Gallium-Catalyzed Domino Arylation/Oxycyclization of Allenes with Phenols

Article abstract of DOI:10.1021/acs.joc.5b00106

The synthesis of dihydrobenzofuran-appended oxindoles has been accomplished taking advantage of an unprecedented reaction between allenols and phenols under metal catalysis. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b00106

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Note
Gallium-Catalyzed Domino Arylation/Oxycyclization of Allenes with Phenols
Benito Alcaide, Pedro Almendros, Fernando Herrera,
Amparo Luna, M. Elena de Orbe, and Maria Rosario Torres
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00106 • Publication Date (Web): 27 Mar 2015
Downloaded from http://pubs.acs.org on March 31, 2015
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Gallium-Catalyzed Domino
Arylation/Oxycyclization of Allenes with
Phenols
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Benito Alcaide,*,† Pedro Almendros,*,‡ Fernando Herrera,† Amparo Luna,† M. Elena
de Orbe,† and M. Rosario Torres§
†Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Química Orgánica I, Unidad
Asociada al CSIC, Facultad de Química, Universidad Complutense de Madrid, 28040ꢀMadrid,
Spain
‡Instituto de Química Orgánica General, IQOGꢀCSIC, Juan de la Cierva 3, 28006ꢀMadrid, Spain
§CAI Difracción de Rayos X, Facultad de Química, Universidad Complutense de Madrid, 28040
Madrid, Spain
Eꢀmail: alcaideb@quim.ucm.es; Palmendros@iqog.csic.es
Table of Content Graphic
R4
Me
HO
OH
•
R3
O
10 mol% Ga(OTf)3
CH2Cl2, 45 oC
O
+
H
R3
N
R1
Me
O
R2
R4
N
R1
R2
major isomer
ABSTRACT: The synthesis of dihydrobenzofuranꢀappended oxindoles has been accomplished
taking advantage of an unprecedented reaction between allenols and phenols under metal catalysis.
The dihydrobenzofuran motif is present in a wide variety of natural products and biologically
relevant compounds,1 and the synthesis of this heterocycle is of current interest.2 Numerous reports
are available on metalꢀcatalyzed cyclization or crossꢀcoupling reactions of functionalized allenes.3
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In contrast, such reactions that involve the coupling of the allene moiety and a phenol are scarcely
accessible in literature.4 Despite that phenols are readily available chemicals, their use is
problematic due to selectivity issues. Recently, we have successfully reported selective
transformations of both indolinoneꢀtethered allenols5 and phenols.6 We envisioned that different
behaviour of the allenol moiety might be achieved utilizing a phenol as coupling partner. Herein,
we present a galliumꢀcatalyzed coupling–cyclization between phenols and indolinoneꢀtethered
allenols towards the preparation of dihydrobenzofuranꢀlinked oxindoles.
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To explore the possibility of an allene–phenol coupling, allenol 1a and phenol 2a were
initially chosen. The AuCl3ꢀcatalyzed reaction of allenol 1a and 4ꢀmethylphenol 2a afforded the
spirocyclic 2,5ꢀdihydrofuran 3a (Scheme 1). Hence, the hydroxy group in allenol 1a exclusively
suffers 5ꢀendo oxycyclization reaction,7 without the participation of the phenol moiety.
Scheme 1. Non-Productive Gold-Catalyzed Reaction of Indolinone-Tethered Allenol 1a and
Phenol 2a
Me
HO
•
O
Me
O
5 mol % AuCl3
CH2Cl2, RT, 5h
O
Me
OH
+
N
N
Me
Me
2a
1a
3a
(98%)
When a π acid such as AuCl3 is used, it might coordinate with one of the allene double
bonds via a monodentade mode. When a Lewis acid is employed, it might coordinate with the OH
of the allenol moiety via monodentade or bidentade modes. This activation might generate a
carbocation intermediate. Consequently, we decided to use a mainꢀgroup salt instead of a transitionꢀ
metal derivative. Happily, after assessing various metal catalysts, we found that a catalytic amount
of metal triflate specifically promoted the domino allenol–phenol coupling reaction (Table 1). The
domino reaction took place at 40ºC under M(OTf)n catalysis, which specifically promoted the
generation of the desired dihydrobenzofuranꢀappended oxindole scaffold, and the domino addition–
cyclization reaction took place readily.8 Diastereoselectivities were modest, in all cases giving rise
to mixtures of adducts 4a and 5a. Based on conversion and isolated yields, gallium(III) triflate
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proved to be the most efficient Lewis acid catalyst (Table 1, entry 12).9,10 An experiment using
molecular sieves as additive led to comparable results, thus indicating that this transformation could
be efficiently catalyzed by metal triflates. A screening of solvents (acetonitrile, tetrahydrofuran,
toluene) revealed that the reaction is best performed in dichloromethane. A Brønsted acid such as
trifluoromethanesulfonic acid (TfOH) was also tested. The corresponding rearranged α,βꢀ
unsaturated ketone was the major reaction product under stoichiometric TfOH conditions.
However, the use of 10 mol% TfOH afforded adducts 4a and 5a along with minor rearranged
ketone, but did not get the reaction to completion, remaining some unreacted starting material.
Comparatively, the use of TfOH led to limited reactivity.
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Table 1. Reaction between Indolinone-Tethered Allenol 1a and Phenol 2a under Modified
Metal-Catalyzed Conditions
Me
Me
Me
HO
OH
•
10 mol%
M(OTf)n
O
O
O
+
+
H
H
CH2Cl2, T
Ar, t
N
Me
O
Me
O
Me
Me
N
N
1a
2a
Me
Me
4a
5a
entry
catalyst
temperature
(oC)
time
(h)
4a:5a
yield (%)a
1
2
3
4
5
6
7
In(OTf )3
40
40
40
40
40
30
11
12
10
12
1
25/8
22/7
29/9
20/6
26/19
23/17
6/4b
Zn(OTf )2
Fe(OTf )3
Yb(OTf )3
Bi(OTf )3
Bi(OTf )3
Bi(OTf )3
3
130/sealed
tube
0.5
8
Bi(OTf )3
80/microwave
0.5
1
19/14
11/15
23/13
30/17
35/20
9
Bi(OTf )3/PTSA
40
40
40
40
c
10
11
12
Ga(OTf )3
30
12
4
d
Ga(OTf )3
Ga(OTf )3
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b
aYield of pure, isolated product with correct analytical and spectral data. Decomposition of the starting allenol 1a was
observed in appreciable extension. cCatalyst loading of 2 mol%. dCatalyst loading of 5 mol%.
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With the optimized reaction conditions in hand we then examined the scope and generality
of the Gaꢀcatalyzed method. Thus, various methylꢀsubstituted allenols and phenols were reacted to
give a range of dihydrobenzofuranꢀappended oxindoles 4 and 5 (Scheme 2).11 The two products
obtained from the coupling reaction are not identical but rather stand in an epimeric relationship at
the allylic position. Although the diastereoselectivity of the reaction between 1a and 2a is poor
under the conditions (Table 1), efforts for further improvements were not in vain. Interestingly,
both the use of NHꢀfree allenols 1b–d and phenols bearing bulkier substituents (such as Br o tꢀBu)
resulted in improved diastereoselectivities (Scheme 2). The influence of the electronic nature of the
substituents at the phenol reactant was first examined by submitting 4ꢀmethoxyphenol 1d to various
allenols 1. In the event, phenol 1e reacted well and the corresponding adducts 4d, 4l, 5d, and 5l
were obtained. Unfortunately, a negative result was observed using either 4ꢀhydroxybenzonitrile or
methyl 4ꢀhydroxybenzoate, which indicated that electronꢀwithdrawing groups on the aromatic ring
were not compatible with this catalytic arylation/oxycyclization reaction sequence. The Rf values of
the two dihydrobenzofuran isomers 4a–l and 5a–l were very close to each other. Fortunately, the
diastereomeric adducts 4 and 5 could be separated by flash chromatography, thus providing readily
two structurally complex and valuable heterocyclic products. However, characterization of minor
adducts 5c, 5d, 5f–i, 5k, and 5l was performed on a mixture containing small amounts of their
major counterparts 4. Because most of the reactions were conducted in a 50 mg scale, it was
desirable to scaleꢀup the procedure. Worthy of note, when we performed a 4 mmolꢀscale reaction
starting from allenol 1a and phenol 2a, adducts 4a and 5a were isolated in a combined yield of
59%, which is slightly higher than that achieved at a smaller scale during the scope study. The
structure of dihydrobenzofuran 5a was unambiguously confirmed with the help of a Xꢀray
diffraction analysis on suitable crystals of this compound (Figure 1, see the Supporting
Information).12
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Scheme 2. Synthesis of Dihydrobenzofuran-Appended Oxindoles 4 and 5 through Domino
Addition–Cyclization Reaction under Gallium Catalysis
R4
R4
8
9
Me
HO
OH
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•
10 mol%
Ga(OTf)3
R3
O
O
+
O
+
H
H
R3
R3
N
R1
CH2Cl2, 40 o
Ar, 4–8h
C
Me
O
Me
O
R2
R4
N
N
R1
R1
R2
R2
1
2
3
4
1a
2b
4b (67%)
5b (17%)
R = Me, R = H, R = H
R = t-Bu
2c R4 = Br
2d R4 = MeO
1a R1 = Me, R2 = H, R3 = H
1a R1 = Me, R2 = H, R3 = H
(50%)
(10%)
4c
5c
4d (42%)
4e (60%)
5d (20%)
5e (24%)
1
2
3
4
1b
2a
R = H, R = H, R = H
R = Me
2b R4 = t-Bu
2c R4 = Br
1b R1 = H, R2 = H, R3 = H
1b R1 = H, R2 = H, R3 = H
(52%)
(6%)
4f
5f
4g (38%)
4h (55%)
5g (6%)
1
2
3
4
1b
2e
5h (10%)
R = H, R = H, R = H
1c R1 = H, R2 = H, R3 = Br
1d R1 = H, R2 = OMe, R3 = H 2a R4 = Me
R = H
2a R4 = Me
(49%)
(9%)
4i
5i
4j (69%)
4k (48%)
5j (7%)
5k (9%)
1
2
3
4
1d
2b
R = H, R = OMe, R = H
1b R1 = H, R2 = H, R3 = H
R = t-Bu
2d R4 = MeO
4l
5l
(50%)
(17%)
Next, the reaction of arylꢀsubstituted allenol derivatives and phenols was examined. To test
the reactivity of aryl allenes 6, we started the initial investigation on the galliumꢀcatalyzed reaction
of phenylꢀsubstituted allene 6a under otherwise identical reaction conditions used for its methylꢀ
counterpart 1a. In the event, it was found that substrate 6a was exclusively transformed into the
rearranged product 7a (Scheme 3).13 Noticeably, despite the above ability (Schemes 1 and 2) of
metal triflateꢀbased catalysis for the coupling reaction of allenols 1 and phenols into
dihydrobenzofurans 4/5, no traces of oxacycles were detected using gallium(III) triflate as promoter.
Possibly, attempts to use arylꢀsubstituted substrates 6 proved to be unsuccessful for the construction
of the corresponding dihydrobenzofurans, because of both unfavourable steric factors as well as a
direct interaction of the πꢀaromatic system with the metal center from the catalyst.
Scheme 3. Reaction of Phenyl-Substituted Allenol 6a under Metal Triflate Catalysis
Me
O
Ph
HO
Ph
OH
•
10 mol%
Ga(OTf)3
O
O
O
+
X
H
CH2Cl2, 40 o
Ar, 6h
C
N
N
Ph
O
Me
Me
7a (30%)
Me
N
2a
6a
Me
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A possible pathway for the galliumꢀcatalyzed generation of dihydrobenzofuranꢀlinked
oxindoles 4 and 5 is outlined in Scheme 4. Initially, Ga(OTf)3 acts as a Lewis acid interacting with
the allene and phenol moieties simultaneously via a bidentade mode. The formation of a complex 1ꢀ
Ga through both πꢀcoordination of the metal to the allene group of allenols 1 as well as σꢀ
coordination to the hydroxy group of phenols 2 may be involved. Subsequent nucleophilic addition
of the phenol moiety at the sterically less hindered carbon center in complex 1ꢀGa would lead to a
ketone intermediate, which after tautomerization afforded the more stable enolꢀform 8. Then, an
elimination of water and Ga(OTf)3 from zwitterionic intermediate 8 occurs to generate gallium
species 9 through ηꢀcoordination of the gallium salt to the more substituted double bond. Species 9
suffers an intramolecular chemoꢀ and regioselective 5ꢀexoꢀtrig oxycyclization reaction to produce
zwitterionic dihydrobenzofurans 10. This nucleophilic attack from the Oꢀphenol site occurs as a
result of the stability of the intermediate oxonium type cation 10. Loss of HOTf in zwitterionic
dihydrobenzofurans 10 generates neutral metal species 11. Finally, protonolysis of the carbon–
gallium bond of 11 liberates dihydrobenzofurans 4 and 5 with concomitant regeneration of the
Ga(III) catalytic species (Scheme 4).
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Scheme 4. Mechanistic Explanation for the Ga(III)-Catalyzed Synthesis of
Dihydrobenzofurans 4 and 5 from Allenols 1 and Phenols
8
9
OH
OH
R2
R1
R2
R1
R3
R3
= oxindole
R4
R2
R1
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+
•
O
1
R4
4, 5
Ga(OTf)3
+HOTf
R3
OH
R4
R2
R1
R2
R1
•
Ga
O
R4
O
R3
Ga(OTf)2
11
(OTf)3
H
1-Ga
–HOTf
R3
R4
R2
R1
Ga(OTf)3
H
H
H
H
O
O
O
R2
R1
R2
R1
R3
Ga(OTf)3
R3
Ga(OTf)3
H
10
R4
R4
Ga(OTf)3
R3
R2
R1
O
−
H
H
OH
O
–Ga(OTf)3
8
R4
+Ga(OTf)3
OH
9
In conclusion, the synthesis of dihydrobenzofuranꢀlinked oxindoles has been accomplished
taking advantage of an unprecedented reaction between allenols and phenols under Lewis acid
catalysis. Probably, Ga(OTf)3 merges allene and phenol moieties simultaneously via a bidentade
mode.
Experimental Section
General methods: NMR spectra were recorded at 25 oC on 700 or 300 MHz spectrometers:
1H NMR (300 or 700 MHz) and 13C NMR (75 or 175 MHz). NMR spectra were recorded in CDCl3
or C6D6 solutions, except otherwise stated. Chemical shifts are given in ppm relative to TMS (1H,
0.0 ppm), or CDCl3 (13C, 76.9 ppm), or C6D6 (13C, 128.4 ppm). Low and high resolution mass
spectra were taken on a QTOF LC/MS spectrometer using the electronic impact (EI) or electrospray
modes (ES).
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Typical Procedure for the Ga(OTf)3-Catalyzed Coupling Reaction of α-Allenols 1 and
Phenols 2. General Procedure for the Preparation of Dihydrobenzofuran-Appended
Oxindoles 4 and 5. To a solution of the appropriate allenol 1 (0.46 mmol) in dichloromethane (5
mL) at room temperature, Ga(OTf)3 (0.046 mmol) was added under argon atmosphere and stirring
was continued for 5 minutes. Then, the corresponding phenol 2 (1.28 mmol) was added and stirring
was continued for other 5 minutes. Then, the reaction mixture was stirred at reflux temperature until
the starting material disappeared as indicated by TLC. After filtration through a pad of Celite, the
mixture was concentrated under vacuum, and purified by flash column chromatography eluting with
ethyl acetate/hexanes or dicloromethane/ethyl acetate mixtures. Spectroscopic and analytical data
for pure forms of compounds 4 and 5 follow.
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Preparation of Dihydrobenzofuran-Appended Oxindoles 4a and 5a. From 32 mg (0.14
mmol) of αꢀallenol 1a, and after chromatography of the residue using hexanes/ethyl acetate (5:1) as
eluent, 15 mg (35%) of the less polar compound 4a and 8 mg (20%) of the more polar compound
5a were obtained.
1
Dihydrobenzofuran-Appended Oxindole 4a. Yellow oil (15 mg, 35%); HꢀNMR (300
MHz, CDCl3, 25 ºC) δ: 7.19 (d, J = 7.5 Hz, 1H), 7.12 (t, J = 7.7 Hz, 1H), 6.99 (m, 1H), 6.91 (s,
1H), 6.78 (d, J = 8.3 Hz, 1H), 6.72 (m, 2H), 5.09 and 4.76 (s, each 1H), 3.88 (s, 1H), 3.20 (s, 3H),
2.20 (s, 3H), 1.94 (s, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 ºC) δ: 173.1, 158.4, 148.0, 144.2, 131.4,
129.7, 128.1, 126.3, 126.1, 125.1, 122.2, 121.0, 109.5, 107.5, 100.0, 91.0, 54.0, 26.1, 25.9, 20.7; IR
(CH2Cl2, cm–1): ν 1710, 1611, 1471; HRMS (ES): calcd for C20H19NO2 [M]+: 305.1416; found:
305.1412.
Dihydrobenzofuran-Appended Oxindole 5a. Colorless solid (8 mg, 20%); mp 134–136 ºC;
1HꢀNMR (300 MHz, CDCl3, 25 ºC) δ: 7.29 (d, J = 7.6 Hz, 1H), 7.17 (m, 2H), 6.91 (dd, J = 6.9, 1.5
Hz, 1H), 6.79 (t, J = 7.6 Hz, 1H), 6.74 (d, J = 7.7 Hz, 1H), 6.53 (d, J = 8.3 Hz, 1H), 5.53 and 4.99
(s, each 1H), 3.63 (s, 1H), 3.20 (s, 3H), 2.27 (s, 3H), 1.80 (s, 3H); 13CꢀNMR (75 MHz, CDCl3, 25
ºC) δ: 174.0, 159.0, 150.8, 145.0, 131.5, 129.8, 128.2, 125.6, 125.2, 124.6, 121.7, 121.0, 109.8,
107.5, 101.0, 90.2, 52.8, 26.1, 24.8, 20.8; IR (CH2Cl2, cm–1): ν 1709, 1612, 1487; HRMS (ES):
calcd for C20H19NO2 [M]+: 305.1416; found: 305.1419.
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Preparation of Dihydrobenzofuran-Appended Oxindoles 4b and 5b. From 43 mg (0.20
mmol) of αꢀallenol 1a, and after chromatography of the residue using hexanes/ethyl acetate (8:1) as
eluent, 47 mg (67%) of the less polar compound 4b and 12 mg (17%) of the more polar compound
5b were obtained.
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Dihydrobenzofuran-Appended Oxindole 4b. Pale yellow solid (47 mg, 67%); mp 90–92
1
ºC; HꢀNMR (300 MHz, CDCl3, 25 ºC) δ: 7.19 (m, 4H), 6.82 (d, J = 8.5 Hz, 1H), 6.77 (m, 1H),
6.73 (t, J = 7.6 Hz, 1H), 5.12 and 4.76 (s, each 1H), 3.89 (s, 1H), 3.21 (s, 3H), 1.94 (s, 3H), 1.22 (s,
9H); 13CꢀNMR (175 MHz, C6D6, 25 ºC) δ: 173.0, 159.7, 149.7, 145.0, 143.8, 129.0, 128.9, 126.9,
126.7, 126.0, 122.5, 118.1, 110.1, 108.0, 100.3, 92.0, 54.5, 34.6, 31.9 (3C), 27.2, 25.9; IR (CH2Cl2,
cm–1): ν 1700, 1610, 1489; HRMS (ES): calcd for C23H25NO2 [M]+: 347.1885; found: 347.1888.
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Dihydrobenzofuran-Appended Oxindole 5b. Yellow oil (12 mg, 17%); HꢀNMR (700
MHz, CDCl3, 25 ºC) δ: 7.39 (d, J = 1.8 Hz,1H), 7.31 (d, J = 7.4 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H),
7.16 (dd, J = 8.5, 2.0 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.74 (d, J = 7.7 Hz, 1H), 6.59 (d, J = 8.5
Hz, 1H), 5.58 and 5.05 (s, each 1H), 3.64 (s, 1H), 3.20 (s, 3H), 1.77 (s, 3H), 1.29 (s, 9H); 13CꢀNMR
(75 MHz, CDCl3, 25 ºC) δ: 174.0, 158.7, 150.9, 144.9, 143.6, 128.2, 128.1, 125.8, 124.8, 124.7,
121.7, 117.3, 109.5, 107.5, 101.1, 90.3, 52.7, 34.3, 31.6 (3C), 26.2, 24.5; IR (CH2Cl2, cm–1): ν
1708, 1612, 1487; HRMS (ES): calcd for C23H25NO2 [M]+: 347.1885; found: 347.1889.
Preparation of Dihydrobenzofuran-Appended Oxindoles 4c and 5c. From 50 mg (0.23
mmol) of αꢀallenol 1a, and after chromatography of the residue using hexanes/ethyl acetate (5:1) as
eluent, 43 mg (50%) of the less polar compound 4c and 9 mg (10%) of the more polar compound 5c
(containing ca. 40% of its epimer 4c) were obtained.
Dihydrobenzofuran-Appended Oxindole 4c. Yellow solid (43 mg, 50%); mp 164–166 ºC;
1HꢀNMR (300 MHz, C6D6, 25 ºC) δ: 7.03 (dd, J = 8.5, 2.2 Hz, 1H), 6.92 (d, J = 2.2 Hz, 1H), 6.88
(s, 1H), 6.80 (t, J = 7.5 Hz, 1H), 6.56 (t, J = 7.6 Hz, 1H), 6.45 (d, J = 8.5 Hz, 1H), 6.13 (d, J = 7.7
Hz, 1H), 4.87 and 4.75 (s, each 1H), 3.58 (s, 1H), 2.68 (s, 3H), 2.0 (s, 3H); 13CꢀNMR (175 MHz,
C6D6, 25 ºC) δ: 172.6, 160.3, 147.5, 145.0, 141.9, 133.9, 129.4, 126.8, 124.7, 123.1, 122.6, 113.4,
112.0, 108.1, 102.8, 92.7, 54.4, 26.7, 25.9; IR (CH2Cl2, cm–1): ν 3334, 1682, 1489; HRMS (ES):
calcd for C19H16BrNO2 [M]+: 369.0364; found: 369.0370.
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Dihydrobenzofuran-Appended Oxindole 5c. Yellow solid (9 mg, 10%; containing ca. 40%
of its epimer 4c); mp 124–126 ºC; 1HꢀNMR (300 MHz, CDCl3, 25 ºC) δ: 7.48 (d, J = 2.0 Hz, 0.4H,
m), 7.20 (m, 3.6H, M+m), 6.77 (m, 2.6H, M+m), 6.52 (d, J = 8.5 Hz, 0.4H, m), 5.56 (s, 0.4H, m),
5.13 (s, 0.6H, M), 5.03 (s, 0.4H, m), 4.85 (s, 0.6H, M), 3.87 (s, 0.6H, M), 3.63 (s, 0.4H, m), 3.20 (s,
3H, M+m), 1.95 (s, 1.8H, M), 1.82 (s, 1.2H, m); 13CꢀNMR (75 MHz, CDCl3, 25 ºC) δ: 173.6 (m),
172.7 (M), 159.3 (M+m), 149.3 (m), 146.6 (M), 144.9 (m), 144.1 (M), 133.3 (m), 133.2 (M), 128.4
(M), 128.3 (M+m), 126.2 (M+m), 125.5 (m), 124.6 (M), 124.1 (m), 123.7 (M+m), 122.3 (M),
121.9 (m), 112.7 (M), 112.6 (m), 111.9 (m), 111.5 (M), 107.8 (M), 107.7 (m), 102.9 (m), 102.1
(M), 91.9 (M), 91.1 (m), 53.9 (M), 52.7 (m), 26.2 (m), 26.0 (M) 26.0 (M), 24.9 (m); IR (CH2Cl2,
cm–1): ν 3299, 1706, 1466; HRMS (ES): calcd for C19H16BrNO2 [M]+: 369.0364; found: 369.0357.
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Preparation of Dihydrobenzofuran-Appended Oxindoles 4d and 5d. From 52 mg (0.24
mmol) of αꢀallenol 1a, and after chromatography of the residue using hexanes/ethyl acetate (8:1) as
eluent, 33 mg (42%) of the less polar compound 4d and 15 mg (20%) of the more polar compound
5d (containing ca. 20% of its epimer 4d) were obtained.
Dihydrobenzofuran-Appended Oxindole 4d. Yellow oil; 1HꢀNMR (300 MHz, CDCl3, 25
ºC) δ: 7.18 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), 6.75 (m, 4H), 6.61 (d, J = 1.6 Hz, 1H),
5.09 and 4.79 (s, each 1H), 3.88 (s, 1H), 3.70 (s, 3H), 3.20 (s, 3H), 1.94 (s, 3H), 1.94 (s, 3H); 13Cꢀ
NMR (175 MHz, CDCl3, 25 ºC) δ: 173.1, 154.8, 148.3, 144.1, 138.3, 128.1, 126.3, 125.0, 122.2,
117.6, 114.1, 110.2, 107.5, 104.9, 100.5, 91.2, 54.8, 54.9, 26.1, 26.0; IR (CH2Cl2, cm–1): ν 1706,
1612, 1482; HRMS (ES): calcd for C20H19NO3 [M]+: 321.1365; found: 321.1373.
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Dihydrobenzofuran-Appended Oxindole 5d. Yellow oil; HꢀNMR (700 MHz, C6D6, 25
ºC) δ: 7.30 (d, J = 7.5 Hz, 0.8H, m), 7.26 (d, J = 8.1 Hz, 0.2H, M), 7.04 (s, 0.2H, M), 6.93 (t, J =
7.7 Hz, 0.2H, M), 6.89 (m, 1.6H, m), 6.74 (d, J = 8.7 Hz, 0.2H, M), 6.70 (t, J = 7.2 Hz, 0.2H, M),
6.61 (t, J = 7.3 Hz, 0.8H, m), 6.48 (d, J = 2.6 Hz, 0.2H, M), 6.43 (d, J = 1.4 Hz, 1.6H, m), 6.20 (d, J
= 7.7 Hz, 0.8H, m), 6.17 (d, J = 7.8 Hz, 0.2H, M), 5.31 (s, 0.8H, m), 4.99 and 4.97 (s, each 0.2H,
M), 4.79 (s, 0.8H, m), 3.33 (s, 0.8H, m), 3.23 (s, 3H, M+m), 3.11 (s, 0.2H, M), 2.71 (s, 2.4H, m),
2.65 (s, 0.6H, M), 1.97 (s, 2.4H, m), 1.84 (s, 0.6H, M); 13CꢀNMR (175 MHz, C6D6, 25 ºC) δ: 173.9
(M+m), 156.7 (m), 155.1 (M), 152.8 (m), 150.4 (M), 146.0 (m), 143.6 (M), 129.7 (m), 128.0 (m),
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127.5 (M), 127.0 (M), 126.6 (M), 126.1 (m), 125.6 (M), 123.1 (m), 122.5 (M), 122.4 (m), 121.9
(m), 121.3 (M), 118.7 (M), 118.2 (m), 111.5 (m), 111.0 (M), 108.3 (M), 108.0 (m), 105.9 (m),
105.6 (M), 101.4 (m), 100.8 (M), 91.5 (M+m), 55.6 (m), 55.4 (M), 53.2 (M+m), 26.1 (M), 26.0 (m)
25.6 (m), 25.5 (M); IR (CH2Cl2, cm–1): ν 1708, 1611, 1482; HRMS (ES): calcd for C20H19NO3
[M]+: 321.1365; found: 321.1372.
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Preparation of Dihydrobenzofuran-Appended Oxindoles 4e and 5e. From 40 mg (0.20
mmol) of αꢀallenol 1b, and after chromatography of the residue using dicloromethane/ethyl acetate
(40:1) as eluent, 35 mg (60%) of the less polar compound 4e and 14 mg (24%) of the more polar
compound 5e were obtained.
Dihydrobenzofuran-Appended Oxindole 4e. Colorless solid (35 mg, 60%); mp 166–168
ºC; 1HꢀNMR (300 MHz, CDCl3, 25 ºC) δ: 7.88 (br s, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.07 (t, J = 7.8
Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.95 (s, 1H), 6.75 (m, 3H), 5.18 and 4.92 (s, each 1H), 3.90 (s,
1H), 2.21 (s, 3H), 1.92 (s, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 ºC) δ: 174.9, 158.4, 147.9, 141.0,
131.4, 129.8, 128.1, 126.7, 126.0, 125.7, 122.2, 121.1, 109.5, 109.0, 100.4, 90.8, 54.4, 26.1, 20.7;
IR (CH2Cl2, cm–1): ν 3252, 1705, 1482; HRMS (ES): calcd for C19H17NO2 [M]+: 291.1259; found:
291.1246.
Dihydrobenzofuran-Appended Oxindole 5e. Colorless solid (14 mg, 24%); mp 164–166
ºC;1HꢀNMR (300 MHz, CDCl3, 25 ºC) δ: 7.53 (br s, 1H), 7.28 (m, 1H), 7.19 (s, 1H), 7.11 (t, J =
7.7 Hz, 1H), 6.92 (dd, J = 7.7, 1.4 Hz, 1H), 6.78 (m, 2H), 6.57 (d, J = 8.2 Hz, 1H), 5.53 and 4.97 (s,
each 1H), 3.65 (s, 1H), 2.27 (s, 3H), 1.80 (s, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 ºC) δ: 175.6,
159.0, 150.5, 141.8, 131.6, 129.9, 128.3, 126.1, 125.8, 125.2, 121.8, 121.1, 109.8, 109.0, 101.2,
90.1, 53.1, 24.7, 20.8; IR (CH2Cl2, cm–1): ν 3253, 1708, 1480; HRMS (ES): calcd for C19H17NO2
[M]+: 291.1259; found: 291.1250.
Preparation of Dihydrobenzofuran-Appended Oxindoles 4f and 5f. From 40 mg (0.20
mmol) of αꢀallenol 1b, and after chromatography of the residue using hexanes/ethyl acetate (6:1) as
eluent, 35 mg (52%) of the less polar compound 4f and 4 mg (6%) of the more polar compound 5f
(containing ca. 50% of its epimer 4f) were obtained.
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Dihydrobenzofuran-Appended Oxindole 4f. Pale yellow solid (35 mg, 52%); mp 203–205
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ºC; HꢀNMR (700 MHz, C6D6, 25 ºC) δ: 7.30 (d, J = 7.5 Hz, 1H), 7.27 (s, 1H), 7.09 (dd, J = 8.5,
2.0 Hz, 1H), 7.05 (s, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.70 (t, J = 7.7 Hz, 1H) 6.49 (t, J = 7.2 Hz, 1H),
6.04 (m, 1H), 5.17 and 5.13 (s, each 1H), 3.66 (s, 1H), 2.06 (s, 3H), 1.07 (s, 9H); 13CꢀNMR (175
MHz, CDCl3, 25 ºC) δ: 174.2, 159.6, 149.5, 143.8 (2C), 142.0, 129.0, 128.0, 127.3, 126.7, 126.6,
122.4, 118.2, 110.1, 109.3, 100.6, 91.9, 54.7, 34.6, 31.9 (3C), 27.0; IR (CH2Cl2, cm–1): ν 3214,
1706, 1487; HRMS (ES): calcd for C22H23NO2 [M]+: 333.1729; found: 333.1721.
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Dihydrobenzofuran-Appended Oxindole 5f. Yellow solid (4 mg, 6%; containing ca. 50%
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of its epimer 4f); mp 182–184 ºC; HꢀNMR (300 MHz, C6D6, 25 ºC) δ: 8.20 (br s, 0.5H, m), 8.14
(br s, 0.5H, M), 7.45 (d, J = 1.9 Hz, 0.5H, m), 7.30 (m, 1.5H, 2M+m), 7.16 (m, 0.5H, M), 7.10 (m,
1H, 2M), 6.81 (m, 2H, 2M+2m), 6.54 (m, 1H, M+m), 6.35 (d, J = 7.7 Hz, 0.5H, m), 6.27 (d, J = 7.7
Hz, 0.5H, m), 5.41 (s, 0.5H, m), 5.18 and 5.15 (s, each 0.5H, M), 4.79 (s, 0.5H, m), 3.70 (s, 0.5H,
M), 3.35 (s, 0.5H, m), 2.06 (s, 1.5H, M), 1.90 (s, 1.5H, m), 1.15 (s, 4.5H, m), 1.08 (s, 4.5H, M);
13CꢀNMR (75 MHz, CDCl3, 25 ºC) δ: 176.6 (m), 175.7 (M), 160.2 (m), 159.6 (M), 152.3 (m),
149.5 (M), 144.0 (m), 143.9 (M), 143.3(m), 142.3 (M), 129.1 (m), 129.0 (M), 128.7 (m), 128.0
(M),127.2 (M), 126.8 (m), 126.7 (M), 126.6 (M), 126.3 (m), 125.7 (m), 122.5 (M), 121.9 (m),
118.2 (M), 117.8 (m), 110.7 (m), 110.1 (M), 109.8 (m), 109.7 (M), 100.9 (m), 100.7 (M), 91.9 (M),
91.3 (m), 55.0 (M), 53.6 (m), 34.7 (m), 34.6 (M), 32.0 (3C, m), 31.9 (3C, M), 27.1 (M), 25.6 (m);
IR (CH2Cl2, cm–1): ν 3212, 1704, 1486; HRMS (ES): calcd for C22H23NO2 [M]+: 333.1729; found:
333.1710.
Preparation of Dihydrobenzofuran-Appended Oxindoles 4g and 5g. From 40 mg (0.20
mmol) of αꢀallenol 1b, and after chromatography of the residue using hexanes/ethyl acetate (4:1) as
eluent, 27 mg (38%) of the less polar compound 4g and 4 mg (6%) of the more polar compound 5g
(containing ca. 20% of its epimer 4g) were obtained.
Dihydrobenzofuran-Appended Oxindole 4g. Pale yellow solid (27 mg, 38%); mp 204ꢀ206
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ºC; HꢀNMR (700 MHz, C6D6, 25 ºC) δ: 7.10 (dd, J = 8.2, 6.2 Hz, 1H), 7.02 (dd, J = 8.5, 2.0 Hz,
1H), 6.95 (d, J = 2.0 Hz, 1H), 6.72 (t, J = 7.7 Hz, 1H), 6.50 (t, J = 7.7 Hz, 1H), 6.44 (d, J = 8.5 Hz,
1H), 6.32 (d, J = 8.7 Hz, 1H), 6.12 (d, J = 7.7 Hz, 1H), 4.99 and 4.83 (s, each 1H), 3.54 (s, 1H),
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1.93 (s, 3H); 13CꢀNMR (175 MHz, C6D6, 25 ºC) δ: 174.0, 160.3, 147.4, 142.1, 133.9, 133.0, 129.4,
127.1, 126.2, 124.8, 122.4, 113.5, 112.0, 109.5, 103.1, 92.5, 54.7, 26.6; IR (CH2Cl2, cm–1): ν 3256,
1699, 1464; HRMS (ES): calcd for C18H14BrNO2 [M]+: 355.0208; found: 355.0192.
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Dihydrobenzofuran-Appended Oxindole 5g. Yellow solid (4 mg, 6%; containing ca. 20%
of its epimer 4g); mp 194–196 ºC; 1HꢀNMR (300 MHz, C6D6, 25 ºC) δ: 7.46 (m, 0.2H, m), 7.31 (d,
J = 2.0 Hz, 0.8H, M), 7.11 (m, 1H, M+m), 7.02 (dd, J = 8.5, 2.0 Hz, 1H, M+m), 6.96 (d, J = 2.0
Hz, 1H, M+m), 6.77 (m, 1H, M+m), 6.52 (td, J = 7.7, 1.0 Hz, 1H, M+m), 6.44 (d, J = 8.5 Hz, 1H,
M+m), 6.20 (m, 1H, M+m), 5.09 (s, 0.2H, m), 5.00 and 4.84 (s, each 0.8H, M), 4.62 (s, 0.2H, m),
3.55 (s, 0.8H, M), 3.18 (s, 0.2H, m), 1.93 (s, 2.4H, M), 1.79 (s, 0.6H, m); 13CꢀNMR (75 MHz,
C6D6, 25 ºC) δ: 174.6 (M+m), 160.3 (M+m), 147.4 (M+m), 142.2 (M+m), 134.1 (m), 133.9 (3C,
2M + 1m), 129.4 (M), 128.9 (m), 127.1 (M), 126.4 (m), 126.2 (M), 125.7 (m), 124.8 (M+m), 124.5
(m), 122.5 (M), 122.0 (m), 113.5 (M), 112.7 (m), 112.0 (M), 109.7 (M+m), 103.1 (M+m), 92.5
(M), 91.9 (m), 54.8 (M), 53.4 (m), 26.6 (M), 25.4 (m); IR (CH2Cl2, cm–1): ν 3187, 1708, 1464;
HRMS (ES): calcd for C18H14BrNO2 [M]+: 355.0208; found: 355.0218.
Preparation of Dihydrobenzofuran-Appended Oxindoles 4h and 5h. From 43 mg (0.21
mmol) of αꢀallenol 1b, and after chromatography of the residue using hexanes/ethyl acetate (7:1) as
eluent, 32 mg (55%) of the less polar compound 4h and 6 mg (10%) of the more polar compound
5h (containing ca. 40% of its epimer 4h) were obtained.
Dihydrobenzofuran-Appended Oxindole 4h. Colorless solid (32 mg, 55%); mp 164–166
ºC; 1HꢀNMR (700 MHz, CDCl3, 25 ºC) δ: 7.65 (s, 1H), 7.20 (td, J = 8.4, 1.3 Hz, 1H), 7.16 (d, J =
7.5 Hz, 1H), 7.14 (dd, J = 7.6, 0.8 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.78
(td, J = 7.5, 0.8 Hz, 1H), 6.73 (d, J = 7.7 Hz, 1H), 6.70 (td, J = 7.7, 0.8 Hz, 1H), 5.22 and 4.96 (s,
each 1H), 3.92 (s, 1H), 1.94 (s, 3H); 13CꢀNMR (175 MHz, CDCl3, 25 ºC) δ: 174.6, 160.3, 147.6,
140.9, 130.6, 128.2, 126.7, 126.2, 125.6, 122.2, 120.8, 120.6, 109.9, 108.9, 100.9, 90.7, 50.4, 26.0;
IR (CH2Cl2, cm–1): ν 3244, 1702, 1468; HRMS (ES): calcd for C18H15NO2 [M]+: 277.1103; found:
277.1105.
Dihydrobenzofuran-Appended Oxindole 5h. Yellow solid (6 mg, 10%; containing ca. 40%
of its epimer 4h); mp 124–126 ºC; 1HꢀNMR (300 MHz, CDCl3, 25 ºC) δ: 7.91 (m, 1H, M+m), 7.38
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(dd, J = 7.6, 0.9 Hz, 0.4H, m), 7.29ꢀ7.04 (m, 3.6H, M+m), 6.90 (d, J = 8.0 Hz, 0.6H, M), 6.86 (dd,
J = 7.5, 0.8 Hz, 0.4H, m), 6.82ꢀ6.65 (m, 3H, M+m), 5.58 (s, 0.4H, m), 5.22 (s, 0.6H, M), 5.02 (s,
0.4H, m), 4.95 (s, 0.6H, M), 3.92 (s, 0.6H, M), 3.66 (s, 0.4H, m), 1.94 (s, 1.8H, M), 1.83 (s, 1.2H,
m); 13CꢀNMR (75 MHz, CDCl3, 25 ºC) δ: 174.5 (M+m), 160.3 (M+m), 147.5 (M+m) 140.9
(M+m), 130.6 (M+m), 128.4 (m), 128.2 (M), 126.8 (m), 126.7 (M), 126.2 (M+m), 125.5 (M+m),
122.3 (m), 122.1 (M), 120.8 (M+m), 120.6 (M+m), 109.9 (M+m), 108.9 (M+m), 100.9 (M+m),
90.7 (M+m), 54.3 (M+m), 26.0 (M+m); IR (CH2Cl2, cm–1): ν 3231, 1707, 1468; HRMS (ES): calcd
for C18H15NO2 [M]+: 277.1103; found: 277.1111.
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Preparation of Dihydrobenzofuran-Appended Oxindoles 4i and 5i. From 50 mg (0.18
mmol) of αꢀallenol 1c, and after chromatography of the residue using hexanes/ethyl acetate (4:1) as
eluent, 33 mg (49%) of the less polar compound 4i and 6 mg (9%) of the more polar compound 5i
(containing ca. 50% of its epimer 4i) were obtained.
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Dihydrobenzofuran-Appended Oxindole 4i. Yellow oil (33 mg, 49%); HꢀNMR (300
MHz, C6D6, 25 ºC) δ: 7.42 (s, 1H), 6.89–6.66 (m, 4H), 5.72 (d, J = 8.2 Hz, 1H), 5.08 and 5.03 (s,
each 1H), 3.47 (s, 1H), 1.97 (s, 3H), 1.88 (s, 3H); 13CꢀNMR (175 MHz, C6D6, 25 ºC) δ: 173.6,
159.7, 149.1, 141.1, 132.6 (2C), 131.5, 131.0, 130.6, 126.9, 122.3, 115.1, 110.7, 110.3, 101.0, 91.4,
55.1, 26.7, 21.0; IR (CH2Cl2, cm–1): ν 3249, 1707, 1485; HRMS (ES): calcd for C19H16BrNO2
[M]+: 369.0364; found: 369.0347.
Dihydrobenzofuran-Appended Oxindole 5i. Yellow oil (6 mg, 9%; containing ca. 50% of
1
its epimer 4i); HꢀNMR (300 MHz, C6D6, 25 ºC) δ: 7.42 (s, 1H, M+m), 7.22ꢀ6.66 (m, 4H, M+m),
6.58 (d, J = 7.4 Hz, 0.5H, m), 6.46 (d, J = 8.2 Hz, 0.5H, m), 5.73 (d, J = 8.3 Hz, 0.5H, M), 5.69 (d,
J = 8.3 Hz, 0.5H, m), 5.26 (s, 0.5H, m), 5.07 and 5.03 (s, each 0.5H, M), 4.69 (s, 0.5H, m), 3.47 (s,
0.5H, M), 3.08 (s, 0.5H, m), 2.00 (s, 1.5H, m), 1.97 (s, 1.5H, M), 1.88 (s, 1.5H, M), 1.80 (s, 1.5H,
m); 13CꢀNMR (75 MHz, C6D6, 25 ºC) δ: 174.4 (M+m), 159.5 (M+m), 149.0 (M+m), 141.1 (M+m),
132.5, (4C, 2M + 2m), 131.4 (M+m), 130.8 (M+m), 130.5 (M), 129.2 (m), 127.5 (m), 126.7 (M),
122.1 (M+m), 115.5 (m), 115.1 (M), 110.8 (M+m), 110.1 (M+m), 100.9 (M+m), 91.2 (M+m), 60.4
(m), 55.2 (M), 26.6 (M+m), 21.0 (M+m); IR (CH2Cl2, cm–1): ν 3245, 1703, 1475; HRMS (ES):
calcd for C19H16BrNO2 [M]+: 369.0364; found: 369.0383.
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Preparation of Dihydrobenzofuran-Appended Oxindoles 4j and 5j. From 40 mg (0.17
mmol) of αꢀallenol 1d, and after chromatography of the residue using hexanes/ethyl acetate (6:1) as
eluent, 38 mg (69%) of the less polar compound 4j and 4 mg (7%) of the more polar compound 5j
were obtained.
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Dihydrobenzofuran-Appended Oxindole 4j. Colorless solid (38 mg, 69%); mp 103–105
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ºC; HꢀNMR (700 MHz, CDCl3, 25 ºC) δ: 7.76 (br s, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.94 (s, 1H),
6.68 (m, 2H), 6.67 (m, 2H), 5.17 and 4.93 (s, each 1H), 3.93 (s, 1H), 3.80 (s, 3H), 2.21 (s, 3H), 1.92
(s, 3H); 13CꢀNMR (175 MHz, CDCl3, 25 ºC) δ: 174.2, 158.4, 147.8, 143.0, 131.3, 129.9, 129.7,
126.5, 126.0, 122.5, 121.0, 119.0, 110.3, 109.5, 100.5, 90.8, 55.4, 55.1, 29.6, 26.0; IR (CH2Cl2,
cm–1): ν 3228, 1709, 1493, 1462; HRMS (ES): calcd for C20H19NO3 [M]+: 321.1365; found:
321.1358.
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Dihydrobenzofuran-Appended Oxindole 5j. Colorless oil (4 mg, 7%); HꢀNMR (700
MHz, CDCl3, 25 ºC) δ: 7.43 (s, 1H), 7.19 (s, 1H), 6.93 (m, 1H), 6.76 (m, 1H), 6.71 (d, J = 8.2 Hz,
1H), 6.59 (d, J = 8.2 Hz, 1H), 5.52 and 4.96 (s, each 1H), 3.82 (s, 3H), 3.67 (s, 1H), 2.27 (s, 3H),
1.79 (s, 3H); 13CꢀNMR (175 MHz, CDCl3, 25 ºC) δ: 174.8, 158.9, 150.4, 143.0, 131.5, 130.8,
129.9, 125.9, 125.3, 122.1, 121.1, 118.5, 110.5, 109.9, 101.2, 90.1, 55.5, 53.7, 29.7, 24.7; IR
(CH2Cl2, cm–1): ν 3221, 1704, 1494, 1461; HRMS (ES): calcd for C20H19NO3 [M]+: 321.1365;
found: 321.1357.
Preparation of Dihydrobenzofuran-Appended Oxindoles 4k and 5k. From 40 mg (0.17
mmol) of αꢀallenol 1d, and after chromatography of the residue using hexanes/ethyl acetate (4:1) as
eluent, 29 mg (48%) of the less polar compound 4k and 6 mg (9%) of the more polar compound 5k
(containing ca. 50% of its epimer 4k) were obtained.
Dihydrobenzofuran-Appended Oxindole 4k. Pale yellow solid (29 mg, 48%); mp 193–195
ºC; 1HꢀNMR (300 MHz, C6D6, 25 ºC) δ: 8.44 (m, 1H), 7.13 (m, 2H), 7.03 (d, J = 7.5 Hz, 1H), 6.89
(dd, J = 8.3, 0.7 Hz, 1H), 6.47 (t, J = 8.0 Hz, 1H), 6.10 (d, J = 8.3 Hz, 1H), 5.23 and 5.16 (s, each
1H), 3.80 (s, 1H), 3.05 (s, 3H), 2.12 (s, 3H), 1.09 (s, 9H); 13CꢀNMR (75 MHz, CDCl3, 25 ºC) δ:
174.9, 159.7, 149.4, 143.9, 143.8, 131.4, 129.0, 127.5, 126.7, 122.9, 119.7, 118.2, 111.1, 110.1,
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100.9, 92.0, 55.7, 55.1, 34.6, 31.9 (3C), 27.0; IR (CH2Cl2, cm–1): ν 3225, 1708, 1490; HRMS (ES):
calcd for C23H25NO3 [M]+: 363.1834; found: 363.1841.
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Dihydrobenzofuran-Appended Oxindole 5k. Yellow solid (6 mg, 9%; containing ca. 50%
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of its epimer 4k); mp 181–183 ºC; HꢀNMR (300 MHz, C6D6, 25 ºC) δ: 8.22 (br s, 0.5H, m), 8.12
(br s, 0.5H, M), 7.47 (d, J = 2.0 Hz, 0.5H, m), 7.13 (m, 1.5H, M+m+M), 7.01 (m, 1H, M+m), 6.91
(m, 1H, M+m), 6.55 (m, 1H, m), 6.48 (t, J = 8.0 Hz, 0.5H, M), 6.22 (d, J = 8.3 Hz, 0.5H, m), 6.10
(d, J = 8.3 Hz, 0.5H, M), 5.45 (s, 0.5H, m), 5.21 and 5.15 (s, each 0.5H, M), 4.868 (s, 0.5H, m),
3.79 (s, 0.5H, M), 3.42 (s, 0.5H, m), 3.12 (s, 1.5H, m), 3.04 (s, 1.5H, M), 2.12 (s, 1.5H, M), 1.94 (s,
1.5H, m), 1.16 (s, 4.5H, m), 1.09 (s, 4.5H, M); 13CꢀNMR (75 MHz, C6D6, 25 ºC) δ: 175.6 (m),
174.8 (M), 160.2 (m), 159.7 (M), 152.5 (m), 149.4 (M), 143.9 (m), 143.9 (m), 143.7 (2C, M), 132.3
(m), 131.3 (M), 129.1 (m), 129.0 (M), 127.5 (M), 127.0 (m), 126.7 (M), 125.8 (m), 122.9 (M),
122.2 (m), 119.7 (M), 119.3 (m), 118.2 (M), 117.8 (m), 111.1 (M), 111.0 (m), 110.8 (m), 110.1
(M), 101.0 (m), 100.8 (M), 92.0 (M), 91.4 (m), 55.7 (M), 55.1 (m), 55.1 (M), 54.1 (m), 34.7 (M),
32.0 (3C, m), 31.9 (3C, M), 30.6 (m), 27.1 (M), 25.5 (m); IR (CH2Cl2, cm–1): ν 3220, 1710, 1391;
HRMS (ES): calcd for C23H25NO3 [M]+: 363.1834; found: 363.1845.
Preparation of Dihydrobenzofuran-Appended Oxindoles 4l and 5l. From 35 mg
(0.17mmol) of αꢀallenol 1b, and after chromatography of the residue using hexanes/ethyl acetate
(6:1) as eluent, 26 mg (50%) of the less polar compound 4l and 9 mg (17%) of the more polar
compound 5l (containing ca. 40% of its epimer 4l) were obtained.
Dihydrobenzofuran-Appended Oxindole 4l. Colorless oil; 1HꢀNMR (700 MHz, C6D6, 25
ºC) δ: 7.31 (d, J = 7.5 Hz, 1H), 6.77 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H), 6.70 (dd, J = 8.7,
2.6 Hz, 1H), 6.57 (t, J = 7.6 Hz, 1H), 6.51 (m, 1H), 6.29 (m, 1H), 5.13 and 5.06 (s, each 1H), 3.69
(m, 1H), 3.12 (s, 3H), 2.1 (s, 3H); 13CꢀNMR (175 MHz, C6D6, 25 ºC) δ: 175.8, 155.9, 155.0, 149.5,
142.3, 128.7, 127.5, 127.4, 126.7, 122.5, 118.7, 111.0, 109.7, 105.6, 101.2, 91.8, 55.4, 55.1, 26.9;
IR (CH2Cl2, cm–1): ν 3263, 1706, 1482; HRMS (ES): calcd for C19H17NO3 [M]+: 307.1208; found:
307.1218.
Dihydrobenzofuran-Appended Oxindole 5l. Yellow oil; 1HꢀNMR (700 MHz, C6D6, 25 ºC)
δ: 7.31 (d, J = 7.5 Hz, 0.4H, M), 7.24 (d, J = 7.5 Hz, 0.6H, m), 7.23 (d, J = 7.7 Hz, 0.6H, m), 6.87
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(m, 0.6H, m), 6.77 (t, J = 7.7 Hz, 0.4H, M), 6.73 (d, J = 8.7 Hz, 0.4H, M), 6.70 (dd, J = 8.7, 2.6 Hz,
0.4H, M), 6.66 (t, J = 7.7 Hz, 0.6H, m), 6.58 (m, 1H, M+m), 6.51 (m, 0.4H, M), 6.45 (m, 0.6H, m),
6.35 (m, 2H, M+m), 5.30 (s, 0.6H, m), 5.12 and 5.05 (s, each 0.4H, M), 4.75 (s, 0.6H, m), 3.69 (s,
0.4H, M), 3.32 (s, 0.6H, m), 3.23 (s, 1.8H, m), 3.13 (s, 1.2H, M), 2.37 (s, 1.8H, m), 2.07 (s, 1.2H,
m); 13CꢀNMR (175 MHz, C6D6, 25 ºC) δ: 176.8 (m), 175.8 (M), 156.6 (m), 155.9 (M), 155.2 (M),
152.4 (m), 151.1 (m), 149.5 (M), 143.4 (m), 142.5 (M), 141.2 (m), 129.8 (m), 128.7 (M), 127.5
(M), 127.3 (M), 126.5 (M), 126.3 (m), 123.5 (m), 122.5 (M), 122.0 (m), 118.7 (M), 118.2 (m),
111.5 (m), 111.0 (M), 110.4 (m), 109.8 (M), 105.9 (m), 105.6 (M), 101.5 (m), 101.3 (M), 91.8 (M),
91.3 (m), 55.6 (m), 55.4 (M), 55.2 (M), 53.7 (m), 28.0 (m), 27.0 (M); IR (CH2Cl2, cm–1): ν 3263,
1707, 1480; HRMS (ES): calcd for C19H17NO3 [M]+: 307.1208; found: 307.1210.
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Ketone 7a. From 44 mg (0.16 mmol) of the allenol 6a and after chromatography of the
residue using hexanes/ethyl acetate (5:1) as eluent, gave compound 7a (14 mg, 30%) as yellow oil;
1HꢀNMR (300 MHz, CDCl3, 25 ºC) δ: 7.27 (m, 1H), 7.00 (m, 2H), 6.79 (d, J = 8.1 Hz, 1H), 6.53
(m, 3H), 3.00 (s, 3H), 2.24 (s, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 ºC) δ: 204.0, 166.7, 151.4,
144.5, 132.8, 130.0, 129.9, 129.8, 129.2, 127.8, 123.8, 123.1, 121.9, 120.6, 115.0, 108.2, 29.0,
25.9; IR (CH2Cl2, cm–1): ν 2926, 1697, 1606, 1487; HRMS (ES): calcd for C18H15NO2 [M]+:
277.1103; found: 277.1104.
Acknowledgment. Support for this work by MINECO and FEDER (Projects CTQ2012ꢀ
33664ꢀC02ꢀ01 and CTQ2012ꢀ33664ꢀC02ꢀ02) and UCMꢀBANCO SANTANDER (Project GR3/14)
is gratefully acknowledged. We thank Dr. D. Molero (CAI de RMN, Universidad Complutense de
Madrid) for technical assistance with the NMR spectra.
Supporting Information Available: ORTEP drawing of compound 5a as well as copies of
the 1H NMR and 13C NMR spectra for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
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(1) For selected reviews, see: (a) Donnelly, D. M. X.; Meegan, M. J. In Comprehensive
Heterocyclic Chemistry; Katritzky, A.R., Rees, C. W., Eds.; Pergamon: Oxford, UK, 1984;
Vol. 4. (b) Ayers, A. C.; Loike, J. K. Lignans: Chemical, Biological and Clinical Properties,
Cambridge, 1990. (c) Watzke, A.; O’Malley, S. J.; Bergman, R. G.; Ellman, J. A. J. Nat.
Prod. 2006, 69, 1231. (d) Veitch, N. C. Nat. Prod. Rep. 2007, 24, 417. (e) Shen, T.; Wang,
X.ꢀN.; Lou, H.ꢀX. Nat. Prod. Rep. 2009, 26, 916.
10
11
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(2) For a review, see: Sheppard, T. D. J. Chem. Res. 2011, 35, 337.
(3) For recent selected reviews, see: (a) Fensterbank, L.; Malacria, M. Acc. Chem. Res. 2014, 47,
953. (b) Alcaide, B.; Almendros, P. Acc. Chem. Res. 2014, 47, 939. (c) Lechel, T.; Pfrengle,
F.; Reissig, H.ꢀU.; Zimmer, R. ChemCatChem 2013, 5, 2100. (d) Yu, S.; Ma, S. Angew.
Chem. Int. Ed. 2012, 51, 3074. (e) Yang, W.; Hashmi, A. S. K. Chem. Soc. Rev. 2014, 43,
2941.
(4) For the coupling of an allene intermediate with halogenated phenols, see: (a) Bi, H.ꢀP.;
Liu, X.ꢀY.; Gou, F.ꢀR.; Guo, L.ꢀN.; Duan, X.ꢀH.; Shu, X.ꢀZ.; Liang Y.ꢀM. Angew. Chem. Int.
,
Ed. 2007, 46, 7068. For the condensation of allenoates and phenols, see: (b) Kim, S.; Kang,
D.; Lee, C.ꢀH.; Lee, P. H. J. Org.Chem. 2012, 77, 6530. For the goldꢀcatalyzed chromane
formation from allenamides and phenols, see: (c) Slater, N. H.; Brown, N. J.; Elsegood, M. R.
J.; Kimber, M. C. Org. Lett. 2014, 16, 4606.
(5) (a) Alcaide, B.; Almendros, P.; Martínez del Campo, T.; Quirós, M. T. Chem. Eur. J. 2009,
15, 3344. (b) Alcaide, B.; Almendros, P.; Luna, A.; Cembellín, S.; Arnó, M.; Domingo, L. R.
Chem. Eur. J. 2011, 17, 11559. (c) Alcaide, B.; Almendros, P.; Luna, A.; Prieto, N. J. Org.
Chem. 2012, 77, 11388.
(6) Alcaide, B.; Almendros, P.; Quirós, M. T.; López, R.; Menéndez, M. I.; SochackaꢀĆwikła, A.
J. Am. Chem. Soc. 2013, 135, 898.
(7) (a) HoffmannꢀRöder, A.; Krause, N. Org. Lett. 2001, 3, 2537. (b) Hashmi, A. S. K.; Blanco,
M. C.; Fischer, D.; Bats, J. W. Eur. J. Org. Chem. 2006, 1387. (c) Asikainen, M.; Krause, N.
Adv. Synth. Catal. 2009, 351, 2305. (d) Brasholz, M.; Dugovič, B.; Reissig, H.ꢀU. Synthesis
2010, 3855. (e) Alcaide, B.; Almendros, P.; Martínez del Campo, T.; Fernández, I. Chem.
Commun. 2011, 47, 9054.
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(8) For a different reactivity of 3ꢀhydroxyꢀ2ꢀoxindoles and phenols under Lewis acid catalysis,
see: (a) Kinthada, L. K.; Ghosh, S.; Babu, K. N.; Sharique, M.; Biswas, S.; Bisai, A. Org.
Biomol. Chem. 2014, 12, 8152. (b) Ghosh, S.; Kinthada, L. K.; Bhunia, S.; Bisai, A. Chem.
Comm. 2012, 48, 10132. (c) Zhou, F.; Cao, Z.ꢀ Y.; Zhang, J. ; Yang, H.ꢀB.; Zhou, J. Chem.
Asian J. 2012, 7, 233. For a different reactivity of 3ꢀhydroxyꢀ2ꢀoxindoles and phenols under
organocatalysis, see: (d) Liu, Y.; Zhang, H.ꢀH.; Zhang, Y.ꢀC.; Jiang, Y.; Shi, F.; Tu, S.ꢀJ.
Chem. Comm. 2014, 50, 12054. For a different reactivity of allenes and phenols, see: (e)
Nemoto, T.; Nozaki, T.; Yoshida, M.; Hamada, Y. Adv. Synth. Catal. 2013, 355, 2693.
(9) Slighly improved yields were obtained by the use of Ga(OTf)3 in comparison with Bi(OTf)3,
In(OTf)3, Zn(OTf)2, Fe(OTf)3, and Yb(OTf)3.
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(10) For a review on the use of Ga(OTf)3 in organic reactions, see: (a) Prakash, G. K. S.; Mathew,
T.; Olah, G. A. Acc. Chem. Res. 2012 , 45, 565. For a recent use, see: (b) Zhang, S.; Xu, Z.;
Jia, J.; Tung, C.ꢀH.; Xu, Z. Chem. Comm. 2014, 50, 12084.
(11) Compounds 4a–i and 5a–i can be considered as hybrid scaffolds as combination of the
biologically relevant oxindole and dihydrobenzofuran frameworks. For reviews on hybrid
chemical entities, see: (a) Decker, M. Curr. Med. Chem. 2011, 18, 1464. (b) Tsogoeva, S. B.
Mini-Rev. Med. Chem. 2010, 10, 773. (c) Meunier, B. Acc. Chem. Res. 2008, 41, 69. (d)
Tietze, L. F.; Bell, H. P.; Chandrasekhar, S. Angew. Chem. Int. Ed. 2003, 42, 3996.
(12) CCDCꢀ907155 contains the supplementary crystallographic data for this paper
(www.ccdc.cam.ac.uk/data_request/cif).
(13) The transformation of isoindolinoneꢀtethered alkoyallenols into oxopropylidene
isoindolinones has been reported by treatment with aqueous sulphuric acid: (a) Kaden, S.;
Reissig, H.ꢀU.; Brüdgam, I.; Hartl, H. Synthesis, 2006, 1351. For the acidꢀcatalyzed synthesis
of α,βꢀdisubstituted conjugated enones by a Meyer–Schusterꢀtype rearrangement in allenols,
see: (b) Alcaide, B.; Almendros, P.; Cembellín, S.; Martínez del Campo, T. Adv. Synth. Catal.
2015, 357, 1070.
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