A carboxylate-assisted amination/unactivated C(sp2)-H arylation reactionviaa palladium/norbornene cooperative catalysis

Article abstract of DOI:10.1039/c9cc09265j

This report describes a carboxylate-assisted palladium-catalysed Catellani reaction, which is compatible withortho-amination and unactivated C(sp²)-H arylation. This method was used to synthesize a series of 1-amino substituted dihydrophenanthridines, phenanthridines and 6H-benzo[c]chromenes. Based on kinetic isotope experiments, the kinetic curve proves that pivalic acid accelerates the reaction rate of unactivated C(sp²)-H activation, and thus this rate can keep up with the five membered aryl-norbornene-palladacycle (ANP) intermediate.

Full text of DOI:10.1039/c9cc09265j

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DOI: 10.1039/C9CC09265J
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Carboxylate-Assisted Amination/Unactivated C(sp2)-H Arylation
Reaction via a Palladium/Norbornene Cooperative Catalysis
Received 00th January 20xx,
Accepted 00th January 20xx
Yang An, Bo-Sheng Zhang, Zhe Zhang, Ce Liu, Xue-Ya Gou, Ya-Nan Ding, and Yong-Min Liang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
change the biological activity of molecules. Therefore, developing a
This report describes a carboxylate-assisted palladium-catalysed
Catellani reaction, which is compatible with ortho-amination and
unactivated C(sp2)-H Arylation. This method was used to
green and convenient method for the synthesis of C1-bioactive
Representative functional molecules related to phenanthridine moieties
OMe
O
MeO
N
N
O
O
O
O
N
MeO
OH
N
O
O
synthesize
dihydrophenanthridines,
a
series
of
1-amino
substituted
and 6H-
MeO
O
O
O
O
OH
N
phenanthridines
Asiaticumine A
Nornitidine
Trisphaeridine
Norchelerythrine
OH
Ungeremine
Representative functional molecules related to dihydrophenanthridine and 6H-benzo[c]chromene moieties
benzo[c]chromenes. Based on kinetic isotopic experiments, the
kinetic curve proves that pivalic acid accelerates the reaction rate
of unactivated C(sp2)-H activation, and thus this rate can keep up
with the five memberd aryl-norbornene-palladacycle (ANP)
intermediate.
O
N
N
OH
NH
N
N
H2
H2
N
N
O
O
O
O
N
OH
HO
O
HN
N
N
HO
Itolide A
N
O
N
O
PARP-1 inhibitors
Wnt agonists
LY 357,489
Previous work
N
N
N
Me
Me
R
Me
Introducing functional groups at C6 position was
widely known.
O
Morgan-Walls reaction
As an important fused heterocyclic compound, phenanthridines are
widely found in natural products such as Ungerernine, Asiaticumine
A, Nornitidine, Trispheridine, and Norchelerythrine.1 Highly
bioactive phenanthridine derivatives exhibit anticancer,
antileukaemia, antibacterial, and enhanced cytotoxic activity.2
Therefore, the synthesis of this skeleton has attracted considerable
attention, and many methods for the preparation of
phenanthridines have been reported. These strategies include the
Pictet-Hubert reaction3, the Bischler-Napieralski reaction4, the
Morgan-Walls reaction5, the aza-Wittig reactions6, palladium-
catalyzed tandem cyclizations7, the radical insertion8, and other
methods9. These promising developments have led to advances in
the synthesis of phenanthridine derivatives, but new functional
groups can only be introduced at the more active C6 position on the
phenanthridine. Furthermore harsh reaction conditions and
incompatibility with complex starting materials hinders the
synthesis of diverse phenanthridine derivatives. Because of the
difficulty synthesizing these skeletons, reports of the synthesis of
dihydrophenanthridine and 6H-benzo[c]chromene derivatives are
limited, however, these molecules display excellent biological
properties such as poly (ADP-ribose) polymerase-1 (PARP-1)
inhibitors,10 Wnt agonist,11 Itolide A,12 and LY 357,48913. In addition,
bioactive amines, such as morpholine, are commonly used to target
lysosomes,14 and other amines, such as piperazine, can effectively
TMSN3
4
O
N
H
3
2
C
aza-Wittig reactions
"R" source
6
N
O
O
7
P
1
Ph
O
Me
H
10
8
9
radical isonitrile insertion
Functional groups could not be directly introduced
at C1 position
R = N, S, P, heteroaryl
alkyl, aryl, CF3
NC
This work
X
N
N
X
N
R1
R2
R1
OBz
TMSI, air
N
R2
Pd/NBE
R2
R2
R1
R1
CHCl3
N
H
H
N
N
R1
R2
I
R1
R1
R2
O
Introduced amines
at C1 position
R2
O
I
R1
R2
R1
R2
Scheme 1. Carboxylate-Assisted Amination/Unactivated C(sp2)-H Arylation Reaction via
a Palladium/Norbornene Cooperative Catalysis.
amino-substituted phenanthridines, dihydrophenanthridines,
and 6H-benzo[c]chromenes derivatives is
research goal. (Scheme 1)
a meaningful
The Catellani reaction was discovered in 1997, thereby establishing
Pd/NBE chemistry.15 In 2000, Lautens greatly expanded the
compatibility of Pd/NBE chemistry by utilizing phosphine ligands,
thus establishing Pd/NBE/ligands cooperative catalysis in the
Catellani-Lautens reaction system.16 Over the past decade,
Catellani, Lautens, Dong, Gu, Zhou and others discovered a variety
of electrophiles to realize ortho-position C-H functionalizations such
as ortho arylation, carbonylation, alkylation, thiolaton and
amination.17 In 2013, the Dong group first achieved ortho-
amination of aryl iodides.18 Since that time, a diversity of
terminating steps have been published including cyanation,19
alkenylation,20 borylation,21 alkynylation,22 arylation,23
methylation,24 α arylation of acetone,25 N-tosylhydrazone
insertion,26 and intramolecular ipso-amidation.27 Although
a. State Key Laboratory of Applied Organic Chemistry, Lanzhou University
Lanzhou 730000, P.R. China. E-mail: liangym@lzu.edu.cn
Electronic supplementary information (ESI) available. CCDC1958314;
CCDC1958515, CCDC1958316, CCDC1958317, CCDC1958318. For ESI and
crystallographic data in CIF or other electronic format see DOI:
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2018, 00, 1-3 | 1
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gratifying achievements have been made in this field, there are still and reports on their synthesis are very limited. Therefore, the
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many challenges in the compatibility of Pd/NBE catalytic system versatility of the
with other reactions.
DOI: 10.1039/C9CC09265J
Table 1. The Scope of Substrates
Palladium-catalyzed C-H bond activation has achieved significant
X
results in modern organic synthesis.28-29 In 2005, Lautens group first
N
Pd(OAc)2, PPh3
norbornene, Cs2CO3
,
N
X
N
R2
R3
TMSI (10 equiv.)
CHCl3, air,
OBz
N
R1
R1
achieved Catellani reaction quenched by C(sp2)-H arylation
R1
tBuCOOH,
toluene, 110 0C, 12h
R2
R4
R2
N
I
70 0C, 48h
R3
R4
N
generated annulated indoles.30
A decade later, Dong group
R3
R4
1
3
6
4
Reaction Scope[a]
O
reported C(sp2)-H arylation via a similar intramolecular pathway,
while only one example was reported.31 Unactivated C-H bond
activation of aromatic hydrocarbon has a high energy barrier, but
density functional theory (DFT) calculations32 and kinetic
experiments33 have demonstrated that carboxylic acid-promoted
concerted metalation deprotonation (CMD) processes may
effectively reduce the energy barrier of C-H bond activation, thus
exploring the feasibility of Catellani reaction quenched by
intermolecular unactivated C(sp2)-H arylation in situ through CMD
processes is necessary.
O
O
O
4a, R = H, 81 %, 42 %[b]
4b, R = F, 64 %
Cl
N
R
N
4e, R = CO2Me, 76 %
4f, R = CF3, 66 %
N
O
N
O
4c, 72 %
O
4g, R = F, 78 %
4h, R = Cl, 83 %
4i, R = Br, 75 %
4j, R = Me, 84 %
4k, R = CF3, 83 %
4l, R = OMe, 90 %
4m, R = NO2, 82 %
4n, R = Ph, 79 %
O
O
O
O
O
N
N
N
N
O
N
S
N
R
O
N
4o, 80 %
4d, 70 %
O
O
O
O
O
O
N
N
Initially, we used methyl benzyl(2-iodophenyl)carbamate (1a)
as a model substrate and morpholino benzoate (3) as an ortho-
amination reagent to investigate this reaction. (more details,
see Table S1-S2 in the Supporting Information). The desired
product (4a) was isolated in a 52% yield (entries 1). A large
quantity of uncyclized byproduct (a reduced hydrogenation
product formed in situ) was identified by gas chromatography-
mass spectrometry (GCMS). We hypothesized that unactivated
C(sp2)-H activation can occur smoothly by changing the leaving
group of our substrates (entries 2-5). Unfortunately, these
modifications did not enhance the yield of product (4a)
significantly. Then, we tried to add some organic acids as
additives to achieve CMD process for unactivated C(sp2)-H
activation (entries 6-12). Gratifyingly, when we used aliphatic
organic acids as additives, the reaction gave improved results,
and formation of the uncyclized byproduct was inhibited as
shown by GCMS. Based on our data, pivalic acid was the
optimal additive to perform C(sp2)-H bond activation, and it
gave an isolated yield of 81% (entries 6, condition A). Finally,
metal catalyst, ligand, temperature, and solvent were
screened
With our optimal reaction conditions in hand, we examined the
substrate scope of methyl benzyl(2-iodophenyl)carbamate. The
reactions of aryl iodides, electron-donating groups and strong
electron-withdrawing groups, such as p-Me, p-F, p-Cl, p-CO2Et and
p-CF3 substituents performed well in the reaction, affording the
corresponding 1-aminoindole products (4a-4f) in good yields.
However, when the 4-position of o-iodoanilines was substitued, the
target product was no obtained. This is possibly due to the large
steric hindrance disfavouring the formation of the Pd(IV)
intermediate. A range of benzyl groups were also examined under
the optimal reaction conditions, including electron-donating groups
p-Me, p-OMe, p-Ph and electron-withdrawing groups p-F, p-Cl, p-Br,
p-CF3, and p-NO2. These functional groups were well tolerated and
gave the expected products (4g-4n) in 75−90% yields. Then, the
substrate scope of electrophilic amination reagents was
investigated. Thiomorpholine (4o), the alkylamino substituted
reagents (4p-4s), the amination reagents of piperidine, pyrrole,
dimethylamine (4aa-4ac), and piperazine substituted reagents (4t,
4x-4z) furnished the desired products in high yields. Finally, amines
protected by N-OAc, N-Ts, and N-Boc (4u-4w) can also be used to
obtain the desired products.
N
N
N
4q, R = CO2Et, 72 %
4s, R = Ph, 78 %
4p, n = 1, 70 %
4ab, n = 0, 59 %
4ac, 51 %
n
R
O
O
N
O
O
R
N
O
O
N
N
4t, R = CO2Et, 75 %
4x, R = COPh, 63 %
4y, R = CO2Bn, 70 %
4z, R = Boc, 80 %
4u
, R = Boc, 55 %
4v, R = Ts, 59 %
4w, R = COMe, 36 %
N
N
N
O
N
N
R
O
O
4r, 58 %
4aa, 64 %
Reaction Scope[c]
R
N
N
N
N
N
N
6c, R = Cl, 62 %
6d, R = Me, 75 %
6e, R = CO2Me, 83 %
6j, R = Me, 83 %
R
O
6n, R = Ph, 79 %
O
O
6a
. 90 %
a Reaction conditions: substrate 1 (0.2 mmol), 3 (2.0 equiv.), Pd(OAc)2 (10 mol%), PPh3
(20 mol%), norbornene (4.0 equiv.), pivalic acid (40 mol%),Cs2CO3 (4.0 equiv.), toluene
(3.0 mL), 110 °C, 12 h. All yields are isolated yields. b ortho-bromoaniline compound
was used to replace 1 as the substrate. c Reaction conditions: substrate 4 (0.2 mmol),
TMSI (2.0 mmol, 10 equiv.), 70 °C, 48 h. All yields are isolated yields.
derivatized product skeleton was studied. We envisioned that
the methyl formate could be deprotected with
iodotrimethylsilane (TMSI), then the secondary benzylamine
could be reduced to obtain the target product. Unexpectedly,
the target product (6a) can be obtained in 90% yield by
removing the methyl formate protecting group with
iodotrimethylsilane (TMSI). Then, we examined a series of
different substrates and obtained the target products in good
yield (6c, 6d, 6e, 6j, and 6n) (Table 1).
Under our previously conditions, we used 1-(benzyloxy)-2-
iodobenzene (2a) as a model substrate.(more details, see
Table S3 in the Supporting Information) Unexpectedly, the
reaction only produces trace amounts of the desired product
while producing a large amount of uncyclized byproduct by
GCMS (entries 1). To improve the yield of product (5a), we
raise the reaction temperature to 150 °C, thus improving our
results. To our delight, the use of phosphine ligands had a
significant influence on the results (entries 4-10), and we were
able to increase the yield to 77% when using tri(furan-2-
yl)phosphane (TFP) as the ligand.
Next, using the optimized conditions, we investigated the
effect of the substituent aromatic ring on the tandem reaction.
The substituent p-CO2Et (5b) on the left aromatic ring and the
substituents o-F, p-Me, and p-CN (5c-5e) on the right aromatic
ring can be used in this reaction, providing the desired
products in good to excellent. It is worth noting that fused ring
substituents also had very good performance in the reaction:
The phenanthridine heterocyclic skeletons are widely found in
drugs, functional material molecules and natural products.
However, research on amino-substituted phenanthridines is rare
2 | J. Name., 2018, 00, 1-3
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the substrate of α-benzofuranyl furnished the desired product intermediate II. Then, the Pd(IV) intermediate IIIViisewgAertnicelerOantleinde
(5g) in 83% yield (Table 2).
Table 2. The Scope of Substrates
by N-benzoyloxyamine oxidatively adding to the ANP
DOI: 10.1039/C9CC09265J
O
R2
C1: 1a + Pd(OAc)2 + PivOH
C2: 1a + Pd(OAc)2
R1
Pd(OAc)2, TFP, norbornene, Cs2CO3
tBuCOOH, toluene, 1500C, 24h
O
I
OBz
N
R1
R2
R3
R4
N
R3
R4
C3: 2a + Pd(OAc)2 + PivOH
C4: 2a + Pd(OAc)2
2
3
5
Reaction Scope[a]
O
O
5a, R = H, 77 % 26 %[b]
5d, R = Me, 65 %
F
N
N
5e, R = CN, 58 %
R
O
5c, 54%
O
O
O
O
O
O
O
N
O
N
O
O
N
N
5g, 83%
5o
, 56%
5b, 66%
5f, 41%
O
O
O
O
5l, R = CO2Et, 51 %
5m,
Scheme 2. Additive Evaluation in Tandem Reaction
5h, R = H, 76 %
5i, R = Ph, 67 %
5j, R = CO2Et, 54 %
N
R = Boc, 50 %
5n, R = CO2Bn, 48 %
N
N
R
N
R
O
O
5k, 61%
O
O
O
O
O
O
O
O
Pd(OAc)2, PPh3, norbornene, Cs2CO3
,
1a
N
I
a Reaction conditions: substrate 2 (0.2 mmol), 3 (2.0 equiv.), Pd(OAc)2 (10 mol%), TFP
(20 mol%), norbornene (4.0 equiv.), pivalic acid (40 mol%), Cs2CO3 (4.0 equiv.), toluene
(3.0 mL), 150 °C, 24 h. All yields are isolated yields. b ortho-bromoaniline compound
was used to replace 2 as the substrate.
D
OBz
N
N
N
toluene, 1100C, 1h
D
without tBuCOOH, KH/KD = 1.5
with tBuCOOH, KH/KD = 1.2
d4
O
N
O
N
O
d5
1a-D
N
I
D
D
D
D
O
O
To elucidate the role of additive in the tandem reaction, we
separately described the conversion rate over time with and
without pivalic acid as an additive. After 24 h, in the presence of
pivalic acid, the product (4a) can be obtain in approximately 80%
yield. Conversely, in the absence of pivalic acid, the reaction
provides merely 50% conversion (Scheme 2). The result of this
reaction is more obvious in the process of generating compound (5a)
after 24 h. The pivalic acid as additive can significantly improve the
conversion rate of the tandem reaction. Notably, the addition of
pivalic acid to the reaction system greatly increases the rate of the
reaction generating compound (4a) or compound (5a). This
indicates that the reaction undergoes the carboxylic acid exchange
process. In addition, compared with benzoic acid, pivalic acid can
promote the CMD process of C-H activation.
To further elucidate the reaction mechanism, we performed
some intramolecular kinetic isotope experiments. In the
presence of pivalic acid, an intramolecular kinetic isotope
experiment using a mixture of (1a) and deuterated (1a-D) (in a
1:1 ratio) gave the corresponding KH/KD approximately 1.2, and
gave KH/KD approximately 1.5 in the absence of pivalic acid.
This result indicates that C-C bond formation of the tandem
reaction in (1a) is not a rate-determining step. However, an
intramolecular kinetic isotope experiment using a mixture of
Pd(OAc)2, TFP, norbornene, Cs2CO3
toluene, 1500C, 4h
,
O
2a
OBz
N
H
H
I
d4
N
N
without tBuCOOH, KH/KD = 2.6
with tBuCOOH, KH/KD = 2.1
d5
O
O
2a-D
O
O
D
D
I
Scheme 3. The Kinetic Isotope Experiment Optimization
intermediate. Next, the Pd(IV) intermediate III urdergoes reductive
elimination providing ortho-aminated compound IV, followed by β-
C
elimination and separation of the norbornene, giving
intermediate VI. Then the acid exchange process occurs rapidly,
generating the pivalic acid intermediate VII. Finally, intermediate
VIII is formed through a concerted metalation deprotonation (CMD)
process on intermediate VII, and intermediate VIII reductively
eliminates to provide the desired product.(see Scheme S1 in the
Supporting Information)
In conclusion, We have developed a carboxylate-assisted palladium
catalyzed tandem version of the Catellani reaction consisting of
amination/unactivated C(sp2)-H arylation. This transformation
features broad substrate scope and generates desirable products in
moderate to good yields. We evaluated the role of the pivalic acid
additive used in this system through a series of kinetic experiments,
leading a proposed reaction mechanism based on preliminary
studies. Furthermore, this strategy provids a way to synthesize
(2a) and deuterated (2a-D) (in
a 1:1 ratio) gave a
challenging
1-amino
substituted
dihydrophenanthridines,
corresponding KH/KD of approximately 2.1 in the presence of
pivalic acid, and in the absence of pivalic acid, KH/KD was
approximately 2.6. These results suggested that C(sp2)-H
activation in the tandem reaction (2a) is a rate-determining
step. These evidence proved that pivalic acid used as additive
can significantly reduce the energy barrier of C-H bond
activation and its rate can keep up with the formation of the
phenanthridines and 6H-benzo[c]chromene derivatives.
We are grateful to the National Natural Science Foundation of
China (NSF 21472073, 21772075 and 21532001) for supporting this
work.
Conflicts of interest
There are no conflicts to declare.
five
intermediate (Scheme 3).
We propose reasonable mechanism based on the
membered
ary-nobornene-palladacycle
(APN)
a
experimental results above and the mechanistic studies of
Lautens, Dong, Ackermann, Rousseaux, and Fagnou, as well as
Notes and references
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Steglich, Phytochemistry, 1986, 25, 2399-2401; (c)A. H. Abou-
35
our previous work.34,
First, oxidative addition of Pd(0) to
iodobenzene I, followed by syn-migratory insertion into
norbornene and ortho-C-H activation, formed the ANP
This journal is © The Royal Society of Chemistry 20xx
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4 | J. Name., 2018, 00, 1-3
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COMMUNICATION
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DOI: 10.1039/C9CC09265J
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Graphic Abstract
View Article Online
DOI: 10.1039/C9CC09265J
This report describes a carboxylate-assisted palladium-catalysed
Catellani reaction, which is compatible with ortho-amination and
unactivated C(sp2)-H Arylation. This method was used to
synthesize
a
series
of
1-amino
substituted
and 6H-
dihydrophenanthridines,
phenanthridines
benzo[c]chromenes. Based on kinetic isotopic experiments, the
kinetic curve proves that pivalic acid accelerates the reaction
rate of unactivated C(sp2)-H activation, and thus this rate can
keep up with the five memberd aryl-norbornene-palladacycle
(ANP) intermediate.
X
N
N
X
N
R2
R1
R1
OBz
N
TMSI, air
CHCl3
R1
R2
Pd/NBE
R2
R1
R2
H
H
N
N
N
I
R1
R2
R1
R2
Introduced amines
at C1 position
O
R2
R1
O
I
R1
R2
R1
R2
6 | J. Name., 2018, 00, 1-3
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