Synthesis of α-indanones via intramolecular direct arylation with cyclopropanol-derived homoenolates

Article abstract of DOI:10.1039/c2cc16758a

A palladium-catalysed, tandem cyclopropanol rearrangement and direct arylation approach for the synthesis of 1-indanones is reported. The reaction is generally high yielding, uses oxygen as the terminal oxidant and tolerates a range of functional groups on the aryl ring.

Full text of DOI:10.1039/c2cc16758a

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COMMUNICATION
Synthesis of a-indanones via intramolecular direct arylation with
cyclopropanol-derived homoenolatesw
David Rosa and Arturo Orellana*
Received 1st November 2011, Accepted 10th December 2011
DOI: 10.1039/c2cc16758a
A palladium-catalysed, tandem cyclopropanol rearrangement and
direct arylation approach for the synthesis of 1-indanones is reported.
The reaction is generally high yielding, uses oxygen as the terminal
oxidant and tolerates a range of functional groups on the aryl ring.
1-Indanones are important substructures in pharmaceutical agents
and natural products with important biological activity, as
exemplified by the acetylcholinesterase inhibitor donepezil and
the anticancer agent nakiterpiosin,1,2 respectively. Although the
Friedel–Crafts acylation of aryls is perhaps the most widely used
method for their synthesis,3 many other methods exist, including
Nazarov-type cyclizations4 and a variety of palladium-catalysed
reactions.5 These methods, although very useful, are not without
inherent limitations. For instance, palladium-catalysed syntheses of
1-indanones often require the use of aryl halides and pseudo-
halides. In addition, many of these reactions deliver indanones that
are either monosubstituted or unsubstituted at the 2-position.
Scheme 1 Envisioned catalytic cycle for the synthesis of a-indanones
via direct arylation with a palladium homoenolate.
A number of important observations informed our reaction
development process. First, while the palladium-catalysed
formation of homoenolates from silyloxy cyclopropanes and
cyclopropane acetals generally require rather forcing conditions,13
the ring opening of unprotected cyclopropanols takes place
under comparatively milder conditions. Park and Cha have
suggested that this process occurs through an initial coordina-
tion of palladium to the cyclopropanol oxygen9 (i.e. II),
followed by a b-carboelimination reaction. Second, we were
cognizant that cyclopropanols are readily converted to the
a-alkyl ketones with base,14 and as a result, we expected that
the nature of the base would play a critical role in the success
of the reaction.15 Specifically, the base utilized would have to
be sufficiently strong to deprotonate the cyclopropanol,8 and
act as a base during the direct arylation event while at the same
time be mild enough to prevent undesired base-catalysed
rearrangement of the cyclopropanol to the corresponding
ketone. Lastly, in our work on the palladium-catalysed
cross-coupling of cyclopropanol derived homoenolates with
aryl halides6a we obtained higher product yields by generating
the cyclopropanol through in situ deprotection of the corresponding
TMS ether instead of employing the unprotected cyclopropanol.
Furthermore, the TMS-protected cyclopropanols are more stable
to chromatographic purification on SiO2 than the corresponding
We have been interested in developing reactions that proceed
through palladium homoenolates generated via strain-releasing
reactions.6 In this connection, we surmised that a strategically
positioned palladium homoenolate could participate in a
direct arylation reaction to deliver substituted a-indanones
in an efficient manner.7 Importantly, such a protocol would
obviate the need for pre-activation of the aryl ring. As outlined
in Scheme 1, we envisioned a catalytic cycle consisting of
(i) deprotonation and coordination of the cyclopropanol to a
palladium(II) intermediate8 (I to II), (ii) palladium(II)-catalysed
cyclopropanol rearrangement to generate a homoenolate
(II to III),9,10 (iii) palladation of the aryl ring (III to IV),
(iv) reductive elimination (IV to V), and (v) catalyst re-oxidation.11,12
Department of Chemistry, York University, 4700 Keele Street,
Toronto, ON, Canada M3J 1P3. E-mail: aorellan@yorku.ca;
Fax: +1 416 736 5936; Tel: +1 416 736 2100 ext 70760
w Electronic supplementary information (ESI) available: Detailed experi-
mental procedures and spectroscopic data. See DOI: 10.1039/c2cc16758a
c
1922 Chem. Commun., 2012, 48, 1922–1924
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Table 1 Summary of reaction development studies
Table 2 Scope of the synthesis of a-indanones through intramolecular
direct arylation with cyclopropanol-derived homoenolatesa,b
Entry Variation from optimized conditionsa
Yieldb (%)
1
2
1.1 equiv. Pd(OAc)2, no base, toluene, 100 1C 81
1.3 equiv. Cu(OAc)2 instead of O2, no base,
0c
toluene, 100 1C
No base
3
4
5
6
7
8
9
0d
0d
72
62
0
K2CO3 instead of KOAc
NaOAc instead of KOAc
KBz instead of KOAc
DCE instead of DMAc
PdCl2 instead of Pd(OAc)2
No Pd(II) source
86
0d
10
11
12
No TBAFꢀH2O
77
84
48
e
0.01 equiv. of Pd(OAc)2
Air (balloon) instead of O2
a
All reactions conducted on a 0.12 mmol scale and 0.1 M concentration
b
of starting material. Isolated yields. Only product A observed.
d
c
e
Only product B observed. 0.60 mmol scale.
a
All reactions conducted on 0.12 mmol scale using optimized conditions.
Isolated yields.
b
cyclopropanols, and they are readily prepared using the Furukawa
modification16 of the Simmons–Smith reaction on the corres-
ponding trimethylsilyl enol ethers.
the reaction proceeds with uniformly good yields (64 to 88%).
Furthermore, a range of functional groups can be tolerated on
the aryl rings including electron-donating methoxy groups
(entries 2 to 5), chloro- and fluoro-substituents (entries 6
and 7), and electron-withdrawing methoxycarbonyl (entries 8
and 9) and trifluoromethyl substituents (entry 10). The nature
of the substituents on the cyclopropanol ring can be
altered without a significant change in yield (entry 11). It is
worthwhile noting that in cases where two regioisomeric
indanones could be obtained, only one of the possible
isomers is observed (entries 4 and 8). It is worth noting that,
in general, substrates bearing electron-withdrawing groups
(cf. entries 8 and 9) provide better yields of the corresponding
indanones than substrates bearing electron donating groups
(cf. entries 2–5). This observation, and the requirement for
an acetate base strongly suggest that the arylation step
Our reaction development experiments17 are summarized in
Table 1. In initial experiments we were pleased to find that
treatment of the silyloxycyclopropane with a slight excess of
Pd(OAc)2 and 1.1 equivalents of TBAFꢀH2O resulted in the
formation of the desired indanone in good isolated yield (entry 1).
In recent years there has been a significant amount of work on
oxidative palladium-catalysed reactions, and a number of ligands
have been shown to be useful.18 We explored a number of potential
ligands for this process, and although the desired product could be
observed in some instances, the yields were uniformly poor. Inter-
estingly, during the screening of oxidants we observed the formation
of the a,b-unsaturated ketone resulting from cleavage of the more
substituted cyclopropane bond when a Cu(II) salt was employed
(i.e. A, entry 2).19 It became clear that a base was required for a
successful reaction (entry 3), and that the nature of the base was
critical (entry 4). While KOAc proved to be the best base, other
acetate bases also worked well (entry 5), and a change from acetate
to benzoate resulted in a lower yield (entry 6).20,21 The reaction
could be performed in a range of solvents, however, not all solvents
are effective22 (entry 7). Other palladium sources were also effective
(entry 8), however it is clear that palladium is required for the
reaction (entry 9). We also noted that the reaction proceeds without
a fluoride source, albeit with a slightly diminished yield (entry 10).
Finally, the loading of Pd(OAc)2 could be reduced to 1 mol%
without a significant reduction in yield (entry 11), and air could be
used as the terminal oxidant albeit with a lower yield (entry 12).
Having developed an optimized protocol we next explored
the scope of this reaction. As can be gleaned from Table 2,
proceeds through a concerted metallation–deprotonation
(CMD) pathway.20,21
At present this approach is limited to 2,2-disubstituted
a-indanones. The attempted direct intramolecular arylation
with homoenolates bearing at least one b-hydrogen23 results in
the exclusive formation of the a,b-unsaturated ketone in good
yield (eqn (1)).
ð1Þ
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1922–1924 1923

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In conclusion, we have developed a conceptually new,
palladium-catalysed direct arylation approach to 2,2-disubstituted
a-indanones. This reaction proceeds in good yields, tolerates a
range of substituents on the aryl rings and uses molecular oxygen
at atmospheric pressure as the terminal oxidant.19,24
1991, 2, p. 441; (j) I. Kuwajima and E. Nakamura, Topics in
Current Chemistry, Springer-Verlag, Berlin, Heidelberg, 1990, 155,
p. 1; (k) I. Kuwajima, Pure Appl. Chem., 1988, 60, 115.
13 For mechanistic studies on this process, see: T. Fujimura, S. Aoki
and E. Nakamura, J. Org. Chem., 1991, 56, 2809.
14 Review: D. H. Gibson and C. H. DePuy, Chem. Rev., 1974,
74, 605.
15 For the cross-coupling of base sensitive strained tertiary alcohols,
see: A. Chtchemelinine, D. Rosa and A. Orellana, J. Org. Chem.,
2011, 76, 9157.
16 (a) J. Furukawa, N. Kawabata and J. Nishimura, Tetrahedron
Lett., 1966, 7, 3353; (b) J. Furukawa, N. Kawabata and
J. Nishimura, Tetrahedron, 1968, 24, 53.
17 See the ESIw for a full list of reaction development experiments.
18 Reviews: (a) S. S. Stahl, Angew. Chem., Int. Ed., 2004, 43, 3400;
(b) M. S. Sigman and D. R. Jensen, Acc. Chem. Res., 2006, 39, 221;
(c) K. M. Gligorich and M. S. Sigman, Chem. Commun., 2009,
3854.
This work was generously supported by York University
and the Natural Science and Engineering Research Council
(NSERC) of Canada. We gratefully acknowledge Professor
Michael Organ for generous sharing of resources.
Notes and references
1 Isolation: (a) T. Teruya, S. Nakagawa, T. Koyama, H. Arimoto,
M. Kita and D. Uemura, Tetrahedron, 2004, 60, 6989;
(b) T. Teruya, S. Nakagawa, T. Koyama, K. Suenaga, M. Kita
and D. Uemura, Tetrahedron Lett., 2003, 44, 5171.
19 L.-Z. Li, B. Xiao, Q.-X. Guo and S. Xue, Tetrahedron, 2006,
62, 7762.
20 Selected references: (a) D. L. Davies, S. M. A. Donald and S. A.
2 The structure of nakiterpiosin has been revised: S. Gao, Q. Wang,
L. J.-S. Huang, L. Lum and C. Chen, J. Am. Chem. Soc., 2010, 132, 371.
3 Selected recent examples: (a) E. Fillion and D. Fishlock, Org. Lett.,
2003, 5, 4653; (b) C. O. Kangani and B. W. Day, Org. Lett., 2008,
10, 2645.
4 Selected recent examples: (a) G. Liang, Y. Xu and D. Trauner, J. Am.
Chem. Soc., 2004, 126, 9544; (b) J. Zhu, C. Zhong, H.-F. Lu, G.-Y. Li
and X. Sun, Synthesis, 2008, 458; (c) A. Saito, M. Umakoshi,
N. Yagyu and Y. Hanzawa, Org. Lett., 2008, 10, 1783.
5 Selected recent examples: (a) A. Minatti, X. Zheng and
S. L. Buchwald, J. Org. Chem., 2007, 72, 9253; (b) J. A. Brekan,
T. E. Reynolds and K. A. Scheidt, J. Am. Chem. Soc., 2010,
132, 1472.
6 (a) D. Rosa and A. Orellana, Org. Lett., 2011, 13, 110;
(b) A. Schweinitz, A. Chtchemelinine and A. Orellana, Org. Lett.,
2011, 13, 232.
7 For the synthesis of a,a-disubstituted indanones through a direct
C(sp3)–H functionalization using an arylpalladium(II) inter-
mediate, see: S. Rousseaux, M. Davi, J. Sofack-Kreutzer,
C. Pierre, C. E. Kefalidis, E. Clot, K. Fagnou and O. Beaudoin,
J. Am. Chem. Soc., 2010, 132, 10706.
Macgregor, J. Am. Chem. Soc., 2005, 127, 13754; (b) D. Garcıa-
´
Cuadrado, A. A. C. Braga, F. Maseras and A. Echevarren, J. Am.
Chem. Soc., 2006, 128, 1066; (c) M. Lafrance, C. N. Rowley,
T. K. Woo and K. Fagnou, J. Am. Chem. Soc., 2006, 128, 8754;
(d) M. Lafrance and K. Fagnou, J. Am. Chem. Soc., 2006,
128, 16496; (e) S. I. Gorelsky, D. Lapointe and K. Fagnou,
J. Am. Chem. Soc., 2008, 130, 10848. Reviews: (f) Y. Boutadla,
D. L. Davies, S. A. Macgregor and A. I. Poblador-Bahamonde,
Dalton Trans., 2009, 5820; (g) D. Balcells, E. Clot and
O. Eisenstein, Chem. Rev., 2010, 110, 749; (h) D. Lapointe and
K. Fagnou, Chem. Lett., 2010, 1118; (i) L. Ackermann, Chem.
Rev., 2011, 111, 1315.
21 The importance of acetate bases and the intermediacy of ‘ligand-
less’ palladium intermediates has recently been investigated, see:
Y. Tan and J. F. Hartwig, J. Am. Chem. Soc., 2011, 133, 3308.
22 DMAc is a particularly useful solvent in oxidative palladium-
catalyzed reactions, see: T. Mitsudome, K. Mizumoto, T. Mizugaki,
K. Jitsukawa and K. Kaneda, Angew. Chem., Int. Ed., 2010, 49, 1238.
23 Direct arylations with alkylpalladium(II) intermediates bearing
b-hydrogens are rare, for a discussion see ref. 11c. For selected
examples, see: (a) Z. Z. Song and H. N. C. Wong, J. Org. Chem.,
1994, 59, 33; (b) M. B. Bertrand and J. P. Wolfe, Org. Lett., 2007,
9, 3073; (c) Y. Hu, C. Yu, D. Ren, Q. Hu, L. Zhang and D. Cheng,
Angew. Chem., Int. Ed., 2009, 48, 5448.
8 A plausible process would involve coordination of the cyclo-
propanol to a Pd(II) intermediate, followed by deprotonation with
a mild base.
9 S.-B. Park and J. K. Cha, Org. Lett., 2000, 2, 147.
10 For a similar report, see: H. Okumoto, T. Jinnai, H. Shimizu,
Y. Harada, H. Mishima and A. Suzuki, Synlett, 2000, 629.
24 Representative experimental procedure: an oven-dried 15 mL test
tube equipped with a magnetic stir bar was charged with trimethyl-
silyloxycyclopropane 1a (0.030 g, 0.12 mmol, 1.0 equiv.), Pd(OAc)2
(0.0010 g, 0.006 mmol, 0.05 equiv.), KOAc (0.024 g, 0.24 mmol,
2.0 equiv.) and N,N dimethylacetamide (1.2 mL). The resulting
solution was stirred at ambient temperature for 5 minutes.
TBAFꢀH2O (0.038 g, 0.14 mmol, 1.2 equiv.) was added in one
portion, the reaction vessel was capped with a septum and purged
with oxygen for 5 minutes. The reaction vessel was placed in an oil
bath heated to 100 1C and a positive pressure of O2 was maintained
using a balloon. The progress of the reaction was monitored by TLC.
Upon completion, the reaction mixture was filtered through a pad of
silica gel using EtOAc. The filtrate was washed with water twice,
washed with brine, dried with magnesium sulfate and concentrated
in vacuo. The crude product was purified by flash column chromato-
graphy using a 2% solution of EtOAc in hexanes. Indanone 1b was
isolated as a yellow oil in 86% yield (0.018 g, 0.010 mmol).
1H-NMR (400 MHz, CDCl3) d 7.67 (d, J = 8.0 Hz, 1H), 7.24
(s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 2.97 (s, 2H), 2.46 (s, 3H), 1.24
(s, 6H). 13C-NMR (100 MHz, CDCl3) d 210.8, 152.6, 145.8, 132.9,
128.6, 126.8, 124.2, 45.5, 42.6, 25.2, 22.0. IR n = 1711, 1610, 1327,
1103, 831 cmꢁ1. HRMS [M + H] calculated: 175.1123, found:
175.1123.
11 For
related
reactions
using
tert-cyclobutanols
see:
(a) T. Nishimura, K. Ohe and S. Uemura, J. Am. Chem. Soc.,
1999, 121, 2645; (b) T. Nishimura, K. Ohe and S. Uemura, J. Org.
Chem., 2001, 66, 1455. For examples of cascade reactions involving
direct arylations with alkylpalladium(II) intermediates incapable of
b-hydride elimination, see: (c) O. Rene
K. Fagnou, Org. Lett., 2009, 11, 4560; (d) G. Satyanarayana,
C. Maichle-Mossmer and M. E. Maier, Chem. Commun., 2009,
1571; (e) R. T. Ruck, M. A. Huffman, M. M. Kim, M. Shelvin,
W. V. Kandur and I. W. Davies, Angew. Chem., Int. Ed., 2008,
47, 4711.
´
, D. Lapointe and
¨
12 For reviews on reactions proceeding through transition-metal
catalyzed b-carboelimination, see: (a) T. Seiser, T. Saget,
D. C. Tran and N. Cramer, Angew. Chem., Int. Ed., 2011,
50, 7740; (b) M. Murakami and T. Matsuda, Chem. Commun.,
2011, 47, 1100; (c) C. Aıssa, Synthesis, 2011, 3389; (d) T. Seiser and
¨
N. Cramer, Org. Biomol. Chem., 2009, 7, 2835; (e) T. Satoh and
M. Miura, Top. Organomet. Chem., 2007, 24, 61; (f) M. Murakami,
M. Makino, S. Ashida and T. Matsuda, Bull. Chem. Soc. Jpn.,
2006, 79, 1315; (g) T. Satoh and M. Miura, Top. Organomet.
Chem., 2005, 14, 1; (h) T. Nishimura and S. Uemura, Synlett, 2004,
201; (i) I. Kuwajima and E. Nakamura, in Comprehensive
Organic Synthesis, ed. B. Trost and I. Fleming, Pergamon, Oxford,
c
1924 Chem. Commun., 2012, 48, 1922–1924
This journal is The Royal Society of Chemistry 2012