Ruthenium-catalyzed intramolecular cyclization of diazo-β-ketoanilides for the synthesis of 3-alkylideneoxindoles

Article abstract of DOI:10.1039/c2ob06985g

With [Ru(p-cymene)Cl₂]₂ as catalyst, diazo-β-ketoanilides would undergo intramolecular carbenoid arene C-H bond functionalization to afford 3-alkylideneoxindoles in up to 92% yields. The reaction occurs under mild conditions and exhibits excellent chemoselectivity. The lack of primary KIE (k_H/k_D ～ 1) suggests that the reaction should not proceed by rate-limiting C-H bond cleavage; a mechanism involving cyclopropanation of the arene is proposed.

Full text of DOI:10.1039/c2ob06985g

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 3749
www.rsc.org/obc
PAPER
Ruthenium-catalyzed intramolecular cyclization of diazo-β-ketoanilides for
the synthesis of 3-alkylideneoxindoles†
Wai-Wing Chan, Tsz-Lung Kwong and Wing-Yiu Yu*
Received 25th November 2011, Accepted 5th March 2012
DOI: 10.1039/c2ob06985g
With [Ru(p-cymene)Cl2]2 as catalyst, diazo-β-ketoanilides would undergo intramolecular carbenoid arene
C–H bond functionalization to afford 3-alkylideneoxindoles in up to 92% yields. The reaction occurs
under mild conditions and exhibits excellent chemoselectivity. The lack of primary KIE (kH/kD ∼ 1)
suggests that the reaction should not proceed by rate-limiting C–H bond cleavage; a mechanism involving
cyclopropanation of the arene is proposed.
intramolecular arylations of N-arylpropiolamides via C–H bond
Introduction
functionalization.7 Yet, these reactions often operate at rather
3-Alkylideneoxindoles are important motifs of bioactive natural
products1 and some pharmaceutical compounds such as Teni-
dap,2a which is used to treat rheumatoid arthritis, and
BIBF07752c, which can be potentially used for the treatment of
fibrotic diseases and cancer (Fig. 1).2 Several strategies have
been pursued for the effective synthesis of the skeleton. For
instance, direct acylation of oxindoles with acyl chlorides and
derivatives offers a simple route to 3-alkylideneoxindoles.3
Another approach involves the carbonylative cyclization of 2
alkynylanilines;4 Pd-, Rh- and Fe-catalyzed cyclizations of 2-
alkynylaryl isocyanates have proven value in the construction of
the oxindole core.5 Lu and Ma also achieved the Cu-catalyzed
intramolecular arylations of β-ketoamides and 3-alkylideneoxin-
doles, which were obtained in good yields.6 Despite these appar-
ent successes, these transformations are limited in substrate
scope because of the need of specially functionalized starting
materials. In this regard, efforts have been directed to the direct
high temperatures (>100 °C) for effective substrate conversion.
Transition metal-catalyzed carbenoid functionalizations consti-
tute a powerful method for C–C bond formation.8 Extensive
investigations have been focused on the use of dirhodium(II, II)
carboxylates as catalysts for carbenoid transformations.9 The
research groups of Doyle and Durst demonstrated that
Rh2(OAc)4 could effect catalytic intramolecular cyclization of
diazo-β-ketoamides in refluxing benzene to afford 3-alkylide-
neoxindoles in up to 95% yield.10 More recently, AgOTf was
also found to catalyze the analogous cyclization of diazo-
β-ketoamides in dioxane at 100 °C.11 As a continuing effort to
develop transition metal catalysis for C–H bond functionalization
under mild conditions,12 we reported earlier that [Ru(p-cymene)
Cl2]2 is a highly effective catalyst for carbenoid cyclization of
α-diazoacetamides to give cis-β-lactams in >99% stereoselecti-
vity.12e Unlike the analogous Rh catalysis, [Ru(p-cymene)Cl2]2
can effect C2-selective catalytic carbenoid C–H bond functiona-
lization of NH-free indoles.12a Here, we describe the [Ru(p-
cymene)Cl2]2-catalyzed intramolecular cyclization of diazo-
β-ketoanilides to afford 3-alkylideneoxindoles in up to 92%
yield at 40 °C.
Results and discussion
When diazo-β-ketoanilide 1a was treated with [Ru(p-cymene)
Cl2]2 (2.5 mol%) in toluene at room temperature overnight,
3-alkylideneoxindole 2a was obtained in 86% yield (entry 1,
Table 1). When the analogous reaction was performed at 40 °C,
complete substrate consumption was achieved in 2.5 h with 2a
being obtained in 95% yield (entry 2, Table 1). In this work, for-
mation of 2a (75% yield) was observed when heating 1a at
100 °C in metal-free toluene for 24 h (entry 3, Table 1).
However, it is noteworthy that no product formation was
observed at 40 °C without the Ru catalyst (entry 4, Table 1).
Fig. 1 Medicinally active 3-alkylideneoxindoles.
State Key Laboratory for Chirosciences and Open Laboratory of
Chirotechnology of the Institute of Molecular Technology for Drug
Discovery and Synthesis, Department of Applied Biology and Chemical
Technology, The Hong Kong Polytechnic University, Hung Hom,
Kowloon, Hong Kong. E-mail: bcwyyu@inet.polyu.edu.hk
†Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra. See DOI: 10.1039/c2ob06985g
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3749–3755 | 3749

View Article Online
Table 1 Reaction optimizationa
of 1d containing a para-OMe group at the anilide ring, the ana-
logous ortho-OMe derivative would afford 2i in 17% yield
(entry 9, Table 2). Similar findings were also obtained in the
related [Ru(p-cymene)Cl2]2 catalyzed intermolecular carbenoid
C–H bond insertion to indoles.15 We hypothesize that the ortho-
OMe group may have coordinated to the putative Ru–carbene
intermediate and it hindered the product formation.
Noting that some pharmaceutically active 3-alkylideneoxin-
doles (Fig. 1) contain an aromatic substituent, we were interested
in testing our protocol for the cyclization of diazoanilides
bearing a benzoyl substituent. When diazoanilide 1j was treated
with [Ru(p-cymene)Cl2]2 (2.5 mol%) in toluene at 40 °C over-
night, 3-arylideneoxindole 2j was obtained in 81% yield (entry
10, Table 2). Likewise, other heteroaryl-substituted diazoanilides
(1k and 1l) were also converted to their product oxindoles in
83–86% yields (entries 11–12, Table 2). As noted earlier, sub-
strates with electron-withdrawing groups at the anilide ring are
less reactive for the cyclization reaction. Yet, comparing the reac-
tivity of 1m and 1n, the presence of a chloro group at the aryl-
keto substituent seems to be well tolerated and 2n was formed in
79% yield (entry 14, Table 2).
Entry Catalyst
Solvent
Temp. (°C) Yieldb (%)
1
[Ru(p-cymene)Cl2]2
—
Catalyst-free
Toluene r.t.
Toluene 40
Toluene 100
Toluene 40
DCM
THF
MeCN
MeOH
Toluene 40
86
95
75
0
2c
3
4
5
6
Catalyst-free
[Ru(p-cymene)Cl2]2
—
r.t.
r.t.
r.t.
r.t.
72
68
55
37
19
18
4
7
8
—
—
9d
10d,e
11d
CpRu(PPh3)2Cl
Ru(pybox-ip)Cl2(C2H4) Toluene 40
[Ru(p-cymene)(OAc)2] Toluene 40
a Reaction conditions: 1a (0.2 mmol), [Ru(p-cymene)Cl2]2 (2.5 mol%),
solvent (1 mL). b Determined by 1H NMR. c Reaction time: 2.5 h.
d Catalyst loading: 5 mol%. e pybox = bis(oxazolinyl)pyridine.
To probe the nature of the cyclization of the diazoanilides, we
performed a primary H/D kinetic isotope effect (KIE) study by
competitive cyclization involving equimolar amounts of 1a and
1a-d5 as substrates. Subjecting 1a and 1a-d5 to the Ru-catalyzed
conditions (i.e., [Ru(p-cymene)Cl2]2 (2.5 mol%), toluene at
40 °C) for 5 min, substrate consumptions were determined by 1H
NMR analysis of the reaction mixture (see Experimental section
for details). By repeating the KIE experiment for three times, the
average KIE (kH/kD) of the Ru-catalyzed cyclization of diazoani-
lides was found to be ∼1.1. This result indicates that the reaction
should not involve rate-limiting C–H bond cleavage. A similar
finding was also obtained for the Ru-catalyzed intermolecular
carbenoid C–H bond functionalization of NH-free indoles.13
Based on the KIE study, we proposed that this cyclization
reaction may be initiated by a reactive ruthenium–carbene inter-
mediate A (Scheme 1).15,16 Then, intramolecular aromatic cyclo-
propanation would occur to form a strained cyclopropane B,17
whose subsequent ring-opening would afford the corresponding
3-alkylideneoxindole 2 (Scheme 1). By inspection of the tran-
sition state model, it is conceivable that the C3 substituents of
the anilide ring would hinder the C(2)-H functionalization.
Other solvents such as dichloromethane, THF, acetonitrile and
methanol failed to give better results (entries 5–8, Table 1).
According to the literature, [CpRu(PPh3)2Cl]13 and [Ru(pybox-
ip)Cl2]14 are known to catalyze some carbenoid transformations
(e.g. cyclopropanations). However, in this work, we found that
these Ru complexes are poor catalysts for the cyclization of 1a
(entries 9–10, Table 1). Notably, [Ru(p-cymene)(OAc)2] is prac-
tically ineffective for the cyclization reaction (entry 11, Table 1).
In principle, 3-acyloxindole may exist in another tautomeric
form, namely 3-acetyl-2-hydroxyindole. According to the litera-
ture, the 3-acetyl-2-hydroxyindole is characterized by
a
downfield 13C NMR signal at δc ∼ 200 ppm, assigned to the car-
bonyl group of the acetyl moiety.10a,11 In this work, it seems that
keto form on C2 is more preferable for 2a. The 3-alkylideneox-
indole skeleton of 2a was confirmed by a characteristic 13C
NMR signal at δc ∼ 173 ppm, which is assigned to the amido
carbon atom.
The substrate scope of the Ru-catalyzed cyclization of diazo-
β-ketoanilides is shown in Table 2. With the N-benzyl diazoani-
lide 1b as substrate, oxindole 2b was exclusively obtained in
70% yield (entry 2), and no β-lactam formation due to carbenoid
C–H bond insertion to the benzyl group was observed. For sub-
strate 1c bearing a meta-methyl substituent at the aryl ring, the
Ru-catalyzed cyclization occurred selectively at the less hindered
C–H bond leading to 2c formation in 86% yield. We found that
cyclizations of the substrates bearing electron-releasing groups
such as Me and OMe at the anilide moiety were more facile
under the standard reaction conditions (i.e., [Ru(p-cymene)Cl2]2
(2.5 mol%), toluene at 40 °C) (entries 3–5, Table 2). However,
cyclizations of the electron-poor derivatives were apparently
slower. For example, complete transformation of 1f to 2f was
achieved at slightly higher temperature (50 °C) overnight (entry
6, Table 2). Nevertheless, the analogous reactions of 1g and 1h
afforded the product oxindoles in 42 and 25% yields under
similar conditions (entries 7–8, Table 2). In contrast to the result
Conclusion
In conclusion, we have developed an effective synthesis of 3-
alkylideneoxindoles via intramolecular carbenoid cyclization of
diazo-β-ketoanilides using [Ru(p-cymene)Cl2]2 as catalyst under
mild conditions. Considering the availability of [Ru(p-cymene)
Cl2]2 and the ease of handling of the diazo compounds, this cata-
lytic carbenoid reaction would complement the current strategies
for 3-alkylideneoxindoles synthesis.
Experimental section
General methods
All the reactions were performed under a nitrogen atmosphere.
All the solvents were freshly distilled and dried according to the
3750 | Org. Biomol. Chem., 2012, 10, 3749–3755
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 2 Ru-catalyzed intramolecular cyclization of diazo-β-ketoanilidesa
Entry
1
Substrate
Product
Yieldb (%)
92
Entry
8c
Substrate
Product
Yieldb (%)
25
2
3
70
86
9c,e,f
17
81
10f
4
5
82
80
11f
12f
83
86
6c,d
70
42
13f
14f
45
79
7c,d
a Reaction conditions: 1 (0.2 mmol), [RuCl2(p-cymene)]2 (2.5 mol%), toluene (1 mL), 40 °C. Consumption of 1 was monitored by TLC. b Isolated
yields. c Catalyst loading: 5 mol%. d Reaction at 50 °C. e Reaction at 70 °C. f Reaction: overnight.
standard methods1 prior to use. Substituted N-methylanilines
were obtained commercially and used without purification. Thin
layer chromatography was performed on silica gel plates. Flash
column chromatography was performed on silica gel (Merck,
spectrometer. Infrared spectra were obtained by a Bruker Vector
22 FT-IR spectrometer.
General procedures for the preparation of diazo-β-ketoanilides
1a–1i
1
230–400 mesh). H and 13C NMR spectra were recorded to a
Bruker DPX-400 MHz spectrometer. The chemical shift (δ)
values are given in ppm and are referenced to residual solvent
peaks, carbon multiplicities were determined by DEPT-135 and
DEPT-90 experiments. Coupling constants (J) were reported in
hertz (Hz). Multiplicity abbreviations are: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, dt = doublet of
triplets, td = triplet of doublets, and br = broad. Mass spectra
and high resolution mass spectra (HRMS) were obtained on a
VG MICROMASS Fison VG platform, a Finnigan Model
Mat 95 ST instrument, or a Bruker APEX 47e FT-ICR mass
A mixture of aniline (10 mmol) and 2,2,6-trimethyl-4H-dioxin-
4-one (11 mmol, 1.1 equiv) in xylene (5 mL) was heated under
reflux at 120 °C for 10–15 min and 150 °C for further 1 h. Upon
complete consumption of the starting materials, the solvent was
removed by vacuum. The residue was purified by flash column
chromatography to afford the acetoacetates. To the corresponding
acetoanilide (5 mmol), triethylamine (10 mmol, 2 equiv) and
tosyl azide (5.5 mmol, 1.1 equiv) in CH3CN (10 mL) were
added. The solution was stirred at room temperature overnight.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3749–3755 | 3751

View Article Online
1
obtained as a yellow solid (98% yield), mp 48–50 °C. H NMR
(400 MHz, CDCl3): δH 7.10 (d, J = 8.8 Hz, 2H, ArH), 6.90 (d, J
= 8.8 Hz, 2H, ArH), 3.80 (s, 3H, OMe), 3.31 (s, 3H, NCH3),
2.48 (s, 3H, COCH3). 13C NMR (100 MHz, CDCl3): δC 192.0
(CvO), 161.1 (CvO), 159.2 (C), 135.6 (C), 127.8 (C–H),
115.4 (C–H), 55.6 (CH3), 39.5 (CH3), 28.5 (CH3). IR (KBr,
cm−1): 2110, 1644, 1510. HRMS (ESI): calcd for
C12H13N3O3Na+: 270.0855, found: 270.0842.
N-Ethyl-N-[3,4-(methylenedioxy)phenyl]-2-diazo-3-oxobutana-
mide (1e). Eluant: 50% n-hexane/50% ethyl acetate. The
product was obtained as a green solid (86% yield), mp
1
78–81 °C. H NMR (400 MHz, CDCl3): δH 6.80 (d, J = 8.8 Hz,
1H, ArH), 6.63 (m, 2H, ArH), 6.03 (s, 2H, OCH2O), 3.75 (q, J
= 7.1 Hz, 2H, NEt), 2.50 (s, 3H, COCH3), 1.16 (t, J = 7.2 Hz,
3H, NEt). 13C NMR (100 MHz, CDCl3): δC 192.1 (CvO),
160.5 (CvO), 148.9 (C), 147.7 (C), 134.8 (C), 121.4 (C–H),
108.9 (C–H), 108.3 (C–H), 102.1 (CH2), 45.7 (CH2), 28.6
(CH3), 12.9 (CH3). IR (KBr, cm−1): 2109, 1642, 1485. HRMS
(ESI): calcd for C13H13N3O4Na+: 298.0804, found: 298.0812.
Scheme 1 Proposed mechanism.
The solvent was removed and the residue was dissolved in
diethyl ether (25 mL) and washed successively with brine sol-
ution (3 × 25 mL) and then H2O (3 × 25 mL). The combined
organic layers were dried over Na2SO4 and concentrated. The
residue was purified by flash column chromatography to afford
the α-diazo anilides.
N-(4-Chlorophenyl)-N-methyl-2-diazo-3-oxobutanamide (1f).
Eluant: 50% n-hexane/50% ethyl acetate. The product was
1
obtained as a pale yellow solid (88% yield), mp 75–76 °C. H
NMR (400 MHz, CDCl3): δH 7.40 (d, J = 6.8 Hz, 2H, ArH),
7.14 (d, J = 6.6 Hz, 2H, ArH), 3.35 (s, 3H, NCH3), 2.46 (s, 3H,
COCH3). 13C NMR (100 MHz, CDCl3): δC 191.2 (CvO), 161.0
(CvO), 141.6 (C), 133.8 (C), 130.4 (C–H), 127.4 (C–H), 38.5
(CH3), 28.3 (CH3). IR (KBr, cm−1): 2111, 1647, 1490. HRMS
(ESI): calcd for C11H10N3O2NaCl+: 274.0359, found: 274.0346.
N-Methyl-N-phenyl-2-diazo-3-oxobutanamide
(1a). Eluant:
50% n-hexane/50% ethyl acetate. The product was obtained as a
yellow oily liquid (85% yield). 1H NMR (400 MHz, CDCl3): δH
7.42 (t, J = 7.6 Hz, 2H, ArH), 7.34 (t, J = 7.4 Hz, 1H, ArH),
7.20 (d, J = 7.2 Hz, 2H, ArH), 3.38 (s, 3H, NCH3), 2.50 (s, 3H,
COCH3). 13C NMR (100 MHz, CDCl3): δC 191.8 (CvO), 161.0
(CvO), 143.1 (C), 130.3 (C–H), 128.0 (C–H), 126.2 (C–H),
38.4 (CH3), 28.4 (CH3). IR (KBr, cm−1): 2112, 1645, 1594.
HRMS (ESI): calcd for C11H11N3O2Na+: 240.0749, found:
240.0742.
N-(3,4-Dichlorophenyl)-N-methyl-2-diazo-3-oxobutanamide (1g).
Eluant: 50% n-hexane/50% ethyl acetate. The product was
1
obtained as a yellow solid (80% yield), mp 96–98 °C. H NMR
(400 MHz, CDCl3): δH 7.49 (d, J = 8.8 Hz, 1H, ArH), 7.32 (s,
1H, ArH), 7.07 (d, J = 8.8 Hz, 1H, ArH), 3.34 (s, 3H, NCH3),
2.45 (s, 3H, COCH3). 13C NMR (100 MHz, CDCl3): δC 190.7
(CvO), 160.9 (CvO), 142.5 (C), 134.0 (C), 132.0 (C), 131.7
(C–H), 127.8 (C–H), 125.3 (C–H), 38.6 (CH3), 28.3 (CH3).
IR (KBr, cm−1): 2111, 1648, 1473. HRMS (ESI): calcd for
C11H9N3O2Cl2Na+: 307.9970, found: 307.9957.
N-Benzyl-N-phenyl-2-diazo-3-oxobutanamide
(1b). Eluant:
50% n-hexane/50% ethyl acetate. The product was obtained as a
1
yellow solid (82% yield), mp 66–67 °C. H NMR (400 MHz,
CDCl3): δH 7.36–7.22 (m, 8H, ArH), 7.06 (d, J = 8,2 Hz, 2H,
ArH), 4.97 (s, 2H, CH2Ph), 2.53 (s, 3H, COCH3). 13C NMR
(100 MHz, CDCl3): δC 191.8 (CvO), 160.9 (CvO), 141.5 (C),
136.8 (C), 130.1 (C–H), 128.6 (C–H), 128.5 (C–H), 128.2
(C–H), 127.7 (C–H), 127.3 (C–H), 54.1 (CH2), 28.6 (CH3). IR
(KBr, cm−1): 2109, 1643, 1593. HRMS (ESI): calcd for
C17H15N3O2Na+: 316.1062, found: 316.1057.
N-Methyl-N-(4-trifluoromethylphenyl)-2-diazo-3-oxobutanamide
(1h). Eluant: 50% n-hexane/50% ethyl acetate. The product was
1
obtained as a yellow solid (83% yield), mp 84–85 °C. H NMR
(400 MHz, CDCl3): δH 7.68 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4
Hz, 2H), 3.39 (s, 3H, NCH3), 2.45 (s, 3H, COCH3). 13C NMR
(100 MHz, CDCl3): δC 190.7 (CvO), 161.1 (CvO), 146.4 (C),
129.5 (q, CF3), 127.4 (C), 126.1 (C–H), 124.9 (C–H), 122.2
(C–H), 38.2 (CH3), 28.2 (CH3). 19F NMR (376 MHz, CDCl3):
δF −69.7 (CF3). IR (KBr, cm−1): 2114, 1650, 1612. HRMS
(ESI): calcd for C12H10N3O2F3Na+: 308.0623, found: 308.0610.
N-Ethyl-N-(3-methylphenyl)-2-diazo-3-oxobutanamide (1c).
Eluant: 50% n-hexane/50% ethyl acetate. The product was
obtained as a pale yellow solid (97% yield), mp 67–68 °C. H
1
NMR (400 MHz, CDCl3): δH 7.29 (t, J = 8 Hz, 1H, ArH), 7.15
(d, J = 7.8 Hz, 1H, ArH), 6.96 (m, 2H, ArH), 3.81 (q, J = 7.1
Hz, 2H, NEt), 2.50 (s, 3H, CH3), 2.36 (s, 3H, COCH3), 1.17 (t,
J = 7.2Hz, 3H, NEt). 13C NMR (100 MHz, CDCl3): δC 192.1
(CvO), 160.4 (CvO), 141.2 (C), 140.4 (C), 129.9 (C–H),
128.9 (C–H), 127.7 (C–H), 124.3 (C–H), 45.6 (CH2), 28.5
(CH3), 21.3 (CH3), 13.0 (CH3). IR (KBr, cm−1): 2109, 1644,
1603. HRMS (ESI): calcd for C13H15N3O2Na+: 268.1062,
found: 268.1051.
N-Methyl-N-(2-methoxyphenyl)-2-diazo-3-oxobutanamide (1i).
Eluant: 50% n-hexane/50% ethyl acetate. The product was
1
obtained as a yellow solid (69% yield), mp 68–70 °C. H NMR
(400 MHz, CDCl3): δH 7.33 (dt, J = 8 Hz, 1H, ArH), 7.13 (dd, J
= 7.6 Hz, 1H, ArH), 6.98 (m, 2H, ArH), 3.83 (s, 3H, OMe),
3.24 (s, 3H, NCH3), 2.46 (s, 3H, COCH3). 13C NMR (100 MHz,
CDCl3): δC 192.2 (CvO), 162.1 (CvO), 154.5 (C), 131.2 (C),
130.0 (C–H), 128.6 (C–H), 121.7 (C–H), 112.3 (C–H), 55.6
N-Methyl-N-(4-methoxyphenyl)-2-diazo-3-oxobutanamide (1d).
Eluant: 50% n-hexane/50% ethyl acetate. The product was
3752 | Org. Biomol. Chem., 2012, 10, 3749–3755
This journal is © The Royal Society of Chemistry 2012

View Article Online
(CH3), 37.2 (CH3), 28.0 (CH3). IR (KBr, cm−1): 2108, 1650,
1500. HRMS (ESI): calcd for C12H13N3O3Na+: 270.0855,
found: 270.0854.
N-(4-Chlorophenyl)-N-methyl-2-diazo-3-oxo-3-phenylpropa-
namide (1m). Eluant: 50% n-hexane/50% ethyl acetate. The
product was obtained as a yellow solid (91% yield), mp
1
124–126 °C. H NMR (400 MHz, CDCl3): δH 7.50–7.48 (m,
1H, ArH), 7.38–7.33 (m, 4H, ArH), 7.15 (d, J = 8.4 Hz, 2H,
ArH), 6.81 (d, J = 8.4 Hz, 2H, ArH), 3.31 (s, 3H, NCH3). 13C
NMR (100 MHz, CDCl3): δC 186.0 (CvO), 162.0 (CvO),
142.1 (C), 137.4 (C), 132.80 (C–H), 132.78 (C), 129.8 (C–H),
128.7 (C–H), 127.9 (C–H), 127.1 (C–H), 38.6 (CH3). IR
(KBr, cm−1): 2113, 1627, 1491. HRMS (ESI): calcd for
C16H12N3O2NaCl+: 336.0516, found: 336.0502.
General procedures for the preparation of diazo-β-ketoanilides
1j–1n
To a mixture of meldrum’s acid (10 mmol) and DMAP
(20 mmol, 2 equiv) in CH2Cl2 (20 mL) at 0 °C, benzoyl chloride
(12 mmol, 1.2 equiv) was added dropwise over 10 min. The
mixture was then allowed to warm to room temperature and
stirred for further 1 h. The reaction was diluted with CH2Cl2
(20 mL) and washed with 10% HCl solution (20 mL), brine sol-
ution (30 mL) and then H2O (30 mL) successively. The com-
bined organic layers were dried over Na2SO4 and concentrated.
The residue was dissolved in dioxane (15 mL) and aniline
(10 mmol) was then added. The mixture was heated under reflux
for 1 h. Upon complete consumption of the starting materials,
the solvent was removed by vacuum. The residue was purified
by flash column chromatography to afford the corresponding
benzoylacetanilides. The procedures of subsequent diazo transfer
reaction were similar with that of the preparation of 1a–1i.
N-Benzyl-3-(4-chlorophenyl)-2-diazo-3-oxo-N-phenylpropana-
mide (1n). Eluant: 50% n-hexane/50% ethyl acetate. The
product was obtained as a yellow solid (91% yield), mp
1
108–109 °C. H NMR (400 MHz, CDCl3): δH 7.33–7.20 (m,
12H, ArH), 6.87 (d, J = 7.6 Hz, 2H, ArH), 4.94 (s, 2H, CH2Ph).
13C NMR (100 MHz, CDCl3): δC 185.7 (CvO), 161.6 (CvO),
141.9 (C), 138.9 (C), 136.9 (C), 135.9 (C), 129.9 (C–H), 129.5
(C–H), 129.1 (C–H), 128.9 (C–H), 128.8 (C–H), 128.1 (C–H),
127.8 (C–H), 127.2 (C–H), 54.5 (CH2). IR (KBr, cm−1): 2112,
1624, 1490. HRMS (ESI): calcd for C22H16N3O2NaCl+:
412.0829, found: 412.0818.
N-(4-Methoxyphenyl)-N-methyl-2-diazo-3-oxo-3-phenylpropa-
namide (1j). Eluant: 50% n-hexane/50% ethyl acetate. The
product was obtained as a yellow solid (91% yield), mp
Typical procedures for the Ru-catalyzed intramolecular
cyclization of diazo-β-ketoanilides 1
1
83–84 °C. H NMR (400 MHz, CDCl3): δH 7.48 (t, J = 7.2 Hz,
A sealed vial equipped with a magnetic stirrer was charged with
[Ru(p-cymene)Cl2]2 (3.1 mg, 2.5 mol%) and diazo-β-ketoanilide
1 (0.2 mmol). The vial was evacuated and refilled with nitrogen
three times. Dry toluene (1 mL) was added via a syringe and the
mixture was stirred and heated at 40 °C. Upon complete con-
sumption of the diazo-β-ketoanilides, based on TLC monitoring,
the reaction was allowed to cool to room temperature and was
then concentrated. The residue was purified by flash chromato-
graphy to give the desired 3-alkylideneoxindoles.
1H, ArH), 7.42–7.34 (m, 4H, ArH), 6.85 (d, J = 8.8 Hz, 2H,
ArH), 6.74 (d, J = 8.8 Hz, 2H, ArH), 3.78 (s, 3H, OMe), 3.30 (s,
3H, NCH3). 13C NMR (100 MHz, CDCl3): δC 186.8 (CvO),
162.0 (CvO), 158.7 (C), 137.7 (C), 136.3 (C), 132.6 (C–H),
128.5 (C–H), 128.0 (C–H), 127.4 (C–H), 115.0 (C–H), 55.8
(CH3), 38.8 (CH3). IR (KBr, cm−1): 2109, 1626, 1510. HRMS
(ESI): calcd for C17H15N3O3Na+: 332.1011, found: 332.1012.
3-(Furan-2-yl)-N-methyl-2-diazo-3-oxo-N-phenylpropanamide
(1k). Eluant: 50% n-hexane/50% ethyl acetate. The product was
3-(1-Hydroxyethylidene)-1-methylindolin-2-one (2a). Eluant:
80% n-hexane/20% ethyl acetate. The product was obtained as a
1
obtained as a yellow solid (91% yield), mp 85–86 °C. H NMR
1
(400 MHz, CDCl3): δH 7.51 (s, 1H, ArH), 7.32 (t, J = 7.6 Hz,
2H, ArH), 7.24–7.21 (m, 1H, ArH), 7.17 (d, J = 7.2 Hz, 2H,
ArH), 7.06 (d, J = 3.6 Hz, 1H, ArH), 6.49 (d of d, 1H, ArH),
3.43 (s, 3H, NCH3). 13C NMR (100 MHz, CDCl3): δC 172.5
(CvO), 161.3 (CvO), 151.3 (C), 145.6 (C), 143.6 (C–H),
129.9 (C–H), 127.6 (C–H), 126.1 (C–H), 117.5 (C–H), 112.8
(C–H), 30.7 (CH3). IR (KBr, cm−1): 2114, 1639, 1594. HRMS
(ESI): calcd for C14H11N3O3Na+: 292.0698, found: 292.0685.
purple solid (92% yield), mp 90–92 °C. H NMR (400 MHz,
CDCl3): δH 13.60 (br, s, 0.8H, OH), 7.35 (d, J = 7.6 Hz, 1H,
ArH), 7.22 (t, J = 7.6 Hz, 1H, ArH), 7.10 (t, J = 7.4 Hz, 1H,
ArH), 6.93 (d, J = 7.6 Hz, 1H, ArH), 3.33 (s, 3H, NCH3), 2.44
(s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δC 172.9 (CvO),
171.1 (CvC), 138.9 (C), 125.2 (C–H), 122.2 (C), 122.1 (C–H),
119.7 (C–H), 108.4 (C–H), 101.8 (C), 25.6 (CH3), 20.3 (CH3).
IR (KBr, cm−1): 3434, 3065, 2924, 1654, 1607. HRMS (ESI):
calcd for C11H10NO2H+: 190.0868, found: 190.0864.
N-Methyl-2-diazo-3-oxo-N-phenyl-3-(thiophen-2-yl)propana-
mide (1l). Eluant: 50% n-hexane/50% ethyl acetate. The product
was obtained as a yellow solid (91% yield), mp 117–119 °C. H
1-Benzyl-3-(1-hydroxyethylidene)indolin-2-one (2b). Eluant:
70% n-hexane/30% ethyl acetate. The product was obtained as a
purple solid (70% yield), mp 117–119 °C. H NMR (400 MHz,
CDCl3): δH 13.67 (br, s, 0.7H, OH), 7.39 (d, J = 7.2 Hz, 1H,
ArH), 7.34–7.24 (m, 5H, ArH), 7.15–7.09 (m, 2H, ArH), 6.86
(d, J = 7.6 Hz, 1H, ArH), 5.06 (s, 2H, CH2Ph), 2.49 (s, 3H,
CH3). 13C NMR (100 MHz, CDCl3): δC 173.3 (CvO), 171.2
(CvC), 138.1 (C), 136.1 (C), 128.8 (C–H), 127.6 (C–H), 127.2
(C–H), 125.2 (C–H), 122.4 (C), 122.2 (C–H), 119.8 (C–H),
109.4 (C–H), 101.7 (C), 43.3 (CH2), 20.4 (CH3). IR (KBr,
1
1
NMR (400 MHz, CDCl3): δH 7.59–7.57 (m, 2H, ArH), 7.30 (t, J
= 7.6 Hz, 2H, ArH), 7.22 (t, J = 7.6 Hz, 1H, ArH), 7.08–7.06
(m, 3H, ArH), 3.41 (s, 3H, NCH3). 13C NMR (100 MHz,
CDCl3): δC 177.6 (CvO), 161.6 (CvO), 143.4 (C), 142.0 (C),
133.4 (C–H), 131.9 (C–H), 130.1 (C–H), 127.9 (C–H), 127.5
(C–H), 126.0 (C–H), 38.7 (CH3). IR (KBr, cm−1): 2117, 1643,
1593. HRMS (ESI): calcd for C14H11N3O2NaS+: 308.0470,
found: 308.0467.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3749–3755 | 3753

View Article Online
cm−1): 3435, 3060, 2920, 1657, 1607, 1465. HRMS (ESI): calcd
for C17H14NO2H+: 266.1181, found: 266.1188.
(C–H), 110.1 (C–H), 100.7 (C), 25.9 (CH3), 20.5 (CH3). IR
(KBr, cm−1): 3410, 2912, 1659, 1612, 1264. HRMS (ESI): calcd
for C11H9NO2Cl2H+: 258.0089, found: 258.0099.
1-Ethyl-3-(1-hydroxyethylidene)-6-methylindolin-2-one (2c).
Eluant: 80% n-hexane/20% ethyl acetate. The product was
obtained as a purple solid (86% yield), mp 51–52 °C. H NMR
5-(Trifluoromethyl)-3-(1-hydroxyethylidene)-1-methylindolin-2-
one (2h). Eluant: 30% n-hexane/70% dichloromethane. The
product was obtained as a purple solid (25% yield), mp
1
(400 MHz, CDCl3): δH 13.50 (br, s, 0.7H, OH), 7.23 (d, J = 7.6
Hz, 1H, ArH), 6.90 (d, J = 7.6 Hz, 1H, ArH), 6.80 (s, 1H, ArH),
3.88 (q, J = 7.2 Hz, 2H, NEt), 2.41 (s, 6H, 2CH3), 1.31 (t, J =
7.2 Hz, 3H, NEt). 13C NMR (100 MHz, CDCl3): δC 171.8
(CvO), 170.9 (CvC), 138.2 (C), 135.2 (C), 122.6 (C–H),
119.8 (C), 119.6 (C–H), 109.3 (CH), 101.8 (C), 34.2 (CH2),
21.8 (CH3), 20.2 (CH3), 13.3 (CH3). IR (KBr, cm−1): 3440,
2971, 2928, 1660, 1615. HRMS (ESI): calcd for C13H14NO2H+:
218.1181, found: 218.1175.
1
104–106 °C. H NMR (400 MHz, CDCl3): δH 13.62 (br, s, 1H,
OH), 7.57 (s, 1H, ArH), 7.50 (d, J = 8 Hz, 1H, ArH), 7.02 (d, J
= 8 Hz, 1H, ArH), 3.39 (s, 3H, NCH3), 2.51 (s, 3H, CH3). 13C
NMR (100 MHz, CDCl3): δC 174.8 (CvO), 171.3 (CvC),
141.1 (C), 126.0 (C), 124.4 (q, CF3), 123.3 (C), 122.5 (C–H),
116.4 (C–H), 108.1 (C–H), 101.1 (C), 25.9 (CH3), 20.5 (CH3).
19F NMR (376 MHz, CDCl3): δF -61.2 (CF3). IR (KBr, cm−1):
3421, 2944, 1663, 1616, 1326, 1277, 1110. HRMS (ESI): calcd
for C12H10NO2F3H+: 258.0742, found: 258.0746.
3-(1-Hydroxyethylidene)-5-methoxy-1-methylindolin-2-one (2d).
Eluant: 70% n-hexane/30% ethyl acetate. The product was
obtained as a purple solid (82% yield), mp 78–81 °C. H NMR
3-(1-Hydroxyethylidene)-7-methoxy-1-methylindolin-2-one (2i).
1
Eluant: 70% n-hexane/30% ethyl acetate. The product was
1
(400 MHz, CDCl3): δH 13.67 (br, s, 0.7H, OH), 6.92 (s, 1H,
ArH), 6.81 (d, J = 8.4 Hz, 1H, ArH), 6.75 (dd, J = 8.4 Hz, 1H,
ArH), 3.82 (s, 3H, OMe), 3.29 (s, 3H, NCH3), 2.40 (s, 3H,
CH3). 13C NMR (100 MHz, CDCl3): δC 173.1 (CvO), 170.9
(CvC), 155.7 (C), 133.1 (C), 123.3 (C), 109.7 (C–H), 108.4
(C–H), 107.2 (C–H), 102.0 (C), 55.9 (CH3), 25.7 (CH3), 20.2
(CH3). IR (KBr, cm−1): 3433, 3052, 2926, 2846, 1658, 1593,
1490, 1284. HRMS (ESI): calcd for C12H13NO3H+: 220.0974,
found: 220.0976.
obtained as a purple solid (17% yield), mp 88–90 °C. H NMR
(400 MHz, CDCl3): δH 14.05 (br, s, 0.8H, OH), 7.02–7.00 (m,
2H, ArH), 6.79–6.76 (m, 1H, ArH), 3.88 (s, 3H, OMe), 3.62 (s,
3H, NCH3), 2.44 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3):
δC 173.7 (CvO), 170.9 (CvC), 146.0 (C), 126.8 (C), 123.9
(C), 122.5 (C–H), 112.9 (C–H), 108.8 (C–H), 101.9 (C), 55.9
(CH3), 29.0 (CH3), 20.4 (CH3). IR (KBr, cm−1): 3433, 2912,
1652, 1588, 1249. HRMS (ESI): calcd for C12H13NO3H+:
220.0974, found: 220.0969.
3-(1-Hydroxyethylidene)-5,6-(methylenedioxy)-1-methylindolin-
2-one (2e). Eluant: 70% n-hexane/30% ethyl acetate. The
product was obtained as a green solid (80% yield), mp
3-(Hydroxy(phenyl)methylene)-5-methoxy-1-methylindolin-2-
one (2j). Eluant: 20% n-hexane/80% dichloromethane. The
product was obtained as a yellow solid (81% yield), mp
120–122 °C. 1H NMR (400 MHz, CDCl3): δH 14.10 (br, s,
0.7H, OH), 7.77 (d, J = 7.6 Hz, 1H), 7.57–7.52 (m, 3H, ArH),
6.82 (d, J = 8.4 Hz, 1H, ArH), 6.78–6.73 (m, 2H, ArH), 3.65 (s,
3H, OMe), 3.37 (s, 3H, NCH3). 13C NMR (100 MHz, CDCl3):
δC 172.2 (CvO), 171.6 (CvC), 155.7 (C), 134.4 (C), 133.7
(C), 131.8 (C–H), 129.0 (C–H), 128.7 (C–H), 123.0 (C), 111.4
(C–H), 108.9 (C–H), 106.9 (C–H), 102.1 (C), 56.0 (CH3), 26.3
(CH3). IR (neat, cm−1): 3471, 2982, 1732.3. IR (KBr, cm−1):
3433, 2924, 1644, 1589, 1473. HRMS (ESI): calcd for
C17H15NO3H+: 282.1130, found: 282.1134.
1
129–130 °C. H NMR (400 MHz, CDCl3): δH 13.62 (br, s, 1H,
OH), 6.89 (s, 1H, ArH), 6.56 (s, 1H, ArH), 5.94 (s, 2H,
OCH2O), 3.83 (q, J = 7.1 Hz, 2H, NEt), 2.38 (s, 3H, CH3), 1.28
(t, J = 7.2 Hz, 3H, NEt). 13C NMR (100 MHz, CDCl3): δC
171.4 (CvO), 170.6 (CvC), 145.5 (C), 143.0 (C), 132.4 (C),
114.9 (C), 102.2 (C), 101.4 (C–H), 101.0 (C–H), 92.1 (CH2),
34.4 (CH2), 20.1 (CH3), 13.2 (CH3). IR (KBr, cm−1): 3389,
2905, 1660, 1614, 1476. HRMS (ESI): calcd for C13H11NO4H+:
246.0766, found: 246.0764.
5-Chloro-3-(1-hydroxyethylidene)-1-methylindolin-2-one (2f).
Eluant: 30% n-hexane/70% dichloromethane. The product was
obtained as a purple solid (70% yield), mp 124–125 °C. 1H
NMR (400 MHz, CDCl3): δH 13.60 (br, s, 0.8H, OH), 7.27 (s,
1H, ArH), 7.16 (d, J = 6.4 Hz, 1H, ArH), 6.82 (d, J = 7.2Hz,
1H, ArH), 3.31 (s, 3H, NCH3), 2.42 (s, 3H, CH3). 13C NMR
(100 MHz, CDCl3): δC 174.3 (CvO), 170.9 (CvC), 137.2 (C),
127.6 (C), 124.8 (C–H), 123.6 (C), 119.7 (C–H), 109.1 (C–H),
101.2 (C), 25.8 (CH3), 20.4 (CH3). IR (KBr, cm−1): 3425, 2916,
1657, 1607. HRMS (ESI): calcd for C11H10NO2ClH+: 224.0478,
found: 224.0474.
3-((Furan-2-yl)(hydroxy)methylene)-1-methylindolin-2-one (2k).
Eluant: 20% n-hexane/80% dichloromethane. The product was
obtained as a yellow solid (83% yield), mp 115–116 °C. 1H
NMR (400 MHz, CDCl3): δH 14.74 (br, s, 0.8H, OH), 8.27 (d, J
= 7.6 Hz, 1H, ArH), 7.80 (s, 1H, ArH), 7.31 (d, J = 3.2 Hz, 1H,
ArH), 7.26 (t, J = 7.6 Hz, 1H, ArH), 7.12 (t, J = 7.6 Hz, 1H,
ArH), 6.96 (d, J = 7.6 Hz, 1H, ArH), 6.70 (d, J = 3.2 Hz, 1H,
ArH), 3.39 (s, 3H, NCH3). 13C NMR (100 MHz, CDCl3): δC
173.1 (CvO), 158.6 (CvC), 149.3 (C), 146.0 (C–H), 139.3
(C), 126.2 (C–H), 122.6 (C–H), 122.5 (C–H), 121.6 (C), 117.2
(C–H), 112.9 (C–H), 108.5 (C–H), 99.9 (C), 26.3 (CH3). IR
(KBr, cm−1): 3421, 3137, 2928, 1625, 1608, 1468. HRMS
(ESI): calcd for C14H11NO3H+: 242.0817, found: 242.0806.
5,6-Dichloro-3-(1-hydroxyethylidene)-1-methylindolin-2-one (2g).
Eluant: 30% n-hexane/70% dichloromethane. The product was
obtained as a purple solid (42% yield), mp 153–155 °C. 1H
NMR (400 MHz, CDCl3): δH 13.63 (br, s, 0.9H, OH), 7.37 (s,
1H, ArH), 7.00 (s, 1H, ArH), 3.32 (s, 3H, NCH3), 2.44 (s, 3H,
CH3). 13C NMR (100 MHz, CDCl3): δC 174.5 (CvO), 171.0
(CvC), 138.1 (C), 128.7 (C), 125.6 (C), 122.2 (C), 120.9
3-(Hydroxy(thiophen-2-yl)methylene)-1-methylindolin-2-one
(2l). Eluant: 70% n-hexane/30% ethyl acetate. The product was
obtained as a yellow solid (86% yield), mp 99–101 °C. 1H NMR
(400 MHz, CDCl3): δH 14.20 (br, s, 0.6H, OH), 7.9 (s, 1H,
3754 | Org. Biomol. Chem., 2012, 10, 3749–3755
This journal is © The Royal Society of Chemistry 2012

View Article Online
ArH), 7.70–7.65 (m, 2H, ArH), 7.25–7.21 (m, 2H, ArH),
7.01–6.96 (m, 2H, ArH), 3.40 (s, 3H, NCH3). 13C NMR
(100 MHz, CDCl3): δC 172.4 (CvO), 164.5 (CvC), 139.4 (C),
136.8 (C), 131.1 (C–H), 127.8 (C–H), 126.4 (C–H), 122.3 (C),
121.8 (C–H), 120.1 (C–H), 108.9 (C–H), 101.1 (C), 26.3 (CH3).
IR (KBr, cm−1): 3436, 3103, 2928, 1644, 1607, 1467. HRMS
(ESI): calcd for C14H11NO2SH+: 258.0589, found: 258.0587.
of Excellence Scheme (AoE/P-10-01) administered by the Uni-
versity Research Grants Council (HKSAR, China).
Notes and references
1 (a) G. Cerchiaro and A. M. da Costa Ferreira, J. Braz. Chem. Soc., 2006,
17, 1473–1485; (b) A. Millemaggi and R. J. K. Taylor, Eur. J. Org.
Chem., 2010, 4527–4547.
5-Chloro-3-(hydroxy(phenyl)methylene)-1-methylindolin-2-one
2 (a) R. P. Robinson, L. A. Reiter, W. E. Barth, A. M. Campeta, K. Cooker,
B. J. Cronin, R. Destito, K. M. Donahue, F. C. Falkner, E. F. Fiese,
D. L. Johnson, A. V. Kuperman, T. E. Liston, D. Malloy, J. J. Matin,
D. Y. Mitchell, F. W. Rusek, S. L. Shamblin and C. F. Wright, J. Med.
Chem., 1996, 39, 10–18; (b) K. E. B. Parkes, P. Ermert, J. Fässler, J. Ives,
J. A. Martin, J. H. Merrent, D. Obrecht, G. Williams and K. Klumpp,
J. Med. Chem., 2003, 46, 1153–1164; (c) G. J. Roth, A. Heckel,
T. Brandl, M. Grauert, S. Hoerer, J. T. Klet, G. Schnapp, P. Baum,
D. Mennerich, A. Schnapp and J. E. Park, J. Med. Chem., 2010, 53,
7287–7295.
3 (a) M. Porcs-Makkay and G. Simig, Org. Process Res. Dev., 2000, 4, 10–
16; (b) M. Jha and B. Blunt, Tetrahedron Lett., 2009, 50, 6044–6047.
4 (a) S. Tang, Q.-F. Yu, P. Peng, J.-H. Li, P. Zhong and R.-Y. Tang, Org.
Lett., 2007, 9, 3413–3416; (b) J. H. Park, E. Kim and Y. K. Chung, Org.
Lett., 2008, 10, 4719–4721.
(2m). Eluant: 20% n-hexane/80% dichloromethane. The product
1
was obtained as a yellow solid (45% yield), mp 163–165 °C. H
NMR (400 MHz, CDCl3): δH 14.15 (br, s, 0.8H, OH), 7.75 (d, J
= 8.0 Hz, 2H, ArH), 7.61–7.55 (m, 3H, ArH), 7.14 (m, 2H,
ArH), 6.85 (d, J = 8.4 Hz, 1H, ArH), 3.39 (s, 3H, NCH3). 13C
NMR (100 MHz, CDCl3): δC 172.7 (CvO), 172.2 (CvC),
137.8 (C), 134.1 (C), 132.2 (C–H), 129.2 (C–H), 128.6 (C–H),
127.8 (C), 125.9 (C–H), 123.4 (C), 120.1 (C–H), 109.5 (C–H),
101.1 (C), 26.4 (CH3). IR (KBr, cm−1): 3435, 2916, 1635, 1598,
1341. HRMS (ESI): calcd for C16H12NO2ClH+: 286.0635,
found: 286.0634.
5 (a) S. Kamijo, Y. Sasaki, C. Kananawa, T. Schüßeler and Y. Yamamoto,
Angew. Chem., Int. Ed., 2005, 44, 7718–7721; (b) T. Miura, Y. Takahashi
and M. Murakami, Org. Lett., 2007, 9, 5075–5077; (c) T. Miura,
T. Toyoshima, Y. Takahashi and M. Murakami, Org. Lett., 2009, 11,
2141–2143; (d) G. Cantagrel, B. Carné-Carnavalet, C. Meyer and
J. Cossy, Org. Lett., 2009, 11, 4262–4265.
1-Benzyl-3-((4-chlorophenyl)(hydroxy)methylene)indolin-2-one
(2n). Eluant: 20% n-hexane/80% dichloromethane. The product
1
was obtained as a yellow solid (79% yield), mp 123–125 °C. H
NMR (400 MHz, CDCl3): δH 13.95 (br, s, 1H, OH), 7.77 (d, J =
8.4 Hz, 2H, ArH), 7.53 (d, J = 8.4 Hz, 2H, ArH), 7.35–7.27 (m,
5H, ArH), 7.19 (d, J = 8.0 Hz, 1H, ArH), 7.11 (t, J = 7.6 Hz,
1H, ArH), 6.92–6.87 (m, 2H, ArH), 5.11 (s, 2H, CH2Ph). 13C
NMR (100 MHz, CDCl3): δC 172.3 (CvO), 170.1 (CvC),
138.7 (C), 137.9 (C), 136.2 (C), 132.9 (C), 130.3 (C–H), 129.4
(C–H), 129.2 (C–H), 128.1 (C–H), 127.7 (C–H), 125.5 (C–H),
122.4 (C–H), 121.8 (C), 120.0 (C–H), 109.9 (C–H), 102.0
(C–H), 43.9 (CH2). IR (KBr, cm−1): 3436, 3056, 2920, 1645,
1608, 1481. HRMS (ESI): calcd for C22H16NO2ClH+: 362.0948,
found: 362.0933.
6 B. Lu and D. Ma, Org. Lett., 2006, 8, 6115–6118.
7 (a) A. Pinto, L. Neuville and J. Zhu, Angew. Chem., Int. Ed., 2007, 46,
3291–3295; (b) S. Tang, P. Peng, S.-F. Pi, Y. Liang, N.-X. Wang and J.-
H. Li, Org. Lett., 2008, 10, 1179–1182; (c) D.-J. Tang, B.-X. Tang and
J.-H. Li, J. Org. Chem., 2009, 74, 6749–6755; (d) T.-S. Jiang, R.-
Y. Tang, X.-G. Zhang, X.-H. Li and J.-H. Li, J. Org. Chem., 2009, 74,
8834–8837.
8 M. P. Doyle, M. McKervey and T. Ye, Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds, John Wiley & Sons Inc.,
New York, 1998, Ch. 3–6, 112–348.
9 For recent reviews, see: (a) M. P. Doyle, R. Duffy, M. Ratnikov and
L. Zhou, Chem. Rev., 2010, 110, 704–724; (b) H. M. L. Davies and J.
R. Manning, Nature, 2008, 451, 417–424; (c) H. M. L. Davies and S.
J. Hedley, Chem. Soc. Rev., 2007, 36, 1109–1119.
Procedure for the KIE experiment
10 (a) M. P. Doyle, M. S. Shanklin, H. Q. Pho and S. N. Mahapatro, J. Org.
Chem., 1988, 53, 1017–1022; (b) N. Etkin, S. D. Bahu, C. J. Fooks and
T. Durst, J. Org. Chem., 1990, 55, 1093–1096.
11 H.-L. Wang, Z. Li, G.-W. Wang and S.-D. Yang, Chem. Commun., 2011,
47, 11336–11338.
12 (a) W.-W. Chan, S.-H. Yueng, Z. Zhou, A. S. C. Chan and W.-Y. Yu, Org.
Lett., 2010, 12, 604–607; (b) C.-W. Chan, Z. Zhou, A. S. C. Chan and
W.-Y. Yu, Org. Lett., 2010, 12, 3926–3929; (c) K.-H. Ng, A. S. C. Chan
and W.-Y. Yu, J. Am. Chem. Soc., 2010, 132, 12862–12864; (d) W.-
Y. Yu, W.-N. Sit, Z. Zhou and A. S. C. Chan, Org. Lett., 2009, 11, 3174–
3177; (e) M. K.-W. Choi, W.-Y. Yu and C.-M. Che, Org. Lett., 2005, 7,
1081–1084.
Competition experiments were designed to determine the
primary KIE (kH/kD) of the Ru-catalyzed intramolecular cycliza-
tion of diazo-β-ketoanilides.
13 (a) W. Baratta, W. A. Herrmann, R. M. Kratzer and P. Rigo, Organo-
metallics, 2000, 19, 3664–3669.
To a mixture of 1a (0.1 mmol), 1a-d5 (0.1 mmol) and [Ru(p-
cymene)Cl2]2 (2.5 mol%), toluene (1 mL) was added. The reac-
tion mixture was stirred for 5 min at 40 °C under a N2 atmos-
phere. The reaction mixture was then concentrated and the
14 (a) H. Nishiyama, Y. Itoh, H. Matsumoto, S.-B. Park and K. Itoh, J. Am.
Chem. Soc., 1994, 116, 2223–2224; (b) H. Nishiyama, Y. Itoh,
Y. Sugawara, H. Matsumoto, K. Aoki and K. Itoh, Bull. Chem. Soc. Jpn.,
1995, 68, 1247–1262; (c) H. Nishiyama, Top. Organomet. Chem., 2004,
11, 81–92.
1
substrate conversion was determined by H NMR analysis using
15 In the case of Ru-catalyzed intermolecular carbenoid C–H bond functio-
nalization of indoles, a diazo compound bearing an ortho-OMe at the
aryl ring was found to be ineffective, see: ref. 12a.
16 C.-M. Che, J.-S. Huang, F.-W. Lee, Y. Li, T.-S. Lai, H.-L. Kwong, P.-
F. Teng, W.-S. Lee, W.-C. Lo, S.-M. Peng and Z.-Y. Zhou, J. Am. Chem.
Soc., 2001, 123, 4119–4129.
CH2Br2 as the internal standard. The KIE values were calculated
based on the substrate conversions of 1a and 1a-d5. The KIE
experiment was repeated three times and the average value
(kH/kD ∼ 1) was obtained.
17 Intramolecular cyclization of arenes with diazo compounds is known as
Buchner cyclization, which is known to form strained fused polycyclic
structures. For reviews, see: (a) H. Lebel, J.-F. Marcoux, C. Molinaro and
A. B. Charette, Chem. Rev., 2003, 103, 977–1050; (b) T. Ye and M.
A. McKervey, Chem. Rev., 1994, 94, 1091–1160.
Acknowledgements
We thank the financial support from the Hong Kong Research
Grants Council (PolyU 5019/06P, SEG_PolyU01) and the Areas
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3749–3755 | 3755