Palladium-Catalyzed Intramolecular Arylative Carboxylation of Allenes with CO2 for the Construction of 3-Substituted Indole-2-carboxylic Acids

Article abstract of DOI:10.1021/acs.orglett.7b01055

Arylative carboxylation of allenes proceeded in an intramolecular manner to afford the corresponding β,γ-unsaturated carboxylic acids in high yields using PdCl₂/PAr₃ (Ar = C₆H₄-p-CF₃) and ZnEt₂ under 1 atm of CO₂. The intermediate of the cyclization/carboxylation sequence is thought to be a nucleophilic η¹-allylethylpalladium, which reacts with CO₂ at the γ-position of palladium. The products obtained could be efficiently converted into 3-substituted indole-2-carboxylate derivatives. One-pot synthesis of strychnocarpine, a β-carboline alkaloid, from the carboxylated product was also demonstrated.

Full text of DOI:10.1021/acs.orglett.7b01055

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Intramolecular Arylative Carboxylation of
Allenes with CO2 for the Construction of 3‑Substituted Indole-2-
carboxylic Acids
Yuki Higuchi, Tsuyoshi Mita,* and Yoshihiro Sato*
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
S
* Supporting Information
ABSTRACT: Arylative carboxylation of allenes proceeded in
an intramolecular manner to afford the corresponding β,γ-
unsaturated carboxylic acids in high yields using PdCl2/PAr3
(Ar = C6H4-p-CF3) and ZnEt2 under 1 atm of CO2. The
intermediate of the cyclization/carboxylation sequence is
thought to be a nucleophilic η1-allylethylpalladium, which
reacts with CO2 at the γ-position of palladium. The products
obtained could be efficiently converted into 3-substituted indole-2-carboxylate derivatives. One-pot synthesis of strychnocarpine,
a β-carboline alkaloid, from the carboxylated product was also demonstrated.
ndole-2-carboxylic acids and their analogues (2-carboxya-
Imides and amidines) are important structural motifs found in
many natural products and biologically active compounds
(Figure 1).1−4 Among these, 3-substituted derivatives are
especially important because the biological activities are mainly
attributed to the chain structure of the 3-substituent1 and
because several naturally occurring substances have an additional
six-membered heterocyclic ring attached at both of the 2,3-
positions (e.g., strychnocarpine,3 rutaecarpine,4 etc.). Thus,
development of concise and robust synthetic protocols to access
3-substituted indole-2-carboxylic acids using a readily available
starting material is highly desirable.
Utilization of gaseous CO2 for the construction of carboxylic
acid derivatives via C−C bond formation has recently received
considerable attention because CO2 is an abundant, relatively
nontoxic, and inexpensive C1 source.5 These advanced
technologies have expanded to carboxylation of indole nucleus
with CO2. Although indole-3-carboxylic acid derivatives can be
Figure 2. Our strategy for the construction of 3-substituted indole-2-
carboxylic acids.
synthesized in the presence of a Lewis acid or a Brønsted base
with/without a catalyst under a CO2 atmosphere,6 fewer
independently reported transition-metal-catalyzed carboxyla-
examples of the preparation of indole-2-carboxylic acids have
tions of 2-indole boronic acid derivatives as one of the
been reported,7 probably because electrophilic aromatic
substitution of the indole nucleus usually occurs at the 3-
position. Recently, the Iwasawa and Hou research groups
substrates,8 but the substrate scope did not cover any 3-
substituted 2-borylindoles. We disclose herein a new catalytic
method for the synthesis of 3-substituted indole-2-carboxylic
acids using nucleophilic allylpalladium species.
We recently reported palladium-catalyzed carboxylation of
allylic alcohols9 and vinylcyclopropanes10 in the presence of
ZnEt2 under 1 atm of CO2 (Figure 2, eq 1). η1-Allylethylpalla-
dium A appears to be formed as an intermediate by reaction of
the generated π-allylpalladium with ZnEt2,11,12 and the
nucleophilic species A reacts with CO2 at the γ-position. We
Received: April 7, 2017
Figure 1. 3-Substituted indole-2-carboxylate skeletons.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01055
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Condition Screening
a
yield (%)
entry
Pd source
ligand
solvent
2a 3a
1
2
3
4
5
6
7
8
9
10
PdCl2
PPh3
THF
THF
THF
THF
THF
THF
THF
dioxane
DMF
DMA
DMA
44 (42)
42
53
41
19
32
34
27
27
22
8
PdCl2
P(C6H4-p-OMe)3
P(C6H4-p-CF3)3
P(2-furyl)3
Figure 4. Carboxylation of 3-indolylmethyl acetate 4.
PdCl2
78
PdCl2
64
Pd(OAc)2
Pd(dba)2
Pd(acac)2
PdCl2
P(C6H4-p-CF3)3
P(C6H4-p-CF3)3
P(C6H4-p-CF3)3
P(C6H4-p-CF3)3
P(C6H4-p-CF3)3
P(C6H4-p-CF3)3
P(C6H4-p-CF3)3
54
26
50
70
PdCl2
81
PdCl2
89 (86)
7
b
c
11
PdCl2
(84)
ND
a
Yields determined by 1H NMR analysis using 1,1,2,2-tetrachloro-
ethane as an internal standard. Isolated yields are given in parentheses.
b
With 6 mmol of 1a in the presence of PdCl2 (1 mol %) and P(C6H4-
c
p-CF3)3 (2 mol %). Product was isolated as carboxylic acid 2a‴. Not
determined.
Figure 5. Plausible catalytic cycle.
bond-forming process between aryl halides and allenes followed
by carboxylation with CO2.16 Furthermore, the exo-olefin at the
3-position of the product appears to be reactive, and it can be
further functionalized by several methods along with aromatiza-
tion, furnishing the desired 3-substituted indole-2-carboxylic acid
derivatives.
First, we investigated the intramolecular arylative carbox-
ylation of N-allenyl-2-iodoaniline 1a using various palladium
sources and ligands in the presence of ZnEt2 at room
temperature under a CO2 atmosphere (1 atm). Substrate 1a
was readily prepared in three steps from 2-iodoaniline.17 Yields
were determined after methyl esterification with TMSCHN2
(Table 1). According to previously established conditions,9
PdCl2 (10 mol %) with PPh3 (20 mol %) was employed as a
catalyst, and the expected carboxylated compound 2a was
obtained in 44% yield with 3-methylindole 3a in 53% yield (entry
1). Regioselectivity was perfect, and regioisomer 2a′ was not
observed at all. Aromatized product 2a″ was not detected even
under basic conditions using ZnEt2. Next, several phosphine
ligands were screened using PdCl2 as a palladium source.
Although the use of P(C6H4-p-OMe)3 resulted in a similar
outcome (entry 2), the use of electron-deficient phosphines such
as P(C6H4-p-CF3)3 and P(2-furyl)3 led to improvement of the
product yield (entries 3 and 4). The trials for other Pd sources
such as Pd(OAc)2, Pd(dba)2, and Pd(acac)2 with P(C6H4-p-
CF3)3 did not improve the yield of 2a (entries 5−7). Among the
potential polar solvents examined, use of DMA afforded product
2a in 89% yield (86% isolated yield; entries 8−10).
Carboxylation could be performed at gram scale (6.0 mmol,
2.14 g) without esterification with TMSCHN2, affording
carboxylic acid 2a‴ in high yield (84%, 1.39 g) using lower
a
Figure 3. Substrate scope. Isolated yields are shown. Product 2k was
partially isomerized into methyl 3-methylbenzofuran-2-carboxylate
(2k″) (17% yield). These two products were separable by standard
b
silica gel column chromatography. ZnEt2 was added using a syringe
pump over 8 h, and the reaction mixture was stirred for an additional 8 h.
next focused on the use of N-allenyl-2-iodoanilines, which are
known to undergo carbopalladation of the allene moiety
intramolecularly, forming the corresponding π-allylpalladium
species. This species has been reported to be trapped by a series
of nucleophiles, including malonate and their derivatives, amines,
acetate, and fluoride.13 However, when ZnEt2 is present, the
polarity of the allylpalladium would be changed to nucleophilic
(eq 2). If species B has sufficient nucleophilicity toward CO2 at
the γ-position (2-position of the indole ring), 3-methyleneindo-
line-2-carboxylates would be formed. We anticipated the
capability of this dearomatization process because the resonance
stabilization of the pyrrole part of the indole nucleus is relatively
weak.14,15 In another important aspect, this transformation
would be the first example of a transition-metal-catalyzed C−C
B
DOI: 10.1021/acs.orglett.7b01055
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Organic Letters
Letter
Figure 6. Derivatization of 2a into 3-substituted indole-2-carboxylates and 3-oxindole-2-carboxylate.
loading of PdCl2 (1 mol %) and P(C6H4-p-CF3)3 (2 mol %)
(entry 11).17
the avoidance of steric interaction between the ligands binding to
the palladium atom and the indole nucleus. Intermediate D
would then attack CO2 at the γ-position to afford carboxylated
product 2a,9,10,12 while β-hydride elimination of an ethyl ligand
of D followed by reductive elimination led to the formation of 3a.
On the basis on the above experimental data, a plausible
catalytic cycle is proposed in Figure 5. First, oxidative addition of
1a to Pd(0)Ln followed by insertion of the allene moiety results
in formation of η3-allylpalladium II. Transmetalation between II
and ZnEt2 then proceeds to give the nucleophilic η1-
allylethylpalladium III, which reacts with CO2 at the 2-position
of the indole skeleton through dearomatization. The resulting
palladium carboxylate IV could be reduced by ZnEt2 to
regenerate Pd(0)Ln with the release of zinc carboxylate V. It
would then be protonated during workup and methylated with
TMSCHN2, affording desired compound 2a. 3-Methylindole 3a
would be generated from intermediate III.
To demonstrate the synthetic utility of this carboxylation, we
investigated the derivatization of 2a into 3-substituted indole-2-
carboxylates by taking advantage of the reactive exo-olefin at the
3-position of 2a (Figure 6).20 First, DBU-promoted isomer-
ization of 2a proceeded quantitatively to give 3-methylindole
2a″. When epoxidation of 2a with DMDO was conducted, 3-
indolylmethanol 5 was obtained in excellent yield via an epoxide
opening/aromatization sequence. By using the
Zn4(OCOCF3)6O/DMAP system,21 5 could be converted into
furoindolone 6, which is a known intermediate for the synthesis
of carbazole alkaloids (e.g., clausamine E and furanoclausamine
B).22 Halogenation with NBS and NIS23 resulted in the
introduction of a bromo and an iodo group, respectively, at the
benzylic position of 3-substituted indoles, affording 7 (X = Br)
and 8 (X = I). In addition, a one-pot process involving the
bromination and addition of nucleophiles such as H2NBn and
KCN23 proceeded, and corresponding products 9 and 10 were
obtained in good to high yields. Moreover, 2a was heated at 80
°C in the presence of N,N-dimethylmethyleneiminium chlor-
ide24 to form N,N-dimethyltryptamine derivative 11 in 95%
yield. C−C bond formation by Heck reactions of the exo-olefin in
2a using electron-neutral, -deficient, and -rich aryldiazonium
salts25 proceeded efficiently to afford the arylated products 12−
With the optimized conditions in hand, substrate scope and
limitations were investigated. As summarized in Figure 3, a
variety of N-allenyl-2-iodoaniline derivatives bearing electron-
withdrawing groups (F, Cl, Br, CF3, and CN) and electron-
donating groups (Me and OMe) on the aromatic ring (1b−j)
could be converted into the corresponding 3-methyleneindoline-
2-carboxylates 2b−j in high yields. Notably, aryl bromide (1d),
which potentially reacts with Pd(0) species,18 was tolerated
during the palladium-catalyzed process. Note that the cyano
group (1f), which is incompatible in the strong base-mediated
carboxylation,7 remained intact. Moreover, the linker structure
between the aromatic ring and the allene moiety was examined,
showing that O-allenyl-2-iodophenol 1k had high reactivity, and
carboxylated products 2k and 2k″ were obtained in 84%
combined yield. The cyclization/carboxylation sequence could
also provide access to 6-membered heterocyclic compounds,
tetrahydroquinoline 2l and tetrahydroisoquinoline 2m, in good
yields.
This arylative carboxylation of allenes is thought to proceed via
the nucleophilic allylethylpalladium intermediate B, as depicted
in eq 2 (Figure 2). To gain a mechanistic insight, we conducted
carboxylation of 3-indolylmethyl acetate 4, which is highly
possible to be converted into η3-allylpalladium intermediate C by
oxidative addition to Pd(0)Ln (Figure 4).19 Although an
electron-deficient phosphine, P(C6H4-p-CF3)3, did not promote
the reaction, probably due to the retardation of oxidative
addition, PPh3 moderately promoted the carboxylation at 60 °C,
affording 2-carboxylated compound 2a in 25% yield with 3a in
20% yield (2a/3a = 56:44) without generation of regioisomeric
carboxylate 2a′. When N-allenyl-2-iodoaniline 1a was subjected
to the same reaction conditions, 2a and 3a were obtained in 57
and 40% yields (2a/3a = 59:41), respectively. The same profiles
between two reactions (similar ratio of 2a and 3a and no
formation of 2a′) strongly indicate that both carboxylations went
through the same allylpalladium species: η1-allylethylpalladium
D was eventually produced via transmetalation of η3-allylpalla-
dium C (X = OAc or I) with ZnEt2. The palladium atom should
be located at the terminal carbon (the benzylic position) due to
C
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01055.
■
S
Experimental details and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: tmita@pharm.hokudai.ac.jp.
*E-mail: biyo@pharm.hokudai.ac.jp.
ORCID
Yoshihiro Sato: 0000-0003-2540-5525
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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This work was financially supported by Grant-in-Aid for
Scientific Research (C) (No. 26410108), Grant-in-Aid for
Scientific Research (B) (No. 26293001) from JSPS, and also
by JST ACT-C (No. JPMJCR12YM). Y.H. thanks JSPS for a
fellowship (No. 16J03988).
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