Palladium-catalyzed selective aminoamidation and aminocyanation of alkenes using isonitrile as amide and cyanide sources

Article abstract of DOI:10.1039/c4cc07743a

A mild and efficient palladium-catalyzed intermolecular aminoamidation and aminocyanation reaction of alkenes with a broad substrate scope has been developed. This cyclization process provides a valuable synthetic tool for obtaining substituted indolines, tetrahydroisoquinolines and pyrrolidines in good to excellent yields. This journal is

Full text of DOI:10.1039/c4cc07743a

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ARTICLE TYPE
Palladium-Catalyzed Selective Aminoamidation and Aminocyanation of
Alkenes Using Isonitrile as Amide and Cyanide Sources
Hanling Gao, Bifu Liu, Wanqing Wu, Huanfeng Jiang*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
an irreplaceable role over carbon monoxide for simple operation,
an extra diversity point and possibilities for further elaboration
using convertible isocyanide.9 Therefore, it is not surprising that
large numbers of reactions with the insertion of isocyanides into
45 the CꢀPd bond have sprung up.10 Recently, we have developed
various methods for Pdꢀcatalyzed isocyanides insertion to the
synthesis of diversified amides and nitrogen heterocyclic
compounds.11 To our knowledge, isocyanides can be utilized as a
source of both carbonyl and amino group to the formation of
50 synthetically useful amide and cyano compounds.11a,12 Inspired
by our previous work11g and the related report about alkene
aminofunctionalization reaction,6b we herein report the first Pdꢀ
catalyzed aminoamidation and aminocyanation of alkenes with
isocyanide insertion to directly give 2ꢀsubstituted indolines and
55 pyrrolidines or tetrahydroisoquinolines (Scheme 1), which
function as versatile precursors of highly important building
blocks such as βꢀamino acids. On the other hand, these class of
scaffolds are embedded widely in natural products or designed
compounds with a broad range of biological activities.13
A mild and efficient palladium-catalyzed intermolecular
aminoamidation and aminocyanation of alkenes with a broad
substrate scope has been developed. This cyclization process
10 provides a valuable synthetic tool for substituted indolines,
tetrahydroisoquinolines and pyrrolidines in good to excellent
yields.
The pursuit of concise strategies for the construction of nitrogenꢀ
heterocyclic compounds continues to be a long sought after target
15 due to their wide existence in biological and medicinal chemistry.
It was an attractive and challenging area of research in organic
synthesis to get direct access to a final molecule from readily
available substrates. In addition, alkene difunctionalization
reactions are an attractive alternative means with significant
20 synthetic potential to rapidly increase molecular complexity.1
These reactions are particularly appealing and of fundamental
importance because they constituted a breakthrough in both
organic synthesis and green chemistry.2 Recently, our group has
successfully developed a series of transitionꢀmetalꢀcatalyzed
25 alkene difunctionalization reactions, such as diacetoxylation of
alkenes and dehydrogenative aminohalogenation of unactivated
alkenes etc.3 Meanwhile, alkene aminofunctionalization reactions
represent a highly versatile synthetic methods for the synthesis of
valuable nitrogenꢀcontaining heterocycles and they are studied
30 extensively as well.4
60
We began our investigation of the aminoamidation reaction
focused on Nꢀsulfonylꢀ2ꢀallylaniline (1a) with tertꢀbutyl
isocyanide (2a) as the substrates to screen the reaction conditions.
When a solution of 1a and 2a in the presence of 10 mol % of
different catalysts with Cu(OAc)2 as oxidant and NaHCO3 as the
65 base in dichloroethane at 100 oC under air, the desired product 3a
could be achieved in 48% yield along with 10% of byꢀproduct (2ꢀ
methylꢀ1ꢀtosylꢀ1Hꢀindole)14 in the presence of Pd(TFA)2 (Table
S1, entry 4; see the Supporting Information), which was superior
to any other catalysts. Then an extensive screening concerning
70 copper salts, solvents, additives and temperature revealed that the
In the past decade, prosperous development of transition metalꢀ
catalyzed aminofunctionalization reactions have emerged as a
very attractive branch of modern organic synthesis.(4g, 4h) Besides
palladium5 catalysts, copper,6 gold7 and other metals8 have also
35 been employed successfully in this catalytic reactions.
o
use of Cu(TFA)2 as oxidant in toluene at 100 C for 10 h turned
out to be the best choice and resulted in 95% yield.
With this optimized reaction conditions in hand, we then
surveyed the generality of this aminoamidation reaction (Table
75 1). With a variety of paraꢀsubstituted Nꢀsulfonylꢀ2ꢀallylanilines
as the substrates, we were pleased to find that functional groups
both electronꢀdonating (Me, OMe, iꢀPr) and electronꢀwithdrawing
groups (CN, F, Cl, Br) could react smoothly with tertꢀbutyl
isocyanide, and the corresponding 2ꢀacetamidated indolines (3aꢀ
80 3h) were obtained in good to excellent yields. Furthermore,
orthoꢀ and metaꢀsubstituted of the aromatic ring could be also
effectively generated in good yields (3i and 3j). In addition, a
Scheme 1 Aminoamidation and aminocyanation of alkenes with
isocyanide.
Isocyanides, a class of unsaturated molecules acting as
40 isoelectronic species similar to carbon monoxide, which yet play
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series of substituents on the nitrogen atom were found to be
efficiently to give the desired products 3kꢀ3r in yields ranging
from 68% to 93% under the standard conditions. Encouraged by
substrate could go smoothly in this reaction to give the
corresponding products in moderate to good yields. Furthermore,
different substituent on the nitrogen atom (4e) was also well
the aforementioned aminoamidation reaction, we extented this 40 tolerated and provide the desired product in moderate yield.
5
catalytic system to the aminoamidation of Nꢀ(2ꢀ
Table 2. Scope of the Aminocyanation of Alkenes and Isocyanide
Insertion a
allylbenzyl)methanesulfonamide and 4ꢀpentenylsulfonamides for
the synthesis of corresponding substituted tetrahydroisoquinolin
(3s) and pyrrolidines (3u-3z) in moderate to good yields. It was
noteworthy that alkenes bearing methyl group at the allylic
10 olefinic carbon atoms (1t, 1v) could not react with tertꢀbutyl
isocyanide (2a) to give the corresponding product unless
employing 2 equivalents of 2a and raising the temperature to 130
oC. Next, we turned our attention to test the reactivity of Nꢀ
sulfonylꢀ2ꢀallylaniline (1a) and 4ꢀmethylꢀNꢀ(4ꢀmethylꢀ2,2ꢀ
15 diphenylpentꢀ4ꢀenꢀ1ꢀyl)benzenesulfonamide (1v) with different
isocyanides. Alkyl isocyanides such as nꢀbutyl isocyanide,
1,1,3,3ꢀtetramethylbutylisocyanide, and cyclohexylisocyanide
(3v-3x, 3zaꢀ3zc) were found to effectively undergo insertion
whereas aromatic isocyanide was unable to provide the desired
20 product.
Table 1. Scope of the Aminoamidation of Alkenes and Isocyanide
Insertion a
Reaction conditions: all reactions were performed with 1 (0.3 mmol), 2a
45 (0.36 mmol), Pd(OAc)2 (10 mol %), TFA (0.3 mmol), Cu(OAc)2 (0.3
mmol), anhydrous toluene (2.0 mL ) at 100 oC for 10 h
Pd(TFA)2 (10 mol%),
Cu(TFA)2 (1.0 equiv),
R2
NH
R2
n
(n=0,1)
R3
n
N
O
R1
R1
N R3
+
DABCO (2 equiv),
toluene, 100 oC, 10 h
NH
To gain insight into the reaction mechanism, a control
experiment was performed as shown in Scheme 215. When Nꢀ
sulfonylꢀ2ꢀallylaniline (1a) and tertꢀbutyl isocyanide (2a) were
50 treated in anhydrous toluene in the presence of external H218O
(5.0 equiv), 3a-18O was was obtained nearly as the sole product.
This result indicated that the oxygen atom of the amide in the
product was derived from H2O.
2
1
3
Ts
N
F
Ts
Ts
3a, R = H, 95%
F
N
3b,
3c,
3d,
R = Me, 76%
R = OMe, 86%
R = i-Pr, 85%
N
NH
R
NH
NH
O
3e, R = F, 85%
3f, R = Cl, 91%
3g, R = Br, 90%
O
O
3i
, 73%
3j
, 73%
3h,
R = CN, 89%
R
N
Ts
N
Ms
H
3k, R = Ms, 93%
3l,
N
O
N
R = CH3CO, 70%
3m,
NH
N
R = PhCO, 84%
3n, R = Boc, 68%
3o,
O
H
O
3s,
72%
b
3t
, 60%
,
R = p-MeOC6H4SO2 93%
3p, R = p-CF3C6H4SO2, 92%
3q,
3r,
55
Scheme 2. Mechanistic Studies.
R = 2,4,6-tri-MeC6H4SO2, 92%
R = 2-naphthylSO2, 86%
Ts
Based on the above results and previous work16, a possible
process of this reaction was proposed in Scheme 3. The reaction
was initiated by the reaction of PdII with 1a to form the
organometallic intermediate A. Followed by aminopalladation of
60 intermediate A generates the alkylpalladium species B, which
may undergo βꢀhydride elimination to give the byꢀproduct 5 (2ꢀ
methylꢀ1ꢀtosylꢀ1Hꢀindole). Subsequent migratory insertion of 2a
H
N
Ph
Ph
N
O
Ph
Ph
R
NH
N
O
N
H
3v, R = t-Bu, 76%b
3w, R = n-Bu, 78%b
N
Ts
O
Ts
3u,
68%
b
3y
, 73%
3x, R
= cyclohexyl, 70%
Ts
N
Ts
O
N
Ms
O
NH
R
NH
N
O
N
H
3za, R = n-Bu, 89%
3zb
3zc
3zd, 90%
3z,
82%
, R = 1,1,3,3-tetramethylbutyl, 92%
, R = cyclohexyl, 90%
a Reaction conditions: all reactions were performed with 1 (0.3 mmol), 2
25 (0.36 mmol), Pd(OAc)2 (10 mol %), DABCO (0.6 mmol), Cu(OAc)2 (0.3
o
b
mmol), in toluene (2.0 mL ) at 100 C for 10 h unless otherwise noted.
Reactions were performed under 2 equivalents of 2 at 130 oC.
To
our
expectation,
the
reaction
with
of
Nꢀ(2ꢀ
1,1,3,3ꢀ
allylphenyl)methanesulfonamides
30 tetramethylbutylisocyanide proceeded very well to afford the
product (3zd) in 90% yield under the optimized conditions.
To expand the generality and scope of this tandem reaction, we
were excited to detect the aminocyanation products (Table S1,
entry 19; see the Supporting Information). Among our
35 exploration of this aminocyanation reaction, electronꢀdonating
(4b and 4c) and electronꢀwithdrawing (4d) groups of the
Scheme 3. Proposed mechanism.
2
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DOI: 10.1039/C4CC07743A
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into the alkylpalladium intermediate B to generate intermediate
C. The intermediate C might go through two pathways: a) βꢀtertꢀ
butyl elimination of intermediate C provides the product 4a
together with concomitant removal of isobutene17 and the
formation of Pd(0); b) with the assistance of the base and H2O
presented in the reaction, intermediate D was formed.
In view of the prevalence of primary amide motifs in the
natural world, we tested the possibility of forming such amides
from our initial products. According to the method reported in the
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5
10 literature,12e for example, when Nꢀ(tertꢀbutyl)ꢀ2ꢀ(1ꢀtosylindolinꢀ
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Scheme 4. Transformation of Nꢀtertꢀbutyl amides 3a.
In summary, we have demonstrated an efficient and rapid
method to the preparation of three important classes of nitrogen
20 heterocycles, 2ꢀsubstituted indolines, tetrahydroisoquinolins and
pyrrolidines from the intermolecular aminoamidation and
aminocyanation of alkenes with isocyanide insertion. This
protocol proved to be effective for a broad substrate scope in
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We are grateful to the National Natural Science Foundation of
China (21172076), the National Basic Research Program of
China (973 Program) (2011CB808600), the Guangdong Natural
Science Foundation (10351064101000000), and the Fundamental
Research Funds for the Central Universities (2014ZP0004 and
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Notes and references
School of Chemistry and Chemical Engineering, South China University
of Technology, Guangzhou 510640, China. Fax: +86 20ꢀ87112906; Tel:
+86 20ꢀ87112906; Eꢀmail: jianghf@scut.edu.cn
35 † Electronic Supplementary Information (ESI) available: Experimental
section, characterization of all compounds, copies of 1H and 13C NMR
spectra for selected compounds. See DOI: 10.1039/b000000x/
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