Rhodium-catalyzed C-H bond activation/[4 + 2] annulation/aromatization cascade to produce phenol, naphthol, phenanthrenol, and triphenylenol derivatives

Article abstract of DOI:10.1021/ol300234g

It has been established that a cationic rhodium(I)/dppp complex catalyzes the aldehyde C-H bond activation/[4 + 2] annulation/aromatization cascade to produce phenol, naphthol, phenanthrenol, and triphenylenol derivatives from readily available conjugated alkynyl aldehydes and alkynes.

Full text of DOI:10.1021/ol300234g

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1492–1495
Rhodium-Catalyzed CꢀH Bond
Activation/[4 þ 2] Annulation/
Aromatization Cascade To Produce
Phenol, Naphthol, Phenanthrenol, and
Triphenylenol Derivatives
Daiki Hojo and Ken Tanaka*
Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of
Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
tanaka-k@cc.tuat.ac.jp
Received January 30, 2012
ABSTRACT
It has been established that a cationic rhodium(I)/dppp complex catalyzes the aldehyde CꢀH bond activation/[4 þ 2] annulation/aromatization
cascade to produce phenol, naphthol, phenanthrenol, and triphenylenol derivatives from readily available conjugated alkynyl aldehydes and
alkynes.
The [4 þ 2] annulation of five-membered acylmetal
intermediates with alkenes or alkynes is a valuable method
for the synthesis of six-membered carbonyl compounds.1
Five-membered acylmetal intermediates can be generated
through the reactions of transition-metal carbonyl com-
plexes withalkynes2,3 and the CꢀC bond cleavage of cyclo-
butenediones4,5 or cyclobutanones6,7 with transition-metal
complexes. However, these strategies suffer from the toxi-
city of transition-metal carbonyl complexes or the difficult
preparation of cyclobutenediones and cyclobutanones.
Recently, convenient generation of five-membered acyl-
metal intermediates has been reported in the reactions of
benzo-fused six-membered carbonyl compounds with
nickel complexes through elimination of small organic
fragments8a,b or acyl migration,8c while the atom replace-
ment strategy conceptually lacks atom economy.8a,b
(1) For reviews of transition-metal-catalyzed [4 þ 2] carbocyclization
reactions, see:(a) Robinson, J. E. In Modern Rhodium-Catalyzed Or-
ganic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, Germany, 2005;
p 241. (b) Yet, L. Chem. Rev. 2000, 100, 2963. (c) Mehta, G.; Singh, V.
Chem. Rev. 1999, 99, 881. (d) Ojima, I.; Tzamarioudaki, M.; Li, Z.;
Donovan, R. J. Chem. Rev. 1996, 96, 635. (e) Lautens, M.; Klute, W.;
Tam, W. Chem. Rev. 1996, 96, 49. (f) Schore, N. E. Chem. Rev. 1988, 88,
1081.
(2) For a review, see:Liebeskind, L. S.; Baysdon, S. L.; South, M. S.;
Iyer, S.; Leeds, J. P. Tetrahedron 1985, 41, 5839.
(3) (a) Reppe, W.; Vetter, H. Justus Liebigs Ann. Chem. 1953, 582,
133. (b) Maruyama, K.; Shio, T.; Yamamoto, Y. Bull. Chem. Soc. Jpn.
1979, 52, 1877. (c) Foust, D. F.; Rausch, M. D. J. Organomet. Chem.
1982, 239, 321. (d) Cabrera, A.; Mondragon, J.; Torres, F.; Gomez, L. J.
Rev. Soc. Quim. Mex. 1983, 27, 311.
(4) (a) Liebeskind, L. S.; Baysdon, S. L.; South, M. S. J. Am. Chem.
Soc. 1980, 102, 7397. (b) Baysdon, S. L.; Liebeskind, L. S. Organome-
tallics 1982, 1, 771. (c) South, M. S.; Liebeskind, L. S. J. Org. Chem.
1982, 47, 3815. (d) Liebeskind, L. S.; Baysdon, S. L. Tetrahedron Lett.
1984, 25, 1747. (e) South, M. S.; Liebeskind, L. S. J. Am. Chem. Soc.
1984, 106, 4181. (f) Liebeskind, L. S.; Leeds, J. P.; Baysdon, S. L.; Iyer, S.
J. Am. Chem. Soc. 1984, 106, 6451. (g) Liebeskind, L. S.; Baysdon, S. L.;
Goedken, V.; Chidambaram, R. Organometallics 1986, 5, 1086. (h) Iyer,
S.; Liebeskind, L. S. J. Am. Chem. Soc. 1987, 109, 2759.
(5) For the rhodium-catalyzed [3 þ 2] cycloaddition of cycloprope-
nones with alkynes, see:Wender, P. A.; Paxton, T. J.; Williams, T. J.
J. Am. Chem. Soc. 2006, 128, 14814.
(6) Murakami, M.; Itahashi, T.; Ito, Y. J. Am. Chem. Soc. 2002, 124,
13976.
(7) For construction of eight-membered rings from cyclobutanones,
see: (a) Wender, P. A.; Correa, A. G.; Sato, Y.; Sun, R. J. Am. Chem.
Soc. 2000, 122, 7815. (b) Matsuda, T.; Fujimoto, A.; Ishibashi, M.;
Murakami, M. Chem. Lett. 2004, 33, 876.
(8) (a) Yoshino, Y.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc.
2009, 131, 7494. (b) Yoshino, Y.; Kurahashi, T.; Matsubara, S. Chem. Lett.
2010, 39, 896. (c) Maizuru, N.; Inami, T.; Kurahashi, T.; Matsubara, S.
Chem. Lett. 2011, 40, 375.
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10.1021/ol300234g
Published on Web 02/24/2012
2012 American Chemical Society

On the other hand, aldehyde CꢀH bond activation with
rhodium followed by intramolecular cis addition of a
rhodium acyl hydride to a CtC triple bond affords a
five-membered acylrhodium intermediate from a substi-
tuted 4-pentynal in a convenient and atom economical
manner.9 The five-membered acylrhodium intermediates
thus generated have been utilized in [4 þ 2] annulation
reactions with alkynes,9,10 alkenes,10,11 and isocyanates.12
Not only substituted 4-pentynal but also 2-alkynylbenzal-
dehydes are able to participate in the [4 þ 2] annulation
with carbonyl compounds13 as well as alkenes11 and iso-
cyanates.12 However, the aldehyde CꢀH bond activation/
[4 þ 2] annulation cascade of 2-alkynylbenzaldehydes with
alkynes has not been reported.
We have previously reported the aldehyde CꢀH bond
activation/[4 þ 2] annulation/aromatization cascade of
2-vinylbenzaldehyde with alkynes, while accessible products
and usable alkyne substrates were limited to 4-methyl-1-
naphthol derivatives and terminal alkynes, respectively.14,15
Herein, we disclose the synthesis of phenol, naphthol,
phenanthrenol, and triphenylenol derivatives via the alde-
hyde CꢀH bond activation/[4 þ 2] annulation/aromatiza-
tion cascade of readily available conjugated alkynyl
aldehydes including 2-alkynylbenzaldehydes and both
internal and terminal alkynes by using a cationic rhodium-
(I)/dppp complex as a catalyst.
As electron-deficient internal alkynes exhibited high
reactivity in the cationic rhodium(I)/dppe complex-
catalyzed [4 þ 2] annulation with substituted 4-pentynals,9
we first examined the [4 þ 2] annulation of 2-alkynylben-
zaldehyde 1a with electron-deficient internal alkyne 2a
(Table 1). In this annulation, not the expected tetralone
4aa but the aromatized product 3aa was isolated. The
ligand screening (Figure 1 and Table 1, entries 1ꢀ4)
revealed that the use of dppp furnished 3aa in the
highest yield with perfect regioselectivity (entry 2).16
The catalyst loading could be reduced to 5 mol %
under the prolonged reaction time without erosion of
the product yield (entry 5).
Table 1. Optimization of Reaction Conditions for Rh-Cata-
lyzed Reaction of 2-Alkynylbenzaldehyde 1a and Alkyne 2aa
(9) Tanaka, K.; Fu, G. C. Org. Lett. 2002, 4, 933.
(10) Recently, the novel rhodium-catalyzed aldehyde CꢀH bond
activation/intramolecular [6 þ 2] annulation of 4-allenals with alkynes
or alkenes was reported. See: Oonishi, Y.; Hosotani, A.; Sato, Y. J. Am.
Chem. Soc. 2011, 133, 10386.
(11) (a) Tanaka, K.; Hagiwara, Y.; Noguchi, K. Angew. Chem., Int.
Ed. 2005, 44, 7260. (b) Tanaka, K.; Hagiwara, Y.; Hirano, M. Eur. J.
Org. Chem. 2006, 3582.
(12) Tanaka, K.; Hagiwara, Y.; Hirano, M. Angew. Chem., Int. Ed.
2006, 45, 2734.
(13) Hojo, D.; Noguchi, K.; Hirano, M.; Tanaka, K. Angew. Chem.,
Int. Ed. 2008, 47, 5820.
entry ligand catalyst (mol %) time (h) conv (%)b yield (%)c
1
dppe
dppp
dppb
dppf
dppp
10
10
10
10
5
18
18
18
18
36
50
100
91
<5
55
21
5
2
3
4
5d
29
100
56
a [Rh(ligand)]BF4 (0.010 mmol), 1a (0.10 mmol), 2a (0.11 mmol), and
(CH2Cl)2 (1.0 mL) were used. b Determined by 1H NMR. c Isolatedyield.
d [Rh(dppp)]BF4 (0.010 mmol), 1a (0.20 mmol), 2a (0.22 mmol), and
(CH2Cl)2 (1.0 mL) were used.
(14) (a) Tanaka, K.; Hojo, D.; Shoji, T.; Hagiwara, Y.; Hirano, M.
Org. Lett. 2007, 9, 2059. For the homo-[4 þ 2] annulation of 2-vinyl-
benzaldehyde, see: (b) Kundu, K.; McCullagh, J. V.; Morehead, A. T.,
Jr. J. Am. Chem. Soc. 2005, 127, 16042.
ꢀ
(15) For recent reviews of cascade reactions, see: (a) Toure, B. B.;
Hall, D. G. Chem. Rev. 2009, 109, 4439. (b) Nicolaou, K. C.; Chen, J. S.
Chem. Soc. Rev. 2009, 38, 2993. (c) Arns, S.; Barriault, L. Chem.
Commun. 2007, 2211. (d) Tejedor, D.; Garcıa-Tellado, F. Chem. Soc.
Rev. 2007, 36, 484. (e) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1. (f)
Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed.
2006, 45, 7134. (g) Dragutan, V.; Dragutan, I. J. Organomet. Chem.
2006, 691, 5129. (h) Domino Reactions in Organic Synthesis; Tietze, L. F.,
Brasche, G., Gericke, K. M., Eds.; Wiley-VCH: Weinheim, Germany, 2006.
ꢀ
(i) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602. (j)
Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005,
105, 1001.
(16) The observed ligand effect is consistent with the chemoselectivity
in the homo-[4 þ 2] annulation of 1a. In our previous report, the reaction
of 1a in the presence of a cationic rhodium(I)/dppb complex furnished
dimer 7 in high yield through the homo-[4 þ 2] annulation with the
carbonyl moiety of 1a (ref 12). On the other hand, the use of dppp as a
ligand furnished dimer 8 as well as dimer 7, through the homo-[4 þ 2]
annulation with the alkyne moiety of 1a. The use of dppe, possessing a
smaller dihedral angle, as a ligand led to poor conversion of 1a.
Figure 1. Structures of bisphosphine ligands.
We then explored the scope of this process with respect
to both alkynes and alkynylarylaldehydes by employing
the above optimal reaction conditions (Table 2). With
respect to alkynes, not only ethyl 2-butynoate (2a, entry 1)
but also ethyl 3-phenylpropiolate (2b, entry 2) could
participate in this reaction to give the corresponding
1-naphthol in moderate yield.17 Interestingly, electron-rich
internal alkyne 2c was found to be more reactive than
electron-deficient ones by using dppf as a ligand (entry 3 vs
entries 1 and 2);18 however, not 1-naphthol but tetra-
lone 4ac was isolated.19 Terminal alkyne 2d could also
Org. Lett., Vol. 14, No. 6, 2012
1493

2-alkynylbenzaldehydes 1b,c could participate in this
reaction (entries 5 and 6).20 Furthermore, phenanthre-
nol derivatives (3da and 3ea, entries 7 and 8) could be
synthesized from alkynylnaphthaldehydes 1d,e. Alky-
nyl phenanthrene aldehyde 1f was also able to react
with 2a to produce triphenylenol 3fa along with pen-
tacyclic compound 5fa, which would be generated
through the intramolecular FriedelꢀCrafts alkylation
of 3fa (entry 9).
Table 2. Rh-Catalyzed Synthesis of Substituted Naphthol,
Phenanthrenol, and Triphenylenol Derivativesa
In our previous aldehyde CꢀH bond activation/[4 þ 2]
annulation/aromatization cascade of 2-vinylbenzaldehyde
with alkynes,14 2-vinyl-1-cyclohexene-1-carboxaldehyde
could not be employed in place of 2-vinylbenzaldehyde.
However, pleasingly, 2-alkynyl-1-cyclohexene-1-carboxal-
dehyde 1g could be employed in place of 2-alkynylbenzal-
dehydes. Alkynylaldehyde1greactedwithvarious internal
Table 3. Rh-Catalyzed Synthesis of Substituted Phenol Deri-
vativesa
a Reactions wereconducted using [Rh(dppp)]BF4 (0.010ꢀ0.020 mmol),
1aꢀf (0.20 mmol), and 2aꢀd (0.22 mmol) in (CH2Cl)2 (1.0 mL) at 60 °C.
b Isolated yield. c Ligand: dppf.
a Reactions were conducted using [Rh(dppp)]BF4 (0.010ꢀ0.020 mmol),
1gꢀi (0.20 mmol), and 2aꢀe (0.22 mmol) in (CH2Cl)2 (1.0 mL) at 60 °C.
b Isolated yield.
participate in this reaction, although the product yield was
low (entry 4). With respect to 2-alkynylbenzaldehydes, not
only 1a but also chloropropyl- and benzyl-substituted
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Org. Lett., Vol. 14, No. 6, 2012

and terminal alkynes 2aꢀe to give bicyclic phenol deriva-
tives in higher yields (Table 3, entries 1ꢀ5) than the use of
2-alkynylbenzaldehyde 1a (Table 1, entries 1ꢀ4).17 In this
annulation, the use of electron-rich internal alkynes 2c,e
furnished not the corresponding tetralones but aromatized
products 3gc and 3ge in good yields (entries 3 and 4).19
Although the product yield was moderate, 2-alkynyl-1-
cycloheptene-1-carboxaldehyde 1h could participate in
this reaction (entry 6). Finally, acyclic alkynyl aldehyde
1i reacted with 2c to give monocyclic phenol 3ic in good
yield (entry 7).
Scheme 2
A combination of the present cascade reaction and
intramolecular olefin metathesis was able to provide a
chrysenol derivative. The reaction of 2-alkynylbenzalde-
hyde 1a with enyne 2f furnished diene 3af. Treatment of
3af with the second generation Grubbs catalyst [1,3-bis-
(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro-
(phenylmethylene)(tricyclohexylphosphine)ruthenium]
furnished chrysenol 6 (Scheme 1).
affording rhodium acyl hydride A. Then cis addition of the
rhodium hydride to the metal-bound CtC triple bond
provides five-membered acylrhodium intermediate B.
Insertion of alkyne 2 followed by reductive elimination
furnishes 4-alkylidene-1-tetralone 4 and regenerates
the rhodium catalyst. This 4-alkylidene-1-tetralone 4
is aromatized to phenol 3 presumably through the
coordination of the cationic rhodium to the carbonyl
oxygen.21
Scheme 1
In conclusion, we have developed the aldehyde CꢀH
bond activation/[4 þ 2] annulation/aromatization cascade
to produce phenol, naphthol, phenanthrenol, and triphenyl-
enol derivatives from readily available conjugated alkynyl
aldehydes and alkynes by using a cationic rhodium(I)/
dppp complex as a catalyst. Future work will focus on
further utilization of cyclic acylrhodium intermediates in
organic synthesis.
Acknowledgment. This work was supported partly by a
Grant-in-Aid for Scientific Research (No. 20675002) from
MEXT, Japan. Wethank Umicore for generous support in
supplying a rhodium complex.
A possible mechanism for the present [4 þ 2] annlation is
shown in Scheme 2. The rhodium catalyst oxidatively
inserts into the aldehyde CꢀH bond of alkynyl aldehyde 1,
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This mater-
ial is available free of charge via the Internet at http://
pubs.acs.org.
(17) In the previous rhodium-catalyzed [4 þ 2] annulations of non-
conjugated 4-alkynals 10 with alkynes 2 or acrylamides, the electron-
deficient groups were located at the meta position with respect to the
ketone moiety (refs 9 and 11). On the contrary, the electron-deficient
ethoxycarbonyl group was located at the ortho position with respect to
the ketone moiety in the present [4 þ 2] annulation of conjugated
4-alkynals 1 with alkynes 2. A possible explanation of these opposite
regioselectivities is the site-selective alkyne insertion to generate inter-
mediate C or C0, which furnishes product 4 or 40, although the precise
reason is not clear at the present stage.
(19) The bulky rhodium(I) complex might coordinate weakly to the
sterically crowded carbonyl oxygen of 4-alkylidene-1-tetralone 4ac,
which deters the aromatization to the 1-naphthol. On the other hand,
the aromatization to 1-naphthol 3ad proceeds smoothly presumably due
to the low steric hindrance, and that to hydroxycarboxylic acid esters
also proceeds smoothly presumably due to the facile bidentate chelation
of rhodium to two carbonyl oxygen atoms of 2-ethoxylcarbonyl-1-
tetralones. On the other hand, the aromatization of 4-alkylidene-1-
cyclohexadienones to phenols proceeds smoothly presumably due to
the thermodynamic stability of products.
(20) The reactions of 2-phenylethynylbenzaldehyde and 2-cyclohex-
1-enylethynylbenzaldehyde with alkynes were also investigated, while
complex mixtures of products were generated.
(21) For an example of the acid-mediated aromatization of 4-alky-
lidene-1-tetralone derivatives to 4-alkenylphenol derivatives through
protonation of the carbonyl oxygen, see: Jansen, R.; Gerth, K.; Steinmetz,
€
H.; Reinecke, S.; Kessler, W.; Kirschning, A.; Muller, R. Chem.;Eur. J.
2011, 17, 7739.
(18) The use of dppp or dppb as a ligand also did not produce the
corresponding 1-naphthol and lowered the yield of tetralone 4ac.
The authors declare no competing financial interest.
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