Synthesis of benzocycloheptanones through coupling of δ,- unsaturated chromium carbene complexes and 2-alkynylbenzoyl derivatives

Article abstract of DOI:10.1021/ol200825j

The coupling of pentenylcarbene complexes and 2-alkynylbenzoyl derivatives affords naphthocycloheptanones in a single step involving simultaneous construction of both the seven-membered ring and one of the aromatic rings. Aryl tethered systems undergo intramolecular cyclopropanation.

Full text of DOI:10.1021/ol200825j

ORGANIC
LETTERS
2011
Vol. 13, No. 11
2848–2851
Synthesis of Benzocycloheptanones
through Coupling of δ,ε-Unsaturated
Chromium Carbene Complexes and
2-Alkynylbenzoyl Derivatives
Rajesh Kumar Patti, Kristopher V. Waynant, and James W. Herndon*
Department of Chemistry and Biochemistry, New Mexico State University, MSC 3C,
Las Cruces, New Mexico 88003, United States
jherndon@nmsu.edu
Received March 29, 2011
ABSTRACT
The coupling of pentenylcarbene complexes and 2-alkynylbenzoyl derivatives affords naphthocycloheptanones in a single step involving
simultaneous construction of both the seven-membered ring and one of the aromatic rings. Aryl tethered systems undergo intramolecular
cyclopropanation.
The hydrophenanthrene carbon skeleton (i.e., E and F,
Scheme 1) is readily accessed through coupling of 2-alky-
nylbenzaldehyde derivatives (A) and γ,δ-unsaturated
chromium carbene complexes (B, n = 1).1 This net [5 þ
5]-cycloaddition approach to hydrophenanthrenes results
from a series of reactions involving (1) regio- and stereo-
selective carbeneꢀalkyne coupling,2 (2) carbonyl ylide
formation,3 (3) isobenzofuran C formation,4 and (4) in-
tramolecular DielsꢀAlder reaction. Subsequent transfor-
mations of the strained and electronically activated
oxanorbornenes D leads to the observed products, dihydro-
phenanthrenes1 F (via dehydration and hydrolysis) or
hydrophenanthrenones5 E(via ring-opening and hydrolysis).
Intramolecular DielsꢀAlder reactions of isobenzofurans and
unactivated alkenes are limited by the instability of isoben-
zofurans, and nearly all of the examples involve the forma-
tion of five- and/or six-membered ring systems.6 Higher
yields and a greater substrate range are generally ob-
served with chromium-generated systems compared to acid-
generated systems;7 however even in the chromium-based
systems primarily six-membered ring formation has been
documented.8 This manuscript focuses on the formation of
seven-membered rings employing this reaction. Furan and/
or isobenzofuran DielsꢀAlder reactions that result in seven-
membered and larger rings are comparatively rare.9 Likely
(6) (a) Kuninobu, Y.; Nishina, Y.; Takai, K. Tetrahedron 2007, 63,
8463–8468. (b) Padwa, A.; Eidell, C. K. ARKIVOC 2003, 14, 62–76. (c)
Peters, O.; DeBaerdemaeker, T.; Friedrichsen, W. J. Chem. Soc., Perkin
Trans. 1 1999, 59–69.
(1) Recent examples: (a) Camacho-Davila, A.; Ranchigoda, L. S. R.;
Herndon, J. W. Tetrahedron 2010, 66, 4954–4960. (b) Jana, G. P.;
Mukherjee, S.; Ghorai, B. K. Synthesis 2010, 3179–3187.
(2) For the most detailed discussion of this issue, see: McCallum,
J. S.; Kunng, F. A.; Gilbertson, S. R.; Wulff, W. D. Organometallics
1988, 7, 2346–2360.
(3) Herndon, J. W.; Wang, H. J. Org. Chem. 1998, 63, 4564–4565.
(4) For a review on the reactivity of isobenzofurans, see: Friedrichsen,
W. Adv. Heterocycl. Chem. 1999, 73, 1–96.
(7) For a direct comparison of similar systems, see: Duan, S. F.;
Cress, K.; Waynant, K.; Ramos-Miranda, E.; Herndon, J. W. Tetra-
hedron 2007, 63, 2959–2965.
(8) In one case, a seven-membered ring forming process was observed
using an alternate tethering scheme; however the yield was considerably
lower than the six-membered ring cases. Luo, Y.; Herndon, J. W.
Organometallics 2005, 24, 3099–3103.
(9) (a) Bobeck, D. R.; France, S.; Leverett, C. A.; Sanchez-Cantalejo,
F.; Padwa, A. Tetrahedron Lett. 2009, 50, 3145–3147. (b) Padwa, A.;
Lynch, S. M.; Mejia-Oneto, J. M.; Zhang, H. J. Org. Chem. 2005, 70,
2206–2218.
(5) For the latest example, see: Menon, S.; Sinha-Mahapatra, D. K.;
Herndon, J. W. Tetrahedron 2007, 63, 8788–8793.
r
10.1021/ol200825j
Published on Web 05/09/2011
2011 American Chemical Society

complications in this investigation include (1) competing
intramolecular cyclopropanation,10 (2) competing alkene
migration,11 and (3) a slower intramolecular DielsꢀAlder
event, thus allowing for competing isobenzofuran
decomposition.
this reaction for the preparation of the more challenging
seven-membered ring systems is investigated.
Scheme 2
Scheme 1
Alkene-containing carbene complexes (1 and 2, Scheme 2)
were synthesized from known or commercially available
compounds according to the Fischer synthetic routes de-
picted in Scheme 2. The organolithium reagents were gener-
ated through reaction of the bromides with lithium metal
wherever possible due to safety concerns. In more sluggish
cases, lithiation of the iodide with tert-butyllithium was
employed. Competing Bailey cyclization of the organo-
lithium intermediates16 was not a problem under the condi-
tions employed. The aryl-tethered carbene complexes were
prepared from 2-bromobenzyl bromide through halogen
ꢀmetal exchange followed by analogous conversion to the
carbene complex. Compound 2a was a very unstable com-
pound and had to be used immediately after its synthesis.
The first reaction examined was the coupling of alky-
nylbenzophenone derivative 5a (Scheme 3) with carbene
complex 1a. The benzophenone derivative 5a had proven
to be the most reliable substrate in related [5 þ 5]-cycload-
dition processes17 owing to the enhanced stability of
arylisobenzofuran intermediates. After treatment of the
crude reaction mixture with aqueous HCl, the naphthalene
derivative 7a was isolated in 77% yield. The more challen-
ging reaction, coupling of complex 1a alkynylbenzalde-
hyde derivative 5b, was examined under a variety of
conditions. Thermolysis in dioxane followed by treatment
with acid led to naphthocycloheptanone 7b in 73% yield.
As noted in previous manuscripts, addition of water17 or
collidine1 to [5 þ 5]-cycloaddition reactions often led to
improved yields of adducts. Addition of either of these
additives led to uncyclized compounds tentatively assigned
asalkylidenephthalans (8b/9b), which result from a net 1,7-
hydride shift of the vinylisobenzofuran intermediate7 and
were often produced when a carbene complex incapable
of the DielsꢀAlder step was employed.18 In related
The coupling of δ,ε-unsaturated carbene complexes
(B, n = 2) and alkynylbenzaldehydes would hypothetically
lead to seven-membered rings fused to a naphthalene ring
system (F, n = 2). Benzo-fused cycloheptanones and their
simple derivatives are a very important structural feature
in numerous medicinal compounds, including the anti-
HIV drug TAK-779,12 intermediates for colchicine syn-
thesis,13 numerous experimental anticancer drugs,14 and
treatments for neurodegenerative disorders.15 The title
reaction is a two-component coupling where a diverse
array of synthetic routes exists for both of the coupling
partners. The basic coupling process is an intermolecular
coupling requiring no preorganization of the reactants and
thus is inherently versatile compared to any process limited
to intramolecular systems. In this manuscript, the use of
(10) (a) Alvarez-Toledano, C.; Rudler, H.; Daran, J. C.; Jeannin, Y.
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Ogawa, Y.; Meguro, K.; Fujino, M. Proc. Natl. Acad. Sci. U.S.A.
1999, 96, 5698–5703. (b) Westby, M.; van der Ryst, E. Antiviral
Chemistry and Chemotherapy 2005, 16, 339–354.
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R. L. J. Am. Chem. Soc. 1959, 81, 6341–6342.
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Chem. 2008, 16, 8161–8171. (b) Tarnus, R. C.; Defoin, A.; Albrecht, S.;
Maiereanu, A.; Faux, N.; Pale, P.; Fr. Demande (2008), FR 2908131 A1
20080509.
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(b) Satoh, Y.; Hatori, C.; Ito, H. Bioorg. Med. Chem. Lett. 2002, 12, 1009–
1011. (c) Itani, H.; Ito, H.; Sakata, Y.; Hatakeyama, Y.; Oohashi, H.;
Satoh, Y. Bioorg. Med. Chem. Lett. 2002, 12, 799–802. (d) Liu, Y.;
(16) Bailey, W. F.; Nurmi, T. T.; Patricia, J. J.; Wang, W. J. Am.
Chem. Soc. 1987, 109, 2442–2448.
(17) Li, R.; Camacho-Davila, A.; Herndon, J. W. Tetrahedron Lett.
€
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Mellin, C.; Bjork, L.; Svensson, B; Csoregh, I.; Helander, A.; Kenne, L.;
2005, 46, 5117–5120.
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Anden, N. E.; Hacksell, U. J. Med. Chem. 1989, 32, 2311–2318. (e)
Hacksell, U.; Arvidsson, L. E.; Svensson, U.; Nilsson, J. L. G.;
(18) (a) Jiang, D.; Herndon, J. W. Org. Lett. 2000, 2, 1267–1269. (b)
Duan, S.; Cress, K.; Waynant, K.; Ramos-Miranda, E.; Herndon, J. W.
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Org. Lett., Vol. 13, No. 11, 2011
2849

six-membered ring-forming processes, competition
from this reaction pathway was seldom an issue. A
likely explanation for these results is that the seven-
membered ring process is slower than the previously
reported six-membered ring-forming process, and the
1,7-hydrogen shift is the preferred fate of the isoben-
zofuran intermediate. Unfortunately, all attempts to
isolate a single derivative of 6b prior to HCl treatment
were unsuccessful. This might be attributed to a lack
of endoexo selectivity in the DielsꢀAlder reaction
using the longer-tethered system or could be due to a
mixture of ketones and enol ethers, and their respec-
tive protiodesilylation products prior to the hydroly-
sis step.
Scheme 3
Several different examples are presented in Table 1,
which vary in composition of the carbene complex tether,
the alkyne substituent, the benzene ring substituents, and
the carbonyl group. As noted in Table 1, the reaction in
dioxane is unaffected by all of these variables. Silylated
alkynes and alkyl-aryl alkynes all produce the naphthocy-
cloheptanone in similar yields; however the yields were
slightly lower using a terminal alkyne (entry 4). The simple
benzene ring substrates and the one substrate featuring a
highly electron-rich aromatic ring (entry 7) work equally
effectively. The yields for the carbene complex featuring a
gem-dimethyl group in the tether (entries 3, 4, and 8) are
equal to that for the carbene complex featuring the un-
substituted tether. It appears as though any steric disad-
vantage has been offset by a favorable gem dialkyl effect.
Use of the propargylic ester 5e (entry 6) led to the elimina-
tion product, methylenecycloheptanone 10. A single ex-
ample afforded the enone-alcohol derivative 11 (entry 5),
which only afforded the naphthalene derivative 7e with
more vigorous HCl treatment. In compound 11, the
hydrogen noted as HA appears as a doublet of doublets
(if D2O was added to the chloroform NMR) with coupling
constants of 12.0 and 3.7 Hz, which suggests that it is in an
axial orientation. The indicated stereochemistry is consis-
tent with complete exo selectivity in the intramolecular
Table 1. Preparation of Naphthocycloheptanones through Coupling of δ,ε-Unsaturated Carbene Complexes and 2-Alkynylbenzoyl
Systems
entry
reactants
R1
R2
R3
R4
product
yield %
1
1a þ 5a
1a þ 5b
1b þ 5b
1b þ 5c
1a þ 5d
1a þ 5e
1a þ 5f
1b þ 5g
H
TMSa
TMSa
TMSa
H
Ph
H
H
7a
7b
7c
7c
11
10
7g
7h
77
73
75
62
78
74
76
80
2
H
H
3
Me
Me
H
H
H
4
H
H
5b
6c
7
n-Bu
H
H
H
CH2OAc
TMSa
TMSa
H
H
H
H
OMe
H
8
Me
Me
a R2 = H in 7 when R2 = TMS in 5. b The exclusive product was the alcohol derivative 11. c The exclusive product was elimination product 10.
2850
Org. Lett., Vol. 13, No. 11, 2011

DielsꢀAlder step, even in the longer tethered systems
with alkyne 5b led to the simple tetralone derivatives 13
(Scheme 4) after HCl treatment. The yields and product
distributions are identical, regardless of whether the alkyne
is present. A likely mechanism for the formation of these
compounds involves intramolecular cyclopropanation10b
followed by acid-catalyzed ring-opening of the alkoxycy-
clopropane derivatives.20 In one case the cyclopropane 12b
was isolated and leads to R-methyltetralone (13b) upon
exposure to acid.
employed in these studies.19
Scheme 4
In summary, we have presented a versatile two-compo-
nent coupling approach to form naphthalene-fused cyclo-
heptanones in a net [5 þ 6]-cycloaddition process, where
both the seven-membered ring and one of the benzene rings
are constructed in a single reaction event. The reaction
proceeds in good yields for all systems examined employing
sp3 carbons in the tether; however aryl-containing tethers
undergo rapid intramolecular cyclopropanation in prefer-
ence to any intermolecular coupling with alkyne groups.
All attempts to make an eight-membered ring using this
methodology failed. Reaction of the hexenylcarbene com-
plex 1c with either of the substrates 5a or 5b resulted in
products where no DielsꢀAlder reaction occurred. The
crude 1H NMR spectra exhibited substantial absorptions
and δ 5.9 and δ 5.0, which is indicative of a monosubstituted
alkene group. The reactions employing the arylcarbene
complexes 2a and 2b did not result in alkyne-coupled
products. Thermolysis of either of these carbene complexes
Acknowledgment. This work was supported by the
SCORE program of the NIH (SC1GM083693).
Supporting Information Available. Complete experi-
mental procedures and photocopies of 1H and 13C NMR
spectra for compounds 1, 2, 7, 10, 11, and 12b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) For a more detailed discussion of this issue see the Supporting
Information.
(20) (a) Sugimura, T.; Futagawa, T.; Yoshikawa, M.; Tai, A. Tetra-
hedron Lett. 1989, 30, 3807–3810. (b) Sugimura, T.; Futagawa, T.; Tai,
A. Tetrahedon Lett. 1988, 29, 5775–5778.
Org. Lett., Vol. 13, No. 11, 2011
2851