The microwave-assisted Doetz benzannulation process

Article abstract of DOI:10.1039/b206981b

Chromium carbene-mediated Doetz benzannulation has been shown to proceed remarkably rapidly and with enhanced efficiency under developed microwave-assisted conditions.

Full text of DOI:10.1039/b206981b

The microwave-assisted Dötz benzannulation process
Edward J. Hutchinson†,b William J. Kerr*a and Euan J. Magennisa
a Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow,
Scotland, UK G1 1XL. E-mail: w.kerr@strath.ac.uk
b Organon Laboratories Ltd, Newhouse, Lanarkshire, Scotland, UK ML1 5SH
Received (in Cambridge, UK) 16th July 2002, Accepted 14th August 2002
First published as an Advance Article on the web 12th September 2002
Table 1 Reactions of 1 with 2 under MW irradiation
Chromium carbene-mediated Dötz benzannulation has been
shown to proceed remarkably rapidly and with enhanced
efficiency under developed microwave-assisted conditions.
In 1975 Dötz reported the first example of the formation of a
highly substituted benzenoid compound from the reaction of a
phenylchromium carbene complex and diphenylacetylene.1
Over the subsequent years the efficiency and scope of this Dötz
benzannulation process have been extensively investigated.2
Traditionally the reaction has been carried out under thermal
conditions in a donor solvent. However, use of such techniques
can often lead to prolonged reaction times and low yields.
Consequently, attempts have been made to address these
drawbacks: e.g. high intensity photolytic irradiation has been
employed3 and work in our own laboratory has led to the
development of both ultrasound4 and dry state techniques4,5 that
provide much more rapid and higher yielding processes.
With regards alternative techniques that have the potential to
provide preparative efficiency, microwave (MW) technology
has been used in organic synthesis since 1986, when domestic
ovens were initially used to accelerate reactions.6 With the more
recent ready availability of dedicated and focused reactors,
which offer reliable and safe operation, there has been an
exponential growth in MW-assisted organic synthesis.7 In this
respect, we envisaged that MW technology provided an
opportunity to further improve the efficiency and flexibility of
the compelling Dötz transformation, whilst potentially afford-
ing additional understanding of the scope and limitations of the
relatively new and focused MW methods. We now describe our
initial findings in this area.
At the outset, the reaction between the phenyl methoxy
carbene complex 1 and phenylacetylene 2 was investigated.
Using a Smith Creator™,‡ MW conditions of 130 °C and 300
seconds reaction time were initially chosen and the benzannula-
tion was attempted, in sealed reactor vials, with a range of
reaction solvents (Table 1). On completion of each short
reaction, and following oxidative work-up with ceric ammo-
nium nitrate (CAN), in every instance, other than the process
performed in water, the desired naphthoquinone 3 was formed
in moderate to excellent yield. In addition to showing that the
Dötz reaction could be rapidly and efficiently mediated under
controlled MW irradiation, this initial study showed that aprotic
donor solvents gave optimal results, with the less basic di-n-
butyl ether providing the highest yield.
Solvent
Yield (%)
Toluene
CH2Cl2
Methanol
Ethanol
Ethylene glycol
Water
THF
Et2O
nBu2O
58
36
50
54
58
0
73
82
88
The optimum techniques developed to this stage were then
implemented in a study with carbene 1 and a range of alkynes in
both di-n-butyl ether and THF (Table 3). Both internal and
terminal alkynes performed well, providing good to excellent
yields of the benzannulated products.§ In each case the reaction
was complete in 300 s. Furthermore, where the equivalent
reaction had previously been attempted under thermal condi-
tions, by comparison the product yields were all substantially
enhanced.8,9 Additionally, on work-up the reaction mixture was
homogeneous in all cases (unlike many thermal processes),
easing product extraction and purification.
In attempts to investigate the reagents tolerated under the
MW conditions, three additional complexes were then subjected
to the developed optimum reaction protocol with a series of
alkynes (Table 4). Once again, where there was literature
precedent for the same transformation using thermal techniques,
the reaction times were consistently far shorter and the product
yields were greater.10 It is also worth noting that the lower
yields obtained for certain aryl alkynes with the furyl methoxy
carbene complex are mirrored in the literature under thermal
conditions.11 In this regard, the developed MW-assisted
methods can be considered to be complementary to our
previously described dry state protocols,4,5 which proved to be
significantly more effective when used with the furyl methoxy
Table 2 Concentration effects in reaction of 1 with 2 under MW
Based on the results shown in Table 1, di-n-butyl ether and,
the commonly used, THF were then selected as the solvents of
choice for further investigations into the effects of reagent
concentration on product yield. It is clear from Table 2 that use
of di-n-butyl ether provided generally higher product yields
than the equivalent reaction in THF; the use of no solvent
provided a substantially lower yield. Overall and for both
solvents, the optimal concentrations were found to be 0.05 M of
complex 1 and 0.1 M of alkyne 2. It is also worth noting that
these optimised MW conditions are now significantly superior
in terms of both reaction time and yield when compared to the
thermal processes described in the literature.8
irradiationa
Solvent
THF
[1] (M)
[2] (M)
Yield of 3 (%)
0.01
0.05
0.5
0.05
0.01
0.05
0.5
0.01
0.05
0.5
70
73
64
78
68
88
65
91
47
0.1
nBu2O
0.01
0.05
0.5
0.1
10.5
0.05
0.05
—
a 130 °C and 300 s MW reaction conditions were used throughout, followed
by oxidative work-up with CAN.
† Present address: Strakan Pharmaceuticals, Buckholm Mill Brae, Gala-
shiels, UK TD1 2HB.
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This journal is © The Royal Society of Chemistry 2002

Table 3 Reaction of complex 1 with alkynes under MW irradiationa
Carbene Alkyne Product Solvent Yield (%)
Table 4 Reaction of a range of complexes and alkynes under MW
irradiationa
Carbene
Alkyne
Product
Yield (%)
52
nBu2O
THF
91
78
nBu2O
THF
70
86
54
57
nBu2O
THF
73
75
nBu2O
THF
91
68
85
29
64
0
a 130 °C and 300 s MW reaction conditions were used throughout (0.05 M
1, 0.1 M alkyne), followed by oxidative work-up with CAN.
complex and such alkynes. In the final entry within Table 4 it
can be seen that the MW methods also proved to be applicable
to the less stable carbocyclic a,b-unsaturated complex, with the
tetrahydronaphthoquinone being formed in a good 75% yield
after only 5 min MW irradiation. In the cases where re-
gioisomeric naphthoquinone products are possible, the sole
isomer isolated was that which was anticipated based on
literature precedent.2¶
In conclusion, we have now shown that modern focused MW
reactors are readily utilisable and reliable tools for promotion of
the Dötz reaction in a fast and effective manner. The use of such
techniques result in remarkably enhanced reaction rates, with
cyclisations being complete inside 5 min, and lead to annulated
product yields which are often significantly greater than those
from the traditional thermal processes. With the increasing use
of such focused preparative MW instruments within pharma-
ceutical laboratories, one can envisage such annulation tech-
niques being employed to gain efficient and rapid access to a
diverse spectrum of functionalised aromatic compounds.
We gratefully acknowledge Organon Laboratories for sup-
port and The University of Strathclyde for a Studentship
(E.J.M.), with further financial support from Lancaster Synthe-
sis Ltd. We are also indebted to Dr Jason Tierny for helpful
discussions, Drs Robert Colman and Eric Cuthbertson for
additional input, and the EPSRC Mass Spectrometry Service,
University of Wales, Swansea, for analyses.
72
75
a 130 °C and 300 s MW reaction conditions were used throughout (0.05 M
carbene, 0.1 M alkyne), followed by oxidative work-up with CAN.
1 K. H. Dötz, Angew. Chem., Int. Ed. Engl., 1975, 14, 644.
2 K. H. Dötz, Angew. Chem., Int. Ed. Engl., 1984, 23, 587; K. H. Dötz and
P. Tomuschat, Chem. Soc. Rev., 1999, 28, 187; A. de Meijere, H.
Schirmer and M. Duetsch, Angew. Chem., Int. Ed., 2000, 39, 3964.
3 Y. H. Choi, K. S. Rhee, K. S. Kim, G. C. Shin and S. C. Shin,
Tetrahedron Lett., 1995, 36, 1871.
Notes and references
‡ Personal Chemistry AB, Hamnesplanaden 5, SE-753 19 Uppsala,
4 J. P. A. Harrity, W. J. Kerr and D. Middlemiss, Tetrahedron, 1993, 49,
5565.
Sweden; www.personalchemistry.com.
5 J. P. A. Harrity, W. J. Kerr and D. Middlemiss, Tetrahedron Lett., 1993,
34, 2995.
§
Representative experimental procedure: All reactions were carried out
using the Smith Creator™ with ‘Fixed Hold Time’ set to ‘Off’ and
‘Absorption Level’ set to ‘High’. Carbene 1 (47 mg, 0.15 mmol) was added
to a solution of alkyne 2 (30 mg, 0.30 mmol) in di-n-butyl ether (3 mL), the
reaction vial sealed and placed in the microwave reactor. The reaction was
irradiated to a temperature of 130 °C for 300 s. The reaction mixture was
then automatically cooled and poured into a solution of CAN (0.6 g, 1.1
mmol) in water (3 mL). The mixture was stirred for a further 20 minutes and
was then extracted with diethyl ether (3 3 20 mL). The organic extractions
were combined and reduced in vacuo and the crude product was purified by
silica column chromatography (eluting with petrol/diethyl ether 7+1).
2-Phenyl-1,4-naphthalenedione 3 was obtained as a yellow crystalline solid
6 R. Gedye, F. Smith, K. Westaway, H. Ali, L. Baldisera, L. Laberge and
J. Rousell, Tetrahedron Lett., 1986, 27, 279.
7 C. R. Strauss and R. W. Trainor, Aust. J. Chem., 1995, 48, 1665; S.
Caddick, Tetrahedron, 1995, 51, 10403; L. Perreux and A. Loupy,
Tetrahedron, 2001, 57, 9199; P. Lidström, J. Tierny, B. Wathey and J.
Westman, Tetrahedron, 2001, 57, 9225.
8 For the equivalent processes to that shown in Table 2 and Table 3, Entry
1 (45–50 °C, THF, 23 h) and Table 3, Entry 4 (45–50 °C, hexanes, 72
h), see: K. S. Chan, G. A. Peterson, T. A. Brandvold, K. L. Faron, C. A.
Challener, C. Hyldahl and W. D. Wulff, J. Organomet. Chem., 1987,
334, 9.
9 For the equivalent process to that shown in Table 3, Entry 2 (45–50 °C,
tert-butyl methy ether, 5 h), see: K. H. Dötz, J. Mühlemeier, U. Schubert
and O. Orama, J. Organomet. Chem., 1983, 247, 187.
(33 mg, 91%), mp 109–110 °C. IR (CH2Cl2): 1666 cm21
;
1H NMR
(CDCl3): d 7.08 (1H, s), 7.47–7.49 (5H, m), 7.77–7.79 (2H, m), 8.11–8.22
ppm (2H, m); 13C NMR (CDCl3): d 126.0, 127.1, 128.5, 129.4, 130.0,
132.1, 132.4, 133.4, 133.8, 133.9, 135.2, 148.1, 184.5, 185.2 ppm.8 All
other compounds exhibited satisfactory spectral and analytical data.
¶ In the cases where the naphthoquinone was known, the regioisomer
isolated was identified as that resulting from the equivalent thermal process;
all other single regioisomers were tentatively assigned by comparison.
10 For the equivalent process to that shown in Table 4, Entry 8 (75 °C,
THF, 18 h), see: W. D. Wulff, J. S. McCallum and F. A. Kunng, J. Am.
Chem. Soc., 1988, 110, 7419. See also: M. W. Davies, C. N. Johnson
and J. P. A. Harrity, J. Org. Chem., 2001, 66, 3525.
11 K. H. Dötz and R. Dietz, Chem. Ber., 1978, 111, 2517.
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