LiCl-Promoted Pd(ii)-catalyzed ortho carbonylation of N,N- dimethylbenzylamines

Article abstract of DOI:10.1039/c0dt00451k

Palladium-catalyzed highly regioselective carbonylation of substituted N,N-dimethylbenzylamines with the assistance of LiCl was developed. The ortho-functionalized N,N-dimethylbenzylamine was further transformed into ortho-methyl benzoate under mild conditions. These two transformations could be combined into one pot to produce the desired product in moderate yield. Applications of this methodology to synthesize the fragments of variolaric acid were also studied.

Full text of DOI:10.1039/c0dt00451k

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PAPER
www.rsc.org/dalton | Dalton Transactions
LiCl-Promoted Pd(II)-catalyzed ortho carbonylation of
N,N-dimethylbenzylamines†‡
Hu Li,a Gui-Xin Caia and Zhang-Jie Shi*a,b
Received 10th May 2010, Accepted 5th July 2010
DOI: 10.1039/c0dt00451k
Palladium-catalyzed highly regioselective carbonylation of substituted N,N-dimethylbenzylamines with
the assistance of LiCl was developed. The ortho-functionalized N,N-dimethylbenzylamine was further
transformed into ortho-methyl benzoate under mild conditions. These two transformations could be
combined into one pot to produce the desired product in moderate yield. Applications of this
methodology to synthesize the fragments of variolaric acid were also studied.
catalyzed by Pd(II) has started to attract widespread attention.3
In these reactions, the metallocycles are considered as the key
intermediates.
Introduction
Carbon monoxide is one of the most important readily available
C1 feedstocks. In recent decades, transition metal-catalyzed car-
bonylation of aryl halides, triflates and tosylates with CO has
been well developed and became one of the most straightforward
and useful methods to produce carboxylic acids.1 Among those
methods, Pd-catalyzed carbonylations of aromatics with CO are
valuable methodologies to synthesize various aryl carboxylic acid
derivatives in organic synthesis.2 Typically, such carbonylation
was initiated by the oxidative addition of aryl halides (or their
derivatives) to Pd(0) species. Nevertheless, direct carbonylation
from easily available arenes would be ideal and environmentally
benign.
Recently, we reported an efficient Pd(II)-catalyzed ortho olefina-
tion of N,N-dimethylbenzylamines and further transformation to
afford ortho-functionalization of substituted toluene in one pot.5
In the report, we successfully controlled the reactivity and binding
ability of N,N-dimethylbenzylamine by tuning the acidity of the
reaction system. As mentioned, the N,N-dimethylaminomethyl
group could be easily transformed into different functionalities,
such as methyl group, aldehyde, and alkene.6 Thus, we further
sought to develop the ortho-carbonylation of C–H bonds to form
ortho-substituted benzoic acid derivatives, which frequently occur
in many natural and synthetic biologically active molecules.
Very recently, Pd-catalyzed direct transformation of C–H bonds
to different functionalities have been well developed.3 Compared
to other transformations, direct carbonylation of C–H bonds
with CO still faces many challenges: 1) strong binding ability
of CO might inhibit the electrophilic attack of Pd(II) species
toward aromatic C–H bonds by occupying the active sites; 2) the
unique p-back bonding might also decrease the electron density
on Pd-center with CO as an excellent p-acid; 3) the excellent
reducing ability of CO might induce the reduction of Pd(II)
species to Pd(0) to inhibit the electrophilic attack. Thus, although
CO insertion to palladacycles has been thoroughly investigated
in carbonylation from aryl halides and their derivatives, the
ortho-selective C–H bond carbonylation is considerably more
difficult because the depalladation process is often complicated by
reduction of Pd(II) to Pd(0) nanoparticles under CO atmosphere.4
In fact, the Pd(II)-catalyzed direct functionalization of C–H bonds
into carboxylic acids was first reported by Fujiwara in 1999.2
However, the investigations in this field are very limited. Recently,
directed regioselective ortho carbonylation of aryl C–H bonds
Results and discussion
Screening of reaction conditions of ortho carbonylation of
N,N-dimethylbenzylamines
In 1975, Heck reported the stoichiometric carbonylation reaction
of N,N-dimethylbenzylamine palladacycle with CO.7 However, a
catalytic transformation faced both challenges of the use of N,N-
dimethylamino group as a directing group and Pd(II)-catalyzed
direct C–H activation in the presence of CO, which were not easily
conquered, as mentioned above.
Considering the palladacycle via electrophilic substitution of
Pd(II) catalyst to aryl C–H bond of N,N-dimethylbenzylamine
was the key intermediate in our previous work (eqn (1)), we
envisioned that Pd(II)-catalyzed ortho carbonylation of N,N-
dimethylbenzylamines with CO via selective aryl C–H activation
might be achieved using this substrate and catalytic system.
To our delight, in the previous PdCl2/Cu(OAc)2 catalyst and
TFEol/HOAc solvent system, the use of CO instead of acrylic
acid esters gave a small amount of carbonylation product of N,N-
dimethylbenzylamine during the initial exploration (eqn (2)).
aBeijing National Laboratory of Molecular Sciences (BNLMS) and Key
Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry
of Education, College of Chemistry and Molecular Engineering, and Green
Chemistry Center, Peking University, Beijing, 100871, China
bState Key laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China
† Based on the presentation given at Dalton Discussion No. 12, 13–15th
September 2010, Durham University, UK.
(1)
‡ Electronic supplementary information (ESI) available: Additional ex-
perimental details, characterization data and NMR spectra. See DOI:
10.1039/c0dt00451k
10442 | Dalton Trans., 2010, 39, 10442–10446
This journal is
The Royal Society of Chemistry 2010
©

Table 1 Optimization of ortho carbonylation of 2a via Pd catalysis.a
Table 2 Pd(II)-catalyzed ortho carbonylation of 2a with different
additives.a
Entry
[Pd]
Oxidant
LiCl
GC yieldb
Entry
Additive
GC yieldb
1
2
3
4
5
6
7
8
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2(PPh3)2
Pd(OAc)2
Pd(OCH2CF3)2
PdCl2
PdCl2
—
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Oxone
—
50
58
70(64)
60
56
52
21
50
63
10 mol%
50 mol%
1.0 equiv.
1.5 equiv.
2.0 equiv.
4.0 equiv.
50 mol%
50 mol%
50 mol%
50 mol%
50 mol%
50 mol%
50 mol%
1
2
3
4
LiF
LiBr
LiI
37
63
<5
70
65
57
<5
54
60
50
42
67
LiOAc
LiOTf
LiOAc
LiOTf
NaCl
KCl
InCl3
ZnCl2
Me4NCl
5
6c
7d
8
9
10
11
12
13
14
59
9
<5
<5
<5
<5
10
11
12
PhI(OAc)2
Cu(OAc)2
—
PdCl2
a The reactions were carried out in 0.50 mmol of 2a in the presence of
the proper catalyst, additive, and oxidant in 1.0 mL EtOH, 0.50 mL
HOAc, and 2.0 mL TFEol as solvent under CO atomsphere in a balloon.
b Determined by GC using dodecane as an internal standard. c Pd(OAc)2
was used as catalyst. d Pd(TFA)2 was used as catalyst, and 0.50 mL
trifluoromethanesulfonic acid was added rather than acetic acid.
a The reactions were carried out in 0.50 mmol of 2a in the presence of the
proper catalyst, additive, and oxidant in 1.0 mL EtOH, 0.50 mL HOAc, and
2.0 mL TFEol as solvent under CO atmosphere in a balloon. b Determined
by GC using dodecane as an internal standard. Isolated yield is given in
parenthesis.
was found to be most effective for the carbonylation reaction,
which was consistent with the previous report.9a–9c
(2)
Carbonylation with different alcohol nucleophiles
Under these optimized conditions, different alcohols were further
surveyed as nucleophiles for this carbonylation. To our interest,
we found that ethanol was the best one. When methanol was
substituted, only 47% yield was obtained (Table 3, 4ab). Longer
chain aliphatic alcohols were also suitable for this transformation
(Table 3, 4ac and 4ae). However, steric hindered alcohols exhibited
lower efficiency (Table 3, 4ad and 4ag). 2-Methoxyethanol was also
tested and the desired product was isolated in 46% yield (Table 3,
4af). Other nucleophiles, such as phenol and amines, completely
failed for this carbonylation.
Such a result encouraged us to further optimize this carbony-
lation. When EtOH was used as the nucleophile, the desired ester
was produced in 50% GC yield at 85 ◦C (Table 1, entry 1). After
the literature search, we found that lithium chloride was generally
considered as Lewis acid to promote the insertion of CO into C–
Pd bond.8 In fact, we observed the enhancement of yield with the
increase of LiCl from 0 to 50 mol% (Table 1, entries 1–3). However,
the yield of desired product dropped with more than 50 mol% of
LiCl (Table 1, entries 4–7).
Evaluation of various N,N-dimethylbenzylamines
Further studies indicated that the counter anions of palladium
catalysts effected the efficacy of carbonylation and PdCl2 showed
the best efficiency (Table 1, entries 8–10). The oxidants were
further screened. Common oxidants in Pd-catalyzed direct C–H
transformations, such as PhI(OAc)2 and oxone, were not efficient
for this transformation (Table 1, entries 11 and 12). Undoubtedly,
both catalyst and oxidant were essential for this reaction since no
desired product was obtained in the absence of either one (Table
1, entries 13 and 14).
Previously, Lu and others reported the effect of halides on
the carbonylation reactions and other transformations of C–Pd
species.9 In our case, the obvious effect of various anion additives
was also observed (Table 2, entries 1–7). Interestingly, the counter
alkali ions also showed different reactivity, which may arise from
the solubility and binding ability of different salts (Table 2, entries 8
and 9). Other Lewis acids were further tested but showed a slightly
lower efficacy (Table 2, entries 10–12). Among the additives, LiCl
Furthermore, the substrate scope of different substituents on
the phenyl ring of N,N-dimethylbenzylamine was expanded.
We found that both electron-donating groups and electron-
withdrawing groups were tolerated under the developed carbony-
lation. Generally, electron-rich substituents were helpful for this
ortho carbonylation due to the enhancement of electron density
of phenyl rings (Table 4, 4ba-4ka). Only mono carbonylation
took place when both ortho-positions were available. Notably,
the meta-substituents obviously affected the reactivity and the
carbonylation took place at the less hindered ortho positions
of the dimethylaminomethyl groups (Table 4, 4ba, 4ea, and
4ia). Obviously, electron-deficient groups decreased the reactivity,
and poor to moderate yields were achieved with even higher
catalyst loading, with the recovery of substrates (Table 4, 4la–4oa).
These results were also consistent with the proposed electrophilic
substitution pathway. It was important to note that the relatively
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Dalton Trans., 2010, 39, 10442–10446 | 10443
©

Table 3 ortho Carbonylation of 2a with different alcohols as
Applications of ortho carbonylation of N,N-dimethylbenzylamines
nucleophiles.a
With the development of ortho carbonylation of N,N-
dimethylbenzylamines in hand, further transformation through
catalytic hydrogenation to substituted toluene was explored.
Under reductive hydrogen atmosphere with Pd/C as catalyst,
the N,N-dimethylaminomethyl group could be converted into
a methyl group in excellent yield (eqn (3)). Thus, the method-
ology offered a useful method to produce ortho-functionalized
toluene in an indirect way. Further studies to combine ortho
carbonylation and hydrogenation into one pot were conducted.
After completion of the carbonylation step, the Pd/C catalyst
and 6.0 equiv of K2CO3 were directly added into the reaction
system followed by changing atmosphere from air to hydrogen
gas. The desired product 10 was obtained in moderate yield, which
offered a process to perform this two-step transformation in one
pot (eqn (4)).
a Conditions: 2a (0.50 mmol), 3 (1.0 mL), PdCl2 (0.025 mmol), LiCl (0.25
mol), Cu(OAc)2 (1.0 mmol), TFEol (2.0 mL), HOAc (0.50 mL), under CO
atomsphere in a balloon, 85 ◦C, 8 h; isolated yields. b 2.0 mL methanol was
used.
stable C–Cl bond survived well under this transformation, which
could be further transformed into different functionalities (Table
4, 4na).
(3)
Proposed mechanism
On the basis of the above results and previous studies, the
mechanism of the carbonylation reaction was proposed as shown
in Scheme 1. As we have reported before, the proper acidic
conditions are critical for tuning the concentration of free tertiary
amine. Chelation-assisted ortho palladation of free tertiary amine
2 by Pd(II) cation formed the key five-membered palladacycle
5. After ligand exchange, intermediate 8 was produced followed
by path I (nucleophilic attack on coordinated ligand) or path II
(migration insertion of CO into the C–Pd bond) with the assistance
of LiCl to form intermediate 9 or 9¢. Finally, reductive elimination
of 9 or 9¢ gave the desired product 4 and Pd(0), which was oxidized
to Pd(II) by Cu(II) to regenerate the catalyst and finish the catalytic
cycle.
(4)
Furthermore, ortho-methylbenzoic acids, which can be easily
constructed from the functionalized N,N-dimethylbenzylamine
derivatives, were important and common building blocks in
natural products.10 Based on the retrosynthetic analysis of nat-
ural variolaric acid, two key segments were proposed as key
Scheme 2 Retrosynthetic analysis of variolaric acid and the syntheses
of its two fragments. Reaction conditions: a. PdCl2 (5.0 mol%), LiCl
(50 mol%), Cu(OAc)2 (2.0 equiv.), EtOH/TFEol/HOAc, CO (balloon
pressure), 85 ◦C, 48 h, 50% yield; b. Pd/C (20 mol%), H2 (40 atm),
EtOH/HCl (1000 : 1), 70 ◦C, 60 h, 70% yield; c. AlCl3 (3.0 equiv.), CH2Cl2,
rt, 10 h, 77% yield; d. ClCO2Et (1.8 equiv.), CHCl3, rt, 3 h, 63% yield; e.
NBS (1.5 equiv.), BPO (10 mol%), CCl4, reflux, 5 h, 79% yield.
Scheme
N,N-dimethylbenzylamine.
1
Proposed mechanism of ortho carbonylation of
10444 | Dalton Trans., 2010, 39, 10442–10446
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©

Table 4 ortho Carbonylation of differently substituted benzylamines with ethanol.a
a Conditions: 2 (0.50 mmol), 3a (1.0 mL), PdCl2 (0.025 mmol), LiCl (0.25 mmol), Cu(OAc)2 (1.0 mmol), TFEol (2.0 mL), HOAc (0.50 mL), under CO
atomsphere in a balloon, 85 ◦C, 48 h; isolated yields. b 1.0 equiv. LiCl (0.50 mmol) was added. c The reactions were catalyzed by 10 mol% of PdCl2
(0.050 mmol).
intermediates for its total synthesis. In fact, such two molecular
segments have similar framework, which can be synthesized by
directed ortho carbonylation through two different pathways
from the same substrate (Scheme 2). This convergent syn-
thetic scheme is considered to have higher efficiency with fewer
steps.
Based on our previous studies, the ortho carbonylation was
performed and the designed ester 4ha was produced in good
yield. After further hydrogenation and deprotection, the first
segment 11 was produced with good efficiency. Meanwhile,
starting from the same intermediate 4ha, the chlorination and
bromination occurred to produce the segment 12, which might be
transformed to the designed lactone fragment (Scheme 2). Thus,
this developed method showed a potential application in organic
synthesis.
Further studies to increase the efficiency and apply such methods
into organic synthesis are in progress.
Experimental section
Typical procedure for Pd(II)-catalyzed ortho carbonylation of
N,N-dimethylbenzylamines
In a typical experiment, PdCl2 (4.4 mg, 0.025 mmol), LiCl (11
mg, 0.25 mmol), Cu(OAc)2 (0.18 g, 1.0 mmol), and TFEol
(2.0 mL) were added into a Schlenk tube. To a solution N,N-
dimethylbenzylamine 2 (0.50 mmol) was added, followed by HOAc
(0.50 mL, 8.0 mmol) and alcohol 3 (1.0 mL). The tube was
stoppered and heated at 85 ◦C in an oil bath under a balloon
CO atmosphere for 48 h. The mixture was neutralized to pH =
7~8 with a saturated Na2CO3 aqueous solution (3.0 mL), and
a light blue precipitate appeared. The suspension was filtered
through a Celite pad and extracted with CH2Cl2 three times. The
combined organic layers were dried over anhydrous Na2SO4 and
evaporated in vacuo. The desired products 4 were obtained in
the corresponding yields as a colorless to light yellow oil after
purification by flash chromatography on silica gel with petroleum
ether/EtOAc (10 : 1, 5% v./v. triethylamine contained).
Conclusions
In summary, we developed a Pd(II)-catalyzed directed ortho
carbonylation of N,N-dimethylbenzylamines via selective aryl C–
H activation with the assistance of LiCl. Further hydrogenation of
desired product could synthesize the ortho-functionalized toluene.
These two transformations could be combined in one pot to
offer a more concise and environmentally friendly process. This
methodology was further used to construct important structural
units of natural products and biologically active compounds.
Acknowledgements
Support of this work by a starter grant from Peking Uni-
versity and a grant from National Sciences of Foundation
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The Royal Society of Chemistry 2010
Dalton Trans., 2010, 39, 10442–10446 | 10445
©

of China (No. 20672006, 20821062, GZ419) and the “973”
Project from the MOST of China (2009CB825300) is gratefully
acknowledged.
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10446 | Dalton Trans., 2010, 39, 10442–10446
This journal is
The Royal Society of Chemistry 2010
©