Fujita, R.;
Kitamura, T.; Sato, Y. J. Org. Chem. 2005, 70, 1066; (c) Bubnov, Yu. N.; Kuznetsov,
N. Yu.; Gurskii, M. E.; Semenova, A. L.; Kolomnikova, G. D.; Potapova, T. V. Pure
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