All-carbon-substituted quaternary carbon atoms in oxindoles by an aerobic palladium(II)-catalyzed ring closure onto tri- and tetrasubstituted double bonds

Article abstract of DOI:10.1002/ejoc.201001526

Oxidative palladium(II)-catalyzed cyclization of α,β-unsaturated amides derived from electron-rich anilines is reported. The aerobic ring closure of tri- and tetrasubstituted alkenes yields oxindoles with congested all-carbon-substituted quaternary carbon atoms. The ring-size selectivity is excellent. Selected unsymmetrically substituted arenes cyclize with perfect regioselectivity. Experimental evidence indicates that the mechanism is likely to involve Friedel-Crafts-type electrophilic substitution rather than direct C-H bond activation. Oxindoles are formed in an aerobic palladium(II)-catalyzed cyclization of tri- and tetrasubstituted double bonds at relatively low catalyst loading. The mechanism likelyinvolves a Friedel-Crafts-type electrophilic substitution rather than direct C-H bond activation.

Full text of DOI:10.1002/ejoc.201001526

FULL PAPER
DOI: 10.1002/ejoc.201001526
All-Carbon-Substituted Quaternary Carbon Atoms in Oxindoles by an Aerobic
Palladium(II)-Catalyzed Ring Closure onto Tri- and Tetrasubstituted Double
Bonds
Julia A. Schiffner[a] and Martin Oestreich*[a]
Keywords: C–H activation / Cyclization / Electrophilic substitution / Cross-coupling / Palladium
Oxidative palladium(II)-catalyzed cyclization of α,β-unsatu-
rated amides derived from electron-rich anilines is reported.
The aerobic ring closure of tri- and tetrasubstituted alkenes
yields oxindoles with congested all-carbon-substituted qua-
ternary carbon atoms. The ring-size selectivity is excellent.
Selected unsymmetrically substituted arenes cyclize with
perfect regioselectivity. Experimental evidence indicates that
the mechanism is likely to involve Friedel–Crafts-type elec-
trophilic substitution rather than direct C–H bond activation.
Introduction
Oxindoles with an all-carbon-substituted quaternary
carbon atom[1] in the C-3 position are particularly valuable
synthetic intermediates in alkaloid synthesis.[2] Of the many
ways to form the oxindole core,[2] a single established
method stands out: the intramolecular Mizoroki–Heck re-
action introduced by Overman (IX Ǟ II, Scheme 1).[3,4] An-
other equally effective palladium(0)-catalyzed approach, in
which the congested carbon atom is installed in the cycliza-
tion event, is the intramolecular α-arylation of amides.[5–7]
On the basis of either C–C[8,9] or unusual C–N[10] discon-
nection, attractive oxindole syntheses involving C–H bond
activation[11] have been disclosed. An oxidative palladi-
Scheme 1. Formation of a congested quaternary carbon atom in
oxindoles by either palladium(0) or palladium(II) catalysis. PG =
protecting group, R = aryl or alkyl, and X = halide or triflate.
into C–H bond functionalization following either direct C–
H bond activation or an electrophilic substitution pathway.
um(II) catalytic process corresponding to the aforemen- Results and Discussion
tioned Mizoroki–Heck reaction is also likely to proceed
We chose electron-rich α,β-unsaturated amide 1 as a test
cyclization substrate to afford oxindole 2 and/or quinolone
3 (Scheme 2). Initial screening of reaction conditions re-
vealed that the ring closure of 1 would not proceed at the
low temperatures reported for related intermolecular cou-
plings.[16] This fact brought into consideration the tendency
of α,β-unsaturated amides to oligomerize at elevated tem-
peratures and the need to use an internal standard for mon-
itoring conversion and yield. We also found that, apart from
a few exceptions,[4c] oxindole 2 is formed exclusively in al-
most all cases (1 Ǟ 2 and not 1 Ǟ 3; Scheme 2).
Major findings from our optimization study are summa-
rized in Tables 1–3. Pd(OAc)2 was used throughout these
experiments because other palladium sources performed
poorly. For instance, PdCl2 or Pd(OAc)2 with added LiCl
failed to catalyze any cyclization at all (for details, see
Table S1 in the Supporting Information). Screening reac-
tions with an assortment of pyridines verified that parent
ligand L1 was already quite effective in the reaction
(Table 1, Entry 1). Sterically demanding substitution flank-
through a (formal) C–H bond activation mechanism (IH
Ǟ
II, Scheme 1),[12] not requiring prefunctionalization of the
benzene ring. This projected ring closure appeared promis-
ing to us, as related Fujiwara–Moritani cyclizations[13] in-
volving electron-rich arenes and hetarenes are known.[14,15]
Moreover, amides were extensively employed as directing
groups in intermolecular variants,[16] and α,β-unsaturated
amide IH would ultimately be a tethered version of such
systems.
We detail herein an aerobic palladium(II)-catalyzed in-
tramolecular arylation of tri- and tetrasubstituted alkenes.
Our investigation also provides useful mechanistic insight
[a] Organisch-Chemisches Institut, Westfälische Wilhelms-
Universität Münster,
Corrensstrasse 40, 48149 Münster, Germany
Fax: +49-251-83-36501
E-mail: martin.oestreich@uni-muenster.de
http://www.uni-muenster.de/Chemie.oc/oestreich
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001526.
1148
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Aerobic PdII-Catalyzed Cyclization of Highly Substituted Alkenes
mon acids by using mesitylene as solvent (Table 2, En-
tries 9–12). The identity of the acid was found to have little
impact on the yield but markedly influenced the reaction
rates. Bulky acids such as 1-AdCO2H[17] and tBuCO2H[18]
considerably reduced the reaction rates while simulta-
neously affording slightly higher chemical yields (Table 2,
Entries 11 and 12). Consequently, the mesitylene/tBuCO2H
combination emerged as the ideal combination of solvent
and acid for use in these reactions.
Table 2. Solvent and acid screening.[a]
Entry
Solvent
Acid
Ratio
t
[h]
C of 1 Yield of 2
[%][b]
[%][b]
Scheme 2. Model system for oxindole synthesis by an oxidative pal-
ladium(II)-catalyzed ring closure.
1
2
3
4
5
6
7
8
9
tAmOH
tAmOH
–
1,4-dioxane
DMF
pinacolone
toluene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
AcOH
–
15
–
3
24
8
10
8
3
4
4
12
15
99
0
41
–
35
37
4
28
19
46
45
42
49
58
–
–
4:1
4:1
4:1
4:1
4:1
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
TsOH·H2O 4:1
PhCO2H 4:1
1-AdCO2H 4:1
tBuCO2H 4:1
98
97
35
90
99
99
97
99
93
99
ing the nitrogen atom as in L2 and L3 (Table 1, Entries 2
and 3) resulted in decomposition, whereas other substitu-
tions such as those of pyridines L4–L7 facilitated cycliza-
tion in yields similar to those found using L1 (Table 1, En-
tries 4–7). The differences were in the reaction rates, and
these parameters were balanced for 3-carboxylated pyridine
L7, agreeing well with earlier findings by the Stoltz
group.[14a,14c,14f] The discrepancy between loss of starting
material and yield of desired product clearly reveals that
side reactions of both 1 and 2 constitute a serious prob-
lem.[14f]
10
11
12
[a] All reactions were conducted with Pd(OAc)2 (10 mol-%), ligand
L7 (40 mol-%),and O2 (balloon) as oxidant with substrate 1 (0.1 m)
in the indicated solvent/acid system at 110 °C. [b] Both conversion
of starting material and yield of desired product were determined
by GLC analysis by using n-tetracosane as an internal standard.
Ad = adamantyl, DMF = N,N-dimethylformamide, Ts = 4-tolu-
enesulfonyl.
Table 1. Pyridine ligand screening.[a]
All optimization reactions used O2 – clearly the preferred
oxidant –, and studies with other oxidants revealed its su-
premacy (Table 3). Although we will not discuss further de-
tails here, we nevertheless mention one noteworthy observa-
tion. The use of either stoichiometric or catalytic amounts
of Cu(OAc)2 gave rise to significant amounts of quinolone
3 along with oxindole 2 (Table 3, Entries 5 and 6).[4c]
Table 3. Oxidant screening (selected examples).[a]
Entry
Oxidant
Quantity
t
[h]
C of 1 Yield of 2
[%][b]
[%][b]
1
2
3
4
5
6
7
8
O2
air
PhCO3tBu
BQ
balloon
–
1.0 equiv.
1.0 equiv.
1.0 equiv.
3
4
3
6
6
4
6
4
99
99
99
96
99
99
65
93
46
35
33
24
Cu(OAc)2
Cu(OAc)2 with O2 10 mol-%
AgOAc
AgOAc with O2
34[c]
31[c]
26
1.0 equiv.
10 mol-%
[a] Unless otherwise noted, all reactions were conducted with
Pd(OAc)2 (10 mol-%), the indicated ligand (40 mol-%), and O2
(balloon) as oxidant with substrate 1 (0.1 m) in tert-amyl alcohol
(tAmOH)/AcOH (4:1) at 95 °C. [b] Both conversion (C) and yield
were determined by GLC analysis by using n-tetracosane as an in-
ternal standard. [c] 20 mol-% instead of 40 mol-%.
36
[a] All reactions were conducted with Pd(OAc)2 (10 mol-%), ligand
L7 (40 mol-%), and the indicated oxidant with substrate 1 (0.1 m)
in mesitylene/AcOH (4:1) at 110 °C. [b] Both conversion of starting
material and yield of desired product were determined by GLC
analysis by using n-tetracosane as an internal standard. [c] Substan-
tial amounts (approx. 15%) of quinolone
(Scheme 2). BQ = 1,4-benzoquinone.
3 were formed
We next turned our attention to the variation of solvent/
acid mixtures (Table 2) and found that 1 would only cyclize
in acidic media (Table 2, Entries 2 and 3). Of the solvents
Before extending the scope of this ring closure, we fur-
tested together with AcOH (Table 2, Entries 4–8), mesit- ther improved the yields of the desired material at lower
ylene was found to promote acceptable yields at good reac- loadings of Pd(OAc)2 (2.0 mol-%) and L7 (8.0 mol-%). Es-
tion rates (Table 2, Entry 8). We then surveyed a few com- sential to this improvement was the portionwise addition of
Eur. J. Org. Chem. 2011, 1148–1154
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1149

J. A. Schiffner, M. Oestreich
FULL PAPER
cyclization precursor 1. By adding 1 in four portions, sub- proach, a 68% yield at full conversion was achieved
strate oligomerization could be minimized. Using this ap- (Table 4, Entry 1). Application of this protocol to a number
Table 4. Aerobic palladium(II)-catalyzed oxindole synthesis.[a]
[a] All reactions were conducted with Pd(OAc)2 (2.0 mol-%), ligand L7 (8.0 mol-%), and O2 as oxidant with the indicated substrate (0.1 m)
in mesitylene/tBuCO2H (4:1) at 110 °C. [b] Determined by GLC analysis by using n-tetracosane as an internal standard. [c] Refers to
isolated material after purification by flash chromatography on silica gel. [d] The remaining cyclization precursor was recovered. [e] Single
regioisomer. [f] 80:20 mixture of regioisomers.
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Eur. J. Org. Chem. 2011, 1148–1154

Aerobic PdII-Catalyzed Cyclization of Highly Substituted Alkenes
of related symmetric dimethoxy- and trimethoxy-substi- cyclization of indoles that accounts for this observation and
tuted substrates produced comparable yields (i.e., 4–8; supports the importance of Friedel–Crafts chemistry in
Table 4, Entries 2–6). It is particularly remarkable that even such transformations.[20]
tetrasubstituted alkenes reacted in very good yields, form-
ing highly congested quaternary carbon atoms (Table 4, En-
Conclusions
tries 4, 5, and 11). Ring closure of unsymmetric dimethoxy-
substituted 9 produced a single regioisomer (Table 4, En-
try 7). Importantly, a mechanistic clue was obtained from
cyclizations of regioisomeric monomethoxy-substituted 10
and 11 (Table 4, Entries 8 and 9); meta-substituted 10 cy-
clized in 50% yield, whereas para-substituted 11 only af-
forded trace amounts of cyclized product. Other electron-
donating groups such as methyl or amino moieties were tol-
erated (i.e., 12–14; Table 4, Entries 10–12). Additionally, C–
C bond formation with monosubstituted 14 again occurred
regioselectively in the less-hindered position (Table 4, En-
try 8 vs. 12).
Inspired by the Mizoroki–Heck route to oxindoles,[3,4] we
disclosed herein unprecedented access to oxindoles passing
through C–H bond functionalization. The tendency of the
α,β-unsaturated amides to oligomerize posed significant
challenges to the development of the desired transforma-
tion. Key features of this oxindole synthesis include excel-
lent ring-size selectivity, high regioselectivity of unsymmet-
rically substituted arenes, and compatibility with uniquely
reactive tetrasubstituted alkenes.
There were expected but also unexpected limitations
(Figure 1). Model compound 1 contains a secondary amide
group, commonly used as a directing group in intermo-
lecular variants.[16] As expected,[19] a tertiary amide (as in
26) prevented cyclization. A precursor without electron-do-
nating groups attached to the arene (as in 27) was also unre-
active and both 26 and 27 were found to decompose over
the course of extended reaction times. Unanticipated was
the finding that 28 and 29 did not undergo ring closure
but, rather, suffered rapid oligomerization. Less-substituted
alkenes were found to be incompatible with this procedure.
Experimental Section
General Methods: See Supporting Information.
General Procedure for Cyclizations of α,β-Unsaturated Amides: A
flame-dried Schlenk tube was charged with the appropriate cycliza-
tion precursor (0.25 equiv.), Pd(OAc)2 (2.0 mol-%), ligand L7
(8.0 mol-%), and pivalic acid (30 equiv.). The tube was then evacu-
ated and backfilled with O2 (3 cycles). Mesitylene (0.125 m for cycli-
zation precursor) was added, and the resulting mixture was heated
at 110 °C. The remaining cyclization precursor was added portion-
wise (3ϫ0.25 equiv.) every 2–3 h. After the indicated time, the reac-
tion mixture was cooled to room temperature, and the residue was
directly purified by flash column chromatography on silica gel (cy-
clohexane/ethyl acetate) to afford the cyclization product.
4,6-Dimethoxy-3-methyl-3-vinylindolin-2-one (2): Prepared from cy-
clization precursor 1 according to the general procedure with sub-
strate addition every 3 h and a total reaction time of 24 h. Purifica-
tion by flash column chromatography on silica gel (cyclohexane/
ethyl acetate = 3:1) afforded the pure product (22.2 mg, 68%) as a
white solid. M.p. 122.7–123.5 °C (cyclohexane). Rf (cyclohexane/
ethyl acetate = 2:1) = 0.27. IR (ATR): ν = 3162 (s, N–H), 2932 (w,
˜
C–H), 1698 (s, C=C), 1626 (s, C=O) cm–1. 1H NMR (400 MHz,
CDCl3): δ = 1.57 (s, 3 H, CH3), 3.80 (br. s, 6 H, OCH3), 5.13 (dd,
2
3
3JH,H = 10.2 Hz, JH,H = 1.0 Hz, 1 H, =CH2Z), 5.14 (dd, JH,H
=
2
3
17.4 Hz, JH,H = 1.0 Hz, 1 H, =CH2E), 6.00 (dd, JH,H = 17.5 Hz,
3JH,H = 10.2 Hz, 1 H, =CH), 6.16 (d, JH,H = 2.1 Hz, 1 H, HAr),
4
Figure 1. Important structural features preventing cyclization.
6.22 (d, JH,H = 2.0 Hz, 1 H, HAr), 9.34 (br. s, 1 H, NH) ppm. 13C
4
Our initial inspiration for this oxidative palladium(II)-
catalyzed transformation was the Fujiwara–Moritani reac-
tion involving direct C–H bond activation of the electron-
rich arene.[13–15] However, seminal work by Horino and In-
oue provides strong evidence that palladium(II)-mediated
NMR (100 MHz, CDCl3): δ = 20.3, 51.8, 55.3, 55.6, 89.4, 93.1,
111.5, 114.8, 137.1, 141.9, 156.9, 161.4, 182.5 ppm. HRMS (ESI):
calcd. for C13H15NO3Na [M + Na]+ 256.0944; found 256.0940.
C13H15NO3 (233.26): calcd. C 66.94, H 6.48, N 6.00; found C
66.59, H 6.43, N 5.96.
C–H bond activation ortho to an α,β-unsaturated amide is 4,6-Dimethoxy-3-phenyl-3-vinylindolin-2-one (15): Prepared from
difficult, if not impossible.[19] An intramolecular Friedel–
Crafts reaction is therefore more likely, and this is clearly
cyclization precursor 4 according to the general procedure with
substrate addition every 3 h and a total reaction time of 230 h.
Purification by flash column chromatography on silica gel (cyclo-
supported by the pronounced difference in reaction effi-
hexane/ethyl acetate = 3:1) afforded the pure product (10.0 mg,
ciencies found using meta- and para-substituted precursors
(i.e., 10 and 11; Table 4, Entries 8 and 9). The ortho-/para-
directing ability of the methoxy group in 10 led to signifi-
cantly faster cyclization than was observed for substrate 11,
in which this same donor group was situated para to the
anilide nitrogen. Liu and Widenhoefer have previously sug-
24%) as a white solid. M.p. 211.3 °C (pentane). Rf (cyclohexane/
ethyl acetate = 2:1) = 0.33. IR (ATR): ν = 3176 (s, N–H), 2846 (w,
˜
C–H), 1721 (s, C=O), 1631 (s, C=C) cm–1. 1H NMR (400 MHz,
CDCl3): δ = 3.66 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 5.31 (dd,
2
3
3JH,H = 11.1 Hz, JH,H = 1.0 Hz, 1 H, =CH2Z), 5.32 (dd, JH,H
=
2
4
17.4 Hz, JH,H = 0.8 Hz, 1 H, =CH2E), 6.18 (d, JH,H = 2.0 Hz, 1
gested a mechanism for oxidative palladium(II)-catalyzed H, HAr), 6.22 (d, JH,H = 2.0 Hz, 1 H, HAr), 6.45 (dd, JH,H
4
3
=
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1151

J. A. Schiffner, M. Oestreich
FULL PAPER
3
17.5 Hz, JH,H = 10.2 Hz, 1 H, =CH), 7.25–7.26 (m, 1 H, HAr), as a white solid. M.p. 146.5–147 °C (cyclohexane). Rf (cyclohexane/
7.27–7.31 (m, 4 H, HAr), 8.59 (br. s, 1 H, NH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 55.3, 55.7, 60.3, 89.5, 93.3, 110.6, 116.2,
127.2, 127.4, 128.3, 135.4, 138.7, 142.1, 156.8, 161.8, 179.3 ppm.
HRMS (ESI): calcd. for C18H17NO3Na [M + Na]+ 318.1101; found
318.1099. C18H17NO3 (295.33): calcd. C 73.20, H 5.80, N 4.74;
found C 72.95, H 5.78, N 4.58.
ethyl acetate = 2:1) = 0.12. IR (ATR): ν = 3147 (s, N–H), 2929 (s,
˜
C–H), 1703 (s, C=O), 1622 (s, C=C) cm–1. 1H NMR (400 MHz,
CDCl3): δ = 1.59 (s, 3 H, CH3), 3.81 (s, 3 H, OCH3), 3.85 (s, 3 H,
OCH3), 3.93 (s, 3 H, OCH3), 5.16–5.21 (m, 2 H, =CH2), 5.99 (dd,
3JH,H = 17.5 Hz,3JH,H = 10.0 Hz, 1 H, =CH), 6.37 (s, 1 H, HAr),
9.20 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.6,
52.3, 56.4, 60.8, 61.0, 91.4, 115.1, 116.6, 136.2, 137.5, 137.6, 150.8,
154.2, 182.2 ppm. HRMS (ESI): calcd. for C14H17NO4Na [M +
Na]+ 286.1050; found 286.1053.
Spiro[2-cyclohexene-1,3Ј-(4,6-dimethoxy)indolin-2Ј-one] (16): Pre-
pared from cyclization precursor 5 according to the general pro-
cedure with substrate addition every 2 h and a total reaction time
of 96 h. Purification by flash column chromatography on silica gel
5,6-Dimethoxy-3-methyl-3-vinylindolin-2-one (20): Prepared from
cyclization precursor 9 according to the general procedure with
substrate addition every 2 h and a total reaction time of 96 h. Puri-
fication by flash column chromatography on silica gel (cyclohex-
ane/ethyl acetate = 3:1) afforded the pure product (18.3 mg, 56%)
as a slightly yellow solid. M.p. 118.8–119 °C (cyclohexane). Rf (cy-
(cyclohexane/ethyl acetate
= 3:1) afforded the pure product
(21.8 mg, 60%) as a white solid. M.p. 211.3 °C (pentane). Rf (cyclo-
hexane/ethyl acetate = 2:1) = 0.28. IR (ATR): ν = 3158 (s, N–
˜
1
H), 2933 (m, C–H), 1700 (s, C=O), 1597 (s, C=C) cm–1. H NMR
(300 MHz, CDCl3): δ = 1.81–1.90 (m, 2 H, CH2), 2.10–2.31 (m, 4
H, CH2, CH2), 3.77 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 5.31–
clohexane/ethyl acetate = 2:1) = 0.12. IR (ATR): ν = 3172 (s, N–
˜
1
H), 1964 (s, C–H), 1693 (s, C=O), 1622 (w, C=C) cm–1. H NMR
4
5.37 (m, 1 H, =CH), 6.10–6.17 (m, 1 H, =CH), 6.13 (d, JH,H
=
4
(300 MHz, CDCl3): δ = 1.50 (s, 3 H, CH3), 3.85 (s, 3 H, OCH3),
2.0 Hz, 1 H, HAr), 6.20 (d, JH,H = 2.0 Hz, 1 H, HAr), 9.12 (br. s,
1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.1, 24.0, 29.5,
49.2, 55.4, 55.6, 89.2, 93.0, 113.0, 124.7, 131.3, 142.1, 157.0, 161.3,
182.7 ppm. HRMS (ESI): calcd. for C15H17NO3Na [M + Na]+
282.1101; found 282.1099. C15H17NO3 (259.30): calcd. C 69.48, H
6.61, N 5.40; found C 68.98, H 6.61, N 5.26.
3
2
3.86 (s, 3 H, OCH3), 5.17 (dd, JH,H = 17.2 Hz, JH,H = 0.8 Hz, 1
3
2
H, =CH2E), 5.20 (dd, JH,H = 10.4 Hz, JH,H = 0.9 Hz, 1 H,
3
3
=CH2Z), 5.94 (dd, JH,H = 16.9 Hz, JH,H = 10.5 Hz, 1 H, =CH),
6.63 (s, 1 H, HAr), 6.72 (s, 1 H, HAr), 9.63 (br. s, 1 H, NH) ppm.
13C NMR (75 MHz, CDCl3): δ = 22.1, 52.2, 56.3, 56.7, 96.0, 108.6,
115.5, 123.8, 133.9, 138.0, 145.0, 149.3, 182.6 ppm. HRMS (ESI):
calcd. for C13H15NO3Na [M + Na]+ 256.0944; found 256.0940.
C13H15NO3 (233.26): calcd. C 66.94, H 6.48, N 6.00; found C
66.74, H 6.38, N 5.86.
4,6-Dimethoxy-3-methyl-3-(prop-1-en-2-yl)indolin-2-one (17): Pre-
pared from cyclization precursor 6 according to the general pro-
cedure with substrate addition every 2 h and a total reaction time
of 96 h. Purification by flash column chromatography on silica gel
6-Methoxy-3-methyl-3-vinylindolin-2-one (21) and 4-Methoxy-3-
methyl-3-vinylindolin-2-one (21Ј): Prepared from cyclization precur-
sor 10 according to the general procedure with substrate addition
every 3 h and a total reaction time of 24 h. A mixture of regioiso-
mers was obtained (21/21Ј = 80:20). Purification and (almost quan-
titative) separation by flash column chromatography on silica gel
(cyclohexane/ethyl acetate
(23.2 mg, 67%) as a slightly yellow solid. M.p. 174.4 °C (cyclohex-
= 3:1) afforded the pure product
ane). R (cyclohexane/ethyl acetate = 2:1) = 0.27. IR (ATR): ν =
˜
f
3161 (s, N–H), 2911 (m, C–H), 1697 (s, C=O), 1614 (s, C=C) cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.56–1.58 (m, 3 H, =CCH3), 1.59
(s, 3 H, CH3), 3.76 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 5.06–5.08
(m, 1 H, =CH2), 5.08–5.09 (m, 1 H, =CH2), 6.13 (d, 4JH,H = 2.0 Hz,
1 H, HAr), 6.23 (d, 4JH,H = 2.1 Hz, 1 H, HAr), 9.51 (br. s, 1 H, NH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 19.2, 19.7, 53.9, 55.3, 55.6,
89.2, 93.1, 112.3, 112.7, 142.4, 143.0, 156.7, 161.3, 183.1 ppm.
HRMS (ESI): calcd. for C14H17NO3Na [M + Na]+ 270.1101; found
270.1097. C14H17NO3 (247.29): calcd. C 68.00, H 6.93, N 5.66;
found C 67.73, H 6.87, N 5.57.
(cyclohexane/ethyl acetate
= 3:1) afforded pure isomers 21
(11.4 mg, 40%) and 21Ј (2.8 mg, 5%) as pale yellow solids along
with mixed fractions (2.8 mg, 5%). Data for 21: M.p. 116.5–
116.8 °C (pentane). Rf (cyclohexane/ethyl acetate = 2:1) = 0.31. IR
(ATR): ν = 3156 (s, N–H), 2968 (m, C–H), 1698 (s, C=O), 1625 (s,
˜
C=C) cm–1. H NMR (400 MHz, CDCl3): δ = 1.50 (s, 3 H, CH3),
1
3
2
3.80 (s, 3 H, OCH3), 5.16 (dd, JH,H = 17.2 Hz, JH,H = 0.8 Hz, 1
3
2
H, =CH2E), 5.18 (dd, JH,H = 10.4 Hz, JH,H = 0.8 Hz, 1 H,
3
3
3-Cyclohexenyl-4,6-dimethoxy-3-methylindolin-2-one (18): Prepared
from cyclization precursor 7 according to the general procedure
with substrate addition every 2 h and a total reaction time of 96 h.
Purification by flash column chromatography on silica gel (cyclo-
hexane/ethyl acetate = 3:1) afforded the pure product (24.1 mg,
60%) as a slightly yellow solid. M.p. 181–182.5 °C (pentane). Rf
=CH2Z), 5.95 (dd, JH,H = 17.1 Hz, JH,H = 10.4 Hz, 1 H, =CH),
6.56 (d, JH,H = 2.2 Hz, 1 H, HAr), 6.59 (dd, 3JH,H = 8.2 Hz, JH,H
4
4
3
= 2.3 Hz, 1 H, HAr), 7.05 (d, JH,H = 8.2 Hz, 1 H, HAr), 8.86 (br.
s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.5, 51.3,
55.5, 97.3, 107.5, 115.3, 124.7, 125.1, 138.2, 141.3, 160.0,
182.0 ppm. HRMS (ESI): calcd. for C12H13NO2Na [M + Na]+
226.0838; found 226.0835. Data for 21Ј: M.p. 134–134.5 °C (pen-
(cyclohexane/ethyl acetate = 2:1) = 0.29. IR (ATR): ν = 3127 (s,
˜
N–H), 2919 (s, C–H), 1710 (s, C=O), 1629 (s, C=C) cm–1. 1H NMR
(300 MHz, CDCl3): δ = 1.53 (s, 3 H, CH3), 1.41–1.61 (m, 4 H,
CH2, CH2), 1.66–1.75 (m, 2 H, =CCH2), 2.05–2.17 (m, 2 H,
=CCH2), 3.75 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 5.74–5.81 (m,
tane). R (cyclohexane/ethyl acetate = 2:1) = 0.38. IR (ATR): ν =
˜
f
3165 (s, N–H), 2975 (m, C–H), 1703 (s, C=O), 1607 (s, C=C) cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.59 (s, 3 H, CH3), 3.83 (s, 3 H,
3
2
OCH3), 5.13 (dd, JH,H = 16.9 Hz, JH,H = 0.9 Hz, 1 H, =CH2E),
4
4
5.14 (dd, 3JH,H = 10.3 Hz, 2JH,H = 0.9 Hz, 1 H, =CH2Z), 5.99–6.06
1 H, =CH), 6.12 (d, JH,H = 2.1 Hz, 1 H, HAr), 6.18 (d, JH,H
=
2.0 Hz, 1 H, HAr), 8.69 (br. s, 1 H, NH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 18.9, 22.1, 22.9, 25.1, 25.5, 53.7, 55.4, 55.6, 89.1, 93.0,
112.9, 123.0, 135.1, 142.2, 156.8, 161.1, 183.2 ppm. HRMS (ESI):
calcd. for C17H21NO3Na [M + Na]+ 310.1414; found 310.1412.
3
4
(m, 1 H, =CH), 6.54 (dd, JH,H = 7.9 Hz, JH,H = 0.7 Hz, 1 H,
HAr), 6.61 (dd, JH,H = 8.5 Hz, JH,H = 0.6 Hz, 1 H, HAr), 7.19
3
4
3
3
(dd, JH,H = 7.9 Hz, JH,H = 8.4 Hz, 1 H, HAr), 7.66 (br. s, 1 H,
NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.2, 51.8, 55.3,
103.0, 105.8, 115.0, 129.4, 136.7, 140.9, 156.4, 180.5 ppm (one qua-
ternary carbon atom was not detected). HRMS (ESI): calcd. for
C12H13NO2Na [M + Na]+ 226.0838; found 226.0839.
4,5,6-Trimethoxy-3-methyl-3-vinylindolin-2-one (19): Prepared from
cyclization precursor 8 according to the general procedure with
substrate addition every 2 h and a total reaction time of 36 h. Puri-
fication by flash column chromatography on silica gel (cyclohex-
ane/ethyl acetate = 3:1) afforded the pure product (24.0 mg, 65%)
3,4,6-Trimethyl-3-vinylindolin-2-one (23): Prepared from cyclization
precursor 12 according to the general procedure with substrate ad-
1152
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1148–1154

Aerobic PdII-Catalyzed Cyclization of Highly Substituted Alkenes
[2]
[3]
B. M. Trost, M. K. Brennan, Synthesis 2009, 3003–3025 and
references cited therein.
For recent summaries, see: a) J. T. Link, C. K. Wada in The
Mizoroki–Heck Reaction (Ed.: M. Oestreich), Wiley, Chiches-
ter, 2009, pp. 433–462; b) A. B. Dounay, L. E. Overman in The
Mizoroki–Heck Reaction (Ed.: M. Oestreich), Wiley, Chiches-
ter, 2009, pp. 533–568.
For representative publications, see: a) A. Ashimori, B. Bach-
and, L. E. Overman, D. J. Poon, J. Am. Chem. Soc. 1998, 120,
6477–6487; b) A. Ashimori, B. Bachand, M. A. Calter, S. P.
Govek, L. E. Overman, D. J. Poon, J. Am. Chem. Soc. 1998,
120, 6488–6499; c) A. B. Dounay, K. Hatanaka, J. J. Kodanko,
M. Oestreich, L. E. Overman, L. A. Pfeifer, M. M. Weiss, J.
Am. Chem. Soc. 2003, 125, 6261–6271.
For a recent review, see: a) F. Bellina, R. Rossi, Chem. Rev.
2010, 110, 1082–1146; b) B. Schlummer, U. Scholz in Modern
Arylation Methods (Ed.: L. Ackermann), Wiley-VCH,
Weinheim, 2009, pp. 69–120.
For selected examples of palladium- and copper-catalyzed in-
tramolecular α-arylations, see: a) K. H. Shaughnessy, B. C.
Hamann, J. F. Hartwig, J. Org. Chem. 1998, 63, 6546–6553; b)
L. Ackermann, R. Vicente, N. Hofmann, Org. Lett. 2009, 11,
4274–4276; c) Y.-X. Jia, E. P. Kündig, Angew. Chem. 2009, 121,
1664–1667; Angew. Chem. Int. Ed. 2009, 48, 1636–1639; d) A.
Perry, R. J. K. Taylor, Chem. Commun. 2009, 3249–3251; e)
J. E. M. N. Klein, A. Perry, D. S. Pugh, R. J. K. Taylor, Org.
Lett. 2010, 12, 3446–3449.
For selected examples of enantioselective palladium-catalyzed
intramolecular α-arylations, see: a) S. Lee, J. F. Hartwig, J. Org.
Chem. 2001, 66, 3402–3415; b) E. P. Kündig, T. M. Seidel, Y.-
x. Jia, G. Bernardinelli, Angew. Chem. 2007, 119, 8636–8639;
Angew. Chem. Int. Ed. 2007, 46, 8484–8487; c) S. Würtz, C.
Lohre, R. Fröhlich, K. Bergander, F. Glorius, J. Am. Chem.
Soc. 2009, 131, 8344–8345; d) X. Luan, L. Wu, E. Drinkel, R.
Mariz, M. Gatti, R. Dorta, Org. Lett. 2010, 12, 1912–1915; e)
Y.-X. Jia, D. Katayev, G. Bernardinelli, T. M. Seidel, E. P.
Kündig, Chem. Eur. J. 2010, 16, 6300–6309.
dition every 3 h and a total reaction time of 160 h. Purification by
flash column chromatography on silica gel (cyclohexane/ethyl acet-
ate = 3:1) afforded the pure product (12.7 mg, 45%) as a white
solid. M.p. 138.5–139 °C (cyclohexane). Rf (cyclohexane/ethyl acet-
ate = 2:1) = 0.36. IR (ATR): ν = 3206 (s, N–H), 2977 (w, C–H),
˜
1718 (s, C=O), 1627 (m, C=C) cm–1. 1H NMR (400 MHz, CDCl3):
δ = 1.59 (s, 3 H, CH3), 2.23 (s, 3 H, CArCH3), 2.30 (s, 3 H, CArCH3),
[4]
3
2
5.17 (dd, JH,H = 17.3 Hz, JH,H = 0.7 Hz, 1 H, =CH2E), 5.26 (dd,
3JH,H = 10.4 Hz, JH,H = 0.7 Hz, 1 H, =CH2Z), 5.88 (dd, JH,H
=
2
3
17.2 Hz, 3JH,H = 10.3 Hz, 1 H, =CH), 6.63 (s, 1 H, HAr), 6.65 (s, 1
H, HAr), 8.63 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3):
δ = 17.9, 19.5, 21.4, 52.0, 108.5, 116.1, 125.5, 127.8, 134.9, 136.5,
138.1, 140.4, 181.4 ppm. HRMS (ESI): calcd. for C13H15NONa [M
+ Na]+ 224.1046; found 224.1045.
[5]
[6]
3,4,6-Trimethyl-3-(prop-1-en-2-yl)indolin-2-one (24): Prepared from
cyclization precursor 13 according to the general procedure with
substrate addition every 2 h and a total reaction time of 140 h.
Purification by flash column chromatography on silica gel (cyclo-
hexane/ethyl acetate = 3:1) afforded the pure product (20.5 mg,
68%) as a pale yellow solid. M.p. 131.6–132.2 °C (pentane). Rf (cy-
clohexane/ethyl acetate = 2:1) = 0.35. IR (ATR): ν = 3167 (s, N–
˜
1
H), 2981 (m, C–H), 1708 (s, C=O), 1627 (s, C=C) cm–1. H NMR
(400 MHz, CDCl3): δ = 1.48–1.52 (m, 3 H, =CCH3), 1.58 (s, 3 H,
CH3), 2.17 (s, 3 H, CArCH3), 2.30 (s, 3 H, CArCH3), 5.16–5.19 (m,
2 H, =CH2), 6.61–6.63 (m, 2 H, HAr), 8.50 (br. s, 1 H, NH) ppm.
13C NMR (100 MHz, CDCl3): δ = 17.0, 19.4, 19.7, 21.4, 54.6,
108.4, 113.8, 125.5, 128.3, 134.8, 137.9, 140.6, 142.4, 181.6 ppm.
HRMS (ESI): calcd. for C14H17NONa [M + Na]+ 238.1202; found
238.1203.
[7]
6-Dimethylamino-3-methyl-3-vinylindolin-2-one (25): Prepared from
cyclization precursor 14 according to the general procedure with
substrate addition every 2 h and a total reaction time of 16 h. Puri-
fication by flash column chromatography on silica gel (cyclohex-
ane/ethyl acetate = 3:1) afforded the pure product (11.5 mg, 38%)
as a slightly yellow solid. M.p. 114.4–114.6 °C (pentane). Rf (cyclo-
[8]
[9]
Palladium-catalyzed intramolecular C–H/C–Cl coupling: E. J.
Hennessy, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125,
12084–12085.
hexane/ethyl acetate = 2:1) = 0.24. IR (ATR): ν = 3178 (s, N–
˜
Related palladium-catalyzed protocols were developed where
alkylidene oxindoles are formed in an intramolecular C–H alk-
enylation with alkynes: a) A. Pinto, L. Neuville, P. Retailleau,
J. Zhu, Org. Lett. 2006, 8, 4927–4930; b) A. Pinto, L. Neuville,
J. Zhu, Angew. Chem. 2007, 119, 3355–3359; Angew. Chem. Int.
Ed. 2007, 46, 3291–3295; c) S. Tang, P. Peng, P. Zhong, J.-H.
Li, J. Org. Chem. 2008, 73, 5476–5480; d) T.-S. Jiang, R.-Y.
Tang, X.-G. Zhang, X.-H. Li, J.-H. Li, J. Org. Chem. 2009, 74,
8834–8837.
Oxidative palladium-catalyzed intramolecular C–H/C–N cou-
pling: a) M. Wasa, J.-Q. Yu, J. Am. Chem. Soc. 2008, 130,
14058–14059; b) T. Miura, Y. Ito, M. Murakami, Chem. Lett.
2009, 38, 328–329.
For a recent reference on palladium(II)-catalyzed C–H bond
activation, see: a) X. Chen, K. M. Engle, D.-H. Wang, J.-Q.
Yu, Angew. Chem. 2009, 121, 5196–5217; Angew. Chem. Int.
Ed. 2009, 48, 5094–5115; for a recent reference on C–H bond
activation, see: b) L. Ackermann, R. Vicente, A. R. Kapdi, An-
gew. Chem. 2009, 121, 9976–10011; Angew. Chem. Int. Ed.
2009, 48, 9792–9826.
In one recent report, the Nagasawa group described an oxidat-
ive palladium-catalyzed intramolecular C–H alkenylation with
alkenes to afford alkylidene oxindoles: a) S. Ueda, T. Okada,
H. Nagasawa, Chem. Commun. 2010, 46, 2462–2464; Neuville
and Zhu et al. published a related cyclization coupled with C–
N or C–O bond formation: b) S. Jaegli, J. Dufour, H.-l. Wei,
T. Piou, X.-H. Duan, J.-P. Vors, L. Neuville, J. Zhu, Org. Lett.
2010, 12, 4498–4501.
1
H), 2888 (s, C–H), 1699 (s, C=O), 1622 (s, C=C) cm–1. H NMR
(400 MHz, CDCl3): δ = 1.49 (s, 3 H, CH3), 2.96 (s, 6 H, NCH3),
3
2
5.16 (dd, JH,H = 10.4 Hz, JH,H = 1.0 Hz, 1 H, =CH2Z), 5.17 (dd,
3JH,H = 17.2 Hz, JH,H = 1.0 Hz, 1 H, =CH2E), 5.97 (dd, JH,H
=
2
3
3
4
17.1 Hz, JH,H = 10.5 Hz, 1 H, =CH), 6.36 (d, JH,H = 2.1 Hz, 1
3
4
H, HAr), 6.39 (dd, JH,H = 8.3, JH,H = 2.4 Hz, 1 H, HAr), 7.00 (d,
3JH,H = 8.2 Hz, 1 H, HAr), 8.74 (br. s, 1 H, NH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 22.5, 40.8, 51.2, 95.2, 106.2, 114.9, 120.7,
124.4, 138.6, 150.9, 182.3 ppm. HRMS (ESI): calcd. for
C13H16N2OH [M + H]+ 217.1335; found 217.1329. C13H16N2O
(216.28): calcd. C 72.19, H 7.46, N 12.95; found C 71.79, H 7.40,
N 12.95.
[10]
[11]
Supporting Information (see footnote on the first page of this arti-
cle): Preparation and characterization data for all cyclization pre-
1
cursors as well as H and 13C NMR spectra of all compounds.
Acknowledgments
[12]
J.A.S. thanks the Fonds der Chemischen Industrie for a predoctoral
fellowship (2008–2010). We thank Alexander Naßmacher for skill-
ful technical assistance.
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Eur. J. Org. Chem. 2011, 1148–1154
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1153

J. A. Schiffner, M. Oestreich
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Received: November 12, 2010
Published Online: January 12, 2011
1154
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Eur. J. Org. Chem. 2011, 1148–1154