1922 Chem. Commun., 2012, 48, 1922–1924 This journal is c The Royal Society of Chemistry 2012

Cite this: Chem. Commun., 2012, 48, 1922–1924

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.

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-indanonesin 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 toV), and (v) catalyst re-oxidation.11,12

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

Scheme 1 Envisioned catalytic cycle for the synthesis of a-indanonesvia direct arylation with a palladium homoenolate.

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 70760w Electronic supplementary information (ESI) available: Detailed experi-mental procedures and spectroscopic data. See DOI: 10.1039/c2cc16758a

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This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 1922–1924 1923

cyclopropanols, and they are readily prepared using the Furukawa

modification16 of the Simmons–Smith reaction on the corres-

ponding trimethylsilyl enol ethers.

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 TBAF�H2O 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,

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

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 inthe exclusive formation of the a,b-unsaturated ketone in good

yield (eqn (1)).

Table 1 Summary of reaction development studies

Entry Variation from optimized conditionsa Yieldb (%)

1 1.1 equiv. Pd(OAc)2, no base, toluene, 100 1C 812 1.3 equiv. Cu(OAc)2 instead of O2, no base,

toluene, 100 1C0c

3 No base 0d

4 K2CO3 instead of KOAc 0d

5 NaOAc instead of KOAc 726 KBz instead of KOAc 627 DCE instead of DMAc 08 PdCl2 instead of Pd(OAc)2 869 No Pd(II) source 0d

10 No TBAF�H2O 7711 0.01 equiv. of Pd(OAc)2

e 8412 Air (balloon) instead of O2 48

a All reactions conducted on a 0.12 mmol scale and 0.1M concentration

of starting material. b Isolated yields. c Only product A observed.d Only product B observed. e 0.60 mmol scale.

Table 2 Scope of the synthesis of a-indanones through intramoleculardirect arylation with cyclopropanol-derived homoenolatesa,b

a All reactions conducted on 0.12 mmol scale using optimized conditions.b Isolated yields.

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1924 Chem. Commun., 2012, 48, 1922–1924 This journal is c The Royal Society of Chemistry 2012

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

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. Kitaand D. Uemura, Tetrahedron Lett., 2003, 44, 5171.

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. Liand 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 andS. 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 directC(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.

8 A plausible process would involve coordination of the cyclo-propanol to a Pd(II) intermediate, followed by deprotonation witha 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, 629.11 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 involvingdirect arylations with alkylpalladium(II) intermediates incapable ofb-hydride elimination, see: (c) O. Rene, D. Lapointe andK. 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.

12 For reviews on reactions proceeding through transition-metalcatalyzed 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 andN. Cramer, Org. Biomol. Chem., 2009, 7, 2835; (e) T. Satoh andM. 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 ComprehensiveOrganic Synthesis, ed. B. Trost and I. Fleming, Pergamon, Oxford,

1991, 2, p. 441; (j) I. Kuwajima and E. Nakamura, Topics inCurrent 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. Aokiand 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, TetrahedronLett., 1966, 7, 3353; (b) J. Furukawa, N. Kawabata andJ. 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.

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.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 andO. Eisenstein, Chem. Rev., 2010, 110, 749; (h) D. Lapointe andK. 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 bearingb-hydrogens are rare, for a discussion see ref. 11c. For selectedexamples, 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.

24 Representative experimental procedure: an oven-dried 15 mL testtube 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 resultingsolution was stirred at ambient temperature for 5 minutes.TBAF�H2O (0.038 g, 0.14 mmol, 1.2 equiv.) was added in oneportion, the reaction vessel was capped with a septum and purgedwith oxygen for 5 minutes. The reaction vessel was placed in an oilbath heated to 100 1C and a positive pressure of O2 was maintainedusing a balloon. The progress of the reaction was monitored by TLC.Upon completion, the reaction mixture was filtered through a pad ofsilica gel using EtOAc. The filtrate was washed with water twice,washed with brine, dried with magnesium sulfate and concentratedin vacuo. The crude product was purified by flash column chromato-graphy using a 2% solution of EtOAc in hexanes. Indanone 1b wasisolated 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 cm�1. HRMS [M + H] calculated: 175.1123, found:175.1123.

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