Rapid synthesis of cyclobutene diesters using a microwave-accelerated ruthenium-catalysed [2+2] cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2010.08.119

A range of cyclobutene diesters was synthesised using a ruthenium-catalysed, microwave-assisted, [2+2] cycloaddition. Excellent yields of the desired products were realised using reaction times of only 2 min.

Full text of DOI:10.1016/j.tetlet.2010.08.119

Tetrahedron Letters 51 (2010) 5889–5891
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rapid synthesis of cyclobutene diesters using a microwave-accelerated
ruthenium-catalysed [2+2] cycloaddition
⇑
Mark D. Johnstone, Adam J. Lowe, Luke C. Henderson, Frederick M. Pfeffer
Deakin University, School of Life and Environmental Sciences, Pigdons Road, Geelong, Victoria 3217, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A range of cyclobutene diesters was synthesised using a ruthenium-catalysed, microwave-assisted, [2+2]
cycloaddition. Excellent yields of the desired products were realised using reaction times of only 2 min.
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Received 10 July 2010
Revised 8 August 2010
Accepted 31 August 2010
Available online 7 September 2010
The photochemical [2+2] cycloaddition of two alkenes to form
cyclobutanes is well known,1 however, the corresponding reaction
of alkynes with alkenes to form cyclobutenes is less common.2
Nevertheless, a number of approaches for the construction of
cyclobutenes have been developed including thermal processes3
(requiring a reactive alkene), Lewis acid-activated methods,4 Wit-
tig reactions5 and metal-catalysed transformations.6,7 In the con-
text of transition metal-catalysed reactions, Mitsudo et al.
identified ruthenium complexes such as [RuH2(PPh3)4], [RuH2
(CO)(PPh3)3], [Ru(cod)(cot)] and [RuCp*Cl(cod)] as efficient cata-
lysts for the [2+2] cycloaddition of norbornenes with acetylenes.8
The scope of these reactions has been further investigated by Tam.9
The [RuH2(CO)(PPh3)3]-catalysed [2+2] reaction of functional-
ised norbornenes with acetylenes (in particular dimethyl acety-
lenedicarboxylate, DMAD (1), Scheme 1) has been widely used in
the synthesis of fused [n]polynorbornanes10 (e.g., 5, Scheme 1), in
which a two-step process involving cyclobutene diester formation
then epoxidation is employed to generate cyclobutane epoxides
(e.g., 4, Scheme 1) to use in ACE (alkene + cyclobutane epoxide)
1,3-dipolar cycloaddition.11 The resulting functionalised [n]poly-
norbornanes have been used in the study of electron transfer pro-
cesses,12 as DNA intercalators,13 and as supramolecular hosts for
anions.14,15
Due to our interest in conformationally preorganised frame-
works, norbornanes and [n]polynorbornanes have been exten-
sively used.16 As such, the [RuH2(CO)(PPh3)3]-catalysed reaction
is routinely employed, and in our hands, when carried out using
conventional heating, reaction times from 6 to 72 h are required
to obtain good yields (50–83%) of the desired functionalised cyc-
lobutene diesters.13–15
Microwave irradiation has been used as a means of accelerating
many reactions17 including cycloadditions18 and those involving
metal catalysts.19 Whilst examples of microwave-accelerated reac-
tions involving Ru catalysts to form [2+2] adducts exist, they are
rare and typically involve intramolecular reaction of highly reac-
tive alkenes such as allenes.20 Indeed, the microwave-mediated
Ru-catalysed intermolecular [2+2] reaction of norbornenes with
acetylenes has hitherto not been explored. Herein we report that
microwave irradiation markedly accelerates the reaction and the
desired cyclobutenes are produced in high isolated yields.
The reaction chosen for initial investigation was taken directly
from previous work where preorganised frameworks were syn-
thesised as hosts for anions.14 The research required the [RuH2
(CO)(PPh3)3]-catalysed reaction of endo norborneneimide 6 with
DMAD (Scheme 2).14
To provide a benchmark for comparison the reaction was car-
ried out under conventional thermal conditions (60 °C) using THF
as solvent and a catalyst loading of 10 mol % (Table 1, entry 1).
Using these conditions the desired cycloadduct 7 was produced
in moderate isolated yield (53%) after an extended reaction time
of 72 h. This reaction was repeated in DMF for 16 h at 100 °C and
excellent conversion (89%) and a high isolated yield (87%) of the
desired product were realised (Table 1, entry 2). As such, the
reaction was repeated for one hour in DMF (Table 1, entry 3) and
again a high conversion rate and isolated yield were noted (88%
and 84%, respectively).
In light of these improved results with a simple solvent change,
our attention turned to further accelerating this reaction in a
microwave reactor. Initially, 20 min reaction times were employed
and a range of common solvents investigated for their effect on
CO2Me
+
MeO2C
MeO2C
Ru
Epoxidation
MeO2C
MeO2C
DMAD
1
2
3
4
O
MeO2C
CO2Me
MeO2C
O
ACE
+
MeO2C
O
140oC
2
4
5
MeO2C
⇑
Corresponding author. Tel.: +61 3 5227 1439; fax: +61 3 5227 1040.
E-mail address: fred.pfeffer@deakin.edu.au (F.M. Pfeffer).
Scheme 1. Sequence of Ru-catalysed [2+2] cycloaddition, epoxidation and ACE
cycloaddition to form a fused [n]polynorbornane.
0040-4039/$ - see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.119

5890
M. D. Johnstone et al. / Tetrahedron Letters 51 (2010) 5889–5891
MeO2C
MeO2C
DMAD
CO2Me
MeO2C
MeO2C
CO2Me
DMAD
Ru
RuH2(CO)(PPh3)3
O
O
CO2Me
CO2Me
DMAD
8
9
10
MW
6
7
N
N
NHBoc
NHBoc
O
O
2 eq. DMAD
RuH2(CO)(PPh3)3
Conventional heating < 10%
Scheme 2. [2+2] cycloaddition optimisation.
Δ
Toluene
14hr, 100 °C
MeO2C
MeO2C
CO2Me
CO2Me
Table 1
11
10
Optimisation of temperature, time and solvent21
2 eq. DMAD
RuH2(CO)(PPh3)3
Solventa
Microwave method 76%
Entry
Time (min)
Temp (°C)
Conversionb (yield)
MW, DMF
1c
2c
3c
4
72 h
16 h
60
60
100
100
90
THF
DMF
DMF
THF
60% (53%)
89% (87%)
88% (84%)
25%
2 min, 100°C
Scheme 3. Synthesis of dicyclobutene tetraester 10.
20
5
6
7
8
20
20
20
20
40
20
20
20
90
90
Toluene
1,4-Dioxane
Acetone
EtOH
THF
DMF
25%
22%
86%
54%
78%
87% (84%)
8%
O
DMAD
MeO2C
MeO2C
O
RuH2(CO)(PPh3)3
N
100
100
140
160
150
150
N
H
H
NHBoc
NHBoc
MW, DMF
NHBoc
NHBoc
N
H
12
2 min, 100 °C
N
H
O
9
O
13
61%
10
11
12
MeCN
1,4-Dioxane
CO2Me
CO2Me
O
O
DMAD
RuH2(CO)(PPh3)3
MeO2C
MeO2C
32%
O
O
a
b
c
Solvent and DMAD used in a 5:1 ratio (v/v).
Isolated yield following column chromatography.
Carried out using conventional thermal conditions.
MW, DMF
MeO2C
15 85%
MeO2C
14
2 min, 100 °C
N
N
O
O
BocHN
BocHN
Scheme 4. Synthesis of additional cyclobutene diesters.
Table 2
Optimisation of catalyst loading and reaction time
reaction time was doubled to compensate for catalyst dilution,
poor conversion was noted (26%, Table 2, entry 2). In light of these
results a catalyst loading of 10 mol % was used in all further exper-
iments. When the reaction time was halved from 20 min to 10 min
(Table 2, entry 3), a conversion (81%) and yield (70%) similar to the
reaction carried out for 20 min were obtained (Table 1, entry 10).
Reducing the reaction duration even further to 5, 2 and 1 min(s)
gave the desired cyclobutene 7 in good yields of 75%, 73% and
77%, respectively (Table 2, entries 4–6). Indeed, the reaction was
so rapid that simply heating the reaction to 160 °C, followed by
immediate cooling,22 resulted in an 87% conversion and 79% iso-
lated yield of cyclobutene 7 (Table 2, entry 7).
Given that the reaction reached completion so quickly at 160 °C
the reaction temperature was lowered to see the effect on conver-
sion and yield. The use of lower temperatures minimises the po-
tential for thermal degradation during the reaction. As such, the
reaction was repeated at 100 °C and again excellent conversion
(94%) and yield (93%) were obtained (Table 2, entry 8). Neverthe-
less, only 45% conversion was realised when the reaction temper-
ature was further reduced to 70 °C (Table 2, entry 9).
As DMF can be troublesome to remove, the reaction was re-
peated in acetone (Table 2, entry 10) using the milder conditions
as this solvent gave encouraging results in the initial investigations
(Table 1, entry 7). Unfortunately, very poor conversion was noted
(18%) when the reaction duration was reduced to 2 min, thus rein-
forcing the key role of DMF as solvent for this reaction.
Given the positive results from the optimisation study, the
DMAD cycloaddition conditions (DMF, 2 min, 100 °C) were applied
to other norbornene substrates.
Entry
Catalyst loading
(mol %)
Timea
(min)
Temp
(°C)
Conversionb
(yield)
1
2
3
4
5
6
7
8
5
5
20
40
10
5
160
160
160
160
160
160
160
100
70
24%
26%
10
10
10
10
10
10
10
10
81% (70%)
84% (75%)
86% (73%)
87% (77%)
87% (79%)
94% (93%)
45%
2
1
0a
2
9
2
2
10c
100
18%
a
This value refers to the duration of time that the reaction was held at the
specified temperature; this does not include the time taken to heat the vessel (cf.
2 min).
b
Isolated yield following column chromatography.
Reaction carried out in acetone.
c
reaction outcome. Poor to moderate conversion into the desired
product was observed when THF, toluene or 1,4-dioxane (Table 1,
entries 4, 5 and 6) were used as the reaction solvent. Finally, ace-
tone and ethanol (Table 1, entries 7 and 8) were trialled with good
and moderate conversion was noted (86% and 54%, respectively).
Higher reaction temperatures (140–160 °C) were next investi-
gated and excellent conversion was observed when THF (Table 1,
entry 9) was used as the solvent, however, an extended reaction
time (40 min) in the microwave reactor was required in addition
to the elevated reaction temperature. Dimethylformamide proved
to be a superior solvent for a 20 min reaction duration giving excel-
lent conversion (87%) and 84% isolated yield (Table 1, entry 10).
The use of 1,4-dioxane or acetonitrile (Table 1, entries 11 and 12)
gave poor conversions to the desired product. Therefore, it was
apparent that DMF was the optimum solvent for this reaction.
Next, additional optimisation studies were undertaken using
microwave irradiation. Variables of interest included: catalyst
loading, reaction time and reaction temperature (Table 2).
Dicyclobutene tetraester 10 (Scheme 3) is a necessary building
block for the synthesis of larger [n]polynorbornanes. Current meth-
odology for the synthesis of 10 involves a two-step approach; first
quadricyclane 8 and DMAD are reacted to form the 1:1 cycloadduct
9 then single Ru-catalysed [2+2] reaction of diester 9 with a second
equivalent of DMAD provides the desired 1:2 adduct 10.23 Whilst
theoretically appealing, the twin cycloaddition from norbornadi-
ene 11 has never provided useful yields of the desired bisadduct
10, and as such, the two-step approach has been required.24 How-
ever, using the microwave method developed herein norbornadi-
Repeating the reaction with half the catalyst loading (5 mol %)
under the optimised conditions gave only poor conversion to the
cyclobutene diester 7 (24%, Table 2, entry 1). Even when the

M. D. Johnstone et al. / Tetrahedron Letters 51 (2010) 5889–5891
5891
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ene 11 was smoothly converted into the desired dicyclobutene 10
in 76% yield. The success of the single step process is a significant
improvement over the existing methodology.
In additional reactions norbornadiene bis-carbamate 1215b
(Scheme 4) was subjected to the optimised reaction conditions to
give cyclobutene 1315b in a good isolated yield of 61%. Finally,
the new methodology was applied to a pre-existing [3]polynor-
bornene scaffold15b (14, Scheme 4), and again the optimised proto-
col gave the desired cyclobutene product 1515b in an excellent
isolated yield (85%).
In conclusion the [RuH2(CO)(PPh3)3]-catalysed [2+2] cycloaddi-
tion of norbornenes with DMAD25 can be accelerated significantly
when microwave irradiation is employed with DMF as the solvent.
High yields can be obtained using only 2 min reaction times. The
methodology was successfully applied to a range of norbornene
scaffolds indicating that the procedure is tolerant to functional
group diversity.
Acknowledgements
The authors would like to thank Deakin University for an Alfred
Deakin Fellowship for L.H. and the Deakin Central Research Grant
Scheme for the financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.08.119.
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21. Representative experimental procedure (see Supplementary data for detailed
experimental information including 1H NMR spectra): a solution of norbornene
(100 mg, 0.33 mmol), dimethyl acetylenedicarboxylate (DMAD) (0.1 mL,
0.82 mmol, 2.5 equiv), RuH2(CO)(PPh3)3 (30 mg, 10 mol %) and 0.5 mL of
solvent were added to a 10 mL microwave vial. The vial was sealed and
subjected to the conditions stated in Table 1 or 2. After cooling, the solvent was
removed under reduced pressure and the conversion rate was determined by
analysing a sample of the crude reaction mixture by 1H NMR spectroscopy. The
crude product was purified by column chromatography (1:1 EtOAc/petroleum
spirits) to afford the pure product in the yield stated.
22. See Supplementary data for temperature, pressure, and power profiles for this
reaction.
23. For the reaction of quadricyclane with DMAD, see: Smith, C. D. J. Am. Chem. Soc.
1966, 88, 4273–4274. . Yields of the second addition of DMAD to form 10 are
typically modest: see Ref. 8d.
24. Mitsudo, in Ref. 8d, reported <10% yield of 10 using the twin addition approach
from norbornadiene.
25. The reaction was trialled using diphenylacetylene as the alkyne partner,
however, only a trace of the desired product was detected in the crude reaction
mixture.