Microwave-accelerated ruthenium-catalyzed [2π+2π] cycloadditions of dimethylacetylene dicarboxylate with norbornenes

Article abstract of DOI:10.1080/00397911.2010.481744

An efficient and convenient procedure has been developed for the ruthenium-catalyzed [2π+2π] cycloadditions of dimethylacetylene dicarboxylate with norbornenes. Reaction is significantly accelerated in microwave conditions, while the commonly used benzene

Full text of DOI:10.1080/00397911.2010.481744

Synthetic Communications1, 41: 1239–1246, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.481744
MICROWAVE-ACCELERATED RUTHENIUM-
CATALYZED [2p þ 2p] CYCLOADDITIONS OF
DIMETHYLACETYLENE DICARBOXYLATE
WITH NORBORNENES
1
Davor Margetic, Pavle Troselj, and Yasujiro Murata
1
2
´
ꢀ
1Laboratory for Physical–Organic Chemistry, Division of Organic Chemistry
´
and Biochemistry, Ruder Boꢀskovic Institute, Zagreb, Croatia
2Institute for Chemical Research, Kyoto University, Uji, Kyoto, Japan
GRAPHICAL ABSTRACT
Abstract An efficient and convenient procedure has been developed for the ruthenium-
catalyzed [2p þ 2p] cycloadditions of dimethylacetylene dicarboxylate with norbornenes.
Reaction is significantly accelerated in microwave conditions, while the commonly used ben-
zene solvent was replaced by environmentally benign tetrahydrofuran.
Keywords Acetylenes; [2 þ 2] cycloadditions; microwave reaction; norbornene derivatives
INTRODUCTION
Much effort by organic chemists has been devoted to the preparation of com-
plex polycyclic rigid compounds that possess functionalities at the desired distance
and spatial orientation. In this respect, synthesis of a polynorbornane skeleton func-
tionalized at both ends[1,2] has been achieved, utilizing several synthetic strategies,
and cycloaddition reactions were shown to be the most effective. In particular, acety-
lene cyclobutene epoxide (ACE) coupling protocol,[3] its aza-ACE variant,[4] and
photochemical [2p þ 2p] dimerisation[5] were employed by Warrener et al. These
methods were based on cyclobutene diester functionalization, where the Mitsudo
reaction has been the cornerstone in the preparation of ester functionalized
norbornene cyclobutenes of type 2 (Scheme 1). The Mitsudo reaction is a thermal
reaction of norbornenes 1 with dimethylacetylene dicarboxylate (DMAD) in the
Received August 10, 2009.
Address correspondence to Davor Margetic, Laboratory for Physical–Organic Chemistry, Division
´
of Organic Chemistry and Biochemistry, Ruder Boskovic Institute, 10001 Zagreb, Croatia. E-mail:
margetid@emma.irb.hr
ꢀ
´
1239

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D. MARGETIC, P. TROSELJ, AND Y. MURATA
1240
Scheme 1. Mitsudo reaction.
presence of ruthenium catalyst, RuH2CO(PPh3)3,[6] with high p-facial selectivity,
taking place specifically at the exo-face exclusively. Double C-C bond formation
between alkynes and acetylenes by ruthenium(0)-catalyzed [2 þ 2] cycloaddition of
strained cycloalkene with highly electron-deficient DMAD afford cyclobutene.[7]
This reaction protocol has several drawbacks—it is limited to the norbornenes
(strained olefins), while cyclohexenes or bicyclo[2.2.2]oct-2-enes do not react. Also,
the number of acetylenes that may be employed is limited.[8] From the practical point
of view, the impractibility of this method lies in the fact that these cycloadditions are
usually carried out in benzene by heating at 60–80 ꢀC for 2–3 days, and some sub-
strates require up to 7 days. The aim of this study is to address this issue and improve
the synthetic protocol.
The most important improvement of the Mitsudo reaction would be significant
shortening of reaction time; therefore, we looked at microwave conditions as the
most promising option. Many reactions can be carried out in microwave conditions
to shorten the reaction time, increase the efficiency, or initiate the formation of new
products compared with conventional heating methods.[9] As far as we know, results
presented in this article are the first account of the use of microwaves to enhance
ruthenium-catalyzed [2p þ 2p] alkene=alkyne cycloaddition. Ruthenium-catalyzed
reactions of olefins in microwave conditions are reported for olefin metathesis,
[2 þ 2 þ 2] cyclotrimerization, and 1,6-diene and 1,6-enyne cycloisomerizations.[10]
On the other hand, just a few examples exist of transition metal–catalyzed addition
of various reagents to norbornenes (chromium complexes in C-C bond–forming
[2 þ 2 þ 1]=[2 þ 1] addition),[11] Pauson–Khand reaction (with cobalt reagents),[12]
and ring-opening methathesis of norbornenes employing Grubb’s Ru catalysts.[13]
These literature examples indicate the stability and suitability of various ruthenium
catalysts to be used in microwave conditions.
RESULTS AND DISCUSSION
As a model norbornene system, diester 3 was used for optimization of the
Mitsudo reaction under microwave conditions, where tetracyclic tetraester 4 is
obtained as the product. A systematic study on variation of catalyst and DMAD
amounts, solvent, and temperature was carried out, and the results are collected
in Table 1. As a major result, dramatic reduction of reaction time with moderate
to good yields was obtained. Inspection of results showed that the toxic benzene sol-
vent could be replaced by less toxic tetrahydrofuran (THF), dimethylformamide
(DMF), or toluene (entries 1, 6, and 7). The best results were obtained in dry

RUTHENIUM [2p þ 2p] CYCLOADDITIONS
1241
Table 1. Optimization of Mitsudo reaction with diester 3 under microwave conditionsa
Entry
Substrate
Product
Conditionsb
Solventb
Yield (%)
1
2
3
4
83
58
25
50
30 min
10 min
30 min
Wet THF
5
6
2 h
86
23
53
50
78
10
98
46
41
42
DMF
Toluene
DMAD
7
8
9
90 ꢀC
60 ꢀC
10
11
12
13
14
2.4 eq DMAD
0.05 eq Ru
0.2 eq Ru
0.2 eq Ru
THF 1 mL
aStandard reaction conditions: DMAD (1.2 equiv), Ru catalyst (0.1 equiv), dry THF (0.5 mL), 80 ꢀC,
1 h. Literature procedure: DMAD (2–5 equiv), Ru catalyst (0.2–0.5 equiv), dry benzene, 80 ꢀC, 24 h, 67%.
bVariation of standard conditions.
THF (83%) without loss of efficiency as compared to benzene. On the other hand,
the use of wet THF, toluene, and DMF resulted in decreased yields. When the
microwave reaction was conducted without a solvent, in neat DMAD (excess),
reduction of yield to 50% was observed (entry 8). However, the use of excess
DMAD (2.4 equivalents, entry 11) in THF obtained full conversion of 3 to product
4 within just 1 h (98%). Reaction times from 3–7 days in thermal reactions could be
reduced to 1 h (entry 1) with 83% yield, while a 2-h reaction gave a slightly better
yield (86%, entry 5). Further shortening of reaction time to 30 and 10 min leaves
much of substrate unreacted (58% and 25%, entries 2 and 3). Temperature variations
from standard 80 ꢀC to 60 ꢀC or 90 ꢀC decreased yields to 10% and 78%, respectively
(entries 10 and 9). Furthermore, the influence of amount of catalyst on the reaction
outcome is analyzed. It was found that reduction of catalyst to 5% diminishes the
reaction yield to 46% (entry 12). Surprisingly, when the amount of catalyst was
doubled to 20%, almost identical yield was obtained (41%, entry 13). This result
could be explained by the presence of an insufficient amount of solvent and there-
fore an increase in viscosity of reaction media. When more solvent was added, a
similar result was obtained (entry 14).
Optimized reaction conditions were used in subsequent experiments, and
results are presented in Table 2. Versatility of the new reaction protocol was tested
for a series of substrates 5–13. Excellent results were obtained for norbornene 5 and
benzonorbornadienes 6 and 7 (96%, 95%, and 79% yields, respectively, entries 15, 16,
and 17), which are superior to the literature reaction conditions. Substrate compati-
bility was investigated in the case of substrates where the norbornene methylene
bridge (CH2) of the norbornene moiety was replaced with oxygen or nitrogen
(molecules 8 and 9). In these cases, good yield was obtained for 7-azabenzonorbor-
nadiene 9 (88%, entry 19), while the 7-oxabenzonorbornadiene reaction yieleded less

´
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D. MARGETIC, P. TROSELJ, AND Y. MURATA
1242
Table 2. Mitsudo reaction with norbornenes under microwave conditionsa
Yield
(%)
Entry
15
Substrate
Product
Conditionsb
Lit.c
24 h, 65%
96
95
20 h 50 ꢀC
65%
16
17
3 d, 75%
79
6 h, 100 ꢀC
39%
18
19
38
88
4 d, 70 ꢀC,
95%
20
21
3 d, 66%
—
75
2.4 eq DMAD
22
2.4 eq DMAD
—
5
23
24
25
2.4 eq DMAD
3 h
1d, 37%e
5=10=
20d
5=15=
40
20=5=
50
aStandard reaction conditions: DMAD (1.2 equiv), Ru catalyst (0.1 equiv), dry THF (0.5 mL), 80 ꢀC, 1 h.
bVariation of standard conditions.
cLiterature procedure: dry benzene, 80 ꢀC, 1–4 days.
dYields for products 3=4=22.
eOnly product 3 was obtained.

RUTHENIUM [2p þ 2p] CYCLOADDITIONS
1243
Figure 1. Molecular structure of product 16.
product (38%, entry 18). The Mitsudo reaction with another 7-oxanorbornene
substrate, 10, was much more efficient, furnishing 75% yield (entry 20).
The exo-cyclobutene structure of all Mitsudo products was fully supported by
correlation spectroscopy (COSY) NMR spectra (W coupling of methylene Ha pro-
tons and endo-protons Hb) and unequivocally proven by the single-crystal x-ray
structure analysis of representative product 10 presented in Fig. 1.
In principle, double [2p þ 2p] cycloaddition could be also achieved in the case
of substrates possessing two double bonds, such as 11, 12, and norbornadiene 13.
However, it was found that the introduction of the second double bond significantly
affects reaction yields. In the case of 11 and 12, just 5% of product was detected
(entries 21 and 22). Even the addition of a larger amount of DMAD (4.8 equiv.) does
not improve reaction efficiency. This unreactivity may be the result of the steric hin-
drance caused by the endo-positioned imide functionalities (as opposed to exo-placed
imide in substrate 10).
Transformation of norbornadiene to product 4 in a one-pot reaction would
represent an improvement over the classical three-step synthesis.[6,14] While the
literature has shown that microwave heating in general significantly reduces
unwanted side reactions compared with conventional heating methods, this is not
true for norbornadiene. In the case of norbornadiene (entries 23–25), a complex pro-
duct mixture was obtained, consisting mainly of three components, 4, 5, and 22,
where the bishomo [2p þ 2p þ 2p] cycloaddition product 22 dominates. Variation
of reaction conditions gives essentially the same outcome.
EXPERIMENTAL
Mixture of DMAD (44 mg, 0.31 mmol), RuH2CO(PPh3)3 catalyst (24 mg,
0.025 mmol), and substrate 3 (60 mg, 0.25 mmol) in dry THF (0.5 mL) was subjected
to microwave reaction. Reactions were conducted in a CEM Discover LabmateTH=
ExplorerPLS single-mode microwave reactor using the closed reaction vessel tech-
nique (power ¼ 125 W). Excess of solvent was removed in vacuo and products were
1
analyzed by thin-layer chromatography (TLC), gas chromatography (GC), or H
NMR spectroscopy. Radial chromatography (with petroleum ether–ethyl acetate)

´
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D. MARGETIC, P. TROSELJ, AND Y. MURATA
1244
1
was used for product isolation. All new compounds gave H and 13C NMR spectra
and high-resolution mass spectra (HRMS) corresponding to their assigned
structures.
Data on Selected Compounds
Compound 3. Oil. 1H (CDCl3), d=ppm: 1.36 (1H, d, J ¼ 9.6 Hz), 1.42 (1H, d,
J ¼ 9.6 Hz), 2.53 (2H, s), 2.63 (2H, s), 3.79 (12H, s), 6.20 (2H, t J ¼ 1.45 Hz).
Compound 4. Mp 141–143 ꢀC. 1H (CDCl3), d=ppm: 1.39 (2H, s), 2.43 (2H, s),
2.58 (4H, s), 3.81 (12H, s).
Compound 14. Oil. 1H (CDCl3), d=ppm: 1.03 (1H, d, J ¼ 11.1 Hz), 1.08 (2H,
d, J ¼ 8.4 Hz), 1.24 (1H, d, J ¼ 11.1 Hz), 1.57 (2H, d, J ¼ 8.4 Hz), 2.24 (2H, s); 2.64
(2H, s), 3.73 (6H, s).
Compound 15. Mp 81–82 ꢀC. 1H (CDCl3), d=ppm: 1.76 (2H, s), 2.73 (2H, s),
3.26 (2H, s), 3.82 (6H, s).
Compound 16. Mp 120–123 ꢀC. 1H (CDCl3), d=ppm: 1.82 (1H, d,
J ¼ 5.2 Hz), 1.90 (1H, d, J ¼ 5.2 Hz), 2.94 (2H, s), 3.88 (6H, s), 4.03 (6H, s), 7.44
(2H, dd, J ¼ 6.6 Hz, J ¼ 3.2 Hz), 8.07 (2H, dd, J ¼ 6.6 Hz, J ¼ 3.2 Hz); 13C (CDCl3),
d=ppm: 37.6, 39.3, 46.2, 52.0, 61.9, 122.1, 125.5, 128.3, 132.9, 142.9, 145.6, 161.5.
HRMS (m=z): calcd. for C23H22O6: 394.1416; found: 394.1420.
1
Compound 17. Mp 150–152 ꢀC. H (CDCl3), d=ppm: 1.92 (2H, s), 3.87 (6H,
s), 5.21 (2H, s), 7.20 (2H, dd, J ¼ 7.5 Hz, J ¼ 1.5 Hz), 7.34 (2H, dd, J ¼ 7.5 Hz,
J ¼ 1.5 Hz).
1
Compound 18. Mp 96–97 ꢀC. H (CDCl3), d=ppm: 2.86 (1H, brs), 2.88 (1H,
brs), 3.66 (3H, s), 3.87 (3H, s), 4.95 (1H, brs), 5.05 (1H, brs), 5.21 (1H, brs), 5.26 (1H,
brs), 7.18–7.24 (9H, m).
Compound 19. Mp 91–94 ꢀC. 1H (CDCl3), d=ppm: 2.91 (2H, s), 2.97 (3H, s),
3.11 (2H, s), 3.80 (6H, s), 4.77 (2H, s).
Crystallographic Data
CCDC 741971 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Crystal data: C23H22O6,
˚
˚
Mr ¼ 394.41, monoclinic, P2(1)=c, a ¼ 7.7234(7) A, b ¼ 27.719(2) A, c ¼ 9.3834(8)
3
ꢀ
˚
˚
A, b ¼ 109.7520(10) , V ¼ 1890.7(3) A , Z ¼ 4, T ¼ 100(2) K, density ¼ 1.386 Mg=
m3, crystal size ¼ 0.23 ꢁ 0.18 ꢁ 0.15 mm3. Final
R
indices I > 2sigma(I),
R1 ¼ 0.0389, wR2 ¼ 0.0999. R indices (all data), R1 ¼ 0.0472, wR2 ¼ 0.1042.
Data=restraints=parameters, 3318=0=266. Goodness of fit on F2, 1.041.

RUTHENIUM [2p þ 2p] CYCLOADDITIONS
1245
ACKNOWLEDGMENTS
This research was funded by grants from the Croatian Ministry of Science,
Education, and Sport (Nos. 098-0982933-3218 and 098-0982933-2920) and the
Croatian Academy of Arts and Sciences.
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