Synthesis of chiral 3-substituted indanones via an enantioselective reductive-heck reaction

Article abstract of DOI:10.1021/jo701741y

(Chemical Equation Presented) An efficient intramolecular palladium-catalyzed, asymmetric reductive-Heck reaction has been developed, which allowed for the synthesis of either enantiomerically enriched 3-substituted indanones or α-exo-methylene indanones depending on the base used.

Full text of DOI:10.1021/jo701741y

Synthesis of Chiral 3-Substituted Indanones via an Enantioselective
Reductive-Heck Reaction
Ana Minatti, Xiaolai Zheng, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
sbuchwal@mit.edu
ReceiVed August 7, 2007
An efficient intramolecular palladium-catalyzed, asymmetric reductive-Heck reaction has been developed,
which allowed for the synthesis of either enantiomerically enriched 3-substituted indanones or R-exo-
methylene indanones depending on the base used.
Introduction
R-arylpropargyl alcohols represent very elegant ways to generate
chiral 3-substituted indanones. Results described by Pu¨schl
attracted our attention, as racemic 3-arylindanones were obtained
in moderate to good yields through a palladium-catalyzed
intramolecular reductive cyclization of (E)-2′-bromochalcones
by using high reaction temperatures (155 °C) or microwave
conditions.6
Herein, we describe the development of a palladium-catalyzed
asymmetric reductive-Heck cyclization7 of 2′-perfluoroalkyl-
sulfonated aryl R,â-unsaturated ketones for the synthesis of
The indan framework is found in a large number of bioactive
and pharmaceutically important molecules.1 Further, chiral
3-substituted indanones serve as valuable intermediates for the
synthesis of a variety of interesting compounds, or possess
inherent biological activity themselves.2 The introduction of
chirality in position 3 of the indanone framework has been
accomplished by using a number of different approaches.3 Most
recently, Morehead4 and Hayashi5 have shown that rhodium-
(I)-catalyzed asymmetric intramolecular hydroacylation of
2-vinyl benzaldehyde systems and isomerization of racemic
(3) (a) Poras, H.; Stephan, E.; Pourcelot, G.; Cresson, P. Chem. Ind. 1993,
206. (b) Stephan, E.; Rocher, R.; Aubouet, J.; Pourcelot, G.; Cresson, P.
Tetrahedron: Asymmetry 1994, 5, 41. (c) Clark, W. M.; Tickner-Eldrige,
A. M.; Huang, G. K.; Pridgen, L. N.; Olsen, M. A.; Mills, R. J.; Lantos, I.;
Baine, N. H. J. Am. Chem. Soc. 1998, 120, 4550. (d) Clark, W. M.; Kassick,
A. J.; Plotkin, M. A.; Eldridge, A. M.; Lantos, I. Org. Lett. 1999, 1, 1839.
(e) Yun, J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 767. (f) Arp, F. O.;
Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482. (g) Natori, Y.; Anada, M.;
Nakamura, S.; Nambu, H.; Hashimoto, S. Heterocycles 2006, 70, 635.
(4) Kundu, K.; McCullagh, J. V.; Morehead, A. T., Jr. J. Am. Chem.
Soc. 2005, 127, 16042.
* Address correspondence to this author. Phone: (+1) 617-253-1885. Fax:
(+1) 617-253-3297.
(1) (a) Bristol-Myers Squibb Company; Preparation of indanes as
modulaters of glucocorticoid receptor, AP-1, or NF-κ B activity for use as
antiobesity, antidiabetic, anti-inflammatory, or immunomodulatory agents.
WO 2007073503 A2, June 28, 2007. (b) Ferraz, H. M. C.; Aguilar, A. M.;
Silva, L. F., Jr. Quim. NoVa 2005, 28, 703. (c) Hong, B.-c.; Sarshar, S.
Org. Prep. Proced. Int. 1999, 31, 1.
(2) (a) Smith, A. B., III; Charnley, A. K.; Harada, H.; Beiger, J. J.; Cantin,
L.-D.; Kenesky, C. S.; Hirschmann, R.; Munshi, S.; Olsen, D. B.; Stahlhut,
M. W.; Schleif, W. A.; Kuo, L. C. Bioorg. Med. Chem. Lett. 2006, 16,
859. (b) Arefalk, A.; Wannberg, J.; Larhed, M.; Hallberg, A. J. Org. Chem.
2006, 71, 1265. (c) Karim, A.; Tolbert, D.; Cao, C. J. Clin. Pharmacol.
2006, 46, 140. (d) Hedberg, C.; Andersson, P. G. AdV. Synth. Catal. 2005,
347, 662. (e) Yu, H.; Kim, I. J.; Folk, J. E.; Tian, X.; Rothman, R. B.;
Baumann, M. H.; Dersch, C. M.; Flippen-Andersen, J. L.; Parrish, D.;
Jacobsen, A. E.; Rice, K. C. J. Med. Chem. 2004, 47, 2624. (f) Llum, R.
T.; Nelson, M. G.; Joly, A.; Horsma, A. G.; Lee, G.; Meyer, S. M.; Wick,
M. M.; Schow, S. R. Bioorg. Med. Chem. Lett. 1998, 8, 209. (g) Bøgesø,
K. P.; Arnt, J.; Frederikson, K.; Hansen, H. O.; Hyttel, J.; Pedersen, H. J.
Med. Chem. 1995, 38, 4380.
(5) (a) Shintani, R.; Yashio, K.; Nakamura, T.; Okamoto, K.; Shimada,
T.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 2772. (b) For Rhodium-
catalyzed asymmetric synthesis of 3,3-disubstituted 1-indanones, see:
Shintani, R.; Takatsu, K.; Hayashi, T. Angew. Chem. 2007, 119, 3809;
Angew. Chem., Int. Ed. 2007, 46, 3735.
(6) Pu¨schl, A.; Rudbeck, H. C.; Faldt, A.; Confante, A.; Kehler, J.
Synthesis 2005, 2, 291.
(7) For reviews on Heck-Mizoroki cross-coupling reactions, see: (a)
Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009. (b) Bra¨se,
S.; de Meijere, A. Cross-Coupling of Organyl Halides with AlkenessThe
Heck Reaction. In Metal-Catalyzed Cross-Coupling Reactions; de Meijere,
A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004; Vol. 1,
pp 217-315.
10.1021/jo701741y CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/30/2007
J. Org. Chem. 2007, 72, 9253-9258
9253

Minatti et al.
TABLE 1. Effect of the Amine and the Ligand on the Pd-Catalyzed Asymmetric Heck-Type Cyclization
entry
X
ligand
(R)-BINAP
(R)-BINAP
(R)-BINAP
(R)-3,5-XylBINAP
(R)-MeOBIPHEP
(R)-3,5-XylMeOBIPHEP
(R)-3,5-tButylMeOBIPHEP
(R)-3,5-XylMeOBIPHEP
(R)-3,5-XylMeOBIPHEP
(R)-3,5-XylMeOBIPHEP
amine
2a:3a
yield [%]a
ee [%]b
1
2
3
4
5
6
7
8
OTf
OTf
OTf
OTf
OTf
MeNCy2
NEt3
psc
ps
ps
ps
ps
ps
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
0:100
32
40
65
75
54
53
55
70
73
79 (78)
70
76
77
81
OTf (ONf)
88d (90)d
45
OTf
I
Br
25
30
74
9
ps
10e
ONf
PMPf
80
a Determined by GC. b Determined by HPLC on a Chiracel OJ column. c ps ) proton sponge. d Isolated yield. e Reaction conducted in 1,4-dioxane.
f PMP ) 1,2,2,6,6-pentamethylpiperidine.
chiral 3-substituted indanones using proton sponge and a related
synthetic route for accessing R-exo-methylene indanones using
1,2,2,6,6-pentamethylpiperidine (PMP).8
under optimized reaction conditions was obtained in 74% yield
and 80% ee (Table 1, entry 10).
Encouraged by these results, we sought to investigate the
scope of this asymmetric reductive-Heck cyclization to chiral
3-substituted indanones 2 (Table 2). We found that electron-
donating as well as electron-withdrawing substituents on the
â-phenyl ring are tolerated, yielding the corresponding indanones
in good yields and enantiomeric excesses (Table 2, 2c-f).
Additionally, using this method, we were able to prepare the
enantiomerically enriched indanone 2e, an intermediate in the
total syntheses of chiral indatraline derivatives,2e as well as the
1,3-benzodioxole-substituted indanone 2f, a framework found
in various biologically active indan derivatives.3c
A significant increase of enantioselectivity was achieved by
introducing an additional substituent in the position ortho to
the leaving group. Thus, indanone 2g was obtained in excellent
yield and 94% ee. Indanone 2h is of particular interest as the
silyl-group allows for further functionalization, such as Hiyama
cross-coupling,12 iodination,13 or fluorination.14 Finally, we were
able to apply our reaction conditions to the cyclization of a
trisubstituted chalcone derivative, yielding trans-2-methyl-3-
phenylindanone (2m) with excellent enantiomeric excess (94%)
and good diastereomeric ratio (83:17), which could be increased
to 91:9 after isomerization by treatment with HCl in a H2O/
THF solvent mixture. 2-Alkyl-3-phenyl-substituted indanones
have proven to be potent inhibitors of tubulin polymerization
and tumor and endothelial cell proliferation in vitro.15 This is
the first time that the introduction of two stereocenters in
positions 2 and 3 of the indanone core in the same reaction
sequence has been reported.
Results and Discussion
After some preliminary screening studies, our initial reaction
conditions for the cyclization of (E)-2′-triflylchalcone 1a (X )
OTf) employed a catalyst system comprised of 5 mol % of Pd-
(OAc)2, 10 mol % of (R)-BINAP, and 2 equiv of Hu¨nig’s base
in DMF at 100 °C (Table 1, entry 1). We observed that the
cyclization provided the desired product 2a in 32% yield with
an enantiomeric excess of 54%.9 Variation of the amine base
revealed that proton sponge gave the highest yield, though no
increase of the enantiomeric excess was observed (Table 1, entry
3). Subsequently, various phosphine ligands were tested and
some representative examples are shown in Table 1. (R)-3,5-
XylMeOBIPHEP was identified as the most effective ligand
yielding product 2a in 88% yield and 79% ee.10 Variation of
temperature, solvent, and/or palladium source did not improve
the yield or the enantiomeric excess obtained for 2a. The use
of the sterically more hindered ligand (R)-3,5-tert-ButylMeO-
BIPHEP had a deleterious effect on both yield and enantiomeric
excess (Table 1, entry 7). This result supports the hypothesis
that the extent of the “3,5-dialkyl-meta-effect” on enantiose-
lectivity is substrate dependent.11 The products derived from
the corresponding (E)-2′-iodo and -bromo chalcone derivatives
1a (X ) I or Br) showed similar enantiomeric excesses under
the optimized reaction conditions, though only moderate reactiv-
ity was observed (Table 1, entries 8 and 9). Interestingly,
replacement of proton sponge with 1,2,2,6,6-pentamethylpip-
eridine (PMP) produced R-exo-methylene indanone 3a, which
As mentioned before, the use of PMP in the palladium-
catalyzed asymmetric reductive-Heck cyclization allowed for
the synthesis of R-exo-methylene indanone 3a. The scope of
this reaction is shown in Table 3. The corresponding R-exo-
methylene indanones 3a-h were obtained in good yields and
good to excellent enantioselectivities, up to 94%, with the
(8) This reaction type can formally be classified as a catalyzed asym-
metric arylation reaction. For a review, see: Bolm, C.; Hildebrand, J. P.;
Mun˜iz, K.; Hermanns, N. Angew. Chem. 2001, 113, 3382; Angew. Chem.,
Int. Ed. 2001, 40, 3284.
(9) The stereochemistry of the product was assigned to be (S) by
comparison of the sign of the optical rotation value with the literature value.3e
(10) Although the results obtained with the nonaflate 1a (X ) ONf) and
the triflate 1a (X ) OTf) were identical, the easier handling of the nonaflate
made it the substrate of choice.
(11) (a) Tschoerner, M.; Pregosin, P. S.; Albinati, A. Organometallics
1999, 18, 670. (b) Trabesinger, G.; Albinati, A.; Feiken, N.; Kunz, R. W.;
Pregosin, P. S.; Tschoerner, M. J. Am. Chem. Soc. 1997, 119, 6315.
(12) Hiyama, T. J. Organomet. Chem. 2002, 653, 58.
(13) Wilson, S. R.; Jacob, L. A. J. Org. Chem. 1986, 51, 4833.
(14) de Meio, G. V.; Pinhey, J. T. J. Chem. Soc., Chem. Commun. 1990,
15, 1165.
(15) Aventis Pharma SA; Preparation of 3-arylindan-1-ones as inhibitors
of tubulin polymerization and their composition for treatment of cancer.
FR 2838432, A1, October 17, 2003.
9254 J. Org. Chem., Vol. 72, No. 24, 2007

Synthesis of Chiral 3-Substituted Indanones
TABLE 2. Scope of the Palladium-Catalyzed Asymmetric Synthesis of 3-Substituted Indanones 2
a Yields of the isolated products are the average of two runs. b Determined by HPLC on a chiral stationary phase. c The triflate was used instead of the
nonaflate. d Dr ) 91:9 after isomerization; the major diastereoisomer is shown.
exception of the p-chloro-substituted R-exo-methylene indanone
3d, which was isolated in only 44% yield (80% ee) due to
instability of the product. We observed that, in the case of (E)-
2′-nonaflyl chalcone 1a, the choice of solvent had a significant
influence on the outcome of the reaction. In 1,4-dioxane
indanone 3a was obtained in 90% yield with 78% ee.16
However, when the same reaction was carried out in DMF, the
sole product observed was the achiral indenone 3i, which was
isolated in 70% yield. Synthesis of the later compound by
palladium-catalyzed annulation of 2-iodobenzonitrile or 2-ha-
lobenzaldehyde with 1-phenyl-1-propyne results in low yields
of inseparable 1:1 mixtures of the isomers, rendering our
reaction protocol an attractive alternative.17 3-Furyl-2-methyl-
indenone (3k) was predominantly formed regardless of the
solvent employed.
aryl nonaflate 1 to the in situ formed Pd(0) phosphine complex
results in the cationic Pd(II) complex I. Carbopalladation of
the (E)-configured double bond in complex I occurs in a syn-
fashion via a 5-endo-trig cyclization leading to the π-oxa-allyl
palladium species II. Since â-hydride elimination is precluded
by the initially formed cationic cyclic cis-configured C-bound
Pd-enolate intermediate II (drawn as a η3-oxoallyl Pd-complex),
a hydride transfer from the R-proton of the proton sponge to
palladium provides the iminium ion III and the Pd(II) hydride
complex IV.19 The Pd(II) hydride complex IV then collapses
to provide 2 with reductive elimination to regenerate Pd(0). By
using our standard reaction conditions with proton sponge as
the amine base, no formation of the indenone type product was
observed in any case (Table 2), which would arise from a
classical Heck reaction. This is not surprising as â-hydride
Analogous to the intermolecular, palladium-catalyzed con-
jugate addition of aryl halides to R,â-unsaturated ketones, we
propose the following reaction mechanism outlined in Scheme
1 for the formation of indanones 2.18 Oxidative addition of the
(18) (a) Cacchi, S.; Arcadi, A. J. Org. Chem. 1983, 48, 4236. (b)
Amorese, A.; Arcadi, A.; Bernocchi, E.; Cacchi, S.; Cerrini, S.; Fedeli,
W.; Ortar, G. Tetrahedron 1989, 45, 813. (c) Friestad, G. K.; Branchaud,
B. P. Tetrahedron Lett. 1995, 36, 7047. (d) Hagiwara, H.; Eda, Y.;
Morohashi, K.; Suzuki, T.; Ando, M.; Ito, N. Tetrahedron Lett. 1998, 39,
4055. (e) Trost, B. M. J. Org. Chem. 2004, 69, 5813.
(19) Complexation of a tertiary amine with palladium(II) followed by
metal insertion and subsequent â-hydride elimination has been described
before: (a) Konopelski, J. P.; Chu, K. S.; Negrete, G. R. J. Org. Chem.
1991, 56, 1355. (b) Stokker, G. E. Tetrahedron Lett. 1987, 28, 3179. (c)
Murahashi, S.-I.; Watanabe, T. J. Am. Chem. Soc. 1979, 101, 7429.
(16) A single report on the generation of racemic 3a in 1% yield by
gas-flow thermolysis has been reported: Koller, M.; Karpf, M.; Dreiding,
A. S. HelV. Chim. Acta 1986, 69, 560.
(17) (a) Pletnev, A. A.; Tian, Q.; Larock, R. C. J. Org. Chem. 2002, 67,
9276. (b) Pletnev, A. A.; Tian, Q.; Larock, R. C. J. Org. Chem. 1993, 58,
4579.
J. Org. Chem, Vol. 72, No. 24, 2007 9255

Minatti et al.
TABLE 3. Scope of the Palladium-Catalyzed Asymmetric Synthesis of 3-Substituted r-exo-Methylene Indanones 3
a Yields of the isolated products are the average of two runs. b Determined by HPLC on a chiral stationary phase. c The triflate was used instead of the
nonaflate. d Reaction conducted in DMF.
SCHEME 1. Proposed Catalytic Cycle (X ) OTf, ONf)
FIGURE 1. ORTTEP illustration of a cationic Pd(II) complex related
to I. Thermal ellipsoids at 50% probability. Solvent and counterions
removed for clarity. Selected bond lengths [Å] and angles [deg]: C77-
O3 1.264(8), C77-C78 1.459(8), C78-C79 1.344(7), Pd1-C71 2.056-
(8), Pd1-O3 2.089(8), Pd1-P1 2.2357(7), Pd1-P2 2.3562(7), C71-
Pd1-O3 81.3(4), O3-Pd1-P2 93.1(6), C71-Pd1-P1 94.3(3), P1-
Pd1-P2 93.79(2)
elimination to yield the 3-aryl-substituted indenone is possible
only if isomerization of the cis-configured intermediate II to
the trans-configured complex via a η3-oxoallyl Pd-complex
occurs.
We were able to obtain an X-ray crystal structure of the
cationic palladium(II) complex I derived from racemic MeO-
BIPHEP (Figure 2). The solid-state structure of the cationic
complex shows the coordination of the carbonyl unit to the
palladium(II) center. As a consequence the carbonyl double bond
[1.264(8) Å vs 1.204(6) Å] and the R,â-unsaturated olefinic
bond [1.344(7) Å vs 1.319(6) Å] are slightly elongated compared
to those of free chalcone.20 The fact that the Pd1-P1 bond
[2.2357(1) Å] is shorter than the Pd1-P2 bond [2.3562 (7) Å]
presumably reflects the higher trans influence of the aryl group
compared with that of the O-carbonyl moiety.
The observed stereochemical outcome of the reaction with
the C2-symmetric, (R)-configured ligand can be rationalized
based on the two diastereomeric intermediates A and B shown
in Figure 2 for the formation of indanone 2g as a representative
example, assuming that the carbopalladation of the (E)-
configured double bond (I f II) is the stereochemistry-
determining step. Molecular mechanics calculations with MMFF
force field were used to visualize the structures A and B. In the
(20) Rabinovich, D. J. Chem. Soc. B 1970, 11.
9256 J. Org. Chem., Vol. 72, No. 24, 2007

Synthesis of Chiral 3-Substituted Indanones
FIGURE 2. Proposed enantiofacial selection with (R)-3,5-XylMeOBIPHEP-Pd(II) template. The backbone of the ligand is omitted for clarity.
SCHEME 2. Deuterium-Labeling Experiment
In conclusion, we have developed a highly efficient synthesis
of chiral 3-aryl-substituted indanones and R-exo-methylene
indanones based upon an asymmetric reductive-Heck reaction
using (R)-3,5-XylMeOBIPHEP as the chiral ligand. Most
important, the described catalyst system provides ready access
to enantiomerically enriched trans-2-alkyl-3-aryl-substituted
indanones or the corresponding cis-isomers by manipulation of
the methylene group in the R-exo-methylene indanones.
favored structure A, the relatively uncrowded quadrants 1 and
3 are occupied by the substrate and the double bond is
coordinating to palladium from its si-re face. Structure B is
disfavored due to steric interactions in congested quadrant 2.
The origin of the R-exo-methylene group in indanones 3 was
probed by using deuterium-labeled PMP. Using our otherwise
standard reaction conditions, 45% of the R-exo-dideuterometh-
ylene indanone 4 was obtained as the sole product (Scheme 2).
On the basis of this result, two possible reaction mechanisms
can be proposed for the formation of indanones 3 (Scheme 3).
Both pathways involve a Mannich-type reaction of the iminium
ion V (Scheme 3), which is obtained after hydride transfer from
PMP to Pd(II)-enolate II (Scheme 1).21 The Eschenmoser salt
V22 can react either with the Pd(II)-enolate IV or with the
already realeased indanone 2 to yield the final product 3.23 We
assume that in the case of proton sponge the Mannich-type
reaction with the Eschenmoser salt III (Scheme 1) is not favored
as the positive charge on the iminium ion is stabilized by the
lone pair electrons of the adjacent nitrogen atom, rendering it
less electrophilic.
The methylene group in the conformationally restricted s-cis
indanones 3 can undergo a variety of synthetic transformations
as is known for related compounds bearing an R-exo-methylene
group.24 Performing a Michael-addition on the enantioenriched
indanone 3a or hydrogenation of the olefinic double bond
generated an additional stereocenter in the R-position. The
enantiomerically enriched 2-alkyl-3-phenyl-substituted in-
danones 5 and cis-2m were each obtained with excellent
diastereoselectivity (Scheme 4). The latter result demonstrates
that the synthetic approaches presented in Tables 2 and 3 are
complementary as both cis- and trans-2m are readily accessible.
Experimental Section
General Procedure for Table 2. An oven-dried screw-cap test
tube equipped with a Teflon septum was charged with a magnetic
stirbar, the corresponding nonaflate or triflate (1 equiv), Pd(OAc)2
(5 mol %), (R)-3,5-XylMeOBIPHEP (10 mol %), and proton sponge
(2 equiv). The tube was evacuated and backfilled with argon; this
procedure was carried out two times. The solids were dissolved in
DMF (4 mL/mmol nonaflate or triflate), the reaction tube was
sealed, and the reaction mixture was stirred in a preheated oil-bath
at 100 °C for 12 h. The reaction mixture was cooled to room
temperature, diluted with ethyl acetate (20 mL/mmol nonaflate),
and washed with an aqueous solution of HCl (1 M, 20 mL/mmol
nonaflate). The organic phase was separated, washed with brine,
and dried over MgSO4. The solvent was evaporated under reduced
pressure and the crude material was purified by column chroma-
tography on silica gel. A representative example is given.
6-Methoxy-(3S)-phenylindan-1-one (2b). Compound 2b was
prepared according to the general procedure with (E)-4-methoxy-
2-(3-phenylprop-2-enoyl)phenyl nonafluorobutanesulfonate 1b (268
mg, 0.500 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol), (R)-3,5-
XylMeOBIPHEP (35 mg, 0.050 mmol), and proton sponge (214
mg, 1.00 mmol) in DMF (2 mL). The crude material was purified
by column chromatography (hexane/ethyl acetate 5:1) to give the
title compound as a white solid (104 mg, 87%, 76% ee). 1H NMR
(400 MHz, CDCl3) δ 7.24-7.34 (m, 4H), 7.17 (2H, J ) 1.5 Hz),
7.13 (m, 2H), 4.53 (dd, 1H, J ) 3.6, 7.8 Hz), 3.87 (s, 3H), 3.27
(dd, 1H, J ) 7.8, 19.2 Hz), 2.71 (dd, 1H, J ) 3.6, 19.2 Hz); 13C
NMR (100 MHz, CDCl3) δ 206.0, 159.7, 150.8, 143.9, 138.0, 128.8,
127.6, 127.5, 126.9, 124.5, 104.3, 55.6, 47.5, 43.7; IR (neat) ν 3400,
3027, 2940, 2836, 1709, 1613, 1489, 1331, 1282, 1243, 1045, 1026,
839, 760, 701 cm-1; Anal. Calcd for C16H14O2: C, 80.65; H, 5.92.
Found: C, 80.36; H, 5.84. Mp 74-75 °C. The enantiomeric excess
of 2b was determined by HPLC analysis (Chiracel OJ column,
i-PrOH/hexane 5:95; 1.0 mL/min, 254 nm); (3R) isomer (minor)
tR ) 18.1 min and (3S) isomer (major) tR ) 22.3 min; [R]D +43.3
(c 0.6, CHCl3).
(21) Roberts, J. L.; Borromeo, P. S.; Poulter, C. D. Tetrahedron Lett.
1977, 19, 1621.
(22) Attempts to synthesize the Eschemoser salt V independently did
not meet with success.
(23) A similar Mannich reaction with cyclic enones and elimination of
the amino group has been reported before: Porzelle, A.; Williams, C. M.
Synthesis 2006, 3025.
(24) (a) Fotiadu, F.; Michel, F.; Buono, G. Tetrahedron Lett. 1990, 31,
4863. (b) Otto, A.; Liebscher, J. Synthesis 2003, 1209. (c) Evans, C. A.;
Miller, S. J. J. Am. Chem. Soc. 2003, 125, 12394. (d) Muthusamy, S.;
Krishnamurthi, J.; Nethaji, M. Chem. Commun. 2005, 3862. (e) Tsuchikama,
K.; Kuwata, Y.; Shibata, T. J. Am. Chem. Soc. 2006, 128, 13686. (f) Mo¨ıse,
J.; Arseniyadis, S.; Cossy, J. Org. Lett. 2007, 9, 1695.
General Procdure for Table 3. An oven-dried Schlenk tube
equipped with a Teflon screw seal was charged with a magnetic
stirbar, the corresponding nonaflate or triflate (1 equiv), Pd(OAc)2
(5 mol %), (R)-3,5-XylMeOBIPHEP (10 mol %), and pentameth-
ylpiperidine (3 equiv). The tube was evacuated and backfilled with
argon; this procedure was carried out two times. The solids were
dissolved in the corresponding solvent (4 mL/mmol nonaflate or
triflate), the reaction tube was sealed, and the reaction mixture was
stirred in a pre-heated oil-bath at 100 °C for 12 h. The reaction
J. Org. Chem, Vol. 72, No. 24, 2007 9257

Minatti et al.
SCHEME 3. Mechanistic Proposal for the Formation of Indanones 3 via a Mannich-Eschenmoser Methylenation Pathway (X
) OTf, ONf)
SCHEME 4. Synthesis of Enantiomerically Enriched 2-Alkyl-3-phenyl-Substituted Indanones
mixture was cooled to room temperature, diluted with ethyl acetate
(20 mL/mmol nonaflate), and washed with an aqueous solution of
HCl (1 M, 20 mL/mmol nonaflate). The organic phase was
separated, washed with brine, and dried over MgSO4. The solvent
was evaporated under reduced pressure and the crude material was
purified by column chromatography on silica gel. A representative
example is given.
tR ) 11.8 min and (3S) isomer (major) tR ) 15.0 min; [R]D +71.0
(c 0.86, CHCl3); A copy of the NMR spectra is provided.
Acknowledgment. Generous financial support from the
National Institutes of Health (GM 46059) is gratefully acknowl-
edged. We thank Hoffmann-La Roche and Dr. R. Schmid for a
generous gift of (R)-3,5-Xyl-MeOBIPHEP and BASF for Pd-
(OAc)2. A.M. thanks the Alexander von Humboldt Stiftung for
a postdoctoral Feodor Lynen Fellowship. We are indepted to
Dr. T. E. Barder for measuring the X-ray crystal structure and
Dr. P. Mu¨ller for refining the structure. We thank A. M. Hyde
for assistance with the calculations. The Bruker Advance 400
MHz used in this work was purchased with funding from the
National Institutes of Health (GM 1S10RR13886-01). The
Varian NMR instruments used for this publication were sup-
ported by National Science Foundation (CHE 9808061 and DBI
9729592).
6-Methoxy-2-methylene-(3S)-phenylindan-1-one (3b). Com-
pound 3b was prepared according to the general procedure with
(E)-4-methoxy-2-(3-phenylprop-2-enoyl)phenyl nonafluorobutane-
sulfonate 1b (268 mg, 0.500 mmol), Pd(OAc)2 (5.6 mg, 0.025
mmol), (R)-3,5-Xyl-MeO-BIPHEP (35 mg, 0.050 mmol), and
pentamethylpiperidine (270 µL, 1.5 mmol) in 1,4-dioxane (2 mL).
The crude material was purified by column chromatography
(hexane/ethyl acetate 5:1) to give the title compound as a white
1
solid (82 mg, 65%, 76% ee). H NMR (400 MHz, CDCl3) δ 7.32
(m, 1H), 7.20-7.29 (m, 3H), 7.15 (m, 2H), 7.07-7.09 (m, 2H),
6.36 (dd, 1H, J ) 0.5, 2.2 Hz), 5.34 (dd, 1H, J ) 0.4, 1.7 Hz),
4.89 (t, 1H, J ) 1.9 Hz), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 193.5, 160.0, 149.8, 146.6, 142.7, 138.9, 128.9, 128.3, 127.5,
127.2, 125.0, 121.0, 105.3, 55.75, 48.5; IR (neat) ν 3027, 2941,
2836, 1704, 1641, 1612, 1489, 1331, 1282, 1251, 1189, 1159, 1026,
1008, 837, 800, 762, 700 cm-1; mp 90 °C; the enantiomeric excess
of 3b was determined by HPLC analysis (Chiracel OJ column,
i-PrOH/hexane 5:95; 1.0 mL/min, 254 nm); (3R) isomer (minor)
Supporting Information Available: Experimental procedures
and characterization data for all new and known compounds and
X-ray crystallographic data for complex I. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO701741Y
9258 J. Org. Chem., Vol. 72, No. 24, 2007