Copper-catalyzed domino coupling reaction: An efficient method to synthesize oxindoles

Article abstract of DOI:10.1039/c2ob26110c

An efficient and novel procedure for a copper catalyzed domino coupling reaction has been developed, which afforded various oxindoles in good to excellent yields with tolerance of various substituents. In addition, this method could be applied to synthesize horsfiline and coerulescine in few steps with high total yields. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob26110c

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PAPER
Copper-catalyzed domino coupling reaction: an efficient method to synthesize
oxindoles†
Jen-Chieh Hsieh,* An-Yi Cheng, Jun-Hao Fu and Ting-Wei Kang
Received 30th April 2012, Accepted 11th June 2012
DOI: 10.1039/c2ob26110c
An efficient and novel procedure for a copper catalyzed domino coupling reaction has been developed,
which afforded various oxindoles in good to excellent yields with tolerance of various substituents. In
addition, this method could be applied to synthesize horsfiline and coerulescine in few steps with high
total yields.
via copper catalysis is desirable. Our experience in transition-
Introduction
metal-catalyzed coupling reactions14,15 encouraged us to explore
Oxindole derivatives are very important compounds in organic
synthesis because of their frequent discovery in the core structure
of natural alkaloids1 and bioactive compounds.2 Although
numerous strategies for the synthesis of oxindoles have been
developed, they often involve palladium catalysis, for instance
the Heck reaction,3 Heck–cyanation,4 cyanoamidation,5 arylami-
dation6 and α-arylation.7 Recent research on the synthesis of oxi-
ndoles has been extended to the use of palladium catalytic C–H
functionalization,8 which has the advantages of atom economy
and the easy preparation of substrates. While palladium catalysis
is powerful, there are still some drawbacks such as high cost and
air-sensitivity.
A copper-catalyzed coupling reaction is an alternative pro-
cedure with low cost and can be utilized under aerobic con-
ditions.9 Because of the advantages, it has received considerable
attention. Many reports also revealed that copper-catalyzed coup-
ling reactions can be involved in domino processes for the syn-
thesis of complicated compounds and alkaloids;10 however, only
a few reports are related to the synthesis of oxindoles. In 2009,
Kündig and Jia developed stoichiometric copper-mediated C–H
functionalization to form oxindoles.11 Later, Taylor realized the
copper catalytic synthesis of oxindoles via C–H activation.12
Typical intramolecular Ullmann type C–N coupling reactions
were also utilized to synthesize oxindoles by Viswanathan and
Katkevics.13 However, the present literature involving copper-
mediated coupling reactions always requires N-protected sub-
strates to facilitate the synthesis of oxindoles. This limitation
toughens the synthesis of natural alkaloids; thus, the develop-
ment of the direct synthesis of oxindoles without N-substituents
the possibility for effecting this transformation via copper cataly-
sis. To the best of our knowledge, this is the first example of the
synthesis of oxindoles via copper-catalyzed multiple bond
formation.
Results and discussion
In a preliminary reaction, treatment of 2-(2-bromophenyl)-2-
methylpropanenitrile (1a) in the presence of 5 mol% CuI and 2.0
equiv NaOH in 5.0 mL DMF at 100 °C for 24 h afforded the
corresponding 3,3-dimethylindolin-2-one (2a) in 21% yield
(Table 1, entry 1). Most of the starting materials were unchanged
even after a longer reaction time. Further investigation was
focused on the effect of ligand, solvent, copper source and the
amount of NaOH, and the results are summarized in Table 1.
The effect of solvent is crucial; among the variously employed
polar solvents, only t-BuOH significantly enhanced the reaction
(entry 4). The employment of amino acids as ligands is very
helpful (entries 5–10),14 and N-acetylglycine showed the best
ability, increasing the yield of 2a to 69% (entry 9). Of the
various copper sources (entries 11–13), CuI provided a better
yield of 2a than the others. It is noteworthy that the present cata-
lytic reaction required NaOH to be the source of the oxygen
atom; the desired product 2a was not obtained without the pres-
ence of NaOH. In addition, the amount of NaOH (entries 14–16)
is also influential, and 3 equivalents of NaOH was found to be
optimal, improving the yield of 2a to 87% (entry 15). The repla-
cement of NaOH by LiOH or KOH slightly decreased the yield
of 2a. It was found that a small amount of KI could greatly
improve the reaction and provide 2a in excellent yield even for
lower loadings of CuI (entries 17, 18);16 however, the reaction
could not provide any desired product 2a unless CuI was
present. In addition, this catalytic reaction proceeded well under
both aerobic conditions and nitrogen atmosphere.
Department of Chemistry, Tamkang University, New Taipei City, 25137,
Taiwan (R.O.C.). E-mail: jchsieh@mail.tku.edu.tw;
Fax: +886-2-26209924; Tel: +886-2-26215656ext2545
†Electronic supplementary information (ESI) available: Experimental
procedure, characterization data, spectral data and copies of all com-
pounds. See DOI: 10.1039/c2ob26110c
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Table 1 Optimization of reaction conditionsa
Entry
[Cu]
L
x
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuSCN
Cu2O
Cu(OTf)2
CuI
CuI
CuI
CuI
CuI
None
None
None
None
L1
L2
L3
L4
L5
L6
L5
L5
L5
L5
L5
L5
L5
L5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
3.0
4.0
3.0
3.0
DMF
DME
21
6
17
36
55
42
48
37
69
46
43
38
47
54
87
DMSO
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
9
10
11
12
13
14
15
16
17c
18c,e
81
99 (96)d
97 (96)d
a 0.5 mmol scale. b 1H NMR yield on the basis of internal standard
mesitylene. c 1.0 mol% KI. d Isolated yield. e 3.0 mol% CuI with
6.0 mol% ligand.
The copper-catalyzed reaction was successfully extended to
various oxindoles; the results are listed in Scheme 1. The elec-
tronic effect of the arene moiety is slightly related to the yields
(2b–2h). Thus, the EWG on the para position of bromide pro-
vided excellent yields of products 2b and 2c, but the EDG gave
products 2d and 2e in slightly lower yields. Substituents on the
meta position did not affect the reaction, the corresponding pro-
ducts 2f, 2g and 2h were obtained in excellent yields. Naphthyl
and pyridine moieties were also tolerated giving products 2i and
2j but they were obtained in moderate yields of 69% and 56%,
respectively.
A wide variety of substituents and spiro rings on the 3,3 posi-
tion of oxindole could be also well tolerated (2k–2D). It was
observed that the size of the substituent on the 3,3 position of
the oxindole dominated the yields of the reactions (2k, 2l). Thus,
the yield of the corresponding product was decreased along with
the increase of the size of the substituent. Products with substitu-
ents on the 3 position containing oxygen and sulfur were
afforded in moderate yields (2m–2p). The comparably lower
yields were caused by the leaving of the RO- and RS-groups. A
spiro ring on the 3,3 position of oxindoles were also obtained in
good to excellent yields (2q–2u); it is interesting that the size of
the substituents on the ring did not significantly affect the yields
of the desired products. 3-Alkenyl oxindole (2v) could be pre-
pared as well, which is related to large number of alkaloids and
medicines.1d However, the low yield of 2v was due to the
nucleophilic addition of hydroxide to olefin. Not only the qua-
ternary carbon on the 3 position, but also the products with sec-
ondary carbon on the 3,3-unsubstituted oxindoles (2w, 2x) can
a
Scheme 1 Copper-catalyzed cyclization to form oxindole. 0.5 mmol
b
c
scale. All reported yields of 2 are isolated yields. 3.0 mol% CuI with
6.0 mol% ligand.
be afforded in moderate yields. It was found that proton abstrac-
tion causing rearrangement and substitution for the secondary
carbon occurs, but as a minor behavior. Cyclization for the six-
membered ring was also possible; the corresponding product 2y
was obtained in good yield. Moreover, the combination
of various substituents on the 3,3 position and on the arene
moiety provided the corresponding products in excellent yields
(2A–2D).
After exploring the scope of the reaction, we tested the reactiv-
ity of aryl iodide 1a′ and found that the reaction processed very
smoothly and provided the corresponding product 2a in excellent
yield at a lower temperature and short reaction time (Scheme 2).
In order to extend the application of this developed method,
the synthesis of alkaloids was attempted. Thus, we created a
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Conclusions
In conclusion, we have developed a novel methodology for a
copper-catalyzed domino coupling reaction. This is a very
efficient synthetic route to provide various oxindole derivatives
in moderate to excellent yields with tolerance of a wide variety
of substrates. Moreover, we can also apply this method to syn-
thesize ( )-coerulescine and ( )-horsfiline in a very efficient way
with few steps and high total yields. Further studies to extend the
application of this catalytic system are currently underway.
Scheme 2 Reaction involving aryl iodide.
Experimental
General information
All reagents were purchased from Sigma-Aldrich, Fisher-Acros,
TCI, or Alfa-Aesar, and were used without further purification
unless otherwise noted. THF and Et2O were distilled from
sodium, and CH3CN was distilled from CaH2. All manipulations
of oxygen- and moisture-sensitive materials were conducted with
a standard Schlenk technique. Flash column chromatography
was performed using silica gel (230–400 mesh). Analytical thin
layer chromatography (TLC) was performed on 60 F254
(0.25 mm) plates and visualization was accomplished with UV
light (254 and 354 nm) and/or an aqueous alkaline KMnO4 solu-
tion followed by heating. Proton and carbon nuclear magnetic
resonance spectra (1H NMR and 13C NMR) were recorded on
Bruck 300 or Bruck 600 spectrometer with Me4Si or solvent
resonance as the internal standard (1H NMR, Me4Si at 0 ppm,
CHCl3 at 7.26 ppm; 13C NMR, Me4Si at 0 ppm, CDCl3 at
77.0 ppm). 1H NMR data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
quint = quintet, sext = sextet, sept = septet, br = broad, m = mul-
tiplet), coupling constants (Hz), and integration. IR spectral data
were recorded on a Brucker TENSOR 37 spectrometer. Melting
points (mp) were determined using a Fargo MP-1D. GC-MS
data were obtained from the HP 5890 Series II GC/HP 5972 GC
MASS Spectrometer System. High resolution mass spectral data
were obtained from the MAT-95XL HRMS by using EI method.
Scheme 3 Synthesis of ( )-coerulescine and ( )-horsfiline.
Scheme 4 Proposed mechanism.
novel synthetic route to form horsfiline17,18 and coerulescine19,20
by using this copper catalysis as the key step (Scheme 3). The
synthesis began from the preparation of 2-(2-bromo-5-methoxy-
phenyl)acetonitrile 5d. Olefination at the 2 position of com-
pounds 5 provided 6 in moderate yields. The [3 + 2]
cycloaddition of compounds 6 in the presence of sarcosine and
formaldehyde gave 1z and 1E in 76% and 71% yields, respect-
ively. Final cyclization by the copper catalytic domino reactions
furnished ( )-coerulescine 2z in 93% yield and ( )-horsfiline 2E
in 88% yield.
After examination of the reaction scope, we turned to studying
the mechanism by doing a series of control experiments (see the
ESI† for details), and a tentative pathway (Scheme 4) can be pro-
posed according to these results. The copper complex in this
reaction plays two different roles, one is acting as a Lewis acid
and another is to couple the C–N bond. Thus, the reaction is
likely to be initiated by the coordination of the nitrile to com-
pound 1 to form a copper complex, which accelerates the follow-
ing nucleophilic addition by hydroxide to form complex A. It
should be noted that without copper complex, the direct hydroly-
sis from nitrile to amide in NaOH–t-BuOH needs almost twice
the reaction time. Tautomerization of A provides complex B,
which undergoes oxidative addition in an intramolecular manner
to generate complex C. Reductive elimination of C affords com-
pound 2 and regenerates copper complex.
General procedure for the copper-catalyzed domino reactions
To a screw-capped vial (10 mL) were added CuI (0.015 mmol,
2.9 mg, 3.0 mol%), KI (0.005 mmol, 0.9 mg, 1.0 mol%), N-acetyl-
glycine (0.03 mmol, 3.5 mg, 6.0 mol%), NaOH (1.5 mmol,
60 mg, 3.0 equiv) and 2,2-disubstituted 2-(2-bromophenyl)
acetonitrile (1, 0.5 mmol, 1.0 equiv) in t-BuOH (tert-butanol,
5.0 mL). The vial was sealed with a cap and allowed to stir at
100 °C for the specific reaction time. The crude reaction mixture
was diluted with CH2Cl2, filtered through a thin Celite pad, and
concentrated in vacuo. The residue was isolated using column
chromatography by using hexane and ethyl acetate as eluent to
give the pure product. Products 2 were obtained according to this
procedure.
3,3-Dimethylindolin-2-one
(2a). White
solid,
mp:
182–184 °C; IR (KBr): 3450, 3096, 1717, 1676, 1410, 1226,
1
1172, 738, 618, 492 cm−1; H NMR (600 MHz, CDCl3): δ 8.62
(br, 1H), 7.20 (t, J = 7.8 Hz, 2H), 7.04 (t, J = 7.8 Hz, 1H), 6.94
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(d, J = 7.2 Hz, 1H), 1.41 (s, 6H); 13C NMR (150 MHz, CDCl3):
δ 183.9, 139.8, 136.3, 127.6, 122.6, 122.4, 109.8, 44.6, 24.3;
HRMS: C10H11NO calculated 161.0841, found 161.0838.
123.5, 108.6, 46.3, 21.3; HRMS: C10H10ClNO calculated
195.0451, found 195.0454.
3,3-Dimethyl-1H-benzo[g]indol-2(3H)-one (2i). White solid,
mp: 222–224 °C; IR (KBr): 3468, 2970, 1703, 1459, 1197, 812,
3,3-Dimethyl-5-(trifluoromethyl)indolin-2-one
solid, mp: 152–154 °C; IR (KBr): 3450, 2930, 2880, 1729,
1629, 1339, 1095, 897, 816, 779, 537 cm−1 1H NMR
(2b). White
1
558 cm−1; H NMR (600 MHz, CDCl3): δ 7.97 (d, J = 8.4 Hz,
;
1H), 7.87 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.57
(t, J = 6.6 Hz, 1H), 7.49 (t, J = 6.6 Hz, 1H), 7.38 (d, J = 7.8 Hz,
1H), 2.17 (br, 1H), 1.53 (s, 6H); 13C NMR (150 MHz, CDCl3):
δ 185.7, 135.7, 133.3, 130.8, 128.6, 126.1, 125.8, 122.4, 121.6,
120.2, 119.8, 46.0, 24.2; HRMS: C14H13NO calculated
211.0997, found 211.0994.
(600 MHz, CDCl3): δ 8.89 (br, 1H), 7.50 (d, J = 8.4 Hz, 1H),
7.43 (s, 1H), 7.02 (d, J = 7.8 Hz, 1H), 1.44 (s, 6H); 13C NMR
(150 MHz, CDCl3): δ 183.8, 142.9, 136.7, 125.5, 125.0 (q, J =
31.5 Hz), 124.4 (q, J = 270 Hz), 119.8, 109.7, 44.8, 24.2;
HRMS: C11H10F3NO calculated 229.0714, found 229.0715.
5-Chloro-3,3-dimethylindolin-2-one (2c). White solid, mp:
162–164 °C; IR (KBr): 3468, 3167, 2874, 2926, 2853, 2304,
3,3-Dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (2j). White
solid, mp: 182–184 °C; IR (KBr): 3450, 3114, 2966, 2874,
1
1731, 1670, 1481, 1204 cm−1; H NMR (600 MHz, CDCl3): δ
1
1731, 1613, 1466, 1200, 1153, 777 cm−1
;
H NMR (600 MHz,
9.14 (br, 1H), 7.18–7.16 (m, 2H), 6.88 (d, J = 8.4 Hz, 1H), 1.40
(s, 6H); 13C NMR (150 MHz, CDCl3): δ 183.9, 138.4, 138.0,
127.9, 127.6, 123.2, 110.9, 45.1, 24.2; HRMS: C10H10ClNO cal-
culated 195.0451, found 195.0453.
CDCl3): δ 8.16 (dd, J1 = 5.4 Hz, J2 = 1.8 Hz, 1H), 7.44 (dd, J1
= 7.2 Hz, J2 = 1.2 Hz, 1H), 6.96 (dd, J = 7.2 Hz, J2 = 5.4 Hz,
1
1H), 1.87 (br, 1H), 1.42 (s, 6H); 13C NMR (150 MHz, CDCl3):
δ 182.1, 155.6, 146.1, 130.5, 130.4, 118.1, 44.6, 23.8; HRMS:
C9H10N2O calculated 162.0793, found 162.0794.
5-Methoxy-3,3-dimethylindolin-2-one (2d). White solid, mp:
154–156 °C; IR (KBr): 3483, 2966, 1702, 1452, 1029,
3,3-Diethylindolin-2-one (2k). White solid, mp: 166–168 °C;
596 cm−1 1H NMR (600 MHz, CDCl3): δ 8.14 (br, 1H),
;
IR (KBr): 3873, 3449, 3136, 2969, 2876, 1667, 1344, 1204,
1
744 cm−1; H NMR (600 MHz, CDCl3): δ 8.40 (br, 1H), 7.20
6.83–6.79 (m, 2H), 6.73 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 3.79
(s, 3H), 1.39 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 183.5,
155.9, 137.7, 133.0, 111.9, 110.1, 110.0, 55.8, 45.1, 24.4;
HRMS: C11H13NO2 calculated 191.0946, found 191.0951.
(td, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 7.12 (d, J = 6.6 Hz, 1H), 7.06
(td, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H),
1.96–1.90 (m, 2H), 1.83–1.78 (m, 2H), 0.64 (t, J = 7.8 Hz, 6H);
13C NMR (150 MHz, CDCl3): δ 182.5, 141.3, 132.4, 127.6,
123.1, 122.4, 109.5, 54.9, 30.6, 8.7; HRMS: C12H15NO calcu-
lated 189.1154, found 189.1159.
7,7-Dimethyl-5H-[1,3]dioxolo[4,5-f]indol-6(7H)-one (2e). White
solid, mp: 244–246 °C; IR (KBr): 3467, 2925, 2284, 1701,
1476, 1118, 1035, 680, 486 cm−1; 1H NMR (600 MHz, CDCl3):
δ 8.63 (br, 1H), 6.70 (s, 1H), 6.53 (s, 1H), 5.91 (s, 2H), 1.36 (s,
6H); 13C NMR (150 MHz, CDCl3): δ 184.4, 146.8, 143.2,
133.5, 128.2, 104.1, 100.9, 93.6, 45.0, 24.5; HRMS: C11H11NO3
calculated 205.0739, found 205.0740.
3,3-Dibenzylindolin-2-one (2l). White solid, mp: 218–220 °C;
IR (KBr): 3450, 3083, 2919, 2854, 1718, 1625, 1241, 754, 696,
1
556 cm−1; H NMR (600 MHz, CDCl3): δ 7.18–7.17 (m, 2H),
7.09–7.00 (m, 8H), 6.93 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz, 4H), 6.45
(dd, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H), 3.31 (d, J = 13.2 Hz, 2H),
3.17 (d, J = 13.2 Hz, 2H); 13C NMR (150 MHz, CDCl3): δ
180.1, 140.5, 135.8, 130.6, 130.1, 127.8, 127.7, 126.5, 124.8,
121.7, 109.2, 56.4, 43.5; HRMS: C22H19NO calculated
313.1467, found 313.1463.
3,3-Dimethyl-6-(trifluoromethyl)indolin-2-one (2f). White solid,
mp: 180–181 °C; IR (KBr): 3449, 2970, 2637, 1676, 1460,
1355, 1157, 1052, 640, 519 cm−1; 1H NMR (600 MHz, CDCl3):
δ 9.35 (br, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 7.8 Hz,
1H), 7.21 (s, 1H), 1.44 (s, 6H); 13C NMR (150 MHz, CDCl3):
δ 184.0, 140.4, 140.0, 130.3 (q, J = 31.5 Hz), 124.0 (q,
J = 270 Hz), 122.8, 119.6 (d, J = 3 Hz), 106.9 (d, J = 3 Hz),
44.9, 24.1; HRMS: C11H10F3NO calculated 229.0714, found
229.0712.
3-Ethyl-3-methoxyindolin-2-one (2m). Yellow solid, mp:
160–161 °C; IR (KBr): 3463, 3274, 2984, 2828, 1729, 1621,
1
1470, 1210, 1139, 765, 706, 646 cm−1; H NMR (600 MHz,
CDCl3): δ 8.65 (br, 1H), 7.30–7.27 (m, 2H), 7.10 (td, J1 = 7.2
Hz, J2 = 0.6 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 3.10 (s, 3H),
2.00 (q, J = 7.2 Hz, 2H), 0.79 (t, J = 7.2 Hz, 3H); 13C NMR
(150 MHz, CDCl3): δ 178.8, 141.3, 129.7, 127.4, 124.6, 123.0,
110.3, 84.0, 53.2, 30.7, 7.3; HRMS: C11H13NO2 calculated
191.0946, found 191.0942.
6-Methoxy-3,3-dimethylindolin-2-one (2g). White solid, mp:
167–169 °C; IR (KBr): 3856, 3449, 3192, 2969, 1712, 1672,
1384, 1351, 1157, 740, 572 cm−1; 1H NMR (600 MHz, CDCl3):
δ 8.42 (br, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.56 (dd, J1 = 7.8 Hz,
J2 = 1.8 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 3.80 (s, 3H), 1.38 (s,
6H); 13C NMR (150 MHz, CDCl3): δ 184.4, 159.7, 140.7,
128.3, 123.2, 107.2, 97.2, 55.5, 44.2, 24.5; HRMS: C11H13NO2
calculated 191.0946, found 191.0948.
3-Ethyl-3-isopropoxyindolin-2-one (2n). White solid, mp:
171–172 °C; IR (KBr): 3449, 2923, 1754, 1689, 1625, 1384,
1
1107, 747, 497 cm−1; H NMR (600 MHz, CDCl3): δ 9.00 (br,
4-Chloro-3,3-dimethylindolin-2-one (2h). White solid, mp:
136–138 °C; IR (KBr): 3469, 3152, 2826, 1723, 1676, 1619,
1247, 1188, 661 cm−1; 1H NMR (600 MHz, CDCl3): δ 9.50 (br,
1H), 7.13 (t, J = 7.8 Hz, 1H), 6.97 (dd, J1 = 7.8 Hz, J2 = 0.6 Hz,
1H), 6.88 (dd, J1 = 7.8 Hz, J2 = 0.6 Hz, 1H), 1.55 (s, 6H); 13C
NMR (150 MHz, CDCl3): δ 183.8, 141.7, 132.0, 130.6, 128.9,
1H), 7.30–7.25 (m, 2H), 7.07 (t, J = 7.8 Hz, 1H), 6.94 (d, J =
7.8 Hz, 1H), 3.46–3.42 (m, 1H), 1.96 (q, J = 7.2 Hz, 2H), 1.12
(d, J = 6.0 Hz, 3H), 0.99 (d, J = 6.6 Hz, 3H), 0.73 (t, J = 7.2 Hz,
3H); 13C NMR (150 MHz, CDCl3): δ 180.1, 141.0, 129.4,
128.8, 124.8, 122.7, 110.3, 83.1, 69.2, 31.6, 24.2, 23.3, 7.1;
HRMS: C13H17NO2 calculated 219.1259, found 219.1261.
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3-Ethyl-3-phenoxyindolin-2-one (2o). White solid, mp:
125–127 °C; IR (KBr): 3449, 2923, 1721, 1619, 1544, 1324,
1,3-Dihydrospiro[indene-2,3′-indolin]-2′-one (2u). White solid,
mp: 210–212 °C; IR (KBr): 3464, 3187, 1707, 1459, 1225,
1
1
1115, 691, 489 cm−1; H NMR (600 MHz, CDCl3): δ 8.42 (br,
1009, 749, 643 cm−1; H NMR (600 MHz, CDCl3): δ 8.71 (br,
1H), 7.28 (d, J = 7.2 Hz, 1H), 7.24 (td, J1 = 7.8 Hz, J2 = 0.6 Hz,
1H), 7.07–7.02 (m, 3H), 6.88–6.84 (m, 2H), 6.72 (q, J = 8.4 Hz,
2H), 2.25–2.17 (m, 2H), 0.91 (d, J = 7.8 Hz, 3H); 13C NMR
(150 MHz, CDCl3): δ 177.6, 155.7, 140.2, 129.7, 129.1, 127.8,
124.8, 123.0, 122.7, 119.0, 110.5, 84.1, 32.2, 7.1; HRMS:
C16H15NO2 calculated 253.1103, found 253.1108.
1H), 7.28–7.24 (m, 4H), 7.18 (t, J = 7.8 Hz, 1H), 6.93 (d, J =
7.8 Hz, 1H), 6.89 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H),
3.65 (d, J = 16.2 Hz, 2H), 3.13 (d, J = 15.6 Hz, 2H); 13C NMR
(150 MHz, CDCl3): δ 182.6, 141.1, 139.6, 136.7, 128.0, 127.0,
124.5, 122.8, 121.9, 109.8, 54.5, 44.0; HRMS: C16H13NO calcu-
lated 235.0997, found 235.1001.
3-Ethyl-3-(phenylthio)indolin-2-one (2p). Yellow solid, mp:
134–136 °C; IR (KBr): 3449, 2923, 2853, 1639, 1384, 1118,
3-Cyclohexylideneindolin-2-one (2v). White solid, mp:
204–206 °C; IR (KBr): 3449, 2926, 2854, 1690, 1618, 1467,
1
742, 492 cm−1; H NMR (600 MHz, CDCl3): δ 8.30 (br, 1H),
1
1217, 736 cm−1; H NMR (600 MHz, CDCl3): δ 8.03 (br, 1H),
7.32 (d, J = 7.2 Hz, 1H), 7.24–7.20 (m, 3H), 7.14 (td, J1 = 7.8
Hz, J2 = 0.6 Hz, 1H), 7.10–7.06 (m, 3H), 6.67 (d, J = 7.8 Hz,
1H), 2.24–2.17 (m, 1H), 2.16–2.10 (m, 1H), 0.77 (d, J = 7.8 Hz,
3H); 13C NMR (150 MHz, CDCl3): δ 178.6, 140.6, 136.4,
129.9, 129.5, 129.3, 128.6, 128.3, 124.6, 122.6, 109.7, 60.1,
28.6, 9.3; HRMS: C16H15NOS calculated 269.0874, found
269.0873.
7.61 (d, J = 7.8 Hz, 1H), 7.16 (td, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H),
6.98 (td, J1 = 7.8 Hz, J2 = 0.6 Hz, 1H), 6.84 (d, J = 7.2 Hz, 1H),
3.35 (t, J = 6.6 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 1.86–1.82 (m,
2H), 1.80–1.76 (m, 2H), 1.72–1.68 (m, 2H); 13C NMR
(150 MHz, CDCl3): δ 169.9, 164.6, 139.3, 127.5, 124.3, 123.8,
121.5, 120.0, 109.3, 33.1, 30.0, 28.1, 27.8, 25.8; HRMS:
C14H15NO calculated 213.1154, found 213.1153.
Spiro[cyclopentane-1,3′-indolin]-2′-one (2q). White solid, mp:
122–124 °C; IR (KBr): 3449, 2956, 2928, 2281, 1703, 1619,
5-Chloroindolin-2-one (2x). White solid, mp: 195–196 °C; IR
1
(KBr): 3444, 2900, 1701 cm−1; H NMR (300 MHz, CDCl3):
1
1384, 747, 492 cm−1; H NMR (600 MHz, CDCl3): δ 8.55 (br,
δ 8.50 (br, 1H), 7.21–7.18 (m, 2H), 7.01 (d, J = 7.8 Hz, 1H),
3.54 (s, 2H); 13C NMR (75 MHz, CDCl3): δ 176.8, 140.9,
127.9, 127.7, 126.9, 125.1, 110.5, 36.1; HRMS: C8H6ClNO cal-
culated 167.0138, found 167.0144.
1H), 7.18 (t, J = 7.8 Hz, 2H), 7.02 (td, J1 = 7.8 Hz, J2 = 1.2 Hz,
1H), 6.90 (dd, J1 = 7.8 Hz, J2 = 0.6 Hz, 1H), 2.20–2.17 (m, 2H),
2.09–2.06 (m, 2H), 2.00–1.98 (m, 2H), 1.90–1.87 (m, 2H); 13C
NMR (150 MHz, CDCl3): δ 184.6, 140.0, 137.4, 127.3, 122.6,
122.5, 109.5, 54.4, 38.4, 26.7; HRMS: C12H13NO calculated
187.0997, found 187.0993.
5H-[1,3]Dioxolo[4,5-f]indol-6(7H)-one (2y). White solid, mp:
1
228–229 °C; IR (KBr): 742, 1295, 1475, 1720, 2915 cm−1; H
NMR (600 MHz, CDCl3): δ 7.91 (br, 1H), 6.74 (s, 1H), 6.47
(s, 1H), 5.92 (s, 2H), 3.46 (s, 2H); 13C NMR (150 MHz,
CDCl3): δ 177.6, 147.1, 143.1, 136.0, 116.7, 106.1, 100.1, 93.3,
36.4; HRMS: C8H7NO calculated 177.0426, found 177.0429.
Spiro[cyclohexane-1,3′-indolin]-2′-one (2r). White solid, mp:
115–117 °C; IR (KBr): 3468, 2924, 2852, 1701, 1637, 1619,
1385, 1101, 746 cm−1; 1H NMR (600 MHz, CDCl3): δ 8.68 (br,
1H), 7.45 (d, J = 7.2 Hz, 1H), 7.21 (td, J1 = 7.8 Hz, J2 = 0.6 Hz,
1H), 7.02 (td, J1 = 7.2 Hz, J2 = 0.6 Hz, 1H), 6.94 (d, J = 7.8 Hz,
1H), 1.97–1.92 (m, 2H), 1.90–1.85 (m, 2H), 1.80–1.73 (m, 3H),
1.66–1.60 (m, 3H); 13C NMR (150 MHz, CDCl3): δ 183.3,
140.0, 135.8, 127.4, 124.2, 121.8, 109.7, 48.0, 32.9, 25.2, 21.1;
HRMS: C13H15NO calculated 201.1154, found 201.1156.
3,3-Dimethyl-3,4-dihydroquinolin-2(1H)-one (2y). Yellow solid,
mp: 159–161 °C; IR (KBr): 3475, 3195, 3071, 2985, 2923,
1672, 1494, 1389, 762, 670 cm−1; 1H NMR (600 MHz, CDCl3):
δ 8.22 (br, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 7.2 Hz,
1H), 7.00 (t, J = 7.2 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 2.81 (s,
2H), 1.22 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 176.9, 136.6,
128.5, 127.4, 123.3, 123.2, 114.8, 40.2, 37.3, 24.3; HRMS:
C11H13NO calculated 175.0997, found 175.0993.
2′,3′,5′,6′-Tetrahydrospiro[indoline-3,4′-pyran]-2-one (2s). White
solid, mp: 238–240 °C; IR (KBr): 3568, 3447, 2913, 1700,
1
1624, 1559, 1092 cm−1; H NMR (600 MHz, CDCl3): δ 8.17
(br, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.23 (t, J = 6.6 Hz, 1H), 7.06
(t, J = 7.8 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 4.27–4.23 (m, 2H),
3.96–3.92 (m, 2H), 1.94–1.86 (m, 4H); 13C NMR (150 MHz,
CDCl3): δ 181.8, 139.8, 134.6, 128.0, 123.5, 122.5, 109.7, 62.9,
44.6, 32.9; HRMS: C12H13NO2 calculated 203.0946, found
203.0944.
4′-Chlorospiro[cyclopentane-1,3′-indolin]-2′-one (2A). White
solid, mp: 168–170 °C; IR (KBr): 3487, 3170, 3134, 2957,
1
2870, 1706, 1619, 1444, 1178, 661 cm−1; H NMR (600 MHz,
CDCl3): δ 9.25 (br, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.96 (d, J =
7.8 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 2.33–2.31 (m, 2H),
2.09–2.03 (m, 6H); 13C NMR (150 MHz, CDCl3): 185.4, 142.5,
131.9, 129.8, 128.6, 123.4, 108.2, 54.6, 35.0, 27.6; HRMS:
C12H12ClNO calculated 221.0607, found 221.0611.
Dispiro[1,3-dioxolane-2,1′-cyclohexane-4′,3′′-[3H]indol]-2′′(1′′-
H)-one (2t). White solid, mp: 214–215 °C; IR (KBr): 3468,
1
2958, 2925, 2854, 1700, 1620, 1444, 1094, 750, 488 cm−1; H
NMR (600 MHz, CDCl3): δ 9.34 (br, 1H), 7.35 (d, J = 7.2 Hz,
1H), 7.20 (t, J = 7.8 Hz, 1H), 7.00 (t, J = 7.8 Hz, 1H), 6.96 (d,
J = 7.8 Hz, 1H), 4.03 (s, 4H), 2.30–2.24 (m, 2H), 2.05–2.00 (m,
2H), 1.93–1.86 (m, 4H); 13C NMR (150 MHz, CDCl3): δ 183.1,
140.2, 134.9, 127.7, 123.3, 122.0, 109.9, 108.1, 64.3, 46.5,
31.2, 30.1; HRMS: C15H17NO3 calculated 259.1208, found
259.1202.
5′-(Trifluoromethyl)spiro[cyclohexane-1,3′-indolin]-2′-one (2B).
White solid, mp: 182–184 °C; IR (KBr): 3467, 2933, 1724,
1
1691, 1113, 825 cm−1; H NMR (600 MHz, CDCl3): δ 9.11 (br,
1H), 7.64 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 7.8 Hz,
1H), 2.00–1.97 (m, 2H), 1.91–1.86 (m, 2H), 1.77–1.64 (m, 6H);
13C NMR (150 MHz, CDCl3): δ 183.3, 143.1, 136.3, 125.2,
124.5 (q, J = 270 Hz), 124.3 (q, J = 33 Hz), 121.0, 109.5, 48.0,
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32.8, 25.0, 21.0; HRMS: C14H14F3NO calculated 269.1027,
found 269.1025.
Notes and references
1 (a) C. Marti and E. M. Carreira, Eur. J. Org. Chem., 2003, 2209;
(b) C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46,
8748; (c) B. M. Trost and M. K. Brennan, Synthesis, 2009, 3003;
(d) A. Millemaggi and R. J. K. Taylor, Eur. J. Org. Chem., 2010, 4527;
(e) M. S. C. Pedras, E. E. Yaya and E. Glawischnig, Nat. Prod. Rep.,
2011, 28, 1381.
5′-Methoxyspiro[cyclopentane-1,3′-indolin]-2′-one (2C). White
solid, mp: 180–182 °C; IR (KBr): 3460, 2956, 2862, 1682,
1652, 1635, 1491, 1209, 1029 cm−1 1H NMR (600 MHz,
;
2 For selected papers see: (a) L. L. Wang, J. J. Li, Z. B. Zheng, H. Y. Liu,
G. J. Du and S. Li, Eur. J. Pharmacol., 2004, 502, 1; (b) G. C. Bignan,
K. Battista, P. J. Connolly, M. J. Orsini, J. Liu, S. A. Middletona and
A. B. Reitz, Bioorg. Med. Chem. Lett., 2005, 15, 5022.
3 (a) A. B. Dounay, K. Hatanaka, J. J. Kodanko, M. Oestreich,
L. E. Overman, L. A. Pfeifer and M. M. Weiss, J. Am. Chem. Soc., 2003,
125, 6261; (b) A. J. B. Lapierre, S. J. Geib and D. P. Curran, J. Am.
Chem. Soc., 2007, 129, 494; (c) M. C. McDermott, G. R. Stephenson,
D. L. Hughes and A. J. Walkington, Org. Lett., 2006, 8, 2917.
4 A. Pinto, Y. Jia, L. Neuville and J. Zhu, Chem.–Eur. J., 2007, 13, 961.
5 (a) Y. Kobayashi, H. Kamisaki, R. Yanada and Y. Takemoto, Org. Lett.,
2006, 8, 2711; (b) Y. Yasui, H. Kamisaki and Y. Takemoto, Org. Lett.,
2008, 10, 3303.
6 R. R. Poondra and N. J. Turner, Org. Lett., 2005, 7, 863.
7 (a) K. H. Shaughnessy, B. C. Hamann and J. F. Hartwig, J. Org. Chem.,
1998, 63, 6546; (b) S. Lee and J. F. Hartwig, J. Org. Chem., 2001, 66,
3402; (c) J. A. Schiffner and M. Oestreich, Eur. J. Org. Chem., 2011,
1148.
8 (a) E. J. Hennessy and S. L. Buchwald, J. Am. Chem. Soc., 2003, 125,
12084; (b) A. Pinto, L. Neuville, P. Retailleau and J. Zhu, Org. Lett.,
2006, 8, 4927; (c) A. Perry and R. J. K. Taylor, Chem. Commun., 2009,
3249; (d) G. An, W. Zhou, G. Zhang, H. Sun, J. Han and Y. Pan, Org.
Lett., 2010, 12, 4482.
CDCl3): δ 8.86 (br, 1H), 6.82 (dd, J1 = 8.4 Hz, J2 = 1.2 Hz, 1H),
6.79 (d, J = 3.0 Hz, 1H), 6.70 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz,
1H), 3.78 (s, 3H), 2.20–2.17 (m, 2H), 2.08–2.05 (m, 2H),
1.98–1.95 (m, 2H), 1.87–1.84 (m, 2H); 13C NMR (150 MHz,
CDCl3): δ 184.7, 155.9, 138.8, 133.6, 111.3, 110.2, 109.7, 55.8,
54.9, 38.4, 26.7; HRMS: C13H15NO2 calculated 217.1103,
found 217.1100.
2′,3′,5′,6′-Tetrahydrospiro[[1,3]dioxolo[4,5-f]indole-7,4′-pyran]-
6(5H)-one (2D). White solid, mp: 276–277 °C; IR (KBr): 3461,
1
2923, 1721, 1631, 1474, 1267, 1176, 1111, 754, 409 cm−1; H
NMR (600 MHz, CDCl3, bad solubility): δ 7.72 (br, 1H), 6.86
(s, 1H), 6.49 (s, 1H), 5.93 (s, 2H), 4.25–4.21 (m, 2H), 3.91–3.88
(m, 2H), 1.86–1.84 (m, 4H); 13C NMR (150 MHz, CDCl3):
δ 182.0, 147.0, 143.2, 133.6, 126.4, 104.9, 101.1, 93.2, 62.8,
44.8, 33.1; HRMS: C13H13NO4 calculated 247.0845, found
247.0844.
9 (a) S. V. Ley and A. W. Thomas, Angew. Chem., Int. Ed., 2003, 42, 5400;
(b) G. Evano, N. Blanchard and M. Toumi, Chem. Rev., 2008, 108, 3054.
10 Selected papers on Cu-catalyzed domino reactions: (a) A. Klapars,
S. Parris, K. W. Anderson and S. L. Buchwald, J. Am. Chem. Soc., 2004,
126, 3529; (b) B. Zou, Q. Yuan and D. Ma, Angew. Chem., Int. Ed.,
2007, 46, 2598; (c) J. Lu, X. Gong, H. Yang and H. Fu, Chem.
Commun., 2010, 46, 4172.
11 Y.-X. Jia and E. P. Kündig, Angew. Chem., Int. Ed., 2009, 48, 1636.
12 (a) J. E. M. N. Klein, A. Perry, D. S. Pugh and R. J. K. Taylor, Org.
Lett., 2010, 12, 3446; (b) C. L. Moody, V. Franckevičius, P. Drouhin,
J. E. M. N. Klein and R. J. K. Taylor, Tetrahedron Lett., 2012, 53,
1897.
13 (a) V. A. Ignatenko, N. Deligonul and R. Viswanathan, Org. Lett., 2010,
12, 3594; (b) T. Kukosha, N. Trufilkina and M. Katkevics, Synlett, 2011,
2525.
14 A.-Y. Cheng and J.-C. Hsieh, Tetrahedron Lett., 2012, 53, 71.
15 J.-C. Hsieh, Y.-C. Chen, A.-Y. Cheng and H.-C. Tseng, Org. Lett., 2012,
14, 1282.
16 J. Zanon, A. Klapars and S. L. Buchwald, J. Am. Chem. Soc., 2003, 125,
2890.
17 A. Jossang, P. Jossang, H. A. Hadi, T. Sevenet and B. Bodo, J. Org.
Chem., 1991, 56, 6527.
18 Selected papers on the synthesis of horsfiline: (a) U. K. S. Kumar, H. Ila
and H. Junjappa, Org. Lett., 2001, 3, 4193; (b) J. A. Murphy, R. Tripoli,
T. A. Khan and U. W. Mali, Org. Lett., 2005, 7, 3287; (c) B. M. Trost
and M. K. Brennan, Org. Lett., 2006, 8, 2027; (d) S. Jaegli, J.-P. Vors,
L. Neuville and J. Zhu, Synlett, 2009, 2997.
( )-Coerulescine (2z). Yellow solid, mp: 129–130 °C; IR
(KBr): 3465, 3242, 2944, 2791, 1709, 1620, 1472, 1338, 1197,
1
753 cm−1; H NMR (600 MHz, CDCl3): δ 9.04 (br, 1H), 7.38
(d, J = 7.8 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.03 (t, J = 7.8 Hz,
1H), 6.91 (d, J = 7.8 Hz, 1H), 3.02–2.98 (m, 1H), 2.90 (d, J =
9.6 Hz, 1H), 2.84–2.78 (m, 2H), 2.46 (s, 3H), 2.44–2.40 (m,
1H), 2.12–2.08 (m, 1H); 13C NMR (150 MHz, CDCl3): δ 183.2,
140.2, 136.3, 127.7, 123.2, 122.7, 109.6, 66.4, 56.8, 53.7, 41.8,
37.9; HRMS: C12H14N2O calculated 202.1106, found 202.1104.
( )-Horsfiline (2E). Yellow solid, mp: 159–160 °C; IR (KBr):
3449, 2922, 2851, 1702, 1492, 1208, 1032, 811, 669, 618 cm−1
;
1H NMR (600 MHz, CDCl3): δ 7.95 (br, 1H), 7.02 (d, J = 2.4
Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.72 (dd, J1 = 8.4 Hz, J2 =
2.4 Hz, 1H), 3.79 (s, 3H), 3.03–2.99 (m, 1H), 2.85 (s, 2H), 2.74
(q, J = 7.2 Hz, 1H), 2.45 (s, 3H), 2.43–2.39 (m, 1H), 2.11–2.06
(m, 1H); 13C NMR (150 MHz, CDCl3): δ 182.4, 156.2, 137.7,
133.2, 112.4, 110.4, 109.6, 66.5, 56.7, 55.9, 54.1, 41.8, 38.1;
HRMS: C13H16N2O2 calculated 232.1212, found 232.1211.
19 N. Anderton, P. A. Cockrum, S. M. Colegate, J. A. Edgar, K. Flower,
I. Vit and R. I. Willing, Phytochemistry, 1998, 48, 437.
Acknowledgements
20 Selected papers on the synthesis of coerulescine: (a) N. Selvakumar,
A. M. Azhagan, D. Srinivas and G. G. Krishna, Tetrahedron Lett., 2002,
43, 9175; (b) C. Li, C. Chan, A. C. Heimann and S. J. Danishefsky,
Angew. Chem., Int. Ed., 2007, 46, 1444; (c) J. D. White, Y. Li and
D. C. Ihle, J. Org. Chem., 2010, 75, 3569.
We thank the National Science Council of the Republic of China
(NSC-99-2113-M-032-003-MY2) for the support of this
research.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2012