Ring-closing olefin metathesis of 2,2′-divinylbiphenyls: A novel and general approach to phenanthrenes

Article abstract of DOI:10.1021/ol048668w

(Chemical Equation Presented) The ring-closing olefin metathesis (RCM) of 2,2′-divinylbiphenyls, using a second-generation RCM ruthenium-based catalyst, leads to differently substituted phenanthrenes in quantitative yield under very mild reaction conditions, independent of both nature and position of the groups present on the biphenyl moiety.

Full text of DOI:10.1021/ol048668w

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3711-3714
Ring-Closing Olefin Metathesis of
2,2 -Divinylbiphenyls: A Novel and
′
General Approach to Phenanthrenes
Anna Iuliano,*,† Paolo Piccioli,† and Davide Fabbri‡
Dipartimento di Chimica e Chimica Industriale, UniVersita` di Pisa,
Via Risorgimento 35, 56126 Pisa, Italy, and CNR Istituto di Chimica Biomolecolare,
sez. Sassari -traVersa La Crucca, 3, 07040 Sassari, Italy
iuliano@dcci.unipi.it
Received July 12, 2004
ABSTRACT
The ring-closing olefin metathesis (RCM) of 2,2′-divinylbiphenyls, using a second-generation RCM ruthenium-based catalyst, leads to differently
substituted phenanthrenes in quantitative yield under very mild reaction conditions, independent of both nature and position of the groups
present on the biphenyl moiety.
Phenanthrenes represent an important class of organic
compounds because they are useful intermediates for natural
product synthesis1 or exhibit various biological activities such
as antimalarial,2 anticancer,3 and emetic activity.4 A number
of methods are known for the synthesis of phenanthrenes,1
which use ring annulation,5 intermolecular,6 and intramo-
lecular7 cyclization. The majority of these methods are char-
acterized by limitations such as accessibility of the starting
substrates, relatively low overall yield, reaction conditions
scarcely compatible with the presence of functional groups,
and the lack of well-defined regiocontrol elements. Some
of these synthetic methods use as starting materials 2,2′-
disubstituted biphenyls, which afford phenanthrenes by
intramolecular condensation,8 cycloisomerization,9 metal-
catalyzed rearrangement of alkene-alkynes,10 and photocy-
clization,11 depending on the functional group present on the
biphenyl moiety. The ready accessibility to differently func-
tionalized biphenyls, by various methods of aryl-aryl cou-
pling,12 and the success of the ring-closing olefin metathesis
(RCM) reaction for the preparation of various compounds,13
prompted us to check the possibility of obtaining phenan-
threnes by RCM of 2,2′-divinylbiphenyls (Scheme 1).14
Scheme 1. Synthesis of Substituted Phenanthrenes by RCM
† Universita` di Pisa.
‡ CNR Istituto di Chimica Biomolecolare.
(1) Floyd, A. J.; Dyke, S. F.; Ward, S. E. Chem. ReV. 1976, 76, 509.
(2) Traxler, J. T.; Krbechek, L. O.; Riter, R. R.; Wagner, R. G.;
Huffmann, C. W. J. Med. Chem. 1971, 14, 90.
(3) Wilson, S.; Ruenitz, P. C. J. Pharm. Sci. 1992, 82, 571.
(4) Cannon, J. G.; Khonji, R. R. J. Med. Chem. 1975, 18, 110.
(5) Bradsher, C. K. Chem. ReV. 1987, 87, 1277; Catellani, M.; Motti,
E.; Baratta, S. Org. Lett. 2001, 3, 3611.
(6) Ramana, M. M. V.; Potnis, P. V. Synthesis 1996, 1090. Radhakrish-
nan, K. V.; Yoshikawa, E.; Yamamoto, Y. Tetrahedron Lett. 1999, 40, 7533.
Paredes, E.; Biolatto, B.; Kneetmann, M.; Mancini, P. Tetrahedron Lett.
2002, 43, 4601.
We focused our attention on RCM because it is well-
known that the mild reaction conditions (ruthenium catalysts,
(8) Ried, W.; Conte, R. Chem. Ber. 1979, 105, 799. Kobayashi, S.;
Kitamura, K.; Miura, M.; Fukuda, M.; Kihara, M. Chem. Pharrm. Bull.
1972, 20, 694. Kraus, G. A.; Hoover, K.; Zhang, N. Tetrahedron Lett. 2002,
43, 5319. Fu, J-m; Snieckus, V. Can. J. Chem. 2000, 78, 905.
(7) Harrowven, D. C.; Nunn, M. I. T.; Fenwick, D. R. Tetrahedron Lett.
2002, 43, 3185. Almeida, J. F.; Castedo, L.; Fernandez, D.; Neo, A. G.;
Romero, V.; Tojo, G. Org. Lett. 2003, 5, 4939.
10.1021/ol048668w CCC: $27.50
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Published on Web 09/18/2004

low temperatures)15 are well tolerated by many functional
groups, which can be introduced on the biphenyl moiety
leading to differently substituted phenanthrenes. Here, we
present the results we have obtained in the RCM of 2,2′-
divinylbiphenyls possessing different substituents on different
positions of the biphenyl moiety. We carried out this study
to verify the applicability of this method for the synthesis
of phenanthrenes.
titative yield, which were separated by flash chromatography
giving the two isomeric divinyl derivatives 4 and 5. The
structure of 5 was determined by 1H NMR analysis (coupling
constant and NOE measurements). In turn, 2,2′-divinylbi-
phenyl 6 was obtained in nearly quantitative yield by Wittig
reaction on 1.
The vinyl groups of compound 9 were introduced in two
steps starting from compound 7, prepared as already de-
scribed18 (Scheme 3).
The choice of method for synthesizing the 2,2′-divinyl-
biphenyl systems depends on the nature of the substituents
as well as their position on the biphenyl moiety.
The unsubstituted 2,2′-divinylbiphenyl as well as the nitro-
substituted substrates were prepared starting from 2,2′-
diformylbiphenyl 1 (Scheme 2), obtained by Ullmann cou-
Scheme 3. Synthesis of
5,5′,6,6′-Tetramethoxy-2,2′-divinylbiphenyl 9
Scheme 2. Synthesis of the 2,2′-Divinylbiphenyls 4-6
According to Scheme 3, standard metal-halide exchange
(BuLi/-78 °C/THF) on compound 7 followed by quenching
with N,N-dimethylformamide and acidic workup afforded,
in quantitative yield, the corresponding diformyl derivative
8, which was subjected to standard Wittig reaction, giving
quantitatively the 2,2′-divinylbiphenyl derivative 9. The use
of the two-step procedure was necessary because attempts
at introducing directly the vinyl groups by cross-coupling
of 7 with vinyl organometallic reagents19 were unsuccessful.
The synthesis of the unsymmetrical 2,2′-divinylbiphenyl
derivative 14 (Scheme 4) required a different approach both
for building up the biphenyl system and for the introduction
of the two vinyl groups.
pling of 2-iodobenzaldehyde.16 Nitration of 1, under the
experimental conditions used for obtaining 3-nitrobenzalde-
hyde,17 afforded a mixture of the two isomers 2 and 3, which
were not separable by recrystallization or by flash chroma-
tography. The Wittig reaction performed on the isomeric
mixture afforded the corresponding olefins in nearly quan-
Classical Suzuki-Miyaura20 coupling of 3-methoxyphe-
nylboronic acid and 2-iodobenzaldehyde gave in excellent
yield the unsymmetrical biphenyl 10.
Bromination of 10 using BTMA‚Br3 at room temperature21
afforded 11 as sole product in quantitative yield, whose
1
(9) Furstner, A.; Mamane, V. J. Org. Chem 2002, 67, 6264.
(10) Katz. T. J.; Sivavec, T. M. J. Am. Chem. Soc. 1985, 107, 737.
(11) Padwa, A., Doubleday: C.; Mazzu, A., J. Org. Chem. 1977, 42,
3271.
(12) For a review on aryl-aryl coupling methods, see: Hassan, J.;
Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem ReV. 2002, 102,
1359.
(13) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. Karle, M.;
Koert, U. Org. Synth. Highlights IV 2000, 91.
(14) The possibility to obtain phenanthrene by RCM was explored by
Katz from a mechanistic point of view: Katz, T. J.; Rotchild, R. J. Am.
Chem. Soc. 1976, 98, 2518.
(15) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 5426. Grubbs,
R. H.; Miller, S. J., Fu, G. C. Acc. Chem. Res. 1995, 28, 446. Dias, E. L.;
Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 3887.
(16) Bacon, R. G. R.; Lyndsay, S. W. J. Chem. Soc. 1958, 1375.
(17) Icke, R. N.; Redemann, C. E.; Wisegarver, B. B.; Alles, G. A.
Organic Syntheses; Wiley: New York, 1955; Collect. Vol. III, p 644.
chemical structure was confirmed by H NMR analysis
(coupling constant and NOE measurements). The first vinyl
group was introduced at this step by reacting 11 with
methyltriphenylphosphonium ylide under standard condi-
tions; the vinyl derivative 12 was obtained in 94% yield after
flash chromatography. The second vinyl group was intro-
duced by formylation (DMF) of the lithium derivative,
obtained by standard metal-halide exchange, followed by
Wittig reaction on the aldehyde 13, as previously described
for the preparation of 9. Compound 14 was obtained in 60%
yield from 12, after chromatographic purification.
All of the 2,2′-divinylbiphenyl derivatives were subjected
to the RCM reaction, using commercial first-generation13 or
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Org. Lett., Vol. 6, No. 21, 2004

Scheme 4. Synthesis of 5-Methoxy-2,2′-divinylbiphenyl 14
Table 1. RCM of 2,2′-Divinylbiphenyls to Phenanthrenes
Figure 1. Structure of first-generation (15a) and second-generation
(15b) ruthenium-carbene catalysts.
second-generation22 ruthenium-carbene catalysts (Figure 1),
to evaluate the effects of both nature and position of the
biphenyl substituents on the outcome of the reaction.
The obtained results are listed in Table 1. All the reactions
were carried out under the experimental condition usually
employed for RCM.
In a typical run the catalyst (5% mol) was added to a 10-2
M solution of the substrate in dry solvent. The mixture was
stirred at the reported temperature (Table 1), and the reaction
was interrupted when TLC or GC analysis showed that the
substrate conversion did not proceed further.
a Reacting 9 for 24 h or using 10% mol of 15a gave the same result.
The reaction of 2,2′-divinylbiphenyl 6 in CH2Cl2 at room
temperature afforded a complete conversion of the substrate
in 2 h, giving chemically pure phenanthrene in quantitative
yield (entry 1). By contrast, under the same reaction con-
ditions the RCM of 5,5′,6,6′-tetramethoxy-2,2′-divinylbi-
phenyl 9 did not take place; not even doubling the catalyst
amount or prolonging the reaction time had any beneficial
effect (entry 2). The lack of reactivity of this substrate can
be attributed to the presence of the 6,6′ substituents which
impart conformational rigidity to the biphenyl system,
preventing the coplanar disposition of the two phenyl rings
and hence the cyclization.23 On increasing the reaction
temperature to 40 °C, the RCM did take place, however,
but afforded only 30% yield of the phenanthrene derivative
(entry 3). A further increase in reaction temperature (reflux-
ing toluene) afforded the same result (entry 4).
(18) Delogu, G.; Fabbri, D.; Dettori, M. A.; Forni, A.; Casalone, G.
Tetrahedron: Asymmetry 2001, 12, 1451.
(19) Kerins, F.; O’Shea, D. F. J. Org. Chem. 2002, 67, 4968.
(20) Miyaura, N., Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513.
(21) Kajigaeshi, S.; Kakinami, T.; Okamoto, T. Bull. Chem. Soc. Jpn.
1987, 60, 4187.
These poor results prompted us to check the second-
generation ruthenium carbene catalyst 15b, which is known
(22) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron.
Lett. 1999, 40, 2247.
(23) Wolf, C.; Koenig, W. A.; Roussel, C. Liebigs Ann. 1995, 781.
Org. Lett., Vol. 6, No. 21, 2004
3713

to often afford a higher yield of metathesis product24 with
respect to the use of 15a. Much to our delight, with 15b as
the RCM catalyst a complete conversion of the substrate to
16b occurred after 2 h reaction at reflux in dichloromethane;
the phenanthrene derivative was obtained in quantitative yield
(entry 5). The RCM of the 4,4′-dinitro-2,2′-divinylbiphenyl
4, performed in the presence of 15a as catalyst, afforded the
corresponding phenanthrene derivative in only 50% yield
after 24 h reaction at 40 °C. Since the presence of substituents
at 4,4′ positions of the biphenyl system does not affect the
conformational flexibility of 2,2′-disubstituted biphenyl
systems the lower yield with respect to the RCM of 6 can
be attributed to the electronic character of the nitro groups.
The effect of the electronic properties of the substituents on
the efficiency of the ring closure is unusual, since it is known,
for example, that chromenes having substituents such as NO2
or OMe could be prepared with the same efficiency.25
By contrast, when 15b was used as catalyst for the RCM
of 4, a quantitative yield of the corresponding phenanthrene
was obtained, after only 2 h of reaction in dichloromethane
at reflux (entry 7). Also, compound 5, where one of the nitro
groups is at the position 6 of the biphenyl moiety, underwent
the RCM in 2 h, affording the corresponding substituted
phenanthrene in quantitative yield. These results point to the
much greater effectiveness of the second generation Grubbs
catalyst in the RCM reactions of 2,2′-divinylbiphenyls. The
trend observed with substrates 4 and 9 was also confirmed
in the case of 14. When the RCM of this substrate was
performed in the presence of 15a, 24 h were required to
obtain a high yield of the corresponding phenanthrene (entry
9), whereas in the presence of catalyst 15b, a quantitative
yield of the cyclization product was achieved only after 2 h
of reaction (entry 10).
In conclusion, the RCM of 2,2′-divinylbiphenyls has
proven to be a general method for obtaining high yields of
substituted phenanthrenes. Using the ruthenium-carbene
complex 15a as catalyst the reaction gives results that depend
on the conformational rigidity of the biphenyl moiety as well
as the electronic properties of the substituents. The use of
the ruthenium-carbene complex 15b as catalyst affords
quantitative yields of the phenanthrene derivative indepen-
dent of the structure of the starting biphenyl. In addition,
the ready accessibility to differently substituted 2,2′-divi-
nylbiphenyls makes this approach very attractive. The sole
limitation of this method is the impossibility to obtain
phenanthrenes having substituents at positions 9 and 10.
Nevertheless, these derivatives can be easily obtained by
electrophilic aromatic substitution on phenanthrene.
Acknowledgment. We thank Dr. G. Delogu for helpful
discussions. Financial support from the University of Pisa
and INFM-Scuola Normale Superiore (NEST outreach
project) is gratefully acknowledged.
Supporting Information Available: Full experimental
details including procedure for the preparation of the biphenyl
derivatives as well as the analytical and spectroscopic data
of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(24) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(25) Chang, S.; Grubbs, R. H. J. Org. Chem. 1998, 63, 864.
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