Cobalt(I) catalysis in the diastereoselective two-step synthesis of tricyclic systems

Article abstract of DOI:10.1055/s-0030-1258433

The diastereoselective two-step synthesis of heterotricyclic systems is accomplished by regioselective cobalt-catalysed [4+2]- and [4+2+2]-cycloaddition reactions generating cyclohexa-1,4-diene and cycloocta-1,3,6-triene derivatives, and a hetero-Diels-Alder reaction. Thus, a set of selected cyclohexadienes and cyclooctatrienes were reacted with cyclic 1,3-diones and formaldehyde in a Knoevenagel-hetero-Diels-Alder multicomponent reaction to produce a variety of tricyclic products. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258433

972
PAPER
Cobalt(I) Catalysis in the Diastereoselective Two-Step Synthesis of Tricyclic
Systems
D
iastereoselec
l
tive
T
w
o
o-Ste
p
Synt
r
hesis of
i
T
ricycl
a
ic System
s
n Erver, Gerhard Hilt,* Klaus Harms
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße, 35043 Marburg, Germany
Fax +49(6421)2825677; E-mail: Hilt@chemie.uni-marburg.de
Received 27 January 2011
Abstract: The diastereoselective two-step synthesis of heterotricy-
clic systems is accomplished by regioselective cobalt-catalysed
[4+2]- and [4+2+2]-cycloaddition reactions generating cyclohexa-
1,4-diene and cycloocta-1,3,6-triene derivatives, and a hetero-
Diels–Alder reaction. Thus, a set of selected cyclohexadienes and
cyclooctatrienes were reacted with cyclic 1,3-diones and formalde-
hyde in a Knoevenagel–hetero-Diels–Alder multicomponent reac-
tion to produce a variety of tricyclic products.
R2
R1
R2
R3
R1
Ph2P
PPh2
Co
+
CoBr2(dppe) (10 mol%)
Zn (20 mol%), ZnI2 (20 mol%)
CH2Cl2, r.t.
R3
2
3
1
1
Co
N
N
iPr
R1
R1
R2
R2
R2
Key words: alkyne, catalysis, cobalt, cycloaddition, diene, multi-
component reaction, hetero-Diels–Alder reaction
+
CoBr2(iPrPyrIm) (5 mol%)
Zn (10 mol%), ZnI2 (10 mol%)
Fe (10 mol%), CH2Cl2, r.t.
2
4
R1 = H, Me; R2 = alkyl, aryl, TMS, CO2R; R3 = alkyl, H, Me
Among the atom economic cobalt-catalysed carbon–car-
bon formation transformations,1 the cobalt-catalysed
[4+2] and [4+2+2] cycloadditions of 1,3-dienes with ter-
minal and internal alkynes are convenient methods for the
synthesis of six- and eight-membered carbocyclic com-
pounds under mild reaction conditions.2 The cobalt-catal-
ysed neutral Diels–Alder reaction represents the more
intensively investigated reaction of the two transforma-
tions and leads to the regioselective formation of cyclo-
hexa-1,4-diene derivatives. Recently, these products
served as substrates for the generation of 1,3-diketones3
and polysubstituted arenes, which were utilised to synthe-
sise functionalised terphenyls.4 The cyclohexa-1,4-dienes
can be produced by using a cobalt catalyst system consist-
ing of a mixture of CoBr2(dppe) {CoBr2[1,2-bis(diphe-
nylphosphino)ethane]}, ZnI2, and zinc powder in
dichloromethane applied at ambient temperature
(Scheme 1). When unsymmetrical 1,3-dienes and alkynes
are used, inversed regiocontrol can be accomplished by
using a CoBr2(pyridinylimine) catalyst precursor.5 Fur-
thermore, the chemoselectivity could be altered by using
a catalyst system consisting of a mixture of CoBr2(i-PrPy-
Scheme 1 Cobalt-catalysed [4+2] and [4+2+2] cycloaddition using
different active catalysts
cloocta-1,3,6-triene derivatives are summarised in
Table 1.
With an atom-economic and efficient route to products 3/
4 thus available, a rapid and diastereoselective construc-
tion of complex structures, realised by a thermal hetero-
Diels–Alder reaction, was envisaged. We were encour-
aged by reports from Koser and Hoffmann describing a
Knoevenagel–hetero-Diels–Alder multicomponent reac-
tion of cyclohexane-1,3-dione and formaldehyde with
monoterpenes leading to tricyclic products in moderate
yields.6
Following the original protocol, 1.0 equivalent of the cy-
clic 1,3-dione was reacted with 2.0 equivalents of
paraformaldehyde and 2.3 equivalents of the dienophile in
the presence of small amounts of hydroquinone and potas-
sium acetate in glacial acetic acid at 70–90 °C. These con-
ditions were necessary to obtain good yields of the hetero-
Diels–Alder product of type 5 (Scheme 2) and to inhibit
side reactions. An example for such an alternative reac-
tion pathway could be the Michael addition, which could
occur between the in situ generated hetero-1,3-diene and
the cyclic 1,3-dione. Koser and Hoffmann inhibited this
side reaction by applying molecular sieves and an excess
of paraformaldehyde for the rapid generation of the hete-
ro-1,3-diene, which is then exposed to an excess of the di-
enophile. In our studies, however, the use of molecular
sieves had no significant influence on the isolated yields
so that their use was abandoned. All other reaction param-
eters remained unchanged (Scheme 2).
rIm)
{CoBr2[N-(pyridin-2-ylmethylene)propan-2-
amine]}, ZnI2, zinc, and iron powder in dichloromethane
to predominantly generate cycloocta-1,3,6-trienes in an
intermolecular and regioselective reaction.2e Accordingly,
1,3-dienes of type 1 could be reacted with terminal or in-
ternal (un)symmetrical alkynes 2 to give cyclohexa-1,4-
dienes 3 or cycloocta-1,3,6-trienes 4 depending on the cat-
alyst systems used (Scheme 1).2c,d,5
The results of the cobalt-catalysed cycloaddition reactions
for the synthesis of selected cyclohexa-1,4-diene and cy-
SYNTHESIS 2011, No. 6, pp 0972–0978
Advanced online publication: 10.02.2011
DOI: 10.1055/s-0030-1258433; Art ID: Z15411SS
x
x
.
x
x
.2
0
1
1
Cyclohexa-1,4-dienes were reacted with cyclohexa-1,3-
dione, cyclopenta-1,3-dione, and 5,5-dimethylcyclohexa-
© Georg Thieme Verlag Stuttgart · New York

PAPER
Diastereoselective Two-Step Synthesis of Tricyclic Systems
973
Table 1 Selected Cyclohexa-1,4-dienes and Cycloocta-1,3,6-tri-
enes Generated by Cobalt-Catalysed [4+2] and [4+2+2] Cycloaddi-
tions
Table 2 Results of the Knoevenagel–Hetero-Diels–Alder Multi-
component Reaction of Cyclohexa-1,4-dienes, Formaldehyde, and
Cyclic 1,3-Diones
Entry 1,3-Diene 1 Alkyne 2 Product 3, 4
Yield (%)
Entry 1,4-Diene 3
Product 5a
Yield
(%)
CH2OMe
OMe
OMe
O
1
98a
H
OMe
OMe
OMe
OMe
1
44
3a
CH2OMe
O
CH2OAc
3a
OAc
OAc
5a
2
80a
O
H
3b
OMe
OMe
CH2OAc
OMe
2
44
40
42
41
50
Ph
OMe
Ph
O
H
3
4
99a
98a
3a
5b
3c
O
TMS
TMS
OAc
OAc
OAc
OAc
3
O
3b
3d
5c
CO2Me
CO2Me
O
CO2Me
CO2Me
H
5
6
78
88
OAc
OAc
OAc
OAc
4
4a
4b
O
3b
CO2Me
CO2Me
5d
O
H
OAc
OAc
OAc
OAc
5
a The product was isolated by filtration over a small plug of silica gel
as pure compounds (>95%) and was used without further purification.
O
3b
5e
O
O
R1
R2
H
H
Ph
O
Ph
+
+
6
7
H
H
3
O
O
3c
1.0 equiv
2.0 equiv
2.3 equiv
5f
hydroquinone (5 mol%)
KOAc (10 mol%)
glacial AcOH
O
TMS
85 °C, 5 d
49
O
O
3d
H
R1
5g
a Only one enantiomer is shown.
O
R2
5
ing arene derivatives. Moreover, the double bonds could
conceivably migrate under the acidic conditions applied
to form the conjugated cyclohexa-1,3-diene derivatives,
which would not undergo the conversion in the way pre-
sented here. Although the thermal cycloaddition could
have given rise to regioisomers only products of type 5
were isolated. In the products, the methyl group is always
found in 2-position with regard to the pyrane oxygen. The
dienophile reacted preferably with the least sterically hin-
dered and electron-richest double bond and only one of
the two possible regioisomers was formed.
Scheme 2 Knoevenagel–hetero-Diels–Alder multicomponent reac-
tion of cyclic 1,3-diones, formaldehyde, and cyclohexa-1,4-dienes to-
wards the construction of tricyclic systems
1,3-dione (dimedone) to yield the corresponding tricyclic
compounds in moderate yields. The results of these trans-
formations are summarised in Table 2.
The yields for the presented conversions are as good as the
yields for the cycloaddition of monoterpenes with the in
situ formed hetero-1,3-diene as reported by Koser and
Hoffmann.6 Nevertheless, the transformations with the
cyclohexa-1,4-diene derivatives are remarkable because
the intermediates can be easily oxidised to the correspond-
Conversions of ether- or ester-substituted cyclohexa-1,3-
dienes 3a and 3b with cyclohexa-1,3-dione, dimedone,
and cyclopenta-1,3-dione led to the corresponding tricy-
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974
F. Erver et al.
PAPER
clic systems in comparable yields of 40–44% (Table 2,
entries 1–5). The use of less polar cyclohexa-1,3-dienes
such as 3c and 3d gave comparable yields of 50% and
49%, respectively (entries 6, 7). It should be mentioned
that the vinylic trimethylsilyl group of 3d was not stable
under the reaction conditions and only the protodesilylat-
ed product could be isolated. Accordingly, the trimethyl-
silyl group in trimethylsilylpropyne utilised for the
synthesis of 3d by cobalt-catalysis served as a strong re-
giodirecting group in the cycloaddition process. Thereby,
a synthon for propyne was realised, which regioselective-
ly afforded the corresponding cyclohexa-1,4-diene deriv-
ative. Surprisingly, the formed tricyclic system 5g did not
react in a second hetero-Diels–Alder reaction to produce
a corresponding pentacyclic by-product. Having explored
the multicomponent reaction of cyclohexa-1,4-dienes
thus far, the use of cobalt-generated cycloocta-1,3,6-
trienes became of significant interest. Specifically, we
were interested in determining if the reactivity of the
[4+2+2] cycloadducts is lowered when the respecting
double bond is not tri- but tetrasubstituted, as was
observed by Koser and Hoffmann as they reacted cyclo-
hexane-1,3-dione with 1,2,3,4,5,6,7,8-octahydronaphtha-
lene.6 The 1,3-diene subunits of the cycloocta-1,3,6-
trienes are electron-deficient and therefore unreactive in
O
R1
CO2Me
CO2Me
O
+
+
H
H
4
O
1.0 equiv
2.3 equiv
2.0 equiv
hydroquinone (5 mol%)
KOAc (10 mol%)
glacial AcOH
85 °C, 5 d
O
R1
CO2Me
R
1 = H, Me
CO2Me
O
6
Scheme 3 Knoevenagel–hetero-Diels–Alder multicomponent reac-
tion of cyclic 1,3-diones, formaldehyde, and cycloocta-1,3,6-trienes
towards the construction of tricyclic systems
the hetero-Diels–Alder multicomponent reaction under
these conditions.
The cycloocta-1,3,6-trienes 4a and 4b were subjected to
the same reaction conditions as the cyclohexa-1,4-dienes
(Scheme 3). Again cyclohexane-1,3-dione, dimedone,
and cyclopentane-1,3-dione were used as the hetero-1,3-
diene components, and the results are summarised in
Table 3.
Table 3 Results of the Knoevenagel–Hetero-Diels–Alder Multicomponent Reaction of Cycloocta-1,3,6-trienes, Formaldehyde, and Cyclic
1,3-Diones
Entry
1,4,7-Triene 4
Product 6a
Yield (%)
49
O
H
CO2Me
CO2Me
CO2Me
CO2Me
1
O
4a
6a
O
H
CO2Me
CO2Me
CO2Me
CO2Me
2
3
4
5
52
40
47
42
O
4a
4a
4b
4b
6b
O
H
CO2Me
CO2Me
CO2Me
CO2Me
O
6c
O
CO2Me
CO2Me
CO2Me
CO2Me
O
6d
O
CO2Me
CO2Me
CO2Me
CO2Me
O
6e
a Only one enantiomer is shown.
Synthesis 2011, No. 6, 972–978 © Thieme Stuttgart · New York

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Diastereoselective Two-Step Synthesis of Tricyclic Systems
975
We were pleased to find that the cycloocta-1,3,6-trienes nent Knoevenagel-hetero-Diels–Alder proceeded with
showed very similar reactivity. The yields were again in excellent regio- and diastereoselectivity and good overall
the range of 40–52%.
yields for the construction of tricyclic products were ob-
tained. Furthermore, the correct constitution of the tricy-
clic products was confirmed by X-ray crystal structure
analysis.
Moreover, the [4+2+2] cycloadduct 4b with a tetrasubsti-
tuted double bond shows the same reactivity as the previ-
ously applied dienophiles with trisubstituted double
bonds 3a–d and 4a (entries 4, 5). This can be explained
through compensation of increased steric hindrance by in-
creased electron density in the dienophile of type 4.
Again, all tricyclic products were formed as single diaste-
reoisomers and represent the first examples of the cy-
cloocta-1,3,6-triene derivatives 4a,b applied.
Column chromatography was performed using silica gel (Mach-
erey-Nagel, 230–400 mesh size) and TLC was carried out using sil-
ica gel (Merck) plates. IR spectra were obtained using a Bruker
Physics IFS 200 Interferometer or a Nicolet Magna IR 750 spec-
trometer. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
recorded using a Bruker Physics Avance-300 instrument with
CDCl3 as the solvent. Low-resolution mass spectra were recorded
using a Varian MAT CH 7A, or a Micromass VG 7070 spectrometer
for EI measurements, or a Micromass VG Autospec spectrometer
for ESI measurements. HRMS were obtained using a Finnigan
MAT 95S instrument for EI measurements or a Micromass VG Au-
tospec spectrometer for ESI measurements
In contrast to the tricyclic systems formed from cyclo-
hexa-1,4-dienes, which were isolated as yellow oils, the
tricyclic products obtained from the conversion of cy-
cloocta-1,3,6-trienes were isolated as solid, white com-
pounds.
The obtained crystallographic data of compounds 6a
(Figure 1) and 6d (Figure 2) confirms the NMR spectro-
scopic assignments and verified the correct constitution
and configuration of the tricylic systems. The cis-config-
uration of the product indicates that the reaction proceed-
ed in a concerted manner and under frontier orbital
control.
Preparative Cobalt-Catalysed [4+2] Cycloaddition; General
Procedure
A Schlenk flask was charged with CoBr2(dppe) (309 mg, 0.5 mmol,
10 mol%), anhyd ZnI2 (319 mg, 1.0 mmol, 20 mol%), and Zn pow-
der (65 mg, 1.0 mmol, 20 mol%) under argon atmosphere. After the
addition of anhyd CH2Cl2 (5.0 mL), the 1,3-diene 1 (6.0 mmol) and
the alkyne 2 (5.0 mmol) were added. The mixture was stirred at r.t.
and the conversion was monitored by GC/MS. After the conversion
was complete, the mixture was diluted with pentane to precipitate
the metal salts and filtered through a small plug of silica gel using
Et2O–pentane or pure pentane as eluent. Further purification by col-
umn chromatography was not necessary.
(4-Methylcyclohexa-1,4-diene-1,2-diyl)bis(methylene) Diace-
tate (3b)
Eluent: pentane–Et2O (5:1); yield: 0.95 g (3.99 mmol, 80%); pale
yellow oil; Rf = 0.80 (pentane–Et2O, 10:1).
IR (KBr): 3420, 2966, 2931, 2820, 1738, 1619, 1507, 1440, 1378,
1226, 1026, 963, 822, 607 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.39–5.38 (m, 1 H), 4.67–4.66 (m,
4 H), 2.78–2.75 (m, 2 H), 2.69–2.64 (m, 2 H), 2.06 (s, 3 H), 2.04 (s,
3 H), 1.68 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 170.9, 130.5, 129.4, 129.3, 117.7,
63.3, 63.2, 34.0, 30.3, 22.7, 20.9.
Figure 1 Crystal structure of compound 6a7
MS (EI, 70 eV): m/z (%) = 178 (4), 133 (1), 118 (100), 105 (24), 91
(14), 77 (6), 65 (2), 51 (1).
HRMS: m/z [M]+ calcd for C21H27NO2: 238.1205; found: 238.1206.
(2,4-Dimethylcyclohexa-1,4-dienyl)trimethylsilane (3d)
Eluent: pentane; yield: 1.76 g (9.78 mmol, 98%); colourless oil;
Rf = 0.86 (pentane).
IR (KBr): 2961, 2911, 2862, 2809, 1698, 1627, 1447, 1384, 1303,
1250, 1205, 1158, 1000, 976, 943, 902, 837, 785, 753, 687, 640
cm–1.
1H NMR (300 MHz, CDCl3): d = 5.47–5.43 (m, 1 H), 2.75–2.69 (m,
2 H), 2.54–2.48 (m, 2 H), 1.80–1.78 (m, 3 H), 1.67–1.65 (m, 3 H),
0.14 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 140.4, 130.8, 126.1, 119.1, 38.2,
31.6, 23.3, 22.9, 0.0.
Figure 2 Crystal structure of compound 6d7
In conclusion, four different types of tricyclic ring sys-
tems were produced in a short two-step reaction sequence.
The cobalt-catalysed reactions as well as the multicompo-
MS (EI, 70 eV): m/z (%) = 180 (4, [M]+), 165 (4), 149 (2), 135 (3),
121 (2), 106 (91), 97 (4), 91 (41), 79 (6), 73 (100), 65 (5), 59 (35),
53 (4).
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F. Erver et al.
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HRMS: m/z [M]+ calcd for C11H20Si: 180.1334; found: 180.1332.
1H NMR (300 MHz, CDCl3): d = 3.97–3.83 (m, 4 H), 3.26 (s, 3 H),
3.25 (s, 3 H), 2.36–2.30 (m, 7 H), 2.06–1.90 (m, 6 H), 1.31 (s, 3 H).
Preparative Cobalt-Catalysed [4+2+2] Cycloaddition; General
Procedure
13C NMR (75 MHz, CDCl3): d = 198.3, 169.7, 130.1, 128.5, 109.4,
77.7, 71.0, 57.8, 37.2, 36.7, 33.3, 31.9, 28.8, 24.7, 21.5, 21.0.
A Schlenk flask was charged with CoBr2(i-PrPyrIm) (185 mg, 0.5
mmol, 5 mol%), anhyd ZnI2 (319 mg, 1.0 mmol, 10 mol%), Zn
powder (65 mg, 1.0 mmol, 10 mol%), and Fe powder (55 mg, 1.0
mmol, 10 mol%) under argon atmosphere. After the addition of an-
hyd CH2Cl2 (5.0 mL), the 1,3-diene 1 (10.0 mmol) and the alkyne 2
(10.0 mmol) were added. The mixture was stirred at r.t. and the con-
version was monitored by GC/MS. After the conversion was com-
plete, the mixture was diluted with pentane to precipitate the metal
salts and filtered through a small plug of silica gel using Et2O–pen-
tane as eluent. After evaporation of the solvent, the residue was pu-
rified by flash chromatography on silica gel.
MS (EI, 70 eV): m/z (%) = 306 (1, [M]+), 291 (2), 274 (52), 259
(16), 242 (57), 227 (9), 213 (4), 199 (6), 186 (8), 171 (8), 163 (62),
149 (61), 132 (63), 119 (70), 105 (100), 91 (45), 75 (28), 55 (25).
HRMS: m/z [M]+ calcd for C18H26O4: 306.1831; found: 306.1836.
6,7-Bis(methoxymethyl)-3,3,10a-trimethyl-2,3,4,5,8,8a,9,10a-
octahydro-1H-xanthen-1-one (5b)
Eluent: Et2O–EtOAc (10:1); yield: 127 mg (0.38 mmol, 44%); yel-
low oil; Rf = 0.33 (Et2O–EtOAc, 10:1).
IR (KBr): 3457, 2925, 2819, 1735, 1622, 1457, 1387, 1293, 1230,
1195, 1153, 1092, 960, 888, 652 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.97–3.83 (m, 4 H), 3.26–3.24 (m,
6 H), 2.45–2.29 (m, 3 H), 2.23–2.17 (m, 5 H), 2.07–1.92 (m, 3 H),
1.30 (s, 3 H), 1.03–1.02 (m, 6 H).
(1E,2E,5Z)-Dimethyl 5-Methylcycloocta-2,5,8-triene-1,2-dicar-
boxylate (4a)
Eluent: pentane–Et2O (3:1); yield: 0.98 g (3.89 mmol, 78%); co-
lourless oil; Rf = 0.38 (pentane–Et2O, 3:1).
13C NMR (75 MHz, CDCl3): d = 198.0, 168.0, 130.3, 128.5, 108.0,
77.7, 71.0, 57.7, 50.6, 42.6, 37.4, 33.1, 32.2, 31.8, 28.5, 28.3, 24.7,
21.3.
MS (EI, 70 eV): m/z (%) = 334 (1, [M]+), 319 (2), 303 (29), 287
(16), 270 (90), 255 (11), 237 (3), 227 (3), 191 (45), 171 (9), 162
(33), 149 (58), 132 (93), 118 (81), 105 (100), 91 (52), 75 (30), 55
(35).
1H NMR (300 MHz, CDCl3): d = 6.78–6.72 (m, 2 H), 5.33–5.28 (m,
1 H), 3.66 (s, 6 H), 2.68–2.63 (m, 4 H), 1.70 (br s, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.2, 138.2, 137.6, 133.2, 131.3,
130.9, 118.0, 51.7, 33.0, 27.4, 27.0.
MS (EI, 70 eV): m/z (%) = 236 (4) [M]+, 221 (1), 205 (7), 177 (100),
175 (26), 119 (12), 117 (24), 105 (7).
HRMS: m/z [M]+ calcd for C13H16O4: 236.1049; found: 236.1044.
HRMS: m/z [M]+ calcd for C20H30O4: 334.2144; found: 334.2143.
(1E,2E,5Z)-Dimethyl 5,6-Dimethylcycloocta-2,5,8-triene-1,2-di-
carboxylate (4b)
Eluent: pentane–Et2O (3:1); yield: 1.10 g (4.38 mmol, 88%); co-
lourless oil; Rf = 0.41 (pentane–Et2O, 3:1).
1H NMR (300 MHz, CDCl3): d = 6.80 (t, J = 8.1 Hz, 2 H), 3.72 (s,
6 H), 2.24 (d, J = 8.1 Hz, 4 H), 1.74 (br s, 6 H).
13C NMR (75 MHz, CDCl3): d = 166.6, 138.7, 131.1, 124.6, 52.0,
35.7, 23.6.
MS (EI, 70 eV): m/z (%) = 250 (6) [M]+, 235 (1), 218 (8), 203 (2),
190 (100), 175 (10), 159 (16), 147 (4), 132 (60).
(4a-Methyl-8-oxo-4,4a,5,6,7,8,9,9a-octahydro-1H-xanthene-
2,3-diyl)bis(methylene) Diacetate (5c)
Eluent: Et2O–EtOAc (10:1); yield: 124 mg (0.34 mmol, 40%); yel-
low oil; Rf = 0.30 (Et2O–EtOAc, 10:1).
IR (KBr): 3463, 2936, 1739, 1650, 1621, 1432, 1389, 1298, 1231,
1189, 1159, 1117, 1073, 1025, 961, 926, 732 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.65–4.54 (m, 4 H), 2.45–2.14 (m,
8 H), 2.05–2.04 (m, 7 H), 1.98–1.92 (m, 4 H), 1.31 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.3, 170.8, 169.5, 129.7, 127.8,
109.4, 77.2, 63.1, 62.9, 37.3, 36.7, 33.1, 31.8, 28.8, 24.6, 21.4, 21.0,
20.8.
HRMS: m/z [M]+ calcd for C14H18O4: 250.1205; found: 250.1192.
MS (EI, 70 eV): m/z (%) = 362 (1, [M]+), 319 (1), 302 (4), 278 (1),
260 (3), 242 (100), 227 (6), 213 (2), 201 (3), 190 (7), 177 (2), 163
(13), 148 (9), 135 (14), 118 (60), 105 (23), 91 (23), 79 (10), 65 (3),
55 (11).
Preparative Knoevenagel-Hetero-Diels–Alder Multicomponent
Reaction of Cyclohexa-1,4-dienes with Cyclic 1,3-Diones and
Formaldehyde; General Procedure
A thick walled Schlenk tube was charged with hydroquinone (5 mg,
0.043 mmol, 5 mol%), KOAc (9 mg, 0.086 mmol, 10 mol%), the
appropriate cyclic 1,3-dione (0.86 mmol, 1.0 equiv), paraformalde-
hyde (52 mg, 1.72 mmol, 2.0 equiv), the appropriate cyclohexa-1,4-
diene 3 (1.98 mmol, 2.3 equiv), and glacial AcOH (1.0 mL). The
mixture was heated to 85 °C and stirred for 5 d, until GC/MS-mon-
itoring indicated no further conversion of the cyclohexa-1,4-diene
3. The mixture was partitioned between CH2Cl2 (20 mL) and H2O
(20 mL) and the aqueous phase was extracted with CH2Cl2
(3 × 20 mL). The combined organic phases were dried (MgSO4),
filtered, and the solvent was evaporated. The residue was purified
by flash chromatography on silica gel.
HRMS: m/z [M]+ calcd for C20H26O6: 362.1729; found: 362.1744.
(4a,6,6-Trimethyl-8-oxo-4,4a,5,6,7,8,9,9a-octahydro-1H-xan-
thene-2,3-diyl)bis(methylene) Diacetate (5d)
Eluent: Et2O–EtOAc (10:1); yield: 129 mg (0.33 mmol, 42%); yel-
low oil; Rf = 0.45 (Et2O–EtOAc, 10:1).
IR (KBr): 3463, 2957, 2932, 1740, 1652, 1623, 1432, 1386, 1293,
1230, 1162, 1119, 1061, 1025, 964, 932, 733 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.67–4.53 (m, 4 H), 2.44–2.17 (m,
8 H), 2.09–1.93 (m, 9 H), 1.30 (s, 3 H), 1.05–1.04 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 198.0, 170.7, 167.9, 129.8, 127.8,
107.9, 77.2, 63.1, 63.0, 50.6, 42.6, 37.7, 33.0, 32.2, 31.7, 28.6, 28.1,
24.6, 21.2, 20.8.
MS (EI, 70 eV): m/z (%) = 390 (1, [M]+), 331 (2), 288 (2), 270
(100), 255 (6), 237 (3), 225 (1), 191 (10), 171 (5), 159 (2), 148 (7),
135 (11), 118 (47), 105 (12), 91 (12), 69 (7), 55 (8).
6,7-Bis(methoxymethyl)-10a-methyl-2,3,4,5,8,8a,9,10a-octahy-
dro-1H-xanthen-1-one (5a)
Eluent: Et2O–EtOAc (10:1); yield: 117 mg (0.38 mmol, 44%); yel-
low oil; Rf = 0.25 (Et2O–EtOAc, 10:1).
IR (KBr): 3473, 2928, 2821, 1732, 1702, 1618, 1440, 1386, 1292,
1236, 1186, 1150, 1087, 921, 731 cm–1.
HRMS: m/z [M]+ calcd for C22H30O6: 390.2042; found: 390.2053.
Synthesis 2011, No. 6, 972–978 © Thieme Stuttgart · New York

PAPER
Diastereoselective Two-Step Synthesis of Tricyclic Systems
977
(4a-Methyl-1-oxo-1,2,3,4a,5,8,8a,9-octahydrocyclopen-
ta[b]chromene-6,7-diyl)bis(methylene) Diacetate (5e)
Eluent: Et2O–EtOAc (1:1); yield: 123 mg (0.35 mmol, 41%); yel-
low oil; Rf = 0.28 (Et2O–EtOAc, 1:1).
(20 mL). The aqueous phase was extracted with CH2Cl2
(3 × 20 mL) and the combined organic phases were dried (MgSO4).
After filtration and evaporation of the solvent, the residue was puri-
fied by flash chromatography on silica gel.
IR (KBr): 3461, 2926, 1739, 1693, 1630, 1441, 1401, 1380, 1297,
1234, 1159, 1114, 1079, 1052, 1026, 985, 962, 881, 830 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.63–4.51 (m, 4 H), 2.51–2.49 (m,
2 H), 2.43–2.38 (m, 3 H), 2.30–2.24 (m, 3 H), 2.04 (s, 3 H), 2.01 (s,
3 H), 2.00–1.93 (m, 3 H), 1.33 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 204.1, 182.6, 170.7, 129.7, 127.6,
112.5, 80.3, 63.0, 62.8, 37.7, 33.2, 32.7, 31.5, 26.6, 20.8, 20.3.
Dimethyl (7E,9E)-5a-Methyl-1-oxo-2,3,4,5a,6,11,11a,12-octa-
hydro-1H-cycloocta[b]chromene-8,9-dicarboxylate (6a)
Eluent: Et2O–EtOAc (10:1); yield: 115 mg (0.32 mmol, 49%);
white solid; mp 93–95 °C; Rf = 0.29 (Et2O–EtOAc, 10:1).
IR (KBr): 3425, 2949, 1724, 1648, 1623, 1437, 1391, 1352, 1266,
1188, 1134, 1098, 1062, 1043, 1015, 1001, 924, 839, 805, 771, 752
cm–1.
MS (EI, 70 eV): m/z (%) = 348 (1, [M]+), 288 (11), 246 (3), 228
(100), 213 (8), 199 (5), 185 (7), 171 (5), 158 (4), 149 (10), 135 (28),
118 (78), 105 (32), 91 (33), 77 (14), 65 (7), 55 (13).
1H NMR (300 MHz, CDCl3): d = 7.22–7.16 (m, 1 H), 7.09–7.04 (m,
1 H), 3.73 (s, 6 H), 2.82–2.32 (m, 7 H), 2.25–1.86 (m, 6 H), 1.30 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 198.1, 168.8, 166.4, 144.4, 140.5,
130.4, 129.3, 107.7, 124.7, 76.1, 52.2, 52.0, 40.4, 36.7, 34.7, 31.6,
28.7, 28.5, 28.1, 25.7, 20.9, 20.8.
MS (EI, 70 eV): m/z (%) = 360 (8, [M]+), 345 (1), 328 (65), 313 (9),
300 (16), 287 (23), 268 (28), 253 (6), 241 (29), 225 (9), 213 (8), 203
(17), 189 (32), 177 (59), 163 (100), 145 (33), 128 (18), 117 (60),
105 (27), 91 (48), 77 (38), 59 (42).
HRMS: m/z [M]+ calcd for C19H24O6: 348.1573; found: 348.1564.
10a-Methyl-7-phenyl-2,3,4,5,8,8a,9,10a-octahydro-1H-xan-
then-1-one (5f)
Eluent: Et2O; yield: 255 mg (0.87 mmol, 50%); yellow oil; Rf = 0.48
(Et2O).
IR (KBr): 3027, 2917, 1739, 1654, 1624, 1493, 1446, 1386, 1325,
1291, 1250, 1223, 1184, 1134, 1087, 1070, 998, 920, 851, 759, 699
cm–1.
HRMS: m/z [M]+ calcd for C20H24O6: 360.1573; found: 360.1578.
1H NMR (300 MHz, CDCl3): d = 7.34–7.15 (m, 5 H), 5.25 (s, 1 H),
2.48–2.44 (m, 2 H), 2.41–2.40 (m, 2 H), 2.35–2.31 (m, 1 H), 2.29–
2.24 (m, 2 H), 2.04–1.99 (m, 2 H), 1.96–1.87 (m, 4 H), 1.62 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.4, 169.9, 144.5, 132.9, 128.5,
127.3, 125.3, 124.7, 117.0, 110.5, 81.0, 36.8, 36.7, 32.8, 28.7, 23.2,
22.0, 21.0.
Dimethyl (7E,9E)-3,3,5a-Trimethyl-1-oxo-2,3,4,5a,6,11,11a,12-
octahydro-1H-cycloocta[b]chromene-8,9-dicarboxylate (6b)
Eluent: Et2O–EtOAc (10:1); yield: 156 mg (0.40 mmol, 52%);
white solid; mp 77 °C; Rf = 0.40 (Et2O–EtOAc, 10:1).
IR (KBr): 3417, 2954, 1724, 1628, 1437, 1393, 1347, 1264, 1135,
1099, 1061, 1044, 1010, 970, 936, 886, 851, 806, 772, 751 cm–1.
MS (EI, 70 eV): m/z (%) = 294 (4, [M]+), 226 (5), 182 (5), 170 (51),
155 (65), 141 (13), 126 (100), 115 (20), 102 (5), 91 (35), 77 (21), 65
(8), 55 (15).
1H NMR (300 MHz, CDCl3): d = 7.22–7.16 (m, 1 H), 7.08–7.02 (m,
1 H), 3.74–3.71 (m, 6 H), 2.89–2.40 (m, 4 H), 2.22–2.20 (m, 4 H),
2.02–1.57 (m, 3 H), 1.30 (s, 3 H), 1.04–0.98 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 197.8, 167.2, 166.4, 144.3, 140.4,
130.3, 129.3, 106.4, 124.7, 76.2, 52.1, 52.0, 50.6, 42.3, 40.4, 34.6,
32.2, 31.6, 28.9, 28.1, 27.7, 25.5.
MS (EI, 70 eV): m/z (%) = 388 (15, [M]+), 373 (3), 356 (64), 341
(31), 324 (33), 313 (21), 296 (42), 281 (16), 269 (41), 253 (13), 241
(8), 229 (12), 218 (11), 204 (34), 192 (98), 177 (100), 163 (41), 145
(46), 128 (25), 117 (80), 105 (36), 83 (63), 59 (52).
HRMS: m/z [M]+ calcd for C20H22O2: 294.1620; found: 294.1611.
6,10a-Dimethyl-2,3,4,5,8,8a,9,10a-octahydro-1H-xanthen-1-
one (5g)
Eluent: pentane–Et2O (1:2); yield: 196 mg (0.84 mmol, 49%); yel-
low oil; Rf = 0.50 (pentane–Et2O, 1:2).
IR (KBr): 3456, 2911, 1739, 1652, 1622, 1436, 1390, 1284, 1231,
1190, 1167, 1134, 1096, 1078, 1025, 994, 935, 855, 822, 796, 637
cm–1.
HRMS: m/z [M]+ calcd for C22H28O6: 388.1886; found: 388.1885.
1H NMR (300 MHz, CDCl3): d = 5.24 (s, 1 H), 2.37–2.24 (m, 6 H),
Dimethyl (6E,8E)-4a-Methyl-1-oxo-1,2,3,4a,5,10,10a,11-octa-
hydrocycloocta[e]cyclopenta[b]pyran-7,8-dicarboxylate (6c)
Eluent: Et2O–EtOAc (2:1); yield: 117 mg (0.34 mmol, 40%); white
solid; mp 96–98 °C; Rf = 0.19 (Et2O–EtOAc, 2:1).
2.07–2.01 (m, 2 H), 1.96–1.83 (m, 5 H), 1.61 (s, 3 H), 1.30 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.6, 169.9, 129.7, 118.2, 109.9,
78.6, 39.0, 36.6, 33.1, 29.3, 28.9, 24.9, 23.1, 21.5, 21.0.
MS (EI, 70 eV): m/z (%) = 232 (25, [M]+), 214 (38), 199 (7), 189
(5), 176 (3), 163 (14), 155 (2), 143 (5), 127 (7), 120 (60), 113 (87),
105 (39), 93 (100), 77 (32), 65 (13), 55 (16).
IR (KBr): 3435, 2951, 1723, 1635, 1440, 1403, 1339, 1266, 1244,
1141, 1095, 1075, 1059, 1038, 985, 938, 842, 806, 782, 772 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.22–7.16 (m, 1 H), 7.11–7.05 (m,
1 H), 3.74–3.71 (m, 6 H), 2.88–2.81 (m, 1 H), 2.56–2.49 (m, 3 H),
2.42–2.37 (m, 2 H), 2.27–2.19 (m, 1 H), 2.18–1.99 (m, 2 H), 1.91–
1.85 (m, 1 H), 1.66–1.91 (m, 1 H), 1.34 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 203.9, 181.8, 166.4, 143.9, 140.1,
130.6, 129.5, 112.0, 111.2, 79.4, 52.1, 52.0, 40.1, 34.6, 33.3, 31.6,
28.1, 26.4, 25.0.
MS (EI, 70 eV): m/z (%) = 346 (9, [M]+), 314 (100), 299 (17), 286
(20), 273 (44), 254 (53), 239 (8), 227 (48), 213 (9), 203 (37), 189
(28), 177 (86), 163 (33), 150 (44), 141 (13), 128 (23), 117 (71), 105
(26), 91 (52), 77 (38), 59 (37).
HRMS: m/z [M]+ calcd for C15H20O2: 232.1463; found: 232.1460.
Preparative Knoevenagel-Hetero-Diels–Alder Multicomponent
Reaction of Cycloocta-1,3,6-trienes with Cyclic 1,3-Diones and
Formaldehyde; General Procedure
A Schlenk tube was charged with hydroquinone (5 mg, 0.043 mmol,
5 mol%), KOAc (9 mg, 0.086 mmol, 10 mol%), the appropriate cy-
clic 1,3-dione (0.86 mmol, 1.0 equiv), paraformaldehyde (52 mg,
1.72 mmol, 2.0 equiv), the appropriate cycloocta-1,3,6-triene 4
(1.98 mmol, 2.3 equiv) and glacial AcOH (1.0 mL). The mixture
was heated to 85 °C and stirred for 5 d until GC/MS-monitoring in-
dicated no further conversion of the cycloocta-1,3,6-triene 4. The
mixture was partitioned between CH2Cl2 (20 mL) and H2O
HRMS: m/z [M]+ calcd for C19H22O6: 346.1416; found: 346.1427.
Synthesis 2011, No. 6, 972–978 © Thieme Stuttgart · New York

978
F. Erver et al.
PAPER
Dimethyl (7E,9E)-3,3,5a,11a-Tetramethyl-1-oxo-2,3,4,
5a,6,11,11a,12-octahydro-1H-cycloocta[b]chromene-8,9-dicar-
boxylate (6d)
Eluent: Et2O–EtOAc (15:1); white solid; yield: 107 mg (0.27 mmol,
47%); mp 113 °C; Rf = 0.47 (Et2O–EtOAc, 15:1).
References
(1) For recent reviews, see: (a) Leboeuf, D.; Gandon, V.;
Malacria, M. In Handbook of Cyclization Reactions, Vol. 1;
Ma, S., Ed.; Wiley-VCH: Weinheim, 2009, 367. (b) Galan,
B. R.; Rovis, T. Angew. Chem. Int. Ed. 2009, 48, 2830.
(c) Omae, I. Appl. Organomet. Chem. 2008, 22, 149.
(d) Hess, W.; Treutwein, J.; Hilt, G. Synthesis 2008, 3537.
(e) Omae, I. Appl. Organomet. Chem. 2007, 21, 318.
(f) Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org.
Chem. 2005, 4741. (g) Malacria, M.; Aubert, C.; Renaud, J.
L. In Science of Synthesis: Houben-Weyl Methods of
Molecular Transformations, Vol. 1; Lautens, M.; Trost, B.
M., Eds.; Thieme: Stuttgart, 2001, 439. (h) Saito, S.;
Yamamoto, Y. Chem. Rev. 2000, 100, 2901.
(2) (a) Hilt, G.; Paul, A.; Harms, K. J. Org. Chem. 2008, 73,
5187. (b) Hilt, G.; Paul, A.; Hengst, C. Synthesis 2009,
3305. (c) Hilt, G.; Hess, W.; Harms, K. Synthesis 2008, 75.
(d) Treutwein, J.; Hilt, G. Angew. Chem. Int. Ed. 2008, 47,
6811. (e) Hilt, G.; Janikowski, J. Angew. Chem. Int. Ed.
2008, 47, 5243. (f) Foralternative cobalt-catalysed reactions
involving cyclopentadienyl cobalt-type catalyst systems, see
reference 1.
(3) For the application of cyclic and acyclic 1,4-dienes as
synthons for 1,3-dicarbonyl compounds, see: (a) Kersten,
L.; Roesner, S.; Hilt, G. Org. Lett. 2010, 12, 4920. (b) Hilt,
G.; Arndt, M.; Weske, D. F. Synthesis 2010, 1321. (c) Hilt,
G.; Weske, D. F. Chem. Soc. Rev. 2009, 38, 3082.
(4) (a) Danz, M.; Hilt, G. Adv. Synth. Catal. 2011, in press.
(b) Auvinet, A.-L.; Harrity, J. P. A.; Hilt, G. J. Org. Chem.
2010, 75, 3893.
(5) (a) Hilt, G.; Janikowski, J. Org. Lett. 2009, 11, 773.
(b) Hilt, G.; Danz, M. Synthesis 2008, 2257. (c) Mörschel,
P.; Janikowski, J.; Hilt, G.; Frenking, G. J. Am. Chem. Soc.
2008, 130, 8952. (d) Hilt, G.; Janikowski, J.; Hess, W.
Angew. Chem. Int. Ed. 2006, 45, 5204.
IR (KBr): 3414, 2955, 1724, 1634, 1437, 1393, 1263, 1230, 1195,
1142, 1121, 1075, 1048, 1028, 931, 807, 773 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.17–7.05 (m, 2 H), 3.73–3.72 (m,
6 H), 2.57–2.25 (m, 4 H), 2.22–2.17 (m, 4 H), 2.15–2.07 (m, 1 H),
1.87–1.81 (m, 1 H), 1.34–1.25 (m, 3 H), 1.05–1.02 (m, 6 H), 0.98–
0.90 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 197.5, 166.7, 166.5, 143.8, 141.7,
130.3, 129.8, 107.3, 106.5, 81.4, 52.1, 52.0, 50.4, 42.0, 36.0, 35.7,
34.6, 33.5, 32.3, 28.8, 27.8, 25.0, 22.4.
MS (EI, 70 eV): m/z (%) = 402 (4, [M]+), 370 (31), 355 (19), 338
(5), 327 (5), 315 (24), 295 (9), 283 (10), 267 (5), 243 (4), 231 (5),
218 (12), 206 (100), 191 (37), 179 (24), 159 (17), 143 (7), 131 (35),
115 (21), 97 (8), 83 (37), 59 (27).
HRMS: m/z [M]+ calcd for C23H30O6: 402.2042; found: 402.2060.
Dimethyl (6E,8E)-4a,10a-Dimethyl-1-oxo-1,2,3,4a,5,
10,10a,11-octahydrocycloocta[e]cyclopenta[b]pyran-7,8-dicar-
boxylate (6e)
Eluent: Et2O–EtOAc (1:1); yield: 130 mg (0.36 mmol, 42%); white
solid; mp 94–96 °C; Rf = 0.24 (Et2O–EtOAc, 1:1).
IR (KBr): 3433, 2951, 1723, 1640, 1439, 1401, 1261, 1234, 1192,
1153, 1116, 1093, 1070, 1046, 1014, 958, 931, 901, 852, 821, 773
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.17–7.06 (m, 2 H), 3.73–3.71 (m,
6 H), 2.64–2.57 (m, 1 H), 2.53–2.47 (m, 2 H), 2.44–2.36 (m, 3 H),
2.23–2.02 (m, 3 H), 1.86–1.79 (m, 1 H), 1.41–1.08 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 203.3, 181.2, 166.5, 166.3, 143.3,
141.3, 130.5, 130.1, 112.2, 84.4, 52.2, 52.0, 35.9, 35.7, 34.7, 33.4,
33.2, 26.2, 24.9, 22.6.
MS (EI, 70 eV): m/z (%) = 360 (6, [M]+), 328 (46), 318 (6), 300
(12), 286 (7), 273 (33), 253 (8), 241 (18), 227 (5), 217 (33), 203
(22), 190 (42), 177 (36), 164 (100), 149 (28), 131 (51), 115 (36),
105 (22), 91 (47), 77 (33), 59 (33).
(6) Koser, S.; Hoffmann, H. M. R. Heterocycles 1994, 37, 661.
(7) The X-ray data have been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition
numbers CCDC 809255 (6a) and CCDC 809256 (6d). These
data can be obtained free of charge at www.ccdc.cam.ac.uk/
conts/retrieving.html [or from the Cambridge
HRMS: m/z [M]+ calcd for C20H24O6: 360.2573; found: 360.1569.
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 (1223)336033, E-mail:
deposit@ccdc.cam.ac.uk].
Synthesis 2011, No. 6, 972–978 © Thieme Stuttgart · New York