Enantioselective synthesis of 3-arylindan-1-ones via intramolecular C-H insertion reactions of -diazo--ketoesters catalyzed by chiral dirhodium(II) carboxylates

Article abstract of DOI:10.3987/com-06-s(w)58

A new, catalytic enantioselective route to 3-arylindan-1-ones, versatile intermediates for the synthesis of a number of bioactive and pharmaceutically interesting molecules, was developed by exploiting the chiral dirhodium(II) complex-catalyzed intramolec

Full text of DOI:10.3987/com-06-s(w)58

HETEROCYCLES, Vol. 70, 2006
635
HETEROCYCLES, Vol. 70, 2006 , pp. 635 - 646. © The Japan Institute of Heterocyclic Chemistry
Received, 12th October, 2006, Accepted, 15th November, 2006, Published online, 17th November, 2006. COM-06-S(W)58
ENANTIOSELECTIVE SYNTHESIS OF 3-ARYLINDAN-1-ONES VIA
INTRAMOLECULAR
C–H
INSERTION
REACTIONS
OF
α-DIAZO-β-KETOESTERS CATALYZED BY CHIRAL DIRHODIUM(II)
†
CARBOXYLATES
Yoshihiro Natori, Masahiro Anada, Seiichi Nakamura, Hisanori Nambu, and
Shunichi Hashimoto*
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812,
Japan
e-mail: hsmt@pharm.hokudai.ac.jp
Abstract – A new, catalytic enantioselective route to 3-arylindan-1-ones, versatile
intermediates for the synthesis of a number of bioactive and pharmaceutically
interesting molecules, was developed by exploiting the chiral dirhodium(II)
complex-catalyzed intramolecular C–H insertion reaction of α-diazo-β-ketoesters
as
a
key step. Dirhodium(II) tetrakis[N-phthaloyl-(S)-tert-leucinate],
Rh2(S-PTTL) , proved to be the catalyst of choice for this process, providing
4
enantioselectivities of up to 72% ee.
3-Arylindan-1-ones (1) are versatile intermediates in the synthesis of a number of important
*
2
pharmaceuticals, such as the antidepressant indatraline,1 the antipsychotic drug tefludazine, the
muscarinic receptor antagonist tolterodine,3 and the endothelin receptor antagonists SB-209670 and
CH2CH2OH
OMe
N
NHCH3•HCl
N
R3
O
R1
O
nPrO
F3C
OH
CO2H
N
O
R2
Cl
Cl
indatraline
F
O
R3 = CO2H SB-209670
R3 = CH2OH SB-217242
tefludazine
tolterodine
1
†
Dedicated to Professor Steven M. Weinreb on the occasion of his 65th birthday.

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HETEROCYCLES, Vol. 70, 2006
SB-217242.4 Because of their importance, several strategies have been developed to achieve the
asymmetric synthesis of 1, including a net stereospecific 1,3-hydrogen transfer of chiral 3-arylinden-1-ols,
prepared by the methyloxazaborolidine (Me-CBS)-catalyzed enantioselective reduction of
3-arylinden-1-ones,3,4a Nazarov-type ring closure of alkylidene-1,3-carbonyl compounds carrying Evans'
oxazolidinone as a chiral auxiliary,4b the enantioselective conjugate reduction of 3-arylinden-1-ones using
baker’s yeast,5 the Friedel–Crafts cyclization of a chiral 3,3-diarylpropionic acid, prepared by an
enantioselective intermolecular C–H insertion reaction with a chiral dirhodium(II) catalyst,1d and the
enantioselective hydroacylation of 2-(1-arylvinyl)benzaldehydes catalyzed by a chiral cationic rhodium(I)
complex.6
In recent years, we have been engaged in the enantioselective construction of five-membered carbocycles
via a C–H insertion process,7 catalyzed by chiral dirhodium(II) complexes, which incorporate
N-phthaloyl- and N-benzene-fused-phthaloyl-(S)-amino acids as the bridging ligands.8-11 These catalysts
mediate intramolecular C–H insertion reactions of a structurally diverse array of α-diazocarbonyl
compounds to give optically active cyclopentane,8 cyclopentanone,9 2-indanone10 and
1,1’-spirobi[indan-3,3’-dione]11 derivatives with a maximum of 95%, 80%, 98%, and 80% ee's,
respectively. In a continuation of our work in this field, we wish to report a new method for the catalytic
enantioselective synthesis of 3-arylindan-1-ones, based on an intramolecular C–H insertion process.
O
N
O
N
R
H
H
O
O
O
O
O
O
Rh Rh
Rh Rh
R = But: Rh2(S-PTTL)4 (2a)
R = Me: Rh2(S-PTA)4 (2b)
R = Bn: Rh2(S-PTPA)4 (2c)
R = Pri: Rh2(S-PTV)4 (2d)
Rh2(S-BPTTL)4 (2e)
In our initial studies, we explored the intramolecular C–H insertion reaction of methyl
3-(2-benzylphenyl)-2-diazo-3-oxopropanoate (3a) using mol of dirhodium(II)
1
%
tetrakis[N-phthaloyl-(S)-tert-leucinate], Rh2(S-PTTL) (2a),12 in the presence of pulverized 4Å molecular
4
sieves (MS).13 The reaction in toluene at 0 °C proceeded smoothly to completion within 1 h, giving cyclic
β-ketoester (4a) in 98% yield as an 85:15 equilibrium mixture of the keto and enol forms (Table 1, Entry
1). After the demethoxycarbonylation of 4a to 3-phenylindan-1-one (1a), the magnitude of
enantioselection at the insertion site (C-3) was determined to be 64% ee by HPLC (Daicel Chiralpak AS).
The preferred absolute stereochemistry of 1a [[α]2D3 –39.7° (c 1.26, CHCl3) for 64% ee] was established
as R by its transformation [mCPBA, cat. TsOH, CH2Cl , reflux, 30 h]3 to the known
2

HETEROCYCLES, Vol. 70, 2006
637
4-phenylchroman-2-one [[α]2D3 –26.5° (c 1.36, CHCl3) for 64% ee; lit.,14 [α]2D0 –45.1° (c 0.98, CHCl3) for
(R)-enantiomer (99.4% ee)]. A survey of solvents revealed that toluene was the optimal solvent for this
transformation in terms of both product yield and enantioselectivity (Entries 1 vs 2 and 3). Using toluene
as the solvent, we next evaluated the performance of some other chiral dirhodium(II) carboxylate
catalysts, Rh2(S-PTA)4 (2b), Rh2(S-PTPA)4 (2c), and Rh2(S-PTV)4 (2d), derived from
N-phthaloyl-(S)-alanine, -phenylalanine, and -valine, respectively. Although a uniform sense of
asymmetric induction was observed in all cases, these catalysts resulted in much lower
enantioselectivities than Rh2(S-PTTL)4 (Entries 4–6). Somewhat disappointingly, switching the catalyst
to Rh2(S-BPTTL)4 (2e)15 characterized by an extension of the phthalimido wall with one additional
benzene ring had no beneficial effect in this system, and the same enantioselectivity as Rh2(S-PTTL)4
was found (64% ee, Entry 7). Thus we were gratified to find that enantioselectivity with Rh2(S-PTTL)4
was enhanced up to 70% ee by lowering the temperature of the reaction to –15 °C without significant loss
Table 1. Enantioselective Intramolecular C–H Insertion Reaction of !-Diazo-"-ketoester (3a)
a)
Catalyzed by Chiral Dirhodium(II) Carboxylates
O
O
O
CO2Me
Rh(II) catalyst (1 mol %)
4Å MS, solvent (0.1 M)
DMSO-H2O
CO2Me
N2
120 °C, 0.5 h
3a
4a
1a
"-Ketoesters 4a 3-Phenylindan-1-one 1a
b)
b)
c)
Entry
Rh(II) catalyst
Solvent
T (°C) Time (h)
Yield (%)
Yield (%)
Ee (%)
e)
01
02
03
04
05
06
07
08
09
10
Rh2(S-PTTL)4 (2a)
Rh2(S-PTTL)4 (2a)
Rh2(S-PTTL)4 (2a)
Rh2(S-PTA)4 (2b)
Rh2(S-PTPA)4 (2c)
Rh2(S-PTV)4 (2d)
Rh2(S-BPTTL)4 (2e)
Rh2(S-PTTL)4 (2a)
Rh2(S-BPTTL)4 (2e)
Rh2(S-PTTL)4 (2a)
toluene
CF3C6H5
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
0
0
1
1
98
89
92
94
96
94
91
91
78
66
93
95
93
95
96
94
93
93
95
92
64
e)
60
e)
0
3
54
e)
0
1.5
1.5
1
19
e)
0
4
e)
0
32
e)
0
1
64
e)
–15
–15
–23
3
70
e)
3
66
e)
7
72
a)
b)
c)
All reactions were performed on a 0.2 mmol scale. Isolated yield. Determined by HPLC (Daicel Chiralpak
AS).

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HETEROCYCLES, Vol. 70, 2006
in product yield (Entry 8), whereas catalysis with Rh2(S-BPTTL)4 under the same condition resulted in
66% ee with a substantial decrease in product yield (Entry 9). Although a further enhancement of up to
72% ee was possible at a temperature –23 °C, –15 °C was found to be the temperature limit in terms of
both reaction rate and product yield (Entry 10).16
Having identified the effectiveness of the combination of Rh2(S-PTTL)4 as the catalyst and toluene as the
solvent, we then applied this protocol to the enantioselective synthesis of a key intermediate (1b) for
serotonin and norepinephrine uptake inhibitors (Scheme 1).17 The Cu(I)-catalyzed cross-coupling reaction
of the arylmagnesium compound, prepared from 5 via an iodine-magnesium exchange, with piperonyl
bromide in the presence of CuCN and LiCl afforded the benzhydryl derivative (6) in 64% yield.18
Saponification of 6 and subsequent conversion to the acid chloride were followed by condensation with
methyl lithioacetate to furnish the β-ketoester (7) in 84% overall yield, which, upon diazo transfer with
methanesulfonyl azide, gave the α-diazo-β-ketoester (3b) in 95% yield.19 The intramolecular C–H
insertion reaction of 3b using 1 mol % of Rh2(R-PTTL)4 at –15 °C proceeded uneventfully to afford the
desired cyclic β-ketoester (4b) in 88% yield. Removal of the methoxycarbonyl group from 4b gave
(S)-3-(3,4-methylenedioxyphenyl)indan-1-one (1b) [[α]2D3 +28.6° (c 1.85, CHCl3)] in 93% yield.20 The
enantiomeric purity of 1b was determined to be 63% ee by HPLC (Daicel Chiralpak AS).
O
1. NaOH, MeOH/H2O
CO2Me
CO2Me
MsN3, Et3N
reflux, 2 h
2. SOCl2, CHCl3
reflux, 2 h
1. iPrMgBr, THF
–30 °C, 0.5 h
CO2Me
I
2. piperonyl bromide
CuCN, LiCl, THF
– 20 °C, 3 h
MeCN
23 °C, 1 h
3. LDA, CH3CO2Me
THF, – 78 to 0 °C
2 h
O
O
O
5
95%
64%
84%
O
6
7
O
O
O
CO2Me
Rh2(R-PTTL)4 (1.0 mol %)
DMSO-H2O
CO2Me
N2
120 °C, 0.5 h
93%
4Å MS, toluene (0.1 M)
–15 °C, 15 h
88%
O
O
O
O
O
O
3b
4b
1b
Scheme 1
In summary, the Rh2(S-PTTL)4-catalyzed intramolecular C–H insertion reaction of α-diazo-β-ketoesters
shows considerable promise for the enantioselective synthesis of 3-arylindan-1-ones. Further evaluation
of the scope of these intramolecular C–H insertion reactions is currently in progress.

HETEROCYCLES, Vol. 70, 2006
639
EXPERIMENTAL
General. Melting points were determined on a Büchi 535 digital melting point apparatus and are
uncorrected. IR spectra were recorded on a JASCO FT/IR-5300 spectrometer and absorbance bands are
1
reported in wavenumber (cm-1). H NMR spectra were recorded on JEOL JNM-AL 400 (400 MHz)
spectrometer. Chemical shifts are reported relative to internal standard (tetramethylsilane; δH 0.00). Data
are presented as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m =
13
multiplet), coupling constant and integration. C NMR spectra were recorded on JEOL JNM-AL 400
(100 MHz) spectrometer. Chemical shifts are reported relative to internal standard (CDCl3; δ 77.0).
Optical rotations were measured on a JASCO P-1030 digital polarimeter at the sodium D line (589 nm).
EI-MS spectra were obtained on a JEOL JMS-HX 110 spectrometer. Column chromatography was
carried out on Kanto silica gel 60 N (63-210 mesh). Analytical thin layer chromatography (TLC) was
carried out on Merck Kieselgel 60 F254 plates with visualization by ultraviolet, anisaldehyde stain solution
or phosphomolybdic acid stain solution. Analytical high performance liquid chromatography (HPLC) was
performed on JASCO PU-1580 intelligent HPLC pump with JASCO UV-1575 intelligent UV/VIS
detector. Detection was performed at 254 nm. Chiralpak AS and Chiralcel OD-H columns (0.46 cm × 25
cm) from Daicel were used. Retention times (tR) and peak ratio were determined with Shimadzu C-R8A
chromatopac integrator or JASCO-Borwin analysis system.
All non-aqueous reactions were carried out in flame-dried glassware under argon atmosphere.
α-Phenyl-o-toluic acid was purchased from Aldrich, Inc. Reagents and solvents were purified by standard
means. Dehydrated THF, CH2Cl2 and toluene were purchased from Kanto Chemical Co., Inc.
Methanesulfonyl azide was prepared according to the procedure of Danheiser.21 4Å MS was used after
pulverized and dried (150 °C, 1 mmHg, 12 h).
Methyl 3-(2-benzylphenyl)-2-diazo-3-oxopropanoate (3a). Thionyl chloride (2.8 mL, 37.7 mmol) was
added to a solution of α-phenyl-o-toluic acid (4.0 g, 18.8 mmol) in CHCl3 (60 mL). The mixture was
refluxed for 4 h and evaporated in vacuo. The residue was dissolved in toluene (20 mL) and evaporated in
i
vacuo. n-BuLi in n-hexane (1.59 M, 26.1 mL, 41.5 mmol) was added to a solution of Pr2NH (6.4 mL,
45.6 mmol) in THF (42 mL) at –78 °C. After stirring at –78 °C for 30 min, methyl acetate (3.3 mL, 41.5
mmol) was added dropwise over 10 min. After stirring at –78 °C for 1 h, a solution of crude acid chloride
in THF (19 mL) was added to the mixture via cannula. After stirring at –78 °C for 30 min, the mixture
was allowed to warm to room temperature over 1 h. The reaction mixture was poured into 5% aqueous
HCl (40 mL) at 0°C. The whole mixture was extracted with EtOAc (2 × 80 mL), and the combined
organic layers were washed successively with water (50 mL) and brine (2 × 50 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude product (5.4 g), which was

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HETEROCYCLES, Vol. 70, 2006
purified by column chromatography (silica gel 150 g, 10:1 hexane/EtOAc) to afford methyl
3-(2-benzylphenyl)-3-oxopropanoate (4.70 g, 93%) as a white solid; Rf 0.46 (3:1 hexane/EtOAc); mp
35.5-36.0 °C (hexane/EtOAc); IR (KBr) ν 1739, 1687 cm-1;1H NMR (400 MHz, CDCl3, 76:24 mixture of
keto/enol tautomers) keto tautomer: δ 3.69 (s, 3H, CO2CH3), 3.85 (s, 2H, COCH2CO2CH3), 4.28 (s, 2H,
ArCH2Ar), 7.13-7.65 (m, 9H, ArH); enol tautomer: δ 3.77 (s, 3H, CO2CH3), 4.19 (s, 2H, ArCH2Ar), 5.25
(s, 1H, =CH–), 7.13-7.65 (m, 9H, ArH), 12.4 (s, 1H, C=COH); 13C NMR (100 MHz, CDCl3) keto
tautomer: δ 39.1 (CH2), 48.2 (CH2), 52.4 (CH3), 125.9 (CH), 126.2 (CH), 128.2 (CH), 128.8 (CH), 129.1
(CH), 131.9 (CH), 132.0 (CH), 136.5 (C), 140.5 (C), 141.5 (C), 167.7 (C), 195.7 (C); enol tautomer: δ
39.0 (CH2), 51.4 (CH3), 91.7 (CH), 125.9 (CH), 126.2 (CH), 128.2 (CH), 128.7 (CH), 128.9 (CH), 130.1
(CH), 130.8 (CH), 134.5 (C), 139.3 (C), 140.7 (C), 172.9 (C), 174.7 (C); LRMS (EI) m/z 268 (M+), 250,
194, 165; HRMS (EI) calcd for C17H16O3 (M+) 268.1099, found 268.1105; Anal. Calcd for C17H16O3: C,
76.10; H, 6.01. Found: C, 76.00; H, 6.05.
To a solution of methyl 3-(2-benzylphenyl)-3-oxopropanoate (2.0 g, 7.45 mmol) and triethylamine (2.1
mL, 14.9 mmol) in MeCN (25 mL) at 0 °C was added methanesulfonyl azide (994 mg, 8.21 mmol). After
stirring at room temperature for 1 h, water (15 mL) was poured into the orange-colored reaction mixture.
The whole mixture was extracted with EtOAc (2 × 30 mL), and the combined organic layers were washed
successively with 5% aqueous NaOH (20 mL), water (20 mL) and brine (2 × 20 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude product (2.5 g), which was
purified by column chromatography (silica gel 50 g, 10:1 hexane/EtOAc) to afford 3a (2.10 g, 96%) as a
yellow solid; Rf 0.39 (3:1 hexane/EtOAc); mp 107-107.5 °C (hexane/EtOAc); IR (KBr) ν 2137, 1726,
1626 cm-1; 1H NMR (270 MHz, CDCl3) δ 3.66 (s, 3H, CO2CH3), 4.06 (s, 2H, ArCH2Ar), 7.10-7.29 (m, 8H,
ArH), 7.38 (dt, J = 2.0, 7.3 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 38.8 (CH2), 52.1 (CH3), 125.6
(CH), 126.0 (CH), 126.7 (CH), 128.1 (CH), 129.2 (CH), 130.3 (CH), 130.5 (CH), 137.8 (C), 138.3 (C),
140.0 (C), 160.4 (C), 188.4 (C); LRMS (EI) m/z 294 (M+), 206, 178; HRMS (EI) calcd for C17H14N2O3
(M+) 294.1004, found 294.1005; Anal. Calcd for C17H14N2O3: C, 69.38; H, 4.79; N, 9.52. Found: C, 69.51;
H, 4.78; N, 9.65.
Representative procedure for the enantioselective intramolecular C–H insertion reaction (Table 1,
Entry 8): (3R)-Methyl 3-phenylindan-1-one-2-carboxylate (4a). Rh2(S-PTTL)4 (2.85 mg, 0.0020
mmol) was added to a solution of 3a (58.9 mg, 0.2 mmol) and pulverized 4Å MS (58.9 mg) in toluene
(2.0 mL) at –15 °C. After stirring at –15 °C for 3 h, the whole mixture was filtrated through a Celite pad.
The filter cake was rinsed with EtOAc (10 mL) and the combined filtrates were evaporated in vacuo. The
crude product (61.0 mg) was purified by column chromatography (silica gel 8 g, 15:1 hexane/EtOAc) to

HETEROCYCLES, Vol. 70, 2006
641
afford 4a (48.5 mg, 91%) as a white solid; Rf 0.48 (3:1 hexane/EtOAc); mp 120-122 °C; IR (KBr) ν 3277,
1719, 1658 cm–1; 1H NMR (270 MHz, CDCl3, 85:15 mixture of keto/enol tautomers) keto tautomer: δ
3.71 (d, J = 4.6 Hz, 1H, COCHCO2CH3), 3.82 (s, 3H, CO2CH3), 5.02 (d, J = 4.6 Hz, 1H, ArCHAr),
7.08-7.38 (m, 6H, ArH), 7.46 (dt, J = 1.3, 7.6 Hz, 1H, ArH), 7.62 (dt, J = 1.3, 7.6 Hz, 1H, ArH), 7.83 (dd,
J = 1.3, 7.6 Hz, 1H, ArH); enol tautomer: δ 3.68 (s, 3H, CO2CH3), 4.75 (s, 1H, ArCHAr), 7.08-7.85 (m,
9H, ArH); 13C NMR (100 MHz, CDCl3) keto tautomer: δ 48.6 (CH), 52.8 (CH3), 63.4 (CH), 124.2 (CH),
126.6 (CH), 127.4 (CH), 127.8 (CH), 128.2 (CH), 128.9 (CH), 134.8 (C), 135.7 (CH), 141.6 (C), 156.1
(C), 168.7 (C), 198.3 (C); LRMS (EI) m/z 266 (M+), 206, 178; HRMS (EI) calcd for C17H14O3 (M+)
266.0943, found 266.0941.
Representative procedure for demethoxycarbonylation (Table 1, Entry 8): (R)-3-phenylindan-1-one
(1a).22 4a (48.5 mg, 0.132 mmol) was treated with 95 % aqueous DMSO (1.5 mL) at 120 °C for 30 min.
After cooling, the reaction was quenched with water (5 mL). The whole mixture was extracted with
EtOAc (2 × 10 mL), and the combined organic layers were washed with brine (4 mL), and dried over
Na2SO4. Filtration and evaporation in vacuo furnished the crude product (49.1 mg), which was purified by
column chromatography (silica gel 7 g, 15:1 hexane/EtOAc) to afford 1a (35.3 mg, 93%) as a white solid;
Rf 0.46 (3:1 hexane/EtOAc); mp 46.0-47.0 °C for 70% ee [lit.,22 mp 77-78.5 °C for racemic 1a]; [α]2D3
1
–43.0° (c 1.66, CHCl3) for 70% ee; IR (KBr) ν 1703 cm–1; H NMR (270 MHz, CDCl3) δ 2.70 (dd, J =
3.6, 19.1 Hz, 1H, COCH2), 3.24 (dd, J = 7.9, 19.1 Hz, 1H, COCH2), 4.51 (dd, J = 3.6, 7.9 Hz, 1H,
ArCHAr), 7.12-7.35 (m, 6H, ArH), 7.42 (dd, J = 7.3, 7.6 Hz, 1H, ArH), 7.58 (t, J = 7.3 Hz, 1H, ArH),
7.82 (d, J = 7.6 Hz, ArH);13C NMR (100 MHz, CDCl3) δ 44.5 (CH), 46.9 (CH2), 123.3 (CH), 126.8 (CH),
126.9 (CH), 127.6 (CH), 127.8 (CH), 128.8 (CH), 135.0 (CH), 136.6 (C), 143.6 (C), 157.8 (C), 205.9 (C);
LRMS (EI) m/z 208 (M+), 179, 165; HRMS (EI) calcd for C15H12O (M+) 208.0888, found 208.0898. The
enantiomeric excess of 1a was determined to be 70% by HPLC with a Chiralpak AS column (9:1
hexane/2-propanol, flow rate = 1.0 mL/min): tR (minor) = 15.2 min for (S)-enantiomer; tR (major) = 30.1
min for (R)-enantiomer. The absolute configuration of 1a was determined to be R by chemical correlation
(vide infra).
Determination of absolute configuration of 1a: (R)-4-phenylchroman-2-one from
(R)-3-phenylindan-1-one (1a).14 The chroman derivative was prepared according to the protocol
reported by Andersson.3 mCPBA (98%, 59.2 mg, 0.336 mmol) and p-TsOH·H2O (3.2 mg, 0.0168 mmol)
were added to a solution of 1a (35.0 mg, 0.168 mmol, 64% ee) in CH2Cl2 (0.84 mL), and the mixture was
refluxed for 30 h. After cooling, the reaction mixture was dissolved in CH2Cl2 (15 mL) and quenched
with saturated aqueous Na2S2O3 (5 mL). The layers were separated, and the organic layer was washed

642
HETEROCYCLES, Vol. 70, 2006
successively with saturated aqueous NaHCO3 (5 mL) and brine (2 × 5 mL), and dried over Na2SO4.
Filtration and evaporation in vacuo furnished the crude product (48 mg), which was purified by column
chromatography (silica gel 5 g, 30:1 toluene/EtOAc) to afford (R)-4-phenylchroman-2-one (28.2 mg,
75%) as a white solid; Rf 0.47 (20:1 toluene/EtOAc); mp 101-102 °C for 64% ee [lit.,23 mp 110-112 °C
for 95% ee]; [α]2D3 –26.5° (c 1.36, CHCl3) for 64% ee [lit.,14 [α]2D0 –45.1° (c 0.98, CHCl3) for
(R)-enantiomer (99.4% ee)]; IR (KBr) ν 1762 cm–1; 1H NMR (270 MHz, CDCl3) δ 2.97-3.14 (m, 2H,
OCOCH2), 4.35 (t, J = 6.9 Hz, 1H, ArCH), 6.98 (d, J = 7.3 Hz, 1H, ArH), 7.06-7.18 (m, 4H, ArH),
7.27-7.39 (m, 4H, ArH); 13C NMR (100 MHz, CDCl3) δ 37.0 (CH2), 40.7 (CH), 117.0 (CH), 124.6 (CH),
125.7 (C), 127.5 (CH), 127.6 (CH), 128.2 (CH), 128.7 (CH), 129.0 (CH), 140.1 (C), 151.6 (C), 167.5 (C).
The enantiomeric excess of 4-phenylchroman-2-one was determined to be 64% by HPLC with a Chiralcel
OD-H column (19:1 hexane/2-propanol, flow rate = 1.0 mL/min): tR (minor) = 14.6 min for
(S)-enantiomer; tR (major) = 16.8 min for (R)-enantiomer.
Methyl 2-piperonylbenzoate (6). The benzhydryl derivative (6) was prepared according to the protocol
reported by Knochel.18 A Grignard reagent was prepared from 2-bromopropane (2.2 mL, 22.9 mmol) and
magnesium (557 mg, 22.9 mmol) in THF (16 mL). The solution of 2-propylmagnesium bromide was
added to a solution of methyl 2-iodobenzoate (5) (5.0 g, 19.1 mmol) in THF (19 mL) at –30 °C. After
stirring at –30 °C for 30 min, CuCN (342 mg, 3.82 mmol) and LiCl (323 mg, 7.63 mmol) were added to
the mixture. After stirring at –20 °C for 30 min, a solution of piperonyl bromide (4.52 g, 21.0 mmol) in
THF (10 mL) was added to the mixture at –20 °C via cannula. After stirring at –20 °C for 2.5 h, the
reaction mixture was poured into saturated aqueous NH4Cl (18 mL) and 25% aqueous NH3 (2.0 mL) at
0 °C. The whole mixture was extracted with CH2Cl2 (2 × 70 mL), and the combined organic layers were
washed successively with water (2 × 50 mL) and brine (2 × 50 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the crude product (4.50 g), which was purified by column
chromatography (silica gel 100 g, toluene) to afford 6 (3.31 g, 64%) as a colorless oil; Rf 0.54 (3:1
1
hexane/EtOAc); IR (neat) 1720 cm-1; H NMR (270 MHz, CDCl3) δ 3.85 (s, 3H, CO2CH3), 4.29 (s, 2H,
ArCH2Ar), 5.90 (s, 2H, OCH2O), 6.60-6.63 (m, 2H, ArH), 6.72 (d, J = 7.9 Hz, 1H, ArH), 7.19-7.31 (m,
2H, ArH), 7.43 (dt, J = 1.7, 7.6 Hz, 1H, ArH), 7.89 (dd, J = 1.7, 7.6 Hz, 1H, ArH); 13C NMR (100 MHz,
CDCl3) δ 39.2 (CH2), 52.0 (CH3), 100.7 (CH2), 108.0 (CH), 109.4 (CH), 121.7 (CH), 126.2 (CH), 129.7
(C), 130.6 (CH), 131.3 (CH), 131.9 (CH), 134.6 (C), 142.2 (C), 145.6 (C), 147.5 (C), 167.9 (C); LRMS
(EI) m/z 270 (M+), 238, 180, 152; HRMS (EI) calcd for C16H14O4 (M+) 270.0892, found 270.0895.
Methyl 3-(2-piperonylphenyl)-3-oxopropanoate (7). A solution of NaOH (884 mg, 22.1 mmol) in water
(15 mL) was added to a solution of 6 (2.98 g, 11.0 mmol) in MeOH (15 mL). The mixture was refluxed

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for 2 h and the MeOH was evaporated in vacuo. The aqueous layer was washed with Et2O (2 × 5 mL),
acidified to pH 3 with 10% aqueous HCl, and extracted with EtOAc (2 × 50 mL). The combined organic
layers were washed with brine (2 × 20 mL), and dried over anhydrous Na2SO4. Filtration and evaporation
in vacuo. The crude methyl 2-piperonylbenzoate (2.69 g) thus obtained was used without further
purification.
According to the procedure for preparation of methyl 3-(2-benzylphenyl)-3-oxopropanoate, 7 was
prepared from crude methyl 2-piperonylbenzoate (2.69 g) and methyl acetate (1.84 mL, 23.1 mmol). The
crude product (3.61 g) was purified by column chromatography (silica gel 130 g, 6:1 hexane/EtOAc) to
afford 7 (2.89 g, 84% for 2 steps) as a white solid; Rf 0.36 (3:1 hexane/EtOAc); mp 77.0-77.5 °C
1
(hexane/EtOAc); IR (KBr) ν 1729, 1687 cm-1; H NMR (270 MHz, CDCl3, almost keto form) δ 3.72 (s,
3H, COCH2CO2CH3), 3.88 (s, 2H, COCH2CO2CH3), 4.19 (s, 2H, ArCH2Ar), 5.90 (s, 2H, OCH2O),
6.59-6.63 (m, 2H, ArH), 6.72 (d, 1H, J = 7.6 Hz, ArH), 7.22-7.25 (m, 1H, ArH), 7.31 (dt, 1H, J = 1.3, 7.6
Hz, ArH), 7.43 (dt, 1H, J = 1.3, 7.6 Hz, ArH), 7.64 (dd, 1H, J = 1.3, 7.6 Hz, ArH); 13C NMR (100 MHz,
CDCl3) δ 38.7 (CH2), 48.2 (CH2), 52.4 (CH3), 100.7 (CH2), 108.0 (CH), 109.6 (CH), 121.9 (CH), 126.2
(CH), 128.8 (CH), 131.7 (CH), 132.0 (CH), 134.3 (C), 136.4 (C), 141.6 (C), 145.6 (C), 147.4 (C), 167.6
(C), 195.7 (C); LRMS (EI) m/z 312 (M+), 294, 238, 152; HRMS (EI) calcd for C18H16O5 (M+) 312.0997,
found 312.0988; Anal. Calcd for C18H6O5: C, 69.22; H, 5.16. Found: C, 69.09; H, 5.12.
Methyl 3-(2-piperonylphenyl)-2-diazo-3-oxopropanoate (3b). According to the procedure for
preparation of 3a from methyl 3-(2-benzylphenyl)-3-oxopropanoate, 3b was prepared from 7 (1.18 g,
3.78 mmol). The crude product (1.42 g) was purified by column chromatography (silica gel 40 g, 15:1
hexane/EtOAc) to afford 3b (1.21 g, 95%) as a yellow solid; Rf 0.27 (3:1 hexane/EtOAc); mp 150 °C
(decomp) (hexane/toluene); IR (KBr) ν 2146, 1724, 1625 cm-1; 1H NMR (270 MHz, CDCl3) δ 3.69 (s, 3H,
CO2CH3), 3.96 (s, 2H, ArCH2Ar), 5.89 (s, 2H, OCH2O), 6.57-6.60 (m, 2H, ArH), 6.69 (d, J = 8.6 Hz, 1H,
13
ArH), 7.21-7.29 (m, 3H, ArH), 7.38 (dt, J = 2.0, 7.3 Hz, 1H, ArH); C NMR (100 MHz, CDCl3) δ 38.4
(CH2), 52.2 (CH3), 100.7 (CH2), 107.8 (CH), 109.7 (CH), 122.2 (CH), 125.6 (CH), 126.7 (CH), 130.3
(CH), 130.3 (CH), 133.8 (C), 137.7 (C), 138.4 (C), 145.7 (C), 147.4 (C), 160.5 (C), 188.4 (C); LRMS
(EI) m/z 338 (M+), 278, 250, 220, 193, 165, 152; HRMS (EI) calcd for C18H14N2O5 (M+) 338.0902, found
338.0904; Anal. Calcd for C18H14N2O5: C, 63.90; H, 4.17; N, 8.28. Found: C, 63.95; H, 4.14; N, 8.39.
Enantioselective intramolecular C–H insertion reaction: (S)-Methyl 3-(3,4-methylenedioxy-
phenyl)indan-1-one-2-carboxylate (4b). According to the procedure for C–H insertion reaction, 4b was
prepared from 3b (67.7 mg, 0.20 mmol) and Rh2(R-PTTL)4 (2.85 mg, 0.0020 mmol) at –15 °C for 15 h.

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HETEROCYCLES, Vol. 70, 2006
The crude product (68.1 mg) was purified by column chromatography (silica gel 10 g, 7:1 hexane/EtOAc)
to afford 4b (54.7 mg, 88%) as a white solid; Rf 0.34 (3:1 hexane/EtOAc); mp 80-82 °C; IR (KBr) ν 3265,
1717, 1662 cm–1; 1H NMR (270 MHz, CDCl3, 84:16 mixture of keto/enol tautomers) keto tautomer: δ
3.64 (d, J = 4.9 Hz, 1H, COCHCO2CH3), 3.82 (s, 3H, CO2CH3), 4.94 (d, J = 4.9 Hz, 1H, ArCHAr), 5.95
(s, 2H, OCH2O), 6.56 (d, J = 1.7 Hz, 1H, ArH), 6.68 (dd, J = 1.7, 7.9 Hz, 1H, ArH), 6.77 (d, J = 7.9 Hz,
1H, ArH), 7.31 (dd, J = 0.7, 7.6 Hz, 1H, ArH), 7.45 (dt, J = 0.7, 7.6 Hz, 1H, ArH), 7.63 (dt, J = 1.3, 7.6
Hz, 1H, ArH), 7.82 (dd, J = 1.3, 7.6 Hz, 1H, ArH); enol tautomer: δ 3.71 (s, 3H, CO2CH3), 4.67 (s, 1H,
13
ArCHAr), 5.90-5.95 (m, 2H, OCH2O), 6.45-6.78 (m, 3H, ArH), 7.29-7.83 (m, 4H, ArH); C NMR (100
MHz, CDCl3) keto tautomer: δ 48.3 (CH), 52.9 (CH3), 63.6 (CH), 101.1 (CH2), 107.9 (CH), 108.5 (CH),
121.3 (CH), 124.2 (CH), 126.6 (CH), 128.3 (CH), 134.8 (C), 135.4 (C), 135.7 (CH), 146.9 (C), 148.1 (C),
156.0 (C), 168.7 (C), 198.2 (C); LRMS (EI) m/z 310 (M+), 278, 250, 220, 165; HRMS (EI) calcd for
C18H14O5 (M+) 310.0841, found 310.0840.
(S)-3-(3,4-methylenedioxyphenyl)indan-1-one
(1b).20
According
to
the procedure
for
demethoxycarbonylation, 1b was prepared from 4b (54.7 mg, 0.176 mmol). The crude product (56 mg)
was purified by column chromatography (silica gel 8 g, 8:1 hexane/EtOAc) to afford 1b (41.2 mg, 93%)
as a white solid; Rf 0.36 (3:1 hexane/EtOAc); mp 89.0-91.0 °C for 63 % ee; [α]2D3 +28.6° (c 1.85, CHCl3)
for 63% ee; IR (KBr) ν 1703 cm–1; 1H NMR (270 MHz, CDCl3) δ 2.63 (dd, J = 3.6, 19.1 Hz, 1H, COCH2),
3.21 (dd, J = 7.9, 19.1 Hz, 1H, COCH2), 4.51 (dd, J = 3.6, 7.9 Hz, 1H, ArCH), 5.93 (s, 2H, OCH2O), 6.51
(d, J = 1.3 Hz, 1H, ArH), 6.65 (dd, J = 1.3, 7.9 Hz, 1H, ArH), 6.75 (d, J = 7.9 Hz, 1H, ArH) 7.28 (d, J =
7.3 Hz, 1H, ArH), 7.42 (dd, J = 7.3, 7.6 Hz, 1H, ArH), 7.58 (t, J = 7.3 Hz, 1H, ArH), 7.82 (d, J = 7.6 Hz,
1H, ArH);13C NMR (100 MHz, CDCl3) δ 44.2 (CH), 46.9 (CH2), 101.0 (CH2), 107.7 (CH), 108.3 (CH),
120.8 (CH), 123.3 (CH), 126.7 (CH), 127.8 (CH), 135.0 (CH), 136.6 (C), 137.4 (C), 146.4 (C), 148.0 (C),
157.8 (C), 205.7 (C); LRMS (EI) m/z 252 (M+), 194, 165; HRMS (EI) calcd for C16H12O3 (M+) 252.0786,
found 252.0784. The enantiomeric excess of 1b was determined to be 63% by HPLC with a Chiralpak AS
column (19:1 hexane/2-propanol, flow rate = 1.0 mL/min): tR = 40.6 min for minor enantiomer; tR = 56.7
min for major enantiomer. A sample for combustion analysis was obtained by recrystallizations from
hexane/EtOAc as colorless needles (56% ee); mp 102-103 °C; Anal. Calcd for C16H12O3: C, 76.18; H,
4.79. Found: C, 76.11; H, 4.69.
ACKNOWLEDGEMENTS
This research was supported, in part, by a Grant-in-Aid for Scientific Research on Priority Areas
"Advanced Molecular Transformations of Carbon Resources" from the Ministry of Education, Culture,
Sports, Science and Technology, Japan. We thank S. Oka, M. Kiuchi, A. Maeda, H. Matsumoto and T.

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Hirose of the Center for Instrumental Analysis at Hokkaido University for mass measurements and
elemental analysis.
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