Direct FeX3-based stereocontrolled access to (Z)-3-alkenyl-oxindoles from allenols

Article abstract of DOI:10.1021/jo302296r

Iron trihalides (FeCl₃ and FeBr₃) smoothly promote the halogenation/rearrangement of 2-indolinone-tethered allenols to efficiently afford 3-halodienyl-oxindoles with good yield and total selectivity. Also, 2-halo-1,3-dienes are synthetically interesting building blocks for the preparation of functionalized 3-alkenyl-oxindoles through a Suzuki-Miyaura reaction.

Full text of DOI:10.1021/jo302296r

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Note
Direct FeX3–Based Stereocontrolled Access
to (Z)-3-Alkenyl-Oxindoles from Allenols
Benito Alcaide, Pedro Almendros, Amparo Luna, and Natividad Prieto
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo302296r • Publication Date (Web): 30 Nov 2012
Downloaded from http://pubs.acs.org on December 1, 2012
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Direct FeX3–Based Stereocontrolled Access to (Z)ꢀ3ꢀ
AlkenylꢀOxindoles from Allenols
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a
Benito Alcaide, Pedro Almendros, b Amparo Luna,a and Natividad Prietoa
*
*
aGrupo de Lactamas y Heterociclos Bioactivos, Departamento de Química Orgánica I, Unidad
Asociada al CSIC, Facultad de Química, Universidad Complutense de Madrid, 28040-Madrid,
Spain
bInstituto de Química Orgánica General, IQOG, CSIC, Juan de la Cierva 3, 28006-Madrid, Spain
Eꢀmail: alcaideb@quim.ucm.es; Palmendros@iqog.csic.es
Table of Content Graphic
R1
HO
R1
R1
•
R2
R2
X
110 mol% FeX3
CH2Cl2, RT
X
O
O
R
O
X
N
N
R4
Fe
X
R4
R3
R3
H
R = oxindole
(Z)-3-Alkenyl-oxindoles
Abstract: Iron trihalides (FeCl3 and FeBr3) smoothly promote the halogenation/rearrangement of 2ꢀ
indolinoneꢀtethered allenols to efficiently afford 3ꢀhalodienylꢀoxindoles with good yield and total
selectivity. Besides, 2ꢀhaloꢀ1,3ꢀdienes are synthetically interesting building blocks for the
preparation of functionalized 3ꢀalkenylꢀoxindoles through a Suzuki–Miyaura reaction.
The carbon–carbon double bond of allenes, a class of compounds with two πꢀorbitals perpendicular
to each other, is around 10kcalꢀmol−1 less stable than that of simple alkenes,1 rendering them
significantly more reactive. Thus, allenes have metamorphosed from a laboratory curiosity to a
versatile and uniquely reactive functional group, allowing chemists to prepare a variety of
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compounds of chemical and biological interest.2 On the other hand, the potent biological activities
of natural and manꢀmade 3ꢀalkenylꢀoxindoles are also increasingly appreciated, mainly due to their
antiangiogenic, antibacterial, antifungal, antitumor, and antiviral properties.3 The 1,3ꢀdiene moiety
is ubiquitous in a variety of natural products of biological interest.4 Besides, the 1,3ꢀdiene
functionality has led to many synthetically useful transformations.5 In particular, 2ꢀhaloꢀ1,3ꢀdienes
are useful compounds in organic synthesis because the halide atom acts as directing group prone to
further transformations.6 Main previous strategies for the preparation of 2ꢀhaloꢀ1,3ꢀdienes have
been centered on coupling protocols, and their syntheses from allenol derivatives usually proceeded
with poor diastereoselectivity.7 Following up on our combined interest in the area of lactams and
allenes,8 and considering the inexpensiveness and environmentally friendliness of iron species we
chose to study the FeX3–promoted reaction of 2ꢀindolinoneꢀtethered allenols as a route to access 3ꢀ
alkenylꢀoxindoles because of the potential biological activities.
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Starting allenols 1a–i were achieved via indiumꢀmediated Barbierꢀtype allenylation
reactions of isatins in aqueous media following our previously described methodology.9 Originally,
we were attempting the ironꢀcatalyzed cycloisomerization reaction of allenol 1a under FeCl3
catalysis (10 mol%); but, surprisingly, a 9% yield of the (Z)ꢀ3ꢀ(3ꢀchlorobutꢀ3ꢀenꢀ2ꢀylidene)indolinꢀ
2ꢀone 2a was obtained. Considering the economic attractiveness and the environmentally
friendliness of iron species, we became interested in developing an allenolꢀbased methodology for
the preparation of functionalized (Z)ꢀ3ꢀalkenylꢀoxindoles. Our initial studies focused on developing
a more efficient transformation and we used the reaction of allenol 1a with FeCl3 as a model
system. The reaction product 2a could only be obtained in reasonable yield using a higher reagent
o
loading. An optimal yield of 2a was obtained at 20 C by using 110 mol% of FeCl3 and
dichloromethane as the solvent (Scheme 1). A brief optimization of the halide source revealed that
employment of other metal halides did not improve the yield of compound 2a. In addition of FeCl3,
BiCl3 was also tested with allenol 1a. Next, both HfCl4 and ZnCl2 were investigated. Substrate 1a
did not react in the presence of HfCl4 or ZnCl2 under otherwise identical conditions. The use of
BiCl3 as halide source provided 2ꢀhaloꢀ1,3ꢀdiene 2a, but in a low 51% yield after three days of
reaction.
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Scheme 1. Chlorination/Rearrangement Reaction of Indolinone-Tethered Allenol 1a to (Z)-3-
6
7
(3-Chlorobut-3-en-2-ylidene)indolin-2-one 2a by FeCl3 Treatment
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9
Me
HO
Me
O
•
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Cl
O
Me
O
110 mol% FeCl3
CH2Cl2, RT, 1d
O
X
N
N
N
Me
Me
Me
1a
2a
(71%)
With optimized conditions in hand, we then examined the generality of this ironꢀpromoted
halogenation/rearrangement protocol. As shown in Table 1, all the reactions proceeded smoothly
and afforded the desired products in reasonable to good yields upon isolation. We observed that
allenic NHꢀindolinones (Table 1, entries 4–7) exhibited excellent reactivity and yielded full
conversion of benchmark substrates. Electronꢀwithdrawing and electronꢀdonating substituents on
the aryl ring of the oxindoles were tolerated with only little influence on the reactivity (Table 1,
entries 1–7). The placement of bromine or chlorine atom at C5 and C7 positions of the indole ring
were tolerated in presence of FeCl3, providing a handle for subsequent orthogonal reactivity. It is
often the case that reaction conditions optimized for one class of halides are less effective with
others. However, the exact same conditions also promote the efficient reaction of FeBr3 with a
diverse range of 2ꢀindolinoneꢀtethered allenols 1. Notably, the bromination/rearrangement reactions
of allenols 1 with FeBr3 gave the corresponding products in fair yields (Table 1, entries 8–11).
Table 1. Halogenation/Rearrangement Reaction of Indolinone-Tethered Allenols 1 to (Z)-3-(3-
Halobut-3-en-2-ylidene)indolin-2-ones 2 by FeX3 Treatmenta
HO
•
R1
R1
X
O
110 mol% FeX3
CH2Cl2, RT
O
N
R3
N
R3
R2
R2
entry
allenol
X
Cl
Cl
time (h)
22
R1
H
R2
R3
Me
Me
yield (%)
2a (71)
2b (63)
1
2
1a
1b
H
H
22
Cl
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1c
1d
1e
1f
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Cl
Br
22
3
H
H
Cl
H
Me
H
2c (88)
2d (70)
2e (82)
2f (93)
2g (65)
2h (74)
2i (50)
2j (72)
2k (75)
2l (77)
2m (70)
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136
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Cl
H
H
H
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Cl
H
7
1g
1a
1b
1e
1h
1i
H
MeO
H
H
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H
Me
Me
H
9
Cl
Cl
H
H
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H
MeO
H
Me
H
Br
Br
1i
H
H
a
The stereochemistry of products 2 was unambiguously determined by the NOE analysis of 2b (see Supporting
Information). NOE irradiation of the Cꢀmethyl group (δ = 2.58 ppm) resulted in enhancements of different intensity in
the signals corresponding to the vinylic protons (δ = 5.42 ppm and δ = 5.58 ppm) and (C4)ꢀaromatic proton (δ = 7.66
ppm). On the basis of these data, a (Z)ꢀstereochemistry was assigned.
Owing to the efficacy and functional group tolerance of transition metal catalyzed crossꢀ
coupling reactions in forming C–C bonds, we envisioned that our 2ꢀhaloꢀ1,3ꢀdienes may be
synthetically interesting building blocks for the preparation of functionalized 3ꢀalkenylꢀoxindoles
through a Suzuki–Miyaura reaction. Indeed, the Pdꢀcatalyzed coupling between bromodienes 2h
and 2k with arylboronic acids afforded products 3a–c (Scheme 2).10
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Scheme 2. Preparation of 2-Aryl-1,3-dienyl Oxindoles 3 through Suzuki–Miyaura Reactiona
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Br
O
R2
i)
O
R2
B(OH)2
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+
N
N
R1
R1
1
Me
Me
1
2
2h
3a
R = H
2k R1 = OMe
R = H, R = Me (79%)
3b R1 = OMe, R2 = OMe (94%)
S
Br
O
i)
O
N
+
N
B(OH)2
S
Me
Me
3c (94%)
2h
aConditions: i) 2.5 mol% Pd(PPh3)4, NaHCO3, toluene–EtOH–H2O (18:1:1), reflux, 4 h.
The proposed mechanism for the formation of our 2ꢀhaloꢀ1,3ꢀdienes is outlined in Scheme
3. In the diene formation, the iron trihalide salt FeX3 acts as a Lewis acid interacting with the
alcohol group in the allenol moiety to give complex 4. The extremely high (Z)ꢀselectivity observed
in the formation of dienes 2, may indicate a concerted pseudopericyclic reaction11 pathway rather
than a stepwise path, namely, separation of the hydroxyl group of allenols 1 by FeX3 leading to
carbonium species. The process probably proceeds via a chairꢀlike sixꢀmembered cyclic transition
structure 5, through delivery of the halide ion (from the less hindered side) with concomitant
detachment of the hydroxyl group, to afford the halobutenylidene indolinones with Z selectivity.
Probably, the C=O moiety takes a (pseudo)axial position. An axial position of the C=O group could
be rationalized by its smaller size compared to the aryl ring system. Furthermore, an axial position
of C=O might be stabilized by the iron center through a coordinating interaction. In other words, the
(Z)ꢀselectivity could be the consequence of chelating both the C=O unit and the OH group of the
indolinone ring to the metal.12
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Scheme 3. Mechanistic explanation for the halogenation/rearrangement of 2-indolinone-
tethered allenols through reaction with iron trihalide
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R2
R1
HO
X
X
H
Fe
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•
X
R2
O
FeX3
O
•
R3
N
R4
N
R1
O
R3
R4
1
4
R1
R1
R2
R2
X
O
X
O
X
–FeX2(OH)
N
R4
Fe
X
H
O
R3
N
R3
R4
2
5
In conclusion, iron trihalides (FeCl3 and FeBr3) smoothly promote the
halogenation/rearrangement of 2ꢀindolinoneꢀtethered allenols to efficiently afford 3ꢀhalodienylꢀ
oxindoles with good yield and total selectivity.
Experimental Section
General methods: 1H NMR and 13C NMR spectra were recorded on 300 MHz
spectrometers. NMR spectra were recorded in CDCl3 solutions, except otherwise stated. Chemical
shifts are given in ppm relative to TMS (1H, 0.0 ppm), or CDCl3 (13C, 76.9 ppm). Low and high
resolution mass spectra were taken on a QTOF LC/MS spectrometer using the electronic impact
(EI) or electrospray modes (ES) unless otherwise stated. All commercially available compounds
were used without further purification.
Indium-promoted reaction between 1-bromo-2-butyne and substituted isatins; general
procedure for the synthesis of α-allenic alcohols 1a–i. 1ꢀBromoꢀ2ꢀbutyne (3.0 mmol) was added
to a well stirred suspension of the corresponding isatin (1.0 mmol) and indium powder (6.0 mmol)
in THF/NH4Cl (aq. sat.) (1:5, 5 mL) at 0 ºC. After disappearance of the starting material (TLC) the
mixture was extracted with ethyl acetate (3 x 5 mL). The organic extract was washed with brine,
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dried (MgSO4) and concentrated under reduced pressure. Chromatography of the residue using
ethyl acetate/hexanes mixtures gave analytically pure compounds. Spectroscopic and analytical data
for previously unreported αꢀallenic alcohols 1g–1i follow.
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α-Allenic Alcohol 1g. From 200 mg (1.13 mmol) of 7ꢀmethoxyisatin, and after
chromatography of the residue using hexanes/ethyl acetate (2:1) as eluent, gave compound 1g (198
mg, 76%) as a pale brown solid; mp 121–123 ºC; 1HꢀNMR (300 MHz, CDCl3, 25 oC) δ: 7.76 (br s,
1H), 7.11ꢀ7.00 (m, 2H), 6.90 (dd, J = 8.2, 0.9 Hz, 1H), 5.08 (q, J = 3.1 Hz, 2H), 3.91 (s, 3H), 1.63
(t, J = 3.1 Hz, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 oC) δ: 204.6, 177.7, 143.9, 130.1, 129.6, 123.7,
116.9, 112.2, 100.5, 80.4, 77.1, 55.7, 13.6; IR (CHCl3, cm–1): ν 3259, 2934, 1715, 1329; HRMS
(ES): calcd for C13H13NO3 [M + H]+: 232.0974; found: 232.0974.
α-Allenic Alcohol 1h. From 90 mg (0.47 mmol) of Nꢀmethyl 7ꢀmethoxyisatin, and after
chromatography of the residue using hexanes/ethyl acetate (2:1) as eluent, gave compound 1h (74
1
o
mg, 64%) as a colorless solid; mp 126–128 ºC; HꢀNMR (300 MHz, CDCl3, 25 C) δ: 7.06ꢀ6.96
(m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 5.02 (q, J = 3.1 Hz, 2H), 3.85 (s, 3H), 3.46 (s, 3H), 3.40 (br s,
o
1H), 1.53 (t, J = 3.1 Hz, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ: 204.7, 176.8, 145.3, 131.4,
130.6, 123.7, 116.9, 113.7, 100.8, 80.2, 76.1, 55.9, 29.6, 13.6; IR (CHCl3, cm–1): ν 3379, 2934,
1715, 1329; HRMS (ES): calcd for C14H15NO3 [M]+: 245.1052; found: 245.1044.
α-Allenic Alcohol 1i. From 600 mg (2.65 mmol) of 5ꢀbromoisatin, and after chromatography
of the residue using hexanes/ethyl acetate (2:1) as eluent, gave compound 1i (494 mg, 67%) as a
pale yellow solid; mp 183–185 ºC; 1HꢀNMR (300 MHz, acetoneꢀδ6, 25 oC) δ: 9.41 (br s, 1H), 7.42ꢀ
7.39 (m, 2H), 6.88 (d, J = 8.9, Hz, 1H), 4.77 (q, J = 3.2 Hz, 2H), 1.75 (t, J = 3.2 Hz, 3H); 13CꢀNMR
(75 MHz, acetoneꢀδ6, 25 oC) δ: 206.9, 177.6, 142.1, 134.7, 133.0, 128.7, 114.7, 112.5, 101.3, 78.4
(2C), 13.9; IR (KBr, cm–1): ν 3323, 2986, 1725, 1618, 1476; HRMS (ES): calcd for C12H11BrNO2
[M + H]+: 279.9973; found: 279.9970.
FeX3-Promoted reaction of allenols 1. Synthesis of 3-halodienyl-oxindoles 2. To a
solution of the appropriate allenol 1 (0.14 mmol) in dichloromethane (2.5 mL), anhydrous FeX3
(0.154 mmol) was added under argon. The reaction mixture was stirred at RT until the starting
material disappeared as indicated by TLC. After filtration through a pad of Celite, the mixture was
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concentrated under vacuum, and purified by flash column chromatography eluting with ethyl
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acetate/hexanes mixtures. Spectroscopic and analytical data for pure forms of compounds 2 follow.
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3-Chlorodienyl-oxindole 2a. From 30 mg (0.14 mmol) of indolinꢀ2ꢀoneꢀtethered allenol 1a,
and after chromatography of the residue using hexanes/ethyl acetate (4:1) as eluent, gave compound
2a (24 mg, 71%) as a yellow solid; mp 96–98 ºC; 1HꢀNMR (300 MHz, CDCl3, 25 oC) δ: 7.71 (d, J
= 7.6 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 6.90 (t, J = 7.8 Hz, 1H), 6.72 (d, J = 7.8 Hz, 1H), 5.53 and
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o
5.41 (d, J = 1.8 Hz, each 1H), 3.16 (s, 3H), 2.57 (s, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ:
167.8, 147.7, 142.7, 139.1, 129.2, 123.8, 123.7, 121.8, 121.2, 115.3, 107.7, 25.7, 19.2; IR (CHCl3,
cm–1): ν 3056, 2927, 1699, 1607, 1474, 1329; HRMS (ES): calcd for C13H13ClNO [M + H]+:
234.0686; found: 234.0686.
3-Chlorodienyl-oxindole 2b. From 30 mg (0.12 mmol) of indolinꢀ2ꢀoneꢀtethered allenol 1b,
and after chromatography of the residue using hexanes/ethyl acetate (5:1) as eluent, gave compound
2b (20 mg, 63%) as a yellow solid; mp 97–99 ºC; 1HꢀNMR (300 MHz, CDCl3, 25 oC) δ: 7.66 (d, J
= 2.0 Hz, 1H), 7.17 (dd, J = 8.3, 2.0 Hz, 1H), 6.64 (d, J = 8.3 Hz, 1H), 5.58 and 5.42 (d, J = 1.9 Hz,
o
each 1H), 3.15 (s, 3H), 2.58 (s, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ: 167.4, 149.6, 141.2,
138.5, 128.8, 127.2, 123.9, 123.0, 122.4, 115.7, 108.6, 25.8, 19.4; IR (CHCl3, cm–1): ν 2930, 1700,
1462; HRMS (ES): calcd for C13H11Cl2NO [M]+: 267.0218; found: 267.0213.
3-Chlorodienyl-oxindole 2c. From 30 mg (0.12 mmol) of indolinꢀ2ꢀoneꢀtethered allenol 1c,
and after chromatography of the residue using hexanes/ethyl acetate (5:1) as eluent, gave compound
2c (28 mg, 88%) as a yellow solid; mp 116–118 ºC; 1HꢀNMR (300 MHz, CDCl3, 25 oC) δ: 7.64 (d,
J = 7.6 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 6.81 (t, J = 7.9 Hz, 1H), 5.52 and 5.38 (d, J = 1.9 Hz,
o
each 1H), 3.55 (s, 3H), 2.58 (s, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ: 167.9, 149.1, 138.9,
138.6, 131.2, 123.8, 122.8, 122.4, 122.3, 115.3, 29.1, 19.9; IR (CHCl3, cm–1): ν 2923, 1698, 1458,
1129; HRMS (ES): calcd for C13H11Cl2NO [M]+: 267.0218; found: 267.0216.
3-Chlorodienyl-oxindole 2d. From 26 mg (0.13 mmol) of indolinꢀ2ꢀoneꢀtethered allenol 1d,
and after chromatography of the residue using hexanes/ethyl acetate (5:1) as eluent, gave compound
2d (20 mg, 70%) as a yellow solid; mp 122–124 ºC; 1HꢀNMR (300 MHz, CDCl3, 25 oC) δ: 8.42 (br
s, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 7.7
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Hz, 1H), 5.54 and 5.43 (d, J = 1.7 Hz, each 1H), 2.57 (s, 3H); CꢀNMR (75 MHz, CDCl3, 25 oC)
δ: 169.7, 148.3, 140.0, 139.0, 129.2, 124.1 (2C), 121.9, 121.8, 115.3, 109.6, 19.2; IR (CHCl3, cm–
1): ν 3199, 1698, 1466; HRMS (ES): calcd for C12H10ClNO [M]+: 219.0451; found: 219.0447.
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3-Chlorodienyl-oxindole 2e. From 30 mg (0.13 mmol) of indolinꢀ2ꢀoneꢀtethered allenol 1e,
and after chromatography of the residue using hexanes/ethyl acetate (2:1) as eluent, gave compound
2e (23 mg, 82%) as a yellow solid; mp 148–150 ºC; 1HꢀNMR (300 MHz, CDCl3, 25 oC) δ: 8.99 (br
s, 1H), 7.71 (d, J = 1.9 Hz, 1H), 7.18 (dd, J = 8.3, 1.9 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 5.66 and
o
5.52 (d, J = 1.9 Hz, each 1H), 2.64 (s, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ: 169.6, 150.3,
138.5, 138.3, 128.9, 127.2, 124.1, 123.4, 123.2, 115.8, 110.5, 19.4; IR (CHCl3, cm–1): ν 3194,
1700, 1462; HRMS (ES): calcd for C12H9Cl2NO [M]+: 253.0061; found: 253.0057.
3-Chlorodienyl-oxindole 2f. From 25 mg (0.10 mmol) of indolinꢀ2ꢀoneꢀtethered allenol 1f,
and after chromatography of the residue using hexanes/ethyl acetate (3:1) as eluent, gave compound
2f (24 mg, 93%) as a yellow solid; mp 138–140 ºC; 1HꢀNMR (300 MHz, CDCl3, 25 oC) δ: 8.19 (br
s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.21 (dd, J = 8.0, 0.6 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H), 5.63 and
o
5.50 (d, J = 1.9 Hz, each 1H), 2.64 (s, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ: 168.4, 150.3,
138.5, 137.5, 128.7, 123.9, 123.2, 122.5, 122.3, 115.6, 114.8, 19.4; IR (CHCl3, cm–1): ν 3144,
2923, 1702, 1440; HRMS (ES): calcd for C12H10Cl2NO [M + H]+: 254.0139; found: 254.0136.
3-Chlorodienyl-oxindole 2g. From 40 mg (0.17 mmol) of indolinꢀ2ꢀoneꢀtethered allenol 1g,
and after chromatography of the residue using hexanes/ethyl acetate (5:1) as eluent, gave compound
2g (27 mg, 65%) as a yellow solid; mp 138–140 ºC; 1HꢀNMR (300 MHz, CDCl3, 25 oC) δ: 7.96 (br
s, 1H), 7.43 (d, J = 7.8 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 5.64 and 5.53 (d,
o
J = 1.8 Hz, each 1H), 3.91 (s, 3H), 2.67 (s, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ: 168.7,
148.7, 143.5, 138.9, 129.2, 124.6, 122.5, 122.0, 116.6, 115.4, 111.3, 55.7, 19.1; IR (CHCl3, cm–1):
ν 3193, 2933 1701, 1210; HRMS (ES): calcd for C13H13ClNO2 [M + H]+: 250.0635; found:
250.0637.
3-Bromodienyl-oxindole 2h. From 40 mg (0.14 mmol) of indolinꢀ2ꢀoneꢀtethered allenol 1a,
and after chromatography of the residue using hexanes/ethyl acetate (4:1) as eluent, gave compound
1
o
2h (29 mg, 74%) as a pale brown solid; mp 123–125 ºC; HꢀNMR (300 MHz, CDCl3, 25 C) δ:
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7.81 (d, J = 7.7 Hz, 1H), 7.28 (td, J = 7.7, 1.0 Hz, 1H), 7.00 (td, J = 7.7, 1.0 Hz, 1H), 6.80 (d, J =
7.7 Hz, 1H), 5.85 and 5.81 (d, J = 2.1 Hz, each 1H), 3.24 (s, 3H), 2.65 (s, 3H); 13CꢀNMR (75 MHz,
CDCl3, 25 oC) δ: 167.4, 149.4, 142.7, 129.6, 129.1, 124.1, 123.0, 121.8, 121.2, 119.0, 107.7, 25.7,
19.4; IR (CHCl3, cm–1): ν 3054, 2926, 1699, 1605, 1474; HRMS (ES): calcd for C13H13BrNO [M +
H]+: 278.0181; found: 278.0180.
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3-Bromodienyl-oxindole 2i. From 40 mg (0.16 mmol) of indolinꢀ2ꢀoneꢀtethered allenol 1b,
and after chromatography of the residue using hexanes/ethyl acetate (4:1) as eluent, gave compound
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2i (25 mg, 50%) as a yellow solid; mp 95–97 ºC; HꢀNMR (300 MHz, CDCl3, 25 C) δ: 7.76 (s,
1H), 7.27ꢀ7.24 (m, 1H), 6.72 (d, J = 8.3 Hz, 1H), 5.88ꢀ5.86 (m, 2H), 3.23 (s, 3H), 2.66 (s, 3H); 13Cꢀ
o
NMR (75 MHz, CDCl3, 25 C) δ: 167.4, 151.3, 141.1, 128.8, 127.3, 124.2 (2C), 122.5, 122.2,
119.5, 108.6, 25.9, 19.7; IR (CHCl3, cm–1): ν 2930, 1700, 1462; HRMS (ES): calcd for C13H12
BrClNO [M + H]+: 311.9791; found: 311.9795.
3-Bromodienyl-oxindole 2j. From 30 mg (0.13 mmol) of indolinꢀ2ꢀoneꢀtethered allenol 1e,
and after chromatography of the residue using hexanes/ethyl acetate (4:1) as eluent, gave compound
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o
2j (28 mg, 72%) as a pale brown solid; mp 136–138 ºC; HꢀNMR (300 MHz, CDCl3, 25 C) δ:
8.88 (br s, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.20 (dd, J = 8.3, 2.0 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H),
5.90 and 5.87 (d, J = 2.3 Hz, each 1H), 2.65 (s, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 oC) δ: 169.5,
151.9, 138.4, 128.9, 128.6, 127.3, 124.5, 123.3, 122.6, 119.5, 110.5, 19.6; IR (CHCl3, cm–1): ν
3198, 2921, 1700, 1464; HRMS (ES): calcd for C12H9BrClNO [M]+: 296.9556; found: 296.9557.
3-Bromodienyl-oxindole 2k. From 27 mg (0.11 mmol) of indolinꢀ2ꢀoneꢀtethered allenol 1h,
and after chromatography of the residue using hexanes/ethyl acetate (4:1) as eluent, gave compound
2k (25 mg, 75%) as a pale brown solid; mp 98–100 ºC; 1HꢀNMR (300 MHz, CDCl3, 25 oC) δ: 7.47
(dd, J = 7.4, 1.0 Hz, 1H), 6.94ꢀ6.84 (m, 2H), 5.82 and 5.78 (d, J = 2.1 Hz, each 1H), 3.85 (s, 3H),
3.51 (s, 3H), 2.64 (s, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 oC) δ: 167.9, 149.6, 145.0, 130.9, 129.7,
123.2, 122.6, 122.0, 118.9, 117.1, 113.0, 56.0, 29.1, 19.6; IR (CHCl3, cm–1): ν 2928, 1693, 1459,
1250; HRMS (ES): calcd for C14H14BrNO2 [M]+: 307.0208; found: 307.0199.
3-Chlorodienyl-oxindole 2l. From 37 mg (0.13 mmol) of indolinꢀ2ꢀoneꢀtethered allenol 1i,
and after chromatography of the residue using hexanes/ethyl acetate (1:1) as eluent, gave compound
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2l (30 mg, 77%) as a yellow solid; mp 149–151 ºC; 1HꢀNMR (300 MHz, CDCl3, 25 oC) δ: 8.85 (br
s, 1H), 7.85 (d, J = 1.9 Hz, 1H), 7.33 (dd, J = 8.2, 1.9 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 5.67 and
o
5.52 (d, J = 1.9 Hz, each 1H), 2.64 (s, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ: 169.4, 150.3,
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138.9, 138.3, 131.8, 126.9, 123.6, 123.2, 115.8, 114.5, 111.0, 19.5; IR (CHCl3, cm–1): ν 3194,
1701, 1466; HRMS (ES): calcd for C12H10BrClNO [M + H]+: 297.9634; found: 297.9626.
3-Bromodienyl-oxindole 2m. From 28 mg (0.10 mmol) of indolinꢀ2ꢀoneꢀtethered allenol 1i,
and after chromatography of the residue using hexanes/ethyl acetate (1:1) as eluent, gave compound
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o
2m (24 mg, 70%) as a pale brown solid; mp 129–131 ºC; HꢀNMR (300 MHz, CDCl3, 25 C) δ:
8.71 (br s, 1H), 7.87 (d, J = 1.9 Hz, 1H), 7.34 (dd, J = 8.2, 1.9 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H),
5.89 and 5.86 (d, J = 2.2 Hz, each 1H), 2.64 (s, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 oC) δ: 169.3,
151.9, 138.8, 131.7, 128.6, 127.2, 123.7, 122.4, 119.6, 114.6, 110.9, 19.6; IR (CHCl3, cm–1): ν
3214, 2923, 1700, 1466; HRMS (ES): calcd for C12H10Br2NO [M + H]+: 341.9129; found:
341.9126.
General procedure for the Suzuki–Miyaura cross-coupling reaction of bromodienes 2
with boronic acids. Preparation aryl-butylidenes 3. The corresponding bromodiene 2 (0.08
mmol) was added under argon to a stirred suspension of the appropriate arylboronic acid (0.12
mmol) and sodium bicarbonate (0.25 mmol) in toluene/ethanol/water (18:1:1) (1.68 mL), and the
resulting mixture was stirred for 15 min. Then, Pd(PPh3)4 (2.5 mol%) was added and the reaction
mixture was heated at reflux temperature for 3 h. The reaction mixture was allowed to cool to
ambient temperature, before being partitioned between ethyl acetate and water. The organic extract
was washed with water (2 x 1 mL), dried (MgSO4), and concentrated under reduced pressure.
Chromatography of the residue eluting with hexanes/ethyl acetate mixtures gave analytically pure
compounds 3.
Aryl-butylidene 3a. From 25 mg (0.09 mmol) of bromodiene 2h, and after chromatography
of the residue using hexanes/ethyl acetate (6:1) as eluent, gave compound 3a (21 mg, 79%) as a
pale yellow oil; 1HꢀNMR (300 MHz, CDCl3, 25 oC) δ: 7.55 (d, J = 7.0 Hz, 1H), 7.36 (d, J = 8.0 Hz,
2H), 7.22ꢀ7.19 (m, 1H), 7.16 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 7.7 Hz, 2H), 5.75 and 5.22 (s, each
o
1H), 3.30 (s, 3H), 2.64 (s, 3H), 2.36 (s, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ: 168.1, 155.0,
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149.5, 142.3, 138.5, 133.2, 129.6 (2C), 128.1, 126.1 (2C), 123.5 (2C), 122.4, 121.6, 111.4, 107.4,
25.7, 21.5, 21.2; IR (CHCl3, cm–1): ν 1695; HRMS (ES): calcd for C20H19NO [M]+: 289.1467;
found: 289.1458.
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Aryl-butylidene 3b. From 18 mg (0.057 mmol) of bromodiene 2k, and after chromatography
of the residue using hexanes/ethyl acetate (7:1) as eluent, gave compound 3b (22 mg, 94%) as a
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pale yellow oil; HꢀNMR (300 MHz, CDCl3, 25 C) δ: 7.38 (d, J = 8.9 Hz, 2H), 7.20 (dd, J = 7.3,
1.5 Hz, 1H), 6.86 (d, J = 8.9 Hz, 2H), 6.79ꢀ6.69 (m, 2H), 5.64 and 5.12 (s, each 1H), 3.84 (s, 3H),
13
3.80 (s, 3H), 3.57 (s, 3H), 2.63 (s, 3H); CꢀNMR (75 MHz, CDCl3, 25 oC) δ: 168.3, 159.8, 155.5,
149.1, 144.9, 130.5, 128.4, 127.4 (2C), 123.8, 123.7, 121.8, 116.7, 114.2 (2C), 112.1, 110.1, 56.0,
55.2, 29.1, 21.8; IR (CHCl3, cm–1): ν 1700; HRMS (ES): calcd for C21H22NO3 [M + H]+: 336.1600;
found: 336.1587.
Aryl-butylidene 3c. From 30 mg (0.11 mmol) of bromodiene 2h, and after chromatography
of the residue using hexanes/ethyl acetate (8:1) as eluent, gave compound 3c (29 mg, 94%) as a
pale yellow oil; 1HꢀNMR (300 MHz, CDCl3, 25 oC) δ: 7.50 (d, J = 7.6 Hz, 1H), 7.25ꢀ7.17 (m, 2H),
6.94ꢀ6.77 (m, 4H), 5.70 and 5.10 (s, each 1H), 3.28 (s, 3H), 2.74 (s, 3H); 13CꢀNMR (75 MHz,
CDCl3, 25 oC) δ: 168.0, 152.8, 143.9, 142.3, 140.6, 128.3, 127.8, 125.7, 125.6, 123.8, 123.6, 121.9,
121.7, 110.7, 107.5, 25.7, 21.6; IR (CHCl3, cm–1): ν 1696; HRMS (ES): calcd for C17H15NOS
[M]+: 281.0874; found: 281.0875.
Acknowledgment. Support for this work by the DGIꢀMICINN (Project CTQ2009ꢀ09318) and
Comunidad Autónoma de Madrid (Project S2009/PPQꢀ1752) are gratefully acknowledged.
1
Supporting Information Available: Copies of the H 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
(1) Padwa, A.; Filipkowski, M. A.; Meske, M.; Murphree, S. S.; Watterson, S. H.; Ni, Z. J. Org.
Chem. 1994, 59, 588.
(2) For selected reviews on allene chemistry, see: (a) Yu, S.; Ma, S. Angew. Chem. Int. Ed. 2012,
51, 3074. (b) Krause, N.; Winter, C. Chem. Rev. 2011, 111, 1994. (c) Alcaide, B.; Almendros,
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P. Adv. Synth. Catal. 2011, 353, 2561. (d) Ma, S. Chem. Rev. 2005, 105, 2829. (e) Modern
Allene Chemistry, Krause, N., Hashmi, A. S. K., Eds.; WileyꢀVCH: Weinheim, 2004.
(3) For a review, see: Millemaggi, A.; Taylor, R. J. K. Eur. J. Org. Chem. 2010, 4527.
(4) For selected references, see: (a) Amans, D.; Bellosta, V.; Cossy, J. Chem. Eur. J. 2009, 15,
3457. (b) Ramamoorthy, G.; Acevedo, C. M.; Alvira, E.; Lipton, M. A. Tetrahedron:
Asymmetry 2008, 19, 2546. (c) A. M. Curr. Opin. Chem. Biol. 2004, 8, 281.
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(5) For a review, see: Xi, Z. F.; Zhang, W. X. Synlett 2008, 17, 2557.
(6) For selected examples, see: (a) Ogasawara, M.; Suzuki, M.; Takahashi, T. J. Org. Chem.
2012, 77, 5406. (b) Ogasawara, M.; Ge, Y.; Okada, A.; Takahashi, T. Eur. J. Org. Chem.
2012, 1656. (c) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2000, 122, 4583.
(7) (a) Deng, Y.; Fu, C.; Ma, S. Org. Lett. 2009, 11, 2169. (b) Ma, S.; Wang, G. Tetrahedron
Lett. 2002, 43, 5723. (c) Horvath, A.; Bäckvall, J.ꢀE. J. Org. Chem. 2001, 66, 8120.
(8) (a) Alcaide, B.; Almendros, P.; Alonso, J. M.; Fernández, I. Chem. Commun. 2012, 48, 6604.
(b) Alcaide, B.; Almendros, P.; Aragoncillo, C.; GómezꢀCampillos, G.; Arnó, M.; Domingo,
L. R. ChemPlusChem 2012, 77, 563. (c) Alcaide, B.; Almendros, P.; Luna, A.; Gómezꢀ
Campillos, G.; Torres, M. R. J. Org. Chem. 2012, 77, 3549. (d) Alcaide, B.; Almendros, P.;
Carrascosa, R. Chem. Eur. J. 2011, 17, 4968.
(9) Alcaide, B.; Almendros, P.; RodríguezꢀAcebes, R. J. Org. Chem. 2005, 70, 3198.
(10) Appart from their biological importance, 3ꢀ(butꢀ3ꢀenꢀ2ꢀylidene)indolinꢀ2ꢀones related to 2
and 3 are also valuable building blocks. (a) Qian, D.; Zhang, J. Chem. Commun. 2012, 48,
7082. (b) Han, Y.ꢀY.; Han, W.ꢀY.; Hou, X.; Zhang, X.ꢀM.; Yuan, W.ꢀC. Org. Lett. 2012, 14,
4054.
(11) For selected examples of pseudopericyclic reactions, see: (a) Abreu, P. E.; Pais, A. A. C. C.;
Formosinho, S. J. Arkivoc 2010, (v), 92. (b) Alajarín, M.; Ortin, M. M.; SánchezꢀAndrada, P.;
Vidal, A. J. Org. Chem. 2006, 71, 8126. (c) Birney, D. M.; Xu, X.; Ham, S. Angew. Chem.
Int. Ed. 1999, 38, 189. (d) Ross, J. A.; Seiders, R. P.; Lemal, D. M. J. Am. Chem. Soc. 1976,
98, 4325.
(12) If an equatorial position applies for the C=O unit, the Eꢀisomer would result. We thank a
reviewer for this stereochemical picture.
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