Direct intramolecular arylation of aldehydes promoted by reaction with IPy2BF4/HBF4: Synthesis of benzocyclic ketones

Article abstract of DOI:10.1002/anie.200504448

(Chemical Equation Presented) Iodine helps: Aldehydes acylate arenes upon treatment at low temperature with IPy₂BF₄ and HBF ₄. This reaction is exploited in a novel intramolecular approach to the preparation of benzocyclic ketones (see scheme). A plausible mechanistic rational is also given.

Full text of DOI:10.1002/anie.200504448

Communications
Carbocyclization
DOI: 10.1002/anie.200504448
Direct Intramolecular Arylation of Aldehydes
Promoted by Reaction with IPy2BF4/HBF4:
Synthesis of Benzocyclic Ketones**
JosØ Barluenga,* Mónica Trincado, Eduardo Rubio, and
JosØ M. Gonzµlez
Dedicated to Professor K. Peter C. Vollhardt
on the occasion of his 60th birthday
The Friedel–Crafts acylation of arenes is a prevailing reaction
for accessing aryl ketones.[1] However, conditions for carrying
out the desired arene acylation directly from an aryl-
substituted aldehyde have not yet been described. Herein,
an intramolecular version of such a process is presented. Thus
arenecarboxaldehydes are converted into benzocyclic
ketones[2,3] in a straightforward one-pot process.
The iodoarylation of alkenes and alkynes is an efficient
tool for the modular assembly of heterocycles with rapid
generation of diversity.[4] During the course of these iodoar-
ylation studies, we discovered by chance that the advanced
intermediate 1 underwent not only the expected arylation of
the alkyne functionality, but also conversion into the benzo-
cyclic ketone 2 [Eq. (1), Py = pyridine]. In this conceptually
attractive transformation, an aryl aldehyde acts formally as a
proper acylating agent in a novel intramolecular reaction
sequence triggered by iodonium ions. We decided to further
[*] Prof. Dr. J. Barluenga, Dr. M. Trincado, Dr. E. Rubio,
Dr. J. M. Gonzµlez
Instituto Universitario de Química Organometµlica “Enrique
Moles”
Unidad Asociada al C.S.I.C.
Universidad de Oviedo
Juliµn Clavería, 8, 33006-Oviedo (Spain)
Fax: (+34)98-510-3450
E-mail: barluenga@uniovi.es
[**] This research was partially supported by the Spanish M.E.C. (Grant
CTQ 2004-08077-C02-01). M.T. thanks the Spanish M.E.C. for a
fellowship. Generous support from Merck Sharp & Dohme is
gratefully acknowledged. The authors thank the referees for helpful
and clarifying suggestions. Py=pyridine.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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À
explore the generality of this formal C H functionalization to
produce ketones. We chose 2-(1-naphthyl)benzenecarboxal-
dehyde (3) as a suitable starting material to test the feasibility
of this challenging reaction with simpler compounds [Eq. (2)].
An initial optimization procedure revealed that the
desired process was most efficient when a 2:1 molar ratio of
HBF4 to the iodinating reagent and a 2:1 ratio of the latter
with respect to 3 were used (Table 1). When the ratio of
experimental conditions described for entry 6 of Table 1,
unless otherwise specified. The structures of the aromatic
polycyclic ketones obtained as well as the yields and the
reaction times are depicted in Scheme 1.
Table 1: Optimization of conditions for the direct conversion of 3 into 4
[Eq. (2)].
Entry
IPy2BF4
[equiv]
HBF4
[equiv]
t [h]
Conversion[a]
[%]
Yield[b]
[%]
1
2
3
4
1
1
2
–
3
2
1
2
4
4
6
4
24
24
18
24
18
15
5
–
20
50
–
75
94
17
46
–
5
48[c]
61[e]
6[d]
[a] Determined by 1H NMR spectroscopic analysis of the crude reaction
mixture with respect to 3. [b] Of isolated 4 with respect to 3. [c ] An
iodinated derivative of 3 was formed in 19% yield. [d] The reaction was
conducted by following the modified experimental protocol discussed in
the text; see also the Experimental Section. [e] Iodinated derivatives of 3
(28%) and 4 (4%) were also formed.
IPy2BF4 was increased, the yield of 4 was not improved.
However, the use of more electrophilic conditions gave better
results (Table 1, entry 6). For entries 1–5, 3 was added to a
cooled solution that contained the iodinating reagent and the
acid. However, in the case of entry 6, a different experimental
protocol was adopted. First, the iodinating agent and the acid
were mixed at À808C, and the pyridinium salts generated in
the neutralization were removed to a great extent by filtration
at low temperature under an inert atmosphere. After 3 had
been added to this solution,[5] the temperature was allowed to
rise to À608C and was kept constant while the mixture was
stirred for the time stated.
Scheme 1. Polycyclic aromatic ketones obtained in the formal Friedel–
Crafts acylation of arenes 5–15 with aldehydes, yields, and reaction
times.
We explored the scope and the selectivity of the process
by preparing and screening the reactivity of the set of
aromatic aldehydes 5–15 (Tf = trifluoromethanesulfonyl).[6]
The arylation reactions were conducted under the modified
The formation of a single isomer was observed consis-
tently for the cyclization of compounds 5–15. However, the
reaction of 2-(9-phenanthrenyl)benzenecarboxaldehyde (28)
gave mixtures of 29 and 30 [Eq. (3)]. When the reaction was
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Communications
carried out under the standard conditions, the two compounds
were isolated in nearly a 1:1 ratio. Interestingly, a larger
amount of 30 was obtained when the reaction was carried out
at 08C.
For the other systems tested, six-membered rings were
formed exclusively when the formation of both six-and five-
membered carbocycles from a given precursor was feasible.
One exception to this trend was found for the indole
derivative 11, which probably reflects the preference for the
attack of electrophilic intermediate species at C2 to that at
C4. Five-membered rings were formed in the reactions of 9
and 10, though the products were only obtained in low to
moderate yields. In the case of six-membered rings, the yields
could reach 74%; however, they were lower when side
reactions were observed, as in the case of product 17
(iodinated 6 was recovered in 81% yield), or for clean
reactions with low conversion, as in the case of 16 (45%
conversion; most of the recovered material was unaltered 5).
In an interesting process, the cyclization of 15 gave 26
smoothly in 74% yield; this product can also be seen as an
attractive substrate for further cyclization. Consequently, 26
was transformed subsequently into the aromatic diketone
structure 27. Overall, 27 is derived from 15 through a formal
Scheme 2. Proposed mechanistic pathways that account for the
observed aldehyde-to-ketone conversion.
cyclic ketone product according to the characteristics of an
electrophilic process, as discussed above.
Alternatively, as outlined in the right-hand part of
Scheme 2, a direct addition of the arene to the activated
carbonyl group can not be ruled out at present. Subsequent
loss of HI would give the ketone and would also account for
the need for a second equivalent of the iodinating reagent.
Both mechanistic pathways are plausible and compatible with
the formation of the observed products and the available
information on the process.
In short, a new reaction promoted by the presence of
iodonium ions has been reported. The reaction makes it
possible to use aldehydes as acylating agents for arenes in a
straightforward synthesis of ketones.
À
double C H functionalization process.
A mechanistic proposal to account for the formation of
the ketones from the aldehydes is outlined in Scheme 2. Two
alternative pathways are compatible with the observed effect
of additional substituents on the aromatic rings and with the
possible occurrence of competing aromatic iodination when
electronically activated aromatic rings are present; this side
reaction has been observed for some substrates.
First, the acid protonates the pyridine molecules, which
are initially associated with the iodonium species. The
pyridinium salt formed precipitates at low temperature and
is removed by filtration to give rise to a more reactive
mixture.[5] The interaction of the resulting solution with the
starting aldehyde would give species A. Such a complex could
then further react to yield the ketone product in two different
ways. As depicted on the left-hand side of Scheme 2, it could
undergo formal addition of IF to form intermediate B.
Further oxidation[7] would give C and liberate HI into the
solution, thus accounting for the use of two equivalents of
IPy2BF4. One equivalent is decomposed by reaction with HI
to form I2. In situ activation of the resulting acyl fluoride by
the BF3 present in the reaction medium would lead to an acyl
cation, which could undergo cyclization to form the benzo-
Experimental Section
Typical procedure: IPy2BF4 (0.74 g, 2 mmol, 2 equiv) was dissolved in
dry CH2Cl2 (10 mL) and the resulting solution was stirred for 5 min at
room temperature. It was then cooled to À808C, and HBF4 (542 mL,
54% solution in diethyl ether, 4 mmol, 4 equiv) was added. After
10 min the mixture was filtered under nitrogen. The aldehyde was
added to the filtrate at À608C, and the resulting mixture was stirred
until the starting material had disappeared or until no further
evolution of the reaction was observed. The reaction mixture was
then poured onto crushed ice (100 g) and vigorously stirred until the
temperature of the mixture had risen to room temperature. The
organic layer was washed with a 5% aqueous solution of Na2S2O3
(50 mL), dried over sodium sulfate, and concentrated under reduced
pressure. The ketone product was purified by column chromatog-
raphy (silica gel, hexane/EtOAc).
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Experimental procedures for the preparation of the starting
aldehydes, as well as characterization data for ketones 2, 4, 16–27, 29,
and 30, are provided in the Supporting Information.
Received: December 14, 2005
Published online: March 30, 2006
À
Keywords: aldehydes · C H activation · electrophilic aromatic
substitution · iodonium ions · ketones
.
[1] For recent studies, see: a) A. Fürstner, D. Voigtländer, W.
Schrader, D. Giebel, M. T. Reetz, Org. Lett. 2001, 3, 417 – 420;
b) L. J. Gooßen, K. Ghosh, Angew. Chem. 2001, 113, 3566 – 3568;
Angew. Chem. Int. Ed. 2001, 40, 3458 – 3460; c) M. H. Sarvari, H.
Sharghi, J. Org. Chem. 2004, 69, 6953 – 6956; d) H. Firouzabadi, N.
Iranpoor, F. Nowrouzi, Tetrahedron 2004, 60, 10843 – 10850; for
an elegant application of a-fluoro carbocations in a related
Friedel–Crafts cyclization reaction, see: e) J. Ichikawa, H. Jyono,
T. Kudo, M. Fujiwara, M. Yokota, Synthesis 2005, 39 – 46; for
studies on the “photo-Friedel–Crafts acylation” of 1,4-naphtho-
quinones, see: f) M. Oelgemöller, C. Schiel, R. Fröhlich, J. Mattay,
Eur. J. Org. Chem. 2002, 2465 – 2474.
[2] Polycyclic aromatic ketone scaffolds found in natural products
show remarkable profiles of biological activity; for example, in
hypericin: a) D. Meruelo, G. Lavie, D. Lavie, Proc. Natl. Acad.
Sci. USA 1988, 85, 5230 – 5234; b) A. M. Prince, D. Pascual, D.
Meruelo, L. Liebes, Y. Mazur, E. Dubovi, M. Mandel, G. Lavie,
Photochem. Photobiol. 2000,71, 188 – 195; c) S. Rahimipour, C.
Palivan, F. Barbosa, I. Bilkis, Y. Koch, L. Weiner, M. Fridkin, Y.
Mazur, G. Gescheidt, J. Am. Chem. Soc. 2003, 125, 1376 – 1384;
d) M. Van de Putte, T. Roskams, J. R. Vandenheede, P. Agostinis,
P. A. M. de Witte, Br. J. Cancer 2005, 92, 1406 – 1413; and in
resistomycin: e) K. Jakobi, C. Hertweck, J. Am. Chem. Soc. 2004,
126, 2298.
[3] For recent syntheses of diaryl ketones by metal-catalyzed
coupling reactions of aldehydes with iodoarenes and with
trifluoroarene borates, see: a) Y.-C. Huang, K. K. Majumdar,
C.-H. Cheng, J. Org. Chem. 2002, 67, 1682 – 1684; b) M.
Pucheault, S. Darses, J.-P. Genet, J. Am. Chem. Soc. 2004, 126,
15356 – 15357; c) S. Ko, B. Kang, S. Chang, Angew. Chem. 2005,
117, 459 – 461; Angew. Chem. Int. Ed. 2005, 44, 455 – 457; for
syntheses of diaryl ketones by metal-catalyzed addition reactions
to arenecarboxylic acid derivatives of aryl magnesium halides and
aryl zinc reagents, see: d) C. Duplais, F. Bures, I. Sapountzis, T. J.
Korn, G. Cahiez, P. Knochel, Angew. Chem. 2004, 116, 3028 –
3030; Angew. Chem. Int. Ed. 2004, 43, 2968 – 2970; e) Y. Zhang, T.
Rovis, J. Am. Chem. Soc. 2004, 126, 15964 – 15965; f) X.-j. Wang,
L. Zhang, X. Sun, Y. Xu, D. Krishnamurthy, C. H. Senayake, Org.
Lett. 2005, 7, 5593 – 5595.
[4] a) J. Barluenga, M. Trincado, E. Rubio, J. M. Gonzµlez, J. Am.
Chem. Soc. 2004, 126, 3416 – 3417; b) J. Barluenga, M. Trincado,
M. Marco-Arias, A. Ballesteros, E. Rubio, J. M. Gonzµlez, Chem.
Commun. 2005, 2008 – 2010.
[5] It had already been shown that the resulting solution was more
active for the iodofluorination of electron-deficient alkenes, see:
J. Barluenga, P. J. Campos, J. M. Gonzµlez, J. L. Suµrez, G.
Asensio, J. Org. Chem. 1991, 56, 2234 – 2237.
[6] The aldehydes were prepared by well-established metal-catalyzed
cross-coupling reactions; see the Supporting Information for
more details.
[7] For the oxidation of aldehydes to acyl fluorides by reaction with
ˇ
CsSO4F in CH3CN at 358C, see: S. Stavber, Z. Planinsek, M.
Zupan, J. Org. Chem. 1992, 57, 5334 – 5337.
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