Flexible synthesis of phenanthrenes by a PtCl2-catalyzed cycloisomerization reaction

Article abstract of DOI:10.1021/jo025962y

Readily available biphenyl derivatives containing an alkyne unit at one of their ortho positions are converted into substituted phenanthrenes upon exposure to catalytic amounts of either PtCl₂, AuCl₃, GaCl₃, or InCl₃ in toluene. This 6-endo-dig cyclization likely proceeds through initial π-coordination of the alkyne unit followed by interception of the resulting η²-metal complex by the adjacent arene ring. The reaction is inherently modular, allowing for substantial structural variations and for the incorporation of substituents at any site of the phenanthrene product except C-9. Moreover, the reaction is readily applied to the heterocyclic series as exemplified by the preparation of benzoindoles, naphthothiophenes as well as bridgehead nitrogen hetero- cycles.

Full text of DOI:10.1021/jo025962y

SCHEME 1
F lexible Syn th esis of P h en a n th r en es by a
P tCl2-Ca ta lyzed Cycloisom er iza tion
Rea ction
Alois Fu¨rstner* and Victor Mamane
Max-Planck-Institut fu¨r Kohlenforschung,
D-45470 Mu¨lheim/ Ruhr, Germany
fuerstner@mpi-muelheim.mpg.de
Received May 23, 2002
Abstr a ct: Readily available biphenyl derivatives containing
an alkyne unit at one of their ortho positions are converted
into substituted phenanthrenes upon exposure to catalytic
amounts of either PtCl2, AuCl3, GaCl3, or InCl3 in toluene.
This 6-endo-dig cyclization likely proceeds through initial
π-coordination of the alkyne unit followed by interception
of the resulting η2-metal complex by the adjacent arene ring.
The reaction is inherently modular, allowing for substantial
structural variations and for the incorporation of substitu-
ents at any site of the phenanthrene product except C-9.
Moreover, the reaction is readily applied to the heterocyclic
series as exemplified by the preparation of benzoindoles,
naphthothiophenes as well as bridgehead nitrogen hetero-
cycles.
thesis of phenanthrenes based on a PtCl2-catalyzed
carbocyclization reaction of alkynylated biphenyl deriva-
tives.11-13
The required substrates 2 are prepared in two steps
as shown in Scheme 1.14 Standard Suzuki cross-coupling
reactions15 employing either 2-bromobenzaldehyde (path
A) or 2-formyl-benzeneboronic acid (path B) afford sub-
Since the pioneering studies of Murai et al.,1 PtCl2 is
rapidly gaining importance as a convenient catalyst for
a host of skeletal rearrangements of enynes and related
substrates.1-8 Although the transformations are seem-
ingly quite diverse in nature, substantial evidence has
accumulated that they are invariably triggered by π-com-
plexation of the alkyne to the transition metal, rendering
the alkyne susceptible to attack by an external or a
tethered nucleophile.9 In pursuit of our previous inves-
tigations in this field,3,10 we now report a flexible syn-
(9) In some cases, however, the formation of vinyl cationic complexes
or metal carbenes may follow the initial π-complexation of the alkyne
along the reaction coordinate; cf. refs 1-7.
(10) (a) Fu¨rstner, A.; Voigtla¨nder, D.; Schrader, W.; Giebel, D.; Reetz,
M. T. Org. Lett. 2001, 3, 417-420. (b) Fu¨rstner, A.; Voigtla¨nder, D.
Synthesis 2000, 959-969.
(11) For related reactions of ω-aryl-1-alkynes catalyzed by Pt(II) or
other metal species leading to (dihydro)naphthalenes, see: (a) Chatani,
N.; Inoue, H.; Ikeda, T.; Murai, S. J . Org. Chem. 2000, 65, 4913-4918.
(b) Inoue, H.; Chatani, N.; Murai, S. J . Org. Chem. 2002, 67, 1414-
1417. (c) Dankwardt, J . W. Tetrahedron Lett. 2001, 42, 5809-5812.
(d) Herndon, J . W.; Zhang, Y.; Wang, K. J . Organomet. Chem. 2001,
634, 1-4.
(1) (a) Chatani, N.; Furukawa, N.; Sakurai, H.; Murai, S. Organo-
metallics 1996, 15, 901-903. (b) Chatani, N.; Kataoka, K.; Murai, S.;
Furukawa, N.; Seki, Y. J . Am. Chem. Soc. 1998, 120, 9104-9105.
(2) (a) Me´ndez, M.; Mun˜oz, M. P.; Nevado, C.; Ca´rdenas, D. J .;
Echavarren, A. M. J . Am. Chem. Soc. 2001, 123, 10511-10520. (b)
Ferna´ndez-Rivas, C.; Me´ndez, M.; Echavarren, A. M. J . Am. Chem.
Soc. 2000, 122, 1221-1222. (c) Me´ndez, M.; Mun˜oz, M. P.; Echavarren,
A. M. J . Am. Chem. Soc. 2000, 122, 11549-11550. (d) Mart´ın-Matute,
B.; Ca´rdenas, D. J .; Echavarren, A. M. Angew. Chem. 2001, 113, 4890-
4893; Angew. Chem., Int. Ed. 2001, 40, 4754-4757.
(3) (a) Fu¨rstner, A.; Szillat, H.; Gabor, B.; Mynott, R. J . Am. Chem.
Soc. 1998, 120, 8305-8314. (b) Fu¨rstner, A.; Szillat, H.; Stelzer, F. J .
Am. Chem. Soc. 2000, 122, 6785-6786. (c) Fu¨rstner, A.; Stelzer, F.;
Szillat, H. J . Am. Chem. Soc. 2001, 123, 11863-11869.
(4) Oi, S.; Tsukamoto, I.; Miyano, S.; Inoue, Y. Organometallics 2001,
20, 3704-3709.
(12) For general reviews on the synthesis of phenanthrenes, see:
(a) Floyd, A. J .; Dyke, S. F.; Ward, S. E. Chem. Rev. 1976, 76, 509-
562. (b) Mallory, F. B.; Mallory, C. W. Org. React. 1984, 30, 1-456.
See the following for leading references on generally applicable
phenanthrene syntheses not yet covered by these reviews: (c) Hanson,
P.; Lo¨venich, P. W.; Rowell, S. C.; Walton, P. H.; Timms, A. W. J . Chem.
Soc., Perkin Trans. 2 1999, 49-63. (d) Harrowven, D. C.; Nunn, M. I.
T.; Fenwick, D. R. Tetrahedron Lett. 2002, 43, 3185-3187. (e) Ramana,
M. M. V.; Potnis, P. V. Synthesis 1996, 1090-1092. (f) Morrow, G. W.;
Marks, T. M.; Sear, D. L. Tetrahedron 1995, 51, 10115-10124. (g) Bao,
J .; Wulff, W. D.; Dominy, J . B.; Fumo, M. J .; Grant, E. B.; Rob, A. C.;
Whitcomb, M. C.; Yeung, S.-M.; Ostrander, R. L.; Rheingold, A. L. J .
Am. Chem. Soc. 1996, 118, 3392-3405. (h) J ung, K.; Koreeda, M. J .
Org. Chem. 1989, 54, 5667-5675. (i) Mallory, F. B.; Rudolph, M. J .;
Oh, S. M. J . Org. Chem. 1989, 54, 4619-4626. (j) Brown, C.; Sikkel,
B. J .; Carvalho, C. F.; Sargent, M. V. J . Chem. Soc., Perkin Trans. 1
1982, 3007-3010. (k) Liu, L.; Yang, B.; Katz, T. J .; Poindexter, M. K.
J . Org. Chem. 1991, 56, 3769-3775. (l) Meier, H.; Fetten, M.;
Schnorpfeil, C. Eur. J . Org. Chem. 2001, 779-786. (m) Fu, J .; Snieckus,
V. Can. J . Chem. 2000, 78, 905-919. (n) de Koning, C. B.; Michael, J .
P.; Rousseau, A. L. J . Chem. Soc., Perkin Trans. 1 2000, 787-797. (o)
Hoarau, C.; Couture, A.; Deniau, E.; Grandclaudon, P. Synthesis 2001,
1462-1470. (p) Kraus, G. A.; Zhang, N.; Melekhov, A.; J ensen, J . H.
Synlett 2001, 521-522 and literature cited therein.
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3810.
(6) Blum, J .; Beer-Kraft, H.; Badrieh, Y. J . Org. Chem. 1995, 60,
5567-5569.
(7) For similar rearrangement reactions catalyzed by metals other
than platinum, see: (a) Chatani, N.; Morimoto, T.; Muto, T.; Murai,
S. J . Am. Chem. Soc. 1994, 116, 6049-6050. (b) Chatani, N.; Inoue,
H.; Morimoto, T.; Muto, T.; Murai, S. J . Org. Chem. 2001, 66, 4433-
4436. (c) Trost, B. M.; Trost, M. K. J . Am. Chem. Soc. 1991, 113, 1850-
1852. (d) Trost, B. M.; Yanai, M.; Hoogsteen, K. J . Am. Chem. Soc.
1993, 115, 5294-5295. (e) Trost, B. M.; Chang, V. K. Synthesis 1993,
824-832.
(8) For a general review, see: Aubert, C.; Buisine, O.; Malacria, M.
Chem. Rev. 2002, 102, 813-834.
10.1021/jo025962y CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/23/2002
6264
J . Org. Chem. 2002, 67, 6264-6267

TABLE 1. Scr een in g of th e Activity a n d Selectivity of Differ en t Ca ta lysts in th e Cycloisom er iza tion of th e
Or th o-a lk yn yla ted Bip h en yl Der iva tives 2a -e
substrate
R
X
catalysta
conditions
GC %
3:4
yieldb (%)
2a
OMe
H
toluene, 80 °C, 22 h
toluene, 80 °C, 22 h
toluene, 80 °C, 22 h
toluene, 80 °C, 22 h
toluene, 80 °C, 16 h
CH2Cl2, rt, 4 h
0
100
100
100
100
100
100
62
GaCl3
InCl3
AuCl3
PtCl2
PtCl2(PhCN)2/2AgSbF6
PtCl2(PhCN)2/2AgBF4
96:4
44:56
97:3
95:5
87:13
92:8
53
44
95
76
56
82
CH2Cl2, rt, 4 h
CH2Cl2, rt, 16 h
PtCl2(PhCN)2/2NH4PF6
90:10
67:33
30:70
[RuCl2(CO)3]2
[(cymene)(PCy3)RuCl2]/2 AgBF4
[Cp*Ru(MeCN)3]PF6
RuCl3
RhCl3
PtCl2
PtCl2
PtCl2
PtCl2
toluene, 80 °C, 21 h
CH2Cl2, 50 °C, 20 h
toluene, 80 °C, 22 h
toluene, 80 °C, 22 h
toluene, 80 °C, 22 h
toluene, 80 °C, 20 h
toluene, 80 °C, 20 h
toluene, 80 °C, 40 h
toluene, 100 °C, 24 h
52
100
0
0
0
100
100
73
17
2b
2c
2d
2e
Me
Me
Me
Me
H
Me
COOMe
C6H4OMe
97:3
100:0
5:95
64
89
100
60:40
87c
a
b
Using 5 mol % monomeric complexes or 2.5 mol % dimeric complexes, respectively. Refers to the isolated yield of the major compound.
c Inseparable mixture of 3e and 4e.
stituted biphenyl aldehyde derivatives 1, which are
converted into the required alkynes 2 according to the
Corey-Fuchs protocol16 or in one step by reaction with
lithio trimethylsilyl diazomethane.17 Addition of an elec-
trophilic metal salt or metal complex leads to an equi-
librium between the alkyne 2 and the corresponding η2-
complex; if the latter is intercepted by the adjacent
aromatic ring, a C-C bond formation with concomitant
release of the catalyst will ensue.
makes it clear that the observed reactions are not just
thermal electrocyclization processes but definitely require
assistance by the metal cation.
A notable feature observed for the whole set of sub-
strates investigated (Tables 1 and 2) is the pronounced
preference for the 6-endo-dig cyclization to give phenan-
threnes over the conceivable 5-exo mode.20 The only
exception is compound 2d in which the strongly electron-
withdrawing ester group on the alkyne not only dimin-
ishes the reaction rate but also overturns this inherent
bias by enforcing a 1,4-addition process formally corre-
sponding to the 5-exo pathway (3d :4d ) 5:95). The tolane
derivative 2e gives a mixture of both possible isomers,
i.e., the phenanthrene 3e and the corresponding 9-alky-
lidene fluorene derivative 4e, in a ∼3:2 ratio.
Screening of a set of different metal species has shown
18
that either PtCl2 or AuCl3 in toluene at 80 °C not only
result in good conversions but also are the most conve-
nient from a practical point of view (Table 1).19 Cationic
platinum complexes formed in situ from PtCl2(PhCN)2
and a suitable halide sequestering agent (AgBF4, AgSbF6,
NH4PF6) as well as GaCl311b also gave appreciable results,
whereas RhCl3, RuCl3, or cationic ruthenium species
resulted in low conversions and/or poor selectivities.
Importantly, heating of the substrate in toluene at 80
°C for 22 h in the absence of any catalyst does not result
in ring closure (Table 1, entry 1); this control experiment
In a formal sense, this new phenanthrene synthesis is
reminiscent of the endo-selective cyclizations of dienyl-
(18) For recent applications of gold catalysts in organic synthesis,
see: (a) Hashmi, A. S. K.; Schwarz, L.; Choi, J .-H.; Frost, T. M. Angew.
Chem. 2000, 112, 2382-2385; Angew. Chem., Int. Ed. 2000, 39, 2285-
2288. (b) Hashmi, A. S. K.; Frost, T. M.; Bats, J . W. J . Am. Chem. Soc.
2000, 122, 11553-11554. (c) Fukuda, Y.; Utimoto, K. J . Org. Chem.
1991, 56, 3729-3731. (d) Teles, J . H.; Brode, S., Chabanas, M. Angew.
Chem. 1998, 110, 1475-1478; Angew. Chem., Int. Ed. 1998, 37, 1415-
1418. (e) Ito, Y.; Sawamura, M.; Hayashi, T. J . Am. Chem. Soc. 1986,
108, 6405-6406. (f) Togni, A.; Pastor, S. D. J . Org. Chem. 1990, 55,
1649-1664. (g) Arcadi, A.; Di Guiseppe, S.; Marinelli, F.; Rossi, E. Adv.
Synth. Catal. 2001, 343, 443-446. (h) Hoffmann-Ro¨der, A.; Krause,
N. Org. Lett. 2001, 3, 2537-2538. (i) Shul’pin, G. B.; Shilov, A. E.;
Suss-Fink, G. Tetrahedron Lett. 2001, 42, 7253-7256. (j) Hashmi, A.
S. K.; Frost, T. M.; Bats, J . W. Org. Lett. 2001, 3, 3769-3771. (k) Shi,
F.; Deng, Y. Q.; Yang, H. Z.; SiMa, T. Chem. Commun. 2001, 345-
346. (l) Short review: Dyker, G. Angew. Chem., Int. Ed. 2000, 39,
4237-4239.
(13) See the following for leading references on phenanthrene
syntheses by palladium-catalyzed annulations: (a) Wu, G.; Rheingold,
A. L.; Geib, S. J .; Heck, R. F. Organometallics 1987, 6, 1941-1946. (b)
Larock, R. C.; Doty, M. J .; Tian, Q.; Zenner, J . M. J . Org. Chem. 1997,
62, 7536-7537. (c) Larock, R. C.; Tian, Q. J . Org. Chem. 1998, 63,
2002-2009. (d) Dyker, G.; Kellner, A. Tetrahedron Lett. 1994, 35,
7633-7636. (e) Mandal, A. B.; Lee, G.-H.; Liu, Y.-H.; Peng, S.-M.;
Leung, M. J . Org. Chem. 2000, 65, 332-336. (f) Yoshikawa, E.;
Radhakrishnan, K. V.; Yamamoto, Y. J . Am. Chem. Soc. 2000, 122,
7280-7286.
(14) Some substrates have been prepared via Sonogashira coupling.
For details concerning the synthesis of all starting materials, see
Supporting Information.
(15) (a) Suzuki, A. J . Organomet. Chem. 1999, 576, 147-168. (b)
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
(16) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 3769-3772.
(17) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 107-108.
(19) For a discussion see: Fu¨rstner, A. Synlett 1999, 1523-1533.
(20) Note that this pattern is distinctly different from the one
described in Murai’s reports on seemingly related PtCl2-catalyzed
dihydronaphthalene syntheses, which occur via an 6-exo-dig cyclization
followed by an isomerization of the exo-methylene product initially
formed; cf. ref 11a.
J . Org. Chem, Vol. 67, No. 17, 2002 6265

TABLE 2. F or m a tion of P h en a n th r en es a n d Heter ocyclic Con gen er s by Cycliza tion of Or th o-a lk yn yla ted Bia r yls; All
Rea ction s Wer e Ca r r ied ou t w ith 5 Mol % P tCl2 in Tolu en e a t 80 °C u n less Sta ted Oth er w ise
a
b
Using AuCl3 (5 mol %) as the catalyst. Using GaCl3 (10 mol %) as the catalyst; in this case, the use of either PtCl2 or AuCl3 led to
<40% conversion. c Using InCl3 (5 mol %) in toluene at 100 °C as the catalyst.
6266 J . Org. Chem., Vol. 67, No. 17, 2002

SCHEME 2
change of the connectivity pattern in the substrate opens
access to the pyrrolo[1,2-a]quinoline skeleton bearing the
heteroatom in the bridgehead position; interestingly
though, substrate 2o (R ) C6H13) required the use of
GaCl3 (entry 13) or InCl3 (entry 14) for efficient cycliza-
tion, while PtCl2 is the best catalyst for the terminal
alkyne 2n (entry 12). Further studies on the scope and
mechanism of this and related platinum-catalyzed trans-
formations are currently in progress.
alkynes A and related substrates catalyzed by either [(η6-
cymene)(PPh3)RuCl2] or W(CO)5‚THF (Scheme 2).21 These
reactions likely involve vinylidene complexes B, which
undergo a 6π-electrocyclization to form the new arene
ring in product C. Since only terminal alkynes can afford
such intermediates via complexation followed by a 1,2-
hydride shift (cf. A f B),22 however, the scope of this
methodology is inherently limited. The platinum-cata-
lyzed phenanthrene synthesis, in contrast, works equally
well or even better with nonterminal alkynes as evident
from entries 3, 8, and 11 in Table 2, suggesting that the
activation of the π-system by coordination to Pt(II) rather
than the formation of metal vinylidenes suffices to trigger
the observed ring closure.
The examples compiled in Table 2 show the generality
of this novel entry into phenanthrenes. In principle, this
method allows the introduction of substituents at any
position exept C-9. The ready reaction of compound 2g
(easily prepared from R-tetralone in three high-yielding
operations)14 illustrates that dihydrophenanthrenes are
equally accessible via this route. Likewise, the phenyl
rings can also be replaced by heteroarene units (entries
9-14). Although in the case of the N-unprotected pyrrole
derivatives 2l-m one might expect the nitrogen atom to
act as the nucleophile, exclusive carbocyclization with
formation of 1H-benzo[g]indoles is observed.23 A simple
Exp er im en ta l Section
Gen er a l. For details, see Supporting Information.
Rep r esen ta tive P r oced u r e. P r ep a r a tion of 1,3,10-Tr i-
m eth yl-6,7-m eth ylen ed ioxy-p h en a n th r en e (3j). A solution
of alkyne 2j (528 mg, 2.0 mmol) and PtCl2 (26.6 mg, 0.1 mmol)
in toluene (10 mL) was stirred for 24h at 80 °C under Ar until
GC showed complete conversion of the substrate. The solvent
was then evaporated, and the residue was purified by flash
chromatography (silica gel, hexanes) to give phenanthrene 3j
as a white solid (495 mg, 94%): mp 126-127 °C; IR (KBr) 2965,
2931, 2904, 1614, 1596, 1504, 1490, 1460, 1438, 1233, 1039, 942,
876 cm-1 1H NMR (400 MHz, CDCl3) δ 2.44 (s, 3H), 2.82 (s,
;
3H), 2.83 (s, 3H), 5.98 (s, 2H), 6.98 (s, 1H), 7.09 (s, 1H), 7.24 (s,
1H), 7.87 (s, 1H), 8.08 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
21.1, 25.7, 26.1, 100.7, 100.9, 104.0, 120.9, 125.4, 127.8, 129.0,
131.4, 131.6, 131.7, 134.4, 135.5, 147.0, 147.1; MS (EI) m/z 264
([M+], 100), 249 (18), 189 (11). Anal. Calcd for C18H16O2
(264.33): C, 81.79; H, 6.10. Found: C, 81.75; H 6.13.
Ack n ow led gm en t. Generous financial support by
the Deutsche Forschungsgemeinschaft (Leibniz award
to A.F.) and by the Fonds der Chemischen Industrie is
gratefully acknowledged. We thank the OMG AG & Co
KG, Hanau, for a generous gift of noble metal salts.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details including procedures for the preparation of the starting
materials 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.
(21) (a) Merlic, C. A.; Pauly, M. E. J . Am. Chem. Soc. 1996, 118,
11319-11320. (b) Maeyama, K.; Iwasawa, N. J . Org. Chem. 1999, 64,
1344-1346. (c) Maeyama, K.; Iwasawa, N. J . Am. Chem. Soc. 1998,
120, 1928-1929.
(22) For recent reviews on the preparation and application of
vinylidene complexes, see: (a) Bruneau, C.; Dixneuf, P. H. Acc. Chem.
Res. 1999, 32, 311-323. (b) McDonald, F. E. Chem. Eur. J . 1999, 5,
3103-3106. (c) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. Rev.
2001, 101, 2067-2096. (d) Bruce, M. I. Chem. Rev. 1991, 91, 197-
257.
J O025962Y
(23) For a related example in which the nitrogen atom is blocked
by a methyl group, see ref 11c.
J . Org. Chem, Vol. 67, No. 17, 2002 6267