Pd-Catalyzed Dearomative Carboxylation of Indolylmethanol Derivatives

Article abstract of DOI:10.1021/acs.orglett.8b03337

By using a new catalytic system (PdCl₂[P(n-Bu)₃]₂ in combination with ZnEt₂), various 3-indolylmethanol derivatives were successfully carboxylated with CO₂ (1 atm) via dearomatization of the indole nucleus, affording 3-methyleneindoline-2-carboxylates. In contrast, carboxylation of 2-indolylmethanol derivatives afforded unexpected doubly carboxylated products, which are useful synthetic precursors for biologically active compounds.

Full text of DOI:10.1021/acs.orglett.8b03337

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd-Catalyzed Dearomative Carboxylation of Indolylmethanol
Derivatives
Tsuyoshi Mita,* Sho Ishii, Yuki Higuchi, and Yoshihiro Sato*
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
S
* Supporting Information
ABSTRACT: By using a new catalytic system (PdCl2[P(n-Bu)3]2 in
combination with ZnEt2), various 3-indolylmethanol derivatives were
successfully carboxylated with CO2 (1 atm) via dearomatization of the
indole nucleus, affording 3-methyleneindoline-2-carboxylates. In
contrast, carboxylation of 2-indolylmethanol derivatives afforded
unexpected doubly carboxylated products, which are useful synthetic
precursors for biologically active compounds.
earomative transformation of (4n+2)π systems has
received much attention because it allows for the direct
catalyst. Unexpectedly, carboxylation of the 2-indolylmethanol
substrates afforded doubly carboxylated products.
D
construction of three-dimensional structures from stable, planar
π-conjugated systems.1 However, the difficulty involved in
breaking the aromaticity often necessitates the use of harsh
conditions, thus limiting the widespread application of this
reaction to organic synthesis. Recently, transition-metal-
catalyzed dearomative substitution of indole derivatives2 under
mild conditions has been developed by taking advantage of the
dearomatization properties of the pyrrole moiety in the indole
nucleus. In these dearomative techniques, however, the use of
readily available indolylmethyl acetates and halides as substrates
has been very limited. The reaction generally occurs at the α-
position of the π-benzyl-Pd(II) (π-indolylmethylene-Pd(II)),
which is expected to be formed by the oxidative addition of the
substrate to Pd(0).3 To realize an unusual dearomative process,
we turned our attention to the nucleophilic allyl-Pd species,
which generally reacts at the γ-position (Figure 1).4
First, N-Boc-3-indolylmethyl acetate 1a was employed for the
dearomative carboxylation using PdCl2 (10 mol %) and
P(C6H4-p-CF3)3 (20 mol %) in DMF at 40 °C for 16 h under
a CO2 (1 atm) atmosphere (Table 1, entry 1). Note that
P(C6H4-p-CF3)3 was reported to be a suitable ligand for the
arylative carboxylation of allenes.7a However, the carboxylation
did not procced at all, and 1a was recovered quantitatively. PPh3
promoted the carboxylation slightly; however, the electron-
donating phosphine P(C6H4-p-OMe)3 promoted the dearoma-
tive carboxylation catalytically, affording 3-methyleneindoline-
2-carboxylate 3a in 22% yield along with 3-methylindole 4a in
11% yield (entry 3). We next screened several trialkylphosphine
ligands in an attempt to accelerate the oxidative addition of
acetate 1a to Pd(0). PMe3, PEt3, and P(n-Bu)3 efficiently
promoted the reaction to afford the product 3a in around 70%
yield together with 4a in around 20% yield (entries 4−6), in
which a trace amount of the aromatized compound 3a′ was also
formed. The bulky trialkylphosphines P(t-Bu)3 and PCy3
completely suppressed the carboxylation (entries 7 and 8).
Potential precursors of the Pd catalyst, such as Pd(acac)2,
Pd(OAc)2, and Pd(dba)2 exhibited similar reactivities (entries
9−11). The air-stable and readily available Pd complex
8
PdCl2[P(n-Bu)3]2 efficiently promoted the reaction, similar
to the case of in situ generation of the catalyst (entry 12).
Interestingly, the unprotected indolylmethanol 2a also under-
went the carboxylation in the presence of 3.5 equiv of ZnEt2,
affording 3a in comparable yield (entry 13). The direct use of
indolylmethanol without protection of the alcohol moiety would
be highly attractive in terms of practical application as well as
academic interest.
Figure 1. Pd-catalyzed dearomative transformations.
CO2 is a fundamental C1 source because it is abundant,
inexpensive, nontoxic, and renewable.5 However, compared to
other carbonyl compounds such as aldehydes and ketones, CO2
is much less reactive toward various nucleophiles. Therefore, the
introduction of CO2 into an aromatic system by electrophilic
dearomatization would be highly challenging in modern organic
chemistry.6 In this letter, we reveal a novel carboxylation of 3-
indolylmethanol and 2-indolylmethanol derivatives by CO2 via
dearomatization of the indole nucleus in the presence of a Pd
Having established the optimal conditions using PdCl2[P(n-
Bu)3]2, we investigated the substrate scope of this trans-
Received: October 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03337
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(81% yield) was observed when using the 5-methyl derivative
(2d). Furthermore, substituents at the 7- and 6-positions were
well tolerated under the reaction conditions (2f−2i).
Benzoindole 2j also underwent this carboxylation effectively.
The presence of acetate in the substrate was necessary;
nevertheless, dearomative carboxylation also proceeded when
Me or Ph was attached to the 2-position (1k, 1l), leading to the
formation of a quaternary carbon center adjacent to the nitrogen
atom. Product 3a could be further derivatized into synthetically
useful compounds via versatile routes by taking advantage of the
reactive exo-olefin at the 3-position (Scheme 1).7a Therefore,
this dearomative carboxylation of simple 3-indolylmethanols
would be a useful strategy for the functionalization of indoles.
Table 1. Screening of Reaction Conditions
a
yield (%)
3a + 3a′
entry substrate Pd source
ligand
(3a/3a′)
4a
b
1
2
3
1a
1a
1a
PdCl2
PdCl2
PdCl2
P(C6H4-p-CF3)3
0
0
2
11
PPh3
P(C6H4-p-
OMe)3
6 (100:0)
22 (100:0)
Scheme 1. Derivatization to 3-Substituted Indoles
4
5
6
7
8
9
10
11
12
13
1a
1a
1a
1a
1a
1a
1a
1a
1a
2a
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PMe3
PEt3
P(n-Bu)3
P(t-Bu)3
PCy3
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
74 (99:1)
78 (91:9)
76 (96:4)
0
12
24
16
0
c
d
0
0
Pd(acac)2
Pd(OAc)2
Pd(dba)2
PdCl2[P(n-Bu)3]2 (10 mol %)
PdCl2[P(n-Bu)3]2 (10 mol %)
68 (98:2)
73 (98:2)
70 (98:2)
24
27
19
22
We next investigated the carboxylation of 2-indolylmethanol
derivatives. When Boc-protected substrate 5a was subjected to
the optimal reaction conditions listed in Table 1, an unexpected
doubly carboxylated product 79 was obtained in 27% yield,
rather than the 2-methylene-3-carboxylate 8′ (Table 2). As the
76 (97:3)
e
f
77 (74 ) (96:4) 23
a
1
Yields and the 3/3′ ratios were determined by H NMR analysis
b
using 1,1,2,2-tetrachloroethane as an internal standard. 1a was
c
d
Table 2. Screening of Double Carboxylation Conditions
recovered in 93% yield. 1a was recovered in 83% yield. 1a was
recovered quantitatively. 3.5 equiv of ZnEt2 was used. Isolated yield.
e
f
formation (Figure 2). Compound 2a could be carboxylated on a
preparative scale (1 mmol) in a similar yield (69%). A variety of
3-indolylmethanol substrates bearing electron-withdrawing
groups (Cl and CN) and electron-donating groups (Me and
OMe) at the 5-position of the indole nucleus underwent the
reaction with comparable efficiency (2a−2e). The highest yield
a
yield (%)
entry
R3
substrate
7
8
9
rec 5 or 6
1
2
3
4
5
6
7
8
9
Boc
Me
MOM
PMB
Bn
Bn
Bn
Bn
Bn
5a
5b
5c
5d
5e
5e
5e
6e
6e
27
41
60
58
63 (58)
62
0
0
1
6
4
15
16
14
0
0
6
0
0
0
34
<1
16
14
9
0
6
2
b
0
c
99
21
32
de
,
42
32
20
30
de f
, ,
a
Yields were determined by 1H NMR analysis using 1,1,2,2-
tetrachloroethane as an internal standard. Isolated yields are given
b
in parentheses. The reaction was conducted under 10 atm of CO2.
c
d
e
Without PdCl2[P(n-Bu)3]2. 3.5 equiv of ZnEt2 was used. Reaction
f
time: 60 h. Reaction temp: 60 °C.
expected intermediate 8′ has an enamine structure, we
considered that the second carboxylation of a nucleophilic
enamine would proceed rapidly to furnish a doubly carboxylated
compound 7 (vide infra). Therefore, the protecting group on the
indole nitrogen was replaced with an electron-donating
substituent in order to enhance the second carboxylation
(entries 2−5). Among Me, MOM, PMB, and Bn, Bn was found
to be the most promising protecting group, affording 7e in 63%
yield (58% isolated yield). In all of these cases, a small amount of
Figure 2. Substrate scope for dearomative carboxylation. Isolated yields
1
are shown. The 3/3′ ratios were determined by H NMR analysis.
aPreparative-scale synthesis (1 mmol).
B
DOI: 10.1021/acs.orglett.8b03337
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
monocarboxylated product 8 was obtained as the side product.
Even under 10 atm pressure, the yield of the doubly carboxylated
product was not improved (entry 6). In the absence of the Pd
catalyst, the reaction did not proceed at all, indicating the
exclusion of the Friedel−Crafts-type carboxylation of the indole
nucleus (entry 7).10 In this system, the unprotected 2-
indolylmethanol 6e was somewhat inferior (entry 8), even
though the reaction temperature was increased to 60 °C (entry
9).
The substrate scope of 2-substituted indolylmethanol
derivatives was then investigated (Figure 3). The reaction
Figure 3. Substrate scope for dearomative double carboxylation.
a
1
Isolated yields are shown. Yields of 8 were determined by H NMR
analysis. bPreparative-scale synthesis (1 mmol).
Figure 4. Proposed catalytic cycle.
carboxylate VII having an enamine structure. After trans-
metalation with ZnEt2, the enamine of VIII would undergo the
second carboxylation with CO2,11 giving iminium intermediate
IX, which undergoes rearomatization, followed by hydrolysis to
give 7e. On the other hand, η1-allylethylpalladium VI′, which is
in equilibrium with another π-benzyl intermediate VI″, is
carboxylated with CO2 at the γ-position to afford the
monocarboxylated byproduct 8e.
To demonstrate the synthetic utility of the doubly
carboxylated compound 7, we investigated the transformation
of 7e to a tricyclic compound (Scheme 2). Cyclic imide 10 was
obtained in 61% yield by treatment with aqueous NH2Me
solution (40%) in a sealed tube. This unique structure can be
found in some biologically active compounds that exhibit
time depended on the substrate structure. Carboxylation of all
the substrates except 5l depicted in Figure 3 proceeded to
completion within 4 h. Preparative-scale synthesis could also be
successfully applied, and product 7e was obtained in comparable
yield (54%). Several substrates bearing electron-donating and
electron-withdrawing substituents underwent the double
carboxylation to afford the corresponding products in moderate
yields (5f−5k). Regardless of the location of the chloro
substituent (5-, 6-, and 7-positions), the products were obtained
in similar yields (5f, 5g, and 5i). When a methyl group was
introduced at the 3-position, the monocarboxylated product 8l
was exclusively obtained in moderate yield.
A plausible catalytic cycle is depicted in Figure 4. In the
carboxylation of 3-indolylmethanols, initially, the oxidative
addition of 2a to Pd(0)Ln results in the formation of η3-
allylpalladium I. Transmetalation between I and ZnEt2 would
give the nucleophilic η1-allylethylpalladium II,4 which reacts
with CO2 at the 2-position of the indole through dearomatiza-
tion. The resulting palladium carboxylate III is reduced by ZnEt2
to regenerate Pd(0)Ln, together with release of zinc carboxylate
IV. It would then be protonated upon acidic workup and
methylated with TMSCHN2, affording the desired compound
3a. 3-Methylindole 4a would be generated from intermediate II
via β-hydride elimination, followed by reductive elimination.
Similarly, 2-indolylmethyl acetate 5e oxidatively adds to
Pd(0)Ln to afford V, which is transmetalated with ZnEt2,
affording VI and VI′. The former is carboxylated at the 3-
position of the indole to afford 2-methyleneindoline-3-
Scheme 2. Derivatization to Cyclic Imide
C
DOI: 10.1021/acs.orglett.8b03337
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
histamine H1 and HDAC6 inhibitory activities.12 In addition, 7a
is known to be converted to the UV-absorbing prenostodione
core by aldol condensation, followed by E selective E1cB
elimination (Scheme 3).13
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In conclusion, we have successfully developed the first Pd-
catalyzed dearomative carboxylation of indole derivatives with
CO2. Carboxylation of 3-indolylmethanol with an unprotected
alcohol moiety afforded 3-methyleneindoline-2-carboxylates in
high yields. On the other hand, 2-indolylmethyl acetates were
converted into doubly carboxylated products. Extensive efforts
are now being undertaken toward the double carboxylation of
various other heterocycles, and the results will be reported in due
course.
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Ema, T. Catal. Sci. Technol. 2014, 4, 1482. (h) Borjesson, M.; Moragas,
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Hernandez, F.; Borjesson, M.; Moragas, T.; Martin, R. Angew. Chem.,
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ASSOCIATED CONTENT
■
S
* Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03337.
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
Tsuyoshi Mita: 0000-0002-6655-3439
Yoshihiro Sato: 0000-0003-2540-5525
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by a Grant-in-Aid for
Scientific Research (C) (No. 18K05096) and Grant-in-Aid for
Scientific Research (B) (No. 26293001) from JSPS, and by JST
ACT-C (No. JPMJCR12YM). T.M. thanks the Naito
Foundation and Takeda Science Foundation for the financial
support. Y.H. thanks JSPS for a fellowship (No. 16J03988).
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