Synthesis of perhydroindenes and perhydroisoindoles via one-pot enyne metathesis/Diels-Alder reaction; remarkable stability of grubbs catalyst under Lewis acidic conditions

Article abstract of DOI:10.1055/s-2000-8211

Perhydroindenes 4a-c and perhydroisoindoles 5a-c were obtained by one-pot enyne metathesis and subsequent Diels-Alder reaction starting from diethyl 4-allyl-4-prop-2-ynyl malonate (1a) or N-allyl-N-prop-2-ynyl p-toluenesulfonamide (1b) and different dieno

Full text of DOI:10.1055/s-2000-8211

1766
FEATURE ARTICLE
Synthesis of Perhydroindenes and Perhydroisoindoles via One-Pot Enyne
Metathesis/Diels Alder Reaction; Remarkable Stability of Grubbs Catalyst
under Lewis Acidic Conditions
Dagmar Bentz, Sabine Laschat*
Institut für Organische Chemie der Technischen Universität Braunschweig, Hagenring 30, D-38106 Braunschweig, Germany
Received 19 May 2000; revised 22 June 2000
Dedicated to Prof. Bernd Giese on the occasion of his 60th birthday.
dimerization route to the perhydroisobenzofuranone rac-
Abstract: Perhydroindenes 4a c and perhydroisoindoles 5a c
differolide,18 a natural product isolated from cultures of
were obtained by one-pot enyne metathesis and subsequent Diels
Alder reaction starting from diethyl 4-allyl-4-prop-2-ynyl malonate
(1a) or N-allyl-N-prop-2-ynyl p-toluenesulfonamide (1b) and dif-
Streptomyces aurantiogriseus.19 However, all of the
above mentioned metathesis/cycloaddition sequences
ferent dienophiles 3a c in the presence of Grubbs catalyst. The were carried out stepwise. This was also true for the syn-
thesis of pseudooligosaccharide by Blechert,20 in which
one-pot reactions proceeded with higher yields as compared to the
stepwise sequence. Due to the surprising stability of Grubbs catalyst
the Diels Alder reaction required either Lewis acid acti-
against Lewis acids such as BCl3 and AlCl3, it was also possible to
vation or high pressure conditions. We thus attempted to
perform one-pot enyne methathesis/Diels Alder reactions with eth-
perform the sequence starting from 1 in a one-pot fashion.
yl acrylate (10) as dienophile giving the perhydroisoindole 11 in
Depending on the type of dienophile 3 perhydroindenes,
perhydroisoindoles and other anellated derivatives 4 with
potential biological and pharmaceutical activity should be
available. For example, perhydroisoindol-4-ones are po-
tent non-peptidic substance P inhibitors, which are selec-
tive for NK1 receptors.21 The corresponding pyridazine
derivatives of 4 are useful precursors for the synthesis of
herbicides.22 We were particularly interested to test
whether the metathesis proceeds in the presence of Lewis
acids, because this would allow the use of dienophiles
which are too unreactive for thermal Diels Alder reac-
tions. Furthermore, this would broaden the scope of the
enyne metathesis/[4+2] cycloaddition sequence. The re-
sults towards this end are reported below.
good yield.
Key words: metathesis, Diels Alder reaction, tandem reactions,
Lewis acids
Tandem or domino reactions are of considerable interest
for the synthetic chemist due to the convenient experi-
mental procedures, which do not require the isolation and
purification of intermediates. An additional advantage is
the minimization of solvents.1 The application of transi-
tion metal-mediated transformations in such tandem se-
quences is also well established. In particular Pd-
catalyzed cross-couplings have been successfully utilized
for this purpose.2 Combinations of cross-couplings, either
multi Heck-type,3 multi cycloisomerizations (Pd-zipper
reaction),4 Suzuki Heck,5 or Stille Heck reactions6 were
reported. The major advantage of Pd chemistry is the high
tolerance against different reaction conditions and substi-
tution patterns. Thus, Pd cross-couplings were also com-
bined with other reaction types, such as Diels Alder
reactions,7 Michael additions,8 6 electrocyclizations,9
ene reactions,10 and anion-capture processes.11 In contrast,
ring closing metathesis and olefin cross metathesis, which
have been elaborated into powerful synthetic tools,12 were
only rarely used in tandem with other reaction types.
Grigg for example reported a sequential metathesis-Heck
reaction.13
Y
Y
Grubbs
cat.
Y
3
Y
X
X
X
1a
b
2a
b
4, 5
X = C(CO2Et)2
NTs
3
Y–Y
4, 5
X
3a
(CO)2O
4a
4b
C(CO2Et)2
C(CO2Et)2
C(CO2Et)2
NTs
3b (N–CO2Et)2
3c
3a
(N–CO)2NPh 4c
(CO)2O
5a
5b
With respect to the broad applications of Diels Alder re-
actions,14 we anticipated that it might be useful to com-
bine an enyne metathesis15,16 of 1 yielding functionalized
dienes 2 with a subsequent Diels Alder reaction (Scheme
1). Mori demonstrated that N-tosyl-3-vinyl-1,2,5,6-tet-
rahydropyridines, which were obtained by enynes met-
athesis, could be used as dienes in thermal [4+2]
cycloadditions.16 A similar approach was used by Heerd-
ing for the solid phase synthesis of isoindolines.17 Very re-
cently, Hoye reported a stepwise enyne metathesis/[4+2]
3b (N–CO2Et)2
3c
NTs
(N–CO)2NPh 5c
NTs
Grubbs cat. = (Cy3P)2Cl2Ru=CHPh
Scheme 1
For comparison, metathesis and cycloaddition were first
performed in separate steps. As shown in Scheme 2,
Synthesis 2000, No. 12, 1766–1773 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Perhydroindenes and Perhydroisoindoles
1767
enynes 1a,b underwent clean cross metathesis in dichlo- diallylmalonate (6) was treated with 10 mol% of Grubbs
romethane at room temperature in the presence of 5 mol% catalyst and 1 equivalent of Lewis acid in dichlo-
of Grubbs catalyst (PCy3)2Cl2Ru=CHPh23 to give vinylcy- romethane at room temperature. The conversion to the de-
clopentene 2a and N-tosyl-1-vinyldihydropyrrole (2b) in sired cyclopentene 7 was monitored by capillary GC. The
72% and 68% yield, respectively.24
results (Table 2) reveal that the formation of the metathe-
sis product 7 is not affected by strong Lewis acids such as
BCl3 and AlCl3 (entries 2, 3). In both cases complete con-
version was achieved after 30 min. Weaker Lewis acids
such as V(acac)2, FeCl3, ZnCl2, ZnBr2 and ZnEt2 resulted
in slightly decreased conversions (entries 6 10). EtAlCl2
required longer reaction times. In contrast, TiCl4 and
SnCl4 led to a pronounced decrease of the conversion,
which could not be improved by prolonged reaction times.
However, even with these Lewis acids the overall conver-
sion was still more than 50%. It should be mentioned that
Fürstner observed during the synthesis of the macrolide
( )-gloeosporone decomposition of the Grubbs catalyst
when he attempted the ring closing metathesis in the pres-
ence of strong Lewis acids.28 However, the yield of the de-
sired macrolide was increased by using catalytic amounts
of Ti(OiPr)4 together with the Grubbs catalyst.29,30
Grubbs cat. (5 mol% )
1a
2a
b
72 %
68 %
CH2Cl2, rt, 17 h
b
Scheme 2
Then dienes 2a,b were submitted to cycloaddition with ei-
ther maleic anhydride (3a), diethyldiazodicarboxylate
(3b), or N-phenyl-1,2,4-triazol-3,5-dione (3c) in dichlo-
romethane at room temperature.25 After 50 hours, the cy-
cloadducts 4, 5 were isolated in good yields (Method A,
Table 1, entries 1, 3, 5, 7, 9, 11). Next the enynes 1a,b
were directly treated with 5 mol% of ruthenium catalyst
and 1 equivalent of dienophile 3 in dichloromethane at
room temperature. We were pleased to find that the de-
sired cycloadducts 4, 5 were formed in most cases in high-
er yields (Method B, Table 1, entries 4, 8, 12) as compared
to the overall yields of the stepwise reaction.
Grubbs cat. (10 mol%)
EtO2C
EtO2C
EtO2C
EtO2C
Lewis acid (1 equiv.)
CH2Cl2, rt, 0.5 - 2 h
The relative configuration of cycloadduct 4a derived from
maleic anhydride (3a) was established via NOE experi-
ments. A similar all-cis configuration was concluded for
5a based on analogous NMR spectra.26
6
7
(for details see Table 2)
Scheme 3
In order to investigate the tolerance of Grubbs catalyst
against Lewis acidic conditions, we examined the ring
closing metathesis of 6.27 As shown in Scheme 3, diethyl
After these exploratory studies, we turned our attention to
the Lewis acid-catalyzed Diels Alder reaction. We antic-
Biographical Sketches
Dagmar Bentz was born in Kiel and finished her diplo- currently working on her
Flensburg in 1967. After ma in 1997 under the guid- Ph.D. thesis under the su-
working as a technician in ance of Prof. Tochtermann. pervision of Prof. Laschat.
the Biochemistry Depart- She then moved to the Tech- Her research interests deal
ment, University in Kiel, nical University of Braun- with catalytic organometal-
she studied chemistry in schweig where she is lic reactions.
Sabine Laschat was born in with Prof. Overman at the now Associate Professor of
Darmstadt in 1963. She re- University of California in Organic Chemistry. Her re-
ceived her diploma in 1987 Irvine, she worked at the search interests deal with
at the University of University of Münster with stereoselective synthesis of
Würzburg under the direc- Prof. Erker to obtain her ha- biologically active com-
tion of Prof. Jäger and a bilitation. In 1997, she pounds, development of or-
Ph.D. in 1990 from the Uni- joined the faculty of the ganometallic reagents and
versity of Mainz under the Chemistry Department at catalysts for organic synthe-
supervision of Prof. Kunz. the Technical University in sis, and liquid crystal chem-
After postdoctoral studies Braunschweig, where she is istry.
Synthesis 2000, No. 12, 1766–1773 ISSN 0039-7881 © Thieme Stuttgart · New York

1768
D. Bentz, S. Laschat
FEATURE ARTICLE
Table 1 Diels−Alder Reaction of Dienes 2a,b and One-Pot Metathesis/Diels−Alder Reaction of Enynes 1 with Different Dienophiles 3a−c a,b
Entry
Enyne
X
Diene
Dienophile
Method
Yield of 4, 5 (%)
Product
O
O
1
2
1a
1a
C(CO2Et)2
C(CO2Et)2
2a
2a
3a
3a
A
B
38 (53)
66
4
3
3a
7a
O
2
EtO2C
EtO2C
5
6
1
7
4a
CO2Et
N
N
CO2Et
3
4
1a
1a
C(CO2Et)2
C(CO2Et)2
2a
2a
3b
3b
A
B
42 (58)
57
EtO2C
EtO2C
4b
Ph
O
N
5
6
1a
1a
C(CO2Et)2
C(CO2Et)2
2a
2a
3c
3c
A
B
46 (64)
44
N
O
N
EtO2C
EtO2C
4c
O
O
4
7
8
1b
1b
NTs
NTs
2b
2b
3a
3a
A
B
49 (72)
75
3
3a
O
2
5
6
Ts
N
7a
1
7
5a
CO2Et
N
N
CO2Et
9
10
1b
1b
NTs
NTs
2b
2b
3b
3b
A
B
56 (82)
78
Ts
N
5b
Ph
O
O
N
11
12
1b
1b
NTs
NTs
2c
2c
3c
3c
A
B
58 (85)
68
N
N
Ts
N
5c
a Reaction conditions: Method A (Diels−Alder reaction of isolated diene 2): CH2Cl2, r.t., 50 h. Method B (one pot metathesis/Diels−Alder re-
action): 5 mol % of (PCy3)2Cl2Ru=CHPh, 1 equiv. of 1, 1 equiv. of 3, CH2Cl2, r.t., 50 h.
b Yields refer to isolated overall yields starting from 1. Yields in parentheses refer to Diels−Alder reaction of isolated dienes 2.
ipated that dihydropyrrol 9 (Scheme 4) should be suffi- treatment of acrylate 10 with 2.5 equivalents of BCl3 in
ciently activated in order to undergo cycloadditions with toluene for 9 hours at room temperature, and subsequent
dienophiles which are less reactive than 3a c.31 Com- hydrolysis with bicarbonate, followed by aqueous work-
pound 9 was obtained via cross metathesis of 8 in 68% up and chromatography yielded 65% of the desired cy-
isolated yield (Scheme 4). Then dihydropyrrole 9 was cloadduct 11.
treated with ethyl acrylate (10) under various conditions
Next, the behavior of BCl3 in the one pot cross metathesis/
Diels Alder reaction was investigated. As shown in
Scheme 4, enyne 8 was treated simultaneously with
to yield the 4-acyl-7-phenyl-hexahydroisoindole 11.32
The results are summarized in Table 3. Preliminary stud-
ies showed that no cycloaddition took place, when the
10 mol% of Grubbs catalyst and 2.5 equivalents of BCl3
amount of Lewis acid was kept below 2.5 equivalents.
in toluene at room temperature. The reaction progress was
Higher conversions were obtained with BCl3 in dichlo-
monitored by capillary GC. After 1.5 hours, conversion
romethane and particularly in toluene (entries 1, 3) as
had reached 87.4% and the reaction was almost complete
compared to AlCl3 (entries 2, 4). On a preparative scale,
Synthesis 2000, No. 12, 1766–1773 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Perhydroindenes and Perhydroisoindoles
1769
Table 2 Ring-closing Metathesis of Diethyl 2,2-diallylmalonate 6
Table 3 Lewis Acid-Catalyzed Diels−Alder Reaction of Diene 9
with Ethyl Acrylate 10 to Hexahydroisoindole 11 under Various Con-
ditions a,b
with Grubbs Catalyst in the Presence of Various Lewis Acids a,b
Entry
Lewis acid
–
Conversion [%]
> 99.0
> 99.0
> 99.0
82.0 c
Entry
Solvent
CH2Cl2
CH2Cl2
toluene
toluene
Lewis acid
BCl3
Conversion [%]
1
2
1
2
3
4
96.0
83.6
98.0
28.6
BCl3
AlCl3
3
AlCl3
EtAlCl2
TiCl4
BCl3
4
AlCl3
5
63.0 d
a Reaction conditions: 2.5 equiv. of Lewis acid, r.t., 5 h. When the
amount of Lewis acid was kept below 2.5 equiv. no conversion was
observed.
6
V(acac)2
FeCl3
ZnCl2
ZnBr2
ZnEt2
SnCl4
97.0 d
7
97.0 d
b Conversions were determined by capillary GC. For isolated yields of
11 see Scheme 4.
8
96.0 d
9
98.4 d
10
11
79.8 d
fashion at ambient temperature. Grubbs catalyst turned
out to be remarkably stable even in the presence of sto-
ichiometric amounts of strong Lewis acids, thus allowing
the use of less activated dienophiles such as ethyl acrylate.
Possible applications of Grubbs catalyst in other Lewis
acid-catalyzed reactions are currently under investigation
in our laboratory.
55.0 d
a Reaction conditions: 10 mol % of (PCy3)2Cl2Ru=CHPh, 1 equiv. of
Lewis acid, CH2Cl2, r.t., 30 min.
b Conversions were determined by capillary GC.
c Complete conversion (> 99.0 %) was observed after 2 h.
d No further conversion was detected after 2 h.
All reactions were carried out under N2 using standard Schlenk
techniques. Solvents were dried and deoxygenated by standard pro-
cedures. Analytical TLC was performed on precoated Merck Si 254
F plates (0.25 mm thickness) and the products were visualized by
spraying with a solution of phosphomolybdic acid in EtOH (5%,
v/v) or I2. Flash chromatography33 was carried out with Merck silica
gel 60 (230 400 mesh). NMR spectra: Bruker AC 200 P [1H (200
MHz), 13C (50 MHz)], Bruker AM 400 [1H (400 MHz), 13C (100
MHz)]. Multiplets in 13C NMR spectra were assigned with the aid
of DEPT experiments. Mps were determined by differential scan-
ning calorimetry with a Rheometric Scientific DSC SP, heating and
after 5 hours (93.5% conversion). Compound 11 was iso-
lated in 60% yield. To verify that the Lewis acid does not
interfere with the ruthenium catalyst, the reaction was per-
formed in a sequential fashion. That is, enyne 8 was
stirred with Grubbs catalyst for 1.5 hours at room temper-
ature in toluene and then the Lewis acid was added. After
5 hours, 91.4% conversion to the desired cycloadduct 9
was obtained.
1
cooling rate: 10 K min . IR: Nicolet 5DXC FT-IR spectrometer.
CO2Et
Grubbs cat.
GC: Hewlett-Packard HP 6890, HP5-fused silica capillary column
(ID 0.32 mm, length 30 m). Temperature program: 80 °C with 8 °C
min 1 up to 280 °C, then isothermal for 20 min. MS: Finnigan Mod-
el MAT 8430 (EI, 70 eV). Diethyl 4-allyl-4-prop-2-inylmalonate
(1a),34 diethyl 1-vinylcyclopenten-3,3-dicarboxylate (2a),35
N-allyl-N-prop-2-inyl-p-toluenesulfonamide (1b),16 N-tosyl-1-vi-
nyl-2,4-dihydro-2H-pyrrole (2b)16 and N-allyl-p-toluenesulfona-
mide,16 were prepared according to literature procedures. Diethyl
2,2-diallylmalonate was commercially available.
3a
(10 mol%)
Ts
N
Ts
N
Ph
CO2Et
10
7a
8
BCl3 (2.5 equiv.)
toluene, rt, 9 h
60 %
Ph
11
Grubbs cat.
(10 mol%)
10
BCl3 (2.5 equiv.)
toluene, rt, 9 h
65 %
toluene, rt, 17 h
68 %
Enyne Metathesis; General Procedure
To a solution of (Cy3P)2Cl2Ru=CHPh (41 mg, 0.05 mmol) in
CH2Cl2 (10 mL) was added dropwise a solution of enyne 1
(5.00 mmol) in CH2Cl2 (2 mL) and the resulting mixture was stirred
for 17 h at r.t. Then the solvent was evaporated and the crude prod-
uct was purified by flash chromatography on SiO2.
Ts
N
Ph
9
Scheme 4
Diels Alder Reaction of Dienes 2;General Procedure
To a solution of diene 2 (1.00 mmol) in CH2Cl2 (1 mL) was added
dropwise a solution of dienophile 3 (1.10 mmol) in CH2Cl2 and the
mixture was stirred for 50 h at r.t. Then the solvent was evaporated
and the crude product was purified by recrystallization or flash
In conclusion, a sequence of Ru-catalyzed enyne metathe-
sis followed by intermolecular Diels Alder reaction has
been elaborated, which allows the convenient preparation chromatography on SiO2 (Method A, Table 1) .
of perhydroindenes and perhydroisoindoles in a one-pot
Synthesis 2000, No. 12, 1766–1773 ISSN 0039-7881 © Thieme Stuttgart · New York

1770
D. Bentz, S. Laschat
FEATURE ARTICLE
One-pot Metathesis/Diels Alder Reaction; General Procedure
To a solution of (Cy3P)2Cl2Ru=CHPh (41 mg, 0.05 mmol) in
Diethyl N-Phenyl-4,4a,5,6,7,8,9,10-octahydro-2-cyclopenta[c]-
pyridazino[1,2-a]-2,4,10-triazoline-1,3-dione 6,6-dicarboxylate
(4c)
CH2Cl2 (5 mL) was added dropwise a solution of enyne
1
(1.00 mmol) and dienophile 3 (1.10 mmol) in CH2Cl2 (2 mL) and
the mixture was stirred for 50 h at r.t. Then the solvent was evapo-
rated and the crude product was purified by recrystallization or flash
chromatography on SiO2 (Method B, Table 1).
Flash chromatography (n-pentane/EtOAc, 1: 1) gave 260 mg (0.64
mmol, 64%) of a colorless solid; mp: 130 °C.
IR (KBr): = 2983, 2939, 2867, 1776, 1723, 1502, 1417, 1364,
1305, 1288, 1235, 1193, 1140, 1074, 1053, 1016, 769, 710, 690
1
cm .
Diethyl 1,3,3a,3b,8,8a-Hexahydrocyclopenta[c]isobenzofuran-
1,3-dione-5,5-dicarboxylate (4a)
UV/VIS (CH3CN): max (lg ) = 194 (2.66), 220 (2.22) nm.
1H NMR (400 MHz, DMSO-d6): = 7.58 7.43 (m, 5H, Ph), 5.81
(br s, 1H, 7-H), 4.38 (dddd, 1H, J = 9.5, 7.5, 2.8, 2.6 Hz, 3a-H), 4.30
(br d, 1H, J = 16.2 Hz, 6-Ha), 4.22 (q, 2H, J = 7.1 Hz, OCH2CH3),
4.20 (q, 2H, J = 7.1 Hz, OCH2CH3), 4.00 (br d, 1H, J = 16.2 Hz, 6-
Hb), 3.07 (m, 2H, 1-H), 3.06 (dd, 1H, J = 13.3, 7.5 Hz, 3-Ha), 2.23
(dd, 1H, J = 13.3, 9.5 Hz, 3-Hb), 1.23 (t, 3H, J = 7.1 Hz, OCH2CH3),
1.22 (t, 3H, J = 7.1 Hz, OCH2CH3).
After evaporation of the solvent, the excess of maleic anhydride was
removed by sublimation under high vacuum to yield 178 mg
(0.53 mmol, 53%) of a colorless oil.
IR (film): = 2984, 2939, 1733, 1447, 1390, 1297, 1256, 1162,
1
1098, 1073, 1017, 953, 862, 755, 697 cm .
UV/VIS (CH3CN): max (lg ) = 206 (5.98), 216 (5.64) nm.
1H NMR (400 MHz, CDCl3): = 5.78 (dddd, 1H, J = 7.3, 5.1, 5.1,
2.5 Hz, 7-H), 4.19 (q, 4H, J = 7.1 Hz, OCH2CH3), 3.43 (ddd, 1H,
J = 9.8, 9.8, 7.6 Hz, 4-H), 3.36 (ddd, 1H, J = 9.8, 6.7, 1.5 Hz, 5-H),
2.93 (dd, 2H, J = 13.5, 1.5 Hz, 1-H), 2.80 2.71 (m, 3H, 6-Ha, 3a-H,
3-Ha), 2.58 (dd, 1H, J = 12.6, 10.5 Hz, 3-Hb), 2.19 (dddd, 1H,
J = 13.4, 6.7, 3.5, 3.0 Hz, 6-Hb), 1.25 (t, 3H, J = 7.1 Hz, OCH2CH3),
1.25 (t, 3H, J = 7.1 Hz, OCH2CH3).
13C NMR (100 MHz, CDCl3): = 171.4 (COOEt), 170.4 (CO),
143.5 (C-7a), 117.9 (C-7), 61.7 (OCH2CH3), 59.8 (C-2), 42.6 (C-4),
41.7 (C-5), 38.3 (C-1), 37.9 (C-3a), 34.7 (C-3), 24.7 (C-6), 14.0
(OCH2CH3).
13C NMR (100 MHz, DMSO-d6): = 171.8 (COO), 171.2 (COO),
154.5 (CO), 152.1 (CO), 136.6 (C-7a), 132.3 (C-i), 129.79 (C-m),
129.0 (C-p), 127.2 (C-o), 114.6 (C-7), 62.7 (OCH2CH3), 62.6
(OCH2CH3), 57.6 (C-2), 57.1 (C-3a), 43.3 (C-6), 38.8 (C-3), 36.1
(C-1), 14.7 (OCH2CH3).
MS (EI): m/z (%) = 413 (M+ 100), 368 (24), 340 (37), 339 (41), 310
(26), 294 (18), 266 (78), 241 (5), 221 (8), 191 (12), 175 (6), 164 (7),
147 (18), 119 (23), 104 (9), 91 (34), 77 (11).
HRMS (EI): m/z calcd. for C21H23N3O6: 413.1587. Found:
413.1581.
Anal. calcd. for C21H23N3O6: C, 61.01; H, 5.61; N, 10.06. Found: C,
61.02; H, 5.63; N, 10.07.
GC-MS (EI): m/z (%) = 336 (M+, 3), 291 (23), 263 (61), 234 (15),
216 (88), 189 (43), 161 (25), 143 (50), 117 (100), 105 (6), 91 (30),
77 (6), 65 (5).
N-Tosyl-2,2a,2b,3,5,7,7a,8-dodecahydroisoindolo[5,6-c]furan-
2,8-dione (5a)
HRMS (EI): m/z calcd. for C17H20O7: 336.1203. Found: 336.1209.
Anal. calcd. for C17H20O7: C, 60.71; H, 5.99. Found: C, 60.53; H,
6.05.
Recrystallization of the crude product from acetone gave 250 mg
(0.72 mmol, 72%) of a colorless solid; mp: 191 °C (dec.).
IR (KBr): = 3065, 2971, 2956, 2921, 2909, 2853, 1839, 1774,
1598, 1471, 1344, 1304, 1223, 1161, 1123, 1099, 1093, 1028, 967,
831, 819, 794 cm .
Tetraethyl 1,2,2a,7-Tetrahydrocyclopenta[c]pyridazin-1,2,6,6-
tetracarboxylate (4b)
Flash chromatography (Et2O/n-pentane, 1: 1) yielded 238 mg
(0.60 mmol, 58%) of a colorless oil.
1
UV/VIS (CH3CN): max (lg ) = 230 (2.78), 196 (3.27) nm.
1H NMR (400 MHz, DMSO-d6): = 7.70 (d, 2H, J = 8.1 Hz, o-H),
7.49 (d, 2H, J = 8.1 Hz, m-H), 5.86 (ddd, 1H, J = 7.4, 2.0, 2.0 Hz,
7-H), 3.73-3.65 (m, 4H, 4-H, 5-H, 1-H), 3.59 (dd, 1H, J = 9.1, 1.7
Hz, 3-Ha), 3.45 (dd, 1H, J = 10.1, 9.1 Hz, 3-Hb), 2.83 (br s, 1H, 3a-
H), 2.55 (ddd, 1H, J = 13.9, 7.4, 1.5 Hz, 6-Ha), 2.44 (s, 3H, CH3),
2.14 (ddd, 1H, J = 13.9, 6.4, 2.0 Hz, 6-Hb).
13C NMR (100 MHz, DMSO-d6): = 176.0 (CO), 173.1 (CO),
144.8 (C-i), 140.9 (C-p), 132.3 (C-7a), 130.8 (C-m), 128.8 (C-o),
118.8 (C-7), 51.6 (C-1), 49.6 (C-9), 42.6 (C-4), 41.5 (C-5), 37.3 (C-
3a), 25.2 (C-6), 21.9 (CH3).
IR (film): = 2985, 1731, 1656, 1467, 1446, 1411, 1378, 1336,
1313, 1299, 1256, 1239, 1176, 1095, 1075, 1049, 1024 cm .
1
UV/VIS (CH3CN): max (lg ) = 192 (2.87) nm.
1H NMR (360 MHz, DMSO-d6, 382 K): = 5.86 (br s, 1H, 7-H),
4.27 4.20 (m, 1H, 3a-H), 4.19 (q, 8H, J = 7.0 Hz, OCH2CH3), 2.94
(br s, 2H, 6-H), 2.92 (m, 2H,1-H) 2.15 (m, 2H, 3-H), 1.27 (t, 6H,
J = 7.0 Hz, OCH2CH3), 1.24 (t, 6H, J = 7.0 Hz, OCH2CH3).
13C NMR (90 MHz, DMSO-d6, 303 K): = 172.1 [(C-2) COOEt],
171.4 [(C-2) COOEt], 156.5 (N-COOEt), 156.1 (N-COOEt), 138.1
(C-7a), 117.2 (C-7), 62.7 (OCH2CH3), 56.6 (C-3a), 55.5 (C-2), 44.4
(C-6), 39.2 (C-3), 35.9 (C-1), 14.7 (OCH2CH3).
MS (EI): m/z (%) = 347 (M+, 1), 319 (1), 274 (1), 192 (100), 164
(10), 155 (14), 146 (5), 139 (2), 118 (11), 91 (59), 77 (4), 65 (15).
MS (EI): m/z (%) = 412 (M+, 39), 366 (57), 339 (100), 323 (21), 310
(9), 292 (42), 267 (21), 265 (25), 249 (69), 237 (11), 221 (20), 193
(39), 176 (22), 165 (22), 147 (13), 119 (24), 104 (22), 91 (26), 73
(16).
HRMS (EI): m/z calcd. for C17H17NO5S: 347.0827. Found:
347.0823.
Anal. calcd. for C17H17NO5S: C, 58.78; H, 4.93; N, 4.03; S, 9.23.
Found: C, 58.68; H, 5.00; N, 3.94; S, 9.41.
HRMS (EI): m/z calcd. for C19H28N2O8: 412.1846. Found:
412.1838.
Diethyl N-Tosyl-1,2,2a,3,4,5,7-octahydropyrrolo[3,4-c]py-
ridazin-1,2-dicarboxylate (5b)
After evaporation of the solvent, the crude product was washed with
CH2Cl2 and dried to give 347 mg (0.82 mmol, 82%) of a colorless
solid; mp: 223 °C.
Anal. calcd. for C19H28N2O8: C, 55.33; H, 6.84; N, 6.79. Found: C,
55.13; H, 6.95; N, 6.51.
Synthesis 2000, No. 12, 1766–1773 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Perhydroindenes and Perhydroisoindoles
1771
IR (KBr): = 2964, 2935, 2929, 2872, 1718, 1598, 1494, 1467,
1436, 1412, 1379, 1347, 1306, 1280, 1224, 1163, 1095, 1066, 1028,
1018, 818 cm .
N-Allyl-N-3-phenylprop-2-inyl-p-toluenesulfonamide (8)
A solution of N-allyl-p-toluenesulfonamide (1.11 g, 5.00 mmol) in
THF (10 mL) was added dropwise at 0 °C to a suspension of NaH
(0.14 g, 6.00 mmol) in THF (80 mL) and the resulting mixture was
stirred for 30 min at 0 °C. Then a solution of phenylproparyl bro-
mide (0.98 g, 5.00 mmol) in THF (10 mL) was added dropwise and
the mixture was refluxed for 90 min. After cooling to r.t., the reac-
tion mixture was poured onto ice (100 mL), the organic layer was
separated and the aqueous layer was extracted with Et2O (3 100
mL). The combined organic layers were dried (MgSO4) and evapo-
rated. The crude product was purified by flash chromatography on
SiO2 (Et2O/n-pentane, 1: 5) to give 1.10 g (3.40 mmol, 68%) of a
colorless solid; mp: 93 94 °C.
1
UV/VIS (CH3CN): max (lg ) = 248 (6.52), 194 (7.66) nm.
1H NMR (200 MHz, DMSO-d6, 313 K): = 7.75 (d, 2H, J = 8.4 Hz,
o-H), 7.46 (d, 2H, J = 8.6 Hz, m-H), 5.95 (br s, 1H, 7-H), 4.20 (q,
2H, J = 7.0 Hz, OCH2CH3), 4.14 (q, 2H, J = 7.0 Hz, OCH2CH3),
4.09 3.93 (m, 4H, 1-H, 3-H), 3.76 (dd, 1H, J = 10.0, 1.0 Hz, 6-Ha),
2.94 (dd, 1H, J = 9.8, 1.0 Hz, 3a-H), 2.78 (dd, 1H, J = 10.0, 1.0 Hz,
6-Hb), 2.43 (s, 3H, CH3), 1.22 (t, 3H, J = 7.0 Hz, OCH2CH3), 2.10
(t, 3H, J = 7.0 Hz, OCH2CH3).
13C NMR (50 MHz, DMSO-d6, 413 K): = 155.4 (COO), 154.7
(COO), 143.6 (C-i), 135.3 (C-p), 133.8 (C-7a), 129.8 (C-o), 127.1
(C-m), 118.9 (C-7), 62.3 (OCH2CH3), 62.0 (OCH2CH3), 54.4 (C-
3a), 50.9 (C-6), 48.8 (C-3), 43.8 (C-1), 20.7 (CH3), 13.9
(OCH2CH3), 13.8 (OCH2CH3).
IR (KBr): = 3202, 3106, 3039, 3025, 2935, 2881, 2805, 1788,
1
1630, 1335, 1138, 954, 930, 727, 650, 515 cm .
UV/VIS (CH3CN): max (lg ) = 252 (7.35), 232 (7.17), 196 (7.35)
nm.
MS (EI): m/z (%) = 423 (M+, 7), 378 (5), 351 (18), 334 (2), 321 (1),
268 (76), 247 (86), 240 (5), 224 (15), 196 (100), 179 (18), 168 (44),
155 (30), 150 (11), 139 (12), 122 (34), 107 (14), 94 (45), 91 (70), 80
(15), 65 (21).
1H NMR (400 MHz, CDCl3): = 7.82 [d, 2H, J = 8.5 Hz, o-H (Ts)],
7.34 7.09 (m, 5H, Ph), 7.29 [d, 2H, J = 10.1 Hz, m-H (Ts)], 5.84
(dddd, 1H, J = 16.7, 9.9, 6.3, 6.3 Hz, = CH), 5.38 (dddd, 1H,
J = 16.7, 1.5, 1.5, 1.5 Hz, = CH2), 5.31 (dddd, 1H, J = 10.1, 1.3, 1.3,
1.3 Hz, = CH2), 4.35 (s, 2H, 1-H), 3.94 (dd, 2H, J = 7.6, 1.3 Hz,
CH2CH = CH2), 2.37 (s, 3H, CH3).
HRMS (EI): m/z calcd. for C19H25N3O6S: 423.1464. Found:
423.1464.
13C NMR (100 MHz, CDCl3): = 143.4 (C-i, Ts), 135.8 (C-p, Ts),
132.0 (C-o, Ph), 131.4 ( = CH), 129.5 (C-m, Ph), 128.3 (C-p, Ph),
128.0 (C-m, Ts), 127.7 (C-o, Ts), 122.1 (C-i, Ph), 119.9 ( = CH2),
85.6 (C-3), 81.5 (C-2), 49.2 (C-1), 36.6 (CH2CH = CH2), 21.3
(CH3).
MS (EI): m/z (%) = 325 (M+, 3), 298 (2), 260 (4), 248 (1), 222 (6),
192 (6), 170 (67), 169 (26), 155 (12), 142 (58), 139 (8), 128 (19),
115 (100), 102 (7), 91 (68), 89 (17), 77 (6).
Anal. calcd. for C19H25N3O6S: C, 53.89; H, 5.95; N, 9.92; S, 7.57.
Found: C, 53.73; H, 6.00; N, 9.64; S, 7.59.
2-N-Phenyl-6-N-tosyl-4,4a,5,6,7,9,10-octahydropyrrolo[3,4-c]-
pyridazino[1,2-a][2,4,10]triazoline-1,3-dione (5c)
Recrystallization from CHCl3 yielded 360 mg (0.85 mmol, 85%) of
a colorless solid; mp: 249 °C.
IR (KBr): = 3070, 2880, 1767, 1714, 1598, 1506, 1494, 1442,
1410, 1369, 1343, 1305, 1284, 1199, 1185, 1160, 1091, 1067, 1016,
HRMS (EI): m/z calcd. for C19H19NO2S: 325.1132. Found:
325.1136.
1
823, 764, 709 cm .
UV/VIS (CH3CN): max (lg ) = 224 (4.35), 196 (4.80) nm.
1H NMR (400 MHz, CDCl3): = 7.76 [d, 2H, J = 8.1 Hz, o-H (N-
Ts)], 7.48 7.38 (m, 5H, Ph), 7.36 [d, 2H, J = 7.9 Hz, m-H (N-Ts)],
5.81 (br s, 1H, 7-H), 4.41 (dd, 1H, J = 10.0, 7.3 Hz, 3-Ha), 4.39
(ddd, 1H, J = 9.9, 3.5, 3.5 Hz, 6-Ha), 4.14 (br d, 2 H, J = 13.3 Hz, 1-
H), 4.00 3.92 (m, 2H, 6-Hb, 3a-H), 3.16 (dd, 1H, J = 10.2, 9.9 Hz,
3-Hb), 2.45 (s, 3H, CH3).
13C NMR (100 MHz, DMSO-d6): = 153.6 (COO), 151.4 (COO),
144.1 [C-i (N-Ts)], 133.3 [C-p (N-Ts)], 133.0 (C-7a), 130.7 [C-i (N-
Ph)], 130.0 [C-m (N-Ts)], 129.2 [C-o (N-Ts)], 128.3 [C-p (N-Ph)],
127.6 [C-m (N-Ph)], 125.3 [C-o (N-Ph)], 114.7 (C-7), 55.2 (C-3a),
51.6 (C-6), 48.9 (C-3), 42.6 (C-1), 21.5 (CH3).
N-Tosyl-1-(1-phenylvinyl)-2,4-dihydro-2H-pyrrole (9)
To a solution of Grubbs catalyst (206 mg, 0.25 mmol) in toluene
(10 mL) was added dropwise a solution of enyne 8 (1.63 g, 5.00
mmol) in toluene (2 mL) and the resulting mixture was stirred for
17 h at r.t. Then the solvent was removed in vacuo and the crude
product was purified by flash chromatography on SiO2 (pentane/
Et2O 70:30) to give 1.10 g (3.40 mmol, 68%) of a colorless amor-
phous solid.
IR (KBr): = 3001, 2942, 2877, 1610, 1320, 1178, 1081, 866, 826,
654, 582, 560
1
cm .
MS (EI): m/z (%) = 424 (M+, 37), 270 (18), 269 (100), 268 (44), 248
(28), 247 (62), 241 (70), 155 (13), 150 (9), 139 (3), 121 (61), 119
(25), 94 (30), 91 (70), 80 (19).
UV/VIS (CH3CN): max (lg ) = 232 (7.38), 194 (7.40) nm.
1H NMR (400 MHz, CDCl3): = 7.74 [d, 2H, J = 8.3 Hz, o-H (Ts)],
7.33 [d, 2H, J = 8.1 Hz, m-H (Ts)], 7.30 7.17 (m, 5H, Ph), 5.45 (dd,
1H, J = 3.8, 2.0 Hz, 4-H), 5.15 (s, 1H, = CH2), 5.05 (s, 1H, = CH2),
4.33 (ddd, 2H, J = 3.8, 3.8, 1.8 Hz, 5-H), 4.18 (dddd, 2H, J = 2.8,
2.8, 2.8, 1.0 Hz, 2-H), 2.42 (s, 3H, CH3).
13C NMR (100 MHz, CDCl3): = 143.5 (C-i, Ts), 142.9 (C-3),
140.0 ( = CPh), 138.2 (C-p, Ts), 134.1 (C-i, Ph), 129.8 (C-m, Ts),
128.2 (C-o, C-m, Ph), 127.8 (C-p, Ph), 127.5 (C-o, Ts), 124.0 (C-4),
115.9 ( = CH2), 55.5 (C-2), 54.7 (C-5), 21.5 (CH3).
HRMS (EI): m/z calcd. for C21H20N4O4S: 424.1205. Found:
424.1200.
Anal. calcd. for C21H20N4O4S: C, 59.42; H, 4.75; N, 13.20; S, 7.55.
Found: C, 59.48; H, 4.73; N, 12.99; S, 7.30.
Ring-closing Metathesis of 6; General Procedure
To a solution of (20 mg, 0.08 mmol) diethyl 2,2-diallylmalonate (6)
in CH2Cl2 (2 mL) were added Grubbs catalyst (6.6 mg, 0.008 mmol)
and Lewis acid (see also Table 2) and the resulting mixture was
stirred at r.t. Aliquots were taken after 30 min and 2 h, respectively,
and analyzed via capillary GC. For analytic and spectroscopic data
of product 7, see ref.27
MS (EI): m/z (%) = 325 (M+, 34), 248 (3), 222 (11), 202 (2), 188 (3),
170 (29), 168 (18), 155 (25), 139 (8), 143 (21), 128 (22), 115 (28),
103 (30), 91 (100), 77 (20).
HRMS (EI): m/z calcd. for C19H19NO2S: 325.1132. Found:
325.1136.
Anal. calcd. for C19H19NO2S: C, 70.13; H, 5.88; N, 4.30; S, 9.85.
Found: C, 69.86; H, 5.83; N, 4.18; S, 9.80.
Synthesis 2000, No. 12, 1766–1773 ISSN 0039-7881 © Thieme Stuttgart · New York

1772
D. Bentz, S. Laschat
FEATURE ARTICLE
Lewis Acid-catalyzed Diels Alder Reaction of Diene 8 with
Ethyl Acrylate (10); General Procedure
Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1992, 31,
1332.
To a solution of ethyl acrylate 10 (6.5 L, 0.06 mmol) in a solvent
(2 mL) were added Lewis acid (2.50 equiv) and diene 9 (20 mg,
0.06 mmol) dropwise and the mixture was stirred for 5 h at r.t. (see
Table 3). Then the mixture was poured onto sat. NaHCO3, the layers
were separated, the aqueous layer was extracted with the solvent (2
mL), and the combined organic layers were dried (MgSO4). An ali-
quot was analyzed by capillary GC.
Ho, L. L. Tandem Organic Reactions; Wiley: New York,
1992.
(2) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.;
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1997.
(3) Plevyak, J. E.; Heck, R. F. J. Org. Chem. 1978, 43, 2454.
Tao, W.; Nesbitt, S.; Heck, R. F. J. Org. Chem. 1990, 55, 63.
Lansky, A.; Reiser, O.; de Meijere, A. Synlett 1990, 405.
Amoroso, A. J.; Thompson, A. M. W. C.; Maher, J. P.;
McCleverty, J. A.; Ward, M. D. Inorg. Chem. 1995, 34, 4828.
Amoroso, A. J.; Maher, J. P.; McCleverty, J. A.; Ward, M. D.
Chem. Commun. 1994, 1273.
4-Carboxyethyl-7-phenyl-N-tosyl-1,3,3a,4,5,6-hexahydroisoin-
dole (11)
To a solution of ethyl acrylate 10 (33 mg, 0.30 mmol) in toluene
(10 mL) were added BCl3 (0.75 mL, 0.75 mmol, 1 M solution in
CH2Cl2) and diene 9 (98 mg, 0.30 mmol) dropwise and the mixture
was stirred for 9 h at r.t. Hydrolysis and work-up was performed as
described above. The crude product was purified by flash chroma-
tography on SiO2 (pentane/Et2O, 70: 30) to give 83 mg (65%) of a
colorless oil.
König, B.; Zieg, H.; Bubenitschek, P.; Jones, P. G. Chem. Ber.
1994, 127, 1811.
Song, Z. Z.; Wong, H. N. C.; Yang, Y. Pure Appl. Chem.
1996, 68, 723.
Gauler, R.; Risch, N. Tetrahedron Lett. 1997, 38, 223.
Trost, B. M.; Dumas, J. J. Am. Chem. Soc. 1992, 114, 1924.
Trost, B. M.; Dumas, J.; Villa, M. J. Am. Chem. Soc. 1992,
114, 9836.
Kucera, D. J.; O'Connor, S. J.; Overman, L. E. J. Org. Chem.
1993, 58, 5304.
IR (KBr): = 3062, 3028, 2976, 2935, 2880, 1731, 1656, 1618,
1598, 1494, 1463, 1448, 1394, 1378, 1366, 1345, 1307, 1292, 1260,
1
1214, 1163, 1095, 1061, 1030, 1019, 953, 816 cm .
UV/VIS (CH3CN): max (lg ) = 260 (3.64), 232 (4.11) nm.
Overman, L. E.; Ricca, D. J.; Tran, V. D. J. Am. Chem. Soc.
1993, 115, 2042.
(4) Trost, B. M.; Shi, Y. J. Am. Chem. Soc. 1991, 113, 701.
Trost, B. M.; Shi, Y. J. Am. Chem. Soc. 1993, 115, 9421.
(5) Kojima, A.; Takemoto, T.; Sodeoka, M.; Shibasaki, M. J. Org.
Chem. 1996, 61, 4876.
1H NMR (400 MHz, CDCl3): = 7.55 [d, 2H, J = 8.3 Hz, o-H (Ts)],
7.25 7.16 [m, 5H, m-H (Ts), p-H, m-H (Ph)], 7.01 [d, 2H, J = 8.0
Hz, o-H (Ph)), 4.06 (br d, 1H, J = 14.2 Hz, 1-Ha), 3.97 (q, 2H,
J = 7.1 Hz, OCH2CH3), 3.61 (ddd, 1H, J = 13.7, 9.6, 1.3 Hz, 3-Ha),
3.53 (br d, 1H, J = 14.1 Hz, 1-Hb), 2.86 (m, 3H, 4-H, 3a-H, 3-Hb),
2.60 2.49 (m, 1H, 6-Ha), 2.33 (s, 3H, CH3), 2.13 (br s, 1H, 6-Hb),
2.02 1.94 (m, 1H, 5-Ha), 1.85 1.75 (m, 1H, 5-Hb), 1.07 (t, 3H,
J = 7.1 Hz, OCH2CH3).
13C NMR (100 MHz, CDCl3): = 172.2 (CO), 143.3 (C-i, Ts),
140.8 (C-p, Ts), 133.4, 131.6 (C-7, C-7a), 129.9 (C-i, Ph), 129.5 (C-
m, Ts), 128.2 (C-o, Ph), 127.4 (C-o, Ts), 127.0 (C-p, Ph), 126.9 (C-
m, Ph), 60.1 (OCH2CH3), 50.2 (C-1), 49.7 (C-3), 40.0, 38.5 (C-4, C-
3a), 27.2 (C-6), 24.6 (C-5), 21.4 (CH3), 14.0 (OCH2CH3).
Kojima, A.; Honzawa, S.; Boden, C. O. J.; Shibasaki, M.
Tetrahedron Lett. 1997, 38, 3456.
Grigg, R.; Sukirthalingam, S.; Sridharan, V. Tetrahedron Lett.
1991, 32, 2545.
Brown, A.; Grigg, R.; Ravishankar, T.; Thornton-Pett, M.
Tetrahedron Lett. 1994, 35, 2753.
Li, C. -S.; Cheng, C. -H. Organometallics 1993, 12, 3553.
(6) Nuss, J. M.; Levine, B. H.; Rennels, R. A.; Heravi, M. M.
Tetrahedron Lett. 1991, 32, 1641.
(7) Ang, K. H.; Bräse, S.; Steinig, A. G.; Meyer, F. E.; Llebaria,
A.; Voigt, K.; de Meijere, A. Tetrahedron 1996, 52, 11503.
Meyer, F. E.; Ang, K.-H.; Steinig, A. G.; de Meijere, A.
Synlett 1994, 191.
MS (EI): m/z (%) = 425 (M+, 34), 380 (6), 352 (2), 348 (3), 270
(100), 242 (7), 224 (6), 196 (29), 182 (4), 169 (17), 155 (6), 141 (5),
128 (3), 118 (3), 91 (6), 77 (1).
Henniges, H.; Meyer, F. E.; Schick, U.; Funke, F.; Parsons, P.
J.; de Meijere, A. Tetrahedron 1996, 52, 11545.
(8) Dyker, G.; Grundt, P. Tetrahedron Lett. 1996, 37, 619.
(9) Parsons, P. J.; Stefanovic, M.; Willis, P.; Meyer, F. E. Synlett
1992, 864.
(10) Mandai, T.; Tsujiguchi, Y.; Tsuji, J.; Saito, S. Tetrahedron
Lett. 1994, 35, 5701.
(11) Balme, G.; Bouyssi, D. Tetrahedron 1994, 50, 403.
Trost, B. M.; Zhi, L.; Imi, K. Tetrahedron Lett. 1994, 35,
1361.
One-pot Enyne Metathesis/Diels Alder Reaction of 8
To a solution of Grubbs catalyst (25 mg, 0.03 mmol) in toluene
(10 mL) was added enyne 8 (98 mg, 0.30 mmol) and the mixture
was stirred for 2 min at r.t. Then a solution of ethyl acrylate 10 (33
mg, 0.30 mmol) in toluene (1 mL) and BCl3 (0.75 ml, 0.75 mmol, 1
M solution in CH2Cl2) were added. The remaining mixture was
stirred for 9 h at r.t. After hydrolysis, work-up, and flash chroma-
tography, as described above, 77 mg (60%) of a colorless oil was
obtained.
Nuss, J. M.; Murphy, M. M.; Rennels, R. A.; Heravi, M. H.;
Mohr, B. J. Tetrahedron Lett. 1993, 34, 3079.
Nuss, J. M.; Rennels, R. A.; Levine, B. H. J. Am. Chem. Soc.
1993, 115, 6991.
Acknowledgement
Generous financial support by the Deutsche Forschungsgemein-
schaft (Gerhard-Hess-Preis for S.L.) and the Fonds der Chemischen
Industrie is gratefully acknowledged. We thank Prof. Karlheinz
Drauz and Dr. Michael Schwarm, Degussa AG for kind donation of
chemicals. Dr. Klaus Bergander and Karin Busse, Universität Mün-
ster are gratefully acknowledged for performing variable tempera-
ture NMR experiments.
Ohshima, T.; Kagechika, K.; Adachi, M.; Sodeoka, M.;
Shibasaki, M. J. Am. Chem. Soc. 1996, 118, 7108.
(12) Reviews: Blechert, S.; Schuster, M. Angew. Chem., Int. Ed.
Engl. 1997,
Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371.
Schmalz, H. -G. Angew. Chem., Int. Ed. Engl. 1995,
Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995,
28, 446.
References
(13) Grigg, R.; Sridharan, V.; York, M. Tetrahedron Lett. 1998,
39, 4139.
(1) For reviews see: Tietze, L. F.; Beifuss, U. Angew. Chem., Int.
Ed. Engl. 1993, 32, 131.
Synthesis 2000, No. 12, 1766–1773 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Perhydroindenes and Perhydroisoindoles
1773
Evans, P.; Grigg, R.; Ramzan, M.; Sridharan, V.; York, M.
Tetrahedron Lett. 1999, 40, 3021.
(25) When the reaction mixtures were refluxed, complete
conversion was achieved after 7 h.
(14) Taber, D. F. Intramolecular Diels Alder and Alder-Ene
Reactions; Springer-Verlag: Berlin, 1984.
Boger, D. L.; Weinreb, S. M. Hetero Diels Alder
Methodology in Organic Synthesis; Academic Press: New
York, 1987.
(26) For easier comparison of the NMR spectra of compounds 4a
c and 5a c the same numbering system based on the indene
skeleton was used for all cycloadducts (see Table 1).
(27) Hosomi, A.; Mikami, M.; Sakurai, H. Bull. Chem. Soc. Jpn.
1983, 56, 2784.
Fringuelli, F.; Taticchi, A. Dienes in the Diels Alder
Reaction; Wiley: New York, 1990.
Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon: Oxford, 1990; pp. 1 139.
Oppolzer, W. In Comprehensive Organic Synthesis, Vol. 5;
Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991; pp.
315 399.
Depres, J. -P.; Greene, A. E. J. Org. Chem. 1984, 49, 928.
Nugent, W. A.; Feldman, J.; Calabrese, J. C. J. Am. Chem.
Soc. 1995, 117, 8992.
(28) Fürstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119,
9130.
(29) Kinetic results by Grubbs showed that CuCl resulted in
increased reaction rates of the ring closing metathesis. For
details, see: Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J. Am.
Chem. Soc. 1997, 119, 3887.
(30) Grubbs reported a template-directed crown ether synthesis via
ring closing metathesis employing 5 equiv of LiClO4. For
details, see: Marsella, M. J.; Maynard, H. D.; Grubbs, R. H.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1101.
Waldmann, H. Synthesis 1994, 535.
Santelli, M.; Pons, J. -M. Lewis Acids and Selectivity in
Organic Synthesis; CRC Press: Boca Raton, 1996; pp. 267
328.
(15) Kinoshita, A.; Sakakibara, N.; Mori, M. J. Am. Chem. Soc.
1997, 117, 12388.
Kinoshita, A.; Sakakibara, N.; Mori, M. Tetrahedron 1999,
55, 8155.
(16) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998,
63, 6082.
(17) Heerding, D. A.; Takata, D. T.; Kwon, C.; Huffman, W. F.;
Samanen, J. Tetrahedron Lett. 1998, 39, 6815.
(18) Hoye, T. R.; Donaldson, S. M.; Vos, T. J. Org. Lett. 1999, 1,
277.
(31) It is known that unsubstituted and alkyl-substituted butadienes
react rather sluggishly in [4+2] cycloadditions. See ref. (16).
(32) Due to partially overlapping signals in the 1H NMR spectra of
11, the assignment of the relative configuration was done by
comparison with the spectral data of 5a. Based on FMO
calculations, the preferred regioisomer in the [4+2]
cycloaddition of electron-rich diene 9 with electron-poor
dienophile 10 is the quasi-para product 11.
(19) Keller-Schierlein, W.; Bahnmüller, U.; Dobler, M.; Bielecki,
J.; Stümpfel, J.; Zähner, H. Helv. Chim. Acta 1986, 69, 1833.
(20) Schürer, S. C.; Blechert, S. Chem. Commun. 1999, 1203.
(21) Garret, C.; Carruette, A.; Fardin, V.; Moussaoui, S.; Peyronel,
J. -F.; Blanchard, J. -C.; Laduron, P. M. Proc. Natl. Acad. Sci.
U.S.A. 1991, 88, 10208.
(33) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923.
(34) Chatani, N.; Takeyasu, T.; Horiuchi, N.; Hanafusa, T. J. Org.
Chem. 1998, 53, 3539.
(35) Chatani, N.; Morimoto, T.; Muto, T.; Murai, S. J. Am. Chem.
Soc. 1994, 116, 6049.
(22) Ohta, H.; Jikihara, T.; Wakabayshi, K.; Fujita, T. Pestic.
Biochem. Physiol. 1980, 14, 153.
(23) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
1996, 118, 100.
Article Identifier:
1437-210X,E;2000,0,12,1766,1773,ftx,en;Z04500SS.pdf
(24) Contrary to the results reported by Mori, the presence of
ethylene gas was not required in our case. See ref. (16) for
details.
Synthesis 2000, No. 12, 1766–1773 ISSN 0039-7881 © Thieme Stuttgart · New York