Preparation of phenalenes and hydronaphthacenes through tandem alkyne Fischer-carbene complex coupling and inter- or intra-molecular Diels-Alder reactions

Article abstract of DOI:10.1016/j.tetlet.2011.06.006

The rapid construction of phenalenes through the reaction of 8-alkynyltetralones with Fischer-carbene complexes followed by either an inter- or intra-molecular Diels-Alder reaction is presented. As a showcase of the synthetic utility of this process, the rapid construction of polycyclic ring systems containing the tetracycline core has been demonstrated through an iterative application of this reaction sequence.

Full text of DOI:10.1016/j.tetlet.2011.06.006

Tetrahedron Letters 52 (2011) 4182–4185
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation of phenalenes and hydronaphthacenes through tandem alkyne
Fischer–carbene complex coupling and inter- or intra-molecular Diels–Alder
reactions
⇑
Rajesh Kumar Patti, Shaofeng Duan, Zhipeng Wang, James W. Herndon
Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM 88003, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The rapid construction of phenalenes through the reaction of 8-alkynyltetralones with Fischer–carbene
complexes followed by either an inter- or intra-molecular Diels–Alder reaction is presented. As a show-
case of the synthetic utility of this process, the rapid construction of polycyclic ring systems containing
the tetracycline core has been demonstrated through an iterative application of this reaction sequence.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 19 April 2011
Accepted 2 June 2011
Available online 13 June 2011
Keywords:
Carbene complexes
Isobenzofurans
Cycloaddition
Phenalenes
Alkynes
Naphthacenes
1. Introduction
formation step. In this manuscript the synthesis of 8-alkynyl-2-
tetralone derivatives and their subsequent reaction with Fischer–
The phenalene ring system comprises the core of several natural
products, including the pseudopterosins and helioporins, com-
pounds which possess antiinflammatory1 and antitumor2 activi-
ties. Non-natural phenalenes have been evaluated as dopamine
receptors.3 Higher annulated aromatic species (e.g., pyrenes and
benzo analogs) form the core structures of several antibiotics4
and of various fluorophores are useful as biological probes.5 Phena-
lenes are substructures of benzo[a]pyrene, which is one of the
most persistent environmental carcinogens and synthetic benzo[a]-
pyrene derivatives are frequently required to assess mechanisms of
carcinogenesis.6 The phenalene ring system is most commonly ac-
cessed through intramolecular electrophilic aromatic substitution
reactions7 and occasionally through Diels–Alder processes.8 The
phenalene ring system is potentially accessible in a single reaction
event through a recently-discovered sequence involving tandem
carbene complexes is presented. An iterative version of this
process leads to compounds possessing the hydronaphthacene
skeleton, a ring system that is potentially useful in the develop-
ment of organic semiconductors.13
2. Results and discussion
The preparation of the o-alkynylbenzocycloalkanones (1, 3, 5)
used in this study from commercially-available starting materials
is depicted in Scheme 2. Alkynyltetralone 1 was prepared from
1-amino-5,6,7,8-tetrahydronaphthalene via the known transfor-
mation to 8-bromo-1-tetralone14 followed by Sonogashira cou-
pling. This method, though lengthy, is superior to the alternative
preparation of 8-bromo-1-tetralone from
a
-tetralol,15 since the
carbene complex alkyne coupling9 / isobenzofuran formation10
/
ortho-metallation process would never go to completion and sepa-
ration of tetralol and bromotetralol was quite difficult. The five-
membered ring analog 3 was prepared from 2-bromobenzoyl
chloride using Nazarov cyclization as a key step.14 The bis(alkyne)
derivative 5 was synthesized from 1,3-dibromobenzene through
regioselective lithiation,16 followed by formylation and double
Sonogashira coupling.
Initial studies focused on the systems depicted in Scheme 3,
involving the three-component coupling of alkynyltetralone 1,
methylcarbene complex 7, and either dimethyl acetylenedicarbox-
ylate (DMAD) (9) or dimethyl fumarate. A complex reaction
and Diels–Alder reaction (Scheme 1).11 Operationally this is a very
simple process involving only thermolysis and avoids a multi-step
series of reactions required to perform similar transformations
without chromium.12 Formation of phenalenes requires the use
of alkynylbenzenes fused to cyclic ketones (A), which are likely
ideal substrates for isobenzofuran formation since the carbonyl
group is locked in the orientation required for the key C–O bond
⇑
Corresponding author. Fax: +1 575 646 2649.
E-mail address: jherndon@nmsu.edu (J.W. Herndon).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.006

R. K. Patti et al. / Tetrahedron Letters 52 (2011) 4182–4185
4183
R1
TMS
Dioxane
100 oC
1. Ac2O
2. KMnO4
3. Aq. NaOH
4. NaNO2 / HCl
5. CuBr
NH2
Cr(CO)5
OMe
B
O
O
+
R2
A
1
6. Sonogashira
2
OMe
TMS
OMe
R2
Noncyclic
Carbonyl
R1
R1
R2
Br
O
1. CH2=CHTMS / AlCl3
COCl
Cr(CO)4
O
Cr(CO)4
Y
2. H2SO4
3. Sonogashira
O
3
4
C
D
TMS
Br
1. LDA, then DMF
2. Double Sonogashira
OMe
R2
CHO
R1
Br
Cr(CO)4
E = COOMe
throughout manuscript
TMS
6
5
O
E
Scheme 2.
Prior Work - Carbonyl compound is acyclic
This Work - Carbonyl compound is cyclic
from 1 would never go to completion, and the reaction was initi-
ated using a 2:3 mixture of the ketone and hydrazone as the start-
ing material.
-Cr(CO)4
OMe
OMe
E
E
OMe
R2
R1
Ketone 1 was also tested as a substrate for the net [5+5]-cyclo-
addition process employing the butenylcarbene complex 12a (see
Scheme 4). In this case the reaction was highly efficient leading
to the tetracycle 15. The anticipated product is simple dehydration
product 14,11 which undergoes an unanticipated oxidation under
the reaction conditions. Interestingly, the product containing the
phenanthrene ring was obtained when the reaction was conducted
in anhydrous dioxane, however, high yields of alcohol 16 were ob-
tained when the reaction was conducted in dioxane/water mix-
tures.20 This latter process was completely diastereoselective. The
stereochemistry of compound 16 was assigned based on the
known exo preference for intramolecular six-membered ring-
forming reactions involving isobenzofurans,21 which would afford
the depicted stereoisomer after the ring opening.
R1
R1
R2
R2
E
E
Cr(0)
O
O
E
E
F
H
G
Me Me
Me
HO
Me
O
HO
HO
H
OH
Me
Me
OH
O
OH
Pseudopterosin A
aglycone
Resistomycin
TMS
Scheme 1.
MeO
TMS
Me
Cr(CO)5
OMe
7
O
O
E
E
Me
mixture resulted when all three components were present at the
onset of the reaction, presumably due to multiple components
present in solution that are reactive to carbene complexes.17 If a
sequential addition involving (1) reaction of the carbene complex
and alkyne at 100 °C for 1 h and (2) addition of DMAD was em-
ployed, a surprisingly excellent yield of phenalene-containing
product 11 was observed after silica gel purification. Initially, an
efficient process was not anticipated under these conditions since
9
Dioxane / 80 o
C
1
8
O
Me
MeO
TMS
Me
E
E
E
E
isobenzofurans bearing
a-hydrogens are unstable with respect to
conversion to alkylidenephthalans,18 and success thus requires this
critical intermediate to survive intact for more than 1 h at 100 °C.
Aromatized products analogous to naphthalene 11 have been ob-
tained directly using N,N-dimethylhydrazones,19 however the yield
of 11 was lower using the N,N-dimethylhydrazone of ketone 1. A
problem with this alternate strategy is that hydrazone formation
O
76%
11
10
Scheme 3.

4184
R. K. Patti et al. / Tetrahedron Letters 52 (2011) 4182–4185
TMS
TMS
Cr(CO)5
OMe
Cr(CO)5
OMe
MeO
R
H
O
TMS
O
CHO
12a
12a R = H
12b R = Me
9:1 Dioxane:Water / 85 oC
Dioxane / reflux or
9:1 Dioxane:Water / 85 oC
1
TMS
13
5
O
TMS
O
H
H
PCC
TMS
12a,b
MeO
OH
O
TMS
O
65%
(from 5)
TMS
22
TMS
21
H
14
TMS
OH
MeO
O
O
H
68%
H
O
TMS
16
OH
TMS
R
15
R
75%
Scheme 4.
25
23
TMS
TMS
O
+
OMe
O
O
Unfortunately, reactions involving the related five-membered
ring systems were unsuccessful (Scheme 5). Coupling of alkynylin-
danone 3 and carbene complex 12a afforded a complex reaction
mixture where the pattern for a monosubstituted alkene is a pre-
dominant feature of the crude 1H NMR spectrum. This observation
suggests a failure in the formation of the isobenzofuran intermedi-
ate,20 which is likely due to ring strain.22 An examination of the
isodesmic reactions in Scheme 5 (based on DFT calculations
employing the B3LYP method and 6-31G(d) basis sets) reveals that
formation of the five-membered fused ring system 20 is unfavor-
able relative to the six-membered fused ring-fused system 18.
The energy for the isodesmic reaction is 26 kcal/mol greater in
the five-membered ring case. A simple MM2 calculation revealed
the angle strain in the five-membered fused ring system to be
34.1 kcal/mol while the strain in the six-membered ring case was
considerably less at only 15.5 kcal/mol.
H
H
TMS
TMS
OH
O
R
R
24
TMS
TMS
26
OMe
O
12 & 23-26
a R = H
b R = Me
25:26
R
H
Me
3:2 (74%)
1:5 (84%)
Scheme 6.
This novel [5+5]-cycloaddition reaction was also examined iter-
atively as a synthetic route to the hydronaphthacene ring system.
The initial product (21, Scheme 6) of net [5+5]-cycloaddition
employing bis(alkyne) derivative 5 and butenylcarbene complex
12a is an incipient alkynyltetralone system, and thus the iterative
[5+5]-cycloaddition can provide rapid access to this medicinally-
important ring system. The crude product from cycloaddition of
bis(alkyne) 5 and carbene complex 12a was subjected to oxidation
with PCC, affording alkyne-dione 22, followed by an additional
[5+5]-cycloaddition sequence. This reaction sequence resulted in
a 3:2 mixture of diastereomers (out of four possible) favoring the
symmetrical isomer 25a. The stereoisomers arise through exo
selective intramolecular Diels–Alder reaction, which proceeds with
relative asymmetric induction from the only stereocenter present
in 22 to afford either of intermediates 23 or 24. The stereochemis-
try of the major isomer (25a) was assigned based on the appear-
ance of only 13 signals in the 13C NMR spectrum, compared with
21 signals in the unsymmetrical minor isomer (26a). This chro-
mium(0-6-0)-based synthesis of the tetracyclines was also demon-
strated for a system employing two different carbene complexes.
Reaction of alkynone 22 with methylbutenylcarbene complex
12b afforded a 5:1 mixture of diastereomers. The structure of the
minor isomer was determined by X-ray crystallography and was
determined to be stereoisomer 25b (see Supplementary data).
TMS
Cr(CO)5
OMe
O
12a
Complex Reaction Mixture
3
CH3
ΔE = +45 kcal/mol
ΔE = +71 kcal/mol
+ H2
O
O
18
17
CH3
+ H2
O
O
20
19
Scheme 5.

R. K. Patti et al. / Tetrahedron Letters 52 (2011) 4182–4185
4185
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c,d-unsaturated carbene
complexes 12a and b proceeded with the opposite stereoselectivity
in the [5+5]-cycloaddition event. The carbene complex featuring a
1,1-disubstituted alkene group likely affords an alkene-isobenzofu
ran that undergoes
a slower and more thermodynamically
selective Diels–Alder reaction due to the more electron rich nature
of the dienophile.
In summary, tandem isobenzofuran generation/Diels–Alder
processes that employ 8-alkynyltetralone systems are quite effi-
cient. In these systems one can employ ketones as substrates in
sequential addition processes due to the enhanced lifetime of the
isobenzofuran intermediate, despite the presence of hydrogens
poised for rearrangement to alkylidenephthalans. Use of dialkylben-
zaldehydes allows for a rapid gain in molecular complexity through
an iterative process leading to selective formation of two out of the
possible four diasteromers in the resulting complex hydronaphtha-
cene ring systems in three reaction events.
3. Experimental
See Ref. 23.
Acknowledgments
This work was supported by the SCORE program of NIH
(SC1GM083693). The Bruker X8 X-ray diffractometer was
purchased via an NSF CRIF:MU award to The University of New
Mexico, CHE-0443580. We thank Dr. Eileen Duesler for X-ray
data collection. We thank Professor William Maio for helpful
comments.
15. Lebedev, A. Y.; Khartulyari, A. S.; Voskoboynikov, A. Z. J. Org. Chem. 2005, 70,
596–602.
Supplementary data
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Heterocycl. Chem. 1999, 73, 1–96.
Supplementary data (general experimental, X-ray parameters
and ORTEP drawing for compound 25b, photocopies of NMR spec-
tra for new compounds employed in successful investigations, SCF
energies for compounds in Scheme 5, and a cif file for the X-ray
structure of 25b) associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2011.06.006.
22. Early investigators of 6,5,5-tricyclic ring systems declared this ring system to
be ‘unsynthesizable’ until the first successful synthesis. Rapoport, H.; Pasky, J.
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References and notes
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