Transition-metal-promoted 6-endo-dig cyclization of aromatic enynes: Rapid synthesis of functionalized naphthalenes

Article abstract of DOI:10.1016/S0040-4039(01)01146-7

Transition-metal-mediated cyclization of aromatic enynes provides high yields of sustituted naphtalene compounds. The reduction can tolerate a wide range of substituents on both the olefin and the alkyne. The most useful catalysts were found to be [Rh(CO)

Full text of DOI:10.1016/S0040-4039(01)01146-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5809–5812
Transition-metal-promoted 6-endo-dig cyclization of aromatic
enynes: rapid synthesis of functionalized naphthalenes
John W. Dankwardt*
Inflammatory Diseases Unit, Roche Bioscience, Palo Alto, CA 94303, USA
Received 29 May 2001; revised 21 June 2001; accepted 26 June 2001
Abstract—Transition-metal-mediated cyclization of aromatic enynes provides high yields of substituted naphthalene compounds.
The reaction can tolerate a wide range of substituents on both the olefin and the alkyne. The most useful catalysts were found
to be [Rh(CO)2Cl]2, PdCl2 and PtCl2. In addition, a facile silyl migration occurs when the acetylene is substituted with a
triorganosilyl group affording 4-silyl-naphthalenes. © 2001 Elsevier Science Ltd. All rights reserved.
The naphthalene ring system plays an important role in
both natural product1 and medicinal chemistry
research.2 As a result, new synthetic methods for the
preparation of naphthalenes are an active area of
research. In recent literature, several methods for the
ring construction of polyaromatic compounds have
been reported.3 Many of the recent contributions to this
field involve transition-metal-promoted ring construc-
tion. In 1996, Merlic described a procedure for the
synthesis of polyarenes via an electrocyclization reac-
tion of dienyne substrates.4 In a related paper, Iwasawa
reported the cyclization reaction of terminal aromatic
enynes R=H (Scheme 1) mediated by W(CO)5–THF.5
Both of these reactions are believed to proceed through
transition metal alkylidene complexes and are thus
restricted to cyclization of terminal alkynes. In addi-
tion, Yamamoto recently reported a single example of
an EtAlCl2-mediated intramolecular addition of a silyl
enol ether to an activated alkyne, which furnished the
desired 1-naphthol in moderate yield.6 Transition-
metal-mediated reactions are becoming more prominent
as methods for the synthesis of carbocyclic compounds
since they allow CꢀC bond formation to occur between
functionalities that otherwise are inert under conven-
tional conditions.7 Nucleophilic attack on transition
metal p-activated alkyne complexes has also been docu-
mented in the literature.8 Recently, Murai has disclosed
the cyclization of p-activated alkynes with electron-rich
aromatic nucleophiles.9 In this letter, we report the
construction of functionalized naphthalenes from vari-
ous aromatic enyne substrates via an intramolecular
6-endo-cyclization mediated by a number of transition
metal catalysts, including a stoichiometric version
which is promoted by silver(I) salts.
Initial investigations were focused on determining
which catalysts efficiently permit cyclization of silyl
enol ether 1a. A number of transition metal catalysts
were surveyed, including Wilkinson’s catalyst, which in
the presence of silver salts, served only to cleave the
silyl enol ether affording the corresponding ketone
without any evidence of cyclization.
OTBS
OTBS
OTBS
+
R
R
R
3f-h
2a-e, i
1a-i
Scheme 1. Transition-metal-promoted cyclization of alkynyl silyl enol ethers 1a–i (see Tables 1–3).
* Present address: DSM Catalytica Pharmaceuticals, 430 Ferguson Drive, Mountain View, CA 94043-5272, USA. Tel.: 650-940-6274; fax:
650-254-0153; e-mail: jdankwardt@mv.catalytica-inc.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01146-7

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J. W. Dankwardt / Tetrahedron Letters 42 (2001) 5809–5812
Wender has recently demonstrated the synthetic value
of [Rh(CO)2Cl]2 in transition-metal-mediated cycload-
dition reactions.10 Application of Wender’s catalyst sys-
tem to the current reaction resulted in clean cyclization
to afford the desired TBS-protected naphthol 2a in high
yield (Table 1, entry 2). Cyclization also occurred at
lower temperature (50 versus 90°C) under catalytic
conditions using [Rh(CO)2Cl]2 providing the naphthol
derivative 2a in 93% yield (Table 1, entry 1). A 1H
NMR study revealed that using stoichiometric
[Rh(CO)2Cl]2 in C6D6 at room temperature provided
pure TBS-protected naphthol 2a. No intermediates
The use of RhCl3 and CpRu(PPh3)2Cl resulted in recov-
ery of the silyl enol ether 1a with no apparent ring
closure occurring at 90°C. Benzannulation of 1a with
Rh(CO)2(acac) or [RuCl2(p-cymene)]2 at 100°C
afforded a mixture of starting material (1a) and the
corresponding cyclized product 2a (7/1 1a/2a for Rh
catalyst and 4.5/1 1a/2a for the Ru catalyst). The
cationic copper catalyst, Cu(MeCN)4PF6 provided a
complex and uncharacterized mixture of products with
no evidence of the desired naphthalene 2a being formed
1
by H NMR.
1
could be detected by H NMR under these conditions.
In the synthesis of TBS-protected naphthols 2, the
steric bulk of the substituent on the alkyne was varied
from R=H to R=t-Bu. Silyl enol ethers 1a–e,i with
R=Me, Bn, n-hexyl, and Ph cyclized smoothly provid-
ing the desired TBS-protected naphthols in 71–89%
yield (Table 2, entries 2–5). The unsubstituted alkyne 1i
also cyclized; however, the yield was lower than the
alkyl substituted systems (Table 2, entry 1). In general,
the sterically more demanding groups, such as t-butyl,
required higher temperatures for complete cyclization
to occur. In the [Rh(CO)2Cl]2 (10 mol%)-mediated
cyclization of the t-butyl silyl enol ether 1e at 130°C a
1/1 mixture of the cyclization product 2e and silyl enol
ether 1e was obtained in a combined yield of 68%. The
PtCl2 catalyst at 140°C (Table 2, entry 6) resulted in
efficient ring closure of 1e; however, reaction at lower
temperature and catalyst loading resulted in incomplete
conversion (10 mol% PtCl2, PhMe, 100°C, 2.1/1 mix-
ture 2e/1e, 66% combined yield). Benzannulation of 1e
at 130°C furnished a 4.2/1 mixture of 2e and 1e with 10
mol% PtCl2 catalyst.
A control experiment was run without any catalyst by
refluxing silyl enyne 1a in toluene. This experiment
1
resulted in complete recovery of starting material by H
NMR. Platinum(II) chloride as well as palladium(II)
catalysts gave the desired cyclization product 2a in high
yield (Table 1, entries 3–5). During the course of our
research, Murai reported the utility of [RuCl2(CO)3]2 in
carbocyclization reactions.9 Application of this catalyst
in the benzannulation reaction of the silyl enol ether 1a
at 80°C provided the desired product 2a; however,
about 10% unreacted starting material (1a) remained. It
was determined that increasing the temperature to
130°C allowed smooth cyclization to occur furnishing
2a in 93% yield (Table 1, entry 6). Catalytic amounts of
silver trifluoroacetate gave low yields of the benzannu-
lation product 2a and resulted mainly in recovery of
starting enol ether 1a. Cyclization of 1a ensued at room
temperature if
a
stoichiometric amount of
Ag(OCOCF3) is used in nitromethane (Table 1, entry
7). Cyclization of 1a in the presence of catalytic
11
amounts (5 mol%) of AuCl3 also provided the naph-
thol derivative 2a in an unoptimized 37% yield. Heating
1a with 9 mol% NiBr2 at 90°C gave a 1/1 mixture of the
TBS-protected naphthol 2a and starting material 1a.
The silyl alkynes (1f–h) also afforded TBS-protected
naphthol products (2f–h and 3f–h); however, in the case
of the rhodium complex, [Rh(CO)2Cl]2, silyl migration
from C3 to C4 was observed. The structure of the TMS
naphthol 3f was verified by conversion of the known
4-bromo-1-naphthol13 to the 4-trimethylsilylnaphthol
derivative 3f. In addition the coupling constant between
protons at C2 and C3 (J2,3=7.55 Hz) also indicates
migration of the trimethylsilyl group. All three silyl
substrates (1f–h) reacted efficiently with C3 to C4 silyl
Table 1. Benzannulation of silyl enol ether 1a (R=n-C6H13):
catalyst optimization12
Entry
Conditions
% Yield (2a)
1
2
3
4
5
6
7
9 mol% [Rh(CO)2Cl]2, PhMe, 50°C
5.5 mol% [Rh(CO)2Cl]2, PhMe, 90°C
8 mol% PtCl2, PhMe, 90°C
93
86
94
87
92
93
76
migration
with
the
organorhodium
complex,
[Rh(CO)2Cl]2. Reaction of the silyl substrates (1f–h)
with 10–15 mol% PtCl2 at 100–130°C provided mix-
tures of products. The more sterically hindered sub-
strates required higher temperatures and catalyst
loadings for complete consumption of the starting
10 mol% PdCl2, PhMe, 90°C
10 mol% Pd(PhCN)2Cl2, PhMe, 90°C
11 mol% [RuCl2(CO)3]2, PhMe, 130°C
1.1 equiv. Ag(OCOCF3), MeNO2, rt
1
material. From careful H NMR analysis the C3 and
Table 2. Transition metal cyclization with variation of the alkyne substituent
Entry
Enol ether
R
Conditions
% Yield (2)
1
2
3
4
5
6
1i
H
Me
CH2Bn
CH2Bn
Ph
10 mol% [Rh(CO)2Cl]2, PhMe, 110°C
10 mol% [Rh(CO)2Cl]2, PhMe, 110°C
10 mol% [Rh(CO)2Cl]2, PhMe, 110°C
1.1 equiv. Ag(OCOCF3), MeNO2, rt
10 mol% [Rh(CO)2Cl]2, PhMe, 100°C
17 mol% PtCl2, PhMe, 140°C
51
89
71
75
79
56
1b
1c
1c
1d
1e
t-Bu

J. W. Dankwardt / Tetrahedron Letters 42 (2001) 5809–5812
5811
C4 silyl naphthol derivatives were found to be the
major cyclization products; however, trace amounts of
1-dimethyl-tert-butylsilyloxynaphthalene from proto-
desilylation, was also produced with R=TMS and
TBS. Cyclization of 1g with PtCl2 afforded only the
silylated naphthol derivatives (2g and 3g) with no traces
of the proto-desilylated compound found in the crude
reaction mixture. In the case of the Pt(II)-mediated
cyclization, some cleavage of the TBS silyl enol ether
1f–h had occurred providing the corresponding methyl
ketone of 1. 2,6-Di-t-butyl-4-methylpyridine (1.1
equiv.) was added to the reaction mixture containing 15
mol% PtCl2 and silyl enol ether 1g with the hope that it
would minimize both the amount of silyl enol ether
producing the rhodium carbene complex 5, which
cyclizes to the final product 3f–h. As can be seen from
the data in Table 3, silyl migration improves as the
steric bulk of the silyl group increases. Thus, the driving
force for the silyl rearrangement is probably to relieve
the non-bonded interactions between the RMe2Si group
and RhLn in intermediate 4.
Expanding the synthetic method to compounds bearing
other electron-rich, unsaturated functionalities such as
a 2-substituted pyrrole is illustrated in Table 4. Cycliza-
tion of pyrrole 6a,b with either [Rh(CO)2Cl]2, PtCl2 or
AuCl311 provided high yields of the cyclization products
7a,b (Scheme 3).
1
hydrolysis as well as the C-desilylation; however, H
NMR analysis indicated that a mixture of cyclized
compounds (C3-TBS, C4-TBS and C-desilylated naph-
thol) and the acetophenone derivative were formed
under these conditions.14 In general, with PtCl2, the
major cyclization adducts were the non-migrated com-
pounds 2f and 2h. Cyclization of 1g with PtCl2 pro-
vided a nearly 1/1 mixture of the C3 and C4 silyl
naphthol derivatives (2g and 3g). Cyclization of the
TMS derivative 1f with 1.05 equiv. Ag(OCOCF3)
resulted in a mixture of the silyl enol ether 2f and the
acetophenone derived from 1. Palladium(II) catalysts
(PdCl2 and PdCl2(PhCN)2) did not provide any of the
desired cyclization products with the silyl alkynes (1g–
h).
In addition, a control experiment was performed under
thermal conditions without any catalyst. Thus, heating
the alkyne 6a in refluxing toluene for 14 h, followed by
analysis of the crude reaction mixture, indicated that no
1
reaction had taken place by H NMR.
Me
Me
N
N
transition metal
catalyst
toluene
90-130 °C
R
R
6a-b
7a-b
A proposed mechanism of the silyl migration utilizing
[Rh(CO)2Cl]2 is shown in Scheme 2. The key feature of
this rearrangement involves the silyl migration of 4
Scheme 3. Transition metal cyclization of alkynyl pyrroles
6a,b.
OTBS
OTBS
1f-h
3f-h
RhLn
+
C
RhLn
SiMe2R
+
SiMe2R
5
4
Scheme 2. A proposed mechanism for the silyl rearrangement of 1f–h.
Table 3. Rearrangement of silyl alkynes 1f–h
Entry
Enol ether
R
Catalyst
C4:C3 (NMR)
% Yield (3)
1
2
3
1f
1g
1h
SiMe3
SiMe2Ph
SiMe2t-Bu
10 mol% [Rh(CO)2Cl]2, 90°C
10 mol% [Rh(CO)2Cl]2, PhMe, 130°C
13 mol% [Rh(CO)2Cl]2, PhMe, 130°C
4.9/1
5.2/1
7.4/1
75
80
91
Table 4. Carbocyclization of alkynyl pyrroles 6a,b15
Entry
1
Substrate
R
Conditions
% Yield (7)
6a
Me
10 mol% [Rh(CO)2Cl]2, 90°C
9 mol% PtCl2, 90°C
1.1 equiv. Ag(OCOCF3), MeNO2, rt
10 mol% AuCl3, PhMe, 100°C
13 mol% PtCl2, PhMe, 110°C
75
94
69
97
77
80
2
6b
n-C6H13
13 mol% [Rh(CO)2Cl]2, PhMe, 130°C

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J. W. Dankwardt / Tetrahedron Letters 42 (2001) 5809–5812
In summary, the intramolecular transition-metal-medi-
ated cyclization of acetylenic silyl enol ethers16 and
pyrroles17 constitutes an efficient method for the con-
struction of substituted naphthalenes. The reaction is
promoted by a number of catalysts and has a wide
synthetic scope. In addition, [Rh(CO)2Cl]2-catalyzed
cyclization of organosilyl alkynes provides a unique
pathway to C4 silyl rearranged naphthalene derivatives
in high yield.
10. Wender, P. A.; Correa, A. G.; Sato, Y.; Sun, R. J. Am.
Chem. Soc. 2000, 122, 7815–7816 and references cited
therein.
11. Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem.
Soc. 2000, 122, 11553–11554.
12. The silyl enol ethers 1 were prepared from o-bromoace-
tophenone by Pd-mediated cross-coupling with the
appropriate alkyne followed by silyl enol ether formation
with TBSOTf (1.05 equiv.) and TEA (5 equiv.) in
dichloromethane. For key references, see: (a) Traditional
Sonogashira conditions for the palladium coupling were
utilized for the preparation of compounds 1a–c and 1f.
See references 3a and 5b; (b) The silyl alkynes (1g–h)
were coupled by a modified Fu–Buchwald procedure
using a higher catalyst loading (6 mol% PdCl2(PhCN)2
and 12.4 mol% P(t-Bu)3) and 2.0 equiv. alkyne, see:
Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G.
C. Org. Lett. 2000, 2, 1729–1731. Compounds 1d,e were
best prepared by a Negishi coupling of o-bromoacetophe-
none and the alkynylzinc chloride with 5–15 mol%
Pd(PPh3)4. The silyl enol ethers were prepared as
described above.
Acknowledgements
The author would like to thank Drs. Sharon
Dankwardt and Keith Walker (both of Roche Bio-
science) for proof-reading the manuscript. Also the
analytical department at Roche Bioscience is acknow-
ledged for obtaining some of the spectral data.
References
13. Carreno, M. C.; Garcia, R. J. L.; Sanz, G.; Toledo, M.
1. Neocarzinostatin and N1999-A2 both contain a naphtha-
lene ring as an important structural feature. See: (a)
Smith, A. L.; Nicolaou, K. C. J. Med. Chem. 1996, 39,
2103–2117; (b) Kobayashi, S.; Reddy, R. S.; Sugiura, Y.;
Sasaki, D.; Miyagawa, N.; Hirama, M. J. Am. Chem.
Soc. 2001, 123, 2887–2888; (c) Michellamines and related
alkaloids also embody a naphthalene ring as an integral
fragment of their structure. See: Lipshutz, B. H.; Keith, J.
Angew. Chem., Int. Ed. 1999, 38, 3530–3533.
2. For example, naproxen utilizes a naphthalene ring as part
of its pharmacophore. See: Harrington, P. J.; Lodewijk,
E. Org. Process Res. Dev. 1997, 1, 72–76 and references
cited therein.
3. (a) For anionic cyclizations, see: Makra, F.; Rohloff, J.
C.; Muehldorf, A. V.; Link, J. O. Tetrahedron Lett. 1995,
36, 6815–6818; (b) For acid-promoted cyclization reac-
tions, see: Ciufolini, M. A.; Weiss, T. J. Tetrahedron Lett.
1994, 35, 1127–1130.
4. Merlic, C. A.; Pauly, M. E. J. Am. Chem. Soc. 1996, 118,
11319–11320.
5. (a) Maeyama, K.; Iwasawa, N. J. Am. Chem. Soc. 1998,
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Chem. 1999, 64, 1344–1346.
6. Imamura, K.-i.; Yoshikawa, E.; Gevorgyan, V.;
Yamamoto, Y. Tetrahedron Lett. 1999, 40, 4081–4084.
7. For reviews on transition-metal-mediated cyclization
reactions, see: (a) Saito, S.; Yamamoto, Y. Chem. Rev.
2000, 100, 2901–2915; (b) Lautens, M.; Klute, W.; Tam,
W. Chem. Rev. 1996, 96, 49–92; (c) Ojima, I.; Tzamariou-
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635–662.
8. Collman, J. P.; Hegedus, L. S.; Norton, J. R.; Finke, R.
G. Principles and Applications of Organotransition Metal
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A.; Urbano, A. Synlett 1997, 1241–1242.
14. PtCl2 cyclization of 1g (R=SiPhMe2) provided a 1/1.06/
1.91/2.47 mixture of acetophenone/silyl enol ether/C3
silyl naphthol/C4 silyl naphthol. Cyclization of 1f (R=
TMS) provided a 2.18/1.17/1.00 mixture of C3 silyl naph-
thol/C4
silyl
naphthol/C-desilylated
naphthol.
Cyclization of 1h (R=TBS) with PtCl2 provided a com-
plex mixture of products comprised of a 2.16/1.12/3.68/
1.00/1.60 of acetophenone/silyl enol ether/C3 silyl
naphthol/C4 silyl naphthol/C-desilylated naphthol. In the
presence of 2,6-di-t-butyl-4-methylpyridine furnished a
4.72/4.05/1.00/2.32 mixture of acetophenone/C3 silyl
naphthol/C4 silyl naphthol/C-desilylated naphthol
derivative.
15. The alkynyl pyrroles 6a,b were prepared from 1-bromo-2-
iodobenzene by a Sonogashira and Negishi coupling pro-
cedures. See reference 5b.
16. Typical procedure (Table 1, entry 3): cyclization of 1a
(R=n-C6H13). To a toluene (15 mL) solution of the silyl
enol ether 1a (63.6 mg, 0.186 mmol) was added PtCl2 (3.9
mg, 0.015 mmol) under Ar. The resulting mixture was
heated at 90°C (oil bath temperature) for 15 h. The
reaction mixture was cooled to rt and concentrated under
vacuum. Crude 1H NMR indicated formation of the
desired product in >95% purity. Purification was accom-
plished by silica-gel chromatography (1/4 ethyl acetate–
hexane) to afford 60.0 mg of product 2a (94% yield).
17. Typical procedure (Table 4, entry 2): cyclization of 6b. To
a toluene (13 mL) solution of the pyrrole 6b (106.5 mg,
0.402 mmol) was added [Rh(CO)2Cl]2 (21 mg, 0.054
mmol) under Ar. The resulting mixture was heated at
130°C (oil bath temperature) for 15 h. The reaction
mixture was cooled and concentrated under reduced pres-
1
sure. Crude H NMR indicated formation of the desired
product 7b. Purification was accomplished by preparative
thin-layer chromatography (silica gel, 3% ether–hexane)
to afford 85.2 mg of product 7b (80% yield).
9. Chatani, N.; Inoue, H.; Ikeda, T.; Murai, S. J. Org.
Chem. 2000, 65, 4913–4918.
.