Efficient syntheses of angularly fused triquinanes via β-amino-substituted α,β-unsaturated fischer-carbene complexes

Article abstract of DOI:10.1055/s-2002-31910

Formal [3+2] cycloadditions of the carbene ligand in the new (3-dimethylamino-1-alkoxyalkenylidene)pentacarbonylchromium complexes 5 and 14 both with cyclopropyl substituents in the 3-position, onto alkynes give 5-dimethylamino-3-ethoxycyclopentadienes 6 and 15a-f, the latter along with regioisomers 16a-d, in good yields (55-72%). Treatment of these with hydrochloric acid liberates two carbonyl groups in each of them, and the resulting 5-dimethylaminocyclopent-1-en-3-ones 7 and 17a-c/18a-c, under basic conditions, undergo a cascade of two cyclizations, to yield angularly fused triquinanes 10 (68%) and 23a-c (30-97%). The overall procedure consists of four operational steps and produces cyclopropane-annelated tricyclo[6.3.0.0^1,5]undecane skeletons from two different alkynes each in 22-47% overall yield.

Full text of DOI:10.1055/s-2002-31910

LETTER
875
Efficient Syntheses of Angularly Fused Triquinanes via -Amino-Substituted
, -Unsaturated Fischer-Carbene Complexes
Efficient
S
e
yntheses
o
l
f
A
ngu
e
larly Fused
n
T
riquinanesa Milic,a Heiko Schirmer,a Bernard L. Flynn,b Mathias Noltemeyer,c Armin de Meijere*a
a
Institute für Organische Chemie der Georg-August-Universität Göttingen, Tammannstrasse 2–4, 37077 Göttingen, Germany
Fax +49(551)399475; E-mail: Armin.deMeijere@chemie.uni-goettingen.de
b
c
Department of Chemistry, Australian National University, Canberra ACT 0200, Australia
Institute für Anorganische Chemie der Georg-August-Universität Göttingen, Tamannstrasse 2–4, 37077 Göttingen, Germany
Received 7 March 2002
carene 17 (Scheme 1), was converted to the Fischer car-
bene complex 5 in 84% yield.10
Abstract: Formal [3+2] cycloadditions of the carbene ligand in the
new (3-dimethylamino-1-alkoxyalkenylidene)pentacarbonylchro-
mium complexes 5 and 14 both with cyclopropyl substituents in the
3-position, onto alkynes give 5-dimethylamino-3-ethoxycyclopen-
tadienes 6 and 15a–f, the latter along with regioisomers 16a–d, in
good yields (55–72%). Treatment of these with hydrochloric acid
liberates two carbonyl groups in each of them, and the resulting 5-
dimethylaminocyclopent-1-en-3-ones 7 and 17a–c/18a–c, under
basic conditions, undergo a cascade of two cyclizations, to yield an-
gularly fused triquinanes 10 (68%) and 23a–c (30–97%). The over-
all procedure consists of four operational steps and produces
cyclopropane-annelated tricyclo[6.3.0.01,5]undecane skeletons
from two different alkynes each in 22–47% overall yield.
Treatment of complex 5 with 2-butyne in pyridine at 80
°C gave the 5-(dimethylamino)-3-ethoxycyclopentadiene
6 as a 1:1 mixture of two diastereomers in 72% yield
Key words: carbenechromium complexes, cycloadditions, cyclo-
pentadienones, cascade reactions, spiro[4.4]nonenones, triquinanes
Within the last two decades, a number of new methods for
the assembly of five-membered carbocycles have been
developed.1–3 Among them, the formal [3+2] cycloaddi-
tion of a (1-alkoxy-3-dialkylaminopropenylidene)penta-
carbonylchromium complex to an alkyne appears to be
particularly versatile, as it readily provides di- and trisub-
stituted 3-alkoxy-5-dialkylaminocyclopentadienes, which
are protected cyclopentenones and essentially even syn-
thetic equivalents of cyclopentadienones.2–4 Due to a high
degree of functional group compatibility of the latter
method, oligofunctional cyclopentenones can easily be
accessed and further elaborated to yield bicyclic skele-
tons.5 In view of the considerable number of sesquiter-
penes with an angularly fused triquinane skeleton,6 we
developed a new short access to such skeletons based on
our [3+2] cycloaddition methodology.
A great variety of -dialkylamino-substituted , -unsat-
urated Fischer carbene complexes is readily available by
the newly developed four-step one-pot operation from ter-
minal alkynes, Cr(CO)6, Et3OBF4 and a secondary
amine.5 Thus, the functionally substituted enantiomerical-
ly pure 2-ethynyl-3,3-dimethylcyclopropane derivative 4,
prepared in three simple operations (for six steps) with an
overall yield of 52% from commercially available (+)-2-
Synlett 2002, No. 6, 04 06 2002. Article Identifier:
1437-2096,E;2002,0,06,0875,0878,ftx,en;G06802ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
Scheme 1

876
J. Milic et al.
LETTER
(Scheme 1). The enol ether and the acetal moiety in 6
were hydrolyzed with concentrated hydrochloric acid in
tetrahydrofuran to give the diketone 7 (88%). Subjecting
7 to basic conditions (KOH, EtOH) at elevated tempera-
ture (80 °C) set off a cascade of reactions with two con-
secutive cyclizations, leading to the angular triquinane 10
in 68% yield.
Mechanistically, this reaction sequence must be initiated
by base-promoted elimination of dimethylamine from
both diastereomers of 6 to yield a highly reactive cyclo-
pentadienone as a common intermediate which, after
deprotonation to the enolate 8, undergoes an intramolecu-
lar Michael addition to give the spiro[4.4]nonenone skel-
eton of 9 (Scheme 1). The newly formed enolate 9 then
cyclizes once more by an intramolecular Michael addition
to form the third five-membered ring. It is obvious that the
formation of the spiro[4.4]nonenone via the thermody-
namically more stable enolate 8 is kinetically favored over
formation of a spiro[6.4]undecenone via the regioiso-
meric enolate, and over the intermolecular [4+2] dimer-
ization.11 Both cyclization steps in this sequence
proceeded with complete diastereoselectivity so that a sin-
gle enantiomer with four new stereocenters resulted from
the enantiomerically pure alkyne 4. The absolute config-
uration of 10 was established on the basis of an X-ray
crystal structure analysis and the known configuration of
the starting (+)-2-carene 1 (see Figure).12
Scheme 2
Surprisingly, the cocyclizations of 14 with 2-butyne, 3-
hexyne, 1-pentyne, and 3-methyl-1-butyne did not only
yield the usual 1,2-dialkyl-3-ethoxy-5-dimethylaminocy-
clopentadienes 15a–d but also the isomeric products 16a–
d with the dimethylamino function at the same carbon
atom as one of the residues from the incoming alkyne
(Scheme 3). The cocyclization with cyclopropylacetylene
yielded two regioisomers of type 15 which differed only
in the position of the cyclopropyl group, and diphenyl-
acetylene gave only the single isomer 15f.
The isomers 15a,b and 16a,b obtained from 2-butyne and
3-hexyne could be separated by column chromatography
on silica gel. The enol ether and acetal moieties in com-
pounds 15 and 16 were cleaved with 1 M hydrochloric
acid in diethyl ether–ethanol (4:1). Under basic conditions
(KOH, EtOH) at elevated temperature (80 °C) the ob-
tained cyclopentenones 17a,b and 18a,b also underwent
cascade bicyclizations, in each case giving the same prod-
uct, 23a and 23b, respectively (Scheme 3). The mixture of
cyclopentenones 17c/18c obtained from the unseparated
mixture of regiomers 15c/16c could be transformed to the
angular triquinane 23c in 65% yield under the same basic
conditions. The structure of 23c was rigorously proved by
an X-ray crystal structure analysis (see Figure).12
Figure Structures of angularly fused triquinanes 10 and 23c in the
crystals.12
Although compound 10 is formally a sesquiterpene
with one additional methyl group, this tetracyclo-
[6.4.0.01,5.010,12]dodecane skeleton has not been found
in nature. In order to access just the tricyclo[6.3.0.01,5]un-
decane skeleton contained in many triquinane sesquiter-
penes, an alkyne starting material analogous to 4, but
without the bridging dimethylcyclopropane ring would
have to be used. While this alkyne could easily be pre-
pared in two steps from 1-trimethylsilylpropyne, it failed
to yield the , -unsaturated -dimethylamino-substituted
carbene complex of type 5.
The angular triquinanes 23a–c must arise from the cyclo-
pentenones 17a–c/18a–c in a mode which is different
from that for the formation of 10. The first two steps are
the same, in that elimination of dimethylamine produces a
cyclopentadienone 19 which cyclizes to a spiro[4.4]non-
enone 20 by an intramolecular Michael addition of the
enolate 19. In fact, in the case of 17b and 18b, the corre-
sponding spiro[4.4]nonenone 20b could be isolated along
with the final product 23b after a shorter reaction time
(30 min). The second cyclization, however, must occur
via the vinylogous enolates 21a–c, rather than an enolate
analogous to 9, and the cyclization step then corresponds
to a vinylogous intramolecular aldol condensation.
Spiro[4.4]nonenones 20d–f were obtained as final pro-
Therefore, the terminal alkyne 13, with a 1,1-disubstituted
cyclopropyl group mimicking a gem-dimethyl sub-
stitution13 in the propargylic position, was prepared in
three steps from 2-(trimethylsilyl)cyclopropylacetylene,14
and converted by the one-pot procedure6 to the corres-
ponding -dimethylamino-substituted complex 14 (84%)
(Scheme 2).
Synlett 2002, No. 6, 875–878 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Efficient Syntheses of Angularly Fused Triquinanes
877
In conclusion, an efficient new approach to oligosubstitut-
ed angular triquinane systems has been developed. This
procedure may be useful for efficient syntheses of some
naturally occurring sesquiterpenes6 with such a tricyc-
lo[6.3.0.01,5]undecane skeleton (e. g. pentalenene15) or
analogues thereof.
References and Notes
(1) Reviews see: (a) Paquette, L. A. Top. Curr. Chem. 1979, 79,
41. (b) Paquette, L. A. Top. Curr. Chem. 1984, 119, 1.
(c) Paquette, L. A.; Doherty, A. M. Polyquinane Chemistry;
Springer: Berlin, 1987.
(2) de Meijere, A. Pure Appl. Chem. 1996, 68, 61.
(3) de Meijere, A.; Schirmer, H.; Duetsch, M. Angew. Chem.
Int. Ed. 2000, 39, 3964; Angew. Chem. 2000, 112, 4124.
(4) Flynn, B. L.; Funke, F. J.; Silveira, C. C.; de Meijere, A.
Synlett 1995, 1007.
(5) Schirmer, H.; Funke, F. J.; Müller, S.; Noltemeyer, M.;
Flynn, B. L.; de Meijere, A. Eur. J. Org. Chem. 1999, 2025.
(6) Review: Metha, G.; Srikrishna, A. Chem. Rev. 1997, 97,
671.
(7) The alkyne 4 has been prepared from (+)-carene previously:
(a) Donkervoort, J. G.; Gordon, A. R.; Johnstone, C.; Kerr,
W. J.; Lange, U. Tetrahedron 1996, 52, 7391. (b) Better
yields of 4, however, were obtained by modifying the
reported procedure in two steps. Firstly, the cyclopropane-
carboxylic acid 2 was converted to the cyclopropyl methyl
ketone according to the protocol of House et al.,8 and
secondly the protocol of Negishi et al.9 was applied to
convert the methyl ketone to the terminal alkyne via the enol
phosphate.
Scheme 3 For details see table.
(8) Bare, T. M.; House, H. O. Org. Synth. 1969, 49, 81.
(9) Negishi, E.-I.; King, A. O.; Tour, J. M. Org. Synth. 1985, 64,
44.
ducts when cyclopentadienes 15d–f/16d–f arising from
cocyclization of 14 with 3-methyl-1-butyne, cyclo-
propylacetylene and diphenylacetylene, respectively,
were transformed by treatment with acid and then base.
(10) All new compounds were fully characterized by IR, NMR
(1H, 13C) mass spectra as well as correct elemental analyses.
Spectroscopic data of representative examples are as
follows:
Table Cocyclizations of Complex 14 with Various Alkynes and Further Transformations of the Resulting Products 15/16 (see Scheme 3).
Entry
R1
R2
Products
15 + 16
Yield (%)
Products
17, 18
Yield (%)
Basea
Time
[h]
Products
20
R1*b
Triquinane
23
Yield (%)c
Yield (%)c
a
b
c
d
e
f
Me
Et
Me
Et
H
38 + 27
37 + 18
62 (2:1)d
44 (1.2:1)d
60 (1.5:1)d,f
46g
96, 80
97, 46
90
NaOH
NaOH
NaOH
NaH
2.5
8
–
H
Me
Et
–
97, 80 (47)
–
82, 30 (24)
Pr
1.5
0.5
0.2
3
40e
65 (22)
iPr
cPr
Ph
H
82
90 (32)
96, 58
54 (20)
–
–
–
H
51 + 34
82
NaH
–
Ph
NaOH
–
a NaOH was used with an excess of 20 equivalents and NaH of 3 equivalents.
b R1* = R1 less one CH2 group.
c Overall yield of dispiroundecenone 20 or triquinane 23 from complex 14 given in parentheses.
d Yield of the mixture of 15 + 16 (ratio in parentheses).
e Isolated after 0.5 h along with 20% of triquinane 23.
f In this case the two regioisomers with the cyclopropyl group in the 1- and in the 2-position could be separated.
g Only 15f was formed.
Synlett 2002, No. 6, 875–878 ISSN 0936-5214 © Thieme Stuttgart · New York

878
J. Milic et al.
LETTER
Pentacarbonyl[(2E/Z)-3-dimethylamino-3-{(1 S,3 R)-cis-
2 ,2 -dimethyl-3 -[2 -(2 -methyl-[1 ,3 ]-dioxolan-2 -
yl)ethyl]cyclopropyl}-1-ethoxy-2-propen-1-yliden]-
chromium(5): Rf = 0.56 (Z-isomer), Rf = 0.39 (E-isomer),
Et2O (10:1)], yellow crystals, mp 75 °C. IR (KBr): 2980 cm–
1 (C-H), 2912 (C-H), 2769 (C-H), 2044 (C=O), 1969 (C=O),
1889 (C=O), 1527 (C=C), 1431, 1376, 1317, 1254, 1148,
1094, 1069, 1038, 982, 923, 869, 782, 671. 1H NMR (250
MHz, CDCl3): = 0.96 (s, 3 H, CH3), 1.01 (mc, 1 H, 3 -H),
1.24 (s, 3 H, CH3), 1.29 (s, 3 H, CH3), 1.35 (mc, 1 H, 1 -H),
1.44 (t, 3J = 7.0 Hz, 3 H, OCH2CH3), 1.44–1.73 (m, 4 H, 4 -
H, 5 -H), 3.13 [bs, 6 H, N(CH3)2], 3.92 (mc, 4 H,
C-4), 56.3 (Cquart, C-1), 60.9 (+, C-8), 217.9, 218.7 (Cquat, C-
3, C-7). MS (70 eV), m/z (%): 246(24) [M+], 218(31) [M+ –
CO], 203(11), 190(8), 175(17), 161(8), 148(56), 133(9),
121(100), 105(55).
4,7-Dimethylspiro{cyclopropane-1,11-tricyclo-
[6.4.0.01,5]undeca-4,6-dien-3-one}(23a): Rf = 0.75 in Et2O,
colorless oil. IR(film): 3066 cm–1 (C-H), 2948 (C-H), 2915
(C-H), 2854 (C-H), 1695 (C=O), 1641 (C=O), 1587, 1436,
1336, 1246, 1014, 971, 843, 728, 668, 592. 1H NMR (500
MHz, CDCl3): = –0.65 to –0.25 (m, 1 H, cPr-H), 0.08–0.13
(m, 1 H, cPr-H) 0.16–0.20 (m, 1 H, cPr-H) 0.33–0.38 (m, 1
H, cPr-H), 1.20–1.30 (m, 1 H, 10-H), 1.65 (s, 3 H, CH3)
1.63–1.73 (m, 1 H, 10-H), 1.92 (s, 3 H, CH3), 1.96–2.08 (m,
2 H, 9-H), 2.32 (AB, d, 2J = 16 Hz, 1 H, 2-H), 2.48 (AB, d,
2J = 16 Hz, 1 H, 2-H), 3.00–3.07 (m, 1 H, 8-H), 6.10 (s, 1 H,
6-H). 13C NMR (62.9 MHz, CDCl3, plus, DEPT): 4.9 (–, cPr-
C), 8.7 (+, CH3), 14.1 (–, cPr-C), 16.5 (+, CH3), 26.5 (–, C-
10), 31.8 (Cquat, C-11), 36.9 (& ndash;, C-9), 48.7 (–, C-2),
OCH2CH2O), 4.65 (q, 3J = 7.0 Hz, 2 H, OCH2CH3), 6.25 (s,
1 H, 2H). 13C NMR (62.9 MHz, CDCl3, plus DEPT):
=
15.2 (+, C-3 ), 15.5 (+, OCH2CH3), 20.8 (–, C-1 ), 23.2
(Cquat., C-2 ), 23.6 (+, CH3), 28.5 (+, CH3), 30.1 (+, C-1 ),
32.3 (+, CH3), 38.8 (–, C-2 ), 41.5 [+, N(CH3)2], 64.4 (–,
OCH2CH2O), 72.9 (–, OCH2CH3), 109.4 (Cquat, C-2 ),
119.8 (+, C-2), 159.7 (Cquat, C-3), 219.3, 224.4 (Cquat, C=O),
279.9 (Cquat, C-1). – MS (70 eV), m/z (%): 501(3) [M+],
473(13) [M+ – CO], 445(5) [M+ – 2CO], 417(6) [M+ – 3 CO],
389(2) [M+ – 4 CO], 361(100) [M+ – 5 CO], 220(21),
204(29), 191(64), 95(25), 87(28), 52(47) [Cr+], 43(34).
4,5,11,11-Tetramethyltetracyclo[6.4.0.01,5.010,12]-dodec-
an-3,7-dione(10): Rf = 0.25 in Pentane–Et2O (3:1, colorless
crystals, mp 101 °C. IR (KBr): 3010 cm–1 (C-H), 2957 (C-
H), 2938 (C-H), 2877 (C-H), 1732 (C=O), 1456, 1390, 1376,
1339, 1266, 1206, 1191, 1124, 1100, 1083, 1008, 931, 895,
841, 647, 542, 465. 1H NMR (500 MHz, CDCl3): = 0.99 (s,
3 H, CH3), 1.01 (s, 3 H, CH3), 1.02 (d, 3J = 7.0 Hz, 3 H, CH3),
1.17 (s, 3 H, CH3), 1.23 (dd, 3J = 6.4, 3J = 6.4 Hz, 1 H, 10-
H), 1.29 (d, 3J = 6.4 Hz, 1 H, 12-H), 1.88 (ddd, 2J = 13.8, 3J
= 8.0, 3J = 6.4 Hz, 1 H, 9-H), 2.01 (AB, d, 2J = 18.1 Hz, 1 H,
6-H), 2.08 (AB, d, 2J = 18.1 Hz, 1 H, 6-H), 2.16 (dd, 2J =
13.8, 3J = 10.7 Hz, 1 H, 9-H), 2.38 (dq, 3J = 7.0, 4J = 1.7 Hz,
1 H, 4-H), 2.40 (AB, d, 2J = 19.9 Hz, 1 H, 2-H), 2.42 (dd, 3J
= 10.7, 3J = 8.0 Hz, 1 H, 8-H), 2.78 (dd, 2J = 19.9, 4J = 1.7
Hz, 1 H, 2-H). 13C NMR (62.9 MHz, CDCl3, plus DEPT):
= 9.2 (+, CH3), 16.3 (+, CH3), 19.3 (Cquat, C-11), 21.5 (+,
CH3), 27.9 (+, CH3), 29.6 (–, C-9), 30.8 (+, C-10), 37.6 (+,
C-12), 48.0 (–, C-2), 49.0 (–, C-6), 50.0 (Cquat, C-5), 53.2 (+,
58.1 (+, C-8), 60.0 (Cquat, C-1), 120.9 (+, C-6), 124.8 (Cquat
,
C-5), 162.8 (Cquat, C-7), 179.5 (Cquat, C-4), 209.6 (Cquat, C-3).
MS (70 eV), m/z (%): 214(100) [M+], 199(19) [M+ – CH3],
185(16) [M+ – C2H5O], 171(35) [M+ – C3H7O], 159(38),
143(21), 132(18), 115(17), 91(16), 77(10), 65(4), 53(4),
41(4).
(11) Milic, J.; Schirmer, H.; de Meijere, A. unpublished results.
(12) Crystallographic data for the angular triquinanes 10 and 23c
have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publications no. CCDC-
180879(10) and CCDC-180718(23c). Copies of the data can
be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax:
+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).
(13) A 1,1-disubstituted cyclopropane moiety can actually also
serve as a masked gem-dimethyl group, which can be
unmasked by catalytic hydrogenation. Cf.: Piers, E.;
Karunaratne, V. Tetrahedron 1989, 45, 1089.
(14) Militzer, H.-C.; Schömenauer, S.; Otte, C.; Puls, C.; Hain, J.;
Bräse, S.; de Meijere, A. Synthesis 1993, 998.
(15) Schizuri, Y.; Shojiro, M.; Ohkubo, M.; Yamamura, S.
Tetrahedron Lett. 1990, 7167.
Synlett 2002, No. 6, 875–878 ISSN 0936-5214 © Thieme Stuttgart · New York