Synthesis of 3,3-disubstituted 2-aminoindolenines by palladium-catalyzed allylic amidination with isocyanide

Article abstract of DOI:10.1055/s-0033-1341241

Synthesis of 3,3-disubstituted 2-aminoindolenines was achieved by palladium-catalyzed allylic amidination with an isocyanide. It was found that isocyanides are effective building blocks in palladium-catalyzed allylic functionalizations, analogous to carbo

Full text of DOI:10.1055/s-0033-1341241

LETTER
▌1473
lSetyternthesis of 3,3-Disubstituted 2-Aminoindolenines by Palladium-Catalyzed
Allylic Amidination with Isocyanide
Synthesis of 3,3-Disubstituted 2-Aminoindolenines
Takeshi Nanjo, Chihiro Tsukano, Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Fax +81(75)7534569; E-mail: takemoto@pharm.kyoto-u.ac.jp
Received: 19.02.2014; Accepted after revision: 24.03.2014
Me
Abstract: Synthesis of 3,3-disubstituted 2-aminoindolenines was
achieved by palladium-catalyzed allylic amidination with an isocy-
N
N
Me
Me
Br
anide. It was found that isocyanides are effective building blocks in
palladium-catalyzed allylic functionalizations, analogous to carbon
monoxide. This approach enables the direct construction of the in-
dolenine ring along with the formation of a quaternary carbon and
the introduction of an amino substituent in one step under mild con-
ditions.
3
Cl
3
N
N
2
Me
2
N
N
Br
H
Cl
flustramine C
perophoramidine
Key words: palladium, isocyanide, allylic amidination, cycliza-
tion, indoles
O
O
H
N
HN
N
3 H
3,3-Disubstituted indole skeletons are one of the most im-
portant structures in alkaloid chemistry and are present in
a wide range of natural products and pharmaceuticals.1
Among these derivatives, 3,3-disubstituted 2-aminoindo-
lenines and 2-aminoindolines are substructures found in
biologically active natural products such as flustramine
C,2 perophoramidine,3 and quinadoline B4 (Figure 1).
These compounds are structurally complex, and much ef-
fort has been put into the synthetic study toward them.5
There are three key aspects in the synthesis of 3,3-disub-
stituted 2-aminoindolenines; (i) construction of the indole
ring, (ii) formation of the quaternary carbon at the 3-posi-
tion, and (iii) introduction of the amino substituent at the
2-position (Scheme 1). A direct, one-step method would
be an efficient approach to these structures, but to date
there have been no published reports on the direct con-
struction of 3,3-disubstituted 2-aminoindolenines.
2
N
N
O
quinadoline B
Figure 1 Bioactive 3,3-disubstituted 2-aminoindole derivatives
Our group has previously developed a synthetic method
for indole derivatives which involves the formation of a
C2–C3 bond.6 Based on this characteristic retrosynthetic
analysis, the efficient construction of various 3,3-disubsti-
tuted indole derivatives was achieved. We also applied
this strategy to the synthesis of 2-iminoindolines via
SmI2-mediated reductive cyclization of carbodiimides.6b
Although this method is an effective approach for 3,3-di-
substituted 2-aminoindolenine derivatives, stepwise intro-
R1
R2
R3
Key aspects in the synthesis
N
(i) construction of indolenine ring
(ii) formation of quaternary carbon
(iii) introduction of nitrogen substituent
R4
N
3,3-disubstituted
2-aminoindolenine
R1
N
R3
R4
R1
OCOR2
R1
N
Pd0
R3
R4
H
3
PdIILn
N
allylic
amidination
oxidative
addition
2
N
NC
C
1
2
Scheme 1 Allylic amidination for 3,3-disubstituted 2-aminoindolenine derivatives
SYNLETT 2014, 25, 1473–1477
Advanced online publication: 30.04.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1341241; Art ID: st-2014-u0140-l
© Georg Thieme Verlag Stuttgart · New York

1474
T. Nanjo et al.
LETTER
duction of the nitrogen unit and construction of the developed chemistry of carbon monoxide, which is iso-
indolenine skeleton was required, meaning a one-step electronic with an isocyanide.11 Usually, palladium-cata-
method was still needed. Herein we describe a direct and lyzed allylic functionalization reactions occur at the less
general approach for the construction of 3,3-disubstituted sterically hindered site.11a,d Our approach, however,
2-aminoindolenines by palladium-catalyzed allylic amid- would enable the formation of a quaternary carbon at the
ination with an isocyanide (Scheme 1).
more sterically hindered site under mild conditions, owing
to intramolecular cyclization. This method would also en-
able the introduction of various amino substituents at the
2-position by using a range of amines.
The reaction shown in Scheme 1 was designed to develop
the direct method. Reaction of isocyanide 1 bearing an al-
lyl ester moiety with an amine in the presence of a palla-
dium catalyst would give 3,3-disubstituted 2- To investigate the allylic amidination, we synthesized
aminoindolenine 2 via oxidative addition and allylic substrate 1a bearing an isocyanide and an allyl carbonate
amidination. Recent publications disclosed that isocya- moiety.12 Treatment of 1a with piperidine and 10 mol% of
nides are useful building blocks for multicomponent reac- Pd(PPh3)4 in toluene at room temperature afforded 2-ami-
tions (e.g., Passerini and Ugi reactions) as well as for noindolenine 2a in 18% yield (Table 1, entry 1). Using
palladium-catalyzed reactions.7–10 However, there are Pd(dba)2 and Ph3P instead of Pd(PPh3)4 increased the
only a few reports of palladium-catalyzed allylic function- yield of 2a to 35% (Table 1, entry 2). Next, several ligands
alization reactions with isocyanides, unlike the well- were screened. It was found that monodentate triarylphos-
phines were effective, and (2-furyl)3P gave the best results
in this reaction (Table 1, entries 3–6), however, the yield
of 2a was still below 50%. We assumed that the low yields
Table 1 Investigation of Reaction Conditions
were caused by high reactivity of the allyl carbonate moi-
ety in substrate 1a, thus substrate 1b bearing an allyl ace-
piperidine (2 equiv)
Pd(dba)2 (10 mol%)
ligand (20 mol%)
base (2 equiv)
Me
Me
tate moiety was used instead. As a result, the yield of the
desired product 2a increased to 55% (Table 1, entry 7).
When substrate 1a was used, additional base was not nec-
essary for this reaction, but the addition of two equivalents
of Et3N when using 1b increased the yield of 2a (Table 1,
entries 7, 8). Further optimization revealed that THF was
the best solvent (Table 1, entries 9–13). Although lower-
ing the amount of catalyst slightly decreased the yield of
2a, catalyst loadings as low as 2 mol% were sufficient for
complete conversion (Table 1, entries 14, 15).
OR
N
solvent, r.t.
N
NC
1a R = CO2Me
1b R = Ac
2a
Entry
R
Ligand
Base
Solvent
Yield (%)a
1b
2
3
4
5
6
7
8
9
CO2Me none
none
none
none
none
none
none
none
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
MeCN
DCE
18
35
15
20
36
42
55
65
19
16
30
CO2Me Ph3P
CO2Me DPPEc
CO2Me BINAPc
CO2Me (o-tolyl)3P
CO2Me (2-furyl)3P
R3R4NH (2 equiv)
R2
Pd(dba)2 (10 mol%)
P(2-furyl)3 (20 mol%)
Et3N (2 equiv)
R2
1
R
R1
NR3R4
OAc
N
2b–l
NC
THF, r.t.
Me
Ac
Ac
Ac
Ac
Ac
Ac
Ac
(2-furyl)3P
(2-furyl)3P
(2-furyl)3P
(2-furyl)3P
(2-furyl)3P
(2-furyl)3P
(2-furyl)3P
(2-furyl)3P
(2-furyl)3P
1c–f
Me
Me
N
N
N
O
10
N
N
N
11
12
13
DMF
2b (58%)
2c (50%)
2d (62%)
1,4-dioxane 71
Me
Bn
N
Me
Me
Bn
H
THF
THF
THF
73
64
63
N
NEt2
14d,e Ac
15d,f
Ac
N
N
N
Me
2e (50%)
2f (60%)
2g (13%)
a Yield of isolated product.
Me
Me
R2
R1
b Pd(PPh3)4 was used instead of Pd(dba)2.
c 10 mol % of ligand were used.
Ph
N
N
N
d The reaction was performed at 50 °C.
Me
N
N
N
e Conditions: 5 mol% of Pd(dba)2 and 10 mol% of (2-furyl)3P were
2i R1 = CF3 (45%)
2j R1 = OMe (69%)
2k R2 = Et (53%)
2l R2 = Bu (65%)
2h (N.D.)
used.
f Conditions: 2 mol% of Pd(dba)2 and 4 mol% of (2-furyl)3P were
used.
Scheme 2 Investigation of substrate scope
Synlett 2014, 25, 1473–1477
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3,3-Disubstituted 2-Aminoindolenines
1475
Next we investigated the substrate scope of the reaction the corresponding products 2i and 2j in 45% and 69%
under the optimal conditions (Scheme 2).13,14 Initially, a yields, respectively. An alkyl substituent on the olefin did
range of amines were examined as the nucleophile. The not significantly influence the yield of the products (2k
reactions of simple cyclic amines gave the desired prod- and 2l).
ucts 2b and 2c in 58% and 50% yields, respectively. Mor-
pholine could also be used in this reaction (2d). The
Next we performed the reactions using a chiral amine and
an allyl acetate 1g derived from a secondary alcohol
reaction of acyclic amines such as diethylamine and ben-
(Scheme 3). The optimal conditions were applied to the
zylmethylamine also gave good results (2e and 2f). How-
reaction using L-proline methyl ester as the nucleophile
and interestingly, the desired product 2m was obtained as
a 3:1 mixture of diastereomers at the 3-position of the in-
dolenine ring (Scheme 3, eq 1). This result indicates that
ever, using a primary amine gave a low yield of the
desired 2-aminoindolenine 2g. When N-methylaniline
was used, the desired product 2h was not obtained, prob-
ably because of the weaker nucleophilicity. Next the reac-
the configuration of the quaternary carbon was influenced
tion was performed using several isocyanides. The
by the steric effect of the nucleophile. When allyl acetate
reactions of substrates bearing trifluoromethyl and me-
1g was used, the desired product 2n was obtained as a 2:1
thoxy groups at the para position of the aromatic ring gave
mixture of olefin geometric isomers (Scheme 3, eq 2).
A plausible mechanism is shown in Scheme 4. Firstly, ox-
idative addition of allyl acetate 1b to palladium(0) gener-
Me
ates allylpalladium complex A. There are two possibilities
for the next step. One is that intramolecular isocyanide in-
OAc
Pd(dba)2 (10 mol%)
(2-furyl)3P (20 mol%)
Et3N (2 equiv)
NC
1b
Me
sertion proceeds to form intermediate B, and then C–N re-
ductive elimination regenerates the palladium(0) species
and affords the desired 2-aminoindolenine 2a (path A).
The other possibility is that nucleophilic addition to the
isocyanide, activated by the palladium(II), occurs to give
palladacycle C followed by C–C reductive elimination
(path B). Path B is analogous to the proposed catalytic cy-
cle of the palladium-catalyzed decarboxylative cycliza-
tion reaction reported by Hayashi and co-workers.11a
Considering the scope of this reaction and the nucleophi-
licity of the amine to isocyanide of intermediate A, we be-
lieve that path B is dominant.15
3
N
(1)
+
2
N
THF, r.t.
CO2Me
MeO2C
2m 44%
(dr = 3:1)
NH
Et
piperidine (2 equiv)
Pd(dba)2 (10 mol%)
(2-furyl)3P (20 mol%)
Et3N (2 equiv)
Me
Me
Et
OAc
(2)
N
THF, r.t.
NC
1g
N
2n 31%
(E/Z = 2:1)
In summary, we have developed the synthesis of 3,3-di-
substituted 2-aminoindolenine derivatives by palladium-
catalyzed allylic amidination of isocyanides. This ap-
proach enables the direct construction of an indolenine
Scheme 3 Investigation using L-proline methyl ester and an allyl ac-
etate 1g
Me
path A
PdIILn
N
Me
C–N
reductive
elimination
B
isocyanide
insertion
OAc
NC
– Pd0
N
H
1b
Me
Me
+ Pd0
N
PdIILn
oxidative
N
N
addition
C
2a
A
– Pd0
Me
N
N
H
C–C
reductive
elimination
nucleophilic
addition
PdIILn
N
path B
C
Scheme 4 Plausible mechanism of allylic amidination
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1473–1477

1476
T. Nanjo et al.
LETTER
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introduction of an amino substituent under mild condi-
tions. We are currently investigating the mechanistic de-
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asymmetric reaction.
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(12) Substrates 1a and 1b were synthesized by Suzuki coupling
of N-formyl-2-iodoaniline with vinyl boronic esters
followed by formation of the carbonate or ester and then the
isocyanide. See the Supporting Information for more detail.
(13) General Procedure for the Synthesis of 3,3-Disubstituted
2-Aminoindolenines
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
on the Innovation Area ‘Molecular Activation Directed toward
Straightforward Synthesis’ from The Ministry of Education, Cultu-
re, Sports, Science and Technology, Japan (C.T.), and JSPS Re-
search Fellowships for Young Scientists (T.N.).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
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To a stirred solution of 1 (0.1 mmol), amine (0.2 mmol), and
Et3N (0.028 mL, 0.201 mmol) in THF (2 mL) were added
Pd(dba)2 (5.8 mg, 0.0101 mmol) and (2-furyl)3P (4.6 mg,
0.0198 mmol). After stirring for 12 h at r.t., the reaction
mixture was diluted with toluene and extracted with 2 M aq
HCl. The combined extracts were basified with 2 M aq
NaOH and extracted with EtOAc. The resultant organic
layers were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The obtained residue
was purified by silica gel column chromatography (hexane–
EtOAc) to give 2.
(14) Analytical Data for 2a
A colorless block, which was recrystallized from Et2O: mp
83.0–86.0 °C. 1H NMR (500 MHz, CDCl3): δ = 7.16–7.12
(m, 2 H), 6.92 (d, 1 H, J = 7.2 Hz), 6.86 (ddd, 1 H, J1 = J2 =
6.6 Hz, J3 = 1.7 Hz), 5.90 (dd, 1 H, J1 = 17.5 Hz, J2 = 10.6
Hz), 5.35 (d, 1 H, J = 17.5 Hz), 5.22 (d, 1 H, J = 10.6 Hz),
3.71–3.63 (m, 4 H), 1.67–1.58 (m, 9 H). 13C NMR (126
MHz, CDCl3): δ = 176.2, 154.7, 140.6, 138.9, 128.1, 121.2,
120.8, 115.7, 113.6, 55.6, 47.4, 26.0, 24.3, 20.7. IR (ATR):
(8) For selected examples of indole synthesis using phenyl
isocyanide, see: (a) Kobayashi, K.; Iitsuka, D.; Fukamachi,
S.; Konishi, H. Tetrahedron 2009, 65, 7523. (b) Tokuyama,
H.; Fukuyama, T. Chem. Rec. 2002, 2, 37. (c) Fukuyama, T.;
Synlett 2014, 25, 1473–1477
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3,3-Disubstituted 2-Aminoindolenines
1477
2934, 1632, 1542, 1458, 1448 cm–1. MS–FAB: m/z = 241 [M
possible. In this case, the diastereoselectivity of 2m would
be derived from a selective reaction of one enantiomer of
racemic B and L-proline methyl ester (i.e., matched pair).
+ H]+. HRMS–FAB+: m/z calcd for C16H21N2 [M + H]+:
241.1705; found: 241.1708.
(15) As previously reported on the synthesis of amidines using
palladium catalysis and isocyanides,9g,h path A is also
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1473–1477