A cyclobutadiene equivalent in the catalytic Pauson-Khand reaction

Article abstract of DOI:10.1002/anie.200460654

A practical and scalable operation: The reaction shown in the scheme, which uses catalytic amounts of hexacarbonyldicobalt, gives access to versatile bicyclic systems, which until now could only be obtained in low quantities by a photochemical process starting from tropolones. An isolation of the primary Pauson-Khand products is not necessary.

Full text of DOI:10.1002/anie.200460654

Communications
[
4a]
Cyclopentenone Synthesis
although there are reports of the use of cyclopropenes and
[
4b–d]
bicyclo[3.2.0]hept-6-enes.
And, recently the donor-sub-
stituted alkenes o-(dimethylamino)phenyl vinyl sulfoxide
and dimethyl(2-pyridyl)(vinyl)silane have been used suc-
cessfully in cobalt-mediated and ruthenium-catalyzed PKRs,
respectively. Very recently, 2,3-disubstituted 1,3-butadienes
have been shown to act as alkene partners in a rhodium-
[
5a]
A Cyclobutadiene Equivalent in the Catalytic
Pauson–Khand Reaction**
[
5b]
Susan E. Gibson,* Nello Mainolfi, S. Barret Kalindjian,
and Paul T. Wright
[
5c]
catalyzed intermolecular PKR.
[
6]
[7]
Our interest in catalytic and asymmetric aspects of the
PKR led us to look for new alkene partners that would
significantly increase the synthetic scope of the reaction.
Cyclobutadiene is a very attractive “alkene” in this context
insomuch as its participation in the reaction would create
highly functionalized bicyclic products that could be manip-
ulated further to produce a wide range of substituted cyclo-
pentanes. The inherent instability of cyclobutadiene, how-
ever, meant that a convenient surrogate was required.
The Pauson–Khand reaction (PKR) is a transition-metal-
mediated carbon–carbon bond-forming reaction that converts
an alkyne, an alkene, and carbon monoxide into a cyclo-
[
1]
pentenone (Scheme 1). The ubiquity of five-membered
2
,5
Dimethyl
anti-tricyclo[4.2.2.0 ]deca-3,7,9-triene-7,8-
Scheme 1. The Pauson–Khand reaction.
dicarboxylate (3) was identified as a potential cyclobutadiene
equivalent in the PKR. It was readily synthesized from
cyclooctatetraene (COT) and dimethyl acetylenedicarboxy-
[
8]
carbocycles in complex organic molecules such as the recently
isolated antimalarial, anticancer diterpene bielschowskysin
late in 10 h by a modified literature procedure (Scheme 2).
[
2]
(
1) means that cyclopentenones are useful as building blocks
Scheme 2. Synthesis of cyclobutadiene equivalent 3. 1.1 Equivalents of
COT were used.
Initially, one equivalent of tricycle 3 was reacted with one
equivalent of phenylacetylene (Table 1). Reaction occurred
selectively at the most strained double bond and work-up led
to the isolation of a single diastereomer of the novel Pauson–
Khand product 4 in 60% yield (all products in Table 1 were
fully characterized by standard analytical techniques). Use of
1.5 equivalents of 3 raised the yield to 77% (Table 1). The
reaction was then performed with a range of monosubstituted
alkynes, and these reactions led to the isolation of the
Pauson–Khand products 5–8 in moderate to good yields
(Table 1). (The disubstituted alkynes 3-hexyne and dipheny-
lacetylene failed to give the expected products, although 1-
phenylpropyne gave a single Pauson–Khand product in 33%
yield when reacted with 1.5 equivalents of 3.)
for the creation of larger organic molecules. Moreover, many
cyclopentenones display their own interesting biological
activity. For example, cyclopentenone prostaglandins such as
7
[3]
D -PG-A (2) have considerable therapeutic potential.
1
To maximize the synthetic attractiveness of the PKR the
development of efficient and versatile catalytic systems is
required, some of which are asymmetric, and all of which
work well for intermolecular reactions. Whilst good progress
has been made in the last three to five years in the fields of
catalysis and asymmetric catalysis using a variety of transition
metals and ligands, almost all of the work reported has been
[
1]
based on intramolecular substrates, that is, enynes.
Traditionally, the intermolecular PKR has been domi-
nated by the strained alkenes norbornene and norbornadiene,
The Pauson–Khand products 4–8 were subsequently
heated to induce a retro-Diels–Alder reaction. After 1 h of
heating at 2058C under a vacuum of 6 Torr, the 3-substituted
bicyclo[3.2.0]hepta-3,6-diene-2-ones 9–13 were isolated in
very good yields (Table 1).
[
*]Prof. S. E. Gibson, N. Mainolfi
Department of Chemistry, Imperial College London
South Kensington Campus, London SW72AY (UK)
Fax: (+44)207-594-5804
The bicyclic compounds 9–13 can be regarded as the
products of a formal PKR involving monosubstituted alkynes
and cyclobutadiene. We have thus introduced a new route to
bicyclo[3.2.0]hepta-3,6-diene-2-ones, a class of molecules
which to date have been synthesized by irradiation of
E-mail: s.gibson@imperial.ac.uk
Dr. S. B. Kalindjian, Dr. P. T. Wright
James Black Foundation
[
9]
68 Half Moon Lane, London SE249JE (UK)
substituted tropolones;
interestingly, investigations of
these bicyclic compounds appear to be limited to explorations
of their photochemical and thermal behavior. In view of this,
[
**]The authors thank the James Black Foundation for generous
[
9]
studentship support (N.M.).
5
680
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200460654
Angew. Chem. Int. Ed. 2004, 43, 5680 –5682

Angewandte
Chemie
[
a]
Table 1: Catalytic intermolecular PKR of diester 3 with various alkynes and thermolysis of the Pauson–
Khand products.
To conclude, we have used a
[
b]
cyclobutadiene equivalent in the
Pauson–Khand reaction for the
first time, to produce a little-stud-
ied class of compounds that has
considerable potential in synthesis.
[
c]
Alkyne Equiv of 3
PK product
Yield [%]Retro-Diels–Alder
product
Yield [%]
1
1
.0
.5
60
77
9
9
9
9
2
0
0
0
1
1
.0
.5
73
85
Experimental Section
: A mixture of dimethyl acetylenedi-
carboxylate (5.29 mL, 43.0 mmol) and
COT (5.32 mL, 47.3 mmol) in a 25-mL
3
1
1
.0
.5
45
60
round-bottomed flask fitted with
a
reflux condenser was heated at 1558C
under an atmosphere of nitrogen for
0 h. Purification of the crude product
by careful (the byproduct dimethyl
phthalate has a very similar polarity)
flash column chromatography (SiO2;
hexane/acetone, 100:0 to 99:1) afforded
1
1
1
.0
.5
67
75
1
5
1
.0
.0
0.0
33
46
86
3
as a colorless oil (6.35 g, 60%). R =
f
85
0
.32 (SiO2; hexane/acetone, 90:10);
1
H NMR (300 MHz, CDCl ): d = 2.71–
3
2
.74 (m, 2H; cyclobutene bridgehead),
3.81–3.91 (m, 8H; 2 OCH3 and cyclo-
hexadiene bridgehead), 6.08–6.18 ppm
[
a]5 mol% [Co (CO) ], CO (1 atm), DME, 75 8C, 4 h (all reactions were performed with 0.5 mmol of
2 8
alkyne). [b]205 8C, 6 Torr, 1 h (reactions performed on a 0.3–0.4 mmol scale). [c]Unreacted 3 could be
fully recovered.
1
3
(m, 4H; vinylic); C NMR (125 MHz,
CDCl ): d = 43.2 and 44.2 (cyclobutene
3
and cyclohexadiene bridgeheads), 52.1
(
OCH ), 129.7 (CH=CH, cyclobutene),
3
and of the potential of bicyclo[3.2.0]hepta-3,6-diene-2-ones
not only in organic synthesis, but also as an alternative to
norbornene-based monomers in the ring-opening metathesis
1
(
38.9 (CH=CH, cyclohexadiene), 143.1 (C=C), 166.7 (C=O); IR
À1
neat): n˜ max = 1560 (C C), 1603 (C C), 1640 (C C), 1727 cm (2 C
=
=
=
=
+
+
O); MS(CI): m/z (%): 264 (8) [M+NH ], 247 (100) [M+H ], 195
4
[
10]
+
polymerisation,
it seemed worthwhile to streamline our
(24) [MÀ(CH)
246.26): C 68.28, H 5.73; found: 68.36, H 5.81.
0: A 250-mL flask fitted with a reflux condenser and a magnetic
stirring bar was charged with 1-octyne (1.47 mL, 10 mmol) and 3
3.69 g, 15 mmol). The reaction vessel was evacuated (three times)
4
+H ]; elemental analysis calcd (%) for C14H O
1
4
4
(
synthetic approach by removing the isolation of the Pauson–
Khand product from the protocol. Indeed, thermolysis of the
crude product mixture from the PKR [Eq. (1)] followed by
1
(
and filled with CO. Anhydrous, CO-saturated DME (100 mL) and
freshly sublimed octacarbonyldicobalt(0) (0.239 g, 0.7 mmol) were
added to the reaction mixture. The flask was lowered into an oil bath
preheated to 758C and left stirring at that temperature under a CO
atmosphere (1.05 atm) for 4 h. The reaction was then stopped, the
solvent evaporated under vacuum, and the flask fitted with a
distillation apparatus. The pressure in the system was reduced to
6
2
Torr and the flask was lowered into a silicone oil bath preheated to
058C. The flask was kept in the bath for 1.5 h, at which point most of
chromatography gave the bicyclic ketones in good to excel-
lent yields on a 0.5-mmol scale (Table 2, entries 1–3). More-
over, scale-up of the reaction with 1-octyne (use of 10 instead
of 0.5 mmol) readily produced 1.71 g of bicyclo[3.2.0]hepta-
the reaction mixture had distilled over into the collecting flask. The
distillate and the remaining reaction mixture were combined.
Purification of the crude product by flash column chromatography
(SiO ; hexane/ethyl acetate, 100:0 to 90:10) afforded 10 as a colorless
2
3
,6-diene-2-one 10 (entry 4).
oil (1.71 g, 90%). R = 0.52 (SiO ; hexane/ethyl acetate, 80:20);
f
2
1
H NMR (500 MHz, CDCl ): d = 0.84–0.88 (m, 3H; CH ), 1.27–1.32
3
3
(
m, 6H; CH (CH ) ), 1.40–1.46 (m, 2H; CH (CH ) CH CH ), 2.05–
3 2 3 3 2 3 2 2
Table 2: Direct conversion of alkynes into bicyclo[3.2.0]hepta-3,6-diene-
2
.15 (m, 2H; CH (CH ) CH CH ), 3.50 (dd, J = 1.3, 2.3 Hz, 1H; C=
[
a]
3 2 3 2 2
2
-ones [Eq. (1)].
OCHCH), 3.80 (m, 1H; C=OCHCH), 6.35 (dd, J = 1.3, 2.3 Hz, 1H;
C=OCHCH=CH), 6.55 (d, J = 2.3 Hz, 1H; C=OCHCH=CH), 7.24–
[
b]
Entry
R
Scale [mmol]Product
Yield [%]
1
3
7
(
(
.25 ppm (m, 1H; CH C=CH); C NMR (125 MHz, CDCl ): d = 14.0
2
3
1
2
3
4
Ph
Hex
CH OTBDMS
Hex
0.5
0.5
0.5
9
75
98
70
90
CH ),
22.5
(CH CH ),
25.3,
27.5,
28.9,
31.5
3
3
2
10
11
10
CH CH CH CH CH CH C), 47.9 (C=OCHCH), 53.8 (C=
3
2
2
2
2
2
2
OCHCH), 136.7 (C=OCHCH=CH), 143.6 (C=OCHCH=CH), 146.8
CH C=CH), 154.9 (CH C=CH), 206.2 ppm (C=O); IR (neat): n˜
1564 (CH=CH), 1620 (CH=C), 1698 cm (C=O); MS(CI): m/z (%):
+ + +
208 (100) [M+NH4 ], 191 (46) [M+H ], 52 (18) [(CH) ]; elemental
4
10.0
=
max
2
2
À1
[
[
a]See Experimental Section for a detailed description for entry 4.
b]Unreacted 3 could be fully recovered.
Angew. Chem. Int. Ed. 2004, 43, 5680 –5682
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5681

Communications
analysis calcd (%) for C H O (190.28): C 82.06, H 9.53; found: C
1
3
18
8
2.15, H 9.54.
Received: May 14, 2004
Revised: July 8, 2004
Keywords: bicycloheptadienes · carbonylation · cycloaddition ·
.
homogeneous catalysis · pericyclic reactions
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5
682
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 5680 –5682