Stereoselective synthesis of thiaerythrinanes based on an α-amidoalkylation/RCM approach

Article abstract of DOI:10.1016/j.tet.2007.11.053

Parham cyclisation-intermolecular α-amidoalkylation and nucleophilic addition-intramolecular α-amidoalkylation sequences constitute diastereocomplementary?routes to 1,10b-cis and trans thiazolo[4,3-a]isoquinolinones. These thiazolidinediones, that incorpo

Full text of DOI:10.1016/j.tet.2007.11.053

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1323e1332
www.elsevier.com/locate/tet
Stereoselective synthesis of thiaerythrinanes based
on an a-amidoalkylation/RCM approach
*
Media Noori Abdullah, Sonia Arrasate, Esther Lete, Nuria Sotomayor
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencia y Tecnolog´ıa, Universidad del Pa´ıs Vasco/Euskal Herriko Unibertsitatea,
Apdo. 644, 48080 Bilbao, Spain
Received 24 October 2007; received in revised form 14 November 2007; accepted 16 November 2007
Available online 21 November 2007
Abstract
Parham cyclisationeintermolecular a-amidoalkylation and nucleophilic additioneintramolecular a-amidoalkylation sequences constitute
diastereocomplementary routes to 1,10b-cis and trans thiazolo[4,3-a]isoquinolinones. These thiazolidinediones, that incorporate allyl groups
at C-1 and C-10b, are efficient precursors of thiaerythrinanes by ring-closing metathesis reactions.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Lithiation; Lithiumehalogen exchange; a-Amidoalkylation; Parham cyclisation; Heterocycles; Thiareythrinanes
1. Introduction
type alkaloids.5 This approach is complementary to the tandem
organolithium additioneN-acyliminium ion cyclisation sequence
with N-phenethylimides, which also constitutes an effective route
to several types of isoquinoline alkaloids. Although intramolecu-
lar a-amidoalkylation reaction6 has been widely used in the ste-
reocontrolled synthesis of nitrogen heterocycles, relatively minor
effort has been dedicated to stereoselective Parham cyclisation.
However, its potential as a useful stereoselective cyclisation
procedure has proven extremely interesting.7 Thus, we have
demonstrated that both types of cyclisations constitute diastereo-
complementary to 1,10b-cis and 1,10b-trans thiazolo[4,3-a]-
isoquinoline systems.8 Besides, we have also achieved the
asymmetric synthesis of C-10b substituted pyrrolo[2,1-a]isoqui-
nolines in both enantiomeric forms.9
In this context, our next challenge was to achieve 7-thiaery-
thrinanes 1 by a strategy that involves Parham cyclisatione
intermolecular a-amidoalkylation or nucleophilic additione
intramolecular a-amidoalkylation sequence of thiazolidinediones
3 or 4 to afford thiazoloisoquinolines 2, which incorporate
two allyl groups on C-1 and C-10b. Finally, ring A could be
assembled through ring-closing metathesis (RCM) (Fig. 1).
In addition, the stereochemical features of these sequences
would be studied using thiazolidinediones 3 or 4 that incorpo-
rate substituents of different size at C-5.
The aromatic metalationecyclisation sequence has become
a valuable protocol for the regioselective construction of carbo-
cyclic and heterocyclic systems. However, certain electrophilic
groups, such as ketones and imides, do not remain passive dur-
ing the metalation process and competitive nucleophilic attack
by organolithium base may occur. In these cases, one can take
advantage of the very fast rate of metalehalogen exchange1
compared with nucleophilic addition to carbonyl groups to al-
low aromatic metalation and subsequent intramolecular cycli-
sation reactions, which are known as Parham cyclisations.2
Our work in this field has demonstrated that iodinated N-
phenethylimides tolerate iodineelithium exchange, giving
rise to the isoquinoline nucleus via a Parham-type cyclisation.3
Since the so-obtained fused isoquinolones posses a a-hydroxy-
lactam function, they represent immediate precursors of bicy-
clic N-acyliminium ions,4 which can be transformed into
a variety of derivatives via intermolecular a-amidoalkylation
with different nucleophiles. This has been illustrated in the syn-
thesis of isoindolo[1,2-a]isoquinoline skeleton of nuevamine-
* Corresponding author. Tel.: þ34 946015389; fax: þ34 946012748.
E-mail address: nuria.sotomayor@ehu.es (N. Sotomayor).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.053

1324
M.N. Abdullah et al. / Tetrahedron 64 (2008) 1323e1332
11
5
6
CH3O
CH3O
16
12
8
CH3O
CH3O
a
CH3O
CH3O
10
4b-d
RCM
O
7
N
N
10b
N
O
6
O
14
10
S
HO
S
R
S
2
3
R1
1
1
R
2
6a R1 = allyl (88%)
b R1 = H
1
2
c R1 = CH3 (53%, dr 7:3)
inter- or intramolecular
-amidoalkylation
1 = H
b
R
X
CH3O
CH3O
CH3O
CH3O
3
N
O
O
CH3O
CH3O
N
N
O
O
5
S
R
S
S
R1
3 X = H
4 X = I
2a R1 = H (59% from 4c,
dr >95:5)
7 (80%)
b R1 = CH3 (53% from 4d,
dr >95:5)
Figure 1.
Scheme 2. Reagents: (a) t-BuLi, THF, ꢀ78 ꢁC, 2e21 h. (b) TiCl4, allyltrime-
thylsilane, CH2Cl2, ꢀ78 ꢁC.
2. Results
To begin our study, a series of thiazolidine-2,4-diones were
prepared as depicted in Scheme 1. Thus, dialkylation of thiazol-
idinedione 58was achieved with sec-BuLi/TMEDA and allyl
iodide at ꢀ50 ꢁC. However, the best yield of the monoalkyl-
ated product 3b was obtained with LDA at ꢀ78 ꢁC. Finally,
methylation of 3b afforded 3c in moderate yield. The iodinated
mono- and dialkylated products were obtained in a similar
fashion, from iodinated thiazolidinedione 4a.8
Firstly, we decided to study the Parham cyclisation on thi-
azolidines 4bed (Scheme 2). To test the reaction conditions
and the regioselectivity of the cyclisation, the C-5 disubsti-
tuted thiazolidine-2,4-dione 4b was chosen as substrate.
Iodineelithium exchange was carried out with t-BuLi at
ꢀ78 ꢁC in THF and, after work-up, 10b-hydroxy thiazoloiso-
quinoline 6a was obtained in high yield. As expected, the
addition of the organolithium intermediate proceeded
regioselectively at the more electrophilic amide carbonyl
group, in spite of steric hindrance of the substituents at C-5.
Under similar conditions, iodineelithium exchange was faster
than C-5 deprotonation on C-5 monosubstituted thiazolidine
4c, and cyclisation took place efficiently with complete regio
and stereoselectivity to afford 10b-hydroxy thiazoloisoquino-
line 6b. However, this product was highly unstable and par-
tially decomposed upon purification to the enamide 7.
Finally, treatment of 4d with t-BuLi afforded thiazoloiso-
quinoline 6c, as a mixture of diastereomers in a 7:3 ratio,
which could not be chromatographically separated. The ste-
reoselectivity of this reaction has no relevance in the global
process, as a planar N-acyliminium ion is going to be gener-
ated in the next step.
As these bicyclic a-hydroxylactams 6 are immediate
precursors of N-acyliminium ions, intermolecular a-amido-
alkylation was undertaken using TiCl4 at ꢀ78 ꢁC and allyltri-
methylsilane as nucleophile to introduce an allyl substituent
on C-10b. However, disubstituted hydroxylactam 6a failed to
give the expected a-amidoalkylation product under various
conditions, recovering unreacted starting material probably
because of steric factors associated with the size of substitu-
ents at C-5, which may block the approach of the nucleophile.
However, thiazoloisoquinolines 2a,b were obtained as single
1,10b-trans diastereomers (Scheme 2).
CH3O
CH3O
CH3O
CH3O
a
N
S
N
O
O
O
O
S
R1
R2
3a R1 = R2 = allyl (40%)
b R1 = allyl, R2 = H (46%)
c R1 = allyl, R2 = CH3
(66%)
5
c
b
I
Our next concern was the intramolecular a-amidoalkylation
route to 10b-substituted thiazolo[4,3-a]isoquinolines. Thus,
addition of allylmagnesium chloride to imides 3aec was car-
ried out under standard conditions (THF, ꢀ78 ꢁC, 6 h), afford-
ing a-hydroxylactams 8aec with complete regioselectivity
and as single diastereomer. As expected, attack of Grignard
reagent took place regioselectively at the more electrophilic
carbonyl group. The stereochemistry of these products was
not determined, as a planar N-acyliminium ion was going to
be generated in the subsequent a-amidoalkylation reaction,
N
S
O
O
CH3O
CH3O
R1
R2
4a R1 = R2 = H (81%)
b R1 = R2 = allyl (73%)
d
d
c R1 = allyl, R2 = H (72%)
d R1 = allyl, R2 = CH3 (78%)
e
Scheme 1. Reagents: (a) LDA or sec-BuLi/TMEDA, allyl iodide or MeI,
ꢀ50 ꢁC. (b) sec-BuLi/TMEDA, allyl iodide or MeI, ꢀ40 ꢁC. (c) ICl, AcOH,
5 h. (d) LDA, allyl iodide, ꢀ78 ꢁC. (e) sec-BuLi/TMEDA, MeI, ꢀ40 ꢁC.

M.N. Abdullah et al. / Tetrahedron 64 (2008) 1323e1332
1325
CH3O
CH3O
disposition of allyl groups in thiazoloisoquinoline 2a. In the
case of thiazoloisoquinoline 9c the NOE enhancement be-
tween methylidene proton at C-10b and methylene group at
C-1 and the absence of NOE between methyl group at C-1
and the methylene group at C-10b confirm the cis disposition
for these substituents.
The stereochemical outcome in both inter- and intramolec-
ular a-amidoalkylation reaction is controlled by the substitu-
ents on the ring. Thus, attack of the nucleophile occurs from
the less hindered side of the intermediate N-acyliminium
ion, opposite to the bulkiest substituent, to afford 1,10b-cis
or 1,10b-trans thiazoloisoquinolines, respectively (Fig. 3).
We next turned our attention to the synthesis of thiaerythri-
nanes 1. Firstly, we studied the ring-closing metathesis reac-
tion of thiazoloisoquinolines 2a,b.
a
3a-c
N
O
HO
S
R1
8a R1 = allyl (88%)
b R1 = H (90%)
c R1 = CH3 (87%)
b
b
R
1 = H
CH3O
CH3O
CH3O
N
S
N
O
O
CH3O
S
R1
Olefin RCM has become a powerful tool in organic synthe-
sis, which is routinely applied to construct cyclic olefins of
virtually all ring sizes bearing ether, ester, amide, amine and
other functionalities.10 However, few examples of substrates
containing sulfur atoms have been so far reported.11 Molybde-
num12 and tungsten13 catalysts were the first known catalysts
to display efficiency in metathesis reactions on substrates con-
taining sulfur atoms. More recently, first generation Grubbs’
catalyst was shown to perform enyne metathesis of sulfur-
containing alkynes and RCM reactions of acyclic sulfones,14
a-thiophosphonate,15 sulfamides16 and phenylthiopyridones.17
The potential of second generation Grubbs’ catalyst (11)18 in
RCM reactions involving acyclic diene sulfides, disulfides
and dithianes has been also investigated.19 This catalyst has
been successfully employed in the synthesis of more complex
9a R1 = allyl (97%)
c R1 = CH3 (96%, dr 70:30)
10 (96%)
Scheme 3. Reagents: (a) allylMgCl, THF, ꢀ78 ꢁC, 6 h. (b) TFA, CH2Cl2,
reflux, 3e4 days.
but attack of the nucleophile presumably occurred from the
less hindered side, opposite to the allyl group. The intramole-
cular a-amidoalkylation was achieved by treatment of hydroxy-
lactams 8a and 8c with an excess of TFA in dichloromethane
under reflux for 3e4 days. The cyclisation of 8a,c occurred ef-
ficiently to afford the thiazoloisoquinoline nucleus, but iso-
merisation of the allyl group at C-10b was also observed.
The formation of a conjugated system in the N-acyliminium
ion intermediate may be the driving force of this process.
cis-Thiazoloisoquinoline 9c was obtained in good yield
(96%) but with a poor diastereoselectivity (dr 70:30). The
mixture of diastereomers could not be chromatographically
separated. However, cyclisation of monosubstituted 8b failed
upon treatment with protic acid (TFA) and different Lewis
acids (TiCl4, BF3$OEt2), under different conditions. In all
cases, the dehydration reaction to the enamide was faster
than intramolecular a-amidoalkylation, obtaining enamide 10
(Scheme 3).
X
N
O
O
CH3O
CH3O
S
R1
3, 4
R2
X = I
X = H
The relative stereochemistry of 1,10b-trans and cis thiazo-
loisoquinolines was confirmed by nuclear Overhauser effect
1
difference spectroscopy and He1H decoupling experiments.
Nu
Selected examples are represented in Figure 2. For example,
the NOE enhancement between H-1 and the methylene group
at C-10b and the absence of NOE between the methylene
groups at C-1 and C-10b were consistent with the trans
O
N
N+
CH3O
CH3O
O
CH3O
CH3O
S
R3
R2
S
R2
R1
R1
no NOE
X
no NOE
X
O
N
S
CH3
O
CH3O
CH3O
O
N
N
CH3O
CH3O
O
CH3O
CH3O
CH3O
CH3O
N
S
R2
Nu
S
S
R3
R1
H
R1
R2
NOE
1,10b-trans
1,10b-cis
NOE
2a
9c
2
9
Figure 2.
Figure 3. Stereochemical outcome of the a-amidoalkylation reactions.

1326
M.N. Abdullah et al. / Tetrahedron 64 (2008) 1323e1332
CH3O
CH3O
CH3O
CH3O
3. Conclusion
a
N
N
O
S
O
We have shown that the Parham cyclisationeintermolecular
S
a-amidoalkylation and nucleophilic additioneintramolecular
a-amidoalkylation sequences constitute diastereocomplemen-
tary routes to 1,10b-trans and cis thiazolo[4,3-a]isoquinol-
inones. Thus, intermolecular a-amidoalkylation reactions with
allyltrimethylsilane allows the stereoselective synthesis of
1,10b-trans diallyl substituted thiazolo[4,3-a]isoquinolinones
2. However, the intramolecular a-amidoalkylation reactions
of a-hydroxythiazolidinones take place with isomerisation of
the 10b-allyl group, thus leading to 1,10b-cis 1-allyl-10b-pro-
penylthiazolo[4,3-a]isoquinolinones 9. The synthesis of thiaery-
thrinanes can be achieved by a strategy that involves Parham
cyclisationeintermolecular a-amidoalkylation sequence, fol-
lowed by ring-closing metathesis (RCM) reaction. This
procedure for the synthesis of thiaerythrinane and spiro-
isoquinoline derivatives shows the synthetic potential of the
methodologies developed for the preparation of thiazolo-
[4,3-a]isoquinolinones.
R1
R1
1a R1 = H (83%)
b R1 = CH3 (79%)
2a, b
Mes N NMes
Ph
Cl
Cl
Ru
PCy3
11
Scheme 4. Reagents: (a) second generation Grubbs’ catalyst 11 (10 mol %),
CH2Cl2, reflux, 12 h.
sulfur-containing heterocycles, such as thienocarbazoles20 and
thiepinpyrones.21
Thus, thiazoloisoquinolines 2a,b were treated with
10 mol % of the second generation Grubbs’ catalyst 11 to afford
the corresponding thiaerythrinane derivatives 1a,b in good
yield (Scheme 4). The relative stereochemistry of the centres
at C-5 and C-6 of the thiaerythrinanes 1a,b was confirmed by
2D NOESY and COSY experiments.
Next, we studied the feasibility of performing the ring-clos-
ing metathesis reaction on thiazoloisoquinolines 9a and 9c.
However, metathesis reaction on 9a using second generation
Grubbs’ catalyst 10 took place between the two terminal double
bonds instead of the internal alkene, to form a five membered
ring, affording spiro derivative 12 in good yield. In case of
9c, the reaction failed and starting material was recovered
(Scheme 5).
4. Experimental section
4.1. General
Melting points were determined in unsealed capillary tubes
and are uncorrected. IR spectra were obtained on KBr pellets
(solids) or neat (oils). NMR spectra were recorded at 20e
25 ꢁC, running at 250 MHz for H and 62.8 MHz for 13C in
1
CDCl3 solutions. Assignment of individual 13C resonances is
supported by DEPT experiments. He{1H} NOE experiments
1
CH3O
CH3O
CH3O
CH3O
a
N
N
were carried out in the difference mode by irradiation of all the
lines of a multiplet.25 Mass spectra were recorded under elec-
tron impact at 70 eV. GCeMS analyses were performed using
a TRB-1 column (methyl polysiloxane, 30 mꢂ0.25 mmꢂ
0.25 mm). TLC was carried out with 0.2 mm thick silica gel
plates. Visualisation was accomplished by UV light. Flash
column chromatography26 on silica gel was performed with
Kiesegel 60 (230e400 mesh). All solvents used in the reac-
tions were anhydrous and purified according to standard
procedures.27 Organolithium reagents were titrated with
diphenylacetic acid periodically prior to use. All air- or mois-
ture-sensitive reactions were performed under argon; the glass-
ware was dried (130 ꢁC) and purged with argon.
O
O
S
S
9a
12(86%)
Scheme 5. Reagents: (a) second generation Grubbs’ catalyst 11, CH2Cl2,
reflux.
To illustrate the synthetic utility of the procedure, we decided
to use a reductive desulfurisation procedure22 to transform these
thiaerythrinanes into the corresponding spiroisoquinoline deriv-
atives, which could posses interesting pharmacological proper-
ties.23 Thus, a Raney nickel slurry was added to a solution of
thiazoloisoquinolone 1a in EtOH, and the solution was heated
under reflux for 7 h to obtain spiroisoquinoline 13 in good yield,
where reduction of the double bond had also occurred (Scheme
6). This method could effectively compete with other methods
for the synthesis of these types of heterocycles.24
4.2. C-Alkylation of N-phenethylimides
4.2.1. 5,5-Diallyl-3-[2-(3,4-dimethoxyphenyl)-
ethyl]thiazolidine-2,4-dione (3a)
s-BuLi (0.8 mL of 0.78 M solution, 0.6 mmol) was added
to a solution of TMEDA (0.09 mL, 0.6 mmol) in dry THF
(5 mL), at ꢀ50 ꢁC. The mixture was stirred at ꢀ50 ꢁC for
30 min, then a solution of 5 (0.16 g, 0.56 mmol) in dry THF
(8 mL) was added slowly and via cannula, and the reaction
mixture was stirred for 1 h 30 min. Allyl iodide (0.05 mL,
0.6 mmol) was added dropwise and the mixture was stirred
for 1 h 30 min. The reaction was quenched by adding 1 M
CH3O
CH3O
CH3O
CH3O
a
N
H
N
O
CHO
S
1a
13 (67%)
Scheme 6. Reagents: (a) Raney Ni, EtOH, reflux, 7 h.

M.N. Abdullah et al. / Tetrahedron 64 (2008) 1323e1332
1327
HCl solution (5 mL) at ꢀ50 ꢁC, allowed to reach room tem-
perature. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (3ꢂ10 mL). The combined
organic extracts were dried (Na2SO4) and evaporated under
vacuum. Flash column chromatography (silica gel 60%
hexane/AcOEt) afforded 5,5-diallyl imide 3a as colourless
(silica gel 60% hexane/AcOEt) to obtain 3c as colourless oil
(0.16 g, 66%): IR (neat) 1746, 1675 cmꢀ1 1H NMR
;
(CDCl3) 1.55 (s, 3H), 2.45e2.59 (m, 2H), 2.80e2.86 (t,
J¼7.5 Hz, 2H), 3.76e3.84 (m, 2H)*, 3.81 (s, 3H)*, 3.84 (s,
3H)*, 5.10e5.16 (m, 2H), 5.52e5.68 (m, 1H), 6.69e6.78
(m, 3H) (* designates partially overlapped signals); 13C
NMR (CDCl3) 25.8, 32.8, 42.6, 43.7, 55.8, 58.1, 111.1,
111.9, 120.9, 121.0, 129.6, 130.9, 147.7, 148.8, 170.4,
177.2; MS (EI) m/z (rel intensity) 336 (Mþþ1, 2), 335 (Mþ,
11), 164 (100), 151 (29), 149 (11), 77 (2). Anal. Calcd for
C17H21NO4S: C, 60.88; H, 6.31; N, 4.18. Found: C, 60.74;
H, 6.29; N, 4.22.
oil (0.08 g, 40%): IR (neat) 1690, 1755 cmꢀ1 1H NMR
;
(CDCl3) 2.53e2.60 (m, 4H), 2.81 (t, J¼7.7 Hz, 2H), 3.73e
3.79 (m, 2H)*, 3.81 (s, 3H)*, 3.84 (s, 3H)*, 5.10e5.15 (m,
4H), 5.51e5.65 (m, 2H), 6.70e6.74 (m, 3H) (* designates
partially overlapped signals); 13C NMR (CDCl3) 32.9, 42.2,
42.5, 55.7, 62.6, 110.9, 111.7, 120.8, 120.9, 129.6, 130,
147.6, 148.7, 170.3, 176; MS (EI) m/z (rel intensity) 361
(Mþ, 14), 165 (15), 164 (100), 151 (28), 149 (13), 85 (10),
77 (5). Anal. Calcd for C19H23NO4S: C, 63.13; H, 6.41; N,
3.88. Found: C, 63.04; H, 6.88; N, 3.88.
4.2.4. 5,5-Diallyl-3-[2-(2-iodo-4,5-dimethoxyphenyl)-
ethyl]-thiazolidine-2,4-dione (4b)
A solution of iodinated thiazolidine-2,4-dione 4a (0.3 g,
0.7 mmol) was added dropwise over a solution of LDA
(2.04 mmol) [prepared from i-Pr2NH (0.28 mL, 2.04 mmol)
and n-BuLi (2.04 mL of 1 M solution, 2.04 mmol)] in THF
(10 mL) at ꢀ78 ꢁC and the resulting solution was stirred for
1 h. Allyl iodide (0.19 mL, 2.1 mmol) was added and the
resulting solution was stirred for 1 h 30 min at ꢀ78 ꢁC. The
reaction was quenched by addition of 1 M HCl solution
(10 mL) and was allowed to warm-up to room temperature.
Ether was added, the two phases were separated, and the aque-
ous layer was extracted with CH2Cl2 (3ꢂ10 mL). The com-
bined organic extracts were dried (Na2SO4) and the solvent
was evaporated under vacuum. Flash column chromatography
(silica gel, 60% hexane/AcOEt) afforded 4b as colourless oil
4.2.2. 5-Allyl-3-[2-(3,4-dimethoxyphenyl)ethyl]thiazolidine-
2,4-dione (3b)
A solution of 5 (0.19 g, 0.66 mmol), in dry THF (20 mL),
was added slowly to a solution of LDA [0.78 mmol, formed
from i-Pr2NH (0.11 mL, 0.78 mmol) and n-BuLi (0.71 mL of
1.1 M solution, 0.78 mmol)] in dry THF (5 mL) at ꢀ78 ꢁC.
After 1 h, allyl iodide (0.07 mL, 0.73 mmol) was added and
the reaction mixture was stirred at this temperature for 1 h 30 min.
HCl (1 M) solution was added (5 mL) and the reaction mixture
was allowed to reach room temperature. Then, organic layer
was separated and the aqueous layer was extracted with
CH2Cl2 (3ꢂ10 mL). The organic layers were combined, dried
(Na2SO4) and the solvent was evaporated under vacuum. Puri-
fication by flash column chromatography (silica gel 60% hex-
ane/AcOEt) afforded 3b as solid, that was crystallised from
pentane: (0.1 g, 46%) mp (pentane) 58e59 ꢁC: IR (neat)
(0.25 g, 73%): IR (neat) 1682, 1747 cmꢀ1
;
1H NMR
(CDCl3) 2.51e2.69 (m, 4H), 2.90e2.96 (m, 2H), 3.78e3.90
(m, 2H)*, 3.84 (s, 3H), 3.85 (s, 3H)*, 5.14e5.20 (m, 4H),
5.55e5.73 (m, 2H), 6.71 (s, 1H), 7.2 (s, 1H) (* designates
partially overlapped signals); 13C NMR (CDCl3) 37.9, 41.2,
42.4, 55.9, 56.0, 62.8, 88.0, 112.5, 121.2, 121.7, 130.6,
132.4, 148.3, 149.3, 170.6, 176.0; MS (EI) m/z (rel intensity)
488 (14), 487 (Mþ, 61), 277 (17), 164 (14), 150 (6), 120
(6), 85 (20), 77 (6). Anal. Calcd for C19H22INO4S: C, 46.83;
H, 4.55; N, 2.87. Found: C, 47.01; H, 4.58; N, 2.88.
1751, 1685 cmꢀ1 1H NMR (CDCl3) 2.40e2.53 (m, 1H),
;
2.80e2.90 (m, 3H), 3.78e3.82 (m, 2H)*, 3.84 (s, 3H)*, 3.86
(s, 3H)*, 4.15e4.20 (m, 1H), 5.12e5.19 (m, 2H), 5.59e5.75
(m, 1H), 6.71e6.80 (m, 3H) (* designates partially overlapped
signals); 13C NMR (CDCl3) 32.9, 36.6, 42.8, 48.9, 55.8, 111.1,
111.8, 119.7, 120.9, 129.6, 131.8, 147.7, 148.8, 171.1, 173.7;
MS (EI) m/z (rel intensity) 321 (Mþ, 18), 165 (12), 164 (100),
151 (39), 149 (13), 107 (5). Anal. Calcd for C16H19NO4S: C,
59.79; H, 5.96; N, 4.36. Found: C, 59.79; H, 6.22; N, 4.41.
4.2.5. 5-Allyl-3-[2-(2-iodo-4,5-dimethoxyphenyl)ethyl]-
thiazolidine-2,4-dione (4c)
A solution of iodinated thiazolidine-2,4-dione 4a (0.22 g,
0.55 mmol) in dry THF (20 mL) was added dropwise over
a solution of LDA (0.62 mmol), [prepared from i-Pr2NH
(0.09 mL, 0.62 mmol) and n-BuLi (0.41 mL of 1.5 M solution,
0.62 mmol)] in dry THF (10 mL) at ꢀ78 ꢁC and the resulting
solution was stirred for 1 h. Allyl iodide (0.05 mL, 0.6 mmol)
was added and the resulting solution was stirred for 1 h 30 min
at ꢀ78 ꢁC. The reaction was quenched by addition of 1 M HCl
solution (10 mL) and was allowed to reach room temperature.
The aqueous layer was extracted with CH2Cl2 (3ꢂ5 mL). The
combined organic extracts were dried (Na2SO4) and the sol-
vent was evaporated under vacuum. Flash column chromato-
graphy (silica gel, 60% hexane/AcOEt) afforded 4c as solid,
that was crystallised from Et2O: (0.18 g, 72%) mp (Et2O)
4.2.3. 5-Allyl-3-[2-(3,4-dimethoxyphenyl)ethyl]-5-
methylthiazolidine-2,4-dione (3c)
To a cold solution of TMEDA (0.12 mL, 0.77 mmol) in dry
THF (3 mL) at ꢀ40 ꢁC, s-BuLi (0.95 mL of 0.8 M solution,
0.77 mmol) was added. After 20 min, a solution of 3b
(0.234 g, 0.730 mmol) in THF (8 mL) was added and the mix-
ture was stirred at this temperature for 20 min. Then, MeI
(0.07 mL, 1.09 mmol) was added and the reaction mixture
was stirred at this temperature for 2 h, allowed to reach
room temperature, and quenched by adding 1 M HCl solution
(3 mL). The aqueous layer was extracted with CH2Cl2
(3ꢂ10 mL) and the combined organic extracts were dried
(Na2SO4). The solvent was evaporated under vacuum and
the residue was purified by flash column chromatography
95e96 ꢁC: IR (neat) 1749, 1681 cmꢀ1 1H NMR (CDCl3)
;

1328
M.N. Abdullah et al. / Tetrahedron 64 (2008) 1323e1332
2.42e2.54 (m, 1H), 2.83e2.90 (m, 1H)*, 2.93e2.99 (m, 2H)*,
3.80e3.87 (m, 2H)*, 3.82 (s, 3H)*, 3.83 (s, 3H)*, 4.15e4.20
(m, 1H), 5.13e5.19 (m, 2H), 5.60e5.77 (m, 1H), 6.66 (s, 1H),
7.18 (s, 1H) (* designates partially overlapped signals); 13C
NMR (CDCl3) 36.6, 37.6, 41.4, 49, 55.9, 56, 88.0, 112.5,
119.8, 121.6, 131.9, 132.4, 148.3, 149.2, 171, 173.6; MS
(EI) m/z (rel intensity) 448 (Mþþ1, 14), 447 (Mþ, 69), 291
(11), 290 (100), 277 (37). Anal. Calcd for C16H18INO4S: C,
42.97; H, 4.07; N, 3.13. Found: C, 43.02; H, 4.18; N, 3.28.
9.1 Hz, 1H), 2.58e2.61 (m, 2H), 2.66e2.68 (m, 1H), 2.71e
2.89 (m, 2H), 3.33e3.45 (m, 1H), 3.45 (s, 1H), 3.85 (s, 3H),
3.90 (s, 3H), 4.27e4.35 (m, 1H), 4.99e5.14 (m, 2H), 5.29e
5.52 (m, 2H), 5.52e5.68 (m, 1H), 5.68e5.83 (m, 1H), 6.53
(s, 1H), 6.90 (s, 1H); 13C NMR (CDCl3) 28.2, 37.2, 43.4,
44.0, 55.9, 56, 62, 90.8, 108.4, 110.5, 119.8, 121.5, 124.3,
129.4, 132.3, 134.5, 148.3, 149.3, 171.9; MS (EI) m/z (rel
intensity) 344 (Mþꢀ17, 100), 303 (59), 207 (23), 192 (37),
85 (59), 77 (29).
4.2.6. 5-Allyl-3-[2-(2-iodo-4,5-dimethoxyphenyl)ethyl]-5-
methylthiazolidine-2,4-dione (4d)
4.3.2. 1-Allyl-8,9-dimethoxy-5,6-dihydrothiazolo[4,3-a]-
isoquinolin-3-one (7)
To a cold solution of TMEDA (0.03 mL, 0.21 mmol) in
THF (3 mL) at ꢀ40 ꢁC, s-BuLi (0.26 mL of 0.8 M solution,
0.21 mmol) was added and after 20 min, thiazolidinedione
4c (90 mg, 0.2 mmol) in THF (8 mL) was added. The mixture
was stirred at this temperature for 20 min, MeI (0.02 mL,
0.4 mmol) was added and stirred for 2 h at ꢀ40 ꢁC. The reac-
tion mixture was allowed to reach room temperature and
quenched by adding 1 M HCl solution (3 mL). The aqueous
phase was extracted with CH2Cl2 (3ꢂ10 mL) and the organic
extracts were dried (Na2SO4), and concentrated under vacuum.
Flash column chromatography (silica gel, 60% hexane/AcOEt)
afforded 4d as colourless oil (70 mg, 78%): IR (neat)
According to general procedure, t-BuLi (0.7 mL of 1.17 M
solution, 0.78 mmol) was added at ꢀ78 ꢁC to a solution of
imide 4c (0.14 g, 0.3 mmol) in dry THF (20 mL) and the
resulting solution was stirred at this temperature for 2 h. Flash
column chromatography (silica gel 60% hexane/AcOEt)
afforded the hydroxythiazoloisoquinoline 7 as colourless oil
1
(0.09 g, 80%): IR (neat) 1655 cmꢀ1; H NMR (CDCl3) 2.89
(t, J¼6.1 Hz, 2H), 3.52e3.55 (m, 2H), 3.87 (s, 3H)*, 3.90
(s, 3H)*, 3.84e3.91 (m, 2H)*, 5.23e5.30 (m, 2H), 5.97e
6.08 (m, 1H), 6.75 (s, 1H), 7.03 (s, 1H) (* designates partially
overlapped signals); 13C NMR (CDCl3) 29.4, 32.0, 40.5, 55.9,
56.0, 109.2, 109.6, 110.9, 117.4, 120.0, 127.6, 127.7, 134.5,
147.9, 149.0, 170.0; MS (EI) m/z (rel intensity) 304 (Mþþ1,
19), 303 (Mþ, 100), 276 (10), 272 (6), 242 (10), 228 (5).
Anal. Calcd for C16H17NO3S: C, 63.35; H, 5.65; N, 4.62.
Found: C, 63.54; H, 5.78; N, 4.41.
1
1678 cmꢀ1; H NMR (CDCl3) 1.57 (s, 3H), 2.45e2.62 (m,
2H), 2.97 (t, J¼7.1 Hz, 2H), 3.82 (s, 3H)*, 3.83 (s, 3H)*,
3.82e3.87 (m, 2H)*, 5.13e5.19 (m, 2H), 5.59e5.7 (m, 1H),
6.67 (s, 1H), 7.19 (s, 1H) (* designates partially overlapped
signals); 13C NMR (CDCl3) 25.9, 37.7, 41.2, 43.8, 55.9,
56.0, 58.3, 88.0, 112.6, 121.2, 121.6, 130.9, 132.4, 148.3,
149.2, 170.5, 177.2; MS (EI) m/z (rel intensity) 461 (Mþ,
12), 290 (100), 277 (31), 77 (13), 59 (46). Anal. Calcd for
C17H20INO4S: C, 44.26; H, 4.37; N, 3.04. Found: C, 44.02;
H, 4.28; N, 3.08.
4.3.3. 1-Allyl-10b-hydroxy-8,9-dimethoxy-1-methyl-
1,5,6,10b-tetrahydrothiazolo[4,3-a]isoquinolin-3-one (6c)
According to the general procedure, t-BuLi (0.2 mL of
0.8 M solution, 0.14 mmol) was added at ꢀ78 ꢁC to a solution
of iodinated imide 4d (0.05 g, 0.10 mmol), in dry THF (20 mL)
and the resulting solution was stirred at this temperature for 3 h.
After work-up, flash column chromatography (silica gel 60%
hexane/AcOEt) afforded the hydroxythiazoloisoquinoline 6c
as a 7:3 mixture of diastereomers. Data of the mixture are given
4.3. Parham cyclisation of iodinated N-phenethylimides:
general procedure
1
To a solution of iodinated imides 4 (1 mmol) in dry THF
(20 mL) at ꢀ78 ꢁC, t-BuLi was added, the reaction mixture
was stirred at this temperature for 2e24 h, quenched by addi-
tion of saturated NH4Cl (5 mL), and allowed to reach room
temperature. The aqueous phase was extracted with CH2Cl2
(3ꢂ15 mL) and the organic extracts were dried (Na2SO4),
filtered and concentrated under vacuum to obtain thiazoloiso-
quinolines 6.
(0.02 g, 53%). IR (neat) 3444, 1643 cmꢀ1; H NMR (CDCl3)
1.54 (s, 3H, minor diast), 1.71 (s, 3H, major diast), 2.35e
2.50 (m, 1H, both diast), 2.61e2.68 (m, 1H, both diast), 2.8e
2.91 (m, 1H, both diast), 3.35e3.45 (m, 1H, both diast), 3.65
(s, 1H, both diast), 3.84 (s, 3H, minor diast), 3.85 (s, 3H, major
diast), 3.88 (s, 3H, major diast), 3.89 (s, 3H, minor diast), 4.25e
4.33 (dd, J¼12.9, 5.9 Hz, 1H, both diast), 4.93e5.09 (m, 1H,
both diast), 5.26e5.47 (m, 1H, both diast), 5.50e5.61 (m,
1H, major diast), 5.85e5.94 (m, 1H, minor diast), 6.52 (s,
1H, minor diast), 6.54 (s, 1H, major diast), 6.88 (s, 1H, minor
diast), 6.92 (s, 1H, major diast); 13C NMR (CDCl3) 27.3 (one
diast), 28.3 (one diast), 27.9 (both diast), 37.1 (one diast),
37.1 (both diast.), 37.2 (one diast), 55.9 (one diast), 56 (one di-
ast), 57.5 (one diast), 57.8 (one diast), 58.5 (both diast), 90.4
(one diast), 91.8 (one diast), 108.2 (one diast), 108.3 (one
diast), 110.5 (one diast), 110.7 (one diast), 119.5 (one diast),
121.3 (one diast), 124.1 (one diast), 124.4 (one diast), 129.5
(one diast), 130 (one diast), 132.6 (one diast), 134.7 (one diast),
148.4, 149.4 (both diast), 173 (one diast), 173.8 (one diast).
4.3.1. 1-Diallyl-10b-hydroxy-8,9-dimethoxy-1,5,6,10b-
tetrahydrothiazolo[4,3-a]isoquinolin-3-one (6a)
According to the general procedure, t-BuLi (0.13 mL of
1 M solution, 0.13 mmol) was added at ꢀ78 ꢁC to a solution
of iodinated imide 4b (0.04 g, 0.08 mmol), in dry THF
(20 mL) and the resulting solution was stirred at this temper-
ature for 2 h. After work-up, flash column chromatography
(silica gel 60% hexane/AcOEt) afforded the hydroxythiazoloi-
soquinoline 6a as colourless oil (0.03 g, 88%): IR (neat)
1666 cmꢀ1
;
1H NMR (CDCl3) 2.40e2.50 (dd, J¼13.5,

M.N. Abdullah et al. / Tetrahedron 64 (2008) 1323e1332
1329
4.4. Intermolecular a-amidoalkylation reactions
the reaction mixture was stirred at this temperature for 6 h.
Water (5 mL) was added and the mixture was allowed to reach
room temperature. Diethyl ether (5 mL) was added and the or-
ganic layer was separated. The aqueous layer was extracted
with dichloromethane (3ꢂ10 mL). The combined organic
layers were dried (Na2SO4), filtered and concentrated under
vacuum to obtain the corresponding a-hydroxylactams 8aec.
4.4.1. (1RS,10bSR)-1,10b-Diallyl-8,9-dimethoxy-1,5,6,10b-
tetrahydrothiazolo[4,3-a]isoquinolin-3-one (2a)
To a solution of crude 6b (88 mg, 0.27 mmol), obtained
from Parham cyclisation, in dry CH2Cl2 (15 mL), TiCl4
(0.06 mL, 0.55 mmol) was added at ꢀ78 ꢁC. After 1 h allyltri-
methylsilane (0.18 mL, 1.1 mmol) was added, and the mixture
was stirred at this temperature for 18 h and at room tempera-
ture for 16 h. The reaction was quenched by the addition of
saturated NaHCO3 solution (15 mL) and the aqueous layer
was extracted with CH2Cl2 (3ꢂ10 mL). The combined organic
extracts were dried (Na2SO4) and concentrated in vacuum.
Flash column chromatography (silica gel, 60% AcOEt/hexane)
afforded 2a as a colourless oil (59 mg, 59%): IR (neat)
4.5.1. 4,5,5-Triallyl-3-[2-(3,4-dimethoxyphenyl)ethyl]-4-
hydroxythiazolidine-2-one (8a)
According to the general procedure, a solution of 3a
(0.18 g, 0.5 mmol) in (20 mL) dry THF was treated with allyl-
magnesium chloride (0.63 mL of 2 M solution, 1.25 mmol), at
ꢀ78 ꢁC. Flash column chromatography (silica gel, 60%
hexane/AcOEt) afforded a-hydroxylactam 8a as colourless
1678 cmꢀ1
;
1H NMR (CDCl3) 1.79e2.04 (m, 2H), 2.62e
oil (0.18 g, 88%): IR (neat) 3414, 1677 cmꢀ1 1H NMR
;
2.87 (m, 3H), 3.14e3.26 (m, 2H), 3.52e3.58 (dd, J¼3.57,
11.1 Hz, 1H), 3.88 (s, 3H), 3.93 (s, 3H), 4.29e4.36 (dd,
J¼5.74, 11.7 Hz, 1H), 4.86e5.15 (m, 4H), 5.57e5.74 (m,
2H), 6.58 (s, 1H), 6.62 (s, 1H); 13C NMR (CDCl3) 29.9,
37.0, 39.0, 45.0, 54.6, 55.8, 56.3, 68.3, 108.9, 111.6, 118.3,
119.6, 126.6, 127.0, 133.0, 134.0, 148, 148.2, 169.2; MS
(EI) m/z (rel intensity) 345 (Mþ, <1), 320 (4), 304 (15), 289
(42), 276 (21), 263 (20), 165 (14), 164 (100), 151 (27).
HRMS Calcd for C19H23NO3S: 345.1415. Found: 345.1408.
(CDCl3) 2.41e2.74 (m, 6H), 2.77e2.86 (m, 2H), 3.25e3.39
(m, 1H)*, 3.39 (s, 1H)*, 3.50e3.62 (m, 1H), 3.78 (s, 3H),
3.82 (s, 3H), 5.11e5.27 (m, 6H), 5.63e5.90 (m, 2H), 5.92e
6.0 (m, 1H), 6.70e6.74 (m, 3H) (* designates partially over-
lapped signals); 13C NMR (CDCl3) 34.7, 39.4, 39.6, 43.9,
44.2, 55.9, 62.7, 94.4, 111.3, 112.1, 119.2, 119.6, 120.8,
131, 132.1, 133.0, 133.9, 147.7, 149.0, 168.8; MS (EI) m/z
(rel intensity) 403 (Mþ, <1%), 362 (2), 361 (5), 164 (100),
91 (6), 77 (4).
4.4.2. (1RS,10bSR)-1,10b-Diallyl-8,9-dimethoxy-1-methyl-
1,5,6,10b-tetrahydrothiazolo[4,3-a]isoquinolin-3-one (2b)
To a solution of crude 6c (51 mg, 0.14 mmol), obtained from
Parham cyclisation, in dry CH2Cl2 (15 mL), TiCl4 (0.03 mL,
0.28 mmol) was added at ꢀ78 ꢁC. After 1 h allyltrimethylsilane
(0.1 mL, 0.56 mmol) was added, the mixture was stirred at this
temperature for 5 h. The mixture was allowed to reach room tem-
perature and stirred for another 22 h. The reaction was quenched
by the addition of saturated NaHCO3 solution (15 mL) and the
aqueous layer was extracted with CH2Cl2 (3ꢂ10 mL). The com-
bined organic extracts were dried (Na2SO4) and concentrated in
vacuum. Flash column chromatography (silica gel, 60% hexane/
AcOEt) afforded 2b as a colourless oil (15 mg, 30%): IR (neat)
4.5.2. 4,5-Diallyl-3-[2-(3,4-dimethoxyphenyl)ethyl]-4-
hydroxythiazolidine-2-one (8b)
According to general procedure, a solution of 3b (0.1 g,
0.3 mmol), in (20 mL) dry THF was treated with allylmagne-
sium chloride (0.4 mL of 2 M solution, 0.8 mmol) at ꢀ78 ꢁC.
Flash column chromatography (silica gel, 60% hexane/AcOEt)
afforded a-hydroxylactam 8b as colourless oil (0.11 g, 90%):
1
IR (neat) 3340, 1650 cmꢀ1; H NMR (CDCl3) 2.24e2.39 (m,
1H), 2.55e2.58 (m, 3H), 2.79e2.93 (m, 2H), 3.33e3.39 (m,
1H), 3.49e3.59 (m, 1H), 3.73e3.83 (m, 1H)*, 3.79 (s, 3H)*,
3.80 (s, 3H)*, 3.83 (s, 1H)*, 5.0e5.18 (m, 4H), 5.57e5.76
(m, 2H), 6.7 (s, 3H) (* designates partially overlapped
signals); 13C NMR (CDCl3) 34.0, 34.4, 41.5, 43.9, 49.7,
55.6, 92.0, 111.1, 111.9, 117.9, 120, 120.5, 131.2, 134.3,
147.4, 148.6, 170.9; MS (EI) m/z (rel intensity) 363 (Mþ, 3),
165 (10), 164 (100), 151 (20), 149 (10), 107 (6), 91 (7), 87
(6), 85 (10), 83 (10), 71 (8), 69 (9), 57 (11), 56 (5), 55 (12).
1
1666.5 cmꢀ1; H NMR (CDCl3) 1.50e1.60 (m, 1H), 1.56 (s,
3H), 2.18e2.22 (dd, J¼13.8, 5.4 Hz, 1H), 2.62e2.66 (m, 1H),
2.80e2.90 (m, 2H), 3.14 (td, J¼12.9, 3.4 Hz, 1H), 3.28e3.33
(m, 1H), 3.87 (s, 3H), 3.88 (s, 3H), 4.38e4.41 (m, 1H), 4.87e
5.12 (m, 4H), 5.53e5.63 (m, 1H), 5.72e5.79 (m, 1H), 6.63 (s,
1H), 6.71 (s, 1H); 13C NMR (CDCl3) 19.3, 29.8, 40.0, 41.5,
42.5, 55.8, 56.2, 62.8, 70.1, 108.5, 111.9, 119.4, 126.5, 128.7,
133.1, 133.4, 148.0, 148.2, 168.9; MS (EI) m/z (rel intensity)
318 (67), 278 (19), 277 (100), 207 (37), 85 (19), 83 (17), 77
(11), 69 (11), 60 (12), 55 (6). HRMS Calcd for C20H25NO3S:
359.1572. Found: 359.1561.
4.5.3. 4,5-Diallyl-3-[2-(3,4-dimethoxyphenyl)ethyl]-4-
hydroxy-5-methylthiazolidine-2-one (8c)
According to the general procedure, a solution of 3c
(0.23 g, 0.7 mmol) in dry THF (20 mL) was treated with
allylMgCl (0.88 mL, 1.74 mmol) at ꢀ78 ꢁC. Flash column
chromatography (silica gel, 60% AcOEt/hexane) afforded a-
hydroxylactam 8c as colourless oil (0.23 g, 87%): IR (neat)
1
4.5. Nucleophilic addition of allylmagnesium chloride
to imides. Synthesis of hydroxylactams 8: general
procedure
3350, 1678 cmꢀ1; H NMR (CDCl3) 1.42 (s, 3H), 2.36e2.62
(m, 2H), 2.62e2.85 (m, 4H), 3.17 (s, 1H), 3.42e3.47 (m,
1H), 3.57e3.6 (m, 1H), 3.82 (s, 3H), 3.84 (s, 3H), 5.1e5.2
(m, 4H), 5.8e5.82 (m, 1H), 5.92e6.1 (m, 1H), 6.73e6.8 (m,
3H); 13C NMR (CDCl3) 23.1, 34.8, 39.6, 41.7, 44.1, 55.8,
60.6, 94.3, 111.2, 112.1, 119.2, 119.5, 120.8, 131.3, 132.3,
To a solution of imide 3aec (1 mmol) in dry THF (20 mL),
allylmagnesium chloride (2.5 mmol) was added at ꢀ78 ꢁC and

1330
M.N. Abdullah et al. / Tetrahedron 64 (2008) 1323e1332
133.9, 147.6, 149, 169; MS (EI) m/z (rel intensity) 377 (Mþ,
<1%), 336 (2), 335 (9), 164 (100), 151 (37), 91 (5), 77 (3).
4.6.3. (1RS,10bRS )-1-Allyl-8,9-dimethoxy-1-methyl-10b-
propenyl-1,5,6,10b-tetrahydrothiazolo[4,3-a]isoquinolin-3-
one (9c)
4.6. Intramolecular a-amidoalkylation reactions:
general procedure
According to the general procedure, to a solution of 8c
(0.14 g, 0.39 mmol) in dry dichloromethane (12 mL), TFA
(2 mL, 26 mmol) was added. The reaction mixture was stirred
under reflux for 4 days. After work-up, flash column chromatog-
raphy (silica gel, 60% hexane/AcOEt) afforded 9c as a mixture
of diastereomers in a 70:30 ratio. Data of the mixture are given
(0.13 g, 96%): IR (neat) 1672 cmꢀ1; 1H NMR (CDCl3) 1.37 (s,
3H, CH3eC1, major diast), 1.47e1.54 (m, 6H, CH3eCH],
both diast, CH3eC1, minor diast), 2.36 (d, J¼6.7 Hz, 2H,
CH2eCH]CH2, minor diast), 2.42 (d, J¼6.7 Hz, 2H, CH2e
CH]CH2, major diast), 3.10e3.20 (m, 1H, H6ax, both diast),
To a solution of a-hydroxylactams 8 (1 mmol) in dry
dichloromethane (12 mL), TFA was added, and the reaction
mixture was heated under reflux for 3e4 days. After cyclisa-
tion was completed, the reaction mixture was allowed to reach
room temperature, and quenched by addition of water and
a saturated solution of NaHCO3. The two layers were sepa-
rated, the aqueous layer was extracted with dichloromethane
(3ꢂ10 mL), the combined organic layers were dried
(Na2SO4), filtered and concentrated under vacuum to obtain
the thiazoloisoquinolines 9.
3.32e3.40 (m, 1H, H6eq, both diast), 3.75e4.17 (m, 1H, H5ax
,
both diast)*, 3.81 (s, 3H, OCH3, both diast)*, 3.82 (s, 3H,
OCH3, both diast)*, 4.20e4.30 (m, 2H, H5eq, CH]CHeCH3,
both diast), 4.5e4.6 (m, 1H, CH]CHeC10b, both diast),
4.91e4.97 (m, 2H, CH2]CHCH2e, minor diast), 5.07e5.13
(m, 2H, CH2]CHeCH2, major diast), 6.6 (s, 1H, H7, both di-
ast), 6.67 (s, 1H, H10, major diast), 6.68 (s, 1H, H10, minor di-
ast); 13C NMR (CDCl3) 26.0 (CH3, minor diast), 31.0 (CH3,
major diast), 31.1 (CH3, major diast), 31.3 (CH3, minor diast),
34.5 (C6, major diast), 35.0 (C6, minor diast), 45.1 (CH2e
CH]CH2, major diast), 45.4 (CH2eCH]CH2, minor diast),
49.2 (C5, both diast), 55.8 (OCH3, both diast), 56 (OCH3, both
diast), 56 (C10b, both diast), 56.7 (C1, both diast), 110.9 (C10,
minor diast), 111 (C10, major diast), 114.6 (eCH]CHeCH3,
both diast), 119.2 (CH2CH]CH2, minor diast), 119.3
(CH2CH]CH2, major diast), 127.7 (CH]CHeCH3, major di-
ast), 128 (CH]CHeCH3, minor diast), 132.5 (CH2]CHe
CH2, major diast), 132.7 (CH2]CHeCH2, minor diast), 135
(C7a, major diast), 135.1 (C7a, minor diast), 146.5 (C10a, both di-
ast), 146.6 (C9, both diast), 147.6 (C8, minor diast), 147.8 (C8,
major diast), 170.5 (C3, minor diast), 170.7 (C3, major diast);
MS (EI) m/z (rel intensity) 360 (Mþþ1, 4), 359 (Mþ, 18), 192
(100), 191 (15), 177 (15), 77 (4).
4.6.1. (1RS,10bRS )-1,1-Diallyl-8,9-dimethoxy-10b-
propenyl-1,5,6,10b-tetrahydrothiazolo[4,3-a]isoquinolin-3-
one (9a)
According to the general procedure, to a solution of a-hy-
droxylactam 8a (0.18 g, 0.45 mmol) in dry dichloromethane
(12 mL), TFA (2.33 mL, 30 mmol) was added. The reaction
mixture was refluxed for 4 days. After work-up, flash column
chromatography (silica gel, 60% hexane/AcOEt) afforded 9a
as colourless oil (0.17 g, 97%): IR (neat) 1679 cmꢀ1 1H
;
NMR (CDCl3) 1.50 (d, J¼7.1 Hz, 3H), 2.38e2.47 (m, 2H),
2.48e2.56 (m, 2H), 3.04e3.19 (m, 1H), 3.39 (dd, J¼15.9,
5.2 Hz, 1H), 3.82 (s, 3H)*, 3.85 (s, 3H)*, 3.77e3.90 (m,
1H)*, 4.25e4.34 (m, 2H), 4.48 (d, J¼6.3 Hz, 1H), 4.92e
4.99 (m, 2H), 5.09e5.16 (m, 2H), 5.27e5.41 (m, 1H),
5.67e5.81 (m, 1H), 6.60 (s, 1H), 6.67 (s, 1H) (* designates
partially overlapped signals); 13C NMR (CDCl3) 31.4, 34.7,
43.7, 45.2, 47.4, 55.9, 56.1, 60.2, 108.1, 111.7, 114.8, 119.1,
119.5, 127.8, 132.3, 132.7, 135.2, 144.6, 146.6, 147.9,
170.8; MS (EI) m/z (rel intensity) 386 (Mþþ1, 3), 385 (Mþ,
12), 193 (20), 192 (100), 177 (14), 91 (11), 77 (4). Anal. Calcd
for C22H27NO3S: C, 68.54; H, 7.06; N, 3.63. Found: C, 68.44;
H, 7.15; N, 4.85.
4.7. Ring-closing metathesis reactions: general
procedure
4.6.2. 4,5-Diallyl-3-[2-(4,5-dimethoxyphenyl)ethyl]-3H-
thiazol-2-one (10)
To a solution of 2 or 9a (1 mmol) in dry CH2Cl2 (200 mL),
second generation Grubbs’ catalyst (10 mol %) was added at
room temperature. The mixture was heated under reflux, for
4 h, another portion of the catalyst was added, and the reaction
mixture was heated for another 8 h. The reaction mixture was
allowed to reach room temperature and the solvent was re-
moved under reduced pressure. Flash column chromatography
afforded 1 or 12.
According to the general procedure, to a solution of 8b
(0.1 g, 0.26 mmol) in dry dichloromethane (10 mL) was added
TFA (1.4 mL, 17.5 mmol) at room temperature, and the mixture
was refluxed for 4 days. After work-up, flash column chroma-
tography (silica gel, 60% AcOEt/hexane) afforded 10 as colour-
less oil (0.09 g, 96%): IR (neat) 1658 cmꢀ1; 1H NMR (CDCl3)
2.80e2.88 (m, 4H), 3.09e3.12 (d, J¼6.3 Hz, 2H), 3.74e3.85
(m, 2H)*, 3.79 (s, 3H)*, 3.82 (s, 3H)*, 4.89e5.10 (m, 4H),
5.61e5.80 (m, 2H), 6.58e6.77 (m, 3H) (* designates partially
overlapped signals); 13C NMR (CDCl3) 28.9, 30.8, 34.2, 45.2,
55.6, 55.7, 110.9, 111.2, 111.9, 116.7, 117, 120.6, 128.7,
130.6, 133, 134.7, 147.6, 148.8, 171.5; MS (EI) m/z (rel inten-
sity) 345 (Mþ, 14), 165 (15), 164 (100), 149 (7). Anal. Calcd for
C19H23NO3S: C, 66.06; H, 6.71; N, 4.05. Found: C, 65.64; H,
6.40; N, 4.05.
4.7.1. (5SR,6RS )-15,16-Dimethoxy-8-oxo-7-thiaerythrinan-
2-ene (1a)
According to the general procedure, a solution of 2a
(50 mg, 0.14 mmol) in dry CH2Cl2 (20 mL) was treated with
second generation Grubbs’ catalyst (10 mol %). After work-
up, flash column chromatography (silica gel, 60% hexane/
AcOEt) afforded 1a as colourless oil (38 mg, 83%): IR

M.N. Abdullah et al. / Tetrahedron 64 (2008) 1323e1332
1331
(neat) 1666 cmꢀ1
;
1H NMR (CDCl3) 2.44e2.51 (m, 1H),
1H NMR (CDCl3) 1.40e1.49 (m, 1H), 1.55e1.60 (m, 1H),
1.71e1.79 (m, 1H), 1.81e1.87 (m, 1H), 1.95 (t, J¼3.7 Hz,
2H), 2.27e2.33 (m, 2H), 2.82 (t, J¼6.29 Hz, 2H), 3.84 (s,
3H)*, 3.88 (s, 3H)*, 3.83e3.88 (m, 4H)*, 6.55 (s, 1H), 6.75
(s, 1H), 8.55 (s, 1H) (* designates partially overlapped sig-
nals); 13C NMR (CDCl3) 21.9, 25.6, 28.0, 34.4, 36.2, 55.8,
56.3, 59.9, 108.1, 111.9, 126.8, 135.2, 147.2, 147.8, 161.3;
MS (EI) m/z (rel intensity) 290 (Mþþ1, 6), 289 (Mþ, 60),
288 (62), 246 (88), 245 (67), 218 (67), 217 (69), 205 (100),
204 (70), 189 (67), 173 (65), 90 (59). HRMS Calcd for
C17H23NO3: 289.1678. Found: 289.1674.
2.66e2.98 (m, 4H), 3.18e3.41 (m, 2H), 3.77 (s, 3H), 3.83
(s, 3H), 4.09e4.20 (m, 2H), 5.88e5.93 (m, 1H), 6.06e6.10
(m, 1H), 6.56 (s, 1H), 6.99 (s, 1H); 13C NMR (CDCl3) 25.9,
27.2, 38.7, 40.2, 49.4, 55.6, 55.7, 64.4, 110.2, 112.3, 126.5,
127.4, 128.4, 129.1, 146.6, 148.1, 175.1; MS (EI) m/z (rel in-
tensity) 318 (Mþþ1, 27), 317 (Mþ, 44), 263 (84), 207 (100),
83 (55). HRMS Calcd for C17H21NO3S: 317.1102. Found:
317.1094.
4.7.2. (5SR,6RS )-15,16-Dimethoxy-6-methyl-8-oxo-7-
thiaerythrinan-2-ene (1b)
According to the general procedure, a solution of 2b
(43 mg, 0.12 mmol) in dry CH2Cl2 (20 mL) was treated with
second generation Grubbs’ catalyst (10 mol %). After work-
up, flash column chromatography (silica gel, 60% hexane/
AcOEt) afforded 1a as colourless oil (31 mg, 79%): IR
Acknowledgements
Financial support from MCYT (BQU2003-03239) and Uni-
´
versidad del Paıs Vasco/Euskal Herriko Unibertsitatea is grate-
fully acknowledged. M.N.A. is grateful to Gobierno Vasco,
´
Fundacion Kawa and Universidad del Paıs Vasco for their
financial support.
(neat) 1660 cmꢀ1 1H NMR (CDCl3) 1.66 (s, 3H), 1.65e
;
´
1.79 (m, 1H), 2.30e2.40 (m, 1H), 2.57e2.65 (m, 1H),
2.80e2.88 (m, 1H), 3.02e3.10 (m, 2H), 3.43e3.52 (m, 1H),
3.91 (s, 3H), 3.94 (s, 3H), 4.39e4.43 (m, 1H), 5.88e5.98
(m, 1H), 6.17e6.22 (m, 1H), 6.64 (s, 1H), 6.83 (s, 1H) (* des-
ignates partially overlapped signals); 13C NMR (CDCl3) 18.7,
29.7, 40.1, 40.7, 41.6, 55.8, 56.2, 59.5, 62.3, 110.3, 112.0,
126.1, 127.4, 128.5, 128.9, 148.0, 148.2, 174.3; MS (EI) m/z
(rel intensity) 331 (Mþ, <1), 277 (33), 117 (100), 115 (62),
91 (23), 68 (16). HRMS Calcd for C18H21NO3S: 331.1254.
Found: 331.1243.
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1
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1H)*, 4.26e4.36 (m, 2H), 4.63 (d, J¼6.3 Hz, 1H), 5.67 (br s,
2H), 6.61 (s, 1H), 6.68 (s, 1H) (* designates partially overlap-
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55.8, 56.0, 60.0, 107.9, 109.7, 114.7, 127.8, 128.5, 129.0,
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1332
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