Palladium(0)-Catalyzed Heck Reaction/C-H Activation/Amination Sequence with Diaziridinone: A Facile Approach to Indolines

Article abstract of DOI:10.1002/anie.201405365

Indolines are important moieties present in various biologically significant molecules and have attracted considerable attention in synthetic chemistry. This paper describes a Heck reaction/C-H activation/amination sequence for forming indolines using di-

Full text of DOI:10.1002/anie.201405365

Angewandte
Chemie
DOI: 10.1002/anie.201405365
Heterocycles
À
Palladium(0)-Catalyzed Heck Reaction/C H Activation/Amination
Sequence with Diaziridinone: A Facile Approach to Indolines**
Huaiji Zheng, Yingguang Zhu, and Yian Shi*
Abstract: Indolines are important moieties present in various
biologically significant molecules and have attracted consid-
erable attention in synthetic chemistry. This paper describes
a Heck reaction/CÀH activation/amination sequence for
Previously, we have shown that palladium(0) can readily
insert into the NÀN bond of 1, and the resulting four-
membered palladium(II) species reacts with dienes to form
[
9]
diamination products. The oxidative insertion of a palla-
forming indolines using di-tert-butyldiaziridinone. The reac-
tion process likely proceeds via a pallada(II)cycle, which is
converted into an indoline by oxidative addition to the
diaziridinone and two subsequent CÀN bond formations.
da(II)cycle into 1 is mechanistically interesting. To further
[10]
probe this process, the known pallada(II)cycle 3 was thus
[
11]
prepared and reacted with 1 (Scheme 2). The palladacycle
I
ndolines are important moieties contained in various
[1]
biologically and pharmaceutically active compounds, and
their syntheses have attracted considerable attention. The
cyclization involving replacement of a leaving group by
a nitrogen atom is among the widely used methods to
[2,3]
Scheme 2. Synthesis of the indoline 4a from the pallada(II)cycle 3.
synthesize indolines.
attractive strategy for the construction of this class of
molecules and has become an active area of research in
Direct CÀH amination presents an
was indeed smoothly transformed into the indoline 4a in 66%
[
4–6]
[12]
recent years.
yield at room temperature.
This result prompted us to
Recently, we reported that a-methylstyrene can be
efficiently transformed into spirocyclic indolines by a palla-
dium(0)-catalyzed sequential CÀN bond formation involving
allylic and aromatic CÀH amination with di-tert-butyldiazir-
investigate if the indoline could be directly formed from an
aryl halide (5), norbornene (6a), and 1 with catalytic amounts
of palladium(0) by in situ formation of 3 by a Heck reaction
and subsequent CÀH activation (Scheme 3). The key issue for
[
7]
idinone (1; Scheme 1). This reaction process likely proceeds
Scheme 1. The formation of spirocyclic indolines from a-methylstyr-
ene.
via the pallada(II)cycle A, which oxidatively inserts into the
[
8]
diaziridinone to form the pallada(IV)cycle B. Upon release
of tert-butyl isocyanate (tBuNCO), B is converted into the
spirocyclic indoline 2 through two consecutive reductive
eliminations.
Scheme 3. Proposed catalytic cycle.
[
*] Dr. H. Zheng, Dr. Y. Zhu, Prof. Dr. Y. Shi
Department of Chemistry, Colorado State University
Fort Collins, CO 80523 (USA)
such a transformation is whether the aryl halide can compete
with the diaziridinone for the oxidative addition by the
palladium(0) catalyst to initiate the catalytic cycle. Herein, we
report our preliminary studies on this subject.
E-mail: yian@lamar.colostate.edu
[
**] We are grateful for generous financial support from the General
Initial studies were carried out with p-iodoanisole (5b) as
a test substrate under various reaction conditions. As shown
in Table 1, the base had a significant effect on the reaction
efficiency. No products were isolated with K CO , Na CO ,
Medical Sciences of the National Institutes of Health (GM083944-
07).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201405365.
2
3
2
3
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[
a]
[a]
Table 1: Studies on the reaction conditions.
Table 2: Substrate scope.
[
b]
[
b]
Entry
5
4
Yield [%]
Entry Solvent
Base
CO
Catalyst
[Pd(PPh
Ligand
Yield [%]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
DMF
K
2
3
3
)
4
]
–
–
–
–
–
–
–
–
–
–
–
–
0
0
0
Na CO3 [Pd(PPh ) ]
2
3 4
Et N
[Pd(PPh ) ]
3
3 4
K3PO4
NaOtBu [Pd(PPh ) ]
[Pd(PPh ) ]
79
82
90
70
84
76
74
89
0
84
81
90
0
3
4
3
4
1
2
3
4
5
6
7
8
5a, R=H
4a
4b
4c
4d
4e
4 f
4g (X-ray)
4h
90
89
91
68
72
78
93
84
Cs CO3 [Pd(PPh ) ]
2
3 4
5b, R=OMe
5c, R=nBu
5d, R=Br
5e, R=F
5 f, R=CF3
5g, R=CO Me
Cs CO3 [Pd(PPh ) ]
2
3 4
MeCN
THF
Cs CO3 [Pd(PPh ) ]
2 3 4
Cs CO3 [Pd(PPh ) ]
2
3 4
0
1
2
3
4
5
6
1,4-dioxane Cs CO3 [Pd(PPh ) ]
2 3 4
[
c]
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
Cs CO3 [Pd(PPh ) ]
2 3 4
Cs CO3 [Pd (dba) ]
2
2
2
3
5h, R=NO2
Cs CO3 [Pd (dba) ] PPh3
2
2
3
Cs CO3 [Pd (dba) ] P(p-MeOC H )
2
2
3
6
5
3
Cs CO3 [Pd (dba) ] P(p-CF C H )
2
2
3
3
6
5
3
Cs CO3 [Pd (dba) ] binap
2
2
3
[a] All reactions were carried out with p-iodoanisole (5b; 0.30 mmol),
norbornene (6a; 0.60 mmol), di-tert-butyldiaziridinone (1; 0.45 mmol),
Pd (0.030 mmol; Pd/P=1/4), base (0.60 mmol), and solvent (0.30 mL)
at 808C under Ar for 36 h unless otherwise stated. For entry 4, the
reaction time was 72 h. [b] Yield of isolated product. [c] The reaction was
carried out with [Pd(PPh ) ] (0.015 mmol) and 1 (0.35 mmol) at 808C for
9
5i, R=OMe
4i
4j
4k
82
97
85
1
1
0
1
5j, R=CH OTBS
2
5k, R=CO Me
2
3
4
4
8 h. binap=2,2’-bis(diphenylphosphino)-1,1’-binaphthyl, dba=diben-
12
zylideneacetone, DMF=N,N-dimethylformamide, THF=tetrahydro-
furan.
5
l
4l
84
and Et N (entries 1–3). To our delight, the reaction proceeded
3
efficiently with bases such as K PO , NaOtBu, and Cs CO
3
3
4
2
(
entries 4–6). For example, treating 5b and 6a with 1.5 equiv-
alents of 1, 10 mol% [Pd(PPh ) ], and 2.0 equivalents of
3
4
[
[
[
c]
c]
c]
Cs CO in toluene at 808C gave 4b in 90% yield (entry 6).
13
5m, R=OMe
5n, R=Br
5o, R=NO2
4m
4n
4o
90
81
88
2
3
1
1
4
5
Polar solvents such as DMF, MeCN, THF, and 1,4-dioxane
gave lower yields as compared to toluene (entries 7–10). A
similar yield (89%) was obtained when the amount of
[
Pd(PPh ) ] was reduced from 10 mol% to 5 mol% (entries 6
3 4
and 11). The effect of the ligand was also briefly investigated
with [Pd (dba) ] as a catalyst (entries 12–16). No product was
2
3
[
[
c]
c]
formed with [Pd (dba) ] alone (entry 12). PPh , P(p-Me-
16
5p, R=OMe
5q, R=NO2
4p
4q
94
80
2
3
3
17
OC H ) , and P(p-CF C H ) were shown to be effective
6
5
3
3
6
5 3
ligands for the reaction, thus giving 4b in 81–90% yield
entries 13–15). However, no desired product was obtained
with binap (entry 16).
(
18
As shown in Table 2, the reaction process can be extended
to various para-, meta-, ortho-, and disubstituted iodoben-
zenes, thus giving the corresponding indoline products in 67–
5r
4r
93
67
9
7% yield (entries 1–19). The Heck reaction occurred from
1
9
the exo face of norbornene as indicated by the X-ray structure
of 4g (see the Supporting Information). For the bromo-
substituted iodobenzenes 5d and 5n, the reaction selectively
occurred at iodide to give the indolines 4d and 4n, respec-
tively, in good yields (entries 4 and 14). For meta-substituted
iodobenzenes (entries 9–12 and entry 18), the CÀH amination
5
s
4s
[
a] All reactions were carried out with the iodobenzene 5 (0.30 mmol),
norbornene (6a; 0.60 mmol), di-tert-butyldiaziridinone (1; 0.35 mmol),
Pd(PPh ) ] (0.015 mmol), Cs CO (0.60 mmol), and toluene (0.30 mL)
at 808C under Ar for 48 h unless otherwise stated. [b] Yield of isolated
product based on 5. [c] Reaction time, 72 h. TBS=tert-butyldimethylsilyl.
[
3
4
2
3
regioselectively occurred at the sterically less hindered
position. Good yields (72–96%) were also obtained for the
2
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[
13]
[a]
corresponding indolines (7–9) when 6b and the bridged
Table 3: Intramolecular process.
[
14]
olefins 6c,d were used (Figure 1). For the indoline 7b, the
reaction process is amenable to gram scale. The indoline 7b
can be converted into the N-tert-butyl indole 10 in 79% yield
[b]
Entry
12
13
Yield [%]
1
2
12a
12b
13a
13b
93
75
Figure 1. Indolines from other bridged olefins.
[
c,d]
3
4
12c
12d
13c (X-ray)
65
with SiO in xylenes by a retro-Diels–Alder reaction, and into
2
the tricyclic indoline 11 in 51% yield over three steps
involving dihydroxylation, oxidative diol cleavage, and reduc-
[
15]
tion (Scheme 4). As shown in the case of 4a, the removal of
the tert-butyl group was accomplished with CF SO H/cyclo-
[c]
13d
81
3
3
hexane, thus giving the deprotected indoline 4a’ in 76% yield
Scheme 4).
(
[
c]
5
12e
13e (X-ray)
62
[a] All reactions were carried out with the iodobenzene 12 (0.30 mmol),
di-tert-butyldiaziridine (1; 0.35 mmol), [Pd(PPh ) ] (0.015 mmol),
3
4
Cs CO (0.60 mmol), and toluene (0.30 mL) at 808C under Ar for 72 h
2
3
unless otherwise stated. [b] Yield of the isolated product based on 12.
c] Used 0.030 mmol of [Pd(PPh ) ]. [d] Reaction time, 120 h.
[
3
4
Scheme 4. Synthetic transformations of 7b and 4a. NMO=N-methyl-
morpholine N-oxide.
The intramolecular reaction process was also found to be
[16]
feasible with alkene-tethered iodobenzenes. As shown in
[
13]
Table 3, polycyclic fused indolines (13a–e)
were readily
obtained in 62–93% yield (entries 1–5). Iodobenzenes bear-
ing nonbridged 1,1-disubstituted olefins were also effective
substrates for the reaction (entries 2–5). When o-iodophenyl
allyl ethers (14) with phenyl substituents on the olefins were
subjected to the reaction conditions, the polycyclic spiroindo-
lines 15 were obtained in 71–79% yield (Scheme 5). In these
cases, the CÀH activation occurred selectively at the phenyl
Scheme 5. Synthesis of the polycyclic spiroindoline 15.
group B rather than phenyl group A to reduce the ring strain.
The pentacyclic indoline 17 was obtained in 90% yield when
the iodobenzene 16, containing an exocyclic olefin, was used
[
17]
as substrate (Scheme 6).
Scheme 6. Synthesis of the pentacyclic indoline 17.
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ÀN bond formation, see: a) J. F.
In summary, we have developed a novel palladium(0)-
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Experimental Section
Representative procedure for intermolecular process (Table 2,
entry 1): Iodobenzene (5a; 0.0612 g, 0.30 mmol), norbornene (6a;
0
0
0
.0564 g, 0.60 mmol), di-tert-butyldiaziridinone (1; 0.0595 g,
.35 mmol), [Pd(PPh ) ] (0.0173 g, 0.015 mmol), Cs CO (0.1956 g,
3
4
2
3
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(0.065 g, 90%).
3
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Received: May 17, 2014
Published online: && &&, &&&&
Keywords: CÀH activation · cyclization · heterocycles ·
.
palladium · synthetic methods
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M. A. Campo, R. C. Larock, J. Am. Chem. Soc. 2004, 126, 7460;
b) R. T. Ruck, M. A. Huffman, M. M. Kim, M. Shevlin, W. V.
Kandur, I. W. Davies, Angew. Chem. 2008, 120, 4789; Angew.
Chem. Int. Ed. 2008, 47, 4711; c) Z. Lu, C. Hu, J. Guo, J. Li, Y.
Cui, Y. Jia, Org. Lett. 2010, 12, 480.
8
175.
[
12] For leading references on indoline formation from a nickel(II)-
cycle and an azide, see: a) K. Koo, G. L. Hillhouse, Organo-
metallics 1995, 14, 4421; b) K. Koo, G. L. Hillhouse, Organo-
metallics 1996, 15, 2669.
13] The stereochemistry of 8 and 13a were tentatively assigned by
analogy to 7 and 4.
[17] Bridged and 1,1-disubstituted olefins were used to avoid the b-
hydride elimination.
[
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Heterocycles
H. Zheng, Y. Zhu, Y. Shi*
&&&& — &&&&
Palladium(0)-Catalyzed Heck Reaction/
CÀH Activation/Amination Sequence
with Diaziridinone: A Facile Approach to
Indolines
Good form: Indolines are important
moieties present in various biologically
significant molecules. Described is the
title sequence for forming indolines with
di-tert-butyldiaziridinone. The reaction
process likely proceeds via a pallada(II)-
cycle, which is converted into an indoline
by oxidative addition to the diaziridinone
and two subsequent CÀN bond forma-
tions.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!