Two-in-One Strategy for Palladium-Catalyzed C?H Functionalization in Water

Article abstract of DOI:10.1002/anie.201813391

Transition metal catalyzed C?H functionalizations have been developed as powerful methods for C?C bond formations. Directing groups, removable directing groups, traceless directing groups, and transient directing groups (TDGs) have been successfully used to improve the reaction efficiencies. For the development of greener and more sustainable methods, C?H functionalization using a TDG that also serves as a reagent in aqueous solvent was investigated. The palladium-catalyzed C?H functionalization of tryptamine derivatives using ketones in water successfully generated tetrahydro-β-carbolines with a quaternary carbon center at C1. Deuterium-labeling experiments are discussed to provide insight into the mechanism. The C2-position of pyridine was also successfully functionalized by this strategy.

Full text of DOI:10.1002/anie.201813391

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: “Two-in-One” Strategy for Palladium-Catalyzed C–H
Functionalization in Water
Authors: Huiying Zeng, Wang Zemin, and Chao-Jun Li
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201813391
Angew. Chem. 10.1002/ange.201813391
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10.1002/anie.201813391
Angewandte Chemie International Edition
COMMUNICATION
“Two-in-One”
Strategy
for
Palladium-Catalyzed
C–H
Functionalization in Water
Huiying Zeng,[a],* Zemin Wang[a] and Chao-Jun Li[a],[b],*
Directing
directed C H functionalization
(DG)
group
(a)
(b)
Abstract: Transition metal-catalyzed C–H functionalizations have
been developed as powerful methods for C–C bond formations.
Directing group, removable directing group, traceless directing group
and transient directing group (TDG) were successively used to
improve the efficiency. For further development of greener and more
sustainable methods, it is highly desirable to develop C–H
functionalization in which the TDG also plays the role of reagent
reacting with the activated C–H position to avoid separating the extra
reversibly linked directing group, especially in aqueous solvent.
Towards this endeavor, herein, palladium-catalyzed C–H
functionalization of tryptamine derivatives in water for synthesizing
tetrahydro-β-carbolines is reported. Various tryptamine derivatives
and ketones reacted successfully to generate tetrahydro-β-carbolines,
including quaternary carbon at C-1 position. Deuterium labeling
experiments were also carried out to understand the mechanism. The
C-2 position of pyridine was also successfully functionalized by this
−
−
M
Cat.
or
X
formation
C C
C
H
R
M
DG
directed C H functionalization
DG
Tracless directing
DG
−
group
−
−
M
Cat.
or
H
C C
X
C formation
M
R
removal
DG
DG
DG
H
−
Transient directing
H
directed C H functionalization
group
(c)
(TDG)
H
M
Cat.
R
−
−
TDG
or
C
formation
X
formation
removal
C C
TDG
FG
FG
auto
TDG
−
"
work
" strategy
H
Two-in-one
for C
functionalization
This
(
(d)
)
R2
O
H2N
N
N
strategy
.
R1
[Pd]
R2
R1 R2
H
Pd
R1
N
H
water
N
N
−
H
Transition-metal catalyzed C–H functionalization has become a
powerful tool to form C–C bonds and C–X bonds over the past
decade,[1] which has enabled more efficient chemical synthesis by
avoiding the traditional requirement of preinstalled functional
handles such as halide, triflate, boron or zinc reagents etc. As only
minute difference in reactivity exists between various C–H bonds,
regioselective activation of these C–H bonds constitutes a great
challenge. To solve such a problem, directing group can help to
direct the catalyst to activate proximal C–H bonds via
cyclometallated intermediates. However, the directing group
needs to be pre-installed in the substrate and, upon finishing its
mission, it is usually hard to remove from the product (Scheme
1a). Therefore, removable or traceless directing group has been
developed to overcome the above challenges.[2] These directing
groups can be removed with further manipulation or in the same
reaction vessel (Scheme 1b). However, stoichiometric removable
or traceless directing groups are generally required. More recently,
to overcome these shortcomings, transient directing groups were
developed by adding catalytic amount of reversibly linked
directing group (Scheme 1c).[3] For greener and more atom-
economical transformations, as well as considering the difficulty
to separate the reversibly linked directing group from product, the
development of a “two-in-one” strategy for
H
TDG
H activation
C
formation
TDG is
reaction
reagent
♦
♦
♦
♦
used as
TDG is aslo
reactive
TDG
group
in
need remove
No
No
to
product)
reversible
linked
(included
NH
need
for additional
solvent
group
R2
Aqueous
N
R1
H
Scheme 1. Representative strategies of C–H bond functionalization.
C–H functionalization in which the transient directing group is
also used as a reagent to react with the activated C–H bond is
highly attractive.
On the other hand, tetrahydro-β-carboline skeleton bearing a
quaternary carbon at C-1 position is an important framework in
natural products and pharmaceutical agents (Figure 1). Examples
include Komavine (1) (and Acetylkomavine)[4], Spiroindolone (2)[5],
Tabertinggine (3)[6], Peharmaline A (4)[7], Subincanadine B (5)[8]
and antimalarial drug NITD609 (6)[9]. Herein, based on the “two-
in-one” strategy, we report a palladium-catalyzed C–H bond
activation at the C-2 position of
Cl
NH
NH
NH
F
N
N
N
Cl
H
O
N
H
H
H
O
N
H
[a]
[b]
Prof. Dr. H. Zeng, Z. Wang and Prof. Dr. C.-J. Li
The State Key Laboratory of Applied Organic Chemistry
Lanzhou University
222 Tianshui Road, Lanzhou, 730000, P. R. China
E-mail: zenghy@lzu.edu.cn; cj.li@mcgill.ca
Prof. Dr. C.-J. Li
Department of Chemistry and FQRNT Centre for Green Chemistry
and Catalysis
McGill University
2:
1: Komavine
3: NITD609
Spiroindolone
NH
N
N
N
O
N
N
H
H
O
N
N
Me
HO
MeO
H
Me
Me
O
4: Tabertinggine
5: Peharmaline A
6:
B
Subincanadine
801 Sherbrooke St. West, Montreal, Quebec H3A 0B8, Canada
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Figure 1. Representative natural products and bioactive molecules with a
tetrahydro-β-carboline skeleton bearing a quaternary carbon at C-1 position.
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10.1002/anie.201813391
Angewandte Chemie International Edition
COMMUNICATION
indole and pyridine in water followed by cyclization with a transient
directing group (imine group) to form the C–C bond, in which the
transient directing group is subsequently integrated into the
product (Scheme 1d). Various tetrahydro-β-carbolines bearing
quaternary carbon at C-1 position, including natural products
Komavine (1) and Spiroindolone (2), are generated by this
method.
sodium formate were tested, and the yield was not increased
(Table 1, entries 15-16). Considering that the Pd(OH)2 could also
play the role of Lewis acid to catalyze the classical Pictet-
Spengler reaction[10], control experiments were performed: in
absence of either HCO2Na or Pd(OH)2, 9a was not detected even
after prolonging the reaction time to 72 h (Table 1, entries 17-18).
This result illustrated that the reaction did not proceed via the
Pictet-Spengler process. For details of studies on the reaction
solvent and others, please see Supporting Information.
With the optimized reaction conditions in hand, we next
proceeded to explore different ketones to react with tryptamine at
100 ºC under an argon atmosphere using 10 mol% of Pd(OH)2/C
as the catalyst and 3.0 equiv of sodium formate in water (1 mL)
for 6 h (Table 2). While cyclopentaone gave the spiro-product 9a
in excellent yield (90%), further increasing the
Our initial efforts were focused on the optimization of reaction
conditions for the C–H bond functionalization of tryptamine (7a)
with cyclopentanone (8a). When these reagents were explored
using 5 equiv of sodium formate with Pd/C as a catalyst in water
at 100 ºC under an argon atmosphere for 24 h, moderate yield
(50%) of spiro-product 9a was obtained (Table 1, entry 1).
Encouraged by this result, different palladium catalysts were
tested (Table 1, entries 2-6), and the best yield (80%) was obtaind
when Pd(OH)2/C was used as the catalyst (Table 1, entry 6).
Without the active carbon support, the yield (39%) was lowered
significantly (Table 1, entry 5). Reducing the amount of sodium
formate to 3 equiv, 9a was obtained with a similar yield (Table 1,
entry 7). Further reducing the amount of sodium formate to 2
equiv reduced the yield (Table 1, entry 8). Shortening the reaction
time to 6 h had no significant effect on the yield (Table 1, entries
9-10). The best yield (93%) was obtained when increasing the
amount of ketone to 3 equiv (Table 1, entry 11). Lowering the
amount of catalyst to 5 mol% decreased the yield (87%) slightly
(Table 1, entry 12). Both elevating and lowering the reaction
temperature reduced the yield (Table 1, entries 13-14). Other
metal formates instead of
Table 2. C–H bond functionalization of tryptamine with various ketones[a]
NH2
+
NH
R2
/C
mol%)
equiv)
O
Pd(OH)2 (10
HCO Na
(3.0
2
R1 R2
R1
N
N
°
H
100
6 h
C,
2O,
H
H
7a
8
9
NH
NH
NH
N
H
N
H
N
H
[c,d]
9a
9b 74%[b]
NH
9c
9f
90%
46%
NH
NH
Table 1. Evaluation of various conditions[a]
N
H
N
H
N
H
O
NH2
+
O
NH
2Na
HCO
100
[Pd],
O
9d
9e
dr=5:1
NH
91%
88%
80%,
°
N
H
C
N
H
9a
2O,
H
7a
8a
NH
NH
Ketone
[mmol]
HCO2Na
[mmol]
Time
[h]
9a[b]
[%]
Entry
Catalyst
Pd/C
N
N
N
H
H
H
NBoc
O
1
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
1.0
1.0
1.0
1.0
1.0
1.0
0.6
0.4
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
-
24
24
24
24
24
24
24
24
12
6
50
trace
55
[b]
9g
9h
9i
90%
80%
67%
2
Pd(PPh3)4
PdCl2
3
NH
NH
4
Pd(OAc)2
Pd(OH)2
37
OMe
10
5
39
N
N
H
H
6
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
-
80
9k
scale:
90%
84%,
85%[d]
7
80
9j
30h
N
gram
8
44
O
9
79
Et
CO2
NH
10
11
12[c]
13[d]
14[e]
15[f]
16[g]
17
18
78
6
93(90)
87
N
H
N
H
6
9l
4h
10
72h
N
82%,
65%,
6
85
O
NH
6
39
6
84
N
6
80
N
H
H
Et
CO2
72
72
0
9m
4h,
11
dr=4:1
72h
61%,
44%,
0.6
0
[a] Reaction conditions: 7a (0.2 mmol), 8 (0.6 mmol), Pd(OH)2/C (10 mol%), and
HCO2Na (0.6 mmol) in water (1 mL) under an argon atmosphere at 100 ºC for
6 h; yields of isolated products. [b] 15 mol% Pd(OH)2/C. [c] 20 mol% Pd(OH)2/C.
[d] 24 h.
[a] General conditions: Tryptamine 7a (0.2 mmol), [Pd] (10 mol%), H2O (1 mL)
at 100 ºC under an argon atmosphere. [b] Yields were determined by 1H NMR
with nitromethane as internal standard; isolated yields in brackets. [c] 5 mol%
Pd(OH)2/C. [d] 80 ºC. [e] 120 ºC. [f] HCO2Li·H2O was used instead of HCO2Na.
[g] HCO2K was used instead of HCO2Na.
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10.1002/anie.201813391
Angewandte Chemie International Edition
COMMUNICATION
ring size of cycloketone lowered the yields of corresponding
products 9b-c consecutively possibly due to the increased
steric hindrance. When 4-methylcyclohexanone was used as
a substrate, the cyclization product 9d was obtained in high
yield with a moderate diastereomeric ratio (Table 2, 9d). With
cyclohexanone bearing a bulky tert-butyl substituent on the
C-4 position, a single diastereoisomer was isolated in
excellent yield (Table 2, 9e). Ketal was also tolerated in this
system (Table 2, 9f). Heterocyclic ketones reacted smoothly
with tryptamine in good to high yields (Table 2, 9g-h). Linear
ketone was also explored and cyclization products 9i-k were
formed with excellent results. To test the scaling-up ability of
the reaction, compound 9k was synthesized on gram scale
in 84% yield when prolonging the reaction to 30 h.
Bifunctional δ-ketoester substrates were also investigated,
We subsequently investigated the generality of the system
with a wide range of substituted tryptamines (Table 3).
Tryptamines bearing electron-donating group at different
positions of the phenyl ring reacted smoothly to give the
corresponding cyclization products (Table 3, 9n-p). Good
yields were also obtained with substrates bearing the
corresponding electron-withdrawing substituents (Table 3,
9q-r) and having alkyl substitutions at the C-1 position of the
chain (Table 3, 9s-t). When methyl tryptophanate
hydrochloride was used as substrate, the spiro-product 9u
was obtained without ester-amide exchange (Table 3, 9u).
Remarkably, tryptophanol reacted smoothly to give the
corresponding product 9v in excellent yield without
hemiaminal
ether
product.
Moreover,
various
tryptophanamide derivatives also reacted with excellent
yields in this system (Table 3, 9w-y).
and good to high yields of C–H functionalization products 9l
and 9m were obtained in 4 h. Prolonging the reaction time to
72 h gave further intramolecular fused-ring amidation
products 10 and bridged-ring amide 11, respectively (Table
2, 10 and 11).
To illustrate synthetic applications of this C-H
functionalization strategy, natural products Komavine (
1) and
Spiroindolone ( ) were synthesized under standard reaction
2
conditions in excellent yields (91% and 85%, respectively) in
water by reacting tryptamine with cyclohexanone and Isatin,
respectively (Scheme 2a and 2b).
Table 3. C–H bond functionalisation of tryptamine derivatives with
cyclopentanone[a]
R2
NH
O
R2
NH2
+
NH
/C
mol%)
equiv)
Pd(OH)2 (10
HCO Na
(3.0
(a)
2
O
/C
mol%)
equiv)
Pd(OH)2 (10
N
H
NH2
+
N
H
°
H
100
6 h
C,
2O,
HCO Na
R1
(3.0
2
R1
°
7a
Komavine
1
91%
N
H
Cyclohexanone
( )
H
2O,
100
6 h
C,
N
H
O
2/C
mol%)
(10
(3.0
7
8a
9
NH2
Pd(OH)
HCO Na
NH
equiv)
2
(b)
O
+
°
H
2O,
100
6 h
N
N
H
C,
N
H
O
H
N
NH
H
NH
MeO
NH
7a
Isatin
2
85%
Spiroindolone
( )
N
Scheme 2. Synthesizing natural products via the C–H functionalization strategy.
N
H
N
H
H
[b]
[b,c]
9n 77%
9o
9p
70%
53%
To further understand the mechanism of this catalytic
reaction, deuterium labeling experiments were carried out.
As shown in Scheme 3, tryptamine (7a) and 3 equiv of
cyclopentanone (8a) were explored under standard reaction
conditions using deuterium oxide instead of water as solvent.
Even though the reaction was run for a very short time (1
min), imine 12 was obtained in 87% yield with ca. 45%
deuteration at the C-2 position of indole ring, together with 2%
yield of cyclization product 9a (Scheme 3a). Considering
amine can also coordinate with palladium catalyst, control
NH
NH
MeO2C
NH
N
N
N
MeO2C
9q
H
H
H
[d]
9r
9s
95%
55%
65%
OH
NH
Me
CO2
NH
NH
experiment
for
the
deuterium
reaction
without
cyclopentanone (8a) was also performed (Scheme 3b), and
the C-2 position of indole ring was only deuterated in 24%.
The results indicated that the imine group is a more effective
ligand than amine group, to coordinate with palladium
catalyst to accelerate the deuteration at C-2 position of the
indole ring. To further corroborate this rationale, 3-
methylindole (13) without coordination site in the chain was
also tested, and only 5% C-2 deuteration was observed
(Scheme 3c). These results illustrated that the intermediate
N
H
N
N
H
H
[e]
9t
9u
9v
95%
75%
97%
N
O
O
O
N
NH
Ph
Ph
NH
NH
NH
N
N
N
H
H
H
[f]
9w
9x
9y
96%
91%
87%
imine functioned as
a
transient directing group and
accelerated the C
indole ring.
–H bond activation of C-2 position on
[a] Reaction conditions: 7 (0.2 mmol), 8a (0.6 mmol), Pd(OH)2/C (10 mol%), and
HCO2Na (0.6 mmol) in water (1 mL) under an argon atmosphere at 100 ºC for
6 h; yields of isolated products were given. [b] 15 mol% Pd(OH)2/C. [c] 10 h. [d]
4 h. [e] HCO2Na (20 equiv) and methyl tryptophanate hydrochloride was used.
[f] 20 mol% Pd(OH)2/C.
This article is protected by copyright. All rights reserved.

10.1002/anie.201813391
Angewandte Chemie International Edition
COMMUNICATION
eq)
Cyclopentanone (3
/C mol%)
reacted successfully with compound 14 to give the corresponding
annulation products 15b-c. Ketal group and hetero-ring were
tolerated in this catalytic system, affording annulation products
15d-e. Compound 15f was generated smoothly by reacting with
acetone.
Pd(OH)2 (5
NH2
N
(a)
HCO Na
eq)
(3
2
H
D
45%
D2
1 min
O
N
(0.25mL)
N
H
°
H
100
C
,
7a
12,
87%
yield
/C mol%)
Pd(OH)2 (5
HCO Na
NH2
NH2
Table 4. C–H bond functionalization of 1-(6-(4-Methoxyphenyl)pyridin-3-
eq)
(3
2
H
yl)propan-2-amine with ketones[a]
D
24%
(b)
(c)
D2
1 min
O
(0.25mL)
N
N
°
/C
mol%)
equiv)
100
C
,
Pd(OH)2 (20
H
H
O
HCO Na
(3.0
2
7a
7a
NH
R1 R2
15
NH3
Ar
Ar
N
R1 R2
Ar
N
/C mol%)
Pd(OH)2 (5
H
2O/benzene
100 o 12h
HCO Na
eq)
(3
2
C,
14
2
H
Ar=4-methoxyphenyl
D
5%
D2
1 min
O
(0.25mL)
N
N
H
13
°
100
C
,
H
13
NH
NH
NH
Ar
N
Ar
Ar
N
N
Scheme 3. Deuterium labelling experiments
Based on these results, a tentative mechanism is proposed in
Figure 2: the HPdIIH species is generated from palladium and
sodium formate in water.[11] The TDG imine A is formed by
condensation of tryptamine and cyclopentanone. Highly selective
C–H activation of the C-2 position[12] is obtained due to the
electron-lone pair coordination of imine to form a cyclopalladated
intermediate B[13] with the loss of hydrogen gas. Then, the
electron-lone pair coordination of imine with palladium is
transformed into the π bond coordination (intermediate C) at an
elevated temperature, which is followed by cyclization with the
polar unsaturated bond[14] of imine to form intermediate D. Finally,
the spiro-product 9a is obtained by ligand exchange of
intermediate D with sodium formate and regenerates the HPdIIH
species.
[b]
15a
15b
15c
57%
92%
78%
NH
O
NH
Ar
N
N
NH
Ar
N
N
O
Boc
[b]
[c]
15e
15f
63%
60%
15d
89%
[a] Reaction conditions: 14 (0.2 mmol), 2 (0.6 mmol), Pd(OH)2/C (20 mol%), and
HCO2Na (0.6 mmol) in water (1 mL) and benzene (0.2 mL) under an argon
atmosphere at 100 ºC for 12 h; yields of isolated products were given. [b] 25
mol% Pd(OH)2/C. [c] Acetone (1.0 mmol) was used.
In conclusion, we have developed a “two-in-one” strategy for
C–H functionalisation of tryptamine derivatives in water. The TDG
played dual roles of directing group and reagent. Various
tetrahydro-β-carboline skeleton products (including natural
products Komavine (1) and Spiroindolone (2)) were synthesized
by this strategy. Furthermore, this strategy can be expanded to
electron-deficient aromatic systems which would not be
effective under the standard Pictet-Spengler conditions. We
envisage that this “two-in-one” strategy will be applicable to the
development of other useful TDG directed C–H functionalization
followed by cyclization processes to construct important structural
motifs rapidly.
To explore the application of the “two-in-one” strategy for C–H
functionalization to other system as well as to further exclude the
classical Pictet-Spengler reaction pathway, electron-deficient
aromatic systems, which would not be effective under the
standard Pictet-Spengler conditions, were investigated. To
our delight, reaction of 1-(6-(4-methoxyphenyl)pyridin-3-
yl)propan-2-amine (14) with cyclopentanone (2a) at 100 ºC under
an argon atmosphere using 20 mol% of Pd(OH)2/C as the
H2O
HCO2Na
H2N
NH
N
H
CO2
N
H Pd H
N
H
O
H
A
N
3a
H
HCO2Na
Acknowledgements
H2
Pd
We thank the Recruitment Program of Global Experts to C.-J.L.,
the Fundamental Research Funds for the Central Universities
(lzujbky-2018-62), the International Joint Research Centre for
Green Catalysis and Synthesis, Gansu provincial Sci. & Tech.
Department (Nos. 2016B01017, 18JR3RA284, 18JR4RA003)
and Lanzhou University for support of our research. We also
thank the Canada Research Chair (Tier I) foundation, the E.B.
Eddy endowment fund, the CFI, NSERC, and FQRNT to C.-J.L.
We thank Mr. Xinlong Han in this group for reproducing products
1 and 2 in Scheme 2 and product 9t in Table 3.
N
N
H
Pd
N
H
N
H
H
B
D
N
Pd
N
H
H
C
Figure 2. Proposed reaction pathway of C–H functionalisation of tryptamine.
catalyst and 3.0 equiv of sodium formate in water (1 mL) (with 0.2
mL benzene) for 12 h gave the C–H functionalization product 15a
in excellent yield (92%) (Table 4). Other cycloketones also
Keywords: C–H functionalisation • aqueous solvent •
tetrahydro-β-carbolines • palladium-catalyzed • tryptamine
This article is protected by copyright. All rights reserved.

10.1002/anie.201813391
Angewandte Chemie International Edition
COMMUNICATION
[1] For selected reviews of transition metal-catalyzed C–H functionalization,
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10.1002/anie.201813391
Angewandte Chemie International Edition
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Entry for the Table of Contents (Please choose one layout)
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R2
R1
“Two-in-one” strategy: Transient
Huiying Zeng,* Zemin Wang and Chao-
Jun Li*
H2N
O
N
N
directing group (TDG) played dual
roles. Tryptamine and 2-(pyridin-3-
yl)ethan-1-amine derivatives reacted
with ketones to form TDG, which
directed C–H activation followed by
cyclization in water to form various
Pd
R1 R2
[
]
R2
H
R1
Pd
a er
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N
W
N
N
H
−
H
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TDG i
H
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va on
H A ti ti
TDG f
C
Page No. – Page No.
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s as o use as reac ve rou
ti
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TDG d
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“Two-in-One” Strategy for Palladium-
(
NH
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N
R1
Catalyzed
C
–
H
Bond
H
tetrahydro-β-carbolines,
including
Functionalisation in Water
natural products readily.
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