Efficient Palladium-Catalyzed Cyclotrimerization of Arynes: Synthesis of Triphenylenes

Full text of DOI:10.1002/(SICI)1521-3773(19981016)37:19<2659::AID-ANIE2659>3.0.CO;2-4

COMMUNICATIONS
[8] The number of nitromethane molecules and perchlorate anions per
unit cell in the tetragonal [Ag(hat)ClO4] ´ 2CH3NO2 crystal indicated
by the crystallography showed excellent agreement with the number
calculated with the PLATON Program[6] on the basis of the electron
density in the framework voids. This agreement affords confidence in
the number of water molecules (4H2O per [Ag(hat)]ClO4) present in
the cubic hydrated crystal calculated in the same way by using the
PLATON program, which in addition accorded well with the 3.5H2O
indicated by elemental analysis.
[9] S. Decurtins, H. W. Schmalle, P. Schneuwly, H. R. Oswald, Inorg.
Chem. 1993, 32, 1888; S. Decurtins, H. W. Schmalle, P. Schneuwly, J.
Ensling, P. Gutlich, J. Am. Chem. Soc. 1994, 116, 9521; S. Decurtins,
H. W. Schmalle, R. Pellaux, P. Schneuwly, A. Hauser, Inorg. Chem.
1996, 35, 1451; Carlucci, G. Ciani, D. M. Proserpio, A. Sironi, J. Am.
Chem. Soc. 1995, 117, 12861; B. F. Abrahams, S. R. Batten, H. Hamit,
B. F. Hoskins, R. Robson, Chem. Commun. 1996, 1313; L. Carlucci, G.
Ciani, D. M. Proserpio, A. Sironi, Chem. Commun. 1996, 1393; C. J.
Kepert, M. J. Rosseinsky, Chem. Commun. 1998, 31.
These preliminary results show that the reaction proceeds in
the presence of catalytic amounts of metal and that it has great
potential for the preparation of triphenylenes, which are
found at the core of many discotic liquid crystals[5] and have
therefore been the target of many synthetic studies.[6]
There are many precedents of triphenylene formation
under conditions that lead to arynes, especially when arynes
are generated from an organometallic system.[7] For example,
triphenylene was obtained in 85% yield from the decom-
position of 2-fluorophenylmagnesium bromide in THF.[8]
Closer to our results, triphenylene was isolated in 30% yield
during attempts at obtaining a platinum complex of benzyne
(1,2-didehydrobenzene).[9] An example of the formation of
triphenylene as side product of a palladium-catalyzed domino
reaction has also been reported.[10] However, to the best of our
knowledge, efficient preparation of triphenylenes by metal-
catalyzed reaction of arynes is without precedent.
[10] G. M. Sheldrick, SHELX-76, Program for Crystal Structure Determi-
nation, University of Cambridge, U. K., 1976.
[11] G. M. Sheldrick, SHELXS-86, Program for Crystal Structure Solution,
Universität Göttingen, 1986.
Development of a catalytic procedure for the trimerization
of arynes requires careful selection of the catalyst and the
method for generation of the aryne. The catalyst was chosen
from among the various metal systems used for trimerization
of alkynes; suitable candidates contained metals such as Ni,
Co, Pd, and Pt. We decided to carry out the first trials with
palladium complexes because they are easy to handle and in
general stable. Among the many procedures available for the
generation of arynes[11] we sought one that could be used
under mild reaction conditions and did not involve strong
bases or oxidants. The method of choice was the fluoride-
induced elimination of Me3Si and TfO groups (Tfˆ trifluoro-
methanesulfonyl), which proceeds at room temperature.[12]
Early in our study we found that when 2-trimethylsilyl-
phenyl trifluoromethanesulfonate (1a) was treated with CsF
and a catalytic amount (3 mol%) of [Pd(PPh3)4] in acetoni-
trile, the only low-polarity product detected was triphenylene
(3), which was isolated in 52% yield [Eq. (1)]. To optimize the
[12] G. M. Sheldrick, SHELXS-97, Program for Crystal Structure Solution,
Universität Göttingen, 1997.
[13] G. M. Sheldrick, SHELXL-97, Program for Crystal Structure Refine-
ment, Universität Göttingen, 1997.
Efficient Palladium-Catalyzed Cyclotrimeriza-
tion of Arynes: Synthesis of Triphenylenes**
Â
Ä
Diego Pena, Sonia Escudero, Dolores Perez,*
Â
Enrique Guitian,* and Luis Castedo
Over the last 15 years much effort has been devoted to the
preparation and characterization of transition metal com-
plexes of arynes.[1] Parallel studies on the reactivity of these
complexesÐparticularly those of Ti, Zr,[2] and Ni[3]Ðhave
shown that characteristic reactions involve insertion of
molecules containing multiple bonds (e.g. alkenes, alkynes,
CO) into the metal ± aryne bond, which in a way is reminiscent
of the chemistry of alkyne complexes. However, while alkynes
participate in a number of synthetically useful metal-cata-
lyzed transformations,[4] the synthetic applications of metal ±
aryne complexes are limited owing to the lack of a general and
mild method for their generation and the need for stoichio-
metric amounts of metal in their reactions.
X
cat.
reagent
(1)
Y
1a, X= TMS, Y= OTf
1b, X=Y=Br
2
3
reaction conditions, exhaustive experimentation was carried
out; some significant results are given in Table 1. The best
results were obtained using 10 mol% of [Pd(PPh3)4][13] and
2 equivalents of anhydrous CsF in acetonitrile at room
temperature (entry 1), which afforded triphenylene in 83%
yield. Use of other sources of Pd0 (entries 2 and 3) or fluoride
(entry 4) gave slightly lower yields. Likewise, alternative
methods to generate benzyne, such as reaction of 1,2-
dibromobenzene (1b) with nBuLi, in the presence of
[Pd(PPh3)4] (entry 5) also gave poorer results. It is noteworthy
that triphenylene was not detected in the reaction mixture
when 1a was treated with CsF in the absence of a Pd catalyst
(entry 6), and that when 1a was treated with [Pd(PPh3)4] in
the absence of fluoride, the starting material was untouched
(entry 7). In our opinion, these two control experiments
provide good evidence of the intermediacy of benzyne as the
As part of a project aimed at the development of new
reactions of arynes promoted by metal complexes, here we
report on the metal-mediated cyclotrimerization of arynes.
Â
Â
[*] Dr. D. Perez, Prof. E. Guitian, D. PenÄa, S. Escudero,
Prof. L. Castedo
Â
Departamento de Química Organica
Universidad de Santiago de Compostela and
Unidad Asociada al CSIC
E-15706 Santiago (Spain)
Fax: (‡34)9-81-595012
E-mail: qoenrgui@usc.es
[**] This work was supported by the DGES (PB96-0967). D.P. and S.E.
thank the Spanish Ministry of Education (MEC) for the award of
research grants.
Angew. Chem. Int. Ed. 1998, 37, No. 19
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3719-2659 $ 17.50+.50/0
2659

COMMUNICATIONS
Table 1. Metal-catalyzed synthesis of triphenylene [3, see Eq. (1)].[a]
Similarly high regioselectivity has been reported in metal-
catalyzed alkyne cyclotrimerizations,[14] suggesting that alkyne
and aryne cyclotrimerizations have similar mechanisms. If this
is the case, isolation of the asymmetrically substituted isomer
11 as major product is explained by selective formation of the
metallacyclic intermediate 13 as a result of C ± C bond
formation between the carbon atoms with less steric hin-
drance [Eq. (2)]. Our approach thus allows efficient prepa-
Entry
Starting
material
Reagent
Catalyst
(0.1 equiv)
Additives Yield
[%][b]
1
2
3
4
5
6
7
1a
1a
1a
1a
1b
1a
1a
CsF
CsF
CsF
Bu4NF
BuLi
CsF
±
[Pd(PPh3)4]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd(PPh3)4]
[Pd(PPh3)4]
±
±
83
70
60
71
40
±
dppe
P(o-tol)3
±
±
±
±
[Pd(PPh3)4]
±
OMe
OMe
[a] Reaction conditions: MeCN, RT, 12 h (entries 1 ± 3, 6, 7); THF, 08C,
12 h (entries 4, 5). [b] Yield of isolated product. dba ˆ trans,trans-dibenz-
ylideneacetone, dppe ˆ 1,2-bis(diphenylphosphanyl)ethane, tol ˆ C6H4Me.
PdL2
(2)
11
[PdLn]
OMe
reactive species, and suggest that the metal promotes the
reaction by acting as a template.
13
Next, we applied the optimized cyclotrimerization proce-
dure developed for benzyne to the substituted arynes 6 and 10,
to see if it was compatible with donor and acceptor substituents
on the aryne and to determine the regiochemistry of the reaction.
Furthermore, we were interested to know if the reaction is of
general utility for the synthesis of functionalized triphenylenes.
The precursor of 4,5-difluorobenzyne (6) was 4,5-difluoro-
2-trimethylsilylphenyl triflate (5), which was prepared from
commercially available 2-bromo-4,5-difluorophenol (4) in
three steps. Treatment of 5 with CsF in the presence of
10 mol% of [Pd(PPh3)4] afforded 2,3,6,7,10,11-hexafluorotri-
phenylene (7) in 52% yield (Scheme 1).
ration of 1,12-substituted triphenylenes, which are currently of
interest owing to their potential application as chiral cores for
liquid crystals.[15]
Experimental Section
A solution of the aryne precursor (1, 5, or 9; 1 mmol) in CH3CN (2 mL) was
added to a suspension of finely powdered anhydrous CsF (2 mmol) and
[Pd(PPh3)4] (0.1 mmol) in CH3CN (1 mL), and the mixture was stirred
under argon at room temperature for 12 h. The solvent was evaporated, and
the residue was purified by column chromatography (silica gel) to isolate
the trimers.[16]
Received: March 31, 1998 [Z11669IE]
German version: Angew. Chem. 1998, 110, 2804 ± 2806
F
F
OH
Br
F
F
OTf
a–c
Keywords: arynes
´
cyclotrimerizations
´
palladium
´
TMS
5
triphenylenes
4
F
F
d
[1] a) S. J. McLain, R. R. Schrock, P. R. Sharp, M. R. Churchill, W. J.
Youngs, J. Am. Chem. Soc. 1979, 101, 263 ± 265; b) M. A. Bennett,
T. W. Hambley, N. K. Roberts, G. B. Robertson, Organometallics 1985,
4, 1992 ± 2000; c) S. L. Buchwald, B. T. Watson, J. Am. Chem. Soc.
1986, 108, 7411 ± 7414; d) M. A. Bennett, H. P. Schwemlein, Angew.
Chem. 1989, 101, 1349; Angew. Chem. Int. Ed. Engl. 1989, 28, 1296 ±
1320; e) J. F. Hartwig, R. G. Bergman, R. A. Andersen, J. Am. Chem.
F
F
F
F
F
7
6
F
Scheme 1. Synthesis of 7 via intermediate 6. a) HMDS. b) 1. nBuLi;
2. TMSCl, THF, 788C. c) 1. nBuLi; 2. Tf2O, 08C. d) [Pd(PPh3)4]
Â
Soc. 1991, 113, 3404 ± 3418; f) J. Campora, S. L. Buchwald, Organo-
metallics 1993, 12, 4182 ± 4187; g) K. Mashima, Y. Tanaka, A.
Nakamura, Organometallics 1995, 14, 5642 ± 5651.
(0.1 equiv), CsF, CH3CN, RT. HMDS ˆ 1,1,1,3,3,3-hexamethyldisilazane,
TMS ˆ trimethylsilyl.
[2] ªTransition Metal Alkyne Complexes: Zirconium ± Benzyne Com-
plexesº: S. L. Buchwald, R. D. Broene in Comprehensive Organo-
metallic Chemistry II, Vol. 12 (Eds.: E. W. Abel, F. G. A. Stone, G.
Wilkinson), Pergamon, Oxford, 1995, pp. 771 ± 784, and references
therein.
Generation of 3-methoxybenzyne (10) from triflate 9 under
the same conditions afforded a mixture of 1,5,12- and 1,5,9-
trimethoxytriphenylenes (11 and 12, respectively) in 93:7
ratio and 81% overall yield (Scheme 2).
[3] M. A. Bennett, E. Wenger, Chem. Ber. 1997, 130, 1029 ± 1042, and
references therein.
OMe
OMe
[4] a) ªTransition Metal Alkyne Complexes: Transition Metal-Catalyzed
Cyclotrimerizationº: D. B. Grotjahn in Comprehensive Organometal-
lic Chemistry II, Vol. 12 (Eds.: E. W. Abel, F. G. A. Stone, G.
Wilkinson), Pergamon, Oxford, 1995, pp. 741 ± 770; b) N. E. Schore,
Chem. Rev. 1988, 88, 1081 ± 1119, c) K. P. C. Vollhardt, Angew. Chem.
1984, 96, 525; Angew. Chem. Int. Ed. Engl. 1984, 23, 539 ± 556.
[5] a) S. Chandrasekhar, Liq. Cryst. 1993, 14, 3 ± 14; b) N. Boden, R. S.
Bushby, J. Clements, J. Chem. Phys. 1993, 98, 5920 ± 5931.
[6] a) P. T. Wright, I. Gillies, J. D. Kilburn, Synthesis 1997, 1007 ± 1009;
b) S. Kumar, M. Manickam, Chem. Commun. 1997, 1615 ± 1616.
[7] a) C. M. Buess, D. D. Lawson, Chem. Rev. 1960, 60, 313 ± 330; b) K. D.
Bartle, H. Heaney, D. W. Jones, P. Lees, Tetrahedron 1965, 21, 3289 ±
3296.
OMe
TMS
OTf
a–c
d
OH
8
9
10
MeO
MeO
MeO
OMe
+
MeO
MeO
11
93 : 7
12
Scheme 2. Synthesis of 11 and 12 via intermediate 10. a) HMDS.
b) 1. LDA; 2. TMSCl. c) 1. nBuLi; 2. Tf2O. d) [Pd(PPh3)4] (0.1 equiv),
CsF, CH3CN, RT. LDA ˆ lithium diisopropylamide.
[8] H. Heaney, P. Lees, Tetrahedron Lett. 1964, 3049 ± 3052.
[9] T. L. Gilchrist, F. J. Graveling, C. W. Rees, J. Chem. Soc. 1971, 977 ±
980.
2660
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3719-2660 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1998, 37, No. 19

COMMUNICATIONS
[10] G. Dyker, Angew. Chem. 1994, 106, 117; Angew. Chem. Int. Ed. Engl.
1994, 33, 103 ± 105.
systems, little is known about the biosynthesis of sponge
metabolites.[2] One class of cytotoxic sponge metabolites
which have recently fascinated organic chemists are the
manzamine alkaloids. The first member of this class, man-
zamine A (1, Figure 1), was isolated in 1986 by Higa et al.[3]
[11] a) R. W. Hoffmann, Dehydrobenzene and Cycloalkynes, Academic
Press, New York, 1967; b) H. Hart in The Chemistry of Functional
Groups, Suppl. C2: The Chemistry of Triple-Bonded Functional
Groups (Ed.: S. Patai), Wiley, Chichester, 1994, pp. 1017 ± 1134.
[12] Y. Himeshima, T. Sonoda, H. Kobayashi, Chem. Lett. 1983, 1211 ±
1214.
[13] Prepared in our laboratory by a published procedure: ªPalladium in
Organic Synthesisº: L. S. Hegedus in Organometallics in Synthesis: A
Manual (Ed.: M. Schlosser), Wiley, 1994. Commercially available
material gave poorer yields.
[14] a) L. S. Meriwether, E. C. Colthup, G. W. Kinnerly, R. N. Reusch, J.
Org. Chem. 1961, 26, 5155 ± 5163; b) Y. Wakatsuki, O. Nomura, K.
Kitaura, K. Morokuma, H. Yamazaki, J. Am. Chem. Soc. 1983, 105,
1907 ± 1912.
N
H
N
H
N
H
N
H
N
N
H
OH
O
N
N
N
H
NH+Cl–
NH
[15] a) N. Boden, R. J. Bushby, A. N. Cammidge, S. Duckworth, G.
Headdock, J. Mater. Chem. 1997, 7, 601 ± 605; b) K. Praefcke, A.
Eckert, D. Blunk, Liq. Cryst. 1997, 22, 113 ± 119.
1
2
3
Figure 1. Manzamine A (1), B (2), and C (3).
[16] Triphenylene and the substituted derivatives gave correct analytical
and spectroscopic data. 3: M.p. 1948C (literature value[6a] 1988C). 7:
1H NMR ([D8]THF) d ˆ 8.42 (t, J ˆ 10.3 Hz, 6H); MS: m/z (%): 336
(100), 168 (16); HR-MS: calcd for C18H6F6: 336.0374, found: 336.0364.
and recently synthesized.[12] The unprecedented structure led
the authors to the conclusion that ªno obvious biogenetic
pathº could be envisaged leading to 1. Manzamines B (2) and
C (3) were subsequently isolated from the same sponge.[4]
In 1992, we put forward a biogenetic hypothesis for the
formation of the manzamines.[5] We proposed that each
structure could be reduced into four building blocks: ammo-
nia, a C10 unit (a symmetrical dialdehyde), tryptophan, and a
C3 unit (an acrolein equivalent), shown in Scheme 1 for
manzamine B (2). The key step in the proposal is the
intramolecular endo Diels ± Alder cycloaddition of the bis-
dihydropyridine 4.[6] To date it is not known whether a
ªDiels ± Alderaseº exists.[7]
1
11: M.p. 1888C; H NMR (CDCl3) d ˆ 9.04 (dd, J ˆ 8.5, 0.8 Hz, 1H),
8.10 (d, J ˆ 8.1 Hz, 1H), 8.00 (d, J ˆ 8.1 Hz, 1H), 7.48 (m, 3H), 4.04 (s,
3H), 3.97 (s, 6H); 13C NMR (CDCl3) d ˆ 158.2, 157.9, 157.0, 133.0,
132.6, 131.9, 127.3, 127.0, 126.8, 121.1, 118.8, 118.4, 118.1, 115.9, 115.0,
110.4, 108.7, 108.5, 56.1, 55.8, 55.7; MS: m/z (%): 318 (100), 303 (25),
288 (15); HR-MS: calcd for C21H18O3: 318.1256, found: 318.1268. 12:
1H NMR (CDCl3) d ˆ 9.00 (dd, J ˆ 8.5, 1.2 Hz, 3H), 7.48 (t, J ˆ 8.2 Hz,
3H), 7.14 (dd, J ˆ 8.1, 1.0 Hz, 3H), 4.02 (s, 9H); MS: m/z (%): 318
(100), 303 (22), 288 (30).
Since the publication of the hypothesis a large number of
manzamine and related alkaloids have been isolated from
various species of sponge worldwide.[8] Despite the lack of
experimental evidence, the proposal has been applied repeat-
edly to explain the biogenetic origin of the manzamine and
related alkaloids. One related alkaloid is keramaphidin B (5,
Scheme 1), which was isolated independently by both the
Kobayashi and Andersen groups.[9] Structurally 5 is simply the
reduced form of the proposed cycloadduct 6 (Scheme 1).
Herein, we report the biomimetic synthesis of 5, the first in
vitro chemical evidence for this proposal.
The synthesis of 7 was first communicated in 1996,[6e] but we
found the route unsatisfactory because of moderate yields
(7% overall) and the instability of one intermediate. Since
then we have modified the synthesis (Scheme 2) with
significant improvements (37% overall yield). Hydroxyphos-
phonium salt 8 was masked as its tetrahydropyranyl (THP)
derivative 9 (93%). Olefin 10 was obtained from the ylide
generated from 9 and 3-(3-pyridyl)propanal in 83% yield.
Acid-mediated deprotection gave the alcohol 11 (94%),
which was treated with p-toluenesulfonyl chloride to give 12
(95%). A one-pot Finkelstein reaction, dimerization and
macrocyclization was effected by the slow addition of 12 into a
mixture of NaI in 2-butanone under reflux. The crude product
was reduced to give bis-tetrahydropyridine 13 in 56% yield
over the two steps. Oxidation of 13 with 3-chloroperbenzoic
acid (mCPBA) furnished diastereomeric N-oxides (98%),
which could be treated with trifluoroacetic anhydride to give
bis-dihydropyridine 7 (100%).
Investigations into the Manzamine Alkaloid
Biosynthetic Hypothesis**
Jack E. Baldwin,* Timothy D. W. Claridge,
Andrew J. Culshaw, Florian A. Heupel, Victor Lee,
David R. Spring, Roger C. Whitehead,
Robert J. Boughtflower, Ian M. Mutton, and
Richard J. Upton
Over the past decade there has been an upsurge in the
discovery of biologically active natural products from marine
sponges.[1] In comparison to terrestrial plant and microbial
[*] Prof. J. E. Baldwin, Dr. T. D. W. Claridge, Dr. A. J. Culshaw,
Dr. F. A. Heupel, Dr. V. Lee, D. R. Spring, Dr. R. C. Whitehead
The Dyson Perrins Laboratory
University of Oxford
South Parks Road, Oxford OX1 3QY (UK)
Fax: (‡44)1865-275-632
E-mail: jack.baldwin@chem.ox.ac.uk
R. J. Boughtflower, I. M. Mutton, Dr. R. J. Upton
Glaxo Wellcome Research and Development
Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY (UK)
[**] This work was supported financially by the EPSRC (A.J.C and D.R.S)
and the Rhodes Trust (F.A.H). We are indebted to Prof. Raymond J.
Andersen (Department of Chemistry, University of British Columbia,
Canada) and Prof. Junꢁichi Kobayashi (Faculty of Pharmaceutical
Sciences, Hokkaido University, Japan), for their generous gifts of
keramaphidin B. We also thank the EPSRC mass spectrometry
service (Swansea) for high resolution mass measurements.
Angew. Chem. Int. Ed. 1998, 37, No. 19
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3719-2661 $ 17.50+.50/0
2661